Copyright by Jennifer Elizabeth Davoren 2006
The Dissertation Committee for Jennifer Elizabeth Davoren Certifies that this is the approved version of the following dissertation:
Studies Towards the Asymmetric Total Synthesis of Solandelactone Oxylipins: The Total Synthesis of Solandelactone E
Committee:
Stephen F. Martin, Supervisor
Philip D. Magnus
Eric V. Anslyn
Jennifer S. Brodbelt
Sean M. Kerwin Studies Towards the Asymmetric Total Synthesis of Solandelactone Oxylipins: The Total Synthesis of Solandelactone E
by
Jennifer Elizabeth Davoren, B.S.
Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of
Doctor of Philosophy
The University of Texas at Austin August 2006
Dedication
This dissertation is dedicated to my family who has provided me with unwavering support through every aspect of this journey
Acknowledgements
Special thanks to my parents, Thomas and Elizabeth, who, without their constant
encouragement, I may not have been able to achieve as much as I have. I would like to
thank Dr. Spiros Liras for taking a chance on me taking me under his wing. I would also
like to thank Professor Stephen F. Martin for his guidance and support through my educational journey, as well as the entire Martin group for their support and overall friendship.
v Studies Towards the Asymmetric Total Synthesis of Solandelactone Oxylipins: The Total Synthesis of Solandelactone E
Publication No.______
Jennifer Elizabeth Davoren, Ph.D. The University of Texas at Austin, 2006
Supervisor: Stephen F. Martin
A stereocontrolled approach to the elaborate skeleton of the solandelactone oxylipins culminating in the total synthesis of solandelactone E in 26 steps and 0.7% overall yield from commercially available D-glyceraldehyde acetonide has been
successfully developed and executed. Highlights of the synthesis include a novel
diastereoselective, acetal directed cyclopropanation of an electron deficient olefin, a
diastereoselective asymmetric dihydroxylation, and a stereoselective [2, 3]-sigmatropic
rearrangement of a chiral selenoxide intermediate. This innovative route can be easily
adapted to gain access to other oxylipins of differing carboskeletal framework.
vi Table of Contents
List of Tables ...... ix
List of Figures...... x
Chapter 1: Cyclopropyl- and Lactone Containing Oxylipins ...... 1 1.1 Introduction...... 1 1.2 Proposed Oxylipin Biogenesis...... 2 1.2.1 White’s Biomimetic of Eicosanoid 1.14 (1993) ...... 4 1.3 Halicholactone and NeoHalicolactone...... 7 1.3.1 Synthesis of Halicholactone and Neohalicholactone...... 10 1.3.1.1 Wills’ Total Synthesis of Halicholactone and Neohalicholactone (1995)...... 10 1.3.1.2 Datta’s Formal Synthesis of Halicholactone and Neohalicholactone (1998)...... 18 1.3.1.3 Tanaka’s Total Synthesis of Halicholactone (2000)...... 21 1.3.1.4 Kitahara’s Total Synthesis of (-)-Halicholactone (2002)26 1.3.1.5 Mohapatra’s Partial Synthesis of Halicholactone: The Stereoselective Synthesis of the C(1)-C(13) Fragment (2004) ...... 30 1.4 Constanolactones A-G ...... 33 1.4.1 Synthesis of Constanolactone A and Constanolactone B ...... 36 1.4.1.1 White’s Biomimetic Total Synthesis of Constanolactones A and B (1995) ...... 36 1.4.1.2 Mohapatra’s Partial Synthesis of the C(1)-C(10) Fragment of Constanolactone A and B (1998)...... 40 1.4.1.3 Pale’s Total Synthesis of Constanolactones A and B (2000) ...... 43 1.4.1.4 Falck’s Total Synthesis of Constanolactones A and B (2002) ...... 46 1.4.1.5 Pietruszka’s Total Synthesis of Constanolactones A and B (2003)...... 50 1.4.1.6 Pivnitsky’s Formal Synthesis of (±) Constanolactones A and B (2003) ...... 53 vii 1.4.2 Synthesis of Constanolactone E...... 54 1.4.2.1 Yamada’s Total Synthesis of Constanolactone E (1996)54 1.5 Solandelactones A-I...... 58 1.5.1 Partial Synthesis of Solandelactones A-H ...... 61 1.5.1.1 Mohapatra’s 1st Generation Partial Synthesis of the Cyclopropyl-Lactone Segment of the Solandelactones (1998) ...... 61 1.5.1.2 Mohapatra’s 2nd generation Partial Synthesis of the Cyclopropyl-Lactone Segment of the Solandelactones (2003) ...... 63 1.6 Miscellaneous Cyclopropane and Lactone Containing Oxylipins...... 64 1.6.1 Hybridalactone...... 64 1.6.1.1 Corey’s Total Synthesis and Structural Assignment of Hybridolactone (1984)...... 65 1.6.2 Aplydilactone...... 67 1.7 Conclusion ...... 68 1.8 Prior Art in the Martin Group ...... 69 1.8.1 First Generation Approach Towards the Total Synthesis of the Solandelactone Oxylipins ...... 69
Chapter 2: Studies Towards the Total Synthesis of the Solandelactone Oxylipins-The Total Synthesis of Solandelactone E...... 85 3.1 First Generation Approach...... 85 3.2 Second Generation Approach ...... 96 3.3 Applications ...... 149 3.4 Conclusion ...... 153
Chapter 3: Experimental Procedures ...... 156 3.1 General...... 156 3.2 Compounds: Approach 1 ...... 157 3.3 Compounds: Approach 2 ...... 181
References:...... 275
Vita…...... 296
viii List of Tables
Table 1.1. Reaction conditions for Wittig olefination of sugar lactol 1.226...... 74 Table 1.2. Reaction conditions for the oxidation of the primary alcohol in diol 1.227... 75 Table 1.3. Reaction conditions for the 1,3-chirality transfer of 1.235 using silyl cuprates and zincates...... 78 Table 1.4. Reaction conditions for the selenation of diester 1.233...... 81 Table 2.1. Reaction conditions for the selenation of allylic alcohol 1.223...... 89 Table 2.2. Conditions of the selenation of phenyl ester 2.8...... 91 Table 2.3. Reaction conditions for the cyclopropanation of allylic alcohol 1.268...... 93 Table 2.4: Conditions for the cyclopropanation of diene 2.23...... 103 Table 2.5. 1H NMR shifts of C(11)-H and C(12)-H in regioisomeric silyl ethers (2.71- 2.73)...... 118 Table 2.6. Reaction conditions for the reductive cleavage of benzylidene acetal 2.86. 123 Table 2.7. 1H NMR shifts of C(2)-H and C(3)-H in regioisomeric PMB-ethers 2.87 and 2.88...... 123 Table 2.7. Reaction conditions for the reductive cleavage of benzylidene acetal 2.89. 124 Table 2.8. 1H NMR shifts of C(11)-H in regioisomeric PMB-ethers 2.90 and 2.91 as compared with starting diol 2.68...... 125 Table 2.9. Reaction conditions for opening epoxide 2.100 with the dianion of pentynoic acid...... 132 Table 2.10. Reaction conditions for the RCM of 2.114...... 138 Table 2.11. Chemical Shifts of C(11)-H and C(12)-H of 2.129, 2.80, and 2.130 in CDCl3...... 142 Table 2.12. 1H NMR chemical shifts in CDCl3 of the cyclopropane protons C(8)-C(10) in isolated solandelactones E and F, and synthetic solandelactone (1.197)...... 145 Table 2.13. 13C NMR chemical shifts in CDCl3 of the cyclopropane protons C(8)- C(10), C(17) in isolated solandelactones E and F, and synthetic solandelactone (1.197) ...... 146
ix List of Figures
Figure 1.1. Prostaglandins isolated from the marine coral Plexaura homomalla...... 1 Figure 1.2. Metabolites of the gorgonian coral Plexaura homomalla...... 3 Figure 1.3. Halicholactone (1.26) and neohalicholactone (1.27)...... 8 Figure 1.4. Constanolactones A-G (1.103-1.109)...... 34 Figure 1.5. Absolute stereochemistry of constanolactone A and constanolactone B...... 35 Figure 1.6. Absolute stereochemistry of constanolactones E and constanolactone F. .... 36 Figure 1.7. Solandelactones A-I (1.195-1.201)...... 59 Figure 1.8. Absolute stereochemistry of solandelactone E and F...... 59 Figure 1.9. Tentative stereochemical assignment of solandelactone I...... 60 Figure 1.10. Hybridolactone (1.210)...... 65 Figure 1.11. Aplydilactone (1.220)...... 68 Figure 1.12. The solandelactones, halicholactones, and constanolactones...... 70 Figure 2.1. Mnemonic device for predicting enantiofacial selectivity in the Sharpless asymmetric dihydroxylation...... 107 Figure 2.2. Phthalazine ligands in the Sharpless asymmetric dihydroxylation...... 108 Figure 2.3. Potential chelates in the RCM of substrates having basic functional groups...... 137 Figure 2.4. Gross structure of solandelactones A-H as depicted in the isolation paper. 145 Figure 2.5. Corrected structures of solandelactone A-H...... 147
x Chapter 1: Cyclopropyl- and Lactone Containing Oxylipins
1.1 INTRODUCTION
In 1969 Weinheimer discovered that the marine coral Plexaura homomalla contained large quantities of previously unknown prostaglandins 1.1-1.6 (Figure 1.1).1
This discovery was responsible for the beginning of a fascinating era of marine invertebrate and algae derived natural product isolation. Close study of marine metabolites has since resulted in the discover of a wide variety of fatty acid derived substances of varied structure and biological activity.
Figure 1.1. Prostaglandins isolated from the marine coral Plexaura homomalla.
CO2R CO2R O O O CO2R
H H OR' OR' OR' 1.1 R, R'= H 1.3 R, R'= H 1.5 R, R'= H 1.2 R= Me, R'= Ac 1.4 R= Me, R'= Ac 1.6 R= Me, R'= Ac
Since marine organisms commonly use 18-, 20-, and 22-carbon fatty acids in their biosynthetic pathways, the term oxylipin was conceived to collectively describe compounds derived from a fatty acid of any length by a series of reactions involving at least one mono- or dioxygenase dependant oxidation.2,3 By contrast, the more commonly
employed term, eicosanoid, exclusively refers to substances derived from the 20-carbon atom arachidonic acid. This review will focus on oxylipin natural products of marine origin containing both a cyclopropyl- and lactone functionality in their architecture.4
1 1.2 PROPOSED OXYLIPIN BIOGENESIS
In 1987, Corey published a general pathway for marine biosynthesis. He proposed that arachidonic acid (1.7) is oxidized by a lipoxygenase to (8R)-8- hydroperoxyeicosatetraenoic acid (8R-HPETE) 1.8 (Scheme 1.1).5 Peroxide 1.8 is then enzymatically converted to allene oxide 1.9. Corey suggested that prostaglandins, such as preclavulone A (1.11), arrive biosynthetically from the closure of derived cation 1.10 at C(12) of the eicosanoid.6 In 1989, Harris found persuasive evidence to support Corey’s proposed biosynthesis.7 By incubating peroxide 1.8 with an acetone powder
derived from the coral Plexaura homomalla, Harris was able to isolate and characterize Corey’s proposed allene oxide 1.9.
Scheme 1.1
HO O HO O HO O OOH O Arachidonic Acid (1.7) 1.8 1.9
1 HO2C 20 O 9
12 12
9 1 HO HO O 20 Preclavulone A (1.11) 1.10
In the hopes of discovering additional intermediates or chemical species that might shed light on the missing steps in the biosynthetic pathway of marine prostaglandins by gorgonian coral Plexaura homomalla, arachidonic acid (1.7) was incubated with its acetone powder. Careful isolation and examination of the resulting
2 metabolites revealed the presence of both preclavulone A (1.11) and a novel cyclopropane containing eicosanoid 1.12.8
Figure 1.2. Metabolites of the gorgonian coral Plexaura homomalla.
HO2C O CO2H
H OH
H O Preclavulone A (1.11) 1.12
An extension of Corey’s proposed biosynthetic pathway5 to include possible
migration of ∆5,6 which would result in the formation of cyclopropyl carbocation 1.13 is required to explain the isolation of this unique cyclopropane containing eicosanoid. In an
aqueous environment, this carbocation would further provide the isolated δ-hydroxy acid 1.12, which upon conversion to its methyl ester was found to undergo facile lactonization to furnish eicosanoid 1.14. This oxylipin is the first cyclopropyl- and lactone containing oxylipin ever characterized. Interestingly, the circular dichroism (CD) spectrum of 1.14 was featureless. This indicates that the lactone is likely racemic, however, all attempts to resolve the enantiomers on the small quantity of available material proved fruitless.
3 Scheme 1.2
HO O HO O HO O OOH O Arachidonic Acid (1.7) 1.8 1.9
O O OH H OH OH H
H 5 HO O O H HO 6 OH 1.12 1.13 1.10
HO2C O
H O O
H O
Eicosanoid (1.14) Preclavulone A (1.11)
1.2.1 White’s Biomimetic of Eicosanoid 1.14 (1993)
Corey’s biosynthetic pathway, from epoxide 1.9 to γ-hydroxyacid 1.12 or euicosainoid 1.14, is founded on the hypothesis that epoxide opening triggers carbocyclization to a cyclopropyl carbinyl cation 1.13 that is subsequently trapped by either water or the terminal carboxyl group (see Scheme 1.2). On the basis of this precept, White designed a biomimetic-like approach for the synthesis of 1.12 and 1.14. His synthetic design features the construction of the cyclopropyl lactone moiety of 1.14 and unambiguously defines its relative configuration to be as depicted.9
4 The synthesis of eicosanoid 1.14 was initiated by the hydrostannylation of methyl 5-hexynoate (1.15) to afford a mixture (4:1) of (E) and (Z) stannanes 1.16, which were difficult to separate (Scheme 1.3). The stannanes were treated with butadiene monoxide
in the presence of PdCl2 to form an even more complicated and inseparable mixture (4:1)
of 1,4- and 1,2-addition products, 1.17 and 1.18, each as a mixture of ∆5,6 olefin isomers.10 This four component mixture was subjected to Sharpless’ asymmetric
epoxidation conditions and, as anticipated, only allylic alcohols 1.18a and 1.18b participated in this oxidation. The choice of (S)-(-)-tartrate as the chiral adjuvant for epoxidation was guided by the knowledge that epoxide 1.9 is known to possess the (R)- configuration. Saponification of the ester moiety gave acids 1.19a and 1.19b, which could be cleanly separated on silica gel impregnated with silver nitrate.
Scheme 1.3
O
n-Bu3SnH, AIBN, PdCl2 (MeCN)2 MeO O
MeO O 89%, 4:1 E/Z SnBu3 94% 1.15 1.16
HO OH MeO O OH HO O MeO O 1. t-BuOOH, Ti(Oi-Pr)4 O (-)-Diethyl Tartrate, 91% 1.17a 1.17b 1.19b 2. LiOH, THF/H2O, 99%
HO MeO O HO O HO HO MeO O O 1.18a 1.18b 1.19a
Carboxylic acids 1.19a and 1.19b were independently treated with a wide variety of Lewis and Bronsted acids in an attempt to initiate the desired cyclization cascade, but only SnCl4 brought about the desired cyclization (Scheme 1.4). It is intriguing to note
5 that the same mixture (1.5:1) of lactones 1.20a and 1.20b were obtained regardless of which epoxide was used as the starting material. This observation is consistent with the theory that the reaction proceeds through a discrete cyclopropyl cation as depicted by 1.23. Presumably, this carbocation can exist in either of the two possible conformations by geometrically distinct pathways emanating from the (E) and (Z) complexed epoxides 1.19a and 1.19b, respectively. The identical ratio of products obtained in both cases, may be the result of a modest thermodynamic preference for closure of the carboxyl terminus at the sterically less hindered top face of the carbocation. The minor diastereomer, possessing the correct C(5) stereochemistry, was oxidatively cleaved to aldehyde 1.21 in excellent yield.
Scheme 1.4
HO HO HO O or HO O O O O 1.19a 1.19b Cl SnCl , MeNO Sn 4 2 HO O 47%, 1.5:1 O Cl 1.22 H H O O O O
HO H HO H OH OH H 1.20a 1.20b HO O NaIO4, 93% O H Cl Sn O Cl H O O 1.23 H H O 1.21
The coupling partner 1.25 for aldehyde 1.21 was prepared in a single step from 4(Z), 4-decanal (1.24) using the Takai homologation method.11 Treatment of vinyl iodide 6 1.25 with chromium (II) chloride12,13 followed by the addition of cyclopropyl aldehyde
1.21 afforded a mixture (1:1) of C(8) stereoisomeric alcohols that were oxidized with Dess-Martin periodinane to give eicosanoid 1.14 (Scheme 1.5).14 Eicosanoid 1.14
displayed 1H and 13C NMR spectra identical to those obtained from the natural eicosanoid. Saponification of the lactone provided the naturally occurring δ-hydroxy acid 1.12. The hydroxy acid rapidly relactonized to 1.14 in the presence of mineral acid
or by simply standing in CDCl3.
Scheme 1.5
H
O
1.24
CrCl2, CHI3, 95%
H H + O O 1. CrCl2, NiCl2 (cat.) 61%. 1:1 O O H H 2. AcO OAc H I I OAc O O 84% O 1.25 1.21 1.14 O
LiOH, THF-H O CDCl3 2 96% O
OH H OH
H O 1.12
1.3 HALICHOLACTONE AND NEOHALICOLACTONE Marine derived eicosanoids halicholactone (1.26) and neohalicholactone (1.27) (Figure 1.3) were isolated from the marine sponge Halichondria okadai in 1989.15 A biological screen revealed that halicholactone (1.25) exhibits an inhibitory activity (IC50
7 = 630 µM) against 5-lipoxygenase, an enzyme that catalyzes oxidation of unsaturated fatty acids with oxygen to yield peroxides and is responsible for the production of leukotrienes. Leukotrienes are involved in asthmatic and allergic reactions and act to sustain an inflammatory response.
Figure 1.3. Halicholactone (1.26) and neohalicholactone (1.27).
5 6 17 18
15 H 8 H 20 HO 1 HO 10O O 12 H O H O OH OH Halicholactone (1.26) Neohalicholactone (1.27)
For several years after their isolation, the relative and absolute stereochemistry of halicholactone (1.26) and neohalicholactone (1.27) was a source of controversy. Initial spectroscopic studies correctly identified the planar structure of these compounds and the presence of a trans-substituted cyclopropane ring, but they were inconclusive as to their relative stereochemistry. The degradation and isolation of the C(15) fragment 1.28 of halicholactone (1.26) established the absolute stereochemistry at that center to be 15R* by comparing the spectral data and the optical rotation of 1.28 with an authentic sample.15 In 1991, two years after isolation, the same research group using X-ray
crystallography determined the relative configuration of neohalicholactone (1.27) to be 8S*, 9R*, 11R*, 12R*, 15R*.16
Scheme 1.6
15 H 1. OsO4 (R) H (R) (S) 2. NaIO4 HO HO O O (R) 15 (R) (R) H O 3. NaBH4 20 AcO H O OH 4. Ac2O, Pyr. OAc OH Halicholactone ( 1.26) 1.28 Neohalicholactone ( 1.27)
8
In 1994, an analysis of the extracts from the brown algae Laminaria sinclairii by an independent research group revealed the presence of a small quantity of neohalicholactone (1.26).17 Comparison of the authentic 1H- and 13C NMR spectra for
H. okadai derived neohalicholactone and L. sinclairii derived neohalicholactone showed that the two samples were spectroscopically identical. A two mg sample of L. sinclairii neohalicholactone (1.26) was converted to derivatized malate 1.29 (Scheme 1.7). GC comparison of the same menthol malate derivatives obtained from authentic R and S malates gave baseline separation under optimized conditions. When subjected to these same conditions, neohalicholactone derived malate 1.29 was analyzed as 100% (S). This indicated that the sample of neohalicholactone obtained from L. sinclairii has a 15S* stereochemistry, which is the opposite of that previously reported for halicholactone 1.26. The optical rotation of both natural samples of neohalicholactone determined they were the same sign and magnitude, thus indicating the possibility that the absolute stereochemistry in the alga derived and sponge derived neohalicholactone (1.27), and possibly that of halicholactone (1.26), might be the opposite of that previously reported in the sponge compounds. The enigma of absolute stereochemistry of these natural products remained a mystery for another year until the first total synthesis18 confirmed
the stereochemistry to be as depicted in scheme 1.6. To date, there is no satisfactory explanation for this anomalous stereochemical proof.
9 Scheme 1.7
OMe
O (S) OMe (R) 1. (-)-menthyl chloroformate, O * H O pyridine O HO O ? H O 2. O3 OH 3. CH2N2 Neohalicholactone (1.27) 1.29
(S) * H HO O H O ? OH L. sinclairii derived Neohalicholactone: 1.30
1.3.1 Synthesis of Halicholactone and Neohalicholactone
1.3.1.1 Wills’ Total Synthesis of Halicholactone and Neohalicholactone (1995)
The first total synthesis of halicholactone (1.26) and neohalicholactone (1.27) was completed in 1995, before the absolute stereochemistry of all five stereocenters were unequivocally determined,18-20 and before Gerwick’s17 controversial finding of L.
sinclairii derived neohalicholactone (1.30) was published. At the time of the first synthetic undertaking, the relative stereochemistry of neohalicholactone (1.26) was established by X-ray crystallography, and the absolute C(15) stereochemistry of halicholactone (1.25) was established as 15R* by degradation to a derivative of known configuration.15,16 Taken together with the assumption of a similar
biosynthetic pathway, the absolute stereochemistry of both halicholactone and neohalicholactone was predicted to be 8S*, 9R*, 11R*, 12R*, 15R* (see Scheme 1.6). This assignment was confirmed by Wills total synthesis of halicholactone (1.26) and neohalicholactone (1.27). His convergent approach to these oxylipins involved the 10 reaction of vinylic iodide 1.31 with cyclopropyl aldehyde 1.32 as the key steps of the synthesis. The C(8) stereocenter found adjacent to the cyclopropane was obtained from the chiral pool by the elaboration of S-malic acid (1.33).
Scheme 1.8
O H 8 H 8 HO OH O HO O O H 8 H H O I O OH OH O HO Halicholactone (1.26) 1.31 1.32 1.33 Neohalicholactone ∆17,18 (1.27)
The conversion of S-malic acid (1.33) to 3-hydroxy γ-lactone 1.34 was achieved in three steps using a literature procedure (Scheme 1.9).21 The free hydroxyl group was
protected as it’s p-methoxybenzyl (PMB) ether without incident. Reduction of the lactone occurred rapidly in the presence of diisobutylaluminum hydride (DIBAL), and
the resultant lactol could be used as a crude mixture in the next step without further purification. A Wittig olefination reaction on lactol 1.35 using a similar procedure as the one developed by Holmes,22 provided the desired (Z)-olefinic carboxylic acid, which was
then converted to its methyl ester 1.36 using an HCl/methanol mixture at pH 4-5. The primary alcohol was oxidized to an aldehyde using the Swern oxidation,23 and subsequent condensation with tert-butyl diethylphosphonoacetate furnished α,β- unsaturated ester 1.37. It was unknown if the key cyclopropanation reaction would be problematic. It was reasoned that if the stereocenter adjacent to the PMB-ether could be controlled then the remaining stereocenter could be equilibrated into its thermodynamically more stable trans-configuration. The ester was treated with two equivalents of dimethylsulfoxonium methylide (DMSY)24-26 in dimethyl sulfoxide
(DMSO), and despite the possible four diastereomers which could potentially be formed,
11 the desired trans-cyclopropane was exclusively obtained as in inseparable mixture (2:5). The most likely explanation for the exclusive formation of the trans-isomers is direct kinetic control in the cyclopropanation reaction.27,28 Upon oxidative deprotection of the PMB ether with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ),29 the two
diastereomeric cyclopropanes 1.38a and 1.38b were easily separated by silica gel chromatography.
Scheme 1.9
O O HO 1. H+, MeOH 1. Cl CCNHOCH C H OMe-p, OH 3 2 6 4 O 2. (CH3)2S· BH3, NaBH4, 88% O cat. TfOH, 73% O
OH OH 2. DIBAL, Tol. 84% OPMB HO 3. CF3CO2H. CH2Cl2, 90% 1.33 1.34 1.35
HO2C(CH2)4PPh3Br, NaHMDS 1. ClCOCOCl, DMSO, Et3N O OPMB O MeO then AcOH, MeOH, 69% OPMB t t OH MeO 2. Bu O2CCH2PO(OEt)2, Bu O2C DBU, LiCl, 66% 2 steps 1.36 1.37
H H 1. Me2S(O)I, NaH, DMSO 9 9 OH O OH O 2. DDQ, H O, CH Cl , MeO MeO 2 2 2 ButO C H ButO C H 69% steps (2:5) 2 2 1.38a 1.38b
The methyl ester of the cyclopropane containing the correct C(9) stereochemistry, 1.38b, was saponified in quantitative yield. The nine-membered lactone 1.39 was formed by subjecting the hydroxy-acid to the macrolactonization conditions developed by Yamaguchi.30 Conversion of the tert-butyl ester to a carboxylic acid was readily achieved
using trifluoroacetic acid (TFA). With the appropriate carboxylic acid in hand, its reduction to the alcohol involved the initial formation of a carbonic carboxylic anhydride 31 that was then reduced in-situ with sodium borohydride (NaBH4). Cyclopropyl alcohol
1.40 was then oxidized to cyclopropyl aldehyde 1.32 with tetrapropylammonium 12 perruthenate (TPAP),32 thereby completing the synthesis of the right hand fragment of
halicholactone and neohalicholactone (1.26 and 1.27) in 15 steps from S-malic acid (1.33).
Scheme 1.10
H H 1. LiOH, THF-MeOH-H2O, 4:1:1, 100% OH O O MeO 2. Yamaguchi Lactonization, 67% t ButO C H Bu O2C H 2 O 1.38b 1.39
H H 1. TFA, CH2Cl2, 100% TPAP, NMO O O 2. EtOCOCl, Et N, THF H 3 H O H O then NaBH3 OH O 1.40 1.32
The key coupling reaction between fragments 1.43 and 1.32 were first studied in a model system (Scheme 1.11). The synthesis of the left hand fragment 1.43 necessary to complete halicholactone (1.26) commenced with commercially available R-(+)-1-octyn- 3-ol. The alcohol was converted in a single step into its PMB and tert-butyl diphenyl silyl (TBDPS) ethers 1.41a and 1.41b to determine if steric environment at the C(15) would have an impact on the diastereoselectivity of the reaction. Alkynes 1.41a and 33 1.41b were treated with CP2ZrHCl and iodine to provide the corresponding vinyl
iodides 1.43a and 1.43b respectively. By coupling PMB-protected vinyl iodide 1.43a and 2-methylpropanal 1.4 in the presence of chromium (II) chloride and catalytic nickel (II) chloride,12,13 the desired product was obtained in quantitative yield, albeit, in a disappointing 1:1 ratio. When the protecting group was swapped for the more sterically demanding TBDPS ether, the yield remained quantitative, and the ratio of diastereomers improved to 2:1.
13 Scheme 1.11
Cp2ZrHCl, I2, THF, rt RO RO 92% I 1.41a R= PMB 1.43a R= PMB 1.41b R = TBDPS 1.43b R = TBDPS
6 eq. CrCl2 cat. NiCl RO H 2 RO
I O DMSO, rt 100% OH 3.0 eq. 1.0 eq. 3.0 eq.
1.43a R= PMB 1.44 1.45a R= PMB 1:1 1.43b R = TBDPS 1.45b R= TBDPS 2:1
In the real system, coupling of TBDPS-protected vinyl iodide 1.43b with cyclopropyl aldehyde 1.32 provided a ratio (2:1) of allylic alcohol 1.46a and its C(12) epimer 1.46b. Separation of the epimers was achieved by flash silica gel chromatography, and the major diastereomer 1.46a was treated with TBAF in refluxing THF to provide halicholactone (1.26) in near quantitative yield. Spectral data obtained from synthetic halicholactone matched the naturally occurring halicholactone, thus confirming that the absolute and relative stereochemistry of this complex natural product is as drawn.
Scheme 1.12
14 H CrCl2, cat. NiCl2, DMSO, H O TBDPSO O TBDPSO H rt, 74%, 2:1, 1.46a:1.46b I H O H O O R1 R2
1.43b: R = TBDPS 1.32 1.46a: R1 = OH, R2 = H 1.46b: R1 = H, R2 = OH
TBAF, THF, reflux H H HO TBDPSO O 2.5 h, 98% O H O H O OH OH 1.46a Halicholactone: 1.26
In an attempt to improve the ratio furnished by the coupling reaction, the mixture of C(12) diastereomers, 1.46a and 1.46b, were oxidized to the enone. Subsequent TBAF
mediated desilylation furnished γ-hydroxy enone 1.47 in excellent yield. Unfortunately, Luche34 reduction of the ketone proceeded without any diastereoselectivity in only a
disappointing 40% yield.
Scheme 1.13
H 1. TPAP, NMO, 91% H TBDPSO O HO O 2. TBAF, 90% H O H O R1 R2 O
1.46a: R1 = OH, R2 = H 1.47 1.46b: R1 = H, R2 = OH
NaBH4, CeCl3 H HO 40%, 1:1 O H O OH 1.46a & 1.46b
Having established what he thought to be an effective route to halicholactone (1.26), Wills turned his attention to the structurally more complex neohalicholactone
15 (1.27) whose left-hand side chain contains an additional cis-double bond relative to halicholactone (1.26).15,16 Lactol 1.47 was synthesized in five steps from commercially available R-malic acid using the using the previously described route.19 A PMB ether
was selected in preference to a TBDPS protecting group due to the propensity of the latter to migrate to the primary alcohol during the Wittig olefination to 1.48. After the Wittig olefination reaction, conventional steps were employed for the conversion of alcohol 1.48 to dibromide 1.49. At this point, the PMB protecting group was swapped for the more sterically demanding TBDPS protecting group to give 1.50. Elimination of the dibromide 1.50 provided alkyne 1.51 whose subsequent hydrozirconation/iodination33 gave the desired left hand fragment 1.52.
Scheme 1.14
OH
propylphosphonium bromide 1. (ClO)2OC, DMSO, Et3N O PMBO PMBO PMBO NaHMDS, 76% OH 2. CBr3, PPh3, Et3N, Br Br 73% 2 steps 1.47 1.48 1.49
1. DDQ, CH2Cl2/H2O n-Buli, 67% Cp2ZrHCl, I2, 92% TBDPSO TBDPSO TBDPSO 2. TBDPSCl, Imid., Br Br 92% I 1.50 1.51 1.52
The coupling of iodide 1.52 and aldehyde 1.32 was achieved using the previously described chromium(II)/nckel(II) method to furnish a separable diastereomeric mixture (2:1) of 1.51a and 1.51b in a 62% yield. Desilylation of the major diastereomer 1.53a under forcing conditions provided neohalicholactone (1.27) in 90% yield. In another attempt to improve the diastereoselectivity, the mixture of C(12) alcohols obtained after 34 the coupling was oxidized to the enone and reduced with NaBH4/CeCl3. This yielded a
16 mixture (3:1) of diastereomers. This time, however, the reduction favored 1.51b, the opposite diastereomer of that favored in the coupling step.
Scheme 1.15
H H 1. CrCl2, cat. NiCl2, 62%, 2:1(1.53a:1.53b) O HO O H TBDPSO H O 2. TBAF, THF, reflux 2 h, 90% H O I O OH 1.52 1.32 Neohalicholactone (1.27)
H 1. TPAP, NMO, 91% H H TBDPSO O TBDPSO O TBDPSO O 12 2. NaBH4, CeCl3, H O 58%, (1:3) H O H O OH OH OH 1.53a & 1.53b 1.53a 1.53b
By the time Wills’ synthetic endeavors towards halicholactone (1.26) and neohalicholactone (1.27) were drawing to a end, he became aware of the report made by Gerwick and Proteau17 of the sample of neohalicholactone obtained from L. sinclarii that
was shown by degradation to posses an anomalous 15S* stereo configuration. Wills hypothesized that Gerwick may have actually isolated a C(15) epimer, 1.30, of halicholactone. To confirm his theory, he proceeded to synthesize an authentic sample of this material, via his established route, for spectrographic comparison. The optical
rotation of synthetic neohalicholactone epimer 1.30 had the same sign and a similar magnitude as L. sinclarii neohalicholactone. The 1H NMR spectral data obtained at a 300 MHz showed no discernable difference between neohalicholactone (1.27) and C(15) epi-neohalicholactone (1.30). At 500 MHz, every peak appeared identical except the signals resulting from the C(16) protons. The splitting pattern of these protons in 1.30 appeared significantly more dispersed than those found in presumed neohalicholactone
(1.27). Since only a 300 MHz 1H NMR spectrum of L. sinclarii derived 17 “neohalicholactone” exists, pending re-isolation, no conclusive explanation for this discrepancy is realized. It is possible that L. sinclarii derived “neohalicholactone” might be the C(15) epimer 1.30.
Scheme 1.16
OH 15 H HO 15 O O 15 TBDPSO H O PMBO I OH 1.35 1.54 C(15) epi-Neohalicholactone: 1.30
In summary, Wills completed the first total synthesis of halicholactone (1.26) and neohalicholactone (1.27) in 19 and 29 steps respectively from malic acid. His synthesis confirmed that the assigned stereochemistry of these natural products to be 8S*, 9R*, 11R*, 12R*, 15R*. The C(8) and C(15) stereocenters were purchased from S and R malic acids respectively. Key transformations of his synthesis include a trans-selective Corey- Chaykovsky cyclopropanation and a moderately diastereoselective Nozaki-Hiyama-Kishi Reaction borrowed from White’s biomimetic synthesis of eicosanoid (1.14) to establish the C(12) stereocenter.
1.3.1.2 Datta’s Formal Synthesis of Halicholactone and Neohalicholactone (1998)
Datta’s formal synthesis35 of halicholactone (1.26) and neohalicholactone (1.27)
terminates with the construction of cyclopropyl aldehyde 1.32 (Scheme 1.17). His strategy towards the construction of this target includes the synthesis of key cyclopropane containing intermediate 1.55 which can be obtained via an asymmetric cyclopropanation of achiral cinnamyl alcohol 1.56.
18 Scheme 1.17
OH H 8 H H HO O O O H H O H O H OH O OAc OH Halicholactone (1.26) 1.55 Neohalicholactone ∆17,18 (1.27) 1.32 1.56
Asymmetric cyclopropanation of trans-cinnamyl alcohol 1.56 proceeded smoothly according to Charette’s protocol36 in the presence of a chiral dioxaborolane
ligand to afford (1R, 2R)-cyclopropyl alcohol 1.57 with good enantioselectivity and yield (Scheme 1.18). Acylation of the hydroxyl group, followed by oxidative degradation of the phenyl moiety to the carboxylic acid provided 1.58. The acid was then converted to its Weinreb amide 1.59 under standard reaction conditions. Treating amide 1.59 with allylmagnesium bromide not only yielded the desired allylic ketone but it cleaved the acetyl functionality concurrently. In a separate operation, the alcohol was reprotected as a TBS ether to give 1.60. Stereoselective reduction of the cyclopropyl ketone was achieved using K- Selectride to provide alcohols 1.61a and 1.61b in a respectable ratio (9:1). The relative configuration of the newly formed C(8) stereocenter of the major diastereomer 1.61a was determined to be 8S* using Mosher’s modified method.37,38 In α-cyclopropyl ketones
there is a delocalization of electrons between the cyclopropyl C-C bonds and the carbonyl
π-orbitals. The degree of conjugative interaction is dependent on the relative orientation of the carbonyl and the cyclopropyl group. Interactions between the cyclopropyl C-C
bonds and the carbonyl π orbitals are maximized when the cyclopropane and the carbonyl are oriented orthogonally. Both the S-(cis)-conformation 1.A and S-(trans)-conformation 1.B in are able to provide maximum stabilization.39-45
19 Computational studies indicate that the S-(cis)-conformation 1.A is favored by 1.6-3.0 kcal over the S-(trans)-conformation 1.B, depending on the substitution pattern of the cyclopropane.40 If the conformation of the transition state of reduction is similar to
that of the substrate, then the ability of the cyclopropyl group to conjugate with the
carbonyl π-system would explain the experimentally observed selectivity in the reduction of 1.60.44,45
Scheme 1.18
Me2NOC CONMe2 OH H H O O B O 1. Ac2O, DMAP, 100% MeNH(OMe).HCl, Bu H H . OH Et2Zn, CH2I2, OH 2. RuCl3 H2O, NaIO4, 93% OAc 1.1'carbonyldiimidazole, 97%, 88% ee Et3N, 87% 1.56 1.57 1.58
Me N OMe 8 H H H R2 1. allylmagnesium bromide, 87% K-Selectride, O O R1 H 2. TBSCl, imidazole, 90% H 91%, 9:1 dr H OAc OTBS OTBS
1.59 1.60 1.61a R1=OH, R2=H 1. DEAD, PPh3, AcOH 2. NaOMe, MeOH, 1.61b R1=H, R2=OH 91% (2 Steps)
TBSO O O H H OH OTBS OH
- H H H OTBS 1.A 1.B OTBS 1.61a S-cis S-trans 1.61b Preferred Conformation Disfavored Conformation
Ozonolysis of the terminal olefin found in 1.61 resulted in the formation of an intractable mixture of products. This problem was circumvented by a two-step sequence involving an osmium catalyzed dihydroxylation followed by oxidative cleavage of the vicinal diol to aldehyde 1.62 (Scheme 1.19). Cis-selective Wittig olefination of this 20 aldehyde with the reagent derived from (4-carboxybutyl)tripenylphosphonium bromide yielded the lactone precursor 1.63 in excellent yield and Z/E selectivity.19,22 Lactonization of the η-hydroxy acid under Yamaguchi’s conditions30 afforded the desired
nine-membered lactone ring 1.64. Lastly, deprotection of the TBS ether and oxidation of the alcohol culminated in the formal synthesis of halicholactone and neohalicholactone by-way-of a known intermediate 1.32. In summary, Datta’s strategy towards the synthesis of intermediate 1.32 was completed in 13 steps, 2 steps shorter than Wills’ previously published synthesis of this same intermediate. It featured the asymmetric cyclopropanation of cinnamyl alcohol36 and a stereoselective reduction of a cyclopropyl ketone as key steps.
Scheme 1.19
H
O OH H H H OH 1. OsO4, NMO OH HO2C(CH2)4PPh3Br, OH O H H H 2. NaIO4, NaHCO3 NaHMDS, 90% OTBS 84% (2 steps) OTBS OTBS
1.61a 1.62 1.63
H H 2,4,6-trichlorobenzoylchloride, 1. TBAF, 92% O O Et N, DMAP, 66% 2. IBX, 89% H 3 H O H O OTBS O
1.64 1.32
1.3.1.3 Tanaka’s Total Synthesis of Halicholactone (2000)
After observing the considerable difficulties that published approaches faced while stereoselectively establishing the C(9) to C(12) stereocenters of halicholactone (1.26), neohalicholactone (1.27) and other structurally related oxylipins, Tanaka set out to
21 establish a general and stereocontrolled approach to these natural products that would elegantly install these problematic stereocenters.46,47 He envisioned that the nine- membered unsaturated lactone could be constructed via a Z-selective RCM reaction (Scheme 1.20). The disconnection of the C(5)-C(6) double bond reveals bis terminal olefin 1.65 as a suitable synthetic intermediate. This compound can be manufactured by the synthetic elaboration of alcohol 1.66 with inversion at C(8). The regio- and diastereoselective introduction of the cyclopropane ring unto the C(9)-C(10) olefin would occur via a modified Simmons-Smith cyclopropanation reaction of allylic alcohol 1.67, while the key steps for the conversion of 1.68 to 1.67 includes a stereoselective [2,3]- sigmatropic rearrangement48,49 of the sulfoxide to establish the stereocenter at C(12).
Triol complex 1.68 can be constructed via a catalytic asymmetric alkylation of the achiral 50,51 dialdehyde Fe(CO)3 complex 1.69.
Scheme 1.20
6 5 OR 15 H 8 15H 8 15 H 8 HO O RO RO OH 12 O H 12 O H O H OH OR OR Halicholactone (1.26) 1.65 1.66
OR H 15 8 OR RO OH RO O 12 8 H OR OR Fe(CO)3 S Fe(CO)3 O O Ph 1.67 1.68 1.69
Meso-(diene)Fe(CO)3 complex 1.69 underwent asymmetric alkylation with dipentyl zinc in the presence of [(S)-(+)-diphenyl-(1-methylpyrrolidin-2-yl) methanol]52 to furnish a chiral allylic alcohol intermediate in excellent yield and ee (Scheme
22 1.21).50,51 The resultant alcohol was protected as its tert-butyldimethylsiloxy (TBS)
ether giving 1.70, and the aldehyde was condensed with triethylphosphonoacetate to give the corresponding α,β-unsaturated ester. The ester moiety was reduced to an alcohol and its proximal olefin was diastereoselectively dihydroxylated to give triol 1.71 as a diastereomeric mixture (9:1).53
The primary alcohol of 1.71 was regioselectively protected as its pivaloyl (Piv) ether and the remaining internal diol was converted to its bis-chloroacetate. This 54 o intermediate was treated with Me2AlSPh at -78 C to regio- and stereoselectively
install the phenylsulfenyl group by substitution with retention of the configuration at C(3) to give 1.72 as a single isomer. This reaction is thought to proceed via a stabilized transient iron cation complex generated in situ by reaction with the more reactive chloroacetate leaving group in the presence of the Lewis acid.55,56
Scheme 1.21
H Ph O Ph 1. (EtO) P(O)CH CO Et, NaH, 99% 1. Pentyl2Zn, TBSO 2 2 2 N OH H 82%, 98%ee H O 2. DIBAL-H, 97% Fe(CO) 3 O 2. TBSOTf, pyridine, 100% Fe(CO)3 H 3. OsO4, pyridine then NaHSO3, 94%, 9:1 dr 1.69 1.70
OH 1. PivCl, pyridine, 97% OPiv TBSO TBSO 2. (ClCH2CO)2O, DMAP, 89% 3 3 OH OCOCH Cl o 2 3. Me2AlSPh, -78 C, 69% Fe(CO)3 OH Fe(CO)3 SPh 1.71 1.72
After decomplexation of the iron tricarbonyl complex with ceric ammonium nitrate (CAN), sulfide 1.72 was oxidized to the sulfoxide with 3-chloroperoxybenzoic acid (MCPBA). Subsequent heating with the thiophile trimethyl phosphite in methanol furnished the desired allylic alcohol 1.73 as a single diastereomer (Scheme 1.22). The (S)
23 stereochemistry and E-olefin were tentatively assigned based on the assumption that the [2,3] sigmatropic rearrangement proceeded via the well documented chair-like transition state.57 The newly installed allylic alcohol was protected as its 2-
(trimethylsilyl)ethoxymethyl (SEM) ether, and the chloroacetate was reductively cleaved with DIBAL to give allylic alcohol 1.74. Hydroxyl-directed modified Simmons-Smith cyclopropanation58 proceeded via the A1,3 minimized conformer to yield 1.75 as a single
diastereomer.
Scheme 1.22
OPiv OPiv 1. CAN, K2CO3, MeCN 97% OCOCH Cl TBSO TBSO 2 2. m-CPBA, 95% OCOCH2Cl 3. P(OMe)3, MeOH, 88% Fe(CO)3 SPh OH 1.72 1.73
OPiv OPiv H 1. SEMCl, i-Pr2NEt, TBAI 100% OH Et Zn, CH I , 69% OH TBSO 2 2 2 TBSO
2. DIBAL, CH2Cl2, 91% H OSEM OSEM 1.74 1.75
With the advanced cyclopropane containing intermediate 1.75 in hand, all that remained was the introduction of the Z-olefin containing nine-member lactone. The
pivaloyl ether was removed with methyllithium, and the resultant vicinal diol was oxidatively cleaved to the aldehyde using lead tetraacetate (Scheme 1.23). This operation destroyed the C(8) stereocenter. The introduction of an allyl group59 proceeded without
stereoselectivity to provided a mixture (1:1) of homo-allylic alcohols 1.76a and 1.76b. The absolute stereochemistry of these diastereomers was determined using the modified MTPA ester method.37,38 Alcohol 1.76a was found to possess the correct
stereochemistry necessary for completion of the synthesis while 1.76b required a two 24 step inversion under Mitsunobu conditions.60 Treatment of 1.76a with ethyl vinyl ether
and pyridinium p-toluenesulfonate (PPTS) was followed by removal of the TBS- and SEM-ethers in a refluxing solution of TBAF in N,N′-dimethylpropylene urea (DMPU).61
Diol 1.77 was reprotected as its diacetate and the ethoxyethyl (EE) group was cleaved in acidic t-BuOH. N,N’-Dicyclohexylcarbodiimide (DCC) mediated esterification provided the key terminal diene intermediate 1.78.
Scheme 1.23
OPiv 1. MeLi, Et2O, 90% H 8 R' H OH TBSO 2. Pd(OAc)4, Na2CO3 TBSO R 1. ethylvinylketone, PPTS, CH2Cl2
H 3. tetraallyltin, Sc(OTf)3, H 2. TBAF, DMPU, 64% OSEM 68% (2 steps), 1:1 dr OSEM 1.75 1.76a R=H, R'=OH 1. DIAD, AcOH, PPh3 2. NaH, MeOH, 1.76b R=OH, R'=H 60%, (2 steps)
1. Ac O, DMAP, Et N, 88% H 2 3 H HO OEE 2. PPTS, t-BuOH, 69% AcO O H 3. Hexanoic acid, DCC, H O DMAP, 88% OH OAc 1.77 1.78
After multiple attempts and lengthy optimization, diene 1.78 was found to undergo efficient ring closing metathesis using Grubbs first generation olefination 62-64 catalyst in the presence of a catalytic amount of Ti(O-i-Pr)4. Under these conditions
the Z-olefin nine-membered lactone derivative was isolated in a 72% yield along with the corresponding dimer (11%). Methanolysis of the two allylic acetates afforded halicholactone (1.26).
25 Scheme 1.24
1. (Cy3P)2RuCl2=CHPh, Ti(Oi-Pr) , 72% H 4 H AcO HO O O 2. K2CO3, MeOH, 61% H H O O OAc OH 1.78 Halicholactone (1.26)
In summary, Tanaka completed a the total synthesis of halicholactone (1.26) in 26 steps, including the Mitsunobu inversion of 1.76b’s C(8) stereocenter from meso-
(diene)Fe(CO)3 complex 1.69. Highlights of this synthesis include an asymmetric
alkylation of 1.69 with dipentylzinc to set the C(15) stereocenter, diastereoselective dihydroxylation, a 1,3-Mislow-Evans chirality transfer with overall retention of stereochemistry, and a Z-selective RCM macrolactonization. Although, Tanaka’s synthesis is by far the most interesting of all the published approaches, it still suffers from a lack of diastereoselectivity when establishing the C(8) stereocenter via allylation of the cyclopropyl aldehyde. This is unfortunate because the C(8) stereocenter in 1.74, for example, was invaluable for setting the stereochemistry of the cyclopropane ring (see Scheme 1.22). There are numerous alternate synthetic strategies one might envision for preserving this center and completing the synthesis, but unfortunately no comment is made regarding their decision to destroy it.
1.3.1.4 Kitahara’s Total Synthesis of (-)-Halicholactone (2002)
Kitahara’s approach to halicholactone (1.26) heavily borrows from previously published synthesis. For example, the key macrolactonization/RCM reaction was first reported by Tanaka,46,47 and the Nozaki-Hiyama-Kishi reaction comes from Wills’ synthesis65 What is unique about this approach is the use of their novel homemade chiral building block 1.8166 to establish the multiple stereocenters of halicholactone.
26 Scheme 1.25
OH H H H H HO OH O HO O H H H H O H O O O OH OH Halicholactone (1.26) 1.79 1.80 1.81
Dimethyl γ-ketopimelate 1.83 was prepared from commercially available furylacrylic acid (1.82) according to the procedure of Marckwalds (Scheme 1.26).67 The ketone reacted smoothly with ethylene glycol to give a dimethyl γ - ethylenedioxypimelate that underwent a smooth Dieckmann condensation upon treatment with base to provide bicyclic cyclohexanone 1.84.68 Asymmetric reduction of the ketone
functionality with baker’s yeast on a multigram scale gave β-hydroxyester 1.85 as the sole product in 67% yield and 98.4% ee.69
The hydroxyl group of 1.85 was protected as its tetrahydropyran (THP) ether and subsequent LiAlH4 reduction of the ester furnished alcohol 1.86. Treatment of 1.86 with p-toluenesulfonyl chloride (TsCl) followed by a high yield two-stage deprotection protocol for the cleavage of the THP ether and acetonide provided the corresponding γ- hydroxyketone. The acidic deprotections were immediately followed by treatment with t- BuOK to afford cyclopropyl ketone 1.81.66
27 Scheme 1.26
O O
O OEt O 1. Ethylene glycol, TsOH, 61% HCl, MeOH, 80% O O O 2. EtOH, EtONa, 61% O O OH O O
1.82 1.83 1.84
OH O THPO OH 1. TsCl, pyridine, DMAP OH 2. TsOH, MeOH H Baker's yeast, OEt 1. DHP, PPTS, CH2Cl2, 100% H 67%, 98.4% ee 3. HClO4 aq, ether, 85% (1-3) 2. LiAlH4, Et2O, 98% H O O O O 4. t-BuOH, t-BuOK 78% O 1.85 1.86 1.81
Ketol 1.81 was converted to its fully protected silyl enol ether 1.87 by treatment with triisopropylsilyl triflate (TIPSOTf) and triethylamine (Scheme 1.27). Ozonolysis of the enol ether followed by Wittig olefination provided the acid 1.88 in good yield over two steps. In order to obtain the requisite trans-cyclopropyl aldehyde 1.91, the corresponding cis-cyclopropyl aldehyde was subjected to base catalyzed isomerization under a variety of conditions, all of which ultimately failed. In each case a complex mixture of products was obtained. Therefore, acid 1.90 was converted to its tert-butyl ester using tert-butyl trichloroacetimidate and then treated with t-BuOK to provide the desired trans-fused cyclopropyl ester 1.89 and its corresponding acid 1.90. The carboxylic acid 1.90 was converted to tert-butyl ester 1.89. Reduction of 1.89, followed by TPAP oxidation furnished key aldehyde intermediate 1.91.
28 Scheme 1.27
OH OTIPS H H H TIPSOTf, Et N 1. O3, CH2Cl2, then PPh3 3 OTIPS HO H CH2Cl2, 98% H 2. PPh3PMeBr, n-BuLi, H O OTIPS 71% (2 steps) O
1.81 1.87 1.88
1. CCl3C(=NH)Ot-Bu, BF3·OEt2 cyclohexane, 96% H 1. LiAlH4, THF, 65% H OTIPS OTIPS 2. t-BuOK, 18-Crown-6-ether RO 2. TPAP, NMO, CH2Cl2 92% H 49% 1.89 & 28% 1.90 H H O O
1.89 R=t-Bu CCl C(=NH)Ot-Bu, BF ·OEt 1.91 1.90 R=H 3 3 2 cyclohexane, 96%
Vinyl iodide 1.93 was prepared in a four step sequence from commercially available (R)-1-octyn-3-ol (1.92) the key step included Schwartz’s hydrozirconation- iodination protocol (Scheme 1.28).33 When aldehyde 1.91 and vinyl iodide 1.93 were
treated with 5 wt % of NiCl2 and CrCl2 in a mixture (1:1) of DMSO and DMF, allylic alcohols 1.94a and 1.94b were obtained as a mixture (2.5:1) separable by silica gel chromatography. The stereochemistry of the major product 1.94a was confirmed by modified Mosher’s method70 to be the desired (R)-isomer.
Scheme 1.28
H OTIPS 1. TBSCl, imidazole, 92% H H H 2. Cp ZrHCl then I 72% 2 2 O 1.91 AcO OTIPS AcO HO 3. TBAF, 83% CrCl , NiCl, (0.5 wt%) H I 2 RR' 4. Ac2O, Et3N, DMAP, 99% DMF-DMSO 1.94a=64%, 1.94b=26% 1.94a R=OH, R'=H 1.92 1.93 1.94b R=H, R'=OH
The allylic alcohol of 1.95a was protected as its acetate, and the cyclopropyl TIPS ether was removed using TBAF-HF (Scheme 1.29). The newly deprotected cyclopropyl alcohol was coupled with 5-hexenoic acid to give terminal diene 1.95. RCM reaction of 29 1.96 using Grubbs first generation olefination catalyst62-64 in the presence of a catalytic 46,47 amount of Ti(OiPr)4 as reported by Takemoto furnished the Z-olefin nine-membered lactone derivative in 93% yield. Methanolysis of the two allylic acetates afforded the target halicholactone (1.26) in 55% yield. This convergent total synthesis was completed in a total of 27 steps from commercially available furylacrylic acid 1.82 with a longest linear sequence of 23 steps. It borrowed chemistry heavily from previously published approaches, but did obtain its chiral centers from an interesting and particularly efficient asymmetric bakers yeast reduction of racemic β–ketoester 1.84.
Scheme 1.29
1. Ac O, Et N, DMAP 2 3 H H 2. TBAF-HF, 88% (2 steps) AcO OTIPS AcO O H 3. 5-Hexenoic acid, DCC, H O DMAP, 95% OH OAc 1.94a 1.95
1. (Cy3P)2RuCl2=CHPh, H Ti(Oi-Pr) , 93% 4 HO O
2. K2CO3, MeOH, 55% H O OH Halicholactone (1.26)
1.3.1.5 Mohapatra’s Partial Synthesis of Halicholactone: The Stereoselective Synthesis of the C(1)-C(13) Fragment (2004)
Mohapatra recognized that the stereoselective construction of the C(12) stereocenter, via a Nozaki-Kishi coupling of a vinyl iodide synthon to a cyclopropyl aldehyde was a problem in most previously published synthesis of the halicholactones. Hoping to circumvent this transformation, he completed a partial synthesis of the C(1)-
30 C(13) fragment 1.96 of halicholactone and neohalicholactone (1.26 and 1.27) (Scheme 1.30).71 It should be noted that intermediate 1.96 has never been used in a total synthesis,
therefore this is not a formal synthesis of halicholactone. The C(12) stereocenter was obtained from the chiral pool from commercially available (R)-2,3-O- isopropylideneglyceraldehyde (1.99).
Scheme 1.30
15 H 8 H 8 HO O O 12 12 H O O H O OH O
Halicholactone (1.26) 1.96 Neohalicholactone ∆17,18 (1.27)
H H H OH O O 12 12 12 O H O H O H O O O 1.97 1.98 1.99 (R)-2,3-O-Isopropylideneglyceraldehyde (1.99) was subjected to an E-selective Wittig olefination (Scheme 1.31). The resultant ester was reduced with DIBAL, and the alcohol was protected as the bulky TBDPS ether 1.100. Orthogonally protected triol 1.100 underwent a diastereoselective cyclopropanation using a literature procedure.72 The silyl ether was cleaved and the alcohol oxidized with 2-iodoxybenzoic acid (IBX)73 to give cyclopropyl aldehyde 1.98. The addition of allylmagnesium bromide to aldehyde 1.98 provided mixture (1:1) of diastereomers 1.97 and 1.101, which could be separated, with difficulty, by silica gel chromatography. To circumvent this tedious separation, the mixture was subjected to an IBX oxidation, and the resultant ketone was stereoselectively reduced with K-Selectride to provide the same mixture of alcohols, albeit, this time in a much improved ratio (9:1). 31 This high degree of selectivity is consistent with results Datta achieved on a very similar substrate (see Scheme 1.9) and can be explained using the same stereoelectronic arguments.35,39-45 The stereochemistry of the minor isomer was confirmed to be the incorrect stereoisomer 1.101 using the modified Mosher’s method.37,38 The undesired
minor diastereomer was easily converted to 1.97 in 71% yield over two steps using a standard Mitsunobu protocol.60
Scheme 1.31
OTBDPS O 1. Ph3P=CHCO2Et, C6H6, 90% 1. Et2Zn, CH2I2, CH2Cl2, 94% 12 O H 2. DIBAL, 82% 2. Bu4NF, THF, 83% O O 3. t-BuPh2SiCl, imidazole, CH2Cl2, 82% O 3. IBX, 97%.
1.99 1.100
H
H 1. H2C=CHCH2MgBr, Et2O, 8 O 87%, 1:1 dr H R2 R1 O H 12 2. IBX,90% O H O 3. K-selectride 91%, 9:1 dr O 1.98 1.97 R1=OH, R2=H 1. DEAD, PPh3, AcOH 2. K2CO3, MeOH, 1.101 R1=H, R2=OH 76% (2 Steps)
Having obtained the required homo-allylic alcohol as a single diastereomer, the next task was to construct the nine-membered lactone ring with the Z-double bond. To this end, alcohol 1.97 was treated with 5-hexanoic acid and 1-ethyl-3-(3’-
dimethylaminopropyl)carbodiimide (EDCI) to afford the corresponding ester in 92% yield (Scheme 1.32). The terminal diene was treated with Grubbs 2nd generation catalyst in the presence of titanium isopropoxide under highly dilute conditions to give the desired lactone 1.102 in 76% yield along with 11% of the corresponding dimer. Having completed the partial synthesis of halicholactone (1.26) and neohalicholactone (1.27), the
32 authors postulated that a total synthesis could be accomplished using a synthetic protocol published for the synthesis of the constanolactones.74
In summary, this partial synthesis was completed in 11 linear steps from commercially available material 1.99 and offers the possibility of an alternative approach to this class of compounds. The C(12) stereocenter was obtained from the chiral pool while the C(9) and C(11) cyclopropyl stereocenters were established in high selectivity using a published protocol. The problem with this synthesis is the lack of diastereoselectivity while establishing the C(8) stereocenter.
Scheme 1.32
H H OH 1. 5-Hexenoic acid, EDCI, 92% O O H O H O 2. RuCl2=CHPh(Cy3P)(IEMS), O O Ti(Oi-Pr)4, 76% 1.97 1.102
H HO O H O OH
Halicholactone (1.26) Neohalicholactone ∆17,18 (1.27)
1.4 CONSTANOLACTONES A-G In 1990, extracts of the temperate red alga Constantinea simplex, harvested off the coast of Oregon, revealed the existence of two new cyclopropane and lactone containing oxylipins, constanolactones A and constanolactone B (1.103 and 1.104).75 Continued
investigation of C. simplex extracts revealed the presence of several additional new constanolactones, C-G (1.105-1.109).76
33 Figure 1.4. Constanolactones A-G (1.103-1.109).
14 15 12 H 51 H 18 HO O O HO O O 17 7 9 H H OH OH Constanolactone A (1.103) Constanolactone B (1.104) Constanolactone C ∆ 17,18 (1.105) Constanolactone D ∆ 17,18 (1.106)
15 5 1 14 H H O O O O 7 11 HO H HO H 9 OH OH Constanolactone E (1.107) Constanolactone F (1.108) Constanolactone G ∆ 17,18 (1.109)
An initial detailed spectroscopic analysis of constanolactones A and B diacetates (1.110 and 1.111) afforded their planar structures and determined the relative stereochemistry of C(5)-C(9) to be 5R*, 6S*, 8S*, 9S* in 1.110 and 5R*, 6S*, 8S*, 9R* in 1.111 (Figure 1.5). The absolute stereochemistry of C(12) in both compounds was determined by forming semi-synthetic (-)-menthoxycarbony1 (MC) derivatives 1.112.
Comparison of the 1H NMR spectra of the two standard D- and L-dimethyl-MC-malates with that produced from constanolactone A and B (1.103 and 1.104) showed the latter to
be identical to the standards prepared from L-malate, thereby establishing the absolute
C(12) stereochemistry as 12S*. These results were confirmed by comparison of the GC retention times of constanolactone derived 1.112 and that obtained from the commercially derived D- and L-malates. The absolute stereochemistry at C(9) was determined by chiroptical measurement of various mono- and dibenzoate derivatives and by comparable rotations within the two series (A-D) and (E-G).
34 Figure 1.5. Absolute stereochemistry of constanolactone A and constanolactone B.
(R) (R) **H (S) H (S) AcO O O AcO O O (S) (R) (S) H (S) H OAc OAc Constanolactone A-diacetate: 1.110 Constanolactone B- diacetate: 1.111
OMe OMe
O O (S) OMe (S) OMe O O O O O O O O
1.112 1.112
By close examination of 1H and 13C NMR spectrums of constanolactone E (1.107) and constanolactone F (1.108), it was deduced that they shared the same relative stereochemical configuration from C(5)-C(8) with that of constanolactones A-D, (5R*,
6S*, 8S*). A relatively small J11-12 value (6.2 Hz) and a dissimilar magnetic
environment of the acetonide methyl groups (∆δ = 0.14 ppm) were indicative of an cis configuration in constanolactone E derivative 1.113. A relatively large J11-12 value (8.1
Hz) and a similar magnetic environment of the acetonide methyl groups (∆δ = 0.01 ppm) established the diol configuration in 1.114 as trans (Figure 1.6). The absolute stereochemistry at C(11) and C(12) of both natural products was determined by CD
analysis of the corresponding bis(p-bromobenzoate) derivatives to be 11R* and 12S* for constanolactone E (1.107) and 11S* and 12S* for constanolactone F (1.108). From the combined data, the absolute stereochemistry of constanolactone E (1.107) and constanolactone F (1.108) could be assigned as 5R*, 6S*, 8R*, 11R*, 12R*, and 5R*, 6S*, 8R*, 11S*, and 12R* respectively.
35 Figure 1.6. Absolute stereochemistry of constanolactones E and constanolactone F.
(R) (R) H (S) H (S) O O O O (S) (S) 11 11 (R) O (R) (R) H O (S) H O O 1.113 1.114
1.4.1 Synthesis of Constanolactone A and Constanolactone B
1.4.1.1 White’s Biomimetic Total Synthesis of Constanolactones A and B (1995)
White completed the first total synthesis of constanolactones A and B (1.103 and 1.104). As in his previously described total synthesis of eicosanoid 1.14 (see Section 1.2.1), the key reaction utilized in White’s biomimetic total synthesis was the pivotal unidirectional cyclization cascade (see Scheme 1.4).77 In contrast to eicosanoid 1.14, the constanolactones are known to be optically active. The relative stereochemistry of the cyclopropane in the constanolactones is identical to that found in eicosanoid 1.14, however, the absolute stereochemistry is opposite. Synthesis of the antipodal key epoxide intermediates 1.116a and 1.116b commenced in an identical fashion to that previously described with the exception that (R,R)-(+)-diisopropyl tartrate was used as the chiral adjuvant in the Sharpless asymmetric epoxidations (Scheme 1.33). These epoxides underwent cyclization and oxidation in an identical manner to that already described to provide antipodal cyclopropyl aldehyde 1.117.
36 Scheme 1.33
1. t-BuOOH, Ti(Oi-Pr)4 MeO O (+)-Diethyl Tartrate, 91% MeO O HO 2. LiOH, THF/H2O, 99% 1.15 1.18
H HO O O HO HO O H HO O H O O O 1.116a 1.116b 1.117
The left hand coupling partner was synthesized in 10 steps from D-arabinose by following a synthesis for a similar compound previously published.78-80 The initial 81 chemistry to arrive at aldehyde 1.121 was developed by Gray. D-Arabinose (1.118) was converted to its thioacetal then protected as its bis-acetonide 1.119 (Scheme 1.34). Base promoted elimination followed by hydroxyl directed hydride reduction furnished the deoxy sugar derivative 1.120.82 This deoxy sugar was protected as its TBDPS ether, and the thioacetal was removed with N-chlorosuccinimide and silver(I) nitrate83 to afford aldehyde 1.121. Z-selective Wittig olefination and acidic hydrolysis of the acetal provided diol 1.122. The latter was treated with lead tetraacetate resulting in the oxidative cleavage to the aldehyde. Takai11 olefination furnished the target left hand coupling partner 1.123.
37 Scheme 1.34
H SEt OH O O EtS 1. EtSH, HCl, 68% 1. t-BuOK, DMSO-THF, 64% HO OH O O 2. (CH3)2O, H2SO4, 92% 2. LiAlH4, 95% OH O
1.118 1.119
SEt H
EtS O 1. NaHMDS, TBDPSCl, 92% 1. Ph3PC6H13Br, NaHMDS, 80% HO O TBDPSO O 2. NCS, AgNO3, CH3CN/H2O 2. TFA, THF/H2O, 72% O -20 °C, 76% O 1.120 1.121
OH 1. Pb(OAc)4, Na2CO3, 89% TBDPSO TBDPSO 2. CHI , CrCl , 54% OH 3 2 I 1.122 1.123
The coupling of aldehyde 1.117 and 1.123 in the presence of chromium (II) chloride and catalytic nickel (II) chloride12 yielded a mixture (2:1) of alcohols 1.124a and
1.124b that could be separated using high-pressure liquid chromatography (HPLC) (Scheme 1.35). This ratio of products was consistent with the ratio Wills obtained in a similar reaction during his synthesis of halicholactone (1.26) and neohalicholactone (1.27) (see Scheme 1.13 and 1.15). All attempts to deprotect the silyl ether were unsuccessful with the use of conventional reagents and conditions resulted in decomposition of the starting material. To circumvent this problem, the silyl protecting group was cleaved from 1.123 with HF to provide allylic alcohol 1.125. This vinyl iodide was coupled with aldehyde 1.117 to provide a mixture (1.4:1) of constanolactone A (1.103) and constanolactone B (1.104). All spectral data were in agreement with those of the natural material, thereby confirming the assigned stereochemistry of these natural products.
38 Scheme 1.35
H H H O O HO O O O O TBDPSO H H H H O OH OH 1.117 1.124a Constanolactone A: 1.103 CrCl , NiCl (cat.) F- or H+ 2 X 70% (2:1)
H H O O HO O O TBDPSO TBDPSO H H I OH OH 1.123 1.124b Constanolactone B: 1.104
1.124, HF, CH3CN, 80%
H O O HO H CrCl , NiCl (cat.), 70%, (1.4:1) H 2 I O 1.125 1.117
In 1996, White attempted to extend his stannyl chloride mediated cascade cyclization to epoxide 1.128 in an attempt to complete the total synthesis of halicholactone and neohalicholactone (1.25 and 1.26). He was unsuccessful. In the event, exposure of epoxide 1.129 to stannic chloride in nitromethane afforded a single product whose spectral properties were consistent with skipped diene 1.130. A plausible mechanism for this anomalous transformation is depicted (Scheme 1.36). Epoxide 1.128 is opened, as expected, to give the cyclopropylcarbinyl cation 1.131. Instead of forming lactone 1.129, this species undergoes loss of a proton to give diene 1.132. Subsequent acid catalyzed lactonization and opening of the cyclopropane, not necessarily in that order, would lead to the formation of 1.130. It was concluded from these results that although epoxide 1.128 reacts initially with stannic chloride in a pathway similar to 1.19 and 1.118 (see Schemes 1.4 and 1.33), the subsequent elimination of a proton diverts the 39 pathway from the formation of the nine-membered lactone, making 1.128 an unsuitable intermediate in the biomimetic cyclization strategy of these compounds.
Scheme 1.36
CO2Me HO O OH OH O 1.126 1.127 1.128
O O
SnCl4, MeNO2 H instead: via: O 46% X HO H O HO OH OH 1.129 1.130
O H H O
H H H O H HO O H HO O H Sn O O H Cl H Cl Cl Sn O O Cl Sn O 1.131Cl 1.132 1.133 Cl
1.4.1.2 Mohapatra’s Partial Synthesis of the C(1)-C(10) Fragment of Constanolactone A and B (1998)
Mohapatra’s approach toward the right-hand fragment of the constanolactones84 is nearly identical to his partial synthesis of halicholactone and neohalicholactone71 previously described in section 1.3.1.5. At the time they published this work, intermediate 1.136 had not been used in any reported total synthesis. Since this report was published, however, Falck has used this intermediate in the total synthesis of both
40 constanolactones A and B (1.103 and 1.104).74 Therefore this work can now be
considered a formal synthesis of these natural products.
Scheme 1.37
H H H O O HO O O PMBO O Ph P H 9 H 3 OH RR1
Constanolactone A, R1=OH, R=H (1.103) 1.134 1.135 Constanolactone B, R1=H, R=OH (1.104)
H H H O O O O
O H O H O H O O O 1.136 1.137 1.138
Key cyclopropyl aldehyde 1.137 was synthesized in six steps from commercially available (S)-glyceraldehyde acetonide 1.138 (Scheme 1.38). Having synthesized the cyclopropyl core, the stereoselective formation of the 2-pyrone ring was all that remained. Reaction of the aldehyde with the Grignard reagent derived from 5- bromopentene afforded a mixture (7:3) of diastereomeric alcohols 1.139a and 1.139b that could be separated by silica gel chromatography. Better selectivity (6:1) could be
achieved if the mixture was first oxidized to the ketone and then stereoselectively reduced with K-Selectride. The absolute stereochemistry of the minor alcohol was determined by the modified Mosher’s method37,38 to be the incorrect stereoisomer. The stereoselectivity
can again be rationalized by conformational analysis. Both the S-(cis)-conformation A and S-(trans)-conformation B provide maximum conjugative interaction between the
cyclopropyl C-C bonds and the carbonyl π orbitals. Since computational studies indicate 41 that the S-(cis)-conformer A is preferred over the S-(trans)-conformation B, alcohol 1.139a is predicted to be the major diastereomer from hydride reduction of cyclopropyl ketone 1.140. Complete recovery of the material could be achieved using the standard Mitsunobu protocol.60 Dihydroxylation of the alkene and oxidative cleavage afforded the
δ-hydroxy aldehyde which, upon formation, spontaneously closed to the lactol. Pyridinium dichromate (PDC) oxidation furnished cyclopropyl lactone 1.136, thus completing the formal synthesis of constanolactones A and B in 12 steps from (S)- glyceraldehyde acetonide 1.138.
Scheme 1.38
H 8 O H R1 H CH CH(CH ) MgBr 6 Steps O 2 2 2 R2 IBX, 87% 9 O H O H O H 80%, 7:3 dr O O O
1.138 1.137 1.139a R1=OH, R2=H 1.139b R1=H, R2=OH
8 H 8 1. OsO , NMO O H R1 4 H K-selectride 2. NaIO4, 95% (2 steps) O O R2 O H 88%, 6:1 dr O H 3. PDC, 92% O H O O O
1.140 1.139a R1=OH, R2=H 1.136 1. DEAD, PPh3, AcOH 2. K2CO3, MeOH, 1.139b R1=H, R2=OH 80% (2 Steps)
O O O O H 8 H 8 OH H H OH
O H O O H O O - O H H- A B 1.139a 1.139b Major S-cis S-trans Minor Preferred Conformation Disfavored Conformation
42 1.4.1.3 Pale’s Total Synthesis of Constanolactones A and B (2000)
Pale completed the second total synthesis of constanolactones A and B (1.105 and 1.106) in 2000.85,86 He also used a Nozaki-Kishi coupling of a vinyl aldehyde species to a cyclopropyl aldehyde as his key step (Scheme 1.39). His convergent strategy toward the construction of the constanolactones required three fragments: (1) the known nucleophilic (E)-vinyl organometallic reagent bearing a hydroxyl group and a Z-double bond on an 11-carbon chain 1.120; (2) a central trans-1,2-diformyl cyclopropane synthon 1.141; and (3) a four carbon chain which is nucleophilic at the γ-position relative to a carbonyl functional group 1.142.
Scheme 1.39
H
12 5 H 12 H O HO O O TMSO HO H 9 H H I OEt RR1 O
Constanolactone A, R1=OH, R=H (1.103) 1.125 1.141 1.142 Constanolactone B, R1=H, R=OH (1.104)
The C(12) stereocenter contained in left-hand fragment 1.125 was purchased in the form of (S)-malic acid (1.33). A complete reduction of the acid moieties to the corresponding triol was accomplished by following Moriwake’s procedure21 followed by regioselective protection of the 1,2 diol as its acetal to give 1.143 (Scheme 1.40). The primary alcohol in 1.143 was oxidized to an aldehyde and subjected to a (Z)-selective Wittig reaction to furnish intermediate 1.144. Deprotection of the diol, followed by re- protection as its para-methoxybenzylidene acetal and regioselective reduction of the benzylidene acetal with DIBAL yielded 1.145. Swern oxidation of the primary alcohol furnished an aldehyde that was used as a crude mixture in a Takai olefination. Treatment
43 of the vinyl iodide intermediate with DDQ removed the PMB-ether giving the desired (Z)-iodoalkene 1.125.
Scheme 1.40
O HO 1. BH .SMe , B(OMe) HO 3 2 2 1. DMSO, (COCl)2, Et3N O O 12 OH HO 2. TsOH, acetone, O 2. Ph3P=C(CH2)4CH3 O 55% (2 Steps) O 86% (2 steps) 1.33 1.143 1.144
1. TsOH, MeOH 12 2. p-MeOPhCHO 1. DMSO, (COCl)2, Et3N PMBO HO 3. DIBAL OH 2. CHI , CrCl , 89% (2 Steps) 68% (2 Steps) 3 2 I 3. DDQ, H2O 1.145 1.125
The left-hand cyclopropane containing portion of the constanolactones was accessed in high enantiomeric purity from commercially available meso- cyclopropanedicarboxylic acid 1.146 (Scheme 1.41). Under carefully controlled conditions, the crude lipase extracted from pig pancreas (PPL), catalyzed the enantioselective hydrolysis of the cyclopropane containing meso propyl diester 1.147 to optically pure monoester 1.148 in near quantitative yield.87 In order to access the correct stereochemistry about the cyclopropane ring required for the synthesis of constanolactones A and B, an epimerization at C(6) was required. Silylation with chlorodimethylthexylsilane,88 hydrolysis of the remaining propyl ester, then Swern oxidation23 provided aldehyde 1.149. The authors did not comment on their choice of
such an unusual silyl protecting group. Isomerization at C(6) with sodium methoxide in refluxing methanol proceeded readily to provide the silyated trans-cyclopropane 1.150 in good yield, but the diastereomeric ratio was not disclosed.
44 The introduction of the right-hand chain was achieved by a Mukaiyama-type γ- addition of 1-silyloxy-1-ethoxy butadiene to the cyclopropyl aldehyde 1.150 to furnish δ- hydroxy α,β-unsaturated esters 1.51a and 1.51b with modest (3:1) diastereoselectivity. 89- 92 The major diastereomer 1.151a, which later proved to be the correct one, was reduced with magnesium powder in methanol93 to give an intermediate hydroxyester that
lactonized with a catalytic amount of TsOH in refluxing benzene. The resultant cyclopropyl lactone 1.152 was found to be unstable in the presence of TBAF, presumably due to TBAF’s high basicity, so desilylation was performed in the presence of a proton
source, NH4Cl, to avoid degradation. Finally, the newly unmasked hydroxy functionality was oxidized with the mild Dess-Martin periodane14 to furnish 1.117 in 12 steps from
commercially available cyclopropane 1.146.
Scheme 1.41
O 1. ClSiMe tHex, Et N, DMAP H H H 2 3 HO 1. LiAlH4 PrOCO Pig Pancreas Lipase (PPL) PrOCO 2. K2CO3, MeOH HO H 2. PrCOCl H DME/H2O, 99%, 99% ee H 3. (COCl)2, DMSO, Et3N 91% (3 Steps) O 93% (2 Steps) OCOPr OH 1.146 1.147 1.148 O
O H OEt SiMe H H 3 H R H O 6 NaOMe, MeOH, 82% 6 OEt R1 H H ZnCl2, 74% H 3:1 dr OSiMe2tHex OSiMe2tHex OSiMe2tHex 1.149 1.150 1.151a R1=OH, R2=H 1.151b R1=H, R2=OH O
OEt H H H OH 1. Mg, MeOH 87% O O 1. TBAF, NH4Cl, 81% O O H H 2. TsOH, PhH, 77% H 2. DMP, 82% H
OSiMe2tHex OSiMe2tHex O 1.151a 1.152 1.117 With both the left- and right-hand fragments complete, they were coupled using the well precedented Kishi-Nozaki procedure (Scheme 1.42).12,13 This is the same key
45 transformation that was reported by White during the course of his total synthesis of the constanolactones. This reaction proceeded to give the anticipated mixture (1.2:1) of constanolactones A and B (1.103 and 1.104) in modest yield. In summary, Pale completed the total synthesis of constanolactones A and B in 23 steps from commercially available materials. The key steps of this strategy included a unique and interesting enzymatic differentiation of a meso-cyclopropane intermediate and a moderately diastereoselective Mukaiyama addition of a silyl ketene acetal to a cyclopropyl aldehyde. Although this is one of the more interesting published approaches, it still suffers from the universal problem plaguing most published synthesis, that being the lack of stereo control while establishing the C(9) and C(5) stereocenters.
Scheme 1.42
H CrCl2, NiCl2, DMSO, H HO O O HO O O H 51% (2 Steps), 1.2:1 dr I H 9 H O RR1
1.125 1.117 Constanolactone A, R1=OH, R=H (1.103) Constanolactone B, R1=H, R=OH (1.104)
1.4.1.4 Falck’s Total Synthesis of Constanolactones A and B (2002)
In his total synthesis of constanolactones A and B (1.105 and 1.106), 74 Falk uses the cyclopropyl lactone fragment 1.135 (Scheme 1.43) previously reported by Mohapatra84 (see Section 1.4.1.2). To date, this is the first and only total synthesis of
these natural products using this fragment. The key transformation in this synthesis is a E-selective Wittig olefination between the β-oxido ylide 1.135 and the protected α- hydroxy aldehyde 1.134.
46 Scheme 1.43
H H H O O HO O O PMBO O Ph P H 9 H 3 OH RR1
Constanolactone A, R1=OH, R=H (1.103) 1.134 1.135 Constanolactone B, R1=H, R=OH (1.104)
H O O O CO2H SO2Ph O H O H O O O O SO2Ph 1.136 1.153 1.99
The synthesis of 1.134 was accomplished using a slightly modified procedure to the one developed by Solladie.94 γ-Chloro β-ketosulfoxide 1.155 was obtained in 82% yield from the reaction of methyl chloroacetate (1.154) and (+)(R) methyl p- tolylsulfoxide. A stereoselective reduction of the ketone with DIBAL gave the R,R diastereomer 1.156. By treating α-chloro alcohol 1.156 with potassium carbonate in an acetonitrile-water mixture the corresponding epoxide 1.157 was isolated. The epoxide moiety in 1.157 was opened with the shown (E) cyanocuprate95 to give the homoallylic
α-hydroxysulfoxide. After protecting the hydroxyl group as a PMB ether, the intermediate was submitted to a Pummerer rearrangement in acetic anhydride. The resultant acetate 1.158 was reductively cleaved with LiAlH4, and final PCC oxidation of
the primary alcohol gave the required homoallylic hydroxy aldehyde 1.134.
47 Scheme 1.44
Cl Cl Cl O O LDA DIBAL K2CO3, CH3CN/H2O, 86% S S O OMe O O : 95%, 95% de HO : Ph Ph Me S : 1.154 Ph 1.155 1.156
1. n-C5H11 CuLi O 1. LiAlH4, 94% O 2 S SPh H : 2. PMBCl, NaH PMBO 2. PCC, 84% PMBO Ph 3. Ac2O, AcONa OAc O 1.157 80% (3 Steps) 1.158 1.134
The synthesis of the right-hand cyclopropyl lactone portion of the constanolactones commenced with the addition of lithiated 6-(tert- butyldiphenylsilyloxy)hexyne96 to (R)-glyceraldehyde acetonide 1.99 to provide a
mixture (45:55), at C(8), of diastereomers 1.159a and 1.159b that were separable by silica gel chromatography (Scheme 1.45). The incorrect isomer 1.159b was converted to the correct diastereomer 1.159a by inversion of the aberrant stereocenter using the two- step Mitsunobu protocol.60 Dehydrative alkylation97 of 1.159a with bis(phenylsulphonyl)methane proceeded
under Mitsunobu conditions with inversion of stereochemistry, thereby diastereoselectively installing the carbon destined to be incorporated into the cyclopropane. Chromium (II) reduction of the acetylene98 provided the E-olefin found in bis-sulfonyl adduct 1.160. Fluoride mediated desilylation and PDC oxidation provided carboxylic acid 1.153. Exposure of the acid to NaH and iodide in refluxing THF generated trans cyclopropyl-γ-lactone 1.161 as the sole product.
48 Scheme 1.45
OTBDPS O
R2 1. (PhO S) CH , DEAD, PPh O H n-BuLi, OTBDPS O 2 2 2 3 R1 O O 84%, 45:55 dr 2. CrSO4, DMF/H2O
1.99 1.159a R1=OH, R2=H 1. DEAD, PPh3, PhCO2H 2. K2CO3, MeOH, 1.159b R1=H, R2=OH 81% (2 Steps)
O H O OTBDPS CO2H SO2Ph NaH, I2, 80% SO Ph 1. TBAF SO Ph SO Ph O 2 O 2 O H 2 2. PDC, DMF, O O SO2Ph 41% (4 steps) O SO2Ph 1.160 1.153 1.161
Following desulfonylation of 1.162 using magnesium97 in aqueous THF, the
derived seco-acid was re-lactonized with inversion of the C(5) stereocenter by an intra- molecular Mitsunobu reaction (Scheme 1.46). Acid catalyzed hydrolysis of the acetonide gave diol 1.163. Tosylation of the primary hydroxyl group and displacement of the leaving group with triphenylphosphine furnished the corresponding β-hydroxy phosphonium salt. The salt was treated with base at low temperature, and the resulting ylide was condensed with previously described aldehyde 1.134 to give 1.164. Mild cleavage of the PBM ether using Cr(II)/LiI99 furnished constanolactone B
1.104 in 24 steps from commercially available materials. Alternatively, inversion of C(9) and deprotection gave constanolactone A (1.103) in 26 steps. This is the only approach that allows for the stereoselective construction of the C(9) stereocenter. However, this synthesis suffers from the lack of diastereoselectivity while establishing the C(8) stereocenter during the addition of the lithiated 6-(tert-butyldiphenylsilyloxy)hexyne96 to
(R)-glyceraldehyde acetonide 1.99.
49 Scheme 1.46
O H H O 1. Mg, HgCl2, THF/H2O O O SO2Ph 2. PPh , DEAD O H SO2Ph 3 HO H 3. CF CO H, THF/H O 3 2 2 OH O 53% (3 Steps) 1.162 1.163
1. TsCl, pyridine 2. PPh3, CH3CN 3. sec-BuLi, then 1.134, 29% (3 Steps)
H CrCl /LiI H HO O O 2 O O PMBO H 85% H OH OH Constanolactone B (1.104) 1.164
1. p-(NO2)PhCO2H, PPh3, DEAD 2. NaOH, THF/H2O 3. CrCl2/LiI, 57% (3 Steps)
H HO O O
H OH Constanolactone A (1.103)
1.4.1.5 Pietruszka’s Total Synthesis of Constanolactones A and B (2003)
At just 17 steps, Pietruszka’s total synthesis of a mixture of constanolactone A and B (1.103 and 1.104) is the shortest to date.100 Like many of its predecessors, this
approach utilizes the proven, but non-diastereoselective, Kishi-Nozaki coupling of vinyl iodide 1.125 and cyclopropyl aldehyde 1.117 as the key step (Scheme 1.47). What makes this synthesis noteworthy is the expedient manner by which these key fragments are constructed. Although it is shorter, it is important to note that it is also one of the pricier syntheses due to the quantitative use of chiral adjuvants in two different chemical transformations early in the synthesis. 50 Scheme 1.47
12 5 H H 5 OH HO O O 12 H HO O O 9 H 9 Ph H H H RR1 I O Constanolactone A, R1=OH, R=H (1.103) 1.125 1.117 1.165 Constanolactone B, R1=H, R=OH (1.104)
Starting from cinnamyl alcohol (1.56), asymmetric cyclopropanation according to a Denmark procedure101 provided essentially enantiomerically pure cyclopropane 1.166
(Scheme 1.48). The ee of cyclopropane 1.166 was further enhanced by kinetic enzymatic resolution.102 TPAP oxidation32 of 1.66 to the aldehyde followed by the addition of an allyl group using the Roush reagent103 yielded allylic alcohols 1.168a and 1.168b as a
mixture (4:1). The minor diastereomer could be converted directly to the desired acrylic ester, but the yields were generally low, and a two-step procedure proved more efficient. Hence, oxidation with Dess-Martin periodinane14 followed by typical CBS-reduction in the presence of a catalytic amount of (S)-(-)-2-methyl-CBS-oxazaborolidine 1.167104 furnished the correct diastereomer 1.168a exclusively. Acylation of 1.68a using acryloyl chloride provided the terminal diene, which, in the presence of Grubbs first generation metathesis catalyst105 was easily cyclized to the unsaturated six-membered lactone.106 Hydrogenation of the lactone under standard
conditions at room temperature resulted in the reductive cleavage of the cyclopropane ring. At reduced temperatures, however, the olefin could be preferentially reduced, and the desired saturated lactone 1.169 could be consistently isolated in high yield. Ozonolysis of the phenyl group and reductive workup furnished the expected carboxylic acid. The acid was subsequently converted to its acid chloride in quantitative yield and subjected to a Rosenmund reduction107 to furnish key intermediate 1.117.
51 Scheme 1.48
H H R2 OH Et2Zn, CH2I2, 98%, 98% ee OH 1. TPAP, NMO, 90% R1 Me NOC CONMe Ph 2 2 Ph H 2. iPrO2C CO2iPr Ph H , 94%, 4:1 dr O O O O 1.56 B 1.166 B 1.168a R1=OH, R2=H Bu 1. DMP, 81% 2. CBS, cat. 1.167, 1.168b R1=H, R2=OH 100%
H 1. CH2=CHCOCl, DMAP, i-Pr2NEt -96% H 1. O3, Me2S 70% H OH O O O O 2. (PCy ) RuCl =CHPh, Ti(O-i-Pr) , 97% 2. SOCl H Ph H 3 2 2 4 Ph H 2 H 3. Pd/C, H2, 89% 3. Pd/BaSO4, H2, i-Pr2NEt 65% (2 Steps) O 1.168a 1.169 1.117
Vinyl iodide 1.125 contains only one stereogenic center at C(12). This chiral center was purchased from the costly ($20/g) (R)-glycidol 1.170 (Scheme 1.49). After protection of the primary alcohol as its TES ether, ring opening of the epoxide with 108 lithiated heptyne in the presence of BF3·OEt2 yielded secondary alcohol 1.171.
Protection of the newly formed alcohol and semi-hydrogenation of the alkynyl subunit with Lindlar catalyst provided Z-olefin 1.172. Under Swern conditions,23 the primary TES-ether was cleaved and the primary alcohol oxidized.109 A Takai-Utimoto reaction11 of the aldehyde provided vinyl iodide 1.173. Fluoride mediated deprotection of the remaining silyl protecting group furnished the second essential coupling partner 1.125. The final step in the synthesis of constanolactones A and B (1.103 and 1.104) was the well established CrCl2-mediated addition of 1.125 to cyclopropyl aldehyde 1.117.
This reaction proceeded in 74% yield to provide a mixture (2:1) of constanolactone A and constanolactone B which were separable by column chromatography. No comment is made to this effect in the paper, but it is of interest to note that this ratio is a slight improvement over that reported by Pale and White.77,85
52 Scheme 1.49
1. TESCl, imidazole, 94% 1. TBSCl, imidazole, 86% O 12 2. Lindlar's cat, H , 90% 2. 1-heptyne, n-BuLi, HO 2 TBSO . OH BF3 OEt, 91% OTES OTES 1.170 1.171 1.172
12 5 12 H 1. (COCl)2, DMSO, Et3N, 72% 1. TBAF, 88% HO O O TBSO 9 2. CrCl3, LiAlH4, CHI3, 77% 2. CrCl2, DMSO, then 1.117 H I 74%, 2:1 dr RR1 1.173 Constanolactone A, R1=OH, R=H (1.103) Constanolactone B, R1=H, R=OH (1.104)
1.4.1.6 Pivnitsky’s Formal Synthesis of (±) Constanolactones A and B (2003)
Pivnitsyky completed the synthesis of cyclopropyl alcohol 1.176 in four steps from commercially available methyl 5-hexynoate 1.15 via a biomimetic-like cyclization (Scheme 1.50).110 Conversion of this material to the racemic epoxide 1.174 proceeded
smoothly, albeit with low to moderate yields. The authors attributed the depressed yields of these transformations to the inherent volatility of the compounds being isolated.
Upon treatment with methanesulfonic acid in wet CH2Cl2, epoxide 1.174 underwent a cyclopropanation and lactonization to give cyclopropyl lactone 1.176 as a single diastereomer in 18% yield. Regioisomeric mesylates 1.175a and 1.175b comprised an additional 51% of the recovered material. Starting epoxide 1.174 could be recovered in quantitative yield by treating mesylates 1.175a and 1.175b with potassium carbonate in methanol. Pivnitsky did not comment on the fate of the remaining 31% of the material. This biomimetic-like cyclization is very similar to the one reported 10 years earlier by White9,77 on the 9-hydroxymethyl homolog of epoxide 1.174, described in section 1.2.1 and section 1.4.1.1.
53 Scheme 1.50
1. H C=CHCH I, CuI, K CO , NaI, 60% CO2Me 2 2 2 3 CO2Me 2. MCPBA, KHCO , 50% 3 O MsOH, CH2Cl2 (wet) 3. H , Lindlar's catalyst, quinoline, 38% 1.15 2 1.174 1.175 51%, 1.176 18%
H OMs O O O OMe RO CO2Me H H O OH OH OR1 OMs 1.175a R=Ms, R1=OH Rac- 1.176 1.177 1.175b R=OH, R1=Ms
K2CO3, MeOH, 100%
12 H 5 HO O O CO Me 2 9 O H RR1
1.174 Constanolactone A, R1=OH, R=H (1.103) Constanolactone B, R1=H, R=OH (1.104)
1.4.2 Synthesis of Constanolactone E
1.4.2.1 Yamada’s Total Synthesis of Constanolactone E (1996)
At the time of Yamada’s total synthesis,111,112 a new method for the asymmetric
construction of cyclopentane derivatives using the anion of a disulfone and a chiral diepoxide113 that culminated in the total synthesis of brefaldin A had been reported.114
Based on this precedent, Yamada sought to explore the potential use of this reaction for the synthesis of chiral cyclopropane derivatives. They chose constanolactone E (1.107) as their target. A Julia olefination at ∆9,10 would give fragments 1.178 and 1.179 as the two coupling partners. Aldehyde 1.178 could be constructed in a straightforward fashion
from acetonide protected 2-deoxy-D-ribose 1.180, while the cyclopropyl sulphone could be obtained using a novel rearrangement of a sulfone and chiral epoxide. 54 Scheme 1.51
20
15 OTBS 5 1 14 H O O O H 7 OTBDPS 11 HO H O H 9 H OH O SO2PH Constanolactone E: 1.107 1.178 1.179
OH OTBS H O OH OH
O PhO2S O 1.180 1.181 1.182
The left-hand side chain of constanolactone E (1.107) was constructed in a two- 115 steps from 2-deoxy-D-ribose-3,4-acetonide 1.180. A Z-selective Wittig reaction on the
open form of the sugar 1.180 gave 1.183 in excellent yield (Scheme 1.52). A subsequent Swern oxidation23 of the primary alcohol proceeded in quantitative yield to furnish the
requisite aldehyde 1.178.
Scheme 1.52
OH
O OH O Ph P=CH(CH ) CH , HMPA, 90% DMSO, (COCl) , Et N, 100% O 3 2 4 3 O 2 3 O H O O O 1.180 1.183 1.178
The acetylenic hydroxy compound 1.184 was prepared from 5-hexyn-1-ol (1.182) by silylation and subsequent hydroxymethylation (Scheme 1.53). Cis-Substituted epoxide 1.185 was generated from 1.184 by Lindlar hydrogenation of the acetylenic 55 subunit followed by Sharpless asymmetric epoxidation.116 Reaction of lithiated allyl phenylsulphone with the chiral epoxy mesylate derived from 1.185 gave cyclopropane 1.181 in 83% yield as a mixture (8:1) of diastereomers at C(8). The formation of the cyclopropane is believed to take place by displacement of the mesylate with the anion of allyl phenyl sulphone to give epoxysulphone 1.186. Deprotonation of 1.186 in situ generates epoxysulphone anion 1.187 which is proposed to undergo intramolecular cyclization to cyclopropane 1.181.
Scheme 1.53
OTBS 1. Pd/CaCO3, quinoline, 1. TBSCl, imidazole, 95% H2, 98% OH i 2. n-BuLi, (CH2O)n, 75% 2. Ti(O Pr)4, L-(+)-DET, OH TBHP, 85%, 97% ee
1.182 1.184
OTBS OTBS H H H 1. MsCl, DMAP, 97% OH O via: 2. allyl phenyl sulfone OH PhO S 8 nBuLi, 83%, 8:1 dr 2
1.185 1.181
OTBS OTBS OTBS H H H H n-BuLi H OH O O
PhO2S
SO2Ph SO2Ph 1.186 1.187 1.181
Without separating the C(8) diastereomers of 1.181, the hydroxyl group was protected as its TBDPS ether, and the phenyl sulfonyl group was removed by treatment with SmI2 in the presence of HMPA. The terminal olefin was ozonolyzed to give the cis- substituted cyclopropyl aldehyde 1.188 (Scheme 1.54). Epimerization at C(8) was effected with K2CO3 in methanol to afford trans-substituted cyclopropane 1.189 as the 56 predominant diastereomer (15:1). Reduction of the aldehyde to the alcohol, thioetherification, and mCPBA oxidation provided sulfone 1.179 in nearly quantitative yield over the three steps. The sulfone was coupled with aldehyde 1.178 by means of a Julia olefination to furnish cyclopropane containing diene 1.190.117
Scheme 1.54
OTBS OTBS H 1. TBSCl, imidazole, 81% H OH OTBDPS 2. SmI2, HMPA, THF, 92% 8 H PhO2S H 3. O3, Me2S, 80% O 1.181 1.188 OTBS H OTBDPS K CO , MeOH, 1. NaBH , 98% 2 3 H 8 4 H 2. PhSSPh, Bu P, pyridine, 98% 99%, 15:1 dr O 3 3. mCPBA, Na2HPO4, 99% 1.189
OTBS 1. nBuLi, then 1.178, 83% OTBS H 2. Ac O, DMAP, pyridine, 70% H OTBDPS 2 OTBDPS 3. Na-Hg, 56% H O H
SO2Ph O 1.179 1.190
With all the carbons and stereocenters in place, a stepwise deprotection and construction of the lactone was all that remained. The primary TBS-ether was selectively
cleaved in the presence of the acetonide under mildly acidic conditions (Scheme 1.55). A two-step oxidation yielded a carboxylic acid that was converted to methyl ester 1.191 using standard reagents and conditions. The diol was unmasked under acidic conditions to provide 1.192. Fluoride mediated cleavage of the cyclopropyl alcohol followed by acid catalyzed lactonization completed the total synthesis of constanolactone E (1.107) in a total of 25 steps from commercially available starting materials. The spectral data and optical rotation were consistent with the reported data of natural constanolactone E. This 57 synthesis confirmed the absolute configuration of constanolactone E to be 5R*, 6S*, 8R, 11R*, and 12S*.
Scheme 1.55
O
OTBS OMe H 1. AcOH-H O, THF, 85% H OTBDPS 2 OTBDPS 2. PDC O H O H 3. NaClO O 2 O 4. CH2N2, 85% (3 steps) 1.190 1.191
O
OMe H H OTBDPS O O AcOH-H2O, TBAF then
77% HO H 1N HCl, 60% HO H OH OH 1.192 Constanolactone E: 1.107
1.5 SOLANDELACTONES A-I Structurally related to the halicholactones and constanolactones, the solandelactones A-I (1.195-1.201) were isolated as oils from the hydroid Solanderia secunda off the Korean coast in 1996 (Figure 1.7).118 They differ by their configuration
at C(11) as well as by the degree of saturation found in the lactone and the fatty acid side chains. Solandelactones C, D, and G show biological activity as inhibitors of farnesyl transferase, an enzyme responsible for the proper expression of ras proteins. Ras
proteins play an important role in intracellular transduction pathways. Mutated ras are found in many types of cancer cells including pancreatic and colorectal cancer.119
58 Figure 1.7. Solandelactones A-I (1.195-1.201).
5 4 5 4
22 14 7 20 H 1 20 H 19 HO O 19 HO O 5 4 11 O O H H 17 OH OH H O Solandelactone A (1.195) Solandelactone B (1.196) 14 O 19, 20 19, 20 HO H Solandelactone C U (1.197) Solandelactone D U (1.198) 11 Solandelactone E U 4, 5 (1.199) Solandelactone F U 4, 5 (1.200) OH 19, 20 4,5 19, 20 4,5 Solandelactone G U , U (1.201) Solandelactone H U , U (1.202) Solandelactone I (1.201 ) The gross structure of the solandelactones was determined by a combination of HMQC and 1H COSY experiments that defined the spin system throughout the entire molecule. Considering the additional rigidity of the lactone, due to the presence of the additional double bond between C(4)-C(5), as well as the high yields of isolation, Solandelactones E and F were selected for further stereochemical studies. By following the methods developed by Nagle and Gerwick for the structural determination of constanolactones A (1.103) and B (1.104),75,76 the relative and absolute configuration of
the stereogenic centers found in solandelactones E and F diacetates 1.202 and 1.203 were assigned as 7R*, 8R*, 10R*, 11S*, 14S* and 7R*, 8R*, 10R*, 11R*, 14S* respectively.
Figure 1.8. Absolute stereochemistry of solandelactone E and F.
(R) (R) * H (R) * H (R) AcO O AcO O (S) (R) (R) H O (R) H O OAc OAc Solandelactone E-diacetate (1.202) Solandelactone F-diacetate (1.203)
OMe OMe
O O (S) OMe (S) OMe O O O O O O O O
1.112 1.112 59
Solandelactone I (1.201) was also isolated as an oil. NMR data showed that solandelactone I possessed the same eight-membered lactone and cyclopropyl ring as the other solandelactones, but the COSY data showed that the C(10) proton was directly coupled to an olefinic proton at C(8) instead of a hydroxyl-bearing methine proton as observed in solandelactones A-H. A combination of 1H COSY and HMQC experiments led to the assignment of the structure of solandelactone I (1.201) as a cyclopropane containing 22-carbon fatty acid lactone possessing double bonds at C-11 and C-16 and with hydroxyl groups at C-13 and C-14, respectively. Comparison of the spectral data with those obtained from the other solandelactones suggests that that the relative configurations of C(7)-C(10) should be 7R*, 8R*, 10S*. Similar comparison of the NMR data with analogous constanolactones E and F (1.107 and 1.108) oxylipins revealed that chemical shifts of the protons and carbons at C(13) and C(14) were almost identical to those of the trans-diol and, therefore, can be tentatively assigned as 11S* and 12S*. Since the epimeric cis-diol was not isolated from this work, the configuration of these asymmetric centers still remain tentative.
Figure 1.9. Tentative stereochemical assignment of solandelactone I.
(R) H (R) O Tentative Stereochemical Assignments (S) (S) O HO (S) H OH 1.201 Solandelactone I
60 1.5.1 Partial Synthesis of Solandelactones A-H
1.5.1.1 Mohapatra’s 1st Generation Partial Synthesis of the Cyclopropyl-Lactone Segment of the Solandelactones (1998)
To date, there is no reported total synthesis of any of the solandelactone oxylipins. Mohapatra, however, has twice prepared cyclopropyl-lactone fragment 1.204 possessing the appropriate stereocenters and saturation to access solandelactones F (1.199).120,121
His synthetic approach to these compounds is nearly identical to his partial synthesis of halicholactone, neohalicholactone, and constanolactones A and B as discussed in sections 1.3.1.5 and 1.4.1.2 respectively.71,84 Since intermediate 1.204 has never been used in a
total synthesis of any solandelactone, these syntheses do not constitute a formal synthesis; however, one can envision the completion of a total synthesis of solandelactone F (1.198) in 12 additional steps using the route developed by Falck74 on a similar intermediate towards the synthesis of constanolactone B (see Section 1.4.1.4).
Scheme 1.56
H H H HO O PMBO O 11 H O O O Ph3P H OH OH Solandelactone F (1.198) 1.134 1.135
H O O 11 O 11 O H O H O O 1.204 1.99
The synthesis began from (R)-2,3-O-isopropylidene glyceraldehyde (1.99) which was converted in six steps to cyclopropyl aldehyde 1.98 Reaction of the aldehyde with
61 allylmagnesium bromide afforded alcohols 1.97 and 1.101 as a mixture of diastereomers (1:1). The mixture was subjected to a Candida cylinracea lipase (CCL) catalyzed enzymatic resolution122 to yield the corresponding acetate 1.205 (45%) and alcohol 1.97
(55%) in high optical purity (> 95%). The undesired isomer 1.97 was recycled to the required acetate 1.205 via a standard Mitsunobu reaction.60,123
Scheme 1.57
H O H H 6 Steps O H2CH=CHCH2MgBr, OH 9 O H 89%, 1:1 dr O O H O H O O
1.99 1.98 1.97 and 1.101
H H Candida cylinracea lipase (CCL) OH OAc + H2C=C(CH3)OAc, 90% 1:1 O H O H O O
1.97 1.205
PPh3, DEAD, AcOH, 85%
Degradative oxidation of the olefin in 1.205 to aldehyde 1.206 was accomplished following the standard two step protocol. A cis-selective Wittig reaction with the reagent derived from 4-carboethoxybutyl triphenylphosphonium bromide yielded ester 1.207 in good yield as a single olefin isomer. Simultaneous hydrolysis of both ester functionalities furnished hydroxy-acid lactone precursor 1.208 in excellent yield. Finally, lactonization under the conditions developed by Yamaguchi30 cleanly afforded the 8-
membered lactone, thereby completing the synthesis of the target cyclopropyl lactone 1.204 in 13 steps from (R)-2,3-O-isopropylidene glyceraldehyde (1.99).
62 Scheme 1.58
H
O O
H 1. OsO (cat), NMO H Ph3P=CHCH2CH2CH2CO2Et H OAc 4 OAc OAc OEt 2. NaIO , 82% (2 Steps) 77% O H 4 O H O H O O O
1.205 1.206 1.207
O H LiOH, THF, 2,3,6-Cl3C6H2COCl H OH OH O MeOH, H O, 94% Et N, DMAP, 63% O 2 O H 3 O H O O 1.208 1.204
1.5.1.2 Mohapatra’s 2nd generation Partial Synthesis of the Cyclopropyl-Lactone Segment of the Solandelactones (2003)
In a second generation, ring-closing metathesis approach to the same intermediate, the acetate of 1.205 was hydrolyzed to give cyclopropyl alcohol 1.101. The alcohol was esterified by treatment with 4-pentenoyl chloride to afford diene 1.209. RCM in the presence of Grubbs’ first generation catalyst afforded only the recovery of starting material. Repeating the reaction in the presence of Grubbs’ second generation catalyst and a catalytic amount of Ti(Oi-Pr)4 under dilute conditions furnished the desired
Z-isomer in 71% yield along with 10% of the corresponding dimer.
In summary, in this second generation approach Mohapatra completed the synthesis of the cyclopropane and lactone containing component of the solandelactone F in 12 steps from commercially available glyceraldehyde 1.99. This synthesis is two steps shorter than his previous attempt. If he had completed his total synthesis using Falck’s route he would have completed the total synthesis of solandelactone F in 24 steps.
63 Scheme 1.59
H H H OAc OH O K2CO3, MeOH, 4-pentenoyl chloride, O H O H O H O O O Et3N, 92% O
1.205 1.101 1.209
H H RuCl2(=CHPh)(PCy3)(IEMS) O HO O O O H 11 H O Ti(Oi-Pr)4, 71% O OH 1.204 Solandelactone F (1.198)
1.6 MISCELLANEOUS CYCLOPROPANE AND LACTONE CONTAINING OXYLIPINS
1.6.1 Hybridalactone
In 1981 the first cyclopropyl and lactone containing oxylipin, hybridalactone (1.210) was isolated from the from the red algae Laurencia hybrida.124 Its gross
structure was determined by 1H NMR and mass spectroscopy. Although a partial assignment of stereochemistry was made, neither the absolute configuration, nor the relative configurations at C(14)-C(16) were ascertained. The absolute and relative stereochemistry were determined three years later by total synthesis125 and independently by X-ray crystallography126 to be as depicted (Figure 1.10). No biological activity is
reported for hybridolactone (1.210), but extracts of this red alga are reported to possess antimicrobial properties.127
64 Figure 1.10. Hybridolactone (1.210)
H H 9 5 O O 11 7
H 12 15 O 14 O 1 H O 16 O H 20 H 17 Hybridalactone 1.210
1.6.1.1 Corey’s Total Synthesis and Structural Assignment of Hybridolactone (1984)
The total synthesis of hybridolactone (1.210) was embarked upon before the absolute and relative configurations at C(14)-C(16) were known. Corey claimed that the relative and absolute configurations were correctly predicted by conformational calculation and biosynthesis and then subsequently confirmed by X-ray crystallography.125 The starting point for the synthesis was the commercially available bicycloheptenone 1.211128 having the absolute configuration as shown (Scheme 1.60).
Slow addition of 1.211 into a solution of NaH and tert-butyl formate in DME followed by
the addition of p-toluenesulfonyl chloride afforded the desired (Z) β-tosyloxy enone 1.212 as the major product. Transmetalation of 1(R)-(tributylstannyl)-2(S)- ethylcyclopropane provided the lithated derivative that was then added to enone 1.212 to give cyclopropylcarbinol 1.213 in 76% yield as a single diastereomer. TBAF mediated fragmentation of 1.213 resulted in an initial conversion to the cis ethynol ketone, which was equilibrated to a separable trans-cis mixture (9:1). 1,2- Reduction of the trans-ketone 1.214 with L-Selectride provided the desired alcohol as a inseparable C(15) mixture (6:1). Selective α-face epoxidation129 was accomplished with tert-butyl hydroperoxide (TBHP) and catalytic vanadyl acetylacetonate (VO(acac)2) to give cyclopropyl alcohol 1.215 in excellent yield.
65 Scheme 1.60
H H OTs Bu Sn , n-BuLi, 76% i. tert-Butyl formate, NaH, DME 3 H H O ii. TsCl, 52%, 16:1 Z/E H H O 1.211 1.212
H H H H OTs O 1. L-Selectride, THF, H TBAF, THF/H O, rt, 10h H 2 O -78 °C, 92%, 6:1 OH H H OH 86%, 9:1 trans-cis H H 2. TBHP, VO(acac)2 (cat) H H CH2Cl2, 87% H H 1.213 1.214 1.215
Treatment of alcohol 1.215 with tert-butyldimethylsilyl triflate in the presence of 2,6-lutidine provided the corresponding silyl ether acetylene. The terminal acetylene was lithiated, converted to the Gilman reagent, then coupled with iodo allene bicyclo[2.2.2]octyl (OBO) ortho ester 1.216130,131 to furnish diyne 1.217 (Scheme 1.61).
Partial hydrogenation and fluoride mediated desilylation produced diene alcohol 1.218. Inversion of the C(15) stereo center to give 15S* carbinol 1.219 was accomplished using a two-step protocol involving oxidation with pyridinium dichromate (PDC) followed by another diastereoselective reduction with L-Selectride to give the desired 15(S)-carbinol 1.219 and the 15R* diastereomer 1.218 as a mixture (5:1). The OBO ortho ester functionality in 1.219 was converted to the desired hydroxy acid. Macrolactonization, accomplished by treatment with bis(4-tert-butyl-N- 132,133 isopropylimidazol-2-yl) disulfide and Ph3P, gave hybridalactone 1.210. The product was spectroscopically indistinguishable from a sample of native hybridalactone obtained by extraction of Laurencia hybrida. This concise and convergent synthesis was the first total synthesis of a cyclopropane and lactone containing oxylipin and the only total synthesis of hybridalactone (1.210). All of the stereocenters with the exception of C(11), C(12) and C(15) were purchased; C(11) and C(12) were set via a
66 diastereoselective epoxidation while the stereochemistry of the alcohol at C(15) was
established by a diastereoselective hydride reduction of the corresponding α-cyclopropyl ketone.
Scheme 1.61
H H H H O O 1. TBSOTf, 2,6-lutidine, 97% H H OH OTBS R' 2. n-BuLi, CuCN, THF/HMPA H I H H then: • , 86% (CH2)3 H H O H O (CH2)3 OO 1.215 O O 1.217 1.216
H H O H (R) OH 1. H2, Lindlar's cat. (CH2)3 1. PDC, 5Å mol seives, MgSO4 H 15 2. TBAF, 92%, 2 Steps OO H O 2. L-Selectride, THF, 75%, H 1.218 H H H H O O H + H (S) 1. H3O , then LiOH OH (CH2)3 O H 15 H OO 2. Lactonization, 83% 2 steps O H O H H H 1.219 Hybridalactone 1.210
1.6.2 Aplydilactone
Aplydilactone (1.220), a novel dimeric fatty acid metabolite, was isolated in 1990 from the marine mollusk Aplysia kurodai in Japan (Figure 1.11).134 It has demonstrated biological activity as an in vitro activator of phospholipase A2, an important enzyme in
prostaglandin biosynthesis as well as other important biological processes. Aplydilactone’s planar structure, as drawn, was elucidated based on both spectral and chemical means. It was hypothesized that it is biosynthesized from two eicosapentaenoic acids via an unsymmetrical dimerization and a subsequent oxidative cyclization to form the two lactones and cyclopropanes. To date, there are no reported 67 syntheses of this compound, nor is there any further information regarding the absolute or relative stereochemistry of its stereogenic centers.
Figure 1.11. Aplydilactone (1.220).
O O
O O O
OH OH
Aplydilactone 1.220
1.7 CONCLUSION Marine organisms produce a fascinating range of secondary metabolites which many times are endowed with unusual and unexpected biological profiles. Cyclopropane containing compounds are rare amongst the isolated metabolites. The first cyclopropane containing oxylipin, hybridolactone (1.210) was isolated in 1981 and since that time, an additional 19 structurally related oxylipins have been characterized. Natural products such as halicholactone (1.26), neohalicholactone (1.27), constanolactones A-D (1.103-1.109), and the most recently isolated solandelactones A-H (1.193-1.200) have unique and complex structures which make them attractive synthetic
targets. The halicholactones and constanolactones, in particular, have drawn considerable interest from the synthetic community culminating in the publication of multiple unique and interesting syntheses. Though similar, notable differences between these oxylipins include size and saturation of the lactone as well as the relative stereochemistry of the cyclopropane ring. The greatest challenge hindering the elegant total synthesis of these compounds is the lack of selectivity while establishing one or more of the stereocenters. In fact, no 68 published total synthesis has been able to conquer the universal difficulty of stereoselectively establishing all five stereogenic centers. This is shortcoming arises primarily because the most common construct usually involves the nucleophilic addition of an organometallic reagent into an aldehyde adjacent to a cyclopropane. The trans- substituted cyclopropane, invariably provides little to no stereocontrol with mixtures varying from 1:1 to 2:1 at the newly formed center.
1.8 PRIOR ART IN THE MARTIN GROUP
1.8.1 First Generation Approach Towards the Total Synthesis of the Solandelactone Oxylipins
The structures of the solandelactone oxylipins A-H (1.195-1.202) vary in their configuration at C(11) and the degree of saturation in the side chain and lactone subunits.118 No total syntheses of the solandelactones have been reported, but other marine derived oxylipins having similar structures such as halicholactone (1.26), neohalicholactone (1.27), and constanolactones A and B (1.103 and 1.104) have been prepared (Figure 1.12).18,20,46,65,77,85,100 The notable differences between the
solandelactones and other oxylipins include the size and saturation of the lactone and relative stereochemistry of the cyclopropane.
69 Figure 1.12. The solandelactones, halicholactones, and constanolactones.
5 4 5 4
14 7 20 H 1 20 H 19 HO O 19 HO O 11 O O H H OH OH Solandelactone A (1.193) Solandelactone B (1.194) Solandelactone C U19, 20 (1.195) Solandelactone D U19, 20 (1.196) Solandelactone E U 4, 5 (1.197) Solandelactone F U 4, 5 (1.198) Solandelactone G U19, 20, U4,5 (1.199) Solandelactone H U19, 20, U4,5 (1.200)
17 18 15 H 8 12 H 5 HO O O HO O 12 9 H O H OH RR1
Halicholactone (1.26) Constanolactone A, R1=OH, R=H (1.103) 17,18 Neohalicholactone ∆ (1.27) Constanolactone B, R1=H, R=OH (1.104)
The oxylipin natural products exhibit a high degree of structural similarity. On closer examination of their structures, one observes that their skeletons embody a prochiral core 1.221 (Scheme 1.62). No total synthesis of these cyclopropane-containing oxylipins exploits this latent symmetry to advantage. It was thus our objective to develop an approach towards the total synthesis of the solandelactone oxylipins that would feature the diastereoselective installation of all the chiral centers and would be sufficiently flexible to be adapted to the congeneric oxylipins. It was envisioned that the 1,4,7-allylic triol core 1.221 could be synthesized via 1,3-chirality transfer of each of the peripheral hydroxyl groups in a prochiral 1,2,3-allylic triol such as 1.222.
70 Scheme 1.62
H H H HO O O HO O HO O O H H H O OH OH OH Solandelactone E (1.197) Constanolactone A (1.103) Neohalicholactone (1.27)
** HO OH 1, 3 Chirality Transfer ** HO OH OH OH 1.221 1.222
Toward this end, Dr. Christian Harcken, a former postdoc in the Martin group, envisioned that solandelactones A, C, E, and G could be synthesized from the 1,2,3-triol diester 1.223, the chiral centers of which could be conveniently obtained in several steps via two stereoselective Wittig reactions from commercially available L-arabinose (1.225) (Scheme 1.63). An acid catalyzed transketalization of 1.223 was expected to provide the diastereomeric diester 1.224. This transformation represents a formal epimerization at C(11) and would thereby allow its use in the total synthesis of solandelactones B, D, F, and H.
71 Scheme 1.63
MeO O O OMe
H O OH HO O 11 O 11 11 OH H O OH HO OH O OH Solandelactone A (1.195) 1.223 L-Arabinose (1.225) Solandelactone C U19, 20 (1.197) 4, 5 Solandelactone E U (1.199) H+ Solandelactone G U19, 20, U4,5 (1.201)
MeO O O OMe MeO O O OMe H HO O 11 = H O 11 11 O OH HO O OH O O Solandelactone B (1.196) 1.224 1.224 Solandelactone D U19, 20 (1.198) Solandelactone F U 4, 5 (1.200) Solandelactone H U19, 20, U4,5 (1.202)
L-Arabinose (1.225) is a commercially available sugar that can easily be converted to the known acetonide 1.226 as a mixture (4β:1α) of anomers (Scheme 1.64).135 The first hurdle to overcome in the synthesis was the installation of the E α,β- unsaturated ester moiety found in the diol 1.227. This may seem a trivial operation since it is well known that reactions of stabilized ylides with aldehydes generally give the α,β- unsaturated esters with very good levels of E-selectivity.136 However, Wittig reactions of stabilized ylides, such as (alkoxycarbonylmethylene) triphenylphosphoranes with sugar lactols typically proceed with low E-selectivity.136-139 It was thus not surprising that the reaction of 1.226 with methyl (triphenylphosphoranylide)acetate under standard Wittig conditions gave α,β-unsaturated ester 1.227 in only moderate yield and with no E/Z selectivity (Table 1.1, Entry 1). The reaction was repeated in various solvents with no significant improvements in yield and/or selectivity. It is known that the E-selective Knoevenagel condensation and Horner-Wadsworth-Emmons reactions cannot be applied
72 to sugar lactols because their basic conditions can lead to racemization of the α-hydroxy aldehyde or cyclization of the initially formed hydroxy enoates.140
No general solution to the problem of effecting a trans-selective Wittig reaction on protected or free polyoxygenated aldehydes or lactols had been developed prior to our work in this area, although the addition of catalytic amounts of benzoic acid was known to enhance trans-selectivity.141-145 The reaction was repeated in the presence of 20 mol
% of benzoic acid (Entry 2) to provide a 68% yield of a trans/cis mixture (80:20) of 1.227 and 1.228, which were inseparable by flash chromatography. Variation of the temperature and amount of acid did not improve the yield or ratio. It was eventually found that using methyl (tributylphosphoranylidene) acetate146- 150 that had been freshly prepared prior to each use from the corresponding phosphonium bromide151 gave markedly improved results. The yield was improved to 78%, and E/Z selectivity to 9:1 (Entry 3). The tributylphosphine oxide was easily separated by flash chromatography, and recrystallization of the mixture gave trans-1.227 as a single olefin isomer in 60% yield from acetonide 1.226. This method for effecting trans-selective olefination of 1.226 was later expanded by Dr. Harken to include a variety of other α- alkoxy aldehydes and sugar lactols.140
73 Scheme 1.64
O OH O OH DMP, TsOH, DMF, rt. 91% Conditions* HO OH O OH OH O
L-Arabinose (1.225) 1.226
O OMe
HO HO OMe
O O OH O OH O O
1.227 1.228
Table 1.1. Reaction conditions for Wittig olefination of sugar lactol 1.226.
Entry Reagent Benzoic Acid Solvent Temp (°C) Yield E/Z
1 Ph3PCHCO2Me - toluene 90 °C 55% 50:50
2 Ph3PCHCO2Me 20% toluene 90 °C 68% 80:20
3 Bu3PCHCO2Me 20% toluene 90 °C 78% 90:10
The regioselective oxidation of diol 1.227 at the primary hydroxy group was now required (Scheme 1.65). Swern oxidation of 1.227 provided a mixture (3:1) of desired lactol 1.229 and the isomeric lactol 1.230, which resulted from oxidation at the allylic position (Table 1.2, Entry 1).23,152 NaOCl in the presence of a catalytic amount of
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) is known to selectively oxidize primary alcohols in the presence of a secondary one.153 Subjection of 1.227 to these conditions,
however, gave 1.229 in low yield while returning significant amounts of starting material and lactone 1.231 that resulted from over oxidation of lactol 1.229 (Entry 2). Corey recently found that the primary alcohol of 1,4-diols could be selectively oxidized using iodoxybenzoic acid (IBX) to provide lactols.154 Unfortunately, under these conditions, 74 the reaction of 1.227 returned the undesired regioisomeric oxidation product 1.230 as the major product (Entry 3).
Scheme 1.65
O OMe
HO HO O O O O Conditions* O O O O O OH O H OH O H O O OMe O OMe O OMe 1.227 1.229 1.230 1.231
Table 1.2. Reaction conditions for the oxidation of the primary alcohol in diol 1.227.
Entry Conditions 1.227 1.229 1.230 1.231
1 Swern 0% 38% 13% 10% 2 1 eq. NaOCl/cat. TEMPO 40% 21% 0% 21% 3 IBX trace 7% 63% 0%
In view of the difficulties, 1.227 was protected as its bis-TMS ether 1.232 by treatment with TMSCl and HMDS (Scheme 1.66), as it is known that primary TMS- ethers can be cleaved and oxidized under Swern oxidation conditions.155,156 Treatment
of 1.232 with the Swern reagent (-40 °C, 3 h) yielded aldehyde 1.233, which was subjected to a Wittig reaction under standard conditions to afford intermediate 1.234. Treatment of diester 1.234 with aqueous HCl cleaved the remaining trimethyl silyl ether and afforded the desired key diester 1.223 in 30-40% yield over the four steps from diol 1.227.
75 Scheme 1.66
O OMe O OMe O OMe
HO TMSO O H TMSCl, HMDS DMSO, ClCOCOCl
O OH THF O OTMS Et3N, CH2Cl2 O OTMS O O O
1.227 1.232 1.233
MeO O O OMe MeO O O OMe
Ph3P=CHCO2Me 1M aq. HCl/MeOH/CH2Cl2
toluene O OTMS 30-40% from 1.227 O OH O O
1.234 1.223
Since diester 1.233 is a 4,5-cis substituted dioxolane, it was reasoned that it could be isomerized under thermodynamic conditions to give a 4,5-trans substituted dioxolane.157,158 Diester 1.233 was treated with amberlyst® 15, a strongly acidic
macroreticular anhydrous bead with sulfonic acid functionality, and 2,2- dimethoxypropane (DMP) in acetone (Scheme 1.67). After several hours at room
temperature, a 1H NMR spectrum of the crude reaction mixture revealed the formation of a mixture (9:1) of acetonide 1.224 and starting material 1.223 which were separated by flash chromatography to provide isomeric acetonide 1.224 in 77% yield. The remainder of the material was composed of an unidentified mixture of non-polar side products. This transformation was significant because 1.224 possesses the proper stereochemistry at C(11) to access solandelactones A, C, E, and G.
76 Scheme 1.67
MeO O O OMe MeO O O OMe MeO O O OMe
amberlyst 15, DMP, acetone, 11 11 11 = O OH O OH 77%, 9:1 (1.223:1.224) HO O O O O 1.223 1.224 1.224
H H HO O HO O 11 O 11 O H H OH OH Solandelactone A (1.193) Solandelactone B (1.194) Solandelactone C U19, 20 (1.195) Solandelactone D U19, 20 (1.196) Solandelactone E U 4, 5 (1.197) Solandelactone F U 4, 5 (1.198) Solandelactone G U19, 20, U4,5 (1.199) Solandelactone H U19, 20, U4,5 (1.200)
The second key step in the synthesis was the first of two 1,3-chirality transfer reactions. Treatment of the diester 1.223 with MsCl/Et3N gave mesylate 1.235 in good
yield (Scheme 1.68). It was envisioned that this mesylate would react with a cuprate in a
stereoselective SN2' fashion retaining the trans-geometry of the olefin. A
(diethylamino)diphenylsilyl cuprate was chosen for this transformation since the product could be oxidized to a hydroxyl group with retention of configuration.159-163 This type of
transformation, albeit with carbon-cuprates, is precedented in the literature to occur with high regio- and stereoselectivity.164
When mesylate 1.235 was treated with (diethylamino)diphenylsilyl cuprate, no
SN2' product 1.236 was isolated (Table 1.3, Entries 1 and 2), but reduced β,γ-enoate
1.237 was obtained insead. Postulating that this might be due to a side reaction single electron transfer (SET) to the enoate and successive fragmentation,165 the otherwise
77 identical silylzincate was used, but once again, 1.237 was the major product (Entry 3).166
An alternate approach to the chirality transfer was thus examined.
Scheme 1.68
MeO O O OMe MeO O O OMe MeO O O OMe
MsCl, Et3N Conditions* Si(NEt2)Ph2 99% O OH O OMs O O O O
1.223 1.235 1.236
MeO O O OMe
instead: O O 1.237
Table 1.3. Reaction conditions for the 1,3-chirality transfer of 1.235 using silyl cuprates and zincates.
Entry Reagent Solvent Temp (°C) 1.235 1.236 1.237
1 [Ph2(NEt2)Si]2Cu(CN)Li2 THF -78 °C trace - 50% . 2 [Ph2(NEt2)Si]2Cu(CN)Li2, BF3 OEt2 THF -78 °C - - 85%
3 [Ph2(NEt2)Si]ZnEt2Li THF -78 °C trace - Major
The [2,3]-sigmatropic rearrangement of allylic sulfoxides, commonly referred to as the Mislow-Evans rearrangement, has been used to prepare a wide variety of allylic alcohols.48,49,167 In this transposition, an allylic sulfoxide 1.238a is converted to a
rearranged alcohol 1.240 by treatment with a thiophile such as trimethylphosphite (Scheme 2.8). This same transposition is also known to occur with selenoxides (1.238b), whose substitution, contrary to sulfoxides, takes place under mild aqueous conditions.168
78 Scheme 1.69
S O P(OEt)3 OH
R R' R R' 1.239 1.240 O Y Se O R R' H2O OH R R' R R' Y=S (1.238a) Y=Se (1.238b) 1.241 1.242
Phenyl selenoxides are prepared by peroxide oxidation of an alkyl phenylselenide 1.243, usually in the presence of water (Scheme 1.70). Following stereoselective [2,3]- sigmatropic rearrangement of 1.244 to the selenate 1.245, nucleophilic attack occurs on selenium by either water or hydroxide ion resulting in the formation of selenol and the trans-allylic alcohol 1.246. The phenylselenol is oxidized by the excess peroxide into selenic acid and then complexed by pyridine.
Scheme 1.70
R' R' R' R'
OH2 H2O2, pyridine 8 O OH SePh CH2Cl2, 0 °C O R SePh R Se R R Ph 1.243 1.244 1.245 1.246
In acyclic systems there is usually a considerable preference for the formation of
the E-isomer. The five-membered transition state 1.248 proposed for this rearrangement
suggests that E-selectivity should increase as R1 becomes larger than R2, since the R1 group would prefer to occupy a pseudo-equatorial position (Scheme 1.71). Indeed, this is 168 the case for 2,3-disubstituted allylic compounds (R2 and R3 = H).
79 Scheme 1.71
R2 Ph O •• R X Se H R >R 2 R1 Se O 1 2 R H 1 X R1 OSePh R2 R3 R3 R3 Ph X 1.247 1.248 1.249
Reaction of the mesylate 1.235 with PhSeNa which had been prepared from 169-171 Ph2Se2 and NaBH4, gave only the reduced product 1.237 (Scheme 1.72).
Considering that PhSeNa prepared in this way is formed as a complex with borane,
PhSeNa was formed in an alternate manner by the reduction of Ph2Se2 with freshly prepared sodium sand.169 However, the PhSeNa prepared in this manner was such a
powerful nucleophile that after a few minutes only polar decomposition products, presumably carboxylic acids or their salts, presumably resulting from nucleophilic attack on the ester functionalities by the uncomplexed PhSeNa were visualized by thin layer chromatography.
Scheme 1.72
MeO O O OMe MeO O O OMe
PhSeNa O OMs O SePh O O 1.235 1.250
More recently, Grieco has developed a facile one-step conversion of an alcohol to an alkyl arylselenide that is in many ways superior to the traditional two-step protocol.172
Treating a variety of primary alcohols with o-nitrophenyl selenocyanate and tri-n- butylphosphine in either tetrahydrofuran or pyridine at room temperature provides excellent yields of the corresponding selenide. The mechanism of this transformation is
80 60,123 similar to the related Mitsunobu reaction. Since it proceeds by an SN2 displacement,
there is an inversion of configuration. When diester 1.233 was treated with o-nitrophenyl selenocyanate173 and tri-n-
butylphosphine in either THF or pyridine, the sterically hindered secondary hydroxyl group was not attacked, even under forcing conditions (Scheme 1.75, Table 1.4, Entries 1, 2 and 3). The use of the more nucleophilic phenylselenocyanate174 in THF at room
temperature, did give the desired product 1.250 (Ar = Ph) (Entry 4). Decreasing the reaction temperature and changing the solvent increased the yield considerably. The highest yield to date was 64% using toluene at –20 °C (Entry 5).
Scheme 1.73
MeO O O OMe MeO O O OMe
Conditions*
O OH O SeAr O O 1.233 1.251
Table 1.4. Reaction conditions for the selenation of diester 1.233.
Entry Selenide (eq) Phosphine (eq) Solvent Temp (°C) Result
1 o -NO2PhSeCN (1.5) Bu3P (1.5) THF rt no rxn
2 o -NO2PhSeCN (1.5) Bu3P (1.5) Pyridine rt no rxn
3 o -NO2PhSeCN (3) Bu3P (1.5) THF reflux no rxn
4PhSeCN (1) Bu3P (1.5) THF rt 7% 5PhSeCN (1.5) Bu P (1.5) Toluene -20 64% 3
The purified selenide 1.250 was treated with hydrogen peroxide and pyridine to provide trans α-hydroxyester 1.252 as a single isomer (Equation 1.1). The depicted stereochemistry at C(8) in 1.252 is in accordance with the proposed five membered transition state of the [2,3]-rearrangement,175 and the olefin geometry is supported by the 81 1 H NMR spectrum with J8,10 = 15.5 Hz. The selectivity is presumably the result of the diol ester fragment preferentially occupying the pseudo-equatorial vs. pseudo-axial position in the transition states shown (Equation 1.2 and 1.3 respectively), 167,176,177 but to prove the configuration a crystal structure of 2.152 or a derivative should be obtained.
MeO O O OMe MeO O O OMe
H2O2, pyridine 8 OH (1.1) CH Cl , 0 °C 95% O SePh 2 2 O 10 O O 1.250 1.252 O O MeO H MeO O O OMe MeO H Ph •• (S)
Se O Se O •• OH (1.2) or H H OO OO O Ph CO2Me CO2Me O 1.253a 1.253b 1.252 •• Ph O OMe
Se • Se Ph O • O (R) CO2Me CO2Me H H OH or O H O (1.3) O O) (H O) ( O MeO O MeO O O OMe 1.254a 1.254b 1.235 Not Observed
Having successfully effected the key chirality transfer, Dr. Harcken turned his attention toward the diastereoselective installation of the required cyclopropane ring.
Directed cyclopropanation of allylic alcohols, particularly those situated adjacent to (Z)- olefins, are known to proceed readily and in many cases with excellent syn selectivity, presumably due to the minimization of A1,3-strain in the transition state.178 However, relatively little work has been done to expand this methodology to (E)-disubstituted olefins.
82 In 1995 Charette performed a comprehensive study and showed that good to excellent (6:1 to >200:1) facial selectivity could be achieved utilizing Furukawa’s 58,179,180 Et2Zn/CH2I2-derived reagent on (E)-allylic alcohols (Scheme 1.74). In organozinc mediated Simmons-Smith cyclopropanations, the reactive species is believed to be (halomethyl)zinc YZnCH2X, where the Y substituent is usually a halogen, Et, or
ICH2 group. Charette asserted that the correct stoichiometry of reagents was important in
order to maximize the ratios. For example, the reagent formed from a mixture (1:1) of
Et2Zn and CH2I2, often written as EtZnCH2I, was far superior to the Zn(CH2I)2 reagent
resulting from a mixture (1:2) of Et2Zn and CH2I2. To maximize the ratios and to
achieve complete consumption of the olefin, Charette found that five equivalents of
EtZn(CH2I)2 were necessary.
Scheme 1.74
Et Et Et O OH H H Zn H OH CH2I H >130:1 = H
1.256 1.257 1.257
When α-hydroxy ester 1.252 was subjected to a chelation controlled Simmons- Smith cyclopropanation utilizing Charette’s protocol, initial results revealed the reaction
to be diastereoselective (Scheme 1.75). However, contrary to the examples reported in the literature, the transformation proceeded slowly even at room temperature. After 48 hours only a 60% conversion was observed. Thus, while successful, the cyclopropanation reaction required further optimization. At this juncture, Dr. Harcken passed this project to me to complete.
83 Scheme 1.75
MeO O O OMe MeO O O OMe
Et Zn (5 eq), CH I (5 eq) H OH 2 2 2 OH CH Cl , -10 °C to rt O 2 2 O H 60% conversion O O 1.252 1.258 In summary, Dr. Harcken developed an efficient eight step synthesis of α-
hydroxy ester 1.252 in 17% overall yield from commercially available L-arabinose (1.225) (Scheme 1.76). En-route to this key intermediate he developed a variation on the Wittig protocol which provides excellent yields and E-selectivity on the olefination of α- alkoxy aldehydes and sugar lactols, demonstrated the feasibility of using a stereoselective [2,3]-sigmatropic rearrangement as a key step en-route to solandelactone E (1.197), and began exploring the diastereoselective cyclopropanation of 1.252.
Scheme 1.76
O OMe
HO O OH 1. TMSCl, Et3N 1. DMP, TsOH, DMF, rt. 91% 2. Swern oxidation HO OH O OH 2. Bu PCHCHCHCO CH , 3. Ph3PCHCHCHCO2CH3 3 2 3 O OH C6H5CO2H, 78% 4. aq. HCl, 40% over 4 steps
L-Arabinose (1.225) 1.227
MeO O O OMe MeO O O OMe
1. PhSeCN, Bu3P, 64% OH O OH 2. H2O2, pyridine, 95% O O O 1.223 1.252
84 Chapter 2: Studies Towards the Total Synthesis of the Solandelactone Oxylipins-The Total Synthesis of Solandelactone E
3.1 FIRST GENERATION APPROACH
At this juncture, the task of completing the total synthesis of solandelactone E (1.197) was passed to me. The synthetic sequence leading toward diester 1.223 was still very attractive, but several steps required optimization. The trans-selective Wittig reaction developed by Dr. Harcken is a key transformation integral to the success of this approach. Operationally, however, the procedure was somewhat cumbersome. It was necessary to prepare the methyl (tributylphosphoranylidene) acetate immediately prior to 151 each use by dissolving corresponding phosphonium bromide in CH2Cl2 and
deprotonating it with aqueous 1 M sodium hydroxide in a separatory funnel. Once the
deprotonation is complete, the solution of ylide is dried (MgSO4), filtered, then diluted
with toluene. The CH2Cl2 is removed under reduced pressure leaving behind the ylide as
a solution in toluene. This solvent swap was found to be unnecessary, as lactol 1.226 underwent
olefination overnight at room temperature in CH2Cl2 to give the corresponding α,β-
unsaturated ester 1.227 in equivalent yield and E/Z ratio as observed in toluene. Alternatively, faster reaction times, but slightly lower yields, could be obtained by refluxing the reaction mixture in CH2Cl2.
Scheme 2.1
O OMe O OH HO Bu3P=CHCO2Me, PhCO2H cat. O OH O CH2Cl2, rt, 83%, 20:1 E/Z O OH O 1.226 1.227 85
Prior protection of diol 1.227 as its bis-TMS ether 1.232 (see Scheme 1.66), was also found to be unnecessary. By using only a single equivalent of the Swern reagent23,152 at -78 °C, the desired lactol 1.229 was obtained in 65% yield;
approximately 18% of the undesired regioisomeric lactol 1.230, the consequence of oxidation at the allylic position, was also isolated (Scheme 2.2). Lactols 1.229 and 1.230 were crystalline solids that could be cleanly separated by flash silica gel chromatography. 1H NMR studies of 1.229 and 1.230 in deuterated chloroform showed that these bicyclic lactols existed in solution exclusively in the closed form, each as a single diastereomer of unknown configuration. Subjecting lactol 1.229 to a second E-selective Wittig reaction under the previously described olefination conditions provided the desired key diester intermediate 1.223 in good yield as a mixture (20:1) of E/Z isomers in four steps and 37% overall yield from L-arabinose (1.225). This route is two steps shorter and has a 9% higher yield than Dr. Harcken’s six step sequence.
Scheme 2.2
O OMe HO HO O O ClCOCOCl, DMSO, Et3N O O O H O OH O OH -78 °C, 65% of 1.229, 18% of 1.230 O O O OMe OMe
1.229 1.227 1.230
MeO O O OMe
1.229, Bu3P=CHCO2Me, PhCO2H cat. O OH CH2Cl2, ∆, 80%, 20:1 E/Z O 1.223
86 Next, the acid-catalyzed trans-ketalization of 1.223, previously reported by Dr. Harcken (see Scheme 1.67) was attempted. By omitting the 2,2-dimethoxypropane (DMP), the reaction proceeded well in acetone using amberlyst® 15 and 4 Å molecular sieves. Under these conditions, a separable mixture (20:1) of acetonide 1.224 and some recovered starting material 1.223 were obtained in a combined quantitative yield. The sieves were necessary to prevent acid catalyzed cleavage of the acetonide by ambient water present in the reaction from acetone. This diastereomeric ratio did not change even after prolonged treatment with acid. When isomeric acetonide 1.224 was resubjected to the reaction conditions, the same diastereomeric mixture of compounds was obtained, thus confirming that this ratio is thermodynamically controlled.
Scheme 2.3
MeO O O OMe MeO O O OMe MeO O O OMe
amberlyst 15, 4 Å seives, acetone 11 11 11 O OH HO O = O OH 100%, 20:1 (1.223:1.224) O O O 1.223 1.224 1.224
That the conversion of 1.223 to 1.224 was so favorable is unusually high for this type of transformation. For example, prolonged treatment of ester 2.2, which may be prepared in two steps from commercially available 2-deoxy-D-ribose, with p- toluenesulfonic acid in acetone provided a mixture (4:1) of acetonide 2.3 and starting
material 2.2. When pure 2.3 was resubjected to the reaction conditions, the 1H NMR spectrum revealed that the thermodynamic mixture of 2.3 to 2.2 was 4:1.
87 Scheme 2.4
O OMe O OMe O OH
Bu3P=CH2CO2Me, HO O cat. TsOH, acetone O cat. Benzoic acid. O O O 67%, 5:1 E:Z 62% of 2.3, O 4:1 (2.3:2.2) OH
2.1 2.2 2.3
cat. TsOH, acetone 4:1 (2.3:2.2)
O OMe O OMe
O HO + O O OH O 2.3 2.2
Having developed a streamlined synthesis of diester 1.223, the chirality transfer was examined. Previously Dr Harcken had obtained selenide 1.250 in 64% yield from 172 the reaction of 1.223 with PhSeCN/Bu3P in toluene at –20 °C. However, I was unable
to reproduce this yield (Scheme 2.5). Using his optimized conditions, up to a 44% yield of desired the selenide 1.250 was consistently isolated on a 20-100 mg scale along with
varied amounts of the trans-β, γ enoate 1.237 (Table 2.1, Entry 1). A variety of variables were examined in an attempt to suppress this destructive side reaction. Switching the solvent to pyridine provided the desired selenide in a 15-30% yield (Entry 2). The downside to using pyridine as a solvent in this early synthetic transformation was the aqueous workup required to remove it. The toxicity, smell, and volatility of phenyl selenocyanate made this an operationally cumbersome process. Greico and Nicolaou independently developed N-phenylselenophthalimide (N- PSP), a stable, relatively odorless crystalline solid for this displacement.181,182 Trading
PhSeCN for the supposedly superior N-PSP was ineffective (Entries 4 and 5). A variety 88 of solvents and temperatures were attempted, but in each case, either no reaction occurred or 1.237 was formed exclusively. Despite continued optimization, on medium scale (~1 g) the yield of isolated selenide 1.250 would unceremoniously drop to about 15% or lower, making it difficult to bring through large quantities of material past this early step.
Scheme 2.5
MeO O O OMe MeO O O OMe MeO O O OMe
Conditions*
O OH O SePh O O O O
1.223 1.250 1.237
Table 2.1. Reaction conditions for the selenation of allylic alcohol 1.223.
Entry Selenide (eq) Phosphine (eq) Solvent Temp (°C) Result
1 PhSeCN (1.1) Bu3P (1) Toluene -20 0%-40%
2 PhSeCN (1.5) Bu3P (1.5) Pyridine rt 15%-30%
3 o -NO2PhSeCN (1.5) Bu3P (1.5) THF rt no rxn
4 PhSe-phthalimide (1.5) Bu3P (3) Toluene -20 no rxn 5 PhSe-phthalimide (1.5) Bu P (2) CH Cl rt 2.9 only 3 2 2
We speculate that the reduced side product 1.237 arose from the nucleophilic attack on selenium in 1.250 by phenylselenide anion, cyanide ion, or tri-n-butylphosphine (Scheme 2.6). Loss of the phenylselenide would result in the formation of dienolate 2.4 that would give the reduced product 1.237 when protonated. To test this hypothesis, purified 1.250 was resubjected to the reaction conditions. Analysis of the crude material by thin layer chromatography indicated the formation of 1.237 thus confirming that the selenide is unstable to the reaction conditions.
89 Scheme 2.6
MeO O O OMe MeO O O OMe MeO O O OMe H+
Nu O SePh O O O O O
1.250 2.4 1.237
- - Nu= PhSe , CN , or Bu3P
The difficulties encountered during this transformation prompted a model study to see if the α,β-unsaturated ester moiety was facilitating the formation of reduced side product 1.237. The non-conjugated phenyl ester 2.8 was thus prepared in a traditional fashion from diol 1.227. All efforts to introduce a selenide to 2.7 proved fruitless (Table 2.2, Entries 1-4). An attempt to induce the same transformation with sulfur183,184 was also unsuccessful and resulted in the formation of an intractable mixture of products (Entry 5).
Scheme 2.7
O OMe O OMe OH
HO TBSO TBSO TBSCl, imidazole, DIBAL-H, CH2Cl2
O OH DMF, 95% O OH -78 °C, 72% O OH O O O
1.227 2.5 2.6
O O
TBSO O TBSO O Benzoyl chloride, Conditions*
Et3N, CH2Cl2, 62% O OH O SePh O O 2.7 2.8
90 Table 2.2. Conditions of the selenation of phenyl ester 2.8.
Entry Selenide/Sulfide (eq) Phosphine (eq) Solvent Temp (°C) Result
1 PhSeCN (2) Bu3P (2) CH2Cl2 rt Intractable Mixture
2 PhSe-phthalimide (2) Bu3P (3) THF rt Recovered Starting Material
3 o -NO2PhSeCN (2) Bu3P (1.5) DMF rt Recovered Starting Material
4 PhSeCN (2) Bu3P (1.5) DMF rt Recovered Starting Material 5 PhSSPh (5) Bu P (4) CH CN rt Intractable Mixture 3 3
When isomeric diester 1.224 was treated with PhSeCN and Bu3P in toluene, this
substrate was found to be remarkably recalcitrant to the transformation (Scheme 2.8). Starting material was recovered in near quantitative yield even after prolonged exposure to the reagents and warming thus indicating that 1.224, unlike its C(11) epimer 1.223, was not even activated by the reagents.
Scheme 2.8
MeO O O OMe MeO O O OMe
PhSeCN, Bu3P
Toluene, -20 °C to rt O OH O SePh O O 1.224 2.9
Once isolated, selenide 1.250 was immediately treated with hydrogen peroxide and pyridine to provide the trans α-hydroxyester 1.258 as a single isomer in quantitative yield (see Equation 1.1). With the first 1,3-chirality transfer successfully completed, attention was turned to the hydroxyl directed cyclopropanation. Minimization of A1,3- strain is accepted as the primary factor driving syn selectivity in these reactions.178
Assuming zinc alkoxide 2.10 adopts a conformation minimizing this allylic interaction, the metallocarbenoid will be delivered from the top face of the olefin to give the desired cyclopropane 1.258 (Equation 2.4). However, coordination of the metal center and the 91 acetal oxygen 2.11 is also possible (Equation 2.2). In this case, however, methylene delivery would come from the opposite face of the olefin, thereby yielding a cyclopropane 2.12 with the incorrect relative stereochemistry.
MeO O O OMe MeO O O OMe MeO O O OMe O H H Zn OH OH CH2I (eq 2.1) O H O = O H O O O
2.10 1.258 1.258
O OMe MeO O O OMe MeO O O OMe O H H OH OH OH MeO (eq 2.2) H CH2I O H Zn O = O O O O CH2I
2.11 2.12 2.12
In the event, α-hydroxy ester 1.254 was subjected to Simmons-Smith cyclopropanation utilizing Charette’s protocol (Scheme 2.9).58 In agreement with Dr.
Harcken’s preliminary observations, initial results revealed that the reaction was diastereoselective, but contrary to the examples reported in the literature, the transformation proceeded slowly even at room temperature (Table 2.7, Entry 1). Prolonged reaction times increased conversion, but they also led to degradation of the product and starting material, resulting in an overall lower percent recovery. To further
complicate the situation, separation of cyclopropane 1.258 from the remaining olefin 1.254 was not possible using flash silica gel chromatography. In attempt to increase conversion, allylic alcohol 1.254 was heated with 10 eq of
Zn(CH2I)2 in a sealed tube at 55 °C. Cyclopropane 1.254 was obtained with good diastereoselectivity, but the conversion was again low (Entry 2). Repeating the reaction under an identical temperature profile using just 2 eq of Zn(CH2I)2, however, resulted in
92 the complete consumption of starting material and a 78% isolated yield of 1.258 (Entry 3). The diethylzinc used for these reactions was a commercially available 1 M solution in hexane. We speculate that the reaction could not be driven to completion when large excesses of diethylzinc were employed (Entry 2) because of the large volume of hexane present as a co-solvent in the reaction. Hoping to avoid the use of a sealed tube, which made scale-up difficult, the reaction was conducted in toluene. Although the reaction was still stereoselective, a considerable amount of unreacted starting material remaining after 18 hours at 65 °C. The best yield of product in this solvent to date is only 46% (Entry 4).
Scheme 2.9
MeO O O OMe MeO O O OMe
H OH Conditions* OH
O O H O O 1.254 1.258
Table 2.3. Reaction conditions for the cyclopropanation of allylic alcohol 1.268.
Entry Et2Zn CH2I2 Solvent Temperature Result Coments
o 1 5 eq 5 eq CH2Cl2 -10 C 40% conversion o o 2* 10 eq 20 eq CH2Cl2 0 C to 55 C mostly RSM Diluted with hexanes o o 3* 1.5 eq 5 eq CH2Cl2 0 C to 55 C 78% yield 22 h- complete conversion 4 1.5 eq 5 eq Toluene rt to 65 oC 46% yield 18h- incomplete conversion *Performed Under Pressure in a Sealed Vial
With a reliable set of cyclopropanation reaction conditions, attention was turned to appending the left-hand and right-hand side chains necessary to complete the total synthesis of solandelactone E (1.197). Although epoxide 2.14 was initially targeted for this purpose, complex mixtures were formed while attempting to reduce cyclopropane 1.258 to triol 2.13 with diisobutylaluminum hydride (DIBAL) and lithium aluminum 93 hydride (Scheme 2,10). Presumably, the first equivalent of aluminum hydride reacted with the alcohol and formed a five-membered chelate with the carbonyl group of the adjacent ester as depicted by 2.15. At low temperatures this chelate could be stable and require warming to dissociate. At warmer temperatures a variety of side reactions took place thus accounting for the mixtures observed. Only milligram quantities of the desired triol 2.14 were ever isolated.
Scheme 2.10
MeO O O OMe HO OH
H H OH DIBAL-H OH
O H or LiAlH4 O H MeO O MeO O O O AlX H 2 O 1.258 2.13 O H HO O O H 2.15 Ph3P, DEAD O H O 2.14
To circumvent this problem, the free hydroxyl group at C(7)was protected as its tert-butyldimethylsilyl ether 2.15 (Scheme 2.11). DIBAL reduction of 2.15 to the bis- diol 2.16 was quite facile. However, attempts to convert the diol into its bis halide (eg. Br, I) using Appel chemistry185 uniformly failed, resulting in an intractable mixture of
products. Mesylation of diol 2.16 with MsCl/Et3N provided 2.17 in reasonable yield.
It was hoped that cleaving the silyl ether would provide the α-hydroxy mesylate 2.19, which would cyclize under basic conditions to epoxide 2.18. Thus, 2.17 was subjected to a variety of reaction conditions known to cleave silyl ethers. The most obvious choice, tetrabutylammonium fluoride (TBAF), provided a mixture of polar
products. A 1H NMR spectrum of the crude reaction mixture indicated the absence of
94 both mesylate groups. Further attempts with a wide variety of alternate fluoride sources such as TBAF/acetic acid, HF·Pyr, KF, and tetrabutylammonium difluorotriphenylsilicate
(TBAT) failed to cleanly return either epoxide 2.18 or α-hydroxy mesylate 2.19.
Scheme 2.11
MeO O O OMe MeO O O OMe HO OH
H 7 H H OH TBSCl, Imidazole, OTBS DIBAL-H, CH2Cl2, 65% OTBS DMF, 83% O H O H O H O O O
1.258 2.15 2.16
MeO2SO OSO2Me MeO2SO MeO2SO OSO2Me O H H H + Et3N, MsCl OTBS F or H OH or O H O H O H CH2Cl2, 62% O O O 2.17 2.18 2.19
Due to the difficulty of obtaining large quantities of selenide 3.30, there was a constant shortage of advanced intermediates. Unfortunately, upon scale-up the selenation usually proceeded in a 10-15% yield on a >1 g scale (Scheme 2.12) The overall yield of
the sequence from L-arabinose (1.225) to bis-mesylate 2.16 was only 1.4% over the 10 steps making it inefficient. Hence, a second strategy which has since culminated in the total synthesis of solandelactone E (1.197) was developed.
95 Scheme 2.12
O OMe MeO O O OMe
O OH HO 1. DMP, TsOH, DMF, rt. 91% 1. Swern Oxidation, 65% HO OH O OH O OH 2. Bu3PCHCHCHCO2CH3, 2. Bu PCHCHCHCO CH , O 3 2 3 O OH C6H5CO2H, 78% C6H5CO2H, 80%
L-Arabinose (1.225) 1.227 1.223
MeO O O OMe MeO2SO OSO2Me 1. Et2Zn, CH2I2, 78% 1. PhSeCN, Bu3P, 15% 2. TBSCl, imidazole, 83% H OH OTBS
2. H2O2, pyridine, 100% 3. DIBAL, 65% O O H 4. MsCl, Et3N, 62% O O 1.252 2.17
3.2 SECOND GENERATION APPROACH
While developing a second strategy toward the synthesis of the solandelactone oxylipins, we still aspired to design and execute a synthesis that was flexible, practical and enantioselective. On paper, our first approach (Section 2.1) met these challenges in an elegant and concise manner. In practice, however, it suffered from several moderate to low yielding transformations early in the synthesis, making it difficult to bring through large quantities of material. We wanted our second approach to maintain many of the attractive features found in the previous one, namely the elegant installation of the five stereocenters and the convergent additions of the two side chains. We also desired to be able to access both series of the solandelactones from a single common intermediate. We envisioned that the stereocenter at C(15) of both series of solandelactones could be established by a 1,3-chirality transfer of the allylic hydroxyl group at C(12) in diols 2.20 and 2.21 (Scheme 2.13). In the case of 2.20, the transfer must proceed with overall inversion of stereochemistry, whereas the transfer would need to proceed with a net retention of stereochemistry with diastereomeric diol 2.21. Diols 2.20 and 2.21 can 96 be constructed in several steps from the same intermediate 2.22. More specifically, the diol moiety found in 2.20 and 2.21 would be installed by a Sharpless asymmetric dihydroxylation of diene 2.22. This diene can either be formed in a single step from known cyclopropyl aldehyde 1.98 previously described by Mohapatra35,71,121 (Scheme
1.31 and 1.57), or via a diastereoselective cyclopropanation of diene 2.23 followed by chain elongation. The stereocenter at C(7) in 2.23 and 1.98 can be purchased from D- glyceraldehyde acetonide (1.99).
Scheme 2.13
15 7 HO O H H 7 HO O OH
11 O 11 H HO H O OH OH 7 H O Solandelactone E (1.197) 2.20 O H 11 OEt 2.22
15 7 HO O H H 7 HO O OH O 11 O 11 H HO H O 7 H O OH OH 7 O O Solandelactone F (1.198) 2.21 11 H O H 11 OEt 1.98 2.23
O
7 H O O 1.99
Although D-glyceraldehyde acetonide (1.99) is commercially available as a polymer, it costs $41.50 per 500 mg and is thus prohibitively expensive. Fortunately, 97 over the past few decades many studies have determined the optimal conditions for
preparing 1.99 cheaply and on an industrial scale. In 1991 the process chemistry department at Lilly Research Laboratories published a procedure for obtaining kilogram
quantities of this aldehyde with high chemical and optical purity from D-mannitol (2.24), which is only $66.10/1 kg.186
Following the Lilly protocol, D-mannitol (2.24) was treated with 2,2-
dimethoxypropane (DMP) and a catalytic amount of SnCl2 in refluxing 1,2-
dimethoxyethane (DME) to provide diacetonide 2.25 in a reproducible 50% yield (Scheme 2.14).187 Oxidative cleavage of the diol in 2.25 to 1.99 was accomplished in
good yield using heterogeneous sodium periodate in CH2Cl2 containing aqueous sodium
bicarbonate. The bicarbonate was necessary to quench any formic acid produced from the oxidative cleavage of the monoprotected form that is present in small quantities due to the adventitious hydrolysis of diacetonide 2.25. Formic acid is known to be detrimental to the aldehyde because it promotes polymerization, racemization, and acetal cleavage. Once the oxidative cleavage was complete, the aldehyde could be distilled from the crude reaction mixture or used without further purification. Since the by-products of the periodate cleavage were benign to the subsequent transformation, it was advantageous to forgo purification.
Scheme 2.14
OH O O
HO OH DMP, DME HO O NaIO4, aq. Sat NaHCO3 H O Sn(II)Cl , 50% CH Cl , 75% O HO OH 2 O OH 2 2 HO O 2.24 2.25 1.99
98 Because phosphonate-stabilized carbanions are more basic than their phosphorane counterparts, there are instances where they are incompatible with groups susceptible to
epimerization. Since (R) and (S)-glyceraldehyde have an α-chiral center, an alternative procedure to traditional HWE technique using lithium chloride and 188 diisopropylethylamine (DIPEA) was utilized. Hence, treatment of D-glyceraldehyde acetonide (1.99) with triethyl 4-phosphonoacetate, lithium chloride, and DIPEA furnished the trans α,β-unsaturated ester 2.26 in excellent yield and E/Z selectivity as determined by the integration of the olefinic protons in the 1H NMR spectrum of the crude material. The ester group in 2.26 was readily reduced with diisobutylaluminum hydride (DIBAL) to alcohol of 2.27 (Scheme 2.15). The target intermediate, cyclopropane 2.28, is a known compound that was first prepared by Taguchi as part of his study on the synthesis of optically active cis- and trans-1,2-disubstituted cyclopropane derivatives by the Simmons Smith reaction of allyl alcohol derivatives derived from glyceraldehyde acetonide.72 Following Taguchi’s
procedure, the primary alcohol in 2.27 was protected as its TBDPS ether 1.100 and treated with excess Zn(CH2I)2 to furnish cyclopropane 2.28 in quantitative yield as a
single diastereomer after only a few hours at -10 ºC.
Scheme 2.15
O O O
H O LiCl, (CH3CH2O)2P(O)CH2CO2Et O DIBAL-H, CH2Cl2, 95% O
O i-Pr2EtN, CH3CN, 95% (95:5) E/Z EtO HO O 1.99 2.26 2.27
O O
O H O TBDPSCl, imidazole Et2Zn, CH2I2 2 1 TBDPSO TBDPSO DMF, 90% 0 oC, 12 h, 95% H 1.100 2.28
99 The diastereoselectivity observed in the Simmons-Smith reaction of chiral secondary allylic alcohols and ethers is assumed to be the result of chelation controlled positioning of the zinc carbenoid in a conformation that minimizes A1,3 -strain in the transition state. In the case of allylic alcohol 2.27, coordination to the primary hydroxyl group will give a mixture of trans-diastereomeric cyclopropanes. The TBDPS ether is employed to prevent coordination of the zinc carbenoid to this center. Therefore the diastereoselectivity observed in this transformation is assumed to result from coordination of the zinc carbenoid to the allylic acetal oxygen as portrayed by 2.29 (Scheme 2.16). To confirm the absolute stereochemistry about the cyclopropane, Taguchi elaborated 2.28 into the known compound ((1R,2R)-2- ((benzyloxy)methyl)cyclopropyl)methanol (2.28b),189 and compared its optical rotation value to a literature value.
Scheme 2.16
O O O O H H O = O IH C Zn CH I TBDPSO 2 2 TBDPSO TBDPSO H H 2.29 2.28 2.28
OH H
BnO H 2.28b 25 lit., [α] D-9.3° (c=0.70, CHCl3), 69%ee
Treating cyclopropane 2.28 with tetrabutylammonium fluoride (TBAF) furnished cyclopropyl alcohol 2.30 (Scheme 2.17). This alcohol was previously described as undergoing facile oxidation to the aldehyde with 2-iodoxybenzoic acid (IBX);73,84
100 however, in our hands this transformation was just as easily accomplished in quantitative yield using the more economical Swern reagent.23,152 Cyclopropyl aldehyde 1.98 could
be purified, but due to its volatility, it was best used without further purification. Hence, treatment of crude 1.98 with the lithium anion of trans-triethyl 4-phosphonocrotonate190 in tetrahydrofuran (THF) at 0 °C provided the key cyclopropyl diene intermediate 2.22 as an inseparable mixture (7:1) of olefin isomers as determined by the integrations of the olefinic protons in the 1H NMR spectrum. The coupling constants of the olefinic protons
of the major product were consistent with the formation of the EE diene (J11,12 = 15.1
Hz, and J13,14 = 15.1 Hz in 2.22). When NaH was used instead of lithium
diisopropylamide (LDA), the reaction proceeded sluggishly and in low yield.
Scheme 2.17
O O
TBAF, THF ClCO2CCl, DMSO, Et3N, H O H O rt, 98% TBDPSO HO CH2Cl2, -78 °C, 97% H H 2.28 2.30
O O
H H O EtO3P(O)CH2CHCHCO2Et, LDA, O 14 12 O O H THF, 0 °C, 65%, 7:1 (EE/EZ) H 13 11 H OEt 1.98 2.22
We envisioned that the two steps required for protection and deprotection of an allylic alcohol could be eliminated if cyclopropane 2.31 could be obtained directly from diene 2.23 (Scheme 2.18). Diene 2.23 is a known compound191 that was prepared in a
single step via HWE olefination of aldehyde 1.99 with trans-triethyl phosphonocrotonate in 72% yield as a mixture (10:1) of olefin isomers as determined by the integrations of the olefinic protons in the 1H NMR spectrum. The coupling constants of the olefinic
101 protons of the major product were consistent with the formation of the EE diene (J8,9 = 190 15.5 Hz, and J10,11 = 15.5 Hz in 2.23).
The γ,δ-olefin in 2.23 is electron deficient compared to the olefin in silyl ether 1.100, the cyclopropanation of which proceeded in only a few hours at 0 °C. Under conditions similar to those used for 1.100 (Table 2.4, Entry 1), the cyclopropanation of 2.23 reached an 80% conversion after 12 hours at room temperature; however, the isolated yield of 2.31 was only 47% due to the formation of polar side products. Since zinc carbenoids are electrophilic, we were not surprised this reaction was sluggish. We found that the cyclopropanation of diene 2.23, proceeded well using the
classic Simmons-Smith reagent Zn(CH2I)2 at elevated temperatures (Entries 2 and 3).
Dichloromethane was again found to be the superior solvent with yields consistently ranging between 69-72% (Entry 2). The optimal temperature for this transformation was
65 °C, so when CH2Cl2 (bp 40 °C) was used as solvent, the reaction was performed in a
sealed tube. Slightly lower yields (56-64%) were obtained using dichloroethane (Entry 3). Due to the higher boiling point (83 °C) of dichloroethane, the reaction was performed under a balloon of argon using a standard rubber septum making this solvent the practical choice for large scale preparations. It is important to note the reaction never reached completion. Higher
temperatures and longer reaction times did enhance the consumption of starting material, but the yield was not improved owing to the formation of polar side products. We
hypothesize that the cyclopropanation proceeded via the A1,3 minimized conformer 2.34 (Scheme 2.18). Diastereomeric trans-cyclopropane 2.36 was never isolated.
102 Scheme 2.18
O O O 8 O H O EtO3P(O)CH2CHCHCO2Et, LDA, Conditions* H 11 O O 9 O THF, 0 °C, 89%, 10:1 (EE/EZ) H O 10 OEt OEt 1.99 2.23 2.31
Scheme 2.19
O O IH2C O O Zn O H O H H O IH2C H O IH2C Zn ( O O O ) O H CH2I H H H OEt OEt OEt OEt 2.342.31 2.35 2.36
Table 2.4: Conditions for the cyclopropanation of diene 2.23.
Result Time Coments ٭Entry Et2Zn (eq) CH2I2 (eq) Solvent Temperature
15 10CH2Cl2 0 °C to rt 47% yield 12h 80% conversion † 2 1.2 4 CH2Cl2 0 °C to 65 °C 72% yield 4 h 7% RSM
31.55CH2ClCH2Cl 0 °C to 65 °C 64% yield 4 h -
† *Bath Temperature, Performed Under Pressure in a Sealed Vial
With efficient and reproducible conditions in hand for effecting the cyclopropanation of diene 2.23, the ester in 2.31 was reduced with DIBAL to give allylic alcohol 2.32 (Scheme 2.20). Treating 2.32 with catalytic tetrapropylammonium perruthenate (TPAP)32 in the presence of N-methylmorpholine N-oxide (NMO) provided
the α, β-unsaturated aldehyde 2.33, which was condensed with the anion of triethyl phosphonoacetate to furnish the cyclopropyl diene 2.22. The 1H and 13C NMR spectra of 2.22 obtained from aldehyde 2.33 was similar to the 1H and 13C NMR spectra obtained from 2.22 synthesized from aldehyde 1.98 (see Scheme 2.17), lending support to our assignment of stereochemistry about the cyclopropane ring. 103 Scheme 2.20
O O O
O H O H O Et2Zn, CH2I2 DIBAL, CH2Cl2,
O O o HO CH2Cl2, 65 °C, 72% H -78 C, 88% H OEt OEt 2.23 2.31 2.32
O O
TPAP, NMO, H O (EtO)2P(O)CH2CO2Et H O
O o O CH2Cl2, rt, 98% H NaH, THF, 0 C, 89% (10:1 E/Z) H H OEt 2.33 2.22
Since the stereochemistry about the cyclopropane ring relative to C(7) could only tentatively be assigned as R*S*, we wanted to confirm this assignment by obtaining a crystalline derivative of 2.31 suitable for X-ray. Towards this end, the primary alcohol of 2.32 was reacted with phenyl isocyanate to provide carbamate 2.37 (Scheme 2.21). Despite the presence of the aromatic residue, this compound existed as a clear oil. Hence, the acetonide was cleaved with acidic methanol to provide diol 2.38 in 93% yield as a white solid. Multiple recrystallizations from CH2Cl2/hexanes provided a crystal
suitable for X-ray. The relative stereochemical relationship of the dioxolane ring and cyclopropane rings in 2.38 were in agreement with the structure depicted.
104 Scheme 2.21
O O
7 7 H O PhCNO, Et3N H O H HO N O H CH2Cl2, rt, 85% H 2.32 O 2.37
OH 7 (R) cat. p- TsOH, H OH H MeOH, rt, 93% N O (S) H O 2.38
With three of the five stereocenters established and confirmed by X-ray crystallography, the next step was to install the chiral centers at C(11) and C(12). Initially, the possibility of performing a diastereoselective epoxidation on allylic alcohol 2.32 was considered. When treated with a nucleophilic aryl selenide (or aryl sulfide) anion, we envisioned that epoxide 2.39 could be regioselectively opened at the less hindered allylic terminus (Scheme 2.22). The resultant allylic selenide (sulfide) would be oxidized and then undergo a spontaneous 2,3-sigmatropic rearrangement to provide the desired 1,3-allylic diol 2.42. The titanium catalyzed Sharpless epoxidation reaction116 was a natural choice for the proposed diastereoselective oxidation. Multiple attempts were made to convert allylic alcohol 2.32 to epoxide 2.39. The reaction was allowed to proceed for several days at -15
105 °C, but only starting material was recovered, indicating the possibility of a mismatched situation.
Scheme 2.22
O O Ti(iOPr) , t-BuOOH 4 HO H O H O (-)-diethyltartrate, HO o H H -15 C O
2.32 2.39
R R R O O O (S) 14 - H H H O PhSe O H2O2 HO O
11 11 11 H PhSe H H O OH OH 2.40 2.41 2.42
Although the C(11) stereochemistry of the solandelactones may either be in the (R)- or (S)-configuration, C(14) exclusively exists in the (S) configuration. Since the
epoxide opening at the allylic terminus would occur by an SN2 mechanism with inversion of stereochemistry, only epoxide 2.39 would lead to the proper 14S* stereochemistry after the [2, 3]-sigmatropic rearrangement. If epoxide 2.43 were used, the [2, 3]- sigmatropic rearrangement would give 2.45 having the C(14)R* configuration (Scheme 2.23). This route was thus abandoned in favor of a diastereoselective dihydroxylation.
Scheme 2.23
R R R O O O (R) 14 - H H H O PhSe O H2O2 HO O
11 11 11 H PhSe H H O OH Incorrect OH Stereochemistry 2.43 2.44 2.45
The Sharpless asymmetric dihydroxylation (AD)192 is an excellent reaction that is
characterized by broad substrate compatibility, high enantioselectivity, high 106 chemoselectivity, and high catalyst turnover rate. Experimental observations and MM2 force field theoretical calculations have permitted the development of a mnemonic device for predicting the enantiofacial selectivity of a reaction (Figure 2.1).193,194 The southeast
and, to a lesser extent, northwest quadrants represent the largest steric barriers for this reaction and therefore require the require the sterically least encumbered groups to be positioned accordingly. The southwest quadrant is considered to be the attractive area and is particularly well suited for flat aromatic substituents or large aliphatic groups. When an olefin is positioned according to these constraints, it will either be attacked from the top face or the bottom face, depending on the ligand selected.
Figure 2.1. Mnemonic device for predicting enantiofacial selectivity in the Sharpless asymmetric dihydroxylation.
Dihydroquinidine Derivatives β- Face
NW NE RS RM
RL H SW SE α-Face Dihydroquinine Derivatives
(E)-Substituted olefins are the best candidates for AD, and representative ee’s range from 90-99.8% using the phthalazine (PHAL) ligand (Figure 2.2).195 The use of
K2OsO2(OH)4 as a non-volatile osmium source in combination with the inorganic co-
oxidant K3Fe(CN)6 allow all the essential ingredients including the ligand to be
premixed. This mixture is commercially available under the common name “AD-mix” α or β, depending on which of the chiral ligands is used (see Figure 2.2). For all but terminal olefins, an additional one equivalent of methane sulfonamide is also necessary to enhance the rate of hydrolysis of the osmate(VI) ester and, hence, the rate of catalyst turnover.196 107 Figure 2.2. Phthalazine ligands in the Sharpless asymmetric dihydroxylation.
Et N N N N Et N Et Et N O O N N H H H O O H MeO OMe MeO OMe
N N N N
(DHQ)2PHAL (DHDQ)2PHAL Dihydroquinine Phthalazine Dihydroquinidine Phthalazine Used in AD-mix-α Used in AD-mix-β
Since OsO4 is an electrophilic reagent, asymmetric dihydroxylation of
unsymmetrical conjugated dienes should, and does take place preferentially at the more electron-rich γ,δ-double bond.197,26 For example, when ethyl sorbitol (2.46) was treated
with AD-mix-β, R*R* diol 2.47 was obtained as the sole product in 86% yield and 93% ee (Scheme 2.24).198 Conversely, when 2.46 treated with AD-mix α, the enantiomeric S*S* diol 2.48 was obtained.199 These results are in accordance with Sharpless’
predictive model, and the absolute stereochemistry of both products was confirmed by subsequent synthetic elaboration to intermediates of known configuration.
Scheme 2.24
EtO O Dihydroquinidine AD-mix β Derivatives (R) (AD-mix β) 86%, 93% ee β- Face HO (R) OH NW NE H 2.47 O H OEt EtO O SWO SE OEt α-Face 2.46 AD-mix α (S) HO Dihydroquinine 80%, 80% ee (S) Derivatives OH (AD-mix α) 2.48
108 In addition to these simple conjugated systems, there are examples where this reaction works well in more complex systems with pre-existing chirality. For example, in Wolbers’ partial synthesis of phorboxazoles A and B,200 chiral unsaturated ester 2.49
was dihydroxylated with AD-mix β to give the corresponding R*R* diol 2.50 as predicted by the Sharpless mnemonic in excellent yield and de (Scheme 2.25).
Scheme 2.25
OTBS OTBS O OH OMe OTBS O OMe OTBS N AD-mix β, rt 3 d N (R) 78%, 92% de EtO (R) EtO O O OH 2.49 2.50
With these results and a handful of other similar transformations as precedent,197,201 we proceeded with the diastereoselective dihydroxylation of the γ ,δ-
olefin of diene 2.22. When 2.22 was treated with commercially available AD-mix α and AD-mix β significant amounts of starting material remained even after 48 hours at room temperature. Despite the low conversion, we were pleased to find that by using the two PHAL ligands we could obtain both diastereomeric diols 2.51 and 2.52 (Scheme 2.26).
When diene 2.22 was treated with AD-mix β, diol 2.51 was isolated as a single diastereomer as determined by it’s 1H and 13C NMR spectra. The same reaction with
AD-mix α, however, provided diols 2.52 and 2.51 as an inseparable mixture (3:1) of diastereomers indicating the possibility of a matching and mismatching ligand/olefin relationship. The stereochemistry of 2.51 and 2.52 were assigned to be 11R*12R* and 11S*12S* respectively by applying the Sharpless model.193,194
To remedy the sluggishness and improve the conversion, a “super” AD-mix consisting of 8 mol% of (DHDQ)2PHAL or (DHQ)2PHAL and 5 mol% of K2OsO2(OH)4 was prepared. The proportions of the non-catalytic ingredients were unaltered. This
109 super AD-mix formula represents an eight-fold increase in ligand and a twenty five-fold increase in catalytic oxidant over the commercially available reagent. Using this mixture at room temperature, the oxidation proceeded in approximately 70-80% yield over 18 hours with some (10-15%) recovered starting material.
Scheme 2.26
EtO O O Dihydroquinidine H Derivatives O (AD-mix β) AD-mix ß (R) (R) β- Face O HO H H 84%, >20:1 dr NW NE OH H H O 2.51 H O H H SWO SE AD-mix α OEt OEt EtO O O α-Face 2.22 78%, 3:1 dr H O Dihydroquinine (S) (S) Derivatives HO H (AD-mix α) OH 2.52
The asymmetric dihydroxylation was pivotal to our synthesis because by using both AD-mix α or AD-mix β, either of the solandelactone series epimeric at C(11) can be accessed from the common intermediate diene 2.22 (Scheme 2.27). Diol 2.51 has the correct stereochemistry at C(11) to access the 11S*-solandelactone series (A, C, E, and G), provided the 1,3-chirality transfer from C(12) to C(14) proceeded with overall inversion of stereochemistry. Similarly diol 2.52 has the appropriate stereochemistry at C(11) to access the 11R* solandelactone series (B, D, F, and H). In this case, however, it would be necessary to effect the 1,3-chirality transfer with net retention of stereochemistry. This could most easily be accomplished by double inversion via an epoxide intermediate 2.54 (Scheme 2.28).
110 Scheme 2.27
EtO O O
AD-mix ß H O H OH O 11 11 O HO H H O OH OH H O 2.51 Solandelactones A,C,E,G O H EtO O OEt O 2.22 AD-mix α H O H OH O 11 HO H 11 H O OH OH 2.52 Solandelactones B,D,F,H
Scheme 2.28
EtO O O H H H O - K2CO3, MeOH PhSe 11 11 11 HO H MsO H H O OH OH 2.52 2.53 2.54
H H H H O HO 2 2 OH O 11 11 PhSe H H 11 H O OH OH OH 2.55 2.56 Solandelactones B,D,F,H
There are many protecting groups available for 1,2-diols, but most are unsuitable for our chemistry.202 Since we wanted the diol moiety to remain masked until the end of the synthesis, we required a protecting group that could be cleaved in the presence of the lactone and the three olefins present in solandelactone E (1.197). We also required a protecting group that would allow us to cleave selectively the primary acetonide in its presence.
111 There several examples indicating that it is possible to cleave selectively an acetonide situated on a primary hydroxyl group in the presence of an internal one in the same molecule.203,204 Hence, diol 2.51 was treated with TsOH in acetone to provide
diacetonide 2.57 in virtually quantitative yield (Scheme 2.29). Reduction of the ester functionality with DIBAL furnished the alcohol 2.58 which was converted to allylic bromide 2.59 in one step using Appel’s halogenation protocol.185
Scheme 2.29
EtO O O EtO O O H O DIBAL-H, CH2Cl2, H O p-TsOH, DMP DMF, rt, 100% O H -78 oC, 95% HO H O OH 2.57 2.51
HO O Br O H H O CBr4, PPh3, CH2Cl2 O
o O H 0 C, 87% O H O O 2.58 2.59
With allylic bromide 2.59 in hand, attention was turned to appending the seven- carbon side chain corresponding to C(17)-C(22) in the solandelactones. Frequently used methods for displacing allylic halides with alkynyl nucleophiles require treating the allylic halide with an alkynyl magnesium halide or alkynyl lithium anion in the presence of copper(I) salt. An alternate procedure gaining popularity in the literature involves a copper(I) and phase-transfer catalyzed allylic substitution (cat. CuX/cat. nBu4NCl/K2CO3). This method is considered very mild and can be used in the presence of sensitive functionalities such as esters, alcohols, and non-allylic halides.205 Since 2.59
112 is fully protected the experimentally simplest method for direct displacement was employed. Thus, the reaction of allylic bromide 2.59 with the lithium anion of 1-heptyne in
the presence of catalytic amounts of CuBr SMe2 provided a 92% yield of a mixture (4:1)
of enynes 2.60 and 2.61, resulting from SN2 and SN2’ displacement respectively, as
determined by examination of the olefinic region in the 1H NMR spectrum of the crude material. The terminal olefinic protons at C(15) are easily distinguished in 2.61 as they are considerably upfield as compared with C(13) and C(14) in 2.60 (Scheme 2.30). The desired product 2.60 was separated from 2.61 by flash chromatography and isolated in 74% yield; however, attempts to remove the primary acetonide moiety using
PPTS/MeOH and CH3CO2H/H2O failed to provide diol 2.62 in a synthetically useful
yield. Mixtures of both diols, tetrol, and some starting material were consistently recovered.
Scheme 2.30
Br O O 15 O 14 H 14 H H O n-BuLi, Heptyne, CuBr·SMe2, O 13 O 13 13 + O H 92%, 4:1 (2.60:2.61) O H O H O O O 2.59 2.60 2.61
PPTS, MeOH
OH
H OH
O H O 2.62
113 Realizing that a more rugged protecting group for the diol array at C(11) and C(12) was required, we chose the robust tert-butyldimethylsilyl (TBS) ether (Scheme 2.31). Diol 2.51 required prolonged reaction times or mild heating to complete its conversion into bis-TBS ether 2.63, presumably due to steric hindrance by the cyclopropane ring. The ester of 2.63 was reduced with DIBAL to provide allylic alcohol 2.64, which was converted to bromide 2.65 in excellent overall yield.185
Scheme 2.31
EtO O O EtO O O
TBSCl, imidazole DIBAL-H, CH2Cl2 H O H O 12 11 DMF, rt, 99% -78 oC, 95% HO H TBSO H OH OTBS 2.51 2.63
HO O Br O
CBr4, PPh3 H O H O
CH2Cl2, rt, 96% TBSO H TBSO H OTBS OTBS 2.64 2.65
Having completed the synthesis of orthogonally protected allylic bromide 2.65, attention was again directed toward the direct displacement of the halide (Scheme 2.32).
CuBr SMe2 provided the desired enyne 2.66 as the sole product in 95% yield. An 1 analysis of the olefinic region of the H NMR spectrum revealed no evidence of SN2’
displacement. The exclusive regioselectivity is likely due to the steric bulk of the TBS silyl ether blocking access to C(13). With the obstacle of regioselectivity resolved, attention was once again turned to the selective deprotection of the primary acetal. A survey of the literature revealed that acidic cleavage of isopropylidene acetals in the presence of TBS ethers can sometimes be difficult, but there are a significant number of successful examples. The most selective 114 conditions require heating in the presence of ethanedithiol and acid.206 In the absence of
an oxygen nucleophile, the TBS ether is usually stable. However, to the malodorous nature of ethanedithiol, other methods were screened. The deprotection of 2.66 was selective in neat acetic acid; however, the reaction was slow and only reached 75% conversion, even after 24 hours. On the other hand, stirring acetal 2.66 in a two-phase solution of CH2Cl2 with an aqueous trifluoroacetic acid (TFA) provided the desired diol 2.67 in only two to three hours.207 When 2.66 was
treated with excess tetrabutylammonium fluoride (TBAF), the bis-TBS ether was cleaved, and the internal diol 2.68 was isolated in near quantitative yield. This allylic diol proved to be an excellent model for testing the 1,3-chirality transfer planned for the end game of the synthesis.
Scheme 2.32
Br O
H O
TBSO H OTBS 2.65
OH n-BuLi, Heptyne CuBr-SMe2, 95% H TFA, H2O, OH
CH2Cl2, rt, 82% TBSO H O OTBS 2.67 H O
TBSO H OTBS O 2.66 H TBAF, THF, O
rt, 97% HO H OH 2.68
115 Vicinal diols are known to cyclize to epoxides under Mitsunobu conditions.123,208
Mechanistically Grieco’s one pot selenation proceeds via a Mitsunobu-type intermediate, so these conditions could not be used to selenate diol 2.68.172,182 Since selenide anions are known to displace various sulfonates and halides,170,171 we attempted to transform
selectively the allylic alcohol at C(12) into its tosylate 2.69 (Scheme 2.33). We found, however, that C(12) was so sterically hindered that tosylation did not proceed in freshly distilled pyridine, even with excess p-toluenesulfonyl chloride. The corresponding mesylate was more easily prepared, but it was too unstable to characterize and decomposed to a black precipitate after only a few hours.
Scheme 2.33
O O H H O TsCl, C5H5N O 12 12 HO H ∆ TsO H OH OH 2.68 2.69
O
H O 1. ArSe- HO
H 2. H2O2 OH 2.70
We then attempted to protect selectively the allylic alcohol at C(12) in the presence of the more sterically hindered one at C(11) in order to better understand the steric environment shared by the alcohols. When diol 2.68 was treated with a single equivalent of tert-butyldimethylsilyl chloride and excess imidazole, a mixture (4:1) of regioisomeric silyl ethers 2.71 and 2.72 was obtained in 72% yield (Scheme 2.34). The
116 remaining 28% of the material comprised recovered starting material 2.68 and bis TBS ether 2.66. Realizing that the steric bulk of the silylating reagent could have an advantageous effect on the yield and ratio of products, the reaction was repeated using the more sterically demanding triisopropylsilyl (TIPS) chloride. To consume starting material, the reaction required over nine equivalents of TIPSCl. However, using this reagent a superior yield (82%) and ratio (9:1) of regioisomeric silyl ethers 2.73 and 2.74 was obtained. Structural assignment between the regioisomeric silyl ethers (2.71-2.74) was not 1 possible using H NMR techniques in CDCl3 since the chemical shifts of the protons at
C(11) and C(12) did not vary significantly for the products and starting diol 2.68 (Table 2.5). Therefore the structural assignments are based on steric arguments and are only tentatively assigned to be as depicted in Scheme 2.34.
Scheme 2.34
O O TBSCl (1 eq) H O H O + imidazole, DMF 12 11 72%, 4:1 (2.71:2.72) O TBSO H HO H OH OTBS H O 2.71 2.72 12 11 HO H OH 2.68 O O TIPSCl (9 eq) H O H O 12 + imidazole, DMF 11 82%, 9:1 (2.73:2.74) TIPSO H HO H OH OTIPS 2.73 2.74
117 Table 2.5. 1H NMR shifts of C(11)-H and C(12)-H in regioisomeric silyl ethers (2.71-2.73).
1 H NMR Shifts in CDCl3 Compound C(11) C(12)
2.68 3.00 ppm 4.05 ppm 2.71 2.84 ppm 3.98 ppm 2.72 3.18 ppm 4.02 ppm 2.73 2.93 ppm 4.08 ppm
To test the stereoselectivity of the 1,3-chirality transfer, the minor tert- butyldimethylsilyl ether regioisomer 2.72 was separated from 2.71 by silica gel chromatography. The allylic alcohol at C(12) was converted to an aryl selenide using phenyl selenocyanate and Bu3P, and the crude mixture was treated with hydrogen
peroxide to give allylic alcohol 2.75, albeit in low yield (Scheme 2.35). The coupling
constant of the olefinic protons (J12,13 = 15.6 Hz) was consistent with the formation of a
trans-olefin. The stereochemistry at C(14) and the olefin geometry of 2.75 is in accordance with the five-membered transition state proposed for this [2,3]-sigmatropic rearrangement.175
Scheme 2.35
O O
14 H 1. PBu3, PhSeCN, THF rt H O HO O 12 2. H2O2, pyridine, rt 12 HO H 10% (2 Steps) H OTBS OTBS 2.72 2.75
We wanted to protect the C(11) hydroxyl group in 2.73 and then selectively remove the C(12) TIPS ether to give us a compound such as acetate 2.77 which could then be converted to an aryl selenide intermediate and subjected to a 1,3-chirality
118 transfer. Hence, 2.73 was treated with Ac2O in the presence of Et3N and DMAP to give
acetate 2.76 in 95% yield (Scheme 2.36). However, TBAF mediated cleavage of the TIPS group to mono-acetate 2.77, resulted in the cleavage of both protecting groups thus returning diol 2.68 from the beginning of the sequence. Repeating the deprotection with pyridine-hydrofluoride and TBAF/acetic acid was futile; starting material was recovered in near quantitative yield in both trials. Since this approach required four-steps from bis- TBS ether 2.66 to differentiate between the C(11) and C(12) alcohols, we decided to shift our attention to a more concise strategy.
Scheme 2.36
O O H O Ac O, Et N, DMAP, TBAF, THF, 87% 2 3 H O 12 11 TIPSO H CH2Cl2, 95% TIPSO H OH OAc 2.73 2.76
O O H H O O instead: HO H HO H OAc OH 2.77 2.68
Benzylidene acetals are known to undergo selective hydride-mediated cleavage at the least hindered carbon-oxygen bond.202 The yield and selectivity are generally good
for this type of transformation, and overall it represents the most concise route to the correct mono-protected diol. DIBAL is the most commonly employed reducing reagent for this type of cleavage, and it usually provides excellent regiocontrol.209-216 For
example, Pale used a DIBAL mediated reductive cleavage en-route to his total synthesis of constanolactones A and B (1.103 and 1.104) (see Scheme 1.40).86 Other reagent
119 217 combinations known to effect this reductive transformation include LiAlH4/AlCl3, 218 219 202 TiCl3/Et3D, MgBr2/Bu3SnH and HCl/NaCNBH3.
Ideally, the chirality transfer should take place at the end of the synthesis to avoid having to protect the newly rearranged free hydroxyl group at C(14). Therefore, the ideal substrate for this reductive cleavage would be would be lactone 2.79 (Scheme 2.37).
However, since lactones are incompatible with DIBAL and LiAlH4, an alternate
acid/hydride system was needed.
Scheme 2.37
H H O Lewis Acid O O O HO H O H Hydride O OPMB H 2.79 2.80
MeO
Two simple model systems were constructed to screen conditions for this reductive cleavage. Initial experiments were performed on cis 1,2-cyclohexanediol benzylidene acetal (2.82) (Scheme 2.38). We decided to focuse on two primary reductants, sodium cyanoborohydride do to its unique chemoselectivity and compatibility with lactones220 and triphenylsilane for its steric bulk. Since only a narrow scope of Lewis acids are known facilitate cleavage,217-219 the purpose of this initial screen was to determine which combinations of Lewis and protic acids and hydride sources were suitable for reducing benzylidene acetals. Acids studied included trifluoroacetic acid, acetic acid, pyridinium p-toluenesulfonate (PPTS), zinc chloride, scandium(III) triflate, and ytterbium(III) triflate.
120 Reductions conducted in the presence of weak protic acids such as PPTS or acetic
acid were sluggish using NaCNBH3, whereas the attempts using triphenylsilane did not
even reduce the acetal moiety. The Lewis acid catalyzed reductions of 2.82 with
NaCNBH3 and Ph3SiH were much more rapid than their protic acid counterparts. Trials
using NaCNBH3 as the reductant and ZnCl2, Sc(OTf)3, and Yb(OTf)3 as Lewis acids
provided mono-PMB ether 2.83 in near quantitative yield. Remarkably, when triphenylsilane was combined with these same Lewis acids, 2.83 was not observed by TLC. Only cis 1,2-cyclohexanediol (2.81) and starting material 2.82 were detected, suggesting that mono-PMB ether 2.83 was being reduced more rapidly than starting acetal 2.82 under these conditions.
Scheme 2.38
PAA, TsOH HO Seives, THF 62% O HO OH 1:1 dr O OPMB H 2.81 2.82 2.83 MeO
Hydrides: NaCNBH3 and Ph3SiH Acids: trifluoroacetic acid, aceitic acid, PPTS, ZnCl2, Sc(OTf)3, Yb(OTf)3
To test these Lewis acids in combination with NaCNBH3 on a more sterically
biased system, 4-methyl-pentane-2,3-diol (2.85) was treated with para-anisaldehyde
dimethyl acetal and TsOH to give 2.86 in 95% yield (Scheme 2.39). Disappointingly,
none of the previously screened Lewis acids, ZnCl2, Sc(OTf)3, and Yb(OTf)3 in combination with NaCNBH3 provided notable regioselectivity in the reductive opening
of 2.86. However, DIBAL provided excellent regiocontrol and returned 2.87 and 2.88 as a mixture (5:1) at -60 °C (Table 2.6, Entry 1).
121 Reasoning that since DIBAL, containing two isobutyl groups on aluminum, was regioselective, triisobutylaluminum (TIBA), with three isobutyl groups on aluminum, in combination with NaCNBH3 as the hydride source, should also be selective. Hence, 2.86
was treated with TIBA/NaCNBH3 in THF (Entry 2). However, after 72 hours at room temperature the reaction did not reached a synthetically useful conversion. When 2.86
was treated with TIBA/NaCNBH3 in the non-coordinating solvent CH2Cl2, starting
material was consumed after approximately 8 hours at room temperature (Entry 3), and a mixture (8:1) of desired PMB ethers 2.87 and 2.88 were obtained. Structural assignments between the two regioisomeric PMB ethers were made by comparing the chemical shift of C(2)-H and C(3)-H of both compounds (Table 2.7). The C(3)-H in 2.87 shows a remarkable upfield shift when compared with the same proton in 2.88 indicating that the C(3) oxygen atom on 2.87 bears the PMB group. Similarily, the C(3)-H in 2.88 shows a remarkable upfield shift when compared with C(3)-H of 2.87 indicating that in this minor regioisomer, the C(3) oxygen atom bears the PMB-ether.
Scheme 2.39
OMe
OMe
Admix β, MeSO2NH MeO t-BuOH-H O, 83% 2 HO OH p-TsOH, 89% 2.84 2.85
4 1 5 23 23 Conditions* + OO HO OPMB PMBO OH H 2.87 2.88 2.86 MeO
122 Table 2.6. Reaction conditions for the reductive cleavage of benzylidene acetal 2.86.
Entry Lewis Acid Hydride Solvent Temperature Ratio (2.87:2.88)
1 DIBAL DIBAL CH2Cl2 -60 °C 5:1
2TIBANaCNBH3 THF rt no reaction 3TIBANaCNBH CH Cl 3 2 2 rt 8:1
Table 2.7. 1H NMR shifts of C(2)-H and C(3)-H in regioisomeric PMB-ethers 2.87 and 2.88
1 H NMR Shifts in CDCl3 Compound C(2) C(3)
2.87 3.75 ppm 2.94 ppm 2.88 3.14 ppm 3.50 ppm
Armed with this positive result, diol 2.68 was treated with anisaldehyde dimethyl acetal in the presence of a catalytic amount of TsOH to furnish the benzylidene acetal 2.89 as a mixture (1:1) of diastereomers in 91% yield. Reaction of this mixture with
TIBA/NaCNBH3 in CH2Cl2 at room was complete within minutes and provided an
inseparable mixture of regioisomers (1:2) whose regiochemistry could not be conclusively determined at that time (Scheme 2.40, Table 2.7, Entry 1) but is now assigned as 2.91:2.90 (see Scheme 2.42).
Treatment of the acetal 2.89 with DIBAL (3 eq) in CH2Cl2 at -78 °C for 48 hours
provided an inseparable mixture (4:1) of regioisomers 2.90:2.91 (Entry 2). The reaction reached completion within hours at -60 ºC, but provided a diminished ratio (2:1) of 2.90 to 2.91. Curiously, based on the integration of the C(11)-H proton and the benzylic
methylene protons of the PMB-ether in the 1H NMR spectrum of the crude reaction mixture, we surmised that the major regioisomer from the DIBAL reductive cleavage was
actually the minor regioisomer obtained from the TIBA/NaCNBH3 reaction. Finally,
123 when acetal 2.89 was reductively opened using TFA and NaCNBH3, a mixture (1.1:1) of
2.90 to 2.91 was obtained (Entry 3). Structural assignments of the two regioisomers were tentatively made based on
1H NMR shifts of the C(11) hydrogen in 2.90 and 2.91 compared to the C(11) hydrogen of starting diol 2.68. Since the C(11) hydrogen in 2.90 is upfield relative to 2.91 and diol 2.68, we assigned the PMB-ether as being on the C(11) oxygen in 2.90.
Scheme 2.40
O O H H O anisaldehyde dimethyl acetal, O Conditions*
HO H TsOH, DMF, 91% (1:1) O H OH O 2.68 2.89
MeO
O O
H O H O 12 11 HO H PMBO H OPMB OH 2.90 2.91
Table 2.7. Reaction conditions for the reductive cleavage of benzylidene acetal 2.89.
Entry Lewis Acid Hydride Solvent Temperature Ratio (2.90:2.91)
1DIBALDIBALCH2Cl2 -85 °C 4:1
2TIBANaCNBH3 CH2Cl2 rt 1:2 3TFANaCNBH THF -0 °C to rt 1.1:1 3
124 Table 2.8. 1H NMR shifts of C(11)-H in regioisomeric PMB-ethers 2.90 and 2.91 as compared with starting diol 2.68.
1 H NMR Shifts in CDCl3 Compound C(11)
2.68 3.00 ppm 2.90 2.80 ppm 2.91 3.05 ppm
With ready access to sizable amounts of 2.90 that were obtained by the DIBAL reduction of acetal 2.89, the 1,3-chirality transfer was reassessed. The inseparable 174 mixture of alcohols 2.90 and 2.91 (4:1) was treated with PhSeCN and Bu3P to furnish selenide 2.94, which was partially purified by filtration through a pad of silica gel to remove any unreacted 2.91 and Bu3P(O) (Scheme 2.41). The semi-crude selenide 2.94
was treated with H2O2 in the presence of pyridine to provide in an overall 46% yield
from 2.89 a separable mixture (1:1) of the desired rearranged alcohol 2.92 and a reduced
compound who’s 1H NMR indicated the presence of four olefinic protons, the coupling constants of which indicated the presence of one cis- and one trans-olefin. We suspect that the side product is the ZE diene 2.93 or an analogous EZ diene. Although no studies were performed, a possible mechanism to account for this disturbing side reaction
involves deprotonation at C(15) of the intermediate selenide 2.94 followed by γ- elimination.
125 Scheme 2.41
O O O 15 H H H O i. PhSeCN, PBu3, THF HO O O ii. H O , Pyr, CH Cl 2 2 2 2 11 HO H H H 46% from 2.89, OPMB 1:1 (2.92:2.93) OPMB OPMB 2.90 2.92 2.93
PhSe- or CN- H O 15 H O
PhSe H OPMB 2.94
Other methods for converting an alcohol into a selenide were then examined to determine if this destructive side reaction could be suppressed. Realizing that the nucleophilicity of the “PhSe” anion derived from PhSeCN could be responsible for the formation of diene 2.93, we turned to the less nucleophilic o-nitrophenyl selenocyanate (Scheme 2.42). Indeed, this reagent proved to be superior. For example, the mixture
(4:1) of allylic alcohols 2.90 and 2.91 was treated with o-NO2PhSeCN and Bu3P to give a mixture of selenide and 2.91. The crude material was filtered through a short plug of silica gel to remove 2.91 and Bu3P(O), and then treated with H2O2 in the presence of
pyridine to give the desired rearranged alcohol 2.92 in 47% yield over three steps from acetal 2.89 (see Scheme 2.41). 1 The olefin geometry of 2.92 was determined by H NMR (J12,13 = 15.6 Hz) and the stereochemistry at C(14) and is in accordance with the five-membered transition state proposed for this [2,3]-sigmatropic rearrangement.175 This experiment confirmed our
hypothesis that the major regioisomer obtained from the DIBAL reduction of benzylidene 126 acetal 2.89 (see Scheme 2.41) was 2.90. If 2.91 was the major adduct, then the maximum theoretical yield expected from a 4:1 mixture of these compounds would be only 18% as opposed to the 47% obtained.
Scheme 2.42
O O
i. o-NO2PhSeCN, PBu3, THF H O H O ii. H2O2, Pyr, CH2Cl2 HO 13
HO H 47%, over 3 steps from 2.89 12 H OPMB OPMB 2.90 2.92
Encouraged by this result, we decided to use allylic alcohol 2.92 as an intermediate in our synthesis. Hence, alcohol 2.92 was deprotonated with NaH in the presence of PMBCl to provide bis-PMB ether 2.95 (Scheme 2.43). Treating 2.95 with catalytic TsOH in MeOH, conditions commonly used for acetal cleavage, provided diol 2.96 as a mixture (1:1) of diastereomers. The introduction of the methyl ether was most likely the result of acidic deprotection of the PMB group followed by ionization of the resultant alcohol thus forming the doubly stabilized allylic and cyclopropyl carbocation depicted by 2.97. In light of this result, other methods for cleaving the isopropylidene acetal were examined.
127 Scheme 2.43
O O PMBCl, NaH H H HO O PMBO O DMF, rt, 88% H H OPMB OPMB 2.92 2.95
OH OH H OH TsOH (cat.) MeOH, rt PMBO via H PMBO OH H H OMe 2.96 2.97
By applying the biphasic reaction conditions of TFA/H2O/CH2Cl2 to 2.95, previously employed to cleave the isopropylidene acetal on 2.66 (see Scheme 2.32), an intractable mixture of products was obtained. After a brief screen of various acids, diol 2.98 could be consistently isolated from 2.95 in 64% yield when 2.95 was treated with homogeneous TFA/H2O/THF (Scheme 2.44). The poor yield of this transformation,
compared with the preparation of similar diol 2.67, coupled with the additional step required to protect the C(14) alcohol mitigated against this route, and we returned to our original approach using bis-TBS ether 2.66 and doing the chirality transfer at the end of the synthesis (see Scheme 2.37).
Scheme 2.44
O OH H O H OH PMBO TFA, H2O, THF, rt, 64% PMBO
H H OPMB OPMB 2.95 2.98
128 Having demonstrated the underlying feasibility of the 1,3-chirality transfer on 2.90 (see Scheme 2.42), we returned our attention to the task of appending the alkynyl side chain corresponding to C(1)-C(5) which was destined to become the lactone. Epoxide 2.100 was envisioned be the ideal substrate for this transformation since it is known that oxiranes can be opened by alkynyl nucleophiles at the less hindered terminal position under a variety of relatively mild conditions.108
Several methods exist for diastereoselective formation of an oxirane from chiral vicinal diols. A commonly used one step procedure is the Mitsunobu reaction,123,208 but
we considered this to be the least desirable approach since purification problems owing to the presence of excess and spent reagents in the crude reaction mixture is often problematic. Therefore we decided to begin with a two-step approach. Treatment of diol 2.67 with TsCl and imidazole proceeded to give tosylate 2.99 in 65% yield. The remaining material was the epoxide 2.100, which was formed under the basic reaction conditions (Scheme 2.45). Although this in situ cyclization could have been developed into a one-pot conversion, attempted purification of epoxide 2.100 using flash silica gel chromatography gave the aldehyde 2.101. This rearrangement was most likely catalyzed by silica gel, which is inherently acidic. The epoxide opened to form the transient cyclopropyl carbocation 2.102, which underwent 1,2-hydride shift to give enol 2.103, tautomerization of which gave aldehyde 2.101. This rearrangement is known as the Meinwald rearrangement.221-223 In order to avoid this deleterious side reaction,
tosylate 2.99 was purified and cyclized with K2CO3/MeOH. After basic aqueous
workup, the crude epoxide 2.100 was clean and could be used in subsequent reactions without further purification. It was later discovered that the epoxidation could be executed in a single step in a superior yield by employing a modification of a Fraser-Reid protocol.224 Thus,
129 deprotonation of the diol with NaH followed by the addition of a single equivalent of N- tosyl imidazole supplied epoxide 2.100 in a single step. The epoxide prepared in this manner was spectroscopically identical to the one prepared via the tosylate intermediate 2.99. After aqueous workup, the 1H NMR spectrum of the crude material revealed that the epoxide was >95% pure.
Scheme 2.45
OH
H OH
TBSO H OTBS 2.67
TsCl, imidizole, NaH, Ts-Imid. o o Et3N 0 C, 67% THF, 0 C,100%
OTs O H O H H OH K2CO3, MeOH H silica gel
rt, 90% chromatography TBSO H TBSO H TBSO H OTBS OTBS OTBS 2.99 2.100 2.101
B:
HO H HO
H H
TBSO H TBSO H OTBS OTBS 2.102 2.103
Oxirane ring cleavage by a metal acetylide to form the corresponding β-hydroxy acetylene is one of many useful synthetic tools in organic chemistry. Appending doubly deprotonated 4-pentynoic acid225 to 2.100 to give 2.104 would result in the most direct
130 route to the solandelactones (Scheme 2.46). However, literature reports regarding this transformation lack experimental details. In each instance the acid was deprotonated at room temperature in HMPT, the epoxide was added, and the resultant solution was stirred for several hours to days at room temperature.225-227 We screened several variations of
these conditions in an endeavor to open epoxide 2.100 with the dianion of pentynoic acid (Table 2.9), but all of these attempts failed to effect the desired transformation in useful yields (Entries 1-4). Although they are well precedented, these conditions present several challenges for our specific substrate. The protons at the at C(15) of the enyne functionality are acidic. For example the pKa of related 1,4-pentadiene is 35228 (in DMSO), while the
pKa of an average acetylene anion is 25, we expect the pka of pentynoic acid dianion to be higher. This potentially small difference opens the possibility for deprotonation at
C(15) followed by the irreversible δ-elimination of tert-butyldimethylsilyl alcohol to give diene 2.105 (Scheme 2.47). The reactions in HMPA resulted in an intractable mixture of products whose 1 usually prominent protons at C(15) (≈ 3.00 ppm in CDCl3) were absent in the H NMR
spectrum. That, in conjunction with the presence of additional olefinic signals, was
consistent with deprotonation at C(15) and γ-elimination (Entries 1-3). Repeating the reaction in neat THF resulted in the complete recovery of starting material (Entry 4). Lewis acid catalyzed attempts with either boron trifluoride ethyl etherate or dimethylaluminum chloride formed an intractable mixture of compounds which varied in polarity (Entries 5 and 6), while the inclusion of a mild copper(I) salt was ineffective and resulted in recovery of the starting material (Entry 7).
131 Scheme 2.46
O O HO O H H OH OH n-BuLi TBSO H Conditions* TBSO H OTBS OTBS 2.100 2.104
Table 2.9. Reaction conditions for opening epoxide 2.100 with the dianion of pentynoic acid.
Entry Lewis Acid Solvent Temperature Result
1 n/a HMPA -0 ºC to rt intractable mixture, conjugated olefins 2 n/a THF/HMPA (30%) -78 ºC to rt 24 h, RSM plus conjugated olefins 3 n/a THF/HMPA (10%) -78 ºC to rt 24 h, RSM plus conjugated olefins 4 n/a THF -78 ºC to rt RSM
5 BF3·OEt THF -78 ºC intractable mixture
6 Me2AlCl Toluene -0 ºC to rt intractable mixture 7 CuBr·SMe THF -78 ºC to rt RSM 2
Scheme 2.47
Acidic Proton :B H O O H Strong Base H
TBSO H H TBSO OTBS OTBS OTBS 2.100 2.105 γ- leaving group
A survey of the most recent literature revealed that the method of choice for epoxide opening with acetylenic nucleophiles involves the use of an alkynyl borane, which is prepared in situ by the reaction of a lithium acetylide with boron trifluoride etherate.108 Since such epoxide openings with acetylide anions are Lewis acid catalyzed,
an additional concern was the propensity of cyclopropyl epoxide 2.100 to undergo 132 Meinwald rearrangement. Indeed, a survey of the literature revealed only one example of a cyclopropyl epoxide being opened with an acetylide nucleophile. In 1997, Taylor reported the formation of the β- hydroxy acetylene 2.107 in 65% yield by the reaction of an alkynyl borane derived from propargyltrimethylsilane with the diastereomeric mixture of cyclopropyl oxiranes 2.106 (Scheme 2.48).229
Scheme 2.48
H H OH O TMS TMS
n-BuLi, BF3·OEt2 H 65% H 2.106 2.107
Wipf has reported the hydrozirconation of alkynyl silyl esters and their subsequent use in a variety of transformations.230-235 Hoping to capitalize upon his success, propylene oxide (2.108) was treated with an alkynyl borane derived from the TBDPS-protected pentynoic acid 2.109, to give hydroxy ester 2.110 in excellent yield (Scheme 2.49). This is the first and only example of an alkynyl borane containing a silyl ester being used to open an epoxide. When the reaction was repeated and then quenched with a solution of TBAF in THF, hydroxy acid 2.111 was isolated in equally high yield thus providing an efficient alternative to the previously described conditions utilizing the pentynoic acid dianion in carcinogenic HMPA as solvent (see Scheme 2.46).
133 Scheme 2.49
O O 2.109 OTBDPS OTBDPS
. n-BuLi, BF3 OEt, THF, -78 °C, 90% OH
2.110
O
2.108 O O 2.109 OTBDPS OH
. n-BuLi, BF3 OEt, THF, -78 °C, OH then acetic acid and TBAF, 86% 2.111
When these conditions were applied to epoxide 2.100, however, a complex mixture of compounds varying in polarity was obtained (Scheme 2.50). There are usually two distinct ddt in the 1H NMR spectrum of β-hydroxy acetylenes (≈ 2.5 ppm), each corresponding to one of the two methylene protons α to the hydroxyl group and
acetylene (Ja,a ≈ 16.5 Hz). Only a small amount of material (approximately 5%) of a
product whose 1H NMR spectrum had the characteristic splitting pattern corresponding to the C(6)-H consistent with the formation of 2.112 was isolated.
Scheme 2.50
6 O O H O H OH OTBDPS OTBDPS TBSO H TBSO H . OTBS n-BuLi, BF3 OEt, OTBS THF, -78 °C, 5% 2.100 2.112
Concurrent with our attempts to open epoxide 2.100 with the dianion of pentynoic acid, an alternative ring closing metathesis (RCM) strategy being explored (Scheme
134 2.51). Alkenyl magnesium cuprates are known to open simple epoxides cleanly and in high yields;95 however, there were no reported reactions of alkenyl cuprates with cyclopropyl epoxides. The reaction of epoxide 2.100 with vinyl magnesium bromide in
the presence of a stoichiometric amount of CuBr⋅SMe2 cleanly provided the expected
homoallylic alcohol 2.113 in good yield. Acylation of cyclopropyl alcohol of 2.113 with 4-pentenoyl chloride provided 2.114.
Scheme 2.51
O Cl H H OH MgBr O
TBSO H CuBr·SMe2, THF, 84% TBSO H DMAP, pyridine, 95% OTBS OTBS 2.100 2.113
H RCM H O O O TBSO H O TBSO H OTBS OTBS 2.114 2.115
The formation of medium-sized rings by RCM constitutes a considerable synthetic challenge because such rings are frequently the most difficult to prepare.236 In addition to the inherent entropic disadvantage of the cyclization, enthalpic influences such as the strain in the transition state and in the ring itself predisposes cycloalkenes containing 8-11 atoms towards ring opening metathesis and potential polymerization.237
In the closest related example of RCM, which the review by Martin and Deiters236 refer to as a rare preparation of a nine-membered lactone moiety, Takemoto formed a nine- membered lactone containing functionality similar to 2.114 in an advanced intermediate en route to halicholactone (see Scheme 1.24).46 135 Successful examples of eight-membered ring formation by RCM are relatively scarce237 and generally rely on conformational bias to position the olefins within close enough proximity for them to react.238-240 To our knowledge, there are only two
successful reports of RCM used in the synthesis of mono-cyclic eight membered lactones. The first, reported by Buszek in 2002, was used to construct the lactone 2.117 found in the octalactin class of natural products (Scheme 2.52).241
Scheme 2.52
O O MPMO MPMO O (Cy3P)2RuCl2=CHPh O H H OTBDPS OTBDPS CH2Cl2, 40 °C, 86%
2.116 2.117
The second example was reported in 2003 by Mohapatra in his approach to the cyclopropyl lactone portion of the solandelactones.120 In the example, cyclization of
1.209 by RCM using Grubbs second generation catalyst in the presence of a catalytic
amount of titanium(IV) isopropoxide under high dilution conditions (0.001M in CH2Cl2 at reflux) formed the desired Z-isomer 1.204 in 71% yield along with the corresponding dimer (10%) (Scheme 2.53).
Scheme 2.53
H H O Grubbs II catalyst O O O H O H O Ti(Oi-Pr)4, 71% O O 1.204 1.209
These two examples together with some seminal research performed by Fürstner106 gave us reason to believe that this transformation could work. It is postulated 136 that the presence of a basic functional group, such as an ester, in the starting material and the distance between this group and the double bonds were of utmost importance when considering the reactivity of a given substrate. For example, if the basic group acts as a relay for the carbene species by drawing together the reacting sites within the coordination sphere of the metal, as in complex 2.118, it will facilitate the reaction (Figure 2.3). However, if the resultant array is too stable and sequesters the catalyst as in complexes 2.119 and 2.120, the cyclization may not take place. If chelation of the carbene with a basic group such as an ester does occur, then the 4-pentenoate substructure in RCM precursor 2.114 (see Scheme 2.51) will likely result in a six membered chelate of type 2.120. In order to destabilize this unproductive chelate, the RCM may be performed in the presence of a Lewis acid that will compete
with the ruthenium carbene for the Lewis basic ester. Catalytic amounts of Ti(Oi-Pr)4
have been shown to be a competent Lewis acid for this purpose.
Figure 2.3. Potential chelates in the RCM of substrates having basic functional groups.
O [M] O [M] O O OR M OR L L 2.118 2.119 2.120
In our hands, all attempts to cyclize diene 2.114 into lactone 2.115 were
unsuccessful (Scheme 2.54, Table 2.10). Using Grubbs I in refluxing CH2Cl2 and catalytic titanium (IV) isopropoxide resulted in the complete recovery of starting material at low and high dilutions (0.01-0.002 M) (Entry 1). Switching to the more reactive Grubbs II catalyst at high dilution (0.0003 M) resulted in the formation of an intractable mixture of products of nearly identical polarity together with some unreacted starting material (Entry 2). A 1H NMR spectrum of the crude material indicated the 137 disappearance of the otherwise prominent protons at C(15), indicating that the enyne may be reacting with the catalyst. Microwave heating was also examined. Benzene is known to be nearly microwave transparent, so the RCM reaction of 2.114 was repeated in benzene in the microwave (0.0017 M) for 15 minutes, 65 °C, 265 watts (Entry 3). Once again, an intractable mixture of products was observed, but only 15 minutes were required as opposed to the 18 hours necessary with conventional heating.
Scheme 2.54
H Conditions* H O O O TBSO H O TBSO H OTBS OTBS 2.114 2.115
Table 2.10. Reaction conditions for the RCM of 2.114.
Entry Lewis Acid Catalyst Solvent Temperature Result
1 Ti(OiPr)4, 0.3 eq G (I), 0.3 eq CH2Cl2 reflux, 48h RSM
2 Ti(OiPr)4, 0.15 eq G (II), 0.15 eq CH2Cl2 reflux, 18h mixture w/some RSM 3 Ti(OiPr) , 0.15 eq G (II), 0.15 eq Benzene (µϖ) 15 min, 65 ºC mixture w/some RSM 4
Frustrated by months of fruitless effort, we turned to opening the epoxide 2.100 with the mono-anion of THP-pentynol using Yamaguchi’s alkynylation procedure (Scheme 2.55).108 An inconsequential diastereomeric mixture of alcohol 2.121 was thus
consistently isolated in approximately 45% yield. The best yield obtained to date is 67%. Although this yield is modest, it is consistent with the 65% Taylor reported for the opening of his simple cyclopropyl epoxide (see Scheme 2.48).229 The other 45-60% of
138 material consisted of side products of varying polarity; these were difficult to separate from one another and were not characterized. Acylation of the free hydroxyl group in 2.121 under standard conditions produced 2.122, an intermediate with sufficiently different polarity allow its purification. Cleaving the THP group of 2.122 in the presence of the two silyl ethers proved tricky. The
conditions of CH2Cl2/TFA/H2O, that were previously used to remove the acetal on 2.66
(see Scheme 2.32) provided a complex mixture. Acetal exchange with the relatively bulky i-PrOH proved to be ideal, allowing us to isolate 2.123 consistently and cleanly in 87% yield.
Scheme 2.55
O OTHP H H OTHP OH Ac2O, DMAP, Et3N,
TBSO H . TBSO CH Cl , rt, 92% n-BuLi, BF3 OEt2, 2 2 OTBS THF, -78 °C, 45% OTBS 2.100 2.121
OTHP OH H H OAc p-TsOH, i-PrOH, OAc rt, 87% TBSO TBSO OTBS OTBS 2.122 2.123
Catalytic semi-hydrogenation of alkynes to Z-alkenes is a fundamental transformation in organic chemistry. Although this reaction is typically presented in sophomore organic chemistry classes as a sure thing, the literature reveals that this is not necessarily true.242 Hydrogenation of 2.123 using Lindlar’s catalyst was rapid and
sometimes difficult to control (Scheme 2.56). Over reduction of the olefins was a significant problem that was compounded by the fact that the over-reduced side products 139 could not be separated by flash silica gel chromatography. Poisoning the palladium catalyst with excess quinoline slowed the reaction enough to allow termination of the
reaction after the uptake of 2 mols of H2 to provide triene 2.124 in good yield after only 10-15 minutes. A two-stage oxidation furnished carboxylic acid 2.126,243 while
saponification of the acetate gave key hydroxy acid intermediate 2.127 in 73% from triene 2.124.
Scheme 2.56
OH H H OAc H2, Lindlar catalyst OAc OH
TBSO Quinoline, MeOH, rt, 94% TBSO H OTBS OTBS 2.123 2.124
H SO3·Pyridine, Et3N, H NaClO2, NaH2PO4, OAc O DMSO, rt, CH2Cl2, 85% 2-methyl 2-butene, TBSO H t-BuOH, H2O, rt, 90% OTBS 2.125
OH OH H H OAc O OH O K2CO3, MeOH TBSO H rt, 95% TBSO H OTBS OTBS 2.126 2.127
Hydroxy acid 2.127 was cyclized to the eight-membered lactone 2.128 in 81% yield under the conditions developed by Yamaguchi30 (Scheme 2.57). TBAF mediated
deprotection of the TBS ethers occurred uneventfully at room temperature to give diol 2.129, which possessed all of the skeletal elements in the oxidation state present in solandelactone E (1.197). All that remained was the final 1,3-chirality transfer step, which would necessitate the differentiation between the two hydroxyl groups. 140 Scheme 2.57
OH H 2,4,6-trichlorobenzoyl chloride, OH O H O Et3N, DMAP, PhMe, ∆, 81% O TBSO H TBSO H OTBS OTBS 2.127 2.128
H H O 1,3 Chirality Transfer HO O TBAF, THF, rt, 72% O O HO H H OH OH 2.129 Solandelactone E (1.197) minimal steric bias
Diol 2.129 was treated with anisaldehyde dimethyl acetal in the presence of a catalytic amount of TsOH and to furnish benzylidene acetal 2.79 (Scheme 2.58). Since the acetal could not be opened using DIBAL due to the presence of the lactone,
NaCNBH3 was chosen because it is a selective reducing agent compatible with lactone and ester functionalities.220 In some examples reported in the literature, a combination of
NaCNBH3/HCl can regioselectively cleave a benzylidene acetal in a sterically biased system.202 However, similar to our attempts with the model system 2.89 (see Scheme
2.40), reaction of acetal 2.79 with NaCNBH3 and TFA gave alcohols 2.80 and 2.130 as a
mixture (1.2:1) of regioisomers that were separable by chromatography.
The structures of the two regioisomers were assigned based on the chemical shifts of the protons at C(11) and C(12) in the 1H NMR (Table 2.11). The C(11) proton of the
major regioisomer 2.80 (δ 2.82 ppm) showed a marked upfield shift compared to the C(11) proton of starting diol 2.129 (δ 2.93 ppm). By contrast, the chemical shift of the C(12) proton was relatively unchanged (δ 4.05 and 3.98 respectively) indicating that the PBM ether was most likely on the C(11) oxygen. By contrast, the C(11) proton of the
minor regioisomer 2.130 remained relatively unchanged compared to diol 2.129 (δ 3.00 141 ppm and 2.93 ppm respectively) while the C(12) proton of 2.130 (δ 3.63 ppm) showed a significant upfield shift compared to 2.129 (δ 3.98 ppm) thereby supporting the assignment of the PMB ether on the C(12) oxygen of this compound. When 2.130 was treated with DDQ in the presence of a pH 7 phosphate buffer, starting benzylidene acetal 2.79 was isolated in 65% yield.244 The remaining material consisted of several polar side products, which were not characterized due to their minute quantities. This transformation allowed us to recycle an otherwise useless material.
Scheme 2.58
H H O anisaldehyde dimethyl acetal O O O HO H TsOH, DMF, rt, 80% O H OH O 2.129 2.79
MeO DDQ, phosphate buffer- pH 7, CH2Cl2, rt, 65%
NaCNBH , TFA, THF, 0 °C, 3 H H O O 91%, 1.2:1 (2.80:2.130) + 12 11 O O HO H PMBO H OPMB OH 2.80 2.130
Table 2.11. Chemical Shifts of C(11)-H and C(12)-H of 2.129, 2.80, and 2.130 in CDCl3.
1 H NMR Shifts in CDCl3 Compound C(11) C(12)
2.129 2.93 ppm 3.98 ppm 2.80 2.82 ppm 4.05 ppm 2.130 3.00 ppm 3.63 ppm
142 Allylic alcohol 2.80 was treated with o-nitrophenylselenocyanate and tri-n- butylphosphine to give a selenate intermediate. The selenate was oxidized to it’s selenoxide which underwent a [2,3]-sigmatropic rearrangement to give alcohol 2.131 as the sole product (Scheme 2.59). The stereochemistry at C(14) and the olefin geometry of 2.131 is in accordance with the five-membered transition state proposed for this [2,3]- sigmatropic rearrangement.175
The stereoselectivity is presumably the result of the cyclopropyl lactone fragment incorporating C(1) to C(11) preferentially occupying the pseudo-equatorial position in the transition state 2.132 (Scheme 2.60). If C(1) to C(11) were to occupy the pseudo-axial position in the transition state, as depicted by 2.133, we would expect cis-olefin 2.134 to be formed (Scheme 2.61).167,176,177
Scheme 2.59
H H 1. o-NO2PhSeCN, Bu3P, THF, rt O HO O O O HO H 2. H2O2, pyridine, CH2Cl2, rt, H 56% (2 Steps) OPMB OPMB 2.80 2.131
Scheme 2.60
H H Ph H H ••
O Se O Se (S) H O •• O HO H H or H H O OPMB OPMB O Ph O O H OPMB 2.132a 2.132b 2.131
143 Scheme 2.61
Ph •• Se Se O Ph O •• H H H H or H O H ( ) H ( ) O PMBO PMBO H H O H O (R) OPMB OH 2.133a O 2.133b O 2.134
An oxidative deprotection of the p-methoxybenzyl ether on 2.131 with DDQ29 provided solandelactone E (1.197) thus completing our total synthesis of this natural product (Scheme 2.62).
Scheme 2.62
H H HO O DDQ, pH 7 phosphate buffer HO O O O H CH2Cl2, rt, 72% H OPMB OH 2.131 Solandelactone E (1.197)
In the paper describing the isolation of the solandelactones, there is a discrepancy between the C(11) stereochemistry of the figures depicting the gross structure of solandelactones A-F and the stereochemical assignment described in the text of the paper.118 Based on their drawings, the absolute stereochemistry of solandelactones A, C,
E and G is 11R* while the absolute stereochemistry in solandelactones B, D, F and H is 11S*. Therefore, based on these drawings, we initially thought we had completed the total synthesis of solandelactone F (1.198).
144 Figure 2.4. Gross structure of solandelactones A-H as depicted in the isolation paper.
5 4 5 4
14 8 7 8 20 H 1 20 H 19 HO 9O 19 HO 9O (R) O (S) O 10 H 10 H OH OH Solandelactone A Solandelactone B Solandelactone C U19, 20 Solandelactone D U19, 20 Solandelactone E U 4, 5 Solandelactone F U 4, 5 Solandelactone G U19, 20, U4,5 Solandelactone H U19, 20, U4,5
After we oxidatively cleaved the PMB-ether found in 2.131 we isolated what we thought was solandelactone F. We were dismayed to find that the 1H NMR spectrum of synthetic solandelactone 1.197 did not match the 1H NMR spectral data reported for natural solandelactone F. The chemical shift of the protons at C(8)-H and C(9)’-H differed by 0.10 ppm and 0.11 ppm respectively (Table 2.12). We did observe, however, that the signals from this region were consistent with those reported from naturally derived solandelactone E.
Table 2.12. 1H NMR chemical shifts in CDCl3 of the cyclopropane protons C(8)- C(10) in isolated solandelactones E and F, and synthetic solandelactone (1.197)
Isolated Synthetic C# Solandelactone F Solandelactone E Solandelactone (1.197)
C(8)-H 1.02 ppm 1.14 ppm 1.12 ppm C(9)-H 0.78 ppm 0.74 ppm 0.72 ppm C(9)'-H 0.70 ppm 0.60 ppm 0.59 ppm C(10)-H 1.02 ppm 1.01 ppm 0.99 ppm
An analysis of the 13C NMR spectrum revealed a similar inconsistency between naturally derived solandelactone F and synthetic solandelactone 1.197. The chemical shift of carbon’s C(8), C(9) and, albeit to a lesser extent, C(17) differed by 0.9 ppm, 1.0
145 ppm, and 0.4 ppm respectively (Table 2.13). Once again, however, the shifts matched those reported for solandelactone E.
Table 2.13. 13C NMR chemical shifts in CDCl3 of the cyclopropane protons C(8)- C(10), C(17) in isolated solandelactones E and F, and synthetic solandelactone (1.197)
Isolated Synthetic C# Solandelactone F Solandelactone E Solandelactone (1.197)
C(8)* 19.7 ppm 20.6 ppm 20.6 ppm C(9)* 9.0 ppm 8.0 ppm 8.0 ppm C(10) 23.5 ppm 23.3 ppm 23.4 ppm C(17)* 133.6 ppm 133.1 ppm 133.2 ppm
These findings prompted a closer examination of the original isolation paper.118
According to the paper, solandelactones E and F were selected by Shin for comprehensive stereochemical studies due to their high isolated yields (35.1 mg and 42 mg respectively). The relative stereochemistry from C(7)-C(11) of these two natural products was determined by an analysis of their diacetates. Close examination of the NOESY spectra obtained from these compounds revealed the relative stereochemistry of solandelactone E diacetate to be 7R*, 8R*, 10R*, 11S* and solandelactone F diacetate to be 7R*, 8R*, 10R*, 11R*. These assignments are inconsistent with Shin’s original drawings that depict the stereochemistry at C(11) to be 11R* for solandelactone E and 11S* for solandelactone F (see Figure 2.4). The isolation paper features additional drawings of solandelactone E and F diacetate which are consistent with the text and feature an 11S* stereochemistry for solandelactone E diacetate and an 11R* stereochemistry for solandelactone F diacetate thus prompting us to ask the question, is the C(11) stereochemistry incorrectly depicted in the paper between the two series of solandelactones?
146 In an e-mail correspondence with Professor Shin, now at Seoul National University, he acknowledged that there is a discrepancy between the C(11) stereochemistry in the Figure depicting the gross stereochemistry of solandelactones A-G and what is written in the text. He noted that the numbering and lettering of these compounds were changed several times during their three dimensional NMR work. It is standard practice that compounds having an R* configuration have a higher priority on their name than those having the S* configuration at the same stereocenter. He therefore speculated that after he drew the structures, he put the alphabetical names from 11R* to 11S* without consulting the structures elucidated from the NMR data. He concurred that the correct stereochemistry for solandelactones A, C, E, and G should be 11S* and solandelactones B. D, F and H are 11R* (Figure 2.5). In addition, he sent us a hard copy of the NMR data he obtained from natural solandelactone E and F. The 1H and 13C NMR data from the synthetic solandelactone E, we prepared was consistent with the 1H and 13C NMR spectra Professor Shin sent us from natural solandelactone E. Combined, these factors provide strong evidence that the C(11) stereochemistry depicted in the isolation paper is inverted between the two series of solandelactones and should be corrected to C(11)S* for solandelactones A, C, E, and G and C(11)R* for solandelactones B, D, F and H (Figure 2.X).
Figure 2.5. Corrected structures of solandelactone A-H.
5 4 5 4
14 8 7 8 20 H 1 20 H 19 HO 9O 19 HO 9O (S) O (R) O 10 H 10 H OH OH Solandelactone A Solandelactone B Solandelactone C U19, 20 Solandelactone D U19, 20 Solandelactone E U 4, 5 Solandelactone F U 4, 5 Solandelactone G U19, 20, U4,5 Solandelactone H U19, 20, U4,5
147 With the endgame complete, it is tempting to look past the problematic portions of a body of work, especially when it is your own. In our total synthesis of solandelactone E (1.197), there are two weak transformations. The first is the nucleophilic opening of the cyclopropyl epoxide 2.100 (Scheme 2.63). Since we have been unable to successfully bring in the required five carbon side chain in the correct oxidation state, a stepwise deprotection and oxidation was necessary. Since opening the epoxide with pentynoic acid dianion was difficult (see Scheme 2.46), a viable alternative would be to bring in this side chain as its TBDPS ester to give 2.112. This is an alternative still being examined.
Scheme 2.63
OTHP
n-BuLi, BF .OEt, 3 H OH THF, -78 °C, 45% OTHP
O TBSO H H OTBS
TBSO H 2.121 OTBS O O 2.100 OTBDPS H OH OTBDPS n-BuLi, BF .OEt, 3 TBSO H THF, -78 °C, 5% OTBS 2.112
The second weakness is the lack of regiocontrol when opening the benzylidene acetal of 2.79. In our model system (see Scheme 2.40), a similar acetal was opened with DIBAL with good regioselectivity (4:1), but due to the lactone, the number of potential reductants was limited in the real system. The modest selectivity we obtained was partially compensated for by the fact the regioisomers could be separated by silica gel chromatography, and the incorrect, minor regioisomer 2.130 could be easily recycled to starting acetal 2.79 when treated with DDQ (Scheme 2.64). 148 Scheme 2.64
NaCNBH3, TFA, THF, 0 °C, H H O 92%, 1:1.2 (2.130:2.80) O O O O H HO H O OPMB 2.79 2.80
MeO DDQ
H H O HO O O O PMBO H H OH OH 2.130 Solandelactone E (1.197)
3.3 APPLICATIONS
Cyclopropane and lactone containing oxylipins are thought to be derived from an aberrant cyclization in prostaglandin biosynthesis.5-8 Prostaglandins are known to mediate a variety of strong physiological effects including muscular constriction, inflammation, calcium movement, hormone regulation and cell growth control. It is thus surprising that the biological potential of these cyclopropane and lactone containing oxylipins has not been thoroughly explored. By exploiting their high degree of structural similarity, we were able to develop a synthetic approach toward the solandelactone oxylipins that was not only elegant but also flexible enough to access the congeneric halicholactone and constanolactone and their analogues. Due to the convergent nature of this approach, the variables that can be easily modified include the absolute configuration of the cyclopropane ring, relative and
149 absolute stereochemistry of the three C-O stereocenters, size of the lactone and the length and functionality of the left-hand side chain.
Scheme 2.65
H H H HO O O HO O HO O O H H H O OH OH OH Solandelactone E (1.197) Constanolactone A (1.103) Neohalicholactone (1.27)
* H O HO OH * H **HO H O O OH OH 2.135 2.136 1.99
O H * OH * H * HO * H O O OH 2.137 1.138
For example, diene 2.22 can be viewed as a common intermediate en-route to halicholactone (1.26) and neohalicholactone (1.27) because diol 2.52 has the appropriate stereochemistry at C(11) and about the cyclopropane ring found in these oxylipins (Scheme 2.66). A caveat to this assertion is that the relative stereochemistry of 2.52 at C(8) is opposite of that found in the halicholactones and would therefore require an inversion at some point in the synthesis. This inversion could easily be accomplished on cyclopropyl alcohol 2.139 which would be formed after epoxide 2.138 is opened with THP-protected hexynol (Scheme 2.67). A Mitsunobu inversion123 of the alcohol in 2.139
with acetic acid would provide acetate 2.140, which has the appropriate stereochemistry to access halicholactone and neohalicholactone (1.26 and 1.27). 150 Scheme 2.66
EtO O O
AD-mix ß H O H OH O 11 11 O HO H H O OH OH H O 2.51 Solandelactones A,C,E,G O H EtO O OEt O 2.22 8 AD-mix α H O H OH O 12 HO H H O OH OH 2.52 Solandelactones B,D,F,H
H 8 HO O 12 H O OH Halicholactone (1.26) Neohalicholactone ∆17,18 (1.27)
Scheme 2.67
H 8 O H 8 OTHP OH OTHP AcOH, Ph3P, DEAD 12 TBSO H n-BuLi, BF3·OEt2 TBSO H OTBS OTBS 2.138 2.139
H 8 H 8 OAc OTHP HO O 12 TBSO H H O OTBS OH 2.140 Halicholactone (1.26) Neohalicholactone ∆17,18 (1.27)
Constanolactones A-D (1.103-1.106) have a stereochemistry about their cyclopropane ring opposite that of the solandelactones and halicholactones. Hence, we 151 envision that cyclopropane 2.141, which possesses the correct absolute stereochemistry for the cyclopropane found in the constanolactones, could be conveniently obtained simply by beginning with L-glyceraldehyde acetonide (1.138) instead of D- glyceraldehyde acetonide (1.99) (Scheme 2.68).245 Sharpless AD of 2.141 would provide diastereomeric diols 2.142 and 2.143, and these intermediates could be used to access either C(9) epimer of the constanolactones. In this case, the C(5) stereochemistry can be corrected after epoxide opening as demonstrated in Scheme 2.66, or alternatively by using an intramolecular Mitsunobu reaction to form the lactone (Scheme 2.69)74
Scheme 2.68
O
H O O
1.138 EtO O O H 5 H 5 AD-mix ß O HO O O
9 9 O HO H H OH OH H O 2.142 Constanolactone A (1.103) O H OEt EtO O O 2.141 AD-mix α H 55H O HO O O
9 9 HO H H OH OH 2.143 Constanolactone B (1.104)
152 Scheme 2.69
O
OH H 5 H OH Ph3P, DEAD O O
9 TBSO H TBSO H OTBS OTBS 2.144 2.145
H 5 HO O O
9 H OH Constanolactone B (1.104)
3.4 CONCLUSION
In summary, a stereocontrolled approach to the elaborate skeleton of the solandelactone oxylipins culminating in the total synthesis of solandelactone E (1.197) in
26 steps and 0.7% overall yield from commercially available D-glyceraldehyde acetonide 1.99 has been successfully developed and executed (Scheme 2.70). This innovative route can be easily adapted to gain access to other oxylipins of differing carboskeletal framework. Highlights of the synthesis include a novel diastereoselective, acetal directed cyclopropanation of an electron deficient olefin, a diastereoselective asymmetric dihydroxylation, and a stereoselective [2, 3]-sigmatropic rearrangement of a chiral selenoxide intermediate. During the course of our work on the solandelactone oxylipins, we have successfully developed a modified Wittig olefination that gives good to excellent E- selectivity on α-alkoxy aldehydes and sugar lactols. We have demonstrated that high degrees of regioselectivity (8:1) can be obtained from the reductive cleavage of
benzylidene acetals using TIBA/NaCNBH3 in CH2Cl2. These conditions are superior to
153 the traditionally used reagent, DIBAL, due to NaCNBH3’s tolerance of a wide variety of functional groups which could otherwise be reduced.220 Lastly, we demonstrated that alkynyl boranes containing TBDPS-silyl esters can be used to open epoxides to furnish the corresponding β-hydroxy acetylenic esters, or acids when quenched with TBAF, in high yields. These conditions can be used to replace the more traditional approach whereby an alkynyl dianion is stirred for days with the epoxide in neat HMPA, a difficult to remove carcinogenic solvent. We are currently in the process of exploring the use of this reaction in our total synthesis of solandelactone E (1.197).
154 Scheme 2.70
O O 1. EtO P(O)CH CHCHCO Et, 3 2 2 H O 1. DIBAL, CH2Cl2, 91% LDA, 89%, 10:1 (EE/ZE) 2. TPAP, NMO, 98% H O O 2. Et Zn, CH I , CH Cl , 72% H 3. EtO P(O)CH CHCHCO Et, O 2 2 2 2 2 3 2 2 OEt LDA, 91%, 10:1 (EE/ZE) 1.99 2.31
Br O O 1. AD-mix β, 78% 1. Heptyne, n-BuLi, Cu(I), 95% 2. TBSCl, Imid. 99% H 2. TFA/H2O, CH Cl , 82% H O O 2 2 3. DIBAL, CH Cl , 95% 3. NaH, Ts-Imid, 100% O 2 2 TBSO H H 4. CBr4, PPh3, 96% OEt OTBS 2.22 2.65
OH O H H 1. THP-pentynol, n-BuLi, BF3·OEt2, 45% OAc 2. Ac2O, Et3N, DMAP, 92% TBSO H TBSO H 3. TsOH, i-PrOH, 87% OTBS OTBS 4. Lindlar's catalyst, H2, quinoline, 94% 2.100 2.123
1. TBAF, 72% 1. SO3•Pyr, Et3N, DMSO, 85% H 2. Anisaldehyde dimethyl acetal 2. NaOCl2, 90% O TsOH, 80% O 3. K CO , MeOH, 95% TBSO H 2 3 3. TFA, NaCNBH3, 92% (1.2:1) 4. 2,4,6-trichlorobenzoylchloride OTBS Et3N, DMAP, 81% 2.128
H 1. o-NO2PhSeCN, Bu3P H HO O O 2. H2O2, Pyr. 56% (2 Steps) O O H HO H 3. DDQ, 72% OPMB OH 2.80 Solandelactone E (1.197)
155 Chapter 3: Experimental Procedures
3.1 GENERAL
Unless otherwise indicated, all starting materials and solvents were obtained from
commercial sources and used without purification. Tetrahydofuran (THF) and diethyl
ether (Et2O) were dried by passage through two columns of activated neutral alumina.
Methanol (MeOH), acetonitrile (CH3CN) and N,N-dimethylformamide (DMF) were dried by passage trough two columns of activated molecular sieves. Toluene was dried by sequential passage through a column of activated neutral alumina followed by a column of Q5 reactant. Ethylene glycol dimethyl ether, diisopropylamine (DIPA), and methylene chloride (CH2Cl2) were distilled from calcium hydride. Chlorotrimethylsilane
and titanium tetrachloride were distilled neat prior to use. Reactions involving air- or
moisture- sensitive reagents or intermediates were performed in flame-dried glassware
under dried nitrogen or argon. Removal of solvent or concentration under reduced
pressure indicates rotary-evaporation (30 mm Hg). Flash chromatography was performed
following the Still246 protocol with ICN Biomedical ICN-SILITech 32-63d silica gel with
the indicated solvents. Analytical TLC was performed with Merck-60 TLC plates and the
indicated solvents.
Proton (1H) and Carbon (13C) NMR spectra were obtained using a 400 MHz or
500MHz spectrometer as solutions in CD3CN, unless otherwise noted. Chemical shifts
are reported as parts per million (ppm, δ) and referenced to the residual protic solvent
156 13 (1.96 ppm) resonance of CD3CN and (118.2 ppm) for C unless otherwise noted.
Coupling constants were reported in hertz (Hz). Splitting patterns were designated as s, singlet; d, doublet; t, triplet; q, quartet; br, broad; m, multiplet; comp, complex multiplet, app, apparent. IR spectra were recorded as films or solutions (with solvent indicated) on sodium chloride plates.
3.2 COMPOUNDS: APPROACH 1
O OH
O OH O
2,2-Dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyran-6,7-diol (1.226). (JED 1-
204). *1.226 was prepared by a literature procedure that does not provide spectral
information.135 p-Toluenesulfonic acid (7.6 g, 40 mmol) was added to a solution of 2,2-
dimethoxypropane (62.4 g, 599 mmol) and L-arabinose (1.225) (30 g, 200 mmol) in DMF
(400 mL) at rt. Stirring continued for 3 h solid NaHCO3 (160 mg, 2.00 mmol) was added, and the reaction was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with EtOAc to give 35.9 g (94%) of 1.226 as a mixture (21:79) of the α and β epimer as a white solid: mp 87-89 °C; 1H NMR (500
MHz, d6-DMSO) α epimer: δ 6.56 (d, J = 6.4 Hz, 1 H), 5.07 (d, J = 5.0 Hz, 1 H), 4.20
(dd, J = 7.2, 6.4 Hz, 1 H), 4.09 (dt, J = 6.0, 2.2 Hz, 1 H), 3.92 (dd, J = 13.3, 2.2 Hz, 1 H),
157 3.86 (dd, J = 7.2, 6.0 Hz, 1 H), 3.65 (dd, J = 13.3, 2.2 Hz, 1 H), 3.18 (td, J = 7.2, 5.0 Hz,
1 H), 1.39 (s, 3 H), 1.25 (s, 3 H); β epimer: δ 6.27 (d, J = 5.8 Hz, 1 H), 4.86 (d, J = 7.0
Hz, 1 H), 4.83 (dd, J = 4.7, 3.2 Hz, 1 H), 4.09 (ddd, J = 4.7, 3.0, 1.3 Hz, 1 H), 3.99 (dd, J
= 7.0, 5.8 Hz, 1 H), 3.97 (dd, J = 12.9, 3.0 Hz, 1 H), 3.65 (dd, J = 12.9, 1.3 Hz, 1 H), 3.38
(td, J = 7.0, 3.2 Hz, 1 H), 1.38 (s, 3 H), 1.25 (s, 3 H).
O OMe 6 HO 8 13 9 12 10 11 O OH 14 O 15
4-Hydroxy-4-(5-hydroxymethyl-2,2-dimethyl-[1,3]dioxolan-4-yl)-but-2-enoic acid methyl ester (1.227). (JED 1-128). A 0.4 M solution of
tributyl(methoxycarbonylmethylene)phosphonium bromide (250 mL, 102.7 mmol) in
CH2Cl2 was washed with 1.0 M aqueous NaOH (2 x 50 mL), dried (MgSO4), and poured
into to a solution of 1.226 (15.4 g, 79.1 mmol) and benzoic acid (1.93 g, 15.8 mmol) in
CH2Cl2 (250 mL). The reaction was stirred for 24 h at rt, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography eluting with
hexanes/EtOAc (3:2) to give a mixture (20:1) of 1.227 to 1.228 as a pale yellow solid.
Trans-diol 1.227 was recrystallized from the mixture to give 16.2 g (83%) of 1.227 as a
single olefin isomer (white crystals from EtOAc): mp 115-117 °C; 1H NMR (400 MHz) δ
6.96 (dd, J = 15.3, 4.5 Hz, 1 H), 6.15 (dd, J = 15.3, 2.0 Hz, 1 H), 4.45 (ddd, J = 4.5, 3.6,
158 2.0 Hz, 1 H), 4.28 (dt, J = 6.9, 4.7 Hz, 1 H), 4.17 (dd, J = 6.9, 3.6 Hz, 1 H), 3.87 (dd, J =
11.9, 4.7 Hz, 1 H), 3.81 (dd, J = 11.9, 4.7 Hz, 1 H), 3.71 (s, 3 H), 2.96 (br. s, 2 H), 1.49
(s, 3 H), 1.34 (s, 3 H); 13C-NMR (100 MHz) δ 166.7, 146.7, 121.8, 108.7, 78.4, 76.9,
68.8, 60.8, 51.7, 26.9, 24.7; IR 3558, 3380, 3024, 2992, 1720, 1438, 1384, 1313, 1276,
1163, 1038; mass spectrum (CI) m/z 247.1174 [C11H19O6 (M+1) requires 247.1182],
229, 215, 189 (base), 171, 157, 129.
NMR Assignments. 1H NMR (400 MHz) δ 6.96 (dd, J = 15.3, 4.5 Hz, 1 H, C9-
H), 6.15 (dd, J = 15.3, 2.0 Hz, 1 H, C8-H), 4.45 (ddd, J = 4.5, 3.6, 2.0 Hz, 1 H, C10-H),
4.28 (dt, J = 6.9, 4.7 Hz, 1 H, C12-H), 4.17 (dd, J = 6.9, 3.6 Hz, 1 H, C11-H), 3.87 (dd, J
= 11.9, 4.7 Hz, 1 H, C13-H), 3.81 (dd, J = 11.9, 4.7 Hz, 1 H, C13-H), 3.71 (s, 3 H, C6-
3H), 2.96 (br. s, 2 H, OH), 1.49 (s, 3 H, C15-H), 1.34 (s, 3 H, C15-H); 13C-NMR (100
MHz) δ 166.7 (C7), 146.7 (C9), 121.8 (C8), 108.7 (C14), 78.4 (C11), 76.9 (C12), 68.8
(C10), 60.8 (C13), 51.7 (C6), 26.9 (C15), 24.7 (C15).
HO 13 O 12 10 11 O O H 14 8 O 15 OMe 6
3-(6-Hydroxy-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-acrylic acid methyl ester (1.229). (JED 2-68). DMSO (0.66 mL, 9.44 mmol) was added to a stirred solution of oxalyl chloride (0.54 mL, 6.29 mmol) in CH2Cl2 (50 mL) at –78 °C.
Stirring continued for 15 min, a solution of diol 1.227 (1.55g, 6.29 mmol) in CH2Cl2 (50
159 mL) was quickly added by syringe. Stirring continued for 15 min, Et3N (2.63 mL, 9.44
mmol) was injected. The ice bath was removed and the reaction was stirred at ambient
temperature for 30 min whereupon a solution of 1 M aqueous HCl (20 mL) was added.
The organic phase was separated, and the aqueous layer was extracted with CH2Cl2 (2 x
20 mL). The combined organic extracts were washed with saturated aqueous NaHCO3
(30 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was
purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 1.00 g (65%)
of the title compound 1.229, a single epimer of unknown C(13) configuration, as a white
solid: mp 119 °C; 1H NMR (400 MHz) δ 6.91 (dd, J = 15.7, 5.2 Hz, 1 H), 6.08 (dd, J =
15.7, 1.6 Hz, 1 H), 5.38 (s, 1 H), 4.76 (dd, J = 5.7, 3.8 Hz, 1 H), 4.71 (dt, J = 5.2, 1.4 Hz,
1 H), 4.59 (d, J = 5.7 Hz, 1 H), 3.84 (s, 3 H), 3.69 (br, 1 H), 1.36 (s, 3 H) 1.31 (s, 3 H);
13C NMR (100 MHz) δ 166.6, 141.6, 122.5, 113.0, 100.9, 85.6, 81.0, 79.0, 51.7, 25.9,
24.8; IR 3597, 3377, 3024, 2953, 1721, 1438, 1375, 1282, 1097; mass spectrum (CI) m/z
245.1020 (base) [C11H17O6 (M+1) requires 245.1025], 227, 213, 187, 169.
NMR Assignments. 1H NMR (400 MHz) δ 6.91 (dd, J = 15.7, 5.2 Hz, 1 H, C9-
H), 6.08 (dd, J = 15.7, 1.6 Hz, 1 H, C8-H), 5.38 (s, 1 H, C13-H), 4.76 (dd, J = 5.7, 3.8
Hz, 1 H, C10-H), 4.71 (dt, J = 5.2, 1.4 Hz, 1 H, C11-H), 4.59 (d, J = 5.7 Hz, 1 H, C12-
H), 3.84 (br, 1 H, OH), 3.69 (s, 3 H, C6-3H), 1.36 (s, 3 H, C15-3H) 1.31 (s, 3 H, C15-
3H); 13C NMR (100 MHz) δ 166.6 (C7), 141.6 (C9), 122.5 (C8), 113.0 (C14), 100.9
(C13), 85.6 (C12), 81.0 (C11), 79.0 (C10), 51.7 (C6), 25.9 (C15), 24.8 (C15).
160 13 O 12 10 11 O O OH 14 8 O 15 OMe 6
3-(4-Hydroxy-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-acrylic
acid methyl ester. (1.230). (JED 2-68) Lactol 1.230 was isolated as a minor product in
the Swern oxidation of diol 1.227; 1H (400 MHz) δ 6.95 (d, J = 15.8 Hz, 1 H), 6.21 (d, J
= 15.8 Hz, 1 H), 4.88 (dd, J = 5.8, 3.2 Hz, 1 H), 4.49 (d, J = 5.8 Hz, 1 H), 4.06 (dd, J =
10.4, 3.6 Hz, 1 H), 4.02 (d, J = 10.4 Hz, 1 H), 3.73 (s, 3 H), 2.85 (s, 1 H), 1.43 (s, 3 H),
1.27 (s, 3 H); 13C (100 MHz) δ 166.7, 144.8, 123.4, 113.2, 104.8, 86.7, 80.9, 72.1, 52.1,
26.5, 25.0; IR 3343, 2986, 1724, 1315, 1175, 1000, 858 cm-1; MS (CI) m/z 245.1026
[C11H17O6 (M+1) requires 245.1025] 227, 213, 187 (base) 169, 154.
NMR Assignments: 1H (400 MHz) δ 6.95 (d, J = 15.8 Hz, 1 H, C9-H), 6.21 (d,
J = 15.8 Hz, 1 H, C8-H), 4.88 (dd, J = 5.8, 3.2 Hz, 1 H, C11-H), 4.49 (d, J = 5.8 Hz, 1 H,
C12-H), 4.06 (dd, J = 10.4, 3.6 Hz, 1 H, C13-H), 4.02 (d, J = 10.4 Hz, 1 H, C13-H), 3.73
(s, 3 H, C6-3H), 2.85 (s, 1 H, OH), 1.43 (s, 3 H, C15-H), 1.27 (s, 3 H, C15-H); 13C (100
MHz) δ 166.7 (C7), 144.8 (C9), 123.4 (C8), 113.2 (C10), 104.8 (C14), 86.7 (C11), 80.9
(C12), 72.1 (C13), 52.1 (C6), 26.5 (C15), 25.0 (C15).
161 16 5 MeO O O OMe 15 6
13 8
11 O OH 17 18 O
4-Hydroxy-4-[5-(2-methoxycarbonyl-vinyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-
but-2-enoic acid methyl ester (1.223). (JED 1-178). A 0.27 M solution of
tributyl(methoxycarbonylmethylene)phosphonium bromide (30 mL, 8.17 mmol) in
CH2Cl2 was washed with 1.0 M aqueous NaOH (3 x 10 mL), dried (MgSO4) and poured
into to a refluxing solution of 1.229 (1.33 g, 5.45 mmol) and benzoic acid (132 mg, 1.09
mmol) in CH2Cl2 (30 mL). Stirring continued for 2 h the reaction was concentrated
under reduced pressure. The residue was purified by flash silica gel chromatography
eluting with hexanes/EtOAc (5:1) to give 1.30 g (80%) of diester 1.223 as a pale yellow
solid: mp 84-86 °C; 1H NMR (500 MHz) δ = 7.00 (dd, J = 15.7, 6.3 Hz, 1 H), 6.86 (dd, J
= 15.7, 4.7 Hz, 1 H), 6.15 (dd, J = 15.7, 1.5 Hz, 1 H), 6.14 (dd, J = 15.7, 1.2 Hz, 1 H),
4.81 (ddd, J = 6.3, 1.5 Hz, 1 H), 4.26-4.22 (comp, 2 H), 3.76 (s, 3 H), 3.75 (s, 3 H), 2.20
(br. s, 1 H), 1.56 (s, 3 H) 1.40 (s, 3 H); 13C NMR (100 MHz) δ 166.4, 166.0, 145.5,
142.5, 123.4, 122.6, 109.8, 79.9, 76.2, 69.1, 51.8, 51.7, 27.0, 24.8; IR 3560, 3025, 2994,
1721, 1662, 1438, 1313, 1282, 1174, 1055 cm-1; mass spectrum (CI) m/z 301.1292 (base)
[C14H21O7 requires 301.1287 (M+1)], 269, 261, 243, 185.
NMR Assignments. 1H NMR (500 MHz) δ = 7.00 (dd, J = 15.7, 6.3 Hz, 1 H,
C13-H), 6.86 (dd, J = 15.7, 4.7 Hz, 1 H, C8-H), 6.15 (dd, J = 15.7, 1.5 Hz, 1 H, C14-H),
162 6.14 (dd, J = 15.7, 1.2 Hz, 1 H, C7-H), 4.81 (ddd, J = 6.3, 1.5 Hz, 1 H, C12-H), 4.26-4.22
(comp, 2 H, C11-H & C10-H), 3.76 (s, 3 H, C5-3H), 3.75 (s, 3 H, C16-3H), 2.20 (br s, 1
H, OH), 1.56 (s, 3 H, C18-3H) 1.40 (s, 3 H, C18-3H); 13C NMR (100 MHz) δ 166.4 (C6),
166.0 (C5), 145.5 (C13), 142.5 (C8), 123.4 (C11), 122.6 (C7), 109.8 (C17), 79.9 (C11),
76.2 (C12), 69.1 (C8), 51.8 (C5), 51.7 (C16), 27.0 (C18), 24.8 (C18).
16 5 MeO O O OMe 15 6
13 8
11 O OH 17 18 O
4-Hydroxy-4-[5-(2-methoxycarbonyl-vinyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]- but-2-enoic acid methyl ester. (1.224). (JED 5-174). Amberlyst® 15 (30 mg) was added to a solution of diester 1.223 (10 mg, 0.033 mmol) and 4 Å molecular sieves (5 mg) in acetone (0.5 mL) at rt. The mixture was stirred for 5 h at rt, then the reaction was filtered through a plug of cotton, and the solvents were concentrated under reduced pressure. The residue was filtered through a plug of silica gel washing with hexanes/EtOAc (1:1) to provide 10 mg of 1.224 and 1.223 (100%) as a mixture (20:1) which could be separated by flash chromatography eluting with hexanes/EtOAc (6:1) to give 9.2 mg (92%) of 1.224 as a clear oil; 1H NMR (500 MHz) δ = 6.89 (dd, J = 15.7,
4.3 Hz, 1 H), 6.83 (dd, J = 15.7, 5.4 Hz, 1 H). 6.21 (dd, J = 15.7, 2.0 Hz, 1 H), 6.08 (dd, J
= 15.7, 1.7 Hz, 1 H), 4.60 (td, J = 4.3, 2.0, 1 H), 4.56 (ddd, J = 7.7, 5.4, 1.7 Hz, 1 H),
163 3.88 (dd, J = 7.7, 4.3 Hz, dd), 3.76 (s, 3 H), 3.74 (s, 3 H), 1.58 (br, 1 H), 1.48 (s, 3 H),
1.43 (s, 3 H); 13C-NMR (125 MHz) δ 166.4, 166.2, 144.8, 144.2, 122.5, 122.0, 110.5,
81.9, 75.9, 70.1, 51.7, 51.7, 26.9, 26.7; IR (neat) 3428, 3025, 1721, 1662, 1437, 1281,
-1 1173, 1064 cm ; MS (CI) m/z 301.1278 (base) [C14H21O7 (M+1) requires 301.1287],
269, 243, 237, 211.
NMR Assignments: 1H NMR (500 MHz) δ =6.89 (dd, J = 15.7, 4.3 Hz, 1 H,
C13-H), 6.83 (dd, J = 15.7, 5.4 Hz, 1 H, C8-H). 6.21 (dd, J = 15.7, 2.0 Hz, 1 H, C14-H),
6.08 (dd, J = 15.7, 1.7 Hz, 1 H, C6-H), 4.60 (td, J = 4.3, 2.0, 1 H, C12-H), 4.56 (ddd, J =
7.7, 5.4, 1.7 Hz, 1 H, C10-H), 3.88 (dd, J = 7.7, 4.3 Hz, dd, C11-H), 3.76 (s, 3 H, OMe),
3.74 (s, 3 H, OMe), 1.58 (br, 1 H, OH), 1.48 (s, 3 H, C18-3H), 1.43 (s, 3 H, C18-3H);
13C-NMR (125 MHz) δ 166.4 (C15), 166.2 (C6), 144.8 (C13), 144.2 (C8), 122.5 (C14),
122.0 (C7), 110.5 (C17), 81.9 (C11), 75.9 (C12), 70.1 (C10), 51.7 (C5), 51.7 (C16), 26.9
(C18), 26.7 (C18).
O OH
O O
2,2-Dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyran-6-ol (2.1). (JED 2-211).
*This compound was first reported by Corey’s total synthesis of leukotriene B,115 however no experimental details were provided and the spectral data for this compound is reported elsewhere.247 Pyridinium p-tolunesulfonate (77 mg, 0.30 mmol) was added to a
164 stirred solution of 2-deoxy-D-ribose (1.84 g, 14.91 mmol) and 2-methoxypropene (1.57
mL, 16.40 mL) in EtOAc (150 mL) at rt. The mixture was stirred for 3 h whereupon
saturated aqueous NaHCO3 (30 mL) was added. The layers were separated and the
organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue
was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to provide 1.24
g (52 %) of the title compound as a syrup and mixture of anomers (1α:4β).
O OMe 1 3 HO 8
6 O 9 O 10
4-(5-Hydroxymethyl-2,2-dimethyl-[1,3]dioxolan-4-yl)-but-2-enoic acid methyl
ester (2.2). (JED 2-181). A 0.18 M solution of
tributyl(methoxycarbonylmethylene)phosphonium bromide (25 mL, 4.39 mmol) in
CH2Cl2 was washed with 1.0 M aqueous NaOH (2 x 10 mL), dried (MgSO4) and poured
into a solution of 2.1 (510 mg, 2.93 mmol) and benzoic acid (35 mg, 0.29 mmol) in
CH2Cl2 (25 mL) at rt then refluxed. Stirring continued for 2 h at reflux whereupon the
reaction was concentrated under reduced pressure. The residue was purified by flash
silica gel chromatography eluting with hexanes/EtOAc (2:1) to give 453 mg (67%) of
diester 2.2 as a pale yellow oil; 1H NMR (400 MHz) δ 6.95 (dt, J = 15.8, 6.8 Hz, 1H),
5.90 (dt, J = 15.8, 1.6 Hz, 1H), 4.26 (ddd, J = 8.8, 6.1, 4.8 Hz, 1H), 4.18 (app q, J = 6.4
165 Hz, 1H), 3.70 (s, 3H), 3.63 (app t, J = 5.8 Hz, 2H), 2.54 (dddd, J = 14.4, 8.7, 6.4, 1.6 Hz,
1 H), 2.45 (dddd, J = 14.4, 6.4, 4.8, 1.6 Hz, 1 H), 2.18 (br, 1H), 1.44 (s, 3H), 1.33 (s, 3H);
13C (100 MHz) δ 166.6, 144.8, 123.1, 108.5, 77.5, 75.3, 61.4, 51.5, 32.4, 27.9, 25.3; IR
(neat) 3424, 2929, 1720, 1657, 1436, 1216, 1165, 1037 cm-1; MS (CI) m/z 231.1239
(base) [C11H19O5 requires 231.1233 (M+1)], 173.
NMR Assignments. 1H NMR (400 MHz) δ 6.95 (dt, J = 15.8, 6.8 Hz, 1H, C9-
H), 5.90 (dt, J = 15.8, 1.6 Hz, 1H, C8-H), 4.26 (ddd, J = 8.8, 6.1, 4.8 Hz, 1H, C12-H),
4.18 (app q, J = 6.4 Hz, 1H, C11-H), 3.70 (s, 3H, C6-3H), 3.63 (app t, J = 5.8 Hz, 2H,
C13-2H), 2.54 (dddd, J = 14.4, 8.7, 6.4, 1.6 Hz, 1 H, C10-H), 2.45 (dddd, J = 14.4, 6.4,
4.8, 1.6 Hz, 1 H, C10-H), 2.18 (br, 1H, OH), 1.44 (s, 3H, C15-3H), 1.33 (s, 3H, C15-3H);
13C (100 MHz) δ 166.6 (C7), 144.8 (C9), 123.1 (C8), 108.5 (C14), 77.5 (C12), 75.3
(C11), 61.4 (C13), 51.5 (C6), 32.4 (C10), 27.9 (C15), 25.3 (C15).
O OMe 6 15 8 O 13 14 11 O OH
5-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-5-hydroxypent-2-enoic acid methyl ester
(2.3). (JED 2-192). p-Toluenesulfonic acid (0.039 g, 0.20 mmol) was added to a
solution of acetonide 2.2 (4.7 g, 20.4 mmol) in acetone (100 mL) at rt. The solution was stirred for 1 h, then NaHCO3 (~ 2 g) was added, and stirring was continued for an
additional 15 min. The reaction was concentrated under reduced pressure, and the
166 residue was purified using flash silica gel column chromatography eluting with
hexanes/EtOAc (2:1) to provide 2.93 g (62%) of the title compound 2.3 as a clear oil; 1H
NMR (300 MHz) δ 6.92 (dt, J = 15.6, 7.2 Hz, 1H), 5.85 (dt, J = 15.6, 1.4 Hz, 1H), 3.93
(dd, J = 11.3, 6.2 Hz, 1 H), 3.89 (dd, J = 11.3, 5.0 Hz, 1 H), 3.83 (dd, J = 6.2, 5.0 Hz, 1
H), 3.73-3.68 (m, 1H), 3.63 (s, 3H), 2.90 (br-d, J = 3.6 Hz, 1H), 2.42 (dddd, J = 15.2, 7.2,
3.9, 1.4 Hz, 1H), 2.32 (dddd, J = 15.2, 7.2, 7.2, 1.4 Hz, 1H), 1.32 (s, 3H), 1.26 (s, 3H);
13C (75 MHz) δ 166.7, 145.1, 123.3, 109.2, 78.0, 70.4, 65.5, 51.4, 36.0, 26.4, 25.0; IR
(neat) 3464, 2987, 1723, 1657, 1436, 1371, 1214, 1063 cm-1; MS (CI) m/z 231.1235
(base) [C11H19O5 requires 231.1233 (M+1)], 199, 173.
NMR Assignments. 1H NMR (300 MHz) δ 6.92 (dt, J = 15.6, 7.2 Hz, 1H, C7-
H), 5.85 (dt, J = 15.6, 1.4 Hz, 1H, C8-H), 3.93 (dd, J = 11.3, 6.2 Hz, 1 H, C13-H), 3.89
(dd, J = 11.3, 5.0 Hz, 1 H, C13-H), 3.83 (dd, J = 6.2, 5.0 Hz, 1 H, C12-H), 3.73-3.68 (m,
1H, C11-H), 3.63 (s, 3H, C6-3H), 2.90 (br-d, J = 3.6 Hz, 1H, OH), 2.42 (dddd, J = 15.2,
7.2, 3.9, 1.4 Hz, 1H, C10-H), 2.32 (dddd, J = 15.2, 7.2, 7.2, 1.4 Hz, 1H, C10-H), 1.32 (s,
3H, C15-3H), 1.26 (s, 3H, C15-3H); 13C (75 MHz) δ 166.7 (C7), 145.1 (C9), 123.3 (C8),
109.2 (C14), 78.0 C(12), 70.4 (C11), 65.5 (C13), 51.4 (C6), 36.0 (C10), 26.4 (C15), 25.0
(C15).
167 16 5 MeO O O OMe 15 6
13 8
11 20 O Se 17 18 O 22
(4R,4'S,5'S)-trans,trans-Methyl-4-{5-[2-(methoxycarbonyl)ethenyl]-2,2- dimethyl-1,3-dioxolane-4-yl}-4-phenylseleno-2-butenoate (1.250). (JED 1-249).
Freshly distilled Bu3P (36 mL, 0.145 mmol) was added dropwise over 5 min to a solution
of diester 1.223 (1.26 g, 4.2 mmol) and freshly distilled phenyl selenocyanate (0.51 mL,
4.2 mmol) in toluene (43 mL) at -20 °C. Stirring continued for 30 min, and the crude reaction mixture was poured on a plug of silica gel and the column was eluted with hexanes/EtOAc (1:0 to 4:1) to give 810 mg (44%) of selenide 1.250 as a bright yellow oil. 1H NMR (300 MHz) δ 7.50-7.47 (comp, 2 H), 7.36-7.26 (comp, 3 H), 7.12 (dd, J =
15.6, 6.2 Hz, 1 H), 6.95 (dd, J = 15.5, 9.5 Hz, 1 H), 6.19 (dd, J = 15.5, 1.5 Hz, 1 H), 5.28
(dd, J = 15.6, 0.6 Hz, 1 H), 4.92 (app td, J = 6.2, 1.5 Hz, 1 H), 4.42 (dd, J = 9.5, 6.2, 1 H),
3.76 (s, 3 H), 3.70 (s, 3 H), 3.53 (app t, J = 9.5 Hz, 1 H), 1.50 (s, 3 H), 1.37 (s, 3 H); 13C
NMR (75 MHz) δ 166.4, 166.2, 144.3, 142.7, 136.6, 129.2, 129.1, 126.1, 123.7, 120.1,
109.9, 78.6, 77.4, 51.7, 51.5, 44.8, 27.6, 25.3; IR 3054, 2987, 2306, 2254, 1720, 1438,
-1 1422, 1264, 908 cm ; MS (CI) m/z 441.0806 [C20H25O6Se requires 441.0816 (M+1)],
409, 597 (M + PhSe), 383 (base), 351, 285, 227.
NMR Assignments. 1H NMR (300 MHz) δ 7.50-7.47 (comp, 2 H, Ph), 7.36-7.26
(comp, 3 H, Ph), 7.12 (dd, J = 15.6, 6.2 Hz, 1 H, C13-H), 6.95 (dd, J = 15.5, 9.5 Hz, 1 H,
168 C8-H)), 6.19 (dd, J = 15.5, 1.5 Hz, 1 H, C14-H), 5.28 (dd, J = 15.6, 0.6 Hz, 1 H, C7-H),
4.92 (app td, J = 6.2, 1.5 Hz, 1 H, C12-H), 4.42 (dd, J = 9.5, 6.2, 1 H, C11-H), 3.76 (s, 3
H, C16-3H), 3.70 (s, 3 H, C5-3H), 3.53 (app t, J = 9.5 Hz, 1 H, C10-H), 1.50 (s, 3 H,
C18-3H), 1.37 (s, 3 H, C18-3H); 13C NMR (75 MHz) δ 166.4 (C6), 166.2 (C15), 144.3
C(13), 142.7 (C8), 136.6 (C20), 129.2 C(21), 129.1 C(22), 126.1 (C19), 123.7 (C14),
120.1 (C7), 109.9 (C17), 78.6 (C12), 77.4 (C11), 51.7 (C5), 51.5 (C16), 44.8 (C10), 27.6
(C18), 25.3 (C18).
16 5 MeO O O OMe 15 6 7 13 8 OH 11 O 17 18 O
(2S,4'R,5'S)-trans, trans-Methyl-2-hydroxy-4-{5-[2-(methoxycarbonyl)
ethenyl] -2,2-dimethyl-1,3-dioxolane-4-yl}-3-butenoate (1.252). (JED 1-249). A 30% aqueous solution of H2O2 (4.7 mL) was added dropwise to a solution of the
phenylselenide 1.250 (810 mg, 4.2 mmol) and pyridine (0.70 mL, 8.65 mmol) in CH2Cl2
(84 mL) at 0 °C. Stirring continued for 1 h, a 2 M aqueous HCl (20 mL) was added, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2 x 5 mL), and
the combined organic extracts were washed with saturated aqueous NaHCO3 (5 mL),
dried (MgSO4), and concentrated under reduced pressure. The residue was purified by
flash chromatography eluting with hexanes/EtOAc (2:1) to give 560 mg (100%) of α-
169 hydroxy ester 1.252 as a clear oil; 1H NMR (500 MHz) δ 6.75 (ddd, J = 15.5, 4.3, 1.5 Hz,
1 H), 6.06 (dd, J = 15.5, 1.0 Hz, 1 H), 5.91 (ddd, J = 15.5, 5.2, 1.0 Hz, 1 H), 5.80 (dddd, J
= 15.5, 4.5, 4.0, 1.5 Hz, 1 H), 4.79-4.75 (comp, 2 H), 4.69 (dd, J = 5.0, 1.5 Hz, 1 H), 3.81
(s, 3 H), 3.75 (s, 3 H), 1.59 (br, 1 H), 1.55 (s, 3 H), 1.41 (s, 3 H); 13C NMR (75 MHz) δ
173.3, 166.2, 143.5, 130.5, 127.9, 122.6, 109.7, 78.1, 77.5, 70.5, 53.0, 51.7, 27.7, 25.4;
IR 3532, 3160, 2988, 2902, 2263, 1726, 1468, 1382, 1263, 910 cm-1; MS (CI) m/z
301.1290 [C14H21O7 requires 301.1287 (M+1)], 283, 275, 243 (base), 225, 169.
NMR Assignments. 1H NMR (500 MHz) δ 6.75 (ddd, J = 15.5, 4.3, 1.5 Hz, 1 H,
C13-H), 6.06 (dd, J = 15.5, 1.0 Hz, 1 H, C14-H), 5.91 (ddd, J = 15.5, 5.2, 1.0 Hz, 1 H),
5.80 (dddd, J = 15.5, 4.5, 4.0, 1.5 Hz, 1 H), 4.79-4.75 (comp, 2 H), 4.69 (dd, J = 5.0, 1.5
Hz, 1 H), 3.81 (s, 3 H, C16-3H), 3.75 (s, 3 H, C5-3H), 1.59 (br, 1 H, OH), 1.55 (s, 3 H,
C18-3H), 1.41 (s, 3 H, C18-3H); 13C NMR (75 MHz) δ 173.3 (C6), 166.2 (C15), 143.5
(C13), 130.5 (C8), 127.9 (C9), 122.6 (C14), 109.7 (C17), 78.1 (C11), 77.5 (C7), 70.5
(C12), 53.0 (C5), 51.7 (C16), 27.7 (C18), 25.4 (C18).
170 18 16 O OMe 6 Si O 8 13 9 12 10 11 O OH 14 O 15
4-[5-(tert-Butyl dimethyl silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-
4-hydroxy-but-2-enoic acid methyl ester (2.5) (JED 2-162). tert-Butyldimethylsilyl
chloride (1.84 g, 12.18 mmol) was added to diol 1.227 (3.0 g, 12.18 mmol) and imidazole
(1.20 g, 18.27 mmol) in anhydrous DMF (120 mL) at 0 °C. Stirring continued for 2 h, whereupon the ice bath was removed and stirring continued for an additional 12 h. The reaction was diluted with Et2O (300 mL) and sequentially washed with aqueous 1 M
NaOH (2 x 100 mL), water (2 x 100 mL), then dried (MgSO4) and concentrated under
reduced pressure. The residue was purified by flash chromatography eluting with
hexanes/EtOAc (5:1) to give 4.15 g (95%) of 2.5 as a tan oil; 1H NMR (500 MHz) δ =
6.98 (dd, J = 15.8, 4.0 Hz, 1 H), 6.07 (dd, J = 15.8, 4.0 Hz, 1 H), 4.44 (dtd, J = 6.0, 4.0,
2.0 Hz, 1 H), 4.11 (app dq, J = 6.5, 4.0 Hz, 1 H), 4.05 ( dd, J = 6.0, 4.5 Hz, 1 H), 3.82
(dd, J = 11.0, 8.0 Hz, 1 H), 3.65 (dd, J = 11.0, 4.0 Hz, 1 H), 3.60 (s, 3 H), 3.3 (d, J = 6.0
Hz, 1 H), 1.36 (s, 3 H), 1.23 (s, 3 H), 0.79 (s, 9 H), -0.01 (s, 3 H), -0.02 (s, 3 H); 13C-
NMR (125 MHz) δ 166.5, 147.1, 120.1, 108.2, 78.8, 76.8, 68.6, 61.3, 51.2, 26.9, 25.6,
18.0, -5.7, -5.8; IR (neat) 3484, 2932, 2858,1727, 1661, 1259, 1103, 838 cm-1; MS (CI) m/z 361.2061 [C17H33O6Si (M+1) requires 361.2046], 303 (base), 149.
171 NMR Assignments: 1H NMR (500 MHz) δ = 6.98 (dd, J = 15.8, 4.0 Hz, 1 H,
C9-H), 6.07 (dd, J = 15.8, 4.0 Hz, 1 H, C8-H), 4.44 (dtd, J = 6.0, 4.0, 2.0 Hz, 1 H, C10-
H), 4.11 (app dq, J = 6.5, 4.0 Hz, 1 H, C12-H), 4.05 ( dd, J = 6.0, 4.5 Hz, 1 H, C11-H),
3.82 (dd, J = 11.0, 8.0 Hz, 1 H, C13-H), 3.65 (dd, J = 11.0, 4.0 Hz, 1 H, C13-H), 3.60 (s,
3 H, OMe), 3.3 (d, J = 6.0 Hz, 1 H, OH), 1.36 (s, 3 H, C15-3H), 1.23 (s, 3 H C15-3H),
0.79 (s, 9 H, C18-9H), -0.01 (s, 3 H, C16-3H), -0.02 (s, 3 H, C16-3H); 13C-NMR (125
MHz) δ 166.5 (C7), 147.1 (C9), 120.1 (C8), 108.2 (C14), 78.8 (C11), 76.8 (C12), 68.6
(C10), 61.3 (C13), 51.2 (C6), 26.9 (C15), 25.6 (C18), 24.7 (C15), 18.0 (C17), -5.7 (C16),
-5.8 (C16).
18 16 OH 6 Si O 8 13 9 12 10 11 O OH 14 O 15
1-[5-(tert-Butyl dimethyl silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-but-2-
ene-1,4-diol (2.6). (JED 2-172). Diisobutylaluminum hydride (1 M solution in CH2Cl2,
10.2 mL, 10.2 mmol) was added to a solution of α, β-unsaturated ester 2.5 in anhydrous
CH2Cl2 (30 mL) at -78 °C. Stirring continued for 2 h at -78 °C, then EtOAc (10 mL) and
saturated aqueous potassium sodium tartrate (20 mL) were added. The resultant
emulsion was stirred for 18 h until the layers were transparent. Once clear, the layers
were separated and the organic layer was dried (MgSO4) and concentrated under reduced
172 pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc
(1:1) to give 736 mg (72%) of allylic alcohol 2.6 as a clear oil.
2 16 18 O 6 7 Si 4 O 8 O 13 9 12 10 11 O OH 14 O 15
Benzoic acid 4-[5-(t-butyldimethylsilanyloxymethyl)-2,2-dimethyl-
[1,3]dioxolan-4-yl]-4-hydroxy-but-2-enyl ester (2.7). (JED 2-174). Et3N (1.87 mL,
13.3 mmol) was added to allylic diol 2.6 (736 mg, 2.22 mmol) and freshly distilled benzoyl chloride (0.77 mL, 6.65 mmol) in anhydrous CH2Cl2 (55 mL) at -40 °C. Stirring
continued for 5 h at -40 °C, the cold bath was removed, and 1 M HCl (25 mL) was added.
The layers were separated, and the organic layer was washed with saturated aqueous
NaHCO3 (25 mL), dried (MgSO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography eluting with hexanes/EtOAc (4:1) to
provide 600 mg (62%) of 2.7 as a clear oil; 1H NMR (500 MHz) δ 8.05-8.01 (m, 2 H),
7.53 (tt, J = 8.5, 1.5 Hz, 1 H), 7.43-7.39 (m, 2 H), 6.07-5.99 (comp, 2 H), 4.84-4.82
(comp, 2 H), 4.41 (app dt, J = 5.5, 4.1 Hz, 1 H), 4.19 (dt, J = 6.2, 3.5 Hz, 1 H), 4.12 (dd,
J = 6.2, 3.5 Hz, 1 H), 3.93 (dd, J = 11.0, 5.5 Hz, 1 H), 3.74 (dd, J = 11.0, 3.5 Hz, 1 H),
3.12 (d, J = 5.5 Hz, 1 H), 1.47 (s, 3 H), 1.35 (s, 3 H), 0.88 (s, 9 H), 0.07 (s, 6 H); 13C
(125 MHz) 166.3, 133.9, 132.9, 130.2, 129.7, 128.3, 125.6, 108.3, 79.6, 77.2, 69.3, 64.9, 173 61.7, 27.2, 25.8, 24.9, 18.3, -5.5; IR (neat) 3484, 2932, 2858, 1727, 1259, 1102, 837 cm-
1 ; MS (CI) m/z 437.2351 [C23H37O6Si (M+1) requires 437.2359], 379 (base), 315, 297,
257, 245, 219.
NMR Assignments. 1H NMR (500 MHz) δ 8.05-8.01 (m, 2 H, C4-2H), 7.53 (tt,
J = 8.5, 1.5 Hz, 1 H, C2-H), 7.43-7.39 (m, 2 H, C3-2H), 6.07-5.99 (comp, 2 H, C8-H &
C9-H), 4.84-4.82 (comp, 2 H, C7-2H), 4.41 (app dt, J = 5.5, 4.1 Hz, 1 H, C10-H), 4.19
(dt, J = 6.2, 3.5 Hz, 1 H, C12-H), 4.12 (dd, J = 6.2, 3.5 Hz, 1 H, C11-H), 3.93 (dd, J =
11.0, 5.5 Hz, 1 H, C13-H), 3.74 (dd, J = 11.0, 3.5 Hz, 1 H, C13-H), 3.12 (d, J = 5.5 Hz, 1
H, OH), 1.47 (s, 3 H, C15-3H), 1.35 (s, 3 H, C15-3H), 0.88 (s, 9 H, C18-3H), 0.07 (s, 6
H, C16-6H); 13C (125 MHz) 166.3 (C6), 133.9 (C9), 132.9 (C2), 130.29 (C5), 129.79
(C4), 128.39 (C5), 125.69 (C8), 108.39 (C14), 79.69 (C11), 77.29 (C12), 69.39 (C10),
64.99 (C7), 61.79 (C13), 27.29 (C15), 25.89 (C18), 24.99 (C15), 18.39 (C17), -5.59
(C16).
16 5 MeO O O OMe 15 6 H 7 13 OH 9 11 O H 17 18 O
3-{5-[2-(Hydroxy methoxycarbonyl methyl)cyclopropyl]-2, 2-dimethyl-[1,3]
dioxolan-4-yl}-acrylic acid methyl ester (1.258). (JED 2-76). Under a blanket of argon, diiodomethane (0.25 mL, 2.68 mmol) was added to a solution of α-hydroxy ester
174 1.252 (183 mg, 0.61 mmol) and diethylzinc (1 M solution in hexane, 0.91 mL, 0.91
mmol) in anhydrous CH2Cl2 (6.1 mL) at 0 °C in a screw cap vial equipped with a rubber
septum. Stirring continued for 30 min at 0 °C, whereupon the septum was quickly
removed and replaced with a screw cap. The joint was carefully wrapped with Teflon
tape then the vial was placed in a 65 °C oil bath. Stirring continued for 18 h, the vial was removed from heat and cooled to 0 °C. Once cool, the vessel was opened saturated aqueous NH4Cl (5 mL) was added. Stirring continued for 10 min whereupon the layers
were separated, and the organic layer was dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to provide 150 mg (78%) of the title compound 1.258 as a clear oil;
1H NMR (500 MHz) δ 6.96 (dd, J = 15.8, 5.5 Hz, 1 H), 6.10 (dd, J = 15.8, 1.5 Hz, 1 H),
4.68 (ddd, J = 6.6, 5.5, 1.5 Hz, 1 H), 4.04 (app t, J = 5.5 Hz, 1 H), 3.77 (s, 3 H), 3.72 (s, 3
H), 3.66 (dd, J = 8.8, 6.8 Hz, 1 H), 2.68 (d, J = 6.0 Hz, 1 H), 1.49 (s, 3 H), 1.31 (s, 3 H),
1.25 – 1.17 (m, 1 H), 1.04 (tt, J = 8.8, 5.2 Hz, 1 H), 0.66 (dt, J = 9.0, 5.2 Hz, 1 H), 0.36
(dt, J = 8.2, 5.2 Hz, 1 H); 13C NMR (125 MHz) δ 175.0, 166.5, 144.2, 122.0, 109.0, 81.4,
77.1, 69.5, 52.6, 51.6, 27.7, 25.3, 20.3, 15.1, 5.0; IR (neat) 3468, 1727, 1261, 1052 cm-1,
MS (CI) m/z 315.1444 [C15H23O7 (M+1) requires 315.1444] 307, 289, 154 (base), 136,
107.
NMR Assignments. 1H NMR (500 MHz) δ 6.96 (dd, J = 15.8, 5.5 Hz, 1 H, C13-
H), 6.10 (dd, J = 15.8, 1.5 Hz, 1 H, C14-H), 4.68 (ddd, J = 6.6, 5.5, 1.5 Hz, 1 H, C12-H),
4.04 (app t, J = 5.5 Hz, 1 H, C7-H), 3.77 (s, 3 H, C16-3H), 3.72 (s, 3 H, C5-3H), 3.66
(dd, J = 8.8, 6.8 Hz, 1 H, C11-H), 2.68 (d, J = 6.0 Hz, 1 H, OH), 1.49 (s, 3 H, C18-3H),
175 1.31 (s, 3 H, C18-3H), 1.25 – 1.17 (m, 1 H, C8-H), 1.04 (tt, J = 8.8, 5.2 Hz, 1 H, C10-H),
0.66 (dt, J = 9.0, 5.2 Hz, 1 H, C9-H), 0.36 (dt, J = 8.2, 5.2 Hz, 1 H, C9-H); 13C NMR
(125 MHz) δ 175.0 (C6), 166.5 (C15), 144.2 (C13), 122.0 (C14), 109.0 (C17), 81.4
(C11), 77.1 (C12), 69.5 (C7), 52.6 (C5), 51.6 (C16), 27.7 (C18), 25.3 (C18), 20.3 (C8),
15.1 (C10), 5.0 (C7).
16 5 MeO O O OMe 15 6 H 7 13 OH 9 11 O H 17 18 O
3-{5-[2-(Hydroxymethoxycarbonylmethyl)cyclopropyl]-2,2-dimethyl-
[1,3]dioxolan-4-yl} acrylic acid methyl ester (2.12). (JED 2-16). The above
compound was sometimes isolated as the minor diastereomer in the preparation of 1.258
above; 1H NMR (500 MHz) δ 6.96 (dd, J = 15.5, 5.4 Hz, 1 H), 6.11 (dd, J = 15.5, 1.6 Hz,
1 H), 4.68 (ddd, J = 6.6, 5.4, 1.5 Hz, 1 H), 3.74 (s, 3 H), 3.59 (dd, J = 8.7, 6.7 Hz, 1 H),
3.46 (d, 6.6 Hz, 1 H), 3.33 (s, 3 H), 1.60 (br, 1 H) 1.48 (s, 3 H), 1.31 (s, 3 H), 1.25 – 1.18
(m, 1 H), 0.99 (tt, J = 8.7, 5.2 Hz, 1H), 0.72 (dt, J = 8.9, 5.5 Hz, 1 H), 0.45 (dt, J = 8.9,
5.5 Hz); 13C NMR (125 MHz) δ 172.2, 166.5, 144.1, 122.0, 109.1, 81.6, 80.7, 77.1,
58.0, 51.6, 27.7, 25.3, 19.5, 15.6, 7.0.
NMR Assignments. 1H NMR (500 MHz) δ 6.96 (dd, J = 15.5, 5.4 Hz, 1 H, C13-
H), 6.11 (dd, J = 15.5, 1.6 Hz, 1 H, C14-H), 4.68 (ddd, J = 6.6, 5.4, 1.5 Hz, 1 H, C12-H),
3.74 (s, 3 H, C16-3H), 3.59 (dd, J = 8.7, 6.7 Hz, 1 H, C7-H), 3.46 (d, 6.6 Hz, 1 H, C11-
176 H), 3.33 (s, 3 H, C5-3H), 1.60 (br, 1 H, OH) 1.48 (s, 3 H, C18-3H), 1.31 (s, 3 H, C18-
3H), 1.21 – 1.18 (m, 1 H, C7-H), 0.99 (tt, J = 8.7, 5.2 Hz, 1H, C10-H), 0.72 (dt, J = 8.9,
5.5 Hz, 1 H, C9-H), 0.45 (dt, J = 8.9, 5.5 Hz, C9-H); 13C NMR (125 MHz) δ 172.2 (C6),
166.5 (C15), 144.1 (C13), 122.0 (C14), 109.1 (C17), 81.6 (C11), 80.7 (C12), 77.1 (C7),
58.0 (C5), 51.6 (C16), 27.7 (C18), 25.3 (C18), 19.5 (C8), 15.6 (C10), 7.0 (C9).
16 5 MeO O O OMe 15 6 7 H 19 13 O 9 Si 11 O H 21 17 18 O
3-(5-{2-[(tert-Butyldimethylsilanyloxy)methoxycarbonylmethyl]cyclopropyl}-
2,2-dimethyl-[1,3]dioxolan-4-yl) acrylic acid methyl ester. (2.15). (JED 2-77). tert- butyldimethylsilyl chloride (107 mg, 0.72 mmol) dissolved in anhydrous DMF (1.5 mL) was added to a solution of imidazole (30 mg, 0.96 mmol) and cyclopropane 1.258 (150 mg, 0.48 mmol) in anhydrous DMF (1.5 mL) at rt. Stirring continued for 15 h, the reaction was diluted with CH2Cl2 (10 mL) and the reaction mixture was washed with
H2O (2 x 15 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc
(6:1) to give 198 mg (97%) of 2.15 as a pale yellow oil; 1H NMR (400 MHz) δ 6.96 (dd,
J = 15.4, 5.4 Hz, 1 H), 6.10 (dd, J = 15.4, 1.4 Hz, 1 H), 4.70 (ddd, J = 6.8, 5.4, 1.4 Hz, 1
H), 4.15 (d, J = 4.4 Hz, 1 H), 3.73 (s, 3 H), 3.71 (s, 3 H), 3.66 (dd, J = 9.0, 6.8 Hz), 1.49
177 (s, 3 H), 1.32 (s, 3 H), 1.32-1.27 (m, 1 H) 0.94 (dt, J = 9,0, 5.0, 5.0 Hz, 1 H), 0.85 (s, 9
H), 0.74 (dt, J = 9.4, 4.8 Hz, 1 H), 0.32 (dt, 9.8, 5.2 Hz, 1 H), 0.03 (s, 3 H), 0.00 (s, 3 H);
13C NMR (100 MHz) δ 173.5, 166.3, 144.3, 121.7, 108.9, 81.5, 77.0, 70.5, 51.7, 51.5,
27.6, 25.5, 25.2, 20.5, 18.1, 15.0, 4.9, -5.0, -5.4.
NMR Assignments. 1H NMR (400 MHz) δ 6.96 (dd, J = 15.4, 5.4 Hz, 1 H, C13-
H), 6.10 (dd, J = 15.4, 1.4 Hz, 1 H, C14-H), 4.70 (ddd, J = 6.8, 5.4, 1.4 Hz, 1 H, C12-H),
4.15 (d, J = 4.4 Hz, 1 H, C15), 3.73 (s, 3 H, C16-3H), 3.71 (s, 3 H, C5-3H), 3.66 (dd, J =
9.0, 6.8 Hz, C11-H), 1.49 (s, 3 H, C18-H), 1.32 (s, 3 H, C18-H), 1.32-1.27 (m, 1 H) 0.94
(dtd, J = 9,0, 5.0, 5.0 Hz, 1 H, C10-H), 0.85 (s, 9 H, C21-9H), 0.74 (dt, J = 9.4, 4.8 Hz, 1
H, C9-H), 0.32 (dt, 9.8, 5.2 Hz, 1 H, C9-H), 0.03 (s, 3 H, C19-H), 0.00 (s, 3 H, C19-H);
13C NMR (100 MHz) δ 173.5 (C5), 166.3 (C16), 144.3 (C13), 121.7 (C14), 108.9 (C17),
81.5 (C11), 77.0 (C7), 70.5 (C12), 51.7 (C5), 51.5 (C16), 27.6 (C18), 25.5 (C21), 25.2
(C18), 20.5 (C8), 18.1 (C20), 15.0 (C10), 4.9 (C9), -5.0 (C19), -5.4 (C19).
HO OH 15 6 7 H 18 13 O 9 Si 11 O H 20 16 O 17
3-(5-{2-[1-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxy-ethyl]-cyclopropyl}-
2,2-dimethyl-[1,3]dioxolan-4-yl)-propenol. (JED 2-33). (2.16). A 1 M solution of
DIBAL-H (1.90 mL, 1.90 mmol) in CH2Cl2 was added to a solution of diester 2.15 (163 mg, 0.38 mmol) in CH2Cl2 at -78 °C. Stirring continued for 2 h at -78 °C and the ice 178 bath was removed. Stirring continued for an additional 1 h at rt whereupon EtOAc (2
mL), and saturated aqueous Rochelle salt (5 mL) was added and stirring continued for an
additional18h whereupon the layers were separated and the aqueous layer extracted with
EtOAc (2 x 10 mL). The combined organic layers were dried (MgSO4) and concentrated
under reduced pressure. The residue was purified by flash chromatography eluting with
hexanes/EtOAc (3:1) to give 98 mg (69%) of diol 2.16 as a clear oil; 1H NMR (400
MHz) δ 5.93 (dtd, J = 15.5, 5.5, 0.8 Hz, 1 H), 5.81 (ddt, 15.5, 7.2, 1.4 Hz, 1 H), 4.57 (app t, J = 6.8 Hz, 1 H), 4.17 (br, 2 H), 3.58-3.55 (m, 2 H), 3.46 (app dd, 9.0, 6.6 Hz, 1 H),
3.12 (dt, J = 11.6, 5.5 Hz, 1 H), 2.53 (br, 1 H), 1.73 (br, 1 H), 1.47 (s, 3 H), 1.31 (s, 3 H),
0.89-0.82 (comp, 11 H), 0.52 (dt, 11.2, 5.6 Hz, 1 H), 0.43 (dt, 10.8, 5.6 Hz,1 H), 0.04 (s,
3 H), 0.02 (s, 3 H); 13C NMR (100 MHz) δ 133.4, 126.8, 108.3, 82.7, 78.1, 75.6, 67.6,
62.8, 27.9, 25.8, 25.3, 21.1, 18.1, 16.4, 7.6, -4.2, -4.6.
NMR Assignments: 1H NMR (400 MHz) δ 5.93 (dtd, J = 15.5, 5.5, 0.8 Hz, 1 H),
5.81 (ddt, 15.5, 7.2, 1.4 Hz, 1 H), 4.57 (app t, J = 6.8 Hz, 1 H), 4.17 (br, 2 H, C15-2H),
3.58-3.55 (m, 2 H, C6-H), 3.46 (app dd, 9.0, 6.6 Hz, 1 H), 3.12 (dt, J = 11.6, 5.5 Hz, 1
H), 2.53 (br, 1 H), 1.73 (br, 1 H, OH), 1.47 (s, 3 H, C17-3H), 1.31 (s, 3 H, C17-3H),
0.89-0.82 (comp, 11 H, C8-H, C10-H & C20-9H), 0.52 (dt, 11.2, 5.6 Hz, 1 H, C9-H),
0.43 (dt, 10.8, 5.6 Hz,1 H, C9-H), 0.04 (s, 3 H, C18-3H), 0.02 (s, 3 H, C18-3H); 13C
NMR (100 MHz) δ 133.4 (C13), 126.8 (C14), 108.3 (C16), 82.7 (C11), 78.1 (C12), 75.6
(C7), 67.6 (C6), 62.8 (C15), 27.9 (C17), 25.8 (C20), 25.3 (C17), 21.1 (C10), 18.1 (C19),
16.4 (C8), 7.6 (C8), -4.2 (C18), -4.6 (C18).
179 16 O O 5 S S O O O 15 6 O 7 H 19 13 O 9 Si 11 O H 21 17 18 O
Methanesulfonic acid 2-(tert-butyldimethyl silanyloxy)-2-{2-[5-(3- methanesulfonyloxy-propenyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-cyclopropyl}-ethyl ester. (JED 2-96). (2.17). Et3N (0.22 mL, 1.58 mmol) was added to a solution of diol
2.16 (195 mg, 0.52 mmol) and methanesulfonyl chloride (0.12 mL, 1.58 mmol) in
CH2Cl2 (5 mL) at -20 °C. Stirring continued for 1 h at -20 °C whereupon saturated
aqueous NaHCO3 (3 mL) was added. The layers were separated, the organic layer was
dried (MgSO4) and concentrated under reduced pressure. The residue was purified by
flash chromatography eluting with hexanes/EtOAc (4:1) to give 171 mg (62%) of
dimesylate 2.17 as a yellow oil; 1H NMR (500 MHz) δ5.98 (dd, J = 15.5, 5.8 Hz, 1 H),
5.93 (dtd, J = 15.5, 5.0, 1.0 Hz, 1 H), 4.75 (d, J = 5.0 Hz, 2 H), 4.59 (app t, J = 5.8 Hz, 1
H), 4.22 (dd, J = 10.0, 4.0 Hz, 1 H), 4.08 (dd, J = 10.0, 7.0 Hz, 1 H), 3.65 (td, J = 7.0, 4.0
Hz, 1 H), 3.50 (dd, J = 9.0, 6.5 Hz, 1 H), 3.02 (s, 6 H), 1.50 (s, 3 H), 1.33 (s, 3 H), 0.98
(dtd, J = 11.0, 5.0 Hz, 1 H), 0.88 (s, 9 H), 0.85 (app dtd, J = 9.5, 5.0, 5.0 Hz, 1 H), 0.63
(dt, J = 10.1, 5.0 Hz, 1 H), 0.39 (dt, J = 10.1, 5.0 Hz, 1 H) 0.08 (s, 3 H), 0.07 (s, 3 H);
13C NMR (125 MHz) δ 133.4, 125.0, 108.6, 82.2, 77.4, 72.9, 71.2, 69.2, 38.1, 37.3, 27.9,
25.7, 25.3, 20.3, 18.0, 15.6, 6.4, -4.5, -4.5.
180 NMR Assignments: 1H NMR (500 MHz) δ5.98 (dd, J = 15.5, 5.8 Hz, 1 H, C13-
H), 5.93 (dtd, J = 15.5, 5.0 1.0 Hz, 1 H, C14-H), 4.75 (d, J = 5.0 Hz, 2 H, C15-2H), 4.59
(app t, J = 5.8 Hz, 1 H, C12-H), 4.22 (dd, J = 10.0, 4.0 Hz, 1 H, C6-H), 4.08 (dd, J =
10.0, 7.0 Hz, 1 H, C6-H), 3.65 (td, J = 7.0, 4.0 Hz, 1 H, C7-H), 3.50 (dd, J = 9.0, 6.5 Hz,
1 H, C11-H), 3.02 (s, 6 H, C5-3H & C16-3H), 1.50 (s, 3 H, C18-3H), 1.33 (s, 3 H, C18-
3H), 0.98 (dtd, J = 11.0, 5.0 Hz, 1 H, C10-H), 0.88 (s, 9 H, C21-9H), 0.85 (app dtd, J =
9.5, 5.0, 5.0 Hz, 1 H, C8-H), 0.63 (dt, J = 10.1, 5.0 Hz, 1 H, C9-H), 0.39 (dt, J = 10.1, 5.0
Hz, 1 H, C9-H) 0.08 (s, 3 H, C19-3H), 0.07 (s, 3 H, C19-3H); 13C NMR (125 MHz) δ
133.4 (C13), 125.0 (C14), 108.6 (C17), 82.2 (C11), 77.4 (C12), 72.9 (C7), 71.2 (C6),
69.2 (C15), 38.1 (C16), 37.3 (C5), 27.9 (C18), 25.7 (C21), 25.3 (C18), 20.3 (C8), 18.0
(C20), 15.6 (C10), 6.4 (C9), -4.5 (C19), -4.5 (C19).
3.3 COMPOUNDS: APPROACH 2
4 6 O 5 8 O 16 12 O 10 11 O
5-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-penta-2,4-dienoic acid ethyl ester (2.23).
Diene 2.23 is a known compound191 and was prepared according to a literature
procedure; 1H NMR (500 MHz) δ 7.19 (ddd, J = 15.5, 11.0, 1.0 Hz, 1 H), 6.35 (ddt, J =
181 15.5, 11.0, 1.0 Hz, 1 H), 5.99 (dd, J = 15.5, 6.6 Hz, 1 H), 5.84 (d, J = 15.5 Hz, 1 H), 4.54
(app dq, J = 6.6, 1.0 Hz, 1 H), 4.13 (q, J = 7.1 Hz, 2 H), 4.07 (dd, J = 8.0, 6.6 Hz, 1 H),
3.56 (dd, J = 8.0, 7.5 Hz, 1 H), 1.37 (s, 3 H), 1.33 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H); 13C
NMR (125 MHz) δ 166.5, 142.9, 138.8, 129.8, 122.4, 109.7, 75.9, 69.1, 60.2, 26.4, 25.7,
14.1; IR (neat) 2985, 1715, 1649, 1619, 1370, 1232, 1138, 1059, 1000, 857 cm-1; MS
(CI) m/z 227.1294 (base) [C12H19O4 (M+1) requires 227.1283] 201, 169.
NMR Assignments: 1H NMR (500 MHz) δ 7.19 (ddd, J = 15.5, 11.0, 1.0 Hz, 1 H, C11-
H), 6.35 (ddt, J = 15.5, 11.0, 1.0 Hz, 1 H, C10-H), 5.99 (dd, J = 15.5, 6.6 Hz, 1 H, C8-H),
5.84 (d, J = 15.5 Hz, 1 H, C12-H), 4.54 (app dq, J = 6.6, 1.0 Hz, 1 H, C7-H), 4.13 (q, J =
7.1 Hz, 2 H, C15-2H), 4.07 (dd, J = 8.0, 6.6 Hz, 1 H, C6-H), 3.56 (dd, J = 8.0, 7.5 Hz, 1
H, C6-H), 1.37 (s, 3 H, C4-3H), 1.33 (s, 3 H, C4-3H), 1.22 (t, J = 7.1 Hz, 3 H, C16-3H);
13C NMR (125 MHz) δ 166.5 (C13), 142.9 (C11), 138.8 (C8), 129.8 (C9), 122.4 (C12),
109.7 (C5), 75.9 (C7), 69.1 (C6), 60.2 (C15), 26.4 (C4), 25.7 (C4), 14.1 (C16).
4 6 O 5 H 8 O 16 12 9 O H 11 O
3-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-acrylic acid ethyl ester
(2.31). (JED 3-36). Diiodomethane (5.4 mL, 67.17 mmol) was added drop wise over 1
min to a stirred solution of Et2Zn (1.0 M solution in hexane, 20.15 mL, 20.15 mmol) and diene 2.23 (3.8 g, 16.8 mmol) in anhydrous CH2Cl2 (200 mL) enclosed in a sealed tube at 182 rt. Once the addition was complete, the tube was sealed and shaken by hand for 5
seconds. The bottom third of the sealed tube was immersed in a 65 ºC oil bath and stirred
for 4 h whereupon the tube was removed from the bath and cooled in a refrigerator at 5
ºC for 12 h. Once cooled, the tube was opened and the contents poured into a separatory
funnel containing 20 mL of aqueous 1 M HCl (100 mL). The remaining salts in the
sealed tube were dissolved and successively washed with aqueous 1 M HCl (2 x 20 mL)
and CH2Cl2 (2 x 20 mL) then poured into the funnel. The biphasic mixture was shaken until both layers were transparent. Additional aqueous 1 M HCl and CH2Cl2 was added
as necessary. Once transparent, the layers were separated and the organic layer was
washed with saturated aqueous NaHCO3 (50 mL), saturated aqueous Na2S3O5 (30 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by
flash chromatography eluting with hexanes/EtOAc (9:1 to 5:1) to give 2.90 g (72%) of
2.31 as a clear oil.
(JED 3-111). Diiodomethane (9 mL, 112 mmol) was added to a solution of diene
2.22 (5.0 g, 22.9 mmol) Et2Zn (1.0 M solution in hexane, 35 mL, 33.1 mmol) in
anhydrous ClCH2ClCH2 in a RBF at rt under an Ar atmosphere. The reaction was heated
to 65 ºC under a balloon of Ar for 2 h, whereupon the reaction mixture was treated with
aqueous 1 M HCl (100 mL) and stirred until the organic layer was transparent. The
layers were separated and the organic layer was washed with saturated aqueous NaHCO3
(50 mL) and saturated aqueous Na2S3O5 (30 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (9:1 to 5:1) to give 3.4 g (64%) of cyclopropane 2.31 as a clear oil; 1H 183 NMR (500 MHz) δ 6.42 (dd, J = 15.1, 9.4 Hz, 1 H), 5.83 (dd, J = 15.1, 0.5 Hz, 1 H), 4.14
(q, J = 7.2 Hz, 2 H), 4.06 (dd, J = 8.0, 5.5 Hz, 1 H), 3.71 (ddd, J = 7.0, 5.5 Hz, 1 H), 3.65
(dd, J = 8.0, 7.0 Hz, 1 H), 1.51 (app dt, J = 9.4, 4.6 Hz, 1 H), 1.39 (s, 3 H), 1.31 (s, 3 H),
1.24 (t, J = 7.2 Hz, 3 H), 1.20 (ddd, J = 8.5, 4.6, 2.5, 1.5 Hz, 1 H), 1.05 (app dt, J = 8.5,
5.5 Hz, 1 H), 0.89 (dt, J = 8.5, 5.0 Hz, 1 H); 13C NMR (125 MHz) δ 166.5, 151.3, 119.0,
109.1, 77.7, 69.0, 60.1, 26.6, 25.6, 24.5, 18.3, 14.3, 12.8; IR (neat) 2984, 2860, 1715,
-1 1645, 1370, 1254, 1146, 1064 cm ; MS (CI) m/z 241.1432 (base) [C13H21O4 (M+1) requires 241.1440], 183, 165.
NMR Assignments: 1H NMR (500 MHz) δ 6.42 (dd, J = 15.1, 9.4 Hz, 1 H, C11-
H), 5.83 (dd, J = 15.1, 0.5 Hz, 1 H, C12-H), 4.14 (q, J = 7.2 Hz, 2 H, C15-H), 4.06 (dd, J
= 8.0, 5.5 Hz, 1 H, C6-H), 3.71 (ddd, J = 7.0, 5.5 Hz, 1 H, C7-H), 3.65 (dd, J = 8.0, 7.0
Hz, 1 H, C6-H), 1.51 (app dt, J = 9.4, 4.6 Hz, 1 H, C10-H), 1.39 (s, 3 H, C4-3H), 1.31 (s,
3 H, C4-3H), 1.24 (t, J = 7.2 Hz, 3 H, C16-3H), 1.20 (ddd, J = 8.5, 4.6, 2.5, 1.5 Hz, 1 H,
C8-H), 1.05 (app dt, J = 8.5, 5.5 Hz, 1 H, C9-H), 0.89 (dt, J = 8.5, 5.0 Hz, 1 H, C9-H);
13C NMR (125 MHz) δ 166.5 (C13), 151.3 (C11), 119.0 (C12), 109.1 (C5), 77.7 (C7),
69.0 (C6), 60.1 (C15), 26.6 (C4), 25.6 (C8), 24.5 (C4), 18.3 (C10), 14.3 (C16), 12.8 (C9).
4 6 O 5 H 8 O 9 HO 10 H 13
184 3-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-prop-2-en-1-ol (2.32)
(JED 3-40). Diisobutylaluminum hydride (1 M solution in CH2Cl2, 20.1 mL, 20.1
mmol) was added to a solution of α, β-unsaturated ester 2.31 in anhydrous CH2Cl2 (40
mL) at -78 °C. Stirring continued for 0.5 h at -78 °C, then EtOAc (20 mL) and saturated
aqueous potassium sodium tartrate (20 mL) were added. The resultant emulsion was
stirred for an additional 18 h until the layers were transparent. The layers were separated
and the organic layer was dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1 to 1:1) to
give 1.66 g (91%) of allylic alcohol 2.32 as a clear oil; 1H NMR (500 MHz) δ 5.64 (ddd,
J = 15.0, 6.3, 0.3 Hz, 1 H), 5.22 (ddd, J = 15.0, 8.5, 1.3 Hz, 1 H), 4.03 (dd, J = 7.6, 5.4
Hz, 1 H), 4.01 (dd, J = 6.3, 1.3 Hz, 2 H), 3.63 (app t, J = 7.6 Hz, 1 H), 3.57 (app dt, J =
7.1, 5.4 Hz, 1 H), 1.71 (br, 1 H), 1.37 (s, 3 H), 1.33-1.28 (comp, 4 H), 0.94 (dddd, J =
8.6, 7.6, 5.5, 4.5 Hz, 1 H), 0.81 (dt, J = 8.6, 5.5 Hz, 1 H), 0.66 (dt, J = 8.6, 5.0 Hz, 1 H);
13C NMR (100 MHz) δ 134.5, 127.4, 108.9, 78.9, 69.1, 63.3, 26.7, 25.6, 22.6, 17.6, 11.4;
IR (neat) 3414, 2985, 2867, 2359, 1371, 1216, 1062 cm-1; MS (CI) m/z 198.1251
[C11H18O3 (M) requires 198.1256] 181 (base), 123, 89.
NMR Assignments: 1H NMR (500 MHz) δ 5.64 (ddd, J = 15.0, 6.3, 0.3 Hz, 1 H,
C12-H), 5.22 (ddd, J = 15.0, 8.5, 1.3 Hz, 1 H, C11-H), 4.03 (dd, J = 7.6, 5.4 Hz, 1 H, C6-
H), 4.01 (dd, J = 6.3, 1.3 Hz, 2 H, C13-2H), 3.63 (app t, J = 7.6 Hz, 1 H, C6-H), 3.57
(app dt, J = 7.1, 5.4 Hz, 1 H, C7-H), 1.71 (br, 1 H, -OH), 1.37 (s, 3 H, C4-3H), 1.33-1.28
(comp, 4 H, C10-H and C4-3H), 0.94 (dddd, J = 8.6, 7.6, 5.5, 4.5 Hz, 1 H, C8-H), 0.81
(dt, J = 8.6, 5.5 Hz, 1 H. C9-H), 0.66 (dt, J = 8.6, 5.0 Hz, 1 H, C9-H); 13C NMR (125 185 MHz) δ 134.5 (C11), 127.4 (C12), 108.9 (C5), 78.8 (C7), 69.1 (C6), 63.3 (C13), 26.7
(C4), 25.6 (C4), 22.6C(8), 17.6 (C10), 11.4 (C9).
4 6 O 5 H 8 O 18 H 9 N 15 O 10 H 13 20 O
Phenyl-carbamic acid 3-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-
allyl ester (2.37). (JED 3-81). Phenyl isocyanate (0.12 mL, 1.0 mmol) was added to a
solution of alcohol 2.32 (0.10 g, 0.50 mmol) and Et3N (0.14 mL, 1.0 mmol) in anhydrous
THF (5 mL) at rt. Stirring continued for 12 h at rt, then the reaction mixture was
concentrated under reduced pressure. The residue was purified by flash chromatography
eluting with hexanes/EtOAc (9:1 to 4:1) to give 130 mg (85%) of carbamate 2.37 as a
clear oil; 1H NMR (500 MHz) δ7.35 (app d, J = 7.9 Hz, 2 H), 7.27 (app t, J = 7.9 Hz, 2
H), 7.04 (t, J = 7.0 Hz, 1 H), 6.63 (br, 1 H), 5.65 (app dt, J = 15.3, 6.8 Hz, 1 H), 5.36 (dd,
J = 15.3, 9.0 Hz, 1 H), 4.56 (d, J = 6.8 Hz, 2 H), 4.06 (dd, J = 7.7, 5.6, 1 H), 3.67 (app t, J
= 7.7 Hz, 1 H), 3.61 (ddd, J = 6.8, 6.8, 5.6 Hz, 1 H), 1.41 (s, 3 H), 1.36 (dtd, J = 9.0, 5.2,
5.2 Hz, 1 H), 1.32 (s, 3 H), 1.01 (m, 1 H), 0.87 (dt, J = 8.4, 5.2 Hz, 1 H), 0.72 (dt, J = 8.4,
5.2 Hz, 1 H); 13C NMR (100 MHz) δ153.9, 138.2, 137.8, 129.0, 123.4, 122.4, 118.6,
108.9, 78.7, 69.1, 65.6, 26.7, 25.7, 22.8, 17.8, 11.6.
NMR Assignments: 1H NMR (500 MHz) δ7.35 (app d, J = 7.9 Hz, 2 H, C18-
2H), 7.27 (app t, J = 7.9 Hz, 2 H, C19-2H), 7.04 (t, J = 7.0 Hz, 1 H, C20-H), 6.63 (br, 1 186 H, NH), 5.65 (app dt, J = 15.3, 6.8 Hz, 1 H, C12-H), 5.36 (dd, J = 15.3, 9.0 Hz, 1 H, C11-
H), 4.56 (d, J = 6.8 Hz, 2 H, C13-H), 4.06 (dd, J = 7.7, 5.6, 1 H, C6-H), 3.67 (app t, J =
7.7 Hz, 1 H, C6-H), 3.61 (ddd, J = 6.8, 6.8, 5.6 Hz, 1 H, C7-H), 1.41 (s, 3 H, C4-3H),
1.36 (dtd, J = 9.0, 5.2, 5.2 Hz, 1 H, C10-H), 1.32 (s, 3 H, C4-3H), 1.01 (m, 1 H, C8-H),
0.87 (dt, J = 8.4, 5.2 Hz, 1 H, C9-H), 0.72 (dt, J = 8.4, 5.2 Hz, 1 H, C9-H); 13C NMR
(100 MHz) δ153.9 (C15), 138.2 (C11), 137.8 (C17), 129.0, 123.4, 122.4, 118.6, 108.9,
78.7 (C7), 69.1 (C6), 65.6 (C`3), 26.7 (C4), 25.7 (C4), 22.8 (C8), 17.8 (C10), 11.6 (C9).
6 OH
H 8 OH 18 H 9 N 15 O 10 H 13 20 O
Phenyl-carbamic acid 3-[2-(1,2-dihydroxyethyl)-cyclopropyl]-allyl ester
(2.38). (JED 3-83). TsOH (1 mg, 0.003 mmol) was added to a solution of carbamate
2.37 (100 mg, 3.15 mmol) in anhydrous MeOH (3.5 mL) at rt. Stirring continued for 12
h at rt, whereupon the reaction mixture was diluted with Et2O (10 mL), and successively
washed with saturated aqueous NaHCO3 (2 x 5 mL), water (5 mL), and brine (5 mL).
The organic layer was dried (MgSO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to give
81 mg (93%) of diol 2.38 as a white solid which was repeatedly recrystallized from
1 hexanes/CH2Cl2 to provide white flakes suitable for X-ray; H NMR (400 MHz) δ 7.35
(app d, J = 7.6 Hz, 2 H), 7.29 (app t, J = 7.6 Hz, 2 H), 7.04 (t, J = 7.6 Hz, 1 H), 6.73 (br, 187 1 H), 5.65 (app dt, J = 15.4, 6.6, 1 H), 5.35 (app dd, J = 15.4, 8.7 Hz, 1 H), 4.55 (d, J =
6.6 Hz, 2 H), 3.74-3.71 (m, 1 H), 3.56 (dd, J = 11.2, 7.2 Hz, 1 H), 3.20 (br, 1 H), 2.12 (br,
2 H), 1.38 (app dtd, J = 8.7, 5.0, 5.0 Hz, 1 H), 0.98 (app dtd, J = 8.0, 5.0, 5.0 Hz, 1 H),
0.84 (app dt, J = 8.6, 5.0 Hz, 1 H), 0.67 (app dt, J = 8.6, 5.0 Hz, 1 H).
NMR Assignments: 1H NMR (400 MHz) δ 7.35 (app d, J = 7.6 Hz, 2 H, C18-
2H), 7.29 (app t, J = 7.6 Hz, 2 H, C19-2H), 7.04 (t, J = 7.6 Hz, 1 H, C20-2H), 6.73 (br, 1
H, NH), 5.65 (app dt, J = 15.4, 6.6, 1 H, C12-H), 5.35 (app dd, J = 15.4, 8.7 Hz, 1 H,
C11-H), 4.55 (d, J = 6.6 Hz, 2 H, C13-2H), 3.74-3.71 (m, 1 H, C6-H), 3.56 (dd, J = 11.2,
7.2 Hz, 1 H, C6-H), 3.20 (br, 1 H, C7-H), 2.12 (br, 2 H, 2 x OH), 1.38 (app dtd, J = 8.7,
5.0, 5.0 Hz, 1 H, C10-H), 0.98 (app dtd, J = 8.0, 5.0, 5.0 Hz, 1 H, C8-H), 0.84 (app dt, J
= 8.6, 5.0 Hz, 1 H, C9-H), 0.67 (app dt, J = 8.6, 5.0 Hz, 1 H, C9-H).
4 6 O 5 H 8 O 9 O 10 H 13 H
3-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-propenal (2.33). (JED 3-
117). Tetrapropylammonium perruthenate (TPAP) (66.0 mg, 0.19 mmol) was added to a solution of alcohol 2.33 (2.49 g, 12.6 mmol), N-methylmorpholine N-oxide (NMO) (2.94 g, 25.1 mmol), and activated 4 Å molecular sieves (12 g) in anhydrous CH2Cl2 at rt.
Stirring continued for 18 h at rt, whereupon the reaction mixture was filtered through a pad of celite rinsing with CH2Cl2 then concentrated under reduced pressure. The residue 188 was purified by flash chromatography eluting with pentanes/Et2O (4:1) to provide 2.40 g
(98%) of 2.33 as a clear oil; 1H NMR (400 MHz) δ 9.39 (d, J = 7.7 Hz, 1 H), 6.29 (dd, J
= 15.3, 9.2 Hz, 1 H), 6.15 (dd, J = 15.3, 7.7 Hz, 1 H), 4.08 (dd, J = 8.1, 6.2 Hz, 1 H), 3.80
(app q, J = 6.5 Hz, 1 H), 3.67 (dd, J = 8.1, 6.8 Hz, 1 H), 1.68 (app tt, J = 9.2, 5.2 Hz, 1
H), 1.40 (s, 3 H), 1.35–1.29 (comp, 4 H), 1.21 (ddd, J = 8.6, 6.4, 5.2 Hz, 1 H), 0.98 (app
dt, J = 8.6, 5.2 Hz, 1 H); 13C NMR (100 MHz) δ 193.0, 161.0, 130.7, 109.3, 77.0, 69.0,
26.6, 25.7, 25.5, 19.2, 13.8; IR (neat) 2986, 2360, 1684, 1628, 1370, 1176, 1063, 668 cm-
1 ; MS (CI) m/z 197.1179 [C11H17O3 (M+1) requires 197.1178] 171, 187, 155, 137 (base)
125, 109.
NMR Assignments: 1H NMR (400 MHz) δ 9.39 (d, J = 7.7 Hz, 1 H, C14-H),
6.29 (dd, J = 15.3, 9.2 Hz, 1 H, C11-H), 6.15 (dd, J = 15.3, 7.7 Hz, 1 H, C12-H), 4.08
(dd, J = 8.1, 6.2 Hz, 1 H, C6-H), 3.80 (app q, J = 6.5 Hz, 1 H, C7-H), 3.67 (dd, J = 8.1,
6.8 Hz, 1 H, C6-H), 1.68 (app tt, J = 9.2, 5.2 Hz, 1 H, C10-H), 1.40 (s, 3 H, C4-3H),
1.35–1.29 (comp, 4 H, C4-H and C8-H), 1.21 (ddd, J = 8.6, 6.4, 5.2 Hz, 1 H, C9-H), 0.98
(app dt, J = 8.6, 5.2 Hz, 1 H, C9-H); 13C NMR (100 MHz) δ 193.0 (C13), 161.0 (C11),
130.7 (C12), 109.3 (C5), 77.0 (C7), 69.0 (C8), 26.6 (C4), 25.7 (C8), 25.5 (C4), 19.2
(C10), 13.8 (C15).
189 4 6 O 5 H 8 O 9 O 10 H 15 13 11 O 17 18
5-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-penta-2,4-dienoic acid
ethyl ester (2.22). (JED 3-206). Triethyl phosphonoacetate (9.9 mL, 50.6 mmol) was
added drop wise to a stirred suspension of NaH (60% dispersion in mineral oil, 1.77 g,
44.0 mmol) in THF (280 mL) at 0 °C. Once the evolution of H2 gas ceased, the reaction
was warmed to rt and stirring continued for 0.5 h, or until the mixture became
transparent, whereupon a solution of aldehyde 1.98 (5.4 g, 27.7 mmol) in THF (30 mL)
was added dropwise. Stirring continued for 1 h at rt, whereupon the reaction mixture was
diluted with Et2O (200 mL) and successively washed with saturated aqueous NH4Cl (100 mL), H2O (2 x 100 mL), brine solution (50 mL) then dried (MgSO4) and concentrated
under reduced pressure. The residue was purified by flash chromatography eluting with
hexanes/EtOAc (9:1) to provide 2.90 g (91%) of diene 2.22 as a pale yellow oil; 1H
NMR (400 MHz) δ 7.18 (ddd, J = 15.1, 11.2, 0.4 Hz, 1 H), 6.20 (dd, J = 15.1, 11.2 Hz, 1
H), 5.73 (d, J = 15.1 Hz, 1 H), 5.61 (dd, J = 15.1, 9.0 Hz, 1 H), 4.16 (q, J = 7.2 Hz, 2 H),
4.10–4.03 (m, 1 H), 3.70-3.62 (comp, 2 H), 1.45 (app dt J = 9.0, 4.6 Hz, 1 H), 1.40 (s, 3
H), 1.31 (s, 3 H), 1.26 (t, 7.2 Hz, 3 H), 1.11 (dddd, J = 9.0, 6.8, 5.6, 4.6 Hz, 1 H), 1.00
(app dt, J = 8.3, 5.6 Hz, 1H), 0.81 (app dt, J = 8.3, 4.8 Hz, 1H); 13C NMR (100 MHz) δ
167.3, 146.0, 144.4, 126.6, 118.7, 109.1, 78.1, 69.1, 60.1, 26.7, 25.6, 24.2, 19.0, 14.3, 190 12.7; IR (neat) 2984, 2874, 1710, 1634, 1370, 1239, 1063 cm-1; MS (CI) m/z 267.1599
(base) [C15H23O4 (M+1) requires 267.1596] 267, 237, 221, 209, 191, 163.
NMR Assignments: 1H NMR (400 MHz) δ 7.18 (ddd, J = 15.1, 11.2, 0.4 Hz, 1
H, C13-H), 6.20 (dd, J = 15.1, 11.2 Hz, 1 H, C12-H), 5.73 (d, J = 15.1 Hz, 1 H, C14-H),
5.61 (dd, J = 15.1, 9.0 Hz, 1 H, C11-H), 4.16 (q, J = 7.2 Hz, 2 H, C17-H), 4.10–4.03 (m,
1 H, C6-2H), 3.70-3.62 (comp, 2 H, C7-2H), 1.45 (app dt J = 9.0, 4.6 Hz, 1 H, C8-H),
1.40 (s, 3 H, C4-3H), 1.31 (s, 3 H, C4-3H), 1.26 (t, 7.2 Hz, 3 H, C18-3H), 1.11 (dddd, J =
9.0, 6.8, 5.6, 4.6 Hz, 1 H, C10-H), 1.00 (app dt, J = 8.3, 5.6 Hz, 1H, C9-H), 0.81 (app dt,
J = 8.3, 4.8 Hz, 1H, C9-H); 13C NMR (100 MHz) δ 167.3 (C15), 146.0 (C13), 144.4
(C11), 126.6 (C12), 118.7 (C14), 109.1 (C5), 78.1 (C12), 69.1 (C13), 60.1 (C2), 26.7
(C15), 25.6 (C11), 24.2 (C15), 19.0 (C9), 14.3 (C1), 12.7 (C10);
17 4 O O 6 O 5 14 H 8 O 9 11 HO H OH
5-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-4,5-dihydroxypent-2-
enoic acid ethyl ester (2.51). (JED 5-68). A dry mixture of “super” AD-Mix β was
prepared by combining K3FeCN6 (7.3 g, 22.5 mmol), K2CO3 (3.11 g, 22.5 mmol),
K2OsO2(OH)4 (183 mg, 0.53 mmol), (DHQD)2PHAL (550 mg, 0.60 mmol), and
methanesulfonamide (1.43 g, 15.0mmol) in a RBF equipped with a stir bar. H2O (40
191 mL) and t-BuOH (40 mL) were added to the dry mixture of reagents and the resultant
solution was stirred at rt until all of the solids were dissolved (ca 0.5 h). The solution of
super AD-Mix β was then poured into a second RBF containing diene 2.22 (2.0 g, 7.51
mmol). Stirring continued for 8 h at rt, whereupon solid Na2SO3 (4.73 g, 37.5 mmol)
was added and stirring continued for an additional 12 h. The layers were separated and
the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic extracts
were dried (MgSO4), and concentrated under reduced pressure. The residue was purified
by flash chromatography eluting with hexanes/EtOAc (2:1 to 1:3) to give a pale yellow
solid contaminated with excess methanesulfonamide. Triturating of the mixture with
CHCl3 removed the crystalline impurity to give 1.76 g (78%) of diol 2.51 as a pale
yellow wax: mp 41-43 ºC. Since this impurity did not hinder the subsequent
transformations its removal was rarely warranted; 1H NMR (500 MHz) δ 6.97 (ddd, J =
15.7, 5.0, 1.7 Hz, 1 H), 6.11 (dt, J = 15.7, 1.6 Hz, 1 H), 4.23 (td, J = 5.0, 1.5 Hz, 1 H),
4.17 (dq, J = 7.2, 1.7 Hz, 2 H), 4.03 (dd, J = 7.4, 4.8 Hz, 1 H), 3.69 (dd, J = 7.8, 4.8 Hz, 1
H), 3.65 (app t, J = 7.4 Hz, 1 H), 2.99 (dd, J = 8.5, 5.0 Hz, 1 H), 1.40 (s, 3 H), 1.31 (s, 3
H), 1.26 (dt, J = 7.2, 1.7 Hz, 3 H), 1.05 (app ddt, J = 8.5, 7.8, 5.0 Hz, 1 H), 0.93 (app tt, J
= 8.5, 5.0 Hz, 1 H), 0.68 (app dt, J = 8.5, 5.0 Hz, 1 H), 0.58 (dt, J = 8.5, 5.0 Hz, 1 H);
13C NMR (100 MHz) δ 166.3, 146.4, 122.0, 109.1, 78.3, 74.6, 76.7, 68.7, 60.6, 26.7,
25.5, 18.5, 18.1, 14.2, 7.9; IR (neat) 3413, 2978, 2884, 2332, 1718, 1261, 1059, 668 cm-
1 ; MS (CI) m/z 301.1654 [C15H25O6 (M+1) requires 301.1651] 283, 265, 243 (base),
225, 207.
192 NMR Assignments. 1H NMR (500 MHz) δ 6.97 (ddd, J = 15.7, 5.0, 1.7 Hz, 1 H,
C13-H), 6.11 (dt, J = 15.7, 1.6 Hz, 1 H, C14-H), 4.23 (td, J = 5.0, 1.5 Hz, 1 H, C12-H),
4.17 (dq, J = 7.2, 1.7 Hz, 2 H, C16-H), 4.03 (dd, J = 7.4, 4.8 Hz, 1 H, C6-H), 3.69 (dd, J
= 7.8, 4.8 Hz, 1 H, C7-H), 3.65 (app t, J = 7.4 Hz, 1 H, C6-H), 2.99 (dd, J = 8.5, 5.0 Hz,
1 H, C11-H), 1.40 (s, 3 H, C4-3H), 1.31 (s, 3 H, C4-3H), 1.26 (dt, J = 7.2, 1.7 Hz, 3 H,
C17-3H), 1.05 (app ddt, J = 8.5, 7.8, 5.0 Hz, 1 H, C8-H), 0.93 (app tt, J = 8.5, 5.0 Hz, 1
H, C10-H), 0.68 (app dt, J = 8.5, 5.0 Hz, 1 H, C9-H), 0.58 (dt, J = 8.5, 5.0 Hz, 1 H, C9-
H); 13C NMR (100 MHz) δ 166.3 (C15), 146.4 (C13), 122.0 (C14), 109.1 (C3), 78.3
(C7), 74.6 (C11), 76.7 (C12), 68.7 (C6), 60.6 (C16), 26.7 (C4), 25.5 (C4), 18.5 (C8), 18.1
(C10), 14.2 (C17), 7.9 (C9).
17 4 O O 6 O 5 14 H 8 O 9 11 O H 5 O
4
3-{5-[2-(2,2-Dimethyl[1,3]dioxolan-4-yl)-cyclopropyl]-2,2-dimethyl-1,3]
dioxolan-4-yl} acrylic acid ethyl ester (2.57). (JED 2-297). p-Toluenesulfonic acid
(3.0 mg, 0.016 mmol) was added to a solution of diol 2.51 (155 mg, 0.52 mmol) and 2,2-
dimethoxypropane (0.11 mL, 0.88 mmol) in anhydrous DMF (5 mL) at rt. Stirring continued for 12 h at rt whereupon the reaction was diluted with Et2O (15 mL) and
successively washed with H2O (3 x 20 mL) and brine (10 mL). The organic layer was
193 dried (MgSO4), and concentrated under reduced pressure. The residue was purified by
flash chromatography eluting with hexanes/EtOAc (9:1 to 5:1) to provide 150 mg (85%)
of diacetonide 2.57 as a clear oil: 1H NMR (500 MHz) δ 6.84 (dd, J = 15.7, 5.5 Hz, 1 H),
6.11 (dd, J = 15.7, 1.5 Hz, 1 H), 4.27 (ddd, J = 8.5, 5.5, 1.5 Hz, 1 H), 4.18 (q, J = 7.2 Hz,
2 H), 4.08-4.04 (m, 1 H), 3.72-3.67 (comp, 2 H), 3.17 (t, J = 8.5, 1 H), 1.40 (s, 3 H), 1.39
(s, 3 H), 1.35 (s, 3 H), 1.31 (s, 3 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.02-0.97 (m, 1 H), 0.88
(dtd, J = 8.5, 5.0, 5.0 Hz, 1 H), 0.69 (dt, J = 8.6, 5.0 Hz, 1 H), 0.55 (dt, J =8.6, 5.2 Hz, 1
H); 13C NMR (125 MHz) δ 166.0, 143.8, 122.6, 109.4, 109.0, 83.4, 80.3, 78.0, 69.2,
60.6, 27.1, 26.7, 26.6, 25.6, 18.4, 16.1, 14.2, 6.3; IR (neat) 2986, 2870, 1725, 1657, 1373,
-1 1237, 1163, 1057, 847 cm ; MS (CI) m/z 341, 339.1803 [C18H27O6 (M-1) requires
339.1808] 265, 311, 283 (base), 225, 155.
NMR Assignments: 1H NMR (500 MHz) δ 6.84 (dd, J = 15.7, 5.5 Hz, 1 H, C13-
H), 6.11 (dd, J = 15.7, 1.5 Hz, 1 H, C14-H), 4.27 (ddd, J = 8.5, 5.5, 1.5 Hz, 1 H, C12-H),
4.18 (q, J = 7.2 Hz, 2 H, C17-H), 4.08-4.04 (m, 1 H,), 3.72-3.67 (comp, 2 H), 3.17 (t, J =
8.5, 1 H, C11-H), 1.40 (s, 3 H, C4-3H), 1.39 (s, 3 H, C4-3H), 1.35 (s, 3 H, C4-3H), 1.31
(s, 3 H, C4-3H), 1.28 (t, J = 7.2 Hz, 3 H, C18-3H), 1.02-0.97 (m, 1 H, C8-H), 0.88 (dtd, J
= 8.5, 5.0, 5.0 Hz, 1 H, C10-H), 0.69 (dt, J = 8.6, 5.0 Hz, 1 H, C9-H), 0.55 (dt, J =8.6, 5.2
Hz, 1 H, C9-H); 13C NMR (125 MHz) δ 166.0 (C15), 143.8 (C13), 122.6 (C14), 109.4
(C5), 109.0 (C5), 83.4 (C11), 80.3 (C7), 78.0 (C12), 69.2 (C6), 60.6 (C17), 27.1 (C4),
26.7 (C4), 26.6 (C4), 25.6 (C4), 18.4 (C8), 16.1 (C18), 14.2 (C10), 6.3 (C9).
194 HO 15 O 5 7 H O 9 4 11 O H 5 O
4
3-{5-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-2,2-dimethyl-
[1,3]dioxolan-4-yl}-prop-2-en-1-ol (2.58). (JED 2-300). Diisobutylaluminum hydride
(1 M solution in CH2Cl2, 0.97 mL, 0.97 mmol) was added to a solution of α, β-
unsaturated ester 2.57 (150 mg, 0.44 mmol) in anhydrous CH2Cl2 (4.5 mL) at -78 °C.
Stirring continued for 2 h at -78 °C, whereupon EtOAc (2 mL) and saturated aqueous
potassium sodium tartrate (5 mL) were added. The resultant emulsion was stirred for an
additional 18 h at rt until the layers were transparent. The layers were separated and the
organic layer was dried (MgSO4), and concentrated under reduced pressure. The residue
was purified by flash chromatography eluting with hexanes/EtOAc (3:1 to 1:1) to give
124 mg (95%) of allylic alcohol 2.58 as a clear oil;1H NMR (500 MHz) δ 5.96 (dtd, J =
15.5, 5.5, 1.0 Hz, 1 H), 5.66 (dtd, J = 15.5, 7.5, 1.7 Hz, 1 H), 4.14 (dd, J = 5.5, 1.7 Hz, 2
H), 4.14-4.12 (m, 1 H), 4.05 (dd, J = 8.0, 6.0, 1 H), 3.70 (dd, J = 8.0, 7.5 Hz, 1 H), 3.64
(dt, J = 7.5, 6.0 Hz, 1 H), 3.17 (dd, J = 8.0, 7.5 Hz, 1 H), 1.74 (br, 1 H), 1.39 (s, 3 H),
1.37 (s, 3 H), 1.34 (s, 3 H) 1.30 (s, 3 H) 1.00-0.95 (m, 1 H), 0.84-0.79 (m, 1 H), 0.63 (app dt, J = 8.6, 5.2 Hz, 1 H), 0.54 (app dt J = 8.6, 5.2 Hz, 1 H); 13C NMR (125 MHz) δ
133.8, 127.7, 109.0, 108.6, 83.2, 81.6, 78.4, 69.3, 62.6, 27.1, 26.9, 26.7, 25.6, 18.1, 16.0,
6.4. 195 NMR Assignments: 1H NMR (500 MHz) δ 5.96 (dtd, J = 15.5, 5.5, 1.0 Hz, 1 H,
C14-H), 5.66 (dtd, J = 15.5, 7.5, 1.7 Hz, 1 H (C13-H), 4.14 (dd, J = 5.5, 1.7 Hz, 2 H,
C15-2H), 4.14-4.12 (m, 1 H, C12-H), 4.05 (dd, J = 8.0, 6.0, 1 H, C6-H), 3.70 (dd, J = 8.0,
7.5 Hz, 1 H, C6-H), 3.64 (dt, J = 7.5, 6.0 Hz, 1 H, C7-H), 3.17 (dd, J = 8.0, 7.5 Hz, 1 H,
C11-H), 1.74 (br, 1 H, OH), 1.39 (s, 3 H, C4-3H), 1.37 (s, 3 H, C4-3H), 1.34 (s, 3 H, C4-
3H) 1.30 (s, 3 H, C4-3H) 1.00-0.95 (m, 1 H, C8-H), 0.84-0.79 (m, 1 H, C10-H), 0.63
(app dt, J = 8.6, 5.2 Hz, 1 H, C9-H), 0.54 (app dt J = 8.6, 5.2 Hz, 1 H, C9-H); 13C NMR
(125 MHz) δ 133.8 (C13), 127.7 (C14), 109.0 (C5), 108.6 (C5), 83.2 (C11), 81.6 (C7),
78.4 (C12), 69.3 (C6), 62.6 (C15), 27.1 (C4), 26.9 (C4), 26.7 (C4), 25.6 (C4), 18.1 (C8),
16.0 (C10), 6.4 (C9).
Br 15 O 5 7 H O 9 4 11 O H 5 O
4
4-(3-Bromo-propenyl)-5-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-
2,2-dimethyl-[1,3]dioxolane (2.59). (JED 2-301). Triphenylphosphine (69 mg, 0.26
mmol) and carbon tetrabromide (100 mg, 0.30 mmol) was added to a solution of allylic
alcohol 2.58 (60 mg, 0.20 mmol) in anhydrous CH2Cl2 (2 mL) at 0 °C. Stirring continued for 15 min at 0 °C whereupon saturated aqueous NaHCO3 (15 mL) was added and the layers were separated. The organic layer was dried (MgSO4), and concentrated 196 under reduced pressure. The residue was purified by flash chromatography eluting with
hexanes/EtOAc (5:1) to provide 63 mg (87%) of 2.59 as a clear oil;1H NMR (400 MHz)
δ 6.02 (dddd, J = 15.2, 7.6, 7.6, 1.0 Hz, 1 H), 5.70 (ddt, J = 15.2, 7.6, 1.2 Hz, 1 H), 4.14
(app t, J = 7.6 Hz, 1 H), 4.07 (dd, J = 7.6, 5.6 Hz, 1 H), 3.96-3.90 (comp, 2 H), 3.71 (app t, J = 7.6 Hz, 1 H), 3.66 (dt, J = 7.9, 5.6 Hz, 1 H), 3.12 (app t, J = 7.6 Hz, 1 H), 1.40 (s, 3
H), 1.38 (s, 3 H), 1.35 (s, 3 H), 1.32 (s, 3 H), 1.01-0.95 (comp, 1 H), 0.83 (app tt, J = 7.9,
5.2 Hz, 1 H), 0.67 (app dt, J = 8.8, 5.2 Hz, 1 H), 0.54 (app dt, J = 8.8, 5.2 Hz, 1 H); IR
(neat) 2929, 2857, 1472, 1368, 1253, 1065, 835 cm-1..
NMR Assignments: 1H NMR (400 MHz) δ 6.02 (dddd, J = 15.2, 7.6, 7.6, 1.0
Hz, 1 H, C14-H), 5.70 (ddt, J = 15.2, 7.6, 1.2 Hz, 1 H, C13-H), 4.14 (app t, J = 7.6 Hz, 1
H, C12-H), 4.07 (dd, J = 7.6, 5.6 Hz, 1 H, C6-H), 3.96-3.90 (comp, 2 H, C15-2H), 3.71
(app t, J = 7.6 Hz, 1 H, C6-H), 3.66 (dt, J = 7.9, 5.6 Hz, 1 H, C7-H), 3.12 (app t, J = 7.6
Hz, 1 H, C11-H), 1.40 (s, 3 H, C4-3H), 1.38 (s, 3 H, C4-3H), 1.35 (s, 3 H, C4-3H), 1.32
(s, 3 H, C4-3H), 1.01-0.95 (comp, 1 H, C8-H), 0.83 (app tt, J = 7.9, 5.2 Hz, 1 H, C10),
0.67 (app dt, J = 8.8, 5.2 Hz, 1 H, C9-H), 0.54 (app dt, J = 8.8, 5.2 Hz, 1 H, C9-H).
197 15 O 5 H 7 22 O 9 4 11 O H 5 O
4
4-Dec-1-en-4-ynyl-5-[2-(2,2-dimethyl[1,3]dioxolan-4-yl)cyclopropyl]-2,2-
dimethyl-[1,3]dioxolane (2.60). (JED 2-302). 1-Heptyne (36 µL, 0.35 mmol) and
butyllithium (2.5 M solution in hexanes, 0.10 mL, 0.25 mmol) was added to a solution of
. CuBr SMe2 (5 mg, 0.003 mmol) in anhydrous THF (1.75 mL) at -78 °C. Stirring
continued for 1.5 h at -78 °C, whereupon a solution of allylic bromide 2.59 (63 mg, 0.17
mmol) in anhydrous THF (5 mL) was added drop wise. The -78 °C bath was removed
and stirring continued for 8 h whereupon Et2O (2 mL) and saturated aqueous NH4Cl (5 mL) was added and stirring continued for 12 h. The layers were separated and the organic layer was dried (MgSO4), and concentrated under reduced pressure. The residue
was purified by flash chromatography eluting with hexanes/EtOAc (20:1) to provide 49
mg (74%) of skipped enyne 2.60 as a pale yellow oil; 1H NMR (500 MHz) δ 5.70 (dtd, J
= 15.2, 5.0, 1.0 Hz, 1 H), 5.67 (ddt, J = 15.2, 7.5, 1.7 Hz, 1 H), 4.12 (app t, J = 7.5 Hz, 1
H), 4.06 (dd, J = 8.0, 5.8 Hz, 1 H), 3.71 (app t, J = 8.0 Hz, 1H), 3.64 (dt, J = 7.5, 5.8 Hz,
1 H), 3.17 (app t, J = 7.5 Hz, 1 H), 2.93-2.91 (m, 2 H), 2.14 (tt, J = 7.2, 2.4 Hz, 2 H), 1.47
(p, J = 7.2 Hz, 2 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.35 (s, 3 H), 1.31 (s, 3 H), 1.35-1.25
(comp, 4 H), 0.98 (app tt, J = 7.6, 5.0 Hz, 1 H), 0.87 (t, J = 7.2 Hz, 3 H), 0.81 (app tt, J =
7.5, 5.0 Hz, 1 H), 0.63 (app dt, J = 8.5, 5.0 Hz, 1 H), 0.56 (app dt, J = 8.5, 5.0 Hz, 1 H); 198 13C NMR (125 MHz) δ 130.3, 128.0, 109.0, 108.4, 83.1, 83.0, 81.8, 78.6, 76.1, 69.3,
31.1, 28.7, 27.1, 27.0, 26.7, 25.7, 22.2, 21.9, 18.7, 18.0, 16.0, 14.0, 6.3.
NMR Assignments: 1H NMR (500 MHz) δ 5.70 (dtd, J = 15.2, 5.0, 1.0 Hz, 1 H,
C14-H), 5.67 (ddt, J = 15.2, 7.5, 1.7 Hz, 1 H, C13-H), 4.12 (app t, J = 7.5 Hz, 1 H, C12-
H), 4.06 (dd, J = 8.0, 5.8 Hz, 1 H, C6-H), 3.71 (app t, J = 8.0 Hz, 1H, C6-H), 3.64 (dt, J =
7.5, 5.8 Hz, 1 H, C7-H), 3.17 (app t, J = 7.5 Hz, 1 H, C11-H), 2.93-2.91 (m, 2 H, C15-
2H), 2.14 (tt, J = 7.2, 2.4 Hz, 2 H, C18-2H), 1.47 (p, J = 7.2 Hz, 2 H, C19-2H), 1.40 (s, 3
H, C4-3H), 1.37 (s, 3 H, C4-3H), 1.35 (s, 3 H, C4-3H), 1.31 (s, 3 H, C4-3H), 1.35-1.25
(comp, 4 H, C20-2H and C21-2H), 0.98 (app tt, J = 7.6, 5.0 Hz, 1 H, C8-H), 0.87 (t, J =
7.2 Hz, 3 H, C22-3H), 0.81 (app tt, J = 7.5, 5.0 Hz, 1 H, C10-H), 0.63 (app dt, J = 8.5,
5.0 Hz, 1 H, C9-H), 0.56 (app dt, J = 8.5, 5.0 Hz, 1 H, C9-H); 13C NMR (125 MHz) δ
130.3 (C14), 128.0 (C13), 109.0 (C5), 108.4 (C5), 83.1 (C11), 83.0 (C16), 81.8 (C12),
78.6 (C7), 76.1 (C17), 69.3 (C6), 31.1 (C20), 28.7 (C19), 27.1 (C4), 27.0 (C4), 26.7 (C4),
25.7 (C4), 22.2 (C21), 21.9 (C15), 18.7 (C18), 18.0 C(8), 16.0 (C10), 14.0 (C22), 6.3
(C9).
199 17 4 O O 6 O 5 14 H 8 O 9 11 TBSO H O Si 18
20
4,5-Bis-(tert-butyldimethylsilanyloxy)-5-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-
cyclopropyl]-pent-2-enoic acid ethyl ester (2.63) (JED 4-200) tert-Butyldimethylsilyl
chloride (8.36 g, 55.5 mmol) was added to a solution of diol 2.51 (5.55 g, 18.5 mmol) and
imidazole (6.3 g, 92.5 mmol) in anhydrous DMF (10 mL) at rt. Stirring continued for 18
h at rt, whereupon the reaction mixture was diluted with Et2O (20 mL) and washed
consecutively with aqueous 1 M HCl (20 mL), aqueous NaHCO3 (20 mL), and brine (10 mL). The organic layer was dried (MgSO4), and concentrated under reduced pressure.
The residue was purified by flash chromatography eluting with hexanes/EtOAc (30:1 to
20:1) to give 9.70 g (99%) of 2.63 as a pale yellow oil; 1H NMR (400 MHz) δ 7.08 (dd, J
= 15.6, 3.4 Hz, 1 H), 6.01 (dd, J = 15.6, 2.3 Hz, 1 H), 4.26 (ddd, J = 5.6, 3.4, 2.2 Hz, 1
H), 4.17 (app ds, J = 10.8, 7.2 Hz, 2 H), 3.87 (dd, J = 8.0, 5.1 Hz, 1 H), 3.51 (app t, J =
8.0 Hz, 1 H), 3.50 (appt, J = 5.1 Hz, 1 H), 3.31 (dt, J = 7.6, 5.6 Hz, 1 H), 1.34 (s, 3 H),
1.25 (t, J = 7.2 Hz, 3 H), 1.25 (s, 3 H), 0.89-0.79 (comp, 20 H), 0.55 (dt, J = 8.3, 5.2 Hz,
1 H), 0.48 (dt, J = 8.3, 5.2 Hz, 1 H), 0.02 (s, 3 H), 0.01 (s, 6 H), 0.00 (s, 3 H); 13C NMR
(100 MHz) δ 166.4, 147.7, 121.2, 108.3, 80.2, 74.9, 74.7, 69.2, 60.3, 26.7, 25.8, 25.7,
25.7, 18.0, 17.9, 16.4, 16.2, 14.2, 6.3, -4.5, -4.7, -4.9, -4.9; IR (neat) 2931, 2859, 1723, 200 -1; 1472, 1367, 1260, 1066, 835, 776 cm MS (CI) m/z 529.3077 [C27H53O6Si2 (M+1)
requires 529.3381] 513, 471 (base), 455, 397, 339, 285, 243.
NMR Assignments: 1H NMR (400 MHz) δ 7.08 (dd, J = 15.6, 3.4 Hz, 1 H, C13-
H), 6.01 (dd, J = 15.6, 2.3 Hz, 1 H, C14-H), 4.26 (ddd, J = 5.6, 3.4, 2.2 Hz, 1 H, C12-H),
4.17 (app ds, J = 10.8, 7.2 Hz, 2 H, C16-H), 3.87 (dd, J = 8.0, 5.1 Hz, 1 H, C6-H), 3.51
(app t, J = 8.0 Hz, 1 H, C6-H), 3.50 (appt, J = 5.1 Hz, 1 H, C7-H), 3.31 (dt, J = 7.6, 5.6
Hz, 1 H, C11-H), 1.34 (s, 3 H, C4-3H), 1.25 (t, J = 7.2 Hz, 3 H, C18-3H), 1.25 (s, 3 H,
C4-3H), 0.89-0.79 (comp, 20 H, C8-H and C10-H and C21-18H), 0.55 (dt, J = 8.3, 5.2
Hz, 1 H, C9-H), 0.48 (dt, J = 8.3, 5.2 Hz, 1 H, C9-H), 0.02 (s, 3 H, C18-3H), 0.01 (s, 6 H,
C18-6H), 0.00 (s, 3 H, C18-3H); 13C NMR (100 MHz) δ 166.4 (C15), 147.7 (C13), 121.2
(C14), 108.3 (C5), 80.2 (C7), 74.9 (C11), 74.7 (C12), 69.2 (C6), 60.3 (C16), 26.7, 25.8,
25.7, 25.7, 18.0, 17.9, 16.4, 16.2, 14.2, 6.3 (C9), -4.5 (C18), -4.7 (C18), -4.9 (C18), -4.9
(C18).
201 4 HO 6 O 5 14 H 8 O 9 11 TBSO H O Si 15
17
4,5-Bis-(tert-butyldimethylsilanyloxy)-5-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-
cyclopropyl]-pent-2-en-1-ol (2.64). (JED 3-235). Diisobutylaluminum hydride (1 M
solution in CH2Cl2, 16.9 mL, 16.9 mmol) was added to a solution of α, β-unsaturated
ester 2.63 (3.57 g, 6.75 mmol) in anhydrous CH2Cl2 (75 mL) at -78 °C. Stirring
continued for 10 min at -78 °C, whereupon EtOAc (5 mL) and saturated aqueous
potassium sodium tartrate (30 mL) were added. The resultant emulsion was stirred for 18
h until the layers were transparent. Once clear, the layers were separated and the organic layer was dried (MgSO4), and concentrated under reduced pressure. The residue was
purified by flash chromatography eluting with hexanes/EtOAc (5:1 to 3:1) to give 3.11 g
(95%) of allylic alcohol 2.64 as a clear oil; 1H NMR (400 MHz) δ 5.88 (dd, J = 15.6, 2.8
Hz, 1 H), 5.82 (dd, J = 15.6, 3.8 Hz, 1 H), 4.17-4.16 (comp, 3 H), 3.93 (dd, J = 8.0, 6.0
Hz, 1 H), 3.68 (t, J = 8.0, 1 H), 3.51-3.45 (comp, 2 H), 1.93 (s, 1 H), 1.42 (s, 3 H), 1.30
(s, 3 H), 0.95-0.86 (comp, 20 H), 0.61 (app dt, J = 8.3, 4.8 Hz, 1 H), 0.45 (app dt, J = 9.3,
5.2 Hz, 1 H), 0.04 (s, 3 H), 0.03 (s, 3 H), 0.03 (s, 3 H), 0.02 (s, 3 H); 13C NMR (100
MHz) δ 130.4, 129.5, 108.6, 80.2, 75.0, 74.8, 68.8, 63.2, 26.8, 25.8, 25.7, 18.0, 17.9,
16.2, 15.8, 6.5, -4.4, -4.7, -4.7, -4.9; IR (neat) 3428, 2954, 2857, 2359, 1472, 1368, 1254, 202 -1 1127, 1064, 836, 775, 668 cm ; MS (CI) m/z 485.3132 [C25H49O5Si2 (M-1) requires
485.3119] 471, 469, 429, 411, 355 (base), 307, 289, 285.
NMR Assignments: 1H NMR (400 MHz) δ 5.88 (dd, J = 15.6, 2.8 Hz, 1 H, C13-
H), 5.82 (dd, J = 15.6, 3.8 Hz, 1 H, C14-H), 4.17-4.16 (comp, 3 H, C15-2H), 3.93 (dd, J
= 8.0, 6.0 Hz, 1 H), 3.68 (t, J = 8.0, 1 H), 3.51-3.45 (comp, 2 H), 1.93 (s, 1 H, OH), 1.42
(s, 3 H, C4-3H), 1.30 (s, 3 H, C4-3H), 0.95-0.86 (comp, 20 H, C8-H and C10-H and C19-
18H), 0.61 (app dt, J = 8.8, 5.0 Hz, 1 H, C9-H), 0.45 (app dt, J = 8.8, 5.0 Hz, 1 H, C9-H),
0.04 (s, 3 H, C17-3H), 0.03 (s, 3 H, C17-3), 0.03 (s, 3 H, C17-3), 0.02 (s, 3 H, C17-3);
13C NMR (100 MHz) δ 130.4 (C13), 129.5 (C14), 108.6 (C5), 80.2 (C7), 75.0 (C11),
74.8 (C12), 68.8 (C6), 63.2 (C15), 26.8, 25.8, 25.7, 18.0 (C18), 17.9 (C18), 16.2 (C10),
15.8 (C8), 6.5 (C9), -4.4 (C17), -4.7 (C17), -4.7 (C17), -4.9 (C17).
20 O2N 18 O
O 4 15 6 O 5 14 H 8 O 9 11 TBSO H O Si 21
31 4-Nitro-benzoic acid 4,5-bis-(tert-butyl dimethyl silanyloxy)-5-[2-(2,2-
dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-pent-2-enyl ester. (2.XX). (JED 5-41). p-
NO2 Benzoyl chloride (109 mg, 0.59 mmol) was added to a solution of allylic alcohol
203 2.64 (144 mg, 0.30 mmol), pyridine (0.12 mL, 1.48 mmol), and DMAP (1 mg, 0.008
mmol) in anhydrous CH2Cl2 (3 mL) at rt. After 18 h at rt, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with hexanes/EtOAc (10:1) to give 150 mg of 2.XX (80%) as a
pale yellow oil; 1H NMR (400 MHz) δ 8.25 (d, J = 8.8 Hz, 2 H), 8.18 (d, J = 8.8 Hz, 2
H), 6.02 (dd, J = 15.6, 4.0 Hz, 1 H), 5.89 (dt, J = 15.6, 6.2, 1.4 Hz, 1 H), 4.88 (dd, J =
6.2, 1.4 Hz, 2 H), 4.17 (br, 1 H), 3.95 (dd, J = 8.0, 6.0 Hz, 1 H), 3.61 (app t, J = 8.0 Hz, 1
H), 3.43-3.39 (comp, 2 H), 1.36 (s, 3 H), 1.27 (s, 3 H), 0.88-0.82 (comp, 20 H), 0.58 (dt,
J = 8.6, 5.0 Hz, 1 H), 0.50 (dt, J = 8.6, 5.0 Hz, 1 H), 0.03 (s, 3 H), 0.02 (s, 3 H), 0.01 (s, 3
H), 0.01 (s, 3 H); 13C NMR (100 MHz) δ 164.3, 150.5, 135.6, 134.6, 130.7, 123.6, 123.5,
108.5, 80.2, 75.1, 74.9, 69.2, 65.9, 26.7, 25.9, 25.8, 25.7, 18.0, 17.8, 16.4, 16.2, 6.6, -4.5,
-4.6, -4.7, -4.9.
NMR Assignments: 1H NMR (400 MHz) δ 8.25 (d, J = 8.8 Hz, 2 H, C19-2H),
8.18 (d, J = 8.8 Hz, 2 H, C18-2H), 6.02 (dd, J = 15.6, 4.0 Hz, 1 H, C13-H), 5.89 (dt, J =
15.6, 6.2, 1.4 Hz, 1 H, C14-H), 4.88 (dd, J = 6.2, 1.4 Hz, 2 H, C15-2H), 4.17 (br, 1 H,
C12-H), 3.95 (dd, J = 8.0, 6.0 Hz, 1 H, C6-H), 3.61 (app t, J = 8.0 Hz, 1 H, C6-H), 3.43-
3.39 (comp, 2 H), 1.36 (s, 3 H), 1.27 (s, 3 H), 0.88-0.82 (comp, 20 H, C8-H and C10-H
and C23-18H), 0.58 (dt, J = 8.6, 5.0 Hz, 1 H, C9-H), 0.50 (dt, J = 8.6, 5.0 Hz, 1 H, C9-
H), 0.03 (s, 3 H, C21-3H), 0.02 (s, 3 H, C21-3H), 0.01 (s, 3 H, C21-3H), 0.01 (s, 3 H,
C21-3H); 13C NMR (100 MHz) δ 164.3 (C16), 150.5 (C20), 135.6 (C17), 134.6 (C13),
130.7 (C18), 123.6 (C14), 123.5 (C19), 108.5 (C5), 80.2 (C7), 75.1 (C11), 74.9 (C12),
204 69.2 (C6), 65.9 (C15), 26.7 (C4), 25.9 (C4), 25.8 (C23), 25.7 (C23), 18.0 (C22), 17.8
(C22), 16.4 (C8), 16.2 (C10), 6.6 (C9), -4.5 (C21), -4.6 (C21), -4.7 (C21), -4.9 (C21).
20 O2N 18 O
O 4 15 6 O 5 14 H 8 O 9 11 HO H OH 4-Nitro-benzoic acid 5-[2-(2,2-dimethyl [1,3]dioxolan-4-yl) cyclopropyl]-4,5-
dihydroxy pent-2-enyl ester (2.XX) (JED 5-42). TBAF (186 mg, 0.59 mmol) was
added to a solution of bis-TBS ether 2.XX in anhydrous THF (2.5 mL) at rt. After 4 h at rt, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to give 80 mg (83%) of diol 2.XX as a clear oil; 1H NMR (400 MHz) δ 8.26 (d, J = 8.8 Hz, 2 H), 8.14 (d, J =
8.8 Hz, 2 H), 6.01 (dt, J = 15.6, 5.6 Hz, 1 H), 5.93 (dd, J = 15.6, 5.4 Hz, 1 H), 4.87 (d, J =
5.6 Hz, 2 H), 4.12 (app t, J = 5.6 Hz, 1 H), 4.03 (ddd, J = 9.6, 7.2, 4.8 Hz, 1 H), 3.70-3.63
(comp, 2 H), 2.96 (dd, J = 7.6, 5.6 Hz, 1 H), 2.45 (br, 2 H), 1.39 (s, 3 H), 1.30 (s, 3 H),
1.04 (app tt, J = 9.2, 5.2 Hz, 1 H), 0.88 (app tt, J = 8.2, 5.2 Hz, 1 H), 0.63 (app dt, J = 8.2,
5.2 Hz, 1 H), 0.59 (app dt, J = 9.2, 5.2 Hz, 1 H).
NMR Assignment: 1H NMR (400 MHz) δ 8.26 (d, J = 8.8 Hz, 2 H, C19-2H),
8.14 (d, J = 8.8 Hz, 2 H, C18-2H), 6.01 (dt, J = 15.6, 5.6 Hz, 1 H, C14-H), 5.93 (dd, J =
15.6, 5.4 Hz, 1 H, C13-H), 4.87 (d, J = 5.6 Hz, 2 H, C15-2H), 4.12 (app t, J = 5.6 Hz, 1
205 H, C12-H), 4.03 (ddd, J = 9.6, 7.2, 4.8 Hz, 1 H, C6-H), 3.70-3.63 (comp, 2 H, C6-H and
C7-H), 2.96 (dd, J = 7.6, 5.6 Hz, 1 H, C11-H), 2.45 (br, 2 H, OH), 1.39 (s, 3 H, C4-3H),
1.30 (s, 3 H, C4-3H), 1.04 (app tt, J = 9.2, 5.2 Hz, 1 H, C8-H), 0.88 (app tt, J = 8.2, 5.2
Hz, 1 H, C10-H), 0.63 (app dt, J = 8.2, 5.2 Hz, 1 H, C9-H), 0.59 (app dt, J = 9.2, 5.2 Hz,
1 H, C9-H).
4 Br 6 O 5 14 H 8 O 9 11 TBSO H O Si 15
17
4-{2-[5-Bromo-1,2-bis-(tert-butyldimethylsilanyloxy)-pent-3-enyl]-
cyclopropyl}-2,2-dimethyl-[1,3]dioxolane (2.65). (JED 5-21). Triphenylphosphine
(1.39 g, 5.29 mmol) and carbon tetrabromide (2.02 g, 6.10 mmol) was added to a solution of allylic alcohol 2.64 (1.98 g, 4.07 mmol) in anhydrous CH2Cl2 (40 mL) at 0 °C.
Stirring continued for 15 min at 0 °C, whereupon saturated aqueous NaHCO3 (15 mL)
was added and the layers were separated. The organic layer was dried (MgSO4), and
concentrated under reduced pressure. The residue was purified by flash chromatography
eluting with hexanes/EtOAc (20:1) to provide 2.15 g (96%) of 2.65 as a clear oil; 1H
NMR (400 MHz) δ 5.90-5.87 (comp, 2 H), 4.14 (app d, J = 4.8 Hz, 1 H), 4.02-3.94
(comp, 3 H), 3.60 (app t, J = 8.0 Hz, 1 H), 3.42 (dt, J = 8.0, 6.0 Hz, 1 H), 3.36 (app t, J =
206 4.8 Hz, 1 H), 1.39 (s, 3 H), 1.30 (s, 3 H), 0.89 (s, 9 H), 0.86 (s, 9 H), 0.87-0.81 (comp, 2
H), 0.59 (app dt, J = 8.2, 5.0 Hz, 1H), 0.52 (app dt, J = 8.2, 5.0 Hz, 1H), 0.03 (s, 3 H), 0.2
(s, 3 H), 0.2 (s, 3 H), 0.01 (s, 3 H); 13C NMR (100 MHz) δ 134.5, 126.7, 108.6, 80.2,
75.7, 74.9, 69.3, 32.7, 26.8, 25.8, 25.8, 18.1, 17.9, 16.6, 16.4, 6.7, -4.4, -4.6, -4.6, -4.9; IR
(neat) 2929, 2857, 1472, 1368, 1253, 1122, 1065 cm-1; MS (FAB) m/z 550, 549,
548.2223 [C25H49BrO4Si2 (M) requires 548.2353] 493, 491, 435.
NMR Assignments: 1H NMR (400 MHz) δ 5.90-5.87 (comp, 2 H, C13-H and
C14-H), 4.14 (app d, J = 4.8 Hz, 1 H, C12-H), 4.02-3.94 (comp, 3 H, C6-H and C15-2H),
3.60 (app t, J = 8.0 Hz, 1 H, C6-H), 3.42 (dt, J = 8.0, 6.0 Hz, 1 H, C7-H), 3.36 (app t, J =
4.8 Hz, 1 H, C11-H), 1.39 (s, 3 H, C4-H), 1.30 (s, 3 H, C4-H), 0.89 (s, 9 H, C16-9H),
0.86 (s, 9 H, C16-9H), 0.87-0.81 (comp, 2 H, C8-H and C10-H), 0.59 (app dt, J = 8.2, 5.0
Hz, 1H, C9-H), 0.52 (app dt, J = 8.2, 5.0 Hz, 1H, C9-H), 0.03 (s, 3 H, C16-3H), 0.2 (s, 3
H, C16-3H), 0.2 (s, 3 H, C16-3H), 0.01 (s, 3 H, C16-3H); 13C NMR (100 MHz) δ 134.5
(C13), 126.7 (C14), 108.6 (C5), 80.2 (C7), 75.7 (C11), 74.9 (C12), 69.3 (C6), 32.7 (C15),
26.8 (C4), 25.8 (C18 + C4), 25.8, (C18) 18.1 (C17), 17.9 (C17), 16.6 (C10), 16.4 (C8),
6.7 (C9), -4.4 (C16), -4.6 (C16), -4.6 (C16), -4.9 (C16).
207 4 15 O 5 H 7 22 O 9 11 TBSO H O Si 23
25
4-{2-[1,2-Bis-(tert-butyldimethylsilanyloxy)-dodec-3-en-6-ynyl]-cyclopropyl}-
2,2-dimethyl-[1,3]dioxolane (2.66). (JED 3-57). 1-Heptyne (0.90 mL, 6.87 mmol) and
butyllithium (2.5 M solution in hexanes, 2.23 mL, 5.58 mmol) was added to a solution of
. CuBr SMe2 (132 mg, 0.64 mmol) in THF (42 mL) at -78 °C. Stirring continued for 1.5 h
at -78 °C, whereupon a solution of allylic bromide 2.65 (2.36 g, 4.29 mmol) in THF (5
mL) was added drop wise. The -78 °C bath was removed and stirring continued for 8 h at
rt whereupon Et2O (10 mL) and saturated aqueous NH4Cl (20 mL) was added. Stirring
continued for an additional 12 h at rt. The layers were separated and the organic layer was dried (MgSO4), and concentrated under reduced pressure. The residue was purified
by flash chromatography eluting with hexanes/EtOAc (20:1) to provide 2.29 g (95%) of
skipped enyne 2.66 as a pale yellow oil; 1H NMR (500 MHz) δ 5.86 (ddt, J = 15.5, 4.5,
2.0 Hz, 1 H), 5.59 (dtd, J = 15.5, 5.0, 1.5, 1 H), 4.13 (app dt, J = 4.5, 1.5 Hz, 1 H), 3.95
(dd, J = 8.0, 6.0 Hz, 1 H), 3.64 (app t, J = 8.0, 1 H), 3.42 (app t, J = 4.5 Hz, 1 H), 3.36
(dt, J = 8.0, 6.0 Hz, 1 H), 2.92 (dt, J = 5.0, 2.0 Hz, 2 H), 2.14 (tt, J = 7.2, 2.0 Hz, 2 H),
1.47 (p, J = 7.6 Hz, 2 H), 1.39 (s, 3 H), 1.30 (s, 3 H), 1.36-1.26 (comp, 4 H), 0.92-0.84
(comp, 23 H), 0.58 (dt, J = 9.4, 4.7 Hz, 1H), 0.47 (dt, J =9.4, 4.7 Hz, 1 H), 0.02 (s, 3 H), 208 0.02 (s, 3 H), 0.02 (s, 3 H), 0.01 (s, 3 H); 13C NMR (125 MHz) δ130.1, 125.4, 108.4,
82.8, 80.8, 76.9, 75.4, 75.1, 69.4, 31.1, 28.8, 26.8, 25.9, 25.9, 25.8, 22.2, 21.9, 18.7, 18.1,
17.9, 16.3, 16.3, 14.0, 6.4, -4.4, -4.6, -4.6, -4.8; IR (neat) 2930, 2858, 2360, 1472, 1368,
-1 1252, 1125, 1065, 913, 836, 743, 668 cm ; MS (CI) m/z 565.4090 [C32H61O4Si2 (M+1)
requires 565.4108], 549, 507, 433, 285 (base), 227.
NMR Assignments: 1H NMR (500 MHz) δ 5.86 (ddt, J = 15.5, 4.5, 2.0 Hz, 1 H,
C13-H), 5.59 (dtd, J = 15.5, 5.0, 1.5, 1 H, C14-H), 4.13 (app dt, J = 4.5, 1.5 Hz, 1 H,
C12-H), 3.95 (dd, J = 8.0, 6.0 Hz, 1 H, C6-H), 3.64 (app t, J = 8.0, 1 H, C6-H), 3.42 (app t, J = 4.5 Hz, 1 H, C11-H), 3.36 (dt, J = 8.0, 6.0 Hz, 1 H, C7-H), 2.92 (dt, J = 5.0, 2.0 Hz,
2 H, C15-2H), 2.14 (tt, J = 7.2, 2.0 Hz, 2 H, C18-2H), 1.47 (p, J = 7.6 Hz, 2 H, C19-2H),
1.39 (s, 3 H, C4-3H), 1.30 (s, 3 H, C4-3H), 1.36-1.26 (comp, 4 H, C20-2H and C21-2H),
0.92-0.84 (comp, 23 H, C8-H and C10-H and C22-3H and C25-9H and C25-9H), 0.58
(dt, J = 9.4, 4.7 Hz, 1H, C9-H), 0.47 (dt, J =9.4, 4.7 Hz, 1 H, C9-H), 0.02 (s, 3 H, C23-
3H), 0.02 (s, 3 H, C23-3H), 0.02 (s, 3 H, C23-3H), 0.01 (s, 3 H, C23-3H); 13C NMR (125
MHz) δ 130.1 (C13), 125.4 (C14), 108.4 (108), 82.8 (C17), 80.8 (C7), 76.9 (C16), 75.4
(C12), 75.1 (C11), 69.4 (C6), 31.1 (C20), 28.8 (C19), 26.8 (C4), 25.9 (C21), 25.9 (C25),
25.8 (C25), 22.2 (C4), 21.9 (C15), 18.7 (C18), 18.1 (C24), 17.9 (C24), 16.3 (C8), 16.3
(C10), 14.0 (C22), 6.4 (C9), -4.4 (C23), -4.6 (C23), -4.6 (C23), -4.8 (C23).
209 15 O 5 H 7 22 O 9 4 11 HO H OH
1-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-dodec-3-en-6-yne-1,2-diol
(2.68). (JED 4-217) A solution of tetrabutylammonium fluoride (1.78 g, 5.65 mmol) in
THF (5 mL) was added to a solution of bis-silyl ether 2.66 (1.45 g, 2.57 mmol) at 0 ºC.
The solution was stirred at 0 ºC for 20 min, whereupon the bath was removed and stirring
continued for an additional 3 h at rt. The reaction mixture was concentrated under
reduced pressure, and the residue was purified by flash chromatography eluting with
hexanes/EtOAc (2:1) to give 843 mg (97%) of diol 2.68 as a clear oil; 1H NMR (400
MHz) δ 5.82 (app dd, J = 15.4, 4.6 Hz, 1 H), 5.76 (app dd, J = 15.4, 4.2 Hz, 1 H), 4.06
(dd, J = 7.8, 6.0 Hz, 1 H), 4.05 (app dd, J = 5.8, 4.6 Hz, 1 H), 3.69 (app t, J = 7.8 Hz, 1
H), 3.62 (app dt, J = 7.6, 6.0 Hz, 1 H), 3.00 (dd, J = 7.6, 5.8 Hz, 1 H), 2.95-2.94 (m, 2 H),
2.16 (tt, J = 7.2, 2.4 Hz, 2 H), 2.10 (br, 2 H), 1.49 (p, J = 7.2 Hz, 2 H), 1.42 (s, 3 H),
1.39-1.24 (comp, 7 H), 1.05 (app tt, J = 7.6, 5.1 Hz, 1 H), 0.89 (t, J = 7.2 Hz, 3 H), 0.92-
0.83 (m, 1 H), 0.65 (app dd, J = 8.0, 5.1 Hz, 1 H), 0.64 (app dd, J = 8.0, 5.1 Hz, 1 H); 13C
NMR (100 MHz) δ 130.2, 128.6, 109.0, 83.1, 79.0, 76.8, 76.3, 75.9, 69.0, 31.1, 28.7,
26.8, 25.7, 22.2, 21.9, 18.7, 18.0, 18.0, 14.0, 7.9; IR (neat) 3416, 2984, 2931, 2872, 1455,
-1 1215, 1061 cm ; MS (CI) m/z 337.2349 [C20H33O4 (M+1) requires 337.2379], 335, 319,
293, 279, 261 (base), 243.
210 NMR Assignments: 1H NMR (400 MHz) δ 5.82 (app dd, J = 15.4, 4.6 Hz, 1 H,
C13-H), 5.76 (app dd, J = 15.4, 4.2 Hz, 1 H, C14-H), 4.06 (dd, J = 7.8, 6.0 Hz, 1 H, C6-
H), 4.05 (app dd, J = 5.8, 4.6 Hz, 1 H, C12-H), 3.69 (app t, J = 7.8 Hz, 1 H, C6-H), 3.62
(app dt, J = 7.6, 6.0 Hz, 1 H, C7-H), 3.00 (dd, J = 7.6, 5.8 Hz, 1 H, C11-H), 2.95-2.94 (m,
2 H, C15-2H), 2.16 (tt, J = 7.2, 2.4 Hz, 2 H, C18-2H), 2.10 (br, 2 H, OH-2H), 1.49 (p, J =
7.2 Hz, 2 H, C19-2H), 1.42 (s, 3 H, C4-3H), 1.39-1.24 (comp, 7 H, C4-3H and C20-2H and C21-2H), 1.05 (app tt, J = 7.6, 5.1 Hz, 1 H, C8-H), 0.89 (t, J = 7.2 Hz, 3 H, C22-3H),
0.92-0.83 (m, 1 H, C10-H), 0.65 (app dd, J = 8.0, 5.1 Hz, 1 H, C9-H), 0.64 (app dd, J =
8.0, 5.1 Hz, 1 H, C9-H); 13C NMR (100 MHz) δ 130.2 (C13), 128.6 (C14), 109.0 (C5),
83.1 (C7), 79.0, 76.8, 76.3, 75.9, 69.0 (C6), 31.1, 28.7, 26.8, 25.7, 22.2, 21.9, 18.7, 18.0,
18.0, 14.0, 7.9 (C9);
15 O 5 H 7 22 O 9 4 11 O H Si OH 25 23
2-(tert-Butyldimethylsilanyloxy)-1-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-
dodec-3-en-6-yn-1-ol (2.71). (JED 4-102). tert-Butyldimethylsilyl chloride (19 mg,
0.13 mmol) was added to a solution of diol 2.68 (40 mg, 0.12 mmol) and imidazole (12 mg, 0.18 mmol) in anhydrous DMF (1.2 mL) at rt. Stirring continued for 24 h at rt whereupon the reaction mixture was diluted with Et2O (5 mL) and washed consecutively
211 with aqueous 1 M HCl (5 mL), aqueous NaHCO3 (5 mL), and brine (2 mL). The organic
layer was dried (MgSO4), and concentrated under reduced pressure. The residue was
purified by flash chromatography eluting with hexanes/EtOAc (10:1) to give 39 mg
(72%) of 2.71 as a pale yellow oil;1H NMR (400 MHz) δ 5.69 (dd, J = 15.2, 6.8 Hz, 1
H), 5.62 (dt, J = 15.2, 4.8 Hz, 1 H), 4.07 (dd, J = 8.0, 6.0 Hz, 1 H), 3.98 (app t, J = 6.8
Hz, 1 H), 3.72 (app t, J = 8.0 Hz, 1 H), 3.50 (app dt, J = 8.0, 8.0 Hz, 1 H), 2.90-2.89 (m, 2
H), 2.84 (br t, J = 6.8 Hz, 1 H), 2.51 (br, 1 H), 2.14 (tt, J = 7.2, 2.4 Hz, 2 H), 1.47 (p, J =
7.2 Hz, 2 H), 1.41 (s, 3 H), 1.37-1.26 (comp, 7 H), 1.03-0.96 (m, 1 H), 0.89-0.86 (comp,
12 H), 0.76-0.69 (m, 1 H), 0.58 (app t, J = 6.8 Hz, 2 H), 0.06 (s, 3 H), 0.03 (s, 3 H).
NMR Assignments: 1H NMR (400 MHz) δ 5.69 (dd, J = 15.2, 6.8 Hz, 1 H, C13-
H), 5.62 (dt, J = 15.2, 4.8 Hz, 1 H, C14-H), 4.07 (dd, J = 8.0, 6.0 Hz, 1 H, C6-H), 3.98
(app t, J = 6.8 Hz, 1 H, C12-H), 3.72 (app t, J = 8.0 Hz, 1 H, C6-H), 3.50 (app dt, J = 8.0,
8.0 Hz, 1 H, C7-H), 2.90-2.89 (m, 2 H, C15-2H), 2.84 (br t, J = 6.8 Hz, 1 H, C11-H),
2.51 (br, 1 H, OH), 2.14 (tt, J = 7.2, 2.4 Hz, 2 H, C18-2H), 1.47 (p, J = 7.2 Hz, 2 H, C19-
2H), 1.41 (s, 3 H, C4-H), 1.37-1.26 (comp, 7 H, C4-3H and C20-3H and C21-3H), 1.03-
0.96 (m, 1 H, C8-H), 0.89-0.86 (comp, 12 H, C22-3H and C25-18H), 0.76-0.69 (m, 1 H,
C1-H), 0.58 (app t, J = 6.8 Hz, 2 H, C9-2H), 0.06 (s, 3 H, C23-3H), 0.03 (s, 3 H, C23-
3H).
212 15 O 5 H 7 22 O 9 4 11 HO H O Si 23
25
1-(tert-Butyldimethylsilanyloxy)-1-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-
dodec-3-en-6-yn-2-ol (2.72). Isolated as a minor regioisomer in JED 4-101; 1H NMR
(400 MHz) δ 5.76 (ddt, J = 15.2, 5.2, 1.4 Hz, 1 H), 5.68 (dtd, J = 15.2, 4.8, 1.4 Hz, 1 H),
4.02 (app dd, J = 8.0, 6.2 Hz, 2 H), 3.68 (app t, J = 8.0 Hz, 1 H), 3.54 (app dt, J = 7.2, 7.2
Hz, 1 H), 3.18 (dd, J = 6.2, 4.2 Hz, 1 H), 2.92-2.91 (m, 2 H), 2.21 (br, 1 H), 2.14 (tt, J =
7.2, 2.0 Hz, 2 H), 1.47 (p, J = 7.2 Hz, 2 H), 1.40 (s, 3 H), 1.37-1.26 (comp, 7 H), 1.00-
0.91 (comp, 2 H), 0.90-0.85 (comp, 12 H), 0.60 (app dt J = 8.8, 4.8 Hz, 1 H), 0.56 (app
dt, J = 8.8, 5.2 Hz, 1 H), 0.05 (s, 3 H), 0.03 (s, 3 H); 13C NMR (100 Mhz) δ 131.2, 127.0,
108.8, 82.9, 79.4, 76.4, 75.5, 69.2, 31.1, 28.7, 26.8, 25.9, 25.7, 22.2, 21.8, 18.9, 18.7,
18.1, 17.9, 14.0, 7.1, -3.9, -4.2.
NMR Assignments: 1H NMR (400 MHz) δ 5.76 (ddt, J = 15.2, 5.2, 1.4 Hz, 1 H,
C13-H), 5.68 (dtd, J = 15.2, 4.8, 1.4 Hz, 1 H, C14-H), 4.02 (app dd, J = 8.0, 6.2 Hz, 2 H,
C6-H and C12-H), 3.68 (app t, J = 8.0 Hz, 1 H, C6-H), 3.54 (app dt, J = 7.2, 7.2 Hz, 1 H,
C7-H), 3.18 (dd, J = 6.2, 4.2 Hz, 1 H, C11-H), 2.92-2.91 (m, 2 H, C15-2H), 2.21 (br, 1 H,
OH), 2.14 (tt, J = 7.2, 2.0 Hz, 2 H, C18-2H), 1.47 (p, J = 7.2 Hz, 2 H, C19-2H), 1.40 (s, 3
H, C4-3H), 1.37-1.26 (comp, 7 H, C4-3H and C20-2H and C21-2H), 1.00-0.91 (comp, 2 213 H, C8-H and C10-H), 0.90-0.85 (comp, 12 H, C22-3H and C25-9H), 0.60 (app dt J = 8.8,
4.8 Hz, 1 H, C9-H), 0.56 (app dt, J = 8.8, 5.2 Hz, 1 H, C9-H), 0.05 (s, 3 H, C25-H), 0.03
(s, 3 H, C25-H); 13C NMR (100 Mhz) δ 131.2 (C14), 127.0 (C13), 108.8 (C5), 82.9 (C7),
79.4, 76.4, 75.5, 69.2 (C6), 31.1, 28.7, 26.8, 25.9 (C25), 25.7, 22.2, 21.8, 18.9, 18.7, 18.1,
17.9, 14.0, 7.1 (C9), -3.9 (C23), -4.2 (C23).
15 O 5 H 7 22 O 9 4 11 O H Si OH 24 25
1-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-2-
triisopropylsilanyloxydodec-3-en-6-yn-1-ol (2.73). (JED 4-114). Triisopropylsilyl
chloride (0.13 mL, 0.62 mmol) was added to a solution of diol 2.68 (70 mg, 0.21 mmol)
and imidazole (84 mg, 1.25 mmol) in anhydrous DMF (2 mL) at rt. Stirring continued
for 24 h at rt, whereupon the reaction mixture was diluted with Et2O (5 mL) and washed
consecutively with aqueous 1 M HCl (5 mL), aqueous NaHCO3 (5 mL), and brine (2
mL). The organic layer was dried (MgSO4), and concentrated under reduced pressure.
The residue was purified by flash chromatography eluting with hexanes/EtOAc (10:1) to
give 84 mg (82%) of 2.73 as a pale yellow oil. An additional 12 mg (18%) of starting
diol 2.68 was also recovered; 1H NMR (500 MHz) δ 5.71 (ddt, J = 15.5, 8.0, 1.8 Hz, 1
214 H), 5.61 (app dt, J = 15.5, 5.0 Hz, 1 H), 4.08 (dd, J =8.0, 7.0 Hz, 1 H), 4.06 (dd, J = 8.0,
6.0 Hz, 1 H), 3.70 (app t, J = 8.00 Hz, 1 H), 3.50 (dt, J = 8.0, 6.0 Hz, 1 H), 2.93 (app t, J
= 7.0 Hz, 1 H), 2.89 (dd, J = 5.0, 1.8 Hz, 2 H), 2.57 (br, 1 H), 2.13 (tt, J = 7.2, 2.0 Hz, 2
H), 1.46 (p, J = 7.2 Hz, 2 H), 1.40 (s, 3 H), 1.35-1.26 (comp, 7 H), 1.07-1.02 (comp, 21
H), 1.00-0.97 (m, 1 H), 0.87 (t, J = 7.2 Hz, 3 H),0.77-0.72 (m, 1 H), 0.60 (app dt, J = 8.5,
5.0 Hz, 1 H), 0.56 (app dt, J = 8.5, 5.0 Hz, 1 H); 13C NMR (100 MHz) δ 131.4, 128.5,
108.9, 82.9, 79.7, 78.2, 77.1, 76.1, 69.5, 31.1, 28.7, 26.7, 25.8, 22.2, 21.8, 18.7, 18.1,
18.0, 17.9, 17.7, 14.0, 12.5, 8.0; IR (neat) 3476, 2939, 2866, 1463, 1379, 1246, 1064,
-1 882, 680 cm ; MS (CI) m/z 492, 491.3559 [C29H51O4Si (M) requires 491.3557], 476
(base), 450, 418, 321, 301.
NMR Assignments: 1H NMR (500 MHz) δ 5.71 (ddt, J = 15.5, 8.0, 1.8 Hz, 1 H,
C13-H), 5.61 (app dt, J = 15.5, 5.0 Hz, 1 H, C14-H), 4.08 (dd, J =8.0, 7.0 Hz, 1 H, C12-
H), 4.06 (dd, J = 8.0, 6.0 Hz, 1 H, C6-H), 3.70 (app t, J = 8.00 Hz, 1 H, C6-H), 3.50 (dt, J
= 8.0, 6.0 Hz, 1 H, C7-H), 2.93 (app t, J = 7.0 Hz, 1 H, C11-H), 2.89 (dd, J = 5.0, 1.8 Hz,
2 H, C15-2H), 2.57 (br, 1 H, OH), 2.13 (tt, J = 7.2, 2.0 Hz, 2 H, C18-2H), 1.46 (p, J = 7.2
Hz, 2 H, C19-2H), 1.40 (s, 3 H, C4-3H), 1.35-1.26 (comp, 7 H, C4-3H and C20-2H and
C21-2H), 1.07-1.02 (comp, 21 H, C23-3H and C24-18H), 1.00-0.97 (m, 1 H, C8-H), 0.87
(t, J = 7.2 Hz, 3 H, C22-3H, C22-3H),0.77-0.72 (m, 1 H, C10-H), 0.60 (app dt, J = 8.5,
5.0 Hz, 1 H, C9-H), 0.56 (app dt, J = 8.5, 5.0 Hz, 1 H, C9-H); 13C NMR (125 MHz) δ
131.4 (C13), 128.5 (C14), 108.9 (C5), 82.9 (C16), 79.7 (C7), 78.2 (C12), 77.1, 76.1, 69.5
(C6), 31.1, 28.7 (C17), 26.7 (C4), 25.8 (C4), 22.2, 21.8, 18.7 (C18), 18.1 (C24), 18.0
(C24), 17.9, 17.7 (C10), 14.0 (C22), 12.5 (C23), 8.0 (C9).
215
15 O 5 H 7 22 HO O 9 4 11 H O Si 23
25
1-(tert-Butyldimethylsilanyloxy)-1-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)- cyclopropyl]-dodec-2-en-6-yn-4-ol. (2.75). (JED 4-111). Freshly distilled tributyl phosphine (21 µL, 0.08 mmol) was added to a solution of 2.72 (25 mg, 0.06 mmol) and phenyl selenocyanate (10 µL, 0.08 mmol) in anhydrous THF (0.5mL) at rt. The reaction turned from a pale yellow to dark brown. Stirring continued for 5 min at rt, whereupon
the crude reaction was filtered through a short plug of silica gel eluting with
hexanes/EtOAc (1:0 to 5:1). The eluted material was concentrated under reduced
pressure. Pyridine (45 µL, 0.57 mmol) and a 30% aqueous solution of H2O2 (63 µL)
were added to a solution of the crude mixture in CH2Cl2 (1 mL) at rt. The solution was
stirred for 5 h at rt, whereupon 1 M aqueous HCl (1 mL) was added. The layers were
separated and the organic layer was washed with saturated aqueous NaHCO3 (1 mL),
dried (MgSO4), and concentrated under reduced pressure. The residue was purified by
flash chromatography eluting with hexanes/EtOAc (5:1) to give 4 mg (13%) of trans- allylic alcohol 2.75 as a pale yellow oil;1H NMR (400 MHz) δ 5.73 (ddd, J = 15.2, 5.4,
216 1.2 Hz, 1 H), 5.66 (app dd, J = 15.2, 5.4 Hz, 1 H), 4.23-4.19 (m, 1 H), 4.03 (dd, J = 7.6,
5.4 Hz, 1 H), 3.72-3.65 (comp, 2 H), 3.45 (dt, J = 7.8, 5.6 Hz, 1 H), 2.44 (ddt, J = 16.4,
5.4, 2.4 Hz, 1 H), 2.35 (ddt, J = 16.4, 6.8, 2.4 Hz, 1 H), 2.14 (tt, J = 7.2, 2.4 Hz, 2 H),
1.98 (br, 1 H), 1.47 (p, J = 7.2 Hz, 2 H), 1.42 (s, 3 H), 1.36-1.27 (comp, 4 H), 1.23 (s, 3
H), 0.96-0.78 (comp, 14 H), 0.61 (app dt, J = 8.5, 5.2 Hz, 1 H), 0.57 (app dt, J = 8.5, 5.2
Hz, 1 H), 0.01 (s, 3 H), -0.02 (s, 3 H).
NMR Assignments: 1H NMR (400 MHz) δ 5.73 (ddd, J = 15.2, 5.4, 1.2 Hz, 1 H,
C12-H), 5.66 (app dd, J = 15.2, 5.4 Hz, 1 H, C13-H`), 4.23-4.19 (m, 1 H), 4.03 (dd, J =
7.6, 5.4 Hz, 1 H), 3.72-3.65 (comp, 2 H), 3.45 (dt, J = 7.8, 5.6 Hz, 1 H), 2.44 (ddt, J =
16.4, 5.4, 2.4 Hz, 1 H, C13-H), 2.35 (ddt, J = 16.4, 6.8, 2.4 Hz, 1 H, C13-H), 2.14 (tt, J =
7.2, 2.4 Hz, 2 H, C18-2H), 1.98 (br, 1 H, OH), 1.47 (p, J = 7.2 Hz, 2 H, C19-2H), 1.42 (s,
3 H, C4-3H), 1.36-1.27 (comp, 4 H, C20-2H and C21-2H), 1.23 (s, 3 H, C4-3H), 0.96-
0.78 (comp, 14 H, C8-H and C10-H and C22-3H and C25-9H), 0.61 (app dt, J = 8.5, 5.2
Hz, 1 H, C9-H), 0.57 (app dt, J = 8.5, 5.2 Hz, 1 H, C9-H), 0.01 (s, 3 H, C23-2H), -0.02
(s, 3 H, C23-2H).
217 15 O 5 H 7 22 O 9 4 11 O H Si 26 O 27 24 25 O
Acetic acid 1-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-2-
triisopropylsilanyloxydodec-3-en-6-ynyl ester (2.76). (JED 4-119). Acetic anhydride
(0.14 mL, 1.48 mmol) and Et3N (0.31 mL, 2.22 mmol) were added to a solution of
alcohol 2.73 (73 mg, 0.148 mmol) and 4-dimethylaminopyridine (1 mg, 0.01 mmol) in
anhydrous CH2Cl2 (2 mL) at rt. Stirring continued for 12 h at rt, whereupon a 1 M
solution of aqueous HCl (1 mL) was added. The layers were separated and the organic
layer was washed with saturated aqueous NaHCO3 (1 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel flash
chromatography eluting with hexanes/EtOAc (10:1) to provide 75 mg (95%) of acetate
2.76 as a pale yellow oil; 1H NMR (400 MHz) δ 5.72 (app dd, J = 15.2, 6.6 Hz, 1 H),
5.61 (app dt, J = 15.2, 5.2 Hz, 1 H), 4.39 (dd, J = 8.0, 6.6 Hz, 1 H), 4.30 (app t, J = 6.6
Hz, 1 H), 4.01 (dd, J = 8.0, 6.0 Hz, 1 H), 3.57 (app t, J = 8.0 Hz, 1 H), 3.44 (app dt, J =
8.0, 8.0 Hz, 1 H), 2.90-2.89 (m, 2 H), 2.13 (tt, J = 7.2, 2.0 Hz, 2 H), 2.01 (s, 3 H), 1.46 (p,
J = 7.2 Hz, 2 H), 1.38 (s, 3 H), 1.35-1.26 (comp, 7 H), 1.01-0.95 (comp, 22 H), 0.91-0.82
(comp, 4 H), 0.65 (app t, J = 6.8 Hz, 2 H); 13C NMR (100 MHz) δ 170.3, 130.7, 127.9,
108.9, 82.8, 79.3, 79.1, 76.3, 74.7, 69.2, 31.0, 28.7, 26.7, 25.7, 22.2, 21.8, 21.1, 18.7,
218 18.3, 18.0, 18.0, 15.8, 14.0, 12.3, 8.8; IR (neat) 2937, 2866, 1738, 1463, 1369, 1238,
1066, 680 cm-1.
NMR Assignments: 1H NMR (400 MHz) δ 5.72 (app dd, J = 15.2, 6.6 Hz, 1 H,
C13-H), 5.61 (app dt, J = 15.2, 5.2 Hz, 1 H, C14-H), 4.39 (dd, J = 8.0, 6.6 Hz, 1 H, C12-
H), 4.30 (app t, J = 6.6 Hz, 1 H, C11-H), 4.01 (dd, J = 8.0, 6.0 Hz, 1 H, C6-H), 3.57 (app t, J = 8.0 Hz, 1 H, C6-H), 3.44 (app dt, J = 8.0, 8.0 Hz, 1 H, C7-H), 2.90-2.89 (m, 2 H,
C15-2H), 2.13 (tt, J = 7.2, 2.0 Hz, 2 H, C18-2H), 2.01 (s, 3 H, C26-3H), 1.46 (p, J = 7.2
Hz, 2 H, C19-2H), 1.38 (s, 3 H, C4-3H), 1.35-1.26 (comp, 7 H, C4-3H and C20-2H and
C21-2H), 1.01-0.95 (comp, 22 H, C10-H and C23-3H and C24-2H), 0.91-0.82 (comp, 4
H, C8-H and C22-3H), 0.65 (app t, J = 6.8 Hz, 2 H, C9-2H); 13C NMR (100 MHz) δ
170.3 (C25), 130.7 (C13), 127.9 (C14), 108.9 (C5), 82.8 (C7), 79.3, 79.1, 76.3, 74.7, 69.2
(C6), 31.0, 28.7, 26.7, 25.7, 22.2, 21.8, 21.1, 18.7 (C24), 18.3 (C24), 18.0, 18.0, 15.8,
14.0, 12.3 (C23), 8.8 (C9).
219 5 4 1 5 3
O 6 O
H 8
10 MeO 11
4-Isopropyl-2-(4-methoxy-phenyl)-5-methyl-[1,3]dioxolane. (2.86). (JED 4-
177). p-Toluenesulfonic acid (128 mg, 0.67 mmol) was added to a solution of p-
anisaldehyde dimethyl acetal (1.73 mL, 10.1 mmol) and diol 2.85 (800 mg, 6.77 mmol)
in anhydrous DMF (10 mL) at rt. Stirring continued for 3 h at rt, whereupon Et2O (15 mL) and saturated aqueous NaHCO3 (15 mL) were added. The layers were separated and
the organic layer was washed with H2O (2 x 10 mL) and brine (5 mL), dried (MgSO4),
and concentrated under reduced pressure. The residue was purified by flash
chromatography eluting with hexanes/EtOAc (5:1) to give 1.43 mg (89%) of a C(6)
diastereomeric mixture of benzylidene acetals 2.86 as a clear oil; 1H NMR (400 MHz) δ
7.41 (d, J = 8.6 Hz, 2 H), 6.88 (d, J = 8.6 Hz, 2 H), 5.83 (s, 0.5 H), 5.77 (0.5 H), 4.07-
3.99 (comp, 1 H), 3.78 (s, 3 H), 3.46 (t, J = 6.4 Hz, 0.5 H), 3.41 (t, J = 6.4 Hz, 0.5 H),
1.95-1.79 (comp, 1 H), 1.40 (d, J = 6.4 Hz, 1.5 H), 1.33 (d, J = 6.0 Hz, 1.5 H), 1.04 (d, J
= 6.8 Hz, 1.5 H), 1.04 (d, J = 6.8 Hz, 1.5 H), 0.98 (d, 6.8 Hz, 1.5 H), 0.95 (d, J = 6.8 Hz,
1.5 H).
NMR Assignments: 1H NMR (400 MHz) δ 7.41 (d, J = 8.6 Hz, 2 H, C7-2H),
6.88 (d, J = 8.6 Hz, 2 H, C7-2H), 5.83 (s, 0.5 H, C6-H), 5.77 (0.5 H, C6-H), 4.07-3.99
220 (comp, 1 H, C2-H, 3.78 (s, 3 H, C10-3H), 3.46 (t, J = 6.4 Hz, 0.5 H, C3-0.5H), 3.41 (t, J
= 6.4 Hz, 1 H, C3-0.5H), 1.95-1.79 (comp, 1 H, C4-H), 1.40 (d, J = 6.4 Hz, 1.5 H, C1-
1.5H), 1.33 (d, J = 6.0 Hz, 1.5 H, C1-1.5H), 1.04 (d, J = 6.8 Hz, 1.5 H, C1-1.5H, C5-
1.5H), 1.04 (d, J = 6.8 Hz, 1.5 H, C5-1.5H), 0.98 (d, 6.8 Hz, 1.5 H, C5’-1.5H), 0.95 (d, J
= 6.8 Hz, 1.5 H C5’-1.5H).
5 4 1 5 3
HO O
6
8 MeO 11 9
3-(4-Methoxy benzyloxy)-4-methyl pentan-2-ol. (2.87). (JED 4-275).
Diisobutylaluminum hydride (1 M solution in CH2Cl2, 0.42 mL, 0.42 mmol) was added
to a solution of benzylidene acetal 2.86 (25 mg, 0.11 mmol) in anhydrous CH2Cl2 (1 mL)
at -78 °C. Stirring continued for 12 h at -78 °C, whereupon EtOAc (1 mL) and saturated
aqueous potassium sodium tartrate (2 mL) were added. The resultant emulsion was
stirred for 18 h at rt or until the layers became transparent. The layers were separated and
the organic layer was dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by flash chromatography eluting with hexanes/EtOAc (5:1 to 2:1) to
give a mixture (5:1) of alcohols 2.87 (more polar) and 2.98 (less polar) as a clear oils;
(JED 2-71). TIBA (1 M solution in hexanes, 1.0 mL, 1.0 mmol) was added to a solution of benzylidene acetal 2.86 (50 mg, 0.21 mmol) in anhydrous CH2Cl2 (2 mL) at rt. 221 Stirring continued for 8 h at rt, whereupon a aqueous solution of 1 M HCl (1 mL) was
added. The layers were separated and the aqueous layer was extracted (2 x 2 mL
CH2Cl2). The combined organic layers were washed with saturated aqueous NaHCO3 (2 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc to give a mixture (8:1) of alcohols
2.87 (more polar) and 2.98 (less polar) as a clear oils; 1H NMR (400 MHz) δ 7.25 (d, J
= 8.8 Hz, 2 H), 6.85 (d, J = 8.8 Hz, 2 H), 4.62 (d, J = 11.0 Hz, 1 H), 4.48 (d, J = 11.0 Hz,
1 H), 3.67 (s, 3 H), 3.75 (p, J = 6.0 Hz, 1 H), 2.94 (app t, J = 5.0 Hz, 1 H), 2.20 (br, 1 H),
1.89 (ddq, J = 6.8, 6.8, 5.0 Hz, 1 H), 1.15 (d, J = 6.0 Hz, 3 H), 0.99 (d, J = 6.8 Hz, 3 H),
0.92 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz) δ 159.2, 130.7, 129.3, 113.8, 88.9, 75.1,
67.9, 55.2, 30.0, 20.3, 20.1, 17.4.
NMR Assignments: 1H NMR (400 MHz) δ 7.25 (d, J = 8.8 Hz, 2 H, C8-2H),
6.85 (d, J = 8.8 Hz, 2 H, C9-2H), 4.62 (d, J = 11.0 Hz, 1 H, C6-H), 4.48 (d, J = 11.0 Hz,
1 H, C6-H), 3.67 (s, 3 H, C11-H), 3.75 (p, J = 6.0 Hz, 1 H, C2-H), 2.94 (app t, J = 5.0
Hz, 1 H, C3-H), 2.20 (br, 1 H, OH), 1.89 (ddq, J = 6.8, 6.8, 5.0 Hz 1 H, C4-H), 1.15 (d, J
= 6.0 Hz, 3 H, C1-3H), 0.99 (d, J = 6.8 Hz, 3 H, C5-3H), 0.92 (d, J = 6.8 Hz, 3 H, C5-
3H); 13C NMR (100 MHz) δ 159.2 (C10), 130.7 (C7), 129.3 (C8), 113.8 (C9), 88.9 (C3),
75.1 (C6), 67.9 (C2), 55.2 (C11), 30.0 (C4), 20.3 (C5), 20.1 (C5), 17.4 (C1).
222 5
4 1 5 3
O OH 6
8
9 MeO 11
2-(4-Methoxy-benzyloxy)-4-methyl-pentan-3-ol. (2.88). Isolated as the minor
regioisomer during the reductive cleavage of 2.86; 1H NMR (400 Hz) δ 7.24 (d, J = 8.8
Hz, 2 H), 6.86 (d, J = 8.8 Hz, 2 H), 4.58 (d, J = 11.4 Hz, 1 H), 4.34 (d, J = 11.4 Hz, 1 H),
3.79 (s, 3 H), 3.50 (p, J = 6.0 Hz, 1 H), 3.14 (dd, J = 6.0, 4.8 Hz, 1 H), 1.76 (ddq, J = 6.8,
6.8, 4.8 Hz, 1 H), 1.15 (d, J = 6.0 Hz, 3 H), 0.99 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.8 Hz,
3 H).
NMR Assignments: 1H NMR (400 Hz) δ 7.24 (d, J = 8.8 Hz, 2 H, C8-2H), 6.86
(d, J = 8.8 Hz, 2 H, C9-2H), 4.58 (d, J = 11.4 Hz, 1 H, C6-H), 4.34 (d, J = 11.4 Hz, 1 H,
C6-H), 3.79 (s, 3 H, C11-H), 3.50 (p, J = 6.0 Hz, 1 H, C3-H), 3.14 (dd, J = 6.0, 4.8 Hz, 1
H, C2-H), 1.76 (ddq, J = 6.8, 6.8, 4.8 Hz, 1 H, C4-H), 1.15 (d, J = 6.0 Hz, 3 H, C1-3H),
0.99 (d, J = 6.8 Hz, 3 H, C5-3H), 0.92 (d, J = 6.8 Hz, 3 H, C5-3H).
223 15 O 5 H 7 22 O 9 4 11 O H O 23
25
MeO 28
1-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-dodec-3-en-6-yne-1,2-
benzylidene acetal (2.89). (JED 4-195). p-Toluenesulfonic acid (10 mg, 0.053 mmol)
was added to a solution of p-anisaldehyde dimethyl acetal (0.28 mL, 1.16 mmol) and diol
2.68 (323 mg, 1.08 mmol) in anhydrous DMF (2.0 mL) at rt. Stirring continued for 3 h at
rt, whereupon Et2O (5 mL) and saturated aqueous NaHCO3 (2 mL) were added. The
layers were separated and the organic layer was washed with H2O (2 x 2 mL) and brine
(2 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was
purified by flash chromatography eluting with hexanes/EtOAc (5:1) to give 408 mg
(91%) of a C(23) diastereomeric mixture of benzylidene acetals 2.89 as a clear oil; 1H
NMR (400 MHz) δ 7.38 (d, J = 8.8 Hz, 2 H), 6.87 (dd, J = 8.8, 2.0 Hz, 2 H), 5.90 (s, 0.5
H), 5.87 (s, 0.5 H), 5.89-5.75 (comp, 2 H), 4.34-4.28 (comp, 1 H), 4.07 (ddd, J = 10.0,
8.0, 6.0 Hz, 1 H), 3.79 (s, 1.5 H), 3.78 (s, 1.5 H), 3.75-3.59 (comp, 2 H), 3.31 (app dt, J =
7.2, 6.0 Hz, 1 H), 2.95 (br, 2 H), 2.19-2.13 (comp, 2 H), 1.52-1.44 (comp, 2 H), 1.40 (s, 3
H), 1.37-1.27 (comp, 7 H),1.09-1.00 (comp, 1 H), 0.99-0.91 (comp, 1 H), 0.88 (t, J = 7.2
Hz, 1.5 H), 0.87 (t, J = 7.2 Hz, 1.5 H), 0.72-0.65 (comp, 1.5 H), 0.60 (app dt, J = 8.8, 5.2
224 Hz, 0.5 H); 13C (100 MHz) δ 160.4, 160.3, 130.6, 130.2, 130.2, 129.9, 128.0, 127.9,
127.4, 113.7, 113.7, 109.0, 103.3, 103.0, 85.0, 83.6, 83.5, 83.2, 78.6, 78.5, 76.3, 76.1,
76.0, 69.3, 69.1, 55.3, 31.1, 29.7, 28.7, 26.7, 25.7, 22.2, 21.9, 18.7, 18.5, 18.4, 16.5, 16.2,
14.0, 6.6, 6.3; IR (neat) 2931, 2871, 1614, 1516, 1369, 1249, 1067, 830 cm-1.
NMR Assignments: 1H NMR (400 MHz) δ 7.38 (d, J = 8.8 Hz, 2 H, C25-2H),
6.87 (dd, J = 8.8, 2.0 Hz, 2 H, C26-2H), 5.90 (s, 0.5 H, C23-0.5H), 5.87 (s, 0.5 H, C23-
0.5H), 5.89-5.75 (comp, 2 H, C13-H and C14-H), 4.34-4.28 (comp, 1 H, C12-H), 4.07
(ddd, J = 10.0, 8.0, 6.0 Hz, 1 H, C6-H), 3.79 (s, 1.5 H, C28-1.5H), 3.78 (s, 1.5 H, C28-
1.5H), 3.75-3.59 (comp, 2 H, C6-H and C7-H), 3.31 (app dt, J = 7.2, 6.0 Hz, 1 H, C11-
H), 2.95 (br, 2 H, C15-2H), 2.19-2.13 (comp, 2 H, C18-2H)), 1.52-1.44 (comp, 2 H, C19-
2H), 1.40 (s, 3 H, C4-3H), 1.37-1.27 (comp, 7 H, C4-3H and C20-2H and C21-2H),1.09-
1.00 (comp, 1 H, C8-2H), 0.99-0.91 (comp, 1 H, C10-H), 0.88 (t, J = 7.2 Hz, 1.5 H, C22-
1.5 H), 0.87 (t, J = 7.2 Hz, 1.5 H, C22-1.5H), 0.72-0.65 (comp, 1.5 H, C9-1.5H), 0.60
(app dt, J = 8.8, 5.2 Hz, 0.5 H, C9-0.5H); 13C (100 MHz) δ 160.4 (C24), 160.3 (C24),
130.6, 130.2, 130.2, 129.9, 128.0, 127.9, 127.4, 113.7, 113.7, 109.0, 103.3, 103.0, 85.0,
83.6, 83.5, 83.2, 78.6, 78.5, 76.3, 76.1, 76.0, 69.3, 69.1, 55.3 (C27), 31.1, 29.7, 28.7,
26.7, 25.7, 22.2, 21.9, 18.7, 18.5, 18.4, 16.5, 16.2, 14.0, 6.6 (C9), 6.3 (C9).
225 15 O 15 O 5 5 H 7 H 7 22 O 22 O 9 4 9 4 11 11 HO H O H O 23 OH 23
25 25
MeO MeO 28 28
1-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-1-(4-methoxy-benzyloxy)- dodec-3-en-6-yn-2-ol (2.90) and 1-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-
2-(4-methoxy-benzyloxy)-dodec-3-en-6-yn-1-ol (2.91). (JED 4-209).
Diisobutylaluminum hydride (1 M solution in CH2Cl2, 1.4 mL, 1.4 mmol) was added to a
solution of benzylidene acetal 2.89 (420 mg, 0.92 mmol) in anhydrous CH2Cl2 (10 mL) at -78 °C. Stirring continued for 5 h at -78 °C, whereupon an additional aliquot of diisobutylaluminum hydride (1 M solution in CH2Cl2, 1.4 mL, 1.4 mmol) was added.
Stirring then continued for an additional 48 h at -78 °C, whereupon EtOAc (5 mL) and
saturated aqueous potassium sodium tartrate (30 mL) were added. The resultant
emulsion was stirred for 18 h at rt or until the layers became transparent. The layers were separated, and the organic layer was dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc
(5:1 to 3:1) to give 345 mg (82%) of an inseparable mixture (4:1) of alcohols 2.90 and
2.91 as a clear oil.
226 15 O 5 H 7 22 HO O 9 4 11 H O 23
25 MeO 28
1-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-cyclopropyl]-1-(4-methoxy-benzyloxy)-
dodec-2-en-6-yn-4-ol (2.92) (JED 4-221 and JED 4-223). Tributylphosphine (1.75 mL,
7.02 mmol) was added drop wise over 0.5 min to a solution of 2.90 and 2.91 (3.6:1) (802
mg, 1.75 mmol) and 2-nitrophenyl selenocyanate (798 mg, 3.51 mmol) in anhydrous
THF (18 mL) at rt. The reaction turned from a pale yellow to dark brown. Stirring
continued for 1 h at rt, whereupon the crude reaction was concentrated under reduced
pressure and filtered through a short plug of silica gel eluting with hexanes/EtOAc (5:1).
The eluted material was concentrated under reduced pressure. Pyridine (0.5 mL) and a
30% aqueous solution of H2O2 (1 mL) were added to a solution of the crude mixture in
CH2Cl2 (20 mL) at rt. The solution was stirred for 5 h at rt, whereupon 1 M aqueous HCl
(5 mL) was added. The layers were separated and the organic layer was washed with
saturated aqueous NaHCO3 (5 mL), dried (MgSO4), and concentrated under reduced
pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc
(5:1) to give 422 mg (46% over 2 steps from 2.89) of trans-allylic alcohol 2.92 as a pale yellow oil; 1H NMR (400 MHz) δ 7.15 (d, J = 8.6 Hz, 2 H), 6.79 (d, J = 8.6 Hz, 2 H),
227 5.65 (app dd, J = 15.6, 4.8 Hz, 1 H), 5.60 (dd, J = 15.6, 5.6 Hz, 1 H), 4.44 (d, J = 12.0
Hz, 1 H), 4.22 (d, J = 12.0 Hz, 1 H), 4.19 (app dt, J = 5.6, 4.8 Hz, 1 H), 4.02 (dd, J = 8.0,
6.4 Hz, 1 H), 3.71 (s, 3 H), 3.66 (app t, J = 8.0 Hz, 1 H), 3.46 (app dt, J = 7.2, 6.4 Hz, 1
H), 3.19 (app t, J = 6.4 Hz, 1H), 2.56 (br, 1 H), 2.47 (ddt, J = 16.0, 4.8, 2.4 Hz, 1 H), 2.40
(ddt, J = 16.0, 6.8, 2.4 Hz, 1 H), 2.07 (tt, J = 7.2, 2.4 Hz, 2 H), 1.41 (p, J = 7.2 Hz, 2 H),
1.36 (s, 3 H), 1.30-1.16 (m, 7 H), 0.89-0.79 (comp, 5 H), 0.54 (app dt, J = 8.0, 5.2 Hz, 1
H), 0.49 (app dt, J = 8.0, 5.2 Hz, 1 H); 13C NMR (100 MHz) δ 158.8, 134.0, 130.3,
130.2, 128.9, 113.5, 108.7, 83.1, 80.4, 79.1, 75.3, 70.1, 69.2, 69.1, 55.0, 30.9, 28.4, 27.9,
26.5, 25.4, 22.0, 19.9, 19.4, 18.5, 13.8, 7.0.
NMR Assignments: 1H NMR (400 MHz) δ 7.15 (d, J = 8.6 Hz, 2 H, C25-2H),
6.79 (d, J = 8.6 Hz, 2 H, C26-2H), 5.65 (app dd, J = 15.6, 4.8 Hz, 1 H, C13-H), 5.60 (dd,
J = 15.6, 5.6 Hz, 1 H, C12-H), 4.44 (d, J = 12.0 Hz, 1 H, C12-H), 4.22 (d, J = 12.0 Hz, 1
H, C12-H), 4.19 (app dt, J = 5.6, 4.8 Hz, 1 H, C14-H), 4.02 (dd, J = 8.0, 6.4 Hz, 1 H, C6-
H), 3.71 (s, 3 H, C28-3H), 3.66 (app t, J = 8.0 Hz, 1 H, C6-H), 3.46 (app dt, J = 7.2, 6.4
Hz, 1 H, C7-H), 3.19 (app t, J = 6.4 Hz, 1H, C11-H), 2.56 (br, 1 H, OH), 2.47 (ddt, J =
16.0, 4.8, 2.4 Hz, 1 H, C15-H), 2.40 (ddt, J = 16.0, 6.8, 2.4 Hz, 1 H, C15-H), 2.07 (tt, J =
7.2, 2.4 Hz, 2 H, C18-2H), 1.41 (p, J = 7.2 Hz, 2 H, C19-2H), 1.36 (s, 3 H, C4-3H), 1.30-
1.16 (m, 7 H, C4-3H and C20-2H and C21-2H), 0.89-0.79 (comp, 5 H, C8-H and C10-H and C22-3H), 0.54 (app dt, J = 8.0, 5.2 Hz, 1 H, C9-H), 0.49 (app dt, J = 8.0, 5.2 Hz, 1 H,
C9-H); 13C NMR (100 MHz) δ 158.8 (C24), 134.0 (C12), 130.3, 130.2, 128.9 (C25),
113.5 (C26), 108.7 (C5), 83.1, 80.4, 79.1, 75.3, 70.1, 69.2, 69.1, 55.0 (C28), 30.9, 28.4,
27.9, 26.5, 25.4, 22.0, 19.9, 19.4, 18.5, 13.8, 7.0 (C9).
228
22
18 4 6 O 5 8 14 H O 9 11 10 H O 23
25
OMe 28
4-{2-[1-(4-Methoxy-benzyloxy)-dodeca-2,4-dien-6-ynyl]-cyclopropyl}-2,2-
dimethyl-[1,3]dioxolane. (2.93). Isolated as a side product of the selenation of 2.90
1 with Bu3P/PhSeCN; H NMR (400 MHz) δ 7.22 (d, J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6, 2
H), 6.66 (dd, J = 15.5, 10.4 Hz, 1 H), 6.31 (app t, J = 10.4 Hz, 1 H), 5.74 (dd, J = 15.5,
7.6 Hz, 1 H), 5.46 (d, J = 10.4 Hz, 1 H), 4.49 (d, J = 11.8 Hz, 1 H), 4.28 (d, J = 11.8 Hz,
1 H), 4.08 (dd, J = 7.6, 6.0 Hz, 1 H), 3.78 (s, 3 H), 3.73 (app t, J = 7.6 Hz, 1 H), 3.51 (dt,
J = 7.6, 7.6 Hz, 1 H), 3.33 (app t, J = 7.4 Hz, 1 H), 2.36 (dt, J = 7.2, 2.4 Hz, 1 H), 1.55 (p,
J = 7.2 Hz, 2 H), 1.53 (s, 3 H), 1.42 (s, 3 H), 1.42-1.28 (m, 4 H), 0.95-0.88 (comp, 2 H),
0.88 (t, J = 7.2 Hz, 3 H), 0.62 (app t, J = 5.6 Hz, 1 H), 0.57 (app t, J = 4.8 Hz, 1 H).
NMR Assignment: 1H NMR (400 MHz) δ 7.22 (d, J = 8.6 Hz, 2 H, C25-2H),
6.85 (d, J = 8.6, 2 H, C26-2H), 6.66 (dd, J = 15.5, 10.4 Hz, 1 H, C13-H), 6.31 (app t, J =
10.4 Hz, 1 H, C14-H), 5.74 (dd, J = 15.5, 7.6 Hz, 1 H, C12-H), 5.46 (d, J = 10.4 Hz, 1 H,
C15-H), 4.49 (d, J = 11.8 Hz, 1 H, C23-H), 4.28 (d, J = 11.8 Hz, 1 H, C23-H), 4.08 (dd, J
229 = 7.6, 6.0 Hz, 1 H, C6-H), 3.78 (s, 3 H, C28-3H), 3.73 (app t, J = 7.6 Hz, 1 H, C6-H),
3.51 (dt, J = 7.6, 7.6 Hz, 1 H, C7-H), 3.33 (app t, J = 7.4 Hz, 1 H, C11-H), 2.36 (dt, J =
7.2, 2.4 Hz, 1 H, C18-H), 1.55 (p, J = 7.2 Hz, 2 H, C19-2H), 1.53 (s, 3 H, C4-3H), 1.42
(s, 3 H, C4-3H), 1.42-1.28 (m, 4 H, C20-2H and C21-2H), 0.95-0.88 (comp, 2 H, C8-H
and C10-H), 0.88 (t, J = 7.2 Hz, 3 H, C22-3H), 0.62 (app t, J = 5.6 Hz, 1 H, C9-H), 0.57
(app t, J = 4.8 Hz, 1 H, C9-H).
15 O 5 H 7 22 PMBO O 9 4 11 H O 23
25 MeO 28
4-{2-[1,4-Bis-(4-methoxy-benzyloxy)-dodec-2-en-6-ynyl]-cyclopropyl}-2,2-
dimethyl-[1,3]dioxolane (2.95). (JED 4-218). 4-Methoxybenzyl chloride (123 µL, 0.79
mmol) was added to a solution of allylic alcohol 2.92 (120 mg, 0.26 mmol) and NaH
(60% suspension in mineral oil, 33 mg, 0.79 mmol) in anhydrous DMF (1.3 mL) at rt.
Stirring continued for 12 h at rt, whereupon the reaction was diluted with Et2O (10 mL) and washed successively with aqueous 1 M HCl (5 mL), saturated aqueous NaHCO3 (5 mL) and brine (2 mL). The organic layer was dried (MgSO4), and concentrated under
reduced pressure. The residue was purified by silica gel chromatography eluting with
230 hexanes/EtOAc (5:1) to give 133 mg (88%) of bis-PMB ether 2.95 as a clear oil; 1H
NMR (400 MHz) δ 7.13 (t, J = 7.8 Hz, 4 H), 6.75 (d, J = 7.8 Hz, 4 H), 5.54 (app dd, J =
15.8, 7.2 Hz, 1 H), 5.46 (app dd, J = 15.8, 7.2 Hz, 1 H), 4.41 (d, J = 11.6 Hz, 2 H), 4.25
(d, J = 11.6 Hz, 1 H), 4.20 (d, J = 11.6 Hz, 1 H), 3.99 (dd, J = 8.4, 6.6 Hz, 1 H), 3.81 (app dt, J = 7.2, 5.1 Hz, 1 H), 3.68 (s, 3 H), 3.68 (s, 3 H), 3.63 (dd, J = 8.4, 7.2 Hz, 1 H), 3.44
(dt, J = 7.2, 5.1 Hz, 1 H), 3.18 (app t, J = 7.0 Hz, 1 H), 2.44 (ddt, J = 16.4, 5.1, 2.4 Hz, 1
H), 2.29 (ddt, J = 16.4, 5.1, 2.4 Hz, 1 H), 2.00 (tt, J = 7.2, 2.4 Hz, 1H), 1.34 (p, J = 7.2
Hz, 2 H), 1.32 (s, 3 H), 1.22 (s, 3 H), 1.22-1.11 (comp, 4 H), 0.89-0.80 (comp, 2 H), 0.76
(t, J = 7.2 Hz, 3 H), 0.53 (app dt, J = 8.8, 5.2 Hz, 1 H), 0.48 (app dt, 8.8, 5.6 Hz, 1 H);
13C NMR (100 MHz) δ 159.1, 159.0, 133.2, 132.6, 130.4, 130.2, 129.2, 129.1, 128.5,
113.7, 113.7, 108.9, 82.2, 80.5, 79.4, 77.6, 76.0, 69.9, 69.3, 64.8, 55.2, 31.0, 28.7, 26.7,
26.1, 25.6, 22.1, 20.2, 19.7, 18.7, 13.9, 7.1.
NMR Assignments: 1H NMR (400 MHz) δ 7.13 (t, J = 7.8 Hz, 4 H, C25-4H),
6.75 (d, J = 7.8 Hz, 4 H, C26-4H), 5.54 (app dd, J = 15.8, 7.2 Hz, 1 H, C12-H), 5.46 (app dd, J = 15.8, 7.2 Hz, 1 H, C13-H), 4.41 (d, J = 11.6 Hz, 2 H, C23-H and C23-H), 4.25 (d,
J = 11.6 Hz, 1 H, C23-H), 4.20 (d, J = 11.6 Hz, 1 H, C23-H), 3.99 (dd, J = 8.4, 6.6 Hz, 1
H, C6-H), 3.81 (app dt, J = 7.2, 5.1 Hz, 1 H, C14-H), 3.68 (s, 3 H, C28-3H), 3.68 (s, 3 H,
C28-3H), 3.63 (dd, J = 8.4, 7.2 Hz, 1 H, C6-H), 3.44 (dt, J = 7.2, 5.1 Hz, 1 H, C7-H),
3.18 (app t, J = 7.0 Hz, 1 H, C11-H), 2.44 (ddt, J = 16.4, 5.1, 2.4 Hz, 1 H, C15-H), 2.29
(ddt, J = 16.4, 5.1, 2.4 Hz, 1 H, C15-H), 2.00 (tt, J = 7.2, 2.4 Hz, 1H, C18-2H), 1.34 (p, J
= 7.2 Hz, 2 H, C19-2H), 1.32 (s, 3 H, C4-3H), 1.22 (s, 3 H, C4-3H), 1.22-1.11 (comp, 4
H, C20-2H and C21-2H), 0.89-0.80 (comp, 2 H, C8-H and C10-H), 0.76 (t, J = 7.2 Hz, 3
231 H, C22-3H), 0.53 (app dt, J = 8.8, 5.2 Hz, 1 H, C9-H), 0.48 (app dt, 8.8, 5.6 Hz, 1 H, C9-
H); 13C NMR (100 MHz) δ 159.1 (C27), 159.0 (C27), 133.2, 132.6, 130.4, 130.2, 129.2,
129.1, 128.5, 113.7 (C26), 113.7 (C26), 108.9 (C5), 82.2, 80.5, 79.4, 77.6, 76.0, 69.9,
69.3, 64.8, 55.2 (C28), 31.0, 28.7, 26.7, 26.1, 25.6, 22.1, 20.2, 19.7, 18.7, 13.9, 7.1 (C9).
15 OH H 7 22 PMBO OH 9 11 H O 23
25 MeO 28
1-{2-[1,4-Bis-(4-methoxy-benzyloxy)-dodec-2-en-6-ynyl]-cyclopropyl}-ethane-
1,2-diol (2.98). (JED 4-227). Trifluoroacetic acid (25 µL, 0.34 mmol) was added to a
solution of acetonide 2.95 (35 mg, 0.061 mmol) in THF (1.0 mL) and H2O (0.1 mL) at rt.
Stirring continued for 12 h at rt, whereupon saturated aqueous NaHCO3 (5 mL) and Et2O
(10 mL) were added. The layers were separated and the organic layer was washed with
brine (5 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was
purified by column chromatography eluting with hexanes/EtOAc (1:1) to give 21 mg
(64%) of diol 2.98 as a clear oil; 1H NMR (400 MHz) δ 7.23 (d, J = 8.6 Hz, 2 H), 7.20 (d,
J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6 Hz, 4 H), 5.66 (app dd, J = 15.6, 7.8 Hz, 1 H), 5.54 (app dd, 15.6, 7.2 Hz, 1 H), 4.52 (d, J = 12.0 Hz, 1 H), 4.52 (d, J = 12.0 Hz, 1 H), 4.35 (d, J =
232 11.8 Hz, 1 H), 4.27 (d, J = 11.8 Hz, 1 H), 3.90 (dt, J = 7.8, 5.2 Hz, 1 H), 3.78 (s, 3 H),
3.78 (s, 3 H), 3.67-3.66 (comp, 2 H), 3.11 (app t, J = 8.2 Hz, 1 H), 3.10-3.05 (comp, 1 H),
2.55 (ddt, J = 16.4, 5.2, 2.8 Hz, 1 H), 2.39 (ddt, J = 16.4, 7.8, 2.8 Hz, 1 H), 2.09 (tt, J =
7.2, 2.8 Hz, 2 H), 1.61 (br, 2 H), 1.43 (p, J = 7.2 Hz, 2 H), 1.33-1.24 (comp, 4 H), 1.04
(dtd, J = 9.2, 4.8, 4.8 Hz, 1 H), 0.84 (t, J = 7.2 Hz, 3 H), 0.74 (dtd, J = 8.8, 5.4, 5.4 Hz, 1
H), 0.61 (dt, J = 8.4, 5.4 Hz, 1 H), 0.53 (dt, J = 8.4, 4.8 Hz, 1 H).
NMR Assignments: 1H NMR (400 MHz) δ 7.23 (d, J = 8.6 Hz, 2 H, C25-2H),
7.20 (d, J = 8.6 Hz, 2 H, C25-2H), 6.85 (d, J = 8.6 Hz, 4 H, C26-4H), 5.66 (app dd, J =
15.6, 7.8 Hz, 1 H, C13-H), 5.54 (app dd, 15.6, 7.2 Hz, 1 H, C12-H), 4.52 (d, J = 12.0 Hz,
1 H, C23-H), 4.52 (d, J = 12.0 Hz, 1 H, C23-H), 4.35 (d, J = 11.8 Hz, 1 H, C23-H), 4.27
(d, J = 11.8 Hz, 1 H, C23-H), 3.90 (dt, J = 7.8, 5.2 Hz, 1 H, C14-H), 3.78 (s, 3 H, C27-
3H), 3.78 (s, 3 H, C27-3H), 3.67-3.66 (comp, 2 H), 3.11 (app t, J = 8.2 Hz, 1 H), 3.10-
3.05 (comp, 1 H), 2.55 (ddt, J = 16.4, 5.2, 2.8 Hz, 1 H, C15-H), 2.39 (ddt, J = 16.4, 7.8,
2.8 Hz, 1 H, C15-H), 2.09 (tt, J = 7.2, 2.8 Hz, 2 H, C18-2H), 1.61 (br, 2 H, 2 x OH), 1.43
(p, J = 7.2 Hz, 2 H, C19-2H), 1.33-1.24 (comp, 4 H, C20-2H and C21-2H), 1.04 (dtd, J =
9.2, 4.8, 4.8 Hz, 1 H, C10-H), 0.84 (t, J = 7.2 Hz, 3 H, C22-3H), 0.74 (dtd, J = 8.8, 5.4,
5.4 Hz, 1 H, C8-H), 0.61 (dt, J = 8.4, 5.4 Hz, 1 H, C9-H), 0.53 (dt, J = 8.4, 4.8 Hz, 1 H,
C9-H).
233 15 OH H 7 22 OH 9 11 TBSO H O Si 23
25
1-{2-[1,2-Bis (tert-butyl dimethyl silanyloxy) dodec-3-en-6-ynyl] cyclopropyl} ethane-1,2-diol (2.67). (JED 4-87). A solution of trifluoroacetic acid (0.35 mL, 4.74 mmol) in H2O (1.8 mL) was added to a solution of acetonide 2.66 (1.34g, 2.37 mmol) in
CH2Cl2 (25 mL) at rt. Stirring continued for 6 h at rt, whereupon saturated aqueous
NaHCO3 (10 mL) was added and stirring continued for 15 min. The layers were separated, and the organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc
(6:1) to provide 1.02 g (82%) of diol 2.67 as a clear oil; 1H NMR (500 MHz) δ 5.92 (ddt,
J = 15.5, 4.5, 2.0 Hz, 1 H), 5.64 (dtd, J = 15.5, 4.5, 2.0 Hz, 1 H), 4.18 (dt, J = 4.5, 2.0 Hz,
1 H), 3.66 (br, 1 H), 3.53 (dd, J = 10.7, 6.7 Hz, 1 H), 3.44 (app t, J = 4.5 Hz, 1 H), 3.04-
3.01 (m, 1 H), 2.92 (dt, J = 4.5, 2.0 Hz), 2.14 (tt, J = 7.2, 2.0 Hz, 2 H), 1.90 (br, 2 H),
1.48 (p, 7.2 Hz, 2H), 1.36-1.27 (comp, 4 H), 1.00 (dtd, J = 9.7, 5.2, 5.2 Hz, 1H), 0.98 (s,
9 H), 0.87 (s, 9 H), 0.86-0.81 (m, 1 H), 0.53 (app dt, J = 8.7, 4.7 Hz, 1 H), 0.42 (app dt, J
= 8.7, 4.7 Hz, 1 H), 0.03 (s, 3 H), 0.03 (s, 3 H), 0.03 (s, 3 H), 0.02 (s, 3 H); 13C NMR
(125 MHz) δ 130.0, 125.6, 82.9, 76.9, 76.2, 75.1, 75.0, 66.4, 31.1, 28.8, 25.9, 25.8, 22.2,
234 21.9, 18.7, 18.2, 18.0, 17.6, 16.4, 14.0, 6.0, -4.4, -4.6, -4.7, -4.8; IR (neat) 3382, 2929,
-1 2857, 1471, 1253, 1079, 835, 774 cm ; MS (CI) m/z 523.3639 [C29H55O4Si2 (M-1) requires 523.3639], 507, 468, 393, 375, 279 (base), 245, 185.
NMR Assignments: 1H NMR (500 MHz) δ 5.92 (ddt, J = 15.5, 4.5, 2.0 Hz, 1 H,
C13-H), 5.64 (dtd, J = 15.5, 4.5, 2.0 Hz, 1 H, C14-H), 4.18 (dt, J = 4.5, 2.0 Hz, 1 H, C12-
H), 3.66 (br, 1 H, C6-H), 3.53 (dd, J = 10.7, 6.7 Hz, 1 H, C6-H), 3.44 (app t, J = 4.5 Hz,
1 H, C11-H), 3.04-3.01 (m, 1 H, C7-H), 2.92 (dt, J = 4.5, 2.0 Hz, C15-2H), 2.14 (tt, J =
7.2, 2.0 Hz, 2 H, C18-2H), 1.90 (br, 2 H, 2 x OH), 1.48 (p, 7.2 Hz, 2H, C19-2H), 1.36-
1.27 (comp, 4 H, C20-2H and C21-2H), 1.00 (dtd, J = 9.7, 5.2, 5.2 Hz, 1H, C8-H), 0.98
(s, 9 H, C24-9H), 0.87 (s, 9 H, C24-9H), 0.86-0.81 (m, 1 H, C10-H), 0.53 (app dt, J =
8.7, 4.7 Hz, 1 H, C9-H), 0.42 (app dt, J = 8.7, 4.7 Hz, 1 H, C9-H), 0.03 (s, 3 H, C23-3H),
0.03 (s, 3 H, C23-3H), 0.03 (s, 3 H, C23-3H), 0.02 (s, 3 H, C23-3H); 13C NMR (125
MHz) δ 130.0 (C13), 125.6 (C14), 82.9 (C11), 76.9 (C16), 76.2 (C17), 75.1 (C12), 75.0
(C7), 66.4 (C6), 31.1, 28.8, 25.9 (C25), 25.8 (C25), 22.2, 21.9, 18.7, 18.2 (C24), 18.0
(C24), 17.6, 16.4, 14.0, 6.0 (C9), -4.4 (C23), -4.6 (C23), -4.7 (C23), -4.8 (C23).
235 28 30
18 O 26 S O 15 6 O
H OH 22 9 11 TBSO H O Si 23
25
Toluene-4-sulfonic acid 2-{2-[1,2-bis-(tert-butyl dimethyl silanyloxy)-dodec-3-
en-6-ynyl]-cyclopropyl}-2-hydroxy ethyl ester (2.99). (JED 3-74). p-Toluenesulfonyl
chloride (73 mg, 0.37 mmol) was added to a solution of diol 2.67 (155 mg, 0.30 mmol),
4-di(methylamino)pyridine (4.0 mg, 0.03 mmol), and Et3N (0.21 mL, 1.48 mmol) in
CH2Cl2 (4 mL) at 0 °C. Stirring continued for 3 h at 0 °C, whereupon saturated aqueous
NH4Cl (4 mL) was added, the layers were separated and the organic layer was dried
(MgSO4), and concentrated under reduced pressure. The residue was purified by flash
chromatography eluting with hexanes/EtOAc (6:1) to give 144 mg (72%) of 2.99 as a
colorless oil; 1H NMR (400 MHz) δ 7.78 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2 H),
5.85 (ddt, J = 15.6, 4.0, 2.0 Hz, 1 H), 5.58 (dtd, J = 15.6, 5.2, 2.0 Hz, 1 H), 4.15-4.11
(comp, 2 H), 3.86 (dd, J = 10.4, 9.0 Hz, 1 H), 3.44 (app t, J = 4.6 Hz, 1 H), 3.27 (app dt, J
= 9.0, 2.0 Hz, 1H), 2.86-2.84 (m, 2 H), 2.43 (s, 3 H), 2.11 (tt, J = 7.2, 2.0 Hz, 2 H), 1.95
(br, 1 H), 1.45 (p, J = 7.2 Hz, 2 H), 1.35-1.23 (comp, 4 H), 0.93 (app dtd, J = 9.6, 4.4, 4.4
Hz, 1 H), 0.88-0.83 (comp, 21 H), 0.80-0.72 (m, 1 H), 0.49 (app dt, J = 9.0, 5.0 Hz, 1 H),
236 0.41 (app dt, J = 9.0, 4.8 Hz, 1 H), 0.02 (s, 3 H), 0.01 (s, 3 H), 0.00 (s, 3 H), -0.04 (s, 3
H); 13C NMR (100 MHz) δ 144.8, 132.9, 130.1, 129.9, 128.0, 125.2, 82.9, 76.9, 75.0,
74.5, 74.0, 72.6, 31.1, 28.8, 25.9, 25.8, 22.2, 21.7, 18.7, 18.1, 17.9, 16.0, 14.0, 5.7, -4.4, -
4.7, -4.9; IR (neat) 3483, 2955, 2857, 1471, 1362, 1178, 835, 775 cm-1.
NMR Assignments: 1H NMR (400 MHz) δ 7.78 (d, J = 8.0 Hz, 2 H, C27-2H),
7.32 (d, J = 8.0 Hz, 2 H, C28-2H), 5.85 (ddt, J = 15.6, 4.0, 2.0 Hz, 1 H), 5.58 (dtd, J =
15.6, 5.2, 2.0 Hz, 1 H), 4.15-4.11 (comp, 2 H), 3.86 (dd, J = 10.4, 9.0 Hz, 1 H, C6-H),
3.44 (app t, J = 4.6 Hz, 1 H, C11-H), 3.27 (app dt, J = 9.0, 2.0 Hz, 1H), 2.86-2.84 (m, 2
H. C15-2H), 2.43 (s, 3 H, C30-H), 2.11 (tt, J = 7.2, 2.0 Hz, 2 H, C18-2H), 1.95 (br, 1 H,
OH), 1.45 (p, J = 7.2 Hz, 2 H, C19-2H), 1.35-1.23 (comp, 4 H, C20-2H and C21-2H),
0.93 (app dtd, J = 9.6, 4.4, 4.4 Hz, 1 H), 0.88-0.83 (comp, 21 H, C22-2H and C25-2H),
0.80-0.72 (m, 1 H), 0.49 (app dt, J = 9.0, 5.0 Hz, 1 H, C9-H), 0.41 (app dt, J = 9.0, 4.8
Hz, 1 H, C9-H), 0.02 (s, 3 H, C25-3H), 0.01 (s, 3 H, C25-3H), 0.00 (s, 3 H, C25-3H), -
0.04 (s, 3 H, C25-3H); 13C NMR (100 MHz) δ 144.8 (C29), 132.9 (C26), 130.1 (C13),
129.9 (C28), 128.0 (C27), 125.2 (C14), 82.9 (C11), 76.9 (C12), 75.0 (C16), 74.5 (C7),
74.0 (C17), 72.6 (C6), 31.1, 28.8, 25.9 (C25), 25.8 (C25), 22.2, 21.7, 18.7, 18.1, 17.9,
16.0, 14.0, 5.7 (C9), -4.4 (C23), -4.7 (C23), -4.9 (C23).
237 18
6 15 O H 8 22 9 11 TBSO H O Si 23
25
2-{2-[1,2-Bis-(tert-butyl dimethyl silanyloxy)-dodec-3-en-6-ynyl]- cyclopropyl}-oxirane (2.100). (JED 3-75). K2CO3 (35mg, 0.03 mmol) was added to a solution of tosylate 2.99 (144 mg, 0.02 mmol) in anhydrous MeOH (2 mL) at rt. Stirring continued for 3 h at rt, whereupon Et2O (5 mL) and saturated aqueous NaHCO3 (3 mL) were added. The layers were separated and the organic layer was washed with brine (3 mL), dried (MgSO4), and concentrated under reduced pressure to give 106 mg (99%) of epoxide 2.100 as a clear oil requiring no further purification.
(JED 4-30). Sodium hydride (60% suspension in mineral oil, 223 mg, 5.58 mmol) was added to a solution of diol 2.67 (997 mg, 1.86 mmol) in anhydrous THF (19 mL) at 0 ºC. Stirring continued for 15 min at 0 ºC, then 1-(p-toluenesulfonyl)imidazole
(413 mg, 1.86 mmol) was added to the solution. Stirring continued for an additional 3 h at 0 ºC, whereupon the ice bath was removed and stirring continued for 12 h at rt. Ether
(20 mL) and saturated aqueous NaHCO3 (10 mL) was added to the reaction, and the layers were separated. The organic layer was further washed with saturated aqueous
NH4Cl (10 mL) and brine (10 mL). The combined organic layers were dried (MgSO4),
238 and concentrated under reduced pressure to provide 975 mg (99%) epoxide 2.100 as a
pale yellow oil which was used without further purification; 1H NMR (400 MHz) δ 5.86
(ddt, J = 15.4, 4.5, 2.0 Hz, 1 H), 5.59 (dtd, J = 15.4, 5.2, 1.6 Hz, 1 H), 4.13 (app dt, J =
4.5, 1.6 Hz, 1 H), 3.55 (app. t, J = 4.2, 1 H), 2.90 (ddd, J = 6.8, 4.4, 2.0 Hz, 2 H), 2.71
(dd, J = 5.0, 4.0 Hz, 1 H), 2.60 (ddd, J = 6.8, 4.0, 2.6 Hz, 1 H), 2.55 (dd, J = 5.0, 2.6 Hz,
1 H), 2.13 (tt, J = 7.2, 2.4 Hz, 2 H), 1.47 (p, J = 7.2 Hz, 2 H), 1.37-1.24 (comp, 4 H),
1.09-1.03 (m, 1 H), 0.89 (s, 9 H), 0.84 (s, 9 H), 0.88-0.75 (comp, 4 H), 0.45-0.39 (comp,
2 H), 0.03 (s, 3 H), 0.02 (s, 3 H), 0.02 (s, 3 H), 0.00 (s, 3 H); 13C NMR (75 MHz) δ
130.3, 125.0, 82.7, 77.0, 75.6, 74.3, 54.2, 47.3, 31.1, 28.8, 25.9, 25.7, 22.2, 21.8, 18.7,
18.2, 18.0, 16.3, 15.1, 14.0, 4.5, -4.3, -4.6, -4.7, -4.8; IR (neat) 2928, 2857, 2363, 1471,
-1 1253, 1124, 1076, 836 cm ; MS (CI) m/z 507.3687 [C29H55O3Si2 (M+1) requires
507.3690], 491, 449, 375, 279 (base), 227.
NMR Assignments: 1H NMR (400 MHz) δ 5.86 (ddt, J = 15.4, 4.5, 2.0 Hz, 1 H,
C13-H), 5.59 (dtd, J = 15.4, 5.2, 1.6 Hz, 1 H, C14-H), 4.13 (app dt, J = 4.5, 1.6 Hz, 1 H,
C12-H), 3.55 (app. t, J = 4.2, 1 H, C11-H), 2.90 (ddd, J = 6.8, 4.4, 2.0 Hz, 2 H, C15-2H),
2.71 (dd, J = 5.0, 4.0 Hz, 1 H, C6-H), 2.60 (ddd, J = 6.8, 4.0, 2.6 Hz, 1 H, C7-H), 2.55
(dd, J = 5.0, 2.6 Hz, 1 H, C6-H), 2.13 (tt, J = 7.2, 2.4 Hz, 2 H, C18-2H), 1.47 (p, J = 7.2
Hz, 2 H, C19-2H), 1.37-1.24 (comp, 4 H, C20-2H and C21-2H), 1.09-1.03 (m, 1 H, C8-
H), 0.89 (s, 9 H, C25-9H), 0.84 (s, 9 H, C25-9H), 0.88-0.75 (comp, 4 H, C10-H and C22-
3H), 0.45-0.39 (comp, 2 H, C9-H and C9-H), 0.03 (s, 3 H, C23-3H), 0.02 (s, 3 H, C23-
3H), 0.02 (s, 3 H, C23-3H), 0.00 (s, 3 H, C23-3H); 13C NMR (75 MHz) δ 130.3 (C13),
125.0 (C14), 82.7 (C11), 77.0 (C16), 75.6 (C17), 74.3 (C12), 54.2 (C7), 47.3 (C6), 31.1,
239 28.8, 25.9 (C25), 25.7 (C25), 22.2, 21.8, 18.7, 18.2, 18.0, 16.3, 15.1, 14.0, 4.5 (C9), -4.3
(C23), -4.6 (C23), -4.7 (C23), -4.8 (C23).
18 5
15 H O
H 7 22 9 11 TBSO H O Si 23
25
{2-[1,2-Bis (tert-butyl dimethyl silanyloxy) dodec-3-en-6-ynyl]-cyclopropyl}
acetaldehyde (2.101) Isolated as the sole product after flash silica gel chromatography
of epoxide 2.101. 1H NMR (400 MHz) δ 9.73 (t, J = 2.6 Hz, 1H), 5.86 (app dtd, J =
15.2, 4.5, 1.8 Hz, 1 H), 5.60 (app dtd, J = 15.2, 6.6, 1.8 Hz, 1H), 4.14 (dt, J = 6.6, 1.8 Hz,
1 H), 3.47 (app t, J = 4.2 Hz, 1 H), 2.91 (app dt, J = 4.5, 1.8 Hz, 1 H), 2.45 (ddd, J = 16.4,
5.6, 1.8 Hz, 1 H), 2.13 (tt, J = 7.2, 1.8 Hz, 2 H) 1.99 (ddd, J = 16.4, 8.8, 1.8 Hz, 1 H),
1.47 (p, J = 7.2 Hz, 2 H), 1.37-1.26 (comp, 4 H), 1.00-0.89 (comp, 2 H), 0.89 (s, 9 H),
0.86 (s, 9 H), 0.57 (app dt, J = 8.6, 4.8 Hz, 1H), 0.25 (app dt, J = 8.6, 4.8 Hz. 1H), 0.03
(s, 3 H), 0.03 (s, 3 H), 0.02 (s, 3 H), 0.00 (s, 3 H); IR (neat) 2929, 2861, 1729, 1467,
1258, 1124, 836 cm-1.
NMR Assignments: 1H NMR (400 MHz) δ 9.73 (t, J = 2.6 Hz, 1H, C6-H), 5.86
(app dtd, J = 15.2, 4.5, 1.8 Hz, 1 H. C14-H), 5.60 (app dtd, J = 15.2, 6.6, 1.8 Hz, 1H,
240 C13-H), 4.14 (dt, J = 6.6, 1.8 Hz, 1 H, C12-H), 3.47 (app t, J = 4.2 Hz, 1 H, C11-H), 2.91
(app dt, J = 4.5, 1.8 Hz, 1 H, C15-2H), 2.45 (ddd, J = 16.4, 5.6, 1.8 Hz, 1 H, C7-H), 2.13
(tt, J = 7.2, 1.8 Hz, 2 H, C18-2H) 1.99 (ddd, J = 16.4, 8.8, 1.8 Hz, 1 H, C7-H), 1.47 (p, J
= 7.2 Hz, 2 H, C19-2H), 1.37-1.26 (comp, 4 H, C20-2H and C21-2H), 1.00-0.89 (comp, 2
H, C8-H and C10-H), 0.89 (s, 9 H,C25-9H), 0.86 (s, 9 H, C25-9H), 0.57 (app dt, J = 8.6,
4.8 Hz, 1H, C9-H), 0.25 (app dt, J = 8.6, 4.8 Hz. 1H, C9-H), 0.03 (s, 3 H, C23-3H), 0.03
(s, 3 H, C23-3H), 0.02 (s, 3 H, C23-3H), 0.00 (s, 3 H, C23-3H).
O 6 12 14 8 O 3 Si 9
1 OH 10
tert-Butyldiphenylsilyl 7-hydroxyoct-4-ynoate (2.110) (JED 5-116).
Butyllithium (2.5 M in hexane, 0.11 mL, 0.30 mmol) was added to a solution of TBDPS
protected pentynoic acid 2.109 (100 mg, 0.30 mmol) in anhydrous THF (3 mL) at -78 ºC.
. Stirring continued for 15 min at -78 ºC, whereupon BF3 OEt2 (0.26 mL, 0.21 mmol) was
added and the mixture was stirred at -78 ºC for an additional 15 min. Propylene oxide
(2.108) (0.06 mL, 0.89 mmol) was added, and stirring continued at -78 ºC for 1 h
whereupon acetic acid (67 µL, 1.17 mmol) was added. The ice bath was removed and the
reaction mixture was warmed to rt over 30 min. An aqueous solution of 1 M HCl (1 mL)
and Et2O (2 mL) was added. The layers were separated and the organic layer was
washed with saturated aqueous NaHCO3 (1 mL), and dried (MgSO4). The solvent was
241 removed under reduced pressure and the residue was purified by flash chromatography
eluting with hexanes/EtOAc (10:1) to give 70 mg (86%) of TBDPS ester 2.110 as a clear
oil; 1H NMR (400 MHz) δ 7.67 (dd, J = 8.2, 1.4 Hz, 4 H), 7.44-7.35 (comp, 6 H), 3.84
(app sex, J = 6.4 Hz, 1 H), 2.68 (t, J = 7.2 Hz, 2 H), 2.53 (tt, J = 7.2, 2.2 Hz, 2 H), 2.32
(ddt, J = 16.4, 4.8, 2.2 Hz, 1 H), 2.23 (ddt, J = 16.4, 6.8, 2.2, 1 H), 1.95 (br, 1 H), 1.12 (d,
J = 6.0 Hz, 3 H), 1.11 (s, 9 H); 13C NMR (100 MHz) δ 171.2, 135.3, 131.6, 130.1,
127.7, 81.0, 77.4, 66.4, 35.7, 29.3, 26.8, 22.2, 19.1, 15.0.
NMR Assignments: 1H NMR (400 MHz) δ 7.67 (dd, J = 8.2, 1.4 Hz, 4 H, C13-
H, C13-H), 7.44-7.35 (comp, 6 H, C12-2H, C12-2H and C14-H, C14-H), 3.84 (app sex, J
= 6.4 Hz, 1 H, C2-H), 2.68 (t, J = 7.2 Hz, 2 H, C7-2H), 2.53 (tt, J = 7.2, 2.2 Hz, 2 H, C6-
2H), 2.32 (ddt, J = 16.4, 4.8, 2.2 Hz, 1 H, C3-H), 2.23 (ddt, J = 16.4, 6.8, 2.2, 1 H, C3-
H), 1.95 (br, 1 H, OH), 1.12 (d, J = 6.0 Hz, 3 H, C1-3H), 1.11 (s, 9 H, C10-9H); 13C
NMR (100 MHz) δ 171.2 (C8), 135.3 (C12), 131.6 (C11), 130.1 (C14), 127.7 (C13), 81.0
(C4), 77.4 (C5), 66.4 (C2), 35.7 (C8), 29.3 (C3), 26.8 (C11), 22.2 (C7), 19.1 (C1), 15.0
(C9).
O 6 8 OH 3
1 OH
7-Hydroxy-oct-4-ynoic acid. (2.111). (JED 5-117). Butyllithium (2.5 M in
hexane, 0.31 mL, 0.78 mmol) was added to a solution of TBDPS protected pentynoic
242 acid 2.109 (300 mg, 0.89 mmol) in anhydrous THF (6 mL) at -78 ºC. Stirring continued
. for 15 min at -78 ºC, whereupon BF3 OEt2 (0.83 mL, .065 mmol) was added and the
mixture was stirred at -78 ºC for an additional 15 min. Propylene oxide (2.108) (0.04
mL, 0.59 mmol) was added, and stirring continued at -78 ºC for an additional 1 h
whereupon acetic acid (67 µL, 1.17 mmol) and a solution of TBAF (562 mg, 1.78 mmol)
in anhydrous THF (2 mL) was added. The ice bath was removed and the reaction
mixture was warmed to rt over 30 min. The solvent was removed under reduced pressure
and an aqueous solution of 1 M HCl (10 mL) and EtOAc (20 mL) was added. The layers
were separated and the aqueous layer was extracted with EtOAc (2 x 10 mL), the
combined organic layers were dried (MgSO4) and concentrated under reduced pressure.
The residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to
give 84 mg (90%) of hydroxy acid 2.111 as a white solid; 1H NMR (400 MHz) δ 3.90
(app sex, J = 6.4 Hz, 1 H), 2.56-2.52 (m. 2 H), 2.49-2.44 (m, 2 H), 2.34 (ddt, J = 16.8,
4.6, 2.2 Hz, 1 H), 2.23 (ddt, J = 16.8, 6.4, 2.2 Hz, 1 H), 1.21 (d, J = 6.4 Hz, 3 H); 13C
NMR (100 MHz) δ 177.1, 80.9, 77.5, 66.6, 33.6, 29.2, 22.0, 14.6.
NMR Assignments: 1H NMR (400 MHz) δ 3.90 (app sex, J = 6.4 Hz, 1 H, C2-
H), 2.56-2.52 (m. 2 H, C7-2H), 2.49-2.44 (m, 2 H, C6-2H), 2.34 (ddt, J = 16.8, 4.6, 2.2
Hz, 1 H, C3-H), 2.23 (ddt, J = 16.8, 6.4, 2.2 Hz, 1 H, C3-H), 1.21 (d, J = 6.4 Hz, 3 H, C1-
3H); 13C NMR (100 MHz) δ 177.1 (C8), 80.9 (C4), 77.5 (C5), 66.6 (C2), 33.6 (C7), 29.2
(C3), 22.0 (C1), 14.6 (C6).
243 15 4 7 H OH 22 9 11 TBSO H O Si 23
25
1-{2-[1,2-Bis-(tert-butyldimethylsilanyloxy)-dodec-3-en-6-ynyl]-cyclopropyl}-but-3- en-1-ol (2.113). (JED 3-208). Vinylmagnesium bromide (1.5 M solution in THF, 0.68
. mL, 1.02 mmol) was added to a suspension of CuBr SMe2 (53 mg, 0.26 mmol) in
anhydrous THF (1.3 mL) at -78 ºC. Stirring continued for 1 h at -78 ºC, whereupon a
solution of epoxide 2.100 (130 mg, 0.26 mmol) in anhydrous THF (1.3 mL) was added
and stirring continued for an additional 4 h at -78 ºC, the ice bath was removed and
saturated aqueous NH4Cl (5 mL) and Et2O (5 mL) were added. Stirring continued for 12
h at rt, the layers were separated, and the aqueous layer was extracted with Et2O (2 x 5
mL). The combined organic layers were dried (MgSO4), and concentrated under reduced
pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc
(9:1) to give 115 mg (85%) of alcohol 2.113 as a colorless oil; 1H NMR (400 MHz) δ
5.92-5.81 (comp, 2 H), 5.61 (dtd, J = 15.2, 6.8, 1.6 Hz, 1 H), 5.13-5.06 (comp, 2 H), 4.14
(td, J = 4.2, 1.6 Hz, 1 H), 3.35 (app t, J = 4.2 Hz, 1 H), 3.03 (ddd, J = 10.8, 7.2, 3.6 Hz, 1
H), 2.91 (app dt, J = 4.8, 1.8 Hz, 2 H), 2.44-2.38 (m, 1 H), 2.21 (dd, J = 14.0, 7.6 Hz, 1
H), 2.14 (tt, J = 7.2, 2.4 Hz, 2 H), 1.6 (br, 1 H), 1.47 (p, J = 7.2 Hz, 2 H) 1.37-1.24
244 (comp, 4 H), 0.95-0.82, (comp, 23 H), 0.49 (app dt, J = 8.2, 4.8 Hz, 1 H), 0.43 (app dt, J
= 8.2, 4.8 Hz, 1 H), 0.02 (s, 9 H), 0.01 (s, 3 H); 13C (100 MHz) δ 135.5, 130.3, 125.5,
117.4, 82.6, 77.2, 75.8, 75.5, 74.2, 41.6, 31.1, 28.8, 25.9, 25.8, 22.2, 21.9, 21.0, 18.7,
18.2, 18.0, 16.8, 14.0, 6.6, -4.3, -4.5, -4.6, -4.8; IR (neat) 3359, 2929, 2857, 2348, 1471,
1361, 1255, 1125, 1078, 835 cm-1.
NMR Assignments: 1H NMR (400 MHz) δ 5.92-5.81 (comp, 2 H, C10-H and
C11-H), 5.61 (dtd, J = 15.2, 6.8, 1.6 Hz, 1 H, C5-H), 5.13-5.06 (comp, 2 H, C4-H), 4.14
(td, J = 4.2, 1.6 Hz, 1 H, C12-H), 3.35 (app t, J = 4.2 Hz, 1 H, C11-H), 3.03 (ddd, J =
10.8, 7.2, 3.6 Hz, 1 H, C7-H), 2.91 (app dt, J = 4.8, 1.8 Hz, 2 H, C15-H), 2.44-2.38 (m, 1
H, C6-H), 2.21 (dd, J = 14.0, 7.6 Hz, 1 H, C6-H), 2.14 (tt, J = 7.2, 2.4 Hz, 2 H, C18-2H),
1.6 (br, 1 H, OH), 1.47 (p, J = 7.2 Hz, 2 H, C19-2H) 1.37-1.24 (comp, 4 H, C20-2H and
C21-2H), 0.95-0.82, (comp, 23 H, C8-H and C10-H and C22-3H and C25-18H), 0.49
(app dt, J = 8.2, 4.8 Hz, 1 H, C9-H), 0.43 (app dt, J = 8.2, 4.8 Hz, 1 H, C9-H), 0.02 (s, 9
H, C23-9H), 0.01 (s, 3 H, C23-3H); 13C (100 MHz) δ 135.5 (C3), 130.3 (C13), 125.5
(C14), 117.4 (C4), 82.6 (C11), 77.2, 75.8, 75.5, 74.2, 41.6 (C6), 31.1, 28.8, 25.9 (C25),
25.8 (C25), 22.2, 21.9, 21.0, 18.7, 18.2, 18.0, 16.8, 14.0, 6.6 (C9), -4.3 (C23), -4.5 (C23),
-4.6 (C23), -4.8 (C23).
245 5 15 4 5' H 7 O 1 22 9 4' 11 3 TBSO H O O Si 23
24
Pent-4-enoic acid 1-{2-[1,2-bis-(tert butyl dimethyl silanyloxy)-dodec-3-en-6-
ynyl]-cyclopropyl}-but-3-enyl ester (2.114). (JED 3-210). 4-Pentenoyl chloride (0.11
mL, 1.00 mmol), DMAP (3 mg, 0.03 mmol), and pyridine (0.21 mL, 2.52 mmol) was
added to a solution of alcohol 2.113 (135 mg, 0.252 mmol) in anhydrous CH2Cl2 (5 mL)
at 0 ºC. The mixture was stirred for 4 h at 0 ºC, whereupon the reaction was concentrated
under reduced pressure. The residue was purified by silica gel flash chromatography
(100:2 hexanes/EtOAc) to give 143 mg (95%) of triene 2.114 as a pale yellow oil. 1H
NMR (400 MHz) δ 5.89 (ddt, J = 15.2, 4.8, 2.0 Hz, 1 H), 5.84-5.70 (comp, 2 H), 5.60
(dtd, J = 15.2, 4.8, 2.0 Hz, 1 H), 5.11-4.95 (comp, 4 H), 4.39 (ddd, J = 8.0, 8.0, 4.0 Hz, 1
H), 4.13 (dt, J = 4.8, 2.0 Hz, 1 H), 3.36 (app t, J = 4.8 Hz, 1 H), 2.91 (app dt, J = 4.8, 2.0
Hz, 2 H), 2.48-2.29 (comp, 6 H), 2.15 (tt, J = 7.2, 2.0 Hz, 2 H), 1.48 (p, J = 7.2 Hz, 2 H),
1.38-1.24 (comp, 4 H), 0.99-0.94 (m, 2 H), 0.89-0.84 (comp, 21 H), 0.48 (app dt, J = 8.0,
5.0 Hz, 1 H), 0.43 (ddd, J = 8.0, 6.4, 5.0 Hz, 1 H), 0.02 (s, 3 H), 0.01 (s, 3 H), 0.01 (s, 6
H); 13C (100 MHz) δ 172.6, 136.8, 134.4, 130.1, 125.7, 117.0, 115.3, 82.6, 77.2, 76.4,
75.6, 75.4, 39.2, 33.8, 31.1, 29.0, 28.8, 25.9, 25.8, 22.2, 21.9, 18.7, 18.6, 18.1, 18.0, 17.5,
14.0, 7.0, -4.3, -4.5, -4.6, -4.8; IR (neat) 2955, 2929, 2857, 1736, 1472, 1361, 1252, 1076, 246 -1 836 cm ; MS (CI) m/z 617.4425 [C36H65O4Si2 (M + 1) requires 617.4421] 518, 486
(base), 386, 335, 279.
NMR Assignments: 1H NMR (400 MHz) δ 5.89 (ddt, J = 15.2, 4.8, 2.0 Hz, 1 H,
C14-H), 5.84-5.70 (comp, 2 H), 5.60 (dtd, J = 15.2, 4.8, 2.0 Hz, 1 H, C13-H), 5.11-4.95
(comp, 4 H), 4.39 (ddd, J = 8.0, 8.0, 4.0 Hz, 1 H, C7-H), 4.13 (dt, J = 4.8, 2.0 Hz, 1 H,
C12-H), 3.36 (app t, J = 4.8 Hz, 1 H, C11-H), 2.91 (app dt, J = 4.8, 2.0 Hz, 2 H, C15-
2H), 2.48-2.29 (comp, 6 H, C2-2H and C3-2H and C4-2H), 2.15 (tt, J = 7.2, 2.0 Hz, 2 H,
C18-2H), 1.48 (p, J = 7.2 Hz, 2 H, C19-H), 1.38-1.24 (comp, 4 H, C20-2H and C21-2H),
0.99-0.94 (m, 2 H, C8-H and C10-H), 0.89-0.84 (comp, 21 H, C22-3H and C25-18H),
0.48 (app dt, J = 8.0, 5.0 Hz, 1 H, C9-H), 0.43 (ddd, J = 8.0, 6.4, 5.0 Hz, 1 H, C9-H),
0.02 (s, 3 H, C23-3H), 0.01 (s, 3 H, C23-3H), 0.01 (s, 6 H, C23-6H); 13C (100 MHz) δ
172.6 (C1), 136.8, 134.4, 130.1, 125.7, 117.0, 115.3, 82.6, 77.2, 76.4, 75.6, 75.4, 39.2,
33.8, 31.1, 29.0, 28.8, 25.9 (C25), 25.8 (C25), 22.2, 21.9, 18.7, 18.6, 18.1, 18.0, 17.5,
14.0, 7.0 (C9), -4.3 (C23), -4.5 (C23), -4.6 (C23), -4.8 (C23).
31 3 1 28 19 O O 32 15 H 7 OH 22 9 11 TBSO H O Si 23
25
247 1-{2-[1,2-Bis-(tert-butyl dimethyl silanyloxy)-dodec-3-en-6-ynyl]-
cyclopropyl}-7-(tetrahydro pyran-2-yloxy)-hept-3-yn-1-ol (2.121). (JED 3-303).
Butyllithium (2.45 M in hexane, 2.35 mL, 5.89 mmol) was added to a solution of 2-(4-
pentynyloxy)tetrahydro-2H-pyran (1.23 g, 7.36 mmol) in anhydrous THF (30 mL) at -78
. ºC. Stirring continued for 1 h at -78 ºC, whereupon BF3 OEt2 (0.56 mL, 4.41 mmol) was
added and the mixture was stirred at -78 ºC for an additional 45 min. The reaction was
cooled to -100 ºC for 15 min and epoxide 2.100 dissolved in THF (10 mL) was added drop wise. Stirring continued for 2 h at -100 ºC, and AcOH (1 mL) was added. After 5 min at -100 ºC, the ice bath was removed and saturated aqueous NH4Cl (30 mL) was
added. When the reaction reached rt (ca 30 min), the layers were separated and the
aqueous layer was extracted with ether (2 x 20 mL). The combined organic layers were
dried (MgSO4), and concentrated under reduced pressure. The residue was purified by
flash chromatography eluting with hexanes/EtOAc (100:3) to give 549 mg (55%) of
alcohol 2.121 as a clear oil; 1H NMR (400 MHz) δ 5.87 (ddt, J = 15.4, 4.4, 1.6 Hz, 1 H),
5.60 (dtd, J = 15.6, 4.6, 1.6 Hz, 1 H), 4.56 (dd, J = 4.4, 2.8 Hz, 1 H), 4.12 (dt, J = 4.4, 1.6
Hz, 1 H), 3.87-3.76 (comp, 2 H), 3.50-3.42 (comp, 2 H), 3.33 (app dt, J = 4.4, 1.6 Hz, 1
H), 3.06 (tdd, J = 7.4, 3.6, 1.6 Hz, 1 H), 2.91 (app dt, J = 4.6, 1.6 Hz, 2 H), 2.51-2.45 (m,
1 H), 2.32 (ddt, J = 16.4, 7.4, 2.4 Hz, 1 H), 2.27 (tt, J = 7.2, 1.4 Hz, 2 H), 2.14 (tt, J = 7.2,
2.4 Hz, 2 H), 2.00 (br, 1 H), 1.83-1.65 (comp, 4 H), 1.59-1.45 (comp, 6 H), 1.37-1.26
(comp, 4 H), 0.96-0.81 (comp, 23 H), 0.52-0.45 (comp, 2 H), 0.02 (s, 3 H), 0.02 (s, 3 H),
0.02 (s, 3 H), 0.01 (s, 3 H); 13C (100 MHz) δ 130.3, 125.6, 98.8, 82.5, 82.1, 77.2, 77.2,
75.8, 75.4, 73.7, 65.9, 62.2, 31.1, 30.7, 29.1, 28.8, 27.6, 25.9, 25.8, 25.4, 22.2, 21.9, 20.1,
248 19.5, 18.7, 18.1, 17.9, 16.8, 15.7, 14.0, 6.7, -4.4, -4.5, -4.5, -4.8; IR (neat) 3467, 2929,
-1 2856, 1471, 1360, 1252, 1121, 835 cm ; MS (CI) m/z 673.4694 [C39H69O5Si2 (M-1)
requires 673.4684] 657, 573, 543, 327, 279 (base) 179.
NMR Assignments: 1H NMR (400 MHz) δ 5.87 (ddt, J = 15.4, 4.4, 1.6 Hz, 1 H,
C13-H), 5.60 (dtd, J = 15.6, 4.6, 1.6 Hz, 1 H, C14-H), 4.56 (dd, J = 4.4, 2.8 Hz, 1 H,
C28-H), 4.12 (dt, J = 4.4, 1.6 Hz, 1 H, C12-H), 3.87-3.76 (comp, 2 H, C32-2H), 3.50-
3.42 (comp, 2 H, C1-2H), 3.33 (app dt, J = 4.4, 1.6 Hz, 1 H, C11-H), 3.06 (tdd, J = 7.4,
3.6, 1.6 Hz, 1 H, C7-H), 2.91 (app dt, J = 4.6, 1.6 Hz, 2 H, C15-2H), 2.51-2.45 (m, 1 H,
C6-H), 2.32 (ddt, J = 16.4, 7.4, 2.4 Hz, 1 H, C6-H), 2.27 (tt, J = 7.2, 1.4 Hz, 2 H, C3-2H),
2.14 (tt, J = 7.2, 2.4 Hz, 2 H, C18-3H), 2.00 (br, 1 H, OH), 1.83-1.65 (comp, 4 H, C2-2H and C19-2H), 1.59-1.45 (comp, 6 H, C29-2H and C30-2H and C31-2H), 1.37-1.26
(comp, 4 H, C2-2H and C21-2H), 0.96-0.81 (comp, 23 H, C8-H and C10-H and C22-H and C25-9H and C25-9H), 0.52-0.45 (comp, 2 H, C9-2H), 0.02 (s, 3 H, C25-3H), 0.02 (s,
3 H, C25-3H), 0.02 (s, 3 H, C25-3H), 0.01 (s, 3 H, C25-3H); 13C (100 MHz) δ 130.3
(C13), 125.6 (C14), 98.8 (C28), 82.5 (C11), 82.1 (C4), 77.2 (C16), 77.2 (C17), 75.8 (C5),
75.4 (C12), 73.7 (C7), 65.9 (C1), 62.2 (C32), 31.1, 30.7, 29.1, 28.8, 27.6, 25.9 (C25),
25.8 (C25), 25.4, 22.2, 21.9, 20.1, 19.5, 18.7, 18.1, 17.9, 16.8, 15.7, 14.0, 6.7 (C9), -4.4
(C23), -4.5 (C23), -4.5 (C23), -4.8 (C23).
249 31 3 1 28 19 O O 32 15 H 7 O 26 22 9 11 O TBSO H O 27 Si 23
25
Acetic acid 1-{2-[1,2-bis-(tert-butyl-dimethyl-silanyloxy)-dodec-3-en-6-ynyl]-
cyclopropyl}-7-(tetrahydro-pyran-2-yloxy)-hept-3-ynyl ester (2.122). (JED 3-296).
Acetic anhydride (0.28 mL, 2.98 mmol) and Et3N (1.26 mL, 8.93 mmol) were added to a
solution of alcohol 2.121 (402 mg, 0.60 mmol) and 4-dimethylaminopyridine (7 mg, 0.06
mmol) in anhydrous CH2Cl2 (12 mL) at rt. Stirring continued for 3.5 h at rt, whereupon
a 1 M solution of aqueous HCl (10 mL) was added. The layers were separated and the organic layer was washed with saturated aqueous NaHCO3 (5 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with hexanes/EtOAc (20:1) to provide 391 mg (92%) of acetate
2.122 as a pale yellow oil; 1H NMR (400 MHz) δ 5.86 (J = 15.2, 4.6, 2.0 Hz, 1 H), 5.60
(dtd, J =15.2, 5.0, 1.6 Hz, 1 H), 4.56 (br, 1 H), 4.37 (app dt, J = 7.5, 4.8 Hz, 1 H), 4.12
(dt, J = 4.6, 1.6 Hz, 1 H), 3.85-3.81 (m, 1 H), 3.76 (dt, J = 9.2, 6.6 Hz, 1 H), 3.49-3.45
(m, 1 H), 3.42 (dtd, J = 9.0, 6.0, 3.0 Hz, 1 H), 3.33 (app t, J = 4.6 Hz, 1 H), 2.92 (app dt,
J = 5.0, 2.0 Hz, 2 H), 2.52 (ddt, J = 16.8, 4.8, 2.2 Hz, 1 H), 2.43 (ddt, J = 16.8, 7.5, 2.2
Hz, 1 H), 2.24-2.20 (m, 2 H), 2.15 (tt, J = 7.2, 2.4 Hz, 2 H), 2.04 (s, 3 H), 1.83-1.65 250 (comp, 4 H), 1.57-1.44 (comp, 6 H), 1.38-1.25 (comp, 4 H), 1.07 (dtd, J = 9.6, 4.8, 4.8
Hz, 1 H), 0.95 (dtd, J = 9.4, 4.8, 4.8 Hz, 1 H), 0.88 (s, 3 H), 0.87 (s, 3H), 0.86-0.81 (m, 3
H), 0.51 (dt, J = 9.0, 4.8 Hz, 1 H), 0.46 (dt, J = 9.0, 4.8 Hz, 1 H), 0.02 (s, 3H), 0.02 (s,
3H), 0.01 (s, 3H), 0.01 (s, 3H); 13C (100 MHz) δ 170.5, 130.1, 125.8, 98.7, 82.5, 81.1,
77.3, 76.2, 75.6, 75.5, 75.3, 66.1, 62.1, 31.1, 30.7, 29.2, 28.8, 25.9, 25.8, 25.5, 24.8, 22.2,
21.9, 21.1, 19.5, 18.7, 18.1, 17.9, 17.6, 15.7, 14.0, 7.0, -4.4, -4.6, -4.6, -4.8; IR (neat)
-1 2929, 2857, 1743, 1471, 1237, 1033, 836 cm ; MS (CI) m/z 717.4919 [C41H73O6Si2
(M+1) requires 717.4946] 658, 617, 525, 437, 279 (base) 161;
NMR Assignments:1H NMR (400 MHz) δ 5.86 (J = 15.2, 4.6, 2.0 Hz, 1 H, C13-
H), 5.60 (dtd, J =15.2, 5.0, 1.6 Hz, 1 H, C14-H), 4.56 (br, 1 H, C28-H), 4.37 (app dt, J =
7.5, 4.8 Hz, 1 H, C7-H), 4.12 (dt, J = 4.6, 1.6 Hz, 1 H, C12-H), 3.85-3.81 (m, 1 H, C32-
H), 3.76 (dt, J = 9.2, 6.6 Hz, 1 H, C32-H), 3.49-3.45 (m, 1 H, C1-H), 3.42 (dtd, J = 9.0,
6.0, 3.0 Hz, 1 H, C1-H), 3.33 (app t, J = 4.6 Hz, 1 H, C11-H), 2.92 (app dt, J = 5.0, 2.0
Hz, 2 H, C15-2H), 2.52 (ddt, J = 16.8, 4.8, 2.2 Hz, 1 H, C6-H), 2.43 (ddt, J = 16.8, 7.5,
2.2 Hz, 1 H, C6-H), 2.24-2.20 (m, 2 H, C3-2H), 2.15 (tt, J = 7.2, 2.4 Hz, 2 H, C18-2H),
2.04 (s, 3 H, C27-3H), 1.83-1.65 (comp, 4 H, THP), 1.57-1.44 (comp, 6 H, C2-2H and
C19-2H and THP), 1.38-1.25 (comp, 4 H, C20-2H and C21-2H), 1.07 (dtd, J = 9.6, 4.8,
4.8 Hz, 1 H, C8-H), 0.95 (dtd, J = 9.4, 4.8, 4.8 Hz, 1 H, C10-H), 0.88 (s, 3 H, C25-3H),
0.87 (s, 3H, C25-3H), 0.86-0.81 (m, 3 H, C22-3H), 0.51 (dt, J = 9.0, 4.8 Hz, 1 H, C9-H),
0.46 (dt, J = 9.0, 4.8 Hz, 1 H, C9-H), 0.02 (s, 3H, C23-3H), 0.02 (s, 3H, C23-3H), 0.01
(s, 3H, C23-3H), 0.01 (s, 3H, C23-3H); 13C (100 MHz) δ 170.5 (C26), 130.1 (C13),
125.8 (C14), 98.7 (C28), 82.5 (C7), 81.1 (C11), 77.3, 76.2, 75.6, 75.5, 75.3, 66.1 (C1),
251 62.1 (32), 31.1, 30.7, 29.2, 28.8, 25.9 (C25), 25.8 (C25), 25.5, 24.8, 22.2, 21.9, 21.1,
19.5, 18.7, 18.1, 17.9, 17.6, 15.7, 14.0, 7.0 (C9), -4.4 (C23), -4.6 (C23), -4.6 (C23), -4.8
(C23).
3 1 19 OH 15 H 7 O 26 22 9 11 O TBSO H O 27 Si 23
25
Acetic acid 1-{2-[1,2-bis-(tert-butyl dimethyl silanyloxy)-dodec-3-en-6-ynyl]-
cyclopropyl}-7-hydroxy hept-3-ynyl ester (2.123). (JED 3-297). p-Toluenesulfonic
acid (318 mg, 1.67 mmol) was added to a solution of THP ether 2.122 in anhydrous i-
PrOH (11.0 mL) at rt. Stirring continued for 6 h at rt, whereupon saturated aqueous
NaHCO3 (5 mL) and Et2O (20 mL) was added. Stirring continued for an additional 5
min at rt, the layers were separated and the organic layer was dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by flash chromatography
eluting with hexanes/EtOAc (6:1 to 3:1) to provide 596 mg (87%) of alcohol 2.123 as a
pale yellow oil; 1H NMR (500 MHz) δ 5.85 (ddt, J = 15.5, 4.6, 2.0 Hz, 1 H), 5.59 (dtd, J
= 15.5, 5.5, 1.5 Hz, 1 H), 4.39 (dt, J = 7.5, 4.3 Hz, 1 H), 4.11 (app dt, J = 4.6, 1.5 Hz, 1
H), 3.69 (dt, J = 6.2, 1.5 Hz, 2 H), 3.35 (app t, J = 4.6 Hz, 1 H), 2.91 (dt, J = 5.5, 2.0 Hz,
252 2 H), 2.50 (ddt, J = 17.0, 4.3, 2.5 Hz, 1 H), 2.41 (ddt, J = 17.0, 7.5, 2.5 Hz, 1 H), 2.21 (tt,
J = 6.5, 2.5 Hz, 2 H), 2.15 (tt, J = 7.2, 2.0 Hz, 2 H), 2.02 (s, 3 H), 1.85 (br, 1 H), 1.67 (p,
J = 6.2 Hz, 2 H), 1.46 (p, J = 7.2 Hz, 2 H), 1.38-1.24 (comp, 4 H), 1.05 (app dt, J = 8.5,
4.6 Hz, 1 H), 0.99-0.92 (m, 1 H), 0.92-0.83 (comp, 21 H), 0.48 (app dt, J = 8.5, 4.9 Hz, 1
H), 0.45 (app dt, 8.4, 4.9 Hz, 1 H), 0.01 (s, 3 H), 0.00 (s, 3 H), 0.00 (s, 3 H), 0.00 (s, 3 H);
13C (125 MHz) δ 170.6, 130.1, 125.9, 82.56, 81.0, 77.0, 76.9, 75.6, 75.4, 75.3, 61.7, 31.3,
31.1, 28.8, 25.8, 25.8, 24.8, 22.2, 21.9, 21.1, 18.7, 18.1, 17.9, 17.9, 15.4, 14.0, 7.0, -4.4, -
4.6, -4.7, -4.9; IR (neat) 3435, 2929, 2557, 1743, 1471, 1369, 1251, 1075, 836 cm-1; MS
(CI) m/z 633.4357 [C36H65O5Si2 (M+1) requires 633.4371], 615, 573, 501, 441, 353
(base) 309, 279.
NMR Assignments: 1H NMR (500 MHz) δ 5.85 (ddt, J = 15.5, 4.6, 2.0 Hz, 1 H,
C13-H), 5.59 (dtd, J = 15.5, 5.5, 1.5 Hz, 1 H, C14-H), 4.39 (dt, J = 7.5, 4.3 Hz, 1 H, C7-
H), 4.11 (app dt, J = 4.6, 1.5 Hz, 1 H, C12-H), 3.69 (dt, J = 6.2, 1.5 Hz, 2 H, C1-2H),
3.35 (app t, J = 4.6 Hz, 1 H, C11-H), 2.91 (dt, J = 5.5, 2.0 Hz, 2 H, C15-2H), 2.50 (ddt, J
= 17.0, 4.3, 2.5 Hz, 1 H, C6-H), 2.41 (ddt, J = 17.0, 7.5, 2.5 Hz, 1 H, C6-H), 2.21 (tt, J =
6.5, 2.5 Hz, 2 H, C3-2H), 2.15 (tt, J = 7.2, 2.0 Hz, 2 H, C18-2H), 2.02 (s, 3 H, C27-H),
1.85 (br, 1 H, OH), 1.67 (p, J = 6.2 Hz, 2 H, C2-2H), 1.46 (p, J = 7.2 Hz, 2 H, C19-2H),
1.38-1.24 (comp, 4 H, C20-2H and C21-2H), 1.05 (app dt, J = 8.5, 4.6 Hz, 1 H, C10-H),
0.99-0.92 (m, 1 H, C8-H), 0.92-0.83 (comp, 21 H, C22-3H and C25-9H and C25-9H),
0.48 (app dt, J = 8.5, 4.9 Hz, 1 H, C9-H), 0.45 (app dt, 8.4, 4.9 Hz, 1 H, C9-H), 0.01 (s, 3
H, C23-3H), 0.00 (s, 3 H, C23-3H), 0.00 (s, 3 H, C23-3H), 0.00 (s, 3 H, C23-3H); 13C
(125 MHz) δ 170.6 (C26), 130.1 (C13), 125.9 (C14), 82.56 (C16), 81.0 (C17), 77.0 (C5),
253 76.9 (C4), 75.6 (C7), 75.4 (C12), 75.3 (C11), 61.7, 31.3 (C2), 31.1 (C20), 28.8 (C19),
25.8 (C25), 25.8 (C25), 24.8 (C6), 22.2 (C21), 21.9 (C5), 21.1 (C27), 18.7 (C18), 18.1
(C24), 17.9 (C10), 17.9 (C24), 15.4 (C3), 14.0 (C22), 7.0 (C9), -4.4 (C23), -4.6 (C23), -
4.7 (C23), -4.9 (C23).
5 22 15 OH H 7 3 O 1 19 9 26 11 O TBSO H 27 O Si 23
25
Acetic acid 1-{2-[1,2-bis-(tert butyl dimethyl silanyloxy)-dodeca-3,6-dienyl]-
cyclopropyl}-7-hydroxy hept-3-enyl ester (2.124). (JED 3-37). A vacuum (0.5 mm
Hg), using a 20 gauge needle plunged through a standard rubber septum, was pulled on a
solution of dialkyne 2.123 (54 mg, 0.085 mmol), quinoline (11 µL), and Lindlar’s
catalyst (11 mg) in anhydrous MeOH (1.7 mL) at rt. Stirring continued under vacuum for
5 sec, or when the reaction began to gently reflux, whereupon the reaction vessel was
backfilled with H2 gas. This procedure was repeated six times. Stirring continued for 15
min at rt, the reaction was diluted with CH2Cl2 (3 mL) and filtered through a pad of celite. The solvent was removed under reduced pressure and the residue was purified by
flash chromatography eluting with hexanes/EtOAc (10:1) to give 51 mg (94%) of triene
2.124 as a colorless oil; 1H NMR (400 MHz) δ 5.61-5.50 (comp, 2 H), 5.46-5.31 (comp,
254 4 H), 4.34 (dt, J = 7.6, 5.6 Hz, 1 H), 4.06 (dd, J = 4.6, 2.8 Hz, 1 H), 3.61 (t, J = 6.6 Hz, 2
H), 3.26 (dd, J = 5.5, 4.6 Hz, 1 H), 2.78-2.75 (m, 2 H), 2.42-2.38 (comp, 2 H), 2.10 (app sex, J = 7.6 Hz, 2 H), 2.03-1.98 (m, 2 H), 1.60 (dp, J = 6.8, 2.6 Hz, 2 H), 1.53 (br, 1 H),
1.36-1.21 (comp, 6 H) 1.02-0.90 (comp, 2 H), 0.88-0.84 (comp, 21 H), 0.51 (dt, J = 8.6,
5.2 Hz, 1 H), 0.46 (dt, J = 8.6, 5.2 Hz, 1 H), 0.01 (s, 3 H), 0.01 (s, 3 H), 0.00 (s, 3 H), -
0.01 (s, 3 H); 13C (100 MHz) δ 170.7, 131.3, 130.8, 129.9, 129.2, 127.0, 125.7, 77.2,
76.3, 75.9, 62.1, 32.6, 32.3, 31.5, 30.2, 29.3, 27.1, 25.8, 25.8, 23.5, 22.5, 21.2, 18.9, 18.1,
17.9, 17.7, 14.0, 7.3, -4.3, -4.5, -4.5, -4.9; IR (neat) 3446, 2929, 2857, 1740, 1471, 1370,
-1 1250, 1076, 836 cm ; MS (CI) 637.4674 [C36H69O5Si2 (M+1) requires 637.4684] 621,
577, 505, 489, 445, 373, 355, 313, 281 (base).
NMR Assignments: 1H NMR (400 MHz) δ 5.61-5.50 (comp, 2 H, C13-H and
C14-H), 5.46-5.31 (comp, 4 H, C4-H and C5-H and C16-H and C17-H), 4.34 (dt, J = 7.6,
5.6 Hz, 1 H, C7-H), 4.06 (dd, J = 4.6, 2.8 Hz, 1 H, C12-H), 3.61 (t, J = 6.6 Hz, 2 H, C2-
H), 3.26 (dd, J = 5.5, 4.6 Hz, 1 H, C7-H), 2.78-2.75 (m, 2 H, C15-H), 2.42-2.38 (comp, 2
H, C6-H and C6-H), 2.10 (app sex, J = 7.6 Hz, 2 H, C3-2H), 2.03-1.98 (m, 2 H, C18-2H),
1.60 (dp, J = 6.8, 2.6 Hz, 2 H, C2-2H), 1.53 (br, 1 H, OH), 1.36-1.21 (comp, 6 H, C19-
2H and C20-2H and C21-2H) 1.02-0.90 (comp, 2 H, C8-H and C1-H), 0.88-0.84 (comp,
21 H, C22-3H and C25-9H and C25-9H), 0.51 (dt, J = 8.6, 5.2 Hz, 1 H, C9-H), 0.46 (dt, J
= 8.6, 5.2 Hz, 1 H, C9-H), 0.01 (s, 3 H, C23-3H), 0.01 (s, 3 H, C23-3H), 0.00 (s, 3 H,
C23-3H), -0.01 (s, 3 H, C23-3H); 13C (100 MHz) δ 170.7 (C26), 131.3 (C4), 130.8 (C5),
129.9 (C13), 129.2 (C14), 127.0 (C16), 125.7 (C17), 77.2 (C11), 76.3 (C7), 75.9 (C12),
62.1 (C2), 32.6, 32.3, 31.5, 30.2, 29.3, 27.1, 25.8 (C25), 25.8 (C25), 23.5, 22.5, 21.2, 18.9
255 (C24), 18.1, 17.9, 17.7 (C24), 14.0, 7.3 (C9), -4.3 (C23), -4.5 (C23), -4.5 (C23), -4.9
(C23).
22 15 O H 7 3 O 1 H 19 9 26 11 O TBSO H 27 O Si 23
25
Acetic acid 1-{2-[1,2-bis-(tert-butyl dimethyl silanyloxy)-dodeca-3,6-dienyl]-
cyclopropyl}-7-oxo-hept-3-enyl ester (2.125). (JED 5-43). Sulfur trioxide pyridine
complex (90 mg, 0.57 mmol) was added to a solution of alcohol 2.124 (240 mg, 0.38
mmol) and Et3N (0.26 mL, 1.88 mmol) in anhydrous dimethyl sulfoxide (1 mL) and
anhydrous CH2Cl2 (4 mL) at rt. Stirring continued for 5 h at rt, whereupon 1 M aqueous
HCl (10 mL) and CH2Cl2 (10 mL) was added. The layers were separated and the organic
layer was washed with saturated aqueous NaHCO3 (5 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (12:1) to provide 205 mg (85%) of aldehyde 2.125 as a pale yellow oil; 1H NMR (400 MHz) δ 9.74 (t, J = 1.6 Hz, 1 H), 5.61-5.51 (comp, 2 H), 5.43
(app dd, J = 11.0, 6.6 Hz, 1 H), 5.41-5.36 (comp, 2 H), 5.32 (app dd, J = 11.0, 7.2 Hz, 1
H), 4.37 (app dt, J = 6.4, 6.4 Hz, 1 H), 4.06-4.04 (m, 1 H), 3.23 (app t, J = 5.0 Hz, 1 H),
2.77-2.74 (m, 2 H), 2.47-2.31 (comp, 6 H), 1.99 (q, J = 6.8 Hz, 2 H), 1.98 (s, 3 H), 1.40-
256 1.20 (comp, 6 H), 1.01-0.89 (comp, 2 H), 0.87-0.84 (comp, 21 H), 0.51 (app dt, J = 8.8,
5.2 Hz, 1 H), 0.45 (app dt, J = 8.8, 5.2 Hz, 1 H), 0.00 (s, 6 H), -0.01 (s, 3 H), -0.02 (s, 3
H); 13C NMR (100 MHz) δ 201.8, 170.6, 130.8, 129.9, 129.4, 129.1, 127.0, 126.7, 77.3,
76.2, 75.9, 43.6, 32.7, 31.5, 30.2, 29.3, 27.1, 25.8, 22.5, 21.2, 20.1, 18.9, 18.1, 17.9, 17.7,
14.0, 7.2, -4.4, -4.5, -4.9; IR (neat) 2929, 2857, 2711, 1737, 1472, 1370, 1240, 836 cm-1;
MS (CI) m/z 635.4528 [C36H67O5Si2 (M + 1) requires 635.4527] 620, 575, 503 (base),
443.
NMR Assignments: 1H NMR (400 MHz) δ 9.74 (t, J = 1.6 Hz, 1 H, C1-H),
5.61-5.51 (comp, 2 H), 5.43 (app dd, J = 11.0, 6.6 Hz, 1 H), 5.41-5.36 (comp, 2 H), 5.32
(app dd, J = 11.0, 7.2 Hz, 1 H), 4.37 (app dt, J = 6.4, 6.4 Hz, 1 H, C7-H), 4.06-4.04 (m, 1
H, C12-H), 3.23 (app t, J = 5.0 Hz, 1 H, C11-H), 2.77-2.74 (m, 2 H, C15-2H), 2.47-2.31
(comp, 6 H, C2-2H and C2-2H and C6-2H), 1.99 (q, J = 6.8 Hz, 2 H, C18-2H), 1.98 (s, 3
H, C27-3H), 1.40-1.20 (comp, 6 H, C19-2H and C20-2H and C21-2H), 1.01-0.89 (comp,
2 H, C8-H and C10-H), 0.87-0.84 (comp, 21 H, C22-3H and C25-18H), 0.51 (app dt, J =
8.8, 5.2 Hz, 1 H, C9-H), 0.45 (app dt, J = 8.8, 5.2 Hz, 1 H, C9-H), 0.00 (s, 6 H, C23-6H),
-0.01 (s, 3 H, C23-3H), -0.02 (s, 3 H, C23-3H); 13C NMR (100 MHz) δ 201.8 (C1),
170.6 (C26), 130.8, 129.9, 129.4, 129.1, 127.0, 126.7, 77.3, 76.2, 75.9, 43.6 (C2), 32.7,
31.5, 30.2, 29.3, 27.1, 25.8 (C25), 22.5, 21.2, 20.1, 18.9, 18.1, 17.9, 17.7, 14.0, 7.2 (C9), -
4.4 (C23), -4.5 (C23), -4.9 (C23).
257 22 15 O H 7 3 O 1 OH 19 9 26 11 O TBSO H 27 O Si 23
25
7-Acetoxy-7-{2-[1,2-bis-(tert-butyl dimethyl silanyloxy)-dodeca-3,6-dienyl]-
cyclopropyl} -hept-4-enoic acid (2.126). (4-143). Sodium chlorite (48 mg, 1.53 mmol)
was added portion wise over 5 min to a solution of aldehyde 2.125 (113 mg, 0.18 mmol),
2 methyl 2-butene (2 M solution in THF, 0.41 mL, 0.82 mmol), and NaH2PO4 (25 mg,
0.18 mmol) in tert-butyl alcohol (6.6 mL) and H2O (1.8 mL) at rt. Stirring continued for
20 min at rt, whereupon the tert-butyl alcohol was evaporated under reduced pressure and
the aqueous residue was dissolved in CH2Cl2 (5 mL), washed with 1 M aqueous HCl (3
mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified
by flash chromatography eluting with hexanes/EtOAc to give 104 mg (90%) of acid
2.126 as a clear oil; 1H NMR (400 MHz) δ 5.61-5.52 (comp, 2 H), 5.45 (app dd, J =
11.0, 5.8 Hz, 1 H), 5.46-5.35 (comp, 2 H), 5.33 (app dd, J = 11.0, 7.0 Hz, 1 H), 4.37 (dt J
= 6.4, 6.4 Hz, 1 H), 4.06-4.04 (m, 1 H), 3.26 (app t, J = 5.0 Hz, 1 H), 2.76 (br, 2 H), 2.42-
2.34 (comp, 6 H), 2.00 (t, J = 6.8 Hz, 2 H), 1.99 (s, 3 H), 1.36-1.23 (comp, 6 H), 1.01-
0.81 (comp, 23 H), 0.51 (app dt, J = 8.8, 4.8 Hz, 1 H), 0.46 (app dt, J = 8.8, 4.8 Hz, 1 H),
0.01 (s, 9H), 0.00 (s, 3H), -0.01 (s, 3H); 13C NMR (100 MHz), δ 179.1, 170.7, 130.8,
129.9, 129.4, 129.1, 127.0, 126.7, 76.7, 76.2, 75.9, 33.9, 32.6, 31.5, 30.2, 29.3, 27.1, 25.8, 258 22.5, 22.4, 21.1, 18.8, 18.1, 17.9, 17.7, 14.0, 7.2, -4.4, -4.5, -4.9; IR (neat) 2929, 2657,
-1 1741, 1713, 1472, 1369, 1249, 1979, 1077, 835 cm ; MS (CI) 651.4461 [C36H67O6Si2
(M + 1) requires 651.4476] 635, 591 (base), 519, 449, 221.
NMR Assignments: 1H NMR (400 MHz) δ 5.61-5.52 (comp, 2 H), 5.45 (app dd,
J = 11.0, 5.8 Hz, 1 H), 5.46-5.35 (comp, 2 H), 5.33 (app dd, J = 11.0, 7.0 Hz, 1 H), 4.37
(dt J = 6.4, 6.4 Hz, 1 H, C7-H), 4.06-4.04 (m, 1 H, C12-H), 3.26 (app t, J = 5.0 Hz, 1 H,
C11-H), 2.76 (br, 2 H, C15-2H), 2.42-2.34 (comp, 6 H, C2-2H and C3-2H and C6-2H),
2.00 (t, J = 6.8 Hz, 2 H, C5-2H), 1.99 (s, 3 H, C27-3H), 1.36-1.23 (comp, 6 H, C19-2H and C20-2H and C21-2H), 1.01-0.81 (comp, 23 H, C8-H and C10-H and C22-3H and
C25-18H), 0.51 (app dt, J = 8.8, 4.8 Hz, 1 H, C9-H), 0.46 (app dt, J = 8.8, 4.8 Hz, 1 H,
C9-H), 0.01 (s, 9H, C23-6H), 0.00 (s, 3H, C23-3H), -0.01 (s, 3H, C23-3H); 13C NMR
(100 MHz), δ 179.1 (C1), 170.7 (C26), 130.8, 129.9, 129.4, 129.1, 127.0, 126.7, 76.7
(C11), 76.2 (C7), 75.9 (C12), 33.9, 32.6, 31.5, 30.2, 29.3, 27.1, 25.8 (C25), 22.5, 22.4,
21.1, 18.8, 18.1, 17.9, 17.7, 14.0, 7.2 (C9), -4.4 (C23), -4.5 (C23), -4.9 (C23).
22 15 O H 73 OH 1 OH 19 9 11 TBSO H O Si 23
25
259 7-{2-[1,2-Bis-(tert-butyldimethylsilanyloxy)-dodeca-3,6-dienyl]-cyclopropyl}-
7-hydroxy-hept-4-enoic acid (2.127). (4-247). K2CO3 (406 mg, 3.82 mmol) was added
to a solution of acetate 2.126 (249 mg, 0.38 mmol) in anhydrous MeOH (8 mL) at rt.
Stirring continued for 12 h at rt, whereupon Et2O (30 mL) and 1 M aqueous HCl (30 mL) was added. The layers were separated and the organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (4:1 to 2:1) to give 217 mg (95%) of acetate 2.127 as a clear oil; 1H NMR (400 MHz) δ 5.62-5.31 (comp, 6 H), 4.07 (app t, J = 4.4 Hz, 1 H), 3.28 (app
t, J = 4.4 Hz, 1 H), 3.04 (dd, J = 12.8, 7.2 Hz, 1 H), 2.76 (app t, J = 5.4 Hz, 2 H), 2.47-
2.27 (comp, 6 H), 2.00 (q, J = 6.8 Hz, 2 H), 1.37-1.17 (comp, 6 H), 0.94-0.83 (comp, 23
H), 0.50 (app dt, J = 8.2, 4.8 Hz, 1 H), 0.45 (app dt, J = 8.2, 4.8 Hz, 1 H), 0.02 (s, 3 H),
0.01 (s, 3 H), 0.01 (s, 3 H), 0.00 (s, 3 H); 13C NMR (100 MHz) δ 178.0, 130.7, 130.1,
129.7, 129.4, 127.6, 127.1, 76.3, 76.0, 75.0, 35.0, 33.5, 31.5, 30.3, 30.2, 29.3, 27.1, 25.9,
25.8, 22.5, 22.4, 21.1, 18.1, 17.9, 17.1, 14.0, 6.9, -4.3, -4.5, -4.5, -4.8; IR (neat) 3383,
-1 2928, 2857, 1713, 1253, 1080, 836, 774 cm ; MS (CI) m/z 609.4368 [C34H65O5Si2
(M+1) requires 609.4371], 592, 534, 477, 460, 345, 328, 281 (base), 195.
NMR Assignments: 1H NMR (400 MHz) δ 5.62-5.31 (comp, 6 H, C4-H and C5-
H and C13-H and C14-H and C16-H and C17-H), 4.07 (app t, J = 4.4 Hz, 1 H, C12-H),
3.28 (app t, J = 4.4 Hz, 1 H, C11-H), 3.04 (dd, J = 12.8, 7.2 Hz, 1 H, C7-H), 2.76 (app t,
J = 5.4 Hz, 2 H, C15-2H), 2.47-2.27 (comp, 6 H, C2-2H and C3-2H and C4-2H), 2.00 (q,
J = 6.8 Hz, 2 H, C18-2H), 1.37-1.17 (comp, 6 H, C19-2H and C20-2H and C21-2H),
0.94-0.83 (comp, 23 H, C8-H and C10-H and C22-3H and C25-18H), 0.50 (app dt, J =
260 8.2, 4.8 Hz, 1 H, C9-H), 0.45 (app dt, J = 8.2, 4.8 Hz, 1 H, C9-H), 0.02 (s, 3 H, C23-3H),
0.01 (s, 3 H, C23-3H), 0.01 (s, 3 H, C23-3H), 0.00 (s, 3 H, C23-3H); 13C NMR (100
MHz) δ 178.0 (C1), 130.7, 130.1, 129.7, 129.4, 127.6, 127.1, 76.3 (C11), 76.0 (C12),
75.0 (C7), 35.0, 33.5, 31.5, 30.3, 30.2, 29.3, 27.1, 25.9 (C25), 25.8 (C25), 22.5, 22.4,
21.1, 18.1, 17.9, 17.1, 14.0, 6.9 (C9), -4.3 (C23), -4.5 (C23), -4.5 (C23), -4.8 (C23).
22 15 3 7 H 1 O 11 9 O TBSO H O Si 23
25
8-{2-[1,2-Bis-(tert-butyl dimethyl silanyloxy)-dodeca-3,6-dienyl]-
cyclopropyl}-3,4,7,8-tetrahydro-oxocin-2-one (2.128). (JED 4-248). 2,4,6-
Trichlorobenzoyl chloride (1.06 mL, 1.03 mmol) was added to a solution of hydroxy acid
2.127 (210 mg, 0.34 mmol) and Et3N (0.24 mL, 1.72 mmol) in anhydrous THF (3.5 mL)
at rt. Stirring continued for 1 h at rt, whereupon the formed triethylamine hydrochloride salt was removed by filtration through a short plug of celite. The filtrate was diluted with anhydrous toluene (300 mL) and added drop wise over 3 h via an addition funnel into a refluxing solution of 4-di(methylamino)pyridine (842 mg, 6.90 mmol) in anhydrous toluene (40 mL). After the addition was complete, the reaction was refluxed for an additional 4 h and concentrated under reduced pressure. The solid was dissolved in
261 CH2Cl2 (30 mL) and washed with 1 M aqueous HCl (2 x 30 mL), aqueous saturated
NaHCO3 (10 mL), dried (MgSO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography eluting with hexanes/EtOAc (30:1) to
provide 165 mg (81%) of lactone 2.128 as a pale yellow oil; 1H NMR (400 MHz) δ 5.76
(dd, J = 11.2, 6.4 Hz, 1 H), 5.70 (dd, J = 11.2, 7.6 Hz, 1 H), 5.62-5.53 (comp, 2 H), 5.44-
5.31 (comp, 2 H), 4.08-4.07 (m, 1 H), 3.88 (ddd, J = 10.4, 8.6, 1.8 Hz, 1 H), 3.33 (app t, J
= 4.6 Hz, 1 H), 3.85 (dtd, J = 12.4, 8.6, 5.9 Hz, 1 H), 2.78-2.75 (m, 2 H), 2.71 (ddd, J =
13.2, 5.9, 2.9 Hz, 1 H), 2.55 (ddd, J = 16.0, 10.4, 5.6 Hz, 1 H), 2.30-2.22 (comp, 2 H),
2.10-2.05 (m, 1 H), 2.01 (q, J = 7.2 Hz, 2 H), 1.36-1.25 (comp, 6 H), 1.03-0.98 (comp, 2
H), 0.92-0.85 (comp, 21 H), 0.59-0.52 (comp, 2 H), 0.02 (s, 6 H), 0.01 (s, 3 H), 0.00 (s, 3
H); 13C NMR (100 MHz) δ 177.2, 132.7, 131.1, 130.2, 129.4, 128.8, 127.2, 82.8, 76.1, 7
6.0, 37.9, 34.6, 31.7, 30.5, 29.6, 27.4, 26.1, 24.7, 22.8, 18.7, 18.3, 18.2, 14.3, 7.9, -4.1, -
4.2; IR (neat) 2929, 2857, 1751, 1472, 1253, 1083, 836 cm-1; MS (CI) m/z 591.4260
[C34H63O4Si2 (M+1) requires 591.4265], 574, 539, 533, 460, 441, 327, 309 (base), 282.
NMR Assignments: 1H NMR (400 MHz) δ 5.76 (dd, J = 11.2, 6.4 Hz, 1 H),
5.70 (dd, J = 11.2, 7.6 Hz, 1 H), 5.62-5.53 (comp, 2 H), 5.44-5.31 (comp, 2 H), 4.08-4.07
(m, 1 H, C12-H), 3.88 (ddd, J = 10.4, 8.6, 1.8 Hz, 1 H, C7-H), 3.33 (app t, J = 4.6 Hz, 1
H, C11-H), 3.85 (dtd, J = 12.4, 8.6, 5.9 Hz, 1 H, C3-H), 2.78-2.75 (m, 2 H, C15-H), 2.71
(ddd, J = 13.2, 5.9, 2.9 Hz, 1 H, C2-H), 2.55 (ddd, J = 16.0, 10.4, 5.6 Hz, 1 H, C6-H),
2.30-2.22 (comp, 2 H, C2-H and C6-H), 2.10-2.05 (m, 1 H, C3-H), 2.01 (q, J = 7.2 Hz, 2
H, C18-2H), 1.36-1.25 (comp, 6 H, C19-2H and C20-2H and C21-2H), 1.03-0.98 (comp,
2 H, C8-H and C10-H), 0.92-0.85 (comp, 21 H, C22-3H and C25-18H), 0.59-0.52 (comp,
262 2 H, C9-2H), 0.02 (s, 6 H, C23-3H), 0.01 (s, 3 H, C23-3H), 0.00 (s, 3 H, C23-3H); 13C
NMR (100 MHz) δ 177.2 (C1), 132.7, 131.1, 130.2, 129.4, 128.8, 127.2, 82.8 (C11), 76.1
(C6), 76.0 (C12), 37.9, 34.6, 31.7, 30.5, 29.6, 27.4, 26.1, 24.7, 22.8, 18.7, 18.3, 18.2,
14.3, 7.9 (C9), -4.1 (C23), -4.2 (C23).
5 22 15 3 7 H 1 19 O 11 9 O HO H OH
8-[2-(1,2-Dihydroxy-dodeca-3,6-dienyl)-cyclopropyl]-3,4,7,8-tetrahydro- oxocin-2-one (2.129). (JED 4-249). A solution of tetrabutylammonium fluoride (264 mg, 0.84 mmol) in THF (1 mL) was added to a solution of bis-silyl ether 2.128 (165 mg,
0.28 mmol) at 0 ºC. The solution was stirred at 0 ºC for 20 min, whereupon the bath was removed and stirring continued for an additional 3 h at rt. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to give 72 mg (72%) of diol 2.129 as a clear oil; 1H NMR (500 MHz) δ 5.78-5.68 (comp, 3 H), 5.50 (ddt, J = 15.5, 7.0, 1.5 Hz,
1 H), 5.45-5.40 (m, 1 H), 5.43-5.29 (m, 1 H), 4.00 (ddd, J = 10.0, 8.0, 1.5 Hz, 1 H), 3.98
(appt, J = 7.0 Hz, 1 H), 2.93 (app t, J = 7.0 Hz, 1 H), 2.82 (app ddt, J = 15.0, 9.0, 6.0 Hz,
1 H), 2.77 (app dt, J = 7.5, 1.5 Hz, 2 H), 2.70 (ddd, J = 13.5, 6.0, 3.0 Hz, 1 H), 2.59 (ddd,
J = 17.0, 10.0, 6.0 Hz, 1 H), 2.50 (br, 1 H), 2.4 (br, 1 H), 2.29-2.21 (comp, 2 H), 2.11-
2.06 (m, 1 H), 1.99 (dq, J = 7.2, 1.2 Hz, 2 H), 1.37 (p, J = 7.2 Hz, 2 H), 1.30-1.21 (comp, 263 4 H), 1.12 (app dtd, J = 9.0, 5.0, 5.0 Hz, 1 H), 0.92-0.84 (comp, 4 H), 0.67 (app dt, J =
9.0, 5.0 Hz, 1 H), 0.55 (app dt, J = 9.0, 5.0 Hz, 1 H); 13C NMR (100 MHz) δ 177.0,
132.7, 132.6, 131.4, 129.1, 128.2, 126.2, 81.0, 77.0, 76.4, 37.7, 34.1, 31.4, 30.1, 29.2,
27.1, 24.4, 22.5, 19.8, 19.6, 14.0, 8.7; IR (neat) 3406, 2928, 2856, 1747, 1458, 1213,
-1 1054, 967 cm ; MS (CI) m/z 363, 345.2420 [C22H33O3 (M+1-H2O) requires 345.2429],
327, 195 179 (base) 149.
NMR Assignments: 1H NMR (500 MHz) δ 5.78-5.68 (comp, 3 H, C4-H and
C5-H and C14-H), 5.50 (ddt, J = 15.5, 7.0, 1.5 Hz, 1 H, C13-H), 5.45-5.40 (m, 1 H, C17-
H), 5.43-5.29 (m, 1 H, C16-H), 4.00 (ddd, J = 10.0, 8.0, 1.5 Hz, 1 H, C7-H), 3.98 (appt, J
= 7.0 Hz, 1 H, C12-H), 2.93 (app t, J = 7.0 Hz, 1 H, C11-H), 2.82 (app ddt, J = 15.0, 9.0,
6.0 Hz, 1 H, C3-H), 2.77 (app dt, J = 7.5, 1.5 Hz, 2 H, C15-2H), 2.70 (ddd, J = 13.5, 6.0,
3.0 Hz, 1 H, C2-H), 2.59 (ddd, J = 17.0, 10.0, 6.0 Hz, 1 H, C6-H), 2.50 (br, 1 H, OH), 2.4
(br, 1 H, OH), 2.29-2.21 (comp, 2 H, C2-H and C6-H), 2.11-2.06 (m, 1 H, C3-H), 1.99
(dq, J = 7.2, 1.2 Hz, 2 H, C18-2H), 1.37 (p, J = 7.2 Hz, 2 H, C19-2H), 1.30-1.21 (comp, 4
H, C20-2H and C21-2H), 1.12 (app dtd, J = 9.0, 5.0, 5.0 Hz, 1 H, C8-H), 0.92-0.84
(comp, 4 H, C10-H and C22-3H), 0.67 (app dt, J = 9.0, 5.0 Hz, 1 H, C9-H), 0.55 (app dt,
J = 9.0, 5.0 Hz, 1 H, C9-H); 13C NMR (100 MHz) δ 177.0 (C1), 132.7, 132.6, 131.4
(C17), 129.1 (C13), 128.2, 126.2 (C16), 81.0 (C12), 77.0 (C11), 76.4 (C7), 37.7 (C2),
34.1 (C6), 31.4 (C21), 30.1 (C15), 29.2 (C19), 27.1 (C18), 24.4 (C3), 22.5 (C20), 19.8
(C8), 19.6 (C10), 14.0 (C1), 8.7 (C9).
264 5 22 15 3 7 H 1 19 O 11 9 O O H 25 23 O H MeO 27 28
8-{2-[5-Deca-1,4-dienyl-2-(4-methoxyphenyl)-[1,3]dioxolan-4-yl]- cyclopropyl}-3,4,7,8-tetrahydrooxocin-2-one (2.79). (JED 5-52). p-Toluenesulfonic acid (4 mg, 0.02 mmol) was added to a solution of p-anisaldehyde dimethyl acetal (25
µL, 0.14 mmol) and diol 2.129 (38 mg, 1.08 mmol) in anhydrous DMF (0.5 mL) at rt.
Stirring continued for 20 min at rt, whereupon saturated aqueous NaHCO3 (2 mL) and
Et2O (5 mL) were added. The layers were separated and the organic layer was dried
(MgSO4) and concentrated under reduced pressure. The residue was purified by flash
chromatography eluting with hexanes/EtOAc (5:1) to give 40 mg (80%) of benzylidene
acetal 2.79, an inconsequential mixture of C(23) diastereomers, as a clear oil; 1H NMR
(400 MHz) δ 7.38 (dd, J = 8.4, 2.4 Hz, 2 H), 6.88 (dd, J = 8.4, 2.4 Hz, 2 H), 5.92-5.68
(comp, 4 H), 5.55-5.42 (comp, 2 H), 5.37-5.31 (comp, 1 H), 4.28 (app t, J = 7.6 Hz, 0.5
H), 4.25 (app t, J = 7.6 Hz, 0.5 H), 4.01 (dt, J = 7.6, 1.5 Hz, 0.5 H), 3.97 (dt, J = 7.6, 1.5
Hz, 0.5 H), 3.80 (s, 1.5 H), 3.79 (s, 1.5 H), 3.33 (app t, J = 7.6 Hz, 0.5 H), 3.30 (app t, J =
7.6 Hz, 0.5 H), 2.88-2.78 (comp, 3 H), 2.74-2.67 (comp, 1 H), 2.67-2.58 (comp, 1 H),
2.32-2.23 (comp, 2 H), 2.12-2.07 (comp, 1 H), 2.00 (app q, J = 7.1 Hz, 2 H), 1.36-1.23
(comp, 6 H), 1.17 (dt, J = 8.8, 4.8 Hz, 0.5 H), 1.16 (dt, J = 8.8, 4.8 Hz, 0.5 H), 1.04-0.95
265 (comp, 1 H), 0.87 (t, J = 6.8 Hz, 1.5 H), 0.86 (t, J = 6.8 Hz, 1.5 H), 0.74 (app dt, J = 8.6,
4.8 Hz, 1 H), 0.63 (app dt, J = 8.6, 4.8 Hz, 0.5 H), 0.58 (app dt, J = 8.6, 4.8 Hz, 0.5 H);
13C (100 MHz) δ 176.8, 176.8, 160.3, 160.2, 134.8, 134.1, 132.6, 131.6, 131.6, 130.3,
130.3, 128.1, 127.9, 127.8, 126.8, 126.3, 125.9, 125.8, 113.7, 113.6, 103.3, 102.9, 84.6,
84.0, 83.3, 80.9, 80.9, 55.2, 37.7, 34.3, 34.2, 31.4, 30.0, 29.2, 27.1, 24.4, 22.5, 19.9, 18.3,
18.0, 14.0, 7.6, 7.4; IR (neat) 3009, 2929, 2855, 1746, 1614, 1516, 1248, 1213, 1077, 966
-1 cm ; MS (CI) m/z 481.2956 [C30H41O5 (M+1) requires 481.2954], 436, 373, 345 (base),
327, 315, 315, 287.
NMR Assignments: 1H NMR (400 MHz) δ 7.38 (dd, J = 8.4, 2.4 Hz, 2 H, C25-
H), 6.88 (dd, J = 8.4, 2.4 Hz, 2 H, C26-H), 5.92-5.68 (comp, 4 H, C13-H and C14-H and
C16-H and C23-H), 5.55-5.42 (comp, 2 H, C4-H and C5-H), 5.37-5.31 (comp, 1 H, C17-
H), 4.28 (app t, J = 7.6 Hz, 0.5 H, C12-0.5H), 4.25 (app t, J = 7.6 Hz, 0.5 H, C12-0.5H),
4.01 (dt, J = 7.6, 1.5 Hz, 0.5 H, C7-0.5H), 3.97 (dt, J = 7.6, 1.5 Hz, 0.5 H, C7-0.5H), 3.80
(s, 1.5 H, C7-1.5H), 3.79 (s, 1.5 H, C7-1.5H), 3.33 (app t, J = 7.6 Hz, 0.5 H, C11-0.5H),
3.30 (app t, J = 7.6 Hz, 0.5 H, C11-0.5H), 2.88-2.78 (comp, 3 H, C15-2H and C2-H),
2.74-2.67 (comp, 1 H, C2-H), 2.67-2.58 (comp, 1 H, C6-H), 2.32-2.23 (comp, 2 H, C18-
2H), 2.12-2.07 (comp, 1 H, C6-H), 2.00 (app q, J = 7.1 Hz, 2 H, C3-2H), 1.36-1.23
(comp, 6 H, C19-2H and C20-2H and C21-2H), 1.17 (dt, J = 8.8, 4.8 Hz, 0.5 H, C8-
0.5H), 1.16 (dt, J = 8.8, 4.8 Hz, 0.5 H, C8-0.5H), 1.04-0.95 (comp, 1 H, C10-H), 0.87 (t,
J = 6.8 Hz, 1.5 H, C22-1.5H), 0.86 (t, J = 6.8 Hz, 1.5 H, C22-1.5H), 0.74 (app dt, J = 8.6,
4.8 Hz, 1 H, C9-H), 0.63 (app dt, J = 8.6, 4.8 Hz, 0.5 H, C9-0.5H), 0.58 (app dt, J = 8.6,
4.8 Hz, 0.5 H, C9-0.5H); 13C (100 MHz) δ 176.8 (C1), 176.8 (C1), 160.3 (C27), 160.2
266 (C27), 134.8, 134.1, 132.6, 131.6, 131.6, 130.3, 130.3, 128.1, 127.9 (C26), 127.8 (C26),
126.8, 126.3, 125.9, 125.8, 113.7 (C25), 113.6 (C25), 103.3 (C23), 102.9 (C23), 84.6,
84.0, 83.3, 80.9, 80.9, 55.2 (C28), 37.7, 34.3, 34.2, 31.4, 30.0, 29.2, 27.1, 24.4, 22.5,
19.9, 18.3, 18.0, 14.0, 7.6 (C9), 7.4(C9);
5 22 15 3 7 H 1 19 O 11 9 O HO H
O 23
25
26
OMe 27
8-{2-[2-Hydroxy-1-(4-methoxy-benzyloxy)-dodeca-3,6-dienyl]-cyclopropyl}-
3,4,7,8-tetrahydro-oxocin-2-one. (2.80). (JED 5-54) Trifluoroacetic acid (14 µL, 0.19
mmol) was added to a solution of benzylidene acetal 2.79 (30 mg, 0.06 mmol) and
NaCNBH3 (39 mg, 0.62 mmol) in anhydrous THF (1 mL) at 0 ºC. Stirring continued for
15 min at 0 ºC, whereupon the ice bath was removed and the reaction was warmed to rt.
Stirring continued for an additional 1 h at rt, and an aqueous solution of 1 M HCl (0.5
mL) was added. The layers were separated and the aqueous layer extracted with Et2O (2 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (1 mL), and brine (1 mL), dried (MgSO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography eluting with hexanes/EtOAc (10:1) to give 267 11 mg (34%) of cyclopropyl alcohol 2.130 (less polar) as a pale yellow oil and 14 mg
(47%) of allylic alcohol 2.80 (more polar) as a pale yellow oil and an additional 3 mg
(10%) of a mixture of 2.80 and 2.130. 1H NMR (400 MHz) δ 7.22 (d, J = 8.6 Hz, 2 H),
6.86 (d, J = 8.6 Hz, 2 H), 5.81-5.69 (comp, 3 H), 5.50 (ddt, J = 15.4, 7.0, 1.5 Hz, 1 H),
5.45-5.31 (comp, 2 H), 4.68 (d, J = 11.0 Hz, 1 H), 4.45 (d, 11.0 Hz, 1 H), 4.08-4.03
(comp, 2 H), 3.78 (s, 3 H), 2.88-2.76 (comp, 4 H), 2.71 (ddd, J = 13.2, 5.6, 2.8 Hz, 1 H),
2.61 (ddd, J = 14.0, 10.0, 6.0 Hz, 1 H), 2.53 (br, 1 H), 2.31-2.23 (comp, 2 H), 2.15-2.07
(m, 1 H), 2.00 (app q, J = 7.2 Hz, 2 H), 1.33 (p, J = 7.2 Hz, 2 H), 1.29-1.23 (comp, 4 H),
1.14 (app tt, J = 8.8, 4.4 Hz, 1 H), 0.94 (app tt, J = 8.8, 4.4 Hz, 1 H), 0.86 (t, J = 7.2 Hz, 3
H), 0.67 (dt, J = 8.6, 5.2 Hz, 1 H), 0.48 (dt, J = 8.6, 5.2 Hz, 1 H); 13C NMR (75 MHz) δ
176.7, 159.4, 132.8, 132.0, 131.3, 130.1, 129.4, 129.2, 128.1, 126.4, 113.9, 84.3, 80.8,
75.4, 72.3, 55.3, 37.6, 34.0, 31.5, 30.1, 29.3, 27.1, 24.4, 22.5, 20.6, 18.0, 14.0, 7.9; IR
(neat) 3469, 3009, 2929, 2856, 1746, 1612, 1514, 1454, 1248, 1212, 1172, 1052, 967 cm-
1 ; MS (CI) m/z 483.3102 [C30H43O5 (M+1) requires 483.3110], 466, 448, 436, 345, 317,
299 (base), 257, 195.
NMR Assignments: 1H NMR (400 MHz) δ 7.22 (d, J = 8.6 Hz, 2 H, C25-2H),
6.86 (d, J = 8.6 Hz, 2 H, C26-2H), 5.81-5.69 (comp, 3 H, C4-H and C5-H and C16-H),
5.50 (ddt, J = 15.4, 7.0, 1.5 Hz, 1 H, C13-H), 5.45-5.31 (comp, 2 H, C14-H and C17-H),
4.68 (d, J = 11.0 Hz, 1 H, C23-H), 4.45 (d, 11.0 Hz, 1 H, C23-H), 4.08-4.03 (comp, 2 H,
C7-H and C12-H), 3.78 (s, 3 H, C28-H), 2.88-2.76 (comp, 4 H, C3-H and C11-H and
C15-2H), 2.71 (ddd, J = 13.2, 5.6, 2.8 Hz, 1 H, C2-H), 2.61 (ddd, J = 14.0, 10.0, 6.0 Hz,
1 H, C6-H), 2.53 (br, 1 H, OH), 2.31-2.23 (comp, 2 H, C2-H and C6-H), 2.15-2.07 (m, 1
268 H, C3-H), 2.00 (app q, J = 7.2 Hz, 2 H, C18-2H), 1.33 (p, J = 7.2 Hz, 2 H, C19-2H),
1.29-1.23 (comp, 4 H, C20-2H and C21-2H), 1.14 (app tt, J = 8.8, 4.4 Hz, 1 H, C8-H),
0.94 (app tt, J = 8.8, 4.4 Hz, 1 H, C10-H), 0.86 (t, J = 7.2 Hz, 3 H, C22-3H), 0.67 (dt, J =
8.6, 5.2 Hz, 1 H, C9-H), 0.48 (dt, J = 8.6, 5.2 Hz, 1 H, C9-H); 13C NMR (75 MHz) δ
176.7 (C1), 159.4 (C27), 132.8 (C16), 132.0 (C4), 131.3 (C17), 130.1 (C24), 129.4
(C25), 129.2 (C5), 128.1 (C13), 126.4 (C14), 113.9 (C26), 84.3 (C7), 80.8 (C12), 75.4
(C11), 72.3 (C23), 55.3 (C28), 37.6 (C3), 34.0 (C6), 31.5 (C21), 30.1 (C15), 29.3 (C19),
27.1 (C18), 24.4 (C3), 22.5 (C20), 20.6 (C8), 18.0 (C10), 14.0 (C22), 7.9 (C9).
5 22 15 3 7 H 1 19 O 11 9 O O H 23 OH 25
26
OMe 27
8-{2-[1-Hydroxy-2-(4-methoxy benzyloxy)-dodeca-3,6-dienyl]-cyclopropyl}-
3,4,7,8-tetrahydro oxocin-2-one (2.130). Isolated as the minor regioisomer in the
reductive cleavage of benzylidene acetal 2.130; 1H NMR (500 MHz) δ 7.21 (d, J = 8.5
Hz, 2 H), 6.86 (dt, J = 8.6,. 2.4 Hz, 2 H), 5.79-5.67 (comp, 3 H), 5.49-5.43 (m, 1 H),
5.39-5.33 (comp, 2 H), 4.54 (app d, J = 11.0 Hz, 1 H), 4.25 (app d, J = 11.0 Hz, 1 H),
3.92 (app dt, J = 9.0, 1.5 Hz, 1 H), 3.79 (s, 3 H), 3.63 (dd, J = 8.0, 7.0 Hz, 1 H), 3.00 (app
269 t, J = 7.0 Hz, 1 H), 2.88-2.77 (comp, 3 H), 2.71 (ddd, J = 13.6, 6.0, 3.0 Hz, 1 H), 2.61
(ddd, J = 16.0, 9.0, 6.0 Hz, 1 H), 2.30-2.23 (comp, 2 H), 2.11-2.07 (m, 1 H), 2.01 (app q,
J = 7.0 Hz, 2 H), 1.35 (p, J = 7.0 Hz, 2 H), 1.30-1.25 (comp, 4 H), 1.12 (app tt, J = 9.0,
5.0 Hz, 1 H), 0.82 (t, J = 7.1 Hz, 3 H), 0.82 (app tt, J = 9.0, 5.0 Hz, 1 H), 0.61 (app dt, J =
8.5, 5.0 Hz, 1 H), 0.54 (app dt, J = 8.5, 5.0 Hz, 1 H); 13C NMR (125 MHz) δ 177.0,
159.3, 135.1, 132.6, 131.5, 130.2, 129.5, 128.4, 127.0, 126.2, 113.9, 83.8, 81.6, 75.9,
69.6, 55.3, 37.7, 34.3, 31.5, 30.3, 29.2, 27.1, 24.4, 22.5, 19.8, 19.5, 14.0, 8.8; IR (neat)
3540, 3010, 2927, 2856, 1745, 1612, 1513, 1454, 1248, 1212, 1052 cm-1; MS (CI) m/z
483.3102 [C30H43O5 (M+1) requires 483.3110], 466, 447, 345, 299, 121 (base).
NMR Assignments: 1H NMR (500 MHz) δ 7.21 (d, J = 8.5 Hz, 2 H, C25-2H),
6.86 (dt, J = 8.6,. 2.4 Hz, 2 H, C26-2H), 5.79-5.67 (comp, 3 H, C4-H and C5-H and C16-
H), 5.49-5.43 (m, 1 H, C17-H), 5.39-5.33 (comp, 2 H, C13-H and C14-H), 4.54 (app d, J
= 11.0 Hz, 1 H, C23-H), 4.25 (app d, J = 11.0 Hz, 1 H, C23-H), 3.92 (app dt, J = 9.0, 1.5
Hz, 1 H, C7-H), 3.79 (s, 3 H, C29-3H), 3.63 (dd, J = 8.0, 7.0 Hz, 1 H, C12-H), 3.00 (app
t, J = 7.0 Hz, 1 H, C11-H), 2.88-2.77 (comp, 3 H, C3-H and C15-2H), 2.71 (ddd, J =
13.6, 6.0, 3.0 Hz, 1 H, C2-H), 2.61 (ddd, J = 16.0, 9.0, 6.0 Hz, 1 H, C6-H), 2.30-2.23
(comp, 2 H, C2-H and C6-H), 2.11-2.07 (m, 1 H, C3-H), 2.01 (app q, J = 7.0 Hz, 2 H,
C18-2H), 1.35 (p, J = 7.0 Hz, 2 H, C19-2H), 1.30-1.25 (comp, 4 H, C20-2H and C21-
2H), 1.12 (app tt, J = 9.0, 5.0 Hz, 1 H, C8-H), 0.82 (t, J = 7.1 Hz, 3 H, C22-3H), 0.82
(app tt, J = 9.0, 5.0 Hz, 1 H, C9-H), 0.61 (app dt, J = 8.5, 5.0 Hz, 1 H, C9-H), 0.54 (app
dt, J = 8.5, 5.0 Hz, 1 H, C9-H); 13C NMR (125 MHz) δ 177.0 (C1), 159.3 (C27), 135.1
(C16), 132.6 (C4), 131.5 (C17), 130.2 (C24), 129.5 (C25), 128.4 (C5), 127.0 (C13),
270 126.2 (C14), 113.9 (C26), 83.8 (C7), 81.6 (C12), 75.9 (C11), 69.6 (C23), 55.3 (C28),
37.7 (C3), 34.3 (C6), 31.5 (C21), 30.3 (C15), 29.2 (C19), 27.1 (C18), 24.4 (C3), 22.5
(C20), 19.8 (C8), 19.5 (C10), 14.0 (C22), 8.8 (C9).
16 5 22 3
14 7 H 1 19 HO O 11 9 O H
O 23
25
26
OMe 27
8-{2-[4-Hydroxy-1-(4-methoxy benzyloxy)-dodeca-2,6-dienyl]-cyclopropyl}-
3,4,7,8-tetrahydro oxocin-2-one (2.131) (JED 5-78). Tributyl phosphine (28 µL, 0.11 mmol) was added drop wise to a solution of 2.80 (9 mg, 0.02 mmol) and o-NO2PhSeCN
(13 mg, 0.06 mmol) at rt. The reaction turned from a pale yellow to dark brown. Stirring continued for 1 h at rt, whereupon the reaction was concentrated under reduced pressure and filtered through a short plug of silica gel eluting with hexanes/EtOAc (5:1). The eluted material was concentrated under reduced pressure. Pyridine (50 µL) and 30%
H2O2 (0.5 mL) were added to a solution of the crude mixture in CH2Cl2 (1 mL) at rt and the solution was stirred for 3 h whereupon 1 M HCl (0.5 mL) was added. The layers were separated, and the organic layer was washed with saturated aqueous NaHCO3 (0.5 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified 271 by flash chromatography eluting with hexanes/EtOAc (5:1) to give 5 mg (56%) of trans- allylic alcohol 2.131 as a pale yellow oil. 1H NMR (400 MHz) δ 7.20 (d, J = 8.8 Hz, 2
H), 6.85 (d, J = 8.8 Hz, 2 H), 5.80-5.40 (comp, 5 H), 5.40-5.33 (m, 1 H), 4.49 (d, J = 11.8
Hz, 1 H), 4.28 (d, J = 11.8 Hz, 1 H), 4.20 (app q, J = 6.4 Hz, 1 H), 3.94 (ddd, J = 10.0,
8.4, 1.6 Hz, 1 H), 3.79 (s, 3 H), 3.28 (app t, J = 6.4 Hz, 1 H), 2.84 (dtd, J = 12.0, 8.8, 6.0
Hz, 1 H), 2.70 (ddd, J = 13.2, 5.6, 3.2 Hz, 1 H), 2.63 (ddd, J = 13.6, 10.0, 5.4 Hz, 1 H),
2.39-2.24 (comp, 4 H), 2.15-2.08 (m, 1 H), 2.04 (app q, J = 7.1 Hz, 2 H), 1.66 (br, 1 H),
1.34 (p, J = 7.1 Hz, 2 H), 1.31-1.23 (comp, 4 H), 1.07-0.95 (comp, 2 H), 0.86 (t, J = 7.1
Hz, 3 H), 0.66 (dt, J = 8.6, 5.2 Hz, 1 H), 0.54 (dt, J = 8.6, 5.2 Hz, 1 H); 13C NMR (75
MHz) δ 177.0, 159.1, 135.1, 133.9, 132.7, 130.6, 130.0, 129.1, 128.3, 124.1, 113.7, 81.4,
80.5, 71.6, 69.6, 55.3, 37.7, 35.4, 34.3, 31.5, 29.3, 27.4, 24.4, 22.5, 22.1, 21.0, 14.0, 8.0;
IR (neat) 3447, 3011, 2928, 2856, 1745, 1612, 1513, 1247, 1051 cm-1; MS (CI) m/z
483.3112 [C30H43O5 (M+1) requires 483.3110], 465, 436, 365, 345 (base), 327, 283,
219.
NMR Assignments: 1H NMR (400 MHz) δ 7.20 (d, J = 8.8 Hz, 2 H, C25-2H),
6.85 (d, J = 8.8 Hz, 2 H, C26-2H), 5.80-5.40 (comp, 5 H, C4-H and C5-H and C12-H and
C13-H and C16-H), 5.40-5.33 (m, 1 H, C17-H), 4.49 (d, J = 11.8 Hz, 1 H, C23-H), 4.28
(d, J = 11.8 Hz, 1 H, C23-H), 4.20 (app q, J = 6.4 Hz, 1 H, C14-H), 3.94 (ddd, J = 10.0,
8.4, 1.6 Hz, 1 H, C7-H), 3.79 (s, 3 H, C28-3H), 3.28 (app t, J = 6.4 Hz, 1 H, C11-H), 2.84
(dtd, J = 12.0, 8.8, 6.0 Hz, 1 H, C3-H), 2.70 (ddd, J = 13.2, 5.6, 3.2 Hz, 1 H, C2-H), 2.63
(ddd, J = 13.6, 10.0, 5.4 Hz, 1 H, C6-H), 2.39-2.24 (comp, 4 H, C2-H and C6-H and C15-
2H), 2.15-2.08 (m, 1 H, C3-H), 2.04 (app q, J = 7.1 Hz, 2 H, C18-2H), 1.66 (br, 1 H,
272 OH), 1.34 (p, J = 7.1 Hz, 2 H, C19-2H), 1.31-1.23 (comp, 4 H, C20-2H and C21-2H),
1.07-0.95 (comp, 2 H, C8-H and C10-H), 0.86 (t, J = 7.1 Hz, 3 H, C22-3H), 0.66 (dt, J =
8.6, 5.2 Hz, 1 H, C9-H), 0.54 (dt, J = 8.6, 5.2 Hz, 1 H, C9-H); 13C NMR (75 MHz) δ
177.0 (C1), 159.1 (C27), 135.1, 133.9, 132.7, 130.6 (C24), 130.0, 129.1 (C25), 128.3,
124.1, 113.7 (C26), 81.4 (C11), 80.5 (C7), 71.6 (C14), 69.6 (C23), 55.3 (C28), 37.7, 35.4,
34.3, 31.5, 29.3, 27.4, 24.4, 22.5, 22.1, 21.0, 14.0 (C22), 8.0 (C9);
16 5 22 3
14 7 H 1 19 HO O 11 9 O H OH
Solandelactone E (1.197). (JED 5-79). 2,3-Dichloro-5,6-dicyano-p- benzoquinone (12 mg, 0.05 mmol) was added to a solution of PMB-ether 2.131 (5 mg,
0.01 mmol) in CH2Cl2 (0.5 mL) and a pH 7 phosphate buffer (0.1 mL) at rt. Stirring
continued for 1 h at rt, whereupon the reaction was washed with H2O (0.2 mL), saturated
aqueous NaHCO3 (0.2 mL), dried (MgSO4) and concentrated under reduced pressure.
The residue was purified by flash chromatography eluting with pentanes/Et2O (1:1) to
provide 2.5 mg (71%) of solandelactone E (1.197) as a clear oil; 1H NMR (500 MHz) δ
5.84-5.70 (comp, 4 H), 5.57 (dtt, J = 11.0, 7.4, 1.5, 1 H), 5.36 (dtt, J = 11.0, 7.0, 1.8 Hz, 1
H), 4.17 (br ddd, J = 7.0, 5.5, 0.0 Hz, 1 H), 4.02 (ddd, J = 10.0, 8.0, 1.5 Hz, 1 H), 3.65
(dd, J = 7.5, 4.5 Hz, 1 H), 2.88-2.80 (m, 1 H), 2.71 (ddd, 13.5, 6.0, 3.0 Hz, 1 H), 2.61
273 (ddd, J = 14.0, 10.4, 5.6 Hz, 1 H), 2.32-2.25 (comp, 3 H), 2.24 (ddd, J = 14.0, 7.5, 1.5
Hz, 1 H), 2.13-2.08 (m, 2 H), 2.03 (app q, J = 7.1 Hz, 2 H), 1.52 (br, 1 H), 1.37-1.24
(comp, 6 H), 1.12 (tt, J = 8.5, 5.5 Hz, 1 H), 0.99 (dtd, J = 8.5, 8.5, 5.0 Hz, 1 H), 0.87 (t, J
= 7.1 Hz, 3 H), 0.72 (dt, J = 9.0, 5.0 Hz, 1 H), 0.59 (dt, J = 8.5, 5.0 Hz, 1 H); 13C NMR
(125 MHz) δ 176.9, 134.0, 133.2, 132.8, 131.7, 128.1, 124.0, 80.9, 74.4, 71.4, 37.7, 35.3,
34.2, 31.5, 29.3, 27.4, 24.4, 23.4, 22.5, 20.6, 14.0, 8.0.
NMR Assignments: 1H NMR (500 MHz) δ 5.84-5.70 (comp, 4 H), 5.57 (dtt, J =
11.0, 7.4, 1.5, 1 H, C17-H), 5.36 (dtt, J = 11.0, 7.0, 1.8 Hz, 1 H, C16-H), 4.17 (br ddd, J
= 7.0, 5.5, 0.0 Hz, 1 H, C14-H), 4.02 (ddd, J = 10.0, 8.0, 1.5 Hz, 1 H, C7-H), 3.65 (dd, J
= 7.5, 4.5 Hz, 1 H, C11-H), 2.88-2.80 (m, 1 H, C3-H), 2.71 (ddd, 13.5, 6.0, 3.0 Hz, 1 H,
C2-H), 2.61 (ddd, J = 14.0, 10.4, 5.6 Hz, 1 H, C6-H), 2.32-2.25 (comp, 3 H, C2-H &
C15-2), 2.24 (ddd, J = 14.0, 7.5, 1.5 Hz, 1 H, C6-H), 2.13-2.08 (m, 2 H, C3-2H), 2.03
(app q, J = 7.1 Hz, 2 H, C18-2H), 1.52 (br, 1 H, OH), 1.37-1.24 (comp, 6 H, C19-2H &
C20-2H, C21-2H), 1.12 (tt, J = 8.5, 5.5 Hz, 1 H, C8-H), 0.99 (dtd, J = 8.5, 8.5, 5.0 Hz, 1
H, C10-H), 0.87 (t, J = 7.1 Hz, 3 H, C1-3H), 0.72 (dt, J = 9.0, 5.0 Hz, 1 H, C9-H), 0.59
(dt, J = 8.5, 5.0 Hz, 1 H, C9-H); 13C NMR (125 MHz) δ 176.9 (C1), 134.0 (C17), 133.2
(C12), 132.8 (C13), 131.7 (C4), 128.1 (C5), 124.0 (C16), 80.9 (C7), 74.4 (C10), 71.4
(C14), 37.7 (C2), 35.3 (C15), 34.2 (C6), 31.5 (C20), 29.3 (C19), 27.4 (C18), 24.4 (C3),
23.4 (C10), 22.5 (C21), 20.6 (C8), 14.0 (C22), 8.0 (C9).
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295 Vita
Jennifer Elizabeth Davoren was born in Rockville, Connecticut on May 23, 1980,
the eldest daughter of Elizabeth Davoren and Thomas Davoren. After graduating from
South Windsor High School, South Windsor, Connecticut, in 1997, she attended Saint
Joseph College. During the course of her undergraduate education, she was fortunate to be employed at Pfizer as an undergraduate research fellow. In 2001, she graduated summa cum laude with a Bachelors degree in Biology and Chemistry. In June 2001, she entered the Graduate School of the University of Texas at Austin and joined the research laboratories of Professor Stephen F. Martin. In September 2006, she will begin a postdoctoral fellowship under the advisement of Professor Peter Wipf at the University of
Pittsburgh, Pittsburg, Pennsylvania.
Permanent Address: 152 Campmeeting Road, Bolton, CT, 06043
This dissertation was typed by the author.