APPLICATION OF SQUARATE ESTER CASCADE REACTIONS TO THE
SYNTHESIS OF (+/-) HYPNOPHILIN.
NEW PHOTOREARRANGEMENTS OF 2-CYCLOPENTENONES.
STUDIES TOWARDS THE TOTAL SYNTHESIS OF PECTENOTOXIN-II
DISSERTATION
Presented in Partial Fulfillment of the Requirements for the Degree of Doctor of
Philosophy in the Graduate School of The Ohio State University
By
Jian Liu
The Ohio State University
2002
Dissertation Committee: Approved By
Leo A. Paquette, Adviser
David J. Hart Adviser
Dehua Pei Department of Chemistry
ABSTRACT
The naturally occurring antibiotic polyquinane, hypnophilin, has attracted synthetic chemists for a number of years due to its reputed antibacterial and antitumor properties. As a highly oxygenated linear triquinane containing six stereocenters, hypnophilin was a suitable target for application of our squarate ester cascade reaction.
The success of constructing 72 via a squarate ester cascade reaction allowed us to
synthesize hypnophilin in a short route.
Two 2-cyclopentenones 137 and 138 were prepared by a convergent pathway
involving the coupling of cyclopentenyl bromide 139 and racemic ketone 150 followed
by desilylation, perruthenate oxidation, and ring-closing metathesis. New
photorearrangements were discovered when 137 and 138 were irradiated through quartz.
Convergent pathways for synthesizing building blocks A and B for pectenotoxin
II were investigated. Advanced precursor 238 was prepared involving the coupling of iodide 184 and Weinreb amide 185 followed by removal of the two PMB ethers, hydrogenolysis, DMP oxidation, Wittig reaction, reduction, Sharpless' asymmetric epoxidation, DMP oxidation, and Wittig reaction. Four more functional group transformations would be needed to construct building block A. Advanced precursor tetrahydrofuran 283 was prepared involving a Julia olefination via the coupling of sulfone
ii 277 and aldehyde 243 followed by a series of chemical operations including Sharpless' asymmetric dihydroxylation. After eight more chemical operations, building block B could be synthesized.
iii
To my wife, Xiaoling
my daughter, Kailin my parents, Hanming and Huijuan
and my brothers An and Yan
iv ACKNOWLEDGMENTS
I would like to thank my advisor, Dr. Leo Paquette for his invaluable support,
guidance, and enthusiasm. He has given me the opportunity and intellectual freedom to
grow in scientific knowledge and creativity. I would also like to thank my other
dissertation committee members Dr. David J. Hart, Dr. Dehua Pei for their time and
cooperation.
I thank Donna Rothe for her unselfish contributions to me and the group. I
would also like to thank Rebecca Martin for her help in a variety of ways.
I would like to acknowledge Dr. Robin Rogers for solving a number of crystal
structures.
I would like to thank the many talented and gifted group members who have
shared their advice and expertise during my graduate tenure. Some group members have
contributed in ways which have made my experience at The Ohio State University
enjoyable. Of them, I thank Drs. Qingbei Zeng, Penglie Zhang, Oliver Yun Long,
Andrew Cooks, Daffyd Owens, Ingo Konezki and Maosheng Duan for sharing their
experiences in the beginning of my graduate studies. A special thanks goes to Drs. Feng
Geng, Zhong Zhao, Fabrice Gallou and Mr. Jiong Yang for their cooperation through
some of my research projects. In particular, I thank Drs. Ray Bishop and Ho-Jung Kang for sharing their talents in chemistry and making my lab life enjoyable. v VITA
April 8, 1971………………………………Born - Shanghai, China
1993………………………………………..B. S. Chemistry, Fudan University
1997………………………………………..M. S. Chemistry, West Virginia University
1997 - present………………………………Graduate Teaching and Research
Associate, The Ohio State Univerity
PUBLICATIONS
1. Geng, F.; Liu, J.; Paquette, L.A. “Three-Component Coupling via the Squarate
Ester Cascade as a Concise Route to the Bioactive Triquinane Sesquiterpene
Hypnophilin” Org. Lett. 2002, 71-73.
2. Paquette, L.A.; Zhao, Z.; Gallou, F.D.; Liu, J. “New Photorearrangements of 2-
Cyclopentenenones. The Genesis and Fate of Cyclopropylcarbinyl Biradical
Intermediates” J. Am. Chem. Soc. 2000, 122, 1540-1541.
vi 3. Paquette, L.A.; Gallou, F.; Zhao, Z.; Young, D.G.; Liu, J.; Yang, J.; Friedrich, D.
“Propensity of 4-Methoxy-4-Vinyl-2-Cyclopentenenones Housed in Tri- and
Tetracyclic Frameworks for Deep-Seated Photochemical Rearrangement” J. Am.
Chem. Soc. 2000, 122, 9610-9620.
4. Soederberg, B.C.; O’Neil, S.N.; Chisnell, A.C.; Liu, J. “A [3.3] Sigmatropic
rearrangement of α, β-unsaturated Fischer chromium carbenes: Synthesis of
alkynol and dienol esters” Tetrahedron 2000, 56, 5037-5044.
5. Soederberg, B.C.; O’Neil, S.N.; Liu, J. “A novel formal [3+3] sigmatropic
rearrangement of alkenyl-substituted Fischer carbenes” Book of Abtracts, 215 th
ACS National Meeting, Dallas, Texas, March 29- April 2, 1998.
6. Soederberg, B.C.; Liu, J.; Ball, T.W.; Turbeville, M.J. “Thermal Decomposition
of Pentacarbonyl(1-acyloxyalkylidene)Chromium(0) Complexes: Formation of Z-
Enol Esters” J. Org. Chem. 1997, 62, 5945-5952.
FIELDS OF STUDY
Major Field: Chemistry
vii
TABLE OF CONTENTS
ABSTRACT……………………………………………………………………………....ii
ACKNOWLEDGEMENTS………………………………………………………………v
VITA……………………………………………………………………………………..vi
LIST OF FIGURES………………………………………………………………………x
LIST OF SCHEMES……………………………………………………………………..xi
CHAPTER 1...... 1
INTRODUCTION ...... 1
CHAPTER 2...... 4
APPLICATION OF SQUARATE ESTER CASCADE REACTIONS TO THE SYNTHESIS OF (+/-) HYPNOPHILIN...... 4 2.1 SQUARATE ESTER CASCADES AND RELATIONSHIP TO POLYQUINANE NATURAL PRODUCTS……………………………………………………………………………… 4 2.2 BACKGROUND AND APPROACHES TO THE SYNTHESIS OF HYPNOPHILIN………. 13 2.3 RETROSYNTHETIC ANALYSIS………………………………………………….. 17 2.4 SYNTHESIS OF VINYL BROMIDE 75 AND ITS UTILIZATION TOWARD THE SYNTHESIS OF (+/-) HYPNOPHILIN…………………………………………………….. 18 2.5 CONCLUSION…………………………………………………………………...28 CHAPTER 3...... 29
NEW PHOTOREARRANGEMENTS OF 2-CYCLOPETENONES...... 29 3.1 INTRODUCTION………………………………………………………………... 29 3.2 SYNTHESES OF 2-CYCLOPENTENONES 137 AND 138…………………………… 37 3.3 PHOTOREARRANGEMENTS OF 2-CYCLOPENTENONES 137 AND 138 AND MECHANISTIC ELUCIDATION………………………………………………………….. 43 3.4 CONCLUSION………………………………………………………………….. 47 CHAPTER 4...... 49
STUDIES TOWARDS THE TOTAL SYNTHESIS OF PECTENOTOXIN-II………..49 4.1 INTRODUCTION………………………………………………………………... 49 viii 4.2 RETROSYNTHETIC ANALYSIS…………………………………………………...53 4.3 STUDIES TOWARD THE SYNTHESIS OF BUILDING BLOCK A…………………… 56 4.3.1 Synthesis of iodide 184…………………………………………………...57 4.3.2 Synthesis of Weinreb amide 185…………………………………………60 4.3.3 Synthesis of spiroketal 183……………………………………………….61 4.3.4 Synthesis of the framework of building block A…………………………. 74 4.3.5 Future work………………………………………………………………79 4.4 STUDIES TOWARD THE SYNTHESIS OF BUILDING BLOCK B…………………….81 4.4.1 Synthesis of sulfone 242…………………………………………………. 82 4.4.2 Synthesis of aldehyde 243……………………………………………….. 85 4.4.3 Efforts on the Julia-Lythgoe olefination and synthesis of the tetrahydrofuran ring……………………………………………………………….. 86 4.4.4 Future work……………………………………………………………… 95 CHAPTER 5...... 97
EXPERIMENTAL SECTION...... 97
APPENDIX……………………………………………………………………………..168 REFERENCES…………………………………………………………………………233
ix LIST OF FIGURES
Figure Page
1 Squaric acid………………………………………………………………………4
2 Selected natural polyquinanes…………………………………………………..13
3 Hypnophilin……………………………………………………………………..13
4 2-ethyl-2-methyl-[1,3]dioxolane……………………………………………….20
5 Ingenol………………………………………………………………………….35
6 Compound 131………………………………………………………………….35
7 2-Cyclopentenones 137 and 138………………………………………………..37
8 First generation Grubbs' catalyst………………………………………………..41
9 Computer-generated perspective drawing of 157 as determined by X-ray
crystallography…………………………………………………………………..45
10 Computer-generated perspective drawing of 159 as determined by X-ray
crystallography…………………………………………………………………..46
11 Pectenotoxins…………………………………………………………………….50
12 MM3 calculations for two possible conformational models 224 and 225 of
spiroketal 183……………………………………………………………………73
13 Modified building block A………………………………………………………75
14 Modified building block B………………………………………………………75
x
LIST OF SCHEMES
Scheme Page
1 Some examples of squarate esters in synthetic applications………..…….6
2 Two-fold addition of 3 to 2……………………………………………….7
3 trans Addition and the electrocyclic reaction channel……………………8
4 cis Addition and the sigmatropic pathway………………………………..8
5 1,4-Addition of the second nucleophile…………………………………..10
6 Helical equilibration………………………………………………………11
7 Regioselective transannular aldol from β-elimination……………………12
8 Little's strategy for the synthesis of Hypnophilin………………………..14
9 Curran's synthesis of Hypnophilin………………………………………15
10 Weinges' enantioselective synthesis of Hypnophilin…………………….16
11 Retrosynthetic analysis for the synthesis of hypnophilin via the squarate
ester cascade………………………………………………………………18
12 Synthesis of vinyl bromide 75…………………………………………….18
13 Possible explanation for the formation of β-chloro ketone 84……………19
14 Mechanism for formation of 86……………………………………………22
15 Formation of β-elimination product 72 and non-b-elimination product 91..23
16 Formation of monoadduct 93……………………………………………….24
xi 17 A possible explanation for the formation of 97…………………………….25
18 Formation of enone 96 from 72 and 91…………………………………….26
19 Modified strategy to install methyl group…………………………………..27
20 Finish the synthesis…………………………………………………………28
21 The photodimerization of 2-cyclopentenone……………………………….29
22 [2+2] photocycloaddition of 2-cyclopentenone with alkenes, acetylenes, and allenes…………………………………………...30
23 Mechanism for the photocycloaddition of 2-cyclopentenone to alkenes………………………………………………………………………..31
24 Application of 2-cyclopentenone [2+2] cycloaddition to the synthesis of
triquinane ring systems……………………………………………………..32
25 Application of 2-cyclopentenone [2+2] cycloaddition to the synthesis of
laurenene……………………………………………………………………33
26 Photo-induced addition of methanol………………………………………..33
27 Photoisomerization………………………………………………………….34
28 Norrish Type 1 cleavage……………………………………………………34
29 Photoinduced 1,2-shift………………………………………………………35
30 Formation of 135 and 136 from irradiation of 131…………………………36
31 Synthesis of enantiomerically pure vinyl bromide 139…………………….40
32 Syntheses of 2-cyclopentenones 137 and 138………………………………42
33 Formation of 157, 158, 159, and 160 by irradiating 137and 138 separately…………………………………………...43
34 Mechanistic explanation for 157, 158, and 159…………………………….48 xii 35 The synthesis of C31-C40 fragment by Murai's group……………………..51
36 The synthesis of C8-C18 fragment by Murai's group………………………52
37 The formation of C, D, E rings of pectenotoxin II by Roush's group………52
38 A proposed epoxide cyclization cascade for formation of the C11-C21 fragment……………………………………………54
39 Retrosynthetic analysis for the synthesis of pectenotoxin II……………….55
40 Retrosynthetic analysis for the synthesis of building block A…………….56
41 Synthesis of iodide 184……………………………………………………59
42 Synthesis of Weinreb amide 185…………………………………………..61
43 Formation of ketones directly from the combination of Weinreb amides and Grignard reagents or organolithium species………………………………61
44 Attempt to synthesize ketone 207 via the coupling reaction between the
Grignard reagent from 184 and 185……………………………………………62
45 Synthesis of bromide 208…………………………………………………..63
46 Synthesis of sulfone 211……………………………………………………64
47 A possible strategy for synthesizing spiroketal 183 from the coupling between the a-sufonyl carbanion from 211 and lactone 200…………………………….65
48 A dianion strategy for the coupling between a-sulfonyl carbanion from 211
and lactone 200……………………………………………………………66
49 Formation of a-sulfonyl ketone 221……………………………………….68
50 Formation of lactone 200 from the reaction between 221 and DDQ………69
51 Removal of a-sulfonyl functionality in 221 to form ketone 207 with three different reducing reagents………………………………………….70 xiii 52 Synthesis of 207 from the reaction between lithiated 184 and 185…………71
53 Synthesis of spiroketal 183…………………………………………………72
54 A potential problem for building bolck A under the basic conditionc……...74
55 Synthesis of epoxy alcohol 231……………………………………………..76
56 Synthesis of epoxy iodide 232………………………………………………77
57 Efforts to synthesize homoallylic epoxide 235 from the coupling between epoxy iodide 232 and vinylmagnesium bromide…..78
58 Synthesis of ester 238……………………………………………………….79
59 Synthetic plan to complete the synthesis of
building block A from ester 238…………………………………………………80
60 Retrosynthetic analysis of building block B…………………………………81
61 Synthesis of sulfone 242……………………………………………………..84
62 Synthesis of aldehyde 243…………………………………………………...86
63 Synthesis of the Windaus and Grundmann C19 ketone……………………..87
64 Julia-Lythgoe olefination between the modified sulfone 266
and aldehyde 242………………………………………………………………..89
65 Synthesis of sulfones 274 and 277………………………………………….90
66 Synthesis of 283…………………………………………………………….91
67 Conditions for formation of 283……………………………………………93
68 Another way to form THF ring……………………………………………..94
69 Synthesis of ester 292……………………………………………………….95
70 The strategy for synthesis of building block B……………………………...96
xiv
CHAPTER 1.
INTRODUCTION
As organic chemistry develops rapidly, chemists are more and more interested in molecules with complicated structures. In order to synthesize such targets efficiently, the practioner not only adopts synthetic strategies such as convergent approaches when they design synthetic routes for molecules, but also seek synthetic methods that minimize the number of requisite steps to maximize the overall efficiency. And thus, new terms such as "atom economy1" and "power reaction2" have come forth recently. From the
"atom economy" vantage point, the ideal reaction is one that produces a minimum amount of waste. If all the starting materials are incorporated in the reaction products without any loss of unwanted by-products, then the reaction is most efficient in terms of
"atom economy". As for "power reaction", it is related to a process that many steps of a reaction can be run in one flask without isolation or loss of material. As a matter of fact,
"power reaction" and "atom economy" are closely related to each other because minimum waste is usually produced as many steps of a reaction sequence are completed in a single operation. Based on the above-mentioned descriptions of the terms of "atom economy" 1 and "power reaction", the squarate ester cascade reaction (vide infra), which was discovered in our group in early 1990's, is no doubt a power reaction. It involves six distinctively unique chemical steps in a single operation to make complex polycyclic products and provides easy entry into the synthesis of polyquinanes.
The polyquinanes have enjoyed long-standing attention in organic chemistry.
These substrates, which occur naturally in a variety of structural frameworks, have provided the synthetic chemist with a plethora of target molecules. It would constitute a milestone in synthetic organic chemistry if we could successfully apply the squarate ester cascade reaction in the synthesis of natural products. During the search of polyquinanes as potential candidates for the application of squarate ester cascade reactions, we found that (+/-) hypnophilin (38, vide infra) might be suitable. Hypnophilin has reputed antibacterial and antitumor properties (vide infra). Three syntheses of 38 have been reported so far and the challenge for us was to transform diisopropyl squarate (2, vide infra) into hypnophilin (38) in as few steps as possible. In chapter 2, I will describe how hypnophilin has been synthesized in a short synthetic route via a squarate ester cascade reaction.
New chemistry normally will not be discovered until chemists try to solve challenging problems in their bench work. There is a very good example to illustrate how new chemistry is discovered. In our ingenol project (vide infra), my colleagues tried to get a key intermediate 134, whose structural features has been a challenge to organic chemists for over a decade, from irradiation of intermediate 131. Instead, lactone 135 and spiro compound 136 were isolated as a surprising result. Mechanistic study was obviously necessary to explain how 135 and 136 were formed under irradiation 2 conditions. In chapter 3, I will include the results of the studies from irradiation of two
2-cyclopentenones 137 and 138, which not only helped us figure out the reason why 135 and 136 were formed but also made us draw the conclusion that we had discovered new photorearrangements of 2-cyclopentenones.
The total synthesis of natural products always attracts synthetic chemists not only because it is the challenge that is almost irresistible to those who are enthusiastically willing to use their knowledge to practice the art of synthesizing naturally occurred substances, but also because it will bring synthetic chemists big rewards to have opportunities to discover and develop new chemistry to solve problems of broader scope.
Meanwhile, natural product total synthesis will also solve the problem of supplying amounts which are normally too small as provided by nature. Also, the total synthesis of natural products opens the door to design molecules which can mimic or inhibit the action of the natural product. Pectenotoxin II is selectively cytotoxic to ovarian, renal, lung, colon, CNS, melanoma, and breast cancer cell lines, which might be a potentially powerful drug candidate for the next generation (vide infra). The structure of pectenotoxin II is a challenge to synthetic chemists (vide infra). The biological importance and challenging structure of pectenotoxin II along with very limited supply from nature prompted us to start the studies towards the total synthesis of pectenotoxin II.
In chapter 4, I will include the studies on the syntheses of building blocks A and B of pectenotoxin II.
3
CHAPTER 2.
APPLICATION OF SQUARATE ESTER CASCADE REACTIONS TO THE
SYNTHESIS OF (+/-) HYPNOPHILIN.
2.1 Squarate Ester Cascades and Relationship to Polyquinane Natural Products
Squaric acid (Figure 1), which was first synthesized by Cohen in 1959,3
is a very strong dibasic 1,2-cyclobutenedione (pK1≅1, pK2=2.2). The strong
acidity of squaric acid (1) is due to the formation of aromatic character upon
ionization.4, 5, 6, 7 The synthesis and properties of 1 and its derivatives were
studied in the 1960s and 1970s, and this chemistry was reviewed in 1978.8
HO O
HO O 1 Figure 1 Squaric acid
4 The readily available diakyl esters of squaric acid are widely recognized to be highly strained and extensively oxygenated building blocks having many varied synthetic applications.9, 10, 11, 12 Early studies were mainly based on the monoaddition of an organometallic reagent to the electrophilic squarate esters followed by further structural change or ring expansion. Some typical examples are shown in Scheme 1.13, 14, 15, 16, 17, 18
5 O H CO O 3 H CO C H -n Xylene 3 4 9 C4H9-n ∆ H3CO OH H3CO O
Moore, ref 10.
H CO O 3 H3CO OCH3 Toluene O 110 0C O H3CO OH Moore, ref 11.
O MeO OMe H3CO O OMe . BF3 Et2O
OMe H3CO O OH MeO H Paquette, ref 12.
O O EtO O EtO Pb(OAc) 4 O + O R 0 toluene, 20 C EtO EtO OH R AcO R Eguchi, ref 13. O EtO O O EtO EtO Bu Bu PhI(OAc)2 BnNH2 Bu I 2 I Et2O NHBn EtO OH EtO EtO O O Eguchi, ref 14. OH i-PrO O i-PrO 165 0C i-PrO i-PrO N OH N O O OtBu O Liebeskind, ref 15.
Scheme 1. Some examples of squarate esters in synthetic applications
6 Investigations involving two-fold addition of organometallics (either the same or different) to squarate esters were initiated in our group in 1993. Results showed that two-fold addition of alkenyl anions to squarate esters triggers a remarkable reaction cascade with formation of complex polycyclic end products
(Scheme 2).
OLi O O i-PrO O i-PrO O 1. 3, 2eq. + i-PrO O i-PrO O 2. NaHCO3 eq. OH OH i-PrO O Oi-Pr O 26% 14% 245
Scheme2. Two-fold addition of 3 to 2
Extensive studies of the mechanism for such a remarkable rearrangement indicate that it proceeds via an ionic ([3,3] sigmatropic or electrocyclic) pathway.19 If steric factors exert their customary influence, trans 1,2-addition of two alkenyl anions would occur, which results in a sequential 4π and 8π electrocyclization to deliver trans-fused bis-enolates such as 9 (Scheme 3).20
7 Oi-Pr Li i-PrO i-PrO O O i-PrO O O 4π conrotatory H H i-PrO O 6 i-PrO O 2 78
anti hydrogen atoms i-PrO Oi-Pr H O O O 8π H2O conrotatory i-PrO OH Oi-Pr 9 10 Scheme 3. trans Addition and the electrocyclic reaction channel
When the proper adjustment of electronic factors causes cis addition to be kinetically favored, dianionic oxy-Cope sigmatropy occurs very rapidly from the boat conformation to generate cis diastereomers of type 12 (Scheme 4).21
i-PrO Oi-Pr O O Li i-PrO i-PrO O O O [3,3] i-PrO sigmatropy i-PrO O 6 2 11 12
H syn hydrogen atoms O H
H2O i-PrO OH Oi-Pr 13
Scheme 4. cis Addition and the sigmatropic pathway
8 Relative stereochemistry at the bond-forming junctions in the products can help distinguish these two reaction channels. The oxy-Cope reaction arises from syn hydrogen atoms at the bond-forming junctions as in 12, while the electrocyclic reaction channel from trans addition gives rise to anti relative stereochemistry as in 9. It can also tell the difference between these two pathways from the mechanistic elucidation of these prodcuts. Because dianionic oxy-Cope rearrangement concertedly transmits all structural information resident in 12 directly into the final product when cis addition operates, product stereochemistry is immediately established in the very early step that gives rise to
12. In contrast, the stereochemistry inherent in trans-dialkoxide 9 is subject to being lost if the desired helical (and therefore chiral) polyolefin were to experience rapid equilibration with the coil of opposite pitch. Furthermore, if the rate-determining step is associated with the conrotatory closure of such helices, an entirely different control element would gain importance. More specifically, the coil experiencing the minimal steric impedance to cyclization would give rise to the major product.22
Although organolithium nucleophiles prefer to add 1,2 and generate dioxido intermediates and trans addition of two alkenyl anions is the customarily dominant reaction, the second step has occasionally been found to proceed in a
1,4 manner to a limited extent (Scheme 5).21
9 Li i-PrO i-PrO O i-PrO O O O 1,4- addition 4π O conrotatory i-PrO O 6 i-PrO i-PrO 2 14 15
O H i-PrO O HO O O i-PrO O 8π H2O H H H conrotatory i-PrO i-PrO i-PrO i-PrO 16 17 18
Scheme 5. 1,4-Addition of the second nucleophile
The distinctive feature of the operation of 1,4-addition is formation of an α-ketol polyquinane product such as 18 in Scheme 5.
These unusual, deep-seated chemical transformations have been screened for their overall scope,23 capacity to accommodate heteroatom incorporation,24 and ability to respond to asymmetric induction.25 Among the more notable findings to emerge from these studies are the remarkable capabilities of dienolates housed in 1,3,5,7-octatetraenyl networks to experience rapid helical equilibration
(Scheme 6)26 and regioselective cyclization (Scheme 7).21
10 Li
OLi i-PrO LiO O i-PrO i-PrO O 24 + i-PrO THF, -78 0C i-PrO O i-PrO O 25 26 2 Initial (1:1) diastereoselection
i-PrO LiO Li O i-PrO Li 27 + O Li 28 6 i-PrO i-PrO O Li
Li i-PrO Oi-Pr Li Loss of initial Li i-PrO Oi-Pr Li O stereochemical O O information O H H 29H H 30
Li Li i-Pr Oi-Pri-PrO Li Oi-Pr O Li O O Stereochemical O O 31outcome decided 32 at this stage
Me3SiCl
i-PrO Oi-Pr i-PrO Oi-Pr HO O TBAF; H2O TMSO OTMS 34 H 33 H
Scheme 6. Helical equilibration
11 OMe Li i-Pr Li Oi-Pr O Li i-PrO O O O 1. 19 Li OCH 2. Li H C 3 i-PrO O 3 H CH 2 203 21
Li Oi-Pr Oi-Pr Oi-Pr OH O O i-PrO H C O CH H 3 3 H 23 22
Scheme 7. Regioselective transannular aldol from β-elimination
Squarate ester cascades provide an easy entry into the synthesis of polyquinanes. The polyquinanes have enjoyed long-standing attention in the synthetic organic chemistry. These substrates, which occur naturally in a variety of structural frameworks, have provided the synthetic chemist with a plethora of target molecules around which a variety of unique and interesting synthetic methodologies have been developed.27
In nature, three basic arrangements of triquinanes have been isolated
(Figure 2). The angular, as depicted by the antibiotic fungal metabolite pentalenene (35), 28 and linear exemplified by hirsutene (36), 29 also a fungal metabolite, are the most common. The [3.3.3] propellane framework is present in the novel sesquiterpene modhephene (37).30
12 H CH3 H C H C H 3 H 3 H C H C 3 H3C 3 CH3 CH3 H C H 3 H3C H CH3 35 36 37 pentalenene hirsutene modhephene
Figure 2. Selected natural polyquinanes
2.2 Background and Approaches to the Synthesis of Hypnophilin
Hypnophilin (38) (Figure 3), an antibiotically active metabolite, was
isolated by Steglich and coworkers in 1981 31 from cultures of Pleurotellus
hypnophilus, a rare fungus that can be found on decaying grasses or mosses.
Spectral investigations of hypnophilin showed that it has a hirsutane skeleton.
Studies concerning the biological activities of hypnophilin show that it displays
activity toward gram-positive and gram-negative bacteria, fungi, and yeasts as
well as antitumor activity.
H O H O OH 38 Figure 3. Hypnophilin
An α-methylene ketone moiety in the Hypnophilin molecule is essential
for its antibiotic activity. This conclusion is based on the reduction of the keto
group in hypnophilin to a hydroxyl group, which results in a complete loss of
13 antimicrobial activity. Similar phenomena can be found in a number of natural
products containing the same α-methylene ketone moiety in their structures.31
Three syntheses of hypnophilin have since been published. Little's
application of the 1,3-diyl trapping reaction constitute the first total synthesis of
hypnophilin as shown in Scheme 8. 32
O OH H O 9 steps hυ 1. MCPBA or ∆ 2. LDA H N OH OH N 39 40 41
H H H
1. PhCOCl Me2Cu(CN)Li2, H 2. PCC O BF .OEt O OH H 3 2 H OH OCOPh OCOPh 43 44 42 H H
1. LDA Pd(OAc)2, LiOH 2. TMSCl CH CN O H O/THF TMSO 3 H 2 H OCOPh OCOPh 45 46
H H H
1. LDA, -78 0C 1. TsCl, py. O O 0 O 2. DBU H 2. CH2O, -30 C H H OH OH OH HO 47 48 49 O H
H2O2, H2O THF, NaHCO3 O H 38 OH
Scheme 8. Little's strategy for the synthesis of hypnophilin
14
The prominent feature in Curran's strategy toward the synthesis of
hypnophilin is a tandem radical cyclization (Scheme 9). 33
TBSO Br TBSO O 1. Li; CuBr 51 OH 1. PCC O 2. 2. LiAlH4 Li TMS 53 50 52 TMS 1. PCC HO TBS + O O 2. (CH2OH)2, H PCC 3. Bu NF OH 4 O 55 54
O HO H O H O SmI2 PTSA acetone O THF O 56 H 57 H H HO H HO H O 1. LDA OTBS DDQ 2. TBSCl 2,6-lutidine
H H 58 59
H H HO H HO H O H2O2, O K2CO3
H H O 38 60
Scheme 9. Curran's synthesis of hypnophilin
15 (-)-Hypnophilin was enantioselectively synthesized by Weinges and
coworkers via a rather lengthy sequence involving suitable structural modification
of commercially available catalpol (Scheme 10).34
HO H H H O OH PCC O O NaOAc H H HOH2C H OG BzO BzO H Catalpol 61 62 63 H 3,3 dichloro- H propene, O Hg(CF3CO2)2 t-BuOK O t-BuOK, t-BuOH t-BuOH BzO H BzO H O Cl 64 65 H H H
O NaOH LDA H O O MeOH CH2O BzO H H HO HO CH2OH 66 67 68
H H O p-TsCl, py.; H2O2 DBU O K CO O H 2 3 H HO HO 69 38
Scheme 10. Weinges' enantioselective synthesis of hypnophilin
16 We have developed a synthetic strategy based on the cascade reaction
initiated by the two-fold addition of alkenyllithiums to squarate esters which
rapidly produces polyquinanes in a facile manner. The synthetic potential for our
β-elimination methodology for construction of linear polyquinanes shall be
evaluated through synthetic efforts towards hypnophilin. The late stages of this
synthesis (vide infra p.24) were performed by Dr. Feng Geng, a post-doc in our
group and the presentation of his results in this chapter is made for completeness.
2.3 Retrosynthetic Analysis.
Our synthetic strategy is based on our knowledge of the capacity of the
squarate ester cascade to produce linear polyquinanes from the addition of at least
one cycloalkenyl anion with a leaving group, which will result in a unidirectional
transannular aldol reaction. Thus, our proposal for the synthesis of hypnophilin
utilizes the readily available starting materials 70, 71, and diisopropyl squarate
ester 2 (Scheme 11). Linear triquinane 72 should result from the squarate ester
cascade and opening of the acetal functionality. The critical chemical
transformation is the installation of the methyl group in 72. Hydrolysis,
functional group transformation, elimination and 1,4-Michael addition by using
cuprate chemistry of 72 should install the methyl group, and 74,33 a known
precursor to coriolin and hypnophilin, is expected after functional group
manipulation.
17 H H O H O
O O i-PrO H H H OH OH Oi-Pr O 38 74 73 O O O H Li 70 i-PrO i-PrO O
i-PrO OH Li i-PrO O O 71
72 OH 2
Scheme 11. Retrosynthetic analysis for the synthesis of hypnophilin via the squarate ester cascade
2.4 Synthesis of Vinyl Bromide 75 and Its Utilization Toward the Synthesis of (+/-)
Hypnophilin
Vinyl bromide 75 was prepared from commercially available methyl
isobutyrate (76) (Scheme 12).
1. LDA, THF, -78 0C KOH, MeOH OCH3 OCH3 OH 2. allyl bromide, quant. O O O -78 0C-r.t., 84% 76 77 78
O O O 1. (COCl) , DCM, 0 0C 1. Br , DCM, 0 0C O 2 2 Br ethylene glycol, Br 0 TsOH, benzene 2. AlCl3, CS2, reflux 2. Et3N, DCM, 0 C reflux, 44% 50% over two steps 70%
79 80 75
Scheme 12. Synthesis of vinyl bromide 75
18 Allylation of the anion of 75 was accomplished with 1.2 equivalents of lithium diisopropylamide and 1.5 equivalents of allyl bromide to afford 77 in 84% yield.35
After saponification of ester 77 with potassium hydroxide in methanol, the so formed acid 78 was converted into its acid chloride derivative. Under aluminum trichloride conditions, cyclization of the acid chloride derivative of 78 occurred to give cyclopentenone 79 in 50% yield over two steps.36 Formation of a side product 84 is the major reason for a moderate yield to make this cyclopentenone.
The possible explanation for formation of this side product is based on the following description as shown in Scheme 13.
AlCl3 Cl - AlCl4 O O 81 82 O
+ O a. -H 79
O b. +Cl- 83 84
Cl
Scheme 13. Possible explanation for the formation of β-chloro ketone 84
When acid chloride 81 was treated with the strong lewis acid AlCl3 to promote a
Friedel-Crafts reaction, a carbocation 82 was formed. Carbocation 82 reacted with the terminal double bond to form a five-membered ring which resulted in 19 formation of a second carbocation 83. Competition arose at this stage between deprotonation which leads to cyclopentenone 79 and addition of chloride anion present in the reaction medium to give β-chloro ketone 84. Low concentration of reactants increased the yield. However, it was difficult to avoid the formation of
84. Bromination followed by dehydrobromination of 79 gave α-bromo ketone 80 in 70% yield over two steps.37 Ketone 80 was treated with ethylene glycol and catalytic amount of PTSA in refluxing benzene, affording vinyl bromide 75 in
44% yield along with unreacted 80. At this stage, the low yield of 75 is the problem. The difficulty in protecting the carbonyl group with ethylene glycol is the steric interaction between the acetal group and the neighboring bromo and methyl groups. In order to improve the yield of compound 75, toluene became the solvent of choice to increase the reaction temperature to help remove water, which was formed during the reaction by formation of toluene-water azeotrope.
However, the reaction system using benzene as solvent was better. Compound
85 (Figure 4), which could substitute for ethylene glycol to convert carbonyl group to acetal group, didn’t improve the yield substantially.
O O
Figure 4. 2-ethyl-2-methyl-[1,3]dioxolane
20 When diisopropyl squarate ester 2 was treated with 1.1 equivalents of lithiated 75 by using t-BuLi-bromine exchange at –78 0C under dry argon atmosphere, reaction started very fast and was monitored by TLC. In less than
30 min, the first 1,2-addition was complete. Without isolation, the reaction mixture was treated with vinyllithium in THF at –78 0C and the reaction mixture was allowed to warm to room temperature overnight prior to being quenched with deoxygenated saturated ammonium chloride solution. After normal work-up, the expected compound 72 was not found. In contrast, 86, an angular triquinane arising from the lack of β-elimination, was isolated in 3% yield along with some unidentified by-products (Scheme 14). When the vinyllithium was generated from tributylvinylstannane and n-butyllithium, consideration about the possible effect of tin by-products emerged. An alternative route for generating vinyllithium was therefore explored. However, the use of vinyl bromide as a precursor for vinyllithium gave worse results. Furthermore, a change of the sequence of addition didn’t improve the result.
21 O Li O Li i-PrO Oi-Pr O O O i-PrO O Li i-PrO O O 70 1. 4π H H O H i-PrOO 2. Li i-PrO O O 71 H 2 87 88 Li i-Pr Oi-Pr O Li + i-PrO Oi-Pr 8π + H O O H O OH O H O H O H O
89 90
O H O i-PrO O O i-PrO i-PrO OH O i-PrO OH 72OH 86
Scheme 14. Mechanism for formation of 86
The isolation of 86 was quite unexpected, for loss of a leaving group to
undergo β-elimination is a facile process in other systems.38 Meanwhile, the
difficulty in synthesis of ketal 75 due to increased steric hinderance should
facilitate β-elimination. In another way, acetal oxygens seem to be in a very
sterically congested environment in 75, which may impede the proper electronic
alignment for opening of the acetal ring, thereby lowering the probability of β-
elimination. These two opposite factors prompted us to re-evaluate the reaction 22 conditions. The major modification for the process was the degree of the
reaction temperature change. During the synthesis of angular triquinane 86, after
completion of the addition of two anions to diisopropyl squarate ester 2 at –78 0C,
the mixture was allowed to warm to 0 0C gradually. When the temperature of the
reaction system was changed dramatically by transferring the reaction flask out of
the –78 0C cold ice-bath to a 0 0C ice-bath, β-elimination occurred to give linear
triquinane 72 along with a tiny amount of linear triquinane 91 with its intact acetal
functionality (Scheme 15).
O O O O i-PrO O Li H H 1. 70 i-PrO i-PrO + 2. OH i-PrO O Li i-PrO OH i-PrO 71 O O O 2 72 OH 91 42% <5%
Scheme 15. Formation of β-elimination product 72 and non-β-elimination product 91
In order to maximize β-elimination while incorporating the appropriate
functionality for hypnophilin, anion 92 with masked synthetic potential was
designed. Anion 92 not only has the appropriate substitution pattern for linear
quinane construction, but also has a substituent which can be easily manipulated.
However, no polyquinanes were isolated from the reaction of diisopropyl squarate
ester 2, lithiated 75, and 92. Only monoadduct 93 was obtained (Scheme 16).
23
O O OHO i-PrO O Li i-PrO O 1. 70
i-PrO O 2. Li 92 i-PrO O 2 OEt 93 25.6%
Scheme 16. Formation of monoadduct 93
Treatment of compounds 72 and 91 with acids such as 10% H2SO4 caused hydrolysis of the enol ether and acetal functionalities respectively to give ketone
94 in 83% yield. In order to replace the hydroxyl group in 94 with methyl without changing the configuration, the strategy of using methylcopper reagents for conjugate addition to enone 96 was adopted. The tertiary alcohols normally could be turned into enones directly by exposure the methanesulfonyl chloride and triethylamine containing a catalytic amount of DMAP.39 However, tertiary alcohol 94 became chloride 97 with retention of configuration in 86% yield. A possible mechanistic explanation for the formation of chloride 97 is shown in
Scheme 17.
24 O O H H B: i-PrO A B MsCl, Et3N, i-PrO C DMAP, CH Cl H 2 2 OMs i-PrO OH i-PrO O O 94 95
O O H H i-PrO i-PrO
i-PrO Cl i-PrO Cl- O O
97 96
Scheme 17. A possible explanation for the formation of 97
Under mild basic conditions with the assistance of DMAP, tertiary alcohol 94 was first converted into mesylate 95. Deprotonation on the α-carbon next to the carbonyl group in C ring with base afforded enone 96. Chloride anion in the reaction system then underwent conjugate addition to enone 96. Because of the relative stereochemistry relationship in the tertiary alcohol 94 which was confirmed by NOE, the cis,anti-fused tricycle 96 added the chloride anion with retention of configuration. From this standpoint, it might be reasonable to apply the strategy of the conjugate addition of various methylcopper reagents such as dimethyllithium cuprate (Me2CuLi) to install the methyl group.
Dehydrochlorination of 97 with DBU as base turned compound 97 in enone 96
(Scheme 18). 25 O H i-PrO
i-PrO OH O O 72 OH H i-PrO 10% H2SO4 83% OH O i-PrO H O i-PrO 94
i-PrO OH O O
91 MsCl, Et3N, DMAP, CH2Cl2 86%
O O H H DBU, benzene i-PrO refluxing, 88% i-PrO
i-PrO i-PrO Cl O O
96 97
Scheme 18. Formation of enone 96 from 72 and 91
However, it turned out that enone 96 didn't provide a feasible forum for that
strategy. Other strategies such as direct replacement of the chlorine atom in 97
with trimethylaluminum led to no reaction.
A modification of the synthetic route was required to introduce the methyl
group. The strategy was to reduce 97 to ketone 98,40 which was to react with a
26 base to form enolate 99 followed by being quenched with iodomethane to put a methyl group in the tricyclic framework (Scheme 19).
O H H LiAlH ; 1N HCl i-PrO 4 i-PrO
i-PrO Cl O O HO
97 98
H H i-PrO i-PrO Protection of OH-; LDA; MeI CH O O 3 Li+ PO PO
99 100
Scheme 19. Modified strategy to install methyl group
When 97 was treated with lithium aluminum hydride, 97 was decomposed with some unidentified products formed. This strategy was finally realized when reduction was performed with lithium in ammonia by Dr. Feng Geng. Li/NH3 removed the chlorine atom in 97 followed by 1,2 reduction with LiAlH4 to give enone 101 in which hydroxyl group was subsequently converted into a MOM group. Installation of a methyl group in the framework was accomplished by treating MOM protected 101 with LDA to form an enolate and quenching of this enolate with iodomethane to give 102. After making the exocyclic double bond by using methyllithium followed by treatment with 30% H2SO4 in THF, the second enone reacted with LDA and TMSCl in sequence to produce a silyl enol ether.33 Oxidation of this silyl enol ether with palladium acetate constructed the 27 cross-conjugated system 103. Finally, selective epoxidation on the internal
double bond in 103 finished the last step (Scheme 20).33
O 0 H 1. Li, NH3, THF, -78 C; H 1. CH3OCH2Cl, 0 i-PrO Li benzoate, -78 C i-PrO (i-Pr)2NEt H H 2. LiAlH , THF; 2. LDA; CH I i-PrO Cl 4 O 3 O 1N HCl HO 97 101
H H i-PrO 1. CH3Li; 30% H2SO4 O 30% H2O2, K2CO3 H H CH 2. LDA; TMSCl; O 3 CH3 MOMO Pd(OAc)2 HO 102 103 O H O H CH3 HO
38
Scheme 20. Finish the synthesis
2.5 Conclusion
A squarate ester cascade was used to provide in one step, via the coupling of three
reactants, a highly oxygenated linear triquinane product. The latter was
transformed in nine steps into hypnophilin.
28
CHAPTER 3.
NEW PHOTOREARRANGEMENTS OF 2-CYCLOPETENONES.
3.1 Introduction
In 1962, Eaton published the results from his lab that, when 2-
cyclopentenone is exposed to light of wavelengths above 300 mµ, this ketone is
converted quickly and in high yield to an approximately equal mixture of two
isomers (Scheme 21).41
O O hυ + O O O 104 105 106
Scheme 21. The photodimerization of 2-cyclopentenone
29 Furthermore, 2-cyclopentenone can react with alkenes, acetylenes, and allenes to give as photocycloaddition products cyclobutanes, cyclobutenes, and methylenecyclobutanes, respectively (Scheme 22).42
O O hυ +
104 107 108
O CH3 O CH hυ 3 +
CH3 CH3 104 109 110
O O O CH CH2 2 hυ + C + CH 2 CH2 104 111 112 113 Scheme 22. [2+2] photocycloaddition of 2-cyclopentenone with alkenes, acetylenes, and allenes
The [2+2] photocycloaddition of 2-cyclopentenones with alkenes and alkynes has played a significant role in the development of mechanistic organic chemistry. Despite a number of extensive and elegant studies, many details of the reaction remain to be elucidated.43 This contributes at least partially to the lack of a uniform mechanistic process for the reaction. It is apparent that the mechanism of the reaction varies depending on the substrates and the experimental conditions of the particular reaction.
30 Despite this lack of uniformity, several general points lead to a working mechanism which shows that the photocycloaddition of 2-cyclopentenone is an excited triplet state reaction.44 It involves excitation to a short-lived singlet E*1 followed by intersystem crossing to the longer lived triplet E*3. The triplet then forms an exciplet with the ground state reactants such as alkenes and the exciplet collapses to a triplet diradical. The triplet diradical spin inverts to the singlet and closes to the cyclobutane (scheme 23).45,46
kinv [1,4-diradical]3 [1,4-diradical]1
0 Enone E [E3---A0]3 Cyclobutane
hυ A0
kisc *1 E E*3
Scheme 23. Mechanism for the photocycloaddition of 2-cyclopentenone to alkenes
In recent years, the 2-cyclopentenone [2+2] cycloaddition reaction has been frequently utilized for the synthesis of complex ring systems and natural products.47 For example, Pattenden and co-workers48 synthesized the cis-trans- cis triquinane 116 by irradiating 2-cyclopentenone 114 in methanol. Apparently, in this system, the initial radical cyclization which occurs at the β-carbon of enone
114 forms a five-membered ring containing a diradical followed by collapse of
31 the diradical to form cyclopropane 115. The ensuing attack of solvent methanol causes the formation of triquinane 116 (Scheme 24).
Me Me hυ OMe OOO 114 115 116
Scheme 24. Application of 2-cyclopentenone [2+2] cycloaddition to the synthesis of triquinane ring systems
The synthesis of the unusual diterpene laurenene highlights the application of the 2-cyclopentenone [2+2] photocycloaddition to the synthesis of natural products.49 In the synthesis of this product, Crimmins et al adopted the strategy of using this reaction to establish the crucial three contiguous quaternary carbons
(Scheme 25).
32 SiMe3
CO2Me Me CO2Me 7 steps hυ Me O Me O Me O Me Me Me Me Me Me
117 118 119
Me CO2Et Me CO Et 1. LiAlH4 1. Li, NH3 2 Me Me 2. Swern O 2. H2, Pd/C O 3. Ph3P=CHCO2Et Me Me Me Me
120 121
Me Me 3 steps 5 steps Me Me O Me Me Me Me Me laurenene
122 123
Scheme 25. Application of 2-cyclopentenone [2+2] cycloaddition to the synthesis of laurenene
Besides their well known [2+2] photocycloaddition reaction behavior, 2- cyclopentenones also serve as the substrates for the photochemically induced addition of simple alcohols such as methanol across the double bond in their structures (Scheme 26).50, 51
HO O O
hυ, Ph2CO O O CH3OH O O
124 125 Scheme 26. Photo-induced addition of methanol
33 Under irradiation, 3-substituted-2-cyclopentenones can isomerize to the
5,6-substituted bicyclo[3.1.0.]hexanones (Scheme 27).52
O O hυ H C6H6 Ph Ph R R
R=Ph, CH3 126 127
Scheme 27. Photoisomerization
Most of photochemical behavior of 2-cyclopentenones is based on activation of the conjugated double bond. Very few examples of Norrish Type 1 cleavage have been reported so far (Scheme 28).53 Here, the high level of α- substitution totally redirects reaction toward generation of the 1,5-diradical.
O RR R RR hυ R O Η2O, CH3CN COOH R=Ph, CH3 128 129 130
Scheme 28. Norrish Type 1 cleavage
During the efforts to develop a possible synthetic entry to ingenol (Figure
5), we studied the behavior of enantiomerically pure tetracyclic systems such as
131 under photoactivation conditions.
34 O
HO HO HO OH
Figure 5. Ingenol
MM3 calculations had demonstrated that the lowest energy conformation of 131 has the C10-C11 bond particularly well stereoaligned with the cyclopentenone π-cloud (Figure 6).
MOMO 11 C 10 O A HOB
H3CO
Figure 6. Compound 131
Examples of efficient photoinduced 1,2-shift for vomifoliol acetate and related compounds 54 (Scheme 29) made us expect that 131 would give rise to 134.
However, none of this enedione was seen.
O OAc OH hυ O ether O OAc 132 133
Scheme 29. Photoinduced 1,2-shift
35 Instead, irradiation of 131 gave two products without changing the structural features of C ring. The connectivity between the A and B rings was totally changed (Scheme 30).
MOMO MOMO O hv O O OH H
H3CO H3CO
131 134
MOMO MOMO O
H CO + 3 O H OH H H3CO O
135 136
Scheme 30. Formation of 135 and 136 from irradiation of 131
In order to elucidate the mechanism of the formation of 135 and 136, we needed to investigate the photochemistry of some 2-cyclopentenones containing the necessary structural features present in 131. Considering that there is no change in the structural features of C ring during the irradiation of 131, we chose the two candidates 137 and 138 (Figure 7). These two compounds have the same structural features as those in A and B rings in 131 but a simple cyclohexane ring without substituents to replace the C ring in 131. The difference between 36 structures 137 and 138 is the connectivity between rings B and C. In 137, the
connectivity is the same as that in 131. The opposite connectivity is present in
138.
C HO C O O A HO A H B B
H3CO H3CO
137 138
Figure 7. 2-Cyclopentenones 137 and 138
3.2 Syntheses of 2-cyclopentenones 137 and 138.
In order to synthesize 137 and 138, the synthetic plan was to prepare vinyl
bromide 139 and couple it with commercially available 2-allylcyclohexanone 150.
The synthesis of enantiomerically pure vinyl bromide 139, based on a developed
strategy, started from cracking of the dimer of cyclopentadiene into its monomer
followed by epoxidation of one double bond with 35% peracetic acid and sodium
carbonate to give epoxycyclopentene 141 in 68% yield after the careful removal
of methylene chloride and distillation at 40 0C under 75 mmHg vacuum.55 The
ring-opening of 141 with acetic acid catalyzed by
tetrakis(triphenylphosphine)palladium gave 4-hydroxy-2-cyclopentenyl acetate
(142) in 56% yield after very careful removal of solvents at room temperature.56
In order to get the enantiomerically pure 4-hydroxy-2-cyclopentenyl acetate (144),
142 was first converted into cis-3,5-diacetoxycyclopentene (143) by treating 142
with acetic anhydride and imidazole at room temperature. The resulting 143 was 37 hydrolyzed by using lyophilized electric eel acetyl cholinesterase (EEAC) in a very clean Erlenmeyer flask at pH=7 controlled by buffer solution at room temperature to get enantiomerically pure 144 in 76% yield.57 Converting 144 to
147 was performed in a three-step sequence. First was the oxidation of the hydroxy group in 144 with PCC, sodium acetate and dry 4Å molecular sieves, which turned alcohol 144 into ketone 145 in 81% yield. In order to keep the chiral center in 145 intact, hydrolysis of the ester group in 145 under mild conditions was performed by treating 145 with wheat germ lipase in buffer solution to give 146 in 73% yield. Protection of the hydroxy group in 146 with
TBSCl gave enone 147 in quantitative yield.58 Bromination of 147 followed by
β-elimination gave rise to 148 in 78% yield.59 1,2-Addition onto the carbonyl group in enone 148 with vinylmagnesium bromide was accomplished by using dry cerium trichloride to give 149 in 63% yield. Because of oxophilic property and ability of softening the extent of hardness for some nucleophiles such as vinylmagnesium bromide in order to prevent the enolisation of ketones during the coupling reaction between nucleophiles and enolizable ketones, dry CeCl3 plays a
60, 61 critical role in this coupling reaction. The drying procedure of CeCl3 is lengthy but very important. Studies have shown that when heating cerium (III) chloride heptahydrate in vacuo, the water of hyration begins to hydrolyze the metal chloride above 90 0C and the liquid collected in the liquid nitrogen trap during the drying was found to be hydrochloric acid.62 Therefore when drying the precursor CeCl3•7H2O, at least ca. 80% of the water has to be removed by increasing the temperature to no more than 90 0C. The residual water could be 38 then removed by raising the temperature to 140 0C without significant
63, 64 deactivation of the CeCl3. A typical drying procedure of CeCl3•7H2O under vacuum includes 4 h of heating at 50 0C, 4 h of heating at 60 0C, 5 h of heating at
70 0C, slowly increasing temperature from 80 0C-110 0C during 6 h, and much more slowly increasing temperature from 110 0C-140 0C in 14 h before it is cooled to room temperature for use. Protection of the hydroxy group in 149 with iodomethane completed the synthesis of 139 (Scheme 31).
39 CH3CO3H, AcOH, HO OAc Na2CO3, 68% O (Ph3P)4Pd, 56% cis +/-
140 141 142
R AcO OAc HOS OAc Ac2O, EEAC, Im. 83% 76% cis +/- (+)
143 144
PCC, NaOAc, OOAcwheat germ lipase, OOH 4Α molecular seive, phosphate buffer, 73% CH2Cl2, 81% 145 146
OOTBS OOTBS TBSCl, Et3N, 1. Br2, CH2Cl2, DMAP, CH2Cl2, 2. Et3N, quant. 78% Br 147 148
HO MeO vinylmagnesium bromide, Br NaH, THF, Br MeI, heat CeCl3, THF, 63% 72% OTBS OTBS
149 139
Scheme 31. Synthesis of enantiomerically pure vinyl bromide 139
Reaction of racemic 2-allylcyclohexanone (150) with the enantiopure
lithiated form of 139 in the presence of dry cerium trichloride gave rise to a
mixture of allylic carbinols 151 and 152, which could be separated by careful
chromatography on silica gel. A distinction between their absolute
stereostructures was not possible until arrival at a crystalline photoproduct (see 40 below). Desilylation and oxidation of these intermediates gave rise quite efficiently to 155 and 156, respectively. Subjecting 155 and 156 separately to
Grubbs’ catalyst (Figure 8) in a high dilution apparatus to accomplish an olefin metathesis reaction completed the synthesis of 2-cyclopentenones 137 and 138 in good yields (Scheme 32).
PCy3 Cl Ph Ru Cl PCy3
Figure 8. First generation Grubbs' catalyst
41 1. 139, t-BuLi;
O CeCl3, THF + -78 0C, 81% OH OH 2. TBAF, THF RO RO MeO 89-93% MeO
150 151, R=TBS 152, R=TBS 153, R=H 154, R=H
TPAP, NMO Grubbs' catalyst, 153 OH 4ΑMS, CH2Cl2 C6H6, ∆ O OH 98% O 84% MeO MeO 155 137
TPAP, NMO Grubbs' catalyst, OH 154 4ΑMS, CH2Cl2 C6H6, ∆ O OH H 86% O 84% MeO MeO
156 138
Scheme 32. Syntheses of 2-cyclopentenones 137 and 138
42 3.3 Photorearrangements of 2-cyclopentenones 137 and 138 and Mechanistic
Elucidation
Irradiation of solutions of 2-cyclopentenones 137 and 138 in
deoxygenated dry dioxane in quartz tubes separately with a 450 W Hanovia lamp
surrounded by a quartz condensor gave a total of four new products (Scheme 33).
In less polar solvents such as benzene, the formation of spiro enones 158 and 160
is favored.
OCH3
hυ H3CO OH + O O O OH MeO O dioxane 61% dioxane <1% 137 157 benzene 41% 158 benzene 38%
OCH O HO 3 hυ O OH H + OH H H O MeO H H3CO
dioxane 50% dioxane <1% 138 159benzene 10% 160 benzene 22%
Scheme 33. Formation of 157, 158, 159, and 160 by irradiating 137and 138 separately
Both product mixtures were readily separated into their pure components
via chromatography. Structural assignments to these four compounds were
initially based on detailed IR, 1H, 13C NMR studies along with comparison of the
structural information obtained with 135 and 136, and ultimately corroborated by
43 X-ray crystallographic analysis. For example, the IR spectrum of 157 shows a
-1 very strong peak at 1777 cm indicating that the carbonyl functional group belongs to a lactone. Compared to that of 157, there is a strong absorption peak
-1 at 1679 cm in the IR spectrum of 137 showing a typical enone component in 137.
1 As for the H NMR spectrum of 157, there is a new set of peaks between 4.05-
4.20 ppm pointing out the existence of hydrogens on a terminal carbon of a
1 double bond in 157. Also in the H NMR spectrum of 157, we can see two interesting protons, one appearing between 3.25-3.35 ppm and the other between
2.15-2.25 ppm. These two AB systems normally belong to the methylene unit of a lactone. Disappeared singlet peak at 6.21 ppm in the spectrum of 157 suggests that something happened at the α-position of the 5-membered enone ring in 137.
13 The position of a carbonyl group is at 175 ppm in the C NMR spectrum of 157 which is compared with that of 137 whose carbonyl group is at 204 ppm. A CH2
13 carbon appears at 85 ppm in the C NMR spectrum of 157 indicating a terminal carbon of a double bond connecting to a CH3O- group. From the mass spectrum of 157, we get a molecular weight of 157, the same as that of 137. A rearrangement of 137 into 157 has definitely happened. And the structure of 157 was finally corroborated by x-ray crystallographic analysis to determine absolute configurations of the three stereogenic centers in 157 (Figure 9).
44
Figure 9. Computer-generated perspective drawing of 157 as determined by X-
ray crystallography
Definition of the absolute configuration of 157 in this manner permitted reliable definition of the stereochemistry of all eight precursors in Scheme 32 as well as the three companion photoproducts.
The spectral features displayed by 159 are entirely different than those of any photoproduct previously encountered in this study. This photoiosmer shows infrared bands at 3376, 1666, and 1599 cm-1 consistent with retention of the hydroxyl and of the conjugated enone chromophore. However, its 1H NMR spectrum is characterized by only two olefinic proton signals, the more deshielded appearing as a triplet at δ 5.97 and the second as a doublet at higher field (δ 5.51).
The presence of a carbonyl 13C absorption at δ 190.9 and four olefinic carbon 45 peaks ( δ 173.9, 165.1, 122.1, and 105.2) indicate that the original cycloheptene double bond has become part of a cross-conjugated dienone network. Final definition of its structure as 159 was achieved by means of X-ray crystallographic analysis (Figure 10). The necessary diastereomeric relationship between 158 and
160 requires that the absolute configuration of the B/C-ring junctures be as shown.
This conclusion is further supported by the data recorded for 159.
Figure 10. Computer-generated perspective drawing of 159 as determined by X-
ray crystallography
The fact that the trans ring fusion across rings B and C in 138 is opposite to 137 is well reflected in the photolysis of these 2-cyclopentenones. While irradiation of 137 gave rise to lactone 157, lactonization is no longer feasible in
138, and thus a significant modification of conformational features in 138 relative to 137 is clearly evident and results in the formation of the cycloheptadienone 159.
These results provide an enlightened mechanistic view to help explain the
46 formation of 135 and 136 (Scheme 34). Our proposed mechanism for these
excited-state events begins with excitation to the triplet state 1,4-diradical in every
case. Since 3-exo cyclizations have rate constants approximating 1000 s-1 65 and
a methoxy group only slightly accelerates the opening of a cyclopropylcarbinyl
radical 66 , the next step is 3-exo cyclization to generate cyclopropylcarbinyl
diradicals. The formation of these intermediates enhances ring strain and allows
the operation of several processes involving fracture of the three-membered ring.
For 162, this involves fragmentation to ketene 163 and thermal cyclization to
spirocycle 164. In contrast, 165 favors expansion to the cyclobutyl radical 166
en route to 159. The cyclization/migration 165 to 166 advanced here carries
some analogy in the migrations of β-ester radicals that result in lactone ring
contractions67 and related expansions.68
3.4 Conclusion
We have discovered unprecedented deep-seated photochemical
rearrangements of 4-methoxy-4-vinyl-2-cyclopentenones housed in tricyclic
frameworks.
47 hυ O OH O OH O OH O MeO MeO Me H 137 161 162
OCH3
H3CO OH O C O O 163 157
OCH3 OCH3
O OH O OH
164 158
O hυ OH H O O OH H OH H H CO MeO 3 O H Me H 138 165 166
O HO
H H H3CO
159
Scheme 34. Mechanistic explanation for 157, 158, and 159
48
CHAPTER 4.
STUDIES TOWARDS THE TOTAL SYNTHESIS OF PECTENOTOXIN-II.
4.1 Introduction
Scientists have found that people may become sick and contract
gastroenteritis after they consume edible fish and shellfish. This problem is
worldwide from Asian areas69, 70 to European areas70 and even further to South
American areas71. Studies made by Korean72 and Japanese scientists70 indicate
that toxins which cause the disease (vide supra) are not a part of a group of toxins
called the Paralytic Shellfish Poisoning Toxins, but are a new family of diarrhetic
shellfish poisoning toxins called Pectenotoxins. The origins of these toxins are
not from the fish themselves but from the dinoflagellate Dinophysis fortii. When
fish digest Dinophysis fortii, this dinoflagellate transmits these toxins into fish
bodies, and finally these toxins enter humans via the food chain. Among the
pectenotoxins, pectenotoxin II is the active component that causes the disease,
which has significant impact on public health and on the aquaculture industries. 49 There are totally 10 analogues isolated so far from shellfish such as the
scallop Patinopecten yessoensis. 73 Chemical structure studies on six of the
pectenotoxins show that they are a group of cyclic polyether macrolides which
contain two spiroketals, three tertiary ethers, three substituted tetrahydrofuran
rings, and totally 19 stereocenters (Figure 11).
Me O Me O O B 10 C 2 15 1 3 7 11 12 A O O O OH 16 33 OH O Me O OH F 32 O 21 18 Me 35 27 37 O 25 22 D R 38 36 E 43 G 20 O Me Me
Figure 11. Pectenotoxins
R C-7
PTX1 (1): CH2OH R PTX2 (2): CH3 R PTX3 (3): CHO R
PTX4 (4): CH2OH S PTX5 (5): unidentified PTX6 (6): COOH R PTX7 (7): COOH S
PTX8 (8): CH2OH S PTX9 (9): COOH S PTX10 (10): unidentified
50 A biological activity screen of pectenotoxin II was made by the U.S.
National Cancer Institute showing that it is selectively cytotoxic to ovarian, renal,
lung, colon, CNS, melanoma, and breast cancer cell lines expressed in the form of
72 LC50 values between sensitive and resistant cell lines of 100-fold or more. The
complex structure and interesting and potential by useful biological activities of
pectenotoxin II prompted us to seek a workable synthetic entry to this target.
Besides Dr. Paquette's research group, Murai's group at Hokkaido
University in Japan and Roush's group at University of Michigan in the USA are
also very interested in this molecule.
In 1997, Murai's group reported the synthesis of the C31-C40 fragment of
the pectenotoxins and the key step is the coupling between the α-lithiated
tetrahydrofuran derivative 167 and aldehyde 168 (Scheme 35).74
OMPM OMPM OMe LiDBB, OTBDPS H BnO OTBDPS 168 O O CHO H PhS BnO OH 167 OMe 169
OMPM
TESO OPiv 6 steps OMe O H O 170
Scheme 35. The synthesis of C31-C40 fragment by Murai's group
51 Three years later, they reported the synthesis of another THF fragment C8-
C18 and the strategy involves formation of the tetrahydrofuran ring based on an
epoxide ring opening by a hydroxy group in the 5-exo mode (Scheme 36).75
TBDPSO OH TESO OTBS OBn CSA, CH2Cl2 OTBS TBDPSO O H TESO O OBn OH OMPM MPMO
171 172
Scheme 36. The synthesis of C8-C18 fragment by Murai's group
One year later, Roush's group reported using their allylsilane [3+2]
annulation twice to construct the C and E tetrahydrofuran rings followed by ring
closure to construct the D ring from three major components (Scheme 37).76
SiMe2Ph Me C 15 PhMe2Si B(IPc)2 MeO2C O 11 O 173 O OTBS Me Me O D HO E O OBn 26 OHC Me MeO2CMe 176 174 175
Scheme 37. The formation of C, D, E rings of pectenotoxin II by Roush's group
52 4.2 Retrosynthetic analysis
There are a total 19 stereocenters in the structure of pectenotoxin II. In
order to make these stereocenters efficiently during construction of the framework
of pectenotoxin II, we need to combine developed methodologies with some
ways that are especially suitable to the structural features of pectenotoxin II.
From this standpoint, we wish to especially pay attention to the part of structure
of pectenotoxin II between C11 and C21 that includes one tetrahydrofuran ring (C
ring) and a spiroketal (including D ring). After careful conformational analysis
of the C11-C21 fragment of this molecule, we proposed a feasible way to
synthesize this fragment efficiently via an epoxide cyclization cascade promoted
under certain reaction conditions. Based on this idea, a possible precursor 177 to
C11-C21 fragment might be converted into C11-C21 fragment under certain
conditions as shown in Scheme 38.
53 O O R1 R LA 2O O O R3 LA OH O O
R2 OH 177 178
LA: Lewis acid O Me R1 11 O OH O LA OH O R1 O 21 O H R2 Me O O R2
180 179
Scheme 38. A proposed epoxide cyclization cascade for formation of the C11-C21 fragment
Meanwhile, our general synthetic strategy to synthesize this complex
molecule is to use a highly convergent approach to construct the framework of
this molecule efficiently. Thus, pectenotoxin II would be made from the three
building blocks A, B, and C. Building blocks A and B could be connected by
Horner-Wittig reaction to give intermediate 181. Attaching building block C to
intermediate 181 would be realized via esterification to give intermediate 182.
Finally, the ring closure of 182 could be accomplished by a McMurry coupling
reaction (Scheme 39).
54 Me O O O Me O O O OH OH O pectenotoxin II OH Me O Me O O Me O Me Me
McMurry coupling
Me O O O Me Esterification O O OH O H O OH MeO O Me O Me O O Me OSEM Me
OMOM 182
Me O OH O O Me OH O O Horner-Wittig Me O O OH OH H O OSEM Me MeO O O Me OMOM Me C 181 O
O P(OEt)2 O Me O O TBDPSO O PMBO Me HOMOM O OHC A B
Scheme 39. Retrosynthetic analysis for the synthesis of pectenotoxin II
55 4.3 Studies Toward the Synthesis of Building Block A.
In building block A, a spiroketal (A, B rings) and an epoxide ring are both
present with a total of six stereocenters. A convergent approach would be
suitable to construct this spiroketal. Under Dr. Paquette's direction, I proposed a
retrosynthetic analysis for building block A (Scheme 40). Building block A
would be synthesized from 183 after certain chemical manipulations and
functional group transformations. Spiroketal 183 would be constructed via a
coupling reaction between iodide 184 and Weinreb amide 185.
O O P(OEt)2 TBDPSO O O O A
TBDPSO O OBn O
183
OMe OPMB TBDPSO I NOBn OPMB O 184 185
Scheme 40. Retrosynthetic analysis for the synthesis of building block A
56 4.3.1 Synthesis of iodide 184
The synthesis of iodide 184 started from 1,4-butanediol (186). Protection
of one hydroxy group in 186 was achieved by using benzyl bromide and KOH at
rt to give 187 in 90% yield.77 The other hydroxy group in 186 was then oxidized
to the aldehyde level with PDC in methylene chloride at rt for 48 h to give 188 in
70% yield.77 Aldol condensation between aldehyde 188 and the Evans chiral
auxiliary 189 in the presence of dibutylboron triflate (190) afforded 191 as the
only isomer with the expected relative stereochemistry in 83% yield.78 The
hydroxy functionality in 191 was subsequently protected in the form of a PMB
ether by 2 equivalents of p-methoxybenzyltrichloroacetimidate (192) in the
79 presence of 10% CSA to afford 193. Treatment of 193 with LiAlH4 removed
the Evans chiral auxiliary in 193 to give alcohol 194 in 62% yield from 191.80
The hydroxy functionality in 194 was converted into a silyl ether with TBDPSCl
and imidazole to give 195.81 At this step, it was difficult to get rid of all the
excess of TBDPSCl. Therefore, the mixture was directly subjected to freshly
made W-2 type Raney nickel under a hydrogen atmosphere to give 196 in 63%
yield over two steps.82 W-2 type Raney nickel played a critical role to selectively
remove the benzyl group in 195 in the presence of PMB ether functionality. A
nickel/aluminum alloy with 50% of nickel component was treated by NaOH
solution to give a very reactive W-2 type Raney nickel which was stored in
absolute ethanol.83 It turned out that freshly made W-2 type Raney nickel gave a
very good result of hydrogenolysis of 195 in a small scale reaction. However,
the reactivity of W-2 type Raney nickel dropped dramatically after two months of 57 being stored in anhydrous ethanol, even if sparks were generated when we put a little bit of nickel on a piece of filter paper. It should be mentioned that, for a several gram scale hydrogenolysis reaction or even larger scale, a large excessive amount of Raney nickel and much longer reaction times are necessary. Finally, treatment of 196 with triphenylphosphine, imidazole, and iodine in benzene84 afforded 184 in 77% yield (Scheme 41).
58 H KOH, BnBr PDC, CH2Cl2, OH OBn OBn HO r.t., 90% HO O 70% 186 187 188
O O MeO O N O CCl3 189 O OOH Ph Me OBn 192 NH O N Bu2BOTf, Et3N 10% CSA, CH2Cl2, r.t. Ph Me 190 83% 191
O OOPMB LiAlH4, 62% over 2 steps OBn HO O N OBn OPMB Ph Me 193 194
TBDPSCl, Imidazole, TBDPSO W-2 Raney Nickel, OBn H , 63% over 2 steps OPMB 2
195
I2, Im., PPh3, TBDPSO TBDPSO OH benzene, 77% I OPMB OPMB
196 184
Scheme 41. Synthesis of iodide 184
59 4.3.2 Synthesis of Weinreb amide 185
The synthesis of Weinreb amide 185 started from commercially available
L-glutamic acid (197). Treatment of 197 with sodium nitrite and 2N
hydrochloric acid in water below 15 0C afforded the crude lactone 198 in 87%
yield.85 Subsequent reduction of the carboxylic acid functionality in lactone 198
was achieved by treating lactone 198 with BH3•Me2S at a temperature below 15
0C to give the alcohol 199 in 81% yield.85 The hydroxy functionality in 199 was
then converted into the benzyl ether by treating 199 with benzyl bromide and
freshly made silver(I) oxide in dry DMF to give 200 in 70% yield.86 The 5-
membered ring of lactone 200 was opened by treating 200 with n,o-
dimethylhydroxylamine hydrochloride (201) in the presence of AlMe3 to form the
n-methoxy-n-methyl amide (Weinreb amide) 202. 87 However during the
purification of 202 by column chromatography on silica gel, 202 was found to be
quite unstable and some of 202 was transformed back to lactone 200. The
instability of Weinreb amides such as 202 was also observed by Marshall et al.88
And the hydroxy functionality in crude 202 was therefore immediately converted
into the PMB ether to finish the synthesis of Weinreb amide 185 in 70% yield
over two steps (Scheme 42).79
60 O O
HO2CCO2H NaNO2, 2N HCl O O BH3.SMe2 H O, 87% NH2 2 THF, 81% HO2C HO
197 198 199
O OMe OH Ag2O, BnBr, O (MeO)MeNH2Cl, 201 NOBn 70% AlMe3 BnO O
200 202
MeO
O CCl3 OMe OPMB 192 NH NOBn
10% CSA, CH2Cl2, r.t. O 70% over two steps 185
Scheme 42. Synthesis of Weinreb amide 185
4.3.3 Synthesis of spiroketal 183
It is well known that Weinreb amides react with Grignard reagents and
organolithium species in THF to form ketones (Scheme 43).87
O H3C M ' O O + O H CO R M H3O 3 NR N R THF RR' CH3 H3CR'
203 204 205
Scheme 43. Formation of ketones directly from the combination of Weinreb amides and Grignard reagents or organolithium species
61 However, it turned out that the Grignard reagent form of iodide 184 did
not react with Weinreb amide 185 as shown in Scheme 44.
Mg TBDPSO TBDPSO I MgI OPMB OPMB
184 206
OMe OPMB NOBn OPMB TBDPSO OBn O 185 OPMB O
207
Scheme 44. Attempt to synthesize ketone 207 via the coupling reaction between the Grignard reagent from 184 and 185
Different reaction conditions were tried , which were based on the
different ways of forming Grignard reagents. For example, magnesium turnings
were first treated with 1,2-dibromoethane followed by the addition of iodide 184.
After 30 min of refluxing in THF, the Grignard reagent of iodide 184 was
assumed to be formed and was added to 0 0C cold amide 185 in THF. But the
amide 185 went unreacted. Instead, the well-known side reactions during the
formation of Grignard reagents such as eliminations, self-coupling reactions,
along with the reduction of iodide 184 were observed by us. Besides the
treatment of 1,2-dibromoethane with magnesium turnings to activate magnesium,
other ways to activate magnesium such as the vigorous stirring of magnesium
62 turnings to smash them into very small pieces and commercially available highly
active magnesium powder were used, but no ketone 207 was formed.
At this point, we assumed that the formation of the Grignard reagent from
the reaction between magnesium and iodide 184 might be problematic. We
thought that bromide 208 might be an alternative way to obtain ketone 207. And
the synthesis of bromide 208 was complete from alcohol 196 in two steps to give
207 in 66% yield (Scheme 45). However, it turned out that bromide 208 was also
a wrong choice to form ketone 207.
TBDPSO MsCl, Et3N, TBDPSO OH 0 OMs CH2Cl2, 0 C OPMB OPMB 196 209
LiBr, THF, r.t., TBDPSO 66% over two steps Br OPMB
208
Scheme 45. Synthesis of bromide 208
The fact that reductions of Weinreb amides with such reducing agents as
DIBAL-H give aldehydes87 prompted us to think about the possibility of applying
sulfone chemistry to the formation of ketone 207. In order to test this possibility,
we first converted the hydroxy functionality in 196 into the phenyl sulfide by
89 treating 196 with (PhS)2, n-Bu3P in dry DMF to give 210 in 78% yield. The
63 sulfide 210 was subsequently oxidized with MCPBA to give sulfone 211 in 70%
yield (Scheme 46).90
(PhS) , nBu P TBDPSO 2 3 TBDPSO OH DMF, r.t., 78% SPh OPMB OPMB
196 210
MCPBA, 70% TBDPSO SO2Ph OPMB
211
Scheme 46. Synthesis of sulfone 211
There is a convenient way to make spiroketals by adding α-sulfonyl
carbanions to lactones.91 One advantage arising from this strategy is that, if the
α-sulfonyl carbanion from sulfone 211 were reacted with lactone 200, it could
save two steps not to synthesize Weinreb amide 185. However, the coupling
reaction between the α-sulfonyl carbanion from sulfone 211 and lactone 200 was
not fruitful (Scheme 47).
64 Li+ TBDPSO n-BuLi TBDPSO SO2Ph SO2Ph OPMB OPMB
211 212 O
O
BnO SO2Ph OH 200 TBDPSO OBn
OPMB O 213
OPMB DDQ TBDPSO O TBDPSO O OBn OH OBn O SO2Ph SO2Ph
214 215
Na(Hg) TBDPSO O OBn O
183
Scheme 47. A possible strategy for synthesizing spiroketal 183 from the coupling between the α-sufonyl carbanion from 211 and lactone 200
Since there is a carbonyl functionality in 213 and this carbonyl
functionality would be subject to potential addition from anion 212,92 a dianion
strategy93 in this coupling reaction would be helpful to circumvent the problem.
The dianion from sulfone 211 could be formed by treating 211 with two
equivalents of n-BuLi.92 The dianion so formed would react with lactone 200 to
form another dianion 217 which is the resonance structure of enolate 218 (Scheme
48).
65 2 Li+ TBDPSO 2 eq. n-BuLi TBDPSO SO2Ph SO2Ph OPMB OPMB
211 216 O
O - SO2Ph O BnO 200 TBDPSO OBn OPMB O 217
- SO2Ph O TBDPSO OBn
OPMB O- 218
Scheme 48. A dianion strategy for the coupling between α-sulfonyl carbanion from 211 and lactone 200
This strategy didn't lead to the formation of either 213 or 214. Although
the presence of HMPA in the reaction system would be helpful to prevent the
formation of any forms of aggregation of dianions94 such as 216, it didn't change
the result of the reaction.
It is well known that α-sulfonyl carbanions react with aldehydes to
introduce alkene functionality (the Julia-Lythgoe olefination).95, 96 This method
involves three or four manipulations to form alkene functionality and each
manipulation is controllable. We took advantage of this method to form
spiroketal 183. First, we used 1.5 equivalents of DIBAL-H to reduce the amide
functionality in 185 at -78 0C to give 219 in quantitative yield.87 Then the α-
sulfonyl carbanion 212, which was formed in situ by the treatment of sulfone 211 66 with 1.1 equivalents of n-BuLi at -78 0C, was reacted with aldehyde 219 at -78 0C to give four diastereoiosmers 220 in 70% yield. Because of the solubility of sulfone 211 in solvents, the selection of solvents for this Julia-Lythgoe type reaction is very important. For example, when the reaction system was in a solution of ether and hexanes (1:1), the yield for the formation of 220 was only
17%. In contrast, when the reaction system was in THF, the yield jumped to
70%. Under Swern oxidation or Dess-Martin reagent conditions, the hydroxy functionality in 220 was oxidized to give α-sulfonyl ketone 221 in 90% yield
(Scheme 49).97, 98
67 Li+ TBDPSO 1 eq. n-BuLi, TBDPSO SO2Ph SO2Ph 0 OPMB -78 C OPMB
211 212
SO2Ph OPMB TBDPSO OBn 219, THF -78 0C, 70% OPMB OH
220
Swern oxidation or SO2Ph OPMB Dess-Martin oxidation TBDPSO OBn 90% OPMB O
221
OMe OPMB OPMB 1.5 eq. DIBAL-H, NOBn HOBn -78 0C, quant. O O 185 219
Scheme 49. Formation of α-sulfonyl ketone 221
After the formation of ketone 221, the next step was to be either the
conversion of the PMB ether functionality into the hydroxy functionality in 221
leading to the formation of the spiroketal 215 or removal of the α-sulfonyl
functionality in 221 to form ketone 223 followed by removal of the PMB ethers
with DDQ to give spiroketal 183.
To our surprise, when we used DDQ to remove the PMB protecting
groups and tried to get spiroketal 215, we isolated the lactone 200 without
obtaining any trace of 215 (Scheme 50). This result indicated that the PMB
68 protecting groups were removed by DDQ, but the resultant diol 222 was not
stable under the mild acidic conditions due to the formation of side product
DDQH during the reaction.99 It also might be the reason why the reaction
between the α-sulfonyl carbanion from 211 and lactone 200 did not result in the
formation of 213 or 214.
SO2Ph OPMB DDQ, wet CH2Cl2, 1.5h, rt, TBDPSO OBn
OPMB O
221
O SO2Ph OH TBDPSO OBn O
OH O BnO
222 200
Scheme 50. Formation of lactone 200 from the reaction between 221 and DDQ
In order to remove sulfonyl functionality in 211, we tested three types of
reagents. SmI2 is a very active reducing agent that reductively removes sulfone
100 groups in α-sulfonyl ketones such as 211. The treatment of 211 with SmI2 at
-78 0C gave ketone 207 in 53% yield. Because 53% was not a satisfactory yield,
we proceeded to use Al(Hg) to reduce the sulfone group in 211.101 We found that
Al(Hg) removed the phenylsulfonyl group in refluxing THF (containing 10%
water). However, for some reason, the reduction process would stop regardless
of how long the reaction would take and how much Al(Hg) was added. The
69 conversion yield was 60% including recovery of starting material 211. Another useful reducing reagent to remove sulfonyl functionality is Na(Hg). In dry methanol, Na(Hg) removed the sulfone functionality in 211 to give ketone 207 in
80% yield. Among these three reducing reagents, Na(Hg) was the best to remove the sulfone group to form ketone 207 (Scheme 51).
SO2Ph OPMB TBDPSO OBn
OPMB O
221
OPMB TBDPSO OBn
OPMB O
207
Conditions:
Reducing reagent Reaction conditions Time Yield
0 SmI2 dry MeOH, -78 C 5 min 53%
Al(Hg) THF (10% H2O), 2 days 60% reflux
Na(Hg) dryMeOH, 0 0C 3hs 80%
Scheme 51. Removal of α-sulfonyl functionality in 221 to form ketone 207 with three different reducing reagents
70 Although the formation of 207 was complete, the synthetic route for 207
seemed a little bit lengthy. Meanwhile, the preparation of saturated primary
alkyllithium by lithium-iodine exchange is not efficient because of the reversible
nature of the reaction and competing reactions such as β-elimination,102, 103 α-
metalation, 104 and Wurtz-type coupling to produce symmetrical and mixed
hydrocarbons.105 However, primary akyllithiums can be made by lithium-iodine
exchange when the reaction systems are in a solution of pentane and diethyl ether
in a 3:2 ratio.106 And thus, iodine functionality in 184 was rapidly attacked by t-
BuLi to form alkyllithium 223 in a solution of pentane and diethyl ether in a 3:2
ratio followed by the reaction between 223 and Weinreb amide 185 in THF at 0
0C to give ketone 207 in 65% yield (Scheme 52).
TBDPSO tBuLi, n-C H , TBDPSO I 5 12 LiI 0 OPMB Et2O, -78 C OPMB
184 223
OMe OPMB NOBn OPMB TBDPSO OBn O 185 OPMB O THF, 0 0C, 65% 207
Scheme 52. Synthesis of 207 from the reaction between lithiated 184 and 185
71 Finally, in wet CH2Cl2, DDQ removed the two PMB ether functionalities to give the spiroketal 183 in 92% yield (Scheme 53).
OPMB TBDPSO OBn
OPMB O
207
DDQ, wet CH2Cl2, 92%
TBDPSO O 7 OBn O
183
Scheme 53. Synthesis of spiroketal 183
MM3 calculations indicated that the stereochemistry at C-7 would be like
224 as shown in Figure 12.
72 O O
O O
O O
O
O
224: Esteric= 33.4 Kcal/mol 225: Esteric= 38.6 Kcal/mol
Figure 12. MM3 calculations for two possible conformational models 224 and 225 of spiroketal 183
73 4.3.4 Synthesis of the framework of building block A
After the synthesis of spiroketal 183, the next task was to finish the
synthesis of building block A. But we noticed that there might be a potential
problem in our original synthetic plan. In our synthetic plan, building blocks A
and B will be coupled via the Horner-Wittig reaction (vide supra). However,
under normal basic conditions for this reaction, it will be problematic for us to
avoid a potential opening of the epoxide ring to form a conjugate enone in
building block A as shown in Scheme 54.
OO O basic conditions such as NaH TBDPSO O P OMe O OMe
A
OO O TBDPSO P OMe O OMe OH 226
Scheme 54. A potential problem for building bolck A under the basic conditionc
Under Dr. Paquette's directions, I modified the structure of building block
A with the same number of carbons as the original one (Figure 13).
74 TBSO Me O TBDPSO O O O H
A
Figure 13. Modified building block A
Because of the change in building block A, the structure of building block
B was also changed accordingly (Figure 14).
OPMB O TBSO H OMOM
SO2 N Ph N N N B
Figure 14. Modified building block B
Hydrogenolysis of benzyl ether in spiroketal 183 with a catalytic amount of 10% Pd/C under a hydrogen atmosphere at rt gave alcohol 226.107 Oxidation of hydroxy functionality in 226 with the Dess-Martin reagent98 gave aldehyde 227 in 71% yield over two steps. Wittig reaction of 227 and ylide 228 afforded α,β- unsaturated ester 229 in 96% yield with the double bond in 229 in the E- configuration. Reduction of ester 229 with DIBAL-H at -40 0C gave allyl alcohol 230 in 73% yield. Asymmetric epoxidation 108 of allyl alcohol 230 afforded epoxy alcohol 231 in 71% yield exclusively as the expected isomer
(Scheme 55).
75 TBDPSO O TBDPSO O OBn Pd/C 10%, H2 OH O EtOH, rt O
183 226
Me 228 Ph3P Dess-Martin, TBDPSO O O COOEt py., DCM, O CH Cl , rt 71% over two steps H 2 2 96% 227
Me TBDPSO O DIBAL-H COOEt O 0 CH2Cl2, -40 C 73% 229 Ti(OiPr) Me 4 TBDPSO O OH (+)-DET O t-BuOOH 0 CH2Cl2, -23 C 230 71%
Me TBDPSO O OH O O
231
Scheme 55. Synthesis of epoxy alcohol 231
In order to finish the synthesis of building block A, we need to add a two-
carbon chain to 231. And the α-hydroxy aldehyde functionality in building block
A prompted us to introduce a terminal double bond in 231 followed by a series of
functionality manipulations, protections and deprotections. Epoxy iodides could
be converted into homoallylic epoxides by reacting with vinylmagnesium
bromide in the presence of catalytic amount of CuI and HMPA.109 Based on this
strategy, we first tried to make epoxy iodide 232 from 231. However, direct 76 displacement of the hydroxy functionality in 231 with iodine in the presence of
84 PPh3 and imidazole failed to give 232. A two step sequence via the
intermediate mesylate 233 or tosylate 234 gave epoxy iodide 232 (Scheme 56).
Me TBDPSO O OMs MsCl, Et3N, O 0 O CH2Cl2, 0 C 82% 233 Me TBDPSO O OH O O Me TBDPSO O OTs TsCl, Et3N, 231 0 O O CH2Cl2, 0 C 90% 234
Me Bu NI, THF, TBDPSO O OMs 4 refluxing, 76% O O
233
Me TBDPSO O I O O
232 Scheme 56. Synthesis of epoxy iodide 232
In order to couple epoxy iodide 232 with vinylmagnesium bromide to
make homoallylic epoxide 235, we combined epoxy iodide with a catalytic
amount of CuI in HMPA together followed by the addition of vinylmagnesium
bromide. 110 Attempts were also made to use vinylmagnesium bromide to
substitute the iodine atom of epoxy iodide 232 in the presence of catalytic
77 111 amounts of Li2CuCl4. However, both ways didn't help us get the homoallylic epoxide 235 (Scheme 57).
Me TBDPSO O I O O
232 Me TBDPSO O O O
235 Reaction conditions Results
vinylmagnesium bromide, decomposition cat. CuI, HMPA, -23 0C
vinylmagnesium bromide, decomposition cat. Li2CuCl4, THF, -40 0C-rt
Scheme 57. Efforts to synthesize homoallylic epoxide 235 from the coupling between epoxy iodide 232 and vinylmagnesium bromide
In order to finish the synthesis of the framework of building block A, under Dr. Paquette's direction, I proposed another strategy. We first oxidized the hydroxy functionality in 231 to the aldehyde level with the Dess-Martin reagent98 to give 236 in 80% yield. A Wittig reaction between aldehyde 236 and the methoxycarbonylmethylidenetriphenylphosphorane (237) afforded α,β- unsaturated ester 238 in 86% yield, which finished the synthesis of the framework of building block A (Scheme 58).
78 Me TBDPSO O OH Dess-Martin, py., DCM, O O 80%
231
237 Me Ph3P TBDPSO O O COOMe O O H CH2Cl2, rt 86% 236
Me TBDPSO O O CH O 3 O O
238
Scheme 58. Synthesis of ester 238
4.3.5 Future work
Hydrogenation of the unsaturated ester 238 would give ester 239.
Reaction between the enolate anion of 239, which would be made in situ by
treating 239 with KHMDS, and Davis' reagent would introduce a hydroxy
functionality at the α- position to the ester to give 240. Conversion of the
hydroxy functionality in 240 into the TBS silyl ether followed by reduction of the
79 ester functionality with DIBAL-H would give building block A as shown in
Scheme 59.
Me H , Pd/C 10% TBDPSO O O 2 CH O 3 O O
238
Me TBDPSO O O CH O 3 KHMDS; O O Davis' reagent
239
Me OH TBDPSO O O CH TBSCl, Et N; O 3 3 O O DIBAL-H
240
Me OTBS TBDPSO O H O O O
Building block A
Scheme 59. Synthetic plan to complete the synthesis of building block A from ester 238
80 4.4 Studies Toward the Synthesis of Building Block B.
In building block B, there are one tetrahydrofuran ring and three
stereocenters. A convergent approach will be continually applied into the
synthesis of building block B as shown in Scheme 60. The strategy for the
formation of THF ring in building block B was based on the epoxide ring opening
by a hydroxy group via 5-exo mode in the intermediate 241. Intermediate 241
would be constructed by a Julia-Lythgoe coupling between sulfone 242 and
aldehyde 243.
O O PMBO Me HOMOM OHC B
O OH
OMOM OH NC
241
CN O OMOM O N S O O O S H 242 243
Scheme 60. Retrosynthetic analysis of building block B
81 4.4.1 Synthesis of sulfone 242
The synthesis of sulfone 242 started from commercially available alcohol
244. A Claisen rearrangement involving alcohol 244 and ethyl orthoacetate (245)
in the presence of a catalytic amount of pivalic acid added two more carbons to
the carbon chain of alcohol 244 to give ester 246 in quantitative yield.112 The
ester functionality in 246 was converted to the hydroxy level by reduction of 246
with LiAlH4 to give alcohol 247 in 81% yield. Under normal Mistunobu reaction
conditions, alcohol 247 would be converted to the sulfide 251. However, the
conversion from alcohol 247 to sulfide 251 was quite low, and the reaction was
very messy. So we decided to add two more steps before forming sulfide 251.
We first converted alcohol 247 to mesylate 248, then proceeded to convert
mesylate 248 into bromide 249. During the formation of bromide 249, we found
that the reaction was quite slow and that most of mesylate 248 was turned into
bromide 249. Sulfide 251 was obtained in 50% yield from alcohol 247 over three
steps by using 2-mercaptobenzothiazole (250) to react with bromide 249 using
NaH as a base. Since there is a terminal double bond in 251, we chose a mild
oxidizing system, H2O2 with ammonium molybdate (252) as a catalyst, to prevent
any potential oxidation on the double bond to produce undesired compounds such
as epoxide. It turned out that oxidation of the sulfide 251 into the sulfoxide 253
was pretty fast but further oxidation of the sulfoxide 253 to the sulfone 254 was
very slow. Finally, we got the sulfone 254 in 61% yield along with some amount
of the sulfoxide 253. Applying Sharpless’ asymmetric hydroxylation protocol113
to the alkene functionality in sulfone 254 smoothly resulted in the formation of 82 diol 255 in 96% yield. The hydroxy group on the primary carbon in diol 255 was converted into tosylate 256 in 85% yield. Displacement of the tosylate functionality in 256 with KCN gave us the desired nitrile 258 in 69% yield with a side product 257 which was an epoxide resulting from an internal SN2 type reaction. The tertiary hydroxyl group in nitrile 258 was protected in the form of
MOM ether functionality114 to give sulfone 242 in 74% yield (Scheme 61).
83 pivalic acid (cat.) LiAlH , 81% OH OEt 4 OH OEt quant. 244 246 O 247 OEt OEt 245 N SH LiBr, THF, r.t. S MsCl, Et3N, OMs Br 0 250, NaH, THF, CH2Cl2, 0 C 248 249 3 steps from 247, 50%
N H2O2, Mo(VI) 252, S EtOH, 00C S 251 61% for 254
O N O N S + S S O S 253 254
(DHQD)2PHAL, O OH N O N S K3Fe(CN)6, K2CO3, OH S O S K OsO (OH) 2 2 4 O S 254 t−ΒυΟΗ/Η2Ο 1:1 255 00C, 96%
OTs TsCl/py. , 00C O OH N KCN/EtOH 85% S 70%, for 258 O S 256 CN O O O N OH N S + S O S O S 257 258
CN CN O O N OH N MOMCl, iPrNEt , OMOM S 2 S CH2Cl2, 74% O S O S 258 242
Scheme 61. Synthesis of sulfone 242
84 4.4.2 Synthesis of aldehyde 243
Synthesis of aldehyde 243 started from alcohol 247, which was one of the
intermediates formed during the synthesis of sulfone 242. Although the
acetonide protected aldehyde 243 is a known compound,115, 116 we found that,
when we used Sharpless’ asymmetric dihydroxylation113 on alcohol 247, we could
get the triol 259 in a yield much higher than the reported one. When we used
2,2-dimethoxypropane to protect the two adjacent hydroxy functionalities in triol
259 under acidic conditions, not only was the expected acetonide protected
alcohol 260 obtained, but the compound in which the third hydroxyl group
reacted with 2,2-dimethoxypropane to give a mixed acetal 261 was also seen.
We assumed the newly formed acetal 261 to not be as stable as acetonide 260 not
only because acetal 261 is a mixed acetal but also because the acetonide in 260 is
a 5-membered ring which is stable to acid to some extent. With that assumption,
we dissolved the acetal 261 in dry acetone, added an equivalent amount of
methanol and a catalytic quantity of TsOH. Under such conditions, the acetal
261 was successfully converted back to the alcohol 260. The yield for the
alcohol 260 with acetonide functionality was 72% over two steps from 247
compared to the reported yield (33%) for the formation of 260.115 Swern
oxidation of the hydroxy functionality in 260 gave us aldehyde 243 in 70% yield
(Scheme 62).
85 (DHQD)2PHAL, OH K3Fe(CN)6, K2CO3, OH 2,2-dimethoxy propane, OH OH K2OsO2(OH)4 CSA, CH2Cl2, 100% for 260 and 261 247t−ΒυΟΗ/Η2Ο 1:1 259 00C, 72%
O O O O OH + O OMe
260 261
O O acetone, TsOH, O O O OMe 100% OH
261 260
O O O Swern oxidation, OH 70% O O
H 260 243
Scheme 62. Synthesis of aldehyde 243
4.4.3 Efforts on the Julia-Lythgoe olefination and synthesis of the tetrahydrofuran ring
After the synthesis of 242 and 243, we tried to utilize the Julia-Lythgoe
olefination to make 241. As we know, reactions involving the linking of two
halves of a complex molecule by means of a convergent synthetic strategy
normally are the first choice for synthetic chemists when they design synthetic
routes to complicated molecules. Reactions such as the Wittig reaction and its
86 variants such as the Horner-Wadsworth-Emmons reaction to form C-C double
bonds are among the most popular methods. However, the Wittig reaction is also
subject to certain limitations. There is a very good example to show that
sometimes Julia-Lythgoe olefination is superior to Wittig reaction. In a paper
published in 1978,117 Kocienski et al reported the utilization of Julia-Lythgoe
olefination to construct the Windaus and Grundmann C19 ketone. Their original
plan to use the Wittig reaction in the construction of a double bond proved not to
be successful due to the difficulty in making ylide 262. Instead, sulfone 264 was
readily made to react with aldehyde 261 to construct a 1,2-disubstituted double
bond in a reductive elimination step with predominant trans geometry (Scheme
63).
CHO
Ph P + 3 H I H BzO BzO
261 262 263
CHO O + S Ph O H H BzO BzO
261 264 263
Scheme 63. Synthesis of the Windaus and Grundmann C19 ketone
87 In our case, trans double bond geometry is required. And thus we hoped that a Julia-Lythgoe type reaction would help us to realize our synthetic goal.
There are several variants for the Julia-Lythgoe olefination based on the type of sulfone used. The classic type using phenyl sulphones commonly includes four subsequent manipulations in one pot.96 To simplify the manipulations of olefination, other sulfones have also been studied. Sylvestre Julia and co- workers reported a new connective one-pot synthesis of alkenes involving the reaction of lithiated 2-benzothiazolyl sulfones with carbonyl compounds.118, 119
Its superiority to the classic one is due to spontaneous elimination. We took advantage of the simplicity of applying 2-benzothiazolyl sulfones to the olefination in our synthetic plan. However, reaction between the aldehyde 243 and the lithiated sulfone 242, which was made in situ by treating 242 with
LiHMDS at -78 0C, was not fruitful. Because the cyano functionality in 242 could serve as a potential leaving group during the Julia-Lythgoe olefination, we slightly modified the sulfone 242 and planned to install the cyano functionality later. We first converted the hydroxy functionality on the primary carbon in the diol 255 into the TBS silyl ether120 to give 265 in 72% yield. The tertiary hydroxy functionality in 265 was next protected in the form of MOM ether by
MOMCl to give 266 in 95% yield. However, reaction between the lithiated 266 and aldehyde 242 was again not successful (Scheme 64).
88 OH OTBS O O N OH N TBSCl, Et N, OH iPr NEt, MOMCl, S 3 S 2 DMAP, CH Cl , 0 O S 2 2 O S CH2Cl2, 0 C-rt, 95% 72%
255 265 OTBS OTBS O N 0 OMOM 1. LiHMDS, THF, -78 C OMOM S 2. 242 O S O O 266 267
Scheme 64. Julia-Lythgoe olefination between the modified sulfone 266 and aldehyde 242
The tendency for self-condensation of some lithiated 2-benzothiazolyl
sulfones with structural features of simple linear alkyl chains119 prompted us to
modify the benzothiazolyl sulfone functionality. Either a phenyl sulfone or a 1-
phenyl-1H-tetrazol-5-yl sulfone might be helpful to form alkene 267. These two
sulfones were synthesized from alcohol 247 (Scheme 65). The primary hydroxy
functionality in 247 was converted into a benzyl ether by treatment of 247 with
BnBr and KOH to give 268 in 90% yield. Sharpless' asymmetric
dihydroxylation113 on the alkene functionality in 268 afforded diol 269 in 85%
yield with 95% ee determined by chiral HPLC. The primary hydroxy
functionality in 269 was converted into the silyl ether with TBSCl to give 270 in
80% yield. And the tertiary hydroxy functionality in 270 was converted into the
MOM ether by MOMCl to give 271 in 88% yield. Hydrogenolysis of the benzyl
ether functionality in 271 in the presence of a catalytic amount of 10% Pd/C107
afforded alcohol 272 in 95% yield. Treatment of 272 with (PhS)2, n-Bu3P in dry
DMF89 followed by oxidation with MCPBA90 afforded phenyl sulfone 274 in
89 75% yield over two steps. 1-Phenyl-1H-tetrazol-5-yl sulfone 276 was
synthesized in 81% yield over two steps under Mitsunobu conditions121 followed
by oxidation with MCPBA.90
OH NaH, DMF; AD-mixβ OH OH OBn OBn BnBr, 90% 85%, 95% ee 269 247 268 OTBS OTBS TBSCl, TEA, MOMCl, iPr2NEt, OH OMOM DMAP, CH2Cl2, OBn CH2Cl2, 88% OBn 80% 270 271 OTBS Pd/C 10%, OMOM EtOH, H2, OH 95% OTBS 272 1. (PhS)2, nBu3P O DMF, r.t. OMOM S 2. MCPBA, CH Cl , Ph 2 2 274 O OTBS 75% over two steps
OMOM OH OTBS 1. DIAD, Ph P, O 272 3 N N THF,275 OMOM S N N N 2. MCPBA, CH2Cl2, O N N 81% over two steps Ph HS N 277 Ph 275 Scheme 65. Synthesis of sulfones 274 and 277
The carbanion of sulfone 277, which was made in situ by treatment with
NaHMDS in DME at -60 0C, reacted with the aldehyde 243 to form the alkene
267 in 96% yield with a 4:1 E/Z selectivity. Considering the sensitivity of TBS
silyl ethers to acids, we removed the TBS silyl ether functionality with TBAF to
give alcohol 278 in 100% yield. And the hydroxy functionality in 278 was
converted into the pivalate ester to give 279 in 80% yield. In order to keep the
90 MOM ether functionality intact, we chose 80% aqueous acetic acid solution to remove the acetonide functionality in 279 at 55 0C to provide diol 280 in 88% yield. Diol 280 was then converted into epoxide 281 in 90% yield with TsCl and
NaH at rt. Sharpless' asymmetric dihydroxylation was applied to 281 to give diol
282. Due to the limited stability of diol 282, it was directly subjected to acidic conditions to generate tetrahydrofuran 283 in 40% yield (Scheme 66).
OTBS OTBS O N OMOM N 0 S 1. NaHMDS, DME, -60 C OMOM TBAF N 0 O N 2. 243, 96%, E/Z=4:1 O THF, 0 C Ph O quant.
277 267
OH OPiv OMOM OMOM PivCl, Pyr. 80% aq. AcOH DMAP, r.t. 0 O O 55 C, 85% 80% O O 278 279
OPiv OPiv OMOM OMOM NaH, TsCl, AD-mixβ OH benzene, r.t. 90% O OH 280 281
OPiv OH OH OMOM AcOH, MOMO H -20 0C-rt, OPiv O OH O 40% over two steps OH 282 283
Scheme 66. Synthesis of 283
91 During the process of synthesizing 283, we noticed the competition between 5-exo ring formation and 6-exo ring formation to make the THF ring in
283. Based on Baldwin's rules,122 the formation of 5-membered rings is faster than the formation of 6-membered rings. In order to maximize the formation of a
5-membered ring in 283, the nature of the acid and the temperature were two major factors considered when we chose reaction conditions. First we chose a pretty strong acid CSA (pKa=~1) and the temperature was from –20 0C to 0 0C.
After careful separation, we isolated 283 in a 30% yield. Then we decreased the initial temperature from –20 0C to –50 0C and gradually warmed the mixture to 0
0C. We got the same result as before. We changed the acid and used a pretty weak acid AcOH (pKa=4.5) which was used by Kishi to open the epoxide ring in the 1970s. 123 Two sets of temperature were used: one is from –200C to room temperature; the other is from –20 0C to 0 0C. The first set gave us 283 in 40% yield. The second one made the reaction proceed very slowly with the same result as the first one (Scheme 67).
92 OPiv OH OH OMOM MOMO H OPiv O OH O OH 282 283
Conditions:
Acid Reaction conditionsTime Yields
0 0 CSA CH2Cl2, -20 C-0 C 5h 30%
0 0 CSA CH2Cl2, -50 C-0 C 3.5h 30%
0 0 AcOH CH2Cl2, -20 C-0 C 6h 40%
0 AcOH CH2Cl2, -20 C-rt 15h 40%
Scheme 67. Conditions for formation of 283
In order to improve the yield for formation of the THF ring, under Dr.
Paquette's direction, I proposed another strategy to try to protect one hydroxy functionality and let the other one attack the epoxide ring to form the THF ring as shown in Scheme 68. From this strategy, if we could get lactone 284, one free hydroxyl group in 284 would attack the epoxide ring exclusively to give 285.
93 OH
OH O H+ O O O O O MOMO MOMO
284 285
Scheme 68. Another way to form THF ring
In order to get 284, we first made ester 289 in a three-step protocol from alcohol 278. First, we oxidized the hydroxy functionality in 278 to the aldehyde level to produce 286. The aldehyde functionality was further oxidized to the carboxylic acid to give 288. Using in situ formed diazomethane to react with acid 288, we obtained the methyl ester 289 in 87% yield over 3 steps. After removal of the acetonide protecting group in 289, we obtained diol 290 in 75% yield. Conversion of the primary hydroxy functionality in 290 to the mesylate followed by cyclization to form the epoxide ring and give 292 in 70% yield over two steps. The precursor for formation of lactone 284 was now in hand
(Scheme 69). At that stage, we noticed that we had synthesized the enantiomer of the natural product (the opposite stereochemistry at C-18 of pectenotoxin II in
Figure 11).
94 OH H O OMOM OMOM Dess-Martin NaH2PO4, NaClO2, O reagent O t-BuOH, rt O O 287 278 286
HO O O OMe OMOM OMOM CH2N2, Et2O 80% aq. AcOH O rt, 87% yield O rt, 75% over three steps O O 288 289
O OMe O OMe OMOM MsCl, Et N OMOM 3 DBU, CH2Cl2, 0 OH CH2Cl2, -10 C OH rt, 70% over OH OMs two steps 290 291
O OMe OMOM
O 292
Scheme 69. Synthesis of ester 292
4.4.4 Future work.
Sharpless' asymmetric dihydroxylation on the ester 292 would form the
lactone 284. Under acidic conditions, the free hydroxy functionality in 284
would attack the epoxide ring in 284 to form the tetrahydrofuran ring 285.
Protection of the hydroxy functionality in 285 with TBSCl followed by reduction
of the lactone functionality with DIBAL-H would give the lactol 287. Wittig
95 reaction involving 287 and Ph3PCH2 followed by protection of the free hydroxy
functionality with PMBCl would give the alkene 289. Hydroboration of the
terminal double bond in 289 would give the alcohol 290. In a two-step sequence,
the hydroxy functionality in 290 would be turned into the sulfone in order to
complete modified building block B (vide supra) (Scheme 70).
OH O OMe 0 OO OMOM ADmixβ, 0 C CSA, CH2Cl2 O O MOMO 292 284
O OH O OMOM O 1. TBSCl OMOM 1. Ph3PCH2 O O HO TBSO H 2. DIBALH 2. KH, PMBCl H
285 287
OPMB OPMB O B2H6, H2O2, NaOH TBSO O OMOM TBSO H H OMOM
OH 289 290
OPMB O TBSO OMOM 1. DIAD, Ph3P, H THF N N N SO2 275 N N HS Ph N N Ph N 2. MCPBA building block B
Scheme 70. The strategy for synthesis of building block B.
96
CHAPTER 5.
EXPERIMENTAL SECTION
General Methods. Melting points were measured on a Thomas Hoover (Uni-melt) capillary melt point apparatus and are uncorrected. A Perkin-Elmer Model 241 Polarimeter was used to measure all optical rotations. Optical rotations were measured at 589 nm with a sodium lamp. A Perkin-Elmer Model 241 spectrometer was used to record infrared spectra. The absorptions are reported in reciprocal centimeters (cm-1). A Bruker AC 300 FT NMR spectrometer was used to record proton (1H) and carbon (13C) nuclear magnetic resonance (NMR) spectra, which were recorded at 300 MHz and 75 MHz, respectively. Chemical shifts are reported in parts per million (ppm) with the residual non-deuterated solvent as an internal standard. Splitting patterns are designated as follows: s, singlet; t, triplet; q, quartet; m, multiplet; br, broad. The high-resolution and fast-bombardment spectra were recorded at The Ohio State University Campus Chemical Instrumentation Center. Elemental analyses were 97 performed at Atlantic Microlab, Inc., Norcross, Georgia, USA. All moisture sensitive reactions were performed under a nitrogen (N2) or argon (Ar) atmosphere in flame-dried glassware. All solvents were pre-dried over 4Α molecular sieves prior to distillation, and, if necessary, stored over 4Å molecular sieves under nitrogen (N2). Acetonitrile (CH3CN), dichloromethane (CH2Cl2), chlorotrimethylsilane (TMSCl), diisopropylamine (i-Pr2NH), N, N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), pentanes (C5H12), and triethylamine (Et3N) were individually distilled over calcium hydride. Benzene
(PhH), tetrahydrofuran (THF), and diethyl ether (Et2O) were distilled from sodium/benzophenone ketyl. Pyridine and 2,6-lutidine were distilled over potassium hydroxide prior to use. All reagents were purchased as “reagent grade” and, unless otherwise noted, used without further purification. Fat extraction Et2O was used for workup extractions, and the combined organic layer extracts were dried over anhydrous magnesium sulfate (MgSO4) or sodium sulfate
(Na2SO4) as noted. The column chromatographic separations were performed with Woelm silica gel (230-400 mesh). The purity of all compounds was shown to be >95% by TLC and high field 1H and 13C NMR.
98
O O Br
75
To a solution of 80 (3.24 g, 17.0 mmol) in dry ethylene glycol (5.30 g, 85.0 mmol) and dry benzene (150 mL) was added p-toluenesulfonic acid (0.162 g, 0.85 mmol). After 6 day refluxing in benzene, the reaction mixture was extracted
with Et2O (3x150 mL). The combined ether layers were washed by water (50
mL), brine (50 mL) in sequence, and dried over MgSO4. After filtration and removal of solvents under house vacuum, the resulted residue was purified by column chromatography on silica gel (elution with hexane-ether 19:1) to give 75
-1 as a colorless oil (1.74 g, 44%): IR (CHCl3, cm ) 1618, 1385, 1285; 1H NMR
(300 MHz, CDCl3): δ 6.10 (t, J=2.7Hz, 1H), 4.23-4.18 (m, 2H), 4.06-3.94 (m, 2H), 13 2.16 (d, J=2.7 Hz, 2H), 1.09 (s, 6H); C NMR (75 MHz, CDCl3): δ134.2, 124.1,
+ 118, 65.9 (2C), 45.0, 43.5, 23.8 (2C); MS m/z (M ) calcd for C9H13O2Br 232.0100, obsd 232.0122.
OHO i-PrO O
i-PrO O
93
Three flasks (one 250-mL, two-necked, round-bottomed flask; two 25-mL, two-necked, round-bottomed flasks), were flame-dried under vacuum, then filled
99 with argon. Three cycles of evacuation and argon fill were carried out. The 250-mL, two-necked, round-bottomed flask was charged with 75 ( 0.233 g, 1.00 0 mmol) and dry THF (15 mL). The solution was cooled to -78 C under argon followed by addition of t-butyllithium (1.18 mL of 1.7M in pentane, 2.00 mmol). 0 After 30 min of stirring at -78 C under argon, lithiation of 75 was done followed 0 by rapid addition of -78 C cold solution of 2 (0.100 g, 0.500 mmol) in dry THF 0 (15 mL). The reaction mixture was kept stirring at -78 C under argon for 1 h (checked by TLC) followed by rapid addition of in situ made ethoxyvinyllithium 0 (92) (-78 C) from the reaction between freshly distilled ethyl vinyl ether (1.91 mL, 2.00 mmol) and t-butyllithium (1.18 mL of 1.7M in pentane, 2.00 mmol) at - 0 0 78 C under argon. The reaction mixture was taken out of the -78 C cooling 0 bath and stirred 2h at 0 C and 16 h at rt before it was quenched with saturated
NH4Cl (6.00 mL), deoxygenated by bubbling argon through the solution for at 0 0 least 30 min, at 0 C under argon. After 1h of stirring at 0 C and 7h of stirring at rt, the mixture was poured into a separatory funnel with ether (150 mL) and water (150 mL). After separation, the water layer was extracted with ether (3x50 mL). The ether layers were combined, dried over anhydrous MgSO4, and filtered. After removal of solvent under reduced pressure by water aspirator, the residue was purified by flash chromatography on silica gel with the eluent of hexanes and
ethyl acetate (1:1) and gave 93 as a pale yellow oil (0.045 g, 26%): IR (CHCl3,
-1 cm ) 3414, 1771, 1628, 1383; 1H NMR (300 MHz, C6D6): δ 6.20 (t, J=2.6Hz, 1H), 4.96 (heptet, J=6.1Hz, 1H), 4.79 (heptet, J=6.1Hz, 1H), 4.53 (br s, 1H),
4.14-4.08 (m, 1H), 3.94-3.89 (m, 1H), 3.55-3.46 (m, 2H), 1.99 (dd, J=16.4, 2.6 Hz, 2H), 1.16-1.09 (m, 12H), 1.04 (s, 3H), 1.03 (s, 3H); 13C NMR (75 MHz,
C6D6): δ 184.0, 165.2, 140.0, 133.2, 132.8, 120.7, 86.0, 76.5, 73.4, 65.6, 65.2,
100 + 45.7, 44.1, 24.5, 23.2, 22.8, 22.6, 22.2, 18.5; MS m/z (M ) calcd for C19H28O6 352.1886, obsd 352.1869.
OH
O
PriO HO
PriO
O 72
Three flasks (one 250-mL, two-necked, round-bottomed flask; two 25-mL, two-necked, round-bottomed flasks), were flame-dried under vacuum, then filled with argon. Three cycles of evacuation and argon fill were carried out. The 250-mL, two-necked, round-bottomed flask was charged with 75 ( 0.233 g, 1.00 0 mmol) and dry THF (15 mL). The solution was cooled to -78 C under argon followed by addition of t-butyllithium (1.18 mL of 1.7M in pentane, 2.00 mmol). 0 After 30 min of stirring at -78 C under argon, lithiation of 75 was done followed 0 by rapid addition of -78 C cold solution of 2 (0.100 g, 0.500 mmol) in dry THF 0 (15 mL). The reaction mixture was kept stirring at -78 C under argon for 1 h (checked by TLC) followed by rapid addition of in situ made vinyllithium 71 (-78 0 C) from tin-lithium exchange between tri-n-butylvinylstannane (0.584 mL, 2.00 0 mmol) and n-butyllithium (1.25 mL of 1.6N in pentane, 2.00 mmol) at 0 C under 0 argon. The reaction mixture was taken out of -78 C cold cooling bath and 0 stirred 2h at 0 C and 16 h at rt before it was quenched with saturated NH4Cl solution (6.00 mL), deoxygenated by bubbling argon through the solution for at 101 0 0 least 30 min at 0 C under argon. After 1h of stirring at 0 C and 22 h of stirring at rt, the mixture was poured in a separatory funnel with ether (100 mL) and water (100 mL). After separation, the water layer was extracted with ether (3x50 mL). The ether layers were combined, dried over anhydrous MgSO4, and filtered. After removal of solvent under reduced pressure by water aspirator, the residue was purified by flash chromatography on silica gel with the eluent of hexanes and 0 ethyl acetate (1:1) and gave 72 as a white solid (0.045 g, 24%); mp 96-97 C; IR (neat, cm -1): 3420 (br, s), 2970 (s), 2865 (m), 1686 (m), 1659 (s), 1608 (vs), 1452 (w), 1381 (s), 1314 (vs), 1291 (vs), 1095 (s), 966 (w), 908 (w); 1H NMR
(300 MHz, C6D6): δ 5.43 (heptet, J=6.1 Hz, 1H), 5.28 (heptet, J=6.2 Hz, 1H), 4.86-4.79 (m, 1H), 4.35-4.28 (m, 1H), 3.87-3.73 (m, 2H), 3.04 (d, J=9.1 Hz, 1H), 2.86-2.75 (m, 1H), 2.34 (dd, J=11.9, 6.5 Hz, 1H), 1.72-1.65 (m, 1H), 1.57-1.46 (m, 1H), 1.43-1.30 (m, 1H), 1.27 (d, J=6.1 Hz, 3H), 1.22 (s, 3H), 1.22 (d, J=6.1 Hz, 3H), 1.21 (d, J=6.1 Hz, 3H), 1.17 (d, J=6.1 Hz, 3H); 13C NMR (75 MHz,
C6D6): δ 199.6, 166.1, 158.7, 133.7, 113.3, 77.6, 73.9, 73.6, 71.7, 62.3, 62.2, 50.4, 44.3, 44.1, 33.8, 27.5, 25.6, 22.5, 22.4, 22.3, 22.1; EI MS m/z (M+) calcd 380.2130, obsd 380.2190.
Anal Cald for C21H32O6: C, 66.30; H, 8.48. Found: C, 66.16; H, 8.07.
O O O i-PrO
i-PrO OH 86
102
To a solution of 75 (0.26 g, 1.10 mmol) in dry THF (10 mL) was added t- BuLi (1.3 mL of 1.70M in pentane) dropwise at -78 0C under argon atmosphere. After 30 min of stirring, to this reaction mixture was added a -78 0C cold solution of 2 (0.198 g, 1.0 mmol) in dry THF (15 mL) rapidly via a cannula tube under argon. The reaction mixture was stirred for 1h at -78 0C. At the same time, to a solution of tri-n-butylvinylstannane (0.58 mL, 2.0 mmol) in dry THF (10 mL) was added n-BuLi (1.25 mL of 1.6N in pentane) at 0 0C under argon and the mixture was stirred for 1h. Then the in situ formed vinyllithium solution was cooled to - 78 0C and transferred to the first addition mixture via a cannula tube at -78 0C under argon. After 2h of stirring at 0 0C and 16 h of stirring at rt, the mixture
0 was re-cooled to 0 C and was quenched by deoxygenated sat. NH4Cl solution (30
mL) via a syringe. After 7 h of stirring at rt, the mixture was extracted with Et2O
(3x100 mL). The combined ether layers were dried over anhy. MgSO4, and filtered. After removal of solvents under house vacuum, the residue was purified by column chromatography on silica gel (elution with hexane-ethyl acetate 9:1) to 0 give 86 as a white solid (12.0 mg, 3%): mp 115-117 C; IR (neat, cm -1): 3486 (m), 2978 (s), 1702 (s), 1636 (s), 1466 (w), 1375 (m), 1304 (m); 1H NMR (300
MHz, CDCl3): δ 5.34 (heptet, J=6.1 Hz, 1H), 5.12 (br s, 1H), 4.90 (heptet, J=6.1 Hz, 1H), 4.09-3.98 (m, 1H), 3.97-3.89 (m, 1H), 3.82-3.73 (m, 2H), 3.60-2.51 (m, 1H), 2.17-2.10 (m, 1H), 1.87-1.77 (m, 1H), 1.62-1.52 (m, 2H), 1.35 (d, J=6.1 Hz, 3H), 1.34-1.29 (m, 2H), 1.27 (d, J=6.1 Hz, 3H), 1.26 (d, J=6.1 Hz, 3H), 1.24 (d,
J=6.1 Hz, 3H), 1.22 (s, 3H), 0.97 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 197.8, 166.2, 132.5, 121.9, 85.8, 73.6, 72.1, 67.0, 65.4, 65.0 (2C), 47.8, 46.2, 43.5, 34.2,
+ + 26.1, 22.8, 22.6, 22.5, 22.3, 21.5; HR MS m/z (M+Na ) calcd for C21H32O6Na 403.2091, obsd 403.2114.
103
O O PriO HO
PriO
O 91 Three flasks (one 250-mL, two-necked, round-bottomed flask; two 25-mL, two-necked, round-bottomed flasks), were flame-dried under vacuum, then filled with argon. Three cycles of evacuation and argon fill were carried out. The 250-mL, two-necked, round-bottomed flask was charged with 75 ( 0.117 g, 0 0.500 mmol) and dry THF (15 mL). The solution was cooled to -78 C under argon followed by addition of t-butyllithium (0.600mL of 1.7M in pentane, 1.00 0 mmol). After 30 min of stirring at -78 C under argon, lithiation of 75 was done 0 followed by rapid addition of -78 C cold solution of 2 (0.0500 g, 0.250 mmol) in 0 dry THF (15 mL). The reaction mixture was stirred at -78 C under argon for 1 h (checked by TLC) followed by rapid addition of in situ made vinyllithium 71 (-78 0 C) from tin-lithium exchange between tri-n-butylvinylstannane (0.290 mL, 1.00 0 mmol) and n-butyllithium (0.63 mL of 1.6N in pentane, 1.00 mmol) at 0 C under 0 argon. The reaction mixture was taken out of the -78 C cooling bath and stirred 0 2h at 0 C and 16 h at rt before it was quenched with saturated NH4Cl solution (3.0 mL), deoxygenated by bubbling argon through the solution for at least 30 0 0 min, at 0 C under argon. After 1h of stirring at 0 C and 7h of stirring at rt, the mixture was poured into a separatory funnel with diethyl ether (50 mL) and water (50 mL). After separation, the water layer was extracted with ether (3x50 mL). The ether layers were combined, dried over anhydrous MgSO4, and filtered.
104 After removal of solvent under the reduced pressure by water aspirator, the residue was purified by flash chromatography on silica gel with the eluent of
hexanes and ethyl aceate (1:1) and gave 91 as a white foam (0.0179 g, 19%); IR
-1 (CHCl3, cm ) 3416, 1697, 1617, 1455, 1381, 1310; 1H NMR (300 MHz, C6D6): δ 5.38-5.26 (m, 2H), 4.15 (s, 1H), 3.67-3.54 (m, 2H), 3.49-3.43 (m, 1H), 3.38-3.32
(m, 1H), 3.00 (dd, J=11.5, 3.2 Hz, 1H), 2.71 (d, J=9.0 Hz, 1H), 2.36-2.28 (m, 1H), 2.23-2.15 (m, 1H), 2.06-1.96 (m, 1H), 1.47 (d, J=7.4 Hz, 2H), 1.16 (s, 3H), 1.15 (d, J=6.6 Hz, 3H), 1.12 (s, 3H), 1.10 (s, 3H), 0.99 (s, 3H); 13C NMR (75 MHz,
C6D6): δ 199.5, 168.2, 132.1, 120.9, 84.0, 73.6, 71.9, 65.8, 65.0, 59.2, 55.8, 47.5, 45.2, 40.3, 34.5, 26.2, 24.0, 23.3, 23.2, 23.1, 23.0; MS m/z (M+) calcd for
C21H32O6 380.2187, obsd 380.2181.
O
PriO HO
PriO
O 94 In a 25-mL round-bottomed flask were added a solution of 72 (0.012 g, 0 0.030 mmol) in diethyl ether (5.00 mL) and 0 C cold 10% H2SO4 solution (15 0 mL). After 30 min of stirring at 0 C, the reaction was complete (monitorred by TLC). The mixture was poured into a separatory funnel with Et2O (15.0 mL). After separation, the water layer was extracted with Et2O (3x10 mL). The combined ether layers were washed with saturated sodium bicarbonate solution (25 mL) and water (25 mL), then dried over anhydrous MgSO4. After removal of solvent, the residue was purified by flash chromatography on silica gel with the 105 eluent of hexanes and ethyl acetate (1:1) to give 94 as a pale yellow oil (0.0084 g, 83%); IR (neat, cm-1): 3382 (br, s), 2970 (s), 2865 (w), 1692 (w), 1659 (m), 1607
(s), 1452 (w), 1381 (s), 1314 (s), 1291 (s), 1094 (s); 1H NMR (300 MHz, C6D6): δ 5.36-5.24 (m, 2H), 4.28 (s, 1H), 2.86 (dd, J=9.5, 4.6 Hz, 1H), 2.72 (d, J=8.2 Hz, 1H), 2.24-2.16 (m, 1H), 2.00-1.91 (m, 1H), 1.69-1.59 (m, 1H), 1.33 (d, J=6.7 Hz, 2H), 1.19 (d, J=6.1 Hz, 3H), 1.16 (d, J=6.1 Hz, 3H), 1.15 (d, J=6.1 Hz, 3H), 1.08
(d, J=6.1 Hz, 3H), 0.97 (s, 3H); 13C NMR (75 MHz, C6D6): δ 222.8, 198.0, 166.2, 131.8, 84.2, 73.9, 71.8, 56.8, 56.5, 46.9, 41.3, 39.3, 32.9, 26.2, 25.0, 23.0, 22.7, 22.5, 22.5; EI MS m/z (M+) calcd 336.1948, obsd 336.1942.
Anal Cald for C19H28O5: C, 67.83; H, 8.39. Found: C, 67.61; H, 8.33.
O
PriO Cl
PriO
O 97
To a solution of 94 (0.021 g, 0.06 mmol) in CH2Cl2 (5.0 mL) were added Et3N (0.08 mL, 0.60 mmol) and DMAP (0.003 g, 0.024 mmol). The mixture 0 was cooled to 0 C followed by the addition of distilled MsCl (0.04 mL, 0.48 mmol). After 3h of stirring at rt, crushed ice was added and the mixture was stirred for 1h. Reaction mixture was poured in a separatory funnel. After
separation, the water layer was extracted with CH2Cl2 (3x10 mL). The combined
CH2Cl2 layers were washed with water and dried over Na2SO4. After removal of solvent, the residue was purified by flash chromatography on silica gel with an eluent of hexanes and ethyl acetate (4:1) to give 97 as a pale yellow oil (0.011g, 106 52%); IR (neat, cm-1): 2974 (w), 2934 (w), 1747 (m), 1705 (m), 1619 (m), 1458
(w), 1381 (m), 1304 (m), 1106 (m); 1H NMR (300 MHz, C6D6): δ 5.50-5.22 (m, 2H), 3.23 (dd, J=8.9, 8.9 Hz, 1H), 2.72 (d, J=6.4 Hz, 1H), 2.18-2.01 (m, 1H), 1.87-1.79 (m, 1H), 1.65-1.55 (m, 1H), 1.43-1.25 (m, 2H), 1.21 (d, J=6.1 Hz, 3H), 1.20 (d, J=6.12 Hz, 3H), 1.10 (d, J=6.1 Hz, 3H), 1.10 (s, 3H), 1.07 (d, J=6.1 Hz,
3H), 0.75 (s, 3H); 13C NMR (75 MHz, C6D6): δ 215.0, 196.5, 165.5, 131.6, 74.4, 73.5, 72.3, 60.2, 59.5, 47.4, 42.5, 42.2, 32.6, 25.3, 23.4, 22.8, 22.6, 22.5, 22.4; FAB MS m/z (M+1) calcd 355.160, obsd 355.120.
Anal Cald for C19H27O4Cl: C, 64.31; H, 7.67. Found: C, 64.40; H, 7.55.
O H i-PrO
i-PrO O
96
In a 10mL round-bottomed flask were charged with 97 (0.011g, 0.030 mmol), dry benzene (5.0 mL), and DBU (0.005 mL, 0.03 mmol). The mixture 0 was refluxed at 80 C for 9 h. Then the mixture was poured in a separation
funnel with CH2Cl2 (5.0 mL) and water (5.0 mL). After separation, the water
layer was extracted with CH2Cl2 (3x5.0 mL). The combined CH2Cl2 layers were washed with 2N HCl solution (15 mL), saturated sodium bicarbonate solution (15 mL), dried over MgSO4. After removal of solvent, the residue was purified by flash chromatography on silica gel with the eluant of hexanes and ethyl acetate (4:1) to give 96 as a white brown solid (0.008g, 83%); IR (neat, cm-1): 2953 (s), 1698 (s), 1618 (s), 1560 (s), 1382 (s), 1312 (s), 1098 (s); 1H NMR (300 MHz,
107 C6D6): δ 5.50-5.35 (m, 2H), 3.48-3.41 (m, 1H), 3.12-2.97 (m, 1H), 2.12-2.00 (m, 1H), 1.58-1.55 (m, 1H), 1.48 (d, J=6Hz, 3H), 1.43.1.25 (m, 2H), 1.18 (d, J=6 Hz, 3H), 1.17 (d, J=6 Hz, 3H), 1.10 (d, J=6 Hz, 3H), 1.00 (s, 3H), 0.88 (s, 3H);13C NMR (75MHz): δ 200.8, 195.4, 156.0, 145.9, 141.1, 133.5,75.2, 73.1, 59.6, 52.2,
48.7, 43.5, 34.3, 24.5, 24.1, 23.1, 22.9, 22.8, 22.7; HR MS m/z (M+Na+) calcd 341.1723, obsd 341.1724.
HO HO
TBSO H + TBSO
OCH3 OCH3 151 152
108 To a slowly dried CeCl3• 7H2O (406 mg, 1.09 mmol) in a 50 ml, single-
necked, round-bottomed flask equipped with a #14 glass adaptor connected with a
two way valve, was purged with dry argon and added a solution of 150 (100 mg,
0.725 mmol) in dry THF (4 ml). The mixture was stirred at room temperature for
2 h to form a colorless gel-like mixture, and cooled to –78 0C with the aid of a dry
ice-isopropanol bath. To a separate oven-dried, 25ml, single–necked, round-
bottomed flask containing a solution of 139 (369 mg, 1.09 mmol) in THF (4 ml)
was added t-BuLi (1.4 ml, 2.18 mmol, 1.58M in hexanes) dropwise at –78 0C
under argon atmosphere, and the resulting yellowish mixture was continually
stirred for 45 min at the same temperature. Then the –78 0C cold mixture was
transferred dropwise via a cannula wrapped with glass wool and aluminium foil
0 into the –78 C cold mixture of CeCl3•7H2O and 150 in THF (vide supra). The
resulting mixture was stirred at –78 0C until no 150 was shown on the TLC plate
(ca. 3h and 50 min). After the addition of sat. aq. NH4Cl solution (7 ml) while
the mixture was vigorously stirred, the resulted mixture was allowed to warm to
ambient temperature and continually stirred over night. The resulting mixture
was then extracted with diethyl ether (3x20ml), and the combined organic layers
were washed with brine (50 ml), dried over anhydrous MgSO4. After the
removal of solvents by a rotary evaporator under a house vacuum, the residue was
purified with flash chromatography on silica gel (elution with hexane-ethyl
acetate 9:1) to afford 151 and 152 as colorless oils (230 mg with a 1:1 ratio; 81%).
151: IR (neat, cm-1): 3507 (w), 2931 (s), 2860 (m), 1637 (w), 1361 (w), 1255 (w),
1 1102 (w), 1073 (s), 926 (m), 832 (s); HNMR (300MHz, CDCl3): δ 6.11 (ddd,
109 J=0.9, 10.9, 17.6Hz, 1H), 5.87-5.64 (m, 1H), 5.34 (d, J=1.6Hz, 1H), 5.15 (dd,
J=0.8, 10.9Hz, 1H), 5.17 (dd, J=0.8, 17.6Hz, 1H), 4.95-4.90 (m, 2h), 4.68 (td,
J=6.6, 1.6Hz, 1H), 3.47 (s, 1H), 3.21 (s, 3H), 2.69 (dd, J=6.2, 12.1Hz, 1H), 2.18-
2.11 (m, 1H), 2.00-1.93 (m, 1H), 1.90-1.12 (m, 10H), 0.91 (s, 9H), 0.10 (s, 6H);
13 CNMR (75MHz, CDCl3): δ 154.5, 139.4, 138.8, 128.0, 115.1, 113.8, 90.2, 76.0,
73.5, 51.1, 45.3, 44.9, 44.5, 35.6, 26.5, 26.1, 25.9 (3C), 21.4, 18.2, -4.5, -4.6;
24 [α]D -38.4 (c 0.19, CHCl3); HR-EI MS m/z (M+) calcd 392.2747, obsd
392.2794.
Anal Cald for C23H40O3Si: C, 70.36; H, 10.27. Found: C, 70.17; H, 10.32.
152: IR (neat, cm-1): 3494 (w), 2930 (s0, 2860 (s0, 1634 (w), 1472 (w), 1360 (w),
1 1307 (w), 1255 (m), 1072 (s), 926 (w), 833.2 (m); HNMR (300MHz, CDCl3): δ
6.14 (ddd, J=0.8, 10.9Hz, 17.6Hz, 1H), 5.83-5.69 (m, 1H), 5.41 (d, J=1.7Hz, 1H),
5.20 (dd, J=0.7, 17.6Hz, 1H), 5.13 (dd, J=0.8, 10.9Hz, 1H), 5.00-4.92 (m, 2H),
4.66 (dt, J=1.7, 6.5Hz, 1H), 4.48 (s, 1H), 3.22 (s, 3H), 2.67 (dd, J=6.7, 12.6Hz,
1H), 2.47-2.40 (m, 1H), 1.94-1.86 (m, 2H), 1.81-1.52 (m, 5H), 1.49-1.35 (m, 2H),
13 1.34-1.10 (m, 2H), 0.90 (s, 9H), 0.09 (s, 6H); CNMR (75MHz, CDCl3): δ
153.8, 193.5, 138.6, 129.5, 115.2, 113.9, 90.0, 75.9, 73.2, 51.2, 47.2, 44.3, 43.2,
24 35.4, 26.6, 26.0, 25.9 (3C), 21.7, 18.1, -4.5 (2C); [α]D =+170 (c 0.03, CHCl3);
HR-EI MS m/z (M+) calcd 392.2747, obsd 392.2758.
110 HO HO H HO + HO
OCH3 OCH3 153 154
To a 00C cold solution of 151 (85 mg, 0.217 mmol) in THF (1.1 ml) was
added TBAF solution (1M in THF, 0.434 ml) dropwise. After the addition was
complete, the ice-water bath was removed, and the reaction mixture was stirred at
ambient temperature for 1h. The mixture was re-cooled to 0 0C with the aid of an
ice-water bath, and sat. aq. NH4Cl (2 ml) was added via syringe followed by
dilution of the mixture with the addition of ether (0.5 ml). The resulted mixture
was extracted with ether (3x5 ml), and the combined organic layers were dried
over anhydrous MgSO4. After filtration and removal of organic solvents by a
rotary evaporator under house vacuum, the residue was purified with flash
chromatography on silica gel (elution with hexane-ethyl acetate 1:1) to give 153
as a colorless oil (53.4 mg, 89%).
The same procedure as making 153 was applied to make 154, which gave 154 as a
colorless oil (35 mg, 93%).
153: IR (neat, cm-1): 3412 (w), 2933 (s), 2855 (m), 1638 (w), 1442 (m), 1308
(m), 1209 (w), 1140 (w), 1093 (m), 1052 (s), 984.8 (m), 911.3(m); 1HNMR
(300MHz, CDCl3): δ 6.10 (ddd, J=0.9, 10.9, 17.6Hz, 1H), 5.75-5.61 (m, 1H), 5.43
(d, J=1.6Hz, 1H), 5.18 (d, J=17.6Hz, 1H), 5.15 (d, J=10.9Hz, 1H), 4.93-4.88 (m,
2H), 4.69 (s, 1H), 3.45 (d, J=1.4Hz, 1H), 3.20 (s, 3H), 2.84 (dd, J=6.7, 12.6Hz,
111 1H), 2.18-2.08 (m, 2H), 1.98-1.87 (m, 1H), 1.85-1.75 (m, 2H), 1.72-1.58 (m, 3H),
13 1.48-1.12 (m, 5H); CNMR (75MHz, CDCl3): δ 156.3, 139.0, 138.5, 127.2,
115.1, 114.3, 99.8, 90.6, 73.1, 51.2, 45.2, 44.9, 44.5, 35.5, 26.4, 26.0, 21.3;
25 [α]D +26.9 (c 0.13, CHCl3); HR-EI MS m/z (M+) calcd 278.1822, obsd
278.1922.
154: IR (neat, cm-1): 3378 (br, w), 2931 (m), 1642 (w), 1443 (w), 1407 (w), 1325
1 (w), 1322 (w), 1091 (m), 1055 (m); HNMR (300MHz, CDCl3): δ 6.18 (ddd,
J=0.7, 10.9, 17.6Hz, 1H), 5.87-5.67 (m, 1H), 5.51 (d, J=1.8Hz, 1H), 5.21 (d,
J=18.3Hz, 1H), 5.14 (d, J=11.3Hz, 1H), 5.00-4.93 (m, 2H), 4.69-4.66 (m, 1H),
4.37 (d, J=1.2Hz, 1H), 3.22 (s, 3H), 2.80 (dd, J=6.7, 12.8Hz, 1H), 2.42-2.34 (m,
13 1H), 1.95-1.13 (m, 12H); CNMR (75MHz, CDCl3): δ 155.8, 139.0, 138.4,
128.5, 115.3, 114.5, 90.3, 77.9, 73.1, 51.3, 47.0, 44.0, 43.0, 35.3, 26.6, 25.9, 21.6;
22 [α]D +70 (c 0.06, CHCl3); HR-EI MS m/z (M+) calcd 278.1822, obsd 278.1884.
HO HO
O H + O
OCH3 OCH3 155 156
0 To a 0 C cold solution of 153 (43.3 mg, 0.156 mmol) in CH2Cl2 (10 ml)
under nitrogen atmosphere was added 4Å MS powder (40 mg), anhydrous NMO 112 (55 mg, 0.468 mmol), and TPAP (13.7 mg, 0.039 mmol). The reaction mixture
was stirred at 0 0C until no 153 was shown on TLC plates (ca. 1.5h). The
mixture was concentrated on a rotary evaporator, and the residue was purified
with flash chromatography on silica gel (elution with hexane-ethyl acetate 4:1) to
afford 155 as a colorless oil (37 mg, 86%).
The same procedure as making 155 was applied to make 156, which gave 156 as a
colorless oil (45.3 mg, 98%).
155: IR (neat, cm-1): 3507 (br, w), 2931 (m), 2861 (m), 1719 (s), 1689 (s), 1602
(m), 1437 (w), 1290 (w), 1249 (w), 1225 (w), 1073 (m), 985 (m); 1HNMR
(300MHz, CDCl3): δ 6.26 (dd, J=10.9, 17.6Hz, 1H), 5.78 (s, 1H), 5.73-5.59 (m,
1H), 5.32 (d, J=10.9Hz, 1H), 5.26 (d, J=17.6Hz, 1H), 4.95-4.89 (m, 2H), 3.31 (s,
3H), 3.23 (d, J=1.6Hz, 1H), 2.83 (d, J=17.1Hz, 1H), 2.68 (d, J=17.1Hz, 1H),
2.07-1.84 (m, 3H), 1.76-1.61 (m, 3H), 1.59-1.41 (m, 2H), 1.41-1.21 (m, 3H);
13 CNMR (75MHz, CDCl3): δ 203.0, 186.5, 137.8, 137.6, 126.2, 117.2, 115.8,
22 87.7, 77.6, 52.5, 45.9, 44.8, 43.7, 35.8, 26.0, 25.8, 21.0; [α]D +65.3 (c 0.27,
CHCl3); HR-EI MS m/z (M+) calcd 276.1725, obsd 276.1725.
156: IR (neat, cm-1): 3495 (br, m), 2931 (s), 2848 (m), 1731 (s), 1702 (s), 1602
(w), 1443 (w), 1290 (w), 1261 (w), 1226 (w), 1202 (w), 1073 (m), 985 (m);
1 HNMR (300MHz, CDCl3): δ 6.34 (ddd, J=0.4, 11.0, 17.8Hz, 1H), 5.82 (s, 1H),
5.81-5.61 (m, 1H), 5.35-5.28 (m, 2H), 4.99-4.91 (m, 2H), 4.19 (d, J=1.8Hz, 1H),
3.31 (s, 3H), 2.81 (d, J=17.6Hz, 1H), 2.66 (d, J=17.6Hz 1H), 2.20-2.11 (m, 1H),
2.07-1.98 (m, 1H), 1.86-1.60 (m, 4H), 1.59-1.17 (m, 5H); 13CNMR (75MHz, 113 CDCl3): δ 203.1, 186.0, 137.4, 137.3, 127.2, 117.6, 115.9, 86.9, 52.5, 47.3, 45.1,
22 44.9, 42.0, 35.5, 26.3, 25.6, 21.2; [α]D +71.25 (c 0.4, CHCl3); HR-EI MS m/z
(M+) calcd 276.1725, obsd 276.1750.
HO HO O H + O
H3CO H3CO
137 138
A 500-ml, single-necked, round-bottomed flask, equipped with a Teflon-
coated magnetic stirring bar, a high dilution adaptor, a water condensor, and a
pressure-equalizing funnel, was flame-dried, purged with dry argon, and added
dry benzene (200 ml). Benzene was refluxed for 30 min followed by addition of
a solution of Grubbs' catalyst in dry benzene (10 ml) via a cannula tube in one
portion. Tilting down the whole system made all of catalyst flow into the 500 ml,
single-necked, round-bottomed flask. A solution of 155 (29 mg, 0.105 mmol) in
dry benzene (30 ml) was then added very slowly through the dropping funnel over
12 h. After the addition of all of compound 155 was complete, the reaction
mixture was refluxed for 12 h followed by the addition of another solution of
Grubbs' catalyst (13 mg) in dry benzene (10 ml) in one portion. The reaction was
finished after 12 h refluxing based on TLC analysis. The reaction mixture was
114 then cooled to ambient temperature, continually stirred with the mouth of the
flask open to air for 6 h before the removal of solvents by a rotary evaporator
under the house vacuum. The resulting residue was purified with flash
chromatography on the silica gel (elution with hexane-ethyl acetate 4:1) to afford
137 as a white solid (25.5mg, 98%): m.p.: 87-890C.
The same procedure as making 137 was applied to make 138, which gave 138 as
a white solid (25.3mg, 84%): m.p.: 131-1330C.
137: IR (neat, cm-1): 3459 (m), 2931 (s), 2849 (m), 1719 (s), 1748 (s), 1602 (m),
1449 (m), 1402 (m), 1261 (m), 1220 (m), 1089 (s), 1061 (m); 1HNMR (300MHz,
CDCl3): δ 6.27-6.19 (m, 1H), 5.90 (s, 1H), 5.60 (dd, J=2.7, 10.8Hz, 1H), 5.07 (d,
J=1.4Hz, 1H), 3.32 (s, 3H), 2.78-2.60 (m, 3H), 1.97-1.89 (m, 1H), 1.80-1.53 (m,
13 7H), 1.50-1.22 (m, 2H); CNMR (75MHz, CDCl3): δ 203.3, 178.3, 139.2, 130.3,
22 127.6, 86.2, 75.1, 52.1, 50.9, 45.2, 38.1, 30.2 (2C), 26.1, 20.6; [α]D +277 (c
0.14, CHCl3); HR-EI MS m/z (M+) calcd 248.1412, obsd 248.1418.
138: IR (neat, cm-1): 3430.3 (m), 2918 (m), 1679 (s), 1604 (w), 1447 (w), 1255
1 (m), 1098 (m); HNMR (300MHz, CDCl3): δ 6.21 (s, 1H), 5.98-5.91 (m, 1H),
5.71 (dd, J=2.05, 11.4Hz, 1H), 3.30 (s, 3H), 2.78 (d, J=17.5Hz, 1H), 2.59-2.50 (m,
2H), 2.35-2.23 (m, 1H), 2.05 (s, 1H), 1.95-1.85 (m, 2H), 1.74-1.51 (m, 4H), 1.50-
13 1.24 (m, 3H); CNMR (75MHz, CDCl3): δ 203.9, 186.5, 138.2, 129.8, 129.3,
24 82.7, 75.2, 51.8, 50.4, 40.6, 39.9, 33.0, 28.3, 25.2, 21.0; [α]D +228 (c 0.025,
CHCl3); HR-EI MS m/z (M+) calcd 248.1412, obsd 248.1430.
Anal Cald for C15H20O3: C, 72.55; H, 8.12. Found: C, 72.45; H, 8.08. 115
O
MeO O H + OH H
H3CO O
157 158
Irradiation of 138 as before in dioxane and in benzene as solvent gave
rather different distributions of 157 and 158.
157: white crystals, mp 97.0-98.5 0C; IR (neat, cm-1) 1777; 1H NMR (300MHz,
C6D6): δ 5.60 (ddd, J=10.0, 5.5, 2.0Hz, 1H), 5.04 (ddd, J=10.0, 2.7, 1.3 Hz, 1H),
3.88 (d, J=2.7Hz, 1H), 3.79 (d, J=2.7Hz, 1H), 3.05 (d, J=16.7Hz, 1H), 2.96 (s,
3H), 2.04 (d, J=16.7Hz, 1H), 1.90-1.77 (m, 1H), 1.75-1.47 (series of m, 5H),
13 1.44-1.32 (m, 3H), 1.15-1.00 (m, 2H); C NMR (75 MHz, CDCl3): δ 175.0,
162.0, 129.5, 127.8, 87.8, 84.7, 55.1, 51.5, 37.7, 34.6, 32.2, 29.4, 27.6, 25.2, 21.8;
+ 21 HRMS (EI) m/z (M ) calcd 248.1412, obsd 248.1416; [α]D – 13 (c 0.1, CHCl3).
Anal. Calcd for C15H20O3: C, 72.55, H, 8.12. Found: C, 72.76, H, 8.31.
158: white crystals, mp 115-117 0C; IR (neat, cm-1) 3436, 1678; 1H NMR
(300MHz, C6D6): δ 5.57-5.52 (m, 1H), 5.07 (s, 1H), 5.01-4.96 (m, 1H), 3.10 (d,
J=18.0Hz, 1H), 2.86 (s, 3H), 2.10 (d, J=18.0Hz, 1H), 2.10-2.03 (m, 1H), 1.80-
13 0.80 (series of m, 11H); C NMR (75 MHz, THF-d8): δ 202.0, 131.1, 129.1,
116 105.7, 59.2, 46.0, 42.6, 38.1, 33.6, 32.7, 30.8, 29.9, 29.8, 27.1, 22.7; HRMS (EI)
+ 20 m/z (M ) calcd 248.1412, obsd 248.1413; [α]D – 53.8 (c 0.08, CHCl3).
O O HO HO
+ H H H3CO H H3CO
159 160
Into a quartz test tube containing 138 (20-60 mg) was introduced the
proper solvent (1-3 mL), and the solution was deoxygenated by bubbling dry N2
through a serum cap seal for 5 min. The needle serving as a gas outlet was
capped and the tube was positioned on the outside wall of a quartz condenser
fitted internally with a 450W Hanovia lamp. The irradiation was performed with
careful monitoring of the reaction progress by TLC. At the end of the process,
the solution was transferred into a round-bottomed flask and evaporated under
reduced pressure without warming. The residue was chromatographed on silica
gel (elution with hexane-ethyl acetate 4:1) in order to separate the isomeric
photoproducts.
159: white crystals, mp 162-163 0C; IR (neat, cm-1) 3376, 1666, 1599; 1H NMR
(300MHz, CDCl3): δ 5.97 (t, J=2.0Hz, 1H), 5.51 (d, J=1.7 Hz, 1H), 3.66 (s, 3H),
3.31-3.21 (m, 1H), 2.83-2.73 (m, 1H), 2.43-2.36 (m, 1H), 2.18-2.07 (m, 1H), 1.97
117 (td, J=2.8, 10.2 Hz, 1H), 1.82-1.18 (series of m, 10H); 13C NMR (75 MHz,
CDCl3): δ 190.9, 173.9, 165.1, 122.1, 105.2, 55.8, 46.8, 39.8, 37.2, 35.2, 33.5,
30.3, 25.7, 24.9, 21.0; HRMS (EI) m/z (M+) calcd 248.1412, obsd 248.1419;
22 [α]D – 115 (c 0.15, CHCl3).
Anal. Calcd for C15H20O3: C, 72.55, H, 8.12. Found: C, 72.29, H, 8.18.
160: white crystals, mp 83-85 0C; IR (neat, cm-1) 3436, 1689; 1H NMR
(300MHz, C6D6): δ 5.60-5.54 (m, 1H), 5.33-5.28 (m, 1H), 5.10 (s, 1H), 2.74 (s,
3H), 2.46 (d, J=18.0Hz, 1H), 2.31 (s, 1H), 2.23 (d, J=18.0Hz, 1H), 1.96-0/83
13 (series of m, 11H); C NMR (75 MHz, THF-d8): δ 200.9, 130.2, 128.2, 106.5,
73.7, 59.5, 54.7, 50.8, 38.2, 32.4, 31.3, 30.8, 30.2, 26.3, 23.0; HRMS (EI) m/z
+ 22 (M ) calcd 248.1412, obsd 248.1412; [α]D +83.3 (c 0.06, CHCl3).
O OOH OBn O N
Ph Me
191
To a cold (0 0C) solution of n-propionyl-(4S,5R)-4-methyl-5-phenyl-2-
oxazolidinone (189) (1.44 g, 6.2 mmol) in CH2Cl2 (35 mL) were added dropwise
Et3N (1.13 mL, 8.1 mmol) and neat Bu2BOTf (1.86 mL, 7.4 mmol) in sequence under an argon atmosphere. After being stirred at this temperature for 1h, the mixture was cooled to –78 0C followed by the dropwise addition of aldehyde 188
0 (1 g, 5.6 mmol) in CH2Cl2 (10 mL). After 1h of stirring at –78 C and 1h at rt, the reaction mixture was quenched with phosphate buffer solution (pH=7.0, 15
118 mL), extracted with CH2Cl2 (3x10 mL), dried over Na2SO4, and concentrated under house vacuum. The residue was dissolved in MeOH (30 mL) followed by
0 0 the addition of 30% aq. H2O2 (20 mL) at 0 C. After 1h of stirring at 0 C, the
excess H2O2 was reduced by adding 10% aq. NaHSO3 solution. The mixture was then extracted with ethyl acetate (3x10 mL), and the combined organic layers
were washed with sat. aq. NaHCO3 solution and brine, then dried over Na2SO4. After purification by chromatography on silica gel (elution with hexanes-ethyl acetate 4:1), 191 was isolated as a viscous colorless oil (1.9 g) in 83% yield; IR (neat, cm-1): 3482 (m), 2936 (m), 2868 (m), 1780 (vs), 1697 (s), 1454 (m), 1366 1 (s), 1345 (s), 1231 (m), 1197 (s); H NMR (300 MHz, CDCl3): δ 7.45-7.25 (m,
10H), 5.64 (d, J=7.2Hz, 1H), 4.79-4.75 (m, 1H), 4.52 (s, 2H), 4.00-3.95 (m, 1H), 3.82-3.77 (m, 1H), 3.55-3.51 (m, 2H), 3.26 (br s, 1H), 1.86-1.58 (m, 4H), 1.24 (d, 13 J=7.0Hz, 3H), 0.88 (d, J=6.6Hz, 3H); C NMR (75 MHz, CDCl3): δ 176.9, 152.6, 138.8, 133.1, 128.7, 128.6 (2C), 128.3 (2C), 127.6 (2C), 127.5, 125.5 (2C), 78.8, 72.8, 71.5, 70.1, 54.7, 42.4, 31.1, 26.3, 14.3, 10.5; HR-MS (Electrospray)
+ 21 m/z (M+Na ) calcd 434.1943, obsd 434.1922; [α]D – 0.19 (c 0.53, CHCl3).
Anal Cald for C24H29O5N: C, 70.05; H, 7.10. Found: C, 69.95; H, 7.16.
O OOPMB OBn O N
Ph Me 193
119 To a solution of 191 (0.35 g, 0.85 mmol) in CH2Cl2 (3 mL) was added p-
methoxybenzyl trichloroacetimidate 192 (0.36 mL, 1.7 mmol) and CSA (0.02 g,
0.085 mmol) at rt. After 24h of stirring at rt, the reaction mixture was diluted
with ether (40 mL), washed with sat. aq. NaHCO3 solution and brine, dried over
MgSO4, filtered, concentrated, and purified chromatographically on silica gel
(elution with hexane-ethyl acetate 8:1) to give 193 as a colorless oil that was used
-1 1 directly; IR (neat, cm ): 1778; H NMR (300 MHz, CDCl3): δ 7.45-7.23 (m,
12H), 6.91-6.78 (m, 2H), 5.28 (d, J=7.0Hz, 1H), 4.52 (s, 2H), 4.49 (s, 2H), 4.44-
4.09 (m, 1H), 3.79 (s, 3H), 3.71-3.66 (m, 1H), 3.53-3.49 (m, 2H), 1.85-1.64 (m,
13 5H), 1.24 (d, J=7.0Hz, 3H), 0.88 (d, J=6.6Hz, 3H); C NMR (75 MHz, CDCl3):
δ 174.5, 159.2, 152.8, 138.6, 133.2, 130.6, 129.8 (2C), 128.6 (2C), 128.3 (2C),
127.6 (2C), 127.5 (2C), 125.5 (2C), 113.7 (2C), 79.3, 78.7, 72.8, 71.5, 70.3, 55.4,
55.2, 41.4, 28.4, 25.8, 14.2, 11.9; HR-MS (Electrospray) m/z (M+Na+) calcd
26 554.2513, obsd 554.2530; [α]D – 13.6 (c 0.14, CHCl3).
HO OBn OPMB
194
0 To a stirred slurry of LiAlH4 (2.14 g, 56.4 mmol) in THF (100 mL) at 0 C
was added a solution of 193 (5.8 g, 11 mmol) in THF (65 mL). After 4 h of
stirring at 0 0C, the reaction mixture was quenched with 3N NaOH (60 mL) at 0
0C. The aqueous layer was extracted with ethyl acetate (3x100 mL) and the
combined organic layers were dried over Na2SO4. After purification by column 120 chromatography on silica gel (elution with hexane-ethyl acetate 4:1), 194 was
isolated as a colorless oil (2.43 g) in 62% yield over two steps; IR (neat, cm-1):
3418 (br), 2921 (s), 2854 (s), 1612 (s), 1513 (s), 1247 (s), 1032 (s), 819 (m), 736
1 (m), 698 (m); H NMR (300 MHz, CDCl3): δ 7.38-7.30 (m, 5H), 7.25 (d,
J=8.7Hz, 2H), 6.87 (d, J=8.7Hz, 2H), 4.53-4.43 (m, 4H), 3.80 (s, 3H), 3.76-3.65
(m, 1H), 3.56-3.41 (m, 4H), 2.56 (br s, 1H),2.14-2.04 (m, 1H), 1.81-1.54 (m, 4H),
0.87 (d, J=7.1Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 159.2, 138.5, 130.4, 129.5
(2C), 128.4 (2C), 127.6 (2C), 127.5 (2C), 113.9, 81.8, 72.9, 71.4, 70.2, 66, 55.2,
36.6, 26.4, 26.3, 12.0; HR-MS (EI) m/z (M+1) calcd 359.2222, obsd 359.2224;
21 [α]D + 0.71 (c 0.7, CHCl3).
TBDPSO OBn TBDPSO + OH OPMB OPMB 195 196
A mixture of 194 (0.64 g, 1.8 mmol), imidazole (0.37 g, 5.4 mmol), and
DMF (18 mL) was cooled to 0 0C before the addition of TBDPSCl (1.4 mL, 5.4
mmol). After 24h of stirring at rt, reaction was complete and tap water (90 mL)
was added. The organic layer was separated and the aqueous layer was extracted
with diethyl ether (3x20 mL). The combined organic layers were dried over
MgSO4. After removal of solvents, 195 was obtained as a colorless oil.
121 The crude 195 was mixed with anhydrous ethanol (165 mL) and W-2 type
Raney nickel (6.6 mL) under atmospheric hydrogen pressure. After 24 h of
stirring at rt, the reaction was complete by TLC. After filtration and removal of
solvents, the residue was purified by column chromatography on silica gel
(elution with hexane-ethyl acetate 4:1) to give 196 as a colorless oil (0.57 g, 63%
yield over two steps); IR (neat, cm-1): 3376 (br), 2930 (s), 2856 (s), 1513 (s),
1247 (s), 1111 (s), 1066 (s), 1036 (s), 822 (s), 702 (s), 505 (s); 1H NMR (300
MHz, CDCl3): δ 7.69-7.66 (m, 4H), 7.47-7.35 (m, 6H), 7.21 (d, J=8.7Hz, 2H),
6.85 (d, J=8.7Hz, 2H), 4.45 (s, 2H), 3.81 (s, 3H), 3.79-3.71 (m, 1H), 3.63-3.53
(m, 4H), 2.00-1.91 (m, 1H), 1.74 (br s, 1H), 1.70-1.55 (m, 4H), 1.08 (s, 9H), 0.96
(d, J=6.9Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 159.2, 135.0 (4C), 133.0 (2C),
131.0, 129.6 (2C), 129.3 (2C), 127.6 (4C), 113.7 (2C), 79.4, 71.8, 65.7, 63.0, 55.2,
38.7, 29.3, 27.7, 26.9 (3C), 19.3, 12.0; HR-MS (EI) m/z (M+1) calcd 507.2931,
24.5 obsd 507.2914; [α]D + 1.35 (c 0.52, CHCl3).
Anal Cald for C31H42O4Si: C, 73.48; H, 8.35. Found: C, 73.54; H, 8.42.
TBDPSO TBDPSO OMs + Br OPMB OPMB
209 208
0 To a stirred cold (0 C) solution of 196 (0.18 g, 0.4 mmol) and Et3N (0.17
mL, 1.2 mmol) in CH2Cl2 (5 mL), was added MsCl (0.06 mL, 0.8 mmol). After
two h of stirring at 0 0C, reaction was deemed complete based on TLC. The 122 reaction mixture was diluted with CH2Cl2 (25 mL), washed with water and brine,
then dried over Na2SO4. After removal of solvents, 209 was obtained as a pale
yellow liquid, which was used as such for making 208.
209 (0.286 g, 0.40 mmol), LiBr (0.042 g, 0.48 mmol), and THF (5 mL)
were mixed together and stirred at rt for 24 h. The reaction mixture was treated
with water and extracted with CH2Cl2 (3x15 mL). The combined organic layers
were washed with water and brine, then dried over Na2SO4. After removal of
solvents and column chromatography on silica gel (elution with hexane-ethyl
acetate 6:1), 208 was isolated as a colorless oil (0.15 g, 66% over two steps); IR
(neat, cm-1): 2930 (s), 1611 (m), 1513 (s), 1247 (m), 1249 (s), 1111 (s); 1H NMR
(300 MHz, CDCl3): δ 7.73-7.70 (m, 2H), 7.60-7.41 (m, 8H), 7.25 (d, J=8.7Hz,
2H), 6.89 (d, J=8.7Hz, 2H), 4.47 (s, 2H), 3.83 (s, 3H), 3.81-3.74 (m, 1H), 3.66-
3.59 (m, 2H), 3.47-3.37 (m, 2H), 2.04-1.65 (m, 5H), 1.12 (s, 9H), 0.99 (d,
J=6.9Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 159.2, 135.5 (4C), 134.7, 133.7,
131.0, 130.0 (2C), 129.0 (2C), 127.6 (4C), 113.7 (2C), 78.0, 71.7, 63.7, 55.2, 38.9,
34.0, 30.0, 29.2, 26.8 (3C), 19.2, 11.8; HR-MS (Electrospray) m/z (M+Na+) calcd
24.5 591.1906, obsd 591.1894; [α]D –1.2 (c 0.83, CHCl3).
TBDPSO I OPMB 184
123 0 To a cold (0 C) solution of 196 (1.0 g, 1.98 mmol), Ph3P (1.04 g, 3.95
mmol), and imidazole (0.27 g, 3.9 5mmol) in dry benzene (45 mL) was added I2
(1.0 g, 3.95 mmol) in one portion under a N2 atmosphere. The ice-water bath
was removed and the reaction mixture was stirred at ambient temperature for 5h.
A precipitate was formed and the color of the mixture was yellow. The reaction
mixture was diluted with ether (150 mL), washed with sat. aq. NaHSO3 solution
(2x30 mL) and brine (30 mL), then dried over anhydrous Na2SO4. After
filtration and removal of solvents the residue was taken up in hexanes (100 mL).
After another filtration and removal of hexanes, the residue was purified by flash
chromatography on silica gel (elution with hexane-ethyl acetate 9:1) to give 184
as a colorless oil (0.93 g, 77%); IR (neat, cm-1): 2930 (s), 2860 (s), 1613 (s),
1 1507 (s), 1247 (m), 1249 (s), 1111 (s); H NMR (300 MHz, CDCl3): δ 7.67-7.64
(m, 4H), 7.43-7.33 (m, 6H), 7.18 (d, J=8.7Hz, 2H), 6.84 (d, J=8.7Hz, 2H), 4.41
(s, 2H), 3.79 (s, 3H), 3.69 (dd, J=6.7, 10.0Hz, 1H), 3.58-3.52 (m, 2H), 3.17-3.09
(m, 2H), 1.88-1.76 (m, 3H), 1.62-1.55 (m, 2H), 1.06 (s, 9H), 0.92 (d, J=6.9Hz,
3H); 13C NMR (75 MHz, CDCl3): δ 159.2, 135.5 (4C), 133.0 (2C), 131.0, 129.7
(2C), 129.4 (2C), 127.8 (4C), 113.8 (2C), 78.3, 71.9, 65.8, 55.4, 39.0, 32.4, 30.1,
27.0 (3C), 19.4, 11.9, 7.3; HR-MS (Electrospray) m/z (M+Na+) calcd 639.1762,
24.5 obsd 639.1740; [α]D –2.7 (c 0.74, CHCl3).
124 OMe OH OMe OPMB NOBn+ NOBn O O 202 185
To a stirred suspension of N,O-dimethylhydroxylamine hydrochloride
(201) (0.96 g, 9.8 mmol) in CH2Cl2 (18 mL) was slowly added AlMe3 (4.9 mL,
0 9.8 mmol, 2M in hexanes) at 0 C under N2. When the addition of AlMe3 was
complete, the mixture was stirred at rt for 15 min to form a clear solution, re-
0 cooled to 0 C, and treated with a solution of 200 (1g, 4.9 mmol) in CH2Cl2 (18
mL). After 20 min of stirring at 0 0C, the reaction mixture was quenched with
1N aq. HCl, extracted with CH2Cl2 (3x20 mL), and concentrated under vacuum to
give crude 202.
To a solution of 202 (0.88g, 3.3mmol) in CH2Cl2 (20 mL) was added p-
methoxybenzyl trichloroaccetimidate (192) (1.4 mL, 6.6 mmol) and CSA (0.08 g,
0.33 mmol) at rt. The mixture was stirred overnight, diluted with ether (150 mL),
washed with sat. aq. NaHCO3 solution and brine, dried over MgSO4, filtered, and
concentrated under house vacuum. The residue was purified by chromatography
on silica gel (elution with hexane-ethyl acetate 4:1) to give 185 (1.14 g) as a
colorless oil in 89% yield; IR (neat, cm-1): 2937 (s), 2860 (s), 1778 (s), 1660 (s),
1613 (s), 1514 (s), 1454 (m), 1248 (m), 1174 (m), 1091 (m), 1032 (m); 1H NMR
(300 MHz, CDCl3): δ 7.33-7.26 (m, 5H), 7.22 (d, J=8.3Hz, 2H), 6.81 (d, J=8.3Hz,
2H), 4.61-4.47 (m, 4H), 3.74 (s, 3H), 3.66-3.60 (m, 1H), 3.56 (s, 3H), 3.56-3.47
(m, 2H), 3.10 (s, 3H), 2.49-2.41 (m, 2H), 1.96-1.76 (m, 2H); 13C NMR (75 MHz, 125 CDCl3): δ 171.0, 159.0, 138.2, 130.8, 129.3 (2C), 128.2 (2C), 127.5 (2C), 127.3,
113.5 (2C), 76.5, 73.2, 72.6, 71.4, 61.0, 60.2, 55.0, 27.5, 26.5; HR-MS
+ 22 (Electrospray) m/z (M+Na ) calcd 410.1938, obsd 410.1927; [α]D –13.7 (c 0.87,
CHCl3).
TBDPSO TBDPSO SPh + SO2Ph OPMB OPMB
210 211
196 (1.2 g, 2.4 mmol), (PhS)2 (0.786 g, 3.6mmol), and n-Bu3P (0.9 mL,
3.6 mmol) were dissolved in dry DMF (1.8 mL) at rt. After 24 h of stirring at
ambient temperature, the reaction mixture was separated with flash
chromatography on silica gel (elution with hexane-ethyl acetate 4:1) to give 210
as a colorless oil in 78% yield.
0 To a solution of 210 (0.359 g, 0.6 mmol) in CH2Cl2 (10 ml) at 5 C was
added solid sodium bicarbonate (0.34 g, 4 mmol) and MCPBA (0.4 g, 2.1 mmol).
The reaction mixture was stirred at ambient temperature for 1 h before quenching
with 10% Na2S2O3 solution (10 mL). The mixture was stirred for 20 min, and the
separated aqueous layer was extracted with CHCl3 (3x20 mL). The combined
organic layers were washed with saturated aqueous NaHCO3 solution, dried over
anhy. Na2SO4, filtered, concentrated in vacuo, and purified by flash
chromatography on silica gel (elution with hexane-ethyl acetate 4:1) to give 211
126 (0.258g) as a colorless oil in 70% yield; IR (neat, cm-1): 3069 (m), 2931 (s),
2857 (s), 1613 (s), 1557 (m), 1513 (s), 1470 (s), 1446 (s), 1427 (s), 1305 (s), 1248
1 (s), 1146 (s), 1111 (s), 1086 (s), 1036 (m); H NMR (300 MHz, CDCl3): δ 7.92-
7.89 (m, 2H), 7.69-7.62 (m, 5H), 7.57-7.52 (m, 2H), 7.48-7.35 (m, 6H), 7.15 (d,
J=8.5Hz, 2H), 6.85 (d, J=8.5Hz, 2H), 4.42 (d, J=10.9Hz, 1H), 4.34 (d, J=10.9Hz,
1H), 3.81 (s, 3H), 3.78-3.68 (m, 1H), 3.58-3.52 (m, 2H), 3.10-3.05 (m, 2H), 1.92-
1.73 (m, 3H), 1.58-1.51 (m, 2H), 1.09 (s, 9H), 0.91 (d, J=6.9Hz, 3H); 13C NMR
(75 MHz, CDCl3): δ 159.0, 139.0, 135.0 (4C), 133.5 (2C), 133.4, 130.6, 129.5
(2C), 129.2 (2C), 129.1 (2C), 127.9 (2C), 127.5 (4C), 113.6 (2C), 78.4, 71.8, 65.4,
56.0, 55.0, 38.7, 30.0, 26.8 (3C); HR-MS (Electrospray) m/z (M+Na+) calcd
22 653.2733, obsd 653.2729; [α]D +1.9 (c 0.58, CHCl3).
OPMB HOBn
O 219
To a solution of amide 185 (0.5 g, 1.3 mmol) in THF (2 mL) at –78 0C
was added DIBAL-H (1.0M in hexanes, 1.95 mL) dropwise. After 1h of stirring
at –78 0C, the reaction mixture was quenched with MeOH (3 mL) and sat. aq.
Rochelle’s salt solution (3 mL) at –78 0C. The mixture was allowed to warm to rt
and stirred for 1 h. The reaction mixture was extracted with ether (3x40 mL).
The combined organic layers were washed with brine and dried over MgSO4.
Purification of the residue by flash chromatography on silica gel (elution with
127 hexane-ethyl acetate 1:1) gave 219 (0.43 g, 1.3 mmol, 100%) as a colorless oil
which was used directly to couple with lithiated 211.
SO2Ph OPMB TBDPSO OBn
OPMB OH 220
A solution of sulfone 211 (0.18 g, 0.29 mmol) in dry THF (2.5 mL) under
argon was cooled to –78 0C before introducing n-BuLi (1.17M in hexanes, 0.25
mL). After 1 h of stirring at –78 0C, a solution of aldehyde 219 (0.049 g, 0.15
mmol) in dry THF (0.5 mL) was added and the mixture was stirred for 2 h at –78
0 C before being quenched with sat. aq. NH4Cl solution (5 mL). The mixture was
then diluted with ether (20 mL), extracted with ether (3x20 mL), dried over anhy.
MgSO4, filtered, concentrated, and separated by flash chromatography on silica
gel (elution with hexane-ethyl acetate 4:1) to give 220 in 70% as a colorless oil.
This material was used for the next step without further purification.
SO2Ph OPMB TBDPSO OBn
OPMB O 221
128 To a solution of oxalyl chloride (0.254 g, 2.0 mmol) in CH2Cl2 (4 mL) at –
0 78 C was added a solution of DMSO (0.2 g, 2.57 mmol, 0.18mL) in CH2Cl2 (3
mL) dropwise. After 10 min of stirring, 220 (0.1 g, 0.1mmol) in CH2Cl2 (8 mL)
0 was added. The mixture was stirred at –78 C before the addition of Et3N (0.71 g,
7 mmol, 0.98 mL) at the same temperature. The reaction mixture was stirred at –
78 0C for 25 min, and at ambient temperature for 3 h before being quenched with
sat. aq. NH4Cl solution (20 mL). The mixture was extracted with ether (3x20
mL), dried over anhy. Na2SO4, filtered, concentrated in vacuo, and purified by
flash chromatography on silica gel (elution with hexane-ethyl acetate 2:1) to give
221 (0.086 g) as a colorless oil in 90% yield. The resulting residue was used in
the next step without further purification.
OPMB TBDPSO OBn
OPMB O 207
SmI2 was used as the reducing agent to remove PhSO2 from 221:
To a well degassed solution of 221 (25.6 mg, 0.03 mmol) in THF/MeOH
0 (2.9:1, 13.5 mL) at –78 C was added SmI2 (0.1M in THF, 0.6 mL) in one portion.
The color of the reaction mixture changed from dark blue to colorless within 25
min. The reaction mixture was quenched with water (2.5 mL) at –78 0C and the
129 reaction mixture was allowed to warm to rt. To the mixture was added sat. aq.
K2CO3 solution (10 mL) and the product was extracted into EtOAc (3x10 mL).
The combined organic layers were washed with brine, dried over anhy. Na2SO4,
concentrated in vacuo, and purified by flash chromatography on silica gel (elution
with hexane-ethyl acetate 2:1) to give 207 (13mg) as a colorless oil in 53% yield.
Al(Hg) was used as the reducing agent to remove PhSO2 from 221:
Al(Hg) was made by treatment of aluminum foil with mercury according
to a literature procedure. To a solution of 221 (25.6 mg, 0.027 mmol) in 10% aq.
THF (0.20 mL) was added Al(Hg) (29.2 mg, 1.08 mmol). The reaction mixture
was stirred vigorously, heated to reflux for 2 days, cooled to ambient temperature,
and filtered. The filtrate was washed with water (0.5 mL) and brine (0.5 mL),
then dried over anhydrous MgSO4. After filtration and removal of solvents, the
residue was purified by flash chromatography on silica gel (elution with hexane-
ethyl acetate 6:1) to give 207 (11.2mg, 60%) as a colorless oil : IR (neat, cm-1):
2960 (s), 2927 (s), 2856 (s), 1713 (s), 1613 (s), 1513 (s), 1463 (m), 1428 (w),
1 1302 (w), 1250 (s); H NMR (300 MHz, CDCl3): δ 7.92-7.72 (m, 4H), 7.63-7.44
(m, 11H), 7.44-7.28 (m, 4H), 7.06-6.89 (m, 4H), 4.81-4.48 (m, 6H), 3.88 (s, 6H),
3.81-3.56 (m, 6H), 2.68-2.50 (m, 1H), 2.50-2.32 (m, 1H), 2.15-1.84 (m, 2H),
1.84- 1.51 (m, 4H), 1.24 (s, 9H), 1.13-0.95 (m, 6H); 13C NMR (75 MHz, CDCl3):
δ 210.6, 159, 158.9, 138.2, 135.6 (4C), 133.8 (2C), 131.2, 130.7, 129.5 (2C),
129.45 (2C), 129.44 (2C), 129.2 (2C), 128.4 (2C), 127.6 (7C), 113.7 (2C), 78.9
(2C), 73.3, 72.6, 71.8, 71.6, 65.8, 55.2, 42.7, 38.8, 38.3, 31, 26.9, 25.9, 20.3, 19.2, 130 11.4, 1.0 (3C); HR-MS (Electrospray) m/z (M+Na+) calcd 839.4319, obsd
27 839.4323; [α]D –8.6 (c 0.07, CHCl3).
Na(Hg)(5%) was used as the reducing agent to remove PhSO2 from 221:
To a mixture of 221 (2 g, 2.09 mmol) and Na2HPO4(1.19 g, 8.36 mmol)
were added dry MeOH (90 mL) and Na(Hg) (5%, 4.8 g) in sequence at 0 0C.
After 7.5 h of stirring at 0 0C, the reaction mixture was poured into water (100 mL)
and the water layer was extracted with ether(5x200 mL). The combined organic
layers were dried over Na2SO4, filtered, concentrated, and purified by flash
chromatography (elution with hexane-ethyl acetate 2:1) to give 207 (1.41g, 83%)
as a colorless oil.
Formation of 207 from direct coupling between lithiated 184 and 185:
To a solution of 184 (0.622 g, 1.01 mmol) in a mixture of pentane (6 mL)
and ether (4 mL) was added titrated t-BuLi (1.42M in pentane, 2.86 mL, 2.02
mmol) dropwise at –78 0C under an argon atmosphere. The reaction mixture was
stirred at –78 0C for 5-10min, warmed to 0 0C for 1 h while stirred, transferred
into a solution of 185 (0.782 g, 2.02 mmol) in THF (20 mL) at 0 0C via a cannula
tube under argon, stirred at 0 0C for 30 min, diluted with ether (100 mL), washed
with sat. aq. NH4Cl solution (50 mL) and brine (50 mL), then dried over MgSO4.
After filtration and removal of organic solvents, the residue was purified by flash
chromatography on silica gel (elution with hexane-ethyl acetate 4:1) to give 207
as a colorless oil (0.534g, 65%).
131
TBDPSO O OBn O
183
To a solution of 207 (7 mg, 0.009 mmol) in CH2Cl2 (5 mL) containing a
small amount of degassed water (0.2 mL) was added DDQ (4 mg, 0.017 mmol).
The mixture was vigorously stirred at rt for 1.5 h prior to the addition of sat. aq.
NaHCO3 solution. The mixture was extracted with CH2Cl2 (3x10 mL). The
combined organic layers were washed with NaHCO3 solution and brine, dried
over Na2SO4, filtered, concentrated in vacuo, then purified by flash
chromatography on silica gel (elution with hexane-ethyl acetate 8:1) to give 183
(4.6 mg) as a colorless oil in 92% yield: IR (neat, cm-1): 2934 (s), 2857 (s),
1454(m), 1428 (s), 1388 (m), 1362 (m), 1268 (m), 1223 (m), 1112 (s), 1027 (s),
1 981 (m), 824 (m), 739 (s), 701 (s); H NMR (300 MHz, C6D6): δ 7.83-7.78 (m,
4H), 7.30-7.06 (m, 11H), 4.39 (s, 2H), 4.37-4.29 (m, 1H), 4.05 (ddd, J=11.5, 5.1,
2.3Hz, 1H), 3.84 (dd, J=9.8, 6.0Hz, 1H), 3.65 (dd, J=9.8, 6.5Hz, 1H), 3.43 (d,
J=5.0Hz, 1H), 3.41 (d, J=5.0Hz, 1H), 2.08-1.91 (m, 2H), 1.89-1.71 (m, 2H), 1.69-
1.46 (m, 4H), 1.42-1.23 (m, 3H), 1.20 (s, 9H), 1.10 (d, J=6.8Hz, 3H); 13C NMR
(75 MHz, CDCl3): δ 139.3, 135.0 (4C), 134.5 (2C), 129.9 (4C), 128.5 (2C), 128.2,
127.9 (2C), 127.5 (2C), 106.6, 77.2, 73.4, 73.1, 70.9, 66.6, 41.3, 37.7, 33.4, 28.4,
27.2 (3C), 26.9, 21.0, 19.6, 12.5; HR-MS (Electrospray) m/z (M+Na+) calcd
22.6 581.3063, obsd 581.3068; [α]D +13.9 (c 0.37, CHCl3). 132 TBDPSO O OH O
226
Pd/C (10%, 15 mg, 0.014 mmol) was added to a solution of 183 (36.9 mg,
0.07 mmol) in degassed EtOH (1.0 mL). After 12 h of stirring at ambient
temperature under H2 atmosphere, the reaction mixture was filtered, and the
filtrate was concentrated under a reduced vacuum and dried under a high vacuum.
The resulting residue was used in the next step without further purification.
TBDPSO O O O H 227
To a solution of 226 (crude) product above in dry pyridine (32.4 µL) and
CH2Cl2 (1 mL) was added DMP (25.4 mg, 0.06 mmol) at ambient temperature
under N2 atmosphere. After 3h of stirring, reaction was stopped by the addition
of solid Na2S2O3 (100 mg) followed by dilution with CH2Cl2 (5 mL). The
mixture was stirred until a clear solution was formed. The mixture was extracted
with CH2Cl2 (3x5 mL), and the organic layers were washed with sat. aq. NaHCO3
solution (5 mL) and brine (5 mL), dried over anhydrous Na2SO4. After filtration
and removal of organic solvents, the residue was chromatographed on silica gel
(elution with hexane-ethyl acetate 4:1) to give 227 (14.5 mg) as a colorless oil in
133 an adjusted 71% yield with the recovery of 183 (15.5mg): IR (neat, cm-1): 2935
1 (m), 2856 (m), 1736(m), 1428 (s), 1112 (s); H NMR (300 MHz, C6D6): δ 9.51 (d,
J=1.6Hz,1H), 7.83-7.74 (m, 5H), 7.30-7.18 (m, 5H), 4.19-4.16 (m, 1H), 3.99-3.94
(m, 1H), 3.75 (dd, J=9.8, 6.3Hz, 1H), 3.60 (dd, J=9.8, 6.3Hz, 1H), 1.99-1.90 (m,
2H), 1.89-1.79 (m, 1H), 1.78-1.58 (m, 2H), 1.57-1.48 (m, 2H), 1.47-1.21 (m, 4H),
1.18 (s, 9H), 1.00 (d, J=6.8Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 201.1, 136.0
(4C), 134.5 (2C), 130.1 (4C), 127.2 (2C), 107.4, 82.0, 71.1, 66.3, 41.0, 37.2, 32.8,
28.1, 27.1 (3C), 26.0, 20.8, 19.5, 12.2; HR-MS (Electrospray) m/z (M+Na+) calcd
21 489.2431, obsd 489.2410; [α]D +10.0 (c 0.16, CHCl3).
Me TBDPSO O COOEt O
229
To a solution of 227 (14.5mg, 0.03mmol) in CH2Cl2 (1mL) was added
ethoxycarbonylethylidene triphenylphosphorane (228) (22.53mg, 0.06mmol) in
one portion at rt under N2 atmosphere. After 24h of stirring at rt, the mixture was
concentrated on a rotary evaporator under house vacuum, and the residue was
chromatographed on the silica gel (elution with hexane-ethyl acetate 4:1) to give
229 (15.9mg, 96%) as a colorless oil: IR (neat, cm-1): 2928 (s), 2856 (s), 1714(s),
1470 (m), 1468 (m), 1428 (m), 1366 (m), 1251 (m), 1111 (m), 1028 (m); 1H
NMR (300 MHz, C6D6): δ 7.80-7.77 (m, 4H), 7.26-7.18 (m, 6H), 7.11 (d,
134 J=7.6Hz, 1H); 4.89-4.81 (m, 1H), 4.05-3.95 (m, 3H), 3.83 (dd, J=9.8, 5.6Hz, 1H),
3.67 (dd, J=9.8, 6.7Hz, 1H), 2.14-1.89 (m, 2H), 1.86 (s, 3H), 1.85-1.76 (m, 2H),
1.64-1.18 (m, 7H), 1.17 (s, 9H), 1.12 (d, J=6.8Hz, 3H), 0.96 (t, J=7.1Hz, 3H);
13C NMR (75 MHz, CDCl3): δ 170.2, 141.9, 135.6(4C), 134.1 (2C), 129.5 (2C),
128.7, 127.6 (4C), 106.5, 73.9, 71.4, 66.2, 60.6, 40.8, 37.9, 33.3, 30.8, 26.9 (3C),
28.0, 20.5, 19.3, 14.0, 12.6, 12.5; HR-MS (Electrospray) m/z (M+Na+) calcd
26 573.3007, obsd 573.3013; [α]D +11.9 (c 0.16, CHCl3).
Me TBDPSO O OH O
230
To a solution of 229 (58 mg, 0.11 mmol) in CH2Cl2 (5 mL) was added
0 DIBAL-H (1.0M in hexanes, 0.32 mL) dropwise at –40 C under N2. After 1h of
stirring at –40 0C, the reaction mixture was quenched with MeOH (6 mL) and sat.
aq. Rochelle’s salt solution (6 mL) and stirred for 50 min at rt. The reaction
mixture was extracted with CH2Cl2 (3x5 mL) , and the combined organic layers
were dried over anhydrous Na2SO4. After removal of organic solvents, the
residue was chromatographed on silica gel (elution with hexane-ethyl acetate 4:1)
to give 230 (41mg, 73%) as a colorless oil: IR (neat, cm-1): 3370 (br), 2829 (s),
1 2856 (s), 1462 (m), 1428 (m), 1384 (m), 1112 (m); H NMR (300 MHz, C6D6): δ
7.83-7.79 (m, 4H), 7.26-7.21 (m, 6H), 5.60 (d, J=7.1Hz, 1H); 4.96-4.85 (m, 1H), 135 4.05-3.99 (m, 1H), 3.86 (dd, J=9.7, 5.2Hz, 1H), 3.74-3.68 (m, 3H), 2.12-1.79 (m,
4H), 1.71-1.57 (m, 4H), 1.54 (s, 3H), 1.51-1.24 (m, 4H), 1.12 (d, J=6.2Hz, 3H),
1.20 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 138.2, 135.6(4C), 133.9 (2C), 129.5
(2C), 127.6 (4C), 126.1, 106.1, 73.4, 71.5, 68.2, 66.3, 41.0, 38.1, 33.2, 30.8, 26.9
(3C), 28.5, 20.5, 14.1, 14.0, 12.8; HR-MS (Electrospray) m/z (M+Na+) calcd
23 531.2900, obsd 531.2904; [α]D +9.0 (c 0.19, CHCl3).
Me TBDPSO O OH O O
231
To a 5mL, round-bottomed, reaction flask was charged with CH2Cl2 (1.0
mL) and 4Å molecular sieves (25 mg). The mixture was cooled to –23 0C
followed by addition of L-(+)-DET (5.7 mg, 0.0276 mmol, 4.73 µL), Ti(O-iPr)4
(6.54 mg, 0.023 mmol, 6.7 µL). The mixture was stirred for 15 min at –23 0C
under argon before the dropwise addition of TBHP (4M in CH2Cl2, 0.02 mL).
After 30 min of stirring at –23 0C, the mixture was treated with a solution of 49
0 (11.5 mg, 0.023 mmol) in CH2Cl2 (0.1 mL) and stirred at –23 C for 12h before
being quenched with 10% aq. tartaric acid (0.1 mL). The mixture was stirred at
-23 0C for 10 min , allowed to warm to ambient temperature until a clear solution
was formed. The organic layer was washed with water (0.5 mL) and dried over
anhydrous Na2SO4. After filtration and removal of solvents under vacuum, the
residue was purified by column chromatography (elution with hexane-ethyl 136 acetate 4:1) to give 50 (8.5mg, 71%) as a colorless oil: IR (neat, cm-1): 3450
(br), 2929 (s), 2856 (s), 1462 (m), 1427 (m), 1261 (m), 1112 (s), 1026 (s); 1H
NMR (300 MHz, CDCl3): δ 7.66-7.65 (m, 4H), 7.44-7.37 (m, 6H), 3.86-3.81 (m,
1H), 3.74-3.70 (m, 2H), 3.65-3.61 (m, 2H), 3.55 (dd, J=10.1, 6.2Hz, 1H), 3.00 (d,
J=8.1Hz, 1H), 2.28-2.21 (m, 1H), 1.95-1.53 (m, 9H), 1.30 (s, 3H), 1.27-1.18(m,
2H), 1.06 (s, 9H), 0.78 (d, J=6.8Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 135.6
(4C), 133.9 (2C), 129.5 (2C), 127.6 (4C), 106.5, 74.9, 71.6, 66.1, 65.1, 61.4, 61.2,
40.7, 37.3, 32.8, 28.2, 28.1, 26.9 (3C), 20.5, 19.3, 14.3, 12.9; HR-MS
+ 20 (Electrospray) m/z (M+Na ) calcd 547.2855, obsd 547.2854; [α]D +13.2 (c 0.42,
CHCl3).
Me TBDPSO O OTs O O
234
To a solution of 231 (27.8 mg, 0.053 mmol) in dry CH2Cl2 (2 mL) were
0 added dry Et3N (0.022 mL, 0.16 mmol) and TsCl (20.2 mg, 0.106 mmol) at 0 C
0 under N2. After 5h of stirring at 0 C, the reaction mixture was diluted with
CH2Cl2 (5 mL), washed with ice-cold water (5 mL), and dried over anhy. Na2SO4.
After filtration and removal of solvents under house vacuum, the residue was
purified by column chromatography on silica gel (elution with hexane-ethyl
137 acetate 4:1) to give 234 (32.3 mg, 90%) as a colorless oil: IR (neat, cm-1): 2931
(s), 1427 (m), 1366 (m), 1177 (m), 1111 (s), 823 (s), 702 (s); 1H NMR (300 MHz,
CDCl3): δ 7.81-7.78 (m, 2H), 7.65-7.62 (m, 4H), 7.44-7.33 (m, 8H), 4.10 (d,
J=10.7Hz, 1H), 3.84 (d, J=10.7Hz, 1H), 3.76-3.64 (m, 2H), 3.60 (dd, J=10.1,
4.8Hz, 1H), 3.51 (dd, J=10.1, 4.8Hz, 1H), 2.74 (d, J=7.9Hz, 1H), 2.44 (s, 3H),
2.21-2.12 (m, 1H), 1.90-1.55 (m, 10H), 1.27 (s, 3H), 1.03 (s, 9H), 0.94 (d,
J=6.8Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 135.6 (4C), 133.9 (2C), 132.4,
129.9 (2C), 129.5 (2C), 129.0, 128.0 (2C), 127.6 (4C), 106.5, 74.5, 73.7, 66.1,
62.0, 61.4, 61.2, 41.2, 37.2, 32.7, 29.7, 28.0, 26.9 (3C), 21.6, 20.5, 19.3, 14.0,
+ 23 12.8; HR-MS (Electrospray) m/z (M+Na ) calcd 701.2939, obsd 701.2960; [α]D
+3.6 (c 0.14, CHCl3).
Me TBDPSO O OMs O O
233
To a solution of 231 (51.3 mg, 0.098 mmol) in dry CH2Cl2 (5 mL) were
added dry Et3N (0.04 mL, 0.294 mmol) and MsCl (0.0152 mL, 0.196 mmol) at 0
0 0 C under N2. After 1h of stirring at 0 C, the reaction mixture was diluted with
CH2Cl2 (5 mL), washed with ice-cold water (5 mL), and dried over anhy. Na2SO4.
After filtration and removal of solvents under house vacuum, the residue was
purified by column chromatography on silica gel (elution with hexane-ethyl 138 acetate 4:1) to give 233 (48.1 mg, 82%) as a colorless oil which was used directly
in the next step.
Me TBDPSO O I O O
232
To a solution of 233 (24 mg, 0.04 mmol) in dry THF (2 mL) was added
Bu4NI (88.7 mg, 0.24 mmol) under N2. The reaction mixture was stirred in
refluxing THF for 3 h, cooled to rt, diluted with ether (5 mL), washed with water
(2 mL) and brine (2 mL), then dried over anhy. Na2SO4. After filtration and
removal under house vacuum, the residue was purified with column
chromatography on silica gel (elution with hexane-ethyl acetate 8:1) to give 232
as a colorless oil (19.3 mg, 76%): IR (neat, cm-1): 2930 (s), 2855 (s), 1462 (m),
1428 (m), 1385 (m), 1261 (m), 1112 (m), 1020 (s), 808 (s), 759 (s), 702 (s); 1H
NMR (300 MHz, CDCl3): δ 7.67-7.63 (m, 4H), 7.44-7.34 (m, 6H), 3.79-3.68 (m,
2H), 3.63 (dd, J=10.1, 4.9Hz, 1H), 3.52 (dd, J=10.1, 4.9Hz, 1H), 3.29 (d,
J=10.1Hz, 1H), 3.14 (d, J=10.1Hz, 1H), 2.90 (d, J=7.9Hz, 1H), 2.21-2.17 (m,
1H), 1.92-1.51 (m, 8H), 1.43 (s, 3H), 1.25-1.18 (m, 2H), 1.04 (s, 9H), 0.96 (d,
J=6.8Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 135.6 (4C), 133.9 (2C), 129.5 (2C),
127.6 (4C), 106.5, 75.6, 71.5, 67.9, 66.0, 60.2, 40.7, 37.2, 32.8, 28.0, 27.9, 26.8
139 (3C), 20.4, 19.3, 16.6, 14.2, 12.9; HR-MS (Electrospray) m/z (M+Na+) calcd
26 657.1867, obsd 657.1861; [α]D +11.3 (c 0.15, CHCl3).
Me TBDPSO O O O O H
236
To a solution of 231 (33.2 mg, 0.0634 mmol) and dry pyridine (0.05 mL)
in CH2Cl2 (1 mL) was added DMP (42 mg, 0.0951 mmol) at ambient temperature
under N2. After 3h of stirring, reaction was stopped by the addition of Na2S2O3
(165 mg) followed by dilution with CH2Cl2 (5 mL). The mixture was stirred
until a clear solution was formed. The mixture was extracted with CH2Cl2 (3x5
mL), and the organic layers were washed with sat. aq. NaHCO3 solution (5 mL)
and brine (5 mL), and dried over anhydrous Na2SO4. After filtration and removal
of organic solvents, the residue was chromatographed on silica gel (elution with
hexane-ethyl acetate 6:1) to give 236 as a colorless oil (26.5 mg, 80%): IR (neat,
cm-1): 2938 (s), 1731 (m), 1427 (m), 1112 (m), 1008 (s), 822 (s), 739 (s), 701 (s);
1 H NMR (300 MHz, CDCl3): δ 8.85 (s, 1H), 7.66-7.63 (m, 4H), 7.45-7.34 (m,
6H), 3.86-3.79 (m, 1H), 3.72-3.66 (m, 1H), 3.61 (dd, J=10.1, 4.9Hz, 1H), 3.52 (dd,
J=10.1, 4.9Hz, 1H), 3.1 (d, J=7.8Hz, 1H), 2.35-2.23 (m, 1H), 1.99-1.50 (m, 8H),
1.41 (s, 3H), 1.26-1.14 (m, 2H), 1.04 (s, 9H), 0.96 (d, J=6.8Hz, 3H); 13C NMR
(75 MHz, CDCl3): δ 199.0, 135.6 (4C), 133.9 (2C), 129.6 (2C), 127.6 (4C), 106.7,
74.4, 71.7, 66.0, 62.5, 61.4, 40.7, 37.3, 32.7, 28.4, 28.0, 26.9 (3C), 20.4, 19.3, 140 12.8, 10.0; HR-MS (Electrospray) m/z (M+Na+) calcd 545.2694, obsd 545.2703;
25 [α]D +20 (c 0.02, CHCl3).
Me TBDPSO O O CH O 3 O O
238
To a solution of 236 (21.2 mg, 0.041 mmol) in CH2Cl2 (1 mL) was added
methoxycarbonylmethylidenetriphenylphosphorane (237) (68 mg, 0.203 mmol) in
one portion at rt under N2. After 24h of stirring at rt, the mixture was
concentrated on a rotary evaporator under house vacuum, and the residue was
chromatographed on silica gel (elution with hexane-ethyl acetate 8:1) to give 238
(20.4 mg, 86%) as a colorless oil: IR (neat, cm-1): 2925 (s), 1729 (S), 1657 (m),
1428 (m), 1308 (m), 1262 (m), 1113 (m), 802 (s), 702 (s); 1H NMR (300 MHz,
CDCl3): δ 7.66-7.63 (m, 4H), 7.45-7.34 (m, 6H), 6.77 (d, J=15.7 Hz, 1H), 6.01 (d,
J=15.7 Hz, 1H), 3.84-3.76 (m, 1H), 3.74 (s, 3H), 3.72-3.68 (m, 1H), 3.62 (dd,
J=10.1, 4.9Hz, 1H), 3.53 (dd, J=10.1, 4.9Hz, 1H), 2.80 (d, J=8.1Hz, 1H), 2.27-
2.18 (m, 1H), 1.94-1.51 (m, 8H), 1.42 (s, 3H), 1.26-1.11 (m, 2H), 1.05 (s, 9H),
0.97 (d, J=6.8Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 166.4, 149.5, 135.6 (4C),
133.9 (2C), 129.5 (2C), 127.6 (4C), 121.2, 106.6, 75.0, 71.6, 66.9, 66.1, 59.1, 51.7,
40.7, 37.3, 32.8, 28.2, 28.0, 26.9 (3C), 20.4, 19.3, 15.3,12.8; HR-MS
141 + 23 (Electrospray) m/z (M+Na ) calcd 601.2956, obsd 601.2946; [α]D +10 (c 0.02,
CHCl3).
N OMs + Br + S S 248 249 251
0 To a stirred, cold (0 C) solution of 247 (10 g, 100 mmol) and Et3N (30.4
g, 300 mmol) in CH2Cl2 (20 mL) was added MsCl (22.9 g, 200 mmol, 15.5 mL).
Color changed instantly from colorless to orange yellow. After 1 h of stirring at
0 0 C, the mixture was diluted with CH2Cl2 (200 mL). The organic layers were
washed with water and brine, dried over anhy. Na2SO4, filtered, and concentrated
in vacuo to give 248 without further purification for the next step.
To a solution of crude 248 in THF (600 mL) was added LiBr (10.44 g, 120
mmol) at rt. The mixture was stirred at rt for 6 days, diluted with water, and
extracted with CH2Cl2 (3x500 mL). The combined organic layers were washed
with water and brine, dried over anhy. Na2SO4, filtered, concentrated in vacuo,
and purified by flash chromatography on silica gel (elution with hexane-ethyl
acetate 4:1) to give 249 for the next step.
To a solution of 2-mercaptobenzothiazole (250) (11.05 g, 66 mmol) in
THF (290 mL) at 0 0C was added NaH (60% in mineral oil, 2.65 g, 66 mmol).
After 10 min of stirring, bromide 249 (9.7 g, 60 mmol) was added into the
mixture dropwise. The reaction mixture was stirred at 0 0C for 30 min and at rt
142 for 24 h. After removal of solvents, the residue was purified by flash
chromatography on silica gel (elution with hexane-ethyl acetate 9:1) to give 251
(12.21g) as a pale yellow oil in 50% yield over three steps: IR (neat, cm-1): 3070
(s), 2934 (s), 1649 (m), 1462 (m), 1374 (s), 1308 (s), 1274 (m), 1077 (s), 995 (s),
1 889 (s), 754(s), 726 (s); H NMR (300 MHz, CDCl3): δ 7.88 (dd, J=6.1, 1.5Hz,
1H), 7.78 (dd, J=6.1, 1.5 Hz, 1H), 7.27 (m, 2H), 4.76 (s, 1H), 4.72 (s, 1H), 3.36-
3.26 (m, 2H), 2.22-2.15 (m, 2H), 1.98(m, 2H), 1.75 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 153.2, 144.3, 135.1, 126.0, 124.1, 121.4, 120.9, 111.0, 99.7, 36.6, 33.0,
27.0, 22.3; HR-MS (Electrospray) m/z (M+Na+) calcd 272.0538, obsd 272.0543.
.
OON N S + S S O S 253 254
Ammonium molybdate (252) (13.1 g, 10.6 mmol) was added to H2O2
(30% aqueous, 18.75 mL) at 0 0C to give a bright yellow solution, which was
added to a solution of 251 (10.55 g, 42.4 mmol) in EtOH (248 mL) at 0 0C.
After 3 days of stirring at rt, the reaction mixture was quenched with Na2SO3 (aq.
1.5M, 250 mL). After removal of solvents, the residue was dissolved in water
(50 mL) and extracted with EtOAc (3x50 mL). The combined organic layers
were dried over anhy. Na2SO4, filtered, concentrated, and purified by flash
chromatography on silica gel (elution with hexane-ethyl acetate 9:1) to give 254
143 (7.23 g) as a colorless oil in 61% yield with 35% of 253 (3.9 g) as a colorless
solid.
254: IR (neat, cm-1): 3072 (s), 2935 (s), 1650 (s), 1554 (s), 1470 (s), 1327 (s),
1 1148 (s); H NMR (300 MHz, CDCl3): δ 8.06 (dd, J=1.5, 6.1Hz, 1H), 7.88 (dd,
J=1.5, 6.1Hz, 1H), 7.47 (m, 2H), 4.63 (s, 1H), 4.56 (s, 1H), 3.39 (m, 2H), 2.03 (m,
2H), 1.90 (m, 2H), 1.53 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 165.3, 152.1,
142.5, 136.1, 127.6, 127.2, 124.7, 122.0, 111.4, 53.4, 35.3, 21.4, 19.5; HR-MS
(Electrospray) m/z (M+Na+) calcd 304.0442, obsd 304.0436.
Anal Cald for C13H15NO2S2: C, 55.49; H, 5.37. Found: C, 55.74; H, 5.23
253: IR (neat, cm-1): 2934 (m), 1473 (m), 1427 (m), 1064 (s); 1H NMR (300
MHz, CDCl3): δ 8.07 (dd, J=1.5, 6.1Hz, 1H), 7.99 (dd, J=1.3, 6.1Hz, 1H), 7.57-
7.43 (m, 2H), 4.76 (s, 1H), 4.68 (s, 1H), 3.32-3.07 (m, 2H), 2.22-2.03 (m, 3H),
1.96-1.78 (m, 1H), 1.67 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 177.5, 153.8,
143.4, 135.9, 126.8, 126.1, 123.8, 122.2, 111.6, 55.7, 36.2, 22.0, 19.2; HR-MS
(Electrospray) m/z (M+Na+) calcd 288.0493, obsd 288.0490.
OH O OH N S O S 255
The ligand (DHQD)2PHAL (28 mg, 0.036 mmol), K3Fe(CN)6 (3.6 g, 10.8
mmol), K2CO3 (1.5 g, 10.8 mmol), and K2OsO2(OH)4 (5.3 mg, 0.0144 mmol) 144 were dissolved in a 1:1 mixture of water and t-BuOH (36 mL totally) at rt to give
a solution with an orange color. The vigorously stirred solution was then cooled
to 0 0C and the sulfone 254 (1 g, 3.6 mmol) was added in one portion. After 11 h
of stirring at 0 0C, the reaction mixture was quenched by adding sodium sulfite
(5.4 g) and then allowed to warm to rt during another 60 min of stirring. The
reaction mixture was extracted with EtOAc (3x50 mL), and the organic layers
were dried over MgSO4, filtered, concentrated in vacuo, and purified by flash
chromatography on silica gel (elution with ethyl acetate) to give 255 (1.08 g) as a
white solid in 96% yield: mp: 94-95 0C; IR (neat, cm-1): 3378 (br), 2921 (m),
1 1468 (m), 1318 (s), 1145 (s); H NMR (300 MHz, CDCl3): δ 8.19-8.16 (m, 1H),
7.99-7.97 (m, 1H), 7.63-7.53 (m, 2H), 4.92-3.58 (m, 2H), 3.41 (d, J=11.1Hz, 1H),
3.35 (d, J=11.1Hz, 1H), 2.86 (br s, 2H), 2.03-1.92 (m, 2H), 1.71-1.51 (m, 2H),
1.09 (s, 3H); 13C NMR (75 MHz, DMSO): δ 166.4, 152.3, 136.3, 128.1, 128.0,
124.9, 123.5, 71.3, 68.8, 54.4, 36.2, 24.3, 16.8; HR-MS (Electrospray) m/z
+ 23.5 (M+Na ) calcd 338.0497, obsd 338.0502; [α]D +3 (c=0.2, CHCl3).
OTs O OH N S O S 256
A solution of TsCl (0.236 g, 1.24 mmol) in dry pyridine (0.8 mL) was
added to a solution of 255 (0.315 g, 1 mmol) in dry pyridine (0.53 mL) at 0 0C
0 under N2. After 0.5h of stirring at 0 C, the mixture was placed in a refrigerator
145 overnight, poured into an ice-water mixture, and extracted with ether (3x5 mL).
The combined organic layers were washed with 4N HCl (5 mL), dried over anhy.
MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography on
silica gel (elution with hexane-ethyl acetate 2:1) to give 256 (0.4 g) as a viscous
colorless oil in 85% yield: IR (neat, cm-1): 3523 (br), 3064 (m), 2975 (s), 1598
(s), 1554 (m), 1471 (s), 1334 (s), 1177 (s), 1097 (s), 1020 (s), 975 (s); 1H NMR
(300 MHz, CDCl3): δ 8.13 (d, J=8.8Hz, 1H), 7.96 (d, J=8.8Hz, 1H), 7.70 (d,
J=8.2Hz, 2H), 7.55 (m, 2H), 7.27 (d, J=8.2Hz, 2H), 3.76 (s, 2H), 3.46 (m, 2H),
2.72 (br s, 1H), 2.37 (s, 3H), 1.89 (m, 2H), 1.58 (m, 2H), 1.09 (s, 3H); 13C NMR
(75 MHz, DMSO): δ 165.3, 152.3, 145.0, 136.4, 131.9, 129.8 (2C), 127.9, 127.6
(2C), 127.5, 125.1, 122.2, 75.6, 70.5, 54.4, 36.0, 23.0, 21.3, 16.4; HR-MS
+ 23.5 (Electrospray) m/z (M+Na ) calcd 492.0585, obsd 492.0592; [α]D +6.7 (c 0.03,
CHCl3).
CN O O OH N O N S + S S O S 258 257
Tosylate 256 (0.292 g, 0.63 mmol) was dissolved in 60% EtOH/H2O (8.4
mL) at 0 0C. KCN (0.2 g, 3.11 mmol) was then added and the mixture was
allowed to warm to rt. After 8 h of stirring at rt, the mixture was concentrated on
a rotary evaporator under house vacuum. Brine (5 mL) was added and the
mixture was extracted with CHCl3 (3x15 mL). The organic layers were dried over 146 anhy. MgSO4, filtered, concentrated in vacuo, and purified by flash
chromatography on silica gel (elution with hexane-ethyl acetate 4:1) to give 258
(0.182 g) as a colorless oil in 69% yield with 30% of 257 as a colorless foam
(0.056 g).
258: IR (neat, cm-1): 3470 (m), 2968 (m), 2927 (m), 2248 (m), 1470 (m), 1316
1 (s), 1145 (vs); H NMR (300 MHz, CDCl3): δ 8.2 (dd, J=1.6, 7.2Hz, 1H), 8.0 (d,
J=1.6, 7.2Hz, 1H), 7.68-7.54 (m, 2H), 3.69-3.50 (m, 2H), 2.52 (s, 1H), 2.51 (s,
1H), 2.45 (br s, 1H), 2.14-1.98 (m, 2H), 1.89-1.71 (m, 2H), 1.36 (s, 3H); 13C
NMR (75 MHz, CDCl3): δ 166.4, 152.5, 136.6, 128.1, 127.7, 125.4, 122.4, 117.3,
70.6, 54.4, 39.1, 31.5, 26.3, 17.0; HR-MS (Electrospray) m/z (M+Na+) calcd
23.5 347.0500, obsd 347.0511; [α]D +0.48 (c 0.46, CHCl3).
Anal Cald for C14H16N2O3S2: C, 51.83; H, 4.97. Found: C, 52.02; H, 4.97.
257: IR (neat, cm-1): 2916 (s), 1472 (s), 1316 (s), 1145 (s); 1H NMR (300 MHz,
CDCl3): δ 8.25-8.15 (m, 1H), 8.07-7.98 (m, 1H), 7.70-7.55 (m, 2H), 3.65-3.40 (m,
2H), 2.60 (d, J=4.8Hz, 1H), 2.57 (d, J=4.8Hz, 1H), 2.10-1.92 (m, 2H), 1.86-1.55
(m, 2H), 1.30 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 165.6, 152.7, 136.7, 128.1,
127.7, 125.5, 122.3, 56.0, 54.4, 53.4, 34.8, 20.6, 18.3; HR-MS (Electrospray) m/z
+ 23.5 (M+Na ) calcd 320.0391, obsd 320.0388; [α]D +0.86 (c 0.35, CHCl3).
147 CN O OMOM N S O S 242
0 To a solution of 258 (45.5 mg, 0.14 mmol) in CH2Cl2 (5 mL) at 0 C were
added dry iPrNEt2 (0.074 mL), a cat. amount of Bu4NI, and MOMCl (28 mg, 0.35
mmol, 0.03 mL). The mixture was stirred at 0 0C for 1 h, then at rt for 10 h,
concentrated under house vacuum and purified by flash chromatography on silica
gel (elution with hexane-ethyl acetate 4:1) to give 242 (13.2 mg) as a colorless oil
in an adjusted 74% yield with recovered 258 (28 mg): IR (neat, cm-1): 2933 (m),
1 2248 (w), 1471 (s), 1316 (s), 1146 (s), 1028 (s); H NMR (300 MHz, CDCl3): δ
8.17-8.14 (m, 1H), 7.99-7.96 (m, 1H), 7.63-7.53 (m, 2H), 4.68 (d, J=7.9Hz, 1H),
4.60 (d, J=7.9Hz, 1H), 3.54-3.49 (m, 2H), 3.30 (s, 3H), 2.57 (s, 2H), 2.01-1.67 (m,
4H), 1.32 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 165.6, 152.6, 136.7, 128.1,
127.7, 125.4, 122.4, 117.1, 91.3, 75.3, 56.0, 54.5, 37.9, 29.7, 22.7, 16.8; HR-MS
+ 21 (Electrospray) m/z (M+Na ) calcd 391.0757, obsd 391.0755; [α]D +0.9 (c 0.23,
CHCl3).
O
O O OMe
261
148 115 To a solution of triol 259 (5.36 g, 40 mmol) in CH2Cl2 (150 mL) were
added 2,2-dimethoxypropane (200 mL) and camphorsulfonic acid (1.05 g, 4.5
mmol) at rt. The reaction mixture was stirred overnight, diluted with CH2Cl2
(300 mL), and washed with sat. aq. NaHCO3 (100 mL). The organic layer was
dried over anhy. Na2SO4, filtered, and concentrated under house vacuum. The
residue was purified by column chromatography on silica gel (elution with
hexane-ethyl acetate 1:1) to give 261 (7.22 g, 75%) as a colorless oil along with
260 (1.95 g, 25%): IR (neat, cm-1): 2935 (s), 2869 (s), 1458 (s), 1377 (s), 1246
1 (m), 1212 (m), 1060 (m); H NMR (300 MHz, CDCl3): δ 3.62 (d, J=9.1Hz, 1H),
3.52 (d, J=9.1Hz, 1H), 3.27-3.16 (m, 2H), 3.00 (s, 3H), 1.57-1.30 (m, 4H), 1.19 (s,
3H), 1.17 (s, 3H), 1.15 (s, 3H), 1.15 (s, 3H), 1.11 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 109.0, 81.0, 74.4, 60.8, 48.4, 36.6, 30.8, 27.1, 27.0, 25.2, 25.1, 25.0,
+ 23 24.6; HR-MS (Electrospray) m/z (M+Na ) calcd 269.1723, obsd 269.1736; [α]D
+0.45 (c 0.3, CHCl3).
OTBS O OH N S O S
265
To a solution of 255 (0.5 g, 1.6 mmol), Et3N (0.26 mL, 1.9 mmol), and
DMAP (7.3 mg, 0.0 6mmol) in CH2Cl2 (10 mL) was added TBSCl (0.264 g, 1.75
149 0 mmol) at 0 C under N2. The mixture was stirred at rt for 24h, concentrated, and
chromatographed on silica gel (elution with ethyl acetate) to give 265 (0.335g) as
a colorless oil in an adjusted 72% yield with the recovery of 255 (0.16 g): IR
(neat, cm-1): 3375 (m), 2925 (m), 1472 (m), 1337 (s), 1147 (s), 1112 (s); 1H
NMR (400 MHz, CDCl3): δ 8.23-8.20 (m, 1H), 8.03-8.00 (m, 1H), 7.66-7.57 (m,
2H), 3.64-3.49 (m, 2H), 3.38 (d, J=9.5Hz, 1H), 3.35 (d, J=9.5Hz, 1H), 2.31 (s,
1H), 2.05-1.95 (m, 2H), 1.68-1.50 (m, 2H), 1.1 (s, 3H), 0.87 (s, 9H), 0.03 (s, 3H),
0.02 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 165.8, 152.7, 136.8, 127.9, 127.6,
125.5, 122.3, 71.9, 70.1, 55.4, 36.7, 25.8 (3C), 23.0, 18.2, 17.2, -5.5 (2C); HR-MS
+ 21 (Electrospray) m/z (M+Na ) calcd 452.1357, obsd 452.1356; [α]D +1.8 (c 0.17,
CHCl3).
OTBS O OMOM N S O S
266
To a solution of 265 (0.335 g, 0.78 mmol) in CH2Cl2 (2 mL) were added
i-Pr2NEt (1.08 mL, 6.17 mmol), and MOMCl (0.3 mL, 3.9 mmol) in sequence at
0 0 C under N2. The reaction mixture was allowed to warm to rt, stirred for 17h,
concentrated, and purified by column chromatography (elution with hexane-ethyl
acetate 4:1) to give 266 (0.351g, 95%) as a colorless oil: IR (neat, cm-1): 2926 (s),
150 2856 (s), 1555 (m), 1470 (s), 1335 (s), 1251 (s), 1144 (s), 1036 (s); 1H NMR (300
MHz, CDCl3): δ 8.13-8.10 (m, 1H), 7.95-7.92 (m, 1H), 7.58-7.47 (m, 2H), 4.61 (s,
2H), 3.48 (d, J=8.4Hz, 1H), 3.46 (d, J=8.2Hz, 1H), 3.43-3.33 (m, 2H), 3.19 (s,
3H), 1.96-1.82 (m, 2H), 1.69-1.50 (m, 2H), 1.1 (s, 3H), 0.76 (s, 9H), -0.08 (s, 3H),
-0.10 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 165.7, 152.5, 136.5, 127.7, 127.4,
125.1, 122.1, 90.9, 77.7, 67.7, 55.1, 54.9, 35.0, 25.5 (3C), 20.7, 17.8, 16.6, -5.9
+ 21 (2C); HR-MS (Electrospray) m/z (M+Na ) calcd 496.1618, obsd 496.1622; [α]D
+1.52 (c 0.46, CHCl3).
OH
OH OBn
269
To a 250-mL round-bottomed flask were added t-BuOH (28 mL), H2O (28
mL), (DHQD)2PHAL (41.3 mg, 0.053 mmol), K2OsO2(OH)4 (7.8 mg, 0.021
mmol), K3Fe(CN)6 (5.2 g, 15.78 mmol), and K2CO3 (2.18 g, 15.78 mmol) in
sequence at rt. After vigorous stirring, the mixture had become a clear solution
before it was cooled to 0 0C and olefin 268 (1 g, 5.26 mmol) was added in one
portion. After overnight stirring at 0 0C, the reaction mixture was quenched with
sodium sulfite (7.89 g) at 0 0C, allowed to warm to rt, stirred for 1h at rt, and
extracted with dichloromethane (3x30 mL). The organic layers were dried over
anhydrous MgSO4, filtered, evaporated under house vacuum, and purified by
151 flash chromatography on silica gel (elution with ethyl acetate) to give 269 (1.0 g,
85%, 95% ee) as a colorless oil: IR (neat, cm-1): 3409 (br); 1H NMR (300 MHz,
CDCl3): δ 7.36-7.25 (m, 5H), 4.5 (s, 2H), 3.50-3.46 (m, 2H), 3.42-3.32 (m, 2H),
3.08 (br s, 2H), 1.74-1.62 (m, 2H), 1.59-1.52 (m, 2H), 1.12 (s, 3H); 13C NMR (75
MHz, CDCl3): δ 137.9, 128.3 (2C), 127.7 (2C), 127.6, 72.9, 72.4, 70.7, 69.6, 35.3,
23.9, 23.1; HR-MS (Electrospray) m/z (M+Na+) calcd 247.1305, obsd 247.1289;
25 [α]D +1.5 (c 0.67, CHCl3).
OTBS
OH OBn
270
To a mixture of diol 269 (0.71 g, 3.2 mmol), Et3N (0.39 g, 0.54 mL, 3.84
mmol), DMAP (15.6 mg, 0.13 mmol) in dichloromethane (20 mL) at 0 0C was
added TBSCl (0.53 g, 3.52 mmol). The mixture was stirred at rt for 12h,
concentrated, and purified by flash chromatography on silica gel (elution with
ethyl acetate) to give 270 (0.87 g, 80%) as a colorless oil: IR (neat, cm-1): 3450
1 (br), 2953 (m), 1462 (m), 1254 (m), 1097 (s); H NMR (400 MHz, CDCl3): δ
7.30-7.18 (m, 5H), 4.48 (s, 2H), 3.48-3.36 (m, 2H), 3.36 (d, J=9.6Hz, 1H), 3.32 (d,
J=9.6Hz, 1H), 2.40 (br s, 1H), 1.75-1.38 (m, 4H), 1.09 (s, 3H), 0.95 (s, 9H), 0.00
(s, 6H); 13C NMR (100 MHz, CDCl3): δ 138.5, 128.3 (2C), 127.6 (2C), 127.5,
72.8, 72.1, 70.9, 70.2, 35.2, 25.9 (3C), 24.2, 23.2, 18.3, -5.5 (2C); HR-MS
152 + 26 (Electrospray) m/z (M+Na ) calcd 361.2169, obsd 361.2151; [α]D +0.83 (c 0.36,
CHCl3).
OTBS
OMOM OBn
271
To a solution of 270 (0.87 g, 2.6 mmol) in dichloromethane (2 mL) at 0 0C
were added iPr2NEt (2.67 g, 3.6 mL, 20.54 mmol) and MOMCl (1.05 g, 0.99 mL,
13 mmol) in sequence. The mixture was stirred, allowed to warm gradually to rt
over 6h, concentrated, and purified by flash chromatography on silica gel (elution
with hexane-ethyl acetate 4:1) to give 271 (0.878 g, 88%) as a colorless oil: IR
(neat, cm-1): 2954 (s), 2856 (s), 1471 (m), 1361 (m), 1252 (m), 1146 (s), 1102 (s),
1 1039 (s); H NMR (300 MHz, CDCl3): δ 7.34-7.25 (m, 5H), 4.75 (s, 2H), 4.51 (s,
2H), 3.57-3.46 (m, 4H), 3.36 (s, 3H), 1.74-1.58 (m, 4H), 1.22 (s, 3H), 0.92 (s, 9H),
0.07 (s, 6H); 13C NMR (75 MHz, CDCl3): δ 138.6, 128.1 (2C), 127.4 (2C), 127.2,
91.1, 78.1, 72.6, 70.7, 68.4, 55.0, 33.0, 25.7 (3C), 23.7, 21.0, 18.0, -5.7 (2C); HR-
+ 25 MS (Electrospray) m/z (M+Na ) calcd 405.2431, obsd 405.2420; [α]D –1.27 (c
0.63, CHCl3).
153 OTBS
OMOM OH
272
A 50mL round-bottomed flask was charged with Pd/C (10%, 136 mg) and
a solution of 271 (0.8 g, 2.1 mmol) in degassed EtOH (95%, 11.5 mL) under a N2.
The reaction system was evacuated and refilled with hydrogen from a balloon full
of hydrogen. The reaction mixture was stirred at rt for 10h under H2, filtered,
concentrated, and purified by flash chromatography on silica gel (elution with
hexane-ethyl acetate 9:1) to give 272 (0.58 g, 95%) as a colorless oil: IR (neat,
cm-1): 3417 (s), 2952 (s), 2858 (s), 1471 (s), 1253 (s), 1145 (s), 1107 (s), 1044 (s);
1 H NMR (300 MHz, CDCl3): δ 4.68 (s, 2H), 3.55-3.52 (m, 2H), 3.48-3.39 (m,
2H), 3.28 (s, 3H), 2.67 (br s, 1H), 1.57-1.49 (m, 4H), 1.13 (s, 3H), 0.82 (s, 9H), -
0.03 (s, 6H); 13C NMR (75 MHz, CDCl3): δ 91.1, 78.3, 68.3, 62.9, 55.1, 32.7,
26.5, 25.7 (3C), 20.9, 18.0, -5.7 (2C); HR-MS (Electrospray) m/z (M+Na+) calcd
25 315.1962, obsd 315.1964; [α]D –1.12 (c 2.77, CHCl3).
OTBS O OMOM S Ph O 274
154 A mixture of 272 (0.57 g, 1.95 mmol), (PhS)2 (0.64 g, 2.93 mmol), n-Bu3P
(0.73 mL, 2.93 mmol) and DMF (1.5 mL) was stirred overnight at rt under N2.
After the addition of EtOH (95%, 20 mL) and aq. NaOH (1N, 8 mL), the mixture
was stirred for 20 min at rt and NaOH (0.5N, 80 mL) was added. The mixture
was extracted with CH2Cl2 (3x50 mL), and the combined organic layers were
dried over anhydrous MgSO4. After filtration and removal of solvents under
vacuum, the residual 273 was used directly in the next step without further
purification.
To a solution of 273 in CH2Cl2 (25 mL) was added NaHCO3 (0.98 g, 11.7
0 mmol) and MCPBA (1.0 g, 5.8 mmol) at 0 C under N2. After 4h of stirring at 0
0 C, the reaction mixture was treated with aq. Na2S2O3 solution (10%, 30 mL),
stirred for 20 min, and extracted with CH2Cl2 (3x30 mL). The combined organic
layers were washed with sat. aq. NaHCO3 solution (25 mL) and dried over
anhydrous MgSO4. After filtration and concentration, the residue was
chromatographed on silica gel (elution with hexane-ethyl acetate 4:1) to give 274
(0.608 g, 75% over two steps) as a colorless oil: IR (neat, cm-1): 3066 (s), 2926
(s), 1470 (s), 1404 (s), 1362 (s), 1304 (s), 1251 (s), 1144 (s); 1H NMR (300 MHz,
CDCl3): δ 7.81-7.78 (m, 2H), 7.55-7.49 (m, 1H), 7.46-7.41 (m, 2H), 4.55 (s, 2H),
3.37-3.27 (m, 2H), 3.14 (s, 3H), 3.02-2.97 (m, 2H), 1.74-1.61 (m, 2H), 1.55-1.39
(m, 2H), 1.04 (s, 3H), 0.74 (s, 9H), -0.10 (s, 6H); 13C NMR (75 MHz, CDCl3):
δ 139.0, 133.2, 128.9 (2C), 127.7 (2C), 90.8, 77.6, 67.7, 56.3, 54.9, 34.9, 25.5
(3C), 20.6, 17.8, 16.8, -5.9 (2C); HR-MS (Electrospray) m/z (M+Na+) calcd
22 439.1945, obsd 439.1926; [α]D +1.2 (c 0.65, CHCl3). 155
OTBS OTBS O N N N N OMOM S OMOM S N + N N O N Ph Ph 276 277
To a stirred solution of alcohol 272 (1 g, 3.42 mmol) in dry THF (15 mL)
was added PPh3 (4.49 g, 17.1 mmol) and 275 (2.74 g, 15.4 mmol) in sequence at
rt. After 12h of stirring, the mixture was concentrated under house vacuum.
The residue was dissolved in ether (50 mL), kept overnight, filtered, concentrated,
and purified by flash chromatography on silica gel (elution with hexane-ethyl
acetate 6:1) to give sulfide 276 (1.41g, 91.2%) which was used without further
purification in the next step.
To a solution of sulfide 276 (0.91 g, 2.01 mmol) in dichloromethane (30
mL) at 0 0C were added sodium bicarbonate (1.01 g, 12.08 mmol) and MCPBA
(1.04 g, 6.04 mmol). The reaction mixture was stirred overnight and treated
with 10% aqueous Na2S2O3 solution (60 mL). After 30 min of stirring at rt, the
mixture was extracted with dichloromethane (3x30 mL). The combined organic
layers were washed with sat. aq. NaHCO3 solution (50 mL), dried over MgSO4,
filtered, concentrated, and purified with flash chromatography on silica gel
(elution with hexane-ethyl acetate 4:1) to give 277 (0.785g, 81%) as a colorless
oil: IR (neat, cm-1): 2954 (s), 2857 (s), 1498 (s), 1463 (s), 1344 (s), 1152 (s),
1 1102 (s), 1039 (s); H NMR (300 MHz, CDCl3): δ 7.67-7.51 (m, 5H), 4.68 (s,
156 2H), 3.75-3.70 (m, 2H), 3.53-3.31 (m, 2H), 3.30 (s, 3H), 2.07-2.00 (m, 2H), 1.79-
1.58 (m, 2H), 1.17 (s, 3H), 0.85 (s, 9H), 0.00 (s, 6H); 13C NMR (75 MHz,
CDCl3): δ 153.4, 133.0, 131.3, 129.6 (2C), 125.0 (2C), 91.2, 77.9, 67.9, 56.4, 55.4,
35.1, 25.7 (3C), 20.9, 18.0, 16.5, -5.7 (2C); HR-MS (Electrospray) m/z (M+Na+)
25 calcd 507.2067, obsd 507.2044; [α]D –3.33 (c 0.42, CHCl3).
OTBS OMOM
O O 267
To a solution of 277 (328 mg, 0.68 mmol) in dry DME (2 mL) at –60 0C
was added NaHMDS (1M in THF, 0.75 mmol, 0.75 mL) dropwise. The mixture
was stirred for 30 min at the same temperature before the addition of aldehyde
243 (162.3 mg, 0.94 mmol). The reaction mixture was stirred for 3h at –60 0C,
allowed to slowly warm to rt, quenched by the addition of water (2.5 mL), and
extracted with ether (3x5 mL). The combined organic layers were dried over
Na2SO4, filtered, and purified by flash chromatography on silica gel (elution with
hexane-ethyl acetate (elution with hexane-ethyl acetate 4:1) to give 267 (0.28 g,
E/Z=4:1, 96%) as a colorless oil: IR (neat, cm-1): 2932 (s), 2858 (s), 1471 (s),
1368 (s), 1251 (s), 1212 (s), 1146 (s), 1107 (s), 1041 (s); 1H NMR (300 MHz,
CDCl3): δ 5.39-5.36 (m, 2H), 4.69 (s, 2H), 3.73 (d, J=8.3Hz, 1H), 3.63 (d,
157 J=8.3Hz, 1H), 3.47 (d, J=9.9Hz, 1H), 3.40 (d, J=9.9Hz, 1H), 3.31 (s, 3H), 2.05-
1.95 (m, 4H), 1.61-1.48 (m, 4H), 1.34 (s, 3H), 1.33 (s, 3H), 1.22 (s, 3H), 1.14 (s,
3H), 0.85 (s, 9H), 0.00 (s, 6H); 13C NMR (75 MHz, CDCl3): δ 130.5, 129.6,
108.9, 91.2, 81.0, 78.3, 73.9, 68.3, 55.2, 39.8, 36.4, 27.5, 27.2, 26.5, 25.8 (3C),
24.8, 22.3, 21.2, 18.1, -5.6 (2C); HR-MS (Electrospray) m/z (M+Na+) calcd
453.3007, obsd 453.3007.
OH OMOM
O O 278
To a solution of 267 (0.27 g, 0.63 mmol) in THF (1.26 mL) at 0 0C was
added TBAF (1M in THF, 1.26 mL, 1.26 mmol) dropwise. The reaction mixture
was allowed to warm to rt immediately, stirred for 5h at rt, treated with water (2
mL), extracted with ether (3x5 mL), washed with brine (5 mL), dried over K2CO3,
filtered, and purified by flash chromatography on silica gel (elution with hexane-
ethyl acetate 4:1) to give 278 (0.199 g, E/Z=4:1, 100%) as a colorless oil: IR
(neat, cm-1): 3477 (br), 2982 (s), 2933 (s), 1454 (s), 1372 (s), 1248 (s), 1213 (m),
1 1143 (m), 1036 (m); H NMR (300 MHz, CDCl3): δ 5.39-5.37 (m, 2H), 4.54 (d,
J=7.4Hz, 1H), 4.50 (d, J=7.4Hz, 1H), 3.58 (d, J=8.2Hz, 1H), 3.48 (d, J=8.2Hz,
1H), 3.43 (d, J=11.9Hz, 1H), 3.37 (d, J=11.9Hz, 1H), 3.12 (br s, 1H), 3.11 (s, 3H),
158 2.13-1.96 (m, 4H), 1.69-1.38 (m, 4H), 1.34 (s, 3H), 1.33 (s, 3H), 1.11 (s, 3H),
1.08 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 130.5, 130.3, 109.1, 91.0, 80.9, 79.2,
74.2, 68.4, 55.1, 40.2, 36.6, 27.9, 27.5, 27.4, 26.9, 24.9, 20.4; HR-MS
(Electrospray) m/z (M+Na+) calcd 339.2142, obsd 339.2159.
OPiv OMOM
O O 279
To a solution of 278 (0.199 g, 0.63 mmol) in dry pyridine (10 mL) were
added DMAP (0.085 g, 0.7 mmol) and pivaloyl chloride (0.4 mL, 3.15 mmol) in
sequence at rt. After 3 h of stirring at rt, the reaction mixture was diluted with
ether (30 mL), and washed with water (15 mL) and brine (15 mL). The organic
layer was dried over anhy. Na2SO4, filtered, and concentrated under house
vacuum. The residue was purified by column chromatography on silica gel
(elution with hexane-ethyl acetate 4:1) to give 279 (0.2 g, 80%) as a colorless oil:
IR (neat, cm-1): 2984 (s), 2928 (s), 2871 (s), 1729 (s), 1480 (s), 1457 (s), 1395
(m), 1373 (s), 1282 (s), 1254 (m), 1214 (m), 1152 (s), 1033 (s); 1H NMR (300
MHz, CDCl3): δ 5.41-5.39 (m, 2H), 4.70 (s, 2H), 4.10 (d, J=7.4Hz, 1H), 3.95 (d,
J=7.4Hz, 1H), 3.76 (d, J=8.1Hz, 1H), 3.65 (d, J=8.1Hz, 1H), 3.35 (s, 3H), 2.21-
1.88 (m, 4H), 1.70-1.48 (m, 4H), 1.37 (s, 3H), 1.36 (s, 3H), 1.25 (s, 3H), 1.22 (s,
159 3H), 1.20 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 178.1, 130.1, 129.9, 91.2, 81.0,
73.9, 68.6, 55.4, 39.8, 38.8, 37.1, 27.6, 27.2, 27.1 (3C), 26.5, 24.8, 21.2, 21.1;
HR-MS (Electrospray) m/z (M+Na+) calcd 423.2717, obsd 423.2719.
OPiv OMOM
OH OH 280
To 279 (30 mg, 0.075 mmol) was added 80% aq. AcOH (10 mL). The
0 reaction mixture was stirred at 55 C for 40 min, cooled to rt, diluted with CH2Cl2
(20 mL), washed with sat. aq. NaHCO3 solution (6x10 mL) and water (10 mL),
and dried over anhy. Na2SO4. After flitration and removal of solvents, the
residue was purified by column chromatography on silica gel elution with hexane-
ethyl acetate 2:1) to give 280 (23 mg, 85%) as a colorless oil: IR (neat, cm-1):
3416 (br), 2970 (s), 1731 (s), 1480 (m), 1462 (m), 1397 (m), 1367 (m), 1285 (m),
1 1147 (m), 1040 (m); H NMR (300 MHz, C6D6): δ 5.49-5.44 (m, 2H), 4.62 (s,
2H), 4.13 (d, J=11.4Hz, 1H), 4.06 (d, J=11.5Hz, 1H), 3.43 (d, J=10.7Hz, 1H),
3.37 (d, J=10.7Hz, 1H), 3.21 (s, 3H), 2.22-2.03 (m, 4H), 1.70-1.48 (m, 4H), 1.17
(s, 9H), 1.14 (s, 3H), 1.13 (s, 3H); 13C NMR (75 MHz, C6D6): δ 177.6, 130.9,
130.3, 100.1, 91.3, 76.8, 72.8, 69.9, 68.9, 55.2, 38.8, 37.5, 27.3 (3C), 26.9, 23.4,
22.1, 21.2; HR-MS (Electrospray) m/z (M+Na+) calcd 383.2404, obsd 383.2416.
160
OPiv OMOM
O
281
To a solution of 280 (0.14 g, 0.39 mmol) in dry benzene (10 mL) were
added TsCl (89 mg, 0.47 mmol) and NaH (75 mg of 60% in mineral oil) in
sequence at rt. The reaction mixture was stirred overnight, quenched with water
(2.5 mL), and extracted with ether (3x15 mL). The combined organic layers
were washed with water (10 mL) and dried over anhy. Na2SO4. After filtration
and removal of solvents under house vacuum, the residue was purified by column
chromatography on silica gel (elution with hexane-ethyl acetate 1:1) to give 281
(0.12 g, 90%) as a colorless oil: IR (neat, cm-1): 2972 (s), 1731 (s), 1480 (m),
1462 (m), 1397 (m), 1368 (m), 1284 (m), 1145 (m), 1089 (m), 1036 (m); 1H
NMR (300 MHz, C6D6): δ 5.39-5.36 (m, 2H), 4.62 (s, 2H), 4.15 (d, J=11.4Hz,
1H), 4.07 (d, J=11.5Hz, 1H), 3.19 (s, 3H), 2.30 (d, J=4.9Hz, 1H), 2.22 (d,
J=4.9Hz, 1H), 2.15-1.98 (m, 4H), 1.67-1.43 (m, 4H), 1.18 (s, 9H), 1.11 (s, 3H),
1.10 (s, 3H); 13C NMR (75 MHz, C6D6): δ 177.3, 130.7, 129.9, 91.3, 76.7, 68.7,
55.9, 55.2, 53.1, 38.8, 37.5, 36.9, 28.6, 27.3 (3C), 26.9, 21.2, 21.0; HR-MS
(Electrospray) m/z (M+Na+) calcd 365.2298, obsd 365.2326.
161 OPiv OH OMOM
OH O
282
To a 5-mL round-bottomed flask were added t-BuOH (0.2 mL), H2O (0.2
mL), (DHQD)2PhAL (6.4 mg, 0.008 mmol), K2OsO2(OH)4 (2.4 mg, 0.006 mmol),
K3Fe(CN)6 (33 mg, 0.1 mmol), K2CO3 (13.8 mg, 0.1 mmol) in sequence at rt.
After vigorous stirring, the mixture became clear before it was cooled to 0 0C and
olefin 268 (11.2 mg, 0.033 mmol) in THF (0.2 mL) was added in one portion.
After overnight stirring at 0 0C, the reaction mixture was quenched with sodium
sulfite (49.5 mg) at 0 0C, allowed to warm to rt, stirred for 1h, and extracted with
dichloromethane (3x2 mL). The organic layers were dried over anhydrous
MgSO4, filtered, evaporated under house vacuum to give 282 which was used
without further purification in the next step.
OH
MOMO H OPiv O
283 OH
To a solution of 282 (14.4 mg, 0.038 mmol) in CH2Cl2 (10 mL) was added
AcOH (0.57 mg, 0.0095 mmol) at -20 0C. The reaction mixture was allowed to
warm to rt gradually during 4 h, washed with sat. aq. NaHCO3 solution (5 mL)
162 and brine (5 mL), and dried over anhy. Na2SO4. After filtration and removal of
solvents, the residue was purified by column chromatography on silica gel
(elution with ethyl acetate) to give 283 (5.7 mg, 40%) as a colorless oil: IR (neat,
-1 1 cm ): 3427 (s), 2964 (s), 1729 (s); H NMR (500 MHz, CDCl3): δ 4.87-4.75 (m,
2H), 4.15-3.98 (m, 2H), 3.98-3.90 (m, 1H), 3.62-3.53 (m, 1H), 3.48-3.38 (m, 2H),
3.35 (s, 3H), 3.27-2.42 (br m, 2H), 2.21-2.06 (m, 1H), 2.06-1.95 (m, 1H), 1.95-
1.78 (m, 2H), 1.76-1.48 (m, 4H), 1.26 (s, 3H), 1.22 (s, 9H), 1.18 (s, 3H); 13C
NMR (75 MHz, CDCl3): δ 178.2, 91.2, 83.9, 82.0, 74.5, 69.3, 68.4, 55.6, 38.9,
33.6, 33.1, 29.1, 28.0, 27.2 (3C), 23.9, 21.3, 21.1; HR-MS (Electrospray) m/z
(M+Na+) calcd 399.2353, obsd 399.2330.
O H O OH O OMe OMOM OMOM OMOM ++ O O O O O O
286 288 289
To a solution of 278 (180 mg, 0.57 mmol) in CH2Cl2 (10 mL) was added
the Dess-Martin reagent (290 mg, 0.68 mmol) at rt. The reaction mixture was
stirred for 2 h at rt before the addition of aq. sat. NaHCO3 solution (20 mL) and
solid Na2S2O3 (1 g). The mixture was diluted with CH2Cl2 (20 mL), stirred until
a clear solution had formed, extracted with CH2Cl2 (3x20 mL), washed with aq.
163 sat. NaHCO3 solution (20 mL) and brine (20 mL) , dried over anhydrous Na2SO4,
filtered, and concentrated under vacuum to give 286, which was used without
further purification in the next step.
Aldehyde 286 from above was mixed with t-BuOH (20.4 ml), aq. sat.
monobasic sodium phosphate (2.87 ml), 2-methyl-2-butene (287) (0.574 mL) and
sodium chlorite (0.082 g). The mixture was stirred at rt for 3.5 h and extracted
with a mixture of hexanes/ethyl acetate (1:1) (3x40 mL). The organic layers
were combined and dried over anhydrous Na2SO4. After removal of solvents, the
residual 288 was used directly in the next step.
Acid 288 from the previous step was dissolved in ether (25 mL) at rt and
treated with freshly prepared CH2N2 in ether. After reaction was complete
(checked by TLC), reaction mixture was quenched with AcOH (1 mL),
neutralized with NaHCO3, dried over Na2SO4, and concentrated under vacuum to
give 289 (170 mg, 0.49 mmol) in 87% yield over three steps as a colorless oil:
IR (neat, cm-1): 2985 (s), 2933 (s), 1743 (s), 1454 (m), 1377 (m), 1247 (m), 1211
1 (m), 1147 (m), 1115 (m), 1059 (m), 1035 (m); H NMR (300 MHz, C6D6): δ
5.41-5.37 (m, 2H), 4.76 (d, J=7.6Hz, 1H), 4.74 (d, J=7.6Hz, 1H), 3.57 (d,
J=8.2Hz, 1H), 3.47 (d, J=8.2Hz, 1H), 3.34 (s, 3H), 3.22 (s, 3H), 2.20-2.04 (m,
4H), 2.02-1.87 (m, 4H), 1.46 (s, 3H), 1.38 (s, 3H), 1.37 (s, 3H), 1.11 (s, 3H); 13C
NMR (75 MHz, C6D6): δ 174.2, 130.8, 129.6, 109.0, 93.0, 80.8, 79.5, 74.2, 55.6,
51.4, 40.1, 39.7, 27.9, 27.5, 27.3, 27.2, 24.8, 21.9; HR-MS (Electrospray) m/z
(M+Na+) calcd 367.2091, obsd 367.2070.
164
O OMe OMOM
OH OH 290
A sample of 289 (54.8 mg, 0.16 mmol) was treated with 80% aq. AcOH
(18 mL) and stirred at rt for 6.5 h. The solution was neutralized with aq. sat.
NaHCO3 and extracted with CH2Cl2 (6x20 mL). The organic layers were washed
with aq. sat. NaHCO3 (30 mL), dried over anhy. Na2SO4, and concentrated under
house vacuum. The residue was purified by column chromatography on silica
gel (elution with ethyl acetate) to give 290 (36mg, 0.12mmol) in 75% yield as a
colorless oil: IR (neat, cm-1): 3418 (m), 2930 (s), 1738 (s), 1454 (m); 1H NMR
(300 MHz, CDCl3): δ 5.51-5.38 (m, 2H), 4.78 (d, J=7.6Hz, 1H), 4.75 (d, J=7.6Hz,
1H), 3.76 (d, J=8.2Hz, 1H), 3.74 (d, J=8.2Hz, 1H), 3.40 (s, 3H), 3.38 (s, 3H), 2.2-
1.95 (m, 5H), 1.95-1.68 (m, 5H), 1.49 (s, 3H), 1.18 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 174.7, 130.5, 129.6, 92.6, 79.5, 72.9, 69.8, 55.9, 52.1, 45.1, 38.9, 38.2,
26.9, 23.3, 21.6; HR-MS (Electrospray) m/z (M+Na+) calcd 327.1778, obsd
327.1765.
O OMe OMOM
OH OMs 291
165
To a solution of 290 (20 mg, 0.07 mmol) in CH2Cl2 (1 mL) were added
0 Et3N (11 µL) and MsCl (5.1 µL) in sequence at -10 C. After 40 min of stirring,
the reaction mixture was diluted with CH2Cl2 (5 mL) and washed with ice-cold
water (2 mL). The organic layer was dried over anhy. Na2SO4, and concentrated
under house vacuum. The residue of 291 was used directly in the next step
without further purification.
O OMe OMOM
O
292
A solution of crude 291 (23.2 mg, 0.061 mmol) in CH2Cl2 (1.5 mL) was
treated with DBU (9.2 µL, 0.061 mmol) at rt. After 2 h of stirring at rt, the
reaction mixture was diluted with CH2Cl2 (5 mL), washed with brine (2 mL).
The organic layer was dried over anhy. Na2SO4, and concentrated under house
vacuum. The residue was purified by column chromatography on silica gel
(elution with hexane-ethyl acetate 2:1) to give 292 (14 mg, 70% over two steps)
as a colorless oil: IR (neat, cm-1): 2919 (s), 1739 (s), 1454 (m); 1H NMR (300
MHz, CDCl3): δ 5.39-5.36 (m, 2H), 4.75 (s, 2H), 3.35 (s, 3H), 3.24 (s, 3H), 2.31
(d, J=4.9Hz, 1H), 2.21 (d, J=4.9Hz, 1H), 2.20-2.05 (m, 4H), 2.05-1.84 (m, 4H),
1.45 (s, 3H), 1.08 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 179.8, 130.2, 129.9,
166 93.0, 79.5, 55.6, 53.1, 51.4, 39.7, 36.8, 30.4, 28.6, 27.2, 22.0, 21.0; HR-MS
(Electrospray) m/z (M+Na+) calcd 309.1672, obsd 309.1662.
167
APPENDIX
168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231
232
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