The Pennsylvania State University
The Graduate School
Eberly College of Science
PROGRESS TOWARD A TOTAL SYNTHESIS OF
THE LYCOPODIUM ALKALOID LYCOPLADINE H
A Dissertation in
Chemistry
by
Joshua R. Sacher
© 2012 Joshua R. Sacher
Submitted in Partial Fulfillment of the Requirements for the Degree of
Doctor of Philosophy
May 2012
ii The dissertation of Joshua Sacher was reviewed and approved* by the following:
Steven M. Weinreb Russell and Mildred Marker Professor of Natural Products Chemistry Dissertation Advisor Chair of Committee
Raymond L. Funk Professor of Chemistry
Gong Chen Assistant Professor of Chemistry
Ryan J. Elias Frederik Sr. and Faith E. Rasmussen Career Development Professor of Food Science
Barbara Garrison Shapiro Professor of Chemistry Head of the Department of Chemistry
*Signatures are on file in the Graduate School
iii ABSTRACT
In work directed toward a total synthesis of the Lycopodium alkaloid lycopladine H
(21), several strategies have been explored based on key tandem oxidative dearomatization/Diels-Alder reactions of o-quinone ketals. Both intra- and intermolecular approaches were examined, with the greatest success coming from dearomatization of bromophenol 84b followed by cycloaddition of the resulting dienone with nitroethylene to provide the bicyclo[2.2.2]octane core 203 of the natural product.
The C-5 center was established via a stereoselective Henry reaction with formaldehyde to form 228, and the C-12 center was set through addition of vinyl cerium to the C-12 ketone to give 272. A novel intramolecular hydroaminomethylation of vinyl amine 272 was used to construct the 8-membered azocane ring in intermediate 322, resulting in establishment of 3 of the 4 rings present in the natural product 21 in 9 steps from known readily available compounds.
OH MeO OMe MeO OMe 1) PhI(OAc)2 OMe MeOH O OH Br Br 2) O2N NO2 5 Br 99% NO2 HO 84b 203 228
12 OH OH OTBDPS OTBDPS Br [Rh(cod)Cl]2, Xantphos Br H2N HN CO (10 bar), H2 (40 Bar) PhMe, HFIPA TBDPSO 135 °C, 18 h TBDPSO 322 272 75%
OH O N
O lycopladine H (21)
iv TABLE OF CONTENTS
LIST OF FIGURES ...... v
LIST OF TABLES ...... vi
ACKNOWLEDGEMENTS ...... vii
CHAPTER 1 – INTRODUCTION AND BACKGROUND ...... 1
1.1 – LYCOPODIUM ALKALOIDS ...... 1 1.2 – THE LYCOPLADINE ALKALOIDS ...... 3 1.2.1 – LYCOPLADINES A–G ...... 3 1.2.2 – LYCOPLADINE H ...... 4 1.2.3 – SYNTHESIS OF LYCOPLADINE A AND RELATED COMPOUNDS ...... 8
CHAPTER 2 – SYNTHETIC EFFORTS TOWARD LYCOPLADINE H ...... 12
2.1 – INITIAL RETROSYNTHETIC ANALYSIS ...... 12 2.2 – OXIDATIVE DEAROMATIZATION ...... 13 2.2.1 – WESSELEY OXIDATION ...... 13 2.2.2 – NUCLEOPHILIC ADDITIONS TO O-QUINONE KETALS ...... 14 2.2.3 – CYCLOADDITION REACTIONS OF O-QUINONE KETALS ...... 17 2.2.4 – STEREOSPECIFIC OXIDATIVE DEAROMATIZATION OF PHENOLS ...... 24 2.2.5 – TANDEM OXIDATIVE DEAROMATIZATION/DIELS-ALDER REACTION IN NATURAL PRODUCTS SYNTHESIS ...... 27 2.3 – DEHYDROAMINO ACIDS AS DIENOPHILES IN DIELS-ALDER REACTIONS ...... 31 2.4 – INTRAMOLECULAR DIELS-ALDER APPROACHES TO LYCOPLADINE H ...... 37 2.4.1 – NITRILE–BASED INTRAMOLECULAR APPROACHES TO THE LYCOPLADINE H CORE ...... 37 2.4.2 – ACID- AND ESTER-BASED APPROACHES TO THE LYCOPLADINE H CORE ...... 40 2.5 – INTERMOLECULAR DIELS-ALDER APPROACHES TO LYCOPLADINE H ...... 45 2.5.1 – REVISED RETROSYNTHETIC ANALYSIS ...... 45 2.5.2 – MODEL STUDY WITH CREOSOL ...... 47 2.5.3 – REACTIONS OF 2-METHOXY-5-METHYLPHENOL AND RELATED SYSTEMS ...... 49 2.5.4 – A MORE CONVERGENT STRATEGY VIA A HENRY REACTION OF AN ALKYL ALDEHYDES ...... 57 2.5.5 – RETURN TO A FORMALDEHYDE-BASED APPROACH ...... 66 2.6 – STUDIES ON THE FORMATION OF THE AZOCANE RING ...... 73 2.6.1 – ATTEMPTED SAMARIUM DIIODIDE BARBIER ROUTE ...... 73 2.6.2 – ATTEMPTED RING-CLOSING METATHESIS APPROACH TO AZOCANE ..... 81
v
2.6.3 – AZOCANE FORMATION VIA HYDROAMINOMETHYLATION ...... 85 2.6.3.1 – HYDROAMINOMETHYLATION ...... 85 2.6.3.2 – INTRAMOLECULAR HYDROAMINOMETHYLATION AND RELATED REACTIONS ...... 90 2.6.3.3 – APPLICATION TO AZOCANE FORMATION ...... 95 2.7 – EFFORTS TOWARD THE FORMATION OF THE LYCOPLADINE H 3-PIPERIDONE RING ...... 98 2.8 – CURRENT AND FUTURE WORK ...... 102 2.8.1 – CURRENT PROGRESS BY P. CHAUHAN ...... 102 2.8.2 – FUTURE STRATEGY FOR THE SYNTHESIS OF LYCOPLADINE H ...... 107 2.9 – CONCLUSION ...... 109
CHAPTER 3 – EXPERIMENTAL PROCEDURES ...... 111
3.1 – GENERAL METHODS ...... 111 3.2 – EXPERIMENTAL PROCEDURES AND ANALYTICAL DATA ...... 112
REFERENCES ...... 180
APPENDIX: LIST OF ABBREVIATIONS ...... 191
vi
LIST OF FIGURES
Figure 1-1: The Classes of Lycopodium Alkaloids ...... 1
Figure 1-2: Phlegmarine (4) from Coniine (5) ...... 2
Figure 1-3: Lycopladines A–G ...... 4
Figure 1-4: Lycopladine H ...... 5
Figure 1-5: COSY and Selected NOESY Correlations and 3D Stick Model of Lycopladine H ...... 6
Figure 2-1: Orbital Interactions in o-Quinone Ketal Dimerization ...... 19
Figure 2-2: o-Quinone Ketal Substituents ...... 20
Figure 2-3: Orbital Diagrams for the Diels Alder Reaction of Cyclopentadiene and Dehydroamino Acids ...... 34
Figure 2-4: Endo/Exo Selectivity in the Desired Lycopladine H Synthesis ...... 36
Figure 2-5: ORTEP Structures of Diels-Alder Adduct 195 (a) and Henry Product 196 (b) ...... 49
Figure 2-6: ORTEP Structure of Henry Product 204 ...... 54
Figure 2-7: ORTEP Structure of Hydrogenation Product 205 ...... 56
Figure 2-8: ORTEP Structure of Nitro Alcohol 225 ...... 65
Figure 2-9: Ball-and-Stick and Space Filling Models of Nitro Ketone 205 ...... 104
vii
LIST OF TABLES
Table 2-1: Diels-Alder of Dehydroamino Acid Derivatives with Cyclopentadiene ...... 33
Table 2-2: Attempted Henry Reactions with Nitro Ketone 203 ...... 63
Table 2-3: Attempted Henry Reaction with Nitro Alcohols 225 and 226 ...... 66
Table 2-4: Attempted Reduction of Nitro Diol 228 ...... 70
Table 2-5: Attempted Reduction of Nitro Diesters 229a and 229b ...... 72
Table 2-6: Ligand Effects in Rhodium-Catalyzed Hydroaminomethylation ...... 89
Table 2-7: Optimization of Hydroaminomethylation of Amine 272 ...... 98
viii
ACKNOWLEDGEMENTS
I would like to thank Professor Steven M. Weinreb for his direction and advice; his insights have been valuable to both my projects and to my understanding of chemistry. I would also like to thank Dr. Raymond Funk, Dr. Gong Chen, and Dr. Ryan Elias for their service as members on my committee.
The Weinreb group members, both past and present, deserve great recognition for their guidance, discussions, and support. They have been some of the most challenging and effective teachers I have known.
Finally, I would like to acknowledge my friends and family for their kindness, understanding, and encouragement. Without their love, support, and patience, none of this would be possible.
1
Chapter 1
Introduction and Background
1.1 – Lycopodium Alkaloids
The Lycopodium family of alkaloids has been of scientific interest since the initial isolation of lycopodine (1) from the club moss Lycopodium complanatum in 1881.1 Since then, more than 250 additional Lycopodium alkaloids have been isolated, many of which show biological activity.2, 3 Members of this family generally contain a 16-carbon multi- cyclic skeleton, although there are known exceptions. These alkaloids are separated into four classes based on their structure: the lycopodine (1) class, the lycodine (2) class, the fawcettimine (3) class, and the miscellaneous class, represented by phlegmarine (4)
(Figure 1-1).4
Figure 1-1. The classes of Lycopodium alkaloids.
H N H H N O N N N O H H OH H N H H
lycopodine (1) lycodine (2) fawcettimine (3) phlegmarine (4)
The Lycopodium family consists of more than 500 species; however, only approximately 50 have been studied for alkaloid content.3 These club mosses are often used in traditional Chinese medicine, and some of the various isolated alkaloids have been
2 shown to have antitumor and acetylcholinesterase inhibitory activity. For example, huperzine A, a lycodine-type alkaloid, has undergone extensive biological testing, culminating in clinical trials as a treatment for Alzheimer’s disease.5 Although it is a promising drug, isolation of huperzine A and other Lycopodium alkaloids on commercial scale has proven problematic due to the difficulty in cultivating these slow-growing plants.
Because most Lycopodium species cannot be successfully cultivated in the lab, the biosynthesis of these alkaloids is not well established. Conroy first proposed a biosynthesis of the phlegmarine scaffold 4 based on the oxidative dimerization of coniine
(5) (Figure 1-2).6 Other members of this family can then be envisioned as coming from this intermediate scaffold, suggesting a unified biosynthesis.
Figure 1-2 Phlegmarine (4) from coniine (5).
3 4 2
5 H α 1 6 N N 11 7 H H H 12 10 8
9 β 13 15 N 14 N H 16 H H 5 4
More recently, feeding of radiolabeled precursors to shoots of Lycopodium species growing in the wild has provided an improved understanding of the phlegmarine
7 biosynthesis (Scheme 1). L-Lysine (6) can undergo decarboxylation to form cadaverine
(7), which can in turn be oxidatively deaminated to 5-aminopentanal (8) and then cyclized to Δ1-piperideine (9). Dimerization of malonyl-CoA (10) gives acetone dicarboxylate derivative 11, which then undergoes a decarboxylative Mannich reaction to give ketoacid derivative 12. Further decarboxylation gives pelletierine (13), which has
3 been isolated from the extracts of L. complanatum. Reaction of pelletierine with 12 with concomitant decarboxylation gives the phlegmarine scaffold 4. Although there is strong evidence for this pathway from isolation of radiolabelled intermediates, the enzymes responsible for the individual transformations have not been identified.
Scheme 1
- CO2 - H2O H2N H2N CO2H H2N NH2 H2N O N
6 7 8 9
O O O O O O O + xx - CO HO S-CoA X X 2 N X - CO2 H 10 11 12 X = OH or S-CoA
O H O X N H H O HN - CO2
NH N H H pelletierine (13) 12 4
1.2 – The Lycopladine Alkaloids
1.2.1 – Lycopladines A–G
The first lycopladine alkaloid, lycopladine A (14) was isolated by Kobayashi and coworkers in 2006 from Lycopodium complanatum (Figure 1-3).8 The Kobayashi group followed shortly after with the isolation of lycopladines B (15),9 C (16),9 D (17),9 E (18),10
4
F (19),11 and G (20).11 All four classes of Lycopodium alkaloids are represented in the lycopladine alkaloids (cf. Figure 1-1). Modest biological activity against murine lymphoma was observed with lycopladine A; lycopladines B–G have no known biological activity to date.
Figure 1-3. Lycopladines A–G
OH O H H O OR O OR O H O H N N N H lycopladine A (14) R = H, lycopladine B (15) lycopladine D (17) R = Ac, lycopladine C (16)
N N N N H H N OAc O H
H2N CO2H O CO2Me
lycopladine E (18) lycopladine F (19) lycopladine G (20)
1.2.2 – Lycopladine H
The most recent member of the lycopladine family to be isolated is lycopladine H
(21, Figure 1-4), which was discovered in the methanolic extracts of L. complanatum in
2009.12 Lycopladine H exhibits a novel tetracyclic ring system composed of a [2.2.2]- bicyclooctane ring system, a spiro-fused 3-piperidone, and a bridging azocane ring.
5
Figure 1-4. Lycopladine H
11 10 12 OH 9 13 O 7 N 6 8 16 14 1 5 15 4 2 O 3 lycopladine H (21)
The structure and relative stereochemistry of this unique alkaloid was established
!! by mass spectrometry, IR, and NMR methods. Polarimetry showed a rotation of [�]! = -
116 for 21 in chloroform. High-resolution mass spectrometry was used to establish a molecular formula of C16H23NO3. The IR spectrum indicated hydroxyl and ketone functionalities with absorption peaks at 3450 and 1720 cm-1, respectively. Analysis of the
13C NMR spectrum of the alkaloid revealed that the ketone IR peak is, in fact, due to two carbonyl groups. Further COSY NMR analysis established three structural units: C-1–C-
3; C-9–C-11; and C-6–C-8, C-15, and C-16 (Figure 1-5 a, bold bonds). HMQC and
HMBC NMR spectra were then used to establish the connectivities of these units through quaternary centers and the nitrogen. The relative stereochemistry and conformation of lycopladine H were elucidated using NOESY experiments (Figure 1-5 a). This analysis revealed a chair-like conformation for the 3-piperidone due to correlations between the axial protons on C-1 and C-3 to the bridgehead proton on C-14. The disposition of the methyl group (C-16) was revealed as being syn to the C-8 Ha, while the Hb proton of C-8 correlated with its counterpart on C-6. The C-6 Ha showed an nOe to C-9 and C-10, which suggests that C-9 is in an axial disposition relative to the piperidone chair, as seen in the
3D model (Figure 1-5 b).13
6
Figure 1-5. COSY and Selected NOESY Correlations (a) and 3D Stick Model (b)
of Lycopladine H
OH 10 O 9 Ha 6 8 Ha N 14 16 1 Hb Hb Hax O 3 Hax
(a) (b)
As with other Lycopodium alkaloids, it has been proposed that lycopladine H originates in nature from pelletierine (13) (Scheme 2).8, 12 Dimerization of 13 through an aldol condensation and oxidation to the bis-enamine would give intermediate 22, which could undergo a second condensation to form tricyclic iminium compound 23. A series of transformations including imine hydrolysis, deoxygenation of C-7 and C-15, hydroxylation at C-12, and formation of a leaving group at C-9 would provide enamine
24. Macrocyclization of 24 through attack of the amine on C-9 followed by tautomerization to the iminium ion (path a) may provide tricyclic compound 25. Tricycle
25 can undergo a Mannich reaction and an oxidation at C-4 to provide lycopladine H
(21). Interestingly, from intermediate 24, enamine attack on C-12 (path b) would give rise
7 to the dearomatized scaffold 26 of lycopladine A, which would be converted to the natural product 14, providing for the possibility of a common biogenetic precursor.
Scheme 2
OH HO O O OH 12 N NH 9 13 H N N NH H H
pelletierine (13) 22 23
OH OH 15 O O OH a 9 b N 14 13 N 14 9 5 5 L NH 4 O 4 O a 25 lycopladine H (21) 24 b
12 13 5 O 4 N O N
HO HO 26 lycopladine A (14)
To date, lycopladine H (21) has no reported biological activity. However, due to the small amount of material isolated, testing has been limited to cytotoxicity assays against L1210 murine leukemia and KB human epidermoid carcinoma cells. Lycopladine
H is an attractive target for total synthesis due to its complex and unprecedented structure and the need for further biological testing. Due to its unique atomic arrangement, such a
8 synthesis would also allow for the development of new strategies and tactics for alkaloid construction, which could then be used in the manufacture of other bioactive analogues.
1.2.3 – Synthesis of Lycopladine A and Related Compounds
To date there have been few attempts to synthesize any members of the lycopladine family. Lycopladine A (14) is the only member of the family to be synthesized to date, and was a target for both the Toste14 and Martin15 labs.
Toste’s synthesis of lycopladine A (14) began with known enantiopure methyl enone 27, which was elaborated to benzyl ether 28 (Scheme 3). TBSOTf-promoted propargylation of 28 followed by iodination of the resulting alkyne gave alkynyl silylenol ether 29. A key gold-catalyzed cyclization reaction of 29 furnished vinyl iodide 30, which underwent a Suzuki coupling to afford hydrazone 31a. At high temperature, hydrazone
31a underwent double bond isomerization to intermediate 31b, which underwent a 6π- electrocyclization and elimination of dimethylamine to construct the pyridine ring to afford O-benzyl lycopladine A (32). Hydrogenolysis of the benzyl group of 32 supplied
(+)-lycopladine A (14) in 16.6% overall yield in 7 steps.
9
Scheme 3
1) (Bu)3Sn 1) I , PhI(OTFA) OTBS O 2 2 O TBSOTf, CH2Cl2 py, CH Cl , rt, 85% 2 2 -78 – -10 °C, 93% BnO BnO 2) (BnOCH CH CH ) B 2 2 2 3 2) NIS, AgNO3, DMF PdCl (dppf), AsPh I 2 3 0 °C – rt, 82% H Cs2CO3, DMF, THF R-(+)-27 H2O, 72% 28 29
Me N BnO 2 OBn N O O AuCl(PPh3)/AgBF4 I B(Pin) N NMe2
CH2Cl2/MeOH Pd(PPh3)4, NaOMe 40 °C, 95% MeOH/PhH, 83% H H 30 31a
OBn BnO O O PhMe, 190 °C 6π 14 60% - HNMe2 Pd/C, EtOH N N 75% H Me2N H 31b 32
Martin’s synthesis of racemic lycopladine A (14) began with a conjugate addition of 2-methyl-3-chloropyridine (33) to cyclohexenone ester 34 (Scheme 4). The resulting enol ester 35 underwent a palladium-catalyzed cyclization to give the tricyclic core 36 of lycopladine A. Lewis acid promoted transesterification then provided allyl ester 37, which underwent palladium-catalyzed decarboxylative allylation to form α-allyl ketone 38.
Hydroboration of 38 promoted by Wilkinson’s catalyst followed by oxidation provided
(±)-lycopladine A (14) in 20.8% overall yield in 9 steps. Interestingly, the Martin group demonstrated a solvent-dependent equilibrium between 14 and the corresponding hemiketal 39 that had not been previously reported.
10
Scheme 4
OH O 1) BuLi, THF, 0 °C MeO2C Cl MeO2C 1) KOtBu, PhMe 2) CuI, -20 °C Cl 3) O 2) cat. Pd (dba) N MeO2C 2 3 N 34 S-Phos, 120°C N H 75% 33 55% 35 36
O O O O cat. Pd(PPh ) cat. Sn4(Bu)8Cl4O2 3 4 allyl alcohol (xs) THF, rt PhMe, µW, 170 °C N 80% N 90% H H 37 38
HO 1) Wilkinson's cat. O catechol borane O OH THF, 0 °C 2) NaBO •4H O 3 2 N aq. THF N H 70% H 15 39
Although lycopladine H (21) was isolated in 2009, the Evans group had earlier produced the ring system of the alkaloid during their efforts to synthesize clavolonine, another lycopodine-type alkaloid.14 Their initial approach involved forming macrocycle
41 in 23% yield over 10 steps from known isoxazolidinone 40 (Scheme 5). Deprotection of the macrocyclic carbamate led cleanly to vinyl enamine 42 through acid-catalyzed closure of the free amine onto the enone carbonyl. When exposed to either a Lewis or
Brønsted acid source, enamine 42 tautomerized to enol iminium compound 43, which underwent a Michael addition and subsequent tautomerization to give tricyclic enamine
44. Further tautomerization to iminium enol compound 45, followed by a Mannich reaction gave tetracycle 46, which possesses the carbon framework of lycopladine H (21).
11
Scheme 5
CO2Et CO2Et Bn O piperidinium acetate EtOH, 80 °C TFA, CH2Cl2 48 h, 81% Ph N O BocN O OBn DMS, 0 °C or 97% N ZnCl2; SiO2 OH O O OBn 40 O 41 42
O CO2Et CO2Et HO EtO2C HO O CO Et N 2 N N N H OBn OBn BnO H OBn 43 44 45 46
12
Chapter 2
Synthetic Efforts toward Lycopladine H
2.1 – Initial Retrosynthetic Analysis
In our first generation retrosynthesis, we envisioned that lycopladine H (21) could be synthesized via 3-piperidone formation from a tricyclic amine through a number of methods including ring closing metathesis, Kulinkovich reaction followed by selective cyclopropane opening,16 or intramolecular nucleophilic addition of the amine to a functionalized ketone such as 47 (Scheme 6). Ketone 47 could be accessed from ester cycloadduct 48, the bicyclo[2.2.2] scaffold of which could be constructed by an intermolecular Diels-Alder reaction of dienone 49b. We hoped this intermediate would adopt reactive conformation 49a (vide infra) to allow access to the tricycle 48. The intermediate 49b would be prepared by the elaboration of amine 50 to the dehydroamino acid derivative, followed by oxidative dearomatization to form the reactive dienone (vide infra). The amine 50 would be obtained through reduction and N-protection of cinnamonitrile 51, which should be easily accessible from known aldehyde 52.17
13
Scheme 6
OH OR OR O O O N RN RN X O O CO2R lycopladine H 47 48 (21)
OR O OH O OR
N CO2R NHR RN R
CO2R 49a 49b 50
OH OH CN O
51 52
2.2 – Oxidative Dearomatization of Phenols
2.2.1 – Wessely Oxidation
In the 1950’s and 60’s, Wessely and coworkers explored the oxidation of phenolic compounds with lead tetraacetate (Scheme 7).18-20 Thus, treatment of o-cresol (53) with
Pb(OAc)4 results in the phenoxy lead (IV) intermediate 54. Subsequent internal delivery of acetate to the more substituted ortho carbon, followed by elimination of lead (II) acetate provides acetoxy dienone 55. Addition of a nucleophile to 55 can then occur to provide a ring-functionalized phenol 56.
14
Scheme 7
AcO OAc OH Pb O OH O OAc OAc Pb(OAc)4 Nu:
-HOAc -Pb(OAc)2 - OAc Nu 53 54 55 56
Similar methodology can be used to transform o-alkoxyphenols 57 to o-quinone ketals 58 (Scheme 8). Oxidative dearomatization of phenols like 57 to form o-quinone
21 22 ketals has been performed with Tl(NO3)3•3H2O, DDQ or o-chloranil, and
23 electrochemically. However, hypervalent iodine reagents such as PhI(OAc)2 and
PhI(O2CCF3)2 have become the most popular choices to effect this transformation due to their ready availability, low cost, and environmentally benign nature. Once formed, o- quinone ketals like 58 can undergo a variety of reactions, including, 1,2-ketone additions,
1,4-conjugate additions, and [4+2] cycloadditions (vide infra).24-26
Scheme 8
OH O OR [O] OR ROH OR R' R' 57 58
2.2.2 – Nucleophilic Additions to o-Quinone Ketals
There are relatively few reported examples of 1,2-additions to o-quinone ketals in the literature. In the earliest reported studies, it was found that organolithium compounds add to the carbonyl group to give functionalized cyclohexadienols.27 Later, a similar
15 strategy was used by Magnus in efforts to synthesize calicheamicinone (Scheme 9).28
Thus, the lithium acetylide derived from 60 was added to o-quinone ketal 59 to furnish tertiary alcohol 61 in high yield.
Scheme 9
H
O OMe HO TIPS 60 OMe OMe LiHMDS, THF OMe TIPS CO2Me 90% CO2Me 59 61
Lithium anions of stabilized carbon nucleophiles also participate in Michael additions to o-quinone ketals. For example, Mitchell reported a method for the synthesis of substituted anthraquinones via a Michael-Dieckmann reaction (Scheme 10).29 For example, oxidative dearomatization of eugenol (62) with iodobenzene diacetate in methanol gives dienone 63. Cyanophthalide (64) was deprotonated with LDA and added to 63 to give intermediate Michael adduct 65. Opening of the lactone followed by elimination of cyanide provided anthraquinone 66 in 92% overall yield from 62.
16
Scheme 10
O
OH O O OMe OMe PhI(OAc)2 64 CN OMe MeOH, rt LDA, THF, -78 °C 92%
62 63
O O OH O OMe OMe O OMe
CN O 65 66
1,4-Additions to o-quinone ketals using organometallic reagents such as cuprates are often problematic. These reagents tend to favor single electron transfer to the o- quinone ketal, forming a radical anion that undergoes elimination to restore aromaticity.25 Heteroatom nucleophiles, however, have been shown to participate in conjugate addition reactions. Therefore, when treated with iodobenzene diacetate in the absence of an external nucleophile, phenols 67 undergo oxidative dearomatization to give the mixed ketal 68 (Scheme 11).30 Desilylation of 68 with TBAF unmasks the primary alcohol functionality, which upon 1,4-addition yields heterocycles 69 after rearomatization via elimination of acetic acid.
17
Scheme 11
OMe AcO OMe OMe OH O OH PhI(OAc)2 TBAF
CH2Cl2 THF 0 °C to rt SiR - 78 °C, 30 min SiR3 O n O 3 n O 1–3 h n n = 1–4 67 68 69
Nitrogen nucleophiles have also been shown to participate in similar conjugate addition reactions.31 Using analogous chemistry, mixed o-quinone ketals 70 were prepared from the corresponding phenols (Scheme 12). Removal of the triisopropylsilyl carbamate (Tsoc) protecting group from 70 generated the cyclic amines 71 after rearomatization.
Scheme 12
AcO OMe OMe O OH TBAF THF 0 °C to rt Tsoc NH n N 1 h n H n = 1, 2 70 71
2.2.3 – Cycloaddition Reactions of o-Quinone Ketals
The most common mode of reactivity for o-quinone ketals involves participation of the dienone moiety in [4+2] cycloaddition reactions. The combination of an oxidative dearomatization with a Diels-Alder reaction can serve as an elegant mode of constructing intricate molecules, installing a great deal of complexity in a single step. However, many
18 o-quinone ketals are extremely reactive and undergo a rapid Diels-Alder self-dimerization, even in the presence of an excess of a dienophile.
Dimerization of o-quinone ketals occurs with impeccable regio- and stereoselectivity. The only observed product of dimerization of dienone 72 involves the endo formation of C-4–C-2’ and C-5–C-5’ bonds through transition state 73 to provide cycloadduct 74 (Scheme 13).26, 32 This endo selectivity is due to secondary orbital overlap of the C-2–C-3 π bond of the dienophile with the diene C-3’ and C-4’ p orbitals (Figure 2-
1 a). The observed regioselectivity arises from the selective reaction of the C-4–C-5 bond
(i.e. 73) rather than the C-2–C-3 bond (i.e. 75) to prevent the loss of resonance of the C-
2–C-3 double bond with the carbonyl group. This results in exclusive formation of 74 rather than the adduct 76. The selectivity for the C-5–C-5’ connectivity (73) over the C-4–
C-5’ (77) is posited to arise from stabilization of the incipient C–C σ bond in the transition state via hyperconjugation from the electron donating C-6/C6’ substituents
(Figure 2-1 b),32 which again favors adduct 74 over 78. If R and R’ are different, then the more electron rich substituent will contribute more to the hyperconjugation, leading to additional selectivity.
19
Scheme 13
O 4 O O 5 MeO MeO 6 OMe 2' O 2 MeO O OMe MeO OMe 3 5 5' OMe 4 OMe OMe 72 73 74
OMe OMe O OMe O OMe MeO O MeO O OMe OMe 2 5 3 4 2' O O 2' O O OMe OMe OMe 5' 5' OMe OMe OMe OMe OMe 75 76 77 78
Figure 2-1. Orbital Interactions in o-Quinone Ketal Dimerization
MeO OMe R' 6' R MeO R' O 6 5 5' 4' O MeO R O 2 3' O 3
a b
The regio- and stereoselectivity of cycloadditions of o-quinone ketals with other dienophiles follows a similar trend. The reaction strongly favors an endo transition state
79, which furnishes cycloadduct 80 (Scheme 14). Both electron donating and withdrawing groups on the dienophile are found to be disposed syn to the ketone of the o- quinone ketal in the product. Although the regioselectivity of cycloadditions can be explained by computational methods in the case of electron-donating groups, the exact orbital interactions of electron-deficient dienophiles with o-quinone ketals remains to be elucidated.33, 34
20
Scheme 14
R R O O OMe OMe OMe OMe 79 80 R = EDG or EWG
The propensity of o-quinone ketals toward Diels-Alder reaction is strongly affected by the substitution patterns of the system (Figure 2-2).35, 36 Bulky or electron withdrawing substituents on the ketal oxygens (R1) both attenuate the reactivity in Diels-Alder cycloadditions due to steric effects and destabilization of hyperconjugation, respectively
(cf. Figure 2-1 b). Electron donating R2 and R4 groups, and electron withdrawing R5 substituents slow the rate of Diels-Alder reaction, with larger groups having a more profound effect. Conversely, electron-withdrawing R4 substituents increase the rate of cycloaddition. Contributions of R3 groups have not been extensively explored, but o- quinone ketals with either electron donating or withdrawing substituents at that position undergo facile dimerization (vide infra).
Figure 2-2. o-Quinone Ketal Substituents
O 1 R2 OR OR1 R3 R5 R4
Due to the ease of dimerization, methods to circumvent this mode of reactivity have been developed. One such method involves purposeful dimerization of the o-quinone ketal, followed by high-temperature cycloreversion in the presence of a different
21 dienophile (Scheme 15).37 In one example, oxidative dearomatization of guaiacol (81) gave the dimer 82 in quantitative yield. Subsequent heating of dimer 82 at 220 °C in a sealed tube with 5 equivalents of dihydrofuran gave the desired cycloadduct 83 in 87% yield. When the o-quinone ketal was generated directly in the presence of 50 equivalents of dihydrofuran, the reaction led to only a 15% isolated yield of the desired product 83.
Scheme 15
O O OH O PhI(OAc) MeO OMe 2 O O MeOH MeO OMe mesitylene OMe 100% 220 °C, 2 h OMe 87% OMe 81 82 83
Although the dimerization/retro–Diels-Alder pathway addresses some of the issues of the practical use of o-quinone ketals as dienes, the harsh reaction conditions required are far from ideal. Another method that has been developed by the Liao group involves a so-called “detour” route to [2.2.2]-bicyclooctanes (Scheme 16).38, 39 Thus, phenols 84a and 84b, whose corresponding o-quinone ketals readily dimerize, can be brominated in high yield to give bromophenols 85. Oxidative dearomatization of these phenols using iodobenzene diacetate in methanol give the ketals 86, which are stable and can be purified by flash chromatography on silica gel with minimal degradation. o-
Quinone ketals 86 can be reacted in situ or after isolation with dienophiles such as methyl methacrylate (87a), methyl acrylate (87b), and methyl vinyl ketone (87c) to give cycloadducts 88 in 62-90% yield. The cycloadducts 88 can then be debrominated using radical or palladium-catalyzed conditions to furnish the desired bicyclooctenes 89. Even though this “detour” adds two additional steps, the Liao group demonstrated that yields
22 of cycloadducts 89 could be improved up to 44% over the more direct methods. The stability of the brominated o-quinone ketals also allows for a reduction in the number of equivalents of dienophile used from as many as 50 to only a slight excess.
Scheme 16
OH O OH OMe R1 OMe R1 1 PhI(OAc) R OMe NBS 2 OMe AcOH R2 MeOH R2 R2 84a: 91% 0 °C, 5 min 84b: 98% Br Br 84a: R1 = Me, R2 = H 85 86 84b: R1 = H, R2 = Me
R3 R4 MeO OMe MeO OMe Bu3SnH, AIBN O PhMe, 110 °C O Br 4 4 3 4 R R 87a: R = CO2Me, R = Me or 1 2 1 2 3 4 3 R R Pd(PPh ) Cl 3 R R 87b: R = CO2Me, R = H R 3 2 2 R 87c: R3 = C(O)Me, R4 = H Bu3N, HCO2H 88 89 DMF, 60–80 °C
Intramolecular reactions can also be exploited to remedy the problem of o-quinone ketal dimerization. Often, by slow addition of the oxidant, the concentration of reactive dienone can be kept low, allowing the desired Diels-Alder reaction to proceed in high yield. One example of this is seen in the Wood group’s approach to a synthesis of the polycyclic natural product CP-263,114 (95, Scheme 17).40 Phenol 90, derived via alkylation of the corresponding catechol, was treated with iodobenzene diacetate in the presence of propargyl alcohol to give mixed ketal 91, which underwent cycloaddition to provide the desired tricyclic compound 92 in 95% yield. Elaboration of this core provided hexacyclic diester 93, which was subjected to selective reduction of the ethyl acetal,
23 followed by Barton radical deoxygenation/ring fragmentation of the resulting tertiary alcohol to furnish the tetracyclic core (94) of CP-263,114.
Scheme 17
CO2Me CO2Me MeO C OH 2 PhI(OAc) MeO2C MeO2C 2 Bu Bu Bu MeO C O propargyl alcohol O O 2 MeCN, rt 95% O O 90 91 92
O O E E O E E 4 steps Bu 4 steps Bu O O OH O O O E = CO2Me O O OEt O O
93 94 O CP-263,114 (95)
Occasionally, o-quinone ketals can also react as the 2π component in a Diels-Alder reaction, as seen in Rodrigo’s synthesis of phenanthrofurans (Scheme 18).41 Treatment of methyl vanillate (96) with iodobenzene bis(trifluoroacetate) in the presence of vinylcyclohexenol 97 gave mixed o-quinone ketal 98. This intermediate furnished tetracycles 99a and 99b in 52% combined yield, along with only 7% of the bridged product in which the dienone acted as the 4π component. Using this method, four of the 5 rings of the opiate alkaloid family can be produced in one step, showing the potential for rapid assembly of morphine and related molecules.
24
Scheme 18
OH
MeO2C H H H H 97 E E H E H OMe + O O O PhI(TFA)2 THF, 0 °C OH OMe OMe OMe O O O 96 98 exo-99 endo-99 31% 21% E = CO2Me
2.2.4 – Stereospecific Oxidative Dearomatization of Phenols
Recently, methods for the synthesis of enantiomerically pure o-quinone ketals have been developed using two general strategies: substrate-controlled and oxidant- controlled desymmetrization. One of the early successful examples involved the use of a tethered chiral alcohol to form a spirocyclic ketal intramolecularly (Scheme 19).42 (R)-
Hydroxyphenol 100 was treated with iodobenzene diacetate in trifluoroethanol (TFE), which furnished (R,R)- and (R,S)-ketals 101a and 101b, respectively, with the former being the major product. This diastereoselectivity in the cyclization is believed to arise from a ligand coupling mechanism, which differs slightly from the usual mechanism of oxidative dearomatization.43 In this case, displacement of an acetate ligand on iodine by chiral alcohol 100 gives hypervalent iodide 102. Intramolecular attack at the iodine center by the ortho phenolic position gives diastereomeric cyclic λ3-iodanes 103a and 103b. The axial disposition of R’ in 103b destabilizes this intermediate, especially when R’ is a large group. The highest diastereoselectivities were observed when R’ was t-butyl, while smaller
25 groups such as ethyl only resulted in a modest diastereoenrichment. Ligand coupling (or reductive elimination) then leads to the major product 101a and the minor product 101b.
Scheme 19
OH OH R' O O (R) O (R) O O (R) PhI(OAc)2 R' R' (S) (R) O + O NaHCO3 TFE, -35 °C R R R 100 101a 101b up to ≥95:5 dr
Ph Ph R' H I O (R) O O O OAc I O R' O (R) O O + I R' O Ph
R R R 102 103a 103b
Another substrate-controlled diastereoselective approach was developed using protected carbohydrates as removable chiral auxiliaries in intramolecular Diels-Alder reactions (Scheme 20).44 Treatment of benzyl-protected glucose derivative 104 with catechol in the presence of PPh3 and DIAD gave the mono-protected catechol 105 in moderate yield. Oxidative dearomatization of 105 using prenyl alcohol (106) afforded the enantiomerically pure tricyclic ketal 107 in good yield. Acidic hydrolysis could then be used to remove the glucose auxiliary 104, which can be recovered and recycled.
26
Scheme 20
OH OBn OH β-GlcBnO O OH 106 BnO O β-GlcBnO BnO OH Ph3P, DIAD HO PhI(OAc)2 OBn THF, 0 °C – rt CH2Cl2 O 60% 74% 104 105 107 (= β-GlcBnOH)
Enantioselective oxidative dearomatization has also been achieved via asymmetric induction using chiral iodoarene additives with mCPBA as a stoichiometric oxidant, albeit with only moderate levels of selectivity, reaching 50% ee (Scheme 21).45 Thus, when naphthol 108 was treated with two equivalents of (R)-biaryl iodoacid 109 and one equivalent of mCPBA, the chiral α-hydroxyketone 110 was obtained in good yield with moderate enantioselectivity. When a catalytic amount of the chiral iodoacid 109 was used, the enantiomeric excess dropped off rapidly, with 1 equivalent giving 47% ee, and
0.1 equivalents giving only 29% ee. Other chiral IBX derivatives performed even more poorly in this reaction.
Scheme 21
CO2H
I OMe OH O 109 OH mCPBA CH2Cl2, rt 83%, 50% ee 108 110
The Porco group has reported a more successful asymmetric oxidative dearomatization procedure for phenols using chiral copper reagents and molecular oxygen as the oxidant (Scheme 22).46, 47 Treatment of phenol 111 with complex 115, which arises upon complexation of Cu(I) with (–)-sparteine and oxygen, in the presence
27 of base furnishes Diels-Alder dimer 112. The dimer 112 can then undergo a tandem retro-
[4+2]/[4+2] sequence in the presence of a dienophile such as N-phenyl maleimide (113) to provide enantiomerically pure cycloadduct 114 in high yield.47
Scheme 22
O O OH Cu(CH3CN)4PF6 OH i-Pr N Ph (–)-sparteine O HO O 113 H OH O H LiOH•H O H mesitylene 2 O 150 °C, 1.5 h i-Pr 3 Å MS, O i-Pr H PhN 2 98% THF, -78 °C, 18 h O 111 80% 112 114
N O N Cu Cu N O N
115
2.2.5 – Tandem Oxidative Dearomatization/Diels-Alder Reactions in Natural Products Synthesis
Owing to the ability to rapidly build up molecular complexity in a stereo- and regioselective manner, the use of oxidative dearomatization has become a popular strategy in natural product synthesis.48, 49 It has even been suggested that such a phenol oxidation can provide a biomimetic route to natural products.50 One such example is an early total synthesis of carpanone (119), a polycyclic lignan, by Chapman (Scheme 23).51
Phenolic styrene 116 underwent palladium-mediated oxidation to provide stabilized o- quinone methide cation 117. A second unit of phenol 116, likely assisted by complexation
28 to palladium, attacks cation 117, providing bis-trienone dimer 118. Subsequent intramolecular hetero–Diels-Alder cyclization provided the natural product 119 in 46% isolated yield. Impressively, in this reaction the relative configuration of 5 contiguous stereocenters was set in one reaction.
Scheme 23
O OH O O HO O PdCl2, NaOAc O O O MeOH/H2O 38 °C, 3 h 116 46% 117
O O O O O O O O H H O O O O
118 carpanone (119)
The Liao group has extensively utilized Diels-Alder reactions of o-quinone ketals in natural product synthesis, and, to date, have synthesized more than a dozen natural products using this key reaction.48, 52 In addition to [2.2.2]-bicyclooctane systems, they have also established methodology to produce other useful motifs. In the synthesis of (±)- cis-clerodane diterpenic acid (124), key reactions included a tandem phenolic oxidative dearomatization/intermolecular Diels-Alder reaction and an oxy-Cope rearrangement
(Scheme 24).53 Brominated o-quinone ketal 86b underwent Diels-Alder reaction with methyl tiglate (120) to give cycloadduct 121. A series of transformations led to allylic alcohol 122, which underwent oxy-Cope rearrangement to provide cis-decalin 123.
29
Decalin 123 was further elaborated to provide the natural product 124. In addition to the oxy-Cope rearrangement in this case, traditional Cope rearrangements have also been utilized to access other cis-decalin ring systems stereoselectively.54
Scheme 24
O MeO2C OMe MeO C 120 2 OMe OMe Br OMe O Br 86b 121
5 1 4 4 2 BnO 5 OH oxy-Cope 6 3 O H 6 2 3 O 1 H OBn CO2H 122 123 124
Other compounds accessible from [2.2.2]-bicyclooctenones are triquinane natural products such as the Lycopodium alkaloid magellanine (131).55 Therefore, oxidative dearomatization of phenol 125 in the presence of cyclopentadiene gave cycloadduct 126 in good yield (Scheme 25). Irradiation of 126 in acetone with long-wave UV light initiated an oxa-di-π-methane rearrangement: homolysis of the carbonyl π bond of 126 and subsequent cyclopropanation provided diradical 127, which was followed by transcyclopropanation and radical recombination to give tetracyclic diketone 128. A number of steps were used to transform 128 into tricyclic enone 129, which was elaborated to allyl diketone 130. Further operations provided the natural product 131 in
10% overall yield over 14 steps.
30
Scheme 25
O O O OMe OMe hν OMe
PhI(OAc)2 OMe acetone OMe 92% OH MeOH, rt O O 79% 125 126 127
O O O H H OMe
OMe O O H H H H MeO OMe O 128a 128b 129
O H O H N H H H H O OH 130 (±)-magellanine (131)
A particularly elegant example of an o-quinone ketal tandem oxidative dearomatization/Diels-Alder reaction was used in Danishefsky’s synthesis of 11-O- debenzoyl-tashironin (136).56 Starting from previously synthesized allenic alcohol 132, treatment with iodobenzene diacetate under microwave irradiation promotes ligand exchange to give phenolic iodide 133 (Scheme 26). Intramolecular cyclization of the allenic alcohol gives mixed o-quinone ketal 134 with the allene positioned directly over the diene moiety. An intramolecular Diels-Alder reaction then provides tetracycle 135, which possesses the entire carbon skeleton of the natural product with the correct relative stereochemistry. Further elaboration of 135 led to the O-debenzoyl natural product 136.
31
Scheme 26
Ph OH OH I OBn O OAc PhI(OAc)2 OBn OH µW 65% OTs OTs 132 133
O O HO OBn H O O OBn O OH
OTs OTs OH O
134 135 (±)-11-O-debenzoyl-tashironin (136)
2.3 – Dehydroamino Acids as Dienophiles in Diels-Alder Reactions
Diels-Alder cycloaddition reactions of dehydroalanines 137 have been studied in detail due to their potential application to the synthesis of unnatural amino acid derivatives (Table 2-1).57-59 The nature of the ester and N-acyl substituents has both been examined, as have the effects of temperature, solvent, and catalysts. In general, thermal
Diels-Alder reactions of 137 with cyclopentadiene provide the bicyclo[2.2.1] derivatives
138 in good yield and with modest diastereoselectivities (entries 1–3), with use of excess diene or higher temperatures giving the best results. Although nonpolar aromatic hydrocarbon are most often used, the reaction was found to be compatible with polar protic solvents (entry 4), albeit with an attenuated yield. Additionally, the use of a Lewis
32 acid catalyst effectively allowed some of the reactions to proceed at room temperature
(entries 5–8, 10, 11) under both solution-phase and solvent free conditions in yields similar to those of the thermal reactions. An increase in the steric bulk of the ester O-alkyl
(R1) substituent resulted in lower yields (entries 1, 9, 12). Interestingly, the reaction conditions did not seem to tolerate phenolic esters, resulting in a poor yield even when elevated temperature and a large excess of cyclopentadiene were employed (entry 13). In all reactions involving the acetamide (R2 = Me), a slight preference for the exo product
138b over the endo product 138a was observed, varying from approximately a 1:1 to a 2:1 ratio. Using a methyl carbamate-protected derivative (R2 = OMe), however, resulted in exclusively the exo product 138b (entry 14).
33
Table 2-1. Diels-Alder Reactions of Dehydroamino Acid Derivatives with
Cyclopentadiene
O H 2 N R 2 + 1 R1O NHCOR CO2R [conditions] 1 2 O CO2R NHCOR 137 138a 138b endo exo
Equiv. Temp Time Yield Entry R1 R2 Solvent Catalyst 138a/138b Ref. diene (°C) (h) (%) 1 Me Me 3 PhMe – 90-110 5 77 43:57 56 2 " " 6 " – 90-100 " 100 31:69 57 3 " " 3 xylenes – 130-140 " 100 28:72 57 4 " " " EtOH – 80-90 " 78 36:64 57
5 " " " CH2Cl2 TiCl4 25 " 100 43:57 57
6 " " 6 – Al2O3 " 24 65 37:63 58
7 " " " – SiO2–Al " " 95 35:65 58
8 " " " – SiO2–Ti " " 100 32:68 58 9 Et " 3 PhMe – 90-110 7 71 36:64 56
10 " " " CCl4 AlCl3 25 " 79 37:63 56
11 " " " Et2O FeCl3 " " 62 36:64 56 12 Bn " " PhMe – 90-110 6 67 33:67 56 13 Ph " 9 xylenes – 130-140 5 25 ND 57 14 Me OMe 3 PhMe – 90-100 " 56 0:100 56
The observed endo/exo selectivity has been rationalized by semiempirical calculations of the energy differences between the HOMO–LUMO gaps for both the normal- and inverse-electron demand cycloadditions (Figure 2-3).58 The calculated difference between the two modes of reactivity is 0.739 eV, which Bueno et al. classify as
“normal, although nearly neutral,” suggesting a slight preference for the endo product
138a. However, orbital coefficient data show significant secondary overlap in the transition state in which the more electron-rich N-acyl group is endo, which would lead to
34 the exo cycloadduct 138b. Taking both factors into consideration, the authors calculated a slight energetic preference for exo cycloadduct 138b, which is in accord with the observed product ratios. By this reasoning, the methyl carbamate (Table 2-1, entry 14) would have an even higher electron density on nitrogen, which would create a stronger preference for the exo adduct 138b, leading to exclusive formation of that product.
Figure 2-3. Orbital Diagrams for the Diels-Alder Reaction of Cylopentadiene and
Dehydroamino Acids
LUMO 0.18 HOMO 0.17
exo -8.985 eV endo -9.724 eV
MeO Ac LUMO HOMO N O NHAc H CO2Me 0.21 0.32
Dehydroalanine derivatives can also be used with other dienes, such as in
Avenoza’s synthesis of substituted pyrrolidines (Scheme 27).60 Thus, Lewis acid catalyzed
Diels-Alder cycloaddition of acetamidoacrylate 139 with butadiene furnished gem- disubstituted cyclohexene 140, which was then converted to azanorbornene 141.
Treatment of azanorbornene 141 with the Hoveyda-Grubbs catalyst effected ring-opening metathesis followed by a cross metathesis reaction with methyl acrylate to furnish the
2,2,5-trisubstituted pyrrolidine 142.
35
Scheme 27
Boc MeO2C N MeO2C NHAc AcHN methylaluminoxane MeO C CH2Cl2, rt 2 139 81% 140 141
Hoveyda-Grubbs II MeO C 2 CO2Me N CO2Me Boc PhMe, 80 °C, 4 h 142 92%
The preparation of [2.2.2]-bicyclooctane derivatives using [4+2] cycloadditions of dehydroalanines with 1,3-cyclohexadienes was studied by the Crossley group in their synthetic efforts toward the amino acid antibiotic anticapsin (Scheme 28).61 When 1- trimethylsilyloxycyclohexa-1,3-diene was combined with a number of different dehydroalanine derivatives 143, a mixture of endo and exo cycloadducts 144 were isolated. With the exception of 144, which was found to be unstable, yields were generally acceptable to good, and only one regioisomeric product was produced. The endo/exo selectivity of these cycloadditions, however, was rather poor, and did not seem to follow the trends established in previous experiments with cyclopentadiene (cf. Table 2-1). A possible rationalization for this observation derives from the longer reaction times required to drive the reaction to completion in the cases of 144a, 144c, and 144d (48, 72, and 24 h, respectively), which might have led to endo/exo equilibration via a retro- cycloaddition/cycloaddition sequence.
36
Scheme 28
OTMS
2 1 2 3 2 3 1 O R R O2C NR R R R N CO2R N 1 3 OTMS + OTMS R O R PhMe, 75–150°C 4–78 h exo endo 143a: R 1 = Me, R 2 = R 3 = Phth 144a: 89%, 1.6 : 1 143b: R1 = Me, R2 = Ac, R3 = H 144b: 21%*, 1 : 2.6 143c: R1 = Bn, R2 = Boc, R3 = H 144c: 48%, 1 : 1.8 143d: R1 = Bn, R2 = Cbz, R3 = H 144d: 72%, 1 : 1.5 1 2 3 143e: R = Bn, R = TFA, R = H 144e: 56%, 1 : 3.3
To overcome the endo/exo selectivity problems inherent with previous intermolecular [4+2] cycloaddition of dehydroamino acid derivatives, we hoped to prepare a tethered aminoacrylate for use in our lycopladine H synthesis (cf. Scheme 6). In this way, the desired cycloadduct stereochemistry could be obtained by limitation of the conformational degrees of freedom, which should favor the desired carbonyl-endo transition state due to steric interactions in the exo transition state (Figure 2-4).
Figure 2-4. Endo/Exo Selectivity in the Desired Lycopladine H Synthesis
OR OR OR OR O O O O
RO2C RO2C RN RN N N CO R CO R R R 2 2
exo endo
37
2.4 – Intramolecular Diels-Alder Approaches to Lycopladine H
2.4.1 – Nitrile-Based Intramolecular Approaches to the Lycopladine H Core
Our synthetic efforts toward lycopladine H (21)62 began with the selective formylation of m-cresol (145) at the C-5 position using paraformaldehyde and magnesium chloride to give known salicylaldehyde derivative 52 in nearly quantitative yield (Scheme 29).17, 63 Aldehyde 52 then underwent condensation/elimination with the anion of acetonitrile to give cinnamonitrile 51. Hydrogenation of nitrile 51 with platinum oxide catalyst in the presence of trifluoroacetic anhydride smoothly provided saturated trifluoroacetamide 146. Since copper-catalyzed couplings of vinyl halides with amides are precedented,64 methyl 1-bromoacrylate (147a)65 and the corresponding triflate 147b66 were prepared from methyl acrylate and methyl pyruvate, respectively. However, coupling of trifluoroacetamide 146 with either 147a or 147b under a variety of copper-catalyzed conditions failed to provide the desired trifluoroacetamidoacrylate 148. Additionally, the use of palladium catalysts failed to effect the desired transformation. The observed products in all cases resulted from oligomerization of the acrylates 147, while the starting amide 146 was usually recovered intact.
38
Scheme 29
OH OH OH (CH O) , MgCl 2 n 2 KOH CN O THF, 65 °C, o/n MeCN, 82 °C, 20 h 99% 77% 145 52 51
MeO C X OH O 2 OH O (CF3CO)2O N CF N CF3 3 H2 (1 atm), PtO2 H 147a: X = Br THF, rt, 18 h 147b: X = OTf CO2Me 92% 146 Cu/amine cat., base 148 X = Br, OTf
In the event that the acidic phenol was interfering with the coupling reaction, a
TBS-protected derivative was examined (Scheme 30). To this end, cinnamonitrile 51 was protected with TBS-chloride under standard conditions to give silylated phenol 149.
Hydrogenation of protected cinnamonitrile 149 over platinum oxide provided amine 150.
Interestingly, the hydrogenation of 149 or unprotected cinnamonitrile 51 only proceeds in the presence of an activating agent, such as an anhydride or acid. Hydrogenation of 149 in the presence of trifluoroacetic anhydride or a catalytic amount of an organic- or inorganic acid resulted in loss of the TBS group. However, the addition of ca. 5% of chloroform was found to allow the reaction to proceed smoothly without any added acid,67 likely due to trace HCl formed during the reaction.
With amine 150 in hand, treatment with trifluoroacetic anhydride gave trifluoroacetamide 151 in 60% unoptimized yield. Unfortunately, copper-catalyzed coupling reactions using acrylates 147 again failed to provide the desired acetamidoacrylate 152.
39
Scheme 30
OH OTBS OTBS H , PtO CN TBS-Cl, Im CN 2 2 NH2 DMF, rt, 18 h EtOH, CHCl3 94% rt, 18 h 51 149 99% 150
MeO C X OTBS O 2 OTBS O 147 (CF3CO)2O N CF N CF3 3 Et3N, DMF H Cu/amine cat., base rt, 2 h X = Br, OTf CO2Me 60% 151 152
We next explored the possibility that amide 151 could be N-alkylated directly by treatment with ethyl bromoacetate (Scheme 31). The resulting ethyl glycinate 153 might then be further elaborated to the desired acetamidoacrylate 154. However, treatment of amide 151 with ethyl bromoacetate using several bases failed to provide any of the desired amide ester 153.
Scheme 31
OTBS O OTBS O O OTBS O Br OEt N CF3 N CF3 N CF3 H base O
CO2Et OEt 151 153 154
We next explored another potential method of forming the requisite N-protected tethered system via the formation of an imine, followed by acylation and tautomerization of the resulting N-acyliminium compound to the enamide 157 (Scheme 32).68 Therefore, amine 152 was condensed with methyl pyruvate (155) to give imine 156, which was immediately treated with various acid chlorides and anhydrides in order to form amidoacrylates 157a–c, respectively. However, no conditions could be found that
40 provided any of the desired acrylates 157. Instead, addition of 158, the enamine tautomer of 156, to methyl pyruvate (155) gives imine 159. Addition of a second equivalent of amine 150 to 159 followed by cyclization gives the pyrrolidinone 160.69 Baker et al. first observed a similar reaction and have studied the reaction pathway and regioselectivity.69
It was noted that this process can be minimized by slow addition of pyruvate over 1 h to a solution of an amine such as 152 at reflux. However, this solution was not effective in our case.
Scheme 32
O OMe O OTBS O OTBS OTBS 155 O R Cl N R NH N 2 PhMe or THF base CO Me 4 Å MS or MgSO4 CO2Me 2 152 156 157a: R = Ac 157b: R = TFA 157c: R = CO2Et
base
OTBS O
OTBS N CF OTBS 3 155 N 152 O NH N CO2Me MeO C ClOCCF3 2 CO Me MeO2C 2 HO 158 159 160 OTBS
2.4.2 –Acid- and Ester-Based Approaches to the Lycopladine H Core
As an alternative to the problems described above, we believed that an o-quinone ketal like 49b might be accessed directly by oxidative dearomatization of phenol 161 already possessing the dienophile moiety (Scheme 33). To prepare this substrate, an
41 aminoacrylate 163 would be coupled with a suitably functionalized phenol derivative 162, which is accessible from a cinnamic acid derivative.
Scheme 33
O OH OTBS OMe R'HN CO R + 2 N CO2R N CO2R X R' R'
49b 161 162 163
Therefore, starting with salicylaldehyde 52, Wittig olefination using commercially available phosphonium ylide 164 provided ethyl cinnamate 165 in nearly quantitative yield (Scheme 34). O-TBS protection of phenol 165 gave silyl ether 166, which was then subjected to LiAlH4 reduction. However, rather than the expected reduction to form saturated alcohol 168,70 ester 166 was instead simply reduced to allylic alcohol 167.
Complete reduction to saturated alcohol 168 could be achieved upon hydrogenation of
167 over palladium on carbon at atmospheric pressure. Alcohol 168 was converted to the corresponding alkyl bromide 169 via an Appel reaction.70 Bromide 169 was used without purification, as silica gel chromatography caused decomposition.70 Crude bromide 169 was then reacted with commercially available methyl 1-acetamidoacrylate (170a) and methyl 1-trifluoroacetamidoacrylate (170b), prepared from serine methyl ester.71
Unfortunately, the desired N-alkylated products 171a and 171b could not be detected.
Rather, the acrylate C-alkylation product 172 was observed as the only isolable product of the transformation.
42
Scheme 34
O OH 164 OH O Ph3P OTBS O OEt TBS-Cl, Im O OEt OEt CH2Cl2, rt, 2 h DMF, rt, 18 h 99% 99% 52 165 166
OTBS OTBS LiAlH4, Et2O H2 (1 atm), 10% Pd/C CBr4, PPh3 OH OH EtOH, rt, 18 h CH2Cl2 0 °C, 1h, rt, 2 h 0 °C to rt, 4 h 96 % 96% 89% 167 168 (98%, 90% purity)
OTBS RHN CO2Me OTBS OTBS NAc CO Me Br N CO2Me 2 170a: R = Ac R 170b: R = TFA base 169 171a: R = Ac 172 171b: R = TFA
As we were having difficulty N-alkylating acetamidoacrylates 170, it was thought that N-acylation might provide a more convenient route to the desired cyclization precursor for intramolecular Diels-Alder reaction (Scheme 35). The desired tricyclic product 173 could be accessed by oxidative dearomatization/Diels-Alder reaction of amidoacrylate 174. In this case, the tether could also act as an electron-withdrawing protecting group, eliminating the need for an additional protection/deprotection sequence. Acrylate 174 could in turn be formed by the coupling of a suitable amine or enamine 176 with an activated form of acid 175.
43
Scheme 35
OMe O O OH O OH O X OMe + HN N OH H HN CO Me O 2 MeO O 174 175 176 173 X = CH2, CH2OR
To this end, ethyl cinnamate 165 was hydrogenated to give the saturated ester
177, which was saponified using lithium hydroxide to give hydrocinnamic acid derivative
175 (Scheme 36). After some experimentation, it was found that coupling of acid 175 and
DL-serine methyl ester hydrochloride (178) using EDC gave a good yield of acylated serine derivative 179. Alternative coupling using DCC led to the formation of an intractable mixture of the desired product along with dicyclohexylurea. Likewise, attempted acid chloride formation from acid 175 gave a variety of products including the lactone resulting from intramolecular closure onto the phenol.
Dehydration of acyl serine derivative 179 with DCC and a catalytic amount of copper (I) chloride72 gave methyl dehydroalanine compound 174. With the desired dehydroamino acid precursor in hand, phenol 174 was subjected to a variety of oxidative dearomatization conditions. However, treatment of 174 with iodobenzene diacetate in methanol at various temperatures did not lead to the desired cycloadduct 181a via the corresponding dienone 180a; rather the p-quinone ketal 182 was isolated in 40% yield. In order to prepare the corresponding o-acetoxy derivative 181b through intermediate 180b, dehydroalanine phenol 174 was treated with iodobenzene diacetate in a variety of non- polar solvents. Additionally, lead (IV) acetate was examined as an oxidant due to its ability
44 to transfer an acetate group intramolecularly.20 In both cases, the reactions resulted in the decomposition of the cycloaddition precursor, along with recovery of a small amount of starting material 174.
Scheme 36
OH O OH O OH O H2 (1 atm), 10% Pd/C LiOH•H2O OEt OH OEt EtOH, rt, 18 h MeOH/H2O 100% 55 °C 18 h 99% 165 177 175
HO OMe OH OH O ClH3N OH O O 178 DCC, CuCl OMe OMe N EDC, DIPEA N DMF, rt, o/n H H 85% O DMF, rt, o/n O 79% 179 174
OR O O O O O OR O O oxidant OMe N N HN H solvent H O O MeO O O O 182 180a: R = Me 181a/b 180b: R = Ac
To both prevent formation of the p-quinone ketal 182 and to generate a more stable, longer-lived o-quinone ketal, phenol 179 was modified according to Liao’s detour method.38 Thus, N-acylated serine phenol 179 was brominated using N- bromosuccinimide in acetic acid to provide the 4-bromophenol derivative 183 in high yield (Scheme 37). Dehydration of 183 using the previously established conditions gave dehydroalanine derivative 184 in 66% unoptimized yield. Treatment of bromophenol 184 with iodobenzene diacetate in methanol did in fact provide the correctly functionalized dienone 185, which could be isolated via an extractive workup. However, prolonged
45 heating of 185 in methanol did not result in cycloaddition reaction to give adduct 186.
Switching the solvent to toluene and heating at reflux or in a microwave reactor at 170 °C also failed to provide any of the desired cycloadduct 186, but instead led to some dimerization of the dienone. Additionally, attempted Lewis acid catalyzed cycloaddition of
186 with either AlCl3, Et2AlCl, or TiCl4 in dichloromethane at temperatures ranging from
-78 °C to reflux did not produce the desired cycloadduct 186.
Scheme 37
OH OH OH O OH O NBS, AcOH OMe DCC, CuCl OMe N N H H rt, 4 h O DMF, rt, o/n O 94% 66% Br 179 183
OH O O O OMe OMe OMe OMe O O N PhI(OAc)2 N H H O MeOH or O HN CH2Cl2 Br Br MeO O 184 185 186
2.5 – Intermolecular Diels-Alder Approaches to Lycopladine H
2.5.1 – Revised Retrosynthetic Analysis
Since the intramolecular Diels-Alder route to lycopladine H (21) described above appeared to be problematic, we instead envisioned that the [2.2.2]-bicyclooctane core could be formed through an intermolecular cycloaddition strategy (Scheme 38).
Retrosynthetically, the natural product 21 would arise via deprotection of the C-13
46 carbonyl subsequent to elaboration of the ester moiety of 187 to a functionalized ketone followed by piperidone formation as in the intramolecular approach (cf. Scheme 6). The
8-membered azocane ring of tricycle 187 would be formed by intramolecular samarium- promoted Barbier coupling of alkyl halide to the C-12 ketone of 188, which in turn would be prepared by alkylation of protected aminoketone 189. Amino ketone 189 would arise from protection of the C-13 ketone of α-keto ketal 190, which is necessary to differentiate the C-12 and C-13 carbonyls of the masked 1,2-diketone functionality. Removal of the dimethyl ketal protecting group from 190 and oxidation of the primary alcohol to the corresponding ester would then furnish amino ketone 189. Protected aminoalcohol 190 would come from nitroalkene 191 via a hydroxyl-directed hydrogenation of the alkene to set the C-15 stereochemistry followed by nitro group reduction and protection of the resulting amine. Nitro alcohol 191 would be prepared from a stereoselective Henry reaction of nitroalkene 192 to set the C-5 stereocenter. Nitroalkene 192 would result from a key intermolecular oxidative dearomatization/Diels-Alder cycloaddition of phenol 84b and nitroethylene (193).
47
Scheme 38
OH OR X O O PG13 PG 12 N RN RN CO R O 2 CO2R lycopladine H 187 188 (21)
O MeO OMe MeO OMe O O PG
RHN O2N RHN 15 5
CO2R HO HO 189 190 191
MeO OMe OH O OMe + NO2
NO2 192 84b 193
2.5.2 – Model Study with Creosol
Since no reaction of nitroethylene with an o-quinone ketal had been previously reported, we decided that a model study should be performed to test the feasibility of this reaction.62 As 2-methoxy-4-methylphenol (i.e. creosol, 194) is far less expensive than the requisite 2-methoxy-5-methylphenol (84b), this substrate was chosen for the initial exploratory reactions.
When iodobenzene diacetate was added to a mixture of creosol (194) and freshly prepared nitroethylene73, 74 in refluxing methanol, bicyclooctene 195 was obtained in good yield as a single regio- and diastereomer possessing a C-8 rather than the necessary
48
C-15 methyl (Scheme 39). Surprisingly, although it is a very good Michael acceptor, nitroethylene reacts as a dienophile in preference to an addition reaction with the methanol solvent. Previous studies have shown that nitroethylene is relatively stable in alcoholic solvents, taking up to a month to achieve full conversion to the ether at room temperature.75 Nonetheless, three equivalents of nitroethylene were required to achieve the highest yield of 195. The regio- and endo-selectivity of the cycloaddition was confirmed by 2D NMR analysis and X-ray crystallography (Figure 2-5 a).
With nitro compound 195 in hand, a Henry reaction was explored to ensure the proper C-5 stereochemistry could be obtained. Thus, treatment of nitro compound 195 with triethylamine in the presence of aqueous formaldehyde furnished nitro alcohol 196 with complete stereoselectivity for the desired C-5 configuration, which was again confirmed by 2D NMR analysis and X-ray crystallography (Figure 2-5 b). We propose that the endo alcohol is favored over the exo isomer due to approach of the formaldehyde from the less congested bottom face rather than the top face, which is blocked by both the ketone and ketal moieties.
Scheme 39
OH MeO OMe MeO OMe OMe O aq. CH O O PhI(OAc)2 2 8 O N 2 5 NO2 15 Et3N, MeCN rt, 36 h MeOH, 68 °C, 12 h NO2 HO 85% 87% 194 195 196
49
Figure 2-5. ORTEP Structures of Diels-Alder Adduct 195 (a) and Henry Product
196 (b)
(a) 195 (b) 196
2.5.3 – Reactions of 2-Methoxy-5-Methylphenol and Related Systems
Having demonstrated the feasibility of o-quinone ketal [4+2] cycloadditions with nitroethylene, we next explored the analogous reaction with the requisite 2-methoxy-5- methylphenol (84b) (Scheme 40). Due to the high cost of the commercially available material, phenol 84b was synthesized in nearly quantitative yield via a Wolff-Kishner reduction of isovanillin (197).76 Oxidative dearomatization of phenol 84b in the presence of nitroethylene (193) or dehydroalanine derivatives 170 resulted only in the rapid Diels-
Alder dimerization of the o-quinone ketal to form cycloadduct 198 rather than the
50 formation of desired adducts 201a. Unfortunately, this process could not be circumvented by slow addition of the oxidant or by performing the reaction at low temperature.
Moreover, subjection of methyl isovanillate (199),77 which could potentially provide the desired methyl compound 201a through complete reduction of the ester of 201b, to identical reaction conditions also resulted exclusively in the dimeric compound 200, with none of the desired cycloadduct 201b observed.
Scheme 40
OH OH O OMe H2NNH2•H2O OMe PhI(OAc)2, MeOH MeO O KOH, (HOCH ) dienophile MeO O 2 2 OMe 130 °C, 1h, 195 °C, 5 h (100%) 99% OMe 197 84b 198
CO2Me MeO OMe OH PhI(OAc) , MeOH O O OMe 2 MeO MeO C O R2 dienophile 2 MeO OMe X MeO2C (100%) R1 OMe 199 200 201a: X = Me 201b: X = CO2Me 1 2 R = NO2, R = H or 1 2 R = CO2R, R = NHR
Because of the rapid dimerization of the o-quinone ketal produced from phenols
197 and 199, “detour” methods for obtaining the desired bicyclooctane core were examined. As the dimers 198 and 200 were readily formed, methodology involving thermal cycloreversion followed by cycloaddition with an added diene37 was first examined (Scheme 41). However, in the presence of an excess of nitroethylene or amidoacrylates 170 at temperatures up to 220 °C, neither dimer 198 or 200 provided the desired bicyclooctenes 201a or 201b.
51
Scheme 41
R MeO OMe O O MeO dienophile R O 2 MeO xylenes R OMe up to 220 °C R R1 OMe 201a or 201b 198: R = Me 1 2 R = NO2, R = H 200: R = CO2Me 1 2 R = CO2Me, R = NHR
Liao’s bromine “detour” methodology39 was next explored as an alternative
(Scheme 42). Phenol 84b was therefore selectively brominated at C-4 using NBS to give bromophenol 85b. Treatment of bromophenol 85b with iodobenzene diacetate in methanol furnished stable o-quinone ketal 86b. The ketal 86b could be used directly in methanol, after a brief extractive workup, or after chromatographic purification on silica gel. Chromatography of crude 86b resulted in an 86% isolated yield of the quinone ketal, but simple partial purification by extraction gave a nearly quantitative yield of 86b of good enough purity for use in the next step.
The o-quinone ketal 86b was reacted with a variety of dehydroalanine derivatives
170 in attempts to generate aminoester adducts 202, which would introduce the desired functionality at C-5 in a single step, improving the overall step economy of the synthesis compared to the use of nitroethylene. In the case of 170a and 170b, however, prolonged reaction times led only to decomposition or polymerization of the amidoacrylate.
Dehydroalanine 170c was recovered unchanged, even after prolonged microwave heating at 180 °C with ketal 86b, along with the Diels-Alder dimer.
52
Scheme 42
OH O OH OMe OMe PhI(OAc) OMe NBS 2 OMe AcOH, rt, 3 h MeOH, 0 °C, 15 min 98% [86%] Br Br 84b 85b 86b
MeO OMe R2R1N CO2Me O Br MeOH or PhMe R2R1N
170a: R 1 = Ac, R 2 = H CO2Me 170b: R1 = TFA, R2 = H 170c, R1, R2 = Phth 202
Since the dehydroalanine derivatives did not appear to participate in the desired
[4+2] cycloadditions with o-quinone ketal 86b, our focus shifted back to the use of nitroethylene as the dienophile (Scheme 43). Accordingly, phenol 85b was treated with iodobenzene diacetate in methanol, followed by an extractive workup, evaporation of the solvent, and reaction with nitroethylene in toluene at room temperature to provide cycloadduct 203 in very high yield. In contrast to the model study (cf. Scheme 39), optimal results were obtained using a slight molar excess of a 1 M stock solution of nitroethylene in toluene. In addition to providing an excellent yield of 203, this method allowed for preparation and storage of a stock solution of nitroethylene74 instead of requiring freshly prepared material. Subsequent Henry reaction of nitro compound 203 with aqueous formaldehyde using the previously established conditions (cf. Scheme 39) generated nitro alcohol 204, the structure of which was confirmed by X-ray crystallography (Figure 2-6).
53
Although Liao and coworkers have most frequently employed tributyltin hydride- mediated debromination in their “detour” methodology,39 this procedure was expected to be incompatible with the nitro functionality.78 Transfer hydrogenation with a homogeneous palladium catalyst, however, easily removed the bromine of 204 to furnish alkene 191 without affecting any of the other functionality.
With the desired compound 191 in hand, the hydroxyl-directed hydrogenation of
79 the alkene was examined next. Previously, both [Rh(nbd)(dppb)]BF4 and the Crabtree catalyst [Ir(cod)(py)(PCy3)]PF6 have been shown to be effective in reducing trisubstituted alkenes with a high degree of facial selectivity facilitated by a hydroxyl directing group.80
The rhodium-based catalysts have also been shown to be chemoselective for alkenes in the presence of a nitro functionality.81 However, upon hydrogenation of alkene 191 using either the Rh or Ir catalysts, the desired alkane 205 was not observed. Increasing temperature and hydrogen pressure had no effect on the reaction, resulting in the recovery of the majority of the starting alkene 191.
54
Scheme 43
OH MeO OMe MeO OMe 1) PhI(OAc)2, MeOH OMe 0 °C, 15 min O CH O , Et N O Br 2 (aq) 3 Br 2) nitroethylene MeCN, rt, o/n O2N PhMe, rt, o/n 82% Br 99% NO2 HO 85b 203 204
[Ir(cod)(py)(PCy3)]PF6 MeO OMe or MeO OMe O O HCO2H, Bu3N [Rh(nbd)(dppb)]BF4
O2N O2N Pd(PPh3)2Cl2 H2 (up to 500 psi) DMF, 80 °C, 16 h CH2Cl2, rt, o/n H 84% HO HO 191 205
Figure 2-6. ORTEP Structure of Henry Product 204.
55
While attempting various directed homogeneous hydrogenation conditions, a standard heterogeneous hydrogenation was attempted in order to generate and characterize the two C-15 diastereomers that we anticipated would be produced (Scheme
44). To our delight, hydrogenation of 191 over 10% palladium on carbon gave the desired
C-15 methyl diastereomer 205 in an approximately 25:1 ratio versus the epimeric compound 206. The stereochemistry of 205 was confirmed by 2D NMR experiments and
X-ray crystallography (Figure 2-7). By lowering the catalyst loading, the diastereomeric ratio was improved to >49:1, which corresponds to the limit of detection by 1H NMR for this compound. This high degree of facial selectivity in the hydrogenation is likely the result of significant steric interactions between the catalyst and the bulky C-12 methoxy group, which shields the top face of the molecule.
Scheme 44
MeO 12 OMe MeO OMe MeO OMe O O O H2 (1 atm), 10% Pd/C + O2N O2N O2N H 15 EtOH, AcOH, rt, 18 h 99% H HO HO HO 191 205 206 10% Pd: 25:1 1-2% Pd: ≥ 49:1
56
Figure 2-7. ORTEP Structure of Hydrogenation Product 205.
To further functionalize the molecule, nitro alcohol 205 was next treated with various oxidants in order to generate the aldehyde 207a (Dess-Martin, Parikh-Doering,
PDC), the carboxylic acid 207b (Jones), or the methyl82-84 or trifluoroethyl esters84 207c, but without success (Scheme 45). Since oxidation of the alcohol did not provide oxidized products 207, reduction of the nitro group of 205 to the corresponding amine 208 was briefly examined. The nitro group was not reduced under hydrogenation conditions with nickel, palladium, or platinum catalysts, even when pressures up to 1000 psi were employed. Reduction of 205 by non-catalytic means with zinc, aluminum, or iron led only to recovery of starting material 205, decomposition, and/or the generation of the corresponding hydroxylamine 209, with none of the desired amine 208 observed in any case.
57
Scheme 45
MeO OMe MeO OMe MeO OMe MeO OMe O O O O [ox] red]
O2N O2N H2N HOHN
O X HO HO HO 207a: X = H 205 208 209 207b: X = OH 207c X = OR
2.5.4 – A More Convergent Strategy via a Henry Reaction of an Alkyl Aldehyde
One method of circumventing some of the difficulties of further reactions with nitro alcohol 205 would involve using an alkyl aldehyde to introduce additional functionality via a Henry reaction, which would also reduce the number of linear steps in the synthesis. We envisioned that spirocyclic piperidone 210, a precursor to lycopladine H
(21), would arise from debromination and selective hydrogenation of bromoalkene 211
(Scheme 46). Piperidone 211 would be formed through intramolecular cyclization of the amine and a suitably functionalized alkyl ketone 212. The amino ketone 212 would come from oxidation of the alcohol and reduction of the nitro group of nitro alcohol 213. Nitro alcohol 213 would then be generated from a stereoselective Henry reaction of an appropriately functionalized aldehyde 214 with previously prepared nitroalkene 203, in a manner similar to what had previously been done with formaldehyde.
58
Scheme 46
MeO OMe MeO OMe MeO OMe O O O Br Br RN RN RHN O O X O 210 211 212 X = Hal, OR, etc.
MeO OMe MeO OMe O O Br O Br + O N X 2 H X OH NO2 213 203 214
To examine the feasibility of this route, we chose hydrocinnamaldehyde (215) as a model system due to the ease of monitoring the reaction by thin-layer chromatography
(Scheme 47). Subjection of nitro compound 203 and aldehyde 215 to previously established Henry reaction conditions failed to provide any of the desired nitro alcohol
218, but instead gave a product as an inseparable 3:2 mixture of diastereomers with the same molecular weight as 218 as determined by mass spectrometry. After careful examination of this mixture via NMR, it was determined that the product was a mixture of epimeric hemiketals 216. We postulate that this product is formed due to the inherent reversibility of the Henry reaction.85 Thus, treatment of nitro compound 203 with a weak base like triethylamine gives an equilibrium mixture of nitronate anion 217 and starting material 203. Approach of aldehyde 215 is expected to occur from the less-hindered face of anion 217 to furnish the desired endo Henry adduct 218. However, this reaction is probably reversible. Approach of aldehyde 215 from the more-hindered face of 217 gives
59 the undesired exo adduct 219, which is likely also in equilibrium with nitronate 217. In this exo case, alcohol 219 can cyclize onto the nearby ketone to form a stable cyclic hemiketal 216. Interestingly, this product 216 does not undergo reversion to the nitronate
217 when resubjected to the reaction conditions (Et3N, CH2Cl2, rt), confirming that it is thermodynamically stable.
Scheme 47
MeO OMe MeO OMe O O O OH Br 215 Br
Et3N, CH2Cl2, rt H 87% NO2 NO2 203 216 3:2 dr
MeO OMe O HO Br
NO2 219 MeO OMe 215 O Br MeO OMe O O N Br 215 O O2N 217 OH
218
Although conventional wisdom suggests that the choice of solvent and base “does not have significant influence on the outcome of the [Henry] reaction,”86 we eventually discovered appropriate reaction conditions to obtain the desired Henry product 218. By using solid-supported tertiary amine base (Amberlyst A21)87 at low temperature and relatively short reaction time, the desired nitro alcohol 218 was obtained as a 2:1
60 diastereomeric mixture in 42% isolated yield after chromatographic purification (Scheme
48). Oxidation of 218 with Jones reagent then furnished nitro ketone 220 in 33% yield.
Forgoing the purification of alcohol 218, which likely caused a significant amount of retro-Henry decomposition, and instead immediately oxidizing the crude alcohol provided ketone 220 in a more respectable 51% isolated yield over the two steps.
To examine the postulate that a retro-Henry/Henry equilibrium was responsible for the formation of the observed cyclic hemiketal 216, purified alcohol 218 was treated with triethylamine, resulting in a 72% yield of ketal 216 in the same 3:2 diastereomeric ratio as produced by the direct reaction of the nitro compound with the aldehyde. In this experiment, a small amount of nitroalkane 203 and hydrocinnamaldehyde (215) were observed as well. This result provides strong evidence in favor of the reaction pathway shown in Scheme 47.
Scheme 48
MeO OMe MeO OMe MeO OMe O O O 215 Br Jones reagent Br Br O2N O2N Amberlyst A21 [33%] THF, -10 °C, 6 h or 51% OH over 2 steps O NO2 42% 203 218 220 2:1 dr
Et N 3 72% CH2Cl2
216 3:2 dr
With these results suggesting that the necessary nitro ketone substrate could be accessed, several functionalized aldehydes were examined in the Henry reaction with 203 under a variety of conditions (Table 2-2). Further optimization was first carried out using
61 hydrocinnamaldehyde (215, cf. Scheme 48). Henry reaction using triethylamine as the base routinely provided the cyclized ketal 216, irrespective of the solvent used (entries 1–
3), although in THF the rate of formation of 216 seemed to be slightly slower. Soluble bases such as tetramethylguanidine88 or LHMDS (entries 4, 5) provided disappointing results, as did the use of alumina with or without added oxidant (entries 6, 7).89 At room temperature, Amberlyst A2187 provided the cyclized ketal 216 (entry 8), but at a relatively slow rate compared to the other bases. By lowering the temperature (entries 9, 10), the ratio of desired Henry product 218 to cyclized ketal 216 was improved to a serviceable amount (cf. Scheme 48). During our screening of oxidants, we determined that Parikh-
Doering and PDC oxidations (entries 10, 11) did not provide ketone 220 fast enough to prevent the competing retro-Henry reaction. Oxidation with more reactive Jones reagent, however, did furnish the desired ketone (entry 12).
When the aldehyde was changed to 4-O-TBS-butanal (221a), homogeneous bases provided the corresponding cyclized ketal 224a, as expected (entries 13, 14). Using the conditions optimized for hydrocinnamaldehyde (i.e., entry 9), no significant reaction was observed with aldehyde 221a at -10 °C (entry 15). When the temperature was raised to 0
°C, the reaction proceeded slowly, giving a mixture of the desired alcohol 222a and the cyclized product 224a (entry 16); further temperature increase led only to the undesired hemiketal 224a (entry 17).
Dimethoxy ketal aldehyde 221b showed reactivity similar to aldehyde 221a when
Amberlyst A21 was used as the base (entries 18–20). Tetrabutylammonium fluoride
(TBAF), which was incompatible with silyl ether 221a, proved to be a more appropriate
62 choice of base with 221b. At -45 °C, the reaction provided the desired Henry product
222b (entry 21), but higher temperatures (-30 °C) gave the undesired cyclic hemiketal
224b (entry 22). When lower temperatures (-78 °C) were employed, the reaction did not proceed at all (entries 23).
Because substrates derived from aldehydes 221a and 221b are likely incompatible with a Jones oxidation, ester aldehyde 221c was examined. Potassium t-butoxide, a previously untested base, caused the decomposition of the starting material 203 (entry
24). Use of Amberlyst A21 as the base gave no appreciable Henry product 222c at 0 °C, and provided only the hemiketal 224c at room temperature (entries 25, 26).
Formation of the silyl nitronate from 203, followed by fluoride-catalyzed Henry reaction90 was attempted in order to form the β-nitro silyl ether, a strategy which would potentially suppress the undesired retro-Henry reaction via formation of the silyl ether corresponding to 222c (entry 27). This process, however, resulted only in the recovery of the starting alkyl nitro compound 203. The TBAF-promoted reaction of 203 and 222c
(entries 28-31) did not proceed well at low temperatures, and the reaction was extremely sluggish at -30 °C. Further warming to 0 °C allowed the reaction to proceed, but the desired ketone 223c was not isolated upon in situ Jones oxidation after the nitro compound 203 was consumed. Instead, only the cyclized hemiketal product 224c could be obtained—unaffected by the Jones reagent—along with a significant amount of decomposition product.
63
Table 2-2. Attempted Henry Reactions with Nitro Ketone 203
MeO OMe MeO OMe O MeO OMe MeO OMe O O O Br O OH Br R H Br R Br O N O N base, solvent 2 2 t, T H NO 2 [ox] R OH R O NO2 203 215: R = Ph 218 220 216 221a: R = CH2OTBS or or or 222a–c 223a–c 221b: R = CH(OMe)2 224a–c 221c: R = CO2Me
Aldehyde Base Solvent Temp Oxidant Result
1 215 Et3N MeCN rt – 216 2 " " CH2Cl2 " – 216 3 " " THF " – 216 4 " TMG THF " – 216 5 " LHMDS " " – decomp
6 " alumina " " CrO3/alumina decomp 7 alumina " " – no reaction 8 " Amberlyst A21 THF rt – 216 9 " " " -10 °C – 218
10 " " " -10 °C SO3•Py/DMSO decomp 11 " " " -10 °C PDC decomp 12 " " " -10 °C Jones 220
13 221a Et3N THF rt – 224a 14 " TMG THF " – 224a 15 " Amberlyst A21 THF -10 °C – no reaction 16 " " " 0 °C – 222a + 224a 17 " " " rt – 224a 18 221b Amberlyst A21 THF -10 °C – no reaction 19 " " " 0 °C – 222b (<10%) 20 " " " rt – 224b 21 " TBAF THF -45 °C – 222b 22 " " " -30 °C – 222b + 224b 23 " " " -78 °C – no reaction 24 221c KOtBu tBuOH/THF rt – decomp 25 " Amberlyst A21 THF 0 °C – no reaction 26 " " " rt – 224c 27 " [TBS nitronate] THF " – no reaction 28 " TBAF THF -78 °C – no reaction 29 " " " -45 °C – no reaction 30 " " " -30 °C – 222c (<10%) 31 " " " 0 °C Jones 224c
64
One possible way to avoid the formation of the undesired cyclic ketals like 216 or
224 was to eliminate the C-13 ketone functionality of 203 by reduction to the corresponding alcohol. This strategy would also provide the added benefit of the clear differentiation of the C-13 ketone and C-12 ketal for subsequent transformations. Thus, nitro ketone 203 was reduced using NaBH4 at low temperature, a process that occurred with selective delivery of hydride to the face opposite the bulky bromine and methyl groups to give nitro alcohol 225 as a single diastereomer (Scheme 49). The relative stereochemistry of 225 was confirmed by 2D NMR analysis and X-ray crystallography
(Figure 2-8). Alcohol 225 was protected as both the acetate 226a and the tetrahydropyranyl (THP) ether 226b.
Scheme 49
MeO OMe MeO OMe MeO OMe Ac2O, DMAP O NaBH4, MeOH H OH CH2Cl2, rt, 16 h OR Br Br Br -78 °C to rt, 2 h or 94% dihydropyran NO2 NO2 NO2 PPTS, CH2Cl2 203 225 rt, 24 h 226a: R = Ac, 78% 226b: R = THP, 100%
65
Figure 2-8. ORTEP Structure of Nitro Alcohol 225.
With compounds 225 and 226 in hand, the corresponding Henry reactions using functionalized aldehydes 221b and 221c were again examined (Table 2-3). Using the unprotected alcohol 225, the reaction with aldehyde ester 221c was attempted with various bases. Use of Amberlyst A21 (entry 1) and TBAF (entries 2, 3), which had performed best in earlier reactions, provided only unreacted starting material or decomposition products. Likewise, treatment of nitro diol 225 and aldehyde 221c with triethylamine, potassium t-butoxide, potassium carbonate, and LHMDS (entries 4–7) led only to the recovery of starting material. The reaction of protected derivatives 226a and
226b (entries 8, 9) using TBAF as a base were also examined. In neither case, however, was any reaction observed. Reaction of THP-protected nitro compound 226b with a large excess of ketal aldehyde 221c did provide a trace of the desired alcohol 227 (ca. 5% by 1H
NMR, entry 10). We postulate that in each of the aforementioned cases, the aldehyde
66 undergoes polymerization or destruction via base-mediated aldol or Cannizzaro reactions, respectively. Additionally, as evidenced in entry 10, we hypothesize that the desired Henry products did form, but are disfavored in the equilibrium established in the reversible reaction. This may be the result of steric crowding at the newly formed C-5 quaternary center and a 1,3-diaxial interaction between the nitro group and the newly introduced hydrogen from reduction of the C-13 ketone.
Table 2-3. Attempted Henry Reaction with Nitro Alcohols 225 and 226.
MeO OMe O MeO OMe H13 OR OR Br R H Br O N base, solvent 2 5 t, T NO2 R OH 221b: R = CH(OMe)2 225, 221c: R = CO2Me 227 226a, 226b
Aldehyde SM Base Solvent Temp Time Result 1 221c 225 Amberlyst A21 THF rt o/n no rxn 2 TBAF " 0 °C 2 h no rxn 3 " " rt o/n decomp
4 Et3N THF rt o/n no rnx 5 KOtBu tBuOH/THF rt o/n no rxn
6 K2CO3 MeOH rt o/n no rxn 7 LHMDS THF -78 °C to rt o/n no rxn 8 226a TBAF THF rt 2 d no rxn 9 226b TBAF THF rt o/n no rxn 10 221b 226b TBAF THF rt 2 d <5% 227
2.5.5 – Return to a Formaldehyde-Based Approach
Based on the poor results using functionalized aldehydes, we decided to revisit the use of formaldehyde in the Henry reaction. We reasoned that this reaction would be more productive, as it is known that reactions of sterically hindered nitro compounds like 203
67 with formaldehyde show lower reversibility than with higher aldehydes such as 221.91
Indeed, when nitro alcohol 225 was reacted with aqueous formaldehyde using the previously developed method (cf. Scheme 39), the desired nitro diol 228 was slowly formed as a single C-5 epimer (Scheme 50). Efforts to increase the reaction rate by raising the temperature or equivalents of formaldehyde led to lower yields and the formation of some of the undesired C-5 epimer. Alcohol 228 was bis-acylated with both acetic anhydride and benzoyl chloride to provide the nitro diesters 229a and 229b, respectively, in high yields.
Scheme 50
MeO OMe MeO OMe MeO OMe H OH HCHO (aq) H OH Ac2O or BzCl H OAc Br Br Br O N O N Et3N, MeCN 2 5 DMAP, py 2 rt, 3 d CH2Cl2, rt, 2-3 h NO2 89% HO AcO 225 228 229a: R = Ac, 99% 229b: R = Bz, 98%
At this point, we decided to attempt reduction of the nitro group of 228 to the C-5 amino group that would eventually become part of the azocane and piperidone functionalities of lycopladine H. This reduction was initially attempted with the unprotected diol 228 (Table 2-4), using with a variety of activated zinc reagents, including zinc amalgam,92 zinc-silver93 and -copper94 couples, and HCl-washed zinc dust. It was thought that the Zn(Ag) or Zn(Cu) couples might also facilitate the simultaneous reduction of the nitro group and debromination of the alkene through the formation and protonolysis of an organozinc intermediate. In all cases, however, reduction of nitro compound 228 at 0 °C in alcoholic solvent afforded only the corresponding
68 hydroxylamine 231a, with no concomitant debromination observed (entry 1). When the temperature was increased, further reduction of the hydroxylamine 231a to the amine
230 did not occur, with increasing amounts of decomposition products being observed instead (entry 2, 3). Zinc reduction of 228 in acetic acid/acetic anhydride, a method that could in principle activate the hydroxylamine 231a as the N- or N-,O- acetate for further reduction to the amine, instead furnished a mixture of mono- and bis-O-acylated hydroxamic acids 231b and 231c at room temperature, and led to decomposition when the reaction was heated (entries 4, 5). Treatment of nitro diol 228 with a variety of other traditional reductants including iron/HCl and aluminum amalgam led only to the recovery of starting material, even when elevated temperatures were employed (entires 6,
7).
Catalytic hydrogenation of 228 at atmospheric and elevated pressures in a variety of solvents using 10% palladium on carbon, active95 Raney nickel, and Raney nickel further activated with hexachloroplatinic acid96 led exclusively to the debrominated alkene
232, with no reduction of the nitro group or further reduction of the alkene (entries 8–
15). Long reaction times and high pressures effected the eventual decomposition of 232
(entry 15), perhaps due to base-promoted retro-Henry reaction.
Transfer hydrogenation conditions proved equally ineffective (entries 16–20), although some interesting results were obtained using these methods. When substrate
228 was subjected to the previously established debromination conditions (cf. Scheme
43), the result was decomposition of the starting material (entry 16). Transfer hydrogenation with ammonium formate or triethylamine/formic acid catalyzed by
69 palladium on carbon at room temperature (entries 17, 20) failed to reduce the nitro group, but emerged as the best methods for debromination of nitro diol 228 to give alkene
232.
When nitro compound 228 was treated with samarium diiodide in THF/MeOH97 or isopropylamine/water98, only decomposition was observed, likely through reduction of other functional groups in the molecule (entries 21, 22). Reduction of 228 was attempted
99 100 with hydrazine monoformate and magnesium, LiAlH4, in situ-formed nickel boride,101 zinc borohydride pyridine complex,102 and low-valent titanium,103 with each failing to provide the desired amine 230 (entries 23-27).
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Table 2-4. Attempted Reduction of Nitro Diol 228.
MeO OMe MeO OMe MeO OMe MeO OMe H OH H OH H OR3 H OH Br [red] Br R1 Br H O2N H2N N O2N HO HO HO R2O HO 228 230 231a: R1, R2, R3 = H 232 231b: R1, R2 = Ac, R3 = H 231c: R1, R2, R3 = Ac
Entry Reductant Solvent T, °C Result 1 Zn/HCl [Zn(Hg), Zn(Ag), Zn(Cu), and HCl washed Zn] i-PrOH 0 231a 2 Zn/HCl i-PrOH 20 231a /decomp 3 Zn/HCl i-PrOH 60 decomp
4 Zn Ac2O/AcOH 20 231b and 231c
5 Zn Ac2O/AcOH 65 decomp 6 Fe/HCl EtOH 60 no rxn 7 Al(Hg) EtOH 20 no rxn
8 H2 (1 atm) Pd/C EtOH 20 232 9 H2 (50 atm) Pd/C EtOH 20 232 10 H2 (1 atm) Pd/C EtOH/AcOH 20 232 11 H2 (30 atm) Pd/C EtOH/AcOH 20 232 12 H2 (50 atm) Pd/C Ac2O 20 232, 231b 13 H2 (25 atm) Ra-Ni EtOH 20 no rxn 14 H2 (25 atm) Ra-Ni, H2PtCl6, Et3N EtOH 20 no rxn 15 H2 (100 atm) Ra-Ni, H2PtCl6, Et3N EtOH 20 decomp 16 Bu3N, HCO2H, Pd(PPh3)2Cl2 DMF 85 decomp 17 NH4O2CH, Pd/C EtOH 20 232 18 NH4O2CH, Pd/C EtOH 40 232, decomp 19 NH4O2CH, Pd/C EtOH 60 decomp 20 1:2 Et3N/HCO2H, Pd/C neat 20 232 21 SmI2 THF/HMPA 20 decomp 22 SmI2, i-PrNH2, H2O THF 20 decomp 23 Mg, H2NNH2•HCO2H MeOH 20 decomp 24 LiAlH4 THF 20 decomp 25 NaBH4. NiCl2 MeOH 20 no rxn 26 ZnBH4•Py THF/EtOAc 20 no rxn 27 TiCl4, Mg THF/t-BuOH 20 no rxn
With the possibility that the free hydroxyl groups were somehow impeding the nitro reduction or leading to decomposition via a retro-Henry process, the protected alcohols 229a and 229b were also examined (Table 2-5). Again, various activated zinc
71 reductants were examined, with no reduction beyond the hydroxylamines 234 at 0 °C
(entry 1) or room temperature (entries 2, 15). Reduction with zinc/HCl at elevated temperature caused the decomposition of both 229a and 229b (entries 3, 16). Zinc reduction in the presence of acetic anhydride led to the corresponding hydroxamic acids
235 (entries 4, 17), while gaseous hydrogen and transfer hydrogenation again only provided debrominated alkenes 236 at ambient temperatures and caused decomposition at elevated temperatures (entries 6–10, 19–22). Magnesium and hydrazine monoformate, nickel boride, low valent titanium, and aluminum amalgam were also unsuccessful at producing the amine 230a from nitro diacetate 229a (entries 11–14). Interestingly, on one occasion, aluminum amalgam reduction of 229b provided the hydroxylamine 234b as the main product, along with roughly 18% of the N-benzoyl amide 237 resulting from an intramolecular transfer of the O-benzoyl protecting group (entry 23).104 However, this reaction was not reproducible under seemingly identical conditions or under any variations in solvent and temperature.
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Table 2-5. Attempted Reduction of Nitro Diesters 229a and 229b.
MeO OMe MeO OMe MeO OMe MeO OMe MeO OMe H OR H OR H OR H OR H OBz Br [red] Br R1 Br H Br O2N H2N N O2N BzHN HO RO RO RO RO HO 229a: R = Ac 233a/b 234a/b: R1 = H 236a/b 237 229b: R = Bz 1 235a/b: R = Ac
Entry Substrate Reductant Solvent T, °C Result 1 229a Zn/HCl [Zn(Hg), Zn(Ag), Zn(Cu), HCl washed Zn] i-PrOH 0 234a 2 Zn/HCl i-PrOH 20 234a
3 Zn/HCl i-PrOH 60 decomp
4 Zn Ac O/AcOH 20 235a 2 5 Zn, Boc O, aq. NH Cl MeOH 20 234a 2 4 6 H (1 atm) Pd/C EtOH 20 236a 2 7 H (50 atm) Pd/C EtOH 20 236a 2 8 NH O CH, Pd/C EtOH 20 236a 4 2 9 NH O CH, Pd/C EtOH 40 236a, decomp 4 2 10 NH O CH, Pd/C EtOH 60 decomp 4 2 11 Mg, H NNH •HCO H MeOH/THF 20 decomp 2 2 2 12 NaBH , NiCl MeOH 20 no rxn 4 2 13 TiCl , Mg THF 20 no rxn 4 14 Al(Hg) THF 65 234a
15 229b Zn/HCl i-PrOH 20 234b 16 Zn/HCl i-PrOH 60 decomp
17 Zn Ac O/AcOH 20 235b 2 18 SmI , i-PrNH , H O THF 20 decomp 2 2 2 19 H (1 atm) Pd/C EtOH 20 236b 2 20 H (50 atm) Pd/C EtOH 20 236b 2 21 NH O CH, Pd/C EtOH 20 236b 4 2 22 NH O CH, Pd/C EtOH 65 decomp 4 2 23 Al(Hg) THF/MeOH 65 236b (73%), 237 (18%)
73
2.6 – Studies on Formation of the Azocane Ring
2.6.1 – Attempted Samarium Diiodide Barbier Route
Since its popularization by Kagan and Molander, samarium diiodide has become a popular reagent for various functional group reductions and carbon-carbon bond-forming reactions in organic synthesis.105-108 One of the more useful reactions developed is the samarium variant of the Barbier reaction, in which an organic halide is added in situ to a carbonyl compound. Samarium is often more suitable than other traditional metals used in Barbier reactions, such as lithium, magnesium, and zinc, due to increased functional group tolerance, high levels of chemoselectivity, and homogenous reaction conditions.
The use of samarium diiodide is noteworthy for intramolecular Barbier reactions, particularly in forming ring systems such as cyclopropanes and cyclobutanes that are difficult to access using other methods.
Samarium iodide also has found use in the synthesis of medium-sized rings. For example, Molander demonstrated that an 8-membered ring such as 239 is accessible in high yield from the intramolecular Barbier reaction of alkyl chloride lactone 238 using
109 SmI2 and a nickel catalyst with irradiation by visible light (Scheme 51a). Likewise, in their approach to vinigrol, the Matsuda group performed a diastereoselective reductive coupling of the allyl chloride and aldehyde moieties in monocyclic substrate 240 to give 8- membered cyclic homoallylic alcohol 241 in excellent yield (Scheme 51b).110 After oxidation of alcohol 242 to the corresponding aldehyde, the Tachibana group used an intramolecular samarium iodide-mediated Reformatsky-like reaction to form a 9-
74 membered ring, which after acetylation provided tricyclic acetate 243 in 68% yield over three steps (Scheme 51c).111 In each of these examples, high-yielding formation of medium rings is facilitated by the substrate conformation, which puts the two reactive centers in suitable proximity.
Scheme 51
O O SmI a) 2 O cat. NiI2, hν 91% OH Cl 238 239
HO BnO O BnO H Cl H SmI2 b) THF/HMPA 99% MOMO MOMO 240 241
H H H O H O 1) SO •Py, DMSO, Et N O O H 3 3 c) H 2) SmI , THF -78°C O 2 O H OH 3) Ac2O, DMAP, 0 °C H OAc O Br 68% O 242 243
Although we could not fully reduce the nitro group of 228 to the corresponding amine, we reasoned that the nitro or hydroxylamine functionalities could be carried through and reduced at a later point in the sequence. We decided to first explore a strategy of using samarium diiodide to close the azocane ring of lycopladine H, a process that could also be used to further reduce the hitherto unreactive hydroxylamine group.
Samarium diiodide has been shown to cleave N–O bonds, especially those activated as N-
75 acyl derivatives.112-114 Thus, we reasoned that reduction and Barbier reaction might be performed in tandem, with the N–O cleavage expected to occur faster than the reaction of
115-117 SmI2 with an alkyl halide.
To explore the feasibility of this route, nitro diol 228 was debrominated by transfer hydrogenation with dry ammonium formate in ethanol to afford alkene 244 (Scheme 52).
The free hydroxyl groups of 244 were acylated with acetic anhydride or benzoyl chloride to provide protected nitro diols 245a and 245b, respectively. The nitro group of protected and unprotected compounds 245a/b and 244 were reduced in excellent yields to the corresponding hydroxylamines 246 using zinc in dilute hydrochloric acid.
Scheme 52
MeO OMe MeO OMe H OH H OH Br NH4O2CH H RCOCl O N O N 2 10% Pd/C, EtOH 2 DMAP, py rt, 2 h CH2Cl2 HO 75% HO rt, 3 h 228 244
MeO OMe MeO OMe H OR Zn0, HCl H OR
O2N HOHN H2O/i-PrOH 0 °C or rt, 1-3 h RO RO 245a: R = Ac, 99% 246a: R = Ac, 98% 245b: R = Bz, 98% 246b: R = Bz, 99% 246c: R = H, 99% (from 244)
Hydroxylamine 246b was then further N-acylated with 3-chloro- or 3- bromopropionyl chlorides to give hydroxamic acids 247a and 247b, respectively (Scheme
53). Removal of the ketal functionality in substrates 247 could not be accomplished under standard aqueous acid-catalyzed conditions. However, after some experimentation,
76 deketalization of 247a and 247b by ketal transfer to acetone catalyzed by indium (III) triflate118 provided the ketones 248a and 248b in good yields.
Scheme 53
X X O MeO OMe MeO OMe O OBz Cl X O OBz In(OTf)3 O OBz HOHN N N Py, CH2Cl2 acetone 0 °C, 15 min HO rt, 15 min HO BzO BzO BzO 246b 247a: X = Cl, 98% 248a: X = Cl, 99% 247b: X = Br, 98% 248b: X = Br, 97%
We next attempted the key intramolecular samarium Barbier reactions of halo ketones 248a and 248b in THF or THF/HMPA at temperatures ranging from -78 °C to reflux (Scheme 54). However, these experiments failed to give any of the desired azocane lactam 249. We also explored an alternative method for Barbier coupling involving the slow addition of a solution of SmI2 to the reaction mixture until the characteristic color change of blue Sm+2 to yellow Sm+3 is no longer observed. Using this procedure, we observed that more than 10 equivalents of SmI2 were needed before this color change ceased instead of the expected 4 equivalents. This observation provided strong evidence that overreduction of 248 was occurring, possibly in preference to SmI2 reacting with the halide.119
Scheme 54
X O OH O OBz O OBz SmI2 HN N THF or HO THF/HMPA BzO BzO 248a/b 249
77
Since alkyl iodides are considerably more reactive than chlorides and bromides in
SmI2 Barbier reactions, we next decided to prepare alkyl iodide 250 via a Finkelstein reaction of chloride 248a (Scheme 55). However, upon subjection of chloride 248a to standard conditions, the isoxazolidinone 251 was isolated instead of the desired iodide
250. When the Finkelstein reaction of 248a was performed at room temperature instead of reflux, only starting material was recovered.
Scheme 55
Cl O I O O O O OBz NaI O H OBz H OBz not but N acetone N N HO 55 °C HO O BzO BzO BzO 248a 250 251
Because we believed it possible that single-electron transfer leading to decomposition may occur with the benzoyl protecting groups of 248, the diacetate 246a was also examined (Scheme 56). Under nearly identical reaction conditions (cf. Scheme
53), hydroxylamine 246a was elaborated to ketone substrate 252. Unfortunately, attempted Barbier reaction with samarium diiodide under a number of conditions led only to decomposition of 252 rather than the formation of the desired azocane 253. Since free alcohols are known to be compatible with samarium reactions and ketones with α- electron withdrawing groups are susceptible to elimination/reduction, the same sequence was attempted with unprotected diol 246c. However, this substrate proved incompatible with the acylation conditions with 3-chloropropionyl chloride to give the corresponding
N-acyl compound 254, preventing examination of the Barbier reaction.
78
Scheme 56
MeO OMe Cl O OH OAc O OAc O OAc SmI2 HOHN N THF or HN HO THF/HMPA AcO AcO AcO 246a 252 253
MeO OMe Cl O
OH O OH HOHN N HO HO HO 246c 254
To further examine the role of the oxygen protecting group, a silyl derivative was desired. The t-butyldiphenylsilyl (TBDPS) group was chosen for its probable stability under the acidic conditions used in the zinc reduction of the nitro group. In order to install the TBDPS group, the ketal of 228 had to first be cleaved to the ketone, as the steric bulk of the methoxy groups only allowed for mono-protection of the less-hindered alcohol
(Scheme 57). The indium triflate method previously used to remove ketal 247 (cf. Scheme
53) proved to be incompatible with the nitro functionality in 228. Use of aqueous acid was also unsuccessful in unmasking the C-12 ketone. After some experimentation, we found that lithium tetrafluoroborate in wet acetonitrile120 furnished the desired α-hydroxy ketone 255 in nearly quantitative yield. O-TBDPS protection of diol 255 using standard conditions gave bis-silyl ether 256 in acceptable yield. Aluminum amalgam reduction of
256 then gave the hydroxylamine 257 in high yield. Zinc/HCl reduction of the nitro group of 256 at room temperature serendipitously provided a mixture of the expected
79 hydroxylamine 257 along with amine 258 as the major product. Increasing the temperature and keeping the reaction time short increased the yield of amine 258 to 71%, with only minimal decomposition.
Scheme 57
MeO OMe O H OH LiBF OH Br 4 Br TBDPS-Cl O N 2 wet MeCN O2N DMF, im 85 °C, 2 h rt, 18 h HO 99% HO 71% 228 255
O O O Al(Hg) OTBDPS THF/MeOH/H2O OTBDPS OTBDPS Br Br + Br O2N or HOHN H2N Zn0, HCl TBDPSO H2O/i-PrOH TBDPSO TBDPSO 256 257 258 Al(Hg): 99% 0% Zn (rt): 26% 53% Zn (60 °C): – 71%
With aminoketone 258 in hand, the azocane ring closure could be examined
(Scheme 58). Acylation of amine 258 with chloropropionyl chloride gave amide 259.
Finkelstein reaction of 259 successfully exchanged the chloride for the desired iodide 260 in excellent yield. Treatment of iodide 260 with SmI2, however, failed to produce the desired cyclized lactam 261. Instead, the products isolated here resulted from reductive dehalogenation of the carbon-iodine bond to the propionamide 262, as well as cleavage of the amide C–N bond to form amine 258.121 No reduction of the ketone or C–Br bonds, or
α-elimination of the silyl ether was observed.
80
Scheme 58
Cl O O O OTBDPS Cl Cl O OTBDPS NaI Br Br H N 2 Et3N, THF HN acetone rt, o/n 50 °C, o/n 98% TBDPSO 97% TBDPSO 258 259
I O OH O O OTBDPS OTBDPS O OTBDPS SmI2 Br O Br + 258 Br not HN but HN THF, rt HN (51%) TBDPSO TBDPSO TBDPSO 260 261 262 (19%)
We next investigated another possible method to close the azocane that involves the samarium iodide induced attack of ketyl radical anion 265 onto an α,β-unsaturated carbonyl species to form samarium enolate 266, methodology that been successfully applied to the synthesis of some 7- and 8-membered ring systems.122, 123 To this end, amine 258 was acylated with acryloyl chloride to give acrylamide 263 (Scheme 59).
However, subjection of acrylamide 263 to samarium diiodide under various conditions failed to furnish the desired 8-membered lactam 264, but instead only led to decomposition of the starting material.
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Scheme 59
O O OH O O OTBDPS OTBDPS O OTBDPS SmI Br Cl Br 2 Br HN H2N HN Et3N, THF rt, o/n TBDPSO 70% TBDPSO TBDPSO 258 263 264
OSmI 2 OSmI2 I2SmO O OTBDPS OTBDPS Br Br HN HN
TBDPSO TBDPSO 265 266
2.6.2 – Attempted Ring-Closing Metathesis Approach to the Azocane Ring
Due to the difficulties encountered in the samarium-based cyclization approach, other options were considered. One well-precedented way of forming medium (7-10 membered) rings involves the ring-closing metathesis (RCM) of a conformationally constrained diene. Such conformational constraints are generally necessary in order to overcome both the enthalpic and entropic barriers that typically disfavor medium ring formation.124 In the case of lycopladine H, we hoped that the rigid bicyclooctane framework could be used in order to facilitate ring closure.
To examine this methodology, nitro ketone 256 was reacted with allyl indium, formed in situ from allyl iodide and indium metal, to provide homoallylic alcohol 267
(Scheme 60). Attack of the organometallic reagent occurred preferentially from the face opposite the bulky TBDPS group due to steric constraints, giving the desired C-12
82 stereochemistry. Attempted formation of alcohol 267 via reaction of ketone 256 with either allyllithium or allylmagnesium bromide resulted in decomposition, while trimethylallylsilane and TiCl4 resulted in no reaction. Nitro compound 267 was then reduced to amine 268 with zinc and hydrochloric acid. A temperature of ca. 45 °C was found to be necessary here to sufficiently solubilize the rather non-polar bis-silyl ether
268.
At this stage we envisioned that amine 268 could be condensed with acetaldehyde followed by acylation to generate the N-protected enamine 269. However, after attempting this transformation under a variety of conditions, it was determined by NMR analysis that the initial condensation of amine 268 with acetaldehyde to form the corresponding imine was not occurring. As the boiling point of acetaldehyde is very low
(ca. 20 °C), the reaction could not be efficiently heated. We instead thought that using phenylacetaldehyde would provide a twofold advantage: the reaction could be heated to drive imine formation, and conjugation with the phenyl ring would stabilize the desired enamine tautomer.
Gratifyingly, when the NMR experiment was repeated with amine 268 and phenylacetaldehyde, conversion to the imine was observed. However, subsequent treatment of the resulting imine with acetic, trifluoroacetic, and Boc anhydrides, as well as acetyl chloride each failed to produce the desired acyl enamine 269, preventing the examination of the RCM reaction to produce tricycle 270.
83
Scheme 60
O 12 OH OH OTBDPS OTBDPS I Zn0, HCl OTBDPS Br Br Br O N O2N 0 2 H2N In , THF/MeOH H2O/i-PrOH rt, 16 h 1 h, 45 °C TBDPSO TBDPSO TBDPSO 68% 87% 256 267 268
R1 OH OH 1 OTBDPS OTBDPS 1) R CH2CHO Br Grubbs' II Br R2N R2N 2 2 2) R 2O/R COCl R1 = H, Ph TBDPSO TBDPSO R2 = Ac, TFA, Boc 269 270
We next turned our attention to an alternative construction of the azocane ring via
RCM of an allylic alcohol and a protected allyl amine rather than the homoallyl alcohol and enamine (Scheme 61). When reacted with vinylmagnesium bromide, ketone 256 rapidly decomposed, even at low temperatures.125, 126 As organocerium reagents are known to be more compatible with enolizable carbonyl compounds than are Grignard or organolithium reagents,125 the vinyl cerium reagent was pre-formed by adding vinylmagnesium bromide to anhydrous cerium chloride in THF at -78 °C. Owing to the instability of vinyl cerium reagents at temperatures above -78 °C, ketone 256 was added slowly to the organometallic suspension at this temperature. These carefully controlled reaction conditions provided allylic alcohol 271 in excellent yield as a single diastereomer, the structure of which was confirmed by 2D NMR analysis.
Reduction of the nitro group of 271 using the previously optimized protocol furnished amine 272, which was acylated with acryloyl chloride to provide acrylamide 273 in 68% unoptimized yield. Ring closing metathesis was expected to take place via an
84 initial Ru-carbene formation with the more electron rich alkene, followed by ring closure onto the acrylamide.127, 128 Regrettably, the desired tricyclic product 274 was not observed, with starting material 273 recovered unchanged even after refluxing in toluene for 24 h.
Scheme 61
O OH OH OTBDPS 0 OTBDPS OTBDPS MgBr Zn , HCl Br Br Br O N O2N H2N 2 CeCl3, THF H2O/i-PrOH -78 °C, 5 h 45 °C, 1 h TBDPSO TBDPSO 96% TBDPSO 96% 256 271 272
OH O OH O OTBDPS O OTBDPS Grubbs' II Br Cl Br RN HN py, CH2Cl2 PhMe rt, 18 h 110 °C, 24 h TBDPSO 68% TBDPSO 273 274
We reasoned that since the acrylamide of 273 was too electron deficient to initiate the metathesis reaction, and the allylic alcohol may have been too sterically hindered, a protected allylamine such as 276 would be a better substrate for RCM (Scheme 62).
However, when amine 272 was treated with allyl bromide or iodide alone or in the presence of various organic or inorganic bases, allylamine 275 did not form, but instead the starting amine was recovered unchanged. The failure of the allylation may be due to the extremely hindered environment around the amino group of 272. Thus, RCM substrate 276 could not be accessed, and we turned to another strategy.
85
Scheme 62
OH OH OH OTBDPS OTBDPS OTBDPS Br X Br Br H2N HN O N R TBDPSO TBDPSO TBDPSO 275 276 272
2.6.3 – Azocane Formation via Hydroaminomethylation
2.6.3.1 – Hydroaminomethylation
The oxo process, also known as hydroformylation, which produces aldehydes from alkenes and alkynes, was discovered by Rolen in the late 1930’s,128 and has since become one of the most common industrial catalytic reactions.129 A decade later, this reaction was extended to the synthesis of amines via reaction of alkenes with carbon monoxide in the
130 presence of water, ammonia, and a nearly stoichiometric amount of Fe(CO)5. Later advances led to the use of carbon monoxide/hydrogen mixtures (syngas) and more efficient transition metal catalytic systems based on rhodium, ruthenium, and iridium.131
Regardless of the catalyst used, the hydroaminomethylation reaction consists of three distinct steps (Scheme 63). An initial metal-catalyzed hydroformylation of alkene
277 gives aldehydes 278 as both the n- and iso- isomers resulting from formylation at the terminal or internal carbon of the alkene, respectively. Condensation of aldehydes 278 with an amine or ammonia provides imines/enamine 279 via attack of the amine on the aldehyde, possibly promoted by the metal, and elimination of water. Imines/enamines
86
279 then undergo transition metal catalyzed hydrogenation to furnish homologated amines 280. The substrate scope of this reaction encompasses both terminal and internal alkenes, and the amine component used can be ammonia or mono- and disubstituted alkyl- and arylamines.
Scheme 63
O R2 R2 R1 N R1 N 1 R H R3 R3 H n-278 N n-279 n-280 [cat] R2 R3 [cat] R1 or or or 2 H 2 H2, CO R 2 R 277 H N N R1 R1 R3 R1 R3 O iso-279 iso-280 iso-278
The mechanism for cobalt-catalyzed hydroformylation of alkenes was elucidated by Heck and Breslow in the 1960’s,132 and the same mechanism is suspected to operate in the rhodium catalyzed variant (Scheme 64). Thus, the stable 18-electron trigonal bipyramidal rhodium precatalyst 281 loses a CO ligand to become the active 16-electron species 282, which then complexes alkene 283 to generate trigonal bipyramidal rhodium
π-complex 284. Migratory insertion and complexation of an additional CO ligand gives alkyl rhodium complex 285. A second insertion, this time into carbon monoxide, gives acyl rhodium intermediate 286, which then undergoes an oxidative addition with molecular hydrogen followed by a reductive elimination of aldehyde 287 to regenerate the active 16-electron rhodium complex 282.
87
Scheme 64
CO P Rh H P CO 281
H O O P C R R H Rh 287 P H 283 282
H2
R H H O R P Rh P P Rh L CO P CO 284 286 L = CO, H 2 CO R
H P Rh CO P CO 285
The selectivity of hydroformylation, and, thereby, hydroaminomethylation, is due in large part to the nature of the phosphine ligand present in the reaction (Table 2-6).133
In the ligand-free reaction of 1-pentene (288) with piperidine (289) (entry 1), the conversion is high, but the reaction shows almost no selectivity for the formation of n- amine 290 over the iso-amine 291. With the addition of triphenylphosphine (entry 2), the total amount of conversion is decreased, but the regioselectivity improves. Tri-o- tolylphosphine (entry 3) gave a lower regioselectivity, as had been previously observed.134
This effect has been explained by the change in the electronic nature of the ligand.135
88
136 However, the larger cone angle of 194° vs. 145° for PPh3 may encourage dissociation to a less sterically demanding P(o-Tol)3 monophosphine-rhodium complex that would not be as sensitive to alkene sterics. The bidentate phosphine bis(diphenylphosphino)ethane
(dppe, entry 4) is not active in hydroaminomethylation, as it tends to bind rhodium in an equatorial/axial mode instead of the necessary bis-equatorial binding. For other bidentate phosphines (entries 5-9), there is a general trend of increased regioselectivity for linear amine 290 over branched amine 291 with increasing bite angle,133 which is in agreement with studies on hydroformylation.137 Xantphos (293, entry 7), with a bite angle of 111.4°, was found to be the ideal ligand for this reaction. NAPHOS (294) and IPHOS (295)
(entries 8 and 9), ligands with a larger bite angle (120°) that have been used successfully for isomerization/hydroaminomethylation of internal alkenes,138 showed greater regioselectivity for linear amine 290 over branched amine 291, but displayed a decrease in overall yield due to the undesired formation of N-formyl piperidine.
89
Table 2-6. Ligand Effects in Rhodium-Catalyzed Hydroaminomethylation.
[Rh(cod) ]BF 2 4 N + HN + N CO (7 bar) H2 (33 bar) 288 289 290 291 MeOH/PhMe
Entry Ligand Bite angle (°) Conversion (%) Linear amine yield (%) 290:291 1 – – 91 50 56:44 a 2 PPh3 145 77 64 86:14 a 3 P(o-Tol)3 194 100 56 57:43 4 dppe 85 0 0 – 5 dppb 98.6 100 73 78:22 6 DPEPhos (292) 102.2 100 91 93:7 7 Xantphos (293) 111.4 100 95 98:2 8 NAPHOS (294) 120 100 84 94:6 9 IPHOS (295) 120 77 50 99:1 a Cone angle values
PR2 O O PR2 PPh2 PPh2 PPh2 PPh2
DPEPhos (292) Xantphos (293) 294: R = Ph, NAPHOS 295: R = (3,5-CF3)Ph, IPHOS
One useful feature of the hydroaminomethylation reaction is the selectivity for amine formation over reaction with hydroxyl groups (Scheme 65). When allylic alcohol
296 is reacted with piperidine (289) in a rhodium-catalyzed hydroaminomethylation, the result is exclusively amino alcohol 297.133 2-Ethyltetrahydrofuran (298), which would arise from the reduction of the hemiacetal intermediate formed via attack of the alcohol on the newly added aldehyde, was not observed. Additionally, it was observed that the use of methanol as a solvent does not interfere with the process, and is in fact critical to the success of the reaction. In aprotic solvents that are often used in hydroaminomethylation
(e.g. PhMe, THF, and MTBE), the hydrogenation of the enamine is likely the rate-limiting
90 step,133 as evidenced by the significant amounts of the enamine intermediate that are isolated. Indeed, in these solvents, it has been shown that electron deficient phosphine- rhodium complexes increase the rate of hydrogenation of neutral enamines, which is in opposition to conventional wisdom.139 A combination of methanol and toluene as the solvent was found to give an optimal yield of amine as well as suppressing the formation of undesired byproducts.
Scheme 65
Rh(cod) BF , Xantphos 2 4 N + OH N CO (7 bar), H (33 bar) OH O H 2 PhMe, MeOH (1/1) 296 289 297 298 125 °C, 6 h not observed 99%
2.6.3.2 – Intramolecular Hydroaminomethylation and Related Reactions
Intramolecular hydroaminomethylation of alkenyl amines, either directly or in a sequential process, is an attractive method of forming nitrogen-containing heterocycles owing to the often straightforward synthesis of the amine precursors as well as the use of low cost syngas as a source of the inserted methylene.131 Hydroformylation followed by reductive amination has been shown to be an efficient method to form piperidine rings from alkenyl azides such as 299 (Scheme 66).140 Mann and coworkers showed that exposure of alkene 299 to syngas under rhodium-catalysis using the ligand biphephos
(300) furnished azido aldehyde 301. Hydrogenation of 301 over Pearlman’s catalyst allowed for the concomitant reductive cyclization to provide 2-substituted piperidines
91
302. Similar methodology was also applied to bis-homoallylic amines 303, which were converted to dialdehydes 304 through double hydroformylation.141 Tandem catalytic reduction of the azide and reductive amination furnished quinolizidines 305. The Mann group successfully applied this methodology to the total syntheses of (+)-lupinine (305a) and (+)-epiquinamide (305b).
In the formation of either piperidines or quinolizidines, the use of the biphephos
(300) ligand was necessary, since phosphines such as Xantphos (293) resulted in significantly lower yields. Rationalization for the attenuation in yield derives from the electron rich triphenylphosphine ligand reacting with the azide functionality of 299 or
303, while the more electron deficient phosphite biphephos does not.
Scheme 66
H2/CO (1:1) 5 bar O Pd(OH)2/C
R N3 Rh(CO)2(acac) R N3 H2 (5 bar) R N biphephos (300) THF, rt, o/n H 299 THF, 65 °C, 4 h 301 302
R R R H2/CO (1:1) 5 bar Pd(OH)2/C
Rh(CO)2(acac) H2 (5 bar) N N3 N 3 300 OHC CHO THF, rt, o/n THF, 65 °C, 4 h 303 304 305a: R = CH2OH, (+)-lupinine 305b: R = NHAc, (+)-epiquinamide
MeO OMe
t-Bu O O t-Bu O P P O O O
biphephos (300)
92
Although the methods using alkenyl azides are synthetically useful, ring closure via hydroaminomethylation of alkenyl amines is a more direct strategy to form nitrogen- containing heterocycles. The Alper group has focused on the development and applications of a diamine rhodium catalyst such as 307.142 Upon treatment with syngas and catalyst 307 at high pressure, o-aminostyrenes 306 were cleanly converted to the corresponding tetrahydroquinolines 308 in high yields (Scheme 67).143 Both primary
(306a) and secondary (306b and 306c) anilines are suitable substrates, as are those containing both electron donating and withdrawing groups on the aromatic ring.
Scheme 67
307 CO/H (55 bar, 7/3) 2 N CO Cl CO Rh Rh PhMe, 120 °C, 48 h CO Cl CO N N NHR R 306a: R = H 308a 89% 307 306b: R = Me 308b 92% 306c: R = Bn 308c 98%
The Alper group extended the scope of their intramolecular hydroaminomethylation methodology to the formation of 7-membered rings via two equally effective reactions (Scheme 68).144 In the first example, alkenyl benzylamine 309 was treated with a CO/H2 gas mixture using catalyst 307, resulting in benzazepines 312 in high yields. Given the success of this reaction, they next examined the intermolecular reaction of aldehyde 310 with anilines 311 under identical conditions. The resulting reductive amination/hydroaminomethylation cascade furnished benzazepines 312 in nearly identical yield.
93
Scheme 68
NHAr 307 309 CO/H2 (55 bar, 7/1) PhMe, 120 °C, 48 h NAr
+ 312 H2N Ar 81–98% CHO 310 311
Hydroaminomethylation has been applied to a limited degree in the formation of medium and large rings. One early example examined the formation of different ring systems via the rhodium-catalyzed reaction of dienes 313 and isopropylamine under a
145 CO/H2 atmosphere at high pressure (Scheme 69). When the unsubstituted diene 313a
(R = H) was employed, the reaction proceeded through hydrocarbonylative cyclization to give intermediate alkyl rhodium cyclic ketone 314. A second insertion of carbon monoxide gave acyl rhodium intermediate 315, which underwent a Paal-Knorr–type reaction with isopropylamine to form pyrrole 316 in low yield.
Alternatively, when the phenyl-substituted alkene 313b (R = Ph) was instead used, the reaction proceeded through hydroformylation and imine formation to give imine
317, which underwent reduction of the imine and a subsequent hydroformylation to provide amino aldehyde 318. A second rhodium-catalyzed reductive amination furnished the 8-membered heterocycle 319 in moderate yield. The authors posited that the observed difference in chemoselectivity between substrates 313a and 313b is mediated by the lower reactivity of the styrenyl alkene, which slows the rate of the second hydroformylation reaction of the styrenyl alkene, allowing for the formation of imine 317.
94
Scheme 69
CO (50 bar) [Rh] [Rh] H (50 bar) 2 O N O O R = H i-Pr 314 315 316 38% [Rh(cod)Cl] R 2 i-PrNH2 120 °C, 3 d 313 Ph Ph CO (90 bar) Ph
H (20 bar) 2 CHO N R = Ph Ni-Pr NHi-Pr i-Pr 317 318 319 58%
Although the ligand-free conditions have shown some utility, the Jackson group demonstrated that the use of a biphephos (300) rhodium catalytic system could provide access to both medium and large rings (Scheme 70).146 A series of terminal alkenyl benzylamines 320 were prepared and subjected to hydroaminomethylation conditions to form the corresponding 7-, 8-, and 10-membered rings (321a–c) in low to moderate yields. When the H2/CO ratio was carefully controlled, the 13-membered heterocycle
321d was formed in good yield with a minimum amount of byproduct formation. The use of triphenylphosphine rather than biphephos (300) led to mixtures of isomeric cyclic amines resulting from non-regioselective hydroformylation of the internal and terminal carbons.
95
Scheme 70
[Rh(OAc)2]2 BnHN n biphephos (300) N n Bn CO/H2 320a: n = 3 PhH, 80 °C, 20 h 321a 60% 320b: n = 4 321b 43% 320c: n = 6 321c 25% 320d: n = 9 321d 85%
2.6.3.3 – Application of Hydroaminomethylation to the Formation of the Azocane Ring of Lycopladine H
Although hydroaminomethylation to form medium rings is still relatively uncommon, it was thought that the constrained nature of our lycopladine H amino alkene intermediate 272 presented a unique opportunity to apply this methodology in the construction of the azocane ring (Scheme 71). To this end, amino alkene 272 was subjected to conditions similar to those used by Beller133 (cf. Scheme 65), but with a slightly higher catalyst loading and a lower substrate concentration in order to favor intramolecular reaction. Gratifyingly, the desired azocane 322 was isolated in 28% yield, along with 41% of the corresponding N,O-acetal 323. We believe that the initial hydroformylation of alkene 272 provides amino aldehyde 324, which undergoes intramolecular condensation to form imine 325. Hydrogenation of the resulting imine furnishes the desired azocane 322, while nucleophilic addition of methanol to the imine produces N,O-acetal 323. Although the addition of methanol should be reversible, the
N,O-acetal appears to be relatively stable under the reaction conditions. However,
96 isolation of N,O-acetal 323, followed by reduction with sodium cyanoborohydride under acidic conditions furnished the azocane 322 in 67% total yield.
Scheme 71
OH OH OH H CO OTBDPS [Rh(cod)Cl] , Xantphos OTBDPS 3 OTBDPS Br 2 Br Br + H2N HN HN CO (10 bar), H2 (40 Bar) PhMe, MeOH TBDPSO 135 °C, 18 h TBDPSO TBDPSO 272 322 323 28% 41% NaCNBH3 HCl, MeOH 0 °C, 30 min hydroformylation 95% H2 MeOH
OH OH O OTBDPS OTBDPS Br imine formation Br H2N N - H2O
TBDPSO TBDPSO 324 325
Although the two-step hydroformylation/sodium cyanoborohydride reduction sequence was serviceable, we sought to streamline this hydroaminomethylation reaction
(Table 2-7). By comparison to the modified Beller conditions used initially (entry 1), the exclusive use of the aprotic solvents toluene or THF (entries 2 and 3) led to an increase in the isolated yield of the azocane 322. However, neither single-solvent system produced a yield of azocane 322 that approached the 67% benchmark from the aforementioned two- step process.
We posited that use of the protic solvent trifluoroethanol (TFE) might improve selectivity for the azocane through both steric and electronic effects. The electron withdrawing CF3 group would make the alcohol a poor nucleophile, and would allow for a faster reversal of N,O-acetal formation due to the enhanced leaving-group ability of TFE
97
(pKa = 12.5147). The increased steric bulk of TFE over methanol would further disfavor
N,O-acetal formation. Additionally, the increased acidity of TFE might even accelerate the hydrogenation of the imine/enamine by shifting the equilibrium toward the protonated iminium ion species, which is more reactive toward hydrogenation, or by promoting the formation of the active catalyst 282 from the catalyst resting state 281 (cf. Scheme 64).129
Indeed, when TFE was employed as a cosolvent (entry 4), azocane 322 was formed in 59% isolated yield, with only 8% of N,O-acetal 326 (R = trifluoroethyl) observed in the 1H NMR spectrum of the crude mixture. Use of hexafluoroisopropanol
(HFIPA), an even less nucleophilic and more sterically encumbered solvent (entry 5, pKa
= 9.3147), furnished azocane 322 in 75% yield, with no N,O-acetal observed. When the purportedly more active catalyst [Rh(cod)2]BF4 (entry 6) was used in conjunction with
HFIPA, the result was nearly identical to that observed with the more stable and less expensive [Rh(cod)Cl]2 catalyst.
98
Table 2-7. Optimization of the Hydroaminomethylation of Amine 272.
OH OH OH OTBDPS OTBDPS RO OTBDPS Br [catalyst]/Xantphos Br Br + H2N HN HN CO (10 bar), H2 (40 Bar) [solvent] TBDPSO 135 °C, 18 h TBDPSO TBDPSO 272 322 326
Entry [Rh] Solvent Azocane 322 (%) N,O-Acetal 326 (%)
1 [Rh(cod)Cl]2 PhMe/MeOH 28 (67) 46 2 " PhMe 46 – 3 " THF 58 – 4 " PhMe/TFE 59 8 5 " PhMe/HFIPA 75 0
6 [Rh(cod)2]BF4 PhMe/HFIPA 71 0
2.7 – Efforts toward the Formation of the Lycopladine H 3-Piperidone Ring
With the requisite azocane ring of lycopladine H formed, we next turned our efforts to the synthesis of the 3-piperidone ring of the alkaloid (Scheme 72). Initial attempts at TBDPS removal from bis-silyl ether 322 with 2 equivalents of TBAF with or without acetic acid led only to decomposition instead of the desired amino triol 327, while treatment with 1 equivalent of TBAF led to a mixture of starting material, decomposition products, and mono-deprotected compound 328.
Because of these difficulties, a selective base-promoted desilylation of the less hindered protected alcohol was attempted.148 Upon treatment of bis-silyl ether 322 with potassium hydroxide, the amino diol 328 was obtained in good yield. Subsequent attempts to oxidize the alcohol moiety of 328 to the aldehyde 329a using Dess-martin
99 periodinane or the acid 329b via Jones oxidation of the in situ-protonated compound, however, did not prove productive, resulting in recovered starting material and decomposition, respectively.
Scheme 72
OH OH OTBDPS OH Br TBAF Br HN [AcOH] HN
TBDPSO HO 322 327
OH OH OTBDPS OTBDPS KOH Br [O] Br 322 HN HN EtOH/H2O rt, 20 h 88% HO O R 328 329a: R = H 329b: R = OH
In addition to examining deprotection conditions, we also explored the possibility of functionalizing the amine moiety of azocane 322 (Scheme 73). Reaction of amine 322 with allyl bromide or iodide, however, failed to give the desired tertiary amine 330, a result similar to previous allylation attempts (cf. Scheme 62). Moreover, catalytic hydrogenation of 322 resulted only in the recovery of starting material without formation of any debrominated alkene/alkane 331, probably due to the steric bulk of the two TBDPS groups. Acylation of amine 322 with acryloyl chloride successfully provided acrylamide
332 in acceptable yield. Desilylation of amide 332 under conditions used for 328 did not provide amido alcohol 333, but instead cleanly removed the N-acyl group, resulting in formation of amine 322.
100
Scheme 73
OH OH O OH OTBDPS X OTBDPS OTBDPS Br Br Cl Br N HN N py, CH2Cl2 70% O TBDPSO TBDPSO TBDPSO 330 322 332
H2 [cat] KOH EtOH/H2O
OH OH OTBDPS OTBDPS Br HN N O TBDPSO HO 331 333
Although the azocane ring had been successfully installed, the bromoalkene functionality was still present in intermediate 322. In order to determine the most appropriate point in the synthesis to perform the desired dehalogenation and alkene reduction, we subjected several intermediates along the successful 9-step (34% overall) reaction sequence shown in Scheme 74 to hydrogenation over 10% palladium on carbon at both atmospheric and high (50 atm) pressures. Hydrogenation of both acetal 228 and the corresponding ketone 255 provided the debrominated products, but further reduction of the alkene was not observed. This result may arise from the 1,3-diaxial strain that develops between the C-16 methyl and the C-13 hydroxy group as the alkene insertion into the Pd-H bond progresses. This may favor β-hydride elimination back to the alkene over reductive elimination to the desired alkane. When the alcohol groups of 255 were protected as the bis-TBDPS derivative 256, debromination is observed, albeit at a greatly attenuated rate and in low yields. The corresponding bis-TBS derivative provides the
101 corresponding dehalogenated alkene in 68% yield. As before (cf. Scheme 73), tricycle 322 was unreactive to further reduction, as was amino diol 328.
Scheme 74
1) PhI(OAc)2 OH MeOH MeO OMe MeO OMe OMe 0 °C, 15 min O NaBH , MeOH H OH Br 4 Br 2) nitroethylene -78 °C to rt, 2 h PhMe, rt, o/n 94% Br 99% NO2 NO2 84b 203 225
MeO OMe O HCHO (aq) 13 OH OH Br LiBF4 Br TBDPS-Cl O N 2 wet MeCN O2N imidazole Et3N, MeCN 16 rt, 3 d 85 °C, 2 h rt, 18 h 89% HO 99% HO 69% 228 255
O OH OH OTBDPS OTBDPS Zn0, HCl OTBDPS Br MgBr Br Br O N H N O2N 2 2 CeCl3, THF H2O/i-PrOH -78 °C, 5 h 45 °C, 1 h TBDPSO 96% TBDPSO 96% TBDPSO 256 271 272
OH OH [Rh(cod)Cl] , Xantphos OTBDPS OTBDPS 2 Br KOH Br HN HN CO (10 bar), H2 (40 Bar) EtOH/H2O PhMe, HFIPA rt, 20 h 135 °C, 18 h TBDPSO 88% HO 322 328 75%
OH O N
O
lycopladine H (21)
102
2.8 – Current and Future Work
2.8.1 – Current Progress by P. Chauhan149
Since many of the more advanced intermediates had proven difficult to hydrogenate (cf. Scheme 74), we returned to the hydrogenation of bromoalkene 204 to alkane 205 (cf. Scheme 43). In the course of a search for a more method of debromination and alkene reduction, we found that subjection of bromoalkene 204 to the transfer hydrogenation conditions with a 1:2 triethylamine/formic acid complex at slightly elevated temperature both debrominated and reduced alkene 204 to provide the bicyclic alkane 205 as a single C-15 isomer (Scheme 75).
In order to continue the sequence in this reduced series, we next examined the reduction of ketone 205 to alcohol 334. However, treatment of ketone 205 with hydride sources such as DIBAL, L-Selectride, and sodium borohydride at various temperatures failed to provide any of alcohol 334, instead resulting in decomposition products. Similar results were found using a Luche reduction and borane. Attempted samarium iodide and
Meerwein-Ponndorf-Verley reductions led to recovery of starting material.
103
Scheme 75
MeO OMe MeO OMe MeO OMe O Et N:HCO H (1:2) O HO Br 3 2 [reduction] O N O2N 10% Pd/C, EtOH O2N 2 45 °C, 18–72 h H HO 99% HO HO 204 205 334
Since we anticipated that the retro-Henry reaction of 205 might be a problem in these attempted reductions, we decided to protect the free alcohol group of 205 (Scheme
76). To this end, nitro alcohol 205 was acylated with benzoyl chloride and silylated with
TBDPS chloride to provide the ester 335a and silyl ether 335b. Both 335a and 335b were subjected to the same series of reduction conditions as unprotected nitro alcohol 205, but with a similar lack of success. Although the protected derivatives 335 appeared more resistant to decomposition, neither compound provided the desired alcohol 336. Silyl ether ketone 335b was also treated with LiAlH4, which did not reduce the carbonyl group at 0 °C, and caused only eventual decomposition at room temperature.
Scheme 76
BzCl, py MeO OMe 60 °C, 3 h MeO OMe MeO OMe O 68% O HO or [reduction] O2N O N O N 5 15 TBDPS-Cl, 2 2 Im, CH2Cl2 HO rt, o/n RO RO 205 79% 335a: R = Bz 336 335b: R = TBDPS
We believe that the difficulty in reducing the carbonyl group of ketones 205 or 335 most likely arises from significant steric interactions due to the C-5 nitro and C-15 methyl groups (Figure 2-9). These groups are positioned to block approach of hydride to the
104 carbonyl carbon, an interaction that is especially evident in the space-filling model (Figure
2-9), which clearly shows these substituents blocking access to the carbonyl π* orbital.
Figure 2-9. Ball-and-Stick (a) and Space Filling (b) Models of Nitro Ketone 20513
(a) (b)
To further test the effects of sterics, unreduced nitro alcohol olefin 204 was protected as the silyl ether 337 and subjected to hydride reduction conditions (Scheme
77). Sodium borohydride reduction of ketone 337 at 0 °C was found to furnish alcohol
338 as a single C-13 diastereomer, the structure of which was established via comparison of the 1H NMR shifts to the similar C-13 epimeric alcohol 228 (cf. Scheme 57) as well as by 2D NMR analysis. The observed diastereoselectivity was as expected, as the C-5 nitro group blocks nucleophilic attack of C-13, while the C-15 methyl group is moved away from the ketone of 337 due to the sp2 carbon center. Attempted reduction of bromoalkene
338 using conditions previously established for the reduction of 204 (cf. Scheme 75),
105 however, did not produce any of the desired bicyclooctane 339, but rather only resulted in formation of the debrominated alkene 340.
Scheme 77
MeO OMe MeO OMe O O Br TBDPS-Cl Br NaBH4 O2N O2N Im, CH2Cl2 MeOH rt, o/n 0 °C to rt, 30 min HO TBDPSO 80% 92% 204 337
MeO OMe MeO OMe MeO OMe HO 13 H Et N:HCO H HO HO Br 3 2 H but O N not O N O N 2 10% Pd/C, EtOH 2 2 45 °C TBDPSO TBDPSO TBDPSO 338 339 340
To remove some steric interference from the hydrogenation step, the ketal of 338 was removed, and the resulting ketone 341 was then subjected to the standard hydrogenation conditions (Scheme 78). However, this reaction again provided only the debrominated product 342 instead of the desired alkane 343.
Scheme 78
O O O 10% Pd/C, HCO2H HO TEA, EtOH, 45 °C HO HO LiBF4 338 Br not but wet MeCN O2N or O2N O2N 75 °C, 3 h Pd/C, H2 90% TBDPSO EtOAc, 50 °C TBDPSO TBDPSO 341 342 343
Since reduction of the carbonyl group of nitro ketone 205 appeared problematic, we turned our attention instead to the reduction of the nitro group. After screening
106 numerous conditions, it was found that, once again, only the hydroxylamine 344 could be obtained from nitro compound 337 (Scheme 79). Carrying on with this hydroxylamine
344, borane reduction of the ketone cleanly provided alcohol 346, probably formed by a directed reduction though coordination of borane to the hydroxylamine to give coordinated compound 345. The stereochemistry of alcohol 346 was confirmed by 2D
NMR analysis. Subjection of hydroxylamine alcohol 346 to catalytic hydrogenation over
10% palladium in carbon in 90% aqueous acetic acid cleaved the N–O bond, providing amine 347.
Scheme 79
MeO OMe MeO OMe O O Zn0, HCl BH3•THF O2N HOHN i-PrOH/H2O THF 45 °C, 18 h 0 °C, 30 min TBDPSO 98% TBDPSO 83% 337 344
MeO OMe MeO OMe MeO OMe H O H2B H OH OH H2, 10% Pd/C
HN HOHN H2N HO AcOH/H2O rt, 18 h TBDPSO TBDPSO 80% TBDPSO 345 346 347
107
2.8.2 – Future Strategy for the Synthesis of Lycopladine H
One possible route to complete a total synthesis of lycopladine H (21) would involve deprotection of the ketal of amino alcohol 347 to give the ketone, possibly with the previously used indium (III) triflate method (Scheme 80). Selective O-silylation of the resulting α-hydroxyketone would give silyl ether aminoketone 348. Although amino ketones have the potential to be unstable, the hindered primary amino group of compounds similar to 348 has proven to be unreactive (cf. Schemes 62 and 73), and similar ketone 258 (Scheme 57) is relatively stable. Selective cleavage of the TBDPS group of 348 under basic conditions148 would furnish the corresponding primary alcohol, which could then be oxidized under Omura–Sharma–Swern conditions in the presence of excess trifluoroacetic anhydride150 to provide ketone aldehyde 349. Addition of an excess of vinyl cerium to dicarbonyl 349 should give the bis-allylic alcohol resulting from addition to the aldehyde and selective addition to the ketone from the less-hindered face of the molecule. The trifluoroacetamide of the resulting amido diol would be removed by hydrolysis to give amine 350. Bis-alkenyl amine 350 is uniquely positioned to undergo a double hydroaminomethylation to close both the lower piperidine and upper azocane rings to provide tetracycle 351 in a process similar to that of Mann141 or Eilbracht145 (cf.
Schemes 66 and 69). Removal of the silyl ether group of 351, followed by oxidation of the two secondary alcohols of 351 to the corresponding ketones would complete the total synthesis of racemic lycopladine H (21).
108
Scheme 80
MeO OMe O OH 1) deketalization OTBS H N 2 2) TBS-Cl H2N
TBDPSO TBDPSO 347 348
O OH OTBS OTBS 1) NaOH, MeOH 1) CeCl2 H N 2) TFAA TFAHN 2) hydrolysis 2 DMSO, Et3N H O OH 349 350
OH OH OTBS - + O [Rh] 1) F or H N N Xantphos 2) [ox] CO, H OH 2 O
351 lycopladine H (21)
109
2.9 – Conclusion
Various approaches to the structurally unique tetracyclic Lycopodium alkaloid lycopladine H (21) have been examined, all of which rely on a tandem oxidative dearomatization/Diels-Alder reaction to construct the [2.2.2]-bicyclooctane core. Various intramolecular Diels-Alder routes that would have provided 3 of the 4 rings of the alkaloid in one step were tested, but none showed promise. The bicyclooctane ring system was successfully prepared via oxidative dearomatization/intermolecular Diels-Alder cycloaddition using Liao’s stabilized bromo-o-quinone ketal methodology and nitroethylene as the dienophile. Functionalization of the nitro-bearing cycloadduct 203 was successfully performed via a Henry reaction with formaldehyde, while use of more complex aldehydes proved to be impractical. It was shown that the C-15 methyl stereochemistry could be set by a stereospecific catalytic hydrogenation. Examination of various strategies led to methodology to set the azocane ring juncture stereochemistry at
C-12 using addition of vinyl cerium to a C-12 ketone, and the 8-membered azocane ring system was then successfully formed through a novel intramolecular rhodium-catalyzed hydroaminomethylation sequence. Initial efforts to further elaborate the tricyclic system
322 were unproductive, but recent research by P. Chauhan in our group has revealed new possibilities for the completion of the total synthesis of lycopladine H.
Our efforts toward a synthesis of lycopladine H have resulted in the expansion of the scope of o-quinone ketal Diels-Alder reactions to include nitroethylene as a dienophile. This represents an attractive strategy to access a variety of tertiary and quaternary nitro, hydroxylamino, and amino compounds. Additionally,
110 hydroaminomethylation, an underutilized reaction in natural products synthesis, has been successfully applied to the construction of a medium-sized ring in a relatively complex system. Furthermore, this transformation involved closure onto a sterically congested nitrogen, a reaction that is not well precedented or explored. These key reactions, along with others used, modified, and developed during our synthetic efforts, represent useful additions to synthetic methodology.
111
Chapter 3
Experimental Procedures
3.1 – General Methods
All non-aqueous reactions were carried out under an argon atmosphere in oven- or flame-dried glassware unless otherwise noted. Anhydrous tetrahydrofuran, diethyl ether, dichloromethane, and toluene were obtained from a solvent dispensing system equipped with alumina drying columns. All other solvents and reagents were used as obtained from commercial sources without further purification unless noted. Reactions using high- pressure gas were performed in a Parr Instruments Series 4760 pressure vessel.
Microwave reactions were performed in a CEM Discovery Labmate microwave reactor system. Flash column chromatography was performed using EMD Chemicals or SiliCycle silica gel 60 (230-400 mesh). Preparative thin-layer chromatography was performed
1 13 using 500 or 1000 µm EMD Chemicals silica gel PF254 plates. H and C NMR spectra were recorded on Bruker DPX-300, CDPX-300, or DRX-400 MHz spectrometers.
Infrared spectra were obtained on a Perkin-Elmer 1600 FT-IR or a Thermo Nicolet iS-10
FT-IR equipped with a Multi-Bounce HATR accessory. Nominal mass spectra were obtained on an Applied Biosystems 150EX. High-resolution mass spectra were obtained on a Waters LCT Premier time-of-flight (TOF) mass spectrometer. X-ray data was collected on a Bruker SMART APEX CCD area detector system.
112
3.2 – Experimental Procedures and Analytical Data
OH OH (CH2O)n, MgCl2 O THF, 65 °C, o/n 99%
2-Hydroxy-4-methylbenzaldehyde (52).17 To a solution of m-cresol (145, 2.00 g,
18.49 mmol) in THF (90 mL) was added paraformaldehyde (3.75 g, 125 mmol), anhydrous magnesium chloride (2.64 g, 27.7 mmol), and triethylamine (9.67 mL, 69.4 mmol). The resulting suspension was heated at reflux and stirred for 18 h. The reaction mixture was cooled, and 1 M HCl (100 mL) was added. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organics were dried over MgSO4, and the solvent was evaporated. The resulting residue was purified by flash column chromatography (20% EtOAc in hexanes) to give benzaldehyde
52 (2.50 g, 99%) as a white solid. Spectral data were consistent with literature values.151
OH OH KOH CN O MeCN, 82 °C, 20 h 77%
(E)-3-(2-Hydroxy-4-methylphenyl)acrylonitrile (51). To a solution of aldehyde
52 (1.36 g, 10.0 mmol) in acetonitrile (20 mL) was added potassium hydroxide (1.12 g,
20.0 mmol). The yellow mixture was heated at reflux and stirred for 20 h. The resulting brown solution was cooled to rt, then poured into a mixture of ice (~50 g) and conc. HCl
(2 mL). The mixture was extracted with Et2O (3 x 20 mL), and the combined organics were dried over MgSO4 and evaporated. The resulting residue was purified by flash
113 column chromatography (40% EtOAc in hexanes) to give cinnamonitrile 51 (1.22 g,
77%) as a yellow solid: mp 149-151 °C; 1H NMR (300 MHz, DMSO-d6) δ 10.37 (br s,
1H), 7.59 (d, J = 16.9 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 6.77 (s, 1H), 6.66 (d, J = 8.0 Hz,
1H), 6.31 (d, J = 16.8 Hz, 1H), 2.23 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 156.8,
146.5, 142.7, 129.1, 120.5, 119.9, 118.0, 116.7, 94.7, 21.2; IR (thin film) 3254, 2216,
1560, 1257 cm-1.
OH OH O CN (CF3CO)2O N CF3 H2 (1 atm), PtO2 H THF, rt, 18 h 92%
2,2,2-Trifluoro-N-(3-(2-hydroxy-4-methylphenyl)propyl)acetamide (146). To a solution of cinnamonitrile 51 (1.00 g, 6.28 mmol) in THF (8 mL) was added trifluoroacetic anhydride (1.05 mL, 7.50 mmol) and PtO2 (143 mg, 0.63 mmol). The reaction mixture was placed under a H2 atmosphere (1 atm) and stirred for 18 h. The reaction mixture was filtered through a pad of Celite, and the solids were washed with
EtOAc. The organic filtrate was evaporated, and the residue was purified by flash column chromatography (1:2 EtOAc:hexanes) to give trifluoroacetamide 146 (1.51 g, 92%) as an
1 off-white semisolid: H NMR (300 MHz, CDCl3) δ 7.51 (br s, 1H), 6.99 (d, J = 7.8 Hz,
1H), 6.71 (d, J = 7.8 Hz, 1H), 6.64 (s, 1H), 6.13 (br s, 1H), 3.33 (q, J = 6.2 Hz, 2H), 2.69
13 (t, J = 6.9 Hz, 2H), 2.27 (s, 3H), 1.87 (quint, J = 6.5 Hz, 2H); C NMR (75 MHz, CDCl3)
δ 157.8 (q), 153.6, 137.8, 130.5, 123.8, 122.0, 116.8 (q), 116.2, 38.8, 29.3, 25.8, 21.0;
+ LRMS (EI) [M+H] calcd for C12H15F3NO2 262.1, found 262.2.
114
MeO2C Br2, CH2Cl2; MeO2C Br
Et3N, pentane/Et2O 86%
Methyl 2-Bromoacrylate (147a).65 To a solution of methyl acrylate (22.4 mL,
250 mmol) in CH2Cl2 (100 mL) at 0 °C was added bromine (12.85 mL, 250 mmol). The solution was stirred for 1 h, then warmed to rt and stirred for an additional 3 h. The solvent was evaporated, and Et2O (150 mL), pentane (150 mL), and triethylamine (35 mL, 251 mmol) were added. The resulting solution was stirred overnight in the dark. The reaction mixture was filtered, the solids were washed with pentane, and the combined organics were evaporated. The residue was purified by vacuum distillation (bp 93-96 °C at
350 Torr) to give bromoacrylate 147a (35.6 g, 86%) as a clear oil. Spectral data were consistent with literature values.152
OH OH H (1 atm), PtO CN 2 2 NH2 EtOH, CHCl3 rt, 20 h 98%
2-(3-Aminopropyl)-5-methylphenol (150b). To a solution of cinnamonitrile 51
(1.00 g, 6.28 mmol) in EtOH (30 mL) and CHCl3 (2 mL) was added PtO2 (143 mg, 0.63 mmol) The resulting suspension was placed under a hydrogen atmosphere (1 atm) and stirred for 20 h. The reaction mixture was filtered through a pad of Celite, and the solids
115 were washed with MeOH. The organic filtrate was evaporated to give amine 150b (1.02 g,
98%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.62 (br s, 1H), 8.10 (br s,
2H), 6.99 (d, J = 7.5 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 6.57 (s, 1H), 2.64, (br m, 2H),
2.48 (t, J = 7.5 Hz, 2H), 2.24 (s, 3H), 1.77 (br m, 2H); 13C NMR (75 MHz, DMSO-d6) δ
155.8, 137.2, 129.4, 124.8, 121.5, 117.1, 39.6, 29.8, 26.6, 21.8.
OH OTBS CN TBSCl CN imidazole, DMF rt, 18 h 94%
(E)-3-(2-((tert-Butyldimethylsilyl)oxy)-4-methylphenyl)acrylonitrile (149). To a solution of phenol 51 (1.10 g, 6.91 mmol) in DMF (14 mL) was added t- butyldimethylsilyl chloride (1.25 g, 8.29 mmol) and imidazole (0.94 g, 13.81 mmol). The resulting solution was stirred overnight at rt, then poured into water (75 mL) and extracted with Et2O (5 x 20 mL). The combined organics were washed with water and brine, dried over MgSO4, and evaporated. The resulting residue was purified by flash column chromatography (20% EtOAc in hexanes) to give silyl-protected phenol 149
1 (1.78 g, 94%) as a yellow oil: H NMR (300 MHz, CDCl3) δ 7.67 (d, J = 16.8 Hz, 1H),
7.31 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 5.83 (d, J = 16.8 Hz, 1H),
13 2.34 (s, 3H), 1.04 (s, 9H), 0.27 (s, 6H); C NMR (75 MHz, CDCl3) δ 154.3, 146.2, 143.2,
126.9, 122.7, 122.3, 120.5, 119.0, 94.5, 25.8, 21.7, 18.4, -4.1; LRMS (EI) [M+H]+ calcd for C16H24NOSi 274.2, found 274.2.
116
OTBS OTBS H (1 atm), PtO CN 2 2 NH2 EtOH, CHCl3 rt, 20 h 100%
3-(2-((tert-Butyldimethylsilyl)oxy)-4-methylphenyl)propan-1-amine (150). To a solution of cinnamonitrile 149 (1.50 g, 5.49 mmol) in EtOH (25 mL) and CHCl3 (1.5 mL) was added PtO2 (125 mg, 0.55 mmol). The solution was placed under a H2 atmosphere (1 atm), and stirred for 20 h. The resulting mixture was filtered through a pad of Celite, and the solids were washed with MeOH. The combined organic filtrate was evaporated to give amine 150 (1.53 g, 100%) as an off-white solid: 1H NMR (300 MHz,
DMSO-d6) δ 8.14 (br s, 2H), 6.95 (d, J = 7.5 Hz, 1H), 6.60 (d, J = 7.5 Hz, 1H), 6.52 (s,
1H), 2.59, (br m, 2H), 2.44 (t, J = 7.4 Hz, 2H), 2.12 (s, 3H), 1.71 (br m, 2H), 0.88 (s,
9H), 0.11 (s, 6H); 13C NMR (75 MHz, DMSO-d6) δ 152.8, 136.6, 129.9, 127.8, 121.9,
+ 119.1, 38.4, 27.4, 26.5, 25.7, 20.8, 17.9, -4.3; LRMS (EI) [M+H] calcd for C16H30NOSi
280.2, found 280.2.
OTBS OTBS O TFAA NH2 N CF3 Et3N, DMF H rt, 2 h 60%
N-(3-(2-((tert-Butyldimethylsilyl)oxy)-4-methylphenyl)propyl)-2,2,2- trifluoroacetamide (151). To a solution of amine 150 (350 mg, 1.25 mmol) in DMF (5 mL) was added triethylamine (350 µL, 2.51 mmol). Trifluoroacetic anhydride (193 µL,
117
1.38 mmol) was added dropwise, and the resulting solution was stirred for 2 h. The reaction mixture was poured into water (25 mL), and the aqueous solution was extracted with Et2O (5 x 5 mL). The combined organics were washed with water and brine, dried over MgSO4, and evaporated. The resulting residue was purified by flash column chromatography (10% EtOAc in hexanes) to give trifluoroacetamide 151 (283 mg, 60%)
1 as a clear oil: H NMR (300 MHz, CDCl3) δ 6.99 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 7.7 Hz,
1H), 6.62 (s, 1H), 6.34 (br s, 1H), 3.37 (q, J = 6.4 Hz, 2H), 2.63 (t, J = 7.3 Hz, 2H), 2.27
(s, 3H), 1.87 (quint, J = 7.1 Hz, 2H), 1.01 (s, 9H), 0.23 (s, 6H); LRMS (EI) [M+H]+ calcd for C18H29F3NO2Si 376.2, found 376.2.
O OH OH O Ph3P OEt O OEt CH2Cl2, rt, 2 h 99%
Ethyl (E)-3-(2-Hydroxy-4-methylphenyl)acrylate (165). To a solution of aldehyde 52 (6.75 g, 49.58 mmol) in CH2Cl2 (150 mL) was added
(carbethoxymethylene)triphenylphosphorane (164, 19.0 g, 545 mmol). The solution was stirred at rt for 2 h, and the solvent was evaporated. The crude material was purified by flash column chromatography (1:2 EtOAc:hexanes) to give cinnamate ester 165 (10.13 g,
1 99%) as a white solid: H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 16.1 Hz, 1H), 7.41 (br s,
1H), 7.34 (d, J = 8.2 Hz, 1H), 6.71 (m, 2H), 6.63 (d, J = 16.1 Hz, 1 H), 4.30 (q, J = 7.1 Hz,
13 2H), 2.29 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); C NMR (100 MHz, CDCl3) δ 169.2, 155.9,
142.5, 141.3, 129.3, 121.6, 119.1, 117.2, 117.0, 60.8, 21.5, 14.4.
118
OH O OTBS O TBS-Cl, Im OEt DMF, rt, 18 h OEt 99%
Ethyl (E)-3-(2-((tert-Butyldimethylsilyl)oxy)-4-methylphenyl)acrylate (166).
To a solution of phenol 165 (1.50 g, 7.27 mmol) in DMF (14 mL) was added tert- butyldimethylsilyl chloride (1.20 g, 7.96 mmol) and imidazole (0.99 g, 14.54 mmol). The resulting solution was stirred overnight at rt, and then poured into water (75 mL). The resulting suspension was extracted with Et2O (5 x 15 mL). The combined organics were washed with water and brine, dried over MgSO4, and evaporated. The residue was purified by flash column chromatography (10% EtOAc in hexanes) to give silyl-protected
1 phenol 166 (2.31 g, 99%) as a clear oil: H NMR (300 MHz, CDCl3) δ 8.07 (d, J = 16.2
Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 6.78 (dd, J = 8.0, 1.0 Hz, 1H), 6.65 (s, 1H), 6.34 (d, J =
16.2 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 2.31 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.05 (s, 9H),
13 0.23 (s, 6H); C NMR (75 MHz, CDCl3) δ 167.4, 154.6, 142.0, 139.9, 127.1, 123.2,
122.7, 120.7, 116.7, 60.2, 25.7, 21.6, 18.4, 14.4, -4.2; LRMS (EI) [M+H]+ calcd for
C18H29O3Si 321.2, found 321.4.
OTBS O OTBS LiAlH4, Et2O OEt OH 0 °C, 1h, rt, 2 h 96 %
(E)-3-(2-((tert-Butyldimethylsilyl)oxy)phenyl)prop-2-en-1-ol (167). To a suspension of lithium aluminum hydride (300 mg, 7.90 mmol) in Et2O (5 mL) at 0 °C was
119 added dropwise a solution of cinnamate ester 166 (1.000 g, 3.12 mmol) in Et2O (3 mL).
The reaction mixture was stirred for 1 h, then warmed to rt and stirred for an additional 2 h. The reaction mixture was diluted with Et2O (20 mL) and cooled to 0 °C. Water (0.3 mL) was added slowly, followed by 10% NaOH (0.6 mL) and additional water (0.9 mL).
The mixture was warmed to rt, stirred for 15 min, and MgSO4 was added. After stirring for 15 min, the mixture was filtered, and the solids were washed with Et2O. The organic filtrate was evaporated to give allylic alcohol 167 (835 mg, 96%) as a clear oil: 1H NMR
(300 MHz, CDCl3) δ 7.36 (d, J = 7.9 Hz, 1H), 6.90 (d, J = 16.0 Hz, 1H), 6.75 (d, J =
7.9Hz, 1H), 6.63 (s, 1H), 6.26 (dt, J = 16.0, 7.3 Hz, 1H), 4.29 (br t, J = 4.6 Hz, 2H), 2.30
13 (s, 3H), 1.97 (br t, J = 4.6 Hz, 1H), 1.04 (s, 9H), 0.23 (s, 6H); C NMR (75 MHz, CDCl3)
δ 152.8, 138.7, 127.4, 126.7, 125.2, 122.4, 120.4, 64.4, 25.9, 21.4, 18.4, -4.1.
OTBS OTBS H2 (1 atm), 10% Pd/C OH OH EtOH, rt, 18 h 96%
3-(2-((tert-Butyldimethylsilyl)oxy)phenyl)propan-1-ol (168). To a solution of cinnamyl alcohol 167 (750 mg, 2.69 mmol) in EtOH (15 mL) was added 10% palladium on carbon (75 mg). The resulting suspension was placed under a H2 atmosphere (1 atm) and stirred overnight. The mixture was filtered through a pad of Celite, and the solids were washed with EtOAc. The combined organic filtrate was evaporated to give alcohol
168 (726 mg, 96%) as a clear oil, which was used without further purification: 1H NMR
(300 MHz, CDCl3) δ 7.03 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.63 (s, 1H), 3.62
120
(t, J = 6.4 Hz, 2H), 2.65 (t, J = 7.5 Hz, 2H), 2.29 (s, 3H), 1.92 (br s, 1H), 1.84 (dt, J = 7.5,
13 6.4 Hz, 2 H), 1.03 (s, 9H), 0.25 (s, 6H); C NMR (75 MHz, CDCl3) δ 153.4, 136.8,
130.1, 129.1, 122.1, 119.5, 62.3, 33.2, 26.2, 25.9, 25.9, 21.2, 18.4, -4.0; LRMS (EI)
+ [M+K] calcd for C16H28KO2Si 319.2, found 319.3.
OTBS OTBS CBr4, PPh3 OH Br DCM, 0 °C to rt, 4 h 89%
(2-(3-Bromopropyl)phenoxy)(tert-butyl)dimethylsilane (169). To a solution of propanol 168 (600 mg, 2.14 mmol) in CH2Cl2 was added CBr4 (710 mg, 2.14 mmol). The solution was cooled to 0 °C, and triphenylphosphine (562 mg, 2.14 mmol) was added.
The reaction mixture was warmed to rt and stirred for 4 h. The solvent was evaporated, and the residue was filtered through a silica gel plug with 1:2 Et2O:hexanes (any further purification caused decomposition70). The solvent was evaporated to give bromide 169
1 (90% purity, 723 mg, 89%) as a clear oil: H NMR (300 MHz, CDCl3) δ 7.06 (d, J = 7.6
Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.65 (s, 1H), 3.43 (t, J = 6.7 Hz, 2H), 2.74 (t, J = 7.3
Hz, 2H), 2.31 (s, 3H), 2.15 (quint, J = 7.6 Hz, 2H), 1.05 (s, 9H), 0.28 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 153.6, 137.1, 130.3, 128.1, 121.9, 119.4, 33.8, 33.0, 29.0, 26.0, 21.3,
18.4, -3.9.
OH O OH O H2 (1 atm), 10% Pd/C OEt OEt EtOH, rt, 18 h 100%
121
Ethyl 3-(2-Hydroxy-4-methylphenyl)propanoate (177). To a solution of cinnamate ester 165 (1.70 g, 8.24 mmol) in EtOH (40 mL) was added 10% palladium on carbon (170 mg). The suspension was placed under hydrogen gas (1 atm) and stirred for
18 h. The reaction mixture was filtered through a pad of Celite, which was washed with
EtOAc. The filtrate was evaporated to yield propanoate ester 177 (1.71 g, 100%) as a clear
1 oil that was used without further purification: H NMR (300 MHz, CDCl3) δ 7.29 (br s,
1H), 6.98 (d, J = 7.5 Hz, 1H), 6.71 (s, 1H), 6.69 (d, J = 7.6 Hz, 1H), 4.15 (q, J = 7.2 Hz,
2H), 2.88 (t, J = 6.5 Hz, 2H), 2.69 (t, J = 6.6 Hz, 2H), 2.27 (s, 3H), 1.25 (t, J = 7.2 Hz,
13 3H); C NMR (75 MHz, CDCl3) δ 175.8, 154.2, 138.0, 130.4, 124.3, 121.6, 117.7, 61.3,
35.4, 24.5, 21.0, 14.2.
OH O OH O LiOH•H2O OH OEt MeOH/H2O 55 °C 18 h 99%
3-(2-Hydroxy-4-methylphenyl)propanoic Acid (175). To a solution of propanoate ester 177 (1.000 g, 4.80 mmol) in MeOH (18 mL) and water (6 mL) was added lithium hydroxide hydrate (1.00 g, 23.83 mmol). The suspension was heated at 55
°C and stirred overnight. The resulting orange solution was cooled and poured into 1 M
HCl (30 mL) and ice (30 g). The aqueous mixture was extracted with EtOAc (3 x 30 mL).
The organic extract was dried over MgSO4 and evaporated to give acid 175 (856 mg,
99%) as an off-white solid sufficiently pure for use in the next step: 1H NMR (400 MHz,
DMSO-d6) δ 12.04 (br s, 1H), 9.20 (br s, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.60 (s, 1H), 6.51
122
(d, J = 7.5 Hz, 1H), 2.71 (t, J = 7.7 Hz, 2H), 2.45 (t, J = 7.7 Hz, 2H), 2.18 (s, 3H); 13C
NMR (100 MHz, DMSO-d6) δ 174.3, 155.0, 136.3, 129.5, 123.9, 119.6, 115.6, 33.9,
25.2, 20.8.
HO O OH OH O ClH3N OH O O O OH N EDC, DIPEA H DMF, rt, o/n O 79%
Methyl 3-Hydroxy-2-(3-(2-hydroxy-4-methylphenyl)propanamido) propanoate (179). To a solution of acid 175 (750 mg, 4.16 mmol) in DMF (20 mL) was added D,L-serine methyl ester hydrochloride (178, 710 mg, 4.56 mmol), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC, 880 mg, 4.59 mmol), and diisopropylethylamine (2.50 mL, 14.35 mmol). The resulting solution was stirred at rt overnight, and the reaction mixture was concentrated to ~5 mL. To the crude mixture was added 0.1 M HCl (50 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organics were washed with 0.1 M HCl (25 mL), water (25 mL), and brine (25 mL), dried over MgSO4, and evaporated to give amide 179 (929 mg, 79%) as a white solid of sufficient purity for use in the next step: mp 132-133 °C; 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.15
(d, J = 7.5 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.58 (s, 1H), 6.50 (d, J = 7.5 Hz, 1H), 5.02 (t,
J = 5.3 Hz, 1H), 4.34 (q, J = 6.5 Hz, 1H), 3.68-3.58 (m, 2H), 3.62 (s, 3H), 2.67 (t, J = 7.7
Hz, 2H), 2.38 (t, J = 7.7 Hz, 2H), 2.16 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 172.2,
123
171.3, 154.9, 136.0, 129.4, 124.3, 119.6, 115.6, 61.3, 54.7, 51.8, 35.1, 25.3, 20.8; MS
+ (EI) [M+H] calcd for C14H20NO5 282.1, found 282.2.
OH OH O OH O DCC, CuCl O O N N DMF, rt, o/n H H 85% O O
Methyl 2-(3-(2-Hydroxy-4-methylphenyl)propanamido)acrylate (174). To a solution of alcohol 179 (250 mg, 0.889 mmol) in DMF (8 mL) was added CuCl (22 mg,
0.222 mmol) and N,N’-dicyclohexylcarbodiimide (DCC, 190 mg, 0.921 mmol). The reaction mixture was stirred for 20 h and the solvent was evaporated. EtOAc (40 mL), water (20 mL), and saturated NH4Cl (20 mL) were added. The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organics were dried over MgSO4 and evaporated. The residue was purified via filtration through a silica gel plug eluting with Et2O to give acrylate 174 (200 mg, 85%) as an off-white solid: mp
1 114-115 °C; H NMR (300 MHz, CDCl3) δ 8.06 (br s, 1H), 7.81 (br s, 1H), 6.95 (d, J =
7.5, 1H), 6.72 (s, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 0.8 Hz, 1H), 5.90 (d, J = 0.8
Hz, 1H), 3.82 (s, 3H), 2.91 (t, J = 6.2 Hz, 2H), 2.74 (t, J = 6.1 Hz, 2H), 2.26 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 173.3, 164.5, 154.5, 138.2, 130.4, 127.8, 124.4, 121.5, 118.2,
+ 110.0, 53.2, 38.4, 24.1, 21.2; LRMS (EI) [M+H] calcd for C14H18NO4 264.1, found
264.3.
124
O O OH O O PhI(OAc)2 N O H N O H MeOH, rt, 20 h O 40% O O
Methyl 2-(3-(3,3-Dimethoxy-4-methyl-6-oxocyclohexa-1,4-dien-1- yl)propanamido)acrylate (182). To a solution of phenolic acrylate 174 (120 mg, 0.456 mmol) in MeOH (9 mL) was added (diacetoxy)iodobenzene (160 mL, 0.498 mmol). The reaction mixture was stirred for 20 h and the solvent was evaporated. The residue was purified by flash column chromatography (40% EtOAc in hexanes) to give p-quinone
1 ketal 182 (53 mg, 40%) as a white solid: H NMR (300 MHz, CD3CN) δ 7.95 (br s, 1H),
6.51 (s, 1H), 6.31 (s, 1H), 6.07 (d, J = 1.3 Hz, 1H), 5.66 (d, J = 1.3 Hz, 1H), 3.70 (s, 3H),
3.05 (s, 6H), 2.53-2.43 (m, 4H), 1.77 (s, 3H).
OH OH OH O OH O NBS, AcOH O O N N rt, 4 h H H O O 94% Br
Methyl 2-(3-(5-Bromo-2-hydroxy-4-methylphenyl)propanamido)-3- hydroxypropanoate (183). To a solution of phenol 179 (500 mg, 1.78 mmol) in AcOH (9 mL) was added N-bromosuccinimide (330 mg, 1.85 mmol). The reaction mixture was stirred for 4 h and the solvent was evaporated. To the residue were added saturated
NaHCO3 and EtOAc. The layers were separated, and the aqueous layer was extracted with
EtOAc. The combined organics were dried over MgSO4 and evaporated to yield
125 bromophenol 183 (605 mg, 94%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 9.57
(s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.23 (s, 1H), 6.75 (s, 1H), 5.05 (t, J = 5.51 Hz, 1H), 4.36
(m, 1H), 3.70-3.59 (m, 2H), 3.63 (s, 3H), 2.69 (br t, J = 7.7 Hz, 2H), 2.43 (m, 2H), 2.22
(s. 3H); 13C NMR (75 MHz, DMSO-d6) δ 172.8, 172.1, 155.4, 136.1, 133.4, 128.4,
+ 118.3, 113.3, 62.2, 55.5, 52.7, 35.5, 25.8, 23.0; LRMS (EI) [M+H] calcd for
C14H19BrNO5 360.0, found 360.0.
OH OH O OH O O O N DCC, CuCl N H H DMF, rt, o/n O O 66% Br Br
Methyl 2-(3-(5-Bromo-2-hydroxy-4-methylphenyl)propanamido) acrylate
(184). To a solution of alcohol 183 (360 mg, 0.999 mmol) in DMF (7 mL) was added
CuCl (25 mg, 0.253 mmol) and N,N’-dicyclohexylcarbodiimide (DCC, 220 mg, 1.07 mmol). The reaction mixture was stirred for 20 h and the solvent was evaporated. EtOAc
(25 mL), water (15 mL), and saturated NH4Cl (15 mL) were added. The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organics were dried over MgSO4 and evaporated. The residue was purified via filtration through a silica gel plug eluting with Et2O to give acrylate 184 (227 mg, 66%) as a white
1 solid: H NMR (400 MHz, CDCl3) δ 8.20 (br s, 1H), 7.80 (br s, 1H), 7.20 (s, 1H), 6.79 (s,
1H), 6.58 (s, 1H), 5.92 (s, 1H), 3.83 (s, 3H), 2.87 (t, J = 5.5 Hz, 2H), 2.75 (t, J = 5.5 Hz,
13 2H), 2.28 (s, 3H); C NMR (100 MHz, CDCl3) δ 173.1, 164.4, 154.1, 137.6, 133.7,
126
+ 130.4, 127.2, 120.2, 115.0, 110.3, 53.2, 38.3, 34.0, 23.7, 22.6; LRMS (EI) [M+H] calcd for C14H17BrNO4 342.0, found 342.1.
OH O O OMe PhI(OAc)2 O
NO2 MeOH, 68 °C, 12 h NO2 85%
endo-3,3-Dimethoxy-5-methyl-7-nitrobicyclo[2.2.2]oct-5-en-2-one (195). To a solution of (diacetoxy)iodobenzene (15.7 g, 48.7 mmol) and nitroethylene (9.0 mL, 132 mmol) in methanol (175 mL) was added 2-methoxy-4-methylphenol (194, 5.6 mL, 44.3 mmol). The mixture was heated at reflux and stirred for 20 h, cooled to rt, and the solvent was evaporated. The residue was purified by flash column chromatography (20% EtOAc in hexanes) to yield cycloadduct 195 (9.08 g, 85%) as a light yellow solid. X-ray quality
153 1 crystals were obtained via slow evaporation from CH2Cl2/hexanes: H NMR (300 MHz,
CDCl3) δ 5.65 (d, J = 6.0 Hz, 1H), 4.85 (m, 1H), 3.76 (dd, J = 6.0, 2.5 Hz, 1H), 3.29 (s,
3H), 3.24 (s, 3H), 2.97 (d, J = 2.6 Hz, 1H) 2.52 (m, 1H), 2.12 (dt, J = 14.3, 3.9 Hz, 1 H),
13 1.89 (s, 3H); C NMR (75 MHz, CDCl3) δ 197.5, 146.6, 116.0, 93.6, 79.8, 52.1, 50.6,
49.8, 42.7, 26.4, 21.0.
O O O O O aq. CH2O O
Et3N, MeCN O2N rt, 36 h NO2 87% OH
127
7-(Hydroxymethyl)-3,3-dimethoxy-5-methyl-7-nitrobicyclo[2.2.2]oct-5-en-2- one (196). To a solution of nitro compound 195 (100 mg, 0.414 mmol) in acetonitrile (2 mL) was added aqueous formaldehyde (35%, 100 µL, 1.26 mmol) and triethylamine (60
µL, 0.430 mmol). The resulting solution was stirred for 2 d at rt and the solvent was evaporated. The residue was purified by flash column chromatography (40% EtOAc in hexanes) to give nitro alcohol 196 (97 mg, 87%) as a white solid. X-ray quality crystals
154 1 were obtained via slow evaporation from CH2Cl2/hexanes: H NMR (300 MHz, CDCl3)
δ 5.80 (dt, J = 6.9, 0.9 Hz, 1H), 4.06, 3.61 (ABq, J = 11.0 Hz, 2H), 3.92 (d, J = 7.0 Hz, 1
H), 3.37 (s, 3H), 3.23 (s, 3H), 3.01 (q, J = 2.6 Hz, 1H), 2.73 (dd, J = 14.8, 3.0 Hz), 1.95
(d, J = 1.6 Hz, 3H), 1.64 (dd, J = 14.8, 2.8 Hz, 1H).
OH OH O H2NNH2•H2O O KOH, (HOCH ) O 2 2 130 °C, 1h, 195 °C, 5 h 99%
2-Methoxy-5-methylphenol (84b). To a solution of isovanillin (197, 20.0 g, 131 mmol) in ethylene glycol (230 mL) was added potassium hydroxide (74 g, 1.32 mol) and hydrazine hydrate (32 mL, 660 mmol). The reaction mixture was heated at 130 °C and stirred for 1 h. The temperature was then increased to 185 – 195 °C and the mixture was stirred for 5 h. The resulting solution was cooled to rt, and then poured into 150 mL of conc. HCl in ~ 750 g of ice. The aqueous suspension was filtered at 0 °C, and the solids were washed with cold water (3 x 50 mL). The organic solids were dissolved in Et2O (150 mL), dried over MgSO4, and evaporated to give phenol 84b (16.6 g, 92%) as a white solid
128 that was used without further purification. Spectral data were consistent with literature values.155
OH OH O O NBS AcOH, rt, 3 h 98% Br
4-Bromo-2-methoxy-5-methylphenol (85b).39 To a solution of phenol 84b
(16.20 g, 117.2 mmol) in AcOH (60 mL) was slowly added a solution of N- bromosuccinimide (21.90 g, 123.0 mmol) in AcOH (400 mL). After the addition was complete, the reaction mixture was stirred at rt for 3 h, and the solvent was evaporated.
Saturated NaHCO3 (200 mL) was added, and the aqueous mixture was extracted with
CH2Cl2 (3 x 100 mL). The combined organics were washed with water and brine, dried over MgSO4, and evaporated to give bromophenol 85b (25.03 g, 98%) as a white solid of
1 sufficient purity to be used in the next step: H NMR (300 MHz, CDCl3) δ 6.99 (s, 1H),
13 6.81 (s, 1H), 5.51 (s, 1H), 3.85 (s, 1H), 2.28 (s, 1H); C NMR (75 MHz, CDCl3) δ 145.3,
144.8, 130.6, 116.6, 114.8, 113.6, 56.4, 22.2.
OH 1) PhI(OAc)2, MeOH O O O 0 °C, 15 min O Br 2) nitroethylene PhMe, rt, o/n Br 99% NO2
endo-5-Bromo-3,3-dimethoxy-6-methyl-7-nitrobicyclo[2.2.2]oct-5-en-2-one
(203). To (diacetoxyiodo)benzene (24.50 g, 76.06 mmol) in MeOH (275 mL) at 0 °C was
129 added bromophenol 84b (15.00 g, 69.10 mmol). The reaction mixture was stirred for 15 min, and water (250 mL) and brine (250 mL) were added. The aqueous mixture was extracted with CH2Cl2 (3 x 100 mL), and the combined organics were dried over MgSO4 and evaporated. To the residue was added a solution of nitroethylene in PhMe (1 M, 120 mL, 120 mmol), and the resulting solution was stirred overnight at rt. The solvent and residual nitroethylene were removed under reduced pressure. The crude material was purified by flash column chromatography (20% EtOAc in hexanes) to give cycloadduct
1 203 (21.95 g, 99%) as a yellow oil: H NMR (400 MHz, CDCl3) δ 4.89 (m, 1H), 3.85 (d, J
= 2.4 Hz, 1H), 3.37 (s, 3H), 3.35 (t, J = 3.0 Hz, 1H), 3.29 (s, 3H), 2.71 (ddd, J = 14.3, 9.8,
2.8 Hz, 1H), 2.33 (ddd, J = 14.4, 4.6, 3.4 Hz, 1H), 2.07 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 194.9, 131.4, 119.6, 93.8, 79.3, 59.0, 50.8, 50.6, 48.3, 28.7, 20.0; IR (thin film)
-1 + 1747, 1556 cm ; HRMS (ES-TOF) [M+NH4] calcd for C11H18BrN2O5 337.0399, found
337.0406.
O O O O O O (CH2O)n, Et3N Br Br MeCN, rt, o/n O2N 82% NO 2 HO .
5-Bromo-7-(hydroxymethyl)-3,3-dimethoxy-6-methyl-7- nitrobicyclo[2.2.2]oct-5-en-2-one (204). To a solution of nitro compound 203 (550 mg,
1.72 mmol) in MeCN (8 mL) was added aqueous formaldehyde (35%, 410 µL, 5.15 mmol) and triethylamine (240 µL, 1.72 mmol). The bright yellow reaction mixture was
130 stirred at rt for 24 h, and the solvent was evaporated. The residue was purified by flash column chromatography (2:1 hexanes:EtOAc) to yield nitro alcohol 204 (492 mg, 82%) as a white solid. X-ray quality crystals were obtained via slow evaporation from
156 1 CH2Cl2/hexanes: mp 147 °C; H NMR (400 MHz, CDCl3) δ 4.14 (dd, J = 12.1, 4.6 Hz,
1H), 3.97 (s, 1H), 3.45 (dd, J = 12.1, 5.4 Hz, 1H), 3.35 (s, 3H), 3.31 (t, J = 2.9 Hz, 1H),
2.69 (dd, J = 14.8, 2.8 Hz, 1H), 2.58 (br t, J = 5.3 Hz, 1H), 1.92 (s, 3H), 1.81 (dd, J =
13 14.7, 2.9 Hz, 1H); C NMR (100 MHz, CDCl3) δ 193.5, 132.7, 120.8, 94.2, 93.3, 66.6,
+ 58.3, 50.6, 49.9, 48.4, 32.6, 19.7; HRMS (ES-TOF) [M+NH4] calcd for C12H20BrN2O6
367.0505, found 367.0492.
O O O O O HCO H, Bu N O Br 2 3 Pd(PPh ) Cl O2N 3 2 2 O2N DMF, 80 °C, 16 h HO 84% HO
7-(Hydroxymethyl)-3,3-dimethoxy-6-methyl-7-nitrobicyclo[2.2.2]oct-5-en-2- one (191). To a solution of bromoalkene 204 (5.50 g, 15.71 mmol) in DMF (30 mL) was added formic acid (1.20 mL, 31.80 mmol), tributylamine (11.25 mL, 47.22 mmol) and bis(triphenylphosphine)palladium (II) dichloride (220 mg, 0.313 mmol). The solution was heated at 80 °C and stirred for 18 h. The reaction mixture was cooled and filtered through a pad of Celite. The pad was washed with EtOAc (150 mL), and the filtrate was washed with water (5 x 50 mL) and brine (50 mL). The organic phase was dried over
MgSO4 and evaporated. The resulting crude material was purified by flash column
131 chromatography (1:1 hexanes:EtOAc) to give nitroalkene 191 (3.67 g, 86%) as a yellow
1 solid: mp 141-142 °C; H NMR (400 MHz, CDCl3) δ 6.07 (dt, J = 6.5, 1.6 Hz, 1H), 4.10,
3.47 (ABq, J = 12.2 Hz, 2H), 3.82 (d, J = 1.2 Hz, 1H), 3.27 (s, 3H), 3.17 (s, 3H), 3.08 (dt,
J = 6.5, 3.1 Hz, 1H), 2.67 (dd, J = 14.6, 2.9 Hz, 1H), 2.43 (br t, J = 7.7 Hz, 1H), 1.90 (d, J
13 = 1.6 Hz, 3H), 1.59 (dd, J = 14.6, 2.9 Hz, 1H); C NMR (100 MHz, CDCl3) δ 195.6,
136.6, 128.9, 94.2, 93.8, 66.6, 56.9, 50.4, 49.2, 37.6, 32.8, 20.5; HRMS (ES-TOF)
+ [M+NH4] calcd for C12H21N2O6 289.1400, found 289.1390.
6-(Hydroxymethyl)-3,3-dimethoxy-7-methyl-6-nitrobicyclo[2.2.2]octan -2-one
(205). To a solution of alkene 191 (1.00 g, 3.69 mmol) in EtOH (18 mL) and AcOH (2 mL) was added 10% palladium on carbon (100 mg). The resulting suspension was placed under a hydrogen atmosphere (1 atm) and stirred for 24 h. The reaction mixture was filtered through a pad of Celite, and the solids were washed with EtOAc. The combined organics were washed with saturated aqueous NaHCO3, dried over MgSO4, and evaporated to give saturated nitro alcohol 205 (1.00 g, 99%) as an off-white solid as a single diastereomer (>49:1). X-ray quality crystals were obtained via slow evaporation
157 1 from Et2O: mp 121-123 °C; H NMR (400 MHz, CDCl3) δ 4.15, 3.88 (ABq, J = 12.4
Hz, 2H), 3.22 (s, 3H), 3.08 (s, 3H), 2.97 (d, J = 1.8 Hz, 1H), 2.76 (dt, J = 15.4, 3.1 Hz,
1H), 2.41 (m, 1H), 1.76 (ddd, J = 14.4, 10.7, 3.6 Hz, 1H), 1.64 (dd, J = 15.4, 2.1 Hz, 1H),
13 1.26 (m, 1H), 0.99 (d, J = 7.0 Hz, 3H); C NMR (100 MHz, CDCl3) δ 202.0, 98.1, 93.5,
132
65.8, 52.2, 49.7, 48.9, 33.6, 31.4, 28.3, 27.9, 20.8; HRMS (ES-TOF) [M+H]+ calcd for
C12H20NO6 274.1291, found 274.1282.
O O O O O O O OH Br Br Et3N, CH2Cl2 H 87% 3:2 NO2 NO2
5-Bromo-7,7-dimethoxy-4-methyl-3-nitro-2-phenethyl-2,3,3a,6,7,7a- hexahydro-3,6-methanobenzofuran-7a-ol (216).
A) To a solution of nitro compound 203 (320 mg, 1.00 mmol) in CH2Cl2 (2 mL) was added hydrocinnamaldehyde (90%, 160 µL, 1.09 mmol) and triethylamine (70 µL, 0.50 mmol). The dark yellow solution was stirred overnight, and then evaporated. The residue was purified by flash column chromatography (20% EtOAc in hexanes) to give hemiketal
216 (395 mg, 87%) as a white solid (3:2 mixture of diastereomers).
B) To a solution of epimeric alcohols 218 (45 mg, 0.099 mmol) in CH2Cl2 (1 mL) was added triethylamine (14 µL, 0.100 mmol). The solution was stirred overnight at rt, and the solvent was evaporated. The residue was purified by preparative TLC (25% EtOAc in hexanes) to give hemiketal 216 (33 mg, 73%) as a white solid (3:2 mixture of diastereomers).
1 H NMR (300 MHz, CDCl3) δ 7.28 (m, 2H), 7.19 (m, 3H), 4.74 (s, 0.4H), 4.69 (s,
0.6H), 4.44 (dd, J = 8.9, 3.2 Hz, 0.6H), 4.02 (dd, J = 10.8, 2.9 Hz, 0.4H), 3.73 (s, 0.6H),
3.62 (s, 0.4H), 3.44 (s, 1.2H), 3.44 (s, 1.8H), 3.38 (s, 1.2H), 3.37 (s, 1.8H), 3.05 (m, 1H),
133
2.92 (m, 1H), 2.67 (m, 2H), 2.20 (dd, J = 14.0, 2.6 Hz, 0.4H), 2.07 (dd, J = 14.0, 2.5 Hz,
0.6H), 2.02 (m, 1H), 1.96 (s, 1.2H), 1.92 (s, 1.8H), 1.83 (m, 0.4H), 1.63 (m, 0.6H); 13C
NMR (75 MHz, CDCl3) δ 141.3, 140.8, 131.8, 131.7, 128.8, 128.7, 128.6, 128.5, 126.3,
126.2, 116.7, 116.4, 103.7, 103.6, 102.2, 101.4, 92.0, 91.1, 81.7, 80.1, 60.3, 55.9, 51.8,
51.7, 51.6, 48.0, 47.9, 40.3, 34.0, 32.6, 32.6, 31.2, 29.9, 20.4; IR (thin film) 3493, 1538 cm-1.
O O O O O O O O O O Br Jones' reagent Br Br O2N O2N Amberlyst A21 [33%] THF, -10 °C, 6 h or 51% for 2 steps OH O NO2 [42%] 2:1
5-Bromo-3,3-dimethoxy-6-methyl-7-nitro-7-(3-phenylpropanoyl) bicyclo[2.2.2]oct-5-en-2-one (220). To a solution of nitro compound 203 (640 mg, 2.00 mmol) in THF (10 mL) at -10 °C was added hydrocinnamaldehyde (400 µL, 3.04 mmol) and Amberlyst A21 ion exchange resin (400 mg). The resulting suspension was stirred and warmed to 0 °C over 6 h. The reaction mixture was filtered, and the resin was rinsed with EtOAc. The solvent was evaporated to give crude alcohol 218 as a 5:3 mixture of diastereomers. The alcohol was unstable to chromatography and was carried on directly to the next step. Alcohol 218 could be isolated by chromatography in low yield (~42%), but isomerizes to hemiketal 216 on standing overnight.
134
1 Alcohol 218: H NMR (400 MHz, CDCl3) δ 7.30 (m, 2H), 7.24 (m, 1H), 7.18 (m,
2H), 4.24 (s, 1H), 3.53 (s, 0.38H), 3.39 (s, 0.62H), 3.35 (s, 1.88H), 3.34 (s, 1.12H), 3.30
(m, 1H), 3.18 (s, 1.88H), 3.13 (s, 1.12H), 3.10-2.83 (m, 2H), 2.78-2.62 (m, 2H), 2.42 (d,
J = 9.4 Hz, 0.38H), 2.29 (d, J = 9.4 Hz, 0.62H), 1.93 (s, 1.88H), 1.93 (s, 1.12H), 1.70 (m,
13 2H); C NMR (100 MHz, CDCl3) δ 194.1, 192.1, 140.6, 140.5, 132.4 (2C), 128.9, 128.8,
128.8, 128.5, 126.6, 126.5, 122.1, 120.9, 96.4, 96.0, 94.0, 93.8, 75.2, 73.6, 60.6, 60.0,
59.6, 50.4, 50.3, 50.2, 49.9, 48.8, 48.1, 33.9, 33.0, 32.7, 31.8, 31.5, 19.7, 19.2; HRMS
+ (ES-TOF) [M+NH4] calcd for C20H28BrN2O6 471.1131, found 471.1135.
Crude alcohol 218 was dissolved in acetone (20 mL). Jones reagent (2.7 M in Cr,
1.10 mL, 2.97 mmol) was added dropwise over 10 min, and the resulting solution was stirred for 12 h at rt. The solution was quenched with i-PrOH (1 mL), and the reaction mixture was filtered through a silica gel plug, eluting with EtOAc. The combined organics were evaporated, and the residue was purified by flash column chromatography (20%
EtOAc in hexanes) to give diketone 220 (457 mg, 51% for 2 steps) as a white solid: mp
1 112-113 °C; H NMR (300 MHz, CDCl3) δ 7.32 (t, J = 6.5 Hz, 2H), 7.21 (m, 3H), 3.85 (d,
J = 0.6 Hz, 1H), 3.44 (dd, J = 18.5, 1.7 Hz, 1H), 3.38 (s, 3H), 3.20 (s, 3H), 2.93-2.84 (m,
13 5H), 2.69 (dd, J = 14.9, 2.8 Hz, 1H), 1.60 (d, J = 0.6 Hz, 3H); C NMR (75 MHz, CDCl3)
δ 196.1, 191.2, 139.6, 130.7, 128.8, 128.5, 126.8, 121.4, 97.8, 93.7, 59.7, 50.5, 50.1,
-1 + 48.4, 37.9, 32.3, 29.7, 19.4; IR (neat) 1737, 1541 cm ; HRMS (ES-TOF) [M+NH4] calcd for C20H26BrN2O6 469.0974, found 469.0978.
135
O O O O TBSO TBSO O O O OH Br Br Et3N, CH2Cl2 rt, 48 h H NO 2 NO2
5-Bromo-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-7,7-dimethoxy-4-methyl-
3-nitro-2,3,3a,6,7,7a-hexahydro-3,6-methanobenzofuran-7a-ol (224a). To nitro compound 203 (320 mg, 1.00 mmol) and aldehyde 221a (203 mg, 1.00 mmol) in CH2Cl2 was added triethylamine (140 µL, 1.00 mmol). The reaction mixture was stirred at rt for 2 d and the solvent was evaporated. The residue was purified by flash column chromatography (10% EtOAc in hexanes) to give hemiketal 224a (464 mg, 89%) as a
1 pale yellow oil in a 3:2 diastereomeric ratio: H NMR (300 MHz, CDCl3) δ 4.64 (s, 0.4H),
4.62 (s, 0.6H), 4.39 (dd, J = 9.1, 2.9 Hz, 0.6H), 4.05 (dd, J = 9.0, 2.8 Hz, 0.4H), 3.70 (s,
0.6H), 3.63-3.56 (m, 2H), 3.55 (s, 0.4H), 3.40 (s, 1.2H), 3.39 (s, 1.8H), 3.31 (s, 1.2H),
3.28 (s, 1.8H), 3.02 (t, J = 2.9 Hz, 1H), 2.58 (m, 1H), 2.18 (dd, J = 12.0, 2.4 Hz, 0.4H),
2.08 (dd, J = 12.0, 2.4 Hz, 0.6H), 1.93 (s, 1.2H), 1.87 (s, 1.8H), 1.75-1.50 (m, 5H), 0.86
13 (s, 3.6H), 085 (s, 5.4H), 0.01 (s, 2.4H), 0.00 (s, 3.6H); C NMR (75 MHz, CDCl3)
δ 131.8, 131.5, 116.6, 116.3, 103.5, 103.5, 102.2, 101.4, 92.1, 91.2, 82.7, 80.7, 62.6,
62.5, 60.5, 55.8, 51.7, 51.6, 51.5, 51.4, 48.0, 47.9, 40.3, 21.6, 29.5, 29.4, 28.8, 28.3, 27.1,
26.0, 20.3, 18.3, -4.8, -4.9; IR (thin film) 3500, 1548 cm-1.
136
O O O O TBSO O O O Br Br Amberlyst A21 O N THF, rt, 24 h 2 NO2 19% TBSO OH
5-Bromo-7-(4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutyl)-3,3-dimethoxy-
6-methyl-7-nitrobicyclo[2.2.2]oct-5-en-2-one (222a). To a solution of nitro compound
203 (720 mg, 2.25 mmol) and aldehyde 221a (500 mg, 2.47 mmol) in THF (2 mL) was added Amberlyst A21 ion exchange resin. The homogenous mixture was stirred for 24 h, then the resin was removed by filtration and washed with EtOAc. The solvent was evaporated, and the residue was purified by flash column chromatography (20% EtOAc in hexanes) to give Henry product 221a (227 mg, 19%) (clear oil) as a single diastereomer
1 as determined by 2D NMR: H NMR (300 MHz, CDCl3) δ 4.46 (d, J = 4.2 Hz, 1H), 4.34
(s, 1H), 3.72 (m, 1H), 3.57 (m, 1H), 3.32 (s, 3H), 3.34-3.28 (m, 2H), 3.12 (s, 3H) 2.99
(dd, J = 10.9, 7.1 Hz, 1H), 1.91 (s, 3H), 1.92-1.78 (m, 2H), 1.61 (m, 1H), 1.32 (m, 1H),
13 0.86 (s, 9H), 0.04 (s, 6H); C NMR (75 MHz, CDCl3) δ 193.6, 133.0, 120.7, 95.7, 93.9,
75.7, 63.5, 59.6, 50.3, 50.0, 48.7, 32.7, 29.8, 28.8, 25.9, 19.8, 18.3, -5.5; IR (thin film)
3499, 1748, 1548 cm-1.
O O O OMe O O H MeO O 1) O O OH Br Br TBAF, THF O 0 °C, 4 h H NO2 2) Jones reag. NO2
137
Methyl 3-(5-Bromo-7a-hydroxy-7,7-dimethoxy-4-methyl-3-nitro-
2,3,3a,6,7,7a-hexahydro-3,6-methanobenzofuran-2-yl)propanoate (224c). To nitro compound 203 (160 mg, 0.500 mmol) in THF (1.75 mL) at 0 °C was added ester aldehyde 221c (1 M in THF, 0.75 mL, 0.75 mmol) and tetrabutylammonium fluoride (1
M in THF, 0.10 mL, 0.10 mmol). The resulting solution was stirred for 4 h at 0 °C. The solvent was quickly evaporated in vacuo, and the residue was dissolved in acetone (5 mL).
Jones reagent (2.7 M in Cr, 0.50 mL, 1.35 mmol) was added dropwise, and the solution was stirred overnight. The reaction was quenched with i-PrOH (1 mL), then filtered through a silica gel plug eluting with EtOAc. The organics were evaporated, and the residue was purified by flash column chromatography (2:1 hexanes:EtOAc) to give hemiketal 224c (118 mg, 54%) as a pale yellow oil in a 1:1 diastereomeric ratio: 1H NMR
(400 MHz, CDCl3) δ 4.66 (s, 0.5H), 4.64 (s, 0.5H), 4.10 (m, 1H), 3.67 (s, 1.5H), 3.66 (s,
1.5H), 3.42 (s, 3H), 3.30 (s, 1.5H), 3.23 (s, 1.5H), 3.05 (m, 1H), 2.62-2.54 (m, 2H), 2.44
(m, 1H), 2.06 (m, 2H), 1.95 (s, 1H), 1.91 (s, 1.5H), 1.85-1.68 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 173.5, 173.4, 132.0, 131.9, 117.0, 116.7, 104.1, 103.9, 102.4, 101.7,
92.1, 91.2, 81.8, 79.9, 60.5, 55.9, 52.1, 52.0, 51.9, 51.8, 48.2, 48.1, 31.0, 30.0, 27.7, 26.3,
20.9, 20.7, 20.6, 20.4; IR (thin film) 3490, 1738, 1543 cm-1.
O O O O O NaBH , MeOH H OH Br 4 Br -78 °C, 2 h 94% NO2 NO2
138
5-Bromo-3,3-dimethoxy-6-methyl-7-nitrobicyclo[2.2.2]oct-5-en-2-ol (225). To nitro ketone 203 (3.20 g, 10.00 mmol) in MeOH (150 mL) at -78 °C was added NaBH4
(415 mg, 10.97 mmol). The reaction mixture was stirred for 30 min, and then warmed to rt over 1.5 h. The solvent was partially evaporated to ~20 mL volume, and saturated aqueous NH4Cl (100 mL) was added. The suspension was stirred for 10 min, and then extracted with EtOAc. The combined organics were dried over MgSO4 and evaporated.
The residue was purified by flash column chromatography (25% EtOAc in hexanes) to give nitro alcohol 225 (3.03 g, 94%) as a white solid as a single diastereomer. X-ray quality crystals were obtained by slow evaporation from hexanes: mp 107-108 °C; 1H
NMR (300 MHz, CDCl3) δ 4.64 (ddd, J = 9.4, 4.4, 2.6 Hz, 1H), 3.68 (dd, J = 5.9, 2.8 Hz,
1H), 3.52 (td, J = 5.3, 0.6 Hz, 1H), 3.41(s, 3H), 3.20 (s, 3H), 3.16 (d, J = 6.0 Hz, 1H),
3.15 (t, 3.0 Hz, 1H), 2.42 (ddd, J = 14.6, 9.4, 2.6 Hz, 1H), 2.23 (ddd, J = 14.6, 7.7, 0.6 Hz,
13 1H), 1.87 (s, 3H); C NMR (75 MHz, CDCl3) δ 134.8, 115.1, 102.0, 80.9, 71.7, 51.4,
50.4, 40.0, 47.1, 27.8, 21.2; IR (thin film) 3518, 1551 cm-1; LRMS (ESI) [M+H]+ calcd for C11H17BrNO5 322.0, found 322.1.
O O O O H OH Ac2O H OAc Br Br DMAP, CH2Cl2 rt, 16 h NO 78% NO 2 2
5-Bromo-3,3-dimethoxy-6-methyl-7-nitrobicyclo[2.2.2]oct-5-en-2-yl Acetate
(226a). To a solution of nitro alcohol 225 (35 mg, 0.109 mmol) in CH2Cl2 (0.5 mL) was
139 added acetic anhydride (12.5 µL, 0.132 mmol) and N,N-dimethylaminopyridine (1 mg,
0.008 mmol). The reaction mixture was stirred for 18 h at rt, and CH2Cl2 (5 mL), water (5 mL), and saturated aqueous NaHCO3 (5 mL) were added. The biphasic mixture was stirred for 1 h, then the organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over MgSO4 and evaporated. The residue was purified by preparative TLC (2:1 hexanes/EtOAc) to give acetate 226a (31 mg, 78%)
1 as a white solid: mp 116 °C; H NMR (300 MHz, CDCl3) δ 4.86 (d, J = 3.0 Hz, 1H), 4.73
(ddd J = 9.5, 4.8, 2.4 Hz, 1H), 3.44 (t, J = 2.7 Hz, 1H), 3.29 (s, 3H), 3.22 (s, 3H), 3.19 (t,
J = 3.0 Hz, 1H), 2.51 (ddd, J = 14.2, 9.6, 2.8 Hz, 1H), 2.13 (ddd, J = 13.7, 4.6, 3.2 Hz,
13 1H), 2.10 (s, 3H), 1.88 (s, 3H); C NMR (75 MHz, CDCl3) δ 170.0, 133.8, 116.3, 103.3,
80.4, 72.8, 50.5, 50.0, 48.3, 47.7, 28.5, 21.2, 20.9.
O O O O H OH dihydropyran H OTHP Br Br PPTS, CH2Cl2 rt, 24 h NO 100% NO 2 2
2-((5-Bromo-3,3-dimethoxy-6-methyl-7-nitrobicyclo[2.2.2]oct-5-en-2- yl)oxy)tetrahydro-2H-pyran (226b). To a solution of nitro alcohol 225 (450 mg, 1.40 mmol) in CH2Cl2 (7 mL) was added 3,4-dihydro-2H-pyran (250 µL, 2.95 mmol) and pyridinium p-toluenesulfonate (18 mg, 0.07 mmol). The reaction mixture was stirred at rt for 24 h, and then poured into water (5 mL) and saturated aqueous NaHCO3 (5 mL). The organic phase was separated, and the aqueous layer was extracted with CH2Cl2. The
140 combined organics were dried over MgSO4 and evaporated. The resulting residue was purified by flash column chromatography (20% EtOAc in hexanes) to give THP-ether
226b (567 mg, 100%) (pale yellow oil) as an inseparable 3:2 diastereomeric mixture: 1H
NMR (300 MHz, CDCl3) δ 4.72 (t, J = 4.1 Hz, 1H), 4.65 (m, 1H), 3.85 (d, J = 2.8 Hz,
0.6H), 3.71 (d, J = 2.8 Hz, 0.4H), 3.56-3.50 (m, 2H), 3.40 (s, 1.8H), 3.30 (s, 1.2H), 3.24
(s, 1.8H), 3.17 (s, 1.2H), 3.13 (t, J = 3.0 Hz, 1H), 2.42 (m, 1H), 2.10 (m, 1H), 1.91 (s,
13 1.2H), 1.83 (s, 1.8H), 1.80-1.45 (m, 6H); C NMR (75 MHz, CDCl3) δ 134.7, 133.6,
116.3, 115.2, 104.4, 104.0, 99.0, 97.3, 81.1, 76.7, 76.2, 64.0, 63.0, 51.6, 50.5, 50.3, 49.5,
49.3, 48.2, 47.6, 47.1, 31.0, 30.5, 28.5, 28.2, 25.5, 25.3, 21.0, 21.0, 20.3, 19.5.
O O O O H OH O OEE Br Br PPTS, CH2Cl2 rt, 12 h NO NO 2 98% 2
3-Bromo-6-(1-ethoxyethoxy)-5,5-dimethoxy-2-methyl-7-nitrobicyclo
[2.2.2]oct-2-ene (226c). To a solution of nitro alcohol 225 (1.40 g, 4.34 mmol) in CH2Cl2
(17 mL) was added ethyl vinyl ether (0.83 mL, 8.67 mmol) and pyridinium p- toluenesulfonate (55 mg, 0.22 mmol). The reaction mixture was stirred for 12 h at rt, and then the solvent was evaporated. The resulting residue was purified by flash column chromatography (20% EtOAc in hexanes) to give ethoxyethyl ether 226c (1.68 g, 98%) as a clear oil that solidified to a waxy solid on standing. The ~1:1 diastereomeric mixture could be separated by careful column chromatography, but was used as the mixture in
141
1 subsequent reactions: H NMR (400 MHz, CDCl3) δ 4.87 (q, J = 5.4 Hz, 1H), 4.64 (m,
1H), 3.75 (d, J = 2.8 Hz, 1 H), 3.52-3.66 (m, 2H), 3.49 (t, J = 2.5 Hz, 1H), 3.36 (s, 3H),
3.22 (s, 3H), 3.13 (t, J = 2.7 Hz, 1H), 2.39 (ddd, J = 14.0, 9.6, 2.8 Hz, 1H), 2.12 (ddd, J =
14.1, 4.1, 3.7 Hz, 1H), 1.85 (s, 3H), 1.36 (d, J = 5.4 Hz, 3H), 1.18 (td, J = 7.1, 0.6 Hz,
13 3H); C NMR (100 MHz, CDCl3) δ 133.7, 116.2, 103.9, 98.7, 81.0, 76.2, 60.7, 51.1,
49.4, 48.3, 47.9, 28.1, 21.0, 20.4, 15.4.
O O O O OEE HCHO (aq) OEE Br Br Et3N, THF O2N 0 °C to rt, 2 d NO 2 97% HO
5-Bromo-7-(1-ethoxyethoxy)-8,8-dimethoxy-6-methyl-2-nitrobicyclo
[2.2.2]oct-5-en-2-yl)methanol (228c). To a solution of nitro compound 226c (450 mg,
1.14 mmol) in THF (10 mL) were added formaldehyde (35% aqueous, 270 µL, 3.40 mmol) and triethylamine (160 µL, 1.15 mmol). The reaction mixture was stirred at rt for
48 h, and then evaporated. The resulting residue was purified by flash column chromatography (25% EtOAc in hexanes) to give nitro alcohol 228c (472 mg, 97%) as a clear oil. The ~1:1 diastereomeric mixture could be separated by careful column chromatography, but was used as the mixture in subsequent reactions.
1 Diastereomer 1 (Rf = 0.29, 25% EtOAc in hexanes): H NMR (400 MHz, CDCl3) δ
4.76 (q, J = 4.4 Hz, 1H), 3.75 (d, J = 2.6 Hz, 1H), 3.49-3.67 (m, 5H), 3.28 (s, 3H), 3.14 (s,
3H), 3.06 (t, J = 2.7 Hz, 1H), 2.81 (dd, J = 14.9, 2.3 Hz, 1H), 2.51 (br t, J = 5.8 Hz, 1H),
142
1.92 (s, 3H), 1.55 (dd, J = 14.9, 3.2 Hz, 1H), 1.30 (d, J = 5.3 Hz, 3H), 1.20 (t, J = 7.0 Hz,
13 3H); C NMR (75 MHz, CDCl3) δ 135.7, 116.2, 104.5, 100.5, 94.1, 74.0, 69.1, 60.4,
50.2, 50.2, 49.2, 48.2, 29.1, 21.0, 20.2, 15.3.
1 Diastereomer 2 (Rf = 0.23, 25% EtOAc in hexanes): H NMR (300 MHz, CDCl3) δ
4.79 (q, J = 5.2 Hz, 1H), 3.79 (d, J = 2.5 Hz, 1H), 3.50-3.64 (m, 5H), 3.33 (s, 3H), 3.18 (s,
3H), 3.07 (t, J = 2.8 Hz, 1H), 2.75 (dd, J = 14.9, 2.3 Hz, 1H), 2.51 (br t, J = 5.8 Hz, 1H),
1.92 (s, 3H), 1.56 (dd, J = 14.9, 3.4 Hz, 1H), 1.33 (d, J = 5.3 Hz, 3H), 1.15 (t, J = 7.0 Hz,
13 3H); C NMR (75 MHz, CDCl3) δ 135.1, 116.8, 104.2, 99.5, 93.9, 74.9, 69.1, 62.0, 50.7,
49.4, 48.5, 58.2, 29.1, 21.1, 20.9, 15.4.
O O O O H OH HCHO (aq) H OH Br Br Et3N, MeCN O2N rt, 3 d NO2 89% HO
5-Bromo-7-(hydroxymethyl)-3,3-dimethoxy-6-methyl-7-nitrobicyclo
[2.2.2]oct-5-en-2-ol (228). To a solution of nitro alcohol 225 (15.75 g, 48.89 mmol) in
MeCN (250 mL) were added aqueous formaldehyde (35%, 7.75 mL, 97.65 mmol) and triethylamine (6.80 mL, 48.79 mmol). The reaction mixture was stirred at rt for 3 d, and then evaporated. The residue was purified by flash column chromatography (2:1 hexanes/EtOAc) to give nitro diol 228 (15.32 g, 89%) as a white solid: 1H NMR (400
MHz, CDCl3) δ 3.70 (dd, J = 5.7, 2.7 Hz, 1H), 3.65 (m, 2H), 3.56 (d, J = 2.6 Hz, 1H), 3.39
143
(s, 3H), 3.17 (s, 3H), 3.11 (d, 5.7 Hz, 1H), 3.11 (br s, 1H), 2.91 (dd, J = 15.0, 2.1 Hz,
1H), 2.41 (br t, J = 5.9 Hz, 1H), 1.94 (s, 3H), 1.63 (dd, J = 15.1, 3.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 135.9, 116.0, 102.5, 94.3, 69.5, 69.0, 51.5, 50.2, 50.1, 47.9, 28.4,
21.2.
O O O O 0 H OH Zn H OH Br HO Br
O2N Ac2O/AcOH AcN rt, 18 h HO 51% AcO
5-Bromo-7-hydroxy-2-(N-hydroxyacetamido)-8,8-dimethoxy-6- methylbicyclo[2.2.2]oct-5-en-2-yl)methyl Acetate (231b). To a solution of nitro diol
92 228 (750 mg, 2.13 mmol) in AcOH (7 mL) and Ac2O (14 mL) was added activated zinc
(1.39 g, 21.26 mmol). The solution was stirred at rt for 18 h, filtered through a pad of
Celite eluting with MeOH, and evaporated. The crude mixture was dissolved in EtOAc, and the organics were washed with saturated aqueous NaHCO3. The organic solution was dried over MgSO4 and evaporated. The residue was purified by flash column chromatography (40% EtOAc in hexanes) to give diacetyl compound 231b (456 mg,
1 51%) as a yellow oil: H NMR (300 MHz, CDCl3) δ 7.79, 4.37 (dd, J = 6.1, 2.7 Hz, 1H),
3.90, 3.66 (ABq, J = 11.3 Hz, 2H), 3.38 (s, 3H), 3.25 (s, 3H), 3.03 (t, J = 1.4 Hz, 1H),
3.00 (br d, J = 6.1 Hz, 1H), 2.85 (d, J = 2.7 Hz, 1H), 2.06 (s, 3H), 2.04 (s, 3H), 1.74 (s,
3H), 1.72 (dd, J = 14.0, 1.8 Hz, 1H), 1.46 (dd, J = 14.0, 3.5 Hz, 1H); 13C NMR (75 MHz,
144
CDCl3) δ 170.9, 170.1, 136.5, 115.5, 102.9, 68.8, 64.9, 62.8, 51.5, 50.2, 49.9, 48.0, 29.1,
21.5, 20.9, 19.2.
O O O O 0 H OH Zn H OAc Br HO Br
O2N Ac2O/AcOH AcN 45 °C, 18 h 40% HO AcO
(7-Acetoxy-5-bromo-2-(N-hydroxyacetamido)-8,8-dimethoxy-6- methylbicyclo[2.2.2]oct-5-en-2-yl)methyl Acetate (231c). To a solution of nitro diol
92 228 (220 mg, 0.625 mmol) in AcOH (3 mL) and Ac2O (3 mL) was added activated zinc
(410 mg, 6.27 mmol). The solution was heated at 45 °C and stirred for 18 h. The reaction mixture was cooled to rt, filtered through a pad of Celite eluting with MeOH, and evaporated. The crude mixture was dissolved in EtOAc, and the organics were washed with saturated aqueous NaHCO3. The organic solution was dried over MgSO4 and evaporated. The residue was purified by flash column chromatography (40% EtOAc in hexanes) to give triacetyl compound 231c (117 mg, 40%) as a white solid: 1H NMR (300
MHz, CDCl3) δ 7.84 (s, 1H), 5.36 (d, J = 3.0 Hz, 1H), 3.92, 3.72 (ABq, J = 11.3 Hz, 2H),
3.29 (s, 3H), 3.26 (s, 3H), 3.10 (t, J = 2.9 Hz, 1H), 2.83 (d, J = 3.0 Hz, 1H), 2.10 (s, 3H),
2.07 (s, 3H), 2.06 (s, 3H), 1.84 (s, 3H), 1.74 (dd, J = 14.2, 2.5 Hz, 1H), 1.46 (dd, J = 14.2,
13 3.3 Hz, 1H); C NMR (75 MHz, CDCl3) δ 170.9, 170.2, 170.1, 135.3, 116.6, 103.9, 71.6,
65.4, 62.6, 50.2, 50.1, 48.9, 48.4, 29.5, 21.3, 21.2, 20.9, 19.2; LRMS (EI) [M+H]+ calcd for C18H27BrNO6 464.1, found 464.1.
145
O O O O H OH H OH Br TBDPS-Cl Br O2N Im, DMF O2N 70 °C, 18 h 66% HO TBDPSO
5-Bromo-7-(((tert-butyldiphenylsilyl)oxy)methyl)-3,3-dimethoxy-6-methyl-7- nitrobicyclo[2.2.2]oct-5-en-2-ol (229c). To a solution of diol 228 (200 mg, 0.568 mmol) in DMF (1 mL) were added t-butylchlorodiphenylsilane (325 µL, 1.25 mmol) and imidazole (116 mg, 1.70 mmol). The resulting solution was heated at 70 °C for 20 h. The reaction mixture was cooled to rt, and water was added. The mixture was extracted with
CH2Cl2, and the organics were washed with 1:1 water/brine, dried over MgSO4, and evaporated. The resulting residue was purified by flash column chromatography (20%
EtOAc in hexanes) to give the mono-silyl ether 229c (222 mg, 66%) as a clear oil: 1H
NMR (300 MHz, CDCl3) δ 7.50-7.56 (m, 4H), 7.38-7.42 (m, 6H), 3.84 (d, J = 2.0 Hz,
1H), 3.68, 3.62 (ABq, J = 10.7 Hz, 2H), 3.65 (d, J = 2.6 Hz, 1H), 3.37 (s, 3H), 3.16 (s,
3H), 3.04 (t, J = 2.8 Hz, 1H), 2.81 (dd, J = 15.2, 2.1 Hz, 1H), 1.79 (s, 3H), 1.61 (dd, J =
13 15.2, 3.5 Hz, 1H), 1.04 (s, 9H); C NMR (75 MHz, CDCl3) δ 136.0, 135.7, 135.6, 134.9,
132.5, 132.1, 130.2, 128.0, 127.8, 116.0, 102.5, 93.6, 69.8, 69.6, 51.3, 50.1, 50.0, 47.8,
28.9, 26.8, 21.3, 19.4.
146
O O O
H OAc In(OTf)3 H OAc HO Br HO Br AcN acetone, µW AcN 100 °C, 5 min 70% AcO AcO
7-Acetoxy-5-bromo-2-(N-hydroxyacetamido)-6-methyl-8- oxobicyclo[2.2.2]oct-5-en-2-yl)methyl Acetate (S1). To a solution of ketal 231c (175 mg, 0.377 mmol) in acetone (5 mL) in a microwave tube was added indium (III) trifluoromethanesulfonate (2.7 mg, 0.0048 mmol). The solution was heated at 100 °C for
5 min in a microwave reactor, and cooled to rt. The solvent was evaporated, and the resulting residue was purified by flash column chromatography (40% EtOAc in hexanes)
1 to give ketone S1 (110 mg, 70%) as a white solid: H NMR (300 MHz, CDCl3) δ 7.82 (s,
1H), 5.55 (d, J = 2.6 Hz, 1H), 3.94, 3.78 (ABq, J = 11.5 Hz, 2H), 3.33 (t, J = 2.7 Hz, 1H),
3.05 (d, J = 2.6 Hz, 1H), 2.05 (s, 3H), 2.05 (s, 3H), 2.04, (s, 3H), 1.90 (s, 3H), 1.77-1.87
13 (m, 2H); C NMR (75 MHz, CDCl3) δ 201.4, 170.5, 169.9 (2C), 139.0, 112.7, 67.5, 63.6,
+ 62.8, 56.7, 48.1, 30.4, 21.4, 20.7, 20.6, 18.9; LRMS (EI) [M+H] calcd for C16H21BrNO7
418.0, found 418.0.
O O O O H OH H2, 10% Pd/C H OH Br
O2N Ac2O, EtOAc O2N 98% HO AcO
147
7-Hydroxy-8,8-dimethoxy-6-methyl-2-nitrobicyclo[2.2.2]oct-5-en-2-yl)methyl
Acetate (232b). To a solution of nitro diol 228 (350 mg, 0.994 mmol) in EtOAc (5 mL) and Ac2O (5 mL) was added 10% palladium on carbon (50 mg, 0.047 mmol). The reaction mixture was placed in a pressure vessel, and the vessel was pressurized with H2 to
50 bar. After stirring the mixture for 18 h, the pressure was released, and the reaction mixture was filtered through a pad of Celite eluting with MeOH. The combined organics were evaporated, and the resulting residue was purified by flash column chromatography
(2:1 hexanes/EtOAc) to give monoacetate 232b (307 mg, 98%) as a white solid: 1H NMR
(300 MHz, CDCl3) δ 5.82 (dd, J = 5.9, 1.4 Hz, 1H), 4.14 (s, 2H), 3.71 (d, J = 2.6 Hz, 1H),
3.28 (m, 1H), 3.22 (s, 3H), 3.11 (s, 3H), 2.85 (dd, J = 14.8, 2.1 Hz, 1H), 2.82 (m, 1H),
2.00 (s, 3H), 1.83 (d, J = 1.5 Hz, 3H), 1.45 (dd, J = 14.7, 3.2 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 170.0, 138.9, 123.8, 102.2, 92.1, 69.6, 68.8, 49.8, 49.5, 37.2, 28.6, 22.3, 20.5;
+ LRMS (EI) [M+Na] calcd for C14H21NNaO7 338.1, found 338.3.
O O O O H OH Ac O H OAc Br 2 Br O2N DMAP, py O2N CH2Cl2, rt, 2h 99% HO AcO
7-Acetoxy-5-bromo-8,8-dimethoxy-6-methyl-2-nitrobicyclo[2.2.2]oct-5-en-2- yl)methyl Acetate (229a). To a solution of nitro diol 228 (1.50 g, 4.26 mmol) in CH2Cl2
(18 mL) were added pyridine (1.70 mL, 21.2 mmol), 4-dimethylaminopyridine (52 mg,
0.426 mmol), and Ac2O (1.20 mL, 12.72 mmol). The reaction mixture was stirred for 2 h
148 at rt, and then poured into water. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with 1 M HCl, dried over
MgSO4 and evaporated to give diacetate 229a (1.84 g, 99%) as a white solid of high
1 purity: mp 124-5 °C; H NMR (300 MHz, CDCl3) δ 5.06 (d, J = 3.0 Hz, 1H), 4.22, 4.07
(ABq, J = 11.9 Hz, 2H), 3.45 (d, J = 3.0 Hz, 1H), 3.26 (s, 3H), 3.19 (s, 3H), 3.14 (t, J =
2.9 Hz, 1 H), 2.94 (dd, J = 15.1, 2.4 Hz, 1H), 2.06 (s, 3H), 2.05 (s, 3H), 1.90 (s, 3H), 1.68
13 (dd, J = 15.3, 3.5 Hz, 1H); C NMR (75 MHz, CDCl3) δ 169.9, 169.7, 134.7, 117.5,
103.1, 90.4, 70.8, 68.4, 50.2, 50.1, 49.0, 48.1, 30.2, 21.1 (2C), 20.6.
O O O O 0 H OAc Zn , HCl H OAc Br Br
O2N i-PrOH, H2O HOHN 0 °C, 2 h AcO 98% AcO
7-Acetoxy-5-bromo-2-(hydroxyamino)-8,8-dimethoxy-6-methylbicyclo
[2.2.2]oct-5-en-2-yl)methyl Acetate (234a). To nitro compound 229a (220 mg, 0.504 mmol) partially dissolved in i-PrOH (10 mL) at 0 °C were added 1 M HCl (2.50 mL, 2.50 mmol) and activated zinc92 (330 mg, 5.05 mmol). The resulting suspension was stirred for 2 h at 0 °C, during which time the white suspension became a clear solution. Saturated
NaHCO3 (20 mL) was added, and the mixture was filtered through a pad of Celite eluting with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc.
The combined organics were washed with brine, dried over MgSO4, and evaporated to give hydroxylamine 234a (208 mg, 98%) as a white solid of high purity: 1H NMR (300
149
MHz, CDCl3) δ 5.73 (br s, 1H), 5.38 (d, J = 2.9 Hz, 1H), 4.20, 3.65 (ABq, J = 10.9 Hz,
2H), 3.28 (s, 3H), 3.24 (s, 3H), 3.05 (t, J = 2.9 Hz, 1H), 2.83 (d, J = 2.9 Hz, 1H), 2.07 (s,
13 3H), 2.06 (s, 3H), 1.83 (s, 3H), 1.45 (m, 2H); C NMR (75 MHz, CDCl3) δ 171.4, 170.4,
135.6, 116.4, 104.1, 71.8, 65.2, 63.0, 50.3, 49.9, 48.4, 48.4, 29.3, 21.3 (2C), 21.0; LRMS
+ (EI) [M+Na] calcd for C16H24NNaO7 444.1, found 444.1.
O O O O H OAc BnO2CCl H OAc Br HO Br
HOHN Et3N, THF CbzN rt, 16 h AcO 44% AcO
7-Acetoxy-2-(((benzyloxy)carbonyl)(hydroxy)amino)-5-bromo-8,8- dimethoxy-6-methylbicyclo[2.2.2]oct-5-en-2-yl)methyl Acetate (S2). To a solution of hydroxylamine 234a (97 mg, 0.23 mmol) in THF (2 mL) were added K2CO3 (63 mg, 0.46 mmol) and benzyl chloroformate (35 µL, 0.24 mmol). After stirring at rt for 16 h, the reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over MgSO4 and evaporated. The resulting residue was purified by flash column chromatography (40% EtOAc in hexanes) to give Cbz-protected hydroxylamine
1 S2 (56 mg, 44%) as a clear oil: H NMR (300 MHz, CDCl3) δ 7.36 (m, 5H), 7.15 (s, 1H),
5.43 (d, J = 3.0 Hz, 1H), 5.21 (d, J = 1.3 Hz, 2H), 3.95, 3.76 (ABq, J = 11.3 Hz, 2H), 3.28
(s, 3H), 3.28 (s, 3H), 3.09 (t, J = 2.8 Hz, 1H), 2.87 (d, J = 3.0 Hz, 1H), 2.06 (s, 3H), 2.02
(s, 3H), 1.83 (s, 3H), 1.69 (dd, J = 14.2, 2.3 Hz, 1H), 1.43 (dd, J = 14.2, 3.2 Hz, 1H); 13C
150
NMR (75 MHz, CDCl3) δ 170.7, 170.0, 155.3, 135.4, 134.8, 128.9, 128.8 (2C), 116.5,
103.9, 71.3, 70.7, 65.8, 62.9, 50.2, 50.1, 48.5, 48.2, 29.5, 21.3, 21.2, 20.8.
O O O O H OAc H OAc Br BzCl HO Br
HOHN Et3N, DCM BzN rt, 5 h 65% AcO AcO
7-Acetoxy-5-bromo-2-(N-hydroxybenzamido)-8,8-dimethoxy-6- methylbicyclo[2.2.2]oct-5-en-2-yl)methyl Acetate (S3). To a solution of hydroxylamine 234a (150 mg, 0.369 mmol) in CH2Cl2 (3.5 mL) was added benzoyl chloride (65 µL, 0.560 mmol) followed by triethylamine (80 µL, 0.574 mmol). The resulting solution was stirred for 5 h at rt, then quenched with saturated aqueous
NaHCO3. The organics were separated, and the aqueous layer was extracted with
CH2Cl2. The organic layer was dried over MgSO4 and evaporated. The resulting residue was purified by flash column chromatography (2:1 hexanes/EtOAc) to give benzoyl-
1 protected hydroxylamine S3 (123 mg, 65%) as a white solid: H NMR (400 MHz, CDCl3)
δ 8.13 (s, 1H), 8.00 (dd, J = 8.2, 1.2 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.45 (td, J = 7.4, 1.4
Hz, 2H), 5.53 (d, J = 3.0 Hz, 1H), 3.94, 3.79 (ABq, J = 11.4 Hz, 2H), 3.32 (s, 3H), 3.31 (s,
3H), 3.14 (t, J = 2.9 Hz, 1 H), 2.97 (d, J = 3.0 Hz, 1H), 2.08 (s, 3 H), 2.03 (s, 3H), 1.88
(dd, J = 14.1, 3.0 Hz, 1H), 1.85 (s, 3H), 1.51 (dd, J = 14.0, 3.2 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 170.7, 170.0, 166.1, 135.3, 133.4, 129.4, 128.7, 128.3, 116.6, 104.0,
71.7, 65.8, 62.8, 50.3, 50.1, 48.8, 48.4, 29.7, 21.3, 21.2, 20.8.
151
O O O O H OH H OBz Br BzCl Br O2N DMAP, py O2N CH2Cl2, rt, 3 h HO 98% BzO
7-(Benzoyloxy)-5-bromo-8,8-dimethoxy-6-methyl-2-nitrobicyclo[2.2.2]oct-5- en-2-yl)methyl Benzoate (229b). To a solution of diol 228 (700 mg, 1.99 mmol) in
CH2Cl2 (8.5 mL) at 0 °C were added 4-dimethylaminopyridine (24 mg, 0.20 mmol), pyridine (800 µL, 9.93 mmol), and benzoyl chloride (700 µL, 6.02 mmol). The resulting solution was warmed to rt and stirred for 3 h. The reaction mixture was quenched with saturated aqueous NaHCO3, the organics were separated, and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over MgSO4 and evaporated.
The resulting residue was purified by flash column chromatography (20% EtOAc in hexanes) to give dibenzoate 229b (1.09 g, 98%) as a clear viscous oil that solidified to a
1 sticky solid on standing: H NMR (300 MHz, CDCl3) δ 7.98 (m, 4H), 7.52 (m, 2H), 7.45
(m, 4H), 5.42 (d, J = 3.1 Hz, 1H), 4.46, 4.40 (ABq, J = 12.0 Hz, 2H), 3.73 (d, J = 3.1 Hz,
1H), 3.30 (s, 3H), 3.26 (t, J = 3.06 Hz, 1H) 3.25 (s, 3H), 3.08 (dd, J = 15.2, 2.5 Hz, 1H),
13 1.99 (s, 3H), 1.84 (dd, J = 15.0, 3.1 Hz); C NMR (75 MHz, CDCl3) δ 165.3, 165.1,
162.4, 134.6, 133.8, 133.3, 130.6, 129.9, 129.8, 128.9, 128.7, 128.6, 117.9, 103.6, 90.4,
71.4, 68.7, 50.3, 50.1, 48.9, 48.0, 30.6, 21.1.
152
O O O O 0 H OBz Zn H OBz Br HO Br
O2N Ac2O/AcOH AcN rt, 3 h 91% BzO BzO
7-(Benzoyloxy)-5-bromo-2-(N-hydroxyacetamido)-8,8-dimethoxy-6- methylbicyclo[2.2.2]oct-5-en-2-yl)methyl Benzoate (235b). To a solution of nitro compound 229b (100 mg, 0.178 mmol) in AcOH (1 mL) and Ac2O (1 mL) was added activated zinc powder92 (115 mg, 1.76 mmol). The heterogeneous mixture was stirred for
3 h at rt, and then filtered through a pad of Celite eluting with EtOAc. The combined organics were evaporated, dissolved in CH2Cl2, and washed with saturated aqueous
NaHCO3. The organic layer was dried over MgSO4 and evaporated, and the resulting residue was purified by flash column chromatography (20% EtOAc in hexanes) to give
1 hydroxamic acid 235b (93 mg, 91%) as a white semisolid: H NMR (300 MHz, CDCl3)
δ 8.04 (m, 5H), 7.48 (m, 2H), 7.44 (m, 4H), 5.61 (d, J = 3.1, 1H), 4.19, 4.10 (ABq, J =
11.4 Hz, 2H), 3.36 (s, 3H), 3.25 (s, 3H), 3.21 (t, J = 2.5 Hz, 1H), 3.11 (d, J = 3.1 Hz, 1H),
2.13 (s, 3H), 1.90 (s, 3H), 1.88 (dd, J = 13.6, 2.6 Hz, 1H), 1.63 (dd, J = 14.2, 3.2 Hz, 1H);
13 C NMR (75 MHz, CDCl3) δ 170.1, 166.3, 165.4, 134.6, 133.4, 133.2, 130.6, 129.8,
129.8, 128.9, 128.6, 128.5, 116.7, 104.2, 72.1, 66.4, 62.5, 50.4, 50.1, 49.0, 48.4, 29.8,
21.2, 19.3.
153
O O O H OAc In(OTf) H OAc HO Br 3 HO Br BzN acetone BzN 40 °C, 4 h 80% AcO AcO
7-Acetoxy-2-benzamido-5-bromo-6-methyl-8-oxobicyclo[2.2.2]oct-5-en-2- yl)methyl Acetate (S4). To ketal 235b (275 mg, 0.539 mmol) in acetone (5 mL) was added indium (III) trifluoromethanesulfonate (3 mg, 0.005 mmol). The resulting solution was warmed at 40 °C and stirred for 4 h. The organics were evaporated, and the residue was purified by flash column chromatography (5% EtOAc in CH2Cl2) to give ketone S4
1 (201 mg, 80%) as an opalescent white solid: H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H),
8.01 (d, J = 8.2 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 5.71 (d, J = 2.7
Hz, 1H), 4.00, 3.84 (ABq, J = 11.5 Hz, 2H), 3.43 (t, J = 2.8 Hz, 1H), 3.25 (d, J = 2.6 Hz,
13 1H), 2.13 (s, 3H), 2.07 (s, 3H), 1.94 (m, 2H), 1.92 (s, 3H); C NMR (75 MHz, CDCl3) δ
201.7, 170.5, 170.1, 166.1, 139.0, 133.8, 129.5, 128.8, 127.7, 113.1, 67.9, 64.3, 63.1,
56.9, 48.3, 30.9, 21.6, 20.8.
O O O O 0 H OBz Zn , HCl H OBz Br Br
O2N i-PrOH, H2O HOHN rt, 1 h 99% BzO BzO
7-(Benzoyloxy)-5-bromo-2-(hydroxyamino)-8,8-dimethoxy-6- methylbicyclo[2.2.2]oct-5-en-2-yl)methyl Benzoate (234b). To a suspension of nitro
154 compound 229b (240 mg, 0.428 mmol) in i-PrOH (8.5 mL) was added 1 M HCl (2.15 mL, 2.15 mmol), followed by zinc powder (280 mg, 4.28 mmol). The resulting suspension was stirred for 1 h. After ~30 min, compound 229b had completely dissolved. Saturated aqueous NaHCO3 (15 mL) was added, and the resulting suspension was stirred for 15 min. The mixture was filtered through a Celite plug eluting with EtOAc. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organics were washed with water and brine, dried over MgSO4, and evaporated to give hydroxylamine 234b (226 mg, 99%) as a white solid of high purity: 1H NMR (400 MHz,
CDCl3) δ 8.02 (m, 4H), 7.58 (m, 2H), 7.42 (m, 4H), 5.64 (d, J = 3.1 Hz, 1H), 5.37 (br s,
1H), 4.54, 3.96 (ABq, J = 11.0 Hz, 2H), 3.32 (s, 3H), 3.28 (s, 3H), 3.17 (t, J = 2.9 Hz,
1H), 3.13 (d, J = 3.1 Hz, 1H), 1.86 (s, 3H), 1.63 (ddd, J = 28.4, 14.1, 2.9 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 167.0, 165.8, 135.9, 133.4, 133.3, 130.2, 129.9, 129.8, 128.7,
128.6 (2C), 116.7, 104.5, 72.6, 66.1, 63.4, 50.6, 50.1, 48.6, 48.6, 29.8, 21.3; IR (thin film) 3448, 3276, 1722, 1716, 1273 cm-1.
O O O O 0 H OH Zn , HCl H OH Br Br
O2N i-PrOH, H2O HOHN rt, 1 h HO 98% HO
5-Bromo-7-(hydroxyamino)-7-(hydroxymethyl)-3,3-dimethoxy-6- methylbicyclo[2.2.2]oct-5-en-2-ol (231a). To nitro diol 228 (350 mg, 0.994 mmol) in i-
PrOH (20 mL) was added 1 M HCl (5.0 mL, 5.0 mmol), followed by zinc powder (650 mg,
155
9.94 mmol). The suspension was stirred for 1 h at rt. Saturated aqueous NaHCO3 (15 mL) was added, and the resulting suspension was stirred for 15 min. The mixture was filtered through a Celite plug eluting with EtOAc. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organics were washed with water and brine, dried over MgSO4, and evaporated to give hydroxylamine diol 231a (315 mg, 98%) as a white solid of good purity: 1H NMR (400 MHz, DMSO-d6) δ 7.17 (s, 1H
NHOH), 5.38 (br s, 1H NHOH), 4.51 (br t, J = 5.1 Hz, 1H CH2OH), 4.21 (dd, J = 6.7, 2.1
Hz, 1H), 3.83 (d, 6.9 Hz, 1H CHOH), 3.21 (s, 3H), 3.20 (dd, J = 10.4, 5.2 Hz, 1H), 3.13
(s, 3H), 3.00 (dd, J = 10.2, 5.2 Hz, 1H), 2.88 (t, J = 3.1 Hz, 1H), 2.54 (d, J = 2.1 Hz, 1H),
1.75 (s, 3H), 1.28 (dd, J = 13.1, 2.9 Hz), 1.16 (dd, J = 13.6, 3.1 Hz, 1H); 13C NMR (100
MHz, DMSO-d6) δ 137.2, 114.1, 104.0, 69.4, 64.0, 62.1, 51.3, 49.4, 49.2, 47.9, 28.3,
21.3.
O O O O H OH HCO2H/Et3N H OH Br H O2N 10% Pd/C, rt, 12 h O2N 72% HO HO
7-(Hydroxymethyl)-3,3-dimethoxy-6-methyl-7-nitrobicyclo[2.2.2]oct-5-en-2- ol (232). To bromoalkene 228 (100 mg, 0.284 mmol) and 10% palladium on carbon (15 mg, 0.014 mmol) was added a triethylammonium formate (2:1 molar ratio triethylamine/formic acid, 3 mL). The solution was stirred for 16 h at rt, and then filtered through a Celite plug eluting with EtOAc. The organics were washed with saturated
156 aqueous NaHCO3, water, and brine, then dried over MgSO4 and evaporated to give nitro
1 diol 232 (56 mg, 72%) as a clear oil: H NMR (400 MHz, CDCl3) δ 5.82 (m, 1H), 3.71 (br d, 1H), 3.65, 3.63 (ABq, J = 12.0 Hz, 2H), 3.38 (t, J = 2.0 Hz, 1H), 3.25 (s, 3H), 3.15 (s,
3H), 2.85 (dd, J = 14.2, 2.3 Hz, 1H), 2.84 (d, J = 2.3 Hz, 1H), 1.90 (d, J = 1.6 Hz, 3H),
13 1.39 (dd, J = 14.9, 3.5 Hz, 1H); C NMR (100 MHz, CDCl3) δ 139.5, 123.3, 102.5, 95.1,
69.9, 69.1, 49.9, 49.6, 49.2, 37.4, 28.4, 22.3.
O O O O H OH HCO2NH4, 10% Pd/C H OH Br H O2N EtOH, rt, 24 h HOHN 71% HO HO
7-(Hydroxyamino)-7-(hydroxymethyl)-3,3-dimethoxy-6- methylbicyclo[2.2.2]oct-5-en-2-ol (S5). To a solution of bromoalkene 228 (100 mg,
0.284 mmol) in EtOH (2 mL) were added 10% palladium on carbon (15 mg, 0.014 mmol) and freshly recrystallized ammonium formate (180 mg, 2.85 mmol). The reaction mixture was stirred for 6 h at rt, and additional ammonium formate (180 mg, 2.85 mmol) was added. The mixture was stirred for an additional 18 h, and then filtered through a Celite plug eluting with MeOH. The organics were evaporated, and the material was taken up in
EtOAc. The organics were washed with 1:1 water/brine, dried over MgSO4, and evaporated. The residue was purified by flash column chromatography (5% MeOH in
1 CH2Cl2) to give debrominated hydroxylamine S5 (52 mg, 71%) as a white solid: H NMR
(400 MHz, CDCl3) δ 5.80 (d, J = 5.0 Hz, 1H), 4.18 (d, J = 2.9 Hz, 1H), 3.56, 3.26 (ABq, J
157
= 11.1 Hz, 2H), 3.27 (s, 3H), 3.25 (s, 3H), 2.83 (td, J = 2.5, 1.7 Hz, 1H), 2.72 (m, 1H),
1.82 (d, J = 1.5 Hz, 3H), 1.30 (dd, J = 13.9, 2.1 Hz, 1H), 1.16 (dd, J = 14.0, 3.1 Hz, 1H);
13 C NMR (100 MHz, CDCl3) δ 140.8, 123.0, 103.5, 70.5, 65.9, 64.0, 50.0, 49.9, 47.7,
37.4, 29.5, 22.8. This reaction was not reproducible.
O O O O H OH BzCl H OBz
O2N DMAP, py O2N CH2Cl2, rt, 12 h 67% HO BzO
7-(Benzoyloxy)-8,8-dimethoxy-6-methyl-2-nitrobicyclo[2.2.2]oct-5-en-2- yl)methyl Benzoate (245b). To a solution of diol 232 (3.00 g, 10.98 mmol), 4- dimethylaminopyridine (240 mg, 1.96 mmol), and pyridine (4.42 mL, 54.87 mmol) in
CH2Cl2 (50 mL) was added benzoyl chloride (3.83 mL, 32.97 mmol). The reaction mixture was stirred for 12 h at rt, and then poured into 1 M HCl. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with saturated aqueous NaHCO3, dried over MgSO4, and evaporated. The residue was purified by flash column chromatography (20% EtOAc in hexanes) to give bis-
1 benzoyl ester 245b (3.54 g, 67%) as a white solid: H NMR (300 MHz, CDCl3) δ 8.04 (m,
4H), 7.55 (m, 2H), 7.44 (m, 4H), 6.07 (dt, J = 8.0, 1.6 Hz, 1H), 5.66 (d, J = 3.1 Hz, 1H),
4.51, 4.01 (ABq, J = 10.9 Hz, 2H), 3.31 (s, 3H), 3.22 (s, 3H), 2.98 (m, 1H), 2.90(dt, J =
6.7, 3.0 Hz, 1H), 1.87 (d, J = 1.6 Hz, 3H), 1.55 (dd, J = 14.0, 2.4 Hz, 1H), 1.39 (dd, J =
13 13.9, 3.1 Hz, 1H); C NMR (75 MHz, CDCl3) δ 167.0, 165.8, 139.3, 133.3, 133.2, 130.3,
158
130.1, 129.9, 129.8, 128.6, 124.6, 104.5, 73.7, 66.1, 63.2, 50.5, 49.8, 45.8, 37.9, 29.7,
22.5.
O O O O 0 H OBz Zn , HCl H OBz
O2N i-PrOH, H2O HOHN 0 °C – rt, 3 h BzO 99% BzO
7-(Benzoyloxy)-2-(hydroxyamino)-8,8-dimethoxy-6-methylbicyclo[2.2.2]oct-
5-en-2-yl)methyl Benzoate (246b). To a solution of nitro compound 245b (1.00 g, 2.08 mmol) in i-PrOH (12 mL) at 0 °C, was added 1 M HCl (10.4 mL, 10.4 mmol), after which the solution became cloudy. To the heterogeneous mixture was added zinc powder (1.36 g, 20.80 mmol), and the solution was stirred for 30 min. The reaction mixture was warmed to rt and stirred for an additional 2.5 h. Saturated aqueous NaHCO3 (15 mL) was added, and the resulting suspension was stirred for 15 min. The mixture was filtered through a Celite plug eluting with EtOAc. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organics were washed with water and brine, dried over MgSO4, and evaporated to give hydroxylamine 246b (962 mg, 99%) as a white solid of high purity: 1H NMR (400 MHz, DMSO-d6) δ 8.04 (m, 4H), 7.54 (m,
2H), 7.43 (m, 4H), 6.05 (dt, J = 6.7, 1.5 Hz, 1H), 5.68 (d, J = 2.9 Hz, 1H), 4.49, 4.03
(ABq, J = 10.8 Hz, 2H), 3.30 (s, 3H), 3.21 (s, 3H), 2.96 (m, 1H), 2.89 (dt, J = 6.6, 3.3 Hz,
1H), 1.86 (d, J = 1.4 Hz, 3H), 1.56 (dd, J = 13.9, 2.3 Hz, 1H), 1.37 (dd, J = 13.9, 3.2 Hz,
159
13 1H); C NMR (100 MHz, CDCl3) δ 167.0, 165.8, 139.2, 133.1, 130.3, 130.1, 129.9,
129.8, 129.8, 128.7, 128.4, 104.5, 73.7, 63.1 (2C), 50.0, 49.8, 45.9, 37.9, 29.5, 25.4.
Cl O O O O O
H OBz Cl Cl O H OBz H N py, CH2Cl2 N HO 0 °C, 15 min, 99% HO BzO BzO
7-(Benzoyloxy)-2-(3-chloro-N-hydroxypropanamido)-8,8-dimethoxy-6- methylbicyclo[2.2.2]oct-5-en-2-yl)methyl Benzoate (247a). To a solution of hydroxylamine 246b (275 mg, 0.588 mmol) in CH2Cl2 (6 mL) at 0 °C were added pyridine
(95 µL, 1.18 mmol), and 3-chloropropionyl chloride (57 µL, 0.597 mmol). The resulting mixture was stirred for 15 min, and then diluted with water. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over
MgSO4 and evaporated. The resulting residue was purified by flash column chromatography (20% EtOAc/hexanes) to give hydroxamic acid 247a (325 mg, 99%) as a
1 clear oil: H NMR (300 MHz, CDCl3) δ 8.11 (br s, 1H), 8.03 (m, 4H), 7.54 (m, 2H), 7.42
(m, 4H), 6.06 (dt, J = 6.7, 1.5 Hz, 1H), 5.58 (d, J = 3.1 Hz, 1H), 4.20, 4.14 (ABq, J = 11.3
Hz, 2H), 3.77 (t, J = 6.8 Hz, 2H), 3.33 (s, 3H), 3.21 (s, 3H), 2.98 – 2.81 (m, 4H), 1.85 (d,
J = 1.5 Hz, 3H), 1.78 (dd, J = 14.0, 2.1 Hz, 1H), 1.35 (dd, J = 14.0, 3.1 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 169.5, 166.2, 165.4, 138.7, 133.2, 133.1, 130.1, 129.7, 129.7, 129.6,
128.5, 128.4, 124.5, 104.0, 73.1, 66.5, 62.6, 50.2, 49.8, 46.0, 38.6, 37.6, 36.1, 29.6, 22.2;
+ LRMS (EI) [M+H] calcd for C29H33ClNO8 558.2, found 558.2.
160
Cl Cl O O O
O H OBz In(OTf)3 O H OBz N acetone N HO rt, 15 min HO 98% BzO BzO
7-(Benzoyloxy)-2-(3-chloro-N-hydroxypropanamido)-6-methyl-8- oxobicyclo[2.2.2]oct-5-en-2-yl)methyl Benzoate (248a). To a solution of ketal 247a
(300 mg, 0.538 mmol) in acetone (5 mL) was added indium (III) trifluoromethanesulfonate (8.0 mg, 0.014 mmol). The reaction mixture was stirred at rt until the starting material was consumed as monitored by TLC (approx. 15 min). The acetone was evaporated, and the residue was dissolved in 1:1 EtOAc/CH2Cl2. The solution was purified by filtration through a silica gel plug eluting with 1:1 EtOAc/CH2Cl2.
Evaporation of the solvent gave ketone 248a (269 mg, 98%) as a white solid: 1H NMR
(300 MHz, CDCl3) δ 8.14 (s, 1H), 8.02 (m, 4H), 7.57 (m, 2H), 7.45 (m, 4H), 6.07 (dt, J =
6.7, 1.5 Hz, 1H), 5.91 (d, J = 2.5 Hz, 1H), 4.28, 4.24 (ABq, J = 11.4 Hz, 2H), 3.77 (t, J =
6.6 Hz, 2H), 3.25 (m, 1H), 3.15 (t, J = 2.2 Hz, 1H), 2.89 (ddd, J = 6.6, 6.5, 3.5 Hz, 2H),
1.95 (d, J = 1.6 Hz, 3H), 1.92 (dd, J = 13.9, 2.1 Hz, 1H), 1.78 (dd, J = 13.9, 3.2 Hz, 1H);
13 C NMR (75 MHz, CDCl3) δ 204.3, 169.5, 166.1, 165.8, 143.0, 133.7, 133.5, 129.9,
129.8, 129.4, 129.3, 128.8, 128.6, 121.5, 68.5, 64.5, 63.2, 47.1, 46.8, 38.7, 36.2, 30.2,
+ 22.5; LRMS (EI) [M+H] calcd for C27H27ClNO7 512.1, found 512.2.
161
Cl O O O O H OBz NaI, acetone H OBz N 55 °C, 18 h N HO 55% O BzO BzO
7-(Benzoyloxy)-6-methyl-8-oxo-2-(3-oxoisoxazolidin-2-yl)bicyclo[2.2.2]oct-5- en-2-yl)methyl Benzoate (251). To a solution of chloride 248a (120 mg, 0.234 mmol) in acetone (5 mL) was added sodium iodide (175 mg, 1.17 mmol). The solution was heated at 55 °C in the dark for 18 h. The acetone was evaporated, and the residue was dissolved in CH2Cl2. The organics were washed with water, dried over MgSO4, and evaporated. The residue was purified by flash column chromatography (short plug, 2:1 hexanes/EtOAc) to
1 give isoxazolidinone 251 (61 mg, 55%) as a white solid: H NMR (400 MHz, CDCl3)
δ 7.99 (m, 4H), 7.56 (m, 2H), 7.45 (m, 4H), 6.06 (d, J = 6.6 Hz, 1H), 5.77 (d, J = 2.6 Hz,
1H), 4.66, 4.31 (ABq, J = 9.6 Hz, 2H), 4.15–3.90 (m, 2H), 3.39 (d, J = 2.8 Hz, 1H), 3.25
(m, 1H), 2.98–2.76 (m, 2H), 2.01 (dd, J = 14.2, 2.6 Hz, 1H), 1.86 (d, J = 1.5 Hz, 3H),
13 1.71 (dd, J = 14.2, 3.3 Hz, 1H); C NMR (100 MHz, CDCl3) δ 203.8, 173.1, 166.2, 165.9,
143.2, 133.7, 133.6, 129.9, 129.6, 129.2, 129.0, 128.8, 128.7, 121.3, 68.2, 66.1, 63.6,
+ 48.8, 47.0, 46.6, 31.7, 22.1; LRMS (EI) [M+H] calcd for C27H26NO7 476.2, found 476.3.
Br Br O O O O O O
H OBz Cl Br O H OBz In(OTf)3 O H OBz H N N Py, CH2Cl2 N acetone HO 0 °C, 15 min HO rt, 15 min HO 97% (2 steps) BzO BzO BzO
162
7-(Benzoyloxy)-2-(3-bromo-N-hydroxypropanamido)-6-methyl-8- oxobicyclo[2.2.2]oct-5-en-2-yl)methyl Benzoate (247b). To a solution of hydroxylamine 246b (470 mg, 1.00 mmol) in CH2Cl2 (10 mL), at 0 °C were added pyridine (160 µL, 1.99 mmol) and 3-bromopropionyl chloride (101 µL, 1.00 mmol). The resulting solution was stirred for 15 min, then poured into water. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over MgSO4 and evaporated. The residue was taken up in acetone (10 mL), and indium (III) trifluoromethanesulfonate (6.0 mg, 0.011 mmol) was added. The reaction mixture was stirred at rt until the starting material was consumed as monitored by TLC
(approx. 15 min). The acetone was evaporated, and the residue was dissolved in 1:1
EtOAc/CH2Cl2. The solution was purified by filtration through a silica gel plug eluting with 1:1 EtOAc/CH2Cl2. Evaporation of the solvent gave ketone 247b (539 mg, 97%) as
1 an off-white solid: H NMR (300 MHz, CDCl3) δ 8.05 (br s, 1H), 8.02 (m, 4H), 7.56 (m,
2H), 7.44 (m, 4H), 6.07 (d, J = 6.4 Hz, 1H), 5.90 (d, J = 2.4 Hz, 1H), 4.30, 4.24 (ABq, J =
11.6 Hz, 2H), 3.59 (t, J = 6.7 Hz, 2H), 3.26 (m, 1H), 3.15 (t, J = 2.1 Hz, 1H), 3.06–2.93
(m, 2H), 1.94 (d, J = 1.5 Hz, 3H), 1.90 (dd, J = 13.9, 2.2 Hz, 1H), 1.76 (dd, J = 14.0, 3.2
13 Hz, 1H); C NMR (75 MHz, CDCl3) δ 204.2, 169.7, 166.1, 165.8, 142.9, 133.6, 133.5,
129.9, 129.8, 129.4, 129.3, 128.7, 128.5, 121.5, 68.5, 64.5, 63.2, 47.1, 46.8, 36.4, 30.2,
+ 25.3, 22.4; LRMS (EI) [M+H] calcd for C27H27BrNO7 556.1, found 556.1.
163
O O O OH LiBF OH Br 4 Br O2N wet MeCN O2N 85 °C, 2 h 99% HO HO
6-Bromo-3-hydroxy-8-(hydroxymethyl)-5-methyl-8-nitrobicyclo[2.2.2]oct-5- en-2-one (255). To a solution of ketal 228 (1.40 g, 3.98 mmol) in wet MeCN (2% H2O,
35 mL) was added lithium tetrafluoroborate (1.0 M in MeCN, 4.40 mL, 4.40 mmol). The reaction mixture was heated at 85 °C for 2 h, then cooled to rt. The MeCN was evaporated, and saturated aqueous NaHCO3 was added to the residue. The aqueous mixture was extracted with EtOAc, and the combined organics were dried over MgSO4 and evaporated to give ketone 255 (1.21 g, 99%) as a white solid: 1H NMR (300 MHz,
CDCl3) δ 3.85 (s, 1H), 3.83 (d, J = 2.5 Hz, 1H), 3.74 (br t, 1H, CH2OH), 3.40 (d, J = 2.6
Hz, 1H), 2.92 (dd, J = 15.5, 1.9 Hz, 1H), 2.79 (d, J = 2.3 Hz, 1H), 2.40 (t, J = 6.4 Hz, 1H),
2.08 (dd, J = 15.4, 3.4 Hz, 1H), 2.04 (s, 3H); 1H NMR (300 MHz, acetone-d6) δ 5.19 (d, J
= 4.4 Hz, 1H), 4.85 (t, J = 5.3 Hz, 1H, CH2OH), 3.94 (dd, J = 11.9, 5.4 Hz, 1H), 3.81 (dd,
J = 11.9, 5.2 Hz, 1H), 3.77 (d, J = 4.2 Hz, 1H), 3.32 (m, 1H), 3.12 (br s, 1H, CHOH), 2.86
(dd, J = 15.5, 1.6 Hz, 1H), 2.27 (dd, J = 15.5, 3.4 Hz, 1H), 2.03 (s, 3H); 13C NMR (75
MHz, acetone-d6) δ 204.9, 140.8, 112.5, 95.0, 69.1, 67.6, 57.4, 52.2, 29.7, 21.6; LRMS
+ (EI) [M+H] calcd for C10H13BrNO5 306.0, found 306.0.
164
O O OH OTBS Br TBS-Cl Br O2N imidazole O2N rt, 18 h 69% HO TBSO
6-Bromo-3-((tert-butyldimethylsilyl)oxy)-8-(((tert- butyldimethylsilyl)oxy)methyl)-5-methyl-8-nitrobicyclo[2.2.2]oct-5-en-2-one (S6). To a solution of diol 255 (305 mg, 0.996 mmol) in DMF (2 mL) were added t- butylchlorodimethylsilane (315 mg, 2.09 mmol) and imidazole (200 mg, 2.94 mmol). The resulting solution was stirred for 18 h at rt, and then poured into water. The mixture was extracted with EtOAc, and the combined organics were washed with water and brine, dried over MgSO4, and evaporated. The residue was purified by flash column chromatography (10% EtOAc/hexanes) to give bis-silyl ether S6 (365 mg, 69%) as a clear
1 oil: H NMR (300 MHz, CDCl3) δ 3.80, 3.74 (ABq, J = 10.6 Hz, 2H), 3.72 (d, J = 2.3 Hz,
1H), 3.63 (d, J = 2.4 Hz, 1H), 3.28 (dd, J = 3.4, 2.2 Hz, 1H), 2.66 (dd, J = 15.6, 2.1 Hz,
1H), 2.06 (dd, J = 15.6, 3.1 Hz, 1H), 1.98 (s, 3H), 0.89 (s, 9H), 0.86 (s, 9H), 0.12 (s, 3H),
13 0.11 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H); C NMR (75 MHz, CDCl3) δ 203.5, 139.7, 111.6,
93.7, 69.3, 67.9, 56.4, 51.6, 29.7, 25.8, 25.8, 18.3, 18.2, -4.6, -5.1, -5.6, -5.7; LRMS (EI)
+ [M+H] calcd for C22H41BrNO5Si2 534.2, found 534.2.
O O
OTBS H (50 bar), Pd/C OTBS Br 2 O2N EtOH, py O2N rt, 22 h TBSO 62% TBSO
165
3-((tert-Butyldimethylsilyl)oxy)-8-(((tert-butyldimethylsilyl)oxy)methyl)-5- methyl-8-nitrobicyclo[2.2.2]oct-5-en-2-one (S7). To a solution of bromoalkene S6 (250 mg, 0.468 mmol) in EtOH (9 mL) and pyridine (1 mL) was added 10% palladium on carbon (25 mg, 0.023 mmol). The reaction mixture was placed in a pressure vessel, and the vessel was pressurized with H2 to 50 bar. After stirring the mixture for 22 h, the pressure was released, and the reaction mixture was filtered through Celite eluting with
EtOAc. The combined organics were evaporated, and the resulting residue was purified by flash column chromatography (20% EtOAc/hexanes) to give alkene S7 (133 mg, 62%) as
1 a clear oil: H NMR (400 MHz, CDCl3) δ 5.81 (d, J = 6.4 Hz, 1H), 3.87, 3.73 (ABq, J =
10.7 Hz, 2H), 3.71 (d, J = 2.2 Hz, 1H), 3.45 (d, J = 2.4 Hz, 1H), 3.05 (m, 1H), 2.66 (dd, J
= 15.3, 2.2 Hz, 1H), 1.94 (d, J = 1.4 Hz, 3H), 1.84 (dd, J = 15.4, 3.4 Hz, 1H), 0.88 (s, 9H),
0.84 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H), 0.02 (s, 3H), 0.00 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 206.5, 143.6, 119.8, 94.4, 69.3, 68.3, 50.2, 46.8, 29.4, 25.8, 25.7, 22.4, 18.3,
+ 18.1, -4.7, -5.1, -5.6, -5.7; LRMS (EI) [M+H] calcd for C22H42NO5Si2 556.3, found
556.2.
O O OH OTBDPS Br TBDPS-Cl Br O2N DMF, im O2N rt, 18 h HO 71% TBDPSO
166
6-Bromo-3-((tert-butyldiphenylsilyl)oxy)-8-(((tert- butyldiphenylsilyl)oxy)methyl)-5-methyl-8-nitrobicyclo[2.2.2]oct-5-en-2-one (256).
To a solution of diol 255 (1.30 g, 4.26 mmol) in DMF (4.25 mmol) were added tert- butylchlorodiphenylsilane (2.75 mL, 10.57 mmol) and imidazole (1.45 g, 21.30 mmol).
The resulting solution was heated at 40 °C for 18 h, and then cooled to rt. Water was added, and the resulting heterogeneous mixture was extracted with Et2O. The combined organics were washed with water and brine, dried over MgSO4, and evaporated. The residue was purified by flash column chromatography (5% EtOAc/hexanes) to give bis-
1 silyl ether 256 (2.38 g, 71%) as a foamy white solid: H NMR (400 MHz, CDCl3) δ 7.69
(m, 4H), 7.46 (m, 2H), 7.40 (m, 14H), 3.84 (d, J = 2.4 Hz, 1H), 3.75, 3.60 (ABq, J = 10.9
Hz, ), 3.54 (d, J = 2.4 Hz, 1H), 3.23 (dd, J = 3.1, 2.3 Hz, 1H), 2.61 (dd, J = 15.6, 1.8 Hz,
1H), 1.94, (dd, J = 15.6, 3.4 Hz, 1H), 1.86 (s, 3H), 1.07 (s, 9H), 1.00 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 202.7, 140.3, 136.1, 136.0, 135.8, 135.7, 135.6, 133.0, 132.5, 132.2,
131.7, 131.3, 130.4, 130.3, 130.1, 128.1, 128.1, 127.8 111.5, 93.2, 69.3, 68.0, 56.4, 51.4,
+ 29.4, 27.0, 26.8, 21.5, 19.5, 19.3; HRMS (ESI) [M+NH4] calcd for C42H52BrN2O5Si2
799.2598, found 799.2567.
O O
OTBDPS Al (Hg) OTBDPS Br Br O N HOHN 2 THF/MeOH/H2O (18:2:1) TBDPSO 3 h, 68 °C TBDPSO 99%
167
6-Bromo-3-((tert-butyldiphenylsilyl)oxy)-8-(((tert- butyldiphenylsilyl)oxy)methyl)-8-(hydroxyamino)-5-methylbicyclo[2.2.2]oct-5-en-2- one (257). Aluminum foil (30 mg, 1.11 mmol) cut into small strips was washed with hexanes and Et2O to remove any machine oils. The cleaned metal was placed in 2% aqueous HgCl2 for ~10 seconds, removed, and washed with water, acetone, and Et2O. The amalgamated aluminum was added to a solution of nitro compound 256 (80 mg, 0.102 mmol) in THF/MeOH/H2O (18:2:1, 2 mL), and the resulting suspension was heated at 68
°C for 3 h. The reaction mixture was cooled, and then filtered through a plug consisting of a layer of Celite on top of a layer of silica gel, eluting with EtOAc. The filtrate was evaporated to yield hydroxylamine 257 (78 mg, 99%) as a foamy white solid: 1H NMR
(300 MHz, CDCl3) δ 7.91 (m, 2H), 7.79 (m, 2H), 7.63 (m, 4H), 7.45 (m, 12H), 5.34 (br s,
1H), 4.37 (d, J = 2.6 Hz, 1H), 3.50 (dd, J = 7.2, 1.8 Hz, 1H), 3.26–3.14 (m, 3H), 2.54 (d, J
= 2.6 Hz, 1H), 1.67 (s, 3H), 1.64 (dd, J = 13.8, 3.4 Hz, 1H), 1.22 (dd, J = 13.9, 3.3 Hz,
13 1H), 1.11 (s, 9H), 1.05 (s, 9H); C NMR (100 MHz, CDCl3) δ 205.8, 140.0, 136.4, 136.1,
135.7, 134.0, 133.1, 133.0, 132.9, 130.3, 130.0, 129.9, 128.1, 127.9, 127.8, 127.8, 127.7,
127.5, 111.4, 68.5, 65.0, 63.1, 57.2, 50.5, 29.8, 27.0 (2C), 26.8, 21.6, 19.5; LRMS (EI)
+ [M+H] calcd for C42H51BrNO4Si2 768.3, found 768.3.
O O
OTBDPS Zn0, HCl OTBDPS Br Br O2N H N H2O/i-PrOH 2 2 h, 60 °C TBDPSO TBDPSO 71%
168
8-Amino-6-bromo-3-((tert-butyldiphenylsilyl)oxy)-8-(((tert- butyldiphenylsilyl)oxy)methyl)-5-methylbicyclo[2.2.2]oct-5-en-2-one (258). To a solution of nitro compound 256 (200 mg, 0.255 mmol) in i-PrOH (5 mL) was added activated zinc92 powder (334 mg, 5.11 mmol) and 1 M HCl (2.50 mL, 2.50 mmol). The solution was heated at 60 °C for 2 h, and then cooled to rt. The reaction mixture was neutralized with saturated aqueous NaHCO3, then filtered through a pad of Celite eluting with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc.
The combined organics were washed with water and brine, dried over MgSO4, and evaporated. The residue was purified by flash column chromatography (20% EtOAc in hexanes) to give amine 258 (137 mg, 71%) as a foamy white solid: 1H NMR (300 MHz,
CDCl3) δ 7.82 (m, 2H), 7.75 (m, 2H), 7.58 (m, 4H), 7.41 (m, 12H), 4.55 (d, J = 2.6 Hz,
1H), 3.24, 3.03 (ABq, J = 10.0 Hz, 2H), 3.14 (t, J = 2.6 Hz, 1H), 2.59 (d, J = 2.5 Hz, 1H),
1.84 (s, 3H), 1.40 (dd, J = 15.1, 3.2 Hz, 1H), 1.27 (dd, J = 15.2, 2.1 Hz, 1H), 1.11 (s, 9H),
13 1.07 (s, 9H); C NMR (100 MHz, CDCl3) δ 206.1, 141.4, 136.3, 136.1, 135.8, 135.8,
134.1, 133.3, 133.0, 130.1, 130.1, 129.8, 127.9, 127.9, 127.8, 127.8, 127.7, 127.6, 110.2,
71.8, 69.0, 57.9, 56.5, 54.1, 34.1, 27.2, 27.1, 21.4, 19.5 (2C); LRMS (EI) [M+H]+ calcd for C42H51BrNO3Si2 752.3, found 752.3.
169
Cl O O O OTBDPS Cl Cl O OTBDPS Br Br H2N Et3N, THF HN rt, o/n TBDPSO 97% TBDPSO
5-Bromo-7-((tert-butyldiphenylsilyl)oxy)-2-(((tert- butyldiphenylsilyl)oxy)methyl)-6-methyl-8-oxobicyclo[2.2.2]oct-5-en-2-yl)-3- chloropropanamide (259). To a solution of amine 258 (125 mg, 0.166 mmol) in THF
(1.6 mL) were added 3-chloropropionyl chloride (19 µL, 0.20 mmol) and triethylamine
(46 µL, 0.33 mmol). The reaction mixture was stirred overnight at rt, and then diluted with EtOAc. The combined organics were washed with saturated aqueous NaHCO3, water, and brine, dried over MgSO4, and evaporated to give amide 259 (136 mg, 97%) as a white solid. NMR spectra provided a showed rotameric mixture; new amide 13C peaks
(169.2, 165.2) were seen along with 2 additional alkyl peaks. LRMS (EI) [M+H]+ calcd for C45H54BrClNO4Si2 842.2, found 842.3.
Cl I O O
O OTBDPS NaI O OTBDPS Br Br HN acetone HN 50 °C, o/n 98% TBDPSO TBDPSO
5-Bromo-7-((tert-butyldiphenylsilyl)oxy)-2-(((tert- butyldiphenylsilyl)oxy)methyl)-6-methyl-8-oxobicyclo[2.2.2]oct-5-en-2-yl)-3- iodopropanamide (260). To a solution of chloroamide 259 (55 mg, 0.065 mmol) in
170 acetone (1 mL) was added NaI (50 mg, 0.33 mmol). The reaction mixture was heated at
50 °C in the dark overnight. The acetone was evaporated, and the residue was suspended in CH2Cl2. The suspension was filtered through a silica plug eluting with CH2Cl2, and the organics were evaporated to provide iodide 260 (60 mg, 98%) as a white solid. NMR
+ spectra showed a complex rotameric mixture; LRMS (EI) [M+NH4] calcd for
C45H57BrIN2O4Si2 951.2, found 951.3.
O OH OTBDPS I OTBDPS Br Br O N O2N 2 In0, THF/MeOH rt, 2 h TBDPSO TBDPSO 68%
2-Allyl-6-bromo-3-((tert-butyldiphenylsilyl)oxy)-8-(((tert- butyldiphenylsilyl)oxy)methyl)-5-methyl-8-nitrobicyclo[2.2.2]oct-5-en-2-ol (267). To a solution of ketone 256 (1.20 g, 1.53 mmol) in THF (5.4 mL) and MeOH (0.6 mmol) were added indium powder (265 mg, 2.31 mmol) and allyl iodide (280 µL, 3.06 mmol).
The reaction mixture was stirred for 2 h at rt, and then quenched with saturated aqueous
NaHCO3. The heterogeneous mixture was extracted with EtOAc, and the combined organics were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography (5–10% EtOAc in hexanes) to provide the desired diastereomer of homoallyl alcohol 267 (861 mg, 68%) as a foamy white solid: 1H NMR (400 MHz,
CDCl3) δ 7.72 (m, 4H), 7.53 (m, 2H), 7.50–7.41 (m, 14H), 5.85 (m, 1H), 5.18 (dd, J =
10.1, 2.1 Hz, 1H), 4.98 (dd, J = 17.1, 2.0 Hz, 1H), 4.26 (d, J = 2.6 Hz, 1H), 3.78–3.55 (m,
171
3H), 2.82 (dd, J = 14.9, 2.3 Hz, 1H), 2.70 (t, J = 2.7 Hz, 1H), 2.36 (dd, J = 14.9, 6.7 Hz,
1H), 2.10 (dd, J = 15.0, 7.9 Hz, 1H), 1.86 (s, 3H), 1.40 (dd, J = 14.9, 3.2 Hz, 1H), 1.18 (s,
13 9H), 1.07 (s, 9H); C NMR (100 MHz, CDCl3) δ 136.2, 136.1, 135.7, 135.7, 135.4,
133.6, 132.1, 130.3, 130.2, 130.1, 130.1, 128.1, 128.0, 127.9, 127.9, 120.8, 117.6, 93.8,
78.7, 69.8, 51.0, 50.4, 40.1, 27.8, 27.4, 27.0, 26.8, 26.8, 21.2, 19.7, 19.3; LRMS (EI)
+ [M+NH4] calcd for C45H58BrN2O5Si2 841.3, found 841.4.
OH OH OTBDPS 0 OTBDPS Br Zn , HCl Br O2N H2N H2O/i-PrOH 1 h, 45 °C TBDPSO 87% TBDPSO
2-Allyl-8-amino-6-bromo-3-((tert-butyldiphenylsilyl)oxy)-8-(((tert- butyldiphenylsilyl)oxy)methyl)-5-methylbicyclo[2.2.2]oct-5-en-2-ol (268). To a solution of nitro compound 267 (400 mg, 0.485 mmol) in i-PrOH (10 mL) at 45 °C was added activated zinc powder92 (630 mg, 9.64 mmol). To the resulting suspension was added dropwise 1 M HCl (4.85 mL, 4.85 mmol). The suspension was stirred at 45 °C for 1 h, cooled to rt, and neutralized with saturated aqueous NaHCO3. The mixture was filtered through Celite eluting with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organics were washed with water and brine, dried over MgSO4, and evaporated. The residue was purified by flash column chromatography
(20% EtOAc in hexanes) to give amine 268 (344 mg, 87%) as a foamy white solid: 1H
NMR (400 MHz, CDCl3) δ 7.70 (m, 4H), 7.56 (m, 4H), 7.42–7.35 (m, 12H), 5.94 (m,
172
1H), 5.16 (dd, J = 10.6, 2.4 Hz, 1H), 5.12 (dd, J = 16.9, 2.3 Hz, 1H), 4.65 (d, J = 3.3 Hz,
1H), 3.06, 3.02 (ABq, J = 10.0 Hz, 2H), 2.82 (t, J = 2.6 Hz, 1H), 2.47 (d, J = 3.2 Hz, 1H),
2.43 (dd, J = 15.0, 6.8 Hz, 1H), 2.31 (dd, J = 15.0, 8.0 Hz, 1H), 1.66 (s, 3H), 1.40 (dd, J =
14.1, 2.2 Hz, 1H), 1.10 (s, 9H), 1.05 (s, 9H), 0.99 (d, J = 13.4, 2.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 136.4, 136.1, 136.0, 135.8, 135.8, 134.8, 134.5, 133.9, 133.3, 133.1,
130.0, 129.9, 127.9, 127.9, 127.8, 119.1, 117.4, 79.2, 78.9, 72.1, 56.5, 53.7, 51.1, 40.3,
+ 33.9, 27.4, 27.2, 21.4, 19.8, 19.5; LRMS (EI) [M+H] calcd for C45H57BrNO3Si2 794.3, found 794.4.
O OH OTBDPS OTBDPS Br MgBr Br O N O2N 2 CeCl3, THF -78 °C, 5 h TBDPSO 96% TBDPSO
6-Bromo-3-((tert-butyldiphenylsilyl)oxy)-8-(((tert- butyldiphenylsilyl)oxy)methyl)-5-methyl-8-nitro-2-vinylbicyclo[2.2.2]oct-5-en-2-ol
(271). CeCl3•7 H2O (1.30 g, 3.50 mmol) was heated at 140 °C under high vacuum for approximately 3 h. The anhydrous CeCl3 was cooled to rt under an argon atmosphere, and then suspended in THF (10 mL). The resulting suspension was stirred vigorously overnight, then cooled to -78 °C. Vinylmagnesium bromide (1 M in THF, 3.00 mL, 3.00 mmol) was added dropwise, and the resulting mixture was stirred for 30 min. A solution of ketone 256 (1.57 g, 2.00 mmol) in THF (7 mL) was added dropwise, and the reaction mixture was stirred 5 h at -78 °C. N,N,N’,N’-Tetramethylethylenediamine (0.52 mL, 3.50
173 mmol) was added, and the reaction mixture was warmed to rt. The mixture was poured into saturated aqueous NaHCO3, and the aqueous layer was extracted with EtOAc. The combined organics were dried over MgSO4 and evaporated, and the resulting residue was purified by flash column chromatography (10% EtOAc in hexanes) through a short column to afford allylic alcohol 271 (1.56 g, 96%) as a foamy white solid: 1H NMR (400
MHz, CDCl3) δ 7.71 (m, 2H), 7.55–7.35 (m, 18H), 5.68 (dd, J = 17.0, 10.7 Hz, 1H),
5.31(dd, J = 17.0, 1.3 Hz, 1H), 5.08 (dd, J = 10.7, 1.3 Hz, 1H), 3.96 (d, J = 2.4 Hz, 1H),
3.79 (s, 1H, R3COH), 3.58, 3.43 (ABq, J = 10.7 Hz, 2H), 3.20 (d, J = 2.4 Hz, 1H), 2.78 (t,
J = 2.8 Hz, 1H), 2.58 (dd, J = 15.7, 2.1 Hz, 1H), 1.78 (s, 3H), 1.55 (dd, J = 15.8, 3.5 Hz,
13 1H), 1.11 (s, 9H), 0.98 (s, 9H); C NMR (100 MHz, CDCl3) δ 136.2, 136.1, 135.7, 135.6,
132.8, 132.4, 132.2, 132.0, 131.5, 130.6, 130.4, 130.2, 130.2, 128.2, 128.0, 128.0, 127.9,
120.1, 115.6, 94.3, 75.6, 72.9, 69.8, 54.1, 50.5, 28.5, 27.2, 26.8, 21.3, 19.4, 19.3; HRMS
+ (ESI) [M+NH4] calcd for C44H56BrN2O5Si2 827.2911, found 827.2890.
OH OH OTBDPS 0 OTBDPS Br Zn , HCl Br O2N H2N H2O/i-PrOH 45 °C, 1 h TBDPSO 96% TBDPSO
8-Amino-6-bromo-3-((tert-butyldiphenylsilyl)oxy)-8-(((tert- butyldiphenylsilyl)oxy)methyl)-5-methyl-2-vinylbicyclo[2.2.2]oct-5-en-2-ol (272). To nitro compound 271 (1.25 g, 1.54 mmol) partially dissolved in i-PrOH (30 mL) at 45 °C was added activated zinc powder92 (1.00 g, 15.30 mmol). To the suspension was added
174 dropwise 1 M HCl (7.60 mL, 7.60 mmol). The reaction mixture was stirred for 1 h at 45
°C, and then cooled to rt. The reaction mixture was neutralized with saturated aqueous
NaHCO3, and filtered through a pad of Celite eluting with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organics were washed with water and brine, dried over MgSO4, and evaporated. The residue was purified by flash column chromatography (10–20% EtOAc in hexanes) to give amine 272
1 (1.16 g, 96%) as a foamy white solid: H NMR (300 MHz, CDCl3) δ 7.70 (m, 2H), 7.61
(m, 2H), 7.51 (m, 4H), 7.44–7.33 (m, 12H), 6.08 (dd, J = 17.1, 10.8 Hz, 1H), 5.50 (dd, J
= 17.1, 1.9 Hz, 1H), 5.07 (dd, J = 10.8, 1.9 Hz, 1H), 4.60 (d, J = 2.6 Hz, 1H), 3.90 (s, 1H,
R3COH), 3.04, 2.87 (ABq, 10.0 Hz, 1H), 2.65 (t, J = 2.8 Hz, 1H), 2.25 (d, J = 2.6 Hz, 1H),
1.76 (s, 3H), 1.25 (dd, J = 15.6, 2.2 Hz, 1H), 1.19 (dd, J = 15.8, 3.4 Hz, 1H), 1.10 (s, 9H),
13 1.01 (s, 9H); C NMR (75 MHz, CDCl3) δ 141.5, 136.4, 136.1, 135.8, 135.7, 133.3,
130.4, 130.1, 130.0, 128.0, 127.8, 127.7, 118.1, 114.2, 76.4, 74.1, 72.5, 56.8, 55.4, 53.4,
+ 33.3, 27.2, 27.1, 21.3, 19.5, 19.4; HRMS (ESI) [M+H] calcd for C44H55BrNO3Si2
780.2904, found 780.2855.
OH O OH OTBDPS Br O OTBDPS Cl Br H N 2 HN py, CH2Cl2 rt, 3 h TBDPSO 68% TBDPSO
5-Bromo-7-((tert-butyldiphenylsilyl)oxy)-2-(((tert- butyldiphenylsilyl)oxy)methyl)-8-hydroxy-6-methyl-8-vinylbicyclo[2.2.2]oct-5-en-2-
175 yl)acrylamide (273). To amine 272 (190 mg, 0.243 mmol) in CH2Cl2 (2.5 mL) were added freshly distilled acryloyl chloride (22 µL, 0.27 mmol) and pyridine (39 µL, 0.48 mmol). The reaction mixture was stirred for 3 h, and quenched with saturated aqueous
NaHCO3. The layers were separated, and the aqueous layer was extracted with CH2Cl2.
The combined organics were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography (10–20% EtOAc in hexanes) to give acrylamide 273
1 (138 mg, 68%) as a foamy off-white solid: H NMR (300 MHz, CDCl3) δ 7.75 (m, 2H),
7.67 (m, 2H), 7.52–7.27 (m, 16H), 6.09 (dd, J = 15.9, 2.6 Hz, 1H), 5.83 (dd, J = 17.0,
10.7 Hz, 1H), 5.65–5.52 (m, 2H), 5.40 (dd, J = 17.1, 1.5 Hz, 1H), 5.09 (dd, J = 10.7, 1.5
Hz, 1H), 4.38 (s, 1H, exchanges), 3.78 (s, 1H, exchanges), 3.78, 2.94 (ABq, J = 10.1 Hz,
1H), 2.69 (dd, J = 3.6, 2.0 Hz, 1H), 2.66 (d, J = 2.2 Hz, 1H), 2.12 (dd, J = 15.3, 1.9 Hz,
1H), 1.85 (s, 3H), 1.18 (15.4, 3.8 Hz, 1H), 1.11 (s, 9H), 1.00 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 165.2, 140.7, 136.3, 136.1, 135.7, 133.2, 133.0, 132.5, 132.1, 130.9, 130.7,
130.5, 130.0, 129.9, 128.3, 128.0, 127.8, 127.7, 126.8, 119.3, 115.1, 77.4, 76.1, 73.4,
65.6, 60.2, 54.6, 52.5, 29.4, 27.2, 27.2, 21.2, 19.5, 19.4; IR (thin film) 3515, 3399, 1682
-1 + cm ; LRMS (EI) [M+H] calcd for C47H57BrNO4Si2 834.3, found 834.4.
OH OH OTBDPS OTBDPS Br [Rh(cod)Cl]2, Xantphos Br H2N HN CO (10 bar), H2 (40 bar) PhMe, HFIPA TBDPSO 125 °C, 18 h TBDPSO 75%
176
12-Bromo-9-((tert-butyldiphenylsilyl)oxy)-3-(((tert- butyldiphenylsilyl)oxy)methyl)-11-methyl-4-azatricyclo[6.4.0.03,10]dodec-11-en-8-ol
(322). To a solution of amino alkene 272 (500 mg, 0.640 mmol) in PhMe (6.4 mL) and
1,1,1,3,3,3-hexafluoroisopropanol (6.4 mL) in a pressure reactor were added di-µ- chlorido-bis[η2,η2-(cycloocta-1,5-diene)rhodium] (3.2 mg, 0.0065 mmol) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (9.3 mg, 0.016 mmol). The reactor was sealed and pressurized with carbon monoxide (10 bar) and hydrogen (40 bar). The pressure reactor was heated at 125–135 °C for 18 h, and then cooled to rt. The gasses were vented, and the solvent was evaporated. The residue was purified by flash column chromatography (10–20% EtOAc in hexanes) to give cyclic amine 322 (384 mg, 75%) as
1 a foamy white solid: H NMR (300 MHz, CDCl3) δ 7.78 (m, 2H), 7.67 (m, 2H), 7.59 (m,
4H), 7.47–7.35 (m, 12H), 4.74 (d, J = 3.8 Hz, 1H), 3.69 (s, 1H), 3.05, 3.02 (ABq, J = 9.7
Hz, 1H), 2.80 (m, 2H), 2.59 (m, 2H), 2.10 (dd, J = 14.3, 3.4 Hz, 1H), 1.74 (s, 3H), 1.65
(m, 2H), 1.27 (m, 2H), 1.14 (s, 9H), 1.06 (s, 9H), 0.72 (dd, J = 13.9, 2.8 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 136.3, 136.2, 136.1, 135.8, 135.8, 134.9, 133.5, 133.4, 133.4,
133.2, 130.2, 130.0, 129.9, 129.8, 129.7, 127.9, 127.8, 127.8, 127.7, 118.0, 75.4, 70.7,
57.8, 56.7, 55.2, 42.8, 37.4, 28.2, 27.3, 27.1, 26.2, 21.5, 19.5, 19.4; IR (thin film) 3515,
-1 + 1472, 1428 cm ; HRMS (ESI) [M+H] calcd for C45H57BrNO3Si2 794.3060, found
794.3051.
177
OH OH OH OTBDPS OTBDPS OTBDPS [Rh(cod)Cl] , Xantphos H3CO Br 2 Br Br + H2N HN HN CO (7 bar), H2 (33 Bar) PhMe, MeOH TBDPSO TBDPSO TBDPSO 135 °C, 18 h 28% 41%
12-Bromo-9-((tert-butyldiphenylsilyl)oxy)-3-(((tert- butyldiphenylsilyl)oxy)methyl)-5-methoxy-11-methyl-4-azatricyclo[6.4.0.03,10]dodec-
11-en-8-ol (323). The reaction was run according to the above procedure for 322 using a
1:1 mixture of PhMe and MeOH using 100 mg (0.128 mmol) of amino alkene 272.
Purification by preparative TLC (15% EtOAc in hexanes) gave amine 322 (28 mg, 28%) as above, and N,O-acetal 323 (46 mg, 41%) as a foamy white solid: 1H NMR for 323 (300
MHz, CDCl3) δ 7.75 (m, 2H), 7.70–7.50 (m, 6H), 7.44–7.33 (m, 12H), 4.53 (m, 2H),
3.29 (s, 3H), 3.27, 3.04 (ABq, J = 9.9 Hz, 2H), 2.95 (d, J = 2.9 Hz, 1H), 2.57 (t, J = 2.8
Hz, 1H), 1.90 (s, 3H), 1.84 (dd, J = 14.3, 3.4 Hz, 1H), 1.45-1.18 (m, 4H), 1.12 (s, 9H),
13 1.07 (s, 9H), 0.70 (m, 1H); C NMR for 323 (75 MHz, CDCl3) δ 136.4, 136.0, 135.8,
135.8, 135.0, 134.8, 133.5, 133.4, 130.0, 130.0, 129.7, 129.4, 127.9, 127.9, 127.8, 127.7,
127.3, 117.1, 105.5, 87.7, 77.0, 72.5, 56.2, 55.6, 54.8 (2C), 35.1, 34.8, 31.7, 27.3, 27.2,
+ 21.6, 19.9, 19.6; LRMS (EI) [M+H] calcd for C46H59BrNO4Si2 824.3, found 824.3.
OH OH OTBDPS OTBDPS Br KOH Br HN HN EtOH/H2O rt, 20 h TBDPSO 88% HO
178
12-Bromo-9-((tert-butyldiphenylsilyl)oxy)-3-(hydroxymethyl)-11-methyl-4- azatricyclo[6.4.0.03,10]dodec-11-en-8-ol (328). To a solution of bis-TBDPS ether 322
(60 mg, 0.075 mmol) in EtOH (1.3 mL) was added 2 M aqueous KOH (0.20 mL, 0.40 mmol). The reaction mixture was stirred for 20 h at rt, and the EtOH was evaporated in vaccuo. Saturated aqueous NaHCO3 was added, and the aqueous mixture was extracted with EtOAc. The combined organics were dried over MgSO4 and evaporated. The resulting residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to
1 give amino alcohol 328 (39 mg, 88%) as an off-white solid: H NMR (300 MHz, CDCl3) δ
7.71 (m, 2H), 7.63 (m, 6H), 7.46–7.35 (m, 12H), 4.56 (d, J = 3.9 Hz, 1H), 4.19 (s, 1H)
3.22, 3.19 (ABq, J = 9.8 Hz, 2H), 2.82 (d, J = 3.8 Hz, 1H), 2.58 (m, 3H), 2.25–2.17 (m,
13 2H), 1.87 (m, 3H), 1.71 (s, 3H), 1.10 (s, 9H), 0.90 (m, 1H); C NMR (75 MHz, CDCl3) δ
135.8, 135.6, 134.9, 133.2, 132.8, 130.1, 130.0, 128.0, 127.9, 118.4, 75.7, 72.4, 70.1,
67.8, 55.9, 55.6, 43.3, 38.3, 31.7, 27.1, 26.3, 21.7, 19.5; LRMS (EI) [M+H]+ calcd for
C29H39BrNO3Si 556.2, found 556.2.
OH O OH OTBDPS OTBDPS Br Cl Br HN N py, CH2Cl2 rt, 2 h O TBDPSO 70% TBDPSO
12-Bromo-9-((tert-butyldiphenylsilyl)oxy)-3-(((tert- butyldiphenylsilyl)oxy)methyl)-8-hydroxy-11-methyl-4-azatricyclo[6.4.0.03,10]dodec-
11-en-4-yl)prop-2-en-1-one (332). To a solution of azocane 322 (120 mg, 0.151 mmol)
179 in CH2Cl2 (1.5 mL) were added acryloyl chloride (13.4 µL, 0.166 mmol) and pyridine (25
µL, 0.31 mmol). The reaction mixture was stirred for 2 h at rt, and then poured into water.
The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over MgSO4 and evaporated. The residue was purified by preparative TLC (25% EtOAc in hexanes) to give acrylamide 332 (90 mg, 70%) as a
1 foamy white solid: H NMR (400 MHz, CDCl3) δ 7.76 (m, 2H), 7.67 (m, 2H), 7.52 (m,
4H), 7.45–7.33 (m, 12H), 6.30 (dd, J = 16.8, 10.7 Hz, 1H), 5.83 (dd, J = 16.8, 1.9 Hz,
1H), 5.46 (dd, J = 10.7, 1.8 Hz, 1H), 4.95, 3.10 (ABq, J = 9.7 Hz, 2H), 4.19 (d, J = 3.3 Hz,
1H), 4.00 (d, J = 3.6 Hz, 1H), 3.66 (m, 1H), 3.33 (s, 1H), 3.27 (m, 1H), 2.59 (m, 2H),
2.49 (dd, J = 16.3, 3.8 Hz, 1H), 1.82 (s, 3H), 1.65–1.30 (m, 5H), 1.10 (s, 9H), 1.01 (s,
+ 9H); LRMS (EI) [M+H] calcd for C48H59BrNO4Si2 848.3, found 848.3.
180
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Appendix
List of Abbreviations
Ac acetate (CH3CO–R)
AIBN azobisisobutyronitrile
Bn benzyl (PhCH2–R)
Boc t-butoxycarbonyl (t-BuOCO–R)
Bu butyl
Bz benzoyl (PhCO–R) cod 1,5-cyclooctadiene
COSY 1H–1H correlation spectroscopy dba dibenzylideneacetone
DCC N,N’-dicyclohexylcarbodiimide
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone de diastereomeric excess
DIAD diisopropyl azodicarboxylate
DIPEA diisopropyl ethylamine, Hünig’s base
DMAP 4-dimethylaminopyridine
DMF dimethylformamide
DMSO dimethylsulfoxide
192
DPEPhos (oxydi-2,1-phenylene)bis(diphenylphosphine) dppb 1,4-bis(diphenylphosphino)butane dppe 1,2-bis(diphenylphosphino)ethane
EDC N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide (hydrochloride)
EDG electron donating group ee enantiomeric excess
Et ethyl
EWG electron withdrawing group
Glc glucose
HFIPA 1,1,1,3,3,3-hexafluoro-2-propanol
HMBC heteronuclear multi-bond correlation
HMDS hexamethyldisilazane (TMS2NH)
HMQC heteronuclear multiple quantum correlation
HMPA hexamethylphosphoramide hν UV or visible light irradiation
HOMO highest occupied molecular orbital
Im imidazole
IPA 2-propanol, isopropanol
IR infrared spectroscopy
LAH lithium aluminum hydride
LDA lithium diisopropylamide
LHMDS lithium bis(trimethylsilyl)amide
193
LUMO lowest unoccupied molecular orbital m- meta mCPBA 3-chloroperbenzoic acid
Me methyl
MeCN acetonitrile
MS mass spectrometry OR molecular sieves
MTBE methyl t-butyl ether
NMR nuclear magnetic resonance
Nbd bicyclo[2.2.1]hepta-2,5-diene; norbornadiene
N(X)S N-(halo)succinimide nOe nuclear Overhauser effect
NOESY nuclear Overhauser effect spectroscopy o- ortho o-Tol 2-methylphenyl; o-tolyl
ORTEP Oak Ridge thermal ellipsoid plot p- para
PCC pyridinium chlorochromate
PDC pyridinium dichromate
Ph phenyl
PPTS pyridinium p-toluenesulfonic acid
Pr propyl py pyridine
194
Ra-Ni Raney nickel rt room temperature
TBAF tetrabutylammonium fluoride
TBDPS t-butyldiphenylsilyl
TBS t-butyldimethylsilyl
THF tetrahydrofuran
Tf trifluoromethane sulfonate; triflate
TFA trifluoroacetate (CF3CO2–R)
TFE 2,2,2-trifluoroethanol
THP tetrahydropyran
TIPS triisopropylsilyl
TMG 1,1,3,3-tetramethylguanidine
TMS trimethylsilyl
Ts p-toluenesulfonyl; tosyl
Tsoc triisopropylsiloxycarbonyl
Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
Vita
Joshua Sacher
Joshua Sacher was born in Wilmington, Delaware in 1984. After graduating from
Brandywine High School in 2002, he obtained his B.S. degree in biochemistry from the
University of Delaware in 2005. While at Delaware, he did undergraduate research with
Douglass Taber, synthesizing model systems related to a total synthesis of aldosterone and arachidonic acid. During the summers of 2002–2005, Joshua worked as an internship at Cephalon, Inc, where he researched novel treatments for neurological and oncological diseases. He then joined the Weinreb group at Penn State University, where he has worked on multiple methodology projects and on total synthesis of complex alkaloids. Joshua received his Masters degree in 2010, and will begin a postdoctoral research appointment with Peter Wipf at the University of Pittsburgh upon completion of his graduate studies.