Total Synthesis of Gomisin O; Asymmetric Total Syntheses of Eupomatilones 1, 2 & 5; and Studies Toward Total Synthesis of Mayolide A
TOTAL SYNTHESIS OF GOMISIN O; ASYMMETRIC TOTAL SYNTHESES OF EUPOMATILONES 1, 2 & 5; AND STUDIES TOWARD TOTAL SYNTHESIS OF MAYOLIDE A
DISSERTATION
Presented in Partial Fulfillment of the Requirements for
the Degree Doctor of Philosophy in the Graduate
School of The Ohio State University
By
SOUMYA MITRA, M.S.
*****
The Ohio State University 2007
Dissertation Committee: Approved by Professor Robert S. Coleman, Advisor
Professor Craig J. Forsyth ______Professor Gideon Fraenkel Advisor Graduate Program in Chemistry
ABSTRACT
Gomisins are oriental medicinal plant lignans characterized by a highly electron- rich dibenzocyclooctadiene core structure with a stereogenic axis about the biaryl bond, exhibiting atropisomerism. The cyclooctane ring is additionally substituted with several stereogenic methyl and hydroxyl groups, thereby diversifying this class of lignans. Most members of this family possess anti-HIV, anti-hepatitis, analgesic, antitussive and central nervous system depressant activities. A convergent, highly efficient total synthesis of gomisins O and E would be discussed in this thesis with complete control of absolute and relative stereochemistry. The key steps involved in the total synthesis are a novel indium- mediated methylcrotylation, a diastereoselective B-alkyl Suzuki−Miyaura alkylborane coupling and an intramolecular oxidative biaryl cuprate cross-coupling with total atropdiastereocontrol.
Eupomatilones are structurally novel fluxional plant lignans with varying degree of oxygenation on the biphenyl system. The α-methylene-γ-lactone moiety attached to the biphenyl, as found in eupomatilones 1, 2 and 5, readily forms covalent bonds to cellular proteins and is a cause of chronic actinic dermatitis (CAD). This moiety also forms photo adducts with DNA base thymine in sunlight and has been also shown to target the Iκβ kinase addition to the transcription factor regulator nuclear factor (NF-κΒ), signifying their
ii potential role in cellular signaling processes. In this thesis, we would discuss a successful
asymmetric strategy for the synthesis of a few members of this unique family of lignans.
The key to the synthesis depends on a nicely optimized Suzuki−Miyaura biaryl cross-
coupling reaction with heavily electron-rich coupling partners. In addition to this, the
synthesis is novel in demonstrating the first example of an asymmetric
carbomethoxycrotylboration approach to the synthesis of the α-methylene-γ-lactone moiety, involving application of Miyaura’s boryl-copper chemistry. This thesis also describes a novel route to the synthesis of the carbomethoxycrotylboronate reagent in enantiomerically pure form. This reagent could be of much use for further application in other natural product synthesis.
Mayolides are cembrane diterpenes found in the lipids of marine soft corals exhibiting potent anti-cancer properties. Mayolide A is an α-methylene-γ-lactone derivative and also the first secocembrane diterpenoid to be isolated. In this thesis, we would discuss the synthetic strategy developed and the progress made towards the total synthesis of this structurally novel molecule, utilizing the carbomethoxycrotylation strategy developed during the total synthesis of eupomatilones as one of the key steps.
iii
DEDICATION
To my parents, Dr. Lakshmi Kanta Mitra
& Mrs. Tapati Mitra
And
My Grandmother, Mrs. Gita Ghosh
iv
ACKNOWLEDGMENTS
My sincerest gratitude goes to my adviser and mentor, Dr. Robert S. Coleman, for
all his intellectual support, for allowing me the freedom of independent scientific thinking,
to achieve my goals and objectives that made this thesis possible. I would also thank him
for all his encouragement and enthusiasm, which motivated me to organize scientific
meetings at Ohio State and in ACS national conferences, for his persistent backing and
mental support in times of need, and lastly for his patience in correcting my stylistic and
scientific errors. It is he who has made me the chemist I am today.
I wish to sincerely thank Dr. Srinivas R. Gurrala, who has helped me master the
finer skills in experimental organic chemistry.
I am also thankful to Dr. Xiaoling Lu and Amy Hayes for being exceptionally
considerate, very understanding and co-operative office mates. I further extend my
gratitude to the past and present members of Coleman group, who have heartily extended
their help, friendship, experience and advice in my research.
I am greatly indebted to my mom, dad, younger brother, and my grandmother for all their love, prayers and inspiration from Calcutta, India.
Lastly, I would also like to thank the Department of Chemistry NMR facility, the computer support and all other dedicated support staff members, who have helped me in
the graduate school at The Ohio State University.
v
VITA
November 23, 1976...... ……...Born – Calcutta, India
1999...... …………………. B.Sc. (Honors) Chemistry, Presidency College, University of Calcutta, India
1999 − 2001……………………………………… M.S. Organic Chemistry, Indian Institute of Technology Bombay, (Mumbai), India
2001 – 2002...... ………... Graduate Student Instructor, Department of Chemistry, University of Michigan, Ann Arbor, MI
2002 – 2007...... ………. Graduate Teaching and Research Associate, The Ohio State University, Columbus, OH, USA
PUBLICATIONS
Research Publications
1. Kyung-Hoon Lee, Manolis Matzapetakis, Soumya Mitra, E. Neil G. Marsh, Vincent L. Pecoraro; “Control of Metal Coordination Number in de Novo Designed Peptides through Subtle Sequence Modifications” J. Am. Chem. Soc. 2004, 126, 9178- 9179.
2. Robert S. Coleman and Soumya Mitra; “2(methyldithio)-1H-isoindole-1,3(2H)- dione”, Electronic Encyclopedia of Reagents for Organic Synthesis, Ed. Leo A. Paquette, Wiley, NY, August 2004.
vi 3. Robert S. Coleman, Srinivas R. Guralla, Soumya Mitra, Amresh M. Raao; “Asymmetric Total Synthesis of Dibenzocyclooctadiene Lignan Natural Products,” J. Org. Chem. 2005, 70, 8932-8941.
4. Francois-Xavier Felpin, Tahar Ayad and Soumya Mitra; “Pd/C: An Old Catalyst for New Applications – Its Use for the Suzuki–Miyaura Reaction”, Eur. J. Org. Chem. 2006, 2679-2690.
5. Soumya Mitra, Srinivas R. Guralla and Robert S. Coleman; “20.7 Product Class 7: Peroxy Acids and Derivatives”, Science of Synthesis: Houben-Weyl Methods of Molecular Transformations, Ed. James S. Panek, Thieme, Stuttgart, 2007, Vol. 20b, 1553-1594.
6. Soumya Mitra, Srinivas R. Gurrala and Robert S. Coleman; “Total Synthesis of Eupomatilones,” J. Org. Chem. 2007, 72, asap article.
FIELDS OF STUDY
Major Field: Chemistry
vii
TABLE OF CONTENTS
Page
Abstract...... ii Dedication...... iv Acknowledgements...... v Vita...... vi List of Schemes...... xii List of Tables ...... xv List of Figures...... xvi List of Abbreviations ...... xvii
Chapters: Page
1. Dibenzocyclooctadiene lignans: Isolation, biological activity and structural elucidation...... 1
2.1. Introduction...... 1 2.2. Isolation and structure determination of gomisin O and structurally related dibenzocyclooctadiene natural products ...... 4 1.3. Biological activity of gomisins and dibenzocyclooctadiene lignans ...... 7
2. Review of previous synthetic strategies towards the construction of the dibenzocyclooctadiene core...... 10
2.1. Kende’s approach ...... 11 2.2. Raphael’s approach...... 12
viii 2.3. Zeigler’s approach ...... 14 2.4. Magnus’ approach ...... 15 2.5. Meyers’ approach ...... 16 2.6. Motherwell’s approach ...... 18 2.7. Molander’s approach ...... 19
3. Brief review of atropisomerism, oxidative biaryl cross coupling, problems in methylcrotylation, and the B-alkyl Suzuki−Miyaura cross-coupling reaction ...... 21
2.1. Atropisomerism in biaryls ...... 21 2.2. Atropselective intramolecular couplings ...... 22 2.3. Oxidative biaryl cross-coupling with Va, Mo, Ni and Cu...... 24 2.4. Lipshutz intramolecular oxidative biaryl coupling...... 27 2.5. Development of methylcrotylation strategy for gomisin...... 33 3.5.1. Diastereoselective methylcrotylation of aryl aldehydes ...... 34 2.6. The B-alkyl Suzuki−Miyaura cross-coupling reaction...... 38
4. Studies towards the total synthesis of gomisin O ...... 42
2.1. Introduction...... 42 2.2. Synthesis of aryl bromide Suzuki−Miyaura coupling partners ...... 43 2.3. Diastereoselective methylcrotylation of aryl aldehydes...... 46 2.4. Basis & proof of diastereoselectivity of B-alkyl Suzuki−Miyaura coupling...... 49 2.5. Suzuki−Miyaura followed by regioselective bromination ...... 54 2.6. Oxidative cuprate biaryl cross-coupling...... 56 2.7. Attempts towards synthesis of gomisin N from gomisin O...... 62 2.8. Conclusion ...... 64
5. Eupomatilones: Structurally novel fluxional plant lignans...... 65
ix 2.1. Introduction...... 65 2.2. Biological properties...... 67 2.3. Previous synthetic approaches to total synthesis of eupomatilones ...... 68 5.3.1. Gurjar’s approach...... 68 5.3.2. McIntosh’s approach...... 70 5.3.3. Buchwald’s approach...... 71 5.3.4. Coleman’s 1st generation approach...... 72 5.3.5. Kabalka’s approach...... 74 5.3.6. Hall’s approach ...... 75
6. Development of asymmetric total synthesis of eupomatilones 1, 2 and 5...... 77
2.1. Introduction...... 77 2.2. Initial attempt to synthesize carbomethoxycrotyl reagent via Si route...... 79 2.3. Further attempts with organoboron chemistry...... 82 2.4. Attempt with nucleophilic boryl-copper species ...... 84 6.4.1. Generation of Miyaura-Hosomi’s nucleophilic boryl-copper...... 84 6.4.2. Ramachandran’s application of boryl-copper chemistry ...... 86 2.5. Progress toward asymmetric total synthesis of eupomatilones 2 and 5...... 88 2.6. Optimization of Suzuki−Miyaura biaryl cross-coupling reaction ...... 98 2.7. Conclusion ...... 104
7. Progress towards total synthesis of mayolide A ...... 106
2.1. Introduction...... 106 2.2. Previous synthetic efforts for mayolide A...... 107 2.3. Retrosynthetic analysis for projected synthesis of mayolide A...... 109 2.4. Synthetic approach towards fragments of mayolide A...... 111 2.5. Conclusion ...... 115
x 8. Experimental procedure...... 116
List of references...... 186
Appendix: Selected Spectra ...... 201
xi
LIST OF SCHEMES
Scheme Page
2.1. Kende’s synthesis of (±)-steganacin...... 12 2.2. Raphael’s synthesis of (±)-steganacin ...... 13 2.3. Zeigler’s synthesis of dibenzocyclooctanone nucleus...... 14 2.4. Magnus’ total synthesis of (±)-steganone...... 16 2.5. Meyer’s asymmetric synthesis of dibenzocyclooctanone core...... 17 2.6. Motherwell’s synthesis of dibenzocyclooctanone core ...... 19 2.7. Molander’s asymmetric synthesis of (+)-isoschizandrin...... 20
3.1. Oxidative coupling of 2-naphthols catalyzed by VO(acac)2...... 24
3.2. MoCl5 –mediated oxidative coupling in presence of additives ...... 25 3.3. CuCl –mediated intramolecular coupling of bis-trimethylstannanes ...... 26
3.4. NiCl2 –mediated biaryl coupling ...... 27 3.5. The selectivity issue for unsymmetrical biaryl product at −125 °C ...... 29 3.6. Intramolecular coupling in heterocycles with mixed cuprates ...... 31 3.7. Effect of increasing ring tether to two, three and four atoms ...... 32 3.8. Axial chirality control by 2,4-pentanediol...... 33 3.9. Intermediate indium species with alkyl halides...... 36 3.10. Regioselectivity of oxidative addition of indium ...... 36 3.11. A few representative reactions employing B-alkyl Suzuki−Miyaura reaction in complex natural products...... 41 4.1. Retrosynthetic analysis for gomisin O...... 43 4.2. Synthesis of O-methyl and O-benzyl aryl bromides...... 44 4.3. Synthesis of aryl bromide 136 for angeloylgomisin R, interiotherin A and eupomatilone 1...... 46 4.4. Diastereoselective methylcrotylation of aryl aldehydes...... 47
xii 4.5. Methylcrotylation attempts with silicon, tin and chromium...... 48 4.6. Tiglylation on aryl aldehyde with crotyl indium reagent...... 49 4.7. Basis of diastereoselectivity in the B-alkyl Suzuki−Miyaura coupling...... 50 4.8. Synthesis of the alkene coupling partner for B-alkyl Suzuki−Miyaura...... 52 4.9. Examining diastereoselectivity for the Suzuki−Miyaura coupling...... 53 4.10. Examining diastereoselectivity for hydroboration-oxidation ...... 54 4.11. Initial regioselective bromination approach, directing effect of –OH ...... 55 4.12. Modified regioselective bromination attempt, directing effect of –Ome ...... 56 4.13. Unsuccessful biaryl oxidative Lipshutz cross-coupling attempt ...... 57 4.14. Formation of natural and non-natural atropisomers of gomisin O ...... 59 4.15. Modified route to the synthesis of epigomisin O and gomisin O ...... 60 4.16. Anti/Anti silyl ether 173 from corresponding anti-alkene 148...... 61 4.17. Attempt by the ionic deoxygenation method...... 62
4.18. Chemoselective reduction using Ph2SiHCl and InCl3 ...... 63 5.1. Rearrangement of the dimeric lignan skeleton ...... 67 5.2. Gurjar’s attempt to synthesize eupomatilone 6...... 69 5.3. McIntosh’s attempt to synthesize eupomatilone 6...... 70 5.4. Buchwald’s asymmetric synthesis of eupomatilone 3...... 72 5.5. Coleman and Gurrala’s synthesis of eupomatilone 6 ...... 73 5.6. Kabalka’s racemic synthesis of eupomatilones 2 and 5...... 74 5.7. Hall’s stereocontrolled synthesis of γ-lactones...... 75 5.8. Hall’s stereodivergent synthesis of diastereomers of eupomatilone 6...... 76 6.1. Carbomethoxycrotylation strategies to form the lactone ring...... 78 6.2. Retrosynthetic analysis of eupomatilone 5 ...... 79 6.3. Attempt using Leighton’s chiral diamine route ...... 80 6.4. Organosilicon promoted reaction with aldehydes...... 81 6.5. A route to functionalized allylsilanes ...... 82 6.6. Attempt using Brown’s chlorodiisopinocampheyl borane route ...... 83 6.7. Attempt for chiral carbomethoxycrotyl reagent via Soderquist’s route...... 84 6.8. Nucleophilic boryl-copper species & conjugate addition reactions ...... 85
xiii 6.9. Ramachandran’s application of boryl-copper to form lactones...... 86 6.10. Postulated catalytic cycle for trans-lactone formation ...... 87 6.11. Synthesis of α-methylene-γ-lactones using achiral crotylboronate ...... 89 6.12. Synthesis of α-methylene-γ-lactones using chiral crotyl boronate ...... 89 6.13. Villiéras’ reaction of chiral allylboronate with aldehyde ...... 91 6.14. Enantioselective allylation by Hoffmann and Herold...... 91 6.15. Asymmetric crotylboration of monoaryl aldehydes with the new diborane reagent 272 using Miyaura’s boryl-copper chemistry ...... 93 6.16. A model for the stereoinduction based on model by Villiéras, et al...... 94 6.17. Generation of carbomethoxycrotylboronate via trifluoroborate trans-esterification route ...... 95 6.18. Asymmetric thermal carbomethoxycrotylboration of biaryl aldehydes ...... 97 6.19. Suzuki−Miyaura biaryl cross-coupling using Buchwald’s conditions ...... 100 6.20. Suzuki−Miyaura coupling for biaryl precursor to eupomatilone 1...... 101 6.21. Synthesis of eupomatilone 1 from biaryl precursor...... 102 6.22. Carbomethoxycrotylboration on methylenedioxy monoaryl aldehyde...... 103 6.23. Hydrogenation of eupomatilone 5 to afford 3-epi-eupomatilone 6 ...... 104 7.1. Yamada’s total synthesis of mayolide A ...... 108 7.2. Retrosynthetic analysis of mayolide A ...... 110 7.3. Preparation of (E)-3-bromobut-2-enal ...... 111 7.4. Preparation of boronic ester for carbomethoxycrotylation ...... 112 7.5. Preparation of bromoketal...... 114 7.6. Stannylcupration and protection of alcohol ...... 115
xiv
LIST OF TABLES
Table Page
3.1. Indium-mediated allylation of carbonyl compounds ...... 35 6.1. Optimization of Suzuki−Miyaura biaryl cross-coupling reaction ...... 99 7.1. Baylis–Hillman reaction optimization ...... 113 8.1 Atomic coordinates (x 10^4) and equivalent isotropic displacement parameters (A^2 x 10^3) for Coleman 1211 ...... 169 8.2 Bond lengths [A] and angles [deg] for Coleman 1211 ...... 175 8.3 Anisotropic displacement parameters (A^2 x 10^3) for Coleman 1211...... 176 8.4 Hydrogen coordinates (x 10^4) and isotropic displacement parameters (A^2 x 10^3) for Coleman 1211 ...... 177 8.5 Atomic coordinates (x 10^4) and equivalent isotropic displacement parameters (A^2 x 10^3) for Coleman 1106 ...... 180 8.6 Bond lengths [A] and angles [deg] for Coleman 1106 ...... 180-184 8.7 Anisotropic displacement parameters (A^2 x 10^3) for Coleman 1106...... 184 8.8 Hydrogen coordinates (x 10^4) and isotropic displacement parameters (A^2 x 10^3) for Coleman 1106 ...... 185
xv
LIST OF FIGURES
Figure Page
1.1 Biosynthetic considerations in the lignan family of plant lignans ...... 2 1.2. Gomisin O and other dibenzocyclooctadiene natural products ...... 3 1.3. Establishment of cis-configuration of gomisin O and epigomisin O...... 5 1.4. X-ray structure of gomisin N as reported by Marek and Slanina ...... 6 3.1. P and M nomenclature for acyclic conformers...... 22 3.2. Temperature effect of unsymmetrical biaryl formation via cuprates...... 30 3.3. Stereodivergent addition of tiglyl and angelyl organometallic reagents for C6/C7 syn or anti stereochemistry...... 34 3.4. Rapidly equilibrating mixture of regioisomeric isomers ...... 38 3.5. B-alkyl Suzuki−Miyaura reaction and a general Suzuki−Miyaura catalytic cycle...... 39 5.1. Structure of eupomatilones ...... 66 6.1. Enhanced stability in the transition state on crotylation with an electron-rich biaryl aldehyde ...... 96 7.1. Mayolide natural products: cembranoid and secocembranoid lactones ...... 107 8.1 B-alkyl Suzuki–Miyaura X-ray crystal structure of 159...... 165 8.2 Hydroboration-oxidation X-ray crystal structure of 160 ...... 176
xvi
LIST OF ABBREVIATIONS (IF NECESSARY)
α alpha
[α] specific rotation
Ac acetyl app Apparent br broad (IR and NMR)
β beta n-Bu normal-butyl t-Bu tert-butyl
Bz benzoyl
°C degrees Celsius calcd calculated
CSA (1S)-(+)-10-camphorsulfonic acid
δ chemical shift in parts per million downfield from tetramethylsilane d doublet (spectra); day(s)
DBCO dibenzocyclooctadiene
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCM dichloromethane
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone xvii DEAD Diethyl azodicarboxylate
DIAD Diisopropyl azodicarboxylate
DMAP 4-(N,N-dimethylamino)pyridine
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
eq. equivalent
Et ethyl
γ gamma
g gram(s)
h hour(s)
IR infrared
J coupling constant in Hz (NMR)
k kilo
KHMDS potassium hexamethyldisilazide
L liter(s)
LAH lithium aluminum hydride
LDA lithium diisopropylamide
m milli; multiplet (NMR)
m- meta
m-CPBA meta-chloroperoxybenzoic acid
μ micro
M moles per liter
Mc chloromethylsulfonyl xviii Me methyl
MHz megahertz
min minute(s)
mol mole(s)
Ms methanesulfonyl
MS mass spectrometry; molecular sieves
m/z mass to charge ratio (MS)
NaHMDS sodium hexamethyldisilazide
NBS N-bromosuccinimide
NMO 4-methylmorpholine N-oxide
NMR nuclear magnetic reasonance
o- ortho p- para
Ph phenyl
PMB p-methoxybenzyl
PMP p-methoxyphenyl ppm parts per million
PPTS pyridinium para-toluene sulfonate py pyridine q quartet (NMR) rt room temperature s singlet (NMR); second(s) t tertiary (tert)
xix t triplet (NMR)
TBAF tetrabutylammonium fluoride
TBAI tetrabutylammonium iodide
TBS tert-butylsilyl
TBDMS tert-butyldimethylsilyl
TES triethylsilyl
Tf trifluoromethanesulfonyl
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethylsilyl
xx
CHAPTER 1
DIBENZOCYCLOOCTADIENE LIGNANS: ISOLATION, BIOLOGICAL ACTIVITY
AND STRUCTURAL ELUCIDATION
1.1 Introduction
Lignans are a class of naturally occurring plant phenols that formally arise
biosynthetically from two cinnamic acid (phenylpropanoid) residues,1 as defined
originally by Howarth in 1936.2 In plant lignans, the aromatic rings are typically highly oxygenated and often fused to other additional carbocyclic or oxygen heterocyclic ring units. Lignans are prevalent in all parts of producing plants (roots, stems, leaves, fruits and seeds), and exhibit a wide range of biological activities. In many cases, the active
principle of lignan-based traditional medicines is not known, and a detailed mechanistic
and synthetic study of the active principles may provide useful leads in the development
of effective pharmaceutical agents.
A typical carbon framework is formed by the β,β-union of two cinnamic acids
(Figure 1.1). Further modification of this framework by biaryl bond formation gives rise
to the dibenzocyclooctadiene framework 3, by a free-radical process first proposed by
Erdtmann in 1933.3 The pathways for the biosynthesis of this family of natural products are well established,1 and give rise to a diverse set of structures. Much of the structural
1 variability arises from oxygenation of the aliphatic and aromatic carbons of the lignans. A
wide variety of stereochemical diversity is observed, particularly with respect to the
stereogenic axis observed in these systems (Figure 1.1).
O O
MeO
CO2H MeO OH MeO 1 2 3 4 MeO cinnamic acid 1,4-diaryl butane framework dibenzocyclooctadiene schizandrol
Figure 1.1 Biosynthetic considerations in the lignan family of plant lignans
The genus Schisandra (Schisandraceae) is represented in China with 19 species, mostly growing in the southwestern part of the country on mountains 1500 m above sea level or higher.4 These natural products have been used medicinally for thousands of years by the Chinese. The dibenzocyclooctadiene family of lignans are widely occurring, and the first examples were isolated from the seeds of Schisandra chinensis in 1961.5
This and a related species, Kadsura coccinea, produce a variety of biologically active dibenzocyclooctadiene lignan such as schizandrol (4). Both of these plants are used in traditional Chinese medicine and are listed in the Pharmacopoeia of the Peoples Republic of China.
2 Gomisin O (6) is a prototypical dibenzocyclooctadiene lignan that was isolated in
1979 along with a number of congeners, including the closely related compounds gomisin N (7) and epigomisin O (or gomisin E) (5) from the Chinese plant Schizandra chinensis6,7(Figure 1.2).
MeO MeO MeO MeO OH OH MeO MeO MeO MeO
MeO MeO MeO MeO MeO MeO MeO MeO OH
O O O O OCOPh O O O O Epigomisin O Gomisin O Gomisin N Gomisin G 5 6 7 8
O MeO HO O OCOPh O MeO MeO O
MeO MeO MeO MeO MeO MeO MeO MeO OH O MeO MeO MeO O O O MeO HO MeO Interiotherin A (+)-Deoxyschizandrin Gomisin J Gomisin B 9 10 11 12
O O O O O O O O OAc
MeO MeO MeO MeO O MeO MeO MeO MeO OH O OH MeO O MeO O OCOPh O MeO O MeO (−)-Wuweizisu C (+)-Gomisin A Schisantherin D (−)-Steganacin 13 14 15 16
Figure 1.2 Gomisin O and other dibenzocyclooctadiene natural products
3
1.2 Isolation and structure determination of gomisin O and structurally related
dibenzocylooctadiene natural products
In 1979, the dibenzocyclooctadiene lignans Gomisin N (7), Gomisin O (6), epigomisin O (5), and another known lignan (+)-deoxyschizandrin (10) were isolated from the fruits of Schizandra chinensis Baill (Schizandraceae).7 Petroluem ether and
methanolic extracts of the fruits afforded twelve fractions (fractions 1-12) on silica gel
column chromatography on eluting with n-hexane, acetone-benzene and acetone solvent
systems. Fraction 4 (12.5 g) was crystallized from ether/n-hexane to give gomisin N (7) as colorless prisms (4.76 g). Fractions 7, 8 and 9 were combined and re-chromatographed on silica gel using benzene/ether as solvent system to afford nine more fractions [sub- fractions a-i]. Sub-fraction-e (4.64 g) was subjected to silica-gel column chromatography
(SiO2, 100 g, 3 x 26.5 cm) using benzene-ether (9:1) as eluents. These fractions were
concentrated to give a residue (2.88 g), which was again re-chromatographed on silica-
gel (60 g, 2.5 x 25.5 cm) using n-hexane and acetone (23:2) as solvent system and were
concentrated to afford a residue (950 mg). Repeated purifications [(i) n-hexane-ethyl acetate (1:1), Rf 0.55 ; (ii) ether and n-hexane (2:1), Rf 0.30] of this residue afforded a
mixture of gomisin O (6) (61 mg, 0.0023 %) and epigomisin O (5) (48 mg, 0.001%).7
UV, IR and circular dichroism (CD) spectra8 of gomisin O indicated that gomisin O (6) is
a dibenzocyclooctadiene lignan possing a hydroxyl group and an S-biphenyl configuration.7 The 1H NMR spectrum suggested the presence of two secondary methyl
groups (d, δ 0.92, 6H, J = 7.0 Hz) on the cyclooctadiene ring. The partial structure of
4 gomisin O (6) was confirmed by NOE experiments (in CDCl3) (Figure 1.3). Interestingly,
Gomisin O is the first lignan to be isolated from this plant that possesses a boat conformation of the cyclooctadiene ring. The rationale for this conformation was that if
Gomisin O (6) had a twist boat chair conformation [as in Gomisin N (7)], the steric interaction between ring A and the C6 axial hydroxy group in addition to that of ring B and C7 axial methyl group would have been significantly large.
0% 0% 12.3% O 13% O O 13% H Me H H Me O Hβ O O Hβ 11 11 H 11 A H A A H MeO MeO 9 H MeO 9 9 8 Me 8 H H H H H 8 H H 6 7 0% 6 H 6 MeO 7 MeO Me MeO 7 B H Hα Me HO α B OH 0% Me B MeO 4 H MeO 4 H 14.7% MeO 4 H 14% 14% OMe OMe 13.6% OMe 10.4% 14% 15% NOE in gomisin N (7) NOE in gomisin O (6) NOE in epigomisin O (5)
Figure 1.3 Establishment of cis-configuration of gomisin O and epigomisin O
5 The important structural feature of the gomisins is that they possess a highly
oxygenated biaryl nucleus with multiple stereogenic centers on the cyclooctadiene ring.
The X-ray crystal structure of Gomisin N (7) is reported by Marek and Slanina9 showing
the stereochemical orientation of the methyl groups in the cyclooctane ring as well as the stereogenic biaryl axis (Figure 1.4) which is ‘Paxial’ (Pax) in the natural product.
Figure 1.4 X-ray structure of gomisin N (7) as reported by Marek and Slanina9
6 The challenge in the synthesis of these lignans is the ability to control the sense of
atropisomerism about the stereogenic biaryl axis of chirality (that can be either Paxial or
Maxial), which is difficult to predict a priori. However, there are previous studies by
Coleman10,11 which documented that existing stereogenic centers (on the cyclooctadiene ring) might dictate the outcome of the stereogenic axis in the biaryl bond formation step.
1.3 Biological activity of gomisins and dibenzocyclooctadiene lignans
Dibenzocyclooctadiene lignans possesses many biological activities. Of the range
of biological activities exhibited by lignans, perhaps the most important effect is
antiviral.12 There are various types of gomisins, A, B, C, D, E, F, G, J, O and N; some
possessing central nervous system depressant, analgesic, antitussive, and/or Ca antagonist
activities. Anti-human immunodeficiency virus (HIV) activity of gomisin J (11) and
dibromo-gomisin J derivatives have been reported.13 They have been found to be new
non-nucleoside inhibitors of HIV type-I reverse transcriptase.14-16 Gomisin G (8), isolated
from Kadsura interior, was found to exhibit the maximum potency in anti-HIV activity
a b 17,18 with EC50 and TI values of 0.006 µg/mL and 300, respectively. Preliminary mechanism of action studies have shown template-primer HIV-1 reverse transcriptase
(RT) inhibition.19 Schisantherin D (15), kadsuranin, and schisandrin C were also quite
active: the respective EC50 values are 0.5, 0.8 and 1.2 µg/mL and TI values are 110, 56,
and 33.3. The position and substitution of the hydroxyl groups in the cyclooctane ring
a IC50 refers to the concentration of drug that causes 50% reduction in total cell number. b Therapeutic Index (TI) is the ratio of the IC50 value/EC50 value. 7 were found to be important for the enhanced anti-HIV activity.20 Interiotherin A (9),
which is closely related to angeloylgomisin R, was found to possess anti-HIV activity
20,21 with IC 50, EC50 and TI values being 41 µg/mL, 3.1 µg/mL and 13.2 respectively.
Further studies of the mechanism of action of these lignans are in progress.
In Oriental countries, natural products have been traditionally used for treatment of certain neurological disorders. Ripe Schisandra fruits have been reportedly used as tonic in Oriental societies.22 A methanolic extract of dried Schisandra fruit (Schisandra
chinensis Baill.; Schisandraceae) afforded gomisin N (7), gomisin A (14), deoxyschisandrin (10), schisandrin and wuweizisu C (13).23 Amongst the five lignans,
gomisin N (7), wuweizisu C (13) and deoxyschisandrin (10) were found to protect
primary cultures of rat cortical neurons from glutamate-induced neurotoxicity in 1.0 to
5.0 µM levels, as measured by: (i) an inhibition in the increase of intracellular [Ca2+], (ii) an inhibition in the formation of cellular peroxidase, and (iii) an improvement in the glutathione defense system, the level of glutathione and the activity of glutathione peroxidase.
Dibenzocylooctadiene lignans (schizarin B, C, D, E) exhibited anti-HBsAg
(human type B hepatitis, surface antigen) and anti-HBeAg (human type B hepatitis, e antigen) activity.24
Semi-synthetic derivatives of the lignan podophylotoxin, etoposide and
teniposide, are used clinically for the treatment of testicular cancer, small-cell lung cancer, lymphoma and lymphocytic leukemia. These chemotherapeutic agents are excellent examples of the utility of exploring traditional medicines for lead compounds,
8 and illustrate the successful development of effective antihepatotoxic, anticancer and anti-HIV agents from plant natural products.
9
CHAPTER 2
REVIEW OF PREVIOUS SYNTHETIC STRATEGIES TOWARDS THE
CONSTRUCTION OF THE DIBENZOCYCLOOCTADIENE CORE STRUCTURE
For the last three decades, several research groups have attempted to synthesize
the dibenzocyclooctadiene lignan core structure because of its extensive abundance in
myriads of bioactive natural products. To date, there has been no reported synthesis of
gomisin O (6) and epigomisin O (5) other than by Coleman and co-workers.25 However,
there have been many successful synthetic strategies to the total synthesis of molecules
bearing this core structure. To mention a few are: (1) Kende’s approach to the total
synthesis of (±)-steganacin (16)26 that relies on non-phenolic oxidation methodology
27 using VOF3; (2) Raphael’s approach to the total synthesis of (±)-steganacin by ring expansion via phenanthrene intermediates; (3) Zeigler’s approach to the synthesis of (±)- steganacin28 by application of Ullmann reaction; (4) Magnus’ approach toward the total
synthesis of (±)-steganone,29 applying a [7,3] ring expansion strategy; (5) Meyers’
approach toward the total synthesis of (−)-steganone30 and total synthesis of (−)- schizandrin and (−)-isoschizandrin,31 which relies on the oxazoline-mediated biaryl
coupling strategy, an auxiliary-based diastereoselective chemistry; (6) Motherwell’s
approach to synthesize steganone analogues32 via a cobalt mediated [2+2+2]
10 cycloaddition of a tethered deca-1,9-diyne; and (7) Molander’s total synthesis of (+)-
isoschizandrin33 utilizing samarium (II) iodide mediated 8-endo ketyl-olefin cyclization
are some of the most distinctive approaches cited in the literature. These approaches
would be discussed first in this chapter to lay the foundation of our work towards the
construction of the dibenzocyclooctadiene nucleus in our total synthesis of gomisin O (6).
It is however important to note that many of the syntheses to be described below mostly dealt with racemic versions of the core structure, and very few actually addressed a way to unequivocally set the stereochemistry of the stereogenic biaryl axis.
2.1 The Kende’s approach to the core structure of dibenzocyclooctanone lignans
In 1976, Kende and Liebeskind26 used diethylmalonate unit (17) as a linchpin into
which they alkylated the trimethoxybenzene unit (18) to obtain the 1,4-diaryl butane sub-
unit (19). This was subsequently subjected to the non-phenolic oxidation conditions using
VOF3 and trifluoroacetic anhydride to afford the dibenzocyclooctadiene structure (20).
This was followed up by late introduction of functionality at C-5 (21) using NBS and
silver trifluoroacetate. Subsequent saponification, decarboxylation afforded the keto acid
(22), which was treated with aqueous formaldehyde to generate the trans-fused lactone
ring (23) as shown below (Scheme 2.1).
11
EtOOC COOEt COOEt O NaH, DMF, 0 oC, 52% O 5% TFA, O COOEt O MeO O VOF3 O EtOOC COOEt Br MeO MeO OMe 17 MeO 18 20 OMe 19 OMe MeO OMe
HO O COOEt O O COOH 1) NBS, CCl4, benzoyl peroxide COOEt 1) dipyridine-CrO3, 2) AgOCOCF3, DMSO, rt, 1 h O CH2Cl2, 60% O
3) aq.Et3N (work-up) MeO 2) KOH, EtOH, reflux, 6 h MeO 3) decarboxylation, MeO OMe 200 oC (neat), 95% 21MeO 22 OMe
O O AcO O
O 1) NaBH4, CH2Cl2/MeOH O 37% HCHO(aq), O O O o 0.4M KOH, rt, 1 h, 77% 2) Ac2O, pyridine, 50 C, 2 h O MeO MeO
MeO OMe MeO OMe 23 24 Steganone Steganacin
Scheme 2.1 Kende’s synthesis of (±)-steganacin
2.2 Raphael’s approach to the total synthesis of (±)-steganacin
In 1977, Raphael strategy was based on a ring expansion approach of a
phenanthrene core using a [2+2] cycloaddition reaction with dimethyl but-2-ynediolate.27
Raphael and co-workers treated a suspension of enamine 26 and potassium t-butoxide in refluxing liquid ammonia to produce phenanthrene 27. This was subsequently heated in 12 dioxane with dimethyl but-2-ynedionate to afford the desired ring expanded enamine diester 28. The diester was transformed to the unsaturated oxo-ester 29 by treatment with methanolic hydrochloric acid, which was converted to a homogenous saturated oxo-ester
30 by catalytic hydrogenation. On subsequent treatment of this dibenzocyclooctadiene core structure with aqueous formaldehyde-potassium hydroxide and Jones oxidation produced the trans-fused γ-lactone isosteganone (31), which was thermally isomerized to
(±)-steganone (23) (Scheme 2.2).
O O O O O O
O N 1) aq.DMSO, reflux, 74% hν, liq.NH3 N Br Br MeO t 2) pyrrolidine, reflux, 88% MeO t-BuOK, 65% MeO CO2Bu
MeO MeO MeO OMe OMe OMe 25 26 27 O O O N O O
CO Me 1) Raney Ni, H2 MeO2C CO2Me 2 HCl, MeOH MeO MeO 2) LiOH reflux, 91% CO2Me 90% CO2Me MeO MeO
MeO 28 MeO 29
O O O O O O O O O 1) KOH, aq.HCHO xylene, reflux O MeO MeO O MeO 2) Jones oxidation COOH O O MeO 75% MeO MeO 30 31 23 MeO MeO MeO Isosteganone Steganone
(±) Steganacin (24)
Scheme 2.2 Raphael’s synthesis of (±)-steganacin
13 2.3 Zeigler’s approach to the synthesis of (±)-steganacin
In 1980, Zeigler and co-workers explored the ambient-temperature Ullmann
reaction for the total synthesis of (±)-steganacin.28 They made an organo-copper
counterpart 33 of the oxathiolane 32, which was subsequently treated with imine 34 to obtain a mixture of diastereomers by virtue of atropisomerism of the biphenyl system and asymmetry in the oxathiolane ring. Application of Knoevenagel conditions afforded the malonylidene derivative 37, which was subsequently converted in a few steps to the α- bromo ketone 39. The dibenzocyclooctanone dicarboxylate 40 was obtained by addition of the α-bromo ketone 39 to the basic solution for ring closure. The end-game approach to (±)-steganacin (24) was similar to that of Kende26 and Raphael27 (Scheme 2.3).
MeO O N O Y O O 1) MeO 34 O O 1. n-BuLi, THF MeO I −78 oC O O MeO X 2. CuI.(OEt)3P Br S M S 2) 20% HOAc 3) dimethyl malonate, MeO 32 M=Li piperidine (cat) OMe M=CuP(OEt) (33) X=NC6H11, Y=SCH2CH2O (35) 3 82% X=O, Y=SCH2CH2O (36)
O O X=C(CO2Me)2, Y=SCH2CH2O (37) O O O O 1) Raney Ni, H (1 atm) Br MeI, H2O 2 2) pyridinium hydrobromide Acetone MeO CO2Me MeO CO2Me perbromide, TFAA, CH2Cl2 CO Me CO2Me MeO 2 MeO OMe 38 OMe 39
(Scheme 2.3 continued)
Scheme 2.3 Zeigler’s synthesis of dibenzocyclooctanone nucleus 14 (Scheme 2.3 continued)
O O O t-BuOK, t-BuOH CO Me 2 Steganacin (24) 73% MeO CO2Me
MeO 40 MeO
2.4 Magnus’ approach toward the total synthesis of (±)-steganone
In 1985, Magnus and co-workers29 elegantly applied a cyclopropane ring
expansion approach to obtain the core structure of steganone. They treated the α,β- unsaturated carbonyl 41 with methylsulfoxonium methylide to obtain a single cyclopropane stereoisomer 42, which was treated with thallium tris(trifluoroacetate) in presence of TFA to obtain the [7,3] biaryl 43. Treatment of 44 with HClO4, sodium acetate and acetic acid afforded the ring expanded dibenzocyclooctane core 46 as a single stereoisomer that was oxidized by Jones oxidation to afford the oxo-acid 30 (Scheme
2.4).
15 O O O O COOMe H O O H + − MeO Me2S (O)CH3I COOMe Tl(OCOCF3)3 MeO MeO COOMe NaH/THF, 82% TFA, 0 oC, 43% MeO E:Z = 2:1 OMe MeO MeO 43 41OMe 42 MeO
O 1. AcOH, AcONa, O O o O HClO4, 45 C O O H OH 2. BH3, THF O DIBAL-H Jones Oxidation 3. H O , NaOH MeO CH2OH 2 2 MeO MeO 4. K CO , H O CH OH 2 3 2 2 COOH O MeO MeO MeO 44 46 30 MeO O MeO MeO 1. KOH, CH2O MeO 2. Jones Oxidation
MeO Steganone (23) MeO 45
Scheme 2.4 Magnus’ total synthesis of (±)-steganone
2.5 Meyers’ approach toward synthesis of (−)-steganone
In contrast to the previous enantioselective syntheses, in which the axial symmetry of the biaryl bond was induced by two asymmetric centers on the lactone,
Meyer’s novel approach was to initially form the axially chiral biaryl system, containing the requisite functional groups in addition to the proper substituents, to avoid any aryl- aryl bond rotation. The failure to hinder bond rotation would result in racemization. In
16 1990, Meyer and co-workers30,31 made optically active (+)-47 (tetramethoxyphenyl oxazoline), the lower portion of steganone, and treated that with the Grignard reagent of the bromide 48 constituting the top half of the target. Biaryls 49 and 50 were separated using flash chromatography. At this juncture, they pursued with both pure diastereomers
49 and 50 to reach the final target. After ketal deprotection, the secondary alcohol 52 was
transformed to its allyl ether 51. Chiral oxazoline deprotection afforded an unstable
benzyl alcohol 51 which was quickly transformed to the bromide with NBS.
Subsequently, the bromide was converted to the malonate ester 54. After allyl
deprotection with (Ph3P)3RhCl to their vinyl ethers followed by hydrolytic cleavage, each
diastereomer were obtained stable with no rotation about the biaryl bond. After
conversion to the α-bromo ketone 55, it was treated without delay with potassium tert- butoxide to afford the cyclized ketone 56, the dibenzocyclooctanone core. The ketone 56
was further converted to (−)-steganone (23) via a series of simple transformations
(Scheme 2.5).
O O O O O Ph O O O O O OMe O O + Ph MeO O Ph MeO O N OMe MgBr O MeO N N MeO MeO MeO OMe MeO (+)-47 OMe MeO OMe 49 (seperated by flash 50 chromatography) H+, −5o C
(Scheme 2.5 continued)
Scheme 2.5 Meyers’s asymmetric synthesis of dibenzocyclooctanone core
17 (Scheme 2.5 continued)
O O O O I, O O O OH 1) CH NaH CH3 MeMgBr 3 CHO Ph Ph MeO 2) HSO O o O OH 4 MeO −78 C MeO
3) LiAlH4 N N MeO MeO MeO OMe 51 OMe MeO OMe MeO 52 53 1) NBS/PPh3
2) CH(CO2Me)2
O O O O O O O O O t-BuOK CH (−)-Steganone (23) 3 Br MeO CO Me MeO CO2Me MeO CO2Me 2
CO2Me CO2Me CO Me MeO MeO MeO 2 OMe OMe MeO 54 55 56
2.6 Motherwell’s approach toward synthesis of steganone analogues
In 1999, Motherwell and co-workers32 perhaps made the most ingenuously short
and highly convergent effort toward the synthesis of the dibenzocyclooctanone core. The
key element of the strategy involved the use of a tethered diyne 59 and a third acetylenic
component Me3SiC CSiMe3, in cobalt mediated [2+2+2] cyclobenzannulation strategy,
thereby enabling the closure of the eight-membered carbocyclic ring with concomitant formation of a northern aryl unit available for further modification. The trans-lactone stereochemistry was fixed by alkylation of the lactone enolate from 58 with the benzylic
18 bromide 57. Deprotection of 62 with TFA afforded further steganone analogues (Scheme
2.6).
SiMe Me Si H 3 3 O O o Me Si O H O LDA, THF, −78 C, 1h 3 K2CO3, MeOH
o O o O MeO then 58 , −35 C, 1h, 80% 20 C, 15 h, 95% Br O O O O MeO 59 60 OMe O Me3Si 58 57 O Me3Si O CpCo O Me3Si O 1) Me Si SiMe O O 3 3 H+ CpCo(CO) , THF, 50-65 oC MeO O 2 MeO O + MeO O
2) Me3Si SiMe3 MeO O O O MeCN, reflux, hν, THF MeO MeO MeO MeO 61 MeO 62 63
Scheme 2.6 Motherwell’s synthesis of dibenzocyclooctanone core
2.7 Molander’s approach toward synthesis of (+)-isoschizandrin
In 2003, Molander and co-workers33 demonstrated a samarium(II) iodide- promoted 8-endo ketyl-olefin radical cyclization34 as a means to provide the cyclooctane ring in a single transformation. The biaryl 64 was formed using an Ullmann coupling protocol. Ethanolic KOH afforded the hydroxyl acid that was lactonized with DCC to produce the desired seven-membered lactone (±)-lactone 65. The racemic lactone was
19 subjected to kinetic resolution using Bringmann’s method35,36 to provide the desired
lactone (+)-66. The lactone was transformed to the aldehyde 68, which under modified
Wittig conditions afforded a keto-olefin 69. The keto-olefin on treatment with SmI2 produced (+)-isoschizandrin (70) in dr >18:1 and with no loss of ee (98%) (Scheme 2.7).
OMe OMe OMe MeO MeO MeO (R)-2-methyl-CBS- 1) KOH, EtOH, O MeO oxazaborolidine MeO MeO reflux, 1.5h O O MeO MeO MeO 2) DCC, DMAP, O BH3.THF, THF, O O _ o CH Cl , rt, 63% 20 C, 61% 2 2 MeO MeO MeO (recycle, 98% ee) OMe OMe kinetic resolution OMe 64 (±)-65 (+)-66 OMe OMe
MeO 1) TIPSCl, DMAP, Im, CH2Cl2, 98% MeO + OH 2) EtPh3P Br , KHMDS, O DIBALH, CH Cl _ o 2 2 MeO THF, 78 C, 85%, (4:1 Z/E) MeO _ o MeO MeO toluene, 78 C, 70% 3) TBAF, THF, 91% O 4) Dess-Martin periodinane, MeO MeO CH2Cl2, 90% OMe OMe (+)-67 (+)-68
OMe MeO 1) (α-methoxyethyl)triphenyl MeO O MeO phosphonium chloride, SmI2, t-BuOH, OH THF/HMPA, 85% n-BuLi, THF MeO MeO MeO MeO 2) p-TsOH, THF, 0 oC MeO MeO OMe MeO (+)-69 (+)- Isoschizandrin (70)
Scheme 2.7 Molander’s asymmetric synthesis of (+)-isoschizandrin
20
CHAPTER 3
BRIEF REVIEW OF ATROPISOMERISM, OXIDATIVE BIARYL CROSS COUPLING, PROBLEM IN METHYL CROTYLATION, AND THE B-ALKYL SUZUKI-MIYAURA CROSS COUPLING REACTION
In this chapter, we will discuss a brief review of the origin of atropisomerism, the variations of biaryl intramolecular and intermolecular oxidative cross coupling reaction, and the development of methylcrotylation strategy, which are the key steps of bond construction in our total synthesis of dibenzocyclooctadiene lignan gomisin O, apart from the widely practiced B-alkyl Suzuki−Miyaura cross coupling reaction.
3.1 Atropisomerism in biaryls
Atropisomerism is a type of stereoisomerism that owes its existence due to the restricted rotation about a single bond, a phenomenon that allows different stereoisomers
(atropisomers) to be isolated. It is manifested in allenes, spiranes, and centrally chiral compounds where the stereochemistry depends on the bulks of the ortho- substituents which restricts the rotation about the single bond.37
Biphenyls 71 and 72 are enantiomers as a consequence of each having a stereogenic axis, with a defined sense of chirality. The configuration of a molecule having a chirality axis may be specified as R or S by application of the Cahn-Ingold-
21 38 Prelog priority rules. The helical nomenclatures (Pax and Max) are often convenient to specify the chiral descriptor of conformational or atropisomeric enantiomers, e.g. for biphenyl derivatives with axial chirality. The highest priority group (by CIP rules) is selected at the front (fiducial group) and related to the highest priority group at the rear. If in doing so a clockwise turn is described, the configuration is P; if it is an counter- clockwise turn, the configuration is M. In the figure below, the two highest priority groups are NO2 in front and NO2 in the rear. Movement from former to latter assigns it as a P (clockwise direction). For compounds with chirality axes, R corresponds to M, and S corresponds to P (Figure 3.1).
OH OH A A OH HO NO2 X Y H H
HO2C NO2 Y X H CO2H HO2C H B B CO2H CO2H CO2H 71 72 P M P
Figure 3.1 P and M nomenclature for acyclic conformers
3.2 Atropselective intramolecular couplings
Introducing an intramolecular variation of a given biaryl coupling can usher in several benefits. The bridge linking the aromatic rings can lead to an improvement in the
22 yield and regioselectivity of the coupling reaction, in addition, that might also influence
the barrier to atropisomerization and be the site of chirality from which any asymmetric
induction emanates. After coupling, all or some part of the bridge may be left in the
molecule or it may be completely removed. There can be three possible cases of bridges
in a molecule: (i) Bridges which are naturally present in the target molecule: This is
oftentimes useful when the target is a natural product. In that case the bridges between
the two aryl moieties can not only be the integral part of the target molecule but can also
influence the steric course of the coupling reaction. (ii) Artificial bridges which can act
as chiral auxiliaries: Even when the target molecule itself does not contain a bridge, it
may be possible to take advantage of an intramolecular reaction to bring about biaryl
bond formation, if the two aryls can be linked together by some artifical linkers; and (iii)
Achiral artifical bridges: Such bridges do not need to be an integral part of the molecule
but may be constructed by harnessing the functional groups already present in the
aromatic rings of the molecule.37
Depending upon the degree of steric hindrance, the bridged system may either be
relatively conformationally stable, or they may interconvert more or less rapidly.
Furthermore, if chiral centers are present in the molecule, the equilibrium distribution of
bridged isomer might favor one or the other diastereomer.
If the ring-opened products are much more conformationally stable than their
bridged counterparts, the corresponding correct atropisomer may then be transformed
into the desired target molecule with retention of configuration at the biaryl axis.39
Moreover, the unwanted atropisomer can even be recycled. Overall this method represents an atrop-enantioselective biaryl synthesis and has been thoroughly investigated
23 by Bringmann and co-workers.35,36,40 As seen before, it has been applied in several
elegant synthesis of biaryl natural products.33
3.3 Oxidative biaryl cross-coupling with vanadium, molybdenum, nickel, copper
The biaryl moiety is the core structural component of many important natural
products,41 just as in the gomisins. Oxidative biaryl coupling of phenols have received a
considerable attention owing to its utility as a synthetic reaction and its involvement in
the biosynthesis of myriads of natural products.40 Vanadium complexes have exhibited rich red-ox chemistry providing potential tools in organic synthesis.42 Huang and co-
workers43 have reported synthesis of phenanthrene derivatives using intramolecular biaryl
oxidative coupling of stilbenes using vanadium oxychloride (VOCl3). Chu and co-
workers44 had reported a method for oxidation of hydroquinones and biaryl coupling of
aromatic alcohols using oxovanadium acetylacetonate (Scheme 3.1).
R1 R3
1 3 R R 2 VO(acac)2 (cat.), O2 R OH R2 OH R2 OH CH2Cl2 R1 R3 73 74
Scheme 3.1 Oxidative coupling of 2-naphthols catalyzed by VO(acac)2
24 Kita and co-workers45 have reported a serendipitous [phenyliodine(III) bis(trifluoroacetate)] (PIFA)-induced intermolecular chiral biaryl coupling using α-D- glucose as chiral templates. Choice of Lewis acid to activate PIFA seemed to be critical and BF3·Et2O seemed to be an efficient activator in this case. Use of hypervalent iodine(III) reagents has gained importance in the recent years as a low-toxicity alternative to alternative heavy metal reagents. There has also been reports of oxidative coupling reactions mediated by molybdenum pentachloride46 by Waldvogel and co-workers for selective eight membered ring formation from 1,4-diarylbutanes, in presence of additives
+ like TiCl4, SiCl4, SnCl4 and chloride scavengers like Ag or molecular sieves. However, prolonged reaction times, higher temperature and higher amounts of MoCl5 did not alter the outcome of the reaction and mostly led to the degradation of the substrates (Scheme
3.2).
MeO MeO
MeO MeO o MoCl5, CH2Cl2, 0 C
additives: SnCl4, SiCl4 87% MeO MeO OMe OMe MeO MeO 75 76
Scheme 3.2 MoCl5 –mediated oxidative coupling in presence of additives
25 An intramolecular Cu(I)-mediated coupling of two aryltrimethylstannane
functions 77 and the “mixed” coupling of aryl- and alkenylmethylstannane moieties have
been reported by Piers and co-workers.47 Copper (I) chloride was used in excess (5 equiv)
to push the reaction toward completion and polar solvents (dry DMF) produced 62%
yield with trimethoxy substituents on the aryl system (Scheme 3.3).
OMe OMe MeO OMe MeO OMe OMe OMe OMe OMe I EtO2C SnMe3 Cu EtO2C CuCl, EtO2C EtO2C OMe EtO C OMe 2 CuII OMe DMF, rt EtO2C EtO2C EtO2C SnMe 60 min CuI 3 OMe OMe Cuo + MeO OMe MeO OMe MeO OMe OMe OMe OMe 77 78 79 80
+ 2 Me3SnCl
Scheme 3.3 CuCl –mediated intramolcular coupling of bis-trimethylstannanes
A new strategy was also reported by Rawal and co-workers48 in which they
performed aryl coupling of conformationally locked dihydroxy-stilbenoids in high
atropisomeric purity. They used a Ni(0) catalyst system, on a carbonate 81 which has
been reported to be a mild, high-yielding alternative to the Ullmann reaction for intramolecular couplings by Semmelhack and co-workers.49 Rawal prepared the required
26 catalyst in situ by heating to 60 °C a mixture of NiCl2 (1.1 equiv), PPh3 (5.5 equiv), NaI
(1.0 equiv), and excess Zn dust (10 equiv) for 1 h with an yield of 33% (Scheme 3.4).
NiCl2 ( 1 equiv) H PPh3 (5 equiv) H O NaI (1 equiv) O Br Br O O O Zn dust (excess) O H H DMF, 70 - 80 oC, 2h 33% 81 (S) - 82
Scheme 3.4 NiCl2 –mediated biaryl coupling
3.4 Lipshutz intramolecular oxidative biaryl couplings via “kinetic” higher order cyanocuprates to form unsymmetrical biaryls
The usual mode of attachment for coupling calls for an electron-rich aryl component with an electron-deficient partner. However, Lipshutz and co-workers50 demonstrated that by controlling two key reaction parameters (temperature and mode of formation), unprecedented “kinetic” higher order cyanocuprates can be generated. Their origin involves two different aryllithiums (ArLi, Ar’Li) together with a Cu(I) salt (e.g.
CuCN). Here, the concept is coming together of two distinctly anionic species to result in one two-electron carbon-carbon bond by invoking a cuprate such as 83. The protocol involves low temperature formation of a mixed diaryl cuprate and oxidation of this 27 species to form the carbon−carbon biaryl bond. The reaction is thought to be insensitive
to steric or electronic features of the aromatic systems when compared to palladium –
mediated processes.
However, reducing it to practice was another matter, because the expected
outcome from an oxidative treatment of a dimeric, mixed diaryl cuprate would be a
potpourri consisting of three biaryls 84, 85 and 86 formed in variable yields with little or
no selectivity and no pragmatic means of predicting the ratio in advance (Scheme 3.4.1).
The workers figured out that (i) temperature, and (ii) the mode of cuprate
formation might be playing a pivotal role. Furthermore, the manner in which the cuprate
was formed was more enlightening. They preformed the lower order cyanocuprate51 [(m-
Ar)Cu(CN)Li] in 2-methyl THF as solvent, pre-cooling this solution to −125 °C and then introducing the p-ArLi followed by oxidation at this low temperature, 93% of the biaryl mixture produced was the unsymmetrically coupled product (Scheme 3.5). In essence, these workers had discovered “kinetic” cuprates.52
28 m-ArLi + CuCN p-ArLi + CuCN
o −40 C −40 oC
(m-Ar)Cu(CN)Li (p-Ar)Cu(CN)Li Higher Order o Cyanocuprate 1. −125 C 1. −125 oC "(m-Ar)(p-Ar)Cu(CN)Li2" 2. p-ArLi 83 2. m-ArLi
[O] −125 oC
OMe OMe OMe
84 ++85 86
OMe OMe OMe 3.5% 93% 3.5%
Scheme 3.5 The selectivity issue for unsymmetrical biaryl product at −125 °C
Further evidence of this phenomenon was sought, and temperature-controlled
experiments were performed to test the structural integrity of such species. Most
unexpectedly, a plot of the data revealed an astonishing linear correlation between the
percentage of unsymmetrical biaryl and the temperature of the cuprate
formation/oxidation,53 (Figure 3.2) which set up a predictive power in cuprate chemistry that was virtually non-existent in the past.50
29
O
O Li R
C Cu N
O Li R"
O
Higher Order Cyanocuprate54 Or “Kinetic Cuprate”
Figure 3.2 Temperature effect of unsymmetrical biaryl formation via cuprates
A few more staggering facts established for this technology was that when ground
3 state molecular oxygen ( O2) gas was employed as an oxidant and TMEDA was used as an additive, the isolated yields were routinely bumped up to 80-90% for all intermolecular cross-couplings.55 The coupling conditions were found to work well with heterocycles (Scheme 3.6).
30 Li OMe
CuCN 89 O2 S S Li Cu(CN)Li _ o S 2-MeTHF, Cu(CN)Li2 125 C _ o OMe 125 C OMe 87 88 S 91 80 % 90
Scheme 3.6 Intermolecular coupling in heterocycles with mixed cuprates
It was also observed that sterics were not a major factor for these coupling
reactions. The corresponding intramolecular variant was also found to be rewarding.
However, while transformation of two-, three-, and four-atom tethered adducts to be converted to their respective tetracycles (95, 96 and 97) under the standard cuprate formation/oxidation conditions, the yields for the formation of larger rings were found to have a decreasing trend with the increase of ring tether55 (Scheme 3.7).
31 OMe MeO
O MeO Br Br O Br Br O Br Br O
92 93 94
82% 76% 56%
MeO MeO O O MeO O O
95 96 97
Scheme 3.7 Effect of increasing ring tether to two, three and four atoms
Sugimura and co-workers have successfully applied this technology as a highly efficient stereocontroller to produce enantiomerically pure materials.56 In the substrate,
two naphthyl groups were connected, by using an optically active 2,4-pentanediol as a
chiral linking bridge between a reagent and a prochiral substrate. The biaryl bridge in 99
was subsequently constructed using the Lipshutz chemistry (Scheme 3.8).
32 Ph Ph Ph Br Br BuLi, CuCN, O O O o then O2 at −78 C O 78% Ph 98 99 ( >99% de)
Scheme 3.8 Axial chirality control by 2,4-pentanediol
3.5 Development of methylcrotylation strategy for gomisin
One of the key challenges in the synthesis of gomisins was developing a
methodology for asymmetric crotylation. There were no examples of the necessary
substitution pattern of the tiglyl [(E)-2-methyl-2-buten-1-yl] organometallic reagent known in literature. The sense of stereoinduction in the oxidative cuprate coupling vide
supra, was solely dependant upon the configuration of the C6 stereogenic center of 116
(Scheme 4.1), which would be set by this methyl crotylation. The C6/C7-anti
stereochemistry should allow for complete stereocontrol of the newly formed stereogenic
biaryl axis. It is noteworthy that the relative configuration about the eight membered ring
is C6/C7-cis for gomisin E (5) and will be introduced in a straightforward manner by the
use of the Mitsunobu inversion at C6 vide infra.
33 3.5.1 Diastereoselective methylcrotylation of aryl aldehydes
The proposed asymmetric synthesis of dibenzocyclooctadiene lignans relied on the enantio- and diastereoselective crotylation of an oxygenated electron-rich aryl aldehyde (Ar-CHO) by an organometallic crotyl reagent (Figure 3.3). The core of the problem was to find a suitable metal that would be the most efficient to provide the required stereochemistry at the C6/C7 stereogenic centers.
Angelylation ≠ H Me H M OH Me M Me Ar O 7 work-up Ar 6 (E) Me Me Me H anti-homoallylic O alcohol Ar H ≠ H Me H M OH Me Me M Ar O 7 H 6 (Z) work-up Ar Me Me Tiglylation Me syn-homoallylic alcohol
Figure 3.3 Stereodivergent addition of tiglyl and angelyl organometallic reagents for
C6/C7 syn or anti stereochemistry
Butsugan, Ito and co-workers have reported indium-mediated allylation of a
variety of aldehydes and ketones afforded excellent yields of the corresponding
homoallylic alcohols under very mild reaction conditions.57,58 Typically they added a
mixture of allyl iodide/bromide and a ketone/aldehyde in DMF to a suspension of indium 34 powder to observe an exothermic reaction. After stirring at room temperature for 1 h,
they quenched the reaction by addition of diluted HCl. Extraction with ether and column
chromatography afforded the corresponding alcohols (Table 3.1). Interestingly none of
the examples tried by them showed the specific type of crotylation that was in our focus.
No. allyl halide (RX) carbonyl compd product yield (%)
O OH 1) I 89
2) Br 81 OH O
3) 94 Br PhCHO Ph OH OH CHO 4) Ph Br 90 Ph OH
5) Br CHO 75
Br 6) CHO 75 OH O OH 7) OP(OPh) 54 2 PhCHO Ph
O OH CHO 8) OP(OPh)2 64
O OH 9) OP(OPh)2 O 62
Table 3.1 Indium –mediated allylation of carbonyl compounds
The intermediate indium species of the reaction of indium metal and alkyl halides were suggested to be a sesquiiodide (100) in the stoichiometric ratio of 2:3:2 (Scheme 3.9).
35
OH R I R 1) 2 n-C H COCH 6 13 3 2 n-C H C−R 3RI + 2In In In 6 13 2) H O+ CH R I I 3 3 100 101
Scheme 3.9 Intermediate indium species with alkyl halides
The regioselectivity of the oxidative addition of indium to allylic halides was examined by Butsugan and co-workers using geranyl bromide59 (102). 1H NMR analysis revealed that the addition occurred exclusively at the α-carbon, giving the indium sesquihalide, geranylindium 103; formation of linalylindium 104 was not detected
(Scheme 3.10).
Hard-center Soft-center
In Br In2Br3 In2Br3 γ α DMF, rt 3 3 102 103 104 (not detected)
Scheme 3.10 Regioselectivity of oxidative addition of indium
36 The region and stereochemistry of the coupling reactions of the allylic indium
reagents 103 with electrophiles largely depend on the nature of the electrophiles. Thus,
hard electrophiles (e.g. proton and carbonyl compounds) attack at the γ-carbon of the
allylic indium reagents, whereas soft electrophiles (e.g. chlorostannane) couple at the α-
carbon. The stereochemistry (E and Z configuration) of the allylic double bond of the
products is determined by the substitution pattern of the allylic system.
Loh and co-workers60 also reported indium-mediated allylations with several
allylic bromides, but none with (E)-1-bromo-2-methylbut-2-ene (tiglyl bromide).
Applying conditions similar to Butsugan58 and co-workers, they obtained modest yields between 51-85% while using bromide (3 equiv), indium (2 equiv) in DMF at room temperature for 24 h. In the review by Yamamoto and Asao,61 it was quite surprising to
find that although various metals and many substrates have been used in the literature for
allylation reactions, none actually used (E)-1-bromo-2-methylbut-2-ene (tiglyl) halide as
a substrate for crotylation reaction. The reason might have been simply the inability to
control the rapidly equilibrating mixture of regio-isomeric allylic isomers when the
organometallic reagent having tiglyl halide was used as the substrate (Figure 3.5.2). This
problem was patently obvious upon formation of the Grignard reagent from the corresponding bromide, as this reagent failed to effect useful diastereoselection on addition to aldehyde at room temperature (Figure 3.4). Our research was thereafter directed towards finding a solution to this problem of methylcrotyation. Efforts were also
focused in our group for an asymmetric strategy to this problem that will be discussed vide infra.
37 MgBr MgBr MgBr
L -M M-Ln M-Ln n
(E)-crotyl (Z)-crotyl methallyl
M-Ln M-Ln (E)-crotyl (Z)-crotyl
Figure 3.4 Rapidly equilibrating mixture of regioisomeric isomers
3.6 The B-alkyl Suzuki−Miyaura cross coupling reaction
The cross-coupling reaction of organoboron reagents with organic halides or
related electrophiles represents one of the most elegant methods for carbon−carbon bond formation and has revolutionized the art of organic synthesis. The reaction has been found to proceed under mild conditions in the presence of a base and a Pd0 catalyst. It is
unaffected by the presence of water, tolerates a broad range of functionality, and yields
non-toxic byproducts.62
The B–alkyl Suzuki−Miyaura reaction is distinguished from other
Suzuki−Miyaura cross-coupling reactions in that a reaction occurs between an alkyl borane (as opposed to an aryl or vinyl borane) and an aryl or vinyl halide, triflate, or enol phosphate as the coupling partner. An important variation involved in this reaction is a 38 sp3 carbon in the coupling event (Figure 3.5). The strength of the B-alkyl
Suzuki−Miyaura cross-coupling lies in the mild and versatile methods for the synthesis of the alkyl borane component, the ease of incorporation of boron ligands, and the
− 63 manageable toxicity of the boron derived waste products (e.g. R2B(OH)2 ). There has
been tremendous application of this powerful coupling method in natural product
synthesis. The mechanism of the reaction and a few selected applications are highlighted
vide infra.
R1⎯ X
oxidative addition R1⎯R2 Pd0
reductive 1) 9-BBN-H elimination R1⎯PdII ⎯ X X 2) Pd0 , base X = I, Br, Cl, OTf, OP(O)(OR) R1⎯PdII ⎯R2 2 transmetallation
4 3 2 4 (R )2BOR R B(R )2 + X − + OR3 −
Figure 3.5 B–alkyl Suzuki–Miyaura and a general Suzuki–Miyaura catalytic cycle
In the hydroboration process, the terminal alkyl borane regioisomer is P R2 Fe Pd highly favored (anti-Markovnikov addition) due to electronic as well P R1 as steric factors, although the steric effects tend to predominate.64
105 39 Electron-rich unhindered olefins generally react the fastest.65 The order of reactivity of the electrophilic partner in Suzuki reaction has been established as:66 I >> Br > OTf >>
Cl. Alkyl halides having a hydrogen atom in the β-position are considered as problematic substrates due to potentially competing β-hydride elimination processes.62 It is also reported that the reductive elimination step increases significantly with increasing diphosphine “bite angle” (∠P-Pd-P) as in 105. Increasing the chelate ring size of the ligand, results in increasing bite angles, chelate flexibility, and steric size, and all would be expected to increase the reductive elimination step.67 Increasing the diphosphine bite angle and sterics, compresses the carbon-palladium-carbon angle (∠C-Pd-C), thereby forcing the two carbon atoms closer together that accelerates C—C bond formation and subsequent elimination.
Miyaura and co-workers have found that stronger bases (e.g. NaOH, TlOH,
NaOMe) performed well in THF/H2O solvent systems, whereas weaker bases (e.g.
68,69 K2CO3, K3PO4) were more successful in DMF.
The B-alkyl Suzuki─Miyaura reaction has been successfully used for inter- as well as intra-molecular cross couplings. Ligands employed sometimes greatly improve the efficiency of the coupling reaction.70,71 A few representative examples on complex molecular systems are provided below63 that demonstrates the reaction to be an extraordinarily useful tool for construction of carbon frameworks (Scheme 3.11).
40 1) 9-BBN-H, THF CO Me 1) 2 2) [PdCl2(dppf)], K3PO4 75% AcO Br CO2Me 106 107
OTf 1) 9-BBN-H, THF 2) 2) [PdCl2(dppf)], K3PO4, dioxane-THF (0.14 M), CO2Me 85 oC, 76% 108 109
B OTBS OTBS 1) [Pd2(dba)3•CHCl3] ligand, K CO , THF 3) TfO 9-BBN-H 2 3 OH THF TfO OTBS 2) 3 M NaOH, 35% H2O2 31% ee 42% 112 110 111 MeO2C B
1) 9-BBN-H, THF 2) vinyl iodide (R-Ι), [Pd(dppf)Cl2], 4) BocHN AsPh3, Cs2CO3, DMF, H2O Me BocHN I CO2Me H R-Ι = Me TBDPSO H 113 TBDPSO 114
Scheme 3.11 A few representative reactions employing B-alkyl Suzuki−Miyaura
reaction in complex natural product synthesis
41
CHAPTER 4
STUDIES TOWARDS THE TOTAL SYNTHESIS OF GOMISIN O
4.1 Introduction
The discussion on the retrosynthetic approach on our general strategy towards the synthesis of dibenzocyclooctadiene systems and the synthesis of gomisins in particular could be categorized into the following key events. We would first focus on the synthesis of the aryl fragment 118 that would be required as a coupling partner in the B-alkyl
Suzuki−Miyaura reaction. The next focus would be on the methyl-crotylation reagent 129 and conditions that needed to be developed in order to set the stereochemistry of the key
C6 stereocenter. Following which we would establish unequivocally the diastereoselectivity in the key B-alkyl Suzuki−Miyaura coupling step in order to form the
1,4-diarylbutane system. Subsequently, regioselective bromination attempt will be discussed to set up the dibromide system for the all important atropdiastereoselective
Lipshutz biaryl oxidative cuprate cross-coupling step (Scheme 4.1). The 1,4-diarylbutane contains three of the four necessary stereogenic elements of gomisin O in the correct absolute and relative configuration, which would be introduced via two highly stereoselective transformations.
42 Mitsunobu inversion O O MeO 6,7-Anti OR" MeO OMe OR" H O 10 15 6 MeO B O MeO 16 "RO Br 8 8 9 9 117 MeO 15 7 6 MeO Br X Oxidative OMe Cuprate O MeO Br 116 + Coupling 16 Hydroboration & O Suzuki Coupling B-alkyl O 115 MeO OMe O P Suzuki axial Miyaura stereogenic axis about C15-C16 Br 10 OMe 118
8 M L* OR" O 7 129 MeO 7 9 MeO 6 8 H
MeO Br MeO Br OMe OMe 119 120 Crotylation
Scheme 4.1 Retrosynthetic analysis for gomisin O
4.2 Synthesis of the aryl bromide Suzuki-Miyaura coupling partners
The Suzuki coupling partner 118 was synthesized starting from o-vanillin.
Bromination with sodium acetate in acetic acid cleanly afforded the
bromomethoxyaldehyde 122. This was demethylated with borontribromide to produce the
diol 123, which on treatment with bromochloromethane and sodium carbonate afforded
the methylenedioxybromo aldehyde 124. On being subjected to Baeyer-Villiger
oxidation72 and subsequent hydrolysis of the intermediate formate ester with methanolic
KOH afforded the key alcohol 127 in 30% yields. The alcohol 127 was subjected to
43 methylation and benzylation conditions to afford the desired aryl bromides 126 and 128 for Suzuki-Miyaura coupling. However, a shortened and more efficient route to the methoxy derivative was developed on treatment of the bromomethoxyaldehyde 122 under
Dakin oxidation conditions73 to produce the dihydroxy bromide 125, which was cleanly transformed to the required methylenedioxybromomethoxy compound 126 on treatment with bromochloromethane and sodium carbonate in DMF in good overall yield of 65% starting from o-vanillin (121) (Scheme 4.2).
HO Br O Br 30% H2O2, 3N NaOH BrCH2Cl, Na2CO3 O rt, 3 h, 80 % HO DMF, 110 oC, OMe 6 h, 90% OMe 125 126 OHC OHC Br OHC Br OHC Br Br2, NaOAc, BBr3, CH2Cl2 BrCH2Cl, Na2CO3
o HO AcOH, 25 C, 91% o o HO − 25 C, 60% HO DMF, 110 C, O OMe OMe OH 6 h, 88% O o-vanillin (121) 122 123 124
HO Br 1. m-CPBA, CH2Cl2, Ar, 4 h BnBr, K2CO3 BnO Br
o 2. methanolic KOH, 0 C DMF, 25 oC, 2 h, O O 1h, 30% (2 steps) O 127 85% O
128 Me2SO4, K2CO3 acetone, 60 oC, 24 h, 97%
O Br
O OMe
126
Scheme 4.2 Synthesis of O-methyl and O-benzyl aryl bromides
44
The regioselective bromination would be an important step prior to the planned
Lipshutz biaryl cross coupling. Hence, we decided to test the directing effect of the
hydroxyl group on a NBS reaction, on an aryl precursor 134. Bromination, demethylation
with pyridine and AlCl3, followed by treatment with bromochloromethane sequentially on vanillin (130) afforded the bromocarbaldehyde 131. The aldehyde was protected with ethylene glycol to form acetal 132. A lithium halogen exchange followed by treatment with trimethoxyborate afforded the intermediate boronate that was subsequently hydrolyzed with NaOH and hydrogen peroxide to produce the alcohol 133. The acetal was deprotected with PPTS in acetone and the hydroxyaldehyde 134 was tested for regioselective bromination with NBS in dioxane to exclusively afford the bromide 135 in excellent yield. The alcohol 135 was methylated to obtain the desired methoxyarylbromide 136, which was subsequently used in the total synthesis of interiotherin A and angeloylgomisin R in our group21 (Scheme 4.3). This aryl bromide
would also be later used as a coupling partner for the biaryl Suzuki−Miyaura cross
coupling reaction in the asymmetric total synthesis of eupomatilone 1 (Scheme 6.20).74
45 OH O O 1. Br /AcOH, 2 h, 90% o MeO 2 O Br OH O Br 1. n-BuLi, THF, 2 h, − 78 C, 2. AlCl , Py, CH Cl , 3 2 2 , p-TSA then B(OMe)3, 12 h, reflux, 97% OH − 78 to 25 oC toluene, reflux, 92% 3. Na CO , BrCH Cl, CHO o CHO 2 3 2 then, NaOH, H2O2, − 78 C, o OO vanillin (130) DMF, 110 C, 81% 98% (overall) 131 132 O O OH O O O O OH O OH O OMe PPTS, acetone NBS, dioxane, 3 h Me2SO4, K2CO3
o o OO 55 C, 4 h, 91% 16 to 18 C, 97% Br acetone, 60 oC, 95% Br CHO CHO CHO 133 134 135 136
Scheme 4.3 Synthesis of aryl bromide 136 for angeloylgomisin R, interiotherin A
and eupomatilone 1
4.3 Diastereoselective methylcrotylation (tiglylation) of aryl aldehydes
The proposed synthesis of dibenzocyclooctadiene lignans relied on the enantio- and diastereoselective crotylation of an oxygenated electron-rich aryl aldehyde (Scheme
4.3.1).75 Given stereodefined allylic organometallic systems 138 [(E)-2-methyl-2-buten-
1-yl (tiglyl)] and 139 [(Z)-2-methyl-2-buten-1-yl (angelyl)], synthesis of the anti-adduct
141 and syn-adduct 140 in diastereomerically and enantiomerically pure form should be possible (Scheme 4.4).76
46 OH M MeO 7 138 6 Tiglylation MeO Br MeO CHO syn OMe 140
MeO Br M OH OMe MeO 7 137 139 6
Angelylation MeO Br anti OMe 141
Scheme 4.4 Diastereoselective methylcrotylation of aryl aldehydes
A non-obvious but precedented pitfall to our strategy was that the precursor allylic organometallic reagents 138 and 139 (M = Mg, Li) underwent allylic equilibration
(Figure 3.4), thereby giving rise to stereochemically scrambled crotylation reagents upon transmetalation (e.g., M = B, Sn, Si). In order to surmount this equilibration problem, we examined25 silicon and tin (Scheme 4.5), which provide configurationally stable
species.77 Using 2-bromo-3,4,5-trimethoxybenzaldehyde (137),33,78 Yamamoto’s CAB-
79 catalyzed crotylsilylation with tiglyltrimethylsilane 142 (CH3CH2CN, −10 °C, 3 h,
56%) afforded poor diastereoselectivity (1.5:1 syn/anti 140/141). The reaction of
80 tiglyltributylstannane 143 in the presence of AgOTf/(S)-BINAP (CH2Cl2, 25 °C, 24 h)
81 or Ti/BINOL (CH2Cl2, 25 °C, 18 h) failed to provide product. The tiglylchromium
82 reagent 144 prepared from tiglyl bromide and CrCl2 in THF underwent addition to the
aldehyde 137 (THF, −30 to + 25 °C, 2 h, 69%) to afford 13:87 ratio of syn/anti adducts
140 and 141, respectively. Attempts to increase the diastereoselectivity at lower reaction 47 temperature were unsuccessful, because the tiglylchromium reagent was unreactive
below −30 °C. [Some of the above experiments were performed in conjunction with
Amresh M. Raao (Master’s Thesis, 2006, The Ohio State University)].
OH
MeO 6 7 + SiMe3
142 MeO Br OMe MeO CHO 140
+ SnBu3 MeO Br 143 OMe 137 OH MeO 6 7 + CrL5 144 MeO Br OMe 141
Scheme 4.5 Methylcrotylation attempts with silicon, tin and chromium
There are a handful of reports on indium-mediated allylations in literature.58-60,83
Based on literature precedences, halogen−metal exchange of tiglyl bromide with indium metal in DMF afforded tiglyl indium reagent, which proved highly effective in diastereoselective crotylation of aryl aldehydes (Scheme 4.6). At room temperature in
DMF, reaction of this reagent with aldehyde 137 afforded an 82% combined yield of products in a 2.5:1 ratio of syn- and anti- alcohol adducts 140 and 141, respectively, which could be improved to 11:1 at −45 °C (85% combined yield) and to >19:1 in 5:1
48 DMF/THF at −78 °C (97%). The indium reagent when generated in THF, however, did
not provide any diastereoselectivity in this addition reaction.
(a) MeO MgBr 95% (1:1) MeO 145 + anti TBS ether(148) 137 (b) 97% MeO (95:5) Br In2Br3 OR 3 146 R = H 140 t-BuMe2SiCl, NaH, 95% R = TBS 147
Scheme 4.6 Tiglylation on aryl aldehyde with crotyl indium reagent
Successful asymmetric methylcrotylation method was ultimately developed by persistent efforts from our group members25 by modification of Leighton’s chiral diamine
84,85 route using (1S,2S)-1,2-diaminocyclohexane-based auxiliary (DBU, CH2Cl2, 25 °C,
14 h) to obtain excellent er of 98:2 for both the desired syn- and anti- adducts in 78% yield.
4.4 Basis and proof of diastereoselectivity of the B-alkyl Suzuki−Miyaura coupling
The setting-up of the relative stereochemistry of the methyl group at the C8 position with respect to the C7 methyl group during the construction of the 1,4- diarylbutane system would be a key to the total synthesis of gomisins. The strategy for the installation of the second aromatic ring relied on a stereoselective 49 hydroboration/Suzuki coupling protocol. Steric arguments based on conformational
analysis using MonteCarlo methods with the MM3 force-field are shown below. The
global minimum A for this model system has a C=C−C−H dihedral of 1°, and the
approach of a dialkylborane would occur syn to the smaller methyl group as shown
(Figure 4.3) to provide the anti-product. The second minimum energy of conformation B is 0.8 kcal/mol above the global minimum, and hence a prediction of the facial selectivity for the hydroboration in this case is less clear-cut than with A. With the third minimum energy conformation C, hydroboration would occur syn to the hydrogen to afford the undesired syn product (Scheme 4.7). Panek and co-workers86 have examined 2,3- dialkoxy-2-methyl-1-alkenes and demonstrated controllable diastereofacial selectivity based on the choice of the hydroboration conditions.
Allylic Methyl H H H OCH Me H Me Me H 3 H3CO Me Me Me Ph H 7 H Ph 6 Ph 6 6 8 6 7 BR2 Ph 8 Ph 6 8 H3CO H CO H 8 H3CO Me 8 H H 3 H Me BR 2 Me Me HH H H anti (B) (C) (A) 0.0 kcal/mol 0.8 kcal/mol 1.2 kcal/mol Allylic Methyl
TBDMSO Me TBDMSO Me TBDMSO Me Me MeO 7 H MeO MeO 7 BR 6 8 6 6 8 2 8 H H H Me Me MeO MeO BR2 MeO OMe OMe H H OMe 150 151 anti
Scheme 4.7 Basis of diastereoselectivity in the B-alkyl Suzuki−Miyaura coupling
50 On the above justification to the origin of diastereoselectivity based on the
A1,3−Strain model, we expected to obtain C7-C8 anti-selectivity when we perform the
hydroboration-oxidation, or the one-pot hydroboration followed by Suzuki−Miyaura
reaction as shown vide supra (Scheme 4.4.1) on the silylether protected alkene 150.
The required aryl alkene 150 was initially prepared from tiglic acid, which was
reduced by LAH to tiglyl alcohol (purified by distillation) and brominated to afford the
tiglyl bromide 153. The bromide under treatment with magnesium in ether at −10 °C
afforded the Grignard reagent which was immediately reacted with the 3,4,5-
trimethoxybenzaldehyde to obtain a 1:1 mixture of cis/trans benzylic alcohols. Oxidation
with IBX cleanly afforded the ketone 154 that was stereoselectively reduced with sodium
borohydride to obtain predominantly the anti alcohol 155 (anti:syn ≤ 20:1) confirmed via
1H NMR. Mitsunobu inversion followed by hydrolysis of the ester afforded syn alcohol
156, which was subsequently protected as silyl ether with TBDMS-Cl in good yield using sodium hydride in THF at −15 °C to obtain the desired aryl alkene 157 (Scheme 4.8).
51 1. Mg, ether, 1,2-dibromoethane O o o MeO 1. LiAlH4, THF, 0 C, 89% N2, −10 to 0 C, 76% OH Br 2. PBr , ether, −25 oC, 69% O 3 2. 3,4,5-trimethoxybenzaldehyde, MeO THF, −78 oC, 5 h, 97% (crude) 153 OMe 152 3. IBX, ethylacetate, DMSO(cat), 154 55 oC, 4 h, 88%
1. p-nitrobenzoic acid, PPh , OH 3 OH NaBH , MeOH, 0 oC, THF, then DIAD, 10 h, 4 MeO −78 oC, 85% MeO 0 to 25 oC, 90%
MeO 2. K2CO3, MeOH:H2O (9:1 v/v) MeO 25 oC, 3 h, 95% OMe 155 OMe 156 anti:syn <20:1 (by 1H NMR)
OTBDMS NaH, THF, −15 oC, 20 min MeO then TBDMS-Cl, −20 to 25 oC 24 h, 65% MeO OMe 157
Scheme 4.8 Synthesis of the alkene coupling partner for B-alkyl Suzuki−Miyaura
The alkene 157 was treated under one-pot B-alkyl Suzuki−Miyaura conditions63 with the aryl bromide 158 to obtain the 1,4-diaryl butane 159 in good yield (70%). The alkene was first hydroborated with 9-BBN at 0 °C and was warmed up to room temperature overnight. The formation of the alkyl-borane complex was confirmed by
TLC. This mixture was cannulated under nitrogen into a flask containing the aryl bromide 158, triphenylphosphine, finely crushed NaOH dissolved in minimum volume of water, and the palladium catalyst and was heated at 65 °C for 12 h. The 1,4-diaryl butane
52 adduct 159 was purified as a colorless solid and was crystallized from hot hexane. Single
crystal X-ray analysis confirmed our prediction about the relative stereochemistry of C7-
C8 methyl groups (Scheme 4.9). [X-Ray crystallographic data for 159 is provided in the
experimentals (Coleman 1211)].
OTBDMS TBDMSO 9-BBN, THF, 0 oC, Br MeO 7 0 to 25 oC, 12 h 6 8 MeO 7 6 8 + MeO Pd(PPh3)4, PPh3 MeO BnO OMe aq. NaOH, THF, 0 oC OMe BnO OMe OMe OMe then 65 oC, 12 h, 70% OMe 157 158 159
Scheme 4.9 Examining diastereoselectivity for the Suzuki−Miyaura coupling
After successfully verifying the diastereoselectivity of the Suzuki−Miyaura reaction in the C6-C7 syn-system, we further proved our interpretation via a hydroboration-oxidation reaction sequence in the C6-C7 anti-system 150 to cleanly afford 160. In both cases we were pleased to observe the emerging relative stereochemistry at the C7-C8 positions to be anti. The alcohol was crystallized from hexane (Scheme 4.10). [X-Ray crystallographic data for 160 is provided in the experimentals (Coleman 1106)].
53 TBDMSO TBDMSO o MeO 7 1. 9-BBN, THF, 0 to 25 C MeO 7 OH 6 8 6 8
o MeO 2. NaOH, H2O2, 0 C, 91% MeO OMe OMe 150 160
Scheme 4.10 Examining diastereoselectivity for hydroboration-oxidation
4.5 Suzuki−Miyaura followed by regioselective bromination
Hydroboration of alkene 147 with 9-borabicyclononane (9-BBN) occurred with complete diastereofacial selectivity to afford an intermediate trialkylborane, which was coupled in situ with aryl bromide 128 under standard Suzuki-Miyaura coupling conditions62,63,68,87 to afford the 1,4-diarylbutane 161 (70%). Initially, it was unclear whether the bromination of the newly installed aromatic ring of 161 could be achieved with regioselectivity (i.e., ortho to the benzyloxy group in 161). Consequently, the benzyloxy compound 161 was used to take advantage of the established ortho-directing effect of a phenolic hydroxyl group (Scheme 4.11).88 Hydrogenolysis of the benzyl ether
161 (MeOH, 25 °C, 5 h, 82%) afforded the corresponding phenol 162, which underwent facile bromination with complete regioselectivity (dioxane, 18 °C, 12 h, 85%) to afford
163. Methylation of 163 (Me2SO4, K2CO3, acetone, 55 to 60 °C, 3 h, 85%) provided 164.
54 TBDMSO TBDMSO
MeO 9-BBN, THF MeO Pd/C, H2(balloon) Br 4 h, MeOH, 82% MeO Br ,Pd(PPh3)4, PPh3, NaOH MeO Br OMe OMe O OBn O OBn 147 O O 128 161
TBDMSO TBDMSO TBDMSO Me2SO4, MeO MeO NBS, dioxane, MeO K2CO3,
o Br acetone, Br 18-20 C, 85% MeO Br MeO Br MeO Br reflux, 85% OMe OMe OMe OH O OMe O OH O O O O 162 163 164
Scheme 4.11 Initial regioselective bromination approach, directing effect of -OH
However, it was subsequently established that the regioselective bromination with
NBS could be achieved with complete regio-control (CHCl3, 22 °C, 5 h), ortho to the
methoxy group of 165, which significantly shortened the route to the 1,4-diarylbutane-
dibromide 166. It is probably because of the steric factor of the bulky tert-
butyldimethylsilylether protecting group close to the trimethoxybromobenzene ring, due to which the bromination does not occur in that ring (Scheme 4.12).
55 TBDMSO TBDMSO MeO 9-BBN, THF MeO Br
MeO Br ,Pd(PPh3)4, PPh3, NaOH MeO Br OMe OMe O OMe 147 165 O OMe O O 126 TBDMSO MeO NBS, CHCl3, Br 18-20 oC, 85% MeO Br OMe O OMe 164 O
Scheme 4.12 Modified regioselective bromination attempt, directing effect of -OMe
4.6 Oxidative cuprate biaryl cross-coupling
Of particular concern in the present case was the issue of atropdiastereoselection
in the key intramolecular biaryl coupling. Tobinaga and co-workers89 have reported that oxidative aryl-aryl coupling of 1,4-diarylbutanes bearing stereogenic centers in the
aliphatic tether results in significant diastereoselection, but in extremely low yields
(5−36% with 85:15 diastereoselection). In the later study, this same group90 reported a
similar oxidation, mediated by Fe (III) salts, to proceed with 4:1 diastereoselection in
36% yield. In a related work, Coleman and co-workers91 observed an 8:1
atropdiastereoselection in the formation of the key biaryl bond during the course of the
total synthesis of calphostin A. In the present case of gomisins, the conformation about
56 the carbon−copper−carbon bond of an intermediate biaryl cuprate will depend most importantly on the conformational biases of the four-carbon tether of the 1,4-diaryl butane system. It was presumed that the relative configuration of the stereogenic center(s) in the butane tether (as in 166) would control the sense of stereoinduction about the stereogenic biaryl axis during the biaryl bond formation.
The initial attempts while carrying out this reaction faced a few hiccups. The
Lipshutz oxidative coupling attempts with 1,3-dinitrobenzene at −40 °C and with oxygen at −78 °C resulted in replacement of the aryl bromides with hydrogens affording 167, resulting due to protodecupration. This observation perhaps hinted us to the fact that we were probably quenching the reaction too early and needed to further lower the temperature for efficient reductive elimination of the copper(II) species (Scheme 4.13).
OTBDMS 1. (a) t-BuLi, MeTHF, −78 oC OTBDMS MeO cannulated to CuCN in MeTHF MeO warmed −78 to −40 oC, 1 h Br H MeO Br (b) 1,3-dinitrobenzene, −40 oC MeO H OMe −40 to 25 oC, 12 to 16 h, 56% OMe O OMe O OMe OR O o O O2 , −78 C, 3 h, 26% 166 167
Scheme 4.13 Unsuccessful biaryl oxidative Lipshutz cross-coupling attempt
57 Consequently, in the following attempt, after ensuring the formation of the
cyanocuprate at −40 °C, the temperature of the reaction mixture was lowered down to
−120 °C before bubbling oxygen via a sintered glass frit tube, in order to avoid
protodecupration after work-up. The temperature was manually maintained around −120
°C for 5 h (via periodic addition of liquid N2 and pentane to the cooling mixture) when
the whole reaction mixture was observed to turn dark brown. The reaction mixture was
quenched around −40 °C with saturated aqueous NH4Cl. The oxidation was found to
proceed smoothly under these conditions with an overall yield of 40%, and a 1:2 mixture
of two atropisomers 169 and 170 were isolated from the reaction mixture (Scheme 4.6.2).
1,3-dinitrobenzene was not found to be effective in this case as an oxidant.
Upon deprotection of the silyl ethers of 169 and 170 (THF, TBAF, 55 °C, 5 h), the minor stereoisomeric product 6 gave identical 1H and 13C NMR spectral data with that
reported for gomisin O (6) and thus must possess P absolute configuration about the
stereogenic axis. Again, the C4-H and C11-H protons were diagnostic of the relationship
between between the C6-stereogenic center and the biaryl stereogenic axis. When the
absolute configuration of C6 is R, as in 6 and 171, the C4-H and C11-H protons
resonated with chemical shifts Δδ = 0.14 ppm in the Paxial (Pax) diastereomer 6 and by Δδ
= 0.50 ppm in the Maxial (Max) diastereomer 171, or opposite to the system with C6
stereogenic center in the S configuration (Scheme 4.14). Hence, it was inferred from the
above observations that in this key biaryl coupling, the C6 stereogenic center seemed to
be the determining element in controlling the relative configuration of the emergent
incipient biaryl axis.
58 MeO MeO O o OTBDMS O t-BuLi, MeTHF, −78 C, MeO MeO OTBDMS TBDMSO Ar, 30 min R R o 6 6 MeO 7 CuCN, MeTHF, −40 C, 2 h MeO MeO 6 8 OMe 7 + 7 MeO 8 MeO 8 Br o o O2, −125 C to −120 C, 5 h, MeO Br o saturated aq. NH4Cl, −30 C, O O OMe 164 39% (total yeild) O O 169 Pax 170 Max
Paxial : Maxial = 1 : 2 o 96% TBAF, THF, 55 C, 5 h 86%
MeO MeO H 4 OH 4 H MeO MeO OH R R MeO 6 6 7 MeO 7 MeO 8 MeO 8
O O 11 H 11 H O O Pax Max gomisin O unnatural atropisomer of gomisin O 6 171
C4-H = δ 6.43 ppm C4-H = δ 6.42 ppm C11-H = δ 6.57 ppm C11-H = δ 6.92 ppm Δδ=0.14 ppm Δδ=0.5 ppm
Scheme 4.14 Formation of natural and non-natural atropisomers of gomisin O
Enlightened by the above observations, we set our goals to make this intramolecular higher-order cuprate, oxidative biaryl cross-coupling reaction atropdiastereoselective, and thereby exclusively obtain gomisin O (6). Deprotection of the silylether protecting group in 164 followed by PCC oxidation allowed us to obtain the benzylic ketone 172, which was subjected to stereoselective reduction by sodium borohydride and subsequently reprotected with tert-butyldimethylsilylether to afford the
6,7-anti/7,8-anti diarylbutane 173. Lipshutz coupling of this system, under the above
59 mentioned conditions, provided a single atropdiastereoisomer 5 in 39% yield (Scheme
4.6.3). Upon deprotection of the silyl ether (TBAF, THF, 55 °C, 4 h), the product 5 provided 1H NMR spectral data identical with that reported for gomisin E (epigomisin
O). Mitsunobu inversion using p-nitrobenzoic acid92 (THF, 0 to 25 °C, 12 h) with subsequent saponification of the inverted ester (methanolic KOH, 25 °C, 10 h) provided gomisin O (6) in excellent yield for the two-step conversion. By this route, gomisin E and gomisin O were synthesized in ten and twelve steps respectively, from the aromatic precursors 126 and 160 (Scheme 4.15).
O O O O TBDMSO O 1. TBAF, THF, 55 oC, 4.5 h, 96% MeO MeO OMe OMe o Br 2. PCC, CH2Cl2, 25 C, 10 h, 93% Br MeO Br MeO Br OMe 164 OMe 172 O O t-BuLi, MeTHF, −78 oC, Ar, 30 min RO CuCN, MeTHF, −40 oC, 2 h MeO NaBH4, CH2Cl2:MeOH (1:1 v/v), OMe o o O2, 5 h, −125 C to −120 C (liq. N2/pentane) 85% Br o MeO Br saturated NH4Cl, −30 C, 39% (total yeild) OMe R = H (166) TBSOTf, 2,6-Lutidine, −78 to 25 oC, 4 h, 98% R = TBDMS (173) O MeO MeO MeO OTBDMS OH O MeO MeO MeO S p-nitrobenzoic acid, o S R 6 TBAF, THF, 55 C, 6 Ph P, DIAD, THF, 6 NO2 MeO 7 MeO 3 MeO P P P MeO 8 MeO MeO 4 h, 79% 0 to 25 oC, 12 h, 91% O O O O 174 O 5 O 129 epigomisin O mitsunobu ester of 3M methanolic KOH, epigomisin O gomisin O (6) 25 oC, 10 h, 98%
Scheme 4.15 Modified route to the synthesis of epigomisin O and gomisin O 60 It is worth mentioning that the C6/C7-anti and C7/C8-anti silyl ether 173 was
later made from the corresponding alkene precursor 148 in two steps, when it was
discovered that 173 would atropdiastereoselectively afford gomisin O (6) (Scheme 4.16).
TBDMSO TBDMSO o 9-BBN, THF, 0 to 10 C, 12 h MeO NBS, CHCl3, MeO 7 7 6 8 148 6 8 126 ,Pd(PPh ) , PPh , 18-20 oC, 85% Br 3 4 3 MeO Br MeO Br NaOH, THF, 70 oC, 28 h, 61% OMe OMe O OMe O OMe 168 O 173 O
Scheme 4.16 Anti/Anti silyl ether 173 from corresponding C6/C7 anti-alkene 148
Hence, with 6S configuration as in 173, the emergent stereogenic axis is Pax and the coupling rection occurs with complete atropdiastereoselectivity. However, when this center is 6R as in 164, the emergent axis is formed with essentially no diastereoselectivity and the major diastereoisomer possess the Max configuration (1:2 Pax/Max). However, we
have not performed biaryl coupling reactions on the complete series of diastereomeric
1,4-diarylbutanes, so more subtle effects may be evident when the other stereogenic
centers are altered in relative configuration.
It is assumed that this stereogenic center affects the chirality of the intermediate
diarylcuprate prior to the reductive elimination step. However, at this point of time we
61 lack the detailed knowledge of the structure of this intermediate. It is difficult to provide
a detailed speculation about the origin of diastereoselectivity.
4.7 Attempts towards synthesis of gomisin N from gomisin O
After successful completion of the synthesis of gomisin O, we investigated a few
routes towards the synthesis of gomisin N, which is gomisin O or epigomisin O without
the hydroxyl group. Gomisin O was treated with triethylsilane and trifluoroacetic acid93,94
(CH2Cl2, reflux, 2 d, 80%) for ionic deoxygenation. However, the trifluoroacetic acid group could not be removed. Hydrolysis of the trifluoroacetate ester 175 with LiOH
returned gomisin O (6) (Scheme 4.17).
O MeO MeO OH O CF3 MeO MeO R R 6 Et SiH, CF CO H, CH Cl 6 MeO 7 3 3 2 2 2 MeO 7 P P MeO 8 MeO 8 0 to 50 oC, 2 d, 80% O O O 6 O 175 gomisin O
Scheme 4.17 Attempt by the ionic deoxygenation method
62 A chemoselective reduction of the secondary alcohol in gomisin O was attempted
invoking the protocol of Baba and co-workers.95 Gomisin O (6) was treated with chlorodiphenylsilane and indium trichloride in 1,2-dichloroethane at 75 °C for 2 h. The product isolated (45%) was a rearranged [3.3.1] bicyclic product 176. These types of rearrangements have been observed in highly oxygenated and electron-rich dibenzocyclooctadiene systems (Scheme 4.18).
OMe MeO MeO OH MeO R o MeO 6 Ph2SiHCl, InCl3, 75 C, 2 h MeO 7 P MeO 8 HO 1,2-dichloroethane, 44%
O O O O 6 176
Scheme 4.18 Chemoselective reduction using Ph2SiHCl and InCl3
Further attempt using the Barton-McCombie radical deoxygenation96,97 route (O-
(p-tolyl)chlorothionoformate, Py, DMAP, CH2Cl2, 25 °C, 12 h followed by AIBN,
Bu3SnH, dioxane, reflux) also proved to be unfruitful, probably due to the sterics and the
stereoelectronics of the electron-rich dibenzocyclooctadiene system.
63 4.8 Conclusion
The total synthesis of dibenzocylcooctadiene lignans gomisins O and E were achieved in a convergent and efficient fashion. Starting from known aromatic systems, the natural products were produced in six to eight steps with complete control of absolute and relative stereochemistry. The key steps involved a novel indium-mediated methyl crotylation (a group effort of an asymmetric crotylation reaction using Leighton auxiliary to provide adducts with 97% ee), a diastereoselective hydroboration reaction coupled with an in situ B-alkyl Suzuki−Miyaura alkylborane coupling that occurred with ≥ 20:1 diastereoselectivity, the basis of which was proven by X-ray crystallographic studies, and an intramolecular oxidative higher order cuprate biaryl cross-coupling that was found to occur with complete atropdiastereocontrol.
64
CHAPTER 5
EUPOMATILONES: STRUCTURALLY NOVEL FLUXIONAL PLANT LIGNANS
5.1 Introduction
Eupomatilones 1-7 (Figure 5.1) were isolated by Carroll and Taylor in 1991 from the Australian shrub Eupomatia bennettii, and were found to co-occur with a structurally diverse set of related lignan natural products.98 The eupomatilones possesses the same
basic skeleton but differ in the degree of oxygenation of the biphenyl portion of the
molecule or in the substitution of the furanone ring. This family of plant natural products
is distributed throughout the producing plants, including the roots, stems, leaves, fruit,
and seeds.
65 O OMe OMe O MeO MeO
MeO MeO MeO O O O O O O MeO OMe MeO OMe O OMe OMe O eupomatilone 1 eupomatilone 2 eupomatilone 5 177 178 179
O O OMe O O O MeO O
MeO MeO MeO MeO O O O O O O O O MeO OMe MeO OMe O O OMe OMe O O eupomatilone-3 eupomatilone-4 eupomatilone 6 eupomatilone 7 180 181 182 183
Figure 5.1 Structure of eupomatilones
In the eupomatilone family of lignans, the dimeric β-cinnamic acid carbon skeleton has undergone an unprecedented rearrangement that involves cleavage of a carbon-aryl bond. Carrol and Taylor proposed that the spirocyclohexadienone skeleton of the eupodienone precursor 184 undergoes hemiketal formation to afford 185, which fragments to lactone 186 (Scheme 5.1).98 All six carbons of the side-chains of the
cinnamic acid precursors end up attached to one of the aromatic rings. The eupomatilones
are found to equilibrate about the biaryl axis, which is stereogenic for eupomatilones 5, 6
66 and 7. Two isomers are observed by both 1H NMR and 13C NMR for eupomatilones 5, 6
and 7. The hydrogens on the trimethoxyphenyl ring of eupomatilone 4 are diastereotopic
and slowly interconverting. The atropisomers are inseparable, and show a coalescence
temperature between 97-102 °C.99
HO O O O O O O–H O MeO MeO MeO MeO OMe OMe O O O 184 185 O O
O OMe OMe OH OMe 186
Scheme 5.1 Rearrangement of the dimeric lignan skeleton
5.2 Biological properties
The α-methylene-γ-lactone found in eupomatilones 1, 2 and 5, readily forms
covalent bonds to cellular proteins via Michael addition of bionucleophiles,100 especially with sulfhydryl-containing enzymes and other functional proteins.101 This produces
antigenic compounds within the cell, which are a cause of chronic actinic dermatitis
(CAD). The moiety is also reported to form [2+2] photoadducts with DNA base thymine 67 in the presence of sunlight, and hence its photochemical role is strongly implicated in
CAD. The α-methylene-γ-lactone moiety has also been shown to target the Iκβ kinase
(IKK) in addition to the transcription factor regulator nuclear factor kappaB (NF-κB),
signifying their potential role in the cellular signaling process.102 The ability of this unsaturated lactone functionality is significant as a physiologically important building block.103
5.3 Previous synthetic approaches to total synthesis of eupomatilones
There have been several synthetic approaches to the total synthesis of members of the
eupomatilone family, namely eupomatilones 2, 3, 4, 5 and 6. Herein, we will discuss a
few notable approaches to the synthesis of eupomatilones.
5.3.1 Gurjar’s approach to synthesis of eupomatilone 6
Gurjar and co-workers104 synthesis involved Sharpless Asymmetric
Dihyroxylation105 as the key step. They subjected the biaryl aldehyde 187 under
modified Wittig conditions to afford the α,β-unsaturated ester in a 85:15 mixture of E/Z
isomers, which was further subjected to the Sharpless conditions to obtain dihydroxy
derivative 189 in 80% yield. A series of standard transformations thereby afforded the
intermediate 193 that was all set for an intramolecular Horner-Wadsworth-Emmons
reaction using NaH in DME to provide the unsaturated-γ-lactone, which on
hydrogenation in presence of Rh/Al2O3 in ethylacetate gave 194 that was subsequently
68 found neither to be 5-epi-eupomatilone 6 or eupomatilone 6 (182) by NOE experiments.
It was later discovered by Coleman and Gurrala that he had actually made 3-epi- eupomatilone 6.106 Nevertheless, it was a fair attempt that perhaps needed a more careful realization about the probable stereochemical outcome (Scheme 5.2).
CO Et CO2Et 2 O HO O O (DHQD)PHAL, K2OsO4.2H2O OH Ph3P=CHCO2Et O
O 189 O CH2Cl2, rt, 3h O MeSO2NH2, K2CO3, tBuOH:H O= 1:1, 0 oC, 2 MeO OMe MeO OMe MeO OMe 18 h, 80% OMe OMe OMe 187 188 Two atropisomers by NMR, seperation by chiral HPLC was not successful
O O 1. TsCl, Et N, CH Cl MEMO 1. protection as O 3 2 2 1. LAH, THF, 0 oC isopropylidene O 2. MeOH, HCl, rt O OH 2. LAH reduction O 3. K2CO3, MeOH, 0.5 h O 2. PDC, CH2Cl2, 4 A Molecular 4. MEMCl, DIPEA, CH2Cl2 sieves MeO OMe MeO OMe 3. PPTS, tBuOH, 80 oC OMe OMe O 190OEt 191 P O O O OEt H O 1 3 HO O O o O (EtO) P(O)-CH(Me)-COCl O 1. NaH, DME, 0 C (H.W.E) O 2 5 H H O DIPEA-CH Cl O 2 2 O 2. Rh/Al2O3, H2, 60 psi, 20h MeO OMe MeO OMe MeO OMe OMe OMe OMe 194 192 193 1H NMR of 194 did not match (a) the natural product, OR (b) the 5-epi-eupomatilone 6 isomer
Scheme 5.2 Gurjar’s attempt to synthesize eupomatilone 6
69 5.3.2 McIntosh’s approach to synthesize eupomatilone 6
McIntosh and co-workers107 made a bis-allylic ester 197 from p-quinone
monoketal 196. Treatment of the allylic ester 197 with KHMDS and TMSCl gave a
sensitive vinyl epoxy acid 199 as (E)-anti stereoisomer going through an Ireland-Claisen
rearrangement via a chairlike transition state 198. Oxidation of phenol 201 with
PhI(OAC)2 afforded monoketal 202 that smoothly underwent Stille coupling with piperonyl tributylstannane to yield the tetracycle 203. This was converted via a series of transformations to 5-epi-eupomatilone 6 (207) as shown below (Scheme 5.3).
O O O
1. H2O2, K2CO3 Br O THF/H2O, 25% (E)-propenyl-Li, THF KHMDS, TMSCl O Br 2. Br2, NEt3, (EtCO)2O _ o O Et2O, 78 C to rt Hexane/Et2O 97% MeO OMe 85% MeO OMe 60% 195 196MeO OMe 197 O O O 3 3 Br 4 O HO O 4 HOAc O 5 H MeO H 80 oC, 86% Br OTMS Br 3' H Br MeO O O OH OH 198 OMe MeO OMe MeO OMe 200 201 199 O O 3 O 3 3 4 4 4 Pd2dba3-CHCl3, PPh3, O O PhI(OAc) O CuI, THF, 80 oC, 67% O O 2 5 DMDO, acetone, 5 H 5 H MeOH, 91% H O Br O CH2Cl2, rt, 55% O O O SnBu3 O O O MeO OMe MeO OMe MeO OMe 202 203 204
(Scheme 5.3 continued)
Scheme 5.3 McIntosh’s attempt to synthesize eupomatilone 6
70 (Scheme 5.3 continued)
O O O 3 3 4 4 O O O Mg, HOAc O O K2CO3, MeI O 5 5 H H H o Acetone, 80% rt to 80 C, 78% O O O
HO O HO OH MeO OMe MeO OMe OMe OMe 205 206 207 1:1 mixture of atropisomers 5-epi-eupomatilone-6
5.3.3 Buchwald’s approach to eupomatilone 3
Buchwald and co-workers made the first asymmetric synthetic attempt to the
family of eupomatilones.108 Buchwald subjected the aryl bromide 208 to biaryl
Suzuki−Miyaura coupling conditions to get the biaryl ester 210. The biaryl methylester
210 was subsequently converted to aldehyde 211, which was further subjected to
Knochel’s method109 for the synthesis of butenolides by the reaction of stabilized vinyl
Grignard reagent 212, in order to form the desired butenolide 213. The unsaturated
lactone 213 was asymmetrically reduced using a chiral copper-hydride catalyst110 to obtain lactone 214 that was enolized with NaHDMS followed by alkylation with iodomethane to produce synthetic eupomatilone-3 (180) (Scheme 5.4).
71 Br OMe OMe MeO MeO CO2Me Pd2(dba)3, S-Phos, MeO o CO2Me 1. BH .THF, THF, 60 oC CHO K3PO4, THF, 80 C 3 MeO MeO O 2. MnO2, CH2Cl2, rt MeO O MeO B(OH) 2 MeO O MeO O 208MeO 209 210 O 211 O
O O
EtO2C OMe OMe 212 MeO O Me MeO O Me CuCl . 2H O, MeO-BIPHEP ClMg Me 2 2 NaOtBu, PMHS MeO THF,_ 40 oC MeO tBuOH, THF, CH2Cl2, RT >46%; 87% ee MeO MeO O at 50% conversion stage O O No trans isomer detected O 213 214
O Me OMe 216 MeO O MeO PPh2 NaHDMS, THF Me = BIPHEP MeO PPh2 O oC, then MeI MeO S-Phos = PCy2 MeO OMe MeO O 215 O 180 Eupomatilone 3
Scheme 5.4 Buchwald’s asymmetric synthesis of eupomatilone 3
5.3.4 Coleman’s 1st generation synthesis via base-induced epimerization
Coleman and Gurrala’s synthesis of eupomatilone 6 (182) involved addition of tiglyl-indium reagent 146 to aryl aldehyde 137 and protecting the alcohol as TBDMS ether 218. Lipshutz methodology was implemented that involved low temperature formation of mixed biarylcuprate and oxidation to form the carbon−carbon biaryl bond to
72 form biaryl 219. Hydroboration-oxidation of the alkene followed by deprotection of the silyl ether 220 with TBAF and PDC oxidation afforded eupomatilone 6 (182) and 3-epi- eupomatilone 6 (222) (Scheme 5.5).
OMe In2Br3 R = H (217) MeO t-BuMe SiOTf 146 2 3 98% R = TBS (218) 137 92% MeO (95:5 syn : anti) Br OR OMe MeO OMe OMe MeO MeO MeO OH X OTBS 51% 1) 9-BBN, THF MeO X = Br MeO t-BuLi OTBS 2) H O , NaOH, OTBS X = Li 2 2 98% 220 CuCN 219 X = CuCNLi O O O O O OMe O MeO X = Br 1) PDC, 85% t-BuLi PDC, 90% X = Li MeO 2) n-Bu NF, 71% X 4 O OH 221 O OMe OMe O MeO MeO
4 4 3 MeO 3 MeO 5 5 + O O O O O O O O 3-epi-eupomatilone 6 (222) eupomatilone 6 (182)
Scheme 5.5 Coleman and Gurrala’s synthesis of eupomatilone 6
73
5.3.5 Kabalka’s approach to the racemic synthesis of eupomatilones 2 and 5
Kabalka and co-workers111 used carbomethoxyallyl bromide and carried out an allylation on the biaryl aldehydes 223 and 224 (precursors to eupomatilones 2 and 5) using powdered indium in a mixture of THF and water to obtain the corresponding homoallylic alcohols 226 which was subsequently cyclized under mild acidic conditions
(PTSA, DCM) to afford racemic eupomatilones 2 and 5 (178, 179) (Scheme 5.6).
Eupomatilone 5 was also later hydrogenated with 10% Pd/C with H2 in ethanol to obtain
Gurjar and Coleman’s 3-epi-eupomatilone 6 (222).
OMe OMe OMe CO2Me MeO MeO MeO O 225 Br MeO CHO MeO OMe PTSA, 10 mol% MeO OH O In, THF/H2O DCM, rt, 12 h (1:1), 2h O 2 2 R OR2 R OR R OR 1 1 OR1 OR OR 226 R = OMe, R1 = R2 = Me, R = OMe, R1 = R2 = Me, 68% (223) eupomatilone 2, 92% (178) 1 2 R = H, R = R = ⎯CH2⎯ , 70%, (224) 1 2 R = H, R = R = ⎯CH2⎯ , eupomatilone 5, 93% (179)
Scheme 5.6 Kabalka’s racemic synthesis of eupomatilones 2 and 5
74 5.3.6 Hall and Kennedy’s approach to eupomatilone 6 and all its unnatural diastereomers via tandem carbocupration strategy
Hall and Kennedy112 ventured on the construction of chiral quarternary carbon centers, one of the most difficult transformations in organic synthesis. Aldol-based methodologies are generally not applicable due to the lack of E/Z selectivity in the enolization of the α,α – disubstituted carbonyl compounds. Hall and coworkers formed 2- alkoxycarbonyl allylboronates by tandem carbocupration of alkynoate esters by electrophilic trapping with halomethylpinacol boronates. Using crucial combination of
HMPA as an additive and iodomethylpinacol boronate as the electrophile, several tetrasubstituted allylboronates were generated in high cis-addition selectivity.
Stereocontrolled syntheses of γ-lactones 232 were achieved when the crude cis- (228) or trans- (229) allylboronates were treated immediately with various aliphatic and aromatic aldehydes (Scheme 5.7).
227 1 R2 CuLn _ o R2 2 CO R' R COOR' THF > 30 C OR' R 2 C 2 _ o + (R )2CuLi 78 C 1 OCu 1 CuLn R1 CO2R R R
O B X O 2 X = Cl, Br, I R B(OR)2 R2 CO2R' + HMPA (additive)
1 1 R CO2R R B(OR)2 cis - addition trans -addition 228 229
(Scheme 5.7 continued)
Scheme 5.7 Hall’s stereocontrolled synthesis of γ-lactones 75 (Scheme 5.7 continued)
1. toluene, 80 oC, rt, 14d O (RO) BO CO R' O R3CHO 2 2 2. PTSA, rt, 4 h R2 B O 3 1 O R R 1 2 3 2 R1 CO2R R R R R (RO)2BOR' 230 231 232
Coupling this strategy with the hydrogenation of the exocyclic alkene, Hall and co-workers113 synthesized all four diastereoisomers of eupomatilone 6 (i.e. 3-epi-, 4-epi-,
3,4-epi-, and eupomatilone 6), two of which are represented below (Scheme 5.8).
O Br O MeO Suzuki H (1 atm) 3,4-epi- 2 eupomatilone 6 O Pd/C, EtOH MeO 235 O rt, 6h OMe MeO O Br O O B(OH) 137 MeO O 237 2 Bpin Br O 4-epi- TfOH (20 mol%) MeO Suzuki eupomatilone 6 toluene, 0 oC, 16 h 234 H2 (1 atm) MeO (>19:1 dr) OMe ClRh(PPh3)3 233 toluene, rt, 6 h (57%, >19:1 dr) MeO 236 OMe
Scheme 5.8 Hall’s stereodivergent synthesis of diastereomers of eupomatilone 6
76
CHAPTER 6
DEVELOPMENT OF ASYMMETRIC TOTAL SYNTHESES OF EUPOMATILONES
1, 2, AND 5
6.1 Introduction
Out of the many syntheses of eupomatilones reported so far, only Buchwald’s
synthesis was asymmetric. There have been many synthetic attempts towards the total
synthesis of eupomatilones 4 and 6; hence our plan was to synthesize eupomatilones 1, 2
and 5 in an asymmetric fashion. Herein, we will discuss a conceptually different asymmetric strategy for the construction of the lactone ring, which is attached to the highly oxygenated biaryl system. It is to be noted that the carbon that is incorporated as
the carbonyl of the lactone ring for eupomatilones 4 and 6 is the allylic carbon, adjacent to indium as in 238 (Coleman’s 1st generation synthesis of eupomatilones106), which subsequently undergoes a late stage oxygenation by hydroboration-oxidation reaction. In the case of eupomatilones 1, 2 and 5, the lactone carbonyl is directly incorporated from the existing carbomethoxy group of the chiral carbomethoxycrotyl organometallic reagent 239. The exo-methylene bond is formed from the methylene group adjacent to the boronate (Scheme 6.1).
77 Me Me Me In Ar Me Ar H 238 O O O ML* eupomatilone 4, 6 Me OMe Me Ar O Ar H 239 CH2 O O O eupomatilone 1, 2, and 5
Scheme 6.1 Carbomethoxycrotylation strategies to form the lactone ring
Herein, we will discuss the first asymmetric total synthesis of eupomatilones 2 and 5, each containing a fluxional biaryl axis and a γ-lactone bearing two stereogenic centers. An attempt at the asymmetric total synthesis of eupomatilone 1 will be discussed later in the chapter. A convergent general synthetic strategy was developed (Scheme 6.2) that was based on a Suzuki−Miyaura biaryl cross-coupling of 237 and 240, and an asymmetric carbomethoxycrotyl reagent to directly install the α-methylene-γ-lactone moiety on aldehyde 137 in an efficient and stereocontrolled manner. A major challenge in this strategy was to make 239 chiral, as well as stable. In addition, how to provide efficient enantioselection in the addition of this reagent to the electron-rich aldehydes was a question we needed to find an answer.
78 OMe MeO OMe HO OH Suzuki-Miyaura MeO B MeO + O Cross Coupling MeO O O Br O O O 240 O 237 O eupomatilone 5 (179) Asymmetric crotylation O OMe OH ML* MeO OMe Baylis 1,3-allylic COOMe + Hillman rearrangement + CO2Me MeO CHO CH3CHO 241 239 137 Br
Scheme 6.2 Retrosynthetic analysis of eupomatilone 5
6.2 Initial attempt to synthesize carbomethoxycrotyl reagent via organosilicon route
Our initial attempt to synthesize a chiral carbomethoxycrotyl reagent targeted the
silane version of 239, using the Leighton’s chiral diamine strategy,84,85 which we had
successfully applied in the asymmetric total synthesis of dibenzocyclooctadiene lignans.25
Hence, we performed a Baylis-Hillman114 reaction of acetaldehyde and methylacryate
that afforded the allyl alcohol 241. This was further treated with NBS and
dimethylsulfide in dichloromethane115,116 to obtain the corresponding allyl bromide 226
via a 1,3-allylic rearrangement. However, in our efforts to make the corresponding
carbomethoxy trichlorosilane, we observed a 5:4 inseparable regio-isomeric mixture of
79 the trichlorosilanes 242 and 243 (Scheme 6.3) observed via 1H NMR of the crude. This
was presumably formed via an allylic rearrangement under the reaction conditions that
required copper chloride as a catalyst. Purification of the trichlorosilanes, using
distillation under reduced pressure (>200 °C, 0.1 mm of Hg), only afforded the mixture
of the trichlorosilanes 242 and 243. All attempts to preferentially crystallize one of the regioisomers of the targeted chiral silane reagent 245 using Leighton’s chiral diamine
strategy also proved to be an exercise in futility (Scheme 6.3).
O OH CH3CHO, DABCO (100 mol%) NBS, Me2S, CH2Cl2 CO2Me CO2Me OMe 1,4-dioxane-H2O (1:1 v/v), rt o 0 C to rt, 24 h, 87% Br N2, 20 h, 85% 241 226
SiCl CuCl (0.1 eq), HSiCl3 (1.1 eq) 3 + i-Pr2NEt (1.1 eq), reflux, ether, Ar, 30h CO2Me Cl3Si CO2Me (other amines tried: Et3N, n-Bu3N) 242 243 5 : 4 inseperable mixture of isomers Br (ratio from 1H- NMR) DBU, CH Cl , Ar, 0 oC to rt, 12 h 2 2 crystallization attempt failed, X and the desired reagent 245 Br N Cl could not be detected CO Me Si 2 N NH 244 245 NH Br
Br
Scheme 6.3 Attempt using Leighton’s chiral diamine route
80 The notion for the development for the new carbomethoxycrotyl organosilicon
reagent for asymmetric induction was based on the literature precedence by Kobayashi117 and Itoh.118 They had used an unsubstituted allyl bromide 246 (Scheme 6.4), to form an
alkylidene carbomethoxycrotyl trichlorosilane intermediate 247, while synthesizing an α- methylene-γ-lactone moiety. Their problem of allylic isomerization was nullified due to the absence of the β-methyl substitution with respect to the carbomethoxy group in 246.
CO Me 2 HSiCl CO Me RCHO OH CO2Me Br 3 2 SiCl 3 o R Cat. CuCl, i-Pr2NEt DMF-CH3CN, 0 C 246 Et2O, reflux 247 248
Scheme 6.4 Organosilicon promoted reaction with aldehydes
A route to functionalized allyltrichlorosilane was also reported by Hoffman and
Rabe.119 They formed allyltrichlorosilane 250 as an intermediate that was quenched with
8 equivalents of methyllithium to give, in a highly convergent step, the desired allylsilane
251 (Scheme 6.5). This one-pot reaction was not optimized and proceeded with only 42%
yield.
81 Br SiCl3 SiMe3 HSiCl , NEt O 3 3 O excess HO HO HO OMe CuI MeLi OH 249 250 OMe 251
Scheme 6.5 A route to functionalized allylsilanes
6.3 Further attempts with organoboron chemistry
The unsuccessful attempts with organosilicon chemistry, directed our attention
into organoboron chemistry. In our total synthesis of gomisins,25 we had made
stereodefined tiglyl Grignard reagent (from corresponding tiglyl bromide) at low
temperature. In the next step, we had transmetallated from magnesium to boron by
treatment with (−)-(Ipc)2BCl, to form the Brown’s diisocampheylborane reagent. We had
observed poor diastereoselectivity but we were able to achieve good enantiomeric excess.
Hence, we invoked Brown’s chlorodiisopincampheyl borane strategy120 once again, in
our quest for making a chiral carbomethoxycrotyl reagent for reaction with an electron-
rich aldehyde.
The allylic bromide 226 was treated with Knochel’s i-PrMgCl· LiCl109,121 at −78
°C, and was gradually warmed up to –20 ºC to form the Grignard reagent. This was cooled back down to –78 ºC to add (−)-(Ipc)2BCl, in order to form the desired Brown’s
diisopinocampheylcrotylborane reagent. After the reaction mixture was gradually
warmed up to 0 °C, the crude 1H NMR and 11B NMR analysis revealed an almost 82 exclusive (>95%) formation of the undesired 1,3-allylic rearranged carbomethoxy
crotylborane species 252 (Scheme 6.6).
i-PrMgCl.LiCl, −78 oC to −20 oC, 10 h CO2Me o then, (−)-(IPc)2B-Cl, −78 C to RT, 6 h MeO2C B(IPc)2 Br 226 252
Scheme 6.6 Attempt using Brown’s chlorodiisopinocampheyl borane route
Inspired by the contributions of Soderquist and co-workers,122,123 we attempted to
modify their version and synthesize the required chiral (E)-carbomethoxycrotyl reagent
253 once again. The carbomethoxyallyl bromide 226 was treated with i-PrMgCl·LiCl
under Knochel’s conditions,109,121 followed by the addition of Soderquist’s air-stable crystalline pseudoephidrine borinic ester complex of of 10-trimethylsilyl-9- borabicyclo[3.3.2]decanes [(+)-R] (254). Unfortunately, the intermediate 253 obtained in this case was once again almost exclusively the undesired 1,3-allylic rearranged carbomethoxycrotyl borane, which was confirmed by 1H NMR and 11B NMR analysis of
the crude reaction mixture (Scheme 6.7).
83 o o i-PrMgCl.LiCl, −78 C to −10 C,10 h Me3Si B CO2Me CO2Me then, (+)-R-borane,−60 oC to −20 oC, Br THF, 24 h Ph 226 253 (predominant intermediate NHMe from 1H and 11B NMR) B (+)-R = Me3Si
254
Scheme 6.7 Attempt for chiral carbomethoxycrotyl reagent via Soderquist’s route
6.4 Attempt with nucleophilic boryl-copper species
The previous unsuccessful attempts with allyl bromide and the problems faced
due to the 1, 3-allylic rearrangement, prompted us to examine allylic acetates,124 and use diboranes to generate boryl-copper species as intermediates thereby harnessing the 1, 3- allylic rearrangement to our advantage.
6.4.1 Generation of Miyaura−Hosomi’s nucleophilic boryl-copper
Studies by Miyaura,125 Hosomi,126 Takahashi127 and co-workers on boryl-copper
species gave an interesting direction for the generation of carbomethoxy allylboronates.
The addition of bis(pinacolato)diboron to α,β-unsaturated esters, ketones and nitriles or
terminal alkynes and the coupling with allyl chlorides were carried out in DMF at room 84 temperature in the presence of CuCl and KOAc to yield the corresponding organoboranes
in 49-90% yield. The transmetalation between diboron and [Cu(Cl)OAc]K generating
boryl-copper species was proposed to be the key step in the reaction, because CuOAc
similarly mediated both addition reactions to enones and alkynes in the presence of LiCl.
Results on the study of B─B bond cleavage by NMR at hourly interval suggested that the
transmetalation to yield the boryl copper species 255 took around 8 h at room temperature. In summary, the generation of nucleophilic boryl-copper species from diboron provides a new access to β-boryl carbonyl compounds via conjugate addition reactions, using a simple experimental procedure of using CuCl and KOAc in DMF
(Scheme 6.8). Lithium chloride when added as an additive was found to enhance the net yield of the reaction by almost 10%.
CuCl + KOAc
pinB-Bpin O Cl Cu OAc K B Cu KCl O 255
CuOAc + KCl Cu KCl O O O O B B B Cu KCl + B OAc O O O O OAc 255 256
O O H O B Cu KCl Z 2 O B O Z = COR, CO2R Z
Scheme 6.8 Nucleophilic boryl-copper species & conjugate addition reactions
85 6.4.2 Ramachandran’s application of Miyaura-Hosomi’s boryl-copper chemistry
Ramachandran and co-workers128 working on allylboration methodology had
applied the Miyaura conditions of 1,4-addition of nucleophilic boryl copper generated in
situ from diboronates to simple α,β-unsaturated carbonyl compounds (Scheme 6.9).
O
OAc O Ph CuCl, LiCl, KOAc, DMF O Ph B pinB-Bpin, rt, 92% O 257 258 E:Z = >95:<5
110 oC pTSA O 24 h rt, 8 h O O O In(OTf)3, 20% 258 + O rt, 6 h Ph H Yb(OTf) Ph 3 Ph trans- cis- 259 rt, 36 h 260
Scheme 6.9 Ramachandran’s application of boryl-copper to form lactones
They reported that strong Lewis acids like In(OTf)3 and Sc(OTf)3 provided trans- stereochemistry 259, whereas weaker Lewis acids, such as ZnCl2, Yb(OTf)3, Et3B and
TiCl4 provided cis-stereochemistry 260 (Scheme 6.4.2) with 90-93% diastereoselectivity
129 on treatment with benzaldehyde. On selection of In(OTf)3 for crotylboration on a series
86 of monosubstituted aldehydes, Ramachandran and co-workers also observed that the
reversal of stereochemistry of a lactone ring was dependant on the electronic environment
of the aldehydes as well. While an electron-donating substituent on the benzene ring
inverted the stereochemistry, an electron-withdrawing group provided the cis-lactone
260. The postulated catalytic cycle for the trans-lactone 259 formation is depicted below
(Scheme 6.10).
O B LA O O CO2Me O O O B LA O O OMe H R' + B O O R +R R = EDG, H, OMe, Me, Br, Cl
CO2Me O LA OMe R R' R' R R O O B OMe + O O R' O O trans-lactone R' Me O B O O LA
Scheme 6.10 Postulated catalytic cycle for trans-lactone formation129
87
6.5 Progress toward asymmetric synthesis of eupomatilones 2 and 5
In essence, from Ramachandran’s results, we realized that Lewis acid catalyzed carbomethoxycrotylboration attempts might not exclusive afford absolute syn-selectivity that we needed for eupomatilones 1, 2 and 5. Our aryl aldehyde had three methoxy groups and bromine, thereby making the system extremely electron-rich. Hence, the outcome of diastereoselectivity of the lactone (cis- versus trans-) under Lewis acid catalysis would be unpredictable. Therefore, we persisted on trying out the thermal crotylboration conditions in the beginning.
Allylic rearrangement of the acetate 261 stereoselectively generated 233 (E:Z ratio = 95:5) via Miyaura’s boryl-copper chemistry (Scheme 6.11). Boronate 233 was subjected to thermal crotylboration conditions under argon in toluene for 3 days at
95−100 °C with 3,4,5-trimethoxybromobenzaldehyde 137 to obtain 262, the top half of eupomatilone 5, in good yield 82%. Synthesis of the pinacolato carbomethoxycrotylboronate reagent 233, by an alternate route (achiral version with boron), has also been reported by Hall and Kennedy112 by tandem carbocupration of alkynoate esters followed by electrophilic trapping with halomethyl boronates at low temperature using HMPA as additive. Hall and Kennedy have also synthesized 262 under
Lewis acid catalyzed conditions113 in their total synthesis of eupomatilone 6 (182).
88 OMe O O CO2Me MeO OAc BB CO Me 137 2 O O O B MeO Toluene, 3d, Ar, CuCl, LiCl, KOAc O Br O DMF, 5 h, RT, 91 % 95-100 oC, 82% O 261 233 262
Scheme 6.11 Synthesis of α-methylene-γ-lactones using achiral crotylboronate
Based on the success of the thermal crotylboration reaction with 3,4,5- trimethoxybromobenzaldehyde 137, attempts were directed towards developing a chiral carbomethoxycrotyl boronate for the asymmetric version of this reaction. Bis[(+)- pinanediolato]diboron was examined (Scheme 6.12) to obtain the chiral crotylboronate
263 in E:Z ratio of 95:5. A thermal one-pot crotylboration was attempted with aldehyde
137 that afforded 262 as a cis:trans mixture (6:1), although surprisingly with no enantioselectivity (er = 1:1).
OMe O O CO2Me B B MeO 137 O O B O 261 MeO CuCl, LiCl, KOAc, O Toluene, 3 d, Ar, DMF, 5 h, rt, 62% 95 to 100 oC, 81% Br O cis/trans = 6:1 O E/Z = 95:5 er = 1:1 263 262
Scheme 6.12 Synthesis of α-methylene-γ-lactones using chiral crotylboronate
89
Based on the above result it was realized that in order to enhance the
enantioselectivity in the thermal crotylborations, a more effective chiral
carbomethoxycrotyl boronate was required, where we can efficiently direct the approach of the aldehyde in the transition state. Villiéras and co-workers130 reported remarkable
enantioselectivity of the chiral allylboronate 264 to aldehyde addition. They interpreted
that the chiral allylboronate 264 must proceed through a classical compact transition state
in which boron is primarily co-ordinated to the carbonyl group of the aldehyde (Scheme
6.13). A few considerations were also mentioned by them based on the model that is
listed as follows:
1. The aldehyde approach was directed by the phenyl group (ring aromatic effect).
2. The stability of the transition state could be due to possible attractive interaction
between the aldehyde proton (which is greatly acidified by co-ordination to the
boron) and the eclipsed co-planar oxygen (which is generally more electron rich
due to the negative charge on boron).131
3. A boron-centered anomeric effect (n-σ* interactions) between the axial lone pairs
of the ring oxygen and the B-O=CH-R single bond.132
They reasoned that the increase in the enantioselectivity of this reagent was primarily due
to the increase of steric bulk and conformational strain of the chiral auxiliary.
90 O EtO C O R CHO CO Et 2 OH 1 O 2 O B B * R CO2Et O 1 H 264 265
R1 T.S R1= CO2Et, Et, (MeO)3Ph
Scheme 6.13 Villiéras’ reaction of chiral allylboronate with aldehyde
Hoffman and Herold133,134 however were the first to use a camphor-derived chiral auxiliary 267 for simple allylation reaction where a maximum enantiomeric excess of
86% was obtained (Scheme 6.14). Another example of a similar chiral auxiliary was also reported by Hall and Kennedy135 in their study of enantioselective additions with dual auxiliary allylboronates.
CH3 O OH OH B(CH2-C=CH2)3 1. RCHO OH O B R 2. N(CH2CH2OH)3 R= Me, Et, Pr, i-Pr, t-Bu, Allyl, Ph 266 267 268
Scheme 6.14 Enantioselective allylation by Hoffmann and Herold 91 Assimilating the above informations, we directed our attention in merging
Hoffmann’s chiral auxiliary concept and Miyaura−Hosomi’s boryl-copper concept in order to efficiently synthesize our desired carbomethoxycrotylboronate reagent, thereby implementing the diborane chemistry into good use. The new diborane reagent 272
would be a dimer containing Hoffman’s camphor-derived diol 270 (Scheme 6.5.5), but its
stability as a reagent was yet to be perceived.
Accordingly, (+)-R-camphorquinone 269 was reduced with L-selectride136 followed by the addition of the phenylcerium reagent in situ to obtain Hoffman’s camphor derived diol 270 in 60% yield. Diol 270 was subsequently subjected to treatment with tetra(pyrrolidino)diborane 271 in freshly distilled benzene with freshly prepared 3N HCl in ether137 and was allowed to stir for 6 h at room temperature. Air-
stable colorless crystals of the diborane reagent 272 were obtained, which were
recrystallized from hexane (Scheme 6.15). This reagent was later subjected to Miyaura’s
boryl-copper protocol to obtain the desired chiral carbomethoxycrotyl boronate 273,
albeit with low yield (25%). This low yield could be attributed to the fact that the oxidative insertion of copper into the boron−boron bond, during the formation of the boryl-copper intermediate (like 255) (Scheme 6.8), is sterically hindered owing to the steric bulk of the phenyl groups and the quaternary methyl groups in the transition state.
However, crotylation of this reagent with aldehyde 137 resulted in completely cis- selective reaction with a moderate enantioselective ratio of 77:23 (reverse phase HPLC,
Chiralpak AD-RH, i-PrOH−H2O 1:1, flow rate = 0.35 mL/min, λ = 254 nm, injection
volume = 20 µL). The diborane reagent was found to be sparingly soluble in DMF at
room temperature. The reagent was found to dissolve slowly upon gently heating the
92 DMF mixture with a heat gun. A THF/DMF mixture (1:1 v/v) was made to dissolve the diborane reagent at room temperature, but that resulted in a complete shut down of the reaction altogether. This observation corroborated to the fact that boryl-copper reactions favorably occur only in highly polar solvents.125,127
1) L-Selectride, THF 2) PhMgBr, CeCl , O 3 OH 0 to 25 oC, 3.5 h 3N HCl, Ether OH 3) NaOH, H2O2, 3 h, O o 269 0 to 25 C, 60 % 270 N N (overall yield) BB N N
271 O O Benzene, 25 oC, O B B O 6 h, 81% CuCl, LiCl, 272 KOAc, 261, Air stable DMF, 48 h, colorless crystals 25 oC, 25%
OMe MeO O 137 O B Toluene, 95 oC, MeO CO2Me 3d, 78% Br O 273 262 O 100 % cis-isomer er = 77:23
Scheme 6.15 Asymmetric crotylboration of monoaryl aldehydes with the new
diborane reagent 272 using Miyaura’s boryl-copper chemistry
93 The justification for a better stereo-induction via Hoffmann’s camphor derived
auxiliary is adapted from the model proposed by Villiéras and co-workers130 (Scheme
6.16). The trimethoxybromobenzaldehyde 137 was directed from one face of the phenyl group. The orientation is likely governed by the stereoelectronics and steric hindrance of the system due to reasons mentioned above.
‡
O O δ− O O CO2Me O B B CO2Me O O O Br H H δ+ Br Br OMe
OMe MeO OMe OMe MeO MeO OMe OMe 262 aldehyde-boronate complex
Scheme 6.16 A model for the stereoinduction based on model by Villiéras, et al.
The poor yield of the camphor-derived carbomethoxycrotyl reagent 273 via the diboron route, however, led us to delve further into the modification of the chemistry, in order to make the process more efficient and high-yielding. We chose to apply
Molander’s138,139 and Hutton’s140 trifluoroborate chemistry to our advantage. The
pinacolylboronate 233 was converted to its corresponding trifluoroborate salt 275, which
94 was re-crystallized from hot acetone and ether to afford 275 in ≥ 95:5 E:Z diastereomeric
ratio. This was further subjected to hydrolysis with LiOH (1:2 = H2O:CH3CN, 20 h, 25
°C) and was trans-esterified in situ with catalytic amount of 1N HCl and solid ammonium chloride, with dropwise addition of diol 270 in ether, to afford close to 70% overall yield of 273 in three steps starting from the acetate 233 (Scheme 6.17).
LiOH aq. KHF2, MeOH, CO2Me CO2Me 233 o 25 C, 20 min, 80% BF K H2O:CH3CN = 1:2 3 o B(OH)2 275 20 h, 25 C
137 NH4Cl, 1N HCl O 262 O 95 oC, 7d, toluene diol 270, Et2O B o er = 77:23 3 h, 25 C, 96% CO Me 2 65 oC, 14d, toluene 273 er = 83:17
Scheme 6.17 Generation of the carbomethoxycrotylboronate via trifluoroborate and
trans-esterification
The enantiomeric ratio of the product after crotylation with aldehyde 137 was
found to be a modest 77:23 at 95 °C. Lowering the reaction temperature to 65 °C led only
to a slight increase of the enantiomeric ratio to 83:17. This implied that the reaction
temperature had a very small effect on the difference in energies of the transition states.
95 The reaction rate was found to be extremely slow below 50 °C (65% brsm, after 16 days
at 65 °C). Addition of Sc(OTf)3 as Lewis acid to enhance the rate of the reaction did not
have any appreciable effect on our system.141 Imbibing inspiration from Villiéras and co-
workers’ Zimmerman-Traxler type transition state model, we extrapolated our logic to
the transition state involving a biaryl aldehyde. We shifted our focus on enhancing the
stability of the transition state, without invoking any Lewis acid chemistry. We thought
of making the transition state more compact and rigid by introducing some non-covalent
stabilizing factors. It was envisioned that an “edge-to-face” aromatic CH−π type interaction142 might induce the desired result. Edge-to-face aromatic interactions and
CH−π interactions143 have been invoked in stabilizing certain protein folding motifs in literature by Burley and Petsko.144-146 We therefore, thought of a model as depicted below
(Figure 6.1).
O δ− O B CO2Me
O MeO δ+ δ+ H MeO H MeO MeO δ− MeO H OMe An Edge-to-Face Interaction MeO MeO OMe An Edge to Face Aromatic C-H π interaction
Figure 6.1 Enhanced stability in the transition state on crotylation with an electron-
rich biaryl aldehyde 96
Having this well conceived notion in mind, the asymmetric thermal
crotylboration was attempted on electron rich biaryl aldehydes that were precursors to
eupomatilones 2 and 5. To our delight, we observed much better enantioselectivity (er =
88:12 and 87:13 respectively), for the natural products (Scheme 6.18). The 1H NMR
spectrum of synthetic eupomatilones 2 (178) and 5 (179) were identical with that reported
for the natural product. This level of enantioselection was the maximum observed in this
work.
O
O B 273 CO2Me OMe CHO CHO OMe OMe MeO MeO MeO OMe MeO O MeO OMe O MeO OMe 223 MeO OMe 224 MeO O O O 75 oC, 8 d, toluene 75 oC, 7 d, Ar, toluene O sealed tube, 74% sealed tube, 65% O MeO OMe er = 88:12 er = 87:13 OMe O eupomatilone 2 (178) eupomatilone 5 (179)
Scheme 6.18 Asymmetric thermal carbomethoxycrotylboration of biaryl aldehydes
97 6.6 Optimization of Suzuki−Miyaura biaryl cross-coupling reaction
During the optimization of the thermal crotylboration reaction, a parallel focus was also emphasized on the optimizing of the Suzuki−Miyaura biaryl cross-coupling
reaction. Several variations of Suzuki coupling conditions were attempted on two
electron-rich boronic acids with various palladium sources and various bases during the
course of the optimization process that are tabulated below (Table 6.1).
B(OH)2 OMe B(OH)2 MeO + + O MeO CHO MeO OMe O Br OMe 237 137 209 (see table)
OMe OMe MeO MeO
MeO CHO MeO CHO
O MeO OMe O OMe 224 223
98
Equiv of 237 Equiv of Yield No. Suzuki-Miyaura Coupling Conditions or 209 137 (%)
Pd(OAc)2 (1 mol%), DABCO (2 1 1.4 (237) 1.0 - mol%), K2CO3 (3.0 eq), acetone, 90 °C, 10 h
Pd(OAc)2 (1 mol%), DABCO (2 2 1.2 (237) 1.0 50 mol%), K2CO3 (3.0 eq), NMP, 80 °C, 22 h
3 1.0 (237) 2.0 Pd[(PPh)3]4 (5 mol%), 85 °C, 21 h 41 toluene/ethanol/2M Na2CO3 (3:2:1.5)
4 1.2 (237) 1.0 Pd[(PPh)3]4 (3 mol%), Cs2CO3 (1.5 59 equiv), DMF, 80 °C, 18 h
Pd[(PPh)3]4 (8 mol%), PPh3 (10 5 1.2 (209) 1.0 76 mol%) Cs2CO3 (1.5 equiv), DMF, 75 °C, 15 h
Pd[(PPh)3]4 (8 mol%), PPh3 (12 6 1.2 (209) 1.0 81 mol%) Cs2CO3 (2.0 equiv), DMF, 75 °C, 24 h
Pd2(dba)3 (4 mol%), S-Phos (8 7 2.0 (209) 1.0 82 mol%), K3PO4 (3.0 equiv), toluene, 95 °C, 6 h
Pd2(dba)3 (4 mol%), S-Phos (8 8 2.0 (237) 1.0 90 mol%), K3PO4 (3.0 equiv), toluene, 100 °C, 6 h
Table 6.1 Optimization of Suzuki−Miyaura biaryl cross-coupling reaction
99
From a series of experimentations, it was observed that Pd-tetrakis and Cs2CO3
(entry 6) afforded descent yield. However, Buchwald conditions71,108 (entry 7 and 8) with
S-Phos ligand was also very efficient for our system. Based on the above optimizations
we carried out the Suzuki conditions on 262 in a sealed tube that was oven-dried and pre-
flushed with argon. All the reaction materials were weighed inside a glove box; it was taken out of the glove box under argon, re-flushed with argon, and sealed and heated for
22 h at 95 to 100 °C. The reaction mixture was then passed through a short pad of celite and washed with ether. Column chromatography on silica-gel (10% ether in hexane) afforded eupomatilone 5 in excellent yield (90%) with a decent enantiomeric ratio of
83:17 (Scheme 6.19).
OMe OMe MeO Pd2(dba)3 (4 mol%) MeO S - Phos (8 mol%) MeO MeO K PO , toluene, 3 4 O Br O 100 oC, 90% 262 O O O B(OH)2 O eupomatilone 5 237 O O 179
Scheme 6.19 Suzuki–Miyaura biaryl cross coupling using Buchwald’s conditions
After successful application of our asymmetric biaryl crotylboration strategy to
the synthesis of eupomatilones 2 and 5, we thought of extending it to the asymmetric total
100 synthesis of eupomatilone 1 using the biaryl aldehyde precursor 211. Buchwald’s Suzuki-
Miyaura conditions71,108 were surprisingly ineffective for this biaryl subunit 136 with a
methylenedioxy and an aldehyde group, previously synthesized during the total synthesis
of gomisins (Scheme 4.2). We subsequently tried Itami and Yoshido conditions147 using bis(tri-tert-butylphosphine)palladium(0), (that proved to be successful in the total synthesis of strobilurin B by Coleman and Liu148) in our system that afforded a decent
yield (56%) producing colorless crystals after purification through silica-gel flash
chromatography (condition A). Addition of Pd(PPh3)4 ( 8 mol%), PPh3 (10 mol%),
Cs2CO3 (2.5 equiv) and heating the mixture of boronic acid and alkyl bromide under argon in DMF (4 mL) at 75 to 80 °C for 32 h also afforded 60% yield of the desired biaryl aldehyde precursor to eupomatilone 1 (condition B) (Scheme 6.20).
O Pd[P(t-Bu)3]2 (5 mol%) O 3,4,5 -(MeO)3C6H2B(OH)2 O A NaOH (3.0 eq), H2O (3.0 eq) O THF, 20 h, Ar, 60 oC, 56% MeO CHO
MeO CHO Pd(PPh3)4 (8 mol%) Br MeO OMe PPh3 (10 mol%), Cs2CO3 (2.5 eq) B OMe 3,4,5 -(MeO)3C6H2B(OH)2 136 DMF, 32 h, Ar, 75 oC, 60% 211
Scheme 6.20 Suzuki−Miyaura coupling for biaryl precursor to eupomatilone 1
101 Quite interestingly, when this methylenedioxy biaryl aldehyde 211 was subjected
to standard thermal crotylboration conditions with the carbomethoxycrotyl reagent 273,
the reaction was found to be extremely sluggish and afforded eupomatilone 1 (177)
(30%) after heating at 80 to 85 °C for 8 days, as an inseparable mixture of cis- (177) and
trans- (276) isomers (Scheme 6.5), albeit with poor diastereoselectivity (cis:trans = 3:1).
The HPLC analysis showed er = 94:6 for the natural cis enantiomer 177, and er = 89:11 for the unnatural trans isomer 276 at temperatures above 80 °C. The thermal asymmetric crotylboration was again attempted at 60 °C for a period of 18 days in toluene in a sealed reaction vessel with argon to observe any temperature effect. However, we observed no further improvement in the results. This implied that temperature does not play any significant role in the lowering of the transition state in this particular case. The role of probable electronic effect of the methylene dioxy group, if any, in the enantioselectivity and diastereoselectivity of thermal crotylboration reactions needed to be further scrutinized (Scheme 6.21).
O O O O
MeO MeO 273 + 211 O toluene, 85 oC, 8 d O 30% O O MeO OMe MeO OMe OMe OMe eupomatilone 1 (177) 276
Scheme 6.21 Synthesis of eupomatilone 1 from biaryl precursor
102
Hence we carried out the thermal carbomethoxycrotylboration reaction with the monoaryl methylenedioxy aldehyde 136 with the crotyl reagent 273 at 80 °C for 6 d. The reaction went to around 65% completion but quite interestingly, the cis: trans diastereomeric ratio of the products 274a: 274b was lowered to 2:1 favoring the cis- isomer (Scheme 6.22). The enantiomeric excess for cis (4.7% ee) and trans (9.6% ee) isomers were also appreciably low. This certainly showed that the electronics of the methylenedioxy group was having a predominant effect on the outcome of the reaction as compared to simple methoxy groups. The rigidity in the transition state here is also perhaps less compact due to the absence of non-covalent aromatic CH–π interactions as seen in biaryl aldehydes earlier (Scheme 6.18).
OMe OMe OMe 273 O O O + Toluene, Ar, 6 d, O O O CHO 75 to 80 oC, 60% Br Br O cis : trans = 2:1 Br O 136 274a O 274b O
Scheme 6.22 Carbomethoxycrotylboration on methylenedioxy monoaryl aldehyde
103 It is worth a passing mention that hydrogenation attempt on eupomatilone 5 (179)
(10% Pd/C on ethanol, H2 (balloon, 1 atm), 24 h, 85%) had cleanly afforded 3-epi-
eupomatilone 6 (277) (Scheme 6.23).
OMe OMe MeO MeO
Pd/C, H2 (balloon, 1 atm) MeO MeO ethanol, 24 h, 85% O O O O O O O O 179 277
Scheme 6.23 Hydrogenation of eupomatilone 5 to afford 3-epi-eupomatilone 6
6.7 Conclusion
A successful strategy has been demonstrated for the synthesis of members of the
eupomatilone family bearing an α-methylene-γ-lactone moeity. The asymmetric total synthesis of eupomatilones 2 and 5 were completed in six linear steps in close to 50%
overall yield. They key to the success of the sequence was the development of highly
efficient Suzuki−Miyaura cross coupling reaction conditions and an efficient asymmetric
crotylboration reaction. The “edge-to-face” aromatic CH−π effect observed in the aryl-
aryl interaction exemplified the importance of weak non-covalent electrostatic 104 components in stabilizing transition states. In the process of developing chiral carbomethoxycrotylboration reagent, a new air-stable diborane reagent was also prepared. It was found to be very sparingly soluble in DMF that considerably slowed down the rate of crotylboration reaction. Hence, other polar solvent system (e.g. NMP) needs to be studied with this reagent, in order to optimize the reaction. Perhaps that would also initiate new directions in the development of asymmetric version of the boryl- copper chemistry. The optimized Suzuki−Miyaura reaction conditions would be also very useful in synthesis of other members of the eupomatilone family as well as for other applications in natural product total synthesis. Furthermore, the interesting electronic effect of the methylenedioxy group in the transition state of monoaryl and biaryl systems perhaps needs to be studied in detail for electron rich aryl systems for better understanding of the thermal carbomethoxycrotylboration reactions.
105
CHAPTER 7
PROGRESS TOWARDS TOTAL SYNTHESIS OF MAYOLIDE A
7.1 Introduction
Cembrane diterpenes are often found in quite large amounts in the lipids of
marine soft corals (alcyonarian) and gorgonians. Soft corals are roughly classified into
two types, those which mainly produce α-methylene lactonic cembranoids, and those
which produce other types of cembranoids with an intact isopropyl side chain or its
derivatives.149 The Sinularia species, which are common and abundant in the coral reefs
of Indo-Pacific coastal waters, mainly contain α-methylene lactone derivatives. Sinularia
mayi is a common species found in the coral reefs of Southern Japan, which contains a
variety of cembranoid lactones and small amounts of two new cembranoid diols which
are plausible precursors of the α-methylene-γ-lactone derivatives.150 Investigation of the
more polar cembranoids of Sinularia mayi resulted in the isolation of four new
compounds, one of which had an unprecedented secocembranoid skeleton. They were
obtained after repeated flash chromatography with a mixture of acetone-CHCl3 (1 : 9) of the lipids of Sinularia mayi and were designated as mayolide A to mayolide D.151
Mayolide A, is a α-methylene-γ-lactone derivative as indicated by its IR (1760 and 1660
106 cm−1). It is also the first secocembrane diterpenoid to be obtained.152 The novel structure
of the molecule has been elucidated by 1H NMR (Figure 7.1), but its absolute
configuration still remains unknown. Hence, there is an urgent need of total synthesis of this molecule for correct structure determination, as well as evaluation of its interesting anti-cancer biological properties.
HO Me Me H HO H O O O O O O Me Mayolide A (278) Mayolide B (279)
Me Me H Me Me H HO H HO H O O O O O O OAc O Me Me Mayolide C (280) Mayolide D (281)
Figure 7.1 Mayolide natural products: cembranoid and secocembranoid lactones
7.2 Previous synthetic efforts for mayolide A
The first synthesis of (+)-mayolide A was carried out in 31 steps (Scheme 7.1)
that provided a clear indication of the configuration of mayolide A. The synthesis
involved two key steps of diastereoselective induction of a two-carbon unit at the β-
position of the butenolide 282 to form C-1 asymmetric center and repeated Claisen
rearrangement to construct the side chain (C-3 to C-20) in mayolide A (278).
107 t CO2 Bu HO i) DIBAL-H, THF 13 H H THPO AcOtBu, LDA, THF −78 oC, 53% 14 O t THPO O 1 CO2 Bu O o −78 C, 82% O ii) NaBH4, MeOH THPO H 0 oC, 66% OH H H 282 283 284
1. LAH, Et O, 0 oC TBDMSO 2 TBDMSO 13 2. MPMBr, NaH, 13 1. TBDMSCl, Im, rt, 88% H DMF-THF, rt H 14 14 OMPM t i 1 CO2 Bu 1 2. BOMCl, Pr2NEt, 100% THPO 3. MgBr2, Et2O OBOM 64% (3 steps) OHC OBOM H 4. DMSO, (COCl) H 285 2 286 Et3N, CH2Cl2, 99%
TBDMSO 1. CH =C(Me)MgBr, THF 2 1. CH2=C(Me)MgBr, THF 78 oC, 85% H o − OMPM −78 C, 76%
2. CH =CHOEt, Hg(OAc) 2 2 2. CH2=CHOEt, Hg(OAc)2 o OHC 135 C, 66% OBOM 135 oC, 63% H 287
TBDMSO TBDMSO H H OMPM O CO2H
OHC OBOM several OBOM 3 7 3 7 H steps H 288 289 TBDMSO H o 1) LDA, THF, HCHO, −30 oC, 71% 1) Li, liq. NH3, THF, −78 C OH O 2) (±) CSA, AcOEt, 93% O 2) Ac2O, Py, DMAP, CH2Cl2, rt o (2 steps) 290 H 3) DBU, benzene, 50 C, 95% (2 steps)
TBDMSO HO H 1) DIBAL-H, THF, −78 oC H OAc 2) PDC, CH2Cl2, rt, 67% O O O O 3) TBAF, THF, rt, 69% O H H 291 (+)-Mayolide A (278)
Scheme 7.1 Yamada’s total synthesis of mayolide A
As seen from the scheme above, the synthesis by Yamada and co-workers153 is too long (31 linear steps) and deals with a number of functional group manipulations. The
108 lactone alcohol 290 was generated as the sole product by deprotection of the BOM group
in 289 with lithium-liq. NH3, followed by treatment with catalytic amount of (±)-CSA in
ethylacetate. The introduction of the exo-methylene at the α-position of the lactone
carbonyl in 291 was carried out by: 1) reaction of the enolate, generated from 290 with
LDA, with HCHO in THF, 2) acetylation with Ac2O and pyridine in the presence of
DMAP, and 3) elimination of acetic acid with DBU in benzene (95% yield in two steps) to give the lactone 291. Adjustment of quite a few functional groups completed the total
synthesis of (+)-mayolide.154
7.3 Retrosynthetic analysis for our projected synthesis of mayolide A
Our retrosynthetic analysis for mayolide A (278) was based on a concise,
stereoselective and convergent synthetic strategy. We intended to employ the
carbomethoxycrotylation strategy developed in the eupomatilone synthesis. In addition to that, key Stille and Suzuki−Miyaura cross-couplings are also involved in the synthetic plan. Described below is the retrosynthetic analysis for the proposed route (Scheme 7.2).
109 HO
O O O Mayolide A (278) TBDMSO
O O O 292 Suzuki-Miyaura
O O TBDMSO BF3K 293 294 O Stille Br O
Carbomethoxy- O O + Br -crotylation Br Bu3Sn 295 298 TBDMSO CHO + Br 301 305 O OH CO2Me Br Bu Sn 3 Br B 296 299 OO OH 302 O Br O O TBDMSO OH 297 300 OAc 306 OH CO2Me 303
TBDMSO CHO OH 304 307 CO2Me
TBDMSO CHO + CO2Me 308
Scheme 7.2 Retrosynthetic analysis of mayolide A
110 7.4 Synthetic approach towards fragments of mayolide A
Our first goal was to synthesize the aldehyde fragment 301. We prepared trans-
155 crotyl alcohol from trans-crotonaldehyde by overnight reduction with LiAlH4 in THF.
The aldehyde 304 was treated with bromine in carbon tetrachloride under Schlosser’s condition156 to obtain 2,3-dibromo-butan-1-ol 302, which was purified by vacuum
distillation under reduced pressure (bp 119-120 °C at 12 to 18 torr Hg) to obtain the
dibromoalcohol 302 in 77% yield. The alcohol 302 was subjected to Corey’s condition157 and treated with LDA and HMPA to obtain pure (E)-3-bromo-2-buten-1-ol158 309 in 50%
yield by distillation under reduced pressure (bp 92-93 °C at 16 mm Hg). Oxidation of this
159 alcohol with MnO2 did not work effectively, and hence we tried the Parikh-Doering oxidation conditions that smoothly afforded the required (E)-3-bromobut-2-enal 301 in 1 h at 0 °C (Scheme 7.3).
1. LiAlH4, THF, 12 h o Me 0 C to rt, N2 Me Br LDA, HMPA,
o CHO 2. Br2, CCl4 , 3h, Br OH THF, 4h, −78 C, o 304−60 to 0 C, distil 302 50% 77%
Me OH SO3•Py, Et3N Me CHO
DMSO:CH Cl (1:1 v/v) Br 2 2 Br 309 1 h, −10 to 0 oC, 90% 301
Scheme 7.3 Preparation of (E)-3-bromobut-2-enal
111 Our next attempt was to synthesize the boronate ester 305. 1,3-Propandiol was
monoprotected as the silylether under standard conditions.160 The alcohol 311 was subsequently oxidized to the corresponding aldehyde 308 using IBX oxidation161 in 80% yield. The aldehyde was found to be volatile when kept in vacuum for extended period of time and was quickly dried in a rotavap. The aldehyde 308 was treated under modified
Baylis-Hillman conditions162 of Iso and Nishitani using methyl acrylate and 3-
quinuclidinol without any solvent at room temperature for 48 h to obtain 82% yield of the allyl alcohol 307. The optimization of the reaction with DABCO afforded moderate
yields (Table 7.1). The alcohol was converted to the corresponding allylic acetate 306 in
91% yield using Ac2O, Et3N, and catalytic DMAP in dichloromethane at room
temperature in 2 h. Following this we resorted to Miyaura’s boryl-copper chemistry to
effect the 1,3-allylic rearrangement using bis(pinacolado)diboron, CuCl, LiCl, KOAc in
DMF at room temperature for 8 h that afforded the desired boronate ester 305 in 88%
yield (Scheme 7.4).
1. TBDMSCl, Im, 0 oC O OH O to rt, 12 h, 85% CHO HO OH TBDMSO TBDMSO OMe 2. IBX, EtOAC, 310 3-quinuclidinol (neat) DMSO(cat), 60 oC, 80% 308 2d, rt, 82% 307
O O OAc O B B O OTBDMS Et3N, Ac2O, DMAP (cat) O O B TBDMSO OMe O CH2Cl2, rt, 3h, 91% CuCl, LiCl, KOAc, DMF, 8h, 88% MeO2C 306 305
Scheme 7.4 Preparation of the boronic ester for carbomethoxycrotylation
112
Yield No. Baylis-Hillmann Reaction Conditions (307)
DABCO (100 mol%), 4 h, 25 °C, 1 Dioxane:H2O = 1:1 (v/v) 10%
DABCO (100 mol%), 2 d, 25 °C, 2 Dioxane:H2O = 1:1 (v/v) 25%
DABCO (200 mol%), 2 d, 25 °C, 3 Dioxane:H2O = 1:1 (v/v) 39%
DABCO (200 mol%), 4 d, 25 °C, 4 Dioxane:H2O = 1:1 (v/v) 46%
3-Quinuclidinol (0.20 equiv.), 1 d, 25 °C 5 (neat) 59%
3-Quinuclidinol (0.25 equiv.), 2 d, 25 °C 6 (neat) 82%
Table 7.1 Baylis-Hillman reaction optimization
The next focus was on the synthesis of the bromoketal 295 and the tributyltin fragment 298. Alkyl bromides are more useful synthetic intermediates than alkyl chlorides. A search in the literature revealed a few convenient methods for a complete transformation of alkyl chloroketones to alkyl bromoketones. 5-Chloro-2-pentanone
(312) was converted to 5-bromo-2-pentanone (296) on treatment with NaBr and a 2:1
(v/v) mixture of DMF and dibromomethane, conditions developed by Babler and
113 Spina.163 Although the conversion was seen to be 90% complete by 1H NMR, distillation
under reduced pressure (bp 48 to 70 °C at 0.4 mm) still showed chloride impurity. Since
we needed pure bromide 296 for the Stille reaction, we needed to search alternative
methods to make the bromide 296. Treatment of 2-acetylbutyrolactone with aqueous HBr and distillation of the product (bp 103 to 105 °C at 20 mm) provided the 5-bromo-2- pentanone (296) in 50% yield as a colorless liquid164,165 that was further protected as a
ketal 295 (Scheme 7.5).
O o CH2Br2, NaBr, 100 C, 6h O Cl Br DMF:CH2Br2 2:1 (v/v) 312 296
OH O aq. HBr, O OH O O Br O O o Br 100 C, 5h p-TSA, Toluene, 110 oC then, distil, ~50% 75% 297 296 295
Scheme 7.5 Preparation of the bromoketal
The stannylcupration on pent-3-yn-1-ol (300) was reported in literature as well as
on similar substrates by Parrain, Pancrazi and co-workers166,167 (Scheme 7.6) to obtain
alcohol 299.
114
Bu3(Bu)SnCuLi.LiCN DHP, PPTS, OH OTHP o Bu Sn Bu3Sn MeOH, −40 C 3 CH2Cl2, rt, 24 h OH 300 299 313
Scheme 7.6 Stannylcupration and protection of alcohol
7.5 Conclusion
The end-game that remains to be completed in this synthesis is to perform a successful Stille cross-coupling168 under Fu conditions using the bromoketal 295 and the
stannane 298, followed by a Suzuki−Miyaura coupling of the trifluroborate 293 and the vinyl bromide 294 to obtain the silyl ether protected mayolide A (292). Deprotection of the silyl ether with fluoride anion would afford the desired target mayolide A (278) in a
linear sequence of 15 steps, i.e., half the number of steps involved in the Yamada’s
synthesis. In addition, by utilization of the asymmetric carbomethoxycrotylation strategy
that was developed in the earlier part of this thesis, the absolute sterereochemistry of this
interesting natural product can be deciphered for the first time.
115
CHAPTER 8
EXPERIMENTAL PROCEDURE
Proton nuclear magnetic resonance spectra were recorded on a Bruker AM-250,
Bruker DPX-400 or Bruker AM-500 spectrometers and recorded in parts per million from
internal chloroform (δ = 7.27 ppm) on the δ scale. The 1H NMR spectra are reported as
follows: chemical shift [multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), integration, coupling constants in hertz, interpretation]. 13C NMR data were obtained with Bruker DPX-400 and Bruker DPX-500 spectrometers.
Multiplicities were determined using DEPT experiments. Infrared spectra were taken with Perkin-Elmer 1600 and 2000 instruments. Mass spectra were obtained on Kratos
MS-25 at an ionization energy of 70 eV and a 3-Tesla Finnigan FTMS-2000. High resolution mass spectroscopies were also performed by the Campus Chemical Instrument
Center (CCIC) Spectrometry Facility on a Micromass Q-Tof II instrument. Compounds for which an exact mass is reported exhibited no significant peaks at m/z greater than that of the parent. X-ray crystallographic data are as provided just as obtained.
Solvents and reagents were dried and purified prior to use as necessary: diethyl ether and tetrahydrofuran were dried over sodium/benzophenone ketyl; triethylamine,
116 acetonitrile, chlorobenzene, 2-butanol and dichloromethane were dried over calcium
hydride. Reactions requiring an inert atmosphere were run under argon or nitrogen.
Analytical thin layer chromatography was conducted using EM Laboratories (Merck)
0.25 mm thick precoated silica gel 60F-254 plates. Column chromatography was
performed over EM bioscience laboratories, ICN, and Whatman silica gel 970-250 or
230-400 mesh). Organolithium reagents were titrated prior to use with menthol using 1,
10-phenanthroline as an indicator, or using diphenylacetic acid169 as an indicator.
The order of the selected experimental procedures follows the order of
appearance in the text:
Dibenzocyclooctadiene lignans (gomisins):
OHC Br
HO OH 5-bromo-2,3-dihydroxybenzaldehyde (123). 5-bromo-2-hydroxy-3-
methoxybenzaldehyde 122 (10 g, 43.3 mmol) was dissolved in dichloromethane (100
mL) and cooled to −78 °C. Boron tribromide (19.5 g, 77.9 mmol, 7.35 mL) was added slowly via a dropping funnel into the reaction mixture. The reaction mixture was allowed to warm up to room temperature overnight. NaOH (4N) was added dropwise to the reaction mixture until the pH was found to be basic. The reaction mixture was extracted with water as a sodium salt and was strongly acidified when the alcohol was found to precipitate out. The precipitate was dissolved in ether (150 mL), the organic layer was washed with saturated aqueous NaCl (2 x 100 mL), dried (Na2SO4), concentrated, and the
residue was purified by flash chromatography (silica, 20% EtOAc/hexane) to afford pure 117 1 diol (123) (6.6 g, 70%) as a light yellow powder: H NMR (CDCl3, 400 MHz) δ 11.05 (br
s, 1H, phenolic-OH), 9.83 (s, 1H, CHO), 7.31 (d, 1H, J = 2 Hz, ArH), 7.28 (d, 1H, J = 2
13 Hz, ArH), 5.80 (br s, 1H, phenolic-OH); C NMR (CDCl3, 100 MHz) δ 195.6, 147.6,
146.0, 126.2, 124.4, 121.2, 111.8.
HO Br
O O 6-bromobenzo[d][1,3]dioxol-4-ol (127). 6-bromobenzo[d][1,3]dioxole-4-
carbaldehyde 124 (730 mg, 3.19 mmol) was dissolved in dichloromethane (10 mL). m-
CPBA (77%, 1.7 g, 9.57 mmol) was added to the reaction mixture drop wise under argon.
The reaction mixture was refluxed for 4 h. It was cooled to room temperature and was washed with saturated aqueous Na2SO3 (3 x 20 mL), saturated aqueous NaHCO3 (3 x 20 mL), saturated aqueous NaCl (2 x 20 mL) and concentrated in vacuo. The residue was dissolved in methanol (5 mL) and a 10% solution of methanolic KOH was added drop wise until the reaction mixture was strongly basic at 0 °C. The reaction mixture was vigorously stirred for 30 min at 0 °C and 30 min at 25 °C, and was concentrated under vacuo and the residue was washed with ether (10 mL). The residue was cooled down to 0
°C and was treated with 3N HCl until the pH was acidic and was stirred for 30 min more.
The reaction mixture was diluted with ether (20 mL), washed with water (3 x 20 mL), saturated aqueous NaCl (2 x 20 mL), dried (Na2SO4), concentrated, and the residue was
purified by flash chromatography (silica, 20% EtOAc/hexane) to afford pure alcohol 127
1 as a colorless powder (208 mg, 30%): H NMR (CDCl3, 400 MHz) δ 6.68 (d, 1H, J = 1.6
Hz, ArH), 6.64 (d, 1H, J = 1.6 Hz, ArH), 5.98 (s, 2H, O-CH2-O), 5.07 (br s, 1H,
118 13 phenolic-OH); C NMR (CDCl3, 100 MHz) δ 149.4, 139.8, 133.7, 114.3, 113.3, 105.8,
101.9; HRMS (ESI), m/z calcd for C7H5BrO3-H 214.9343; found: 214.9356.
MeO Br
O O 6-bromo-4-methoxybenzo[d][1,3]dioxole (126). Bromo-alcohol 127 (200
mg, 0.92 mmol) was taken in acetone (2 mL) in an oven-dried round bottom flask.
Dimethyl sulfate (139.3 mg, 1.1 mmol, 0.1 mL) was added to the flask via a syringe at 25
°C under nitrogen, followed by addition of K2CO3 (190.7 mg, 1.38 mmol) in one portion.
The reaction mixture was heated at 60 °C for 24 h. It was cooled down to room
temperature, filtered, and the acetone was evaporated to get the crude. The crude material
was dissolved in EtOAc (10 mL), washed with water (5 mL), saturated aqueous NaCl (2 x 10 mL), dried (Na2SO4), and purified by column chromatography (silica, 5%
1 EtOAc/hexane) to afford 127 as a white solid (215 mg, 97%): H NMR (CDCl3, 500
13 MHz) δ 6.68 (m, 2H, ArH), 5.97 (s, 2H, O-CH2-O), 3.89 (s, 3H, OCH3); C NMR
(CDCl3, 125 MHz) δ 149.5, 144.2, 134.9, 113.3, 111.1, 106.2, 101.9, 56.8; IR (film) νmax
3085, 2915, 1626, 1495, 1488, 1446, 1421, 1403, 1298, 1220, 1184, 1106, 1034, 963,
928, 816, 771.
O O OH
Br CHO 6-bromo-7-hydroxybenzo[d][1,3]dioxole-5-carbaldehyde (135). A solution of 7-hydroxybenzo[d][1,3]dioxole-5-carbaldehyde 134 (2.0 g, 12.0 mmol) in dioxane (80
mL) was cooled to 15 °C. A solution of N-bromosuccinimide (2.14 g, 12.0 mmol) in 119 dioxane (20 mL) was added dropwise by syringe over 3 h at this temperature. The
reaction mixture was stirred for 12 h between 16 °C to 18 °C and was quenched by the
addition of saturated aqueous Na2S2O3 (10 mL). The mixture was concentrated, and the
residue was dissolved in EtOAc (100 mL) and washed with saturated aqueous Na2S2O3, water, and saturated aqueous NaCl. The organic layer was dried (Na2SO4), concentrated,
and the residue was purified by flash chromatography (silica, 15% EtOAc/hexane) to
1 afford pure 135 (2.84 g, 97%) as a solid: H NMR (DMSO-d6, 500 MHz) δ 10.75 (s, 1H),
13 10.12 (s, 1H), 6.94 (s, 1H), 6.19 (s, 2H); C NMR (DMSO-d6, 125 MHz) δ 191.0, 148.6,
141.4, 138.6, 128.2, 112.6, 103.3, 100.8; IR (KBr) νmax 3042, 2362, 1660, 1594, 1497,
1480, 1460, 1416, 1355, 1256, 1124, 1083, 1040, 994, 922, 836, 747, 668 cm–1; HRMS
(ESI), m/z calcd for C8H5BrO4Na: 266.9269; found: 266.9270.
O O OMe
Br CHO 6-Bromo-7-methoxybenzo[d][1,3]dioxole-5-carbaldehyde (136). A
mixture of 6-bromo-5-hydroxypiperonal (135) (1.8 g, 7.4 mmol), K2CO3 (1.52 g, 11.0
mmol) and dimethyl sulfate (0.84 mL, 8.8 mmol) in acetone (20 mL) was heated at 55 to
60 °C for 2 h. After cooling to room temperature, the mixture was filtered and concentrated. The residue was dissolved in EtOAc (50 mL), and was washed with water
and saturated aqueous NaCl. The organic layer was dried (Na2SO4), concentrated, and the
residue was recrystallized from CH2Cl2/hexane to afford pure 136 (1.62 g, 85%) as a light
1 yellow solid: H NMR (CDCl3, 500 MHz) δ 10.26 (s, 1H), 7.16 (s, 1H), 6.09 (s, 2H), 4.06
13 (s, 3H); C NMR (CDCl3, 125 MHz) δ 190.7, 149.2, 143.0, 140.3, 128.6, 115.8, 103.2,
120 102.7, 60.4; IR (KBr) νmax 3042, 2362, 1660, 1594, 1497, 1480, 1460, 1416, 1355, 1256,
1124, 1083, 1040, 994, 922, 836, 747, 668 cm–1;HRMS (ESI), m/z calcd for
C9H7BrO4Na: 280.9424; found: 280.9425.
O MeO
MeO MeO 1-(3,4,5-trimethoxyphenyl)-2,3-dimethylbut-3-en-1-one (154). A solution of (E)-2-methyl-2-butene-1-ylmagnesium bromide (153) in dry ether (0.10 M, 54 mL, 5.4 mmol) was added dropwise by syringe over 30 min to a solution of 3,4,5- trimethoxybenzaldehyde (0.75, 4.52 mmol) in THF (10 mL) at –78 °C. The reaction mixture was stirred for 2 h at –78 °C and was quenched by the addition of saturated aqueous NH4Cl (10 mL). The volatiles were removed and the residue was dissolved in
EtOAc (100 mL) and was washed with water and saturated aqueous NaCl. The organic layer was concentrated to afford 1-(3,4,5-trimethoxyphenyl)-2,3-dimethylbut-3-en-1-ol
(crude wt. 0.96 g, 3.6 mmol), which was used without further purification. The alcohol
was dissolved in ethyl acetate (15 mL) under nitrogen atmosphere and IBX (2.18 g, 7.77
mmol) and DMSO (5 drops) were added. The reaction mixture was warmed at 55 °C for
3 h and was cooled and washed with saturated sodium thiosulfate, saturated aqueous
NaCl, water. The organic layer was dried (MgSO4), filtered, and concentrated and the residue was purified by flash chromatography (10% EtOAc/hexane) to afford 1-(3,4,5-
trimethoxyphenyl)-2,3-dimethylbut-3-en-1-one 154 as a colorless solid (1.12 g, 89%): 1H
NMR (CDCl3, 400 MHz) δ 4.89 (d, 2H, J = 7.4 Hz), 4.09 (q, 1H, J = 6.7 Hz), 3.86 (s,
13 9H), 1.70 (s, 3H), 1.29 (d, 3H, J = 6.7); C NMR (CDCl3, 100 MHz) δ 199.9, 153.3,
121 146.2, 142.8, 132.3, 113.7, 106.4, 61.3, 56.6, 49.7, 20.7, 16.6; IR (film) νmax 2938, 1678,
–1 1585, 1415, 1342, 1129 cm ; HRMS (ESI), m/z calcd for C15H20O4Na: 287.1259; found:
287.1260.
HO MeO
MeO MeO 1-(1R*,2R*)-1-(3,4,5-trimethoxyphenyl)-2,3-dimethylbut-3-en-1-
ol (155). A solution of the above ketone 154 (1.08 g, 4.09 mmol) in anhydrous methanol
(20 mL) under nitrogen was cooled to –78 °C and treated with sodium borohydride (0.23 g, 6.13 mmol) portionwise. The reaction mixture was stirred for 10 h at –78 °C and quenched at that temperature by the addition of AcOH (0.36 mL, 6.13 mmol). The solvent was removed and the residue was dissolved in EtOAc (50 mL) and washed with water and saturated aqueous NaCl. The organic layer was dried (MgSO4), filtered, and
concentrated, and the residue was purified by flash chromatography (5-25%
EtOAc/hexane) to afford the anti-alcohol 155 as a colorless solid (0.92 g, 85%): 1H NMR
(CDCl3, 500 MHz) δ 6.58 (d, 2H, J = 2.4 Hz), 4.99 (d, 2H, J = 1.0 Hz), 4.30 (d, 1H, J=
9.5 Hz), 3.88 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H), 2.50-2.40 (m, 1H), 2.28 (br s, 1H), 1.79
13 (s, 3H), 0.82 (d, 3H, J= 6.9 Hz); C NMR (CDCl3, 125 MHz) δ 153.6, 147.7, 138.5,
138.0, 114.2, 104.4, 106.4, 76.9, 61.2, 56.6, 50.4, 18.9, 16.5; IR (film) νmax 3592, 3542,
2968, 2839, 1593, 1508, 1462, 1423, 1386, 1326, 1271, 1238, 1184, 1129, 1005, 903,
–1 838, 745 cm ; HRMS (ESI), m/z calcd for C15H22O4Na: 289.1416; found: 289.1418.
122 t-BuMe2SiO MeO
MeO MeO ((1R*,2R*)-1-(3,4,5-trimethoxyphenyl)-2,3-dimethylbut-3-
enyloxy)(tert-butyl)dimethylsilane (rac-150). Imidazole (0.11 g, 1.8 mmol) was added
to a solution of 1-(3,4,5-trimethoxyphenyl)-2,3-dimethylbut-3-en-1-ol (0.15 g, 0.6 mmol)
in DMF (5 mL) at 25 °C. After 15 min, t-BuMe2SiCl (0.13 g, 0.48 mmol) was added and
the reaction mixture was stirred for 14 h at this temperature. The reaction mixture was
diluted with water (10 mL) and extracted with diethyl ether. The organic layer was
washed with saturated aqueous NaCl and water, and was dried (MgSO4), concentrated,
and the residue was purified by flash chromatography (5% EtOAc/hexane) to afford rac-
1 150 (0.17 g, 79 %) as a syrup: H NMR (CDCl3, 500 MHz) δ 6.50 (s, 2H), 4.77 (s, 1H),
4.69 (s, 1H), 4.42 (d, 1H, J = 7.3 Hz), 3.85 (s, 9H), 2.40 (quintet, 1H, J = 7.1 Hz), 1.73 (s,
13 3H), 0.86 (s, 9H), 0.82 (d, 3H, J = 7.0 Hz), 0.02 (s, 3H), –0.22 (s, 3H); C NMR (CDCl3,
125 MHz) δ 152.6, 147.4, 139.7, 137.0, 111.7, 104.0, 78.4 61.0, 56.1, 49.6, 25.7, 20.8,
18.2, 16.1, –4.6, –5.2; IR (film) νmax 3071, 2958, 2856, 1646, 1593, 1506, 1462, 1421,
1348, 1326, 1270, 1234, 1127, 1090, 1006, 943, 891, 857, 837, 776, 694 cm–1; HRMS
(ESI), m/z calcd for C21H36O4SiNa: 403.2280; found: 403.2274.
123 HO MeO
MeO Br OMe (1R,2S)-1-(2-bromo-3,4,5-trimethoxyphenyl)-2,3-dimethylbut-3-
en-1-ol (rac-140). A mixture of indium powder (1.0 g, 8.7 mmol) and tiglyl bromide 153
(2.59 g, 17.4 mmol) was stirred in anhydrous DMF (10 mL) for 2.5 h at room
temperature. Tetrahydrofuran (2.0 mL) was added and the reaction mixture was cooled to
–78 °C. A solution of 2-bromo-3,4,5-trimethoxybenzaldehyde (137) (1.20 g, 4.36 mmol) in THF (3.0 mL) at –78 °C was added dropwise over 10 min using a syringe pump, and the reaction mixture was stirred for 2 h at this temperature. The reaction was quenched by the addition of water (3 mL) and was diluted with ether (100 mL). The organic layer was washed with water (3 x 100 mL) and saturated aqueous NaCl (3 x 100 mL), and was dried (Na2SO4), filtered, and concentrated to afford 140 as a colorless solid (1.5 g, 95%):
1 H NMR (CDCl3, 500 MHz) δ 6.98 (s, 1H), 5.13 (d, 1H, J = 1.6 Hz), 4.98 (t, 1H, J = 1.6
Hz,), 4.90 (s, 1H), 3.90 (s, 3H), 3.89 (s, 6H), 2.74 (dq, 1H, J = 6.8, 3.2 Hz), 1.97 (d, 1H, J
13 = 1.6 Hz), 1.95 (s, 3H), 0.91 (dd, 3H, J = 6.8, 4 Hz); C NMR (CDCl3, 100 MHz) δ
152.5, 150.5, 148.1, 136.9, 111.73, 107.9, 107.3, 72.4, 61.1, 61.0, 56.1, 43.8, 22.3, 11.3;
IR (film) νmax 3472, 2969, 2937, 1642, 1568, 1481, 1448, 1426, 1394, 1324, 1194, 1162,
–1 1105, 1037, 1009, 893, 817, 738 cm ; HRMS (ESI), m/z calcd for C15H21BrO4Na:
367.0515; found: 367.0512.
OH MeO
MeO Br OMe
124 The data for the corresponding anti-alcohol obtained via angelyl organometallic reagent
(1S,2S)-1-(2-bromo-3,4,5-trimethoxyphenyl)-2,3-dimethylbut-3-en-1-ol (141). 1H
NMR (CDCl3, 500 MHz) δ 6.87 (s, 1H, ArH), 5.05 (d, 1H, J = 9.06 Hz, CH-OH), 4.99 (s,
2H, C=CH2), 3.89 (s, 9H, 3 x OCH3), 2.50 (m, 1H, CH-CH3), 2.27 (br s, 1H, OH), 1.80
13 (s, 3H, CH3), 0.92 (d, 3H, J = 7.09 Hz, CH-CH3); C NMR (CDCl3, 100 MHz) δ 153.2,
150.3, 147.2, 142.6, 137.4, 113.7, 110.5, 106.6, 73.7, 61.1, 61.0, 56.2, 50.5, 18.8, 15.6;
IR (film) νmax 3472, 2969, 2937, 1642, 1568, 1481, 1448, 1426, 1394, 1324, 1194, 1162,
–1 1105, 1037, 1009, 893, 817, 738 cm ; HRMS (ESI), m/z calcd for C15H21BrO4Na:
367.0521; found: 367.0525.
t-BuMe2SiO MeO
MeO Br MeO (1R*,2R*)-(1-(2-Bromo-3,4,5-trimethoxyphenyl)-2,3-
dimethylbut-3-enyloxy)(tert-butyl)dimethylsilane (rac-147). A dispersion of NaH
(1.10 g, 27.4 mmol) in THF (10 mL) was cooled to –15 °C. A solution of rac-140 (3.15 g, 9.10 mmol) in THF (20 mL) was added dropwise over 10 min and the resulting slurry was stirred at –25 °C for 1 h. A solution of tert-butyldimethylsilyl chloride (2.75 g, 18.2 mmol) in THF (25 mL) was added to the slurry at –15 °C over 20 min using a syringe pump. The reaction mixture was allowed to warm to room temperature, and was stirred for 24 h. Excess NaH was quenched by the addition of water at 0 °C. The reaction mixture was diluted with ether (200 mL) and was washed with saturated aqueous NaCl (4 x 150 mL). The organic layer was dried (Na2SO4), filtered, concentrated, and the residue
was purified by flash chromatography (silica gel, 10% EtOAc/hexane) to afford 147 (4.0 125 1 g, 95%) as a colorless solid: H NMR (400 MHz, CDCl3) δ 6.94 (s, 1H), 5.07 (d, 1H, J =
3.2 Hz), 4.82 (s, 1H), 4.77 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.89 (s, 3H), 2.43 (m, 1H),
1.86 (s, 3H), 0.97 (d, 3H, J = 6.8 Hz), 0.90 (s, 9H), 0.03 (s, 3H), –0.21 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 152.1, 150.0, 147.2, 141.8, 139.2, 111.8, 107.9, 107.8, 74.7, 61.1,
61.0, 55.9, 45.7, 25.9, 25.7, 22.2, 18.2, 12.0, –4.8, –5.2; IR (film) νmax 2933, 1481, 1254,
–1 1108, 890 cm ; HRMS (ESI), m/z calcd for C21H35BrO4SiNa: 481.1386; found:
481.1351.
t-BuMe2SiO MeO
MeO MeO ((1R*,2S*)-1-(3,4,5-trimethoxyphenyl)-2,3-dimethylbut-3-
enyloxy)(tert-butyl)dimethylsilane (rac-157). Reaction of imidazole (60 mg, 0.96
mmol) and t-BuMe2SiCl (70 mg, 0.90 mmol) with (1R*,2S*)-1-(3,4,5-
trimethoxyphenyl)-2,3-dimethylbut-3-en-1-ol 156 (80 mg, 0.32 mmol) in DMF (3 mL) at
1 25 °C for 14 h afforded rac-157 (90 mg, 76 %) as a syrup: H NMR (CDCl3, 400 MHz) δ
6.50 (s, 2H), 4.73 (s, 1H), 4.65 (s, 1H), 4.49 (d, 1H, J = 5.9 Hz), 3.84 (s, 9H), 2.30
(quintet, 1H, J = 6.7 Hz), 1.60 (s, 3H), 1.05 (d, 3H, J = 6.9 Hz), 0.90 (s, 9H), 0.02 (s, 3H),
13 –0.18 (s, 3H); C NMR (CDCl3, 100 MHz) δ 152.8, 147.6, 140.7, 137.0, 112.0, 104.0,
78.2, 61.2, 56.4, 50.0, 26.0, 21.1, 18.5, 16.4, –4.5, –4.9; IR (film) νmax 3048, 2959, 2856,
1592, 1461, 1427, 1326, 1279, 1235, 1127, 1090, 1006, 943, 856, 837 cm–1; HRMS
(ESI), m/z calcd for C21H36O4SiNa: 403.2281; found: 403.2307.
126 t-BuMe2SiO MeO OH
MeO MeO Primary alcohol (rac-160). A solution of 150 (0.3 g, 0.79 mmol)
in THF (2 mL) was cooled to 0 °C, and a solution of 9-BBN in THF (0.5 M, 0. mL, 0.94
mmol) was added dropwise by syringe over 20 min. The reaction mixture was allowed to
warm to 25 °C over 3 h, and was stirred at this temperature for 16 h. The reaction mixture
was cooled to 0 °C, and treated with NaOH (94 mg, 2.36 mmol) that was dissolved in
mixture of EtOH (1 mL) and THF (1 mL) and aqueous 30% H2O2 (0.13 mL, 1.13 mmol).
The reaction mixture was allowed to warm to 25 °C. After 10 h at this temperature, the
volatiles were removed and the residue was diluted with EtOAc (25 mL) and washed
with water and saturated aqueous NaCl. The organic layer was dried (Na2SO4),
concentrated, and the residue was purified by flash chromatography (30%
1 EtOAc/hexane) to afford rac-160 (0.28 g, 91%) as a solid: H NMR (CDCl3, 400 MHz) δ
6.52 (s, 2H), 4.64 (d, 1H, J = 4.8 Hz), 3.84 (s, 9H), 3.53 (dd, 1H, J = 8.8, 11.1 Hz), 3.31
(dd, 1H, J = 4.9, 5.5 Hz), 2.05-1.90 (m, 1H), 1.85-1.80 (m, 1H), 1.25 (bs, 1H), 0.93 (s,
13 12H), 0.84 (d, 3H, J = 7.1 Hz), 0.09 (s, 3H), –0.13 (s, 3H); C NMR (CDCl3, 125 MHz)
δ 152.8, 139.1, 136.7, 103.7, 79.1, 64.0, 61.0, 56.1, 45.7, 34.0, 25.8, 18.2, 17.3, 12.2, –
4.6, –5.0; IR (film) νmax 3403, 2959, 2858, 1593, 1506, 1463, 1420, 1329, 1263, 1235,
1184, 1127, 1078, 1054, 1005, 934, 918, 838, 778, 725, 674 cm–1; HRMS (ESI), m/z calcd for C21H38O5SiNa: 421.2380; found: 421.2355. X-Ray crystal structure provided
[Coleman 1106].
127 OMe OMe t-BuMe2SiO MeO OBn
MeO OMe (1R,2S,3S)-4-(3-(Benzyloxy)-4,5-dimethoxyphenyl)-1-
(3,4,5-trimethoxyphenyl)-2,3-dimethylbutoxy)(tert-butyl)dimethylsilane (rac-159). 9-
Borabicyclo[3.3.1]nonane (0.15 g, 1.26 mmol) was added dropwise at 0 °C over 30 min to a solution of alkene rac-157 (0.40 g, 1.05 mmol) in THF (3.0 mL). The reaction mixture was allowed to warm to 25 °C and was stirred for 12 h before being cooled to 0
°C. The alkylborane formed was added dropwise using a syringe over 15 min to a mixture of aryl bromide 158 (0.26 g, 1.05 mmol), Ph3P (0.04 g, 0.16 mmol), Pd(PPh3)4
(0.07 g, 0.06 mmol), and aqueous NaOH (4 M 0.87 mL, 3.47 mmol) in THF (5 mL) at 0
°C. The pale yellow reaction mixture was warmed at 70 °C for 8 h. The volatiles were removed and the residue was dissolved in CH2Cl2 (8 mL) and was passed through a pad of Celite. Water (2 mL) was added to the filtrate followed by dropwise addition of 5%
aqueous HCl until neutral. The mixture was washed with water (2 x 15 mL), dried
(MgSO4), filtered, and concentrated, and the residue was purified by flash
chromatography (silica, 5-25% EtOAc/hexane) to afford the Suzuki product rac-159 as a
colorless solid (0.45 g, 70%), which was recrystallized from hot hexane: 1H NMR (400
MHz, CDCl3) δ 7.44-7.31 (m, 5H), 6.55 (s, 2H), 6.29 (d, 1H, J = 1.6 Hz), 6.21 (d, 1H, J =
1.6 Hz), 5.04 (d, 2H, J = 6.1 Hz), 4.53 (d, 1H, J = 6.9 Hz), 3.85 (s, 9H), 3.77 (s, 6H), 2.75
(dd, 1H, J = 13.4, 3.2 Hz), 2.04 (m, 1H), 1.86 (m, 1H), 1.67 (m, 1H), 1.02 (d, 3H, J = 6.7
Hz), 0.89 (s, 9H), 0.81 (d, 3H, J = 6.6 Hz), 0.05 (s, 3H), –0.20 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 153.5, 153.3, 152.4, 140.9, 137.7, 137.5, 137.2, 128.8, 128.1, 127.7,
108.7, 106.5, 104.4, 78.6, 71.5, 61.3 (2C), 56.6, 56.4, 47.6, 38.5, 35.9, 26.3, 18.8, 18.7, 128 – 11.5, –3.9, –4.5; IR (neat) νmax 2932, 2855, 1590, 1506, 1461, 1327, 1235, 1124, 836 cm
1 ; HRMS (ESI), m/z calcd for C36H52O7SiNa: 647.3375; found: 647.3371. X-Ray crystal
structure provided [Coleman 1211].
t-BuMe2SiO MeO
Br MeO Br OMe O OH O tert-Butyldimethylsilylether of 5-bromo-6-((2R,3R,4S)-4-(2-
bromo-3,4,5-trimethoxyphenyl)-4-hydroxy-2,3-dimethylbutyl)benzo[d][1,3]dioxol-4-
ol (163). Alcohol 162 (198 mg, 0.33 mmol) was dissolved in dioxane (2 mL) in a dry
round bottom flask. NBS (59.8 mg, 0.336) recrystallized from hot water, was dissolved in
dioxane (2 mL) and was added to the alcohol dropwise via a syringe at 18-20 °C. After
vigorous stirring for 9 h, the dioxane was evaporated. The residue was taken in EtOAc
and was washed with saturated aqueous Na2S2O3 (1 x 20 mL), saturated aqueous NH4Cl
(2 x 20 mL), saturated aqueous NaCl (2 x 20 mL), dried (Na2SO4) and concentrated. The
residue was purified by flash chromatography (silica gel, 10% EtOAc/Hexane) to afford
1 163 as a colorless oil (191 mg, 85%): H NMR (CDCl3, 400 MHz) δ 6.93 (s, 1H, ArH),
6.35 (s, 1H, ArH), 5.99 (d, 2H, J = 1.2 Hz, O-CH2-O), 5.48 (s, 1H, -OH), 5.23 (d, 1H, J =
3.2 Hz, CH-OTBDMS), 3.91 (s, 6H, OCH3), 3.87 (s, 3H, OCH3), 3.03 (dd, 1H, J = 13.6,
3.2 Hz, CH2-Ar), 2.36 (app t, 1H, J = 11.6 Hz, CH2-Ar), 1.89 (m, 1H, CH3-CH), 1.70 (m,
1H, CH3-CH), 1.27 (app s, 3H, CH3), 1.01 (d, 3H, J = 8.0 Hz, CH3); 0.95 (s, 9H,
13 (CH3)3Si), 0.01 (s, 3H, Si-CH3), −0.22 (s, 3H, Si-CH3); C NMR (CDCl3, 100 MHz) δ
152.2, 150.2, 148.1, 141.9, 139.4, 134.6, 132.5, 108.2, 108.0, 106.2, 103.5, 101.9, 74.3,
61.1, 61.0, 56.0, 44.9, 40.0, 35.9, 31.6, 25.9, 22.6, 18.2, 17.1, 14.1, 10.3, −4.3, −4.8; IR 129 (film) νmax 3418, 2955, 2932, 2856, 1623, 1567, 1503, 1481, 1423, 1395, 1358, 1323,
1255, 1196, 1162, 1105, 1069, 1036, 930, 836, 776, 733 cm−1; HRMS (ESI), m/z calcd
for C28H40Br2O7SiNa: 697.0808; found: 697.0788.
HO MeO
Br MeO Br OMe O OMe O (1S,2S,3S)-1-(2-bromo-3,4,5-trimethoxyphenyl)-3-((5- bromo-4-methoxybenzo[d][1,3]dioxol-6-yl)methyl)-2-methylbutan-1-ol (164). The corresponding ketone 172 (79 mg, 0.138 mmol) was taken in MeOH:CH2Cl2 (2 mL) (1:1
v/v) and NaBH4 (12 mg, 0.27 mmol) was added to the reaction mixture at −78 °C. The reaction mixture was warmed up to room temperature on vigorous stirring for 12 h. The
reaction was quenched by the addition of EtOAc (1 mL) and saturated aqueous solution
of NH4Cl (0.5 mL). The resultant mixture was washed with saturated aqueous NaCl (2 x
5 mL). The organic layer was dried (Na2SO4), filtered, concentrated, and the residue was
purified by flash chromatography (silica gel, 5-10% EtOAc/hexane) to afford the anti-
1 anti alcohol (164) as a colorless liquid (67 mg, 85%): H NMR (CDCl3, 400 MHz) δ 6.89
(s, 1H, ArH), 6.56 (s, 1H, ArH), 5.95 (s, 2H, O-CH2-O), 5.23 (d, 1H, J = 9.6 Hz, CH-
OH), 4.01 (s, 3H, OCH3), 3.88-3.89 (s, 9H, OCH3), 3.05 (dd, 1H, J = 12.0, 2.4 Hz, Ar-
CH2-CH(CH3)), 2.51-2.43 (m, 2H, Ar-CH2-CH(CH3), CH(CH3)), 2.34 (br s, 1H, OH),
1.87 (m, 1H, CH3-CH), 0.96 (d, 3H, J = 6.4 Hz, CHCH3), 0.70 (d, 3H, J = 7.2 Hz,
13 CHCH3); C NMR (CDCl3, 100 MHz) δ 153.2, 150.1, 148.2, 142.4, 140.4, 139.1, 135.6,
135.3, 110.1, 109.3, 106.6, 105.6, 101.4, 74.5, 61.0, 60.4, 60.1, 56.1, 46.0, 38.0, 33.8,
21.0, 17.6, 14.2, 10.7; IR (film) νmax 3510, 2963, 2937, 1606, 1568, 1477, 1396, 1277, 130 1197, 1163, 1104, 1050, 1010, 959, 930, 833, 737 cm−1; HRMS (ESI), m/z calcd for
C23H28Br2O7Na: 599.0081; found:599.0079.
O O t-BuMe2SiO MeO OMe
MeO Br OMe ((1S,2S,3S)-1-(2-bromo-3,4,5-trimethoxyphenyl)-4-(4-
methoxybenzo[d][1,3]dioxol-6-yl)-2,3-dimethylbutoxy)(tert-butyl)dimethylsilane
(165). A solution of 160 (0.042 g, 0.093 mmol) in THF (0.50 mL) was cooled to 0 °C,
and a solution of 9-BBN in THF (0.50 M, 0.32 mL, 0.16 mmol) was added dropwise over
10 min. The reaction mixture was allowed to warm to 10 °C over a period of 2 h and was
stirred at this temperature for 10 h. In another flask, aryl bromide 126 (0.032 g, 0.14 mmol), Pd(PPh3)4 (0.012 g, 0.01 mmol), Ph3P (0.010 g, 0.037 mmol) and NaOH (0.015 g,
0.372 mmol) in wet THF (1.0 mL) was warmed at 40 °C for 2h when a light green
solution formed. This solution was cooled to 0 °C and the the solution of alkylborane was
added dropwise over a period of 10 min. The reaction mixture was warmed at 70 °C for
28 h, cooled to room temperature, and the volatiles were removed. The residue was
diluted with CH2Cl2 (10 mL), passed through a pad of Celite, and the filtrate was washed with water (2 x 10 mL), and saturated aqueous NaCl (2 x 10 mL). The organic layer was dried (Na2SO4), filtered, concentrated, and the residue was purified by flash
chromatography (silica gel, 5-10% EtOAc/hexane) to afford 165 (0.034 g, 61%) as a
1 colorless oil: H NMR (CDCl3, 400 MHz) δ 6.92 (s, IH), 6.41 (s, 1H), 6.36 (s, 1H), 5.94
(s, 2H), 5.10 (d, 1H, J = 8.0 Hz), 3.90 (s, 3H), 3.89 (s, 6H), 3.88 (s, 3H), 3.00 (dd, 1H, J =
13.0, 2.8 Hz), 2.24 (m, 1H), 2.14 (m, 1H), 1.85 (m, 1H), 0.90 (s, 9H), 0.80 (d, 3H, J = 6.8 131 13 Hz, 0.87), 0.74 (d, 3H, J = 7.2 Hz), 0.14 (s, 3H), −0.27 (s, 3H); C NMR (CDCl3, 100
MHz) δ 152.7, 149.9, 148.6, 143.3, 142.1, 139.9, 136.8, 133.1, 109.5, 108.1, 107.3,
103.1, 101.1, 75.8, 61.2, 61.0, 56.5, 56.0, 46.3, 37.2, 33.9, 29.7, 25.9, 18.3, 18.1, 14.1,
10.6, –4.7, -4.8; IR (film) νmax 2929, 2856, 2367, 1458, 1426, 1395, 1253, 1196, 1106,
−1 836, 776 cm ; HRMS (ESI) m/z calcd for C29H43BrO7SiNa: 633.1859; found: 633.1855.
633.1855.
O O t-BuMe2SiO MeO OMe Br MeO Br OMe ((1S,2S,3S)-1-(2-Bromo-3,4,5-trimethoxyphenyl)-4-(5-
bromo-4-methoxybenzo[d][1,3]dioxol-6-yl)-2,3-dimethylbutoxy)(tert-butyl)dimethyl
silane (166). A solution of NBS (11.6 mg, 0.065 mmol) in CHCl3 (0.7 mL) was added to
a solution of 165 (4.0 mg, 0.065 mmol) in CHCl3 (0.7 mL) at 22 °C and the reaction
mixture was stirred vigorously for 4.5 h at this temperature. The volatiles were removed,
and the residue was diluted with EtOAc (5 mL), washed with saturated aqueous Na2S2O3
(10 mL), saturated aqueous NH4Cl (2 x 10 mL), and saturated aqueous NaCl (2 x 10 mL).
The organic layer was dried (Na2SO4), filtered, concentrated, and the residue was purified
by flash chromatography (silica gel, 5-10% EtOAc/hexane) to afford 166 (4.0 mg, 89%)
as a colorless oil: IR (film) νmax 2929, 2855, 1606, 1567, 1477, 1395, 1256, 1106, 1053,
−1 1 836, 776 cm ; H NMR (CDCl3, 500 MHz) δ 6.94 (s, 1H), 6.56 (s, 1H), 5.95 (s, 2H),
5.09 (d, 1H, J = 7.6 Hz), 4.03 (s, 3H), 3.90 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 2.97 (dd,
1H, J = 13.8, 4.2 Hz), 2.69 (dd, 1H, J = 13.7, 10.9 Hz), 2.25 (m, 1H), 1.89 (m, 1H), 0.84
(d, 3H, J = 7.0 Hz), 0.81 (d, 3H, J = 7.3 Hz), 0.90 (s, 9H), 0.11 (s, 3H), –0.29 (s, 3H); 13C
132 NMR (CDCl3, 125 MHz) δ 152.7, 150.1, 148.3, 142.1, 140.3, 139.8, 135.8, 135.5, 109.9,
109.3, 108.7, 107.5, 104.6, 101.4, 76.1, 61.2, 61.0, 60.0, 56.0, 45.9, 37.6, 33.9, 29.7, 25.9,
18.1, 17.6, 11.9, –4.6, –4.7; HRMS (ESI), m/z calcd for C29H42Br2O7SiNa: 711.0964;
found: 711.0961.
t-BuMe2SiO MeO
MeO Br OMe O OH O tert-butyldimethylsilylether of 6-((2R,3R,4S)-4-(2-bromo-
3,4,5-trimethoxyphenyl)-4-hydroxy-2,3-dimethylbutyl)benzo[d][1,3]dioxol-4-ol
(162). The silylether 161 (84.4 mg, 0.123 mmol) was taken in methanol (2 mL) and a
spatula of Pd on charcoal was added to it. Hydrogen gas (balloon) was bubbled through
the reaction mixture via a needle for 4 h. The reaction mixture was filtered through a
short pad of celite. Methanol was evaporated and the residue was purified by flash
chromatography (silica gel, 10% EtOAc/hexane) to afford 162 (66 mg, 90%): 1H NMR
(CDCl3, 400 MHz) δ 6.90 (s, 1H, ArH), 6.26 (s, 1H, ArH), 5.91 (s, 2H, O-CH2-O), 5.17
(d, 1H, J = 4.0 Hz, CH-OTBDMS), 5.05 (br s, 1H, OH), 3.91 (s, 6H, 2 x OCH3), 3.86 (s,
3H, OCH3), 2.93 (m, 1H, Ar-CH2-), 2.03 (m, 1H, Ar-CH2-), 1.68 (m, 2H, 2 x CH(CH3)),
0.96 (d, 3H, J = 6.4 Hz, CH(CH3)), 0.92 (s, 9H, (CH3)3Si), 0.86 (d, 3H, J = 6.4 Hz,
13 CH(CH3)), 0.08 (s, 3H, Si(CH3)), −0.17 (s, 3H, Si(CH3)); C NMR (CDCl3, 100 MHz) δ
152.4, 150.0, 148.5, 142.0, 139.6, 138.8, 136.8, 131.9, 111.3, 108.5, 108.0, 102.6, 101.1,
75.1, 61.2, 61.0, 56.0, 45.4, 39.1, 36.9, 25.9, 18.1, 17.8, 14.2, 14.1, 10.4, −4.4, −4.9 ; IR
(film) νmax 3411, 2954, 2932, 2856, 1637, 1568, 1504, 1482, 1394, 1376, 1324, 1255, 133 1234, 1197, 1164, 1106, 1064, 1033, 1009, 931, 836, 776, 734 cm−1; HRMS (ESI), m/z calcd for C28H41BrO7SiNa: 619.1703; found: 619.1704.
OSiMe2t-Bu Ha MeO
Hx MeO Hb Hy OMe O OMe O ((1R,2S,3S)-4-(4-methoxybenzo[d][1,3]dioxol-6-yl)-1-(3,4,5-
trimethoxyphenyl)-2,3-dimethylbutoxy)(tert-butyl)dimethylsilane (167). A solution
of 166 (0.10 g, 0.15 mmol) in MeTHF (3.5 mL) was treated with t-BuLi (2.5 M, 0.23 mL,
0.58 mmol) at –78 °C under argon. After 30 min the pale yellow reaction mixture was
transferred via cannula to a flask containing CuCN (13 mg, 0.15 mmol) in MeTHF (10
mL) at –78 °C under argon. The heterogeneous reaction mixture was allowed to warm to
–40 °C over 1.5 h, and was stirred until homogeneous. The reaction mixture was cooled
to –78 °C, and oxygen gas was bubbled in through a fritted glass tube for 3 h. The
reaction mixture was purged with argon, and placed under high vacuum for 1 min to
remove residual dissolved oxygen at –78 °C. The reaction was warmed to –30 °C, and
was quenched by the addition of a solution of 10% NH4OH in saturated aqueous NH4Cl
(6 mL). The two-phase mixture was stirred for 30 min as it was allowed to warm to room temperature. The organic layer was separated, and the aqueous phase was extracted with
EtOAc (2 x 20 mL). The combined organics were washed with water (10 mL) and saturated aqueous NaCl (2 x 10 mL), and were dried (Na2SO4), filtered, concentrated, and
the residue was purified by flash chromatography (silica gel, 5% EtOAc/hexane) to
1 afford 167 (16 mg, 26%), (and very trace amount of 168): H NMR (CDCl3, 400 MHz) δ
6.54 (s, 2H, ArHa, ArHb), 6.38 (d, 1H, J = 1.2 Hz, ArHx), 6.32 (d, 1H, J = 1.2 Hz, ArHy),
134 5.93 (s, 2H, O-CH2-O), 4.48 (d, 1H, J = 8.0 Hz, CH-OTBDMS), 3.90 (s, 3H, OCH3),
3.86 (s, 9H, 3 x OCH3), 2.94 (dd, 1H, J = 13.2, 3.2 Hz, CH-CH(CH3)-CH), 2.18 (m, 1H,
(CH3)CH-CH(CH3)-CH(CH3)), 2.08 (m, 1H, ArCH2CH(CH3)), 1.79 (m, 1H,
ArCH2CH(CH3)), 0.92 (s, 9H, C(CH3)3), 0.80 (d, 3H, J = 6.8 Hz, CH(CH3)), 0.71 (d, 3H,
13 J = 7.2 Hz, CH(CH3)), 0.09 (s, 3H, Si(CH3)), −0.23 (s, 3H, Si(CH3)); C NMR (CDCl3,
125 MHz) δ 152.8, 148.6, 143.3, 140.5, 137.0, 136.8, 133.1, 108.1, 104.0, 103.1, 101.1,
78.4, 60.9, 56.5, 56.1, 46.5, 37.4, 34.0, 25.9, 18.2 (2C), 11.6, −4.4, −4.8.
TBDMSO MeO
MeO Br OMe MeO O O
((1S,2S,3S)-1-(2-bromo-3,4,5-trimethoxyphenyl)-4-(4-methoxybenzo[d][1,3]dioxol-6-
yl)-2,3-dimethylbutoxy)(tert-butyl)dimethylsilane (168). A solution of 148 (0.042 g,
0.093 mmol) in THF (0.50 mL) was cooled to 0 °C, and a solution of 9-BBN in THF
(0.50 M, 0.32 mL, 0.16 mmol) was added dropwise over 10 min. The reaction mixture
was allowed to warm to 10 °C over a period of 2 h and was stirred at this temperature for
10 h. In another flask, aryl bromide 126 (0.032 g, 0.14 mmol), Pd(PPh3)4 (0.012 g, 0.01
mmol), Ph3P (0.010 g, 0.037 mmol) and NaOH (0.015 g, 0.372 mmol) in wet THF (1.0
mL) was warmed at 40 °C for 2h when a light green solution formed. This solution was
cooled to 0 °C and the alkylborane solution was added dropwise over a period of 10 min.
The reaction mixture was warmed at 70 °C for 28 h, cooled to room temperature, and the
volatiles were removed. The residue was diluted with CH2Cl2 (10 mL), passed through a
pad of Celite, and the filtrate was washed with water (2 x 10 mL), and saturated aqueous 135 NaCl (2 x 10 mL). The organic layer was dried (Na2SO4), filtered, concentrated, and the
residue was purified by flash chromatography (silica gel, 5-10% EtOAc/hexane) to afford
1 168 (0.034 g, 61%) as a colorless oil: H NMR (CDCl3, 400 MHz) δ 6.92 (s, IH), 6.41 (s,
1H), 6.36 (s, 1H), 5.94 (s, 2H), 5.10 (d, 1H, J = 8.0 Hz), 3.90 (s, 3H), 3.89 (s, 6H), 3.88
(s, 3H), 3.00 (dd, 1H, J = 13.0, 2.8 Hz), 2.24 (m, 1H), 2.14 (m, 1H), 1.85 (m, 1H), 0.90
(s, 9H), 0.80 (d, 3H, J = 6.8 Hz, 0.87), 0.74 (d, 3H, J = 7.2 Hz), 0.14 (s, 3H), −0.27(s,
13 3H); C NMR (CDCl3, 100 MHz) δ 152.7, 149.9, 148.6, 143.3, 142.1, 139.9, 136.8,
133.1, 109.5, 108.1, 107.3, 103.1, 101.1, 75.8, 61.2, 61.0, 56.5, 56.0, 46.3, 37.2, 33.9,
29.7, 25.9, 18.3, 18.1, 14.1, 10.6, −4.7, −4.8; IR (film) νmax 2929, 2856, 2367, 1458,
1426, 1395, 1253, 1196, 1106, 836, 776 cm−1; HRMS (ESI), m/z calcd for
C29H43BrO7SiNa: 633.1859; found: 633.1855.
TBDMSO MeO
Br MeO Br OMe O OMe O ((1S,2S,3S)-1-(2-bromo-3,4,5-trimethoxyphenyl)-4-(5-
bromo-4-methoxybenzo[d][1,3]dioxol-6-yl)-2,3-dimethylbutoxy)(tert-
butyl)dimethylsilane (173). A solution of NBS (11.6 mg, 0.065 mmol) in CHCl3 (0.7
° mL) was added to a solution of 168 (4.0 mg, 0.065 mmol) in CHCl3 (0.7 mL) at 20 C
and the reaction mixture was stirred vigorously for 4.5 h at this temperature. The volatiles
were removed, and the residue was diluted with EtOAc (5 mL), washed with saturated
aqueous Na2S2O3 (10 mL), saturated aqueous NH4Cl (2 x 10 mL), and saturated aqueous
NaCl (2 x 10 mL). The organic layer was dried (Na2SO4), filtered, concentrated, and the 136 residue was purified by flash chromatography (silica gel, 5-10% EtOAc/hexane) to afford
1 173 (4.0 mg, 89%) as a colorless oil: H NMR (CDCl3, 500 MHz) δ 6.94 (s, 1H), 6.56 (s,
1H), 5.95 (s, 2H), 5.09 (d, 1H, J = 7.6 Hz), 4.03 (s, 3H), 3.90 (s, 3H), 3.89 (s, 3H), 3.87
(s, 3H), 2.97 (dd, 1H, J = 13.8, 4.2 Hz), 2.69 (dd, 1H, J = 13.7, 10.9 Hz), 2.25 (m, 1H),
1.89 (m, 1H), 0.84 (d, 3H, J = 7.0 Hz), 0.81 (d, 3H, J = 7.3 Hz), 0.90 (s, 9H), 0.11 (s,
13 3H), −0.29 (s, 3H); C NMR (CDCl3, 125 MHz) δ 152.7, 150.1, 148.3, 142.1, 140.3,
139.8, 135.8, 135.5, 109.9, 109.3, 108.7, 107.5, 104.6, 101.4, 76.1, 61.2, 61.0, 60.0, 56.0,
45.9, 37.6, 33.9, 29.7, 25.9, 18.1, 17.6, 11.9, −4.6, −4.7; IR (film) νmax 2929, 2855, 1606,
1567, 1477, 1395, 1256, 1106, 1053, 1010, 836, 776 cm−1; HRMS (ESI), m/z calcd for
C29H42Br2O7SiNa: 711.0964; found: 711.0961.
O MeO NO2 O MeO
MeO MeO
O O p-Nitrobenzoate ester of epigomisin O (129). Epigomisin
O (5) (9 mg, 0.022 mmol) was taken in an oven dried round bottom flask in THF (1 mL).
In another oven dried round bottom flask triphenyl phosphine (8.7 mg, 0.033 mmol) and
DIAD (6.7 mg, 0.033 mmol, 6.8 µL) were premixed in THF (1 mL). The solution of
gomisin O was added dropwise via a syringe under nitrogen and was set to stir for 10 min at 0 °C. This was followed by the addition of p-nitrobenzoic acid (5.3 mg, 0.033 mmol) in one portion to the reaction mixture. The reaction mixture was warmed up to 25 °C overnight. Subsequently, the solvent was removed in vacuo, the residue was diluted with
ether ( 5 mL), and the reaction mixture was washed with saturated aqueous NaHCO3 (4 x
137 4 mL), and saturated aqueous NaCl (2 x 4 mL). The organic layer was dried (Na2SO4),
filtered, concentrated, and the residue was purified by flash chromatography (silica gel,
5-10% EtOAc/hexane) to afford the p-nitrobenzoate ester 129 as a colorless liquid (6.3
1 mg, 92%): H NMR (CDCl3, 400 MHz) δ 8.17 (d, 2H, J = 8.4 Hz, ArH), 7.77 (d, 2H, J =
8.8 Hz, ArH), 6.74 (s, 1H, ArH), 6.51 (s, 1H, ArH), 5.95 (d, 2H, J = 8 Hz, O-CH2-O),
5.90 (s, 1H, O-CH), 3.92 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 3.64 (s, 3H, OCH3), 3.53 (s,
3H, OCH3), 2.26 (m, 2H, -CH2-), 1.29 (m, 2H, (CH3-CH)2), 1.03 (d, 3H, J = 7.2 Hz,
13 CH3), 0.87 (d, 3H, J = 7.0 Hz, CH3) ; C NMR (CDCl3, 100 MHz) δ 163.5, 152.0, 151.8,
150.4, 148.9, 142.0, 141.1, 135.7, 135.6, 134.2, 131.5, 130.7, 123.0, 121.4, 110.5, 102.4,
100.7, 82.6, 60.9, 60.5, 60.4, 59.1, 56.0, 37.6, 36.6, 22.9, 21.7, 21.6, 21.0, 14.2 ; IR (film)
−1 νmax 2942, 1723, 1599, 1529, 1464, 1332, 1270, 1207, 1106, 1052, 721 cm ; HRMS
(ESI), m/z calcd for C30H31NO10Na: 588.1846; found:588.1834.
O MeO CF3 O MeO
MeO MeO
O O Trifluoroacetate ester of gomisin O (175). (An effort to make
Gomisin N from Gomisin O). Gomisin O (6) (7.0 mg, 0.017 mmol) was taken in dichloromethane (1.0 mL) in an oven dried round bottom flask under nitrogen. TFA (3.9 mg, 0.034 mmol, 2.6 µL), was added to the reaction mixture via a micro-syringe followed by the dropwise addition of triethylsilane (3.0 mg, 0.025 mmol, 4.2 µL). The reaction mixture was stirred from 0 °C to 25 °C for 12 h. It was quenched by the addition of water
138 (1 mL). The residue was diluted with EtOAc (4 mL), washed with saturated aqueous
NaHCO3 (2 x 5 mL), and saturated aqueous NaCl (2 x 5 mL). The organic layer was dried (Na2SO4), filtered, concentrated, and the residue was purified by flash
chromatography (silica gel, 5-10% EtOAc/hexane) to afford the trifluoroacetate ester of
1 gomisin O (175) as a colorless oil (5.2 mg, 60.5%): H NMR (CDCl3, 500 MHz) δ 6.62
(s, 1H, ArH), 6.45 (s, 1H, ArH), 5.99 (dd, 2H, J = 12.60, 1.43 Hz, O-CH2-O), 5.47 (d,
1H, J = 9.18 Hz, CH-OCOCF3), 3.92 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 3.78 (s, 3H,
OCH3), 3.68 (s, 3H, OCH3), 2.60 (dd, 1H, J = 15.42, 4.45 Hz, (CH3)CH-CH2); 2.42 (dd,
1H, J = 15.52, 10.30 Hz, (CH3)CH-CH2), 2.02 (m, 1H, CH(CH3)), 1.76 (m, 1H,
13 CH(CH3)), 0.98 (d, 3H, J = 6.95 Hz, CH3), 0.86 (d, 3H, J = 6.94 Hz, CH3); C NMR
(CDCl3, 125 MHz) δ 156.4, 153.8, 151.9, 148.8, 141.3, 141.2, 136.0, 134.3, 133.5, 121.1,
120.7, 105.6, 101.2, 101.1, 80.5, 61.0, 60.9, 59.9, 55.9, 44.1, 39.6, 33.4, 31.6, 18.2, 12.5;
HRMS (ESI), m/z calcd for C25H27F3O8Na: 535.1556; found:535.1552.
MeO MeO
MeO OSiMe2t-Bu MeO OSiMe2t-Bu
6 6 MeO MeO P M MeO MeO
O 169O 170 O O Dibenzocyclooctadienes 169 and 170. A
solution of 166 (0.10 g, 0.15 mmol) in MeTHF (3.5 mL) was treated with t-BuLi (2.5 M,
0.23 mL, 0.58 mmol) at –78 °C under argon. After 30 min the pale yellow reaction
mixture was transferred via cannula to a flask containing CuCN (13 mg, 0.15 mmol) in
MeTHF (10 mL) at –78 °C under argon. The heterogeneous reaction mixture was
139 allowed to warm to –40 °C over 1.5 h, and was stirred until homogeneous. The reaction
° mixture was cooled to –125 C (liquid N2/n-pentane), and oxygen gas was bubbled in
through a fritted glass tube for 4 h. The reaction mixture was purged with argon, and
placed under high vacuum for 1 min to remove dissolved oxygen. The reaction was
warmed to –30 °C, and was quenched by the addition of a solution of 10% NH4OH in saturated aqueous NH4Cl (6 mL). The two-phase mixture was stirred for 30 min as it was
allowed to warm to room temperature. The organic layer was separated, and the aqueous
phase was extracted with EtOAc (2 x 20 mL). The combined organics were washed with
water (10 mL) and saturated aqueous NaCl (2 x 10 mL), and were dried (Na2SO4),
filtered, concentrated, and the residue was purified by flash chromatography (silica gel,
5% EtOAc/hexane) to afford 169 and 170 (combined yield: 30 mg, 39%) as a colorless
1 oil. (P)-169 (10 mg, 13%) was characterized: H NMR (CDCl3, 500 MHz) δ 6.46 (s, 1H),
6.37 (s, 1H), 5.90 (ABq, 2H, J = 1.5 Hz, Δν = 19.4 Hz), 4.46 (br s, 1H), 3.90 (s, 3H), 3.89
(s, 3H), 3.88 (s, 3H), 3.52 (s, 3H), 2.14 (m, 1H), 2.05-1.95 (br m, 2H), 1.72-1.67 (br m,
1H), 0.92 (d, 3H, J = 6.95 Hz), 0.77 (d, 3H, J = 6.3 Hz), 0.71 (s, 9H), –0.04 (s, 3H), –0.26
13 (s, 3H); C NMR (CDCl3, 125 MHz) δ 152.2, 151.1, 148.3, 141.3 (2C), 135.5, 133.9,
121.9, 101.9, 100.4, 81.9, 60.9, 60.4, 59.1, 56.0, 40.8, 25.8 (2C), 18.1, –4.8, –5.1; IR
–1 (film) νmax 2953, 1618, 1473, 1107, 1056, 835 cm ; HRMS (ESI), m/z calcd for
1 C29H42O7SiNa: 553.2598; found: 553.2604. (M)-170 (20 mg, 26%) was characterized: H
NMR (CDCl3, 400 MHz) δ 6.86 (s, 1H), 6.39 (s, 1H), 5.95 (ABq, 2H, J = 1.4 Hz, Δν =
16.1 Hz), 4.17 (d, 1H, J = 8 Hz), 3.92 (s, 3H), 3.90 (s, 3H), 3.82 (s, 3H), 3.64 (s, 3H),
2.57 (dd, 1H, J = 15.2, 4.4 Hz), 2.35 (dd, 1H, J = 15.6, 10.4 Hz), 1.61 (m, 2H), 0.94 (d,
3H, J = 6.8 Hz), 0.87 (s, 9H), 0.78 (d, 3H, J = 6.4 Hz), –0.14 (s, 3H), –0.23 (s, 3H); 13C 140 NMR (CDCl3, 125 MHz) δ 153.0, 151.1, 148.1, 140.9, 140.8, 139.9, 134.5, 120.8, 120.1,
104.7, 103.0, 100.7, 74.3, 61.0, 60.8, 59.3, 55.7, 47.9, 40.1, 33.3, 25.9 (2C), 18.9, 18.1,
–1 12.8, –4.6, –5.2; IR (film) νmax 2955, 2358, 1597, 1464, 1108, 1054, 836 cm ; HRMS
(ESI), m/z calcd for C29H42O7SiNa: 553.2598; found: 553.2604.
MeO 4 OH MeO
MeO P MeO
O 11 O Gomisin O (6). A solution of n-Bu4NF (1.0 M, 20 µL, 0.015 mmol) in
THF was added to a solution of 169 (8.0 mg, 0.015 mmol) in THF (0.80 mL) at room
temperature, and the reaction mixture was warmed at 55 °C for 6 h. The volatiles were
removed, and the residue was dissolved in EtOAc (5 mL) and washed with saturated aqueous NH4Cl (5 mL) and saturated aqueous NaCl solution (2 x 5 mL). The organic
layer was dried (Na2SO4), filtered, and concentrated, and the residue was purified with
flash chromatography (silica gel, 30% EtOAc/hexane) to afford gomisin O (6) (6.0 mg,
1 95%) as colorless oil: H NMR (CDCl3, 500 MHz) δ 6.57 (s, 1H), 6.43 (s, 1H), 5.97
(ABq, 2H, J = 1.4 Hz, Δν = 8.6 Hz), 4.35 (dd, 1H, J = 8.0 Hz), 3.90 (s, 3H), 3.91 (s, 3H),
3.92 (s, 3H), 3.54 (s, 3H), 2.32 (dd, 1H, J = 13.0, 5.6 Hz), 2.03 (dd, 1H, J = 12.9, 9.8 Hz),
1.86 (m, 1H), 1.67 (br s, 1H), 0.94 (d, 3H, J = 7.4 Hz), 0.92 (d, 3H, J = 6.9 Hz); 13C
NMR (CDCl3, 125 MHz) δ 152.1, 152.0, 149.3, 141.6, 141.5, 137.0, 135.5, 134.6, 122.2,
120.6, 110.1, 102.6, 100.8, 81.4, 60.9, 60.4, 59.5, 56.0, 40.0, 37.1, 31.6, 22.7, 14.1; IR
-1 (film) νmax 3482, 2937, 2361, 1723, 1617, 1474, 1327, 1105, 1050 cm ; HRMS (ESI) m/z
calcd for C23H28O7Na 439.1733, found 439.1740.
141
MeO 4 MeO OH
6 MeO MeO M
O 11 O epi-Gomisin O (M)-171. A solution of n-Bu4NF (1.0 M, 50 µL, 0.05
mmol) in THF was added to a solution of 170 (18.0 mg, 0.034 mmol) in THF (1.0 mL) at
room temperature, and the reaction mixture was warmed at 55 °C for 6 h. The volatiles
were removed and the residue was dissolved in EtOAc (5 mL) and washed with saturated
aqueous NH4Cl (5 mL) and saturated aqueous NaCl solution (2 x 5 mL). The organic
layer was dried (Na2SO4), filtered, concentrated, and the residue was purified by flash
chromatography (silica gel, 30% EtOAc/ hexane) to afford 171 (12 mg, 86%) as a
1 colorless solid: H NMR (CDCl3, 400 MHz) δ 6.93, 6.42, 5.95 (ABq, 2H, J = 1.2 Hz, Δν
= 6.3 Hz), 4.32 (dd, 1H, J = 8.0, 2.4 Hz), 3.93 (s, 3H), 3.92 (s, 3H), 3.84 (s, 3H), 3.64 (s,
3H), 2.61 (dd, 1H, J = 15.6, 4.8 Hz), 2.37 (dd, 1H, J = 16.0, 10.4 Hz), 1.72 (d, 1H, J = 2.8
13 Hz), 1.61 (m, 2H), 1.02 (d, 3H, J = 6.8 Hz), 0.82 (d, 3H, J = 6.8 Hz); C NMR (CDCl3,
100 MHz) δ 153.5, 151.5, 148.3, 140.9, 140.4, 140.0, 135.1, 134.6, 120.9, 120.4, 105.1,
102.2, 100.9, 74.2, 61.0, 60.9, 59.6, 55.9, 46.9, 40.2, 33.5, 19.4, 12.3; IR (film) νmax 3410,
-1 2958, 1597, 1463, 1404, 1107, 1050 cm ; HRMS (ESI) m/z calcd for C23H28O7Na
439.1733, found 439.1753.
142 MeO 4 OTBDMS MeO s MeO P MeO
O 11 O O-tert-Butyldimethylsilyl 6-epi-gomisin O (174). A solution of
anti-anti dibromosilyl ether 173 (0.052 mg, 0.075 mmol) in MeTHF (4 mL) was treated
with a solution of t-BuLi (2.5 M, 0.12 mL, 0.30 mmol) at −78 °C under argon. After 30
min, the pale yellow mixture was transferred via cannula to a flask containing CuCN (7.0
mg, 0.075 mmol) in MeTHF (7 mL) at −78 °C under argon. The heterogeneous reaction
mixture was allowed to warm to −40 °C over 1.5 h and was stirred vigorously until
homogeneous at this temperature. The resulting solution was cooled to −125 °C (liquid
N2/n-pentane), and oxygen gas was bubbled into the reaction for 4 h using a fritted glass
tube. The reaction mixture was purged with argon and kept under high vacuum for 1 min
to remove any dissolved oxygen. The reaction mixture was warmed to −30 °C and was quenched by the addition of 10% NH4OH in saturated aqueous NH4Cl (4 mL). The two-
phase mixture was stirred for 30 min as it was allowed to warm to room temperature. The
aqueous layer was extracted with EtOAc (2 x 20 mL), and the combined organics were
washed with saturated aqueous NH4Cl (10 mL) and saturated aqueous NaCl (2 x 10 mL).
The organic layer was dried (Na2SO4), filtered, and concentrated, and the residue was
purified by flash chromatography (silica gel, 5% EtOAc/ hexane) to afford 174 (14 mg,
1 35%) as a colorless solid: H NMR (CDCl3, 500 MHz) δ 6.99 (s, 1H), 6.43 (s, 1H), 5.95
(ABq, 2H, J = 1.5 Hz, Δν = 17.6 Hz), 4.42 (d, 1H, J = 1.4 Hz), 3.91 (s, 3H), 3.90 (s, 3H),
3.80 (s, 3H), 3.57 (s, 3H), 2.12 (dd, 1H, J = 13.3, 9.1 Hz), 1.93 (d, 1H, J = 13.3 Hz), 1.88
(m, 2H), 0.99 (d, 3H, J = 7.0 Hz), 0.86 (s, 9H), 0.65 (d, 3H, J = 6.9 Hz), −0.13 (s, 3H),
143 13 −0.19 (s, 3H); C NMR (CDCl3, 125 MHz) δ 151.6, 150.7, 148.9, 140.9, 140.5, 140.1,
137.9, 137.0, 120.6, 119.8, 107.2, 102.5, 100.7, 73.7, 60.9, 60.6, 59.9, 55.7, 44.5, 39.3,
34.7, 26.0, 25.8, 22.1, 18.1, 7.8, −4.6, −5.3; IR (film) νmax 2954, 1597, 1471, 1268, 1200,
-1 1107, 1053 cm ; HRMS (ESI) m/z calcd for C29H42O7SiNa 553.2598, found 553.2574.
MeO 4 OH MeO
6 MeO P MeO
O 11 O Gomisin E (epigomisin O) (5). A solution of n-Bu4NF (1.0 M, 25 µL,
0.024 mmol) in THF was added to a solution of 174 (9.0 mg, 0.02 mmol) in THF (0.80
mL) at room temperature, and the reaction mixture was warmed at 55 °C for 6 h. The
volatiles were removed, and the residue was dissolved in EtOAc (5 mL) and washed with
saturated aqueous NH4Cl (5 mL) and saturated aqueous NaCl solution (2 x 5 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated, and the residue was purified by flash chromatography (silica gel, 30% EtOAc/hexane) to afford epigomisn O (5) (5.5
1 mg, 79%) as a colorless liquid: H NMR (CDCl3, 500 MHz) δ 7.02 (s, 1H), 6.45 (s, 1H),
5.95 (s, 2H), 4.58 (d, 1H, J = 1.4 Hz), 3.93 (s, 3H), 3.92 (s, 1H), 3.86 (s, 1H), 3.55 (s,
3H), 2.12 (dd, 1H, J = 13.4, 9.4 Hz), 2.02 (m, 1H), 1.97 (d, 1H, J = 13.2 Hz), 1.93 (m,
13 1H), 1.65 (br s, 1H), 1.02 (d, 3H, J = 7.2 Hz), 0.71 (d, 3H, J = 7.0 Hz); C NMR (CDCl3,
100 MHz) δ 152.2, 151.1, 149.1, 140.8, 140.6, 137.9, 136.4, 134.5, 121.2, 119.4, 106.2,
102.8, 100.8, 73.4, 61.0, 60.6, 59.6, 55.9, 42.4, 39.2, 34.6, 22.0, 7.8; IR (film) νmax 3437,
2934, 1618, 1463, 1402, 1269, 1203, 1106, 1050 cm-1; HRMS (ESI) m/z calcd for
C23H28O7Na 439.1733, found 439.1753.
144 OMe MeO
MeO
HO
O O Rearranged biarylbicyclo compound (176). Gomisin O (6) (2.4 mg,
5.76 µM) was taken in 1, 2-dichloroethane (0.4 mL) in an oven dried round bottom flask under nitrogen. Indium trichloride (64 µg, 0.29 µM) was added followed by the addition of chlorodiphenylsilane (2.5 mg, 11.5 µM, and 2.3 µL) via a micro-syringe when the reaction mixture was observed to turn bright reddish-pink. After being heated to 55-60 °C for 25 min, the reaction mixture was found to turn yellow ochre. The reaction mixture was quenched by the addition of water (0.5 mL) after 60 min. The residue was dissolved in ether (2 mL) and was washed with saturated aqueous NaCl solution (2 x 4 mL). The organic layer was dried (Na2SO4), filtered, and concentrated, and the residue was purified by chromatography using a glass pipette (silica gel, 10% EtOAc/hexane) to afford 176
1 (1.1 mg, 45%) as a colorless liquid: H NMR (CDCl3, 500 MHz) δ 9.42 (s, 1H, phenolic
OH) (vanishes on D2O exchange), 6.74 (s, 1H, ArH), 6.00 (dd, 2H, J = 10.16, 1.35 Hz,
O-CH2-O), 4.17 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.38 (d, 1H, J =
11.4 Hz, Ar-CH(Ar)-CH(CH3)), 2.88 (dd, 1H, J = 17.2, 7.2 Hz, Ar-CH2), 2.56 (dd, 1H, J
= 17.2, 2.4 Hz, Ar-CH2), 2.19 (m, 1H, CH(CH3)), 1.76 (m, 1H, CH(CH3)), 1.47 (d, 3H, J
13 = 6.9 Hz, CH3), 1.15 (d, 3H, J = 6.9 Hz, CH3); C NMR (CDCl3, 125 MHz) δ 164.0,
160.1, 152.4, 145.2, 144.8, 143.0, 139.4, 134.3, 128.1, 120.5, 112.0, 101.5, 78.9, 61.2,
60.7, 56.3, 46.1, 35.9, 33.8, 29.8, 17.9, 15.5; HRMS (ESI) m/z calcd for C22H26O6Na
407.1471; found 407.1479.
145 Eupomatilones:
MeO2C OH Methyl 3-hydroxy-2-methylenebutanoate (241). Dioxane (5.0 mL) and
methylacrylate (11.72 g, 12.3 mL, 136.2 mmol) were added to a solution of DABCO
(5.12 g, 45.4 mmol) in water (5.0 mL). The reaction mixture was cooled to 0 °C and
stirred for 10 min following by dropwise addition of acetaldehyde (2.0 g, 2.54 mL, 45.4
mmol). The reaction mixture was stirred for 24 h at 25 °C. The mixture was diluted with
tert-butyl methyl ether (30 mL), the organic layer was separated, and the aqueous layer
was re-extracted with tert-butylmethylether (2 x 20 mL). The combined organic extracts
were washed with saturated aqueous NaCl (3 x 20 mL), and were dried (Na2SO4) and
concentrated in vacuo to obtain crude 241 (93%), which was used without further
1 purification: H NMR (CDCl3, 400 MHz) δ 6.19 (s, 1H), 5.82 (s, 1H), 4.60 (bd, 1H, J =
4.3 Hz), 3.76 (s, 3H), 2.85 (bs, 1H), 1.35 (d, 3H, J = 6.5 Hz).
MeO2C OAc Methyl 3-acetoxy-2-methylenebutanoate (261). A solution of methyl 3-
hydroxy-2-methylenebutanoate (241) (7.5 g, 57.5 mL) in dichloromethane (40 mL) was treated with pyridine (5 mL, 6.37 g, 80.53 mmol) for 10 min at 0 °C and acetic anhydride
(8.0 mL, 8.63 g, 84.56 mmol) was added. The reaction mixture was cooled to −15 °C and
was stirred below 0 °C for 30 h. The reaction mixture was quenched by the addition of
water (20 mL), and washed with 5% HCl (3 x 10 mL), water (2 x 10 mL), saturated
aqueous NaCl (3 x 20 mL), and was dried (Na2SO4) and concentrated in vacuo. The 146 residue was passed through a short pad of silica (10% ether/hexane) to obtain 261 as a
1 colorless oil (9.5 g, 96%): H NMR (CDCl3, 500 MHz) δ 6.28 (s, 1H), 5.82 (t, 1H, J = 1
Hz), 5.70 (dq, 1H, J = 6.5, 0.5 Hz), 3.78 (s, 3H), 2.07 (s, 3H), 1.40 (d, 3H, J = 6.5 Hz);
13 C NMR (CDCl3, 125 MHz) δ 169.8, 165.7, 141.1, 124.7, 68.2, 51.9, 21.1, 20.2; IR
−1 (film) νmax 3461, 2107, 1642, 525 cm ; HRMS (ESI), m/z calcd for C8H12O4Na:
195.0633; found: 195.0624.
O B O CO2Me (E)-Methyl-2-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)methyl)but-2-enoate (233). A flame dried round bottom flask was charged with CuCl
(257.4 mg, 2.60 mmol) and LiCl (110.2 mg, 2.60 mmol). DMF (3 mL) was added and the mixture was stirred for 30 min at 25 °C under argon. A solution of bis-pinacolatodiboron
(660 mg, 2.60 mmol) in DMF (2 mL) was cannulated into the reaction mixture, which was stirred for 5 min. Dried KOAc (255.2 mg, 2.60 mmol) was added to the reaction mixture in one portion, and the reaction mixture turned blackish-brown. A solution of acetate 261 in DMF (1 mL) was added dropwise. The reaction mixture was stirred for 6.5 h at 25 °C during which the color of the reaction mixture turned blue. The reaction mixture was quenched by the addition of water (4 mL). The mixture was extracted with ether (3 x 10 mL) and the combined organic extracts were washed with saturated aqueous
NaCl (2 x 10 mL), and were dried (Na2SO4) and concentrated. The residue was quickly
purified by flash chromatography (SiO2, 10% ether/hexane) to afford 233 as a colorless
oil (437 mg, 91%) that was found to be a 93:7 E/Z mixture by 1H NMR. The major Z
147 1 diastereomer was characterized: H NMR (CDCl3, 500 MHz) δ 6.83 (tq, 1H, J = 7.5, 1.0
13 Hz), 3.71 (s, 3H), 1.86 (s, 2H), 1.78 (d, 3H, J = 7.0 Hz); 1.24 (s, 12H); C NMR (CDCl3,
125 MHz) δ 168.6, 135.7, 130.0, 83.3, 83.2, 51.6, 24.9, 24.7 (4C), 14.5; IR (thin film)
νmax 2979, 2950, 1712, 1650, 1436, 1354, 1324, 1271, 1195, 1163, 1146, 1124, 1051,
–1 968, 884, 847, 756, 675, 542 cm ; HRMS (ESI), m/z calcd for C12H21BO4Na: 263.1431;
found: 263.1426.
OMe MeO
MeO Br O O (4S,5S)-5-(2-bromo-3,4,5-trimethoxyphenyl)-dihydro-4-methyl-
3-methylenefuran-2(3H)-one (262). A solution of trimethoxybromoaldehyde 137 (212
mg, 0.77 mmol) in toluene (2 mL) was added to a solution of carbomethoxycrotyl
boronate 233 (318 mg, 0.86 mmol) in toluene (3 mL) under argon. The reaction vessel
was sealed with Teflon and the reaction mixture was warmed at 95 °C for 72 h. The
reaction mixture was quenched by the addition of water (2 mL). The mixture was diluted
with ether (5 mL) and the aqueous layer was re-extracted with ether (2 x 5 mL).The
combined organic extracts were washed with saturated aqueous NaCl (2 x 10 mL), and
were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography
1 (silica, 10% Et2O/hexane) to afford 262 as a colorless syrup (240 mg, 78%): H NMR
(CDCl3, 500 MHz) δ 6.72 (s, 1H), 6.35 (d, 1H, J = 2.5 Hz), 5.85 (d, 1H, J = 7.5 Hz),
5.68 (d, 1H, J = 2.0 Hz), 3.92 (s, 3H), 3.91 (s, 3H), 3.86 (s, 3H), 3.70 (m, 1H), 0.80 (d,
13 3H, J = 7.5 Hz); C NMR (CDCl3, 100 MHz) δ 170.0, 153.1, 150.8, 142.7, 140.5, 131.4,
148 122.9, 107.4, 106.0, 80.9, 61.1, 56.3, 37.3, 16.9; IR (thin film) νmax 2926, 2853, 1772,
1570, 1484, 1452, 1397, 1360, 1324, 1267, 1244, 1148, 1108, 1004, 972, 813 cm−1;
HRMS (ESI), m/z calcd for C15H17BrO5Na: 379.0157; found: 379.0161; er = 77:23
(HPLC, chiralpak AD-RH column, i-PrOH–H2O 1:1, flow rate = 0.35 mL/min, λ = 254 nm, injection volume = 20 µL).
CO2Me
B O O (E)-i-Pinanecamphenyl Crotylboronate (263). An oven dried round bottom flask was charged with CuCl (143.5 mg, 1.45 mmol) and LiCl (61.5 mg, 1.45 mmol). DMF (3 mL) was added and the mixture was stirred for 1 h at 25 ºC under argon when the solution became brownish-yellow. A solution of bis((+)-pinanediolato)diboron
(465 mg, 1.30 mmol) in DMF (5 mL) was added via cannula to the reaction mixture over
5 min. Dry KOAc (140 mg, 1.45 mmol) was added to the reaction mixture in one portion, and the reaction mixture turned blackish brown. A solution of allyl acetate 261 (178 mg,
1.03 mmol) in DMF (2 mL) was added dropwise. The reaction mixture was stirred for 5 h
at 25 °C, during which the color of the reaction mixture gradually faded to light pink and
finally turned blue. The reaction mixture was quenched by the addition of water (4 mL).
The mixture was extracted with ether (2 x 10 mL) and the aqueous layer was re-extracted
with ether (2 x 10 mL). The combined organic extracts were washed with saturated
aqueous NaCl (2 x 20 mL), and were dried (Na2SO4), and concentrated. The residue was
quickly purified by flash chromatography (silica, 5% EtOAc/hexane) to afford boronate
1 263 (95:5 = E/Z) as a colorless oil (180 mg, 86% brsm): H NMR (CDCl3, 500 MHz) δ
149 6.84 (q, 1H, J = 7.0 Hz), 4.27 (dd, 1H, J = 9.0, 2.0 Hz), 3.72 (s, 3H), 2.32 (m, 1H), 2.21
(m, 1H), 2.05 (t, J = 5.7 Hz, 1H), 1.82 (m, 1H), 1.90 (m, 3H), 1.79 (d, J = 7 Hz, 3H), 1.38
13 (s, 3H), 1.29 (s, 3H), 1.22 (d, J = 10.9 Hz, 1H), 0.84 (s, 3H); C NMR (CDCl3, 125
MHz) δ 168.5, 135.7, 130.1, 85.7, 77.9, 51.6, 51.3, 39.5, 38.2, 35.5, 29.7, 28.6, 27.1,
11 26.3, 24.0, 14.5; B NMR (CDCl3, 80 MHz) δ 32.06; IR (thin film) νmax 2922, 1712,
1649, 1440, 1380, 1344, 1279, 1191, 1160, 1123, 1028, 755 cm−1; HRMS (ESI), m/z
calcd for C16H25O4BNa: 315.1744; found: 315.1736.
OH OH
1,7,7-Trimethyl-2-phenylbicyclo[2.2.1]heptane-2,3-diol (270). A 1M
solution of L-selectride in THF (15.0 mL, 15.0 mmol) was added via syringe to a solution
of (+)-(R)-camphorquinone (269) (2.50 g, 15.0 mmol) in THF (50 mL) at 0 °C under
nitrogen. The reaction mixture was stirred for 30 min between 0−5 °C. A second flask was charged with CeCl3 (6.75 g, 18.05 mmol) (pre-dried at 140 °C, at 10 mm Hg for 2
days) and THF (50 mL) was added. A 3M solution of PhMgBr (6.0 mL, 18.0 mmol) was
added dropwise to the slurry of CeCl3 to form a white suspension. The resulting
suspension was stirred for 30 min at 0 °C. To this white suspension, the reduction reaction mixture (L-selectride and (+)-(R)-camphorquinone) was added by cannula under nitrogen at 0 °C. The reaction mixture was allowed to warm to 25 °C and was vigorously stirred for 3 h. The mixture was slowly poured onto a saturated aqueous solution of
NH4Cl, and the mixture was extracted with ether (3 x 20 mL). The combined organic
150 extracts were dried (Na2SO4), filtered, and concentrated to afford a yellow oil (5.7 g). The
resulting oil was dissolved in a mixture of THF (25 mL) and water (12.5 mL). Aqueous
1M NaOH (25 mL) and 30% H2O2 (10 mL) were added, and the resulting biphasic reaction mixture was stirred for 3 h at 25 °C. The reaction mixture was extracted with ether (3 x 15 ml) and the combined extracts were washed with water (1 x 20 mL),
saturated aqueous NaCl (2 x 20 mL), and were dried (Na2SO4) and concentrated. The
resulting oil (3.6 g) was left under high vacuum (< 1mm Hg) for 6 h and was re-
crystallized from petroleum ether to afford after four crops, colorless crystals of the
1 desired diol 270 (2.2 g, 60 %): H NMR (CDCl3, 500 MHz) δ 7.52 (d, 2H, J = 2.5 Hz),
7.35 (m, 2H), 7.29 (m, 1H), 4.41 (d, 1H, J = 6.5 Hz), 2.92 (s, 1H), 2.62 (d, 1H, J = 6.5
Hz), 1.92 (d, 1H, J = 5.0 Hz), 1.77 (m, 1H), 1.35 (s, 3H), 1.99 (m, 2H), 1.03 (m, 1H),
13 0.95 (s, 3H), 0.90 (s, 3H); C NMR (CDCl3, 100 MHz) δ 144.5, 127.7, 127.1, 126.8,
84.3, 80.5, 53.2, 51.9, 50.7, 31.6, 30.4, 24.4, 23.1, 22.3, 14.1, 9.9; IR (thin film) νmax
3461, 3286, 2949, 1481, 1460, 1443, 1390, 1369, 1328, 1284, 1211, 1093, 1075, 1040,
−1 951, 899, 759, 723, 702 cm ; HRMS (ESI), m/z calcd for C16H22O2Na: 269.1517; found:
269.1511.
O O O B B O
Diboron reagent (272). A solution of
tetra(pyrrolidino)diborane (61.3 mg, 0.20 mmol) in freshly distilled benzene (0.5 mL)
was added to a vigorously stirred solution of diol 270 (100 mg, 0.41 mmol) in benzene
151 (0.2 mL) at 25 °C. A solution of 3M HCl in ether (0.5 mL) was added to the resulting mixture. After 6 h of vigorous stirring, the reaction mixture was filtered and benzene was removed under vacuum to afford the crude product as a yellow oil that was purified by flash chromatography (silica, 10% Et2O/hexane) to obtain the desired diborane reagent
272 (82 mg, 78%) as colorless crystals, which were found to be air-stable for several
1 days: H NMR (CDCl3, 500 MHz) δ 7.42 (s, 1H), 7.41 (s, 1H), 7.31-7.22 (m, 3H), 4.72
(s, 1H), 2.21 (d, 1H, J = 5 Hz), 1.83 (m, 1H), 1.27 (s, 3H), 1.20-1.14 (m, 2H), 1.03-0.95
13 (m, 1H), 0.99 (s, 3H), 0.91 (s, 3H); C NMR (CDCl3, 125 MHz) δ 141.5, 127.4, 127.2,
11 126.7, 96.0, 88.4, 52.2, 50.5, 48.8, 29.6, 24.9, 23.7, 20.7, 9.5; B NMR (CDCl3, 80
MHz) δ 31.90; IR (film) νmax 2958, 1485, 1445, 1369, 1265, 1244, 1145, 992, 956, 749,
−1 703 cm ; HRMS (ESI), m/z calcd for C32H40B2O4Na: 533.3010; found: 533.2998.
BF3K
CO2Me Carbomethoxycrotyl potassium trifluoroborate salt (275). An aqueous
solution of KHF2 (4.5 M, 1.7 mL) was added dropwise under nitrogen to a solution of
carbomethoxy pinacolylcrotylboronate 233 (520 mg, 2.17 mmol) in MeOH (10 mL). The reaction mixture was stirred for 25 min at 25 °C, concentrated in vacuo and the residue was dissolved in hot acetone. The reaction mixture was filtered and the filtrate was concentrated and re-crystallized from minimum volume of hot acetone and few drops of ether several times to obtain the required (E)-diastereomer of the potassium trifluoroborate salt 275 (380 mg, 80%) as colorless needle-like crystalline solid: 1H NMR
(acetone-d6, 400 MHz) δ 6.40 (q, 1H, J = 6.8 Hz), 3.59 (s, 3H), 1.69 (d, 3H, J = 6.8 Hz),
1.38 (bs, 2H); 13C NMR (DMSO-d6, 125 MHz) δ 169.9, 137.1, 128.9, 51.2, 14.5; 11B
152 NMR (acetone-d6, 80 MHz) δ 4.07 (q, J = 60 Hz); IR (film) νmax 2947, 2916, 1698, 1438,
1283, 1239, 1200, 1125, 1056, 1020, 935, 765 cm−1; HRMS (ESI), m/z calcd for
C6H9BF3O2K: 258.9919; found: 258.9918.
O O B
CO2Me
Carbomethoxycrotyl boronate (273). Trifluoroborate 275 (226
mg, 1.03 mmol) was dissolved in a mixture of acetonitrile and water (9 mL, 2:1), and
LiOH (74 mg, 3.09 mmol) was added in one portion. The reaction mixture was stirred for
20 h at 25 °C, and solid NH4Cl (70 mg, 1.31 mmol) was added to the reaction mixture. A
solution of 1N HCl (0.05 mL) was added dropwise by syringe. After vigorous stirring for
4 h, the reaction mixture was separated, the aqueous layer was extracted with ether (3 x
10 mL), and the combined organic extracts were washed with water (3 x 10 mL),
saturated aqueous NaCl (2 x 10 mL), and were dried (Na2SO4) and concentrated.
Purification of the residue by flash chromatography (silica, 10% Et2O/hexane) afforded boronate 273 (367 mg, 97%) as a colorless oil (≥95% (E)-isomer by NMR): 1H NMR
(CDCl3, 400 MHz) δ 7.40 (m, 2H), 7.33 (m, 3H), 6.82 (q, 1H, J = 7.2 Hz), 4.73 (s, 1H),
3.41 (s, 3H), 2.14 (d, 1H, J = 5.2 Hz), 1.88 (d, 2H, J = 2.0 Hz), 1.83 (m, 1H), 1.72 (d, 3H,
J = 7.2 Hz), 1.57 (s, 1H), 1.23 (s, 3H), 1.18 (m, 2H), 1.05 (m, 1H), 0.94 (s, 3H), 0.93 (s,
13 3H); C NMR (CDCl3, 125 MHz) δ 168.4, 141.8, 135.8, 129.6, 127.4, 127.2, 126.7,
95.7, 88.9, 88.4, 52.0, 51.3, 50.2, 48.8, 29.6, 24.9, 24.7, 23.6, 20.8, 14.5, 9.4, 9.3; 11B
NMR (CDCl3, 80 MHz) δ 34.23; IR (film) νmax 3448, 2956, 2365, 1718, 1648, 1341,
153 −1 1270, 1156, 1012 cm ; HRMS (ESI), m/z calcd for C22H29BO4Na: 391.2057; found:
391.2051.
OMe MeO
MeO CHO
O O 2-(Benzo[d][1,3]dioxol-6-yl)-3,4,5-trimethoxybenzaldehyde (224). 2-
Bromo-3,4,5-trimethoxybenzaldehyde (137) (200 mg, 0.73 mmol), 3,4-(Methylenedioxy) phenylboronic acid (237) (241.3 mg, 1.45 mmol), Pd2(dba)3 (26.6 mg, 0.03 mmol), S-
Phos (23.8 mg, 0.06 mmol) and anhydrous K3PO4 (462.8 mg, 2.18 mmol) were added to an oven-dried conical vial in a glove-box. The vial was taken out of the glove-box and flushed with argon. Toluene (3 mL) was added and the conical vial was sealed with a
Teflon cap and heated at 100 °C for 6 h. After cooling to 25 °C, the reaction mixture was passed through a short pad of Celite (ether wash, 20 mL). Concentration of the filtrate and purification of the residue by flash chromatography (silica, 5-10% EtOAc/hexane)
1 afforded 224 (216 mg, 90 %): H NMR (CDCl3, 500 MHz) 9.70 (s, 1H), 7.34 (s, 1H),
6.89 (d, 1H, J = 7.88 Hz), 6.85 (s, 1H), 6.74 (d, 1H, J = 7.84 Hz), 6.05 (s, 2H), 4.00 (s,
13 3H), 3.96 (s, 3H), 3.65 (s, 3H); C NMR (CDCl3, 125 MHz) δ 191.3, 153.1, 151.2,
147.6, 147.5, 134.0, 130.0, 126.3, 124.8, 111.3, 107.9, 105.2, 101.3, 61.1 (2C), 56.1,
29.7; IR (film) νmax 2937, 1681, 1587, 1504, 1480, 1461, 1438, 1390, 1325, 1288, 1235,
1197, 1159, 1129, 1083, 1039, 1005, 929, 860, 810, 757 cm−1; HRMS (ESI), m/z calcd for C17H16O6Na: 339.0845; found: 339.0845.
154 OMe MeO
MeO CHO
MeO OMe OMe 2-( 3,4,5-Trimethoxyphenyl)-3,4,5-trimethoxybenzaldehyde (223).
2-Bromo-3,4,5-trimethoxybenzaldehyde (137) (100 mg, 0.36 mmol), 3,4,5-
trimethoxyphenylboronic acid (154.4 mg, 0.73 mmol), finely powdered K3PO4 (231.8 mg, 1.09 mmol), Pd2(dba)3 (14 mg, 0.015 mmol) and S-Phos (11.9 mg, 0.03 mmol) were
added to an oven-dried conical vial in a glove-box. The vial was taken out of the glove-
box and flushed with argon. Toluene (3 mL) was added and the conical vial was sealed
with a Teflon screw-cap and heated at 100 °C for 8 h. After cooling to 25 °C, the reaction
mixture was passed through a short pad of Celite (ether wash, 20 mL). The filtrate was
evaporated and the residue was purified by flash chromatography (silica, 10%
1 EtOAc/hexane) to afford 223 (108 mg, 82%): H NMR (CDCl3, 400 MHz) δ 9.69 (s, 1H),
7.35 (s, 1H), 6.54 (s, 2H), 4.01 (s, 3H), 3.96 (s, 3H), 3.92 (s, 3H), 3.86 (s, 6H), 3.69 (s,
13 3H); C NMR (CDCl3, 100 MHz) δ 191.3, 153.2, 152.8, 151.1, 147.6, 137.8, 134.3,
129.8, 128.3, 108.4, 105.1, 61.3, 61.1, 61.0, 60.4, 56.3, 56.2, 21.0, 14.2; IR (film) νmax
2940, 1682, 1584, 1482, 1464, 1401, 1316, 1252, 1238, 1196, 1127, 1102, 1007, 929
−1 cm ; HRMS (ESI), m/z calcd for C19H22O7Na: 385.1263; found: 385.1263.
155 O O
MeO CHO
MeO OMe OMe 7-methoxy-6-(3,4,5-trimethoxyphenyl)benzo[d][1,3]dioxole-5-
carbaldehyde (211). Pd[P(t-Bu)3]2 (10 mg, 0.019 mmol) and 6-bromo-7-
methoxybenzo[d][1,3]dioxole-5-carbaldehyde (136) (100 mg, 0.386 mmol) were added to an oven-dried conical vial in a the glove box. The vial was taken out of the glove-box
and flushed with argon. THF (2 mL) was added to the mixture and was stirred for about 8
min. 3,4,5-trimethoxyphenyl boronic acid (164 mg, 0.772 mmol) in THF (2 mL) was
added by cannula to the reaction mixture (THF wash, 1 mL). Finely powdered NaOH
(46.3 mg, 1.16 mmol) was quickly added to the reaction mixture in one portion followed by dropwise addition of d-H2O (22 µL, 1.16 mmol) by a micro-syringe. The reaction
mixture was heated at 60 °C for 22 h. It was quenched by the addition of water (10 mL)
and diluted with ether (10 mL). The aqueous phase was extracted with ether (3 x 10 mL).
The combined organic extracts were collected, washed with saturated aqueous NaCl (2 x
10 mL), and was dried (Na2SO4). Concentration of the filtrate and purification of the
residue by flash chromatography (silica, 5% to 10% EtOAc/hexane) afforded 211 (73 mg,
1 55%) as a colorless crystalline solid: H NMR (CDCl3, 500 MHz) δ 9.56 (s, 1H), 7.21 (s,
13 1H), 6.49 (s, 2H), 6.01 (s, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 3.85 (s, 6H); C NMR (CDCl3,
125 MHz) δ 190.8, 153.4, 152.8, 149.1, 142.2, 140.7, 137.8, 135.4, 129.9, 128.3, 108.4,
104.7, 102.2, 101.0, 60.9, 60.2, 56.3, 56.2; IR (film) νmax 2936, 1679, 1606, 1582, 1509,
−1 1462, 1411, 1362, 1285, 1243, 1126 cm ; HRMS (ESI), m/z calcd for C18H18O7Na:
369.0950; found: 369.0947. 156
OMe MeO
MeO O O MeO OMe OMe Eupomatilone 2 (178). A solution of hexamethoxybiarylaldehyde
223 (36.3 mg, 0.10 mmol) in toluene (1 mL) was added to a solution of the
carbomethoxycrotyl boronate 273 (39 mg, 0.106 mmol) in toluene (1 mL) via a syringe.
The reaction vessel was flushed with Argon, sealed with Teflon and was heated at 75 °C
for 9 days. The reaction mixture was quenched by the addition of water (2 mL). The
aqueous layer was washed with ether (2 x 10 mL). The combined organic extracts were
washed with saturated aqueous NaCl (2 x 10 mL), and were dried (Na2SO4), concentrated. Purification of the residue by flash chromatography (silica, 10-50%
Et2O/hexane) afforded eupomatilone 2 (178) (34 mg, 74%) as a colorless syrup, in an
88:12 enantiomeric ratio (chiralpak AD-RH, i-PrOH/H2O = 50:50, flowrate = 0.35
1 mL/min, injection volume = 20 µL, λ=254 nm); H NMR (CDCl3, 500 MHz) δ 6.69 (s,
1H), 6.46 (d, 1H, J = 1.5 Hz), 6.37 (d, 1H, J = 2.0 Hz), 6.26 (d, 1H, J = 2.5 Hz), 5.55 (d,
1H, J = 2.0 Hz), 5.52 (d, 1H, J = 7.0 Hz), 3.92 (s, 6H), 3.89 (s, 3H), 3.87 (s, 3H), 3.85 (s,
3H), 3.70 (s, 3H), 2.88 (app tp, 1H, J = 7.5, 2.0 Hz), 0.87 (dd, 3H, J = 4.0, 2.5 Hz); 13C
NMR (CDCl3, 125 MHz) δ 170.2, 153.3, 153.1, 153.0, 151.3, 141.9, 140.9, 137.3, 131.1,
129.9, 127.7, 122.2, 107.4, 106.4, 104.9, 79.3, 61.4, 61.0, 60.9, 56.3, 56.2, 56.1, 38.3,
16.9; IR (film) νmax 2965, 2935, 2836, 1767, 1583, 1489, 1463, 1404, 1363, 1313, 1247,
−1 1127, 1103, 1002, 974 cm ; HRMS (ESI), m/z calcd for C24H28O8Na: 467.1682; found:
467.1675. 157 OMe MeO
MeO O O O O Eupomatilone 5 (179) (Method A – Suzuki–Miyaura). Aryl
bromide 137 (17 mg, 0.048 mmol), 3,4-(methylenedioxy) phenylboronic acid (237) (20.4 mg, 0.096 mmol), Pd2(dba)3 (2.0 mg, 0.002 mmol), S-Phos (1.6 mg, 0.004 mmol) and
finely powdered K3PO4 (30.6 mg, 0.144 mmol) were added to an oven dried round
bottom flask in a glove-box. The reaction vessel was taken out of the glove-box and
flushed with argon. Toluene (2 mL) was added, and the reaction mixture was warmed at
95 °C for 22 h. The reaction mixture was cooled to 25 °C and passed through a short pad
of Celite, and the filtrate was diluted with ether (5 mL) and was washed with water (2 x 5
mL), saturated aqueous NaCl (2 x 5 mL), and was dried (Na2SO4) and concentrated.
Purification of the residue by flash chromatography (silica, 10-20% Et2O/hexane) to
afford eupomatilone 5 (179) (18 mg, 95%) as a colorless oil: 83:17 enantiomeric ratio
(chiralpak AD-RH, i-PrOH/H2O=50:50, flowrate = 0.35 mL/min, injection volume = 20
µL, λ=254 nm).
(Method B - carbomethoxycrotylboration). An oven dried round bottom flask (5 mL)
was charged with carbomethoxycrotyl boronate 273 (30.2 mg, 0.082 mmol) in toluene
(1.0 mL) under argon. A solution of biaryl aldehyde 224 (23.4 mg, 0.074 mmol) in toluene (0.75 mL) was added via a syringe. The reaction mixture was vigorously stirred at 75 °C for 7 days and was quenched by the addition of water (2 mL) and diluted with ether (5 mL). The water layer was extracted with ether (2 x 5 mL). The combined organic 158 extracts were washed with saturated aqueous NaCl (2 x 5 mL), and was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 10-20%
Et2O/hexane) to afford eupomatilone 5 (179) (17 mg, 65%) as a colorless oil: 87:13
enantiomeric ratio (chiralpak AD-RH, i-PrOH/H2O=50:50, flowrate = 0.35 mL/min,
1 injection volume = 20 µL, λ=254 nm); H NMR (CDCl3, 500 MHz) δ 6.88 (d, 2H, J = 8
Hz), 6.73 (dd, 2H, J = 5.6, 1.6 Hz), 6.69 (s, 2H), 6.65 (d, 1H, J = 1.2 Hz), 6.60 (dd, 1H, J
= 8.0, 1.2 Hz), 6.24 (d, 2H, J = 2 Hz), 6.03 (ABq, 4H, J = 1.0 Hz, Δν = 8.7 Hz), 5.54 (d,
3H, J = 7.2 Hz), 5.45 (d, 1H, J = 7.2 Hz), 3.91 (s, 6H), 3.88 (s, 6H), 3.66 (s, 3H), 3.65 (s,
3H), 2.87 (dq, 2H, J = 5.0, 2.5 Hz), 0.83 (d, 3H, J = 7.6 Hz), 0.80 (d, 3H, J = 7.6 Hz); 13C
NMR (CDCl3, 125 MHz) δ 170.2, 152.9, 151.5, 147.7, 147.1, 141.9, 141.2, 130.1, 129.0,
127.2, 123.4, 122.8, 122.0, 110.6, 110.0, 108.6, 108.2, 104.8, 101.2, 79.4, 61.2, 60.9,
56.2, 38.4, 38.2, 17.3, 17.1; IR (film) νmax 2929, 2853, 2253, 1766, 1598, 1482, 1459,
1403, 1362, 1325, 1266, 1236, 1196, 1156, 1128, 1089, 1038, 1002, 971, 936, 912, 811,
−1 733 cm ; HRMS (ESI), m/z calcd for C22H22O7Na: 421.1263; found: 421.1265.
O O
MeO O O MeO OMe OMe Eupomatilone 1 (177). An oven-dried round bottom flask (5 mL) was charged with carbomethoxycrotyl boronate 273 (27 mg, 0.073 mmol) in toluene (0.5 ml)
under argon. A solution of biaryl aldehyde 211 (23 mg, 0.067 mmol) in toluene (1 mL)
was added via a syringe. The resulting reaction mixture was vigorously stirred at 85 °C
for 8 days. It was quenched by the addition of water (1 mL) and diluted with ether (5 159 mL). The water layer was extracted with ether (2 x 2 mL). The combined organic extracts
were washed with saturated aqueous NaCl (2 x 5 mL), and was dried (Na2SO4) and
concentrated. The residue was purified by chromatography (silica, 10-40 % ether/hexane)
to afford eupomatilone 1 (177) (9.2 mg, 32 %) as a colorless oil: 3.3:1 inseparable
1 diastereomeric cis:trans mixture 177 and 276: H NMR (CDCl3, 400 MHz) δ 6.56 (s,
1H), 6.44 (d, 1H, J = 2.0 Hz), 6.33 (d, 1H, J = 2.0 Hz), 6.25 (d, 1H, J = 2.8 Hz), 6.00 (s, 2
H), 5.53 (d, 1H, J = 2.4 Hz), 5.44 (d, 1H, J = 7.6 Hz), 3.91 (s, 3H), 3.856 (s, 3H), 3.852
13 (s, 3H), 3.846 (s, 3H), 2.93 (m, 1H), 0.88 (d, 3H, J = 7.2 Hz); C NMR (CDCl3, 100
MHz) δ 170.1, 153.3, 153.0, 148.8, 140.7, 137.3, 136.6, 131.0, 128.9, 127.4, 121.9,
107.7, 106.7, 101.4, 100.8, 79.3, 60.9, 60.0, 56.2, 56.1, 29.7, 22.7, 14.1; IR (thin film)
-1 νmax 2922, 2851, 2361, 2340, 1764, 1581, 1464, 1410, 1237, 1127, 1089, 1055, 974 cm ;
HRMS (ESI), m/z calcd for C23H24O8Na: 451.1369; found: 451.1366. (enantiomeric ratio, er = 94:6 for the cis-isomer, er = 89:11 for trans isomer) [Chiralpak-AD-RH
column; λ = 254 nm; flow rate: 0.25 mL/min; injection volume = 20 µL; i-PrOH:H2O =
50:50]
CH3O CH3O
CH3O O O O O 3-epi-Eupomatilone 6 (277). Eupomatilone 5 (179) (10 mg, 0.025
mmol), was taken in an oven-dried round bottom flask and was dissolved in methanol (5
mL). A spatula of palladium on charcoal was added to the reaction mixture and hydrogen
(balloon, 1 atm) was bubbled through the reaction mixture for 48 h at 25 °C. The reaction 160 mixture was filtered through a short pad of celite and was purified using column
chromatography (silica, 5% EtOAc/hexane) to afford 277 (two atropisomers) (9.3 mg,
1 92%): H NMR (CDCl3, 500 MHz) δ 6.88 (d, 1H, J = 7.9 Hz), 6.87 (d, 1H, J = 7.9 Hz),
6.83 (s, 1H), 6.82 (s, 1H), 6.73 (d, 1H, J = 1.4 Hz), 6.70 (dd, 1H, J = 1.4, 7.9 Hz), 6.62
(d, 1H, J = 1.4 Hz), 6.57 (dd, 1H, J = 1.4, 7.9 Hz), 6.05 (dd, 2H, J = 1.1, 4.3 Hz), 6.03
(m, 2H), 5.40 (d, 1H, J = 4.9 Hz), 5.32 (d, 1H, J = 4.9 Hz), 3.91 (s, 6H), 3.90 (s, 6H),
3.66 (s, 3H), 3.65 (s, 3H) 2.74 (app sextet, 2H, J = 7.0 Hz), 2.20-2.10 (m, 2H), 1.12 (d,
13 6H, J = 7.3 Hz), 0.56 (d, 3H, J = 7.3 Hz), 0.54 (d, 3H, J = 7.3 Hz): C NMR (CDCl3, 125
MHz) δ 178.7, 152.9, 151.5, 147.7, 147.6, 147.0, 146.9, 141.6, 130.2, 129.2, 129.1,
126.3, 126.2, 123.5, 122.4, 110.6, 109.6, 108.5, 108.2, 105.0, 104.9, 101.2, 101.1, 80.6,
80.5, 61.2, 61.1, 60.8, 56.2, 40.7, 38.9, 38.6, 29.7, 9.9, 9.8, 9.7; IR (neat) νmax 2972,
2938, 1775, 1598, 1482, 1458, 1436, 1402, 1360, 1340, 1323, 1273, 1226, 1173, 1127,
1092, 1057, 1038, 1006, 970, 934, 910, 859, 810, 734 cm–1; HRMS (ESI), m/z calcd for
C22H24O7Na: 423.1420; found: 423.1416.
Mayolide A:
TBDMSO
OH
CO2Me Methyl-3-hydroxy-5-(tert-butyl)dimethylsilyloxy-2-
methylenepentanoate (307). Methyl acrylate (115 mg, 0.12 mL, 0.106 mmol) was added
to aldehyde 308 (100 mg, 0.531 mmol) in an oven-dried round bottom flask under
nitrogen. 3-quinuclidonol (13.5 mg, 0.106 mmol) was added to the reaction mixture and
the reaction mixture was stirred neat for 2 d at 25 °C. Toluene (5 mL) was added to the 161 reaction mixture and was concentrated under reduced pressure. The crude mixture was
charged on to a silica-gel column and flash chromatography was performed
[toluene:ethylacetate 16:1 (v/v)] to afford the desired carbomethoxy allyl alcohol 307 as a
1 colorless oil (108 mg, 82 %): H NMR (CDCl3, 500 MHz) δ 6.30 (t, 1H, J = 1.0 Hz,
CH2=CH(OH)), 5.98 (t, 1H, J = 1.5 Hz, CH2=CH(OH)), 4.71 (app dp, 1H, J = 4.0, 1.0
Hz, CH-OH ), 3.96 (d, 1H, J = 4.5 Hz, -OH), 3.88-3.81 (m, 2H, CH2CH2OTBDMS), 3.76
(s, 3H, COOCH3), 1.99-1.95 (m, 1H, CH2CH2OTBDMS), 1.78-1.71 (m, 1H,
13 CH2CH2OTBDMS), 0.91 (s, 9H, (CH3)3C), 0.86 (t, 6H, J = 3.0 Hz, Si(CH3)2); C NMR
(CDCl3, 100 MHz) δ 166.7, 142.3, 125.0, 70.6, 62.2, 51.7, 37.6, 25.9 (2C), 18.1, −5.5; IR
(film) νmax 3477, 2951, 2927, 2855, 2359, 2338, 1718, 1471, 1437, 1255, 1194, 1155,
−1 1090, 836, 776 cm ; HRMS (ESI), m/z calcd for C13H26O4SiNa: 297.1498;
found:297.1490.
O OTBDMS B O MeO2C (E)-methyl 5-(tert-butyl)dimethylsilyloxy-2-((4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)pent-2-enoate (305). An oven dried round
bottom flask was charged with CuCl (18.5 mg, 0.187 mmol) and LiCl (7.9 mg, 0.187
mmol). DMF (2 mL) was added and the mixture was stirred for 1 h at 25 ºC under argon
when the solution became yellowish. A solution of bis(pinacolato)diboron (47.5 mg,
0.187 mmol) in DMF (2 mL) was added via cannula to the reaction mixture over 5 min when the solution became light green. Dry KOAc (18.4 mg, 0.187 mmol) was added to the reaction mixture in one portion, and the reaction mixture gradually turned blackish brown. A solution of allyl acetate 306 (45.6 mg, 0.144 mmol) in DMF (2 mL) was added 162 dropwise. The reaction mixture was stirred for 8 h at 25 °C, during which the color of the
reaction mixture gradually faded to light pink and finally turned blue. The reaction
mixture was quenched by the addition of water (4 mL). The mixture was extracted with
ether (2 x 10 mL) and the aqueous layer was re-extracted with ether (2 x 10 mL). The
combined organic extracts were washed with saturated aqueous NaCl (2 x 20 mL), and
were dried (Na2SO4), and concentrated. The residue was quickly purified by flash
chromatography (silica, 5% EtOAc/hexane) to afford boronate 305 (90:10 = E/Z) as a
1 colorless oil (49 mg, 88 %): H NMR (CDCl3, 400 MHz) δ 6.74 (t, 1H, J = 7.2 Hz, CH-
CH2CH2OTBDMS), 3.72 (s, 3H, COOCH3), 3.70-3.67 (m, 2H, CH2CH2OTBDMS),
2.40 (q, 2H, J = 7.2 Hz, CH2OTBDMS), 1.87 (s, 2H, BCH2), 1.24 (s, 12H,
13 BO2C2(CH3)4), 0.90 (s, 9H, (CH3)3C), 0.07 (s, 6H, Si(CH3)2); C NMR (CDCl3, 100
MHz) δ 168.5, 137.0, 130.6 (2C), 83.2 (2C), 61.8, 51.6 (2C), 32.7, 29.7, 25.9 (3C), 24.7
(4C), 18.3, −5.2; IR (film) νmax 3477, 2951, 2927, 2855, 2359, 2338, 1718, 1471, 1437,
−1 1255, 1194, 1155, 1090, 836, 776 cm ; HRMS (ESI), m/z calcd for C19H37BO5SiNa:
407.2401; found: 407.2408.
OH Bu3Sn (E)-4-(tributylstannyl)pent-3-en-1-ol (299). An oven-dried round
bottom flask was flushed with argon and was charged with CuCN (0.64 g, 7.14 mmol) in
a glove box. It was taken out from the glove box and the CuCN was suspended in THF
(20 mL), cooled to −78 °C and treated with n-BuLi in hexane (1.6 M, 8.92 mL, 14.3
mmol). The mixture was vigorously stirred till a homogeneous solution was obtained. n-
Bu3SnH (3.84 mL, 14.3 mmol) was added dropwise via a syringe at −78 °C. Stirring was
163 continued over ca. 10 min. The solution turned yellow with some frothing. MeOH (10.6
mL, 0.26 mmol) was added to the reaction mixture, and was allowed to warm up to −50
°C and pent-3-yn-1-ol (0.2 g, 2.38 mmol) was added via a syringe. The reaction was stirred for 6 h at this temperature. The reaction was followed by TLC and was quenched at −20 °C with saturated aqueous NH4Cl (10 mL) solution. The mixture was filtered and the aqueous layer was extracted with EtOAc (3 x 25 mL). The organic layer was washed with saturated aqueous NaCl (2 x 30 ml), dried (Na2SO4), and concentrated under
vacuum. The crude product was purified by column chromatography on silica gel (5 to
10% ethylacetate/hexane) to afford the alcohol 299 as a colorless oil (440 mg, 50 %): 1H
NMR (CDCl3, 500 MHz) δ 5.53 (tq, 1H, J = 8.75, 15 Hz, C=CH-CH2 ), 3.66 (q, 2H, J =
6.5 Hz, CH2-CH2OH), 2.43 (q, 2H, J = 6.5 Hz, CH-CH2-CH2OH), 1.93 (s, 3H, CH3), 1.52
13 (m, 6H, Sn(CH2)3), 1.31 (m, 6H, (CH2)3), 0.90 (m, 15H, (CH3CH2-)3); C NMR (CDCl3,
100 MHz) δ 142.4, 135.6, 62.3, 31.7, 29.2 (2), 29.1, 27.6, 27.4, 27.1, 19.3, 17.5, 13.7,
10.4, 9.1, 7.8; IR (film) νmax 3331, 2958, 2927, 2853, 1611, 1464, 1376, 1340, 1292,
−1 1181, 1046, 1021, 960, 874, 688, 662 cm ; HRMS (ESI), m/z calcd for C17H36OSnNa:
399.1686; found: 399.1687.
OAcO
TBDMSO OMe Methyl-3-acetoxy-5-tert-butyldimethylsilyloxy-2-
methylenepentanoate (306). Alcohol 307 (100 mg, 0.36 mmol) was taken in CH2Cl2 (2 mL) at room temperature in an oven-dried round bottom flask, flushed with nitrogen.
Freshly distilled triethylamine (46 mg, 0.43 mmol, 62 µL) was added via a microsyringe.
Freshly distilled acetic anhydride (44 mg, 0.43 mmol, 41 µL) was added via a
164 microsyringe and was followed by addition of catalytic DMAP crystals (5 mg). The reaction mixture was stirred for 2 h 30 min at 25 °C, quenched with saturated aqueous
NH4Cl solution (1 mL). The reaction mixture was diluted with CH2Cl2 (5 mL), the
organic layer was separated, washed with water (2 x 5 mL), saturated aqueous NaCl (2 x
5 mL), dried (Na2SO4), concentrated and the crude was purified by column
chromatography (silica, 5% ether/hexane (100 mL)) to obtain the acetate 306 as a
1 colorless oil (105 mg, 91%): H NMR (CDCl3, 400 MHz) δ 6.28 (s, 1H, CH=CH2), 5.77
(s, 1H, CH=CH2), 5.72 (m, 1H, CHOAc), 3.77 (s, 3H, CH3OCO), 3.66 (m, 2H, -CH2-
OTBDMS), 2.07 (s, 3H, CH3CO), 2.00 (m, 1H, CH2-CHOAc), 1.90 (m, 1H, CH2-
13 CHOAc), 0.89 (s, 9H, (CH3)3Si-), 0.03 (s, 6H, -Si(CH3)2-); C NMR (CDCl3, 100 MHz)
δ 169.8, 165.6, 140.1, 125.3, 69.5, 59.2, 51.9, 37.3, 25.9, 21.0, 18.2, -5.5; HRMS (ESI),
m/z calcd for C15H28O5SiNa: 339.1604; found: 339.1611.
TBDMSO OH tert-butyldimethylsilyloxy-1-propanol. In an oven-dried round
bottom flask was taken 1,3-propandiol (5 g, 65.71 mmol, 4.75 mL) in THF (30 mL).
Imidazole (4.7 g, 69 mmol) was added in one portion to the reaction flask and the
resulting solution was stirred at 0 °C for 10 min. tert-Butyldimethylsilylchloride (10.4 g,
69 mmol) in THF (25 mL) was added to the reaction mixture dropwise via a syringe at 0
°C for a period of 10 min. The reaction mixture was vigorously stirred and warmed up to
25 °C overnight. The reaction mixture was washed with saturated aqueous NaHCO3 (2 x
25 mL), distilled water (2 x 25 mL), saturated aqueous NaCl (2 x 25 mL), dried
(Na2SO4), filtered, concentrated and purified by column chromatography (silica, 5 to 10%
ethylacetate/hexane) to affored the silyl ether as a colorless oil (10.6 g, 85%): 1H NMR 165 (CDCl3, 500 MHz) δ 3.83 (m, 4H, HO-CH2-CH2-CH2-), 2.55 (t, 1H, J = 5.0 Hz, -OH),
1.79 (pent, 2H, J = 5.5 Hz, CH2-CH2-CH2-), 0.91 (s, 9H, C(CH3)3), 0.08 (s, 6H, Si(CH3)2)
13 ; C NMR (CDCl3, 100 MHz) δ 62.9, 62.8, 62.4, 62.3, 34.2, 25.9, 18.2, −5.3; IR (film)
−1 νmax 3353, 2955, 2930, 2858, 1472, 1389, 1362, 1256, 1098, 1007, 963, 837, 776 cm .
HRMS (ESI), m/z calcd for C9H22O2SiNa: 213.1287; found: 213.1285.
CHO
Br (E)-3-bromobut-2-enal (301). An oven-dried round bottom flask was equipped with an oven-dried stir-bar and trans-bromoallyl alcohol (309) (56 mg, 0.37 mmol) was taken in CH2Cl2 (1 mL). Freshly distilled triethylamine (160 µL, 1.11 mmol) was added dropwise using a microsyringe at −10 °C under nitrogen. SO3·Pyridine complex (176 mg, 1.11 mmol) was taken in DMSO (1 mL) and was added dropwise to the reaction mixture at −10 °C. The reaction mixture was vigorously stirred and was warmed up to 0 °C in 1 h. The reaction mixture was poured into an Erlenmyer flask (100 mL) containing crushed ice and saturated aqueous NaCl (20 mL) at 0 °C. The organic and aqueous layers were separated. The aqueous layer was back-washed with ether (3 x 20 mL). The combined organics were washed with 10% citric acid (2 x 10 mL), saturated aqueous NaCl (2 x 20 mL), dried (Na2SO4) and concentrated very carefully on a rotavap
as the product was volatile. (It is recommended to keep the temperature of the waterbath
of the rotavap close to 0 °C, and concentrate under mild aspirator suction). The residue
was quickly purified by passing through a short bed of silica in Pasteur pipette (10%
1 ether/hexane) to afford 301 as colorless oil (55 mg, 99%): H NMR (CDCl3, 400 MHz) δ
166 9.80 (d, 1H, J = 7.2 Hz, -CHO), 6.53 (dq, 1H, J = 7.2, 1.2 Hz, =CH–CHO), 2.78 (d, 1H, J
−1 = 1.2 Hz, CH3); IR (film) νmax 2923, 2853, 1717, 1463. 1377, 721 cm .
t-BuMe2SiO MeO
MeO OMe BnO OMe OMe Suzuki–Miyaura X-Ray Crystal Structure (159) (Figure 8.1).
[Coleman 1211]
Figure 8.1 B-alkyl Suzuki−Miyaura X-ray crystal structure of X
167 Crystallographic details for Coleman 1211
Empirical formula C36 H52 O7 Si
Formula weight 624.87
Temperature 150(2) K
Wavelength 0.71073 A
Crystal system monoclinic
Space group P2(1)/c
Unit cell dimensions a = 15.786(2) A b = 20.987(2) A c = 10.7670(10) A beta = 98.914(4) deg.
Volume 3524.0(6) A^3
Z 4
Density (calculated) 1.178 Mg/m^3
Absorption coefficient 0.112 mm^-1
F(000) 1352
Crystal size 0.04 x 0.15 x 0.38 mm
Theta range for data collection 2.15 to 25.03 deg.
Index ranges -18<=h<=18, -24<=k<=24, -12<=l<=12
Reflections collected 35800
Independent reflections 6210 [R(int) = 0.038]
Refinement method Full-matrix least-squares on F^2
Data / restraints / parameters 6209 / 0 / 553
Goodness-of-fit on F^2 1.025
Final R indices [I>2sigma(I)] R1 = 0.0449, wR2 = 0.1046
R indices (all data) R1 = 0.0716, wR2 = 0.1177
Largest diff. peak and hole 0.244 and -0.290 e/A^3
168
______
x y z U(eq) ______
Si 6767(1) -804(1) 1703(1) 30(1) O(1) 6429(1) -323(1) 2736(1) 30(1) O(2) 7498(1) -1016(1) 7216(1) 43(1) O(3) 9048(1) -496(1) 7758(1) 45(1) O(4) 9575(1) 412(1) 6306(1) 44(1) O(5) 7278(1) 4080(1) 4079(1) 43(1) O(6) 8184(1) 3965(1) 6349(1) 37(1) O(7) 8844(1) 2808(1) 7187(1) 34(1) C(1) 6879(1) 232(1) 3270(2) 27(1) C(2) 6194(1) 729(1) 3456(2) 30(1) C(3) 6543(1) 1324(1) 4212(2) 29(1) C(4) 7109(1) 1743(1) 3509(2) 31(1) C(5) 5675(2) 889(1) 2172(2) 42(1) C(6) 5811(2) 1710(1) 4618(2) 43(1) C(7) 7459(1) 2329(1) 4237(2) 29(1) C(8) 7221(1) 2930(1) 3774(2) 32(1) C(9) 7495(1) 3471(1) 4464(2) 32(1) C(10) 8011(1) 3421(1) 5632(2) 30(1) C(11) 8293(1) 2818(1) 6062(2) 29(1) C(12) 8010(1) 2277(1) 5372(2) 30(1) C(13) 9312(2) 2231(1) 7477(2) 42(1) C(14) 10025(1) 2331(1) 8552(2) 33(1) C(15) 10544(2) 2863(1) 8652(2) 45(1) C(16) 11230(2) 2919(1) 9611(2) 51(1) C(17) 11411(2) 2436(1) 10479(2) 48(1) C(18) 10904(2) 1901(1) 10385(2) 48(1) C(19) 10217(2) 1851(1) 9432(2) 42(1) C(20) 6958(2) 4175(1) 2781(2) 44(1) C(21) 9052(2) 4170(1) 6584(2) 39(1) C(22) 7456(1) 46(1) 4474(2) 26(1) C(23) 8259(1) 325(1) 4788(2) 29(1) C(24) 8782(1) 160(1) 5900(2) 33(1) C(25) 8508(1) -298(1) 6689(2) 34(1) C(26) 7706(1) -576(1) 6371(2) 31(1) C(27) 7178(1) -403(1) 5273(2) 29(1) C(28) 6683(2) -1312(1) 6927(2) 59(1) C(29) 8947(2) -125(1) 8837(2) 53(1) C(30) 9889(2) 862(1) 5488(3) 45(1) C(31) 6660(2) -408(1) 150(2) 56(1) C(32) 7902(2) -1033(1) 2226(3) 54(1) C(33) 6030(1) -1511(1) 1639(2) 30(1) C(34) 5105(2) -1286(1) 1317(3) 60(1) C(35) 6218(2) -1977(1) 627(3) 61(1) C(36) 6124(2) -1850(1) 2912(2) 56(1) U(eq): one third of the trace of the orthogonalized Uij tensor. ______
Table 8.1: Atomic coordinates ( x 10^4) and equivalent isotropic displacement parameters (A^2 x 10^3) for Coleman 1211.
169 ______
Si-O(1) 1.6508(14) Si-C(31) 1.852(2) Si-C(32) 1.856(3) Si-C(33) 1.880(2) O(1)-C(1) 1.437(2) O(2)-C(26) 1.372(2) O(2)-C(28) 1.418(3) O(3)-C(25) 1.385(2) O(3)-C(29) 1.428(3) O(4)-C(24) 1.367(2) O(4)-C(30) 1.431(3) O(5)-C(9) 1.371(2) O(5)-C(20) 1.424(3) O(6)-C(10) 1.382(2) O(6)-C(21) 1.421(3) O(7)-C(11) 1.377(2) O(7)-C(13) 1.428(2) C(1)-C(22) 1.515(3) C(1)-C(2) 1.539(3) C(1)-H(1) 0.99(2) C(2)-C(5) 1.531(3) C(2)-C(3) 1.544(3) C(2)-H(2) 0.97(2) C(3)-C(6) 1.530(3) C(3)-C(4) 1.536(3) C(3)-H(3) 1.00(2) C(4)-C(7) 1.515(3) C(4)-H(4A) 0.98(2) C(4)-H(4B) 1.01(2) C(5)-H(5A) 1.00(3) C(5)-H(5B) 1.04(3) C(5)-H(5C) 0.97(3) C(6)-H(6A) 1.00(3) C(6)-H(6B) 1.06(3) C(6)-H(6C) 1.01(3) C(7)-C(8) 1.387(3) C(7)-C(12) 1.390(3) C(8)-C(9) 1.388(3) C(8)-H(8) 0.97(2) C(9)-C(10) 1.393(3) C(10)-C(11) 1.395(3) C(11)-C(12) 1.393(3) C(12)-H(12) 0.96(2) C(13)-C(14) 1.500(3) C(13)-H(13A) 1.00(2) C(13)-H(13B) 0.97(2) C(14)-C(15) 1.379(3) C(14)-C(19) 1.384(3) C(15)-C(16) 1.381(3) C(15)-H(15) 0.95(2) C(16)-C(17) 1.378(3) C(16)-H(16) 0.97(3) C(17)-C(18) 1.372(3)
170 C(17)-H(17) 0.94(2) C(18)-C(19) 1.377(3) C(18)-H(18) 0.95(2) C(19)-H(19) 0.97(2) C(20)-H(20A) 1.00(3) C(20)-H(20B) 0.98(3) C(20)-H(20C) 0.96(3) C(21)-H(21A) 0.97(3) C(21)-H(21B) 0.89(3) C(21)-H(21C) 0.97(2) C(22)-C(23) 1.389(3) C(22)-C(27) 1.392(3) C(23)-C(24) 1.389(3) C(23)-H(23) 0.96(2) C(24)-C(25) 1.395(3) C(25)-C(26) 1.387(3) C(26)-C(27) 1.385(3) C(27)-H(27) 0.97(2) C(28)-H(28A) 0.96(3) C(28)-H(28B) 0.98(3) C(28)-H(28C) 1.05(3) C(29)-H(29A) 0.97(3) C(29)-H(29B) 0.99(3) C(29)-H(29C) 1.02(3) C(30)-H(30A) 0.96(3) C(30)-H(30B) 1.02(3) C(30)-H(30C) 0.99(3) C(31)-H(31A) 0.99(3) C(31)-H(31B) 0.92(3) C(31)-H(31C) 0.97(3) C(32)-H(32A) 0.92(3) C(32)-H(32B) 0.99(3) C(32)-H(32C) 0.95(3) C(33)-C(34) 1.523(3) C(33)-C(35) 1.526(3) C(33)-C(36) 1.531(3) C(34)-H(34A) 0.98(3) C(34)-H(34B) 1.05(3) C(34)-H(34C) 0.98(3) C(35)-H(35A) 1.03(3) C(35)-H(35B) 1.01(3) C(35)-H(35C) 1.00(3) C(36)-H(36A) 0.98(3) C(36)-H(36B) 1.00(3) C(36)-H(36C) 1.03(3)
O(1)-Si-C(31) 109.82(11) O(1)-Si-C(32) 110.56(10) C(31)-Si-C(32) 109.8(2) O(1)-Si-C(33) 104.18(8) C(31)-Si-C(33) 110.64(11) C(32)-Si-C(33) 111.70(12) C(1)-O(1)-Si 125.08(12) C(26)-O(2)-C(28) 116.8(2) C(25)-O(3)-C(29) 112.3(2)
171 C(24)-O(4)-C(30) 116.4(2) C(9)-O(5)-C(20) 117.4(2) C(10)-O(6)-C(21) 116.8(2) C(11)-O(7)-C(13) 116.1(2) O(1)-C(1)-C(22) 109.2(2) O(1)-C(1)-C(2) 106.8(2) C(22)-C(1)-C(2) 113.9(2) O(1)-C(1)-H(1) 109.6(11) C(22)-C(1)-H(1) 108.2(11) C(2)-C(1)-H(1) 109.2(11) C(5)-C(2)-C(1) 108.6(2) C(5)-C(2)-C(3) 113.4(2) C(1)-C(2)-C(3) 114.6(2) C(5)-C(2)-H(2) 107.7(12) C(1)-C(2)-H(2) 107.1(12) C(3)-C(2)-H(2) 105.1(11) C(6)-C(3)-C(4) 111.1(2) C(6)-C(3)-C(2) 110.8(2) C(4)-C(3)-C(2) 113.0(2) C(6)-C(3)-H(3) 107.6(11) C(4)-C(3)-H(3) 105.6(11) C(2)-C(3)-H(3) 108.4(11) C(7)-C(4)-C(3) 113.8(2) C(7)-C(4)-H(4A) 109.2(12) C(3)-C(4)-H(4A) 109.5(12) C(7)-C(4)-H(4B) 106.9(11) C(3)-C(4)-H(4B) 109.5(11) H(4A)-C(4)-H(4B) 108(2) C(2)-C(5)-H(5A) 112.0(14) C(2)-C(5)-H(5B) 110.0(13) H(5A)-C(5)-H(5B) 110(2) C(2)-C(5)-H(5C) 112.1(14) H(5A)-C(5)-H(5C) 103(2) H(5B)-C(5)-H(5C) 109(2) C(3)-C(6)-H(6A) 110.2(14) C(3)-C(6)-H(6B) 109.4(13) H(6A)-C(6)-H(6B) 110(2) C(3)-C(6)-H(6C) 112.6(14) H(6A)-C(6)-H(6C) 105(2) H(6B)-C(6)-H(6C) 110(2) C(8)-C(7)-C(12) 119.0(2) C(8)-C(7)-C(4) 119.7(2) C(12)-C(7)-C(4) 121.3(2) C(9)-C(8)-C(7) 120.4(2) C(9)-C(8)-H(8) 121.4(12) C(7)-C(8)-H(8) 118.1(12) O(5)-C(9)-C(8) 123.9(2) O(5)-C(9)-C(10) 115.3(2) C(8)-C(9)-C(10) 120.8(2) O(6)-C(10)-C(9) 118.6(2) O(6)-C(10)-C(11) 122.5(2) C(9)-C(10)-C(11) 118.7(2) O(7)-C(11)-C(12) 124.3(2) O(7)-C(11)-C(10) 115.6(2) C(12)-C(11)-C(10) 120.1(2)
172 C(7)-C(12)-C(11) 120.7(2) C(7)-C(12)-H(12) 117.8(12) C(11)-C(12)-H(12) 121.4(12) O(7)-C(13)-C(14) 110.5(2) O(7)-C(13)-H(13A) 108.3(13) C(14)-C(13)-H(13A) 108.6(13) O(7)-C(13)-H(13B) 108.2(14) C(14)-C(13)-H(13B) 111.0(13) H(13A)-C(13)-H(13B) 110(2) C(15)-C(14)-C(19) 118.1(2) C(15)-C(14)-C(13) 122.7(2) C(19)-C(14)-C(13) 119.0(2) C(14)-C(15)-C(16) 121.0(2) C(14)-C(15)-H(15) 119.4(14) C(16)-C(15)-H(15) 119.6(14) C(17)-C(16)-C(15) 120.1(2) C(17)-C(16)-H(16) 120.5(14) C(15)-C(16)-H(16) 119.4(14) C(18)-C(17)-C(16) 119.6(2) C(18)-C(17)-H(17) 122(2) C(16)-C(17)-H(17) 118(2) C(17)-C(18)-C(19) 120.0(2) C(17)-C(18)-H(18) 120.0(14) C(19)-C(18)-H(18) 119.9(14) C(18)-C(19)-C(14) 121.2(2) C(18)-C(19)-H(19) 121.8(13) C(14)-C(19)-H(19) 116.9(13) O(5)-C(20)-H(20A) 106.2(14) O(5)-C(20)-H(20B) 111.6(14) H(20A)-C(20)-H(20B) 108(2) O(5)-C(20)-H(20C) 112(2) H(20A)-C(20)-H(20C) 111(2) H(20B)-C(20)-H(20C) 108(2) O(6)-C(21)-H(21A) 106.3(14) O(6)-C(21)-H(21B) 111(2) H(21A)-C(21)-H(21B) 110(2) O(6)-C(21)-H(21C) 110.6(14) H(21A)-C(21)-H(21C) 109(2) H(21B)-C(21)-H(21C) 109(2) C(23)-C(22)-C(27) 119.9(2) C(23)-C(22)-C(1) 120.3(2) C(27)-C(22)-C(1) 119.8(2) C(24)-C(23)-C(22) 120.2(2) C(24)-C(23)-H(23) 119.4(12) C(22)-C(23)-H(23) 120.4(12) O(4)-C(24)-C(23) 124.9(2) O(4)-C(24)-C(25) 115.3(2) C(23)-C(24)-C(25) 119.8(2) O(3)-C(25)-C(26) 120.0(2) O(3)-C(25)-C(24) 120.2(2) C(26)-C(25)-C(24) 119.8(2) O(2)-C(26)-C(27) 124.6(2) O(2)-C(26)-C(25) 115.0(2) C(27)-C(26)-C(25) 120.4(2) C(26)-C(27)-C(22) 119.9(2)
173 C(26)-C(27)-H(27) 121.3(11) C(22)-C(27)-H(27) 118.8(11) O(2)-C(28)-H(28A) 107(2) O(2)-C(28)-H(28B) 111(2) H(28A)-C(28)-H(28B) 107(2) O(2)-C(28)-H(28C) 112(2) H(28A)-C(28)-H(28C) 109(2) H(28B)-C(28)-H(28C) 110(2) O(3)-C(29)-H(29A) 108(2) O(3)-C(29)-H(29B) 111(2) H(29A)-C(29)-H(29B) 109(2) O(3)-C(29)-H(29C) 109(2) H(29A)-C(29)-H(29C) 108(2) H(29B)-C(29)-H(29C) 111(2) O(4)-C(30)-H(30A) 104(2) O(4)-C(30)-H(30B) 112.3(14) H(30A)-C(30)-H(30B) 109(2) O(4)-C(30)-H(30C) 113(2) H(30A)-C(30)-H(30C) 110(2) H(30B)-C(30)-H(30C) 108(2) Si-C(31)-H(31A) 111(2) Si-C(31)-H(31B) 110(2) H(31A)-C(31)-H(31B) 109(2) Si-C(31)-H(31C) 111(2) H(31A)-C(31)-H(31C) 110(2) H(31B)-C(31)-H(31C) 106(3) Si-C(32)-H(32A) 113(2) Si-C(32)-H(32B) 114(2) H(32A)-C(32)-H(32B) 109(2) Si-C(32)-H(32C) 110(2) H(32A)-C(32)-H(32C) 104(2) H(32B)-C(32)-H(32C) 106(2) C(34)-C(33)-C(35) 108.8(2) C(34)-C(33)-C(36) 107.8(2) C(35)-C(33)-C(36) 109.8(2) C(34)-C(33)-Si 109.2(2) C(35)-C(33)-Si 110.1(2) C(36)-C(33)-Si 111.1(2) C(33)-C(34)-H(34A) 114(2) C(33)-C(34)-H(34B) 109(2) H(34A)-C(34)-H(34B) 106(2) C(33)-C(34)-H(34C) 109(2) H(34A)-C(34)-H(34C) 109(2) H(34B)-C(34)-H(34C) 110(2) C(33)-C(35)-H(35A) 111(2) C(33)-C(35)-H(35B) 110(2) H(35A)-C(35)-H(35B) 109(2) C(33)-C(35)-H(35C) 108(2) H(35A)-C(35)-H(35C) 112(3) H(35B)-C(35)-H(35C) 107(2) C(33)-C(36)-H(36A) 108(2) C(33)-C(36)-H(36B) 111(2) H(36A)-C(36)-H(36B) 110(2) C(33)-C(36)-H(36C) 113(2) H(36A)-C(36)-H(36C) 109(2)
174 H(36B)-C(36)-H(36C) 106(2) ______
Table 8.2: Bond lengths [A] and angles [deg] for Coleman 1211
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U11 U22 U33 U23 U13 U12 ______
Si 33(1) 29(1) 27(1) -4(1) 3(1) -6(1) O(1) 31(1) 27(1) 30(1) -6(1) 0(1) -7(1) O(2) 55(1) 38(1) 32(1) 4(1) 1(1) -4(1) O(3) 43(1) 49(1) 37(1) -2(1) -9(1) 15(1) O(4) 27(1) 53(1) 49(1) -4(1) -7(1) -4(1) O(5) 71(1) 25(1) 33(1) 3(1) 5(1) 3(1) O(6) 39(1) 30(1) 45(1) -13(1) 12(1) -6(1) O(7) 36(1) 30(1) 34(1) -6(1) -1(1) 4(1) C(1) 28(1) 26(1) 28(1) -5(1) 1(1) -6(1) C(2) 26(1) 31(1) 32(1) -1(1) 2(1) -1(1) C(3) 30(1) 28(1) 29(1) -1(1) 2(1) 4(1) C(4) 38(1) 27(1) 28(1) -3(1) 3(1) 0(1) C(5) 37(1) 38(1) 45(1) -4(1) -11(1) 2(1) C(6) 40(1) 37(1) 52(1) -7(1) 11(1) 2(1) C(7) 30(1) 29(1) 30(1) -3(1) 8(1) -2(1) C(8) 38(1) 30(1) 28(1) -1(1) 6(1) -1(1) C(9) 39(1) 26(1) 32(1) 2(1) 13(1) 0(1) C(10) 34(1) 25(1) 32(1) -5(1) 12(1) -3(1) C(11) 27(1) 32(1) 29(1) -3(1) 5(1) 1(1) C(12) 32(1) 23(1) 35(1) 0(1) 6(1) 2(1) C(13) 41(1) 30(1) 50(1) -4(1) -7(1) 3(1) C(14) 33(1) 30(1) 35(1) -4(1) 4(1) 1(1) C(15) 55(2) 37(1) 40(1) 11(1) -3(1) -6(1) C(16) 52(2) 45(2) 50(1) 5(1) -8(1) -17(1) C(17) 50(2) 49(2) 40(1) 1(1) -10(1) -5(1) C(18) 60(2) 43(2) 39(1) 11(1) -2(1) 0(1) C(19) 44(1) 35(1) 45(1) 4(1) 3(1) -9(1) C(20) 59(2) 39(1) 33(1) 9(1) 5(1) -2(1) C(21) 44(1) 35(1) 37(1) -2(1) 2(1) -6(1) C(22) 28(1) 22(1) 29(1) -7(1) 4(1) 1(1) C(23) 27(1) 26(1) 34(1) -6(1) 4(1) 1(1) C(24) 25(1) 34(1) 39(1) -10(1) 0(1) 4(1) C(25) 33(1) 33(1) 32(1) -6(1) -5(1) 10(1) C(26) 40(1) 26(1) 27(1) -3(1) 5(1) 4(1) C(27) 29(1) 27(1) 30(1) -7(1) 2(1) -1(1) C(28) 82(2) 51(2) 41(1) 5(1) 6(1) -27(2) C(29) 57(2) 60(2) 35(1) -7(1) -12(1) 8(1) C(30) 26(1) 45(2) 61(2) -8(1) 0(1) -4(1) C(31) 91(2) 44(2) 35(1) -1(1) 13(1) -25(2) C(32) 35(1) 55(2) 71(2) -22(1) 8(1) -3(1) C(33) 35(1) 26(1) 29(1) -2(1) 3(1) -3(1) C(34) 38(2) 51(2) 85(2) 1(2) -7(1) -14(1)
175 C(35) 87(2) 38(2) 65(2) -22(1) 32(2) -26(2) C(36) 75(2) 45(2) 46(1) 11(1) 6(1) -17(2)
______
Table 8.3: Anisotropic displacement parameters (A^2 x 10^3) for Coleman 1211. The anisotropic displacement factor exponent takes the form: -2 pi^2 [ h^2 a*^2 U11 + ... + 2 h k a* b* U12 ]
______
x y z U(eq) ______
H(1) 7244(13) 403(9) 2676(17) 33 H(2) 5809(13) 530(9) 3957(18) 36 H(3) 6923(13) 1179(9) 4992(18) 35 H(4A) 7590(14) 1489(10) 3294(17) 37 H(4B) 6763(13) 1899(9) 2696(19) 37 H(5A) 5334(16) 516(12) 1795(22) 63 H(5B) 6080(16) 1049(12) 1568(23) 63 H(5C) 5235(16) 1208(12) 2233(22) 63 H(6A) 6048(16) 2066(12) 5192(23) 64 H(6B) 5427(16) 1408(12) 5089(22) 64 H(6C) 5445(16) 1926(12) 3890(23) 64 H(8) 6847(13) 2960(9) 2966(19) 38 H(12) 8165(13) 1857(10) 5679(17) 36 H(13A) 9567(14) 2100(10) 6717(21) 50 H(13B) 8916(15) 1908(11) 7678(20) 50 H(15) 10429(14) 3195(11) 8048(21) 54 H(16) 11577(16) 3300(12) 9671(21) 61 H(17) 11878(16) 2489(11) 11126(23) 58 H(18) 11013(15) 1575(11) 10994(22) 58 H(19) 9833(15) 1489(11) 9365(20) 50 H(20A) 6857(16) 4646(13) 2671(22) 65 H(20B) 6408(18) 3957(12) 2531(23) 65 H(20C) 7351(17) 4024(12) 2247(24) 65 H(21A) 9044(15) 4599(13) 6908(21) 58 H(21B) 9288(16) 4168(11) 5884(24) 58 H(21C) 9384(16) 3901(12) 7205(23) 58 H(23) 8461(13) 630(10) 4232(18) 35 H(27) 6615(13) -589(9) 5045(17) 35 H(28A) 6638(19) -1612(14) 7584(28) 88 H(28B) 6638(19) -1551(14) 6140(29) 88 H(28C) 6185(20) -979(14) 6884(26) 88 H(29A) 9307(18) -308(13) 9558(27) 79 H(29B) 8343(20) -123(13) 8984(25) 79 H(29C) 9155(18) 326(14) 8726(24) 79 H(30A) 10436(18) 988(12) 5935(23) 67 H(30B) 9500(17) 1252(13) 5324(22) 67 H(30C) 9958(16) 675(12) 4661(24) 67 H(31A) 6899(18) -678(14) -469(27) 84
176 H(31B) 6949(19) -24(15) 228(25) 84 H(31C) 6065(20) -303(14) -156(26) 84 H(32A) 8111(18) -1301(14) 1668(26) 81 H(32B) 8010(18) -1224(13) 3074(27) 81 H(32C) 8259(19) -667(14) 2255(25) 81 H(34A) 4975(19) -1062(15) 513(28) 90 H(34B) 4981(19) -959(14) 2006(27) 90 H(34C) 4719(20) -1655(15) 1306(26) 90 H(35A) 6122(19) -1765(14) -246(29) 92 H(35B) 5838(19) -2363(15) 616(27) 92 H(35C) 6822(22) -2131(14) 867(28) 92 H(36A) 6716(20) -2009(14) 3112(26) 83 H(36B) 5711(19) -2214(14) 2896(25) 83 H(36C) 6005(18) -1554(13) 3625(27) 83
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Table 8.4: Hydrogen coordinates ( x 10^4) and isotropic displacement parameters (A^2 x 10^3)for Coleman 1211
t-BuMe2SiO MeO OH
MeO OMe Hydroboration-oxidation X-Ray Crystal Structure (160) (Figure 8.2). [Coleman 1106]
177
Figure 8.2 Hydroboration-oxidation X-Ray Crystal Structure for 160
Crystallographic details for Coleman 1106
Empirical formula C21 H38 O5 Si
Formula weight 398.60
Temperature 200(2) K
Wavelength 0.71073 A 178
Crystal system monoclinic
Space group P2(1)/n
Unit cell dimensions a = 6.679(1) A b = 33.845(5) A c = 10.224(2) A beta = 97.29(1) deg.
Volume 2292.6(7) A^3
Z 4
Density (calculated) 1.155 Mg/m^3
Absorption coefficient 0.129 mm^-1
F(000) 872
Crystal size 0.04 x 0.31 x 0.35 mm
Theta range for data collection 2.10 to 25.03 deg.
Index ranges -7<=h<=7, -40<=k<=40, -12<=l<=12
Reflections collected 22262
Independent reflections 4018 [R(int) = 0.032]
Refinement method Full-matrix least-squares on F^2
Data / restraints / parameters 4018 / 0 / 257
Goodness-of-fit on F^2 1.019
Final R indices [I>2sigma(I)] R1 = 0.0611, wR2 = 0.1503
R indices (all data) R1 = 0.0808, wR2 = 0.1641
Largest diff. peak and hole 1.504 and -0.627 e/A^3
______
x y z U(eq) ______
Si 1268(1) 8043(1) 1885(1) 37(1) O(1) 2324(3) 8389(1) 2909(2) 32(1) O(2) 6268(4) 8438(1) 4017(3) 81(1) O(3) 4077(3) 9741(1) 1190(2) 35(1) O(4) 1591(3) 10254(1) 2077(2) 39(1)
179 O(5) -1304(3) 10022(1) 3528(2) 38(1) C(1) 1290(4) 8655(1) 3698(3) 29(1) C(2) 2202(4) 8635(1) 5168(3) 30(1) C(3) 4347(4) 8812(1) 5509(3) 37(1) C(4) 6101(5) 8536(1) 5329(3) 54(1) C(5) 1988(5) 8218(1) 5713(3) 42(1) C(6) 4635(6) 8964(1) 6939(3) 56(1) C(7) 3459(5) 7741(1) 1453(3) 47(1) C(8) -487(5) 7736(1) 2747(3) 43(1) C(9) -118(5) 8260(1) 332(3) 45(1) C(10) -1771(5) 8548(1) 657(4) 57(1) C(11) 1353(7) 8474(1) -465(4) 63(1) C(12) -1098(7) 7920(1) -516(4) 74(1) C(13) 1301(4) 9074(1) 3172(3) 28(1) C(14) 2731(4) 9199(1) 2382(3) 28(1) C(15) 2752(4) 9591(1) 1978(2) 27(1) C(16) 1390(4) 9862(1) 2386(3) 29(1) C(17) -49(4) 9735(1) 3165(3) 29(1) C(18) -104(4) 9340(1) 3545(3) 30(1) C(19) 5389(5) 9469(1) 647(3) 42(1) C(20) -57(5) 10427(1) 1247(4) 54(1) C(21) -2915(5) 9902(1) 4234(3) 43(1) U(eq): one third of the trace of the orthogonalized Uij tensor. ______
Table 8.5: Atomic coordinates (x 10^4) and equivalent isotropic displacement parameters (A^2 x 10^3) for Coleman 1106
______
Si-O(1) 1.668(2) Si-C(8) 1.868(3) Si-C(9) 1.882(3) Si-C(7) 1.884(3) O(1)-C(1) 1.442(3) O(2)-C(4) 1.400(4) O(2)-H(1O2) 0.78(4) O(3)-C(15) 1.368(3) O(3)-C(19) 1.430(3) O(4)-C(16) 1.377(3) O(4)-C(20) 1.427(4) O(5)-C(17) 1.365(3) O(5)-C(21) 1.429(4) C(1)-C(13) 1.515(4) C(1)-C(2) 1.549(4) C(1)-H(1) 1.00 C(2)-C(5) 1.529(4) C(2)-C(3) 1.552(4) C(2)-H(2) 1.00 C(3)-C(4) 1.528(5) C(3)-C(6) 1.538(4) C(3)-H(3) 1.00 C(4)-H(4A) 0.99 C(4)-H(4B) 0.99
180 C(5)-H(5A) 0.98 C(5)-H(5B) 0.98 C(5)-H(5C) 0.98 C(6)-H(6A) 0.98 C(6)-H(6B) 0.98 C(6)-H(6C) 0.98 C(7)-H(7A) 0.98 C(7)-H(7B) 0.98 C(7)-H(7C) 0.98 C(8)-H(8A) 0.98 C(8)-H(8B) 0.98 C(8)-H(8C) 0.98 C(9)-C(11) 1.535(5) C(9)-C(12) 1.535(5) C(9)-C(10) 1.543(5) C(10)-H(10A) 0.98 C(10)-H(10B) 0.98 C(10)-H(10C) 0.98 C(11)-H(11A) 0.98 C(11)-H(11B) 0.98 C(11)-H(11C) 0.98 C(12)-H(12A) 0.98 C(12)-H(12B) 0.98 C(12)-H(12C) 0.98 C(13)-C(18) 1.388(4) C(13)-C(14) 1.393(4) C(14)-C(15) 1.391(4) C(14)-H(14) 0.95 C(15)-C(16) 1.392(4) C(16)-C(17) 1.391(4) C(17)-C(18) 1.396(4) C(18)-H(18) 0.95 C(19)-H(19A) 0.98 C(19)-H(19B) 0.98 C(19)-H(19C) 0.98 C(20)-H(20A) 0.98 C(20)-H(20B) 0.98 C(20)-H(20C) 0.98 C(20)-H(20D) 0.96 C(20)-H(20E) 0.93 C(20)-H(20F) 0.98 C(21)-H(21A) 0.98 C(21)-H(21B) 0.98 C(21)-H(21C) 0.98 O(1)-Si-C(8) 109.59(12) O(1)-Si-C(9) 112.28(12) C(8)-Si-C(9) 110.1(2) O(1)-Si-C(7) 104.45(14) C(8)-Si-C(7) 111.2(2) C(9)-Si-C(7) 109.1(2) C(1)-O(1)-Si 126.5(2) C(4)-O(2)-H(1O2) 114(3) C(15)-O(3)-C(19) 117.7(2) C(16)-O(4)-C(20) 116.2(2) C(17)-O(5)-C(21) 117.6(2)
181 O(1)-C(1)-C(13) 111.1(2) O(1)-C(1)-C(2) 110.9(2) C(13)-C(1)-C(2) 111.6(2) O(1)-C(1)-H(1) 107.7 C(13)-C(1)-H(1) 107.7 C(2)-C(1)-H(1) 107.7 C(5)-C(2)-C(1) 110.6(2) C(5)-C(2)-C(3) 113.7(2) C(1)-C(2)-C(3) 116.0(2) C(5)-C(2)-H(2) 105.1 C(1)-C(2)-H(2) 105.1 C(3)-C(2)-H(2) 105.1 C(4)-C(3)-C(6) 108.3(3) C(4)-C(3)-C(2) 115.8(3) C(6)-C(3)-C(2) 110.1(2) C(4)-C(3)-H(3) 107.4 C(6)-C(3)-H(3) 107.4 C(2)-C(3)-H(3) 107.4 O(2)-C(4)-C(3) 114.6(3) O(2)-C(4)-H(4A) 108.6 C(3)-C(4)-H(4A) 108.6 O(2)-C(4)-H(4B) 108.6 C(3)-C(4)-H(4B) 108.6 H(4A)-C(4)-H(4B) 107.6 C(2)-C(5)-H(5A) 109.5 C(2)-C(5)-H(5B) 109.5 H(5A)-C(5)-H(5B) 109.5 C(2)-C(5)-H(5C) 109.5 H(5A)-C(5)-H(5C) 109.5 H(5B)-C(5)-H(5C) 109.5 C(3)-C(6)-H(6A) 109.5 C(3)-C(6)-H(6B) 109.5 H(6A)-C(6)-H(6B) 109.5 C(3)-C(6)-H(6C) 109.5 H(6A)-C(6)-H(6C) 109.5 H(6B)-C(6)-H(6C) 109.5 Si-C(7)-H(7A) 109.5 Si-C(7)-H(7B) 109.5 H(7A)-C(7)-H(7B) 109.5 Si-C(7)-H(7C) 109.5 H(7A)-C(7)-H(7C) 109.5 H(7B)-C(7)-H(7C) 109.5 Si-C(8)-H(8A) 109.5 Si-C(8)-H(8B) 109.5 H(8A)-C(8)-H(8B) 109.5 Si-C(8)-H(8C) 109.5 H(8A)-C(8)-H(8C) 109.5 H(8B)-C(8)-H(8C) 109.5 C(11)-C(9)-C(12) 108.0(3) C(11)-C(9)-C(10) 109.9(3) C(12)-C(9)-C(10) 109.3(3) C(11)-C(9)-Si 110.6(2) C(12)-C(9)-Si 108.3(2) C(10)-C(9)-Si 110.7(2) C(9)-C(10)-H(10A) 109.5
182 C(9)-C(10)-H(10B) 109.5 H(10A)-C(10)-H(10B) 109.5 C(9)-C(10)-H(10C) 109.5 H(10A)-C(10)-H(10C) 109.5 H(10B)-C(10)-H(10C) 109.5 C(9)-C(11)-H(11A) 109.5 C(9)-C(11)-H(11B) 109.5 H(11A)-C(11)-H(11B) 109.5 C(9)-C(11)-H(11C) 109.5 H(11A)-C(11)-H(11C) 109.5 H(11B)-C(11)-H(11C) 109.5 C(9)-C(12)-H(12A) 109.5 C(9)-C(12)-H(12B) 109.5 H(12A)-C(12)-H(12B) 109.5 C(9)-C(12)-H(12C) 109.5 H(12A)-C(12)-H(12C) 109.5 H(12B)-C(12)-H(12C) 109.5 C(18)-C(13)-C(14) 120.0(2) C(18)-C(13)-C(1) 118.3(2) C(14)-C(13)-C(1) 121.7(2) C(15)-C(14)-C(13) 119.7(2) C(15)-C(14)-H(14) 120.1 C(13)-C(14)-H(14) 120.1 O(3)-C(15)-C(14) 124.1(2) O(3)-C(15)-C(16) 115.4(2) C(14)-C(15)-C(16) 120.5(2) O(4)-C(16)-C(17) 121.6(2) O(4)-C(16)-C(15) 118.7(2) C(17)-C(16)-C(15) 119.6(2) O(5)-C(17)-C(16) 115.4(2) O(5)-C(17)-C(18) 124.7(2) C(16)-C(17)-C(18) 119.9(2) C(13)-C(18)-C(17) 120.2(3) C(13)-C(18)-H(18) 119.9 C(17)-C(18)-H(18) 119.9 O(3)-C(19)-H(19A) 109.5 O(3)-C(19)-H(19B) 109.5 H(19A)-C(19)-H(19B) 109.5 O(3)-C(19)-H(19C) 109.5 H(19A)-C(19)-H(19C) 109.5 H(19B)-C(19)-H(19C) 109.5 O(4)-C(20)-H(20A) 109.5 O(4)-C(20)-H(20B) 109.5 H(20A)-C(20)-H(20B) 109.5 O(4)-C(20)-H(20C) 109.5 H(20A)-C(20)-H(20C) 109.5 H(20B)-C(20)-H(20C) 109.5 O(4)-C(20)-H(20D) 113.6 O(4)-C(20)-H(20E) 111.0 H(20D)-C(20)-H(20E) 121.4 O(4)-C(20)-H(20F) 102.0 H(20D)-C(20)-H(20F) 100.0 H(20E)-C(20)-H(20F) 105.9 O(5)-C(21)-H(21A) 109.5 O(5)-C(21)-H(21B) 109.5
183 H(21A)-C(21)-H(21B) 109.5 O(5)-C(21)-H(21C) 109.5 H(21A)-C(21)-H(21C) 109.5 H(21B)-C(21)-H(21C) 109.5 ______
Table 8.6: Bond lengths [A] and angles [deg] for Coleman 1106
______
U11 U22 U33 U23 U13 U12 ______
Si 45(1) 31(1) 34(1) -2(1) 6(1) -5(1) O(1) 38(1) 28(1) 31(1) -2(1) 6(1) -2(1) O(2) 34(2) 137(3) 71(2) -39(2) 8(1) 8(2) O(3) 38(1) 31(1) 40(1) 8(1) 15(1) 1(1) O(4) 38(1) 27(1) 53(1) 8(1) 4(1) 0(1) O(5) 35(1) 36(1) 46(1) 0(1) 14(1) 6(1) C(1) 28(1) 29(1) 31(1) 1(1) 5(1) -1(1) C(2) 31(2) 30(1) 29(1) 2(1) 8(1) 1(1) C(3) 37(2) 42(2) 30(2) 2(1) 3(1) -2(1) C(4) 36(2) 72(2) 52(2) -4(2) 1(2) 2(2) C(5) 52(2) 38(2) 37(2) 7(1) 7(1) -2(2) C(6) 59(2) 68(2) 39(2) -10(2) -3(2) -13(2) C(7) 47(2) 43(2) 53(2) -1(2) 12(2) 9(2) C(8) 48(2) 36(2) 45(2) -1(1) 8(2) -8(1) C(9) 55(2) 39(2) 39(2) -2(1) -1(2) 0(2) C(10) 50(2) 52(2) 63(2) -6(2) -13(2) 15(2) C(11) 87(3) 61(2) 42(2) 8(2) 11(2) -5(2) C(12) 100(3) 58(2) 57(2) -11(2) -22(2) -9(2) C(13) 27(1) 29(1) 28(1) 0(1) 0(1) -3(1) C(14) 27(1) 29(1) 28(1) 1(1) 3(1) 2(1) C(15) 25(1) 31(1) 25(1) 2(1) 1(1) -4(1) C(16) 32(2) 25(1) 28(1) 1(1) -3(1) 0(1) C(17) 25(1) 32(2) 29(1) -3(1) -1(1) 2(1) C(18) 25(1) 34(2) 31(1) 2(1) 3(1) -3(1) C(19) 41(2) 40(2) 47(2) 7(1) 20(2) 5(1) C(20) 56(2) 45(2) 61(2) 21(2) 10(2) 15(2) C(21) 32(2) 49(2) 49(2) -7(2) 14(1) 2(1) ______
Table 8.7: Anisotropic displacement parameters (A^2 x 10^3) for Coleman 1106. The anisotropic displacement factor exponent takes the form: -2 pi^2 [h^2 a*^2 U11 + ... + 2 h k a* b* U12]
______x y z U(eq) ______
H(1O2) 5240(57) 8422(10) 3567(35) 42(10)* H(1) -148(4) 8567(1) 3637(3) 35
184 H(2) 1306(4) 8804(1) 5645(3) 36 H(3) 4446(4) 9045(1) 4920(3) 44 H(4A) 7375(5) 8663(1) 5718(3) 65 H(4B) 5941(5) 8290(1) 5826(3) 65 H(5A) 2525(29) 8213(2) 6651(6) 63 H(5B) 2744(27) 8031(1) 5230(14) 63 H(5C) 560(6) 8143(3) 5607(19) 63 H(6A) 5915(19) 9108(6) 7106(8) 85 H(6B) 4656(38) 8739(1) 7546(3) 85 H(6C) 3519(21) 9141(6) 7075(8) 85 H(7A) 2956(6) 7525(4) 859(18) 71 H(7B) 4197(21) 7630(6) 2260(4) 71 H(7C) 4365(19) 7909(2) 1016(20) 71 H(8A) -1088(25) 7530(4) 2149(8) 64 H(8B) -1557(19) 7905(2) 3016(19) 64 H(8C) 264(8) 7614(5) 3529(12) 64 H(10A) -2626(24) 8418(3) 1238(21) 85 H(10B) -2598(25) 8629(6) -160(4) 85 H(10C) -1140(5) 8782(4) 1100(23) 85 H(11A) 1894(32) 8708(5) 20(13) 95 H(11B) 640(12) 8554(7) -1321(11) 95 H(11C) 2464(23) 8296(3) -603(23) 95 H(12A) -2104(33) 7789(6) -48(14) 111 H(12B) -60(10) 7729(5) -688(26) 111 H(12C) -1757(41) 8026(2) -1355(13) 111 H(14) 3689(4) 9017(1) 2121(3) 34 H(18) -1107(4) 9252(1) 4059(3) 36 H(19A) 6132(24) 9608(2) 18(16) 62 H(19B) 4588(5) 9256(3) 193(18) 62 H(19C) 6346(21) 9358(5) 1358(4) 62 H(20A) 242(5) 10705(1) 1090(4) 81 H(20B) -1284(5) 10409(1) 1677(4) 81 H(20C) -260(5) 10286(1) 404(4) 81 H(20D) -1200 10253 1058 81 H(20E) 400 10581 590 81 H(20F) -600 10614 1852 81 H(21A) -3701(20) 10134(1) 4430(19) 64 H(21B) -2358(5) 9774(6) 5060(10) 64 H(21C) -3791(19) 9716(5) 3695(9) 64 ______
Table 8.8: Hydrogen coordinates (x 10^4) and isotropic displacement parameters (A^2 x 10^3) for Coleman 1106 (*Refined isotropically)
185
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200
APPENDIX
SELECTED SPECTRA
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222 e
M
O
O
O
)
5
6
1
(
r
B
O
i
e
S
2
M
e
O
M
u
B
-
t
O O
e e
M M
223
224
225
226
227
228
229
230
231 r
e
)
1 m
H
7 o
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s 1
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p
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t
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s l
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M u M
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232
233
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235
236
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H
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239 u
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311