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Laney Graduate School

Emory College

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Application of IMDAF and Rh(II)-Catalyzed Cascade Reactions for Total Synthesis of Natural Products

Boonsombat, Jutatip (2008)
Dissertation (457 pages)
Committee Chair / Thesis Adviser: Padwa, Albert
Committee Members: McDonald, Frank ; Blakey, Simon
Research Fields: Chemistry, Organic
Keywords: strychnos; strychnine; IMDAF; Diels-Alder; Rh; diazo; komaroviquinone; fawcettimine; furanether; 1,3-dioxoles ; oxabicyclo[3.2.1]octane ; hydroindole; hydroquinoline
Program: Laney Graduate School, Chemistry
Permanent url: http://pid.emory.edu/ark:/25593/16wnr

Abstract

There are two major themes to this thesis. In part A, an intramolecular [4 + 2]-cycloaddition/rearrangement cascade of an indolyl-substituted amidofuran (IMDAF) was utilized as a key strategy for the synthesis of various natural products containing the hydroindole or hydroquinoline ring system. The total synthesis of several Strychnos alkaloids were developed. The central step consists of an IMDAF reaction that delivers an aza-tetracyclic ABCE-rings of the Strychnos alkaloid family. Closure of the remaining D-ring was carried out by an intramolecular palladium-catalyzed enolate-driven cross-coupling reaction. The IMDAF approach was successfully applied to the synthesis of (±)-strychnopivotine, (±)-tubifolidine, and (±)-valparicine. A variation of this tactic was utilized for a synthesis of the heptacyclic alkaloid (±)-strychnine. Another aspect of the thesis was to test the IMDAF strategy for an approach toward the fawcettimine alkaloid family. We were able to assemble the BCD core structure of the carbinolamine portion of fawcettimine. An efficient route for the construction of the methyl furanyl carbamate necessary for the alkaloids was also developed. However, attempts to cyclize the A-ring using an internal displacement reaction were unsuccessful. Further work is therefore necessary to determine the appropriate precursor for A-ring formation.
Part B of the thesis involves the application of Rh(II)-catalyzed cyclization/cycloaddition cascade for preparing natural products containing the oxabicyclo[3.2.1]octane ring system. The intramolecular Rh(II)-catalyzed reactions of an ortho-carbomethoxy aryl diazo dione was investigated as a potential route to the oxatricyclo[6.3.1.00,0]dodecane substructure found in komaroviquinone. Preparation of the hexa-substituted arene required for the natural product is also described. Part B also describes attempts to prepare a furan precursor for a synthesis of furanether B by a Rh(II)-catalyzed reaction. An efficient strategy to prepare the requisite 3,4-disubstituted furan is described. Further investigations dealing with the critical diazo furanyl ketone needed are underway. We have also investigated the Rh(II)-catalyzed reaction of the Z-isomer of 2-diazo-3,6-dioxo-6-phenyl-hex-4-enoic acid methyl ester and found that we were unable to trigger a [5+2]-cycloaddition. Instead, an unknown dimer was formed as the major product. The Rh(II)-catalyzed reaction of the E-isomer was carried out in the presence of various carbonyl compounds and was found to give 1,3-dioxoles as products.

Table of Contents

Table of Contents


Part A: The IMDAF reaction for the construction of natural products containing hydroindole or hydroquinoline system
Chapter A.1. General introduction……………………………………..… 2
Chapter A.2. Application of the cycloaddition/rearrangement cascade of
2-amidofurans for the synthesis of Strychnos alkaloids…….26
A.2.1. Total synthesis of (±)-strychnopivotine……………………..... 37
A.2.2. Total synthesis of (±)-tubifolidine (118)………………….…… 48
A.2.3. Total synthesis of (±)-valparicine (119)…………………..….. 49
A.2.4. Total synthesis of (±)-strychnine (120)……………………….. 51
A.2.5. Lewis acid promoted IMDAF reaction……………………...… 62
Chapter A.3. Application of the cycloaddition/rearrangement cascade of 2-amidofuran toward the synthesis of Fawcettimine alkaloids………………………………………………………….75
Experimental section…………………………………………………………... 101
X-Ray Data……………………………………………………………�� 219
References..............………………………….......……….... 241


Part B: Application of Rh(II) catalyzed reactions for natural product synthesis containing oxabicyclo[3.2.1]octane ring
Chapter B.1. General introduction………………………………….………… 265
Chapter B.2. Application of the Rh(II)-Catalyzed [3+2]-cycloaddition towards the synthesis of

komaroviquinone.................287
Chapter B.3. The application of Rh(II)-catalyzed [3+2]-cycloaddition
towards the synthesis of furanether B………………..………. 317
Chapter B.4. Investigation of novel cycloaddition reaction toward ylides... 339
Experimental section……………………………………………………………... 350
References…………………...……………………………………………………. 415

Table of Schemes

Part A
Scheme 1. Cyclization to a hydroindole core by amine with carbonyl tether……………………………………………………………….4
Scheme 2. Reductive amination approach to hydroindole and hydroquinoline………………………………………………...……. 5
Scheme 3. 1,4-addition pathway via phenolic oxidation to hydroindole and hydroquinoline system……………….…....6
Scheme 4. Ring closure to hydroindole by cyclization of amine tether onto a cyclohexene ring………………………….. 7
Scheme 5. Synthesis of hydroquinoline by cyclization of amine tether 8
Scheme 6. Transition-metal assisted cyclization to hydroindole and hydroquinoline…………....……………………………... 9
Scheme 7. Zirconium-catalyzed cyclization reactions……………………… 10
Scheme 8. A [4+1]-cycloaddition reaction to hydroindole ring…………….. 11
Scheme 9. Diels-Alder approach to hydroindole and hydroquinoline skeletons………………………………………………………12
Scheme 10 Hanessian's tandem intramolecular N-acyloxyiminium ion carbocyclization................................... 13
Scheme 11. Intramolecular Diels-Alder reaction to hydroindole and hydroquinoline system………………………………… 14
Scheme 12. Pearson's azaallyl anion cycloaddition…………………………. 15
Scheme 13. Banwell‘s approach to hexahydroindole……………………….. 15
Scheme 14. Overman's aza-Cope Mannich Approach……………………… 16
Scheme 15. Ene-yne-ene ring closing metathesis to hydroindoline……….. 17
Scheme 16. The IMDAF cycloaddition/rearrangement cascade sequence of amidofurans…………………...…………….. 18
Scheme 17. Rate enhancement with carbonyl present in tether..………….. 19
Scheme 18. IMDAF reaction of 2-amidofuran employing indole as dienophile………………………………………………………….20
Scheme 19. Padwa's IMDAF cycloaddition/rearrangement approach to mesembrane ..................……………….….. 21
Scheme 20. Synthesis of dendrobine via IMDAF reaction………………….. 22
Scheme 21. Efficient synthesis of epi-zephyranthine via oxabicyclic cycloadduct from IMDAFreaction…………………23
Scheme 22. The synthesis of lycoridine via one-pot Stille/IMDAF cascade on model substrate…………………………….24
Scheme 23. Rapid construction of the pentacyclic skeleton of the aspidosperma Alkaloid via IMDAF reaction…….25
Scheme 24. Harley-Mason's transannular approach………………………... 29
Scheme 25. Overman's aza-Cope/Mannich approach …………................. 30
Scheme 26. Bonjoch's approach using cis-3a-(2-nitrophenyl)octahydroindol-4-ones (137) as a key intermediate. ........................................................................................................................31
Scheme 27. Kuehne's condensation-sigmatropic rearrangement-cyclization cascade approach……………………………33
Scheme 28. Martin's biomimetic approach…………………………………… 34
Scheme 29. Retrosynthetic analysis for pentacyclic framework of Strychnos alkaloids…………………………………………36
Scheme 30. Preparation of enolate coupling precursor 166………………... 38
Scheme 31. Previous examples of Pd-catalyzed enolate coupling of alkenyl halides……........…………………………….. 39
Scheme 32. Initial attempt at Pd-catalyzed D-ring closure………………….. 40
Scheme 33. The IMDAF reaction of compound 178………………………… 42
Scheme 34. Acyl group migration in compound 179 and 182……………… 43
Scheme 35. Enamide reduction………………………………………………... 44
Scheme 36. Preparation of the pentacyclic common intermediate 193…… 46
Scheme 37. Attempts to use benzoyl protecting group approach………….. 47
Scheme 38. Completion of synthesis of strychnopivotine…………………... 48
Scheme 39. Completion of synthesis of tubifolidine…………………………... 49
Scheme 40. Biogenetic synthesis of valparicine……………………………... 50
Scheme 41. Completion of synthesis of valparicine…………………………. 51
Scheme 42. Biosynthesis of strychnine……………………………………….. 53
Scheme 43. Conversion of isostrychnine or Wieland-Gumlich aldehyde into Strychnine……………………………………… 55
Scheme 44. Retrosynthetic analysis of strychnine…………………………... 56
Scheme 45. Attempt for enolate coupling with TBS-protected side chain… 57
Scheme 46. Synthesis of methyl ether protected side chain……………...... 57
Scheme 47. Optimization of Pd-enolate coupling reaction………………….. 58
Scheme 48. Preparation of PMB and MOM protected side chains………… 59
Scheme 49. Enolate coupling with PMB and MOM protected side chains... 60
Scheme 50. Completion of strychnine synthesis…………………………….. 62
Scheme 51. An irreproducible IMDAF reaction…………………...………….. 63
Scheme 52. Preparation of amidofuran……………………..…………….. 69
Scheme 53. Attempts to prepare trifluoroacetyl indole 257.......................... 71
Scheme 54. Biological synthesis of fawcettimine alkaloids…………………. 78
Scheme 55. Inubushi's synthesis of fawcettimine……………………………. 80
Scheme 56. Heathcock's fawcettimine synthesis……………………………. 81
Scheme 57. The effect of equilibration of the keto-amine forms for the generation of fawcettimine…………………..82
Scheme 58. Toste's organocatalytic/gold catalyzed cyclization approach to (+)-fawcettimine………….………….....83
Scheme 59. Retrosynthetic analysis of fawcettidine………………………… 85
Scheme 60. The preparation of IMDAF precursor…………………………… 86
Scheme 61. The IMDAF reaction studies to BCD ring of fawcettimine core 88
Scheme 62. Preparation of IMDAF precursor with protected acetal……….. 90
Scheme 63. The first approach for a preparation of methyl furan………….. 91
Scheme 64. The second approach for a preparation of methyl furan……… 93
Scheme 65. The formation of IMDAF reaction with methyl furan…………... 94
Scheme 66. The double deprotection of tricyclic system 330…………........…. 96
Scheme 67. Attempts for the generation of A-ring................................... 97
Scheme 68. Attempts toward the generation of fawcettimine core using benzyl protected alcohol……………………99


Part B
Scheme 1. Extension of the oxabicyclo[3.2.1]octane system to other natural products…………………………………267
Scheme 2. SmI2-mediated tandem conjugate addition/nucleophile acyl substitution……………………………….……268
Scheme 3. Prins-Pinacol reaction for the formation of oxabibyclo[3.2.1]octane 269
Scheme 4. 1,5 Michael-type reactions of 5-oxo-η3-allylmolybdenum complexes……………………………………………270
Scheme 5. Intramolecular oxymercuration to form oxabicyclo[3.2.1]octane. 271
Scheme 6. Oxabicyclo[3.2.1]octane derivatives from D-arabinose……… 272
Scheme 7. Tandem cyclization to bridged ethers by Friedel-Craft cyclization………………………………………………………273
Scheme 8. Variations of intramolecular Friedel-Crafts cyclization to generate benzene-fused oxabicyclo[3.2.1]octane……………. 273
Scheme 9. An example of [4+3]-annuation approach using furan and allyl cation…………………...…………………………275
Scheme 10. A Lewis acid-mediated [4+3]-annualation approach to the oxabicyclo[3.2.1]octane ring system….275
Scheme 11. The [5+2]-cycloaddition approach to the oxabicyclo[3.2.1]octane derivative in the formal synthesis of polygalolides A and B……276
Scheme 12. Liebeskind's [5+2]-cycloaddition reaction using Mo-ï°-complex scaffolds…………………………….……..277
Scheme 13. Generation of carbonyl ylides from oxiranes and 1,3,4-oxadiazolines…………………………………….………..278
Scheme 14. The construction of bicyclo[3.2.1]octane from Pt-containing carbonyl ylides…………………………………279
Scheme 15. The Rh(II)-catalyzed tandem reactions of diazo compounds..................................................280
Scheme 16. The use of intramolecular Rh(II)-catalyzed [3+2]-cycloaddition toward the synthesis of zaragozic acid……………………………281
Scheme 17. Intramolecular Rh-catalyzed [3+2]-cycloaddtion to oxabicyclo[3.2.1]octane…………………………….281
Scheme 18. Synthesis of polygalolides A and B………………….…………. 282
Scheme 19. Padwa's synthesis of brevicomin…………………..…………… 283
Scheme 20. The use of Rh(II)-mediated [3+2]-cycloaddition in the synthesis of illudin M and pterosin Z, I

and H…………………….………….284
Scheme 21. A [3+2]-cycloaddition reaction for the synthesis of aspidophytine 285
Scheme 22. General acess to vinca and tacaman alkaloids using Rh(II)- catalyzed [3+2]-cycloaddition……………286
Scheme 23. Proposed biological transformation of komaroviquinone to Komarovispirone…………………………….………289
Scheme 24. The first total synthesis of (±)-komaroviquinone by Banerjee.................................................290
Scheme 25. Majetich's total synthesis of (±)-komaroviquinone…….……… 291
Scheme 26. Majetich's enantiospecific total synthesis of (+)-komaroviquinone.. 292
Scheme 27. Padwa's retrosynthetic analysis of komaroviquinone……….. 293
Scheme 28. The formation of the oxa-tricyclo[6.3.1.00,0]dodecane skeleton using the Rh(II)-catalyzed reaction……………………….……..295
Scheme 29. Example of oxirane formations by Rh(II)-catalyzed decomposition of diazo compounds………..…….…297
Scheme 30. The hydrolytic conversion to the corresponding hemiketal……..… 298
Scheme 31. The generation of 4,4-dimethyl-hex-5-enal side chain….......… 299
Scheme 32. The Rh(II)-catalyzed reaction of the related dimethyl substituted -Compound………………………..…. 300
Scheme 33. The retrosynthetic analysis of the diazo key precursor….…… 301
Scheme 34. Application of Moore/Liebeskind method for the synthesis of requisite phenol……………………..……..303
Scheme 35. Moore's synthesis of phenanthridinediols by a ring expansion procedure……..……………………………..304
Scheme 36. The attempts to phenol using thermolysis of cyclobutenone 305
Scheme 37. Attempts to achieve the desired electrophilic aromatic substitution reactions from protected benzyl alcohol…….……306
Scheme 38. An alternative route to penta-substituted aromatic ring system 306
Scheme 39. Attempts to synthesize penta-substituted arene…………….… 308
Scheme 40. The synthesis of pentasubsituted arene using Carreño's method……………………………………………………309
Scheme 41. The synthesis of the model side chain……………………….… 310
Scheme 42. Introduction of diketone tether by Friedel-Crafts acylation.….. 310
Scheme 43. Introduction of the tether by addition of the dianion with the aldehyde………………………………..…..311
Scheme 44. Attempt to direct lithiation of MOM protected benzyl alcohol 202 …..............………………………….312
Scheme 45. White's success of electrophilic aromatic substitution nucleophilic.. 312
Scheme 46. The success synthesis of hexa-substituted arene…………..… 313
Scheme 47. The synthesis of an arene model system…………………….... 314
Scheme 48. Formation of the lactone product from IBX oxidation……..….. 315
Scheme 49. Proposed mechanism for lactone formation………………….... 316
Scheme 50. Schore's first total synthesis of furanether B……………….….. 320
Scheme 51. Schore's second total synthesis of furanether B…………..….. 321
Scheme 52. The total synthesis by Molander via [3+4]-annulation reaction….. 322
Scheme 53. The total synthesis by de Groot using a base induced rearrangement…………………………………………….323
Scheme 54. Retrosynthetic analysis to furanether B……..…………….…… 324
Scheme 55. Examples of [3+2]-cycloaddition reactions of various substrates.. 325
Scheme 56. Different stereoselectivity of [3+2]-cycloadditions in different steric environment ………………………326
Scheme 57. Changes in stereoselectivity of [3+2]-cycloaddition caused by different metal catalysts………………327
Scheme 58. Examples of 3,4-disubstituted furan formation…………….….. 329
Scheme 59. The synthesis of diethyl furan-3,4-diacetates by Wenkert….... 330
Scheme 60. Attempts to synthesize 3,4-disubstituted furan 277 using a one-carbon homologation process…...331
Scheme 61. Itoh's entry to 3- and 3,4-disubstituted furans from Z-2-butene-1,4-Diols…………………………….………332
Scheme 62. Synthetic route to furan 284 starting from Z-2-butene-1,4-diols……………………………………………………333
Scheme 63. The synthesis of dihydro-isobenzofuran 290…………….……. 334
Scheme 64. Attempts for oxidative cleavage of isolated double bound of furan 290……………………………………………335
Scheme 65. Attempts for selective ozonolysis…………………….…………. 336
Scheme 66. The synthesis of furan 300 containing the required side chains...... 336
Scheme 67. Attempts to the key diazo furan 301……………………….…… 337
Scheme 68. Example of [5+2]-cycloaddition reactions to oxabicyclo[3.2.1]octane............341
Scheme 69. The cycloaddition reaction analysis toward oxidopyrylium ylide using Rh(II)-catalyzed chemistry….342
Scheme 70. Unusual formation of pyranone 314 from 5-phenylfuran-2,3-dione………………………………………………343
Scheme 71. The purposed mechanism of the formation of pyranone 314............................................... 344
Scheme 72. The preparation of -diazo compounds 307 and 324……..…. 345
Scheme 73. The attempts for a [5+2]-cycloaddition of a Z-isomer of a-diazo compounds 307………………...…. 345
Scheme 74. The formation of 1,3-dioxoles from E-isomer of a -diazo compounds 324…………………………………… 346
Scheme 75. The reaction of profile of Rh(II)-carbenoid of Z-and E- a -diazo ketoesters…………��…………………….. 348

Table of Figures

Part A
Figure 1. Representative examples of natural products containing hydroindole unit………………………………………... 3
Figure 2. Some representative Strychnos alkaloids………………………... 27
Figure 3. The temperature measurement using internal fiber optic probe. 65
Figure 4. Four related classes of Lycopodium alkaloids…………….…….. 77
Figure 5. Various members of carbinolamine form fawcettimine alkaloids 84
Figure 6. ORTEP of compound 370…………..…………..…………………. 98
Figure 7. ORTEP of cycloadduct 330b………………………………………. 189

Part B
Figure 1. Example of natural products containing the oxabicyclo[3.2.1]octane system……………………................266
Figure 2. Some representative examples of lactarane sesquiterpenes … 318


Table of Tables
Part A
Table 1. Ratio of starting material to product and yield of product in a variety of Lewis acids…………………………. 66
Table 2. Ratio of starting material to product in different amounts of catalysts and temperatures …………………..68
Table 3. The ratio of starting material and product of benzofuran 247 with and without MgI2 catalyst in different temperature…………. 70
Table 4. The ratio of starting material and product of cyclohexene 257 with and without MgI2 catalyst in different temperature…………72
Table 5. % ee obtained from initial studies of enantioselective IMDAF reaction………………………………………………….73

Part B
Table 1. Reaction of E-isomer of ï¡-diazo compound (24) with various carbonyl compounds……………………………..347

List of Abbreviations

µ micro
[a] specific rotation
Ac acetyl
anal analysis
Aq aqueous
Ar argon
Bn benzyl
Boc tert-butoxycarbonyl
br broad
Bu butyl
oC degree Celsius
calcd calculated
d chemical shift(s)
d doublet
DIBAL-H Diisobutylaluminum hydride
DMAP demethylamino pyridine
Decomp decomposition
DMF dimethyl formamide
DMSO dimethyl sulfoxide
E entgegen
ee enantiomeric excess
ESI electrospray ionization
EDG electron donating group(s)
EWG electron withdrawing group(s)
Et ethyl
FT Fourier transform
g gram(s)
h hour(s)
HPLC high performance liquid chromatography
HRMS high resolution mass spectroscopy
Hz hertz
IBCF Isobutylchloroformate
i-Pr isopropyl
IR Infrared Spectroscopy
J coupling constant
LA Lewis acid
LHMDS lithium bis(trimethylsilyl)amide
mol mole
m multiplet
m-CPBA meta-chloroperbenzoic acid
Me methyl
mg milligram(s)
MHz megahertz
min minute(s)
mL milliliter(s)
µL microliter(s)
mmol millimole(s)
mp melting point
Ms Methanesulfonyl
NMM 4-methylmorpholine
NMR Nuclear Magnetic Resonance
q quartet
rt room temperature
s singlet
SM starting material
t triplet
TBAF Tetrabutylammonium fluoride
TBAHS Tetrabutylammonium hydrogen sulfate
TBS tert-butyldimethylsilyl
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
p-TsOH para-toluenesulfonic acid

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