Synthetic Studies Towards the Total Syntheses of the Tetracyclic Diquinane Lycopodium Alkaloids Magellanine and Magellaninone Aimin Wang

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2005 Synthetic Studies Towards the Total Syntheses of the Tetracyclic Diquinane Lycopodium Alkaloids Magellanine and Magellaninone Aimin Wang

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COLLEGE OF ARTS AND SCIENCES

SYNTHETIC STUDIES TOWARDS THE TOTAL SYNTHESES OF THE

TETRACYCLIC DIQUINANE LYCOPODIUM ALKALOIDS MAGELLANINE

AND MAGELLANINONE

AIMIN WANG

A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy

Degree Awarded: Spring Semester, 2005

The members of the Committee approve the dissertation of Aimin Wang defended on March 29, 2005.

______Marie E. Krafft Professor Directing Dissertation

______Laura R. Keller Outside Committee Member

______Robert A. Holton Committee Member

______Martin A. Schwartz Committee Member

______Kenneth A. Goldsby Committee Member

The Office of Graduate Studies has verified and approved the above named committee members.

ACKNOWLEDGMENT

Finishing this dissertation turned out to be quite an adventure and I would like to thank the following people who helped along the way:

Professor Marie E. Krafft, my research adviser, for her guidance and help in these years.

Past and current Krafft group members, thank you all for the help and laughter in the lab. To name a few, Dr. Chitaru Hirosawa, Dr. Masaharu Sugiura, Dr. Peter Schmidt, James Wright, Moonki Seok.

Florida State University and the Chemistry department for this opportunity and the International Student Center staff for their genuine help!

iii

TABLE OF CONTENTS

LIST OF SCHEMES...... vi LIST OF FIGURES ...... ix LIST OF ABBREVIATIONS...... xii ABSTRACT...... xv INTRODUCTION ...... 1 Retrosynthetic analysis...... 9 PAUSON-KHAND APPROACH...... 12 Pauson-Khand reaction...... 12 Mechanism...... 12 Scope of the reaction...... 16 Regioselectivity...... 19 Triquinane-type tricyclic systems...... 21 Results and Discussion...... 32 Summary and Conclusions...... 43 Experimental Section...... 46 PALLADIUM ASSISTED DOMINO PROCESS APPROACH ...... 57 Heck Reaction ...... 57 Mechanism...... 58 Dehydropalladation...... 60 Palladium Assisted Domino Reactions ...... 63 Intermolecular carbopalladations...... 64 Intramolecular carbopalladations...... 66 Results and Discussion...... 74 Summary and Conclusions...... 87 Experimental Section...... 90 iv REFERENCES...... 157 BIOGRAPHICAL SKETCH ...... 162

LIST OF SCHEMES

Scheme Page

Scheme 1. Acid-promoted Prins-pinacol reaction ...... 2 Scheme 2. Overman’s approach ...... 3 Scheme 3. Sequential Michael reactions ...... 4 Scheme 4. Paquette’s approach ...... 5 Scheme 5. Oxa-di-π-methane (ODPM) rearrangement...... 6 Scheme 6. Liao’s approach...... 7 Scheme 7. Hoshino’s approach...... 8 Scheme 8. Pauson-Khand Approach ...... 9 Scheme 9. Palladium assisted domino process approach ...... 10 Scheme 10. Biscyclization...... 11 Scheme 11. Pauson-Khand Reaction...... 12 Scheme 12. Working Pauson-Khand reaction mechanism...... 13 Scheme 13. Interrupted Pauson-Khand Reaction...... 15 Scheme 14. Cis labilization ...... 15 Scheme 15. Labilization trans to an electron-donating group ...... 16 Scheme 16. Electron deficient alkenes...... 17 Scheme 17. Conjugated 1,3-diene ...... 18 Scheme 18. Multicomponent cycloadditions...... 19 Scheme 19. Interrupted Pauson-Khand of 11 and 12 ...... 20 Scheme 20. Regioselectivity...... 21 Scheme 21. Endo-cyclic enynes ...... 21 Scheme 22. Exo-cyclic enynes ...... 22 vi Scheme 23. Tricyclic angularly fused [5.5.5] enone 17 ...... 23 Scheme 24. Intramolecular cycloaddition of enyne 19...... 24 Scheme 25. (+)-15-nor-pentalenene ...... 25 Scheme 26. Tricyclic angularly fused [5.5.5] and [5.5.6] enones ...... 26 Scheme 27. Tricyclic angularly fused [5.6.5] and [5.6.6] enones ...... 26 Scheme 28. Tricyclic angularly fused [5.5.6] and [5.6.6] enones ...... 27 Scheme 29. Pauson-Khand reaction of enyne 22 and 23...... 28 Scheme 30. Pauson-Khand reaction of enyne 24 ...... 28 Scheme 31. Pauson-Khand reaction of enyne 25, 26, 27, 28 ...... 29 Scheme 32. Dendrobine...... 29 Scheme 33. Asymmetric synthesis of (-)-dendrobine...... 30 Scheme 34. Tetracyclic pyrrolidine (+)-30...... 30 Scheme 35. Tricyclic core of nakadomarin and manzamine...... 31 Scheme 36. α- and β-cedrene ...... 32 Scheme 37. Synthesis of 38 ...... 33 Scheme 38. Enyne 39 and 40...... 35 Scheme 39. Synthesis of 48 ...... 36 Scheme 40. Synthesis of 53 ...... 38 Scheme 41. Substrates 54-64...... 38 Scheme 42. Syntheses of 54 and 55...... 39 Scheme 43. Synthesis of 56 ...... 39 Scheme 44. Synthesis of 59 ...... 40 Scheme 45. Synthesis of 60 ...... 40 Scheme 46. Synthesis of 57 ...... 41 Scheme 47. Synthesis of 58 ...... 41 Scheme 48. Syntheses of 61-64...... 42 Scheme 49. Heck reaction ...... 57 Scheme 50. Mechanism...... 58 Scheme 51. Reduction ...... 59

vii Scheme 52. Dehydropalladation...... 60 Scheme 53. Carbamate chelation of the σ-palladium intermediate...... 61 Scheme 54. Vinyl iodide 67...... 62 Scheme 55. Stable palladium-containing compounds 72, 73 ...... 63 Scheme 56. Migratory insertion...... 65 Scheme 57. Intermolecular three-component coupling ...... 65 Scheme 58. Linear fused mode carbopalladation ...... 66 Scheme 59. Dumbbell-mode carbopalladation...... 67 Scheme 60. Zipper-mode carbopalladation ...... 67 Scheme 61. Scopadulcic acid B...... 68 Scheme 62. Palladium-mediated intramolecular cyclization...... 68 Scheme 63. Mechanism...... 70 Scheme 64. Palladium catalyzed tris-cyclization ...... 71 Scheme 65. Synthesis of tetracycle 85...... 71 Scheme 66. Synthesis of 87 ...... 73 Scheme 67. Syntheses of 91 and 93...... 73 Scheme 68. Zipper-mode cascade of iodide 94 ...... 74 Scheme 69. Synthesis of 105 ...... 76 Scheme 70. Synthesis of 109 ...... 78 Scheme 71. Synthesis of 115 ...... 80 Scheme 72. Palladium assisted domino biscyclization...... 81 Scheme 73. Substrates 122, 123, 124 ...... 84 Scheme 74. Synthesis of 122 ...... 85 Scheme 75. Synthesis of 123 ...... 85 Scheme 76. Synthesis of 124 ...... 86

viii

LIST OF FIGURES

Figure Page

1. 300 MHz 1H NMR Spectrum of 33 ...... 104 2. 300 MHz 1H NMR Spectrum of 35 ...... 105 3. 75 MHz 13C NMR Spectrum of 35 ...... 106 4. 500 MHz 1H NMR Spectrum of 36 ...... 107 5. 300 MHz 1H NMR Spectrum of hexacarbonyldicobalt-36 complex...... 108 6. 75 MHz 13C NMR Spectrum of 36 ...... 109 7. 300 MHz 1H NMR Spectrum of 37 ...... 110 8. 75 MHz 13C NMR Spectrum of 37 ...... 111 9. 500 MHz 1H NMR Spectrum of 38 ...... 112 10. 75 MHz 13C NMR Spectrum of 38 ...... 113 11. 300 MHz 1H NMR Spectrum of 41 ...... 114 1 12. 300 MHz H NMR Spectrum of HC≡CCH2CH2OMs ...... 115 13. 300 MHz 1H NMR Spectrum of 42 ...... 116 14. 300 MHz 1H NMR Spectrum of hexacarbonyldicobalt-42 complex...... 117 15. 300 MHz 1H NMR Spectrum of 43 ...... 118 16. 300 MHz 1H NMR Spectrum of 44 ...... 119 17. 300 MHz 1H NMR Spectrum of 45 ...... 120 18. 300 MHz 1H NMR Spectrum of 46 ...... 121 19. 300 MHz 1H NMR Spectrum of 47 ...... 122 20. 300 MHz 1H NMR Spectrum of 48 ...... 123 21. 500 MHz 1H NMR Spectrum of 100 ...... 124 ix 22. IR Spectrum of 100 ...... 125 23. 300 MHz 1H NMR Spectrum of 101 ...... 126 24. 500 MHz 1H NMR Spectrum of 102 ...... 127 25. 500 MHz 1H NMR Spectrum of 103 ...... 128 26. 500 MHz 1H NMR Spectrum of 104 ...... 129 27. 500 MHz 1H NMR Spectrum of 105a ...... 130 28. 75 MHz 13C NMR Spectrum of 105a ...... 131 29. IR Spectrum of 105a ...... 132 30. 300 MHz 1H NMR Spectrum of 105b ...... 133 31.. 500 MHz 1H NMR Spectrum of 106 ...... 134 32. 75 MHz 13C NMR Spectrum of 106 ...... 135 33. 75 MHz 13C NMR Spectrum of 106 ...... 136 34. IR Spectrum of 106 ...... 137 35. 500 MHz 1H NMR Spectrum of 107 ...... 138 36. 75 MHz 13C NMR Spectrum of 107 ...... 139 37. IR Spectrum of 107 ...... 140 38. 500 MHz 1H NMR Spectrum of 108 ...... 141 39. 75 MHz 13C NMR Spectrum of 108 ...... 142 40. IR Spectrum of 108 ...... 143 41. 500 MHz 1H NMR Spectrum of 109 ...... 144 42. IR Spectrum of 109 ...... 145 43. 500 MHz 1H NMR Spectrum of 110 ...... 146 44. 75 MHz 13C NMR Spectrum of 110 ...... 147 45. IR Spectrum of 110 ...... 148 46. 500 MHz 1H NMR Spectrum of 111 ...... 149 47. 75 MHz 13C NMR Spectrum of 111 ...... 150 48. IR Spectrum of 111 ...... 151 49. 500 MHz 1H NMR Spectrum of 112 ...... 152 50. 75 MHz 13C NMR Spectrum of 112 ...... 153

x 51. IR Spectrum of 112 ...... 154 52. 500 MHz 1H NMR Spectrum of 115 ...... 155 53. 500 MHz 1H NMR Spectrum of 116a ...... 156

LIST OF ABBREVIATIONS

Å Angstrom Ac acetyl aq aqueous Ar aryl atm atmosphere(s) 9-BBN 9-borabicyclo[3.3.1]nonane Bn benzyl br broad (spectral) t-Bu tert-butyl BuLi n-butyl lithium ºC degrees Celsius Calc’d calculated CI chemical ionization (mass spectrometry) cm centimeter(s) Cy cyclohexyl d doublet (spectral) D deuterium DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DIBAL-H diisobutylaluminum hydride DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone DMSO dimethylsulfoxide xii DSAC dry state absorption condition equiv equivalent(s) EI electron impact (mass spectrometry) Et ethyl FAB fast atom bombardment (mass spectrometry) g gram(s) h hour(s) HRMS high resolution mass spectrometry Hz Hertz IR infrared J coupling constant (in NMR) L liter LDA lithium diisopropylamide m multiplet (spectral), milli M Molarity of solution (moles per liter) Me methyl MHz megahertz min minute(s) mL milliliter mol mole(s) MS molecular sieves n normal (isomer) NMO 4-methylmorpholine N-oxide

NMO·H2O 4-methylmorpholine N-oxide monohydrate NMR nuclear magnetic resonance Ph phenyl

Ph3P triphenylphosphine

PhNTf2 N-phenyl-bis(trifluoromethanesulfonimide) PMP p-methoxyphenyl

xiii ppm chemical shifts parts per million (in NMR) i-Pr isopropyl q quartet (spectral) rt room temperature s singlet (spectral) t triplet (spectral) TBAF tetrabutylammonium fluoride TBDMS tert-butyldimethylsilyl TBDMSOTf tert-butyldimethylsilyl trifluoromethanesulfonate TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl TFA trifluoroacetic acid THF tetrahydrofuran TMANO trimethyl amino N-oxide TMS tetramethylsilane Ts p-toluenesulfonyl p-TsOH p-toluenesulfonic acid μ micro

xiv

ABSTRACT

The synthetic studies towards the total synthesis of the tetracyclic diquinane Lycopodium alkaloids magellanine and magellaninone were designed around utilizing two intramolecular Pauson-Khand reactions to deliver the magellanane skeleton. The model study went relatively well, but when the same reaction conditions were applied to substrates 48, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, none of them produced the corresponding enone products. Our explanation is that additional substitution at the allylic and homoallylic position interferes with the insertion of the alkene π-bond into one of the formal cobalt-carbon bonds of the alkyne complex to form the cobalt metallocycle. Because of the failure of this crucial Pauson-Khand step we could not move forward although we spent a lot of time and screened a variety of conditions known in the literature. After a switch to an alternative route, an intramolecular Pauson-Khand reaction and domino Heck reaction have been successfully utilized to deliver the magellanane skeleton. As anticipated for substrate 115 the second C-Pd/C=C insertion was favored over β-hydride elimination. This domino Heck reaction is not favorable when the new σ-alkylpalladium species has a β-hydrogen atom as is evident from the result with substrate 124. For substrate 115 the second C-Pd/C=C insertion was favored over β-hydride elimination. Possibly chelate formation prevents proper alignment between the syn-β-hydrogen and the carbon-palladium σ-bond. Another possibility is that the β-hydride elimination produces a highly strained ring system and in situ hydropalladation regenerates the σ-alkylpalladium so the second C-Pd/C=C insertion can take over.

xv We haven’t optimized the conditions for the domino Heck reaction yet. By fine tuning the precatalyst, solvent and base we believe the intermolecular reactions and the β-hydride elimination may be largely suppressed and the smooth second C-Pd/C=C insertion will deliver the tetracyclic magellanane skeleton in higher yield. Further transformation of the diene to enone and oxidative cleavage of the cyclopentane ring followed by the double reductive amination will finalize the total synthesis of the tetracyclic diquinane Lycopodium alkaloids magellanine and magellaninone.

xvi

CHAPTER I

INTRODUCTION

Magellanine, 1, magellaninone, 2, and paniculatine, 3, have been isolated from Lycopodium magellanicum and Lycopodium paniculatum.1-4 These alkaloids possess a highly condensed tetracyclic nucleus with 5-7 contiguous stereogenic centers, one of which is a quaternary carbon atom. Not surprisingly, the structural novelty of the magellanine skeleton has evoked a great deal of attention from the synthetic community, and several approaches to the skeleton have been reported.5- 7 To date, Overman and co-workers,8 Paquette et al.,9, 10 and Liao et al.11 have completed the total synthesis of magellanine in enantiomerically pure or racemic forms. Also recently, Hoshino et al.12 accomplished a formal total synthesis of racemic magellanine. Sha and co-workers achieved the total synthesis of paniculatine.13

N N N

O O OH H H H OH O O

Magellanine, 1 Magellaninone, 2 Paniculatine, 3

Overman and co-workers in 1993 used a stereoselective acid-promoted Prins-pinacol reaction of a dienyl acetal to deliver the angularly fused carbotetracyclic core of the magellanane alkaloids (Scheme 1). Treatment of the dienyl acetal 4 with 1.1 equiv of SnCl4 at −78 ºC → −23 ºC in dichloromethane 1 provided carbotetracycle 5 in 57 % yield as a 2:1 mixture of β and α methoxy epimers. Prins cyclization of the intermediate oxocarbenium ion took place from the less hindered convex face of the cis-bicyclooctadiene moiety. Pinacol rearrangement of the β-siloxy carbenium ion simultaneously installed the crucial quaternary carbon stereocenter and formed the core of the magellanane alkaloids. Notably, intermediate 5 possesses the carbotricyclic unit and five stereocenters common to the magellanane alkaloids.

Scheme 1. Acid-promoted Prins-pinacol reaction

O TESO SnCl4 H OMe OMe -MeOTES OMe H 45

pinacol rearr.

Prins cycl.

OMe OMe OTES H OTES

The first enantioselective total synthesis of (-)-magellanine and (+)- magellaninone were accomplished in 25-26 steps and 1.4 % yield from (1R, 5S)- bicycloheptenone 6 (Scheme 2).8 Paquette and his group completed the synthesis of the structurally novel Lycopodium alkaloids magellanine and magellaninone in stereocontrolled fashion by a three-fold annulation of the cyclopent-2-enone (Scheme 4).9, 10 Key steps include sequential Michael reactions (Scheme 3), use of a lithiated species for 1,4-

2 Scheme 2. Overman’s approach

t o a b -BuLi, Et2O, -110 C; O X 70% 49% A O ; TBAF, THF, 71% 6 MeS c X = OTf 80% X = I

OH Et3SiO d f O g H 85% R 57% 60% OH OMe e R = CHO 85% H R = CH(OMe)2 CHPh2 N BOC Me N N O i 89% k O O + H j 85% OR H H OTBS OH H R=Me h H H R=TBS 76% magellanine, 1 (50%)

Me Me N N O O l O H 85% H OTBDPS OH O H H A magellaninone, 2 18%

o Reaction conditions: (a) LiCH(SMe)2, THF, 0 ºC; Cu(OTf)2·PhH, (i-Pr)2NEt, PhH, 50 C; (b) Li, NH3-THF, - o o 40 C; TMSCl, THF; MeLi, THF, -78 → 0 °C; PhN(Tf)2, -78 → 23 C; (c) (Me3Sn)2, Pd(Ph3P)4, LiCl, THF, o o o 60 C; N-iodosuccinimide, THF, 0 C; (d) Et3SiCl, imidazole, DMAP, DMF, 50 C; Swern oxidation; (e) o o (MeO)3CH, PPTS, CH2Cl2, 23 C; (f) 1.1 equiv of SnCl4, CH2Cl2, -78 → 23 C; (g) OsO4 (cat.), NaIO4, o o o dioxane-H2O, 23 C; Ph2CHNH3Cl, NaBH3CN, i-PrOH, 23 C; (h) Cl3SiMe, NaI, MeCN, 80 C; TBSCl, o o o imidazole, DMF, 23 C; (i) H2, Pd(OH)2, EtOAc, 23 C; (BOC)2O, Et3N, DMAP, MeCN, 23 C; (j) LDA, o o o Me3SiCl, THF, -78 C; Pd(OAc)2, MeCN, 80 C; (k) LiMe2Cu, TMEDA, Me3SiCl, -78 → 0 C; Pd(OAc)2, o o o MeCN, 80 C; CF3CO2H, 23 C, concentrate; HCHO, NaBH3CN, MeCN, 23 C; HF, CH3CN; (l) Jones oxidation, 23 oC. addition to enones, and an economic adjustment of oxidation levels with simultaneous incorporation of a methyl substituent late in the synthesis. 3 Scheme 3. Sequential Michael reactions

O EtO O EtO COOEt O O COOEt

S S S S

O OH EtO EtO O O COOEt COOEt

S S S S

Liao et al. accomplished a concise and efficient synthesis of racemic magellanine in 16 steps and 12 % overall yield from commercially available acetovanillone (Scheme 6).11 The first two steps of their synthesis involved a masked benzoquinone Diels-Alder and an oxa-di-π-methane (ODPM) rearrangement which set four of the stereogenenic centers (Scheme 5). The other two were formed via a selective 1,4 cuprate addition and selective reduction. Hoshino and co-workers completed a formal total synthesis of racemic magellanine in 18 overall steps using a stereoselective Ireland-Claisen rearrangement and an intramolecular Pauson-Khand reaction of exocyclic enynes as their key reactions (Scheme 7).12 In summary, the total syntheses of magellanine and magellaninone were accomplished by several groups. The key strategic feature from Overman and co- workers8 is the use of Prins-pinacol rearrangement to assemble, with complete stereocontrol, the angular tetracyclic core of the alkaloid targets. Noteworthy tactical elements from Paquette et al.9, 10 include a Michael-Michael ring closure to

4 Scheme 4. Paquette’s approach

OH O O OH EtO COOEt d, e a, b O c O S S S S S S

O OH OMOM

f h, i j, k TBSO TBSO O g

O OH OMOM

OMOM OMOM OMOM

HO l m. n o, p O EtOOC EtOOC H OMOM OMOM OMOM N NC NC H3C

O O q, r, s, t u H H H O H O H OH H OH N N N H3C H3C H3C

Reaction conditions: (a) MsCl, Et3N; (b) (E)-EtOCH=CHC(O)CH2COOEt, K2CO3, A12O3, THF/C2H5OH, rt; (c) TsOH (cat.), C6H6; NaCl, DMF; (d) NaBH4, EtOH, CH2C12, 0 ºC; TBSOTf, imidazole, CH2Cl2, rt; (e) Tl(NO3)3, MeOH, THF; (f) Dibal-H, CH2C12, -78 ºC; (g) PCC on Al2O3, CH2C12, rt; (h) MOMCl, (i-Pr)2NEt, + - CH2Cl2; Bu4N F , HMPA, 3-Å sieves, rt; PCC on Al2O3, CH2Cl2; (i) LiN(SiMe3)2, THF; PhSeC1; H2O2, Py; (j) LiCH(CN)SiMe3, HMPA, THF; KF, aqueous CH3CN; LDA, NCCOOMe; (k) NaBH4, MeOH, -20 ºC; (l) + COCl2, Py, THF; PhSeH; (Me3Si)3SiH, AIBN, C6H6; (m) NaBH4, CoCl2, CH3OH; KOH, CH3OH; H3O ; (n) NaH, CH3I, THF; (o) LDA, THF, -78 ºC → -10 ºC; H2O at -78 ºC; (p) HCl, H2O, THF; (q) MnO2, CHCl3; (r) CH3Li, THF, -78 ºC; (s) LiAIH4, THF; (t) Jones oxidation; (u) NaBH4, C2H5OH; Ph3P, DEAD, HCOOH,THF; 10% KOH, CH3OH.

5 elaborate the highly functionalized six-membered ring, a new means for constructing the piperidine part of the structure that has the latitude for epimerization, and economic adjustment of oxidation levels with concomitant incorporation of a methyl group late in the synthetic scheme. The efficient total synthesis from Liao et al.11 illustrates the power of the masked o-benzoquinone Diels-Alder protocol and serves to show how highly condensed molecular architectures can be synthesized from simple 2-methoxyphenols. It is noteworthy that all 13 carbon atoms of the tricyclic skeleton, including the acetyl functionality, served in its elaborate functionalization to the target molecule. The other salient features of the current synthesis include the photochemical ODPM rearrangement, intramolecular cyclization of an alkenyl ketone, and the selective oxidative cleavage and double reductive amination. Key steps from the formal total synthesis12 include stereoselective Ireland-Claisen rearrangement and intramolecular Pauson–Khand reaction of exo-cyclic enynes as key steps.

Scheme 5. Oxa-di-π-methane (ODPM) rearrangement

O O O OMe OMe OMe

OMe OMe OMe O O O O H O O OMe OMe O OMe OMe H H MeO OMe O O

6 Scheme 6. Liao’s approach

O O H O OMe OMe a b c + OMe O OH 79% 92% H H 99% O MeO OMe

O O O O O O H d H e H f 98% O 99% O TfO 97% HH HH HH MeO OMe MeO OMe MeO OMe

O O O H H g h H i, j H 95% 72% 78% TfO H H H H H H O O O

O O O H k, l H m, n, o H H H H 65% 57% N H H H H H H OTBS OTBS OR R=TBDMS p R=H 96%

o Reaction conditions: (a) DAIB, MeOH, rt; (b) hv, acetone, rt; (c) (CH2OTMS)2, TMSOTf, CH2Cl2, -78 C → o o o rt; (d) AIBN, nBu3SnH, PhH, 80 C; (e) LHMDS, 2-PyNTf2, THF, -78 C;. (f) HCl (10%), THF, 100 C; (g) o o [PdCl2(PPh3)2], HCO2H, nBu3N, DMF, 80 C; (h) Allyltributyltin, nBuLi, CuCN, TMSCl, THF, -78 C → rt; (i) L-Selectride, THF, -78 oC → -20 oC; (j) imidazole, TBDMSCl, DMF, rt. (k) LDA, TMSCl, THF, 0 oC → RT; (l) Pd(OAc)2, MeCN, rt; (m) OsO4, NMO, tBuOH/THF/H2O (2.5:5:1), rt; (n) NaIO4, H2O/ CH2Cl2, rt; (o) CH3NH3Cl, NaBH3CN, IPA, 4-Å MS, rt; (p) TBAF, THF, rt.

7 Scheme 7. Hoshino’s approach

O OR OTIPS

CH2OR CH2OAc b d, e g 70% R 82% Me 100% Me Me

R = H a R = H c R = CH2OH f R = OAc 82% R =TIPS 74% R = CHO 98% NHBoc NHBoc O NHBoc OH OTIPS OH hi R1 R1 Me R R Me 2 Me 2 OH H 35% R = OH, R = H ( 40% ) R = OH, R = H ( 35% ) 1 2 1 2 j 70% 98% R1 = H, R2 = OH ( 44% ) R1 = H, R2 = OH ( 70% )

Reaction conditions: (a) Ac2O, Et3N, CH2Cl2, rt, 24 h; (b) CeCl3·7H2O, NaBH4, MeOH, rt, 1.5 h; (c) TIPSOTf, o 2,6-lutidine, CH2Cl2, 0 C, 1 h; (d) LDA, HMPA, THF, −78 ºC → rt, 1 day then rt, 2 days; (e) LiAlH4, THF, 1 o h; (f) Dess–Martin periodinane, CH2Cl2, rt, 2 h; (g) BuLi, HCCCH2CH2NHBoc, THF, HMPA, 0 C, 1.5 h; (h) TBAF, THF, 2.5h; (i) Co2(CO)8, THF, rt, 1 h then TMANO, rt, 1 h; (j) PhCO2H, PPh3, DEAD, THF, rt, 4 h; 1 M NaOH, THF–MeOH, rt,1 h.

NHBoc NHBoc NHBoc O O OH OR MOMO a H c H OH 80% OR 44% OMOM Me Me Me H H H R = H b R = MOM 95% BOC Me OH NHBoc N N R e H d MOMO H f h MOMO OR H 95% H 64% H 99% 43% H H OMOM OMOM OR Me H Me Me H H R = β-H R = MOM g R = α-H R = H 100%

8 Me Me Me N N N H i H j H OH H O H O H 1 H 55% H 59% H OTBS OTBS OTBS Me Me Me H H H

Reaction conditions: (a) 10% Pd/C, H2, MeOH–H2O, rt, 38.5 h; (b) i-Pr2NEt, MOMCl, CH2Cl2, rt, 18.5 h; (c) Tebbe reagent, THF, 0 °C, 1 h; (d) BH3·THF, THF, 0 °C, 3 h then 3 M NaOH, 30% H2O2, rt, 0.5 h; (e) MsCl, Et3N, CH2Cl2, 0 °C, 0.5 h; t-BuOK, THF, 0 °C, 1 h; (f) LiAlH4, THF, 2 h; (g) 6 M HCl, THF, rt, 24 h; (h) TBSOTf, 2, 6-lutidine, CH2Cl2, −78 °C, 10 min; (i) Dess–Martin periodinane, CH2Cl2, 0 °C, 1 h; (j) LDA, THF, −78 °C then Ph(Cl)S=NOt-Bu, 0 °C, 1 h. Retrosynthetic analysis

The retrosynthetic analysis to which we were attracted at the beginning involved disconnection of the strategic bonds indicated by the wavy lines in Scheme 8. Two intramolecular Pauson-Khand reactions would deliver the A, B and C, D rings respectively.

Scheme 8. Pauson-Khand Approach

Ts Ts N N N D D O PK C C H H A B OH O RO 7 8 OR Ts Ts Ts N N N PK

TfO O 9

9 We anticipated that enone 7, containing the A, B, C, D rings of the magellanine skeleton, could be obtained from enyne 8 via an intramolecular Pauson-Khand reaction. The C, D rings could be conveniently obtained from another intramolecular Pauson-Khand reaction. The reduction of enone 9 and in situ trap of the enolate by PhNTf2 would provide the enol triflate with the cis configuration at the ring junction. An alternative route which is shown in Scheme 9 relies on a domino Heck reaction and intramolecular Pauson-Khand reaction to deliver the magellanane skeleton. Oxidative cleavage of the cyclopentane ring followed by the double reductive amination would finalize the D ring.

Scheme 9. Palladium assisted domino process approach

N O O O O D D O Pd C H C H A B OH I RO

O O O O O O PK

TfO O

The cyclization of iodide 10 is expected to start with the formation of a σ- dienylpalladium intermediate by oxidative addition to the palladium(0) complex. An association-insertion process, involving the unsaturation of the cyclopentene moiety, gives a new σ-alkylpalladium species which has β-hydrogen atom residing 10 on a conformationally rigid β-carbon atom. It’s anticipated that the second C- Pd/C=C insertion will be favored over β-hydride elimination because of the proximity of the metal and the dienyl group. Chelate formation prevents proper alignment between the syn-β-hydrogen and the carbon-palladium σ-bond or the β- hydride elimination produces a highly strained ring system and in situ hydropalladation regenerates the σ-alkylpalladium so the second C-Pd/C=C insertion can take over (Scheme 10).

Scheme 10. Biscyclization

O O O O O O

D D D C C C Pd I t-BuO t-BuO 10 t-BuO

CHAPTER II

PAUSON-KHAND APPROACH

Pauson-Khand reaction

Metal mediated and catalyzed reactions have made significant contributions to organic synthesis over the past decades. The Pauson-Khand reaction, formally a [2+2+1] cycloaddition involving an alkene, an alkyne and carbon monoxide to form a cyclopentenone was first discovered in 1971 and has become nowadays one of the most convergent and versatile methods for the synthesis of cyclopentenones (Scheme 11).14-19

Scheme 11. Pauson-Khand Reaction

Co2(CO)6

stoichoimetric approach

Transition metal O CO complex ( Cat. )

catalytic version

Mechanism

Beyond the fact that a hexacarbonyldicobalt-alkyne complex is involved, little is actually known about the mechanism of the Pauson-Khand reaction. Whatever the mechanistic sequence that follows alkyne complexation, the rate

12 determining step apparently occurs early in the sequence, precluding the build-up of any subsequent intermediates to observable levels. The current level of mechanistic understanding is inferred from observations of regio- and stereochemistry in a large number of examples. A working and widely accepted mechanistic pathway was first proposed by Magnus for the stoichiometric intramolecular cycloaddition reaction (Scheme 12).20

Scheme 12. Working Pauson-Khand reaction mechanism

RS R - CO + Co2(CO)8 RL RL RS - 2 CO Co(CO)3 R (OC)3Co + CO - Ligand substitution

RS RS RL RL Co(CO)3 (OC)2Co Co(CO) R 3 Cobaltacycle CO insertion formation Co(CO)2 R

RS R L Co(CO)3Co RS R R Co(CO) RL S CO L 3 O reductive O R Co CO elimination R O R

It is usually assumed that complexation of the alkene to one cobalt atom takes place via a dissociative mechanism involving initial loss of CO. This process is almost certainly reversible. In the amine N-oxide promoted reaction, CO2 is liberated in the first step thus this step becomes irreversible. Subsequent insertion of the alkene π-bond into one of the formal cobalt carbon bonds of the alkyne complex occurs. The metallocycle that forms proceeds to product by a standard

13 sequence of steps beginning with migratory insertion of a cobalt bound CO, reductive elimination and loss of the cobalt moiety. Additional mechanistic insight to the Pauson-Khand reaction was seen when a reaction intermediate was intercepted by oxygen. Krafft suggested that both the enone product from the interrupted Pauson-Khand and the expected cyclopentenone product could arise from a common intermediate in the proposed mechanism (Scheme 13).21 A DFT study was carried out on alkyne dicobalt hexacarbonyl complexes to probe whether electronic differences in the acetylenic substituents could impact the regiochemistry of the Pauson-Khand reaction.22 A cis labilization, relative to the electron-donating group, is argued by Gimbert et al. for an unsymmetrically substituted alkyne-Co2(CO)6 complex (Scheme 14). This is consistent with the generally accepted role of an electron-donating group in a position trans to carbon monoxide in metal carbonyl complexes. The metal-CO bond is strengthened by an increase in π bonding from the metal to an antibonding orbital on CO when trans to an electron donating group. By this reasoning the trans position is less likely to dissociate and the cis position should be relatively more labile. In a theoretical study Pericas et al. favored labilization trans to an electron- donating group.23 It is argued that the CO trans to the amine-substituted alkyne carbon, in (trimethylsilylyneamine)Co2(CO)6, is activated for dissociation (Scheme 15). In a separate theoretical study Gimbert et al. showed that irrespective of the site of CO dissociation and initial alkene coordination, the alkene moved to the axial site prior to addition to the bridging alkyne.24 The cobalt atoms are five coordinate (if the alkyne is treated as occupying a single equatorial position) in

(alkyne)Co2(CO)6, and thus capable of facile pseudorotation. This gives the coordinated alkene access to both axial and equatorial positions. The transition state calculated to be optimal for the insertion of the alkene is the axial position.

14 ax OC CO Me OC CO down the Co-Co bond Co H and only the groups Co bonded to the visible CO cobalt are shown CH OC H 3 eq eq

Scheme 13. Interrupted Pauson-Khand Reaction

CO - CO CO Co CO + CO Co CO OC Co CO Co CO OC CO OC CO

CO O2 CO Co CO Co CO Co O Co CO CO OC CO OC CO

+L -L

CO Co CO Co CO OC L O O

Scheme 14. Cis labilization

OC CO cis pseudoequatorial OC CO positions Co − OC − B trans pseudoeqatorial δ+ δ most labile δ positions ABCO OC Co CO OC Co CO δ+ CO pseudoaxial positions A

cis and trans positions are defined with respect to the position of Substituent B 15 Scheme 15. Labilization trans to an electron-donating group

CO OC CO OC CO Co CO Co N N H H Co Co CO OC CO CO Co CO

Yamanaka and Nakamura evaluated potential reaction intermediates in the Pauson-Khand reaction by density functional theory.25 In this study the best transition state for alkene insertion also places the alkene in the axial position. Further, the authors suggest that it is the alkene insertion step that determines the reaction regio- and stereochemistry with substituted alkenes. Gimbert et al. investigated the reactivity of olefins in the Pauson-Khand rection.26 The LUMO of the coordinated olefin appears to have a crucial role in olefin reactivity in the Pauson-Khand reaction. It determines to a large degree the back donation in the complex, which impacts significantly the effectiveness of the

LUMO overlap with the HOMO of the Co2(CO)6-acetylene complex, and it is this interaction that is key in the subsequent C-C bond formation.

Scope of the reaction

The Pauson Khand reaction is highly tolerant of the common organic functional groups such as ethers, alcohols, tertiary amines, thioethers, ketones, ketals, esters, amides, alkyl and aryl halides, vinyl ethers and esters, aromatic rings including benzene, furan, and thiophene, and even Fischer carbene complexes. All simple alkynes are good substrates although the yields are quite dependent upon the degree of substitution and bulkiness of substituents. In particular, ethyne and simple terminal alkynes are the most satisfactory substrates. Internal alkynes usually give lower yields of cyclopentenones. In general, polar

16 groups remote from the triple bond have little effect, but those in close proximity are commonly detrimental. The scope of the reaction with respect to the alkene is typically somewhat more limited. Strained cyclic alkenes such as norbornadiene, norbornene, and cyclobutene are the best substrates and cyclopentenes, cyclohexenes, and simple acyclic alkenes are also suitable substrates. Alkenes bearing strongly electron-withdrawing groups are not good substrates. As an alkene becomes more electron deficient, formation of diene by alkene-alkyne coupling without carbon monoxide insertion becomes competitive (Scheme 16).

Scheme 16. Electron deficient alkenes

R CO EWG + R Co2(CO)8 H Co CO Co COCO EWG = CHO, COR, CO2R, CN EWG OC CO O EWG β-H elimination CO insertion R R EWG

Conjugated 1,3-diene

Reaction of ethyl crotonate with (phenylacetylene)hexacarbonyl-dicobalt delivers a mixture of the trans, trans and 2-cis, 4-trans ester isomers.27, 28 When (phenylacetylene)hexacarbonyldicobalt reacts with divinylsulphone, 2,7- 28 dihydrothiepin-1,1-dioxide is generated. 4-Methylstyrene-phenylacetylene coupling affords mixtures of cyclepentenones and dienes (Scheme 17). Despite the common perception that alkenes possessing electron- withdrawing groups are not adequate substrates for Pauson−Khand reactions, a number of successful examples of this reaction involving electron-deficient alkenes, such as α,β-unsaturated ketones, esters, nitriles, sulfoxides and alkenes, 17 such as α,β-unsaturated ketones, esters, nitriles, sulfoxides and sulfones, have been reported in recent years. In the case of the intramolecular Pauson-Khand reaction of 1-sulfinyl-1,6-enynes and 1-sulfonyl-3-oxygenated-1,6-enynes these processes have been applied in asymmetric synthesis.29, 30

Scheme 17. Conjugated 1,3-diene

a Ph MeCH=CHCO2Et PhCH=CHC(Me)=CHCO2Et CO Co CO + OC Co CO OO OC CO S O a S 29% O Ph O

Ph 13% Ph + Ph H + Ph

26%

Reaction conditions: (a) toluene, N2, 80 – 90 ºC, 4h

Steric hindrance around the double bond exerts significant deleterious effect on the cycloaddition. As the number of alkene substituents or steric bulk of the substituents at the carbon atom of attachment increases, initial complexation and carbon-cobalt bond insertion become more difficult. Tri- and tetra-substituted double bonds, and double bonds containing large allylic substituents, even when contained in a strained ring, frequently give cyclopentenones only in low yields, if at all. This is apparently due to a reduction in the ability of the alkene to compete with additional molecules of alkyne for reaction with the initially formed

18 Co2(CO)6RC≡CR′ complex. As a result, when the alkene is not suitable, reactions such as alkyne trimerization, and multicomponent cycloadditions involving only alkyne and carbon monoxide, normally only minor side reactions, become the principal processes taking place, leading to a variety of products (Scheme 18).31

Scheme 18. Multicomponent cycloadditions O O O a H H + + O O O benzene: 9% 3% trace DME: 1% 10% 1%

Reaction conditions: (a) Co2(CO)8; 65 º C, 5d

Perez-Castells et al. applied three substrates 11, 12 and 13 to Pauson- Khand conditions with TMANO and molecular sieves. In all these cases the depropargylation product was the only one identified from the reaction. When using molecular sieves as the only promoter in refluxing toluene, and after 48 h, compound 13 led to complex mixtures. Compounds 11 and 12, however, yielded new products, in moderate yields (20-30 %), which turned out to be compounds 14 and 15. These compounds can be considered as interrupted Pauson-Khand products. In these cases, after the formation of complex, the combined steric demand of the substituents seems to make the subsequent CO insertion difficult and lead directly to the decomplexation of the cobalt (Scheme 19).32

Regioselectivity

The reaction is very regioselective with respect to the acetylene, and the CO group is normally found next to the bulkier group of the alkyne in the final cyclopentenone, i.e., with terminal acetylenes, the substituted terminal is exclusively found at the C-2 position of the cyclopentenone (Scheme 20). 19 Regioselectivity with respect to the olefin however is rather limited. To enforce a particular preferred orientation of the olefin upon coordination to cobalt and then in the C-C bond-forming step and to enhance the reaction rates, Krafft et al. tethered coordinating heteroatoms to the olefin, thus making it a bi- or even tridentate ligand.33

RL CO OC Co CO L Co CO

Scheme 19. Interrupted Pauson-Khand of 11 and 12

Co Co O O O

n n n=1, 11 13 a n=2, 12

O (CO)3 O Co Co(CO)3 X Co Co OC CO O CO

O O Co(CO)3 Co(CO)2

n=1, 14 (30 %) 15 n=2, (20 %)

Reaction conditions: (a) MS, toluene, reflux, 48h

20 Scheme 20. Regioselectivity

O O Ph a C H + 6 13 Ph + Ph 18%

C6H13 1:1

Reaction conditions: (a) Co2(CO)8; toluene

Triquinane-type tricyclic systems

Angularly fused tricycles such as [5.5.5] (triquinane sesquiterpenes), [5.6.5], [5.5.6], [5.6.6] have proved to provide challenging testing grounds for many cyclopentane syntheses using a Pauson-Khand approach (Scheme 21 and 22).

Scheme 21. Endo-cyclic enynes

[5.5.5]

[5.6.5] O

[5.5.6]

[5.6.6]

21 Triquinane sesquiterpenes can be divided into two main groups, the linearly and the angularly fused on the basis of the fusion pattern of three five- membered rings. Coriolin is a representative compound of the former group, and the basic carbon framework of pentalenic acid exhibits the structure of typical angularly fused sesquiterpene.

OH O H H O CO2CH

H O HO H

Coriolin Pentalenic acid

Scheme 22. Exo-cyclic enynes

[5.5.5]

[5.6.5]

[5.5.6]

[5.6.6]

22 The cyclization of 1-(4-pentynyl)cyclopentene 16 to tricyclic enone 17 was first studied by Schore to test the structural latitude that the Pauson-Khand reaction can endure (Scheme 23).34 This conversion requires that a trisubstituted alkene react to give rise to a tricyclic angularly fused enone containing a quaternary carbon.

Scheme 23. Tricyclic angularly fused [5.5.5] enone 17

a 35%

16 17

Reaction conditions: (a) benzene, reflux, 3-4d

Enyne 18 failed to cyclize and led to alkyne trimerization, forming ill- characterized benzenoid products in moderate yield, and returning considerable amounts of unreacted alkyne complex even after several days at reflux.

18 Schore et al. established that the intramolecular cycloaddition of enyne 19 formed the desired triquinane possessing the necessary exomethyl stereochemistry 35 at C9 as the major cycloadduct (Scheme 24). Reaction of alcohol 20 with dicobalt octacarbonyl under the conditions used for cycloaddition of enyne 19 (heptane, sealed tube, 115 °C, 19 h) gave a 33 % yield of a mixture of enones. The dicobalthexacarbonyl complex of dienyne 21 was submitted to several sets of cycloaddition conditions but no enone products

23 were observed. The product mixture showed evidence of alkyne trimerization products and other unidentifiable materials, but no cyclopentenones were formed.

20 21

Scheme 24. Intramolecular cycloaddition of enyne 19

9 a or b H H + Co(CO)3 Co(CO)3 Co H Co H (CO)3 (CO)3 19

H H H O O H (+-)-pentalenene benzene (29%) 5 : 1 heptane (51%) 8 : 1

Reaction conditions: (a) Co2(CO)8; benzene, CO, reflux, 20h; (b) heptane, 110 ºC, 22h

Moyano and Pericas reported an asymmetric synthesis of 15-nor- pentalenene via an analogous approach incorporating a chiral directing group into the precyclization substrate (Scheme 25).36 Ishizaki and co-workers investigated the synthesis of angular tricyclic compounds by intramolecular Pauson-Khand reaction of exo- and endo-cyclic enynes.37 Both [5.5.5] and [5.5.6] angular tricyclic skeletons including contiguous 24 quaternary centers were constructed by the reaction of exo-cyclic enynes in good to high yield (Scheme 26). Cyclization of homologues of the above enynes did not afford the desired tricyclic compound, except for the reaction of an enyne containing an aromatic ring (Scheme 27). Under conditions similar to those noted for exocyclic enynes, the reaction of endocyclic enynes did not give [5.5.6] and [5.6.6] angular tricyclic compounds at all (Scheme 28). Attempts to perform the Pauson-Khand reaction with substrates 22 and 23 under conventional conditions using thermolysis in solution (hexane, 80 ºC, several hours, sealed vessel) were rather fruitless as only trace amounts of the metal-free polar compound, supposedly of the expected cycloadduct type, were 38 detected. On the contrary, under the dry state adsorption conditions (SiO2, 100 ºC), the cyclization of both isomers proceeded smoothly, albeit with low efficiency (Scheme 29).

Scheme 25. (+)-15-nor-pentalenene

H CH C(CH ) 2 3 3 O SMe O a; b SMe 82%, 5.4:1 d.r. O

(CH3)3CH2C

69% H

H (+)-15-nor-pentalenene

Reaction conditions: (a) Co2(CO)8; isooctane, rt, 0.5h; (b) CO, 60 ºC, 24h

25 Scheme 26. Tricyclic angularly fused [5.5.5] and [5.5.6] enones O

a [5.5.5] 89%

O a [5.5.6] O 86% O O O

Reaction conditions: (a) benzene, reflux, TMANO

Scheme 27. Tricyclic angularly fused [5.6.5] and [5.6.6] enones

a or b X n

n=1 [5.6.5] n=2 [5.6.6]

c 11% CO Et 2

Reaction conditions: (a) NMO, CH2Cl2, rt; (b) benzene, reflux; (c) toluene, reflux

The dicobalt hexacarbonyl complex of the 1,6-enynes 24, bearing a carbonyl group at position C-3 of the enyne framework, underwent an intramolecular Pauson-Khand reaction in the presence of Florisil as promoter of

26 the process, affording the corresponding cyclopentenones in acceptable to good yields (Scheme 30).

Scheme 28. Tricyclic angularly fused [5.5.6] and [5.6.6] enones

a or b X O n=1 [5.5.6] n=2 [5.6.6]

Reaction conditions: (a) NMO, CH2Cl2, rt; (b) benzene, reflux

The structurally related enones 25 and 26 failed to react under the same conditions. Treatment of enyne 27 or 28 with Co2(CO)8 followed by the Pauson- Khand reaction reaction under DSAC led to the formation of the tricyclic adduct in good yield (Scheme 31).38 Takano established the carbocyclic skeleton of dendrobine in one process (Scheme 32).39 The reaction proceeded in 89% yield and set the correct stereochemistry at the ring fusions. Using a similar approach, Cassayre and Zard successfully completed an asymmetric synthesis of (-)-dendrobine, setting the stereochemical features of the tricycle with a Pauson-Khand cycloaddition.40 Model studies on N-propargyl derivative 29 indicate that formation of ring-opened products can be supressed by using more coordinating solvents such as acetonitrile (Scheme 33). Jiang and Xu reported a concise and efficient synthesis of the optically active tetracyclic pyrrolidine (+)-30 under mild conditions. The entire chiral tetracyclic framework was created in one step by a Pauson–Khand reaction (Scheme 34).41

27 Scheme 29. Pauson-Khand reaction of enyne 22 and 23

OMe OMe OMe M a O + O OH 41% OH OH 22 3 :5

OMe OMe OMe M a OH O + O 30% OH OH

23 M = Co2(CO)6 1.1 : 1

Reaction conditions: (a) SiO2, Ar, 100 ºC, 1h

Scheme 30. Pauson-Khand reaction of enyne 24

M MeO OMe O a 73 % O 24 O M MeO a X

O M MeO O b [ - MeOH ] 53% O O

M = Co2(CO)6

Reaction conditions: (a) ether, pentane, sealed vessel, 60 ºC, 9h; (b) Florisil, 85 ºC, 12h 28 Scheme 31. Pauson-Khand reaction of enyne 25, 26, 27, 28

M M MeO MeO a a X X

O O 25 26

O O MeO MeO MeO b Me + Me H H H H OR OR OR R = H 27 R=H, 87 % 3.8 : 1 R = OAc 28 R=OAc, 73 % 3.3 : 1

O MeO MeO O MeO

+ H H H OH H OH OH c 70 % 1 : 1 M = Co (CO) 2 6 : d 65 % 2 1

Reaction conditions: (a) SiO2, 100 ºC, 1h; (b) Co2(CO)8; SiO2, 50 ºC, 4h; (c) Co2(CO)8; SiO2, 55 ºC, 4h; (d) Co2(CO)8; ether, sealed vessel, 50 ºC, 10h

Scheme 32. Dendrobine

MeO C N O N MeO2C N a; b 2 H 89% HMeH HMeH HH O O

Reaction conditions: (a) Co2(CO)8, benzene, rt; (b) NMO, CH2Cl2, 0 ºC → rt

29 Scheme 33. Asymmetric synthesis of (-)-dendrobine

H H

N O N N a; b HH HH OAc 51% OAc O O

c O N O NHBn N + Bn HHH 29 Solvent a b CH2Cl2 34% 14% CH2Cl2 / THF 52% 10% CH3CN 63% -

Reaction conditions: (a) Co2(CO)8; NMO.H2O, CH3CN; (b) Pd/C. H2; (c) Co2(CO)8; NMO.H2O, solvent

Scheme 34. Tetracyclic pyrrolidine (+)-30

N N N a

67% O O MeO MeO MeO 6 : 1

N H

30 MeO

Reaction conditions: (a) ) Co2(CO)8; DMSO, THF, 65 ºC, 6h

30 Magnus utilized the Pauson-Khand reaction to deliver the tricyclic core of nakadomarin and manzamine.42 Treatment of the amide analog 31 under the n- BuSMe accelerated Pauson–Khand reaction conditions did not produce any of the tricyclic amide. It is apparent that the added conformational rigidity of the amide linking chain is sufficient to prevent cyclization (Scheme 35). An intermolecular Pauson-Khand reaction was used as a key step for the synthesis of the cedrene skeleton (Scheme 36).43 The starting material is a monocyclic enyne with an exocyclic olefin fragment. A bridged adduct is obtained in high yield which is further manipulated to provide a total synthesis of α- and β- cedrene.

Scheme 35. Tricyclic core of nakadomarin and manzamine

Boc N a O N Ts N 63-69% Ts N BOC

Boc N X HN

O 31

Reaction conditions: (a) Co2(CO)8; 1,2-Cl(CH2)2Cl, n-BuSMe, 83 ºC

In summary, the Pauson-Khand reaction allows for a rapid increase in molecular complexity from relatively simple starting materials. The scope of the reaction with respect to the alkene is typically somewhat more limited compared to the alkyne. Tricyclic [5.6.5] and [5.5.5] angularly fused systems containing a quaternary carbon have proved to be challenging testing grounds for a Pauson- Khand approach. 31 Scheme 36. α- and β-cedrene

a O O O + O 95% O O O O 1: 2

+ H H

α-cedrene β-cedrene

Reaction conditions: (a) BuSMe, DCE, 83 ºC

Results and Discussion

The key steps of our initial approach to magellanine and magellaninone include two intramolecular Pauson-Khand reactions to deliver the tetracyclic magellanane skeleton. The second Pauson-Khand reaction generates the tetracyclic angularly fused magellanane core containing a quaternary carbon starting from the trisubstituted alkene.

Ts Ts Ts N N N PK

O TfO

Ts Ts N N N D D O PK C C H H A B OH O TBSO OTBS 32 In order to test the Pauson-Khand strategy we initially carried out a model study. tert-Butyl(1-cyclopentenylhex-5-yn-3-yloxy)dimethylsilane, 36, was chosen as the substrate to study. To begin the synthesis 1-(bromomethyl)cyclopent-1-ene was alkylated by the lithium enolate of tert-butyl acetate.44, 45 Reduction of the resulting ester 33 with DIBAL-H gave aldehyde 3446 and subsequent Grignard reaction by treatment 47 with BrMgCH2C≡CH delivered enyne 35. Further transformation of the alcohol to the tert-butyldimethylsilane derivative delivered enyne 36 (Scheme 37). With the desired cyclopentenyl-derived alkyne in hand, we undertook the study of the demanding intramolecular Pauson-Khand reaction. After the formation of the enyne cobalt complex in petroleum ether with Co2(CO)8 it was subjected to the typical thermal Pauson-Khand conditions (toluene, 80 °C). The cyclization proceeded slowly and TLC indicated the formation of enone. After the mixture was stirred for 36 h the starting material had almost disappeared. The

Scheme 37. Synthesis of 38

O O a b c Br 77% t 32 33 O -Bu 34 2 steps 62% OTBS OH OTBS d e f 95% 2 steps 35 36 37 60% O OH

O 38

Reaction conditions: (a) LDA, CH3CO2t-Bu, THF, DMPU, −78 ºC; (b) DIBAL-H, DCM; NaSO4⋅10H2O; (c) Mg, HC≡CCH2Br, HgCl2, Et2O, THF; (d) TBSOTf, 2,6-lutidine, DCM, rt; (e) Co2(CO)8, petroleum ether; Toluene, 80 ºC, 1.5 d; (f) TBAF, THF, rt

33 reaction mixture was passed through a short pad of Celite and silica gel and the filtrate was concentrated to dryness. Analysis of the 1H NMR spectrum of the crude reaction mixture indicated the presence of an enone peak around 5.8 ppm. The crude reaction mixture was then treated with TBAF in THF to deliver the free alcohol. After purification the desired enone was obtained in 60 % yield. The high- field proton NMR spectrum displayed a characteristic signal for the enone proton at δ 5.86 and a signal at δ 2.42 (d, J = 8.3 Hz) due to the methine α to the ketone 2.28 (d, J = 9.4) which is comparable to the methine chemical shift of tricyclo[6.3.0.04,8]undec-l-en-3-one.34

5.86 H H 5.82,d, 1.7 Hz H H O O 2.42, d, J=8.3 Hz 2.28, d, J=9.4 Hz

When enyne 39 or 40 were subjected to the above condition, traces of the corresponding enone were observed. Both substrates generated the dienone presumably resulting from elimination of water or methanol after the initial formation of the enone (Scheme 38). With the initial success of the model study we moved to the route based on our retrosynthesis. N-Allyl-4-methylbenzenesulfonamide, 41 obtained from the alkylation of allylamine48 was dissolved in THF and NaH was then slowly added to the solution at 0 ºC. The mixture was warmed to rt and but-3-ynyl methanesulfonate was added. After refluxing overnight the mixture was worked up and enyne 42 was obtained in 68 % yield with recovered starting material. Tertiary amine N-oxide promoted Pauson-Khand reaction conditions (NMO·H2O, DCM, rt) were applied to the crude cobalt-complexed enyne 42 to give enone 43 in 68 % yield. The resulting enone 43 obtained was first treated with L-Selectride® in THF

34 Scheme 38. Enyne 39 and 40

OH O

39 40

OR OR - HOR

O O HRMS CI+ C H O R=H, CH3 12 15 calc.175.1123 found 175.1137 at -78 ºC followed by quenching the resulting enolate with N-phenyltriflimide in situ to deliver the vinyl triflate 44.49 The cis configuration at the ring junction was derived from the 1H NMR NOE experiments of the following ketone which was obtained by quenching the enolate with water.

H H H 3 1 H H H NMR NOE C6D6 H 6 H irradiate H-7 H-6β + H-3, 6.14% 7 H NTs H O Ts N H O H H

The cross-coupling reaction of 9-(3,3-diethoxypropyl)-9-bora- bicyclo[3.3.1]nonane with triflate 44 in the presence of K3PO4 (1.5 equiv) and a catalytic amount of Cl2Pd(dppf) resulted in the formation of acetal 45 in 74 % yield. The formation of the 9-(3,3-diethoxypropyl)-9-bora-bicyclo[3.3.1]nonane from 9-BBN and acrolein dimethyl acetal in THF is very tricky and only use of the 9-BBN dimer gave consistent results. Deprotection of acetal 45 to the 35 corresponding aldehyde, Grignard reaction and subsequent introduction of the tert- butyldimethylsilyl (TBDMS) group on alcohol 47 delivered enyne 48 for testing of the challenging intramolecular Pauson-Khand reaction.

Scheme 39. Synthesis of 48

Ts Ts NHTs a b N c N TsN O OTf 68% 68% 83% 41 42 43 44

Ts N Ts d OEt e N f O 74% 2 steps 45 OEt 46 83% Ts Ts N N OH g OTBS 95% 47 48

Reaction conditions: (a) NaH; HCCCH2CH2OMs, THF, reflux; (b) Co2(CO)8, petroleum ether; NMO·H2O, DCM; (c) L-selectride, THF, −78 ºC; PhNTf2, −78 ºC → rt; (d) H2C=CHCH(OEt)2, 9-BBN; K3PO4, PdCl2(dppf), THF, reflux; (e) TsOH, Acetone/H2O (4:1); (f) Mg, HC≡CCH2Br, HgCl2, Et2O, THF; (g) TBSOTf, 2,6-lutidine, DCM

When the dicobalthexacarbonyl complex of enyne 48 was subjected to the thermal Pauson-Khand conditions (toluene, 80 °C), a streak of spots on the TLC resulted and no UV active enone was detectable even after 12 h. Recovered were decomplexed starting material and unidentifiable materials. Analysis of the 1H NMR spectrum of the crude reaction material showed no enone signal either. A wide variety of conditions have been reported for Pauson–Khand reactions. We applied the following typical conditions to substrate 48. Toluene or benzene, 80 °C or reflux

NMO·H2O , DCM, rt

Anhydrous TMANO, DCM, O2, rt 36 SiO2, 100 °C n-BuSMe (3.5 equiv.), 1,2-dichloroethane, 83 °C These conditions gave either no reaction or decomposition to complex mixtures that contained no detectable amounts of the tetracyclic adduct. It’s well-known that the Thorpe-Ingold effect helps to bring the alkene moiety close to the cobalt complex hence facilitate subsequent insertion of the alkene π-bond into one of the formal cobalt carbon bonds of the alkyne complex. The Thorpe–Ingold or gem-dimethyl (more generally dialkyl) effect is defined by the increase in both rate and equilibrium constants of cyclization reactions resulting from the introduction of substituents in the linking chain. We pursued the synthesis of substrate 53 which bears a geminal diester group between the double and triple bonds. Triflate 44 was coupled with tributyl(vinyl)tin in the presence of 2 mol % of tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] and 3 equiv of lithium chloride in refluxing THF to give 1,3-diene 49.50 After the generation of disiamy1borane from 2-methyl-2-butene (2 M in THF) and borane-methyl sulfide complex (2 M in THF) at 0 °C it was then added to solution of 1,3-diene 49 in THF at 0 °C. After 2 h the reaction mixture was treated with 3 N NaOH and 30 % 51 H2O2 to deliver alcohol 50 in high yield (2 steps, 92% yield). The alcohol 50 was then transformed to iodide 51 quantitatively using Ph3P, I2 and pyridine. Malonate derivative 52, obtained from reaction of iodide 51 with diethyl malonate anion, was alkylated with propargyl bromide to deliver enyne 53 for investigation into the intramolecular Pauson-Khand reaction. Exposure of enyne 53 to a wide variety of conditions, thermal or tertiary amine N-oxide promoted, stoichiometric or catalytic conditions that have been used for Pauson–Khand reactions gave mostly decomplexed starting material or decomposition to complex mixtures that contained no detectable amounts of the tetracyclic compound.

37 Scheme 40. Synthesis of 53

Ts Ts N a N b Ts OTf N c 2 steps 87% OH 44 49 91% 50 Ts Ts Ts d N e N N CO2Et 74% 86% CO Et I 2 EtO2C 51 52 CO Et 53 2

Reaction conditions: (a) Bu3Sn(CH=CH2), LiCl, Pd(PPh3)4, THF, reflux; (b) BH3·Me2S, (CH3)2C=CHCH3, THF, 0 ºC; 3N NaOH, 30% H2O2; (c) Ph3P, I2, DCM, Pyridine; 87% (d) (EtO2C)2CH2, NaH,THF; (e) NaH, HC≡CCH2Br

We decided to screen a variety of enynes shown in Scheme 41 to determine the underlying reason for the difficulty of the cyclization. Synthetic routes to make these enynes are listed in Schemes 42 to 48.

Scheme 41. Substrates 54-64

OH OMOM

54 55 Ts N O O

56 57 OTBS

TBSO Ts OBn N OTBS

58 59

38 Ts Ts N N X

60 OMs

R2O 61 R1=TBDPS, R2=MOM

R2O OR1 62 R1=TBDPS, R2=TBS 63 R1=TBDMS, R2=MOM 64 R1=MOM, R2=MOM

Scheme 42. Syntheses of 54 and 55

a O + SO NHNH SO NHN 2 2 80% 2

OH OMOM b c 60% 85% 55 54

Reaction conditions: (a) HCl, MeOH; (b) BuLi, TMEDA, Hexane, HC≡C(CH2)3CHO, −78 ºC → rt; (c) MOMCl, i-PrNEt2, DCM

Scheme 43. Synthesis of 56

OH O O O a b 40% 80% 56

Reaction conditions: (a) PCC, DCM; (b) HOCH2CH2CH2OH, p-TsOH

39 Scheme 44. Synthesis of 59

TBSO TBSO O OH a b OH c d O 2 steps 94% 66% 50% TBSO TBSO TBSO e f O OTf O 83% 70% O HO HO gh i O OH 80% 77% 90%

TBSO

OTBS

Reaction conditions: (a) PCC, NaOAc, DCM; (b) H2C=CHMgBr, THF; (c) TBSOTf, 2,6-lutidine, DCM; (d) Co2(CO)8, petroleum ether; TMANO, DCM; (e) L-selectride, THF, −78 ºC; PhNTf2, −78 ºC → rt; (f) H2C=CHCH(OEt)2, 9-BBN; K3PO4, PdCl2(dppf), THF, reflux; (g) TsOH, Acetone/H2O (4:1); (h) Mg, HC≡CCH2Br, HgCl2 (cat.), Et2O, THF; (i) TBSOTf, 2,6-lutidine, DCM

Scheme 45. Synthesis of 60

Ts Bu Sn OTHP Ts N 3 a N b OTf + 70% 85%

OTHP Ts Ts Ts N c N N X 98%

OH OMs

Reaction conditions: (a) LiCl, [(C6H5)3P]2PdCl2, DMF, 65 ºC; (b) SnCl2, MeOH; (c) CH3SO2Cl, Et3N, Et2O

40 Scheme 46. Synthesis of 57

Ts Ts N Bu Sn OH ab OTf + 3 N 65%

OH Ts Ts Ts N N N c d 2 steps 95% 82% 57 O OH OTBS

Reaction conditions: (a) LiCl, [(C6H5)3P]2PdCl2, DMF, 80 ºC; (b) Swern oxidation; (c) Mg, HC≡CCH2Br, HgCl2 (cat.), Et2O, THF; (d) TBSOTf, 2,6-lutidine, DCM

Scheme 47. Synthesis of 58

Ts Ts Ts N abN N OTf SnBu I 80%3 95%

Ts OH Ts OH Ts OBn c N d N e N 82% 95% 80%

58 TMS

Reaction conditions: (a) (CH3)6Sn, LiCl, Pd(PPh3)4, THF; (b) I2, (C2H5)2O; (c) t-BuLi; TMSC≡C(CH2)3CHO; (d) TBAF, THF, rt; (e) NaH, BnBr, THF

Unfortunately when the corresponding dicobalthexacarbonyl complexes of compounds 54, 55, 56, 57, 58, 59, 61, 62, 63, 64 were exposed to a wide variety of conditions, thermal or amine N-oxide promoted, stoichiometric or catalytic conditions mostly decomplexed starting material was isolated or decomposition to

41 complex mixtures that contained no detectable amounts of the desired enone resulted.

Scheme 48. Syntheses of 61-64

OTBDPS O O a O b O 88% O O

OTBDPS OTBDPS O c d HO O 2 steps HO 60%

OTBDPS OTBDPS HO TBSO e HO 92%TBSO 62

OTBDPS MOMO f g 89% MOMO 90% 61

MOMO MOMO

MOMO OR h or i MOMO OH

R=TBS, 63 92% R=MOM, 64 83%

Reaction conditions: (a) Multisteps described in next chapter; (b) CH3OH, PPTS; (c) NaIO4, THF/H2O; (d) NaBH4, EtOH; (e) TBSOTf, 2,6-lutidine, DCM; (f) MOMCl, i-PrNEt2; (g) TBAF, THF; (h) TBSOTf, 2,6- lutidine, DCM; (i) MOMCl, i-PrNEt2, DCM

42 Summary and Conclusions

Angularly fused tricycles such as [5.5.5] (triquinane sesquiterpenes), [5.6.5] systems have proved to be challenging testing grounds for a Pauson-Khand approach.

[5.5.5]

[5.6.5] O

The conversion creates a quaternary carbon atom as part of the tricyclic angularly fused heterocycle. This is a particularly demanding test of the structural latitude that the Pauson–Khand reaction can endure. Schore has described the conversion of enyne 16 into enone 17 using standard Pauson–Khand reaction conditions, but the corresponding conversion of enyne 65 into enone 66 has not been reported. The substrate for our model study has a tert-butyldimethylsiloxy group β to the triple bond. The tert-butyldimethylsiloxy group probably served as a factor restricting the conformational mobility of the side chain in such way that the double bond becomes more proximate to the reacting Co-complexed moiety. By doing so it facilitated the insertion of the alkene π-bond into one of the formal cobalt carbon bonds of the alkyne complex to form the cobalt metallocycle.

43 O O 35% X

16 17 65 66

O n

X X O n n=1 [5.5.6] n=1 [5-6-5] n=2 [5.6.6] n=2 [5-6-6]

OTBS OH OTBS

36 37 38 O O

Enynes 55 and 56 did not cyclize under the same reaction conditions, indicating that the position of substitution on the 1,6-enyne framework played an important role in the formation of the cobalt metallacycle.

OMOM O O

55 56

Steric hindrance around the double bond exerts a significant deleterious effect on the cycloaddition. As the number of alkene substituents or steric bulk of the substituents at the carbon atom of attachment increases, carbon-cobalt bond insertion becomes more difficult. This is apparently due to a reduction in the 44 ability of the alkene to compete with additional molecules of alkyne for reaction with the initially formed Co2(CO)5RC≡CR′ complex. This was evidently true in our case. When there were substitutions at the allylic and homoallylic position the Pauson-Khand reaction turned out to be very difficult even though the reaction went well without these additional groups. A possible explanation for this is that the putative intermediate dimetallacycle suffers a 1,3-pseudodiaxial interaction as indicated by the arrows. Additional substitutions at the allylic and homoallylic position interfere with the insertion of the alkene π-bond into one of the formal cobalt carbon bonds of the alkyne complex to form the cobalt metallacycle.

CO Co(CO) H OC 3 Co Co Co OR Co H R1 OC - CO H Co H H H R 2 R2 OR R1 R1 R2 RO

We have tested compounds 48, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64. None of them produced the corresponding enone product. Because of the failure of this crucial Pauson-Khand step we could not move forward although we spent a lot of time and screened a variety of compounds. An alternative approach is described in the next chapter.

45 Experimental Section

Solvents were reagent grade and in most cases dried prior to use. All other commercially available reagents were used as received unless otherwise noted.

The organic extracts were dried over anhydrous MgSO4. Tetrahydrofuran (THF) was distilled from lithium aluminum hydride (LiAlH4) prior to use. Methylene chloride (CH2Cl2), and triethylamine (Et3N) were distilled from calcium hydride.

Diethyl ether (Et2O) was distilled from sodium-benzophenone ketyl. Infrared spectra (IR) were obtained on a Perkin Elmer Paragon 1000 FT-IR Spectrophotometer. Elemental analyses were performed by Atlantic Microlab, Inc., Norcross, GA. 1H NMR spectra were obtained at 300 MHz on a Varian Gemini spectrometer or at 500 MHz on a Varian VXR500 spectrometer. Carbon spectra were obtained at 75 MHz on a Varian Gemini spectrometer. Mass spectra (MS) were recorded on a Jeol JMS-600. Chemical shifts are reported in parts per million downfield relative to tetramethylsilane (δ 0.00) and coupling constants are reported in Hertz (Hz). The following abbreviations are used for the multiplicities: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet; and br = broad. tert-butyl 3-cyclopentenylpropanoate (33)

Br Ot-Bu

To a solution of LDA in THF (15 mL), prepared at −20 °C from diisopropylamine (1.15 mL, 8 mmol) and BuLi (5 mL of 1.6 M in hexanes, 8 mmol), was added at −78 °C a solution of t-butyl acetate (0.94 g, 8 mmol) in THF (mL). After stirring at −78 °C for 1 h, the resulting mixture was added at −78 °C to a solution of 1-(bromomethyl)cyclopent-1-ene (0.44 g, 2.73 mmol) in THF-DMPU (30 mL, 2:1). The reaction was stirred for 4 hours at −78 °C, and treated with 0.5 46 mL of acetic acid. The resulting mixture was poured into H2O. The aqueous layer was extracted with Et2O, and the combined organic layers were washed with brine, dried and concentrated. Flash chromatography afforded 0.41 g (77 %) of ester 33. 1 H NMR (CDCl3, 300 MHz): δ 5.34 (br s, 1H), 2.18-2.45 (m, 8H), 1.78-1.95 (m, 2H), 1.43 (s, 9H).

3-cyclopentenylpropanal (34)

O O

Ot-Bu H

Diisobutylaluminum hydride (1.84 mL of 1 M in hexane, 1.84 mmol) was added dropwise to 33 (0.33 g, 1.67 mmol) in DCM (20 mL) at −78 ºC. After the solution was stirred for 3.5 h at −78 ºC, sodium sulfate decahydrate (0.54 g, 1.67 mmol) was added slowly. The reaction mixture was slowly warmed to rt and stirred for 1 h. Filtration through Celite and removal of the solvent afforded the crude aldehyde (34) as a colorless oil which was used in the next step without 1 further purification. H NMR (CDCl3, 300 MHz): δ 9.78 (t, J = 1.5 Hz, 1H,

CH2CH2CHO), 5.35 (d, J = 2 Hz, 1H, CH=C), 2.59 (t, J = 6.9 Hz, 2H), 2.40 (m, 2H), 2.27 (m, 4H), 1.86 (tt, J = 7.4, 7.4 Hz, 2H).

1-(1-cyclopentenyl)hex-5-yn-3-ol (35)

O OH

To a flame-dried flask under argon containing magnesium (0.20 g, 0.84 mmol) and ether (19 mL) was added propargyl bromide (0.96 mL, 0.86 mmol) and 47 mercury(II) chloride (0.12 g, 0.04 mmol). Once the reaction had been initiated by gentle heating, the solution was kept in oil bath (40 ºC) for 1 h. The mixture obtained was added to the aldehyde in THF (17 mL) at 0 ºC. The mixture was warmed to rt slowly, after which it was poured into water. The aqueous layer was extracted with ether, and the combined organic layers were washed with water, brine, dried and concentrated. Flash chromatography afforded 0.17 g (2 steps, 62 1 %) of enyne 35. H NMR (CDCl3, 300 MHz): δ 5.37 (br s, 1H, CH2CH=C), 3.77

(tt, J = 6.0, 6.0 Hz, 1H, HC≡CCH2CH(OH)CH2), 2.44 (ABdd, JAB = 16.5, 5.4, 2.7

Hz, 1H, HC≡CCHHCH(OH)CH2), 2.34 (ABdd, JAB = 16.5, 5.4, 2.7 Hz, 1H,

HC≡CCHHCH(OH)CH2), 2.10-2.39 (m, 6H), 2.06 (t, J = 2.69 Hz, 1H, 13 HC≡CCH2), 1.85 (m, 2H), 1.71 (m, 2H). δ C NMR (CDCl3, 75 MHz): δ 144.07, 123.88, 80.83, 70.71, 69.65, 34.91, 33.99, 32.27, 27.14, 27.10, 23.25. tert-butyl(1-cyclopentenylhex-5-yn-3-yloxy)dimethylsilane (36)

OH OTBS

To alcohol 35 (0.17 g, 1 mmol) in DCM (5 mL) at −78 º C was added 2,6- lutidine (0.19 mL, 1.6 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (0.28 mL, 1.2 mmol). The mixture was allowed to warm to rt, diluted with hexane and washed with water, brine, dried and concentrated. Purification of 1 the residue on silica gel gave 0.27 g (95 %) of enyne 36. H NMR (CDCl3, 300

MHz): δ 5.34 (br s, 1H, CH2CH=C), 3.81 (tt, J = 5.37, 5.37 Hz, 1H,

HC≡CCH2CH(OH)CH2), 2.00-2.40 (m, 8H), 1.97 (t, J = 2.68 Hz, 1H, HC≡CCH2),

1.91-1.73 (m, 3H), 1.57-1.73 (m, 1H), 0.89 (s, 9H, (CH3)3CSi(CH3)2O), 0.07 (s, 13 3H, (CH3)3CSiCH3CH3O), 0.06 (s, 3H, (CH3)3CSiCH3CH3O). C NMR (CDCl3,

48 75 MHz): δ 144.49, 123.30, 81.65, 70.62, 69.87, 35.14, 34.60, 32.35, 27.23, 26.62, 25.74, 23.31, 17.96, -4.62, -4.82.

7-(tert-butyldimethylsilyloxy)-1,2,3,3a,6,7,8,9-octahydrocyclopenta[i]inden-4-one 37 7-hydroxy-1,2,3,3a,6,7,8,9-octahydrocyclopenta[i]inden-4-one (38)

OTBS OH OTBS

O O

Co2(CO)8 (47 mg, 0.14 mmol) was added to a solution of an enyne 36 (32 mg, 0.12 mmol) in petroleum ether (2 mL) at rt. After stirring for 1 h, the petroleum ether solution was filtered through Celite and evaporated to leave a residue which was taken up in toluene (2 mL). The mixture was stirred in an oil bath (80 ºC) for 1.5 d and passed through a short pad of Celite and the resulting filtrate was concentrated to dryness. To the crude oil was added THF (1.5 mL) and TBAF (0.14 mL of 1 M in THF, 0.14 mmol). The mixture was stirred for 2 h. The resulting mixture was poured into H2O. The aqueous layer was extracted with

Et2O, and the combined organic layers were washed with water, brine, dried and concentrated. Flash chromatography on silica gel afforded 13 mg (60 %) of enone 1 38. H NMR (CDCl3, 500 MHz): δ 5.86 (d, J = 1.7 Hz, 1H, COCH=C), 3.74 (tt, J

= 10.8, 4.7 Hz, 1H, H2CCHOHCH2C=CH), 3.06 (ddd, J = 12.9, 5.0, 2.0 Hz, 1H,

H2CCHOHCHHC=CH), 2.37 (ddd, J = 12.6, 11.4, 1.3 Hz,

H2CCHOHCHHC=CH), 2.28 (d, J = 9.4 Hz, CH2CHCOCH=C), 1.99 (m, 1H), 1.87-1.98 (m, 3H), 1.71-1.80 (m, 2H), 1.64-1.71 (m, 1H), 1.50-1.64 (m, 2H), 1.40- 13 1.48 (ddd, J = 11.8, 12.4, 6.4 Hz, 1H), 1.24-1.36 (m, 1H). C NMR (CDCl3, 75 MHz): δ 212.23, 182.23, 128.99, 70.94, 57.80, 54.52, 38.09, 35.71, 35.27, 32.19,

49 28.49, 24.82. IR (cm-1): 3401, 2936, 2864, 2360, 1681, 1619, 1444, 1346, 1053.

HRMS (m/z) (EI+) calc. for C12H16O2 192.1150, found 192.1140. 13 37 C NMR (CDCl3, 75 MHz): δ 212.17, 182.71, 128.77, 71.81, 57.83, 54.58, 38.88, 35.71, 35.33, 32.72, 28.51, 25.56, 24.84, 17.99, -4.87.

N-allyl-4-methylbenzenesulfonamide (41)

H TsNH2 TsN

To a stirred solution of allylamine (8 g, 0.14 mol) in THF (500 mL) was added triethylamine (26.6 mL, 0.19 mol) and tosyl chloride (32 g, 0.17 mol) at 0 ºC. After being stirred at the same temperature for 4 h, the reaction mixture was diluted with H2O and extracted with ether. The organic phase was washed with

H2O, dried, and concentrated. Purication of the residue by recrystallization (hexane/ether) afforded sulfonamide 41 (28.4 g, 96 %) as pale yellow crystals. 1H ortho NMR (CDCl3, 300 MHz): δ 7.77 (d, J = 8.7, 2H, Aromatic H ), 7.32 (d, J = 8.7 meta Hz, 2H, Aromatic H ), 5.73 (m, 1H, NHCH2CH=CH2), 5.06-5.22 (m, 2H,

NHCH2CH=CH2), 4.32 (br s, 1H, NHCH2CH=CH2), 3.59 (s, 2H,

NHCH2CH=CH2), 2.43 (s, 3H, CH3C6H4SO2N). but-3-ynyl methanesulfonate

OH OMs

Methanesulfonyl chloride (5.2 mL, 67 mmol) was added at 0 ºC to a solution of 3-butyn-1-ol (4.3 g, 61 mmol) and Et3N (10.2 mL, 73 mmol) in Et2O (500 mL). The resulting solution was stirred for 1.5 h at rt. The precipitate was then dissolved by addition of water and the aqueous phase was repeatedly 50 extracted with ether. The combined organic layers were subsequently washed with

H2O, saturated NH4Cl solution, brine, dried over MgSO4, and finally concentrated. Evaporation of the solvent afforded but-3-ynyl methanesulfonate (9 g, 100 %) as a 1 pale yellow syrup which was used without further purification. H NMR (CDCl3,

300 MHz): δ 4.31 (t, J = 6.6 Hz, 2H, CH3SO2CH2CH2C≡CH), 3.06 (s, 3H,

CH3SO2CH2CH2C≡CH), 2.66 (dt, J = 2.7, 6.9 Hz, 2H, CH3SO2CH2CH2C≡CH),

2.06 (t, J = 2.7 Hz, 1H, CH3SO2CH2CH2C≡CH).

N-allyl-N-(but-3-ynyl)-4-methylbenzenesulfonamide (42)

H TsN TsN

To a stirred solution of 41 (2.53 g, 12 mmol) in THF (250 mL) at 0 ºC was added NaH (0.59 g, 24 mmol). The mixture was warmed to rt and but-3-ynyl methanesulfonate (2.13 g, 14 mmol) was added. The resulting suspension was refluxed overnight. The precipitate was then dissolved by addition of water and the aqueous phase was repeatedly extracted with EtOAc. The combined organic layers were subsequently washed with H2O, saturated NH4Cl solution, brine and dried. Evaporation of the solvent afforded the crude product which contained unreacted starting matarial. Purification by flash chromatography gave enyne 42 (2.2 g, 68 1 ortho %). H NMR (CDCl3, 300 MHz): δ 7.71 (d, J = 8.7, 2H, Aromatic H ), 7.31 (d, J = 8.1 Hz, 2H, Aromatic Hmeta), 5.66 (ddt, J = 16.8, 10.1, 6.7 Hz, 1H,

CH2CH=CH2), 5.19 (dd, J = 17.5, 1.3 Hz, 1H, CH2CH=CHH), 5.17 (dm, J = 10.1

Hz, 1H, CH2CH=CHH), 3.84 (d, J = 6.1 Hz, 2H, CH2CH=CH2), 3.29 (t, J = 7.7

Hz, 2H, HC≡CCH2CH2N), 2.47 (dt, J = 8.1, 2.7 Hz, 2H, HC≡CCH2CH2N), 2.42

(s, 3H, CH3C6H4SO2N), 1.96 (t, J = 2.7 Hz, 1H, HC≡CCH2CH2N).

51 2-tosyl-1,2,3,4,7,7a-hexahydrocyclopenta[c]pyridin-6-one (43)

Ts N TsN O

Co2(CO)8 (3.57 g, 10 mmol) was added to a solution of enyne 42 (2.29 g, 9 mmol) in petroleum ether (270 mL) at rt. After being stirred for 2 h, the petroleum ether solution was filtered through Celite and evaporated to leave a residue, which was taken up in DCM (300 mL). NMO·H2O (10.89 g, 80 mmol) was added in portions at 0 ºC and the mixture was stirred overnight, during which time the color changed to pink. The reaction mixture was passed through a short pad of Celite and the filtrate was concentrated to dryness. Flash chromatography of 1 the residue gave 1.7 g (68 %) of enone 43. H NMR (CDCl3, 300 MHz): δ 7.66 (d, J = 8.7 Hz, 2H, Aromatic Hortho), 7.33 (d, J = 8.1 Hz, 2H, Aromatic Hmeta), 5.90 (s,

1H CH2COCH=C), 4.20 (ddd, J = 10.7, 6.0, 2.0 Hz, 1H), 4.12 (ddt, J = 12.1, 6.0, 2.0 Hz, 1H), 2.96-3.10 (m, 1H), 2.80 (dt, J = 13.4, 2.5 Hz, 1H), 2.68 (td, J = 12.8, 6.0 Hz, 1H), 2.54 (dd, J = 18.8, 6.7 Hz, 1H), 2.43 (s, 3H), 2.36 (td, J = 12.1, 3.4 Hz, 1H), 2.03 (t, J = 11.4 Hz, 1H), 1.90 (dd, J = 18.8, 2.7 Hz, 1H).

2-tosyl-2,3,4,4a,7,7a-hexahydro-1H-cyclopenta[c]pyridin-6-yl trifluoromethanesulfonate (44)

Ts Ts N N O OTf

To a solution of enone 43 (0.43 g, 1.5 mmol) in THF (15 mL) at – 78 ºC was added L-Selectride (1.5 mL of 1 M in THF, 1.5 mmol) followed after 1 h at – 78 ºC by solid N-phenyltriflimide (0.59 g, 1.6 mmol). The resulting solution was then allowed to warm to rt overnight. The solution was diluted with ether and washed with water. The aqueous layer was back extracted with ether. The 52 combined organic phases were then washed with a 10 % sodium hydroxide solution, followed by water and brine, dried and concentrated. Purification by 1 column chromatography gave 0.53 g (83 %) of triflate 44. H NMR (CDCl3, 500 MHz): δ 7.64 (d, J = 8.3 Hz, 2H, Aromatic Hortho), 7.32 (d, J = 8.3 Hz, 2H, meta Aromatic H ), 5.52 (d, J = 2.0 Hz, 1H, CH=C(OTf)CH2), 3.07 (dd, J = 12.2, 4.9

Hz, 1H, NCHHCHCH2C(OTf)=CH), 3.05 (td, J = 11.7, 3.9 Hz, 1H,

NCHHCH2CHCH=C(OTf)CH2), 2.98 (dd, J = 12.2, 5.9 Hz, 1H,

NCHHCHCH2C(OTf)=CH), 2.90 (ddd, J = 11.7, 7.8, 3.9 Hz, 1H,

NCHHCH2CHCH=C(OTf)CH2), 2.73 (dm, J = 4.4 Hz, 1H, NCHHCH2CHCH=C),

2.54-2.68 (m, 2H, NCHHCHCHHC(OTf)=CH), 2.44 (s, 3H, CH3), 2.34-2.41 (m, 1H, NCHHCHCHHC(OTf)=CH), 1.94 (dddd, J = 14.0, 6.0, 7.8, 3.9 Hz, 1H,

NCH2CHHCHCH=C(OTf)CH2), 1.62 (dddd, J = 14.4, 7.3, 7.3, 3.9 Hz, 1H, 13 NCH2CHHCHCH=C(OTf)CH2). C NMR (CDCl3, 75 MHz): δ 149.74, 144.04, 143.78, 129.82, 127.63, 120.64, 100.67, 46.42, 43.44, 37.60, 35.42, 34.26, 27.10, 21.40.

6-(3,3-Diethoxy-propyl)-2-(toluene-4-sulfonyl)-2,3,4,4a,7,7a-hexahydro-1H-[2]pyrindine (45)

Ts Ts N N OTf O

To an oven-dried flask under argon was added acrolein diethyl acetal (0.08 g, 0.54 mmol) and 9-BBN (1.1 ml of 0.5 M in THF, 0.55 mmol) at 0 ºC. The mixture was warmed up slowly to rt and stirred for 4 h. The borane solution obtained was transferred to a flask containing triflate 44 (0.21 g, 0.49 mmol) in

THF (2 mL). Powdered K3PO4 (0.16 g, 0.73 mmol), PdCl2(dppf) (8.90 mg, 0.01 mmol) was then added. The mixture was stirred under reflux for 14 h. The reaction mixture was diluted with hexane at rt, and the residual borane was oxidized with 3

53 M NaOH (0.5 mL) and 30% H2O2 (0.5 mL) for 1 h. The solution was extracted with EtOAc, washed with brine, dried and concetrated. Flash chromatography of 1 the residue gave 0.15 g (74 %) of acetal 45. H NMR (CDCl3, 300 MHz): δ 7.63 (d, J = 8.7 Hz, 2H, Aromatic Hortho), 7.30 (d, J = 8.1 Hz, 2H, Aromatic Hmeta), 5.16

(d, J = 1.3 Hz, 1H, CH=C), 4.42 (t, J = 5.7 Hz, 1H, CH2CH(OEt)2), 3.54-3.68 (m,

2H, CH3CH2OCHCH2CH3), 3.38-3.52 (m, 2H, CH3CH2OCHCH2CH3), 3.09 (dd, J = 12.1, 5.4 Hz, 1H), 2.97 (ddd, J = 11.4, 6.7, 4.0 Hz, 1H), 2.87 (ddd, J = 11.4, 8.1,

4.0 Hz, 1H), 2.72 (dd, J = 12.1, 7.4 Hz, 1H), 2.61 (br s, 1H), 2.42 (s, 3H, CH3SO2), 2.35-2.50 (m, 1H), 2.29 (dd, J = 15.4, 6.7 Hz, 1H), 2.05 (t, J = 7.7 Hz, 2H), 1.96 (dd, J = 16.1, 4.7 Hz, 1H), 1.76-1.89 (m, 1H), 1.64-1.76 (m, 2H), 1.44-1.60 (m,

1H), 1.185 (t, J = 6.7 Hz, 3H, CH3CH2OCHCH2CH3), 1.180 (t, J = 6.1 Hz, 3H,

CH3CH2OCHCH2CH3).

3-(2-tosyl-2,3,4,4a,7,7a-hexahydro-1H-cyclopenta[c]pyridin-6-yl)propanal (46)

Ts Ts N N O O

O H

Acetal 45 (0.15 g, 0.37 mmol) was dissolved in acetone/H2O (4:1, 4 mL) and a catalytic amount of TsOH was added. The mixture was stirred at rt until the disappearence of the acetal was determined by TLC. Saturated NaHCO3 solution was added to the reaction mixture until the solution was basic. After evaporation of most of the solvent, the residue was diluted with Et2O and washed with water, brine, dried and concentrated. The crude aldehyde 46 was used in the next step 1 without further purification. H NMR (CDCl3, 300 MHz): δ 9.73 (t, 1.3, 1H, ortho CH2CHO), 7.63 (d, J = 8.1 Hz, 2H, Aromatic H ), 7.31 (d, J = 8.1 Hz, 2H, Aromatic Hmeta), 5.20 (d, J = 1.3 Hz, 1H, CH=C), 3.04 (dd, J = 11.4, 5.4 Hz, 1H), 2.92 (m, 2H), 2.82 (dd, J = 12.1, 6.7 Hz, 1H), 2.48-2.66 (m, 3H), 2.42 (s, 3H),

54 2.42-2.48 (m, 4H), 2.02 (dd, J = 15.5, 5.4 Hz, 1H), 1.84 (m, 1H), 1.44-1.60 (m, 1H).

1-(2-tosyl-2,3,4,4a,7,7a-hexahydro-1H-cyclopenta[c]pyridin-6-yl)hex-5-yn-3-ol (47)

Ts Ts N N O OH

To a flame-dried flask under argon containing magnesium (54 mg, 2.21 mmol) and ether (8 mL) was added propargyl bromide (0.25 mL, 2.21 mmol) and mercuric chloride (30 mg, 0.11 mmol). The reaction was initiated by gentle heating and kept in an oil bath (40 ºC) for 1 h. The solution obtained was added to aldehyde in THF (4 mL) at 0 ºC. The mixture was warmed to rt slowly. The resulting mixture was poured into H2O. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water, brine, dried and concentrated to leave a residue. Flash chromatography afforded alkyne 47 as a 1:1 1 mixture of isomers (0.11 g, 83 %). H NMR (CDCl3, 300 MHz): δ 7.64 (d, J = 8.1 Hz, 2H, Aromatic Hortho), 7.31 (d, J = 8.7 Hz, 2H, Aromatic Hmeta), 5.21 (d, J =

1.3 Hz, 1H, CH=C), 3.71 (br s, 1H, HC≡CCH2CHOH), 3.06 (dd, J = 11.4, 5.4 Hz, 1H), 2.93 (m, 2H), 2.79 (m, 1H), 2.55-2.66 (m, 1H), 2.43 (s, 3H), 2.25-2.50 (m, 4H), 1.95-2.20 (m, 4H), 1.78-1.95 (m, 2H), 1.47-1.70 (m, 2H).

6-(3-(tert-butyldimethylsilyloxy)hex-5-ynyl)-2-tosyl-2,3,4,4a,7,7a-hexahydro-1H- cyclopenta[c]pyridine (48)

Ts Ts N N OH OTBS

55 To a solution of 47 (0.11 g, 0.29 mmol) in DCM at −78 º C was added 2,6- lutidine (55 μl, mmol) and TBDMSOTf (81 μl , 0.35 mmol). The mixture was warmed to rt, then diluted with ether and washed with water, brine and dried. Filtration, concentration and column chromatography afforded enyne 48 (0.14 g, 1 ortho 95 %). H NMR (CDCl3, 300 MHz): δ 7.64 (d, J = 8.1 Hz, 2H, Aromatic H ), 7.31 (d, J = 8.1 Hz, 2H, Aromatic Hmeta), 5.18 (s, 1H, CH=C), 3.74 (m, 1H,

HC≡CCH2CHOSi(CH3)2C(CH3)3), 3.05-3.15 (m, 1H), 2.84-3.00 (m, 1H), 2.70- 2.82 (m, 1H), 2.60 (m, 1H), 2.42 (s, 3H), 2.43-2.50 (m, 4H), 1.92-2.14 (m, 4H), 1.66-1.92 (m, 2H), 1.48-1.66 (m, 2H), 0.87 (s, 9H,

HC≡CCH2CHOSi(CH3)2C(CH3)3), 0.03 (4s, 2isomers, 6H,

HC≡CCH2CHOSi(CH3)2C(CH3)3).

CHAPTER III

PALLADIUM ASSISTED DOMINO PROCESS APPROACH

Heck Reaction

Transition metal-catalyzed C-C bond forming reactions have gained steadily increasing importance over the past decades. Palladium, formerly used only for redox reactions, has recently achieved a prominent role in synthesis due to the manifold and unique transformations that it is capable of mediating, often in a catalytic mode. The palladium-catalyzed arylation and alkenylation of alkenes, discovered independently by Mizoroki et al. in Japan52 and Heck et al. in the US53 around 1970, now generally called the Heck reaction, have become one of the most frequently applied metal-catalyzed C-C bond forming processes and have therefore attracted a great deal of interest (Scheme 49). The rapid development of new and vastly improved reaction protocols, the discovery of diastereoselective and even ligand-induced enantioselective couplings have made it possible to apply the Heck reaction in elegant syntheses of various biologically active compounds.

Scheme 49. Heck reaction

"Pd" + R2 R1X R1 R2

R1 = alkenyl, aryl, allyl, alkynyl, benzyl, alkoxycarbonylmethyl, alkyl R2 = alkyl, alkenyl, aryl, CO2R', OR', SiR3', etc. X = I, Br, Cl, OTf

57 Mechanism

Scheme 50. Mechanism

Pd (0) or Pd (II) Precatalyst

R Oxidative addition Pd (0) RX

R R R X Pd Pd Pd H X

reductive elimination R Pd R Pd migratory insertion

The entry into the catalytic cycle includes the reduction of Pd(II) complexes to Pd(0) and the generation of the active species through multiple ligand exchange equilibria. Due to the labile character of Pd(0) complexes, in most cases there must be a manifold of more and less reactive species with varying coordination shells. Catalytic systems commonly used in Heck reactions, consisting of Pd(OAc)2(PPh3)2 or a mixture of Pd(OAc)2 and nPPh3 (n ≥ 2), which spontaneously and quantitatively generate in situ a zerovalent palladium complex able to activate aryl iodides via an oxidative addition.54, 55 The reduction is assisted by hard nucleophiles, of which the most common are hydroxide, alkoxide ions, water and acetate ion, though in special cases even fluoride in the presence of water can play the role. Most probably the nucleophile either attacks the coordinated phosphine in a way that can be simplistically viewed as a nucleophilic substitution at phosphorus atom. An inner-shell mechanism involving the reductive elimination of phosphonium species is also possible. The 58 liberated phosphonium intermediate is transformed into phosphine oxide via one of several possible mechanisms (Scheme 51).

Scheme 51. Reduction

Nu-

o Pd PR3 Pd + NuPR3 OPR3

Nu o Pd PR3 Pd + NuPR3 OPR3

Nu = OH, RO, H2O, AcO

The oxidative addition of low-valent transition metal complexes to C-X bonds is among one of the basic processes of organometallic chemistry. The oxidative addition proceeds as a concerted process in which C-X bond rupture is more or less perfectly synchronized with the formation of M-C and M-X bonds. The organic substrates that interact with Pd(0) are usually classified into polar and non-polar substrates. Polar substrates are represented by organic halides, susceptible to nucleophilic attack by palladium by virtue of their good leaving group. Non-polar substrates, such as arenes, activated alkanes and terminal alkynes react via C-H breaking. Aryl and vinyl halides afford the corresponding σ-aryl and σ-vinyl palladium complexes via oxidative addition, the order of reactivity being I>OTf>Br>Cl. Migratory insertion is the product-forming step of the Heck cycle, in which a new C-C bond is formed. It is this step which is most likely responsible for regio- and stereodiscrimination as well as substrate selectivity. After the migratory insertion comes the step in which palladium(0) is released and launches the next turn of the Heck cycle. The σ-palladium(II) complexes formed may undergo intramolecular coupling of two ligands, extruding

59 Pd(0). In this reaction, the reverse of the oxidative addition, a wide variety of ligand types can be coupled leading to the formation of C-C, C-H, C-N, and C-O bonds (Scheme 50).

Dehydropalladation

The most common termination step is dehydropalladation. Palladium hydride is eliminated to release the double bond. Syn-elimination defines the stereoselectivity of the Heck reaction. In the great majority of cases, the elimination obeys the well-known Curtin-Hammett kinetic control principle and the ratio of E- and Z-isomers reflects the relative energy of the respective transition states. Unless R is very small (CN is the best known example), the E- isomer is predominant and the reaction is highly stereospecific even for very simple models, which is one of the major advantages of the Heck protocol over such classical methods of olefination as the Wittig-Horner reaction (Scheme 52).

Scheme 52. Dehydropalladation

Ar H H Ar RH R H HHR H H H XPd Ar XPd XPd Ar

R' Ar R'

In some cases, in spite of the availability of a β-hydrogen, the usual β- elimination of palladium hydride does not occur. Several reasons are discernible for the lack of dehydropalladation: (a) the complex is supported by stabilizing ligands (phosphines, arsines, cyclopentadienyl, olefins); (b) the alkyl group is a part of an energetically favored five or six-membered metallacycle where the β- hydrogens are conformationally locked and thus can not adopt the cisoid

60 conformation needed in the transition state; (c) chelate formation prevents proper alignment between the syn-β-hydrogen and the carbon-palladium σ-bond. Rawal and Michoud reported an unexpected Heck reaction involving inversion of olefin geometry facilitated by the apparent intramolecular carbamate chelation of the σ-palladium intermediate.56 In situ trapping of the reactive carbon- palladium bond by the exocyclic alkene afforded cyclopropane 65. A 120° rotation about the σ-bond allows proper alignment for fragmentation of the other cyclopropane bond. The σ-palladium complex produced after fragmentation is no longer stabilized by chelation and undergoes a fast β-elimination to provide the isolated product 66 (Scheme 53).

Scheme 53. Carbamate chelation of the σ-palladium intermediate

Me N Me N N I H Me a L H Pd L 84% N N Pd L N O O L MeO CO2Me MeO H Me N Me Me N PdLn H N PdLn - Pd(0) H H N N O N MeO MeO O O 66 MeO 65

Reaction conditions: (a) Pd(OAc)2, K2CO3, DMF, n-Bu4NCl, 60 ºC

Vinyl iodide 67 undergoes a smooth intramolecular Heck coupling reaction to provide, after tautomerization of the intermediate enamine, dehydrotubifoline 68

61 as the sole product. This outcome suggests that by judicious placement of coordinating groups it may be possible to intercept the α-palladium Heck cyclization intermediate (Scheme 54).

Scheme 54. Vinyl iodide 67

N I N Me Pd(0) H N H N H 67 68

Stable σ-alkyl palladium complexes possessing a β-hydrogen have been reported by several groups. Some four-membered cyclic (σ-alky1amino)palladium complexes containing conformationally free hydrogens were prepared.57, 58 Their relative stabilities correlate with the extent that geometrical rigidity around the metal center is maintained by the ligands. Chloro[2-(dimethylamino)-l- methylpropyl-C,N](dimethylamine) palladium(II) 69 can be kept in crystalline form for at least an hour at 25 ºC without noticeable decomposition and can be stored for months at − 20 ºC. Daves and Arai made a stable glucopyranosylpalladium compound 70 with a cis β-hydrogen.59 It can be stored at rt for periods exceeding 2 months with little decomposition. AcO H H3C CH H H3C 3 AcO O AcO H H Pd Cl Ph3P Pd H3C NH(CH3)2 Cl O NMe MeN O 70 69

62 Overman et al. reported a stable, palladium-containing compound which has β-hydrogen atoms residing on a freely rotating β-carbon atom.60 When 71 was cyclized in the presence of 100 mol % Pd(OAc)2 and 150 mol % (R)-BINAP, substantial amounts (~ 35 % - 55 % ) of a stable, palladium-containing compound 72 were isolated after workup and flash chromatography (Scheme 55).

Scheme 55. Stable palladium-containing compounds 72, 73

O O O β O N H H 1 H Bn O 6 H 4 N N H α 2 9 O BnN Pd P Pd 10 OTf OTf O P 73 71 72

The fully characterized Pd-σ-alkyl complex 73 is remarkably stable in 61 CDCl3 solution (≤ 20 % decomposition after 5 d at 25 ºC). Single-crystal X-ray diffraction shows that a non-syn-relationship between the Pd and the four β- hydrogens (C(4) and C(6)) is enforced by coordination of the C(1)=C(2) and C(9)=C(10) alkene units to Pd. Unusually large primary 2H/1H kinetic isotope effects accompanying a syn-β-H elimination reaction in the σ-alkyl-palladium complex are observed (Scheme 55).62

Palladium Assisted Domino Reactions

In recent years, the pioneering work of a couple of research groups has demonstrated that, using a single catalytic starter, many cascading reactions could be devised from suitable precursor substrates.63 Multiple consecutive one-pot reactions, thereafter named domino reactions, are not, of course, confined to organometallic chemistry. The large number of organic transformations mediated, 63 the wide functional group tolerance, and the catalytic nature of most of these processes, however, make palladium an ideal basis for devising unbeatable domino processes. In order to recognize and classify a domino process, it is useful to locate three types of functional groups in the substrate: a starting functionality, one or more relay groups, and a terminating species. It is important to note that the second stage is invariably a migratory insertion (i.e. a carbopalladation or a CO insertion) and conditions must be met to in order to avoid premature termination of the relay species. Termination of the cascade may take place internally (via dehydropalladation) or externally (via a trapping agent). In the latter case, the trapping agent must react slowly enough to allow the cascade to proceed to completion without premature termination, and, at the same time, rapidly enough to prevent undesired side reactions. The most signifcant transformation of palladium catalyzed domino processes is unquestionably migratory insertion. This intramolecular process involves migration of the atom σ-bonded to palladium to an adjacent coordinated ligand. A vacant coordination site is created during the reaction and the formal oxidation state of the metal is not changed. The fact that alkynes are considerably more reactive than alkenes toward a Pd(II) species is of high relevance to domino processes. Allyl moieties may participate as migrating groups, whereas allenes and acetylenes easily undergo insertion to give π-allyl- and σ-vinyl-Pd(II) complexes, respectively (Scheme 56).

Intermolecular carbopalladations.

Aryl iodides, nonconjugated dienes, and carbon nucleophiles react in the presence of a palladium catalyst to give good yields of coupled products formed by arylpalladium generation and addition to the less substituted end of the diene, palladium migration down the carbon chain though sequential reversible

64 dehydropalladation, hydropalladation events to form a π-allylpalladium intermediate, and carbanion displacement of the palladium moiety. Iodobenzene reacted in this way with α,ω-dialkenes, in the presence of Pd(0), to give an intermolecular three-component coupling (Scheme 57).64, 65

Scheme 56. Migratory insertion

RPdX RPdX R Pd X R Pd X R = H hydropalladation R = C carbopalladation PdX Pd+ X- R + X Pd R Pd X- R' R' allene insertion alkene insertion into π allyl

Scheme 57. Intermolecular three-component coupling

PdI Ph EtO2C a + + PhI 52% EtO2C

HPdI PdI IPdH Ph Ph Ph

Ph Ph Ph

EtO2C HPdI IPd CO2Et 52%

Reaction conditions: (a) Pd2(dba)3, NaHCO3, n-Bu4NCl, DMSO, 80 ºC

65 Intramolecular carbopalladations

Depending on the relative disposition of the unsaturation in the precursor backbone, and on the sequence of the reaction events, linear-fused mode carbopalladation, spiro-mode carbopalladation, dumbbell-mode carbopalladation and zipper-mode carbopalladation can be distinguished in cyclic carbopalladations. A linear fused mode carbopalladation may be obtained with substrates having the starting, the relay, and the terminating groups each connected by a trisubstituted atom (Scheme 58). When a 1,1-disubstituted alkene acts as relay, a spiro-mode cyclization is realized. If the relay function is an endocyclic alkene bearing the starting and the terminating moieties on two allylic cis disposed arms, triquinane-type structures maybe obtained. If the relay species is an exocyclic alkene, and the starting and the terminating species reside on the two vicinal geminally-disposed arms, propellane-type structures may be formed. The dumbbell-mode carbopalladation cascade involves generation of the starting C-Pd bond in a linear structure in a distal position with respect to other juxtaposed units of unsaturations (Scheme 59). This cyclization mode, which works well with alkynes, allows the building up of pairs of Csp2-linked ring systems. Upon iteration of the process, however, intramolecular processes may follow this linear process giving rise to a circular-mode cyclization. Pericyclic reactions such as Diels-Alder, ene, electrocyclic, and Cope rearrangement, may serve as the final cyclization step.

Scheme 58. Linear fused mode carbopalladation

R R PdX X

66 Scheme 59. Dumbbell-mode carbopalladation

R PdX R PdX

The zipper-mode carbopalladation cascade can be performed when the starting C-Pd bond is located in a linear backbone between the reacting unsaturated moieties (usually alkynes). Repeated carbopalladations sequentially join the unsaturated functionalities of the two opposite arms leading to a polycyclic structure. These exceptionally selective and clean transformations rely on the fact that five- and six-membered ring formation is much faster than the formation of four-membered and medium-sized rings. This cyclization represents an elegant approach to the synthesis of polyfused systems, and is complementary to the well-known enzymatic cyclization of oxidosqualene to sterols (Scheme 60).

Scheme 60. Zipper-mode carbopalladation

X PdX

Overman et al. reported the first total synthesis of scopadulcic acid B.66 In this elegant spiro-mode Pd(0) catalysed bis-cyclization, the initial oxidative addition of the dienyl iodide is followed by two consecutive intramolecular carbopalladations and a final dehydropalladation. Preparative scale cyclizations were carried out in refluxing acetonitrile in the presence of 10 mol % of a coordinatively-unsaturated catalyst prepared from Pd(OAc)2 and Ph3P.

67 Cyclizations conducted on scales as large as 14 g provided the enones 74 and 75 in a combined yield of 80-85% (Scheme 61).

Scheme 61. Scopadulcic acid B

O I a H + 80-85%

O H O O HO2C OBz 74 75 scopadulcic acid

Reaction conditions: (a) Pd(OAc)2, Ph3P, MeCN, 80 ºC

Sinou et al. have developed a one-component palladium-mediated intramolecular cyclization on a glucal-derived template, obtaining an enantiopure triquinane-type product.67, 68 The unsaturated carbohydrate 76 was transformed

Scheme 62. Palladium-mediated intramolecular cyclization

TBDMSO TBDMSO O O a OO O O 75% Br

76 77

TBDMSO TBDMSO TBDMSO O O O O O O 72% O O Br 78% Br

78 80 79

Reaction conditions: (a) CH3CN/H2O (1/1), Pd(OAc)2, PPh3, Bu4NHSO4, NEt3, 80 ºC, 15-24h 68 into the tricyclic compound 77 in 75 % yield. When the reaction was extended to the unsaturated carbohydrates 78 and 79, only the bicyclic compound 80 was obtained in 72 % and 78 % yield, respectively (Scheme 62). The mechanism of this cyclization starts with the formation of a σ- vinylpalladium intermediate A by oxidative addition to the palladium(0) complex (Scheme 63). An association-insertion process, involving the pyranose moiety, gives a new σ-alkylpalladium species B. Another association insertion sequence involving the double bond of the aglycon moiety leads to the formation of the σ- alkylpalladium complex C via a 5-exo-trig process. In the case of bromide 76, a β- hydride elimination occurs leading to the tricyclic compound 77. For bromide 78, there is no hydrogen atom available for the β-hydride elimination so the σ- alkylpalladium intermediate B leads to the bicyclic compound 80 via a β- dealkoxypalladation reaction. Concerning the cyclization of substrate 79, the formation of the bicyclic compound 80 instead of a tricyclic one indicates that 6- exo-trig cyclization is disfavored versus β-dealkoxypalladation (Scheme 63). Oppolzer and De Vita have reported an interesting linear-fused palladium catalyzed tris-cyclization of a bis-allylic substituted cycloheptene.69 The tetracyclic product 84 is formed via Pd-ene cyclization of acetate 81 (closing ring A) followed by two intramolecular Heck reactions (closing rings C and D). Hydrogen atoms Ha/Hb in product 82 are cis related in agreement with a suprafacial Pd-ene process and subsequent Heck insertion with retention of configuration at C(9c) giving σ- alkylpalladium intermediate 83. A Dreiding model of postulated tricyclic σ-Pd complex exhibits a relatively rigid conformation enforcing proximity of the metal and the vinyl group. Hence the second C-Pd/C=C insertion 83 → 84 becomes favored over β-elimination of 83 (Scheme 64). The intramolecular carbopalladation on a linear structure containing sequentially and properly disposed gem disubstituted alkenes generates a cascade of living alkylpalladium complexes until the metal is internally or externally

69 released. Using this strategy Trost et al. succeeded in synthesizing tetracycle 85 from a totally acyclic precursor (Scheme 65).70

Scheme 63. Mechanism

TBDMSO TBDMSO O O Pd(0) O O O O Br BrPd A R R

TBDMSO TBDMSO O O OO O O R PdBr R C PdBr B

-hydride -alkoxy β R = H R=CH β elimination 3 elimination

TBDMSO TBDMSO O O O O O

Under palladium catalysis polyene 86 afforded only the expected tricycle 87 in a yield of 83% as a single diastereomer with the phenyl and methoxy groups in a trans orientation (Scheme 66). The mechanism involves an initial 5-exo-dig, followed by a 5-exo-trig cyclization. Dehydropalladation affords the hexatriene intermediate which suffers a 6π-electrocyclic rearrangement.71 When bromide 88 was subjected to the cyclization conditions three products were observed, two of which were isolated by column chromatography. One was the tetracycle 91, which was apparently formed by a 5-exo-trig

70 Scheme 64. Palladium catalyzed tris-cyclization

H B H E E E E E E E a 9c E A Hb 50% Ha PdL2 H

81 82 OAc

E=CO2Me

H H H H E B E E B E E E C 9c C 9c E E A H A Hb b Ha Ha H D H H H PdL2 84 83

Reaction conditions: (a) Pd(dba)2, trifurylphosphine, HOAc, 110 ºC, 2h

Scheme 65. Synthesis of tetracycle 85

OCH3

OCH3 PhSO2 a PhSO2 84% PdX PhSO2 PhSO2

OCH3

PhSO2 H3CO PhSO 2 PdX PhSO2

PhSO2 85

Reaction conditions: (a) Pd2(dba)3.CHCl3, Ph3P, AcOH, PhH, 40-55 ºC

71 cyclization of the neopentylpalladium intermediate 89 giving the tricyclic neopentylpalladium bromide 90, in which β-hydride elimination was still precluded, so that attack of the remaining double bond in a sterically favored 3- exo-trig mode occurred. Finally β-hydride elimination afforded the cyclopropane- bridged triquinane derivative 91, The second product (35% yield) was the bicyclo[3.1.0]hexane derivative 93, apparently formed from 92 by a 3-exo trig attack on the nearest double bond, and ensuing β-hydride elimination (Scheme 67). A zipper-mode cascade involving vinyl iodides as starting species, and alkynes or 1,1-disubstituted alkenes as relays, was reported by Grigg.72 When iodide 94 was treated with allene (l atm) and a nucleophile in DMF an intermolecular queuing process ensued proceeding via the vinylpalladium(II) species 95. The latter intermediate reacts with allene at the center carbon atom to afford a π-allyl species 96 which is then captured by a suitable nucleophile. When piperidine was employed as the nucleophile, polyene 97 proved to be very unstable and could only be isolated in 40% yield. However, when sodium phenylsulphinate was employed as the nucleophile, the product 98 could be isolated in 65% yield. In the case of 97/98 the vinyl initiator engages two alkyne moieties in the relay phase followed by an alkyne terminating group (Scheme 68). In summary, the ability of palladium to interact with organic moieties, to mediate both inter- or intramolecular reactions of alkenes or alkynes in domino processes is unlimited. The astonishing simplicity of realizing many complex polycyclizations is sometimes directly proportional to the labor required for the synthesis of the cyclization precursor.

72 Scheme 66. Synthesis of 87

Ph Ph Ph Br a Br 5-exo-dig Pd Br 83% Pd OMe EtO C EtO C OMe EtO2C 2 2 EtO C OMe EtO2C 2 EtO2C 86 Ph PdBr Ph Ph 5-exo-trig

EtO2C EtO2C OMe OMe EtO2C EtO2C EtO2C OMe CO2Et 87

Reaction conditions: (a) Pd(OAc)2, PPh3, K2CO3, MeCN, 60 ºC, 3d

Scheme 67. Syntheses of 91 and 93

Me BrLnPd Me Me

a Br 3-exo-trig EtO C PdLnBr 2 EtO C EtO2C 2 CO Et EtO2C CO2Et 2 88 89 92

Me Me Me 3-exo-trig BrLnPd

EtO2C EtO2C EtO2C CO2Et CO2Et CO2Et 91 90 93 30% 35%

Reaction conditions: (a) DME/MeCN 1:1, Pd(OAc)2, PPh3, Ag2CO3, 60 ºC, 2d

73 Scheme 68. Zipper-mode cascade of iodide 94

PdX MeO2C MeO2C MeO2C MeO2C I

94 95 (1 atm)

Nu MeO2C MeO2C PdX R MeO2C MeO2C

97 R = HN 40% a. HN 96 Nu = 98 R = NaO2SPh 65% b. NaO2SPh

Reaction conditions: (a) Pd(PPh3)4, K2CO3, DMF, 70 – 75 ºC, 15h Results and Discussion

Because our initial Pauson-Khand approach was unsuccessful the following alternative route which relies on an intramolecular Pauson-Khand reaction and a domino Heck reaction to deliver the magellanane skeleton was pursued.

O O O O O O PK

TfO O

74 O O N O O D O C Pd H I H OH

t-BuO t-BuO

We chose 2,3-O-isopropylidene-D-erythronolactone as our starting material which is commercially available from Aldrich (Scheme 69). Diisobutylaluminum hydride (DIBAL-H) reduction of lactone 99 in DCM at -78 °C furnished the lactol 100 in 90 % yield.73 The Wittig reaction afforded alkenol 101 in 83 % isolated yield.74 Treatment of alkenol 101 with triflic anhydride gave the corresponding triflate, which was subsequently exposed to lithium (trimethylsilyl)acetylide at -20 °C to provide, after desilylation with TBAF, enyne 104. To the enyne in petroleum ether was added Co2(CO)8 at rt. After stirring for 2 h, the petroleum ether solution was filtered through Celite and evaporated to leave the enyne cobalt complex which was taken up in 2,2-dimethoxypropane under O2. Anhydrous TMANO was added in portions to the mixture. The mixture was stirred until the color changed from dark red to pink. Workup delivered the enone in 56 % yield over 4 steps.75, 76 When the Pauson-Khand reaction was carried out under Ar significant amounts of reductive Pauson-Khand product were obtained. This Pauson-Khand reaction was best carried out in 2,2-dimethoxypropane to avoid the potential deprotection of the acetonide. After several tries it was realized that in the conversion of alcohol 101 to enone 105 only minimal purification was needed and the procedure was significantly simplified (Scheme 69). Enone 105 was formed as two separable isomers 105a, 105b in the ratio of 1.7:1. The stereochemical assignments for 105a and 105b followed directly from 1H NMR NOE experiments carried out on the separate isomers.

75 Scheme 69. Synthesis of 105

O OH O a O b O c O O O OH OTf O 90 %O 83 % O O 99 100 101 102

O H O deO O f H O O O O O O 105a O H 4 steps 56 % O O 103TMS 104 105 105b

+ − Reaction conditions: (a) DIBAL-H, THF, −78 ºC; (b) Ph3PCH3 Br , BuLi, THF, , −78 ºC → reflux; (c) Tf2O, Et3N, DCM, −20 ºC; (d) BuLi, TMSC≡CH, THF, DMPU, −78 ºC → −20 ºC; (e) TBAF, THF, rt; (f) Co2(CO)8, petroleum ether; anhydrous TMANO, 2,2-dimethoxypropane, O2

Enyne 103 or the corresponding diol derivative needs to be used for the Pauson- Khand reaction in order to achieve high stereoselectivity. If acetonide 103 is used for the Pauson-Khand reaction, one of the intermediate cobalt metallocycles is expected to be favored. Intermediate B has a cis arrangement between the oxygen functionality (OR) and ring-junction hydrogen, and a trans alignment with the TMS group as well. In intermediate A, the OR appendage is placed in the concave face and therefore suffers from not only an unfavourable cis-1,2-relationship with the carbon–carbon framework of the five-membered metallacyclic ring but also a 1,4-pseudo-nonbonding interaction with the TMS group. The enone which has a cis arrangement between the oxygen functionality (OR) and ring-junction hydrogen is expected to be the major product. Different high stereoselectivity is expected to be observed when the corresponding diol derivative of enyne 103 is used. Hydrogen bonding of the vicinal diol functionality of the cobalt-complexed enynes would give rise to two possible conformers, C and D. With conformer D, the allylic 1,3-strain between

76 the olefinic proton (H-1) and the C3-C4 bond would occur; thereby, the H-1 would also suffer from nonbonding interaction with the axial-like H-4. The conformer C, however, might have much less serious interaction between the H-2 and the axial- like H-4. High stereoselectivity would be achieved by the simple comparison of stability of these two conformers.75, 76 We chose enone 105a to continue our synthesis initially. Enone 105a was then treated with L-Selectride® in THF at -78 ºC followed by quenching the resulting enolate with N-phenyltriflimide in situ to deliver the vinyl triflate 106. The cross- coupling reaction of 9-(3,3-diethoxypropyl)-9-bora-bicyclo[3.3.1]nonane with triflate 106 in the presence of K3PO4 (1.5 equiv) and a catalytic amount of

Cl2Pd(dppf) delivered acetal 107 in 74 % yield. Deprotection of the acetal in the presence of 10 mol % TsOH in acetone afforded aldehyde 108. To shorten the reaction time 10 mol % more acid was added and the deprotection was normally finished in one hour. Longer stirring resulted in significant amounts of undesired product which was presumably from deprotection of the acetonide. Subsequent treatment of 108 with BrMgCH2C≡CH delivered enyne 109 (Scheme 70).

O OC O CO Co CO Cobalt-complexed 103 OC Co TMS OC CO

O H O H O H O H O Co O O O Co O O TMS TMS Co TMS Co TMS Major AB

77 HO 1 OC HO 3 CO R = H, TMS Co CO M=Co2(CO)6 OC Co R OC CO H H H HO H HO H H O H O H O HO O O H H O H M HO R R TMS TMS H H M H Major H H C D

TMS TMS 1) Co2(CO)8 HO 2) CH3CN, O + O TMS 70-75°C HO HO HO 74 % HO H HO H 93 : 7 M H M HO M H H O O H TMS TMS H TMS O H O H HO H H H H H

Scheme 70. Synthesis of 109

O H O H O H a O b O O O OTf OEt 83 % 74 % 105a H 106H 107 OEt O H O H c O O d OH O H H 2 steps 82 % 108 109

Reaction conditions: (a) L-selectride, THF, −78 ºC; PhNTf2, −78 ºC → rt; (b) H2C=CHCH(OEt)2, 9-BBN; K3PO4, PdCl2(dppf), THF, reflux; (c) TsOH, acetone; (d) Mg, HC≡CCH2Br, HgCl2 (cat.), Et2O, THF

78 Alcohol 109 was converted to the corresponding t-butyl ether 110 by treatment with t-butyl trichloroacetimidate (1.1 equiv) in cyclohexane in the presence of a catalytic amount of boron trifluoride etherate at rt. Because it was a secondary alcohol the reaction was very slow and addition of excess boron trifluoride etherate led to unwanted byproducts. At first we chose TBS as the protecting group but in the following hydroalanation and iodination steps the TBS group was mostly cleaved. A similar result was obtained when the protecting group was TBDPS. After many different protecting groups were tried we finally settled on the t-butyl group because the t-butoxy functionality is too weak a Lewis base to impede the hydroalanation reaction and also it is very stable to the hydroalanation and iodination conditions. Ether 110 was then converted to the corresponding lithium alkynylide with BuLi at -78 ºC followed trapping with methyl chloroformate to produce ester 111. To a solution of ester 111 in DCM was added DIBAL-H (1M in hexane) at -78 ºC. The resulting mixture was warmed to -50 ºC over a two hour period. The reduction did not go to completion when it was carried out -78 ºC. Hydroalanation of propargylic alcohol 112 with Red-Al in THF followed by addition of N- iodosuccinimide afforded exclusively 3-iodo (Z)-allylic alcohol 113.77-79 Oxidation of iodoallylic alcohol 113 with MnO2 gave aldehyde 114 and subsequent reaction with Ph3P=CH2 furnished triene 115 for the palladium catalyzed cascade cyclization (Scheme 71).80 The key bis-cyclization of trienyl iodide 115 was carried out in refluxing acetonitrile in the presence of 10 mol % of Pd(PPh3)4 and 6 equiv K2CO3. Two diene cyclization products were obtained in 62 % yield along with small quantities of complicated alkene products. The dienes showed bright purple color on the TLC plate when applied to the anisaldehyde dip and were unstable in CDCl3 while NMR experiments were carried out. The distinctive color shown in anisaldehyde TLC dip helped us to identify the two cyclization products which were tentatively assigned as 116a and 116b. 1H NMR spectroscopy indicated the existence of the

79 H2C=CR-CH=CR’2 moiety and HRMS FAB+ (NBA+NaI) confirmed the molecular weights of both isomers.

Scheme 71. Synthesis of 115

O H O H O OH a O Ot-Bu b H 50% 95% H 109 110

O H O H O Ot-Bu c O Ot-Bu d H 90% 98% H

MeO2C HOH2C 111 112

O H O H O Ot-Bu O Ot-Bu e f H I H 2 steps I 83%

113 114 OH O O H

O Ot-Bu

H I

115

Reaction conditions: (a) cat. BF3·Et2O, Cl3C(NH)Ot-Bu, cyclohexane; (b) BuLi, ClCO2Me; (c) DIBAL-H, + − DCM, −78 ºC → −50 ºC; (d) Red-Al, THF, rt; NIS, −78 ºC; (e) MnO2, DCM, rt; (f) Ph3PCH3 Br , BuLi, THF

80 Scheme 72. Palladium assisted domino biscyclization

O H t O Ot-Bu O H O -Bu a O H I H 115 116

O H Ot-Bu O H Ot-Bu O O

H H

116a 116b

Reaction conditions: a) (Ph3P)4Pd, CH3CN, K2CO3 or 1,2,2,5,5-pentamethylpiperidine, reflux

Analysis of 1H NMR spectra of the byproducts revealed that they were presumably formed through intermolecular reactions, instead of simple β-hydride elimination of the σ-alkylpalladium formed by oxidative addition to the palladium(0) complex and the subsequent association-insertion, involving the unsaturation of cyclopentene moiety. Chelate formation may prevent proper alignment between the syn-β-hydrogen and the carbon-palladium σ-bond. 69 Another possibility is that the β-hydride elimination produces a highly strained ring system and in situ hydropalladation regenerates the σ-alkylpalladium so the second C-Pd/C=C insertion can take over. Intermolecular side reactions may happen before or after the formation of a σ-dienylpalladium intermediate by oxidative addition to the palladium(0) complex and the subsequent association- insertion, involving the unsaturation of cyclopentene moiety. When we used the TBS as the protection group instead of tert-butyl the domino Heck coupling also delivered two isomers. Their molecular weights were 81 O H O H O OH O OTBS

H H 109 117

O H

O OTBS O H OTBS

H O I H 118 119

also confirmed by HRMS. The less polar diene 119 based on TLC was treated with TBAF in THF and the corresponding free alcohol 120 obtained was then transformed to 3,5-dinitrobenzoate derivative 121. 1H NMR NOE experiments were carried out.

irradiate H-5 (δ 2.67) → H-16β (δ 4.80, 1.5 %); no NOE at H-4 (δ 2.18)

irradiate H-16α (δ 4.91) → H-16β (δ 4.80, 29.8 %); H-5 (δ 2.67, 1.8 %)

irradiate H-7 (δ 5.65) → H-16α (δ 4.91, 3.8 %); H-9β (δ 2.77, 2.6 %)

irradiate H-16α (δ 4.91) and H-10 (δ 4.89) → H-16β (δ 4.80, 22.2 %); H-7 (δ 5.65, 8.0 %)

irradiate H-9β (δ 2.77) → H-9α (δ 2.14, 22.3 %); H-7 (δ 5.65, 7.9 %); H-10 (δ 4.89, 5.8 %)

82 O H OTBS O H OH O O H H 119 120 O O H O 1 10 O 15 9 2 4 NO2 5 H H 7 H O2N Hβ 16 Hα 121

The stereochemical assignment accorded to 121 was corroborated by high- field 1H NOE spectroscopy measurements. Due to the the steric hindrance at the concave surface of the bicycle[3.3.0]octene subunit the formation of a σ- dienylpalladium intermediate by oxidative addition to the palladium(0) complex and the subsequent association-insertion, involving the unsaturation of cyclopentene moiety, should take place from the convex face and give a new σ- alkylpalladium species.

O H O H O H O OR O O H Pd I H I H Pd tert concave face I R= -butyl, TBS not favorable

O H O H OR O -HPdI O H H PdI 83 We also synthesized three substrates 122, 123, 124 to test the generality of this process (Scheme 73). Their syntheses were similar to the synthesis of iodide 115 and are outlined in Scheme 74, Scheme 75 and Scheme 76. Iodide 124 bearing a monosubstituted alkene did not give the desired bicyclic diene product. It was not surprising because of the favorable β-hydride

Scheme 73. Substrates 122, 123, 124

Ot-Bu O O O I I

122 123 I 124

85%

Ot-Bu Ot-Bu

O O O O - [HPdI] O PdI I O

O PdI PdI O O O IPd H H PdI O O O O

84 elimination of the σ-alkylpalladium. Iodide 123 delivered the formal 6-endo cyclization product probably involving a cyclopropane intermediate.56 Compound 122 delivered the desired palladium assisted domino process product in 85 % yield (Scheme 73).

Scheme 74. Synthesis of 122

O OH a OH b c O O 12590% 126 1272 steps 128 66% Ot-Bu Ot-Bu Ot-Bu Ot-Bu d e f g 80% 94% 88% 96% 129 130 131 132 I HO O O HO

Ot-Bu Ot-Bu h i 2 steps I 80% I 133 122 O

Reaction conditions: (a) LAH, Et2O; NaSO4⋅10H2O; (c) PCC, DCM; (c) Mg, HC≡CCH2Br, HgCl2, Et2O, THF (d) cat. BF3·Et2O, Cl3C(NH)Ot-Bu, cyclohexane; (e) BuLi, ClCO2Me; (f) DIBAL-H, DCM, −78 ºC → −50 ºC; + − (g) Red-Al, THF, rt; NIS, −78 ºC; (h) MnO2, DCM, rt; (i) Ph3PCH3 Br , BuLi, THF

Scheme 75. Synthesis of 123

MeO C O 2 a HOH2C b MeO C 83% 90% 2 HOH2C O 134 135 136

85 O O cdCO2Me CH2OH 90% 95% O O 137 138

O O O O O O e f g 93% 2 steps 76% I I I 139 140 123 OH O

Reaction conditions: (a) LAH, Et2O; NaSO4⋅10H2O; (b) 2,2-dimethoxypropane, p-TsOH, DCM; (c) BuLi, ClCO2Me; (d) DIBAL-H, DCM, −78 ºC → −50 ºC; (e) Red-Al, THF, rt; NIS, −78 ºC; (f) MnO2, DCM, rt; (g) + − Ph3PCH3 Br , BuLi, THF

Scheme 76. Synthesis of 124

a b c Ot-Bu H 88% OH 89% 95% O 141 142 143

Ot-Bu d e O Ot-Bu Ot-Bu 90% 91% HO HO O 144 145 146 I

Ot-Bu Ot-Bu f g 2 steps I 80% I 124 147 O

Reaction conditions: (a) Mg, HC≡CCH2Br, HgCl2, Et2O, THF (b) cat. BF3·Et2O, Cl3C(NH)Ot-Bu, cyclohexane; (c) BuLi, ClCO2Me; (d) DIBAL-H, DCM, −78 ºC → −50 ºC; (e) Red-Al, THF, rt; NIS, −78 ºC; + − (f) MnO2, DCM, rt; (g) Ph3PCH3 Br , BuLi, THF

86 Summary and Conclusions

We have successfully utilized an intramolecular Pauson-Khand reaction and a domino Heck reaction to deliver the magellanane skeleton. This domino Heck reaction is not favorable when the new σ-alkylpalladium species has a β- hydrogen atom as is evident from the reaction of iodide 119.

Ot-Bu Ot-Bu O I X H Pd

119

Ot-Bu

For substrate 115 the second C-Pd/C=C insertion was favored over β- hydride elimination. Possibly chelate formation prevents proper alignment between the syn-β-hydrogen and the carbon-palladium σ-bond. Another possibility is that the β-hydride elimination produces a highly strained ring system and in situ hydropalladation regenerates the σ-alkylpalladium so the second C-Pd/C=C insertion takes over. Analysis of the byproducts generated from this domino process revealed that they were presumably formed through intermolecular reactions instead of simple β-hydride elimination of the σ-alkylpalladium formed by oxidative addition to the palladium(0) complex and the subsequent association- insertion, involving the unsaturation of cyclopentene moiety.

87 O O O O O O D D C D C C Pd I t t-BuO -BuO t-BuO ? 115

O O

D C PdH

t-BuO

In published syntheses of the magellanine family the closest intermediate to our diene acetonide is the dienone alcohol 143 shown below.11 The alcohol was subjected to sequential regiospecific oxidative cleavage of cyclopentene ring with osmium tetraoxide/NMO and sodium periodate, and double reductive amination with methylamine hydrochloride to provide racemic magellanine (±)-1.

O 1) OsO , NMO, O H 4 H t-BuOH/THF/H2O (2.5:5:1) H H N 2) NaIO4, H2O/DCM H H 3) CH3NH3Cl, NaBH3CN, H H OH 2-propanol, 4-Å MS OH 143

We anticipate that after transformation of diene 116 to enone 144, L-Selectride reduction of 144 is expected to afford exclusively the β-alcohol 145.10 After protection of alcohol 145 the t-butyl ether can be transformed to the free alcohol 147.81 Oxidation, regioselective addition of methyllithium and further Jones 88 O t H O -Bu O H Ot-Bu O H Ot-Bu O ? O O H H H 116 144O 145 HO t O H O -Bu O H OH O H O O O O

H H H R=Protection 146 RO RO RO group 147 148 OH O H O O H O H O O O O

H H H RO RO RO 149 150 151 O HO H O H O H HO N N

H H H HO HO HO 1 152 153 oxidation are expected to occur with allylic rearrangement and deliver acetonide 151.10 Deprotection of acetonide and oxidative cleavage of the cyclopentane ring followed by the double reductive amination will deliver alcohol 153.11 Submission of alcohol 153 to conventional Mitsunobu conditions will produce magellanine, (1).10

89 Experimental Section

(3aR,6aR)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-ol (100)

O OH O O O O O O

A solution of lactone 99 (17.2 g, 109 mmol) in DCM (300 mL) was stirred rapidly at −78 ºC while diisobutylaluminum hydride (126 mL of 1 M in hexanes, 126 mmol) was added dropwise. The reaction mixture was stirred for 4 h at −78 ºC and cautiously decomposed by the dropwise addition of methanol (22 mL). The mixture was then slowly poured into a cold (ice bath) stirred mixture of water (260 mL) and ethyl acetate (300 mL). To the resulting mixture was then added 1 M aqueous sulfuric acid (240 mL) until the final pH was approximately 3. The mixture was filtered and transferred to a separatory funnel. The aqueous phase was extracted EtOAc. The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution. The bicarbonate wash was back-extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated to afford lactol 100 (15 g, 90 %), which was a colorless oil that was 73 1 used without further purification. H NMR (CDCl3, 500 MHz): δ 5.43 (d, J = 2.9 Hz, 1H, HOCHO), 4.84 (dd, J = 5.8, 2.9 Hz, 1H, HOCH(O)CHO), 4.59 (d, J = 5.8

Hz, 1H, HOC(O)CHOCHOCH2), 4.09 (dd, J = 10.7, 3.9 Hz, 1H, HOC(O)CHOCHOCHH), 4.03 (d, J = 10.7 Hz, 1H, HOC(O)CHOCHOCHH),

2.18 (d, J = 2.0 Hz, 1H, HOCHO), 1.48 (S, 3H, CH3CCH3), 1.33 (s, 3H, -1 CH3CCH3). IR (cm ): 3416, 2985, 2942, 2880, 1637, 1458, 1374, 1209, 1161, 1099, 968, 927, 874, 762, 666.

90 ((4R,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)methanol (101)

OH O O O OH O O

To a stirred suspension of methyltriphenylphosphonium bromide (80 g, 224 mmol) in THF at −78 ºC was added BuLi (126 mL of 1.6 M in hexanes, 202 mmol) and the resulting yellow suspension was warmed to rt in 1 h. After cooling to −78 ºC, a solution of the lactol 100 (10.8 g, 67 mmol) in THF (30 mL) was added dropwise. The resulting mixture was slowly warmed to rt overnight. The mixture was refluxed for 3 h, then water was added and the aqueous phase extracted with DCM. The combined organic phases were washed with water, brine, dried and concentrated. Flash column chromatography afforded alcohol 101 74 1 (8.8 g, 83 %). H NMR (CDCl3, 300 MHz): δ 5.88 (ddd, J = 17.1, 10.8, 7.4 Hz,

1H, H2C=CHCHO), 5.40 (d, J = 17.4 Hz, 1H, HHC=CH), 5.29 (d, J = 10.1 Hz,

1H, HHC=CH), 4.65 (t, J = 7.1 Hz, 1H, H2C=CHCHO), 4.27 (q, J = 6.0 Hz, 1H,

H2C=CHCHOCHOCH2OH), 3.58 (d, J = 6.0 Hz, 2H, H2C=CHCHOCHOCH2OH),

1.51 (s, 3H, CH3CCH3), 1.40 (s, 3H, CH3CCH3).

(3aS,7aR)-2,2-dimethyl-3b,4,7,7a-tetrahydropentaleno[2,1-d][1,3]dioxol-5(3aH)-one (105)

O O O TMS OH OTf O O O

O O H O O O

91 To a solution of alcohol 101 (4.5 g, 28 mmol) and triethylamine (12 mL, 85 mmol) in methylene chloride (284 mL) was added a solution of trifluoromethane-sulfonic anhydride (13.6 g, 48 mmol) in DCM (mL) at −40 ºC. The reaction mixture was slowly warmed to −20 ºC and stirred for 1 h at the same temperature, washed successively with saturated aqueous NaHCO3, water and brine, dried and concentrated to dryness. The residue was passed through a short pad of silica gel with hexane–EtOAc (4: 1) to give triflate 102 (8.9 g). BuLi (21 mL of 1.6 M in hexanes, 34 mmol) was added to a solution of (trimethylsilyl)acetylene (3.9 g, 40 mmol) in THF (180 mL) at −78 ºC. The resulting solution of acetylide in THF was warmed to 0 ºC and then cooled to −78 ºC again, after which a solution of the crude triflate in a mixture of THF and DMPU (360 and 90 mL, respectively) was added. The reaction mixture was stirred at −20 ºC overnight and quenched by addition of saturated NH4Cl solution. After being washed several times with water, the organic layer was concentrated under atmosphere pressure and extracted with hexane repeatedly. The combined organic layers were washed with water and brine. After removal of most of the solvent under atmosphere pressure the residue was distilled under reduced pressure. The colorless liquid obtained was a mixture of acetonides 103 and 104. To the above mixture was added THF (180 mL) and tetrabutylammonium fluoride (40 mL of 1 M in THF, 40 mmol) was added. The reaction mixture was stirred at rt for 1 h and diluted with ether. The solution was then washed successively with water, brine, dried and concentrated under atmosphere pressure. The mixture was distilled under reduced pressure to deliver a colorless solution.

To the enyne in petroleum ether (300 mL) was added Co2(CO)8 (11.6 g, 34 mmol) at rt. After being stirred for 2 h, the petroleum ether solution was filtered through Celite and evaporated to leave a residue, which was dissolved in 2,2- dimethoxypropane (300 mL) under O2. Anhydrous TMANO (12.6 g, 168 mmol) was added in portions to the mixture. The mixture was stirred until the color changed to pink. The reaction mixture was passed through a pad of Celite and

92 silica gel and the filtrate was concentrated to dryness. Chromatography of the residue gave 3.1 g (4 steps, 56 %) of enone 105.

((4R,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)methyl trifluoromethanesulfonate (102) 1 H NMR (CDCl3, 300 MHz): δ 5.80 (ddd, J = 17.1, 10.1, 6.7 Hz, 1H,

H2C=CHCHO), 5.49 (d, J = 17.4 Hz, 1H, HHC=CH), 5.37 (d, J = 10.2 Hz, 1H,

HHC=CH), 4.76 (t, J = 6.3 Hz, 1H, H2C=CHCHO), 4.3-4.5 (m, 3H,

H2C=CHCHOCHOCH2OH, H2C=CHCHOCHOCH2OTf), 1.52 (s, 3H,

CH3CCH3), 1.40 (s, 3H, CH3CCH3).

(3-((4R,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)prop-1-ynyl)trimethylsilane (103) 1 H NMR (CDCl3, 300 MHz): δ 5.91 (ddd, J = 17.1, 10.1, 6.7 Hz, 1H,

H2C=CHCHO), 5.38 (d, J = 16.8 Hz, 1H, HHC=CH), 5.37 (d, J = 10.2 Hz, 1H,

HHC=CH), 4.62 (dd, J = 6.7, 6.7 Hz, 1H, H2C=CHCHO), 4.31 (dt, J = 6.5, 6.5 Hz,

1H, H2C=CHCHOCHOCH2), 2.47 (ABd, JAB = 15.8, 5.4 Hz, 1H, HHCC≡CTMS),

2.39 (ABd, JAB = 15.8, 8.1 Hz, 1H, HHCC≡CTMS), 1.49 (s, 3H, CH3CCH3), 1.38

(s, 3H, CH3CCH3), -0.14 (s, 3H, Si(CH3)3).

(4R,5S)-2,2-dimethyl-4-(prop-2-ynyl)-5-vinyl-1,3-dioxolane (104) 1 H NMR (CDCl3, 300 MHz): δ 5.87 (ddd, J = 17.1, 10.1, 6.7 Hz, 1H,

H2C=CHCHO), 5.40 (d, J = 16.8 Hz, 1H, HHC=CH), 5.30 (d, J = 9.9 Hz, 1H,

HHC=CH), 4.64 (dd, J = 6.7, 6.7 Hz, 1H, H2C=CHCHO), 4.33 (dt, J = 6.7, 6.7 Hz,

1H, H2C=CHCHOCHOCH2), 2.40 (ABdd, JAB = 16.8, 7.4, 2.7 Hz, 1H,

HHCC≡CH), 2.32 (ABdd, JAB = 16.8, 6.7, 2.7 Hz, 1H, HHCC≡CH), 2.00 (t, J =

2.68 Hz, 1H, C≡CH), 1.51 (s, 3H, CH3CCH3), 1.38 (s, 3H, CH3CCH3).

(3aS,3bS,7aR)-2,2-dimethyl-3b,4,7,7a-tetrahydropentaleno[2,1-d][1,3]dioxol-5(3aH)-one (105a) 1 H NMR (CDCl3, 500 MHz): δ 5.99 (s, 1H, CH2COCH=C), 4.97 (dd, J =

6.1, 6.1 Hz, 1H, CH2CH(O)CH(O)CH), 4.64 (dd, J = 5.6, 5.6 Hz, 1H, 93 CH2CH(O)CH(O)CH), 2.98 (br s, 1H, CH2CH(O)CH(O)CH), 2.76 (d, J = 17.1 Hz,

1H, CHβHCH(O)CH(O)CH), 2.65 (dd, J = 17.1, 6.8 Hz, 1H,

CHHαCH(O)CH(O)CH), 2.57 (dd, J = 18.1, 3.4 Hz, 1H, HβHCCOCH=C), 2.44

(dd, J = 17.6, 6.8 Hz, 1H, HHαCCOCH=C), 1.31 (s, 3H, CH3CCH3), 1.30 (s, 3H, 13 CH3CCH3). C NMR (CDCl3, 75 MHz): δ 210.58, 183.23, 126.83, 109.84, 81.27, 76.87, 48.09, 36.13, 35.53, 25.95, 24.12. IR (cm-1): 3583, 3075, 2985, 2933, 1713, 1694, 1667, 1649, 1643, 1456, 1372, 1263, 1208, 1144, 1119, 984, 939, 868, 833,

729, 651. Calc’d for C11H14O3: C 68.02; H, 7.27. Found: C, 68.16; H, 7.28.

(3aS,3bR,7aR)-2,2-dimethyl-3b,4,7,7a-tetrahydropentaleno[2,1-d][1,3]dioxol-5(3aH)-one (105b)

1 H NMR (CDCl3, 500 MHz): δ 5.90 (obscured t, 1H, CH2COCH=C), 4.83

(ddd, J = 6.5, 6.5, 3.5 Hz, 1H, CH2CH(O)CH(O)CH), 4.22 (dd, J = 6.5, 6.5 Hz,

1H, CH2CH(O)CH(O)CH), 3.16 (br s, 1H, CH2CH(O)CH(O)CH), 3.08 (dd, J = 17.0, 6.5 Hz, 1H, CHHαCH(O)CH(O)CH), 2.82 (d, J = 17.0 Hz, 1H,

CHβHCH(O)CH(O)CH), 2.76 (dd, J = 18.0, 7.0 Hz, 1H, HβHCCOCH=C), 2.24

(dd, J = 18.0, 3.5 Hz, 1H, HHαCCOCH=C), 1.57 (s, 3H, CH3CCH3), 1.36 (s, 3H,

CH3CCH3).

(3aS,3bS,6aS,7aR)-2,2-dimethyl-3a,3b,4,6a,7,7a-hexahydropentaleno[2,1-d][1,3]dioxol-5-yl trifluoromethanesulfonate (106)

O O H H O O O OTf H

To a solution of enone 105a (0.82 g, 4.2 mmol) in THF (28 mL) at – 78 ºC was added L-selectride® (4.4 mL of 1 M in THF, 4.4 mmol) followed after 1 h at – 78 ºC by solid N-phenyltriflimide (1.54 g, 4.3 mmol). The resulting solution was then allowed to warm to rt overnight. The solution was diluted with Et2O and 94 washed with water. The aqueous layer was back extracted with ether. The combined organic phases were then washed with a 10 % sodium hydroxide solution, followed by water and brine, dried and concentrated. Purification by 1 column chromatography gave triflate 106 (1.15 g, 83 %). H NMR (C6D6, 500

MHz): δ 5.17 (s, 1H, CH=COTf), 4.17 (dd, J = 5.8, 5.8 Hz, CH2CH(O)CH(O)CH),

3.95 (dd, J = 6.5, 6.5 Hz, 1H, CH2CH(O)CH(O)CH), 2.79 (d, J = 16.2 Hz, 1H,

HβHC(OTf)=CH), 2.54 (tt, J = 8.3, 2.9 Hz, 1H, CH2C(OTf)=CHCH), 2.36 (ddt, J = 16.2, 8.8, 2.5 Hz, 1H, HHαC(OTf)=CH), 1.88 (dt, J = 8.3, 8.3 Hz, 1H,

CHCH2C(OTf)=CH), 1.64 (d, J = 14.7 Hz, 1H, HβHCCH(O)CH(O)CH), 1.34 (s,

3H, CH3CCH3), 1.17 (ddd, J = 15.0, 8.8, 5.9 Hz, 1H, HHαCCH(O)CH(O)CH), 13 1.11 (s, 3H, CH3CCH3). C NMR (CDCl3, 75 MHz): δ 147.35, 120.71, 118.47 (q,

J = 318.7, CF3SO3), 110.41, 82.19, 81.51, 47.09. 42.89, 34.53, 31.22, 25.82, 24.09. IR (cm-1): 2938, 1654, 1420, 1380, 1245, 1141, 1070, 995, 907, 835, 608. HRMS + (m/z) (FAB NBA+NaI) calc. for C12H15O5F3SNa (M+Na) 351.0490, found 351.0494.

(3aS,3bS,6aR,7aR)-5-(3,3-diethoxypropyl)-2,2-dimethyl-3a,3b,4,6a,7,7a-hexahydropentaleno- [2,1-d][1,3]dioxole (107)

O H O H O O OTf O

H H O

To an oven-dried flask under argon was added acrolein diethyl acetal (0.25 g, 1.95 mmol) and THF (3.5 mL). The solution was cooled to 0 ºC and 9-BBN dimer (0.28 g, 1.12 mmol) was added. The mixture was slowly warmed up to rt and stirred for 6 h. The borane solution obtained was transferred to a flask containing triflate 106 (0.53 g, 1.63 mmol) in THF (mL). Powdered K3PO4 (0.52

95 g, 2.45 mmol), PdCl2(dppf) (33 mg, 0.04 mmol) was then added and the mixture was stirred under reflux for 14 h. The mixture was diluted with hexane and the residual borane was oxidized with 3 M NaOH (1 mL) and 30% H2O2 (1 mL) for 1 h. The solution was extracted with ethyl acetate, washed with brine, dried and concentrated. Chromatography of the residue gave 0.40 g (74 %) of acetal 107. 1H

NMR (C6D6, 500 MHz): δ 5.26 (d, J = 1.5 Hz, 1H, HC=C), 4.51 (t, J = 5.9 Hz, 1H,

(CH3CH2O)2CH), 4.40 (td, J = 5.9, 1.5 Hz, CH2CH(O)CH(O)CH), 4.25 (t, J = 6.6

Hz, 1H, CH2CH(O)CH(O)CH), 3.57 (ABq, JAB = 4.2, 6.8, 1H, (CH3CHHO)2CH),

3.54 (ABq, JAB = 4.2, 6.8, 1H, (CH3CHHO)2CH), 3.38 (ABq, JAB = 4.2, 6.8, 1H,

(CH3CHHO)2CH), 3.36 (ABq, JAB = 4.2, 6.8, 1H, (CH3CHHO)2CH), 3.04 (m, 1H,

H2C(CH2)C=CHCHCH2), 2.73 (d, J = 15.1 Hz, 1H, HβHC(CH2)=CH), 2.16-2.36

(m, 4H, H2CCH(O)CH(O)CH, HHαC(CH2)=CH, (CH3CH2O)2CHCH2CH2), 1.89-

2.02 (m, 3H, (CH3CH2O)2CHCH2CH2, HβHCCH(O)CH(O)CH), 1.51 (ddd, J =

14.6, 8.3, 5.9 Hz, HHαCCH(O)CH(O)CH), 1.40 (s, 3H, CH3CCH3), 1.22 (s, 3H,

CH3CCH3), 1.121 (t, J = 7.1 Hz, 1H, (CH3CH2O)CH(CH3CH2O)), 1.116 (t, J = 7.1 13 Hz, 1H, (CH3CH2O)CH(OCH2CH3)). C NMR (CDCl3, 75 MHz): δ 142.80, 126.97, 110.01, 102.67, 82.89, 82.57, 60.94, 60.76, 51.82, 45.26, 35.25, 35.17, 31.56, 26.15, 26.10, 24.34, 15.31. IR (cm-1): 2941, 1658, 1421, 1381, 1210, 1141,

1113, 996, 907, 865, 835. HRMS (m/z) (FAB NBA+NaI) calc. for C18H30O4Na (M+Na)+ 333.2042, found 333.2030.

3-((3aS,3bS,6aR,7aR)-2,2-dimethyl-3a,3b,4,6a,7,7a-hexahydropentaleno[2,1-d][1,3]dioxol-5- yl)propanal (108)

O H O H O O O O H O H H

96 TsOH (52 mg, 0.27 mmol) was added to acetal 107 (0.85 g, 2.75 mmol) in acetone (130 mL). The mixture was stirred for 1 h at rt. Saturated NaHCO3 solution was added to the reaction mixture until the solution was basic. After evaporation most of the solvent the residue was diluted with ether and washed with water, brine, dried and concentrated. The crude aldehyde (108) was used in the 1 next step without further purification. H NMR (CDCl3, 500 MHz): δ 9.77 (t, J =

1.7 Hz, 1H, CH2CH2CHO), 5.23 (d, J = 1.5 Hz, 1H, HC=C), 4.68 (td, J = 5.9, 1.5

Hz, 1H, CH2CH(O)CH(O)CH), 4.52 (dd, J = 7.9, 5.9 Hz, 1H,

CH2CH(O)CH(O)CH), 3.22 (m, 1H, H2C(CH2)C=CHCHCH2), 2.55-2.67 (m, 3H,

H2CCH(O)CH(O)CH, CH2CH2CHO), 2.50 (d, J = 16.19 Hz, 1H,

HβHC(CH2)=CH), 2.26-2.45 (m, 3H, HHαC(CH2)=CH, CH2CH2CHO), 1.97 (d, J

= 14.7 Hz, 1H, HβHCCH(O)CH(O)CH), 1.80-1.90 (m, 1H, 13 HHαCCH(O)CH(O)CH), 1.30 (s, 3H, CH3CCH3), 1.27 (s, 3H, CH3CCH3). C

NMR (CDCl3, 75 MHz): δ 201.96, 141.13, 127.70, 109.64, 82.52, 82.22, 51.58, 45.01, 41.54, 34.99, 34.73, 25.93, 23.97, 23.13. IR (cm-1): 3424, 2979, 2928, 2713, 2359, 1724, 1376, 1299, 1249, 1207, 1077, 1060, 991, 879, 825, 674. HRMS (m/z) + (FAB NBA+NaI) calc. for C14H20O3Na (M+Na) 259.1310, found 259.1303.

1-((3aS,3bS,6aR,7aR)-2,2-dimethyl-3a,3b,4,6a,7,7a-hexahydropentaleno[2,1-d][1,3]dioxol-5- yl)hex-5-yn-3-ol (109)

O H O H O O O OH

H H H

To a flame-dried flask under argon containing magnesium (0.4 g, 16 mmol) and ether (33 mL) was added propargyl bromide (1.83 mL, 16 mmol) and mercuric chloride (0.22 g, 0.82 mmol). The reaction was initiated by gentle heating and was occasionally cooled with an ice-bath. It was then kept in oil bath (40 ºC) for 1 h.

97 The solution obtained was added to aldehyde 108 in THF (40 mL) at 0 ºC. The mixture was warmed up to rt slowly. The resulting mixture was poured into saturated NH4Cl solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water, brine, dried and concentrated. Flash chromatography afforded alcohol 109 as a 1:1 mixture of 1 diasteromers (0.62 g, 82 %). H NMR (CDCl3, 500 MHz): δ 5.25 (s, 1H, HC=C),

4.68 (dd, J = 5.9, 5.9 Hz, 1H, CH2CH(O)CH(O)CH), 4.52 (dd, J = 6.4, 6.4 Hz, 1H,

CH2CH(O)CH(O)CH), 3.72-3.82 (m, 1H, HC≡CCH2CHOHCH2), 3.22 (m, 1H,

H2C(CH2)C=CHCHCH2), 2.62 (br dd, J = 7.8, 7.8 Hz, 1H, CH2CH(O)CH(O)CH),

2.49 (dd, J = 15.6, 6.3 Hz, 1H, CH2CH(O)CH(O)CHCHH), 2.40-2.49 (m, 1H,

HC≡CCHHCHOHCH2), 2.28-2.38 (m, 2H, HC≡CCHHCHOHCH2,

CH2CH(O)CH(O)CHCHH), 2.12-2.20 (m, 1H, HC≡CCH2CHOHCH2CHH), 2.04 (t, J = 2.40 Hz, 1H, HC≡C), 1.93-2.00 (dm, J = 14.7 Hz, 1H, CHHCH(O)CH(O)CH), 1.80-1.93 (m, 2H, CHHCH(O)CH(O)CH,

HC≡CCH2CHOHCHHCH2), 1.65-1.80 (m, 2H, HC≡CCH2CHOHCH2CHH, 13 HC≡CCH2CHOHCHHCH2), 1.32 (s, 3H, CH3CCH3), 1.27 (s, 3H, CH3CCH3). C

NMR (CDCl3, 75 MHz): δ 142.72, 142.58 (diastereomer), 127.32, 127.19 (diastereomer), 109.915, 82.75, 82.46, 80.75, 70.65, 69.69, 69.48 (diastereomer), 51.68, 45.12, 35.07, 33.94, 27.26, 27.08, 26.96 (diastereomer), 26.11, 24.23. IR (cm-1): 3442, 3303, 3036, 2981, 2935, 2117, 1738, 1650, 1433, 1371, 1270, 1248, 1208, 1153, 1060, 991, 942, 879, 824, 750, 632. HRMS (m/z) (CI+) calc. for

C17H25O3 277.18038, found 277.17975.

(3aS,3bS,6aR,7aR)-5-(3-tert-butoxyhex-5-ynyl)-2,2-dimethyl-3a,3b,4,6a,7,7a-hexahydropentaleno[2,1-d][1,3]dioxole (110)

98 O H O H O O OH Ot-Bu

H H

A catalytic amount of boron trifluoride etherate was added to solution of alcohol 109 (2.43 g, 8.78 mmol) and t-butyl trichloroacetimidate (7.68 g, 35 mmol) in cyclohexane and the mixture was stirred overnight. Solid NaHCO3 was added and the reaction mixture was filtered through a short plug of Celite. The solution was washed with saturated NaHCO3 solution, brine, dried and concentrated. Purification on silica gel afforded enyne 110 as a 1:1 mixture of diasteromers (1.46 g, 50 %) and recovered starting material (45 %). 13C NMR

(CDCl3, 75 MHz): δ 143.22, 143.13, 126.51, 109.84, 82.75, 82.45, 81.63, 73.52, 69.68, 69.56, 69.45, 51.72, 45.18, 35.30, 35.04, 33.30, 28.44, 28.39, 26.56, 26.35, 26.04, 24.22. IR (cm-1): 3310, 3041, 2975, 2932, 2117, 1649, 1433, 1389, 1369, 1231, 1249, 1207, 1154, 1063, 1002, 881, 825, 631. methyl 5-tert-butoxy-7-((3aS,3bS,6aR,7aR)-2,2-dimethyl-3a,3b,4,6a,7,7a-hexahydropentaleno- [2,1-d][1,3]dioxol-5-yl)hept-2-ynoate (111)

O H O H O O Ot-Bu Ot-Bu

H H

MeO2C

Enyne 110 (0.18 g, 0.53 mmol) in THF (6 mL) was cooled to −78 ºC and BuLi (0.43 mL of 1.6 M in hexane, 0.69 mmol) was added. After 45 min chloromethylformate (61 μl, 0.80 mmol) was added and the resulting mixture was 99 allowed to warm to rt overnight. The mixture was diluted with ether and washed successively with saturated NH4Cl solution, brine, dried and concentrated. Purification on silica gel afforded ester 111 as a 1:1 mixture of diasteromers (0.20 13 g, 95 %). C NMR (CDCl3, 75 MHz): δ 153.80, 142.73, 142.65, 126.73, 109.73, 86.86, 82.63, 82.35, 73.92, 73.73, 68.85, 65.58, 52.23, 51.62, 45.08, 35.16, 35.10, 34.94, 33.69, 28.28, 28.24, 26.47, 26.38, 26.32, 25.91, 24.10. IR (cm-1): 3413, 3034, 2974, 2932, 2326, 2238, 1715, 1651, 1434, 1368, 1255, 1207, 1154, 1075, 1000, 881, 822, 752.

5-tert-butoxy-7-((3aS,3bS,6aR,7aR)-2,2-dimethyl-3a,3b,4,6a,7,7a-hexahydropentaleno[2,1- d][1,3]dioxol-5-yl)hept-2-yn-1-ol (112)

O H O H O O Ot-Bu Ot-Bu

H H

MeO2C HO

DIBAL-H (1 mL of 1 M in hexanes, 1 mmol) was added to a solution of ester 111 in Et2O at −78 ºC. After 1 h the mixture was warmed to −50 ºC over 2 h.

The solution was then cooled to −78 ºC and NaSO4·10H2O (0.32 g, 1 mmol) was added. After being stirred overnight the mixture was filtered through Celite and washed with ether. The residue after concentration was purified on silica gel to afford alcohol 112 as a 1:1 mixture of diasteromers (0.16 g, 90 %). 13C NMR

(CDCl3, 75 MHz): δ 143.07, 142.94, 126.49, 109.77, 82.65, 82.32, 80.02, 73.57, 69.67, 69.47, 51.55, 50.60, 45.04, 44.97, 35.07, 34.86, 33.18, 28.30, 28.25, 26.45, 25.84, 24.08. IR (cm-1): 3435, 3039, 2932, 2932, 2284, 2244, 1649, 1432, 1432, 1369, 1207, 1060, 1019, 880, 825, 732, 646.

100 (Z)-5-tert-butoxy-7-((3aS,3bS,6aR,7aR)-2,2-dimethyl-3a,3b,4,6a,7,7a-hexahydropentaleno- [2,1-d][1,3]dioxol-5-yl)-3-iodohept-2-en-1-ol (113)

O O H H O O Ot-Bu Ot-Bu H H I

HO OH

To a stirred solution of the propargylic alcohol 112 (0.11 g, 0.30 mmol) in THF (2 mL) was added Red-A1 (0.16 mL of 65+ wt. % in toluene, 0.51 mmol). After stirring at rt for 4 h, the reaction solution was cooled to -78 ºC and N- iodosuccinimide (0.12 g, 0.54 mmol) in THF (2 mL) added dropwise. After 30 min the mixture was diluted with ether and 10% sodium thiosulfate was added. The aqueous layer was extracted with ether and the combined organic layers were washed with saturated NaHCO3 solution, water and brine, dried and concentrated. Purification on silica gel afforded alcohol 113 as a 1:1 mixture of diasteromers (0.15g, 98%).

(Z)-5-tert-butoxy-7-((3aS,3bS,6aR,7aR)-2,2-dimethyl-3a,3b,4,6a,7,7a-hexahydropentaleno- [2,1-d][1,3]dioxol-5-yl)-3-iodohept-2-enal (114)

O H O H O O Ot-Bu Ot-Bu

H H I I

OH O

101 Activated MnO2 (0.28 g, 3.18 mmol) was added portionwise to a stirred solution of allylic alcohol 113 (0.16 g, 0.32 mmol) in DCM (8 mL) at rt, and the mixture was stirrred for 6 h. The mixture was filtered through a pad of Celite rinsing with ether and ethyl acetate, and evaporated to leave an oil which was used in the next step without further purification.

(3aS,3bS,6aR,7aR,Z)-5-(3-tert-butoxy-5-iodoocta-5,7-dienyl)-2,2-dimethyl-3a,3b,4,6a,7,7a- hexahydropentaleno[2,1-d][1,3]dioxole (115)

O H O H O O Ot-Bu Ot-Bu

H H I I

BuLi (0.34 mL of 1.6 M in THF, 0.54 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (0.20 g, 0.57 mmol) at -78 ºC. The mixture was then warmed to 0 ºC in 1 h. It was then recooled to -78 ºC upon which crude enal 114 in THF was added. The mixture was slowly warmed to rt and diluted with ether and washed successively with saturated NH4Cl solution, water and brine, then dried and concentrated. Purification on silica gel afforded iodide 115 (83 %).

Diene (116)

t-BuO H O O H Ot-Bu I O O H H H

102 To a solution of iodide 115 (52 mg, 0.11 mmol) in CH3CN (35 mL) were added Pd(PPh3)4 (12 mg, 0.01 mmol) and K2CO3 (88 mg, 64 mmol). The mixture was refluxed for 22 h under Ar. Removal of the solvent, plug through a pad silica gel and purification by column chromatography gave the mixture of the dienes 116a and 116b. 1 116a: H NMR (C6D6, 500 MHz): δ 5.89 (s, 1H), 4.90 (s, 1H), 4.72 (s, 1H), 4.371, 4.366(br s, 2H), 3.58 (br s, 1H), 2.74 (obscured d, 1H), 2.10-2.40 (m, 5H), 1.85-2.10 (m, 3H), 1.70-1.85 (m, 2H), 1.50-1.65 (m, 2H), 1.57 (s, 3H), 1.23 (s, + 3H), 1.03 (s, 9H). HRMS (m/z) (FAB NBA+NaI) calc. for C23H34O3Na (M+Na) 381.2406, found 381.2424. + 116b: HRMS (m/z) (FAB NBA+NaI) calc. for C23H34O3Na (M+Na) 381.2406, found 381.2420.

103 E O{ a

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161

BIOGRAPHICAL SKETCH

AIMIN WANG

EDUCATION

Florida State University, Tallahassee, FL

• August, 1998-Present • Ph.D. Candidate in Organic Chemistry • Dissertation: Synthetic studies towards the total syntheses of the tetracyclic diquinane Lycopodium alkaloids magellanine and magellaninone • Research Advisor: Professor Marie E. Krafft

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

• August, 1994-July, 1997 • M.S. in Medicinal Chemistry • Thesis: Study of selective high potency and less addictive opioid receptor agonists-Ohmefentanyl analogues • Reserch Advisor: Professor Youchen Zhu

Wuhan University, Wuhan, China

• August 1990-July 1994 • B.S. in Environmental Chemistry

RESEARCH/TEACHING EXPERIENCE

• Graduate Research Associate, May, 1999 – Present with Professor Marie E. Krafft

• Teaching Assistant, January, 1999 - August 1999. Organic Chemistry Laboratory

162 SEMINARS

• “Enantioselective Formation of Vicinal Stereogenic Quaternary Carbon Centers” Organic Chemistry Division Seminar, Florida State University.

• “Direct Catalytic Asymmetric Aldol Reaction” Organic Chemistry Division Seminar, Florida State University.

ORAL RESEARCH PROPOSAL

• “Synthetic Studies Toward Alstonisines” Organic Chemistry Division, Florida State University.

163