CHAPTER 1
Furanobutenolide Cembranoid and Norcembranoid Natural Products:
Biosynthetic Connections and Synthetic Efforts
Scheme 1.4.1.1. Biosynthetic Proposal for the Construction of Bielschowskysin (BSK, 6) ... 6 Scheme 1.4.1.2. Proposed Biosynthesis of Verrillin (13) ... 7 Scheme 1.4.1.3. Biosynthetic Speculation Concerning the Formation of Intricarene (7) ... 8 Scheme 1.4.1.4. Proposed Biosynthetic Construction of the Plumarellides and Mandapamates ... 9 Scheme 1.4.2.1. Proposed Biosynthesis of Ineleganolide (9), Horiolide (20), and Kavaranolide (21) .. 11 Scheme 1.4.2.2. Biosynthetic Formation of Sinulochmodin C (10), Scabrolide B (23),
Scabrolide A (24), and Yonarolide (25) ... 12 Scheme 1.4.2.3. Biosynthetic Conjectures for the Formation of Dissectolide A (22) ... 13 Scheme 1.5.1.1.1. Retrosynthetic Analysis of BSK Employing Photo-Induced [2 + 2] ... 14 Scheme 1.5.1.1.2. Copper-Catalyzed Light-Induced [2 + 2] Cycloaddition (Ghosh) ... 15 Scheme 1.5.1.1.3. Tandem Inversion of Configuration at C(8) and C(10) with
Core Cyclobutane 52 (Ghosh) ... 16 Scheme 1.5.1.1.4. Retrosynthetic Strategy Employed by Sulikowski ... 16 Scheme 1.5.1.1.5. Model System for Intramolecular Butenolide [2 + 2] Cycloaddition (Sulikowski) .. 17 Scheme 1.5.1.1.6. Intramolecular [2 + 2] Cycloaddition with Elaborated Butenolide (Sulikowski) ... 18 Scheme 1.5.1.1.7. Mulzer’s Retrosynthesis of BSK Employing an Allene [2 + 2] Cycloaddition ... 18 Scheme 1.5.1.1.8. Allene [2 + 2] Cycloaddition (Mulzer) ... 19 Scheme 1.5.1.1.9. Unexpected Cyclooctane Product Formation (Mulzer) ... 19 Scheme 1.5.1.1.10. Nicolaou’s Macrocyclic [2 + 2] Cycloaddition Strategy
and Model Macrocycle Synthesis ... 20 Scheme 1.5.1.1.11. Stereochemical Outcome of Macrocyclic [2 + 2] Cycloaddition (Nicolaou) ... 21 Scheme 1.5.1.1.12. Lear’s Macrocyclic Tandem [2 + 2] and [4 + 2] Cycloaddition Strategy ... 22 Scheme 1.5.1.1.13. Planned Tandem [2 + 2] and [4 + 2] Cycloaddition
in the Forward Sense (Lear) ... 22 Scheme 1.5.1.1.14. Model System Studies on Allene Cycloaddition with a Butenolide (Lear) ... 23 Scheme 1.5.1.1.15. Model System Studies on Allene Cycloaddition with a Butenolide (Lear) ... 23 Scheme 1.5.1.1.16. Alternative Retrosynthetic Analysis of Cyclobutane Moiety of BSK (6, Mulzer) ... 24 Scheme 1.5.1.1.17. Limitations of Targeted [2 + 2] Cycloaddition (Mulzer) ... 25 Scheme 1.5.1.2.1. Mulzer’s 3rd Generation Retrosynthetic Analysis of BSK (6) ... 25
Scheme 1.5.1.2.2. Advancement of Enantioenriched Cyclobutanol (+)-92 Toward BSK (Mulzer) ... 26 Scheme 1.5.1.2.3. Stoltz’s Retrosynthetic Analysis of BSK Core Scaffold 97 ... 27 Scheme 1.5.1.2.4. Synthesis and Exploration of Cyclopropane Intermediate 101 (Stoltz) ... 27 Scheme 1.5.2.1. Retrosynthetic Analysis of Verrillin (Theodorakis) ... 28 Scheme 1.5.2.2. Theodorakis’ Synthetic Approach Toward Verrillin (13) ... 29 Scheme 1.5.3.1. Mehta’s Retrosynthetic Analysis of Havellockate (14) ... 29 Scheme 1.5.3.2. Construction of the Havellockate Core (Mehta) ... 30 Scheme 1.5.3.3. Barriault’s Retrosynthesis of Havellockate (14) ... 31 Scheme 1.5.3.4. Synthesis of Elaborated Core Tetracycle of Havellockate (14, Barriault) ... 32 Scheme 1.5.3.5. Scheme 1.5.3.5. Alternative Synthetic Approach
Toward Havellockate (14, Barriault) ... 33 Scheme 1.5.4.1. Proposed Biosynthesis of Intricarene (7) ... 33 Scheme 1.5.4.2. Synthesis of Common Intermediate Vinyl Iodide 137 (Pattenden and Trauner) ... 34 Scheme 1.5.4.3. Completion of the Asymmetric Total Synthesis of
Bipinnatin J (26, Pattenden and Trauner) ... 35 Scheme 1.5.4.4. Biomimetic Syntheses of Intricarene (7) from
Bipinnatin J (26, Pattenden and Trauner) ... 35 Scheme 1.5.5.1. Mehta’s Retrosynthetic Analysis of Rameswaralide (8) ... 36 Scheme 1.5.5.2. Synthesis of Corey Lactone Derivative 151 (Mehta) ... 37 Scheme 1.5.5.3. Synthesis of Bicyclic Metathesis Substrates 153 and 154 (Mehta) ... 37 Scheme 1.5.5.4. Construction of the Rameswaralide Tricyclic Core (Mehta) ... 38 Scheme 1.5.5.5. Srikrishna’s Proposed Construction of Two Rameswaralide
Cores from a Common Intermediate ... 38 Scheme 1.5.5.6. Synthesis of the [6,7]-Bicyclic Core of Rameswaralide (Srikrishna) ... 39 Scheme 1.5.5.7. Formation of the [5,7]-Bicyclic Core of Rameswaralide (Srikrishna) ... 39 Scheme 1.5.5.8. Trost’s Retrosynthetic Approach Toward Rameswaralide Core 166 ... 40 Scheme 1.5.5.9. Trost’s Construction of the Rameswaralide Tricyclic Scaffold (Trost) ... 41 Scheme 1.5.6.1. Substrates for Exploration of Proposed Biosynthesis (Pattenden) ... 42 Scheme 1.5.6.2. Synthesis of the Mandapamate and Rameswaralide Core Scaffolds (Pattenden) ... 43 Scheme 1.5.6.3. Formation of Rameswaralide Core from Diol 179 (Pattenden) ... 43 Scheme 1.5.6.4. Synthesis of Unexpected Novel Cembranoid Core (Pattenden) ... 44 Scheme 1.5.6.5. Alternative Proposal for Biosynthesis of Mandapamates and Plumarellides ... 45 Scheme 1.5.7.1. Retrosynthesis of Common Carbocyclic Core (Mehta) ... 45 Scheme 1.5.7.2. Synthesis of Macrocyclic Diene 195 (Mehta) ... 46 Scheme 1.5.7.3. Construction of Tricycle 202 by Diels–Alder Cycloaddition (Mehta) ... 47
Scheme 1.5.8.1. Retrosynthetic Analysis of Yonarolide (25, Ito) ... 47 Scheme 1.5.8.2. Diels–Alder Cycloaddition of Butenolide 206 (Ito) ... 48 Scheme 1.5.8.3. Synthesis of the Yonarolide Core by Tandem
Isomerization-Aldol Cyclization (Ito) ... 48 Scheme 1.5.9.1. Biomimetic Semisynthesis of Ineleganolide (9)
and Sinulochmodin C (10, Pattenden) ... 49 Scheme 1.5.9.2. Attempted Biomimetic Semisynthesis of Additional Norcembranoids (Pattenden) .... 50 Scheme 1.5.9.3. Vanderwal’s Retrosynthetic Analysis of Ineleganolide (9) ... 50 Scheme 1.5.9.4. Synthesis of Enantioenriched Cyclopentenone (+)218 (Vanderwal) ... 51 Scheme 1.5.9.5. Construction of Ketofurans 221 and 222 (Vanderwal) ... 51 Scheme 1.5.9.6. Completion of Tricyclic Coupling Partner (Vanderwal) ... 51 Scheme 1.5.9.7. Asymmetric Synthesis of Complimentary Cyclohexenone (+)-213 (Vanderwal) ... 52 Scheme 1.5.9.8. Coupling of Ineleganolide Fragments (Vanderwal) ... 52 Scheme 1.5.9.9. Alternative Advancement Toward Ineleganolide (Vanderwal) ... 53
CHAPTER 2
Enantioselective Synthesis of a Hydroxymethyl-cis-1,3-cyclopentenediol Building Block
Scheme 2.2.1. Retrosynthetic Analysis of cis-1,3-Cyclopentenediol 241 ... 63 Scheme 2.3.1. Enantioselective Allylic Alkylation and Elaboration of
Cyclohexanone and Dioxanone Substrates ... 63 Scheme 2.4.1. Proposed Construction of Cyclopentenone 250 Using
Intramolecular Wittig Cyclization ... 64 Scheme 2.4.2. Construction of Enone 250 by Epoxidation of Chloroallylketone 254 ... 65 Scheme 2.4.3. Construction of Enone 250 by Oxidative Bromination of Chloroallylketone 254 ... 65 Scheme 2.4.4. Synthetic Route Enabled by the Crucial Choice of the Cyclohexyl Ketal Group ... 67 Scheme 2.5.1. Synthetic Advancement Toward the Desired Hydroxylmethyl-
cis-1,3-Cyclopentenediol Framework ... 69
APPENDIX 1
Synthetic Summary for Chapter 2
Scheme A1.1. Synthetic Summary for Construction of cis-1,3-Cyclopentenediol 262 ... 99
APPENDIX 3
Alternative Construction of Hydroxymethyl-cis-1,3-cyclopentenediol Building Block by Ring-Closing Metathesis
Scheme A3.1.1. Alternative Retrosynthetic Analysis of Hydroxymethyl-cis-
1,3-cyclopentenediol Building Block 241. ... 133 Scheme A3.2.1. Ketal Substrates for Exploration of Diastereoselective Addition. ... 133 Scheme A3.2.2. Synthesis of Diethyl Ketal Allylic Alkylation Product 291. ... 134 Scheme A3.5.1. Ring-Closing Metathesis of Allyl Dioxanones. ... 137 Scheme A3.6.1. Attempted 1,3-Allylic Transposition of Bicyclic Acetonide 306. ... 138 Scheme A3.6.2. Isomerization of Acetonide 306. ... 138
CHAPTER 3
Progress Toward the Asymmetric Total Syntheses of the Furanobutenolide Norcembranoid Diterpene Natural Products
Scheme 3.1.1. Postulated Biosynthetic Conversion of Ineleganolide (9) to Kavaranolide (21) ... 173 Scheme 3.1.2. Postulated Biosynthetic and Proposed Synthetic
Relationship of [7,6]-Norcembranoids ... 173 Scheme 3.2.1. Retrosynthetic Analysis of Ineleganolide (9) and Scabrolide A (10) ... 174 Scheme 3.2.2. Retrosynthetic Analysis of Divergent Tetracyclic Diol 314 ... 176 Scheme 3.3.1. Synthesis of Hydroxymethyl-1,3-cis-cyclopentenediol Building Block ... 177 Scheme 3.4.1. Completion of Building Blocks ... 178 Scheme 3.4.2. Fragment Coupling and Synthesis of Cyclopropanation Precursor ... 179 Scheme 3.4.3. Construction of Tetracycle 324 by Tandem
Cyclopropanation-Cope Rearrangement ... 179 Scheme 3.4.4. Diastereoselective 1,2-Reduction of Enone Byproduct 325 ... 181 Scheme 3.5.1. Advancement of Diene 324 and Formation of Isoineleganolide A (328) ... 181 Scheme 3.5.2. Hypothesized Completion of Ineleganolide ... 182 Scheme 3.5.3. Isomerization of Isoineleganolide A (328) to Isoineleganolide B (331) ... 183 Scheme 3.6.1. Alternative Retrosynthetic Disconnection of Divergent Intermediate 314 ... 183 Scheme 3.6.2. Construction of Methyl Ketone 338 ... 184 Scheme 3.6.3. Advancement of Silyl Ether 338 ... 185 Scheme 3.6.4. Fragment Coupling with Methyl Ketone Diol ent-335 ... 185 Scheme 3.6.5. Formation of Pyrazole 341 ... 186 Scheme 3.6.6. Attempted Stepwise Formation of ent-316 from Diazoester 340 ... 186
Scheme 3.7.1. Originally Hypothesized Completion of ent-Ineleganolide (ent-9) ... 187 Scheme 3.7.2. Reactivity of Isoineleganolide A (328) with In(OTF)3 in Stabilized CHCl3 ... 188 Scheme 3.7.3. Formation of Requisite 1,4-Diketone Oxidation Pattern ... 188 Scheme 3.7.4. Reductive Furan Opening ... 190 Scheme 3.7.5. Core Isomerization of Divergent Intermediate Diol 349 ... 191 Scheme 3.7.6. Selective Dehydration of Diol 349 ... 192 Scheme 3.7.7. Intended Completion of ent-Ineleganolide (ent-9)
through Vinylogous Diketone 330 ... 192 Scheme 3.7.8. Attempted Functionalization of Isoineleganolide C (ent-313) by C–H Oxidation ... 193 Scheme 3.8.1. Consideration of Three-Dimensional Structures of Late-Stage Intermediates ... 194
APPENDIX 5
Synthetic Summary for Chapter 3
Scheme A.5.1. Construction of cis-1,3-Cyclopentenediol ent-322 ... 239 Scheme A.5.2. Construction of the Tetracyclic Core and Isomers of ent-Ineleganolide (ent-9) ... 239 Scheme A.5.3. Synthesis of Alternative cis-1,3-Cyclopentenediol ent-335 ... 240 Scheme A.5.4. Advancement of Methyl Ketone Fragment ent-335 ... 240
APPENDIX 8
Alternative Synthetic Strategies Toward Ineleganolide
Scheme A.8.1.1. Synthesis of Acid ent-321 Using Isopropyl Acetate ... 366 Scheme A.8.2.1. 1,3-Allylic Transposition of Alcohol 324 ... 369 Scheme A.8.3.1. Attempted 1,4-Reduction of Enone 324 with Wilkinson’s Catalyst ... 369 Scheme A.8.3.2. Attempted Oxidation of Doubly Allylic C–H Bonds ... 369 Scheme A.8.4.1. Attempted Olefin Isomerization of Enone 328 ... 370 Scheme A.8.5.1. Nucleophilic Opening of Epoxide 328 ... 371 Scheme A.8.5.2. Nucleophilic Opening of Epoxide 328 with Halogen Ions ... 372 Scheme A.8.5.3. Kornblum Oxidation of Halogenated Furanopentacycles ... 373
CHAPTER 4
Revised Plan for the Synthesis of Ineleganolide: Alternative Advancement Toward the Asymmetric Total Synthesis of Ineleganolide by Late-Stage Oxidation State Manipulation
Scheme 4.1.1. Adapted Retrosynthetic Analysis of ent-Ineleganolide with Late-Stage Oxidation .... 409 Scheme 4.2.1. Conjugate Reduction of Diene 324 ... 409 Scheme 4.2.2. Unsuccessful Epoxide Rearrangement of Epoxide 371 ... 410 Scheme 4.2.3. Attempted Kornblum Oxidation of Epoxide 371 ... 410 Scheme 4.2.4. Sequential Reductive Epoxide Opening and Carbinol Oxidation ... 411 Scheme 4.2.5. Attempted C(5) Oxidation by C–H Activation ... 413 Scheme 4.2.6. Representative Reaction Conditions for Attempted C(4)–C(5) Oxidation ... 414 Scheme 4.2.7. Advancement of Tetracycle 372 by Diastereoselective C(3) Reduction ... 414 Scheme 4.3.1. Retrosynthetic Analysis of ent-Ineleganolide Employing a 1,2-Reduction ... 415 Scheme 4.4.1. 1,2-Reduction of Enone 328 ... 416 Scheme 4.4.2. Attempted Epoxide Rearrangement ... 416 Scheme 4.4.3. Silyl Ether Formation with Unexpected Olefin Isomerization ... 417 Scheme 4.4.4. Assessment of Configurational Stability of Unsaturated Lactone Moiety ... 417 Scheme 4.4.5. Reductive Epoxide Opening of Isomeric Silyl Ethers ... 418 Scheme 4.4.6. Silyl Enol Ether Formation from Ketone 397 ... 419 Scheme 4.4.7. Attempted Formation of TMS Enol Ether of Ketone 401 ... 419 Scheme 4.4.8. Lactol Formation ... 421 Scheme 4.4.9. Advancement of Lactol 403 ... 422 Scheme 4.5.1. Retrosynthetic Analysis of ent-Ineleganolide Employing Late-Stage Reduction ... 423 Scheme 4.6.1. Oxidation of 1,4-Diketone 347 ... 423 Scheme 4.6.2. Reduction of Vinylogous Diketone 412 ... 424 Scheme 4.6.3. Dienol Ether Formation ... 425 Scheme 4.6.4. Attempted Reductive Epoxide Opening of Disilyl Enol Ether of Enone 328 ... 425 Scheme 4.6.5. Attempted Reductive Epoxide Opening of Dienol Ether 416 ... 426 Scheme 4.6.6. Construction of α-Bromolactone 420 ... 426 Scheme 4.6.7. Oxidation of Isoineleganolide A (328) to Cycloheptadiene 422 ... 427 Scheme 4.6.8. Formation of Cycloheptatrienone 423 ... 428 Scheme 4.7.1. Redesigned Retrosynthetic Strategy Toward ent-Ineleganolide (ent-9) ... 429 Scheme 4.8.1. Asymmetric Allylic Alkylation Stereoselectively Determines
All Remaining Chiral Information ... 430
APPENDIX 9
Synthetic Summary for Chapter 4
Scheme A.9.1. Synthesis of 2H-Ineleganolide (273) Through Conjugate Reduction of Diene 324 ... 484 Scheme A.9.2. Formation of Translactonized Polycycle 378 ... 484 Scheme A.9.3. 1,2-Reduction of Isoineleganolide A (328) and Subsequent Silyl
Ether Formation with Concomitant Olefin Isomerization ... 484 Scheme A.9.4. Advancement of Isomeric Allylic Silyl Ether 389 and Unsaturated Lactone 390 ... 485 Scheme A.9.5. Construction and Transformation of Lactol 403 ... 485 Scheme A.9.6. Oxidative Desaturation of Isoineleganolide A (328) ... 485
CHAPTER 5
Lewis Acid Mediated (3+2) Cycloadditions of Donor–Acceptor Cyclopropanes with Heterocumulenes
Scheme 5.2.1. Substrate Scope of Isothiocyanate (3 + 2) Cycloaddition ... 610 Scheme 5.3.1. Structural Reassignment of Li’s Aryl Isothiocyanate (3 + 2) Products ... 612 Scheme 5.4.1. Substrate Scope of Carbodiimide (3 + 2) Cycloaddition ... 613 Scheme 5.5.1. Substrate Scope of Isocyanate (3 + 2) Cycloaddition ... 614 Scheme 5.6.1. Investigations into the Stereochemical Outcome of the (3 + 2) Cycloaddition ... 615 Scheme 5.6.2. Proposed Mechanism for (3 + 2) Cycloaddition ... 616
CHAPTER 6
Stereoselective Lewis Acid Mediated (3 + 2) Cycloadditions of N-H- and N- Sulfonylaziridines with Heterocumulenes
Scheme 6.3.1. Substrate Scope of Isothiocyanate (3 + 2) Cycloadditions ... 778 Scheme 6.3.2. (3 + 2) Cycloaddition with 2-Alkylaziridine 517 ... 779 Scheme 6.5.1. Substrate Scope of Carbodiimide (3 + 2) Cycloaddition ... 780 Scheme 6.6.1. Diastereoselective (3 + 2) Cycloaddition with Aziridine 535 ... 781 Scheme 6.6.2. Diastereoselective (3 + 2) Cycloaddition with Aziridine 537 ... 781 Scheme 6.6.3. (3 + 2) Cycloaddition with Aziridine 540 ... 782 Scheme 6.8.1. Substrate Scope of Stereoselective Isothiocyanate (3 + 2) Cycloaddition ... 784 Scheme 6.10.1. Proposed General Reaction Mechanism for
Stereoselective (3 + 2) Cycloaddition ... 786
Scheme 6.11.1. (3 + 2) Cycloaddition with Diester Aziridine 549 ... 786 Scheme 6.12.1. Desulfonylation and Deallylation of Iminothiazolidine Products ... 787
APPENDIX 16
Synthesis of Functionalized Thiouracils as G Protein-Coupled Receptor Agonists
Scheme A.16.2.1. Retrosynthetic Analaysis of PEGylated Thiouracil ... 1048 Scheme A.16.3.1. Saponification of Lactone 600 ... 1049 Scheme A.16.3.2. Attempted Condensation of Carboxylate Salt 601
onto Meldrum’s Acid (602) ... 1049 Scheme A.16.3.3. β-Ketoester Formation from Carboxylate Salt 601 ... 1049 Scheme A.16.3.4. Synthetic Access to Alkyne 610 ... 1050 Scheme A.16.3.5. Construction of β-Ketoester 613 ... 1050 Scheme A.16.3.6. Thiouracil Formation ... 1051 Scheme A.16.3.7. Attempted PEGylation of Thiouracil 597 by Click Reaction ... 1051