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. 2009 Sep 14;15(36):9223-34.
doi: 10.1002/chem.200900776.

Enantioselective total synthesis of brevetoxin A: unified strategy for the B, E, G, and J subunits

Michael T Crimmins  1 , J Michael Ellis, Kyle A Emmitte, Pamela A Haile, Patrick J McDougall, Jonathan D Parrish, J Lucas Zuccarello
Affiliations

Enantioselective total synthesis of brevetoxin A: unified strategy for the B, E, G, and J subunits

Michael T Crimmins et al. Chemistry. .

Abstract

Brevetoxin A is a decacyclic ladder toxin that possesses 5-, 6-, 7-, 8-, and 9-membered oxacycles, as well as 22 tetrahedral stereocenters. Herein, we describe a unified approach to the B, E, G, and J rings based upon a ring-closing metathesis strategy from the corresponding dienes. The enolate technologies developed in our laboratory allowed access to the precursor acyclic dienes for the B, E, and G medium-ring ethers. The strategies developed for the syntheses of these four monocycles ultimately provided multigram quantities of each of the rings, supporting our efforts toward the completion of a convergent synthesis of brevetoxin A.

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Figures

Figure 1
Figure 1
Initial retrosynthetic analysis of the B ring 10.
Figure 2
Figure 2
Aldol-based retrosynthetic analysis of the B ring 27.
Figure 3
Figure 3
Key features of the strategy for the B ring 47.
Figure 4
Figure 4
Key strategic elements for the E ring synthesis.
Figure 5
Figure 5
Key features of the first generation synthesis of the G ring 82.
Figure 6
Figure 6
Key features of the second generation synthesis of the G ring.
Figure 7
Figure 7
Key features of the first generation synthesis of the J ring 106.
Figure 8
Figure 8
Key features of the second generation synthesis of the J ring 115.
Scheme 1
Scheme 1
Retrosynthetic analysis
Scheme 2
Scheme 2
First generation B ring synthesis. Reagents and conditions: a) (+)-DIPT, Ti(O-iPr)4, tBuOOH, CH2Cl2, 4 Å MS, −20 °C, 63%; b) NaH, BnBr, nBu4NI, THF, 91%; c) KCN, LiClO4, CH3CN, 80 °C, 84%; d) NaOH, H2O, MeOH, 65 °C; e) LiAlH4, Et2O, 35 °C, 78% for 2 steps; f) TIPSCl, imid., DMF, 89%; g) NaH, BrCH2CO2H, THF, 88%; h) PivCl, Et3N, (R)-5-lithio-4-isopropyl-oxazolidin-2-one, THF, 80%; i) NaN(SiMe3)2, E-ICH2CH=CHCH2OPMB (16), THF, PhMe, −78 to −45 °C, 80%; j) LiBH4, MeOH, Et2O, 0 °C, 96%; k) (COCl)2, DMSO, Et3N, CH2Cl2; l) (4-dIcr)2BCH2C(Me)=CH2, Et2O, THF, −78 °C, 94% for 2 steps; m) Ac2O, pyr., DMAP, CH2Cl2, 92%; n) DDQ, H2O, CH2Cl2, 0 °C, 85%; o) (+)-DET, Ti(O-iPr)4, tBuOOH, CH2Cl2, 4 Å MS, −20 °C, 93%; p) K2CO3, MeOH, Et2O, 89%; q) NaIO4, THF, H2O; r) NaBH4, EtOH, 0 °C, 92% for 2 steps; s) Cl2(Cy3P)(IMes)Ru=CHPh, CH2Cl2, 40 °C, 70%.
Scheme 3
Scheme 3
Attempted incorporation of the C8 methyl. Reagents and conditions: a) LiBH4, MeOH, Et2O, 0 °C, 96%; b) (COCl)2, DMSO, Et3N, CH2Cl2; c) MeMgI, Et2O, 0 °C, 90%; d) (COCl)2, DMSO, Et3N, CH2Cl2; e) (4-dIcr)2BCH2C(Me)=CH2, Et2O, THF, −78 °C, 89% for 2 steps, 10:1 dr; f) DDQ, H2O, CH2Cl2, 0 °C, 85%; g) (+)-DET, Ti(O-iPr)4, tBuOOH, CH2Cl2, 4 Å MS, −20 °C, 93%; h) NaIO4, THF, H2O; i) NaBH4, EtOH, 0 °C, 92% for 2 steps; j) Cl2(Cy3P)(IMes)Ru=CHPh, CH2Cl2, 40 °C, no reaction.
Scheme 4
Scheme 4
Second generation B ring synthesis. Reagents and conditions: a) TiCl4, iPr2NEt, CH2=C(Me)CH2CHO, CH2Cl2, −78 °C; b) LiBH4, MeOH, Et2O, 0 °C, 58% for 2 steps; c) cyclohexanone, PPTS, MgSO4, C6H6, 80 °C, 87%; d) Cl2(Cy3P)(IMes)Ru=CHPh, CH2Cl2, 40 °C, 83%; e) Na, naphthalene, THF, 0 °C, 91%; f) TBSOTf, 2,6-lut., CH2Cl2, 90%; g) PPTS, EtOH, 78 °C, 72%; h) Ac2O, DMAP, CH2Cl2, 87%; i) nBu4NF, THF, 100%; j) cyclohexanone, PPTS, MgSO4, C6H6, 80 °C, 94%; k) Pd(OH)2/C, H2 (45 psi), EtOH, 90%, 1:1 dr.
Scheme 5
Scheme 5
First stereocontrolled completion of the B ring 46. Reagents and conditions: a) TiCl4, (−)-sparteine, CH2=C(Me)CH2CHO, CH2Cl2, −78 °C, 64%, 9:1 dr; b) LiBH4, MeOH, Et2O, 0 °C, 78%; c) TIPSCl, imid., DMF, 95%; d) PMBBr, NaH, DMF, 86%; e) Ti(O-iPr)4, nBuMgCl, Et2O, 0 °C, 86%; f) NaH, BrCH2CO2H, THF, DMF, 91%; g) PivCl, Et3N, (R)-5-lithio-4-isopropyl-oxazolidin-2-one, THF, 90%; h) NaN(SiMe3)2, (BnO)2CH2, TMSI, THF, −78 °C, 93%; i) LiBH4, MeOH, Et2O, 0 °C, 81%; j) (COCl)2, DMSO, Et3N, CH2Cl2; k) CH2=CHMgBr, THF, 0 °C, 76% for 2 steps, 3:1 dr; l) Cl2(Cy3P)(IMes)Ru=CHPh, CH2Cl2, 40 °C, 75%; m) [PCy3] [COD] [pyr]Ir+PF6-, H2, CH2Cl2, −50 °C, 93%; n) Dess–Martin periodinane, CH2Cl2, 89%; o) MeMgCl, Et2O, −78 °C, 89%; p) LiDBB, THF, −78 °C, 98%; q) Dess–Martin periodinane, CH2Cl2, 88%; r) PPh3, p-NO2C6H4CO2H, DEAD, C6H6; iBu2AlH, CH2Cl2, −78 °C, 50% for 2 steps.
Scheme 6
Scheme 6
Homologated B ring synthesis. Reagents and conditions: a) NaN(SiMe3)2, CH2=C(Me)CH2I, THF, −78 °C, 78%; b) LDA, EtOAc, THF, −78 °C, 84%; c) LiAlH4, Et2O, 0 °C, 80%; d) TIPSCl, imid., CH2Cl2, 100%; e) (COCl)2, DMSO, Et3N, CH2Cl2, 100%; f) Zn(BH4)2, Et2O, −25 °C, 79%; g) NaH, BrCH2CO2H, THF, DMF, 90%; h) PivCl, Et3N, (R)-5-lithio-4-isopropyl-oxazolidin-2-one, THF, 90%; i) NaN(SiMe3)2, (BnO)2CH2, TMSI, THF, −78 °C, 83%; j) LiBH4, MeOH, Et2O, 0 °C, 86%; k) (COCl)2, DMSO, Et3N, CH2Cl2, 99%; l) CH2=CHMgBr, THF, 0 °C, 86% (3:1 dr); m) Cl2(Cy3P)(IMes)Ru=CHPh, CH2Cl2, 40 °C, 71%; n) [PCy3] [COD] [pyr]Ir+PF6-, H2, CH2Cl2, −50 °C, 94%; o) (COCl)2, DMSO, Et3N, CH2Cl2, 95%; p) MeMgCl, Et2O, −78 °C, 88%; q) Raney Ni, H2, EtOH, 95%; r) Dess–Martin periodinane, CH2Cl2, 85%; s) (COCl)2, DMSO, Et3N, CH2Cl2, 64%; t) CeCl3•7H2O, NaBH4, MeOH, 82%.
Scheme 7
Scheme 7
Initial E ring synthesis. Reagents and conditions: a) NaN(SiMe3)2, CH2=CHCH2I, THF, −78 °C, 82%; b) NaBH4, H2O, THF, 95%; c) (COCl)2, DMSO, Et3N, CH2Cl2; d) Propionate 62, TiCl4, (−)-sparteine, NMP, CH2Cl2, 92% for 2 steps; e) LiBH4, MeOH, Et2O, 0 °C, 91%; f) TIPSCl, imid., DMF, 70 °C, 96%; g) NaH, BrCH2CO2H, THF, 81%; h) PivCl, Et3N, (R)-5-lithio-4-isopropyl-oxazolidin-2-one, THF, 77%; i) NaN(SiMe3)2, (Me)2C=CHCH2I, −78 °C, 83%; j) LiBH4, MeOH, Et2O, 0 °C, 87%; k) (COCl)2, DMSO, Et3N, CH2Cl2; l) (2-dIcr)2BCH2CH=CH2, Et2O, THF, −78 °C, 89% for 2 steps; m) Ac2O, Et3N, DMAP, CH2Cl2, 96%; n) m-CPBA, CH2Cl2, −20 °C, 97%; o) Cl2(PCy3)Ru=CHPh, CH2Cl2, 40 °C, 99%; p) HClO4, H2O, THF, 59%; q) NaIO4, nBu4NHSO4, THF, H2O, 92%; r) LiAlH4, Et2O, 0 °C, 96%; s) NaH, BnBr, DMF, THF, 40 °C, 75%; t) nBu4NF, THF, 96%.
Scheme 8
Scheme 8
Second generation E ring synthesis. Reagents and conditions: a) NaH, BrCH2CO2H, THF, 81%; b) PivCl, Et3N, (S)-5-lithio-4-benzyl-2-oxazolidinethione, THF, 66%; c) TiCl4, (−)-sparteine, CH2=CHCH2CHO, CH2Cl2, −78 °C, 50% (5:1 dr), 89% brsm; d) LiBH4, MeOH, Et2O, 0 °C, 80%; e) Na, naphthalene, THF, 0 °C, 98%; f) NaH, PMBBr, DMF; g) nBu4NF, THF, 90% for 2 steps.
Scheme 9
Scheme 9
Third generation E ring synthesis. Reagents and conditions: a) NaN(SiMe3)2, CH2=CHCH2I , THF, −78 °C, 76%; b) NaBH4, H2O, THF, 93%; c) (COCl)2, DMSO, Et3N, CH2Cl2; d) Propionate 62, TiCl4, (−)-sparteine, NMP, CH2Cl2; e) NaBH4, H2O, THF, 78% for 3 steps; f) TIPSCl, imid., CH2Cl2, 97%; g) NaH, BrCH2CO2H, THF, DMF, 92%; h) PivCl, Et3N, (R)-5-lithio-4-isopropyl-oxazolidin-2-one, THF, 89%; i) NaN(SiMe3)2, BrCH2CN, −78 °C; j) NaBH4, H2O, THF, 75% for 2 steps; k) (COCl)2, DMSO, Et3N, CH2Cl2; l) CH2=CHCH2SnBu3, AlMe3, CH2Cl2, −78 °C; m) HCl, MeOH, 65 °C, 69% for 3 steps; n) TBSCl, imid., DMF, 80 °C, 80%; o) LiAlH4, Et2O, −20 °C, 88%; p) NaH, BnBr, DMF, 98%; q) HF•pyr, THF, 72%.
Scheme 10
Scheme 10
First generation synthesis of the G ring 82. Reagents and conditions: a) CH2=CHCH2MgBr, Et2O, 35 °C, 80%; b) (−)-DCHT, Ti(iPrO)4, tBuOOH, 4Å mol. sieves, CH2Cl2, −20 °C, 43% (98% ee); c) BnBr, NaH, THF, 87%; d) Me2C=CHMgBr, CuI, THF, 86%; e) BrCH2CO2H, NaH, THF, 87%; f) PivCl, Et3N, THF; then (S)-5-lithio-4-benzyl-2-oxazolidinone (R1= Bn) or (S)-5-lithio-4-isopropyl-2-oxazolidinone (R1= iPr), −78 to 0 °C, 80% or 85% respectively; g) TiCl4, (−)-sparteine, acrolein, CH2Cl2, -78 to 0 °C, 25%; h) NaN(SiMe3)2, (BnO)2CH2, TMSI, THF, −78 to -45 °C, 70%; i) NaBH4, THF, H2O, 88%; j) Dess–Martin periodinane, CH2Cl2; k) CH2=CHMgBr, THF, −78 °C, 80% (2 steps); l) m-CPBA, CH2Cl2, −20 °C, 80%; m) Cl2(PCy3)(sIMes)Ru=CHPh, CH2Cl2, 40 °C, 85%.
Scheme 11
Scheme 11
Preparation of Diols 98. Reagents and conditions: a) NaN(SiMe3)2, CH2=CHCH2I, THF, -78 to -45 °C, 80%; b) LiBH4, MeOH, Et2O, 0 °C, 90%; c) (COCl)2, DMSO, Et3N, CH2Cl2, −78 to 0 °C, 97%; d) tBuO2CCH2Li, THF, −78 °C, 85% from 96, 75% from ent-75; e) LiAlH4, Et2O, 0 °C, 92% from 97, 67% from 99 brsm.
Scheme 12
Scheme 12
Second generation synthesis of the G ring 8. Reagents and conditions: a) TIPSCl, imid., CH2Cl2, 99%; b) (COCl)2, DMSO, DIEA, CH2Cl2, −78 to 0 °C, 94%; c) MeMgCl, Et2O, -78 °C, 97%; d) BrCH2CO2H, NaH, DMF, 30 h, 84% (after 1 recycle); e) PivCl, Et3N, THF; then (S)-5-lithio-4-isopropyl-2-oxazolidinone, -78 to 0 °C, 86%; f) NaN(SiMe3)2, (BnO)2CH2, TMSI, THF, −78 °C; g) LiBH4, MeOH, Et2O, 0 °C, 70% (2 steps); h) (COCl)2, DMSO, Et3N, CH2Cl2, −78 to 0 °C, 99%; i) CH2=CHMgBr, THF, 0 °C, 80%; j) Cl2(PCy3)(sIMes)Ru=CHPh, CH2Cl2, 40 °C, 85%; k) o-NO2C6H4SO2NHNH2, Et3N, DME, 85 °C, 95%; l) (COCl)2, DMSO, Et3N, CH2Cl2, −78 to 0 °C, 96%; m) iBu2AlH, CH2Cl2, −78 °C, 98%.
Scheme 13
Scheme 13
First Generation Synthesis of the J Ring 106. Reagents and conditions: a) TiCl4, DIEA, CH2Cl2, −78 °C; then trans-cinnamaldehyde or trans-2-hexenal, 76% (dr = 10:1) or 64% (dr = 7:1), respectively; b) NaBH4, H2O, THF, 80% (R = Ph), 82% (R = nPr); c) TIPSCl, imid., DMF, 92% (R = Ph), 73% (R = nPr); d) BrCH2CO2H, NaH, THF, 83% (R = Ph), 87% (R = nPr); e) PivCl, Et3N, THF; then (R)-5-lithio-4-isopropyl-2-oxazolidinone, −78 to 0 °C, 80% (R = Ph), 67% (R = nPr); f) NaN(SiMe3)2, CH2=CHCH2I, THF, −78 to −45 °C, 28% (R = Ph), 90% (R = nPr); g) NaBH4, H2O, THF, 86%; h) BnBr, NaH, THF, 99%; i) Cl2(PCy3)2Ru=CHPh, CH2Cl2, 40 °C, 95%; j) OsO4, NMO, THF, H2O, 78% (dr = 3:1).
Scheme 14
Scheme 14
Second generation synthesis of the J ring 115. a) TBDPSCl, imid., CH2Cl2, 0 °C to RT, 95%; b) Me3S+I-, BuLi, THF, 0 °C, 86%; c) (EtO)2CHCH2CH=CH2, PPTS, C6H6, 60 °C, 35 mm Hg, 87%; d) Cl2(PCy3)2Ru=CHPh, CH2Cl2, 40 °C, 95%; e) RuCl3, NaIO4, H2O, EtOAc, CH3CN, 75%; f) CDI, THF, 65 °C, 90%; g) CH2=CHCH2SiMe3, TMSOTf, CH3CN, −10 °C, 87% (dr >10:1); h) K2CO3, MeOH, 76%; i) PPTS, (MeO)2CMe2, 92%; j) 9-BBN, THF; NaOH, H2O2 (aq), 90%.
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