Total synthesis of (+)-azaspiracid-1. An exhibition of the intricacies of complex molecule synthesis

Abstract

The synthesis of the marine neurotoxin azaspiracid-1 has been accomplished. The individual fragments were synthesized by catalytic enantioselective processes: A hetero-Diels-Alder reaction to afford the E- and HI-ring fragments, a carbonyl-ene reaction to furnish the CD-ring fragment, and a Mukaiyama aldol reaction to deliver the FG-ring fragment. The subsequent fragment couplings were accomplished by aldol and sulfone anion methodologies. All ketalization events to form the nonacyclic target were accomplished under equilibrating conditions utilizing the imbedded configurations of the molecule to adopt one favored conformation. A final fragment coupling of the anomeric EFGHI-sulfone anion to the ABCD-aldehyde completed the convergent synthesis of (+)-azaspiracid-1.

Figure 1

Originally proposed structure (1) and correct structure of (−)-azaspiracid-1 (2).

Figure 2

3D-representation of (−)-azaspiracid-1 (2) highlighting stabilizing anomeric effects in the molecule.

Figure 3

Depiction of C6 CO*-orbital in AB-ring fragment 7.

Figure 4

Key NOEs for spiroaminal 117 (C₆D₆, 500 MHz).

Scheme 1

Retrosynthetic analysis of (+)-azaspiracid-1 (ent-2). See ref for abbreviations.

Scheme 2

Synthesis of the C1–C12 chain of the AB-ring fragment. Reagents and conditions: a) 27 (5 mol%), CH₂Cl₂, 40 °C, 88%; b) PhSH, Et₃N, CH₂Cl₂; c) allenylMgBr, Et₂O, 0 °C, 96% (2 steps); d) 29, n-BuLi, Et₂O, −78 °C, then MgBr₂·OEt₂, then 30, −78 to 0 °C, THF added, then RT; e) Ac₂O, DMAP, pyr, CH₂Cl₂, 83% (2 steps). See ref for abbreviations.

Scheme 3

Synthesis of the AB-Ring Fragment 7. Reagents and conditions: a) 32 (2 equiv), BH₃·SMe₂, THF, 0 °C, 86%, 94–97% ee; b) H₂ (1 atm), Pd/CaCO₃/Pb (5%), pyr, benzene; c) TBSCl, DMAP, imidazole, DMF, 92%, 3–5% C4–C5 alkane (2 steps); d) K₂CO₃, MeOH; e) SO₃·Pyr, DMSO, i-Pr₂NEt, CH₂Cl₂, −25 °C, 91% (2 steps); f) HF·pyr, pyr, THF, 0 °C, 74%; g) PPTS, HC(OMe)₃, MeOH, CH₂Cl₂, −10 °C, 92%; h) H₂O₂, (NH₄)₆Mo₇O₂₄, MeOH, 0 °C, 88%; i) LiAlH₄, Et₂O, −20 °C, 92%; j) TIPSCl, imidazole, DMF, 98%. See ref for abbreviations.

Scheme 4

Initial synthesis of the CD-ring fragment. Reagents and conditions: a) NaH, BnBr, CH₂Cl₂, 0 °C to RT, 99%; b) DIBALH, toluene, −94 °C; c) ZnCl₂, 36, 59% (2 steps), dr 93:7; d) O₃, MeOH, CH₂Cl₂, −78 °C, then Me₂S, RT, 79%; e) Et₃SiH, BF₃·OEt₂, CH₂Cl₂, −78 °C, 82%, dr 90:10. See ref for abbreviations.

Scheme 5

C14-Methylation. Reagents and conditions: a) i-PrMgCl, morpholine, THF, −78 to −20 °C, 82%; b) LiHMDS, MeI, THF, −78 °C, 96%, dr 86:14. See ref for abbreviations.

Scheme 6

Second synthesis of the CD-ring fragment 8. Reagents and conditions: a) MeNH(OMe)·HCl, Me₃Al, THF, 98%; b) PMBBr, NaH, DMF, 0 °C, 95%; c) 47, t-BuLi, Et₂O, −78 °C, then 46, 90%; d) L-Selectride, THF, −78 °C, 96%, dr > 95:5; e) i) O₃, pyridine, CH₂Cl₂/MeOH (5:1 v/v), −78 °C, then Me₂S, −78 °C to RT; ii) PPTS, MeOH, 90%; f) Et₃SiH, BF₃·OEt₂, CH₂Cl₂, −78 °C, 84%, dr >95:5; g) DDQ, CH₂Cl₂/pH 7 buffer (9:1 v/v), 0 °C, 94%; h) TESCl, imidazole, DMF, 97%; i) LiDBB, THF, −78 °C, 96%; j) SO₃·Pyr, DMSO, i-Pr₂NEt, CH₂Cl₂, −30 °C, 97%. See ref for abbreviations.

Scheme 7

Synthesis of the ABCD-aldehyde 3. Reagents and conditions: a) 7 (1.6 equiv), LDA, THF, −78 °C; then 8 (1.0 equiv); b) Dess-Martin periodinane, pyr, CH₂Cl₂, 92% (2 steps); c) Na/Hg (5%), NaH₂PO₄, THF/MeOH, −10 °C, 92%; d) TBAF, THF, −20 °C (workup); e) PPTS, CH₂Cl₂, 0 °C (83%, 2 steps); f) TBAF, AcOH, DMF, 86%; g) SO₃·Pyr, DMSO, i-Pr₂NEt, CH₂Cl₂, −30 °C, 91%. See ref for abbreviations.

Scheme 8

Syn-1,3-dimethyl synthons embedded in azaspiracid-1.

Scheme 9

Synthesis of the tetrahydropyran 59. Reagents and conditions: a) KOt-Bu, DMSO, 70 °C, 70%; b) 2-propenylMgBr, THF/Et₂O, −78 °C, 80%; c) 15 (2 mol%), 3Å MS, Et₂O, −40 °C, dr 94:6, 97% ee, 84% 60; d) H₂ (1 atm), Pd/C (5 mol%), EtOAc, dr 98:2, 95% 59. See ref for abbreviations.

Scheme 10

Synthesis of the E-ring vinyl iodide 71. Reagents and conditions: a) t-BuOK, THF, −50 °C, quant.; b) 1,3-propanedithiol, BF₃·OEt₂, CH₂Cl₂, 95% (2 steps); c) LiBH₄, THF, quant; d) 2,2-dimethoxypropane, PPTS, CH₂Cl₂, 98%; e) t-BuLi, HMPA, THF, −78 °C, then MeI, 92%; f) Hg(ClO₄)₂, CaCO₃, H₂O, THF, 88%; g) trisylhydrazine, THF, 93%; h) t-BuLi, THF, −78 to 0 °C, then I₂, −78 °C, 86%. See ref for abbreviations.

Scheme 11

Synthesis of the ABCDE-region 77. Reagents and conditions: a) TBAF, AcOH, THF 97%; b) SO₃·Pyr, DMSO, i-Pr₂NEt, CH₂Cl₂, −30 °C, 94%; c) 71 (2 equiv), t-BuLi, Et₂O, −78 °C, then 72, MgBr₂·OEt₂, CH₂Cl₂, −20 °C, 80%, dr > 99:1; d) Ac₂O, DMAP, Et₃N, CH₂Cl₂, 96%; e) i) O₃, MeOH, CH₂Cl₂, −78 °C, then Me₂S; ii) MeOH, HC(OMe)₃, PPTS, 75% (2 steps); f) TBDPSCl, imidazole, CH₂Cl₂; g) DDQ, CH₂Cl₂/pH 7 buffer (9:1 v/v), 0 °C; 78% (2 steps); h) TESCl, imidazole, CH₂Cl₂, 90%; i) H₂, RaNi (W-2), EtOH, 93%; j) SO₃·Pyr, DMSO, i-Pr₂NEt, CH₂Cl₂, −30 °C, 75%. See ref for abbreviations.

Scheme 12

Synthesis of cyclic E-ring fragments. Reagents and conditions: a) PhSH, BF₃·OEt₂, CH₂Cl₂, −20 °C, dr 96:4, 83% 78; b) t-BuOK, THF, −50 °C, dr 96:4, 88% 79; c) Me(OMe)NH·HCl, i-PrMgCl, THF, −78 to −20 °C, 93%; d) 79, DIBALH, toluene, −94 to −78 °C, 93%. See ref for abbreviations.

Scheme 13

Model studies of final C20–C21 sulfone fragment coupling and product elaboration. Reagents and conditions: a) EtMgBr, THF, −78 °C, 99%; b) TMSCH₂Li, THF, −78 °C, 70%; c) KH, THF, 99%; d) H₂O₂, Na₂WO₄·2H₂O, MeOH, 91%; e) 81 (1 equiv), LDA (1.2 equiv), THF, then 82 (1.5 equiv), −78 °C, dr(C21): 6:1, 51% 83; f) PhSLi, Et₂O, −78 °C, 99%; g) KHBEt₃, THF, −78 to −20 °C, dr 5–6:1, 56% major isomer; h) HgCl₂, pH 7 buffer, MeCN/THF, 0 °C, 86%; i) KHBEt₃, CH₂Cl₂, −78 to −20 °C, dr 10:1, 91% major isomer. See ref for abbreviations.

Scheme 14

Model studies of final C20–C21 sulfone fragment coupling via the C20-aldehyde 3. Reagents and conditions: a) LiAlH₄, Et₂O, −20 °C; b) TBDPSCl, imidazole, DMF, 99% (2 steps); c) m-CPBA, NaHCO₃, CH₂Cl₂, 94%; d) 87 (2.3 equiv), n-BuLi, THF, −78 °C, then 3 (1.0 equiv), then sat. aq. NH₄Cl, −78 °C to RT, 65%, 3:1 88:89. See ref for abbreviations.

Scheme 15

Synthesis of the FG-ring fragment 11. Reagents and conditions: a) O₃, MeOH, CH₂Cl₂, −78 °C, then Me₂S, 61%; then vacuum sublimation, 73%; b) 10 mol% 93, CH₂Cl₂, −78 °C, 94% conversion, dr > 40:1, 97% ee (67% after recrystallization, >99% ee); c) H₂ (1 atm), 2 mol% [(COD)Ir(PCy₃)(py)]PF₆, CH₂Cl₂, 98%, dr > 95:5; d) PMBBr, NaH, DMF, −40 to −20 °C, 67%; e) KHBEt₃, THF, 0 °C to RT, 94%; f) TBSCl, imidazole, DMF, 99%; g) HF·pyr, THF, −10 °C, 87%; h) TsCl, DMAP, pyridine, 98%; i) NaCN, DMSO, 55 °C, 99%; j) Boc₂O, DMAP, CH₃CN, 99%;kj) LiBH₄, H₂O, THF, 0 °C to RT, 99%; l) TMSCl, imidazole, CH₂Cl₂, 99%; m) MeLi, Et₂O, 0 °C, 84%; n) SO₃·Pyr; DMSO, i-Pr₂NEt, CH₂Cl₂, −30 °C, 99%. See ref for abbreviations.

Scheme 16

Auxiliary-based synthesis of the HI-ring fragment 12. Reagents and conditions: a) 104, LiAlH₄, THF, 0 °C, 95%; b) TsCl, Et₃N, CH₂Cl₂, 0 °C to RT, 95%; c) NaN₃, TBAI, DMF, 60 °C, 93%; d) (COCl)₂, DMSO, Et₃N, CH₂Cl₂, −78 °C to RT, 95%. See ref for abbreviations.

Scheme 17

Catalytic enantioselective synthesis of the HI-ring fragment 12. Reagents and conditions: a) Et₃SiH, BF₃·OEt₂, CH₂Cl₂, 0 °C, 91%; b) LiAlH₄, Et₂O, 0 °C, 91%; c) I₂, PPh₃, imidazole, CH₃CN/benzene, RT to 60 °C, 94%; d) t-BuLi, THF, −78 °C, then TsCl, −78 to 0 °C, 95%; e) O₂, PdCl₂, CuCl, H₂O, DMF, 89%; f) NaN₃, DMSO, 60 °C, 97%. See ref for abbreviations.

Scheme 18

Chelate-controlled Mukaiyama aldol reaction and initial investigations of FG-ketalization. Reagents and conditions: a) LiHMDS, TMSCl, Et₃N, THF, −78 °C, 89%; b) MgBr₂·OEt₂, CH₂Cl₂, 0 °C, 93%, dr > 95:5; c) HF, H₂O, CH₃CN, 0 °C, 92%; d) TBSCl, imidazole, DMF, 99%. See ref for abbreviations.

Scheme 19

Assembly of the EFGHI carbon skeleton and formation of the FG bicyclic ketal 115. Reagents and conditions: a) Cy₂BCl (2.4 equiv), i-Pr₂NEt, CH₂Cl₂, −78 °C, then 10 (1.4 equiv), −78 to 0 °C; then H₂O₂, MeOH, pH 7 buffer, 0 °C to RT, dr 60:40; b) HF, H₂O, CH₃CN, 0 °C, 92% (2 steps); c) Dess-Martin periodinane, pyr, CH₂Cl₂, 85%. See ref for abbreviations.

Scheme 20

Completion of the EFGHI-sulfone 4. Reagents and conditions: a) DDQ, pH 7 buffer, CH₂Cl₂, 0 °C; b) H₂ (1 atm), Pd/C, THF, dr >95:5, 77% (2 steps); c) TeocCl, i-Pr₂NEt, THF, 0 °C, 89%, dr > 97:3; d) Tebbe reagent, pyr, toluene, −40 °C, 55%; (41% recovered ketone); e) H₂O₂, pyr, (NH₄)₆Mo₇O₂₄, t-BuOH, 96%. See ref for abbreviations.

Scheme 21

Final fragment coupling and completion of the synthesis. Reagents and conditions: a) 4 (2.2 equiv), n-BuLi, −78 °C, then 3 (1.0 equiv), then NaOAc/AcOH buffer, −78 °C to RT, 50% (27% 118, 23% 119); b) (COCl)₂, DMSO, Et₃N, CH₂Cl₂, −78 to −20 °C, 63%; c) LiBH₄(THF), CH₂Cl₂, −40 °C, dr > 20:1, 56%; d) TBAF, THF, 0 °C, 93%; e) Dess-Martin periodinane, CH₂Cl₂, 0 °C; f) NaClO₂, NaH₂PO₄·H₂O, 2-methyl-2-butene, t-BuOH, 90% (2 steps). See ref for abbreviations