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. 2004 Aug 17;101(33):11955-9.
doi: 10.1073/pnas.0401247101. Epub 2004 Jun 1.

Total synthesis of (-)-spinosyn A

Dustin J Mergott  1 , Scott A Frank, William R Roush
Affiliations

Total synthesis of (-)-spinosyn A

Dustin J Mergott et al. Proc Natl Acad Sci U S A. .

Abstract

A convergent, highly stereoselective total synthesis of (-)-spinosyn A (1) is described. Key features of the synthesis include the transannular Diels-Alder reaction of macrocyclic pentaene 11 and the transannular Morita-Baylis-Hillman cyclization of 12 that generates tetracycle 26. The total synthesis of (-)-spinosyn A was completed by a sequence involving the highly beta-selective glycosidation reaction of 13 and glycosyl imidate 30.

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Figures

Scheme 1.
Scheme 1.
Biomimetic strategy for synthesis of 1.
Scheme 2.
Scheme 2.
Results of IMDA reactions of trienes 5a and 5b (9).
Scheme 3.
Scheme 3.
Transition states for the IMDA reaction of 8.
Scheme 4.
Scheme 4.
Transition-state analysis of the TDA reaction of 11.
Scheme 5.
Scheme 5.
Retrosynthetic strategy for synthesis of 1.
Scheme 6.
Scheme 6.
Synthesis of aldehyde 14. a, TBS trifluoromethanesulfonate, 4 Å MS, CH2Cl2, 23°C, 15 min, 84%; b, tetrabutylammonium fluoride, THF, 0°C → 23°C, 1.5 h, 84%; c, Dess–Martin periodinane, pyridine, wet CH2Cl2, 0°C → 23°C, 2.5 h, 92%; d, CBr4, Ph3P, CH2Cl2, 0°C → 23°C, 30 min, 94%; e, O3, 4:1 CH2Cl2/MeOH, KHCO3, -78°C → 23°C, 3 h; f, Ph3Pformula imageCHCO2Me, CH2Cl2, 23°C, 12 h, 82% from 19, ds = 95:5; g, diisobutylaluminum hydride, CH2Cl2, -78°C → 0°C, 1.25 h, 89%; h, SO3·pyridine, DMSO, i-Pr2NEt, CH2Cl2, 0°C, 20 min.
Scheme 7.
Scheme 7.
Synthesis of β-ketophosphonate 15. a, PMB—Br, Et3N, potassium hexamethyldisilazane, THF, -78°C → 23°C, 13 h, 91%; b, BH3·SMe2, 2-methyl-2-butene, THF, 0°C, 5 h, then H2O2, NaHCO3, 85%; c, SO3·pyridine, DMSO, i-Pr2NEt, CH2Cl2, 0°C, 30 min, 91%; d, Et2Zn (1 M in hexanes), (–)-N,N-dibutylnorephedrine, toluene, 0°C → 23°C, 76 h, 94%, ds = 90:10; e, triethylsilyltrifluoromethanesulfonate, 2,6-lutidine, CH2Cl2, 0°C, 1 h, 94%; f, (MeO)2P(O)CH3, BuLi, THF, -78°C, 30 min, 96%.
Scheme 8.
Scheme 8.
Synthesis of pseudoaglycon 28. a, Ba(OH)2, 40:1 THF/H2O, 23°C, 8 h, 93% over two steps; b, 8:8:1 THF/HOAc/H2O, 23°C, 4 h, quantitative; c, (EtO)2P(O)CH2CO2H, N-ethyl, N′-(3-dimethylaminopropyl)-carbodiimide·MeI, DMAP, CH2Cl2, 23°C, 1.5 h, 98%; d, 24, Pd(PPh3)4, Tl2CO3, 3:1 THF/H2O, 2 h, 82%; e, SO3·pyridine, DMSO, i-Pr2NEt, CH2Cl2, 0°C, 30 min; f, i-Pr2NEt, LiCl, CH3CN (1 mM), 23°C, 19 h, 75%, (E)/(Z) = ≥95:5, ds = 73:12:9:6; g, Me3P (8 eq), tert-amyl alcohol (0.005 M), 23°C, 6 h, quantitative; h, (trimethylsilyl)3SiH, AIBN, dioxane, 80°C, 1.5 h; i, DDQ, CH2Cl2/pH 7 buffer, 0°C, 3 h, 73%.
Scheme 9.
Scheme 9.
Synthesis of glycosyl imidate donor 30. a, (PhO)2P(O)N3, Ph3P, diethyl azodicarboxylate, THF, 0°C, 2 h, 82%; b, K2OsO4(OH)2, (dihydroquinidine)2-pyr, K3Fe(CN)6, K2CO3, 0°C, 7.5 h, 96%, ds = 86:14; c, TBSCl, imidazole, dimethylformamide, 4 h; d, HOAc/THF/H2O (3:3:1), 23°C, 55 h, 62%; e, SO3·pyridine, DMSO, i-Pr2NEt, CH2Cl2, 0°C, 15 min, 66%; f, DDQ, CH2Cl2/pH 7 buffer, 0°C, 4 h; g, Ac2O, Et3N, DMAP, CH2Cl2; h, tetrabutylammonium fluoride, THF, 0°C, 2 h; i, Ac2O, Et3N, DMAP, CH2Cl2, 87% from 33, 1.3:1 β/α; j, ethylenediamine, HOAc, THF, 23°C, 24 h, 78%; k, 1,8-diazabicyclo[5.4.0]undec-7-ene, CH2Cl2/Cl3CCN (1:1), 0°C, 1.5 h, 5:1 β/α.
Scheme 10.
Scheme 10.
Completion of the total synthesis of (–)-spinosyn A (1). a, DDQ, CH2Cl2/pH 7 buffer, 0°C, 4 h, quantitative; b, 30 (2.1 eq), trimethylsilytrifluoromethanesulfonate (30 mol %), CH2Cl2, -78°C, 1h, 90–97%; c, guanidinium nitrate, NaOMe, MeOH, CH2Cl2, 2 h, 95%; d, SnCl2, PhSH, Et3N, THF, 15 min, 92%; e, NaBH3CN, CH2O, MeOH, HOAc, NaOAc, 87%; f, thiocarbonyldiimidazole, DMAP, Ph—CH3, 65°C, 2 h; g, Bu3SnH (25 eq), AIBN, dioxane, 100°C, 20 min, ≈35% of 1, ≈10% of 39 after HPLC.
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