Concise Total Synthesis of (+)-Gliocladins B and C

Abstract

The first total synthesis of (+)-gliocladin B is described. Our concise and enantioselective synthesis takes advantage of a new regioselective Friedel-Crafts-based strategy to provide an efficient multigram-scale access to the C3-(3'-indolyl)hexahydropyrroloindole substructure, a molecular foundation present in a significant subset of epipolythiodiketopiperazine natural alkaloids. Our first-generation solution to (+)-gliocladin B involved the stereoselective formation of (+)-12-deoxybionectin A, a plausible biosynthetic precursor. Our synthesis clarified the C15 stereochemistry of (+)-gliocladin B and allowed its full structure confirmation. Further studies of a versatile dihydroxylated diketopiperazine provided a concise and efficient synthesis of (+)-gliocladin B as well as access to (+)-gliocladin C.

Fig. 1

Representative natural C3-(3′-indolyl)hexahydropyrroloindole alkaloids.

Scheme 1

Retrosynthetic analysis of (+)-gliocladin B (1), (+)-gliocladin C (4), and (+)-12-deoxybionectin A (11).

Scheme 2

First-generation total synthesis of (+)-gliocladin B (1). Reagents and conditions: (a) Br₂, CH₂Cl₂, 0 °C (75%); (b) AgBF₄, DTBMP, EtNO₂, 0 °C (83%, 5g-scale); (c) H₂, Pd/C, NEt₃, MeOH, EtOAc, 23 °C; Et₃N•3HF, 23 °C (100%); (d) n-Bu₄NMnO₄, CH₂Cl₂, 23 °C (41%); (e) H₂S, TFA–CH₂Cl₂ (1:9 v/v), 0 °C; i-PrCOCl, pyr, CH₂Cl₂, 0→23 °C (82%, 2-steps); (f) hν (350 nm), 1,4-dimethoxynaphthalene, ascorbic acid, sodium ascorbate, H₂O, MeCN, 25 °C (57%); (g) N₂H₄, THF, 0 °C; Ph₃CSCl, NEt₃, THF, 0 °C (81%, 2-steps); (h) Hf(OTf)₄, MeCN, 23 °C (80%); (i) NaBH₄, MeI, pyr, MeOH, 23 °C (80%); DTBMP = 2,6-di-tert-butyl-4-methylpyridine, TFA = trifluoroacetic acid, i-PrCOCl = isobutyryl chloride, pyr = pyridine.

Scheme 3

Second-generation total synthesis of (+)-gliocladin B (1). Reagents and conditions: (a) MeSNa, TFA–MeNO₂ (1:1 v/v), 0→23 °C (77%); (b) hν (350 nm), 1,4-dimethoxynaphthalene, ascorbic acid, sodium ascorbate, H₂O, MeCN, 25 °C (88%).

Scheme 4

Total synthesis of (+)-gliocladin C (4). Reagents and conditions: (a) TIPSCl, DMAP, CH₂Cl₂, 23 °C (95%); (b) hν (350 nm), 1,4-dimethoxynaphthalene, ascorbic acid, sodium ascorbate, H₂O, MeCN, 25 °C (92%); (c) TFAA, DTBMP, MeCN, 23 °C (88%); (d) (HF)•pyr, THF, 23 °C; (e) IBX, DMSO, 23 °C; (f) AcOH, H₂O, acetone, 23 °C (54%, 3-steps); TIPSCl = triisopropylsilyl chloride, DMAP = 4-(dime-thylamino)pyridine, TFAA = trifluoroacetic anhydride, IBX = o-iodoxybenzoic acid.