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. 2012 Jan 1;3(6):1798-1803.
doi: 10.1039/C2SC20270K. Epub 2012 Mar 30.

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

Nicolas Boyer  1 , Mohammad Movassaghi
Affiliations

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

Nicolas Boyer et al. Chem Sci. .

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.

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Figures

Fig. 1
Fig. 1
Representative natural C3-(3′-indolyl)hexahydropyrroloindole alkaloids.
Scheme 1
Scheme 1
Retrosynthetic analysis of (+)-gliocladin B (1), (+)-gliocladin C (4), and (+)-12-deoxybionectin A (11).
Scheme 2
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
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
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.
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