Enantioselective Total Synthesis of (+)-Gliocladine C. A Convergent Construction of Cyclotryptamine-Fused Polyoxopiperazines and a General Approach for Preparing Epidithiodioxopiperazines from Trioxopiperazine Precursors

Abstract

A concise second-generation total synthesis of the fungal-derived alkaloid (+)-gliocladin C (11), in ten steps and 11% overall yield from isatin, is reported. In addition, the ETP natural product (+)-gliocladine C (6) is prepared in six steps and 29% yield from the di-(tert-butoxycarbonyl) precursor of 11. The total synthesis of (+)-gliocladine C (6) constitutes the first total synthesis of an ETP natural product containing a hydroxyl substituent adjacent to a quaternary carbon stereocenter in the pyrrolidine ring.

Epipolythiodioxopiperazine (ETP) toxins are fungal secondary metabolites that possess unique molecular structures and a wide range of biological activities (Figure 1).¹ The toxicity of these amino acid-derived natural products is attributed to the di- or polysulfide bridge of the dioxopiperazine subunit, which either can directly conjugate to cysteine residues or generate reactive oxygen species. A number of recent studies point to the potential utility of epidithiodioxopiperazines in cancer chemotherapy,² as impressive selectivity towards both myeloma³ and solid tumors⁴ has been demonstrated and novel molecular targets have been identified.⁵ The structure and chemical lability of epipolythiodioxopiperazines pose a number of challenges for chemical synthesis. In a remarkable accomplishment, Fukuyama and Kishi disclosed the total synthesis of gliotoxin (1) in 1976,⁶ with the chemistry developed in these investigations for incorporating an epidithiodioxopiperazine unit⁷ being subsequently used for the synthesis of various other ETP natural products.⁸ In an incisive total synthesis of dideoxyverticillin A (2) reported in 2009 by Movassaghi and co-workers, biosynthetically inspired oxidation of cyclotryptamine-fused dioxopiperazines and sulfidation was employed to elaborate epidithio bridges onto dimeric dioxopiperazine precursors.^9,10 Shortly thereafter, Sodeoka and co-workers reported the synthesis of (+)-chaetocin A (3) using a related strategy for forging the epidithiodioxopiperazine units.¹¹

Figure 1.

Some ETP natural products.

The largest group of ETP natural products is derived from tryptophan and contains an ETP ring fused to a cyclotryptamine fragment. (Figure 1).¹ In many of these structures, the carbon of the pyrrolidine ring adjacent to the quaternary carbon stereocenter bears a hydroxyl substituent (e.g., 4–10, Figure 1). Herein we disclose a general approach for preparing ETPs having this highly labile hydroxyl substituent,¹² which we illustrate by an enantioselective total synthesis of gliocladine C (6).^13,14 Critical to our success was the development of a new convergent method for constructing cyclotryptamine-fused polyoxopiperazines.

Our approach for preparing (+)-gliocladine C (6) and congeners is outlined in Scheme 1. We hypothesized that the simpler alkaloid (+)-gliocladin C (11)¹⁵ might serve as a synthetic precursor of this family of ETPs by three potentially straightforward transformations: i) nucleophilic addition of a C3 substituent¹⁶ to the α-ketoimide carbonyl group, ii) dihydroxylation of the alkylidene dioxopiperazine double bond, and iii) disulfide bridge formation.

Scheme 1.

Retrosynthetic Analysis of ETPs 6–10

The opening phase of this endeavor was the development of an efficient second-generation total synthesis of (+)-gliocladin C (11), whose first total synthesis was reported from our laboratory in 2007.¹² Our plan was to assemble the tetracyclic core of (+)-gliocladin C from the union of enantioenriched dielectrophile 12 and dinucleophile 13,¹⁷ with the quaternary carbon stereocenter of the former arising from catalytic enantioselective Steglich-type rearrangement of indolyl carbonate 14.^18,19

The synthesis of (+)-gliocladin C commenced with acid-promoted ionic reduction of readily available 3-hydroxy-3,3′-biindolin-2-one 15,²⁰ followed by Boc protection to give intermediate 16 (Scheme 2).²¹ Reaction of oxindole 16 with 2,2,2-trichloro-1,1-dimethylethyl chloroformate and Et₃N delivered prochiral indolyl carbonate 17 in 66% overall yield from biindolinone 15. Catalytic rearrangement of 17 took place efficiently and with high enantioselectivity at room temperature in the presence of 5 mol % of Fu’s (S)-(−)-4-pyrrolidinopyrindinyl(pentamethylcyclopentadienyl)iron catalyst^19a to give 3,3-disubstituted oxindole 18 in 96% yield and a 98:2 enantiomer ratio (er) on scales up to 15 g. In addition, direct reaction of oxindole 16 with 2,2,2-trichloro-1,1-dimethylethyl chloroformate, Et₃N, and 10 mol % of Fu’s catalyst at 40 °C provided oxindole ester 18 in 88% yield and identical high enantioselectivity (er = 98:2).

Scheme 2.

Preparation of Enantioenriched Dielectrophile 20^a

^a Reaction conditions: (a) TFA, Et₃SiH, CH₂Cl₂, rt; (b) i. (Boc) ₂O, 15 mol % DMAP, CH₂Cl₂, rt; ii. MeOH (68% from 15); (c) 2,2,2-trichloro-1,1-dimethylethylchloroformate, Et₃N, THF, 0 °C (97%); (d) (S)-(−)-4-pyrrolidinopyridinyl(pentamethylcyclopentadienyl)-iron, THF, rt (96%, 98:2 er); (e) 2,2,2-trichloro-1,1-dimethylethylchloroformate, Et₃N, (S)-(−)-4-pyrrolidinopyridinyl(pentamethylcyclopentadienyl)iron, THF, 40 °C (88%, 98:2 er); (f) NaBH₄, MeOH, 0 °C (81%); (g) HC(OMe) ₃, 10 mol % PPTS, MeOH, 65 °C (83%; 1.2:1.0 dr); (h) LiBH₄–MeOH, Et₂O, rt to 40 °C (84%); (i) Dess–Martin periodinane, pyridine, CH₂Cl₂, rt (95%).

After several shorter approaches proved inefficient or resulted in partial racemization,²² oxindole 18 was elaborated to indoline 20 in good yield as follows. The oxindole carbonyl group of 18 was reduced selectively with NaBH₄ at 0 °C, and the resulting 2-hydroxyindoline intermediate was exposed to a methanolic solution of trimethyl orthoformate and a catalytic amount of pyridinium p-toluenesulfonate (PPTS) at 65 °C to afford indoline N,O-acetal 19, a 1.2:1.0 mixture of α and β-N,O-acetal epimers, in 67% overall yield. Sequential Soai reduction,²³ and Dess–Martin oxidation²⁴ provided enantioenriched dielectrophile 20 in 80% yield from 19.

In two additional steps, indoline aldehyde 20 was united with trioxopiperazine derivative 21 to provide (+)-gliocladin C (11) (Scheme 3). Aldol condensation of aldehyde 20 with the lithium enolate of piperazinedione 21²⁵ in THF at −78 °C, followed by quenching the reaction with excess acetic acid and warming to room temperature delivered condensation product 22, as exclusively the Z stereoisomer, in 75% yield. Exposure of 22 to BF₃·OEt₂ at −40 °C promoted cyclization and concomitant demethylation to provide trioxopiperazine-fused cyclotryptamine 23 in 80% yield. The Boc protecting groups of 23 were then removed thermolytically²⁶ to afford crystalline (+)-gliocladin C (11) in 89% yield. Alternately, coupled intermediate 22 could be transformed directly to (+)-gliocladin C (11), [α]²³_D +127 (c 0.23, pyridine),²⁷ in 60% yield upon reaction with excess Sc(OTf)₃ in acetonitrile at 0 °C to room temperature. Single-crystal X-ray diffraction of synthetic (+)-gliocladin C (11) confirmed the constitution and relative configuration of this natural product.²⁸

Scheme 3.

Second-Generation Synthesis of (+)-Gliocladin C (11)^a

^a Reaction conditions: (a) i. LDA, 21, THF, −78 °C; ii. 20, −78 °C; iii. AcOH, −78 °C to rt (75% from 20); (b) BF₃·OEt₂, CH₂Cl₂, −78 to −40 °C (80%); (c) neat, 175 °C (89%); (d) Sc(OTf) ₃, MeCN, 0 °C to rt (60%).

With substantial quantities of trioxopiperazine-fused pyrrolidinoindoline 23 in hand, we turned to its transformation to (+)-gliocladine C (6) (Scheme 4). Chemoselective addition²⁹ of methylmagnesium chloride to trioxopiperazine 23 at −78 °C provided a 9:1 mixture of epimeric tertiary alcohols, which was silylated to give dioxopiperazine 24, a 3:2 mixture of siloxy epimers, in 81% overall yield. Although it was most convenient to prepare ETP product 27 directly from this mixture of stereoisomers (see below), insight into the dihydroxylation step was obtained when epimers 24a and 24b were separated and individually examined. As summarized in Scheme 4, catalytic dihydroxylation of the minor siloxy epimers was highly substrate controlled yielding α diol 25 with 20:1 diasteroselectivity using OsO₄/NMO, AD-Mix-α or AD-Mix-β.³⁰ Although no diasteroselectivity was observed in dihydroxylation of the major epimer 24a with OsO₄, diastereoselection in forming the α-diol product was improved to 14:1 using AD-Mix-α. Employing this oxidant, the initially produced 3:2 mixture of siloxy epimers 24 was dihydroxylated and the crude diol products acetylated to provide diacetates 26 in 76% yield over the two steps.^30b,31 Reaction of this mixture of siloxy epimers with condensed hydrogen sulfide and BF₃·OEt₂ in CH₂Cl₂ at −78 °C to room temperature,³² followed by exposure of the product to oxygen, delivered ETP product 27 in 62% yield.^33,34 We speculate that stereoselection in this step is the result of initial iminium ion formation at C11a, followed by kinetically controlled trapping with H₂S from the face opposite both the angular indolyl substituent and the adjacent acetate.

Scheme 4.

Synthesis of (+)-Gliocladine C (6)^a

^a Reaction conditions: (a) MeMgCl, THF, −78 ºC (86%, 9:1 dr); (b) TBSOTf, DMAP, Et₃N, DMF, rt (94%, 3:2 dr); (c) mixture of 24a and 24b (3:2), AD-Mix-α, H₂NSO₂Me, K₂OsO₄·2H₂O, (DHQ) ₂PHAL, t-BuOH/H₂O/acetone, rt (82%, >14:1 dr); (d) Ac ₂O, DMAP, CH₂Cl₂, rt (93%); (e) i. H₂S, BF₃·OEt ₂, CH₂Cl₂, −78 ºC to rt; ii. O₂, MeOH/EtOAc, rt (62%); (f) La(OTf)₃, MeOH, 40 ºC (75%).

At this stage, all that remained was removal of the acetate and this transformation was accomplished by heating ETP intermediate 27 in a methanolic solution of La(OTf)₃ at 40 °C,³⁵ which gave (+)-gliocladine C (6) as a colorless amorphous solid in 75% yield. The optical rotation of synthetic 6, [α]²³_D +505 (c 0.47 pyridine), compared well with the value reported for the natural sample, [α]^18.7_D +513 (c 0.33, pyridine), as did spectroscopic data.

In conclusion, the total synthesis of (+)-gliocladine C (6) constitutes the first total synthesis of an ETP natural product containing hydroxy substitution in the pyrrolidine ring. Moreover, the total syntheses of (+)-gliocladin C (11) and (+)-gliocladine C (6) disclosed herein showcase two short synthetic sequences that we expect will find broader utility. First, the assembly of (+)-gliocladin C (11) from enantioenriched aminal aldehyde 20 and dioxopiperazine derivative 21 illustrates a convergent construction of oxopiperazine-fused pyrrolidinoindolines that can be employed to access more widely distributed dioxopiperazine variants. Second, the construction of epidithiodioxopiperazine alkaloid (+)-gliocladine C (6) from trioxopiperazine precursor 23 illustrates a sequence wherein diversity in the dioxopiperazine unit of an ETP product can be introduced at a late stage in a synthetic sequence.