Letter pubs.acs.org/OrgLett
Syntheses of Gliocladin C and Related Alkaloids Timothy R. Hodges, Noah M. Benjamin, and Stephen F. Martin*,* *
Department of Chemistry, The University of Texas, Austin, Texas 78712, United States S Supporting Information *
ABSTRACT: A unique approach to gliocladin C and related alkaloids was developed that features an unprecedented nucleophilic addition of a diketopiperazine to an isatin derivative followed by a Friedel−Crafts alkylation of the resultant tertiary alcohol with indole to set the key quaternary center. Chemoselective oxindole reduction and cyclization delivered a pivotal hexahydropyrrolo[2,3-b]indole diketopiperazine intermediate that was readily converted into (±)-gliocladin C, (±)-T988C, and (±)-gliocladine C, culminating in the shortest approach to these alkaloids reported to date.
T
ETP natural products and related derivatives exhibit significant biological activity that has been attributed, in part, to the ability of polysulfide bridges to conjugate to cysteine residues and/or generate reactive oxygen species in vivo.8−11 We now report a novel strategy for the synthesis of DKP alkaloids and its facile application to gliocladin C and related natural products. In our retrosynthetic analysis of the challenges associated with (±)-gliocladin C, we sought to avoid any potential chemical sensitivity of the trioxopiperazine moiety by unveiling the third carbonyl group at a late stage via oxidative cleavage of an enamide olefin in the penultimate intermediate 4 (Scheme 1). The N,N-aminal functionality present in 4 could be generated by a chemoselective reduction of the oxindole amide moiety in 5 followed by cyclization to form the tetracyclic ring system. The critical quaternary center in 5 would be created by a novel sequence in which the isatin 7 and the unsaturated DKP derivative 8 are first united to give 6 followed by a Friedel−Crafts-like reaction of indole with the carbocation generated by ionization of the tertiary alcohol group in 6. Although unsaturated DKP derivatives similar to 8 are well-known,12 reactions of the enamide subunits of these DKPs as nucleophilic partners do not appear to have been examined in the context of total synthesis. There was thus little precedent to support the key transformation of 7 into 5 in our synthetic plan. This uncertainty notwithstanding, we envisioned that 8 could be easily prepared from dipeptide 9. In order to test the key bond constructions that occur early in our planned approach, it was first necessary to synthesize the diketopiperazine 8 by cyclization and double dehydration of the
he hexahydropyrrolo[2,3-b]indole diketopiperazine (DKP) alkaloids are a large and diverse class of tryptophan derived natural products.1 Compounds of this family that bear an indole moiety at the C-3 position, of which a few representative members are exemplified in Figure 1, have
Figure 1. C-3 indolyl hexahydropyrrolo[2,3-b]indole diketopiperazine alkaloids.
attracted considerable attention for their complex molecular structures and their potential as anticancer, antiviral, and antibacterial agents.2−4 For example, gliocladin C (1), which was first isolated in 2004 by Usami and co-workers, exhibits potent cytotoxic effects in P388 lymphocytic leukemia cells in vitro with a reported EC50 value of 2.4 μg/mL.5,6 Although the core skeletal framework in 1 is common to other DKP alkaloids, it uniquely contains a trioxopiperazine moiety that is not found in any other alkaloid in this family. Given its status as an archetypal member of the DKP family, gliocladin C has been the focus of numerous synthetic efforts, and these efforts have culminated in five total syntheses and several formal approaches to 1.7 Moreover, Overman and co-workers have nicely shown that gliocladin C can be used as a key intermediate in the syntheses of several related epipolythiodiketopiperazine (ETP) alkaloids, including T988C (2) and gliocladine C (3).8,9 These © 2017 American Chemical Society
Received: March 14, 2017 Published: April 17, 2017 2254
DOI: 10.1021/acs.orglett.7b00735 Org. Lett. 2017, 19, 2254−2257
Letter
Organic Letters Scheme 1. Retrosynthetic Analysis of Gliocladin C
Scheme 3. Synthesis of (±)-Gliocladin C
serine-derived dipeptide 9. Examination of the literature quickly revealed that this task would be somewhat cumbersome and lengthy because selective N-monomethylation of serine is typically achieved by multistep procedures via alkylation of Nbenzylated intermediates or by reduction of substituted oxazolidinones.13 Accordingly, we developed a more direct route (Scheme 2) based upon the known conversions of available, completed this facile, one-pot operation and delivered the addition product 15 as a single regioisomer and diastereomer in 83% yield. To our knowledge, this is the first time a dehydro DKP has been used as a nucleophilic partner in a reaction with an isatin derivative. Creation of the quaternary center required trapping the stabilized carbocation intermediate formed upon ionization of the tertiary alcohol group in 15 with indole as a π-nucleophile.16 After some experimentation, we discovered that the O-silylated derivative of 15, which was generated in situ, underwent facile ionization and reaction with indole in the presence of excess TMSOTf to deliver 16 as a single diastereomer in 86% yield.17 Notably, no regioisomeric products arising from reaction at other nucleophilic carbon atoms of indole were observed.7d From the outset, we realized that selective reduction of the oxindole carbonyl moiety in 16 and cyclization to provide 17 might prove challenging owing to the presence of other reducible functional groups. Indeed, many common amide reducing reagents such as LiAlH4, DIBAL, and Red-Al offered no selectivity for the oxindole carbonyl group.18 We eventually discovered that reaction of 16 with BF3·OEt2 followed by rapid addition of AlH3·NEtMe2 furnished 17 in 54% yield. To our knowledge this is the first example of the use of alane in combination with a strong Lewis acid to achieve selective reduction of a lactam carbonyl group. Catalytic removal of the N-allyl protecting group using N,N-dimethylbarbituric acid (DMBA) as an allyl scavenger delivered 4 in 94% yield. Cleavage of the exocyclic methylene group in 4 to give (±)-gliocladin C (1) could be achieved by either a one- or twostep protocol, the latter of which was cleaner and more efficient overall. For example, reaction of 4 with KMnO4 in a mixture of acetone and acetic acid (20:1) furnished 1 in 48% yield.19 Alternatively, dihydroxylation of 4 under Upjohn-like conditions followed by oxidative cleavage of the resultant vicinal diol with Pb(OAc)4 in pyridine afforded (±)-gliocladin C in 67% yield over two steps.20
Scheme 2. Synthesis of Cyclodipeptide 13
oxazolidines to N-alkylated β-alcohols by reduction.14 In the event, oxazolidine 10, which is commercially available or easily accessible in a single pot from L-serine, was converted to the known dipeptide derivative 12 in 86% yield by an improved procedure that involved reaction with isobutylchloroformate to form a mixed anhydride that was coupled in situ with serine methyl ester hydrochloride (11) in the presence of N-methyl morpholine (NMM) (Scheme 2).15 Simultaneous catalytic reduction and hydrogenolysis (H2, 10% Pd/C) of 12 in the presence of hydrochloric acid followed by treatment with aqueous ammonium hydroxide furnished the desired DKP 13 in 87% yield and only two chemical operations from compound 10. With 13 in hand, the stage was set to test the feasibility of our approach to the C-3 indolyl hexahydropyrrolo[2,3-b]indole DKP alkaloid framework. Reaction of 13 with MsCl in the presence of Hünig’s base afforded a putative bis-mesylated intermediate that underwent facile double elimination to furnish 8 in situ upon exposure to DBU (Scheme 3). Subsequent addition of N-allyl isatin 14, which is commercially 2255
DOI: 10.1021/acs.orglett.7b00735 Org. Lett. 2017, 19, 2254−2257
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Organic Letters
access to 4 also enabled the shortest syntheses reported to date of (±)-T988C (2) and (±)-gliocladine C (3),8,23 with each requiring only 13 transformations and proceeding in 7.9% and 4.7% overall yields, respectively. This novel and efficient approach to gliocladin C may be easily adapted for the syntheses of a number of DKP alkaloids and their derivatives for further investigation as potential anticancer agents.
It is noteworthy that compound 4 is well suited as a pivotal intermediate in the syntheses of several other ETP natural products. For example, reaction of 4 with Boc anhydride in the presence of catalytic DMAP furnished 18 in 98% yield (Scheme 4). Inasmuch, as 18 was transformed by Overman to T988C in six steps and 30% overall yield,8 the preparation of 18 completes a synthesis of (±)-T988C in a formal sense.
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Scheme 4. Synthesis of (±)-T988C
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00735. Experimental procedures, spectroscopic data, and scans of NMR spectra (PDF)
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In another example showcasing the utility of 4 as a versatile intermediate, regioselective hydration of the less-substituted enamide in 4 using Mukaiyama conditions21 furnished 19 in 82% yield as a mixture (∼1:1) of diastereomers (Scheme 5). Silylation of 19 followed by global Boc protection provided 20 as a mixture (∼3:2) of diastereomers in 62% yield. Overman has previously converted 20 into gliocladine C (3) via a fourstep sequence in approximately 34% yield, 8,22 so the preparation of 20 from 4 represents a formal synthesis of (±)-gliocladine C (3).
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Stephen F. Martin: 0000-0002-4639-0695 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Robert A. Welch Foundation (F-0652) for generous support of this research.
Scheme 5. Synthesis of (±)-Gliocladine C
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We have developed a general entry to C-3 indolyl hexahydropyrrolo[2,3-b]indole diketopiperazine alkaloids and applied it to the syntheses of (±)-gliocladin C (1), (±)-T988C (2), and (±)-gliocladine C (3) from the common intermediate 4. The assembly of 4 features several notable steps. For example, the oxazolidine moiety in 10 serves as a useful surrogate of N-methyl serine in a short synthesis of the unsaturated DKP 8. The key quaternary center in these alkaloids is formed in a novel two-step sequence that features reaction of 8 with an isatin derivative to produce 15 that undergoes facile ionization and nucleophilic capture by indole to give 16 in only two chemical operations from 13. A remarkably chemoselective reductive ring closure of 16 followed by catalytic removal of the N-allyl group gives 4. The enamide olefin of 4 then provides a critical functional handle for further extrapolation to the alkaloids 1−3. This strategy led to the most concise synthesis of (±)-gliocladin C (1) reported to date, requiring only 8 steps and proceeding in 18.2% overall yield from commercially available 10. Efficient 2256
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