The convergent total synthesis of cryptophycins C and D is described. It has been shown that in both natural products the absolute configuration of the a-amino acid corresponds to the D-series. The structural assignment for cryptophycin C has been corrected to reflect this fact. Since the structure of cryptophycin A has been correlated to cryptophycin C, the chloro-0-methyltyrosine unit in cryptophycin A has the D-configuration.Cryptophycins are potent tumor-selective cytotoxins associated with the terrestrial blue-green algae Nostoc sp. GSV 224' and Nostoc sp. ATCC 53789.2 The major cytotoxin in each alga, cryptophycin A, shows excellent activity against solid tumors implanted in mice, including a drug-resistant tumor. Over 20 related cytotoxins are present in the GSV 224 strain as minor constituent^,'^^ and some of these compounds, e.g., cryptophycins B and C, have been isolated in sufficient amounts for in vivo e~aluation.~ In order to acquire adequate quantities of selected naturally-occurring cryptophycins and synthetic analogs for structure-activity relationship (SAR) studies, preclinical evaluation, and human clinical trials, we have designed a general synthesis. Cryptophycins C and D, as described in the original paper, were chosen to be the initial targets as they represented examples from both of the alleged L-and D-tyrosine series. We report here the total syntheses of cryptophycins C and D which (1) revise the structures of cryptophycins A and C to reflect the D-configuration for the a-amino acid unit as depicted in the structural drawings in this paper and (2) confirm the structures of cryptophycins B and D.Retrosynthetic analysis of the cryptophycins was straightforward: the structure is composed of four units (A-D, Figure 1); consequently several convergent approaches could be envisioned. The combination of two pairs of units (e.g., A-B and C-D) appeared to be optimally convergent. Since the success of the synthesis depended on the formation of a 16-membered depsipeptide from an acyclic precursor, a macrolactamization involving the amino group of unit C and the carboxylate of unit B appeared to be the best choice. The acyclic precursor to cryptophycin D would therefore be 1. This, in turn, suggested a disconnection into two fragments, one represented by 2 and composed of (S)-( -)-2-hydroxy-4-methylvaleric (L-leucic) acid (D) and (R)-3-amino-2-methylpropanoic acid (C) units, and the other by 3 and composed of O-methyl-D-tyrosine (B) and (2E,7E,5S,6R)-5-hydroxy-6-methyl-8-phenyloctadienoic acid (A) units. In the direction of the synthesis, @ Abstract published in Advance ACS Absfracts, February 15, 1995. (1) Trimurtulu, G.; Ohtani, I.; Patterson, G. M. L.; Moore, R. E.; Corbett, T. H.; Valeriote, F. A.; Demchik, L. J. Am. Chem. SOC. 1994, 116, 4729-4731. (2) Schwartz, R. E.; Hirsch, C. F.; Sesin, D. F.; Flor, J. E.; Chartrain, M.; Fromtling, R. E.; Harris, G. H.; Salvatore, M. J.; Liesch, J. M.; Yudin, K. J. Ind. Microbiol. 1990, 5, 113-24. (3) Trimurtulu, G.; Ogino, J.; Heltzel, C. E.; Patterson, G...

The variant of the Nazarov cyclization that makes use of allenyl ethers is suitable for the preparation of diverse, highly functionalized cyclopentenones. Three variants of the basic reaction, differing in the nature of the electrophile that is combined with the allene to prepare the precursor for the pentadienyl cation, are described. One variant, which utilizes an alpha,beta-unsaturated morpholino amide, has been successfully employed in an enantioselective version of the cyclopentannelation.

The cannabinoid side chain is a key pharmacophore in the interaction of cannabinoids with their receptors (CB1 and CB2). To study the stereochemical requirements of the side chain, we synthesized a series of cannabinoids in which rotation around the C1'-C2' bond is blocked. The key steps in the synthesis were the cuprate addition of a substituted resorcinol to (+)-apoverbenone, the TMSOTf-mediated formation of the dihydropyran ring, and the stereospecific introduction of the beta-11-hydroxymethyl group. All the analogs tested showed nanomolar affinity for the receptors, the cis-hept-1-ene side chain having the highest affinity for CB1 (Ki = 0.89 nM) and showing the widest separation between CB1 and CB2 affinities. The parent n-heptyl-beta-11-hydroxyhexahydrocannabinol was the least potent binding to CB1 (Ki = 8.9 nM) and had the lowest selectivity between CB1 and CB2.

STAT3 offers an attractive target for cancer therapy but small molecule inhibitors with appealing pharmacologic properties have been elusive. Here we report hydroxamic acid-based and benzoic acid-based inhibitors (SH5-07 and SH4-54, respectively) with robust bioactivity. Both inhibitors blocked STAT3 DNA binding activity in vitro and in human glioma, breast, and prostate cancer cells and in v-Src-transformed murine fibroblasts. STAT3-dependent gene transcription was blocked along with Bcl-2, Bcl-xL, Mcl-1, Cyclin D1, c-Myc and Survivin expression. Nuclear magnetic resonance analysis of STAT3-inhibitor complexes defined interactions with the SH2 and DNA binding domains of STAT3. Ectopic expression of the SH2 domain in cells was sufficient to counter the STAT3 inhibitory effects of SH4-54. Neither compound appreciably affected STAT1 or STAT5 DNA binding activities, STAT3-independent gene transcription or activation of a panel of oncogenic kinases in malignant cells. Each compound decreased the proliferation and viability of glioma, breast and prostate cancer cells and v-Src-transformed murine fibroblasts harboring constitutively active STAT3. Further, in mouse xenograft models of glioma and breast cancer, administration of SH5-07 or SH4-54 effectively inhibited tumor growth. Our results offer preclinical proof of concept for SH5-07 and SH4-54 as candidates fof further development as cancer therapeutics.

No abstract

The enantiospecific total synthesis of natural roseophilin has been completed in 7.0% overall yield over 15 steps by means of an asymmetric cyclopentannelation. This establishes the absolute configuration of the natural product as 22R,23R. Cyclopentenone (+)-12 was prepared in 78% yield and 86% ee in the key step.

The Nazarov cyclization is a 4π-electron conrotatory cyclization of a pentadienyl cation that leads to a five-membered ring, typically a cyclopentenone. Because the mechanism is well defined, it is often possible to make accurate and useful stereochemical predictions regarding the course of the reaction. Because the reaction intermediates are carbocations, it is also possible to devise tandem processes whereby the initial cyclization is followed by one or more C-C bond forming

An organocatalytic asymmetric Nazarov cyclization of diketoesters has been developed that proceeds by means of a dual activation mechanism. Screening of a number of catalysts led to a new thiourea that incorporates a primary amino group. The method gives rise to cyclic products with two adjacent quaternary asymmetric carbon atoms, one of which is an all carbon atom stereocenter, with complete or nearly complete diastereoselectivity, and in high or very high enantiomeric excess. A brief and very convenient synthesis of the acyclic diketoester starting materials through nucleophilic addition to a ketene has been described.In earlier work we have described cyclizations of α-ketoenones under a variety of mild reaction conditions. For example, ketoenone 1 can be converted to α-hydroxycyclopentenone 2 in 71% yield by exposure to silica gel and triethylamine in the absence of solvent at room temperature (eq 1).1 Alternatively, treatment of 1 with lithium tetramethylpiperidide or with Yb(OTf) 3 and pyrrolidine leads to 2 in 71% and 63% yield, respectively.2 There are earlier examples of diketone cyclizations that lead to α-hydroxycyclopentenones that may may proceed through a similar mechanism. For example, in 1975 Weinreb and Auerbach, inspired by an observation published in 1965 by Muxfeldt and coworkers,3 described the cyclization of diketone 3 to 4 under the influence of Mg(OMe) 2 during their synthesis of cephalotaxine (eq 2).4 , 5 Both Muxfeldt andCorrespondence to: Marcus A. Tius, tius@hawaii.edu. Supporting Information Available: Detailed experimental and spectroscopic data and reproductions of 1 H and 13 C NMR data for 18-30, and of the intermediates leading to 18-30. X-ray structure of the (−)-camphanic acid derivative of 19. This material is available free of charge via the Internet at http://pubs.acs.org. Weinreb described the cyclization as an intramolecular Michael reaction of a chelated magnesium enolate. Moreover, both groups noted that the cyclization did not proceed in the absence of Lewis acidic metal species. Although we cannot rule out the intramolecular Michael addition, we have described our reactions as Nazarov cyclizations6 for two reasons. First, the intramolecular Michael addition is a forbidden 5-endo-trig process7 and second, many of our cyclizations are favored by enolate substitution, whereas steric encumbrance of the nucleophile would be expected to inhibit a Michael reaction. NIH Public AccessA longstanding goal in our group has been to develop a useful asymmetric organocatalytic Nazarov cyclization of α-ketoenones.8 , 9 Many Nazarov cyclizations require strongly acidic conditions, but the mild conditions for the cyclizations of 1 gave us reason to believe that an organocatalytic process could be developed. Our first iminium ion-mediated Nazarov cyclization of α-ketoenones proceeded via exposure of 1 to stoichiometric diamine triflate 5 to give (S)-2 in 60% yield and 97/3 er (eq 3).10 The reaction was slow (7.5 d) and a catalytic cycle was not established, presumably due to the e...