The potent cytotoxins pederin and psymberin have been prepared through concise synthetic routes (10 and 14 steps in the longest linear sequences, respectively) that proceed via a late-stage multicomponent approach to construct the N-acyl aminal linkages. This route allowed for the facile preparation of a number of analogs that were designed to explore the importance of the alkoxy group in the N-acyl aminal and functional groups in the two major subunits on biological activity. These analogs, including a pederin/psymberin chimera, were analyzed for their growth inhibitory effects, revealing several new potent cytotoxins and leading to postulates regarding the molecular conformational and hydrogen bonding patterns that are required for biological activity. Second generation analogs have been prepared based on the results of the initial assays and a structure-based model for the binding of these compounds to the ribosome. The growth inhibitory properties of these compounds are reported. These studies show the profound role that organic chemistry in general and specifically late-stage multicomponent reactions can play in the development of unique and potent effectors for biological responses.

Adjacent quaternary and tertiary stereocenters as in structure 1 are common structural motifs in complex natural products. In principle, the stereocontrolled conjugate addition of a prochiral trisubstituted carbon nucleophile to a prochiral bsubstituted Michael acceptor with a chiral catalyst could provide a one-step construction of such highly congested motifs from simple precursors [Eq. (1)]. However, this requires the catalyst to impart both high enantioselectivity and diastereoselectivity in a sterically demanding, intermolecular CÀC bond formation that simultaneously creates both the quaternary and tertiary stereocenters. This task has proven to be a formidable challenge. Among numerous literature examples, [1][2][3] to our knowledge there are only two catalytic asymmetric conjugate additions that afford the 1,4-adducts containing adjacent carbon-substituted quaternary and tertiary stereocenters in excellent enantioselectivity and with a diastereomeric ratio (d.r.) of greater than 10:1 for a substantial number of trisubstituted carbon Michael donors.[2]Herein, we report an asymmetric conjugate addition mediated by a chiral bifunctional organocatalyst that affords high enantioselectivity and diastereoselectivity for several structurally distinct classes of trisubstituted carbon nucleophiles. This reaction allows the direct and stereocontrolled construction of a wide variety of adjacent carbon-or heteroatomsubstituted quaternary and tertiary stereocenters.Readily accessible cinchona alkaloids 2 have been identified recently as effective catalysts for the enantioselective conjugate addition of dimethyl malonate and ethyl acetoacetate to nitroalkenes. [4,5] These results prompted us to examine

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The aldehyde is arguably the most versatile carbonyl functionality. Furthermore, it is more active than any other carbonyl functionality toward a plethora of nucleophilic reactions. This unique combination of functional versatility and activity renders chiral aldehydes highly valuable intermediates in asymmetric synthesis. The emergence of numerous catalytic enantioselective reactions that involve aldehydes as either nucleophiles or electrophiles further enhances the synthetic value of chiral aldehydes. Enantioselective transformations of the readily available prochiral aldehydes are now emerging as a fundamentally important approach toward optically active aldehydes. In particular, great strides have been made in the development of enantioselective bond formations with the a-carbon atom of prochiral aldehydes with chiral enamine catalysis, [1,2] enantioselective cycloadditions and Friedel-Crafts reactions with chiral immonium catalysis, [3] and conjugate additions of aryl boronic acids and silyl nitronates to a,b-unsaturated aldehydes by chiral transition-metal catalysis [4] and chiral phase-transfer catalysts, [5] respectively. Despite its synthetic importance, the highly enantioselective and general conjugate addition of carbonyl donors to a,b-unsaturated aldehydes remains elusive, even with considerable efforts. [6][7][8] Herein, we wish to report significant progress toward the development of such a reaction with cinchona-alkaloid-derived organic catalysts.At the outset of our investigations, we were concerned that the decomposition of 3 a could be triggered by cinchona alkaloids as nucleophilic catalysts (Scheme 1) in light of the well-documented nucleophilic catalysis of 1,4-diazabicyclo-[2.2.2]octane (DABCO) and quinuclidine in the MoritaBaylis-Hillman (MBH) reaction.[9] Indeed, 3 a was found to rapidly undergo decomposition to form insoluble oligomers or polymers in the presence of DABCO, quinuclidine, or bisocupreidine. On the other hand, mechanistic studies by us established that cinchona alkaloids, such as dihydroquinidine

Complementary to enantioselective transformations of planar functionalities, catalytic desymmetrization of meso compounds is another fundamentally important strategy for asymmetric synthesis. However, experimentally established stereochemical models on how a chiral catalyst discriminates between two enantiotopic functional groups in the desymmetrization of a meso substrate are particularly lacking. This article describes our endeavor to elucidate the chemical mechanism and characterization of the active conformation of the cinchona alkaloid-derived catalyst for a desymmetrization of meso cyclic anhydrides via asymmetric alcoholysis. First, our kinetic studies indicate that the cinchona alkaloid-catalyzed alcoholysis proceeds by a general base catalysis mechanism. Furthermore, the active conformer of the cinchona alkaloid-derived catalyst DHQD-PHN was clarified by catalyst conformation studies with a designed, rigid cinchona alkaloid derivative as a probe. These key mechanistic insights enabled us to construct a stereochemical model to rationalize how DHQD-PHN differentiates the two enantiotopic carbonyl groups in the transition state of the asymmetric alcoholysis of meso cyclic anhydrides. This model not only is consistent with the sense of asymmetric induction of the asymmetric alcoholysis but also provides a rationale on how the catalyst tolerates a broad range of cyclic anhydrides. These mechanistic insights further guided us to develop a novel practical catalyst for the enantioselective alcoholysis of meso cyclic anhydrides.cinchona alkoloid | desymmetrization | organocatalysis | general base catalysis | hydrogen bonding C omplementary to enantioselective transformations of planar functionalities, catalytic desymmetrization of meso compounds is another fundamentally important strategy for asymmetric synthesis (1-5). However, our understanding of how a chiral catalyst discriminates between two enantiotopic functional groups in a meso substrate at the molecular level is particularly lacking. Our group reported a desymmetric alcoholysis of a wide range of meso cyclic anhydrides with modified cinchona alkaloids to generate highly enantiomerically enriched hemiesters (5-10). Thus, we have initiated mechanistic studies to investigate how the modified cinchona alkaloids are able to efficiently differentiate the two enantiotopic carbonyl groups while tolerating variations of the substituents of the anhydrides. Herein we describe the experimental results that have enabled us to construct a transition state model to answer these mechanistic questions and to develop a practical catalyst guided by insights gained from our mechanistic studies. Results and DiscussionIn order to shed light on the origin of the catalytic activity on the enantioselective alcoholysis of meso cyclic anhydrides, we carried out kinetic studies on the methanolysis of cis-2,3-dimethyl succinic anhydride (1a) (SI Appendix). Upon treatment with the mono cinchona alkaloid DHQD-PHN (3) and the bis cinchona alkaloid ðDHQDÞ 2 AQN (4) in diethyl ether at...

The proposed structures of jenamidines A, B, and C (1-3) were revised to jenamidines A1/A2, B1/B2, and C (8-10). Jenamidines A1/A2 (8) were synthesized from activated proline derivative 43 by conversion to 26 in two steps and 50% overall yield. Acylation of 26 with acid chloride 38d gave 39d, which was deprotected with TFA and then mild base to give 8 in 45% yield from 26. (-)-trans-2,5-Dimethylproline ethyl ester (49) was prepared by the enantioselective Michael reaction of ethyl 2-nitropropionate (51) and methyl vinyl ketone (50) using modified dihydroquinine 60 as the catalyst. Further elaboration converted 49 to natural (+)-NP25302 (12). A Wittig reaction of proline NCA (76) with ylide 79 gave 72 as a 9/1 E/Z mixture in 27% yield, completing a one-step formal synthesis of SB-311009 analogues.

The conjugate addition of a-substituted b-ketoesters to a,bunsaturated ketones represents a highly versatile strategy for the creation of all-carbon quaternary stereocenters, because of the accessibility of a wide range of these Michael donors and acceptors and the proven wide utility of the 1,4-adducts. The successful coupling of the strategic power of this C À C bond formation process with an operationally simple protocol for efficient and reliable enantioselective/diastereoselective control will lead to a direct and exceptionally versatile approach for the stereocontrolled construction of all-carbon quaternary stereocenters.[1] Consequently, this task has captured the attention of synthetic chemists since Wynbergs seminal report on the cinchona alkaloid-catalyzed addition of cyclic b-ketoesters to methyl vinyl ketone (MVK), which is the first documented catalytic enantioselective conjugate addition. [2][3][4][5][6][7][8] In spite of the numerous great strides made since then in catalytic asymmetric synthesis, [9] this task remains a formidable challenge of undiminished synthetic significance.A breakthrough in the development of a highly enantioselective catalytic conjugate addition of a-substituted bketoesters to vinyl ketones was reported by Shibasaki and co-workers in 1994.[4a] A bifunctional chiral La-Na-binol complex (binol = 2,2'-dihydroxy-1,1'-binaphthyl) allowed the addition of cyclic and acyclic a-substituted b-ketoesters to MVK to proceed in 62-91 % ee. More recently, Sodeoka and co-workers reported a Pd-binap complex (binap = 2,2'-bis-(diphenylphosphanyl)-1,1'-binaphthyl) that afforded 86-93 % ee for the conjugate addition of a-substituted b-ketoesters to methyl and ethyl vinyl ketones.[5] These chiral metalcomplex-mediated reactions, which demonstrated substantial scope with respect to ketoester donors, gave greater than 90 % ee only with MVK as the Michael acceptor. While representing remarkable progress, these results also underscore the importance as well as the challenge of the development of an operationally simple and efficient enantioselective catalytic conjugate addition of broad substrate scope for both a-substituted b-ketoesters and a,b-unsaturated ketones.Herein, we report the first efficient and general conjugate addition of a-substituted b-ketoesters to a,b-unsaturated ketones catalyzed by a chiral organic catalyst. The reaction affords excellent enantioselectivity, diastereoselectivity, and yield, not only for a wide variety of a-substituted b-ketoesters but also, importantly, for a wide range of a,b-unsaturated ketones. Furthermore, the high stereoselectivity is often achieved at or near room temperature in air with as little as 1.0 mol % of the chiral organic catalyst.Although 6'-hydroxy cinchona alkaloids 1 (Scheme 1) were shown to be efficient bifunctional chiral organic catalysts for the conjugate addition of various carbon nucleophiles to nitroalkenes and vinyl sulfones, [10] our initial attempts to apply 1 to promote the enantioselective addition of a-substituted b-ketoesters 2 ...

Adjacent quaternary and tertiary stereocenters as in structure 1 are common structural motifs in complex natural products. In principle, the stereocontrolled conjugate addition of a prochiral trisubstituted carbon nucleophile to a prochiral bsubstituted Michael acceptor with a chiral catalyst could provide a one-step construction of such highly congested motifs from simple precursors [Eq. (1)]. However, this requires the catalyst to impart both high enantioselectivity and diastereoselectivity in a sterically demanding, intermolecular CÀC bond formation that simultaneously creates both the quaternary and tertiary stereocenters. This task has proven to be a formidable challenge. Among numerous literature examples, [1][2][3] to our knowledge there are only two catalytic asymmetric conjugate additions that afford the 1,4-adducts containing adjacent carbon-substituted quaternary and tertiary stereocenters in excellent enantioselectivity and with a diastereomeric ratio (d.r.) of greater than 10:1 for a substantial number of trisubstituted carbon Michael donors.[2]Herein, we report an asymmetric conjugate addition mediated by a chiral bifunctional organocatalyst that affords high enantioselectivity and diastereoselectivity for several structurally distinct classes of trisubstituted carbon nucleophiles. This reaction allows the direct and stereocontrolled construction of a wide variety of adjacent carbon-or heteroatomsubstituted quaternary and tertiary stereocenters.Readily accessible cinchona alkaloids 2 have been identified recently as effective catalysts for the enantioselective conjugate addition of dimethyl malonate and ethyl acetoacetate to nitroalkenes. [4,5] These results prompted us to examine