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...

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Triphenylphosphane (TPP) has been utilized as a novel and efficient catalyst for the Knoevenagel condensation of aldehydes with acidic methylene compounds such as ethyl cyanoacetate and malononitrile to afford substituted olefins. The reaction proceeds smoothly under mild and solvent‐free conditions and the products are obtained in excellent yields with an E‐geometry. This method is applicable for a wide range of aldehydes including aromatic, aliphatic and heterocyclic substrates. Microwave irradiation has been used to achieve enhanced reaction rates and improved yields. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

The mono-triflate salts of some chiral non-racemic 1,2-diamines react with α-ketoenones in a stoichiometric reaction to form products of the Nazarov cyclization in high enantiomeric ratios. The mechanism appears to involve rearrangement of an enamine -iminium ion.Recent years have seen a resurgence of interest in the Nazarov cyclization. 1,2 An attractive approach to the asymmetric Nazarov cyclization is through iminium ion catalysis. 3 For example, treatment of divinyl ketone 1 (Scheme 1) with an asymmetric secondary amine 2 can be expected to lead to equilibrium with iminium ion 3. Nazarov cyclization of the pentadienyl carbocation (cf. 4) might lead to cyclic species 5 through a conrotatory process. Through appropriate choice of amine 2 and reaction conditions, asymmetric induction might be observed during this process. Although this general approach appears to be sound, in fact the pentadienyl cation (cf. 4) is rendered more stable than the cyclic allylic cation 5 by conjugation with the non-bonding electron pair on the nitrogen atom. 4 This generally results in an equilibrium favoring the acyclic iminium ion. This obstacle may be overcome by incorporating a structural feature into 1 that raises the energy of 3/4 compared to 5.To the best of our knowledge the Nazarov cyclization of an iminium ion has been reported only twice. The first example is summarized in Scheme 2. 5 Addition of lithioallenyl ether 7 to E-α-methyl cinnamonitrile 6 leads to N-lithio imine 8. Workup with mild aqueous acid protonates the imine that then undergoes Nazarov cyclization to 9. N-Acetylation in a separate step gave acetamide 10 in 73% overall yield from 6. The success of this reaction is probably due to release of allene strain (10.76 kcal/mol) 3g as well as the irreversible loss of methoxymethyl cation during the cyclization. In the second example of an imino Nazarov cyclization the stability of the iminium ion was attenuated by N-tosylation. 6 We first screened a small set of monoamines to determine whether they would catalyze the asymmetric conversion of 11 to 15 (Scheme 3). Stoichiometric L-proline, (S)-α-methylbenzylamine or (1R,2S)-(−)-ephedrine in the presence of a Brønsted acid led to small tius@hawaii.edu. ‡ Author to whom inquiries regarding the crystal structure of 51 should be directed. amounts (<10%) of racemic 15 in a very slow reaction. These negative results suggested a solution to the problem through a cooperative mechanism (vide infra).We conceived of an alternative approach to the ones described above that would allow us to use iminium ion catalysis for a Nazarov cyclization. Scheme 3 summarizes the approach. Exposure of an α-ketoenone such as 11 to a diamine salt 12 is expected to generate enamineiminium ion 13 under Brønsted acid catalysis. The carbonyl group of the methyl ketone is likely to be the more reactive of the two, and will form an enamine. Subsequent reaction of the free amino group with the enone carbonyl group leads to enamine-iminium ion 13. Intermediate 13 should be an excellent substr...