The conversion of simple precursors into optically active products is a continuing goal in chemistry to efficiently access complex architectures for use in total synthesis and medicinal chemistry. 1 An especially important substitution pattern is a carbon atom bonded to four other carbon substituents (i.e., quaternary), and the generation of these congested centers is a significant challenge. 2 The desymmetrization of achiral molecules is a powerful strategy for the synthesis of optically active materials and presents a distinct method for the construction of stereogenic quaternary carbon centers.3 In this Communication, we report the enantioselective synthesis of α,α-disubstituted cyclopentenes (2) by an intramolecular aldol reaction of achiral tricarbonyl compounds (1) catalyzed by chiral N-heterocyclic carbenes (eq 1).
The direct nucleophilic acylation of nitroalkenes is reported utilizing a fluoride-initiated rearrangement of protected thiazolium carbinols. The key combination of fluoride anion and thiourea accesses carbonyl anion reactivity without the use of amine or amide bases typically employed in the generation of these Umpolung nucleophiles. The mild reaction conditions used to generate the reactive carbonyl anion species in situ allow for conjugate additions in good yield to sensitive nitroalkene electrophiles. The process is tolerant of a variety of thiazolium carbinols and nitroalkene substrates and can be rendered enantioselective and diastereoselective by the addition of a chiral thiourea derived from quinine.
Harnessing unconventional reactivity for new bond-forming processes provides unusual avenues for the synthesis of target molecules. Non-traditional cycloadditions outside the venerable [4 + 2] and [3 + 2] processes also facilitate access to desired compounds in a highly convergent manner by combining at least two simple starting materials. 1 A relatively unexplored class of powerful transformations utilizes unusual reactivity patterns, such as homoenolates, in the context of non-traditional, formal cycloadditions. In this communication, we report the highly diastereo-and enantioselective combination of α,β-unsaturated aldehydes (1) with nitrones (2) catalyzed by N-heterocyclic carbenes to afford γ-amino esters, such as 4, upon the addition of an alcohol (eq 1). A unique aspect of this process is the rare sixmembered heterocycle that is generated as the initial product of the reaction (3).
Silyloxyallenes serve as highly useful α-acylvinyl anion equivalents. These latent allenolates undergo conjugate additions to alkylidene malonates in the presence of 10 mol% Sc(OTf) 3 . The reaction delivers intermolecular Rauhut-Currier products in excellent yields and regioselectivities for a wide scope of substrates. Notably, the formal cross-coupling of two different αβ-unsaturated carbonyl compounds (a cross Rauhut-Currier reaction) is achieved. Preliminary investigations have demonstrated good levels of enantioselectivity for the addition of a racemic silyloxyallene with a chiral Lewis acid.α-Acylvinyl anion equivalents are atypical nucleophiles that generate valuable α,β-unsaturated carbonyl compounds in a highly convergent manner. 1 One method of interest that employs this type of unconventional reactivity is the Rauhut-Currier reaction in which the α-acylvinyl anion undergoes a Michael addition. 2,3 Similar to the Morita-Baylis-Hillman reaction, the method involves the initial conjugate addition of a Lewis base catalyst to generate a zwitterionic enolate that then undergoes a conjugate addition onto a second equivalent of an electron-deficient olefin (Scheme 1, Option 1). While dimerizations of the activated alkenes (e.g., acrylates) are well-known, the reaction between two different α,β-unsaturated carbonyl compounds (a cross Rauhut-Currier) is much more challenging with few reported examples. 4 The key problem is that self-condensations compete under the reaction conditions and the products, which are electron-deficient alkenes as well, are susceptible to polymerizations. In 2002, Krische and Roush independentlyreportedanintramolecularversionoftheRauhut-Currier employing bisenone substrates. 5 Miller has recently reported an elegant enantioselective intramolecular Rauhut-Currier variant with similar bis-enones using one equivalent of N-acetyl cysteine as the promoter. 5k Despite the progress of the intramolecular manifold, a successful intermolecular Rauhut-Currier reaction has not emerged to date. A useful bimolecular process could indeed expand the utility of this bond-forming process. In this Communication, we disclose that the Lewis acid-catalyzed conjugate additions of silyloxyallenes afford a wide variety of 1,5-dicarbonyl compounds that map directly onto what would be products of an intermolecular Rauhut-Currier process (Scheme 1, Option 2).Silyloxyallenes have emerged as versatile and useful R-acylvinyl anion equivalents. 6,7 These latent enolates are prepared readily from the corresponding acylsilanes by way of the Kuwajima-Reich rearrangent of α-hydroxypropargylsilanes. that silyloxyallenes undergo additions to aldehydes in the presence of Lewis acids and high yields are achieved for a wide scope of substrates with excellent control over the resulting double bond geometry. Encouaged by the full potential of these unusual nucleophiles, we have developed an enantioselective variant of this reaction using racemic silyloxyallenes and a chiral (salen)Cr(III) Lewis acid catalyst. 9 In an e...
Highly substituted α,β-unsaturated ketones are prepared by the N-heterocyclic carbene-initiated addition of α-hydroxypropargylsilanes to aldehydes. This strategy serves as a highly efficient alternative to the standard Morita-Baylis-Hillman (MBH) approaches for these types of compounds. In contrast to the MBH reaction, different substitution in the β-position of the product (R 1 ) can be accommodated in moderate to excellent yields with a high degree of control over the resulting alkene.The Morita-Baylis-Hillman (MBH) reaction is an efficient reaction that generates highly functionalized compounds by employing α-acylvinyl anion reactivity. 1 Significant advances in the MBH reaction have been made recently, including mechanistic studies as well as asymmetric and intramolecular variants. 2,3 Despite this progress, the intermolecular MBH reaction has intrinsic limitations. In particular, the β-substituents of the activated alkene starting materials (e.g., ethyl acrylate, vinyl ketones) are almost always hydrogen atoms. Recently, we reported the scandium(III)-catalyzed addition of silyloxyallenes to aldehydes as a valuable alternative to the MBH and other α-acylvinyl anion processes (Option I, Figure 1). 4-6 These reactions proceed under very mild conditions (10 mol % Sc(OTf) 3 ) and accommodate a wide scope of β-substitution with excellent yields and a high degree of control over the resulting alkene geometry. Also, enantioenriched products could be synthesized by the (-)-(salen)Cr (III)-catalyzed additon of racemic silyloxyallenes. 4 One aspect of the transformation is the prerequisite of preparing the silyloxyallenes in a separate step through the Kuwajima-Reich rearrangement of the α-hydroxypropargylsilane precursors. 7 Herein, we present an alternative single-flask approach starting directly from the propargylsilanes, thus further enhancing the applicability of this unconventional α-acylvinyl addition reaction (Option II, Figure 1).Our current interests include the development of reactions employing Lewis base activation to efficiently access unconventional reactivity. Several transformations from our laboratory, including acyl anion additions, homoenolate reactions, alkyne additions, disilylations of activated alkenes, and hydroacylations of ketones have been facilitated by the use of Lewis bases. 8 Given our strong interest in the combination of Lewis basic promoters/catalysts, we reasoned that Lewis bases may activate silyloxyallenes toward addition. In particular, they scheidt@northwestern.edu. Supporting Information Available: Experimental procedures and spectral data for all new compounds, and a CIF file for H14·Cl. This material is available free of charge via the Internet at http://pubs.acs.org. should be more compatible with the rearrangement conditions (substoichiometric n-BuLi, THF) of the α-hydroxypropargylsilanes to the allenes and facilitate a single flask procedure. NIH Public AccessStarting with α-hydroxypropargylsilane 1 in THF at 0 °C, the allene was formed with use of 5 mol % of n-B...
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