Kwunmin Chen

Pyrrolidinyl–Camphor Derivatives as a New Class of Organocatalyst for Direct Asymmetric Michael Addition of Aldehydes and Ketones to β‐Nitroalkenes

Practical and convenient synthetic routes have been developed for the synthesis of a new class of pyrrolidinyl-camphor derivatives (7 a-h). These novel compounds were screened as catalysts for the direct Michael addition of symmetrical alpha,alpha-disubstituted aldehydes to beta-nitroalkenes. When this asymmetric transformation was catalyzed by organocatalyst 7 f, the desired Michael adducts were obtained in high chemical yields, with high to excellent stereoselectivities (up to 98:2 diastereomeric ratio (d.r.) and 99 % enantiomeric excess (ee)). The scope of the catalytic system was expanded to encompass various aldehydes and ketones as the donor sources. The synthetic application was demonstrated by the synthesis of a tetrasubstituted-cyclohexane derivative from (S)-citronellal, with high stereoselectivity.

Efficient Synthesis of Tetrasubstituted Furans from Nitroallylic Acetates and 1,3-Dicarbonyl/α-Activating Ketones by Feist–Bénary Addition–Elimination

Furans represent an important subclass of five-membered aromatic heterocycle that has been used for the synthesis of many pharmaceutical molecules and industrial materials. The functionalization of furans often allows for further structural elaboration and adornment. As a consequence, many valuable synthetic protocols have been devised for the construction of polysubstituted furans, and these are based either on introducing substituents onto the existing furan ring or furan ring construction from acyclic precursors. Derivatization of furans often requires the application of a metal–halogen exchange reaction or a transition-metal-catalyzed cross-coupling, with the halide precursor emanating from an electrophilic substitution process. On the other hand, some excellent methods have been developed for the build-up of functionalized furans from acyclic precursors, some of which utilize alkynyl epoxides, a-alkenyl-bdiketones, cyclopropenyl ketones, g-acyloxy butynoates, alkynyl ketones, b-acyloxy acetylenic ketones, aalkynyl enones, thioalkynone, alkynol/alkyne, alkynoate/1,3-dicarbonyls, propargylic alcohols/1,3-dicarbonyls, propargylic alcohols/ketones, allenyl ketones, propargylic esters, propargyl vinyl ethers, alkynyl cyclopropyl ketones, alkenyl carbene/enones, b-alkynyl enals, acyloxy sulfones, enynols, and various other substrates. The application of these methods often requires the preparation of specially tailored starting substrates utilizing transition-metal catalyzed reactions. The Paal–Knorr reaction has proven particularly useful for furan ring assembly. The reaction of 1,3-dicarbonyl compounds with a-haloketones (the Feist–B nary reaction) under metal-free conditions, is another longstanding historical protocol that has provided rapid access to many different types of substituted furans. The development of facile new methods for the efficient ring assembly of tetrasubstituted furans remains a highly desirable and challenging objective for many in the field. We present herein a unique and generally efficient synthetic strategy for accessing tetrasubstituted furans that exploits a Feist–B nary type reaction between electron-deficient nitroallylic acetates 1 and 1,3-dicarbonyl/a-activating ketones. The corresponding multifunctional 3,5-alkyl/aryl-2-carboxylate-4-keto/cyano-containing tetrasubstituted furans were typically obtained in respectable to excellent yield (52– 99 %) via an interesting SN2 addition–elimination sequence that proceeds under very mild reaction conditions [Eq. (1)].

Novel Prolinamide–Camphor‐Containing Organocatalysts for Direct Asymmetric Michael Addition of Unmodified Aldehydes to Nitroalkenes

The Michael reaction is generally regarded as one of the most efficient, atom-economical and powerful carbon– carbon bond-forming reactions in organic chemistry. The development of organocatalytic asymmetric Michael reactions has been a significant research focus for several years. The direct asymmetric Michael addition of carbonyl compounds with nitroalkenes to produce enantiomerically enriched nitroalkanes has been described. Among these reactions, the Michael addition of unmodified aldehydes to nitroalkenes is of particular interest because of the valuable synthetic intermediates that are generated. Betancort and Barbas originally reported the organocatalytic asymmetric Michael addition of unmodified aldehydes to nitroalkenes with moderate to good enantioselectivities. Recently 3,3’bimorpholine derivatives, a chiral primary amine/thiourea catalyst and l-prolinol organocatalysts have been developed for the Michael addition of aldehydes to nitroolefins. Highly diastereoand enantioselective conjugate additions that involve aldehydes were independently reported by the research groups of Wang, Hayashi, and Palomo using pyrrolidine sulfonamide (1), diphenylprolinol silyl ether (2) and trans-4-hydroxyprolylamide (3) respectively. However, some of these reactions required a large excess of donor source (up to 10 equiv of aldehyde) and high catalyst loadings (between 10 and 20 mol %). Despite the excellent results achieved from previous studies, the development of an efficient organocatalyst for direct asymmetric Michael addition of aldehydes to various aryland alkylnitroalkenes with low catalyst loading remains challenging in asymmetric synthesis. The metal-free, small, privileged organic molecules that catalyze enantioselective reactions have attracted much attention in recent years. Organocatalysts are usually highly efficient and selective, stable under aerobic and aqueous reaction conditions, nontoxic, environmentally friendly, and thus highly desirable as catalysts/catalytic systems. In light of this, we have recently developed a series of camphor-based pyrrolidinyl organocatalysts that have proven their efficacy as catalysts in asymmetric synthesis. In continuation of our research interest in organocatalysis, we designed and synthesized a new prolinamide–camphor organocatalysts and have shown it to be efficient catalysts for direct asymmetric Michael reaction. Herein, we wish to report an excellent diastereoand enantioselective direct Michael addition of aldehydes with nitroalkenes catalyzed by bifunctional organocatalysts 4 a–c. The desired Michael products were obtained with high chemical yields (up to 94 %) and excellent stereoselectivities (up to 99:1 d.r. and >99 % ee) with 5 mol % of organocatalyst 4 b. In asymmetric organocatalysis there is a strong demand for the design and synthesis of highly stereoselective, readily accessible, and tunable catalysts. The synthesis of novel prolinamide–camphor organocatalysts 4 a–c begins with the Boc-protected l-proline and trans-4-hydroxy l-proline. Treatment of Boc l-proline and trans-4-hydroxy l-proline with 1-amino-7,7-dimethylbicycloACHTUNGTRENNUNG[2.2.1]heptan-2-one (5) under standard coupling conditions (ethyl chloroformate and Et3N in CHCl3) to give the corresponding amides (6 a and 6 b) in 85 and 88 % isolated yields, respectively (Scheme 1). Sodium borohydride reduction of 6 a and 6 b to [a] Dr. R. J. Reddy, H.-H. Kuan, T.-Y. Chou, Prof. K. Chen Department of Chemistry National Taiwan Normal University Taipei 116 (Taiwan) Fax: (+886) 2-29324249 E-mail : kchen@ntnu.edu.tw Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200901254.

Highly Efficient Organocatalytic Kinetic Resolution of Activated Nitroallylic Acetates with Aldehydes via Conjugate Addition−Elimination

A novel, efficient, and unprecedented organocatalytic kinetic resolution has been developed. For the first time, a variety of nitroallylic acetates 1a-i have been resolved with aldehydes in the presence of 2 (2.5 mol %) via conjugate addition-elimination. The densely functionalized products 3a-o were obtained with excellent enantioselectivities (up to >99% ee), and unreacted substrates 1a-i were recovered with good to excellent optical purity (up to 98% ee).

Organocatalytic synthesis of multiple substituted bicyclo[4.4.0]decalin system.

An efficient and unprecedented organocatalytic reaction of γ-nitroketones with α,β-unsaturated aldehydes to give polyfunctionalized [4.4.0] bicyclic skeletons was developed. The diphenylprolinol silyl ether mediated nitro-Michael/Aldol reaction afforded the hexa-substituted decalin carboaldehydes with excellent diastereo- and enantioselectivity (up to >99:1 dr and >99% ee) via a formal [4 + 2] carbocyclization process.

Organocatalytic Synthesis of Substituted Spirocyclohexane Carbaldehydes via [4 + 2] Annulation Strategy between 2-Arylideneindane-1,3-diones and Glutaraldehyde

An organocatalytic domino reaction between 2-arylideneindane-1,3-diones and glutaraldehyde has been devised that gives functionalized spirocyclohexane carbaldehydes with an all-carbon quaternary center. The reaction proceeds through a Michael/Aldol sequence in good-to-high chemical yields and with high levels of stereoselectivity (up to >95:5 dr and 99% ee) in the presence of the α,α-L-diphenylprolinol trimethylsilyl ether 3 (20 mol %) and DIPEA (20 mol %) in ether at 0 °C.

Synthesis of fully substituted dispirocyclohexanes by organocatalytic [2 + 2 + 2] annulation strategy between 2-arylideneindane-1,3-diones and aldehydes

An interesting organocatalytic reaction between 2-arylideneindane-1,3-diones and aldehydes has been developed that gives fully substituted cyclohexanes that bear two all-carbon quaternary centers. The dispirocyclohexanes were obtained in reasonable-to-good chemical yields and with high stereoselectivities (>95:5 d.r. and up to 99% ee) using a catalytic amount of commercially available α,α-l-diphenylprolinol trimethylsilyl ether (5 mol %) and DABCO (20 mol %) in DMF at -20 °C. The reaction proceeds through a unique Michael/Michael/aldol reaction that requires 2 equiv of the 2-arylideneindane-1,3-dione.

Three-Component Organocascade Kinetic Resolution of Racemic Nitroallylic Acetates via Sequential Iminium/Enamine Asymmetric Catalysis

Nitroallylic acetates 1a-f have been kinetically resolved via an asymmetric three-component coupling that involves indoles, acrolein, and nitroolefin allylic acetates and is mediated by the chiral catalyst 2 (5 mol %). The reactions proceed via iminium/enamine cascade catalysis. Both recovered starting substrates and reaction products are typically obtained in high chemical yield and in good to excellent enantiopurity (79-95% ee for 1a-f and 83-99% ee for 3a-n). For the first time, a highly efficient three-component, organocascade kinetic resolution has been demonstrated.

Diastereoselective [3+2] cycloadditions of a camphor-derived chiral N-acryloylhydrazide with nitrile oxides: the preparation of optically pure Δ2-isoxazolines

Reaction of a novel chiral N-acryloylhydrazide with various nitrile oxides proceeded smoothly to afford the cycloadduct with high diastereoselectivity (99:1). The auxiliary can be easily removed from the cycloadducts under mild conditions.

Diastereoselective conjugate addition of thiols to camphor pyrazolidinone derived chiral α,β-unsaturated carbonyls: Synthesis of β-mercaptocarboxylic acid derivatives

Abstract Reaction of chiral α,β-unsaturated carboxylic acid derivatives 2a – e derived from camphor pyrazolidinone 1 with thiols affords β-mercaptocarboxylic acid derivatives 3a – e with a wide range of stereoselectivities (up to >90% de). The stereoselectivity as a function of Lewis acid is described. The auxiliary can be easily recovered from the Michael adducts under mild conditions.