Total synthesis of (R)-tylophorine by using an asymmetric hydrogenation of the allyl alcohol

An efficient synthesis of naturally occurring (R)-tylophorine is described. The alkaloid was prepared in seven steps from a known phenanthryl aldehyde with an overall yield of 14.2%. Asymmetric hydrogenation of an allyl alcohol was employed as a key step for installing a stereogenic center with good enantioselectivity (77% ee), and the ee value of the ω-chloro alcohol was improved to 95% by recrystallization. After azidation and oxidation of the enantio-enriched ω-chloro alcohol to the precursor of the Schmidt reaction, the chirality transfer in the stereospecific 1,2-migration furnished the chiral carbon in the alkaloid. Finally, a one-pot deformylation/Pictet-Spengler cyclization completed the total synthesis of (R)-tylophorine.     

An asymmetric route to total synthesis of the furano lignan (+)-veraguensin

Total synthesis of the furano lignan (+)-veraguensin is described. The key steps involve a diastereoselective aldol-type condensation of an ester enolate having an α-chiral center with an aromatic aldehyde and a novel isomerization of the syn vicinal substituents on the furan ring via a ring opening-ring closing protocol.     

One-pot synthesis of α-diazo-β-hydroxyesters under phase-transfer catalysis and application to the catalytic asymmetric aldol reaction

The one-pot (three steps) synthesis of α-diazo-β-hydroxyesters from tosyl chloride under phase-transfer catalysis is described. The catalytic asymmetric aldol reaction between a diazoester and aldehydes was also investigated and gave moderate to good enantioselectivity.     

Design of a C2-symmetric chiral pyrrolidine-based amino sulfonamide: application to anti-selective direct asymmetric Mannich reactions

The anti-selective direct asymmetric Mannich reaction was found to be efficiently catalyzed by the novel pyrrolidine-based amino sulfonamide (R,R)-2 prepared from l-tartaric acid.     

Amino alcohol catalyzed direct asymmetric aldol reactions: enantioselective synthesis of anti-α-fluoro-β-hydroxy ketones

Prolinol but not proline-(a recently established catalyst of simple intermolecular aldol reactions) was found to be an efficient catalyst for fluoroaldol reactions providing anti-α-fluoro-β-hydroxy ketones with good regio-, diasterio-, and enantioselectivities.     

Catalytic asymmetric Payne oxidation under the catalysis of P-spiro chiral triaminoiminophosphorane: application to the synthesis of N-sulfonyl oxaziridines

The studies on the development of a highly enantioselective oxidation of N-sulfonyl imines with hydrogen peroxide–trichloroacetonitrile system utilizing P-spiro chiral triaminoiminophosphoranes as an organic base catalyst are detailed. This method is general and scalable, and exhibits unique chemoselectivity, providing a practical stereoselective route to structurally diverse N-sulfonyl oxaziridines. The mechanistic investigations reveal that the reaction proceeds through the Payne-type oxidation pathway. The synthetic utility of the optically active N-sulfonyl oxaziridines as versatile organic oxidants and chiral building blocks is also demonstrated.     

The first example for the asymmetric synthesis of allenes by the Doering-LaFlamme allene synthesis with enantiopure cyclopropylmagnesium carbenoids

The reaction of lithium α-sulfinyl carbanion of enantiopure dichloromethyl p-tolyl sulfoxide with α,β-unsaturated carbonyl compounds gave optically active 1-chlorocyclopropyl p-tolyl sulfoxides having a carbonyl group with high asymmetric induction from the sulfur chiral center. Reduction of the carbonyl group followed by treatment with Grignard reagent, the 1-chlorocyclopropyl p-tolyl sulfoxides resulted in the formation of enantiopure allenic alcohols via the Doering-LaFlamme-type rearrangement of enantiopure cyclopropylmagnesium carbenoid intermediates. This is the first example for the asymmetric synthesis of allenes by the Doering-LaFlamme allene synthesis.     

The stereoselective synthesis of α-substituted β-amino secondary alcohols based on the proline-mediated, asymmetric, three-component Mannich reaction and its application to the formal total synthesis of nikkomycins B and Bx

A general method for the asymmetric synthesis of α-substituted β-amino secondary alcohols is described, which comprises the four-reaction sequence (1) the proline-mediated, asymmetric, three-component Mannich reaction of two different aldehydes, (2) nucleophilic carbon addition to aldehyde, (3) oxidation of the resulting alcohol to the corresponding ketone, and (4) diastereoselective reduction with LiAlH(O-t-Bu)₃ or catecholborane. The former reductant afforded the 1,2-syn isomer, while the latter gave the 1,2-anti isomer stereoselectively. The present method was successfully applied to the efficient asymmetric synthesis of the N-terminal amino acid moiety of nikkomycin B and B_X.     

Highly efficient synthesis of spirocyclic (1R)-camphor-derived triazolium salts: application in the catalytic asymmetric benzoin condensation

New (1R)-camphor-derived triazolium salts, incorporating a spirocyclic system, are described. Benzoin condensation of aromatic aldehydes, mediated by these salts affords α-hydroxyketones in good yields and moderate enantiomeric excesses.     

Chiral diamines for asymmetric synthesis: an efficient RCM construction of the ligand core of (−)- and (+)-sparteine

An efficient RCM-based approach was applied to the total asymmetric synthesis of a tricyclic diamine and, formally, of its enantiomer, widely known as efficient and versatile chiral ligands of the sparteine-like type.     

From determination of enantiopurity to the construction of complex molecules: The Horeau principle and its application in synthesis

In 1973, Horeau and co-workers reported a technique capable of upgrading the enantiopurity of a scalemic mixture (for example, [(R)-enantiomer]?>?[(S)-enantiomer]). This method involved coupling the compound of interest to a simple, bifunctional reagent in order to form a statistical mixture of (R,R)-, (S,S)-, and (R,S)-stereoisomers. Separation of the two diastereomers and cleavage of the incorporated coupling agent effectively removes the minor, (S)-enantiomer from the major, (R)-enantiomer; thereby increasing the enantiopurity of the starting compound. Since that time, this concept of removing a minor enantiomer through the statistical formation of diastereomeric compounds (the Horeau principle) has also been applied when sequential enantioselective reactions are performed on a substrate, when multiple enantioenriched fragments are coupled together, and for determining the enantiopurity of the initial scalemic mixture. Under the right circumstances, the Horeau principle can be deployed in an iterative fashion in order to access material with extremely high enantiopurity (>99.999% ee). This review provides comprehensive coverage of the underlying theory behind the Horeau principle and its application in organic synthesis.     

Asymmetric epoxidation of cis-alkenes with arabinose-derived ketones: enantioselective synthesis of the side chain of Taxol

The ee values of asymmetric epoxidation of cis-ethyl cinnamate 15 with arabinose-derived ketones as catalyst and Oxone^® as the terminal oxidant were found to increase inversely with the size of the catalyst acetal blocking group. Ketone catalyst 2, with the least bulky methoxy acetal group, displayed the best enantioselectivity and afforded ethyl (2R,3R)-3-phenylglycidate 16 in 68% ee. Epoxide 16 was readily converted into a protected side chain of Taxol^® in five steps with an overall yield of 89%. The enantioselectivity of the epoxidation of other cis-alkenes was moderate to poor.     

Synthesis of 2,6-dimethyl-9-aryl-9-phosphabicyclo[3.3.1]nonanes: their application to asymmetric synthesis of chiral tetrahydroquinolines and relatives

Synthesis of 2,6-dimethyl-9-aryl-9-phosphabicyclo[3.3.1]nonanes from 1,5-cyclooctadiene and their application to asymmetric cyclization leading to chiral tetrahydroquinolines and relatives through palladium-catalyzed allylic alkylation are described.     

A new (R)-hydroxynitrile lyase from Prunus mume: asymmetric synthesis of cyanohydrins

A new hydroxynitrile lyase (HNL) was isolated from the seed of Japanese apricot (Prunus mume). The enzyme has similar properties with HNL isolated from other Prunus species and is FAD containing enzyme. It accepts a large number of unnatural substrates (benzaldehyde and its variant) for the addition of HCN to produce the corresponding cyanohydrins in excellent optical and chemical yields. A new HPLC based enantioselective assay technique was developed for the enzyme, which promotes the addition of KCN to benzaldehyde in a buffered solution (pH=4.5).     

A facile approach to trans-4,5-pyrrolidine lactam and application in the synthesis of nemonapride and streptopyrrolidine

An efficient approach to trans-4-hydroxylpyrrolidine lactams 1 starting from amino acid is described. The utility of this method has been demonstrated in the synthesis of antipsychotic nemonapride 3 and antiangiogenic streptopyrrolidine 4. Compared four synthetic stereoisomers of natural streptopyrrolidine 4 in term of spectroscopic and physical data, the absolute structure of the natural product was proposed as (4S,5S)-configuration.     

Convenient route to enantiopure substituted butyrolactones: application in a formal synthesis of both enantiomers of enterolactone

A simple route for the synthesis of enantiopure substituted γ-butyrolactones involving a highly diastereoselective alkylation of an enantiomerically pure substituted latent succinate ester is described. This route provides entry into both enantiomers of 3,4-disubstituted butyrolactones from a single enantiomer, 2,3-di-O-cyclohexylidine-R-(+)-glyceraldehyde. The synthetic potential of this methodology has been demonstrated by a formal synthesis of both enantiomers of enterolactone.     

Design and synthesis of a new polymer-supported Evans-type oxazolidinone: an efficient chiral auxiliary in the solid-phase asymmetric alkylation reactions

Wang resin-supported Evans' chiral auxiliary (23) was designed based on a novel polymer-anchoring strategy, which utilizes the 5-position of the oxazolidinone ring, and its new synthetic route applicable to multi-gram preparation in just a day was developed. Solid-phase Evans' asymmetric alkylation on 23-derived N-acylimide resin and following lithium hydroperoxide-mediated chemoselective hydrolysis afforded the corresponding α-branched carboxylic acids in desired high stereoselectivities (up to 97% ee) and moderate to good overall yield (up to 70%, for 3 steps), which were comparable to those of the conventional solution-phase methods. Furthermore, recovery and recycling of the polymer-supported chiral auxiliary were successfully achieved without decreasing the stereoselectivity of the product. Therefore, this is the first successful example that the solid-phase Evans' asymmetric enolate-alkylation was efficiently performed on the solid-support, and it is concluded that the connection to the solid-support via the 5-position of the oxazolidinone ring is an ideal strategy in the solid-phase Evans' chiral auxiliary.     

Stereoselective synthesis of N-heterocycles: application of the asymmetric Cu-catalyzed addition of Et2Zn to functionalized alkyl and aryl imines

The preparation of N-heterocycles from alkyl- and aryl-substituted imines is described. The key step involves a copper-catalyzed addition of diethylzinc to functionalized alkyl-substituted imines that were generated in situ from the sulfinic acid adducts. The nucleophilic addition products were then converted to 2-substituted pyrrolidines and piperidines. Aryl-substituted imines were transformed into enantioenriched 1- and 1,4-substituted tetrahydroisoquinolines.     

A simplified catalytic system for direct catalytic asymmetric aldol reaction of thioamides; application to an enantioselective synthesis of atorvastatin

A new catalytic system was developed for the direct catalytic asymmetric aldol reaction of thioamides. The new lithium-free Cu catalyst (second-generation catalyst) exhibited enhanced catalytic efficiency over the previously developed catalyst comprising [Cu(CH₃CN)₄]PF₆/Ph-BPE/LiOAr (first-generation catalyst), which required a tedious catalyst preparation process. In the reaction with the second-generation catalyst, the intermediate Cu-aldolate functioned as a Brønsted base to generate thioamide enolate, efficiently driving the catalytic cycle. The present aldol methodology culminated in a concise asymmetric synthesis of atorvastatin (Lipitor^®: atorvastatin calcium), a widely prescribed HMG-CoA reductase inhibitor for lowering low-density lipoprotein cholesterol.