An improved asymmetric total synthesis of (+)-biotin via the enantioselective desymmetrization of a meso-cyclic anhydride mediated by cinchona alkaloid-based sulfonamide

The highly enantioselective total synthesis of (+)-biotin 1 via the Hoffmann–Roche lactone–thiolactone strategy has been achieved starting from cis-1,3-dibenzyl-2-imidazolidone-4,5-dicarboxylic acid 2 with an overall yield of 35%. Two contiguous stereogenic centers at C-3a and C-6a were established through a rapid cinchona alkaloid-based sulfonamide-mediated enantioselective alcoholysis of meso-cyclic anhydride 3 to afford (4S,5R)-cinnamyl hemiester 4h, the direct precursor to (3aS,6aR)-lactone 5 with high enantioselectivity. A one-pot installation of the 4-carboxybutyl side chain was accomplished by a Fukuyama coupling reaction of (3aS,6aR)-thiolactone 6 with the organozinc reagent prepared from ethyl 5-bromopentanoate.     

Synthetic approach toward cis-disubstituted γ- and δ-lactones through enantioselective dialkylzinc addition to aldehydes: application to the synthesis of optically active flavors and fragrances

A versatile and straightforward approach to optically active cis-4,5-disubstituted γ- and δ-lactones by catalytic enantioselective addition of dialkyzincs to cinnamic aldehydes and RCM ring closure has been reported. The synthetic importance of the enantioselective dialkylzinc alkylation of aldehydes has been thus widened. Such an approach has then been employed for the enantioselective synthesis of naturally occurring γ-lactone flavors like (S)-5-ethyl-butanolide (6a) and (4S,5S)-cis-whisky lactone (6b) and extended to the preparation of δ-lactones like (5S,6S)-5-methyl-6-ethylpentanolide (9a), precursor of the pheromone serricornin.     

Enantioselective syntheses of isoprostane and iridoid lactones intermediates by enzymatic transesterification

Crude Pseudomonas cepacia lipase (Amano PS-30) is a suitable biocatalyst for the kinetic resolution of the 1,2-cis-disubstituted cyclopentanoid building block (3aR*,4R*,6aS*)-(±)-4-hydroxymethyl-3,3a,4,6a-tetrahydrocyclopenta[b]furan-2-one through enantioselective transesterification. Enantiomerically enriched acetic acid (3aS,4S,6aR)-(+)-2-oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-4-yl methyl ester was utilized in a formal synthesis of the iridoids (+)-isoiridomyrmecin and (−)-teucriumlactone.     

First enantioselective synthesis of isagarin,a natural product isolated from Pentas longiflora Oliv.

For the first time, an enantioselective synthesis of both 1R,4S-isagarin 1a and 1S,4R-isagarin 1b was achieved starting from 1,4-dimethoxy-2-vinylnaphthalene 2. The key steps involve a Sharpless asymmetric dihydroxylation and reaction with an acetonylating pyridinium ylid. The different optical rotations and melting points of the enantiopure 1R,4S-isagarin 1a and 1S,4R-isagarin 1b with respect to the isolated natural product will be addressed.     

Total Synthesis of (+)‐Gracilamine Based on an Oxidative Phenolic Coupling Reaction and Determination of Its Absolute Configuration

The enantioselective total synthesis of (+)‐gracilamine ( 1 ) is described. The strategy features a diastereoselective phenolic coupling reaction followed by a regioselective intramolecular aza‐Michael reaction to construct the ABCE ring system. The configuration at C3a in 1 was controlled by the stereocenter at C9a, which was selectively generated (91 % ee) by an organocatalytic enantioselective aza‐Friedel–Crafts reaction developed by our research group. This synthesis revealed that the absolute configuration of (+)‐gracilamine is 3aR, 4S, 5S, 6R, 7aS, 8R, 9aS.     

Reduced collagen cross links: the first synthesis of all the possible (2S,2′S)-stereoisomers of 5-hydroxylysinonorleucine and of 5,5′-dihydroxylysinonorleucine in enantiomerically pure form

The paper reports the first enantioselective synthesis of all the possible collagen reduced cross links as described: (2S,2′S,5R)- and (2S,2′S,5S)-5-hydroxylysinonorleucine 3a and 3b, (2S,2′S,5R,5′R)-5,5′-dihydroxylysinonorleucine 4a, (2S,2′S,5R,5′S)-5,5′-dihydroxylysinonorleucine 4b and (2S,2′S,5S,5′S)-5,5′-dihydroxylysinonorleucine 4c. The Williams’ glycine template methodology was used both for the introduction of a stereogenic at the α-position and for an easy protection of the amino acidic functionalities during the synthesis of the dimeric amino acids.     

Masked constrained cysteines: diastereoselective and enantioselective synthesis of 1-amino-2-mercaptocyclopropanecarboxylic acid derivatives

A diastereoselective and enantioselective synthesis of (Z)-1-benzoylamino-2-tritylsulfanylcyclopropanecarboxylic acid derivatives 8a,b and 9a,b was achieved starting from (−)- or (+)-menthyl 2-benzoylamino-3-tritylsulfanylacrylates 3a,b. Compounds 3 were reacted with diazomethane giving the corresponding pyrazolines 4a,b and 5a,b. These compounds, on melting, were transformed, under steric control, into the cyclopropaneamino acid derivatives (R,R)-8a,b and (S,S)-9a,b. The synthesis of a large class of chiral 2-S-alkyl-1-aminocyclopropanecarboxylic acid derivatives is possible after removing the trityl protecting group and subsequent alkylation reactions.     

Synthesis of (−)-okundoperoxide and determination of the absolute configuration of natural (+)-okundoperoxide

The first enantioselective synthesis of (3S,4aR,8aR)-1 (the enantiomer of natural okundoperoxide) has been accomplished. The synthesis features: 1) stereoselective installation of the peroxy functionality (16 → 17); 2) ring opening of peroxyacetal and subsequent intramolecular reaction between the hydroperoxide and the vinyl epoxide to form the peroxy six-membered ring (5 → 1). The absolute configuration of okundoperoxide was determined to be 3R,4aS,8aS by comparing specific rotations of the synthetic sample and the natural product.     

Efficient synthesis of an optically pure β-bromo-β,β-difluoroalanine derivative,a general precursor for β,β-difluoroamino acids

A highly efficient enantioselective preparation of a β-bromo-β,β-difluoroalanine derivative, a promising general precursor for optically active β,β-difluoroamino acids, is described. Alkylation of the hydroxypinanone glycinate Schiff base 2a with CF₂Br₂ resulted in the production of undesired dehydrobrominated product 4a promoted by the lithium alkoxide moiety on the hydroxypinanone chiral auxiliary. Dehydrobromination was prevented by protection of the hydroxyl group on the chiral auxiliary. Utilization of TMSOTf resulted in production of (S,S,S,S)-3b as the sole diastereomer without dehydrobromination. Further transformations of (S,S,S,S)-3b to other optically active β,β-difluoroamino acids were demonstrated.     

Enantioselective synthesis of C2-symmetric hexols from β,δ-diketosulfoxides

An enantioselective synthesis of (1,2S,4S,8S,10S,11)-hexahydroxyundecane, a C₂-symmetric hexol precursor of the alkaloid (−)-lythranidine, is described. This convergent synthesis was based on the stereoselective reduction of two different β,δ-diketosulfoxides.     

Synthesis of (−)-(1′S,4aS,8aR)- and (+)-(1′S,4aR,8aS)-4a-ethyl-1-(1′-phenylethyl)-octahydroquinolin-7-ones

A synthesis of the enamine (−)-(1′S)-5-ethyl-1-(1′-phenylethyl)-1,2,3,4-tetrahydropyridine 4 and its application in a synthesis of (−)-(1′S,4aS,8aR)- and (+)-(1′S,4aR,8aS)-4a-ethyl-1-(1′-phenylethyl)-octahydroquinolin-7-ones 5 and 6 is described. In addition, an X-ray study of 6 is reported. Finally, the preparation of (+)-(4aS,8aR)-4a-ethyl-octahydroquinolin-7-one 7 is described.     

Enantiomer separation and absolute configuration of densely functionalized 2-oxatricyclo[4.3.1.03,8]decanes by CD spectroscopy and chemical correlation

Enantiomer separation by HPLC on a swollen microcrystalline triacetylcellulose column of highly substituted 2-oxatricyclo[4.3.1.0^3,8]decane (2-oxaprotoadamantane) structures afforded enantiomers of this molecule. Application of the octant rule to the carbonyl chromophore to establish the absolute configuration of the enantiomers did not lead to an unequivocal conclusion. The enantioselective synthesis of 4-bromo-3-methoxy-oxaprotoadamantanone was performed from homochiral (+)-(1S,5S)-bicyclo[3.3.1]nonane-2,6-dione thus permitting the assignment of the (1R,3S,4S,6R,8R)-configuration to the title structures.     

An enantioselective synthesis of (+)-azimic acid

Herein we report a concise enantioselective synthesis of (+)-azimic acid starting from (5S,6S)-6-methyl-5-benzyloxy-2-piperidinone 8a, which was prepared from protected (S)-3-hydroxyglutarimide 6 according to a method recently disclosed in our laboratory. The key step is a stepwise regioselective reductive alkylation of the imide 10, which established the 2,6-cis-stereochemistry in excellent diastereoselectivity.     

Perhydro-1,3-benzoxazines derived from (−)-8-aminomenthol as ligands for the catalytic enantioselective addition of diethylzinc to aldehydes

The catalytic potency of a series of perhydro-1,3-benzoxazines prepared from (?)-8-aminomenthol was examined in the enantioselective addition of diethylzinc to aldehydes. When (2R,3S,3aS,4aR,6R,8aS)-2-isopropyl-6,9,9-trimethyl-3-phenyldecahydro-4aH-pyrrolo[2,1-b][1,3]benzoxazin-3-ol 7b was used as a chiral ligand, 1-substituted propanols with an (R)-configuration were obtained in high yields and enantiomeric excesses up to >99%. The catalyst can be recovered and used without any loss in its activity.     

An enantioselective synthesis of the cyclopentene fragment of nucleoside Q

An enantioselective synthesis of (3S,4R,5S)-(+)-3-amino-4,5-dihydroxycyclopentene, a segment of nucleoside Q and Q base, is reported utilizing an amino acid-derived acylnitroso Diels-Alder cycloaddition.     

A greener enantioselective synthesis of the antiviral agent North-methanocarbathymidine (N-MCT) from 2-deoxy-d-ribose

An enantioselective synthesis of suitably protected (1R,2S,4S,5S)-4-amino-1-(hydroxymethyl)bicyclo[3.1.0]hexan-2-ol, a key starting material for the synthesis of conformationally locked carbocyclic nucleosides, including the antiviral active North-methanocarbathymidine, is reported. Starting from 2-deoxyribose the target Boc-protected amine was prepared in 33% overall yield under conditions that are ecologically friendlier than previous methods.     

Synthesis of (−)- and (+)-8-fluoro-galanthamine

The synthesis of racemic 8-fluorogalanthamine and its separation into (−)- and (+)-8-fluorogalanthamine (= (4aS,6R,8aS)- and (4aR,6S,8aR)-1-fluoro-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol) is described.     

Facile preparation of methyl 5-aryl-4-hydroxyhex-2(E)-enoate,chiral synthon of bisabolane-type sesquiterpenes,based on lipase-catalyzed kinetic resolution and rearrangement of an aryl group

The lipase-catalyzed enantioselective acetylation of racemic methyl (4S¹,5S¹)-4-aryl-5-hydroxyhex-2(E)-enoates 1a–h was performed and efficient resolutions were achieved (E >400) by using CAL-B. After brosylation of the obtained optically active 1a–h, solvolysis of brosylates 13a–h afforded the corresponding methyl (4S¹,5S¹)-5-aryl-4-hydroxyhex-2(E)-enoates 3a–h (26–94% yield). The yields of 3a and 3c on the solvolysis of the corresponding 13 were 92% and 40%, respectively, while solvolysis of the corresponding tosylate was reported at 70% and 17%, respectively. This procedure is a facile and practical route to the synthesis of bioactive and optically active bisabolane-type sesquiterpenes.     

Enantioselective synthesis of preclavulone A and its methyl ester

A highly enantioselective synthesis of the (8S,12S)-enantiomer of preclavulone A and its methyl ester is described featuring the Julia protocol for installing the (Z)-double bond in the lower chain. This procedure is suitable for the preparation of labeled preclavulone analogues for biosynthetic studies on marine clavulones.     

First enantioselective synthesis of (+)-quinolizidine 207I: determination of the absolute stereochemistry

First enantioselective synthesis of quinolizidine 207I has been achieved and the absolute stereochemistry of natural quinolizidine 207I was determined to be 1S,4S,10S by the present chiral synthesis using GC analysis with β-dextrin chiral column on co-injection with racemate.