Pd(0) catalyzed intramolecular alkylation: stereoselective synthesis of furan and isoxazoline-2-oxide analogs

New optically pure isoxazoline-2-oxide and furan analogs have been synthesized using Pd(0) catalyzed intramolecular cyclizations. Starting from a meso-diol, optically pure compounds were prepared without utilizing chiral ligands at any stage of the synthesis. The stereochemical outcome of the product (>99% ee) was influenced by desymmetrization catalyzed by Pseudomonas cepacia lipase and the stereoselective nature of the palladium catalyzed transformations.     

[2,3]-Wittig rearrangement approach to iminosugar C-glycosides: 5-epi-ethylfagomine, 2-epi-5-deoxyadenophorine and formal synthesis of indolizidine 167B and 209D

A new strategy for the synthesis of 1,2-dideoxy iminosugar C-glycosides and indolizidines involving highly stereoselective [2,3]-Wittig rearrangement from Garner aldehyde has been developed. This rearrangement yielded an optically pure, highly functionalized key intermediate, which has been further utilized for the synthesis of 5-epi-ethylfagomine, 2-epi-5-deoxyadenophorine, and 5-hydroxymethyl indolizidine.     

γ-Amino vinyl sulfoxides in asymmetric synthesis. Synthesis of optically pure α-substituted β-amino nitriles

The synthesis of optically pure (E)- and (Z)-γ-amino vinyl sulfoxides derived from commercially available protected α-amino esters is reported. Hydrocyanation of the double bond with Et₂AlCN is completely stereoselective and provides enantiomerically pure α-substituted β-amino nitriles with complete control of the configuration at the α-carbon being exerted by the sulfinyl group.     

Stereoselective synthesis of optically active forms of δ-multistriatin,the attractant for european populations of the smaller european elm bark beet

A stereoselective synthesis of highly optically pure enantiomers of δ-multistriatin [(1S,2S,4S,5R)-2,4-dimethyl-5-ethyl-6, 8-dioxabicyclo[3.2.1)octane and its antipode] was accomplished starting from tartaric acid enantiomers.     

Total synthesis of (+)-trans- dihydronarciclasine from (+)-7-azabicyclo[2.2.1]heptanone

A concise asymmetric total synthesis of Amaryllidaceae alkaloid (+)-trans-dihydronarciclasine is accomplished starting from optically pure 7-azabicyclo[2.2.1]heptanone scaffold in 13 linear steps. Key features of the strategy include substrate-directed stereoselective installation of the trans B-C ring junction and regioselective Wacker-type internal olefin oxidation to provide a rapid access to all hydroxyl functionalities over the key cyclohexane ring in a stereocontrolled manner.     

Syntheses of tetrahydropyridin-3-ol and tetrahydroazepin-3-ol from a chiral aziridine-2-carboxylate

A method for the stereoselective preparation of 1,2,3,6-tetrahydropyridin-3-ols and 2,3,4,7-tetrahydro-1H-azepin-3-ols, potentially versatile intermediates in the asymmetric synthesis of various piperidine alkaloids and azasugars, has been developed. The routes start with a readily available optically pure aziridine-2-carboxylate. The design strategy relies on four key transformations involving (1) stereoselective reduction of an acyl-aziridine intermediate derived from the aziridine-2-carboxylate, (2) regioselective aziridine ring opening, (3) N-allylation, and (4) ring-closing metathesis. The method developed in this investigation provides ready access to stereochemically defined and highly functionalized 3-hydroxy-substituted tetrahydropyridines and tetrahydroazepines.     

Novel synthesis of 3-pyrrole substituted β-lactams via microwave-induced bismuth nitrate-catalyzed reaction

Highly stereoselective synthesis of 3-pyrrole substituted β-lactams is accomplished. The first step involves the synthesis of 3-phthalimido substituted β-lactams following Staudinger cycloaddition reaction of acid chloride equivalent with imines. Synthesis of 3-amino β-lactams is achieved via the deprotection of phthalimido group with ethylenediamine. These 3-amino β-lactams are converted to a new series of N-substituted pyrroles at room temperature as well as using microwave-induced bismuth nitrate-catalyzed reaction with an excellent yield. Exclusive formation of trans pyrrole-substituted β-lactams is observed with N-chrysenyl system. The method is equally efficient for the synthesis of racemic as well as optically pure 3-pyrrole substituted β-lactams.     

Highly diastereoselective synthesis of 2-substituted-1,3-diols catalyzed by ketoreductases

The stereoselective reduction of α-substituted-β-hydroxy ketones for the preparation of the corresponding optically pure 2-monosubstituted or 2-disubstituted-1,3-diols is described. These transformations proceed in high optical purities and yields. Ketoreductases were able to catalyze the formation of either the syn or the anti diol, depending on the enzyme. By replacing the α-alkyl substituent for an OAc moiety, in low conversion time (≤24 h), ketoreductases catalyzed the formation of the OAc-protected 1,2,3-triol, in high yield and with high optical purity (>99% de, >99% ee). This is a simple and highly stereoselective method for the synthesis of different diastereomers of chiral diols.     

Studies towards the total synthesis of hygrocins A and B

The western segment of hygrocins A–B has been synthesized through the coupling of a chiral C5–C13 synthon with the sterically demanding hexasubstituted naphthalenic core. The C5–C13 chiral fragment has been assembled via a stereoselective Johnson orthoester rearrangement of an optically pure allylic alcohol derived from d-glucose. Our studies lay the platform for the determination of the absolute configuration of the unassigned C8-stereocenter of the title compounds in addition to the completion of the total synthesis of the unique ansamacrolides hygrocins A and B.     

Stereoselective synthesis of fluorinated β-aminoacids from ethyl trans-N-benzyl-3-trifluoromethylaziridine-2-carboxylate

trans-N-Benzyl-3-trifluoromethyl-2-ethoxycarbonylaziridine 2a, easily obtainable in enantiopure forms by CAL-catalysed enzymatic resolution, allowed the regio- and stereoselective synthesis of chiral fluorinated anti-α-functionalised-β-aminoacids, such as trifluoroisoserinates or trifluoro-β-alanine, and trans-3-halo- or 3-hydroxy-β-lactams. Starting from the enantiomerically pure methyl analogue of the title compound, 2c, pure enantiomers of trifluoroisoserine can be obtained in high overall chemical yield. Absolute configurations of optically active β-aminoacids were determined by chemical correlation.     

A two-step, one-pot enzymatic synthesis of 2-substituted 1,3-diols

A biocatalytic cascade reaction was designed for the stereoselective synthesis of optically pure 2-alkyl-1,3-diols employing two enzymes. The cascade process consists of two consecutive steps: a stereoselective diketone reduction and a hydroxy ketone reduction. Chiral diols were formed by the addition of ketoreductases in the same vessel, in high stereoselectivity and chemical yield, without the isolation of the intermediate β-hydroxy ketones.     

Stereoselective 5-exo-trig radical cyclization in the enantioselective synthesis of Pregabalin

A practical stereoselective 5-exo-trig radical cyclization procedure was developed in order to prepare enantiomerically pure GABA derivative precursors (4-alkyl-pyrrolidin-2-ones). This procedure allows much more rapid access to optically pure GABA derivatives, such as the powerful antiepileptic agent (S)-(+)-3-aminomethyl-5-methylhexanoic acid (Pregabaline).     

An efficient and versatile approach for optical resolution of C2-symmetric axially chiral biaryl dials. Synthesis of enantiopure biaryl-derived cyclic trans-1,2-diols

An efficient and practical method for optical resolution of axially chiral biaryl dials using enantiomeric tert-butanesulfinamide as resolving agent was developed. The approach offers a very convenient and straightforward access to versatile enantiomerically pure C2-symmetric biaryl dials in good yields. With the obtained axially chiral dials, stereoselective synthesis of a series of cyclic trans-1,2-diols in optically pure form was investigated.     

Synthesis of bicyclo[3.1.0]hexanones via 1,3-dipolar cycloaddition of diazoalkanes to homochiral α-sulfinyl-2-cyclopentenones

The reactions of diazomethane, diazoethane, and (trimethylsilyl)diazomethane with (S)-2-p-tolylsulfinylcyclopent-2-en-1-one have been studied. The sulfinyl group increases the reactivity and controls the π-facial and endo/exo selectivities. The π-facial selectivity can be inverted in the presence of Yb(OTf)₃, which makes possible the stereodivergent synthesis of both diastereoisomeric pyrazolines. Completely stereoselective denitrogenation of optically pure pyrazolines into cyclopropanes was achieved under substoichiometric Yb(OTf)₃ catalysis.     

Free radical synthesis of benzofused tricyclic β-lactams by intramolecular cyclization of 2-azetidinone-tethered haloarenes

o-Halogenophenyl- and o-halogenobenzyl-4-alkenyl-β-lactams can be prepared both in the racemic form and in optically pure form using the ketene-imine cyclization. These 2-azetidinone-tethered haloarenes were used for the regio- and stereoselective preparation of benzofused tricyclic β-lactams including benzocarbapenems and benzocarbacephems via intramolecular aryl radical cyclisation.     

Asymmetric Total Synthesis of Propindilactone G,Part 2: Enantioselective Construction of the Fully Functionalized BCDE Ring System

The enantioselective synthesis of the fully functionalized BCDE tetracyclic ring system of propindilactone G ( A ) is reported. Several synthetic methods were developed and applied to achieve this goal, including: 1) an asymmetric Diels–Alder reaction in the presence of Hayashi′s catalyst for the synthesis of optically pure key intermediate 3 ; 2) an intramolecular Pauson–Khand reaction (PKR) for the stereoselective synthesis of the BCDE ring with an all‐carbon chiral quaternary center at the C13 position by using the TMS‐substituted acetylene as the substrate; and 3) Pd‐catalyzed reductive hydrogenolysis for the stereoselective synthesis of the fully functionalized BCDE tetracyclic ring system. The chemistry developed herein provided a greater understanding of the total synthesis propindilactone G ( A ) and its analogues.     

Stereoselective cyanation of 4-formyl and 4-imino-β-lactams: application to the synthesis of polyfunctionalized γ-lactams

The stereoselective reaction of 4-oxoazetidine-2-carbaldehydes and their corresponding imines with cyanide-based reagents give β-lactam α-aminonitriles, which are chameleonic building blocks for the controlled synthesis of a variety of new compounds including functionalized γ-lactams, succinimide derivatives, and diamino-lactams derivatives in optically pure form.     

Diastereoselective synthesis of 1,2-O-isopropylidene-1,6-dioxaspiro[4,4]nonane applying the methodology of generation of radical cations under non-oxidizing conditions

We report the stereoselective synthesis of an optically pure spiroketal via an intramolecular tandem hydrogen abstraction reaction promoted by an alkoxy radical. Expanding the use of alkene radical cation under non-oxidizing conditions in the synthetic scenario.     

Optically pure trans-2,3-disubstituted N-sulfinyl aziridines. Regio- and stereoselective opening mediated by the sulfinyl group

A new entry to optically pure trans-2,3-disubstituted N-sulfinyl aziridines starting from 1,2-aminosulfides, involving formation of a sulfonium salt intermediate followed by intramolecular nucleophilic attack by the sulfinamide nitrogen atom, is reported. The regio- and stereoselective opening of the aziridine ring can be achieved by anchimeric assistance of the sulfinyl group.     

Alkylative ring opening of N-methylaziridinium ions and a formal synthesis of tyroscherin

Alkylative ring-opening reactions of stable 2-substituted N-methylaziridinium ions proceeded with various alkyl- or arylmagnesium bromides in the presence of CuI to yield synthetically valuable and optically pure alkylated acyclic amines in a completely regio- and stereoselective manner. This was applied to a formal synthesis of the cytotoxic natural product tyroscherin.