Application of acyl cyanophosphorane methodology to the synthesis of protease inhibitors: poststatin, eurystatin, phebestin, probestin and bestatin

Full details are given for the syntheses of the protease inhibitors, poststatin and eurystatin by the acyl cyanophosphorane coupling procedure used for the formation of α-keto amides. We have also extended this methodology to the syntheses of the related α-hydroxy amide natural products, phebestin, probestin and bestatin. The key step in the latter synthetic sequences involved diastereomeric selectivity in the reduction of the α-keto precursor to the corresponding α-hydroxy amide by the use of zinc borohydride.     

Diastereoselective synthesis of α,β-unsaturated systems

Functionalized Z-vinylic tellurides were used in substitution reactions with lower order cyanocuprates leading to α,β-unsaturated ketones and esters in good yields. In the case of acyclic tellurides, the product was obtained in high diastereoselectivity. The control of the stereoselectivity was achieved by simple change of the reaction temperature.     

New chemo and chemo-enzymatic synthesis of β-benzyl-γ-butyrolactones

β-Benzyl-γ-butyrolactones, important intermediates for the synthesis of butyrolactone lignans, have been synthesized by a new route involving preparation of α-β-unsaturated formyl esters. The formyl esters can easily be converted into the desired butyrolactones either through chemical transformations or by enzymatic methods.     

Tandem reduction-olefination for the stereoselective synthesis of (Z)-α-fluoro-α,β-unsaturated esters

A tandem stereoselective reduction-olefination reaction of ethyl 2-acyl-2-fluoro-2-diethylphosphonoacetate employing NaBH₄ in EtOH was developed. The one-pot reaction gave α-fluoro-α,β-unsaturated esters with excellent (Z)-selectivity. A plausible mechanism involving a diastereoselective reduction predicted by the Felkin-Anh model, followed by olefination similar to the Horner-Wadsworth-Emmons reaction, has been proposed.     

The stereoselective total synthesis of (−)-cleistenolide

The stereoselective total synthesis of (−)-cleistenolide is described employing the Barbier allylation, MacMillan α-hydroxylation, Stille-Gennari olefination, and CeCl₃·7H₂O mediated lactonization as key steps.     

Water-promoted highly regio- and stereoselective synthesis of α-dehydro-β-amino esters and nitriles from Baylis-Hillman acetates

The nucleophilic addition of amines to Baylis-Hillman acetates has been efficiently carried out in water at room temperature in the absence of any base, acid, or metal catalyst to produce α-dehydro-β-amino esters and nitriles. This procedure addresses a variety of aliphatic open-chain and cyclic amines and anilines. All the reactions are highly regio- and stereoselective, fast and high yielding.     

anti Ethyl β-thienyl-β-amino-α-hydroxy propionate: a regio and stereoselective ring opening of trans ethyl 2-thienyl-glycidate

anti Ethyl β-thienyl-β-amino-α-hydroxy propionate was obtained regio- and diastereo-selectively in three steps and 45% overall yield, while 95% syn ethyl β-chloro-β-thienyl-α-hydroxy ester was obtained regio-selectively in two steps and 50% overall yield, both from 2-thienyl aldehyde.     

Efficient and versatile stereoselective synthesis of cryptophycins

The cryptophycins are a family of cyclic depsipeptides with four retrosynthetic units A to D which correspond to the respective amino acids and hydroxy acids. A new synthetic route to unit A allows the selective generation of all four stereogenic centres by introducing two of them in a catalytic asymmetric dihydroxylation, followed by substrate-controlled diastereoselective reactions. The diol also serves as the epoxide precursor. This approach provides selective access to stereoisomers of unit A (enantiomers, epimers) for structure-activity relationship studies. The unit A derivatives were incorporated into cryptophycin-1, cryptophycin-52 and a novel epimer of cryptophycin-52.     

Condensation of orthoacetates with aldehydes: a new strategy for the preparation of α,β-unsaturated esters

α,β-Unsaturated esters are formed in good yields when aldehydes are heated with orthoacetates in the presence of a catalytic amount of phenol.     

Radical-mediated hydroxyalkylation of α,β-unsaturated esters

The radical-mediated hydroxyalkylation of α,β-unsaturated esters with alkyl iodides, trialkylborane, water and KF in THF gave the corresponding α-hydroxy esters. The synthetic advantage of the method was demonstrated by a short-step total synthesis of (±)-tanikolide.     

New stereoselective methodology for the synthesis of dihydroxerulin and xerulin, potent inhibitors of the biosynthesis of cholesterol

A new stereoselective methodology for the synthesis of both dihydroxerulin and xerulin has been devised. The key step required cross-coupling reactions between the bromo trienyne, (1E,3E,5E)-1-bromo-8-trimethylsilyl-1,3,5-octatrien-7-yne and the appropriate conjugated diynes. The palladium-catalyzed tandem cross-coupling/cyclization reaction of the resulting polyenynes with (Z)-3-iodo-2-propenoic acid led directly to dihydroxerulin or xerulin with a high degree of stereoselectivity.     

β-Nitro acrylic esters as precursors for the one pot synthesis of polyfunctionalized α,β-unsaturated esters

Conjugate addition of activated methylene derivatives to β-nitro acrylic esters in acetonitrile with DBU (2 equiv) as base, allows the one pot formation of polyfunctionalized α,β-unsaturated esters. The procedure is based on a tandem ‘Michael addition-elimination’ process favoured by the simultaneous behaviour of the nitro group as both an electron-withdrawing and leaving group.     

Radical-mediated hydroxytrifluoromethylation of α,β-unsaturated esters

Treatment of α,β-unsaturated esters with trifluoromethyl iodide and triethylborane in the presence of KF and H₂O gave the corresponding hydroxytrifluoromethylated esters.     

A facile and highly diastereoselective synthesis of carbocyclic spiro-pyrazolones via DABCO catalyzed Michael-Michael domino reaction

An efficient domino Michael-Michael reaction of ω- and δ-nitro α,β-unsaturated esters with alkylidenepyrazolones has been accomplished using DABCO as the organocatalyst under mild reaction conditions. Under the present organocatalytic method, a wide range of carbocyclic spiro-pyrazolones with three tertiary stereogenic centers and a quaternary stereocenter has been prepared in high yields and excellent diastereoselectivities. An ester and nitro groups present in the spiro-pyrazolones have been utilized for further structural transformations.     

One-pot synthesis of polyfunctionalized α,β-unsaturated nitriles from nitroalkanes

The reaction of nitroalkanes with 2-chloro-3-phenylsulfonylpropanenitrile, in the presence of three equivalents of DBU at −10°C, allows the synthesis of polyfunctionalized α,β-unsaturated nitriles. The method proceeds through three different reactions carried out in a tandem sequence, allowing the one-pot formation of the α,β-unsaturated nitriles, generally, with complete E stereochemistry.     

One pot synthesis of unsymmetrical dihydropyridines by green,catalyst free and environmentally benign protocol

Abstract

A facile and ecofriendly synthesis of β-enamino esters is reported by reaction of both aliphatic and aromatic amines with β-keto esters by refluxing in ethanol in absence of any catalyst. Addition of α,β-unsaturated aldehydes to the reaction mixture leads to the formation of unsymmetrical dihydropyridine derivatives which generally are metal free hydrogen sources for asymmetric reduction reactions.     

Mukaiyama aldolisation reactions of α,β-epoxyaldehydes in aqueous media

The Mukaiyama aldolisation reaction in aqueous media of cis and trans α,β-epoxyaldehydes with tert-butyldimethylsilyl ketene acetal in the presence of Lewis's acids was studied. Sc(OTf)₃ gave the best results in terms of selectivity. The same reaction of cis and trans α,β-epoxyaldehydes with the enoxysilane of ethyl pyruvate resulted in epoxy substituted ulosonic derivatives issued from a double sequential condensation of the pyruvate on the epoxy derivatives.     

Enzymatic synthesis of gallic acid esters

Esters of gallic acid were synthesized by enzymatic means using tannase fromAspergillus niger. Alcohols ranging from C₁ through C₁₂ and diols from C₃ through C₆ were tested and found to form esters in the presence of the enzyme.     

New and efficient conditions for the Z-selective synthesis of unsaturated esters by the Horner-Wadsworth-Emmons olefination

The Horner-Wadsworth-Emmons reaction of both 1 (Still's reagent) and 2 (Ando's reagent) with aldehydes was studied. Tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) was shown to be an efficient additive when the reaction was performed in THF at −78 °C. Selectivities close to 95% were obtained in the condensation of 1 with aromatic aldehydes. The use of a 5-fold excess of 18C6 in this reaction had already been reported. However, we have defined conditions in which only catalytic amounts are required.