Allyltrichlorostannane additions to chiral aldehydes

Chiral and achiral allyltrichlorostannanes reacted with chiral β-alkoxy and syn and anti α-methyl-β-alkoxy aldehydes to give the corresponding homoallylic alcohols with moderate to high diastereoselectivities.     

Efficient synthesis of syn-α-alkoxy epoxide via a diastereoselective Darzens reaction

A highly diastereoselective Darzens reaction was developed by using a MEM- or TBDPS-protected α-hydroxy aldehyde with di-tert-butyl bromomalonate. This method effectively provides a syn-α-alkoxy epoxide, and a possible reaction mechanism was proposed to explain the high syn selectivity.     

Lewis acid promoted aldol additions of α-thiosilylketeneacetals to α-alkoxy aldehydes: diastereoselective synthesis of syn-α-methylene-β-hydroxy-∂-alkoxy esters.

MgBr₂ mediated addition of Methyl α-methylthio propionate silylketene acetal to α and α,β-alkoxy aldehydes is highly 3,4 $\text{syn}$-selective (18:1). $\text{syn}$-α- methylene-β- hydroxy-?-alkoxy esters (6) and (8) are synthesized.     

Addition of kinetic boron enolates generated from β-alkoxy methyl ketones to aldehydes. Density functional theory calculations on the transition structures

Herein we report that good to excellent levels of 1,5-anti stereoinduction are obtained in boron enolate aldol reactions of 1,2-syn β-alkoxy methyl ketones with achiral aldehydes, when the β-alkoxy protecting group is part of a benzylidene acetal. We have also investigated the effects of the ligands on boron, the α-, β-, and γ-substituents and the β-alkoxy protecting group on the boron enolates, using density functional theory (B3LYP) and Møller-Plesset perturbation theory (MP2) calculations.     

Stereoselective synthesis of malyngic acid and fulgidic acid

A new stereoselective total synthesis of malyngic acid has been achieved from a known oxazolidinone derivative via eight steps involving the Evans asymmetric alkylation as the chirality-inducing step and chelation-controlled Zn(BH₄)₂ reduction of an α-hydroxy ketone intermediate for the installation of the 12,13-anti stereochemistry. Fulgidic acid, the C12-epimer of malyngic acid, has also been synthesized in eight steps from the same starting material by using syn-selective K-Selectride reduction of an α-alkoxy ketone intermediate.     

An enantioselective synthesis of the C1C9 segment of antitumor macrolide peloruside A

A stereocontrolled synthesis of the C₁C₉ segment of the marine natural product peloruside A is described. The key steps involve Sharpless's catalytic asymmetric dihydroxylation reaction, a chelation-controlled reduction of chiral β-alkoxy ketones to elaborate the syn-1,3-diol functionality and a ring-closing olefin metathesis of a homoallylic alcohol-derived acrylate ester to form an α,β-unsaturated δ-lactone.     

Stereoselective synthesis of vicinal diols by the stannous chloride-mediated reaction of unprotected hydroxyallylic stannane with carbonyl compounds

The highly stereoselective synthesis of vicinal diols was accomplished by the reaction of hydroxymethyl anion equivalents with carbonyl compounds. The reaction of hydroxyallylic stannanes with various aldehydes gave but-3-en-1,2-diols in the presence of SnCl₂. The diol moiety showed syn-diastereoselectivity. A mechanism for this reaction was proposed: transmetalation of the hydroxyallylic stannane with SnCl₂ gives an active rearranged allylic tin(II) species, which adds to carbonyl compounds through a cyclic transition state. The use of either α-alkoxy or hydroxy carbonyl compounds instead of aldehydes also gave the corresponding vicinal diols with high selectivity. In this case, either the alkoxy or the hydroxy group effectively coordinates to the tin(II) center to form a transition state that leads to high selectivity. The reaction of hydroxyallylic stannane with α-alkoxy aldehyde afforded the product through a cyclic transition state according to the Felkin-Anh model. This system was applied to sugar synthesis because conventional treatment of protected (R)-glyceraldehyde led to d-arabinose. The configurations of the major products were determined by means of X-ray structural analysis.     

Addition of a 3-alkoxy allenylzinc to N-acyliminium ions: new entry to propargyl syn-1,2-aminoalcohol units

A new addition reaction of a 3-alkoxy allenylzinc reagent to N-acyliminiums prepared in situ from imines and acid halides is reported. Unlike addition onto imines or nitrones that affords the trans adducts, acetylenic syn-1,2 amino ethers are yielded with good selectivities, thus providing a new entry to propargyl syn-1,2-aminoalcohol units.     

A General Method for the Vinylation of Nitrones. Synthesis of Allyl Hydroxylamines and Allyl Amines

An examination of the vinylation of several nitrones is presented. Whereas a complete diastereofacial discrimination was observed upon the addition of vinyl organometallic reagents to α-alkoxy nitrones, the same reaction with α-amino nitrones gave syn adducts in all cases, with the only exception of a L-serine-derived α-amino monoprotected nitrone. The obtained allyl hydroxylamines were easily transformed into synthetically valuable allyl amines.     

Stereoselective allylation reactions of acyclic and chiral α-amino-β-hydroxy aldehydes

Stereoselective allylation reactions of acyclic and chiral α-amino-β-hydroxy aldehydes affording chiral β-amino-α,γ-diols are described. Several Lewis acids (BF₃·OEt₂, SnCl₄, TiCl₄, ZnCl₂, and MgBr₂·OEt₂) were employed to mediate the allylation reactions. The reactions of anti-α-NHCbz-β-OTBS substrates mediated by SnCl₄ afforded syn-selective products. The same reaction conditions also gave satisfactory results for the reactions of syn-α-NHCbz-β-OTBS substrates. The mechanism involves α-chelation between the amido group and aldehyde oxygen.     

Synthesis of α,β-diamino acid derivatives via asymmetric Mannich reactions of glycine imino esters catalyzed by a chiral phosphoramidite·silver complex

AgOTf·phosphoramidite complexes efficiently catalyze the enantioselective Mannich-type reaction between benzophenone-imine glycine methyl ester and N-tosyl aldimines in the absence of a base. The corresponding syn-adducts, which are the direct precursors of α,β-diamino acids, are obtained with moderate to good syn-diastereoselectivities (up to 9:1) and high enantioselectivities (up to 99% ee).     

SmI2-coupling reaction of chiral non-racemic α-bromo-α′-sulfinyl ketones with imines: synthesis of enantiomerically pure 2-methyl-3-amino-1-ol moieties

Chiral non-racemic α-bromo-α′-sulfinyl ketones were shown to react with imines in the presence of SmI₂ to give the corresponding 1,3-aminoketo derivatives with good syn-diastereoselectivity. Further reduction of these adducts either with DIBAL-H only or with DIBAL-H in the presence of Yb(OTf)₃ afforded syn- and anti-2-methyl-3-amino-1-ol moieties, respectively, in good yields and diastereoselectivities.     

Highly stereoselective titanium-mediated aldol reactions from chiral α-silyloxy ketones. A reliable tool for the synthesis of natural products

Chiral α-silyloxy ketones participate in highly stereoselective TiCl₄-mediated aldol reactions that afford diastereomerically pure syn-syn adducts in high yield irrespective of the R¹ and R² substituents flanking the carbonyl or the silicon protecting group. Further manipulation of the resulting aldol adducts provide in a straightforward manner highly functionalized fragments that facilitate the synthesis of natural products.     

Highly enantioselective synthesis of syn- and anti-propionate aldols without diastereoselection in the chiral oxazaborolidinone-promoted aldol reaction with a silyl ketene acetal derived from ethyl 2-(methylthio)propionate

A mixture of syn- and anti-aldol products containing an α-methylthio group were obtained in good yields with high enantioselectivities in the chiral oxazaborolidinone-promoted aldol reactions of a novel silyl ketene acetal, derived from ethyl 2-(methylthio)propionate, with aldehydes. Subsequent desulfurization resulted in an effective preparation of essentially enantiopure syn- and anti-propionate aldols which were separable.     

1,4-syn-Asymmetric induction in the titanium-mediated aldol reactions of chiral methyl α-silyloxy ketones

Good levels of 1,4-syn asymmetric induction are obtained in the TiCl₄-mediated aldol reaction of methyl α-silyloxy ketones with achiral aldehydes. Such methodology represents a new approach to the substrate-controlled acetate aldol reaction, which can be useful to design more efficient syntheses of natural products.     

Stereoselective allylation of acyclic and chiral α-amino-β-Hydroxy aldehydes part 2: Application to the formal synthesis of the polyhydroxylated γ-amino acid (+)-Detoxinine

Stereoselective allylations of acyclic, chiral α-amino-β-hydroxy aldehydes mediated by BF₃·OEt₂ and its application to the formal synthesis of the polyhydroxylated γ-amino acid (+)-detoxinine are described. The reactions of syn-α-NHCbz-β-OTBS substrates mediated by BF₃·OEt₂ afforded syn-selective products. The same reaction conditions gave anti-selective products from syn-α-NCbzBn-β-OTBS substrates. A hydrogen-bonded transition state and Felkin-Anh model have been suggested to account for the stereochemical outcomes of the two reactions, respectively. One of the allylation products was used for the formal synthesis of the polyhydroxylated γ-amino acid (+)-detoxinine.     

Stereoselective titanium-mediated syn-aldol reaction from a lactate-derived chiral ethyl ketone

Stereoselectivity of the titanium-mediated aldol process based on (S)-2-benzyloxy-3-pentanone, 1, is dramatically modified by the presence of a Lewis acid. Among the Lewis acids surveyed, TiCl₄ has given access to the corresponding 2,4-anti-4,5-syn aldol adducts with the highest diastereomeric ratios. The excellent stereocontrol exerted by the aforementioned ketone has been demonstrated in double asymmetric reactions involving chiral α-methyl-β-OTBDPS aldehydes.     

Diastereoselective synthesis of γ-hydroxy α,β-epoxyesters and their conversion into β-hydroxy α-sulfenyl γ-butyrolactones

The diastereoselectivity of the nucleophilic epoxidation of γ-hydroxy-α,β-unsaturated esters has been studied. The γ-hydroxy-α,β-unsaturated esters were obtained through treatment of ethyl (E)-4-oxo-2-butenoate with the corresponding Grignard reagent and were used as a racemic mixture. The resulting γ-hydroxy α,β-epoxyesters were treated with thiophenol for transformation into α-phenylsulfanyl trisubstituted γ-butyrolactones. The syn,syn-lactones isomerize easily in basic media into the syn,anti structures. In order to explain this interconversion, a retroaldol-aldol sequence has been proposed and a sulfur-oxygen interaction has been invoked to explain the syn stereochemical preference of the α-sulfured aldols resulting from the intramolecular aldol reaction.     

Diastereoselective conjugate addition of organocuprates to N-[4-(Dibenzylaminobutenoyl)]oxazolidinone. Synthesis of chiral β-substituted γ-aminoacids

The first conjugate addition reaction of organocuprates to N-enoyl oxazolidinone where a γ-nitrogen atom is present into α,β-unsaturated system is described. The reaction gave syn-products in moderate yields and high diastereomeric ratios. The removal of chiral oxazolidinone moiety and N-deprotection of amino group furnished chiral β-substituted γ -amino acids.     

Cross-metathesis of allyl halides with olefins bearing an α-alkoxy amide group

We have examined whether the allyl halide cross-metathesis reaction tolerates α-alkoxy amide groups. Ruthenium-based catalysts I-III did not catalyze the cross-metathesis of allyl halides in the presence of an α-alkoxy N,N-dimethylamide group to any appreciable extent, but the reaction could tolerate either a bulky N,N-diisopropylamide or Weinreb amide group. In particular, the Grubbs-Hoveyda-Blechert 2nd generation catalyst (III) efficiently catalyzed the cross-metathesis of allyl halides with olefins bearing a Weinreb amide group.