Asymmetric synthesis of chloroisothreonine derivatives via syn-stereoselective Mannich-type additions across N-sulfinyl-α-chloroimines.

Mannich-type reactions of O-Boc glycolic esters across chiral N-sulfinyl-α-chloroaldimines resulted in the efficient and syn-stereoselective synthesis of new γ-chloro-α-hydroxy-ß-amino esters (dr > 99 : 1). The α-coordinating ability of the chlorine atom was of great importance for the diastereoselectivity of the Mannich-type reaction and overruled the chelation of the sulfinyl oxygen with the lithium ion of the incoming E-enolate in the transition state model. These novel chloroisothreonine derivatives proved to be excellent building blocks in asymmetric synthesis of novel syn-ß,γ-aziridino-α-hydroxy esters and biologically relevant trans-oxazolidinone carboxylic esters.

Rearrangement of N-tert-butanesulfinyl α-halo imines with alkoxides to N-tert-butanesulfinyl 2-amino acetals as precursors of N-protected and N-unprotected α-amino carbonyl compounds.

Reaction of N-tert-butanesulfinyl α-halo imines with alkoxides afforded new N-tert-butanesulfinyl 2-amino acetals in good to excellent yield. These N-tert-butanesulfinyl 2-amino acetals are convenient precursors for the TMSOTf-promoted synthesis of the corresponding N-protected α-amino aldehydes and ketones, as well as for the HCl-promoted synthesis of 2-amino acetal hydrochlorides and α-amino ketone and α-amino aldehyde hydrochlorides in high yield. Via this method, an asymmetric synthesis of (S)-cathinone hydrochloride (er 94:6) was achieved.

Diastereoselective aldol reaction of zincated 3-chloro-3-methyl-1-azaallylic anions as key step in the synthesis of 1,2,3,4-tetrasubstituted 3-chloroazetidines.

Zincated 3-chloro-3-methyl-1-azaallylic anions undergo a stereoselective aldol addition across aromatic aldehydes and subsequent mesylation to produce syn α-chloro-ß-mesyloxyketimines, which were isolated in 80-84% yield and high diastereomeric excess (dr > 97/3) after purification via flash chromatography. The syn α-chloro-ß-mesyloxyketimines were further stereoselectively reduced to give stereochemically defined 3-aminopropyl mesylates, which were cyclized to 1,2,3,4-tetrasubstituted 3-chloroazetidines containing three contiguous stereogenic centers. DFT calculations on the key aldol addition revealed the presence of a highly ordered bimetallic six-membered twist-boat-like transition state structure with a tetra-coordinated metal cyclic structure. DFT calculations revealed that chelation of both zinc and lithium cations in the transition state structure leads to the experimentally observed high syn diastereoselectivity of aldol reactions.

Asymmetric synthesis of α-chloro-ß-amino-N-sulfinyl imidates as chiral building blocks.

New chiral α-chloro-ß-amino-N-sulfinyl imidates were synthesized in high yield and excellent diastereomeric excess via highly anti-selective Mannich-type reactions of (R(S))-methyl N-tert-butanesulfinyl-2-chloroethanimidate with aromatic aldimines. The α-chloro-ß-amino-N-sulfinylimidates proved to be excellent building blocks for the asymmetric synthesis of ß-amino-α-chloro amides and esters, aziridine-2-carboxylic amides and esters, trans-2-aryl-3-chloroazetidines, and methyl 4-phenyloxazolidin-2-one-5-carboxylate. The obtained absolute anti-diastereoselectivity is the opposite of the stereochemical outcome observed for α-methyl-substituted imidates.

New general synthesis of α-alkoxyketones via α'-alkylation, α-alkylation and α,α'-dialkylation of α-alkoxyketimines.

α-Methoxy- and α-ethoxyketones, as important intermediates in organic synthesis and flavor compounds in food chemistry, were synthesized by deprotonation of N-(1-alkoxy-2-propylidene)isopropylamine, prepared by condensation of the corresponding α-alkoxyacetone with isopropylamine, and subsequent reaction of the corresponding 1-azaallylic anions with alkyl halides to afford α'-alkylated, α-alkylated and α,α'-dialkylated ketimines. Hydrolysis of the imino function led to the desired substituted α-alkoxyketones. The ratio of α-, α'-, and α,α'-(di)alkylated compounds depended on the amount of base used and on the nature of the alkylating reagent.

Asymmetric synthesis of chiral N-sulfinyl 3-alkyl- and 3-arylpiperidines by α-alkylation of N-sulfinyl imidates with 1-chloro-3-iodopropane.

α-Alkylation of N-sulfinyl imidates with 1-chloro-3-iodopropane successfully led to 2-substituted N-tert-butanesulfinyl-5-chloropentanimidates in acceptable diastereomeric ratios (dr 67/33 to 72/28) and good yields (74-86%). Subsequent reduction with NaBH(4) led to the corresponding 2-substituted N-tert-butanesulfinyl-5-chloropentylamines, which could be cyclized to a range of new chiral 3-substituted N-tert-butanesulfinylpiperidines using NaH in DMSO. Finally, the N-tert-butanesulfinylpiperidines could be efficiently deprotected to enantiomerically pure 3-alkyl- and 3-arylpiperidine hydrochlorides.

Asymmetric synthesis of new chiral N-sulfinyl 2,2-disubstituted aziridines by Grignard additions across alpha-chloro N-sulfinyl ketimines.

Reaction of chiral alpha-chloro N-tert-butanesulfinyl ketimines with Grignard reagents afforded new chiral N-sulfinyl 2,2-disubstituted aziridines in good to excellent diastereomeric ratio (dr up to 98 : 2). The 1,2,2-trisubstituted aziridines were isolated in high overall yield (51-85%) and with excellent enantiomeric excess (>98% ee). The stereoselectivity obtained in the Grignard addition is rationalized by the coordinating ability of the alpha-chloro atom resulting in the opposite stereochemical outcome as observed for nonfunctionalized N-sulfinyl ketimines.

Asymmetric synthesis of new chiral beta-amino acid derivatives by Mannich-type reactions of chiral N-sulfinyl imidates with N-tosyl aldimines.

New chiral beta-(sulfonylamino)sulfinylimidates are synthesized in high overall yield and excellent diastereomeric excess via highly anti-selective Mannich-type reactions of chiral N-tert-butanesulfinyl imidates with N-tosyl aldimines. Deprotection of the beta-(sulfonylamino)sulfinylimidates gave access to enantiopure imidate hydrochlorides in high yields, as useful intermediates for an easy transformation to new chiral beta-sulfonylamino amides upon simple heating in chloroform. Hydrolysis of the imidate hydrochlorides afforded the corresponding chiral beta-sulfonylamino esters with >98% ee as new chiral beta-amino acid derivatives.

Asymmetric synthesis of alpha-alkylated N-sulfinyl imidates as new chiral building blocks.

Alpha-alkylation of N-sulfinyl imidates, prepared via condensation of tert-butanesulfinamide with ortho esters, led to alpha-substituted N-sulfinyl imidates in good-to-excellent diastereomeric ratios (dr up to >99:1) and yields. Deprotection of the alkylated N-sulfinyl imidates gave access to the corresponding imidate hydrochlorides in outstanding yields. These imidate hydrochlorides proved to be excellent intermediates for an easy transformation to chiral amides in good yields and enantiomeric excess upon simple heating in chloroform. Hydrolysis of the alpha-benzylated imidate hydrochlorides afforded the corresponding chiral esters with >95% ee.

New synthesis of 3-fluoropyrroles.

5-Alkoxymethyl-2-aryl-3-fluoro-1H-pyrroles and 2-aryl-3-fluoro-1H-pyrrole-5-carbaldehydes were efficiently prepared from the corresponding 2-aryl-5-(bromomethyl)-1-pyrrolines via electrophilic alpha,alpha-difluorination of the imino bond, using Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bistetrafluoroborate) and subsequent aromatization by dehydrofluorination. This methodology provides a new and easy entry toward various new 3-fluorinated pyrroles.

Synthesis and reactivity of 1-substituted 2-fluoro- and 2,2-difluoroaziridines.

A straightforward synthesis toward 2-fluorinated aziridines was developed via ring closure of beta-fluorinated beta-chloroamines, which were obtained via reduction of the corresponding alpha-fluorinated amides by borane. When 1-benzyl-2-fluoroaziridine was treated with methanol, reaction occurred at the 2-position, giving rise to N-benzyl-2,2-dimethoxyethylamine, while in the case of 1-benzyl-2,2-difluoroaziridine the 3-position was attacked, giving rise to N-benzyl-2-methoxyacetamide. These reactions point to the divergent reactive behavior of monofluoro- and difluoroaziridines.