Synthesis of enantiopure 1,2-azido and 1,2-amino alcohols via regio- and stereoselective ring-opening of enantiopure epoxides by sodium azide in hot water.

A practical and convenient method for the efficient and regio- and stereoselective ring-opening of enantiopure monosubstituted epoxides by sodium azide under hydrolytic conditions is reported. The ring-opening of enantiopure styryl and pyridyl (S)-epoxides by N3- in hot water takes place preferentially at the internal position with complete inversion of configuration to produce (R)-2-azido ethanols with up to 99% enantio- and regioselectivity, while the (S)-adamantyl oxirane provides mainly the (S)-1-adamantyl-2-azido ethanol in excellent yield. In general, 1,2-amino ethanols were obtained in high yield and excellent enantiopurity by the reduction of the chiral 1,2-azido ethanols with PPh3 in water/THF, and then converted into the Boc or acetamide derivatives.

Asymmetric synthesis of nonracemic primary amines via spiroborate-catalyzed reduction of pure (E)- and (Z)-O-benzyloximes: applications toward the synthesis of calcimimetic agents.

Highly enantiopure (1-aryl)- and (1-naphthyl)-1-ethylamines were synthesized by the borane-mediated reduction of single-isomeric (E)- and (Z)-O-benzyloxime ethers using the stable spiroborate ester derived from (S)-diphenyl valinol and ethylene glycol as the chiral catalyst. Primary (R)-arylethylamines were prepared by the reduction of pure (Z)-ethanone oxime ethers in up to 99% ee using 15% of catalyst. Two convenient and facile approaches to the synthesis of new and known calcimimetic analogues employing enantiopure (1-naphthalen-1-yl)ethylamine as chiral precursor are described.

Synthesis and stability of new spiroaminoborate esters.

New spiroaminoborate esters derived from 1,1-diphenylprolinol, ephedrine and dihydroquinine with different alkoxy substituents were prepared as stable crystalline compounds and characterized by spectroscopical analysis and specific rotation. The structure of the spiroborate 4 derived from 1,1-diphenylprolinol and dicyclohexyl-1,1'-diol was confirmed by X-ray analysis.

Chiral epoxides via borane reduction of 2-haloketones catalyzed by spiroborate ester: application to the synthesis of optically pure 1,2-hydroxy ethers and 1,2-azido alcohols.

An enantioselective borane-mediated reduction of a variety of 2-haloketones with 10% spiroaminoborate ester 1 as catalyst is described. By a simple basic workup of 2-halohydrins, optically active epoxides are obtained in high yield and with excellent enantiopurity (up to 99% ee). Ring-opening of oxiranes with phenoxides or sodium azide is investigated under different reaction conditions affording nonracemic 1,2-hydroxy ethers and 1,2-azido alcohols with excellent enantioselectivity (99% ee) and in good to high chemical yield.

Spiroborate ester-mediated asymmetric synthesis of beta-hydroxy ethers and its conversion to highly enantiopure beta-amino ethers.

Borane-mediated reduction of aryl and alkyl ketones with alpha-aryl- and alpha-pyridyloxy groups affords beta-hydroxy ethers in high enantiomeric purity (up to 99% ee) and in good yield, using as catalyst 10 mol % of spiroborate ester 1 derived from (S)-diphenylprolinol. Representative beta-hydroxy ethers are successfully converted to beta-amino ethers, with minor epimerization, by phthalimide substitution under Mitsunobu's conditions followed by hydrazinolysis to obtain primary amino ethers or by imide reduction with borane to afford beta-2,3-dihydro-1H-isoindol ethers. Nonracemic Mexiletine and nAChR analogues with potential biological activity are also synthesized in excellent yield by mesylation of key beta-hydroxy pyridylethers and substitution with five-, six-, and seven-membered ring heterocyclic amines.

Novel dimethoxy(aminoalkoxy)borate derived from (S)-diphenylprolinol as highly efficient catalyst for the enantioselective boron-mediated reduction of prochiral ketones.

The novel dimethoxyl(aminoalkoxy)borate 1 was isolated as a white crystalline dimer joined by H-bonding as evidenced by X-ray analysis, and demonstrated to be a highly effective catalyst for the asymmetric reduction of representative prochiral ketones with borane-DMS. Optically pure alcohols were obtained using only 1 mol% of catalyst 1 in up to 99% ee.

Chiral spiroaminoborate ester as a highly enantioselective and efficient catalyst for the borane reduction of furyl, thiophene, chroman and thiochroman containing ketones.

Prochiral heteroaryl ketones containing furan, thiophene, chroman and thiochroman moieties were successfully reduced in the presence of 1 - 10 mol % of spiroaminoborate ester 1 with different borane sources to afford non-racemic alcohols in up to 99% ee. In addition, modest enantioselectivity, around 80% ee, was achieved in the reduction of linear α,ß-unsaturated heteroaryl ketones.

A New and Efficient Approach to the Synthesis of Nicotine and Anabasine Analogues.

A straightforward and practical approach was established for the synthesis of nicotine and anabasine analogues by the cyclization of mesylated 1-(3-pyridinyl)-1,4, and 1,5-diol derivatives to form the pyrrolidino or piperidino fragments. Nicotine analogue (S)-15 was prepared with good enantioselectivity using the developed azacyclization procedure of nonracemic (R)-1-pyridin-3-yl-butane-1,4-diol, which was obtained by the borane-mediated reduction of ketone 12 in the presence of the spiroborate ester derived from diphenyl prolinol and ethylene glycol.

A practical and efficient route for the highly enantioselective synthesis of mexiletine analogues and novel beta-thiophenoxy and pyridyl ethers.

A practical and efficient procedure for the enantioselective synthesis of mexiletine analogues with use of 10% of spiroborate ester 6 as chirality transfer agent is presented. A variety of mexiletine analogues were prepared in good yield with excellent enantioselectivities (91-97% ee) from readily available starting materials. The developed methodology was also successfully applied for the synthesis of novel beta-amino ethers containing thiophenyl and pyridyl fragments.

Highly enantioselective borane reduction of heteroaryl and heterocyclic ketoxime ethers catalyzed by novel spiroborate ester derived from diphenylvalinol: application to the synthesis of nicotine analogues.

An asymmetric synthesis for the preparation of nonracemic amines bearing heterocyclic and heteroaromatic rings is described. A variety of important enantiopure thionyl and arylalkyl primary amines were afforded by the borane-mediated enantioselective reduction of O-benzyl ketoximes using 10% of catalyst 10 derived from ( S)-diphenylvalinol and ethylene glycol with excellent enantioselectivity, in up to 99% ee. The optimal condition for the first asymmetric reduction of 3- and 4-pyridyl-derived O-benzyl ketoxime ethers was achieved using 30% of catalytic loading in dioxane at 10 degrees C. ( S)- N-ethylnornicotine ( 3) was also successfully synthesized from the TIPS-protected ( S)-2-amino-2-pyridylethanol in 97% ee.

Asymmetric synthesis of primary amines via the spiroborate-catalyzed borane reduction of oxime ethers.

[reaction: see text] The enantioselective borane reduction of O-benzyloxime ethers to primary amines was studied under catalytic conditions using the spiroborate esters 5-10 derived from nonracemic 1,2-amino alcohols and ethylene glycol. Effective catalytic conditions were achieved using only 10% of catalyst 5 derived from diphenylvalinol in dioxane at 0 degrees C resulting in complete conversion to the corresponding primary amine in up to 99% ee.

Enantioselective Reduction of Prochiral Ketones using Spiroborate Esters as Catalysts.

Novel spiroborate esters derived nonracemic 1,2-aminoalcohols and ethylene glycol are reported as highly effective catalysts for the asymmetric borane reduction of a variety of prochiral ketones with borane-dimethyl sulfide complex at room temperature. Optically active alcohols were obtained in excellent chemical yields using 0.1 to 10 mol % of catalysts with up to 99% ee.

Spiroborate esters in the borane-mediated asymmetric synthesis of pyridyl and related heterocyclic alcohols.

The effectiveness of several spiroborate ester catalysts was investigated in the asymmetric borane reduction of 2-, 3-, 4-acetylpyridines under different reaction conditions. Highly enantiomerically enriched 1-(2-, 3- and 4-pyridyl)ethanols and 1-(heterocyclic)ethanols were obtained using 1 to 10% catalytic loads of the spiroborate 5 derived from diphenylprolinol and ethylene glycol.

Facile rearrangement of O-silylated oximes on reduction with boron trifluoride/borane.

[reaction: see text] Aromatic O-triisopropylsilyl ketoximes were efficiently rearranged to cyclic and acyclic aniline derivatives on reduction with BF3-ethearate/borane. The bulk of the substituents on the silicon atom, the size of the aliphatic ring, and the presence of alkoxy substituents on the aryl group all play an important role in the aniline.

A 1,3,2-oxazaborolidine dimer derived from (S)-alpha,alpha-diphenylprolinol.

The reaction of (S)-alpha,alpha-diphenylprolinol with an excess of borane-tetrahydrofuran complex yields a stable crystalline material with the composition C34H38B2N2O2, which features a borane adduct of a spirocyclic structure with two oxazaborolidine rings joined by a central tetrahedral B atom. This dimeric oxazaborolidine complex, viz. 3,3,3',3'-tetraphenyl-1,1'-spirobi(3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole)-7-borane, is the dominant product under various reaction conditions; its crystal structure is consistent with 11B, 1H and 13C NMR and IR analyses.

Efficient synthesis of B-alkylated oxazaborolidines derived from ephedrine and norephedrine.

[reaction: see text] Representative B-butyl- and B-methyl-1,3,2-oxazaborolidines derived from ephedrine and norephedrine were prepared in good yield and excellent purity by one-pot treatment of B-H oxazaborolidines with the corresponding organolithium reagent and subsequent hydrolysis of the cyclic borohydride intermediate with anhydrous ammonium chloride.