Margarita Ortiz-Marciales

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.

A Practical and Efficient Route for the Highly Enantioselective Synthesis of Mexiletine Analogues and Novel β-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.

Spiroborate Ester-Mediated Asymmetric Synthesis of β-Hydroxy Ethers and Its Conversion to Highly Enantiopure β-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 Mitsunobus 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.

N-tert-Butyldimethylsilyl Imines as Intermediates for the Synthesis of Amines and Ketones

Abstract Grignard reagents add to benzonitrile at low temperature catalyzed by CuBr and TBSCl affording N-TBS ketimines, which were investigated as intermediaries for the synthesis of primary amines and ketones. N-silylimines were easily obtained by an organolithium addition to benzonitrile followed by a reaction with TBSCl in CH2Cl2. In situ reduction of these imines by BH3 and 1,3,2-oxazaborolidines 1 or 2 as chiral templates afforded the corresponding amines with modest to good enantiomeric excess.

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.

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.

New Method for the Synthesis of Nitriles via the O-TERT-Butyldimethylsilyl Aldoximes

Abstract The reaction of aromatic aldehyde oximes with TBSCl and imidazole in DMF generates the corresponding O-silylated derivative, which undergoes elimination, affording the nitrile with a high yield. For the fragmentation of the predominantly (E) isomer, a base-catalyzed syn elimination mechanism is proposed.

Steric and electronic effects on the reduction of O-silylated aromatic ketoximes with borane

4-Methoxy acetophenone oximes substituted at the oxygen with TMS, TBS, TIPS and MDPS groups were reduced with borane–THF obtaining the 4-methoxy-N-ethyl aniline as the principal product, up to a 95% yield in the case of the more hindered TIPS group. The 2-methoxy- and 2,4-methoxyacetophenone O-TBS oximes produced only the rearranged secondary aniline. Reduction of 1-indanone O-TBS oximes afforded only the tetrahydroquinoline, whereas the 2-indanone analog provided only 2-aminoindan.

Efficient α-alkylation and silylation of aromatic O-tert-butyldimethylsilyl ketoximes

Abstract The α-alkylation and silylation of para substituted acetophenones, 1-and 2-indanone (O-TBS) oximes at various reaction conditions, were studied. Optimum conversions from 82% to 100% were afforded for the alkylation and silylation of these (O-TBS) ketoximes with LDA at −78 °C, using electrophiles, such as, methyl iodide, ethylbromide, benzyl bromide and trimethylchlorosilane.

A General Uncatalyzed Method for the Synthesis of O- Silylated Oximes

Abstract Aldoximes and ketoximes were smoothly and efficiently O-silylated at room temperature with diverse chlorosilanes such as TMSCl, TBSCl, or TIPSCl in dichloromethane or THF, using imidazole as a base to trap the generated hydrochloric acid.