Synthesis of nitrogen containing heterocycles and polyfunctionalized compounds from N-tert-butanesulfinyl alkyl, alkenyl and homopropargyl amine derivatives

Abstract

Various applications of chiral N-tert-butanesulfinyl amine derivatives as valuable intermediates in organic synthesis are presented in this dissertation. These amine derivatives were accessed by addition of different nucleophiles to the corresponding N- tert-butanesulfinyl imines (t-BS imines). This work has been divided into six main parts. - Diastereoselective homoallylation and bis-homoallylation of N-tert-butanesulfinyl imines. A general method for the preparation of N-tert-butanesulfinyl bis-homoallyl and tris-homoallyl amine derivatives has been developed. The addition of but-3- enylmagnesium bromide and pent-4-enylmagnesium bromide, obtained from magnesium and 4-bromobut-1-ene or bromomethylcyclopropene and 5-bromopent-1- ene, respectively, to chiral t-BS imines in dry toluene at -78 oC generates the corresponding amino alkene derivatives in good yields (44-85%) and diastereoselectivities (up to >95:5 dr). - Stereoselective synthesis of 2-alkyl pyrrolidine alkaloids. An efficient stereoselective preparation of the 2-alkyl pyrrolidine alkaloids (-)-bgugaine and (+)- villatamine B has been accomplished, in which the key step of the synthesis is a diastereoselective addition of the corresponding alkylmagnesium bromide to the t-BS imine derived from 4-bromobutanal. The formation of the pyrrolidine ring is achieved then through desulfinylation followed by an N-alkylation. - Stereoselective synthesis of N-tert-butanesulfinyl amino ketone derivatives. The addition of organolithium compounds derived from 2-methoxy-1-alkenyl chlorides to t- BS imines and a subsequent hydrolysis of the enol ether moiety yielded different N-tert- butanesulfinyl γ- and ε-amino ketone derivatives in moderate yields (30-65%) and diastereoselectivities. The utility of these compounds in organic synthesis was demonstrated by the preparation of 2-substituted 6-methylpiperidines and azepanes in a stereoselective manner. - Allylic oxidation of N-tert-butanesulfinyl homoallyl amine derivatives. A variety of terminal allyl acetates were obtained in moderate yields (35-49%) but with excellent regioselectivity by means of a palladium(II)-mediated allylic oxidation of N-tert- butanesulfinyl homoallyl amine derivatives resulting from the allylation of the corresponding t-BS imines with allyl bromide. In contrast, the allylic oxidation of N-tert- butanesulfinyl homoallyl amine derivatives prepared using 3-bromocyclohexene as the allylating reagent occurred with better yields (40-85%) and high regio- and diastereoselectivity. - Stereoselective synthesis of 9-amino-9,10-dihydrophenanthrene derivatives. The [2+2+2] cycloaddition of N-tert-butoxycarbonyl homopropargyl amine derivatives, obtained from t-BS aromatic aldimines bearing an ortho-alkynyl substituent, with different alkynes was carried out in the presence of Wilkinson’s catalyst leading to the formation of 9-amino-9,10-dihydrophenanthrene derivatives in low yields (15-45%). - Stereoselective synthesis of 3-substituted 1,2,3,4-tetrahydroisoquinoline derivatives. 4-Azaocta-1,7-diynes were prepared by N-propargylation and a subsequent oxidation of the corresponding N-tert-butanesulfinyl homopropargyl amine derivatives in high yields. These diynes reacted with different alkynes by means of a [2+2+2] cycloaddition promoted by Wilkinson’s catalyst, and were transformed into 3- substituted 1,2,3,4-tetrahydroisoquinolines in variable yields, depending on the nature of the alkyne employed in each case. Similarly, azaocta-1,7-enynes were synthesized by N-allylation or N-propargylation of N-tert-butanesulfinyl homopropargyl or homoallyl amine derivatives, respectively, followed by an oxidation step. Ruthenium-catalyzed ring-closing metathesis of these enynes gave the corresponding cyclic 1,3-dienes, that were finally converted into 3-substituted 1,2,3,4-tetrahydroisoquinolines with a different substitution pattern at the aromatic ring to the ones obtained from the diynes, through a [4+2] cycloaddition and a subsequent oxidation.