Enantioselective synthesis of beta-Amino acids. 12. experimental and theoretical study of the diastereoselectivity of alkylation of the dianion of N',N'-Bis(alpha-phenylethyl)-N -carbobenzyloxypropionamide
Achiral, inexpensive beta-alanine was converted into the title chiral amide 1 in 53% overall yield. C-Alkylation of (R,R)-1 required formation of its dianion derivative, (R,R)-1-Li2, which was best achieved by direct metallation with two equivalents of n-BuLi in THF solution and at -78°C. Treatment of (R,R)-1-Li2 with various alkyl halides afforded the monoalkylated products 3-6 in 24-85% yield and 65-86% diastereoselectivity. The effect of LiCl additive or HMPA co-solvent on the diastereoselectivity of the alkylation reaction was essentially negligible, although reaction yields generally improved. Chemical correlation of the major diastereomer from the methylation reaction with (S)-alpha-methyl-beta-alanine shows that addition of the electrophile takes place preferentially on the enolate's Si face. This conclusion is also supported by molecular modelling studies (ab initio HF/3-21G), which indicate that the conformation of lowest energy for (R,R)-1-Li2 presents a more sterically hindered Re face of the enolate. The theoretical studies also provided useful insight into the importance of hydrogen bonding and attractive <FONT FACE=Symbol>p-p</FONT> interactions in (R,R)-1. Furthermore, the calculations predict a determining role for N-Li-O chelation in (R,R)-1-Li, as well as an interesting ion triplet configuration for dilithium dianion (R,R)-1-Li2.
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Sociedade Brasileira de Química
2001
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oai:scielo:S0103-505320010005000082001-11-01Enantioselective synthesis of beta-Amino acids. 12. experimental and theoretical study of the diastereoselectivity of alkylation of the dianion of N',N'-Bis(alpha-phenylethyl)-N -carbobenzyloxypropionamideGutiérrez-García,Víctor ManuelReyes-Rangel,GloriaMuñoz-Muñiz,OmarJuaristi,Eusebio Amino acids diastereoselective alkylation enolates theoretical studies Achiral, inexpensive beta-alanine was converted into the title chiral amide 1 in 53% overall yield. C-Alkylation of (R,R)-1 required formation of its dianion derivative, (R,R)-1-Li2, which was best achieved by direct metallation with two equivalents of n-BuLi in THF solution and at -78°C. Treatment of (R,R)-1-Li2 with various alkyl halides afforded the monoalkylated products 3-6 in 24-85% yield and 65-86% diastereoselectivity. The effect of LiCl additive or HMPA co-solvent on the diastereoselectivity of the alkylation reaction was essentially negligible, although reaction yields generally improved. Chemical correlation of the major diastereomer from the methylation reaction with (S)-alpha-methyl-beta-alanine shows that addition of the electrophile takes place preferentially on the enolate's Si face. This conclusion is also supported by molecular modelling studies (ab initio HF/3-21G), which indicate that the conformation of lowest energy for (R,R)-1-Li2 presents a more sterically hindered Re face of the enolate. The theoretical studies also provided useful insight into the importance of hydrogen bonding and attractive <FONT FACE=Symbol>p-p</FONT> interactions in (R,R)-1. Furthermore, the calculations predict a determining role for N-Li-O chelation in (R,R)-1-Li, as well as an interesting ion triplet configuration for dilithium dianion (R,R)-1-Li2.info:eu-repo/semantics/openAccessSociedade Brasileira de QuímicaJournal of the Brazilian Chemical Society v.12 n.5 20012001-10-01info:eu-repo/semantics/articletext/htmlhttp://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532001000500008en10.1590/S0103-50532001000500008 |
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Gutiérrez-García,Víctor Manuel Reyes-Rangel,Gloria Muñoz-Muñiz,Omar Juaristi,Eusebio |
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Gutiérrez-García,Víctor Manuel Reyes-Rangel,Gloria Muñoz-Muñiz,Omar Juaristi,Eusebio Enantioselective synthesis of beta-Amino acids. 12. experimental and theoretical study of the diastereoselectivity of alkylation of the dianion of N',N'-Bis(alpha-phenylethyl)-N -carbobenzyloxypropionamide |
author_facet |
Gutiérrez-García,Víctor Manuel Reyes-Rangel,Gloria Muñoz-Muñiz,Omar Juaristi,Eusebio |
author_sort |
Gutiérrez-García,Víctor Manuel |
title |
Enantioselective synthesis of beta-Amino acids. 12. experimental and theoretical study of the diastereoselectivity of alkylation of the dianion of N',N'-Bis(alpha-phenylethyl)-N -carbobenzyloxypropionamide |
title_short |
Enantioselective synthesis of beta-Amino acids. 12. experimental and theoretical study of the diastereoselectivity of alkylation of the dianion of N',N'-Bis(alpha-phenylethyl)-N -carbobenzyloxypropionamide |
title_full |
Enantioselective synthesis of beta-Amino acids. 12. experimental and theoretical study of the diastereoselectivity of alkylation of the dianion of N',N'-Bis(alpha-phenylethyl)-N -carbobenzyloxypropionamide |
title_fullStr |
Enantioselective synthesis of beta-Amino acids. 12. experimental and theoretical study of the diastereoselectivity of alkylation of the dianion of N',N'-Bis(alpha-phenylethyl)-N -carbobenzyloxypropionamide |
title_full_unstemmed |
Enantioselective synthesis of beta-Amino acids. 12. experimental and theoretical study of the diastereoselectivity of alkylation of the dianion of N',N'-Bis(alpha-phenylethyl)-N -carbobenzyloxypropionamide |
title_sort |
enantioselective synthesis of beta-amino acids. 12. experimental and theoretical study of the diastereoselectivity of alkylation of the dianion of n',n'-bis(alpha-phenylethyl)-n -carbobenzyloxypropionamide |
description |
Achiral, inexpensive beta-alanine was converted into the title chiral amide 1 in 53% overall yield. C-Alkylation of (R,R)-1 required formation of its dianion derivative, (R,R)-1-Li2, which was best achieved by direct metallation with two equivalents of n-BuLi in THF solution and at -78°C. Treatment of (R,R)-1-Li2 with various alkyl halides afforded the monoalkylated products 3-6 in 24-85% yield and 65-86% diastereoselectivity. The effect of LiCl additive or HMPA co-solvent on the diastereoselectivity of the alkylation reaction was essentially negligible, although reaction yields generally improved. Chemical correlation of the major diastereomer from the methylation reaction with (S)-alpha-methyl-beta-alanine shows that addition of the electrophile takes place preferentially on the enolate's Si face. This conclusion is also supported by molecular modelling studies (ab initio HF/3-21G), which indicate that the conformation of lowest energy for (R,R)-1-Li2 presents a more sterically hindered Re face of the enolate. The theoretical studies also provided useful insight into the importance of hydrogen bonding and attractive <FONT FACE=Symbol>p-p</FONT> interactions in (R,R)-1. Furthermore, the calculations predict a determining role for N-Li-O chelation in (R,R)-1-Li, as well as an interesting ion triplet configuration for dilithium dianion (R,R)-1-Li2. |
publisher |
Sociedade Brasileira de Química |
publishDate |
2001 |
url |
http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532001000500008 |
work_keys_str_mv |
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