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Diastereoselective Lewis Acid Mediated Reductions of α‐Alkyl‐β‐Functionalized Carbonyl Compounds
Author(s) -
Bartoli Giuseppe,
Bartolacci Massimo,
Giuliani Arianna,
Marcantoni Enrico,
Massaccesi Massimo
Publication year - 2005
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200500038
Subject(s) - chemistry , lewis acids and bases , stereocenter , nucleophile , moiety , alkyl , borane , chelation , medicinal chemistry , diastereomer , stereochemistry , organic chemistry , enantioselective synthesis , catalysis
A high stereochemical induction has often been observed in the reduction of ketones with stereogenic centres close to the carbonyl function. The level of stereoselectivity is particularly high when “hard” donor groups such as nitrogen or oxygen atoms are present in the molecule. These results have been commonly explained in terms of a chelate‐controlled process. However, this interpretation has recently been challenged, and in many cases an open‐chain mechanism can better account for the observed results. Thus, Lewis‐acid‐mediated chelation and nonchelation control is one of the most fundamental and practical concepts in transferring a nucleophile moiety to carbonyl compounds. In order to clarify the role of a hard Lewis acid in controlling the stereochemical outcome of a given reaction, the Lewis acid mediated reduction of a series of α‐alkyl‐β‐functionalized carbonyl compounds with metallic hydrides in various solvents was recently investigated. In particular, the results derived from the reductions in the presence of dry CeCl 3 were compared to those obtained under the same experimental conditions but in the presence of TiCl 4 , whose ability to form chelation complexes is well established. These investigations show a stereochemical outcome that is fully consistent with a chelation‐controlled pathway in the case of titanium, and an open‐chain‐controlled pathway in the case of CeCl 3 . The strongly chelating TiCl 4 led to the syn isomer in high diastereomeric excess in noncoordinating solvents at –78 °C with borane–Lewis base complex reducing agents, while nonchelating CeCl 3 produced a high excess of the anti isomer in coordinating solvents at the same temperature with metal borohydrides as reducing agent. Therefore, our method based on the choice of CeCl 3 or TiCl 4 as a Lewis acid under the reported conditions represents a significant contribution to the development of new stereoselective reductions of α‐alkyl‐β‐functionalized ketones. These procedures are one of the best known ways to obtain an alcoholic moiety. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)