Application of the chiral base desymmetrisation of imides to the synthesis of the alkaloid jamtine and the antidepressant paroxetine

The synthesis of the alkaloid jamtine and the antidepressant paroxetine have been addressed by a strategy involving asymmetric desymmetrisation of prochiral imides by a chiral lithium amide base. A short reaction sequence, starting with a cyclohexane fused succinimide, led to the structures originally reported for the alkaloid jamtine and its derived N-oxide. The structures synthesised are shown not to correspond with those originally reported. A second sequence involves desymmetrisation of a 4-arylglutarimide, and provides a short enantioselective synthesis of the drug substance paroxetine.     

Metal Amides as the Simplest Acid/Base Catalysts for Stereoselective Carbon–Carbon Bond‐Forming Reactions

In this paper, new possibilities for metal amides are described. Although typical metal amides are recognized as strong stoichiometric bases for deprotonation of inert or less acidic hydrogen atoms, transition‐metal amides, namely silver and copper amides, show interesting abilities as one of the simplest acid/base catalysts in stereoselective carbon–carbon bond‐forming reactions.     

MM3 force field prediction of the enantioselective preference in the asymmetric synthesis of a chiral 2-cyclohexen-1-ol using a chiral lithium amide reagent

Enantioselective preference in the asymmetric synthesis where cyclohexene oxide is transformed enantioselectively to chiral (S)- or (R)-2-cyclohexen-1-ol by the reaction with the appropriate chiral lithium amide reagent has been evaluated theoretically using the MM3 force field. The plausible possible structures for each precursor (reaction intermediate complex) leading to a (S)- or (R)-2-cyclohexen-1-ol have been optimized with the extended MM3 force field applicable to the lithium amide functional group, and the populations of their (S)- or (R)-reaction intermediate complexes at an ambient temperature (298 K) were calculated. The initial structure for evaluating the reaction intermediates of this asymmetric synthesis was constructed on the basis of the optimized ab initio transition state structure (MP2/6-31+G^∗) comprising lithium amide LiNH₂ and propene oxide. To the thus obtained transition state structure composed of LiNH₂ and propene oxide, the other remaining Cartesian coordinates for the actual reaction intermediates composed of the chiral lithium amides and cyclohexene oxide were added to make the reaction intermediate structure. The conformational search for the reaction intermediate has been carried out by using the Stochastic search Algorithm, and the optimized geometries and their conformational energies (steric energies) have been calculated by the MM3 force field. The populations calculated from the conformational energies of the reaction intermediate leading to the (S)- or (R)-2-cyclohexen-1-ol were shown to be linearly well correlated with the experimentally reported enantiomer excess (% ee) values. The critical factors to control the enantioselectivity were investigated on the basis of the optimized structures of the reaction intermediate complexes. The MM3 force field approach was shown to be applicable to the theoretical evaluation of the enantioselectivity and be useful for designing a new functional chiral lithium amide reagent for the asymmetric synthesis.     

Chiral relay: a novel strategy for the control and amplification of enantioselectivity in chiral Lewis acid promoted reactions

Chiral Lewis acid catalysis has emerged as one of the premiere method to control stereochemistry. Much effort has gone into the design of superior ligands with increasing steric extension to shield distant reactive sites. We report here an alternative and complementary approach based on a "chiral relay". This strategy focuses on the improved design of achiral templates which may relay and amplify the stereochemistry from ligands. The essence of this strategy is that the chiral Lewis acid would effectively convert an achiral template into a chiral non-racemic template. This approach combines the advantages of enantioselective catalysis (substoichiometric amount of the chiral inducer) with the ones of chiral auxiliary control (efficient and predictable stereocontrol).     

Strategy for enantio- and diastereoselective syntheses of all possible stereoisomers of 1,3-polyol arrays based on a highly catalyst-controlled epoxidation of alpha,beta-unsaturated morpholinyl amides: application to natural product synthesis

We describe a new strategy for enantio- and diastereoselective syntheses of all possible stereoisomers of 1,3-polyol arrays. This strategy relies on a highly catalyst-controlled epoxidation of alpha,beta-unsaturated morpholinyl amides promoted by the Sm-BINOL-Ph(3)As[double bond]O (1:1:1) complex, followed by a conversion of morpholinyl amides into ketones and diastereoselective ketone reduction. Highly enantio- (up to >99 % ee) or diastereoselective (up to >99.5:0.5) epoxidation was achieved using 5-10 mol % of the Sm complex to afford synthetically very useful, nearly optically pure alpha,beta-epoxy morpholinyl amides. Stereoselectivity of the epoxidation was controlled by the chirality of BINOL with overwhelming inherent diastereofacial preference for the substrate. Combination with the syn- and anti-selective ketone reduction with the highly catalyst-controlled epoxidation allowed for an iterative strategy for the syntheses of all possible stereoisomers of 1,3-polyol arrays. Eight possible stereoisomers of 1,3,5,7-tetraol arrays were synthesized with high to excellent stereoselectivity. Moreover, the efficiency of the present strategy was successfully demonstrated by enantioselective syntheses of several 1,3-polyol/alpha-pyrone natural products, for example, cryptocaryolone diacetate.     

Diastereo- and enantioselective aldol reaction of granatanone (pseudopelletierine)

Granatanone (granatan-3-one, 9-methyl-9-azabicyclo[3.3.1]nonan-3-one, pseudopelletierine or pseudopelletrierin) undergoes deprotonation with lithium amides giving a lithium enolate, which reacts with aldehydes diastereoselectively giving exclusively exo isomers and anti/syn selectivity up to 98:2. Granatanone can be enantioselectively lithiated by chiral lithium amides and the resulting non-racemic enolate can be reacted with aldehydes giving aldols with enantiomeric excess up to 93% (99% ee after recrystallization). The absolute and relative configuration of the aldol products was determined by NMR spectroscopy and X-ray analysis.Granatanone; aldol reaction; asymmetric synthesis; enantioselective deprotonation; chiral lithium amide.     

手性氨基酸酰胺催化剂的发现及研究进展

自从L-脯胺酰胺被发现能高效催化不对称aldol反应以来,手性氨基酸酰胺催化剂的设计及不对称催化研究一直受到关注.特别是“烯胺-双氢键”模型的提出为设计新型有机小分子催化剂提供了理论依据,使催化剂的结构设计趋于多样化.本文重点总结了含有单氢键给体、双氢键给体及多氢键给体的氨基酸酰胺催化的不对称催化反应,主要包括不对称直...     

Efficient treatment of out-of-plane bend and improper torsion interactions in MM2, MM3, and MM4 molecular mechanics calculations

Simple and very efficient formulas are presented for four-body out-of-plane bend (used in MM2 and MM3 force fields) and improper torsion (used in the MM4 force field) internal coordinates and their first and second derivatives. The use of a small set of bend and stretch intermediates allows for order of magnitude decreases in calculation time for potential energies and their first and second derivatives, which are required in molecular mechanics calculations. The formulas are eminently suitable for use in molecular simulations of systems with complicated bond networks. © 1997 John Wiley & Sons, Inc. J Comput Chem 18 : 1804–1811, 1997