A highly efficient direct asymmetric aldol reaction of a glycinate Schiff base with aldehydes has been achieved under mild organic/aqueous biphasic conditions with excellent stereochemical control, using chiral quaternary ammonium salt 1b as a phase-transfer catalyst. The initially developed reaction conditions, using 2 equiv of aqueous base (1% NaOH (aq)), exhibited inexplicably limited general applicability in terms of aldehyde acceptors. The mechanistic investigation revealed the intervention of an unfavorable yet inevitable retro aldol process involving the chiral catalyst. On the basis of this information, a reliable procedure has been established by use of a catalytic amount of 1% NaOH (aq) and ammonium chloride, which tolerates a wide range of aldehydes to afford the corresponding anti-beta-hydroxy-alpha-amino esters almost exclusively in an essentially optically pure form.

The construction of organic molecules containing chiral quaternary carbon centers by catalytic enantioselective reactions represents a very challenging and demanding area in organic synthesis, [1] because in addition to the inherent difficulty of developing an appropriate catalyst system, chiral fully substituted carbon centers are often essential for the biological activity of natural products and pharmaceuticals. Among the various transformations suitable for this purpose, the catalytic asymmetric alkylation of b-keto esters facilitates the direct stereocontrolled formation of quaternary stereocenters with structurally diverse substituents, which offers ample opportunity for further structural elaboration. However, few examples have been demonstrated to date, and only palladium-catalyzed asymmetric allylic alkylation has proved to be promising as an alternative strategy.[2] Although a method for asymmetric alkylation under phase-transfer catalysis should provide a simple yet potential solution to this problem, it is far being a synthetically useful method. [3, 4] Herein we wish to report highly enantioselective phasetransfer alkylation of b-keto esters catalyzed by N-spiro C 2 -symmetric chiral quaternary ammonium salt 1, [5] which results in the catalytic asymmetric establishment of a quaternary stereogenic center (Scheme 1). We also describe further utilization of our approach to establishing chirality by asymmetric Michael addition to a,b-unsaturated carbonyl compounds.As expected based on the relatively low reactivity of metal enolates of 1,3-dicarbonyl compounds, attempted treatment of 2-tert-butoxycarbonyl-1-indanone (2) with benzyl bromide (1.2 equiv) in toluene/50 % KOH aqueous solution at 0 8C for several hours led to gradual formation of the alkylation product 3 a (13 % yield after 6 h). In marked contrast, however, the benzylation in the presence of 1 mol % of chiral ammonium bromide 1 under otherwise similar conditions proceeded instantaneously to give 3 a in 94 % yield and, fortunately, the selectivity was determined to be 89 % ee (Scheme 1). To improve the enantioselectivity, we examined the effect of temperature on the reaction with solid inorganic bases and found that vigorous stirring of the mixture of 2, benzyl bromide (1.2 equiv), 1 (1 mol %), and powdered KOH (5 equiv) in toluene at À20 8C for 1.5 h afforded 3 a in 87 % yield with 92 % ee.[6] Even higher selectivity (94 % ee) was achieved by conducting the reaction at À40 8C, though the reaction was slower. The reactivity was improved when CsOH·H 2 O was used as a base, leading to the production of 3 a in 90 % yield with 95 % ee after a reaction time of 3 h. [7] With these optimized conditions in hand, we explored the general applicability of the present phase-transfer catalytic asymmetric alkylation system; the results are summarized in Table 1. The catalytic asymmetric creation of quaternary carbon centers by introduction of methyl and allylic substituents to substrate 2 has been demonstrated with appropriate electrophiles. Excelle...

C57BL/6J (BL6J) and C57BL/6N (BL6N) inbred substrains are most widely used to understand the pathological roles of target molecules in a variety of diseases, including non-alcoholic steatohepatitis (NASH), based on transgenic mouse technologies. There are notable differences in the metabolic phenotypes, including glucose tolerance, between the BL6J and BL6N substrains, but the phenotypic differences in NASH are still unknown. We performed a comparative analysis of the two mouse substrains to identify the pathological phenotypic differences in NASH models. In the CCl4-induced NASH model, the BL6J mice exhibited a more severe degree of oxidative stress and fibrosis in the liver than the BL6N mice. In contrast, in the high-fat diet-induced NASH model, more accumulation of hepatic triglycerides but less weight gain and liver injury were noted in the BL6J mice than in the BL6N mice. Our findings strongly suggest caution be exercised with the use of unmatched mixed genetic background C57BL6 mice for studies related to NASH, especially when generating conditional knockout C57BL6 mice.

As naturally occurring a-amino acids as well as components of many complex biologically active cyclic peptides and enzyme inhibitors, optically active b-hydroxy-a-amino acids are extremely important chiral units, especially from the pharmaceutical viewpoint. [1] Furthermore, they are useful chiral building blocks in organic synthesis [2] as exemplified by their transformation into blactams, [3] b-halo-a-amino acids, [4] and aziridines. [5] Accordingly, numerous methods for the asymmetric synthesis of b-hydroxy-aamino acids have been elaborated, most of which unfortunately involve multistep procedures and/or the inevitable use of a stoichiometric amount of chiral auxiliaries. [6±8] In this regard, the construction of their primary structure with the correct stereochemistry by the direct catalytic asymmetric aldol reaction of a glycine donor with aldehyde acceptors has been considered to be an ideal protocol. [9] However, there have been few successful examples to date, [10,11] except for the chemoenzymatic process with glycine-dependent aldolases. [9b, 12] We report herein an efficient and direct asymmetric aldol reaction of glycine Schiff base 2 [13] with aldehydes under organic/aqueous biphasic conditions by using enantiomeri-cally pure, C 2 -symmetric chiral quaternary ammonium salt 1 [14] as a phase-transfer catalyst (Scheme 1). This approach provides a practical and environmentally benign chemical process for the synthesis of optically active b-hydroxy-aamino acids.Initially, we examined the direct asymmetric aldol reaction of prochiral glycine Schiff base 2 and 3-phenylpropanal as a representative acceptor under phase-transfer conditions. Thorough optimization of the catalyst structure and reaction conditions revealed that treatment of 2 with 3-phenylpropanal (2 equiv) in toluene/aqueous NaOH (1 %) (v/v 1.25:1; 2 equiv of base for 2) in the presence of chiral quaternary ammonium salt (R,R)-1 a (2 mol %) [14d] at 0 8C for 2 h and subsequent hydrolysis with HCl (1n) in THF resulted in the formation of the corresponding b-hydroxy-a-amino ester 3 (R ¼ PhCH 2 CH 2 ) in 76 % yield with the anti/syn ratio of 3.3:1. The enantiomeric excess of the major anti isomer was determined to be 91 % by chiral HPLC analysis (Table 1, entry 1). Significantly, use of (R,R)-1 b (which contains a 3,5bis(3,5-bis(trifluoromethyl)phenyl)phenyl substituent) as a catalyst enhanced both diastereo-and enantioselectivities in this system (anti/syn 12:1; 96 % ee for anti isomer) ( Table 1, entry 2). [15] A variety of aldehydes were examined for this direct asymmetric aldol reaction with (R,R)-1 and the results are listed in Table 1. Generally, the reaction proceeded smoothly at 0 8C for 2 h to afford the anti isomer predominantly, with excellent enantioselectivity. Heptanal, an aliphatic aldehyde with a long hydrocarbon chain, was found to be a good candidate (Table 1, entry 3), thus indicating the feasibility of direct asymmetric synthesis of a variety of lipo b-hydroxy-aamino acids, a useful component for the preparation of lipophil...

The construction of organic molecules containing chiral quaternary carbon centers by catalytic enantioselective reactions represents a very challenging and demanding area in organic synthesis, [1] because in addition to the inherent difficulty of developing an appropriate catalyst system, chiral fully substituted carbon centers are often essential for the biological activity of natural products and pharmaceuticals. Among the various transformations suitable for this purpose, the catalytic asymmetric alkylation of b-keto esters facilitates the direct stereocontrolled formation of quaternary stereocenters with structurally diverse substituents, which offers ample opportunity for further structural elaboration. However, few examples have been demonstrated to date, and only palladium-catalyzed asymmetric allylic alkylation has proved to be promising as an alternative strategy.[2] Although a method for asymmetric alkylation under phase-transfer catalysis should provide a simple yet potential solution to this problem, it is far being a synthetically useful method. [3, 4] Herein we wish to report highly enantioselective phasetransfer alkylation of b-keto esters catalyzed by N-spiro C 2 -symmetric chiral quaternary ammonium salt 1, [5] which results in the catalytic asymmetric establishment of a quaternary stereogenic center (Scheme 1). We also describe further utilization of our approach to establishing chirality by asymmetric Michael addition to a,b-unsaturated carbonyl compounds.As expected based on the relatively low reactivity of metal enolates of 1,3-dicarbonyl compounds, attempted treatment of 2-tert-butoxycarbonyl-1-indanone (2) with benzyl bromide (1.2 equiv) in toluene/50 % KOH aqueous solution at 0 8C for several hours led to gradual formation of the alkylation product 3 a (13 % yield after 6 h). In marked contrast, however, the benzylation in the presence of 1 mol % of chiral ammonium bromide 1 under otherwise similar conditions proceeded instantaneously to give 3 a in 94 % yield and, fortunately, the selectivity was determined to be 89 % ee (Scheme 1). To improve the enantioselectivity, we examined the effect of temperature on the reaction with solid inorganic bases and found that vigorous stirring of the mixture of 2, benzyl bromide (1.2 equiv), 1 (1 mol %), and powdered KOH (5 equiv) in toluene at À20 8C for 1.5 h afforded 3 a in 87 % yield with 92 % ee.[6] Even higher selectivity (94 % ee) was achieved by conducting the reaction at À40 8C, though the reaction was slower. The reactivity was improved when CsOH·H 2 O was used as a base, leading to the production of 3 a in 90 % yield with 95 % ee after a reaction time of 3 h. [7] With these optimized conditions in hand, we explored the general applicability of the present phase-transfer catalytic asymmetric alkylation system; the results are summarized in Table 1. The catalytic asymmetric creation of quaternary carbon centers by introduction of methyl and allylic substituents to substrate 2 has been demonstrated with appropriate electrophiles. Excelle...