Both enantiomers of the novel amino alcohol (R)-and (S)-2 are prepared from the corresponding enantiomer of the mandelic acid-derived ethanediol 3. The regioisomeric amino alcohols 1 and 2 are converted into the imines 7 and 8, respectively. Titanium complexes 9 and 10 derived therefrom are used as catalysts for the addition of diethylzinc to benzaldehyde and yield the alcohol 11 in up to 92% ee. On the other hand, the chloro-substituted titanium complexes 14 and 15 are able to mediate the Torgov cyclization reaction of the diketone 16 to give the estrone derivative 17. In both reactions titanium complexes 10 and 15 derived of the novel amino alcohol 2 give higher enantioselectivities than the complexes 9 and 14 that are based on the regioisomeric amino alcohol 1.

The TiCl 4 -mediated reaction of enone 3 with the silyl ketene acetal 2 derived from (R)-propionate 1 occurs in a stereoselective manner. The major aldol adduct 4, whose configuration was proven by an X-ray structure analysis of 6, affords the enantiomerically pure carboxylic acid 5 upon hydrolysis. Impressive progress has been made in the development of stereoselective aldol additions during the last two decades, so that a large variety of b-hydroxy carbonyl compounds have become available. 1 Whereas in the beginning of this evolution, covalently bound chiral auxiliary reagents were used in order to bring about diastereofacial selectivity, 2 enantioselective variants were developed more recently, most of which rely on chiral catalysts. 3 In almost all cases aldehydes were chosen as electrophiles. However, stereoselective aldol additions to prochiral ketones are extremely rare, 4 undoubtedly due to their low reactivity and the fact that they are more difficult substrates for enantiofacial and diastereofacial differentiation. Indeed, the very few examples described rely widely on activated ketones, in particular a-ketoesters and adiketones. 5 In this communication, we report on a novel Mukaiyama-type aldol addition 6 to non-activated ketones, a protocol which provides both simple diastereoselection and diastereofacial selectivity. 7 It is based on 2-hydroxy-1,2,2-triphenylethyl propionate 1 8 and makes enantiomerically pure tertiary alcohol derivatives easily accessible.For this purpose, (R)-propionate 1, readily available from (R)-1,1,2-triphenyl-1,2-ethanediol, 9 was deprotonated with 2 equivalents of lithium diisopropylamide and the dianion formed thereby was treated with chlorotrimethylsilane to give the ketene acetal 2 which formed under simultaneous protection of the tertiary hydroxyl group. 8 It turned out that the (E)-isomer of the ketene acetal 2 was formed predominantly, with an E : Z ratio of 87 : 13. The enone 3, considered to be a representative non-activated ketone, was submitted to a titanium tetrachloride-mediated reaction with ketene acetal 2. It should be noted that, in this reaction, four diastereomeric aldol-type products could arise beside four diastereomeric 1,4-adducts. Amazingly, the crude product formed in 91% yield contained a single isomer to a large extent. NMR analysis revealed that the ratio of 1,2-to 1,4-adducts exceeded 95 : 5. Furthermore, one diastereomer had formed predominantly among the aldol adducts so that the ratio of major stereoisomer 4 to the sum of all others was 91 : 9. Careful column chromatography delivered not only the main product as a single isomer but also the three minor diastereomers which differ, as expected, in their NMR spectra.Reagents and conditions: a) 1) LDA, THF, -78 °C, 2) ClSiMe 3 , -78°C , 94-98%; b) 1) TiCl 4 , CH 2 Cl 2 , -78 °C, 3 h, 77%, 2) H 2 O; c) LiOH∑H 2 O, CH 3 OH, H 2 O, rt, 3 d, 65%; d) n-Bu 4 NF∑3 H 2 O, THF, 12 h, rt, 74% Scheme 1A smooth alkaline hydrolysis of ester 4, isolated in 77% yield, afforded the enantiomerically and diastereome...

Keywords: Asymmetric synthesis / Aldol reaction / Michael addition / TitaniumThe TiCl 4 -mediated Mukaiyama-type reaction of the silyl ketene acetal 2, derived from (R)-propionate 1, with the ketones 3a−d occurs in a stereoselective manner. The aldol product 4c is obtained from the enone 3c, whereas the homologous compound 3d undergoes a 1,4 addition and leads to the keto ester 5. The configurations of the deprotected aldol adduct 6 (obtained from 3c) and the Michael product 5 are determined