New 4‐substituted acyloxyproline derivatives with different hydrophobic properties of the acyl group were easily synthesized and used as catalysts in the direct asymmetric aldol reaction between cyclic ketones (cyclohexanone and cyclopentanone) and several substituted benzaldehydes. Reactions were carried out using water, this being the best reaction medium examined. Screening of these catalysts showed that compounds bearing the most hydrophobic acyl chains [4‐phenylbutanoate and 4‐(pyren‐1‐yl)butanoate] provided better results. The latter catalysts were successfully used in only 2 mol% at room temperature without additives to give aldol products in excellent stereoselectivities. These results demonstrate that derivatization of the proline moiety with the proper simple hydrophobic substituent in the 4‐position can furnish highly active and stereoselective catalysts without the need of additional chiral backbones in the molecule. Finally, an explanation of the observed stereoselectivities in the presence of water is provided.

S y n t h e s i s o f t h e f i r s t 2 4 -A m i n o v i t a m i n D 3 D e r i v a t i v e sAbstract: The synthesis of the first 24-aminovitamin D 3 derivatives is reported. A stereoselective convergent synthetic approach was employed to prepare 24(S)-benzoylamino-25-hydroxyvitamin D 3 and 24(S)-benzoylamino-1a,25-dihydroxyvitamin D 3 in six steps from iodide 2 in 34% and 42% overall yields, respectively. The key step in the synthesis is a novel diastereoselective ultrasonically induced conjugate addition, promoted by the zinc-copper couple, of iodide 2 to methyleneoxazolidinone 4 in aqueous media. The conjugate vitamin D triene system was constructed using the Lythgoe approach.Vitamin D 3 (1a, Figure 1), through its major active metabolites 1a,25-dihydroxyvitamin D 3 [1a,25-(OH) 2 -D 3 , 1b, calcitriol] and 24(R),25-dihydroxyvitamin D 3 [24(R),25-(OH) 2 -D 3 , 1c, secalciferol], exhibits a wide range of biological functions. 1 Besides the regulation of calcium and phosphorus homeostasis, vitamin D 3 participates in cellular proliferation and differentiation processes as well as in some functions related to the immune system. However, its utility as a drug in the treatment of tumors and skin diseases is limited since effective doses provoke undesirable calcemic side effects. 1a For this reason, the search for vitamin D 3 analogues with selective biological function -i.e. a low calcemic effect and high activity as a cellular differentiation agent -has been extensively pursued in the last two decades. 2 The numerous analogues of vitamin D 3 synthesized to date has allowed the establishment of some structure-activity relationships (SAR). These relationships show that the side chain plays a crucial role and that small structural modifications have dramatic effects on the biological activity. 3 Indeed, the most important analogues of vitamin D in terms of therapeutic utility are those containing a modified side chain. 4 We report here the stereoselective synthesis of the first 24-aminovitamin D analogues (1d).Bearing in mind the influence of the hydroxyl groups at C-24 or C-25 on both the binding to the vitamin D receptor (VDR) and the associated biological responses, 3 we considered that the replacement of one of these groups by another polar unit, particularly an amino group or derivative thereof, could give rise to novel analogues with a modified affinity for the VDR and hence different biological activity. The amino group is a very important group in drug development but, despite the large number of modifications that have been made in the vitamin D 3 side chain, the synthesis of amino analogues of vitamin D 3 has not been reported previously.As part of our program devoted to the synthesis of vitamin D analogs and metabolites, as well as to the rational understanding of related biological functions, we recently discovered 5 that 24,25-(OH) 2 -D 3 active metabolites such as secalciferol can be synthesized by employing a diastereoselective conjugate addition in aqueous media 6 of iodide 2 to Seebach's dioxolanone 3....

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