Mahavir Prashad

A new, economical, practical and racemization-free method for the reductive removal of 2-oxazolidinones from N-acyloxazolidinones with sodium borohydride

Abstract A new, economical, practical and racemization-free method for the reductive removal of 2-oxazolidinones by a reduction of N-acyloxazolidinones with sodium borohydride in THF and water is described.

A Facile Asymmetric Synthesis of Either Enantiomer of 2-Substituted Pyrrolidines

A new and general method for asymmetric synthesis of either enantiomer of 2-substituted pyrrolidines from a single starting material is described. Reductive cyclization of (S(S))-gamma-chloro-N-tert-butanesulfinyl ketimines with LiBHEt(3) in THF at -78 to 23 degrees C afforded (S(S),R)-N-tert-butanesulfinyl-2-substituted pyrrolidines in excellent yields (88-98%) and with high diastereoselectivity (99:1). The diastereoselectivity is controlled effectively by the choice of reducing agent. Thus, the corresponding epimers of (S(S),S)-2-substituted pyrrolidines were synthesized in good yields (87-98%) and with high diastereoslectivity (1:99) by simply switching the reducing agent from LiBHEt(3) to DIBAL-H/LiHMDS. Deprotection of N-tert-butanesulfinyl-2-substituted pyrrolidines using 4 N HCl in dioxane and MeOH gave the corresponding enantiomers of 2-substituted pyrrolidines in quantative yield. This method was found to be effective for a variety of substrates including aromatic, heteroaromatic, and aliphatic substituents. Extension of this methodology to the formation of 2-substituted piperidines is also illustrated. Reductive cyclization of (S(S))-delta-chloro-N-tert-butanesulfinyl ketimine with LiBHEt(3) in THF at -78 to 23 degrees C or DIBAL-H/LiHMDS in toluene at -78 to 0 degrees C afforded the (S(S),R)-N-tert-butanesulfinyl-2-substituted piperidines in excellent yield (98%) and with high diastereoselectivity (99:1) or (S(S),S)-N-tert-butanesulfinyl-2-substituted piperidines in good yield (98%) and with high diastereoselectivity (1:99), respectively.

Asymmetric Synthesis of Homoallylic Amines Bearing Adjacent Stereogenic Centers by Addition of Substituted Allylic Zinc Reagents to N-tert-Butanesulfinylimines†

A highly diastereoselective addition of substituted racemic allylic zinc reagents to chiral N- tert-butanesulfinylimines resulting in the formation of homoallylic amines is reported. This method is quite general and also efficient for the preparation of enantiomerically pure homoallylic amines bearing quaternary centers and also adjacent quaternary centers.

An Unexpected Reaction of Arenesulfonyl Cyanides with Allylic Alcohols: Preparation of Trisubstituted Allyl Sulfones

For an ongoing program within our research group we needed to synthesize sulfinates of the type 1. We reasoned that 1 could be easily prepared by a reaction of Baylis– Hillman adduct 3 with p-toluenesulfonyl cyanide (Scheme 1). These reaction conditions, however, led to an unexpected trisubstituted allyl sulfone 2. To the best of our knowledge, such a reaction of a Baylis–Hillman adduct with ptoluenesulfonyl cyanide 3] to form substituted allyl sulfones has not been reported. These types of substituted allyl sulfones are important intermediates in organic synthesis and have been recently found to be highly potent against cancer and abnormal cell proliferation diseases. The synthesis of these substituted compounds has received scant attention in the literature, with only two methods outlined. Kabalka et al. reported the nucleophilic addition of sodium p-toluene sulfinate to an acetate of the Baylis–Hillman adduct, and found that the reaction only proceeded in ionic liquids at high temperatures. Later, Chandrasekhar et al. reported a nucleophilic addition of sodium p-toluene sulfinate to the Baylis–Hillman adduct in polyethylene glycol as the solvent at high temperatures. It is therefore significant that the new method we report herein is unprecedented, quite general, and proceeds efficiently at ambient temperature. Treatment of methyl 2-(hydroxyphenylmethyl) acrylate (3a, 1 equiv) with p-toluenesulfonyl cyanide (4b, 1.2 equiv) in the presence of diisoproylethylamine (1.3 equiv) in dichloromethane at room temperature for 12 hours afforded trisubstituted allyl sulfone 2a in high yield (92 %) with good selectivity (E/Z 5:95; Table 1, entry 1). The structure of 2a was assigned based on H,C NMR spectroscopy and mass spectrometry as well as by comparison with literature data. The E/Z ratio was determined to be 5:95 by H NMR analysis of the crude product. Similarly, the reaction of 3a with benzenesulfonyl cyanide (4 a) in the presence of iPr2NEt in CH2Cl2 at room temperature for 12 hours also proceeded to give the trisubstituted allyl sulfone 2b in 95 % yield and with an E/Z ratio of 6:94 (Table 1, entry 2). Encouraged by these results, we turned our attention to other substituted aromatic acrylates. Interestingly, a large number of these acrylates such as p-methyl, o-bromo, cinnamyl, and furfuryl derivatives reacted cleanly with benzenesulfonyl cyanide (4a) or p-toluenesulfonyl cyanide (4b) in the presence of base leading to the corresponding trisubstituted allyl sulfones 2c–2h (Table 1, entries 3–8) in high yields (80–86 %) and with good selectivity (E/Z ratio from 6:94 to 2:98). In the same way, aliphatic Baylis–Hillman adducts such as methyl 3-hydroxy-2-methylenehexanoate (3 f) and methyl 3-hydroxy-2-methyleneoctanoate (3 g) reacted smoothly with 4 a to afford the corresponding trisubstituted allyl sulfones 2 i (75 % yield) and 2j (72% yield) with an E/Z ratio of 7:93 and 6:94, respectively (Table 1, entries 9 and 10). Interestingly, the reaction of other Baylis–Hillman adducts such as 3-(hydroxymethylphenyl)but-3-en-2-one (3h) with 4a in the presence of iPr2NEt in CH2Cl2 at room temperature for 12 hours afforded trisubstituted allyl sulfone 2k in high yield (85 %) and with high selectivity (E/Z 5:95; Table 1, entry 11). Likewise, the reaction of 4a with 2Scheme 1. Reaction of arenesulfonyl cyanides with various allylic alcohols. Scheme 2. A possible mechanism and conformations.

A convenient and practical method for N-acylation of 2-oxazolidinone chiral auxiliaries with acids

Abstract A one-pot, convenient and practical method for N-acylation of 2-oxazolidinone chiral auxiliaries directly with acids in the presence of pivaloyl chloride and triethylamine is described.

Approaches to the Preparation of Enantiomerically Pure (2R,2'R)-(+)-threo-Methylphenidate Hydrochloride

Various approaches to the preparation of enantiomerically pure (2R,2R)-(+)-threo-methyl- phenidate hydrochloride (1) are reviewed. These approaches include synthesis using enantiomeri- cally pure precursors obtained by resolution, classi- cal and enzyme-based resolution approaches, enan- tioselective synthesis approaches, and approaches based on enantioselective synthesis of (2S,2R)-ery- thro-methylphenidate followed by epimerization at the 2-position. 1 Introduction 2 Methods for the Enhancement of Enantiomeric Purity of 1 3 Approaches Using Enantiomerically Pure Pre- cursors Obtained by Resolution

Enantioselective hydrogenation of α-aminomethylacrylates containing a free N H group for the synthesis of β-amino acid derivatives

We describe highly enantioselective synthesis of β-amino acid derivatives (1a-c) using asymmetric hydrogenation of α-aminomethylacrylates (2a-c), which contain a free basic NH group, as the key step. The α-aminomethylacrylates (2a-c) were prepared using the Baylis–Hillman reaction of an appropriate aldehyde with methyl acrylate followed by acetylation of the resulting allylic alcohols (4a-b) and SN2′-type amination of the allylic acetates (3a-b).

Enantioselective synthesis of (2S,2′R)-erythro-methylphenidate

Abstract A new approach towards the enantioselective synthesis of (2S,2′R)-erythro-methylphenidate (1) is described. The key step in the synthesis utilizes Evans 4-substituted-2-oxazolidinone chiral auxiliary to control the diastereofacial selectivity in the hydrogenation of enamine intermediate 6, yielding the hydrogenated product 7 with excellent diastereoselectivity. Methanolysis of 7 afforded 1 with excellent enantiopurity.

Double Heck reaction of bridged o, o'-dibromobiaryls with ethyl acrylate

Abstract An inter- followed by an intramolecular double Heck reaction of bridged o,o′-dibromobiaryls with ethyl acrylate is described. The nature of the bridging atom/group determined the outcome of the reaction. This double Heck reaction strategy afforded a safe and convenient synthesis of 9-(ethoxycarbonylmethylene)-9H-xanthene and a novel route to 9 and/or 10-substituted anthracene derivatives.

Enzymatic resolution of (±)-threo-methylphenidate

Abstract The resolution of (±)-threo-methylphenidate by enzymatic hydrolysis with α-chymotrypsin or subtilisin carlsberg to afford (2S,2′S)-(−)-threo and (2R,2′R)-(+)-threo-methylphenidate hydrochlorides in high enantiomeric purities is described.