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Asymmetric Halohydrination, Haloazidation and Epoxidation of α,β-Unsaturated Carboxylic Acids and Chlorination of Silyl Enol Ethers: ABSTRACT 1,2-Halofunctionalization of alkenes via three member halonium ion such as halohydrination, haloazidation etc. are the oldest oxidative reactions in organic synthesis. Since the discovery in 1906, a little attention was paid on asymmetric halohydrin reaction. Chiral halohydrins, especially carboxyhalohydrins are versatile and useful synthetic intermediates because of their facile transformation to a variety of important compounds such as α,β-epoxy-, aminohydroxy- and hydroxy carboxylic acid derivatives, and these moieties are either present in or precursors to many biologically active compounds. β-Methoxy/alkoxy-α-amino acids are unusual amino acid constituents of many biologically active cyclic peptide and depsipeptide antibiotics. Similar to carboxyhalohydrins, α-halo-β-methoxy/alkoxy carboxylic acid derivatives are important precursors to β-methoxy/alkoxy-α-amino acids. A potentially straight forward method for the synthesis of α-halo-β-hydroxy/alkoxy carboxylic acid derivatives is the regio- and stereoselective halohydrination (halohydroxylation/haloalkoxylation) reaction of chiral α,β-unsaturated carboxylic acid derivatives. Yb(OTf)3 (15 mol%) catalyzed asymmetric halohydrin reaction of chiral α,β-unsaturated carboxylic acid derivatives were efficiently carried out using 1.5 equiv of N-halosuccinimide (NXS; X = Br, I) as the halogen source to yield anti-α-halo-β-hydroxy/alkoxy carbonyl compounds(Scheme 1). Regio- and anti-selectivity of 100% and Scheme 1 Yb(OTf)3 (15 mol%)NXS (1.5 equiv)NSR1ONSR1ONSR1OOOOOOOORORR1 = alkyl, arylR2 = H, MeR2XR2R2XX = Br, Idr: up to 82:18ROHOrganic solvent, 25 C°12R = H, Me, t-Bu, i-Pr, C6H13,SiMe3 moderate to good diastereoselectivities (up to 82:18) were obtained when (2R)-bornanesultam was used as the chiral auxiliary. This Yb(OTf)3 catalyzed halohydrin reaction could be extended using less nucleophilic and hindered alcohols such as n-hexanol, i-PrOH, t-BuOH and TMS-propergyl alcohol. Similar to halohydrins, 1,2-haloazide compounds are also versatile chemical intermediates for the synthesis of numerous functionalized compounds. Asymmetric bromoazidation of chiral α,β-unsaturated carboxylic acid derivatives were performed with NBS (1.2 equiv) and TMSN3 (1.5 equiv) catalyzed by Yb(OTf)3 (10 mol%) with high regio- and anti-selectivity (100%) (Scheme 2). Moderate to high diastereoselectivities (up to >95:05) were obtained on variation of chiral auxiliaries. Scheme 2 XcROXcROXcRON3BrBrN3Yb(OTf)3 (10 mol%)NBS (1.2 equiv)TMSN3 (1.5 equiv)CH2Cl2, -20 to 45 C°Xc = Chiral auxiliaryR = alkyl, aryl1, (2R)-bornanesultam6, (4S)-oxazolidinone9, (2S,5S)-diphenyl pyrrolidine4:5; dr up to 89:117:8; dr up to 41:5910:11; dr up to >95:05 Enanatioselectively pure halogenated compounds are important precursors for the synthesis of numerous functionalized compounds by replacing the halogen atom with a variety of nucleophiles. Enantioselective synthesis of halogenated organic compounds is, therefore, a challenging task in organic chemistry. New chiral imidodicarbonates 12 and N-chloroimidodicarbonates 13 are designed and synthesized (Figure 1). N-chloroimidodicarbonates 13 function as efficient chiral chlorinating agents. Among these, C2-symmetry (1R,2S,5R)- Figure 1 ONOOORONOOOR12c: R = H13c: R = ClONOOOR12b: R = H13b: R = Cl12a: R = H13a: R = Cl menthyl-N-chloro imidodicarbonate 13a was found to be the best chlorinating agent. Enantioselective chlorination of silyl enol ethers was carried out using N-chloroimidodicarbonate 13a (1.0 equiv) and Sm(OTf)3 (1.1 equiv) in CH2Cl2/THF (3:1 v/v) at -78 °C to provide α-chlorinated carbonyl compounds with moderate enantioselectivity (up to 40%) depending upon silyl groups (Scheme 3). This methodology was generalized with a number of cyclic and acyclic enol ethers. Scheme 3 ONOOOClR1R2R'3SiOR1R2OCl*THF: CH2Cl2, -78 °C13a, Sm(OTf)3ee: up to 40%13a1415 Non-C2-symmetric N-chloroimidodicarbonate 16a and N-chloro-N-acyl carbamates 16b and 16c have also been synthesized (Figure 2). Mono-chiral (1R,2S,5R)-menthyl-N-chloro imidodicarbonate 16a and (1R,2S,5R)-menthyl-N-acetyl-N-chloro carbamate 16b also showed 16% and 10% enantioselectivity, respectively under the same reaction conditions Figure 2 ONOOONOOOONOORRR16a: R = Cl16b: R = Cl16c: R = Cl Epoxidation is an important oxidative reaction in organic chemistry. α,β-Epoxy carbonyl compounds could readily and stereoselectively be transformed by ring opening into a variety of oxyfunctionalized compounds. Chiral auxiliary based asymmetric epoxidation is one of the important strategy to obtain the optically pure epoxy carbonyl compounds. Asymmetric epoxidation of α,β-unsaturated carbonyl compounds by in-situ generated dioxiranes, derived from acetone and different α-chloroacetones, was performed with oxone (1.2-6 equiv) in combination with NaHCO3 (3-14 equiv) in 50% aqueous CH3CN at room temperature (Scheme 4). It was observed that the reaction rate and conversion both increases and oxone loading in epoxidation decreases as the number of chlorine atom increases on acetone.1,1-Dichloroacetones and 1,1,1-trichloroacetones (DCA and TCA) were found to be the most effective ketones to promote the asymmetric epoxidation by in-situ generated dioxirane in connection with reaction rate, conversion and the oxone loading. Moderate to good diastereoselectivity upto 90:10 and good yields were obtained depending on the chiral auxiliaries. Scheme 4 ArROArROClmH(3-m)CCOCH3 (1.1 equiv)Oxone (1.2-6 equiv)NaHCO3 (3-14 equiv)50% aqueous CH3CN, 25 oCO**R = Chiral auxiliarydr upto: 90:10m = 0-3