Chiral Epoxides via Borane Reduction of 2-Haloketones Catalyzed by Spiroborate Ester: Application to the Synthesis of Optically Pure 1,2-Hydroxy Ethers and 1,2-Azido Alcohols

Abstract

An enantioselective borane-mediated reduction of a variety of 2-haloketones using 10% of spiroaminoborate ester 1 as catalyst is described. By a simple basic workup of 2-halohydrins, optically active epoxides are obtained in high yield and with excellent enantiopurity (up to 99% ee). Ring opening of oxiranes with phenoxides or sodium azide is investigated under different reaction conditions affording nonracemic 1,2-hydroxy ethers and 1,2-azido alcohols with excellent enantioselectivity (99% ee) and in good to high chemical yield.Nonracemic epoxides are not only recognized for their biological importance, 1 but also as key intermediates in diverse chemical transformations for the synthesis of chiral auxiliaries, natural products and chiral drugs. 2,3 Moreover, chiral epoxides have been recently used as catalysts for asymmetric induction in the auto-catalyzed organozinc addition to an aldehyde. 4 Consequently, in the last thirty years, a variety of direct epoxidation and resolution methods for the synthesis of enantiopure oxiranes have been successfully developed. [5][6][7][8] More convenient and efficient routes to prepare optical pure styrene oxides involve the initial enzymatic 9 or chemical asymmetric reduction of α-halogenated acetophenones.10 -12 Asymmetric transfer hydrogenation of 2-chloroacetophenones has been recently applied using Rh, Ru or Ir diamino complexes as chiral catalysts. Environmentally friendly boron reagents have been used for the reduction of a variety of α-haloketones and the halohydrins are easily converted to nonracemic epoxides without racemization.11 ,12 These methods can be considered, essentially, as a "one pot" procedures valuable for substrates with sensitive groups due to the very mild reaction conditions. Lithium and sodium borohydride reduction of α-haloacetophenones with an stoichiometric amount of (L)-TarB-NO 2 , prepared from tartaric acid and m-nitrophenylboronic acid, was employed recently to afford styrene oxides in moderate to high enantiopurity. 11a The most recognized chiral catalysts for the enantioselective borane-mediated reduction of unsymmetrical ketones with outstanding and predictable stereoselectivities are 1,3,2-oxazaborolidines (OAB) derived from nonracemic 1,2-amino alcohols. 12 These remarkable reagents were initially discovered by Itsuno and further developed and studied by Corey and others. A series of stable crystalline aminoborate esters, derived from a variety of nonracemic 1,2-amino alcohols, ethylene glycol and inexpensive triisopropyl borate, were previously reported by our group. 14,15 The most effective and convenient aminoborate complexes used as catalyst for the borane-mediated reduction of ketones 14, 15a-g and benzyl oximes 15h are shown in Fig. 1.Spiroaminoborate ester 1 derived from diphenylprolinol was highly effective for the reduction of a variety of aryl,15a-d heteroaryl,15e, α-alkoxy15f and aliphatic 15g ketones providing the desired secondary alcohols in excellent yield with excellent enantioselectivity, higher or similar to C...

Production of Enantiopure Chiral Epoxides with E. coli Expressing Styrene Monooxygenase

“…The combined organic layers were dried over anhydrous MgSO 4 , and the solvent was evaporated under reduced pressure (max 120 mbar in a 25 °C water bath or max 50 mbar in a 35 °C water bath for long-chain aliphatic epoxides). The crude product was purified by FCC using hexanes as the eluent to give ( S )-4-chlorostyrene (60 mg, 34% of theoretical yield) oxide as a colourless liquid with spectroscopic data in good agreement with those reported in the literature [ 36 , 37 ].…”

“…Reported rotation for ( S )-4-chlorostyrene oxide = +26 ( c 1.29, CHCl 3 ) for 99% ee [ 36 ], = +26 ( c 1.2, CHCl 3 ) for 99% ee [ 37 ].…”

Selective Asymmetric Transfer Hydrogenation of α‐Substituted Acetophenones with Bifunctional Oxo‐Tethered Ruthenium(II) Catalysts

“…The catalytic ATH system also proved effective for the stereoselective synthetic route to BMS‐960, a potent S1P 1 receptor agonist, as an alternative to the reported borane and enzymatic reaction ,. With slightly modified reaction conditions, the highlighted asymmetric reduction of bromomethyl 4‐cyanophenyl ketone 11 with ( S , S )‐ 3 afforded ( R )‐(−)‐4‐(2‐bromo‐1‐hydroxyethyl)benzonitrile 12 in 87% isolated yield and 88% ee (Scheme ).…”

A New Entry of Highly Selective and Nucleophilic BrH2C‐ and ClH2C‐Titanium Complexes for Carbonyl Coupling

“…General Procedure for the TiCl4‐Mg‐Promoted CH 2 Br Transfer to Idehydes and Ketones as Exemplified for the Preparation of 2‐Bromo‐1‐cyclohexylethanol (2a): The suspension of Mg (97 mg, 4 mmol) and TiCl 4 (3 mL, 1 m in CH 2 Br 2 , 3 mmol) were stirred for 1 min at 0 °C, then added a solution of cyclohexanecarbaldehyde 1a (112 mg, 1 mmol) in C 2 H 4 Cl 2 (2 mL). After being stirred for 5 min, DME (1 mL) was added.…”