Direct Trifluoroacetylation Across a Trimethylsilyloxy System as a Stereo­specific, Chemo- and Regioselective Approach to C3-Vicinal Halohydrins

Abstract

Trifluoroacetylation across the silyloxy system of 1-acyl-2-O-trimethylsilyl-3-haloglycerols with trifluoroacetic anhydride (TFAA) in the presence of a halide anion (e.g. Bu 4 NX; X = Cl, Br or I), followed by removal of the trifluoroacetyl transient protection, provides a new, efficient entry to configurationally pure C3-vicinal halohydrins.Despite the increasing need for configurationally pure vicinal halohydrins as valuable precursors to diverse functional groups manipulation in natural product synthesis, 1-3 access to these compounds is still limited as direct methods for their preparation (e.g. addition of hypohalous acids and hypohalites to olefins, 4 the ring opening of epoxides by means of metal halides, 5,6 ammonium halides, 7 hydrohalides, 8 elemental halogens, 9 etc.) often suffer from low to moderate regioselectivity, 4,10 substrate incompatibility, 11 excessive expense 12 or poor availability 13,14 of the reagents employed, or afford mixtures of stereoisomers. 6 An alternative two-step approach, involving insertions of organosilicon halides into oxiranes 15 with a subsequent deprotection of thus produced O-silylated derivatives of vicinal halohydrins, 14 is not only incapable of circumventing the aforementioned shortcomings but also introduces additional synthetic problems since cleavage of even relatively labile silyl ethers (e.g. trimethylsilyl-or tert-butyldimethylsilyl derivatives) require conditions that either preclude presence of acid, 14 base, 16 or oxidation-reduction sensitive functionalities 17 in the molecule or are known to trigger prohibitive structural rearrangements of the molecular skeleton (e.g. acyl migration, racemization, etc.) after exposure of a free hydroxyl group. 16,18 For cyclic halohydrins, a method based on the catalytic transfer hydrogenation of a-haloketones via dynamic kinetic resolution has also been reported. 19 Recently, 2-O-silylated glycerol derivatives have become easily accessible in high yields and under mild conditions from glycidyl precursors; 2 thus, we were interested in the development of an efficient protocol for their transformation, preferably via a direct conversion to avoid drawbacks of stepwise deprotection-protection procedures, into the corresponding trifluoroacetyl esters.The important point of having a trifluoroacetyl functionality in a molecule is that it confers stability to glycerol derivatives (e.g. prevents migration of fatty acid residues within the glycerol skeleton) and thus such compounds can be considered as storage forms for labile, biologically important mono-or diacyl glycerols. 20 The added value of the trifluoroacetyl protection is that this group can be removed practically quantitatively under mild conditions, and the produced mono-or diglycerides usually do not require chromatographic purification. 20 So far, examples of direct transformation of various silyloxy systems (e.g. trimethylsilyl-, tert-butyldimethylsilyl-, triisopropylsilyl-, tert-butyldiphenylsilyl ethers, etc.) into either acetyl group (e.g. using FeCl 3 -acetic anh...

Regioselective and Stereospecific Halosilylating Cleavage of the Oxirane System of Glycidol Derivatives as an Efficient Strategy to C2‐O‐Functionalized C3‐Vicinal Halohydrins

“…[47] The important point of introducing a trifluoroacetyl functionality into a molecule is that it confers stability to the framework organization (e.g., prevents scrambling of acyl residues within the glycerol skeleton) and on this basis a convenient storage form for labile, biologically active glycerolipids has been proposed. [48] The added value of the trifluoroacetyl protection is that this group can be removed quantitatively under mild conditions to provide pure target compounds without any additional workup or chromatographic purification.…”