Halohydrins reduction

The reductive elimination of halohydrins provides a means of introduction of double bonds in specific locations, particularly as the halohydrin may be obtained from the corresponding a-halo ketone. This route is one way of converting a ketone into an olefin. (The elimination of alcohols obtainable by reduction has been covered above, and other routes will be discussed in sections IX and X.) An advantage of this method is that it is unnecessary to separate the epimeric alcohols obtained on reduction of the a-bromo ketone, since both cis- and tran -bromohydrins give olefins (ref. 185, p. 251, 271 cf. ref. 272). Many examples of this approach have been recorded. (For recent examples, see ref. 176, 227, 228, 242, 273.) The preparation of an-drost-16-ene (123) is illustrative, although there are better routes to this compound. 

Formation of oxiranes on the sterically more hindered side of the steroid ring system is usually carried out via /raw -halohydrins which afford oxiranes on treatment with base (c -Halohydrins yield ketones on exposure to base). Two general methods are available for the synthesis of tm s-halohydrins (1) the reduction of a-halo ketones and (2) the addition of a hypohalous acid to unsaturated steroids. 

The success of the halo ketone route depends on the stereo- and regio-selectivity in the halo ketone synthesis, as well as on the stereochemistry of reduction of the bromo ketone. Lithium aluminum hydride or sodium borohydride are commonly used to reduce halo ketones to the /mm-halohydrins. However, carefully controlled reaction conditions or alternate reducing reagents, e.g., lithium borohydride, are often required to avoid reductive elimination of the halogen. 

Bartonand Wolft achieved a similar transformations after introduction of a 5,6-double bond by zinc reduction of a 5,6-halohydrin. 

Poessl, T.M., Kosjek, B., Ellmer, U. et al. (2005) Non-racemic halohydrins via biocatalytic hydrogen-transfer reduction of halo-ketones and one-pot cascade reaction to enantiopure epoxides. Advanced Synthesis and Catalysis, 347 (14), 1827-1834. 

Below are described five approaches to epoxide synthesis by way -.if haLohydrins. These halohydrina may be isol ble purifi ble intermediates or they may be transient, unstable species that undergo spontaneous ring closure under the conditions used to generate them. Jho former are typical of (1) addition of hypobalous acids to olefins 111 chemical reduction of a-h Iocarbonyl compounds, and (3) addition if organometallic reagents to o-halocarbonyl compounds the latter,... 

Chiral halohydrins epoxides.1 The esters (2) of the chiral alcohol 1 derived from camphor-10-sulfonic acid, are converted to a-chloro esters (3) by O-silylation and reaction with NCS with high diastereoselectivity. Reduction of 3 with Ca(BH4)2 results in the recovered auxiliary and the chlorohydrin 4 with clean retention. Cyclization of 4 to the terminal epoxide 5 proceeds with clean inversion. 

Enantioselective reductions. The neat reagent (1), prepared from ( + )-< -pinene, reduces aryl a-halomethyl ketones slowly but in high chemical yield to (R)-halohydrins in 90-96% ee, but optical induction is mediocre in the case of aliphatic a-halo ketones (35-66% ee). The chiral halohydrins are useful precursors to chiral epoxides. 

Three inosamines were obtained in the course of efforts to synthesize myo-inositol by the nitro-sugar cyclization (see p. 142). However, the methods which have been the most productive of new inosamines are those which are well known as means of preparing amino sugars and aminopolyhydric alcohols, namely, reduction of imine derivatives of carbonyl compounds (in this case, inososes) and ammonolysis of halohydrins and epoxides. 

Based on the (/ )-specific ADH from L. kefir, a recombinant E. coli strain was constructed as a whole-cell biocatalyst, and co-expressed GDH was used for regeneration of NADPH [157]. These designer cells were applied for the reduction of 4-fluoroacetophenone to the corresponding optically active (/ )-4-fluorophe-nylethan-l-ol at 0.5 M educt concentration [158]. After a reaction time of 23 h, a conversion of >95% has been achieved, and the purified isolated chiral alcohol showed an ee value of >99% (87% yield). (S)-p-Halohydrins were obtained with this whole-cell catalyst by means of an enantioselective reduction of the corresponding ketones with both high conversions of >95% and enantioselectivities of >99% (Fig. 40). Base-induced cyclization of the [S-halohydrin led to enantiomeri-cally pure (S)-epoxides in high yield and enantiomeric purity (>99% ee) [159]. 

As fas as reaction conditions are concerned, two main approaches are usually taken. Either the nucleophilicity of the R5OH to be added is further enhanced by addition of base (normally R50 M +, or nitrogen bases of low nucleophilicity), i.e., base catalysis, or the electrophilicity of the accepting double bond is further increased by adding, e.g., mercuric salts (alkoxymercu-ration), or sources of halonium ions (formation of / -halohydrins). Clearly, the latter protocol, from now on abbreviated as "onium-methods , necessitates a subsequent step for the removal of the auxiliary electrophile, e.g., reductive demercuration of an intermediate /i-alkoxymercu-rial. Whereas base catalysis has successfully been employed with all varieties of acceptors, application of onium-methods thus far appears to be restricted to a,/ -unsaturated carbonyl compounds. Interestingly, conjugate addition of alcohols to a,/l-enones could also be effected photochemically in a couple of cases. 

Halohydrin formation with subsequent reductive dehalogcnation represents an interesting variation on the theme. For example, when the enone rac-1 was treated with A -bromosuccin-imide in aqueous dimethyl sulfoxide, the bromohydrin roc-2 was formed, predominantly as one diastereomer (the relative configuration at C-3 was not established)23. Reduction with tri-butyltin hydride gave the diastereomeric products exo-3 and endo-3 in 27% and 63% yield, respectively. Here, the product distribution can be explained by the preferred attack of the hydride reagent on the exo-face of the intermediate bicyclic carbon radical, i.e., by kinetic control. Thus, the predominant endo-orientation of the 2-(2-hydroxypropyl) substituent at C-3 was achieved, in contrast to what may be expected from a reversible, i.e., thermodynamically controlled, hydration of the enone rac-1. 

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