Halo alcohols reduction

If the carbonyl group must be regenerated under nonhydrolytic conditions, (3-halo alcohols such as 3-bromopropane-l,2-diol or 2,2,2-trichloroethanol can be used for acetal formation. These groups can be removed by reduction with zinc, which leads to (3-elimination. 

Although lithium p-lithioalkoxides can also be generated from p halo alcohols by deprotonation and subsequent reductive lithiation of the carbon-halogen bond73 8 or from p-halo ketones by organolithium addition to the carbonyl group followed by reductive lithiation,8 the current method is more direct as well as more convenient, since epoxides are readily available either commercially or by a variety of procedures. 

In some circumstances, the production of a 2-halo alcohol by reduction of the carbonyl group of an a-halo ketone with metal hydrides is a useful synthetic reaction ... 

The second Tsuji synthesis, which appeared (see Scheme 1.6) in the latter part of 1978, employed a strategy similar to his earlier work for construction of the basic carbon framework. Ketal diene 19 was transformed to halo alcohol 22 by the use of chemistry established in his previous synthesis. Acylation with phenylthioacetyl chloride readily afforded ester 23. Intramolecular alkylation resulting in ring closure was brought about by deprotonation with sodium hexa-methyldisilazane to give lactone 24 in 71% yield. Synthetic 1 was then obtained in 90% yield following Raney nickel reduction. 

Srebnik, M., Ramachandran, P. V., Brown, H. C. 1988. Chiral synthesis via organoboranes. 18. Selective reductions. 43. Diisopinocampheylchloroborane as an excellent chiral reducing reagent for the synthesis of halo alcohols of high enantiomeric purity. A highly enantioselective synthesis of both optical isomers of Tomoxetine, Fluoxetine, and Nisoxetine. J. Org. Chem. 53 2916-2920. 

A large variety of methods is applicable to the formation of isolated double bonds. This permits selection of reagents compatible with other functionality present. Alcohol dehydration, ester elimination and other nonreductive p eliminations are the most common methods. Reductive elimination of halo-hydrins, vic-dihalides, etc., and of a variety of ketone derivatives has also been used. 

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. 

Borohydrides reduce a-substituted ketones to the corresponding a-substituted alcohols, and such products can be further reduced to olefins (see section VIII). Other reagents serve, through participation of the carbonyl group, to remove the substituent while leaving the ketone intact. The zinc or chromous ion reduction of a-halo ketones is an example of this second type, which is not normally useful for double bond introduction. However, when the derivative being reduced is an a,jS-epoxy ketone, the primary product is a -hydroxy ketone which readily dehydrates to the a,jS-unsaturated ketone. Since... 

This procedure illustrates a general method for the stereoselective synthesis of ( P)-disubstitnted alkenyl alcohols. The reductive elimination of cyclic /3-halo-ethers with metals was first introduced by Paul3 and one example, the conversion of tetrahydrofurfuryl chloride [2-(chloromethyl)tetrahydrofuran] to 4-penten-l-ol, is described in an earlier volume of this series.4 In 1947 Paul and Riobe5 prepared 4-nonen-l-ol by this method, and the general method has subsequently been applied to obtain alkenyl alcohols with other substitution patterns.2,6-8 (I )-4-Hexen-l-ol has been prepared by this method9 and in lower yield by an analogous reaction with 3-bromo-2-methyltetra-hydropyran.10... 

In contrast to the behavior of primary alcohols, which resist reduction by organosilicon hydrides even in the presence of very strong acids, primary halo alkanes, including methyl iodide and ethyl bromide,186 undergo reduction when treated with aluminum chloride and organosilicon hydrides.146,185,186 Slow addition of a catalytic amount of aluminum chloride to a nearly equimolar... 

Selective reduction of the ester function in products (37), step (2), affords nitro alcohols (38), which are either transformed into halo-containing compounds... 

Another method for ketone reduction, BINAL-H asymmetric reduction, can also be used in co-side chain synthesis. An example of applying BINAL-H asymmetric reduction in PG synthesis is illustrated in Scheme 7-27. This has been a general method for generating the alcohol with (15. -configuration. The binaphthol chiral auxiliary can easily be recovered and reused. As shown in Scheme 7-27, when the chiral halo enone 91 is reduced by (S -BINAL-H at — 100°C, product (15S)-92 can be obtained with high enantioselectivity. 

A third route developed by this group started with the commercially available alcohol 32," a compound which has also been the subject of considerable process development due to its use as a common intermediate in the synthesis of several HMGR inhibitors.Conversion of 32 to the 4-halo or 4-nitrobenzenesulfonate 33 followed by displacement with sodium cyanide provided 34 in 90% yield, which is the z-butyl-ester analog of 29. It was noted that this procedure was most scaleable employing the 4-chlorobenzenesulfonate 33a due to the instability of the 4-bromo and 4-nitro-analogs to aqueous hydrolysis. Ra-Ni reduction as before provided the fully elaborated side-chain 35 as the f-butyl ester (Scheme 8). 

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