A,/?-Epoxy alcohols

In light of the previous discussions, it would be instructive to compare the behavior of enantiomerically pure allylic alcohol 12 in epoxidation reactions without and with the asymmetric titanium-tartrate catalyst (see Scheme 2). When 12 is exposed to the combined action of titanium tetraisopropoxide and tert-butyl hydroperoxide in the absence of the enantiomerically pure tartrate ligand, a 2.3 1 mixture of a- and /(-epoxy alcohol diastereoisomers is produced in favor of a-13. This ratio reflects the inherent diasteieo-facial preference of 12 (substrate-control) for a-attack. In a different experiment, it was found that SAE of achiral allylic alcohol 15 with the (+)-diethyl tartrate [(+)-DET] ligand produces a 99 1 mixture of /(- and a-epoxy alcohol enantiomers in favor of / -16 (98% ee). 

Deoxygenation of a,/ -Epoxy Alcohols with Concomitant Fragmentations... 

Oxidations. The reagent 1 oxidizes primary and secondary alcohols to carbonyl compounds in fair to good yield. It is not useful for epoxidation of simple alkenes, but it epoxidizes allylic alcohols to form a,/ -epoxy alcohols in 60-70% yield, In general, this epoxidation is more stcreospccific than that observed with r-butyl hydroperoxide in combination with Mo(CO)6 (9, 81-82). 

Regioselective cleavage of a, -epoxy alcohols. In the presence of TifO-t-Prlj (1 equiv.), a variety of nucleophiles react with 1 regioseicctively by cleavage at C,. No reaction occurs in the absence of Ti(0-/-Pr)j except in the case of C H,SNa. 

Epoxidations of the allylic alcohols (144), (145), (146 equation SO) and (148 equation SI) are highly stereoselective. The transformation of (148) to (149) is an example of the use of silyloxyalkenes in the stereoselective synthesis of trans a, -epoxy alcohols. The epoxidatitm of the ester (150), which has a hydroxy allylic to a rrans-disubstituted double bond, does not exhibit high stereoselectivity (equation S2) the epoxidation is regioselective, involving only the C(13)—C(14) double bond. 

Moreover, a-cyano-a-epoxy esters are easily reduced to a-cyano-a-epoxy alcohols by NaBH4 in aqueous THF [MR4]. Ethanedithiol can also be an additive for the reduction of esters by NaBH4, except r-butyl esters. Nitrile groups remain unperturbed under these conditions [GEl]. Methyl benzoate is reduced to benzylalcohol by NaBH4-ZrCl4 in THF [ISl],... 

The first practical method for asymmetric epoxidation of primary and secondary allylic alcohols was developed by K.B. Sharpless in 1980 (T. Katsuki, 1980 K.B. Sharpless, 1983 A, B, 1986 see also D. Hoppe, 1982). Tartaric esters, e.g., DET and DIPT" ( = diethyl and diisopropyl ( + )- or (— )-tartrates), are applied as chiral auxiliaries, titanium tetrakis(2-pro-panolate) as a catalyst and tert-butyl hydroperoxide (= TBHP, Bu OOH) as the oxidant. If the reaction mixture is kept absolutely dry, catalytic amounts of the dialkyl tartrate-titanium(IV) complex are suflicient, which largely facilitates work-up procedures (Y. Gao, 1987). Depending on the tartrate enantiomer used, either one of the 2,3-epoxy alcohols may be obtained with high enantioselectivity. The titanium probably binds to the diol grouping of one tartrate molecule and to the hydroxy groups of the bulky hydroperoxide and of the allylic alcohol... 

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... 

The acid-catalyzed opening of 16,17-epoxy-20-ketones has also been studied in some detail. In this instance, jS elimination to give a, -unsaturated ketone cannot occur, and in the simplest examples 16 -substituted 17a-alcohols are formed. However, in the presence of a 16jS-methyl substituent, 16-methylene compounds are produced [(167), (168), for example]. Lithium bromide-lithium carbonate in refluxing dimethylformamide gives the A -17a-alcohol. ... 

The Sharpless-Katsuki asymmetric epoxidation reaction (most commonly referred by the discovering scientists as the AE reaction) is an efficient and highly selective method for the preparation of a wide variety of chiral epoxy alcohols. The AE reaction is comprised of four key components the substrate allylic alcohol, the titanium isopropoxide precatalyst, the chiral ligand diethyl tartrate, and the terminal oxidant tert-butyl hydroperoxide. The reaction protocol is straightforward and does not require any special handling techniques. The only requirement is that the reacting olefin contains an allylic alcohol. 

The application of the AE reaction to kinetic resolution of racemic allylic alcohols has been extensively used for the preparation of enantiomerically enriched alcohols and allyl epoxides. Allylic alcohol 48 was obtained via kinetic resolution of the racemic secondary alcohol and utilized in the synthesis of rhozoxin D. Epoxy alcohol 49 was obtained via kinetic resolution of the enantioenriched secondary allylic alcohol (93% ee). The product epoxy alcohol was a key intermediate in the synthesis of (-)-mitralactonine. Allylic alcohol 50 was prepared via kinetic resolution of the secondary alcohol and the product utilized in the synthesis of (+)-manoalide. The mono-tosylated 3-butene-1,2-diol is a useful C4 building block and was obtained in 45% yield and in 95% ee via kinetic resolution of the racemic starting material. 

Desymmetrization of meso-bis-allylic alcohols is an effective method for the preparation of chiral functionalized intermediates from meso-substrates. Schreiber et al has shown that divinyl carbonyl 58 is epoxidized in good enantioselectivity. However, because the product epoxy alcohols 59 and 60 also contain a reactive allylic alcohol that are diastereomeric in nature, a second epoxidation would occur at different rates and thus affect the observed ee for the first AE reaction and the overall de. Indeed, the major diastereomeric product epoxide 59 resulting from the first AE is less reactive in the second epoxidation. Thus, high de is easily obtainable since the second epoxidation removes the minor diastereomer. 

The asymmetric epoxidation of an allylic alcohol 1 to yield a 2,3-epoxy alcohol 2 with high enantiomeric excess, has been developed by Sharpless and Katsuki. This enantioselective reaction is carried out in the presence of tetraisopropoxyti-tanium and an enantiomerically pure dialkyl tartrate—e.g. (-1-)- or (-)-diethyl tartrate (DET)—using tcrt-butyl hydroperoxide as the oxidizing agent. 

With this epoxidation procedure it is possible to convert the achiral starting material—i.e. the allylic alcohol—with the aim of a chiral reagent, into a chiral, non-racemic product in many cases an enantiomerically highly-enriched product is obtained. The desired enantiomer of the product epoxy alcohol can be obtained by using either the (-1-)- or (-)- enantiomer of diethyl tartrate as chiral auxiliary ... 

The 2,3-epoxy alcohols are often obtained in high optical purity (90% enantiomeric excess or higher), and are useful intermediates for further transformations. For example by nucleophilic ring opening the epoxide unit may be converted into an alcohol, a /3-hydroxy ether or a vicinal diol. 

The synthesis of key intermediate 12, in optically active form, commences with the resolution of racemic trans-2,3-epoxybutyric acid (27), a substance readily obtained by epoxidation of crotonic acid (26) (see Scheme 5). Treatment of racemic 27 with enantio-merically pure (S)-(-)-1 -a-napthylethylamine affords a 1 1 mixture of diastereomeric ammonium salts which can be resolved by recrystallization from absolute ethanol. Acidification of the resolved diastereomeric ammonium salts with methanesulfonic acid and extraction furnishes both epoxy acid enantiomers in eantiomerically pure form. Because the optical rotation and absolute configuration of one of the antipodes was known, the identity of enantiomerically pure epoxy acid, (+)-27, with the absolute configuration required for a synthesis of erythronolide B, could be confirmed. Sequential treatment of (+)-27 with ethyl chloroformate, excess sodium boro-hydride, and 2-methoxypropene with a trace of phosphorous oxychloride affords protected intermediate 28 in an overall yield of 76%. The action of ethyl chloroformate on carboxylic acid (+)-27 affords a mixed carbonic anhydride which is subsequently reduced by sodium borohydride to a primary alcohol. Protection of the primary hydroxyl group in the form of a mixed ketal is achieved easily with 2-methoxypropene and a catalytic amount of phosphorous oxychloride. 

It is appropriate at this juncture to address some of the more useful transformations of 2,3-epoxy alcohols.913 A 2,3-epoxy alcohol such as compound 14 possesses two obvious electrophilic sites one at C-2, and the other at C-3. But in addition, C-l of a 2,3-epoxy alcohol also has latent electrophilic reactivity. For example, exposure of 14 to aqueous sodium hydroxide solution results in the formation of triol 19 in 79% yield (see Scheme 5). In this interesting transformation, hydroxide ion induces the establishment of an equilibrium between 2,3-epoxy-l-ol 14 and the isomeric 1,2-epoxy-3-ol 18. This reversible, base-induced epoxide migration reaction is a process known as the Payne rearrangement.14... 

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