Epoxides, enantiomerically pure

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. 

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. 

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). 

The emergence of the powerful Sharpless asymmetric epoxida-tion (SAE) reaction in the 1980s has stimulated major advances in both academic and industrial organic synthesis.14 Through the action of an enantiomerically pure titanium/tartrate complex, a myriad of achiral and chiral allylic alcohols can be epoxidized with exceptional stereoselectivities (see Chapter 19 for a more detailed discussion). Interest in the SAE as a tool for industrial organic synthesis grew substantially after Sharpless et al. discovered that the asymmetric epoxidation process can be conducted with catalytic amounts of the enantiomerically pure titanium/tartrate complex simply by adding molecular sieves to the epoxidation reaction mix-... 

Especially in the early steps of the synthesis of a complex molecule, there are plenty of examples in which epoxides are allowed to react with organometallic reagents. In particular, treatment of enantiomerically pure terminal epoxides with alkyl-, alkenyl-, or aryl-Grignard reagents in the presence of catalytic amounts of a copper salt, corresponding cuprates, or metal acetylides via alanate chemistry, provides a general route to optically active substituted alcohols useful as valuable building blocks in complex syntheses. 

The epoxidation of allylic alcohols can also be effected by /-butyl hydroperoxide and titanium tetraisopropoxide. When enantiomerically pure tartrate ligands are included, the reaction is highly enantioselective. This reaction is called the Sharpless asymmetric epoxidation.55 Either the (+) or (—) tartrate ester can be used, so either enantiomer of the desired product can be obtained. 

This synthesis is shown in Scheme 13.59. Two enantiomerically pure starting materials were brought together by a Wittig reaction in Step C. The aldol addition in Step D was diastereoselective for the anti configuration, but gave a 1 1 mixture with the 6S, 1R-diastereomer. The stereoisomers were separated after Step E-2. The macrolactonization (Step E-4) was accomplished by a mixed anhydride (see Section 3.4.1). The final epoxidation was done using 3-methyl-3-trifluoromethyl dioxirane. 

An effective deoxygenation using enantiomerically pure epoxides from primary allylic alcohols ( Sharpless epoxides ) [44] to give enantiomerically pure secondary allylic alcohols was described by Yadav [45]. This approach circumvented a kinetic resolution of secondary allylic alcohols that implies a maximum yield of 50% ( Scheme 5). 

Attempts have been made to exploit the intrinsic C2 symmetry of the phenolate-based dinickel core in enantioselective catalytic reactions. Therefore, enantiomerically pure C2-symmetric ligands such as (736a) and the corresponding dinickel systems (736b) have been prepared ( Equation (27)),1890 and (736b) was tested in the epoxidation of unfunctionalized alkenes with sodium hypochlorite as the oxidant. The catalytic reaction was found to be highly pH dependent with an optimum at a pH of 9. While the complex is catalytically active, significant enantioselectivity was not achieved. 

Annual Volume 71 contains 30 checked and edited experimental procedures that illustrate important new synthetic methods or describe the preparation of particularly useful chemicals. This compilation begins with procedures exemplifying three important methods for preparing enantiomerically pure substances by asymmetric catalysis. The preparation of (R)-(-)-METHYL 3-HYDROXYBUTANOATE details the convenient preparation of a BINAP-ruthenium catalyst that is broadly useful for the asymmetric reduction of p-ketoesters. Catalysis of the carbonyl ene reaction by a chiral Lewis acid, in this case a binapthol-derived titanium catalyst, is illustrated in the preparation of METHYL (2R)-2-HYDROXY-4-PHENYL-4-PENTENOATE. The enantiomerically pure diamines, (1 R,2R)-(+)- AND (1S,2S)-(-)-1,2-DIPHENYL-1,2-ETHYLENEDIAMINE, are useful for a variety of asymmetric transformations hydrogenations, Michael additions, osmylations, epoxidations, allylations, aldol condensations and Diels-Alder reactions. Promotion of the Diels-Alder reaction with a diaminoalane derived from the (S,S)-diamine is demonstrated in the synthesis of (1S,endo)-3-(BICYCLO[2.2.1]HEPT-5-EN-2-YLCARBONYL)-2-OXAZOLIDINONE. 

Recently, Italian researchers have developed a new procedure for the synthesis of five-membered cyclic nitronates with the use of enantiomerically pure epoxides (65-67) and aziridines (68) as the starting substrates (15) (Scheme 3.18, see also substrate B in Scheme 3.11, Eq. 1). 

The wide scope application of this transformation arises not only from the utility of epoxide compounds but also from the subsequent regiocontrolled and stereocontrolled nucleophilic substitution (ring-opening) reactions of the derived epoxy alcohol. These, through further functionalization, allow access to an impressive array of target molecules in enantiomerically pure form. 

Another interesting application of the deoxygenation reaction is shown in Scheme 12.6. Sharpless epoxides are transformed to enantiomerically pure allylic alcohols [14]. It should be noted that the disadvantage of the loss of one-half of the allylic alcohol, as in the case of kinetic resolutions of allylic alcohols, is not a problem when this protocol is employed. 

More recently, Doris et al. have described the reductive ring-opening of a-keto epoxides [16]. In this manner, p-hydroxy ketones can be obtained in high yields. The synthesis of enantiomerically pure compounds can easily be realized. The titanocene] 111) reagents are distinctly superior to samarium diiodide, which is also known to induce this transformation. 

In 1980 a useful level of asymmetric induction in the epoxidation of some alkenes was reported by Katsuki and Sharpless121. The combination of titanium (IV) alkoxide, an enantiomerically pure tartrate ester and tert-butyl hydroperoxide was used to epoxidize a wide variety of allylic alcohols in good yield and enantiomeric excess (usually >90%). This reaction is now one of the most widely applied reactions in asymmetric synthesis131. 

In 1980, Katsuki and Sharpless[1] reported that, with the combination of a titanium(IV) alkoxide, an enantiomerically pure tartrate ester [for example (+)-diethyl tartrate ((+)-DET) or (+) di-iso-propyltartrate ((+)-DIPT)] and tert-butyl hydroperoxide, they were able to carry out the epoxidation of a variety of allylic alcohols in good yield and with a good enantiomeric excess (Figure 5.1). 

Table 5.1 Catalytic asymmetric epoxidation of allylic alcohols using a combination of titanium wopropoxide. enantiomerically pure tartrate ester ((+)-DET or (+)-DIPT) and rerr-butyl hydroperoxide (yield and enantiomeric excess, according to the relevant publication). ...

Regiospecific trans-fi-bromo - acetoxy elimination of readily accessible 2-bromodeoxyaldono-1,4-lactones with NaHS03 afforded (211) good yields of such butenolides as 159c and 162b. Enantiomerically pure 5,6-epoxides and 5,6-diols were obtained from 162b. 

Thus, the sole remaining stereocenter after epoxide opening controls the formation of three other stereocenters. It should be noted that the synthesis of enantiomerically pure substrates via palladium-catalyzed allylic alkylation [80] is possible and offers an access to the products in enantiomerically pure form. This possibility and the diastereoconvergent course of our reaction are extremely attractive for the synthesis of complex molecules. 

Carbonylative kinetic resolution of a racemic mixture of trans-2,3-epoxybutane was also investigated by using the enantiomerically pure cobalt complex [(J ,J )-salcy]Al(thf)2 [Co(CO)4] (4) [28]. The carbonylation of the substrate at 30 °C for 4h (49% conversion) gave the corresponding cis-/3-lactone in 44% enantiomeric excess, and the relative ratio (kre ) of the rate constants for the consumption of the two enantiomers was estimated to be 3.8, whereas at 0 °C, kte = 4.1 (Scheme 6). This successful kinetic resolution reaction supports the proposed mechanism where cationic chiral Lewis acid coordinates and activates an epoxide. 

Fig. 25) (Baldwin, 1976). By raising antibodies to the charged hapten [67], Janda and co-workers produced an abzyme which accelerated 6-exo attack of the racemic epoxide to yield exclusively the disfavoured tetrahydropyran product [68] and in an enantiomerically pure form (Appendix entry 14.1) (Janda et al 1993). 

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