Alcohol enantioselectivity

Additionally, the use of unsymmetrical TEMPO analogues, able to perform enantioselective alcohol oxidations22 and silica-supported TEMPO,23 must be mentioned. 

Scheme 3. CHCI3 conditions for enantioselective alcohol oxidation [8].

The dienophile may also be activated by hydrogen bonding of the carbonyl oxygen with suitable protic molecules and it has been observed that Diels-Alder reactions are accelerated when performed in protic solvents such as 2-butanol. Thus the opportunity exists for the development of an enantioselective alcohol-catalysed asymmetric Diels-Alder reaction. Indeed, Rawal and coworkers have recently discovered that the use of catalytic amounts of the enantiomerically pure diol a,a,a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol (TADDOL) (8.113) in the Diels-Alder reaction of aminosilyloxydiene (8.114) with 2-substituted acroleins such as (8.24), results in the formation of the cycloadduct (8.115) with high ee. Simiharly, the strong Bronsted acid (8.116) effectively catalyses the Diels-Alder reaction of sUyloxydienes such as (8.117) with a,P-enone (8.105). ... 

Scheme 3 Diastereo- and enantioselective alcohol-mediated hydrohydroxyalkylation of butadienes. Yields are of material isolated by flash chromatography on silica gel. Diastereoselectivity was determined through NMR analysis of crude reaction mixtures. Enantiomeric excess was determined by chiral stationary phase HPLC analysis. DM-SEGPHOS = 5,5 -fots-[di(3,5-xylyl)phosphino]-4,4 -bi-l,3-benzodioxole. dppf = 1,1-(>M-(diphenylphosphino)ferrocene. SEGPHOS = 5,5 -Ws-(diphenylphosphino)-4,4 -bi-l,3-benzodioxole...

The biocatalytic counterpart for this transformation is done by the alcohol dehydrogenases [ADHs, EC 1.1.1.x., also called ketoreductases (KREDs) or carbonyl reductases (CRs)], which are able to perform stereoselective carbonyl reductions or enantioselective alcohol oxidations [5-8]. These enzymes are probably the most employed oxidoreductases and make use of a nicotinamide cofactor such as NADH or NADPH to transfer electrons into and from the target substrate. Depending on their substrate scope, ADHs can be divided into primary alcohol dehydrogenases, preferentially reducing aldehydes, and secondary alcohol dehydrogenases that have... 

Finally the influence of the temperature and addition of ethanol on the enantioselectivity of the Diels-Alder reaction was studied. Table 3.3 summarises the results for different aqueous media. Apparently, changes in temperature as well as the presence of varying amounts of ethanol have only a modest influence on the selectivity of the Cu(tryptophan)-catalysed Diels-Alder reaction in aqueous solution. However, reaction times tend to increase significantly at lower temperatures. Also increasing the alcohol content induces an increase of the reaction times. 

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... 

Silyl ethers serve as preeursors of nucleophiles and liberate a nucleophilic alkoxide by desilylation with a chloride anion generated from CCI4 under the reaction conditions described before[124]. Rapid intramolecular stereoselective reaction of an alcohol with a vinyloxirane has been observed in dichloro-methane when an alkoxide is generated by desilylation of the silyl ether 340 with TBAF. The cis- and tru/u-pyranopyran systems 341 and 342 can be prepared selectively from the trans- and c/.y-epoxides 340, respectively. The reaction is applicable to the preparation of 1,2-diol systems[209]. The method is useful for the enantioselective synthesis of the AB ring fragment of gambier-toxin[210]. Similarly, tributyltin alkoxides as nucleophiles are used for the preparation of allyl alkyl ethers[211]. 

The ratio of yy -epoxide (shown above) to ant -eipoxide is 10—25 1 with TYZORTPT catalysis, whereas vanadjdacetylacetonate is less selective and y -chloroperoxybenzoic acid gives the reverse 1 25 ratio. It is supposed that TYZOR TPT esterifies the free hydroxyl, then coordinates with the peroxide to favor yy -epoxidation (135). This procedure is related to that for enantioselective epoxidation of other allyflc alcohols in 9—95% enantiomeric excess (135). 

Optically Active Acids and Esters. Enantioselective hydrolysis of esters of simple alcohols is a common method for the production of pure enantiomers of esters or the corresponding acids. Several representative examples are summarized ia Table 4. Lipases, esterases, and proteases accept a wide variety of esters and convert them to the corresponding acids, often ia a highly enantioselective manner. For example, the hydrolysis of (R)-methyl hydratropate [34083-55-1] (40) catalyzed by Hpase P from Amano results ia the corresponding acid ia 50% yield and 95% ee (56). Various substituents on the a-carbon (41—44) are readily tolerated by both Upases and proteases without reduction ia selectivity (57—60). The enantioselectivity of many Upases is not significantly affected by changes ia the alcohol component. As a result, activated esters may be used as a means of enhancing the reaction rate. 

Two more examples ia Table 5 iaclude the hydrolysis of esters of trans-alcohols that proceed with high efficiency practically regardless of the nature of the substituents (72) and resolution of P-hydroxynitriles with Upase from Pseudomonas sp. In the latter case the enantioselectivity of the hydrolysis was improved by iatroduciag sulfur iato the acyl moiety (73). 

Cychc alcohols are excellent targets for enantioselective enzymatic acylations. For example, acylation of (65) with vinyl acetate catalyzed by Hpase SAM-II gives the (R),(3)-ester with 95% ee (81). Similarly (66), which is a precursor for seratonin uptake inhibitor, is resolved in a high yield and selectivity with Amano Hpase P (82). The prostaglandin synthon (67) is resolved by the same method into the optically pure alcohol in 35% yield (83). 

Although alcohol dehydrogenases (ADH) also catalyze the oxidation of aldehydes to the corresponding acids, the rate of this reaction is significantly lower. The systems that combine ADH and aldehyde dehydrogenases (EC 1.2.1.5) (AldDH) are much more efficient. For example, HLAD catalyzes the enantioselective oxidation of a number of racemic 1,2-diols to L-a-hydroxy aldehydes which are further converted to L-a-hydroxy acids by AldDH (166). 

The most successful of the Lewis acid catalysts are oxazaborolidines prepared from chiral amino alcohols and boranes. These compounds lead to enantioselective reduction of acetophenone by an external reductant, usually diborane. The chiral environment established in the complex leads to facial selectivity. The most widely known example of these reagents is derived from the amino acid proline. Several other examples of this type of reagent have been developed, and these will be discussed more completely in Section 5.2 of part B. 

The hydride-donor class of reductants has not yet been successfully paired with enantioselective catalysts. However, a number of chiral reagents that are used in stoichiometric quantity can effect enantioselective reduction of acetophenone and other prochiral ketones. One class of reagents consists of derivatives of LiAlH4 in which some of die hydrides have been replaced by chiral ligands. Section C of Scheme 2.13 shows some examples where chiral diols or amino alcohols have been introduced. Another type of reagent represented in Scheme 2.13 is chiral trialkylborohydrides. Chiral boranes are quite readily available (see Section 4.9 in Part B) and easily converted to borohydrides. 

The necessity for producing large amounts of synthetic prostaglandins and analogs provided the impetus for a number of improvements in the bicyclo[2.2.1]heptene approach. Especially important was the development of an enantioselective modification for the synthesis of chiral prostanoids without resolution (1975) and the invention of a chiral catalyst for the stereocontrolled conversion of 15-keto prostanoids to either 15(5)- or 15(7 )- alcohols. 

The first asymmetric Mn(salen)-catalyzed epoxidation of silyl enol ethers was carried out by Reddy and Thornton in 1992. Results from the epoxidation of various silyl enol ethers gave the corresponding keto-alcohols in up to 62% ee Subsequently, Adam and Katsuki " independently optimized the protocol for these substrates yielding products in excellent enantioselectivity. 

In 1980, Katsuki and Sharpless communicated that the epoxidation of a variety of allylic alcohols was achieved in exceptionally high enantioselectivity with a catalyst derived from titanium(IV) isopropoxide and chiral diethyl tartrate. This seminal contribution described an asymmetric catalytic system that not only provided the product epoxide in remarkable enantioselectivity, but showed the immediate generality of the reaction by examining 5 of the 8 possible substitution patterns of allylic alcohols all of which were epoxidized in >90% ee. Shortly thereafter. Sharpless and others began to illustrate the... 

In general, 2-substituted allylic alcohols are epoxidized in good enantioselectivity. Like glycidol, however, the product epoxides are susceptible to ring opening via nucleophilic attack at the C-3 position. Results of the AE reaction on 2-methyl-2-propene-l-ol followed by derivatization of the resulting epoxy alcohol are shown in Table 1.6.1. Other examples are shown below. 

As with i -substituted allyl alcohols, 2,i -substituted allyl alcohols are epoxidized in excellent enantioselectivity. Examples of AE reactions of this class of substrate are shown below. Epoxide 23 was utilized to prepare chiral allene oxides, which were ring opened with TBAF to provide chiral a-fluoroketones. Epoxide 24 was used to prepare 5,8-disubstituted indolizidines and epoxide 25 was utilized in the formal synthesis of macrosphelide A. Epoxide 26 represents an AE reaction on the very electron deficient 2-cyanoallylic alcohols and epoxide 27 was an intermediate in the total synthesis of (+)-varantmycin. 

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