Alcohol Allylation, enantioselective

Figure 6.4 Some successful examples of kinetic resolution of allylic alcohols by enantioselective epoxidation [21, 27].

In 2004, Yang and Tseng reported the synthesis of a series of new chiral amino thiol ligands derived from L-valine, which were further employed (1 mol%) in the enantioselective alkenylzinc addition to aldehydes, providing an efficient route for chiral ( )-allylic alcohols with enantioselectivities of up to >99% ee, as shown in Scheme 3.67. ... 

Asymmetric cyclization was also successful in the rhodium-catalyzed hydrosilylation of silyl ethers 81 derived from allyl alcohols. High enantioselectivity (up to 97% ee) was observed in the reaction of silyl ethers containing a bulky group on the silicon atom in the presence of a rhodium-BINAP catalyst (Scheme 23).78 The cyclization products 82 were readily converted into 1,3-diols 83 by the oxidation. During studies on this asymmetric hydrosilylation, silylrhodation pathway in the catalytic cycle was demonstrated by a deuterium-labeling experiment.79... 

Reactions of aldehydes with complexes 13—17 provide optically active homoallylic alcohols. The enantioselectivities proved to be modest for 13—16 (20—45% ee). In contrast, they are very high (> 94% ee) for the (ansa-bis(indenyl))(r]3-allyl)titanium complex 17 [32], irrespective of the aldehyde structure, but only for the major anti diastereomers, the syn diastereomers exhibiting a lower level of ee (13—46% ee). Complex 17 also gives high chiral induction (> 94% ee) in the reaction with C02 [32], in contrast to complex 12 (R = Me 11 % ee R = H 19% ee) [15]. Although the aforementioned studies of enan-... 

Vedejs has explored the KR of allylic alcohols via enantioselective acylation mediated by his 2,5-di-tert-butylphenyl PBO catalyst 2b (Scheme 8.9) [40, 42, 45, 130]. 

Achiral primary allylic alcohols undergo enantioselective epoxidation (cf. Figure 3.35), whereas—chiral primary allylic alcohols undergo diastereoselective oxidation. So the reagent... 

Second, if tin(II) catecholate is ligated by an optically active dialkyl tartrate, it will react with an allylic bromide or iodide and an aldehyde, in the presence of Cul as catalyst, to give the optically active homoallylic alcohol. The enantioselectivity is highest when the alkyl groups of the tartrate are bulky (t-butyl or cyclohexyl). Aromatic aldehydes give higher enantioselectivities than do aliphatic aldehydes, and the reaction is also successful with a-carbonylketones 74... 

Titanium-tartrate complexes also catalyze the epoxidation of homo- and bishomoaiiyiic alcohols but their reactions are considerably slower as compared with reactions of allylic alcohols [55]. Enantioselectivity also drops to moderate levels (Scheme 10). When the substrates are cis-homoallylic alcohols, use of the zirconium N,iV-dicyclohexytartramide complex as catalyst improves the enantioselectivity to some extent [56]. 

Bu02H, Ti(0-i -Pr)4, dialkyl tartrate (allylic alcohols, Sharpless, enantioselective)... 

In the case of the observation of poor overall enantioselectivity due to the presence of two competing enzymes with different enantioselectivities, one of the most straightforward methods to improve the enantioselectivity is the use of the inhibitor of the unnecessary enzyme(s). Ethyl chloroacetate, methyl vinyl ketone, allyl alcohol, allyl bromide, sulfur compounds, Mg2+, Ca2+, etc. have been reported as inhibitors of enzymes in yeast [87 97l... 

Martin VS, oodard SS, Katsuki T et al (1981) Kinetic resolution of racemic allylic alcohols by enantioselective epoxidation - a route to substances of absolute enantiomeric purity. J Am Chem Soc 103 6237-6240... 

In contrast to less efficient allylation of alcohols, allylation of phenols proceeds much more smoothly. In the enantioselective synthesis of (—)-galanthamine by Trost, two Pd-catalyzed reactions were utilized. Asymmetric allylation of the bro-movanillin 191 with the cyclic allylic carbonate 192 gave the ether 193 by using ( ] -allyl-PdCl)2 and chiral Trost L-2. Subsequent Heck reaction of 194 afforded 195 in 91 % yield when DPPP was used as a ligand. DPPF and DPPE gave lower yield [74]. 

Allyl Alcohols, Allyl Ethers, and Allyl Thioethers Allyl alcohol as substrate favors commonly the formation of the terminal aldehyde [48] however, the branched minor compound can be achieved with high enantioselectivity (95% ee) [43]. 1 With cin-namyl alcohol, the y-directing effect is supported by the iso-directing effect of the aromat. Therefore, in the AHF with a (/ ,S)-BINAPHOS catalyst, followed by oxidation, exclusively the lactone was formed (Scheme 4.76) [48]. 

While the chiral aldehydes or allyl nucleophiles are based on stoichiometric amounts for the control of diastereoselectivity [74, 77], it has been found that catalytic amounts of titanium complexes derived from BINOL can mediate the enantioselective addition of allyl stannanes to aldehydes, giving the homoallyl alcohols high enantioselectivity. Mikami reported that the BINOL-Ti complexes prepared in situ in the presence of 4A molecular sieves (MS) catalyze the carbonyl addition reaction of allyl silanes or stannanes to afford the syn product in high enantiomeric excess [78] (Scheme 14.21). 

Asymmetric cycHzation was also successful in the rhodium-catalyzed hydrosilyla-tion of sUyl ethers 57 derived from allyl alcohols. High enantioselectivity (up to 97%... 

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]. 

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. 

Although the limited examples of AE reactions on 2,3Z-substituted allyl alcohols appear to give product epoxides in good enantioselectivity, the highly substituted nature of these olefins can have a deleterious effect on the reactivity. For example, Aiai has shown that the 2,3E-substituted allyl alcohol 30 can be epoxidized with either (-)-DET or (+)-DET in good yields and enantioselectivity. However, the configurational isomer 32 is completely unreactive using (-)-DET, even after a 34 h reaction time. 

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