Reagent control diastereoselectivity

The tartrate-derived allyl and crotyl boronates 25 developed by Roush [33, 42-48] represent a convenient and elegant alternative to the terpene-derived boranes described above, as a consequence of their ease of handling and configurational stability (Equation 3). Representative examples are summarized in Table 5.2 [42, 45, 47]. These reagents have also enjoyed widespread applications in diastereoselective, reagent-controlled additions to chiral aldehydes, displaying superb levels of diasteroinduction [43, 44, 48], An explanation for the observed stereoselectivity has been proffered by Roush [32] and supported by ab initio calculations [62] minimization of lone pair/lone pair interactions as well as an attractive interaction between the ester lone pairs and the polarized aldehyde are believed to result in a preference for transition state structure 26. 

Starting from (R)-(—)-carvone, the half-protected dialdehyde 392 was prepared. Diastereoselective reagent-controlled oxyaUyltitanations (with TADDOL as... 

Boland applied this methodology to Garner s aldehyde, and found the addition to be substrate-controlled rather than reagent-controlled (Scheme 9.13b) [68]. Viny-lepoxide 15 could thus also be obtained with high diastereoselectivity with achiral 9-MeO-9-BBN. 

In addition to the problems of substrate- or reagent-controlled stereoselectivity, the problem of simple synjanti diastereoselectivity arises. Most studies have been performed on the crotyl derivatives. Table 2 summarizes some of these under the latter aspect. Essentially all types of reagents related to the appropriate 2-propenylmetal reagents collected in Table 1 are known. 

The reactions with (25,35,45,55)-5-(tm-butyldimethylsilyloxy)-3-(4-methoxyphenylmethoxy)-2,4-dimethylheptanal (15) are particularly informative reagent (5)-3 is incapable of overriding the intrinsic diastereofacial preference of 15, and the normal Felkin product 17 is obtained with >95% selectivity. In contrast, reagent-controlled mismatched double diastereoselectivity is evident in the reaction with (5)-4 that provides 16 as the major component of a 73 22 5 mixture. The minor product 18 apparently derives from a reaction with the contaminating (/ )-4, since (5)-4 that was used is not enantiomerically pure. 

Early work on the asymmetric Darzens reaction involved the condensation of aromatic aldehydes with phenacyl halides in the presence of a catalytic amount of bovine serum albumin. The reaction gave the corresponding epoxyketone with up to 62% ee.67 Ohkata et al.68 reported the asymmetric Darzens reaction of symmetric and dissymmetric ketones with (-)-8-phenylmenthyl a-chloroacetate as examples of a reagent-controlled asymmetric reaction (Scheme 8-29). When this (-)-8-phenyl menthol derivative was employed as a chiral auxiliary, Darzens reactions of acetone, pentan-3-one, cyclopentanone, cyclohexanone, or benzophenone with 86 in the presence of t-BuOK provided dia-stereomers of (2J ,3J )-glycidic ester 87 with diastereoselectivity ranging from 77% to 96%. 

The enantioselectivity of these reagents is explained by comparison of transition structures 72 and 73 shown in Scheme 7. The disfavored transition structure 73 leading to the minor enantiomer displays a steric interaction between the methylene of the allylic unit and the methyl group of one of the pinane units. Unlike the tartrate boronates described above, the directing effect of the bis(isopinocampheyl) allylic boranes is extremely powerful, giving rise to high reagent control in double diastereoselective additions (see section on Double Diastereoselection ). 

The present method is practical and efficient as it employs readily available enantioenriched propargylic alcohols as precursors to the allenylindium reagents. With achiral aldehydes the diastereoselectivity is high for branched aldehydes, moderate for unbranched aldehydes, and low for benzaldehyde (Table I). With cHral a-methyl aldehydes the additions proceed under effective reagent control to afford anti adducts of high ee and with excellent diastereoselectivity (eq. 1 and 2). Comparable results were obtained with 3 1 dimethyl sulfoxide-tetrahydrofuran (DMSO-THF) as the solvent. 

Fig. 3.30. Asymmetric hydration of an achiral alkene via hydroboration/oxidation/hydro lysis AFa corresponds to the extent of reagent control of diastereoselectivity.

Fig. 3. 32. Thought experiment II reagent control of stereoselectivity as a method for imposing on the substrate a diastereoselectivity that is alien to it (mismatched pair situation).

If, as in the reaction example in Figure 3.32, during the addition to enantiomerically pure chiral alkenes, substrate and reagent control of diastereoselectivity act in opposite directions, we have a so-called mismatched pair. For obvious reasons it reacts with relatively little diastereoselectivity and also relatively slowly. Side reactions and, as a consequence, reduced yields are not unusual in this type of reaction. However, there are cases in which mismatched paris still give rise to highly diastereoselective reactions, just not as high as the matched pair. 

Conversely, the addition of enantiomerically pure chiral dialkylboranes to enantiomerically pure chiral alkenes can also take place in such a way that substrate control and reagent control of diastereoselectivity act in the same direction. Then we have a matched pair. It reacts faster than the corresponding mismatched pair and with especially high diastereoselectivity. This approach to stereoselective synthesis is also referred to as double stereodifferentiation. 

Finally, it should be noted that enantiomerically pure derivatives of the Schwartz reagent are very appealing candidates for reagent controlled enantioselective and diastereoselective radical reductions. This is because a plethora of enantiomerically pure zirconocenes are available from other applications in enantioselective catalysis. 

The nitrido complex was applied to the direct asymmetric animation with a silyl enol ether as a substrate. Although several examples for achiral aminations of silyl enol ethers have been reported [32], an asymmetric version of reagent-controlled reaction has not appeared except for the one recent example [33] and the diastereoselective reactions with silyl enol ethers having a chiral auxiliary [34], The amination, which is presumed to take place via an aziridine intermediate [5g, lid,32], proceeded smoothly to give the A-tosylated a-aminoketone in 76% yield with 48% ee. When the same silyl enol ether was treated with complex 15 under Carreira s condition, the TV-trifluoroacetylated a-aminoketone was obtained in 58 % yield with 79 % ee (Scheme 24). 

BBN attacks the C=C double bond of 3-ethyl-l-methylcyclohexene according to Figure 3.20 exclusively from the side that lies opposite the ethyl group at the stereocenter. Consequently, after oxidation and hydrolysis, a fra s,fra s-configured alcohol is produced. The question that arises is Can this diastereoselectivity be reversed in favor of the cis,trans isomer The answer is possibly, but, if so, only by using reagent control of stereoselectivity (cf. Section 3.4.4). 

Thought Experiments II and III on the Hydroboration of Chiral Olefins with Chiral Boranes Reagent Control of Diastereoselectivity, Matched/Mismatched Pairs,... 

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