Reagent control of diastereoselectivity

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

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. 

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

A quick analysis of 9(S)-dihydroerythronolide A 19 shows that 7 of the 11 stereocenters could be created using reagent control of diastereoselectivity by crotylboration reactions. The stereogenic centers at C6 and C12 having a tertiary alcohol function are presently outside the scope of stereoselective crotylboration reactions. Here we have to rely on other methods. For instance, the use of lactic acid enolates developed by Seebach [28] appeared attractive to generate the tertiary centers both at C6 and Cl2. 

The reaction led to two products. The major one had an E-configurated double bond from which we conclude that it must be the anti-Cram isomer 35. Therefore reagent control of diastereoselectivity dominated the reaction. The minor product of the reaction contained a Z-double bond. It must arise via transition state 36 and should therefore be the product of substrate 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).

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). 

The reagent control of the diastereoselectivity originating from phosphonate A (which you know from the olefination of Figure 9.17). 

The control of diastereoselectivity in the allylation reaction of carbonyl compounds with allylic indium reagents has been an important issue since the discovery of the indium-mediated carbonyl allylation. As earlier discussions have been summarized in the precedent reviews,6-24 only relatively recent references are cited below. 

For the sake of comparison, the regio- and stereo-selectivity of some nucleophilic openings of vinyl-oxiranes with organometallic reagents derived from copper, lithium, sodium and other metals indicate the control avail le under some conditions. Complete control of diastereoselectivity in the opening of cyclic vinyloxiranes is available, for example by utilizing palladium(0)-catalyzed conditions in the reaction of die sodium salt of dimethyl malonate with cyclic vinyloxiranes.Increased substitution on the vinyl portion of the vinyloxirane leads to isomerization with opening, as in the case of the disub-stituted vinyloxirane (150 equation 49). ... 

Since the introduction of this reagent in 1983 (/2), it has been utilized in key steps in several syntheses. The reagent can be prepared by the treatment of allyl Grignard reagent with either B-chlorodiisopinocampheylborane (DIP-Chloride M) 34, 35) or B-methoxydiisopinocampheylborane 12). A variety of aldehydes, including perfluoroalkyl 36) and heterocyclic aldehydes (57) have been tested with this reagent to demonstrate its capability. In all of the cases examined thus far the product homoallyl alcohols were obtained in >92% ee (Scheme 2). It has been established that in the case of chiral aldehydes, the reagent controls the diastereoselectivity 38). 

Subsequent study revealed that the chiral LBA (16) canbeusedas artificial cyclases for the asymmetric syntheses of (-)-caparrapi oxide (17) and (+)-8-epicaparrapi oxide (18) [28a,b]. (17) and (18) can be diastereoselectively synthesized from (S)-(19) (prepared in three steps from commercially available famesol) by reagent control of (R)-16 and (S)-16, respectively, regardless of the chirality of (S)-19 (Scheme 1.25). 

The additions of allyl-, crotyl-, and prenylborane or -boronate reagents to aldehydes are among the most widely studied, well developed, and powerful reactions in stereoselective synthesis. The additions not only display excellent levels of absolute induction in enantioselective synthesis, but also exhibit superb levels of reagent control in diastereoselective additions. The additions of ( )- or (Z)-crotyl pinacol boronates to aldehydes have been observed to give predominantly 1,2-anti- and 1,2-syn-substituted products, respectively (Scheme 5.3) [31, 50]. The inherent stereospecificity of the reaction is consistent with a closed, cyclic Zimmerman-Traxler transition state structure [51], In the accepted model, coordination of the aldehyde to the allylation reagent results in synergistic activation of both the electrophile and the nucleophile... 

Besides the addition of vinylation reagents, methyllithium and methyl Grignard reagents can react with a,/1-epoxy aldehydes in a nonchelation-controlled mode79. However, the level of diastereoselectivity is moderate. 

As with oxathianes 3 (R1 = CH, R2 = H), which bear a close structural resemblance to 17, the addition of organometallic reagents is highly diastereoselective with a predominant chelation-controlled attack of the nucleophile from the Rc-sidc35 -40. In the case of vinylmagnesium bromide a considerable enhancement of the diastereo selectivity could be attained by adding... 

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. 

However, the use of ordinary achiral alkylcopper reagents instead of the chiral lithium bis(l-alkenyljcuprate also produced the same level of high diastereoselectivity, and thus it seems that the chirality at the y-position of 1 did not exert a significant influence upon the diastereoselectivity. The stereoselectivity was controlled by the stereogenic centers in the substrate. 

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