Double asymmetric reaction

With an appropriate chiral reactant, high enantioselectivity can be achieved, as a result of asymmetric induction If both reactants are chiral, this procedure is called the double asymmetric reaction and the observed enantioselectivity can be even higher. 

On the other hand, high levels of diastereoselectivity are relatively easy to achieve in matched double asymmetric reactions since the intrinsic diastereofacial preference of the chiral aldehyde reinforces that of the reagent, and in many cases it has been possible to achieve synthetically useful levels of matched diastereoselection by using only moderately enantioselective chiral allylboron reagents. Finally, it is worth reminding the reader that both components of double asymmetric reactions need to be both chiral and nonracemic for maximum diastereoselectivity to be realized. 

Many of the chiral allylboron reagents discussed in Section 1.3.3.3.3.1.4. have been utilized in double asymmetric reactions with chiral aldehydes. Chiral 2-(2-butenyl)-3.5-dioxa-4-boratri-cyclo[5.2.1.02-6]decanes were among the first chiral reagents of any type to be used in double asymmetric reactions52a,b. 

The reaction of methyl 4-formyl-2-mcthylpentanoate and the chiral (Z)-2-butenylboronate clearly shows 52b-103, however, that the chiral auxiliary is not sufficiently enantioselective to increase the diastereoselectivity to >90% in either the matched [( + )-auxiliary] or mismatched [(—)-auxiliary] case. This underscores the requirement that highly enantioselective chiral reagents be utilized in double asymmetric reactions. 

Table 11. Double Asymmetric Reactions of Chiral 1- and fl-Alkoxy Aldehydes...

Dimethylphenylsilyl-2-propenylboronate 7 is more enantioselective (81-87% ee with achiral aldehydes) than the 2-[cyclohexyloxy(dimethyl)silyl] compound 8 (64-72% ee), and consequently the former generally gives better results especially in mismatched double asymmetric reactions. Nevertheless, the examples show that appreciable double diastereoselection may be achieved with both reagents in many cases. 

The cyclohexyloxy(dimethyl)silyl unit in 8 serves as a hydroxy surrogate and is converted into an alcohol via the Tamao oxidation after the allylboration reaction. The allylsilane products of asymmetric allylboration reactions of the dimethylphenylsilyl reagent 7 are readily converted into optically active 2-butene-l, 4-diols via epoxidation with dimethyl dioxirane followed by acid-catalyzed Peterson elimination of the intermediate epoxysilane. Although several chiral (Z)-y-alkoxyallylboron reagents were described in Section 1.3.3.3.3.1.4., relatively few applications in double asymmetric reactions with chiral aldehydes have been reported. One notable example involves the matched double asymmetric reaction of the diisopinocampheyl [(Z)-methoxy-2-propenyl]boron reagent with a chiral x/ -dialkoxyaldehyde87. 

Chiral, nonracemic allylboron reagents 1-7 with stereocenters at Cl of the allyl or 2-butenyl unit have been described. Although these optically active a-substituted allylboron reagents are generally less convenient to synthesize than those with conventional auxiliaries (Section 1.3.3.3.3.1.4.), this disadvantage is compensated for by the fact that their reactions with aldehydes often occur with almost 100% asymmetric induction. Thus, the enantiomeric purity as well as the ease of preparation of these chiral a-substituted allylboron reagents are important variables that determine their utility in enantioselective allylboration reactions with achiral aldehydes, and in double asymmetric reactions with chiral aldehydes (Section 1.3.3.3.3.2.4.). 

Double asymmetric reactions of chiral a-substituted allylboron reagents 1-5 and chiral aldehydes are summarized in this section. 

The matched double asymmetric reactions with (7 )-l and (a.R,S,S)-2 provide the (S,Z)-diastereomer with 94% and 96% selectivity, while in the mismatched reactions [(S)-l and (aS,R,R)-2] the (S.Z)-diastereomer is obtained with 77% and 92% selectivity, respectively. Interestingly, the selectivity of the reactions of (/ )-2,3-[isopropylidenebis(oxy)]propanal and 2 is comparable to that obtained in reactions of (7 )-2,3-[isopropylidenebis(oxy)]propanal and the much more easily prepared tartrate ester modified allylboronates (see Table 7 in Section 1.3.3.3.3.1.5.)41. However, 2 significantly outperforms the tartrate ester allylboronates in reactions with (5)-2-benzyloxypropanal (Section 1.3.3.3.3.1.5.), but not the chiral reagents developed by Brown and Corey42-43. 

The greater diastercosclectivity of (Z)-l-methoxy-2-butenylboronate 412-25 compared with the 1-chloro derivative 31 33 demonstrated in reactions with achiral aldehydes (Section 1.3.3.3.3.1.) suggests that double asymmetric reactions of chiral aldehydes with 4 will also be more selective than reactions with 3. The data summarized below provide an indication of the magnitude of this effect. 

By way of comparison, the mismatched double asymmetric reaction of (5)-2-methylbu-tanal and E)- -methoxy-2-butenylboronate (5)-4 exhibits much greater selectivity. Dia-stereomers 9 (ca. 95%) and 7 (ca. 5%) are the only observed products, indicating that the diastereofacial selectivity of the 9/10 pair is >95 5. Here again, the small amount of 7 that was obtained (5 %) probably derives from the reaction of (S)-2-methylbutanal and the enantiomeric reagent (/ )-4, since (S)-4 is not enantiomerically pure (ca. 90% ee). 

The greater diastereofacial selectivity of 4 is also evident in the attempted mismatched double asymmetric reactions of 3 and 4 with aldehydes 11 and 15. which have greater intrinsic diastereofacial preferences than (S)-2-methylbutanal. 

Reagent 4 is the most selective ( )-2-butenylboron reagent available for application in demanding cases of mismatched double diastcrcosclcction. considerably more so than the chiral reagents discussed in Section 1.3.3.3.3.1.5. It is noted that the mismatched double asymmetric reactions are often very slow, particularly in the most stereochemically demanding eases, and the reactions of 11 and 15 with 4 are thus performed at 4 kbar pressure12 25. 

Three examples of double asymmetric reactions of (Z)-l-methyl-2-butenylboronate (a5,5,5)-5 are provided10a 44. The matched reaction of methyl (2/, 45)-2,4-dimcthyl-5-ox-opentanoate and (a5,5,5)-5 is extremely selective, although very slow, and provides 19 as the only observed product. 

The matched double asymmetric reaction of the diastereomeric aldehyde methyl (2SAS)-2.4-dimethyl-5-oxopentanoate and (otS,S,S)-5 was performed under 4kbar pressure at room temperature giving 20 as the only observed isomer. 

Difficulties have been encountered in mismatched double asymmetric reactions involving (a-S,S,S)-5, as illustrated by the reaction with 21. 

Double asymmetric synthesis was pioneered by Horeau et al.,87 and the subject was reviewed by Masamune et al.88 in 1985. The idea involves the asymmetric reaction of an enantiomerically pure substrate and an enantiomerically pure reagent. There are also reagent-controlled reactions and substrate-controlled reactions in this category. Double asymmetric reaction is of practical significance in the synthesis of acyclic compounds. 

Note that in aldol reaction IV (from 31 to 42 in Scheme 7-9), the methodology differs from that used in I, II, and III (see Scheme 7 7). Aldol reaction IV is also a double asymmetric reaction involving the coupling of two structurally... 

This example suggests that veiy high levels of selectivity will be realized in matched double asymmetric reactions involving chiral y-alkoxyallylboronates of general structure 66 and 67 (Figure 19), but also foreshadows potential problems in applications of these reagents in... 

We began these studies with the intention of applying this tandem asymmetric epoxidation/asymmetric allylboration sequence towards the synthesis of D-olivose derivative 63 (refer to Figure 18). As the foregoing discussion indicates, our research has moved somewhat away from this goal and we have not yet had the opportunity to undertake this synthesis. This, as well as the synthesis of the olivomycin CDE trisaccharide, remain as problems for future exploration. Because it is the enantioselectivity of the tartrate ester allylboronates that has limited the success of the mismatched double asymmetric reactions discussed here, as well as in several other cases published from our laboratorythe focus of our work on chiral allyiboronate chemistry has shifted away from synthetic applications and towards the development of a more highly enantioselective chiral auxiliary. One such auxiliary has been developed, as described below. 

The increased enantioselectivity of 88 is also apparent in reactions with chiral aldehydes (Figure 28). p-Alkoxypropionaldehydes 90 were relatively poor substrates when 36 was used.3 The best selectivity ever obtained for syn diastereomer 91 in the matched double asymmetric reactions was 89 11 [(S,S)-36 and 90a], whereas the best selectivity for anti diastereomer 92 was 87 13 [reaction of 90b and (R,R)-36. In contrast, the allylborations of 90a,b with the new reagent 88 now proceed with up to 97 3 selectivity for either product diastereomer. Even more impressive results were obtained with glyceraldehyde acetonide (23) the matched double asymmetric reaction leading to 29 now proceeds with 300 1 diastereoselectivity, while the mismatched combination leading to 30 proceeds with 50 1 selectivity. 

Related Allylboronate Reagents. A stereoselective synthesis of anti 1,2-diols has been achieved by using a DIPT-modified ( )-y-[(cyclohexyloxy)dimethylsilyl]allylboronate reagent. This reagent is best applied in double asymmetric reactions with chiral aldehydes such as o-glyceraldehyde acetonide (eq 9). 

The tartrate-derived crotylboronate reagents are most useful in the context of double asymmetric reactions with chiral aldehydes [118, 203]. Equations (11.16)-(11.19) demonstrate the utility of ( )-219 and (Z)-213 in the synthesis of dipropionate adducts 105-108. 

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