Asymmetric double

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

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. 

Scheme 3. Asymmetric epoxidation of allylic alcohol 12 double asymmetric induction.

I.3.3.3.3.I.5. Double Asymmetric Induction Reactions of Chiral Aldehydes with Chiral Allylboron Reagents... 

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 Induction Reactions of Chiral a-Substituted Allylboron... 

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. 

After 12 hours at 4 kbar. this reaction provided only 35% of a 63 27 mixture of 22 and a compound which was tentatively assigned structure 23. It is assumed that 23 derives from epimerization of 21 prior to reaction with (aS,S,S)-5l0b. Whether this stereochemical assignment is correct or not, this result shows that 5 may have problems with configurationally labile aldehydes in demanding cases of mismatched double diastereosclcction. For further examples of double asymmetric induction with 5 or related reagents, see refs 31, 34 and 47. 

An example of double asymmetric induction has been reported. The resolved enantiomers of rac-4 have been converted to the aluminum enolates and reacted at —78 °C with enantiomer-ically pure ter/-butyl (S)-2-fonnyl-l-pyrrolidine carboxylate46. A comparison of the two reactions reveals that the reaction pair leading to the (5Fe,/ ,5)-product is matched while the alternative reaction pair is mismatched. 

Double asymmetric synthesis and a new strategy for stereochemical control in organic synthesis [95]... 

When an optically active substrate reacts with an optically active reagent to form two new chiral centers, it is possible for both centers to be created in the desired sense. This type of process is called double asymmetric synthesis (for an example, see p. 1222). 

Double asymmetric induction operates when the azomethine compound is derived from a chiral a-amino aldehyde and a chiral amine, e.g., the sulfin-imine 144 [70]. In this case, the R configuration at the sulfur of the chiral auxihary, N-tert-butanesulfinamide, matched with the S configuration of the starting a-amino aldehyde, allowing complete stereocontrol to be achieved in the preparation of the diamine derivatives 145 by the addition of trifluo-romethyl anion, which was formed from trifluoromethyltrimethylsilane in the presence of tetramethylammonium fluoride (Scheme 23). The substituents at both nitrogen atoms were easily removed by routine procedures see, for example, the preparation of the free diamine 146. On the other hand, a lower diastereoselectivity (dr 80 20) was observed in one reaction carried out on the imine derived from (it)-aldehyde and (it)-sulfinamide. 

Scheme 23 Double asymmetric induction in the addition of Grignard reagents to chiral a-amino imines and a-amino iminium ions...

Scheme 5-40 ALB-catalyzed double asymmetric addition of methyl phosphinate to aldehydes ALB = AI/Li/BINOL...

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