Double asymmetric induction

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). 

The enantiomers are obtained as a racemic mixture if no asymmetric induction becomes effective. The ratio of diastereomers depends on structural features of the reactants as well as the reaction conditions as outlined in the following. By using properly substituted preformed enolates, the diastereoselectivity of the aldol reaction can be controlled. Such enolates can show E-ot Z-configuration at the carbon-carbon double bond. With Z-enolates 9, the syn products are formed preferentially, while fi-enolates 12 lead mainly to anti products. This stereochemical outcome can be rationalized to arise from the more favored transition state 10 and 13 respectively ... 

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... 

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... 

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. 

Substantially high diastereoselectivity was accomplished by the conjugate addition of Grignard reagents to the amide 1 derived from 1-ephedrine32. The reagent attacked from the Re-face of the double bond, as shown in 2, via a chelated intermediate. Low asymmetric induction was observed when butyllithium was used instead of butylmagnesium bromide. 

The sense of the asymmetric induction at the /J-carbon of 10 is opposite to that of 7, indicating that 10 reacts with the Gilman reagents in a conformation where the carbonyl is s-trans to the a,(i double bond to avoid steric repulsion of the a-substituent and the camphor residue. 

Fluoboric acid is also an efficacious promoter of cyclic oxo-carbenium ions (Scheme 4.24) bearing an activated double bond which, in the presence of open-chain and cyclic dienes, rapidly undergo a Diels-Alder reaction [91]. Chiral a, -unsaturated ketones bearing a -hydroxy substituents, protected as acetals, react with various dienes in the presence of HBF4, affording Diels-Alder adducts that were isolated as alcohols by hydrolysis of the acetal group by TsOH. Some examples of reactions with isoprene are reported in Table 4.23. The enantios-electivity of the reaction is dependent on the size of the substituent R on the of-carbon high levels of asymmetric induction were observed with R = z-Pr (90 1) and R = t-Bu (150 1) and low levels with R = Me (2.7 1) and R = Ph (3.0 1). Scheme 4.24 shows the postulated reaction mechanism. 

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...

The 1,3-dipolar cycloadditions of nitrones (551), (595), (614), (615) and their enantiomers (595 ent), (614 ent), (615 ent) (Fig. 2.40) to a.p-unsaturated y-lactones, such as achiral D7 g and D-glycero D7 h, provide an interesting example of double asymmetric inductions. The reactions are kinetically controlled. However, on heating and at longer reaction times, the reversibility of the cycloaddition (595 + D7 h) was observed, and the presence of a more stable thermodynamic product (620) was detected. Moreover, in the case of lactone D7 h, a... 

In the case of tri-substituted alkenes, the 1,3-syn products are formed in moderate to high diastereoselectivities (Table 21.10, entries 6—12). The stereochemistry of hydrogenation of homoallylic alcohols with a trisubstituted olefin unit is governed by the stereochemistry of the homoallylic hydroxy group, the stereogenic center at the allyl position, and the geometry of the double bond (Scheme 21.4). In entries 8 to 10 of Table 21.10, the product of 1,3-syn structure is formed in more than 90% d.e. with a cationic rhodium catalyst. The stereochemistry of the products in entries 10 to 12 shows that it is the stereogenic center at the allylic position which dictates the sense of asymmetric induction... 

As described hitherto, diastereoselectivity is controlled by the stereogenic center present in the starting material (intramolecular chiral induction). If these chiral substrates are hydrogenated with a chiral catalyst, which exerts chiral induction intermolecularly, then the hydrogenation stereoselectivity will be controlled both by the substrate (substrate-controlled) and by the chiral catalyst (catalyst-controlled). On occasion, this will amplify the stereoselectivity, or suppress the selectivity, and is termed double stereo-differentiation or double asymmetric induction [68]. If the directions of substrate-control and catalyst-control are the same this is a matched pair, but if the directions of the two types of control are opposite then it is a mismatched pair. 

Striking examples of this phenomenon are presented for allyl and homoallyl alcohols in Eqs. (5) to (7). The stereodirection in Eq. (5) is improved by a chiral (+)-binap catalyst and decreased by using the antipodal catalyst [60]. In contrast, in Eq. (6) both antipode catalysts induced almost the same stereodirection, indicating that the effect of catalyst-control is negligible when compared with the directivity exerted by the substrate [59]. In Eq. (7), the sense of asymmetric induction was in-versed by using the antipode catalysts, where the directivity by chiral catalyst overrides the directivity of substrate [52]. In the case of chiral dehydroamino acids, where both double bond and amide coordinate to the metal, the effect of the stereogenic center of the substrate is negligibly small and diastereoface discrimination is unsuccessful with an achiral rhodium catalyst (see Table 21.1, entries 9 and 10) [9]. 

Figure 1-31. Strategy for generation of new chiral centers on a chiral substrate. A and B must be homochiral. A-C(x), chiral substrate B-C(y), chiral reagent I, desired transformation II, double asymmetric induction III, removal of the chiral auxiliary. Reprinted with permission by VCH, Ref. 88.

Double asymmetric induction (See section 1.5.3) can also be employed in aldol reactions. When chiral aldehyde 15 is treated with achiral boron-mediated enolate 14, a mixture of diastereomers is obtained in a ratio of 1.75 1. However, when the same aldehyde 15 is allowed to react with enolates derived from Evans auxiliary 8, a syn-aldol product 16 is obtained with very high stereo-... 

Now, we examine the interaction of chiral aldehyde (-)-96 with chiral enolate (S )-lOOb. This aldol reaction gives 104 and 105 in a ratio of 104 105 > 100 1. Changing the chirality of the enolate reverses the result Compound 104 and 105 are synthesized in a ratio of 1 30 (Scheme 3-38).66 The two reactions (—)-96 + (S )-lOOb and (—)-96 + (7 )-100b are referred to as the matched and mismatched pairs, respectively. Even in the mismatched pair, stereoselectivity is still acceptable for synthetic purposes. Not only is the stereochemical course of the aldol reaction fully under control, but also the power of double asymmetric induction is clearly illustrated. 

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