Asymmetric double stereodifferentiation

Asymmetric Bond Formation with Double Stereodifferentiation... 

The above observations are quite pertinent here since they introduce us to "relative stereoselective induction" (or "double stereodifferentiation") studied by Heathcock [23]- and to "double asymmetric induction" [29] developed by Masamune [22]. 

The multiplicative combination of two effects is known as double stereodifferentiation 62. One problem is to achieve high asymmetric induction in the catalytic hydrogenation of 2-acetylamino-3-phenylpropenoic acid63. 

Intramolecular C-H insertions of aryldiazoacetates have been effectively achieved with high asymmetric induction by using either Rh2(S-DOSP)4[13] or Rh2(S-PTLL)4[14] as catalyst. An impressive recent example is a key step (18 to 19) in the synthesis of (-)-ephedradine A (20) (Scheme 8) [15]. In this particular case, a double stereodifferentiation with a chiral catalyst and auxiliary gave the best asymmetric induction. 

The boron-aldol reaction of the p-methoxyben-zyl(PMB)-protected methylketone 16 proceeds with excellent 1,5-anti-selectivity (Scheme 4). In cases where the asymmetric induction is lower it may be improved by a double stereodifferential aldol reaction with chiral boron ligands [7]. The reason for this high stereoselectivity is currently unknown. Ab initio calculations suggest the involvement of twisted boat structures rather than chair transition structures [6]. 

The asymmetric hydroxylation of ester enolates with N-sulfonyloxaziridines has been less fully studied. Stereoselectivities are generally modest and less is known about the factors influencing the molecular recognition. For example, (/J)-methyl 2-hydroxy-3-phenylpropionate (10) is prepared in 85.5% ee by oxidizing the lithium enolate of methyl 3-phenylpropionate with (+)-( ) in the presence of HMPA (eq 13). Like esters, the hydroxylation of prochiral amide enolates with N-sulfonyloxaziridines affords the corresponding enantiomerically enriched a-hydroxy amides. Thus treatment of amide (11) with LDA followed by addition of (+)-( ) produces a-hydroxy amide (12) in 60% ee (eq 14). Improved stereoselectivities were achieved using double stereodifferentiation, e.g., the asymmetric oxidation of a chiral enolate. For example, oxidation of the lithium enolate of (13) with (—)-(1) (the matched pair) affords the a-hydroxy amide in 88-91% de (eq 15). (+)-(Camphorsulfonyl)oxaziridine (1) mediated hydroxylation of the enolate dianion of (/J)-(14) at —100 to —78 °C in the presence of 1.6 equiv of LiCl gave an 86 14 mixture of syn/anti-(15) (eq 16). The syn product is an intermediate for the C-13 side chain of taxol. 

Of particular concern with a-hydroxy carbonyl compounds is the stereochemistry of the hydroxy group attached to the stereogenic carbon because biological activity is often critically dependent on its orientation. A-Sulfonyloxaziridines have played a prominent role in the stereoselective synthesis of this key structural element (Scheme 25). Enantiomerically and diastereomerically enriched materials have been prepared by (1) the hydroxylation of chiral nonracemic enolates with racemic A-sulfonyloxaziridines, for example (63a) (2) the asymmetric hydroxylation of prochiral enolates with enantiopure A-sulfonyloxaziridines and (3) a combination of the first two, double stereodifferentiation. 

As pointed out in an earlier section, the ees for the asymmetric hydroxylation of acyclic enolates derived from a-branched carbonyl compounds is often low because of the difficulty in generating a specific enolate geometric isomer as well as poor enantiofacial discrimination between the re and si faces of the enolate (Scheme 25). In one example of a double stereodifferentiation process, the asymmetric oxidation of a chiral enolate, was successfully employed to circumvent these difficulties <87JOC5288>. For the matched pair, (—)-(179) and oxaziridine (—)-(114), the de was 88-91% (Equation (43)) whereas with the mismatched pair, (—)-(179) and (+)-(114), the de dropped to 48.4%. The pyrrolidine methanol chiral auxiliary in (180) was removed without racemization by basic hydrolysis affording nonracemic atrolactic acid in 70-89% yield. 

Asymmetric induction from a stereocenter in a chiral group bound to N has also been studied, and good to excellent levels of relative diastereoselection have been observed (Scheme 35). Interestingly, incorporation of a N-phenethyl unit of appropriate absolute stereochemistry into (214) resulted in substantially improved selectivity for the 1,3-syn product diastereomer (compare results with 210, Scheme 34) 120b jhis is an example of double stereodifferentiation, a synthetic strategy that is discussed in Section 1.1.5. 

The phenomenon has also been referred to as "double asymmetric induction." (9) We have used the term double stereodifferentiation, first introduced by Izumi and Tai (1J)) in order to avoid confusion in cases involving racemates. 

Bisituselectivity is operative in double differentiation, double stereodifferentiation, and double asymmetric induction, and, has led to the terms matched/mismatched pairs. 

Similarly, the reaction of an achiral aldehyde with a chiral enolate leads to some degree of diastereofacial selectivity and the two diastereomeric products are not produced in equal amounts. Further enhancement to the selectivity is possible using a chiral aldehyde with a chiral enolate. When both the nucleophile and the electrophile contain a chiral centre then double stereodifferentiation (or double asymmetric induction) can occur. Most of the studies in these areas use chiral, non-racemic enolates, which are discussed in the next section. 

The [3+4] annulation approach to the hydroazulenes is achieved with high asymmetric induction (greater than 90% de) by using (/ )-pantolactone as a chiral auxiliary (Table 7). The nature of the catalyst has a considerable effect on the level of asymmetric induction. A sterically crowded catalyst, such as rhodium pivalate, results in much lower diastereoselectivity than rhodium(II) acetate or rho-dium(II) hexanoate. Consequently, even though the enantiomers of rhodium(II) mandelate exhibit double stereodifferentiation with the (/ )-pantolactone auxiliary (entries 5,6), both catalysts are bulky and result iinferior asynunetric induction compared to that obtained with an uncrowded achiral catalyst (entries 1-3). 

Asymmetric oxidation of 2,3-epoxy sulfides with (—)-(l), double stereodifferentiation, gives 2,3-epoxy sulfoxide diastereoiso-mers (eq 3). Lower de values were observed for the other epoxy sulfide enantiomer. The modified Sharpless reagent gave better de values (5.1 1) with the methyl sulfides. 

Heathcock and White" and Masamune et al." developed independently the double stereodifferentiation to enhance 1,2-diastereoselection in aldol condensations of chiral aldehydes. As shown in Scheme 8.32," Masamune et al. examined the effect of stereochemistry of an enolate and an aldehyde in asymmetric aldol reaction. Benzaldehyde, the achiral aldehyde, reacted with the chiral enolate S-207 to... 

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