Anri-Felkin product

The second total synthesis of swinholide A was completed by the Nicolaou group [51] and featured a titanium-mediated syn aldol reaction, followed by Tishchenko reduction, to control the C21-C24 stereocenters (Scheme 9-30). The small bias for anri-Felkin addition of the (Z)-titanium enolate derived from ketone 89 to aldehyde 90 presumably arises from the preference for (Z)-enolates to afford anti-Felkin products upon addition to a-chiral aldehydes [52], i.e. substrate control from the aldehyde component. 

Furthermore, the reductive aldol reaction can be used for the construction of ot,p,y-stereotriads. When the racemic phebox-Rh acetate complex 32 was subjected to the coupling reactions of (5)-2-phenylpropanal with acrylate, the Felkin-Anh product 31a with (2R,3/ ,45)-configuration was predominantly formed (Scheme 22) [27]. The anri -Felkin-Anh product 31b (enantiomer) was a minor diastereomer. The use of the chiral (S,S)-phebox-Rh complex 5- Pr for the coupling reaction with (S)-2-phenylpropanal resulted in the formation of the Felkin-Anh product with high ee and de. On the other hand, the use of (R)-2-phenylpropanal afforded the anti-Felkin-Anh product 31b as a major diastereomer with moderate enantioselectivity. Thus, a combination of (S)-2-phenylpropanal with the (S,S)-phebox-Rh complex 5- Pr is a matched pair. 

A possible transition state based on the Felkin-Anh model was shown in Scheme 23. Judging from the (2/ ,3R,4S)-configuration of the product 31a, the major product is likely formed via the Felkin TS 33 showing the Si face attack of the Rh-( )-enolate. This step could be the catalyst-controlled reaction with the chiral catalyst. According to the prochiral face discrimination in the phebox-Rh-catalyzed reductive aldol reaction with the linear substrate, the Re face attack of the Rh (fij-enolate in TS 34 is unfavorable. In the case of the (R)-aldehyde, the anri-Felkin-Anh s TS 35, which gives the (2R,3R,4R)-product 31b, takes the unfavorable conformation with the bulky phenyl group at the apical position. 

Thus chelation control " may lead to either product, depending on the relative stabilities of the respective ot- and /(-chelates. In cases with predominant formation of the anri-diastereomer, it is often difficult to establish whether the formation of a /(-chelate or an open-chain Felkin - Anh transition state is responsible for the observed stereochemistry the decision usually rests on plausibility considerations. Thus, with regard to the results obtained for a-alkoxy carbonyl... 

Addition of -butylmagnesium bromide to 624 followed by Swem oxidation affords the ketone 642. Zinc borohydride addition occurs with almost exclusive anri-selectivity (>99 1), leading to 646 in accordance with an a-coordinated transition-state model in which the r -face of the carbonyl is exposed to the reagent. Presumably the MOM-ethers display a crown ether effect to facilitate a-chelation. In marked contrast, L-Selectride shows excellent 5y -selectivity to provide 645 (92 8), consistent with a j5-chelation and/or Felkin— Anh model. The a ri-adduct 646 is converted in five steps to ketone 647, which undergoes a similar highly selective hydride reduction with zinc borohydride to yield the anti,syn,syn-alcohol 648 (96 4). This product is converted in six steps to the r n5-(2i ,57 )-pyrroline 649, which undergoes a Wacker oxidation followed by catalytic reduction to (— )-indolizidine 195B (650) and its C-5 epimer (86 14) (Scheme 142). 

---