Zimmerman-Traxler transition state diastereoselective synthesis

An effective control of the simple diastereoselectivity in boron-mediated aldol reactions of various propionate esters (162) was achieved by Abiko and coworkers (equation 45) °. They could show that under usual enolization conditions (dialkylboron triflate and amine) enol borinates are formed, which allowed the selective synthesis of 5yw-configured aldol products (Table 11). The enolization at low temperature (—78 °C) generated a (Z)-enolate selectively, which afforded mainly the syn diastereomer 164 after reaction with isobu-tyraldehyde (163), following a Zimmerman-Traxler transition-state. The anti diastereomer 164 instead was obtained only in small amounts (5-20%). 

A common example for auxiliary-contfolled anti-aldol reactions is the Masamnne-Abiko process since the procedure covers the synthesis of both enantiomers depending on the nature of the auxiliary, which is readily available in both enantiomeric forms [15]. This anti-selective aldol reaction has been performed by using enantiomerically pure carboxylic esters derived from (-)- or (-i-)-norephedrine. The method is applicable to a wide range of aldehydes with high selectivity (both antilsyn and diastereoselectivity of anti-isomer) [16]. A typical example of this aldol approach is depicted in Scheme 2.113. It is proposed that the reaction proceeds via a six-membered Zimmerman-Traxler transition state. 

Evans aldol reaction between the functionalized 4-phenyl-oxazohdinone 6 and 5-chloropentanal 7, securing the 1,2-syn stereochemistry " in the resultant chlorohydrin 9. The diastereoselectivity of this process is governed by the preferential formation of a (Z)-enolate and dipole minimization in the Zimmerman-Traxler transition state 8. Conversion of the aldol adduct into the corresponding mesylate was followed by reductive removal of the auxiliary to provide the hydroxymesylate 10, an advanced intermediate in the enantioselective synthesis of (-l-)-methylphenidate hydrochloride 11. The active pharmaceutical ingredient was produced in >99% ee after lecrystaUization. 

In investigations of double diastereodifferentiating Mukaiyama aldol reactions, Evans demonstrated that the coupling of end silane 195 either to aldehyde 196 or to aldehyde 198 affords the Felkin products 197 and 199, respectively, with excellent diastereoselectivity (Scheme 4.21) [36]. Because of the involvement of open transition states in these aldol reactions, no direct correlation was found between the starting end silane geometry and the observed simply selectivity (syn versus anti). This contrasts with the simple diastereoselectivity typically observed for cis- and trans-metal enolates that react through cyclic Zimmerman-Traxler transition states. By this strategy, the addition of enol silane 201 to 200 provided an advanced intermediate 202 in the synthesis of 6-deoxyerythronolide B (187, Scheme 4.22) [97]. 

The additions of allyl-, crotyl-, and prenylborane or -boronate reagents to aldehydes are among the most widely studied, well developed, and powerful reactions in stereoselective synthesis. The additions not only display excellent levels of absolute induction in enantioselective synthesis, but also exhibit superb levels of reagent control in diastereoselective additions. The additions of ( )- or (Z)-crotyl pinacol boronates to aldehydes have been observed to give predominantly 1,2-anti- and 1,2-syn-substituted products, respectively (Scheme 5.3) [31, 50]. The inherent stereospecificity of the reaction is consistent with a closed, cyclic Zimmerman-Traxler transition state structure [51], In the accepted model, coordination of the aldehyde to the allylation reagent results in synergistic activation of both the electrophile and the nucleophile... 

In 1986, Nagao demonstrated the effectiveness of the acetyl thiazolidi-nethione 80 in combination with Sn(OTf)2 and N-ethylpiperidine for highly stereoselective acetate aldol additions (Scheme 4.9) [57]. It was proposed that the stereochemical outcome was the result of the intermediacy of a closed Zimmerman-Traxler-type transition state 81. This method was utilized in Romo s synthesis of the immunosuppressive agent (-)-pateamine A (84) [58]. The Nagao acetate aldol reaction was implemented twice in the route, giving excellent yields and superb diastereoselectivity. 

---