Enol borinate, chiral

The syntheses in Schemes 13.45 and 13.46 illustrate the use of oxazolidinone chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.45 established the configuration at the carbon that becomes C(4) in the product. This is an enolate alkylation in which the steric effect of the oxazolidinone chiral auxiliary directs the approach of the alkylating group. Step C also used the oxazolidinone structure. In this case, the enol borinate is formed and condensed with an aldehyde intermediate. This stereoselective aldol addition established the configuration at C(2) and C(3). The configuration at the final stereocenter at C(6) was established by the hydroboration in Step D. The selectivity for the desired stereoisomer was 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methylalkenes in which the remainder of the alkene constitutes a relatively bulky group.28 A TS such as 45-A can rationalize this result. 

Masamune et al. applied the newly developed enantioselective anti-aldol reaction to the syntheses of two key fragments of miyakolide 5, a bryostatin-like marine metabolite5 (Scheme 2.2e). The readily synthesized aldehyde 8 was treated with chiral enol borinate generated from the ester 3 to give the aldol 9 in 85%... 

Goodman, J. M., Kahn, S. D., Paterson, I. Theoretical studies of aldol stereoselectivity the development of a force field model for enol borinates and the investigation of chiral enolate -face selectivity. J. Org. Chem. 1990, 55, 3295-3303. 

Vulpetti, A., Bemardi, A., Gennari, C., Goodman, J. M., Paterson, I. Origins of rc-face selectivity in the aldol reactions of chiral E-enol borinates a computational study using transition state modeling. Tetrahedron 1993,49, 685-696. 

Gennari, C. Rationally designed chiral enol borinates powerful reagents for the stereoselective synthesis of natural products. Pure Appl. Chem. 1997, 69, 507-512. 

A chiral aldehyde, attached through a silyl linker to a hydroxymethyl Merrifield resin, was employed for expanding polyketide diversity. Aldol reaction with preformed (H)-enol borinate derived from a suitable chiral (R)-ketone afforded the anti-anti aldol product. Titanium-mediated enolization of the enantiomer (S)-ketone afforded the syn-syn product. 

Good levels of 1,3-anti induction can be achieved with aldehyde 199 when it is attacked by silyl enol ether 198. The aldehyde hydroxyl is the chiral centre and p-methoxybenzyl (PMB) is the best protecting group. Chelating Lewis acids (Ti, Li) are less effective than the combination of a silyl enol ether and BF3 as the Lewis acid. The nature of the enol derivative is important and good selectivity is not achieved when an enol borinate is used.32 We shall see in a moment that this lack of influence can be useful too. 

Now, whether this local syn arrangement is anti or syn to the more remote chiral centre in the enol borinate (1,3-control) can be controlled by the use of one enantiomer or other of a chiral boron reagent. The cis enol borinate with achiral boron reagent does not have much will of its own and leads to a 1 1.2 ratio of syn, syn anti, syn. 

Reaction C in Fig. 4 is an aldol condensation between an achiral aldehyde and an ester enol borinate featuring a bidentate chiral substituent at the boron atom [24]. Upon enolate-boron/aldehyde-oxygen co-ordination, two chair-like TS can be formed, both featuring the aldehyde phenyl group in a pseudo-equatorial position. Preferential attack on the aldehyde Si face is determined by the spatial arrangement of the metal ligand. The almost exclusive formation of the anti diastereoisomers arises from control of the enolate geometry. 

Paterson I, Tillyer RD. High rr-face selectivity in anti aldol reactions of E-enol borinates from chiral alkoxy-methyl ketones stereocontrolled synthesis of a C24—C32 polyol subunit of rapamycin. J. Org. Chem. 1993 58 4182 184. 

Waldmann and coworkers employed the aldol reactions of chiral boron enolates as the key stereoselective transformations toward the solid-phase synthesis of 6,6-spiroketals, a scaffold often found in biologically interesting complex natural products. The polymer-bound aldehyde 1 with a loading of 0.75 mmol/g was treated at —78°C with the preformed (Z)-diisopinocampheyl borinate 2 in dichloromethane for 1.5 h (Scheme 7.1). After storing the reaction mixture at —27°C for 16 h, the resin was filtered and the whole process was repeated once. An oxidative workup followed by TBS protection of the secondary alcohol yielded immobilized s yw-aldol product 3. 

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