Mandelic acid boron enolate

In contrast, highly stereoselective aldol reactions are feasible when the boron etiolates of the mandelic acid derived ketones (/ )- and (5,)-l- t,r -butyldimethylsiloxy-l-cyclohexyl-2-butanone react with aldehydes33. When these ketones are treated with dialkylboryl triflate, there is exclusive formation of the (Z)-enolates. Subsequent addition to aldehydes leads to the formation of the iyn-adducts whose ratio is 100 1 in optimized cases. 

Recently, the improved chiral ethyl ketone (5)-141, derived in three steps from (5)-mandelic acid, has been evaluated in the aldol process (115). Representative condensations of the derived (Z)-boron enolates (5)-142 with aldehydes are summarized in Table 34b, It is evident from the data that the nature of the boron ligand L plays a significant role in enolate diastereoface selection in this system. It is also noteworthy that the sense of asymmetric induction noted for the boron enolate (5)-142 is opposite to that observed for the lithium enolate (5)-139a and (5>139b derived from (S)-atrolactic acid (3) and the related lithium enolate 139. A detailed interpretation of these observations in terms of transition state steric effects (cf. Scheme 20) and chelation phenomena appears to be premature at this time. Further applications of (S )- 41 and (/ )-141 as chiral propionate enolate synthons for the aldol process have appeared in a 6-deoxyerythronolide B synthesis recently disclosed by Masamune (115b). 

Equation B5.6 depicts the reaction of an achiral aldehyde with a homochiral boron enolate derived from (5)-mandelic acid. Again the geometry of the enolate controls the relative stereochemistry of C2 and C3 and so only the two erythro isomers are formed. In this case, however, the homochiral centre in the boron enolate results in approach to one face of the aldehyde being strongly preferred over approach to the other face and a product ratio of 2R,3S 2S,3R = 28 1 is observed. 

If the boron enolate derived from (/ )-mandelic acid is used in Equation B5.6 then a reversal of selectivity to 2R,3S 2S,3R — 1 28 is anticipated. Thus, on combination of the (/ )-boron enolate with (-)-dimethylglutaric hemialdehyde, the stereochemical preferences of the two reagents work against each other (they are said to be mismatched ) and relatively low stereoselectivity is observed. The stereochemistry of the major diastereoisomer is that produced by the partner with the strongest control over the reaction (Equation B5.8). 

Treatment of products derived from the mandelic acid-based boron enolates with aqueous HF followed by NalOq releases a carboxylic acid. For example, the aldol product formed in Equation B5.7 is converted into a carboxylic acid (which lactonizes under the reaction conditions) as shown in Equation B5.9. 

Thus the two mandelic acid-based boron enolates described in this section may be regarded as sources of propionic acid which add to aldehydes to give erythro aldol products of high stereochemical purity. An elegant synthesis of the macrolide, 6-deoxyerythronolide B, uses three mandelic acid-based boron enolate/aldehyde reactions. The retrosynthetic analysis of the synthesis is shown in Figure B5.ll. 

In the actual synthesis, aldol reaction 1 involved a lithium enolate whilst aldol reactions 2-4 used boron enolates based on the mandelic acid derivatives described above to incorporate fragments A, B, and C. The aldol products of reactions 2 1 were treated with fluoride and then NaIC>4 to release carboxylic acids which were derivatized or reduced as appropriate. 

Mandelic acid and its derivatives are utilized as convenient precursors for the introduction of a chiral center, and they possess the extra advantage of bearing a useful functional group. Many mandelic acid derivatives also act as chiral auxiliaries for the induction of a chiral center in stereoselective transformations. Numerous natural products, such as macrolides and ionophore antibiotics, possess a carbon framework that may be viewed synthetically as arising from a sequence of highly stereo- and enantioselective aldol condensations. Boron enolates, chiral auxiliaries derived from mandelic acids 1 or 2, provide remarkably high aldol stereoselectivity. 

These boron enolates can be considered as chiral nucleophiles wherein chirality observed in the products of the aldol reactions arises from the chiral auxiliary mandelic acid. An alternative approach to the diastereo- and enantioselective carbon-carbon bond forming reaction is to react an achiral anion precursor with an electrophilic equivalent containing a chiral auxiliary derived from mandelic acid. 

Commercially available (5)- and (i )-mandelic acids have been used to prepare the boron enolates (90) and (91), which react with aldehydes RCHO to give [in the case of (90)] products (92) and (93) in which (92) predominates by a factor of at least 75 1. In the case of aldehydes with an a-substituent greatest selectivity is observed when R = 9-BBN in (90) and (91), whereas the corresponding dicyclohexyl boron enolate is recommended for aldehydes without an a-substituent. 

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