Chiral haptens

The first antibody-catalyzed asymmetric 1,3-dipolar cycloaddition was reported recently by Janda and co-workers (382). The reaction of the relatively stable nitrile oxide 280 and dimethyl acrylamide 281 was catalyzed by antibody 29G12 having turnover numbers >50, and the product 282 was obtained in up to >98% ee (Scheme 12.89). The antibody 29G12 was formed for hapten 283 and coupled to a carrier protein by standard protocols. The hapten 283 contains no chiral center and therefore the immune system elicited a stereochemical environment capable of stabilizing the enantiomeric transition state leading to 282. 

Phosphonates and phosphonamidates, which mimic the tetrahedral geometry and anionic character of the transition state for hydrolysis, have proven especially reliable as haptens. Antibodies generated against such compounds readily promote the cleavage of esters and, in a few cases, amides. High levels of stereospecificity are attainable even at chiral centers remote from the reaction site [11]. 

Mu YQ, Gibbs RA. Design and synthesis of chiral and racemic phosphonate-based haptens for the induction of aldolase catalytic antibodies. Biooig. Med. Chem. 1997 5(7) 1327—1337. 

Scheme 15 illustrates the asymmetric hydrogenation of 3-keto phosphonates catalyzed by a BINAP-Ru complex, giving P-hydroxy phosphonates in up to 99% ee [61]. The sense of enantioface differentiation is the same as that of hydrogenation of P-keto carboxylic esters (see table of Scheme 3). The reactivity of the phosphonates is much higher than that of the carboxylic esters so that the hydrogenation proceeds even at 1 to 4 atm of hydrogen and at room temperature. A Ru complex of BDPP also shows high enantioselectivity [46b]. Chiral P-hydroxy phosphonates thus obtained are useful intermediates for the syntheses of phosphonic acid-based antibiotics as well as haptens of catalytic antibodies. Similarly, P-keto thiophosphates are hydrogenated enantioselectively with a MeO-BIPHEP-Ru catalyst [61b].

One of the first demonstrations of antibodies as chiral determinants in an organic reaction involved the enantioselective perturbation of a raeso-substrate [14]. For this case phosphonate 1 was used as a hapten and the raeso-diacetate 2 as the substrate for antibodies elicited to this hapten (Scheme 1). This strategy engages... 

Scheme 2. Antibody 27B5 elicited to the phosphonate hapten 4 catalyzes the enantiofacial protonation of the enolate intermediate 6 during the acid-catalyzed hydrolysis of the enol ester 5 to yield the chiral ketone 7 with 42% ee...

Schemes. Enantiofacial protonation of the enol ethers 10,11,13 by antibody 14D9, elicited to hapten 8a, yields chiral products 12,14 with upto 96% ee...

Scheme4.Antibody A5, elicited to hapten 15, catalyzes the highly enantiospecific reduction of a-ketoamide 16 (>99% de) with sodium cyanoborohydride (NaCNBHj) as a cofactor. This is a good example of an achiral hapten generating a catalyst possessing exquisite chiral discrimination...

To escape product inhibition, unstable boat-like haptens are used to prepare Diels-Alderase antibodies. Braisted and Schultz raised antibody 39-All with hapten 124 fixed in a boat form. The antibody 39-All catalyzed the Diels-Alder reaction between 121 and 122 to yield the chiral adduct 123 (Scheme 21). 

Fig. 3 (A) [33] Sigrnatropic rearrangement of chorismate to prephenate catalyzed by antibody 11F1-2E11. The hapten is a shape mimic of the cyclic transition state. (B) Antibody 1E9 catalyzes a Diels-Alder reaction of tetrachlorothiophene dioxide and yV-ethylmaleimide. The hapten is comprised of the endo hexachloronorbornene unit. (C) Antibody 21H3A catalyzes the transesterification reaction between iec-phenethyl alcohol and an enolic ester to form a chiral ester. The hapten here is racemic phosphonate.

The first example of a diastereoselective addition of an H-phosphonate to chiral imines was reported by Gilmore and McBride in 1972. a-Methylbenzylamine was used as a chiral auxiliary, and the reaction carried out at 140 °C led to a 2 1 mixture of diastereomers. Later, the procedure was improved and applied to the synthesis of hapten 87... 

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