Lipase lactam hydrolysis

Scientists from Bristol-Myers Squibb developed a new side chain for Taxol, making it water-soluble. A kinetic resolution with Pseudomonas cepacia lipase (lipase PS-30 from Amano) was applied to obtain the desired material enantiopure (Scheme 6.10). After the lipase-catalysed hydrolysis of the wrong enantiomer (49% conversion) the ester was obtained with an ee of >99%. Separation and subsequent chemical cleavage of the ester yielded the desired enantiomer of the lactame, which could then be coupled to baccatin III [44]. 

Likewise, lipase-catalyzed hydrolysis of racemic lactam 99 gave both 100 and 101 in almost enantiomerically pure form (see Scheme 9.23). Conventional chemical conversion of the isobutenyl moiety of 101 to difluoromethyl and trifluoromethyl groups provided lactams 103 and 104, which were further transformed to dipeptide 106 by ring-opening coupling with amino esters [48]. 

CAL-B lipase has been appHed to the resolution of some P-amino esters, by means of N-acylation or transesterification [27]. Resolution using CAL-B is complicated by the tendency of the en2yme to catalyze competing reactions at the amino and ester functional groups. However, CAL-B has proved very useful for resolution by means of P-lactam hydrolysis. 

Lipases are generally inactive on the amide bond. One notable exception is the hydrolysis and alcoholysis of P-lactams by CAL-B [108-112]. For example, CAL-B... 

Lipase-catalyzed acylation of one isomer of iV-hydroxymethyl /3-lactam 121 by vinyl butyrate in acetone yielded the ester 122, which afforded 123 after acidic hydrolysis and ion-exchange chromatography (Scheme 7). The unesterified alcohol 124 gave the /3-amino acid 125. Similar reactions yielded 2-aminocyclohex-3-en-l-carboxylic acid and 2-aminocyclohex-4-ene-l-carboxylic acid from l-azabicyclo[4.2.0]oct-3-en-8-one and l-azabicyclo[4.2.0]oct-... 

A highly enantioselective enzymatic acylation was observed on N-hydroxymethylated P-lactam 50, which was prepared from ( )-14 with paraformaldehyde by sonication in tetrahydrofuran [88]. Lipase AK-catalysed butyrylation with vinyl butyrate gave the readily separable azetidinones 51 and 52. Hydrolysis of 51 and 52 resulted in the 2-ACPC hydrochlorides 53 and 54, respectively (Scheme 8) [88]. 

In contrast to y- and 8-lactams, highly strained p-lactams are more easily susceptible to enzymatic hydrolysis and thus can be (slowly) hydrolyzed by carboxyl ester hydrolyses, such as esterases [162] and lipases [163] (Scheme 2.20). 

Scheme 2.20 Enzymatic hydrolysis of strained p-lactams using lactamases and lipases...

The enantioselective preparation of pyridone photoisomers has been described by several laboratories, motivated in part by the importance of 5-lactams as antibiotics. Lipase hydrolysis of racemic 104 and similar Dewar pyridones has led to resolutions with high enantiomeric purities. Isomerization of pyridones when complexed to the chiral scaffold 106 gave the isomerized product with good to excellent levels of enantioselectivity. ... 

A number of research groups have been interested in die synthesis of aminodiol 22. This compound is believed to mimic the transition state for the renin-catalyzed hydrolysis of the peptide angiotensinogen and therefore can be useful as a potential antihypertensive drug. The enzymatic resolution of the 3-acetoxy-P-lactam 23 (Fig. 6) by lipase PS-30 has been demonstrated by Spero et al. [37]. A new approach to the BOC-protected aminodiol 24 via opening of 3,4-cis-disubstituted j3-lactam has been demonstrated. 

Recently, preparation of taxol side chain precursors by the lipase-catalyzed enantio-selective esterification of methyl rra s-p-phenylglycidate has been demonstrated [55]. Preparation of enantiomerically pure 3-hydroxy-4-phenyl ji-lactam by lipase-catalyzed en-antioselective hydrolysis and transesterification of racemic esters and alcohols, respectively, have also been described by Brieva et al. [56]. 

For the synthesis of p-lactam antibiotics, the presence of asymmetrical carbon at the 3 and 4 positions is critical to prepare optically active -lactams [197]. Nagai et al. [198] developed enzymatic synthesis of optically active p-lactams by lipase-catalyzed kinetic resolution using the enantioselective hydrolysis of iV-acyloxymethyl p-lactams 108 in an organic solvent (isopropyl ether saturated with water) and the transesterification of N-hydroxymethyl P-lactam 109 in organic solvent (metiiylene chloride) in tiie presence of vinyl acetate as acyl donor (Fig. 37). The reaction yield of 35-50% and e.e. s of 93 to more than 99% were obtained depending on the specific substrate used in the reaction mixture, Lipase B from Pseudomonas fragi and lipase PS-30 from Pseudomonas sp. were used in the reaction mixture. 

Aziridine carboxylates are chiral intermediates for the synthesis of -lactams and amino acids [200]. The use of enantioselective ester hydrolysis in the synthesis of optically active A -unsubstituted and A-substituted aziridine carboxylate by Candida cylindraceae lipase has been demonstrated by Bucciareli et al. [199]. Racemic methyl aziridine-2-car-boxylate and 2,3-dicarboxylate 110 were used as substrates both for enzymatic hydrolysis and for the synthesis of AAchloro, iV-acyl and A-sulfonyl derivatives (Fig. 38). The reaction yield of 35-45% (theoretical maximum yield is 50%) and the e.e. s of 90-98% were obtained depending on substrate used in the reaction mixture. 

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