Enzymatic Resolution of Aminocyclopentenols as Precursors to <scp>d</scp>- and <scp>l</scp>-Carbocyclic Nucleosides

Mulvihill, Mark J.; Gage, Jennifer L.; Miller, Marvin J.

doi:10.1021/jo972265a

Cited by 70 publications

(59 citation statements)

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“…Merlo et al (76) have used a lipase from Pseudomonas cepacia for the separation of the two enantiomers of a precursor of 5Ј-noraristeromycin, a potent antiviral compound. Lipases from Candida antarctica B and Pseudomonas species have also been used for the kinetic resolution of (Ϯ)-cis-N-(benzylcarbamoyl)-4-aminocyclopent-2-enol and its corresponding acetate by enzymatic acetylation and deacetylation, respectively, the enantiomerically pure cyclopentane precursor was further used for the preparation of carbocyclic nucleosides (77). The enzymes, nucleoside oxidase purified from Pseudomonas maltophilia LB-86 and a cell free extract of Streptomyces citricolor have been used to carry out oxidation (78) and reduction (79), respectively, in the sugar moiety of carbocyclic nucleosides.…”

Section: Miscellaneous Reactionsmentioning

confidence: 99%

Nucleoside Synthesis Mediated by Glycosyl Transferring Enzymes

Prasad

Trikha

Parmar

1999

Bioorganic Chemistry

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Section: Miscellaneous Reactionsmentioning

confidence: 99%

Nucleoside Synthesis Mediated by Glycosyl Transferring Enzymes

Prasad

Trikha

Parmar

1999

Bioorganic Chemistry

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“…Conversely, extensive studies with CAL B provided an effective solution. Candida antarctica lipase B was chosen based on its broad utility and general experience in our group 12. After exploring solvents,13 temperatures, and adding n -butanol,14 cephalosporin 4 was obtained (Table 1).…”

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confidence: 99%

Enzymatic Deprotection of the Cephalosporin 3′-Acetoxy Group Using Candida antarctica Lipase B

Patterson

Miller

2010

J. Org. Chem.

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Cephalosporins remain one of the most important classes of antibiotics. A useful site for derivatization involves generation of and chemistry at the 3′-hydroxymethyl position. While 3′-acetoxymethyl substituted cephalosporins are readily available, deacetylation to access the free 3′-hydroxymethyl group is problematic when the carboxylic acid is protected as an ester. Herein we report that this important transformation has been efficiently accomplished using Candida antarctica lipase B. Although this transformation is difficult to carry out using chemical methods, the enzymatic deacetylation has been successful on gram scale, when the cephalosporin is protected as either the benzhydryl or t-butyl esters, and on the corresponding sulfoxide and sulfone of the tbutyl ester.Cephalosporin antibiotics have been in use for more than 40 years and are still being employed to fight bacterial infections despite the rising incidence of resistance. 1 Decades of intense research have given rise to an arsenal of synthetic methods that have allowed many analogs to be prepared, including four generations of cephalosporins that have reached clinical use. 2 Although this research has led to many breakthroughs in cephalosporin-specific chemical methodology, accessing precursors for further elaboration is still not straightforward. Numerous derivatives have been made through modification at the 3′-hydroxymethyl group of cephalosporins. However, the deprotection of the common 3′-acetoxy precursor in the presence of the protected cephalosporanic acid, and without lactonization and/or double bond isomerization to give the Δ 2 isomer, has yet to be accomplished in a high yielding and reproducible manner (Scheme 1). Herein we report a selective enzymatic approach to the deprotection of the cephalosporin acetoxy group, using commercially available Candida antartica lipase B (CAL B), on acrylic resin. mmiller1@nd.edu. Supporting Information Available: Experimental methods for compounds 1-3 and 5-9, and all 1 H and 13 C NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org. Commercially available 7-amino cephalosporanic acid (7-ACA) was converted, in reasonable yields, to 3 using a modified literature procedure to introduce the t-butyl ester 4 and standard Schotten-Baumann conditions to install the phenylacetyl group as a simple representative side chain (Scheme 2). Despite considerable effort, the 3′-acetoxy substituent was unable to be removed in acceptable yields and in the absence of double bond isomerization using the following methods (see supporting information for details): saponification, 4 KCN, HCl, 5 TMSI/trifluoroacetate/pH 7.0, 6 or bis(tributyltin) oxide. 7 Based on these findings, enzymatic deacetylation methods were explored. NIH Public AccessEnzymatic deprotection of the cephalosporin acetoxy group has been demonstrated in the literature. 8 Similar to chemical deacetylations, 4,6,8c,d,f,9 the enzymatic deacetylation reactions have only been reported when the cephalosporin co...

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“…For example, oxazine 1 may be reduced with Mo(CO) 6 to afford syn -1,4 aminocyclopentenol 3 ,12 a key intermediate in the synthesis of noraristeromycin 4a 8c and carbocyclic uracil polyoxin C 4b 8b (Scheme 1). …”

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confidence: 99%