Angiotensin-converting enzyme synthesis

The final stages of the synthesis of (—)-A-58365B, a Streptomyces metabolite that inhibits the angiotensin-converting enzyme, involve several reactions at substituents attached to ring carbon atoms of a quinolizidine system. Thus, ozonolysis of the exocyclic methylene side chain of compound 107, followed by base-induced elimination and carboxyl deprotection, gave 108 (Scheme 12) <1999JOC1447>. 

Petrillo, E.W. and Spitzmiller, E.R., Synthesis of 2-phosphonopyrrolidine and its substitution for proline in an inhibitor of angiotensin-converting enzyme, Tetrahedron Lett., 4929, 1979. 

Compound (—)-A58365A 285, whose new synthesis was reported, is an angiotensin-converting enzyme (ACE) inhibitor, active at nanomolar concentrations <19990L83>. 

There is evidence that camosine is a vasodilator (Ririe et al., 2000) and thus can lower blood pressure (Niijima et al., 2002 Tanida et al., 2005). It has been shown that camosine promotes synthesis of nitric oxide (Nicoletti et al., 2007 Tomonaga et al., 2005), a well-known dilator of blood vessel walls. Also camosine can inhibit angiotensin-converting enzyme (ACE) activity (Hou et al., 2003 Nakagawa et al., 2006) possibly via effects on cGMP and nitric oxide, which again points to the possibility that the dipeptide or camosine-enriched foods could be explored to combat raised blood pressure in humans. 

Split synthesis of the library using four amino acids, four aldehydes, and five olefins in the presence of four mercaptoacyl chlorides (Scheme 3.110) generated the required proline library that was screened, after TEA cleavage of the products from the solid support, for inhibition of angiotensin converting enzyme ACE. 

Enalapril Angiotensin-converting enzyme 2 Chemical synthesis... 

S)-2-carbethoxy indolene hydrochloride (52) was catalytically hydrogenated (Pd-C) in ethanol to (2S, 3aS, 7aS)-2-carbethoxy perhydroindole hydrochloride (53) which was purified by crystallization 86). (53) was used in the synthesis of a potent inhibitor of the angiotensin converting enzyme. 

E. M., Gallop, M. A. (1995) Combinatorial organic synthesis of highly functionalized pyrrolidines identification of a potent angiotensin converting enzyme inhibitor from a mercaptoacyl proline library. J Am Chem Soc 117, 7029-7030. 

The next example originates from our own laboratory Two potential intermediates for the angiotensin-converting enzyme inhibitor benazepril can be synthesized using cinchona modified noble metal catalysts (3). While the hydrogenation of the a-ketoester has been developed and scaled-up into a production process (10-200 kg scale, chemical yield >98%, ee 79-82%), the novel enantioselective hydrodechlorination reaction (see Section in) could be a potential alternative to the established synthesis where the racemic a-bromobenzazepinon is used [75]. At the moment both selectivity and productivity of the catalyst are too low and substitution reactions occur less readily with the chloro analog. 

Peptides with C-terminal phosphonates, initially reported to have antibacterial properties, have also been found to possess inhibitory properties toward serine proteases)28 The synthesis of peptide phosphonates (Section 15.1.8) usually requires protection of the phos-phonic moiety as a diester, followed by selective deprotection in the final stage. The importance of peptide thiols (Section 15.1.9) is exemplified by captopril, an orally active angiotensin converting enzyme inhibitor used as a treatment for hypertension)29 These peptide thiols are prepared by the reaction of sulfanylalkanoyl amino acids with a-amino esters followed by deprotection of carboxy and sulfanyl groups. Other peptide thiols have been reported to be inhibitors of zinc metalloproteases, collagenases, and aminopeptidases. 

An important step in the asymmetric synthesis of the angiotensin-converting enzyme inhibitor, benazepril HC1 132, was the reduction of the ketoester 128 (obtained from 127 by condensation with diethyl oxalate) with baker s yeast to give the chiral cr-hydroxy ester 129 in high yield and ee (Scheme 17). Direct formation of the 1//-1-benzazepin-2-one 131 from 129 proceeded in 42% yield (without racemization at C-3) or in 74% yield in two steps via 130, again with no racemization <2003TA2239>. 

The 1,2-diazepine Cilazapril 98 is an angiotensin-converting enzyme inhibitor and its design and synthesis have been reported <1986J(P1)1011 1999W099/55724>. 

With both enantiomers of le in hand, the asymmetric synthesis of (S)-N-acetylindoline-2-carboxylate 33 was carried out, this being a key intermediate in the synthesis of the angiotensin-converting enzyme (ACE) inhibitor 34 (Scheme 5.18) [7e], The structure and stereochemical integrity of 33 was simultaneously constructed by the asymmetric alkylation of 2 with o-bromobenzyl bromide in the presence of (R,R)-le, and subsequent hydrolysis and N-acetylation afforded 32 in 86% yield with 99% ee. According to the Buchwald procedure, almost enantiopure 32 was efficiently converted to 33 (94%, 99% ee) [7e],... 

Novartis (Ciba Geigy) has reported the synthesis of Benazepril (163) (Scheme 12.63), an angiotensin-converting enzyme inhibitor, via an intermediate prepared by cinchona-modified Pt asymmetric hydrogenation (10-200-kg scale, >98%, 79-82% ee).5 The low optical purities can be tolerated because enantio-enrichment is relatively easy in the latter stages of the synthesis.22... 

Ondetti, M.A., Willimans, N.J., Sabo, E.F., Plusces, J., Weaver, E.R., and Kocy, O. 1971. Angiotensin-converting enzyme inhibitors from the venom of Bothrops jararaca. Isolation, elucidation of structure and synthesis. Biochemistry 19, 4033-4039. 

Today, captopril (Capoten ) ranks among the most frequently used drugs in the treatment of hypertension. Enalapril (Xanef ) has been commercially available since 1985 as a second ACE inhibitor. The discovery of captopril started an avalanche of research into the synthesis of angiotensin-converting enzyme inhibitors. Some new developments should be mentioned at this point ... 

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