Bioorganic & Medicinal Chemistry Letters 16 (2006) 4612–4615
Synthesis of novel keto-ACE analogues as domain-selective
angiotensin I-converting enzyme inhibitors
Aloysius T. Nchinda,a Kelly Chibale,a,b Pierre Redelinghuysa and Edward D. Sturrocka,*
aInstitute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, Cape Town, South Africa
bDepartment of Chemistry, University of Cape Town, Rondebosch 7701, Cape Town, South Africa
Received 17 April 2006; revised 2 June 2006; accepted 2 June 2006
Available online 19 June 2006
Abstract—Novel analogues of the angiotensin I-converting enzyme (ACE) inhibitor keto-ACE were synthesized via a facile Horner–
Emmons olefination of a phosphonoketone precursor with ethyl glyoxylate. Introduction of a bulky aromatic tryptophan at the P20
position of keto-ACE resulted in a significant increase in C-domain-selectivity.
Ó 2006 Elsevier Ltd. All rights reserved.
Angiotensin-converting enzyme (ACE) inhibitors are
widely used in the treatment of hypertension and myo-
cardial infarction. ACE is comprised of two enzymati-
cally active (N- and C-) domains with different
physiological functions. The adverse drug effects associ-
ated with current generation ACE inhibitors are thought
to arise from inadequate domain-selectivity.1 The recent
determination of the X-ray structure of ACE in complex
with various inhibitors2–4 has paved the way for the pro-
tein structure-based design of new more domain-selec-
tive inhibitors with improved pharmacological profiles.
Ketomethylene derivatives have been used extensively
in the design of protease inhibitors.5,6 5-S-5-Benzami-
do-4-oxo-6-phenylhexanoyl-L-proline (keto-ACE), the
first of such compounds, was shown to be a good inhib-
itor of ACE with modest domain selectivity.7 Various
strategies and modifications to the synthesis of keto-
ACE have been described.8–10 These synthetic approach-
es have a number of limitations: a modified Dakin–West
reaction,9 which proceeds via a 5-oxazolone intermedi-
ate, is accompanied by racemization; the use of a Grig-
nard reagent with 2-pyridyl thiolate generates the keto
acetal intermediate in low yield;8,10 and the synthesis
of ketomethylene dipeptide analogues using diazome-
thane is unattractive.11,12 Here, we report a simple and
facile synthesis of keto-ACE and its analogues as well
as their ACE inhibitory profiles.
In synthesizing new analogues of keto-ACE, we chose a
general strategy outlined in Scheme 1. The starting
materials, N-protected-L-phenylalanine methyl esters 1
and 2, were prepared from L-phenylalanine in the pres-
ence of either benzoyl chloride or di-tert-butyl dicarbon-
ate in 1,4 dioxane and 1 M NaOH followed by
treatment with thionyl chloride and methanol to give
the resulting esters in quantitative yield. The methyl es-
ters 1 and 2 were converted into the b-keto phospho-
nates 3 and 4 by treatment with 8 equiv of lithiated
dimethyl methyl phosphonate in anhydrous THF at
13
´
ꢀ78 °C as described by Dezil et al. (Scheme 1). The
key intermediates, a,b-unsaturated keto derivatives 5
and 6, were obtained in excellent yield as isomeric mix-
tures by the Horner–Emmons olefination of 3 and 4,
respectively, with 1 equiv of freshly prepared ethyl gly-
oxylate14 in the presence of potassium carbonate and
1
dry ethanol at ambient temperature. However, the H
NMR spectra of 5 and 6 showed that the above reaction
conditions gave a substantial amount of the cis-isomer
[ratio, 85:15 (trans:cis)]. Separation of this isomeric mix-
ture was unnecessary as catalytic hydrogenation of the
double bond over 10% Pd on activated carbon afforded
the intermediate ketomethylene esters 7 and 8 in 80%
and 92% yields, respectively (Scheme 1). These esters
were hydrolysed in the presence of 0.5 N LiOH in
THF–MeOH (8:2) at room temperature to give the de-
sired acids 9 and 10 in 84% and 98% yields, respectively.
Coupling of the free acids 9 and 10 with the correspond-
ing O-protected amino acids was effected under typical
peptide coupling conditions using EDCÆHCl in the pres-
ence of HOBt and diisopropylethylamine as a base to
provide the corresponding esters 11–16 in excellent
Keywords: ACE inhibitor; Keto-ACE; Horner–Emmons; Olefination.
*
Corresponding author. Tel.: +27 21 406 6312; fax: +27 21 406
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.06.003