To confirm the feasibility of this methodology, we next
focused on the preparation of several dipeptides. For this
purpose, the reaction between ketoxime esters8 of R-(L)-
amino acids and unprotected R-(L)-amino acids in acetonitrile
was explored in the presence of a phosphazene base (Scheme
1).
end, we focused on the dipeptide product enalapril, which
belongs to a class of dipeptides of major significance for
controlling hypertension and congestive heart failure.11 The
N-substituted ethyl (S)-2-amino-4-phenyl-butyrate moiety is
common to these angiotensin-converting enzyme (ACE)
inhibitors, as exemplified in the therapeutic agents quinapril,
trandolapril, and moexipril (Figure 3).
Scheme 1a
a Reaction conditions: (a) ketone oxime (1 equiv), CH2Cl2, EDC
(1.4 equiv), DMAP (cat.), 2 h, rt. (b) H-L-AA-OH (1.2 equiv), P1-
tBu (1.2 equiv) for 9, 10, and 12 or P2-Et (1.2 equiv) for 11, CH3CN,
rt, 5 min for 6 and 7, 4 h for 8.
Figure 3. Representative ACE inhibitors characterized by the
presence of the N-substituted-(S)-2-amino-ethyl-4-phenylbutyrate
moiety.
The ketoxime esters were easily obtained from Cbz-(L)-
alanine 3, Cbz-(L)-valine 4, or the O-protected BOC-(L)-
serine 5 by treatment with di-2-pyridyl ketone oxime or
acetone oxime (1 equiv) and N-(3-dimethylaminopropyl)-
N′-ethylcarbodiimide hydrochloride (EDC) (1.4 equiv) in
dichloromethane in the presence of a catalytic amount of
4-N,N-(dimethylamino)pyridine (DMAP) (85-88% yields).
Isolated oxime esters 6-8 were reacted with free R-amino
acids (L)-phenylalanine, (L)-valine, and (L)-alanine in aceto-
nitrile in the presence of a phosphazene base to afford the
expected dipeptides 9-12 in excellent yields (80-92%). The
general protocol consisted of the addition of 1.2 equiv of
the phosphazene base (P1-tBu or P2-Et) to a suspension of
the amino acid in dry acetonitrile under a nitrogen atmo-
sphere. Usually, after 5-10 min of stirring at room temper-
ature, complete solubilization of the starting amino acid was
observed. This solution was added at once to a solution of
the oxime ester in acetonitrile cooled to 0 °C. After the
solution was stirred for 5 min at room temperature (4 h for
the acetone oxime esters), TLC showed no presence of the
starting di-2-pyridyl ketone oxime ester and the formation
of the free di-2-pyridyl ketone oxime. Acidic workup
followed by purification of the resulting crude products by
column chromatography and/or crystallization in dichlo-
romethane/hexane afforded the pure dipeptides.9 In these
instances, the di-2-pyridyl ketone oxime can easily be
recovered in 80-85% yields.10
As illustrated in Scheme 2, compound 13, which is readily
accessible in bulk from ethyl 2-oxo-4-phenylbutyrate12 or
ethyl-2-hydroxy-4-phenylbutyrate,13 was converted into the
acetoxime ester 14 over three steps (95% yield).14 This
compound, upon treatment with a solution of the phos-
phazene salt of (L)-proline in acetonitrile as a solvent, gave
enalapril, which was isolated as maleate salt 15 in 92% over
the last two steps. In this case, substitution of P1-tBu for DBU
(9) Data of compounds: 9, [R]25D +4.2 (c 1.3, Cl2CH2); 10, [R]25D -20.0
(c 0.8, MeOH); 11, [R]25 +4.6 (c 0.5, DMF); 12, [R]25 +8.8 (c 0.84,
D
D
Cl2CH2). The diastereomeric excess for each compound 9-12 (g 99%)
was determined by comparison of the analytical HPLC chromatograms of
the methyl ester crude dipeptides with those obtained by coupling the first
amino acid with the racemic mixture of the second. For details, see
Supporting Information.
(10) The reaction was quenched by the addition of 1 N HCl, and
extractions with Cl2CH2 yielded the crude dipeptides, which were later
purified. Treatment of the aqueous phase with a buffer solution (pH ) 7),
followed by extraction with dichloromethane and subsequent elimination
of the solvent under vacuum, afforded the di-2-pyridyl ketone oxime. For
details, see Supporting Information.
(11) For a comprehensive review on ACE inhibitors, see: (a) Wyvratt,
M. J.; Patchett, A. A. Med. Res. ReV. 1985, 7, 483. (b) Angiotensin
ConVerting Enzyme Inhibitors; Kostis, J. B., Defelice, E. A., Eds.; Alan R.
Liss, Inc.: 1987. (c) Adang, A. E. P.; Hermkens, P. H. H.; Linders, J. T.
M.; Ottenheijm, H. C. J.; van Staveren, C. J. Recl. TraV. Chim. Pays-Bas
1994, 13, 63. (d) For a survey of ACE inhibitors, see: Natoff, I. L.;
Redshaw, S. Drugs of The Future 1987, 12, 475.
(12) Flynn, G. A.; Beight, D. W. Tetrahedron Lett. 1988, 29, 423.
(13) Urbach, H.; Henning, R. Tetrahedron Lett. 1984, 25, 1143.
(14) This compound can be stored at room temperature without
The potential of the methodology for the preparation of
N-alkyl R-amino acid dipeptides was also evaluated. To this
25
decomposition for at least 2 months. Colorless oil; [R]D -24.1 (c 2.0,
(8) (a) Fujino, M.; Nishimura, O. Chem. Pharm. Bull. 1969, 17, 1937.
(b) Miyasaka, T.; Noguchi, S. Chem. Lett. 1985, 701.
Cl2CH2). Analytical HPLC: Lichrosorb Si 60 (5 µm), 70:30 AcOEt:hex,
retention time ) 4.94 min, UV detection at 254 nm.
Org. Lett., Vol. 4, No. 23, 2002
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