Synthesis of enantiomerically pure 4-aryl-3,4-dihydropyrimidin-2(1H)-ones via enzymatic resolution: preparation of the antihypertensive agent (R)-SQ 32926

Article abstract of DOI:10.1016/S0957-4166(00)00081-1

A practical and short synthesis of the enantiomerically pure dihydropyrimidone antihypertensive agent (R)-SQ 32926 has been developed. The key step in the synthesis is the enzymatic resolution of an N3-acetoxymethyl-activated dihydropyrimidone precursor b

Full text of DOI:10.1016/S0957-4166(00)00081-1

Tetrahedron: Asymmetry 11 (2000) 1449±1453
Synthesis of enantiomerically pure 4-aryl-3,4-dihydro-
pyrimidin-2(1H)-ones via enzymatic resolution:
preparation of the antihypertensive agent (R)-SQ 32926y
Barbara Schnell, Ulrike T. Strauss, Petra Verdino, Kurt Faber and
C. Oliver Kappe*
Institute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria
Received 16 December 1999; accepted 28 February 2000
Abstract
A practical and short synthesis of the enantiomerically pure dihydropyrimidone antihypertensive agent
(R)-SQ 32926 has been developed. The key step in the synthesis is the enzymatic resolution of an N3-
acetoxymethyl-activated dihydropyrimidone precursor by Thermomyces lanuginosus lipase. The absolute
con®guration of (R)-SQ 32926 was con®rmed by circular dichroism spectroscopy. # 2000 Elsevier Science
Ltd. All rights reserved.
4-Aryl-3,4-dihydro-2(1H)-pyrimidone esters of type 1 (DHPMs) represent a heterocyclic sys-
tem of remarkable pharmacological ecacy.1 11 In recent years, appropriately functionalized
derivatives have emerged as, e.g., calcium channel modulators,2 a1a-adrenoceptor-selective
antagonists,3 mitotic kinesin Eg5 inhibitors,4 and neuropeptide Y (NPY) antagonists.5 Close
structural analogs derived from 1 have been reported as e€ective antiviral (hepatatis B) agents6
and as group 2 metabotropic glutamate receptor antagonists.7 Of particular importance are the
N3-acyl substituted analogs SQ 32926 28 and SQ 32547 39 which have been identi®ed as potent
orally active antihypertensive agents.8 10 These substances can be considered as close structural
analogs of the therapeutically widely used calcium channel blockers of the 1,4-dihydropyridine
type (DHPs, e.g. nifedipine, amlodipine, nilvadipine).
* Corresponding author. Fax: +43-316-3809840; e-mail: oliver.kappe@kfunigraz.ac.at
y
Synthesis and reactions of Biginelli compounds, part 20; for part 19, see: Kappe, C. O.; Shishkin, O. V.; Uray, G.;
Verdino, P. Tetrahedron 2000, 56, 1859±1862.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00081-1

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B. Schnell et al. / Tetrahedron: Asymmetry 11 (2000) 1449±1453
DHPMs of type 1 are inherently asymmetric molecules and the in¯uence of the absolute
con®guration at the stereogenic center at C4(*) on molecular activity is well documented.11 In SQ
32926 2, for example, it is exclusively the (R)-enantiomer that carries the therapeutically desired
antihypertensive e€ect.8 Access to enantiomerically pure DHPMs is therefore a prerequisite for
the development of useful drugs of this structural type. In the absence of any known asymmetric
synthesis for this heterocyclic target system we became interested in obtaining enantiomerically
pure DHPM analogs via a chemoenzymatic synthesis. In the past, enantiomerically pure DHPMs
were obtained by classical resolution of the corresponding racemic carboxylic acids,12 by separa-
tion of diastereomeric derivatives bearing chiral auxiliaries at N3,2,3,8,9 or by enantioselective
HPLC.13,14
Herein we report the ®rst application of a lipase-catalyzed kinetic resolution for the gram-scale
synthesis of enantiomerically pure DHPMs.15 The usefulness of the method is further demon-
strated by the synthesis of the antihypertensive agent (R)-SQ 32926.
Our strategy towards enantiomerically pure DHPMs (e.g. SQ 32926) is outlined in Scheme 1.
Racemic DHPM precursor 4 was available in 94% yield by Biginelli three-component cyclo-
condensation of isopropyl acetoacetate, 3-nitrobenzaldehyde and urea, using polyphosphate ester
(PPE) as reaction mediator.16 An enzymatically cleavable ester functionality was readily intro-
duced in proximity to the C4 stereogenic center at N3 by hydroxymethylation with formaldehyde,
followed by standard acetylation with acetyl chloride.17 The resulting N3-acetoxymethyl
activated DHPM (rac)-6 was obtained in ca. 80% overall yield and high purity from 4 as a single
regioisomer (no N1- or bis-functionalized products could be detected). Enantioselective enzy-
matic hydrolyses of (rac)-6 were carried out in diisopropyl ether/phosphate bu€er (pH 7.0)
mixtures at room temperature. After screening a set of commonly used lipases, Thermomyces
lanuginosus (Amano CE lipase) was identi®ed as the biocatalyst of choice. Using dextran as

B. Schnell et al. / Tetrahedron: Asymmetry 11 (2000) 1449±1453
1451
Scheme 1. Reagents and conditions: (i) polyphosphate ester, THF, re¯ux, 24 h; (ii) 37% CH2O, EtOH, K2CO3, re¯ux,
48 h; (iii) AcCl, THF, Et3N, 0ꢀC, 1 h; (iv) lipase (see Ref. 19); (v) aq. NH3 (concd), MeOH, rt, 48 h; (vi) CCl3CO±
NCO, THF, rt, 24 h; then MeOH, SiO2, rt, 48 h
additive18 excellent enantioselectivities (E>200) were achieved in a highly reproducible manner.
After 72 h at 23ꢀC a 50:50 mixture of hydroxymethyl DHPM (S)-6 (96% ee) and acetoxymethyl
DHPM (R)-5 (98% ee) was obtained after simple silica gel chromatography.19 Upon treatment
with ammonia in methanol17 both products were degraded in good yield into the N3-unsub-
stituted derivatives (S)- and (R)-4, respectively, without any racemization. The desired target
molecule (R)-2 (SQ 32926) was ®nally obtained in one step from (R)-4 by N3-carbamoylation
with trichloroacetyl isocyanate.20 The physical and spectral data of this material were in excellent
agreement with literature values.21 The enantiomeric excess of (R)-2 was 98% based on chiral
HPLC measurements (Whelk-O1, heptane:2-propanol 70:30). The biologically inactive enantio-
mer (S)-2 was obtained in an analogous manner.
The absolute con®gurations of (R)- and (S)-2 were con®rmed by circular dichroism (CD) spectro-
scopy. Fig. 1 shows the CD spectra of both enantiomers of DHPM 2. Based on comparsion with
reference CD spectra of DHPMs with known absolute con®guration22 the enantiomer showing
a positive Cotton e€ect at 288 nm was assigned the (S)-con®guration. Comparison of the
speci®c rotations for (R)- and (S)-2 with reference literature data yielded identical/matching
results.21
In conclusion we have developed a chemoenzymatic synthesis for enantiomerically pure dihydro-
pyrimidine derivatives of type 1 that is based on a lipase-catalyzed kinetic resolution. Key to the
success of this approach is the regioselective hydroxymethylation of dihydropyrimidones at N3,
which allows the introduction of the enzymatically cleavable ester functionality. We anticipate

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B. Schnell et al. / Tetrahedron: Asymmetry 11 (2000) 1449±1453
Figure 1. CD spectra of (R)- and (S)-2 in methanol
that the methodology introduced herein can be employed for the resolution of a variety of other
DHPM analogs, e.g. potential drug candidates.
Acknowledgements
This work was supported by the `Jubilaumsfonds der Osterreichischen Nationalbank' (Project
7904) and the Austrian Science Fund (FWF, Projects P-11994-CHE and F115). Amano Pharm.
Co. is thanked for the generous donation of enzymes.
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