Enantioselective synthesis of (R)- and (S)-cizolirtine; application of oxazaborolidine-catalyzed asymmetric borane reduction to azolyl phenyl ketones

Article abstract of DOI:10.1055/s-1999-2712

An efficient enantioselective synthesis of (R)- and (S)cizolirtine 1 is described. The key step of the procedure is the CBS-oxazaborolidine asymmetric reduction of phenyl pyrazolyl ketone 2. Related enantioselective reductions of several azolyl phenyl ketones are also reported.

Full text of DOI:10.1055/s-1999-2712

LETTER
765
Enantioselective Synthesis of (R)- and (S)-Cizolirtine; Application of
Oxazaborolidine-Catalyzed Asymmetric Borane Reduction to Azolyl Phenyl
Ketones
Antoni Torrens,* José A. Castrillo, Alex Claparols, Jordi Redondo
Department of Medicinal Chemistry, Laboratorios Dr. Esteve, Av. Mare de Déu de Montserrat 221, E-08041 Barcelona, Spain
Fax +34 93 4501611; E-mail: atorrens@esteve.es
Received 22 February 1999
Since then, numerous publications6 have described opti-
Abstract: An efficient enantioselective synthesis of (R)- and (S)-
mization, variations, mechanistic proposals and applica-
tions in total synthesis of this methodology which has
cizolirtine 1 is described. The key step of the procedure is the CBS-
oxazaborolidine asymmetric reduction of phenyl pyrazolyl ketone
been extensively applied to aryl alkyl ketones. It has been
reported that the CBS catalyst works well when the two
groups attached to the carbonyl group to be reduced have
significantly different steric bulk,7 but conformational8
and electronic effects9 are also important. When strong
coordinating groups such as pyridine or nitrogen hetero-
cycles are close to the carbonyl, the site selectivity of the
chiral reducing reagent must generally decrease due to the
coordination effect of the heteroatom.10 Therefore, very
few examples dealing with diaryl ketones,9,11 and even
less with phenyl heteroaryl ketones have been described.
Only several benzoylpyridines have been reduced by Co-
rey et al. with a remarkable modified procedure.11 The
lone pair of the pyridyl nitrogen atom was masked
through the formation of an N-allylpyridinium salt, or by
addition of a Lewis acid before asymmetric reduction.
2. Related enantioselective reductions of several azolyl phenyl ke-
tones are also reported.
Key words: asymmetric synthesis, cizolirtine, oxazaborolidine,
azolyl phenyl ketones, enantioselective reduction
Cizolirtine 1 is an analgesic developed in our company
that is currently undergoing Phase II clinical trials.1 The
two enantiomers (+)-1 and (-)-1 have been previously ob-
tained in our laboratory by optical resolution of the race-
mate with (-)- and (+)-di-p-toluoyltartaric acid.2 In
addition, an EPC synthesis starting from ethyl (R)-mande-
late permitted the assignation of the R absolute configura-
tion to the isomer (+)-1.3 We report herein the
enantioselective synthesis of (R)- and (S)-cizolirtine by a
short and efficient procedure which utilizes as a key step
the oxazaborolidine-catalyzed reduction of prochiral ke-
tone 2 to the corresponding secondary alcohol 3 (Scheme
1).
Table 1. Enantioselective Reduction of Ketone 2
Scheme 1 Reagents and conditions: (i), n-BuLi, THF –40°C; (ii),
benzonitrile –40°C to rt 20 h; (iii), HCl 2N, reflux, 10 h; (iv), (R)-Me-
CBS, catecholborane, toluene –15°C to rt , 20 h; (v), NaOH 40%, 2-
chloro-1-dimethylaminoethane hydrochloride, triethylbenzylammo-
nium chloride, toluene, reflux, 10 h
Oxazaborolidines are well known catalysts for the effi-
cient asymmetric borane reduction of ketones. After the
pioneering work of Itsuno and co-workers,4 Corey et al.
were the first to report the enantioselective reduction of
ketones to chiral secondary alcohols (CBS reduction).5
Synlett 1999, No. 6, 765–767 ISSN 0936-5214 © Thieme Stuttgart · New York

766
A. Torrens et al.
LETTER
The present approach to the synthesis of 1 required the in Table 2. Initially, we investigated the reduction of the
enantioselective reduction of 5-benzoyl-1-methyl-1H- isomeric 4-benzoyl-1-methyl-1H-pyrazole18 and 2-ben-
pyrazole 2, previously obtained from 1-methylpyrazole zoyl-1-methyl-1H-imidazole.19 As expected, better results
by lithiation with n-BuLi, followed by reaction with ben- were obtained in the preparation of the pyrazolyl
zonitrile and hydrolysis with hydrochloric acid1a (Scheme carbinol1a than in the synthesis of the corresponding 2-im-
1). We thought that the similar steric bulk of the aromatic idazolyl derivative.20 In this case, a low ee (8%) was ob-
rings attached to the carbonyl group and the presence of served, probably due to the proximity of the second
two nitrogen atoms in the pyrazole ring of 2 might be an nitrogen atom to the carbonyl group.
additional difficulty to obtain high enantioselectivity, so
we tested a large battery of conditions to carry out the re-
duction. The results are summarized in Table 1.
Table 2. Asymmetric Reduction of Prochiral Azolyl Phenyl Ketones
Contrary to our expectations, carbinol 33 was obtained
with moderate to high ee in almost all conditions tested. It
is noteworthy that the temperature did not affect dramati-
cally the enantioselectivity while the solvent and reducing
reagent used were very important. Borane-methyl
sulfide complex in toluene and particularly cate-
cholborane gave the best results. Commercially available
(R)-3,3-diphenyl-1-methyl-l-pyrrolidino[1,2-c]-1,3,2-ox-
azaborole [(R)-Me-CBS] catalyst proved to be excellent
to afford high ee, and n-Bu-CBS12 did not enhance signif-
icantly the enantioselectivity. On the other hand, the per-
centage of catalyst could be reduced to 2.5 mol % without
drastic decrease of the ee. Optimum conditions for the re-
duction of 2 (entry 6) were 15 mol % (R)-Me-CBS cata-
lyst, catecholborane as reducing reagent and toluene as
solvent. Carbinol (R)-3 was obtained in 98% ee13 deter-
mined by chiral HPLC.14 Similarly, when (S)-Me-CBS
was used the corresponding enantiomer (S)-3 was ob-
tained in 98% ee. The observed high enantioselectivity
may suggest that because of the steric interaction between
the methyl group at position 1 and the carbonyl oxygen in
ketone 2, the pyrazole ring twists out of the plane,11 in-
creasing the distance between the second nitrogen atom
and the carbonyl group thus avoiding interaction with the
catalyst15 (Figure 1). The observed absolute configuration
A very interesting effect was observed when a Cl atom
of the products3 indicates that the pyrazole ring behaves as
the small group. The stereochemical pathway of the reac-
tion is in agreement with the mechanism described in the
literature.9, 11
was introduced in the ortho position of the phenyl group.21
An important increase of enantioselectivity was achieved
(59% ee)22 suggesting that a non-planar arrangement of
the imidazole ring relative to the benzoyl group is
favoured.
Next, we examined the effect of a bulky heterocyclic ring
in the case of 2-benzoyl-1-methyl-1H-benzimidazole.23
The corresponding carbinol was obtained with
moderate ee (Table 2). In order to assign the absolute
configuration of a-(1-methyl-1H-benzimidazol-2-yl)-a-
phenyl-methanol20 we carried out an EPC synthesis,
starting from (R)-mandelic acid. Phillips condensation24
with N-methyl-o-phenylenediamine gave the (R)-carbinol
with 62% yield and 99% ee14,25 (Scheme 2).
Figure 1 Representation of planar and molecular mechanics optimi-
zed structures of ketone 2
To the best of our knowledge, the synthesis of carbinols
(R)- and (S)-3 represents the first application of CBS re-
duction to an azolyl phenyl ketone.16 Alkylation of (R)-3
with 2-chloro-1-dimethyl-aminoethane and NaOH under
phase transfer conditions led to (R)-(+)-cizolirtine (R)-1 in
92% yield and with 98% ee17 (Scheme 1).
Encouraged by these results, we extended the reaction to
other azolyl phenyl ketones. The results are summarized
Scheme 2
Synlett 1999, No. 6, 765–767 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of (R)- and (S)-Cizolirtine via CBS Reduction
767
(13) A typical experimental procedure is as follows: To a stirred
solution of (R)-(+)-2-methyl-CBS-oxazaborolidine 1M in
toluene (7.5 mL, 7.5 mol) under argon cooled to -10° C, a
solution of catecholborane 1M in THF (100 mL, 100 mmol)
was slowly added. To the mixture was then added a solution
of 5-benzoyl-1-methyl-1H-pyrazole 2 (9.30 g, 50 mmol) in
dry toluene (100 mL) and the reaction was stirred 1 h a
-15° C and 20 h at room temperature. MeOH (10 mL) was
added carefully with stirring for 2 h. The mixture was
concentrated at reduced pressure to 100 mL, washed
successively with water, HCl 1N and brine, dried and
evaporated to give an oil which was purified by silicagel
column chromatography, using ethyl acetate: petroleum ether
(7:3) as eluent to afford (R)-(+)-1-methyl-a-phenyl-1H-
pyrazole-5-methanol (R)-3 in 98% ee (7.82 g, 83%).; mp:
81-83° C; [a]D= +16.6 (c= 1.02, CHCl3).
It is noteworthy that the difference in steric bulk of benz-
imidazole ring versus pyrazole of ketone 2 did not affect
the enantioselective site of the reaction. In both cases the
(R)-carbinol was obtained confirming that in these two ex-
amples the heterocyclic ring behaves as the small group.
In conclusion, we have achieved the asymmetric synthesis
of the enantiomers of cizolirtine with high enantiomeric
excess. The application of CBS reduction to other het-
eroaryl phenyl ketones will be further investigated.
Acknowledgement
We thank Dr. Jordi Quintana for performing the molecular mecha-
nics calculations.
(14) Enantiomeric excess determined on a Chiralcel OD-H column
at l= 230 nm; flow rate: 1 mL/min; eluent: hexane: i-PrOH
(93:7) with 0.1% diethylamine.
References and Notes
(15) The structure of 2 was optimized by molecular mechanics
using the modelling software Chem-X (Chemical Design Ltd.,
UK). The calaculated distance between carbonyl oxygen and
pyrazole N-2 increased from 4.21 Å in the planar structure to
4.46 Å in the optimized structure.
(16) During the preparation of this manuscript an unsuccessful
attempt of CBS reduction of a bis-oxazolyl ketone using
catecholborane has been reported: Chittari, P.; Yasumasa, H.;
Shiori, T. Synlett 1998,1022.
(17) (S)-Cizolirtine was obtained in the same manner starting from
(S)-3. For ee determination and physical data of (R)- and (S)-
cizolirtine see reference 2.
(18) Effenberger, F.; Krebs, A. J. Org. Chem. 1984, 49, 4687.
(19) Pinkerton, F. H.; Thames, S. F. J. Heterocycl. Chem. 1972, 9,
67.
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Article Identifier:
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Synlett 1999, No. 6, 765–767 ISSN 0936-5214 © Thieme Stuttgart · New York