Effective tuning of the arene and alkanesulfinamides for highly enantioselective synthesis of (S)-4-chlorophenylphenylmethylamine, a key intermediate for antihistamic (S)-cetirizine

Article abstract of DOI:10.1016/S0040-4039(03)00903-1

High diastereoselectivity (>94%) has been achieved in the phenylMgBr addition process to chlorophenyl aldimine derived from the new and sterically hindered triisopropylbenzene sulfinamide (TIPBSA) in the synthesis of a key intermediate of (S)-Cetirizine. Surprisingly, under the same reaction conditions, toluenesulfinamide derived chlorophenyl aldimine provided only 10% ee.

Full text of DOI:10.1016/S0040-4039(03)00903-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4195–4197
Effective tuning of the arene and alkanesulfinamides for highly
enantioselective synthesis of
(S)-4-chlorophenylphenylmethylamine, a key intermediate for
antihistamic (S)-cetirizine
Zhengxu Han,* Dhileepkumar Krishnamurthy,† Paul Grover, Q. Kevin Fang, Derek A. Pflum and
Chris H. Senanayake†*
Chemical Process Research and Development, Sepracor, Inc., 84 Waterford Dr., Marlborough, MA 01752, USA
Received 12 February 2003; revised 5 April 2003; accepted 7 April 2003
Abstract—High diastereoselectivity (>94%) has been achieved in the phenylMgBr addition process to chlorophenyl aldimine
derived from the new and sterically hindered triisopropylbenzene sulfinamide (TIPBSA) in the synthesis of a key intermediate of
(S)-Cetirizine. Surprisingly, under the same reaction conditions, toluenesulfinamide derived chlorophenyl aldimine provided only
10% ee. © 2003 Elsevier Science Ltd. All rights reserved.
Enantioselective synthesis of diarylmethylamines has
drawn much interest recently due to their importance as
intermediates in the synthesis of biologically active
compounds.1,2 (S)-4-chlorophenylphenylmethylamine
(S)-1, for example, is the key intermediate for the
asymmetric synthesis of enantiomerically pure (S)-ceti-
rizine·2HCl (2) (Scheme 1), a non-sedating histamine
H1-receptor antagonist used for the treatment of
allergy, and is currently marketed as Xyzal™ in
Europe. The (S)-enantiomer displays a better pharma-
cological profile than the racemate.3 Several methods
have been reported for the synthesis of enantiomeric
pure (S)-cetirizine employing resolution techniques,4 a
stoichiometric heavy metal,5 or chromatography.6
A
process for efficient asymmetric synthesis of enan-
tiomeric pure (S)-cetirizine, however, is rather limited.
Recent literature revealed that tert-butanesulfinamide
and toluenesulfinamide have been applied to many
important asymmetric processes.7–9 Herein, we disclose
an efficient design of the arenesulfinamide for the asym-
metric synthesis of (S)-cetirizine intermediate 1 with
high diastereoselectivity (94% de).
Identification of an effective asymmetric method for the
synthesis of enantiopure (S)-1 plays a major role in the
practical synthesis of (S)-cetirizine. Recently, Bolm et
al.2a developed a remarkably effective catalytic enan-
tioselective process for the asymmetric addition of
phenylzinc reagent to N-formylimine derived from N-
[4-chlorophenylmethyl-(toluene-4-sulfonyl)]formamide
to generate diarylamine 1 in excellent enantioselectivity
(94% ee). We also disclosed our initial results for rapid
assembly of (S)-cetirizine using (S)-diarylamine, (S)-1,
that was constructed employing readily available and
pharmaceutically acceptable reagents.3 Thus, addition
of PhMgBr to N-tert-butanesulfinyl-p-chloro-benz-
aldimine (R)-3a (R=tert-butyl) derived from the con-
densation of (R)-tert-butanesulfinamide and p-chloro-
benzaldehyde gave, after mild acidic hydrolysis, (S)-1
as the major enantiomer with only moderate enantio-
purity of 75% ee at 0°C in toluene (Scheme 2).
Further optimization of reaction conditions to improve
Scheme 1.
* Corresponding
authors.
E-mail:
steve.han@sepracor.com;
csenanay@rdg.boehringer-ingelheim.com
† Present address: Boehringer Ingelheim Pharmaceuticals, Inc. 900
Ridgebury Rd./PO Box 368 Ridgefield CT 06877, USA.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00903-1

4196
Z. Han et al. / Tetrahedron Letters 44 (2003) 4195–4197
Scheme 2.
the selectivity was unsuccessful. Toluene was found to
be the solvent of choice for this process. We, therefore,
turned our attention toward tuning the structure of the
chiral sulfinamides to moderate the diastereoselectivity
of the adduct.3
optimal selectivity. First, Davis’ toluenesulfinamide
(pTSA) (5e) was used as chiral auxiliary for the study.
Surprisingly, 5e gave very low selectivity with only 10%
ee for (S)-1 (Table 1, entry 5). It is interesting to note
that by increased the bulk of the aromatic ring to
2,4,6-mesityl (TMPSA) (5f), the selectivity increased
dramatically to provide the amine (S)-1 in 50% ee
(Table 1, entry 6).
To tune the diastereoselectivity of the organometallic
addition process, a wide range of structurally diverse
arene- and alkanesulfinamides was required. This ulti-
mately led us to discover and develop a new technology
for modular synthesis of enantiopure tertiary alkane
and arene sulfinamides from arane N-sulfonyl-1,2,3-
oxathiazolidine-2-oxide (4, ASOO) (Scheme 3, Fig. 1).10
With the new technology for the preparation of chiral
sulfinamides, our focus centered on the finding of new
sulfinamide for achieving high selectivity in the asym-
metric synthesis of (S)-1.
With this result, we envisioned that further increases in
the steric bulk on the aromatic ring of the sulfinamide
might give high diastereoselectivity for PhMgBr addi-
tion to imine 3. Thus, a new sulfinamide was designed
by substituting the 2, 4 and 6 positions of the phenyl
ring with isopropyl groups to give sulfinamide
(TIPPSA) 5g,11 which was prepared according to
Initial attempts were focused on the asymmetric addi-
tion of PhMgBr to imine derived from tertiary alkane-
sulfinamides. We envisioned that introduction of a
more bulky group to alkanesulfinamides might increase
the diastereoselectivity for organometallic addition to 3.
Thus, a variety of (R)-alkanesulfinamides were synthe-
sized as shown in Figure 1 (5a–d).11 As outlined in
Scheme 2, condensation of p-chlorobenzaldehyde with
the sulfinamides using Ellman’s method provides the
desired imines.7b The diastereoselectivity for PhMgBr
asymmetric addition was investigated in toluene at 0°C
and the results are outlined in Table 1. Surprisingly,
when bulky admantylsulfinamide (5b, AdSA, entry 2)
was used as an auxiliary, the ee decreased from 75 to
68% as compared to tert-butanesulfinamide (TBSA,
entry 1). Increasing the steric bulk of branched alkyl
sulfinamide provided comparable selectivity. Using 2-
methylbutanesulfinamide (DMESA) (5c) gave 76% ee
for (S)-1 (entry 3). More bulky 3-ethylpentanesulfin-
amide (TESA) 5d increased the ee from 75 to 79%
(entry 4).12 It was noted that modification of alkyl
groups imparted little change in selectivity and per-
formed similar to the use of TBSA.
Figure 1. Structure of alkane and arene sulfinamides.
Table 1. Results for the PhMgBr addition to the sulfinyl
imine for the asymmetric synthesis of (S)-1 at 0°C in
toluene
Entry
5
% Yielda
% Eeb
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5a
5g
81
85
79
88
77
83
84
83
80
75
68
76
79
10
50
91
At this point, we turned our efforts to evaluate the use
of arene sulfinamide for the synthesis of (S)-1 with
82 (−20 to 0°C)
94 (−20 to 0°C)
a Yield was based on wt% assay by HPLC analysis.
b Enantiomeric excess (ee) was based on chiral HPLC analysis on
chiralcel OD column, 250×5 mm, 10 mm; 220 nm; eluted with
hexane/IPA/DEA (90:10:0.1).
Scheme 3.

Z. Han et al. / Tetrahedron Letters 44 (2003) 4195–4197
4197
Scheme 3. We are pleased to find that when PhMgBr is
added to 3g in toluene at 0°C for 5 h, after acidic
hydrolysis with HCl/MeOH, (S)-1 is obtained in 84%
yield with 91% ee. The selectivity for this reaction was
further improved by lowering the reaction temperature.
A 94% ee of (S)-1 was obtained when PhMgBr is added
to 3g at −20°C and aged for 4 h, followed by warming
the reaction mixture to 0°C. However, only 82% ee of
the final product was observed when tert-butanesulfin-
amide was used under the same reaction condition. To
the best of our knowledge, this disclosure reports the
first systematic evaluation of the structure sulfinyl chi-
ral auxiliary for the asymmetric synthesis of diaryl-
methylamines with high selectivity. After achieving a
higher selectivity for the asymmetric synthesis of (S)-1,
the synthesis of (S)-cetirizine was efficiently accom-
plished as reported.3
B. Org. Lett. 2000, 2, 303; (g) Borg, G.; Chino, M.;
Elmann, J. A. Tetrahedron Lett. 2001, 42, 1433; (h)
Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org. Lett.
2001, 3, 2847; (i) Prakash, G. K. S.; Mandal, M.; Olah, G.
A. Angew. Chem., Int. Ed. 2001, 40, 589; (j) Lee, A.;
Elman, J. A. Org. Lett. 2001, 3, 3707; (k) Barrow, J. C.;
Ngo, P. L.; Pellicore, J. M.; Selnick, H. G.; Nantermet, P.
G. Tetrahedron Lett. 2001, 42, 2051.
8. For the use of Davis’ p-toluenesulfinamide as auxiliary in
the synthesis of chiral nitrogen containing compounds,
see: (a) Davis, F. A.; Reddy, R. E.; Szewezyk, J. M.;
Portonovo, P. S. Tetrahedron Lett. 1993, 34, 6229; (b)
Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998,
27, 13; (c) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.;
Reddy, G. V.; Portonovo, P. S.; Zhang, H.; Fanelli, D.;
Reddy, R. T.; Zhou, P.; Carroll, P. J. J. Org. Chem. 1997,
62, 2555; (d) Zhou, P.; Chen, B.-C.; Davis, F. A. Advances
in Sulfur Chemistry, Rayner, C. M., Ed.; JAL Press, 2000,
Vol. 2, p. 249; (e) Davis, F. A.; Lee, S.; Zhang, H.; Fanelli,
D. L. J. Org. Chem. 2000, 2, 8704.
9. For the first evaluation of the effect of the structure of
chiral sulfinamides in asymmetric synthesis of chiral
amines, see: Han, Z.; Krishnamurthy, D.; Pflum, D.;
Grover, P.; Wald, S. A.; Senanayake, C. H. Org. Lett.
2002, 4, 4025.
In conclusion, we have systematically studied the effect
of arene- and trialkylmethyl sulfinamides for the asym-
metric synthesis of (S)-diarylmethylamine-1. From this
study, we identified a novel and hindered arenesulfin-
amide, TIPPSA (triisopropylphenylsulfinamide), as an
optimal sulfinamide for highest diastereoselectivity in
the addition of PhMgBr to chlorophenyl aldamine 3g.
Applications of the steric outcome for TIPPSA to other
important asymmetric processes are under investigation
and will be reported in due course.
10. Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, K. Q.;
Senanayake, C. H. J. Am. Chem. Soc. 2002, 124, 7880.
11. Synthesis of enantiopure sulfinamides 5a–f and their ana-
lytical data were reported in Ref. 10. Same method was
applied for the synthesis of 5g. Triisopropylphenylmagne-
sium bromide (TIPPMgBr) was prepared in situ by reac-
tion of TIPPBr in ether with magnesium in the presence
of dibromoethane. N-Mesityl-aminoindanol derived
oxathiazolidine-2-oxide was used in the preparation of
TIPPSA according Scheme 3 to give a 87% overall yield
and >99% ee. Chiral HPLC analysis: Chiralcel OD, 250×
4.6 mm, Hex/IPA 9:1, 222 nm, 1 mL/min. (H1 CDCl3):
1.24 (d, J=6.96 Hz, 6H), 1.27 (d, J=6.71, 6H), 1.33 (d,
J=6.96, 6H), 2.88 (septet, J=6.9 Hz, 1H), 4.04 (septet,
J=6.78 Hz, 2H), 458 (s, 2H), 7.08 (s, 2H). 13C (l CDCl3):
23.9, 24.3, 24.5, 28.4, 34.4, 123.1, 138.9, 147.9, 152.0.
12. Typical experiment procedure for the asymmetric synthe-
sis of (S)-1 using 5g. Preparation of 3g: To a mixture of
5g (0.45 g, 1.68 mmol) and 4-chlorobenzaldehyde (0.25g,
1.82 mmol) in THF (10 mL) was added Ti(OEt)4 (4.0 g),
the mixture was stirred at 50°C for 4 h and reaction was
monitored by TLC analysis. The reaction mixture was
worked up and final compound was purified on chro-
References
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1
matography to afford 3g (0.62 g) in 95% yield. H NMR
(CDCl3): l 1.14 (d, J=6.84 Hz, 6H), 1.25 (d, J=6.95 Hz,
6H), 1.28 (d, J=6.71 Hz, 6H), 2.89 (m, 1H), 3.82 (m, 2H),
7.09 (s, 2H), 7.40–7.46 (m, 2H), 7.76–7.82 (m, 2H), 8.81 (s,
1H). 13C NMR (CDCl3): l 23.9, 24.2, 24.5, 24.9, 28.2,
34.6, 123.2, 129.5, 130.7, 132.9, 134.5, 138.7, 149.9, 153.1,
160. Anal calcd for C22H28ClNOS: C, 67.76; H, 7.24; N,
3.59. Found: C, 68.15; H, 7.45; N, 3.14. Preparation of 1:
To a 3g (0.11 g, 0.28 mmol) solution in toluene (3 mL)
under argon at −20°C was PhMgBr (0.19 mL, 3 M in
ether) slowly. After stirring at −20°C for 5 h, the reaction
mixture was warmed to 0°C, stirred, and the reaction was
monitored by TLC analysis. The reaction was quenched
with 4 M HCl in methanol and worked up to furnish 1 in
80% yield and 94% ee based on HPLC analysis.3