First application of tunable alkyl or aryl sulfinamides to the stereoselective synthesis of a chiral amine: asymmetric synthesis of (R)-didesmethylsibutramine ((R)-DDMS) using (R)-triethylmethylsulfinamide ((R)-TESA).

Article abstract of DOI:10.1021/ol026699q

A highly diastereoselective addition of i-BuLi to a triethylmethylsulfinamide derived aldimine was used as the key step in the first asymmetric synthesis of (R)-didesmethylsibutramine, a metabolite of sibutramine for the potential treatment of CNS disorders. [reaction: see text]

Full text of DOI:10.1021/ol026699q

ORGANIC
LETTERS
2002
Vol. 4, No. 23
4025-4028
First Application of Tunable Alkyl or
Aryl Sulfinamides to the Stereoselective
Synthesis of a Chiral Amine:
Asymmetric Synthesis of
(R)-Didesmethylsibutramine ((R)-DDMS)
Using (R)-Triethylmethylsulfinamide
((R)-TESA)†
Zhengxu Han, Dhileepkumar Krishnamurthy,* Derek Pflum, Paul Grover,
Stephen A. Wald, and Chris H. Senanayake*
Chemical Process Research and DeVelopment, Sepracor Inc., 84 Waterford DriVe,
Marlborough, Massachusetts 01752
dkrishna@sepracor.com
Received August 8, 2002
ABSTRACT
A highly diastereoselective addition of i-BuLi to a triethylmethylsulfinamide derived aldimine was used as the key step in the first asymmetric
synthesis of (R)-didesmethylsibutramine, a metabolite of sibutramine for the potential treatment of CNS disorders.
Among nitrogen-containing biologically active organic com-
pounds, chiral amines represent an important class for the
development of active pharmaceutical ingredients and other
pharmaceutical intermediates. Despite their prime importance
in the pharmaceutical industry, the economically viable and
practical asymmetric synthesis of chiral amines poses
significant challenges to organic chemists.1 One such chiral
amine of interest to Sepracor is (R)-didesmethylsibutramine
(DDMS, 1), a single enantiomeric version of a pharmaco-
logically active metabolite of sibutramine 2.2 Preliminary
preclinical studies indicate that (R)-DDMS is a potent
serotonin, norepinephrine, and dopamine re-uptake inhibitor
that can be potentially used in the treatment of CNS
disorders.3 To evaluate this unique triple mechanism of
action, process research efforts were directed toward the
synthesis of optically pure (R)-DDMS. We recently reported
the synthesis of optically pure (R)-DDMS using a novel
resolution process with 20% overall yield.4 To identify an
efficient high- yielding synthesis for (R)-DDMS, we have
focused our research efforts in the development of an
asymmetric synthesis of DDMS. Herein, we disclose the first
(2) Buckett, W. R.; Thomas, P. C.; Luscomb, G. P. Prog. Neuro-
Psychopharmacol. Biol. Psychiatry 1988, 12, 575.
(3) Jerussi, T. P.; Senanayake, C. H.; Fang, Q. K. (Sepracor Inc.) PCT
Appl. WO 00/10551, March 2, 2000.
(4) Senanayake, C. H.; Fang, Q. K.; Han, Z.; Krishnamurthy, D. (Sepracor
Inc.) PCT Appl. WO 01/51453, July 29, 2001.
* E-mail address for C.H.S.: csenanay@rdg.boehringer.ingelheim.com.
† Dedicated to Professor Carol Johnson on the occasion of his retirement.
(1) (a) Enders, D.; Reinhold: U. Tetrahedron: Asymmetry 1997, 8, 1895.
(b) Kobayashi, S.; Ishitani. H. Chem. ReV. 1999, 99, 1069. (c) Senanayake,
C. H.; Krishnamurthy, D. Curr. Opin. Drug DiscoVery DeV. 1999, 2, 590.
10.1021/ol026699q CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/18/2002

practical asymmetric synthesis of (R)-DDMS using the novel
(R)-triethylmethylsulfinamide ((R)-TESA).
Scheme 2. Modular Asymmetric Synthesis of Chiral
Sulfinamides
We envisioned that application of an enantio- or diaste-
reoselective addition to imine 3 (asymmetric C-C bond
forming reaction) would provide a straightforward route to
a high-yielding synthesis for optically pure DDMS. Imine 3
could be obtained from the corresponding hindered aldehyde
4b, which in turn can be readily accessed from known nitrile
4a (Scheme 1).5
Scheme 1. Retro-Synthetic Analysis for DDMS
We thought that application of enantiopure sulfinamide6,7
as a chiral auxiliary for preparation of optically pure DDMS
was a viable alternative method, provided a range of chiral
sulfinamides with both antipodes can be accessed in large
quantities with a reasonable price.8 In this context, we recent-
ly reported the first, practical, and modular approach for
production of several enantiopure sulfinamides using a key
chemoselective ring opening of a recyclable, aminoindanol
based endo-1,2,3-oxathiazolidine-2-oxide (6, Scheme 2).9
With these optically pure chiral sulfinamides in hand, our
initial effort in the asymmetric synthesis of (R)-DDMS was
focused on the identification of an efficient and scalable
chiral sulfinamide auxiliary for the diastereoselective addition
to imine 3. To begin our investigations, a variety of chiral
alkyl or aryl sulfinyl aldimines 9a-f were prepared from
aldehyde 4b and the corresponding sulfinamides 8a-f in
excellent yields using known method.10 Additions of i-BuLi
to imines were conducted at -20 °C in the presence of BF3‚
OEt2,11a and the results are summarized in Table 1.
Table 1. Addition of i-BuLi to Sulfinyl Aldimines 9a
(5) Krishnamurthy, D.; Han, Z.; Wald, S. A.; Senanayake, C. H.
Tetrahedron Lett. 2002, 43, 2331.
(6) For the use of p-toluenesulfinamide as auxiliary in the synthesis of
chiral nitrogen containing compounds see: (a) Davis, F. A.; Reddy, R. E.;
Szewczyk, 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: Greenwich, CT, 2000; Vol. 2,
p 249. (e) Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D. L. J. Org. Chem.
2000, 65, 8704.
(7) For the use of tert-butylsulfinamide as auxiliary in the synthesis of
chiral nitrogen containing compounds see: (a) Liu, G.; Cogan, D. A.;
Ellman, J. A. J. Am. Chem. Soc. 1997, 119, 9913. (b) Owens, T. D.;
Hollander, F. J.; Oliver, A, G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123,
1539 and references therein. (c) Borg, G.; Cogan, D. A.; Ellman, J. A.
Tetrahedron Lett. 1999, 40, 6709. (d) Cogan, D. A.; Liu, G.; Ellman, J. A.
Tetrahedron 1999, 55, 8883. (e) Davis, F. A.; McCoull, W. J. Org. Chem.
1999, 64, 3396. (f) Tang, T. P.; Volkman, S. K.; Ellman, J. A. J. Org.
Chem. 2001, 66, 8772. (g) Lee, Y.; Silverman, R. B. Org. Lett. 2000, 2,
303. (h) Borg, G.; Chino, M.; Ellman, J. A. Tetrahedron Lett. 2001, 42,
1433. (i) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org. Lett. 2001, 3,
2847. (j) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int.
Ed. 2001, 40, 589. (k) Lee, A.; Ellman, J. A. Org. Lett. 2001, 3, 3707. (l)
Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Selnick, H. G.; Nantermet, P.
G. Tetrahedron Lett. 2001, 42, 2051. (m) Pflum, D. A.; Krishnamurthy,
D.; Han, Z.; Wald, S. A.; Senanyake, C. H. Tetrahedron Lett. 2002, 43,
923. (n) Plobeck, N.; Powell, N. Tetrahedron: Asymmetry 2002, 13, 303.
(8) (R)-TBSA is available from Aldrich Chemical Co. only in gram
quantities ($130/g).
entry
9, R
% yieldb
% eec
1
2
3
4
5
6
C(CH3)3 (9a )
85
82
77
75
-
88
88
80
80
-
C(C2H5)3 (9c)
C(CH3)2C2H5 (9b)
Ad (9e)
4-methylphenyl (9d )d
2-mesityl (9f)
60
50
a See Supporting Information for detailed experimental procedures.
b Except for entry 1, yields are based on the HPLC analysis. c % ee values
are determined by chiral HPLC analysis. d No desired product was formed.
Treatment of i-BuLi with aldimine 9a followed by acidic
removal of the tert-butylsulfinyl group provided 88% ee of
(10) (a) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A.
J. Org. Chem. 1999, 64, 1278. (b) All new sulfinyl aldimine gave satisfactory
analytical data.
(11) (a) Preliminary studies showed the use of BF3‚OEt2 minimizes the
formation of byproducts. (b) Observed stereochemistry is consistent with
previously proposed nonchelation controlled models.7n
(9) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake,
C. H. J. Am. Chem. Soc. 2002, 124, 7880.
4026
Org. Lett., Vol. 4, No. 23, 2002

Table 2. Stereoselective Addition of i-BuM to Aldimine 9aa
% eec
chemical
purityd
entry
nucleophile
additive
solvent
temp, °C
% yieldb
(R/S)
1
2
3
4
5
6
7
8
9
10
11
12
13
i-BuMgBr
i-BuMgBr
i-BuMgBr
i-BuLi
i-BuLi
i-BuLi
i-BuLi
i-BuLi
i-BuLi
i-BuLi
-
THF or toluene
THF or toluene
THF
MTBE
MTBE
toluene
THF
THF
toluene
THF
toluene
THF
-78 to 100
-78 to 100
-20 to 25
-78 to 25
-78 to 25
-78
-78
-78
-45
-78
-
-
-
-
40e (R)
-
-
-
-
-
BF3‚OEt2
Me3Al
-
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
Me3Al
Me3Al
Oct3Al
Oct3Al
TMEDA
TMEDA
90e
-
-
-
-
78
90
90
36
85
37
84
85
98 (R)
99 (R)
99 (R)
38 (S)
98 (R)
76 (S)
99 (R)
95 (R)
99.0
99.2
98.7
62.0
96.5
55.0
99.7
98.4
i-BuLi
i-BuLi
i-BuLi
-20
-78
-78
toluene
a For detailed experimental procedures see the Supporting Information. b Yields are determined by HPLC quantification. c Ee values are determined using
the chiral HPLC method. d Chemical purity was determined by HPLC area %. e Yield and ee refers to methyl transfer product 10.
(R)-DDMS with 85% yield.11b Surprisingly, change of
trimethylmethylsulfinyl aldimine 9a to triethylmethylsulfinyl
aldimine 9c provided no further increase in the ee (entry 2).
Interestingly, use of dimethylethylmethylsulfinyl aldimine
9b decreased the ee from 88% to 80%. Introduction of a
more hindered adamantyl group in imine 9 (9e) also
decreased the ee to 80%. The attempted use of p-tolylsul-
finamide was not fruitful, as it provided many byproducts.
2-Mesitylsulfinamide 9f provided 60% yield and 50% ee,
and proved to be less effective in this diastereoselective
process. It should be noted that in most cases reaction yields
are not affected by modification of sulfinyl aldimine
structures. Among the various chiral sulfinamides, only the
triethyl derivative performed similar to tert-butyl sulfinamide,
and none gave >88% ee at -20 °C.
On the basis of the above results, imines 9a and 9c proved
to be better than other imines, and hence, further optimization
studies to obtain (R)-DDMS in high yield with excellent %
ee and high chemical purity were centered on these imines.
Since imines 9a and 9c gave identical results, tert-butyl-
sulfinyl aldimine 9a was used as the representative substrate
for further experimentation. Thus, after obtaining large
quantities of imine 9a, our attention focused on the systematic
screening studies on the organometallic addition process, as
depicted in Table 2. These studies included an examination
of various additives, solvents, and nucleophiles for the
addition process to produce (R)-DDMS in high yield,
excellent enantioselectivity, and high purity. The use of
i-BuMgBr was not effective in this reaction and gave no
desired product in any of the cases (entries 1-3).
the more reactive i-BuLi in MTBE with or without BF3‚
OEt2 gave disappointing results (entry 4 and 5). However,
when toluene or THF is used as the solvent, i-BuLi added
to imine 9a in the presence of BF3‚OEt2 to provide
(R)-DDMS in >75% yield and >98% ee (entries 6 and 7).
The use of Al based Lewis acids provided similar results,
as compared to BF3‚OEt2 when THF is used as solvent (entry
8 and 10). Interestingly, when THF is replaced with toluene,
Al-based Lewis acids provided the (S)-enantiomer albeit in
low % ee (entries 9 and 11). Use of the Lewis base TMEDA
provided comparable results with BF3‚OEt2 either in THF
or in toluene.13 It is important to mention that the decrease
of % ee with increase in temperature is more pronounced
when toluene is used as solvent (Figure 1). However, a minor
fluctuation in % ee with respect to temperature is observed
when THF is used as the solvent (Figure 1).14 Thus, optimal
o
conditions were established in THF at -78 C, using BF3‚
OEt2 as additive and i-BuLi as nucleophile, to provide (R)-
DDMS in excellent yield with >98% ee and >99% chemical
purity.
Although (R)-DDMS can be prepared in high yield and
excellent enantiomeric purity using (R)-TBSA, during the
acidic removal of the tert-butylsulfinyl group to form (R)-
DDMS, a malodorous odor was generated, which limited
the large-scale operation of TBSA. Therefore, we turned our
attention to other sulfinamide auxiliaries which can ef-
fectively provide outstanding induction compared to (R)-
(12) For a similar methyl transfer process in ketimine see ref 7f.
(13) Isolation of DDMS as the DDMS‚D-TA salt may not be effective
in the presence of TMEDA. Therefore the use of TMEDA was not
considered for further optimization.
(14) Use of 1:1 THF:toluene as solvent has the same effect of temperature
on % ee as THF alone.
Interestingly, the use of i-BuMgBr in the presence of
Me3Al gave a methyl transfer product 10.12 Utilization of
Org. Lett., Vol. 4, No. 23, 2002
4027

Scheme 3. Single Vessel Asymmetric Synthesis of
(R)-DDMS‚D-TA
Figure 1. Effect of temperature on percent ee of (R)-DDMS.
TBSA without evolution of an unpleasant odor15 during the
removal of the sulfinyl group. It is gratifying to mention that
use of (R)-TESA derived imine 9c retained the excellent
induction and did not evolve any odor during the acidic
removal of the sulfinyl group.
After identifying (R)-TSEA as the practical chiral auxiliary
and optimal condition for the diastereoselective addition
process, a chromatography free asymmetric synthesis of (R)-
DDMS was demonstrated in a single vessel using imine 9c,
as depicted in Scheme 3.
Thus, treatment of Red-Al with nitrile 4a in toluene
provided aldehyde 4b,16 which was then subjected to
Ellman’s condition with (R)-TESA to provide imine 9c.
Diastereoselective addition of i-BuLi in the presence of BF3‚
OEt2 at -78 °C was followed by cleavage of the chiral
auxiliary to afford (R)-DDMS in 99% ee. Isolation of (R)-
DDMS is accomplished by treating crude DDMS solution
in toluene with an aqueous solution of D-TA. The overall
yield for this process from nitrile 4a is 83% with >99% ee
and >99.5% chemical purity.
i-BuLi addition has been evaluated. Application of tert-butyl
and triethylmethylsulfinamide at -20 °C gave DDMS in 88%
ee; on the other hand, use of aryl sulfinamides such as 2,4,6-
mesitylsulfinamide gave only 50% ee. Due to practical
limitation in the use of (R)-TBSA, (R)-TESA was developed
as a practical auxiliary for the asymmetric synthesis of (R)-
DDMS. Using (R)-TESA as an auxiliary, a single vessel
protocol was developed for the asymmetric synthesis of (R)-
DDMS that provided an overall yield of 83% and >99%
ee. Further insight into the role of the sulfinamide structure
in sulfinyl imines toward the outcome of nucleophillic
addition processes, and further evaluation of structurally
unique sulfinamide auxiliaries, such as (R)-TESA, for the
preparation of challenging chiral amines are being pursued,
and will be reported in due course.
In summary, for the first time, the effect of the structure
of various chiral sulfinamides on the stereoselectivity of
Supporting Information Available: 1H and 13C NMR
and MS data and description of experimental procedures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) In the production environment 9c is preferred over 9a due to low
volatility of byproducts from hydrolysis reaction.
(16) Red-Al is less expensive and more efficient in the large-scale
reduction of 4a to 4b.
OL026699Q
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Org. Lett., Vol. 4, No. 23, 2002