Control of diastereoselectivity by solvent effects in the addition of Grignard reagents to enantiopure t-butylsulfinimine: Syntheses of the stereoisomers of the hydroxyl derivatives of sibutramine

Article abstract of DOI:10.1021/ol0507017

(Chemical Equation Presented) An efficient method has been developed to prepare all four isomers of the hydroxyl derivatives of sibutramine by addition of Grignard reagents (R)- or (S)-5 to a single enantiomer of sulfinyl imine (R)-1 simply by tuning the

Full text of DOI:10.1021/ol0507017

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2599-2602
Control of Diastereoselectivity by
Solvent Effects in the Addition of
Grignard Reagents to Enantiopure
t-Butylsulfinimine: Syntheses of the
Stereoisomers of the Hydroxyl
Derivatives of Sibutramine
Bruce Z. Lu,*,† Chris Senanayake,*,‡ Nansheng Li, Zhengxu Han,
Roger P. Bakale, and Stephen A. Wald
Chemical Process Research and DeVelopment, Sepracor, Inc., 84 Waterford DriVe,
Marlborough, Massachusetts 01752
zlu@rdg.boehringer-ingelheim.com
Received April 1, 2005
ABSTRACT
An efficient method has been developed to prepare all four isomers of the hydroxyl derivatives of sibutramine by addition of Grignard reagents
(R)- or (S)-5 to a single enantiomer of sulfinyl imine (R)-1 simply by tuning the reaction solvent. The phenomenon of the reversed
diastereoselectivity in CH2Cl2 and THF implied that the reaction may proceed through a chelated cyclic transition state in CH2Cl2 and nonchelated
acyclic transition state in THF.
Organic compounds with chiral amine functionality represent
an important class of active pharmaceutical ingredients,
catalysts, and materials. Despite this fact, practical synthesis
of enantiomerically pure chiral amines still remains a
challenging task.1 Enantiomerically pure aldimines or ketimines
generated from an aldehyde or ketone with an alkyl or aryl
sulfinamide are versatile building blocks in the construction
of chiral amines, and their application has attracted a large
amount of interest.2 However, methods for the preparation
† Current address: Department of Chemical Development, Boehringer-
Ingelheim Pharmaceuticals, Inc., 800 East Leigh Street, Suite 205,
Richmond, VA 23219.
‡ Current address: Boehringer Ingelheim Pharmaceuticals, Inc., 900
Ridgebury Road, Ridgefield, CT 06877.
10.1021/ol0507017 CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/25/2005

of enantiomerically pure sulfinamides are rather limited. We
disclosed previously a general process for rapid access to a
variety of aryl or alkyl sulfinamides in optically pure form
with equal accessibility to either enantiomer. Included in this
list of examples is tert-butanesulfinamide prepared from
optically pure N-sulfonyl [1,2,3]-oxathiazolidine-2-oxide and
its application for the syntheses of several drug candidates.3
Recently, we reported another efficient asymmetric synthesis
of enantiopure sulfinates, which are common precursors to
access both sulfoxides and sulfinamides.4 High diastereo-
selectivity for the addition of nucleophiles such as Grignards,
lithium reagents, or enolates to sulfinimines has been
demonstrated, and a chelated cyclic transition state has been
proposed for the high selectivity observed in this process.5
However, the concept of obtaining a reversal of diastereo-
selectivity while utilizing the same enantiomer of either (R)-
or (S)-sulfinimines by altering the transition state has not
yet been well documented for these reaction systems (Scheme
1).6
Scheme 2. Retrosynthetic Analysis for Preparation of the
Hydroxyl Derivatives of Sibutramine
uptake inhibitors that can be potentially used for the treatment
of CNS disorders.7 To identify the absolute configuration
of the active metabolite, as well as conduct a comparison of
the biological activities of these stereoisomers, efficient
synthetic methods were needed to prepare the stereoisomers.
Herein, we report the first efficient stereoselective syntheses
of all four isomers of 1-OH-DDMS using (R)-tert-butane-
sulfinamide-derived sulfinimine intermediate (1) as the
common synthon for preparation of each stereoisomer. In
this case, we demonstrated the above concept to manipulate
the diastereoselectivity by taking advantage of solvent effects.
The synthesis starts with the preparation of a common
single enantiomer of the key intermediate, the (R)-tert-
butanesulfinyl imine 1. Condensation of the aldehyde 2 with
(R)-tert-butylsulfinamide in THF at 22 °C, catalyzed by
Ti(OEt)4, gave 1 in 94% yield (Scheme 3). Next, addition
Scheme 1. Mechanistic Models to Predict the Stereochemical
Outcomes of the Nucleophilic Additions
Scheme 3. Diastereoselective Addition of Lithium Reagent
(R)-3 to (R)-t-Butanesulfinimide 1
As part of our program to develop improved chemical
entities (ICEs) from important existing drugs, we were
interested in investigating each of the potential metabolites
of the antiobesity drug sibutramine (Scheme 2). Preliminary
preclinical studies indicated that the hydroxylated derivatives
of sibutramine (1-OH-DDMS) are potent monoamine re-
(1) (a) Johansson, A. Contemp. Org. Synth. 1995, 2, 393. (b) Enders,
D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895. (c) Bloch, R.
Chem. ReV. 1998, 98, 1407. (d) Kobayashi, S.; Ishitani. H. Chem. ReV.
1999, 99, 1069. (e) Senanayake, C. H.; Krishnamurthy, D. Curr. Opin. Drug
DiscoVery DeV. 1999, 2, 590.
(2) For recent reviews, see: (a) Ellman, J.; Owens, T. D.; Tang, T. P.
Acc. Chem. Res. 2002, 35, 984. (b) Ellman, J. A. Pure Appl. Chem. 2003,
75, 39. (c) Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003.
(3) (a) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake,
C. H. J. Am. Chem. Soc. 2002, 124, 7880. (b) Pflum, D. A.; Krishnamurthy,
D.; Han, Z.; Wald, S. A.; Senanyake, C. H. Tetrahedron Lett. 2002, 43,
923. (c) Han, Z.; Krishnamurthy, D.; Pflum, D. A.; Grover, P.; Wald, S.
A.; Senanyake, C. H. Org. Lett. 2002, 4, 4025.
(4) Lu, B. Z.; Jin, F.; Zhang, Y.; Wu X.; Wald, S. A.; Senanayake, C.
H. Org. Lett. 2005, 7, 1465.
(5) Cogan, D. A.; Liu, G. C.; Ellman, J. Tetrahedron 1999, 55, 8883.
(6) Reversal in the diastereoselectivity was observed for addition of
arylmetal species to sulfinimines derived from aromatic aldehydes. Plobeck,
N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303.
of the THP-protected organolithium reagent (R)-3 to imine
1 was examined. In both Et2O and THF, the addition
occurred at -78 °C and gave consistently anti-4 as the major
(7) Senanayake, C. H.; Lu, Z.-H.; Li, N. S.; Rubin, P. D.; Jerussi, T. P.
(Sepracor, Inc.). PCT Appl. WO 02/046138 A2, June 13, 2002.
2600
Org. Lett., Vol. 7, No. 13, 2005

product in high yield after cleavage of the chiral auxiliary
with methanolic HCl. These results are summarized in Table
1. A diastereomeric ratio of up to 99:1 was achieved when
sulfinyl oxygen, which would enhance the acyclic transition
state pathway. On the other hand, when the reaction was
carried out in THF, poor diastereoselectivity resulted, giving
6 and 7 in a ratio of 40:60, thus indicating a mismatched
addition of (R)-5 to (R)-1 via the nonchelated pathway (Table
2, entry 3). Addition of a Lewis acid such as 1.2 equiv of
Al(Oct)3 improved the diastereoselectivity of the mismatched
addition when run in THF from 40:60 to 14:86 (Table 2,
entry 4).
Table 1. Addition of Organolithium (R)-3 with
(R)-t-butanesulfinimine 1
entry
solvent
Lewis acid
yield (%) anti/cisa
1
2
3
4
5
6
Et2O
N/A
N/A
93
88
79
85
99
82
95:5
85:15
96:4
98:2
96:4
99:1
THF-Et2O (2:1)
THF-Et2O (2:1)
THF-Et2O (2:1)
Et2O-hexane (3:1) Al(Oct)3 (1.2 equiv)
THF-Et2O-hexane Al(Oct)3 (1.2 equiv)
(2:1:1)
BF3‚OEt2 (1.1 equiv)
BF3‚OEt2 (2.2 equiv)
Scheme 4. Diastereoselective Addition of Grignard Reagent
(R)- or (S)-7 to (R)-t-Butanesulfinimide 1
a Ratios were measured by HPLC.
the reaction was catalyzed with 1.2 equiv of Al(Oct)3 or 2
equiv of BF3‚Et2O (Table 1, entries 4 and 6). In these cases,
it is proposed that the additions occurred predominantly
through the nonchelated acyclic transition state pathway. To
reverse the facial selectivity, via the chelated cyclic transition
state, it was believed that a nonchelating solvent would be
essential to prevent competitive coordination of the solvent
to the metal cation (nonchelated acyclic TS#). Chlorinated
or hydrocarbon solvents such as toluene were expected to
meet this criterion. The potential incompatibility of reacting
certain lithio reagents in these solvents prompted us to first
study the addition with Grignard reagents.
The Grignard reagents (S)- and (R)-5, were derived from
(R)- and (S)-3-bromo-2-methyl propanol, respectively, by a
modified procedure according to literature.8 The results of
addition to (R)-tert-butylsulfinimine (1) are summarized in
Table 2. As we anticipated, a remarkable solvent effect was
observed. For instance, when (R)-5 was added to 1 in CH2Cl2,
the reaction proceeded at 22 °C to form a diastereomeric
mixture of 6 and 7, with a ratio of 97:3, favoring the chelated
cyclic transition state product (Table 2, entry 1). Not
surprisingly, in the case where Al(Oct)3 was added, the
diastereoselectivity deteriorated to 76:24 and retarded the
reaction (Table 2, entry 2). This is likely due to the
competitive coordination of the added Lewis acid to the
Similarly, the addition of (S)-5 to 1 afforded a higher
diastereoselectivity of addition when run in CH2Cl2 to give
8 and 9 in a ratio of 91:9 (Table 2, entry 5) and a lower
opposite selectivity in THF to afford 8 and 9 in a ratio of
Table 2. Addition of Grignard Reagents (R)- or (S)-5 to Sulfinimide 1
entry
5
solvents
Lewis acid
temp (°C)/time (h)
yielda (%)
74
drb
1
2
3
4
5
6
7
8
9
R
R
R
R
S
S
S
S
S
S
CH2Cl2-Et2O (2:1)
CH2Cl2-Et2O-hexane (4:2:1)
THF
THF-hexane (7:1)
CH2Cl2-Et2O (2:1)
CH2Cl2 -Et2O-hexane (4:2:1)
THF
THF-hexane (7:1)
toluene-Et2O (2:1)
CH2Cl2-Et2O (2:1)
N/A
-48 to rt/24
-78 to rt/36
-78 to rt/2
-78 to rt/48
0 to rt/10
-78 to rt/24
0 to rt/2
-78 to rt/2
rt/24
6/7 97:3
6/7 76:24
6/7 40:60
6/7 14:86
8/9 91:9
8/9 95:5
8/9 15:85
8/9 19:81
8/9 94:6
Al(Oct)3 (1.2 equiv)
N/A
Al(Oct)3 (1.2 equiv)
N/A
Al(Oct)3 (1.2 equiv)
N/A
Al(Oct)3 (1.2 equiv)
N/A
57 (95)c
76.5 (84.5)
65
75 (88)
30
0
10
BF3‚OEt2 (2.2 equiv)
-78 to rt/24
a Isolated yield of pure major isomer. b Measured by HPLC.
Org. Lett., Vol. 7, No. 13, 2005
2601

15:85 (Table 2, entry 7). In contrast to the addition of (R)-5
to 1, the addition of (S)-5 to 1 in CH2Cl2, in the presence of
1.2 equiv of Al(Oct)3, gave improved diastereoselectivity
from 91:9 to 95:5 (Table 2, entry 6), whereas a slight
decrease of selectivity (from the original 15:85 to 19:81) was
observed when 1.2 equiv of Al(Oct)3 was added to the
mixture of (S)-5 and 1 in THF (Table 2, entry 8). The
addition of BF3‚Et2O to the reaction mixture in CH2Cl2
resulted in no product formation, probably due to the
reactivity of the Grignard reagent with BF3‚Et2O at 22 °C
(Table 2, entry 10). Although the reaction in toluene gave
better selectivity, the addition was much slower (Table 2,
entry 9). After separation by column chromatography, all
four isomers 6-9 were converted into their respective target
molecules by treatment with methanolic HCl to cleave the
chiral auxiliary.
of the other isomers were deduced from 8 on the basis of
1
comparisons of both H and 13C NMR data.
In summary, an efficient synthetic method has been
developed whereby addition of the Grignard reagents (R)-
or (S)-5 to the common synthon 1 readily allows access to
each of the four stereoisomers of the hydroxyl sibutramine
by proper choice of reaction conditions. The reversed
diastereoselectivity observed in CH2Cl2 and THF implies that
the reactions may undergo chelated cyclic transition state
and nonchelated acyclic transition states, respectively. From
these preliminary results, it is conceivable that the presence
of a Lewis acid would facilitate the nonchelated pathway
but disfavor the chelated one, providing that more than 2
equiv of a Lewis acid are added. When the nucleophile
contains chirality, matched and mismatched additions could
occur. Therefore, it is conceivable to design a kinetic
resolution by reaction of enantiopure sulfinimines with a
racemic nucleophile to provide one diastereomer preferen-
tially as the major adduct. The differing aggregation states
of Grignard reagents in CH2Cl2 or THF should have an
influence on the reaction rates. Further applications of
enantiomerically pure sulfinimines for the preparation of a
variety of chiral amines with important therapeutic indica-
tions are under investigation and will be reported in due
course.
The absolute stereochemistry at C-4 was assigned by X-ray
crystallography on intermediate 8 (Figure 1). The structures
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0507017
Figure 1. Diagram of the X-ray crystal structure of 8.
(8) Jeffery, J. E.; Kerrigan, F.; Miller, T. K.; Smith, G. J.; Tometzki, G.
B. J. Chem. Soc., Perkin Trans. 1 1996, 21, 2583.
2602
Org. Lett., Vol. 7, No. 13, 2005