A new and direct asymmetric synthesis of a hindered chiral amine via a novel sulfinate ketimine derived from N-tosyl-1,2,3-oxathiazolidme-2-oxide: Practical asymmetric synthesis of (R)-sibutramine

Article abstract of DOI:10.1021/op050182n

A novel and direct approach for the asymmetric synthesis of (R)-sibutramine via chiral amine 5 using N-tosyl-1,2,3-oxathiazolidine-2-oxide (13) as a recyclable chiral auxiliary is described. Chiral sulfinate imine 16e was obtained by treatment of 13e with

Full text of DOI:10.1021/op050182n

Organic Process Research & Development 2006, 10, 327−333
Communications to the Editor
A New and Direct Asymmetric Synthesis of a Hindered Chiral Amine via a Novel
Sulfinate Ketimine Derived from N-Tosyl-1,2,3-oxathiazolidine-2-oxide:
Practical Asymmetric Synthesis of (R)-Sibutramine
Zhengxu Han,† Dhileepkumar Krishnamurthy,† and Chris H. Senanayake*,†
Chemical Process Research and DeVelopment, Sepracor Inc., 84 Waterford DriVe,
Marlborough, Massachusetts 01752, U.S.A.
Abstract:
provided hindered ketone 6 in good yield. Although prepara-
tion of tert-butanesulfinyl imines from ketones has been
reported with high yield, preparation of ketimine 7 from
sterically hindered ketone 6 using the known procedure3
resulted in only 5% yield.
Nevertheless, ketimine 7 could be reduced at elevated
temperature, followed by hydrolysis of sulfinamide 4, which
provided 5 in 70% ee. However, both routes (Schemes 1
and 2) suffered from the use of nonrecyclable chiral auxiliary
(R)-TBSA, and other practical limitations for larger-scale
production of (R)-sibutramine.
We identified the following objectives in devising our new
synthetic strategy: (1) the N atom of the nitrile should
become the amine N atom in the product, (2) the chiral imine
should be formed in high yield even for sterically challenging
substrates, (3) high diastereoselectivity with high yield should
be obtained in the asymmetric reduction process, and (4)
the chiral auxiliary should be readily recycled. As reported,1
chiral amine can be prepared in excellent stereoselectivity
by reduction of chiral sulfinyl ketimines derived from
sulfinamide and ketone. The drawback of this method is that
the auxiliary, sulfinamide, is destroyed during hydrolysis with
acid and the auxiliary cannot be recycled and reused. Our
plan was to construct the chiral ketimine with a recyclable
chiral auxiliary using a Grignard addition to nitrile 8 followed
by trapping the resulting magnesium imine 9 with a suitable
electrophilic chiral auxiliary Xc-Y (Scheme 3). Stereoselec-
tive reduction of imine 10 would provide 11, which would
then be subjected to mild cleavage conditions to provide
chiral amine 12 and chiral auxiliary precursor Xc-Z. The
direct formation of chiral ketimine 10 from nitrile 8 using a
suitable electrophilic chiral auxiliary and diastereoselective
reduction of imine 10 to 11 plays a vital role in our reaction
design.
A novel and direct approach for the asymmetric synthesis of
(R)-sibutramine via chiral amine 5 using N-tosyl-1,2,3-oxathia-
zolidine-2-oxide (13) as a recyclable chiral auxiliary is described.
Chiral sulfinate imine 16e was obtained by treatment of 13e
with the imine intermediate formed from the reaction of a nitrile
i
1 and BuMgCl that, upon reduction, provides an optically
active amine 5 with high enantiopurity.
During the past few decades, many synthetic drug groups
have been engaged in the development of single enantiomeric
drug targets that exhibit an amine functionality at the chiral
center.1 Despite the fact that these chiral amines are regarded
as an important class for the development of active phar-
maceutical ingredients, their practical asymmetric synthesis
poses significant challenges for synthetic organic chemists.
In this context, we recently reported an asymmetric synthesis
of 5 (a precursor for the anti-obesity drug sibutramine) in
excellent ee using BuLi addition to Ellman’s tert-butane-
sulfinamide ((R)-TBSA) derived aldimine 3 (Scheme 1).2
Although the use of BuLi gave excellent results, this route
suffers from poor cost-effectiveness due to the use of
nonrecyclable (R)-TBSA and from the low stability of iBuLi
at ambient temperature, which limits the use of this method
on large scale. To circumvent the use of BuLi, the diaste-
reoselective reduction of a ketimine derived from ketone 6
and (R)-TBSA was envisioned (Scheme 2). Treatment of
i
i
i
i
nitrile 1 with BuMgCl followed by acidic hydrolysis
* To whom correspondence should be addressed. E-mail: csenanay@
rdg.boehringer-ingelheim.com.
† Current address: Boehringer Ingelheim Pharmaceuticals, Inc. 900
Ridgebury Rd., Ridgefield, CT, 06877, U.S.A.
(1) For examples, see: (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem.
Res. 2002, 35, 984 and references cited therein. (b) Hermanns, N.; Dahman,
S.; Bolm, C.; Braese, S. Angew. Chem., Int. Ed. 2002, 41, 3692. (c) Porter,
J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc.
2001, 123, 10409. (d) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q.
K.; Pflum, D. A.; Senanayake, C. H. Tetrahedron Lett. 2003, 44, 4195. (e)
Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837. (f) Bloch, R.
Chem. ReV. 1998, 98, 1407 and references cited therein. (g) Davis, F. A.;
Lee, S.; Zhang, H.; Fanelli, D. L. J. Org. Chem. 2000, 65, 8704. (h)
Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou, I.
Aldrichimica Acta 2005, 38, 93.
We envisioned that, due to the unique reactivity (S-O
vs S-N bond) of our recently reported activated oxathia-
zolidine-2-oxide derivatives (13, ASOO, Scheme 4) towards
nucleophiles,4 which also proved useful in the preparation
of chiral sulfinamides4a and chiral sulfoxides,4b we may be
(2) (a) Jeffery, J. E.; Kerrigan, F.; Miller, T. K.; Smith, G. J.; Tometzki, G. B.
J. Chem. Soc., Perkin Trans. 1 1996, 2583. (b) Han, Z.; Krishnamurthy,
D.; Pflum, D.; Grover, P.; Wald, S. A.; Senanayake, C. H. Org. Lett. 2002,
4, 4025.
(3) (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119, 9,
9913. (b) 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.
10.1021/op050182n CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/10/2006
Vol. 10, No. 2, 2006 / Organic Process Research & Development
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327

Scheme 1. Asymmetric synthesis of (R)-sibutramine using (R)-TBSA
Scheme 2. Synthesis of 5 using diastereoselective reduction
of 7
activated chiral oxathiazolidine-2-oxide derivatives and the
utilization of these sulfinyl ketimines for the practical
asymmetric synthesis of (R)-sibutramine (Scheme 4).
To verify the hypothesis shown in Scheme 3, our initial
effort focused on the preparation of diastereopure sulfinate
imines 16a-c from readily available oxathiazolidine-2-
oxides 13a-c (Figure 1)4 followed by finding proper
stereoselective reduction conditions for the corresponding
sulfinate imines. The strategy for using ketimines 16a and
16b in our primary study was to investigate the effect of the
auxiliary framework (open chain 16a vs rigid cyclic system
16b) on the stereoselective reduction process. In addition,
the comparison of 16b and 16c would demonstrate the effect
of different aryl sulfonyl groups on the stereoselectivity.
With this strategy in mind, we first prepared ketimine 16.
After a number of experiments, it was found that both
norephedrine- and amino indanol-derived sulfinate ketimines
16a-c (Figure 1) could be prepared in >95% yield by slow
addition of imine 15 in toluene to oxathiazolidine-2-oxide
13 in THF at -45 °C. It should be noted that, like the
reaction of carbon nucleophiles with 13,4 reaction of this
nitrogen nucleophile provided the corresponding sulfinyl
ketimine 16 with inversion of configuration at the sulfur atom
(Scheme 4).5
Scheme 3. New synthetic strategy for conversion of nitriles
to chiral amines
able to use this chiral auxiliary for the formation of various
structurally diverse imines. Furthermore, a range of oxathia-
zolidine-2-oxide derivatives can be accessed from the cor-
responding amino alcohols. Here we disclose the first
preparation and characterization of sulfinate ketimines from
With the sulfinate ketimines in hand, next we chose 16a
as the representative substrate for the identification of
reaction conditions for the stereoselective reduction of
ketimines (Table 1, entries 1-13). Addition of NaBH4 to a
THF solution of 16a at -45 °C provided an 80:20 diaster-
Scheme 4. Asymmetric synthesis of (R)-sibutramine from nitrile 1
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sibutramine using a known procedure.2a As reported, enan-
tiopure oxathiazolidine 13a can be readily regenerated by
simple treatment of N-sulfonyl-norephedrine (14a) with
4c
SOCl2 in the presence of pyridine in excellent yield.
Excited by this important result, our immediate attention
was focused on the optimization of the stereoselective
reduction using various reducing agents, additives, and
solvents (Table 1).6 When the reduction was carried out in
the presence of NaBH4 and Ti(OEt)4 in THF, the selectivity
is increased to 82:18. Surprisingly, use of Ti(OiPr)4 further
increased the selectivity to 88:12, with 95% yield. Modifica-
tions of reaction conditions by changing the solvent to EtOH
or MTBE and using different additives such as Zr(OEt)4 or
ZnCl2 gave moderate selectivity or low yield. Replacement
of NaBH4 with LiBH4 (51:49) or DIBAL-H in the presence
of ZnCl2 also provided poor results. Interestingly, reduction
of the sulfinate imine 16a with borane-based reducing agents
such as BH3, catecholborane, or L-selectride, provided
moderate to low selectivity for the opposite diastereomer as
confirmed by chiral HPLC analysis of the corresponding
hydrolysis product 5. On the other hand, sterically hindered
borane reagent 9-BBN provided the desired diastereomer
with good selectivity in 80% yield. When 16b was subjected
to the reduction, optimum conditions gave 84:16 selectivity
(Table 1, entry 14). As anticipated, mesityl derivative 16c
gave a similar selectivity compared to 16b (with p-tosyl on
N), indicating that the aryl group on nitrogen has little effect
on the selectivity (Table 1, entry 15). It is important to note
that good to excellent yields were observed under all
conditions studied (except for entry 12).
On the basis of the above results it is clear that only 76%
ee of (R)-5 can be obtained using an N-tosyl-norephedrine-
based backbone 16a (Table 1, entry 5). It occurred to us
that we could rectify this shortcoming by tuning the amino
alcohol backbone of the sulfinate chiral imine. Therefore,
we began our investigation with preparation of various
oxathiazolidines-2-oxide. The advantage of our system is that
a variety of structurally diverse amino alcohols can be easily
accessed using readily available amino acids. Therefore, a
range of amino alcohols were prepared from inexpensive
amino acids and then were conveniently converted to
oxathiazolidines-2-oxides 13d-g (Table 2) in good yield
with excellent selectivity.7 Treatment of imine 15 with
oxathiazolidines 13d-g provided corresponding sulfinate
ketimine derivatives 16d-g. Purification using silica gel
chromatography provided analytically pure sulfinate ketimines
in good yields.8 With these diversified chiral sulfinyl
ketimines in hand, we next examined the stereoselective
reduction process, using the optimal conditions for 16a. Thus,
the series of sulfinate ketimines 16d-g were subjected to
NaBH4 reduction in the presence of Ti(OiPr)4, and the results
are listed in Table 2. Interestingly, switching the phenyl and
methyl group of the oxathiazolidine oxide framework (16a
Figure 1.
Table 1. Diastereoselective reduction of sulfinate imines
16a-c
entry imine 16
reaction conditions
(R)/(S)a % yield b
1
2
16a
16a
NaBH4/THF, -45 °C
NaBH4/THF/Ti(OEt)4
-45 to -20 °C
80:20
82:18
97
93
3
4
5
6
7
8
16a
16a
16a
16a
16a
16g
NaBH4/EtOH/Ti(OEt)4
-45 to -20 °C
72:28
83:17
88:12
82:18
77:13
51:49
95
78
95
95
95
95
NaBH4/MTBE/Ti(OEt)4
20 °C
NaBH4/THF/Ti(OiPr)4
-45 to -10 °C
NaBH4/THF/Zr(OEt)4
-45 to -10 °C
NaBH4/THF/ZnCl2
-45 to -20 °C
LiBH4/THF
-78 to -30 °C
9
10
11
16a
16a
16a
BH3/THF -78 to -10 °C 32:68
75c
80
96
9-BBN/THF, 0 °C
catechoborane/THF
-45 to -20 °C
84:16
49:51
12
13
14
15
16a
16a
16b
16c
L-Selectride/THF
-78 to -20 °C
40:60
79:21
84:16
81:19
<5
75
90
95
DIBAL-H/THF/ZnCl2
-45 to 0 °C
NaBH4/THF/Ti(OiPr)4
-45 to -10 °C
NaBH4/THF/Ti(OiPr)4
-45 to -10 °C
a Ratio was determined by chiral HPLC analysis. b Yield is determined on
HPLC based on A%. c Isolation yield.
eomeric ratio with 97% yield of 17a. The stereoselectivity
was determined using chiral HPLC analysis of 5 obtained
after acidic hydrolysis of 17a. We were pleased to find that
use of the norephedrine-derived sulfinate ketimine not only
provides reasonable selectivity with simple reducing agents
such as NaBH4 but also can be readily hydrolyzed to provide
the desired chiral amine 5 with complete recovery of
N-sulfonyl-norephedrine.4b Amine 5 can be converted to (R)-
(4) (a) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake, C.
H. J. Am. Chem. Soc. 2002, 124, 7880. (b) See Experimental Section for
details on recovery of the auxiliary. (c) Han, Z.; Krishnamurthy, D.; Grover,
P.; Wilkinson, H. C.; Fang, Q. K.; Su, X.; Lu, Z.; Magiera, D.; Senanayake,
C. H. Angew. Chem., Int. Ed. 2003, 42, 2032.
(6) See ref 2 for the determination of the stereochemistry of 5.
(7) The Experimental Section gives the detail for the preparations of amino
alcohols and oxathiazolidines. The absolute stereochemistry of 13e was
unambiguously established by single-crystal X-ray analysis.
(8) See Experimental Section for details for the preparation 16d-g. Only one
diastereomer was observed for chiral sulfinate ketimines based on 1H NMR
analysis.
(5) (a) Kagan, H. B.; Rebiere, F. Synlett. 1990, 643. (b) Wudl, F.; Lee, T. B.
K. J. Am. Chem. Soc. 1973, 95, 6349.
Vol. 10, No. 2, 2006 / Organic Process Research & Development
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329

Table 2: Structures of oxathiazolidines (13d-g) and the
results for diastereoselective reduction of their
corresponding chiral sulfinate ketimines (16d-g) with
NaBH4/Ti(OiPr)4 for the synthesis of (R)-5
unless otherwise noted, were carried out in oven-dried
glassware under inert argon atmosphere. Chromatography
was carried out using Silicycle 60, 230-400 mesh silica gel.
Thin-layer chromatography (TLC) analysis was performed
with Merck Kieselgel 60 F 254 plates, and visualized using
1
UV light and/or phosphomolybdic staining. H NMR and
proton-decoupled 13C NMR spectra were obtained with a
Varian Inova 300 spectrometer in CDCl3 with TMS as an
internal standard at room temperature. Proton and carbon
spectra chemical shifts were reported using TMS and/or
CDCl3 as an internal standard at 0 and at 77.23 ppm,
1
respectively. Diastereomeric ratios were determined on H
NMR spectrum analyses. Elemental analysis was performed
by Quantitative Technologies, Inc. Whitehouse, NJ. Enan-
tiomeric excess (ee) of 5 was obtained by chiral HPLC
analysis on Ultron ES-OVM column, 50 mm × 4.6 mm;
mobile phase, 0.01 M KHPO4/MeOH (70/30); flow rate, 1.0
mL/min; wavelength, 220 nm; (R)-5, rt ) 4.6 min, (S)-5, rt
) 5.6 min).
entry
16
% yield for 5
% ee for 5
1
2
3
4
16d
16e
16f
16g
95
91
95
90
50
90
76
86
1-[1-(4-Chloro-phenyl)cyclobutyl]-3-methyl-butan-1-
one (6). To a round-bottomed flask containing a magnetic
stirring bar and a distillation condenser were charged 1-(4-
chloro-phenyl)cyclobutanecarbonitrile 1 (10.0 g, 95%, 49.7
mmol), toluene (30 mL), and isobutylmagnesium chloride
(30 mL, 2.0 M in THF). The mixture was distilled until the
internal temperature reached >105 °C and was refluxed for
3 h. The mixture was cooled to 0 °C, and HCl/MeOH (4 M
prepared by dilution of concentrated aqueous HCl with
MeOH) was added slowly to pH < 1. After the mixture was
stirred at ambient temperature for 2 h, saturated aqueous
sodium bicarbonate was added slowly to the mixture to pH
≈ 7. The aqueous phase was separated from the organic
phase and extracted with EtOAc (50 mL). The combined
organic phases were evaporated to dryness, and the residue
was purified by flash chromatography eluting with EtOAc/
vs 16d) provided a decreased selectivity (75:25). We were
pleased to find that introducing a gem dimethyl group next
to the hydroxyl functionality (16e) increased the selectivity
from 75:25 to 95:5. Hoping to further increase the diaste-
reoselectivity, we used gem diethyl (16f) derivative which
provided only an 88:12 ratio of diastereomers. Replacement
of the phenyl group in 16e with isobutyl (16g) slightly
decreased the selectivity (93:7). In conclusion, using imine
16e in the diastereoselective reduction process, (R)-5 (precur-
sor to (R)-sibutramine),2a can be obtained in an excellent yield
with 90% ee. To the reaction mixture, D-tartaric acid (D-
TA) was added to form a (R)-5. D-TA salt. The salt was
collected by filtration to yield the desired intermediate in
>85% overall yield with >99% ee. This synthetic sequence
has been consistently demonstrated in a telescoped process
starting from nitrile 1 and 13e.9
1
hexane (3:7) to afford 6 (10.5 g) in 80% yield. H NMR
In summary, a practical asymmetric synthesis of (R)-
sibutramine intermediate with excellent enantiopurity was
developed by using a novel diastereoselective sulfinate
ketimine reduction strategy. The sulfinate ketimine can be
easily prepared by reaction of an imine nucleophile with an
oxathiazolidine-2-oxide. These oxathiazolidine-2-oxides are
readily reformed and recycled after treatment of recovered
N-tosyl amino alcohol with thionyl chloride. Furthermore,
it has been demonstrated that the structural backbone of these
auxiliaries could be readily altered by simply varying the
starting amino alcohol derivatives. Hence, these enantiopure
oxathiazolidine-2-oxides can be used to tune the diastereo-
selective reduction process of chiral sulfinate ketimines in
the production of valuable optically active amines.
(CDCl3): δ 0.66 (d, J ) 8.27 Hz, 6H), 1.80-1.95 (m, 1H),
2.0-2.15 (m, 3H), 2.36-2.42 (m, 3H), 3.68-2.80 (m, 2H),
7.15-7.2 (m, 2H), 7.26-7.4 (m, 2H). 13C NMR (CDCl3):
δ 16.09, 22.46, 24.251, 30.61, 45.63, 58.86, 127.97, 128.88,
132.69, 141.75, 209.67.
(R)-2-Methyl-propane-2-sulfinic Acid {1-[1-(4-Chloro-
phenyl)cyclobutyl]-3-methyl-butylidene}amide (7).1 To a
round-bottomed flask contained a magnetic stirring bar were
charged 6 (4.9 g), THF (30 mL), (R)-tert-butanesulfinamide
(2.4 g), and titanium ethoxide (44 mL, 20% ethanol solution),
and the mixture was refluxed for 2 days. After cooling to
ambient temperature, the mixture was poured into a brine
solution (40 mL) and stirred. The mixture was filtered and
the wet cake washed with EtOAc (50 mL). The organic phase
was separated from the aqueous phase, washed with water
(10 mL), and evaporated to dryness. The residue was purified
by flash chromatography eluting with EtOAc/hexane (4:6)
to afford 7 (0.4 g) in 5.8% yield. 1H NMR (CDCl3): δ 0.61
(d, J ) 6.59, 3H), 0.80 (d, J ) 6.59, 3H), 1.33 (s, 9H), 1.78-
1.92 (m, 2H), 1.92-2.04 (m, 1H), 2.14-2.22 (m, 1H), 2.52-
2.34 (m, 2H), 2.68-2.80 (m, 2H), 2.80-2.92 (m, 1H), 7.15-
7.2 (m, 2H), 7.26-7.4 (m, 2H). 13C NMR (CDCl3): δ 15.99,
Experimental Section
General. Unless otherwise noted, all reagents were
obtained from commercial suppliers and were used without
further purification. Only anhydrous solvents were used for
the reaction and were purchased from Aldrich. All reactions,
(9) See Experimental Section for the one-pot procedure for the preparation 5
from 1 and 13e.
330
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Vol. 10, No. 2, 2006 / Organic Process Research & Development

22.52, 22.69, 23.00, 26.28, 32.53, 32.80, 40.97, 57.19, 57.92,
128.45, 128.73, 132.70, 142.73, 187.99. Anal. Calcd for
C19H28ClNOS: C, 64.47; H, 7.97; N, 3.96; S, 9.06. Found:
C, 64.54; H, 7.62, N, 3.87, S, 8.85.
(d, 5.0 Hz, 2H). 13C NMR (CDCl3): δ 17.43, 21.69, 65.26,
86.37, 127.82, 128.33, 128.54, 128.93, 129.47, 132.55,
136.03, 144.48. Anal. Calcd for C16H17NO4S2: C, 54.68; H,
4.88; N, 3.99. Found: C, 54.75; H, 4.76, N, 3.84.
1
N-Tosyl Amino Alcohol 14e. To a 1-L three-neck round-
bottom flask were added (R)-phenylglycine methyl ester HCl
salt (25 g, 0.12 mol), NaHCO3 (38 g), EtOAc (200 mL),
and THF (60 mL). After the mixture was stirred at room
temperature for 20 min, p-toluenesulfonyl chloride (22.2 g)
was added, and the mixture was stirred at room temperature
for 15 h. After the aqueous phase was removed, the organic
phase was washed with 20% NaCl aqueous solution (40 mL)
and 1.0 M HCl (20 mL) and then dried over Na2SO4.
Evaporation of the organic solvent gave 36 g (94%) of
13e: H NMR (CDCl3): δ 1.20 (s, 3H), 1.53 (s, 3H),
2.34 (s, 3H), 4.62 (s, 1H),7.02-7.22 (m, 7H), 7.42-7.48
(m, 2H). 13C NMR (CDCl3): δ 21.68, 26.04, 28.93, 71.60,
98.22, 127.84, 128.37, 128.61, 129.51, 133.12, 135.60,
144.58. Anal. Calcd for C17H19NO4S2: C, 55.87; H, 5.24;
N, 3.83; S, 17.55. Found: C, 56.02; H, 5.12; N, 3.80; S,
17.83.
1
tosylate. H NMR (CDCl3): δ 2.36 (s, 3H), 3.53 (s, 3H),
5.06 (d, J ) 8.3 Hz, 1H), 6.00 (d, 8.2 Hz, 1H), 7.15-7.26
(m, 7H), 7.63 (dd, J ) 1.8 Hz, 6.8 Hz, 2H). 13C NMR
(CDCl3): δ 21.6, 53.1, 59.5, 127.2, 127.3, 128.6, 128.9,
129.6, 135.4, 137.0, 144.4, 170.6
To the tosylate (7.2 g. 22.6 mmol) solution in THF (100
mL) under argon at 0 °C was slowly added MeMgBr (26.3
mL, 3.0 M in ether). After addition of the Grignard, the
reaction mixture was warmed to ambient temperature and
stirred for 4-6 h, and the reaction was monitored by TLC
analysis. The reaction was quenched by 30% aqueous NH4Ac
and diluted with EtOAc (300 mL). Evaporation of the organic
solvent gave a solid residue that was crystallized from
MTBE/heptane to afford 14e (6.0 g) in 83% yield and >99%
ee. 1H NMR (CDCl3): δ 1.03 (s, 3H), 1.33 (s, 3H), 2.28 (s,
3H), 4.16 (d, J ) 8.67 Hz, 1H), 5.80 (d, J ) 8.79 Hz, 1H),
6.95-7.18 (m. 7H), 7.43 (d, J ) 8.18 Hz, 2H). 13C NMR
(CDCl3): δ 21.6, 26.9, 27.8, 66.3, 73.1, 127.2, 127.5, 128.1,
129.2, 137.4, 137.6, 142.9.
1
13f: H NMR (CDCl3): δ 0.739 (t, J ) 7.40 Hz, 3H),
0.968 (t, J ) 7.42 Hz, 3H), 1.153 (h, J ) 7.33 Hz, 1H),
1.588 (h, J ) 7.30 Hz, 1H), 1.860 (dh, J1 ) 3.05, J2 ) 7.30
Hz, 2H), 2.310 (s, 3H), 4.806 (s, 1H), 6.98-7.22 (m, 7H),
7.40-7.46 (m, 2H). 13C NMR (CDCl3): δ 7.89, 8.34, 21.69,
28.64, 29.86, 68.61, 103.51, 127.78, 128.08, 128.35, 129.11,
129.42, 133.42, 135.90, 144.36. Anal. Calcd for
C19H23NO4S2: C, 57.99; H, 5.89; N, 3.56; S, 16.30. Found:
C, 58.10; H, 5.73; N, 3.43, S, 16.28.
14f and 14g were prepared by following the above
procedure.
1
13g: H NMR (CDCl3): δ 0.80 (d, J ) 6.59 Hz, 3H),
0.83 (d, J ) 6.47, 3H), 1.30 (s, 3H), 1.59 (s, 3H), 1.44-
1.70 (m, 3H), 2.46 (s, 3H), 3.60-3.66 (m, 1H), 7.36-7.42
(m, 2H), 7.81-7.87 (m, 2H). 13C NMR (CDCl3): δ 21.8,
22.2, 22.9, 24.6, 24.9, 28.7, 40.1, 65.0, 98.9, 127.7, 130.1,
136.5, 145.0. Anal. Calcd for C15H23NO4S2: C, 52.15; H,
6.71; N, 4.05; S, 18.56. Found: C, 52.10; H, 6.67; N, 3.92;
S, 18.43.
Imine 16a (Scheme 4). To a 150-mL three-necked flask
equipped with a magnetic stir bar, an argon inlet, a
thermometer probe, and rubber septum were charged 1 (8.0
14f: 1H NMR (CDCl3): δ 0.76 (t, J ) 7.33 Hz, 3H), 0.91
(t, J ) 7.33 Hz, 3H), 1.02 (h. J ) 7.33 Hz, 1H), 1.17 (h, J
) 7.33 Hz, 1H), 1.72 (h, J ) 7.33 Hz, 1H), 1.85 (h, J )
7.33 Hz, 1H), 2.27 (s, 3H), 4.29 (d, J ) 8.06 Hz, 1H), 5.62
(d, J ) 8.80 Hz, 1H), 6.92-7.11 (m, 7H), 7.35 (d, J ) 8.43
Hz, 2H). 13C NMR (CDCl3): δ 7.56, 8.12, 21.54, 27.32,
28.32, 62.30, 77.80, 127.01, 127.35, 128.18, 128.37, 129.13,
137.67, 137.90, 142.64.
1
14g: H NMR (CDCl3): δ 0.58 (d, J ) 6.00 Hz, 3H),
0.76 (d, J ) 6.10 Hz, 3H), 1.13 (s, 3H), 1.16 (s, 3H), 1.16-
1.36 (m, 3H), 2.42 (s, 3H), 2.51 (s, 3H), 3.13-3.28 (m, 1H),
4.99 (d, J ) 8.55 Hz, 1H), 7.27-7.33 (m, 2H), 7.77-7.83
(m, 2H). 13C NMR (CDCl3): δ 21.1, 21.7, 24.0, 24.5, 25.1,
27.6, 41.2, 61. 8, 72.8, 127.3, 129.8, 138.2, 143.6
The preparation of 14a-c was reported in the literature.
N-Tosyl-1,2,3-oxathiazolidine-2-oxide. A literature method
has been used for the preparation of N-tosyl-1,2,3-oxathia-
zolidine-2-oxides 13a-g with >90% yield and 99% de.2
13a-c. Analytical data for compound 13a-c were
reported in the literature.2
i
g, 41.9 mmol (96%)), toluene (70 mL), and BuMgCl (69
mL, 0.61 mol in MTBE), and the reaction mixture was
distilled until the internal temperature reached >100 °C. The
reaction mixture was stirred at that temperature, and the
reaction was monitored on HPLC for the disappearance of
1. After cooling to ambient temperature, the reaction mixture
was added dropwise to a solution of 13 (15.0 g, 42 mmol)
in THF (100 mL) at -78 °C. After 4 h the reaction mixture
was warmed 10 °C. After completion of the reaction, the
reaction mixture was cooled to 0 °C, and aqueous ammonium
acetate (30%, 50 mL) was added, followed by MTBE (200
mL); the mixture was then warmed to ambient temperature.
The organic phase was washed with 30% KHCO3 (50 mL)
and 20% NaCl (50 mL) and then dried over Na2SO4. After
1
13d: H NMR (CDCl3): δ 1.06 (d, J ) 6.35 Hz, 3H),
2.30 (s, 3H), 4.90 (d, J ) 6.53 Hz, 1H), 5.08 (p, J ) 6.0
Hz, 1H), 7.01 (d, J ) 8.0 Hz, 2H), 7.11-7.17 (m, 5H), 7.46
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evaporation of the organic solvent, the residue was purified
by flash chromatography using CH2Cl2/EtOAc (9.6:0.4) to
furnish 16a (3.4 g) in 95% yield. 1H NMR (CDCl3): δ 0.640
(d, J ) 6.0 Hz, 6H), 1.043 (d, J ) 6.6 Hz, 3H), 1.660 (b,
1H), 1.835-1.912 (m, 2H), 2.223-2.308 (m, 2H), 2.417 (s,
3H), 2.417-2.536 (m, 2H), 2.733-2.885 (m, 2H), 3.670-
3.748 (m, 1H), 5.5.562 (d, J ) 2.1 Hz, 1H), 5.905 (d, J )
9.0 Hz, 1H), 7.125-7.151 (m, 3H), 7.224-7.366 (m, 8H),
7.851 (d, J ) 8.4 Hz, 2H).
(m, 2H), 4.209 (d, J ) 9.52, 1H), 6.034 (d, J ) 9.52, 1H),
6.94-7.14 (m, 7H), 7.22-7.26 (m, 4H), 7.36-7.42 (m, 2H).
13C NMR (CDCl3): δ 15.92, 21.55, 22.0.70, 26.86, 26.98,
27.56, 32.06, 33.03, 42.59, 56.69, 66.07, 77.34, 85.43,
126.99, 127.64, 127.88, 128.43, 128.91, 129.10, 129.18,
133.04, 136.80, 137.88, 141.70, 142.73, 186.75. Anal. Calcd
for C32H39ClN2O4S2: C, 62.47; H, 6.39; N, 4.55; S, 10.42.
Found: C, 62.47; H, 6.25; H, 4.39; S, 10.12.
1
16f: H NMR (CDCl3: δ 0.62-0.78 (m, 9H), 1.07 (t, J
13C NMR (CDCl3): δ 15.19, 15.83, 21.61, 22.44, 22.56,
27.87, 32.67, 42.16, 54.27, 56.80, 77.79, 126.10, 127.28,
128.16, 128.45, 128.57, 128.87, 129.77, 133.05, 137.65,
138.24, 141.05, 143.41, 188.55. Anal. Calcd for C31H37Cl-
N2O4S2, C, 61.93; H, 6.20; N, 4.66; S, 10.67. Found: C,
61.68; H, 6.12; N, 4.47; S, 10.67.
The above method was used for the preparation of imines
16b-g in 90-95% yield. The analytical data for compounds
16b-g are given below.
) 7.32 Hz, 3H), 1.14-1.1.28 (m 1H), 1.33-1.47 (m, 1H),
1.72 (b, 1H), 1.78-1.90 (m, 2H), 2.02-2.16 (m, 2H), 2.18-
2.24 (m, 1H), 2.25 (s, 3H), 2.30-2.60 (m, 3H), 2.74-2.86
(m, 2H), 4.42 (d, J ) 10. 5 Hz, 1H), 6.49 (d, J ) 10. 26 Hz,
1H), 6.87-6.93 (m, 2H), 6.98-7.12 (m, 4H), 7.14-7.20 (m,
2H), 7.24 (s, 3H), 7.30-7.36 (m, 2H). 13C NMR (CDCl3):
δ 7.692, 8.849, 15.910, 21.518, 22.736, 25.669, 27.660,
27.923, 31.957, 33.054, 42.676, 56.814, 61.568, 92.458,
126.880, 127.337, 127.786, 128.434, 128.887, 129.021,
129.708, 133.047, 136.506, 138.210, 141.754, 142.369,
187.15. Anal. Calcd for C34H43ClN2O4S2: C, 63.48; H, 6.74;
N, 4.35; S, 9.97. Found: C, 63.10; H, 6.76; N, 4.04, S, 9.95.
16g: 1H NMR (CDCl3): δ 0.62-0.84 (m, 12H), 1.32-
1.52 (m, 3H), 1.42 (s, 3H), 1.51 (s, 3H), 1.64-1.74 (m, 1H),
1.80-1.90 (m, 2H), 2.16-2.30 (m, 2H), 2.32-2.40 (m, 2H),
2.41 (s, 3H), 2.74-2.88 (m, 2H), 3.30-3.44 (m, 1H), 5.16
(d, J ) 9.52 Hz, 1H), 7.24-7.34 (m, 6H), 7.73-7.78 (m,
2H). 13C NMR (CDCl3): δ 15.9, 21.5, 21.7, 22.7, 22.8, 24.0,
24.2, 26.5, 27.4, 27.7, 32.1, 32.9, 40.4, 42.5, 56.7, 60.7, 86.9,
126.8, 128.5, 128.9, 129.6, 133.0, 139.5, 141.7, 143.1, 186.5.
Anal. Calcd for C30H43ClN2O4S2: C, 60.53; H, 7.28; N, 4.71;
S, 10.77. Found: C, 60.16; H, 7.22; N, 4.45; S, 10.56.
16b: 1H NMR (CDCl3): δ 0.680 (t, J ) 6.59 Hz, 3H),
0.949-1.150 (m, 6H), 1.700 (s, 1H), 1.857-1.951 (m, 2H),
2.180-2.358 (m, 2H), 2.432 (s, 2H), 2.430-2.544 (m, 2H),
2.720-2.920 (m, 2H), 3.660-3.770 (m, 1H), 5.574 (d, J )
2.19 Hz, 1H), 5.886 (d, J ) 9.28 Hz, 1H), 7.099-7.130 (m,
2H), 7.256-7.362 (m, 8H), 7.851 (d, J ) 8.30 Hz, 2H).
13C NMR (CDCl3): δ 15.90, 21.75, 22.65, 22.75, 27.74,
32.18, 32.79, 39.02, 42.38, 56.80, 60.42, 76.26, 124.16,
125.24, 127.33, 127.40, 128.69, 128.96, 129.96, 133.03,
138.44, 138.89, 139.84, 143.68, 187.98.
1
16c: H NMR (CDCl3): δ 0.64-0.70 (m, 6H), 1.61 (m,
1H), 1.74-1.92 (m, 2H), 2.16-2.26 (m, 2H), 2.32 (s, 3H),
2.72 (s, 6H), 2.83-2.98 (m, 4H), 3.18 (dd, J1 ) 4.64 Hz, J2
) 16.965 Hz, 1H), 3.36 (d, J ) 16.84 Hz, 1H), 4.98 (dd, J1
) 4.85 Hz, J2 ) 9.27 Hz, 1H), 5.40 (d, J ) 9.03 Hz, 1H),
5.87 (m, 1H), 6.84 (d, J ) 7.45 Hz, 1H), 6.99 (s, 2H), 7.10-
7.15 (m, 1H), 7.18-7.23 (m, 2H), 7.31-7.41 (m, 4H). 13C
NMR (CDCl3): δ 15.89, 21.14, 22.62, 23.33, 27.63, 32.00,
32.86, 39.10, 42.41, 56.95, 60.42, 76.34, 124.13, 125.27,
127.44, 128.70, 128.94, 132.22, 132.99, 135.18, 138.96,
139.13, 140.13, 141.68, 142.44, 187.86. Anal. Calcd for
C33H39ClN2O4S2: C, 63.19; H, 6.27; N, 4.47; S, 10.22.
Found: C, 63.17; H, 6.21; N, 4.32; S, 9.86.
Typical Procedure for Reduction of 16a to 5 Using
NaBH4 in the Presence of Titanium Isopropoxide. To a
two-necked round-bottomed flask containing a magnetic
stirring bar, a temperature probe, and an argon inlet were
charged imine 16a (0.1 g, 0.167 mmol, 1.0 equiv), THF (3
mL), and Ti(OiPr)4 (0.076 g, 2.0 equiv), and the mixture was
stirred at ambient temperature for 1 h. The mixture was then
cooled to -45 °C, and NaBH4 (0.025 g, 4.0 equiv) was
added. After stirring for 3 h, the reaction mixture was
warmed slowly to -10 to -15 °C and stirred. The reaction
was monitored by TLC analysis. HCl/MeOH (4.0 mL, 4 M)
was added slowly to quench the reaction, and the resulting
mixture was stirred at rt for 3 h. The mixture was cooled to
0 °C, and NaOH (5.0 M) was added to a pH > 10 and diluted
with EtOAc (20 mL). The organic phase was washed with
brine (5 mL) and evaporated to dryness. The residue was
then purified by flash chromatography, eluting with EtOAc/
hexane/Et3N (80:20:0.1) to afford 14a (50 mg, 98%) and 5
(40 mg) in 95% yield and 76% ee.
1
16d: H NMR (CDCl3): δ 0.67-0.76 (m, 6H), 1.12 (d,
J ) 6.60 Hz, 3H), 1.60-1.80 (m, 1H), 1.80-1.95 (m, 2H),
2.24-2.40 (m, 2H), 2.34 (s, 3H), 2.40-2.60 (m, 2H), 2.75-
2.82 (m, 2H), 2.90-3.00 (m, 1H), 4.53 (b, 1H), 5.32 (d, J
) 4.00 Hz, 1H), 6.15 (d, J ) 6.96 Hz, 1H), 7.00-7.20 (m,
7H), 7.30-7.40 (m, 4H), 7.45-7.50 (m, 2H). 13C NMR
(CDCl3): δ 16.10, 19.59, 21.26, 22.50, 27.88, 30.64, 32.67,
34.88, 42.31, 45.67, 61.24, 72.39, 127.22, 127.90, 128.00,
128.13, 128.73, 128.80, 128.91, 129.10, 129.31, 129.37,
133.26, 135.93, 137.95, 143.05, 188.78. Anal. Calcd for
C31H37ClN2O4S2: C, 61.93; H, 6.20; N, 4.66. Found: C,
61.93; H, 6.15; N, 4.43.
The above procedure is also used for the reduction of
imines 16b-g.
Typical Procedure for Reduction of Imines 16 with
Other Reducing Reagents without a Lewis Acid. To a two-
necked round-bottomed flask containing a magnetic stirring
bar and temperature probe with an argon inlet was charged
the imine (1.0 equiv). After cooling the mixture to the
16e: 1H NMR (CDCl3): δ 0.586 (d, J ) 6.4 Hz, 3H),
0.637 (d, J ) 6.4 Hz, 3H), 1.174 (s, 3H), 1.644 (m, 1H),
1.802 (s, 3H), 1.78-1.85 (m, 2H), 2.08-2.20 9m, 2H), 2.280
(s, 3H), 2.32-2.39 (m, 1H), 2.40-2.50 (m, 1H), 2.74-2.88
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reaction temperature, reducing reagent (1.5 equiv) was added
dropwise with stirring, and the reaction was monitored on
TLC. The reaction was then worked up by following the
above procedure.
material. To the reaction mixture was slowly added aqueous
HCl dissolved in MeOH (60 mL, 4 M), and the mixture was
warmed to ambient temperature and stirred for 3 h. After
the mixture was cooled to 0 °C, NaOH (5 M) was added
slowly until the pH ≈ 12; the mixture was diluted with
toluene (200 mL) and distilled under reduced pressure to
remove the low boiling point solvents. The organic phase
was allowed to separate for 20 min, and the organic phase
was washed twice with aqueous NaCl (50 mL, 20%). The
mixture was heated to 60-70 °C, and D-tartaric acid (6.3 g)
in water (13 mL) and acetone (6 mL) were added slowly.
The mixture was distilled under azeotropic conditions until
the internal temperature reached >95 °C. The mixture was
then cooled to ambient temperature and stirred for 1 h. The
slurry formed was filtered, and the wet cake was washed
with toluene (30 mL × 2) and MTBE (30 mL) and dried at
45 °C for 24 h under reduced pressure to afford 14.6 g of
(R)-5‚D-TA (86%) with 99% ee.
The mother liquor was concentrated under reduced
pressure, and EtOAc (100 mL) was added. The organic phase
was washed with saturated aqueous NaHCO3 (30 mL × 2),
brine (30 mL), and water (20 mL). The resulting mixture
was distilled, heptane was added (100 mL), and the mixture
was then cooled to room temperature and stirred for 2 h.
The slurry was filtered to afford 14e (12.5 g) in 92%
yield.
One-Pot Procedure for the Preparation of (R)-5‚D-TA.
To a 250-mL three-necked flask equipped with a magnetic
stir bar, an argon inlet, a thermometer probe, and rubber
septum were charged toluene (80 mL), 1 (8.0 g, 41.9 mmol),
and iBuMgCl (68.5 mL, 0.61 mol in MTBE) under an argon
atmosphere, and the reaction mixture was distilled until the
temperature reached >100 °C. The reaction mixture was
stirred at that temperature and monitored by HPLC for the
disappearance of 1. The reaction mixture was cooled to
ambient temperature and added dropwise to the solution of
13e (15.5 g, 42.4 mmol) in THF (100 mL) in a 500-mL
round-bottomed flask at -45 °C. The reaction mixture was
stirred for 4 h and warmed to 10 °C under stirring. The
reaction was monitored by TLC analysis. The reaction
mixture was cooled to 0 °C, aqueous ammonium acetate
(30%, 50 mL) was added, followed by MTBE (200 mL),
and the mixture was warmed to ambient temperature. The
organic phase was washed with 30% KHCO3 (50 mL) and
20% NaCl (50 mL) and was polish filtered. After the
resulting organic phase was distilled under reduced pressure
to about 50 mL (KF ) 0.58%), anhydrous THF (80 mL)
and Ti(O-i-Pr)4 were added, and the mixture was stirred at
ambient temperature for 1 h and cooled to -45 °C. NaBH4
(6.4 g, 168 mmol) was added in one portion, and the mixture
was stirred for 6 h and warmed to -10 °C, and the reaction
was monitored on TLC for the disappearance of starting
Received for review September 29, 2005.
OP050182N
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