Catalytic asymmetric synthesis of tert-butanesulfinamide. Application to the asymmetric synthesis of amines

Full text of DOI:10.1021/ja972012z

J. Am. Chem. Soc. 1997, 119, 9913-9914
9913
Table 1. Optimization of Catalytic Asymmetric Oxidation of
Catalytic Asymmetric Synthesis of
tert-Butanesulfinamide. Application to the
Asymmetric Synthesis of Amines
tert-Butyl Disulfide (Eq 1)a
ligand
entry
R1
R2
R3
conversion (%)b
ee (%)c
Guangcheng Liu, Derek A. Cogan, and Jonathan A. Ellman*
1
2
3
4
5
6
7
8
9
t-Bu
t-Bu
t-Bu
t-Bu
H
OMe
NO2
Br
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
NO2
OMe
H
H
H
Br
Br
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
i-Pr
Bn
94
18
85
88
50
17
15
23
16
69
47
98
82
45
79
83
46
>10
>10
50
45
53
Department of Chemistry, UniVersity of California
Berkeley, California 94720
ReceiVed June 18, 1997
Greater than 75% of drugs and drug candidates incorporate
amine functionality.1 Nonetheless, the asymmetric synthesis of
amines,2 excluding R-amino acids, is much less developed than
the asymmetric synthesis of other common functional groups.
p-Toluenesulfinamide and the corresponding sulfinimines have
become the focus of increasing attention for the asymmetric
synthesis of aziridines, R- and â-amino acids, and, in very
limited studies, R-branched amines.3,4 Davis, who pioneered
efforts on the study of p-toluenesulfinimines, demonstrated that
the sulfinyl group serves as an ideal auxiliary because it activates
the imine for nucleophilic addition, provides diastereofacial
selectivity, and is easy to remove simply by treatment with mild
acid. In our own efforts to develop N-acylsulfinamides for
diastereoselective enolate alkylation chemistry,5 we found tert-
butanesulfinamide to be superior to p-toluenesulfinamide due
to the lower molecular weight, enhanced diastereofacial selec-
tivity,6 and enhanced nucleophilicity of the amine functionality.
Unfortunately, expedient methods have not been reported for
the preparation of optically pure tert-butanesulfinamide.6 Herein
we report a highly practical two-step procedure to prepare large
quantities of optically pure tert-butanesulfinamide with the key
step being the catalytic asymmetric oxidation of tert-butyl
disulfide, which serves as an extremely inexpensive starting
material (<2 cents/g). We further describe the utility of tert-
butanesulfinamide for the general and expedient asymmetric
synthesis of R-branched amines.
10
11
12
Ph
t-Bu
25
91d
a All reactions were performed at room temperature and unless
otherwise noted in CH2Cl2 with 2% VO(acac)2 and 3% ligand.
b Conversions determined by GC analysis with tridecane as an internal
standard. c Enantioselectivity determined by chiral HPLC analysis.
d Reaction performed in CHCl3 with 1% VO(acac)2 and 1.1% ligand.
and sulfoxide products, respectively. The most expedient
method for the preparation of the thiosulfinate would be catalytic
asymmetric oxidation of tert-butyl disulfide, although previous
oxidative approaches toward optically pure thiosulfinates have
resulted in disappointing selectivities.9 We considered a number
of different oxidation catalysts but were most attracted to a
recent report by Bolm on the asymmetric oxidation of thio-
ethers.10 The vanadium catalysts employed are highly catalytic
(as little as 0.01% catalyst) and are compatible with the
inexpensive stoichiometric oxidant hydrogen peroxide. The
only detraction was the generally modest reported enantiose-
lectivities (53-70% for thioethers and 85% ee for 2-phenyl-
1,3-dithiane).
We envisaged that tert-butanesulfinamide could be derived
from a tert-butyl tert-butanethiosulfinate intermediate (1, eq 1).
The chemistry of scalemic thiosulfinates has not been explored
extensively, but limited precedent did indicate that addition of
metal amides7 and carbanion8 nucleophiles to enantioenriched
thiosulfinates occurs stereospecifically to provide sulfinamide
We first explored a number of different ligands at 2% catalyst
loading using the general reaction conditions reported by Bolm,
room temperature with CH2Cl2 as the solvent. Data for selected
ligands are provided in Table 1. Steric effects at the 5-position
of the aryl ring are not important, but electronic effects play a
critical role in both catalyst turnover and selectivity (entries 1-4,
Table 1). Both electronic and steric factors were found to be
important for substituents at the 3-position of the aryl ring
(entries 5-8). Finally, steric effects play an important role at
R3, with the tert-butyl group providing significantly higher
selectivity than other substituents. On the basis of these studies,
the optimal ligand is prepared by condensation of 3,5-di-tert-
butylsalicylaldehyde with tert-leucinol, both of which are
commercially available (entries 1 and 12, Table 1).
Solvent was also found to have a dramatic effect upon catalyst
selectivity. In particular, while 1,2-dichloroethane provides
comparable selectivities to CH2Cl2 (82% ee), CHCl3 provides
much higher enantioselectivity (91% ee). The reaction did not
proceed in CCl4 due to the poor solubility of the catalyst. Other
solvents including acetonitrile, toluene, nitromethane, tert-butyl
alcohol, and THF resulted in much poorer selectivities. Em-
ploying the optimized conditions, the reaction has been per-
formed reproducibly on half mole scale at 1.5 M concentrations
with 1% catalyst to provide a 96-98% yield of pure product in
(1) MDL Drug Data Report, MDL Information Systems, Inc., San
Leandro, CA.
(2) For reviews, see: (a) Johansson, A. Contemp. Org. Synth. 1995, 2,
393-407. (b) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8,
1895-1946. For leading reports, see: (c) Uematsu, N.; Fujii, A.; Hashiguchi,
S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916-4917. (d)
Verdaguer, X.; Lange, U. E. W.; Reding, M. T.; Buchwald, S. L. J. Am.
Chem. Soc. 1996, 118, 6784-6785.
(3) For a recent comprehensive compilation of research in this area,
see: 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, 2555-2563.
(4) Annunziata, R.; Cinquini, M.; Cozzi, F. J. Chem. Soc, Perkin Trans.
1 1982, 339-343.
(5) Backes, B. A.; Ellman, J. A. 213th American Chemical Society
National Meeting, San Francisco, CA, April 1997; ORGN 066.
(6) tert-Butanesulfinimines have also been observed to provide enhanced
diastereoselectivity relative to p-toluenesulfinimines in aziridine synthesis.
Ruano, J. L. G.; Ferna´ndez, I.; Catalina, M. P.; Cruz, A. A. Tetrahedron:
Asymmetry 1996, 7, 3407-3414.
(7) Mikolajczyk, M.; Drabowicz, J. J. Chem. Soc., Chem. Commun. 1976,
220-221.
(8) Sagramora, L.; Koch, P.; Garbesi, A.; Fava, A. J. Chem. Soc., Chem.
Commun. 1967, 985-986.
(9) (a) Davis, F. A.; Jenkins, R. H.; Awad, S. B.; Stringer, O. D.; Watson,
W. H.; Galloy, J. J. Am. Chem. Soc. 1982, 104, 5412-5418. (b) Nemecek,
C.; Dun˜ach, E.; Kagan, H. B. New J. Chem. 1986, 10, 761-764.
(10) Bolm, C.; Bienewald, F. Angew. Chem., Int. Ed. Engl. 1995, 34,
2640-2642.
(11) The tert-butanesulfinamide has been stored over 6 months at room
temperature without decomposition or loss of optical purity.
S0002-7863(97)02012-X CCC: $14.00 © 1997 American Chemical Society

9914 J. Am. Chem. Soc., Vol. 119, No. 41, 1997
Communications to the Editor
Table 2. Asymmetric Synthesis of R-Branched Amines (Eq 4)a
91% ee, after bulb-to-bulb distillation. We have increased the
reaction concentration to 2 M and have decreased the catalyst
loading to 0.5% with little loss in conversion or enantioselec-
tivity and suspect that further reductions in catalyst loading are
possible.
Addition of lithium amide in ammonia to thiosulfinate 1
provides tert-butanesulfinamide 2 (eq 2). This transformation
has been performed on half mole scale, and a single crystal-
lization provides optically pure tert-butanesulfinamide 2 in 75%
overall yield from tert-butyl disulfide.11 It is important that
sulfinamide 4
amine 5
entry R1
R2 yield (%)b dr (%)c yield (%)b configuration
1
2
3
4
5
6
7
8
9
Et
Et
Et
Me
i-Pr
Ph
96
97
100
99
100
98
96
93:07
92:08
96:04
98:02
97:03
89:11
97:03
92:08
97:03
97
92
90
97
S
R
R
S
S
R
S
S
S
i-Pr Me
i-Pr Et
i-Pr Ph
Ph
Ph
Ph
93 (85)d
91 (76)d
88
Me
Et
i-Pr
98
29
94
a All reactions were performed with CH2Cl2 as solvent and the
magnesium bromide derivative as 3 M in Et2O. b Yields are determined
by mass balance of analytically pure material. c Diastereoselectivity (dr
) diastereomer ratio) is determined by preparation of the Mosher
amides from the crude amine product after treatment of the sulfinamide
4 with HCl in MeOH. d Yield of optically pure material after a single
crystallization.
ammonia be used as solvent in the lithium amide addition step,
since the poor solubility of lithium amide in other solvents
results in extensive racemization. Carbanion nucleophiles also
add to thiosulfinate 1 in high yields and stereospecifically, with
inversion, as demonstrated by the addition of methyl Grignard
(91% yield). Because tert-butyl tert-butanethiosulfinate can be
crystallized to optical purity, tert-butyl disulfide oxidation and
Grignard addition also provide an extremely practical two-step
preparation of tert-butyl sulfoxides, which have advantages over
the commonly used p-tolyl sulfoxides for some applications.12
The straightforward preparation of tert-butanesulfinimines 3
(eq 3) from tert-butanesulfinamide is central to the preparation
of chiral amines. Direct condensation of tert-butanesulfinamide
with aldehydes in the presence of MgSO4 provides tert-
butanesulfinimines 3 in high yield. No racemization is observed
proceeds from the same face with high diastereoselectivity as
determined by GC analysis of the Mosher amides, which are
prepared upon removal of the tert-butanesulfinyl group (vide
infra). The addition reactions are exceptionally clean, often
providing analytically pure material after extractive workup, and
proceed in near quantitative yields with the exception of the
addition of isopropyl Grignard to the sulfinimine of benzalde-
hyde. Only for this reaction does reduction compete with
Grignard addition (entry 9, Table 2). The highest diastereose-
lectivities are observed when CH2Cl2 is used as the solvent.
Final isolation of the amine is extremely straightforward and
proceeds in high yield by treatment of the sulfinamide with HCl
in methanol, followed by precipitation of the amine hydrochlo-
ride with ether. As demonstrated for entries 5 and 6 (Table 2),
recrystallization readily provides the optically pure amine
hydrochlorides.
A highly practical and efficient two-step synthesis of optically
pure tert-butanesulfinamide in 75% overall yield is described.
The key step is asymmetric catalytic oxidation of tert-butyl
disulfide to provide tert-butyl tert-butanethiosulfinate. The
direct preparation of tert-butanesulfinimines is also described,
and a general and expedient synthesis of scalemic R-branched
amines from these intermediates is demonstrated. Further
applications of tert-butanesulfinimines, tert-butanesulfinamide,
and the tert-butyl tert-butanethiosulfinate intermediate are under
investigation.
in the condensation step as determined by chiral HPLC analysis.
In contrast to tert-butanesulfinamide, p-toluenesulfinamide is a
poorer nucleophile and does not cleanly condense with alde-
hydes.3 The sulfinimines are instead prepared by addition of
lithium bis(trimethylsilyl)amide to optically pure p-toluene-
sulfinate esters followed by treatment with CsF and aldehyde,
or by reaction of the p-toluenesulfinate esters with imine anions
prepared by DIBAL reduction of the corresponding nitrile
followed by addition of methyllithium. Both routes proceed in
modest yields, particularly for the preparation of sulfinimines
from aliphatic aldehydes, and require the separation of the chiral
alcohol byproduct.
The utility of tert-butanesulfinimines was demonstrated by
the preparation of R-branched amines 5 (eq 4, Table 2).13 In
all cases addition of Grignard reagents to the sulfinimines
Acknowledgment. This research was supported by the NSF. G.L.
thanks Pharmacia & Upjohn for a graduate fellowship. Important
contributions by Bradley J. Backes and Kyungjin Kim are also gratefully
acknowledged.
(12) Casey, M.; Manage, A. C.; Gairns, R. S. Tetrahedron Lett. 1989,
30, 6919-6922 and references therein.
(13) To our knowledge, the only study reporting Grignard additions to
p-toluenesulfinimines prepared from aldehydes explores the addition of
benzyl Grignard reagents to sulfinimines of aryl aldehydes (60-74% de).
Addition of the more basic MeMgBr occurred exclusively at sulfur. Moreau,
P.; Essiz, M; Merour, J.-Y.; Bouzard, D. Tetrahedron: Asymmetry 1997,
8, 591-598.
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