Addition of Bu3SnLi to tert-Butanesulfinimines as an Efficient Route to Chiral, Nonracemic α-Aminoorganostannanes

Article abstract of DOI:10.1021/ol035702i

(Equation presented) Addition of Bu₃SnLi to tert- butanesulfinimines proceeds with high diastereoselectivities to provide the expected adducts in excellent yields and typically with dr = >99:1. These adducts are readily converted to enantiomeri

Full text of DOI:10.1021/ol035702i

ORGANIC
LETTERS
2
003
Vol. 5, No. 22
215-4218
Addition of Bu SnLi to
3
4
tert-Butanesulfinimines as an Efficient
Route to Chiral, Nonracemic
r-Aminoorganostannanes
Kevin W. Kells and J. Michael Chong*
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry (GWC)2,
Department of Chemistry, UniVersity of Waterloo, Waterloo,
Ontario, Canada N2L 3G1
jmchong@uwaterloo.ca
Received September 5, 2003
ABSTRACT
3
Addition of Bu SnLi to tert-butanesulfinimines proceeds with high diastereoselectivities to provide the expected adducts in excellent yields
and typically with dr ) >99:1. These adducts are readily converted to enantiomerically enriched N-Boc-protected r-aminoorganostannanes
with complete retention of configuration.
R-Aminoorganostannanes have emerged as useful reagents
for organic synthesis, particularly as precursors of R-ami-
noorganolithiums. Access to enantiomerically pure R-ami-
Imidoylstannanes (1) have been described in the literature,
and their reduction to racemic R-aminoorganostannanes is
known. However, no asymmetric reductions have been
1
8
noorganostannanes has thus far been limited to resolutions
reported, and we have found that diastereoselective reduc-
tions of chiral imidoylstannanes (1, R* ) 1-phenylethyl or
1-naphthylethyl) proceeded with only modest selectivity
(up to dr ) 81:19). Furthermore, we were unable to
2
of diastereomeric derivatives, enantioselective deprotonation/
3
4
5
stannylation in select (cyclic and allylic /benzylic ) cases,
6
,7
or via enantiomerically enriched R-hydroxystannanes.
9
Routes from R-hydroxystannanes typically involve multiple
efficiently remove the chiral auxiliary from adducts 3. Also,
steps, which detracts from their synthetic appeal.
we were unable to find conditions to effect the addition of
tributylstannylmetallics to simple imines such as 2 (R* )
alkyl).
In principle, facile entry to enantiomerically pure R-amino-
organostannanes might be realized by asymmetric reduction
of imidoylstannanes or by asymmetric addition of a stan-
nylmetallic reagent to an imine derivative (Scheme 1).
Scheme 1
(
1) (a) Gra n˜ a, P.; Paleo, M. R.; Sardina, F. J. J. Am. Chem. Soc. 2002,
1
2
6
24, 12511-12514. (b) Haeffner, F.; Brandt, P.; Gawley, R. E. Org. Lett.
002, 4, 2101-2104. (c) Iula, D. M.; Gawley, R. E. J. Org. Chem. 2000,
5, 6196-6201 and references therein.
(
2) Ncube, A.; Park, S. B.; Chong, J. M. J. Org. Chem. 2002, 67, 3625-
3
636.
(
3) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994,
1
16, 3231-3239.
(4) Pippel, D. J.; Weisenburger, G. A.; Faibish, N. C.; Beak, P. J. Am.
Chem. Soc. 2001, 123, 4919-4927.
(
(
5) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. 1997, 36, 2282-2316.
6) Chong, J. M.; Park, S. B. J. Org. Chem. 1992, 57, 2220-2222.
1
0.1021/ol035702i CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/09/2003

Recently, Ellman has shown that various organometallic
reagents may be added to tert-butanesulfinimines with high
diastereoselectivities.10 Subsequent acidic cleavage of the
tert-butanesulfinyl group affords amines with good enantio-
meric purity. This chemistry has been extended for the
3
reasoned that perhaps addition of Bu SnLi to 4e occurs at
-78 °C, but at higher temperatures the initial adduct is
unstable and decomposes to form the products observed. We
were very satisfied to observe that when Bu
were admixed at -78 °C and the reaction was quenched
(MeOH then aqueous NH Cl) at -78 °C, adduct 5e could
be isolated in good yield and, very significantly, as a single
3
SnLi and 4e
11
12
preparation of 1,2- and 1,3-amino alcohols, R-amino
acids,13 and R-trifluoromethylamines.14 Recent advances in
the enantioselective preparation of tert-butanesulfinamide
will undoubtedly stimulate more applications of this chiral
4
1
13
diastereomer by H and C NMR spectroscopy (Scheme 2).
1
5,16
auxiliary.
All of the additions to tert-butanesulfinimines
thus far have been limited to carbon-based nucleophiles.
Phosphorus-based nucleophiles have been added to other
chiral sulfinimines,1 but additions of heteroatom nucleo-
philes such as tributylstannylmetallics to tert-butanesulfin-
imines appear to be unknown. We now report that such
additions are possible and, in fact, can serve as the basis for
a short and reliable entry to enantiomerically pure R-ami-
noorganostannanes.
Scheme 2
7,18
We anticipated that tert-butanesulfinimines, due to the
electron-withdrawing sulfinyl moiety, would be more reactive
than simple imines such as 2 toward stannylmetallics.
As an additional bonus, stannylsulfinamide 5e proved to be
quite stable, surviving chromatography on silica gel and
storage under ambient conditions for months.
To verify the high diastereoselectivity, adduct 5e was
benzoylated and then treated with HCl/MeOH to provide
benzamide 6e (Scheme 3). HPLC analysis of this benzamide
3
However, initial results for the addition of Bu SnLi to
aldimine 4e under conditions similar to those previously
reported for additions of Grignard reagents (-78 °C then
warmed to 0 °C) to such imines were disappointing.
Considerable amounts of Bu
desired adduct were isolated along with byproducts not
containing a Bu Sn group. While Bu SnLi has been added
3
SnH and only traces of the
3
3
Scheme 3
to CdO functionalities (as a now routine method of preparing
R-hydroxystannanes),19 there have been no reports of suc-
cessful additions to CdN groups. With aldehydes and
ketones, additions of Bu SnLi are very rapid at -78 °C and
3
reactions must be quenched at low temperatures to realize
high yields. Also, the product R-hydroxystannanes are
thermally unstable and must be handled carefully. We
(7) Kells, K. W.; Nielsen, N. H.; Armstrong-Chong, R. J.; Chong, J. M.
Tetrahedron 2002, 58, 10287-10291.
(
8) (a) Ahlbrecht, H.; Baumann, V. Synthesis 1993, 981-984. (b)
Ahlbrecht, H.; Baumann, V. Synthesis 1994, 770-772. (c) Jousseaume,
B.; Vilcot, N.; Ricci, A.; Tiekink, E. R. T. J. Chem. Soc., Perkin Trans. 1
1
994, 2283-2288.
(
9) Ncube, A. Ph.D. Thesis, University of Waterloo, 1999.
(
10) (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997,
on a ChiralCel OD column along with an independently
prepared sample of racemic 6e indicated the presence of only
one enantiomer. Thus, adduct 5e must have been formed with
very high diastereoselectivity.
Other tert-butanesulfinimines were prepared and treated
3
with Bu SnLi (Table 1). In all cases, good to excellent yields
of adducts were obtained and diastereoselectivities were
uniformly high. In most cases, only small (<1%) amounts
of the minor enantiomer were detected by chiral HPLC
analysis of the derived benzamides. Only in the case of
aldimine 4a with a relatively small methyl group was >1%
of the minor enantiomer detected. The uniformly high
1
1
5
19, 9913-9914. (b) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999,
21, 268-269. (c) Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999,
5, 8883-8904. (d) Review: Ellman, J. A.; Owens, T. D.; Tang, T. P.
Acc. Chem. Res. 2002, 35, 984-995.
(
11) (a) Tang, T. P.; Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001,
6, 8772-8778. (b) Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Selnick, H.
G.; Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051-2054.
12) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002, 124,
518-6519.
13) (a) Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D. L. J. Org. Chem.
6
(
6
(
2
6
000, 65, 8704-8708. (b) Davis, F. A.; McCoull, W. J. Org. Chem. 1999,
4, 3396-3397.
(14) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int. Ed.
2
001, 40, 589-590.
(15) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake,
C. H. J. Am. Chem. Soc. 2002, 124, 7880-7881.
(
16) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317-1320.
selectivities observed with these Bu
3
SnLi additions are quite
(17) Davis, F. A.; Lee, S.; Yan, H.; Titus, D. D. Org. Lett. 2001, 3,
remarkable since it is known that with typical organolithiums
1
757-1760.
18) Mikolajczyk, M.; Lyzwa, P.; Drabowicz, J. Tetrahedron: Asymmetry
002, 13, 2571-2576.
19) , (a) Still, W. C. J. Am. Chem. Soc. 1977, 99, 4836-4838. (b)
Sawyer, J. S.; Macdonald, T. L.; McGarvey, G. J. J. Am. Chem. Soc. 1984,
06, 3376
0c
(
RLi as opposed to Bu
3
SnLi) selectivities are rather modest.1
(
2
In fact, even under optimal conditions (Grignard reagents
in noncoordinating solvents) organometallics usually give
(
1
0
1
selectivities in the 95:5 range.
4216
Org. Lett., Vol. 5, No. 22, 2003

sulfinimines, reversal of diastereoselectivity was never
observed. Our inability to form the other diastereomer proved
to be an inconvenience as it precluded determination of
diastereomer ratios directly and derivatization of the adducts
3
Table 1. Addition of Bu SnLi to Sulfinimines 4
5
was required. However, this is not a major drawback from
a synthetic perspective since both enantiomers of tert-
butanesulfinamide are readily available, and thus, either
enantiomer of the desired R-aminoorganostannane should be
accessible.
aldimine 4
adduct 5
One of the big advantages of the tert-butanesulfinyl group
as opposed to other chiral sulfinyl auxiliaries) is that it can
entry
R
R/S no. no. yielda (%)
drb
R/S
(
1
2
3
4
5
6
7
Me
Et
i-Pr
t-Bu
SS
SS
SS
SS
SS
4a 5a
4b 5b
4c 5c
4d 5d
4e 5e
83
92
96
94
84
80
89
98.7:1.3
99.2:0.8
99.3:0.7
R
R
R
R
R
S
usually be readily removed by treatment with acid to provide
10
free amines (as salts). Unfortunately, with tributylstannyl-
substituted sulfinamides 5, treatment with protic or Lewis
>99:1c
2
2
>200:1d
acids under a variety of conditions gave only returned
starting material or intractable mixtures. Our inability to
directly remove the tert-butanesulfinyl group is likely due
to the instability of R-stannylamines under acidic conditions
and necessitated the development of alternative protocols to
remove the tert-butanesulfinyl group.
n-C5H11
BnO(CH2)7 RS
c-C6H11 SS
4f
5f
99.5:0.5
99.5:0.5
4g 5g
R
a
Percent isolated yields of chromatographed products. b Determined by
c
HPLC analysis of derived benzamides with a Chiralcel OD column. Only
one diastereomer was observed by C NMR spectroscopy. d Only one
13
isomer was detected by HPLC.
2
,6
3
Since we and others have previously shown that the
t-Boc group is useful as a nitrogen protecting group for
R-aminoorganostannanes and organolithiums, we looked for
conditions wherein such a group could be introduced to the
sulfinamides 5. Selective removal of the tert-butanesulfinyl
group would then give t-Boc-protected R-aminoorganostan-
The absolute configuration of the major adduct was
determined by conversion to benzamides and comparison
(HPLC elution times) with compounds of known absolute
6
configuration prepared independently. In all cases, the
formation of the major isomer may be rationalized by
invoking a six-membered-ring transition state as suggested
by Ellman (for Grignard reagents, Scheme 4).1
2
nanes directly. Many of the usual methods [e.g., (Boc) O in
23
24
25
26
combination with Et
3
N/DMAP, LDA, n-BuLi, or NaH ]
for the introduction of t-Boc groups to amide-type function-
0c
2
7
alities failed completely with the stannylsulfinamides,
yielding intractable mixtures or returned starting material.
Eventually, it was found that deprotonation of the sulfina-
mides with n-BuLi (THF, -78 °C) followed by treatment
of the resulting anion with a premixed combination of
Scheme 4. Model To Rationalize the Stereochemistry of
3
Bu SnLi Addition to tert-Butanesulfinimines
2
(Boc) O and DMAP (-78 °C to room temperature) could
give the mixed imides 7 in reasonable yields. These mixed
imides could be transformed into the desired Boc-protected
amines 8 in high yields by selective cleavage of the sulfinyl
group with MeLi (Table 2).
For amides 5 possessing an unbranched alkyl group, this
two-step protocol worked very well. However, for com-
pounds such as 5c, with an isopropyl group, the Boc group
could be introduced in only very low yields, likely due to
steric crowding. Unfortunately, the instability of the inter-
mediate (lithiated 5, the same intermediate formed on initial
It is known that the sense of asymmetric addition to tert-
butanesulfinimines may be reversed by changing the nature
of the nucleophile. For example, Plobeck has shown that
addition of aryl Grignard reagents to a series of imines gave
diastereomeric ratios ranging from 80:20 to 97:3 while the
2
0
corresponding aryllithiums gave ratios of 29:71 to 8:92.
addition to Bu SnLi to imines 4) thwarted attempts to put
3
In each case, the major diastereomer with the Grignard
reagents could be rationalized on the basis of a six-membered
transition state while the opposite isomers arising from
aryllithium additions could be explained by a nonchelated
open transition-state model. In our case, use of other
the Boc group onto more hindered substrates as more forcing
conditions lead to decomposition.
(
21) Krief, A.; Provins, L.; Dumont, W. Angew. Chem., Int. Ed. 1999,
3
1
6
7
8, 1946-1948.
(22) Baudin, J. B.; Julia, S. A.; Wang, Y. Bull. Soc. Chim. Fr. 1995,
32, 739-753.
tributylstannylmetallics afforded either no adduct (Bu
SnMgCl) or the same diastereomer (Bu SnZnEt Li) as with
Bu SnLi. Interestingly, it has been shown that Bu SnZnEt
Li gives opposite facial selectivity compared to Bu SnLi in
conjugate additions to γ-alkoxy enoates. With tert-butane-
3
-
(23) Papaioannou, N.; Blank, J. T.; Miller, S. J. J. Org. Chem. 2003,
3
2
8, 2728-2734.
24) Pilli, R. A.; Dias, L. C.; Maldaner, A. O. J. Org. Chem. 1995, 60,
17-722.
25) Giovannini, A.; Savoia, D.; Umani-Ronchi, A. J. Org. Chem. 1989,
(
3
3
2
-
3
(
21
54, 228-234.
(26) Takahata, H.; Takamatsu, T.; Yamazaki, T. J. Org. Chem. 1989,
5
4, 4812-4822.
(
10.
20) Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303-
(27) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
3
Synthesis, 3rd ed.; Wiley: New York, 1999; pp 518-525.
Org. Lett., Vol. 5, No. 22, 2003
4217

Table 2. Conversion of Sulfinamides 5 to Boc-Protected
Stannanes 8
Table 3. Conversion of Sulfinamides 5 Containing Branched
Side Chains to Boc-Protected Stannanes 8
a
a
entry
R
% yield (7)
% yield (8)
1
2
3
4
Me
Et
n-C5H11
69 (7a )
82 (7b)
80 (7e)
73 (7f)
87 (8a )
94 (8b)
98 (8e)
98 (8f)
BnO(CH2)7
entry
R
% yield (9) % yield (10) % yield (11) % yield (8)
a
Percent isolated yields of chromatographed products.
1
2
i-Pr
c-C6H11
59
51
100
98
96
95
100
100
For compounds such as 5c with a branched group, another
protocol was developed to allow access to Boc-protected
amines 8 (Table 3). Since a Boc group proved to be very
difficult to introduce directly, the much smaller formyl group
was initially introduced to give mixed imides 9 in moderate
yields. Subsequent acidic cleavage of the tert-butanesulfinyl
group, addition of the Boc group under standard conditions,
and hydrazinolysis of the formyl group all proceeded in near-
quantitative yields. This procedure with hindered substrates
is not ideal because of its length but the steps are all
operationally simple. Taken together with the two-step
procedure developed earlier (Table 2), this chemistry should
allow access to virtually any Boc-protected R-aminoorga-
nostannane (8) with a primary or secondary alkyl side chain.
It was not possible to acylate sulfinamide 5d, containing a
bulky tert-butyl group, under any of the conditions tried.
routes to stereodefined R-aminoorganostannanes and may
become the method of choice for the preparation of such
compounds. Work to examine other synthetic applications
of sulfinamides 5 is in progress.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for financial
support and a postgraduate scholarship (to K.W.K.). We are
also grateful to Mr. Scott Wilkinson (Sepracor) for generous
gifts of (R)- and (S)-tert-butanesulfinamide and synthetic
precursors.
Supporting Information Available: Experimental details
for the preparation of and spectral data for compounds 5
and 7-11; details for the chiral HPLC separation of
benzamides 6; and details for determination of absolute
configurations. This material is available free of charge via
the Internet at http://pubs.acs.org.
3
In summary, we have shown that addition of Bu SnLi to
tert-butanesulfinimines proceeds with very high diastereo-
selectivities and a predictable sense of asymmetric induction.
The sulfinamides thus formed are readily transformed to
enantiomerically enriched Boc-protected R-aminoorganostan-
nanes. This approach compares very favorably with other
OL035702I
4218
Org. Lett., Vol. 5, No. 22, 2003