Sml2-promoted intramolecular asymmetric pinacol-type ketone-tert-butanesulfinyl lmine reductive coupling: Stereoselectivity and mechanism

Article abstract of DOI:10.1021/ol901296u

The asymmetric ketone-fert-butanesulfinyl (t-BS) imine pinacol-type reductive coupling promoted by Sml₂ is described. Trans-1,2-vicinal amino alcohols were formed predominantly in excellent er and high dr. The stereochemical outcome provided ev

Full text of DOI:10.1021/ol901296u

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3410-3413
SmI2-Promoted Intramolecular
Asymmetric Pinacol-Type
Ketone-tert-Butanesulfinyl Imine
Reductive Coupling: Stereoselectivity
and Mechanism
Bing Wang* and Yong-Jun Wang
Department of Chemistry, Fudan UniVersity, 220 Handan Road, Shanghai 200433, China
wangbing@fudan.edu.cn
Received June 10, 2009
ABSTRACT
The asymmetric ketone-tert-butanesulfinyl (t-BS) imine pinacol-type reductive coupling promoted by SmI2 is described. Trans-1,2-vicinal
amino alcohols were formed predominantly in excellent er and high dr. The stereochemical outcome provided evidence for a radical mechanism
for SmI2-induced reductive couplings of t-BS imines.
1,2-Amino alcohol is a ubiquitous structural feature in natural
products as well as a key pharmacophore in therapeutical
agents possessing a wide spectrum of biological activities.1
Moreover, it is also a pivotal moiety in chiral ligands and
auxiliaries for asymmetric synthesis.2 In view of its impor-
tance in both organic synthesis and medicinal chemistry,
numerous efforts have been devoted to the stereoselective
construction of this key unit.1,3 One of the most straightfor-
ward methods to construct vicinal amino alcohols is the direct
pinacol-type aldehyde-imine reductive coupling. Recently,
an efficient and highly enantioselective SmI2-induced4 reduc-
tive coupling of aldehydes with N-tert-butanesulfinyl (t-BS
hereafter) imines5 has been reported.6 However, although
reactions of ketone with other CdN functions (imine,7
nitrone,8 hydrazone,9 oxime10) have been studied, mostly in
racemic form, the asymmetric ketone-sulfinimine coupling
is very rare, and only a single example using the symmetric
(4) For leading reviews on SmI2-mediated synthesis, see: (a) Molander,
G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307. (b) Kagan, H. B. Tetrahedron
2003, 59, 10351. (c) Edmonds, D. J.; Johnson, D.; Procter, D. J. Chem.
ReV. 2004, 104, 3371.
(5) For reviews, see: (a) Ferreira, F.; Botuha, C.; Chemla, F.; Pe´rez-
Luna, A. Chem. Soc. ReV. 2009, 38, 1162. (b) Lin, G.-Q.; Xu, M.-H.; Zhong,
Y.-W.; Sun, X.-W. Acc. Chem. Res. 2008, 41, 831. (c) Ellman, J. A.; Owens,
T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984.
(1) For leading reviews, see: (a) Bergmeier, S. C. Tetrahedron 2000,
56, 2561. (b) Burchak, O. N.; Py, S. Tetrahedron 2009, DOI: 10.1016/
j.tet.2009.06.003.
(6) Zhong, Y.-W. Dong, Y.-Z. Fang, K. Izumi, K. Xu, M.-H. Lin, G.-
Q. J. Am. Chem. Soc. 2005, 127, 11956. However, the mechanism of this
reaction has not been rationalized.
(2) For reviews, see: (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem.
ReV. 1996, 96, 835. (b) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757.
(3) Representative examples: (a) Evans, J. W.; Ellman, J. A. J. Org.
Chem. 2003, 68, 9948. (b) Hoffman, R. V.; Maslouh, N.; Cervantes-Lee,
F. J. Org. Chem. 2002, 67, 1045. (c) Andersson, M. A.; Epple, R.; Fokin,
V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 472. (d) Kobayashi,
S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120, 431. (e) Zietlow,
(7) For selected papers, see: (a) Roskamp, E. J.; Pedersen, S. F. J. Am.
Chem. Soc. 1987, 109, 6551. (b) Clerici, A.; Clerici, L.; Porta, O.
Tetrahedron Lett. 1995, 36, 5955. (c) Machrouhi, F.; Namy, J.-L. Tetra-
hedron Lett. 1999, 40, 1315. For an asymmetric coupling of planar chiral
substrates via a bis-ketyl radical mechanism, see: (d) Taniguchi, N.; Hata,
T.; Uemura, M. Angew. Chem., Int. Ed. 1999, 38, 1232.
A.; Steckhan, E. J. Org. Chem. 1994, 59, 5658
.
10.1021/ol901296u CCC: $40.75
Published on Web 07/15/2009
 2009 American Chemical Society

acetone has been reported so far.11 Conceivably, such a
reaction would afford a chiral amine juxtaposed with a
tertiary carbinol, a challenging key structure of many chiral
ligands (I-III) as well as natural products (IV) (Figure 1).
The absolute configuration of 3a was determined by single-
crystal X-ray diffraction (Figure 2, top).14 It turned out that
Figure 1. Representative chiral ligands and natural products
possessing juxtaposed tertiary carbinol and amine.
Furthermore, results obtained in ketone-sulfinimine coupling
might provide clues to the origins of stereoselectivity in
closely related reactions and improve our understanding of
the chemistry of Ellman’s imine. As part of our continuing
interest in the area of amino alcohols,12 herein we describe
the asymmetric intramolecular reductive coupling between
ketones and t-BS imines.
Our initial attempt to effect intermolecular SmI2-mediated
coupling between acetophenone and t-BS imine 1 was
unsuccessful. Under various conditions (additives, proton
sources), only the reduction and pinacol coupling of ac-
etophenone were observed, whereas 1 was untouched.
Apparently, the ketyl radical anion formed upon single-
electron reduction of acetophenone was much less reactive
toward t-BS imine as compared to aldehyde-derived ana-
logues, due to the profound steric and electronic effects of
the extra methyl. Nevertheless, it is still of interest to fathom
the reactivity of ketyls toward imines in an intramolecular
fashion, as in this way favorable spatial proximity of the
reacting partners could possibly overcome unfavorable
thermodynamics. Thus, a simple substrate 2a, a chimera
joining acetophenone and 1, was prepared and subjected to
conditions employed in the aldehyde-imine coupling6
(Scheme 1). To our delight, a cyclization product 3a was
Figure 2. X-ray crystal structures of 3a (top) and 3b (bottom).
the hydroxyl and the sulfinylamino groups were trans to each
other, showing a diaxial substitution pattern. This might
(8) For selected papers, see: (a) Masson, G.; Py, S.; Valle´e, Y. Angew.
Chem., Int. Ed. 2002, 41, 1772. (b) Masson, G.; Philouze, C.; Py, S. Org.
Biomol. Chem. 2005, 3, 2067.
(9) (a) Sturino, C. F.; Fallis, A. G. J. Org. Chem. 1994, 59, 6514. (b)
Sturino, C. F.; Fallis, A. G. J. Am. Chem. Soc. 1994, 116, 7447.
(10) (a) Shono, T.; Kise, N.; Fujimoto, T.; Yamanami, A.; Nomura, R.
J. Org. Chem. 1994, 59, 1730. (b) Tormo, J.; Hays, D. S.; Fu, G. C. J.
Org. Chem. 1998, 63, 201. (c) Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri,
K.; Kiguchi, T.; Naito, T. J. Org. Chem. 1998, 63, 4397. (d) de Garcia,
I. S.; Dietrich, H.; Bobo, S.; Chiara, J. L. J. Org. Chem. 1998, 63, 5883.
(e) Boiron, A.; Zillig, P.; Faber, D.; Giese, B. J. Org. Chem. 1998, 63,
5877. (f) Riber, D.; Hazell, R.; Skrydstrup, T. J. Org. Chem. 2000, 65,
5382.
Scheme 1. Pinacol-Type Ketone-Imine Reductive Coupling
(11) Lin, X.; Bentley, P. A.; Xie, H. Tetrahedron Lett. 2005, 46, 7849.
(12) (a) Wang, B.; Zhong, Z.; Lin, G.-Q. Org. Lett. 2009, 11, 2011. (b)
Wang, B.; Liu, R.-H. Eur. J. Org. Chem. 2009, 2845. (c) Liu, R.-H.; Fang,
K.; Wang, B.; Xu, M.-H.; Lin, G.-Q. J. Org. Chem. 2008, 73, 3307. (d)
Wang, B.; Fang, K.; Lin, G.-Q. Tetrahedron Lett. 2003, 44, 7981. (e) Wang,
B.; Yu, X.-M.; Lin, G.-Q. Synlett 2001, 904. (f) Liu, D.-G.; Wang, B.; Lin,
G.-Q. J. Org. Chem. 2000, 65, 9114.
(13) The dr was determined by 1H NMR, and the er was determined by
chiral HPLC of N-Ac derivatives of 3; see the Supporting Information.
(14) Enantiopure 3a did not afford suitable single crystals for X-ray
analysis; instead, the racemic sample (1:1 mixture of RS,1R,2S- and SS,1S,2R-
isomers) was used. Nevertheless, it is safe to conclude that RS-2a produced
RS,1R,2S-3a, since the absolute configuration of sulfur was not disturbed
during the reaction.
obtained in good yield (69%) and excellent stereoselectivity
(dr > 20:1, er > 99:1).13
Org. Lett., Vol. 11, No. 15, 2009
3411

suggest that chelation of the heteroatoms of the sulfinylamino
group to the Sm(III) cation did not play a significant role
for the stereoselection during the course of the reaction, and
the high dr was the result of inherent stereoelectronic effects.
Table 2. Intramolecular Asymmetric Ketone-Imine Couplinga
With this promising result, the reaction conditions were
then optimized with regard to the amount of reductant, the
additive and the proton source across both aryl and alkyl
ketones (Table 1). It was found that the reaction of 2a did
Table 1. Optimization of Coupling Conditions
entry
2, R
SmI2 (equiv)
additives (equiv)
t-BuOH (2)
t-BuOH (3)
none
t-BuOH (2), HMPA (8) NR
t-BuOH (2)
HMPA (12)
t-BuOH (4), HMPA (16) 76
3 (%)a
1
2
3
4
5
6
7
8
2a, Ph
2a
2a
2a
2b, i-Pr
2b
2.0
3.0
3.0
2.0
2.0
3.0
4.0
4.0
63
69
42 (64)
NR
11 (22)
2b
2b
t-BuOH (4), DMPU (16) 18 (35)
a Isolated yields; conversion indicated in parentheses.
a Conditions: For aryl ketones, see Table 1, entry 2; for alkyl ketones,
see Table 1, entry 7. b Isolated yields of pure major diastereomers; dr
determined by H NMR of the crude products. c dr 2.4:1 at C-6.
1
not require HMPA as an additive, while for alkyl substrate
2b, 4 equiv of t-BuOH and 16 equiv of HMPA were both
necessary to obtain the optimal results, and the latter could
not be replaced by DMPU.15 For alkyl ketones, 4 equiv of
SmI2 was employed, while a further increase of its amount
would not improve the yield. The structure of 3b was also
determined to be the diaxial trans- configuration by single-
crystal X-ray analysis (Figure 2, bottom). The fact that the
sense of diastereoselection remained the same for both types
of substrates, with or without HMPA, suggested that the
course of reaction was not affected by this additive.
mixture) afforded fused bicyclic products in 82% yield, with a
dr of 2.4:1 at the former ketonic R-position. This significant
deviation from statistical product distribution suggested that
there was a certain equilibrium before the event of cyclization.
Notably, the oxa-heterocyclic product 3n can be obtained in a
moderate yield (45%), while analogous ketone-alkene coupling
was reportedly overridden by SmI2-promoted R-deoxygen-
ation.17 Unfortunately, formation of a 5-membered ring was
less effective (28%), whereas attempts to form 7-membered
rings failed.
With the optimum conditions in hand, we probed the scope
and limitation of this reductive coupling reaction (Table 2).
Unlike the nitrone-t-BS imine coupling,16 little restriction in
the nature of ketone appendages was observed. Both aryl and
alkyl ketones gave moderate to excellent yields. The reaction
of an aryl ketone bearing multiple halogen nucleus substitutions
was more complex and gave a lower yield (entry 7), probably
due to its higher oxidative potential which favored further
reduction of the ketyl to carbanion before cyclization. Such an
R-oxygenated carbanion was too reactive and prone to cause
side reactions. A bulky 2-naphthyl appendage also decreased
the yield (entry 8). In the alkyl ketone series, even the highly
hindered tert-butyl ketone gave a 36% yield of the expected
product at an eroded dr. Cyclohexanone 2m (1:1 diastereomeric
The interesting stereoselectivity of this ketone-imine
reductive coupling can be best elucidated without invoking
complicated chelation models (Scheme 2). The ketone
carbonyl was first reduced to a ketyl via SET from 1 equiv
of SmI2. In the transition state for the cyclization (TS 1),
Scheme 2. Plausible Ketyl Cyclization Mechanism
(15) For recent studies on the role of HMPA, see: (a) Faran, H.; Hoz,
S. Org. Lett. 2008, 10, 865. (b) Sadasivam, D. V.; Antharjanam, P. K. S.;
Prasad, E.; Flowers, R. A. J. Am. Chem. Soc. 2008, 130, 7228.
3412
Org. Lett., Vol. 11, No. 15, 2009

the t-BS imine adopted its less energetic conformation,18
whereas the ketone appendage R occupied the more stable
equatorial orientation17a,19 and the attack of the ketyl
occurred at the less hindered face of the imine. Both the
carbonyl reduction and C-C bond formation may be
reversible,20 which could be key to the high dr. In the
extreme case of 3k where the exceedingly bulky R (t-Bu)
caused appreciable R-t-BS interaction and partially altered
the imine orientation, a lower dr was observed, while in
general such interaction was tolerated.21 Postcyclization
reduction of the N-centered radical afforded product 3. The
resemblance of TS 1 to that of ketyl-olefin cyclization17a
and the absence of chelation between Sm(III) and the
sulfinylamino moiety22 both argue for the radical mechanism
instead of an anionic pathway.23
effective chiral catalyst for the asymmetric addition of Et2Zn
to aldehydes.24 Removal of t-BS followed by double N-
alkylation with 1,5-dibromopentane afforded the piperidine
derivatives 4a,b in one pot (Scheme 3). Unfortunately, in
Scheme 3. Utility of the Coupling Products
The synthetic utility of this ketone-imine reductive
coupling was demonstrated by the facile synthesis of 4a, an
our preliminary tests the alkyl analogue 4b did not show
catalytic activity for this reaction.25
(16) Zhong, Y.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2004, 6, 3953.
(17) (a) Molander, G. A.; McKie, J. A. J. Org. Chem. 1995, 60, 872.
(b) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135.
(18) The S-O bond and the nitrogen lone pair of electrons should be
anti-periplanar; see: (a) Ferreira, F.; Audouin, M.; Chemla, F. Chem.sEur.
J. 2005, 11, 5269. (b) Bharatam, P. V.; Uppal, P.; Amita; Kaur, D. J. Chem.
Soc., Perkin Trans. 2 2000, 43.
To summarize, we have achieved an asymmetric intramo-
lecular pinacol-type ketone-imine reductive coupling. The
substrate scope covers both aryl and alkyl ketones, and the
reaction of the former did not require HMPA as the additive.
For both types of substrates, the resulting tertiary ꢀ-amino
alcohols possessed a diaxial (trans) substitution pattern,
which provided the backbones of some excellent chiral
ligands. From a mechanistic point of view, the stereochemical
outcome favors the ketyl cyclization mechanism via single-
electron transfer, instead of the alternative anionic pathway
via a two-electron reduction. Potential applications of this
protocol along with its products in asymmetric synthesis are
currently under investigation.
(19) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073.
(20) Reversibility of carbonyl reduction: (a) Curran, D. P.; Fevig, T. L.;
Jasperse, C. P.; Totleben, M. J. Synlett 1992, 943. Reversibility of ring
formation: (b) Hays, D. S.; Fu, G. C. J. Org. Chem. 1998, 63, 6375.
(21) The tolerance of the R-sulfinyl gauche-interaction in this reaction
could be due to the fact that an N-radical might be roughly triagonal (sp2),
similar to its imime precursor; while for polar 1,2-addition to sulfinimines
directly yielding a sterically demanding tetrahedral (metallated) N-anion,
such R-sulfinyl interaction becomes the determining factor (ref 18a). In
the latter case, the shift in hybridization state of nitrogen could also affect
the conformation of the sulfinyl group.
(22) In most polar additions to sulfinimines, coordination of substrate
O/N atoms to metal cation was proposed to explain the observed
stereoselectivity. If anionic cyclization mechanism predominated in the
present case, chelation of the hydroxyl and the sulfinylamino groups to
Sm(III) would afford either the cis- products or the opposite sense of
chiral induction.
(23) We tentatively interpret the diastereoselectivity for aldehyde-t-
BS imine coupling (ref 6) by an analysis along the same line: the unfavorable
R-R′ gauche-interaction in TS 3 was avoided in TS 2, which produced
the observed anti- diastereomer. It should be noted that in TS 1, OSmLn
occupied the axial orientation as the result of stereoelectronic effects in
cyclic systems (ref 17a), and this does not reflect its bulk relative to R in
acyclic systems (OSmLn > R>H).
Acknowledgment. Funding from the National Natural
Science Foundation of China (Nos. 20832005 and 20602008)
is gratefully acknowledged. We thank Drs. Min-Qin Chen
and Xiao-Di Yang (Fudan University) for X-ray analysis.
Supporting Information Available: Characterization
1
data, H and 13C NMR spectra for 3a-o and 4b. X-ray
structures of 3a, 3b, and 3k. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL901296U
(24) Ianni, J. C.; Annamalai, V.; Phuan, P.-W.; Panda, M.; Kozlowski,
M. C. Angew. Chem., Int. Ed. 2006, 45, 5502.
(25) Its utility in other asymmetric transformations is being probed.
Org. Lett., Vol. 11, No. 15, 2009
3413