A highly efficient and direct approach for synthesis of enantiopure β-amino alcohols by reductive cross-coupling of chiral N-tert- butanesulfinyl imines with aldehydes

Article abstract of DOI:10.1021/ja054401w

A highly efficient and practical approach for the synthesis of optically pure β-amino alcohols by the SmI₂-induced reductive cross-coupling of chiral N-tert-butanesulfinyl imines with aldehydes was developed. This method allows the preparation of a broad range of chiral β-amino alcohols, including functionalized ones under mild conditions. It provides a straightforward access to enantiopure β-amino alcohols that are widely applicable in asymmetric synthesis. Copyright

Full text of DOI:10.1021/ja054401w

Published on Web 08/06/2005
A Highly Efficient and Direct Approach for Synthesis of Enantiopure â-Amino
Alcohols by Reductive Cross-Coupling of Chiral N-tert-Butanesulfinyl Imines
with Aldehydes
Yu-Wu Zhong,† Yi-Zhou Dong,† Kai Fang,† Kenji Izumi,† Ming-Hua Xu,*,†,‡ and Guo-Qiang Lin*,†
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, and
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai 201203, China
Received July 4, 2005; E-mail: xumh@mail.sioc.ac.cn
Scheme 1
Optically active â-amino alcohols are versatile building blocks
for medicinal chemistry and natural product synthesis.1 They have
also been used as powerful chiral ligands or auxiliaries in
asymmetric synthesis.2 Due to their great importance, considerable
efforts have been made to develop efficient methods for their
preparation.3 Among them, the pinacol-type cross-coupling between
carbonyls and imines is one of the most direct ways to construct
Table 1. SmI2-Induced Reductive Cross-Coupling of Aldehydes
â-amino alcohols. However, a serious issue is that achievement of
both good chemoselectivity and stereoselectivity is often difficult.
Because of this, only a few examples of intermolecular cross-
coupling to form racemic â-amino alcohols have been reported;4 a
highly diastereo- and enantioselective crossed pinacol coupling
remains a significant synthetic challenge. To our knowledge, only
recently has asymmetric synthesis of â-amino alcohols by cross
pinacol coupling using planar chiral substrates been realized,5 but
the products are limited to ferrocenyl or Cr(CO)3 aromatic deriva-
tives; new approaches with broader substrate generality are still in
high demand. In this communication, we wish to report a highly
promising asymmetric pinacol-type coupling of chiral N-tert-
butanesulfinyl imines with aldehydes, leading to enantiopure
â-amino alcohols directly.
Our laboratory recently documented the first use of samarium
diiodide-induced cross-coupling of nitrones with chiral N-tert-
butanesulfinyl imines6 for the asymmetric synthesis of unsym-
metrical vicinal diamines.7 Excellent enantioselectivities, as well
as high diastereoselectivities, were observed in this reaction. On
the basis of this success, we wondered whether this approach could
be extended to asymmetric synthesis of vicinal amino alcohols. In
our effort to develop such a process, we discovered that the cross-
coupling between chiral N-tert-butanesulfinyl imines and aldehydes
in the presence of samarium diiodide could lead to the formation
of â-amino alcohols with excellent enantiomeric excesses and in
good yields.
with N-tert-Butanesulfinyl Imines
entrya
R1
R2
2
T (h) yield (%)b
drc
eed
1
2
3
4
5
6
7
8
9
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
Ph
4-FC6H4
4-ClC6H4
4-BrC6H4
iPr
C6H11
(Et)2CH 2c
n-C5H11 2d
PhC2H4 2e
2a
2b
4
7
7
7
7
7
4
4
4
4
4
7
7
6
6
6
8
92
90
73
90
95
86
89
71
70
82
84
90
73
88
87
95
82
>99:1
99:1
>99:1
91:9
88:12
99:1
98:2
98
>99
99
95
95
97
iPr
iPr
iPr
iPr
iPr
iPr
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
>99
98
99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
96:4
>99
>99
>99
>99
>99
98
>99
97
97
10 4-AcOC6H4
11 4-CH3OC6H4
12 3,4-(MeO)2C6H3 iPr
13 2,4-(MeO)2C6H3 iPr
14 iPr
iPr
iPr
iPr
iPr
15 PhCH2CH2
16 CH3(CH2)4
17 BnOCH2
98:2
>99:1
a See Supporting Information for reaction details. b Isolated yield.
1
c According to HPLC-MS and H NMR of the crude materials. d Enantio-
meric excess for the free â-amino alcohols after acidic hydrolysis of 2; see
Supporting Information for details.
Cross-coupling of N-sulfinyl imine 1a with benzaldehyde was
initially examined using our previously reported conditions.7
However, the result was disappointing. Considerable amount of the
pinacol formation from benzaldehyde was found, and no desired
cross-coupling product was isolated. With p-tolualdehyde, trace
amounts of cross-coupling product were observed. Considering the
relatively high reactivity of aromatic aldehydes under SmI2,8 we
turned our attention to aliphatic aldehydes. To our delight, when
isobutyraldehyde (1.2 equiv) was used as substrate, the reaction
proceeded smoothly in the presence of 2 equiv of SmI2. After 4 h,
the expected â-amino alcohol derivative 2a was obtained in 88%
yield with extremely high diastereoselectivity (>99% de)9 (Scheme
1), and no pinacol formation was detected in this reaction.
Subsequent optimization of the reaction condition indicated that a
further improvement of the yield (92%) could be achieved by
employing a little more excess (1.5 equiv) of aldehyde substrate.
Also, tert-butyl alcohol was found to be essential in the reaction
for the achievement of high yield.10
The success of the cross-coupling between N-sulfinyl imine 1a
and isobutyraldehyde prompted us to extend the general scope of
the reaction. Under the optimized conditions, we were pleased to
find that a series of N-sulfinyl imines reacted with various aldehydes
smoothly to give the desired cross-coupling products in good to
excellent yields and extremely high diastereomeric ratios (up to
>99:1) (Table 1). Relatively lower yields (70-71%) were observed
in the cases of aromatic imine substrates having para-Br and Cl
substituents because of the formation of some homocoupling
† Shanghai Institute of Organic Chemistry.
‡ Shanghai Institute of Materia Medica.
9
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10.1021/ja054401w CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
then easily cleaved by acidic hydrolysis in one step to afford
optically pure (3R,4S)-statine (4) in high yield. To our knowledge,
this approach represents one of the most convenient and direct
syntheses of 3 and 4 reported to date.17
In summary, we have developed a highly efficient and practical
approach for the synthesis of enantiomerically pure â-amino
alcohols by the SmI2-mediated reductive cross-coupling of chiral
N-tert-butanesulfinyl imines with aldehydes. This method is found
to be very effective for the preparation of a broad range of chiral
â-amino alcohols, including functionalized ones under mild condi-
tions. Diastereoselectivities and enantioselectivities in these reac-
tions are excellent in most cases. Moreover, it provides a solution
to a long-standing difficulty in direct construction of enantiopure
â-amino alcohols via the pinacol-type cross-coupling between
carbonyls and imines. We believe that both this methodology and
the obtained â-amino alcohols will find wide use in asymmetric
synthesis. The application in natural product synthesis is currently
in progress.
product (entries 8 and 9). As previously reported,11 these two
substrates are subject to easy homocoupling under the similar
reaction conditions. Fortunately, the absolute structure of the
obtained cross pinacol product was unambiguously established by
X-ray crystallography, and the stereochemistry of the two newly
formed carbon centers was revealed to possess R,S-configuration.12
When the R1 or R2 substituent became more bulky, the coupling
reaction still proceeded well (entries 2, 3, 12, and 13). In the reaction
with isobutyraldehyde, different substituted aromatic imines gave
similar selectivities (entries 1 and 6-13), suggesting that the
diastereoselectivity was primarily controlled by the stereochemistry
of the N-sulfinyl group rather than by the electronic effect. However,
the diastereoselectivity was found to be influenced by the steric
hindrance of the aldehyde substrate (entries 1-5). Less hindered
aldehydes, such as hexanal and 3-phenylpropanal, resulted in a
decrease in diastereoselectivity (91:9 and 88:12) (entries 4 and 5).
Besides the aromatic N-sulfinyl imines, we also evaluated the cross-
coupling of aliphatic imines with isobutyraldehyde and found that
the reactions could equally be accomplished in high yields and high
diastereomeric ratios (entries 14-17). Thus, the reaction substrate
scope is largely expanded, indicating the great compatibility and
efficiency of the method. Notably, for those â-amino alcohol
products 2h-2k, the para-halogen, acetoxy, or methoxy substituent
on the benzene ring would be a useful functionality for further
modification, such as adjustment of the solubility or attachment
onto support materials via O-alkylation or coupling reactions.13 For
product 2q, it is also worth noting that removal of the N-sulfinyl
and benzyl groups will afford the chiral 2-amino-1,3-propanediol
derivative, which is a synthetically very useful building block.
Cleavage of the sulfinyl group under acidic conditions (HCl/
MeOH) was subsequently accomplished to afford â-amino alcohols
in high yields. Very gratifyingly, excellent enantiomeric excesses
(>95%) were observed in all cases (Table 1). These results clearly
indicate that the N-sulfinyl serves as a powerful chiral directing
group and predominates the stereoselectivity of the reaction.
As described above, this highly diastereo- and enantioselective
crossed pinacol coupling method offers a significantly more efficient
and direct construction of â-amino alcohol scaffolds. To further
demonstrate the synthetic value, the rapid preparation of two
biologically active compounds D-erythro-sphinganine (3) and
(3R,4S)-statine (4) was then carried out (Scheme 2).
Acknowledgment. Financial support from the NSFC (20402018,
203900506), Shanghai Rising-Star Program (05QMX1467), the
Major State Basic Research Development Program (G2000077506),
and the Chinese Academy of Sciences is acknowledged.
Supporting Information Available: Experimental procedures and
characterization data, including X-ray data of 2i. This material is
available free of charge via the Internet at http://pubs.acs.org.
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