Auxiliary strategies for the preparation of β-amino alcohols with reductive cross-coupling and a synthesis of (-)-cytoxazone

Article abstract of DOI:10.1016/j.tetlet.2005.09.002

Imine auxiliaries including chiral N-tert-butanesulfinyl imines have been successfully utilized to provide stereochemical control to the reductive cross-coupling of imines with aldehydes or ketones. This methodology has been applied to the synthesis of (-)-cytoxazone.

Full text of DOI:10.1016/j.tetlet.2005.09.002

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7849–7852
Auxiliary strategies for the preparation of b-amino alcohols
with reductive cross-coupling and a synthesis of (À)-cytoxazone
Xiangjie Lin, Paul A. Bentley* and Hexin Xie
Department of Chemistry, MSC03 2060, University of New Mexico, Albuquerque, NM 87131-0001, USA
Received 16 August 2005; revised 1 September2005; accepted 1 September2005
Abstract—Imine auxiliaries including chiral N-tert-butanesulfinyl imines have been successfully utilized to provide stereochemical
control to the reductive cross-coupling of imines with aldehydes or ketones. This methodology has been applied to the synthesis
of (À)-cytoxazone.
Ó 2005 Published by Elsevier Ltd.
The application of auxiliaries has successfully controlled
the stereochemical outcomes in a range of radical reac-
tions.1 We considered this to be a potential approach
towards the preparation of b-amino alcohols from the
reductive coupling of imines and carbonyls.2 b-Amino
alcohols are a frequent functional motif in natural prod-
ucts and drugs of significant biological activity3–5 and
have thus merited much synthetic attention.6–9 How-
ever, few approaches offered potential access to b-amino
alcohols with high stereoselectivity for either diastereo-
isomer as secondary or tertiary alcohols and incorporat-
ing a carbon–carbon bond forming event. This potential
is present in the ÔPinacol-typeÕ cross-coupling discussed
in this paper.
Identification of an enantiopure auxiliary that would
provide high stereocontrol for the cross-coupling reac-
tion was crucial. Initially oxazolidinones (Scheme 1)
(e.g., 1) were focused upon in light of the success that
Friestad et al. have found in radical alkylations.14
Aromatic aldehydes (e.g., benzaldehyde) were found to
be too reactive and only gave a homocoupled product
(Table 1; entry 1). However aliphatic aldehydes (Scheme
1) provided more promise and gave moderate to excel-
lent diastereoselectivity, but problematically in poor
yield (Table 1; entries 2 and 3).
Amongst other auxiliaries studied were chiral N-tert-
butanesulfinyl imines (4) first used by Ellman et al. with
great effect in alkylation.15 Recently, Xu et al. have,
utilized this as an auxiliary with high stereocontrol in
homocoupling16 and cross-coupling with nitrones.17
Thus this auxiliary was selected for cross-coupling
initially with aldehydes (Scheme 2).
This ideal picture has been fraught with difficulties of
chemo- and diastereo- control.2 There are a very limited
numberof examples encompassing enantio-conotrl.
Uemura et al. have utilized enantiopure ferrocenyl10,11
and Cr(CO)3 aromatic aldehydes,12 thus prohibiting a
widerrange of aldehydes forcoupling such as aliphatic
aldehydes. We viewed the introduction of the chiral auxi-
liary on the imine nitrogen as offering a more flexible
strategy and there existed numerous enantiopure amine
precursors. During preparation of this manuscript a
O
O
O
O
Bn
13
N
HN
OH
similarplan was achieved by Xu and Lin et al.
N
i.
H
O
R
N
R
+
R
H
Bn
H
R
OH
H
HO
2
1
3
Keywords: Reductive cross-coupling; N-tert-Butanesulfinyl imine;
Scheme 1. The synthesis of a b-amino alcohol by the cross-coupling of
Chiral auxiliary; Cytoxazone; Pinacol.
*
aldehydes with an imine oxazolidinone auxiliary. Reagents and
Corresponding author. Tel.: +1 505 243 8073; fax: +1 505 277
t
conditions: i. SmI2, BuOH, THF, ZnX2 (see Table 1), 25 °C.
2609; e-mail: pbentley@unm.edu
0040-4039/$ - see front matter Ó 2005 Published by ElsevierLtd.
doi:10.1016/j.tetlet.2005.09.002

7850
X. Lin et al. / Tetrahedron Letters 46 (2005) 7849–7852
Table 1. Cross-coupling of aldehydes with an imine oxazolidinone
auxiliary shown in Scheme 1
(e.g., Table 2; entry 1 compared to entry 4, or entry 2
compared to entry 6). Pentanal (5 R2 = nBu) was also
found to give good diastereoselectvity (Table 2; entry
5) when coupled with phenyl imine (4 R1 = Ph).
Entry
Reagent/product
Diastereomeric
ratio (dr)a
Yield (%)
1
2
3
X = Br ,2 R = Ph
X = Br ,3 R = nBu
X = Cl, 3 R = iPr5:1
—
20:1
90
30
Variation of the aromatic (R)-N-tert-butanesulfinyl
imine (4) was sought in an attempt to improve the dia-
stereoselectivity of the cross-coupling even further. The
poorest aldehyde (5 R2 = sBu), in terms of the cross-
couplingÕs diastereoselectivity (Table 2; entry 4), was
the partner for this study. The introduction of elec-
tron-withdrawing substituents on the phenyl ring such
as p-chloro (Table 2; entry 8) caused a slight decrease
in the diastereoselectivity and yield of the cross-coupling
reaction. However, electron-donating substituents on
the phenyl ring such as p-methoxy (Table 2; entr y 9)
provided a significant improvement in the diastereose-
lectivity of b-amino alcohol formation.
46
a Diastereomeric ratio determined by 1H NMR.
O
O
S
O
S
O
i.
ii.
N
HN
R1
O
HN H
R1
+
R2
H
R2
R1
H
R2
HO
H
6
7
5
4
Scheme 2. The synthesis of a b-amino alcohol by the cross-coupling of
aldehydes with an imine (R)-N-tert-butanesulfinyl auxiliary. Reagents
An aliphatic (R)-N-tert-butanesulfinyl imine was also
prepared (4 R2 = iPr) and was coupled with 5 (R2 = iPr)
with good diastereoselectivity (Table 2; entry 11). The
(R)-N-tert-butanesulfinyl auxiliary was removed under
acidic conditions and the resulting amino alcohol was
protected as the oxazolidinone 7 (R1 = R2 = iPr) in high
yield. The cis-diastereomer had been previously synthe-
sized,18 and its H1 and C13 NMR data matched 7
(R1 = R2 = iPr). Crystallization of 6 (R1 = p-MeOC6H4,
R2 = sBu) from ether allowed investigation by X-ray
analysis (Fig. 1) and demonstrated the anti-diastereomer
to be the majordiastereomer.
t
and conditions: i. SmI2, BuOH, THF, À78 °C; ii. (a) HCl, MeOH,
25 °C (b) triphosgene, Et3N, DCM, 25 °C.
Given the experiences with the oxazolidinone auxiliary
(1) aromatic aldehydes were avoided. The cross-coupling
in Table 2; entry 2 was studied, initially at À20 °C giving
only 21% yield of the b-amino alcohol (6 R1 = Ph,
R2 = iPr). However, reduction of the reaction tempera-
ture to À78 °C saw a dramatic improvement. The reac-
tion displayed very good diastereoselectivity (14:1) and
chromatography allowed isolation of a single diastereo-
mer( 6 R1 = Ph, R2 = iPr) in high yield (91%) (Scheme
2).
A derivative of aldehyde 5 (R2 = CH2OBn), which
contained a protected alcohol was perceived to have
greater synthetic utility and cross-coupling with 4
(R1 = Ph) gave good diastereoselectivity and yield
(Table 2; entry 7). Improved diastereoselectivity of the
cross-coupling was again observed when the p-methoxy
substituent was introduced to the phenyl ring (4 R1 =
p-MeOC6H4) (Table 2; entry 10). Repeating this coup-
ling with epi-4 (R1 = p-MeOC6H4), removal of the auxi-
liary and transformation to the oxazolidinone followed
by deprotection of the primary alcohol gave a high
yield of (À)-cytoxazone (8, Scheme 3).19,20 Cytoxazone
is a cytokine modulator, which has been isolated from
Streptomyces sp. and has been shown to inhibit Th2
cellÕs signalling pathway.21,22
Following this success, the phenyl imine (4 R1 = Ph) was
cross-coupled with a variety of aliphatic aldehydes.
Trends in the reactions of 5, from R2 = Et to R2 =
iPrto R 2 = tBu (Table 2; entries 1–2–3) suggested that
an increase in size of the substituent in close proximity
of the aldehydeÕs a-carbon displayed increased dia-
stereoselectvity. Thus the aldehyde with the bulkiest
substituent (5 R2 = tBu) provided the highest diastereo-
selectivity, but regrettably at the cost of a low yield and
a comparatively long reaction time (Table 2; entry 3).
Increase in the size of the aldehyde further from the a-
carbon gave a slight reduction in diastereoselectivity
Table 2. Cross-coupling of aldehydes with an imine (R)-N-tert-butanesulfinyl auxiliary shown in Scheme 2
Entry
R1
R2
Reaction time (h)
Dra crude
Dra afterseparation
Yield (%)
90
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
4
14:1
20
3
3
3
3
3
4
8
8:1
>25:1
>25:1
6:1
8:1
7:1
9:1
iPr3
91
tBu
>25:1
10:1
9:1
>25:1
10:1
10:1
>25:1
>25:1
51
31
86
69
88
70
73
83
85
iBu
nBu
cC6H11
BnOCH2
sBu
—
p-ClC6H4
p-MeOC6H4
p-MeOC6H4
iPr
5:1
9
10
11
sBu
14:1
15:1
>25:1
BnOCH2
iPr10
8:1
a Diastereomeric ratio determined by 1H NMR.

X. Lin et al. / Tetrahedron Letters 46 (2005) 7849–7852
7851
Table 3. Cross-coupling of ketones with an imine N-tert-butanesulfinyl
auxiliary shown in Scheme 4
Entry
Additive
Reaction time (h)
Yield (%)
1
2
3
—
Et3N
TMEDA
10
2
0.5
33
53
56
an amine additive resulted in a faster reaction that gave
the b-amino alcohol as a single diastereomer in moder-
ate yield (Table 3).
The very efficient synthesis of b-amino alcohols by
the highly stereoselective cross-coupling of N-tert-
butanesulfinyl imine and aldehyde (complementing
UemuraÕs methodology12,11
) offers a broad scope
towards numerous natural product/drug targets, which
our group is in the process of exploiting. The imine
ketone cross-coupling is being studied further with
unsymmetric ketones.
Figure 1. The ORTEP image of b-amino alcohol 6 (R1 = p-MeOC6H4,
Acknowledgements
R2 = sBu).
Financial support from the Department of Chemistry
and the Research Allocation Committee, University of
New Mexico is gratefully acknowledged. We would like
to thank Eileen Dueslerforassistance with X-ary
analysis.
O
S
HN
H
O
S
OBn
N
i.
Supplementary data
HO
H
MeO
H
H
OBn
+
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.09.002.
MeO
O
O
O
HN
HN
O
O
iii.
ii.
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OH
OBn
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´
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1772–1775.
t
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HO
Scheme 4. The synthesis of a b-amino alcohol by the cross-coupling of
ketones with an imine (R)-N-tert-butanesulfinyl auxiliary. Reagents
t
and conditions: i. SmI2, BuOH, THF, À78 °C.

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