Samarium dienolate mediated stereoselective synthesis of anti-1,3-diol monoesters via aldol-Tishchenko reaction

Article abstract of DOI:10.1016/j.tetlet.2006.04.091

The reaction of an (E)-samarium dienolate, generated by the regioselective reductive cleavage of a phenylsulfonyl activated cyclopropyl ketone with samarium(II) iodide, with aliphatic and aromatic aldehydes gives the 2-substituted anti-1,3-diol monoester

Full text of DOI:10.1016/j.tetlet.2006.04.091

Tetrahedron Letters 47 (2006) 4753–4757
Samarium dienolate mediated stereoselective synthesis of
anti-1,3-diol monoesters via aldol-Tishchenko reaction
*
Vichai Reutrakul, Jaray Jaratjaroonphong, Patoomratana Tuchinda, Chutima Kuhakarn,
Palangpon Kongsaeree, Samran Prabpai and Manat Pohmakotr*
Department of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
Received 9 February 2006; revised 11 April 2006; accepted 19 April 2006
Available online 19 May 2006
Abstract—The reaction of an (E)-samarium dienolate, generated by the regioselective reductive cleavage of a phenylsulfonyl acti-
vated cyclopropyl ketone with samarium(II) iodide, with aliphatic and aromatic aldehydes gives the 2-substituted anti-1,3-diol
monoester derivatives, stereoselectively, in good to excellent yields. The results represent the first report of a dienolate in the
aldol-Tishchenko reaction and also provide an optically active polyol with (R)-glyceraldehyde.
ꢀ
2006 Elsevier Ltd. All rights reserved.
6
The Tishchenko reaction is a powerful tool in organic
synthesis that allows the highly effective synthesis of
(Scheme 1). To the best of our knowledge, there are
only a few reports on the reactions of samarium dieno-
lates with various electrophiles. In this letter, we re-
port the first example of the tandem aldol-Tishchenko
reaction of samarium dienolate 3 with various aldehydes
to afford 2-substituted anti-1,3-diol monoesters in high
yields and excellent stereoselectivity.
1
6,7
many natural products such as polyketides, macro-
2
lides, and coalescing agents in the paint industry. In
general, the tandem aldol-Tishchenko reaction is
employed to access anti-1,3-diol monoesters from the
+
2+
4+
intermediate metal-enolates (e.g., M = Li , Zn
,
,
3
+
2+
3+
3+
3+
3+
3+
Al , Sm , Sm , Yb , Y , Ga , La , Ti
4
+
4+
Zr , or Hf ) with 2 mol of aldehyde through intra-
molecular hydride transfer in the hemiacetal formed
from the aldehyde and the b-metaloxy carbonyl com-
We first examined and optimized the reaction of samar-
ium dienolate 3 with propanal in THF (Scheme 1 and
3
,4
pound. Among these metal complexes, samarium(II)
iodide is one of the most effective agents for catalyzing
both the Tishchenko reduction and the tandem aldol-
Tishchenko reaction of b-hydroxy ketones and ketones
or aliphatic aldehydes with aldehydes, respectively, to
give anti-1,3-diol monoester adducts in high yields and
O
O
b
Ph
SmI , THF
Ph
2
Ph
a
SO Ph
2
R
Ph
4
a: R = H; 4c: R = allyl
1
4
b: R = Me; 4d: R = Bn
SmI2
I2SmO
Ph
bond a cleavage
SO Ph
- SO Ph
H+ or RX
I2SmO
1
,3b,h,5
excellent stereoselectivity.
2
2
Recently, we reported the synthetic applications of
samarium(II) iodide-mediated regioselective cleavage
of phenylsulfonyl activated cyclopropyl ketone 1 to
give the (E)-b,c-unsaturated ketone 4a in high yield.
Samarium dienolate 3 was proposed as the intermediate,
which could be electrophilically trapped with alkylating
agents. Only a-alkylated products 4b–d were isolated
Ph
Ph
Ph
2
3
EtCHO 5a
O
OH
Et Ph
OH OCOEt EtOCO
Et Ph
OH
Et
4a
Ph
6a
7a
8a
Ph
Ph
Ph
Keywords: Samarium dienolate; Aldol-Tishchenko reaction.
Scheme 1. Possible mechanism for the SmI
2
-mediated formation of
*
Corresponding authors. Tel.: +66 2 2015152; fax: +66 2 6445126;
e-mail addresses: scvrt@mahidol.ac.th; scmpk@mahidol.ac.th
samarium dienolate 3 from activated cyclopropyl ketone 1 and its
reactions with electrophiles.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.091

4754
V. Reutrakul et al. / Tetrahedron Letters 47 (2006) 4753–4757
Table 1). With 10 equiv of propanal and stirring the
reaction at ꢀ78 ꢁC for 15 min and then at room temper-
ature for an additional 5 h (entry 1), the aldol-Tish-
chenko adducts 7a and 8a were isolated in 44% and
Table 2. The aldol-Tishchenko reaction of samarium dienolate 3 with
various aldehydes
8
O
OH OCOR ROCO
Ph
OH
1) 1.2 equiv SmI2
THF
b
Ph
Ph
Ph
R
R
3
0% yields, respectively. The addition of HMPA as
a
SO Ph
2
cosolvent (entry 2) caused a reduction of the yields.
We then searched extensively for the optimum condi-
tions for the reaction. In Table 1, the conditions giving
the highest yield of the aldol-Tishchenko adducts 7a
2
) 3 equiv RCHO
Ph
1
o
7
8
-78 C to rt, 1 h
Ph
OH OCOR ROCO
Ph
Ph
OH
R
R
(
68%) and 8a (17%) are shown in entry 5. A longer reac-
tion time caused equilibration (transesterification of 7a)
3
a,e
of the adducts 7a and 8a.
9
10
Ph
Ph
Products (% yield)
a
Entry
Aldehyde 5
Overall
yields (%)
The generality of the reaction was secured through
experiments with different aldehydes as electrophiles
R
7
8
9
10
(
5
Table 2) under the optimum conditions (Table 1, entry
). All the aldehydes studied gave the aldol-Tishchenko
1
2
3
4
5
6
7
8
9
Ethyl
a
b
c
d
e
f
68
63
62
33
55
28
21
10
27
30
17
22
27
3
14
28
34
22
26
6
—
—
—
32
—
—
—
—
—
—
—
—
—
10
—
—
—
—
—
—
85
85
89
78
69
56
55
32
53
36
8
n-Butyl
n-Heptyl
i-Propyl
i-Butyl
Phenyl
4-ClC
4-BrC
4-CH
4-CH
adducts in good to excellent yields, except for p-bromo-
benzaldehyde (entry 8) and the less electrophilic anis-
aldehyde (entry 10), as might be expected. Comparable
levels of diastereoselection [7:9 and 8:10 (>99:1)] were
obtained with all long chain aliphatic, aromatic and b-
alkyl substituted aldehydes. However, the a-alkyl substi-
tuted aldehyde, isobutyraldehyde (entry 4), appeared to
exhibit lower diastereoselectivity under the current reac-
tion conditions, compounds 7 and 9 were isolated in
almost equal amounts.
6
H
4
g
h
i
6 4
H
3
C
6
H
4
1
0
3
OC
6
H
4
j
a
Isolated yield.
The structures and relative stereochemistries of the anti-
of products 7 and 8 for all entries except entry 4, Table
2, could be explained by the fast and irreversible reac-
tion of anti-aldolate A with a second mole of aldehyde
via the favorable transition state C compared to the less
energetically favorable transition state F due to the axial
position of the styryl group. In these cases, presumably
the fast isomerization from syn-aldolate B to anti-aldo-
late A surpasses the rate of Tishchenko reaction. Thus
syn-aldolate B can isomerize to an anti-aldolate A,
which undergoes subsequent Tishchenko reduction via
the more favorable transition state C to afford the de-
sired product 7 and its transesterification isomer 8 (via
1
,3-diol monoesters 7–10 were established based on their
1
H NMR spectra. The relative stereochemistry of the
unusual aldol-Tishchenko adduct 9d (Table 2, entry 4)
was confirmed by X-ray crystallographic analysis as
shown in Figure 1. The mechanism of the aldol-Tish-
chenko reaction has been proposed in both step-
3
b,g,h,j,4a,9,10
3c
wise
and concerted manners. Based on
previous reports and our current studies, a possible
mechanistic pathway of the aldol-Tishchenko reaction
of the samarium dienolate 3 with an aldehyde is illus-
trated in Scheme 2. The aldol reaction is reversible,
whereas the stereospecific Tishchenko reaction is irre-
0
3a,g
a six-membered intermediate E and D ).
3
a,g,h,5a
versible.
The rate difference of these two reactions
is an important factor that determines the stereochemi-
cal outcome of the final diol monoester adducts.
In the case of isobutyraldehyde (Table 2, entry 4), the
steric effect caused by the isopropyl group resulted in
both a slow down in equilibration of the anti-aldolate
A and syn-aldolate B, and a lowering of the energy dif-
3
h,m
Previous studies
firmly established that the fast
interconversion of anti- and syn-aldolates occurred via
a dissociation–recombination pathway. The formation
3
h
ference between the transition states C and F. These
combined effects, presumably, led to the formation of
7
, its transesterification isomers 8 and 9 and its trans-
esterification isomer 10 (via a six-membered intermedi-
ate H and G ).
a
Table 1. Optimization studies
0
b
Entry EtCHO Temp
equiv) (ꢁC)
Time
(h)
Products (% yield)
(
4
a
6a 7a 8a 7a+8a
The tandem aldol-Tishchenko reaction of the samarium
dienolate 3 is also applicable to the stereoselective
synthesis of optically pure polyoxygenated organic
compounds. The reaction of cyclopropyl ketone 1 with
(R)-glyceraldehyde acetonide 11 in the presence of
1
2
3
4
5
6
7
10.0
10.0
1.5
2.0
3.0
ꢀ78 to rt
ꢀ78 to rt
ꢀ78 to rt
ꢀ78 to rt
ꢀ78 to rt
ꢀ78 to rt
ꢀ78 to rt
5
5
1
1
1
5
1
—
5
10
3
—
—
—
—
—
—
—
—
—
—
44 30 74
36 11 47
c
49
7
56
61 12 73
68 17 85
48 29 77
61 18 79
SmI in THF (Scheme 3) gave only the transesterified
2
2
D
9
3.0
4.0
aldol-Tishchenko adducts 13 [5%, ½aꢁ ꢀ61.82 (c 0.11,
3
D
1
CHCl )] and 15 [38%, ½aꢁ +70.00 (c 0.10, CHCl )].
3
3
a
b
c
The results indicated that three stereogenic centers of
the corresponding anti-diol monoester could be created
in a single operation.
All reactions were performed using 1.2 equiv of SmI
2
(0.1 M) in THF.
Isolated yield.
HMPA (10 equiv) was used as cosolvent.

V. Reutrakul et al. / Tetrahedron Letters 47 (2006) 4753–4757
4755
Figure 1. ORTEP plot of the X-ray crystal structure of compound 9d.
O
O
O
I2SmO
Ph
R
SmI , THF
O
O
RCHO
2
Ph
OH
O
OH
O
1
H
O
rt, 1 h
O
O
O
Ph
O
Ph
O
O
OSmI2
R
samarium dienolate 3
O
OSmI
2
(
R)-11
O
O
Ph
Reversible
Ph
R
Ph
Ph
1
2 (not observed)
14 (not observed)
O
O
Ph
Ph
R
R
anti aldolate A
syn aldolate B
O
OH
R
O
OH
O
O
R
S
R
fast RCHO
slow
RCHO
Sm
O
O
Ph
S
S
OH
Ph
O
R
R
Sm
O
O
O
O
O
O
Ph
Ph
Ph
H
R
Ph
H
R
Ph
H
13 (5%)
15 (38%)
O
O
R
R
F
H
C
Scheme 3. The aldol-Tishchenko reaction of samarium dienolate 3
with (R)-glyceraldehyde acetonide 11.
Irreversible
Ph
SmO
Ph
OCOR
R
SmO
OCOR
R
Ph
Ph
OSm Ph OSm
and confirmed by X-ray crystallographic analysis of
compound 16 derived from 3,5-dinitrobenzoylation of
alcohol 15 (Fig. 2). The origin of the 1,3-anti stereoselec-
tivity can be rationalized by two consecutive stereo-
selective reactions, that is the anti selective aldol
condensation of samarium dienolate 3 with the enantio-
merically pure aldehyde (R)-11 (via chelated transition
state I) followed by the anti stereoselective Tishchenko
reduction (via K) to afford transition state L (Scheme
O
R
O
R
O
Ph
Ph
O
Ph
D
7
R
R
G
E
H
H+
H+
Ph
OSm ROCO
Ph
ROCO
OSm
R
9
H+
H+
Ph
R
1
0
8
1
1
D' Ph
Ph
4). Intramolecular acyl migration in L decreases the
G'
R = Et, n-Butyl, n-Heptyl, i-Propyl,
i-Butyl, Ph, 4-ClC H , 4-BrC H ,
R = i-Propyl
steric effect and dipole–dipole interaction between the
two acetonide groups (via M and L ). The absolute con-
0
6
4
6
4
4
-CH C H , 4-CH OC H
3 6 4 3 6 4
figuration at the C-3 and C-4 positions in the transition
state L was attributed to the chelation control of the
oxophilic Lewis acid, samarium salt to the oxygen atom
of the carbonyl group and the oxygen atom in the a
position of the acetonide (via I and J). Therefore, the
samarium dienolate 3 would attack preferentially at
the re face of (R)-glyceraldehyde acetonide 11.
Scheme 2. Possible mechanism for the tandem aldol-Tishchenko
reaction of samarium dienolate 3 with aldehydes.
The relative and absolute stereochemistries of com-
pound 15 were established by spectroscopic techniques

4756
V. Reutrakul et al. / Tetrahedron Letters 47 (2006) 4753–4757
Acknowledgments
We wish to thank the Thailand Research Fund for the
award of Senior Research Scholar to V.R., a grant to
P.K. (TRF 4780020) and a Ph.D. scholarship to J.J.
through the Royal Golden Jubilee Ph.D. program.
The financial support from the Postgraduate Education
and Research Program in Chemistry (PERCH) are also
gratefully acknowledged.
References and notes
1
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Sm
I
I
. Examples of tandem aldol-Tishchenko reactions, see: (a)
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Organometallics 1990, 9, 30–44; (b) Curran, D. P.; Wolin,
R. L. Synlett 1991, 317–318; (c) Baramee, A.; Chaichit, N.;
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Horiuchi, Y.; Taniguchi, M.; Oshima, K.; Utimoto, K.
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M.; Shaw, J. T.; Woerpel, K. A. J. Org. Chem. 1997, 62,
5674–5675; (g) Abu-Hasanayn, F.; Streitwieser, A. J. Org.
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Blacque, O.; Mo ¨ı se, C. J. Chem. Soc., Perkin Trans. 1
Sm
O
O
Sm
O
R O
O
Ph
Re
OSmI2
O
O
H
Ph
H
I
Ph
J
Ph
3
(
R)-11
O
Sm
H
O
O
O
SmO
Ph
O
Ph
O
O
O
S
R
O
Ph
Ph
1
4
X
O
O
R
O
Sm
O
O
K
L
Ph
2
000, 2265–2270; (j) Schneider, C.; Hansch, M. Chem.
O
Commun. 2001, 1218–1219; (k) Simpura, I.; Nevalainen,
V. Tetrahedron Lett. 2001, 42, 3905–3907; (l) Simpura, I.;
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Schneider, C.; Klapa, K.; Hansch, M. Synlett 2005, 91–94;
R
OSm Ph
H+
O
OSm
O
O
1
5
S
R
O
O
Ph
R
R
O
O
Sm
O
O
(
5
n) Hon, Y.-S.; Chang, C.-P. Tetrahedron 2005, 61, 5267–
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O
L' Ph
M
4
. Examples of catalytic asymmetric aldol-Tishchenko reac-
tions, see: (a) Mascarenhas, C. M.; Miller, S. P.; White, P.
S.; Morken, J. P. Angew. Chem., Int. Ed. 2001, 40, 601–
Scheme 4. Possible transition state for the formation of compound 15
through tandem aldol-Tishchenko reaction of samarium dienolate 3
with (R)-glyceraldehyde acetonide 11.
6
4
03; (b) Mlynarski, J.; Mitura, M. Tetrahedron Lett. 2004,
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In summary, the stereoselective synthesis of anti-1,3-diol
monoesters could be smoothly carried out via the reac-
tion of samarium dienolate with various aldehydes via
the tandem aldol-Tishchenko reaction. Our results also
provide a complementary insight of the reaction mecha-
nism. Moreover, the aldol-Tishchenko process is also
applicable to the stereoselective synthesis of optically ac-
tive anti-1,3-diol monoesters in one step. Further inves-
tigations into the scope and limitations of this reaction
are in progress.
5
. Examples of Tishchenko reactions using SmI
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, see: (a)
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V. Reutrakul et al. / Tetrahedron Letters 47 (2006) 4753–4757
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4757
3
2
(1.2 mmol) solution freshly
guchi, S.; Ishii, Y. Tetrahedron Lett. 1998, 39, 6901–6902.
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prepared from samarium (60 mesh, 300 mg, 2 mmol) and
diiodomethane (0.1 mL, 1.2 mmol) in THF (10 mL). The
reaction mixture was stirred at ꢀ20 ꢁC for 15 min and then
was allowed to warm to rt for an additional 15 min. The
reaction mixture was cooled to ꢀ78 ꢁC before a solution
of freshly distilled aldehyde (3 mmol) in THF (1 mL) was
added. Stirring was continued at ꢀ78 ꢁC for 15 min, then
at rt for 1 h. The reaction was quenched with saturated
aqueous NaHCO3 (25 mL). The layers were separated,
and the aqueous layer was extracted with EtOAc
(3 · 50 mL). The combined organic layer was washed with
water (3 · 50 mL), saturated NaCl (50 mL), dried over
6
recent review on the use of SmI
2
in organic synthesis, see:
(
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7
8
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4
solid as a crude product.
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. Typical procedure for the tandem aldol-Tishchenko reac-
tion (Table 2): Under an atmosphere of argon at ꢀ20 ꢁC
(
MeOH–ice), a solution of phenylsulfonyl activated cyclo-
propyl ketone 1 (362 mg, 1 mmol) in THF (5 mL) was