Highly stereoselective indium trichloride-catalysed asymmetric aldol reaction of formaldehyde and a glucose-derived silyl enol ether in water

Article abstract of DOI:10.1039/a800486b

The yield and stereochemical outcome of the reaction between D-glucose-derived silyl enol ether 1 (Z and E isomers) and commercial formaldehyde in water catalysed by indium(III) choride was studied.

Full text of DOI:10.1039/a800486b

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Highly stereoselective indium trichloride-catalysed asymmetric aldol reaction
of formaldehyde and a glucose-derived silyl enol ether in water
Teck-Peng Loh,*† Guan-Leong Chua, Jagadese J. Vittal and Meng-Wah Wong
Department of Chemistry, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260
The yield and stereochemical outcome of the reaction
HO
O
TBDMSO
O
between D-glucose-derived silyl enol ether 1 (Z and E
isomers) and commercial formaldehyde in water catalysed
by indium(III) choride was studied.
HO
O
iii, iv
90%
i, ii
O
O
O
OBn
OH
OBn
97%
O
O
O
The many possible advantages of performing carbon–carbon
bond formation in aqueous media has resulted in studies by
several groups. This relatively unfamiliar territory, especially
reactions that are done without organic solvents, lends itself to
exploration in terms of reaction characteristics and stereo-
chemical behaviour.1
Here we report an efficient and highly stereoselective aldol
reaction between commercially available aqueous formal-
dehyde (37% in water) and silyl enol ether 1, which can be
easily obtained using glucose as starting material (Scheme 1).
The reaction conditions chosen have allowed for formaldehyde
to be used without prior dissolution or in situ generation in
highly basic or acidic conditions from paraformaldehyde, as
compared to reactions in organic solvents.
O
O
O
3
4
5
Scheme 2 Reagents and conditions: i, NaH, BnBr, Bu4NI, THF, room
temp., 48 h; ii, 0.06 m HCl, MeOH, room temp., 3 days; iii, TBDMSCl,
Et3N, DMAP, CH2Cl2, room temp., 18 h; iv, DMSO, (COCl)2
TBDMSO
OTBDMS
TMSO
TMSO
O
O
i or ii
+
5
OBn
OBn
ca. 90%
O
O
O
O
The use of 1 has allowed for the study of asymmetric
induction via the chiral centers and steric bulk of the various
groups. In addition, we aim to provide a stereoselective one-
carbon extension of glucose under mild conditions employing
readily available starting materials, in contrast to existing
methodologies.2 Previously reported use of commercial formal-
dehyde solution for Mukaiyama aldol reactions using lantha-
nide triflates was unable to be carried out efficiently in the
absence of organic solvents.3 Our aim in completely excluding
organic solvents had led us to our choice of InCl3 as a water-
stable Lewis acid from our earlier work.4 We had also studied
the characteristics of the unexplored In(OTf)3 and did a
comparative study with the lanthanide triflate Yb(OTf)3. Our
study demonstrated the superiority of InCl3 in terms of yield and
selectivity.
Ketone 5, precursor of silyl enol ether 1, was derived from
diacetone d-glucose in two steps (Scheme 2). Deprotonation of
C-6 using LDA and subsequent trapping of the enolate with
trimethylsilyl chloride gave (Z)-1 and (E)-1 in an approximate
ratio of 80:20 [Scheme 3, reaction conditions (i)]. The ratio of
the isomers was determined via 1H NMR spectroscopy, through
integration of the a-vinylic proton resonances, with the
Z-isomer at a lower field than the E-isomer.5‡
(E)-1
(i) 80
(ii)
(Z)-1
:
:
20
0
100
Scheme 3 Reagents and conditions: i, LDA, SiMe3Cl, THF, 278 °C to
room temp.; ii, Et3N, SiMe3Cl, DMF, 70 °C, 2 days
solution to the silyl enol ether. The reaction mixture was then
stirred vigorously§ at room temperature and monitored by TLC
for complete consumption of 1. Aqueous workup followed by
flash chromatography gave the desired products. The results are
shown in Table 1 (entries 1 to 3). The low yield observed for the
reaction catalysed by triflates was due to the significant
conversion of 1 to the ketone, particularly with 0.4 equiv. of
In(OTf)3, and deprotection of C-6 hydroxy group from the
product 2. Diastereoselectivities obtained were good, with
catalysis by InCl3 proceeding with excellent selectivity.¶ The
stereochemistry about C-6 of product (R)-2 was determined by
X-ray crystallographic analysis of (R)-6 obtained from depro-
tection of the C-6 hydroxy group (Scheme 4).∑
The lack of correlation between the isomer ratio of 1 and the
diastereoselectivities of the products suggests that both isomers
gave the same major product via conformational preference
The aqueous Mukaiyama aldol-type reaction was performed
by first activating the formaldehyde (commercial solution, 37%
in water, 2 equiv.) using Lewis acid (0.4 equiv. InCl3, 0.02
equiv. In(OTf)3 or 0.4 equiv. Yb(OTf)3) and then adding this
Table 1 Yields and diastereoselectivities for reactions described in
Scheme 1
Yielda
(%)
TBDMSO
Entry
E:Z
Lewis acid (equiv.)
t
R:S
OTBDMS
OH
H
O
TMSO
1
2
3
4
5
6
7
80:20
80:20
80:20
80:20
0:100 InCl3 (0.4)
0:100 In(OTf)3 (0.02)
0:100 Yb(OTf)3 (0.4)
InCl3 (0.4)
4–7 d
30 min
73
0b
96:4
—
O
O
i
In(OTf)3 (0.4)
In(OTf)3 (0.02)
Yb(OTf)3 (0.4)
OBn
OBn
0.5–1 d 38
93:7
88:12
82:18
70:30
54:46
O
O
O
2–3 d
4–7 d
40
68
O
0.5–1 d 37
2–3 d 35
1
2
Scheme 1 Reagents and conditions: i, CH2O (37% in H2O), Lewis acid,
room temp.
a Purified yield. b Extensive decomposition occurs.
Chem. Commun., 1998
861

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R
initio7,8 studies carried out for the four possible conformers of
silyl enol ether 4 are in good accord with the experimental
finding that the R-isomer is the preferred observed product
(Fig. 1).
In effect, this methodology exploits the structure provided by
the glucose derivative to achieve a highly stereoselective means
of one carbon extension under mild and readily accessible
reaction conditions. This, together with the well-established
chemistry of the carbohydrates, would provide for its adaptation
to natural product syntheses.
HO
OH
O
H
O
i
O
(R)-2
95%
OBn
O
6
Scheme 4 Reagents and conditions: i, TBAF, THF, 0 °C, 1 h
governed by thermodynamic factors. To further investigate this,
we managed to obtain exclusively (Z)-1 by use of Et3N as base
instead of LDA [Scheme 3, reaction conditions (ii)].6 Reaction
of (Z)-1 with formaldehyde using InCl3 as catalyst results in a
(R)-2 : (S)-2 ratio of 82:18 (Table 1, entry 5), a lower
diastereoselection from that previously obtained. Similar trends
were also observed with the triflates as Lewis acids (Table 1,
entries 6 and 7).
To rationalise our results, we propose the existence of a
preferred path of approach of the formaldehyde nucleophile
owing to the steric requirements imposed by the rigid silyl enol
ether. Hence, diastereofacial selection would depend on the
favoured conformation of the silyl enol ether. Standard ab
We acknowledge financial support for this project from the
National University of Singapore (Grant RP 9300657, RP
940633 and RP 950609).
Notes and References
† E-mail: chmlohtp@nus.edu.sg
‡ Chemical shifts of a-vinylic protons: (Z)-1 (s, 1 H, d 6.21); (E)-1 (s, 1 H,
d 6.08).
§ The heterogeneous nature of the mixture demands good continuous
mixing.
¶ Selectivities were determined from 13C NMR analysis of the purified
product through comparison of the signal intensities due to the carbonyl
carbon at d 205 for (R)-2 and d 206 for (S)-2.
∑ The assignment of the stereochemistry via X-ray crystallography is based
TBDMSO
TBDMSO
on the known and unchanged stereochemistry of the four chiral centres in
OTMS
O
the furanose ring. Crystal data for (R)-6: C17H22O7, M
296(2) K, orthorhombic, space group P212121,
b = 13.5051(1), c = 21.8795(5) Å, U = 1788.75(5) Å3, Z = 4, Dc = 1.256
Mg m23 0.098 mm21
m(Mo-Ka radiation, 0.71073 Å)
2qmax 58.76°, F(000) 720. Absorption correction: SADABS
=
338.35,
O
O
O
T
=
a = 6.0536(1),
TMSO
O
O
O
,
l
=
=
,
O
=
=
(Sheldrick, 1996), independent reflections = 4327, final R indices [I >
2s(I)]: R1 = 0.0566, wR2 = 0.1413, R indices (all data): R1 = 0.0899,
wR2 = 0.1596, GOF on F2 = 1.051.
(3)
(0)
H
OTBDMS
H
R
S
1 C. J. Li, Chem. Rev., 1993, 93, 2023.
2 A. Dondoni and A. Marra, in Preparative Carbohydrate Chemistry, ed. S.
Hanessian, Marcel Dekker, New York, 1997, p. 173.
3 S. Kobayashi and I. Hachiya, J. Org. Chem., 1994, 59, 3590.
4 T. P. Loh, J. Pei and G. Q. Cao, Chem. Commun., 1996, 1819.
5 D. A. Evans, in Asymmetric Synthesis, Vol. 3, Part B, ed. J. D. Morrison,
Academic Press, New York, 1984, p. 12.
HO
HO
OTBDMS
O
O
O
O
O
O
O
O
O
O
6 M. E. Garst, J. N. Bonfiglio, D. A. Grudoski and J. Marks, J. Org. Chem.,
1980, 45, 2307.
7 W. J. Hehre, L. Radom, P. V. R. Schleyer and J. A. Pople, Ab Initio
Molecular Theory, Wiley: New York, 1986.
OTBDMS
O
OTMS
O
8 Calculations were performed using the GAUSSIAN 92/DFT program:
M. J. Frisch, G. W. Tucks, H. B. Schlegel, P. M. Gill, B. G. Johnson,
M. W. Wong, J. B. Foresman, M. A. Robb, M. Head-Gordon,
E. S. Replogle, R. Gomperts, J. L. Andres, K. Raghavachari, J. S.
Binkley, C. Gonzalez, R. L. Martin, D. J. Fox, D. J. DeFrees, J. Baker,
J. J. P. Stewart and J. A. Pople, GAUSSIAN 92/DFT, Gaussian Inc.,
Pittsburgh PA, 1992.
TMSO
O
O
O
TBDMSO
(6)
O
O
O
(20)
Fig. 1 Numbers in parentheses denote the calculated relative energies in
kJ mol21
Received in Cambridge, UK, 19th January 1998; 8/00486B
862
Chem. Commun., 1998