Tandem aldol-reduction reaction of dimethylsilyl enolates: A new method for stereoselective preparation of 1,3-diols

Article abstract of DOI:10.1246/cl.2000.150

In the presence of a catalytic amount of TBAF (Bu₄NF), dimethylsilyl enolates derived from acyclic ketones reacted with aldehydes to give syn,syn-1,3-diols 7a and 8a with moderate to high diastereoselectivity. The stereochemical outcome can be attributed to a syn-selective aldol reaction and the subsequent 1,2-syn-selective intramolecular reduction.

Full text of DOI:10.1246/cl.2000.150

Chemistry Letters 2000
150
Tandem Aldol-Reduction Reaction of Dimethylsilyl Enolates:
A New Method for Stereoselective Preparation of 1,3-Diols1
Katsukiyo Miura, Takahiro Nakagawa, Shuntaro Suda, and Akira Hosomi*
Department of Chemistry and Graduate School of Chemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8571
(Received November 12, 1999; CL-990971)
In the presence of a catalytic amount of TBAF (Bu4NF),
The formation of 3a and 3c,d should proceed via syn- and
anti-isomers of β-siloxyketone, 4a and 4b, respectively. This
was ascertained by the experiments using 4a and 4b prepared
by silylation of 2a and 2b with HN(SiHMe2)2 (Scheme 1). As
expected, 4a was converted to 3a by heating in DMF. No for-
mation of 3b was observed. Under the same conditions, the
reaction of 4b gave a diastereomeric mixture of 3c and 3d in a
low yield. Accordingly, the preferred formation of 3a to 3b-d
in the uncatalyzed tandem reaction would be due to fast intra-
molecular reduction of 4a leading to 3a although the rate dif-
ference between 4a and 4b is insufficient to promote exclusive
formation of 3a at 100 °C.
dimethylsilyl enolates derived from acyclic ketones reacted
with aldehydes to give syn,syn-1,3-diols 7a and 8a with mod-
erate to high diastereoselectivity. The stereochemical outcome
can be attributed to a syn-selective aldol reaction and the sub-
sequent 1,2-syn-selective intramolecular reduction.
Stereoselective preparation of the 1,3-diol unit has been
strongly required in synthetic organic chemistry due to its
prevalence in biologically active natural products.2-4 For this
reason, the stereo-controlled reduction of β-hydroxyketones,
which are readily prepared by the directed aldol reaction in
regio- and stereoselective manner, has been extensively stud-
ied, and it nowadays provides an efficient and reliable method
for the stereoselective synthesis of 1,3-diols.3c,5,6 Tandem
reactions, in which two or more types of processes take place
in a single step, are useful for expeditious synthesis of complex
molecules.7 However, the tandem aldol-reduction reaction
directly forming 1,3-diols from ketone enolates and aldehydes
is largely unexplored.8
Previously, we have found that, in the uncatalyzed aldol
reaction of dimethylsilyl (DMS) enolates with aldehydes, 1,3-
diols are formed as a by-product with high diastereoselecti-
vity.9 This fact indicates that DMS enolates can serve as a
bifunctional reagent10 accomplishing the tandem aldol-reduc-
tion reaction. Thus, our interest focused on an efficient and
stereoselective synthesis of 1,3-diols using DMS enolates. We
herein report the results of the tandem reaction of DMS eno-
lates with aldehydes.
We first examined the uncatalyzed reaction of DMS eno-
late 1 with benzaldehyde in DMF and attempted optimization
of the reaction conditions to obtain 1,3-diols selectively (Eq.
1). As reported previously,8 the reaction with 2 equiv. of 1 at
50 °C for 48 h followed by an acidic work-up gave aldol 2
(79%, 2a:2b = 58:42) along with 1,3-diol 3 (14%, 3a:3c+3d =
97:3). A prolonged reaction time was not so effective in
improving the yield of 3 (27% after 96 h). The reaction at 100
°C gave 3 as a major product (66% after 48 h), but the
diastereoselectivity was not so high (3a:3c:3d = 75:2:23).11
The present tandem process can realize highly stereoselec-
tive and efficient preparation of 1,3-diols when both the initial
aldol reaction and the subsequent reduction efficiently proceed
with high diastereoselectivity. The fluoride ion-catalyzed aldol
reaction of certain silyl enolates is known to exhibit high syn-
selectivity.12 In addition, the fluoride ion also catalyzes car-
bonyl reduction with hydrosilanes.13 Therefore, we next inves-
tigated the fluoride ion-catalyzed system.
In the presence of TBAF (6 mol%), the reaction of DMS
enolate 1 (1.1 equiv.) with benzaldehyde at -78 °C for 15 h
gave a diastereomeric mixture of 3 (3a:3b:3c:3d = 27:6:53:14)
in 75% yield. The low stereoselectivity is reasonable in view
of the unsuccessful stereochemical result in the fluoride ion-
catalyzed aldol reaction of TMS enolate of cyclohexanone.12
In contrast, the use of DMS enolate 5 (1.2 equiv.) achieved
high yield and stereoselectivity (91%, 7a:7b = 97:3, Eq. 2). In
this case, syn,syn-1,3-diol 7a was formed exclusively, and no
aldol adduct 6 was detected.14 Lowering the reaction tempera-
ture to -98 °C improved the selectivity (7a:7b = >99:1)
although the yield decreased to 51% due to a considerable for-
mation of aldol adduct 6 (30%). Other examples of the tandem
aldol-reduction reaction are summarized in Table 1. The reac-
tions of 5 with aromatic aldehydes gave good results in both
yield and stereoselectivity. 3-Phenylpropanal was less reactive
to 5. DMS enolates of aliphatic ketones also reacted with ben-
zaldehyde to afford the corresponding syn,syn-1,3-diols 8a pre-
dominantly.
The exclusive formation of syn,syn-1,3-diol 7a indicates
that the aldol reaction of 5 with benzaldehyde proceeds with
high syn-selectivity. This is consistent with the previously
reported results with TMS enolate of propiophenone.12a The
formation of 7a also suggests that the subsequent carbonyl
Copyright © 2000 The Chemical Society of Japan

151
Chemistry Letters 2000
In the tandem reaction of acyclic DMS enolates, the syn-
selectivity of the initial aldol reaction can be rationalized by
consideration of the antiperiplanar transition state as proposed
by Noyori et al.12a The reason for the 1,2-syn-selectivity of the
carbonyl reduction is probably that the intramolecular hydride
transfer proceeds via conformation A rather than the unfavor-
able conformation B including the steric repulsion between the
methyl and R1 groups (Scheme 4). In the transition state of the
hydride transfer, the repulsive interaction would be enhanced
by a torsional effect. It may also work against the reduction
via B.
In conclusion, the fluoride-ion catalyzed reaction of DMS
enolates with aldehydes provides a convenient method for the
stereoselective synthesis of certain 1,3-diols.
References and Notes
1
2
Studies on Organosilicon Chemistry. No. 150.
Reviews on 1,3-diol synthesis: T. Oishi and T. Nakata,
Synthesis, 1990, 635; C. Schneider, Angew. Chem., Int. Ed.
Engl., 37, 1375 (1998).
reduction is highly 1,2-syn-selective.15 Indeed, the fluoride
ion-catalyzed reduction of 9a and 9b derived from syn- and
anti-isomers of 6 proceeded with high levels of 1,2-syn-selec-
tivity to give 7a and 7b, respectively, without another possible
isomer (Scheme 2).
3
Recent papers on 1,3-diol synthesis: a) N. A. Powell and S. D.
Rychnovsky, J. Org. Chem., 64, 2026 (1999). b) Y. Q. Tu, L. D.
Sun, and P. Z. Wang, J. Org. Chem., 64, 629 (1999). c) D.
Blanc, V. Ratovelomanana-Vidal, A. Marinetti, and J.-P. Genêt,
Synlett, 1999, 480.
4
5
Natural products including 1,3-diol unit: S. D. Rychnovsky,
Chem. Rev., 95, 2021 (1995); R. D. Norcross and I. Paterson,
Chem. Rev., 95, 2041 (1995); R. W. Hoffmann, Angew. Chem.,
Int. Ed. Engl., 26, 489 (1987).
N. Greeves, in "Comprehensive Organic Synthesis," ed by B. M.
Trost and I. Fleming, Pergamon Press, Oxford (1991), Vol. 8,
Chap. 1.1, p. 1.
6
7
8
S. Anwar, G. Bradley, and A. P. Davis, J. Chem. Soc., Perkin
Trans. 1, 1991, 1383 and references cited therein.
L. F. Tietze, Chem. Rev., 96, 115 (1996); G. A. Molander and C.
R. Harris, Chem. Rev., 96, 307 (1996).
R. Mahrwald and B. Gundogan, Chem. Commun., 1998, 2273; P.
M. Bodnar, J. T. Shaw, and K. A. Woerpel, J. Org. Chem., 62,
5674 (1997); R. Mahrwald and B. Costisella, Synthesis, 1996,
1087.
In order to prove that the reduction of 9 proceeds intra-
molecularly, the fluoride ion-catalyzed reactions of TMS
ethers 10a and 10b with (benzyloxy)dimethylsilane were per-
formed (Scheme 3). As a result, no reduction of 10a was
observed under the same conditions as those shown in Scheme
2. On the other hand, the reaction of 10b gave anti,anti-1,3-
diol 7c as a major product in a moderate yield. The slow reac-
tion rate and the reversed stereoselectivity in this inter-
molecular system strongly support that the reduction of 9 is an
intramolecular process.
9
K. Miura, H. Sato, K. Tamaki, H. Ito, and A. Hosomi,
Tetrahedron Lett., 39, 2585 (1998).
10 L. M. Frost, J. D. Smith, and D. J. Berrisford, Tetrahedron Lett.,
40, 2183 (1999).
11 We also attempted the uncatalyzed reaction of 5 with benzalde-
hyde. However, it hardly afforded 1,3-diol 7 even at 100 °C.
12 a) R. Noyori, I. Nishida, and J. Sakata, J. Am. Chem. Soc., 105,
1598 (1983). b) E. Nakamura, M. Shimizu, I. Kuwajima, J.
Sakata, K. Yokoyama, and R. Noyori, J. Org. Chem., 48, 932
(1983).
13 M. Fujita and T. Hiyama, J. Org. Chem., 53, 5405 (1988).
14 The Lewis acid (SnCl4, TiCl4, and BF3·Et2O)-mediated reaction
of 5 with benzaldehyde gave only 6 without 7, although it was
known that a Lewis acid induced the intramolecular hydrosilyla-
tion of ketones. S. Anwar and A. P. Davis, J. Chem. Soc., Chem.
Commun., 1986, 831. See also Ref. 6.
15 Fujita and Hiyama have reported that the fluoride ion-catalyzed
intramolecular reduction of a β-(dimethylsilyloxy)ketone pro-
ceeds with moderate 1,3-anti-selectivity. See Ref. 13.