Aldol reaction under solvent-free conditions: Highly stereoselective synthesis of 1,3-amino alcohols

Article abstract of DOI:10.1021/ol000042s

(formula presented) A method for the highly stereoselective synthesis of 1,3-amino alcohols based on the indium trichloride-catalyzed Mukaiyama aldol reaction of keto ester (R,S)-1 under solvent-free conditions has been developed. The high selectivity obs

Full text of DOI:10.1021/ol000042s

ORGANIC
LETTERS
2000
Vol. 2, No. 9
1291-1294
Aldol Reaction under Solvent-Free
Conditions: Highly Stereoselective
Synthesis of 1,3-Amino Alcohols
Teck-Peng Loh,* Jing-Mei Huang, Swee-Hock Goh, and Jagadese J. Vittal
Department of Chemistry, The National UniVersity of Singapore, 3 Science DriVe 3,
Singapore 117543
chmlohtp@nus.edu.sg
Received February 29, 2000 (Revised Manuscript Received March 23, 2000)
ABSTRACT
A method for the highly stereoselective synthesis of 1,3-amino alcohols based on the indium trichloride-catalyzed Mukaiyama aldol reaction
of keto ester (R,S)-1 under solvent-free conditions has been developed. The high selectivity observed can be explained on the basis of the
shielding of one face by a remote substituent.
Organic reactions under solvent-free conditions have gained
in popularity in recent years.1 This is because no-solvent
reactions usually need shorter reaction times and simpler
reactors and result in simple and efficient workup procedures.
This relatively unfamiliar territory lends itself to exploration
in terms of reaction characteristics and stereochemical
behavior. Furthermore, reactions that are performed under
organic solvent-free conditions especially important and have
attracted much attention.
Recent research from our group has shown that indium
trichloride can function as a Lewis acid for many C-C bond
formation reactions such as an aldol reaction in aqueous
media as well as under solvent-free conditions.2 Our interest
in the application of this indium trichloride-catalyzed aldol
reaction under solvent-free conditions for the total synthesis
of a natural product has encouraged us to investigate the
aldol reaction of keto ester (R,S)-1a and (R,S)-1b with silyl
enol ethers as well as ketene silyl acetals. In this paper, we
report an efficient and highly stereoselective aldol reaction
of keto ester (R,S)-1a or (R,S)-1b with various silyl enol
ethers and ketene silyl acetals (Scheme 1). A new stereo-
chemical model based on the remote substituent effect is
proposed to explain the excellent level of 1,3-induction
observed for these reactions.
First, we investigated the reactivity as well as the selectiv-
ity of ketone (R,S)-1a3 with acetophenone-derived silyl enol
ether under neat conditions with a wide variety of Lewis
(3) Excellent stereoselectivity has also been observed in the indium-
mediated allylation of ketone ester (R,S)-1a in aqueous media. Submitted
for publication.
(4) (a) Mukaiyama, T.; Narasaka, K.; Banno, T. Chem. Lett. 1974, 1011.
(b) Mukaiyama, T.; Banno, T.; Narasaka, K. J. Am. Chem. Soc. 1974, 96,
7503. (c) Mukaiyama, T. Org. React. 1982, 28, 203.
(5) Kobayashi, S. Chem. Lett. 1991, 2187.
(6) (a) Cram, D. J.; Abd Elhafez, F. A. J. Am. Chem. Soc. 1952, 74,
5828. (b) Prelog, V. HelV. Chim. Acta 1953, 36, 308. (c) Cornforth, J. W.;
Conforth, R. H.; Mathew, K. K. J. Chem. Soc. 1959, 112. (d) Karabatsos,
G. J. J. Am. Chem. Soc. 1967, 89, 1367. (e) Cherest, M.; Felkin, H.; Prudent,
N. Tetrahedron Lett. 1968, 2199 (f) Anh, N. T.; Eisenstein, O. NouV. J.
Chem. 1977, 1, 61. (g) Anh, N. T. Top. Curr. Chem. 1980, 88, 145. (h)
Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353. (i)
Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 2819. (j)
Evans, D. A.; Michael J. D.; Joseph, L. D.; Micheal G. Y. J. Am. Chem.
Soc. 1996, 118, 4322-4343 and references therein.
(1) (a) Metzger, J. O. Angew. Chem., Int. Ed. 1998, 37, 2975 and
references therein. (b) Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55, 11149.
(2) (a) Loh, T. P.; Wei, L. L. Tetrahedron 1998, 54, 7615. (b) Loh, T.
P.; Pei, J.; Lin, M. Chem. Commun. 1996, 2315. (c) Li, X. R.; Loh, T. P.
Tetrahedron: Asymmetry 1996, 7, 1535. (d) Loh, T. P.; Wei, L. L. Synlett
1998, 975. (e) Loh, T. P.; Xu, K. C.; Sim, K. Y. Synlett 1998, 369. (f) Loh,
T. P.; Pei, J.; Cao, G.-Q. J. Chem. Soc., Chem. Commun. 1996, 1819. (g)
Loh, T. P.; Pei, J.; Koh, K. S.-V.; Cao, G.-Q.; Li, X.-R. Tetrahedron Lett.
1997,38, 3465; (corrigendum) Tetrahedron Lett. 1997, 38, 3993.
10.1021/ol000042s CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/08/2000

Scheme 1
Table 1. Reaction of Silyl Enol Ethers and Ketene Silyl
Acetals with (R,S)-1a and (R,S)-1b
acids. This neat Mukaiyama aldol reaction was performed
by first activating the ketone (solid, 1 equiv) using Lewis
acid (0.2 equiv) and then adding the silyl enol ether or ketene
silyl acetal (5 equiv). The reaction mixture was then stirred
at room temperature for 16 h. THF and 1 M hydrochloric
acid were then added followed by stirring for 2 h before
normal aqueous work up. The pure product was obtained
after purification by flash column chromatography. The
results are shown in Table 1.
1
a Selectivity was determined by H NMR and 13C NMR analyses. b 5a
and 5b were obtained instead of 3a and 3b. c 6a and 6b were obtained
instead of 4a and 4b.
It should be noted that the use of classical Lewis acids
such as BF3‚OEt2 (1 equiv) in dichloromethane under strict
anhydrous condition (-78 °C to room temperature, 20 h)
afforded no desired product (run 1).4 We also did a
comparative study of indium trichloride with lanthanide
triflates5 such as Sc(OTf)3, Yb(OTf)3, and La(OTf)3. Our
study demonstrated the superiority of InCl3 in terms of yield
and selectivity under solvent-free conditions. The InCl3-
catalyzed aldol reaction in water afforded the product in
lower yield although excellent selectivity was observed (run
4). Therefore, subsequent studies were carried out using
indium trichloride as the catalyst for the aldol reactions of
keto ester (R,S)-1a with a wide variety of silyl enol ethers
and ketene silyl acetals under solvent-free conditions. In all
cases, the reactions were clean and only the excess silyl enol
ethers or ketene silyl acetals and the aldol products were
detected after aqueous workup. The desired aldol products
4 were obtained in moderate to good yields with very high
1,3-induction (runs 5-9). The reactions with ketene silyl
acetal furnished the cyclized aldol products 5 in high
diastereoselectivity (runs 8 and 9). Similarly, the reaction
of (R,S)-1b with various silyl enol ethers or ketene silyl
acetals afforded the aldol products in very high selectivity.
Especially noteworthy is the higher selectivity observed when
ketone ester (R,S)-1b (R ) 1-naphthyl) was used instead of
(R,S)-1a (R ) phenyl) (runs 5 and 6).
The determination of the stereochemistry deserves com-
ment. The absolute stereochemistry of one of the products 2
(run 9) was determined by X-ray crystallographic analysis
(Figure 1). All the other products were determined on the
1
basis of the similarities of the polarities and the H NMR
and 13C NMR chemical shifts.
The X-ray structure of the olefin analogue (R,S)-7b was
obtained, and the structure is depicted in Figure 2. NMR
spectroscopy of the olefin analogues provides hints of the
molecular structure in solution (Figure 3). The proximity of
the naphthyl ring and the alkene double bond in (R,S)-7b is
indicated by the high field chemical shift of one of the vinyl
protons Ha (δ ) 4.47 ppm), which is in the plane of the
aromatic ring and hence is shielded by the ring current
compared to that of (R,R)-7b (δ ) 5.79 ppm). On the other
hand, the proximity of the naphthyl group with the R-amino
ester in (R,R)-7b manifests itself by the unusual high
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Org. Lett., Vol. 2, No. 9, 2000

Figure 3. 1H NMR spectra of (R,S)-7b and (R,R)-7b.
tion of ketone 10 in which the phenyl group was replaced
by a cyclohexyl group. To our surprise, the product was
obtained in 72% yield with excellent diastereoselectivity
(Scheme 2). This results obtained provide evidence that π-π
Figure 1. Crystal structure of 2.
Scheme 2
chemical shift of the methyl ester (δ ) 2.73 ppm) compared
with that (δ ) 3.73 ppm) in (R,S)-7b. This difference in
chemical shift of the R-amino methyl ester is preserved in
the corresponding ketone series.
The increase in diastereoselectivity for keto ester (R,S)-
1b where R is a more π-basic substituent provides possible
involvement of π-stacking in the transition state. To prove
whether π-π interaction is playing a role in this reaction,
we investigated the indium trichloride-catalyzed aldol reac-
attractive interaction plays no significant role in the control
of the stereoselectivity.
On the basis of the above evidence and the observed
stereochemistry of the products, we propose that the reaction
proceeded via transition state as shown in Scheme 3. The
phenyl group serves to shield one face of the carbonyl group,
thereby rendering the nucleophilic addition processes highly
stereoselective.
Scheme 3
Figure 2. Crystal structure of (R,S)-7b.
Org. Lett., Vol. 2, No. 9, 2000
1293

The traditional acyclic stereochemical control methods
usually derive their controlling power from steric repulsion
in a chelated rigid cyclic transition state; however, this
method of controlling chirality based on the remote sub-
stituent effect due to conformational preference has further
been demonstrated to be a useful method for acyclic
stereocontrol in the absence of any cyclic transition state.6
In conclusion, this work demonstrates that a remote
substituent can be used as a controlling element in the indium
trichloride-catalyzed aldol reaction under solvent-free condi-
tions. Efforts to apply this new acyclic stereocontrol model
to other organic transformations are under way.
Acknowledgment. This research was supported by the
grants from The National University of Singapore.
Supporting Information Available: Preparation of (R,S)-
1, X-ray crystallographic data of (R,S)-7 and 2, procedure
of indium trichloride-catalyzed aldol reaction of (R,S)-1a,
1
(R,S)-1b, and 10 and H, 13C NMR, mass spectra of all the
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL000042S
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Org. Lett., Vol. 2, No. 9, 2000