Synthesis of enantiomerically pure anti-aldols: A highly stereoselective ester-derived titanium enolate aldol reaction

Full text of DOI:10.1021/ja9539148

J. Am. Chem. Soc. 1996, 118, 2527-2528
2527
Scheme 1a
Synthesis of Enantiomerically Pure Anti-Aldols: A
Highly Stereoselective Ester-Derived Titanium
Enolate Aldol Reaction
Arun K. Ghosh* and Masanobu Onishi
Department of Chemistry
UniVersity of Illinois at Chicago
845 West Taylor Street, Chicago, Illinois 60607
ReceiVed NoVember 21, 1995
The aldol reaction leading to enantioselective construction
of carbon-carbon bonds has emerged as an extremely powerful
method in organic synthesis. In this context, a number of
excellent synthetic methods have been developed over the
years.1 The control of both relative and absolute acyclic
stereochemistry in aldol reactions can now be achieved in a
highly stereoselective manner with a high degree of predict-
ability. Such control has become particularly sophisticated in
the synthesis of various syn-aldol products and is used widely.2
We have recently reported that commercially available optically
active cis-1-amino-2-indanol-derived oxazolidinones are highly
effective chiral auxiliaries for syn-aldol reactions.3 The corre-
sponding enantioselective anti-aldol methodologies are currently
an active area of research.4 Herein, we report the development
of a convenient cis-1-arylsulfonamido-2-indanol-derived tita-
nium ester enolate based aldol reaction to provide anti-aldol
products with excellent diastereoselectivity and isolated yields.
Optically active cis-1-arylsulfonamido-2-indanols are readily
accessible by sulfonylation of commercially available, enan-
tiomerically pure cis-1-amino-2-indanols. The optically pure
anti-R-methyl-â-hydroxy acids are conveniently obtained after
removal of the chiral auxiliary under mild saponification
conditions, and the chiral auxiliary is recovered without loss of
optical purity.
a Key: (a) CH3CH2COCl, Et3N, CH2Cl2, 23 °C; (b) TiCl4, iPr2NEt,
23 °C then RCHO and TiCl4, CH2Cl2, -78 °C; (c) LiAlH4, THF, 0-23
°C; (d) Me2C(OMe)2, PPTS, CH2Cl2, 23 °C; (e) LiOH, THF-H2O, 23
°C; (f) CH2N2, Et2O, 23 °C.
and triethylamine (3 equiv) in CH2Cl2 in the presence of a
catalytic amount of DMAP at 23 °C for 12 h (85-92% yield).
The acylation of hydroxy sulfonamide 1 with propionyl chloride
(1.2 equiv) and triethylamine (3 equiv) in CH2Cl2 at 23 °C for
12 h afforded the propionate ester 2 (mp 106 °C; R23D +86°, c
0.98, CHCl3) after silica gel chromatography (91% yield). The
titanium enolate of 2 was generated by reaction with 1.2 equiv
of TiCl4 in CH2Cl2 at 0-23 °C for 15 min followed by addition
of 4 equiv of N-ethyldiisopropylamine at 23 °C and stirring of
the resulting brown solution for 1 h.6,7 The 1H-NMR (400 MHz)
studies of the titanium enolate generated in a mixture of CDCl3
and CH2Cl2, as described above, established that the enolization
is complete under these conditions, providing a single enolate
presumably with Z-geometry.8 The titanium enolate thus
generated was reacted with 2 equiv of butyraldehyde or
isobutyraldehyde at -78 to 23 °C for several hours; interest-
ingly, however, no aldol product was obtained, and the starting
propionate ester 2 was recovered unchanged. However, the
reaction of the above titanium enolate with various aldehydes
precomplexed with TiCl4 proceeded with good to excellent
diastereoselectivities and isolated yields. The reactions are
typically carried out by addition of the above titanium enolate
to a solution of 2 equiv of aldehyde precomplexed with 2.4
equiv of TiCl4 in CH2Cl2 at -78 °C followed by stirring the
resulting mixture for 1 h and workup with aqueous NH4Cl
The 1R,2S-chiral sulfonamide 1 was prepared (Scheme 1)
by reaction with commercially available5 optically active 1(R),2-
(S)-cis-aminoindan-2-ol, p-toluenesulfonyl chloride (1 equiv),
(1) (a) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1984; Vol. 3, p 111. (b) Evans, D. A.; Nelson,
J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1. (c) Masamune, S.; Choy,
W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24, 1.
(d) Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24. (e) Franklin, A.
S.; Paterson, I. Contemp. Org. Synth. 1994, 317.
(2) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127. (b) Evans, D. A. Aldrichimica Acta 1982, 15, 23. (c) Paterson,
I.; Lister, M. A.; McClure, C. K. Tetrahedron Lett. 1986, 27, 4787. (d)
Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am. Chem. Soc.
1989, 111, 5493. (e) Oppolzer, W.; Blagg, J.; Rodriguez, I.; Walther, E. J.
Am. Chem. Soc. 1990, 112, 2767. (f) Roder, H.; Helmchen, G.; Peters,
E.-M.; Peters, K.; von Schmering, H.-G. Angew. Chem., Int. Ed. Engl. 1984,
23, 898. (g) Sankhavasi, W.; Yamamoto, M.; Kohmoto, S.; Yamada, K.
Bull. Chem. Soc. Jpn. 1991, 64, 1425. (h) Drewes, S. E.; Malissar, D. G.
S.; Roos, G. H. P. Chem. Ber. 1991, 124, 2913.
(3) Ghosh, A. K.; Duong, T. T.; McKee, S. P. J. Chem. Soc., Chem.
Commun. 1992, 1673.
(4) (a) Meyers, A. I.; Yamamoto, Y. Tetrahedron 1984, 40, 2309. (b)
Helmchen, G.; Leikauf, U.; Taufer-Knopfel, I. Angew. Chem., Int. Ed. Engl.
1985, 24, 874. (c) Gennari, C.; Bernardi, A.; Colombo, L.; Scolastico, C.
J. Am. Chem. Soc. 1985, 107, 5812. (d) Palazzi, C.; Colombo, L.; Gennari,
C. Tetrahedron Lett. 1986, 27, 1735. (e) Oppolzer, W.; Marco-Contelles,
J.; HelV. Chim. Acta 1986, 69, 1699. (f) Masamune, S.; Sato, T.; Kim, B.
M.; Wollman, T. A. J. Am. Chem. Soc. 1986, 108, 8279. (g) Danda, H.;
Hansen, M. M.; Heathcock, C. H. J. Org. Chem. 1990, 55, 173. (h) Corey,
E. J.; Kim, S. S. J. Am. Chem. Soc. 1990, 112, 4976. (i) Corey, E. J.; Kim,
S. S. Tetrahedron Lett. 1990, 31, 3715. (j) Meyers, A. G.; Widdowson, K.
L. J. Am. Chem. Soc. 1990, 112, 9672. (k) Duthaler, R. O.; Herold, P.;
Helfer, S.-W.; Riediker, M. HelV. Chim. Acta. 1990, 73, 659. (l) Walker,
M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56, 5747. (m) Oppolzer,
W.; Lienard, P. Tetrahedron Lett. 1993, 34, 4321. (m) Gennari, C.;
Moresca, D.; Vieth, S.; Vulpetti, A. Angew. Chem., Int. Ed. Engl. 1993,
32, 1618. (n) Paterson, I.; Wren, S. P. J. Chem. Soc., Chem. Commun.
1993, 1790 and references cited therein.
(6) While alkyl esters are known7a to be not enolizable with TiCl4/Et3N,
formation of titanium enolate from esters through internal chelation with
the sulfonamido group has been reported; see: Xiang, Y.; Olivier, E.;
Ouimet, N.; Tetrahedron Lett. 1992, 33, 457.
(7) For formation of other titanium enolates from N-propionyloxazoli-
dinones, see: (a) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.;
Bilodeau, M. T. J. Am. Chem. Soc. 1990, 112, 8215. (b) Evans, D. A.;
Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem. Soc. 1991, 113,
1047. (c) Bonner, M. P.; Thornton, E. R. J. Am. Chem. Soc. 1991, 113,
1299. (d) Siegel, C.; Thornton, E. R. J. Am. Chem. Soc. 1989, 111, 5722.
(e) Siegel, C.; Thornton, E. R. Tetrahedron Lett. 1986, 27, 457.
(8) 1H-NMR (CDCl3, 400 MHz): δ 7.78 (d, 2 H, J ) 8.3 Hz), 7.16-
7.35 (m, 6 H), 5.55 (d, 1 H, J ) 5.7 Hz), 4.67 (q, 1 H, J ) 7 Hz), 4.28 (m,
1 H), 3.05-3.14 (m, 2 H), 2.50 (s, 3 H), 1.51 (d, 3 H, J ) 7.0 Hz).
(5) Available from Aldrich Chemical Co., Milwaukee, WI and Sepracor
Inc., Marlborough, MA 01752.
0002-7863/96/1518-2527$12.00/0 © 1996 American Chemical Society

2528 J. Am. Chem. Soc., Vol. 118, No. 10, 1996
Communications to the Editor
Table 1. Aldol Reaction of Propionate Ester 2 with Representative
Aldehydes
entry
aldehyde
MeCHO
EtCHO
nPrCHO
iPrCHO
iBuCHO
MeCHdCHCHO
PhCHO
PhCH2CH2CHO
PhCHdCHCHO
% yielda
anti:syn (3/4)b
1
2
3
4
5
6
7
8
9
50c
50
74
91
97
41
85
44
63
85:15
85:15
95:5
85:15
>99:1
95:5
45:55
96:4
99:1
A
Figure 1.
derived anti-aldol product was converted to the optically pure
methyl ester 7 (R23 -4°, c 2.0, CHCl3; lit.4a R23 -2.5°, c
D
D
1.03, CHCl3). The relative and absolute stereochemistries of
the isobutyraldehyde-derived syn-aldol product 4 (entry 4) were
established by comparison of 1H-NMR (400 MHz) and optical
rotation of 4 with an authentic sample prepared utilizing Evan’s
boron enolate based syn-aldol reaction.2a The assignment of
stereochemistry for other syn-aldol products was made on the
a Isolated yield of both isomers after silica gel chromatography.
Time ) 1 h. b Diastereomeric ratios were determined by 1H-NMR and
HPLC. c Isolated anti-isomer only.
solution. The results are summarized in Table 1. The ester
enolate aldol reaction with a variety of conjugated and non-
conjugated aldehydes proceeded with excellent anti-diastereo-
selectivity except in the case of benzaldehyde, which did not
exhibit any selectivity.9 The diastereomeric mixture ratio was
determined by 1H-NMR (400 MHz) as well as by HPLC analysis
of the aldol products prior to chromatography. Aldol reaction
with butyraldehyde (entry 3) afforded an anti-diastereoselectivity
of 95:5. Both anti- and syn-isomers could be separated by silica
gel chromatography (74% combined yield). The reaction with
isovaleraldehyde proceeded with almost complete anti-diaste-
reoselectivity (>99% de by HPLC; 400 MHz 1H-NMR revealed
only one diastereomer) with 97% isolated yield after silica gel
chromatography. Similarly, the reaction with conjugated alde-
hydes also provided excellent anti-diastereoselectivity.10
In order to establish the relative stereochemistry, the anti-
isomer 3 derived from crotonaldehyde (entry 6) was converted
to the isopropylidene derivative 5 by reduction with LAH in
THF at 0 °C followed by exposure of the resulting diol to
dimethoxypropane in CH2Cl2 in the presence of a catalytic
1
basis of comparisons of H-NMR spectra.
The high degree of stereoselection associated with this current
asymmetric anti-aldol process could be rationalized by a
Zimmerman-Traxler type transition state model A (Figure 1).12
The model is derived based on the following assumptions: (1)
the geometry of the titanium enolate is Z; (2) the titanium enolate
is a seven-membered metallocycle with a chairlike conformation;
(3) a second titanium metal is involved in the transition state
where it is chelated to indanyloxy oxygen as well as to the
aldehyde carbonyl in a six-membered chairlike transition state.
The involvement of two titanium metal atoms is supported by
the fact that the titanium enolate derived from 2 does not react
with aldehydes without precomplexation with TiCl4. The above
transition state model accounts for the observed stereoselection
except in the case of benzaldehyde, which has shown no
selectivity. While this model explains much of the present
stereoselection, the evidence of such a model requires further
experimentation which is currently in progress.
In summary, the present chiral ester derived titanium enolate
aldol reaction with various aldehydes represents a highly
effective synthetic protocol for providing anti-aldol products
with high levels of diastereo- and enantioselectivity. The
generality of the current anti-selective aldol process has been
demonstrated with nine different aldehydes. Since both enan-
tiomers of cis-1-arylsulfonamido-2-indanol are readily prepared
from the commercially available optically active cis-1-amino-
2-indanols, the present anti-aldol methodology provides a
convenient access to either anti-aldol enantiomer with high
optical purity. Mechanistic investigations as well as synthetic
applications of the current anti-aldol methodology are the subject
of ongoing research in our laboratory.
1
amount of pyridinium p-toluenesulfonate. The H-NMR (400
MHz) analysis of 5 firmly established the identity of the anti-
isomer in this chiral ester enolate based aldol reaction. Of
particular interest, a coupling constant (JCD) of 10.1 Hz was
measured between the HC and HD protons of 5.11 The absolute
configurations of the new asymmetric centers of 3 were assigned
after removal of the chiral sulfonamides, conversion of the
resulting anti-R-methyl-â-hydroxy acids to the corresponding
methyl ester, and comparison of the optical rotations of the
resulting 7 with literature values.4a For example, treatment of
the isobutyraldehyde-derived anti-aldol product (entry 4) with
aqueous lithium hydroxide in THF at 23 °C for 2 h afforded
the corresponding acid which was converted to optically pure
methyl ester 7 (R23D -14.2°, c 1.04, CHCl3; lit.4a R23D -12.5°,
c 1.04, CHCl3) with an excess of diazomethane in diethyl ether.
The chiral sulfonamide 1 was recovered (95% after silica gel
chromatography) after saponification without loss of optical
purity (R23D -34°, c 1.5, CHCl3). Similarly, the butyraldehyde-
Acknowledgment. Financial support for this work was provided
by the University of Illinois at Chicago. The authors thank Professor
Steven Zimmerman and Donald Wink for helpful discussions. M.O.
is a visiting scientist from Nihon Nohyaku Co. Ltd., Japan.
Supporting Information Available: Experimental procedures and
spectral data for aldols and their derived â-hydroxy acids (11 pages).
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(9) When the aldol reaction was carried out with a 1:1 mixture of
benzaldehyde and isovaleraldehyde, the 1H-NMR of crude products revealed
the presence of a 65:35 ratio of anti/syn-diastereomers of benzaldehyde
and a single anti-isomer of isovaleraldehyde as seen in entry 5.
(10) All new compounds gave satisfactory spectroscopic and analytical
results.
(11) 1H-NMR (CDCl3, 400 MHz): δ 5.73 (dq, 1 H, J ) 6.5, 15.3 Hz,
HF), 5.38 (ddd, 1 H, J ) 1.3, 7.7, 15.3 Hz, HE), 3.84 (dd, 1 H, J ) 8.1,
10.1 Hz, HD), 3.73 (dd, 1 H, J ) 5.1, 11.7 Hz, HB), 3.54 (dd, 1 H, J )
11.5, 11.5 Hz, HA), 1.72 (dd, 3 H, J ) 1.3, 6.5 Hz), 1.66 (m, 1 H, He),
1.47 (s, 3 H), 1.41 (s, 3 H), 0.7 (d, 3 H, J ) 6.8 Hz).
JA9539148
(12) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920.