Enantioselective aldol-type reaction using diketene

Article abstract of DOI:10.1081/SCC-200043192

An aldol-type reaction catalyzed by a Ti-(S)-BINOL complex using with a diketene as substrate is described herein. The complex derived from 1.0 molar equivalent of Ti(O-i-Pr)₄ and 2.0 molar equivalents of (S)-BINOL gave (5)-isopropyl 5-hydroxy-7-phenyl-3-oxo-6-heptenoate with high enantioselectivity.

Full text of DOI:10.1081/SCC-200043192

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Enantioselective Aldol‐Type
Reaction Using Diketene
Takahiro Kawase a , Shinobu Takizawa a , Doss
Jayaprakash a & Hiroaki Sasai a
a The Institute of Scientific and Industrial
Research (ISIR), Osaka University, Mihogaoka,
Ibaraki, Osaka, 567‐0047, Japan
Version of record first published: 10 Jan 2011.
To cite this article: Takahiro Kawase, Shinobu Takizawa, Doss Jayaprakash &
Hiroaki Sasai (2004): Enantioselective Aldol‐Type Reaction Using Diketene, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:24, 4487-4492
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 24, pp. 4487–4492, 2004
Enantioselective Aldol-Type Reaction
Using Diketene
Takahiro Kawase, Shinobu Takizawa, Doss Jayaprakash,
*
and Hiroaki Sasai
The Institute of Scientific and Industrial Research (ISIR), Osaka
University, Mihogaoka, Ibaraki, Osaka, Japan
ABSTRACT
An aldol-type reaction catalyzed by a Ti-(S)-BINOL complex using with
a diketene as substrate is described herein. The complex derived from 1.0
molar equivalent of Ti(O-i-Pr)4 and 2.0 molar equivalents of (S)-BINOL
gave (S)-isopropyl 5-hydroxy-7-phenyl-3-oxo-6-heptenoate with high
enantioselectivity.
Key Words: Aldol-type reaction; Diketene; Enantioselective; Titanium-
BINOL complexes.
*
Correspondence: Hiroaki Sasai, The Institute of Scientific and Industrial Research
(ISIR), Osaka University, Mihogaoka, Ibaraki, Osaka 567-0047, Japan; E-mail:
sasai@sanken.osaka-u.ac.jp.
4487
DOI: 10.1081/SCC-200043192
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4488
Kawase et al.
Optically active 5-hydroxy-3-oxoester derivatives 1 and 2 (which is easily
obtained from 1) are useful synthetic intermediates for various biologically
active compounds.[1] An enantioselective aldol-type reaction of silylenolate
3 with an aldehyde catalyzed by a chiral metal complex serves an effective
method for the preparation of 1.[2,3]
However, 3 must be synthesized from diketene and is unstable against aqueous
conditions. Thus, the direct use of diketene in this reaction is desirable
(Sch. 1).[4] Recently, the catalytic enantioselective reaction of diketene with
aldehyde promoted by a chiral Schiff base and Ti(O-i-Pr)4 was reported to
be achieved by Oguni et al. and Yanagisawa et al. (Sch. 2).[5,6]
In the present study, a simple and efficient alternative to the aldol-type
reaction was explored. Among the chiral ligands and Lewis acids screened
for the reaction, the Ti-(S)-BINOL complex[7] generated from Ti(O-i-Pr)4
and (S)-BINOL provided the most encouraging results; it afforded adduct 4
with 53% ee (Table 1, entry 1).[8,9] The ester moiety of the adduct originated
from titanium alkoxide; therefore, the effect of alkoxide on the enantiomeric
excess was examined. However, the use of various titanium alkoxides with
smaller alkoxide than isopropoxide groups was not effective, and enantio-
meric excesses of the products were always low (,29% ee).[10] In addition,
the reaction did not proceed when Ti(O-t-Bu)4 was used. In an effort to
improve the enantioselectivity of this reaction, catalysts generated using
various ratios of Ti(O-i-Pr)4 and (S)-BINOL were examined. In contrast to
the catalyst derived with 1.0 molar equivalent of (S)-BINOL (entry 1), the
catalyst derived with 2.0 molar equivalents of (S)-BINOL afforded higher
selectivity[11] (entry 2). In the absence of (S)-BINOL, the reaction afforded
a racemic adduct in high yield (entry 4).
The low yield may be attributed to the strong coordination of the oxo-
functionalized product to the highly oxophilic titanium center, thereby inhibit-
ing further reaction. The formation of byproduct 5 as a result of proton
Scheme 1. Direct aldol-type reaction using diketene.

Enantioselective Aldol-Type Reaction Using Diketene
4489
Scheme 2. Catalytic enantioselective reaction of diketene using Schiff bases as a
ligand.
abstraction by the reaction intermediate was confirmed by NMR analysis of
the crude products.
The use of a Proton-Sponge as an additive to this reaction was then exam-
ined in an effort to further improve the yields of the product. As expected, in
the presence of the Proton-Sponge, the reaction proceeded smoothly, yielding
the adduct in an 85% yield. Interestingly, the absolute configuration of the
major enantiomer was reversed and the (S)-product was obtained with 25%
ee (Sch. 3).
The use of a Proton-Sponge was determined to enhance the yield of 4;
therefore, the ability of a chiral amine [(R)-6][12] to promote this reaction in
the absence of (S)-BINOL was examined. The reaction was completed in
Table 1. Aldol-type reaction of cinnamaldehyde and diketene catalyzed by Ti(O-i-
Pr)4-BINOL complexes.
Entry
BINOL (equiv)
Yield (%)
ee (%)
1
2
3
4
1.0
2.0
28
40
35
88
53
90
84
—
3.0
none

4490
Kawase et al.
Scheme 3. Effect of Proton-Sponge as additive.
only 6 h and the product was obtained in 92% yield. To our disappointment,
however, the obtained product was almost racemic.
In conclusion, the direct use of diketene in an aldol-type reaction with cin-
namaldehyde was attempted. The catalyst was prepared using 1.0 equivalent
of Ti(O-i-Pr)4 and 2.0 equivalents of BINOL, and yielded the (S)-4 with
high enantioselectivity. Further investigation of the aldol-type reactions
using diketene will be the focus of our continued research efforts.
EXPERIMENTAL
General Procedure
1H NMR and 13C NMR spectra were recorded on JEOL JNM-EX270 (1H
NMR-270 MHz, 13C NMR-67.7 MHz, Japan). All signals were expressed as
ppm down field from tetra methylsilane, which was used as the internal
standard. IR spectra were obtained using a SHIMADZU FTIR-8300
(Japan). Optical rotations were measured on a JASCO DIP-370 Polarimeter
(Japan). Column chromatography was performed on Kanto Silica Gel 60
(40–100 mm, Japan). Anhydrous CH2Cl2 was distilled from calcium hydride.

Enantioselective Aldol-Type Reaction Using Diketene
4491
General Procedure for Ti-(S)-BINOL Catalyzed Aldol-Type
Reaction Using Diketene
A mixture of (S)-BINOL (286 mg, 1.0 mmol) and Ti(O-i-Pr)4 (148 mL,
0.50 mmol) in 2.5 mL of CH2Cl2 was stirred at rt for 2 h. Cinnamaldehyde
(63 mL, 0.50 mmol) and diketene (77 mL, 1.0 mmol) were added to this
solution, and the reaction mixture was stirred for 24 h. The reaction was
quenched with 1 N HCl. After stirring for 2 h the mixture was extracted
using CH2Cl2. The extract was washed with saturated NaHCO3, dried over
MgSO4, and then concentrated. The residue was purified by silica column
chromatography (hexane/ethyl acetate ¼ 3/1) to give the product as a
yellow oil (55.3 mg, 40%). The optical purity of the product was determined
as 90% by HPLC analysis using a chiral stationary phase column [DAICEL
CHIRALPAK AD (Japan), hexane/i-PrOH ¼ 16/1, flow rate ¼ 0.5 mL/
min]: tR ¼ 50.2 min (R), tR ¼ 57.4 min (S). [a]2D5 215.28 (C ¼ 1.2, CHCl3)
1
[Lit.[5b] (90% ee); [a]D24 –16.78 (C ¼ 1.0, CHCl3)]. H NMR (CDCl3): d
1.26 (d, J ¼ 6.2 Hz, 6H), 2.86 (d, J ¼ 5.9 Hz, 2H), 2.94 (br s, 1H), 3.47
(s, 2H), 4.79 (q, J ¼ 5.9 Hz, 1H), 5.06 (m, J ¼ 6.2 Hz, 1H), 6.20 (dd,
J ¼ 15.9, and 6.2 Hz, 1H), 6.64 (d, J ¼ 15.9 Hz, 1H), 7.29 (m, 5H).
13C NMR (CDCl3): d 21.7, 49.6, 50.3, 68.4, 69.2, 126.4, 127.7, 128.4,
129.8, 130.5, 136.2, 166.2, 202.6. IR (neat): 3518, 2982, 1734, 1707, 1312,
1103 cm21. FAB-MS. 277 [M þ H]þ.
ACKNOWLEDGMENTS
We thank the technical staff at the Materials Analysis Center of our
institute.
REFERENCES AND NOTES
1. (a) Endo, A.; Kuroda, M.; Tsujita, Y.J. Antibiot. 1976, 29, 1346;
(b) Brown, A.G.; Smale, T.C.; King, T.J.; Hasenkamp, R.;
Thompson, R.H. J. Chem. Soc., Perkin Trans. 1976, 1165;
(c) Hayashi, M.; Yoshimoto, K.; Hirata, N.; Tanaka, K.; Oguni, N.;
Harada, K.; Matsushita, A.; Kawachi, Y.; Sasaki, H. Isr. J. Chem. 2002,
41, 241.
2. (a) Singer, R.A.; Carreira, E.M. J. Am. Chem. Soc. 1995, 117, 12360;
(b) De Rosa, M.; Soriente, A.; Scettri, A. Tetrahedron: Asymmetry
2000, 11, 3187; (c) Denmark, S.E.; Beutner, G.L. J. Am. Chem. Soc.
2003, 125, 7800.

4492
Kawase et al.
3. Soriente, A.; De Rosa, M.; Stanzione, M.; Villano, R.; Scettri, A. Tetra-
hedron: Asymmetry 2001, 12, 959.
4. Izawa, T.; Mukaiyama, T. Chem. Lett. 1975, 161.
5. (a) Oguni, N.; Tanaka, K.; Ishida, H. Synlett 1998, 601; (b) Hayashi, M.;
Tanaka, K.; Oguni, N. Tetrahedron: Asymmetry 1995, 6, 1833.
6. Other catalytic aldol-type reactions of diketene using BINAP have been
reported: Yanagisawa, A.; Matsumoto, Y.; Asakawa, K.; Yamamoto, H.
J. Am. Chem. Soc. 1999, 121, 892.
7. For reviews on binaphthol and binaphthol-titanium complexes, see: Pu, L.
Chem. Rev. 1998, 98, 2405.
8. The use of (S)-BINOL and M(O-i-Pr)3 (M ¼ Al, Y, La, Pr, Sm, Gd,
Er, Yb), BH3, and Et2Zn resulted in low yields. In the case of catalyst
derived from AlMe3, the reaction proceeded smoothly but enantiomeric
excess was very low.
9. Results of other titanium alkoxides; Ti(O-n-Bu)4 (29% ee), Ti(OEt)4
(22% ee), Ti(OMe)4 (5% ee).
10. Effect of reaction temperature: 2208C (37%, 23% ee, 96 h), 2408C
(23%, 9% ee, 96 h), reflux (trace, 24 h). Result of other solvents: THF
(30%, 23% ee, 24 h), ether (trace, 24 h), MeCN (trace, 24 h).
11. Results of reactions using other aldehydes under identical condition;
4-methoxycinnnamaldehyde (31%, 83% ee), 2-methoxycinnamaldehyde
(34%, 73% ee), cyclohexanecarboxaldehyde (18%, 31% ee).
12. Benson, S.C.; Cai, P.; Colon, M.; Haiza, M.A.; Tokles, M.; Snyder, J.K.
J. Org. Chem. 1988, 53, 5335.
Received in Japan May 24, 2004