β-isocupreidine-catalyzed asymmetric Baylis-Hillman reaction of imines

Article abstract of DOI:10.1021/ol035102j

(Matrix presented) β-Isocupreidine (β-ICD)-catalyzed asymmetric Baylis-Hillman reactions of aromatic imines with 1,1,1,3,3, 3-hexafluoroisopropyl acrylate (HFIPA) give (S)-enriched N-protected-α -methylene-β-amino acid esters. In contrast to the corresponding aldehydes, imines show the opposite enantioselectivity. A mechanistic proposal governed by hydrogen bonding is presented.

Full text of DOI:10.1021/ol035102j

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3103-3105
â-Isocupreidine-Catalyzed Asymmetric
Baylis−Hillman Reaction of Imines
Sakie Kawahara, Ayako Nakano, Tomoyuki Esumi, Yoshiharu Iwabuchi, and
Susumi Hatakeyama*
Graduate School of Biomedical Sciences, Nagasaki UniVersity,
Nagasaki 852-8521, Japan
susumi@net.nagasaki-u.ac.jp
Received June 16, 2003
ABSTRACT
â-Isocupreidine (â-ICD)-catalyzed asymmetric Baylis−Hillman reactions of aromatic imines with 1,1,1,3,3,3-hexafluoroisopropyl acrylate (HFIPA)
give (S)-enriched N-protected-r-methylene-â-amino acid esters. In contrast to the corresponding aldehydes, imines show the opposite
enantioselectivity. A mechanistic proposal governed by hydrogen bonding is presented.
The Baylis-Hillman reaction has attracted considerable
interest due to the fascinating tandem Michael-aldol se-
quence catalyzed by a Lewis base (such as a tertiary amine)
and the promising utility of the multifunctional products.
Recent literature continues to record impressive progress in
rate acceleration as well as asymmetric induction based on
imaginative ideas.1
We previously reported a highly enantioselective asym-
metric Baylis-Hillman reaction of aldehydes giving (R)-
products by the combination of â-isocupreidine (â-ICD)2 as
a chiral amine catalyst and 1,1,1,3,3,3-hexafluoroisopropyl
acrylate (HFIPA) as an activated alkene (Scheme 1).3 In
addition, we have successfully demonstrated the synthetic
utility of this reaction via syntheses of biologically intriguing
natural products.4
In our ongoing work to exploit the synthetic potential of
the â-ICD-catalyzed Baylis-Hillman reaction, we became
interested in examining the reaction of imine-type substrates,5
which allows us to construct valuable R-methylene-â-amino
acid derivatives in optically active form. Recently, Shi et
al.6 and Adolfsson et al.7 reported that the â-ICD-catalyzed
(1) For reviews: (a) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988,
44, 4653. (b) Basavaiah, D.; Darma Rao, P.; Suguna Hyma, R. Tetrahedron
1996, 52, 8001. (c) Ciganek, E. In Organic Reactions; Paquette, L. A.,
Ed.; Wiley: New York, 1997; Vol. 51, p 201. (d) Langer, P. Angew. Chem.,
Int. Ed. 2000, 39, 3049. (e) Iwabuchi, Y.; Hatakeyama, S. J. Synth. Org.
Chem. Jpn. 2002, 60, 4. (f) Basavaiah, D.; Rao, A. J.; Satyanarayana, T.
Chem. ReV. 2003, 103, 811.
(2) We recently found that this compound was named â-isocupreidine
in the early study of cinchona alkaloids: Suszko, J. Rocz. Chem. 1935, 15,
209. For structural elucidation: Dega-Szafran, Z. Bull. Acad. Pol. Sci., Ser.
Sci. Chim. 1966, 14, 529.
(3) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am.
Chem. Soc. 1999, 121, 10219.
Scheme 1. â-ICD-Catalyzed Baylis-Hillman Reaction of
Aldehydes
(4) (a) Iwabuchi, Y.; Furukawa, M.; Esumi, T.; Hatakeyama, S. Chem.
Commun. 2001, 2030. (b) Iwabuchi, Y.; Sugihara, T.; Esumi, T.; Hatakeya-
ma, S. Tetrahedron Lett. 2001, 42, 7867.
(5) For recent studies on Baylis-Hillman reaction of imines: (a) Richter,
H.; Jung, G. Tetrahedron Lett. 1998, 39, 2729. (b) Aggarwal, V. K.; Castro,
A. M. M.; Mereu, A.; Adams, H. Tetrahedron Lett. 2002, 43, 1577. (c)
Balan, D.; Adolfsson, H. J. Org. Chem. 2002, 67, 2329. (d) Azizi, N.; Saidi,
M. R. Tetrahedron Lett. 2002, 43, 4305.
(6) Shi, M.; Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 41, 4507.
(7) Balan, D.; Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521.
10.1021/ol035102j CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/02/2003

reaction of N-tosyl imines and methyl acrylate produced (R)-
enriched adducts. However, we report herein that this type
of aza-Baylis-Hillman reaction gives (S)-enriched adducts.
We first surveyed the reaction of a series of imines8
derived from benzaldehyde with HFIPA using 0.1 equiv of
â-ICD in DMF at -55 °C, which revealed that appropriate
activation of the imine by the electron-withdrawing group
is essential for promotion of the reaction (Table 1). Thus,
â-ICD methyl ether 3 as a catalyst suggest the key role of
the phenolic OH of â-ICD on the rate acceleration as well
as the enantiocontrolling event (entries 6 and 7). The absolute
configurations of 2d-g were unambiguously determined to
be (S)-enriched by transforming the products to the corre-
sponding phenylglycine derivatives 49 and comparing them
to authetic samples10 prepared from (R)-(-)-phenylglycine
as shown in Scheme 2.11
Table 1. Reaction of N-Protected Imines of Benzaldehydea
Scheme 2. Determination of the Absolute Configuration
We next focused on the reaction of diphenylphosphinoyl
imines due to ease of removal12 of the activating group (Table
2). Fortunately, the products were crystalline and the optical
Table 2. Reaction of Diphenylphosphinoyl Iminesa
a Reactions were carried out at -55 °C in DMF (1.0 M) using imine 1
(1.0 equiv), HFIPA (1.3 equiv), and catalyst (â-ICD, QN, or 3) (0.1 equiv).
b Isolated yield. c Determined by the comparison with the degradation
product as shown in Scheme 2. d Determined by HPLC analysis using a
chiral column of the corresponding methyl ester obtained by methanolysis.
a Reactions were carried out at -55 °C in DMF (1.0 M) using imine 1
(1.0 equiv), HFIPA (1.3 equiv), and â-ICD (0.1 equiv). b Isolated yield.
c Determined by HPLC analysis using a chiral column. d Not determined.
reactions of 1a-c did not give any Baylis-Hillman products
and, instead, gradually afforded di(1,1,1,3,3,3-hexafluoroiso-
propyl) 2-methyleneglutarate via self-dimerization of HFIPA
(entries 1-3). In contrast, imines 1d-g activated by benzoyl,
sulfonyl, and diphenylphosphinoyl groups gave the desired
products 2d-g in good chemical yields (entries 4-9).
Among them, N-methanesulfonyl imine 1e and N-diphenyl-
phosphinoyl imine 1g turned out to exhibit better enantio-
selectivity (entries 5 and 9). The observed poor chemical
and optical yields of the reaction employing quinidine or
purity was easily enriched by simple recrystallization. It is
interesting to note that the electron-donating p-methoxy
group as well as the bulkier 1-naphthyl group increased the
enantioselectivity (entries 2 and 4), whereas the electron-
withdrawing p-nitro group markedly decreased the enantio-
selectivity (entry 3). The reaction of 2-naphthyl substrate was
very sluggish because of its poor solubility in the reaction
3104
Org. Lett., Vol. 5, No. 17, 2003

media (entry 5). Concerning aliphatic imines, satisfactory
results were not obtained because of their extremely labile
nature.
more severe steric interaction than intermediate B as depicted
in Scheme 4. Thus, the difference in the reaction rate of the
elimination step of B and C would result in (S)-enriched
enantioselectivity through equilibration.
Scheme 3 exemplifies the synthetic utility of the above-
mentioned methodology. Upon acid hydrolysis of 2g in
Scheme 4. Proposed Reaction Mechanism
Scheme 3. Conversion of 2g to â-Lactam 6
boiling hydrochloric acid, the diphenylphosphinoyl group
was cleaved cleanly to give â-amino acid hydrochloride 5.
Treatment of 5 with BOPCl in the presence of triethylamine
gave â-lactam 6. It is important to note that no racemization
occurred during this transformation.
We rationalize the observed enantioselectivity via a
reaction mechanism governed by hydrogen-bonding. Michael
addition of â-ICD to HFIPA forms enolate A, which in turn
undergoes Mannich reaction with the imine to furnish an
equilibrium mixture of several diastereomers. Among them,
there would be two betaine intermediates B and C that are
stabilized through hydrogen-bonding between the amidate
ion and the phenolic OH. On taking the anti-periplanar
arrangement13 of the ammonium portion and the R-hydrogen
of the ester group in the subsequent E2 or E1cb reaction
(see Newman projection D), intermediate C suffers from
In conclusion, we have shown for the first time that the
â-ICD-catalyzed Baylis-Hillman reaction of aromatic imines
with HFIPA proceeds with (S)-selectivity, in contrast to
reactions of aldehydes, which afford (R)-selectivity. The
present work provides an effective method for the preparation
of aryl-substituted R-methylene â-amino acid derivatives in
>93% ee by the reaction of diphenylphosphinoyl imines
followed by recrystallization.
(8) Imines were prepared according to the following procedures. For 1a
and 1b: Xue, S.; Yu, S.; Deng, Y.; Wulff, W. D. Angew. Chem., Int. Ed.
2001, 40, 2271. For 1c: Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy,
G. V.; Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.;
Carroll, P. J. J. Org. Chem. 1997, 62, 2555. For 1d: Gizecki, P.; Dhal, R.;
Toupet, L.; Dujardin, G. Org. Lett. 2000, 2, 585. For 1e and 1f: Georg, G.
I.; Harriman, G. C. B.; Peterson, S. A. J. Org. Chem. 1995, 60, 7366. For
1g-k: Yamada, K.; Harwood, S. J.; Gro¨ger, H.; Shibasaki, M. Angew.
Chem., Int. Ed. 1999, 38, 3504.
(9) (a) Li, G.; Wei, H.-X.; Whittlesey, B. R.; Batrice, N. N. J. Org. Chem.
1999, 64, 1061. (b) Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998,
120, 1207.
(10) Kobayashi, K.; Okamoto, T.; Oida, T.; Tanimoto, S. Chem. Lett.
1986, 2031.
(11) For example, 2f (46% ee) was converted to methyl (+)-N-(p-
toluenesulfonyl)phenylglycinate, [R]D17 +57.4° (c 0.51, CHCl3). Since the
(R)-enantiomer prepared from (R)-(-)-phenylglycine showed [R]D25 -113.6°
(c 2.33, CHCl3),11 2f was found to be (S)-enriched. The corresponding (S)-
enriched methyl ester obtained by methanolysis of 2f showed [R]17D +11.7°
(c 1.80, CHCl3). These results allowed us to conclude that Shi et al.6 and
Adolfsson et al.7 incorrectly determined the (+)-ester {+19.5° (83% ee),6
+16.8° (68% ee)7} to be (R)-enriched. Shi et al. did not clearly mention
how they deduced the absolute configuration. Adolfsson et al. determined
it on the basis of the specific rotation reported by Shi et al.
(12) (a) Ramage, R.; Hopton, D.; Parrott, M. J. J. Chem. Soc., Perkin
Trans. 1 1984, 1357. (b) Yamada, K.; Moll, G.; Shibasaki, M. Synlett 2001,
980. (c) Tsuritani, N.; Yamada, K.; Yoshikawa, N.; Shibasaki, M. Chem.
Lett. 2002, 276. (d) Cantrill, A. A.; Osborn, H. M. I.; Sweeney, J.
Tetrahedron 1998, 54, 2181.
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research on Priority Areas (A)
“Exploitation of Multi-Element Cyclic Molecules” from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan.
Supporting Information Available: Experimental details
and characterization data for all new compounds and 1H and
13C NMR spectra of 2d-k and 6. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL035102J
(13) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon: Oxford, 1983; pp 252-257.
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