C O M M U N I C A T I O N S
Table 2. Mannich Reactions Catalyzed by 1c
the Strecker reaction. This raises the interesting possibility that the
mechanism of substrate activation may be different in the two
reactions, thereby suggesting great promise for the application of
this catalyst class to an even broader range of asymmetric reactions.
Acknowledgment. This work was supported by the NIH (GM-
43214) and by predoctoral fellowships from the National Science
Foundation and Pfizer to A.G.W. We thank Professor D. A. Evans
and Dr. M. Movassaghi for valuable discussions.
entry
imine
R
temp (°C)
yield (%)a
ee (%)b
1
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
Ph
-40
-30
-30
-30
4
-30
-30
-30
-30
-30
-40
-30
-30
-30
95
88
98
87
91
88
96
93
93
88
84
95
99
99
97
91
94
96
86
93
92
94
87
96
91
92
96
98
Supporting Information Available: Detailed experimental pro-
cedures and characterization data (PDF). This material is available free
o-CH3C6H4
m-CH3C6H4
p-CH3C6H4
p-OMeC6H4
p-FC6H4
m-BrC6H4
p-BrC6H4
1-naphthyl
2-naphthyl
2-furyl
3
4
5
6
7
References
8
9
(1) EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E., Ed.; Wiley-
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10
11
12
13
14
2-thienyl
3-quinolinyl
3-pyridyl
a Isolated yield after silica gel chromatography. b Absolute stereochem-
istry determined via correlation to authentic material17 and literature values.18
within 2 h, but no uncatalyzed reaction was observed at -40 °C
over 48 h.
Further catalyst optimization was achieved through the construc-
tion of a small, parallel library of 22 compounds, with systematic
variation of salicylaldimine, diamine, amino acid, and amide
components.14 Enantioselectivity in the Mannich reaction remained
invariant with changes in the para substituent of the salicylaldimine
ring. Accordingly, commercially available di-tert-butylsalicylalde-
hyde was used for the preparation of subsequent catalysts. In
contrast, replacement of the secondary amide with a tertiary amide
derivative, as in catalyst 1c, resulted in a significant improvement
in enantioselectivity (e.g., 5a was obtained in 95% yield and 97%
ee, Table 2, entry 1). The presence of the tertiary amide also served
to prevent undesired formation of thiohydantoin byproducts during
catalyst preparation.15 This allowed the preparation of catalyst 1c
in five steps from commercially available starting materials in 86%
overall yield with only a single chromatographic purification step.
The scope of the reaction of 4c with N-Boc arylimine derivatives
is summarized in Table 2. Ortho-, meta-, and para-substituted
arylimines underwent addition with generally high enantioselectivity
and in excellent yield. One of the attractive features of this
methodology is the remarkable tolerance for Lewis basic substrates,
enabling the highly enantioselective synthesis of thienyl-, furyl-,
pyridyl-, and quinolinyl-substituted 3-amino propionic esters (entries
11-14). Indeed, all N-Boc imines screened to date have proven to
be excellent substrates with respect to both enantioselectivity and
yield.16 Reactions were carried out using 2 equiv of 4c relative to
the imine, as this was found to have a beneficial effect on rate,
particularly with electron-rich substrates. Electron-deficient imines
proved more reactive, however, and their efficient conversion could
be achieved with 1.2 equiv of nucleophile. For example, when
3-pyridinecarboxaldimine 3n was combined with 1.2 equiv of 4c
in the presence of 1c, 5n was obtained in 99% yield and 98% ee
within 48 h. This and similar reactions have been carried out on
scales as high as 10 mmol with no detrimental effect on yield or
enantioselectivity. The resulting Boc-protected, â-amino acid
derivatives are readily deprotected under mildly acidic conditions
and are well suited for direct use in peptide synthesis.17
(5) For recent reports on the catalytic asymmetric Mannich reaction in the
synthesis of â-amino acid derivatives, see: (a) Ishitani, H.; Ueno, M.;
Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 8180-8136. (b) Xue, S.;
Yu, S.; Deng, Y.; Wulff, W. D. Angew. Chem., Int. Ed. 2001, 40, 2271-
2274. (c) Co´rdova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C.
F., III. J. Am. Chem. Soc. 2002, 124, 1866-1867. (d) Kobayashi, S.;
Matsubara, R.; Kitagawa, H. Org. Lett. 2002, 4, 143-145.
(6) For examples of alternative enantioselective catalytic routes to â-amino
acid derivatives, see: (a) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperese, C.
P. J. Am. Chem. Soc. 1998, 120, 6615-6616. (b) Myers J. K.; Jacobsen,
E. N. J. Am. Chem. Soc. 1999, 121, 8959-8960. (c) Nelson, S.; Spencer,
K. L. Angew. Chem., Int. Ed. 2000, 39, 1323-1325. (d) Hodous, B. L.;
Fu, G. C. J. Am. Chem. Soc. 2002, 124, 1578-1579. (e) Zhou, Y.-G.;
Tang, W.; Wang, W.-B.; Li, W.; Zhang, X. J. Am. Chem. Soc. 2002, 124,
4952-4953. (f) Davies, H. M. L.; Venkataramani, C. Angew. Chem., Int.
Ed. 2002, 41, 2197-2199.
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Tetrahedron Lett. 1996, 37, 1691-1694. (c) Mu¨ller, R.; Ro¨ttele, H.; Henke,
H.; Waldmann, H. Chem.-Eur. J. 2000, 6, 2032-2043.
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32, 5287-5290. (b) Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.;
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(9) (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901-
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Ed. 2000, 39, 1279-1281. (c) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000,
2, 867-870. (d) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
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(10) Other imine protecting groups examined under the same reaction condi-
tions: N-Cbz benzaldimine, 26% ee; N-tosyl benzaldimine, 0% ee.
(11) The enantioselectivity of this reaction is relatively insensitive to dilution,
stoichiometry, and rate of nucleophile addition. No change in enantiose-
lectivity was observed with solvents of low polarity, while strongly polar
aprotic solvents led to dramatically poorer ee’s. Use of protic solvents
resulted in rapid decomposition of the imine.
(12) Thiourea catalysts also display enhanced enantioselectivity relative to their
urea counterparts in the case of the Strecker reaction.9d
(13) While HMPA has traditionally been used as a cosolvent for tert-
butyldimethylsilylation of lithium enolates, both DMPU or 1-methyl-2-
pyrrolidinone (NMP) are effective alternatives.
(14) Full details of catalyst structure/enantioselectivity profiles for both the
Mannich and the Strecker reactions will be reported in due course.
(15) Thiohydantoin formation proved problematic in the preparation of thiourea
derivatives bearing secondary amides. Detailed experimental procedures
are provided as Supporting Information.
(16) Aliphatic N-Boc imines have as yet not been investigated because no useful
method currently exists for their synthesis.
(17) (a) Podlech, J.; Seebach, D. Liebigs Ann. 1995, 1217-1228 and references
therein. (b) Gademann, K. Ph.D. Dissertation, Eidgeno¨ssische Technische
Hochschule, Zu¨rich, Switzerland, 2000.
In summary, urea derivatives of general structure 1 serve as
highly effective catalysts for the asymmetric addition of silyl ketene
acetal derivatives to aldimines. From a steric and electronic
standpoint, the N-Boc imine substrates utilized in this reaction are
fundamentally different from the N-alkyl derivatives employed in
(18) (a) Hanessian, S.; Sanceau, J.-Y. Can. J. Chem. 1996, 74(4), 621-624.
(b) Davis, F. A.; Szewczyk, J. M. Tetrahedron Lett. 1998, 39, 5951-5954.
JA028353G
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