C O M M U N I C A T I O N S
Table 3. VAPOL Phosphoric Acid-Catalyzed Asymmetric
Reduction of R-Imino Esters
overall yields (10-20%) but identical ee’s. However, in the three
cases utilizing alkyl-substituted R-imino esters, we found good yield.
These investigations provide clear evidence that this methodology
can be adapted to a general one-pot procedure, albeit with some
potential loss in yield.
In conclusion, we have developed chemistry whereby the CdN
group of R-imino esters can be reduced with excellent yield and
enantioselectivity utilizing hindered chiral phosphoric acids.
entry
R1
R2
time, h
yield, %a
ee
Acknowledgment. We thank the University of South Florida
for generous start-up funds and a New Researcher Award. J.C.A.
also thanks the Petroleum Research Fund for additional funding
(PRF 45899-G1). The authors also thank Emily B. Rowland for
catalyst preparation.
1
2
3
4
5
6
7
8
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
Ph
19
22
22
18
18
21
18
18
21
18
19
93
98
96
95
93
98
95
94
88
90
85c
96(R)d
96
94
98
98
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
3,5-FC6H3
Ph
96
98
95
Supporting Information Available: Experimental procedures,
characterization, chiral HPLC conditions, and spectra. This material is
9b
10b
11b
OMe
OMe
OMe
Me
99(S)d
96
(CH2)5CH3
CH2CH2Ph
98
References
a Isolated yields. b Imino esters were formed in situ from the correspond-
ing keto ester and p-anisidine in the presence of 4 Å molecular sieves
(reductive amination). Entries 9 and 10 were run at room temperature.
c Yield was determined after LAH reduction to the corresponding alcohol
(see Supporting Information). d The absolute stereochemistry of 3a and 3k
was determined after deprotection by comparison with literature rotation
data for the known amino acid esters (see Supporting Information).
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Wiley-VCH: Weinheim, Germany, 1998; Vol. 2.
(6) (a) Brown, J. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds; Springer: Heidelberg, 1999. (b)
Asymmetric Catalysis in Organic Synthesis; Noyori, R., Ed.; Wiley: New
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Shang, G.; Yang, Q.; Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 6360.
described conditions. It is interesting that, while our previously
reported imine amidation chemistry11 was particularly sensitive to
the purification methods for 1e, the above chemistry shows no
deleterious effects even with batches of catalyst that have given
less than ideal results with the methodology in ref 11.
In an effort to establish generality, we initiated a study where
we varied the R-imino ester substrate (Table 3). Aryl substitution
on the imine carbon (R2) showed no deleterious effects when para-
electron-donating groups were used (entries 2 and 3). Likewise,
the use of para-electron-withdrawing groups on the arene ring gave
a substrate that could be reduced with excellent yield and selectivity
(entries 4-6). A meta-substituted (3,5-FC6H3) arene was also a
suitable substrate for this reaction (entry 7).
(7) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int.
Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004,
126, 5356. (c) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem.
Soc. 2004, 126, 11804.
(8) For recent review articles on the use of chiral Brønsted acids as catalysts,
see: (a) Schreiner, P. R. Chem. Soc. ReV. 2003, 32, 289. (b) Pihko, P. M.
Angew. Chem., Int. Ed. 2004, 43, 2062. (c) Bolm, C.; Rantanen, T.;
Schiffers, I.; Zani, L. Angew. Chem., Int. Ed. 2005, 44, 1758. (d) Taylor,
M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (e)
Akiyama, T.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2006, 348, 999. (f)
Connon, S. J. Angew. Chem., Int. Ed. 2006, 45, 3909.
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Chem., Int. Ed. 2005, 44, 7424. (c) Storer, R. I.; Carrera, D. E.; Ni, Y.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84. (d) Rueping, M.;
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When the imine nitrogen was substituted with a phenyl group
(R1 ) H, entry 8), the chemistry was virtually identical to the
p-methoxyphenyl-substituted case (entry 1). We were pleased to
find that in our initial evaluation the use of primary alkyl-substituted
ketimines is suitable for reductions, providing high yield and
enantiomeric excess in three cases (entries 9-11). It should be noted
that in these three examples the imines were not preformed but
generated in situ in the presence of molecular sieves, before the
asymmetric reduction (reductive amination). In the last case (entry
11), the resulting R-amino ester could not be separated cleanly from
the Hantzsch ester byproduct, so subsequent LAH reduction was
necessary to provide an isolated yield (85% over two steps). We
determined the absolute stereochemistry of products 3a and 3k via
CAN deprotection of the PMP group and comparison with the
absolute rotation and ee of the respective known amino acid ester.12
During the discovery of this chemistry, we have found that, in
general, the use of in situ generated R-imino esters gave lower
(10) Note: for details on the current commercial availability of VAPOL,
VANOL, and their phosphoric acids, see the Supporting Information. For
their synthesis, see: Bao, J.; Wulff, W. D.; Dominy, J. B.; Fumo, M. J.;
Grant, E. B.; Rob, A. C.; Whitcomb, M. C.; Yeung, S.-Y.; Ostrander, R.
L.; Rheingold, A. L. J. Am. Chem. Soc. 1996, 118, 3392.
(11) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni, S.; Wang,
Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696.
(12) See Supporting Information for requisite details.
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