Catalytic asymmetric addition of alcohols to imines: Enantioselective preparation of chiral N,O-aminals

Article abstract of DOI:10.1021/ja8033334

The enantioselective addition of alcohols to imine electrophiles has been shown to proceed in the presence of a catalytic amount of a chiral phosphoric acid catalyst. The reaction allows for the formation of the respective chiral N,O-aminals in excellent yield and enantioselectivity. A total of 11 different alcohols and 11 different imines were successfully used as a clear demonstration of the reaction generality. Copyright

Full text of DOI:10.1021/ja8033334

Published on Web 08/23/2008
Catalytic Asymmetric Addition of Alcohols to Imines: Enantioselective
Preparation of Chiral N,O-Aminals
Guilong Li,† Frank R. Fronczek,‡ and Jon C. Antilla*,†
Department of Chemistry, UniVersity of South Florida, 4202 East Fowler AVenue CHE205A, Tampa, Florida 33620,
Department of Chemistry X-Ray Laboratory, Louisiana State UniVersity, Baton Rouge, Louisiana, 70803
Received May 5, 2008; E-mail: jantilla@cas.usf.edu
The use of nonmetal based asymmetric catalysis has witnessed an
extremely rapid advancement since 2000.1 Led by the independent
pioneering studies of Akiyama and Terada in 2004, a variety of chiral
phosphoric acids were first shown to be excellent nonmetal chiral
catalysts for the asymmetric activation of imines.2 In relatively rapid
succession numerous methodological studies have recently shown that
the addition of nucleophiles to imines could provide potentially
synthetically useful amines with excellent enantioselectivity.3
Chiral N,O-aminals are structural motifs found in a number of
interesting natural products and pharmaceuticals. For example, chiral
N,O-aminal subunits are found in important natural products like
zampanolide,4a,b echinocandin B, spergualin, the tallysomycins, my-
calamide A,4c and other compounds in the pederin4d family along with
important targets like psymberin4e-h (Figure 1). The stereochemical
Figure 1. Natural products containing chiral N-acyl hemiaminals.
importance of this motif to biological activity is significant and well-
known as evidenced through cytotoxicity studies against various human
tumor cell lines in studies by De Brabander with psymberin4g and by
others in the pederin/mycalamide series.5 Another important aspect
of the chiral N-acyl hemiaminal subunit was that it represents a
particularly difficult synthetic challenge that had to be addressed in
the previous preparative studies.4d
Although some elegant methods were developed to construct N,O-
aminals, the preparation of chiral N,O-aminals via asymmetric catalysis
is still unknown.6 In 2005, we reported a highly enantioselective
amidation of imines7a catalyzed by VAPOL-phosphoric acid as part
of our ongoing studies involving asymmetric catalysis with chiral
Brønsted acids.7 We envisioned that because of this prior work the
Figure 2. Chiral phosphoric acid catalysts.
addition of an alcohol to an activated imine could reasonably present
a direct approach to chiral N,O-aminal products (Figure 2). Herein,
we would like to report our preliminary results, the first highly
enantioselective synthesis of N,O-aminals utilizing catalytic methodology.
Our best solvent was determined to be ethyl acetate, with the reaction
providing 3a in 52% ee in that case (entry 5).
The result of our catalyst screening showed that VAPOL-phosphoric
acid (A2) was a poor enantioselective catalyst for this reaction (entry
The development of methodology that can construct chiral N,O-
aminals was initially believed to be challenging to us due to their
presumed instability under basic, acidic, and other relatively harsh
conditions. Another significant issue arises from the fact that the
addition of alcohols to N-acyl imines can take place smoothly even
without catalytic promotion. We initiated our studies by running the
reactions under low temperature, believing that we could slow this
competitive background reaction. Using toluene as the solvent, we
treated imine 1 with methanol in the presence of catalyst (R)-A1.
However, upon addition a very low enantioselectivity was obtained
for product 3a. For example, in toluene at -30 °C the yield of 3a was
84%, but the ee, while nonzero, was still quite low (12% ee).
Unexpectedly at ambient temperature the ee value of 3a increased to
30%, albeit in a lower yield (Table 1, entry 1). A significant solvent
effect was found, with higher polarity solvents giving improved ee.
6). However, catalyst A3 provided for a 93% isolated yield of 3a with
a 94% ee (entry 7).8 Surprisingly lowering (entry 8) or slightly raising
the temperature (entry 9) had a deleterious effect on the enantiose-
lectivity. As indicated above, the reaction was found to proceed
smoothly even without adding any catalyst (entry 10). At this time, it
is not entirely clear how our catalytic reaction dominated the obvious
background reaction to provide such high enantioselectivities for the
desired product. Finally, it should be mentioned that anhydrous alcohols
and solvents are necessary to achieve high enantioselectivity.
It is clear that the chiral phosphoric acid-catalyzed addition of
alcohols to N-acyl imines is quite general (Table 2). For instance, the
use of primary alcohols like methanol, ethanol, and longer chain
varieties provide excellent yield and ee of the respective chiral aminal
(90-95% ee, entries 1-2 and 5-10) as determined by chiral HPLC.
Secondary alcohols, such as isopropanol, allowed for slightly lower
enantioselectivity (88% ee, entry 3). It is noteworthy that relatively
sterically hindered tert-butanol still afforded a high enantioselectivity
† University of South Florida.
‡ Louisiana State University.
9
12216 J. AM. CHEM. SOC. 2008, 130, 12216–12217
10.1021/ja8033334 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Optimized Conditions for the Addition of Methanol to
N-Acyl Imine 1
ring gave a lower enantioselectivity (83% ee, entry 16). While the
imine with m-methyl substitution gave slightly low selectivity (84%
ee, entry 17), the o-substituted (2-methyl) imine provided the same ee
with that of p-substituted (4-methyl) substrate (91% ee, entries 15 and
18). A lower enantioselectivity for an aliphatic imine was noted (65%
ee, entry 20). This was believed to be due to the level of imine purity
that could be obtained due to isomerization to the corresponding
enamine.
The absolute stereochemistry of the chiral N,O-aminal products was
determined by the single crystal X-ray diffraction of 3e (entry 5). This
unambiguously shows that the absolute configuration to be (R)-3e.9
In conclusion, we have successfully developed the first catalytic
asymmetric addition of alcohols to N-acyl imines catalyzed by chiral
phosphoric acids. The chiral N,O-aminal could be prepared in a
straightforward procedure in high yields with excellent enantiomeric
excess under mild reaction conditions. Future work will be directed
toward the extension of substrate scope, mechanistic studies, and
synthetic application.
entrya
solvent
catalyst
temp, °C
yield, %b
ee, %d
1
2
3
4
5
6
7
8
9
toluene
CHCl3
THF
CH3CN
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
A1
A1
A1
A1
A1
A2
A3
A3
A3
none
rt
rt
rt
rt
rt
rt
rt
0
35
rt
49
37
41
37
74
30
30
30
32
52
0
94
86
87
0
83
99(93)c
99
97
>95
10
a The reaction employed a molar ratio of 1:2 ) 1:2 (equiv), with a
concentration of 1 being 0.17 M. b Yield determined by 1H NMR. c 93%
Isolated yield. d Determined by chiral-HPLC analysis.
Table 2. Asymmetric Addition of Alcohols to N-Acyl Iminesa
Acknowledgment. We thank the Petroleum Research Fund for
funding (PRF 45899-G1).
Supporting Information Available: Experimental procedures, X-ray
details, and spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
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a Molar ratio of 1:2 ) 1:2 (equiv). b Isolated yield. c Determined by
chiral-HPLC analysis.
for product 3d (92% ee, entry 4). With the cyclic secondary
cyclohexanol substrate, a slightly lower enantioselectivity was found
presumably due to its rigid structure (81% ee, entry 6). In addition,
the reaction was found to tolerate alcohols with double and triple bond
functionality, which could provide a synthetic handle for further useful
transformations (entries 8 and 9). This methodology was also shown
to be quite efficient for a variety of N-acyl imines. All of the aromatic
N-acyl imines evaluated could provide the desired chiral N,O-aminals
in high yields and enantioselectivities. For instance, the reactions of
N-acyl imines derived from p-halogenated aromatic aldehydes afforded
88-93% ee values (Table 2, entries 11-13). The N-acyl imine bearing
a strong EWG such as a trifluoromethyl group also provided a product
with an excellent yield and high enantioselectivity (89% ee, entry 14).
Use of N-acyl imines substituted with a p-methoxy group on the phenyl
(8) Note that N-Boc substitution on the imine gave lower yields with good
selectivity (61% yield, 84% ee) while the corresponding N-3,5-dimethoxy-
bezoyl imine gave similar results (83% yield, 86% ee).
(9) Please see Supporting Information for X-ray crystallographic details.
JA8033334
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