Ag-Catalyzed Asymmetric Mannich Reactions of Enol Ethers with Aryl, Alkyl, Alkenyl, and Alkynyl Imines

Article abstract of DOI:10.1021/ja049388e

An efficient catalytic and enantioselective method (up to >98% ee) for Mannich reactions between trimethylsilyl enol ethers derived from acetone and acetophenone and aryl, alkenyl, alkynyl, and alkyl imines is disclosed. A large variety of β-amino ketones

Full text of DOI:10.1021/ja049388e

Published on Web 03/06/2004
Ag-Catalyzed Asymmetric Mannich Reactions of Enol Ethers with Aryl, Alkyl,
Alkenyl, and Alkynyl Imines
Nathan S. Josephsohn, Marc L. Snapper,* and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received February 3, 2004; E-mail: amir.hoveyda@bc.edu
Table 1. Ag-Catalyzed Enantioselective Mannich Reactions of
â-Amino carbonyls represent a class of compounds that can be
Silyl Ethers with Aryl Imines
used in the synthesis of biologically active molecules. The design
and development of catalytic asymmetric methods for the prepara-
tion of these building blocks is thus a critical objective in chemical
synthesis.1 Several laboratories have disclosed significant advances
regarding catalytic asymmetric additions of silyl ketene acetals to
imines (mostly aryl imines).2 Notable progress involving reactions
of the less nucleophilic enol ethers to afford â-amino ketones has
also been made; nonetheless, numerous challenges have not yet
1, AgOAc
T
yield
(%)b
ee
been effectively addressed. Two protocols are in connection with
additions of ketones with non-metal-based catalysts;3 however,
typically high loadings (20-35 mol %)3a,b are required, and, in
certain cases, reactions proceed with low enantioselectivities (<90%
ee).3a Some of the more efficient enantioselective metal-catalyzed
processes are particular to enol ethers and activated imines, such
as those derived from glyoxylates.4 One method has been designed
for the synthesis of R-hydroxyl,â-amino carbonyls and is limited
to reactions of enol ethers with an R-heteroatom (only aryl imines).5
Another approach deals with transformations of ketones that contain
an activating acyl substituent as well as a hydroxyl group adjacent
to the carbonyl (predominantly aryl imines).6
Herein, we report a general Ag-catalyzed asymmetric method
for additions of silyl enol ethers to aryl, alkyl, alkenyl, and alkynyl
imines. â-Amino ketones are obtained efficiently and in high optical
purity (up to >98% ee) in the presence of 1-5 mol % of AgOAc
and the readily available iso-Leu-derived phosphine 1. All catalytic
transformations can be effected with undistilled solvents and in air.
Amides or amines can be accessed by efficient removal of the
o-anisyl activating group. The utility of the method is demonstrated
by a concise enantioselective synthesis of alkaloid sedamine.
We first investigated the ability of chiral phosphine 1 and AgOAc
in promoting catalytic Mannich-type reactions, based on recent
results in connection with related cycloadditions.7 Our studies
focused on transformations involving TMS enol ethers 3a and 3b
with imines derived from aromatic and heterocyclic aldehydes.
Reactions of 3a and 3b are promoted efficiently (>98% conv) by
1-5 mol % 1 and AgOAc in undistilled THF without the need for
an inert atmosphere (Table 1). As was the case with the related
cycloadditions,7 1 equiv of i-PrOH is required for high conversion.
Unsubstituted (2a), as well as para- and meta-substituted phenyl
groups bearing electron-rich or electron-deficient aryl imines (entries
3-12, Table 1), undergo Ag-catalyzed reactions to afford the
desired â-amino ketones in 86-98% ee. Electron-poor imines are
more reactive such that their transformations can be effected at
lower temperatures, giving rise to improved optical purities.
Reactions of the electron-rich substrates (entries 3 and 4) are more
selective when carried out in toluene (e.g., 4b is obtained in 82%
ee in THF). Catalytic asymmetric reactions of the more sterically
demanding imines that bear an ortho substituent (entries 13 and
entry
R
R1
(mol %)
(
°
C)
(%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph
Ph
2a Ph
2a Me 3b
3a
p-OMeC6H4 2b Me 3b
3a
3
5
5
5
3
5
1
5
3
3
3
3
5
5
3
3
-10
-10
22
54
65
61
71
88
91
84
79
97
96
88
94
70
46
84
78
94
92
96
90
92
92
96
90
86
86
98
92
80
76
86
90
p-OMeC6H4 2b Ph
22
p-NO2C6H4
p-NO2C6H4
p-ClC6H4
p-ClC6H4
m-NO2C6H4 2e
2c
2c
2d Ph
Ph
Me 3b
3a
2d Me 3b
Ph
Me 3b
Ph 3a
Me 3b
3a
2g Me 3b
2h Ph 3a
2h Me 3b
3a
-5
-10
4
-10
-10
-5
-5
-5
4
3a
m-NO2C6H4 2e
2-naphth
2-naphth
o-BrC6H4
o-BrC6H4
2-furyl
2f
2f
2g Ph
4
4
4
2-furyl
a Reactions in THF except entries 3 and 4 which were run in toluene.
b Isolated yields. c By chiral HPLC.
14) proceed efficiently but with lower asymmetric induction (74-
80% ee). Heterocyclic imines also participate in facile and
enantioselective additions (entries 15 and 16).
The Ag-catalyzed method can be applied to alkenyl (2i-k, Table
2) and alkynyl imines (2l)8 as well. As the data in Table 2
demonstrate, a range of unsaturated â-amino ketones 4i-l have
been prepared in synthetically useful yields and high enantiose-
lectivities. The corresponding reactions involving aliphatic imines
2m-o,9 summarized in Table 3, can be carried out through a three-
component process that affords the desired amines 5m-o in 92-
94% ee; the relatively low isolated yields are likely due to the
instability of the aliphatic imine substrates. It should be noted that
the equivalent of water released through in situ formation of the
aliphatic imines obviates the need for the use of i-PrOH (cf., Tables
1 and 2).
The optically enriched Mannich products obtained through the
Ag-catalyzed method can be converted to amines or Boc amide
derivatives in >70% isolated yield through a simple oxidative
procedure.9 Two representative examples, involving an aryl (6) and
an alkynyl â-amino ketone (7), are shown in eq 1. The unmasking
operation is carried out in a single vessel at ambient temperature,
9
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J. AM. CHEM. SOC. 2004, 126, 3734-3735
10.1021/ja049388e CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Enantioselective Synthesis of Sedamine
Table 2. Ag-Catalyzed Enantioselective Mannich Reactions of
Silyl Enol Ethers with Unsaturated Imines
conversion to the cyclic amine), followed by reductive amination
in the presence of formaldehyde and NaCNBH3,13 affords the natural
product in 89% yield.
Development of additional catalytic asymmetric Mannich reac-
tions and related mechanistic studies are in progress.
a Reactions in THF except entries 3 and 4. b Isolated yields. c By chiral
HPLC.
Acknowledgment. Financial support was provided by the NIH
(GM-57212). N.S.J. is grateful for a graduate fellowship from
Schering-Plough.
Table 3. Three-Component Ag-Catalyzed Asymmetric Mannich
Reactions Involving Aliphatic Imines
Supporting Information Available: Experimental procedures and
spectral and analytical data for reaction products (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
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1, AgOAc
T
yield
(%)a
ee
entry
R
(mol %)
(
°
C)
(%)b
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3
n-C10H21
Cy
m
n
o
5
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41
92
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i-Bu
a Isolated yields. b By chiral HPLC.
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Because of the range of imines and silyl enol ethers that can be
effectively employed and the ubiquity of â-amino carbonyls, the
Ag-catalyzed protocol should find utility in the synthesis of
biologically active molecules.10 One such application is depicted
in Scheme 1 in the context of a brief total synthesis of optically
pure (-)-sedamine.11 The Ag-catalyzed three-component enantio-
selective reaction shown in Scheme 1 proceeds smoothly in the
presence of an ester group, giving rise to 8 in >98% ee and 56%
isolated yield. Oxidative removal of the o-anisyl group gives cyclic
amide 9. Diastereoselective reduction of the carbonyl group (16:1)
(DIBAL-H)12 and subsequent addition of LAH (to ensure complete
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J. F., Shibasaki, M., Eds.; Wiley-VCH: Weinheim, 2000; pp 145-162.
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(13) Borch, R. F.; Hassid, A. I. J. Org. Chem. 1972, 37, 1673-1675.
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