Catalytic asymmetric reductive Michael cyclization

Article abstract of DOI:10.1021/ja055735o

A highly efficient and chemo-, regio-, diastereo-, and enantioselective organocatalytic tandem conjugate reduction-Michael cyclization of enal enones has been developed. Accordingly, treating the enal enone with a Hantzsch dihydropyridine in the presence

Full text of DOI:10.1021/ja055735o

Published on Web 10/06/2005
Catalytic Asymmetric Reductive Michael Cyclization
Jung Woon Yang, Maria T. Hechavarria Fonseca, and Benjamin List*
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim an der Ruhr, Germany
Received August 22, 2005; E-mail: list@mpi-muelheim.mpg.de
Table 1. Catalyst Screening for the Reductive Michael Cyclization
Asymmetric catalysis of carbonyl transformations using amines
or ammonium salts as catalysts has recently gained considerable
attention.1 While enamine catalysis has been used mostly in the
context of carbonyl R-substitution reactions,2 iminium catalysis is
typically employed in conjugate and cycloadditions of enals.3 The
two strategies are closely related, and the same catalysts can often
be utilized in both approaches. In fact, enamine catalysis generally
proceeds via iminium ion formation, while iminium catalysis often
leads to an enamine intermediate. Combining the two catalysis
principles in tandem sequences using a single catalyst is obviously
attractive but has rarely been realized. Here we disclose an efficient
asymmetric in situ iminium catalytic conjugate reduction followed
by an enamine catalytic intramolecular Michael reaction. Our
process gives five- and six-membered carbacycles in excellent yields
and enantioselectivities.
We have previously developed an organocatalytic, metal-free
asymmetric transfer hydrogenation of R,â-unsaturated aldehydes.4
In this reaction, an enal (1) is activated with a MacMillan
imidazolidinium salt (2) via iminium ion formation (3). A subse-
quent hydride transfer to intermediate 3 from Hantzsch ester 4a
presumably gives enamine intermediate 5. In situ hydrolysis then
provides saturated aldehyde 6, usually in high yields and enanti-
oselectivities (eq 1). We reasoned that the reductively generated
enamine intermediate 5, in addition to hydrolysis, should also be
able to react in situ with various electrophiles (X ) Y) to give an
R-modified aldehyde 7. To the best of our knowledge, such a
combination of iminium and enamine catalysis has not been realized
before.
time
[h]
yield
[%]
ee
catalyst
R1
R2
R3
X
[%]
9a
9b
9c
9d
9e
9f
H
H
H
Bn
t-Bu
t-Bu
2,6-Ph2Ph
t-Bu
t-Bu
H
CF3CO2
2
12
12
3
6
6
82 93
90 95
75 16
98 96
91 95
90 95
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
p-BnOBn
p-t-BuOBn t-Bu
Bn Me
9g
Me Cl
24
<10
catalytic reductive aldol reactions have been described,7 the
corresponding reductive Michael reactions are unknown.8
We have developed an imidazolidinone-catalyzed Michael cy-
clization of formyl enones to give useful cyclic keto aldehydes in
high yields and enantiomeric excesses.9,10 Since these reactions are
catalyzed with the same type of catalyst that is used in our
organocatalytic conjugate reduction, we expected the two reactions
to work well in an in situ tandem sequence. Indeed, when we treated
enal enone 10 with Hantzsch ester 4 in the presence of different
imidazolidinone salts (9), clean reductive Michael cyclization to
keto aldehyde 11 was observed (Table 1). Independent of the
catalyst, the reaction furnished the anti-product highly diastereo-
selectively. Moreover, excellent yield and enantioselectivity was
obtained when we used commercially available imidazolidinone
catalyst 9d. Catalyst 9g, which we have previously used in the
intermolecular Michael reaction, proved ineffective.
We have also screened different Hantzsch esters as hydrogen
donors and found commercially available Hantzsch ester 4 to give
the best results (see Supporting Information).
After identifying suitable reaction conditions for the reductive
Michael cyclization of substrate 10, we set up a study toward
exploring the scope of the process. The results are shown in Table
2. The Michael acceptor portion tolerates both aromatic and aliphatic
enones giving the products in comparable yields and stereoselec-
tivities (entries 1-6). Substituents at the aromatic portion are well
tolerated (entries 5 and 6). We have also investigated an alkylidene
malonate Michael acceptor (22) and obtained reasonably good
results when we used catalyst 9c.
Diastereoselectivities are generally high, and products resulting
from the conjugate reduction of the enone were not observed. Our
tandem reaction constitutes a nonasymmetric conjugate reduction
followed by an asymmetric Michael cyclization. The alternative
sequence consisting of an asymmetric conjugate reduction of a â,â-
disubstituted enal followed by its diastereoselective Michael cy-
The tandem sequence would be related to previously developed
metal-mediated reductive enolate generation-electrophile trapping
processes.5 For example, catalytic inter- and intramolecular reduc-
tive aldol and Michael reactions of unsaturated carbonyl compounds
via metal enolates have been developed.6 While asymmetric
9
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J. AM. CHEM. SOC. 2005, 127, 15036-15037
10.1021/ja055735o CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Organocatalytic Reductive Michael Cyclization
With the proof of concept being made, a variety of different
single flask, tandem enamine-iminium catalysis sequences seem
possible and will be investigated.
Acknowledgment. Kind donations by Lanxess and Degussa and
technical assistance by the analytical departments of the Max-
Planck-Institut fu¨r Kohlenforschung are gratefully acknowledged.
This study was funded in part by the DFG-Priority Program
Organocatalysis (SPP 1179). We thank William R. Roush for
providing an experimental procedure for the synthesis of substrates
24 and 26, and Nicola Vignola, Arno Do¨hring, and Michael Stadler
for the preparation of Hantzsch esters and catalysts.
Supporting Information Available: Experimental procedures,
compound characterization, NMR spectra, and HPLC traces (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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(2) For the first enamine catalytic asymmetric intermolecular aldol, Mannich,
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2396. (b) List, B. J. Am. Chem. Soc. 2000, 122, 9336-9337. (c) List, B.
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Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369-
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a Using catalyst 9a. b Using catalyst 9c.
clization is likely to proceed equally and will be reported in the
future. The spacer between the enal and the Michael acceptor
portion is not limited to a (substituted) benzene ring. As expected
from our previous studies, the cyclization of aliphatic enal 24 with
catalyst 9d gives product 25 in somewhat reduced enantioselectivity
(eq 2). In contrast, the corresponding higher homologue 26 provides
the product (27) in excellent enantiomeric excess when we used
catalyst 9a (eq 3).
(7) For example, see: (a) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am.
Chem. Soc. 2000, 122, 4528-4529. (b) Nishiyama, H.; Shiomi, T.;
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Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7, ASAP.
(8) For a catalytic asymmetric tandem Michael addition-H2 hydrogenation,
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Chem. 2002, 67, 8331-8338. For significantly improved catalyst systems,
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In summary, we have developed a highly enantioselective
organocatalytic reductive Michael cyclization of enal enones. We
assume that the reaction proceeds via an iminium catalytic conjugate
reduction followed by an in situ enamine catalytic asymmetric
Michael cyclization. Notable features of our reaction include (a)
the high selectivity (chemo-, regio-, diastereo-, and enantioselec-
tivity); (b) the not fully explored but already broad scope; (c) the
practical and user-friendly reaction conditions; and (d) potential
application in the synthesis of natural products.
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