Catalytic asymmetric oxa-Michael-Michael cascade for facile construction of chiral chromans via an aminal intermediate

Article abstract of DOI:10.1021/ol9003433

An unprecedented highly enantioselective cascade oxa-Michael-Michael reaction has been developed. The simple and practical process, efficiently catalyzed by chiral diphenylprolinol TMS ether, affords a powerful access to highly functionalized syntheticall

Full text of DOI:10.1021/ol9003433

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1627-1630
Catalytic Asymmetric oxa-Michael-
Michael Cascade for Facile Construction
of Chiral Chromans via an Aminal
Intermediate
Liansuo Zu, Shilei Zhang, Hexin Xie, and Wei Wang*
Department of Chemistry and Chemical Biology, UniVersity of New Mexico,
Albuquerque, New Mexico 87131-0001
wwang@unm.edu
Received February 16, 2009
ABSTRACT
An unprecedented highly enantioselective cascade oxa-Michael-Michael reaction has been developed. The simple and practical process,
efficiently catalyzed by chiral diphenylprolinol TMS ether, affords a powerful access to highly functionalized synthetically useful chiral chromans.
Moreover, notably a new activation mode involving an aminal is disclosed for the first time.
An important goal of asymmetric catalysis is the development
of novel activation modes that enable us to promote
unprecedented transformations. In the recent past, organo-
catalysis has significantly advanced the field as a result of
the novelty of concept and unique activation modes.1
Furthermore, the scope of organocatalyzed asymmetric
reactions has been dramatically expanded by their ability for
catalyzing highly powerful cascade processes that generate
complex molecular architectures.2 Recently, we and other
groups have reported organocatalyzed oxa-Michael-aldol
reactions for forming chromenes.3 In the cascade process,
only one stereogenic center in the products was created due
Tetrahedron Lett. 2008, 49, 1899. (g) Hayashi, Y.; Gotoh, H.; Masui, R.;
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(1) For recent reviews of organocatalysis, see: (a) MacMillan, D. W. C.
Nature 2008, 455, 304. (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List,
B. Chem. ReV. 2007, 107, 5471. (c) Erkkila, A.; Majander, I.; Pihko, P. M.
Chem. ReV. 2007, 107, 5416. (d) Berkessel, A.; Groger, H. Asymmetric
Organocatalysis-From Biomimetic Concepts to Applications in Asymmetric
Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany,
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(2) For recent reviews of organocatalytic cascade reactions, see: (a)
Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46,
1570. (b) Yu, X.-H.; Wang, W. Org. Biomol. Chem. 2008, 6, 2036. And
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Chem., Int. Ed. 2008, 47, 7539. (d) Zhu, D.; Lu, M.; Chua, P. J.; Tan, B.;
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10.1021/ol9003433 CCC: $40.75
Published on Web 03/03/2009
2009 American Chemical Society

to the spontaneous dehydration of the ꢀ-hydroxy aldimine
highly functionalized chromans with the creation of three
new stereogenic centers (eq 2).5 The cascade process is
efficiently catalyzed by a commercial diphenylprolinol silyl
ether from simple achiral substances and provides one-pot
access to enantioenriched chromans. Significantly, a novel
activation mode of the chiral amine-catalyzed cascade
process involving formation of aminal 5, which serves as a
nucleophile, rather than a free phenol -OH group for the
Michael addition, has been identified for the first time.
In our exploratory study, we decided to choose 2-hydroxy
cinnamaldehyde 1a and trans-ꢀ-nitrostyrene 2a as substrates
for the proposed cascade oxa-Michael-Michael reaction in
the presence of a chiral amine in CH2Cl2 at rt since the
aldehyde and nitro groups are highly versatile functionalities
in organic transformations (Table 1). Initial optimization
(Scheme 1, eq 1).3a Mechanistically, these reactions share
Scheme 1
.
Organocatalytic, Asymmetric oxa-Michael-Initiated
Cascade Reactions
Table 1. Organocatalytic Asymmetric Cascade
Michael-Michael Reaction of 2-Hydroxy-3-phenyl-propenal
(1a) with trans-ꢀ-Nitrostyrene (2a)a
entry
cat.
additive
% yieldb
% eec
drd
1
2
3
4
5f
6
7
I
none
none
<5
65
78
80
78
77
<5
NDe
96
96
96
98
NDe
4:1
4:1
5:1
6:1
II
II
II
II
III
IV
PhCO2H
NaOAc
NaOAc
NaOAc
NaOAc
97
4:1
NDe
NDe
a Reaction conditions: unless specified, a mixture of 1a (0.12 mmol),
2a (0.10 mmol), additive (0.02 mmol), and a catalyst (0.02 mmol) in CH2Cl2
(0.2 mL) was stirred at rt. b Isolated yields. c Determined by HPLC analysis
(Chiralcel OD-H). d Determined by 1H NMR. e Not determined. f CHCl3
as solvent.
the same pathway, involving the direct conjugate addition
of the free phenol -OH group to the activated enal derived
iminium.
It is noteworthy that chiral chromenes and chromans are
important “privileged” structures found in a myriad of
biologically intriguing molecules.4 In our continuing effort
on the construction of the synthetically useful scaffold with
stereochemical and functional diversity, herein we wish to
disclose an unprecedented organocatalyzed asymmetric
cascade oxa-Michael-Michael reaction, which affords chiral
investigation revealed that the catalyst reactivity varied
significantly among the commonly used chiral secondary
amines probed. It was found that the class of chiral
diarylprolinol silyl ethers was promising for the cascade
process (eq 2).6 No reaction occurred when diphenylprolinol
I was employed (entry 1). Nevertheless, the encouraging
results (65% yield, 96% ee and 4:1 dr, entry 2) were obtained
(3) For examples of organocatalytic asymmetric oxa-Michael-aldol
reaction, see: (a) Li, H.; Wang, J.; E-Nunu, T.; Zu, L.; Jiang, W.; Wei, S.;
Wang, W. Chem. Commun. 2007, 507. (b) Wang, W.; Li, H.; Wang, J.;
Zu, L. J. Am. Chem. Soc. 2006, 128, 10354. (c) Li, H.; Zu, L.-S.; Xie,
H.-X.; Wang, J.; Jiang, W.; Wang, W. Angew. Chem., Int. Ed. 2007, 46,
3732. (d) Sunde´n, H.; Ibrahem, I.; Zhao, G. L.; Eriksson, L.; Co´rdova, A.
Chem.-Eur. J. 2007, 13, 574. (e) Rueping, M.; Sugiono, E.; Merino, E.
Angew. Chem., Int. Ed. 2008, 47, 3046. (f) Liu, K.; Chougnet, A.; Woggon,
W.-D. Angew. Chem., Int. Ed. 2008, 47, 5827. (g) Kotame, P.; Hong, B.-
C.; Liao, J.-H. Tetrahedron Lett. 2009, 50, 704.
(5) There are only a handful of examples of organocatalytic cascade
Michael-Michael reactions: (a) Hoashi, Y.; Yabuta, T.; Yuan, P.; Miyabe,
H.; Takemoto, Y. Tetrahedron 2006, 62, 365. (b) Sriramurthy, V.; Barcan,
G. A.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 12928. (c) Sun, X.; Sengupta,
S.; Petersen, J. L.; Wang, H.; Lewis, J. P.; Shi, X.-D. Org. Lett. 2007, 9,
4495. (d) Li, H.; Zu, L.; Xie, H.; Wang, J.; Jiang, W.; Wang, W. Angew.
Chem., Int. Ed. 2007, 46, 3732. (e) Wang, J.; Xie, H.; Li, H.; Zu, L.; Wang,
W. Angew. Chem., Int. Ed. 2008, 47, 4177.
(4) For reviews of chromans: (a) Zeni, G.; Larock, R. C. Chem. ReV.
2004, 104, 2285. (b) Keay, B. A. In ComprehensiVe Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford,
1996; Vol. 2, p 395. (c) Trost, B. M.; Shen, H. C.; Dong, L.; Surivet, J.-P.;
Sylvain, C J. Am. Chem. Soc. 2004, 126, 11966, and references cited therein.
(d) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.;
Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939, and
references cited therein.
(6) For a review of diaryl prolinol ether catalysis, see: (a) Vicario, J. L.;
Reboredo, S.; Badia, D.; Carrello, L. Angew. Chem., Int. Ed. 2007, 46,
5168. (b) Palomo, C.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876.
(c) Mielgo, A.; Palomo, Chem. Asian. J. 2008, 3, 922. And leading
references, see: (d) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2005, 44, 794. (e) Hayashi, Y.; Gotoh, H.;
Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (f) Chi,
Y.-G.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804.
1628
Org. Lett., Vol. 11, No. 7, 2009

with silyl ether II. Additives could improve the reaction
yields (entries 3 and 4) without sacrificing enantioselectivity.
Slightly better dr (5:1) was achieved with base additive
NaOAc (entry 4). Under the same reaction conditions, a
similar trend was observed for the analogue III (entry 6),
while the IV catalyzed process proceeded very sluggishly
(entry 7). Examination of solvents showed that comparable
outcomes were provided for CH2Cl2 and CHCl3, but CHCl3
was chosen for probing the scope of the cascade process
owing to the enhanced dr (entry 5).
Figure 1. X-ray crystal structure of 8.
The II-promoted cascade oxa-Michael-Michael reaction
between a variety of 2-hydroxy cinnamaldehydes 1 and
nitroolefins 2 under the optimized conditions was investi-
gated. As revealed in Table 2, the new methodology provided
(Scheme 2, eq 1).7 An aminal intermediate 5, which was
isolated and characterized (see Supporting Information), was
Table 2. Scope of Catalyst II Promoted Cascade
Scheme 2. Reaction Mechanism of the Cascade
oxa-Michael-Michael Reactionsa b
,
oxa-Michael-Michael Reactions
entry
X, R
H, Ph (3a)
time (h) % yieldc % eed dre
1
2
3
4
5
6
7
8
12
24
36
12
12
24
24
72
72
48
20
12
78
75
80
85
73
73
79
61
60
65
71
73
98
6:1
5:1
4:1
5:1
4:1
6:1
5:1
10:1
10:1
8:1
6:1
2:1
H, 4-MeOC6H4 (3b)
H, 2-MeOC6H4 (3c)
H, 4-ClC6H4 (3d)
H, 3-BrC6H4 (3e)
H, 2-furanyl (3f)
H, 2-thienyl (3g)
3-Cl, Ph (3h)
3-MeO, Ph (3i)
4-MeO, Ph (3j)
5-Me, Ph (3k)
97f
98g
97
95f
96f
94g
95g
96g
96g
93g
93f
9
10
11
12
H, i-Pr (3l)
a Reaction conditions: unless specified, see footnote a in Table 1.
b Absolute configuration of the products determined by single X-ray analysis
of a derivative 8 of 3d (see Figure 1 and Supporting Information). c Isolated
yields. d Determined by chiral HPLC analysis (Chiralpak AS-H or Chiralcel
OD-H). e Determined by 1H NMR. f Determined by converting to corre-
sponding alcohol for HPLC analysis. g Determined by converting to
corresponding enone with Ph3PdCHCOPh for HPLC analysis.
involved in the reaction pathway. Compound 5 was formed
very quickly from reaction of 1a with catalyst II in an almost
quantitative yield. It is believed that it was produced through
an iminium 4-activated isomerization of the CdC bond and
subsequent intramolecular “O” addition to the iminium
sequence. The formation of an aminal from an amine has
been reported.8 However, its function as a nucleophile
involved in the organocatalysis is unprecedented. Specifi-
cally, it was conceived that the aminal 5 served as a
nucleophile for the first Michael addition to nitroolefin 2a
to produce intermediate 6. We believed that the “O” of the
aminal 5 was more active as a nucleophile than that of the
“OH” of a phenol. This assumption was confirmed by a
controlled study (Scheme 2). In the presence of catalyst II,
under the same reaction conditions, no reaction occurred
a facile and general approach to a range of trisubstituted,
highly functionalized chiral chromans with the generation
of three new stereogenic centers in excellent levels of
enantiomeric excess (93 to 98% ee) and good to high
diastereoselectivities (2:1 to 10:1). The reactions were
applicable to a variety of nitroolefins 2 bearing different aryl
groups with good yields and excellent enantioselectivities.
Significant variation of 2-hydroxy cinnamaldehydes 1 in their
electronic and steric features could be tolerated for the II-
catalyzed cascade processes. Moreover, the process was
applicable for less reactive aliphatic enals with high ef-
ficiency (entry 12).
(7) A Diels-Alder pathway was also possible, but it was ruled out.
(8) A recent study related to proline-catalyzed reactions involved aminals.
See:Seebach, D.; Beck, A. K.; Badine, D. M.; Limbahc, M.; Eschemoser,
A.; Treasurywala, A. M.; Hobi, R. HelV. Chim. Acta 2007, 90, 425.
The unusual organocatalytic cascade process stimulated
us to carry out a preliminary mechanistic investigation
Org. Lett., Vol. 11, No. 7, 2009
1629

between phenol and trans-ꢀ-nitrostyrene (eq 2), indicating
that the “OH” of phenol was not a nucleophile for the first
Michael reaction. This observation was in contrast to that
seen in the oxa-Michael-aldol reactions,3 where the phenol
was directly added to the enal due to the significant activation
by a chiral amine via formation of an iminium (see above).
We also isolated and characterized the relatively stable 6
(see Supporting Information). The catalyst II was released
for the next cycle reaction via exchange of 6 with 1a, and
meanwhile compound 7 was produced. Therefore, it is
essential to use a slight excess of 1a (e.g., 1.2 equiv) in the
cascade process. Finally, an intramolecular Michael reaction
in 7 gave rise to the product 3a.
reactions with the new activation mode. Further application
of this organocatalytic activation mode in new organic
transformations, the elaboration of the highly versatile chiral
chromans in organic synthesis, and the detailed mechanistic
aspects will be reported in due course.
Acknowledgment. Financial support for this work pro-
vided by the National Science foundation (CHE-0704015)
is gratefully acknowledged. Thanks are expressed to Dr.
Elieen N. Duesler (UNM) for performing X-ray analysis.
The Bruker X8 X-ray diffractometer was purchased via an
NSF CRIF:MU award to the University of New Mexico,
CHE-0443580.
In summary, we have developed a new powerful catalytic
cascade oxa-Michael-Michael strategy for the facile con-
struction of biologically significant, heavily functionalized
chiral chromans containing multiple stereogenic centers.
Moreover, an unprecedented aminal serving as an activated
nucleophile in the cascade process is first discovered. The
study significantly expands the scope of organocatalyzed
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR and HRMS data for experi-
mental procedures and characterization of the products 3, 4,
and 6 and X-ray crystal data (CIF file) for 8. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL9003433
1630
Org. Lett., Vol. 11, No. 7, 2009