One-Pot Access to 4 H-chromenes with formation of a chiral quaternary stereogenic center by a highly enantioselective iminium-allenamine involved oxa-Michael-aldol cascade

Article abstract of DOI:10.1021/ol102096s

An unprecedented organocatalytic highly enantioselective cascade Michael-aldol reaction has been developed in high yields under mild reaction conditions. The one-pot process affords an efficient approach to the synthetically and biologically important chiral 4H-chromenes bearing a quaternary stereogenic center. The study significantly expands the scope of less explored organocatalytic iminium-allenamine chemistry.

Full text of DOI:10.1021/ol102096s

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4948-4951
“One-Pot” Access to 4H-Chromenes
with Formation of a Chiral Quaternary
Stereogenic Center by a Highly
Enantioselective Iminium-allenamine
Involved Oxa-Michael-Aldol Cascade
Chunliang Liu,†,‡ Xinshuai Zhang,‡ Rui Wang,*,† and Wei Wang*,‡,§
Key Laboratory of Preclinical Study for New Drugs of Gansu ProVince, Institute of
Biochemistry and Molecular Biology, State Key Laboratory of Applied Organic
Chemistry, Lanzhou UniVersity, Lanzhou 730000, China, Department of Chemistry and
Chemical Biology, UniVersity of New Mexico, Albuquerque, New Mexico 87131-0001,
United States, and Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, 555 Zuchongzhi Road, Shanghai 20203, China
wangrui@lzu.edu.cn; wwang@unm.edu
Received September 2, 2010
ABSTRACT
An unprecedented organocatalytic highly enantioselective cascade Michael-aldol reaction has been developed in high yields under mild
reaction conditions. The “one-pot” process affords an efficient approach to the synthetically and biologically important chiral 4H-chromenes
bearing a quaternary stereogenic center. The study significantly expands the scope of less explored organocatalytic iminium-allenamine
chemistry.
Despite the fact that 4H-chromenes are an important class
of core structures featured in a number of naturally occurring
and biologically active molecules,1,2 asymmetric methods
allowing rapid access to this molecular architecture are
extremely rare.3,4 The ability to access the complex members
of the chiral 4H-chromene family in an enantioselective
manner allows chemists to explore their potential biological
properties. Therefore, the development of catalytic asym-
metric strategies for the efficient construction of structurally
diverse chiral 4H-chromenes is quite valuable to the fields
of organic synthesis and chemical biology/medicinal chem-
istry.
† Lanzhou University.
(2) For selected examples of bioactive natural products containing 4H-
chromene core structures, see: (a) Demyttenaere, J.; Syngel, K. V.;
Markusse, A. P.; Vervisch, S.; Debenedetti, S.; Kimpe, N. D. Tetrahedron
2002, 58, 2163. (b) Huang, Z.-W. US006660871B2, 2003. (c) Das, S. G.;
Doshi, J. M.; Tian, D. F.; Addo, S. N.; Srinivasan, B.; Hermanson, D. L.;
Xing, C.-G. J. Med. Chem. 2009, 52, 5937. (d) Corey, E. J.; Wu, L.-I.
J. Am. Chem. Soc. 1993, 115, 9327. (e) Shaheen, F.; Ahmad, M.; Khan,
S. N.; Hussain, S. S.; Anjum, S.; Tashkhodjaev, B.; Turgunov, K.;
Sultankhodzhaev, M. N.; Choudhary, M. I.; Rahman, A. Eur. J. Org. Chem.
2006, 10, 2371.
‡ University of New Mexico.
§ Chinese Academy of Sciences.
(1) For reviews of chemistry and biology of chromenes: (a) Schweizer,
E. E.; Meeder-Nycz, O. In Chromenes, Chromanes, Chromones; Ellis, G. P.,
Eds.; Wiley-Interscience: New York, 1977. (b) Keay, B. A. In Compre-
hensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven,
E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 2, p 395. (c) 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
.
10.1021/ol102096s  2010 American Chemical Society
Published on Web 10/11/2010

Toward this end, our group has recently reported the first
enantioselective cascade oxa-Michael-Michael reactions of
ynals involving an unprecedented iminium-allenamine ac-
tivation mode (Scheme 1, eq 1).3b Despite the extensively
cylaldehyde or -ketone with phenyl ynal in the presence of
20 mol % (S)-diphenylpyrrolinol TMS ether I7 in toluene
were frustrated by the failure of delivering the desired
products as a result of very poor reaction yield. These studies
underscored the completely different reaction behavior
between ynals and enals since we have shown that enals can
efficiently engage in the Michael-aldol cascade process with
salicylaldehydes.4b We turned our attention to the more
reactive ketone ester 2a (Figure 1 and Table 1).8 To our
delight, the oxa-Michael-aldol cascade sequence proceeded
smoothly to give the desired product 3a in an excellent yield
(97%) and with excellent enantiomeric excess (ee) (97%)
under the same reaction conditions in toluene at rt in the
presence of 20 mol % catalyst I within 3 h (entry 1), albeit
the highly steric ketoester substrate employed. Notably, the
process provides an efficient entry to useful chiral R-hydroxy
carboxylates with formation of a quaternary stereogenic
center in a cascade fashion. The screening of other diaryl-
prolinol silyl ether analogues II-III revealed that the bulky
Scheme 1. Alkynals Participating in Enantioselective Cascade
Oxa-Michael-Michael and -Aldol Reactions Promoted by a
Chiral Secondary Amine Involving a Novel Iminium-allenamine
Activation Mode
(3) Surprisingly, only three examples of the catalytic asymmetric
synthesis of 4H-chromenes have been reported. See: (a) Nishikata, T.;
Yamamoto, Y.; Miyaura, N. AdV. Synth. Catal. 2007, 349, 1759. (b) Zhang,
X.-S.; Zhang, S.-L.; Wang, W. Angew. Chem., Int. Ed. 2010, 49, 1481. (c)
Aleman, J.; Nunez, A.; Marzo, L.; Marcos, V.; Alvarado, C.; Ruano, J. L. G.
Chem.sEur. J. 2010, 16, 9453.
(4) Our laboratory has developed several organocatalytic enantioselective
oxa-cascade reactions for constructions of chromanes and 2H-chromenes:
(a) Wang, W.; Li, H.; Wang, J.; Zu, L. J. Am. Chem. Soc. 2006, 128, 10354.
(b) Li, H.; Wang, J.; E-Nunu, T.; Zu, L.; Jiang, W.; Wei, S.; Wang, W.
Chem. Commun. 2007, 507. (c) Zu, L.-S.; Zhang, S.-L.; Xie, H.-X.; Wang,
W. Org. Lett. 2009, 11, 1627. From other groups of organocatalytic oxa-
Michael aldol cascades: a review: (d) Nising, C. F.; Bra¨se, S. Chem. Soc.
ReV. 2008, 37, 1218. (e) Govende, T.; Hojabri, L.; Moghaddam, F. M.;
Arvidsson, P. I. Tetrahedron: Asymmetry 2006, 17, 1763. (f) Bidle, M. M.;
Lin, M.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 3830. (g) Sunde´n,
H.; Ibrahem, I.; Zhao, G. L.; Eriksson, L.; Co´rdova, A. Chem.sEur. J.
2007, 13, 574. (h) Rueping, M.; Sugiono, E.; Merino, E. Angew. Chem.,
Int. Ed. 2008, 47, 3046. (i) Liu, K.; Chougnet, A.; Woggon, W.-D. Angew.
Chem., Int. Ed. 2008, 47, 5827. (j) Xu, D.-Q.; Wang, Y.-F.; Luo, S.-P.;
Zhang, S.; Zhong, A.-G.; Chen, H.; Xu, Z.-Y. AdV. Synth. Catal. 2008,
350, 2610. (k) Kotame, P.; Hong, B.-C.; Liao, J. Tetrahedron Lett. 2009,
50, 704. (l) Reyes, E.; Talavera, G.; Vicario, J. L.; Badia, D.; Carrillo, L.
Angew. Chem., Int. Ed. 2009, 48, 5701. (m) Zhang, F.-L.; Xu, A.-W.; Gong,
Y.-F.; Wei, M.-H.; Yang, X.-L. Chem.sEur. J. 2009, 15, 6815.
(5) For recent reviews of using iminium-enamine chemistry in cascade
reactions, see: (a) Enders, D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem.,
Int. Ed. 2007, 46, 1570. (b) Yu, X.-H.; Wang, W. Org. Biomol. Chem.
2008, 6, 2037. (c) Grondal, C.; Jeanty, M.; Enders, D.; Hu¨ttl, M. R. M.
Nature Chem. 2010, 2, 167.
investigated iminium-enamine strategy with cascade se-
quences,5 the respective iminium-allenamine chemistry is
much less appreciated. Expanding the scope of the chemistry
will not only add a new domain in organocatalysis but also,
more importantly, afford new potentially useful platforms
for the facile assembly of important molecular scaffolds. We
questioned whether the conceptually novel tactic could be
extended to an oxa-Michael-aldol cascade sequence, which
would generate the structurally diverse 4H-chromenes with
installation of new functionalities. Herein, we wish to report
the results which have led to an asymmetric iminium-
allenamine approach to chiral 4H-chromenes bearing chiral
R-hydroxy carboxylate functionality in high yields (84-99%)
and with excellent enantioselectivities (93->99% ee) for a
wide range of substrates (eq 2). A powerful “one-pot” oxa-
Michael-aldol cascade reaction between (2-hydroxy-phen-
yl)-2-oxoacetates and ynals is realized for the first time.
Furthermore, a quaternary stereogenic center involving
formation of versatile R-hydroxy carboxylate motif, a still
synthetically unmet issue in organic synthesis,6 is created
highly enantioselectively.
(6) For recent reviews of catalytic asymmetric construction of quaternary
stereocenters, see: (a) Quaternary Stereocenters-Challenges and Solutions
for Organic Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH:
Weinheim, 2005. (b) Fuji, K. Chem. ReV. 1993, 93, 2037. (c) Corey, E. J.;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (d) Christoffers,
J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591. (e) Douglas, C. J.;
Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363. (f)
Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005, 347, 1473. (g) Bella,
M.; Gasperi, T. Synthesis 2009, 10, 1583.
(7) For a recent review of prolinol ether catalysis, see: Mielgo, A.;
Palomo, C. Chem. Asian J. 2008, 3, 922. and leading references. (b) Marigo,
M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2005, 44, 794. (c) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew.
Chem., Int. Ed. 2005, 44, 4212. (d) Chi, Y.; Gellman, S. H. Org. Lett. 2005,
7, 4253.
(8) For selected examples of direct aldol reactions of keto esters
involving stereoselective construction of quaternary stereocenters, see: (a)
Bøgevig, A.; Kumaragurubaran, N.; Jørgensen, K. A. Chem. Commun. 2002,
620. (b) Holland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2004, 43, 1272. (c) Tokuda, O.; Kano, T.; Gao, W.-G.; Ikemoto, T.;
Maruoka, K. Org. Lett. 2005, 7, 5103. (c) Dambruoso, P.; Massi, A.;
Dondoni, A. Org. Lett. 2005, 7, 4657. (d) Tang, Z.; Cun, L.-F.; Cui, X.;
Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Org. Lett. 2006, 8, 1263–1266. (e)
Samanta, S.; Zhao, C.-G. J. Am. Chem. Soc. 2006, 128, 7442. (f) Cao, C.-
L.; Sun, X.-L.; Kang, Y.-B.; Tang, Y. Org. Lett. 2007, 9, 4151.
Initial efforts on the proposed organocatalytic enantiose-
lective oxa-Michael-aldol cascade reaction of simple sali-
Org. Lett., Vol. 12, No. 21, 2010
4949

With the optimal conditions in hand, the scope of the
cascade oxa-Michael-aldol reaction was investigated. Re-
markably, as shown in Table 2, the cascade process exhibits
Table 2. Catalyst III Promoted Enantioselective Cascade
Oxa-Michael-Aldol Reactions of Alkynals 2 with Ethyl
2-(2-Hydroxyphenyl)-2-oxoacetates 5a
entry
R, X, 6
t (h)
% yieldb
% eec
1
2
3
Ph, 5-MeO, 6a
Ph, H, 6b
Ph, 4-MeO, 6c
Ph, 4-Me, 6d
6
8
8
9
6
6
6
6
6
10
9
6
9
6
98
97
84
93
99
99
99
97
99
92
98
99
93
98
98
92
97
91
69
75
99
99
96
98
93
99
99
99
99
98
98
>99
98
99
99
99
96
98
97
99
4
5d
6
Ph, 4-Cl, 6e
Figure 1. X-ray structure of 6h.
4-MeOC6H4, 5-MeO, 6f
4-MeC6H4, 5-MeO, 6g
4-ClC6H4, 5-MeO, 6h
4-BrC6H4, 5-MeO, 6i
4-BrC6H4, 4-Me, 6j
4-BrC6H4, H, 6k
4-FC6H4, 5-MeO, 6l
3-FC6H4, 4-Me, 6m
4-NO2C6H4, 5-MeO, 6n
3-NO2C6H4, 5-MeO, 6o
2-thienyl, 5-MeO, 6p
2-furanyl, 5-MeO, 6q
t-Bu, 5-MeO, 6r
7
8
9
Table 1. Development and Optimization of Reaction Conditions
of an Organocatalytic Enantioselective Cascade
Oxa-Michael-Aldol Cascade Reactiona
10
11
12
13
14
15
16
17
18
19e
20e
6
10
10
10
60
60
PhCH2CH2, 4-Me, 6s
n-C5H11, 4-Me, 6t
a Reaction conditions: unless specified, see footnote a in Table 1 and
Supporting Information. b Isolated yields. c Determined by chiral HPLC
analysis (Chiralcel AD or Chiralpak IC). d 15 mol % of I and 10 mol % of
IV were used. e 25 mol % of III was used.
entry
cat.
solvent
t (h)
% yieldb
% eec
1
2
3
4
5
6
7
8e
I
II
toluene
toluene
toluene
THF
3
3
3
2
3
3
3
6
97
98
98
<5
96
99
94
98
97
98
a broad substrate tolerance, and a quaternary stereogenic
center is generated highly enantioselectively in all cases. A
full range of aromatic ynals 2, including electron-neutral
(Table 2, entries 1-5), -donating (entries 6 and 7), and
-withdrawing substituents (entries 8-15), as well as hetero-
cyclic examples (entries 16 and 17), can participate in the
cascade reactions in excellent yields (84%∼99%) and with
excellent enantioselectivities (93->99%). It is noteworthy
that the substrate scope can also be expanded to highly steric
demanding aliphatic alkynal, providing the desired product
in 91% yield and 98% ee (entry 18). Moreover, alkyl alkynals
(R ) CH2CH2Ph and n-C5H11, Table 2, entries 19 and 20,
respectively) were also probed for the cascade process. It
was found that they efficiently participated in the reaction
with excellent enantioselectivities (97 and 99% ee, respec-
tively), although the reaction occurred slower (60 h) than
aryl ones and higher catalyst loading (25 mol %) was needed
as a result of their poorer reactivity. The variation in ethyl
2-(2-hydroxyphenyl)-2-oxoacetate components 5 was also
possible, as demonstrated by the aromatic structures carrying
electron-donating (entries 1, 3, 4, 6-10, and 12-18), -neutral
III
IV
III
III
III
III
98
NDd
98
xylene
CH2Cl2
Cl(CH2)2Cl
toluene
97
96
99
a Reaction conditions: unless specified, a mixture of phenyl-propynal
2a (0.080 mmol), ethyl 2-(2-hydroxy-4-methoxyphenyl)-2-oxoacetate 5a
(0.080 mmol), and catalyst (0.016 mmol) in solvent (0.5 mL) was stirred
at rt for a specified time. b Isolated yields. c Determined by chiral HPLC
analysis (Chiralcel AD). d Not determined. e Performed at -15∼-10 °C,
and 15 mol % of catalyst III was applied.
TBDMS catalyst III gave a slightly higher enantioselectivity
(Table 1, entries 2-3). Quinine alone was not effective for
this transformation (entry 4). Therefore, the catalyst III was
defined as the optimal promoter for this process. A survey
of solvents led to choose toluene as the reaction medium
for the process (entries 5-7). Better ee (99%) was observed
when decreasing the reaction temperature to -15∼-10 °C
and lowering the catalyst loading to 15 mol % (Table 1, entry
8).
4950
Org. Lett., Vol. 12, No. 21, 2010

(entries 2 and 11), and -withdrawing (entry 5) groups. It is
observed that with respect to substrate 5e having electron-
withdrawing Cl (entry 5) poor ee was observed. However,
we found that quinine IV as cocatalyst was essential to ensure
high enantioselectivity presumably due to its interaction with
the ketone moiety in the ketoester. The absolute configuration
of 6h was determined to be R configuration by X-ray
crystallographic analysis (Figure 1).9
In conclusion, we have described a new protocol for
asymmetric organocatalysis through the first iminium-alle-
namine engaged oxa-Michael-aldol cascade reaction. In
addition to the potential of this powerful “one-pot” approach
to the catalytic generation of chiral 4H-chromenes bearing
a quaternary stereogenic center, it is a rare example of a
highly enantioselective cascade reaction with ynals. The
operationally friendly reaction conditions and high efficiency
(cascade, high yields and ee, and readily available achiral
starting materials) render the process particularly attractive
in the practice of organic synthesis and medicinal chemistry.
Chiral 4H-chromene products with a versatile R-hydroxy
carboxylate moiety are valuable structures for the synthesis
of biologically active molecules.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20932003 and
90813012, R.W.) and the National S&T Major Project of
China (2009ZX09503-017, R.W.) and the NSF (Chem-
0704015, W.W.) is gratefully acknowledged. C.-L. Liu and
X.-S. Zhang make equal contributions to this work.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR and HRMS data for products
6 and X-ray crystallographic information of 6h (CIF file).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(9) See Supporting Information for detail.
OL102096S
Org. Lett., Vol. 12, No. 21, 2010
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