One-pot approach to chiral chromenes via enantioselective organocatalytic domino oxa-Michael-aldol reaction

Article abstract of DOI:10.1039/b611502k

A highly enantioselective (S)-diphenylpyrrolinol triethylsilyl ether promoted tandem oxa-Michael-aldol reaction of α,β-unsaturated aldehydes with salicylaldehydes has been developed; the method affords one-pot access to chiral and synthetically useful chr

Full text of DOI:10.1039/b611502k

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One-pot approach to chiral chromenes via enantioselective
organocatalytic domino oxa-Michael–aldol reaction{
Hao Li,a Jian Wang,a Timiyin E-Nunu,a Liansuo Zu,a Wei Jiang,a Shaohua Wei*b and Wei Wang*a
Received (in Bloomington, IN, USA) 9th August 2006, Accepted 16th October 2006
First published as an Advance Article on the web 1st November 2006
DOI: 10.1039/b611502k
A highly enantioselective (S)-diphenylpyrrolinol triethylsilyl
ether promoted tandem oxa-Michael–aldol reaction of a,b-
unsaturated aldehydes with salicylaldehydes has been
developed; the method affords one-pot access to chiral and
synthetically useful chromenes in high yields and high
enantioselectivities from readily available compounds.
Functionalized chiral chromene skeleton is found in a myriad of
medicinally important compounds that have a broad and interest-
ing range of biological activities.1,2 Accordingly, a number of
synthetic strategies have been reported for the construction of this
‘‘privileged’’ structural motif.3 Although asymmetric methods
would furnish enantiomerically enriched chromenes, their develop-
Scheme 1 Domino organocatalyzed enantioselective Michael–aldol
ment has proven to be a synthetic challenging task. To date,
reactions.
approaches to chiral chromenes involving ring-closing metathe-
sis2e,4 and Pt-catalyzed cyclization5 of chiral precursors and
nucleophile than that of the sulfur of thiophenol.10,13 Generally, a
base is used to activate the Michael donor phenol group 2 and
these methods are non-asymmetric.10 The strategy we present here
is the utilization of a chiral organocatalyst as a promoter for
activation of the Michael acceptor 1 in a highly enantioselective
controlled manner (Scheme 1).
enzyme-catalyzed kinetic resolution6 have been described. An
enantioselective procedure, based on a chiral metal–ligand com-
plex, has been recently reported by Malinakova and co-workers7
for generation of this chiral scaffold. However, it is noted that a
stoichiometric amount of the complex is used. In this communica-
tion, we wish to report a new one-pot, enantioselective organoca-
talytic domino oxa-Michael–aldol reaction for the facile
preparation of chiral chromenes. The process takes place in high
yields (up to 98%) and with good to excellent levels of enantio-
selectivities (up to .99% ee). Importantly, this approach allows for
the construction of complex benzopyran structures starting with
simple a,b-unsaturated aldehydes and salicylaldehydes.
A model reaction between trans-cinnamaldehyde 1a and
salicylaldehyde 2a in toluene at r.t. under the same reaction
conditions used for the tandem thio-Michael–aldol reaction11 in
the presence of organocatalyst I was evaluated for the oxa-
Michael–aldol process (Fig. 1 and Table 1). It was found that,
surprisingly, no reaction occurred even using 30 mol% catalyst
(Table 1, entry 1). The result prompted us to survey (S)-
diphenylpyrrolinol TMS ether II for the process (Fig. 1).14–16 To
our delight, the reaction proceeded with achieving a good yield
(70%), but a moderate ee (52%) (entry 2). After extensive
optimization reaction conditions including screening solvents17
and reaction temperature, we found that using Cl(CH2)2Cl as a
solvent provided the highest enantioselectivity (80% ee, entry 3).
Lowering the reaction temperature to 0 uC resulted in an improved
ee (89%) but the time required for completion was significantly
lengthened (60 h) and the yield was decreased as well (entry 4).
Switching the TMS silyl ether in catalyst II to the TES in III (entry
5) and TBS in IV (entry 6) showed that III was a superior catalyst
(87% yield and 88% ee, entry 5).
By taking advantage of the capability of chiral pyrrolidine
derivatives to participate in the reversible formation of enamine
and iminium intermediates, Barbas, Yamamoto, List, MacMillan,
Jørgenson, and Enders have independently developed novel types
of organocatalyzed cascade reactions.8,9 Michael addition initiated
cascade Michael–aldol processes serve as powerful methods for the
generation of complex structures. We envisioned that an ‘‘S’’ or
‘‘O’’ could serve as a Michael donor for initiating the process
(Scheme 1). Recently, we have demonstrated that 2-mercaptoben-
zaldehydes can participate in the tandem reactions with attaining
high enantioselectivity (85–95% ee).10–12 However, the develop-
ment of ‘‘O’’ invoked Michael–aldol process has created a
formidable challenge since the oxygen in phenol is a much weaker
aDepartment of Chemistry, University of New Mexico, Albuquerque,
NM, 87131, USA. E-mail: wwang@unm.edu; Fax: (+1) 505 277 2609;
Tel: (+1) 505 277 0756
bDepartment of Chemistry, Nanjing Normal University, Nanjing,
210097, P. R. China. E-mail: weishaohua@njnu.edu.cn
{ Electronic supplementary information (ESI) available: Experimental and
NMR data. See DOI: 10.1039/b611502k
Fig. 1 Screened organocatalysts.
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The III-catalyzed processes also took place with less reactive alkyl-
Table 1 Organocatalytic asymmetric domino oxa-Michael–aldol
reaction of trans-cinnamaldehyde (1a) with salicylaldehyde (2a)a
substituted a,b-unsaturated aldehydes (entries 11 and 12), albeit
with lower yields and enantioselectivities. Significant structural
variation in the salicylaldehydes 2 was tolerated in the process.
Aromatic rings, bearing electron neutral (entries 1–2), withdrawing
(entries 4, 8, 10 and 11) and donating (entries 3, 5–7, 9 and 12)
groups could undergo the III-promoted cascade process efficiently.
In summary, we have uncovered a one-pot organocatalyzed
domino oxa-Michael–aldol reaction that transforms readily
available a,b-unsaturated aldehydes and 2-salicylaldehydes to
synthetically and biologically useful chiral chromenes in high
enantiomeric purities. Investigations of the full scope of the
cascade reaction, and its application to the synthesis of biologically
interesting compounds are underway and the results will be
reported in due course.
Entry
Cat.
Solvent
t/h
Yieldb (%)
ee (%)c
1
2
3
I
Toluene
Toluene
Cl(CH2)2Cl
Cl(CH2)2Cl
Cl(CH2)2Cl
Cl(CH2)2Cl
36
48
22
60
60
96
,5
70
91
51
87
52
NDd
52
80
89
88
80
II
II
II
III
IV
4e
5e
6e
a
Unless otherwise specified, the reaction was carried out with 1a
(0.1 mmol) and 2a (1.0 mmol) in the presence of an organocatalyst
˚
(0.03 mmol), benzoic acid ( 0.03 mmol), 4 A MS (50 mg), and
b
solvent (0.5 mL). Isolated yield. Determined by chiral HPLC
c
Financial support for this work provided by the Department of
Chemistry and the Research Allocation Committee, the University
of New Mexico, the ACS-PRF and NIH-INBRE (P20 RR016480)
is gratefully acknowledged.
d
e
analysis (Chiralpak AS-H). Not determined. Performed at 0 uC.
Table 2 Catalyst III promoted domino oxa-Michael–aldol reactions
of a,b-unsaturated aldehydes (1) with salicylaldehydes (2)a
Notes and references
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Entry
R
X
T/uC t/h
Yieldb (%) eec (%)
88
1
2
3
4
5
6
7
8
Ph
4-NO2C6H4
4-NO2C6H4 5-Me
4-NO2C6H4 5-Cl
4-NO2C6H4 4-MeO r.t.
4-NO2C6H4 3-MeO
4-NO2C6H4 5-MeO 215
2-NO2C6H4 5-Cl
Ph
4-MeOC6H4 5-Cl
Me
Me
H
H
0
0
0
0
60 87
24 96
95
96
91
86
90
94
.99
87
18 98
18 96
120 64
36 98
24 95
0
215 144 82
9
5-MeO
0
4
0
0
48 97
72 53
36 67
48 84
10
11
12
a
75
82
85
5-Cl
5-MeO
Reaction conditions: unless specified, see footnote a in Table 1.
Isolated yields. Determined by chiral HPLC analysis (Chiralpak
AS-H, or Chiralcel OD-H).
b
c
Having established optimal conditions for reaction of trans-
cinnamaldehyde 1a and salicylaldehyde 2a to form the chromene
3a in ClCH2CH2Cl promoted by catalyst III, we next probed the
scope of the domino oxa-Michael–aldol process by using a variety
of a,b-unsaturated aldehydes 1 and salicylaldehydes 2. As the data
in Table 2 show, the reactions proceeded in respectively high yields
(53–98%) and with good to excellent levels of enantioselectivities
(75–99% ee) (Table 2). The process appeared to have a broad
scope, but efficiencies and ees varied with the electronic and steric
nature of the a,b-unsaturated aldehydes 1 and salicylaldehydes 2.
a,b-Unsaturated aldehydes 1 bearing electron-withdrawing groups,
such as nitro group, generally afforded products in higher yields
(82–98%) and higher ee values (86–99%, entries 2–8) than those
not possessing electron withdrawing groups. Relatively lower ees
were observed for reactions of a,b-unsaturated aromatic aldehydes
1 that bear neutral (entries 1 and 9) or electron-donating (entry 10)
substituents. Also, the results showed that steric hindrance
retarded the reactions but enhanced enantioselectivities (entry 8).
508 | Chem. Commun., 2007, 507–509
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17 Xylenes: 96% yield, 40% ee; anisole: 56% yield, 66% ee; CH2Cl2: 81%
yield, 76% ee; CHCl3: 68% yield, 67% ee; CCl4: 65% yield, 47% ee;
Et2O: 85% yield, 43% ee; dioxane: ,5% yield; DMSO: 66% yield,
60% ee.
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Chem. Commun., 2007, 507–509 | 509