Organocatalytic direct vinylogous michael addition of α,β- unsaturated γ-butyrolactam to α,β-unsaturated aldehydes and an illustration to scaffold diversity synthesis

Article abstract of DOI:10.1002/chem.201001350

(Figure Presented) Ideal for scaffold diversity synthesis: The first organocatalytic direct vinylogous Michael addition of N-Boc α, βunsaturated γ-butyrolactam to α,βunsaturated aldehydes has been developed. The products with multiple orthogonal sets of f

Full text of DOI:10.1002/chem.201001350

COMMUNICATION
DOI: 10.1002/chem.201001350
Organocatalytic Direct Vinylogous Michael Addition of a,b-Unsaturated
g-Butyrolactam to a,b-Unsaturated Aldehydes and an Illustration to Scaffold
Diversity Synthesis
Xin Feng,[a] Hai-Lei Cui,[a] Shi Xu,[a] Li Wu,[a] and Ying-Chun Chen*[a, b]
The development of efficient synthetic protocols to access
small-molecule libraries that contain structurally and stereo-
chemically diverse scaffolds is highly desirable because of
the increasing demand for collections of probe and drug
candidates.[1] Therefore, the design of asymmetric reactions
from readily available starting materials, which can deliver
enantioenriched and multifunctional products and allow
subsequent skeletal variation constructions, is extremely at-
tractive. Not surprisingly, the vinylogous reactions of a,b-un-
saturated systems, which can supply an additional and versa-
tile olefinic functionality in the products, trigger increasing
attention in modern synthetic organic chemistry,[2] and inten-
sive studies have been concentrated on the applications of
g-butenolides and their O-silyl derivatives.[3] Over the past
years we have developed a number of asymmetric direct vi-
nylogous-type reactions, which provide facile access to
useful chiral materials with structural diversity and complex-
ity.[4] Later we were fascinated by the utilization of the aza
analogues of g-butenolides, a,b-unsaturated g-butyrolactams,
not only because they have been much less explored,[5] but
also the associated aza heterocycles might have more poten-
tial in the subsequent synthetic transformations and related
biological investigation.[2d] In particular, we envisaged that
the unprecedented stereoselective direct vinylogous Michael
vation of secondary amine 1a,[6] would afford chiral adducts
that have fruitful and orthogonal sets of functional groups in
an atom-economic fashion, which would be ideal for the fol-
lowing couple and pair reactions for scaffold diversity syn-
thesis (Scheme 1).[7]
Scheme 1. Direct vinylogous Michael addition to multifunctional adducts
for scaffold diversity synthesis.
We initially studied the possible direct vinylogous Michael
addition of N-Boc a,b-unsaturated g-butyrolactam 2a to cin-
namaldehyde 3a catalyzed by 1a and benzoic acid in tolu-
ene at room temperature.[8] Gratifyingly, the reaction pro-
ceeded smoothly with high regio- and chemoselectivity, and
the desired major syn adduct 4a and its minor anti dia
ACHTUNGTRENNUNGster-
AHCTUNGTREGeNNNU omer 4a’ were obtained in fair yield and stereoselectivity
after 43 h (Table 1, entry 1). A few solvents have been
tested (Table 1, entries 2–5), and an excellent ee value was
attained in acetonitrile (Table 1, entry 5). In addition, we
found that higher yield could be gained when some H2O
(10% v/v) was added (Table 1, entry 6), and a slight im-
provement could be reached when more 3a was applied
(Table 1, entry 7). Acid additives also have apparent effects
on the outcomes (Table 1, entries 8–10), and finally, we
addition of a,b-unsaturated g-butyrolacACTHNUTRGNEUNG
tams[5a,b] to a,b-unsa-
turated aldehydes, under the well-established iminium acti-
[a] X. Feng, H.-L. Cui, S. Xu, L. Wu, Prof. Dr. Y.-C. Chen
Key laboratory of Drug-Targeting and
Drug Delivery System of Education Ministry
Department of Medicinal Chemistry
West China School of Pharmacy, Sichuan University
Chengdu, 610041 (China)
AHCTUNGTREGaNNUN chieved the optimal results in regard to yield, diastereose-
lectivity, and enantioselectivity in the presence o-fluoroben-
zoic acid (Table 1, entry 10). It was pleasing that the minor
diastereomer 4a’ was also afforded in remarkable enantio-
purity (Table 1, entry 10).[9]
With the established conditions in hand, the scope of the
direct vinylogous Michael addition of N-Boc a,b-unsaturat-
ed g-butyrolactam 2a[10] to an array of a,b-unsaturated alde-
Fax : (+86)28-85502609
E-mail: ycchenhuaxi@yahoo.com.cn
[b] Prof. Dr. Y.-C. Chen
State Key Laboratory of Biotherapy, West China Hospital
Sichuan University, Chengdu, 610041 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001350.
Chem. Eur. J. 2010, 16, 10309 – 10312
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10309

Table 1. Screening studies of the organocatalytic direct vinylogous Mi-
chael addition of a,b-unsaturated g-butyrolactam 2a to cinnamaldehyde
3a.[a]
Table 2. Substrate scope in the organocatalytic direct vinylogous Michael
addition reaction.[a]
Entry
R
t [h]
Yield [%][b]
d.r.[c]
4:1
19:1
>20:1
>20:1
>20:1
13:1
ee [%][d]
Entry Solvent
Acid
t [h] Yield [%][b] d.r.[c] ee [%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17[h]
Ph
46
58
58
56
46
63
64
44
48
46
58
60
54
38
68
64
82
4a, 63 (80)
4b, 80
4c, 73
4d, 78
4e, 77
93 (99)
97
97
p-ClC6H4
p-BrC6H4
p-CF3C6H4
3,4-Cl2C6H3
m-ClC6H4
o-BrC6H4
p-MeC6H4
m-MeC6H4
p-MeOC6H4
Ar[f]
2-thienyl
2-furyl
3-pyridinyl
Me
Et
o-BrC6H4
1
2
3
4
5
toluene
THF
DCM
CHCl3
CH3CN
CH3CN/H2O BA
CH3CN/H2O BA
CH3CN/H2O AcOH 56
CH3CN/H2O PNBA 56
CH3CN/H2O OFBA 46
BA
BA
BA
BA
BA
43
46
46
46
46
41
58
62
60
55
60
55
66
76
73
76
80
2.5:1 76
2.0:1 87
3.6:1 90
3.0:1 85
2.0:1 93
2.0:1 93
2.0:1 93
2.0:1 73
2.0:1 87
4.0:1 93 (99)[f]
94
98[e]
4 f, 72 (79)
4g, 70
91
97
97
96
98 (96)
96 (96)
98 (96)
93 (90)
93 (92)
90 (83)
79 (76)
97
19:1
6
7[e]
8[e]
9[e]
10[e]
4h, 66 (85)
4i, 66 (82)
4j, 54 (85)
4k, 52 (76)
4 l, 39 (61)
4m, 31 (52)
4n, 89[g]
4o, 51[g]
5.7:1
4.9:1
1.5:1
2.3:1
1.6:1
1.5:1
2.4:1
1.1:1
2.0:1
19:1
[a] Unless noted otherwise, reaction conditions were 2a (0.1 mmol), 3a
(0.15 mmol), 1a (0.02 mmol), and acid (0.02 mmol) in solvent (0.5 mL) at
RT. BA: benzoic acid; PNBA: p-nitrobenzoic acid; OFBA: o-fluoroben-
zoic acid. [b] Combined isolated yield of diastereomers. [c] Determined
4p, 42[g]
4g, 62
1
by crude H NMR analysis. [d] Determined by chiral HPLC analysis after
reaction with Ph3PCHCOPh for major 4a. [e] Compound 3a (0.2 mmol)
was used. [f] The data in parenthesis is related to minor 4a’.
[a] Unless noted otherwise, reactions conditions were 2a (0.1 mmol), 3
(0.2 mmol), 1a (0.02 mmol), and OFBA (0.02 mmol) in CH3CN/H2O
(0.5 mL/0.05 mL) at RT. [b] Isolated yield of pure isomer 4 (the data in
parentheses is related to the combined isolated yield of the diastereo-
mers). [c] Determined by crude 1H NMR analysis. [d] Determined by
chiral HPLC analysis after reaction with Ph3PCHCOPh (the data in pa-
rentheses is related to the minor isomer 4’). [e] The absolute configura-
tion of 4e has been determined by X-ray crystallographic analysis after
conversion to 5e, see Figure 1.[11] The other products were assigned by
analogy. For the structural assessment of the minor 4’, see the Supporting
Information. [f] Ar=3-cyclopentoxy-4-methoxyphenyl. [g] Combined
yield of inseparable diastereomers. [h] At the 1.0 mmol scale.
hydes 3 was explored by the catalysis of 20 mol% of 1a and
OFBA in a mixture of CH3CN/H2O (10:1) at room tempera-
ture. In general, the pure syn-4 and anti-4’ could be directly
separated. As summarized in Table 2, excellent diastereo-
and enantioselectivities have been obtained for enals with
various electron-withdrawing aryl groups (Table 2, entries 2–
7). Outstanding ee values were also attained for enals that
have electron-donating aryl substitutions (Table 2, entries 8–
11). The diastereocontrol was less satisfying, especially for
substrates with alkyloxy-substituted aryl groups; neverthe-
less, the ee data of the separable minor diastereomers were
outstanding (Table 2, entries 10 and 11). The diastereoselec-
tivity was also low for heteroaryl-substituted enals, but the
enantiocontrol for both diastereomers was still remarkable
(Table 2, entries 12–14). The linear alkyl-substituted enals
could be applied, and moderate to high enantioselectivity
with low d.r. ratios was gained (Table 2, entries 15 and 16).
Unfortunately, enals with b-branched alkyl groups failed to
give the desired adducts, and nonclean reactions were ob-
served. The catalytic reaction could proceed smoothly at a
larger scale, and the similar results were attained (Table 2,
entry 17).
Because the vinylogous adducts have multifunctional
properties, we devoted much effort to exemplify the con-
structions of natural-product-like or drug-like libraries with
versatile skeletal diversity through branching pathways.[7] As
outlined in Scheme 2, a domino reductive amination–intra-
molecular aza Michael addition with 4e or 4g could be effi-
ciently performed to afford diaza bicycles 5e or 5g, respec-
tively, in excellent diastereocontrol. The relative and abso-
lute configuration of 5e was unambiguously determined by
X-ray crystallographic analysis (Figure 1).[11] Moreover, an
indoline derivative 6g was smoothly prepared from 5g
through a copper-catalyzed intramolecular N-arylation reac-
tion, the analogues of which have exhibited significant bio-
logical activities.[12] In addition, another tandem N-Boc de-
protection–hemiaminal formation–dehydroxylation reaction
with 4g successfully delivered the N-fused bicycle 7g,[13]
which could be further converted to a polycyclic framework
8g through Bu3SnH-mediated radical addition, also in excel-
lent diastereoselectivity. The similar tandem reaction was
conducted with 4k, and a cAMP-specific phosphodiesterase
(PDE IV) inhibitor 9k was produced, following a simple hy-
drogenation.[14] On the other hand, the aldehyde functionali-
ty could actively contribute to more scaffold diversity in dif-
ferent ways. A Bu3SnH-mediated direct reductive radical
conjugate addition with 4a afforded a diastereomeric mix-
ture 10a, which was easily converted to a single ketone
product 11a in good yield after oxidation.[15] Moreover, 4a
was coupled with functionalized ylides to give 12a and 12b,
respectively, which have two activated olefin systems. A sep-
arable major diastereomer 13a was obtained via a Bu3SnH-
mediated intramolecular ketyl addition reaction of 12a.[16]
Interestingly, we found that Yoonꢁs Ru-based photoredox
catalysis[17] could be successfully applied to the pair reaction
of intermediate 12b, and a tricyclic alkaloid 14a with six
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Chem. Eur. J. 2010, 16, 10309 – 10312

Organocatalytic Direct Vinylogous Michael Addition Reaction
COMMUNICATION
tion of N-Boc a,b-unsaturated g-butyrolactam to a,b-unsatu-
rated aldehydes. The desired adducts with multiple orthogo-
nal sets of functionalities were obtained in excellent enan-
tioselectivity (up to 98% ee) with low to outstanding dia-
AHCTUNGTRENNUNG
stereoselectivity (d.r. up to>20:1).[18] Moreover, we have
demonstrated that the products were quite valuable for scaf-
fold diversity synthesis. A number of enantioenriched natu-
ral-product-like or drug-like molecules with fused bi-, tri-,
and polycyclic structures have been efficiently constructed,
which might have potentials in the later explorations for the
biologically related studies. More synthetic explorations are
underway in our laboratory.
Acknowledgements
We are grateful for the financial support from NSFC (20772084),
PCSIRTC (IRT0846) and National Basic Research Program of China
(973 Program) (2010CB833300).
Keywords: aldehydes
· lactams · Michael addition ·
organocatalysis · scaffold diversity synthesis
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In conclusion, we have presented the first organocatalytic
regio- and chemoselective direct vinylogous Michael addi-
Chem. Eur. J. 2010, 16, 10309 – 10312
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10311

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[9] For more screening studies, see the Supporting Information.
Published online: July 28, 2010
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Chem. Eur. J. 2010, 16, 10309 – 10312