N-Heterocyclic carbene-catalyzed diastereoselective synthesis of β-lactone-fused cyclopentanes using homoenolate annulation reaction

Article abstract of DOI:10.1039/c5cc02960k

NHC-catalyzed annulation of enals with 2-enoylpyridines or 2-enoylpyridine N-oxides leading to the diastereoselective synthesis of β-lactone-fused cyclopentanes is reported. The reaction proceeds via the generation of homoenolate equivalent intermediates and tolerates a broad range of functional groups.

Full text of DOI:10.1039/c5cc02960k

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N‐Heterocyclic carbene‐catalyzed diastereoselective synthesis of
β‐lactone‐fused cyclopentanes using homoenolate annulation
reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Subrata Mukherjee,a Santigopal Mondal,a Atanu Patra,a Rajesh G. Gonnade,b and Akkattu T. Biju*,a
DOI: 10.1039/x0xx00000x
www.rsc.org/
uncovered a conceptually new NHC‐catalyzed reaction of enals with
chalcones to afford functionalized cyclopentenes (eq 1).7 The
reaction proceeds via the generation of homoenolate equivalents,8
and the product formation took place by the spontaneous
decarboxylation of the β‐lactone‐fused cyclopentane intermediate.
Subsequently, the enantioselective version of the Nair reaction was
developed by Bode and co‐workers (using chiral NHCs),9 and
Scheidt and co‐workers (employing NHC/Lewis acid cooperative
catalysis).10 Moreover, the synthesis of β‐lactone‐fused
cyclopentane derivatives was demonstrated by the groups of
Bode,11 Scheidt,12 Lupton13 and Studer.14 However, the isolation of
the β‐lactone‐fused cyclopentane intermediate in the NHC‐
catalyzed cyclopentannulation reaction of enals with chalcones has
not been demonstrated.15 In the context of our recent success on
NHC‐catalyzed reaction of enals with 2'‐hydroxy chalocones leading
to the diastereoselective synthesis of cyclopentane‐fused
coumarins,16 we have carried out the reaction of enals with 2‐
enoylpyridines/2‐enoylpyridine N‐oxides under NHC‐catalysis.
Herein, we report the results of our studies leading to the
diastereoselective synthesis of β‐lactone‐fused cyclopentane
derivatives (eq 2).
NHC‐catalyzed annulation of enals with 2‐enoylpyridines or 2‐
enoylpyridine N‐oxides leading to the diastereoselective synthesis
of β‐lactone‐fused cyclopentanes is reported. The reaction
proceeds via the generation of homoenolate equivalent
intermediates and tolerates a broad range of functional groups.
Functionalized β‐lactones are ubiquitous in numerous
biologically active natural products and various pharmaceutically
relevant molecules.1 Among the β‐lactones, the β‐lactone‐fused
cyclopentanes are important because these structural motifs are
found in natural products such as vibralactone (A, a pancreatic
lipase inhibitor),2 and spongiolactone (B, antiproliferative activity
towards the K562 cell line) (Figure 1).3 Moreover, the rocaglate‐
derived β‐lactone (C) has been recently reported to have serine
hydrolase activity.4 Due to the biological importance of β‐lactone‐
fused cyclopentanes, development of atom‐economic and flexible
synthetic routes to these targets are highly desirable.
O
Me
O
O
Me
O
Me
H
MeO
O
HO
OH
O
O
Ph
O
O
Me Me
H
MeO
OMe
Cyclopentannulation reaction catalyzed by NHC
A
)
Vibralactone (
Spongiolactone (B)
Rocaglate-derived β-lactone (C)
R1
Figure 1. Selected biologically important β‐lactone‐fused cyclopentanes
NHC
R1
O
+
O
(1)
R1
-CO2
O
R2
Romo and co‐workers developed efficient methods for the
synthesis of functionalized β‐lactones.1b,1d,1e N‐heterocyclic carbene
(NHC)‐catalyzed formal [2+2] cycloaddition of ketenes with
aldehydes/activated ketones has been a convenient method for the
construction of β‐lactones.5,6 In 2006, Nair and co‐workers
R2
H
O
R2
not isolable
NHC-catalyzed reaction of enals with 2-enoylpyridines (this work)
H
R1
(+) mild
(+) versatile
N
NHC
N
O
+
O
(2)
(+) good yields
(+) diastereoselective
R1
O
a. Organic Chemistry Division, CSIR‐National Chemical Laboratory (CSIR‐NCL), Dr.
Homi Bhabha Road, Pune‐411008, India. E‐mail: at.biju@ncl.res.in; Fax: +91‐20‐
25902629; Tel: +91‐20‐25902441.
H
R2
H
O
R2
b. Centre for Materials Characterization, CSIR‐National Chemical Laboratory (CSIR‐
NCL), Dr. Homi Bhabha Road, Pune‐411008, India.
The present studies were initiated by treating 2‐enoylpyridine
(1a)17 with cinnamaldehyde (2a) in the presence of carbene
generated from the imidazolium salt 4 using DBU as base.
Interestingly, under these conditions, the β‐lactone‐fused
Electronic Supplementary Information (ESI) available: Details on experimental
procedure, characterization data of all compounds, and single crystal X‐ray data
of compounds 3e, and 10a. CCDC 1057298 and 1057299. See
DOI: 10.1039/x0xx00000x
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cyclopentane 3a was isolated in 63% yield as a single diastereomer
(Table 1, entry 1).18 It is noteworthy that the reaction of enals with
3‐enoylpyridine and 4‐enoylpyridine afforded the corresponding
cyclopentene derivatives via the spontaneous decarboxylation.19
Compared to the NHC derived from 4, other common NHCs derived
from precursors 5‐8 are not found to be beneficial in this reaction
(entries 2‐5). Additionally, other organic and inorganic bases
afforded the desired β‐lactone in reduced yield, but as a single
diastereomer (entries 6‐9). A rapid solvent screen revealed that
solvents other than THF furnished the β‐lactone in only moderate
yield (entries 10‐13). Interestingly, when the NHC precursor 4
loading was increased in 20 mol %, the yield of 3a was improved to
76% (entry 14). Finally, by employing 20 mol % of 4 and 1.2 equiv of
2a, the β‐lactone 3a was isolated in 86% yield as a single
diastereomer (entry 15).20
structure and the trans geometry of the two aryl groups are
confirmed by single‐crystal X‐ray analysis.21 Moreover,
β‐aryl
ring having substituents at the 3‐position and 2‐position as
well as disubstitution did not affect the reactivity, and the
corresponding products were isolated in good yields (3f‐3i).
The substrate having the extended conjugation at the
β‐
position afforded the desired product 3j in 92% yield.
Additionally, enones having heteroaryl group and ferrocenyl
moiety at the
β‐position underwent smooth annulation
reaction to afford the target products in moderate to good
yields (3k‐3l). Furthermore, bromo substitution at the pyridine
ring of
1 was also tolerated to afford the β‐lactone 3m in 72%
yield thus showing the versatile nature of the present reaction.
R2
O
O
N
4 (20 mol %)
DBU (40 mol %)
N
H
R2
O
+
R1
R1
THF, 24 h, 25 °C
Ph
O
Table 1. Optimization of the reaction conditionsa
H
Ph
2a
3a-m
1
R = H, 3a, 86%
N
N
Cl
R = OMe: 3b, 85%
R = Me: 3c, 76%
R = Cl: 3d, 76%
R = NO2: 3e, 62%
O
O
R
O
O
H
H
N
Ph
Ph
3f, 71%
N
N
yield of 3a
R1
entry
variation of the standard conditionsa
(%)b,c
63
O
O
O
R2
1
2
none
O
O
O
H
H
H
Ph
Ph
Ph
5 instead of 4
<5
<5
<5
32
15
25
27
35
57
41
44
57
76
86
R1 = NO2, R2 = H, 3g, 76%
1 = R2 = Cl, 3h, 81%
3
6 instead of 4
R
3j, 92%
3i, 78%
4
7 instead of 4
5
8 instead of 4
N
N
N
Br
6
Et3N instead of DBU
DABCO instead of DBU
KOt-Bu instead of DBU
Cs2CO3 instead of DBU
DME instead of THF
1,4-dioxane instead of THF
toluene instead of THF
CH2Cl2 instead of THF
20 mol % of 4 instead of 10 mol %
20 mol % of 4, 1.2 equiv of 2a
O
O
O
7
Fe
O
O
O
O
H
H
H
Ph
Ph
Ph
8
3k, 84%
3l, 52%
9
3m, 72%
10
11
12
13
14d
15d
Scheme 1. Substrate scope for the synthesis of β‐lactone‐fused cyclopentanes.
Variation of 2‐enoylpyridines. General reaction conditions: 1 (0.50 mmol), 2a
(0.60 mmol), 4 (20 mol %), DBU (40 mol %), THF (2.5 mL) at 25 °C for 24 h. Given
are isolated yields after flash column chromatography.
Next, we studied the scope of this reaction with
substituted enals (Scheme 2). A series of substrates having
a Standard conditions: 1a (0.25 mmol), 2a (0.25 mmol), 4 (10 mol %), DBU (20 mol
%), THF (1.0 mL), 25 °C and 24 h. b Isolated yield after column chromatography.!! electron‐releasing and ‐withdrawing groups at the 4‐position
c
A single!diastereomer was observed in all cases. d 40 mol % of DBU was used.
of the
β‐aryl ring of 2 underwent smooth annulation reaction
affording the
β‐lactone derivatives as a single diastereomer in
good yields (3n‐3r). Besides, substitution at the 3‐position and
2‐position was well‐tolerated (3s‐3t). Additionally, enals having
β‐heteroaryl group, dienals having
δ‐aryl and alkyl
substitution, and enals bearing ‐alkyl groups furnished the
β
desired products in good yields thereby further expanding the
scope of this annulation reaction.
With the interesting results obtained using 2‐
enoylpyridines, we then focused our attention on 2‐
enoylpyridine N‐oxides as the enal coupling partner in this
With these conditions in hand, we then evaluated the
substrate scope of this reaction. First we examined the
variation of 2‐enoylpyridine moiety (Scheme 1). The
unsubstituted
β‐phenyl 2‐enoylpyridine worked well and a
variety of electron‐releasing and ‐withdrawing groups at the 4‐
reaction. Gratifyingly, treatment of unsubstituted
β‐aryl 2‐
position of the
synthesis of
β
‐aryl ring was well‐tolerated leading to the
enoylpyridine N‐oxide 9a17a,22 with enal 2a under the NHC‐
β‐lactone‐fused cyclopentanes as single
a
catalyzed reaction conditions resulted in the formation of
diastereomer in good yields (3a‐3e). In the case of 3e, the
2 | J. Name., 2012, 00, 1‐3
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D
from enal and NHC undergoes a conjugate addition to the 2‐
enoylpyridine followed by an intramolecular proton transfer
results in the formation of the enolate intermediate . This
intermediate undergoes an intramolecular aldol reaction to
generate acylazolium intermediate , which on highly selective
1
E
E
F
β
‐lactonization affords the
.
β
‐lactone
3
via the intermediate
G 23
Mes
N
OH
Mes
N
N
R1
N
N
O
Mes
R1
D
R2
NHC
Mes
O
+
O
homoenolate equivalent
R2
R1
H
3
H
2
NHC
N
O
1
N
N
O
N
R2
O
R2
R2
O
NHC
R1
NHC
O
R1
R1
NHC
O
O
F
E
G
Scheme 2. Variation of the enal moiety. General reaction conditions: 1a (0.50
mmol), 2 (0.60 mmol), 4 (20 mol %), DBU (40 mol %), THF (2.5 mL) at 25 °C for 24
h. Given are isolated yields after flash column chromatography. a The product was
formed in 5:1 dr determined by 1H‐NMR of the crude reaction mixture.
Scheme 4. Tentative mechanism of the reaction.
To shed light on the kinetics of the reaction, intermolecular
competition experiments were carried out. Competition
experiment performed between the 2‐enoylpyridine 1a and
chalcone 1a' indicated that 1a reacted ~4 times faster than 1a'
showing the preferential formation of 3a over 3a' (eq 3).20 The
fast rate of formation of 3a over 3a' indicates the relatively
high reactivity of 2‐enoylpyridine 1a due to the pyridine
moiety, which makes the double bond electron deficient for
separable mixture of diastereomers in 3:1 ratio and 82% yield
(Scheme 3). The structure of the major diastereomer 10a was
confirmed by single‐crystal X‐ray analysis.21 Notably, the 2‐
enoylpyridine N‐oxides react faster compared to the
corresponding 2‐enoylpyridines in the present annulation
reaction. Interestingly, electronically dissimilar
β‐aryl 2‐
the facile addition of homoenolate equivalent intermediate D.
enoylpyridine N‐oxides readily afforded the ‐lactone‐fused
β
cyclopentanes as a single diastereomer in good yields (10b‐
10c). Moreover, electronically different cinnamaldehyde
derivatives also furnished the desired β‐lactones as a single
diastereomer in good yields (10d‐10e).
We have also carried out the preliminary studies on the
enantioselective version of this reaction. Interestingly,
treatment of enone 1a with enal 2a in the presence of chiral
NHC derived from 11 using DBU resulted in the
enantioselective synthesis of the β‐lactone‐fused cyclopentane
chiral‐3a in 56% yield, and in excellent diastereoselectivity of
>20:1, and enantiomeric excess of 99% (eq 4).
Scheme 3. NHC‐catalyzed annulation of enals with 2‐enoylpyridine N‐oxides.
General reaction conditions: 9 (0.50 mmol), 2 (0.50 mmol), 4 (10 mol %), DBU (20
mol %), DME (2.5 mL) at 25 °C for 4 h. Given are isolated yields after flash column
chromatography. a The reaction performed in 0.25 mmol scale.
The proposed mechanism of this NHC‐catalyzed
β‐
lactonization reaction can be delineated as follows (Scheme 4).
The initially generated homoenolate equivalent intermediate
In conclusion, we have developed the NHC‐
organocatalyzed
homoenolate
annulation
with
2‐
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from the Nair group, see: (b) K. C. S. Lakshmi, J. Krishnan, C.
R. Sinu, S. Varughese and V. Nair, Org. Lett., 2014, 16, 6374;
(c) K. C. S. Lakshmi, C. R. Sinu, D. V. M. Padmaja, A.
Gopinathan, E. Suresh and V. Nair, Org. Lett., 2014, 16, 5532;
(d) C. R. Sinu, D. V. M. Padmaja, U. P. Ranjini, K. C. S.
Lakshmi, E. Suresh and V. Nair, Org. Lett., 2013, 15, 68; (e) V.
Nair, C. R. Sinu, B. P. Babu, V. Varghese, A. Jose and E.
Suresh, Org. Lett., 2009, 11, 5570; (f) V. Nair, B. P. Babu, S.
Vellalath, V. Varghese, A. E. Raveendran and E. Suresh, Org.
Lett., 2009, 11, 2507; (g) V. Nair, B. P. Babu, S. Vellalath and
E. Suresh, Chem. Commun., 2008, 747; (h) V. Nair, S.
Vellalath, M. Poonoth, R. Mohan and E. Suresh, Org. Lett.,
enoylpyridines or 2‐enoylpyridine N‐oxides leading to the
diastereoselective synthesis of
in moderate to good yields. The pyridine moiety in the enone
plays a vital role in stabilizing the ‐lactone intermediate. Mild
β‐lactone‐fused cyclopentanes
β
reaction conditions, broad substrate scope and good yield of
products are the notable features of the present reaction.
Further studies towards the asymmetric version of this
reaction and the related NHC‐catalyzed reactions are ongoing
in our laboratory.
Generous financial support by CSIR‐New Delhi (as part of
12th Five‐Year plan program under ORIGIN‐CSC0108), and
CSIR‐OSDD (HCP0001) is greatly acknowledged. Su. M. and Sa.
M thank UGC, and A.P. thanks CSIR‐New Delhi for the research
fellowship. We thank Dr. Sunita S. Kunte for support for HPLC
analysis, Dr P. R. Rajamohanan for the excellent NMR support
and Ms B. Santhakumari for the HRMS data.
2006, 8, 507.
8
9
For initial reports on NHC‐catalyzed homoenolate chemistry,
see: (a) C. Burstein and F. Glorius, Angew. Chem., Int. Ed.,
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(a) P.‐C. Chiang, J. Kaeobamrung and J. W. Bode, J. Am.
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He and J. W. Bode, J. Am. Chem. Soc., 2008, 130, 418.
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Chem. Soc., 2010, 132, 5345; see also: (b) M. Wadamoto, E,
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11 J. Kaeobamrung and J. W. Bode, Org. Lett., 2009, 11, 677.
12 (a) D. T. Cohen, R. C. Johnston, N. T. Rosson, P. H.‐Y. Cheong
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Eichman, E. M. Phillips, E. R. Zarefsky and K. A. Scheidt,
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1
For reviews and selected references on
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3
,
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2
3
4
5
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‐lactone synthesis reported by our group, see: (b) S.
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15 For a related cyclopentannulation of enals with
enones, see ref 11.
Cravatt and J. A. Porco, Jr., J. Am. Chem. Soc., 2014, 136
,
α‐hydroxy
2659.
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18 It is reasonable to believe that the presence of pyridine
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hence inhibits decarboxylation. For related electronic effects
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20 For details, see the Supporting Information.
21 CCDC 1057298 (3e), and 1057299 (10a).
22 For selected recent reports using
9 as Michael acceptor, see:
(a) S. Rout, S. K. Ray, R. A. Unhale and V. K. Singh, Org. Lett.,
2014, 16, 5568; (b) S. K. Ray, P. K. Singh and V. K. Singh, Org.
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Lett., 2010, 12, 80.
6
7
23 The β‐lactone‐fused cyclopentanes are found to be stable
upon heating. When a THF solution of 3a was heated at 60 °C
for 12 h, we did not observe any decomposition to the
corresponding cyclopentene and CO2.
(a) V. Nair, S. Vellalath, M. Poonoth and E. Suresh, J. Am.
Chem. Soc., 2006, 128, 8736; for related selected reports
4 | J. Name., 2012, 00, 1‐3
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