Cyclization cascades initiated by 1,6-conjugate addition

Article abstract of DOI:10.1021/ja308451y

Dienyl diketones containing tethered acetates selectively undergo two different 1,6-conjugate addition-initiated cyclization cascades. One is a 1,6-conjugate addition/cyclization sequence with incorporation of the nucleophile, and the other is catalyzed by DABCO and is thought to proceed via a cyclic acetoxonium intermediate. The reaction behavior of substrates lacking the tethered acetate was also studied. The scope of both types of cyclization cascades, the role of the amine additive, and the factors controlling reactivity and selectivity in the two different reaction pathways is discussed.

Full text of DOI:10.1021/ja308451y

Communication
pubs.acs.org/JACS
Cyclization Cascades Initiated by 1,6-Conjugate Addition
Joshua L. Brooks and Alison J. Frontier*
Department of Chemistry, University of Rochester, Rochester, New York 14627, United States
S
* Supporting Information
We found that conjugate addition-initiated Nazarov cycliza-
tion proceeded smoothly with pyrrolidine to give products of
type 5 (Table 1, entries 1 and 3) and with dimethyl malonate to
ABSTRACT: Dienyl diketones containing tethered ace-
tates selectively undergo two different 1,6-conjugate
addition-initiated cyclization cascades. One is a 1,6-
conjugate addition/cyclization sequence with incorpora-
tion of the nucleophile, and the other is catalyzed by
DABCO and is thought to proceed via a cyclic
acetoxonium intermediate. The reaction behavior of
substrates lacking the tethered acetate was also studied.
The scope of both types of cyclization cascades, the role of
the amine additive, and the factors controlling reactivity
and selectivity in the two different reaction pathways is
discussed.
Table 1. Lewis Acid Catalyzed Conjugate Addition/
a
Electrocyclization Cascade
yield
entry
R1 =
4a, H
nucleophile
pyrrolidine
base
Et3N
(product; %)
1
2
5a; 87
6a; 83
4a, H
dimethylmalonate
(DMM)
Et3N
unctionalized cyclopentenones containing quaternary
3
4
5
6
4b, Me
4b, Me
4b, Me
4c,
pyrrolidine
DMM
Et3N
5b; 85
6b; 78
6b; 72
6c; 89
F
stereogenic carbon centers are valuable building blocks
for the preparation of interesting small molecules. Efficient,
catalytic methods for the assembly of these targets via Nazarov
cyclization have been studied extensively in recent years1 and
capitalize on the conservation of orbital symmetry2 as a means
to control relative stereochemistry. Typically, either a Brønsted
or a Lewis acid is used to promote the 4π cationic
electrocyclization.
Et3N
b
b
DMM
DABCO
Et3N
DMM
(CH2)2OAc
7
8
4c
DMM
DMM
DABCO
Et3N
see Table 2
4d,
(CH2)3OAc
6d; 87
a
Reaction conditions: Diketone 4 added to a stirring solution of
Recently, we reported that 1,6-conjugate addition of a
nucleophile to dienyl diketone 1 could initiate Nazarov
cyclization, via pentadienyl cation 2 (Scheme 1).3 Further
Y(OTf)3 (1 mol %), LiCl (2 equiv), base (1 equiv), and the
b
nucleophile in THF (1 M) at rt. DABCO = 1,4-diazabicyclo[2.2.2]-
octane.
Scheme 1. Conjugate Addition-Initiated Nazarov Cyclization
give products of type 6 (entries 2, 4−7, and 9). Both
triethylamine and DABCO (1,4-diazabicyclo[2.2.2]octane)
could be used as the basic additive for the reaction of substrate
4b (entries 3 and 4). As would be expected in an electrocyclic
reaction, only a single diastereoisomer was observed in each
case. These reactions occur at ambient temperature, employ
inexpensive reagents and catalysts, and are neither air- nor
moisture-sensitive.
In the case of dienyl diketone 4c, a dramatic change in
reaction outcome was observed when DABCO was used
instead of Et3N as the basic additive (Table 1, entry 8). None of
the expected product 6c was obtained: instead, a new type of
cyclization cascade took place resulting in cyclopentenone 7
(74% yield, Table 2). Strangely, no incorporation of the
malonate nucleophile had occurred. This result is especially
surprising in light of the entry 5 result, in which use of DABCO
as the basic additive uneventfully produced malonate adduct 7b
(entry 4 vs 5; Table 1).
study of nucleophile-initiated cyclization of this kind has
revealed a new type of cascade cyclization, which occurs under
neutral reaction conditions, yet produces a stereochemical
result consistent with cationic electrocyclization. In this
communication, we describe the two reaction pathways
available to dienyl diketones upon treatment with nucleophiles
and present a mechanistic rationale for the unusual reactivity
observed.
A series of diketone substrates of type 4 were prepared for
examination in the conjugate addition-initiated reaction.
Substrates in which R1 ≠ H were of particular interest, since
conrotatory cyclization would install adjacent tertiary and all-
carbon quaternary centers stereospecifically in these systems.
Received: August 25, 2012
Published: September 24, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a b
,
Table 2. Optimization of DABCO-Catalyzed Cyclization
Cascade
Table 3. Substrate Scope
a
entry Lewis acid
base
catalyst loading (mol %)
yield (%)
92
1
2
3
4
5
6
7
8
9
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
−
−
−
−
DABCO
Et3N
100
100
100
100
−
b
c
20
DMAP
DBU
83
64
−
no reaction
DABCO
DABCO
DABCO
DABCO
100
97
96
95
54
10
5
c
1
a
All reactions run at 1 M concentration in THF at rt for 8 h, except
b
when otherwise noted. Heating to 50 °C was required for the
reaction to occur. Reaction took 24 h to reach completion.
c
When malonate was excluded from the reaction, the yield of
product 7 improved to 92% (Table 2, entry 1). Further
experimentation revealed that treatment of 4c with Y(OTf)3
and various amine bases also led to formation of 7 in good
yield. While Et3N facilitated the reaction to some extent (20%
yield; entry 2), long reaction times and elevated temperatures
were required. Nucleophilic bases such as DMAP, DBU, and
DABCO (entries 3 and 4) were found to be efficient
promoters. Still, DABCO was the optimal promoter, and we
were interested to find that when the Lewis acid was excluded,
an even higher yield of 7 was obtained (entry 6, 97% yield).
Furthermore, DABCO facilitated the reaction at catalytic levels
(entries 7−9), operating with catalyst loadings as low as 1 mol
% (54% yield). However, 10 mol % was found to be optimal, in
terms of both yield (96%) and reaction time (1 h). The
reaction was equally efficient when run open to air.
Once optimized conditions were identified, substrate scope
was evaluated (Table 3). Acetate 4d cyclized efficiently to
produce cyclopentenone 8 in nearly quantitative yield (entry
2). Treatment of secondary acetates 4e and 4f gave 9 and 10,
respectively, as single diastereoisomers (entries 3 and 4). Figure
1 shows the key NOE correlations used to assign the
stereochemistry of compound 9. Acetate 4g underwent
cyclization to give cyclopentenone 11 in 84% yield (entry 5).
For this experiment, elevated temperature was required to
facilitate the reaction.
A mechanistic hypothesis consistent with the results shown
in both Tables 1 and 3 is presented in Scheme 2. In the absence
of DABCO, 1,6-conjugate addition of either pyrrolidine or
malonate leads to adducts 2 (Scheme 1), which undergo
electrocyclization. In the presence of DABCO, 1,6-conjugate
addition of DABCO4,5 to the dienyl diketone gives a
zwitterionic DABCO adduct (see 12, Scheme 2). We
hypothesize that this species does not undergo 4π electro-
cyclization, and if formed reversibly. Thus, when both malonate
and DABCO are present, the malonate adduct 6b is formed
(Table 1, entry 5), and DABCO acts as a simple base. However,
if the substrate has an acetate tether (such as 4c−4g, Table 3),
another reaction pathway is available to DABCO adduct 12. In
these cases, we propose that the allylic quaternary ammonium
moiety of 12 is displaced by the pendant acetate to produce
cyclic zwitterion 13, which contains a stereogenic center. The
a
Reaction conditions: The diene was dissolved in THF (1 M), and
DABCO (10 mol %) was added. The solution was stirred at rt until all
b
starting material was consumed as judged by TLC. Reaction time was
1 h unless otherwise stated. Reaction time was 24 h. Reaction time
was 8 h. Reaction was heated to 50 °C for 8 h.
c
d
e
Figure 1. Key NOE correlations for compound 9.
intramolecular SN2 reaction is related to the anchimeric
assistance acetates sometimes demonstrate during solvolysis,6
and glycosylation,7 but we could find only one example of a
displacement reaction thought to proceed via a seven-
membered acetoxonium intermediate.8 This stereocenter then
controls the torquoselectivity of the subsequent electro-
cyclization, which produces spirocyclic zwitterions 14. The
ring stereochemistry is consistent with conrotatory closure and
analogous to the results of cyclization of the type 2
intermediate to cyclopentenones 5 and 6. The cascade is
concluded with intramolecular ether formation (Table 3).
Remarkably, the proposal implies that seven-, eight-, and nine-
membered zwitterions 13 readily participate as intermediates in
the cyclization cascades.
In conclusion, two different cyclization cascades can be
carried out beginning with 1,6-conjugate addition to a dienyl
diketone. One is Lewis acid catalyzed and involves incorpo-
ration of a nucleophile, producing highly substituted cyclo-
pentenones containing a quaternary stereogenic center. The
second is a novel, metal-free cascade catalyzed by 1,6-conjugate
addition of DABCO and involves three successive cyclizations:
formation of a cyclic acetoxyonium, putative 4π electro-
cyclization, and opening of the acetoxonium to form a cyclic
ether. The stereochemical outcome of both reactions is
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Journal of the American Chemical Society
Communication
Scheme 2. Proposed Mechanism for 1,6-Conjugate Addition/Cyclization Cascades
(5) For use of DABCO in Morita−Baylis−Hilman reactions, see:
(a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103,
811−892. (b) Declerck, V.; Martinez, J; Lamaty, F. Chem. Rev. 2009,
109, 1−48. (c) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev.
2010, 110, 5447−5674.
consistent with conrotatory electrocyclization, even though the
DABCO-catalyzed cyclization cascade must proceed via a
zwitterionic rather than a cationic intermediate.9,10 The study of
other varieties of conjugate addition-initiated cascade cycliza-
tions is currently underway in our laboratory.
(6) For other examples of reactions initiated by conjugate addition of
DABCO, see: (a) Yeo, J. E.; Yang, X.; Kim, H. J.; Koo, S. Chem.
Commun. 2004, 2, 236−237. (b) Franck, X.; Figadere, B. Tetrahedron
Lett. 2002, 43, 1449−1451. (c) Lesch, B.; Brase, S. Angew. Chem., Int.
Ed. 2004, 43, 115−118.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedure and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org
(7) Capon, B. Chem. Soc. Rev. 1964, 18, 45−111.
(8) For a discussion of the role of remote acetates in glycosylation,
see: Crich, D.; Hu, T.; Cai, F. J. Org. Chem. 2008, 73, 8942−8953 and
references therein.
AUTHOR INFORMATION
(9) Wilen, S. H.; Delguzzo; Saferstein, R. Tetrahedron 1987, 43,
5089−5094.
(10) For an example of a Nazarov cyclization that occurs under
neutral conditions, see: Douelle, F.; Tal, L.; Greaney, M. F. Chem.
Commun. 2005, 660−662.
■
Corresponding Author
frontier@chem.rochester.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (NIGMS R01
GM079364) and ARRA supplement (3R01GM079364-03S2)
for funding this work. We are also grateful to Dr. Sandip Sur for
assistance with the NOE experiments.
REFERENCES
■
(1) For recent reviews on Nazarov cyclization, see: Pellissier, H.
Tetrahedron 2005, 61, 6479−6517. (b) Frontier, A. J.; Collison, C.
Tetrahedron 2005, 61, 7577−7606. (c) Tius, M. A. Eur. J. Org. Chem.
2005, 2005, 2193−2206. (d) Grant, T. N.; Rieder, C. J.; West, F. G.
Chem. Commun. 2009, 5676−5688. (e) Nakanishi, W.; West, F. G.
Curr. Opin. Drug Discov. Dev. 2009, 12, 732−751. (f) Shimada, N.;
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(3) Brooks, J. L.; Caruana, P. A.; Frontier, A. J. J. Am. Chem. Soc.
2011, 133, 12454−12457.
(4) Dienyl diketone substrates of type 4 are readily available via a
convenient reaction sequence featuring reductive coupling of aryl
glyoxals and enynes, using a protocol pioneered by Krische:
(a) Huddleston, R. R.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc.
2003, 125, 11488−11489. (b) Jang, H.-Y.; Huddleston, R. R.; Krische,
M. J. J. Am. Chem. Soc. 2004, 126, 4664−4668. See Supporting
Information for details.
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