Highly enantioselective cyclizations of conjugated trienes with low catalyst loadings: A robust chiral N-heterocyclic carbene enabled by acetic acid cocatalyst

Article abstract of DOI:10.1021/ol203375y

Densely functionalized cyclopentenones are useful synthetic intermediates. We report herein a new method to synthesize this important class of compounds through a highly enantioselective (98→99% ee) triene cyclization that is cocatalyzed by acetic acid an

Full text of DOI:10.1021/ol203375y

ORGANIC
LETTERS
2012
Vol. 14, No. 3
858–861
Highly Enantioselective Cyclizations of
Conjugated Trienes with Low Catalyst
Loadings: A Robust Chiral N-Heterocyclic
Carbene Enabled by Acetic Acid
Cocatalyst
Guansai Liu, Phillip D. Wilkerson, Christopher A. Toth, and Hao Xu*
Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State
University, Atlanta, Georgia 30303, United States
hxu@gsu.edu
Received December 17, 2011
ABSTRACT
Densely functionalized cyclopentenones are useful synthetic intermediates. We report herein a new method to synthesize this important class of
compounds through a highly enantioselective (98 f 99% ee) triene cyclization that is cocatalyzed by acetic acid and a chiral N-heterocyclic
carbene (NHC). We discovered that acetic acid not only could coexist with NHCs but also could greatly stabilize the active catalyst, which enables
a long-lived catalyst with high reactivity and selectivity.
Selective catalysis of triene cyclizations has long been a
challenge for synthetic chemists. The cyclized products con-
tain unique functional groups, and they are often difficult to
access by other means. One possible Stetter cyclization
product, a densely functionalized cyclopentenone, is of
particular importance, since it contains a quaternary
stereogenic center and an adjacent conjugated diene. The
cyclization product can be easily elaborated to tetrahy-
drocyclopenta[b]furan-dione, a structural motif identified
in a variety of natural products and analogs in the ginkgo-
lide family (Scheme 1).1 However, asymmetric catalysis
of this type of transformation on a conjugated triene
remained largely unexplored, because the ease of stereo-
chemical control often falls off with increased substrate
rigidity and conjugation, such as in the extended 6π system
under study.
Chiral N-heterocyclic carbenes (NHCs) belong to a class
of privileged Lewis bases in asymmetric organocatalysis.2,3
Although afew impressive examples of NHC catalysiswith
low catalyst loadings have been reported, most intramole-
cular Stetter cyclizations with activated olefins require
relatively high catalyst loadings (g10 mol %).4 Therefore,
(2) For reviews of privileged catalysts and Lewis base catalysis, see:
(a) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691. (b) Denmark,
S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560.
(3) For selective reviews of organocatalysis, especially on chiral NHC
catalysis, see: (a) Jacobsen, E. N.; MacMillan, D. W. C. Proc. Natl.
Acad. Sci. U.S.A. 2010, 107, 20618. (b) Enders, D.; Balensiefer, T. Acc.
Chem. Res. 2004, 37, 534. (c) Enders, D.; Niemeier, O.; Henseler, A.
Chem. Rev. 2007, 107, 5606. (d) de Alaniz, J. R.; Rovis, T. Synlett 2009,
1189. (e) Moore, J. L.; Rovis, T. Top. Curr. Chem. 2010, 291, 77. (f)
Rovis, T.; Vora, H. U. Aldrichimica Acta 2011, 44, 3. (g) Nair, V.;
Vellalath, S.; Babu, B. P. Chem. Soc. Rev. 2008, 37, 2691. (h) Phillips,
E. M.; Chan, A.; Scheidt, K. A. Aldrichimica Acta 2009, 43, 55. (i) Biju,
A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182. (j) Hirano,
K.; Piel, I.; Glorius, F. Chem. Lett. 2011, 40, 786.
(1) For selective references for isolation and medicinal chemistry
research of ginkgolide family natural products, see: (a) Sakabe, N.;
Takada, S.; Okabe, K. Chem. Commun. 1967, 259. (b) Nakanishi, K.;
Habaguch, K. J. Am. Chem. Soc. 1971, 93, 3546. (c) Hu, L. H.; Chen,
Z. L.; Xie, Y. Y.; Jiang, Y. Y.; Zhen, H. W. Biorg. Med. Chem. 2000, 8,
1515.
(4) For selective examples of NHC catalysis with low catalyst load-
ings, see: (a) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128,
15088. (b) Rommel, M.; Fukuzumi, T.; Bode, J. W. J. Am. Chem. Soc.
2008, 130, 17266. (c) Biju, A. T.; Wurz, N. E.; Glorius, F. J. Am. Chem.
Soc. 2010, 132, 5970. (d) Bugaut, X.; Liu, F.; Glorius, F. J. Am. Chem.
Soc. 2011, 133, 8130.
r
10.1021/ol203375y
Published on Web 01/20/2012
2012 American Chemical Society

reducing catalyst loading, while preserving catalyst reac-
tivity, has been a major challenge in chiral NHC catalysis.
We described here the development of highly enantiose-
lective Stetter cyclizations to densely functionalized cyclo-
pentenones. We discovered that a catalytic amount of
external acetic acid could stabilize the activeNHC catalyst,
which enables efficient reactions with low catalyst loadings
(down to 2.5 mol %).
Table 1. Correlation of NHC Reactivity with Brønsted Bases
and AcOH Cocatalyst
Scheme 1. Enantioselective Triene Cyclizations to Densely
Functionalized Cyclopentenones
The proposed transformations were explored with a
geometrically defined (2E,4Z,6E) triene (2).5 Preliminary
catalyst screening with several privileged chiral NHC
catalysts revealed that a chiral aminoindanol-derived tria-
zolium catalyst (1) was most effective in converting the
triene (2) to the cyclopentenone (3) (Table 1).6À8 It is
important to note that the catalytic efficiency of 1 seemed
to depend crucially on the Brønsted base and acid
a Yields refer to isolated yields after column chromatography. b Final
yields are obtained after 48 h, when there is no further conversion. c ee
was determined by chiral HPLC. Absolute stereochemistry was deter-
mined by X-ray crystallographic analysis of its derivative. d 0.1 equiv of
AcOH was applied.
(5) For details of substrate synthesis, see Supporting Information.
(6) Absolute stereochemistry of the product was determined by X-ray
crystallographic analysis of its derivative.
(7) For a selection of privileged chiral NHCs, see: (a) Enders, D.;
Breuer, K.; Teles, J. H. Helv. Chim. Acta 1996, 79, 1217. (b) Knight,
R. L.; Leeper, F. J. Tetrahedron Lett. 1997, 38, 3611. (c) Dvorak, C. A.;
Rawal, V. H. Tetrahedron Lett. 1998, 39, 2925. (d) Kerr, M. S.; de
Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298. (e) He, M.;
Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418. (f)
Mennen, S. M.; Blank, J. T.; Tran-Dube, M. B.; Imbriglio, J. E.; Miller,
S. J. Chem. Commun. 2005, 195. (g) Piel, I.; Steinmetz, M.; Hirano, K.;
Froehlich, R.; Grimme, S.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50,
4983.
(8) For a selection of application of Mes-substituted catalyst 1a in
asymmetric catalysis, see: (a) Chiang, P. C.; Kaeobamrung, J.; Bode,
J. W. J. Am. Chem. Soc. 2007, 129, 3520. (b) He, M.; Bode, J. W. J. Am.
Chem. Soc. 2008, 130, 418. (c) Kaeobamrung, J.; Kozlowski, M. C.;
Bode, J. W. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20661. (d)
Kaeobamrung, J.; Mahatthananchai, J.; Zheng, P. G.; Bode, J. W.
J. Am. Chem. Soc. 2010, 132, 8810. (e) Mahatthananchai, J.; Zheng,
P. G.; Bode, J. W. Angew. Chem., Int. Ed. 2011, 50, 1673. (f) Fang, X. Q.;
Jiang, K.; Xing, C.; Hao, L.; Chi, Y. R. Angew. Chem., Int. Ed. 2011, 50,
1910. (g) Wadamoto, M.; Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A.
J. Am. Chem. Soc. 2007, 129, 10098. (h) Phillips, E. M.; Reynolds, T. E.;
Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 2416. (i) Raup, D. E. A.;
Cardinal-David, B.; Holte, D.; Scheidt, K. A. Nat. Chem. 2010, 2, 766. (j)
Cardinal-David, B.; Raup, D. E. A.; Scheidt, K. A. J. Am. Chem. Soc.
2010, 132, 5345. (k) Cohen, D. T.; Cardinal-David, B.; Scheidt, K. A.
Angew. Chem., Int. Ed. 2011, 50, 1678. (l) Rong, Z. Q.; Jia, M. Q.; You,
S. L. Org. Lett. 2011, 13, 4080. (m) Zhu, Z. Q.; Zheng, X. L.; Jiang, N. F.;
Wan, X.; Xiao, J. C. Chem. Commun. 2011, 8670.
cocatalysts. To our surprise, well-established reaction
conditions for intramolecular Stetter cyclizations were
ineffective in this system: Catalyst 1 barely achieved a
single turnover, in the presence of strong non-nucleophilic
bases, including KHMDS and KOt-Bu (entries 1À2).9
Neither organic bases (entries 3À5) nor K2CO3 (entry 6)
could effectively turn over the catalytic cycle. The incom-
plete conversion under these conditions suggests that the
integrity of the catalyst was largely compromised, a finding
rarely reported in the literature.
The aforementioned Brønsted bases (entries 1À6) are
capable of generating sufficient quantities of NHC through
deprotonation. However, the data suggest the decomposi-
tion of active catalyst significantly compromises the reaction
efficiency (turnover number of 1 < 3.0). For this reason, we
explored carboxylates that have a much weaker Brønsted
basicity, which emerge as uniquely effective reagents (entries
7À12).10 A catalytic amount (20 mol % each) of NaOAc
and triazolium salt (1) (entry 7) cocatalyzed a highly
enantioselective reaction with excellent efficiency (97% ee
and 85% yield within 5 h). Although NaOBz (entries 8)
provided a less impressive rate acceleration compared to
(9) For standard conditions to generate chiral NHCs, see: (a) Kerr,
M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876. (b) de Alaniz, J. R.;
Rovis, T. J. Am. Chem. Soc. 2005, 127, 6284. (c) Reynolds, N. T.; Rovis,
T. J. Am. Chem. Soc. 2005, 127, 16406. (d) Liu, Q.; Rovis, T. J. Am.
Chem. Soc. 2006, 128, 2552. (e) DiRocco, D. A.; Oberg, K. M.; Dalton,
D. M.; Rovis, T. J. Am. Chem. Soc. 2009, 131, 10872. (f) Lathrop, S. P.;
Rovis, T. J. Am. Chem. Soc. 2009, 131, 13628. (g) Vora, H. U.; Rovis, T.
J. Am. Chem. Soc. 2010, 132, 2860. (h) DiRocco, D. A.; Rovis, T. J. Am.
Chem. Soc. 2011, 133, 10402. (i) Kawanaka, Y.; Phillips, E. M.; Scheidt,
K. A. J. Am. Chem. Soc. 2009, 131, 18028. (j) Jousseaume, T.; Wurz,
N. E.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 1410.
(10) For a recent example using carboxylates in chiral NHC catalysis,
see: Zhao, X. D.; DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2011, 133,
12466.
Org. Lett., Vol. 14, No. 3, 2012
859

that of NaOAc, the same ee was observed in each case.
These data suggest that carboxylates are likely involved in
the rate-determining step (RDS), but not in the enantios-
electivity-determining step, in the catalytic cycle. We subse-
quently noted a few interesting discoveries: First, increasing
the ratio of NaOAc to triazolium salt (1) significantly
accelerated the reaction (entries 9À11). Since NaOAc is only
sparingly soluble in THF, the exact mechanism for rate
dependence on the amount of solid NaOAc is unclear.
Second, solvent is crucial for reactivity and selectivity.
Catalyst 1 is most reactive and selective in diethyl ether
(entry 12).11 Most intriguingly, we discovered that the
loading of 1 could be decreased further down to 2.5 mol %
without sacrificing the yield and ee, as long as a catalytic
amount of AcOH was used as the cocatalyst (entries 13À14).
maintaining the robustness of catalyst 1. Although weak
Brønsted acids, especially catechols, are sometimes known
to be beneficial for NHC catalysis, carboxylic acids with
much lower pKa values are uniquely effective in maintain-
ing the catalyst integrity in this system.12
Since the reversibility of catalyst generation could be a
safeguard against catalyst decomposition, we hypothe-
sized that the NHC generation could become readily
reversible when a catalytic amount of AcOH was used as
a cocatalyst. We subsequently designed a hydrogen/deu-
terium exchange experiment and observed that formyl-H
in triazolium salt 1 was readily exchanged witha deuterium
of d4-AcOH under synthetically relevant conditions
(2.5 mol % of 1, 0.25 equiv of solid NaOAc, and 0.05
equiv of d4-AcOH in d6-benzene).13 (Scheme 2)
Scheme 2. Reversible NHC Generation under Reaction Conditions
Under optimized conditions, a variety of (2E, 4Z, 6E)
trienes with different steric (R1 through R3 substituents)
and electronic properties were studied (Table 2). We
applied 5 mol % of catalyst 1 for most substrates so that
most reactions can complete within 40 h. Electron with-
drawing and moderately donating groups on the aromatic
region (R3 position) were well tolerated, and cyclopente-
nones 3 were isolated with excellent yields and ee’s
(92À96% yield, 98À99% ee). The presence of strong
electron donating groups retarded the reaction rate
(entries 5 and 7), but the isolated yields were minimally
affected (75% and 87% yield, 99% ee). The introduction
of an additional alkyl group (R2) was tolerated (entries
8À10, up to 94% yield, >99% ee), and the cyclization
efficiency of substrates with large substituents (R1) at the
C2 position was maintained as well (entries 11À14).
Figure 1. Kinetic studies to reveal the crucial role of AcOH to
stabilize the active catalyst.
The application of carboxylates as weak Brønsted bases
in NHC catalysis is precedented, but not under conditions
of low catalyst loadings in the presence of an external acid
cocatalyst (pKa (in water) = 4.75). It is plausible that
AcOH confers certain advantages, by either protecting the
chiral NHC from decomposition or promoting catalyst
turnover. To test this hypothesis, we compared the kinetics
of a few model reactions for the AcOH effect. In each case,
the loading of chiral NHC was decreased to 2.5 mol %
(Figure 1). Interestingly, the initial rates of reactions
A1ÀA3 (with 0.05À0.25 equiv AcOH as the additive) were
significantly higher than the one without it (reaction B).
Reaction B seemed to have a relatively long induction
period (around 1%conversionat1 h), butitsrateincreased
significantly after 2 h. Although reactions A1ÀA3 reached
full conversion within 10 h, reaction B stopped at around
8 h, failing to reach full conversion even after 24 h
(53% yield). The kinetic studies suggest that external
AcOH is crucial in preventing catalyst decomposition and
The immediate synthetic application of this reaction
discovery becomes apparent after the following two-step
transformation (Scheme 3A). Saponification of 3a, fol-
lowed by halo-lactonizations, delivered enantiopure bicyc-
lic lactones with three contiguous stereogenic centers
(5aÀ6a). The bicyclic moiety with the aforementioned
stereochemical array can be identified in a variety of
natural products and their analogs in the ginkgolide family.1
The enantiopure bicyclic allylic halides (5aÀ6a) are versatile
intermediates for further transformations. Isomeric trienes
(7) also readily participate in an NHC-catalyzed annulation
(12) Phenols and catechols are noneffective in stabilizing the catalyst
or assisting the catalyst turnover, when its loading is low (2.5 mol %).
(13) For a hydrogen-deuterium exchange experiment of thiamine in
water, see: Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.
(11) For a complete solvent effect screen, see Supporting Information.
860
Org. Lett., Vol. 14, No. 3, 2012

Table 2. Substrate Scope of the Cyclization Reaction
Scheme 3. Synthetic Application of (A) Chiral Cyclopentanones
and (B) This Method in Functionalized Phenol Synthesisa
yield
(%)a
ee of
3 (%)b
entry
R1
R2
R3
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
H
Ph
96
92
93
95
75
94
87
80
94
94
80
82
71
74
99
99
2
H
p-Br-Ph
p-Cl-Ph
p-Me-Ph
p-OMe-Ph
m-Cl-Ph
O-CH2-O-Ph
Ph
3
H
98
4
H
99
5
H
99
a Reagents and conditions: (a) LiOH, THF, 22 °C, 3 h, 95%; (b) N-
Iodosuccinimide, THF, 0 °C, 1 h, 90%; (c) N-Bromosuccinimide, THF,
25 °C, 6 h, 86%; (d) 1 (0.05 equiv), HOAc (0.25 equiv), NaOAc (0.5
equiv), diethyl ether, 25 °C, 6 h, 95%.
6
H
99
7
H
>99
>99
>99
>99
99
8
Me
Me
Me
H
9
p-Br-Ph
m-Cl-Ph
Ph
10
11c
12c
13c
14c
turnover. The design and discovery of other robust cata-
lytic systems enabled by cooperative catalysis is underway.
H
p-Cl-Ph
p-Br-Ph
m-Cl-Ph
>99
99
H
H
>99
a Yields refer to isolated yields after column chromatography.
Acknowledgment. This work was supported by Georgia
State University and the American Chemical Society
Petroleum Research Fund (ACS PRF 51571-DNI1). We
thank Professors A. L. Baumstark and Binghe Wang
(Georgia State University) for helpful discussions and
the generous share of instruments and chemicals. We
thank Dr. Shao-Liang Zheng (Harvard University) for
X-ray crystallographic analysis to determine the absolute
stereochemistry of a cyclization product.
b ee was determined by chiral HPLC. c 10 mol % of 1 was applied.
under the same conditions to deliver a highly functionalized,
tetrasubstituted benzenoid 8, which seems prohibitively
difficult to access by other means (Scheme 3B).14
In summary, we have developed a highly enantioselec-
tive Stetter cyclization of a conjugated triene to access
highly functionalized cyclopentenones with low catalyst
loadings (down to 2.5 mol %). The substrate scope for this
method is general, and the cyclization products are synthe-
tically useful. Through mechanistic studies, we discovered
that the AcOH cocatalyst is crucial in preventing active
NHC catalyst decomposition and facilitating the NHC
Supporting Information Available. Experimental pro-
cedures, characterization data, NMR, HPLC, and X-ray
analysis spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
(14) For a detailed synthesis of 7, see Supporting Information.
Org. Lett., Vol. 14, No. 3, 2012
861