A cooperative N-heterocyclic carbene/chiral phosphate catalysis system for allenolate annulations

Article abstract of DOI:10.1002/anie.201403446

The highly enantioselective NHC-catalyzed [3+2] annulation reaction with α,β-alkynals and α-ketoesters has been developed. A new mode of cooperative catalysis involving the combination of a chiral Bronsted acid and a C₁-symmetric biaryl saturated-imidazolium precatalyst was required to generate the desired γ-crotonolactones in high yields and levels of enantioselectivity.

Full text of DOI:10.1002/anie.201403446

Angewandte
Chemie
DOI: 10.1002/anie.201403446
Asymmetric Catalysis
A Cooperative N-Heterocyclic Carbene/Chiral Phosphate Catalysis
System for Allenolate Annulations**
Anna Lee and Karl A. Scheidt*
Dedicated to the memory of Jeremiah P. Freeman
Abstract: The highly enantioselective NHC-catalyzed [3+2]
annulation reaction with a,b-alkynals and a-ketoesters has
been developed. A new mode of cooperative catalysis involving
the combination of a chiral Brønsted acid and a C1-symmetric
biaryl saturated-imidazolium precatalyst was required to
generate the desired g-crotonolactones in high yields and
levels of enantioselectivity.
diastereoselective annulation reactions toward the securinega
family of alkaloids.[5b]
Cooperative NHC catalysis has been employed as a strat-
egy to expand the capabilities of NHC catalysis and has
resulted in marked improvements in efficiency and selectivity
in several cases. Notably, the use of NHC/Lewis acid or
Brønsted acid cooperative catalysis for enhancing selectivity
and incorporating previously inactive reaction partners has
seen significant success.[7,8] Despite the demonstrated utility
of chiral Brønsted acids (CBAs) for a variety of asymmetric
transformations,[9–11] the combination of NHCs and chiral
Brønsted acids represents new opportunity for small molecule
activation. Herein we report a general cooperative NHC/
chiral Brønsted acid strategy to achieve a highly enantiose-
lective addition of alkynals to a-ketoesters (Figure 1).
We postulated that the lack of reports detailing NHC-
H
omoenolate additions to various electrophiles catalyzed
by N-heterocyclic carbenes (NHCs)[1] represent an enabling
class of transformations that have been employed for the
construction of complex hetero- and carbocyclic systems
through unconventional reactivity achieved by Umpolung.[2]
While significant advancements have been achieved through
this approach, only a limited number of reports on NHC-
catalyzed homoenolate additions involving alkynyl aldehydes
have appeared. In 2006, Zeitler reported the NHC-catalyzed
redox esterification of alkynal aldehydes[3] and subsequently
Bode, Xiao, Du, and Alexakis independently reported NHC-
catalyzed oxidative transformations of alkynals.[4] Common to
these studies is the protonation of the allenolate intermediate
to afford activated, electrophilic a,b-unsaturated carbonyl
intermediates. To date, the complimentary reaction of nucle-
ophilic NHC-bound allenolates and electrophiles to forge
À
catalyzed reactions with alkynals in new C C bond-forming
processes might be explained by the nature of the allenolate
intermediate,[12] wherein this transient species is rapidly
protonated rather than productively interacting with a more
complex electrophile. We envisioned that under a more
À
new C C bonds at the b position of the alkynal has received
significantly less attention.[5] There have been a few pioneer-
ing studies of this type of reaction, however, the development
of efficient and highly enantioselective methods has remained
elusive. For example, the She group recently extended the
NHC/Lewis acid catalysis concept and reported an approach
for the relatively unselective [3+2] annulation of alkynals and
b,g-unsaturated a-ketoesters to generate g-crotonolactones
with low stereoinduction.[6] Independently, the Snyder group
has shown the potentially powerful application of the
allenolate reactivity through NHC/Lewis acid catalysis for
[*] Dr. A. Lee, Prof. K. A. Scheidt
Department of Chemistry Center for Molecular Innovation and Drug
Discovery, Northwestern University
2145 Sheridan Road, Evanston, IL 60208 (USA)
E-mail: scheidt@northwestern.edu
[**] Financial support has been generously provided by the NIH (R01-
GM073072). We thank Prof. Paul Ha-Yeon Cheong and Ryne C.
Johnston (Oregon State Univeristy) for assistance with DFT studies
and Dr. Paul W. Siu (NU) and Dr. Ki Po Jang (NU) for providing
X-ray crystallography support (NU).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403446.
Figure 1. NHC-catalyzed annulation of alkynals.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
efficient mode of activation, a-ketoesters could be a suitable
class of allenolate acceptors. Hence, the combination of
alkynal 1a with a-ketoester 2a in the presence of lithium tert-
butoxide and IMes·Cl as precatalyst was explored (A, Table 1,
activating methyl benzoylformate toward addition. The
introduction of chiral Brønsted acid F (20 mol%) with achiral
NHC from B produced a significant increase in yield (54%),
but the annulation product was effectively racemic (entry 4).
We then turned our attention toward exploring the use of
a chiral NHC in combination with a chiral Brønsted acid
(CBA). While established chiral triazolium-based NHC
catalysts are ineffective for this transformation (see the
Supporting Information), it became apparent that C1-sym-
metric biaryl saturated-imidazolium-derived NHC catalyst C,
originally developed by the Hoveyda group,[13,14] provided the
desired product in excellent yield (entry 6). Indeed, the use of
these 2,3-dihydroimidazole-2-ylinene structures in carbene
catalysis is far less developed than their imidazolium- and
triazolium- derived counterparts. Interestingly, conducting
the reaction under more dilute conditions in the presence of
molecular sieves resulted in a further enhancement in
enantioselectivity (from 79:21 to 90:10 e.r., entry 7). With
these intriguing results in hand, we investigated various C1-
symmetric biaryl saturated-imidazolium precatalysts, with the
highest yield and enantioselectivity observed with catalyst D
(entry 9). The introduction of more sterically demanding aryl
or naphthyl groups on the chiral phosphoric acid, such as G
(i.e., (S)-TRIP) and H, or on the imidazolium salt, such as E,
resulted in decreased reactivity and enantioselectivity
(entries 10–12). Therefore, precatalyst D and chiral phospho-
ric acid F were chosen as our optimized catalysts for further
study (entry 9). The use of the (R)-phosphoric acid instead of
its (S)-enantiomer did not diminish catalyst reactivity and
enantiomeric ratio, thereby indicating a lack of an expected
match/mismatch relationship between the phosphoric acid
chirality and the NHC (entry 13). However, racemic phos-
phoric acid F provides the desired product with slightly
decreased yield and enantioselectivity (entry 14). At our
current level of understanding of this complex reaction, we
assume that unexpected inactive species might be formed
between the lithium ion and the (R)- and (S)-phosphate that
generates the product in lower yield and a slightly decreased
enantiomeric ratio. Clearly, this is a multivariable system and
further investigations to delineate more fully the specific roles
of the lithium cation, NHC, and Brønsted acid/chiral phos-
phate are ongoing. In addition, achiral phosphoric acid I can
also serve as a co-catalyst, albeit with diminished yield and
selectivity (entry 15). However, other Brønsted acids, such as
4-nitrobenzoic acid, did not provide any desired product
(entry 19).
Table 1: Optimization of reaction conditions.[a]
Entry
Azolium
Co-catalyst
Yield [%][b]
e.r.[c]
1
2
3
4
A
B
B
B
C
C
C
D
D
D
D
E
D
D
D
C
C
C
C
–
–
no reaction
–
–
–
trace
24
54
trace
90
85
34
85
85
trace
52
84
74
LiCl (1 equiv)
F
–
F
F
52:48
n.d.
79:21
90:10
89:11
93:7
91:9
n.d.
92:8
93:7
91:9
89:11
n.d.
–
5
6
7[d]
8[d]
LiCl (1 equiv)
9[d]
F
G
H
F
ent-F
rac-F
I
F
F
F
J
10[d]
11[d]
12[d]
13[d]
14[d]
15[d]
16[d,e]
17[d,f]
18[d,g]
19[d]
77
trace
no reaction
no reaction
no reaction
–
–
[a] Conditions: 1a (0.05 mmol, 1 equiv), 2a (1.5 equiv), azolium
(0.2 equiv), phosphoric acid (0.2 equiv), LiOtBu (0.4 equiv) in THF
(0.15m) at 238C for 48 h. [b] Determined by GC-MS with n-dodecane as
internal standard. [c] Determined by HPLC analysis. [d] 4 ꢀ molecular
sieves (M.S.) were used at 0.014m concentration in THF. [e] 20 mol%
LiOtBu was used. [f] NaOtBu was used as the base instead of LiOtBu.
[g] Mg(OtBu)2 was used as the base instead of LiOtBu. Entry in bold
marks optimized conditions.
To gain further information about the role of the CBA, the
reaction was performed using a decreased amount of base
(20 mol%; Table 1, entry 16). This modification provided
only trace amounts of the product. Considering the pKa values
of the azolium and Brønsted acids,[15,16] it is likely that under
these conditions phosphoric acid F would be deprotonated
initially, and the NHC might not be generated in high enough
concentrations from the azolium salt precatalyst. A second
aspect is whether the lithium cation is involved in organizing
the transition state[7f,17] or if lithium tert-butoxide was simply
acting as a base. To probe this possibility, sodium tert-butoxide
or magnesium di-tert-butoxide were employed as the base, but
no product was obtained, suggesting the involvement of the
entry 1). These conditions did not produce any of the desired
product. However, the use of saturated imidazolium
(SImes·Cl) B afforded trace amounts of butenolide 3a
(entry 2). Guided by our previous NHC/Lewis acid studies,
a slightly improved yield was observed with one equivalent of
lithium chloride (entry 3).[7f] Even though the reaction yield
was poor, this result indicated that lithium cations may be
2
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
Table 2: Substrate scope.[a]
lithium cation in the reaction mechanism (entries 17 and 18).
Furthermore, 31P NMR spectroscopy was employed to probe
the state of the phosphoric acid/phosphate under the reaction
conditions, and we observed a noticeable change in chemical
shift of phosphoric acid F in the presence of LiOtBu (see the
Supporting Information for details). Notably, alkali or
alkaline salts of BINOL-derived phosphates are known as
efficient catalysts,[11a,18] and in some cases, the counterion
plays a significant role.[18b,19] Based on this precedent, our
working hypothesis is that the lithium ion coordinates the
phosphate and a-ketoester, and could be part of an activation
system under the reaction conditions (see Figure 1).
Subsequent to these initial mechanistic probe experi-
ments, the scope of this formal [3+2] annulation was explored
(Table 2). The reaction is tolerant of both electron-deficient
and electron-rich aromatic alkynals and a-ketoesters. The
desired products are obtained in good to excellent yield (62–
92%) with high enantioselectivities (up to 96:4 e.r.). In
particular, alkynals that possess meta or para substituents on
the aromatic structure perform well (3b–3e), however, ortho-
substituted aromatic alkynals are not suitable substrates
under the current optimized conditions.[20] The variation of
the a-ketoester was also explored. The a-ketoester that bears
a para-methyl group provides the butenolide product (3 f)
with excellent enantioselectivity (96:4 e.r.). a-Ketoesters that
possess an electron-withdrawing group afford the products in
excellent yield (3g–3j), but with a slight decrease in
enantioselectivity (up to 90:10 e.r.). The combination of
substituted alkynals with a-ketoesters enabled the prepara-
tion of various highly functionalized butenolides (3k–3o). In
addition, the indole-derived alkynal produces indole-substi-
tuted lactone 3p in good yield and high enantioselectivity.
The proposed pathway for this annulation reaction is
shown in Scheme 1. The initial addition of catalyst D to
alkynyl aldehyde 1a and subsequent formal 1,2-H migration
generates Breslow intermediate (Z)-I.[21] The NHC-bound
allenolate may undergo addition to the a-ketoester activated
[a] See the Supporting Information for details. Yields are of isolated
product after column chromatography. Enantiomeric ratio was deter-
mined by HPLC analysis using a chiral stationary phase. [b] Absolute
configuration was determined by X-ray crystallography.
by the chiral Brønsted acid derived co-catalyst (II). Carbon–
carbon bond formation and subsequent tautomerization gives
acyl azolium intermediate III, which then undergoes O acy-
lation to afford the lactone product (3a) and retrieve the
NHC catalyst.
The butenolide products can be converted into enan-
tioenriched g-butyrolactones by selective hydrogenation
reactions (Scheme 2). The use of Pearlmanꢀs catalyst fur-
nished cis-g-butyrolactone 4a as the major product (2.6:1 d.r.)
in 92% yield. An ester-directed homogeneous hydrogenation
with Crabtreeꢀs catalyst afforded trans-g-butyrolactone 4b as
Scheme 1. Proposed reaction pathway.[6,14]
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
Ed. 2013, 52, 5789 – 5794; c) R. Han, J. Qi, J. Gu, D. Ma, X. Xie,
X. She, ACS Catal. 2013, 3, 2705 – 2709.
[6] J. Qi, X. Xie, R. Han, D. Ma, J. Yang, X. She, Chem. Eur. J. 2013,
19, 4146 – 4150. Only moderate enantioselectivities (up to
53% ee) were obtained for this reaction.
[7] a) B. Cardinal-David, D. E. A. Raup, K. A. Scheidt, J. Am.
Chem. Soc. 2010, 132, 5345 – 5347; b) E. M. Phillips, M. Riedrich,
K. A. Scheidt, J. Am. Chem. Soc. 2010, 132, 13179 – 13181;
c) D. E. A. Raup, B. Cardinal-David, D. Holte, K. A. Scheidt,
Nat. Chem. 2010, 2, 766 – 770; d) D. T. Cohen, B. Cardinal-
David, J. M. Roberts, A. A. Sarjeant, K. A. Scheidt, Org. Lett.
2011, 13, 1068 – 1071; e) D. T. Cohen, B. Cardinal-David, K. A.
Scheidt, Angew. Chem. 2011, 123, 1716 – 1720; Angew. Chem.
Int. Ed. 2011, 50, 1678 – 1682; f) J. Dugal-Tessier, E. A. OꢀBryan,
T. B. H. Schroeder, D. T. Cohen, K. A. Scheidt, Angew. Chem.
2012, 124, 5047 – 5051; Angew. Chem. Int. Ed. 2012, 51, 4963 –
4967; g) J. Mo, X. Chen, Y. R. Chi, J. Am. Chem. Soc. 2012, 134,
8810 – 8813.
[8] a) X. Zhao, D. A. DiRocco, T. Rovis, J. Am. Chem. Soc. 2011,
133, 12466 – 12469; b) G. Liu, P. D. Wilkerson, C. A. Toth, H. Xu,
Org. Lett. 2012, 14, 858 – 861; c) Z. Fu, H. Sun, S. Chen, B. Tiwari,
G. Li, Y. R. Chi, Chem. Commun. 2013, 49, 261 – 263; d) E. O.
McCusker, K. A. Scheidt, Angew. Chem. 2013, 125, 13861 –
13865; Angew. Chem. Int. Ed. 2013, 52, 13616 – 13620.
[9] a) T. Akiyama, J. Itoh, K. Fuchibe, Adv. Synth. Catal. 2006, 348,
999 – 1010; b) S. J. Connon, Angew. Chem. 2006, 118, 4013 –
4016; Angew. Chem. Int. Ed. 2006, 45, 3909 – 3912; c) T.
Akiyama, Chem. Rev. 2007, 107, 5744 – 5758; d) A. G. Doyle,
E. N. Jacobsen, Chem. Rev. 2007, 107, 5713 – 5743; e) B. List,
Chem. Rev. 2007, 107, 5413 – 5415; f) S. J. Connon, Chem.
Commun. 2008, 2499 – 2510; g) A. Dondoni, A. Massi, Angew.
Chem. 2008, 120, 4716 – 4739; Angew. Chem. Int. Ed. 2008, 47,
4638 – 4660; h) D. W. C. MacMillan, Nature 2008, 455, 304 – 308;
i) G. Bartoli, G. Bencivenni, R. Dalpozzo, Chem. Soc. Rev. 2010,
39, 4449 – 4465; j) D. Kampen, C. M. Reisinger, B. List, Top.
Curr. Chem. 2010, 291, 395 – 456; k) M. Terada, Synthesis 2010,
1929 – 1982; l) M. Rueping, A. Kuenkel, I. Atodiresei, Chem.
Soc. Rev. 2011, 40, 4539 – 4549; m) K. Brak, E. N. Jacobsen,
Angew. Chem. 2013, 125, 558 – 588; Angew. Chem. Int. Ed. 2013,
52, 534 – 561; n) J. Lv, S. Z. Luo, Chem. Commun. 2013, 49, 847 –
858; o) M. Mahlau, B. List, Angew. Chem. 2013, 125, 540 – 556;
Angew. Chem. Int. Ed. 2013, 52, 518 – 533. For a review on super
Brønsted acid catalysis, see: C. H. Cheon, H. Yamamoto, Chem.
Commun. 2011, 47, 3043 – 3056. For selected examples of super
Brønsted acid catalysis, see: D. Nakashima, H. Yamamoto, J.
Am. Chem. Soc. 2006, 128, 9626 – 9627; C. H. Cheon, H.
Yamamoto, J. Am. Chem. Soc. 2008, 130, 9246 – 9247.
Scheme 2. Synthetic transformations. Conditions: a) Pd(OH)2/C, H2,
EtOAc. b) Crabtree’s catalyst, H2, CH2Cl2. c) InBr3 (10 mol%), Et3SiH,
CHCl3.
the major product (3.1:1 d.r.).[22] In the presence of catalytic
indium(III) bromide and triethylsilane, g-butyrolactone 4a
can also be selectively reduced to provide the corresponding
multisubstituted tetrahydrofuran (5),[23] a scaffold found in
numerous biologically active compounds.[24]
In conclusion, a highly efficient asymmetric [3+2] annu-
lation reaction of alkynyl aldehydes with a-ketoesters
through NHC/chiral phosphate cooperative catalysis has
been developed. Alkynyl aldehydes can be converted into
the corresponding enantiomerically enriched substituted
butenolides in good yield and enantioselectivity. This chal-
lenging transformation features a new mode of cooperative
catalysis, utilizing the combination of an underexplored
saturated-imidazolium catalyst and a chiral phosphoric acid,
which was required to achieve the observed enhanced yields
and enantioselectivities. Investigations involving the use of
these C1-symmetric catalysts and this new mode of cooper-
ative catalysis are ongoing.
Received: March 18, 2014
Revised: April 8, 2014
Published online: && &&, &&&&
Keywords: annulation · asymmetric synthesis ·
.
cooperative catalysis · N-heterocyclic carbene ·
synthetic methods
[1] For a recent review on NHC-derived homoenolate additions,
see: a) V. Nair, R. S. Menon, A. T. Biju, C. R. Sinu, R. R. Paul,
A. Jose, V. Sreekumar, Chem. Soc. Rev. 2011, 40, 5336 – 5346. For
the first reports on NHC-catalyzed homoenolate reactions, see:
b) C. Burstein, F. Glorius, Angew. Chem. 2004, 116, 6331 – 6334;
Angew. Chem. Int. Ed. 2004, 43, 6205 – 6208; c) S. S. Sohn, E. L.
Rosen, J. W. Bode, J. Am. Chem. Soc. 2004, 126, 14370 – 14371.
[2] For selected reviews on NHC organocatalysis, see: a) D. Enders,
O. Niemeier, A. Henseler, Chem. Rev. 2007, 107, 5606 – 5655;
b) E. M. Phillips, A. Chan, K. A. Scheidt, Aldrichimica Acta
2009, 42, 55 – 66; c) X. Bugaut, F. Glorius, Chem. Soc. Rev. 2012,
41, 3511 – 3522; d) H. U. Vora, P. Sheeler, T. Rovis, Adv. Synth.
Catal. 2012, 354, 1617 – 1639.
[10] For selected reviews on metal/Brønsted acid combined catalysis,
see: a) Z. Shao, H. Zhang, Chem. Soc. Rev. 2009, 38, 2745 – 2755;
b) M. Rueping, R. M. Koenigs, I. Atodiresei, Chem. Eur. J. 2010,
16, 9350 – 9365; c) see Ref. [9n].
[11] For selected examples of metal/Brønsted acid combined catal-
ysis, see: a) K. Shen, X. Liu, Y. Cai, L. Lin, X. Feng, Chem. Eur. J.
2009, 15, 6008 – 6014; b) T. Yue, M.-X. Wang, D.-X. Wang, G.
Masson, J. Zhu, J. Org. Chem. 2009, 74, 8396 – 8399; c) Q.-W.
Zhang, C.-A. Fan, H.-J. Zhang, Y.-Q. Tu, Y.-M. Zhao, P. Gu, Z.-
M. Chen, Angew. Chem. 2009, 121, 8724 – 8726; Angew. Chem.
Int. Ed. 2009, 48, 8572 – 8574; d) B. Zhao, H. Du, Y. Shi, J. Org.
Chem. 2009, 74, 8392 – 8395; e) M. Hatano, K. Moriyama, T.
Maki, K. Ishihara, Angew. Chem. 2010, 122, 3911 – 3914; Angew.
Chem. Int. Ed. 2010, 49, 3823 – 3826; f) F. Drouet, C. Lalli, H.
Liu, G. Masson, J. Zhu, Org. Lett. 2011, 13, 94 – 97; g) G. K. Ingle,
Y. Liang, M. G. Mormino, G. Li, F. R. Frondzek, J. C. Antilla,
Org. Lett. 2011, 13, 2054 – 2057; h) Z. Zhang, W. Zheng, J. C.
Antilla, Angew. Chem. 2011, 123, 1167 – 1170; Angew. Chem. Int.
Ed. 2011, 50, 1135 – 1138; i) W. Zheng, Z. Zhang, M. J. Kaplan,
J. C. Antilla, J. Am. Chem. Soc. 2011, 133, 3339 – 3341.
[3] K. Zeitler, Org. Lett. 2006, 8, 637 – 640.
[4] a) J. Kaeobamrung, J. Manattananchai, P. Zheng, J. W. Bode, J.
Am. Chem. Soc. 2010, 132, 8810 – 8812; b) Z.-Q. Zhu, J.-C. Xiao,
Adv. Synth. Catal. 2010, 352, 2455 – 2458; c) Z.-Q. Zhu, X.-L.
Zheng, N.-F. Jiang, X. Wan, J.-C. Xiao, Chem. Commun. 2011,
47, 8670 – 8672; d) D. Du, Z. Hu, J. Jin, Y. Lu, W. Tang, B. Wang,
T. Lu, Org. Lett. 2012, 14, 1274 – 1277; e) F. Romanov-Michai-
lidis, C. Besnard, A. Alexakis, Org. Lett. 2012, 14, 4906 – 4909.
[5] a) Y.-M. Zhao, Y. Tam, Y.-J. Wang, Z. Li, J. Sun, Org. Lett. 2012,
14, 1398 – 1401; b) A. M. ElSohly, D. A. Wespe, T. J. Poore, S. A.
Snyder, Angew. Chem. 2013, 125, 5901 – 5906; Angew. Chem. Int.
4
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
[12] For a mechanistic investigation involving NHC catalysis with
alkynals, see: J. Mahatthananchai, P. Zheng, J. W. Bode, Angew.
Chem. 2011, 123, 1711 – 1715; Angew. Chem. Int. Ed. 2011, 50,
1673 – 1677.
[16] For examples of pKa value determination of Brønsted acids, see:
a) P. Christ, A. G. Lindsay, S. S. Vormittag, J.-M. Nuudoerfl, A.
Berkessel, A. C. OꢀDonoghue, Chem. Eur. J. 2011, 17, 8524 –
8528; b) D. Seebach, A. K. Beck, H. Bichsel, A. Pichota, C.
Sparr, R. Wꢁnsch, W. B. Schweizer, Helv. Chim. Acta 2012, 95,
1303 – 1324; c) C. Yang, X.-S. Xue, J.-L. Jin, X. Li, J.-P. Cheng, J.
Org. Chem. 2013, 78, 7076 – 7085.
[13] For selected examples, see: a) J. J. Van Veldhuizen, S. B. Garber,
J. S. Kingsbury, A. H. Hoveyda, J. Am. Chem. Soc. 2002, 124,
4954 – 4955; b) J. J. Van Veldhuizen, D. G. Gillingham, S. B.
Barber, O. Kataoka, A. H. Hoveyda, J. Am. Chem. Soc. 2003,
125, 12502 – 12508; c) A. H. Hoveyda, D. G. Gillingham, J. J.
Van Veldhuizen, O. Kataoka, S. B. Garber, J. S. Kingsbury,
J. P. A. Harrity, Org. Biomol. Chem. 2004, 2, 8 – 23; d) K.-s.
Lee, M. K. Brown, A. W. Hird, A. H. Hoveyda, J. Am. Chem.
Soc. 2006, 128, 7182 – 7184; e) M. K. Brown, T. L. May, C. A.
Baxter, A. H. Hoveyda, Angew. Chem. 2007, 119, 1115 – 1118;
Angew. Chem. Int. Ed. 2007, 46, 1097 – 1100; f) Y. Lee, K.
Akiyama, D. G. Gillingham, M. K. Brown, A. H. Hoveyda, J.
Am. Chem. Soc. 2008, 130, 446 – 447; g) H. Wu, S. Radomkit,
J. M. OꢀBrien, A. H. Hoveyda, J. Am. Chem. Soc. 2012, 134,
8277 – 8285.
[14] K. P. Jang, G. E. Hutson, R. C. Johnston, E. O. McCusker, P. U.-
Y. Cheong, K. A. Scheidt, J. Am. Chem. Soc. 2014, 136, 76 – 79.
[15] For examples of pKa value determination of NHCs, see: a) R. W.
Alder, P. R. Allen, S. J. Williams, J. Chem. Soc. Chem. Commun.
1995, 1267 – 1268; b) Y. J. Kim, A. Streitweiser, J. Am. Chem.
Soc. 2002, 124, 5757 – 5761; c) T. L. Amyes, S. T. Diver, J. P.
Richard, F. M. Rivas, K. Toth, J. Am. Chem. Soc. 2004, 126,
4366 – 4374; d) A. M. Magill, K. J. Cavell, B. F. Yates, J. Am.
Chem. Soc. 2004, 126, 8717 – 8724; e) Y. Chu, H. Deng, J. P.
Cheng, J. Org. Chem. 2007, 72, 7790 – 7793; f) E. M. Higgins,
J. A. Sherwood, A. G. Lindsay, J. Armstrong, R. S. Massey, R. W.
Alder, A. C. OꢀDonoghue, Chem. Commun. 2011, 47, 1559 –
1561.
[17] a) Z.-Q. Rong, M.-Q. Jia, S.-L. You, Org. Lett. 2011, 13, 4080 –
4083; b) see Ref. [6].
[18] M. Hatano, T. Ikeno, T. Matsumura, S. Torii, K. Ishihara, Adv.
Synth. Catal. 2008, 350, 1776 – 1780.
[19] a) S. Xu, Z. Wang, X. Zhang, X. Zhang, K. Ding, Angew. Chem.
2008, 120, 2882 – 2885; Angew. Chem. Int. Ed. 2008, 47, 2840 –
2843; b) M. Rueping, T. M. Theissmann, A. Kuenkel, R. M.
Koenigs, Angew. Chem. 2008, 120, 6903 – 6906; Angew. Chem.
Int. Ed. 2008, 47, 6798 – 6801.
[20] We also tested aliphatic alkynals, however, the reaction provided
numerous peaks by UPLC and no desired product was observed.
Current studies to engage this substrate class are ongoing.
[21] A computational study at the M06-2X/6-31 + G(2df,p)/PCM-
(THF)//M06-2X/6-31G(d) level of theory indicates that the Z-
alkene isomer is more stable by ꢀ 0.6 kcalmolÀ1 compared to the
E-alkene isomer because of the minimization of steric inter-
actions.
[22] For a comprehensive review on substrate-directed reactions, see:
A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93,
1307 – 1370.
[23] a) N. Sakai, T. Moriya, T. Konakahara, J. Org. Chem. 2007, 72,
5920 – 5922; b) N. Sakai, T. Moriya, K. Fujii, T. Konakahara,
Synthesis 2008, 3533 – 3536.
[24] a) F. M. Dean, Adv. Heterocycl. Chem. 1982, 30, 167 – 238; b) Y.
Zhu, C. Zhai, L. Yang, W. Hu, Chem. Commun. 2010, 46, 2865 –
2867.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Asymmetric Catalysis
A. Lee, K. A. Scheidt*
&&&& — &&&&
A Cooperative N-Heterocyclic Carbene/
Chiral Phosphate Catalysis System for
Allenolate Annulations
Cooperation: A highly enantioselective
NHC-catalyzed [3+2] annulation of a,b-
alkynals and a-ketoesters generates the
desired g-crotonolactones in high yields.
The reaction is based on the cooperative
catalysis of a chiral Brønsted acid and
a precatalyst consisting of a C1-symmetric
biaryl and a saturated-imidazolium
moiety.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!