Remarkable Enhancement of Enantioselectivity in the Asymmetric Conjugate Addition of Dimethylzinc to (Z)-Nitroalkenes with a Catalytic [(MeCN)4Cu]PF6-Hoveyda Ligand Complex

Article abstract of DOI:10.1002/anie.201406247

An enantioselective copper-catalyzed asymmetric conjugate addition of Me₂Zn to (Z)-nitroalkenes led to the formation of all-carbon quaternary stereogenic centers with high stereoselectivity. The key features of the new method are the unprecedented use of [(MeCN)₄Cu]PF₆ in conjunction with the Hoveyda ligand L1 and the use of (Z)-nitroalkene substrates so that undesired nitroalkene isomerization is minimized and enantioselectivity is enhanced dramatically. We also describe a novel, practical, and highly (Z)-selective nitroalkene synthesis.

Full text of DOI:10.1002/anie.201406247

Angewandte
Chemie
DOI: 10.1002/anie.201406247
Asymmetric Catalysis
Remarkable Enhancement of Enantioselectivity in the Asymmetric
Conjugate Addition of Dimethylzinc to (Z)-Nitroalkenes with
a Catalytic [(MeCN)4Cu]PF6–Hoveyda Ligand Complex**
Xingzhong Zeng,* Joe J. Gao, Jinhua J. Song, Shengli Ma, Jean-Nicolas Desrosiers,
Jason A. Mulder, Sonia Rodriguez, Melissa A. Herbage, Nizar Haddad, Bo Qu,
Keith R. Fandrick, Nelu Grinberg, Heewon Lee, Xudong Wei, Nathan K. Yee, and
Chris H. Senanayake
Abstract: An enantioselective copper-catalyzed asymmetric
conjugate addition of Me2Zn to (Z)-nitroalkenes led to the
formation of all-carbon quaternary stereogenic centers with
high stereoselectivity. The key features of the new method are
the unprecedented use of [(MeCN)4Cu]PF6 in conjunction
with the Hoveyda ligand L1 and the use of (Z)-nitroalkene
substrates so that undesired nitroalkene isomerization is
minimized and enantioselectivity is enhanced dramatically.
We also describe a novel, practical, and highly (Z)-selective
nitroalkene synthesis.
able separation by HPLC on a chiral stationary phase,[1a–c,e,f]
or the synthesis of diastereomers through the use of
a stoichiometric amount of an oxazolidinone-based chiral
auxiliary, followed by chromatographic separation of the
diastereomers.[1d] Clearly, the development of a more efficient
and enantioselective catalytic approach to the synthesis of this
family of biologically important compounds is highly desir-
able. One of our strategies has been to install the all-carbon
stereocenter through an asymmetric conjugate addition
(ACA) reaction.
A
ll-carbon quaternary ste-
reocenters are increasingly
being incorporated into the
design and synthesis of novel
therapeutic agents. The
structures
shown
in
Scheme 1 represent a class
of biologically active com-
pounds pursued by several
major pharmaceutical com-
panies in the past decade.[1]
However, medicinal chem-
ists have met with remark-
able challenges during the
synthesis of compounds of
this type. The preparation of
optically pure chiral inter-
mediates has often involved
the synthesis of the racemic
compounds, followed by
tedious, costly, and nonscal-
Scheme 1. A structural motif of medicinal interest. EWG=electron-withdrawing group.
Over the past two decades, the copper-catalyzed ACA of
enones, nitroalkenes, and Meldrum acid derivatives with
organozinc, organoaluminum, organomagnesium, or boronic
acid reagents has emerged as a powerful approach to access
chiral molecules with quaternary stereogenic centers.[2]
Whereas there are many documented successes in the ACA
of cyclic enones,[3] the use of acyclic substrates has met with
formidable challenges.[2g,h,4] Furthermore, although methyl-
substituted all-carbon quaternary stereocenters are by far the
most commonly occurring all-carbon quaternary stereocen-
ters in natural products, the conjugate addition of Me2Zn to
generate quaternary stereogenic centers is the most challeng-
ing transformation and suffers from low reactivity and
enantioselectivity.
[*] Dr. X. Zeng, J. J. Gao, Dr. J. J. Song, Dr. S. Ma, Dr. J.-N. Desrosiers,
Dr. J. A. Mulder, Dr. S. Rodriguez, Dr. M. A. Herbage, Dr. N. Haddad,
Dr. B. Qu, Dr. K. R. Fandrick, Dr. N. Grinberg, Dr. H. Lee, Dr. X. Wei,
Dr. N. K. Yee, Dr. C. H. Senanayake
Chemical Development
Boehringer Ingelheim Pharmaceuticals, Inc.
900 Ridgebury Road, Ridgefield, CT 06877 (USA)
E-mail: xingzhong.zeng@boehringer-ingelheim.com
[**] We thank the Boehringer Ingelheim-Pfizer-GlaxoSmithKline-AbbVie
Non-Precious Metal Catalysis Consortium for general discussions
in this area.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406247.
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In 2005, Hoveyda and co-workers[4a] reported two inter-
esting examples of the enantioselective ACA of Me2Zn to E-
trisubstituted nitroalkenes (R = nPr or iPr; Scheme 2). The
products were obtained in 40–85% yield with 73–85% ee
using complexes of (CuOTf)2·PhH and Hoveyda dipeptide
4 reached full conversion after 72 h at À108C, 2 was obtained
with only 52% ee (R). These initial observations led us to
decide to focus our research efforts on optimizing the ACA
reaction of (Z)-4a with dimethylzinc [Eq. (1)].
Further screening confirmed that À308C is the optimal
temperature for the use of chiral ligand L1, under which
conditions full conversion and 65% ee were observed.[6] Next,
we examined a number of chiral ligands and solvents in the
hope of improving the enantioselectivity. To our dismay, we
did not find a chiral ligand that was better than L1. However,
during these studies, an interesting observation caught our
attention: When non-effective chiral ligands were used,
although the desired product of conjugate addition was not
observed, we isolated and characterized (E)-4a (Scheme 4) as
the major by-product. The formation of (E)-4a is strong proof
that olefin isomerization of (Z)-4a took place during the
Scheme 2. Pioneering studies by Hoveyda and co-workers on the ACA
reaction of (E)-nitroalkenes with dialkylzinc reagents. Tf=trifluoro-
methanesulfonyl.
ligands. In sharp contrast, reactions with Et2Zn and other
diorganozinc species gave the corresponding products with up
to 98% ee. Despite some limited success reported recently in
the methylation of acyclic Meldrum acid derivatives[4b] and
acyclic enones[4c] with improved enantioselectivity, the ACA
of Me2Zn remains significantly underdeveloped. We now
report that with a new CuI catalyst, [(MeCN)4Cu]PF6, the use
of which to our knowledge has not previously been reported
for this type of transformation, and acyclic (Z)-nitroalkenes
as substrates, high reactivities and enantioselectivities were
observed in the ACA of Me2Zn to create all-carbon
quaternary stereogenic centers.
We first investigated the addition of Me2Zn to nitro-
alkenes 4 and 5 under conditions reported by Hoveyda and
co-workers (Scheme 3). Preliminary results showed that for
the addition of dicyclopropylzinc[5] to (E)-5, no reaction
occurred at À208C; after 65 h at 08C, only 8% ee was
observed. On the other hand, the addition of dimethylzinc to
(Z)-4 at À308C gave product 2 with an encouraging ee value
of 65% (S), with full conversion and 96% yield. The addition
to (E)-4 furnished 2 with a slightly higher ee value (76% ee,
R), but with poor conversion. Although the reaction with (E)-
Scheme 4. E/Z isomerization of nitroalkenes during asymmetric con-
jugate addition.
Scheme 3. Comparison of three ACA strategies. R=Br, Bn=benzyl.
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Table 1: Investigation of background isomerization with Cu salts during asymmetric
conjugate addition to (Z)-4a or (E)-4a.
the starting material, 7% olefin isomerization was
observed (Table 1, entry 10). Similarly,
Entry Reaction mixture[a]
T [8C] (Z)-4a 2a
(E)-4a
[(MeCN)4Cu]BF4, CuTC, and CuOAc also induced
low levels of isomerization (Table 1, entries 11–13).
These four Cu salts were then further evaluated
in the actual ACA reactions (Table 2). The ACA
reaction was very sluggish with Cu(OCOCF3)2·xH2O
(Table 2, entry 3), CuTC (entry 5), or CuOAc
[%][b]
[%][b] [%][b,c]
1
2
3
4
5
6
7
8
9
10
11
12
13
(Z)-4a+(CuOTf)2·PhH
25
25
97
99
43
34
47
70
97
100
99
7
0
0
0
0
0
0
0
0
0
0
0
0
0
3
1
(Z)-4a+(CuOTf)2·PhH+L1
(Z)-4a+(CuOTf)2·PhH+Me2Zn
(E)-4a+(CuOTf)2·PhH+Me2Zn
À30
57
66
53
30
3
0
1
93
2
5
À30
(Z)-4a+Cu(OCOCF3)2·xH2O+Me2Zn À30
(entry 7).
Reactions
with
[(MeCN)4Cu]BF4
(Z)-4a+(MeCN)4CuOTf+Me2Zn
(Z)-4a+(MeCN)4CuPF6 +Me2Zn
(Z)-4a+(MeCN)4CuPF6
À30
À30
25
(Table 2, entry 4) or [(MeCN)4Cu]OTf (entry 6)
were not satisfactory in terms of their enantioselec-
tivity and/or reactivity. To our delight, the use of
[(MeCN)4Cu]PF6 led to superior enantioselectivity
as compared to the reaction with (CuOTf)2·PhH.
This observation is consistent with the background-
isomerization results in Table 1, thus suggesting that
(Z)-4a+(MeCN)4CuPF6 +L1
(E)-4a+(MeCN)4CuPF6 +Me2Zn
(Z)-4a+(MeCN)4CuBF4 +Me2Zn
(Z)-4a+CuTC+Me2Zn
25
À30
À30
À30
À30
98
95
96
(Z)-4a+CuOAc+Me2Zn
4
[a] Reaction conditions: 4 mol% Cu, L1 (4 mol%), Me2Zn (1.2 equiv), 65 h. [b] The [(MeCN)4Cu]PF6 indeed significantly suppressed the
yield is based on the consumption of the substrate and was determined by HPLC
analysis. [c] (E)-4a was isolated and fully characterized (see the Supporting
Information for details).
undesired olefin isomerization and that (Z)-4a was
more advantageous as a substrate than isomer (E)-
4a with regard to both reactivity and enantioselec-
course of the reaction. It has been reported previ-
Table 2: Screening of Cu salts in the ACA of (Z)-4a or (E)-4a.[a]
ously[7] that olefin isomerization could be responsible
Entry Substrate CuI (mol%)
L1
t
Conv.
ee
for lower enantioselectivities in conjugate addition
reactions owing to the different reactivity and/or
selectivity of the (E)- and (Z)-isomers, as illustrated
in Scheme 4. Indeed, in our case, opposite enantio-
selectivities were observed for the reactions of (E)-
and (Z)-4a (Scheme 3).
To fully understand how severe the isomerization
was, we investigated the background isomerization
with (Z)-4a and (E)-4a (Table 1).[6] When (Z)-4a
(1 equiv) and (CuOTf)2·PhH (2 mol%) with or
without chiral ligand L1 (4 mol%) were stirred in
toluene in the absence of Me2Zn, olefin isomer-
ization was minimal, even at room temperature
(Table 1, entries 1 and 2). However, in the reaction
mixture of pure (Z)-4a (1 equiv) with (CuOTf)2·PhH
(2 mol%) and Me2Zn (1.2 equiv), isomer (E)-4a was
formed in 57% yield and 43% of (Z)-4a remained
after 65 h at À308C (Table 1, entry 3). When pure
[mol%] [h] [%][b]
[%][c]
1
2
3
4
5
6
7
8
9
(Z)-4a
(E)-4a
(Z)-4a
(Z)-4a
(Z)-4a
(Z)-4a
(Z)-4a
(Z)-4a
(E)-4a
(CuOTf)2·PhH (2)
(CuOTf)2·PhH (2)
Cu(OCOCF3)2·xH2O (4)
[(MeCN)4Cu]BF4 (4)
CuTC (4)
[(MeCN)4Cu]OTf (4)
CuOAc (4)
[(MeCN)4Cu]PF6 (4)
[(MeCN)4Cu]PF6 (4)
4
4
4
4
4
4
4
4
4
24 100 (96) 65 (S)
24
65
65
65
24
65
65
96
32 (26) 76 (R)
5 (3)
42 (42) 50 (S)
5 (1)
10 (98) 63 (S)
8 (5)
–
–
–
98 (95) 95 (R)
16 (15) 85 (R)
[a] Reactions were carried out in toluene at À308C. [b] The reported conversion is
based on the consumption of the substrate and was determined by HPLC analysis.
The number in parenthesis indicates the HPLC assay yield. [c] The ee value was
determined by HPLC on a chiral stationary phase. The absolute configuration was
determined by our internal program and by analogy.
(E)-4a was used in place of (Z)-4a in this control experiment,
isomer (Z)-4a was formed in 34% yield (Table 1, entry 4).
These observations, coupled with the fact that under the
standard reaction conditions with (CuOTf)2·PhH, 2a was
formed with a moderate ee value of 65%, suggested that
nitroolefin isomerization during the course of ACA is
probably the cause of the poor enantioselectivity. Accord-
ingly, if we could suppress the undesired nitroolefin isomer-
ization during the ACA reaction, we might be able to improve
the enantioselectivity significantly. We suspected that the
nature of the Cu salt could play a critical role in the observed
olefin isomerization and examined the effect of a variety of
Cu salts on olefin isomerization. As with (CuOTf)2·PhH, the
use of Cu(OCOCF3)2·xH2O or [(MeCN)4Cu]OTf resulted in
significant olefin isomerization (Table 1, entries 5 and 6). In
contrast, the use of a catalytic amount of [(MeCN)4Cu]PF6
and Me2Zn (1.2 equiv) induced only 3% olefin isomerization
(Table 1, entry 7). Under the same conditions with (E)-4a as
tivity (Table 2, entries 8 and 9). Thus, through the use of
[(MeCN)4Cu]PF6 as the catalyst and the (Z)-nitroalkene 4a as
the substrate, dramatically improved enantioselectivity was
observed in the ACA reaction with Me2Zn. Interestingly,
when (CuOTf)2·PhH was used as the catalyst, the ACA of
(Z)-4a gave the S enantiomer of 2a as the major product,
whereas the ACA of (E)-4a gave the R enantiomer as the
major product. However, when [(MeCN)4Cu]PF6 was used as
the catalyst, ACA of either (Z)-4a or (E)-4a gave (R)-2a as
the major product, thus suggesting that nucleophilic attack by
Me2Zn from the Re face was favored, irrespective of the
nitroolefin geometry.
To explore the scope of the [(MeCN)4Cu]PF6–L1-cata-
lyzed ACA reaction of (Z)-nitroalkenes with Me2Zn, we first
needed an efficient and stereoselective method for the
synthesis of Z nitroalkenes. These compounds have been
synthesized previously by the b-elimination of mesylates,[8a]
by the oxidative elimination of b-phenylselenides[8b] or b-
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sulfides,[8c] by the photoisomerization of E nitroalkenes,[8d]
and by dehydration of the corresponding tertiary alcohols,[8e]
but the reported methods suffer from long reaction times, low
yields, poor functional-group compatibility, and low Z/E
selectivity, which often requires chromatographic separation
of the two isomers. After intensive investigations, we discov-
ered a new method for the efficient and highly Z-selective
synthesis of nitroalkenes [Eq. (2) and Table 3].
Table 4: ACA of nitroalkenes (Z)-4a–j.
Entry
(Z)-4a–j (R1; R2)
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
9
(Z)-4a (4-BrC6H4; cPr)
(Z)-4b (4-ClC6H4; cPr)
(Z)-4c (6-Cl-3-Py; cPr)
(Z)-4d (4-BrC6H4; Et)
(Z)-4e (4-BrC6H4; nPr)
(Z)-4 f (4-BrC6H4; iPr)
(Z)-4g (4-ClC6H4; nBu)
(Z)-4h (6-Cl-3-Py; nBu)
(Z)-4i (4-BrC6H4; cHex)
(Z)-4j (4-BrC6H4; cPent)
91 (2a)
92 (2b)
91 (2c)
88 (2d)
94 (2e)
92 (2 f)
91 (2g)
92 (2h)
96 (2i)
91 (2j)
95
91
93
93
95
98
89
93
94
94
Table 3: Synthesis of nitroalkenes (Z)-4a–j.
Entry R1; R2[a]
Yield of Yield of Yield of
Z/E ratio
7 [%][b]
8 [%][b]
(Z)-4 [%][b] of 4[c]
1
2
3
4
5
6
7
8
9
4-BrC6H4; cPr
96
93
72
96
96
96
93
72
96
88
84
91
83
85
90
81
87
79
78
85 (4a)
82 (4b)
76 (4c)
82 (4d)
88 (4e)
87 (4 f)
86 (4g)
73 (4h)
92 (4i)
98 (4j)
ꢀ99:1
ꢀ99:1
ꢀ99:1
ꢀ99:1
ꢀ99:1
ꢀ99:1
ꢀ99:1
ꢀ99:1
ꢀ99:1
ꢀ99:1
4-ClC6H4; cPr
6-Cl-3-Py; cPr
4-BrC6H4; Et
4-BrC6H4; nPr
4-BrC6H4; iPr
4-ClC6H4; nBu
6-Cl-3-Py; nBu
4-BrC6H4; cHex
10
[a] Yield of the isolated product. [b] The ee value of the product was
determined by HPLC on a chiral stationary phase.
10
4-BrC6H4; cPent 96
were also found to be suitable substrates (Table 4, entries 3
and 8). It is well-established that nitroalkanes can be readily
converted into a range of functionalities, such as aldehydes,[11]
carboxylic acids,[12] amines,[13] oximes,[14] and nitriles.[14b,15]
Thus, the current methodology could be used to access
a library of biologically important compounds with all-carbon
stereogenic centers in an efficient and practical way. As an
example, nitroalkane 2a was converted in a Nef reaction into
aldehyde 3a, which was then reduced to the chiral alcohol 9
[Eq. (4)].
[a] cPr=cyclopropyl, cHex=cyclohexyl, cPent=cyclopentyl, 6-Cl-3-Py =
6-chloro-3-pyridyl. [b] Yield of the isolated product. [c] The Z/E ratio was
1
determined by H NMR spectroscopy of the crude product.
The commercially available carboxylic acids 6 were
activated by CDI in DMF to form a reactive N-acyl imidazole
species, which reacted with the carbanion generated from
nitromethane and NaH to give nitroketones 7.[9] Nitroketones
7 are crystalline solids and were conveniently precipitated
from the reaction mixtures upon the addition of aqueous HCl.
They were converted into nitroalcohols 8 by the B(OMe)3-
mediated addition of a Grignard reagent.[10] The use of
B(OMe)3 is critical for this transformation to avoid the
otherwise serious retro-Henry reaction. Nitroalcohols 8
underwent facile dehydration in a chloroacetic anhydride
(CAA)–DMSO system to afford (Z)-nitroalkenes 4 in high
yield with high diastereoselectivity. The use of CAA is critical
for the desired reaction rate and high Z/E selectivity. Most
(Z)-nitroalkenes 4 are crystalline solids that can be crystal-
lized out during workup, thus eliminating the need for
chromatographic separation and making practical scaleup
possible.
In conclusion, we have described a highly enantioselective
copper-catalyzed asymmetric conjugate addition with Me2Zn
for the formation of all-carbon quaternary stereogenic
centers. The key features of the new methodology are the
unprecedented use of [(MeCN)4Cu]PF6 as the catalyst and the
employment of (Z)-nitroalkene substrates. We also devel-
oped a novel and practical synthesis of (Z)-nitroalkenes.
Considering the low cost of the sustainable Cu catalyst and
the ready availability of the Hoveyda dipeptide ligand L1, the
present discovery provides a practical synthetic route to
biologically active and synthetically useful molecules with
a methyl-substituted all-carbon quaternary chiral center.
Extensions of this methodology to other diorganozinc
These (Z)-nitroalkenes 4 were then subjected to our
newly established ACA conditions to give nitroalkanes 2
[Eq. (3) and Table 4]. High yields and high enantioselectiv-
ities were observed for all substrates for the formation of the
all-carbon quaternary stereogenic center. Pyridine derivatives
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g) M. K. Brown, A. H. Hoveyda, J. Am. Chem. Soc. 2008, 130,
reagents and other heterocyclic compounds are being pursued
in our laboratories.
12904; h) R. Shintani, M. Takeda, T. Nishimura, T. Hayashi,
Angew. Chem. Int. Ed. 2010, 49, 3969; Angew. Chem. 2010, 122,
4061; i) R. Shintani, T. Hayashi, Org. Lett. 2011, 13, 350; j) T. L.
May, J. A. Dabrowski, A. H. Hoveyda, J. Am. Chem. Soc. 2011,
133, 736; k) K. Kikushima, J. C. Holder, M. Gatti, B. M. Stoltz, J.
Am. Chem. Soc. 2011, 133, 6902; l) A. L. Gottumukkala, K.
Matcha, M. Lutz, J. G. de Vries, A. J. Minnaard, Chem. Eur. J.
2012, 18, 6907; m) M. Tissot, D. Poggiali, H. Hꢃnon, D. Mꢀller, L.
Guꢃnꢃe, M. Mauduit, A. Alexakis, Chem. Eur. J. 2012, 18, 8731.
[4] a) For an ACA reaction of acyclic nitroalkenes with diorgano-
zinc reagents, see: J. Wu, D. M. Mampreian, A. H. Hoveyda, J.
Am. Chem. Soc. 2005, 127, 4584; b) for an ACA reaction of
acyclic Meldrum acid derivatives with Me2Zn, see: A. Wilsily, T.
Lou, E. Fillion, Synthesis 2009, 2066; c) for an ACA reaction of
acyclic enones with Me3Al, see: K. Endo, D. Hamada, S.
Yakeishi, T. Shibata, Angew. Chem. Int. Ed. 2013, 52, 606;
Angew. Chem. 2013, 125, 634; d) the challenge to create all-
carbon quaternary stereogenic centers, especially in acyclic
systems, has recently been highlighted: I. Marek, Y. Minko, M.
Pasco, T. Mejuch, N. Gilboa, H. Chechik, J. P. Das, J. Am. Chem.
Soc. 2014, 136, 2682.
Received: June 15, 2014
Revised: August 11, 2014
Published online: September 15, 2014
Keywords: asymmetric conjugate addition · copper ·
.
nitroalkenes · quaternary stereocenters · zinc
[1] a) M. G. Bell, K. Gavardinas, D. L. Gernert, T. A. Grese, P. K.
Jadhav, P. A. Lander, M. I. Steinberg, WO 2004067529, 2004;
b) M. G. Bell, D. L. Gernert, T. A. Grese, M. D. Belvo, P. S.
Borromeo, S. A. Kelley, J. H. Kennedy, S. P. Kolis, P. A. Lander,
R. Richey, V. S. Sharp, G. A. Stephenson, J. D. Williams, H. Yu,
K. M. Zimmerman, M. I. Steinberg, P. K. Jadhav, J. Med. Chem.
2007, 50, 6443; c) T. I. Richardson, C. A. Clarke, K.-L. Yu, Y. K.
Yee, T. J. Bleisch, J. E. Lopez, S. A. Jones, N. E. Hughes, B. S.
Muehl, C. W. Lugar, T. L. Moore, P. K. Shetler, R. W. Zink, J. J.
Osborne, C. Montrose-Rafizadeh, N. Patel, A. G. Geiser, R. J.
Sells Galvin, J. A. Dodge, ACS Med. Chem. Lett. 2011, 2, 148;
d) A. Bailey, A. Mete, G. Pairaudeau, M. Stocks, M. Wenlock,
WO 2007123465, 2007; e) P. Kolkhof, A. Brꢀns, K. Thede, K.-H.
Schlemmer, A. Hillisch, D. Lang, M. Gerisch, A. Gçller, R.
Grosser, C. Schmeck, E. Woltering, O. Prien, H. Paulsen, A.
Kern, US 20100105744, 2010; f) A. Bartolozzi, T. Bosanac, Z.
Chen, S. De Lombaert, J. Huber, H. Y. Lo, P. L. Loke, W. Liu,
T. M. Morwick, A. Olague, D. Riether, H. Tye, L. Wu, R. Zindell,
WO 2012024150, 2012.
[5] We thank Albemarle for a gift of dicyclopropylzinc (2.0m
solution in toluene).
[6] See the Supporting Information for more details.
[7] M. Vuagnoux-dꢄAugustin, A. Alexakis, Eur. J. Org. Chem. 2007,
5852, and references therein.
[8] a) M. A. Swiderska, J. D. Stewart, Org. Lett. 2006, 8, 6131;
b) S. E. Denmark, L. R. Marcin, J. Org. Chem. 1993, 58, 3850;
c) Y.-J. Jang, W.-W. Lin, Y.-K. Shih, J.-T. Liu, M.-H. Hwang, C.-F.
Yao, Tetrahedron 2003, 59, 4979; d) A. Fryszkowska, K. Fisher,
J. M. Gardiner, G. M. Stephens, J. Org. Chem. 2008, 73, 4295;
e) N. J. A. Martin, X. Cheng, L. Benjamin, J. Am. Chem. Soc.
2008, 130, 13862.
[9] a) D. C. Baker, S. R. Putt, Synthesis 1978, 478; b) V. N. G.
Lindsay, W. Lin, A. B. Charette, J. Am. Chem. Soc. 2009, 131,
16383; c) S. Radl, K.-K. Chan, J. Heterocycl. Chem. 1994, 31, 437.
[10] S.-y. Tosaki, K. Hara, V. Gnanadesikan, H. Morimoto, S. Harada,
M. Sugita, N. Yamagiwa, S. Matsunaga, M. Shibasaki, J. Am.
Chem. Soc. 2006, 128, 11776.
[11] R. Ballini, M. Petrini, Tetrahedron 2004, 60, 1017.
[12] C. Matt, A. Wagner, C. Mioskowski, J. Org. Chem. 1997, 62, 234.
[13] C. Czekelius, E. M. Carreira, Angew. Chem. Int. Ed. 2003, 42,
4793; Angew. Chem. 2003, 115, 4941.
[14] a) A. Corma, P. Serna, Science 2006, 313, 332; b) C. Czekelius,
E. M. Carreira, Angew. Chem. Int. Ed. 2005, 44, 612; Angew.
Chem. 2005, 117, 618; c) D. Albanese, D. Landini, M. Penso,
Synthesis 1990, 333; d) D. H. R. Barton, I. Fernandez, C. S.
Richard, S. Z. Zard, Tetrahedron 1987, 43, 551.
[2] For reviews, see: a) T. Hayashi, K. Yamasaki, Chem. Rev. 2003,
103, 2829; b) A. H. Hoveyda, A. W. Hird, M. A. Kacprzynski,
Chem. Commun. 2004, 1779; c) A. Alexakis, J. E. Bꢁckvall, N.
Krause, O. Pꢂmies, M. Diꢃguez, Chem. Rev. 2008, 108, 2796;
d) T. Jerphagnon, M. G. Pizzuti, A. J. Minnaard, B. L. Feringa,
Chem. Soc. Rev. 2009, 38, 1039; e) T. Thaler, P. Knochel, Angew.
Chem. Int. Ed. 2009, 48, 645; Angew. Chem. 2009, 121, 655; f) J.
Wencel, M. Mauduit, H. Hꢃnon, S. Kehrli, A. Alexakis,
Aldrichimica Acta 2009, 42, 43; g) C. Hawner, A. Alexakis,
Chem. Commun. 2010, 46, 7295 – 7306; h) A. M. Dumas, E.
Fillion, Acc. Chem. Res. 2010, 43, 440.
[3] For selected ACA reactions of cyclic enones, see: a) A. W. Hird,
A. H. Hoveyda, J. Am. Chem. Soc. 2005, 127, 14988; b) M.
dꢄAugustin, L. Palais, A. Alexakis, Angew. Chem. Int. Ed. 2005,
44, 1376; Angew. Chem. 2005, 117, 1400; c) K.-s. Lee, M. K.
Brown, A. W. Hird, A. H. Hoveyda, J. Am. Chem. Soc. 2006, 128,
7182; d) D. Martin, S. Kehrli, M. dꢄAugustin, H. Clavier, M.
Mauduit, A. Alexakis, J. Am. Chem. Soc. 2006, 128, 8416; e) M.
Vuagnoux-dꢄAugustin, A. Alexakis, Chem. Eur. J. 2007, 13, 9647;
f) M. K. Brown, T. L. May, C. A. Baxter, A. H. Hoveyda, Angew.
Chem. Int. Ed. 2007, 46, 1097; Angew. Chem. 2007, 119, 1115;
[15] a) L. E. Kaim, A. Gacon, Tetrahedron Lett. 1997, 38, 3391; b) F.
Urpꢅ, J. Vilarrasa, Tetrahedron Lett. 1990, 31, 7497.
Angew. Chem. Int. Ed. 2014, 53, 12153 –12157
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