Enantioselective Copper-Catalyzed Quinoline Alkynylation

Article abstract of DOI:10.1002/anie.201507848

A highly enantioselective copper-catalyzed alkynylation of quinolinium salts is reported. The reaction employs StackPhos, a newly developed imidazole-based chiral biaryl P,N ligand, and copper bromide to effect a three-component reaction between a quinoline, a terminal alkyne, and ethyl chloroformate. Under the reaction conditions, the desired products are delivered in high yields with ee values of up to 98 %. The transformation tolerates a wide range of functional groups with respect to both the alkyne and the quinoline starting materials and the products are easily transformed into useful synthons. Efficient, enantioselective syntheses of the tetrahydroquinoline alkaloids (+)-galipinine, (+)-angustureine, and (-)-cuspareine are reported.

Full text of DOI:10.1002/anie.201507848

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201507848
German Edition: DOI: 10.1002/ange.201507848
Enantioselective Catalysis
Enantioselective Copper-Catalyzed Quinoline Alkynylation
Mukesh Pappoppula, Flavio S. P. Cardoso , B. Owen Garrett, and Aaron Aponick*
Abstract: A highly enantioselective copper-catalyzed alkyny-
lation of quinolinium salts is reported. The reaction employs
StackPhos, a newly developed imidazole-based chiral biaryl
P,N ligand, and copper bromide to effect a three-component
reaction between a quinoline, a terminal alkyne, and ethyl
chloroformate. Under the reaction conditions, the desired
products are delivered in high yields with ee values of up to
98%. The transformation tolerates a wide range of functional
groups with respect to both the alkyne and the quinoline
starting materials and the products are easily transformed into
useful synthons. Efficient, enantioselective syntheses of the
tetrahydroquinoline alkaloids (+)-galipinine, (+)-angustur-
eine, and (À)-cuspareine are reported.
Owing to this importance, a variety of synthetic methods
have been developed to access these molecules in both the
racemic and scalemic sense. This work has been nicely
reviewed in several comprehensive articles.[7] Generally
speaking, some of the most broadly applicable methods of
preparation include the Povarov reaction,[8] organocatalytic
cascade reactions,[9] inverse electron demand aza-Diels–Alder
reactions, and a variety of enantioselective reduction or
hydrogenation reactions of substituted quinolines.[10] Consid-
ering these methods, it seems advantageous from a versatility
standpoint, to stereoselectively introduce substitution at the
quinoline C2-position, as the 2-substituted quinoline sub-
strates required for reductive methods are often expensive or
not commercially available. To this end, nucleophilic addition
to aromatic heterocycles has been demonstrated as a highly
versatile method.[11] These reactions can be conducted under
a variety of conditions, including catalytic systems, and
typically involve an N-alkylation/acylation event to generate
an iminium ion, followed by addition of a nucleophile to
afford the 1,2-adducts.[12]
T
he tetrahydroquinoline (THQ) motif is an important
structural construct found in a myriad of natural products
and biologically active molecules.[1] While many substitution
patterns are known within this broad family of compounds,
a particularly important core constituent is substitution at the
2-position.[2] Examples are highly varied with respect to both
structure and biological activity. Select examples include
martinellic acid (1), a nonpeptide bradykinin antagonist,[2]
torcetrapib (2), a recent hypocholesterolemia drug candi-
date[3] the THQ 3, an acetyl-coA carboxylase 2 inhibitor,[4]
and angustereine, a natural product with activity against
Mycobacterium tuberculosis (Figure 1),[5] among countless
others.[6]
Examination of the tetrahydroquinolines shown in
Figure 1 suggests that a unified approach to this class of
molecules (e.g., 1–4) might be developed from alkynes (5) by
a straightforward functionalization of the carbon–carbon
triple bond (Scheme 1). This approach could be realized
Scheme 1. Enantioselective alkynylation approach to THQ alkaloids.
using an enantioselective alkyne addition reaction to generate
5 from 6. However, despite the significant attention from the
synthetic community described above, an efficient catalytic
enantioselective acetylide addition to quinolines has yet to be
developed. Herein we report a highly enantioselective
reaction that is tolerant of a wide variety of alkyne
substitution and not dependent on the electronic nature of
the quinoline starting material.
As part of a ligand development program exploring the
use of StackPhos (9),[13] we became interested in the question
of how to catalytically install alkynes at the quinoline C2 with
stereocontrol, thus envisioning a new synthetic approach to
martinellic acid (1).[2,14] P, N ligands such as QUINAP (7) and
PINAP (8) have been reported for copper-catalyzed alkyne
addition reactions. Interestingly, while Taylor and Schreiber
reported the use of 7 in the enantioselective addition to
isolated dihydroisoquinolinium salts,[15] satisfactory results
were not obtained in the related reaction of the fully aromatic
Figure 1. Select examples of biologically active tetrahydroquinolines.
[*] M. Pappoppula, F. S. P. Cardoso , B. O. Garrett, Prof. A. Aponick
Department of Chemistry, Center for Heterocyclic Compounds,
University of Florida
Gainesville, FL 32611 (USA)
E-mail: aponick@chem.ufl.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507848.
15202
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 15202 –15206

Angewandte
Chemie
Table 1: Optimization studies.
Entry[a]
Solvent
T [8C]
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
toluene
acetonitrile
CH2Cl2
CH2Cl2
CH2Cl2
RT
RT
RT
RT
0 to RT
-20
18
18
4
4
18
22
50
55
92
90
80
74
n.a.[d]
n.a.[d]
n.a.[d]
93
95
98
quinolines.[16] After ligand screening, Arndtsen and co-work-
ers found 8 to be the best ligand, but the highest selectivity
reported was 84% ee.[16] Axially chiral P, N ligands appear to
be optimal for this application but limited by the current
state-of-the-art. A series of excellent ligands have been
reported by the groups of Brown, Guiry, and Carreira among
others.[17] These ligands share a common structural
CH2Cl2
[a] Reactions run with 1.0 equivalents of 10a, 11a, and ethyl chlorofor-
mate. [b] Yield of isolated product. [c] Determined by HPLC employing
a chiral stationary phase. [d] Racemic StackPhos ligand employed.
DIPEA=diisopropylethylamine.
motif, more specifically, the biaryl system always
Table 2: Substrate scope with respect to alkyne.
consists of two six-membered aromatics that provide
similar binding modes, which may be suboptimal in
certain reactions.[17e] Encouraged by our success with
StackPhos,[13] an axially chiral imidazole-based
P, N ligand, we decided to investigate quinoline
addition reactions as the electron-rich five-mem-
bered biaryl ring system with different dihedral and
bite angles may help overcome this limitation.
Entry Product[a]
ee
Entry Product[a]
ee
[%][b]
[%][b]
To this end, we set out to screen reaction
conditions employing (S)-StackPhos as a ligand in
a copper-catalyzed three component coupling of
quinoline, phenyl acetylene, and ethyl chloroformate
(Table 1). Initial reaction conditions with a racemic
ligand employed toluene as the solvent and, although
somewhat slow, did cleanly afford the desired
product 12a in 50% yield (entry 1). While switching
to acetonitrile had minimal effect (entry 2), the use
of methylene chloride drastically improved the yield
and reaction rate, thus providing 12a in 92% yield in
just 4 hours at room temperature (entry 3). These
enhancements can likely be attributed to the sol-
ubility of the in situ generated quinolinium salt,
which appeared to be readily soluble with dichloro-
methane. With excellent reactivity uncovered, we
turned our attention to selectivity. Much to our
delight, when the nonracemic 9 was employed under
otherwise identical reaction conditions, 12a was
obtained in 93% ee (entry 4). Lowering the temper-
ature increased the enantioselectivity to 95% ee and
98% ee at 08C and À208C, respectively, with
a longer reaction time providing slightly diminished
yields (entries 5 and 6). While the reaction condi-
tions in entry 5 (08C to room temperature) strike
a good balance of yield and selectivity, using lower
temperatures (À208C) do indeed provide increased
selectivity and the conditions in entry 6 were selected
as standard conditions for the reaction.
1
98
96
7
95
92
2[c]
8
9
3[c]
96
91
4[c]
96
90
96
10
11
12
90
90
92
5
6[c]
[a] Yield is that of the isolated product. [b] Determined by HPLC employing a chiral
stationary phase. [c] Reaction temperature=08C to RT. Cbz=benzyloxycarbonyl,
PMP=p-methoxyphenyl.
After establishing optimal reaction conditions, we
explored the reaction scope with respect to the alkyne
nucleophile (Table 2). It seemed particularly important to
survey a variety of alkynes classes (aryl, alkyl, silyl, propio-
late, heteroatom substituted, etc.) as all types of substrates
would be required for THQ alkaloid syntheses. With this goal
Angew. Chem. Int. Ed. 2015, 54, 15202 –15206
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 15203

.
Angewandte
Communications
in mind, the study commenced with aryl alkynes (11b–f)
ranging from electron-rich to electron-deficient and hetero-
aromatics. As can be seen (entries 1–5), a variety of aromatic
groups are well tolerated and provide the alkynylation
products 12b–f with extremely high ee values. Silyl-substi-
tuted alkynes such as trimethylsilylacetylene worked exceed-
ingly well, thus yielding 12g in 96% ee (entry 6) and even
alkyl-substituted substrates perform quite well in the reaction
(entries 7 and 8). Additionally, protected propargyl alcohols
(entry 9) and propargyl amines (entries 10 and 11), as well as
propiolates (entry 12) all smoothly afford the desired prod-
ucts in high enantiomeric excess.
It was also important to understand how the electronic
character of the quinoline affects the reaction and this was
briefly explored. Electron-donating and electron-withdraw-
ing groups were included on 10b and 10c, respectively, and
reactions with 11 were conducted under the standard reaction
conditions (Table 3). As can be seen in each entry, very high
synthetic applications the absolute configuration of the
products needs to be determined. To do so, we applied our
methodology to the synthesis of three tetrahydroquinoline
alkaloids, (+)-galipinine (13),[18] (+)-cuspareine (14),[19] and
(À)-angustureine (4),[5] which are natural products isolated
from the bark of Galipea officinalis Hancock, and have well-
documented absolute configuration and optical rotation data.
With (S)-StackPhos (stereochemistry depicted as in 9), 12b,
12d, and 12i were produced in high ee value with heretofore
unknown absolute stereochemistry (Table 2). For conversion
into the natural products, reduction of the olefin and alkyne
moieties and transformation of the ethyl carbamate into an N-
methyl group was required. This conversion was readily
accomplished in two steps by hydrogenation and reduction of
the carbamate (Scheme 2). In each case, the sign and
magnitude of the rotation nicely corresponded to previously
reported values[20] and allowed the stereochemical assignment
shown in Scheme 2.
Table 3: Substrate scope with respect to quinoline.
Entry
1
Product
Yield [%][a]
66
ee [%][b]
96
2
66
80
97
90
Scheme 2. Assignment of absolute configuration by alkaloid synthesis.
3[c]
The likely mechanistic scenario for this reaction involves
generation of a quinolinium salt followed by acetylide
addition with the chiral (S)-StackPhos complex 15
(Figure 2). A possible rationale for the absolute stereochem-
istry observed using the C1-symmetric complex 15 must rely
on the chiral biaryl axis creating a chiral environment around
the metal center. With biaryl ligands such as BINAP, this is
achieved by arrangement of the phenyl groups in a propeller-
shaped orientation, thus efficiently transmitting the chiral
information towards the reactive center.[21] In StackPhos
complexes, this likely occurs in a similar fashion with the
phenyl groups on the phosphine and the proximal phenyl
group on the imidazole, as seen in 16 (blue phenyl groups),
represented as the quadrant diagram 17. To preserve the
Burgi–Dunitz angle, the addition must occur either via the
quinolinium ion 18 or 19. Considering both the steric
environment and the stereochemistry of the observed prod-
ucts, the addition likely occurs via 19 to minimize steric
interactions and produce the alkyne 20.
4
77
92
[a] Yield of isolated product. [b] Determined by HPLC employing a chiral
stationary phase. [c] Reaction temperature=08C to RT. TMS=trime-
thylsilyl.
ee values were achieved. While electron-deficient quinolines
afforded slightly lower chemical yields, electron-rich quino-
lines smoothly provided the products, thus further expanding
the reaction scope.
This broad substrate scope is, to the best of our knowl-
edge, unknown in catalytic enantioselective alkynylation
reactions. It is particularly noteworthy that alkyl- and
propargyl-substituted alkynes function well in the reaction.
While compounds such as 12g could be desilylated and
further functionalized, this methodology should obviate the
need for such manipulations and enable highly convergent
synthetic strategies to tetrahydroquinolines.[14] However, for
In conclusion, we have developed a new catalytic enan-
tioselective method for the dearomative alkynylation of
15204 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 15202 –15206

Angewandte
Chemie
towards martinella alkaloids see: c) M. Nyerges, Heterocycles
2004, 63, 1685 – 1712; d) C. J. Lovely, V. Badarinarayana, Curr.
Org. Chem. 2008, 12, 1431 – 1453.
[3] a) J. A. Sikorski, J. Med. Chem. 2006, 49, 1 – 22; b) M. E.
Brousseau, E. J. Schaefer, M. L. Wolfe, L. T. Bloedon, A. G.
Digenio, R. W. Clark, J. P. Mancuso, D. J. Rader, N. Engl. J. Med.
2004, 350, 1505 – 1515; c) M. Pal, Tetrahedron 2009, 65, 433 – 447;
d) M. DePasquale, G. Cadelina, D. Knight, W. Loging, S. Winter,
E. Blasi, D. Perry, J. Keiser, Drug Dev. Res. 2009, 70, 35 – 48.
[4] D. W. Barnes, G. R. Bebernitz, K. Clairmont, S. L. Cohen, R. E.
Damon, R. F. Day, S. K. Dodd, C. Gaul, H. B. Gulgeze
Efthymiou, M. Jain, R. G. Karki, L. C. Kirman, K. Lin, J. Y. C.
Mao, T. J. Patel, B. K. Raymer, L. Su, Bicyclic acetyl-coa
carboxylase inhibitors and uses thereof, U.S. Patent 8697739
B2, April 15, 2014.
[5] a) I. Jacquemond-Collet, S. Hannedouche, N. Fabre, I. Fouraste,
C. Moulis, Phytochemistry 1999, 51, 1167 – 1169; b) I. Jacque-
mond-Collet, F. Benoit-Vical, M. A. Valentin, E. Stanislas, M.
Mallie, I. Fouraste, Planta Med. 2002, 68, 68 – 69; c) Y. Garg, S.
Gahalawat, S. K. Pandey, RSC Adv. 2015, 5, 38846 – 38850, and
references cited therein.
Figure 2. Working stereochemical model. Im=imidazolyl.
[6] For reviews on the chemistry of quinoline, quinazoline, and
acridone alkaloids, see: a) J. P. Michael, Nat. Prod. Rep. 2008, 25,
166 – 187; b) J. P. Michael, Nat. Prod. Rep. 2007, 24, 223 – 246;
c) J. P. Michael, Nat. Prod. Rep. 2005, 22, 627 – 646; d) J. P.
Michael, Nat. Prod. Rep. 2004, 21, 650 – 668; e) J. P. Michael, Nat.
Prod. Rep. 2003, 20, 476 – 493; f) J. P. Michael, Nat. Prod. Rep.
2001, 18, 543 – 559; g) J. P. Michael, Nat. Prod. Rep. 2000, 17,
603 – 620 and other previous reports in this series.
[7] a) V. Sridharan, P. A. Suryavanshi, J. C. Menendez, Chem. Rev.
2011, 111, 7157 – 7259; b) A. R. Katritzky, S. Rachwal, B.
Rachwal, Tetrahedron 1996, 52, 15031 – 15070; c) B. Nammal-
war, R. Bunce, Molecules 2014, 19, 204 – 232; d) G. D. MuÇoz,
G. B. Dudley, Org. Prep. Proced. Int. 2015, 47, 179 – 206; e) K.
Vladimir, P. Alirio, E. Claude, V. Alexei, J. Heterocycl. Chem.
1998, 35, 761 – 785; f) M. Fochi, L. Caruana, L. Bernardi,
Synthesis 2014, 46, 135 – 157.
quinolines enabled by use of the ligand StackPhos. The
reaction is high yielding, operationally simple, and delivers
the products in high enantiomeric excess under mild reaction
conditions. The absolute configuration of the products was
assigned by conversion into galipea alkaloids with known
optical rotation, and an extremely broad range of substrates
with regard to both the alkyne and quinoline was demon-
strated. This should allow application of the method in
complex molecule synthesis, which is underway in our
laboratory and will be reported in due course.
Acknowledgements
[8] a) F. Shi, G. J. Xing, R. Y. Zhu, W. Tan, S. Tu, Org. Lett. 2013, 15,
128 – 131; b) V. V. Kouznetsov, J. S. B. Forero, D. F. A. Torres,
Tetrahedron Lett. 2008, 49, 5855 – 5857; c) V. V. Kouznetsov,
D. R. M. Arenas, F. Arvelo, J. S. B. Forero, F. Sojo, A. Munoz,
Lett. Drug Des. Discovery 2010, 7, 632 – 639; d) B. Gerard, M. W.
OꢀShea, E. Donckele, S. Kesavan, L. B. Akella, H. Xu, E. N.
Jacobsen, L. A. Marcaurelle, ACS Comb. Sci. 2012, 14, 621 – 630.
[9] a) T. Akiyama, H. Morita, K. Fuchibe, J. Am. Chem. Soc. 2006,
128, 13070 – 13071; b) H. Liu, G. Dagousset, G. Masson, P.
Retailleau, J. Zhu, J. Am. Chem. Soc. 2009, 131, 4598 – 4599;
c) G. Dagousset, J. Zhu, G. Masson, J. Am. Chem. Soc. 2011, 133,
14804 – 14813; d) F. Shi, G. J. Xing, Z. L. Tao, S. W. Luo, S. J. Tu,
L. J. Gong, J. Org. Chem. 2012, 77, 6970 – 6979; e) L. He, M.
Bekkaye, P. Retailleau, G. Masson, Org. Lett. 2012, 14, 3158 –
3161; f) K. L. Jensen, G. Dickmeiss, B. S. Donslund, P. H.
Poulsen, K. A. Jørgensen, Org. Lett. 2011, 13, 3678 – 3681;
g) G. Bergonzini, L. Gramigna, A. Mazzanti, M. Fochi, L.
Bernardi, A. Ricci, Chem. Commun. 2010, 46, 327 – 329; h) H.
Xu, S. J. Zuend, M. G. Woll, Y. Tao, E. N. Jacobsen, Science 2010,
327, 986 – 990; i) G. Dagousset, P. Retailleau, G. Masson, J. Zhu,
Chem. Eur. J. 2012, 18, 5869 – 5873; j) J. H. Lin, G. Zong, R. B.
Du, J. C. Xiao, S. Liu, Chem. Commun. 2012, 48, 7738 – 7740.
[10] a) W. B. Wang, S. M. Lu, P. Y. Yang, X. W. Han, Y. G. Zhou, J.
Am. Chem. Soc. 2003, 125, 10536 – 10537; b) S. M. Lu, X. W.
Han, Y. G. Zhou, Adv. Synth. Catal. 2004, 346, 909 – 912; c) P. Y.
Yang, Y. G. Zhou, Tetrahedron: Asymmetry 2004, 15, 1145 –
1149; d) L. Xu, K. H. Lam, J. Ji, J. Wu, Q.-H. Fan, W.-H. Lo,
A. S. C. An, Chem. Commun. 2005, 1390 – 1392.
We thank the ACS PRF (53964-ND1) and the National
Science Foundation (CHE-1362498) for their generous sup-
port of our programs. B.O.G thanks the University of Florida
for a Graduate Research Fellowship
Keywords: alkynes · copper · heterocycles · ligand design ·
synthetic methods
How to cite: Angew. Chem. Int. Ed. 2015, 54, 15202–15206
Angew. Chem. 2015, 127, 15417–15421
[1] a) A. Kumar, S. Srivastava, G. Gupta, V. Chaturvedi, S. Sinha, R.
Srivastava, ACS Comb. Sci. 2011, 13, 65 – 71; b) E. H. Demont,
N. S. Garton, R. L. M. Gosmini, T. G. C. Hayhow, J. Seal, D. M.
Wilson, M. D. Woodrow, Tetrahydroquinolines derivatives and
their pharmaceutical use, Europe Patent PCT Int. Appl.
WO2011054841A1, 2011; c) Z. X. Jia, Y. C. Luo, P. F. Xu, Org.
Lett. 2011, 13, 832 – 835; d) G. Satyanarayana, D. Pflasterer, G.
Helmchen, Eur. J. Org. Chem. 2011, 6877 – 6886 and references
cited therein; e) P. M. Dewick, Medicinal Natural Products—A
Biosynthetic Approach, 2nd ed., Wiley, Chichester, 2001,
pp. 291 – 398.
[2] a) K. M. Witherup, R. W. Ransom, A. C. Graham, A. M. Ber-
nard, M. J. Salvatore, W. C. Lumma, P. S. Anderson, S. M.
Pitzenberger, S. L. Varga, J. Am. Chem. Soc. 1995, 117, 6682 –
6685; b) S. G. Davies, A. M. Fletcher, J. A. Lee, T. J. A. Lorkin,
P. M. Roberts, J. E. Thomson, Org. Lett. 2013, 15, 2050 – 2053 and
references cited therein. For reviews on synthetic studies
[11] a) D. L. Comins, Y. Zhang, J. Am. Chem. Soc. 1996, 118, 12248 –
12249; b) A. B. Charette, M. Grenon, A. Lemire, M. Pourashraf,
Angew. Chem. Int. Ed. 2015, 54, 15202 –15206
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 15205

.
Angewandte
Communications
J. Martel, J. Am. Chem. Soc. 2001, 123, 11829 – 11830; c) D. L.
Comins, S. P. Joseph, Comprehensive Heterocyclic Chemistry II,
Elsevier, Oxford, 1996, p. 37; d) D. L. Comins, S. OꢀConnor, Adv.
Heterocycl. Chem. 1988, 44, 199 – 267; e) W. Sliwa, Heterocycles
1986, 24, 181 – 219; f) J. S. Yadav, B. V. S. Reddy, M. Sreenivas, K.
Sathaiah, Tetrahedron Lett. 2005, 46, 8905 – 8908; g) S. Zhankui,
Y. Shouyun, D. Zuoding, D. Ma, J. Am. Chem. Soc. 2007, 129,
9300 – 9301; h) A. G. Myers, N. J. Tom, M. E. Fraley, S. B. Cohen,
D. J. Mader, J. Am. Chem. Soc. 1997, 119, 6072 – 6094. For recent
articles on alkynylation of aromatic oxygen heterocycles, see:
i) P. Maity, H. D. Srinivas, M. P. Watson, J. Am. Chem. Soc. 2011,
133, 17142 – 17145; j) P. Maity, H. D. Srinivas, G. P. A. Yap, M. P.
Watson, J. Org. Chem. 2015, 80, 4003 – 4016 and references cited
therein.
[14] For a synthesis of martinellic acid using this approach as a key
step, see: M. Pappoppula, A. Aponick, Angew. Chem. Int. Ed.
2015, 54, 10.1002/anie.201507849; Angew. Chem. 2015, 127,
10.1002/ange.201507849.
[15] A. M. Taylor, S. L. Schreiber, Org. Lett. 2006, 8, 143 – 146.
[16] D. A. Black, R. E. Beveridge, B. A. Arndtsen, J. Org. Chem.
2008, 73, 1906 – 1910.
[17] a) N. W. Alcock, J. M. Brown, D. I. Hulmes, Tetrahedron:
Asymmetry 1993, 4, 743 – 756; b) T. F. Knçpfel, P. Aschwanden,
T. Ichikawa, T. Watanabe, E. M. Carreira, Angew. Chem. Int. Ed.
2004, 43, 5971 – 5973; Angew. Chem. 2004, 116, 6097 – 6099; c) E.
Fernµndez, P. J. Guiry, K. P. T. Connole, J. M. Brown, J. Org.
Chem. 2014, 79, 5391 – 5400; d) M. P. Carroll, P. J. Guiry, Chem.
Soc. Rev. 2014, 43, 819 – 833; e) M. P. Carroll, P. J. Guiry, J. M.
Brown, Org. Biomol. Chem. 2013, 11, 4591 – 4601.
[18] J. H. Rakotoson, N. Fabre, I. Jacquemond-Collet, S. Hannedou-
che, I. Fouraste, C. Moulis, Planta Med. 1998, 64, 762 – 763.
[19] P. J. Houghton, T. Z. Woldemariam, Y. Watanabe, M. Yates,
Planta Med. 1999, 65, 250 – 254.
[12] a) M. Takamura, K. Funabashi, M. Kanai, M. Shibasaki, J. Am.
Chem. Soc. 2000, 122, 6327 – 6328; b) M. Takamura, K. Funaba-
shi, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2001, 123, 6801 –
6808; c) L. Cointeaux, A. Alexakis, Tetrahedron: Asymmetry
2005, 16, 925; d) Y. Yamaoka, H. Miyabe, Y. Takemoto, J. Am.
Chem. Soc. 2007, 129, 6686 – 6687; e) J. D. Shields, D. T. Ahne-
man, T. J. A. Graham, A. G. Doyle, Org. Lett. 2014, 16, 142 – 145;
f) M. S. Taylor, N. Tokunaga, E. N. Jacobsen, Angew. Chem. Int.
Ed. 2005, 44, 6700 – 6704; Angew. Chem. 2005, 117, 6858 – 6862
and references cited therein.
[20] See the Supporting Information for full details.
[21] R. Noyori, M. Kitamura, T. Ohkuma, Proc. Natl. Acad. Sci. USA
2004, 101, 5356.
[13] F. S. P. Cardoso, K. A. Abboud, A. Aponick, J. Am. Chem. Soc.
2013, 135, 14548 – 14551.
Received: August 21, 2015
Published online: October 30, 2015
15206 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 15202 –15206