Activity-Directed Synthesis with Intermolecular Reactions: Development of a Fragment into a Range of Androgen Receptor Agonists

Article abstract of DOI:10.1002/anie.201506944

Activity-directed synthesis (ADS), a novel discovery approach in which bioactive molecules emerge in parallel with associated syntheses, was exploited to develop a weakly binding fragment into novel androgen receptor agonists. Harnessing promiscuous intermolecular reactions of carbenoid compounds enabled highly efficient exploration of chemical space. Four substrates were prepared, yet exploited in 326 reactions to explore diverse chemical space; guided by bioactivity alone, the products of just nine of the reactions were purified to reveal diverse novel agonists with up to 125-fold improved activity. Remarkably, one agonist stemmed from a novel enantioselective transformation; this is the first time that an asymmetric reaction has been discovered solely on the basis of the biological activity of the product. It was shown that ADS is a significant addition to the lead generation toolkit, enabling the efficient and rapid discovery of novel, yet synthetically accessible, bioactive chemotypes.

Full text of DOI:10.1002/anie.201506944

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201506944
German Edition: DOI: 10.1002/ange.201506944
Lead Generation
Activity-Directed Synthesis with Intermolecular
Reactions: Development of a Fragment into a Range of
Androgen Receptor Agonists
George Karageorgis, Mark Dow, Anthony Aimon, Stuart Warriner,* and
Adam Nelson*
Angewandte
Chemie
13538
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 13538 –13544

Angewandte
Chemie
Abstract: Activity-directed synthesis (ADS), a novel discovery
approach in which bioactive molecules emerge in parallel with
associated syntheses, was exploited to develop a weakly bind-
ing fragment into novel androgen receptor agonists. Harness-
ing promiscuous intermolecular reactions of carbenoid com-
pounds enabled highly efficient exploration of chemical space.
Four substrates were prepared, yet exploited in 326 reactions to
explore diverse chemical space; guided by bioactivity alone, the
products of just nine of the reactions were purified to reveal
diverse novel agonists with up to 125-fold improved activity.
Remarkably, one agonist stemmed from a novel enantioselec-
tive transformation; this is the first time that an asymmetric
reaction has been discovered solely on the basis of the
biological activity of the product. It was shown that ADS is
a significant addition to the lead generation toolkit, enabling
the efficient and rapid discovery of novel, yet synthetically
accessible, bioactive chemotypes.
ure 1A). However, in this validation work, reliance on
intramolecular reactions meant that the structural diversity
of possible products was largely encoded by the substrates
used. We envisaged that ADS would be enhanced by
exploiting intermolecular reactions as the range of possible
T
he discovery of biologically active molecules typically
involves the synthesis and testing of many compounds, each
individually crafted to optimize the arrangement of function-
ality. Such workflows tend to induce scientists to exploit
a limited palette[1–3] of reliable chemical transformations. As
a direct consequence, designed arrays comprise compounds
that are readily prepared, tending to limit diversity and,
potentially, to focus on unproductive areas of chemical space.
We recently introduced activity-directed synthesis
(ADS),[4] a novel discovery approach in which bioactive
small molecules emerge together with associated syntheses.
ADS is iterative, borrowing concepts from biosynthetic
pathway evolution.[5] In each round, the components of
diverse reaction arrays are widely varied; by exploiting
reactions with many possible outcomes, diverse chemical
space is explored. After catalyst removal, the crude product
mixtures are screened, and reactions that yield active
products inform subsequent reaction array design. Only
reactions that yield bioactive product mixtures are ever
scaled up to enable the characterization and identification of
the responsible products. ADS is function-driven,[6] focusing
resources on reactions that yield bioactive products.
Figure 1. Discovery of novel androgen receptor agonists by ADS.
A) Discovery of novel chemotypes enabled by intramolecular metal-
catalyzed carbenoid reactions.[4] B) Core fragment for elaboration.
C) Envisaged exploitation of intermolecular metal-catalyzed reactions
to drive productive fragment elaboration.
reaction outcomes—and thus the chemical space explored—
would be dramatically increased. It was proposed to exploit
ADS to drive the productive elaboration of the 4-cyano-3-
trifluoromethylphenylacetamide fragment found in many
modulators of AR.[7] Although the core motif displayed
only modest agonism (1; EC50 = 92 Æ 13 mm; EC50 = concen-
tration of ligand needed to induce the half-maximal observed
effect), we reasoned that intermolecular reactions of related
diazo acetamides could help identify productive strategies for
fragment growth (Figure 1C).[8–10]
We recently harnessed intramolecular metal-catalyzed
carbenoid reactions in the ADS of androgen receptor (AR)
agonists. ADS drove the discovery of both novel ligands—
based on scaffolds with no annotated activity against the
receptor—and associated high-yielding syntheses (Fig-
[*] Dr. G. Karageorgis, Dr. M. Dow, Dr. A. Aimon, Dr. S. Warriner,
Prof. A. Nelson
The a-diazo amides 2–5 incorporate the 4-cyano-3-tri-
fluoromethylphenyl fragment and bear a group (N-methyl or
N-cyclopropyl) expected to suppress intramolecular reac-
tions.[11] In round one, we performed an array of 192 reactions
randomly chosen from 480 possible combinations of four
substrates (2–5), ten co-substrates (6a–6i or no co-substrate),
six catalysts, and two solvents (CH2Cl2 or toluene; Fig-
ure 2A). The co-substrates were selected on the basis of
diversity of possible intermolecular reactions with metal
carbenoids[12–14] and the catalysts on the basis of their diverse
reactivity. We initially showed that the diazo substrates and
School of Chemistry and Astbury Centre for Structural Molecular
Biology, University of Leeds
Leeds, LS2 9JT (UK)
E-mail: s.l.warriner@leeds.ac.uk
a.s.nelson@leeds.ac.uk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506944.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
Angew. Chem. Int. Ed. 2015, 54, 13538 –13544
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 13539

.
Angewandte
Communications
significant exploration of chemical space, we showed that
a random selection of reactions yielded several products,
including, in general, those of both inter- and intramolecular
reactions (see the Supporting Information). After 48 h, the
crude reaction mixtures were scavenged to remove metal
contaminants, evaporated, and assayed for agonism of AR
(total concentration of products: 10 mm in 1% DMSO in
pH 7.5 aqueous buffer) using an established assay.[15]
Remarkably, only two of the 192 reactions yielded
products that were significantly active (Figure 2B; see also
the Supporting Information): both reactions involved diazo
substrate 3, [Rh2{(S)-DOSP}4], and CH2Cl2, together with
either cyclohexene (6a) or indole (6 f) as the co-substrate.
These data suggest that the fate of 3—both with 6a and 6 f—
depends critically on the specific catalyst and solvent used,
which determine whether the substrate is steered towards
active products. The lack of activity without a co-substrate
strongly suggests that the active products are derived from
intermolecular reactions. At this stage, no products were
isolated or identified; instead, the most promising reactions
informed subsequent reaction array design.
Round two focused on N-methyl diazo substrate 3 and its
closely-related N-cyclopropyl variant 5, the co-substrates
cyclohexene (6a) and indole (6 f) as well as structurally
related compounds, and rhodium carboxylate catalysts. The
86 reactions were randomly chosen from 360 possible
combinations of the two substrates, 18 co-substrates, five
catalysts, and two solvents (CH2Cl2 or toluene; Figure 3A).
To drive the development of efficient activity-directed
syntheses, the crude product mixtures were assayed at two-
fold lower total product concentration (5 mm). Five promising
combinations of substrate and co-substrate were identified:
N-methyl diazo substrate 3 with dihydronaphthalene (6m),
dihydropyran (6o), or indene (6r), and N-cyclopropyl diazo
substrate 5 with indole (6 f) or 7-azaindole (6n; see Figure 3B
and the Supporting Information). All of these combinations
were superior to the most promising combinations from
round one.
In round three, substrate 3 was combined with all possible
combinations of 12 co-substrates (6a, 6 f, 6m, 6n, 6o, 6r, and
six structurally related compounds) and four catalysts in
CH2Cl2 (Figure 4A). After scavenging and evaporating, the
crude product mixtures were assayed at five-fold lower total
product concentration (1 mm) to increase the selection
pressure (Figure 4B). With co-substrate 6e’, the substrate
yielded active product mixtures with all four catalysts, with
the highest activity for [Rh2(OAc)4]. However, with dihydro-
pyran 6 f’, significant activity was only observed when
[Rh2{(R)-DOSP}4] had been used; remarkably, no significant
activity was observed with the enantiomeric catalyst, suggest-
ing that the most active product is chiral and that
[Rh2{(R)-DOSP}4] catalyzes the formation of the more
active enantiomer.
Figure 2. Round one of ADS. A) Substrates, co-substrates, and cata-
lysts used. B) Activities of product mixtures derived from substrate 3
relative to 5 mm testosterone. Reactions involved combinations of
substrates, co-substrates, catalysts (represented by different colors;
[Rh2{(S)-DOSP}4] black), and solvents (CH2Cl2 squares; toluene cir-
cles). Experiments were performed in duplicate. See the Supporting
Information for the activities of product mixtures derived from
substrates 2, 4, and 5.
To understand the basis for the emergence of bioactive
structures and associated synthetic routes, prioritized reac-
tions were scaled up from all three rounds of ADS. The
reactions were performed on fifty-fold larger scale; the
products were purified by column chromatography and their
dose-dependent activities determined (Table 1). In all but one
co-substrates were all inactive in our assay (see the Support-
ing Information). The array was performed in 96-well plates
with reactions involving a diazo substrate (100 mm), a co-
substrate (1.0m), and a catalyst (1 mm). To demonstrate
13540 www.angewandte.org
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 13538 –13544

Angewandte
Chemie
Figure 4. Round three of ADS. A) Substrate, co-substrates, and cata-
lysts used. B) Activities of product mixtures relative to 5 mm testoster-
one for combinations of co-substrates and catalysts (represented by
different colors: [Rh2{(R)-DOSP}4] green; [Rh2{(S)-DOSP}4] black;
[Rh2(OAc)4] red; [Rh2(esp)2] dark yellow). The blue diamond highlights
the activity obtained with the enantiomer of the most promising
catalyst with co-substrate 6 f’. Experiments were performed in dupli-
cate.
However, the combination of 5, 6n, and [Rh2(OAc)4] (from
round two) gave the a,b-unsaturated g-lactam 9 in low (18%)
yield together with recovered starting material 5 (67%): here,
the observed activity must have stemmed from g-lactam 9
(EC50 = 790 Æ 60 nm) rather than the recovered starting
material 5 (EC50 > 500 mm). Crucially, in each case, we were
confident that the product that was responsible for the
observed activity had been identified.
Figure 3. Round two of ADS. A) Substrates, co-substrates, and cata-
lysts used. B) Activities of product mixtures derived from substrates 3
(top) and 5 (bottom) relative to 5 mm testosterone for combinations of
co-substrates, catalysts (represented by different colors: [Rh2{(S)-
DOSP}4] black; [Rh2(esp)2] dark yellow; [Rh2(OAc)4] red), and solvents
(CH2Cl2 squares; toluene circles). Experiments were performed in
duplicate.
In round one, two reactions had yielded product mixtures
with significant activity (Figure 5). In each case, the bioactive
product was formed in an intermolecular reaction. Amide 7
À
was the product of C H insertion into the 3-position of indole
(6 f), whereas amide 8 was formed by cyclopropanation of
cyclohexene (6a). In the other 190 reactions, the product
mixtures did not have biological activity that was detectable
in the assay. Analysis of a selection of reactions in round one
case, a product whose activity accounted for that observed in
the original array was obtained in good (71–82%) yield.
Angew. Chem. Int. Ed. 2015, 54, 13538 –13544
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 13541

.
Angewandte
Communications
Table 1: Yields and activities of the purified products of reactions that
were scaled up.
had revealed that a wide range of products had been
produced: thus, significant chemical space had been
explored—yet discarded—in the search for bioactive prod-
ucts.
[d]
Round[a] Reaction conditions[b]
Product
(yield)[c]
EC50
In round two, the reaction array had been informed by the
reactions that yielded amides 7 and 8. Thus, success with
cyclohexene (6a) led to the inclusion of dihydronaphthalene
(6m), dihydropyran (6o), and indene (6r) as alternative co-
substrates. In each case, screening at lower total product
concentrations (5 mm) had enabled the identification of
alternative cyclopropanation products (10–12) with signifi-
cantly higher biological activities than 8. Interestingly, with
substrate 5, the introduction of indole (6 f) or 7-azaindole
(6n) changed the outcome of the reaction. Rather than acting
as co-substrates, these additives steered the reaction towards
1
1
3, 6 f, [Rh2{(S)-DOSP}4]
3, 6a, [Rh2{(S)-DOSP}4]
7
8.8Æ0.7 mm
7.3Æ0.2 mm
(80%)[e]
8
(71%)[e]
2[f]
2
5, 6n, [Rh2(OAc)4]
9
790Æ60 nm[h]
4.7Æ0.1 mm
4.9Æ0.1 mm
3.8Æ0.2 mm
(18%)[g]
10
3, 6o, [Rh2{(S)-DOSP}4]
(82%)[e]
2
3, 6m, [Rh2{(S)-DOSP}4] 11
(76%)[e]
12
(73%)[e]
2
3, 6r, [Rh2(esp)2]
the rearranged product (9)[16,17] of an intramolecular C H
À
insertion: These reactions were discovered because product 9
is a potent partial agonist.
3
3
3, 6 f’, [Rh2{(R)-DOSP}4] (S)-13
(73%; 56% ee)[e]
14
(75%)[e]
1.1Æ0.1 mm[i]
730Æ30 nm
In round three, dihydropyran 6 f’ and benzopyran 6e’ had
been included as co-substrates on the basis of their similarity
to dihydropyran (6o) and dihydronaphthalene (6m). The
additional functional groups in both 6e’ and 6 f’ offer
opportunities for different types of intermolecular reactions.
In both cases, these new possibilities were exploited in the
formation of more bioactive products: amide 13, which is the
3, 6e’, Rh2(OAc)4
[a] Round of ADS. [b] Co-substrate 6 (10 equiv), catalyst (1 mol%),
CH2Cl2. [c] Yield of purified product (see Figure 5 for the structures).
[d] Dose-dependent activity of the purified product. [e] Additional
products were also isolated whose activity was not significant (see the
Supporting Information). [f] See the Supporting Information for the
products obtained with 6 f in place of 6n. [g] Substrate 5 was recovered
in 67% yield. [h] Partial agonist (see the Supporting Information).
[i] Activity of the purified reaction product that had 56% ee.
[18,19]
À
product of an O H insertion,
and oxazole 14, which is
formed by reaction with the nitrile moiety of 6e’.[20]
Our retrospective analysis revealed two mechanisms by
which activity-directed syntheses can develop. First, by
varying the specific catalyst and solvent used, the yield of
the bioactive products may be optimized. As an example, in
round three, the activity of the product mixtures derived from
substrate
3 and co-substrate 6e’ varied widely. With
[Rh2(OAc)4] as the catalyst, oxazole 14 (EC50 = 730 Æ 30 nm)
was formed in 75% yield; however, with other catalysts, the
observed activity was lower, presumably as a result of 14
being produced in a lower yield. The choice of total product
concentration in the assay is crucial as, to optimize the yield of
a bioactive product, it is important to screen at concentrations
that do not saturate the target protein.
Second, ADS can be used to optimize the structure of
bioactive products. For example, the cyclopropanes 10, 11,
and 12, which were formed in round two, all had significantly
higher activities than cyclopropane 8, which was formed in
round one. Furthermore, introducing reactants with new
functional groups can offer new opportunities for forming
more active products. For example, amide 13 and oxazole 14
were both formed in types of reaction that were not possible
in round two. Such possibilities can expand the chemical space
that is explored during the optimization process, enabling the
emergence of new synthetically accessible bioactive chemo-
types. The emergence of oxazole 14 was particularly interest-
ing: Such heterocycles are widely exploited as peptidomi-
metics in medicinal chemistry.[21–24] In future ADS campaigns,
the inclusion of more functionalized substrates in round one
may increase the diversity of the explored chemical space
from the outset. It remains to be seen whether other
promiscuous reaction classes can be configured to support
the discovery of novel bioactive chemotypes using ADS.
Figure 5. Evolution of bioactive structures driven by ADS. The arrows
indicate the relationship between the bioactive compounds formed in
prioritized reactions in consecutive rounds. Ar=4-cyano-3-trifluorome-
thylphenyl.
13542 www.angewandte.org
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 13538 –13544

Angewandte
Chemie
In round three, the activity of the product mixture derived
from substrate 3 and racemic dihydropyran 6 f’ was dependent
upon the enantiomer of the [Rh2(DOSP)4] catalyst used.
HPLC analysis on a chiral stationary phase showed that
kinetic resolution of the dihydropyran had occurred to give
product 13 in 56% ee. To determine the absolute config-
uration and activity of both enantiomers, we prepared[25,26]
samples of both enantiomers of 6 f’ and hence 13: It was found
that (S)-13 was approximately five-fold more active than (R)-
13 [(S)-13: EC50 = 860 Æ 40 nm; (R)-13: EC50 = 4.5 Æ 0.2 mm]
and had indeed been selectively formed in the kinetic
resolution of dihydropyran 6 f’ catalyzed by [Rh2{(R)-
DOSP}4]. To the best of our knowledge, enantioselective
approach also led to the discovery of a novel asymmetric
transformation on the basis of the biological activity of the
product alone. Overall, ADS is a significant addition to the
lead generation toolkit, enabling the rapid discovery of novel,
yet synthetically accessible, bioactive small molecules.
Acknowledgements
We acknowledge the University of Leeds and the EPSRC
(EP/K039292/1) for funding, and Dr. Richard Foster for
useful discussions.
À
O H insertion reactions of rhodium carbenoids have not
Keywords: activity-directed synthesis · agonists ·
bioactive molecules · carbenoids · reaction discovery
previously been described:[27] Hence, ADS has enabled
a novel asymmetric transformation to be identified for the
first time solely on the basis of the biological activity of
a product.
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13538–13544
Angew. Chem. 2015, 127, 13742–13748
To demonstrate the value of ADS in lead generation, we
performed a limited SAR study inspired by amide 13 and
oxazole 14. A range of 17 analogues was prepared by Rh-
catalyzed reactions of a-diazo amide 3 with either alcohols or
nitriles. The activity of the analogues spanned well over two
orders of magnitude in both series, allowing key structural
features to be identified (Figure 6; see also the Supporting
Information, Table S2). Therefore, ADS can enable the
discovery of bioactive chemotypes that provide options for
subsequent lead optimization.
[1] S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451 –
3479.
[2] W. P. Walters, J. Green, J. R. Weiss, M. A. Murcko, J. Med. Chem.
2011, 54, 6405 – 6416.
[3] T. W. J. Cooper, I. B. Campbell, S. J. F. Macdonald, Angew.
Chem. Int. Ed. 2010, 49, 8082 – 8091; Angew. Chem. 2010, 122,
8258 – 8267.
[4] G. Karageorgis, S. Warriner, A. Nelson, Nat. Chem. 2014, 6, 872 –
876.
[5] R. A. Maplestone, M. J. Stone, D. H. Williams, Gene 1992, 115,
151 – 157.
[6] For another recent function-driven approach, see: Y.-L. Huang,
J. W. Bode, Nat. Chem. 2014, 6, 877 – 884.
[7] a) W. Gao, C. E. Bohl, J. T. Dalton, Chem. Rev. 2005, 105, 3352 –
3370; b) H. Fang, W. Tong, W. S. Branham, C. L. Moland, S. L.
Dial, H. Hong, Q. Xie, R. Perkins, W. Owens, D. M. Sheehan,
Chem. Res. Toxicol. 2003, 16, 1338 – 1358.
[8] M. Congreve, G. Chessari, D. Tisi, A. J. Woodhead, J. Med.
Chem. 2008, 51, 3661 – 3680.
[9] R. A. E. Carr, M. Congreve, C. W. Murray, D. C. Rees, Drug
Discovery Today 2005, 10, 987 – 992.
[10] C. W. Murray, M. L. Verdonk, D. C. Rees, Trends Pharmacol.
Sci. 2012, 33, 224 – 232.
[11] H. M. L. Davies, R. E. J. Beckwith, Chem. Rev. 2003, 103, 2861 –
2904.
[12] H. M. L. Davies, D. Morton, Chem. Soc. Rev. 2011, 40, 1857 –
1869.
Figure 6. Structures of the most active analogues and summary of the
limited SAR study. See the Supporting Information for information on
analogues 21–37. Ar=4-cyano-3-trifluoromethylphenyl.
[13] M. P. Doyle, R. Duffy, M. Ratnikov, L. Zhou, Chem. Rev. 2010,
110, 704 – 724.
[14] A. Padwa, D. J. Austin, J. Org. Chem. 1996, 61, 63 – 72.
[15] M. S. Ozers, B. D. Marks, K. Gowda, K. R. Kupcho, K. M. Ervin,
T. De Rosier, N. Qadir, H. C. Eliason, S. M. Riddle, M. S.
Shekhani, Biochemistry 2007, 46, 683 – 695.
[16] E. Carlson, J. Haner, M. McKee, W. Tam, Org. Lett. 2014, 16,
1776 – 1779.
[17] The rearrangement is reminescent of those of some substituted
bicyclo[3.1.0]hexan-3-ones; see: H. E. Zimmerman, R. J. Paste-
ris, J. Org. Chem. 1980, 45, 4876 – 4891.
[18] E. Aller, D. S. Brown, G. G. Cox, D. J. Miller, C. J. Moody, J. Org.
Chem. 1995, 60, 4449 – 4460.
[19] G. G. Cox, C. J. Moody, D. J. Austin, A. Padwa, Tetrahedron
1993, 49, 5109 – 5126.
[20] C. J. Moody, K. J. Doyle, Prog. Heterocycl. Chem. 1997, 9, 1 – 16.
[21] M. Falorni, G. Giacomelli, A. Porcheddu, G. Dettori, Eur. J. Org.
Chem. 2000, 3217 – 3222.
In conclusion, intermolecular reactions add significant
value to ADS by dramatically expanding the range of reaction
outcomes. By exploiting intermolecular reactions of diazo
acetamides, ADS enabled the rapid elaboration of a fragment
(1) to produce sub-micromolar agonists, all based on chemo-
types with no previously reported activity against AR. In
total, just four substrates were prepared, yet exploited in
a total of 326 reactions to explore diverse chemical space;
however, the products of just nine reactions were purified to
reveal a range of novel bioactive ligands. In just three rounds
of ADS, the activity of the fragment was improved by up to
a factor of 125. Retrospective analysis showed that ADS had
enabled the efficient exploration of chemical space and
facilitated the identification of increasingly active AR ago-
nists, together with associated syntheses. Remarkably, the
[22] R. M. J. Liskamp, Recl. Trav. Chim. Pays-Bas 1994, 113, 1 – 19.
Angew. Chem. Int. Ed. 2015, 54, 13538 –13544
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 13543

.
Angewandte
Communications
À
[23] E. Biron, J. Chatterjee, H. Kessler, Org. Lett. 2006, 8, 2417 –
2420.
[24] A. Plant, F. Stieber, J. Scherkenbeck, P. Lçsel, H. Dyker, Org.
Lett. 2001, 3, 3427 – 3430.
[27] For some examples of enantioselective O H insertions catalyzed
by other metals, see: A. Ford, H. Miel, A. Ring, C. N. Slattery,
A. R. Maguire, M. A. McKervey, Chem. Rev. 2015, 115, DOI:
10.1021/acs.chemrev.5b00121.
[25] P. G. Jagtap, Z. Chen, K. Koppetsch, E. Piro, P. Fronce, G. J.
Southan, K.-N. Klotz, Tetrahedron Lett. 2009, 50, 2693 – 2696.
[26] S.-K. Kang, J.-H. Jeon, T. Yamaguchi, R.-K. Hong, B.-S. Ko,
Tetrahedron: Asymmetry 1995, 6, 97 – 100.
Received: July 27, 2015
Published online: September 11, 2015
13544 www.angewandte.org
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 13538 –13544