Light-Enabled Enantiodivergence: Stereospecific Reduction of Activated Alkenes Using a Single Organocatalyst Enantiomer

Article abstract of DOI:10.1021/acs.orglett.9b04263

Light-enabled enantiodivergence is demonstrated in which the alkene substrate configuration is manipulated (E → Z) prior to organocatalytic reduction with a chiral thiourea and Hantzsch ester. This allows stereodivergent reduction to be regulated at the substrate level with high fidelity and mitigates the need for a second, enantiomeric catalyst (up to 93:07 and 95:5 er). The synthetic utility of this strategy has been demonstrated in the synthesis of the weight-loss drug (R)-Lorcaserin (Belviq) and a potent AMPA modulator.

Full text of DOI:10.1021/acs.orglett.9b04263

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Light-Enabled Enantiodivergence: Stereospecific Reduction of
Activated Alkenes Using a Single Organocatalyst Enantiomer
Theresa Hostmann, John J. Molloy, Kathrin Bussmann, and Ryan Gilmour*
̈
̈
̈
̈
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Corrensstrasse 40, 48149 Munster, Germany
S
* Supporting Information
ABSTRACT: Light-enabled enantiodivergence is demonstrated in which the alkene substrate configuration is manipulated (E
→ Z) prior to organocatalytic reduction with a chiral thiourea and Hantszsch ester. This allows stereodivergent reduction to be
regulated at the substrate level with high fidelity and mitigates the need for a second, enantiomeric catalyst (up to 93:07 and
95:5 er). The synthetic utility of this strategy has been demonstrated in the synthesis of the weight-loss drug (R)-Lorcaserin
(Belviq) and a potent AMPA modulator.
nantioselective, catalytic hydrogenation of π-bonds
isomerization of E-1 was necessary to provide access to Z-1
Eremains an expansive strategy to access saturated, chiral (Table 1). The ubiquity of E-α-substituted nitrostyrenes as
building blocks from inexpensive feedstocks.1 The importance
precursors for asymmetric organocatalysis, and as masked β-
chiral amines, has resulted in a rich variety of methods for their
preparation. In contrast, Z-isomers continue to present a
synthetic challenge. To address this, absorption spectra of both
isomers (Table 1, insert) were measured, indicating that
selective excitation of the E-isomer may be achievable, thereby
generating the Z-isomer without an external photosensitizer.
Gratifyingly, irradiation at λ = 402 nm in acetonitrile afforded
Z-1 with good selectivity (Z/E 89:11), albeit, with low yield
due to competing degradation (Table 1, entry 1).
Changes to the reaction media were generally detrimental to
selectivity, and only modest improvements to yield were
observed (entries 2−4). A screen of concentration and reaction
time (entries 5−9), followed by an increase in scale (entry 10)
and reduction in reaction time, furnished Z-1 in a synthetically
useful yield and with a Z/E ratio of 92:08 (entry 11). Further
improvement by the introduction of common photosensitizers
was not possible (see Supporting Information). To that end,
scope exploration was conducted on a 0.5 mmol scale (1.0 M
in acetonitrile) for 7 h. To explore the scope of this
photocatalyst-free isomerization of E-α-substituted nitrostyr-
enes, a series of derivatives were investigated (Figure 2).
In general, para-substituents were well tolerated irrespective
of their electronic effect (Z-2−Z-6, up to Z:E 92:08), as were
the ortho- and meta-derivatives Z-7−Z-9 (up to Z/E 95:05).
Executing the reaction on a 2.5 mmol scale furnished Z-9 in
82% isolated yield as a single geometric isomer (see
Supporting Information). As a control series, the α-methyl
of this technology in an industrial context remains a powerful
impetus to explore new conceptual avenues to generate both
chiral antipodes in an efficient, cost-effective manner.2
Catalysis-based approaches are frequently reliant on chiral
pool-derived stereoregulatory elements to encode enantiose-
lection;3 hence, availability is a precondition of enantiodiver-
gence (Figure 1A). Often the unnatural enantiomer is
prohibitively expensive or may have to be synthesized de
novo, a persistent consideration for asymmetric catalysis in a
broader sense.4 Consequently, stereodivergent strategies5,6 to
access both products using a single catalyst enantiomer would
be of significance, if the intrinsic directionality could be
inverted by an external, physical stimulus such as light,7 heat,
or mechanical force. To validate this approach to alkene
hydrogenation, it was envisaged that the directionality might
be regulated at the alkene substrate level utilizing light. It was
reasoned that E → Z geometric isomerization would provide a
platform for divergence, when coupled to a stereospecific
reduction of the alkene:8,9 This would facilitate 2D to 3D
translation of the stereochemical information. The renaissance
of alkene photoisomerization,10,11 together with advances in
the hydrogenation of substituted nitrostyrenes12 via organo-
catalytic strategies13 provides a platform for concept validation
(Figure 1B and C). This enantiodivergent, catalytic route to β-
chiral amines conceptually complements the stereoconvergent,
chemoenzymatic reduction of 2-phenyl maleic esters based on
photocatalytic isomerization reported by Hartwig and co-
workers.14
To explore the viability of an enantiodivergent reduction
using light as the external stimulus, an efficient, catalyst-free
Received: November 27, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04263
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Organic Letters
Letter
Figure 1. Catalysis-based strategies for enantiodivergence and a
conceptual overview of this study.
Figure 2. Exploring the scope of the isomerization. Reaction
conditions: Substrate (0.5 mmol), MeCN (0.5 mL), 402 nm, 7 h.
Table 1. Photo-isomerization of E-1 to Z-1 Optimization
no relevance to the subsequent asymmetric hydrogenation, it
underscores the role of the methyl group in inducing 1,3-allylic
strain in the α-substituted nitrostyrenes. This prevents
reconjugation of the π-system chromophore and ensures
directionality.11d Indeed, this manifestation of 1,3-allylic strain
is evident from the subtle introduction of an ortho-fluoro
substituent (Z-12, Z/E = 67:33 versus 46:54). Having devised
conditions for the photoisomerization of nitrostyrenes,
organocatalytic hydrogenation strategies based on chiral
thioureas derived from a natural amino acid were explored
(Figure 3). The enantioselective hydrogenation of E-nitro-
styrenes reported by List and co-workers using an unnatural
tert-leucine derivative provided inspiration.13a However, to
validate our concept of only requiring one (natural)
enantiomer of the catalyst, a system based on inexpensive L-
valine was conceived. Moreover, the diethylamino scaffold was
replaced by a dimethylamino motif due to the negligible
impact that these groups have on catalytic efficiency.
Gratifyingly, these alterations to generate catalyst A had little
impact on reaction efficiency with substrate E-1 generating the
S-configured product S-13 (96% isolated yield and er 04:96
versus 97% conversion and er 02:98. See SI for full details).
Exposing Z-1 to identical reaction conditions with catalyst A
led to a marginal decrease in er (84:16), but the sense of
enantioinduction was inverted to favor the R-enantiomer R-13.
While these data constitute preliminary validation of concept, a
slight matched−mismatched scenario was apparent. To
improve the enantioselectivity of the R-series, further catalyst
optimization was performed resulting in catalyst B (full details
in the SI). Gratifyingly, stereospecific reduction was preserved,
this time enhancing the yield (94%) and enantioselectivity to
93:07 R/S-13). The remainder of the scope was performed in
scale
molarity
(M)
time
(h)
yield
(%)
a
entry
solvent
MeCN
1,4-dioxane
toluene
c-hexane
MeCN
MeCN
MeCN
MeCN
MeCN
(mmol)
Z/E
1
2
3
4
5
6
7
8
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
1.0
0.5
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.5
1.0
0.2
1.0
16
16
16
16
4
33
25
29
38
60
43
34
39
47
69
72
89:11
78:22
57:43
85:15
80:20
85:15
86:14
90:10
89:11
90:10
92:08
6
16
16
16
16
7
9
10
11
MeCN
MeCN
a
1
Determined by H NMR spectroscopy.
group substituted by a cyclopropyl ring was investigated (10),
together with trans-nitrostyrene (11). Although the latter is of
B
DOI: 10.1021/acs.orglett.9b04263
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Organic Letters
Letter
discrete catalyst systems. From the perspective of optimization,
it may be concluded that the highest levels of enantioselectivity
with the E-substrates can generally be obtained with catalyst A,
whereas, for Z-configured alkenes, catalyst B is optimum.
However, exceptions were found with the p-CH3 and p-Cl
substituted substrates (14 and 17), whereby catalyst A gave
similar or marginally higher er values for the Z-substrate.
Since the reduced products belong to a venerable class of β-
chiral amine precursors, isomers E-5 and Z-5 were
independently converted to (S)-17 and (R)-17, respectively
(Figure 4, top). These intermediates were processed to the
Figure 4. Application to the synthesis of selected bioactive small
molecules. Reaction conditions: (a) Zn (5 equiv), AcOH (30 equiv),
THF/MeOH (10:1), 0 °C−rt, 16 h; (b) NEt3 (5.74 equiv), MsCl
(1.50 equiv) CH2Cl2; (c) NEt3 (1.13 equiv), TFAA (1.65 equiv),
CH2Cl2, 0 °C−rt, 16 h, 83% (er: 95:05); (d) HO(CH2O)nH (2
equiv), AcOH/H2SO4 (3:2), K2CO3 (3 equiv), 0 °C−rt, 16 h, 43%;
(e) Boc2O (1.1 equiv), NEt3 (1.2 equiv), 16 h, 59% (er 95:05); (f)
TMSCHN2 (2.4 equiv), TEMPO N-oxoammonium BF4 salt (1.5
equiv), CH2Cl2, 80 °C, 1 h, 33%; (g) HSiEt4 (2 equiv), TFAA (7% v/
v), HCl (30 equiv), CH2Cl2, rt, 2 h, 8% (er 81:19).
corresponding sulfonamides, enabling a formal total synthesis
of either the (R,R)- or (S,S)-configured dimer core of positive
allosteric modulators of ionotropic glutamate receptors.15
Finally, the m-Cl nitrostyrene Z-9 was hydrogenated with
catalyst B to generate (R)-20. The reaction was performed on
a 2 mmol scale with no drop in enantioselectivity (er 93:07).
The product was converted to the selective 5-HT2C receptor
agonist and marketed drug (R)-Lorcaserin (Belviq) (24) via a
known six-step procedure (Figure 4, bottom).16 A one-pot
protocol was also conducted as a proof of concept (Figure 5)
Figure 3. Establishing the scope of the stereospecific, enantiodiver-
gent reduction of activated alkenes. Reactions conditions: (E) or (Z)-
substrate (0.20 mmol, 1.0 equiv), A or B (0.01 mmol, 5 mol %), HE
(0.22 mmol, 1.1 equiv), toluene (0.33 M), 40 °C, 48 h.
duplicate with both catalysts derived from L-valine, and it was
demonstrated that E → S and Z → R. For each entry
(compounds 13−21) a series of four experiments were
conducted to demonstrate enantiodivergency with these two
C
DOI: 10.1021/acs.orglett.9b04263
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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental details and NMR spectra (PDF). The
Supporting Information is available free of charge at https://
pubs.acs.org/doi/10.1021/acs.orglett.9b04263.
(9) (a) Shi, S.-L.; Wong, Z. L.; Buchwald, S. L. Copper-catalyzed
enantioselective stereodivergent synthesis of amino alcohols. Nature
2016, 532, 353−356. (b) Appella, D. H.; Moritani, Y.; Shintani, R.;
Ferreira, E. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473−
(PDF)
9474. (c) Bell, S.; Wustenberg, B.; Kaiser, S.; Menges, F.; Netscher,
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AUTHOR INFORMATION
T.; Pfaltz, A. Asymmetric hydrogenation of unfunctionalized, purely
alkyl-substituted olefins. Science 2006, 311, 642−644.
■
Corresponding Author
*E-mail: ryan.gilmour@uni-muenster.de.
ORCID
(10) Molloy, J. J.; Morack, T.; Gilmour, R. Positional and
Geometrical Isomerisation of Alkenes: The Pinnacle of Atom
Economy. Angew. Chem., Int. Ed. 2019, 58, 13654−13664.
(11) (a) Singh, K.; Staig, S. J.; Weaver, J. D. Facile Synthesis of Z-
Alkenes via Uphill Catalysis. J. Am. Chem. Soc. 2014, 136, 5275−5278.
(b) Metternich, J. B.; Gilmour, R. A Bio-Inspired, Catalytic E→Z
Isomerization of Activated Olefins. J. Am. Chem. Soc. 2015, 137,
11254−11257. (c) Metternich, J. B.; Gilmour, R. A “One Photo-
catalyst, n Activation Modes” Strategy for Cascade Catalysis:
Emulating Coumarin Biosynthesis with (−)-Riboflavin. J. Am.
Chem. Soc. 2016, 138, 1040−1045. (d) Metternich, J. B.; Artiukhin,
Ryan Gilmour: 0000-0002-3153-6065
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge generous financial support from the WWU
nster and the Alexander von Humboldt Foundation
(Fellowship to J.J.M.).
■
Mu
̈
D. G.; Holland, M. C.; von Bremen-Kuhne, M.; Neugebauer, J.;
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Gilmour, R. Photocatalytic E→Z Isomerization of Polarized Alkenes
Inspired by the Visual Cycle: Mechanistic Dichotomy and Origin of
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Metternich, J. B.; Daniliuc, C. G.; Watson, A. J. B.; Gilmour, R.
Contra-Thermodynamic, Photocatalytic E→Z Isomerization of
Styrenyl Boron Species: Vectors to Facilitate Exploration of 2D
Chemical Space. Angew. Chem., Int. Ed. 2018, 57, 3168−3172.
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