A Bio-Inspired, Catalytic e → Z Isomerization of Activated Olefins

Article abstract of DOI:10.1021/jacs.5b07136

Herein, Natures flavin-mediated activation of complex (poly)enes has been translated to a small molecule paradigm culminating in a highly (Z)-selective, catalytic isomerization of activated olefins using (-)-riboflavin (up to 99:1 Z/E). In contrast to the prominent Z → E isomerization of the natural system, it was possible to invert the directionality of the isomerization (E → Z) by simultaneously truncating the retinal scaffold, and introducing a third olefin substituent to augment A1,3-strain upon isomerization. Consequently, conjugation is reduced in the product chromophore leading to a substrate/product combination with discrete photophysical signatures. The operationally simple isomerization protocol has been applied to a variety of enone-derived substrates and showcased in the preparation of the medically relevant 4-substituted coumarin scaffold. A correlation of sensitizer triplet energy (E_T) and reaction efficiency, together with the study of additive effects and mechanistic probes, is consistent with a triplet energy transfer mechanism.

Full text of DOI:10.1021/jacs.5b07136

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A Bio-Inspired, Catalytic E#Z Isomerization of Activated Olefins
Jan Benedikt Metternich, and Ryan Gilmour
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b07136 • Publication Date (Web): 26 Aug 2015
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A Bio-Inspired, Catalytic E→Z Isomerization of Activated Olefins
Jan B. Metternich,a and Ryan Gilmour*a,c
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Institute for Organic Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster,
Germany.
Supporting Information Placeholder
has been limited by an extremely narrow substrate scope. In
ABSTRACT: Herein, Nature’s flavin-mediated activation of
an effort to extend the substrate scope of photosensitized
isomerizations beyond electron rich styrenes and stilbenes,
Nature’s photochemical (Z→E) isomerization of retinal10 was
taken as a blueprint for reaction design (Scheme 1, upper).
Whilst the overall directionality of the natural system favors
the E-isomer, an elegant study by Walker and Radda in 1967
described the qualitative observation that riboflavin catalyzes
the reverse E→Z photoisomerization of retinal.11
complex (poly)enes has been translated to a small molecule
paradigm culminating in a highly (Z)-selective, catalytic
isomerization of activated olefins using (–)-riboflavin (up to
99:1 Z:E). In contrast to the prominent Z → E isomerization
of the natural system, it was possible to invert the direction-
ality of the isomerization (E→Z) by simultaneously truncat-
ing the retinal scaffold, and introducing a third olefin sub-
stituent to augment A1,3-strain upon isomerization. Conse-
quently, conjugation is reduced in the product chromophore
leading to a substrate / product combination with discrete
photophysical signatures. The operationally simple isomeri-
zation protocol has been applied to variety of enone-derived
substrates and showcased in the preparation of the medically
relevant 4-substituted coumarin scaffold. A correlation of
sensitizer triplet energy (ET) and reaction efficiency, together
with the study of additive effects and mechanistic probes, is
consistent with a triplet energy transfer mechanism.
Scheme 1 Reaction design considerations. Upper: the
Z→E photoisomerization of retinal. Lower: a bio-
inspired catalytic, Z-selective isomerization.
Of the plethora of fundamental reactions that can be
achieved by (organo)-catalysis,1 a strategy for the selective
E→Z isomerization of olefins remains conspicuously absent.
Indeed, the development of a generic catalyst to realize this
pinnacle of atom economy2 has yet to be reported.3 Despite
the value of Z-olefins in contemporary organic synthesis,4 the
development of a highly selective transformation remains
formidable on account of the “uphill” energetics of the net
process.5 To circumvent this obstacle, a strategy relying on
an energy ratchet mechanism is necessary; this has proven to
be highly successful in the design of functional supramolecu-
lar systems.6 By translating the notion of an (irreversible)
energy ratchet to the paradigm of olefin isomerization, con-
cerns pertaining to microscopic reversibility, and the unde-
sired formation of thermodynamic mixtures, are mitigated.
Photochemical activation via a sensitiser7 is a logical energy
ratcheting tactic that is ideally suited to catalytic olefin
isomerisation. Not only does the initial excitation ensure that
all subsequent steps are energetically “downhill”, the princi-
ple of microscopic reversibility does not apply to transfor-
mations initiated by photochemical excitation. Hammond’s
pioneering stilbene photoisomerization studies8 and Arai’s β-
alkylstyrene isomerization9 beautifully exemplify this notion.
However, the synthetic utility of this isomerization strategy
To improve this reversal to useful levels, and thus translate
biological photo-isomerization into a small molecule para-
digm, a process of substrate re-engineering was applied. In
retinal, isomerization about the 1,2-disubstituted olefin in-
duces a change in conformation and photo-physical proper-
ties. By simultaneously truncating the retinal scaffold, and
introducing a third olefin substituent to augment A1,3-strain
upon E→Z isomerization, it was envisaged that this same
phenomenon might be exploited to discriminate the sub-
strate and product based on de-conjugation of the π-system.
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This in turn would ensure that only the starting E-isomer
ratio. Having confirmed a general tolerance for modifications
at R1 and the aryl substituent, attention was focused on the
carbonyl group. Aldehyde 21, Weinreb amide 22 and ketone
23 (Figure 1, lower) all proved to be excellent substrates for
this isomerization, with Z:E ratios of up to 96:4 having been
observed.
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interacts with the photo-catalyst, thus ultimately resulting in
a Z-selective transformation. It was expected that the excited
state species generated by an initial energy transfer process
would induce cleavage of the π-bond to generate a delocal-
ized biradical intermediate12 where C-C bond rotation is
possible (cf Paterno-Büchi reaction13). This species could, in
theory, be transposed to the corresponding radical cation or
anion depending on the environment (Scheme 1, lower). For
simplicity, activated olefins based on cinnamaldehyde were
Table 1 The (–)riboflavin-catalyzed isomerization of
activated olefins
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selected as substrates for investigation. (–)-Riboflavin was
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investigated as a cheap, commercially available photocatalyst
(25g, 27.50 USD, Sigma-Aldrich).14-16 Inspection of the respec-
tive triplet energies of cinnamaldehyde and riboflavin indi-
cate a productive match for this partnership (full details in
the SI).
As a start point for this investigation, the isomerization of
α,β-unsaturated esters was investigated (Table 1). To the best
of our knowledge, this transformation has only been
achieved with modest selectivities using sub-stoichiometric
loadings of Lewis-acids.17 A screen of common solvents and
catalysts loadings quickly identified acetonitrile with 5 mol%
(–)-riboflavin to be the optimal conditions. The E→Z isomer-
ization of ethyl (E)-3-phenylpent-2-enoate (1) proceeded
smoothly within 24 h under UV-light irradiation. Quantita-
tive material recovery was achieved by simple filtration, and
analysis of the crude mixture revealed a Z:E mixture of 99:1.
Encouraged by the first results obtained for 1, a variety of
substrates were successively modified at i) the β-substituent
(R1), ii) the aryl ring and iii) the carbonyl functionality (R2),
and investigated under the standard reaction conditions.
Substituting R1=Et by Me led only to a very minor erosion of
selectivity (1 and 2, Z:E 99:1 and 95:5, respectively). However,
the installation of F or H at R1 led to a decrease in selectivity
(3 and 4, Z:E 32:68 and 59:41, respectively), thus implicating a
steric parameter in influencing the reaction outcome. The
higher selectivity of the vinyl fluoride 3 compared to 4 may
be attributed to the improved α-radical stabilizing ability of
fluorine as compared to hydrogen.18 Modification of R1 was
found to be well tolerated as is demonstrated by compounds
5 (Z:E 99:1) and 6 (Z:E 93:7). Interestingly, a slight erosion of
the isolated yield was observed in the cyclopropyl derivative
(94%), possibly due to ring opening. This observation would
later prove to be useful in formulating a working mechanistic
hypothesis.
Standard reactions conditions: Reactions were performed
with 0.1 mmol substrate (E:Z >20:1) at ambient temperature
in MeCN using 5 mol% catalyst loading under 24 hours of
UV-light irradiation (402 nm). Z:E ratios were determined by
1H NMR spectroscopy and HPLC analysis. [a] N.B. product E:Z
ratio is inverted to reflect the higher IUPAC priority of F than
C. [b] Under standard conditions the product distribution was
24% cinnamic acid (Z:E 99:1) plus coumarin (76%).
Electronic modulation of the aryl ring was found to have a
negligible effect on stereoselectivity for both the ethyl and
methyl derivatives (7 and 8, Z:E 99:1 and 97:3, respectively; 9-
15 Z:E up to 99:1). To probe for radical abstraction phenome-
na, the deuterated analogue 16 was subjected to the stand-
ards reaction conditions. No exchange was observed and the
isolated yield and geometric ratio was identical to that of 2
(quant. Z:E 95:5). To explore the effect of breaking conjuga-
tion of the π-system, the ortho-fluorophenyl derivative 17 was
explored to subtly tilt the ring out of plane. This small modi-
fication led to a notable decrease in stereoselectivity (Z:E
81:19). Replacing the phenyl ring by pyridyl resulted in a
slightly lower yield but with high Z:E selectivity (95:5). Inter-
estingly a slight decrease in the geometric ratio was noted for
substrate 19 bearing a larger naphthyl substituent. Finally,
By extension, the behavior of (E)-cinnamic acid 24 was also
explored under the optimized reaction conditions. Again,
this substrate furnished the expected (Z)-isomer with excel-
lent levels of geometric control (Z:E 99:1) but in a lower yield
(24%): the major product of this process was found to be the
corresponding 4-substitued coumarin (25). By performing
the reaction under an oxygen atmosphere, the intramolecu-
lar cyclisation of the (Z)-isomer could be driven to comple-
exposure of the highly electron deficient system 20 to (
–)-
riboflavin resulted in quantitative conversion and with a 3:97
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tion (Scheme 2, 96% yield): this constitutes a facile route to
diphenyl substituted cyclopropane.22 Repeating this reaction
in the absence of ( )-riboflavin led to the quantitative recov-
ery of 26 with no loss of stereochemical information. Addi-
tional support for the intermediary benzylic radical is reflect-
ed in the increasing Z:E ratio when improving the stabilizing
auxiliary R1 (H < F < Me < Et ≈ Pr).18
an important drug scaffold.19 The isomerization reaction also
proved amenable to scale-up with the (Z)-isomer of 1 having
been isolated in 82% yield on a 1 mmol scale. The slightly
lower yield is attributable to the low intensity of the UV-
lamp (1150 mW), thus preventing the photo-stationary state
from being reached.20 When performing the isomerization of
(E)-1 with a catalyst loading of only 1 mol%, the product was
isolated in quantitative yield and with excellent levels of
stereocontrol (Z:E 99:1).
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Figure 1 Mechanistic investigations of the title reac-
tion.
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Scheme 2 A one-pot isomerization/cyclization strate-
gy to generate the 4-substituted coumarin scaffold
Left: The E→Z photoisomerization of cinnamic acid 24 by (
–
)-riboflavin led to the formation of the corresponding cou-
marin 25 (96% yield). X-ray structural data for coumarin 25 is
provided in the SI.
Pursuant to Hammond’s mechanistic analyses, correlation of
the sensitizer triplet energies (ET) of various photocatalysts
with reaction efficiency,8 together with the study of additive
effects and mechanistic probes, and a Stern-Volmer pho-
toquenching experiment, indicated that a mechanism con-
sistent with triplet energy transfer was operational (full
details are provided in the SI). The Stern-Volmer analysis
revealed that increased quenching of the photoexcited state
of (-)-riboflavin by the E-isomer (E)-1 is at least one order of
magnitude more effective than with the corresponding Z-
isomer (Z)-1, thus a photostationary state with constant Z:E
ratios might be expected. Consequently, pure E-(1), Z-(1) and
a 1:1 mixture of both isomers were independently subjected
to the standard photocatalysis conditions for validation. In
all cases, quantitative formation of the expected product was
observed with a Z:E-ratio of 99:1. A time-course analysis of
the isomerization of (E)-1 revealed that the photostationary
state was reached after 4 hours (full details provided in the
SI). Moreover, by correlating the triplet state energy (ET) of
(–)-riboflavin and other common photocatalysts, a clear
guideline can be deduced and translated to related isomeri-
zation paradigms: Sensitizers with an ET below that of the
excited state of the substrate[21] lead to little or no isomerisa-
tion. In contrast, sensitizers with ET values greater than that
of the (E)-isomer, but less than that of the (Z)-isomer, result
The initial supposition that a deconjugation-induced change
in photophysical signature facilitates selective excitiation was
then examined. Probing the effect of ring size (Ar) indicates
that (i) distortion (deconjugation) in the product and (ii)
planarity (conjugation) in the substrate are key to ensuring
high levels of stereocontrol. To illustrate the first condition,
substrates 28 and 29 were investigated, where the 5-
membered rings retain the requisite aromatic character, but
reduce A1,3-strain in the (Z)-isomer. In both cases, the (E)-
and (Z)-isomers are conjugated and planar,23 and the subse-
quent selectivity is low (Z:E 27:73 and 41:59 for 28 and 29,
respectively). To validate the second condition, substrates 17
and 30 were investigated which subtly introduce allylic strain
by virtue of ortho-fluoro substituents. In both cases, where
the aryl ring is distorted from planarity,24 a decrease in selec-
in effective isomerisation (i.e. (–)-riboflavin).
To provide experimental support for the delocalized radical
intermediate outlined in Scheme 1, the cyclopropyl-based
radical clock 26 was prepared and subjected to the standard
conditions used throughout this study. Both diastereoiso-
mers (Z)-27a and (Z)-27b were isolated as a 60:40 mixture
(52% yield). Stereomutation in (Z)-27a is consistent with
configurational scrambling via a benzylic radical. The reten-
tion of stereochemical information in (Z)-27b suggests that
the lifetime of the postulated biradical is comparable to the
radical-induced ring opening and closure of the trans-2,3-
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2484-2485; (g) For a recent isomerization of terminal alkenes see S.
tivity was noted: this was most pronounced in the disubsti-
W. M. Crossley, F. Barabe, R. A. Shenvi, J. Am. Chem. Soc. 2014, 136,
16788-16791.
1
2
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tuted system 30 (Z:E 1:99).
By emulating the flavin-mediated activation of complex
(poly)enes, an operationally simple, highly (Z)-selective
isomerization of activated olefins has been developed em-
(4)
33-58.
(5)
W. Y. Siau, Y. Zhang, Y. Zhao, Top. Cur. Chem. 2012, 327,
For a recent transition metal based photocatalytic isomer-
5
6
7
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ization of allylic amines see K. Singh, S. J. Staig, J. D. Weaver, J. Am.
Chem. Soc. 2014, 136, 5275-5278.
ploying inexpensive, commercially available (–)-riboflavin as
the photo-catalyst. In contrast to the signature Z → E isomer-
ization of the natural system, the directionality of the isom-
erization (E → Z) was inverted by truncating the retinal scaf-
fold, and introducing a third olefin substituent to augment
A1,3-strain upon isomerization. The transformation is gener-
ally applicable to substrates in which the cinnamyl motif is
embedded: this includes esters, aldehydes, ketones, Weinreb
amides and carboxylic acids. In this latter case the method
can be extended to generate 4-substituted coumarins direct-
ly. Correlation of sensitizer triplet energy (ET) and reaction
efficiency, together with the study of additive effects and
mechanistic probes (see SI), has allowed a mechanistic hy-
pothesis to be formulated based on selective excitation. It is
envisaged that the guidelines delineated from this study will
facilitate the rapid development of a (photo)-catalyst tool
box25 to address the need for highly selective, generic isomer-
ization catalysts.
(6)
M. N. Chatterjee, E. R. Kay, D. A. Leigh, J. Am. Chem. Soc.
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(8)
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ASSOCIATED CONTENT
Supporting Information
(9)
For examples of cis-trans isomerizations of styrenes see (a)
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AUTHOR INFORMATION
Corresponding Author
*ryan.gilmour@uni-muenster.de
(11)
A. G. Walker, G. K. Radda, Nature 1967, 215, 1483.
(12)
E. García-Expósito, M. J. Bearpark, R. M. Ortuño, M. A.
Notes
Robb, V. Branchadell, J. Org. Chem. 2002, 67, 6070-6077.
This study is dedicated to Prof. Dr. Albert Eschenmoser (ETH
(13)
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T. Bach, Synthesis 1998, 683-703.
For examples of oxidation chemistry catalyzed by RF see:
Zürich) on the occasion of his 90th birthday.
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3020-3027; (b) S. Murahashi, T. Oda, Y. Masui, J. Am. Chem. Soc.
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Murahashi, T. Naota, Angew. Chem. Int. Ed. 2005, 44, 1704-1706;
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König, Chem. Eur. J. 2008, 14, 1854-1865; (f) H. Schmaderer, P.
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ACKNOWLEDGMENT
We acknowledge generous financial support from the WWU
Münster, the Deutsche Forschungsgemeinschaft (SFB 858,
and Excellence Cluster EXC 1003 “Cells in Motion – Cluster of
Excellence”), and the Fonds der Chemischen Industrie (FCI
Fellowship to J. B. Metternich).
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