Photocatalytic e → Z Isomerization of β-Ionyl Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b03842

An operationally simple E → Z isomerization of activated dienes, based on the β-ionyl motif intrinsic to retinal, is reported using inexpensive (-)-riboflavin (vitamin B₂) under irradiation at 402 nm. Selective energy transfer from photoexcited (-)-riboflavin to the starting E-isomer enables geometrical isomerization. Since the analogous process with the Z-isomer is inefficient, microscopic reversibility is circumvented, thereby enabling a directional isomerization to generate the contra-thermodynamic product (up to 99% yield, up to 99:1 Z/E). Prudent choice of photocatalyst enables chemoselective isomerization to be achieved in both inter- and intramolecular systems. The principles established from this study, together with a molecular editing approach, have facilitated the development of a regioselective isomerization of a truncated triene based on the retinal scaffold.

Full text of DOI:10.1021/acs.orglett.9b03842

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photocatalytic E → Z Isomerization of β‑Ionyl Derivatives
Keith Livingstone,†,‡ Marius Tenberge,† Felix Pape,† Constantin G. Daniliuc,† Craig Jamieson,*,‡
and Ryan Gilmour*,†
†
̈
̈
̈
̈
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Corrensstraβe 40, 48149 Munster, Germany
‡Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, U.K.
S
* Supporting Information
ABSTRACT: An operationally simple E → Z isomerization of activated dienes, based on the β-ionyl motif intrinsic to retinal, is
reported using inexpensive (−)-riboflavin (vitamin B2) under irradiation at 402 nm. Selective energy transfer from photoexcited
(−)-riboflavin to the starting E-isomer enables geometrical isomerization. Since the analogous process with the Z-isomer is
inefficient, microscopic reversibility is circumvented, thereby enabling a directional isomerization to generate the contra-
thermodynamic product (up to 99% yield, up to 99:1 Z/E). Prudent choice of photocatalyst enables chemoselective
isomerization to be achieved in both inter- and intramolecular systems. The principles established from this study, together with
a molecular editing approach, have facilitated the development of a regioselective isomerization of a truncated triene based on
the retinal scaffold.
etinal isomerization in the mammalian visual cycle is an
R
exemplar of biological precision.1 Centered on the
regioselective geometrical isomerization of a complex polyene,2
Nature’s efficiency masks the intrinsic challenges associated
with manipulating cross-conjugated alkene units. Conse-
quently, general solutions to enable the site-selective isomer-
ization of polyenes using small molecule catalysts remain
challening.3 The discovery that flavins are effective photo-
sensitizers in manipulating retinal geometry by Walker and
Radda,4a together with seminal studies from Liu and co-
workers on the regioselective isomerization of cross-conjugated
polyenes,4b provides valuable guidelines on how to reconcile
the strategic value of this goal with the current lack of
synthetically viable methods. Inspired by these blueprints, and
given the ubiquity of the β-ionyl scaffold in human medicine
(e.g., vitamin A),5 the 2,6,6-trimethylcyclohexene core of the
retinoids provided a versatile starting point for this study
(Figure 1). Specifically, the truncated diene inherent to β-
ionone would allow the photochemical isomerization6 to be
explored under biomimetic, flavin-catalyzed conditions. It is
pertinent to note that studies by Liu and co-workers have
established that formation of the Z-isomer of β-ionol can be
achieved when employing an appropriate triplet sensitizer with
a broad-band Hg lamp.3a,6,7 NMR spectroscopic evidence from
the same group implicates limited planarity of the strained Z-
alkene as being an important factor in stereoselection.8
Figure 1. Truncating the complex retinoid template to explore the
isomerization of simple dienes based on the β-ionyl system.
larger, naturally occurring polyenes, (−)-riboflavin was
evaluated as a biomimetic photosensitizer for contra-
thermodynamic alkene isomerization. Herein, we report
molecular editing studies together with the conceptual
extension to model triene systems based on truncated retinal.
This vitamin catalysis approach9 enables orthogonality relative
Encouraged by these reports, and with the ultimate goal of
devising guidelines to enable the regioselective isomerization of
Received: October 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03842
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to reactions using Ir(III)-based photosensitizers.10,11 More-
over, the structural editing process allows speculation to be
cast on the importance of fractional bond distances, as
reported by Dunitz,12 in selective alkene isomerization
following excitation.
a
Table 2. Exploring Substrate Scope
An initial optimization employing conditions developed
previously in this laboratory10b validated (−)-riboflavin as
being a competent photosensitizer for the E → Z isomerization
of β-ionyl ester E-1 to Z-1 under irradiation at 402 nm using a
narrow-band LED (Table 1, entries 1−4). Control experiments
a b
,
Table 1. Reaction Optimization for E-1 → Z-1
entry
catalyst
time (h)
conversion (%)
Z/E ratio
1
2
3
4
5
6
thioxanthone
benzil
Ir(ppy)3
(−)-riboflavin
−
14
14
14
14
14
14
87
76
99
99
>99
>99
59:41
92:8
99:1
99:1
10:90
c
d
(−)-riboflavin
0:100
a
Reactions were performed on a 0.1 mmol scale under an argon
atmosphere, using 5 mol % of the specified catalyst at a concentration
a
Reactions were performed under an argon atmosphere at a 0.2 mmol
b
c
scale, at 0.05 M concentration. Decomposition observed. 5 mol %
b
1
of 0.05 M. Conversion and Z/E ratios were determined using H
NMR with 1,3,5-trimethoxybenzene as an internal standard. 365 nm
LED used. Reaction performed in the dark.
lumichrome was used as the catalyst.
c
d
yield. Intrigued by the sensitivity of isomerization efficiency to
the seemingly innocuous installation of the N(OMe)Me group
(cf. NMe2), the aldehyde and ketone substrates originally
examined by Liu under different conditions were investigated.
Surprisingly, no isomerization was observed in E-15 and E-16
(Table 2c). This result indicates that chemoselective isomer-
ization of activated alkenes may be achievable through simple
molecular editing processes. To formalize this notion, and
cognizant of their differing triplet energy, ester E-1 was directly
compared with the corresponding allylic alcohol E-17 (Scheme
1a). As anticipated, the allylic alcohol proved recalcitrant to
energy-transfer-mediated isomerization (entry 1). The in-
troduction of thioxanthone as a photocatalyst generated Z-17
with >99:1 Z/E selectivity (entry 2). An intermediate triplet
energy sensitizer [Ir(ppy)3, entry 3] facilitated isomerization of
both E-17 and E-1, enabling near-quantitative isomerization of
both substrates (Z/E 99:1). As a final proof of concept, an
intramolecular variant of this concept was investigated. The
first protocol utilizing (−)-riboflavin furnished Z-18a, with the
α,β-unsaturated ester unit selectively isomerized in the
presence of the masked allylic alcohol (37%, Z/E 97:3). In
contrast, switching the photocatalyst to Ir(ppy)3 isomerized
both alkenes to furnish Z-18b. While the isolated yield of Z-
18a was considerably lower than the analogous Z,Z species, the
majority of the remaining mass balance was comprised of the
E-18 starting material, which was easily separated from the
desired reaction product.
established the need for both a light source and photocatalyst
(entries 5 and 6). On the basis of the identified general
reaction conditions, the scope of the transformation was
investigated. To complement the studies by Liu and co-
workers, focus was placed on esters and amides. Gratifyingly,
the steric footprint of the ester functionality had little influence
on the reaction outcome (Table 2a). Starting from the
benchmark carboxylic acid Z-2, which was itself a competent
isomerization substrate (>99:1 Z/E), augmenting steric bulk
had little effect on stereoselectivity with ratios of >99:1, >99:1,
and 96:4 being observed for the OMe (Z-3), OEt (Z-1), and
OtBu (Z-4) derivatives, respectively. In the case of Z-4,
lumichrome proved to be the superior photocatalyst. Further
enlargement of the ester such as Z-5 and Z-6 did not erode
selectivity (96:4 and 95:5), nor did the inclusion of the phenol
motif (Z-7, 98:2). Similarly, the benzyl derivative Z-8 proved
to be a highly effective substrate (99:1, Z/E) as did the di-tert-
Bu derivative (80:20 Z-9). This latter example would likely be
challenging to prepare in a stereoselective manner by
conventional olefination methodology. Having explored the
efficiency of (−)-riboflavin in enabling geometrical isomer-
ization of esters via selective energy transfer catalysis, the
methodology was extended to amide derivatives (Table 2b).
Primary, secondary, and tertiary systems were all found to
furnish the desired Z-isomer with excellent selectivity. Primary
amide Z-10 showed comparable isomerization efficiency to
carboxylic acid Z-2, but with significant improvement in yield
(98% versus 65%). Methyl ester Z-3 and methyl amide Ζ-11
behaved comparably (>99:1). By extension, the benzyl
derivative Z-13 was isolated with essentially the same Z/E
ratio as its ester counterpart (98:2 and >99:1). Synthetically
versatile Weinreb amides such as Z-14 could be accessed using
this approach with a Z/E ratio of 96:4, but with a reduction in
To further interrogate the origin of stereoselectivity, crystals
of both E-10 and Z-10 were isolated and subject to X-ray
crystallographic analysis (Scheme 2). The E-isomer was found
to have two independent molecules in the asymmetric unit
(10a/b). Inspection of the dihedral angles φ1 and φ2,
representing the diene and α,β-unsaturated carbonyl π-
systems, reveal differences in the substrate structures (φ1 =
B
DOI: 10.1021/acs.orglett.9b03842
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. (a) Exploring Photosensitizer ET; (b) An
Scheme 3. Molecular Editing Study
Intramolecular Example
a
Reactions were performed under an argon atmosphere on a 0.1
mmol scale, using MeCN (0.05 M) as the solvent and 5 mol % of
photocatalyst for 14 h.
a b
,
Table 3. Regioselective Isomerization of a Model Triene
catalyst [ET
conversion (%)
(E,E:7Z:9Z:Z,Z)
entry
(kJ mol−1)]
triene
13a benzanthrone (192)
21 (Me)
n.r. (0:56:0:44)
>99 (16:44:14:26)
99 (33:60:0:7)
2
3
4
(−)-riboflavin (209)13a 21 (Me)
(−)-riboflavin (209)13a 22 (H)
eosin Y (190)13a
22 (H)
62 (0:90:0:10)
c
a
Reactions performed on a 0.1 mmol scale under Ar, using 5 mol % of
b
the specified catalyst (0.05 M). Conversion and Z/E ratios were
determined using 1H NMR with 1,3,5-trimethoxybenzene as an
a
Reactions were performed under an argon atmosphere on a 0.1
c
internal standard. Isolated yield.
mmol scale, using MeCN (0.05 M) as the solvent and 5 mol % of
b
photocatalyst for 14 h. Conversion determined by 1H NMR with an
c
internal standard. Reactions were performed under argon on a 0.2
d
mmol scale, using MeCN (0.05 M) for 24 h. An additional 5 mol %
(−)-riboflavin was added after 24 h.
alteration together with a switch in photocatalyst to eosin Y
(ET = 190 kJ mol−1)13a enabled the highly selective and
exclusive isomerization of the 7-position (Table 3, entries 3
and 4).
a
Scheme 2. Structural Analysis of E- and Z-10
Inspired by the efficiency with which flavins photoisomerize
complex polyenes in the visual cycle, E → Z isomerization of
dienes based on the ubiquitous 2,6,6-trimethylcyclohexene
core of retinal was accomplished via a vitamin catalysis
approach. Variation in the alkene substituent enables α,β-
unsaturated carbonyl systems to be selectively manipulated in
the presence of allylic alcohol derivatives. Moreover, molecular
editing studies confirmed the structural importance of the
pendant methyl groups of ionoid derivatives in achieving high
Z-selectivity. These structural insights were then synergistically
matched to the triplet energy of the photocatalyst to enable the
site selective isomerization of a model triene based on retinal
(90% selective for the 7Z isomer). This approach that builds
on the seminal Walker/Radda4a and Liu4b studies provides a
foundation from which to further expand the π-system to
address the challenge of selective polyene isomerization.
a
Data extrapolated from crystal structures of E-10a/b (CCDC
1951892) and Z-10 (CCDC 1951893). See SI for further details.
57.8° and 84.1°, and φ2 = 20.6° and 0.6° for 10a/b,
respectively). In Z-10, the φ1 is similar to the E-isomer
(84.9°) but the φ2 value is 165.1° (see Supporting
Information). To explore the origin of selectivity further, the
impact of the three methyl groups was assessed by systematic
deletion (Scheme 3). Using model substrate E-1 as a template,
this molecular editing approach revealed a sequential erosion
of selectivity.
Finally, the regioselective isomerization of substrates E-21
(R = Me) and E-22 (R = H) was investigated (Table 3).
Exposure of E-21 to the standard reaction conditions yielded a
complex mixture, with decreased selectivity relative to Liu’s
earlier work (Table 3, entries 1 and 2).3a Interestingly, deletion
of the 9-methyl group improved selectivity. This structural
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03842.
Experimental protocols and selected NMR spectra
(PDF)
C
DOI: 10.1021/acs.orglett.9b03842
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
Letter
Preference. Tetrahedron Lett. 1972, 13, 3915−3916. (b) Liu, R. S. H.;
Zingoni, J. P.; Kini, A.; Trammell, M.; Chu, D.; Asato, A. E.; Bopp, T.
T. Restricted Rotation and Ring-Chain Conformation in Hindered 7-
cis Isomers of Retinal and Related Compounds. A Nuclear Magnetic
Resonance Study. J. Org. Chem. 1983, 48, 4817−4821.
CCDC 1951892−1951893 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(9) Morack, T.; Metternich, J. B.; Gilmour, R. Vitamin Catalysis:
Direct, Photocatalytic Synthesis of Benzocoumarins via (−)-Ribo-
flavin-Mediated Electron Transfer. Org. Lett. 2018, 20, 1316−1319.
(10) (a) Singh, K.; Staig, S. J.; Weaver, J. 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. One Photocatalyst,
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, D. G.;
Holland, M. C.; Von Bremen-Kuhne, M.; Neugebauer, J.; Gilmour, R.
Photocatalytic E → Z Isomerization of Polarized Alkenes Inspired by
the Visual Cycle: Mechanistic Dichotomy and Origin of Selectivity. J.
Org. Chem. 2017, 82, 9955−9977. (e) Cai, W.; Fan, H.; Ding, D.;
Zhang, Y.; Wang, W. Synthesis of Z-Alkenes via Visible Light
Promoted Photocatalytic E → Z Isomerization Under Metal-Free
Conditions. Chem. Commun. 2017, 53, 12918−12921. (f) Molloy, J.
J.; 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 Two-
Dimensional Chemical Space. Angew. Chem., Int. Ed. 2018, 57, 3168−
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ryan.gilmour@uni-muenster.de.
*E-mail: craig.jamieson@strath.ac.uk.
ORCID
Craig Jamieson: 0000-0002-6567-8272
Ryan Gilmour: 0000-0002-3153-6065
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge financial support from the WWU Mu
the Royal Society of Chemistry (Mobility Grant RM1802-6141
to K.L.) and the Deutsche Forschungsgemeinschaft (DFG
Return Fellowship to F.P.).
■
̈
nster,
3172. (g) Faßbender, S. I.; Molloy, J. J.; Muck-Lichtenfeld, C.;
̈
Gilmour, R. Geometric E→Z Isomerisation of Vinyl Silanes by
Selective Energy Transfer Catalysis: Stereodivergent Synthesis of
Triarylethylenes via a Formal Anti-Metallometallation. Angew. Chem.,
Int. Ed. 2019, DOI: 10.1002/anie.201910169.
REFERENCES
■
(1) O’Leary, B.; Duke, B.; Eilers, J. E. Isomerisation of the Visual
Chromophore All-trans to 11-cis Retinal. Nature 1973, 246, 166−167.
(2) Kiser, P. D.; Golczak, M.; Palczewski, K. Chemistry of the
Retinoid (Visual) Cycle. Chem. Rev. 2014, 114, 194−232.
(3) For examples of selective diene isomerization, see: (a) Ram-
amurthy, V.; Liu, R. S. H. Photochemistry of Polyenes. IX: Excitation,
Relaxation, and Deactivation of Dienes, Trienes, and Higher Polyenes
in the Vitamin A Series in the Sensitized Isomerization Reaction. J.
(11) 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.
(12) Burgi, H. B.; Dunitz, J. D. Fractional Bonds: Relations Among
̈
Their Lengths, Strengths, and Stretching Force Constants. J. Am.
Chem. Soc. 1987, 109, 2924−2926.
(13) (a) Chambers, R. W.; Kearns, D. R. Triplet States of Some
Common Photosensitising Dyes. Photochem. Photobiol. 1969, 10,
215−219. (b) Meier, K.; Zweifel. Thioxanthone Ester Derivatives:
Efficient Triplet Sensitizers for Photopolymer Applications. J.
Photochem. 1986, 35, 353−366. (c) Hofbeck, T.; Yersin, H. The
Triplet State of fac-Ir(ppy)3. Inorg. Chem. 2010, 49, 9290−9299.
Am. Chem. Soc. 1976, 98, 2935−2942. (b) Punner, F.; Schmidt, A.;
̈
Hilt, G. Up the Hill: Selective Double-Bond Isomerization of
Terminal 1,3-Dienes towards Z-1,3-Dienes or 2Z,4E-Dienes. Angew.
Chem., Int. Ed. 2012, 51, 1270−1273. (c) Naskar, S.; Chowdhury, S.
R.; Mondal, S.; Maiti, D. K.; Mishra, S.; Das, I. Visible-Light-Activated
Divergent Reactivity of Dienones: Dimerization in Neat Conditions
and Regioselective E to Z Isomerization in the Solvent. Org. Lett.
2019, 21, 1578−1582.
(4) (a) Walker, A. G.; Radda, G. K. Photoreactions of Retinol and
Derivatives Sensitized by Flavins. Nature 1967, 215, 1483. (b) Denny,
M.; Liu, R. S. H. Sterically Hindered Isomers of Retinal From Direct
Irradiation of the All-trans Isomer. Isolation of 7-cis-Retinal. J. Am.
Chem. Soc. 1977, 99, 4865−4867.
(5) Parker, G. L.; Smith, L. K.; Baxendale, I. R. Development of the
Industrial Synthesis of Vitamin A. Tetrahedron 2016, 72, 1645−1652.
(6) (a) Ramamurthy, V.; Butt, Y.; Yang, C.; Yang, P.; Liu, R. S. H.
Preparation of 7-cis-Ionyl and -Ionylidene Derivatives and Other
Sterically Hindered Olefins by One-Way Sensitized Geometric
Isomerization. J. Org. Chem. 1973, 38, 1247−1249. (b) Ramamurthy,
V.; Liu, R. S. H. Preferred Directions of Photoisomerization of
Ionylideneacetaldehyde and the C18-Tetraene Ketone in the Retinal
Series. Synthesis of the Hindered 7-cis Isomers. J. Am. Chem. Soc.
1974, 96, 5625−5627. (c) Ramamurthy, V.; Tustin, G.; Yau, C. C.;
Liu, R. S. H. Preparation of Sterically Hindered Geometric Isomers of
7-cis-β-ionyl and β-ionylidene Derivatives in the Vitamin A Series.
Tetrahedron 1975, 31, 193−199.
(7) Liu, R. S. H.; Hammond, G. S. Photochemical Reactivity of
Polyenes: From Dienes to Rhodopsin, From Microseconds to
Femtoseconds. Photochem. Photobiol. Sci. 2003, 2, 835−844.
(8) (a) Ramamurthy, V.; Bopp, T. T.; Liu, R. S. H. NMR Studies of
7-cis-β-ionol and Related Compounds. Ring-Chain Conformational
D
DOI: 10.1021/acs.orglett.9b03842
Org. Lett. XXXX, XXX, XXX−XXX