Lewis Acid Catalyzed Enantioselective Photochemical Rearrangements on the Singlet Potential Energy Surface

Article abstract of DOI:10.1021/jacs.9b12068

The oxadi-methane rearrangement of 2,4-cyclohexadienones to bicyclic ketones was found to proceed with high enantioselectivity (92-97% ee) in the presence of catalytic amounts of a chiral Lewis acid (15 examples, 52-80% yield). A notable feature of the transformation is the fact that it proceeds on the singlet hypersurface and that no triplet intermediates are involved. Rapid racemic background reactions were therefore avoided, and the catalyst loading could be kept low (10 mol %). Computational studies suggest that the enantioselectivity is determined within a Lewis acid bound singlet intermediate via a conical intersection. The utility of the method was demonstrated by a concise synthesis of the natural product trans-chrysanthemic acid.

Full text of DOI:10.1021/jacs.9b12068

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Communication
Lewis Acid Catalyzed Enantioselective Photochemical
Rearrangements on the Singlet Potential Energy Surface
Malte Leverenz, Christian Merten, Andreas Dreuw, and Thorsten Bach
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b12068 • Publication Date (Web): 08 Dec 2019
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Lewis Acid Catalyzed Enantioselective Photochemical
Rearrangements on the Singlet Potential Energy Surface
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Malte Leverenz,† Christian Merten,‡ Andreas Dreuw,§ and Thorsten Bach†*
+ Department Chemie and Catalysis Research Center (CRC), Technische Universität München, Lichtenbergstrasse 4,
85747 Garching, Germany
‡ Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstraße 150, 44801 Bochum, Germany.
§ Interdisciplinary Center for Scientific Computing, Ruprecht-Karls Universität, Im Neuenheimer Feld 205A, 69120
Heidelberg, Germany
Supporting Information Placeholder
Scheme 1. Photochemical Reactivity Modes of
Complexes between a Chiral Lewis Acid (L.A.*) and a
Substrate
ABSTRACT: The oxadi--methane rearrangement of 2,4-
cyclohexadienones to bicyclic ketones was found to proceed
with high enantioselectivity (92-96% ee) in the presence of
catalytic amounts of a chiral Lewis acid (15 examples, 52-80%
yield,). A notable feature of the transformation is the fact that
it proceeds on the singlet hypersurface and that no triplet
intermediates are involved. Rapid racemic background
reactions were therefore avoided and the catalyst loading
could be kept low (10 mol%). Computational studies suggest
that the enantioselectivity is determined within a Lewis acid
bound singlet intermediate via a conical intersection. The
utility of the method was demonstrated by a concise synthesis
of the natural product trans-chrysanthemic acid.
L.A.*
via
O
O
chiral Lewis
acid (L.A.*)
T1
h
product
O
ISC
I
L.A.*
L.A.*
R1
O
O
chiral Lewis
acid (L.A.*)
H
R
R
R
h
R
R
R1
R1
R
via
R2
R2
R2
S1
1
2
1
L.A.*
The construction of a complex molecular skeleton in a single
step is arguably the most fascinating hallmark of
photochemical transformations. The high energy content of a
light-excited substrate enables the formation of bonds which
are not accessible by thermal methods.1,2 Although
photoredox catalysis has opened several new avenues for
enantioselective synthesis via ground state intermediates,3,4
the control of competing enantiomorphic reaction pathways
in the excited state continues to pose a formidable challenge.
After seminal contributions to the field in the last decades of
the 20th century,5,6 recent efforts towards catalytic
enantioselective photochemical reactions in solution7-9 have
mainly aimed at the formation of cyclobutanes by [2+2]
photocycloaddition reactions.10-16 Our group has exploited
chiral Lewis acids in this context17-19 and we found that
reversible coordination to an enone substrate I (Scheme 1)
leads to a bathochromic shift of the allowed * transition
(absorption coefficient  > 10 000 M1 cm1). Excitation of
complex I·L.A.* at long wavelength generates via a singlet
intermediate (S1) the reactive * triplet state (T). Since
intersystem crossing (ISC) from * to * is slow while ISC
from n* to * is fast20 the catalyzed reaction is retarded.21 As
When searching for enone reactions which would occur from
the S1 state we came across a study by Griffith and Hart that
dealt with the photochemical behavior of substituted 2,4-
cyclohexadienones 1.22 It had been found that typical triplet
reaction observed for this substrate class were suppressed in
polar media and that an oxadi--methane rearrangement23,24
occurred. In a later study by Uppili and Ramamurthy,25 the
photochemical
rearrangement
of
a
single
2,4-
cyclohexadienone was performed within a zeolite and an
enantiomeric excess (ee) of up to 49% was achieved with ()-
ephedrine as superstoichiometric (10 equiv.) inductor at 55
°C. We hypothesized that complexation of substrates 1 with a
chiral Lewis acid would lead to a complex 1·L.A.* which would
upon direct excitation generate enantiomerically enriched
products 2 via a singlet intermediate. We now report on our
studies in this area which have led to the first catalytic
enantioselective26 oxadi--methane rearrangement.27
Initial
experiments
were
conducted
with
2,4-
cyclohexadienone 1a the absorption properties of which were
examined in the absence and in the presence of Lewis acids
(Figure 1). Successive addition of BF3·OEt2 to a solution of the
compound in dichloromethane (c = 2 mM) led to a shift of the
* band ( = 310 nm,  = 5380 M1 cm1). Due to coordination
of BF3 to the oxygen lone pair the n* absorption (shoulder at
 = 365 nm,  = 335 M1 cm1) vanished. A new band appeared
a
result, the uncatalyzed reaction initiated by direct
irradiation of  via its n* state becomes competitive which in
turn requires a high Lewis acid loading (50 mol%) to secure
high enantioselectivities.
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at  = 360 nm which was assigned to the * transition of the
racemate (Scheme 2). At  = 420 nm, neither the product nor
its BF3 complex show a detectable absorption and secondary
photochemical reactions are avoided (Figure S2).
1
2
3
4
5
6
7
Lewis acid complex 1a·BF3. Assuming the complex formation
to be complete upon addition of two equivalents of the Lewis
acid the absorption coefficient was calculated as  = 6920 M1
cm1. Isosbestic points at  = 272 nm and at  = 330 nm indicate
that no other species contribute to the absorption spectra
except for 1a and 1a·BF3. Similar spectra were obtained with
EtAlCl2 as the Lewis acid (Figure S1).
Scheme 2. Lewis-acid Catalyzed Photochemical
Rearrangement 1a → 2a and ent-2a
O
 = 420 nm
10 mol% BF3OEt2
r.t. (CH2Cl2)
O
O
H
H
+
8
60%
9
1a
2a
-
ent 2a
1.6
1.2
0.8
0.4
0
0.00 eq
0.05 eq
0.10 eq
0.20 eq
0.50 eq
1.00 eq
2.00 eq
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Having established a catalytic protocol for the oxadi--
methane rearrangement of substrate 1a we started to screen
potential chiral Lewis acids. The screening commenced with
typical AlBr3-activated oxazaborolidines which we had
previously used for enantioselective photochemical
reactions.17-19 They are derived from bis(3,5-dimethylphenyl)-
2-pyrrolidinyl-methanol and prepared by condensation with a
boronic acid.19,28 However, it turned out that the
enantioselectivities remained unsatisfactory (< 50% ee) which
forced us to consider variations of the aryl groups at the
methanol carbon atom. Catalyst 3 (Table 1) with sterically
bulky 3',5'-dimethyl-2-biphenyl groups as aryl substituents
both at the carbon and at the boron atom evolved from these
experiments as the superior Lewis acid that promoted the
reaction 1a → 2a at  = 420 nm (10 mol%, 75 °C in CH2Cl2) in
a yield of 60% with 85% ee. Optimization of the irradiation
conditions led to an improved performance if a light emitting
diode (LED) with an emission maximum at  = 437 nm was
employed (Figures S4-S8). Product 2a was obtained in 68%
yield with 92% ee. The absolute configuration of the product
was established by vibrational circular dichroism (VCD)29
comparing experimental and calculated spectra (for details,
see Figures S9, S10). The absolute configuration of the other
products 2 was assigned based on analogy. The assignment is
supported by the identical direction of the specific rotation for
all compounds (dextrorotatory) and was later confirmed by a
natural product synthesis (vide infra). It was possible to extend
the method to a large variety of 3-alkyl substituted 2,4-
cyclohexadienones (1b-1o) which had not been previously
employed for the reaction (Table 1).
220
320
λ [nm]
420
Figure 1. UV/Vis spectra of 2,4-cyclohexadienone 1a in the
absence and in the presence of different equivalents of
BF3.OEt2 (c = 2 mM in CH2Cl2, r.t.).
In general, the absorption difference of complexed vs.
uncomplexed enones  (in nm) increases if the original *
absorption of the chromophore occurs at higher wavelength.
For 2,4-cyclohexadienone 1a, the absorption maximum of
complex 1a·EtAlCl2 was at  = 368 nm with  = 58 nm.
Compared with other enones, which absorb at shorter
wavelength, the shift was larger.18,19 Together with the
expectation of a singlet reaction pathway, an enantioselective
transformation even at low Lewis acid catalyst loading seemed
therefore feasible.
The fact that the Lewis acid-induced shift tailed into the
visible region (Figure 1) invited a reaction with visible light.
While irradiation of 1a at  = 420 nm in the absence of a Lewis
acid did not lead to a detectable conversion (for details, see
Table S1), 10 mol% of BF3 as the Lewis acid induced the
expected rearrangement. The product was formed as a 1:1
mixture of the two enantiomers 2a and ent-2a, i.e. as the
Table 1. Enantioselective Photochemical Rearrangement 1 → 2 Mediated by Chiral Lewis Acid 3
h ( = 437 nm)a
O
O
O
O
O
O
H
H
H
O
3
H
H
H
10 mol%
O
R
H
(CH2Cl2)
R
N
O
78 °C, t = 5 h
R
B
Br3Al
Et
iPr
tBu
Bu
H
H
H
H
H
R1
R1
R
R2
R2
2a
ee 2b
ee
2c
ee
2d
93%
ee
2e 93% ee
2f 93% ee
92%
93%
95%
1
2
68% yield
52% yield
65% yield
53% yield
70% yield
75% yield
3
O
H
O
O
O
O
O
O
O
O
H
O
Cl
H
H
H
H
NPhth
H
H
H
O
Ph
O
F3C
O
H
H
H
H
H
H
H
H
H
2jb
ee
2k
ee
2l
ee
2m
ee
2n
ee
2o
ee
2g
ee
2h
ee
2i
93%
93%
94%
ee
93%
93%
92%
92%
97%
96%
67% yield
56% yield
78% yield
86% yield
66% yield
57% yield
54% yield
60% yield
80% yield
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a Reactions were carried out on a 150 µmol scale at a concentration of c = 20 mM. b The reaction was carried out on a 750 µmol
scale at a concentration of c = 100 mM and at a wavelength of  = 425 nm for 24 h. c Phth = phthaloyl.
1
2
3
4
5
6
7
8
The enantioselectivity remained consistently high (>90% ee)
with yields varying between 52% and 86%. The reaction is
compatible with functional groups as demonstrated for aryl
(product 2g), alkenyl (2h), methoxy (2i, 2j), chloro (2k),
acyloxy (2l), trifluoromethyl (2m), and protected amino (2n).
O
F
F
B
F
TS1
Scheme 3. Enantioselective Total Synthesis of trans-
Chrysanthemic Acid (6)
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1. HO-NTCP, DIC, r.t. (CH2Cl2)
2.
50 mol% Ni(acac)2
50 mol% bpy
O
O
NaIO4, 3.5 mol% RuCl3
r.t. (DCE/H2O = 5/4)
H
OH
O
ClZn
85 °C (DMF)
2j
1
66%
35%
H
4
2 M NaOH, 60 °C
H
H
H
3
Figure 2. Reaction mechanism of the photochemical
rearrangement illustrated for substrate 1a
(MeOH/THF = 2/1)
1
O
OH
98%
H
O
O
It was found that the Lewis acid complex 1a·BF3 reaches the
first excited singlet state (S1) by an allowed ππ* transition.
Remarkably, the preferred conformation of this intermediate
is not planar but the gem-dimethylated carbon atom C6 bends
out of the plane in which the remaining five carbon atoms
reside (Figure 2). The C1-C5 distance has a value of 218 pm at
the equilibrium geometry of the S1 state. Proceeding along the
5
(93% ee)
6
a
Acac = acetylacetone; bpy = 2,2’bipyridine; DCE = 1,2-
dichloroethane, DIC = N,N’-dicarbonyldiimide; DMF = N,N-
dimethylformamide; Me
=
methyl; NTCP
=
N-
tetrachlorophthaloyl; THF = tetrahydrofuran.
Products 2 display several sites for further functionalization
and lend themselves to a potential use in synthesis. The gem-
dimethyl substituted cyclopropane ring is a notable feature in
terpene natural products and the monoterpene trans-
chrysanthemic acid seemed to be a viable target (Scheme 3).
Employing an oxidative cleavage protocol,30 we could
successfully convert oxadi--methane rearrangement product
2j into acid 4 without loss of enantiopurity (93% ee). Since the
projected Ni-catalyzed coupling step31 was known to proceed
in low yield, we synthesized the starting material 2j on larger
scale (100 mg) confirming that the photochemical reactions
can be run successfully at a higher concentration (Table 1).
After conversion to the N-tetrachlorophthaloyl (NTCP)
derivative, the coupling31 was performed without isolation of
the intermediate. The reaction produced the trans-compound
5 (d.r. > 95/5) with a consistent enantiopurity of 93% ee. The
stereogenic center at C1 is retained in this operation while the
stereogenic center at C3 is inverted. Saponification of the ester
delivered acid 6 as the levorotatory enantiomer which is
known to be (1S,3S)-configured.32 The synthesis consequently
supports the previous assignment of the absolute
configuration for photoproduct 2j.
relaxation pathway,
a
sloped conical intersection is
energetically accessible only 0.09 eV above the minimum
structure, which predominantly leads to relaxation back to the
ground state S0. At the optimized geometry of the conical
intersection, the critical C1-C5 distance decreases to only 193
pm. Those molecules not returning to the electronic ground
state enter the productive exit channel that proceeds via an
intermediate zwitterion now with a C1-C5 bond lengths of 1.50
Å. Thereby, the conical intersection avoids the population of
triplet states and secures a clean product formation with
however low quantum yield. The C-C bond formation between
carbon atoms C1 and C5 occurs via the trajectory
predetermined by the bending of carbon atom C6. The
reaction is completed by a typical 1,4-migration of the
cyclopropyl group via TS1 to the cationic carbon atom, which
proceeds via a small energy barrier of 0.15 eV leaving the
complex of product rac-1a·BF3 as the final reaction product.
The calculation also provides a plausible explanation for the
observed enantioselectivity. Bending of carbon atom C6 out of
the dienone plane in complex 1a·L.A. leads after C-C bond
formation to two enantiomeric intermediates 7 and ent-7
which in turn deliver products 1a and ent-1a (Figure 3).
Coordination of compound 1a to oxazaborolidine Lewis acids
is assumed to occur as previously established for cyclic
enones.37-39 In the presence of chiral Lewis acid 3, there is a
preference for formation of intermediate 7 because the C6
carbon atom in complex 1a·3 will not move in the direction of
the bulky 3',5'-dimethyl-2-biphenyl substituent at the boron
atom but will bend away from it. Product formation via
intermediate 7 leads to enantiomer 2a by 1,4-migration. The
importance of the hydrogen bond at carbon atom C2 to the
oxygen atom of the catalyst was corroborated in the present
The reaction 1a → 2a was performed under otherwise
unchanged conditions (Table 1) in the presence of up to 10
equiv. piperylene which is an established triplet quencher.33
There was no decrease in rate nor in yield for product 2a
indicating that triplet intermediates are not involved in the
reaction (for details, see Figures S11, S12). The hypothesis that
the reaction proceeds via a singlet intermediate was further
supported by quantum chemical calculations using density
functional theory (DFT) as well as spin-flip linear-response
time-dependent DFT (TDDFT)34,35 as implemented into Q-
Chem 5.0.36
study by the fact that
a
2-methyl-substituted 2,4-
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(3) Visible Light Photocatalysis in Organic Chemistry; Stephenson,
C. R. J.; Yoon, T. P.; MacMillan, D. W. C., Eds.; Wiley-VCH: Weinheim,
2018.
cyclohexadienone did not react enantioselectively (Figure
S13).
1
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3
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5
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7
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enantioselective organocatalysis with light. Nature 2018, 554, 41-49.
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that increases with temperature in a photochemically induced
enantiomeric isomerization. Nature 1989, 341, 225-226.
O
L.A.
L.A.
H
H
Br3Al
O
N
H
L.A.
O
B
7
Ar
6
6
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H
O
5
(7) Sherbrook, E. M.; Yoon, T. P. Asymmetric Catalysis of Triplet-
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induction in photocatalysis – Discovering a new side to light-driven
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energy transfer. Science 2016, 354, 1391-1395.
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7
1a
ent-
1a 3

L.A.
Figure 3. Migration of carbon atom C5 in Lewis acid
complex 1a·L.A. as the enantioselectivity determining step
leading either to enantiomer 7 or ent-7
In summary, we have discovered an enantioselective
photochemical rearrangement reaction that enables the rapid
formation of structurally unique, multifunctional products. A
remarkable feature of the transformation is the fact that Lewis
acid coordination opens a reaction channel that allows the
substrate to escape intersystem crossing via a conical
intersection. In addition, the Lewis acid governs the absolute
configuration of the product within a singlet intermediate.
This mode of action promises to be a useful design element for
enantioselective photocatalysis.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at http://pubs.acs.org.
Experimental procedures, analytical data and NMR spectra for
all new compounds, GLC and HPLC traces of chiral products,
VCD data, Cartesian coordinates, including Figures S1−S13,
Table S1 (PDF).
AUTHOR INFORMATION
Corresponding Author
*thorsten.bach@ch.tum.de
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support by the European Research Council under
the European Union’s Horizon 2020 research and innovation
programme (grant agreement No 665951  ELICOS) is
gratefully acknowledged. CM thanks the Fonds der
chemischen Industrie for a Liebig fellowship and the Deutsche
Forschungsgemeinschaft for support through the Cluster of
Excellence RESOLV (“Ruhr Explores SOLVation”, EXC 2033).
We thank O. Ackermann and J. Kudermann for their help with
the HPLC and GLC analyses.
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Table of Contents artwork
h ( = 437 nm)
cat.
O
10 mol%
(CH2Cl2)
O
R
H
R
N
O
78 °C, t = 5 h
R
B
Br3Al
R1
R1
R
R2
R2
15 examples
54-80%, 92-96% ee
cat.
 Singlet reaction pathway passing a conical intersection
 High functional group tolerance (COOMe, CF3, NPhth, OMe, Cl, Ph)
 Application to the synthesis of trans-chrysanthemic acid
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