Olefin-Supported Cationic Copper Catalysts for Photochemical Synthesis of Structurally Complex Cyclobutanes

Article abstract of DOI:10.1002/anie.202013067

The sole method available for the photocycloaddition of unconjugated aliphatic alkenes is the Cu-catalyzed Salomon–Kochi reaction. The [Cu(OTf)]₂?benzene catalyst that has been standard in this reaction for many decades, however, is air-sensitive, prone to photodecomposition, and poorly reactive towards sterically bulky alkene substrates. Using bench-stable precursors, an improved catalyst system with superior reactivity and photostability has been designed, and it offers significantly expanded substrate scope. The utility of this new catalyst for the preparation of sterically crowded cyclobutane structures is highlighted through the preparation of the cores of the natural products sulcatine G and perforatol.

Full text of DOI:10.1002/anie.202013067

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Accepted Article
Title: Olefin-Supported Cationic Copper Catalysts for Photochemical
Synthesis of Structurally Complex Cyclobutanes
Authors: Christopher Gravatt, Luis Melecio-Zambrano, and Tehshik
Peter Yoon
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COMMUNICATION
Olefin-Supported Cationic Copper Catalysts for Photochemical
Synthesis of Structurally Complex Cyclobutanes
Christopher S. Gravatt, Luis Melecio-Zambrano, and Tehshik P. Yoon*
[
a]
C.S. Gravatt, L. Melecio-Zambrano, Prof. T. P. Yoon
Department of Chemistry
University of Wisconsin–Madison
1
101 University Avenue, Madison, Wisconsin 53706 (USA)
E-mail: tyoon@chem.wisc.edu
Supporting information for this article is given via a link at the end of the document.
Abstract: The sole method available for the photocycloaddition of
formation of a copper bis(alkene) complex that is relatively
unstable, and a variety of common substrate structural features
unconjugated aliphatic alkenes is the Cu-catalyzed Salomon–Kochi
2
reaction. The [Cu(OTf)] •benzene catalyst that has been standard in
this reaction for many decades, however, is air-sensitive, prone to
photodecomposition, and is poorly reactive towards sterically bulky
alkene substrates. Using bench-stable precursors, we have designed
an improved catalyst system with superior reactivity and photostability
that offers significantly expanded substrate scope. The utility of this
new catalyst for the preparation of sterically crowded cyclobutane
structures is highlighted through the preparation of the cores of the
natural products sulcatine G and perforatol.
A. The Salomon and Kochi [2+2] reaction9
·
Cu(I) UV photoexcitation · unactivated alkenes · valuable bicyclic cyclobutanes
OH
H
CuOTf
Et2O, 254 nm, 18 h
OH
H
8
6% Yield12b
H
OTf
HO
· "Bare" copper source stabilized by anion
· Highly moisture and air sensitive precatalyst
Cu
·
Sterically hindered substrates leads to both
Anion Stabilized
substrate and catalyst decomposition
Cyclobutane rings feature in more than 2600 known natural
1
B. Enabling synthesis
products, and the challenge of synthesizing these compounds
HO
HO
CHO
has motivated the development of photochemical cycloaddition
reactions for many decades. Numerous mechanistically distinct
strategies for [2+2] photocycloadditions are known.2 The most
well-developed of these involve: (1) direct photoexcitation of
olefinic compounds featuring optical transitions in the visible or
H
H
H
Me
HO
OHC
O
Me
H
Me
Me
Me
Me
H
Me
H
Me
Me
3
Grandisol11a
Proposed Structure
Robustadiol A11b
Kelsoene11c
near-UV range; (2) triplet photosensitization of substrates with
triplet state energies sufficiently low enough to enable Dexter
C. Steric bulk presents challenges
4
energy transfer; and (3) photoredox reactions of alkene radical
OH
5
ions generated via photoinduced electron transfer. Notably, each
OH
CuOTf
of these activation modes requires the use of alkene substrates
with extended π conjugation. Unconjugated aliphatic alkenes
generally have short-wavelength optical transitions (<200 nm)2a
that are not accessible with commercial UV photoreactors. They
also feature higher-energy triplet excited states (76–84 kcal/mol)6
Et2O, 254 nm, 18 h
H
not observed12a
complex mixture of alkene
(
derived byproducts)
Me
Me
OH
O
OH
O
7
HO
Me
H
Me
and electrochemical potentials that lie outside of the range of
H
O
Me
8
most common photoredox catalysts. The sole method suitable
H
Me
Me
O
for the [2+2] photocycloaddition of aliphatic alkenes is the
Me
Me
Me
Me
H
Cu(OTf)-catalyzed process originally reported by Kochi and
Salomon in 1973.9,10 The key intermediate in this reaction is a 2:1
O
Br
(+)-Sulcatine G
Nemoralisin-type Diterpeniod
Perforatol
alkene-copper complex that absorbs at wavelengths that are
easily accessible using standard benchtop UV reactors (ca. 270
D. A new strategy
WCA
H
HO
Cu
nm). This absorbance corresponds to a metal-to-ligand charge
transfer (MLCT) transition,11 which initiates an inner-sphere bond-
· COD-stabilized cationic complex
· in situ generation from bench stable Cu(I) complex
· WCA decreases complex disruption
Me
Me
forming cascade that can convert simple aliphatic alkenes into
cyclobutanes that are simply not accessible using direct,
sensitized, or electron-transfer photochemistry (Figure 1A).
Although the Salomon–Kochi photocycloaddition has
featured in several total syntheses (Figure 1B),12 the conditions
for this reaction have not been significantly reinvestigated since
its early reports, and the utility of this method has been hampered
by its narrow scope. Successful cycloaddition requires the
Olefin Ligand Stabilized
· Enhanced steric tolerance enables reactivity
Figure 1: a) Salomon–Kochi reaction and catalyst limitations b) Total synthesis
application of Salomon–Kochi reaction c) Sterically challenging target natural
products d) Newly developed catalyst system employing weakly coordinating
anions.
1
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COMMUNICATION
can destabilize the formation of this complex, thereby preventing
the reaction from occurring. Most critically, sterically bulky
alkenes bind less well to Cu(I) and thus are poor substrates for
this strategy. 13 Consequently, many of the most interesting
complex cyclobutane natural products cannot be efficiently
synthesized using the Salomon–Kochi protocol or indeed by any
known photocycloaddition methodology (Figure 1C). This
represents a significant gap in chemists’ ability to synthesize the
diverse family of cyclobutane-containing natural products.
reaction and were delighted to observe increased reactivity, with
a correlation between the calculated gas-phase acidities16 of the
WCA conjugate acids and the yield of the cycloaddition (entries
5–7). The optimal SbF –
complex afforded 94% yield of the [2+2]
6
cycloadduct in just 1 h. Indeed, the reaction proceeds essentially
to completion in only 30 min (entry 8), highlighting the substantial
rate improvement using this optimal catalyst over the canonical
triflate salt.
To test the importance of the Cu(I):COD stoichiometry, we
One notable consequence of the relative instability of the
cationic copper bis(alkene) intermediate is a strong dependence
on the coordinating ability of the counteranion. Salomon reported
that photocycloadditions catalyzed by CuOTf occur at least an
2 6
next independently prepared [Cu(COD) ]SbF and found it to be
a less effective catalyst (entry 9), consistent with the expected
slow rate of exchange of the second COD ligand with substrate.
Excess COD ligand also has a strong inhibitory effect on the
cycloaddition (entry 10). Similarly, the use of CuCl as a
precatalyst in the absence of COD ligand proved ineffective (entry
11). 17 Finally, control experiments excluding the Cu catalyst,
silver salt, or light source resulted in no observable consumption
of the substrate (entries 12–14), demonstrating the necessity of
each of these reaction components.
9
order of magnitude faster than those conducted using CuCl. This
observation was attributed to the ability of more nucleophilic
counteranions to displace the labile olefin ligands. We
hypothesized that complexes bearing even more weakly
coordinating counteranions (WCAs) than triflate would result in a
more electrophilic Cu(I) metal center that could productively
engage bulky alkenes in this reaction.
Table 1: Optimization of in situ catalyst generation with silver salts of WCAs
As a platform to test these ideas, we first examined the
photocycloaddition of diene 1, which Salomon had reported was
a poor substrate.13a Consistent with precedent, conditions that
have most commonly been utilized for the Salomon–Kochi
Cu(I) cat.
OTBS
or
Me
OTBS
Me
[
Cu(COD)Cl]2/AgX
2
cycloaddition (1 mol% [Cu(OTf)] •benzene) afforded only 28% of
0
.025 M Et2O, 254 nm, 0.5-1 h
Me
Me
cyclobutane product (Table 1, entry 1). The reaction does not
proceed to completion upon extended irradiation times, and the
observation of Cu0 depositing in the reaction vessel indicated
significant catalyst decomposition (entry 2). We imagined that
Cu(I) complexes bearing even more weakly coordinating anions
might increase the reaction rate. However, attempts to synthesize
Cu(I)•benzene complexes featuring a range of WCAs, either
alone or in situ, were not successful due to the propensity of these
unstabilized Cu(I) salts to undergo rapid decomposition. We
wondered if alternate ancillary ligands might better stabilize the
cationic Cu(I) center. Nitrogen and phosphine donor ligands
commonly utilized in copper catalysis, however, have been shown
to inhibit photocycloaddition, either by disfavoring formation of the
bis(alkene) complex or by producing other low-energy charge-
transfer excited states that outcompete formation of the requisite
alkene MLCT state.12a,14
1
2
Entry
[Cu]
[Ag]
Time
Yielda,b
1
2
3
4
5
6
7
8
9
1 mol% [CuOTf]
1 mol% [CuOTf]
2
•C
•C
6
H
6
6
-
1 h
18 h
1 h
28% 4:1 d.r.
42% 4:1 d.r.
33% 4:1 d.r.
91% 4:1 d.r.
52% 4:1 d.r.
57% 8:1 d.r.
94% 4:1 d.r.
81% 4:1 d.r.
18% 4:1 d.r.
0%
2
6
H
-
1 mol% [Cu(COD)Cl]
1 mol% [Cu(COD)Cl]
1 mol% [Cu(COD)Cl]
1 mol% [Cu(COD)Cl]
1 mol% [Cu(COD)Cl]
2
2
2
2
2
AgOTf (299.5)c
AgOTf (299.5)c
18 h
1 h
(288.0)c
4
AgBF
AgNTf
AgSbF
(286.5)c
(255.5)c
1 h
2
6
1 h
1 mol% [Cu(COD)Cl]2
2 mol% Cu(COD) SbF
AgSbF6
-
0.5 h
0.5 h
0.5 h
0.5 h
0.5 h
0.5 h
0.5 h
2
6
1
0d
1 mol% [Cu(COD)Cl]
2 mol% CuCl
2
2
2
,
AgSbF
AgSbF
-
6
6
We hypothesized instead that a diene ligand such as
cyclooctadiene (COD) might stabilize the highly electron-deficient
Cu(I) center without engendering competitive low-energy charge-
transfer states. Because displacement of a COD ligand by a less
conformationally rigid bis(alkene) substrate would likely be
11
9%
1
1
2
3
1 mol% [Cu(COD)Cl]
-
0%
AgSbF
AgSbF
6
6
0%
14e
1 mol% [Cu(COD)Cl]
0%
Cu(I) complexes15
thermodynamically unfavorable, known (COD)
2
seemed unlikely to be suitable precatalysts. We wondered
instead if coordinatively unsaturated Cu(I) complexes could be
[
a] Reactions conducted in quartz tubes equipped with a cold finger. Irradiation
took place in a Rayonet RP-100 photoreactor with 254 nm bulbs. [b] NMR yields
taken with TMS-Ph as internal standard. [c] Gas phase acidity constants of
corresponding acid. [d] Reaction conducted in the presence of 50 mol%
additional COD ligand. [e] No UV irradiation.
generated in situ by anion metathesis of dimeric [Cu(COD)Cl]
2
with Ag(I) salts of WCAs (Figure 1D). This strategy would enable
use of bench-stable catalyst precursors in this reaction instead of
the air- and moisture-sensitive [Cu(OTf)]
has been the catalyst of choice for this reaction for decades.
As a control, we first treated [Cu(COD)Cl] with AgOTf in situ,
and the resulting complex performed similarly to the standard
Cu(OTf)] •benzene catalyst (entry 3). However, extended
2
•benzene complex that
Studies examining the scope of the photocycloaddition
using this new catalyst system are summarized in Table 2. We
first examined the reactivity of variously substituted 1,6-
2
heptadienes
(2–8).
/AgSbF
•benzene catalyst in all cases examined. This
As
expected,
the
optimized
[
2
[
[
Cu(COD)Cl]
Cu(OTf)]
2
6
catalyst system outperforms the standard
irradiation results in complete conversion, demonstrating that
diene ligands are indeed able to stabilize the highly electron-
deficient cationic Cu(I) center without attenuating its photoactivity
2
advantage became more evident with greater steric bulk on the
alkene, consistent with our catalyst design strategy. Cyclization of
naturally occurring terpenes linalool and nerolidol demonstrate
(
entry 4). We next examined the use of a series of WCAs in this
2
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COMMUNICATION
Table 2: Scope and Comparison Studies for the Cu(I)-Catalyzed Photocycloaddition
X mol% [Cu(COD)Cl]
OTBS
2
OTBS
Me
1
0X mol% AgSbF
6
2
0.025 M Et O, rt, 254 nm
Me
Me
Me
1
2
OTBS
OTBS
OTBS
OTBS
Me
OTBS
H
Me
H
Me
H
Me
H
H
2
3
4
5
6
1
mol% 1 h,
yield = 94% 4:1 d.r.
CuOTf yield = 28% 4:1 d.r.
1 mol% 30 min,
yield = 95% , 89%
CuOTf yield = 39%a
1 mol% 30 min,
1 mol% 30 min,
1 mol% 1 h,
a
a
b,c
a
a
a
yield = 94% >20:1 d.r.
yield = 91% >20:1 d.r.
yield = 89% >20:1 dr
a
CuOTf yield = 43% >20:1 d.r.a
CuOTf yield = 17% >20:1 d.r.a
CuOTf yield = 85% >20:1a
Me
OH
Me
OH
Me
H
H
H
H
H
O
CO
2
2
Me
Me
CO
2
Me
Me
Me
Me
Me
Me
CO
CO
H
2
Me
H
Me
H
H
H
Me
7
8
9
10
11
1 mol% 8 h,
1
mol% 6 h,
1 mol% 1 h,
1 mol% 3 h,
yield = 68%b
1 mol% 3 h,
a
a
a
yield = 42%
yield = 90%
yield = 87% 1:1 d.r.b
yield = 48%
CuOTf yield = 4%a
CuOTf yield = 51%a
CuOTf yield = 16%a
CuOTf yield = 28 1.5:1 d.r.%a
H
H
N
H
H
H
H
HO
O
O
O
OH
OH
O
N
N
OEt
OEt
OtBu
H
H
Me
H
1
2
13
14
15
16
1
mol% 1 h,
2.5 mol% 20 h,
2.5 mol% 20 h,
2.5 mol% 20 h,
2.5 mol% 7 h,
b
yield = 74%a
yield = 97%a
yield = 64%a
yield = 86%a
yield = 84% 1.5:1 d.r.
CuOTf yield = 62% 1:1 d.r.
CuOTf yield = 23%a
a
OPG
Protecting Group
Yield
H
H
H
PinB
O
CO
2
Me
Me
PG= Piv
TES
19 5 h, 97% 5:1 d.r.b
20 2 h, 80% 2:1 d.r.a,d
21 3 h, 77% 6:1 d.r.a
22 5 h, 85% 5:1 d.r.b
O
CO
2
H
H
H
MOM
Alloc
Bn
1
1
9-23
mol%
1
7
18
1
mol% 1 h,
yield = 92%
1 mol% 3 h,
yield = 76% 2.5:1 d.r.b
23 5 h, 64% >20:1 d.r.b (CuOTf <5%)a
a
[
a] NMR Yields based on TMS-Ph internal standard; [Cu(OTf)]
2
•benzene yields at same catalyst loading, concentration and timepoint; [b] Isolated yields; [c]
gram-scale reaction;. [d] 2.5 mol% AgSbF , 0.0125 M in Et O.
6
2
tolerance both for a free hydroxyl group and pendant substituted
olefins (9–10). Interestingly, nerolidol cycloadduct 10 was isolated
as a 1:1 mixture of diastereomers, despite the well-defined
geometry of the starting alkene. Even with the increased Lewis
acidity of the reactive Cu(I) center, a range of Lewis basic
functional groups including amides, ethers, and alcohols are
readily tolerated (11–15). The rate of reaction slowed using a
chelating 1,3-diol-containing substrate (16), which required longer
reaction time and higher catalyst loading. Protection of the diol,
however, fully restores reactivity (17). Vinyl boronate esters also
cyclize in good yield (18) without any observed unproductive
of the protecting group (22). Interestingly, benzyl protecting
groups are uniquely tolerated by the new catalyst system; we
observed complete decomposition of this substrate when the
reaction was conducted using CuOTf (23). For ease of synthesis,
many of the substrates examined bear oxygen substituents in the
allylic position. Regardless of the alkene substitution or the
identity of the allylic coordinating functional group, the
cycloaddition preferentially results in the formation of the
thermodynamically less favourable anti-cycloadduct. This result is
consistent with Salomon’s observations using allylic alcohol
substrates, suggesting a chelating interaction with the Cu(I)
deborylation, providing
a
synthetic handle for further
center in the reactive complex.13b
Finally, these reaction
derivatization. A range of common alcohol protecting groups were
also investigated (19–23). A base-sensitive pivalate protecting
group (19) is well tolerated. An acid-sensitive TES group can be
utilized in place of TBS (20), albeit with somewhat diminished
endo diastereoselectivity. Highly chelating MOM protecting
groups are well tolerated (21). Furthermore, allyl carbonate with a
third alkene binding site gives good yields without decomposition
conditions were found to be readily scalable: a batch reaction
conducted on gram-scale afforded 3 in 89% yield after 5 h of
irradiation.
Given the observation that geometrically well-defined
alkene substrates result in the formation of diastereomeric
products, we became interested in the origin of the loss of
stereochemical integrity. First, we prepared the trans and cis
3
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COMMUNICATION
a.
TBSO
isomers of O-allyl but-2-ene-1,4-diol and irradiated them under
the optimized reaction conditions. Both afford a mixture of
diastereomers in good yields, but importantly, the identity of the
major diastereomer differs (Scheme 3). For a more detailed
insight, we conducted a time-course experiment using cis isomer
OH
Me
TBSO
H
O
Me
Me
2
.5 mol% [Cu(COD)Cl]2
10 mol% AgSbF6
HO
H
H
0.0125 M Et2O,
254 nm, 1h
Me
Me
Me
Me
H
Me
H
Me
H
Me
Me
2
8. We observed the formation of trans alkene 26 over the course
2
9
30
9
8% 3:1 d.r.
(+)-Sulcatine G
of this experiment, and the rate of its formation is competitive with
the production of the cycloadducts.18 Furthermore, the alkene
isomerization occurs only upon irradiation. We conclude,
therefore, that the cycloaddition itself is stereospecific, and that
the loss of stereochemical fidelity is due to an alternate Cu-
catalyzed photoreaction that scrambles the geometry of the
starting alkene.
CuOTf 48% 2:1 d.r.
b.
Me 1 mol% [Cu(COD)Cl]2
2.5 mol% AgSbF6
Me
Me
Me
HO
Me
Br
0.025 M Et O,
2
254 nm, 1h
Me
Me
3
2
Me
3
1
97%
Perforatol
CuOTf 44%
syn Major
1
mol% [Cu(COD)Cl]2
0 mol% AgSbF6
H
Scheme 4. Cyclization of Sterically Hindered Natural Product Cores 3.
OH
HO
1
O
O
0.025 M Et2O, 254 nm,
1
h
H
In summary, we have developed a new catalyst system that
extends the useful scope of the Cu-catalyzed Salomon–Kochi
photocycloaddition reaction, enabling the cycloaddition of
sterically encumbered substituted alkenes. Two features are
critical to the success of this strategy. First, the use of a weakly
2
6
27, 84% 2.8:1 dr
H
[Cu]
OH
trans isomer
coordinating SbF –
counteranion increases the reactivity of the
6
Background photochemical
E/Z isomerization
catalyst by favoring the formation of the requisite
copper:bis(alkene) complex. Second, while weakly coordinated
cationic Cu(I) salts are prone to decomposition under the reaction
conditions, a COD ligand can stabilize the Cu(I) center without
engendering the unproductive competitive low-energy LMCT
transitions that would be introduced using more traditional
nitrogen or phosphorous ligands. The optimal catalytic complex is
capable of engaging hindered polysubstituted alkene substrates,
can be generated from bench-stable precursors, and enjoys
H
[Cu]
OH
cis isomer
anti Major
OH
H
1
mol% [Cu(COD)Cl]2
0 mol% AgSbF6
HO
1
O
O
0
.025 M Et2O, 254 nm,
2
greater stability compared to the standard [Cu(OTf)] •benzene
H
1
h
precatalyst. The preparation of the cores of the natural products
sulcatine G and perforatol demonstrate the utility of this reaction
in accessing structurally complex cyclobutane natural products.
2
8
12, 83% 1.4:1 dr
Scheme 3. Origins of observed diastereoselectivity.
Acknowledgements
The enhanced reactivity of this new catalyst system,
particularly towards substituted alkene substrates, significantly
expands the applicability of photocycloaddition methodology to
the synthesis of a broader class of complex cyclobutane natural
products. To highlight this potential, we used this new method to
prepare the core of the natural product sulcatine G19 in 98% yield.
As expected, the improved method provides significantly superior
results compared to [Cu(OTf)]•benzene (Scheme 4a). Importantly,
this reaction favors formation of the highly sterically disfavored
anti configuration of the bridgehead substituents (30) due to allylic
hydroxyl coordination, a key structural feature of this molecule.
We also prepared the core of perforatol20 in high yield and as a
single diastereomer (32), the new catalyst again showing faster
rates of cycloaddition (Scheme 4b).
We gratefully acknowledge funding from the NIH (GM095666)
and ACS-PRF (49817-ND1) for support of this research. NMR
and MS facilities at UW–Madison are funded by the NSF (CHE-
1048642), NIH (1S10 OD020022-1), and a generous gift from the
Paul J. and Margaret M. Bender Fund.
Keywords: alkene ligands • copper • cycloaddition •
cyclobutanes • photocatalysis
1
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COMMUNICATION
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6
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5
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Angewandte Chemie International Edition
10.1002/anie.202013067
COMMUNICATION
Entry for the Table of Contents
SbF6
H
TBSO
Cu
OTBS
Me
Base metal photocatalyst
COD-stabilized Cu(I) complex
Bench-stable precursors
Me
Me
Me
25 examples, 2 natural product cores
Olefin-Supported
Cationic Cu(I) Catalyst
complex
cyclobutanes
We describe herein a new catalytic method for the [2+2] photocycloaddition of simple aliphatic alkenes. The Cu(I) catalyst features a
weakly-coordinating anion that enable the formation of a long-lived Cu-bis(alkene) complex and supporting olefin ligands that
stabilize the cationic Cu(I) center without disrupting its photochemistry. This catalyst enjoys increased reaction rates and substrate
scope compared to previous Cu-templated photocycloaddition methods.
Institute and/or researcher Twitter usernames: @UWMadisonChem @TehshikYoon
6
This article is protected by copyright. All rights reserved.