Tandem dienone photorearrangement-cycloaddition for the rapid generation of molecular complexity

Article abstract of DOI:10.1021/ja409992m

A tandem dienone photorearrangement-cycloaddition (DPC) reaction of novel cyclohexadienone substrates tethered with various 2π and 4π reaction partners resulted in the formation of polycyclic, bridged frameworks. In particular, use of alkynyl ether-tether

Full text of DOI:10.1021/ja409992m

Article
pubs.acs.org/JACS
Tandem Dienone Photorearrangement−Cycloaddition for the Rapid
Generation of Molecular Complexity
Pieter H. Bos, Mitchell T. Antalek, John A. Porco, Jr.,* and Corey R. J. Stephenson*,†
Department of Chemistry, Center for Chemical Methodology and Library Development (CMLD-BU), Boston University,
590 Commonwealth Avenue, Boston, Massachusetts 02215, United States
S
* Supporting Information
ABSTRACT: A tandem dienone photorearrangement−cycloaddition
(DPC) reaction of novel cyclohexadienone substrates tethered
with various 2π and 4π reaction partners resulted in the formation
of polycyclic, bridged frameworks. In particular, use of alkynyl
ether-tethered substrates led to (3 + 2) cycloaddition to afford
strained alkenes which could be further elaborated by intra- and
intermolecular cycloaddition chemistry to produce complex,
polycyclic chemotypes.
As part of a program directed toward the synthesis of novel
chemotypes, we have been interested in leveraging the powerful
transformations enabled by photochemical excitation for the rapid
generation of molecular diversity from simple, readily available
scaffolds.4 Moreover, photochemical transformations are easily
parallelized with simple reactor designs5 and scale-up can be
readily accomplished using continuous processing technology.6
Equally important, photochemical transformations provide access
to products with rich topological complexity and stereochemical
diversity.
We wished to investigate the photochemical rearrangement of
substituted cyclohexadienones to oxyallyl cations,7 versatile
intermediates which have found broad applicability in reaction
development and complex molecule synthesis.8 In 1985, Schultz
and co-workers demonstrated that dienone photorearrangement
of cyclohexadienone 1 led to the formation of an oxyallyl cation
intermediate which underwent dipolar cycloaddition with a
pendant furan to afford the (4 + 3) cycloadduct 2 (Scheme 1a).9
While the majority of examples conducted were intramolecular
cycloadditions involving carbon-tethered alkenes, Schultz and
co-workers also observed intermolecular reactions, albeit in
lower chemical yields.10 A limited study on the factors controlling
the mode of cycloaddition showed that substituent effects (both
steric and electronic) appear to play dominant roles in
determining product distributions.11
INTRODUCTION
■
Photochemistry is a useful tool for the generation of
architecturally interesting small molecules1 and is often used as
a key step in the synthesis of natural products.2 In light of these
developments, it is surprising that photochemistry is underutilized
in the development of novel scaffolds for drug development.3
Scheme 1. (a) Tandem Dienone Photorearrangement by
Schultz et al.;9 (b) Possible Reaction Pathways for
Intramolecular (3 + 2) or (5 + 2) Cycloaddition with Tethered
Alkene Substrates
With the advent of powerful strategies for the oxidative
dearomatization of phenols,12 we were interested in examining
the potential of a modular dearomatization-photorearrangement-
cycloaddition strategy to generate topologically rich molecular
architectures from readily available materials (phenols and
ω-alkenols or ω-alkynols). Specifically, we were interested in
determining the factors responsible for divergent, intramolecular
(3 + 2) and (5 + 2) photocycloaddition pathways of oxyallyl
Received: September 27, 2013
Published: October 25, 2013
© 2013 American Chemical Society
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cations 3 derived from substrates 4 (Scheme 1b) to produce
bridged (5, 6, and 7) or fused frameworks (e.g., 8).
Herein, we report use of tandem dienone photorearrangement-
intramolecular cycloaddition (DPC) of alkenyl and alkynyl
ether-tethered cyclohexadienone substrates to produce a variety
of structurally complex cycloadducts. In particular, use of alkynyl
ether-tethered substrates led to (3 + 2) cycloaddition to afford
strained alkenes which could be further elaborated to polycyclic
chemotypes.
Scheme 3. Mechanistic Rationale for Selective Formation of
5,1-Bonded Cycloaddition Products
RESULTS AND DISCUSSION
■
Our initial investigations focused on substituted cyclohexadie-
none substrate 9, readily available via oxidative dearomatization
of 2,4,6-trimethylphenol.13 Having optimized reaction parame-
ters (solvent/concentration/reaction time) for the conversion of
1 → 2 in a multiwelled photoreactor (Scheme 1),13 we examined
dienone photorearrangement−cycloaddition of alkene-tethered
substrate 9 (Scheme 2). Indeed, 9 was smoothly converted to a
Scheme 4. Mechanistic Proposal for Selective Formation of
1,3-Bonded Cycloaddition Products
Scheme 2. Dienone Photorearrangement−Cycloaddition of
Alkene-Tethered Substrate 9
to complete regioselectivity in which case products 16 and 18
could be obtained in 85% and 78% yield, respectively (Table 1,
entries 3 and 4).
Upon replacement of the methyl group in the 4-position of the
cyclohexadienone substrate with aromatic substituents, a
decrease in regioselectivity was observed in some cases (cf.
Table 1, entry 5). Irradiation of diallyl acetal 27 provided the
DPC product in 52% yield as a 9:1 mixture of regioisomers
(Table 1, entry 6). Substitution of the terminal position of the
alkene with an ester moiety led to selective formation of
cycloadduct 30 in 80% yield (Table 1, entry 7). Photoirradiation
of substrate 31 provided silyl ether product 32 in 53% yield as a
12:1 mixture of 5,1-/1,5-product (Table 1, entry 8); whereas, its
corresponding Z-isomer gave an indiscernible mixture. Upon
irradiation of cyclic alkene-substituted cyclohexadienone sub-
strates, a decrease in yield and regioselectivity was observed
(Table 1, entries 9 and 10).
As depicted in Scheme 1, irradiation of cyclohexadienone
substrate 1 bearing a tethered furan led solely to the formation of
(4 + 3) cycloadduct 2 in excellent yield. Substrate 37 bearing a 3-
furyl ether connected to the cyclohexadienone moiety did not
lead to the formation of the corresponding (4 + 3) cycloadduct.
In this case, (5 + 2) cycloaddition was observed to provide a 7:1
mixture of the 5,1- and the 1,5-bonded products in 51% isolated yield
(Table 1, entry 11). Substitution of the 5-position of the furyl group
of substrate 1 with an ester moiety cleanly afforded the (4 + 3)
cycloadduct 40 in 81% isolated yield (Table 1, entry 12).
10:1 mixture of the 5,1- and 1,5-bonded products (10 and 11,
respectively) in 83% isolated yield upon irradiation (λ > 300 nm)
in benzene at 20 °C for 20 min. Interestingly, 1,3- and 1,6-
cycloaddition products were not observed upon irradiation of
substrate 9. In addition, cycloadduct 10 was observed as the
major regioisomeric cycloadduct. Although the reason for this
outcome was unclear at the time, we observed that the selectivity
was attenuated (10/11 = 6:1) when the reaction mixture was not
degassed prior to irradiation, presumably due to degradation of
the major product under the reaction conditions. The use of
polar solvents to potentially stabilize the oxyallyl cation did not
change the product distribution.13,14 Structural assignment of the
major isomer was confirmed by X-ray crystallographic analysis of
alcohol 12, obtained as a single diastereomer from reduction of
10:11 with NaBH4 in methanol (Scheme 2).13
We next focused our efforts on evaluating the scope of the
reaction (Table 1). Irradiation of substrate 9 with >300 nm light
in degassed benzene for 20 min afforded the DPC product in a
10:1 ratio of 5,1-/1,5-bonded product in 83% isolated yield
(Table 1, entry 1). In most cases, isolation of pure 5,1-products
such as 10 was accomplished by a reduction/oxidation
sequence.13 Switching from methallyl- to allyl-substituted
cyclohexadienone substrate 13 provided similar regioselectivity
to afford the 5,1-product 14 in 80% isolated yield (Table 1, entry 2).
Elongation of the carbon spacer with an extra methylene group led
To rationalize the observed preference for 5,1- vs 1,5-bonded
products, we examined molecular models of the zwitterionic
intermediate formed after dienone photorearrangement
(Scheme 3).15 Formation of the 1,5-bonded product appears
to be disfavored due to steric hindrance between one of the
methyl groups on the cyclohexadienone core and the tethered
alkene. This disfavored steric interaction is particularly apparent
in the case of substrate 15 which provided exclusively the 5,1-
product 16 in 85% isolated yield.
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a
Table 1. Substrate Scope for Dienone Photorearrangement−Cycloaddition
a
Reaction conditions: substrate (0.25 mmol) in benzene (10 mL) degassed for 30 min followed by irradiation (>300 nm) at room temperature
b
c
d
1
for 20 min. Isolated yield. Regioselectivity determined by H NMR analysis of the crude reaction mixture in parentheses. Isolated yield of the
5,1-product.
On the basis of these results, we surmised that the use of a
tethered alkyne in the cycloaddition may provide a surrogate for
the formation of the 1,3-bonded cycloaddition product.
Examination of transition state models for dienone photo-
rearrangement of substrate 41 (Scheme 4) shows that as a
consequence of the linear geometry of the alkyne, cycloaddition
to form 5,1- or 1,5-adducts is geometrically impossible.
To test this hypothesis, we prepared alkyne-tethered cyclo-
hexadienone substrate 4116 in analogous fashion to the alkene
counterparts.13 Photoirradiation of substrate 41 led to the
formation of the (3 + 2) cycloaddition product 42 as predicted by
our hypothetical transition state model (Scheme 4). Although
adduct 42 was cleanly formed during the photochemical reaction
as observed by 1H NMR analysis of the crude reaction mixture,
the product proved to be unstable to attempted chromatographic
purification and other isolation attempts (Scheme 5). This
instability can be explained by the strained nature of the system
which was also confirmed by DFT calculations (B3LYP/6-31g**),
predicting torsion angles for strained alkene 42 up to 45.9° out of
the plane (χC’ = 45.9° and χC” = 10.8°, see Scheme 5).17,18 We were
able to leverage this high energy intermediate in cycloaddition
chemistry by successfully trapping the alkene in an intramolecular
(4 + 2) cycloaddition with furan providing a 3:2 mixture of
regioisomers (43/44) in 70% isolated yield (Scheme 5).19,20
Although the two diastereomeric cycloadducts were inseparable, the
major isomer could be assigned on the basis of coupling constant
analysis (43, Ha, singlet, calculated dihedral angle Ha:Hb = 87.5° and
44, Ha′, doublet, J = 4.9 Hz, calculated dihedral angle Ha′:Hb′ =
39.7°).21 Intramolecular dipolar cycloaddition with in situ-generated
benzonitrile oxide22 afforded a 5.5:1 mixture of tetracyclic
regioisomers 45/46.
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Scheme 5. Trapping of Unstable, Strained Alkene 42 by
Cycloaddition with Furan or a Nitrile Oxide
Figure 1. X-ray crystal structure of polycyclic compound 50.13
CONCLUSION
■
In summary, we have employed a dienone photorearrangement−
cycloaddition (DPC) sequence for the synthesis of highly
functionalized, bridged tri- and tetracyclic frameworks. Photo-
irradiation of alkenyl ether-tethered cyclohexadienones led to
the favored production of 5,1-bonded (5 + 2) cycloaddition
products. Alternatively, use of alkynyl ether-tethered substrates
led to (3 + 2) cycloaddition to afford strained alkenes which
could be further elaborated by both inter- and intramolecular
cycloaddition chemistry to produce complex polycyclic adducts.
Further studies on reactions of strained alkenes produced by
DPC as well as biological studies of the chemotypes and derived
adducts are currently in progress and will be reported in due
course.
Scheme 6. Tandem DPC/Intramolecular (4 + 2)-
Cycloaddition To Afford Complex Polycyclic Chemotypes
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental procedures and spectral data including H NMR,
13C NMR, and HRMS for all new compounds and X-ray
structure analysis of compounds 12 and 50. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
porco@bu.edu; crjsteph@umich.edu
■
Present Address
†Department of Chemistry, University of Michigan, 930 N.
University Avenue, Ann Arbor, MI 48109, United States.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Inspired by the successful intermolecular transformations
utilizing strained alkene intermediate 42, we envisioned that the
use of alkynol ether substrates tethered with furfuryl ethers
(Scheme 6, 48 and 49) would lead to the formation of highly
complex, polycyclic structures. Oxidative dearomatization of
trimethylphenol with 1,4-butynediol using PIDA followed by
etherification of the resulting alkynol 47 provided the substituted
dienone substrates 48 and 49 in two steps. Photoirradiation of
48, 49 for 20 min cleanly afforded polycyclic compounds 50 and
51 in good isolated yield as single diastereomers. The structural
assignment of 50 was confirmed by X-ray crystallographic
analysis (Figure 1).13 It is noteworthy that four new bonds are
formed in the tandem DPC/(4 + 2) sequence which produces
a highly complex architecture, containing six rings and seven
stereogenic centers.
Financial support from the NIH-NIGMS (P50 GM067041) is
gratefully acknowledged. We thank Prof. Aaron Beeler (Boston
University) for assistance with photochemistry equipment, Drs.
Kiel Lazarski (Boston University) and Alexander Grenning
(Boston University) for helpful discussions, and Dr. Jeffrey
Bacon (Boston University) for X-ray crystal structure analysis.
NMR (CHE-0619339) and MS (CHE-0443618) facilities at BU
are supported by the NSF.
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