The double [3 + 2] photocycloaddition reaction

Article abstract of DOI:10.1021/ja906163s

(Chemical Equation Presented) A remarkable double [3 + 2] photocycloaddition reaction that results in the formation of fenestrane 2 from aromatic acetal 1 is reported. During the formation of 2, four carbon-carbon bonds, five new rings, and seven new stereocenters are created in a one-pot process. The reaction occurs in a sequential manner from the linear meta photocycloadduct 3, while the angular meta photocycloadduct 4 undergoes an alternative fragmentation-translocation photoreaction to afford angular tricycle 6.

Full text of DOI:10.1021/ja906163s

Published on Web 12/11/2009
The Double [3 + 2] Photocycloaddition Reaction
Clive S. Penkett,* Jason A. Woolford, Iain J. Day, and Martyn P. Coles
Department of Chemistry and Biochemistry, UniVersity of Sussex, Brighton BN1 9QJ, U.K.
Received July 23, 2009; E-mail: c.s.penkett@sussex.ac.uk
A common challenge confronting synthetic organic chemists is
the atom-efficient creation of molecular complexity.1 The meta
photocycloaddition reaction2 is useful in this context, as three new σ
bonds, three new rings, and up to six new stereocenters are formed in
a single step. More complexity can be added by tethering the two
reacting partners together,3,4 and the elegant work of Wender2c-j
pioneered the reaction’s application in natural product synthesis.
While investigating the photochemistry of aromatic acetal 1, we
discovered a unique double [3 + 2] photocycloaddition reaction
that resulted in the formation of the fenestrane5 derivative 26
(Scheme 1). This dramatic transformation represents the creation
of five new rings, four new carbon-carbon σ bonds, and seven
new stereocenters in a one-pot process.
Figure 1. The four principal photoadducts formed by irradiation of aromatic
acetal 1 in cyclohexane for 4 h using 254 nm UV light.
also formed during this secondary irradiation process. It should be
noted that compound 6 was difficult to obtain free of other
contaminants because of coelution with 3.
Scheme 2. Conversion of Linear Meta Photoadduct 3 into
Fenestrane 2a
Scheme 1. The Double [3 + 2] Photocycloaddition Reaction To
Form Fenestrane 26 a
a Conditions: (a) hν (254 nm), cyclohexane, 16 h, 38%.
The minor meta photoadduct 4 could also be converted into 2
under the same photolytic conditions, although it primarily led to
the formation of photoproduct 6.
a Conditions: (a) hν (254 nm), cyclohexane, 18 h, 8%.
Although the synthetic utility of fenestrane-type structures has
yet to be fully explored, a recent synthesis of the insecticide (-)-
penifulvin A5d might suggest an untapped potential. Theoretical
interest in fenestranes remains high because of the distortion of
the central quaternary carbon away from the standard tetrahedral
bond angle of 109.5°. In the case of compound 2, the transverse
bond angle (C7-C8-C9) is 120.2° and the longitudinal bond angle
(C12-C8-C1) is 128.5°.
To aid in obtaining a mechanistic understanding of these
transformations and interpreting the NMR spectra, we prepared 1D,
a deuterated version of the aromatic starting material, from 5-bromo-
2-anisaldehyde (7) (Scheme 3).
a
Scheme 3. Formation and Photolysis of Deuterated Substrate 1D
Compound 1 was prepared in 98% yield using Noyori’s acetal-
forming procedure7 by the reaction of allyloxytrimethylsilane with
o-anisaldehyde in the presence of trimethylsilyl triflate. Irradiation
of 1 in cyclohexane using 254 nm UV light for 18 h led to the
formation of a multitude of products, including the pentacycle 2 in
8% yield (Scheme 1). In a separate experiment, 1 was irradiated to
the point of its total consumption (4 h) to yield four major
components: linear meta photocycloadduct 3, angular meta pho-
tocycloadduct 4, and two ortho-derived cycloadducts3d,8 5a and
5b whose relative configuration could not be determined (Figure
1). The absence of any fenestrane adduct 2 formation under these
conditions led us to conclude that it must have been generated
sequentially from one of the monocyclized compounds shown in
Figure 1.
a Conditions: (a) 2.5 equiv of Me3SiOCH2CHdCH2, 0.01 equiv of
Me3SiOTf, -84 °C, CH2Cl2, 87%; (b) n-BuLi, -78 °C, THF then MeOD,
78%; (c) hν (254 nm), cyclohexane, 18 h, 14%; (d) hν (254 nm),
cyclohexane, 2 days, 11%; (e) hν (“old lamp”), cyclohexane, 7 days, 16%.
After conversion of 7 to bromoacetal 8 via the Noyori procedure7
with allyloxytrimethylsilane, metal-halogen exchange was ac-
complished using n-butyllithium, and the resulting anion was
quenched with MeOD to afford 1D with >80% deuterium incorpora-
To investigate this, a solution containing only the major meta
photoadduct 3 in cyclohexane was irradiated using 254 nm UV
light for 16 h; this resulted in the formation of fenestrane 2 in 38%
yield (Scheme 2). We also discovered that small amounts of the
angular meta photoadduct 4 and a rearranged photoproduct 6 were
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tion. The deuterated linear meta photoadduct 3D was obtained
following an initial photolysis step, and this was then converted
into the deuterated products 2D and 6D in secondary photolysis steps.
We found this process to be lamp-dependent, as our initial attempt
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J. AM. CHEM. SOC. 2010, 132, 4–5
10.1021/ja906163s  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 5. Photoconversion of o-Tolualdehyde-Derived Meta
Photoadduct 14 into Fenestrane Adduct 15a
to irradiate 3D using an old 16 W low-pressure mercury vapor lamp
resulted in the formation of 6D as the principal product instead of
2D. This extended irradiation period also caused the complete
consumption of 3D, which aided in the chromatographic isolation
of 6D.
The presence of various triplet sensitizers (acetone, acetophenone,
and benzophenone) during the irradiation of compound 3 enhanced
its conversion into the fenestrane product 2. The efficiency of this
process was sensitizer-dependent, with acetone forming significant
quantities of 2 in a matter of hours, although it had the disadvantage
of forming other impurities. Benzophenone appeared to inhibit the
transformation, with comparatively little conversion of 3 to 2 even
after several days of irradiation. Acetophenone presented a better
compromise, although the subsequent purification process was
hampered by coeluting impurities. During these sensitized reactions,
a small amount of photoequilibration between 3 and 4 was observed,
although the formation of the rearranged product 6 was completely
suppressed. The addition of isoprene as a triplet quencher inhibited
the formation of 2 from 3, providing further evidence that a triplet
state is involved in this process.
A plausible mechanistic rationale to account for the formation
of 2D and 6D is presented in Scheme 4. Linear and angular meta
photoadducts (3D and 4D) are known to interconvert under photolytic
conditions.10 This could occur either by homolytic fission of the
cyclopropyl ring (see 9D) or by a [1,3]-sigmatropic rearrangement.
Photoinduced homolytic fission of the external cyclopropyl ring
bond of the linear meta photoadduct 3D may afford diradical 10D,
which could cyclize onto the terminal alkene to create two new
five-membered rings and hence 2D. Photoexcitation of the angular
meta photoadduct 4D followed by single electron transfer (SET)
from the methoxy group’s lone pair of electrons to the external
cyclopropyl ring bond would result in the fragmentation of the three-
membered ring to afford 11D. The allylic radical of 11D could
combine homolytically with the oxygen radical cation to form
pseudo-methylated epoxide 12D, which would fragment to give the
doubly allylic ether 6D.
a Conditions: (a) hν (254 nm), cyclohexane, 9.5 h, 24%; (b) hν (254
nm), cyclohexane, 8 days, <10%.
In conclusion, a remarkable double [3 + 2] photocycloaddition
reaction resulting in the formation of fenestrane 2 from aromatic
diene 1 has been reported. During this process, four carbon-carbon
bonds, five new rings, and seven new stereocenters are created.
The photoreaction occurred in a sequential manner from linear meta
photocycloadduct 3, while rearranged photoproduct 6 was derived
from angular meta photocycloadduct 4.
Acknowledgment. We thank the EPSRC, Rachel Kahan, and
the Nuffield Foundation and John Plater, Philip Parsons, Penny
Chaloner and John Turner for enlightening chemical discussions.
Supporting Information Available: Experimental details, charc-
terization data for all new compounds, and crystallographic data (CIF)
for 2. This material is available free of charge via the Internet at http://
pubs.acs.org.
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Wender, Dore, and deLong11 prepared a similar fenestrane
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derived from the bisallyloxy acetal of o-tolualdehyde (13) with an
acetonitrile radical. We found that 14 could be converted to
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isolated free of other contaminants (Scheme 5). Use of acetophenone
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impurities again hindered purification.
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