A photochemical synthesis of functionalized trans-cyclooctenes driven by metal complexation

Article abstract of DOI:10.1021/ja8001919

Described is a scalable procedure for driving photochemical sytheses of trans-cyclooctene derivatives through metal complexation. During photoirradiation, reaction mixtures are continuously pumped through a column of a AgNO₃-impregnated silica gel. The trans-cyclooctene derivative is selectively retained by the AgNO₃-impregnated silica, but the cis-isomer elutes from the column back to the reaction flask, where it is photoisomerized and recirculated through the column. The method provides access to a range of usefully functionalized derivatives of trans-cyclooctene, including a derivative of 5-aza-trans-cyclooctene that underwent transannular cyclization upon treatment with bromine. The alkene stereochemistry is transferred with high fidelity to the hexahydropyrrolizine framework in the transannular cyclization. Copyright

Full text of DOI:10.1021/ja8001919

Published on Web 03/06/2008
A Photochemical Synthesis of Functionalized trans-Cyclooctenes Driven by
Metal Complexation
Maksim Royzen, Glenn P. A. Yap, and Joseph M. Fox*
Brown Laboratories, Department of Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
Received January 14, 2008; E-mail: jmfox@udel.edu
Scheme 1. Multistep Synthesis of trans- from cis-Cyclooctene
The unusual reactivity and well-defined chiral structure of trans-
cyclooctene make it an attractive framework for stereocontrolled
synthesis. trans-Cyclooctene has a chiral plane and a high barrier
to racemization (35.6 kcal/mol),1a and the most stable “crown” 1b,c
conformer of trans-cyclooctene has an alternating sequence of
equatorial and axial hydrogens (Scheme 1) that is akin to chair
cyclohexane. The double bond of trans-cyclooctene is twisted
severely in the crown conformation,2 and as a consequence the
HOMO of trans-cyclooctene is relatively high in energy.3 As a
result, trans-cyclooctene displays unusual reactivity in HOMO-
alkene controlled cycloaddition reactions with dienes,4 1,3-dipoles,3
and ketenes.5 trans-Cyclooctene derivatives also serve as excellent
ligands for transition metals,6 and they are useful monomers for
polymerization in the presence of radical initiators or metathesis
catalysts.7
Although there are many routes to the parent trans-cyclooctene,
there are few methods for preparing functionalized derivatives.3,8
trans-Cyclooctene was first prepared as a mixture with cis-
cyclooctene via Hoffman elimination of trimethylcyclooctyl am-
monium iodide.9 Several elegant and stereospecific methods for
preparing trans-cyclooctene from cis-cyclooctene have also been
described,10 as exemplified by the sequence of epoxidation/LiPPh2
addition/elimination shown in Scheme 1.10e However, a limitation
of such protocols is that multistep synthesis is required to invert
the alkene stereochemistry. A direct method for olefin inversion
would facilitate the synthesis and application of functionalized
derivatives of trans-cyclooctenes.
The photochemical isomerization of cis-cyclooctene represents
a direct method for the synthesis of trans-cyclooctene. Elegant
studies by Inoue have greatly expanded the scope and understanding
of the photoisomerization, which is typically run under singlet
sensitized conditions.11 While the photochemical procedures are
effective for the preparation of the parent hydrocarbon, the
photochemical synthesis of functionalized trans-cyclooctenes has
been limited by low trans/cis ratios under preparatively useful
conditions and by the photodegradation of the trans-cyclooctene.
For example, we observed that 18-h photolysis of 500 mL of a
0.016 M solution of (Z)-cyclooct-4-enol (9:1 Et2O/hexane, 1 equiv
of PhCO2Me) gave <5% (E)-cyclooct-4-enol along with unchar-
acterized photodegradation products and 24% recovered (Z)-
cyclooct-4-enol.
reactions do not provide direct access to the trans-cycloalkenes
themselves.14
The apparatus for preparing trans-cyclooctenes is illustrated
schematically in Figure 1. A quartz reaction flask containing methyl
benzoate (a singlet sensitizer) and a 0.018 M solution of a cis-
cyclooctene derivative is photoirradiated at 254 nm. During
photoirradiation, the reaction mixture is continuously pumped
through a bed of a AgNO3-impregnated silica gel on column of
silica gel. The trans-cyclooctene derivative is selectively retained
by the AgNO3 impregnated silica, but the cis-isomer elutes back
to the reaction flask, where it is photoisomerized and recirculated
through the column. After complete consumption of the cis-
cyclooctene, the silica is removed and stirred with NH4OH, which
liberates the trans-cyclooctene from the AgNO3. The trans-
cyclooctene derivative is then recovered by extraction.
A Rayonet RPR 200 reactor is a convenient light source for the
apparatus illustrated by Figure 1, although a 450-W Hanovia
mercury arc lamp is also effective. The apparatus was constructed
using a common metering pump, an inexpensive plastic column,
and standard LC tubing and fittings. No “homemade” parts are
required for the apparatus for preparations on a gram scale.
The scope of the photochemical trans-cyclooctene synthesis using
the described apparatus was investigated as shown in Table 1. The
method was successful for the synthesis of trans-cyclooctenes that
were substituted by alkyl, hydroxyl, acetal, amide, and oxazolidi-
none functionalities.15 It was also demonstrated that aza-trans-
cyclooctene derivative 2h could be prepared. The yields in Table
1 (63% on average) compare favorably with the overall yields from
multistep preparations of trans-cyclooctene from cis-cyclooctene,9,10
To improve the practicality of the photochemical protocol, we
devised a strategy that would drive the photoisomerization through
selective metal complexation of the trans-isomer. Our experiments
were based on the earlier observation that trans-cyclooctene forms
a water soluble complex with AgNO3, whereas cis-cyclooctene
binds only weakly to AgNO3.9b,12 Our strategy was also grounded
in classic studies on the photoprotonation reactions of cyclic alkenes,
which had shown that the cis/trans equilibria could be driven by
selective addition reactions of trans-cycloalkenes.13 However, such
Figure 1. Schematic of apparatus for trans-cyclooctene synthesis.
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C O M M U N I C A T I O N S
Table 1. Synthesis of trans-Cyclooctene Derivativesc
In summary, selective complexation to AgNO3/silica was used
to facilitate photochemical syntheses of trans-cyclooctene deriva-
tives on a useful scale. A derivative adopts a crown conformation
despite an axial substituent, and it was shown that alkene stereo-
chemistry is transferred to the hexahydropyrrolizine framework in
the transannular cyclization of 5-aza-trans-cyclooctene.
Acknowledgment. This work was supported by NIH Grant
GM068640-01.
Supporting Information Available: The photochemical apparatus
is described in detail. Provided are experimental and characterization
details, 1H and 13C NMR spectra for new compounds, NOE data for 4,
and CIF files for 2c, 3, and the desmethyl analogue of 2g. This material
is available free of charge via the Internet at http://pubs.acs.org.
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Figure 2. (a) Preparation and X-ray structure of a trans-cyclooctene with
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and all of the preparations in Table 1 were carried out on a useful
scale. The preparations of 2a-2g were carried out with 1 g of the
cis-cyclooctene in 500 mL of solvent (∼0.015 M). Preparations of
2b and 2f were also demonstrated on a larger scale: 5.0 g of the
cis-alkene in 500 mL of solvent gave 3.9 g of 2b and 3.1 g of 2f.
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framework that is common to a range of natural products.17 Thus,
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