Angewandte
Chemie
DOI: 10.1002/anie.200703034
Photochemical Activation
Creating a Reactive Enediyne by Using Visible Light: Photocontrol of
the Bergman Cyclization**
David Sud, Tony J. Wigglesworth, and Neil R. Branda*
The use of light to interconvert chemical structures between
two isomeric forms has matured into an exciting field. It has
the potential to impact a wide range of applications from
optoelectronics to photorelease because it offers a convenient
means to modulate the way materials absorb, emit, and rotate
light, or the way they accept and transport charge.[1] Only
Scheme 1. Photochemical rearrangement used to create the enediyne
structure. Only isomer B has the conjugated p system that undergoes
the Bergman cyclization and produces the diradical A. Isomer C is
inactive.
recently have some research groups refocused their efforts to
apply the concepts of molecular photoswitching to control
chemical reactivity, despite the fact the concept was intro-
duced over 20 years ago.[2]
The potential role of light integrated with chemical
reactivity is especially significant in modern therapeutic
technologies. It can be used to trigger the rearrangement of
a molecular structure to activate “masked” chemotherapeutic
agents that are broadly toxic, have severe side effects and
cannot be administered in their “unmasked” forms. One
notable example that would benefit from such photocontrol is
the Bergman cyclization of the enediyne architecture, a
reaction that is important in antitumor activity and one where
the presence of a precise arrangement of p bonds is essen-
tial.[3,4] The attempts made to regulate the activity of
enediynes have all met with different levels of success,[5] and
suitable photoactivation of enediynes for clinical settings has
remained an elusive goal. Here we describe our approach to
activate enediynes by taking advantage of the fact that the
hexatriene structures found in the dithienylethene (DTE)
backbones (compounds B, 1o, and 6, for example) undergo
reversible ring-closing reactions when irradiated with UVand
visible light.[6]
This concept is illustrated in Scheme 1. By integrating the
hexatriene and enediyne structures into a single molecule
(compound B), we have developed a system that uses visible
light to control the Bergman cyclization. Only ring-open
isomer B contains the enediyne architecture (highlighted in B
by the shaded box) that undergoes spontaneous cyclization
and yields the active diradical (A), which is the chemical
species responsible for the high antitumor activity. UV light
triggers the photocyclization of the hexatriene in B and
converts it to its ring-closed counterpart C. This photo-
chemical reaction also rearranges the p system and localizes it
along the rigid backbone formed during the ring-closing
reaction (highlighted in C by the shaded box). The conse-
quence is the removal of the enediyne architecture necessary
for spontaneous conversion to the diradical, making ring-
closed isomer C inactive. Visible light activates the system by
triggering the ring-opening reaction, regenerating enediyne B.
The fact that this system is activated with visible light, which
penetrates tissue deeper and with less damage than the more
commonly used UV-light, is particularly important and adds
to the appeal of the system. This offers a significant advantage
over previously reported examples that require extended
irradiation periods with high-energy UV light to alter ring
strain,[7] cleave a protecting group[8] or create the enediyne
structure.[9]
Two enediyne derivatives are described herein. Both
compounds, 1o and 6, can be prepared from the same alkyne-
linked bis(thiophene) 4 as shown in Scheme 2. Compound 4 is
prepared in four steps from 3-bromo-2-methyl-5-phenylthio-
phene (2)[10] by first converting the bromide into the iodide in
order for it to undergo a more facile palladium-catalyzed
Sonogashira coupling reaction with trimethylsilylacetylene.
After removing the silyl protecting group, alkynylthiophene 3
can be subjected to another Sonogashira coupling with the
same iodothiophene as was used to prepare it in the first
place. The enediyne portions of compounds 1o and 6 are
installed by one-pot alkylzirconations with halogenated
phenylacetylene (for 6) or trimethylsilylacetylene (for
1o).[11] This multistep method ensures that the two alkyne
groups are appropriately positioned cis to each other so that
the enediynes can eventually undergo the Bergman cycliza-
tion. This step completes the synthesis of compound 6. In the
case of compound 1o, the ten-membered ring is best formed
by deprotecting the trimethylsilylacetylene moieties using
strong base and quenching the generated anion with 1,4-
diiodobutane.
[*] D. Sud, T. J. Wigglesworth, Prof. N. R. Branda
4D LABS, Department of Chemistry
Simon Fraser University
8888 University Drive, Burnaby, BC V5A 1S6 (Canada)
Fax: (+1)604-291-3765
E-mail: nbranda@sfu.ca
[**] This work was supported by the Natural Sciences and Engineering
Research Council of Canada, the Canada Research Chair Program
and the Simon Fraser University.
Because the distance between the two alkyne groups in
enediyne 6 is large enough to prevent spontaneous cyclization
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2007, 46, 8017 –8019
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8017