682
J . Org. Chem. 1999, 64, 682-683
Sch em e 1
Syn th esis a n d DNA Clea va ge Stu d y of a
10-Mem ber ed Rin g En ed iyn e F or m ed via
Allylic Rea r r a n gem en t
Wei-Min Dai,*,† Kin Chiu Fong,† Chi Wai Lau,†
Ling Zhou,‡ Wataru Hamaguchi,‡ and
Sei-ichi Nishimoto‡
Department of Chemistry, The Hong Kong University of Science
and Technology, Clear Water Bay, Kowloon, Hong Kong, China,
and Department of Energy and Hydrocarbon Chemistry,
Graduate School of Engineering, Kyoto University, Sakyo-ku,
Kyoto 606-01, J apan
Received October 8, 1998
The naturally occurring enediynes1 represent a novel class
of antitumor antibiotics that feature a (Z)-hex-3-ene-1,5-
diyne moiety constrained in a 9- or 10-membered ring.
Coupled with other structural domains responsible for drug
activation and delivery, the enediyne antitumor antibiotics
present challenging targets for chemical synthesis.1a-c Stimu-
lated by the intriguing mechanism of action and promising
biological activity, extensive chemical and biological inves-
tigations on enediynes have been carried out during the past
decade.1 It is known that cycloaromatization2 of enediynes
such as 2 will give the diradical species 3, which can damage
DNA through hydrogen atom abstraction from the deoxyri-
bose residue (Scheme 1).1a,d,e,3 This event is regarded as the
origin of the biological activity of enediynes. However, the
extreme lability of simple 9- or 10-membered ring enediynes
presents an obstacle for the development of synthetic ene-
diyne drugs. In our recent work, we have established an
efficient methodology for conversion of the thermally stable
1,2-diynyl-substituted allyl alcohols into acyclic enediynes
by rearrangement of the allylic double bond.4 A relatively
unstrained 11-membered ring enediyne was synthesized
similarly.4b Our methodology is conceptually related to the
intramolecular allylic rearrangement proposed for the action
of artifacts of the maduropeptin chromophore5,6 and repre-
sents one of the emerging strategies7 for enediyne prodrug
design and synthesis. In this paper, we disclose the synthesis
and DNA cleavage activity of the 10-membered ring ene-
diyne 2, formed in situ from precursor 1 via the allylic
rearrangement (Scheme 1).
In our previous studies,4 we realized that the phenyl group
attached at the exocyclic double bond of the precursor is
essential for successful conversion into the enediyne. Thus,
we decided to synthesize compound 1 according to the bond
disconnection b shown in Scheme 1. The previously used
pathway (a) for 11-membered ring formation4b failed to give
10-membered ring product. Starting from the known com-
pound 5 readily available from R-bromocinnamaldehyde in
three steps,4a alcohol 6 was prepared by protection of the
allylic hydroxyl group (DHP, PPTS, CH2Cl2, 20 °C, 4 h) and
subsequent removal of the silyl groups (n-Bu4NF, THF, 20
°C, 4 h) in 66% yield (Scheme 2). Oxidation of 6 using PDC
(4 Å MS, CH2Cl2, 20 °C, 1 h) gave aldehyde 7, which cyclized
in the presence of LDA-CeCl3 (2 equiv each, THF, HMPA,
-78 °C, 7 f 8) under high dilution conditions (0.01 M).
Compound 8 was obtained in 10% yield from 7 along with a
byproduct (20%) resulting from an intermolecular addition
of the lithium acetylide of 7. At this stage, we envisaged the
introduction of a DNA-recognition moiety into 8 using the
propargylic hydroxyl group as the tethering point. Ester 9
was synthesized from 8 and anthraquinone-2-carboxylic acid
under the DCC-DMAP conditions (CH2Cl2, 20 °C, 12 h) in
60% yield. The THP ether in 9 was then unmasked using
PPTS in MeOH (20 °C, 24 h) to furnish alcohol 1 in 58%
* To whom correspondence should be addressed. Fax: int. + 2358-1594.
E-mail: chdai@ust.hk.
† The Hong Kong University of Science and Technology.
‡ Kyoto University.
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10.1021/jo9820263 CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/13/1999