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New Efficient Routes to Cyclic Enediynes.

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HIGHLIGHTS
New, Efficient Routes to Cyclic Enediynes
Burkhard Konig*
The special fascination of strained cyclic enediynes lies in their
intrinsic tendency to undergo thermal cyclization. This aspect
has been stimulating the research on enediynes since its beginnings more than 20 years ago,"] and it is this reactivity of the
enediyne structure that brings about the pharmacologicai effectiveness of natural products like dynemicin
The synthesis of an enediyne parent system calls for mild
conditions with, at the same time, a strong driving force for the
A
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OR
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'
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ring closure reaction. Various approaches have been taken to
generate strained cyclic enediynes. Scheme 1 summarizes the
major ones: Most often, an acetylide carbonyl addition is used
as the ring closure reaction (Scheme 1, routes a and b) .L3] Danishefsky et al., however, efficiently obtained highly substituted,
10-membered enediyne cycles by two-fold palladium-catalyzed
coupling of iodoacetylene with cis-I ,2-bis(trimethylstannylethylene) (route c).f41Substitution reactions can yield 10-membered enediyne cycles as well, though only after the ring strain
has been reduced (route d). ['I In contrast to ring closure, Nicolaou et al. employed a ring contraction of cyclic sulfones to
synthesize strained cyclic enediynes (route e) .[61
Jones, Huber, and Mathews now could demonstrate that
strained cyclic enediynes are accessible via carbenoid intermediates, too.['] Their method is based on a sequence of tandem
carbenoid coupling and ejimination of two propynylic bromide
units, a strategy published last year by the same group:['] Here
the synthesis of the acyclic enediyne bis(trimethylsily1)hexadiyne (3) was achieved by reaction of trimethylsilylpropynylic
bromide (1) with lithium hexamethyldisilazide (LiHMDS) in
THF/HMPT (HMPT = hexamethylphosphoric triamide) at
-85 "C. A cis-trans seIectivity of about 2: 1 was attained with
good yields. Probably, a propynylic carbene is formed, which
can insert intermolecularly into the C-H bond of another
propynylic bromide. The E2 elimination of HBr from the intermediate bromide 2 then leads to the product. As this method
proved to be broadly applicable for substituted propynylic substrates, Jones et al. even had it patented.['] Recently still more
highly substituted acyclic enediynes like 4 and 5 were obtained
with this approach.[10]
1) Tf20
2) CAN
53 Yo
LiHMDS
___)
\
KTMl
96 %
TMS
&/trans 2.1 :1
KOfBu or
MeLi
(n= 2 -
Scheme 1
CAN
=
cerium ammonium nitrate
Clierir. Irir Ell. Engl 1996. 35. N o . 2
TMS
VTMS
AT,,
4
e-rnail: koenigvr sgi3.org-chern.nat.tu-bs.de
Anpii .
a)
TMS
[*] Dr. B K6nig
lnstitut fur O r p n i s c h e Chemie der Technischen Universitit
Hagenring 30. D-38106 Braunschweig (Germany)
Fax: Int. code +(531)391-5388
J.:
3
2
1
A
20 - 80 %
TMS
VCH V e r l a ~ . ~ ~ e . ~ e l l .n?hH.
~ c l ~ u0.69451
fi
Wernheim. 1996
TMS
5
0570-0X33/9613502-0165$ 10.00f 2 . C '0
165
HIGHLIGHTS
The intramolecular variant of this synthesis renders cyclic
enediynes. Ten-membered functionalized enediyne cycles (7)
were generated in yields of up to 9 5 % using slightly altered
reaction conditions. Since the starting materials are easily accessible, a synthesis of enediynes in multigram scale can be
achieved. Thus, it should be possible to use these functionalized
enediyne components to build libraries of enediyne diversomers
by the approach of Nicolaou and others.["] As Jones et al.
stated, enediyne steroid conjugates like 8 have been synthesized
already.['01
LiHMDS
69 - 95 %
Br
6
7
With the mechanistically interesting new approaches described here, the spectrum of methods for the synthesis of
strained cyclic enediynes could be enlarged markedly. It is to be
expected that the search for simple pharmacologically active
enediyne derivatives will benefit accordingly.
German version: Angeir. Citem. 1996, 108. 177- 178
Keywords: carbenes . cyclizations . enediynes . macrocycles
[ I ] a) R R. Jones. R. G. Bergman. J Am.Cliein Suc. 1972,94,660-661; b) R. G.
Bergman, Acc Chen?. Rrs. 1973. 6, 25-31.
[21 Recent reviews on the synthesis and properties ofenediyne prodrugs: a) M. E.
Maier. S j n k r t 1995. 13-26: b) K. C Nicolaou, W.-M. Dai Angeu.. Chem.1991.
103. 1453-1481 ; Angeir. Chrm. In!. Ed Engl. 1991.30, 1387-1415. Enediynes
as building blocks for new carbon allotropes: c) F. Diederich. Nulure 1994,369.
199-207. Previous enediyne highlight. d) R. Gleiter, D. Katz, A n g e w Chem.
1993, 105, 884-887; Angeu.. CAent. I m . Ed. Eng/. 1993, 32, 842-845.
[3] a) P. A. Wender. S. Beckham, D. L. Mohler. Tetruhedron Lett. 1995,36, 209212; b) T.Brandstetter. M. E. Maier, Tetruhedron 1994, SO, 1435-1448.
[4] M. D. Shdlr. T. Yoon. S. J. Danishefsky. J. Org. Cliem 1994, 59, 3755-3757.
IS] P. Magnus. ?%trultrr/ron 1994, SO. 1397-1418.
[6] K. C. Nicolaou. G. Zuccdrello. Y Ogawa, E. J. Schweiger. T. Kumazawd. J
A m . Client. Soc. 1988, 110, 4866-486s.
[7] G. B. Jones. R. S. Huber. J. E. Mathews, J. Cliern. Suc. Chem. Commun. 1995,
1791 1792
[XI a ) G. B. Jones, R. S. Huber, f i w u l i d r u n Lert. 1994. 35, 2655-2658, b) the
synthesis of 3 from 1 was reproduced in our laboratory without difficulties.
However, the yield and the stereoselectivity were slightly lower than reported.
[9] A N o i , Roure 10 E n d i ~ n ~G.
s , B. Jones, R. S. Huber. US-A 5436361. 1995.
[lo] G. B. Jones, Clemson University, Clemson. SC (USA), personal communication.
[ l l ] a) K. C. Nicolaou, A. L. Smith, E. W. Yue. Proc. Nu!/. Acurl. Sci. USA 1993.
YO. 5881 -5892; b) K. Toshima. K. Otha, A. Ohahsi, T.Nakamurd. M. Nakata.
S. Matsumura, J. Cheni.Sac. Chrm. Comn?un. 1993. 1525-1527, c) M. Tokuda.
K. Fujiwara, T Gomibuchi. M. Hirdmd. M. Uesugi, Y. Sugiura, Terralt~dron
Let!. 1993. 34. 669-672. d) M. F. Semmelhack. J. J Gallagher, W. Ding, G.
Krishnamurthy, R. Babine, G. A. Ellestad, J Org. Chem. 1994. SY, 4357-4359,
e) D. L. Boger. J. Zhou. r M . 1993. 58. 301X-3024
[12] a ) H. Hopf, C. Werner, P. Bubenitschek, P. G. Jones, Angeii. Client. 1995, 107.
2592-2594: Angc,w. Clwm Ini. Ed. Engl. 1995, 34. 3367-2368: for the first
synthesis of a cyclooctaenediyne, stabilized as the alkynecarbonylcobdh complex, see: b) G. G. Melikyan, M . A. Khan, K. M Nicholas. Orgunonwfullic.~
1995. 14. 2170 -2172.
[13] H. Sato, N. Isono. K. Okamura. T. Date. M. Mori. Teiruhedriron Lpif. 1994.35.
2035-2038.
-
Starting from the propynylic bromide 9, Hopf, Werner, et al.
successfully synthesized an only 8-membered cyclic aryl-I ,2diyne (10).[''I The remarkably stable molecule was obtained by
cyclization with Bu,SnSiMe,/CsFrL3] in 60 Yo yield.
BugSnSiMeg,
CsF, DMF
60 %
9
166
10
l-* VCH
Yerlag.~gesellsc./~~ift
mbH. 0-69451 Weinherm, 1996
0570-0833196/3502-0166 3 lO.OO+ .2S/O
Angew. Clien?.Int. Ed. Engl. 1996. 35, Nu. 2
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enediyne, efficiency, cyclic, new, route
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