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Synthesis of Enediynes by DielsЦAlder Addition.

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an oily solid' ' H N M R (250 MHz. CDCI,): 6 = 2.15 (s. 1 2 H ) . 3.75 (s. 4 H ) , 7.27.45 (m. 3 H);"Si N M R (200 MHz, CDC1,): 6 = - 30.5; MS (70 eV): mlli 410
[ M - 2CIl'. 38%
Received: December 7. 1993 [Z 6545 IE]
German version. Angrn. Chrm. 1994, 106, 1152
We now present a fundamentally new route to enediynes.
which generates the highly unsaturated system in a simple manner by a [2 41cycloaddition and thereby permits the introduction of (different) substituents in all four positions of the parent
hydrocarbon.
+
[l] a) S. N. Tandura. M. G. Voronkov, N. V. Alekseev, 7bp. C u r r . Cheni. 1986,
131.99; h) C. Chuit. R. J. P. Corriu. C. Reye, J. C. Young. Chcm. Rev. 1993, 93,
1371. c ) C. Breliere, F. Carre, R. J. P. Corriu, M. Poirier. G . Royo.
O r , s u n f ~ ~ i i c r n1986,
/ l ~ ~5.~ 388; d) J. Boyer, C. Breliere, F. Carre, R. J. P. Corriu.
A. Kpoton. M. Poirier, G. Royo. J. C. Young, J. Chem. SOC.Dullon Truna 1989,
43.
[2] C. BreltCre. F. Carre, R. J. P. Corriu, M. Poirier, G. Royo. J. Zwecker,
O r p [ ~ i i ~ ~ f ? i [ , f ~1989.
l / / ; ~ .8
\ , 1831.
131 C Breliere, F. Carre. R. J. P. Corriu, G . Royo. Orgu/ifi"""/l/~.s 1988. 7. 1006,
N . Auner. R. Probst. F. Hahn. E. Herdtweck, J Orpunomer. Chem. 1993. 45Y,
25: C. Breliere. F. Carre, R. J. P. Corriu. G Royo. M. Wong Chi Man. J.
L.dp,isset.
. . Ur,~oiiaii~rruNir.s
1994, 13, 307.
[4] G. van Koten. Purr, Appl. Chem. 1989,61. 3681; rhid. 1990.62. 1155: 1. T. B. H
JastrLebski. G. van Koten, Adv. Orpnomc,r. Chem. 1993. 35. 241
[S] F. Carre, C Chuit, R. J. P. Corriu. A. Mehdi, C. Reye. J. OryrmomPr. Chrm.
1993. 446. Cb.
[6] G. \ a n Koten. J. T. B. H. JaatrLehski, J G. Noltes. A. L Spek, J. C. Schoone,
J. I ~ , w o n o m ~Chmi.
r.
1978, 148. 233.
[7] C . Chiiit. R. J. P. Corriu. A. Mehdi. C. Reye. Angrn.. Cheni. 1993. 105. 1372:
,41rxc,11Chon. / n l . Ed. Dip/. 1993. 32, 1311.
[XI X-ra) crystal structure data of 6: monoclinic, spice group C2;c. u = 18.491(2).
h = c).086(2). c =16.352(1) A, fl = 111.838(8)', V = 2550.2(7) A3, prrlrd=
1.075 pcm --'.ji(Mo,J =1.01 cni-I, Z = 4.2174. unique i-eflectiona up to (sin
O ' L ) = 0 639. 849 with F;, < 2.8 (i (F"). Enraf-Nonius CAD4 diffractometer.
Mo,, radiation. A = 0.71069. T = 22°C. Solution by direct methods (MULTAN-XO). I<(&) = 0.059 (0.062), M' = l / ( u 2 ( F o ) 0.0049 F 2 ) for 121 refined
pxrameters (anisotropic temperature factors for all atoms; the hydrogen atoms
werc taken into account in the refinement with isotropic temperature factors
arid C H , a s rigid groups. SHELX-76). Residual electron density: 0.72 e k ' .
Further details of the crystal structure investigation are available on requcst
from thc Cambridge Crystallographic Data center. University Chemical Laboratory. 12 Union Road. CambridgeCB21EZ(UK), on quolingthe fulljournal
citation
[9] a).I Terheijdcn. G. van Koten. J. L. de Booys, H . J. C. Uhbels, C . H . Stam.
O~,~anonieru//iLs
1983. 1. 1882: b) D. M. Grove, G. van Koten. W P. Mul.
A. A t l . v a n der Zeijden. J. Terheijden, M. C. Zoutberg, C. H. Stam, ibrd.
1986. .i.
372, c ) A. A. H. van der Zeijden, G. van Koten. R Luijk. K. Vrieze.
C. Slob. H. Krahbendam. A. L. Spek. Inorg. Chein. 1988. 77. 3014.
[lo] P. I U ~ L I . E. A . Bunte, Angcw Chem. 1992, 104. 1636; A n g w . Chem. / f i r . Ed.
Dig/. 1992. 31, 1605.
1'
+
Synthesis of Enediynes by Diels-Alder
Addition**
Henning HopP and Marcus Theurig
Dediccitcti t o Professor Maxin2illian Zunder
on thc occcisiow qf his 65th birthday
The hex-3-en-I .5-diyne system forms the core structural element and reaction-initiating component of enediyne antibiotics,
which, owing to their DNA-cleaving properties, have catapulted
to the forefront in the development of antitumor agents."] The
synthesis of enediynes has been accomplished to date either
through elimination reactions (generation of the central double
bond with the ethynyl groups already presenti2]) o r through
coupling reactions (connection of the triple bonds to an existing,
usually halogenated ~ l e f i n [ ~ ~ ) .
['I
Prof. H . Hopf, Dipl.-Chem. M. Theurig
lnstitut fur Organische Chemie der Technischen Universitat
Hogenriny 30. D-38106 Braunschwetg (FRG)
T c l d a x : Int. code (531)391-5388
+
[**I
New Dieneq and Dienophiles, Part 5. This research way supported by the
Fonds derChemischen Industrie. -Part 4: H. Hopf. B. Witulski. Nadir. Chem
7i.c / i n . Luh. 1991, 39. 286.
5
8
Coupling of 2,3-dichloro-I ,3-butadiene (1) with the terminal
alkenes 2, in the presence of the catalyst [I .3-bis(diphenylphosphino)propane]nickel(rr) chloride [NiCl,(dppp)] (tetrahydrofuran, - 78 + 20 "C) generates the 3,4-bis(methylene)-l.5-hexadiyne derivatives 3 in 62-80% yield, in addition to the side
products 4, which arise through dimerization of 2. The structure
of 3 is derived unambiguously from spectroscopic and analytical
data.(41As hoped, the derivatives 3 undergo [2 + 41 cycloadditions smoothly. Thus, reaction with maleic anhydride under the
conditions given in the scheme affords the 1 : 1 cycloadduct 5 ,
which is obtained as a colorless solid in 36 % yield.14' The double
dienophile p-benzoquinone (7) furnishes the bis(enediyne) system 8 (32%) in the form of yellow needles.141Since 7 was used
in excess, the formation of this bis(didehydr0) derivative of the
primary adduct is not surprising. We attribute the comparatively
low yields for the unoptimized addition to the susceptibility of the
2,3-functionalized butadienes towards polymerization, which
was not taken into account during workup. The cycloadducts
are nevertheless conveniently accessible in gram quantities.
We shall report shortly on the use of this synthesis in the
preparation of enediynes with additional functionalization in
the side chain R, as well as on further reactions of 5 and 8
(aromatization, annelation) .
E.xperimenta1 Procedure
Synthesis of 3b: A solution of methylmagnesium bromide (3 M. 16.7 mL. 50 mmol)
in ether was added dropwise a t 0 ' C to a solutlon of trimethylsilylacetyleiie (4.Yl g.
50 mmol) in anhydrous T H F (50 mL). The white suspension was allowed to warm
to room temperature over 30 min and was then heated at reflux for 1 h. After the
reactioii mixture was cooled to - 78 'C. I (2.66 g. 22 mmolf and [NiCI,(dppp)]
(0 92 g, 1.7 mmol) were added. The red-brobn reaction mixture was allowed to
warm to room temperature over 2 h a n d then stirred for an additional 4 h. Saturated
ammonium chloride solution (50mL) was added to quench the rcaction. and the
organic phase was separated, washed with water. and then dried over magnesium
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sulfate After the solvent was removed in vacuo. the residue was purified by column
material."] Both micelles in water and inverted micelles were
chromatography (silica gel. pentane) to give 3 b (3.35 g. 62%) as a yellow solid. m.p.
recently reported to form cylindrical micelles; as the surfactant
56 C . - ' H N M R ( 4 0 0 M H ~ .CDC'I,. 25 C, TMS): 3 = 0.21 Is, IXH). 5.71 (d.
concentration
J = ~ . ~ H L . ~ H ) . ~ ~ ~ ( ~ . J = ~ . ~ H ~ , ~ H ) . - ~ ' C ' NC.M R ( I
~ ~ M H ~ . C DisC increased,
I , . ~ ~ they start to entangle and form a
dynamic network similar to semidilute polymer solutions.[2-31
TMS): 6 = - 0.11 (s). 97.XX (s). 101.25 (s). 125 44 (t). 128.55 (\).-IR (KBr):
? = 1960. 2900. 2161. 1698. 1517. 1470. 250cin-'. UV:VIS (acetonitrile):
Structures composed of packed. compartmentalized domains
;.,,,3x(~.) = 212 (7x01)). 210 (9700). 144 (10000). 280 (5900). 292 (5100). 326 iiiii
can
also display a gel-like appearance. Microemulsion gels (so( 7 5 0 ) . ~M S ( 7 0 e V ) ~ ~ l i ' ~ ( " ~ " ) = 2 4 6 ( 2 2 ) [ ~ (40).
~ ~ t ] lOX(1X).
.?31
73(100).
called ringing gels), which require large amounts of surfactant.
were shown to consist of closely packed globular aggregates filled
with hydrocarbon, while water forms the continuous
Such systems can form cubic phases.'51 When large volumes of a
[ l ] Recent reviews on the synthesis of enediyne antibiotics: a ) K. C. Nlcolaou.
dispersed
phase and small amounts of surfactant are used, other
W.-M. Dai. ~ P I ~ L V I .C. h m . 1991. 103. 1453. A i i g w . C/KW?.hir. Ed Eil,?/ 1991.
viscoelastic gels referred to as high internal phase ratio emul311. 13x7. b) H. Waldrnann. A'urhr. Chrnl Edi. Luh. 1991. .IY. 21 I : c) K. C.
Nicolaou, A. L. Smith. A u . C/ion. Rc.s. 1992. 25. 497: d ) K . C . Nicolaou,
sions (HIPRE) can be obtained. These were shown to consist of
Aii,qcii. Clirni 1993. 105. 1462; ,4/1pni%.
('hcn?. Itit. Ed. Dig/. 1993. 32. 1377.
polyhedral hydrocarbon cells (polyaphron) delimited by a layer
[ 2 ] Generation of the double bond through a ) 1,2-elimination: H. Audrain. 7:
of hydrated surfxtant.[6. Gels of this type. which contain up
Skrydstrup. G. Uliobarri. D. S. Grierson. Sj,n/etr 1993. 20. and references
to 99% v/v of a hydrocarbon, were obtained.I4]Their preparatherein; h) McMuri-y coupling: H. Hopf. C. Horn, W. R. Roth. C l k m Ller . in
press: Core) Winter fragmentation: M. F. Semmelhack. J. Gnllagher. Terrahction usually requires the use of two surfactants -one oil-soluble
~/rc)nLrit. 1993. 34, 4121 ; d) Rainherg Bdcklund r c ~ c t i o n :K . C.Nicolaou. G
and the other water-soluble. As Far as water-in-oil emulsions are
Zuccarello. C . Riemer. V. A . Esteve7. W M . Dai. .I A m Clwn. So( 1992. 114.
concerned. concentrated aqueous gels have been reported that
7360.
contain roughly 50-98 % v;v of water as the internal phase and
Review. R. Gleiter. D. KratL. . 4 n g ~ 1 1C'hcni
..
1993. I R i . 8x4. An'yiw. Choir. Inr.
Ed. Engl. 1993. 32. 842: cf: a) S. L . Schreiher. L. L. Kiessliiig. J ,4m. Clieiii. So<
a hydrocarbon or a fluorocarbon as the continuous
1988. 110.631; b) K. N. Bharuchii. R. M.Marsh. R. E. Minto. R G. Bergman.
We wondered whether gels with a high internal fluorocarbon
ihid 1992. 114. 3120; c) P. Maenus, P. Carter, .I. Elliot, R. Lewis. J. Harling, T.
content
could be obtained with low amounts of a single fluorinatPitterna. W. E. Bauta. S. Fortt, ihd. 1992.114.2544. d) D. Schinrer. J. Kabhara.
ed surfactant and water as components of the cell walls. Such gels
Swi/i,tt 1992. 766. e) Y:F.
Lu. C. W Harwig. A. G Fallis, J. Or,?. C/wn?.1993.
would exploit the unique properties of fluorocarbons to spread
5H, 4202; 1)M. E. Maier, T. Brandstctter. Terruiirduin Lc,tr. 1992.33, 751 1. g) R.
Brtickner. J. Suffert. ;hid. 1991, 31. 1453.
easily on amphiphilic surfaces and of fluorinated surfactants to
Selected spectroscopic data for the no4 compounds: 3 a : ' H NMR (400 MHr.
stabilize fluorocarbon dispersions, as demonstrated for fluoroCDCI,, 25 C . TMSj: 6 = 0.98 (t. J =7.3 Hz. 6 H ) . 1.56 (m. 4 H ) . 2.32 It.
carbon emulsions formulated for in vivo oxygen delivery.[" - 'I
J =7.0 Hr. 4H). 5.54 (5. 2 H ) . 5-92 (\, 2 H ) -"C N M R (100 MHr. CDCI,,
We found it possible to prepare stable gels consisting of very
25 C. TMS): 6 =13.47 (q), 21.26 (t). 22.08 ( t ) , 77.34 (s). 93.30 (s). 1 2 2 M (t).
129 55 (5) -MS (70 eV): ni:z(%) =186 (79) [ M i ] . 171 (4). 158 (48). 141 (56).
large amounts of fluorocarbons, exceptionally low amounts of
130 (88). 128 (100). 115 (67). 91 (41). 77 (40).-~3b:See Experimental Procea fluorinated surfactant. and water. We utilized a variety of
dure: 5 : ' H N M R (400 MHL. [DJacetone. 15 C'. TMS): b =1.00 (t.
linear and cyclic fluorocarbons, including some lipophilic ones.
J = 7 . 2 H 7 . 6 H ) . 1.53(tn.4H).1.32(t.J=6.9H7.4H),Z.h3(m.4H)..1.08(iii,
with a range of molecular weights. for example perfluorooctyl
2 H ) . i3CNMR(100MH~.[D,]acetone.25 C.TMS).ii =13.61(q).21.X8(t).
22.86 (1). 31.74 (t). 39.45 (d). 82.6 (s). 94.43 (s). 124.07 ( s ) . 173.93 (s).-IR
ethane, perfluorooctyl bromide, perfluorodecalin. a mixture of
(KBr): i. = 2936,2874.2210.1706.1427.1296,1256,1204,949 cm- I . -UV:VIS
perfluoro-rz-butyldecalin
( I 5 -20 Y ) and perfluoroperhydro= 200 (5100). 218 (3900). 256 (10900). 2358 ( 1 1500). 264
(acetonitrile): ;.,,,,,x(~)
phenanthrene (80-85 YO)(APF 21 5 ) , perfluorodiisopropylde(13500).268 (12 500). 276(11400). 290 mm (670). -MS (70 eV): 111:: (Yo)= 2x4
calin (APF-240). and a mixture of perfluorodixylylmethane
(100) [ . W + ] . 256 (841, 227 (35). 169 (37). 158 (36). 128 (26). 115 (29). 91 (17).
77(12).-8. ' H N M R ( 4 0 0 M H 7 . C D C I , , 2 i C.TMS):d = l . 0 2 ( t . J = ~ . ~ H L . (60 YO)and perfluorodixylylethane (40 YO)(APF-260)"21 Fluo1 2 H ) . 1.58 (m. XH). 2.36 (t. J = 6 . 9 H r . 8 H ) . 3 2 2 (s, 8H).--'"C N M R
rocarbons with a higher boiling point were chosen preferentially
(100 MH7. CDCI,. 25 'C. TMS): 6 =13.4X ( q ) . 21.66 ( t ) . 22.12 ( t ) . 29.29 (1).
to meet the requirement of one of the targeted applications
8 0 . 0 2 ( ~ ) . 9 5 . 7 7 ( s120.66(5).
).
137.30(s). 185.12(s).-~I R ( K B r ) : ? = 2964.2873,
(topical administration of drugs) to prevent the system from
2212. 1648. 1411, 1335. 3295. 691 cm-'.--UV:VIS (acetonitrile): ?n>dx(c)= I 9 2
(27800), 246 (30500). 266 (27400). 280 (26400). 306 (35700). 328 (7200).
rapid evaporation when left open to air. The fluorinated surfac358 nm (4x00).-MS (70 eV). w : (9")= 476 (100) [ M '1.449 (14), 435 (10). 397
tants used were the neutral amine oxide 1 and the zwitterionic
(19). 25X (12). 183 ( 1 1 ) .
phosphocholine derivative 2.['3. 14' Both were monodispersed,
pure, and well defined.
Received- December 17. 1993 [Z65X5IE]
German bersion: .4n,yeu. Cliiwi. 1994. 106. 11 73
~
Stable Highly Concentrated Fluorocarbon Gels**
Marie-Pierre Krafft and J. G. Riess*
Highly viscous phases are often found in ternary hydrocarbon/
waterjsurfactant systems. Gels can be found in systems composed
of two interlocking continuous phases, one of which is liquid and
the other of which consists of long-chain solid or liquid-crystalline
[*I
[**I
Prof. J. G. Riess. Dr. M.-P. Krafft
Unite de Chimie Moleculaire. associke a u CNRS
Universite de Nice Sophia Antipolis, Faculte des Sciences
F-06108 Nice Cedcx 2 (France)
Telefax: Int. code + 9352-9020
This research was supported by the Centre National de la Recherche Scleiitifique and the ATTA. The authors thank Dr. Gulik-Krzywicki (Gif sur Yvette)
for freeze fracture electron microsgraphs and Drs. Ni and Weers (Alliance
Pharmaceutical. San Diego. CA) for viscosity measurements.
The new gels were prepared under nitrogen at room temperature by slowly adding the fluorocarbon to a foamy aqueous
solution of the fluorinated surfactant. Little energy is required,
gentle shaking by hand suffices. As the gel forms, the rate of
fluorocarbon addition can be increased. Gels did not form when
the surfactant solution was added all at once to a relatively large
amount of fluorocarbon. Interestingly, high-energy mechanical
homogenization or sonication lead to rapid phase separation.
After preparation the gels can be degassed by centrifugation at
room temperature (1000 rpm, 15 min).
Typical formulations used for one high molecular weight
fluorocarbon, perfluorodiisopropyldecdin, are listed in Table I .
These gels contain up to 99Y0 vlv of the fluorocarbon and
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