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Efficient Total Synthesis of the Pharmacophore of the Anticancer Antibiotic CC-1065 by Zirconocene- and Palladium-Initiated Cyclizations.

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COMMUNICATIONS
[ l ] a ) J. L. Sussman. M. Harel. F. Frolow. C. Oefner. A. Goldman. L. Toker. I .
Silman. Scicvw 1991. 2S3, 872; b) M. Harel, I . Schalk. L. Ehret-Sabatier. E
Bouet. M. Goeldner, C. Hirth. P. H. Axelsen. I. Silman, 1. L. Sussman. Pror.
Nor/. Acud. Sci. U S A 1993, YO. 9031.
[2] a) M. A. Petli. T. J. Shepodd. R. E. Barrdns. Jr., D. A. Dougherty. J. Am.
Chrm. Soc. 1988. 110. 6825: b) D. A. Stauffer. R. E. Barrans, Jr., D. A.
Dougherty. Afigvw. Chmi. 1990. 102. 953; Angeir. Chcm. h i t . €d. €ng/. 1990.
29. 91 5.
[3] P. C. Kearney. L. S. Mizoue. R. A. Kumpf, J. E. Forman, A. McCurdy. D. A.
Dougherty, J. A m C/imi. Sue. 1993. 115. 9907.
[4] H.-J. Schneider. D. Giitles. U. Schneider. J. Am. Chcm. Sue. 1988. 110, 6449.
[5] a ) S . Shinkai, K. Araki. T. Matsuda, N. Nishiyama. H. Ikeda. 1. Takasu. M.
Iwamoto. J. Am. Chon. Soc. 1990. 112. 9053; b) K. Araki. H. Shimizu. S.
Shinkai, Chrm. Lcw. 1993. 205.
[6] K . S . Kim. J. Y. Lee. S. J. Lee. T.-K. Ha. D. H. Kim. J. An,. Clion. Soc. 1994.
116. 7399.
[7] J. Sunner. K. Nishimwa, P. Kebarle. J. Phxs. Chon. 1981. X.C. 1814.
[8] a) R. W. Taft, F. Anvia. J.-F. Gal. S. Walsh. M. Capon. M. C. Holmes. K. Hosn.
G. Oloumi, R. Vasanwala. S. Yazdani. P i m Appl. C h m . 1990.62. 17; b) B. C.
Guo. J. W. Purnell. A. W. Castleman Jr.. Chrni. P h y . Lcrr. 1990. / 6 8 . 155.
191 H. Bock, K. Ruppert. Z. Havlas. D. Fenske. A n g w . Cheni. 1990. 102. 1095.
Angew. Chem. Inr. W .€ng/. 1990. 2Y. 1042.
[lo] a) C. Lambert. P. von R. Schleyer. A n g w . Chcm. 1994. 106. 1187; Anges..
Chmi. In/. €d. D i g / . 1994. 33. 1129; b) D. Hoffmann. W. Bauer. P. von R.
Schleyer. U. Pieper. D Stalke. Orgunomc~ru//iu.s1993. 12. 1193.
[l I] 1.Heginbotham. R. MacKinnon. N e w o n 1992. 8. 483.
[I21 R. A. Kumpf. D. A. Dougherty. Srioice 1993. 261. 1708.
[I31 R. Leppkes. F. Vogtle. Chem. Brr. 1983. //6.215.
[14] L L . Pierre, P. Baret. P. Chautemps. M. Armand. J. Am. Chon. Sue. 1981. 103.
2986.
[I51 H. C. Kang, A. W. Hanson, B. Eaton. V. Boekelheide. 1 A m . Chew Soc. 1985.
107. 1979.
[I61 a) A. lkeda, S . Shinkai, 7Wuhcdron LA,//.
1992.33.7385; b) J. Am. Chem. Sou.
1994. //6.3102. and references therein.
[I71 a) K. Iwamolo. A. Ikeda, K. Araki. T. Harada, S. Shinkai. 72fruhiv/rlron1993,
49. 9937; b) A. Ikeda. H. Tsuzuki, S. Shinkai, J. Chrni. Sue. P d i n Trun.5. 2
1994.2073.
[I81 a ) F. Inokuchi. Y. Shiomi. H. Kawabala, T. Sakaki. S . Shinkai. Chvm. L P ! ~ .
1993.1595; b) F. Inokuchi. K. Araki. S . Shinkai, h i d . 1994. 1 3 8 3 : ~ )H.-F. Wu.
J. S. Brodbelt. J. Am. Chmn. Soc. 1994. / l 6 . 6418. d ) S . R. Wilson. Y. Wu.
Suprumokc. Cliim. 1994. 3, 273.
1191 a) Z. Goren. S. E. Biali. J. Chcwi. Sou. Perkin Truns. 1 1990. 1484: b) F. Grynszpan. Z. Goren. S. E. Biali. J. Org. Chein. 1991. 56. 532.
[20] Y. Miyahara. T. Inazu. T. Yoshino. Tc,rruhrdrun Lerr. 1983. 24. 5277.
1211 Even when the signal intensities of ( I + M ) ' or ( I + M ) + / I ' are plotted
versus the ionic radius very similar plots are obtained. When an equimolar
mixture of 1. 2. and 3 was analyzed in the absence of metal cations. the ratio
of the signal intensities was 1 ' : 2 + : 3 ' = 2.81:7.13:1.00. indicating the relatively stability of the host cations.
[22] The attempt to detect [ 3 . Cs]' in solution by 'H NMR spectroscopy and
solvent extraction failed.
[23] A. Bondi. J. P/iI.\. Clicm. 1964. 68.441.
[24] C. Schade. P. van R. Schleyer. Adr. Orgonomrr. Cheni. 1987. 27. 169.
[25] Very recently. Ungaro etal. reported on cation-n interactions in a [calix[4]arene-crown-6. Cs]' complex (R. Ungaro. A. Casnati. F. Ugozzoli. A.
Pochini. J.-F. Dozol. C. Hill, H. Rouquette. .4ngew. Chej77. 1994. 106. 1551;
Angrw. Chcw7. I n [ . €d. EngI. 1994.33. 1506). Although the X-ray crystal structure shows that the distance between benzene rings and Cs' is short. the
presence of cation-interactions is doubtful due to the presence of manv metalcoordinating oxygen atoms (as in the complexes [I . MI'.
Efficient Total Synthesis of the Pharmacophore
of the Anticancer Antibiotic CC-1065 by
Zirconocene- and Palladium-Initiated
Cyclizations**
Lutz F. Tietze* and Wilm Buhr
Dedicated lo Professor Richard R. Schmidt on the occasion of' his
60th hirrhday
The antibiotic CC-1065 (l), which was first isolated from
Strepromyces ze1etisi.s in 1978, is one of the most potent antitumor agents known at present."] It contains three pyrrolo[3,2-e]dihydroindole moieties; the A-unit with an unusual spirocyclopropyl group is the pharmacophore. whereas the B- and
C-units are responsible for the strong binding to DNA. It has
been shown that the A-unit of 1, called CPI, selectively alkylates
pH
$0
H-N
'H
'.ON&o.,
0
bCH,
H
A
C
B
CC-1065 1
AT-rich regions of the minor groove of double-stranded
DNA.['] However, 1 cannot be used as a drug because of delayed fatal hepatotoxicity. In contrast, derivatives of the CPI
unit having similar antitumor activity do not show this negative
property.[''
For the design of selective anticancer agents["] we have developed a new and highly efficient synthesis of the (N2-benzenesulfonyl)-CPI derivative 2. This synthesis is superior to the known
procedures and is distinguished by its short reaction sequence.
The key steps are two consecutive cyclizations mediated by
organo transition metal complexes which allow the formation of
first the pyrroline and then the pyrrole ring in 2.
Retrosynthetically, 2 can be traced back to the N2-benzenesulfonyl-seco-CPI 3, which via 5 leads to the starting material 4.
The special feature of this synthesis is that not only is the pyrroline ring constructed in the first cyclization with zirconocene
methyl chloride,'". 5g. 6a. b1 but during the quenching with iodine,
in addition to the formation of a iodomethyl group, a second
iodine atom is simultaneously introduced at the arene. This can
be used for the construction of the pyrrole ring in the subsequent
Heck reaction.['"
Substrate 4 was synthesized in 66% yield in four steps starting from the commercially available 2-methoxy-4-nitroaniline
through Pt-catalyzed hydrogenation in dioxane, twofold N-ben['I
Prof. Dr. L. F. Tietze. Dipl.-Chem. W. Buhr
lnstitut fur Orgdnische Chemie der Universitlt
Tammannstrasse 2. D-37077 Gottingcn (Germany)
Telefax: Int. code + (551)39-9476
[**I Anticancer Agents. Part 22. This work was supported by the Fonds der
Chemischen Industrie. We wish to thank the Degussa AG for their generous
gifts of noble metal compounds. Part 21: ref. [4b].
1366
[c; V C H ~r/iigsg~,,srl/,sc/iitJr
mhH. 0-69451 Weinhrim. 1995
o.C7o-0833/Y5/12/2-1366$ 1 0 . 0 0 + .2.(/0
Angeu. Cheni. In[. Ed. €fig/. 1995. 34. No. 12
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R
OR
OR1
3a: R = OH
2
8a:R=H
b: R = AC
b: R = CI
9a: R 1 = H, R2 = Me
b: R 1 = Ac, R2 = Me
R 1 = Ac, R 2 = H
d:Rl=H, R2=H
C:
4
5a:R=1
b:R=OH
C: R = OAc
d:R=H
zenesulfonization with benzenesulfonyl chloride in pyridine,'']
bromination with N-bromosuccinimide in tetrahydrofuran, and
double allylation with ally1 bromide in the presence of tetrabutylammonium iodide also in tetrahydrofuran. Halogenmetal exchange in 4 with tBuLi in tetrahydrofuran and subsequent metal exchange with [Cp,ZrCl(CH,)] proceeded supposedly through a zirconium -didehydrobenzene complex 6 to the
zirconacyclopentene derivative 7,[6cl which gave 5a in 60 %
yield as a single product after quenching with two equivalents of
iodine in dichloromethane. In the reaction of 7 with iodine, first
the aryl-zirconium bond and then the alkyl-zirconium bond
was cleaved. This was deduced from the reaction of 7 with only
one equivalent of iodine followed by aqueous workup, which
gave 5d exclusively. Somewhat surprising is the high regioselectivity of the cyclization of 4; the insertion of the alkene group in
complex 6 occurs exclusively para to the methoxy group.[']
Experimental Procedure
'$
p
y cyp -gn N 3 0 2 P h
\
Ph02S
Ph02k
OMe
6Me
6
[Pd(PPh,),], CH,CN/Et,N, 60 "C, 18 h). In contrast, reaction
of 5 c with palladium acetate in the presence of silver carbonate
led in 90 YOyield exclusively to 8 b (2 mol O/O Pd(OAc), , 1.5 equiv
Ag,CO,, DMF, 20 "C, 2 h). Without further workup the respective mixtures of 8a/9a and 8b were isomerized with camphorsulfonic acid quantitively to give 9a and 9b (CH,C12, 2 0 T ,
1 h). The cleavage of the aryl methyl ether in 9b to give 9 c was
achieved with boron tribromide in 80% yield (CH,Cl,, - 10 "C,
1 h); under these conditions 9a provided only a mixture of products.
Solvolysis of 9 c in methanol in the presence of potassium
carbonate afforded 9d, and successive cleavage of the benzenesulfonyl group at the indole nitrogen with sodium bis(2-methoxyethoxy)dihydroaluminate (Red-Al) led to the deThe conversion
sired seco-CPI 3 a with an overall .yield of 70 YO.
of 3 a to 2 is known1"] and was carried out not only by means
of Mitsunobu's method["] with diethyl azodicarboxylate, but
also via the chloride 3 b with a subsequent base-induced cyclization.
In summary, the pharmacologically important CPI derivative
2 was prepared in 11 steps with an overall yield of 12% starting
from commercially available 2-methoxy-4-nitroaniline. The
double cyclization mediated by zirconocene and palladium
complexes is of general synthetic value, and we are currently
testing it for the construction of other complex bis-ortho-annelated arenes.
Ph02S
OMe
7
Compound 5 a could not be used directly in the Heck reaction
since both the iodobenzene moiety and the iodomethylpyrroline
group react to form a methylpyrrole unit. For this reason 5a
was first converted into the hydroxymethyl derivative 5 b with
silver oxide on silica gel in 90% yield (acetone/water, 20"C,
24 h). The transformation of the iodomethyl group in 5 a caused
many problems at the beginning since all attempts at nucleophilic substitution, for example with acetate, failed; instead
elimination with partial isomerization of the formed double
bond occurred.
The Heck reaction for the preparation of 3 can be carried out
with 5b as well as with 5c, which is obtained quantitively from
5 b by acetylation with sodium acetate in acetic anhydride. With
catalytic amounts of tetrakis(tripheny1phosphane)palladium 5 b
gave a 17:1 mixture of 8 a and 9a in 90% yield (2 mol%
Angew. Chcm. Int. E d Engl. 1995, 34, No. 12
To a solution of 4 (0.34 mmol) and [Cp,ZrCH,Cl] (0.35 mmol) in dry T H F (10 mL)
was added slowly with stirring at - 78 "C a solution of ter/-butyllithium in hexane
(0.70mmol). Stirring was continued for 1 h at -78°C and 18 h at 20°C. The
solvent was evaporated in vacuo and the residue dissolved in dry CH,CI, (20 mL)
and cooled to 0°C. To this solution was slowly added a suspension of iodine
(0.72 mmol) in dry CH2C1, (20 mL), and the mixture was stirred for 1 h a t 0 "C and
36 h a t 20 "C. The reaction mixture was filtered through celite, washed with saturated Na,SO, solution, water, and brine (10 mLeach), dried over MgSO,. and concentrated to dryness. After chromatography (petroleum ether/ethyl acetate 3: 1) 5a was
obtained in 60% yield. Recrystallization from ethyl acetate gave colorless needles.
5a:M.p.206.9'C;'HNMR(300MHz,CDC1,):6=2.34(dd,J=l0,9.0Hz,lH,
3-CHJ. 3.32 (s, 3H, 0-CH,), 3.34-3.46 (m. 2H, 3-H. 3-CH4),3.85-4.00 (m, 2H,
2-H,.l'-H,).4.10(d, J = 1 2 H z , 1 H , 2 - H b ) , 4 . 4 9 ( d d ,J = 1 3 . 5 . 6 . 0 H ~ ,l H , l ' - H b ) ,
4.93 (d. J = 6 H z , I H , truns-CH=CH,), 4.98 (s, l H , cis-CH=CH,), 5.83-5.97
(cm. IH,CH=CH,).7.14(s, 1H,7-H), 7.48-7.69(m,6H.Ph-H),7.72-7.79(m,
ZH, Ph-H), 7.82 (d, J = 8.0Hz, Ph-H).
9 ~'H: NMR (200 MHz. CDC1,): 6 = 2.01 (s. 3H, OAc), 2.21 (s, 3H. 8-CH3), 3.10
(dd. J = 10,9.0 Hz, 1 H, 1-CH,). 3.52-3.78 (m, 2H, 1-H, 1-CHb),4.06(dd,J =11.5,
3.5 Hz, 1 H, 2-H,) 4.16 (d, J =11.5 Hz, 2-Hb), 7.15 (s, 1 H, 7-H), 7.37 ( s , 1 H, 4-H),
7.38-7.63(m,6H,Ph-H),7,76(d,
J = 8.0Hz,2H,Ph-H).7,85(d, J = 8.0Hz,2H.
Ph-H), 8.85 (s, 1 H, Ph-OH).
Received: November 10, 1994 [Z 7469 IE]
German version: Angew. C h e m 1995, 107. 1485-1487
Keywords: antibiotics . antitumor agents . cyclizations . Heck
reactions . zirconium compounds
(i=
VCH
J V~rlug~~ge.sell.schufr
mbH, D-6Y4.51
Weinheim,1995
0570-0X331YS~12f2-1367$10.00f .2S/0
1367
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[I] L. J. Hanka, A. Dietz, S. A. Gerpheide, S . L. Kuentzel, D. G. Martin. J. Antihior. 1978, 31, 1211.
[2] a) D. L. Boger, S. M. Sakya, J. Org. Chem. 1992, 57, 1277; b) M. A. Warpehosky, L. H. Hurley, Chenr. Res. Toxicol. 1988, 1, 3 1 5 ; c) V. L. Reynolds. I .
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[3] J. P. Gorren. G . L. Clarke, E. A. Prutt, 1 An/lhio/.1984. 37, 63.
[4] a) Reviews: L. F. Tietze in Moleculur Aspects 0 1 Chemolherupy (Eds.: E.
Borowski, D. Shugar), Pergamon, New York, 1990, pp. 55-70; b) L. F. Tietze,
A. Fischer-Beller. Curhohydr. RPS.1994. 254, 169, and references therein.
[5] a) W. Wierenga, J. Am. Chem. SOC.1981,103.5621; b) P. Magnus. Y. S. Or, J.
Chem. Soc. Chem. Commun. 1983,26;cj G. A. Kraus. S. Yue, ihid. 1983,1198;
d ) D. L. Boger, R. S. Coleman, J. Am. Ciiem. Soc. 1988. 110, 4796; e) hid.
1988, flu,1321 ; f) L. E Tietze, T. Grote, Chem. Ber. 1993,126,2733;g) J. Org.
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59, 4542.
[6] a) J. H. Tidwell, D. R. Senn, S. L. Buchwald, J. Am. Chem. SOC.1991, 113.
4685; b) J. H. Tidwell, S . L. Buchwald, J. Org. Chem. 1992, 57, 6380;
c) G . Erker, Angew,. Chem. 1989, 101.41 1 ; Angeu. Chem. Int. Ed. Engl. 1989,
28, 391.
171 a) T. Jeffery, J. C h m . SOC.Chem. Commun. 1984, 1287; b) Synthe.sis 1987.70;
cj R. C. Larock, 5. E. Baker, Terruhedron Left. 1988, 29,905.
[8] R. Adams, T. E. Young, J. Am. Chem. Sot. 1951, 75, 3235.
[9] Based on the N M R data of 5 a the two possible regioisomeric cyclization
products cannot be differentiated. The assignment relied on a comparison of
the product 3b with authentic material.
[lo] P. Magnus;T. Gallagher. J C[iem. Soc. Chem. Commun. 1984. 289.
[Ill 0. Mitsunobu, Synthesis 1981, 1 .
Corrigendum
Several literature citations should be corrected in the review
"Stereospecific Olefin Polymerization with Chiral Metallocene
Catalysts" by H. H. Brintzinger et al. (Angew. Chem. Int. Ed.
Engl. 1955, 34, 1143-1170). On p. 1162, in the left-hand
column, third paragraph, last line, reference [95 b] should be
reference [125]; three lines below [140, 141 b, 143 b] should be
[142,143b, 1471; in the right-hand column five lines from the top
[213, 2171 should be [214, 2171.
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