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Directed Synthesis of Nonsymmetrical Bis-Steroidal Pyrazines and the First Biologically Active Cephalostatin Analogues.

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[6] For an enzymatic strategy combined with Pdo chemistry: N. B Dyatkina, F.
Thiel, M. von Janta. Tetrahedron 1995, 51, 761 and 3i.
[7] For other recent syntheses see ref. [ 3 b,d,e, h]; T. Berranger, Y. Langlois, Teetrahedron Let!. 1995. 36, 5523; M. Legraverend, A. M. Aubertin, G. Obert, C.
Huel, E. Bisagni, Nucleosides. Nucleotides 1994. 13. 915; M. Asami. J. Takahashi, s. Inoue, Teetruhedron. Asymmetry 1994, 5, 1649; M. Diaz, J. Ibarzo,
N. M. Jimenez. R. M. Ortuno, ibid. 1994, 5, 129; M. E. Jung, H. Rhee, Teirahedron Lett 1993,34,4449; R. A. Mac Keith, R. Mc Cague, H. F. Olivo. C F.
Palmer. S. M Roberts. J. Chem SOC.Pcrkin Trans. 1 1993, 313: L. Gundersen,
T. Benneche, F. Rise, A Gogoll, K. Undheim, Acta Chem. Scand. 1992,46,761;
M. R. Peel, D. D. Sternbach. M. R. Johnson, J Org. Chmt. 1991, 56, 4990;
A . M . Exall, M. F. Jones. C.-L. Mo. P. L. Myers, I.L. Paternoster, H. Singh,
R. Storer, G . G Weingarten, C . Williamson, A. C. Brodie. J. Cook, D. E.
Lake, C. A. Meerholz, P J. Turnbull, R. M. Highcock, J. Chcm. Soc. Perkin
Trans. 1 1991, 2467.
[8] The proposed structure was confirmed by spectroscopy.
[9] B. M. Trost, J. L. Belletire, S . Godleski, P. G . McDougdl, J. M Balkovec, J J.
Baldwin, M. E. Christy, G . S. Ponticello, S. L. Varga, J. P. Springer. J. Org.
Chem. 1986, 51, 2370.
[lo] Notable differences in the ' H NMR spectra of the 0-methylmandelates.
(S,S,RI-diastereomer: 6 = 1 . 9 3 ( d t , J = 1 5 . 3 , 2 . 5 H z , 1 H ) . 3.06(dt. J=15.3.
workers prepared the cephalostatins 7 and 12 together with
ritterazin K from two precursors in a statistical way and had to
separate the three products.[5b1For the first synthesis of nonsymmetrical pyrazines from cr-acetoxy ketones and a-amino
oximethers, which was not yet been applied to
l 5 steroids,
(1 45 "C)
1.9 Hz, 1 H), 7.72 (5, 1 H), 8.56 ( s , 1 H); (S,R,Si-diastereomer. 6 =1.72 (dt,
J =15.3. 3.0Hz, 1 H ) , 3.00 (dt. J =15.3, 7.6 Hz, 1 H). 340 (s, 3 H ) , 6.19 (dd,
J = 5.5, 1.9 Hz, 1 H), 6.34 (dt, J = 5.5, 1.9 Hz, 1 H), 7.79 (s, I H), 8.54 (s. I H).
Systematic investigations in our laboratories indicated two
11 11 In this case, a comparison of relative ee values was only obtained by compariindependent routes to easily accessible cephalostatin analogues,
son of rotations. The optical rotation of enantiomerically pure products were
which can provide information on the substructures essential
not obtained since 1Oc proved to be a better guanine equivalent.
for cytostatic activity. One approach, called the symmetrical
[I21 Prepared in a one-pot procedure from guanine, see: R. Zou. M. J. Robins,
Can. J. Chem 1987.65, 1436.
route, aimed at the straightforward synthesis of symmetrical
[13] The ee value was determined by N M R spectroscopy by using [Eu(hfc),]
bis-steroidal pyrazines by dimerization of the usual a-amino
(hfc = 3-(heptafluoropropylhydroxymethylene)-d-camphorate)as the chiral
ketone prec~rsor.~']
These pyrazines have then to be desymshift reagent after further transformation to the ester 14.
metrized and further functionalized at a later stage of the syn[14] The higher ee value may arise, in part, from a kinetic resolution of the
monoalkykated product superimposed upon the initial asymmetric induction.
thesis. The other approach, called the nonsymmetrical route,
[15] B. M. Trost, R. Brdslau, J. Org. Chem. 1988, 53, 532.
called for the direct synthesis of unsyminetrical bis-steroidal
[16] S. Daluge, R. Vince, J. Org. Chem. 1978, 43. 2311.
pyrazines by coupling of two different steroids.
At the beginning we elaborated the symmetrical route, which
afforded in a short and efficient seven-step synthesis the symmetric diketone 3a from easily available hecogenine acetate 2.[@
Desymmetrization of this diketone by diastereoselective reduction with L-Selectride afforded the cr-hydroxy ketone 4a,while
borohydride reduction provided the 8-hydroxy ketone 48.
Directed Synthesis of Nonsymmetrical BisThese reduction processes under proper conditions also gave
Steroidal Pyrazines and the First Biologically
rise to the a-diol 5a and 8-diol 58 (see Scheme 1).
Active Cephalostatin Analogues**
Submitting the selected compounds 3a, 3b, 48, and 58 to the
U. S. National Cancer Institutes (NCI) in vitro, human-cancerMichael Drogemuller, Rolf Jautelat, and
focused evaluation system,"' we found that the symmetrical and
Ekkehard Winterfeldt*
saturated diketone 3br9](affecting only 4 of 58 cell lines; GI5':
Dedicated to Professor Ernst Mutschler
MG M I D (MG M I D =mean graph midpoint; that is mean
on the occasion of his 65th birthday
activity over all cell lines) > - 4.0) showed weak activity. In
contrast the symmetrical but unsaturated substances diketone
Cephalostatin 1 (1) is the prototype of the cephalostatins and
3a (affecting 32 of 58 cell lines;
M G M I D > - 4.3) and
the ritterazins, a family of 30 trisdecacyclic pyrazines, isolated
p-diol58 (affecting 21 of 58 cell lines; GI5': M G M I D > - 4.2)
by Pettit and his co-workers since 1988 from the Indian Ocean
showed moderate tumor-inhibiting capacity. Finally the nonmarine worm Cephalodiscus gilchristi"] and by the group of
symmetrical and unsaturated 8-hydroxy ketone 48 (affecting 58
Fusetani from the tunicate Riterella tokioka.[2' The extraordiof 58 cell lines; GI5': M G M I D = - 5.3) revealed significant
narily strong cytostatic activity,[1b.31 together with the new and
cytostatic action on all tested tumor cells."'] Therefore the 8interesting structure and very limited availability,""' immediatehydroxy ketone 48 reaches affecting concentrations of standard
ly led to attempts at syntheses in various l a b ~ r a t o r i e s . ' ~ -Al~'
chemotherapeutics (e.g., cyclophosphamide GI5o:M G M I D =
though recently Fuchs et al. reported quite impressive achieve- 3.7; 5-fluorouracil GI5': M G M I D = - 4.7; cisplatin GI5o:
ments in the total synthesis of cephalostatins and ritterazins, the
M G M I D = - 5.7; adriamycin GI5o: M G M I D = - 6.9).["]
crucial problem of a direct synthesis of nonsymmetrical bisTheir activities are similar to those of tamoxifen (GI5':
steroidal pyrazines was not properly solved. Fuchs and his COM G M I D = 5.3)" and 4000 times weaker than that of the
very potent cephalostatin 1 (1) (GI5o: M G M I D = - 8.9),[lC1
[*I Prof. Dr. E. Winterfeldt, Drpl.-Chem. M. Drogemuller.
which itself shows a tenfold stronger tumor-inhibiting activity
Dip1.-Chem. R. Jautelat
than taxol (GI5o: M G M I D = -7.9).'"'
Institut fur Organische Chemie der Universitdt
Schneiderberg 1b, D-30167 Hannover (Germany)
By comparison to the noncytostatic saturated cephalostatin
Fax: Int. code +(511)762-3011
analogue^[^.^"' we recognized that the A L 4 . I 5 double bond is
e-mail: wmterfeldt(c~
indispensable for the biological activity in general and that the
[**I This work wassupported by the Fonds derchemischen Industrie, the Deutsche
nonsymmetrical structure is of particular importance for the
Forschungsgemeinschaft, and the Schering AG, Berlin. R. J. thanks the Fonds
broad scope of this action. Therefore we focused our efforts o n
der Chemischen lndustrie for a scholarship.
~ ~ r / ~ i ~ . ~ f i ~ ~ . ~mhH.
e N s ~ D-69451
h f ~ / r f r We~rtheim,1996
$ 15.00+ ,2510
Angew. Chem. In[. Ed. Engl. 1996, 35, N o . 13114
As expected treatment of azirine 6, easily prepared from
with enamino ketone 7 and trifluoracetic
acid (TFA) at 0 "C in THF gave pyrazine 8 in 63 % yield (see
Scheme 3 ) .
3a X.Y = 0
Scheme 3. Preparation of pyrazine 8. a) THF, TFA, O"C, 3 h (63%).
4p X = a H , POH
4a X = a W PH
5P X = aH, POH
Y = aH, POH
With the intention of combining two steroids we appliedafter substantial improvementsf131-Zbiral's['41 method to prepare steroidal vinyl azides as precursors for the corresponding
azirines." However, all attempts to generate and isolate these
ring-fused azirines failed. When a literature survey['61 confirmed that this kind of compound is indeed highly strained and
less stable than monocyclic azirines like 6, we conducted the
azirine formation in the presence of enamino ketone 10 in order
to capture in situ the formed azirine. In the event the decomposition of the vinyl azide 9 in refluxing dioxane in the presence of
10 and pyridine-para-toluenesulfonate (PPTS)as a mild proton
source did generate the unsymmetrical pyrazine 11 in 67 YOyield
(see Scheme 4).
Sa X = aOH, PH
Y = aOH,PH
Scheme 1 . Synthesis of compounds 4a, 48, Sa,and 58. a) 0.7 equiv L-Selectride, dry
toluene. -78 C. (49% in one step, 82% with recovery of starting material); b)
0.7 equiv NaBH,. CH,CI,/MeOH, - 78 "C (47% in one step, 81 % with recovery of
starting material). c) L-Selectride, dry toluene, - 78 "C (96%); d) NaBH,, CH,CI,/
MeOH. -78 C (98%).
a direct formation of nonsymmetrical compounds of this type
by the already mentioned nonsymmetrical route.
Having noticed that enamino ketones of type B are stable
under thermal conditions and do not undergo dimerization, we
expected that reaction of B with azirines A as nondimerizing
analogues of a-amino ketones could give an easy access to nonsymmetrical pyrazines C (see Scheme 2).
/ a
Scheme 4. Synthesis of pyrazine 11. a) Dioxane, PPTS, 90 min at reflux (67%)
By this method we prepared pyrazine 13 from vinyl azide 12
and enamino ketone 10 in 51 % yield and obtained cephalostatin
analogues with promising biological activity.[' 'I Pyrazine 13
was also available independently by the symmetrical route described above, followed by an esterfication of the cr-hydroxy
ketone 4u (96% yield). Both products were identical (according
Scheme 2
Angea.. Chem Inr. Ed. Engl. 1996, 35. No. 13/14
Verlagsgesellschaft mbH. 0-69451 Wernheim. 1996
$ 15.00+.25/0
to TLC and IR, 'H, I3C spectroscopy) and verified the regioselectivity of this new pyrazine-forming reaction. Reduction of
pyrazine 13 with sodium borohydride and diisobutylaluminum
hydride (DIBAH) gave the a,/?-diol 5ap, which was also prepared by reduction of a-hydroxy ketone 4a with sodium borohydride (see Scheme 5).['*]
Received: February 19, 1996 [ZSSlS IE]
German version: Angew Chem. 1996. 108. 1669-1671
Keywords: azirines cephalostatins enamine ketones * pyrazines - synthetic methods
41.24. 41.65. 44.21, 44.52. 45.17. 45.75. 49.75, 49.89. 49.92, 53.14, 53.60. 62.29.
67.09. 67.12, 77.71. 83.93. 85.00. 106.64. 107,05, 120.67, 121.56, 148.09, 148.10.
148.58, 148.64, 153.85. 154.28, 177.60, 210.73; FAB-MS (nitrobenzyl alcohol matrix): m / z ("/.): 932 (100) [ M H ' ] , 818 (27); C,,H,,O,N, (931.31): found C 76.09.
H 8.60. N 3.16; calcd C 76.09, H 8.87, N 3.01.
[l] a) G. R. Pettit. M. Inoue. Y. Kamano. D. L. Herald, C. Arm, C. Dufresne,
N. D. Christie. J. M. Schmidt. D. L. Doubek, T. S. Krupa, J. Am. Chem. SOC.
1988, 110, 2006: b) G. R. Pettit, J. Xu. Y. Ichihara, M. D. Williams, M. R.
Con. J. Chem. 1994. 72, 2260; c) G. R. Pettit. J. Xu, M. D. Williams, N. D.
Christie, D. L. Doubek. J. M. Schmidt, J. N a f . Prod. 1994, 57, 52.
[2] S. Fukuzdwa, S. Matsunaga, N. Fusetani, Tetrahedron 1995. 51, 6707.
[3] These series of compounds are among the most potent cytostatics ever screened
by the National Cancer Institute (USA). For a short review see A. Ganesan,
Angex. Chem. 1996, 108, 667; Angen. Chem. Int. Ed. Engl. 1996. 35. 611
[4] a) S. C. Smith. C. H. Heathcock, J. Org. Chem. 1992,57.6379; b) C. H. Heathcock, s. C. Smith. ibid. 1994. 59, 6828.
[5] a) Y. Pan, R. L. Merriman. L. R. Tanzer. P. L. Fuchs, Eioorg. Med. Chem. Lett.
1992. 9.967; b) J. U. Jeong. S. C. Sutton, S. Kim, P. L. Fuchs. J. Am. Chem.
Soc. 1995. 117. 10157.
[6] A. Kramer, U. Ullmann. E. Winterfeldt. J. Chem. SOC.Perkin. Trans. I 1993.
2865. The yields of the diketone 3a synthesis have been substantially improved
in the meantime.
[7] Preparation and chemistry of pyrazines: Comprehensive Hererocyclic Chemisfry (Eds.. A. R. Katritzky, C. W Rees), 1st ed.. Pergamon, Oxford, 1984, pp.
157- 197.
181 a) M. R. Boyd, K. D. Paull, L. R. Rubinstein in Antifumor Drug Discovery and
Developmenf (Eds.: E A. Valeriote. T. Corbett, L. Baker). Kluwer, Amsterdam. 1992, pp. 11-34; b) K. D. Paull. R. H. Shoemaker, L. Hodes, A. Monks,
D. A. Scudiero, L. R. Rubinstein, J. Plowman, M. R. Boyd, J. Null. Cancer
Insr. 1989.81.1088.c) A. Monks, D. A. Scudlero, P. Skehan. R. H. Shoemaker,
K. D. Paull, D. Vistica. C. Hose, J. Langley, P. Cronise, A. Vaigro-Wolff, M.
Gray-Goodrich. H. Campbell, M. R. Boyd. ibid. 1991,83, 757.
191 S. Flemming, PhD Thesis. Universitit Hannover. 1991.
[lo] Substances 3a (NSC D-674135-0/0-1/55). 3b (NSC D-674136-P/0-1/56), 58
(NSC D-674133-M/0-1/53), and 4p (NSC D-674134-N/0-1/54) were tested by
the NCI (Experiment ID 9411MD95). Detailed results will be published elsewhere. We thank the team of Development Therapeutics Program of the NCI
fot testing the compounds.
[l I] Detailed information about cyclophosphamide (NSC 26271). 5-fluorouracil
(NSC 19893). asplatin (NSC 119875). adriamycin (NSC 123127), tamoxifen
(NSC 180973). and taxol (NSC 125973)is available on the World Wide Web:
http://epnwsl 2345/dis3d/itb/stdagnt tab.html.
[12] E W. Fowler, A. Hassner. L. A. Levy, J. Am. Chem. Soc. 1967.89.2077.
[13] The vinyl azides were obtained by a sequence of a modified Mitsunobu reaction
and an elimination process from the 2p-chIoro-3~1-hydroxyderivatives in up to
50% yield. Detailed results will be published soon in a full paper.
1141 J. Schweng, E. Zbiral, Liebrgs Ann. Chem. 1978. 1089.
[lS] V. Nalr. K. H. Kim, Heterocycies 1977, 7, 353.
[16] A. Hassner, F. W. Fowler. J. Am. Chem. Soc. 1968, 90. 2869.
[17] In this special case the 3 A molecular sieve is crucial to avoid acid-catalyzed
hydrolysis of enamino ketone 10 to the corresponding a-diketone. This seems
to be the only annoying side reaction. and its complete suppression leads to
even better yields of unsymmetrical pyrazines.
1181 Antitumor-screening of the newly prepared cephalostatin analogues is in progress at the Medizinische Hochschule Hannover (MHH). We especially thank
Prof. Dr. W. Beil (MHH).
Scheme 5. Synthesis of compounds 13 and 5afl a) PPTS, dioxane, 3 A molecular
sieves, reflux (51 X ) ; b) pivaloyl chloride, dimethylaminopyridine, pyridine, 100"C
(96%); c) 1) NaBH,, CH,CI,/MeOH, -78°C: 2. DIBAH, toluene (68%); d)
NaBH,, CH,CI,/MeOH, -78°C (96%).
In conclusion, we were successful in preparing easily accessible, biologically active cephalostatin analogues and in developing a novel method for the directed and flexible synthesis of
nonsymmetrical bis-steroidal pyrazines.
Experimental Procedure
13: A degassed solution of 10 (51 mg, 0.11 mmol), 12 (64mg, 0.12 mmol), PPTS
( 5 mg), and 3 A molecular sieves (23 mg) in dry dioxane (2 mL) was heated at reflux
under an argon atmosphere for 2 h. After filtration through silica. the solvent was
removed and the residue purified by flash chromatography (silica, light petroleum/
ethyl acetate = 2/l) to yield 55 mg (51 %). White crystals, m.p. 269°C; UV/Vis
(CH,OH): A,,, = 305 (sh), 288,210 nm; IR (KBr): < = 2956,2932,2872.1716(br),
1400, 1376, 1192. 1156, 980, 908cm-'; ' H N M R (400MHz. CDCI,): 6 =0.771.03 (m. 24H). 1.18 (s, 9 H ) . 1.20-2.43 (m, 32H). 2.47-2.92 (m, SH), 3.31-3.53
(m,4H),4.78(dd,J=8.1 and2.0Hz,lH),4.90(dd,J=7.9and2.0Hz,lH),4.93
( s , 1 H), 5.49 ( s , 1 H), 5.52 ( s , 1 H); I3C NMR (100.6 MHz. CDCI,): 6 = 11.52.
11.75, 13.76, 14.10. 17.14. 18.79, 20.75, 26.08, 27.14, 27.85. 27.95. 28.74, 28.77.
30.31, 30.39, 31.09, 31.26, 33.95, 34.20. 35.15, 35.21. 35.68. 36.36, 37.20, 3891.
VCH Verlugsgedschajr mbH, 0.69451 Weinhelm. 1996
0570-0833/96~3513-1574S 15.00+.25/0
Angen. Chem. Inr. Ed Engl. 1996. 35, No. 13/14
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synthesis, first, pyrazines, activ, biological, cephalostatin, bis, nonsymmetric, directed, steroidal, analogues
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