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Borane complexes of vinblastine type diindole derivatives
Tow&v&m lass,
Vol 36, No. 2l. pp. 4341-4391.1993
Ri88dholo*~
Borane Complexes of Vinbladne mpe Diindole Derivatives
Abdmctz
Wdlc
invutigati~ the ferric chloride mdiated coupling’cf cathwmUhln6(1) tith vinhli8e (3)
and their fkFidv@ and N-drmdhyl-AW
(x,4), the bamlw lEo?n#m of 1s:m~ (AvLB)# 2huhyA4~ (9,lO,ll)hawbeenspthuimi llrscomspondlneWu(6,7audS)~&keen
obtahedinhisl,y*ld
Vincristine - vinblastine type diindole alkaloids are well known for their anticancer activity? Besides the naturally occmriq compounds (isolated from C&uru&r Ra#us), synthetic derivatives are alsoused in cancer chemotherapy (e.g. Navelbine@).’Earlier we reported on the methodical inve&ation of the ferric chloride couplhtg method, in which catharanthine (1) was coupled to vindoline (3) to give anhydro+inblastine(AVLB)(6) inover 70% isolated yield2 Unfortunately AVLB is usually contaminated by significant amounts of oxidahve side-products (most notably let&sine), which encmnbam the transformation of AVIE into navelbine. Slightly modified conditions of the coupling reaction led us to a new derivative, the borane complex of AVLB (9), in 80% yield ‘fhe latter proved to be highly atable against oxidative influences, and could easily be transformed into the desired base (6). The borane complexation of the basic nitrogen of the catharanthine part presumably prevents, sterically and electronically, the tet&j&opyridine ring from oxidative side-reactions. We have employed the ferric chloride coupling method to ‘other catharanthine and vindoline derivatives. Sundberg and Langlois coupled 2Odeethylcatharanthine (2) with vindoline (3) via the Polonovski-Potier reaction in 16% yield:’ In aqueous medium in the presence of ferric chloride we obtained 2O’deethyLAVLB (7) in 28% yield A mod&ation of the reductive work-up led us to the 20’deethyLAVLB borane complex (10) (mp 2OOT, decomp.). When couplii catharanthine (1) to Ndemethylvindoline (4), the Polonovski-Potier method resulted in Ndemethyl-AVI..B (8) in 40% yield6 By using the ferric chloride procedure we isolated 8 in more than 70% yield. When applying an extreme excess of sodium borohydride, a new derivative, the N&methyl-AVLB borane complex (11)wasobphcd (mp 208-21m decomp.). Similarly to our earlier results reported for the AVLB borane complex (9): detailed spectroscopic studies verified that the complexation site involves.y’4, with the BHs group being in apositi~inthenewbqranecamp1aes11and10?RdluxationoEthecolnplaes10snd11in methanol in the presence of sodium carbonate* allowed the easy production of the correspond@ bases, 7 and8,respectively.~The6,7and8canbetransformedintotheirbo~complwesdirectlyby sodiumborohydrideindichloromethane orintetrahydroiuqne-horane. Assumiqtheforn+onofthedication5 aspr~pesedbyVukov+etaL~, 5 canattackthearomatic ring of vindoline and subsequently stab&e as the dimeric compound When 1 is involved in the coupling reaction, the electron donating effect of the 20-ethyl group facilitates the formation of 5, giving similar yields for 6 and 8. However, in the case of 2Odeethylcatharanthme (2) the beneficial influence of the
4397
I(
4398
ethyl group is absent, and formation of the dication is less favoured which results in a dramatic decrease in tbe yield of 20’deethyLAVLB (7). These observations conform to the depicted mechanism.
1.
2. 3. 4. 5.
6. 7. 8.
Vukovic, J.; Gkuxlbody, k E; Kutney, J. P.; Misawa, M. Ten, 1988 (44, 325-331. S&my, CL, Jr.; Baks, &I.;BtWkci, H.; Sz&q, C!s. Tetmhdm, 1991,47, 1265-1274. Z&a, F.; Guenard,D.; Potier,P. Erpcrientia1978 ,34, 1497-1499. EP 10.458 patent (Pierre Fabre). ’ a) Gueritte, F.; tangldis, N.; Langlois, Y.; Smdberg, NJ.; Bloom,I.D. J. 0g. Ckm 1981,46, 5393-5395:b) Lauglois, N.; Gueritte, F.; Langtois, Y.; Potier, P. J. Am Char Sm., 1976, 98, 7017-7m4. Gedeon Ricbtkr LkBklg. 867.255.(CLCWD), Hung. Appl. 632, CA90 138 081 S. Details and other physical data are.available upon request. a) picot, A;; Lusincbi,‘X ML Sm. chim I%, 1!377,1227-1234.b) !kbwar@ M. A.; Rose, B. F.; Vishmajjala, B. .X&I. Chm Sot, 1973,95, 612613.
(Receivedin UK 18 May 1993)
Vol 36, No. 2l. pp. 4341-4391.1993
Ri88dholo*~
Borane Complexes of Vinbladne mpe Diindole Derivatives
Abdmctz
Wdlc
invutigati~ the ferric chloride mdiated coupling’cf cathwmUhln6(1) tith vinhli8e (3)
and their fkFidv@ and N-drmdhyl-AW
(x,4), the bamlw lEo?n#m of 1s:m~ (AvLB)# 2huhyA4~ (9,lO,ll)hawbeenspthuimi llrscomspondlneWu(6,7audS)~&keen
obtahedinhisl,y*ld
Vincristine - vinblastine type diindole alkaloids are well known for their anticancer activity? Besides the naturally occmriq compounds (isolated from C&uru&r Ra#us), synthetic derivatives are alsoused in cancer chemotherapy (e.g. Navelbine@).’Earlier we reported on the methodical inve&ation of the ferric chloride couplhtg method, in which catharanthine (1) was coupled to vindoline (3) to give anhydro+inblastine(AVLB)(6) inover 70% isolated yield2 Unfortunately AVLB is usually contaminated by significant amounts of oxidahve side-products (most notably let&sine), which encmnbam the transformation of AVIE into navelbine. Slightly modified conditions of the coupling reaction led us to a new derivative, the borane complex of AVLB (9), in 80% yield ‘fhe latter proved to be highly atable against oxidative influences, and could easily be transformed into the desired base (6). The borane complexation of the basic nitrogen of the catharanthine part presumably prevents, sterically and electronically, the tet&j&opyridine ring from oxidative side-reactions. We have employed the ferric chloride coupling method to ‘other catharanthine and vindoline derivatives. Sundberg and Langlois coupled 2Odeethylcatharanthine (2) with vindoline (3) via the Polonovski-Potier reaction in 16% yield:’ In aqueous medium in the presence of ferric chloride we obtained 2O’deethyLAVLB (7) in 28% yield A mod&ation of the reductive work-up led us to the 20’deethyLAVLB borane complex (10) (mp 2OOT, decomp.). When couplii catharanthine (1) to Ndemethylvindoline (4), the Polonovski-Potier method resulted in Ndemethyl-AVI..B (8) in 40% yield6 By using the ferric chloride procedure we isolated 8 in more than 70% yield. When applying an extreme excess of sodium borohydride, a new derivative, the N&methyl-AVLB borane complex (11)wasobphcd (mp 208-21m decomp.). Similarly to our earlier results reported for the AVLB borane complex (9): detailed spectroscopic studies verified that the complexation site involves.y’4, with the BHs group being in apositi~inthenewbqranecamp1aes11and10?RdluxationoEthecolnplaes10snd11in methanol in the presence of sodium carbonate* allowed the easy production of the correspond@ bases, 7 and8,respectively.~The6,7and8canbetransformedintotheirbo~complwesdirectlyby sodiumborohydrideindichloromethane orintetrahydroiuqne-horane. Assumiqtheforn+onofthedication5 aspr~pesedbyVukov+etaL~, 5 canattackthearomatic ring of vindoline and subsequently stab&e as the dimeric compound When 1 is involved in the coupling reaction, the electron donating effect of the 20-ethyl group facilitates the formation of 5, giving similar yields for 6 and 8. However, in the case of 2Odeethylcatharanthme (2) the beneficial influence of the
4397
I(
4398
ethyl group is absent, and formation of the dication is less favoured which results in a dramatic decrease in tbe yield of 20’deethyLAVLB (7). These observations conform to the depicted mechanism.
1.
2. 3. 4. 5.
6. 7. 8.
Vukovic, J.; Gkuxlbody, k E; Kutney, J. P.; Misawa, M. Ten, 1988 (44, 325-331. S&my, CL, Jr.; Baks, &I.;BtWkci, H.; Sz&q, C!s. Tetmhdm, 1991,47, 1265-1274. Z&a, F.; Guenard,D.; Potier,P. Erpcrientia1978 ,34, 1497-1499. EP 10.458 patent (Pierre Fabre). ’ a) Gueritte, F.; tangldis, N.; Langlois, Y.; Smdberg, NJ.; Bloom,I.D. J. 0g. Ckm 1981,46, 5393-5395:b) Lauglois, N.; Gueritte, F.; Langtois, Y.; Potier, P. J. Am Char Sm., 1976, 98, 7017-7m4. Gedeon Ricbtkr LkBklg. 867.255.(CLCWD), Hung. Appl. 632, CA90 138 081 S. Details and other physical data are.available upon request. a) picot, A;; Lusincbi,‘X ML Sm. chim I%, 1!377,1227-1234.b) !kbwar@ M. A.; Rose, B. F.; Vishmajjala, B. .X&I. Chm Sot, 1973,95, 612613.
(Receivedin UK 18 May 1993)