Hexacyclic derivatives

Denitrocyclization reaction was also used for the preparation of hexacyclic derivative 278, which was obtained in 80% yield by heating of 277 with a solution of sodium hydroxide in aqueous DMF (66JCS(C)1245, 70JCS(C)2647). Low to moderate yields of 3,6-dinitroxanthen-9-one (281) is formed by a treatment of tetranitro derivative 279 with either potassium hydroxide or sodium... 

The novel DNA topoisomerase I inhibitor, DX-8951f (exatecan mesylate, 264) which does not require metabolic activation is fluorinated, hexacyclic derivative of camptothecin. Compound 264 was reported to be 6- and 28-fold more potent than SN-38 and topotecan, respectively.Compound 264 has shown efficacy in a variety of human mmor xenografts. 

Synthesis <1984CHEC(4)443, 1996CHEC-II(8)967>, spectroscopy <1996CHEC-II(8)967>, and reactivity <1984CHEC(4)443> of [2.2.3]cyclazines and their aza-derivatives have been previously reviewed. Pyridylcyclazine 485 was obtained as an intermediate in the synthesis of hexacyclic cyclazinocyclazines (Scheme 38) <1997H(45)2223>. 

Moreover, polycyclic indole alkaloid-type molecules 225 with a ketopiperazine were prepared by Wang et al. using Ugi-Pictet-Spengler process [68]. Ketocar-boxylic acids 227 were used as bifunctional substrates in Ugi reaction to yield lactams of varying ring sizes (Scheme 41). A diastereomer of hexacyclic indole derivative was crystallized and yielded X-ray diffraction suitable crystal to assign the stereochemistry. 

The same hexacyclic enedione has been converted to a series of Cj -heptaquinane derivatives via the alcohol 819 which is produced by condensation with ethyl formate in base The hydroxyl group in 819 can be readily functionalized, although loss of water to arrive at 820 occurs remarkably readily, despite the inherent strain of this system (Scheme XCIX). The conjugated double bond in 820 is understandably a good Michael acceptor, a property which was utilized to prepare 821. 

The bromo derivative of A -mcthylsuccinimide did also undergo Suzuki coupling when treated with naphthylboronic acid in the presence of palladium acetate, triphenylphosphine and potassium carbonate (6.3.). The coupled product was deprotected under the reaction conditions and an indole derivative was isolated in good yield, which was successfully converted into the hexacyclic naphthopyrrolo[3,4-c]carbazole structure. Using the analogous trimethylstannyl-naphthalene derivative and optimised Stille coupling conditions the desired product was isolated only in 56% yield.5... 

From the stem bark, a new carbazole derivative, named murrayanine, has been isolated. It has been formulated as l-methoxy-3-formylcarbazole (I) (Chakraborty et al., 1965). Roy and Chakraborty (1974) reported the isolation of mahanimbine. The structure of a new hexacyclic carbazole alkaloid, isomur-rayazoline, from stem bark has been shown to be 9a,10,11,12,13,13a-hexahydro-5,9,9,12-... 

Substituted derivatives (83CCC1878,84MI701-01) and pentacyclic (238)-(241) and hexacyclic (242)-(245) polyaza systems were prepared analogously from intermediates (236) and (237). 

When methyl 3-dehydroreserpate (XX) is treated with ethylbromo-acetate at steam bath temperature, a new hexacyclic methyl reserpate derivative (XXI) is obtained (173). This reaction has also been carried... 

The stereochemistry of ajmaline (II) has been the subject of discussion (41, 42), although no later experimental evidence to support these deductions has been formulated. It is, of course, clear that except for centers at 17, 20, and 21, it is largely a problem of the absolute stereochemistry, since the hexacyclic system can only be put together in two ways, epimerization being possible at C-2. The absolute stereochemistry has been derived (16) (Chart III) as a result of a stereospecific chemical unfolding of 21-deoxyisoajmaline to 1 -methyltetradehydrodihydro-corynantheane (XVI epimeric 20-ethyl) whose absolute stereochemistry... 

Exatecan is a novel synthetic camptothecin derivative with a unique hexacyclic structure. It does not require metabolic activation, whereas irinotecan does. In vitro experiments in various cell lines have suggested that exatecan may be 6 and 28 times more active than SN-38 (7-ethyl-lO-hydroxycamptothecin, the active metabolite of irinotecan) and topotecan respectively. Furthermore, it has a 2-10 times higher therapeutic index than irinotecan and topotecan. In addition, exatecan may even be active in P-glycoprotein-mediated multidrug-resistant tumor cells. Its dose-limiting adverse effects are neutropenia and liver dysfunction. The recommended dosages of exatecan for phase II trials are 0.5 mg/m /day or 0.3 mg/ m /day as a 30-minute infusion on 5 consecutive days for minimally pretreated and heavily pretreated patients respectively (14,15). 

For example, acetone sensitized photocyclization of 16 ° resulted in smooth conversion to 17 in 85% yield. Exposure of the hexacyclic compound 17 to silver(I) tetrafluoroborate in chloroform at room temperature resulted in a very slow [ 2 -I- 2 ] transposition. However after refluxing for 5-7 days with intermittent introduction of small additional quantities of silver(I) tetrafluoroborate, followed by removal of the silver salts by filtration through silica gel and recrystallization from ethanol gave a diazasnoutene derivative 18 in 80% yield, which on treatment with excess potassium hydroxide in aqueous ethylene glycol at 100°C afforded semibullvalene (l9)3 -308 in 65-70% yield. ... 

The N-C-6 bridge found in hetisine, delnudine, miyaconitine etc. probably forms by displacement of a 6-j8-pyrophosphate group. The facile formation of the bridge has already been demonstrated in ajaconine chemistry and the mobile equilibrium between 6-keto-derivatives and the carbinolamines in hetidine (5), delnudine (8), and kobusine methiodide (9) attests to the strain-free nature of the hexacyclic skeleton. 

The vinylogous amide lactam 411 prepared by the route described previously (203) was N-tosylated in 44% yield by reaction with sodium hydride in boiling monoglyme followed by treatment with tosyl chloride. On treating the tosyl derivative 428 with excess acrylonitrile in tert-butanol-dimethyl sulfoxide in the presence of potassium re/t-butoxide, two products were formed the pentacylic derivative 429 and the hexacyclic compound 430. Further base treatment of the former compound gave 430 in quantitative yield, thereby bringing the overall reaction yield to a respectable 50%. 

---