Tetracyclic compounds

A variety of l,2,3,4-tetrahydro-j8-carbolines have been prepared from 3-piperidone phenylhydrazone derivatives. Used initially to obtain pentacyclic derivatives (35) related to the yohimbe alkaloids, this route was later extended to the synthesis of tetracyclic compounds (36). l-Methyl-5,6,7,8-tetrahydro-j8-carboline (37) was prepared in low yield by heating cyclohexanone 2-methyl-3-pyridylhydrazone with zinc chloride, a synthesis probably based on the similar preparation of the tetracyclic compound 38 starting from the corresponding quinolylhydrazine. Abramovitch and Adams extended this approach to the cyclization of cyclohexanone 3-pyri-dylhydrazone (39) itself. The main product was 6,7,8,9-tetrahydro-8-carboline (40), a smaller amount of the j8-isomer (41) also being obtained. This provides a convenient and readily reproducible route to the otherwise difficultly accessible 8-carboline ring system. The favored attack at carbon-2 over carbon-4 of the pyridine nucleus... 

Similarly, compound 81 treated with 391 provided a mixture of both possible tetracyclic compounds 392 and 393 in overall yield of 99% (Eq. 34) (91ZOR185). 

The phenylhydrazones of 2-[(2-alkenyl)amino]-3-formyl-4//-pyrido-[1,2-n]pyrimidin-4-ones 242 underwent a thermally induced intramolecular 1,3-dipolar cycloaddition leading to a mixture of tetracyclic compounds 243 and 244 at room temperature or to 244 under reflux (96T901). Derivatives 243 were not stable and converted to compounds 244 gradually on standing or on heating their ethanolic solutions in air. The ( )-hydrazones 245 could be isolated only in the case of... 

Reaction of 2-[A -(rra -crotyl)-A -benzylamino]-3-formyl-4/f-pyrido[l,2-n]pyrimidin-4-one (269) with chiral primary amines 270 and 271 gave mixtures of diastereoisomers of tetracyclic compounds 273 and tricyclic 275 (96T131]]). The chiral centers in 272 and 274 did not provide any stereocontrol for the formation of diastereomers 273 and 275, respectively. 

CuCl/THF followed by catalytic hydrogenation to give the pyrroloquinoline 134. Nitration of the later gave the 9-nitro derivative 135. Reduction of 135 followed by reaction with ethyl trifluoroacetoacetate gave 136 that upon cyclization gave the tetracyclic compound 137 (98JMC623) (Scheme 26). 

The reaction of relatively simple starting materials, coumarin 40, piperidone 37 and ammonium acetate, leads in a single step to the complex bridged tetracyclic compound 44. The reaction can be rationalized by assuming formation of the iminc 38 from reaction of 37, with ammonia. Conjugate addition of the eneamine-like tautomer 39 to the excellent Michael acceptor 40 will... 

The dihydronaphthalene-annelated pyranylidene complex 178, prepared according to reaction route E in Scheme 4 from /J-tetralone and complex 35, upon treatment with the pyrrolidinocyclopentene 174 n-1) or -cyclohexene 174 (n=2) at room temperature gave the tetracyclic compounds 179 in excellent... 

Scheme 8 Efficient formation of the conjugated cycloheptadiene core in tetracyclic compounds 42 during studies toward solanoeclepin A (39) [31]...

Similarly, cycloaddition of the cyclohexenone-like dienophile 40 with 2-tri-methylsilyloxy-1,3-butadiene (41) allowed [7] the regio- and stereoselective synthesis of tetracyclic compound 42, in high yield (Equation 5.5). 

Fig. 8.10 The X-ray crystal structure of a tetracyclic compound bound to hepatitis C virus NS5B544 polymerase. The observed dihedral angle between the indole ring and phenyl ring is 47°, which is in agreement with the predictions.

Noji, S., Yamanaka, H., Hara, Y., Adachi, T., Tsuruha, J. I., Doi, S., Hase, Y., Noguchi, T., Ando, I., Ogura, N., Ikeda, S., Hashimoto, H. Discovery of conformationally constrained tetracyclic compounds as potent hepatitis G virus NS5B RNApolymerase inhibitors./. Med. Chem. 2006, 49, 6950-6953. 

Tetracyclic compounds in which the C3 side chain is conformationally restricted by linking to either the C2 or the C4 position have been described by Khanolkar et al. [99]. All the tetracyclic compounds had lower CBi and CB2 affinity than the analogous non-constrained compounds (84). The best-tolerated constraint was the southbound constraint in compound (173). 

The reaction starts with the formation of a mixed anhydride and an acetate on treatment with an excess of acetic anhydride at 80 °C. There follows a Dieckmann condensation to give 2-590 and an intramolecular rearrangement/Michael addi-hon/retro Michael addition to afford the desired tetracyclic compound 2-592 via 2-591 in an overall yield of remarkable 92%. 

Knolker and coworkers also used a domino [3+2] cycloaddition for the clever formation of a bridged tetracyclic compound 4-172, starting from a cyclopentanone 4-168 and containing two exocydic double bonds in the a-positions (Scheme 4.36) [57]. The reaction of 4-168 with an excess of allylsilane 4-169 in the presence of the Lewis acid TiCLj led to the spiro compound 4-170 in a syn fashion. It follows a Wag-ner-Meerwein rearrangement to give a tertiary carbocation 4-171, which acts as an electrophile in an electrophilic aromatic substitution process. The final step is the... 

An unusual domino process was observed by Biehl and coworkers [69] in the reaction of 2-bromo-l-naphthol 4-196 with arylacetonitriles in the presence of LDA or LiTMP by employing 3-thienylacetonitrile 4-197, the tetracyclic compound 4-200 was obtained in 57% yield (Scheme 4.43). The reaction probably includes the formation of an aryne and a ketenimine which undergo [2+2] cycloaddition to give 4-198, followed by rearrangement and allylic addition to the intermediately formed aryl cyano compound 4-199. 

Scheme 4.48. Synthesis of tetracyclic compounds from pyrone 4-224.

Very recently, de Meijere and coworkers reported on a 6it electrocyclization/ Diels-Alder reaction [114]. The domino transformation provides access to highly substituted tri- and tetracyclic compounds. 

Chung and coworkers [280] combined a [2+2+1] with a [2+2+2] cycloaddihon for the synthesis of multi-ring skeletons, angular triquinanes, and fenestranes. For the preparation of tetracyclic compounds such a 6/4-17, these authors used diynes as 6/4-16 and CO as substrates (Scheme 6/4.5). Fully substituted alkynes gave low yields, and 1,5- as well as 1,7-dialkynes, did not react... 

The same authors also combined the [2+2+1] cycloaddihon with a Diels-Alder reaction [281]. For this multicyclization, the dienediyne 6/4-18 was treated with 5 mol% C02(C0)8 under 30 atm CO at 130 °C for 18 h to give the tetracyclic compound 6/4-19 (Scheme 6/4.6). 

Depending on the reaction temperature and reaction time, tetrahydroisoquinoline 357 afforded different mixtures of 1,2,3,4,11,11 a-hcxahydro-6//-pyrazino[ 1,2-3]isoquinolines 358-361 and tetracyclic compound 362 (Scheme 30) <2005JA16796>. Each of the individual diastereoisomers 358-361 could be transformed into the compound 362. z7r-3//,4a//-3-Phcnylpcrhydropyra/ino[ 1,2-7]isoquinoline-l,4-dione was prepared via automated parallel solid-phase synthesis on Kaiser oxime resin <1998BML2369>. l,2,3,5,6,7-Hexahydropyrido[l,2,3-r/f ]quinoxaline-2,5-dionc was obtained by catalytic hydrogenation of ethyl 3-(2-oxo-l,2,3,4-tetrahydro-5-quinoxalinyl)acrylate in the presence of TsOH over 5% Pd/C catalyst under 40 psi of hydrogen <1996JME4654>. 

Six-membered ring ADC compounds can be generated by oxidation of the corresponding cyclic hydrazides. Pyridazine-3,6-dione (12) and phthalazine-1,4-dione (13, R = H), often called diazaquinones,4 are stable in solution only at low temperature, but can be generated, and intercepted at higher temperatures.39-43 Fusion of an extra benzene ring increases stability44 and the tetracyclic compound 14 is relatively stable.45 Substituted phthala-zine-l,4-diones have been widely studied because of their involvement in... 

New tri- and tetracyclic compounds containing the pyridazine moiety were synthesized in a multistep reaction sequence from commercially available pyridazine 173 <00AP231>. Acid chloride 173 reacted- readily with 174 to yield 175. Cyclized product 176 was then produced by treatment of tethered pyridazine 175 with sodium hydride in an intramolecular SNAr displacement. 

The reaction of 79a with MeLi (salt-free) or of 79b and 79c with NaN (SiMe3>2 afforded the tetracyclic compound 81a, or respectively, 81b and 81c in yields of 54%, 73%, and 88%.26 The structure of 81 leads one to assume that carbene 82 is the precursor of 81, which is formed by CH insertion of the car-benic center C7 into the axial hydrogen of C4 of 82. Looking somewhat closer... 

Diver has recently reported new entries for the assembly of tetracyclic compounds.304 Interestingly, ruthenium catalysts for metathesis have also yielded tricyclic products by incorporating a cyclopropane from dienynes, a process reminiscent of Dixneuf s work (see above). 

In the reaction with 6-bromo-2-naphthol, no simple glycosides were obtained, but a mixture of tetracyclic compounds in yields of 32 % and 44 %, respectively (zirconocene activator). The hafnium reagent gave the same products in a similar ratio (21% and 44% yield) [30]. 

Yohimbenone (370) has been synthesized by Kline (212) via the Robinson reaction of the 374 tetracyclic compound with 4-diethylaminobutan-2-one methiodide, followed by hydrolysis and decarboxylation of intermediate 375. 

Additional work around the benzimidazole scaffold on compounds related to 29 [72,73] suggested that the dihedral angle between the heterocycle and the phenyl ring is a crucial determinant of binding affinity, leading to the design of tetracyclic compounds with the aromatic moieties linked [74], Thus, indole... 

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