Syntheses of tetracyclic and pentacyclic

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... 

In 1951-1953 Rabindran and Tilak51,52 introduced a new dibenzo-thiophene synthesis and extended it to tetracyclic and pentacyclic systems. This method involves a two-step process of condensing a thioarenol with an a-halo ketone or a-haloacetal to form an a-(arylthio) ketone or a-(arylthio)-acetal intermediate, which is subsequently cyclized intramolecularly. The three principal variations introduced by Tilak and co-workers are presented in Schemes 3, 5, and 6 and were summarized in I960.528... 

Cationic cyclization. A key step in the synthesis of the diterpenes cafestol5 and atractyligenin4 involves a novel cation cyclization of bicyclic cyclopropanes to the tetracyclic systems of the diterpenes (equations I and II). Thus treatment of 1 with a slight excess of triflic anhydride and 2,6-lutidine effects cyclization to the rather unstable pentacycle 2 with the kaurene system. The related conversion of 3 to 4 can be effected with triflic anhydride and 2,6-di-r-butyl-4-methylpyridine in 1-nitropropane. 

In Kuehne s total synthesis of vincadifformine (89), the pentacyclic natural product was obtained when tetracyclic phenylselenide 88 was treated with 2.5 equivalents of n-Bu SnH and the radical initiator AIBN in refluxing benzene [52]. The stereochemistry of the phenylselenyl substituent in the tetracyclic precursor had no impact on the product yield. After the tertiary radical intermediate 90 was generated (Scheme 17), the 5-exo-trig cyclization was prohibited... 

The diastereospecific synthesis of novel [3.6.6.4.7]-fused pentacyclic /3-lactams via a novel 6-exo-trig,7-endo- %-tandem radical cyclization has been reported. The use of this method for the construction of a polycyclic system fused to an azetidin-2-one template has been very little exploited. The mixture of /3-lactams 509 and 510 (R = -f 4 I—Cl C. -Cl I—Cl ICH3) in their racemic forms on treatment with tributyltin hydride gave diastereomeric mixtures of tetracyclic 511 and 512 in the same ratio as in the starting materials (Equation 84) <2003TL1827>. 

The known pentacyclic lactam (219), prepared from 2-hydroxytryptamine and dimethyl 4-ethyl-4-formylpimelate, has been used in an improved synthesis of ( )-quebrachamine.106a Conversion of (219) into the thiolactam, acetylation to (220), desulphurization, and hydrolysis yielded 1,2-dehydroaspidospermidine (221), which on reduction gave ( )-quebrachamine (222) (Scheme 31). A new synthesis of the tetracyclic amino-alcohols (223) constitutes another formal synthesis of quebrachamine.1066... 

An impressive cationic domino polycyclization has been developed by Corey and coworkers in their short and efficient enantioselective total synthesis of aegicer-adienol (1-150), a naturally occurring pentacyclic nor-triterpene belonging to the 3-amyrin family [42]. Thus, the treatment of the enantiopure monocyclic epoxy tet-raene 1-147 with catalytic amounts of methylaluminum dichloride induces a ca-tion-JT-tricyclation by initial opening of the epoxide to form the tetracyclic ketone 1-148 in 52 % yield, and its C-14 epimer 1-149 in 23 % yield, after silylation and chromatographic separation (Scheme 1.37). Further transformations led to aegicer-adienol (1-150) and its epimer 1-151. 

Three successive [2+4] cycloadditions were used in the synthesis of the pentacyclic methyl ether of G-2N by Kraus and Zhao [92] and later, by a slightly modified procedure, also of the natural product G-2N (118) [93] (Scheme 31). Thermal reaction of the cyclobutanol 112 with acrylic ester gave the dihydronaphthalene 113 which was demethylated by treatment with boron tribromide and converted into the exocyclic ketene acetal 114. This unstable diene was reacted in a second cycloaddition with 2,6-dichlorobenzoquinone (115) to afford the tetracyclic chloroquinone 116. In a last Diels-Alder reaction, ring E was anella-ted by treatment of 116 with l-methoxy-l,3-bis[(trimethylsilyl)oxy]-l,3-buta-diene (117) to yield the pentacyclic natural product G-2N (118) [93]. 

The synthesis of alnusenone (119) utilized a different method of assembling the pentacyclic skeleton. Condensation of the ketones (120) and (121) led via the tetracyclic ketone (122) to two pentacyclic ethers (123) and (124). The trans,anti,cis-stereochemistvy of (123) was confirmed by X-ray analysis. The desired trans,anti,trans-ether (124) was transformed into alnusenone (119). 

Other applications of the 6-exo Heck cyclization strategy can be found in Ihe synthesis of pentacyclic Strychnos alkaloids by Bosch et al. [98] and tabersonine by Kuehne et al. (99). As illustrated in Scheme 35, 6-exo Heck cyclization of substrate 20S was successful only when Grigg s [100] modified Heck conditions [Pd(OAc), LiCN] were employed to give the tricyclic intermediate 206. Another 6-exo reductive Heck reaction successfully cyclized tetracyclic substrate 207 into pentacyclic tabersonine (208). 

The enantioselective approach to quebrachamine adopted by Fuji and collaborators (Scheme 41) (279) has also been modified to afford a new synthesis of (-)-aspidospermidine (251). Here, the lactone 446 was converted by titanium trichloride into the lactone hemiacetal 485, which, after appropriate reduction and oxidation stages, gave the acetal acid 486. Condensation with tryptamine gave the tetracyclic lactam 487, which was then rearranged by means of trifluoromethanesulfonic acid to the pentacyclic indolenine lactam 488, reduction of which gave (-)-aspidospermidine (251) (Scheme SI). 

Following their recent synthesis of ( )-vincadifformine (Scheme 75) (343,344), Szantay and his collaborators have contributed another s3mthesis of pseudovincadifformine and its epimers (392). Condensation of the trypt-amine derivative 587 with the aldehydoester 698 gave, via an unstable secodine derivative, the epimeric tetracyclic esters 715, which, without separation, were subjected to debenzylation, with partial epimerization and cyclization. The product, a mixture of the two cis C/D-fused pentacyclic... 

The benzonaphthopyranone system 47, the basic structure of the gilvocarcins, has been assembled in one step using a Hauser-Kraus annulation. The key feature is the incorporation of a suitably placed ester function in the Michael acceptor which generates the lactone ring. Thus, isobenzofuranones and esters of ethyl citmamate form the tetracycle directly in high yields. Methyl 6-methylcoumarin-5-carboxylate behaves in an identical manner providing a total synthesis of the pentacycle chartarin <04TL7895>. 

---