Tetracyclic ring system

Cholesterol was isolated m the eighteenth century but its structure is so complex that Its correct constitution was not determined until 1932 and its stereochemistry not verified until 1955 Steroids are characterized by the tetracyclic ring system shown m Figure 26 9a As shown m Figure 26 9b cholesterol contains this tetracyclic skeleton modified to include an alcohol function at C 3 a double bond at C 5 methyl groups at C 10 and C 13 and a C Hn side chain at C 17 Isoprene units may be discerned m var lous portions of the cholesterol molecule but the overall correspondence with the iso prene rule is far from perfect Indeed cholesterol has only 27 carbon atoms three too few for It to be classed as a tnterpene... 

Tetracyclic ring system 741 was prepared by condensation of 739 with a-diketones to give 740, whose treatment with /3-diketones gave 741 (73MI1 80UKZ1092) (Scheme 153). 

The anthracyclines represent a broad family of antibiotics that exhibit activity in numerous tumors. The first anthracyclines, doxorubicin (DOX) and dau-notubicin (DNR), were isolated from Streptomyces var peucetius they were shown to be composed of a tetracyclic ring system with adjacent quinone-hydro-quinone moieties, a short side chain with a carbonyl group, and an aminosugar bound to the C-7 of the four-ring system. DOX and DNR only differed in the side chain terminus (-CH2OH in DOX vs. -CH3 in DNR). Second generation anthracyclines, like epitubicin (EPI) and idatubicin (IDA), were obtained after minor chemical modifications of DOX or DNR, respectively (Fig- 1). 

The construction of novel tetracyclic ring systems 1-142, which can be considered as hybrids of the I e Ira h y dropy r ro I o 12,3 - fo] i ndo le and tetrahydroimidazol[l,2-o]in-dole ring system, has been described by Herranz and coworkers [40]. The exposure of tryptophan-derived a-amino nitrile 1-140 to acidic conditions triggers a stereoselective tautomerization to give 1-142 in quantitative yield (Scheme 1.35). 

The Bennasar group has reported a regioselective 6-endo reductive cyclization of 2-indolylacyl radicals, generated from 154, to afford entry into the tetracyclic ring system 155 found within guatambuine 156 <06JOC1746,06OL561>. 

The utilization of the Robinson annellation method for the synthesis of cory-nanthe-type alkaloids has been thoroughly investigated by Kametani and coworkers (149-152). The tetracyclic ring system was efficiently formed via the Michael addition of dimethyl 3-methoxyallylidenemalonate (247) to the enamine derived from 3,4-dihydro-1 -methyl-(3-carboline (150). Alkylation of 248, followed by hydrolysis and decarboxylation, resulted in a mixture of stereosiomeric enamides 250 and 251. Hydrogenation of 250 afforded two lactams in a ratio of 2 1 in favor of the pseudo stereoisomer 253 over the normal isomer 252. On the other hand, catalytic reduction of 251 gave 254 as the sole product in nearly quantitative yield. Deprotection of 254, followed by lithium aluminum hydride reduction, yielded ( )-corynantheidol (255) with alio relative configuration of stereo centers at C-3, C-15 and C-20. Similar transformations of 252 and 253 lead to ( )-dihydrocorynantheol and ( )-hirsutinol (238), respectively, from which the latter is identical with ( )-3-epidihydrocorynantheol (149-151.). 

A series of transformations via nitrene formation similar to the previously discussed case was also found under flash vacuum thermolytic (FVT) conditions by the same team as shown in Scheme 8 <2003JOC1470>. 9-Phenyltetrazolo[l,5- ]quinoline 29 underwent nitrene 30 and cyclic carbodiimide 31 formation, and this intermediate - similar to the previous case - could open up to the isoquinoline nitrene 32 in which, however, proximity of the nitrene to the phenyl substituents allowed the ring closure to the stable tetracyclic ring system 33 which was obtained in 73% yield. 

Steroids all contain a tetracyclic ring system comprised of three six-membered rings and one five-membered ring fused together. Cholesterol is the best known of the steroids. It is an essential structural component of animal cells, though the presence of excess cholesterol in the blood is definitely associated with the incidence of heart disease and heart attacks. 

Van der Westhuizen, J.H., Steenkamp, J.A., and Ferreira, D., An unusual reaction of flavan-3-ols with acetone of relevance to the formation of the tetracyclic ring system in peltogynoids, Tetrahedron, 46, 7849, 1990. 

The steroids are modified triterpenoids containing the tetracyclic ring system of lanos-terol (Figure 5.55), but lacking the three methyl groups at C-4 and C-14. Cholesterol (Figure 5.76) typifies the fundamental structure, but further... 

The reaction of steroidal ketones with Lawesson s reagent led to the spiroannelation of the 1,3,2-dithiaphos-phetane nucleus on the tetracyclic ring system <2003PS2003>. 

Fluorous aminoesters have also been used in DOS of three unique triaza tricyclic and tetracyclic ring systems (Scheme 22) [44], Bicyclic pyrrolidines 12 generated from one-pot, three-component 1,3-dipolar cycloaddition of azomethine ylides were further converted to hydantoin-, piperazinedione-, and benzodiazepine-fused compounds 31-33, respectively. Each of these three heterocyclic scaffolds has four stereocenters on the central pyrrolidine ring and up to four points of diversity (R1 to R4). The structure of compound... 

Tetracyclic derivatives 97 were prepared from 5-methylthio and 5-phenylthio derivatives of 7-oxo-7//-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylates 95 and 96, according to Scheme 7 (87EUP228661). Reaction of 5-methyl-7-oxo-7//-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylate 98 with isocyanates afforded derivatives of tetracyclic ring system 99 [92JAP(K)92/91090],... 

Further development of (-)-sparteine s remarkable success story is marred by two unfortunate aspects of (-)-sparteine chemistry. Firstly, as mentioned above, its (-h)-enantiomer is not readily available. And secondly, it is difficult to make small modifications to the structure of (-)-sparteine without resorting to a lengthy total synthesis of the tetracyclic ring system. Recently, progress towards solving both of these problems has been made in the form of the synthesis of either enantiomer of the simplified sparteine-like ligand 70.71 Early results suggest that 70 can perform as well as (-)-sparteine in asymmetric deprotonation reactions. 

Steroid (Section 28.5) A naturally occurring compound that has a tetracyclic ring system con-... 

Intramolecular cycloaddition reactions have been performed on the furan-containing indoles 143, to provide an efficient route to numerous derivatives of the tetracyclic ring system 144, a structural motif of Aspidosperma and Strychnos alkaloids <02OL4643>. 

Benzo[c]cinnolines have been conveniently prepared by the cyclization of symmetrically disubstituted 2,2-diami-nobiphenyls using iodobenzene diacetate as the oxidant <1996J(P1)83, CHEC-III(8.01.9.1)72>. A similar oxidation of 2,2,6-triamino-6-propylthiobiphenyl 49 afforded a new tetracyclic ring system 50 (Scheme 25) <2000JOC6388>. 

In a final example, Coldham and co-workers have used an azomethine ylide strategy for constructing the tetracyclic ring system of 142, a precursor to iboga alkaloid deethylibophyllidine <07TL873>. In the event, condensation of indole C3-aldehyde and N-allyl glycine in refluxing toluene provided the requisite ylide dipole for cyclization onto a C2 tethered alkene. 

In general, the reactions of steroids that are presented in this book are familiar and uncomplicated. Keeping track of the stereochemistry of the tetracyclic ring system is somewhat more complicated. 

---