Tetracycles

A tetracyclic benzenoid hydrocarbon suspected of being a carcinogen. 

The achiral triene chain of (a//-rrans-)-3-demethyl-famesic ester as well as its (6-cis-)-isoiner cyclize in the presence of acids to give the decalol derivative with four chirai centres whose relative configuration is well defined (P.A. Stadler, 1957 A. Escherunoser, 1959 W.S. Johnson, 1968, 1976). A monocyclic diene is formed as an intermediate (G. Stork, 1955). With more complicated 1,5-polyenes, such as squalene, oily mixtures of various cycliz-ation products are obtained. The 18,19-glycol of squalene 2,3-oxide, however, cyclized in modest yield with picric acid catalysis to give a complex tetracyclic natural product with nine chiral centres. Picric acid acts as a protic acid of medium strength whose conjugated base is non-nucleophilic. Such acids activate oxygen functions selectively (K.B. Sharpless, 1970). 

Recent syntheses of steroids apply efficient strategies in which open-chain or monocyclic educts with appropiate side-chains are stereoselectively cyclized in one step to a tri- or tetracyclic steroid precursor. These procedures mimic the biochemical synthesis scheme where acyclic, achiral squalene is first oxidized to a 2,3-epoxide containing one chiral carbon atom and then enzymatically cyclized to lanostetol with no less than seven asymmetric centres (W.S. Johnson, 1%8, 1976 E.E. van Tamden, 1968). 

Proton-catalyzed olefin cyclizations of open-chain educts may give tri- or tetracyclic products but low yields are typical (E.E. van Tamelen, 1968, 1977 see p. 91). More useful are cyclizations of monocyclic educts with appropriate side-chains. The chiral centre to which the chain is attached may direct the steric course of the cyclization, and several asymmetric centres may be formed stereoselectively since the cyclizations usually lead to traas-fused rings. 

The dienyne 394 undergoes facile polycyclization. Since the neopentylpalla-dium 395 is formed which has no hydrogen /J to the Pd after the insertion of the disubstituted terminal alkene, the cyclopropanation takes place to form the tt-allylpalladium intermediate 396, which is terminated by elimination to form the diene 397(275]. The dienyne 398 undergoes remarkable tandem 6-e. o-dig. 5-cxo-trig. and -exo-trig cyclizations to give the tetracycle 399 exclu-sively(277]. 

Decahn ring systems appear as structural units m a large number of naturally occur ring substances particularly the steroids Cholic acid for example a steroid present m bile that promotes digestion incorporates as decahn and trans decahn units into a rather complex tetracyclic structure... 

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... 

Atypical Antidepressants. StmcturaHy diverse dmgs such as the tetracyclic mianserin (46) and various bicyclic and tricyclic compounds such as trazodone (47), venlafaxine (48), nefazodone (49), and amfebutamone (50) are atypical antidepressants. The exact mechanism of action is unclear but probably... 

With some special diazirines interconversion with diazoalkanes was observed on illumination (79AHC(24)63), e.g. with diazirinecarboxylic acid piperidide (194), spirodiazirine (195) and the tetracyclic ketodiazirine (196) (78CC442). 

Pentacyclosqualene, the symmetrical hydropicene corresponding to squalene, has not been made by acid-induced cation-olefin cyclization of squalene, despite considerable experimental study. A simple, convergent synthesis of pentacyclosqualene using cation-olefin cyclization to generate ring C was developed. The Cjo-framework was constructed by radical coupling to a tetracyclic intermediate that was also used for the synthesis of onoceradiene. 

Schroder and Witt ° have reported the synthesis of crown ethers having fluctuating ring sizes which they have termed breathing crown ethers . The structures are based on the bullvalene subunit and, as the tetracyclic subunit undergoes Cope rearrangement, the size of the macroring likewise varies. The synthetic steps follow the conventional routes used for the preparation of crown ethers and are illustrated in Eq. (3.44). 

Several formulae for the lysergic acids have been proposed by Jacobs and Craig and their collaborators. The tetracyclic nucleus was suggested in 1986. Its present form is shown by formula (2) and is based mainly on the following considerations —... 

The assumption of these conjugated double bonds makes possible a tetracyclic nucleus which accords with the suggestion previously made by the authors that these alkaloids might be structurally related to the diterpenes. It may also be noted that one of the nitric acid oxidation products of pseudaconitine has been recorded as unexpectedly giving a pyrrole reaction on destructive distillation. ... 

Recent improvements in the total synthesis of steroids which give as the first tetracyclic products 19-norsteroids bearing a hydroxyl or keto group at C-17 have revived interest in the conversion of androstanes to pregnanes. 

The 2,7-naphthyridine system 53 (Scheme 8.4.18) was combined with 2,4-dinitrochlorobenzene and 2-amino glycerol for in situ reaction of the resulting Zincke salt. The resulting naphthyridinium 54 was trapped by Bradsher cycloaddition with (Z)-vinyl ether 55, providing tetracycle 56 (X-ray) upon internal addition of one of the diastereotopic hydroxymethyl groups to the resulting iminium. This approach was also extended to the use of chiral 2,7-naphthyridinium salts, prepared via the analogous Zincke process. ... 

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... 

An extension of this synthetic route to tetracyclic systems of type 36 was described by Thesing and his co-workers, who reduced the /3-(3-indolyl)ethyl-l-pyridinium salt 55 (R = H) catalytically and... 

Emphasis in recent applications of the method has been placed on the synthesis of tetra- and penta-cyclic structures containing a di-hydro-j8-carboline system or its equivalent. Thus the tetracyclic system 100 was obtained from the amide (99) of tryptamine and hip-puric acid. ... 

A number of instances in which application of the Fischer synthesis led to extended 3,4-dihydro-j8-carbolinium derivatives have been recorded. Typical for this approach is the ring closure of the phenyl-hydrazone 123 to the expected tetracyclic product... 

Polycyclic derivatives have been prepared by straightforward amide formation. The tetracyclic amide 166 was obtained by reductive cyclization of 3-o-nitrophenylindole-2-carboxylic acid (165).22 When l-(2 -ethoxycarbonylskatyl)isoquinoline (167) was heated the pentacyclic j8-carboline derivative 168 was formed. If,... 

The tetracyclic y-carboline derivative 233 was obtained via an interesting ring contraction when the seven-membered ring compound 232 was heated with selenium. 

A synthetic approach to the same tetracyclic y-carboline nucleus (235) is the consecutive Fischer indole and Bischler-Napieralski ring closure of o-acetamidoacetophenone methylphenyUiydrazone (234). The Bischler-Napieralski reaction has also been used in the synthesis of 3,4-benz-j8-carbolines (236) and 3,4-benz-3-carbolines, e.g. 237... 

Starting from 393, de Stevens and co-workerssynthesized some new tetracyclic derivatives (399 and 400) using conventional... 

The interesting work of Hahn and Hansel, who prepared a tetracyclic lactam by intramolecular cyclization of the condensation product of tryptamine and a-ketoglutaric acid, is referred to in Section IV, B, 2. Condensation of tryptamine with a,a -diketopimelic acid (403) led, presumably by way of the 1-substituted tetrahydro-)S-carboline (404), which could not be isolated, to a product to which the tetracyclic structure 405 was assigned. 

---