Tetracyclic products

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. 

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. 

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... 

This reaction also represents an example of the intramolecular Heck reaction, a variant that has gained some importance in recent years. Another instructive example of the potential of this reaction for the construction of ring systems has been reported by de Meijere and coworkers, taking advantage of a sequence of four consecutive intramolecular Heck reactions. The bromodiene-yne 18 reacts in a sequence of domino reactions within 3 d at 80 °C under Heck conditions to give the tetracyclic product 19 in 74% yield ... 

Utilization of a similar [Sc(OTf)3-promoted)] approach by Overman on the ger-anylgeraniol-derived cyclization substrate 98 provided the desired tetracyclization product 99, in which the terminator of the cationic cyclization is an arene group. Compound 99 is then transformed into the kinesin motor protein inhibitor adocia-sulfate 1 (Scheme 8.27) [47]. 

The reaction of 1,2-dithiolanes with 2- and 4-picolyllithium has been examined <96PS(112)101> and the reactions of thioanhydrides such as 94 with both thiols <95JOC3964> and amines <96TL5337> have been reported. Treatment of 1,2-dithiolium salts with lithium or thallium cyclopentadienide results in formation of a variety of bi-, tri- and tetracyclic products <96LA109>. Reaction of 95 with trimethyl phosphite gives some of the desired coupling product but also the phosphonates 96 <96PS(109)557>. 

The pyrido[3, 4 4,5]furo[3,2-A]indole 24 can be prepared by Curtius rearrangement of 3-[5-(2-nitrophenyl)-2-furyl]-propenoic azide 25, followed by reduction of the nitrophenyl functionality of the product 26, chlorination of the tetracyclic product (PCI5), then reduction (Zn/AcOH) to give the parent compound 24 <1987CCC192> (Scheme 7). 

Dimethyl-3/7-indole reacts with diethyl oxaloacetate in acetic acid to give the pyrrolizine 157. Upon reaction of this product with guanidine for extended periods of time, the tetracyclic product 158 is formed in low yield <1988J(P1)451> (Scheme 46). 

The isoquinolinium ylide 241 reacts with allyl alcohol in a [3+2] cycloaddition to give the tetracyclic product 242 (Equation 32) the primary cycloaddition product spontaneously undergoes an intramolecular transesterification to give the isolated furanone. Similarly, reaction of such ylides with vinylene carbonate gives the tetracycles 243 (Equation 33) <1988BCJ2513>. 

Synthetic routes to the benzocyclazines are analogues of those which lead to the cyclazines themselves. Representatives of the benzoh ]cycl[3.2.2]azine (indolizi no [3,4,5- ] isoindole, 365) ring system result from cycloaddition of, for example, DMAD to pyrido[2,l-tf]isoindole-6-carbonitrile 370 <1986H(24)3071> (Scheme 100). An alternative synthesis, which starts from the cyclazine 371 and involves construction of the additional benzenoid ring by a double Horner-Wadsworth-Emmons type of reaction, apparently gives the tetracyclic product 365 in only very low yields (Scheme 101) <1988H(27)2251>. 

The doubly protected indolinethiol 275 undergoes deprotection by treatment with silica gel at low pressure the intermediate heterodiene then reacts with the protected glucal 276 in an inverse electron demand Diels-Alder reaction to give the fused tetracyclic product 277 (Equation 96) <2003JOC7907>. 

Treatment of the protected aldehyde 342 with a TFA/water/chloroform mixture results in the formation of a 10-membered intermediate iminium cation intramolecular attack of this electrophile at C-2 of the indole (an intramolecular Pictet-Spengler reaction) gives the isolated tetracyclic product 343 in good yield (Equation 124) <1995T4841>. 

In what is essentially a one-pot reaction, iV-alkynyl-2-bromoindole-3-carbaldehydes such as 371 are converted into their tert-butylimine derivatives, and these then react with palladium(O) to give tetracyclic products 372 in good yield (Equation 133) <20020L3035>. A modification of this method has been used for the synthesis of pyranoindolizines (Equation 134) <2003JOC5132>. 

Vedejs developed an enantiocontrolled synthesis of aziridinomitosenes involving internal alkylation of the oxazole 132 to produce an oxazolium salt 133 followed by nucleophilic addition of cyanide providing the adduct 134 <00JA5401>. Electrocyclic ring opening of 134 to the azomethine ylide 135 with internal [2+3] trapping produces the tetracyclic product 137 via the pyrroline 136. 

In Scheme 33, ring closure to a related benzologue is also shown <2002PS2675> reaction of 2-(2 -hydroxyphe-nyl)benzimidazole 213 with Lawesson s reagent yielded the tetracyclic product 214 in one single step in medium... 

The treatment of 23 with methyllithium in the presence of furan gave rise to the tetracyclic product 26, which is obviously a [4 + 2]-cycloadduct of furan to the 1,2-cyclopentadiene derivative 25 [27]. The feature that the oxanorbornene system of 26 carries its saturated substituent in the endo-position is analogous to the [4 + 2]-cycloadducts of furan to all six-membered cyclic allenes (see Section 6.3). Balci et al. [36] also provided evidence for the generation of l-phenyl-l,2-cyclopentadiene. They postulated this species to be an intermediate in the reaction of l-phenyl-2-iodocydo-pentene with potassium tert-butoxide in benzene at 240 °C, which resulted in the formation of 1-phenyl- and 1,2-diphenylcyclopentene. Both products were considered as evidence in favor of the diradical nature rather than the allene structure of 1-phe-nyl-1,2 -cyclopentadiene. 

Also, in the form of N-(2-pyridylcarbonyl)proline Pro undergoes 1,3-dipolar cycloaddition with 2-chloroacrylonitrile to give two tetracyclic products and 61b in 5% yield (85TL5447). When Pro-OMe was heated with methyl cinnamate and benzaldehyde in toluene for several hours, two iso-... 

Confalone et al. (85) also made use of an intramolecular cycloaddition step in the construction of a range of tri- and tetracyclic products. Phenyl allyl ethers, of the type shown in Scheme 3.94, underwent dehydrative condensation with the requisite amine to furnish the intermediate ylides, which suffered cycloaddition resulting in 285 and 286 in essentially quantitative yield. The ratio of cis/trans fused products was in the range of 10 1. Such a process has been developed to construct the alkaloid (+ / ) sceletium A4 by reaction of the intermediate 287 with amine 288 via the cycloaddition protocol already developed, followed by further chemical manipulation, in an efficient five step synthesis (Scheme 3.94). 

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