And polyene cyclization

This chapter summarizes those transannular reactions in medium ring carbocycles which result in carbon-carbon bond formation via alkylation of carbon, in the presence of electrophilic reagents. It is therefore a logical extension of two other chapters in this volume, covering Friedel-Crafts Alkylations (Chapter 1.8), and Polyene Cyclizations (Chapter 1.9). The discussion of these processes is organized according to the size of the cycloalkene from which transannular cyclization is effected. 

Ziegler and Wang have achieved a synthesis of ( )-estrone from 6-methoxy-tetralone based on Cope rearrangement and polyene cyclization methodology (Scheme 28). ... 

Other, removable cation-stabilizing auxiliaries have been investigated for polyene cyclizations. For example, a sdyl-assisted carbocation cyclization has been used in an efficient total synthesis of lanosterol. The key step, treatment of (257) with methyl aluminum chloride in methylene chloride at —78° C, followed by acylation and chromatographic separation, affords (258) in 55% yield (two steps). When this cyclization was attempted on similar compounds that did not contain the C7P-silicon substituent, no tetracycHc products were observed. Steroid (258) is converted to lanosterol (77) in three additional chemical steps (225). 

Acyl radicals can be generated and they cyclize in the usual manner. A polyene-cyclization reaction generated four rings, initiating the sequence by treatment of a phenylseleno ester with Bu3SnH/AIBN to form the acyl radical, which added to the first alkene unit. The newly formed carbon radical added to the next alkene, and so on. Acyl radicals generated firom Ts(R)NCOSePh derivatives cyclize to form lactams. ... 

Polyene Cyclization. Perhaps the most synthetically useful of the carbo-cation alkylation reactions is the cyclization of polyenes having two or more double bonds positioned in such a way that successive bond-forming steps can occur. This process, called polyene cyclization, has proven to be an effective way of making polycyclic compounds containing six-membered and, in some cases, five-membered rings. The reaction proceeds through an electrophilic attack and requires that the double bonds that participate in the cyclization be properly positioned. For example, compound 1 is converted quantitatively to 2 on treatment with formic acid. The reaction is initiated by protonation and ionization of the allylic alcohol and is terminated by nucleophilic capture of the cyclized secondary carbocation. 

The incorporation of silyl substituents not only provides for specific reaction products but can also improve the effectiveness of polyene cyclization. For example, although cyclization of 2a gave a mixture containing at least 17 products, the allylic silane 2b gave a 79% yield of a 1 1 mixture of stereoisomers.13 This is presumably due to the enhanced reactivity and selectivity of the allylic silane. 

Scheme 10.1 gives some representative examples of laboratory syntheses involving polyene cyclization. The cyclization in Entry 1 is done in anhydrous formic acid and involves the formation of a symmetric tertiary allylic carbocation. The cyclization forms a six-membered ring by attack at the terminal carbon of the vinyl group. The bicyclic cation is captured as the formate ester. Entry 2 also involves initiation by a symmetric allylic cation. In this case, the triene unit cyclizes to a tricyclic ring system. Entry 3 results in the formation of the steroidal skeleton with termination by capture of the alkynyl group and formation of a ketone. The cyclization in Entry 4 is initiated by epoxide opening. 

As with carbocation-initiated polyene cyclizations, radical cyclizations can proceed through several successive steps if the steric and electronic properties of the reactant provide potential reaction sites. Cyclization may be followed by a second intramolecular step or by an intermolecular addition or alkylation. Intermediate radicals can be constructed so that hydrogen atom transfer can occur as part of the overall process. For example, 2-bromohexenes having radical stabilizing substituents at C(6) can undergo cyclization after a hydrogen atom transfer step.348... 

Both the E- and Z-isomers of vinylsilane 13-A have been subjected to polyene cyclization using TiCl4-Ti(0-i-Pr)4. Although the Z-isomer gives an 85-90% yield, the -isomer affords only a 30-40% yield. Offer an explanation. 

Besides taxodione and taxodone, these synthetic approaches have been conveniently modified to synthesize other related derivatives such as ferruginols, sugiols, and royleanones.51-52,56-57,60-62 In addition, the enantiomeric-selective synthesis of (+ )-taxodione 1 has been reported using (—)-abietic acid as the starting material63 or with a chiral ligand in the polyene cyclization process.64... 

Scheme 25 Oltra s and Cuerva s catalytic epoxy polyene cyclizations...

HWE reaction has been used extensively for the synthesis of dienes and polyenes. Examples from recent literature are shown in Table 16 (dienes) and Table 17 (polyenes). HWE reaction also has been used for intramolecular cyclizations leading to polyene macrolides (Table 18). 

The tetracyclic alcohol 179 is produced by the action of boron trifluoride etherate or tin(IV) chloride on the oxirane 178 (equation 85)95. A similar cyclization of the oxirane 180 yields DL-<5-amyrin (181) (equation 86)96. In the SnCLt-catalysed ring-closure of the tetraene 182 to the all-fraws-tetracycle 183 (equation 87) seven asymmetric centres are created, yet only two of sixty-four possible racemates are formed97. It has been proposed that multiple ring-closures of this kind form the basis of the biosynthesis of steroids and tetra-and pentacyclic triterpenoids, the Stork-Eschenmoser hypothesis 98,99. Such biomimetic polyene cyclizations, e.g. the formation of lanosterol from squalene (equation 88), have been reviewed69,70. 

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