Carbocations polyene cyclization

Stereoisomeric alcohols (93) and (94) yielded identical ring-expansion products [e.g. (97)] on formation of carbocations.168 This is evidence of a stepwise reaction in sterol biosynthesis, whereby a tertiary cation [e.g. the model (95)] rearranges to a secondary cation (96)-an anti-Markovnikov rearrangement . The synthetic aspects of biomimetic cyclizations of isoprenoid polyenes were reviewed.169 Included was a detailed discussion of carbenium ion-initiated cyclizations, with a discussion of the different mechanisms that have been proposed. A novel biomimetic carbocation polyene cyclization of a daurichromenic ester was reported an unusual 2 + 2-carbocation cyclization occurred as a side reaction.170... 

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). 

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. 

As the intermediate formed in a polyene cyclization is a carbocation, the isolated product is often found to be a mixture of closely related compounds resulting from competing modes of reaction. The products result from capture of the carbocation by solvent or other nucleophile or by deprotonation to form an alkene. Polyene cyclizations can be carried out on reactants that have structural features that facilitate transformation of the carbocation to a stable product. Allylic silanes, for example, are stabilized by desilylation.12... 

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... 

As with carbocation-inititated polyene cyclizations, radical cyclizations can proceed through several successive steps if the steric and electronic properties of the reactant 249 250 251 252... 

Paschall CM, Hasserodt J, Jones T, Lemer RA, Janda KD, Christianson DW. Convergence of catalytic antibody and terpene cyclase mechanisms polyene cyclization directed by carbocation-p interactions. Angew. Chem. Int. Ed. Engl. 1999 38(12) 1743-1747. 

A reaction called the Johnson polyene cyclization (based on the Stork-Eschenmoser hypothesis) converts triene A into the polycyclic molecule B. When first discovered, an initially formed carbocation at one end of the polyene reacted with a nearby alkene to form a ring containing a new cation. This reacted with another nearby alkene, etc. The reaction was plagued by low yields and formation of polymeric material and decomposition products. This transformation required many years to perfect and two improvements were the use of a cyclopentenol unit on the left to initiate the sequence, which became a cyclopentene unit, and an alkyne unit on the right to end the sequence by generating a methyl ketone. Briefly discuss why these two improvements helped the problems inherent to this reaction. 

Bicyclization of polyenes provides access to fused ring systems. When the cyclization leads to a cyclohexane ring, the reaction usually proceeds via a chairlike transition state. Thus, the allylic cation-promoted cyclization of the butenylcyclo-hexenol below presumably proceeds via formation of the allylic carbocation followed by cyclization. Equatorial interception of the resultant cation by the solvent furnishes the bicyclic formate ester. ... 

To be of maximum synthetic value, the generation of the cationic site that initiates cyclization must involve mild reaction conditions. Formic acid and stannic chloride have proved to be effective reagents for cyclization of polyunsaturated allylic alcholos. Acetals generate a-alkoxy carbocations in acidic solution and can also be used to initiate the cyclization of polyenes ... 

Fig. 31.12 (a) Non-stop polycyclization/rearrangement controlled by teipene cyclase enzymes [54d]. The enzyme folds the polyene chain, ionizes the polyene, sequesters the pyrophosphate anion, and stabilizes the highly reactive carbocation formed, (b) Results of the THT cyclization of alcohol substrates performed in [6e6(H20)g]. Compound (31) is first cyclized mainly to a-terpineol (32), which is then converted into eucalyptol (33) other products are also shown (34-37) [54c]. (c) Ismnerization of transoid cation (38a) to cisoid finm (38b) [54c]... 

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