Cyclizations and ring enlargements

Because several cyclizations have already been described in previous chapters, these are usually not repeated in this chapter but only referred to by the number of their chemical formulas, schemes, or sections. 

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The first remarkable transannulation reaction of humulene involved treatment with jV-bromo-succinimide in aqueous acetone leading to the tricyclic bromohydrin62. Cyclization is induced by attack of a bromonium ion on the trialkylated, electron-rich 1.2-double bond followed by a sequence of 3-exo and 4-exo transannulation reactions. After substitution of bromine by hydroxyl, elimination of water and ring enlargement, caryophyllene (1) is generated stereoselec-tively in 25 % yield. Reaction of humulene in the presence of aqueous sulfuric acid led to a mixture of bi- and tricyclic products although the formation of bicyclo[5.3.0] systems predominates63. 

Scott and Sumpton (1993) described an Organic Syntheses procedure in which l-diazo-4-phenylbutan-2-one (8.122) is used for a cyclization. Compound 8.122 is comparable, to a certain extent, to the diazoketo ester 8.118, as there is also an alkyl chain between the diazo group and a phenyl substituent. As shown in Scheme 8-56, the reaction is, however, different, as, in addition to a cyclization, a ring enlargement of the benzene ring takes place. The primary product 8.123 is unstable and forms 3,4-dihydro-2/f-azulen-l-one (8.124). 

In the latter process Dieckmann cyclization of diester (11) using high dilution conditions failed. However, A-homo-5a-cholestan-3-one (5b) identical to the product of diazomethane ring enlargement of (lb) was obtained in 35 % yield when diester (11) was hydrolyzed to the bis-homo diacid and this converted to the thorium salt and pyrolyzed. 

The synthesis takes advantage of the well-documented sulfoxide - sulfenate rearrangement , as well as of its retro-process, leading to cyclization and formation of the desired four-membered ring sulfoxide system (i.e. 211, 212). A closely related ring enlargement is based on the reversibility of this rearrangement and has found wide use in penicillin chemistry . 

Kazansky et al. (5) estimated the role of C5 cyclic intermediates in aromatization to be about 5% over platinum on carbon. Dautzenberg and Platteeuw found about 11% C5 cyclic pathway with nonacidic platinum on alumina (23). 2,2,4-Trimethylpentane is forced to produce aromatics via C5 cyclization because of its structure here the quaternary carbon atom facilitates ring enlargement (5, 23). 

In a new method of ring enlargement of oxiranes to oxetanes, the intramolecular Williamson reaction is the essential last step. Reaction of an oxirane with selenomethyl-lithium reagents, followed by bromination, gives y-bromo alcohols, which can be cyclized by base to oxetanes. Since the oxiranes can be prepared readily from ketones and the selenomethyllithium reagent, this is also a synthesis of oxetanes from ketones (80TL585). 

Available methods for the synthesis of macrolides involve the cyclization of long-chain bifunctional precursors,3 depolymerization processes,4 ring-enlargement reactions,5 and special methods... 

Complications may however arise in this type of synthesis, besides the rcgioselec-tivity involved in the cyclization step, due mainly to the possibility of cleavage of the bond linking the heterocyclc ring to the benzylic carbon atom during the formation of the methyleneimmonium ion. In this way, rupture of the molecule, heterocyclic ring enlargement (sec Fig. 69, Chap. I), and the abovementioned racemization" may take place. 

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