Six-Membered Aromatic Ring Construction

Lycorine is the most abundant alkaloid in plants of the Amaryllidaceae. Several syntheses of racemic lycorine had been reported prior to our initiation of studies directed at an asymmetric synthesis of the unnatural enantiomer 64. 2 a common theme in all of the syntheses of ( )-lycorine has been the utilization of either an intermolecular or intramolecular Diels-Alder construction of the key C-ring of the alkaloid. This six-membered ring presents a rather formidable synthetic challenge because of the four contiguous stereogenic centers, the trans 1,2-diol moiety, and the juxtaposition of the aromatic substituent and the carbon-carbon double bond. 

Participation by aromatic rings is also possible and there are now several examples of electro M]ic aromatic substitution involving Pummerer intermediates. Equation (20), the alkylation of benzene with dimethyl sulfoxide in trifluoroacetic anhydride, illustrates the process in its inq>lest foim. As widi al-kenes, reaction with aromatics has been more widely exploit in intramolecular versions for the construction of carbocycles and heterocycles. In many cases the sulfoxide precursor is of the keto variety, thus ensuring regiospecificity in the point of cyclization. Equation (21) (formation of a six-monber carbocycle), equation (22) (formation of a six-membered sulfur heterocycle), equation (23) (formation of a six-membered nitrogen heterocycle) and equation (24) (formation of a seven-membered nitrogen, sulfur heterocycle) provide illustrations of the versatility of diis form of intramolecular aromatic alkylation. 

PROBLEM 13.36 Try to construct an aromatic heterocycle in which there is an oxygen and a nitrogen in a neutral six-membered ring. 

Transition-metal carbene complexes have proven especially useful in the construction of six-membered rings, primarily in the synthesis of naphthalenes and higher aromatic ring systems. The major method employed is the Dbtz benzannulation reaction (depicted in Scheme 17.12), where an a,p-unsaturated or aryl carbene complex of chromium (78) couples with an alkyne to afford a phenol derivative (76). This reaction has been demonstrated for a vast array of molecular architectures and functionalities and has proven to be a very reliable and efificient process. Perhaps the major limitation on the synthetic utility is the construction of the carbene complex for systems that require structural complexity in the carbene complex. In addition to the Dotz reaction itself, several efforts to develop alternative procedures have been inspired by a detailed understanding of the mechanism of the Dotz reaction. 

Aliphatic substrates displaying increased conformational freedom proved more challenging. Although the formation of five-membered rings proceeded uneventfully, the construction of six-membered rings required more electrophilic acceptor moieties such as alkylidene malonates. Both aliphatic and aromatic aldehydes tethered to a p,p-disubstituted acceptor (62) efficiently provided five-membered rings (63) featuring a new tetrasubstituted stereocenter with up to 99% ee (Scheme 18.9) [46]. 

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