The Olofsson Research Group

 

Research

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Enantioselective α-Arylation of Cyclohexanones with Diaryliodonium Salts:
Application to the Synthesis of (-)-Epibatidine

with Prof. V. K. Aggarwal, Bristol University, UK

The enantioselective introduction of electrophiles α to carbonyl compounds occupies a central position in asymmetric synthesis. Although asymmetric α-alkylations have been well developed, high enantioselectivity in α-arylation of ketones has only been achieved in a very limited number of cases. These involve arylation of trisubstituted enolates using binap-Pd complexes which gives non-epimerizable, tetrasubstituted ketones. However, this strategy cannot be used in the desymmetrization/ arylation of cyclic ketones, since even if the enolate was generated enantioselectively; the ketone product would racemize the starting enolate (through proton transfer) at the high temperatures required for arylation.
An alternative strategy involves α-arylation of β-ketoesters with aryl lead reagents. This strategy can be rendered asymmetric through (i) desymmetrization/ β-ketoester formation (ii) arylation (iii) decarboxylation and subsequent equilibration.
 
A direct asymmetric arylation of cyclohexanones would clearly be superior. If this could be achieved, we envisaged that this strategy could be applied to a short asymmetric synthesis of the alkaloid (–)-epibatidine (1), which was isolated from the Ecuadorian poison frog Epipedobates tricolor in 1993.
 
Epibatidine is 400 times more potent than morphine as an analgesic, and an extremely potent agonist of the nicotinic acetylcholine receptor.
     
A direct arylation reaction of cyclohexanones was developed, employing diaryl iodonium(III) salts as electrophiles. The coupling reaction afforded α-arylated products in high yields and diastereoselectivities. The reaction could successfully be made asymmetric by employing a chiral base, resulting in 2,4-disubstituted products in high yields and ee's.
 
Having established the asymmetric methodology for the α-arylation of cyclic ketones, we applied it in a short, enantioselective synthesis of (–)-epibatidine. The synthesis was accomplished in 6 steps and 31% overall yield, thus providing the shortest and most efficient asymmetric route to this important compound to date. A short formal synthesis of (+)-epibatidine was also performed.

Conclusions
A direct, asymmetric a-arylation of cyclohexanones has been developed. The methodology employs Simpkins’ base to desymmetrize 4-substituted cyclohexanones by asymmetric enolization followed by coupling with diaryl iodonium salts, leading to 2-aryl ketones in moderate-good yields and high enantioselectivities. The methodology expands the scope of the desymmetrization strategy pioneered by Simpkins and Koga, and highlights the utility of iodonium salts for aryl transfer reactions in synthesis. This methodology has been applied in a short and efficient total synthesis of (–)-epibatidine and a formal synthesis of (+)-epibatidine.

References

  • V. K. Aggarwal, B. Olofsson: "Enantioselective α-Arylation of Cyclohexanones with Diaryl Iodonium Salts: Application to the Synthesis of (–)-Epibatidine" Angew. Chem. Int. Ed. 2005, 44, 5516-5519. PDF
  • B. Olofsson, V. K. Aggarwal: "Synthesis of Novel Heteroaryl Iodonium Salts and Enantioselective α-Arylation of Cyclohexanones" Proc. 2nd Int. Conf. on Hypervalent Iodine, 2006, 47-50. PDF

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