Qing-Wei Zhang, K. Xiang, Y. Tu
May 1, 2012
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Influential Citations
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Chemistry, an Asian journal
Abstract
( )-Cephalotaxine 1 was first isolated from Cephalotaxus drupacea and C. fortunei as a major alkaloid among a series of its ester derivatives in 1963. Much attention has been paid towards the studies of cephalotaxine due to the unique pentacyclic structure and antileukemic activity of its derivatives. As a classic target for organic chemists, the syntheses of cephalotaxine have been continuing since the pioneering work of Weinreb and Semmelheck in 1972. Among the various strategies reported, the establishment of the 1azaspiroACHTUNGTRENNUNG[4.4]nonane ring system 2 followed by benzazepine formation were most frequently introduced (Figure 1). Thus, an effective construction of this unit would be of great importance in the synthesis of cephalotaxine and other structurally related alkaloids such as serratine and stemonamine. Azaspiro ACHTUNGTRENNUNG[4.4]nonane 2-type azaspirocycles have long been recognized as useful building blocks and recently been selected as templates for pharmaceutical investigations. A number of methods have been developed to construct this structural unit in the context of total synthesis. However, these methods often require multiple manipulations, installing the aza-quaternary carbon center and each of the spiro rings in separate steps. Additionally, chiral syntheses of this unit are mainly based either on chiral auxiliaries or chiral starting materials. As far as we are aware, catalytic asymmetric synthesis of this kind of azaspirocycles has not been reported. In connection with our longstanding works on the semipinacol rearrangement reaction and its application in total synthesis of polycyclic alkaloids, we intended to develop a highly efficient catalytic asymmetric formal synthesis of ( )-1, taking advantage of the tandem hydroamination/semipinacol rearrangement reaction. As shown in Scheme 1, according to the procedure by Isono and Mori, ( )-cephalotaxine 1 could be obtained in four steps from 3, which has generally been introduced as