Synthesis of Medium Ring Ethers. 5. The Synthesis of (+)-Laurencin

The enantioselective synthesis of (+)-laurencin 1 has
been achieved in 27 steps from (R)-malic acid
20.
The key steps involved methylenation of the lactone 49
followed by intramolecular hydrosilation of the enol ether
14 (Scheme ) and one carbon homologation of the diol
13 to give the key ethyl substituted cyclic ether
59 (Scheme
). The lactone 49 was obtained by two efficient
routes, namely a Claisen ring expansion (Scheme ) followed
by
α-hydroxylation (Scheme ) and a Yamaguchi lactonization (Scheme ).
Elaboration of the (E)-pentenynyl side
chain (Scheme ) and introduction of bromine (Scheme ) completed the
synthesis of (+)-laurencin 1.