Download (3249Kb) - D-Scholarship@Pitt - University of Pittsburgh

2.0 Design and Synthesis of the Pivotal Intermediates
2.1 Design of the Pivotal Intermediates
In designing a pivotal allene intermediate for the planned DOS strategy, three aspects
were considered: (1) incorporating higher number of N and O heteroatoms was important since
compounds containing them are more likely to have a desirable pharmacological profile and
exhibit interesting biological effects via specific interactions with proteins; (2) potential for
diversification of the molecular scaffolds by employing both front-end and back-end appendage
diversity strategies; and (3) ease of preparation and availability of the starting precursors.
Incorporating nitrogen and oxygen containing functional groups in the pivotal allenes is also
important because they would allow for rapid attachment of pre-functionalized alkynes and
alkenes used in the carbocyclization reactions, thereby incorporating front-end diversity into the
scaffolds. Additionally, the reactivity of nitrogen and oxygen containing functional groups can
be exploited in back-end functionalization of the scaffolds subsequent to their formation.
With this in mind, several known methods for preparation of functionalized allenes were
considered. 48a Claisen rearrangement of propargyl ethers and esters is a versatile method for
preparation of allenes. 54 In 1985, Fujusawa reported the Claisen rearrangement of α-hydroxy-
propargyl ester 42 via ester-enolate 43 leading to α-hydroxy-β-allenic acid 44 (Scheme 2.1). 55
However, the scope of this transformation was limited to the rearrangement of α-unsubstituted
15