Synthesis of N-[(3S)-2,6-Dioxo-1-(2-phenylethyl)-3-piperidinyl]-(2S)-2-methylbutanamide ((−)-Julocrotine)

Abstract

The total synthesis of (-)-julocrotine (1) starting from l-glutamic acid in 41% overall yield is described. The methodology utilizes protection, deprotection, and regioselection (carbonyl differentiation via oxazolidinone) protocols, and glutarimide ring formation is the key step.

Synthesis of (−)-julocrotine and a diversity oriented Ugi-approach to analogues and probes

“…The key intermediate 4 was hydrogenated on Pd/C at room temperature to afford 5 , which was coupled with ( S )-2-methylbutanoic acid in the presence of EDCl and HOBt to afford (−)-julocrotine ( 1 ) in 73% yield, over two steps. The HRMS, 1 H and 13 C NMR spectra, optical rotation, and melting point of 1 were consistent with the reported data [2,14–15]. …”

“…Because of the low yields of julocrotine obtained through isolation from natural sources and the necessity to gain access to larger quantities of this substance for further biological screening, Silva and Joussef developed a straightforward total synthesis in six steps [14]. Starting from L-glutamic acid, their chiral-pool approach yielded the desired optically active natural product in 41% overall yield.…”

Versatile synthesis of the signaling peptide glorin

“…A key challenge in the syntheses of glorin and analogs is the differentiation between the α- and the γ - carboxylic acid groups of L-glutamic acid for selective esterification or amidation. α-Selective functionalization was achieved via synthesis of oxazolidinone 6 from Cbz-L-glutamic acid ( 5 ) with paraformaldehyde and p -toluenesulfonic acid under dehydrating conditions [ 18 ]. Opening of the oxazolidinone with sodium ethoxide as nucleophile thus yielded ester 7a , while addition of ethylamine yielded amide 7b .…”

Glutarimide Alkaloids Through Multicomponent Reaction Chemistry

“…The scaffold is present in the structure of julocrotine, which has shown antiproliferative effects in in vitro tests against the promastigote and amastigote forms of Leishmania amazonensis. [11] Shortly afterwards, a four-step synthesis was described starting from Cbz-glutamine. [10] In 2011, a six step synthesis starting from L-glutamic acid was described.…”