Novel Concise Synthesis of (−)‐Clausenamide

Abstract

A six-step synthesis of (−)-clausenamide is described. Optically pure (R,E)-1,3-diphenylallylic alcohol was acetylated and then subjected to an Ireland-Claisen rearrangement, giving the γ,δ-unsaturated acid, which underwent a substrate-induced stereoselective bromolactonization to afford the expected all-equatorial substituted bromo-δ-lactone. An unusual chemo-selective aminolysis of the lactone resulted in the formation of a γ,δ-epoxy-amide in stereospecific manner. Base-promoted cyclization of this intermediate and the subsequent Davis oxidation furnished the synthesis, delivering the final product in ＞99% ee and up to 34% overall yield.

Efficient synthesis of (-)-clausenamide

“…Optical rotation was determined using the P8000 automatic polarimeter. 1 HNMR and 13 CNMR spectra were recorded on a 500 MHz/300MHz spectrometer (AVANCE) with trimethylsilane (TMS) as the internal standard. Chemical shifts expressed in (δ) are given in ppm, whereas J-values for 1 H-1 H coupling constants are represented in Hertz (Hz).…”

“…Liu Di and workers synthesized (-)clausenamide starting from cinnamic aldehyde (1d) (Scheme 1, route C). 13 The overall yield of the eight-step synthesis of (-)-clausenamide was 11.5% (99% ee). This method is limited by the Sharpless asymmetric epoxidation of (2c), which needs harsh conditions (anhydrous environment and long-term low temperature).…”

Why do thioureas and squaramides slow down the Ireland–Claisen rearrangement?

“…Its key step is a [3,3]-sigmatropic rearrangement of a silyl ketene acetal, which is generated in situ by deprotonation of an allyl ester using a strong base [1][2][3]. The products of the Ireland-Claisen rearrangement, γ,δ-unsaturated acids, are useful precursors of biologically active compounds and natural products [4][5][6][7][8][9][10][11]. The ready availability of allylic esters, the ability to control the E/Z geometry of enolates as well as its stereospecificity make this transformation synthetically appealing [12,13].…”

A Common Precursor Approach to Structurally Diverse Natural Products: The Synthesis of the Core Structure of (±)‐Clausenamide and the Total Synthesis of (±)‐Hyalodendrin

“…There have been a number of methods reported in the literature to access the core structure of hyalodendrin (3) and the ETPs, with most efforts directed towards the synthesis of the diketopiperazine ring prior to incorporation of sulfur. [21][22][23][24][25][26][27][28][29][30][31][32] As a result of the structural complexities and potent biological activities of both the ETPs and pyrrolidine alkaloids we were interested in the development of separate novel methodology to access both classes of compound. [1] Notable synthetic endeavours involve work by Kishi, Fukuyama, Movassaghi, Williams and others, which have led to the synthesis of the natural products.…”

“…[17][18][19][20] As a result of its potent biological activity, clausenamide (5) has also attracted significant synthetic attention over a number of years due to its potential to treat neurological disorders and the synthetic challenge associated with its four contiguous stereocentres. [21][22][23][24][25][26][27][28][29][30][31][32] As a result of the structural complexities and potent biological activities of both the ETPs and pyrrolidine alkaloids we were interested in the development of separate novel methodology to access both classes of compound. However, we were also attracted to the development of synthetic routes, which would be amenable to the synthesis of small molecular libraries to access related structural analogues for biological evaluation for each class of compound.…”