Determination of the Absolute Structure of (+)-Akaterpin

Abstract

We describe the total synthesis and structural determination of ( )-akaterpin (1), an inhibitor of phosphatidylinositol-specific phospholipase C (PI-PLC). The key features of the synthetic strategy include the resolution of β,γ-unsaturated ketone ( )-2a with chiral sulfoximine 6. The absolute stereochemistry was determined by comparison of the specific optical rotation data of ( )-1 and ( )-1 with that of natural akaterpin.Key words total synthesis; absolute stereochemistry; optical resolution Umezawa and co-workers originally isolated akaterpin (1) from the marine sponge Callyspongia sp. as an inhibitor of phosphatidylinositol-specific phospholipase C (PI-PLC).1) PI-PLC triggers phosphatidylinositol turnover by hydrolyzing phosphatidylinositol 4,5-bisphosphate (PIP 2 ) into diacylglycerol (DG) and 1,4,5-trisphosphate (IP 3 ). Thus, a specific PI-PLC inhibitor is considered a promising anti-tumor candidate and a valuable tool for the investigation of signal transduction. 2,3)Until recently the precise structure of akaterpin had not been determined because of difficulties in isolating this compound from the natural source. We have been investigating a synthetic study of akaterpin and recently reported the relative stereochemistry of the compound by synthesizing possible isomers in racemic form and comparing the corresponding spectral data with those of the authentic natural product.4) Herein we describe the determination of the absolute stereochemistry of (+)-akaterpin. Our approach was to synthesize optically active akaterpin by resolution of the key intermediate in the racemic synthesis. We reasoned that β,γ-unsaturated ketone 2a was suitable for this purpose. Having resolved the key intermediate 2a, each enantiomer was then separately transformed to akaterpin following the same synthetic procedure as used for the racemate.In this regard, we previously reported the successful resolution of methyl-protected 2b by using chiral sulfoximine 6, which was developed by Johnson. 5,6) The absolute stereochemistry of both enantiomers of 2b was then established by X-ray crystallographic analysis of 7b and 9b 7) (Chart 2). We envisaged the resolution of benzyl-protected 2a, the synthetic intermediate of racemic akaterpin, 8) would also be possible as 2b. Thus, both enantiomers of akaterpin could be synthesized

Marine natural products

“…687 established the absolute stereostructure as shown. 688 The merotriterpenoids halicloic acid A 808 and B 809 were isolated from a Haliclona sponge (Culasian Point, Leyte, Philippines). Both compounds inhibited indoleamine 2,3dioxygenase, which is required for tumour immune-response escape, but were unstable in deuterated DMSO.…”

Biogenetic Relationships of Bioactive Sponge Merotriterpenoids

“…Despite their useful biological activities, sponge meroterpenoids are often unobtainable due to a lack of practical chemical syntheses and the difficulties associated with obtaining material from biological sources [ 23 , 24 , 25 , 26 ]. For this reason, studies using these compounds in biological applications are scarce and relatively infrequent.…”