Total Synthesis of Jiadifenolide

Abstract

As a potent neurotrophic agent, the sesquiterpenoid jiadifenolide represents a valuable small-molecule lead for the potential therapeutic treatment of neurodegenerative diseases. A stereocontrolled total synthesis of this densely functionalized natural product is reported, central to which is an adventurous samarium-mediated cyclization reaction to establish the tricyclic core and the adjacent C5 and C6 quaternary stereocenters.

An eight-step gram-scale synthesis of (−)-jiadifenolide

“…This tertiary alcohol then directed reduction of the proximal ketone by trimethylammonium triacetoxyborohydride 15 , to yield diol 15, the structure and stereochemistry of which were assigned by X-ray crystallography (Fig. 3b, 15 X-ray).…”

“…The potentiating activity of 6 was not determined because, like 1-5, it is produced in only trace amounts (0.00008% yield from the pericarps (fruit) of I. jiadifengpi). Although chemical synthesis has provided some material to verify 12,13 the neurotrophic activity disclosed in the original isolation reports, only basic structure-activity relationships (SAR) have been gleaned from these studies and the production of 1 through multistep syntheses (≥20 steps) has yielded quantities comparable to isolation (<9 mg) [13][14][15][16] . Validation of these neurotrophic terpenes for the treatment of neurodegenerative diseases is therefore restricted to cell culture-scale assays 17 .…”

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

“…Taking inspiration from Paterson and coworkers, the authors closed the central 6-membered ring of the target through a reductive radical cyclization. 112 Thus treating 97 with the powerful reductant SmI 2 /H 2 O accomplished this transformation, 131–133 producing tricycle 98 in excellent yield (80%) and with good diastereoselectivity (7:1). Swern oxidation of 98 led to aldehyde 99 , thus setting the stage for a second pivotal annulation reaction wherein the authors envisioned formally “inserting” one-carbon to construct the final γ-lactone ring in the target.…”

“…108 Among this large family, jiadifenolide ( 81 , Scheme 7) has recently attracted significant synthetic attention owing to its compact and highly oxidized molecular framework coupled with its ability to promote neurite outgrowth at very low concentrations. 109 To date, total syntheses of 81 have been disclosed by the groups of Theodorakis, 110,111 Paterson, 112 Sorensen, 113 Shenvi, 114 and Zhang, 115 in addition to a recent formal synthesis by Gademann. 116 Herein we discuss the three chiral pool-based total syntheses of 81 by Sorensen (2014), Zhang (2015), and Shenvi (2015).…”

“…The extended boron enolate of butenolide 95 was then coupled with this material via an aldol reaction, and following treatment with acetic anhydride to induce dehydration, compound 96 was produced (a similar disconnection was utilized by Paterson in an earlier 2014 synthesis of 81 ). 112 Treating 96 with excess LDA masked both the butenolide and cyclopentenone carbonyl groups as transient enolates, thereby allowing for reduction of the ester group with DIBAL. Following hydrogenation (PtO 2 , H 2 ), alcohol 97 was forged, setting up a key step in the synthesis.…”