Synthesis and Molecular Editing of Callyspongiolide, Part 1: The Alkyne Metathesis/trans‐Reduction Strategy

Abstract

A path‐scouting investigation into the highly cytotoxic marine macrolide callyspongiolide is reported that capitalizes on the selective formation of the C10−C11 alkene site. While the closure of the macrocycle by ring closing alkyne metathesis (RCAM) with the aid of a molybdenum alkylidyne complex was high yielding, the envisaged semi‐reduction of the cycloalkyne to the corresponding E‐alkene proved challenging. The reasons are likely steric in origin, in that the methyl branches on either side of the alkyne seem to prevent effective coordination of the substrate to the ruthenium catalyst, which must carry a bulky Cp* ligand to ensure high trans‐selectivity. This notion is supported by the preparation of a callyspongiolide analogue, in which the two methyl groups in question are excised; its formation by RCAM followed by trans‐hydrostannation/proto‐destannation was straightforward. In parallel work the formation of the fully functional building block 54 showed that the presence of an unprotected ‐OH group allows even hindered substrates to be processed: the protic group adjacent to the triple bond engages with a chloride ligand on the ruthenium catalyst in hydrogen bonding and hence assists in substrate binding. Moreover, the preparation of an alkynylogous callyspongiolide analogue is described.

Total Synthesis of Callyspongiolide, Part 2: The Ynoate Metathesis/cis‐Reduction Strategy

“…The required aldehyde partner was attained by adaptation of a fragment synthesis described in the accompanying paper . To this end, the readily available butyrolactone derivative 12 was subjected to Stahl oxidation and the resulting aldehyde transformed into dibromoolefin 13 by standard means (Scheme ) .…”

“…With a robust access to 20 secured, the total synthesis of callyspongiolide was completed by cleavage of the remaining TBS‐ether and installation of the conspicuous carbamate functionality . In the final step the side chain was attached via Sonogashira coupling of 21 with alkyne 24 , for which an efficient asymmetric synthesis is outlined in the accompanying paper . The analytical and spectral data of our synthetic samples of callyspongiolide were in excellent accord with those reported in the literature, except that we had been misled at the outset of our project by the mis‐assigned absolute configuration in the original report to pursue the non‐natural enantiomer ent ‐ 1 …”

“…For our longstanding interest in bioactive marine natural products, we wanted to develop an independent access route to this promising lead compound. As reported in the accompanying paper, our approach had originally predicated on the formation of the macrocyclic ring by ring closing alkyne metathesis (RCAM) at the C10−C11 bond followed by trans ‐reduction of the cycloalkyne primarily formed ( D → C → A ) (Scheme ). Whereas the metathesis step worked nicely, the projected trans ‐addition of R 3 EH (E=Sn, Si) was unsatisfactory, most likely because the methyl branches adjacent to the triple bond in C prevent reactive encounter of the sterically hindered substrate with the required bulky [Cp*Ru]‐based catalyst (Cp*=pentamethylcyclopentadienyl)…”

Ring-Closing Metathesis Approaches towards the Total Synthesis of Rhizoxins

“…At the point where our numerous attempts at synthesizing the macrocyclic portion of rhizoxin F ( 2 ) by means of RCM/RRCM had all met with failure, we felt that a radical change in strategy was necessary. Triggered by Fürstner’s groundbreaking work on RCAM in the field of natural product synthesis (for early examples, see in [ 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ]; for more recent examples, see in [ 23 , 79 , 80 , 81 ], we reasoned that this method would be a promising alternative to RCM. (For a review on the use of RCAM in natural product synthesis, see in [ 82 ].)…”

A Ring Closing Metathesis Approach to the Formal Synthesis of (+)‐Callyspongiolide

“…Further total syntheses of (+)-callyspongiolide (1 a) by Fürstner et al [24,25] and the natural enantiomer (À )-callyspongiolide (2) by Harran et al [26] and S. Ghosh et al [27] were reported in 2018. Partial syntheses of this natural product have also been reported, with the synthesis of the macrocyclic core of (+)-callyspongiolide (1 a) by S. Ghosh [28] and the synthesis of the unsaturated side-chain of (À )-callyspongiolide (2) by Kotora [29] both reported in 2016, and a further synthesis of C3-C15 fragment of the macrocyclic core of (+)-callyspongiolide (1 a) published by Mohapatra in 2018.…”