Total Syntheses of Nominal and Actual Prorocentin

Abstract

The dinoflagellate-derived polyether prorocentin is a co-metabolite of the archetypical serine/threonine phosphatase inhibitor okadaic acid. Whereas a structural relationship cannot be missed and a biosynthetic link was proposed, it is currently unknown whether there is any parallel in the bioactivity profile of these natural products. However, it was insinuated in the past that the structure assigned to prorocentin might need to be revised. Indeed, re-examination of the published spectra cast doubts as to the constitution of the fused/spirotricyclic BCD-ring system in the core. To clarify this issue, a flexible synthesis blueprint was devised that allowed us to obtain the originally proposed structure as well as the most plausible amended structure. The key to success was late-stage gold-catalyzed spirocyclization reactions that furnished the isomeric central segments with excellent selectivity. The lexicon of catalytic transformations used to make the required cyclization precursors comprised a titanium-mediated ester methylenation/metathesis cascade, a rare example of a gold-catalyzed allylic substitution, and chain extensions via organocatalytic asymmetric aldehyde propargylation. A wing sector to be attached to the isomeric cores was obtained by Krische allylation, followed by a superbly selective cobalt-catalyzed oxidative cyclization of the resulting di-unsaturated alcohol with the formation of a 2,5-trans-disubstituted tetrahydrofuran; the remaining terminal alkene was elaborated into an appropriate handle for fragment coupling by platinum-catalyzed asymmetric diboration/oxidation. The assembly of the different building blocks to the envisaged isomeric target compounds proved that the structure of prorocentin needs to be revised as disclosed herein.

Studies toward Providencin: The Furanyl-Cyclobutanol Segment

“…The ester terminus of 12 was then converted via the Weinreb amide into the corresponding TMS-capped alkynoate 13 as an adequate substrate for Noyori transfer hydrogenation . As expected, this transformation worked exceedingly well and provided multigram amounts of propargyl alcohol 15 with virtually perfect optical purity and quantitative yield. Base-mediated cleavage of the TMS-group preceded protection of the alcohol and hydroboration of the terminal alkyne upon treatment with pinB–H at elevated temperature to give product 16 ; this reaction was promoted by catalytic amounts of the 9- H -9-BBN dimer. − …”

Hexafluoroisopropanol (HFIP) as a multifunctional agent in gold-catalyzed cycloisomerizations and sequential transfor-mations

“…59 Gold-catalyzed cycloisomerization followed by Brønsted acid-mediated rearrangements can be a powerful sequence of reactions, with recent application in total synthesis. 60 In this fashion, the library of hexafluoroisopropyl ω-ketoesters derived from the lactones of Scheme 2 and HFIP or TFE was rapidly generated without the need for tedious purification procedures (Scheme 3). A simple extraction with diethyl ether and water was sufficient in removing MsOH, while evaporating the organic phase and removing the residual gold catalyst by filtration through short (ca.…”

Second-Generation Total Synthesis of Prorocentin

“…While a detailed reassessment of the published spectra certainly reinforced the doubts, an unambiguous decision as to the actual constitution of prorocentin could not be made; moreover, the data did not provide any indication whatsoever concerning the absolute configuration. Therefore, our group embarked on an extensive synthesis campaign, which targeted the originally proposed as well as a revised structure that was deemed to most likely represent the actual natural product . In doing so, we conjectured that the absolute configuration shown in Figure was most likely based on the assumption that prorocentin might be a remote relative of limaol ( 3 ), a spirocyclic dinoflagellate-derived polyketide with confirmed stereostructure. − In the end, this project allowed us to prove that prorocentin comprises an equatorially oriented hydroxy group at the C17 positon of the central B-ring rather than an axially disposed −OH at the adjacent C16 site, as had originally been proposed by the isolation team .…”

“…Therefore, our group embarked on an extensive synthesis campaign, which targeted the originally proposed as well as a revised structure that was deemed to most likely represent the actual natural product . In doing so, we conjectured that the absolute configuration shown in Figure was most likely based on the assumption that prorocentin might be a remote relative of limaol ( 3 ), a spirocyclic dinoflagellate-derived polyketide with confirmed stereostructure. − In the end, this project allowed us to prove that prorocentin comprises an equatorially oriented hydroxy group at the C17 positon of the central B-ring rather than an axially disposed −OH at the adjacent C16 site, as had originally been proposed by the isolation team . The stereochemical relationship between core and wing section in 1 was established, and the absolute configuration was found to, indeed, correspond to that of limaol.…”

“…In order to reach an improved material throughput, a shorter entry into building block IV representing the revised B-ring seemed necessary (Scheme ). Originally, this sector had been derived from d -glucose in 20 steps; it was actually not so much the length of the route, which proved robust and scalable, but the fact that formation of the C15–C16 bond by ester carbonyl methylenation/olefin metathesis ( V → VI ) − mandated overstoichiometric amounts of Tebbe’s reagent [Cp 2 TiCH 2 ] generated in situ that urged us to develop an alternative approach.…”