Total Syntheses of Hexacyclinol, 5‐epi‐Hexacyclinol, and Desoxohexacyclinol Unveil an Antimalarial Prodrug Motif

Abstract

Hexacyclinol (1) was isolated by Gräfe and co-workers from the basidiospores collected from Panus rudis growing on dead betula woods in Siberia. [1] In 1999, our exploration into German fungal cultures provided a strain of P. rudis 99-329 that was not only capable of the biosynthesis of 1 but also provided trace amounts of epi-5-hexacyclinol (2) and desoxohexacyclinol (3). [2] Further study indicated that the retrocycloaddition of 1 and 2 released oxygen to afford a mixture of trienes 3 (Scheme 1). Subsequent [2+2+2] cycloaddition of 3 with singlet oxygen returned a mixture of 1 and 2. As this process could be cycled, it offered a key handle in expediting the synthesis of this family of terpenes.The synthesis of 1 and 2 through 3 simplifies the complexity of the hexacyclinol ring system by removal of the D/E rings (Scheme 1). On the basis of this argument, a campaign to 3 was launched using the synthetic plan outlined in Scheme 2. The plan began with an intact A ring as shown in intermediate A. The first stage of this project sought a rapid appendage of C7 and C17 onto A followed by the installation of the lower half of the B ring as given by the conversion of D into E. From E, a series of three sequences (E!F, F!G, and G!I, Scheme 2) were used to stitch the molecule together, beginning with the insertion of C15-C16, followed by creation of the C17-C18 bond, and ending with installation of the C14-C15 epoxide.Intermediate A was developed from bisA C H T U N G T R E N N U N G (acetate) 4.[3] Protection with TBS, deacetylation, and nosylation of the primary alcohol afforded 5 (Scheme 3). Under these conditions, nosylate 5 was obtained along with a bisA C H T U N G T R E N N U N G (nosylate) derivative (3-5 % yield), which was removed after treatment of the mixture with sodium cyanide in DMSO to convert 5 into 6. This sequence was conducted on a multigram scale to provide 6 after a single chromatographic purification step. The synthesis of 6 completed the installation of C7 as indicated by the conversion of A into B (Scheme 2).The next stage in this synthesis involved the installation of C17, as given by the conversion of B into C (Scheme 2). This operation was accomplished through the conversion of 6 into bromoacetal 7 by reaction with 1,2-dibromoethylmethyl ether (Scheme 3). [4] Treatment of crude 7 with NaHMDS at À78 8C followed by warming to room temperature resulted in 3:2 mixture of 8 a/8 b. Fortunately, protonation of the enolate of 8 a/8 b with triphenylacetic acid afforded a mixture favoring the desired nitrile 8 a by 11:1. To increase the material throughput to 8 a, the cyclization and isomerization steps were conducted in a one-pot operation.With intermediate C in hand, the next step required correction of the stereochemistry at C13. As provided by 4, this center required inversion as illustrated by the conversion into D (Scheme 2). The process began by convertion of the nitrile of 8 a to dithiane 13 (Scheme 3). Slow addition of DIBAL-H at À20 8C to 8 a at À78 8C in toluene afforded 9 in high yield. The ...

Oxygen‐Bearing Lithium Compounds in Modern Synthesis

“…Interestingly, dilithiated ethers 14 at the benzylic and ortho positions, obtained by treating the corresponding readily available benzyl 2-halophenyl ethers 13 with 3 equiv. A crucial intermediate (22) en route to antimalarian prodrug motifs such as hexacyclinol, 5-epi-hexacyclinol, and desoxohexacyclinol, could be recently synthesized through the anchimeric-assisted addition of the unstabilized α-lithioether 20 (prepared by reductive lithiation of the corresponding phenylsulfide with LN) to epoxide 21 (Scheme 6.6) [18]. In particular, the reaction of dianion 14 with carboxylic esters proved to be a practical and efficient route to get dihydrobenzo [b]furan derivatives 15 (mixture of isolable diastereomers).…”

Mn(OAc)3 catalyzed intermolecular oxidative peroxycyclization of naphthoquinone

“…In particular, synthesis of 1,2-dioxanes can be realized with oxygen. Such reactions were described with singlet oxygen, 9 with thiols by oxidation of 1,5-dienes 10,11 or by the Isayama-Mukaiyama method. 12 Ozonolysis of double bonds also afforded hydroperoxides, which can be then cyclized.…”

Structural Revisions of Natural Products with the Aid of the Structure Elucidator System

“…The intriguing story about the structure elucidation of hexacyclinol was described in a series of publications. [61][62][63][64][65] 13 C chemical shift calculation should be considered as the most severe filter to reject all invalid structures and to select the most probable one. However, the average deviations between experimental and predicted spectra that serve as effective criteria for structure assessment are calculable only if chemical shift assignment is completed.…”