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 ...