Synthesis of the Alleged Structures of Fortisterol and Herbarulide and Structural Revision of Herbarulide

Abstract

The alleged structures of 5,6-epoxy-5,6-secosteroids fortisterol and herbarulide differ only in the stereoconfiguration of C24. Applying insights into the hypothetical biosynthesis of this class of natural products, we devised a short synthetic access (four and eight steps, respectively) starting from commercial ergosterol and featuring an alkoxy radical rearrangement. The comparison of nuclear magnetic resonance spectroscopic data revealed herbarulide having the proposed structure of fortisterol, whereas synthesis of another two diastereomers could not conclusively prove the true structure of fortisterol. Along the way, a high-yielding and scalable access to the infamous Burawoy’s ketone not requiring chromium­(VI) reagents was developed.

Discoveries and Challenges en Route to Swinhoeisterol A

“…Initially, 5α‐hydroxy enone 7 was chosen as a substrate for the envisioned radical rearrangement (Scheme ). As we described in our synthesis of herbarulide, the preparation of Burawoy's ketone ( 6 ) following reported procedures has proven to lack reproducibility . Aiming for a stepwise oxidation of ergosterol ( 1 ), 6 was available in 62 % yield over 4 steps .…”

“…As we described in our synthesis of herbarulide, the preparation of Burawoy's ketone ( 6 ) following reported procedures has proven to lack reproducibility . Aiming for a stepwise oxidation of ergosterol ( 1 ), 6 was available in 62 % yield over 4 steps . Reduction with zinc in acetic acid provided 5α‐enone (not shown) in 47 % along with 20 % of its 5β‐epimer (not shown).…”

“…In recent years, our group as well as others have demonstrated that key synthetic transformations (possibly biomimetic in nature) can indeed be carried out using radical reactivity, giving the desired skeletal modifications with high selectivity as shown in the syntheses of rearranged steroids cortistatin A, aplysiasecosterol A, strophasterol A, pleurocin A/matsutakone, and herbarulide . It was also a cascade of rearrangements initiated by an alkoxy radical that cleared the way to the dankasterone [13(14→8) abeo ‐steroids] and the swinhoeisterol class of natural products [13(14→8),14(8→7)di abeo ‐steroids] .…”

A Concise Synthesis of 24,25-Dihydro-6-epi-Monanchosterol A

“…In accordance with the strategy outlined above (Scheme 1), we began our investigation with the conversion of 7-dehydrocholesterol (6) into the trans-glycol 5 through epoxidation (mCPBA, K 2 CO 3 ) and subsequent alkaline epoxide hydrolysis 11 (Scheme 2). However, while this method allowed the regioselective oxidation of the Δ 5 -double bond in a highly efficient manner, the resulting trans-glycol (trans-5) proved recalcitrant to the planned oxidative cleavage, for instance, with NaIO 4 or Pb(OAc) 4 .…”

“…Since their discovery a century ago, steroids have always fascinated scientists because of their outstanding biological activities and the immense diversity of structures, all derived from the tetracyclic sterane skeleton. 1 Moreover, steroids have played a most prominent role in the development of organic chemistry, 2 and even in recent years, the discovery of fundamentally new classes of steroids with rearranged carbon skeletons has triggered a wealth of new and fruitful scientific research. 3 An interesting example are the cyclocitrinols, such as isocyclocitrinol A (1), the correct structure of which was elucidated by Crews and Clardy in 2003 (Figure 1).…”