Approach for Expanding Triterpenoid Complexity via Divergent Norrish-Yang Photocyclization

Abstract

Triterpenoids comprise a very diverse family of polycyclic molecules that is well-known to possess a myriad of medicinal properties. Therefore, triterpenoids constitute an attractive target for medicinal chemistry and diversity-oriented synthesis. Photochemical transformations provide a promising tool for the rapid, green and inexpensive generation of skeletal diversity in the construction of natural product-like libraries. With this in mind, we have developed a diversity-oriented strategy, whereby the parent triterpenoids bryonolic acid and lanosterol are converted to the pseudo-symmetrical polyketones by sequential allylic oxidation and oxidative cleavage of the bridging double bond at the B/C-ring fusion. The resultant polyketones were hypothesized to undergo divergent Norrish-Yang cyclization to produce unique 6/4/8-fused triterpenoid analogs. The subtle differences between parent triterpenoids led to dramatically different spatial arrangements of reactive functionalities. This finding was rationalized through conformational analysis to explain unanticipated photoinduced pinacolization, as well as the regio- and stereochemical outcome of the desired Norrish-Yang cyclization.

Natural products as starting points for the synthesis of complex and diverse compounds

“…5). 26,27 Treatment with ruthenium chloride yields three distinct products (25)(26)(27). The newly created macrocycle (25) can undergo a transannular aldol fusion to give products such as 28 and 29 in varying ratios, depending on the conditions used.…”

“…The newly created macrocycle (25) can undergo a transannular aldol fusion to give products such as 28 and 29 in varying ratios, depending on the conditions used. 26,27 By altering the oxidation patterns, as well as the conditions used to form additional rings across the core of bryonolic acid, several unique scaffolds can be formed.…”

“…22 Efforts in the mid 2000s employed reagent control to afford products in a selective fashion, 23,24 and work since 2011 has systematized this process to clearly and predictably create complex small molecules. [25][26][27][28] In contrast to the single transformation model, use of multiple structural transformations (Fig. 1B) relies on NPs with rich functional diversity.…”

Underexplored Opportunities for Natural Products in Drug Discovery

“…In recent years, several research groups have expanded on this theme, demonstrating that diverse sets of complex natural product-based libraries can be accessed via the architectural remodeling of natural product cores . Hergenrother and co-workers have reported on the application of ring cleavage, expansion, fusion, and rearrangement reactions of gibberellic acid, andrenosterone, quinine, abietic acid, and pleuromutilin, a strategy they coined complexity-to-diversity (CtD). − A similar strategy has been applied to lanosterol and bryonolic acid by Tochtrop and co-workers. − …”

Direct Access to 6/5/7/5- and 6/7/5/5-Fused Tetracyclic Triterpenoids via Divergent Transannular Aldol Reaction of Lanosterol-Derived Diketone

“…4 In order to gain access to the desired diketone 2 , the starting material 1 was oxidized with ruthenium tetroxide under Sharpless conditions. 25 Under these conditions the bridging double bond at the B/C ring fusion underwent competing oxidative cleavage reaction to give diketone 2 , and non-selective allylic oxidation at C-11 and C-7 to give α,β-unsaturated ketones 3 and 4 , respectively (Scheme 1).…”