The remodelling of a natural product core framework by means of diversity-oriented synthesis (DOS) is a valuable approach to access diverse/biologically relevant chemical space and to overcome the limitations of combinatorial-type compounds. Here we provide proof of principle and a thorough conformational analysis for a general strategy whereby the inherent complexity of a starting material is used to define the regio- and stereochemical outcomes of reactions in chemical library construction. This is in contrast to the traditional DOS logic employing reaction development and catalysis to drive library diversity

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.

In an effort to access biologically important scaffolds, a concise branch-selective synthesis of C3 tertiary oxindoles by Cu(I)-catalyzed aryl amidation and 2,2-dimethyl indene by Pd(0)-catalyzed Heck cyclization has been accomplished from acyclic reverse-prenylated intermediates. Oxindole C3-enolate generation using NaH followed by alkylation in the presence of appropriate electrophiles provides a novel route to quaternary C3 reverse-prenylated oxindoles.

In an effort to access biologically relevant chemical space, a complex natural product-derived non-symmetrical diketone was prepared as a substrate for divergent transannular aldol reactions. The use of common aldol conditions resulted in predominant syn-addition via pathway a, while the use of alumina provided access to the anti-adduct. Screening of a range of Lewis acids of varying strength unexpectedly resulted in the formation of aldol products with 6/7/5/5-fused molecular skeleton via pathway b.

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