Pteridinone-based Toll-like receptor 7 (TLR7) agonists were identified as potent and selective alternatives to the previously reported adenine-based agonists, leading to the discovery of GS-9620. Analogues were optimized for the immunomodulatory activity and selectivity versus other TLRs, based on differential induction of key cytokines including interferon α (IFN-α) and tumor necrosis factor α (TNF-α). In addition, physicochemical properties were adjusted to achieve desirable in vivo pharmacokinetic and pharmacodynamic properties. GS-9620 is currently in clinical evaluation for the treatment of chronic hepatitis B (HBV) infection.

An overview of the chemistry and biology of the diterpene natural products known as the furanocembranoids, pseudopteranes, and gersolanes is provided; 85 references are cited.

The asymmetric total synthesis of (-)-bipinnatin J and its conversion into (+)-intricarene through a transannular 1,3-dipolar cycloaddition is described. In addition, the conversion of (-)-bipinnatin J into (+)-rubifolide and (+)-isoepilophodione B is reported. Biosynthetic relationships among furanocembranoids and the possible role of 1,3-dipolar cycloadditions in biosynthesis are discussed. [reaction: see text]

A highly convergent synthesis of archazolid B, a potent and highly selective V-ATPase inhibitor, is described. A relay ring-closing metathesis reaction was used to form the 24-membered macrocyclic lactone, whereas the sensitive cis-triene moiety of the archazolids was assembled with a modified Stille coupling.The archazolids are a family of unsaturated polyketides with low nanomolar inhibitory activity and excellent selectivity against mammalian V-ATPases (Scheme 1). 1 The isolation of archazolids A (1) and B (2) from the myxobacterium Archangium gephyra and the constitutions of these natural products were reported by Höfle et al. several years ago. 2 In 2006, Menche and coworkers disclosed the relative and absolute configurations of 1 and 2, which were obtained through careful analysis of 13 C-1 H coupling constants combined with degradation studies. 1b Shortly thereafter, this impressive exercise in structure elucidation was matched by a total synthesis of archazolid A. 3 The structure of archazolid C (3), the βglucoside of archazolid A isolated from the myxobacterium Cystobacter violaceus, was also disclosed in 2007. 4 We now report an efficient total synthesis of archazolid B, the least stable and least abundant member of the family.The archazolids attracted our interest due to their exceptional bioactivity and unusual structural features. Their 24-membered macrolactone ring includes a rare cis-triene moiety, whose chemistry we were familiar with from our previous work on highly unsaturated pyrone polyketides. 5 From the outset, our synthetic plan was governed by a desire to install the (Z,Z,E)-triene unit as late as possible to avoid potentially troublesome (cyclo)isomerizations. As our plan for archazolid B unfolded, however, we found it more appealing to close the 24-membered macrolactone through ring-closing metathesis (RCM), rather than intramolecular cross-coupling reactions (Scheme 1). 6,7 This strategy would confine protecting group operations and oxidation state adjustments to a minimum. We had doubts however, whether a "simple" RCM involving diene 4a (R = H) would initiate at the more electron rich diene moiety rather than at the other terminal alkene, which would presumably result in an unproductive excision of an unsaturated δ-lactone. Therefore, we decided to promote the desired initiation through relay-ring closing metathesis (RRCM) using 4b as a precursor [R = (CH 2 ) 3 CH=CH 2 ].

[reaction: see text] A nine-step, stereoselective synthesis of bipinnatin J is described, which features a ruthenium-catalyzed Alder-ene reaction, a Stille cross coupling, and an intramolecular Nozaki-Hiyama-Kishi allylation as key steps. The biosynthetic relationship between bipinnatin J and complex polycyclic diterpenes isolated from gorgonian corals is discussed.