Nodulisporic acid side-Chain modifications: access to the 2″, 3″, 4″, and 6″ registers

Total Synthesis of (−)-Nodulisporic Acids D, C, and B: Evolution of a Unified Synthetic Strategy

“…Subsequent structure–activity relationship studies at Merck revealed that the highly substituted indole core and secondary C(24) hydroxyl group are the key structural elements required for the insecticidal activity . These two functionalities, in conjugation with the dienoate side chain, also lead to significant instability both in vitro and in vivo; , for example, the C(24) hydroxyl group undergoes facile dehydration mediated by the carboxylic acid, while exposure to air leads to oxidative ring opening of the indole core. , This sensitivity pattern clearly conspires to add significant chemical challenge vis-à-vis structural modifications and/or synthetic strategies toward the nodulisporic acids. , …”

“…Shortly after the Merck structural/medicinal chemistry program, , we launched synthetic studies toward the total synthesis of members of the nodulisporic acid family. From the outset, this program had two major goals: (1) the construction of the highly strained CDE tricyclic indole–indoline scaffold found only in these natural products and (2) the development of a unified synthetic strategy to obtain not only the naturally occurring nodulisporic acids but also unnatural analogues.…”

“…1a,c This sensitivity pattern clearly conspires to add significant chemical challenge vis-a-vis structural modifications and/or synthetic strategies towards the nodulisporic acids. 5,6…”

Development of a Scalable Synthesis of a Common Eastern Tricyclic Lactone for Construction of the Nodulisporic Acids

“…A medicinal chemistry campaign, in conjunction with a chemical mutagenesis program, was thus launched at Merck & Co. to develop (+)- 1 as a novel anti-flea therapeutic agent for companion animals. To date over 1000 synthetic analogues have been prepared. , …”

A New Modular Indole Synthesis. Construction of the Highly Strained CDEF Parent Tetracycle of Nodulisporic Acids A and B

“…Although exhibiting good in vitro and in vivo activity against fleas, the potency, stability, and pharmacokinetic profile were not optimal; Merck and Co. therefore launched a medicinal chemistry campaign to optimize the profile of this lead compound. A chemical mutagenesis program was also initiated to prepare a large number (>1000) of analogues . To date, however, none of the reported analogues exhibit more potency than (+)- 1 , although some improvement in pharmacokinetic properties has been achieved.…”