Emulating the logic of monoterpenoid alkaloid biogenesis to access a skeletally diverse chemical library

Abstract

We have developed a synthetic strategy that mimics the diversity-generating power of monoterpenoid indole alkaloid biosynthesis. Our general approach goes beyond diversification of a single natural product-like substructure and enables production of a highly diverse collection of small molecules. The reaction sequence begins with rapid and highly modular assembly of the tetracyclic indoloquinolizidine core, which can be chemoselectively processed into several additional skeletally diverse structural frameworks. The general utility of this approach was demonstrated by parallel synthesis of two representative chemical libraries containing 847 compounds with favorable physicochemical properties to enable its subsequent broad pharmacological evaluation.

Figure 1

A. Biosynthetic interconversions of representative monoterpenoid indole alkaloids via intermediacy of strictosidine 3. B. Synthetic strategy to a skeletally diverse chemical library via rapid assembly and subsequent transformations of indoloquinolizidine 10, which served as a biomimetic branching point.

Figure 2

Synthesis of 476-Member Library of Indoloquinolizidines. The assembly process entailed two chromatographic steps, inculding initial purification of each of the fourty acids 10 and subsequent LCMS purification of all final library members 17.

Figure 3

Synthesis of 371-member skeletally diverse small-molecule library. The assembly process mimics skeletal branching of monoterpenoid alkaloid biosynthesis and enables efficient conversion of the initially produced set of 96 indoloquinolizidines 17 into collections of skeletally distinct polycyclic products 12, 13 and 14. The figure shows structures of building blocks used for library generation, depicts reaction conditions and scales, average yields, molecular weights, chemical purities as well as LogP distributions.

Scheme 1

One-Flask Synthesis of Indoloquinolizidine 10a

Scheme 2

One-Flask Synthesis of Indoloquinolizidine 10b

Scheme 3

Synthesis of Hydroxyindoline 11a

Scheme 4

Synthesis of Spirocyclic Dihydroindolone 12a

Scheme 5

Synthesis of Tricyclic Ketone 13a

Scheme 6

Synthesis of Pyrroloquinolone 14a