Chemo- and site-selective derivatizations of natural products enabling biological studies

Abstract

Bioactive natural products and derivatives remain an enduring starting point for the discovery of new cellular targets for disease intervention and lead compounds for the development of new therapeutic agents. The former goal is accomplished through the synthesis of bioactive cellular probes from natural products, enabling insights into the mechanism of action of these natural products by classical affinity chromatography or more recent proteome profiling methods. However, the direct and selective modification of native natural products for these purposes remains a challenge due to the structural complexity and the wide functional group diversity found in these natural substances. The lack of selective synthetic methods available to directly manipulate unprotected complex small molecules, in particular to perform structure-activity relationship studies and prepare appropriate cellular probes, has recently begun to be addressed, benefitting from the broader emerging area of chemoselective synthetic methodology. Thus, new reagents, catalysts and reaction processes are enabling both chemo- and site-selective modifications of complex, native natural products. In this review, we describe selected recent examples of these functionalization strategies in this emerging area.

Figure 1

Bioactivity and cellular target identification of eupalmerin acetate through CH amination by Romo and Cravatt.

Scheme 1

Site-selective acylation of erythromycin by S. Miller and amphotericin B by Burke.

Scheme 2

Romo and Liu’s simultaneous arming/SAR studies of alcohol-containing natural products by Rh(II)-catalyzed O–H insertions with diazo esters.

Scheme 3

Mild halogenations by Romo and site-selective halogenations by S. Miller of arene containing-natural products.

Scheme 4

Romo’s simultaneous SAR/arming studies through cyclopropanation of olefin-containing natural products.

Scheme 5

S. Miller’s site-selective epoxidation of polyene-containing natural products.

Scheme 6

M. Miller’s nitroso Diels-Alder reactions for the selective derivatization of diene-containing natural products.

Scheme 7

Romo and Cravatt’s simultaneous arming/SAR studies via C- and N- amination and alkene aziridination of natural products.

Scheme 8

Ritter’s late-stage fluorination and White’s C-H oxidation of natural products.

Scheme 9

S. Miller’s deoxygenation of alcohols based on peptide-catalyzed, site-selective thiocarbonylations and phosphoramidite transfers.

Scheme 10

Myer’s aryl carboxylate Pd(II) reagents for alkene labelling in aqueous media.

Scheme 11

Romo’s synthesis of an FK506-biotin conjugate from O–H insertion derivatization.

Scheme 12

Romo’s synthesis of forskolin and bexarotene-biotin conjugates through cyclopropanation derivatization.

Scheme 13

Site-selective acylations of apoptodilin A by Miller and Wender.

Scheme 14

Romo/Robles’ microscale derivatization of resiniferatoxin.

Scheme 15

Baran’s C–H functionalization of natural products and pharmaceuticals with azide-terminated linkers.