Biomimetic Total Synthesis of (+)-Nocardioazine B and Analogs

Abstract

Nocardioazines A and B are prenylated, bioactive pyrroloindoline natural products, isolated from Nocardiopsis, with a desymmetrized cyclo-D-Trp-D-Trp DKP core. Based on our deeper biosynthetic understanding, a biomimetic total synthesis of (+)-nocardioazine B is accomplished in merely seven steps and 23.2% overall yield. This pathway accesses regio-and stereoselectively C3-isoprenylated analogs of (+)-nocardioazine B, using the same number of steps and in similar efficiency. The successful strategy mandated that the biomimetic C3-prenylation step be executed early. The use of an unprotected carboxylic acid of Trp led to high diastereoselectivity toward formation of key intermediates exo-12a, exo-12b, and exo-12c (>19:1). Evidence shows that N1methylation causes the prenylation reaction to bifurcate away to result in a C2-normal-prenylated isomer. Nocardioazine A, possessing an isoprenoidal-epoxide bridge, inhibits P-glycoprotein (P-gp)-mediated membrane efflux, in multidrug-resistant mammalian colon cancer cells. As several P-gp inhibitors have failed due to their toxicity effects, endogenous amino-acid-derived noncytotoxic inhibitors (from the nocardioazine core) are worthy leads toward a rejuvenated strategy against resistant carcinomas. This total synthesis provides direct access to Trp-derived isoprenylated DKP natural products and their derivatives.

Unveiling an indole alkaloid diketopiperazine biosynthetic pathway that features a unique stereoisomerase and multifunctional methyltransferase

“…Observed products of these C 3 and C 3’ indole alkaloid DKP prenylation reactions all feature annulation. From our prior observation of annulation concomitant to C 3’ biomimetic indole alkaloid DKP prenylation reactions 27 – 29 , we infer that annulation is likely spontaneous following enzyme-catalyzed prenylation at C 3’.…”

“…Nocardioazine A ( 1 ) reverses drug resistance in cancer cell lines by acting as a noncytotoxic inhibitor of P-glycoprotein 24 . Hypotheses about the biosynthetic pathway for C 3’ prenylation inspired our prior biomimetic strategies to access the nocardioazines and related natural products 27 – 29 . Our earlier work also established that CDPSs NozA and NcdA from the noz and ncd genomic loci (Fig.…”

Support studies toward the hicksoane alkaloids reveal cascade reactions of a (tryptophanamido)methylglycinate

“…tert-Butyl 3-((tert-butoxycarbonyl)-D-tryptophyl)-4oxoimidazolidine-1-carboxylate (5) To a solution of (tert-butoxycarbonyl)-D-tryptophan 12 (409 mg, 1.34 mmol) in acetonitrile (10 mL) was added HATU (562 mg, 1.48 mmol) and the mixture was stirred at room temperature for 10 min. A solution of tert-butyl 4imidazolidinone 13 (4) (250 mg, 1.34 mmol) in acetonitrile (10 mL) was added slowly over 5 min.…”

“…Efforts focused on the initial synthetic strategy are shown in Scheme 2. Amide coupling between N -Boc- d -tryptophan 12 with the known imidazolidinone 4 13 gave 3-(tryptophyl)imidazolidin-4-one 5 that upon facile removal of both carbamate protecting groups gave 2 (as the dihydrochloride salt; 2·2HCl ), the substrate for the proposed cyclisation-ring expansion. Subjecting 2·2HCl to Brønsted (HCl, AcOH) and a Lewis acid (MgBr 2 ) revealed the substrate did not react at ambient temperature, with rapid degradation observed upon heating in several different solvents.…”

Marine natural products

“…[68][69][70][71] Two structural revisions of bacterial MNPs were reported in 2022; the absolute congurations of the cyclic peptides ogipeptin A 237 and tumescenamide A 238 were corrected via total synthesis. 72,73 Other total syntheses of bacterial NPs included cyanogramides A and C, 74 (±)-nesteretal A, 75 lucentamycin A together with barmumycin, oxotomaymycin and oxoprothracarcin, 76 rakicidin F, 77,78 anthracimycin and anthracimycin B, 79 xiamycins C-F, 80 seongsanamide E, 81 salimabromide, 82 (+)-nocardioazine B, 83 the indolocarbazole alkaloid ZHD-0501, 84 (±)-spiroindimicins A, D, G and H, 85 bahamaolide A, 86 aqabamycin G, 87 and elmonin and pratenone A. 88 Reviews focused on marine bacterial NPs published during 2022 included publications on the biosynthesis of microbial terpenoids, 89 polyketides and non-ribosomal peptides, 90 ribosomal peptides, 91 and the anthracyclines.…”