Structures, reactivities, and antibiotic properties of the marinopyrroles A-F

Abstract

Cultivation of actinomycete strain CNQ-418, retrieved from a deep ocean sediment sample off the coast of La Jolla, CA, has provided marinopyrroles A-F. Sharing just 98% 16S rRNA gene sequence identity with S. sannurensis, the strain likely represents a new Streptomyces species. The metabolites contain an unusual 1,3'-bipyrrole core decorated with several chlorine and bromine substituents and possess marked antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). The congested N,C-biaryl bond establishes an axis of chirality that, for marinopyrroles A-E, is configurationally stable at room temperature. Moreover, the natural products are fashioned strictly in the M-configuration. The Paal-Knorr condensation was adapted for the synthesis of the 1,3'-bipyrrole core. Halogenation of this material with N-bromosuccinimide cleanly furnished the 4,4',5,5'-tetrahalogenated core that characterizes this class of marine-derived metabolites.

Figure 1

Partial NMR-based structure of marinopyrrole A (1)

Figure 2

ORTEP drawing of marinopyrrole F (6)

Scheme 1

“Capping” the polar functionality in 1^{a a} Reagents and conditions: (a) Ac₂O, DMAP, pyr., rt, 62%; (b) Me₂SO₄, K₂CO₃, Me₂CO, rt, quant.; (c) CH₂N₂, ether, 0 °C, 86%. DMAP = 4-(dimethylamino)pyridine

Scheme 2

Nucleophilic aromatic substitution at C-5′^{a a} Reagents and conditions: (a) K₂CO₃, MeOH, 65 °C, 42% (63% b.o.r.s.m); (b) N-acetylcysteamine, K₂CO₃, DMF, 80 °C, 55%; (c) NMe₂, THF, 65 °C, 42%; (d) DMA, 145 °C, 62%; (e) NMe₂, THF, 55 °C, quant. DMF = N,N-dimethylformamide, DMA = N,N-dimethylacetamide. b.o.r.s.m. = based on recovered starting material.

Scheme 3

Imine formation at C-6

Scheme 4

Proposed Ullman coupling for the synthesis of (±)-1

Scheme 5

Synthesis of monodeoxypyoluteorin (10) and 3-halo analogues^{a a} Reagents and conditions: (a) aq. HCl, MeOH, rt, 83%; (b) NBS (1 equiv), DCE, 90 °C, 57%; (c) NIS, DCE, 90 °C, 65%; (d) NBS (2 equiv), DCE, 90 °C, 82%; (e) aq. HCl, MeOH, rt, 19: 94%, 20: 94%. NBS = N-bromosuccinimide, NIS = N-iodosuccinimide, DCE = 1,2-dichloroethane.

Scheme 6

1H-chromeno[3,2-b]pyrrol-9-one 25 via intramolecular Ullman reaction

Scheme 7

Synthesis of the tetrahalogenated 1,3′-bipyrrole core of the marinopyrroles^{a a} Reagents and conditions: (a) 1. 27, THF, −78 °C, 90%; 2. O₃, −78 °C, then Me₂S; (b) 29, THF, PTSA, 23% (two steps); (c) NBS, DCE, 90 °C, 86%. PTSA = p-toluenesulfonic acid, NBS = N-bromosuccinimide, DCE = 1,2-dichloroethane

Chart 1

Marinopyrroles A-F (1–6)

Chart 2

Axially chiral bipyrroles 7–9