Efficient construction of the securine A carbon skeleton

Abstract

Securamine A is a structurally intriguing alkaloid possessing a pyrroloindole core joined via a modified isoprene subunit to a functionalized imidazole ring. Recent synthetic efforts in this laboratory have resulted in the efficient construction of key lactone 36, which undergoes tandem azide reduction͞ring expansion to macrolactam 37. Macrolactam 37 possesses the complete macrocyclic core of securamine A. T he bryozoans Flustra foliacea and Chartella papyracea have proven to be a rich source of structurally unprecedented halogenated indole-alkaloids. A series of investigations resulted in the isolation of a host of novel natural products, including the flustramines (1-3) , chartellines (4-6), and chartellamides (7). Additionally, two reports describe the securamines (8, 9), which are characterized by a central tricyclic pyrroloindole core and a highly substituted imidazole ring linked via a modified isoprene subunit and a macrocyclic cis-enamide (Fig. 1). Interestingly, pyrroloindole securamine A (1) exists in a synthetically exploitable solvent-dependent equilibrium with ring-opened isomer securine A (2) (8, 9).Despite synthetic work toward both the flustramines (10-12) and chartellines͞chartellamides (13,14), no efforts toward the construction of the securamine͞securine skeleton have yet been reported (15,16). Intrigued by the densely functionalized heterocycles characterizing the securamines, in addition to reports that securine A serves as a biogenic precursor for a variety of other natural products (8, 9), we have focused our efforts on the efficient construction of 1 and 2.Retrosynthetically, securine A was visualized as the union of two heterocyclic subunits (pyrroloindole and imidazole) joined into a macrocycle via two tethers (the isoprene and enamide) (Fig. 2). We envisioned that the elimination-prone C(10) neopentyl chloride moiety (13,14) could be installed at a late stage via direct chlorination of the corresponding alcohol, whereas the sensitive enamide-moiety could be generated from a C(2)-C(3) amido-alcohol (5). Orthogonal diol 5 would arise via macrocyclization of the corresponding amino alcohol, which could be accessed directly from a C(2)-C(3) olefin (17, 18). Key indole 6 could be accessed from internal alkyne 7, which would be generated from elaboration of 8. Imidazole 8 could be derived from the condensation of two equivalents of formamide with ␣-bromo ketone 9 (19). MethodsUnless otherwise stated, reactions were performed in flamedried glassware under a nitrogen atmosphere by using freshly distilled solvents. Experimental and spectral data pertaining to compounds 7, 11-15, 18-20, 22, and 25-40 can be found in Supporting Text, which is published as supporting information on the PNAS web site. ResultsExposure of 10 to bromine and acetic acid gave smooth conversion to the corresponding ␣-bromoketone. Subsequent dissolution in neat formamide and prolonged heating gave imidazole 8 in 80% overall yield after two recrystallizations (19). Benzylation at N(5) and bromination at C(4) proceeded in a...

Secondary Metabolites from Marine Sources with Potential Use as Leads for Anticancer Applications

“…Securamines are halogenated indole-imidazole alkaloids characterized by a central tricyclic pyrroloindole core and a highly substituted imidazole ring linked via a modified isoprene subunit and a macrocyclic cis -enamide [ 49 , 50 ]. Examples of these compounds have been identified and isolated from Securiflustra securifrons (Pallas, 1766) , a marine bryozoan native to the North Sea ( Figure 1 ) [ 33 , 50 , 51 ].…”

Synthetic Studies on Chartelline C: Stereoselective Construction of the Core Skeleton

“…Our synthesis commenced with preparation of an imidazole unit bearing an alkyne moiety (14; Scheme 3). Diiodination of known imidazole 7 [9] with NIS followed by regioselective deiodination with sodium sulfite [10] led to formation of 5-iodoimidazole 8 in good yield. After protection of the imidazole with an SEM group, [11] the resultant iodide 9 was coupled with tributyl(vinyl)tin under standard Stille cross-coupling conditions to afford vinyl imidazole 10.…”

Studies toward the Synthesis of Chartelline C

“…To a solution of imidazole 2 (28.1 g, 0.154 mol) in CH 2 Cl 2 (500 mL) was added NBS (5.0 g, 0.028 mol) at 0 °C. After the mixture was stirred for 15 min at 0 °C, NBS (5.0 g, 0.028 mol) was added.…”

“…The synthesis of imidazole segment 9 commenced with the bromination of the known imidazole 2 with NBS followed by protection of the imidazole by an SEM group to give 3b (Scheme ). Suzuki–Miyaura coupling of 3b with vinyltrifluoroborate 4 gave vinylimidazole 5 in 89% yield; aminohydroxylation of which provided N -Boc amino alcohol 6 in 86% yield.…”