Synthesis of (±)-Eusynstyelamide A

Abstract

The synthesis of (±)-eusynstyelamide A has been accomplished in six steps in 13% overall yield from 6-bromoindole, methyl glycidate, and Boc-protected agmatine. If oxygen is carefully excluded from the reaction, the key NaOH-catalyzed aldol dimerization of the α-ketoamide proceeded efficiently to give Boc-protected eusynstyelamide A.Tapiolas and co-workers recently reported the isolation of eusynstyelamides A (1), B (2), and C (3) from the Great Barrier Reef ascidian Eusynstyela latericius and assigned their structures from analysis of the spectral data (see Figure 1). 1 The spectral data for 1 are virtually identical to those reported for eusynstyelamide (4), isolated from E. misakiensis ,2 indicating that the structure of 4 should be reassigned as 1, rather than the acyclic ketone dihydrate. Eusynstyelamides A-C (1-3) inhibit neuronal nitric oxide synthase (nNOS), with IC 50 values * snider@brandeis.edu . Supporting Information Available: Complete experimental procedures, comparison of the NMR spectral data of natural and synthetic eusynstyelamide A, and copies of 1 H and 13 C NMR spectral data. This material is available free of charge via the Internet at http://pubs.acs.org. We were intrigued by these structures because the dihydroxybutyrolactam core is identical to that of anchinopeptolide D (7b), which we synthesized several years ago (see Scheme 1). 3 α-Ketoamide 5 underwent an aldol dimerization on treatment with KOH in THF/MeOH. The amide nitrogen of the initially formed aldol adduct cyclized to the remaining ketone to form a dihydroxybutyrolactam. The phenol acetate was also hydrolyzed under these reaction conditions. We isolated three of the four possible diastereomeric products. The major product was anchinopeptolide D precursor 7a, which was formed in 58% yield. Lactam 6a, which was isolated in 19% yield, has the opposite stereochemistry at the hemiaminal center, but was formed from the same aldol adduct 10 (see Scheme 2) as 7a. The third product 8a, which was isolated in <5% yield, was formed from the diastereomeric aldol product. Cleavage of the four Boc groups of 6a and 7a in 1:1 TFA/CH 2 Cl 2 for 1 h at 25 °C afforded 6b (94%) and anchinopeptolide D (7b, 91%), respectively. NIH Public AccessThe stereochemistry of the major aldol adduct 10 can be rationalized by consideration of a chelated transition state for the aldol reaction. Enolization should give the Z-enolate to avoid steric interactions between the amide and the R 1 substituent. Transition state 9, which leads to aldol product 10, might be favored for the aldol reaction since the metal can bind to all four oxygens. The amide nitrogen of adduct 10 can then add to either face of the ketone carbonyl group to give products 6 or 7.As expected, equilibration occurred readily at the hemiaminal center. Heating either 6a or 7a at reflux in CD 3 OD for 1 h afforded an equilibrium 2:1 mixture of 6a and 7a, presumably by ring opening to give the aldol adduct 10. Equilibration of either 6a or 7a with KOH in THF/ MeOH for 17 h at 25 °C afforde...

Synthesis of Phidianidines A and B

“…1 The mode of action is not known, but the closely related dodecylguanidinium acetate ( 4 , dodine) has been in widespread use since 1956 as a fungicide and may act by membrane disruption. 3 As part of an ongoing program in the synthesis of structurally novel guanidine-containing natural products, 4 we planned to prepare phidianidines A ( 1a ) and B ( 1b ) by coupling of the appropriate ethyl indole-3-acetate ( 2a or 2b ) with hydroxyguanidine 3 containing a suitably protected nitrogen on the other end of the five carbon side chain. There is limited precedent for the synthesis of 3-amino-1,2,4-oxadiazoles by coupling of esters with hydroxyguanidines 5 and nature may use a related route for the biosynthesis of the phidianidines.…”

“…Eventually we found that reduction of the azide with activated zinc 10 and ammonium formate in MeOH for 7 h at 25 °C proceeded cleanly to give polar amine 12b that was used without purification. 11a Coupling of 12b with Boc-protected S -methylisothiourea 13 using Et 3 N and AgNO 3 4b, 12 in DMF for 2 h at 0 °C and 5 h at 25 °C afforded protected guanidine 14b in 60% yield from 11b . Deprotection of 14b by stirring in 10:1 CH 2 Cl 2 /TFA for 8 h at 25 °C removed the Boc protecting groups providing phidianidine B ( 1b ) in 92% yield.…”

Chemical Insights into the Anchinopeptolide Series

“…3 ), may originate from the condensation of two β‐ketoamides. This hypothesis was strengthened by Snider's et al “biomimetic” syntheses of anchinopeptolide D ( 1d ), and eusynstyelamide A ( 3 ) . In their seminal study, Minale et al also reported the isolation of cycloanchinopeptolide C ( 2c ), obviously formed by an intramolecular [2+2] cycloaddition from anchinopeptolide C ( 1c ).…”

“…This hypothesis was strengthened by Snider's et al "biomimetic" syntheses of anchinopeptolide D (1d), [6] and eusynstyelamide A (3). [7] In their seminal study, Minale et al also reported the isolation of cycloanchinopeptolide C (2c), [2] obviously formed by an intramolecular [2+2] cycloaddition from anchinopeptolide C (1c). Later, Snider et al could synthesize the non-natural cycloanchinopeptolide D (2d) thereby giving clues concerning the origin of the natural cycloanchinopeptolide C. Herein, we report our reinvestigation of the Mediterranean sponge Phorbas tenacior providing i-new insight into the stereocontrol in the biosynthesis of the central pyrrolidinone ring with the structure elucidation of the new anchinopeptolide E (1e) and ii-conclusions concerning the origin of cycloanchinopeptolide C (2c).…”

Facile Synthesis of Glycidates via Oxidation of Acrylates with Aqueous Solution of NaOCl in the Presence of Ammonium Salts

“…[5][6][7]9,17 Typical oxidants employed for this oxidation are NaOCl, 5-10 dimethyldioxirane, 11 t-BuOOH with BuLi, 12,13 and H 2 O 2 with hetero-polyacid 14 or Mn 15 catalysts and NaHCO 3 as the activator. The appropriate choice of ammonium salts fitting to the polarity of the substrates and the reaction under slightly basic conditions were essential for efficient reactions.…”