Total Synthesis of Belizentrin Methyl Ester: Report on a Likely Conquest

Abstract

Preparation of the Tetrahydrofuran Segment (S)-5-(Hydroxymethyl)dihydrofuran-2(3H)-one (S-2). conc. aq. HCl (25 mL) was slowly added to a stirred solution of L-glutamic acid 3 (25.0g, 170 mmol) in water (60 mL) at ambient temperature. The resulting solution was cooled to 0 °C before a solution of NaNO 2 (15.2 g, 221 mmol) in water (80.0 mL) was added dropwise over the course of 45 min, causing a gentle evolution of N 2 gas. Once the addition of NaNO 2 was complete the colorless mixture was warmed to ambient temperature and stirring was continued for 23 h. The solvents were evaporated and the resulting white solid was triturated with EtOAc (100 mL) and filtered off. The filter cake was washed with EtOAc (2 x 100 mL) and the combined filtrates were dried over anhydrous Na 2 SO 4. The drying agent was filtered off and the solvent was evaporated to give acid S-1 as a white solid (17.5 g, 79%) which was used in the next step without further purification. BH 3 •SMe 2 (15.2 mL, 170 mmol) was slowly added to a stirred solution of the crude carboxylic acid S-1 (17.5 g, 170 mmol) in THF (280 mL) at 0 °C over the course of 15 min. Once the addition of BH 3 •SMe 2 was complete, the resulting mixture was allowed to reach ambient temperature and stirring was continued for 18 h. The mixture was cooled to 0 °C and the reaction was quenched with MeOH (70 mL). The solvents were evaporated and the resulting oil was passed through a short plug of Celite ® , eluting with EtOAc. Evaporation of the combined filtrates afforded compound S-2 as a white solid (10.8 g, 69%). 1 H NMR (400 MHz,

Total Synthesis of Limaol

“… 7 Although the isolation team did not mention any particular stability issues, it seemed prudent to bear the nonthermodynamic character of this peculiar motif in mind during retrosynthetic planning ( Scheme 2 ). A late-stage attachment of the polyunsaturated side chain to the core region seemed advisible, 8 − 10 preferably by cross-coupling of an alkenyl nucleophile with an allylic electrophile under essentially neutral conditions to minimize the risk of deleterious rearrangement into a partly or fully conjugated tetraene. For the same reasons, it was planned to use only silyl protecting groups to avoid (strongly) acidic, basic, oxidative, or reductive conditions during global deprotection.…”

“…For the synthesis of the central fragment, cheap 20 was subjected to C-glycosylation with allyltrimethylsilane on multigram scale 8 and the resulting primary product was elaborated into aldehyde 22 by standard protecting group and oxidation state management ( Scheme 4 ). When reacted with allenylboronate 33 in the presence of catalytic ( R )-3,3′-dibromo-BINOL ( 32 ), the desired homopropargyl alcohol 23 was obtained as a single diastereomer (96%, 1 mmol scale).…”

Lessons from Natural Product Total Synthesis: Macrocyclization and Postcyclization Strategies

“…Desired macrolactam 19 was indeed cleanly formed, but the reaction invariably stalled at about 60% conversion. Control experiments proved that this outcome is due to reversible amide bond formation in this case: 26 the alcohol group in 19 is poised to snap back and close the original spirolactone. Despite the formation of an equilibrium mixture, this key step proved robust and allowed the first total synthesis of this intricate natural product to be completed.…”

“…Inherent instability also overshadowed our pursuit of the methyl ester of potently neurotoxic, dinoflagellate-derived compound belizentrin ( 22 ). 25 Its scaffold provides several opportunities for macrocyclization: 26 after careful consideration, we opted for macrolactamization rather than macrolactonization or C–C bond formation, not the least because we saw a possibility to effect this step by an intramolecular aminolysis of a lactone precursor; such a tactic is exceedingly rare in the literature.…”

Total Synthesis of (±)-Sceptrin

“…Building block 9 was prepared by initial hydroboration of commercially available N -Boc-propargylamine ( 6 ) with dicyclohexylborane (Cy 2 BH) and pinacolborane (HBpin) to give the known vinylboronic pinacol ester 7 . 16 A tandem Suzuki–Miyaura cross-coupling 17 was executed by reaction with aqueous potassium carbonate (K 2 CO 3 ), 3-bromoimidazopyrimidine ( 8 ), and bis(triphenylphosphine)palladium(II) dichloride (5 mol %) in refluxing tetrahydrofuran (THF) to deliver monomer 9 in 63% yield (one pot). The key dimerization was best accomplished by irradiating a methanolic solution of 9 with blue LEDs (440–450 nm) in the presence of catalytic Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (1.8 mol %).…”