Bouvardin and deoxybouvardin, antitumor cyclic hexapeptides from Bouvardia ternifolia (Rubiaceae)

Formal synthesis of piperazinomycin, a novel antifungal antibiotic

“…The acetone layer was concentrated under vacuum. Purification by column chromatography (silica, 7:3 hexane/EtOAc) provided arylbromide 5 as an off white solid (on storing at rt slowly became solid) (5.5 g, 96% yield), R f = 0.6 ( 7:3 ; heptanes/EtOAc), mp 66-70 °C, 1 Methyl 2-(tert-butoxycarbonyl)-3-(4-methoxy-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propanoate (6). Aryl bromide 5 (5 g, 12.88 mmol), bis (pinacolato) diboron (4.23 g, 16.75 mmol), KOAc (3.78 g, 38.65 mmol) and PdCl 2 (dppf) (0.525 g, 0.644 mmol) were suspended in dry 1, 2-dimethoxyethane (50 mL, degassed by sparging with N 2 ), and heated to 110 ºC for 18 h. Water (30 mL) and EtOAc (30 mL) were added.…”

“…The combined organic layers were dried (MgSO 4 ), filtered, and concentrated in vacuum. Purification by column chromatography (silica, 7:3 hexane/EtOAc) provided aryl boronate 6 as an off white solid (on storing at rt slowly became solid) (5 g, 90% yield), R f = 0.5 ( 7:3 ; heptanes/EtOAc), mp 92-95 °C, 1 …”

“…The mixture was stirred at room temperature for 24 h. To the reaction mixture ethyl acetate (50 ml) was added and organic layer was separated and concentrated. Purification by column chromatography (silica, 5:5 hexane/EtOAc) provided arylboronic acid 7 as an off white solid (on storing at rt slowly became solid) (3.6 g, 90% yield ), R f = 0.3 ( 5:5 ; heptanes/EtOAc), mp 95-100 °C, 1 …”

“…The aqueous layer was extracted with EtOAc ( 3X30 mL). The combined organic layers were dried (MgSO 4 ), filtered, and concentrated in vacuum to afford compound 8 as an off white solid (on storing at rt slowly became solid) (3.3 g, 96% yield), mp 98-102 °C, 1 2-(tert-butoxycarbonyl)-3-((S)-3-(4-hydroxyphenyl)-1-methoxy-1-oxopropan-2-ylamino)-3-oxopropyl)-2-methoxyphenylboronic acid (10). A suspension of 8 (3 g, 6.89 mmol) in dry DCM (50 mL) was added compound 9 (1.35 g, 6.89 mmol), EDCI (1.97 g, 10.34 mmol), HOBt (0.93g, 6.89 mmol) and DIPEA (1.33 g 10.34 mmol) at room temperature.…”

“…Piperazinomycin 1, constitutes the simplest naturally occurring agent possessing the parent 14-membered para-and metacyclophane diary1 ether structural subunit found in bouvardin, 1 deoxybouvardin, 1 RA-I-X, 2 OF4949-I-OF494-IV, 3 and K-13. 4 This has renewed the interest in the synthesis and evaluation of piperazinomycin and structurally related agents since 1 and notably 2.…”