Short and Efficient Synthesis of Cadiolide B

Abstract

The first synthesis of cadiolide B has been achieved in 6 steps and 42% overall yield from 4-bromo-2(5H)-furanone. The pathway involves sequential, regiocontrolled introduction of the three furanone substituents by means of aldol reactions and Suzuki cross coupling.Reported by Ireland in 1998, 1 cadiolides A and B (1, 2) are a pair of densely functionalized 3,4,5-trisubstituted furanones obtained from an Indonesian ascidian of the genus Botryllus ( Figure 1). Structurally, the cadiolides belong to a family of biogenetically related non-nitrogenous marine metabolites derived from phenylalanine or tyrosine that includes the antibiotic rubrolides, 2-4 exemplified by rubrolide A (3), which was also isolated from Botryllus sp. 1 Although both cadiolides and rubrolides share the same 4-aryl-5-arylmethylenefuranone unit, the former are distinguished by an additional 3-ketoaryl substituent and a novel carbon skeleton. These unusual structural features along with the useful biological activities of related lactones, such as Merck's selective COX-2 inhibitor rofecoxib (VIOXX ® , 4), 5 make cadiolides worthwhile targets for synthesis.In keeping with our interest in the expedient construction of arylfuranones, 3 we now report the first synthesis of cadiolide B which demonstrates a new pathway for regiocontrolled assemblage of 3-ketoaryl-4-aryl-5-arylmethylenefuranones.The starting point of our synthesis is the readily available 4-bromo-2(5H)-furanone 6 (5, Scheme 1). Attachment of the requisite C3-substituent was accomplished by conversion of 5 to the corresponding dibutylboron 2-furanolate using n-Bu 2 BOTf in the presence of di-isopropylethylamine, 7 followed by in situ aldolization with p-anisaldehyde. In contrast to previous experience with aliphatic aldehydes which provided excellent yields of 3-(1-hydroxyalkyl)furanones under the same conditions, 7 the desired alcohol 6 was obtained only in modest yield (43%). We reasoned that 6 may be prone to base-induced decomposition by a retroaldol reaction which could conceivably be suppressed by the use of a weaker base. Indeed, when diisopropylethylamine was replaced by 2,6-lutidine the yield of 6 was improved to 64%. 8With a supply of 6 in hand, we initially explored its conversion to 8 by oxidation to the corresponding ketone (not shown) followed by Pd(0)-catalyzed cross coupling with 4-methoxyphenylboronic acid. 3 This sequence, however, proved to be problematic due to the low yield and/or instability of the intermediate ketone. Accordingly, we decided to perform cross coupling before oxidation, as depicted in Scheme 1. Although we had previously found the original Suzuki regimen [Pd(PPh 3 ) 4 , aq Na 2 CO 3 , PhH, EtOH, 80°C] to work well for arylating simple 4-bromo-2(5H)-furanones, 3 the propensity of 6 to undergo base-catalyzed retroaldol reaction (vide supra) entailed the use of a milder procedure. Gratifyingly, adaptation of Johnson's protocol 9,10 [PdCl 2 (PhCN) 2 , Ag 2 O, AsPh 3 , aq THF, 23°C] delivered the desired alcohol 7 in 86% yield after purification by flash...

Versatile Synthesis of Acylfuranones by Reaction of Acylketenes with α‐Hydroxy Ketones: Application to the One‐Step Multicomponent Synthesis of Cadiolide B and Its Analogues

“…(5 Z )‐3‐(4‐Methoxybenzoyl)‐5‐(4‐methoxybenzylidene)‐4‐(4‐methoxyphenyl)furan‐2(5 H )‐one (34a): Following procedure I, α‐hydroxy ketone 2e (83 mg, 0.5 mmol), dioxinone 1d (234 mg, 1.0 mmol) and p ‐methoxybenzaldehyde ( 33 ; 0.06 mL, 0.5 mmol) were used to afford 34a as a yellow solid in 77 % yield (170 mg, 0.77 mmol) after purification by flash chromatography on silica gel (cyclohexane/EtOAc, 60:40). Analyses are similar to those described in the literature 21. M.p.…”

“…The crude product was purified by chromatography on silica gel by using cyclohexane/EtOAc (40:60) as eluent to give the acylfuranone 35 as a yellow solid in 94 % yield (79 mg, 0.20 mmol). Analyses are similar to those described in the literature 21. M.p.…”

“…Finally, cadiolide B was synthesized in an overall yield of 48 % from dioxinone 1d after removal of the methyl groups with BBr 3 and bromination21 of the phenolic groups (Scheme ).…”

Transition metals in organic synthesis: Highlights for the year 2005

“…Synthetic targets included, prodigiosines [198], chartelline alkaloids [199], eupomatilone-3 [200], 9,10-deoxytridachione [201], hamigeran B [202], leprapinic acid and calycin [203], dehydrocoelenterazine analogs [204], gymnocin A (Eq. (11)) [205], murrastifoline A [206], styelsamine C and norsegoline [207], trispheridine [208], dragmacin F [209], ningalin D [210], eupomatilones [211], lucilactaene [47], epoxyquinols A-C and epoxytwinol A [212], mukonine [213], cepharanone [214], ␣ v ␤ 3 antagonist [215], alternariol [216], core of roseophilin [21], (−)-callystatin A [217], dibenzo[c,p]chrysene [218], GABA agonist [219,220], diazonamide A [221], dityrosine, trityrosine, pulcherosine [222], lamellarin D [223], integramycin [224], (+)-discodermolide and analogues [225,226], AB-ring system of hexacyclinic acid [227], ␦-trans-tocotrienoloic acid [135], spirofungins [228], kwakhurin [229], toward (+)-and (−)-deplanchein [230], combretastatin analogs [231], diazonamide A [75], cadiolide B [232], pukeleimide A [233], toward apoptolidin [234], polycitone A and B …”

Inibição Do Crescimento De Microrganismos Patogênicos Induzida Por Butenolídeos Análogos Aos Cadiolídeos

“…Um aspecto importante sobre os cadiolídeos que são antimicrobianos é que todos os estudos realizados revelaram que esses compostos apresentam baixa atividade citotóxica. 10,[11][12][13][14][15] Em função das atividades listadas anteriormente, várias estratégias de síntese foram desenvolvidas para esses compostos (Esquema 1). [15][16][17][18] A primeira síntese total de um cadiolídeo foi relatada em 2005 (Esquema 1, Estratégia 1).…”