Synthesis of Ovalicin Starting from d-Mannose

Abstract

[reaction: see text] A new synthesis of epoxyketone 22 is described that is a key intermediate in Barton's synthesis of ovalicin (2), a powerful anti-angiogenetic inhibitor. The key process for the construction of 22 was ring-closing metathesis of olefins 11 and 12 obtained from 2,3:5,6-di-O-isopropylidene-alpha-D-mannofuranose (4) and regioselective desilylation of tri-TES ether 19. Furthermore, an alternative stereoselective route from 22 into 2 has also been developed, and the overall yield of 2 from 4 was 10.0%.

Syntheses of Fumagillin and Ovalicin

“…[25b] In the following years, five syntheses of 7 were reported by the groups of Pollini, [27] Takahashi, [28] Hayashi, [22] Mulzer, [29] and Yadav. [30] The key traits of each synthesis are summarized in Figure 3.…”

“…Takahashis synthesis: [28] Takahashis ovalicin synthesis in 2005 utilized a readily available, chiral-pool-derived d-mannose to construct the complex cyclohexane ring (Scheme 15). The synthesis commenced with regioselective silylation of alcohol 152 (obtained from mannose derivative 151 in 76 % yield) [63] to give the silyl-protected species 153 in 85 % yield.…”

“…[28] An interesting note, however, is that although Mulzers group utilized the same vinyllithium species 47, they had prepared it by an alternative method to Coreys original procedure. [25a, 41] Whereas Coreys group made use of a Shapiro reaction and used acetone sulfonylhydrazone to forge 47, Mulzers group modified, in a few steps, a vinylstannane that was used in Tabers synthesis [18] (i.e., the desilylated form of 39), which originally arose from 2,3-dihydrofuran.…”

Oxidation of Alcohols, Carbohydrates and Diols

“…[170]; the vinca alkaloid (+)-catharanthine [171]; 2-epibotcinolide (primary alcohol to aldehyde TPAP oxidation also involved) [89]; the spirobicyclic sesquiterpene (±)-erythrodiene (nitro to ketone oxidation also involved; cf. 5.6.4) [172]; a secondary alcohol to an enone as a step in the synthesis of the biologically active sequiterpene (−)-diversifolin [51]; the cytotoxic fasicularin [173]; the limonoid fraxinellone [174]; the plasmodial pigment fuligorubin A [160]; the antifungal gambieric acids A and C (also a primary alcohol to aldehyde step) [90]; the ether toxin gambierol (two primary alcohol to aldehyde steps) [91]; the cytotoxic gymnocin-A (also a primary to aldehyde step) [92]; the alkaloid (±)-lapidilectine B [175]; the antiparasitic and insecticide (+)-milbemycin-b 1 , (involving both oxidation of a primary alcohol group to an aldehyde and, in a later step, of a secondary alcohol to a ketone) [98]; the acetogenin muricatetrocin C [176] and the sesquiterpenes nortrilobolide, thapsivillosin F and trilobolide [64]; the glutamate receptor neodysiherbaine [177]; the marine alkaloid norzoanthamine (primary alcohol to aldehyde step also) [99]; the anticarcinogenic agent ovalicin [178]; the cytotoxic agent phorboxazole (hemi-acetal to lactone) [179]; the antibacterial agent pseudomonic acid C [180]; the antifungal agent rapamycin (cf. 1.11) [181,182]; the antigen daphane diterpene (+)-resiniferatoxin [183]; the antitumour macrolide (+)-rhizoxin D [184]; the heliobactericidal (+)-spirolaxine methyl ether [185]; the SERCA thapsigargin inhibitors [112,152,153]; the antitumour agent tonatzitlolone [186] and the therapeutic hypercholesterolemia agent zaragozic acid A [187].…”

Total syntheses of (±)-ovalicin, C4(S∗)-isomer, and its C5-analogs and anti-trypanosomal activities

“…Our retrosynthetic analysis of ovalicin (1) is depicted in Scheme 1 utilizing compound 2, a key intermediate reported by Barton 8 and others,10,12 because the stereochemistry at C5 and 6 of compound 2 controls the stereochemistry at C4 of 1 in the subsequent addition reaction. Compound 2 is synthesized via an epoxidation of the exo-methylene function of diene 3 followed by dihydoxylation and functional group transformation.…”