Diversonol

Diversonol (97), a fungal metabolite, was isolated by Turner from Penicillium diversum and its structural motif has also been found in some mycotoxins such as secalonic acids with interesting biological activity. Therefore, the total synthesis of diversonol will also promote the total synthesis of these 

In 1978, Turner reported the isolation of several fungal metabolites, including a compound from the phenolic fraction of cultured Penicillium diversum that was named subsequently diversonol (932) 642). It was not made clear in the initial publication if diversonol (932) was obtained as a racemate or, if this was not the case, the absolute configuration. Mention was made in this initial publication to X-ray crystallographic data that were to be reported later, but it evidently such work did not come to completion (Fig. 13.12). 

Michael-aAAition of methyl cyanocuprate to afford 290. Debrominatioii and diastereoselective oxidation with manganese monoperoxophthalate gave alcohol 292, which was deprotected and finally reduced to give the polyhydroxylated core, and thus racemic diversonol (932), in ten steps starting from 4-hydroxycyclohexen-2-one (266). 

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Tetrahydroxanthones from fungi include the blennolides (895-901), dihydroglobo-suxanthone (931) (632), diversonol (932) and the diversonolic esters (972, 973) (Fig. 13.15). Tetrahydroxanthones are the monomeric components of interesting mycotoxins such as the beticolins (1063-1070) and the secalonic acids (1034-1046) (see Sect. 13.5.3). 

In 2008, Nicolaou and Li reported the synthesis of blennolide C (897), in addition to the racemic synthesis of diversonol (932) and the diversonolic esters... 

Krohn and co-workers reported in 2009 the isolation of 3,4-dihydroglobosuxanthone A (931) as a result of their reinvestigation of a. Microdiplodia sp. (559). As with the diversonolic esters (A and B, 972, 973) (Fig. 13.15) this compound has the methyl ester located at the C-1 position, rather than the usual C-4a position, as foxmd for remaining monomeric and dimeric members of the tetrahydroxanthone family. This compound was demonstrated to have potent antibacterial activity against Escherichia coli. Bacillus megaterium, and Chlorellafusca (Fig. 13.11). 

Diversonol (932) was selected as a target by the Erase group in their ongoing studies on the synthesis of the secalonic acids (1034-1046) and related natural products 556,560-566), and the successful synthesis of the racemate was reported in 2006 643). The synthesis started with the synthetic intermediate 270 (Scheme 13.13), common with the group s synthesis of blennolide C (897) (see Scheme 13.9). Enone substrate 270 was doubly activated for diastereoselective... 

Scheme 13.13 Brdse s synthesis of diversonol (932). Reagents and conditions a) MeLi, CuCN, Et20, —78°C, 5 h, 52% b) t-BuLi, THF, —78°C, NaHCOs, 4 h, 93% c) manganese monoperoxo-phthalate, EtOH, rt, 5 h, 57% d) BBra, CHjCb, rt, 7 h, 40% e) NaBR, MeOH, -78°C, 0.3 h, 66%...

In 2008, Nicolaou andLi reported a synthesis of diversonol (932) (Scheme 13.14) (635). The synthesis involved the nucleophilic addition of a lithiated cyclohexene species derived from bromide 938 with the allyl-protected aldehyde 939, followed by oxidation, desilylation, deallylation, and spontaneous xanthone-ring closure of the intermediate phenol (not shown). As in the Brdse synthesis, the enol moiety is oxidized and the C-ring ketone reduced with NaBH4 to generate diversonol (932), which was obtained in eight steps from cyclohexenone 937. 

Scheme 13.14 Nicolaou synthesis of diversonol (932). Reagents and conditions a) Br2, Et3N, 90% b) DiBAL-H, 95% c) MeLi, t-BuLi then aldehyde d) IBX, DMSO, it, 1 h, 72% (two steps) e) HF pyridine, THF, it, 96% f) n-Bu3SnH, Pd(PPh3)4, benzene, it, 90% g) magnesium monoperoxophthalate, EtOH, rt h) NaBILt, MeOH, CH2CI2, —78°C, 0.3 h, 73%, two steps...

The final steps involved demethylation with boron tribromide, then a sequence of oxidation and reduction steps taken directly from the Nicolaou racemic synthesis (635), dehvering the unnatural isomer of diversonol (ent-932), with a superimpos-able CD spectrum to that supphed by Krohn and coworkers of the natural product (647). Hence, natural diversonol (932) is the enantiomer of the product ent-932 shown in Scheme 13.17, namely, that of (5S, 5a5,85,8af ) configuration. Also in this study, the chromone lactones lachnone C (969) and cp/-lachnone C (not shown) were synthesized enantioselectively for the first time, utihzing common synthesis intermediates (Fig. 13.14). 

In 1983 Holker, Simpson, and O Brien reported the isolation of the diversonolic esters (972, 973) (Fig. 13.15), which they obtained from Penicillium diversum, along with lichexanthone (840a) and several other known compounds (634). The authors performed a structural analysis for these new compounds based on methyl-ation, proton-NMR analysis, chelate ferric effects, and other spectroscopic techniques, which led to the assignment of the structures of these new compounds as 970 and 971. These substances appear reminiscent of hemisecalOTiic acids (ergochrome monomers), but the structures originally proposed were later found to be incorrect (see below). 

Twenty-five years later, the racemic syntheses of diversonolic esters (972, 973) were reported by Nicolaou and Li, almig with the synthesis of blennolide C (897) and diversonol (932) (see entries above) (S5). In a twist of good fortune, the use of MOM-protecting groups as an alternative to allyl groups (see diversonol synthesis)... 

Holker JSE, O Brien E, Simpson TJ (1983) The Structures of Some Metabolites of Penicil-lium diversum a-and (3-Diversonolic esters. J Chem Soc Perkin Trans 1 1365... 

Nicolaou KC, Li A (2008) Total Syntheses and Structural Revision of a- and p-Diversonolic esters and Total Syntheses of Diversonol and Blennolide C. Angew Chem Int Ed 47 6579... 

Gerard EMC, Brase S (2008) Modular Syntheses of Diversonol-type Tetrahydroxanthone Mycotoxins Blennolide C (epi-Hemirugulotrosin A) and Analogues. Chem Eur J 14 8086... 

Turner WB (1978) The Isolation and Structures of the Fungal Metabolites Lapidosin and Diversonol. J Chem Soc Perkin Trans 1 1621... 

Nising CF, Ohnemuller (nee Schmid) UK, Brase S (2006) The Total Synthesis of the Fungal Metabolite Diversonol. Angew Chem 45 307... 

Brohmer MC, Bourcet E, Nieger M, Brase S (2011) A Unified Strategy for the Asymmetric S mthesis of Diversonol and Lachnone C. Chem Eur J 49 13706. 

Scheme 7.40 Domino reactions for an asymmetric syntheses of diversonol and lachnone C.

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