The Asymmetric Total Synthesis of Cinbotolide: A Revision of the Original Structure

Abstract

The structure 3,4-dihydroxy-2,4,6,8-tetramethyldec-8-enolide (1) was assigned to a metabolite of Botrytis cinerea, but the spectra of several synthetic analogues had significant differences from that of 1. Examination of the constituents of a B. cinerea mutant that overproduces polyketides gave sufficient quantities of 1, now named cinbotolide, for chemical transformations. These led to a revised γ-butyrolactone structure for the metabolite. This structure has been confirmed by an asymmetric total synthesis, which also established its absolute configuration.

Identification of the Sesquiterpene Cyclase Involved in the Biosynthesis of (+)-4-Epi-eremophil-9-en-11-ol Derivatives Isolated from Botrytis cinerea

“…8,9 Several nonspecific phytotoxins were isolated and identified (Figure 1), that is, the sesquiterpene botrydial (1) and its related compounds 10 and the polyketides 2−6. 11−13 Furthermore, a structurally different group of compounds with the same polyketide chain as that of botcinins (4,5), the most wellknown being cinbotolide A (7) 14 and sesquiterpenoid ABA, abscisic acid (8), were isolated from several strains of Botrytis. 15 Studies previously conducted by our research group demonstrated that in culture media supplemented with sublethal doses of CuSO 4 (5 ppm), B. cinerea biosynthesized a new family of cryptic metabolites with a (+)-4-epi-eremophil-9-en-11-ol skeleton (9−20).…”

“…Gray mold is a necrotrophic and polyphagous pathogen, which kills plant host cells by the excretion of bioactive metabolites (toxins) and active oxygen species (AOS) and by inducing plant-produced oxidative bursts. , Several nonspecific phytotoxins were isolated and identified (Figure ), that is, the sesquiterpene botrydial ( 1 ) and its related compounds and the polyketides 2 – 6 . − Furthermore, a structurally different group of compounds with the same polyketide chain as that of botcinins ( 4 , 5 ), the most well-known being cinbotolide A ( 7 ) and sesquiterpenoid ABA, abscisic acid ( 8 ), were isolated from several strains of Botrytis …”

Diastereoselective and enantioselective preparation of nor-mevaldic acid surrogates through desymmetrisation methodology. Enantioselective synthesis of (+) and (−) nor-mevalonic lactones

“…Consequently, solvent-free conditions, 20 which have been shown to lead to better selectivity than the use of dry THF for the preparation of lactone (+)-6a, 21 were applied to a series of commercially available chiral alcohols 10-14, achieving an optimal 14.7% overall yield and 96% de with (+)-(R) or (-)-(S)-1-(naphthalen-2-yl)ethanol (Scheme 2 and 3, Table 1, entry 6). Best yields and de were obtained when 1-arylethanols were used as chiral auxiliaries (6 and 14), suggesting that efficient desymmetrisation required not only a stereogenic center directly attached to the hydroxyl group, but also a large aromatic group attached to the stereogenic center, as use of (-)-myrtenol resulted in no asymmetric induction (Table 1, Stereochemistries of the compounds 10a-14a, 10c-13c and 14b were established by a combination of NOESY studies, analysis of 1 H-NMR coupling constants and comparison with related lactones 6a, 6b, 7a and 7c, whose absolute stereochemistries have been reported before.…”

“…18 As part of our strategy for the design of antifungal agents against Botrytis and Colletotrichum species, 19 we have recently reported the preparation of 4-hydroxy-6-(1-phenylethoxy)tetrahydro-2H-pyran-2-one (2) as a selective antifungal agent against the phytopathogen Botrytis cinerea via the desymmetrisation reaction of a suitable meso-dialdehyde precursor 3 with chiral phenylethanol. 20,21 In this paper we extend this methodology to the preparation of a range of 6-alkyloxy-4-silyloxytetrahydro-2H-pyran-2-ones using different chiral alcohols. The use of the dialdehyde 3 as a building block for the enantioselective preparation of 1,3,5-trioxygenated substrates related to methyl nor-mevaldate 1, such as nor-mevalonic acid lactones (-)-(R)-4 and (+)-(S)-5 is also described (Figure 1).…”

The complemented mutant ΔBcstc7, in the STC7 of Botrytis cinerea led to the characterization of 11,12,13-tri-nor-eremophilenols derivatives

“…1, which have exhibited interesting activity as effectors involved in different life cycle processes of this pathogen (Pinedo et al, 2016;Suárez et al, 2018); and ii) polyketides, mainly botcinic (14) and botcineric (15) acids and their botcinin derivatives (16, 17), the second family of toxins involved in the infection mechanism (Tani et al, 2005(Tani et al, , 2006. Additionally, botrylactone ( 18), an intermediate in the biosynthesis of 14 and 15 (Moraga et al, 2011) and an interesting different group of polyketides called cinbotolides (19)(20)(21), stereochemically related to botcinins whose biological role is unknown, have been isolated from several strains of B. cinerea (Botubol et al, 2014;Moraga et al, 2016).…”