Solanapyrone synthesis

Total synthesis of (-)-solanapyrone A via enzymatic Diels-Alder reaction of prosola-napyrone [81b]... 

In the laboratory of FI. Flagiwara, the first total synthesis of the polyketide natural product (-)-solanapyrone E was achieved. The installation of the pyrone moiety required the addition of the b/s(trimethylsilyl) enol ether of methyl acetoacetate to a bicyclic aldehyde precursor in the presence of titanium tetrachloride. The resulting -hydroxy- -ketoester was oxidized with the Jones reagent to afford the corresponding -diketoester in good yield. 

Hagiwara, H., Kobayashi, K., Miya, S., Hoshi, T., Suzuki, T., Ando, M. The First Total Synthesis of (-)-Solanapyrone E Based on Domino Michael Strategy. Org. Lett. 2001,3, 251-254. 

In order to confirm the structures of solanapyrones, chemical synthesis of these phytotoxins were attempted based on biogenetic consideration [55], The retro synthesis envisaged intramolecular Diels-Alder reaction of the achiral polyketide triene (a), a key intermediate, which is further divided into a pyrone moiety (b) and a diene moiety (c). The moieties a and b were prepared from dehydroacetic acid and hexadienyl acetate, respectively. Aldol condensation of the aldehyde (72) with the dithioacetal (73) gave a dienol, which was further converted to a triene (74). The intramolecular Diels-Alder reaction of 74 in toluene at 170-190 °C for 1 hr in a sealed tube yielded a mixture of the adducts (75) and (76) in a ratio of 1 2. This product ratio depends on the solvents, i.e. in water (1 7), and should be useful in differentiating between artificial and enzymatic reactions in biosynthetic studies. Removal of the thioacetal groups in 75 and 76 yielded solanapyrone A (67) and D (70) in a ratio of 3 5. Though solanapyrone D (70) had not been isolated from the natural resources at this stage, the structure and stereochemistry were confirmed by H NMR spectrum. 

Alderase, to which presumably growing polyketide chain is binding. It is noteworthy that this enzyme catalizes also the Diels-Alder reaction after preceding polyketide synthesis similar to other two Diels-Alderases, solanapyrone synthase and macrophomate synthase. 

In 2005, MacMillan reported an enantioselective organocatalytic intramolecular Diels-Alder reaction (IMDA) of a,p-unsaturated aldehyde and diene, as well as the application in the asymmetric synthesis of solanapyrone D (6), Scheme 3.1 [5]. Later, Danishefsky and Christmann individually reported the total synthesis of UCS1025A (9) by coupling reaction with MacMillan aldehyde (8) [6]. The malim-ide analogue 10 of the telomerase inhibitor UCS1025A (9) was also prepared by Christmann et al. by modified MacMillan s conditions (10 mol% catalyst loading in nitromethane, affording 74% yield and >99% ee after a sequence of recrystallization and oxidation). Scheme 3.2 [7]. 

In 2005, MacMillan and co-workers [52] employed their second-generation imidazolidinone catalyst 117 for the organocatalytic total synthesis of solanapyrone D (139) as shown in Scheme 17.24. Diels-Alder cycloaddition of aldehyde 137 using catalyst 117 provided bicycle 138 in 71% yield (20 1 dr, 90% ee), which was transformed into solanapyrone D (139) in a straightforward manner. 

Scheme 54 Intramolecular Diels-Alder reaction in the total synthesis of solanapyrone D (235)...

Wilson RM, Jen WS, MacMillan DWC (2005) Enantioselective Organocatalytic Intramolecular Diels-Alder Reactions. The Asymmetric Synthesis of Solanapyrone D. J Am Chem Soc 127 11616... 

The influence of solvents [64] and comparisons with catalysts of the diarylpro-linol series [65] were reported. For theoretical calculations on stereocontrol see Reference [66]. In addition, imidazolidin-4-one catalyzed cycloadditions have been used in several total syntheses of natural products. Intramolecular Diels-Alder reactions (IMDA) were reported as key steps in the synthesis of bicyclo-undecenes [67], amaminols [68], solanapyrones [69], telomerase inhibitor UCS1025A [70], englerin A [71], (-)-nor-platencin [72], and muironolide A [73]. In addition, asymmetric [3-1-2]-cycloadditions of azomethines were accomphshed in the presence of chiral imidazoUdinones [74]. Intermolecular cycloadditions of dihydropyridine 53 and acrolein catalyzed by imidazolidin-4-ones were reported. The chiral azabicyclo-octenol 54 was isolated as the important key intermediate in the total synthesis of lycopodium alkaloids [75] (e.g., ludduline) and oseltamivir (Scheme 4.19) [76]. 

Wilson, R.M., Jen, W.S., and MacMillan, D.W.C. (2005) Enantio-selective organocatalytic intramolecular Diels-Alder reactions. The asymmetric synthesis of solanapyrone D. J. Am. Chem. Soc., 127, 11616-11617. 

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