Diels-Alder reaction aglycones

Chlorothricolide, the aglycon of the chlorothricin antibiotic, is a complex molecule containing an octahydronaphthalene unit. Roush and Sciotti [121] recently reported the total enantioselective synthesis of chlorothricolide. The multiple Diels-Alder reaction between poliene 130 and chiral dienophile (R)-131 was the key step in the synthetic process (Scheme 2.50). The interaction... 

Recently, Mander and coworkers [122] reported the total synthesis of sordaricin (4-347), the aglycone of the potent antifungal diterpene sordarin which was first isolated in 1971 from the ascomycete Sordaria araneosa. Two approaches were explored the first method utilized a possible biogenetic Diels-Alder reaction the second was based on a domino retro-Diels-Alder/intramolecular Diels-Alder process. Thus, heating of 4-348 led, with extrusion of cyclopentadiene, to a 1,3-butadiene as intermediate which underwent an intramolecular Diels-Alder reaction to give the desired 4-349 as the main product, together with a small amount of 4-350 (Scheme 4.77). 

The oxidative formation of p-benzoquinones from anilides such as 7-108 was used for the synthesis of the core scaffold of the natural products elisabethin A (7-106) and pseudopterosin A aglycone (7-107) (Scheme 7.30). Exposure of anilide 7-108 to DMP [53] led to the formation of the o-imidoquinone 7-109, which underwent an intramolecular Diels-Alder reaction to give 7-110 in 28% yield after hydration. In a competitive pathway, the p-quinone 7-111 is also formed from 7-108, which on heating in toluene again underwent an intramolecular Diels-Alder reaction to give cycloadduct 7-112 in 25% overall yield. Hydrolysis of 7-112 furnished the carbocyclic skeleton 7-113 of elisabethin A (7-106). 

Clive and coworkers have reported a total synthesis of calicheamicinone, the aglycon of the antitumor agent calicheamicin starting from the Diels-Alder reaction of methyl 3-nitro-propenoate with ketene acetal (Eq. 8.32).54 An asymmetric Diels-Alder reaction between ketene acetal presented in Eq. 8.32 and 3-nitropropenoate derived from (-)-8-phenyl-menthol affords the optically pure adduct, which can be converted into either enantiomer of calicheamicinone (Eq. 8.33).55... 

Intermolecular cycloadditions or Diels-Alder reactions have proved to be a successful route to several valuable intermediates for natural product syntheses. In creating new chiral centers, most of these reactions apply single asymmetric induction. As mentioned in Chapter 3, in the asymmetric synthesis of the octa-hydronaphthalene fragment, the Roush reaction is used twice. Subsequent intramolecular cyclization leads to the key intermediate, the aglycones, of several natural antitumor antibiotics. On the other hand, the Diels-Alder reaction of a dienophile-bearing chiral auxiliary can also be used intramolecularly to build... 

B. H. Lipshutz, S. L. Nguyen, and T. R. Elworthy, Preparation and Diels-Alder reactions of a pyranoid vinyl glycal Model studies for anthraquinone aglycone and carbohydrate syntheses, Tetrahedron 44 3355 (1988). 

Diels-Alder Reaction. The Diels-Alder reaction of methacrolein with 1,3-dienol derivatives can also be catalyzed by the chiral BINOL-derived titanium complex BINOL-T1CI2. The endo adduct was obtained in high enantioselectivity (eq 15). The sense of asymmetric induction is exactly the same as observed for the asymmetric catalytic reactions shown above. Asymmetric catalytic Diels-Alder reactions with naphthoquinone derivatives as a dienophile provide an efficient entry to the asymmetric synthesis of anthracyclinone aglycones (eq 16). ... 

Diels-Alder reactions have played an eminent role (c/. Schemes 25, 26, 45, 53, 107, 109 and 124) in the synthesis of analogs of daunomycinone (624) and aldavinone (625), two representative aglycones of the tumor-inhibiting anthracyclines (Scheme 140). ... 

Shing, T K M, Chow, H E, Chung, IH E, Sugarometallic chemistry aglycone-chromium complex as chiral auxiliary in asymmetric Diels-Alder reaction. Tetrahedron Lett., 37, 3713-3716, 1996. Akiyama, T, Horiguchi, N, Ida, T, Ozaki, S, Stereodivergent Diels-Alder reactions employing cyclitols as chiral auxiliaries, Chem. Lett., 975-976, 1995. 

The total synthesis of the rubrolone aglycon was accomplished in the laboratory of D.L. Boger as part of the ongoing research to explore the cycloaddition reaction of cyclopropenone ketals. The key step in the production of the seven-membered C-ring was the intermolecular Diels-Alder reaction of an electron-rich diene with the very strained dienophile. The cycloaddition took place in excellent yield (97%) and with complete disastereoselectivity. 

In the laboratory of J.D. Winkler, the synthesis of the carbon framework of the eleutherobin aglycon was developed using a tandem Diels-Alder reaction and a Grob fragmentation as key steps.The tricyclic fragmentation precursor was subjected to potassium carbonate in DMF at 75 °C to afford the fragmentation product in 68% yield via a dianion intermediate that underwent a spontaneous hemiketalization. 

In large measure syntheses of aglycones have relied on the employment of one (or more) of three general reaction classes Friedel Crafts alkylations or acylations, nucleophilic condensations, and Diels Alder reactions the various routes are conveniently discussed under these three headings. (Note unless otherwise Indicated, all compounds described in the section on aglycone synthesis are racemic.)... 

Kigoshi, H., Sawada, A., Niwa, H., andYamada, K., Synthesis of a functionalized carbocychc skeleton of ptaquUosin, the aglycone of a bracken carcinogen ptaquiloside based on an intramolecular Diels-Alder reaction. Bull. Chem. Soc. Jpn., 62, 1639, 1989. 

Oppolzer et al. developed useful auxiliaries based on a camphor precursor,231 and one of the best was a sultam (277). When this sultam was converted to an acrylamide (278) and reacted with butadiene, cycloadduct 280 was produced (85% yield, 95 % ee).232 Selectivity in this Diels-Alder reaction is due to chelation of the amide oxygen and the sulfonyl group, as shown in 279. Oppolzer and co-workers applied this methodology to a chiral synthesis of the aglycone of loganin.233... 

Aklavinone (70), which is the aglycone of aclacinomycin A, remains a popular synthetic target, and Kishi et al have now outlined an asymmetric synthesis of the molecule which is based on a slight modification of their earlier route. The synthesis starts with the acetal (67), which is first converted into the keto-ester (68). Treatment of (68) with potassium carbonate in methanol resulted then in smooth asymmetric crossed-aldol condensation, leading to (69), which was easily transformed into optically pure aklavinone. An alternative route to aklavinone is based on a key Diels-Alder reaction between (71) and (72). ... 

Two final examples of cross-coupling to furnish [3]dendralenes via C2-C3 bond formation are part of very short and efficient total syntheses, and highlight the versatility and attractiveness ofthe approach. As an extension of their work on 1,1-divinylallene (153) (Scheme 1.22), Sherburnel /. [123] synthesized allenic [3]den-dralene 188 via Kumada cross-coupUng of a metallated alkene 187 and a chiral, propargyl mesylate. A subsequent Diels-Alder reaction produced cyclic [3]den-dralene 190 en route to a pseudopterosin aglycone 191 (Scheme 1.29). Allenic [3]dendralenes are prone to decomposition [136], so the subsequent DA reaction was carried out in situ. 

In 2014, Sherbum and coworkers disclosed a short synthesis of (-)-psendopterosins (G-J) aglycone 75 (Scheme 8.10) [30]. To bnild the carbocyclic scaffold, they delineated an unconventional strategy, which relies upon the nse of a diene-transmissive triple Diels-Alder reaction. The enantio-enriched 1,1-divinylallene 78 was prepared in three steps from the chiral propargyl alcohol 77 (chiral pool). This unusual diene was then subjected to a Diels-Alder reaction to provide the cycloadduct 79 in 61% yield and in good diastereomeric ratio. A second [4h-2] cycloaddition of 79 with acrolein using high-pressure conditions took place to afford the expected cycloadduct 80 in 15% yield. Although a... 

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