Highly functionalized 1,7-diene

Cinnamyl bromide 24 and the iodocarbohydrate 23 are combined in a zinc-mediated fragmentation/allylation reaction to afford a highly functionalized 1,7-diene, which is then treated with Hoveyda-Grubbs second-generation catalyst to produce a mixture of diastereomeric cyclohexenes 25 (35% yield) and 26 (32% yield). From the major isomer 25, subsequent Overman rearrangement, dihydroxylation, and deprotection afford the natural product pancrastistatin (28) (Scheme 3.10). 

A 51 was disclosed by a British team (Scheme 9)3 The highly functionalized diene 49 was prepared from iodo compound 48 via Vasella-type reductive ring opening followed by Julia-Kocienski methylenation of the resulting aldehyde. The ring closure to cyclopentene 50 in the presence of catalyst D proceeded smoothly, despite the complex functionalization. 

S. Danishefsky, Cycloaddition and Cyclocondensation Reactions of Highly Functionalized Dienes Applications to Organic Synthesis, Chemtracts Org. Chem. 1989, 2, 273—297. 

As a matter of fact compound I was designed with this particular purpose in mind, as part of a broad research program aimed at the development of highly functionalized dienes that would pave the way towards more reactive cyclohexenes than those previously obtained by means of this sort of cycloaddition. The fundamental concept is illustrated in Scheme 13.l. ... 

TBHP yielded an allylic alcohol, which was benzylated to provide 97. This highly functionalized diene underwent RCM with Schrock s catalyst affording cyclopentene 98 in a yield of 91%. Under the action of hydrogen and Pd/C, hnal reduction and debenzylation were performed simultaneously to give 5a-carba-(3-D-fmctofuranose [54]. 

In another metal-mediated coupling reaction, the highly functionalized dienes 136a and 136b were allowed to react with Ni(PPh3)4 in the presence of excess zinc/copper couple at 50 ""C and 1 atm of carbon monoxide to provide the octakis(methoxycarbonyl) 137a and the tetrabenzo derivatives 137b in excellent yields (77 and 84%, respectively), (see Scheme 17 compare also Scheme 12 for the formation of the related [4]radialene 10686-88) 373 s treated with excess LiBr H2O in HMPA at temperatures... 

Danishefsky, S. Cycloaddition and cyclocondensation reactions of highly functionalized dienes applications to organic synthesis. Chemtmcts Org. Chem. 1989, 2, 273-297. 

Okauchi, T., Fukamachi, T., Nakamura, F., Ichikawa, J., and Minami, T., 2-Phosphono-l,1,4,4-tetrathio-l,3-butadienes. Synthesis and synthetic application to highly functionalized dienes and heterocycles, Bull. Soc. Chim. Belg.. 106, 525, 1997. 

The synthesis of more complex monosaccharides requires the construction of more complex and highly functionalized dienes and aldehydes. Furyl diene (124) serves as an important starting material in syntheses of KDO and NeuAc. This diene is easily synthesized from the condensation of benzoyloxy acetyl chloride with acetylfuran, followed by treatment with diazomethane. Cyclocondensation of diene (124) with chiral aldehyde (125a) using BFa-OEta as a catalyst gives the CF-type products (126) in a S l ratio of syn and anti isomers (126a and 126b). Aldehyde (125) is also available in optically pure form from... 

Although the cyclization reactions described above represent a potentially powerful means for carbon-carbon bond formation, under reductive (hydrogenoly-sis) conditions the method utilizes a highly functionalized diene substrate and leaves an essentially unfunctionalized product in its wake. The utilization of silylation as a chain terminating event provides a way to place functionality back into the molecule after the cyclization (Fig. 8). 

A synthetically useful application of this methodology to protected glucals 77 appeared recently (Scheme 40) [70]. It involves a variety of activated terminal olefins 78 and gives access to highly functionalized dienes 79, ready for [4-t2] cycloadditions, used for instance in the synthesis of natural products such as Olivin or Forsolin. 

Benzo[Z)]furans and indoles do not take part in Diels-Alder reactions but 2-vinyl-benzo[Z)]furan and 2- and 3-vinylindoles give adducts involving the exocyclic double bond. In contrast, the benzo[c]-fused heterocycles function as highly reactive dienes in [4 + 2] cycloaddition reactions. Thus benzo[c]furan, isoindole (benzo[c]pyrrole) and benzo[c]thiophene all yield Diels-Alder adducts (137) with maleic anhydride. Adducts of this type are used to characterize these unstable molecules and in a similar way benzo[c]selenophene, which polymerizes on attempted isolation, was characterized by formation of an adduct with tetracyanoethylene (76JA867). 

Intramolecular Diels-Alder reactions of the furan diene (IMDAF) rapid construction of highly functionalized isoquinoline skeletons [65i]... 

Waldmann used (R) and (5>aminoacid methyl esters and chiral amines as chiral auxiliaries in analogous aza-Diels-Alder reactions with cyclodienes.111 The diastereoselectivity of these reactions ranged from moderate to excellent and the open-chain dienes reacted similarly. Recently, the aza-Diels-Alder reaction was used by Waldmann in the asymmetric synthesis of highly functionalized tetracyclic indole derivatives (Eq. 12.45), which is useful for the synthesis of yohimbine- and reserpine-type alkaloids.112... 

In 1987, Vaultier and coworkers [27] developed a combination of a [4+2] cycloaddition of a bora-1,3-diene to provide an allylborane, which then reacts with an aldehyde to give a highly functionalized alcohol. The Lallemand group, as well as Hall and colleagues, has recently used this procedure. In an approach for the synthesis of the antifeedant natural product clerodin (4-83), Lallemand and coworkers performed a three-component domino reaction of 4-80, 4-81 and methyl acrylate to give 4-82 (Scheme 4.18) [28]. 

The scope and efficiency of [4+2] cycloaddition reactions used for the synthesis of pyridines continue to improve. Recently, the collection of dienes participating in aza-Diels Alder reactions has expanded to include 3-phosphinyl-l-aza-l,3-butadienes, 3-azatrienes, and l,3-bis(trimethylsiloxy)buta-l, 3-dienes (1,3-bis silyl enol ethers), which form phosphorylated, vinyl-substituted, and 2-(arylsulfonyl)-4-hydroxypyridines, respectively <06T1095 06T7661 06S2551>. In addition, efforts to improve the synthetic efficiency have been notable, as illustrated with the use of microwave technology. As shown below, a synthesis of highly functionalized pyridine 14 from 3-siloxy-l-aza-1,3-butadiene 15 (conveniently prepared from p-keto oxime 16) and electron-deficient acetylenes utilizes microwave irradiation to reduce reaction times and improve yields <06T5454>. 

Inspired by the well-established nickel-catalyzed co-oligomerization of 1,3-dienes with CO2, which proceeds via bis-TT-allyl intermediate, Mori has developed a powerful intramolecular version of this process (Scheme 103). After insertion of C02 into the bis-vr-allyl complex, a transmetallation with an organozinc reagent takes place to generate the Ni(0) catalyst. Highly functionalized carbo- and heterocyclic compounds with complete stereocontrol can372 be synthesized by this method. 

Alkoxyallenes turned out to be excellent starting materials also for the synthesis of highly functionalized 1,3-dienes, two examples being depicted in Schemes 8.61 and 8.62. As described by Kantlehner et al., 1,3-dienes such as 238 were obtained from methoxyallene derivative 50 by condensation with CH-acidic compounds 237 [135]. Hoppe and co-workers explored the stereochemical course of the allene Claisen rearrangement under Johnson s conditions, e.g. the reaction of 239 with trimethyl orthoacetate, which furnished intermediate 240 followed by rearrangement to the isomeric dienes 241a,b [136],... 

The transition metal cross-couplings of allenes described here offer practical solutions for the modification of 1,2-dienes and access to the preparation of highly functionalized 1,3-dienes, alkynes and alkenes, which are often not easily accessible in a regio- and stereoselective manner by classical methods. Some of the prepared alkynes or functionalized allenes serve as important intermediates in syntheses of natural products, biologically active compounds, e.g. enynes and enyne-allenes, and new materials. It can be predicted that further synthetic efforts will surely be focused on new applications of allenes in transition metal-catalyzed cross-coupling reactions. 

While linear dimerization of dienoic esters can also be accomplished with nickel-AMP systems, other functionalized dienes undergo little or no conversion. The reaction of methyl hexa-2,4-dienoate, 81, furnishes diastereomeric trienoic diesters (82) in high yields (equation 43). 

The reaction of 1,4-diphenylbuta-l,3-diene (2) with trithiazyl trichloride (3) yields a bi(thiadiazole) (4), an isothiazoloisothiazole (5), a dithiazolothiazine (6), and two thiazin-odithiatriazepines (7) and (8) by 1,2-, 1,3-, and 1,4-cycloaddition reactions (Scheme 2). The bridged-mode (/3-tether) tandem inter-[4 -E 2]/intra-[3 -E 2] cycloaddition of (ii)-2-methyl-2-nitrostyrene (9) with 1-butoxypenta-1,4-diene (10) produces stable tricyclic nitroso acetals (11) which afford, after reduction and protection, highly functionalized aminocyclopentanedimethanol triacetates (12) (Scheme 3). ... 

Inverse type hetero-Diels-Alder reactions between p-acyloxy-a-phenylthio substituted a, p-unsaturated cabonyl compounds as 1-oxa-1,3-dienes, enol ethers, a-alkoxy acrylates, and styrenes, respectively, as hetero-dienophiles result in an efficient one step synthesis of highly functionalized 3,4-dihydro-2H-pyrans (hex-4-enopyranosides). These compounds are diastereospecifically transformed into deoxy and amino-deoxy sugars such as the antibiotic ramulosin, in pyridines having a variety of electron donating substituents, in the important 3-deoxy-2-gly-culosonates, in precursors for macrolide synthesis, and in C.-aryl-glucopyranosides. 

---