Danishefsky substituted

A highly successful route to stereoisomers of substituted 3-cyclohexene-l-carboxylates runs via Ireland-Claisen rearrangements of silyl enolates of oj-vinyl lactones. The rearrangement proceeds stereospeaifically through the only possible boat-like transition state, in which the connecting carbon atoms come close enough (S. Danishefsky, 1980 see also section 4.8.3, M. Nakatsuka, 1990). 

In most of the successful Diels-Alder reactions reported, dienes containing no heteroatom have been employed, and enantioselective Diels-Alder reactions of multiply heteroatom-substituted dienes, e.g. Danishefsky s diene, are rare, despite their tremendous potential usefulness in complex molecular synthesis. Rawal and coworkers have reported that the Cr(III)-salen complex 15 is a suitable catalyst for the reaction of a-substituted a,/ -unsubstituted aldehydes with l-amino-3-siloxy dienes [21] (Scheme 1.28, Table 1.12). The counter-ion of the catalyst is important and good results are obtained in the reaction using the catalyst paired with the SbFg anion. 

The 6-substituted 1,4-dioxocins can be used to prepare other 6-substituted derivatives by simple functional group transformations.4,8,9 Especially interesting is the synthesis of the 4/7-4-oxo-2,3-dihydropyran-2-yl-substituted derivative 16 from l,4-dioxocin-6-carbaldehyde (15) by a cyclocondcnsation with Danishefsky s diene.9 Dehydrogenation of 16 yields 2 which can be isomerized to the corresponding isomeric. sr/i-benzene dioxide 3 (X = 4/f-4-oxopyran-2-yl), which is identical with and proved the structure of the naturally occurring antibiotic LL-Z 1220.10... 

Danishefsky and coworkers using the same approach have synthesized substituted cyclohexadienones 563s65,666 (equation 361). A highly stereoselective (96%) cycloaddition of diastereoisomerically pure (Ss)-menthyl 3-(3-trifluoromethylpyrid-2-ylsulphinyl)acrylate 564 to 2-methoxyfuran 565 leads to the cycloadduct 566 which was elaborated by Koizumi and coworkers to glyoxalase I inhibitor 567667 (equation 362). 

Electronically rich 1,3-butadienes such as Danishefsky s diene react with chromium alkenylcarbene complexes affording seven-membered rings in a formal [4S+3C] cycloaddition process [73a, 95a]. It is important to remark on the role played by the metal in this reaction as the analogous tungsten carbene complexes lead to [4S+2C] cycloadducts (see Sect. 2.9.1.1). Formation of the seven-membered ring is explained by an initial cyclopropanation of the most electron-rich double bond of the diene followed by a Cope rearrangement of the formed divinylcyclopropane (Scheme 65). Amino-substituted 1,3-butadienes also react with chromium alkenylcarbene complexes to produce the corre-... 

When electron-withdrawing groups are introduced at the vinyl moiety, ary-lethenes may behave as dienophiles. Thus a-trifluoromethyl styrene (111) interacted with Danishefsky s diene (12b) under thermal or high pressure conditions [37] to regioselectively afford a 1 1 mixture of cycloadducts which were then converted to 4-phenyl-4-trifluoromethyl-2-cyclohexen-l-one (112) (Equation 5.12). A direct access to angularly trifluoromethyl-substituted tricyclic compounds may be achieved by cycloaddition of the l-trifluoromethyl-3,4-di-hydronaphthalene (113) with diene 12b (Equation 5.13). 

Very recently, Cook and Danishefsky [24] reported an interesting regioselectivity of intramolecular Diels-Alder reactions reversed by the change in the dienophihc moieties from vinyl to allenyl group (Scheme 19). For R = 2-propenyl group, C is bonded to the methyl substituted carbon Cj of the cyclohexadienone ring. For R = 2,3-butadienyl, C is bonded to Cy... 

Complete diastereoselection is observed in the HDA reaction of Danishefsky s diene with o-substituted benzaldehyde chromium tricarbonyl complexes. Decomplexation is facile and good yields of 2-aryl-2,3-dihydropyran-4-ones result <96SL258>. Cis-2,3-disubstituted pyranones are accessible from the Lewis-acid catalysed HDA reaction between (triisopropylsilyloxy) dienes and aldehydes and dehydrogenation of the resulting dihydropyrans <96JOC7600>. 

The montmorillonite KlO-catalyzed aza-Diels-Alder reaction of Danishefsky s diene with aldimines, generated in situ from aliphatic aldehydes and p-anisidine, proceeded smoothly in H20 or in aqueous CH3CN to afford 2-substituted 2,3-dihydro-4-pyridones in excellent yields (Eq. 12.47).115 Also, complex [(PPh3)Ag(CBiiH6Br6)] was shown to be an effective and selective catalyst (0.1 mol% loading) for a hetero-Diels-Alder reaction with Danishefsky s diene and the reaction showed a striking dependence on the presence of trace amounts of... 

In this context, also mentionable are several publications by the groups of Dlaz-de-Villegas [242], Guarna [243], Kunz [244] and Waldmann [245], which describe the formation of six-membered azaheterocycles via treatment of an imine with an appropriate substituted diene. For instance, as described by Waldmann and coworkers, reaction of the enantiopure amino acid-derived imines 2-452 with Danishefsky s diene 2-453 in the presence of equimolar amounts of a Lewis acid provided diastereomeric enaminones 2-456 and 2-457 (Scheme 2.105) [245a]. 

Kobayashi and his team have utilized a catalytic system similar to that used in their development of a Zr-catalyzed Mannich reaction (Schemes 6.27—6.29) to develop a related cycloaddition process involving the same imine substrates as used previously (Scheme 6.35) [105]. As the representative examples in Scheme 6.35 demonstrate, good yields and enantioselectivities (up to 90% ee) are achieved. Both a less substituted version of the Danishefsky diene (—> 110) and those that bear an additional Me group (e. g.— 111) can be utilized. Also as before, these workers propose complex 89, bearing two binol units, to be the active catalytic species. 

As far as catalytic enantioselective cycloadditions to imines are concerned, the only non-Zr-catalyzed process is a Cu-catalyzed protocol reported by Jorgensen (Eq. 6.22) [112]. It should be noted, however, that high enantioselectivities are attained only with highly substituted versions of the Danishefsky diene. 

J0rgensen and co-workers (229,230) examined the use of a-ketoesters and 1,2-diones as heterodienophiles in reactions with Danishefsky s diene. Catalyst 269c was found to exert the highest facial bias in these reactions, and is generally tolerant of substitution on the dione. These reactions may be conducted with as little as 0.05 mol% catalyst loadings. 

The ionic liquid [bmim][BF ] is known to catalyze the aza-Diels-Alder reaction in the synthesis of pyrano- and furanoquinolines [190]. This reaction was also catalyzed by the enantiopure bis-imidazolinium salt 67 in 67% yield with an endo. exo ratio of 60 40 (Scheme 69) [191]. The product was obtained as a race-mate. In addition the aza-Diels-Alder reaction with imines and Danishefsky s diene was catalyzed by the salt 67 giving racemic product. The salt and its analogues could be easily prepared via the oxidation of the corresponding aminals [192]. Investigation of the influence of the counter anion in achiral C2-substituted imidazolinium salts, which can be also described as 4,5-dihydroimidazolium or saturated imidazolium salts, in the aza-Diels-Alder reaction showed, that the catalytic activity increased, the more lipophilic the counter anion and therefore the more hydrophobic the salt was [193]. 

Notes See Brassard s. Danishefsky s and Rawal s Diene and for similar reactions different substitution patterns. 

The aza-Diels-Alder reaction of Danishefsky s diene with imines provides a convenient method for the synthesis of 2-substituted 2,3-dihydro-4-pyridones, a compound class that has important synthetic applications. Kobayashi and co-workers have studied the reaction in detail using ytterbium (III) triflate as the Lewis acid30. Although the reaction is often run at low temperature (—78°C to 0°C) for a number of hours, we have found that the reaction also worked well at elevated temperatures (150°C) in the microwave for a few minutes (J. Westman and A. Hurynowics, unpublished results) (see Scheme 5.15). The imines could either be preformed prior to the addition of the Danishefsky s diene or the reaction could be performed as a multi-component protocol, where all components were added at once. 

Pancratistatln. The first total synthesis of ( )-pancratistatin (94) (Scheme 14), the structurally most complex of narciclasine alkaloids, was achieved by Danishefsky [27]. The requisite starting material, the substituted benzaldehyde 95 prepared from pyrogallol in six steps in 18% overall yield, was converted via the homoallylic alcohol 96 into the diene 97. Reaction of 97 with 2-nitrovinylsulphone yielded the cycloadduct 98, which on treatment with tributyltinhydride and 2,2 -azobisisobutyronitrile furnished the cyclohexadiene 99. Whilst the cyclisation of the silylether 99 or the derived phenol, under the influence of iodine, could not be accomplished, the more nucleophilic stannylether did participate in the desired ring closure and provided via the iminium salt, the iodolactone 100 on aqueous work-up. 

The polymer-bound Mn and Cr complexes were used as catalysts for epoxidations of six phenyl-substituted olefins with m-CPBA/NMO and for dihydropyranone formation from the Danishefsky diene and aldehydes. There are several remarkable features of the novel immobilized salens ... 

The reactivity of 47/-benzopyran-4-ones in Diels-Alder reactions is well documented <1987T3075>, and recently high asymmetric induction has been achieved in the reaction of 3-alkoxycarbonyl-substituted chromones with chiral auxiliaries and Danishefsky s diene <1991JOC2058>. It should be noted that 3-formylchromones can react as heterodienes in the stereoselective inverse electron Diels-Alder reaction with enol ethers <1994T11755> to provide a route to pyrano[4,3-A][l]benzopyrans a heterocyclic nucleus which occurs naturally in the fungal metabolite fulvic acid <1984CC1565>. The thermal Diels-Alder reaction of 477-pyran-4-one 405 in the presence of an excess of Danishefsky s diene 404 provided cycloadduct 406 (Equation 32) <1996H(43)745>. 

In contrast, the Hoveyda and Snapper groups reported the efficient catalysis of silver acetate complexes of imine 204.86 These authors first established the superior performance of IV-ort/zo-methoxyaniline-substituted imines in the reaction with Danishefsky diene 195. Because of the modular nature of ligand 206, optimization of its structure could be achieved by surveying a combinatorial library of amino acid derivatives. The /-isoleucine para-methoxyaniline conjugate 206 proved the best. This ligand facilitated full conversion within 2-3 h with high yield and enantioselectivity (Scheme 2.53). 

We have seen that the appropriate choice of the catalyst and/or the olefin substitution pattern can dramatically shift the equilibrium in favor of the macrocyclic product. Other factors are important as well, such as the general experimental conditions. Danishefsky and coworkers have highlighted the effects of solvent, temperature, and concentration on the yield of macrocyde RCM for the synthesis of analogs of epothilone 490 [14]. As shown in Scheme 2.4, RCM of compound 7 in... 

The chiral piperidinones 46 formed by the reaction between Danishefsky s diene and the glycosyl imines are valuable synthons for the synthesis of higher substituted piperidine derivatives. 2,6-Disubstituted piperidinones 49 are obtained by addition of organocuprates complexes with boron trifluoride [53]. The reaction pathway is illustrated in Scheme 30. 

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