Of Danishefsky’s diene

The mechanism of the cycloaddition reaction of benzaldehyde 2a with Danishefsky s diene 3a catalyzed by aluminum complexes has been investigated theoretically using semi-empirical calculations [14]. It was found that the reaction proceeds as a step-wise cycloaddition reaction with the first step being a nucleophilic-like attack of Danishefsky s diene 2a on the coordinated carbonyl compound leading to an aldol-like intermediate which is stabilized by interaction of the cation with the oxygen atom of the Lewis acid. The next step is the ring-closure step, giving the cycloaddition product. 

An asymmetric version of this reaction was achieved by the use of complexes derived from chiral imidazolidinones. For example, the reaction of Danishefsky s diene with these chiral complexes occurs with both high exo endo selectivity and high facial selectivity at the dienophile [103] (Scheme 56). 

Bronsted acid catalyzed aza-Diels-Alder reaction of Danishefsky s diene with aidimine generated in situ from aldehyde and amine in aqueous media [107]... 

Scheme 18 Two pathways of the reactions of Danishefsky s diene with aldehydes...

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>. 

Bis(trifluoromethanesulfonylamides) ligand was also used by Mikami et al., in 1995, for the lanthanide-catalysed hetero-Diels-Alder reaction of Danishefsky s diene with butyl glyoxylate. This reaction produced the corresponding... 

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... 

Similar aza-Diels-Alder reactions of Danishefsky s diene with imines or aldehydes and amines in water took place smoothly under neutral conditions in the presence of a catalytic amount of an alkaline salt such as sodium triflate or sodium tetraphenylborate to afford dihydro-4-pyridones in high yields (Eq. 12.49).117 Antibodies have also been found to catalyze hetero-Diels-Alder reactions.118... 

Schaus et al.41 have also reported an asymmetric hetero Diels-Alder reaction of Danishefsky s diene 10042 with aldehyde 101 catalyzed by chromium(III) complex 99 bearing a similar chiral salen ligand. Product 102 is obtained in moderate to good yield and stereoselectivity (Scheme 5-31 and Table 5-5). 

Ghosh et al. (228) investigated the cycloaddition of Danishefsky s diene (1-methoxy-3-trimethylsiloxybutadiene, 334) and glyoxylate esters. The reaction provides a mixture of the Mukaiyama aldol product (336) and dihydropyrone (335). Treatment of the unpurified reaction mixture with trifluoroacetic acid induced the cyclocondensation to provide dihydropyrone (335) in 70% combined yield and 72% ee, Eq. 188. 

In the reaction of benzylideneaniline with cyclopentadiene, the imine functions as an azadiene to yield the rearranged Diels-Alder adduct 77 (equation SI)44,453. In a study of the effect of various Lewis acids (ZnCl2, TiCU, Et2AlCl and SnCU) on diastereoselective cycloadditions of Danishefsky s diene to the imines 79, obtained from the chiral aldehydes 78 (R = MeO or Cl), it was found that SnCLj was the most effective, giving the optically active products in high yields and excellent ee values (equation 52)46. 

Reaction of Danishefsky s Diene with Benzaldehyde Another Example for Catalysis by Cooperative Hydrogen Bonding... 

Scheme 9 Enantioselective hetero-Diels-Alder (HDA) reaction of Danishefsky s diene with benzaldehyde...

Scheme 36 Aza-Diels-Alder reaction of Danishefsky s diene...

TADDOL-Promoted Enantioselective Hetero-Diels-Alder Reaction of Danishefsky s Diene 37... 

In 1995, Mikami reported that chiral lanthanide complex 35 catalyzed the enan-tioselective hetero-Diels-Alder reachon of Danishefsky s diene and various glyoxy-lates [121]. Interestingly, the addition of water to the reachon mixture resulted in increases in both chemical yield and enanhoselechvity. It was later reasoned that... 

Inda-box ent-9a has been used recently in the production of the natural product (-)-malyngolide 265. " The key step of the synthesis by Ghosh and Shirai, as shown in Figure 9.80, is the hetero-Diels-Alder reaction of Danishefsky s diene 112 and cx-ketoester 263 to afford the pyranone derivative 264 in 77% yield and 47% ee that was converted into (—)-malyngolide in several additional steps. The preparation of different pyranones was investigated using different ot-ketoesters. 

TABLE 9.18 HETERO DIELS-ALDER REACTION OF DANISHEFSKY S DIENE WITH GLYOXYLATE ESTERS, 558... 

The cyclocondensation of Danishefsky s diene 35 with alaninals of type 25, contrary to diene 32, requires neither elevated pressure nor high temperature. The zinc bromide-mediated reaction of 35 with alaninal 25 was followed by acidic workup, resulting in removal of both the trimethylsilyl protection and the ethoxy group [45,46] (Scheme 13). 

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. 

A similar chiral bis(oxazoline)/Cu(II) catalyst is useful for the asymmetric hetero Diels-Alder reaction of Danishefsky s diene and glyoxylates [63] (Eq. 8A.39). Other bis(oxa-zoline)/M(OTf)2 (M = Sn, Mg) complexes are not effective. This method provides new routes to asymmetric aldol synthesis upon hydrolysis of the resulting adducts. 

Jacobsen studied the efficiency of a series of chiral (salen)Cr(III)X complex (X = Cl, N 3, F, BF4) for the asymmetric hetero Diels-Alder reaction of Danishefsky s diene with aldehydes. The best result was obtained with the terafluoroborate catalyst [65] (Eq. 8A.41). 

A series of trivalent lanthanoid complexes, scandium, and ytterbium tris-(R)-(-)-1,1 -binaphthyl-2,2 -diyl phosphonate, have been introduced as new chiral and stable Lewis acids for the asymmetric hetero Diels-Alder reaction of Danishefsky s diene and aldehydes. 2,6-Lutidine was found to be an effective additive to improve the enantioselectivity up to 89% ee [66] (Eq. 8A.42). 

The chiral boron complex prepared in situ from chiral binaphthol and B(OPh)3 is utilized for the asymmetric aza-Diels-Alder reaction of Danishefsky s diene and imines [67] (Eq. 8A.43). Although the asymmetric reaction of prochiral imine affords products with up to 90% ee, the double asymmetric induction with chiral imine by using oc-benzylamine as a chiral auxiliary has achieved almost complete diastereoselectivity for both aliphatic and aromatic aldimines. This method has been successfully applied to the efficient asymmetric synthesis of anabasine and coniine of piperidine alkaloides. 

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>. 

Table 6.39 Bis-triflylamide-catalyzed HDA reactions of Danishefsky s diene.

With the relative air and water stability of silver phosphine complexes in mind, the Frost and Weller groups reported the use of a silver(I) carborane triphenylphosphine complex as a catalyst for the aza-Diels-Alder reaction.82,83 These unique catalyst complexes were able to catalyze the reaction of Danishefsky s diene (195) with 196 in... 

Further studies revealed that a 10 mol% loading of AgOTf was sufficient to catalyze the reaction of Danishefsky s diene (195) with a variety of aromatic phenylimines bearing electron-withdrawing/donating substituents, in 57-92% yield within 2-3 h. These studies were carried out in water. Electron-poor imines generally required the use of 3 equiv of diene 195 to obtain satisfactory yields. The method was extended to a one-pot three-component protocol with in situ formation of the imine from the aniline and 1.5 equiv of the aldehyde (Scheme 2.51, Table 2.13). Because of... 

A particularly elegant example is the application of Danishefsky s diene [107] to the total synthesis of carbohydrates and carbohydrate derivatives. While it was known that activated aldehydes undergo cycloaddition with electron-rich dienes, the process was not efficient with typical aldehydes under thermal conditions. A major breakthrough was realized [108] with the development of the Lewis acid-catalyzed diene-aldehyde cyclocondensation (LACDAC) reaction, which provided a new strategy for the synthesis of carbohydrates and other polyoxygenated natural products (Scheme 1.4) [109],... 

The first papers dealing with the use of optically active sulfinyl nitroalkenes were published by Fuji et al. in 1991 [71,72]. These papers describe the reaction of Danishefsky s diene with compound 70 (the dienophile containing a six-membered ring does not react) to afford a 1 1 mixture of two compounds (endo-71 and exo-71) resulting from desulfinylation of the endo t) and exo(t) adducts. The optical purity of these compounds ee > 95 %) indicates a complete 7r-facial selectivity in the cycloaddition. X-ray diffraction studies of dienophile 70 showed the s-trans conformation of the sulfinyl oxygen (like that depicted in Scheme 38) in the solid state. By assuming steric approach control for the Diels-Alder reaction, the stereochemistry of endo-71 and exo-71 suggests that such a con-... 

In the field of [4 + 2]-cycloadditions, silver catalysts have been used mainly for aza-Diels-Alder reactions of Danishefsky s diene 447 with various imines. Kobayashi and co-workers364 have recently shown that this transformation can be carried out with catalytic amounts of silver(i) triflate in water (Scheme 133). Various aryl- or alkenyl-substituted pyridone derivatives 448 were obtained in high yields. A survey of other silver catalysts revealed that... 

Table 10. Diastereoselective Cycloaddition Reactions of Danishefsky s Diene with 2-Formyl-2-methyl-1,3-dithiane 1 -Oxide...

EnantiocontroUed Diels-Alder reaction. The P-D-glucopyranoside 1, an analog of Danishefsky s diene, undergoes a diastereocnntrolled Diels-Alder reaction with the... 

Yamamoto and Maruoka demonstrated that ATPH can discriminate between structurally similar aldehydes, thereby facilitating selective functionalization of the less-hindered aldehyde carbonyl [163]. Treatment of an equimolar mixture of valeralde-hyde (149) and cyclohexanecarbaldehyde (150) with ATPH (1.1 equiv.) in CH2CI2 at -78 °C, then addition of Danishefsky s diene gave hetero-Diels-Alder adduct 151 and 152 in the ratio > 99 1. It is worthy of note that the complexed aldehyde could react with the diene only. The reaction gave relatively low chemoselectivity with other types of Lewis acid (ratio of 1517152 6.2 1 with (Pr 0)2Ti2Cl2 5 1 with McsAl 3.7 1 with MAD 2 1 with TiCU 1.3 1 with BF3-OEt2). This emphasizes that the cavity of ATPH plays an important role in differentiating between the reactivities of the two different aldehydes. In a similar manner, the aldol reaction of a mixture of 149 and 150 was effected with ATPH to furnish 4-hydroxy-2-octanone (153) without formation of 154 (Sch. 122). 

Sc(OTf)3-catalyzed three-component coupling reactions of aldehydes, amines, and dienes have been examined. In the presence of 10 mol % Sc(OTf)3 and magnesium sulfate, benzaldehyde was treated with aniline and Danishefsky s diene. The desired three-component reaction proceeded smoothly to afford the corresponding tetrahydropyridine derivative in 83 % yield (Eq. 9) [24b]. Under the same reaetion conditions, cyclopentadiene was used instead of Danishefsky s diene to afford the corresponding tetrahydroquinoline derivative (Eq. 10). Different combinations of aldehydes, amines, and alkenes are possible in these reactions, and afford diverse tetrahydroquinoline derivatives in high yields. 

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