Dienes Danishefsky diene

A major difficulty with the Diels-Alder reaction is its sensitivity to sterical hindrance. Tri- and tetrasubstituted olefins or dienes with bulky substituents at the terminal carbons react only very slowly. Therefore bicyclic compounds with polar reactions are more suitable for such target molecules, e.g. steroids. There exist, however, several exceptions, e. g. a reaction of a tetrasubstituted alkene with a 1,1-disubstituted diene to produce a cyclohexene intermediate containing three contiguous quaternary carbon atoms (S. Danishefsky, 1979). This reaction was assisted by large polarity differences between the electron rich diene and the electron deficient ene component. 

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. 

There have been few mechanistic studies of Lewis acid-catalyzed cycloaddition reactions with carbonyl compounds. Danishefsky et ah, for example, concluded that the reaction of benzaldehyde 1 with trans-l-methoxy-3-(trimethylsilyloxy)-l,3-di-methyl-1,3-butadiene (Danishefsky s diene) 2 in the presence of BF3 as the catalyst proceeds via a stepwise mechanism, whereas a concerted reaction occurs when ZnCl2 or lanthanides are used as catalysts (Scheme 4.3) [7]. The evidence of a change in the diastereochemistry of the reaction is that trans-3 is the major cycloaddition product in the Bp3-catalyzed reaction, whereas cis-3 is the major product in, for example, the ZnCl2-catalyzed reaction - the latter resulting from exo addition (Scheme 4.3). 

Yamamoto et al. were probably the first to report that chiral aluminum(III) catalysts are effective in the cycloaddition reactions of aldehydes [11]. The use of chiral BINOL-AlMe complexes (R)-S was found to be highly effective in the cycloaddition reaction of a variety of aldehydes with activated Danishefsky-type dienes. The reaction of benzaldehyde la with Danishefsky s diene 2a and traws-l-methoxy-2-methyl-3-(trimethylsilyloxy)-l,3-pentadiene 2b affords cis dihydropyrones, cis-3, as the major product in high yield with up to 97% ee (Scheme 4.6). The choice of the bulky triarylsilyl moiety in catalyst (J )-8b is crucial for high yield and the en-antioselectivity of the reaction in contrast with this the catalysts derived from AlMe3 and (J )-3,3 -disubstituted binaphthol (substituent = H, Me, Ph) were effective in stoichiometric amounts only and were less satisfactory with regard to reactivity and enantioselectivity. 

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. 

A series of chiral binaphthyl ligands in combination with AlMe3 has been used for the cycloaddition reaction of enamide aldehydes with Danishefsky s diene for the enantioselective synthesis of a chiral amino dihydroxy molecule [15]. The cycloaddition reaction, which was found to proceed via a Mukaiyama aldol condensation followed by a cyclization, gives the cycloaddition product in up to 60% yield and 78% ee. 

Chiral boron(III) Lewis acid catalysts have also been used for enantioselective cycloaddition reactions of carbonyl compounds [17]. The chiral acyloxylborane catalysts 9a-9d, which are also efficient catalysts for asymmetric Diels-Alder reactions [17, 18], can also catalyze highly enantioselective cycloaddition reactions of aldehydes with activated dienes. The arylboron catalysts 9b-9c which are air- and moisture-stable have been shown by Yamamoto et al. to induce excellent chiral induction in the cycloaddition reaction between, e.g., benzaldehyde and Danishefsky s dienes such as 2b with up to 95% yield and 97% ee of the cycloaddition product CIS-3b (Scheme 4.9) [17]. 

A series of chiral boron catalysts prepared from, e.g., N-sulfonyl a-amino acids has also been developed and used in a variety of cycloaddition reactions [18]. Corey et al. have applied the chiral (S)-tryptophan-derived oxazaborolidine-boron catalyst 11 and used it for the conversion of, e.g., benzaldehyde la to the cycloaddition product 3a by reaction with Danishefsky s diene 2a [18h]. This reaction la affords mainly the Mukaiyama aldol product 10, which, after isolation, was converted to 3a by treatment with TFA (Scheme 4.11). It was observed that no cycloaddition product was produced in the initial step, providing evidence for the two-step process. 

Keck et al. reported that a catalyst generated from (S)- or (l )-BINOL 12 and Ti(0-i-Pr)4 in a 2 1 ratio is more selective than the catalyst formed from a 1 1 mixture [19fj. The former catalyst was shown to catalyze the cycloaddition reaction of aldehydes 1 with Danishefsky s diene 2a affording the dihydropyrones 3 with moderate to excellent enantioselectivity (Scheme 4.12). The reaction proceeds well for different aldehydes with up to 97% ee and good yield of the cycloaddition products. 

The chiral BIN0L/Ti(0-i-Pr)4 combination has also been used as a very enantio-selective catalyst for the cyclocondensation of polyfluoroalkylaldehydes with Danishefsky s diene leading to polyfluoroalkyldihydropyrenones in moderate yields (35-60%) and with high ee (90-98.5% ee) [20]. 

A chiral vanadium complex, bis(3-(heptafluorobutyryl)camphorato)oxovana-dium(IV), can catalyze the cycloaddition reaction of, mainly, benzaldehyde with dienes of the Danishefsky type with moderate to good enantioselectivity [21]. A thorough investigation was performed with benzaldehyde and different activated dienes, and reactions involving double stereo differentiation using a chiral aldehyde. 

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition mechanism. 

Danishefsky et al. were probably the first to observe that lanthanide complexes can catalyze the cycloaddition reaction of aldehydes with activated dienes [24]. The reaction of benzaldehyde la with activated conjugated dienes such as 2d was found to be catalyzed by Eu(hfc)3 16 giving up to 58% ee (Scheme 4.16). The ee of the cycloaddition products for other substrates was in the range 20-40% with 1 mol% loading of 16. Catalyst 16 has also been used for diastereoselective cycloaddition reactions using chiral 0-menthoxy-activated dienes derived from (-)-menthol, giving up to 84% de [24b,c] it has also been used for the synthesis of optically pure saccharides. 

It has been shown that ytterbium tris-(l )-(-)-l,l -binaphthyl-2,2 -diyl phospho-nate can catalyze the reaction of aromatic aldehydes with Danishefsky s diene to... 

Chiral boron(III) complexes can catalyze the cycloaddition reaction of glyoxy-lates with Danishefsky s diene (Scheme 4.18) [27]. Two classes of chiral boron catalyst were tested, the / -amino alcohol-derived complex 18 and bis-sulfonamide complexes. The former catalyst gave the best results for the reaction of methyl glyoxylate 4b with diene 2a the cycloaddition product 6b was isolated in 69% yield and 94% ee, while the chiral bis-sulfonamide boron complex resulted in only... 

The cycloaddition reaction between ethyl glyoxylate 4a and Danishefsky s diene 2a has been investigated by Ghosh et al. applying catalyst systems derived from Cu(OTf)2 and ligands (S)-Ph-BOX (S)-21a, (S)-t-Bu-BOX (S)-21b, and the confer-... 

Few investigations have included chiral lanthanide complexes as catalysts for cycloaddition reactions of activated aldehydes [42]. The reaction of tert-butyl glyoxylate with Danishefsky s diene gave the expected cycloaddition product in up to 88% yield and 66% ee when a chiral yttrium bis-trifluoromethanesulfonylamide complex was used as the catalyst. 

Polymer-supported BINOLs thus prepared were treated with Zr(Ot-Bu)4 to form polymer-supported zirconium 20. In the presence of 20 mol% of various zirconium 20, the model aza Diels-Alder reactions of imine Id with Danishefsky s diene (7a) were performed results from selected examples are shown in Table 5.8. Whereas the 4-t-butylphenyl group resulted in lower enantiomeric excess (ee), higher ee were obtained when 3,5-xylyl, 4-biphenyl, 4-fluorophenyl, and 3-tri-... 

For imines, a-imino esters with an N-p-methoxyphenyl substituent (21b) also reacted with Danishefsky s diene in the presence of 10 mol% of CUCIO4-T0I-BINAP to give the corresponding adduct in high yield with good enantiomeric excess (Scheme 5.10). Remarkably, reverse enantioselectivity was observed when the a-imino esters 21a and 21b were used. This notable selectivity was explained by as-... 

The mechanism for the hetero-Diels-Alder reaction of benzaldehyde 9 with the very reactive diene, Danishefsky s diene 10, catalyzed by aluminum complexes has been investigated from a theoretical point of view using semi-empirical calculations [27]. The focus in this investigation was to address the question if the reaction proceeds directly to the hetero-Diels-Alder adduct 11, or if 11 is formed via a Mukaiyama aldol intermediate (Scheme 8.4) (see the chapter dealing with hetero-Diels-Alder reactions of carbonyl compounds). 

Fig. 8.13 Schematic representation of the change in energies for the concerted hetero-Diels-Alder reaction of benzaldehyde with Danishefsky s diene and the step-wise reaction...

The structures along the reaction path in Fig. 8.13 are outlined in Fig. 8.14 starting with benzaldehyde activated by (MeO)2AlMe in the reaction with Danishefsky s diene 10 leading to the transition-state structure for the formation of the al-dol-like intermediate, and finally the formation of the hetero-Diels-Alder adduct. 

Danishefsky s diene 154 DBFOX 232 dendrimers 229 DPT calculations 308 diacetone glucose derived-titanium(IV) 178 diastereoselectivity 216 diazo compounds 242 diazoalkane cycloadditions 278 diazoalkanes 213, 231 (R,R)-4,6-dibenzofurandiyl-2,2 -bis(4-phenylox-azoline) 250... 

Node and co-workers have found that the Diels-Alder reaction of nitroalkenes v/ith 1-methoxy-3-trimethylsilyloxy-l,3-butadiene (Danishefsky s dienesi exhibit abnormal exo-se-lecdvity Electrostadc repulsion between the nitro and the silyloxy group of the diene induces this abnormal exc-selecdvity (Tq 8 10 This selecdve reacdon has been used for the asymmetric synthesis of various naniral products as shovm in Scheme 8 6... 

The Diels-Alder reaction of nitroalkenes with Danishefsky s dienes is applied to synthesis of truncated carbocyclic analogues of a potent neuraminidase inhibitor 4-guanidino-NemAc en fsee Scheme 8.5. Carbocyclic analogs are found to retain interesting levels of antiviral activity comparable to those shovm by their oxygen-containing compounds in Scheme 8.5. 

Node and coworkers have used this aromadzadon strategy for the synthesis of (-) aphanor-phineThe Diels-Alder reacdon of chiral nitroalkene, prepared by the asymmecdc nitrooleft-nation reacdon of ct-methyl-o-valerolactone, with the Danishefsky s diene followed by aromadzadon is used as a key step for this total synthesis, as shown in Scheme 8 6... 

Asyrrunetiic Diels-Alder reacdons using chuMsulfinylalkenes have been extensively snidied by Koiziuru and coworkers Fuji and coworkers have extended this strategy to chirM 1-falkyl-sulfinyl -2-nitroalkenes Such nltroalkenes react v/ith reacdve dienes such as Danishefsky s dienes to produce an adduct v/ith a high enandomeric excess fee fsee Eqs 8 34 and 8 35 ... 

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... 

IPreparation of l-methoxy-3-trimethylsilyloxybuta-l, 3-diene (Danishefsky s Idiene) and Diels-Alder addition with maleic anhydride. 

Danishefsky s diene, 134 Darzens reaction. 21 ( )-Dec-4-enoicacid, 115-14 Desilylation... 

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