Siloxy dienes

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. 

This novel Bronsted acid catalyzes the Diels-Alder reaction between ethyl vinyl ketone and various acycUc siloxy dienes to furnish adducts in uniformly high yields and ee s. Further, the corresponding chiral phosphoric acid was unable to catalyze this reaction. 

The key intermediate in the synthesis of the derivatives of 19-F3-androstane is the trifluoro analogue of the Wieland-Miescher ketone. Its preparation involves a Diels-Alder reaction between a trifluoromethyi ketone and a siloxy diene. Another original step is the regioselective reduction of a diketone only the ketone function in P of CF3 (probably activated by this substituent) is reduced (Figure 4.6). " Then, a succession of classical reactions leads to derivatives of androstane from the trifluoro analogue of the Wieland-Miescher ketone (Figure 4.7). ... 

Cyclocondensation of 2-siloxy dienes and aldehydes is catalyzed by 1 mol % of a soluble lanthanide complex, Eu(hfc)3, and gives the hetero-Diels-Alder adduct in up to 58% ee (Scheme 107) (263). Upon treat-... 

The control of regiochemistry has been rationalized on the basis of the orbital coefficients of the HOMOs and LUMOs, but in fact, it is not well understood. In most cases such cycloadditions are not regiospecific and isomeric mixtures are formed, although one regioisomer usually predominates. Qualitative estimation of the electron distributions in the diene and dienophile can often be used to predict the major product. For example, C-l of siloxy diene (A) should be much more electron rich than C-4. In addition C-3 of acrylate (B) should be more electron deficient than C-2. 

The HDA reaction allows for rapid access to chiral six-membered heterocyclic structures that serve as valuable intermediates in organic synthesis. The first highly enantioselective HDA reaction promoted by a chiral hydrogen bond donor was reported from the Rawal laboratory. While investigating the cycloaddition reactions of amino-siloxy diene 115, it was observed that this diene was exceptionally reactive to heterodienophiles, and underwent HDA reactions with various aldehydes at room temperature, even in the absence of any added catalyst (Scheme 6.14). Subsequent treatment of the intermediate cycloadducts (116) with acetyl chloride afforded the corresponding dihydro-4-pyrones (117) in good overall yields [101]. Further studies of this reaction revealed a pronounced solvent effect,... 

Scheme 6.14 Uncatalyzed HDA reactions of amino-siloxy diene with aldehydes.

Taddol-Catalyzed Hetero-Diels-Alder Reaction of l-Aldimine-3-Siloxy Dienes [87] (p. 236)... 

Recently, a few examples of imino Diels-Alder reactions using azetinones as dienophiles have been described in work aimed at synthesis of carbapenems. In one sequence of reactions, acetate (34) was treated with a Lewis acid in the presence of a siloxy diene to afford adduct (36) (equation ll). This transformation presumably involves imine (35) which reacts both regio- and stereo-selectively with the diene. Adduct (36) was converted in a few steps to carbapenem (37). 

Danishefsky et al. [9] reported that stereochemical outcome of cyclocondensation of aldehydes and siloxy dienes was highly dependent on the nature of Lewis acid catalysts. When the reaction of diene 1 and benzaldehyde 2 was performed using BF3 OEt2 consistent tram (threo) selectivity was observed (cis-3/trans-3 = 13) (Sch. 1). High cis specificity was, however, observed in the presence of MgBr2 or ZnCl2 cisitrans = 38 1 and 39 1, respectively). 

Aben and Scheeren discovered that bornyloxyaluminum dichloride, which can be easily prepared from bomeol, aluminum chloride, and lithium alanate, acts as an effective catalyst for the hetero Diels-Alder reaction of siloxy dienes and a variety of aldehydes, as illustrated in Sch. 18 [37]. 

Danishefsky, S., Kitahara, T. Useful diene for the Diels-Alder reaction. J. Am. Chem. Soc. 1974, 96, 7807. Danishefsky, S. Siloxy dienes in total synthesis. Acc. Chem. Res. 1981, 14, 400-406. 

Aminosiloxy dienes have been found to exhibit unusually high reactivity in Diels-Alder reactions with a wide range of electron-deficient dienophiles.2 5 Determination of the second order rate constants with methacrolein showed the parent aminosiloxy diene to be about 103 more reactive than the analogous 1-alkoxy-3-siloxy diene.4 The reactions of aminosiloxy dienes with various dienophiles occur under mild conditions and afford the corresponding cycloadducts in high yields and with complete regioselectivity. An extensive study on the preparation and cycloadditions of amino siloxy dienes has been carried out.3... 

The three-step procedure above illustrates the usefulness of a 1-amino-3-siloxy diene for the synthesis of functionalized cyclohexenones and is representative of the general usefulness of the dienes. The first step in the sequence, the Diels-Alder reaction between the parent aminosiloxy diene nd methyl acrylate, cleanly produces the cycloadduct as a mixture of endo and exo diastereomers. This diene also reacts with many other dienophiles and the results are summarized in Table I.3 The cycloadducts are generally obtained as mixtures of endo-exo diastereomers, except for the reactions with N-phenylmaleimide and methacrolein, which proceed with high endo selectivity, and with dimethyl maleate, which gives predominantly the exo adduct. 

Heteroatom-based siloxy dienes have received attention in recent years as an efficient method for building up ring frameworks. The subject has been reviewed, and only a few applications are illustrated here [135], This is a powerful process, since in a relatively small number of steps several rings can be joined together. The hrst two equations [136,137] of Scheme 80 show how a single butenolide unit can be attached, while the last sequence illustrates an iterative methodology [138]. It should he noted that in the addition of trimethylsiloxy furan to the anomeric acetate. 

Siloxy dienes have been shown to be highly effective in both the Diels-Alder reaction and the hetero Diels-Alder (diene-aldehyde cyclocondensation) reactions. Diene 3 has been used in the synthesis of several important naturai products including zincophorin, rifamycin, and the Prelog-Djerassi laclone. Recently, under the aegis of chiral catalysts, 3 has been shown to participate in the diene-akJehyde cyclocondensation reaction with several aldehydes to afford cycloadducts of very high enantiomeric excess. ... 

In the dienol silyl ether (63), where the 7-selectivity of the siloxy diene is enhanced by the second sil-oxy substituent, reactions with electrophiles occur exclusively in the 7-position as illustrated in Scheme... 

The a-germylated ester (164) reacts with a number of aldehydes and acetals in the presence of Lewis acid to give, regioselectively, the y-products (Scheme 55). In that sense the germanium-masked di-enolate behaves like the siloxy dienes in their regioselection. 

Nucleophiles other than hydrides can be used, such as aUylsilanes, siloxy-dienes, or silyl enol ethers, to access substituted THPs from cyclic ketals. Rych-novsky et al. and Wipf et al. synthesized one THP of leucascandrolide A from ketal 76 by using a nucleophilic addition of aUylsilane in the presence of BF3 Et20. The diastereoselectivity of the reaction was explained by an axial attack on the half-chair oxocarbenium intermediate. The double bond was then transformed into the corresponding aldehyde by ozonolysis to afibrd further functionalizations (Scheme 38) (2001JA8420 2002CC2066). 

Danishefsky et al. have achieved a synthesis of a methyl peracetyl-oc-hikosaminide (216), an undecose degradation product of the anthelmintic hikizimycin, in which use is twice made of the siloxy-diene aldehyde Diels-Alder reaction. Thus, the reaction between the diene (211) and furfural with [EuCfod) ] catalysis leads to the pyrone (212) which, after elaboration to (213), is again condensed with (211), but this time with magnesium bromide catalysis, which causes addition of the remaining four carbon atoms of the undecose in a chelation-controlled and, notably, a topically exo reaction. Elaboration of (215) to the required protected hikosamine (216) then follows in a straightforward manner. 

Silyl enol ethers, silyl ketene acetals, silyl triflatcs and siloxy dienes. ... 

Synthetic routes to siloxy dienes are described, these ccnnpounds... 

Siloxy dienes can be converted to bicyclo-[3.2.1]octane derivatives via 2-siloxy-2-alkenyl-l,l-dichlorocyclopropanes synthesized from the former. The dichlorocyclopropanes with aryl-terminated side chains undergo silver-assisted electrocyclic opening to furnish 2-siloxycyclopentenyl cations, which in turn are intercepted by the pendant arenes to furnish the product, that is, by Nazarov cyclization (Scheme 6.44) [49]. 

Synthesis of Vinylogous Esters.—The versatility of 3-ethoxycyclohex-2-enone as a starting material for the synthesis of substituted cyclohexanones has again been demonstrated. A range of vinylogous esters are obtained by the Lewis-acid-catalysed cyclocondensation of siloxy-dienes with saturated and ap-unsaturated aldehydes (Scheme 80). The reactions are applied to the synthesis of several compounds of biological interest. 

Another cycloaddition, in which this time the silyl enol ether functions as a dienophile, is the SnCl4-catalysed addition of butadiene to (180 R = Me) giving (181). If R = H in the starting material a 4 + 3 reaction takes place, producing the seven-membered ring (182). Flash-vacuum thermolysis of P-keto-trimethylsilyl enol ethers has been used in a substituted furan synthesis, and the same process has been used to prepare a-allenic acids (183) from siloxy-dienes. ... 

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