Substituted 1,3-dienes, synthesis

Petrzilka, M., Grayson, J. I. Preparation and Diels-Alder Reactions of Hetero-Substituted 1,3-Dienes. Synthesis 1981, 753-786. 

M. Petrzilka and S. I. Grayson, Preparations and Diels-Alder Reactions of Hetero-substituted 1,3-Dienes, Synthesis, 1981, 753. 

The Diels-Alder adduct of sulpholene and cyclopen tadiene is a useful starting material for substituted diene synthesis The diene moiety is unmasked by retro-Diels-Alder reaction and sulphur dioxide extrusion under flash vacuum pyrolysis conditions (equations 74 and 75) . ... 

Cycloaddition involves the combination of two molecules in such a way that a new ring is formed. The principles of conservation of orbital symmetry also apply to concerted cycloaddition reactions and to the reverse, concerted fragmentation of one molecule into two or more smaller components (cycloreversion). The most important cycloaddition reaction from the point of view of synthesis is the Diels-Alder reaction. This reaction has been the object of extensive theoretical and mechanistic study, as well as synthetic application. The Diels-Alder reaction is the addition of an alkene to a diene to form a cyclohexene. It is called a [47t + 27c]-cycloaddition reaction because four tc electrons from the diene and the two n electrons from the alkene (which is called the dienophile) are directly involved in the bonding change. For most systems, the reactivity pattern, regioselectivity, and stereoselectivity are consistent with describing the reaction as a concerted process. In particular, the reaction is a stereospecific syn (suprafacial) addition with respect to both the alkene and the diene. This stereospecificity has been demonstrated with many substituted dienes and alkenes and also holds for the simplest possible example of the reaction, that of ethylene with butadiene ... 

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. 

Zard and coworkers have developed a synthesis of substituted dienes by reductive elimination of allylic nitroacetates (equation 33)66. Allylic nitroacetates can be prepared by condensation of nitromethane with the carbonyl compound followed by addition of formaldehyde and acetylation67. Reductive elimination can be carried out by employing either chromous acetate or samarium iodide. 

In this case, symmetrical substituted dienes are condensed to their respective ADMET polymers followed by hydrogenation to give a completely saturated polymer backbone. This technique gives control over the number of methylenes between branch points as well as the length and identity of the branch itself. However, synthesis of the required monomer 17 is a challenging six-step procedure. 

Complex hydrides have been used rather frequently for the conjugate reduction of activated dienes92-95. Just and coworkers92 found that the reduction of a,ft-unsaturated ketene 5,5-acetals with lithium triethylborohydride provided mixtures of 1,4- and 1,6-reduction products which were transformed into enals by treatment with mercuric salts (equation 27). Likewise, tetrahydro-3//-naphthalen-2-ones can be reduced with L-Selectride to the 1,6-reduction products93 -95 this reaction has been utilized in the stereoselective synthesis of several terpenes, e.g. of (/ )-(—)-ligularenolide (equation 28)95. Other methods for the conjugate reduction of acceptor-substituted dienes involve the use of methylcopper/diisobutylaluminum hydride96 and of the Hantzsch ester... 

Michael additions of organocopper reagents to acceptor-substituted dienes have found widespread application in target-oriented stereoselective synthesis [12]. For... 

The scope of the dienophile partner within the Diels-Alder reaction was further expanded in an insightful synthesis of (H-)-hapalindole Q by Kerr and co-workers [216]. Cycloaddition of A-protected indole 166 and substituted diene 167 catalysed by imidazoMinonium salt 12 HC1 (40 mol%) gave the densely functionalised Diels-Alder adduct 168 (35% yield 93% ee), which was converted to the target alkaloid (169) in eight steps (Scheme 67). 

Our initial studies focused on the transition metal-catalyzed [4+4] cycloaddition reactions of bis-dienes. These reactions are thermally forbidden, but occur photochemically in some specific, constrained systems. While the transition metal-catalyzed intermole-cular [4+4] cycloaddition of simple dienes is industrially important [7], this process generally does not work well with more complex substituted dienes and had not been explored intramolecularly. In the first studies on the intramolecular metal-catalyzed [4+4] cycloaddition, the reaction was found to proceed with high regio-, stereo-, and facial selectivity. The synthesis of (+)-asteriscanoHde (12) (Scheme 13.4a) [8] is illustrative of the utihty and step economy of this reaction. Recognition of the broader utiHty of adding dienes across rc-systems (not just across other dienes) led to further studies on the use of transition metal catalysts to facilitate otherwise difficult Diels-Alder reactions [9]. For example, the attempted thermal cycloaddition of diene-yne 15 leads only... 

Sundaram and co-workers [90TL(31)7357] prepared 1-methoxycarbonyl-substituted diene 354 and reported its reaction with dimethyl acet-eylenedicarboxylate in refluxing benzene affording cycloadduct 355 in 72% yield (Scheme 78) there is no comment in the report on the aromatiza-tion step, which should imply loss of both dimethylamino and methoxycar-bonyl groups. Similarly, the synthesis of pyrimidinone 356 (96% yield) was described to occur when 354 was stirred with phenylketene at room temperature. 

Systematic studies of topochemical reactions of organic solids have led to the possibility of asymmetric synthesis via reactions in chiral crystals. (A chiral crystal is one whose symmetry elements do not interrelate enantiomers.) (Green et al, 1979 Addadi et al, 1980). This essentially involves two steps (i) synthesis of achiral molecules that crystallize in chiral structures with suitable packing and orientation of reactive groups and (ii) performing a topochemical reaction such that chirality of crystals is transferred to products. The first step is essentially a part of the more general problem of crystal engineering. An example of such a system where almost quantitative asymmetric induction is achieved is the family of unsymmetrically substituted dienes ... 

Figure 8.14 Packing of unsymmetrically substituted diene molecules in a crystal, favouring photopolymerization leading to asymmetric synthesis. (After Addadi et al, 1980.)...

As an example of conversion of complex 111 to 113, optically pure complex 126 was used for the enantioselective total synthesis of shikimic acid (129) [30]. The hydroxy-substituted diene complex 127 was prepared from 126. Silylation and decomplexation of 127 gave 128. Stereoselective dihydroxylation of the more reactive double bond of the decomplexed silyl ether derivative 128, followed by desilylation afforded (—)-methyl shikimate (129). 

Alkyl-substituted oxazoles have been found to react with maleic acid or its anhydride in a diene synthesis to yield substituted pyridine readily converted to pyridoxine (39). In this route, ethyl d, 1-alaninate hydrochloride is treated with formic-acetic anhydride to yield ethyl N-formyl d,1-alaninate (78%). This compound is refluxed in chloroform with phosphorous pentoxide (40), quenched with aqueous potassium hydroxide, and the organic layer distilled to give 4-methyl-5-ethoxyoxazole (I) (60%). The resulting oxazole (I) is condensed readily with a number of appropriate dienophiles to form 2-methyl-3-hydroxy-4,5-disubstituted-pyridines containing substituents (III, a, b, c) which could be converted to pyridoxine as follows ... 

The latest paper in this field [83] concerns the synthesis of the (S,S)-l,l-bis-ethoxycarbonyl-2,2-bis-p-tolylsulfinylethene (83) and its dienophilic behavior. Reactions with cyclopentadiene occur neither under thermal conditions nor in the presence of Lewis acids, but required the use of high pressure (13 kbar) to afford an 87 13 mixture of 84a and 84b adducts. With acyclic 1-substituted dienes, the combined use of ZnBr2 catalysis and high pressures was required to achieve high yields of cyclohexadienes 84c, resulting from spontaneous pyrolytic desulfinylation of the adducts (Scheme 44). The optical purity of these cyclohexadienes (ee >97%) revealed that both the regioselectivity and diastereo-selectivity of these reactions are complete. 

The Lewis acid-promoted reaction of our oximinosulfonate with dienes and the conversion of the resulting cycloadducts to pyridines comprises a new annulation method for the synthesis of substituted pyridines from conjugated dienes. As illustrated in the Table, very good overall yields are obtained in reactions of 2-substituted dienes, providing 5-substituted pyridine-2-carboxylates. Reactions with 1-substituted dienes yield 3-substituted pyridines, and disubstituted dienes react smoothly to afford trisubstituted pyridines in good yield. Polycyclic systems are obtained when dienes such as 1-vinyl-1-cyclohexene are employed in the annulation. 

Serrano, J A, Caceres, L E, Roman, E, As3mimetric Diels-Alder reactions between chiral sugar nitroalkenes and 1-O-substituted buta-l,3-dienes. Synthesis and reactivity of new cyclohexenyl derivatives, J. Chem. Soc. Perkin. Trans 1, 1863-1871, 1995. 

An S 2 copper-catalyzed nucleophilic substitution of the chloride in a cyclic chloroacetate by butylmagnesium bromide was employed in a synthesis toward perhydrohistrionicotoxin [Eq.(47)] [79]. Histrionicotoxins are found in South American dart-poison frogs of the Dendrobatid family. Palladium-catalyzed chloroacetoxylation of 2-substituted diene 68 gave a highly regio- and stereoselective 1,4-addition product where the chloride ends up in the 1-position. Copper-catalyzed reaction of the chloroacetate 69 with butylmagnesium... 

The cycloadditions of achiral oxy-substituted dienes with aldehydes in the presence of enantiomerically pure (+)-Eu(hfc)3 [hfc = 3-(heptafluoropropylhydroxymethylene)-(+)-cam-phorate] shows only modest enantioselectivities. Similarly, modest diastereoselectivities are observed for the reactions of chiral oxy-substituted dienes with aldehydes in the presence of achiral Eu(fod)3 (fod = 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedienoate). However, the combination of chiral dienes with chiral (+)-Eu(hfc)3 catalyst shows interesting interactivities, resulting in some instances in diastereoselectivities of 97 3. This has permitted a total synthesis of L-glucose [336,337,338]. 

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