DIELS-ALDER Cyclohexene Synthesis

DIELS - ALDER Cyclohexene synthesis A 2 Thermal cycloaddition between a diene and an activated alkene or alkyrte, sometimes catalyzed by Lewis acids. 

DIELS - ALDER Cyclohexene synthesis 95 DtMROTH Rearrangement 96 DJERASSI - RYLANDER Oxidation 97 Doebner 205... 

A number of cyclohexene derivatives can be cleaved thermally to an olefin and a diene, preferably by passage in the vapor phase over red-hot metal wires. This is the reverse of the Diels-Alder diene synthesis. The oldest example is the formation of isoprene from dipentene described by Harries and Gottlob 96... 

Cyclopentene-l-carboxaldehydes are obtained from cyclohexene precursors by the sequence cyclohexene - cyclohexane-1,2-diol -> open-chain dialdehyde - cyclopentane aldol. The main advantage of this ring contraction procedure is, that the regio-and stereoselectivity of the Diels-Alder synthesis of cyclohexene derivatives can be transferred to cyclopentane synthesis (G. Stork, 1953 G. BUchi, 1968). 

Diels-Alder reaction (Section 10 12) Conjugate addition of an alkene to a conjugated diene to give a cyclohexene denva tive Diels-Alder reactions are extremely useful in synthesis... 

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 ... 

Diels-Alder reaction of 2-cyclohexen-l-one (37) with diene 38 mainly afforded the exo adduct 39, the key intermediate in the synthesis of the bottom half of chlorothricolide [14] (Equation 5.4). 

Posner G. H. Stereocontrolled Synthesis of Functionalized Cyclohexenes Via Diels-Alder Cycloadditions of 2-Pyrones and 2-Pyridones-Applications to Synthesis of Physiologically Active Compounds in Stereocontrolled Org. Synth. 1994 177, Ed. Trost B. M., Pb. Blackwell Oxford... 

Neier and coworkers have used a domino Diels-Alder/Ireland-Claisen process for the synthesis of (rac)-juvabione 4-46 and (rac)-epijuvabione [15]. Since neither the Diels-Alder reaction of the acetal 4-44 and methyl acrylate nor the sigmatropic rearrangement seemed to be stereoselective, these authors obtained the cyclohexene derivative 4-45 as a mixture of three diastereomers (Scheme 4.9). 

The Diels-Alder reaction is one of the most important carbon-carbon bond forming reactions,521 522 which is particularly useful in the synthesis of natural products. Examples of practical significance of the cycloaddition of hydrocarbons, however, are also known. Discovered in 1928 by Diels and Alder,523 it is a reaction between a conjugated diene and a dienophile (alkene, alkyne) to form a six-membered carbo-cyclic ring. The Diels-Alder reaction is a reversible, thermally allowed pericyclic transformation or, according to the Woodward-Hoffmann nomenclature,524 a [4 + 2]-cycloaddition. The prototype reaction is the transformation between 1,3-butadiene and ethylene to give cyclohexene ... 

METHOXYCARBONYL-1,1,6-TRIMETHYL-1,4,4a,5,6,7,8,8a-OCTAHYDRO-2,3-BENZOPYRONE, an intramolecular Diels-Alder reaction is responsible for the diastereoselectivity. The stereoselective 1,4-functionalization of 1,3-dienes is exemplified by a two-step process leading to cis- and trans-1-ACETOXY-4-(DICARBOMETHOXYMETHYL)-2-CYCLOHEXENE. The effectiveness of a silyl hydride in providing a means for erythro-directed reduction of a p-keto amide is applied in a route to ERYTHRO-1 -(3-HYDROXY-2-METHYL-3-PHENYL-PROPANOYLJPIPERIDINE. This is followed by an asymmetric synthesis based on a chiral bicyclic lactam leading to (R)-4-ETHYL-4-ALLYL-2-CYCLOHEXEN-1-ONE. The stereoselectivity with which acetoxy migration can operate to an adjacent radical center is reflected in the one-step reaction that gives rise to 1,3,4,6-TETRA-O-ACETYL-2-DEOXY-a-D-GLUCOPYRANOSE. 

Diels-Alder reactions are, of course, reversible, and the pathway followed for the reverse reaction (2,3 arrows) can sometimes be as telling as the pathway for the forward reaction. The direction in which any pericyclic reaction takes place is determined by thermodynamics, with cycloadditions, like the Diels-Alder reaction, usually taking place to form a ring because two n-bonds on the left are replaced by two Diels-Alder reaction can be made to take place in reverse when the products do not react with each other rapidly, as in the pyrolysis of cyclohexene 2.3 at 600°. It helps if either the diene or the dienophile has some special stabilization not present in the starting material, as in the formation of the aromatic ring in anthracene 2.15 in the synthesis of diimide 2.16 from the adduct 2,14, and in... 

Another strategy for the synthesis of lycorine commenced with the Diels-Alder reaction of l-methylenedioxyphenyl-2-nitroethylene with butadiene to provide the cyclohexene derivative 85, which on reaction with MCPBA gave 86 together with the diastereomeric epoxide (1 1) (Scheme 6) (112). Hydrogena-... 

The cyclohexene 121, which was readily accessible from the Diels-Alder reaction of methyl hexa-3,5-dienoate and 3,4-methylenedioxy-(3-nitrostyrene (108), served as the starting point for another formal total synthesis of ( )-lycorine (1) (Scheme 11) (113). In the event dissolving metal reduction of 121 with zinc followed by reduction of the intermediate cyclic hydroxamic acid with lithium diethoxyaluminum hydride provided the secondary amine 122. Transformation of 122 to the tetracyclic lactam 123 was achieved by sequential treatment with ethyl chloroformate and Bischler-Napieralski cyclization of the resulting carbamate with phosphorus oxychloride. Since attempts to effect cleanly the direct allylic oxidation of 123 to provide an intermediate suitable for subsequent elaboration to ( )-lycorine (1) were unsuccessful, a stepwise protocol was devised. Namely, addition of phenylselenyl bromide to 123 in acetic acid followed by hydrolysis of the intermediate acetates gave a mixture of two hydroxy se-lenides. Oxidative elimination of phenylselenous acid from the minor product afforded the allylic alcohol 124, whereas the major hydroxy selenide was resistant to oxidation and elimination. When 124 was treated with a small amount of acetic anhydride and sulfuric acid in acetic acid, the main product was the rearranged acetate 67, which had been previously converted to ( )-lycorine (108). 

The total synthesis of ( )-lycoricidine (214) from the aryl cyclohexene 272, which was accessed by a Diels-Alder reaction of the carbinol 46, has been... 

Strained cyclohexenes, such as norbornene derivatives, can undergo retro-Diels-Alder reactions even at relatively low temperatures, and this reaction can be used to prepare 1,3-dienes and alkenes (e.g. synthesis of cyclopentadiene by thermolysis of... 

Fig. 9.5 The prototypical Diels-Alder reaction is that between 1,3-butadiene and ethene, to form cyclohexene. The Diels-Alder reaction has been used in the synthesis of complex natural products above, methyl 2,4-pentadienoate reacts with 1,4-benzoquinone to form an intermediate in the synthesis of the drug reserpine. In a one-pot reaction two carbon-carbon bonds are made and three chiral centers ( ) are created with the correct relative orientations (i.e. essentially one diastereomer is formed)...

The Diels-Alder reaction,1 e.g. 1 + 2, is one of the most important reactions in organic synthesis because it makes two C-C bonds in one step and because it is regio- and stereoselective. It is a pericyclic reaction between a conjugated diene 1 and an alkene 2 or 4 (the dienophile) conjugated with, usually, an electron-withdrawing group Z forming a cyclohexene 3 or 5. 

Heathcock required diester 23 for his synthesis of the antibiotic pentalenolactone.3 Reconnecting the esters gives the cyclohexene 24. We must change the two ether groups into carbonyl groups and one obvious starting material is 25, the Diels-Alder adduct of butadiene and maleic anhydride 26. 

Finally we can investigate the 1,6-dicarbonyl approach by reconnection 2d to give a cyclohexene that seems destined for synthesis by a Diels-Alder reaction from isoprene 11 and the enone 10 that can probably be made by a Mannich reaction on ethyl acetoacetate. 

Most importantly, the scope of the Diels-Alder reaction is very high - not only allowing the synthesis of cyclohexenes and 1,4-cyclohexadienes using 1,3-butadienes and alkenes and alkynes, respectively, but also giving access to a multitude of different heterocycles by exchanging the atoms a-d in the butadiene as well as the atoms e and f in the alkene by hetero atoms such as oxygen, nitrogen and sulfur. However, also dienes and dienophiles with several other atoms as phosphorous, boron, silicone, and selenium have been described. Thus, many different heterodienes and heterodienophiles have been developed over the years (Tables 1-1 and 1-2). 

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