Reserpine synthesis using Diels-Alder reaction

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)...

Waldmann used (R) and (5>aminoacid methyl esters and chiral amines as chiral auxiliaries in analogous aza-Diels-Alder reactions with cyclodienes.111 The diastereoselectivity of these reactions ranged from moderate to excellent and the open-chain dienes reacted similarly. Recently, the aza-Diels-Alder reaction was used by Waldmann in the asymmetric synthesis of highly functionalized tetracyclic indole derivatives (Eq. 12.45), which is useful for the synthesis of yohimbine- and reserpine-type alkaloids.112... 

Easily prepared from glycols, enones have been investigated as dienophiles. They react with butadiene under Lewis acid catalysis to form chiral cyclohexenes used in the synthesis of compactin analogs [353]. Levoglucosenone has been used in a Diels-Alder reaction with acetoxy-butadiene to construct a part of the indole alkaloid reserpine [354], and in synthetic studies toward tetrodotoxin [355]. Analogs of the anthracycline rhodomycinone have been similarly prepared [356]. [4 + 2]-Cycloaddition of the same enone with silyloxydiene allowed the creation of the fused ring system present in actinobolin [357]. 

A second milestone in organic synthesis is the total synthesis of the indole alkaloid reserpine by Woodward in 1956 [2] using a Diels-Alder reaction as the key step (Scheme 2), and finally with the total synthesis of palytoxin in 1994, the toxin of dinofiagellate Ostreopsis siummsis, with 64 stereogenic centers and several (Eland (Z)-double bonds, Kishi [3] has shown that chemists can prepare any organic compound (Scheme 3). 

Oxy-Cope rearrangements (95, 98, 99) have been extensively used in natural product synthesis to generate l-oxo-hexa-l,5-diene systems which are then elaborated to introduce the functionality presented in the selected targets. Wender and his coworkers have utilized this methodology in a key step in the synthesis of reserpine (36, 37). They envisioned that the DE-ring precursor 128 could arise from the hydroisoquinoline 129 which could be generated by oxy-Cope rearrangement of isoquinuclidene 130 (Scheme 3.20). This key intermediate, in turn, could be prepared by Diels-Alder reaction of dihydropyridine 131 with an appropriately substituted dienophile 132. 

A new multistep synthesis of ( )-reserpine (109) has been published by Wender et al. (258). The key building block of the synthesis is cw-hexahydroiso-quinoline derivative 510, prepared by the extension of the previously elaborated (259) Diels-Alder addition-Cope rearrangement sequence. Further manipulation of 510 gave 2,3-secoreserpinediol derivative 512, which already possesses the required stereochemistry in ring E. Oxidative cyclization of 512 yielded 3-isoreserpinediol (513), which was transformed by the use of simple reaction... 

---