Oxindole total synthesis

Asymmetric cyclization using chiral ligands has been studied. After early attempts[142-144], satisfactory optical yields have been obtained. The hexahy-dropyrrolo[2,3-6]indole 176 has been constructed by the intramolecular Heck reaction and hydroaryiation[145]. The asymmetric cyclization of the enamide 174 using (S j-BINAP affords predominantly (98 2) the ( )-enoxysilane stereoisomer of the oxindole product, hydrolysis of which provides the ( l-oxindole aldehyde 175 in 84% yield and 95% ec. and total synthesis of (-)-physostig-mine (176) has been achieved[146]. 

Yu, Q.S. Lu, B.Y (1994) Total Synthesis of Racemic Physostigmine, Physovenine and its Sulfur Analog by the Oxindole-5-O-tetrahydropyranyl Ether Route. Heterocycles, 39, 519-525. 

ABSTRACT The acid-catalysed epimerization reaction of bioactive indole alkaloids and their derivatives is reviewed. The three mechanisms, which have been proposed for the (J-carboline-type indole alkaloids, are discussed. Through recent developments, evidence for all three mechanisms has been obtained, which shows the complexity of the epimerization reaction. The epimerization seems to depend on structural features and reaction conditions making it difficult to define one universal mechanism. On the other hand, the isomerization mechanism of oxindole alkaloids has been widely accepted. The acid-catalysed epimerization reaction provides a powerful tool in selectively manipulating the stereochemistry at the epimeric centre and it can also have a marked effect on the pharmacology of any epimerizable compound. Therefore, examples of this reaction in die total synthesis of indole alkaloids are given and pharmacological activities of some C-3 epimeric diastereomers are compared. Finally, literature examples of acid-catalysed epimerization reactions are presented. 

In the event, formation of the enolatc of 18 using lithium hcxamethyldisilazide in THF at -78 "C followed by quenching with allyl bromide gave oxindole 19 in 88% yield, establishing the quaternary center at the C(3) position. Since the conversion from oxindole 19 to geneserine (20) was known [18], this constitutes a formal total synthesis of the natural product. 

The versatile oxindole nucleus has been stitched into designs for the total synthesis of other heterocyclic systems including the hexahydropyrroloindoles esermethole and physostigmine <07CEJ961> as well as pyrrolidinoindoline natural products <07TL1805>. ... 

The transformation of indole into corresponding oxindole alkaloids has been possible for some time now the reverse sequence has been achieved. The type of 2,3-seco-intermediate (47) arrived at by total synthesis above has been pro-duced " and then cyclized, in both heteroyohimbine (Scheme 12) and yohimbine... 

The total synthesis of d/-21-oxo-gelsemine reported by Hart and collaborators (107) features two free radical cyclizations (C-5-C-16 bond formation in gelsemine) to construct both a tricyclic substructure 314 in the terpene part of gelsemine and the spiro-oxindole moiety. The synthesis was initiated with the Diels-Alder reaction between A-methylmaleimide and the diene 302, followed by treatment of the crude cycloadduct with 2,2-dimethyl-l,3-propanediol and a catalytic amount of p-toluenesulfonic acid, to give the perhydro-isoindole 304 in 43% yield. By application of the Grieco dehydra-... 

Abstract This chapter provides an overview of emerging strategies for the selective introduction of functionality at oxindole C3. Specific emphasis has been devoted toward asymmetric methods for the introduction of C3 quaternary centers and spirocyclic ring systems. The chapter has been divided into two sections oti general methodology for the stereoselective synthesis of oxindoles and spirooxin-doles, respectively. A third section is devoted toward efforts in natural product total synthesis involving oxindole or spirocyclic variants as targets or key intermediates. 

Within the following sections on general methodology, examples of oxindoles with relatively simple substitution patterns have been selected for making reasonable comparisons between different strategies for bond construction. Applications of methods toward the synthesis of densely functionalized oxindoles within sensitive chemical environments appear within the section on natural product total synthesis. 

The rich and diverse history of investigation within the realm of oxindole natural product total synthesis has resulted in an outpouring of literature on that topic. As the confines of this chapter prevent a comprehensive review of those works, this... 

The attempted total synthesis " of 6-hydroxy-2 -(2-methylpropyl)-3,3 -spiro-(tetrahydropyrrolidino)-oxindole (127), an alkaloid of the dried root bark of Eleagnus communis (Wolf willow, or silverberry), " resulted in the formation of the epimer (128), or a mixture of (127) and (128) (Scheme 14). The final product showed great similarity to, but was not identical with, the alkaloid (127) however, (127) and the synthetic material gave the same product on acetylation, the reaction conditions for which presumably allowed epimerization at C-2. ... 

Wittig reaction on ketone 300 was followed by acidic hydrolysis of the vinyl ether to provide aldehyde 290. Reduction of the aldehyde group with NaBHa resulted in the synthesis of (—)-affinisine oxindole (118) in 34% yield (over three steps). Consequently, the stereospecific total synthesis of the sarpagine-related (—)-affinisine oxindole (118) was accomplished in 11 steps and in 10% yield from d-(+)-tryptophan (155). 

Asymmetric intramolecular carbopalladation is an effective reaction for producing enantioenriched polycycles. Most examples are intramolecular Heck reactions. One seminal example from natural product synthesis is the 5-exo carbopalladation of eneamide 201 to oxindole 202 (after acid treaunent) from a total synthesis of ( )-physostigmine 203 (Scheme The reaction occurs in 84% yield with 95% ee,... 

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