Asymmetric oxindoles

An intermolecular cyclization approach to C3 asymmetric oxindoles has been devised by Smith and coworkers who paired chiral A-phenylnitrone nucleophiles with ketene electrophiles, e.g., intermolecular fusion of 54 and 55 [37]. As illustrated in Scheme 16, the oxindole skeleton 57 materialized in 87% ee following a proposed sequence of nitrone addition to the ketene, a hetero-Claisen rearrangement, imine hydrolysis and, finally, cyclization to generate the lactam linkage. As an extension of this methodology, (5)-3-allyl-3-phenyloxindole 57 was transformed into enantiopure 3-phenyl-hexahydropyrroloindole scaffold 58. 

Oxindoles with defined stereochemistry at C3 have served as valuable precursors for entry into tetrahydro- or hexahydropyrroloindole natural product scaffolds. As illustrated in Table 1, a variety of approaches to asymmetric oxindole synthesis have been applied for introduction of the key C3 stereocenters embodied within (+)-aUine [84, 85], CPC-1 [86], ( )-esermethole (a formal synthesis of ( )-physostigmine) [87-90], (+)-gliocladin C [91], and (-l-)-asperazine [92]. 

Figure 4.24 Asymmetric oxindole synthesis via intramolecular a-arylations.

Scheme 8.45 Asymmetric oxindole synthesis with Pd-NHC catalyst, as described by Dorta and coworkers...

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]. 

Trost and his co-workers succeeded in the allylic alkylation of prochiral carbon-centered nucleophiles in the presence of Trost s ligand 118 and obtained the corresponding allylated compounds with an excellent enantioselec-tivity. A variety of prochiral carbon-centered nucleophiles such as / -keto esters, a-substituted ketones, and 3-aryl oxindoles are available for this asymmetric reaction (Scheme jg) Il3,ll3a-ll3g Q jjg recently, highly enantioselective allylation of acyclic ketones such as acetophenone derivatives has been reported by Hou and his co-workers, Trost and and Stoltz and Behenna - (Scheme 18-1). On the other hand, Ito and Kuwano... 

Organometallic compounds asymmetric catalysis, 11, 255 chiral auxiliaries, 266 enantioselectivity, 255 see also specific compounds Organozinc chemistry, 260 amino alcohols, 261, 355 chirality amplification, 273 efficiency origins, 273 ligand acceleration, 260 molecular structures, 276 reaction mechanism, 269 transition state models, 264 turnover-limiting step, 271 Orthohydroxylation, naphthol, 230 Osmium, olefin dihydroxylation, 150 Oxametallacycle intermediates, 150, 152 Oxazaborolidines, 134 Oxazoline, 356 Oxidation amines, 155 olefins, 137, 150 reduction, 5 sulfides, 155 Oxidative addition, 5 amine isomerization, 111 hydrogen molecule, 16 Oxidative dimerization, chiral phenols, 287 Oximes, borane reduction, 135 Oxindole alkylation, 338 Oxiranes, enantioselective synthesis, 137, 289, 326, 333, 349, 361 Oxonium polymerization, 332 Oxo process, 162 Oxovanadium complexes, 220 Oxygenation, C—H bonds, 149... 

An isomerization reaction closely similar to that observed with indole alkaloids has been noted with oxindole alkaloids. Due to their facile isomerization, it is pharmacologically difficult to test the individual oxindole isomers expected to have different activities. Instead of epimerization the term isomerization has been used with oxindole alkaloids since inversion of configuration can occur in more than one asymmetric centre. Isomerization was employed mainly to provide structural proof of different oxindole epimers isolated in nature. As early as 1959, Wenkert and co-workers [42] proposed a mechanism for the isomerization of oxindole alkaloids, Scheme (17). Almost simultaneously, Seaton et al. [43] reported analogous findings. 

Asymmetric Heck cyclizations to form chiral 3,3-disubstituted oxindoles were key strategic steps in enantioselective syntheses of the pyrroloindoline alkaloids (-)-phy sostigmine fl.l [39], (-)-physovenine (fl.2) [39], and complex dodecacyclic polyindolines such as fl.3 (Figure 8G. 1) [40],... 

Both experimental and theoretical studies have been reported of fluoro-denitration and fluoro-dechlorination reactions using anhydrous tetrabutylammonium fluoride in DMSO. The absences of ion pairing and strong solvation are critical in contributing to the reactivity of the fluorinating agent24 Quaternary ammonium salts derived from cinchona alkaloids have been shown to be effective catalysts in an improved asymmetric substitution reaction of /1-dicarbonyl compounds with activated fluoroarenes. The products may be functionalized to yield spiro-oxindoles.25... 

Organocatalytic asymmetric alkylation methodology has also been efficiently applied in a practical multi-gram synthesis of pharmaceutically interesting, optically active (—)-physostigmine analogs [7]. In the presence of 15 mol% of the catalyst 13 alkylation of the oxindole substrate 12 with chloroacetonitrile furnished the desired product 14 in 83% yield and 73% ee (Scheme 3.3, Eq. 2). The counter-ion of the... 

Interestingly, cyclic / -keto esters, e.g. 69, can be also fhiorinated with enantioselectivity up to 80% ee, although the yield and enantioselectivity depend strongly on the type of substrate. A representative example of asymmetric fluorination of a cyclic ester is shown in Scheme 3.27, Eq. (2). In addition, oxindoles 71 have been successfully fhiorinated, as shown in Scheme 3.27, Eq. (3). Under optimized conditions, the desired 3-substituted 3-fluorooxindole, 72, was obtained in 79% yield and with enantioselectivity of 82% ee. 

This chapter summarizes three related and highly effective approaches to the catalytic asymmetric generation of quaternary stereocenters - organocatalytic rearrangements of O-acyl azlactones to their C-acylated isomers and analogous isomer-izations of O-acyl oxindoles and O-acyl benzofuranones. All three processes hold great promise for application in, e.g., natural product synthesis [91-93],... 

The asymmetric Heck cyclization of 5.15 takes place with high enantioselectivity (71-98%) with the Pd-BINAP catalyst to form the corresponding 3-alkyl-3-aryloxindole ° 5.16. A wide variety of aryl and heteroaryl substituents can be introduced into an oxindole by this method. This asymmetric synthesis of 3-aryl- or 3-heteroaryl oxindoles is very useful for the enantioselective synthesis of a range of indole alkaloids k... 

Asymmetric Alkylation. 7Y-[4-(Trifluoromethyl)benzyl]-cinchoninium bromide (1) has been used as chiral phase-transfer catalyst in the alkylation of indanones (eq 1). For the alkylation of a-aryl-substituted carbonyl compounds the diastere-omeric 7Y-[4-(trifluoromethyl)benzyl]cinchonidinium bromide (2) was used to obtain the opposite stereochemistry (eqs 2 and 3). The asymmetric alkylation of oxindoles was used as the key step in an asymmetric synthesis of (—)-physostigmine (eq 4). ... 

The first examples of asymmetric Heck cyclizations that form quatemaiy carbon centers with high enantioselectivity came from our development of an asymmetric synthesis of the pharmacologically important alkaloid (—)-physostigmine (184) and congeners (Scheme 6-31) [68]. In the pivotal reaction, (Z)-2-butenanilide iodide 182 was cyclized with Pd-(5)-BINAP to provide oxindole 183 in 84% yield and 95% ee after hydrolysis of the intermediate silyl enol ether. With substrates of this type, cyclizations in the presence of halide scavengers took place with much lower enantioselectivity [68]. 

Cravotto, G., Giovenzana, G. B., Pilati, T., Sisti, M., Palmisano, G. Azomethine Ylide Cycloaddition/Reductive Heterocyclization Approach to Oxindole Alkaloids Asymmetric Synthesis of (-)-Horsfiline. J. Org. Chem. 2001, 66, 8447-8453. 

There has also been considerable interest and progress in the development of asymmetric Heck reactions (AHR) [68], This methodology allows for the preparation of enantiomerically enriched products from achiral substrates using a catalytic amount of a chiral palladium complex, making the process practical and economical. For example, treatment of triflate 71 with catalytic Pd(OAc)2/(R)-BlNAP provided oxindole 72 in 96% yield and 88% ee [69]. 

A radical cyclization approach to spiro-oxindoles was revealed <05OL151>. Treatment of p-trityloxybenzamide 125 with triethylborane and tris(trimethylsilyl)silane gave cyclohexadienone 126 via an ipso cyclization. The nucleophilic aromatic substitution of aryl fluorides was utilized in an asymmetric approach to spiro-pyrrolidone oxindoles <05JA3670>. 

Two ° independent and different degradations have been carried out to establish the absolute stereochemistry, and in each case the final compound contained only the C(3a) asymmetric centre. One approach was to degrade the alkaloid to the oxindole (10), the enantiomorph of which was then synthesised starting from (R)-( — )-2-methyl-2-phenylbutyric acid. In the second approach the molecule was broken down to an amino-acid (11) which was characterised as its 2,4-dinitrophenyl derivative. Its enantiomer was synthesised from 3-ethyl-3-methoxycarbonyl-3-methylpropionic acid of known absolute configuration. 

In a homolytic cyclization, a side-chain alkene displaces a neighbouring nuclear bromine atom on heating the compound in toluene with tributyltin hydride and AIBN. An optical purity of 39% is observed when an asymmetric A/ -substituent is present. Palladium dia< tate-catalysed cyclization (reviews [B-41,3069,3505] of the bromoester (39.1) gives the oxindole in moderate yield the product may consist of a mixture of stereoisomers for example, when R = Ph, one isomer predominates in the ratio 60 13. 

With Ag3P04 as additive for an intramolecular Heck reaction to form 3,3-disubstituted oxindoles considerable variation of enantioselectivity and direction of asymmetric induction is observed. ... 

The tetracyclic oxindole alkaloids possess four asymmetric centers (C-3, C-7, C-15, and C-20) and therefore can exist as sixteen possible diastereoisomers. However, since all naturally occurring indole alkaloids of the corynane type possess a C-15a hydrogen [17), the total number of isomers is restricted to eight. Taking into consideration the asymmetric... 

All naturally occurring pentacyelic oxindoles either are stereoisomers of the general formula 50 or differ from each other by the pattern of substituents on the aromatic ring. In all there are five asymmetric centers (C-3, 0-7, C-15, C-19, and C-20) so that 32 diastereoisomers of... 

The heteroyohimbine alkaloids and their oxindole counterparts form a large group of compounds that provide an ideal exercise in conformational analysis the oxindole bases, which contain in C-7 an additional asymmetric center, have been particularly thoroughly studied. The oxindole alkaloids that occur in Mitragyna and related genera have previously been discussed in Volumes VIII and X of this series and by 1967 the complete conformations of most of these alkaloids had been elucidated. The known facts concerning the stereochemistry of these alkaloids at that time have been summarized by Shamma et al. (46, 47), and the stereochemistry of the uncarines-A-F has also been... 

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