Oxindole, enol ether

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]. 

Iniino ethers. Harley-Mason and Leeney found that triethyloxonium fluoroborate converts oxindole (1) into the enol ether (2, m.p. 110°) and that (2) on being heated in vacuum is isomerized to the imino ether (3, m.p. 63°). If (3) is heated above its... 

This group continuously enlarged the scope of substrate to allylsilane, silyl enol ether 113 and oxindoles 115 for enantioselective catalytic a-fluorination (Scheme 6.34) [62]. They employed N-fluorobenzenesulfonimide (NFSI) as a fluorinating reagent with bis-cinchona alkaloid catalysts and excess base to provide the corresponding fluorinated compounds 114,115 in excellent enantioselectivities up to 95% ee. 

Chiral indole-2-sulfoxides have been employed by Feldman and Karatjas for asymmetric spirooxindole synthesis [70]. In one example, treatment of 115 with triflic anhydride initiated a Pummerer-type cyclization of the silyl enol ether side chain onto C3 (Scheme 30). Sequential hydrolysis of the resulting thioimidate intermediate with aqueous HgCl2 afforded the spirocyclohexanone functionalized oxindole 116 in modest yield and enantioselectivity at —78°C (33, 67% ee). Improved selectivity (58, 86% ee) was observed at lower reaction temperature (-110°C). 

Shibata successfully adapted the asymmetric transfer fluorination to cyclic silyl enol ethers, cyclic allyl silanes and oxindoles, illustrated in Schemes 13.1-13.3, as a catalytic method (Scheme 13.6) [16]. Similar reaction conditions were identified for all three substrates, including the use of stoichiometric NFSI as the electrophilic fluorine source and a stoichiometric inorganic base additive. It was observed that bis-Cinchona alkaloid (DHQ)2PHAL was best for cyclic silyl enol ethers (X = 0), (DHQ)2PYR (Scheme 13.2) was best for cyclic allyl silanes (X = CH2), while (DHQD)2AQN was best for oxindoles. A similar method was applied to cyclic enol ethers, providing products in modest ee s [17]. 

Silyl enol ethers and ketene silyl acetals add to aromatic nitro compounds in the presence of TASF(Me) to give intermediate dihydro aromatic nitronates which can be oxidized with bromine or 2,3-dichloro-5,6-dicyano-l,4-benzoquinone to give a-nitroaryl carbonyl compounds the latter are precursors for indoles and oxindoles. The reaction is widely applicable to alkyl-, halo-, and alkoxy-substituted aromatic nitro confounds, including heterocyclic and polynuclear derivatives (eq 7). 

SCHEME 44.14. Catalytic enantioselective fluorination of silyl enol ethers and oxindoles. 

The ease of preparation and generality of fluorination make the [N-F] class of reagents an excellent choice for enantioselective electrophilic fluorination. Advantageously, enantioselective electrophilic fluorination was also achieved with silyl enol ethers and oxindoles as substrates using a catalytic amount of bis-cinchona alkaloids and NFSI in the presence of excess base (Scheme 44.14). Applications of these [N-F] reagents include the enantioselective syntheses of a-fluoro-a-amino acid derivatives (Scheme 44.15), a potent opener of maxi-K channels (BMS-204352, MaxiPost Xi an Unique Electronics Chemical Co., Ltd, Xi an, P.R. China), and 20-deoxy-20-fluorocamptothecin (see section 3). 

Ishimaru T, Shibata N, Horikawa T, Yasuda N, Nakamura S, Tom T, Shiro M. Cinchona alkaloid catalyzed enantioselective fluorination of allyl silanes, silyl enol ethers, and oxindoles. Awgew. Chem. Int. Ed. 2008 47 4157-4161. 

---