Oxime ethers cyclizations onto

Several lupin alkaloids have been derived from the unsaturated quinalozidine 433, that was obtained in the treatment of amine 431 with ortho-quinone 432. This quinone behaves as a model of topaquinone, the cofactor of copper-containing amine oxidases. The cyclization step involved a nucleophilic attack of the piperidine nitrogen of 431 onto a side-chain aldehyde function that is unmasked by the oxidative deamination. Quinolizine 433, when treated with dehydropiperidine, gave the oxime ether 434 that, on ozonolysis followed by reduction, afforded sparteine 10, presumably via the bis(iminium) system 435 (Scheme 102) <1996JOC5581>. 

On the other hand, since oxime ethers were electrochemically more inert than ketones under the electroreduction conditions, the electroreductive intra- and inter-molecular coupling of ketones with oxime ethers proceeded via anion radicals in good yields (equations 5 and 6) °4i. Moreover, cobaloxime-mediated intramolecular radical addition onto oxime functions in the electrolysis media proceeded to afford the cyclized aminoethers (equation 7). ... 

Radical cyclizations are often used in ring formations and are an effective methodology in the synthesis of piperidines. The intramolecular cyclization of an oxime ether, such as 63 onto an aldehyde or ketone gives a new entry into cyclic amino alcohols <99JOC2003, 99H(51)2711>. Similarly, reaction of a terminal acetylene with BujSnH generates a vinyl radical, which will cyclize with an imine moiety to give 3-methylenepiperidine <99TL1515>. The indolizidine alkaloid ipalbidine was prepared by a sulfur-controlled 6-exo-selective radical cyclization of an a/p/ia-phenylthio amide <99H(50)31>. 

Furthermore, we also performed kinetic studies for alkyl radical additions onto different types of C=N bonds such as imines and oxime ethers. The kinetic data are summarized in Figure S. Kinetic analysis of the intramolecular addition of alkyl radicals to C=N bonds provides several experimentally important results. First, alkyl radical additions to C=N bonds are much faster than the corresponding additions to C=C bonds, indicating that C=N bonds are much better radical acceptors than C=C bonds. Furthermore, 5-exo cyclization is faster than 6-exo cyclization. Second, the intramolecular additions of alkyl radicals to C=N bonds are essentially irreversible. Third, alkyl radical additions to oxime ethers and hydrazones are faster than alkyl radical additions to imines, suggesting the possibility of a dependence of the cyclization rate on the electron density at the carbon atom of the radical acceptor. 

Oxime ethers are the first of three different types of C=N bonds to be used as radical acceptors. After the cyclization of an alkyl radical onto the oxime ether using zinc-trimethylchlorosilane was first reported by Corey in 1983 [5], n-tributyltin hydride-mediated radical cyclization onto oxime ethers has been successfully applied to the conversion of carbohydrate derivatives to carbocycles (Scheme 1) [6]. Parker employed the oxime ether as the radical trap in the synthesis of the morphine skeleton... 

Similarly, in the synthesis of (+)-7-deoxypancratistatin, a 6-exo cyclization of a benzylic radical onto the oxime ether was employed as a key step [8],... 

Keck has reported a short, enantioselective synthesis of lycoricidine as outlined in Scheme 10 [70]. The synthesis began with the acetonide of D-gulonolactone (104). This material was converted in 6 steps to oxime ether 105. Irradiation of 105 with thiophenol in toluene gave a 90% yield of 106, resulting from addition of a thio-phenoxy radical to the alkyne and cyclization of the resulting vinyl radical onto the oxime ether. It is notable that tri- -butylstannyl radicals failed to mediate this ad-dition-cyclization sequence. The synthesis of lycoricidine was completed from 106 in two steps. Keck also reported that the enantiomer of lycoricidine could be prepared in a similar manner starting from D-lyxose [71], and also described a modification of this route that provided (+)-narciclasine [70]. 

Iminyl radicals, generated by microwave irradiation of ( -phenyl oxime ethers such as 224, cychzed onto the indole 2-position to afford indolopyridine derivatives (225) [117]. The most likely pathway involves a 6-endo cyclization and was further exploited into a formal synthesis of neocryptolepine from gramine in five steps. 

A new reaction of iV-acyl thiazolidinethione enolates with enolizable aldoxime ethers has been reported to give 2-(thiazolidine-2-thione)-l-azetines 608 with excellent diastereoselectivity (Equation 235) <2003JA3690>. The absence of either a methoxy or a carbonyl group in the 1-azetines indicated a complex mechanism rather than a simple addition reaction. The formation of azetines has been rationalized by combination of the oxime and TiCh to give a highly electrophilic trichlorotitanium iminium intermediate 609, which adds onto enolate 610 to form intermediate 611, which cyclizes to azetidines 612 (Scheme 81). An irreversible elimination of bis-trichlorotitanium oxide provides the ultimate driving force to produce azetines. 

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