Pyrrolidine ring, intramolecular cyclization

The converse situation in which ring closure is initiated by the attack of a carbon-based radical on the heteroatom has been employed only infrequently (Scheme 18c) (66JA4096). The example in Scheme 18d begins with an intramolecular carbene attack on sulfur followed by rearrangement (75BCJ1490). The formation of pyrrolidines by intramolecular attack of an amino radical on a carbon-carbon double bond is exemplified in Scheme 19. In the third example, where cyclization is catalyzed by a metal ion (Ti, Cu, Fe, Co " ), the stereospecificity of the reaction depends upon the choice of metal ion. 

Formation of five-membered heterocycles through radical methodologies has been investigated extensively. Inter-, intramolecular, and cascade reactions have been reported for the synthesis of heterocycles. In the case of intramolecular cyclizations, 5-exo pathway is the preferred mode of reactivity. Rate constant for the formation of pyrrolidine by radical ring closure has been reported [95AJC2047],... 

Pyrrolizidine alkaloids ( )-trachelanthamidine (240) and ( )-supinidine (244) were synthesized, based on the Michael addition of an aziridine to an a,/J-unsaturated ester and subsequent ring opening of an aziridinium intermediate. Interest in these alkaloids stems from their biological activities. Treatment of ethyl 6-chloro-2-hexenoate (236) with excess aziridine at 0°C gave the pyrrolidine derivative 238 in one step, probably via the aziridinium salt 237 in 73% yield. The intramolecular cyclization of 238 with lithium diisopropylamide in tetrahydrofuran provided the thermodynamically more stable ester 239 as the sole product, (86%), which was then converted to ( )-trachelanthamidine (240) by reduction with lithium aluminum hydride. Since necine bases must contain a 1,2-didehydro system in their molecule to exhibit physiological activity, the following reactions were carried out to introduce a 1,2-didehydro system. Treatment of 238 with 2.4 equiv of lith-... 

A-Benzylimines have also been reported to react with acrylonitriles under solidrliquid conditions in which the initial anionic intermediate undeigoes an intramolecular nucleophilic ring closure to produce a diastereoisomeric mixture of the pyrrolidine (Scheme 6.23) [30-32], Similar cyclized products have been reported for the reaction of benzylidene-protected a-amino esters and vinyl ketones [33, 34],... 

Most cyclizations to form five-membered rings involve the 5-exo mode of cyclization. An exception has been reported in the intramolecular sulfenoamination of 3-alkenylamines used in the synthesis of pyrrolidine alkaloids (equation 102).215 229 Other examples include the aminomercurations of Af-sub-stituted-l-amino-3-butenes162,23° and the methylsulfenilium ion-initiated cyclization of 0-(2-propenyl)-/V-tosylaniline 231... 

The addition of alkyl radicals to less reactive alkenes becomes more efficient if the addition is conducted intramolecularly. The Kolbe electrolysis of A 7- and A -unsaturated carboxylates produces five-and six-membered rings in a 5- or 6-cj o-rng-cyclization. ° Such a cyclization was first observed by Weedon and later studied in more detail." By intramolecular addition of appropriate precursors, 3-substituted tetrahydrofurans (Scheme 10 40, 41%), pyrrolidines (41, 53%), and cyclopentanes (42, 74%), and (43, 75%) are obtained. In the reactions leading to cyclopentanes the extent of cyclization... 

Five- and six-membered rings have also been formed by participation of the amino groups of amino sugars in intramolecular displacements. Thus, hydrogenation of the azido compound (256) gave the pyrrolidine (258) clearly, the intermediate amino sugar derivative (257) cyclizes... 

Intramolecular ene reactions take place readily, even with compounds containing a normally unreactive enophile. The cyclization is parhcularly effective for the formation of hve-membered rings, although six-memhered rings can also be formed from appropriate unsaturated compounds. The geometrical constraints imposed on the transition state often result in highly selective reactions. For example, the homoallylic alcohol 242 with an axial alcohol substituent was the exclusive product from the cyclization of the unsaturated aldehyde 241 (3.157). In a synthesis of the neuroexcitatory amino acid (—)-a-kainic acid 245, the diene 243, itself prepared from (5)-glutamic acid, was cyclized to the pyrrolidine derivative 244 with almost complete stereoselectivity (3.158). ... 

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