Formation of Some Oxygen-Containing Heterocycles by Radical Cyclization:  The Stereochemical Influence of Anomeric Effects

Abstract

The influence of the anomeric effect on radical cyclization has been examined by determining the stereochemical outcome of the ring closure of 10 suitably substituted radicals. The stereochemistry of the products formed from the acyclic precursors 4a-f indicates that for suitably constituted radicals anomeric interactions stabilize pseudoaxially substituted transition structures 14 thus affording products with stereochemistry the reverse of that normally observed.In recent times, the use of free radical reactions for chemical synthesis has grown steadily in popularity as the processes which govern and control their outcomes have become better understood. 1 Intramolecular addition reactions of suitably constituted alkenyl radicals and related species are particularly interesting since they readily afford a variety of ring systems commonly found in many natural products. 1 The advantages offered by such reactions generally include high regioselectivity, modest to good stereoselectivity, 1-5 and high chemoselectivity. [1][2][3][4][5] The highly regioselective exo-cyclization of the hex-5-enyl radical has been intensively studied. The accurate determination of its kinetics 6 has underpinned its widespread use as a mechanistic probe and as a radical clock. 7 Most monosubstituted hex-5-enyl radicals also undergo regioselective exo-cyclization while conforming to the general stereochemical guideline that 1-or 3-substituted radicals afford predominantly cis-disubstituted products, while 2-or 4-substituted radicals give mainly transdisubstituted products. 5 It is now generally accepted that the cyclization behavior of simple hex-5-enyl systems reflects the stereoelectronic demands of the transition structure. [2][3][4][5] The hypothesis that the strain energy engendered in attaining the optimum orbital overlap for 1,6-ring closure outweighs the steric and thermodynamic factors which would otherwise favor six-membered ring formation 2-5 has received support from theoretical analyses 8 and the modeling of transition structures by a combination of molecular orbital and molecular mechanics calculations. 8 These calculations confirm the original hypothesis that the transition structure for 1,5-exo-cyclization of hex-5-enyl radicals and related species resembles cyclohexane in its chair form. 2-5 Hence the stereoselectivity exhibited in the ring closure of monosubstituted hexenyl radicals and related species is seen to arise from the propensity of cyclizations to proceed through the more stable pseudoequatorially substituted cyclohexane-like conformation of the transition structure rather than through its less stable pseudoaxially substituted conformer. 8 Since calculations of the relative selectivities of the cyclized products tend to be overestimated when only axially substituted chairlike structures are considered, it appears that boatlike transition structures might also be involved in some reactions. 4,8 Cyclizations of hex-5-enyl type radicals containing heteroatoms have also been studied. 1,9,10 In general such spec...

Iron‐Catalyzed Reductive Radical Cyclization of Organic Halides in the Presence of NaBH4: Evidence of an Active Hydrido Iron(I) Catalyst

“…Primary iodoalkene 1 d gave the 5‐ exo product 2 d (70 %; Table 1, entry 3). The O ‐homoallyl derivative 1 e gave the 6‐ exo product 2 e (Table 1, entry 4), which was obtained in relatively low yield, together with the directly reduced compound 2 e′ , thus showing, as expected, that the 6‐ exo ‐trig cyclization is less favored than the 5‐ exo ‐trig cyclization 14. The iodoalkyne 1 f gave 2 f through a 5‐ exo ‐dig cyclization (52 %; Table 1, entry 5).…”

Iron‐Catalyzed Reductive Radical Cyclization of Organic Halides in the Presence of NaBH4: Evidence of an Active Hydrido Iron(I) Catalyst

“…The O-homoallyl derivative 1 e gave the 6-exo product 2 e ( Table 1, entry 4), which was obtained in relatively low yield, together with the directly reduced compound 2 e', thus showing, as expected, that the 6-exo-trig cyclization is less favored than the 5-exo-trig cyclization. [14] The iodoalkyne 1 f gave 2 f through a 5-exo-dig cyclization (52 %; Table 1, entry 5). The method was successfully extended to the reduction of tertiary iodide 1 g (94 %; Table 1, entry 6) and aryl iodides 1 h (96 %; Table 1, entry 7).…”

Radical Cyclization of Haloacetals: The Ueno-Stork Reaction

“…Beckwith has reported that the acetal systems (Scheme 35, Equation b) behave quite differently from the non-acetal derivatives (Scheme 35, Equation a). 128 The stereochemical outcome of the non-acetal system (Equation a) was anticipated based on the well-established Beckwith-Schiesser-Houk 129-131 model for radical cyclization, where the main stereoisomer is produced through a chair-like transition state with all substituents in a pseudo-equatorial position (see Scheme 35). Interestingly, the acetal derivatives afford mainly the 2,5-cis disubstituted tetrahydrofurans in contravention to these guidelines.…”