Diastereofacial selectivity in reactions of substituted cyclohexyl radicals. An experimental and theoretical study

Damm, Wolfgang; Giese, Bernd; Hartung, Jens; Hasskerl, T.; Houk, K. N.; Hueter, Ottmar; Zipse, Hendrik

doi:10.1021/ja00037a007

Cited by 105 publications

(59 citation statements)

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“…[18,20,73] This selectivity can be explained by a combination of conformational (the methyl substituent at C1 is preferentially situated in the pseudo-equatorial position) and torsional effects (Bu 3 SnH preferentially delivers its hydrogen from the axial face to a radical center in a saturated six-membered ring unless unfavorable steric blocking by vicinal substituents occurs). [75] The 4-phenyl-substituted alkoxyl radical 51u affords, after hydrogen trapping, 2-phenyltetrahydropyran 59u as the major product (5-exo:6-endo ϭ 5:95). [20] Comparison of k rel values for both ring-closure reactions of 51u (k 6-endo rel ϭ 8.0 Ϯ 0.7, k 5-exo rel ϭ 0.48 Ϯ 0.04) indicates that, in this case, a favorable rate constant for the 6-endo ring-closure is the driving force for tetrahydropyran formation from intermediate 51u.…”

Section: Mechanistic Studies -Cyclizations Of Substituted 4-penten-1-mentioning

confidence: 99%

Stereoselective Construction of the Tetrahydrofuran Nucleus by Alkoxyl Radical Cyclizations

Hartung¹

2001

Eur. J. Org. Chem.

142

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Whereas carbon radical cyclizations have been applied for many years in the stereoselective synthesis of carbocyclic compounds, intramolecular C−O bond formations using alkoxyl radical reactions are less well understood. Since the discovery of N‐alkoxypyridine‐2(1H)‐thiones 8 as efficient sources of oxygen‐centered radicals, and the marked progress in the synthesis of these and related compounds which has been made in the last five years, however, a systematic study of O‐radical cyclizations under neutral conditions has become available. Kinetic experiments using the radical clock technique found that the parent 4‐penten‐1‐oxyl radical 1 undergoes an extremely fast 5‐exo‐trig ring‐closure [(4 ± 2) × 108 s−1 (30 °C)] which, after hydrogen trapping, selectively affords 2‐methyltetrahydrofuran (50). Tetrahydropyran (56), which originates from the slower 6‐endo‐trig cyclization, was observed in minor amounts. This observation pointed to a more diverse regioselectivity of O‐radicals in intramolecular addition reactions to olefinic double bonds than had been predicted from earlier experiments. A mechanistic study of ring‐closure reactions of the substituted 4‐penten‐1‐oxyl radicals 51 led to two major conclusions. Firstly, 1‐, 2‐, 3‐, and 5‐substituted radicals cyclize stereoselectively and 5‐exo‐trig‐regioselectively. The degree of stereoselectivity is governed by steric effects. To date, the only exceptions to this rule remain cyclizations of the para‐substituted 1‐aryl‐4‐penten‐1‐oxyl radicals 51e−m. These intermediates cyclize regioselectively, but not stereoselectively. Secondly, substituents at position 4 of the 4‐penten‐1‐oxyl radical are the key for controlling regioselectivities in O‐radical ring‐closure reactions. Thus, the 4‐phenyl‐4‐penten‐1‐oxyl radical 51u cyclizes 6‐endo‐trig‐selectively to afford, after hydrogen trapping, 2‐phenyltetrahydropyran (59u) as the major product (5‐exo:6‐endo = 5:95). Results from mechanistic and theoretical studies have been combined in order to derive a general model for predicting alkoxyl radical selectivities in ring closure reactions. The utility of this predictive device has recently been confirmed in the course of a new stereoselective synthesis of the central ring in muscarine alkaloid 72.

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Section: Mechanistic Studies -Cyclizations Of Substituted 4-penten-1-mentioning

confidence: 99%

Stereoselective Construction of the Tetrahydrofuran Nucleus by Alkoxyl Radical Cyclizations

Hartung¹

2001

Eur. J. Org. Chem.

142

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“…However, based on the above mentioned issues, the authors expected that trans-diaxial opening of a supposedly preferred "anomeric effect" conformer 110a, would lead to actinobolin rather than to a diastereoisomer arising from oxirane ring opening of the "nonanomeric effect" conformer 110b. According to these guidelines, the synthesis of actinobolin started from cycloadduct 108 [84] (Scheme 28), readily prepared by reaction of methyl 2,3,6-trideoxy--D-hex-2-enopyranosid-4-ulose (106) with Danishefsky's diene (107). Thus, oximation of 108, followed by lithium aluminum hydride reduction afforded allylic alcohol 112, which upon oxidation (MnO 2 ), followed by -acetoxylation with lead tetraacetate led to acetoxy ketone 113, as the sole isomer.…”

Section: Actinobolin Via the Anomeric Effect Of An Annulated Pyranosidementioning

confidence: 99%

Unsaturated Sugars: A Rich Platform for Methodological and Synthetic Studies

Fraser‐Reid¹,

López²

2009

COC

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“…[23] Axial attack is also consistent with the observations of Giese and co-workers on atom transfer to cyclohexyl radicals. [24] …”

Section: -Exo Versus 6-endo Cyclizationsmentioning

confidence: 99%

Synthesis of Oxacycles by Tandem Radical Addition−Cyclization Reactions

2004

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Keywords: Radicals / Diastereoselectivity / Lanthanides / Cyclization / Lewis acids β-Alkoxyalkylidenemalonates undergo tandem radical addition−cyclization reactions to provide oxacycles of different ring sizes in good chemical efficiency. A variety of nucleophilic radicals participate in the addition−cyclization reactions, and the reaction requires the use of lanthanide triflates as Lewis acids. Compound 9 gave the 5-exo cyclization product 13 in 80 % yield and greater than 50:1 diastereoselectivity favoring the trans isomer. Radical addition−cyclization reactions using substrate 26, in which the 5-exo pathway was blocked, gave exclusively the 6-endo products 27−32 in good yields (68−88 %) and moderate to good selectivity (1.2:1 to 14:1). Generally, 7-endo cyclization dominated over the 6- IntroductionDevelopment of new methodologies using radical intermediates continues to attract interest from synthetic chemists.[1] Radical chemistry offers complementary (or at times even superior) reaction characteristics to ionic methods for carbonϪcarbon bond formation. Radical methods are especially well suited for the construction of rings and for setting up reaction sequences, so that multiple carbonϪcarbon bonds can be formed in a single operation.Oxacycles constitute an important structural unit in many biologically active natural products. Numerous radical methodologies have been reported that offer routes towards oxacycles, especially substituted furans, [2] however, most have achieved only modest success in obtaining products with consistently high levels of diastereoselectivity, in cases when two or more chiral centers are formed in a single operation. In contrast to the large number of reports on the synthesis of five-membered rings, the formation of larger rings by radical methods has received less attention. One prominent method for the formation of oxacycles by radical chemistry involves intramolecular cyclization of a carbon radical onto an acceptor, by which an oxygen atom can be incorporated into the substrate (Figure 1, Method A). The selectivities in these reactions are generally good.[3] Alterna- exo mode. Addition of various nucleophilic radicals to substrate 33 using ytterbium triflate as a Lewis acid gave the 7-endo products 34−39 in moderate to good yield (49−75 %). Substrate 41, in which the 6-exo pathway was blocked, gave the 7-endo products 42−47 cleanly. The diastereoselectivities in these cyclizations were dependent on the size of the radical; bulky radicals gave lower selectivities. Radical addition−cyclization using 48 gave the 8-endo products 49−53 in good yield (58−86 %).

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Diastereofacial selectivity in reactions of substituted cyclohexyl radicals. An experimental and theoretical study

Abstract: Gottingen was made possible through a mobility grant by the A N R T-D A A D within the PROCOPE program.

Cited by 105 publications

References 0 publications

Stereoselective Construction of the Tetrahydrofuran Nucleus by Alkoxyl Radical Cyclizations

Stereoselective Construction of the Tetrahydrofuran Nucleus by Alkoxyl Radical Cyclizations

Unsaturated Sugars: A Rich Platform for Methodological and Synthetic Studies

Synthesis of Oxacycles by Tandem Radical Addition−Cyclization Reactions

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