Origin of Huisgen's factor x: staggering of allylic bonds promotes anomalously rapid exo attack on norbornenes

Rondan, Nelson G.; Paddon‐Row, Michael N.; Caramella, Pierluigi; Mareda, Jiri; Mueller, P.; Houk, K. N.

doi:10.1021/ja00382a052

Cited by 90 publications

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“…1c The computational study described here reveals that the origin of stereoselective β-attack in this epoxidation is a strong torsional control of stereoselectivity that we have named torsional steering. 2 The computed epoxidation transition structures of a model alkene containing all the substituents of the cyclopentene ring of guanacastepene precursor 1, computed with density functional theory (B3LYP/6-31G*), 3 are shown in Figure 1. 4 The α-epoxidation transition structure TS-(S,S)-3, with the dimethyldioxirane (DMDO) approaching from the sterically less hindered face of the cyclopentene ring is 4 kcal/mol higher in energy than the analogous β-epoxidation process TS-(R,R)-3, in agreement with experimental observations that only the β-epoxide is formed.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Such torsional control of electrophilic or nucleophilic reactions has been observed in many reactions. 2 The chair product (S,S)-4, which arises from the α-epoxidation, is also higher in energy by 3 kcal/mol than the boat product (R,R)-4, from β-epoxidation. Bicyclo[3.1.0]hexane systems are known to prefer the boat conformation over the chair due to torsional interactions with the bridgeheads.…”

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“…2 The importance of such an effect was first identified by Felkin in the discussion of nucleophilic additions to cyclohexanones, 6 but it is now clear that it governs stereoselectivity in a wide variety of situations. 2 It can actually be identified in the conformation of the alkene reactant, shown in Figure 2. The effect influences the relative energies of diastereomeric conformations that involve torsional factors not present in the reactants, but which become significant in the products of the reaction.…”

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Torsional Steering Controls the Stereoselectivity of Epoxidation in the Guanacastepene A Synthesis

2006

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The stereoselectivity of the key epoxidation step in the synthesis of Guanacastepene A is shown to be controlled by torsional steering. In this particular epoxidation reaction, the transition structure energetic difference is enhanced by the great asynchronicity of the forming C-O bonds that intensifies the torsional interactions.The stereoselective epoxidation of the Guanacastepene A precursor 1 constitutes a key step which provides the correct stereochemistry of the β-acetoxy ketone, as shown above. 1 Cursory inspection of the structure suggests that attack should occur on the α-face, yet exclusive formation of the β-epoxide was observed experimentally. The crystal structure of the hydroxyketone formed from 2 shows that the isopropyl group is in equatorial position, imparting little steric differentiation between the α-and β-faces. 1c The computational study described here reveals that the origin of stereoselective β-attack in this epoxidation is a strong torsional control of stereoselectivity that we have named torsional steering. 2 The computed epoxidation transition structures of a model alkene containing all the substituents of the cyclopentene ring of guanacastepene precursor 1, computed with density functional theory (B3LYP/6-31G*), 3 are shown in Figure 1. 4 The α-epoxidation transition structure TS-(S,S)-3, with the dimethyldioxirane (DMDO) approaching from the sterically less hindered face of the cyclopentene ring is 4 kcal/mol higher in energy than the analogous β-epoxidation process TS-(R,R)-3, in agreement with experimental observations that only the β-epoxide is formed.Both transition structures are very asynchronous; one of the forming C-O bond is ~1.8 Å, while the other forming C-O bond length is ~2.4 Å. This high asynchronicity is the result of electron donation from the acetoxy group and the conjugated alkene.The inherent stability difference between the transition structures is due to the difference in torsional strain between bonds linking the forming epoxide to the rest of the skeleton, as shown in the insets Newman projections in Figure 1. The α-epoxidation transition structure TS-(S,S)-3 exhibits substantial eclipsing, in contrast to the substantially more staggered β-epoxidation transition structure TS-(R,R)-3. Such torsional control of electrophilic or nucleophilic reactions has been observed in many reactions. 2The chair product (S,S)-4, which arises from the α-epoxidation, is also higher in energy by 3 kcal/mol than the boat product (R,R)-4, from β-epoxidation. Bicyclo[3.1.0]hexane systems are known to prefer the boat conformation over the chair due to torsional interactions with the bridgeheads. 5 In the case of parent 6-oxabicyclo[3.1.0]hexane, this preference is computed to be 4.0 kcal/mol. 5d As shown in the corresponding insets, the difference between the eclipsing in (S,S)-4 and (R,R)-4 is reduced as compared to the transition state.It is noteworthy that the energy difference between the transition structures is greater than the energy difference between the products by ...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Torsional Steering Controls the Stereoselectivity of Epoxidation in the Guanacastepene A Synthesis

2006

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“…This phenomenon has previously been ascribed to torsional strain, 15 steric crowding, 16 nonequivalent orbital extension, 17 and a combination of alkene pyramidalization 18 and transition state allylic bond staggering. 19 Interaction of the pentadienyl termini in the pericyclic transition state of the Nazarov reaction is not analogous to electrophilic addition, but should be similarly subject to any of these effects with the possible exception of crowding by the remote ethylene bridge. Any steric impediment by the dimethyl substitution on the onecarbon bridge is clearly outweighed by the factor(s) responsible for the expected exo preference.…”

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Stereoselective Nazarov Cyclizations of Bridged Bicyclic Dienones

et al. 2005

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Bridged bicyclic dienones underwent silyl-directed Nazarov cyclization with generally very high diastereoselectivity. In most cases, a strong preference for cyclization to the product with an exodisposed cyclopentenone was seen. However, the presence of additional unsaturation in the threecarbon bridge of a bicyclo[3.2.1]octadiene system caused complete reversal in selectivity with exclusive formation of the endo-cyclopentenone. The observed selectivities are believed to result from a combination of steric and electronic effects.The Nazarov cyclization 1 and related annulations 2 offer an efficient method for construction of cyclopentenone rings from simple acyclic precursors. Recent variations include methods for diverting the initially formed oxyallyl cation intermediate into domino bond-forming processes, 3 conditions employing catalytic amounts of Lewis acid, 4 retrograde Nazarov reaction, 5 and asymmetric catalysis. An important question for this and other electrocyclic processes is whether the absolute configuration at the newly formed sp 3 centers can be controlled. There are a number of examples of diastereoselective Nazarov processes in which preexisting stereogenic centers exerted significant control. 6 Asymmetric induction by pendant chiral auxiliaries has been observed, 7 and allenes have been shown to participate in the Nazarov cyclization with a high degree of chirality transfer. 8 Most recently, preliminary examples of asymmetric catalysis by chiral Lewis acids have been reported. 5c,9One potential drawback to asymmetric Nazarov reactions is the annihilation of one of the two sp 3 stereocenters generated during the electrocyclization by the usual eliminative termination event (Scheme 1), although the remaining stereocenter may influence the configuration at the α' position during protonation. Coupling the cyclization with a subsequent bond-forming reaction in an overall domino process 4 is one possible solution. In an alternative strategy, cis ring-fusion preferences of strained bicyclic systems could permit the remaining chiral center to dictate the configuration at the neighboring cyclopentenone α' carbon upon enol protonation. We have applied the latter strategy in a series of bridged bicyclic dienones, and here report their Nazarov cyclization to provide complex tricyclic products with moderate to complete diastereoselectivity.The silyl-directed Nazarov cyclization was used in this study to assure complete regioselectivity in the elimination step. 10 Dienone substrate 6a was prepared by addition of bornenyllithium 1a into enal 2a and oxidation of the resulting dienol (Scheme 2). Unsatisfactory yields in this route prompted an examination of an alternative strategy. A more direct approach was found in the form of Stille cross-coupling of enol triflates (4 a -f) with frederick.west@ualberta.ca. † Current address: Department of Chemistry, University of Alberta, Edmonton, AB, T6G 2G2, Canada. alkenylstannanes (5a,b) under carbonylative conditions 11 using co-catalytic copper(I) iodide 12 t...

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Molecular and Electronic Structure and Gas-Phase Pyrolytic Generation of 7,7′-Dioxasesquinorbornenes

et al. 1998

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Origin of Huisgen's factor x: staggering of allylic bonds promotes anomalously rapid exo attack on norbornenes

Cited by 90 publications

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Torsional Steering Controls the Stereoselectivity of Epoxidation in the Guanacastepene A Synthesis

Torsional Steering Controls the Stereoselectivity of Epoxidation in the Guanacastepene A Synthesis

Stereoselective Nazarov Cyclizations of Bridged Bicyclic Dienones

Molecular and Electronic Structure and Gas-Phase Pyrolytic Generation of 7,7′-Dioxasesquinorbornenes

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