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

Abstract

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 ...

Fluorine as a Regiocontrol Element in the Ring Opening of Bicyclic Aziridiniums

“…The chair conformers of these bicyclic rings contain two pairs of eclipsing interactions between a pseudoaxial C–H bond in the five-membered ring (as shown in Fig. 3, A for 4a ) and either an N + –R bond or a C–H bond at one of the ring junctions (not shown), as documented previously [27–29]. When C(4) is fluorinated, the so-called electrostatic gauche effect [30][31], i.e.…”

Torsional control of stereoselectivities in electrophilic additions and cycloadditions to alkenes

“…9 Danishsky’s group showed that the epoxidation of guanacastepene A precursor 5 , which consists of a fused cyclopentene, takes place exclusively from the β–face to give β–epoxide 6 as the major product. 35 This is surprising since it appears from the drawing of 5 , that the i Pr and Me substituent should block the β–face.…”

“…9 Torsional effects steer the reactant to approach the π-system in a manner that minimizes eclipsing interactions at the reaction center. The importance of a staggered arrangement with respect to forming bonds was first identified by Felkin in 1968 for nucleophilic additions to cyclohexanones.…”

The isolation and synthesis of neodolastane diterpenoids

“…This intriguing stereoselectivity was the subject of computational studies performed by Houk, Danishefsky and coworkers. 89 The corresponding transition structures and energies leading to the a-and b-selectivities were calculated employing density functional theory investigations as shown in Scheme 23. Because of the eclipsing interactions, the a-epoxidation transition structure 192a is less stable by 2.6 kcal mol À1 compared to staggered transition structure 192b for b-epoxidation, as shown by the Newman projections.…”