Conformational analysis of small molecules: NMR and quantum mechanics calculations

Fluorinated Rings: Conformation and Application

“…The carbonyl group in 36 introduced an electrostatic repulsion in the equatorial conformer 36 eq leading to an axial preference in the gas phase (36 ax is favored by 0.45-0.6 kcal mol À1 ). [58,72] In addition to electrostatic forces, hyperconjugative interactions, mainly through s CÀH !s* CÀF , s CÀF !p* C=O and p C= O !s* CÀF orbital interactions, cooperatively attribute to the stabilization of the axial conformer (36 ax ). However, with the increase of solvent polarity, the electrostatic repulsion is attenuated and orbital interactions, particularly through s CÀH !p* C=O , override other interactions to shift the equilibrium towards the equatorial conformer36 eq .…”

Conformational Design Principles in Total Synthesis

“…[2,3] In pharmaceutical and pharmacologic research, tuning the conformation of drug molecules by structural modification is often an effective way to enhance their target affinity and other desired physical properties. [4] Since the definition of conformation was coined by Barton [5] in the 1950s,w ith the advent of many powerful analysis techniques [6] and the support of more reliable computational chemistry, [7] conformational analysis has become af undamental tool to predict and interpret the mechanisms,r ates,a nd selectivities of organic reactions.I n the history of natural-product synthesis,the total synthesis of vitamin B12 by Woodward and Eschenmoser [8] and the total synthesis of erythromycin by Woodward and coworkers [9] are two landmarks that demonstrated that proper conformational preorganization of the precursors was critical for the macrocycle formation. In modern organic synthesis,c onformational analysis,e specially intentional control of conformational preferences by conformation designs, [10] has often been involved in the early planning stage of naturalproduct synthesis by guiding the formation of bonds,s tereocenters,o r rings.O wing to its importance in organic synthesis,s everal elegant review articles on the topic of conformational design have appeared over the years.I nm ost cases,t hese review articles only focused on an arrow substrate type.Hoffmann emphasized stereoselective control through allylic 1,3strain [11] and the conformational design of open-chain compounds [2] in two reviews.B lankenstein and Zhu highlighted the critical role of conformational preorganization of linear substrates in macrocyclization reactions in 2005.…”

Conformational Design Principles in Total Synthesis

“…[2,3] In pharmaceutical and pharmacologic research, tuning the conformation of drug molecules by structural modification is often an effective way to enhance their target affinity and other desired physical properties. [4] Since the definition of conformation was coined by Barton [5] in the 1950s,with the advent of many powerful analysis techniques [6] and the support of more reliable computational chemistry, [7] conformational analysis has become af undamental tool to predict and interpret the mechanisms,r ates, and selectivities of organic reactions.Inthe history of naturalproduct synthesis,t he total synthesis of vitamin B12 by Woodward and Eschenmoser [8] and the total synthesis of erythromycin by Woodward and co-workers [9] are two landmarks that demonstrated that proper conformational preorganization of the precursors was critical for the macrocycle formation. In modern organic synthesis,c onformational analysis,e specially intentional control of conformational preferences by conformation designs, [10] has often been involved in the early planning stage of natural-product synthesis by guiding the formation of bonds,s tereocenters, or rings.O wing to its importance in organic synthesis,s everal elegant review articles on the topic of conformational design have appeared over the years.I nm ost cases,t hese review articles only focused on an arrow substrate type.H offmann emphasized stereoselective control through allylic 1,3-strain [11] and the conformational design of open-chain compounds [2] in two reviews.B lankenstein and Zhu highlighted the critical role of conformational preorganization of linear substrates in macrocyclization reactions in 2005.…”