Rational alignment

Molecular similarity indices can be optimized by fixing one molecule and translating and rotating the other one until their similarity reaches an optimum. This ASP-implemented procedure constitutes another promising tool for the rational alignment of molecules in 3D space, also considering the flexibility of molecules [1075]. 

Dipole-dipole interactions may also be important in determining the stereoselectivity of Mukaiyama aldol reactions proceeding through an open TS. A BF3-catalyzed reaction was found to be 3,5-anti selective for several (3-substituted 5-phenylpentanals. This result can be rationalized by a TS that avoids an unfavorable alignment of the C=0 and C-X dipoles.97... 

The rather confusing conformational dependences in Fig. 3.52 can be rationalized in a simple way. From the total of 7t-a and a-7t stabilizations at their respective coplanar alignments with the pi system, one can confirm that C—H bonds are better overall hyperconjugating groups than C—I bonds. The most favorable hyperconjugative alignment is therefore to place both C—H bonds maximally out-of-plane (i.e., C—F in-plane) at = 0°, whereas a secondary favorable alignment... 

Diastereoface selection has been investigated in the addition of enolates to a-alkoxy aldehydes (93). In the absence of chelation phenomena, transition states A and B (Scheme 19), with the OR substituent aligned perpendicular to the carbonyl a plane (Rl = OR), are considered (Oc-or c-r transition state R2 Nu steric parameters dictate that predoniinant diastereoface selection from A will occur. In the presence of strongly chelating metals, the cyclic transition states C and D can be invoked (85), and the same R2 Nu control element predicts the opposite diastereoface selection via transition state D (98). The aldol diastereoface selection that has been observed for aldehydes 111 and 112 with lithium enolates 99, 100, and 101 (eqs. [81-84]) (93) can generally be rationalized by a consideration of the Felkin transition states A and B (88) illustrated in Scheme 19, where A is preferred on steric grounds. 

A number of intramolecular cycloadditions of alkene-tethered nitrile oxides, where the double bond forms part of a ring, have been used for the synthesis of fused carbocyclic structures (18,74,266-271). The cycloadditions afford the cis-fused bicyclic products, and this stereochemical outcome does not depend on the substituents on the alkene or on the carbon chain. When cyclic olefins were used, the configuration of the products found could be rationalized in terms of the transition states described in Scheme 6.49 (18,74,266-271). In the transition state leading to the cis-fused heterocycle, the dipole is more easily aligned with the dipolarophile if the nitrile oxide adds to the face of the cycloolefin in which the tethering chain resides. In the trans transition state, considerable nonbonded interactions and strain would have to be overcome in order to achieve good parallel alignment of the dipole and dipolarophile (74,266). 

MacGillivray, L. R. Atwood, J. L. Rational Design of Multi-Component Resor-cin[4]arenes and Control of Their Alignment in the Solid State. J. Am. Chem. Soc. 1997, 119, 6931-6932. 

Lewis DF, Lake BG. Molecular modelling of CYP1A subfamily members based on an alignment with CYP102 rationalization of CYP1A substrate specificity in terms of active site amino acid residues. Xenobiotica 1996 26 723-753. 

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