Molecular mechanics stereoselectivity

A theoretical analysis is presented for the binding of the four dia-stereoisomers of benzo[a]pyrene diol epoxides (BPDEs) to N2(g), N6(a), 06(G) and NU(c). Molecular models for binding and stereoselectivity involving intercalation, intercalative covalently and externally bound forms are presented. Molecular mechanics calculations provide the energetics which suggest possible structures for the formation of each of the principal DNA-BPDE complexes. Stereographic projections are used to illustrate the molecular structures and steric fits. The results of previous calculations on intercalation and adduct formation of BPDE l(+) in kinked DNA (37) are summarized and extended to include the four diastereoisomers l( ) and II( ). The theoretical model is consistent with the observed experimental data. 

According to analogous molecular mechanics analyses,38 this stereoselectivity mechanism would also operate for catalytic systems with oscillating stereocontrol, leading to atactic-isotactic stereoblock polymers,39,40 like those based on two unbridged 2-phenyl-indenyl ligands.40... 

Molecular mechanics analyses of the kind described in previous sections are able to rationalize not only the stereoselectivity (and stereospecificity) of regioregular primary insertion steps but also the stereoselectivities relative to occasional secondary monomer insertions as well as relative to primary insertions following these secondary insertions.37d... 

A necessary (but not sufficient) prerequisite for models of catalysts for the stereospecific polymerization of 1-olefins polymerization, is the stereoselectivity of each monomer insertion step. The possible origin of stereoselectivity in this class of systems was investigated through simple molecular mechanics calculations [11, 14, 24, 32, 52, 78-80, 82-86]. 

The mechanisms of regioselective and stereoselective 2 -E 2-photocycloadditions have been extensively reviewed. The intramolecular 2 -E 2-photocycloaddition of 2-allyl-2-(l//)-naphthalenone (13) on the surface of silica produces all four cycloadducts (14)-(17) (Scheme 4). ° Molecular mechanics have been used to study the regio- and stereo-selectivity of the 2 -E 2-photocycloadditions in complexes containing crown ether styryl dyes and alkaline earth metal cations."... 

In the approach of Puddephatt et al., the P-phenyl-phosphonitocavitand 2 was obtained by the reaction of phenylphosphonous chloride on re-sorc[4]arene lb (1, R=CH2CH2C6H5) in presence of pyridine as base. The reaction is stereoselective and yielded the bowl-shaped molecule 2 with the four P-phenyl groups directed outwards and the four lone pairs directed inwards ini configuration) [45-49] (Scheme 6). Molecular mechanics calculations performed on the six possible isomers of 2, showed that the iiii isomer is preferred and the orientation of one phenyl group toward the macrocyclic cavity is probable iiio isomer), but two or more phenyl groups oriented inwards are highly unlikely [48]. 

The different stability of the diastereomeric lithio compounds involved was rationalized using molecular mechanics studies22. The selectivity of the second alkylation step was exploited for the stereoselective synthesis of 1,1-disubstituted tetrahydroisoquinolines23. 

The use of isopropylidine acetals (112) as tethers in the intramolecular Diels-Alder reactions of dienes with alkenes facilitates the formation of civ-fused cycloadducts (113) from an endo transition state (Scheme 41).218 The intramolecular Diels-Alder reaction of 4-[tris-(2-mcthylcthyl)silyl]oxy-2//-thiopyran derivatives with potential dienophiles tethered at C(2), C(3), C(5), and C(6) positions yielded cycloadducts when the dienophiles were activated with a carbomethoxy group.219 By the substitution of a phenylsulfonyl group on the dienophile of 2-benzopyran-3-ones, it is possible to enhance exo addition during intramolecular Diels-Alder cyclizations to yield a predominance of trans-fused hexaphenanthrenes related to natural products.220 The intramolecular Diels-Alder reaction of 2-furfuryl fumarates has been investigated by molecular mechanics (SIBFA)/continuum reaction field computations.221 The intramolecular 4 + 2-photo-cycloaddition of A-benzylcinnamamides (114) in the presence of C(,H6 gives 3-azatricyclo[5.2.2.01,5]undeca-8,10-dien-4-ones (115) with high stereoselectivity (Scheme 42).222... 

Addition of bromine in dichloromethane or of thioacetic acid in ethanol onto the methylene group of 9-arylidene and 9-carboxymethylene moieties of 6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyrimidines 546 stereoselectively gave 9-substituted 6,7,8,9-tetrahydro derivatives 547 and 548, respectively, at ambient temperature (Scheme 34) (90JHC247). Addition was also stereoselective with respect to the C(9) and C(9)—C centers, giving the erythro diastereomers as the primary products, which may then undergo epimerization to the threo isomers. The structure and epimerization of the products were studied by H and l3C NMR spectroscopy and by molecular mechanics calculations. 

The ability to predict structures can be important in the design of ligands. Chapter 7 deals with stereoselectivities predicted and interpreted by molecular mechanics. 

The copper(II)-mediated condensation of primary amines with formaldehyde and nitroethane (Fig. 7.6) is highly stereoselective. With [Cu((S),(/ )-ala)2] as starting material only one out of three possible isomeric products is formed (A in Fig. 7.6), and with [Cu(en)2]2+ one out of two isomers (B in Fig. 7.6) is obtained135,64 1. One possible intermediate is shown in Fig. 7.6[65]. Molecular mechanics calculations indicated that the intermediates leading to the observed species are less strained than any others. However, these calculations are only of limited value since the exact nature of the intermediate responsible for the selectivity is not known with certainty. 

The determination of the structure of the encounter complex (relative orientation of the two reactants) and the ensuing information on the stereoselectivity of the electron transfer is a further possible application of molecular mechanics in this field but this has not yet been evaluated. 

Also, metal ion directed stereoselective syntheses often involve organometallic complexes. While, in terms of a molecular-mechanics description of the structures, there is no fundamental difference between metal-carbon and metal-heteroatom bonds, modeling rc-bonded ligands is not trivial. Given a known reaction mechanism (which is not possible for many catalytic reactions) the main problem is the parameterization of the potential energy functions for the intermediates and transition states. The problem is that force field parameters are generally carefully... 

A combination of molecular mechanics, based on the dummy atom technique described above, with a QSAR-type treatment and a linear free energy relationship (LFER)-based model was used successfully to analyze the relative importance of steric influences on regioselectivity and stereoselectivity in the palladium-catalyzed allylation reaction[453]. 

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