Substrate conformation

Optically active 2-allylpiperidines and -pyrrolidines arc obtained by treating hydroxylactams containing the l-[(S)-l-arylethyl]substituent as an auxiliary (see Appendix) with tin(IV) chloride and trimethyl(2-propenyl)silane46. Interestingly, the moderate diastereoselection when the aryl group is phenyl decreases when 2-chlorophenyl is used, whereas the sense of the stereoselectivity reverses for 2,6-dichlorophenyl or pentachlorophcnyl. These results are rationalized by application of molecular orbital theory and substrate conformational preferences46. 

Flatness Conforms to substrate Distorts substrate Conforms to substrate... 

Vergely, I. Laugaa, P. Reboud-Ravaux, M. Interaction of human leukocyte elastase with a /V-aryl azetidinone suicide substrate conformational analyses based on the mechanism of action of serine proteinases. j. Mol. Graphics 1996, 14, 158-167. 

Diastereoselective hydroformylation can be achieved in special cases through passive substrate control in which conformational preferences are transferred in the corresponding selectivity-determining hydrometalation step [4-6]. A recent example is the highly diastereoselective hydroformylation of a kainic acid derivative (Scheme 17) [64], The selective formation of the major diastereomer has been explained via a reactive substrate conformation in which allylic 1,2-strain has been minimized. In this situation the czs-positioned methylene carbonylmethoxy group controls the catalyst attack to occur from the si face exclusively. 

R. T. The DegP and DegQ periplasmic endoproteases of Escherichia coli Specificity for cleavage sites and substrate conformation./. Bacterid. 1996, 178, 5925-5929. 

While this is in principle a valid approach to collagenase inhibitor design, there is some question as to whether or not the assumptions on which this model is based are valid. Specifically, there are several reasons for challenging the assumption that collagenases prefer substrate conformations that mimic those found in collagen. First, an examination of a model of collagen... 

The initial step in the alternative hydrolysis mechanism is protonation of the ring 0i by Glu 35 (Scheme I). Cleavage of the endocyclic C1-O5 bond forms the acyclic oxocarbonium ion intermediate, which is stabilized by Asp 52. Attack by water, cleavage of the C1-O4 bond, and ring closure then lead to the observed products. Existing experimental data on lysozyme hydrolysis are consistent with Scheme I (see references in Post and Karplus ( )). Moreover, distortion of the ring in site D is not required and the antiperiplanar orientation of an exocyclic O4 lone pair orbital relative to the cleaved C1-O5 bond found in the simulation (see section on "Enhancement of a Substrate Conformation Optimum for Catalysis") is in accord with stereoelectronic requirements (1 ). ... 

Davies, Renaud, and Sibi independently reported the chiral relay approach to control the enhanced steric extension inside a substrate to achieve increased asymmetric induction. However, as our study proves, the asymmetric activation of a tropos catalyst clearly differs from the chiral relay approach, in which substrate conformational control is utilized, since asymmetric activation controls the chiral environment of a tropos catalyst by the addition of a chiral external source (a chiral activator). 

Table 1, a kinetic study suggested both polar and homolytic mechanisms for conjugate addition, depending on the substrate and the substrate conformation . ... 

U. Kragl, A. Godde, C. Wandrey, N. Lubin, and C. Auge, New synthetic applications of sialic acid aldolase, a useful catalyst for KDO synthesis. Relation between substrate conformation and enzyme stereoselectivity, J. Chem. Soc. Perkin Trans. 7 119 (1994). 

Staphylococcal nuclease is a phosphodiesterase which can cleave either DNA or RNA to produce 3 -phosphomononucleosides (3-16, 20,25). The rates of hydrolysis of these substrates are dependent on the conformation of the substrate, Ca2+ concentration, and the ionic strength and the pH of the buffer (3, 54). Denatured DNA is hydrolzed more rapidly than native DNA (3, 12, 54-56), which reflects the important effect of substrate conformation on catalysis. In native DNA the Xp-dTp and Xp-dAp bonds are preferentially attached (7, 12, 14, 15, 55). With denatured DNA the order of cleavage appears to be nearly random (14, 15, 56, 57). The Xp-dCp and Xp-dGp linkages in the helical regions of DNA, which are more extensively stabilized, are more resistant to hydrolysis. The specific order of release of various mononucleotides from native compared to denatured DNA suggests that in the hydrolysis of DNA specificity toward the constitutent bases is less important than the substrate conformation (54-57). 

The stereochemical outcome of all these reactions may be explained in terms of a stereoelectronically assisted syn Sn2 process, assuming a substrate conformation as shown in (67a), and a preferred coordination of the Lewis acid to the less hindered acetal oxygen.67... 

Raleigh JA, Blackburn BJ (1978) Substrate conformation in 5 -AMP-utilizing enzymes 8,5 -cyclo-adenosine 5 -monophosphate. Biochem Biophys Res Commun 83 1061-1066 Raleigh JA, Fuciarelli AF (1985) Distribution of damage in irradiated 5 -AMP 8,5 -cyclo-AMP, 8-hy-droxy-AMP, and adenine release. Radiat Res 102 165-175 Raleigh JA, Whitehouse R, Kremers W (1974) Effect of oxygen and nitroaromatic cell radiosensitizers on radiation-induced phosphate release from 3 - and 5 -nucleotides A model for nucleic adds. Radiat Res 59 453-465... 

Once the most reactive substrate conformations are known, it remains to look for the best approach of the nucleophile. An anti attack is promoted by a favorable secondary overlap between the nucleophile and o (C L), which is shown by the double arrow. Syn attack is disfavored, both by a negative secondary overlap (wavy line) and by the eclipsed relationship between C L and Nu---C (Figure 6.6). To summarize, the Felkin transition states are favored because they correspond to the best trajectories for attacking the most reactive conformations. 

In these cases, the interplay of a preferred substrate conformation as well as catalyst delivery via the catalyst-directing group form the basis for the diastereoselectivity observed... 

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