Strained conformation

The synthesis of key intermediate 6 begins with the asymmetric synthesis of the lactol subunit, intermediate 8 (see Scheme 3). Alkylation of the sodium enolate derived from carboximide 21 with allyl iodide furnishes intermediate 26 as a crystalline solid in 82 % yield and in >99 % diastereomeric purity after recrystallization. Guided by transition state allylic strain conformational control elements5d (see Scheme 4), the action of sodium bis(trimethylsilyl)amide on 21 affords chelated (Z)-enolate 25. Chelation of the type illustrated in 25 prevents rotation about the nitrogen-carbon bond and renders... 

No large conformational changes occur in the enzyme during catalysis, but many small movements take place. The structural basis for the catalytic power of ribonuclease thus resides in several different features tight, specihc binding of a strained conformation of the substrate, general acid-base catalysis by His-12 and His-119, and preferential stabilization of the transition state by ionic interactions with Lys-41. 

ATP binds, crosslinking the N and P domains. The ATP s y-phosphate and its bound Mg + ion bend the P domain. The N-domain makes contact with the A domain in a strained conformation. Part of the Ml helix is pulled up and forms a barrier to Ca + ion exchange with the cytoplasm. Calcium ions are occluded. 

Based on this assumption, it can easily be understood why in the case of R = t-C4H<) no incorporation of the label in the 6-hydrazino compound was found. The addition at C-3, the required initial step for incorporation in the tetrazine ring, is prevented by the strained conformation in 142 (R = t-C4H9). 

A) No. Three- and six-membered rings cannot be fused trans, since there is too much strain. CONFORMATIONS OF CYCLOHEXANE... 

Possible conformations for cycloheptane include the comfortable appearing chair form, 7. However, this form has eclipsed hydrogens at C4 and C5 as well as nonbonded interactions between the axial-like hydrogens on C3 and C6. The best compromise conformation is achieved by a 30°-40° rotation around the C4-C5 bond to relieve the eclipsing of the hydrogens. This spreads the interfering hydrogens at C3 and C6 and results in a somewhat less strained conformation called the twist chair. The twist chair, 8, is very flexible and... 

In the Felkin model (5), the important steric interactions involve R1 and R rather than the carbonyl oxygen as assumed by Cram (2-4) and also Karabat-sos (6). On this basis, the preferred mode of attack is 4 + 5 yielding 6, the least strained of six possible staggered conformations (three staggered conformations are possible for each of the diastereoisomers 2 and 3 6 is equivalent to the least strained conformation of 2). Recently, Anh and Eisenstein (7) have concluded from their ab initio calculations that the transition 4+ 5 6 does indeed correspond to the minimum energy transition state. 

Molecular models show that rotation about the Ca—Gp bond is strongly hindered and that the least strained conformation is that in which Ha and H6, the two /J-protons, each have 0=30°, and with the polymer chain, R, at 90° to the nodal plane of the 2p-orbital. We expect that eq. (18)... 

What information does the difference spectrum provide concerning the intramolecular mechanism of the BR to K transition The frequency shifts observed (Fig 6.6-10) between 1300 and 1100 cm characterize an all-trans to 13-cis isomerization of retinal. The unusually strong out-of-plane vibrations at 960 cm and 814 cm indicate considerable distortion of the terminal part of the chromophore. In summary, the BR-K difference spectrum shows that isomerization forces the chromophore and the protein backbone into a strained conformation, generating tension in the protein, which in turn drives the ensuing reactions. 

An example of this approach is demonstrated in an antibody mimic of the enzyme ferrochetalase (39). Ferrochelatase catalyzes the insertion of Fe + into protoporphyrin IX (3) as the last step in the heme biosynthetic pathway (40). Interestingly, N-alkylporphyrins are known to be potent inhibitors of this enzyme, because alkylation at one pyrrole lutrogen distorts the planarity of the porphyrin macrocycle (41). This finding was used in the design of hapten 4 to catalyze the incorporation of metal ions into mesoporphyrin IX (5) by eliciting an antibody that binds the substrate in a ring-strained conformation. 

The lone-pair electrons on the pyrrole nitrogen of the porphyrin ring are more accessible to chelation of metal ions in the ring-strained conformation and leads to metalation of mesoporphyrin IX. Antibody 7G12 catalyzes the incorportain of Zn +, Cn +, Co, and Mn into mesoporphyrin IX, whereas ferrochetalase uses Fe, ZrP , and Ni as substrates in... 

It is thought that in a small number of enzyme-catalyzed reactions, the enzyme binds the substrate in a strained conformation, which is closer to the transition state than the ground state conformation. In these cases, the difference in energy between the bound conformation and the transition state will be reduced and the reaction will be accelerated (Fig. 13). 

Unreasonable docked binding mode. Fast docking tools cannot produce reliable solutions for all compounds often, even some well-scoring compounds are simply docked to the outer surface of the protein or adopt rather strained conformations to achieve good surface complementarity within the binding pocket. Computational filters help to detect such situations (329). 

Therefore, the ring strain values in the six-membered rings are attributable to compression of the M-O-M linkages to angles narrower than their equilibrium values. The minimum strain conformations are planar, as ring puckering would cause further angular compression. 

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