Conformational lock

The importance of the o-hydroxyl moiety of the 4-benzyl-shielding group of R,R-BOX/o-HOBn-Cu(OTf)2 complex was indicated when enantioselectivities were compared between the following two reactions. Thus, the enantioselectivity observed in the reaction of O-benzylhydroxylamine with l-crotonoyl-3-phenyl-2-imi-dazolidinone catalyzed by this catalyst was 85% ee, while that observed in a similar reaction catalyzed by J ,J -BOX/Bn.Cu(OTf)2 having no hydroxyl moiety was much lower (71% ee). In these reactions, the same mode of chirality was induced (Scheme 7.46). We believe the free hydroxyl groups can weakly coordinate to the copper(II) ion to hinder the free rotation of the benzyl-shielding substituent across the C(4)-CH2 bond. This conformational lock would either make the coordination of acceptor molecules to the metallic center of catalyst easy or increase the efficiency of chiral shielding of the coordinated acceptor molecules. 

Norbornane has a conformationally locked boat cyclohexane ring (Section 4.5) in which carbons 1 and 4 are joined by an additional CH group. Note how, in drawing this structure, a break in the rear bond indicates that the vertical bond crosses in front of it. Making a molecular mode) is particularly helpful when trying to see the three-dimensionality of norbornane. 

The synthesis of the 2-acyloxathianes 3 makes use of the fact that for stereoelectronic reasons1, electrophilic attack on conformationally locked 2-lithiated oxathianes 1 leads exclusively to equatorially substituted products 2. A subsequent oxidation step completes the synthesis. 

Simple allyl alkali metal compounds have only a small capability for discriminating between diastereotopic faces of carbonyl compounds. Although a matter of simple diastereoselectivity, this can be concluded from the reaction of conformationally locked 4-/erf-butylcyclohexanone... 

The conformationally locked racemic enamine, 4-(4-rOT-butyl-1-cyclohexenyl)morpholine, reacts with (l-nitroethenyl)benzene to give a mixture of diastereomeric 1,2-oxazine 2-oxides 1 and 2 (ratio 1/2 75 25). Whether these arise via an ionic or a cycloaddition mechanism is unclear. Hydrolysis of 1 and 2 with dilute acid gave a 80 20 mixture of trans- and cis-ketones, 3 and 414. 

Ikegashira et al. reported another recent example of the successful exploitation of conformational locks. They describe the discovery of a novel class of hepatitis C virus NS5B RNA polymerase inhibitors [42]. By designing and synthesizing conformationally constrained analogs of 40 (see Fig. 8.9), they obtained a series of novel compounds with significantly improved potency. Compound 41 was, for example, shown to be 7-fold more potent, see Fig. 8.9. 

Photorefractivity is a property exhibited by some materials in which the redistribution in space of photogenerated charges will induce a nonuniform electric space-charge field which can, in turn, affect the refractive index of the material. In a new material the active species is a highly efficient cyclopalladated molecule97,98 shown in Figure 5. The palladium-bonded azobenzene molecule is conformationally locked, and gratings derived from cis—trans isomerizations can be safely excluded. 

The molecule is not conformationally locked . It still flips from one chair conformation to the other. 

Similarly, in a 1,3-dipolar cycloaddition of DMAD to the conformationally locked cyclic a-alkoxycarbonylnitrone (727), bicyclic ring systems, containing a nitrogen atom at the bridgehead position have been synthesized. A mechanistic interpretation of the origin of the fused pyrroles (729) includes the intermediate formation of the aziridine ring in (728) (Scheme 2.303) (820). 

Intramolecular conformation-locking Si...F coordination in non-coordinating solvents ==> rigid diastereomeric helices... 

The conformationally locked [46] bisallene 127 was first prepared by subjecting the allene dimer 126 to the DMS allene synthesis (Scheme 5.17) [47]. 

The different 3D-shapes adopted by aminoglycosides in the RNA- and enzyme-bound states suggest a possible structure-based chemical strategy to obtain antibiotics with better activity against resistant bacteria. Assiun-ing that, in these cases, some degree of conformational distortion of the substrates is required for enzymatic activity, it should be possible to design a conformationally locked oHgosaccharide that still retains antibiotic activity, but that is not susceptible to enzymatic inactivation (Fig. 8) [41]. 

Fig. 9 Schematic representation of the target conformationally locked aminoglycosides (2-4) and the deoxy derivatives (5, 6). The numbering employed for the different sugar units is indicated for neomycin-B (compound 1)...

To this point, all the examples presented have been ones in which the origin of the asymmetric induction has been unimolecular in nature, that is, the molecules adopt homochiral conformations in the solid state that favor the formation of one enantiomer over the other, usually through the close intramolecular approach of reactive centers bimolecular crystal packing effects appear to play little or no role in governing the stereochemical outcome of such reactions. This raises the interesting question of whether the soUd-state ionic chiral auxiUary approach to asymmetric synthesis could be made to work for conformationally unbiased reactants, i.e., those possessing symmetrical, conformationally locked structures. Two such cases are presented and discussed below. 

S. Sahabuddin, A. Roy, M. G. B. Drew, B. G. Roy, B. Achari, and S. B. Mandal, Sequential ringclosing metathesis and nitrone cycloaddition on glucose-derived substrates A divergent approach to analogues of spiroannulated carbanucleosides and conformationally locked nucleosides, J. Org. Chem., 71 (2006) 5980-5992. 

The target molecule is 2-hydroxymethyl-4-methoxy-3,7-dioxabicyclo[4.3.0]nonan-8-one (15), a key intermediate in several synthetic routes to thromboxane B2 8. The sequence9 begins with levoglucosan (9) in which the pyranose chair of D-glucose is conformationally locked by 1,6-etherification. Tosylation occurs chemoselectively at the unhindered positions (C-2 and -4). 

A diene system with unsymmetrical 1,4-disubstitution is converted to the iron carbonyl complex 1 which is resolved into its enantiomers. The aldehyde function is conformationally locked in the transoid position and is diastereofacially shielded from the bottom face. Nucleophiles attack from the top face with high selectivity. Alternatively, chain elongation leads to the triene 2 which is reacted with diazomethane. Cerium(IV) oxidation removes the metal and furnishes the substituted cyclopropane 3. 

In six-membered chelate rings such as those formed by 1,3-propanediamine (tn), at least two conformational energy minima, which correspond to an achiral chair structure (23a) and the chiral skew- or twist-boat forms (25b) and (25c),166-168 occur and both have been observed in crystal structures.169 176 The possible conformational isomerism in tn complexes is therefore even more involved than in en complexes.177 In (OC-6-12)-[CoCl2(tn)2]+ (tratns-[CoCl2(tn)2]+), for example, there are two achiral bis(chair) forms (26a and 26b), two enantiomeric (chair, skew-boat) forms (26c and 26d), one achiral form (26e) and two enantiomeric bis (skew-boat) forms (26f and 26g). Several of these have been isolated in conformationally locked systems.178 180... 

The rather obscure term vicinal is used to denote ligand-based sources of chirality, other than those due to conformation.181 These sources may, be the donor atom itself (the free ligand may or may not be chiral), or the framework of the ligand, in which case central, axial or planar chirality may be involved.16-115116 129 As noted previously, vicinal and conformational effects are often interdependent, since the substitution of a ligand required to introduce chirality may simultaneously result in conformational locking. 

NMR spectroscopic studies of two rhodium complexes 18 and 19 also indicate that the binding of the C2F4 group to rhodium is better pictured as a conformationally locked metallacyclopropane (59). The activation barrier for rotation of the C2H4 ligands around the Rh-olefin (centroid) vector in 19 was determined to be 15.0 0.2 kcal/mol. In contrast, the rotational barrier for the C2H4 ligand in 18 was demonstrated to be 13.6 0.6 kcal/mol... 

Deprotonation of carbonyl compounds by chiral amide bases followed by trapping with silylating agents or aldehydes has become a common method for de-symmetrizing prochiral and conformationally locked 4-substituted cyclohexanones and bicyclic ketones. The literature through 1997 has been reviewed [45]. 

Chiral BINOL (60) is a bifunctional organocatalyst in addition to the phenolic Brpnsted acid groups, it has a Lewis base unit attached via a spacer moiety.167 This particular combination holds the groups in a conformational lock, where they can doubly activate a substrate while giving a high level of stereocontrol. For this example of an aza-Morita-Baylis-Hillman reaction of an enone and an imine, yields up to 100% and ees up to 96% have been achieved. 

Fig. 52. Steric course of lithiation of conformationally locked 1,3-dithiane...

The stereochemical analysis depends on converting a chiral[160,170,180]phosphate monoester into two diastereoisomeric conformationally locked six membered cyclic phosphate triesters (2 ). In the cyclization step any one of the peripheral oxygen isotopes will be lost with equal probability, and the residual oxygen isotopes will take up axial and equatorial positions. Methylation of the isotopically labelled cyclic phosphate... 

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