Rotamer control

The nature of the iminic nitrogen substituent influences the cycloaddition pathway (4 + 2 versus 3 + 2) followed in the reactions of a-nitrosoalkenes with alkyl/aryl-substituted acyclic imines.4 The problem of rotamer control in Lewis acid-catalysed 3 + 2- and 4 + 2-cycloaddition reactions of a./S-disubstituted acryloylimides was solved by the use of N-H imide templates.5... 

The C=N bond of simple imines possesses modest reactivity toward intermolecular radical additions, so such acceptors have rarely been exploited. To enhance their reactivity toward nucleophilic radicals, electron-withdrawing groups at the imine carbon have been effective, as demonstrated by Bertrand in radical additions to a-iminoesters prepared from chiral amines [25]. Also, more reactive oxime ethers have been exploited extensively for radical addition, mainly through the longstanding efforts of Naito [26]. In most cases, stereocontrol has been imparted through the substituents on the imino carbon chiral O-substituents on oximes for stereocontrol were ineffective, presumably due to poor rotamer control [27, 28]. 

Although the aforementioned routes provided the desired y-amino acids, it was desirable to develop a synthesis which incorporates the carboxylic acid oxidation state prior to coupling. We hypothesized that manganese-mediated radical addition would accomplish this objective, and therefore initiated a study of manganese-mediated coupling of alkyl iodides with y-hydrazonoesters [104]. We had already shown that the manganese-mediated radical addition conditions offer excellent chemoselectivity, but it remained to be seen whether the stereocontrol model would be disrupted would an additional Lewis basic ester function in the hydra-zone interfere with the role of In(III) in two-point binding and rotamer control ... 

Higher selectivities are generally obtained in the presence of a Lewis acid as the reactive conformation is essentially locked into place. The reaction in the absence of a Lewis acid, in contrast, is prone to rotamer control problems as the. v-trans to s-cis interconversion can result in lower selectivities depending on the size of substituents and reaction temperatures. Larger substituents and lower reaction temperatures counteract the s-trans to s-cis rotation. 

The reaction of 77 and a,P-disubstituted acrylamides 78 mediated by Cu(OTl)2-79 afforded C-4 disubstituted isoxazolidines 80 with good diastereo- and enantioselectivity. In this case, the N-H imide template was chosen to accomplish rotamer control and improve... 

There are few addition reactions to a,/J-disubstituted enoyl systems 151 that proceed in good yield and are able to control the absolute and relative stereochemistry of both new stereocenters. This is a consequence of problematic A1,3 interactions in either rotamer when traditional templates such as oxazolidinone are used to relieve A1,3 strain the C - C bond of the enoyl group twists, breaking conjugation which results in diminished reactivity and selectivity [111-124], Sibi et al. recently demonstrated that intermolecular radical addition to a,/J-disubstituted substrates followed by hydrogen atom transfer proceeds with high diastereo- and enantioselectivity (151 -> 152 or 153, Scheme 40). 

The foregoing examples of differential reactivities of rotamers may be summarized by saying that the reactivity is controlled by the steric factor. The difference in the reactivities of rotamers of 9-(2-bromomethyl-6-methyl-phenyl)fluorene (56) in SN2 type reactions falls in the same category (176). However, the substituent effect is not limited to a steric one there can be conformation-dependent electronic effects of substituents as well. A pertinent example is found in the reactivity of the bromomethyl compound (56) when the rotamers are heated in a trifluoroacetic acid solution (Scheme 10). The ap form gives rise to a cyclized product, whereas the sp form remains intact (176). The former must be reacting by participation of the it system of the fluorene ring. 

By comparing time-resolved and steady-state fluorescence parameters, Ross et alm> have shown that in oxytocin, a lactation and uterine contraction hormone in mammals, the internal disulfide bridge quenches the fluorescence of the single tyrosine by a static mechanism. The quenching complex was attributed to an interaction between one C — tyrosine rotamer and the disulfide bond. Swadesh et al.(()<>> have studied the dithiothreitol quenching of the six tyrosine residues in ribonuclease A. They carefully examined the steady-state criteria that are useful for distinguishing pure static from pure dynamic quenching by consideration of the Smoluchowski equation(70) for the diffusion-controlled bimolecular rate constant k0,... 

The use of chiral auxiliaries to induce (or even control) diastereoselectivity in the cycloaddition of nitrile oxides with achiral alkenes to give 5-substituted isoxazolines has been investigated by a number of groups. With chiral acrylates, this led mostly to low or modest diastereoselectivity, which was explained in terms of the conformational flexibility of the vinyl-CO linkage of the ester (Scheme 6.33) (179). In cycloadditions to chiral acrylates (or acrylamides), both the direction of the facial attack of the dipole as well as the conformational preference of the rotamers need to be controlled in order to achieve high diastereoselection. Although the attack from one sector of space may well be directed or hindered by the chiral auxiliary, a low diastereomer ratio would result due to competing attack to the respective 7i-faces of both the s-cis and s-trans rotamers of the acrylate or amide. 

The known preference for transoid elimination of the elements of water from alcohols such as (6-3) controls the stereochemistry of the product. The arrangement in the starting material of the groups about the incipient olefin actually determines the steric identity of the product. The two rotamers of alcohol (6-3) that have the trans hydrogen and hydroxyl shown as their Newman projections (6-3a) and (6-3b) are equally probable since they differ only in the placement of the remote basic ether. The dehydration in fact gives a mixmre of the trans isomer (7-2) and the cis isomer (7-3) presumably from rotamers (6-3a) and (6-3b), respectively. Reaction... 

It is known that the geometries of the reactants play an important role in the regio-and stereochemical outcome of radical reactions since they are commonly involved in early transition states. Previous attempts to affect rotamer populations during the reaction included, among others, control of temperature and addition of a Lewis acid. It was recently reported75 that organotin halides, common byproducts of radical reactions, act... 

An intramolecular acyl radical cyclization of acyl selenide 1024 uses a (Z)-vinylogous sulfonate to control rotamer population, affording ry -2,6-disubstituted tetrahydropyran-4-one 1025, a key intermediate during synthesis of the tetrahydropyran unit of mucocin (Equation 399) <1997TL5249>. This methodology is also applicable to the synthesis of polycyclic ethers <1996JOC4880>. 

So, due to the high reactivity, it captures the various rotamers of the substrate, all of which are populated in the ground state (Sch. 15) [10d], More satisfactory results have been achieved by steric control using optically active 2,2-dimethyloxazolidines as chiral auxiliaries (Sch. 16) [10c],... 

The sulfinyl group has been widely used in asymmetric synthesis to achieve an efficient control of the 7r-facial selectivity of different types of cycloadditions of vinyl or dienyl sulfoxides. All authors agree that its success is due mainly to the large steric and stereoelectronic differences induced by sulfinyl group on the diastereotopic faces of the neighboring double bonds. It is a consequence of the high conformational polarizability of these substrates around the C-S bond, which means that their conformational equilibrium are easily shifted toward some of the possible rotamers. 

Discrepancies between different researchers derive from the character inter-or intramolecular of the interactions presumably controlling the reactive conformation. Thus, in most of the cases, the population of the different rotamers in the sulfinylated substrate (only governed by intramolecular interactions) is the only factor considered for explaining the observed 7r-facial selectivity. This explanation (static conformational polarization) was formulated by Koizumi and used by many authors to justify the behavior of vinyl sulfoxides acting as dienophiles and dipolarophiles. A second explanation assumes that the interactions of the two reagents in the transition states determine a different reactivity of the rotamers around the C-S bond. This intermolecular factor can become the most important one in the control of the 7r-facial selectivity of the cycloadditions, and therefore the tendency expected from conformational stability criteria was not observed in those cases where the most reactive conformation is not the most populated one. This dynamic conformational polarization has been used just to explain some of the results obtained for sulfinyl quinones and sulfinyl dienes (unexplainable with the above model) but it can be applied to many other cases. 

Interestingly, if the separate epimers of the (ft)-PROPHOS complexes (i75-C5H< )[(R)-PROPHOS]Ru=C=CHR + are employed, then the two rotamers of the vinylidene are diastereomeric [Eq. (65)]. Consiglio and Morandini (76) found that the difference in population of these interchangeable conformers appears to be controlled by steric factors and presumably reflects the relative ability of the two rotamers to fit into the chiral pockets formed by the phosphines. 

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