Stereoselectivity allylic strain

The rationalization of stereoselectivity is based on two assumptions. (1) The 1-arylthio-1-nitroalkenes adopt a reactive conformation in which the ally lie hydrogen occupies the inside position, minimizing 1,3-allylic strain. (2) The epoxidation reagent can then either coordinate to the ally lie oxygen (in the case of Li), which results in preferential syn epoxidation or in the absence of appropriate cation capable of strong coordination (in the case of K) steric and electronic effects play a large part, which results in preferential anti epoxidation (Scheme 4.7).52... 

In conjunction with our studies on the synthetic utility of amide enolates (35,36), we have postulated that the high (Z)-stereoselection observed in the deprotonation of dialkylamides is a consequence of ground state allylic strain considerations (37), which strongly disfavor amide conformation B (Scheme 8), and consequently the associated transition state T (Scheme 7) for deprotonation, to give ( )-enolates. 

In studies not yet published (66), the A/-acyl-oxazolidine-2-one 62 has been found to exhibit exceptionally high levels of (Z)-enolization stereoselection with either amide bases (LDA, THF, -78°C) or boryl triflates [(n-C4H9)2BOTf, CH2CI2, -78°C] in the presence of diiso-propylethylamine (DPEA). Upon aldol condensation, the enolates 63a and 63b afford the aldolates 64 (Scheme 11), which react readily with nucleophiles at the carbonyl function (Table 22). As discussed earlier, the large preference for (Z)-enolate formation in this system can be attributed to allylic strain considerations (37)... 

While reaction of the acetate 40 as well as the acetyl- and phthalimide derivatives of chiral amine (41b and 41c) proceeded with erythro diastereoselectivity (in accordance with the classical cis effect, minimization of 1,3-allylic strain) (Table 6, entries 8, 10, 11), for the allylic alcohols 39, primary allylic amine 41a, silyl enol ethers 42 and enol ether 43 threo selectivity was observed (Table 6, entries 1-7, 9, 12-14) (see also Scheme 24). For allylic alcohols with an alkyl group R4 cis to the substituent carrying the hydroxyl group, diastereoselectivity was high (Table 6, entries 1-7) in contrast, stereoselection was low for allylic alcohols which lack such an R4 (cis) substituent (substrates 39h and 39i, see Figure 4). 

The stereoselectivity of the allylic hydroperoxidation also depends on se eral factors. With chiral allylic alcohols or allylic amines 200, a hydrogen is developed between ]02 and the vicinal hydroxyl or amino group. The fac differentiation results from an approach of 102 in the transition state that mi mizes 1,3-allylic strain. 201 and 202 can be obtained with a diastereoisome excess higher than 90% in CCI4. As previously indicated for the formation dioxetanes and 1,4-endoperoxides, the selectivity decreases considerably in presence of hydroxylic solvents [123]. When hydrogen bonding is no more pos ble in 203, the stereofacial differentiation is steered by steric and electronic rep sion effects at the level of the possible diastereoisomeric transition states 204 is formed selectively (Scheme 54). 

Furthermore, in (Z)-l,3-disubstituted allylic sulfoxides the transoid transition state is free of severe 1,3-allylic strain which destabilizes the corresponding cisoid transition state12. Such systems show nearly complete chirality transfer as well as absolute E stereoselectivity. 

Considerable attention was given to the stereochemistry for the alkylation of metal enolates of y-butyrolactones during the past 1980 s decade. It is well recognized that electrophihc attack on the enolates of -substituted y-butyrolactones is controlled exclusively by the -substituent leading to the trans addition products . However, Iwasaki and coworkers reported the reverse diastereofacial differentiation in the alkylation of the enolates of a, S-dibenzyl-y-butyrolactones. These authors proposed that the factor controlling the selectivity in this case was allylic strain. Also, y-substituted y-lactones give stereoselective trans alkylation . ... 

Alkenic stereoselection in the Still-Wittig rearrangement results presumably from conformational control in a very early transition state (Scheme 2). There, the substituent R prefers equatorial (15) over axial (16) orientation, if the 1,2-allylic strain is smaller than the 1,3-allylic strain, and vice versa. This implies trans products in the former vide supra) and (Z)-products in the latter case vide infra). 

In 1978, Larcheveque and coworkers reported modest yields and diastereoselectivities in alkylations of enolates of (-)-ephedrine amides. However, two years later, Evans and Takacs and Sonnet and Heath reported simultaneously that amides derived from (S)-prolinol were much more suitable substrates for such reactions. Deprotonations of these amides with LDA in the THF gave (Z)-enolates (due to allylic strain that would be associated with ( )-enolate formation) and the stereochemical outcome of the alkylation step was rationalized by assuming that the reagent approached preferentially from the less-hindered Jt-face of a chelated species such as (133 Scheme 62). When the hydroxy group of the starting prolinol amide was protected by conversion into various ether derivatives, alkylations of the corresponding lithium enolates were re-face selective. Apparently, in these cases steric factors rather than chelation effects controlled the stereoselectivity of the alkylation. It is of interest to note that enolates such as (133) are attached primarily from the 5/-face by terminal epoxides. ... 

If the initial addition (A, Scheme 3) is essentially irreversible, the net stereoselectivity can be controlled by interactions that exist in the transition state for the Michael addition. However, if there is not a rapid intervening process (cyclization or proton transfer), the initial dipolar adducts would be expected to reform starting materials at an appreciable rate (vide supra). Based on the reports described previously, a significant possibility exists that this initial addition is reversible, at least in most cases. If indeed step A is reversible or if the configuration of 3.1 is not stable to reaction conditions, then the net stereoselectivity can be determined by the relative stability of the dias-tereomers of 3.1 or by the relative rates of the diastereomeric transition states for some subsequent reaction (e.g., B-F).+ For example, selectivity could be induced by preferential cyclization (paths D and E) or by selective proton transfer (path B) from one of the components of the initial diastereomeric mixture (3.1). Also, it is possible that selective protonation (path F) of enamine 3.5 could give the observed products. This prospect is less likely as the generation of enamine 3.5 is disfavored by allylic strain considerations. 

Chiral Z-substituents strongly influence the stereoselectivity and reaction rate because they exist near to the titanium ion and lack conformational freedom due to the allylic strain caused by the small 0-C-C=C dihedral angle (Fig. 1). 

A related carbocycle is synthesized starting from carbohydrate precursors. The radicals are generated via Barton deoxygenation of the intermediate 5-heptenolsiei. The effect of 1-, 2-, 3-and 4-substituents on the stereoselectivity of the cyclization reaction has also been described 17-18. The formation of the 1,5-m-product is rationalized by the Beckwith modelThe 4,5-configuration of the main product is tram and is explained by the influence of allylic strain. 

A further example of the stereoselective synthesis of /ran.v-subsiituted tetrahydropyrans is the radical cyclization of ethyl (4R)-(Z)-4-(2-bromo-l-ethoxyethoxymethyl)-2-hexenoate3" The radical cyclization is performed by heating the bromoacetal in the presence of tributyltin hydride and AIBN in benzene. A mixture of two diastereomers is formed in 97% yield. Reduction, benzylation, hydrolysis and oxidation gives the /ran.v-substituted ( + )-(4S,57 )-4-(2-benzyloxyethyl)-5-ethyltetrahydro-2//-pyran-2-one (5), which is a potential synthetic intermediate for (—)-emetine35. The highly selective formation of the tram-substituted pyrans is rationalized by an allylic strain effect that destabilizes the transition state leading to the cis- isomers. 

Scheme 6.7. The effects of allylic strain on the stereoselectivity of alkene formation [32]. (a) AL2 strmn and the selective formation of 2-alkenes. (b) AL3 strain causes selective formation of -a kenes. (c) If one or both of the partners cf Figure 6.5a, R,. R2, or Z) is hydrogen, the selectivity is diminished, d) Al.3. t ain produces 100% selectivity when the carbanionic carbon is propargylic [48].

This interaction is an example of 1,3-allylic strain ° This type of steric strain arises in eclipsed conformations when substituents on the double bond and the C(3) group, which are coplanar, are large enough to create a nonbonded repulsion. The conformation of alkenes is an important facet with regard to the stereoselectivity of addition... 

Figure 6.33 1,3-Allylic strain, in combination with stereoelectronic preferences, can be used for the design of stereoselective reactions of allylic systems.

Also, it was demonstrated that acyclic radicals can react with high stereoselectivity [45]. In order for the reactions to be stereoselective, the radicals have to adopt preferred conformations where the two faces of the prochiral radical centers are shielded to different extents by the stereogenic centers. Giese and coworkers [49] demonstrated with the help of Electron Spin Resonance studies that ester-substituted radicals with stereogenic centers in (3-positions adopt preferred conformations that minimize allylic strain [49] (shown below). In these conformations, large (L) and medium sized substituents (M) shield the two faces. The attacks come preferentially from the less shielded sides of the radicals. Stereoselectivity, because of A-strain conformation, is not limited to ester-substituted radicals [50]. The strains and steric control in reactions of radicals with alkenes can be illustrated as follows [50] ... 

A stereoselective electrocyclization developed for the synthesis of reserpine results from a stereocentre six atoms away from the newly fornoing chiral centre that is responsible for the diastereoselectivity of the ring closure. The presence of allylic strain in the disfavoured transition state results in the torquoselective ring closure (Scheme 38). 

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