Pseudoequatorial substituent

With a-alkyl-substituted chiral carbonyl compounds bearing an alkoxy group in the -position, the diastereoselectivity of nucleophilic addition reactions is influenced not only by steric factors, which can be described by the models of Cram and Felkin (see Section 1.3.1.1.), but also by a possible coordination of the nucleophile counterion with the /J-oxygen atom. Thus, coordination of the metal cation with the carbonyl oxygen and the /J-alkoxy substituent leads to a chelated transition state 1 which implies attack of the nucleophile from the least hindered side, opposite to the pseudoequatorial substituent R1. Therefore, the anb-diastereomer 2 should be formed in excess. With respect to the stereogenic center in the a-position, the predominant formation of the anft-diastereomer means that anti-Cram selectivity has occurred. 

Enantioselective synthesis of 2-substituted piperidines with 60% ee has been reported via radical precursors being trapped in an intramolecular reaction (Scheme 17) <2003OL3767>. These cyclizations were rationalized in terms of chair-like transition states, with the maximum number of pseudoequatorial substituents, in which the nucleophilic amine attacks the alkene radical cation on the face opposite to the phosphate anion. 

This is readily explained by torsional interactions, which force the encfo-substituent into a pseudoaxial position trans to the partially formed C-0 bond. The steric interaction of the substituent with the second pseudoaxial substituent, even with hydrogen, is then stronger than that of a pseudoequatorial substituent with the transferred oxygen. 

A more rigorous way of dealing with the problem is to flip the chair. When you flip the chair, all the axial substituents at C(sp3) centers become equatorial, and vice versa. Be careful to preserve the stereochemistry about the double bonds the pseudoaxial and pseudoequatorial substituents of the double bonds retain their orientation in the flipped chair ... 

According to the Beckwith modelthe preferred transition state of a 6-e.w-radical cyclization resembles a cyclohexane ring in the chair conformation with pseudoequatorial substituents. Thus 2- and 4-substituted precursors preferentially give m-products, and 1-, 3- and 5-substituted precursors give /rum-products. 

If two geometric isomers can be formed, the (Z,iT)-product dominates over the (Z.Z)-product by a rate ratio (Z, /Z,Z) of 20-30 1 (Table 2, entries 8, 10/12. 17/19). Besides the higher stability of the (Z, )-produet. this can also be rationalized by different reaction paths involving the transition states 2b-ax and 2b-eq7 >0. As a result of fewer non-bonded interactions, the transition state 2b-eq, with a pseudoequatorial substituent R leading to the (Z, )-product, should be preferred to 2b-ax, where R is pseudoaxial forming the (Z.Z)-product. 

Oxo compounds such as 80 and 81 have had their stereochemistry elucidated by means of PMR spectroscopy and optical rotations. " Steric interaction between the N-acetyl group and adjacent pseudoequatorial substituents favors formation of the pseudoaxial isomer when this is possible. This was demonstrated by the PMR spectrum of compound 81... 

The addition of nucleophiles to cyclic acetals and hemiacetals is an efficient method to access substituted THFs in high diastereoselectivity which is, in general, predictable and can be explained by stereoelectronic effects (1999JA12208). In this transformation, the intermediate is an oxocarbe-nium, which preferentially adopts an envelope conformation, and the nucleophile attacks on the inside face of the envelope. In the presence of a methyl at C3, the conformer possessing pseudoequatorial substituents is favored and the, 2>-trans product is obtained as the major product (63 64) (Scheme 33). It is worthy of note that when an alkoxy group is present at C3, the 1,3-ds product, resulting from an inside attack on the diaxial conformer, is favored (65 66) (Scheme 33). 

Figure 1. Interaction between pseudoequatorial substituents in ring-saturated uracil derivatives. (Reproduced with permission from ref. 30. Copyright 1994 New York Academy of Sciences)...

The stereochemical features of the Claisen rearrangement are very similar to those described for the Cope rearrangement, and reliable stereochemical predictions can be made on the basis of the preference for a chairlike transition state. The major product has the -configuration at the newly formed double bond because of the preference for placing the larger substituent in the pseudoequatorial position in the transition state. ... 

Similar to cyclohexanones, substituted cyclopentanones also adopt a conformation with the substituents in a sterically favorable position. In the case of 2-substituted cyclopentanones 1 the substituent occupies a pseudoequatorial position and the diastereoselectivity of nucleophilic addition reactions to 1 is determined by the relative importance of the interactions leading to predominant fra s(equatorial) or cw(axial) attack of the nucleophile. When the nucleophile approaches from the cis side, steric interaction with the substituent at C-2 is encountered. On the other hand, according to Felkin, significant torsional strain between the pseudoaxial C-2—H bond and the incipient bond occurs if the nucleophile approaches the carbonyl group from the trans side. 

As one would expect, the tri-substituted eis-trans-2,4-diaryl-3-dimethylaminothietanes (187c,d) were shown by NMR to have all three substituents in pseudoequatorial positions with the remaining hydrogens in axial positions202. 

Cyclization of an organolithium tethered to a suitably positioned carbon-carbon jt-bond is a thermodynamically favorable process that proceeds in a totally regioselective exo-fashion with a high degree of stereocontrol via a transition state in which the lithium atom is intramolecularly coordinated with the remote rc-bond.9 The stereochemical outcome of the cyclization of a substituted 5-hexenyllithium follows from the preference of the substituent to occupy a pseudoequatorial position in the chair-like transition state depicted below.7... 

Compounds 225a-f showed interesting dynamic phenomena on the NMR time scale with broad lines at room temperature and appearance of two sets of sharp peaks at -50 °C corresponding to conformers 226 and 227 (Fig. 3). By contrast, 225 g-1 exist essentially as one conformer. These results show that the presence of a Me substituent adjacent to the 0 atom in ring B and syn to the ring junction hydrogen (see 225 g) prejudices the molecule in favor of conformer 226, thus placing the Me substituent pseudoequatorially (cf. 226, = Me). Sim-... 

Entries 3 to 6 are examples of ester enolate alkylations. These reactions show stereoselectivity consistent with cyclic TSs in which the hydrogen is eclipsed with the enolate and the larger substituent is pseudoequatorial. Entries 4 and 5 involve SN2 substitutions of allylic halides. The formation of the six- and five-membered rings, respectively, is the result of ring size preferences with 5 > 7 and 6 > 8. In Entry 4, reaction occurs through a chairlike TS with the tertiary C(5) substituent controlling the conformation. The cyclic TS results in a trans relationship between the ester and vinylic substituents. 

Internal nucleophilic capture of seleniranium ion is governed by general principles similar to those of other electrophilic cyclizations.96 The stereochemistry of cyclization can usually be predicted on the basis of a cyclic TS with favored pseudoequatorial orientation of the substituents. 

In Entry 13, the dioxinone ring undergoes thermal decomposition to an acyl ketene that is trapped by the solvent methanol. The resulting (3-keto-y,8-enoate ester then undergoes stereoselective cyclization. The stereoselectivity is controlled by the preference for pseudoequatorial conformations of the C(6) and C(9) substituents. 

This stereoselectivity can be explained by a five-membered TS for the sigmat-ropic rearrangement step. The observed A-stereochcmistry results if the larger alkyl substituent adopts a pseudoequatorial conformation. 

The conformation bearing the substituent at the asymmetric center in a pseudoequatorial position (R1) is more stable than that bearing the substituent... 

One can attribute the selective formation of materials with the ester and allyl units trans to one another, to the preference for the allyl unit to occupy a pseudoequatorial rather than a pseudoaxial orientation in the product-determining transition state. Compare, for example, transition state formulation 68 with 69. This stereochemical outcome is fortunate, as later on in the sequence, it is necessary for the allyl unit (after functional group modification) to swing across the top face of the cyclopentyl ring system during the conversion of 62 to 63. Were the substituents cis to one another, this would not be possible. 

The synthesis of modhephene (54), which proceeds according to plan in an overall yield of >16%, with complete control of relative stereochemistry, demonstrates the ability of radical cyclisations to form propellane systems and generate highly crowded neopentyl quaternary centres. The accepted pathway for the cyclisation of the vinyl trimethylstannane is shown in Scheme 7.25. The chair-like transition state in which the methyl substituent on the radical is pseudoequatorial, accounts for the observed endo stereoselectivity. 

It is apparent from Table 1 that the cyclohexadiene ring in 1,2-dihydrocorannule-nes is significantly flatter than either 1,3-cyclohexadiene itself or 9,10-dihy-drophenanthrene due to the constriction imposed by the remainder of the bowl-shaped ring system. Nonetheless, the lack of planarity means that substituents at may adopt either pseudoaxial (pa) or pseudoequatorial (pe) positions. However, the surface of the corannulene system is curved, and, unlike 1,3-cyclohexadiene and 9,10-dihydrophenanthrene, neither the two pa positions nor the two pe positions are equivalent. Thus, substituents in 1 -/ -1,2-dihydrocorannulenes may be (1) endo-pseudoaxial (endo-pa), (2) e do-pseudoequatorial (e/ido-pe), (3) exo-pseudoaxial (exo-pa), and (4) exo-pseudoequatorial (exo-pe), where endo and exo are related to concave and convex orientations, respectively. 

The greater stability of the anti isomer is attributed to the pseudoequatorial position of the methyl group in the chair-like chelate. With larger substituent groups, the thermodynamic preference for the anti isomer is still greater.10 11 Thermodynamic equilibration can be used to control product composition if one of the desired stereoisomers is significantly more stable than the other. 

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