Pseudoaxial methyl group

The high diastereoselectivity can be explained by looking at the conformations of 5 with either a pseudoaxial methyl group 5a or a pseudoaxial trialkylsiloxypropyl group 5b which shield the enolate from attack of an electrophile on the same side. 

Conformational analysis of 4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyrimidine-3-acetates and -3-carboxylates 30 (R = H) and their mono-methylated (R = Me, R1 = H) and 6,9-, 7,9-, and 8,9-dimethylated derivatives were carried out by H and l3C NMR spectroscopy (86JOC394). At ambient temperature the 6-methyl derivatives predominantly adopt the energetically most favorable half-chair conformation with a pseudoaxial methyl group. In the other half-chair conformation a serious 1-3 allylic strain exists between the pseudoequatorial methyl group and the adjacent carbonyl group. At the 7- and 8-methyl derivatives the half-chair conformations with equatorial methyl group occur almost exclusively, but the 9-... 

The stereoselective formation of 9 can be explained by assuming that transition states A and B, as shown in Fig. 7, are involved in this cyclization. If the nucleophilic displacement of the n-allylpaUadium intermediate with the anion of the p-ketoester moiety proceeds through a product-like transition state, transition state A, which should lead to the more stable product 9 with a pseudoequatorial C-6 unit and a pseudoaxial methyl group, probably favors over transition state B, producing a less stable product with the opposite stereochemistry at the quaternary center. 

When an additional methyl substituent is placed at C(3), there is a strong preference for alkylation anti to the 3-methyl group. This is attributed to the conformation of the enolate, which places the C(3) methyl in a pseudoaxial orientation because of allylic strain (see Part A, Section 2.2.1). The axial C(3) methyl then shields the lower face of the enolate.55... 

The anion of cyclohexanone /V,/V-dimclhyl hydrazone shows a strong preference for axial alkylation.122 2-Methylcyclohexanone N,N-dimethylhydrazonc is alkylated by methyl iodide to give d.v-2,6-dimclhylcyclohcxanone. The 2-methyl group in the hydrazone occupies a pseudoaxial orientation. Alkylation apparently occurs anti to the lithium cation, which is on the face opposite the 2-methyl substituent. 

Two possibilities can be distinguished with compound 10 for an exo-E-anti transition state the methyl group might occupy either a pseudoequatorial or a pseudoaxial position. Product 11a arises from the energetically more favorable state 20a, whereas lib is derived from transition state 20b. It is in this way that the methyl group of citronellal (9) determines the ratio of 20a to 20b. 

The chemical shifts for hydrogens and methyl groups at C-4 of 5-hydroxy-and 5-amino-A2-1,2,3-triazolines depend on the orientation relative to the hetero substituent at C-5. This has been extensively used for assignment of relative configurations at C-4 and C-5 of variously substituted A2-tria-zolines.216,259 lH-NMR spectra show that 5-alkoxy- and 5-hydroxy-A2-1,2,3-triazolines prefer an envelope conformation218 (63) with the hetero substituent at C-5 pseudoaxial at the flap and the N-l substituent pseudoequatorial, probably because of the anomeric effect. The cis and trans coupling constants in the 5-amino-, 5-hydroxy-, and 5-aIkoxy-A2-l,2,3-triazolines are very constant, being 7.0-9.8 and 2.0-3.4 Hz, respectively.218... 

Conformational analysis of some 9-chloro- and 9-bromo-6,7,8,9-tetrahy-dro-4//-pyrido[ 1,2-a]pyrimidin-4-ones 31 and their 9,9-dichloro and 9,9-dibromo derivatives was also carried out by I3C NMR spectroscopy (83JHC619). The halogen atoms in the 9-chloro and 9-bromo derivatives 31 (R = H) in the predominantly half-chair conformation occupy the pseudoaxial position. This conformer is probably stabilized by a favorable orbital interaction, while the other one, with a presudoequatorial halogen atom, is destabilized by the unfavorable dipole-dipole interaction between the 9-halogen and C(9a)=N(l) bonds. The methyl group in the 6-methyl derivatives in predominantly half-chair conformations is in the pseudoaxial position (83JHC619). 

For 9-phenylamino-6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyrimidin-4-ones 32 (R = NHPh R1 = H R2 = H, COOH) the half-chair conformation with a pseudoaxial 9-phenylamino group was the predominant one. But with the 6-methyl-9-phenylamino derivatives 32 (R = NHPh, R1 = Me) the cis-trans ratio was near 1 1 in the imine form. The presence of a methyl group on the nitrogen atom of the 9-anilino group 32 (R = NMePh) increased the amount of the cis form which contained the 9-substituent in a pseudoequatorial position [85JCS(P1)1015]. The 6-methyl group was in a pseudoaxial position in all tautomers. 

What selectivity there is (about 3 1) favours pseudoaxial attack in the conformation drawn as is reasonable for a small nucleophile. The use of a much more bulky reducing agent such as Lil3II(s-Bu)3 dramatically reverses and increases the stereoselectivity. Essentially only the cis compound is formed hecau.se the hulky reagent attacks the side of the carbonyl opposite to the methyl group. 

In drawing this chair, we have one choice do we allow the aldehyde to place R equatorial or axial Both are possible but, as you should now expect, there are fewer steric interactions if R is equatorial. Note that the enolate doesn t have the luxury of choice. If it is to have three atoms in the six-membered ring, as it must, it can do nothing but place the methyl group pseudoaxial. 

The ring was built up from a cetyl a ted (S)-lactic acid, and a cy clization step introduced the second chiral centre—the methyl group goes pseudoequatorial while the pseudoaxial position is preferred by the methoxy group because of the anomeric effect (Chapter 42). 

Unnatural (—)-ABA shows one-half to one-third of the activity of (+)-ABA in many bioassays,634 and this small difference in activity between the enantiomers has been explained by the pseudosymmetry of the molecule, which is derived from the 2,6,6-trimethyl-cyclohex-2-en-4-one.635 Figure 26 shows the steric structures of (+)- and (—)-ABAs with the preferable conformation, a half-chair with the pseudoaxial side chain, viewed from the carbonyl group at C-4. In the molecule of (—)-ABA, the C-7 corresponds to the C-9 of (+)-ABA, the C-9 corresponds to the C-7 of (+)-ABA, and the C-8 occupies the space facing the rtf-face of the C-2 in (+)-ABA, whereas a methyl group corresponding to the C-8 of (+)-ABA is absent. This hypothesis has been supported by the achiral analog (38), which shows activity intermediate between (+)- and (—)-ABAs.592 The activity of (—)-ABA is low in the assay of stomatal closure,618 which suggests that the receptor of stomata is more specific to (+)-ABA than to (—)-ABA. 

The introduction of a methyl group at C(6) of aminocyclohexenes causes a downfield shift of the resonance of this carbon ( + 2.7 ppm for compound 84) and an upfield shift of C(4) (— 4.6 ppm for 84). Comparison of these shifts with those corresponding to methyl-substituted cyclohexanes (equatorial a-Me group + 5.96 ppm axial a-Me 1.40 ppm equatorial y-Me + 0.05 ppm axial y-Me — 6.37 ppm)23 indicates that the methyl group is in preference in the pseudoaxial disposition 84a, than in 84e as shown below15. This conformation is free from allylic 1,2-strain (A1,2) and had been proposed24 on the basis of reactivity studies. 

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