Alkylation Reactions Nucleophilic Substitution

The C1 methyl building unit is supplied from L-methionine and is introduced by a nucleophilic substitution reaction. In nature, the leaving group is enhanced by converting L-methionine into S -adenosylmethionine (SAM) [Figure 2.4(a)]. This gives a positively charged sulphur and facilitates the nucleophilic substitution (SN2) type mechanism [Figure 2.4(b)]. Thus, O -methyl and N -methyl linkages may be obtained using hydroxyl and amino functions as nucleophiles. The generation of C -methyl linkages requires the participation of nucleophilic carbon. Positions ortho or para to a phenol group, or positions adjacent to one or more carbonyl groups, are thus candidates for C-methylation [Figure 2.4(c)].

A C5 isoprene unit in the form of dimethylallyl diphosphate (DMAPP) may also act as an

Alkylation reactions: nucleophilic substitution (a) formation of SAM

CO2H co2h

L-Met S-adenosylmethionine

,CO2H sn2 reaction © NH2

(c) C-alkylation using SAM

Ss neutral molecule is good leaving group

,CO2H

S-adenosylhomocysteine

ortho (and para) positions are activated by OH

II nh2

CO2H

carbonyl groups increase acidity and allow formation of enolate anion

'J^YCO2H

(d) O-alkylation using DMAPP

PTOp dimethylallyl diphosphate diphosphate is (DMAPP)

good leaving or group

PPOp sn1 reaction

© i . mi .. . ©s resonance stabilized allylic carbocation

Figure 2.4

alkylating agent, and a similar SN2 nucleophilic displacement can be proposed, the diphosphate making a good leaving group [Figure 2.4(d)]. In some cases, there is evidence that DMAPP may ionize first to the resonance-stabilized allylic car-bocation and thus an SN1 process operates instead. C -Alkylation at activated positions using DMAPP is analogous to the C -methylation process above.

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