AWER GUIDE APRIL/MAY 2006 EXAMIATI CEMITRY 249 1. (a) PDC / C 2 2 (b) t-bume 2 i (1 equiv) / imidazole (1 equiv) i TBDM protection of the less sterically hindered alcohol (c) BuLi (1 equiv) then (d) 2 F a / / 2 (e) (i) mcpba (ii) Me / + (cat) (f) (i) B 3 (ii) 2 2 / a Page 1 or 9
(g) C 2 2 (h) (i) Li (2 equiv) (j) and Me Me ame / Me Me Me Page 2 or 9
2. (a). reduction ab 4 dihydroxylation s 4 (cat) / Me 3 / Ts (cat) / acb 3 / p 6 Ph 3 PC 2 reductive amination (note: cannot use Pd/ 2 due to competing alkene reduction) LDA / -78 C then PhC 2 Br ketalization Wittig reaction enolate alkylation (b) p-ts (cat.) intramolecular ketalization Page 3 or 9
3. (a) There are various possible mechanisms. ere electrophilic aromatic substitution is followed by activation of the sulfonic acid/sulfonate to an activated sulfonate ester which is attacked by chloride anion. "X" E Ar + Wheland intermediate conversion to an activated sulfonate ester (this is similar to the reaction of a carboxylic acid with 2 ) "Y" (b) The reaction of ( X to Y ) gives the para substituted product because the CMe group is electron donating an othro/para directing group. teric effects favour the para product over the ortho product. (c) This mechanism is analogous to the reaction of an amine to an acyl chloride. The initial addition step gives a pentavalent sulfur intermediate which has trigonal bipyramidal geometry. addition elimination + "Y" 3 3 2 2 "Z" Page 4 or 9
(d) ee notes for the full mechanism of amide hydrolysis to an amine under acidic conditions. 2 2 / + / sulfanilamide "Z" 2 2 (e) A major problem here is that the aniline will remove a proton from 2 and be converted into the unreactive salt. This is why the aniline nitrogen must first be converted into an amide, with the acetyl group acting as a protecting group for the otherwise basic nitrogen. 2 2 "K" 3 + 3 (f) 2 2 3 / 2 4 n / 3 C / pyridine "X" Page 5 or 9
4. (a) Draw BT pairs of synthons that relate to this disconnection. Me Gingerol approach A approach B Me donor (nucleophilic) Me acceptor (electrophilic) acceptor (electrophilic) donor (nucleophilic) (b) The more natural disconnection is Approach A. This can be determined by consideration of the position of the electronegative oxygen atoms they have a 1,3- functional relationship. They polarize the neighbouring carbons (positions 1 and 3) to be δ+. Ideally in a chain one can use alternating positive and negative charges to show the natural disconnections, thus placing the carbon number 2 to be the nucleophile (i.e., δ-) and carbon number 3 to be the electrophile (i.e., δ+). Me δ δ 1 2 3 δ+ δ+ δ The species that correspond to these synthons are the enolate anions (derived from deprotonation of the ketone) and the aldheyde: Page 6 or 9
Me Li ote: will need to deprotonate or protect At first sight this approach looks reasonable: Me LDA / TF / -78 C then add Gingerol an Aldol condensation approach via the kinetic enolate this should be k, except for the presence of the acidic phenol group, which is more acidic that the α-protons of the ketone. Using 1 equiv of LDA would only deprotonate the phenol, and no gingerol would be obtained! It should however be possible to use 2 equivalents of the LDA to deprotonate both groups. Alternatively, you can protect the first, as for example as silyl ether. Thus, the synthesis would be, (i) protection of the phenol as a TBDM ether (using TBDM / imidazole), (ii) the Aldol condensation (as above), and then (iii) deprotection to the product (i.e., with TBAF / TF / water). (ote: a disconnection between C-1 and C-2 would lead again to two approaches, but in this case the better approach is the Umpolung approach i.e., lithiated dithiane as the C-1 nucleophile and an epoxide as the C-2 electrophile). Page 7 or 9
(c) Cooking fresh ginger transforms gingerol into zingerone. Me heat (cooking) Me Gingerol Zingerone This reaction proceeds via the retro-aldol reaction. i.e., the reverse of the Aldol condensation. The retro Aldol is favored at very high temperature (the reaction is an equilibrium) since entropy effects start to dominate enthalpy (i.e., bond energies). (d) Me C "A" (i) tbume 2 i / imidazole (ii) Ph 3 P=CCMe (iii) 2 / Pd/C (iv) Bu 4 F / 2 Me step (i): TBDM ether protection of phenol step (ii): Wittig reaction step (iii): alkene reduction step (iv): deprotection of TBDM group Zingerone Me (i) tbume 2 i / imidazole (ii) B / (PhC) 2 / Me "B" (iii) Li Zingerone (iv) Bu 4 F / 2 step (i): TBDM ether protection of phenol step (ii): benzylic bromination (free-radical conditions) step (iii): enolate alkylation step (iv): deprotection of TBDM group Me Br (i) tbume 2 i / imidazole (ii) t-buli (2 equiv) then CuI Me "C" then Zingerone (iii) Bu 4 F / 2 step (i): TBDM ether protection of phenol step (ii): Lithium-halogen exchange (to make ArLi), then cuprate formation, and then conjugate addition step (iii): deprotection of TBDM group Page 8 or 9
5. (a) Al 3 (1 equiv) ab 4 a then (b) mcpba PBr 3 Br t-buli (2 equiv) Li CuLi 2 6..(a) CMPUD A: (b) CMPUD B: 3 C Page 9 or 9