Q6(a). Chemoselective reductions

Introduction. Each reagent reduces only one of the groups present. The choice depends on whether the reducing agent is a nucleophilic hydride (NaBH₄, LiAlH₄), an electrophilic, Lewis-acidic hydride (borane) or an electron donor (sodium in ammonia).

(i) Luche reduction

CeCl₃ is a hard Lewis acid; in methanol it converts NaBH₄ into NaBH(OMe)₃-type hard hydrides and activates the C=O. Hard hydride attacks the hard carbonyl carbon (1,2-addition) instead of the soft β-carbon. Product: cyclohex-2-en-1-ol (allylic alcohol), C=C kept.

(ii) Dissolving-metal reduction

Sodium gives an electron to the enone (radical anion); protonation at the β-carbon and a second electron give the enolate, which is protonated on work-up. The C=C is reduced (conjugate reduction) and the C=O survives as the enolate. Product: cyclohexanone.

Scheme: 1,2-reduction (Luche) and conjugate reduction (Na/NH₃) of the same enone.

(iii) and (iv) Borane and LiAlH₄ on the half-ester

• (iii) B₂H₆ is electrophilic: it reacts fastest with the electron-rich, acidic CO₂H (forming an acyloxyborane) and leaves the ester alone. The acid is reduced to CH₂OH: ethyl 5-hydroxy-3-methylpentanoate. On acidification the alcohol attacks the ester intramolecularly and closes the δ-lactone.
• (iv) LiAlH₄ first deprotonates the CO₂H; the carboxylate is negatively charged and is reduced only slowly. The nucleophilic hydride reduces the ester to CH₂OH: 5-hydroxy-3-methylpentanoic acid, which lactonises on acidification.

Scheme: (iii) via the hydroxy ester, (iv) via the hydroxy acid: the same δ-lactone.

Both give 4-methyltetrahydro-2H-pyran-2-one; the opposite ends of the chain are reduced. (If the half-ester were a single enantiomer, the two routes would give the two enantiomers of the lactone.)

(v) Borane with a lactam ester

Borane reduces amides (here the lactam C=O) quickly, because the nitrogen lone pair makes the oxygen basic enough to coordinate boron; esters react only slowly. The lactam C=O becomes CH₂, and the methyl ester is kept.

Scheme: Amide reduced to amine; ester untouched.

Conclusion. (i) Cyclohex-2-en-1-ol; (ii) cyclohexanone; (iii) and (iv) 4-methyl-δ-valerolactone (borane reduces the acid, LiAlH₄ the ester); (v) methyl 1-benzylpyrrolidine-3-carboxylate.

Application. Luche and borane chemoselectivity are routine in drug synthesis (prostaglandin allylic alcohols; amine drugs from amides without touching esters).