Q7(b). Kishi dihydroxylation; ketal protection; Na/NH₃ on a terpene alcohol

Introduction. Each reagent acts on one functional group: OsO₄ adds two OH syn to a C=C, LiAlH₄ reduces C=O groups (unless one is protected as a ketal), and dissolving sodium reduces only C=C bonds that can take an electron.

(i) OsO₄/pyridine: syn dihydroxylation, Kishi's rule

Scheme: The new 3-OH is anti to the 2-OBn in the zigzag chain; 3-OH and 4-OH come from the same face (syn addition to a Z-alkene).

1. OsO₄ adds in one concerted [3+2] step to give a cyclic osmate ester; pyridine accelerates the addition and the ester is cleaved (aqueous NaHSO₃) to the diol: syn addition.
2. The substrate is chiral (C-2, OBn on the wedge = (S)). In the reactive conformation the allylic C–O bond eclipses the C=C and OsO₄ attacks the face anti to the allylic OBn (Kishi's rule): the new C-3 OH is anti to the C-2 OBn.
3. Syn addition to the Z-alkene puts the C-3 and C-4 OH on opposite sides of the zigzag drawing. Z = (2R,3S,4S)-1,2-bis(benzyloxy)heptane-3,4-diol (major diastereomer).

(ii) Ethyl acetoacetate

Scheme: Without protection both carbonyls are reduced; the cyclic ketal protects the ketone.

1. Direct LiAlH₄: the ketone gives a secondary and the ester a primary alcohol: Z = butane-1,3-diol.
2. Propane-1,3-diol/H⁺ converts the more reactive ketone into a cyclic ketal (2-methyl-1,3-dioxane); the ketal is stable to LiAlH₄, which reduces only the ester to CH₂OH. Aqueous acid removes the ketal: Z = 4-hydroxybutan-2-one.

(iii) Na, NH₃, ethanol

1. The substrate is (2Z)-2-methyl-6-(4-methylcyclohex-3-en-1-yl)hepta-2,6-dien-1-ol: three C=C bonds, none conjugated with another or with an aryl or C=O group (the two chain alkenes are separated by CH₂CH₂).
2. Dissolving metals reduce a C=C only when its radical anion can form, i.e. when the π* orbital is lowered by conjugation (arenes, enones, conjugated dienes, alkynes). Isolated trisubstituted and 1,1-disubstituted alkenes have too high a LUMO and are not reduced (compare the isopropenyl group that survives Na/NH₃ in 8(c)).
3. The OH only exchanges its proton (sodium alkoxide, H₂ evolved); work-up returns the alcohol.
4. Z = the unchanged alcohol (all three C=C kept). If an examiner takes the least hindered =CH₂ as reducible, the answer would be its dihydro derivative, 2-methyl-6-(4-methylcyclohex-3-en-1-yl)hept-2-en-1-ol.

Conclusion. (i) (2R,3S,4S)-1,2-bis(benzyloxy)heptane-3,4-diol (syn addition, anti to OBn). (ii) LiAlH₄: butane-1,3-diol; ketal route: 4-hydroxybutan-2-one. (iii) no C=C is reduced: all three double bonds are isolated, so Z is the starting alcohol.

Application. Kishi's rule guides the dihydroxylation steps in syntheses of polyol natural products and carbohydrates; ketal protection of the ketone of acetoacetate is the standard way to reduce or alkylate only its ester end.