Page 1203 - Advanced Organic Chemistry Part B - Reactions & Synthesis

by singlet oxygen to give a mixture of hydroperoxides, with oxygen bound mainly at 1179
C(2). The mixture was reduced to the corresponding alcohols, which was then oxidized
to the acid via an aldehyde intermediate. SECTION 13.2
In Scheme 13.8, the side chain was added in one step by a borane carbonylation Illustrative Syntheses
reaction. This synthesis is very short and the first four steps were used to transform
the aldehyde group in the starting material to a methyl ester. The stereochemistry at
C(4)–C(7) is established in the hydroboration in Step B, in which the C(7)–H bond is
formed. A 1:1 mixture of diastereomers resulted, indicating that the configuration at
C(4) has little influence on the direction of approach of the borane reagent.
Another synthesis, shown in Scheme 13.9, that starts with the same aldehyde
(perillaldehyde) was completed more recently. The C(8)−C(9) bond was established
by an allylic chlorination and addition of the corresponding zinc reagent to isobu-
tyraldehyde. In this synthesis, the C(7) stereochemistry was established by a homoge-
neous hydrogenation of a methylene group, but this reaction also produces both
stereoisomers.
The first diastereoselective syntheses of juvabione are described in Schemes 13.11
and 13.12. Scheme 13.10 is a retrosynthetic analysis corresponding to these syntheses,
which have certain similarities. Both syntheses started with cyclohexenone, and there
is a general similarity in the fragments that were utilized, although the order of
construction differs, and both led to ± -juvabione.
A key step in the synthesis in Scheme 13.11 was a cycloaddition between an
electron-rich ynamine and the electron-poor enone. The cyclobutane ring was then
opened in a process that corresponds to retrosynthetic step 10-IIa ⇒ 10-IIIa in
Scheme 13.10. The crucial step for stereochemical control occurs in Step B. The
stereoselectivity of this step results from preferential protonation of the enamine from
the less hindered side of the bicyclic intermediate.

O O O
H H H H H
H + C
N(C H ) H N(C H ) H CO H
2 5 2
2 5 2
CH 3 CH 3 + CH 3 2
The cyclobutane ring was then cleaved by hydrolysis of the enamine and ring
opening of the resulting -diketone. The relative configuration of the chiral centers is
unaffected by subsequent transformations, so the overall sequence is stereoselective.
Another key step in this synthesis is Step D, which corresponds to the transfor-
mation 10-IIa ⇒ 10-Ia in the retrosynthesis. A protected cyanohydrin was used
as a nucleophilic acyl anion equivalent in this step. The final steps of the synthesis in
Scheme 13.11 employed the C(2) carbonyl group to introduce the carboxy group and
the C(1)–C(2) double bond.
The stereoselectivity achieved in the synthesis in Scheme 13.12 is the result of
a preferred conformation for the base-catalyzed oxy-Cope rearrangement in Step B.
Although the intermediate used in Step B was a mixture of stereoisomers, both gave
predominantly the desired relative stereochemistry at C(4) and C(7). The stereo-
selectivity is based on the preferred chair conformation for the TS of the oxy-Cope
rearrangement.