Page 1200 - Advanced Organic Chemistry Part B - Reactions & Synthesis

1176 Schemes 13.4 and 13.5. These syntheses use achiral reactants and provide mixtures of
both stereoisomers. The final products are racemic. The first disconnection is that of the
CHAPTER 13 ester functionality, which corresponds to a strategic decision that the ester group can be
Multistep Syntheses added late in the synthesis. Disconnection 2 identifies the C(9)−C(10) bond as one that
can be formed by addition of some nucleophilic group corresponding to C(10)−C(13)
to the carbonyl center at C(9). This corresponds to disconnection shown above.
The third retrosynthetic transform recognizes that the cyclohexanone ring could be
obtained by a Birch reduction of an appropriately substituted aromatic ether. The
methoxy substituent would provide for correct placement of the cyclic carbonyl group.
The final disconnection identifies a simple starting material, 4-methoxyacetophenone.
A synthesis corresponding to this pattern that is shown in Scheme 13.4 relies
on well-known reaction types. The C(4)–C(7) bond was formed by a Reformatsky
reaction. The adduct was dehydrated during work-up and the product was hydro-
genated after purification. The ester group was converted to the corresponding aldehyde
by Steps B-1 through B-4. Step B-5 introduced the C(10)–C(13) isobutyl group by
Grignard addition to an aldehyde. In this synthesis, the relative configuration at C(4)
and C(7) was established by the hydrogenation in Step D. In principle, this reaction
could be diastereoselective if the adjacent chiral center at C(7) strongly influenced the
direction of addition of hydrogen. In practice, the reduction was not very selective and
a mixture of isomers was obtained. Steps E and F introduced the C(1) ester group.
The synthesis in Scheme 13.5 also makes use of an aromatic starting material
and follows a retrosynthetic plan similar to that in Scheme 13.3. The starting material
was 4-methoxybenzaldehyde. This synthesis was somewhat more convergent in that
the entire side chain except for C(14) was introduced as a single unit by a mixed
aldol condensation in step A. The C(14) methyl was introduced by a copper-catalyzed
conjugate addition in Step B.
Scheme 13.6 is a retrosynthetic outline of the syntheses in Schemes 13.7 to 13.9.
The common feature of these syntheses is the use of terpene-derived starting materials.
The use of such a starting material is suggested by the terpenoid structure of juvabione,
which can be divided into “isoprene units.”

CO CH 3
2
CH 3
CH 3 O CH 3
isoprene units in juvabione

The synthesis shown in Scheme 13.7 used limonene as the starting material (R =
CH in Scheme 13.6), whereas Schemes 13.8 and 13.9 use the corresponding aldehyde
3
(R = CH=O . The use of these starting materials focuses attention on the means
of attaching the C(9)−C(13) side chain. Furthermore, since the starting material is
an enantiomerically pure terpene, enantioselectivity controlled by the chiral center at
C(4) of the starting material might be feasible. In the synthesis in Scheme 13.7, the
C(4)−C(7) stereochemistry was established in the hydroboration that is the first step
of the synthesis. This reaction showed only very modest stereoselectivity and a 3:2
mixture of diastereomers was obtained and separated. The subsequent steps do not
affect these stereogenic centers. The side chain was elaborated by adding i-butyllithium
to a nitrile. The synthesis in Scheme 13.7 used a three-step oxidation sequence to
oxidize the C(15) methyl group to a carboxy group. The first reaction was oxidation