Page 1221 - Advanced Organic Chemistry Part B - Reactions & Synthesis

CH 3 5 4 CH OH 1197
1 3 7 5 3 1
6 C 6 4 2 CO H
3 2 HO 2 2 SECTION 13.2
CO 2 H
O 7 O
H CH 3 CH 3 CH 3 Illustrative Syntheses
CH 3 3
The synthesis in Scheme 13.34 is based on a bicyclic starting material that can
be prepared in enantiomerically pure form. In the synthesis, C(7) of the norbornenone
starting material becomes C(4) of P-D lactone and the methyl group in the starting
material becomes the C(4) methyl substituent. The sequence uses the cyclic starting
material to control facial selectivity. The configuration of the C(3) hydroxy and C(2)
and C(6) methyl groups must be established relative to the C(4) stereocenter. The exo-
selective alkylation in Step A established the configuration at C(2). The Baeyer-Villiger
oxidation in Step B was followed by a Lewis acid–mediated allylic rearrangement,
which is suprafacial. This stereoselectivity is dictated by the preference for maintaining
a cis ring juncture at the five-membered rings.
CH CH CH
CH 3 3 3 3 CH 3 H
H H CH 3
CH 3 CH 3 CH 3 4 2
BF 3
+ O
O O _ O O
O OBF
O 3 O H
The stereochemistry of the C(3) hydroxy was established in Step D. The Baeyer-
Villiger oxidation proceeds with retention of configuration of the migrating group (see
Section 12.5.2), so the correct stereochemistry is established for the C−O bond. The
final stereocenter for which configuration must be established is the methyl group at
C(6) that was introduced by an enolate alkylation in Step E, but this reaction was not
very stereoselective. However, since this center is adjacent to the lactone carbonyl, it
can be epimerized through the enolate. The enolate was formed and quenched with
acid. The kinetically preferred protonation from the axial direction provides the correct
stereochemistry at C(6).

Scheme 13.34. Prelog-Djerassi Lactone Synthesis: P. A. Grieco and Co-Workers a

CH A B C
3 CH H
3 O
LDA, 1) MCPBA O 1) LiAlH
CH 3 4
CH I 2 2) BF O 2) H , Pt TBDMSOCH
3 3 2 2 4
2 4
3) TBDMS Cl
O H
O CH H CH 4) CrO 3 pyr CH CH 3
3 3 3
D MCPBA
E
CH CH
3 6 4 3 1) LDA, CH I 3 4 CH 3
2) LDA, then H +
2 CO 2 H CH 2 OTBDMS
O O 3) CrO 3 O O
H H
CH 3 CH
3
stereoisomerization occurs
on the basis of kinetic protonation
a. P. A. Grieco, Y. Ohfune, Y. Yokoyama, and W. Owens, J. Am. Chem. Soc., 101, 4749 (1979).
Lett., 26, 3711 (1985); M. Isobo, Y. Ichikawa, and T. Goto, Tetrahedron Lett., 22, 4287 (1981); M. Mori,
T. Chuman, and K. Kato, Carbohydrate Res., 129, 73 (1984).