Download (3249Kb) - D-Scholarship@Pitt - University of Pittsburgh

Table 2.2 Claisen rearrangement examples reported by Kazmaier.
R 3
PHN
R 1
O
48
O
R 2
LDA, ZnCl 2
THF, -78 o C to rt
R 3
HO 2C
•
50
R2 H
R
NHP
1
Entry P R 1 R 2 R 3 Yield (%) diastereoselectivity (%) a
1 Boc H H t-Bu 58
2 Boc H Me t-Bu 54 93
3 Cbz H Et Bu 78 95
4 Cbz Me i-Pr Pr 66 > 95
5 Boc Bn i-Pr Pr 59 > 95
6 Tos i-Bu i-Pr Pr 57 > 95
a diastereoselectivity was determined by 1 H NMR
Therefore, initial efforts were focused on reproducing Kazmaier’s protocol by preparing
trisubstituted allenes. Propargylic esters 64a and 64b were obtained by coupling of the
corresponding acid 62 and alcohol 63 using DCC and DMAP in 88% and 77% yield,
respectively (Scheme 2.7). Claisen rearrangement of 64a using the reported conditions (LDA,
ZnCl2, THF, -78 °C to rt) proceeded to give the intermediate allenic acid, which was converted
to the methyl ester 65a by treatment with MeI and KHCO3 in 22% overall yield. Since following
both reactions by TLC did not reveal significant formation of any byproducts, the low yield was
attributed to loss of the intermediate carboxylic acid during silica gel chromatography due to
increased polarity. To circumvent this problem, in all subsequent reactions, the crude reaction
mixture after Claisen rearrangement was immediately treated with MeI and KHCO3 without
intermediate purification. a Applying this strategy to the preparation of 65b resulted in 73% yield
after one final purification step.
a Since sufficient amounts of 65a were prepared using the unoptimized protocol this reaction was not repeated.
22