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intermediate in the reaction we sought a method to independently prepare this compound and
subject it to the same reaction conditions. Acid 177 was synthesized starting with propargylic
ester 179 as outlined in Scheme 3.37. k Claisen rearrangement under dehydrative conditions gave
allenyl oxazolone 180 which was isolated and hydrolyzed to allenic-acid 181 using 1M HCl.
Then, 181 was carefully N-alkylated with 1-bromo-2-butyne to give allenyne-acid 182. Rh(I)-
catalyzed cycloisomerization of this precursor was acheved using 10 mol % of catalyst, and
heating to 35 °C for 2h. The reaction time for the cycloisomerization of the free acid was
considerably longer compared to the methyl ester (2h vs 10 min, see 111a, Scheme 3.1) and
resulted in relatively low yield of the triene 177 (60%).
Scheme 3.37 Synthesis of carboxylic acid 177.
BzHN
O
179
O
PPh 3
CCl 4
Et 3N
MeCN
N O
Ph
•
O
H
1M HCl
70 o C
>95%
BzHN
HOOC
180 181
•
H
Br
1 equiv.
NaH, DMF
85%
BzN
HOOC
•
H
10 mol %
[Rh(CO) 2Cl] 2
toluene, 35 o C
2h, 60%
When 177 was subjected to the the catalytic Rh(I) conditions ([Rh(dppe)Cl]2, AgSbF6, 1,2-
dichloroethane) the reaction resulted in 73% yield of 178 (Scheme 3.38). Thus, the free acid 177
is a probable intermediate in the cyclization of propargyl ester 176. Heating 177 in presence of
20 mol% AgSbF6 alone gave no reaction, indicating that the cyclization is not catalyzed by the
silver salt additive. 119 Furthermore, heating 177 in 1,2-dichloroethane also gave recovered
starting material. These experiments demonstrate that presence of the Rh catalyst is necessary for
transforming acid 177 to 178, however the exact mechanism is not clear. The overall
k Initially we attempted to prepare acid 177 by saponification of the corresponding methyl ester with LiOH in
THF/H2O (conditions utilized previously to cleave the methyl ester of lactam-triene 145a, Scheme 3.27). However,
these conditions did not cause saponification and the starting material was recovered. The resistance of this ester to
saponification under basic conditions is presumably due to electronic and/or steric effects imposed by the
neighboring benzoyl protecting group.
67
182
O
Bz
OH
N
177