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General procedure E for the preparation of 65d-f via a three step reaction sequence.
TMS
CbzHN
O
O
1. LDA, ZnCl 2, THF, -78 o C to rt
2. KHCO 3, MeI, DMF, rt
TMS
MeO 2C
•
H
NHCbz
TBAF, THF
pH = 7.0 buffer, rt
MeO 2C
64d 67d 65d
The following is a general procedure based on using 4.0 mmol of propargylic ester:
H
•
H
NHCbz
General procedure for preparation of a THF solution of LDA: i-Pr2NH (10.0 mmol) was added to
a flame dried 100 mL round-bottomed flask, followed by THF (10 mL) under nitrogen
atmosphere. The reaction flask was cooled to -20 °C and n-BuLi (10.0 mmol of 1.6 M solution in
hexanes) was added dropwise over 5 min. The colorless solution was then cooled to -78 °C and
held at that temperature for 30 min.
Step 1. Ester-enolate Claisen rearrangement: The amino acid propargylic ester (4.0 mmol) was
placed in a pear-shaped flask as a solution in benzene and the solvent was removed under
vacuum. The atmosphere was subsequently replaced with nitrogen and THF (10 mL) was added.
The resulting solution was added via a syringe to a freshly prepared solution of LDA (10 mmol)
at -78 °C over 5 min. After 3-5 min of stirring, ZnCl2 (4.8 mmol of a 0.5 M solution in THF) was
added in dropwise manner over 5 min at -78 °C. The reaction mixture was allowed to warm to rt
over 12 h. The reaction mixture was then poured in Et2O (200 mL), and treated with 1M HCl
(200 mL). The aqueous layer was extracted with Et2O (2 x 100 mL), and the organic layers were
combined and washed with brine. Concentration under vacuum afforded an oily residue.
Step 2. Methyl ester formation: The residue from step 1 was dissolved in DMF (10 mL).
Pulverized KHCO3 (10 mmol) was added at rt, followed by MeI (8 mmol). The reaction mixture
was stirred for 2-4 h until complete based upon TLC analysis, and then diluted with water (100
mL). The cloudy mixture was extracted with EtOAc, the organic layers were combined, washed
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