in CH2Cl2 did not improve the yield. However, when the
initial reaction temperature was decreased to -10 °C, the
overall yield improved to 50%. It was interesting to observe
that all of the (E,Z)-diene 10 had been consumed during the
reaction. Only (E,E)-diene 13 was isolated with these two
adducts. The two Diels-Alder adducts could be carefully
separated by column chromatography. However, it was
difficult to differentiate the cis and trans adducts only by
comparison of the coupling constants in the NMR spectra.
For the purpose of structure assignment, we synthesized the
cis adduct 12 by using the known (E,E)-diene 13 as starting
material.8 Using sodium periodate as the oxidizing agent in
methanol-water only provided traces of product with most
of the diene being recovered due to the poor solubility of
(E,E)-diene 13 in methanol-water. However, employing
tetra-n-butylammonium periodate as the oxidizing agent in
CH2Cl2 led to the formation of adduct 12 in 68% yield with
recovered starting material. The structure of 12 was con-
firmed by comparison of the NMR spectra of the products
from the two cycloaddition reactions. It became apparent that
the unstable (E,Z)-diene 10 was transformed into the more
stable (E,E)-diene 13 under the above reaction conditions.
The mechanistic details for the isomerization still need to
be explored in further studies.
to difficulty of purification of the resulting diacid, the crude
diacid was treated with N,N′-dicyclohexyl-O-benzylisourea
in toluene at 100 °C for 2 h to provide dibenzyl ester 15 in
46% overall yield over three steps.11
Diester 15 was subsequently subjected to Boc deprotection
by treatment with TFA in CH2Cl2 at room temperature to
give the corresponding free amine 16. A variety of coupling
methods (HOAt/EDC, HOBt/EDC, and DCC/DMAP) were
unsuccessful in an effort to synthesize 17 from 16 and
N-acetyl-â-tert-butyl-L-aspartic acid. However, the use of
isobutyl chloroformate and N-methylmorpholine as coupling
reagents afforded 17 smoothly as an inseparable mixture of
diastereomers.12 Removal of the tert-butyl group by treatment
with TFA, followed by hydrogenolytic cleavage of the benzyl
protecting groups and ion exchange chromatography (Dowex,
K+), gave the trans-potassium salt 4a as a diastereomeric
mixture in 75% yield.13
The unambiguous synthesis of the cis compound 4b was
completed as shown in Scheme 6. Diels-Alder adduct 18
Scheme 4. Acylnitroso Diels-Alder Reaction and Structural
Assignment of Products
The TBS protecting groups were removed by TBAF in
THF to provide olefin diol 14, which was subjected to
hydrogenation to reduce the double bond. Pd-C was first
employed as the catalyst, which we found to be problematic
due to a lack of reproducibility. We then turned to the use
of ClRu(PPh3)3 as a catalyst,9 and obtained more reproducible
results. However, the catalyst could not be easily separated
by column chromatography from the product. Thus, the crude
material was used directly for the next step without purifica-
tion.
Early efforts to oxidize diol 14 to the dialdehyde using
Dess-Martin, PCC, and Swern oxidation conditions failed.
We then attempted to oxidize the diol to the corresponding
diacid through a one-step approach using RuCl3-NaIO4 as
the oxidizing agent.10 The reaction proceeded well, and the
diacid was readily obtained. This method provided a one-
step approach to the diacid from the corresponding diol. Due
was treated with TFA to provide free amine 19,14 which was
coupled with suitably protected aspartic acid using EDC and
HOAt as coupling reagents in CH3CN to afford 20 in 75%
yield.15 Then, the Boc group was removed, and the resulting
free amine was treated with acetic anhydride in the presence
of pyridine in CH2Cl2 to give 21 in excellent yield. Oxidative
cleavage of the double bond of 21 with KMnO4 in the
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