Alkenyl tricarbonyl derivatives of α-amino acids as trielectrophiles. Formation of heterocyclic-substituted products

Article abstract of DOI:10.1016/S0040-4039(02)00548-8

Alkenyl tricarbonyl esters have been prepared by reaction of mono aldehydes of dibasic amino acids with tricarbonyl esters. These systems undergo reaction with diamines and other dinucleophiles by a combination of Michael addition and nucleophilic attack at the electrophilic central carbonyl to form pyrrole derivatives. These monoaldehydes may also be used to incorporate imidazole and furan residues into the amino acid starting materials.

Full text of DOI:10.1016/S0040-4039(02)00548-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3351–3353
Alkenyl tricarbonyl derivatives of a-amino acids as
trielectrophiles. Formation of heterocyclic-substituted products
Harry H. Wasserman,* Yun Oliver Long, Rui Zhang and Jonathan Parr
Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA
Received 4 March 2002; accepted 13 March 2002
Abstract—Alkenyl tricarbonyl esters have been prepared by reaction of mono aldehydes of dibasic amino acids with tricarbonyl
esters. These systems undergo reaction with diamines and other dinucleophiles by a combination of Michael addition and
nucleophilic attack at the electrophilic central carbonyl to form pyrrole derivatives. These monoaldehydes may also be used to
incorporate imidazole and furan residues into the amino acid starting materials. © 2002 Elsevier Science Ltd. All rights reserved.
The 1,2,3-vicinal tricarbonyl (VTC) system represents a
potent electrophilic unit which has unique applicability
in organic synthesis, due to the enhanced reactivity of
the central carbonyl group with nucleophiles. In recent
years, the chemistry of this system has been extensively
explored1–3 in connection with the synthesis of varied
products of biological interest.
earlier work, numerous examples have been reported
showing how this array may serve as an unusually
versatile building block for generating structural units
not readily accessible by conventional synthetic meth-
ods.5 We now report the extension of earlier vinyl VTC
studies to the reactions of alkenyl VTC esters with
amines, diamines and other polynucleophiles.
One generally useful method for forming tricarbonyl
esters involves the reaction of carboxylic acids with
alkyl triphenylphosphoranilidine acetates, yielding sta-
ble diacyl ylides which can readily be converted to
tricarbonyl esters by oxidizing agents such as ozone.
Recent work by Baldwin4 has shown how monocar-
boxylic acid derivatives of protected aspartic and glu-
tamic acids could be transformed to tricarbonyl esters
by this route. The amino acids, activated in this way,
were then converted to novel heterocyclic products by
reactions with aromatic diamines and other
dinucleophiles.
In this work we followed up on earlier studies by
Martin and co-workers6 on the selective reduction
(DIBAL) of aspartic and glutamic acid diesters to form
monoaldehydes as reagents for Wittig reactions, yield-
ing unsaturated derivatives of the amino acids.
These aldehydes were then used in reactions with
diylides 2 previously reported by Chopard.7 Our inter-
ests were focused on mono Wittig processes in order to
generate products 3 which could lead to heterocyclic-
substituted amino acids through precursors 4.
Our reaction sequence began with the aldehyde 1, n=2
prepared by the reduction of a di-Boc-protected glu-
tamic acid dimethyl diester.6 Wittig reaction of 1 with
the bis phosphorane 27 yielded the a,b-unsaturated keto
As discussed in the preceding paper,5a a tricarbonyl
aggregate which has received particular attention incor-
porates the vinyl VTC ester grouping. In this and
O
O
Ph3P
OBn
PPh3
2
O
MMPP
(84%)
PPh3
CO2Bn
O
(CH2)n
NBoc2
MeO2C
(CH2)n
(CH2)n
NBoc2
MeO2C
MeO2C
CO2Bn
(73%)
H
O
O
NBoc2
1
4
3
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00548-8

3352
H. H. Wasserman et al. / Tetrahedron Letters 43 (2002) 3351–3353
In a second phase of this work, our goal was the
preparation of imidazole derivatives from the aldehydo
amino acid core. The formation of imidazole carboxylic
acids from the reaction of aldehydes with tricarbonyl
esters in the presence of ammonium acetate was previ-
ously reported by Brackeen.12 In the present work we
allowed 10, X=Boc2 to react with the tricarbonyl ester
11, R=Me in the presence of ammonium acetate form-
ing the imidazole carboxylate 12a. Low yields in this
transformation may have resulted from the presence of
considerable enol in 11, R=Me, as evidenced by the 1H
NMR spectrum. With a non-enolizable tricarbonyl 11,
R=Ph and an aldehyde ester containing the phthal-
imide protecting group 10, X=Phth the imidazole
product was formed in improved yield.
ylido ester 3, which was then oxidized to yield the
alkenyl tricarbonyl 4. In the course of related work, we
have employed a number of oxidizing agents to cleave
the carbon–phosphorous double bond in ylides of this
type: ozone,8a singlet oxygen,8b Oxone®8c or dimethyl
dioxirane.8d In the present case, we found that magne-
sium monoperphthalate (MMPP)9 gave excellent
results.
Along the lines of our earlier synthesis of prodigiosin,10
the first use of an alkenyl tricarbonyl as a trielec-
trophile, we treated 4, n=2 with primary amines,
including benzylamine, p-anisidine, 1,6-diaminohexane
and tryptamine. As observed in previous studies,5b the
intermediate labile hydroxy pyrrolidone carboxylates 5
were readily converted to the stable N-substituted
pyrroles 6.
Based on procedures which we have previously devel-
oped,13 this methodology could also be applied to the
formation of furan derivatives of a-amino acids. Thus,
the phthalimide protected aldehyde ester 13 derived
from aspartic acid dibenzyl ester underwent reaction
with the lithiated tricarbonyl derivative 14 in the pres-
ence of TMSCl to form the TMS protected alcohol 15.
Deprotection of the alcohol (HCl) followed by ozonoly-
sis yielded a tricarbonyl which underwent cyclization to
16, and then conversion to the furan 17 in the presence
of TsOH.
1,6-Diamino hexane underwent bis addition to the
alkenyl tricarbonyl yielding the alkyl-bridged bipyrrole
7. With tryptamine, the reaction took place through the
typical pyrrole-forming route yielding 8 along with a
secondary product 9 involving intramolecular addition
of the indole ring to the iminium intermediate. The
1
structural assignment to 9 was based on the H, 13C
NMR and HRMS. Similar reactions were carried out
using aspartic acid as the starting material.11
OH
O
O
O
OH
RNH2
CO2Bn
MeO
CO2Bn
MeO
4
N
N
R
R
NBoc2
NBoc2
a, R=PhCH2, (47%)
b, R=CH3O
6
5
, (64%)
OH
O
CO2Bn
MeO
N
NH2
Boc2N
Boc2N
H2N
(CH2)6
4
N
MeO
CO2Bn
O
OH
(49%)
7
NH2
NBoc2
CO2Me
OH
CO2Bn
O
MeO
N
N
N
NBoc2
H
4
+
N
H
O
HN
CO2Bn
9
(19%)
(28%)
8

H. H. Wasserman et al. / Tetrahedron Letters 43 (2002) 3351–3353
3353
Acknowledgements
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This work was supported by grants from the NIH and
NSF. We thank Dr. Walter McMurray of the Yale
Center for Cancer Research for expert help in deter-
mining the HRMS spectra of all new compounds.
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