α,β-Diketo nitriles as dielectrophiles. Formation of heterocyclic derivatives of amino acids

Article abstract of DOI:10.1016/S0040-4039(02)02486-3

The reactions of mono Boc-protected amino monocarboxylic acids with phosphoranylideneacetonitrile yield ylido nitriles which on ozonolysis at low temperature form labile α,β-diketo nitriles. These derivatives may be used in situ for reaction with diamines or related dinucleophiles to yield hetero derivatives of interest as unnatural amino acid building blocks.

Full text of DOI:10.1016/S0040-4039(02)02486-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 361–363
a,b-Diketo nitriles as dielectrophiles. Formation of heterocyclic
derivatives of amino acids
Harry H. Wasserman,* Yun Oliver Long and Jonathan Parr
Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA
Received 28 October 2002; revised 5 November 2002; accepted 6 November 2002
Abstract—The reactions of mono Boc-protected amino monocarboxylic acids with phosphoranylideneacetonitrile yield ylido
nitriles which on ozonolysis at low temperature form labile a,b-diketo nitriles. These derivatives may be used in situ for reaction
with diamines or related dinucleophiles to yield hetero derivatives of interest as unnatural amino acid building blocks. © 2002
Elsevier Science Ltd. All rights reserved.
The synthesis of unnatural amino acids is an area of
research that has attracted a great deal of attention in
recent years.1,2 Some of these systems exhibit important
biological properties, such as antibiotic and antitumor
activity and others have been shown to serve as
protease inhibitors useful in the preparation of new
drug candidates. Incorporated into polypeptides, they
have been used to probe enzyme structure and function
or to develop new libraries for DNA binding.3
acids. In this report we describe application of this
methodology to the formation of novel heterocyclic
derivatives of a-amino acids.
We first studied the behavior of N-Boc 6-aminohex-
anoic acid (1) in the sequence outlined in Scheme 1.
Reaction of
1 with ylido nitrile 2 gave a-keto
cyanophosphorane 3 which was then subjected to
ozonolysis at −78°C to form the cyano dicarbonyl
product 4. This labile electrophile was not isolated but
allowed to react directly with 1,2-phenylenediamine,
yielding a mixture of the substituted quinoxalines 5 and
6.
Synthetic methodology based upon the vicinal tricar-
bonyl aggregate has proven to be extremely versatile. In
particular, the route which allows ready conversion of a
carboxylic acid to the highly electrophilic vicinal tricar-
bonyl (VTC) system has made possible the generation
of a varied range of heterocyclic systems4 not readily
available by conventional methods. A notable applica-
tion of this chemistry has recently been reported by
Baldwin who has shown that vicinal tricarbonyl esters
formed from aspartic and glutamic acids may be con-
verted to derivatives of interest as heterocycle-substi-
tuted non-proteinogenic amino acids.5
The same reaction was then applied to the mono benzyl
ester of N-Boc aspartic acid 7. As outlined in Scheme 2,
generation of the cyano ylide 8 was followed by ozonoly-
sis to yield the diketo nitrile 9 which was immediately
treated with 1,2-diphenylenediamine, forming the
hydroxy quinoxaline 11 (96%). We suggest that this
reaction takes place through the addition product 10
(X=H) followed by the elimination of HCN. When
4,5-dichloro-1,2-diphenylenediamine was used as a
nucleophile, the corresponding cyano quinoxaline (12)
was formed (71%). In this case, it appears that the
electronegative chlorine substituents on the aromatic
ring increase the lability of the NH hydrogen in 10,
X=Cl, favoring the competing loss of H2O.
In our ongoing research on tricarbonyl and related
compounds, we have studied the chemistry of cyano
dicarbonyl analogues of VTC.6 These electrophiles are
more reactive than the corresponding tricarbonyls, and
undergo unique reactions with nucleophiles in which
the nitrile function behaves as a leaving group. Due to
their enhanced reactivity, they are most conveniently
prepared in situ at low temperature, and used without
isolation as precursors to a-keto amides, esters and
The above reactions yielded products substituted with
either hydroxy, nitrile, or a mixture of the two. We
found that selectivity could be achieved by a modifica-
tion in the procedure involving the generation in situ of
the a-keto ester 4a (Scheme 1) corresponding to the
a-keto nitrile 4. Thus, in the ozonolysis of 3, we per-
* Corresponding author.
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02486-3

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H. H. Wasserman et al. / Tetrahedron Letters 44 (2003) 361–363
Scheme 1.
formed the oxidative cleavage in CH3OH/CH2Cl2, in
which case the hydroxy substituted product 6 was
formed exclusively (70%) from 4a. In the same way, 13,
the hydroxy analog of 12 formed from 9 (Scheme 2),
could also be prepared (72%) through the a-keto ester
route as the only quinoxaline product.
CH2Cl2 yielding an a-keto ester intermediate, for the
amination.
With thiourea (Scheme 3), a mixture of diastereomeric
products 16 and 17 was obtained (83%) in CH2Cl2.
1
Supporting information available. H, 13C and HRMS
With 2-aminobenzylamine, only compound 14 was
formed (64%) in both solvent systems (Scheme 3).7,8a
Using 2,3-diaminopyridine as the dinucleophile in reac-
tion with 9 employing CH2Cl2 as the solvent, we
obtained the pyrido pyrazine 15 as the sole product
(40%).8b This compound was isolated in improved yield
(85%), when the ozonolysis was carried out in CH3OH/
spectroscopic data for all new compounds.
Acknowledgements
This work was supported by grants from the NIH and
NSF. We thank Dr. Walter McMurray of the Yale
Scheme 2.

H. H. Wasserman et al. / Tetrahedron Letters 44 (2003) 361–363
363
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6. For earlier work on the study of a-keto amides, esters, and
acids, see: (a) Wasserman, H. H.; Ho, Wen-Bin J. Org.
Chem. 1994, 4364; (b) Wasserman, H. H.; Lee, K.; Xia, M.
Tetrahedron Lett. 2000, 41, 2511.
Scheme 3.
7. In CH2Cl2, the yield was 64%; in CH3OH/CH2Cl2, the
yield was 82%.
Cancer Center Mass Spectrometry Resource for help in
determining HRMS spectra of new compounds pre-
pared in this synthesis.
8. (a) We assign structure 14 to this addition product rather
than the closely related alternative 14a based on the expec-
tation that the more basic primary amine would react
preferentially and irreversibly with the a-keto carbonyl
group in 9;
References
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(b) In the same way, we assume that the more basic amino
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ridine would take part in an initial attack at the a-keto
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