Easy access to orthogonally protected α-alkyl aspartic acid and α-alkyl asparagine derivatives by controlled opening of β-lactams

Article abstract of DOI:10.1016/S0040-4039(03)01453-9

The controlled opening of the N1-C2 bond in 1-carbamate-substituted 2-azetidinones derived from amino acids by O- and N-nucleophiles provided a straightforward access to orthogonally protected α-alkyl aspartic acid and asparagine derivatives. The use of DBU or sodium azide as additive is essential for expedient cleavage by amino acids to the corresponding β-aspartic acid dipeptides.

Full text of DOI:10.1016/S0040-4039(03)01453-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6145–6148
Easy access to orthogonally protected a-alkyl aspartic acid and
a-alkyl asparagine derivatives by controlled opening of b-lactams
Guillermo Gerona-Navarro, Ma6 Teresa Garc´ıa-Lo´pez and Rosario Gonza´lez-Mun˜iz*
Instituto de Qu´ımica Me´dica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
Accepted 5 June 2003
Abstract—The controlled opening of the N1ꢀC2 bond in 1-carbamate-substituted 2-azetidinones derived from amino acids by O-
and N-nucleophiles provided a straightforward access to orthogonally protected a-alkyl aspartic acid and asparagine derivatives.
The use of DBU or sodium azide as additive is essential for expedient cleavage by amino acids to the corresponding b-aspartic
acid dipeptides.
© 2003 Elsevier Ltd. All rights reserved.
The discovery of Ca,a-disubstituted a-amino acids in
natural bioactive compounds and their propensity to
induce secondary structures when incorporated into
peptides has resulted in an increased interest in novel
methods for their synthesis.1 In this respect, aspartic
acid derivatives are especially interesting subjects for
study because of their relevant role in physiological
events and in the stabilization of reverse turns through
interactions between backbone NH and side chain CgO
bonds.2 Moreover, the Asp residue possesses multiple
functional groups appropriate for structural diversifica-
tion using parallel synthesis or combinatorial chemistry
methodologies.3 Several methods have been reported
that describe the enantioselective synthesis of a-alkyl-
ated aspartic acid derivatives. These include alkylation
of enolates derived from chiral imidazolidinones,4 oxa-
zolidinones,5 oxazolones,6 oxazinones,7 and pyrazi-
nones,8 double alkylation of aldimine Schiff base of Gly
esters under chiral phase-transfer catalysis,9 and alkyla-
tion of Asn derivatives with ‘self-regeneration’ of the
stereogenic center.10 Other procedures comprise the
asymmetric allylic alkylation with chiral palladium cat-
alysts,11 and the cycloaddition reaction to pyrazolines
followed by alkaline fragmentation.12 However, most of
these methods required a final acid hydrolysis affording
the corresponding a-alkyl aspartic acid derivative in
fully deprotected form.
of the 2-azetidinone ring.13 In this sense, the opening of
the N1ꢀC2 bond by nucleophiles has been widely used
for the preparation of b-amino acids and b-amino
ketones.14,15 The intramolecular version of this cleavage
has served for the generation of different heterocyclic
systems like bis-g-lactams, indolizidines and pyrrolizidi-
nes.16–18 In a similar way, the macrocyclization process
based on the 2-azetidinone amide bond opening has
been successfully used for the synthesis of several natu-
ral products and some internal b-turn mimetics.19–21
In connection with our current concern in conforma-
tionally constrained amino acids, we recently reported
the first synthesis of 4-alkyl-4-carboxy-2-azetidinone
derivatives 1 from commercially available amino acid
alkyl esters.22–24
These b-lactams have the appropriate substitution pat-
tern to be considered as convenient precursors in the
synthesis of a-alkyl Asp (X=O) and Asn (X=NH)
derivatives 2, by controlled aperture of the N1ꢀC2
bond. Moreover, orthogonally protected Asp and Asn
derivatives could be prepared by suitable selection of
the R2, R3, and R4 groups.
By other hand, b-lactams have long been recognized as
useful synthetic intermediates for the preparation of a
variety of compounds through selective bond cleavage
To explore this possibility, b-lactams 4 and 5, derived
from
L
-Phe-OtBu, were selected as model substrates,
* Corresponding author. Tel.: +34-91-562-2900; fax: +34-91-564-4853;
e-mail: iqmg313@iqm.csic.es
and then have been subjected to the action of different
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01453-9

6146
G. Gerona-Na6arro et al. / Tetrahedron Letters 44 (2003) 6145–6148
O- and N-nucleophiles. Compounds 4 and 5 were
prepared in 75 and 76% yield by the treatment of the
2-azetidinone derivative 3 with tert-butyldicarbonate
and benzyl chloroformate, respectively (Scheme 1). The
N-urethane substituent in 4 and 5 (Boc and Z, respec-
tively) has a double function, as an activating moiety
facilitating the ring cleavage and, after the ring open-
ing, as a protector of the resulting amino group.
Activated b-lactams 4 and 5 underwent regioselective
alcoholysis, by treatment with alkoxides, to the
expected fully protected a-benzyl Asp derivatives 6
Scheme 1. Reagents and conditions: (a) (tBuO)2CO/DMAP/CH2Cl2; (b) ZCl/DBU/CH2Cl2; (c) R1ONa/R1OH; (d) R1OH/DBU/
THF; (e) 2N NaOH/THF; (f) satd NH3/MeOH; (g) dilute NH3/MeOH; (h) H-Ala-OMe/additive/solvent (see Table 1).
Table 1. Results of the controlled cleavage of N-carbamate-substituted 2-azetidinones by O- and N-nucleophiles
Entry
Starting compd
Cleavage conditions
Time
Final compd (yield %)a
1
2
3
4
5
6
7
8
4
5
5
5
4
5
4
4
4
4d
5
5
5
5
MeONa/MeOH
EtONa/EtOH
MeONa/MeOH
MeOH/DBU
NaOH/THF
NaOH/THF
24 h
24 h
24 h
10 min
24 h
6 (75)
7 (90)
8 (89)
8 (96)
9 (71)
10 (92)
11 (89)
24 h
NH3/MeOH (satd)
NH3/MeOH (dilute)
5 min
10 min
6 days
6 days
25 days
15 daysf
24 hf
11 (30)b
13ab (53)c
13ab (49)e
14ab (93)
14ab (85)
14ab (40)g
14ab (77)
9
H-L
H-L
H-L
H-L
H-L
H-L
-Ala-OMe/MeOH
-Ala-OMe/MeOH
-Ala-OMe/DBU/THF
-Ala-OMe/DBU/THF
-Ala-OMe/KCN/DMF
-Ala-OMe/NaN3/DMF
10
11
12
13
14b
11 days
a Yield of isolated compound.
b 12 (37%) was also obtained.
c Compound 6 (23%) was also isolated.
d 6 equiv. of the amino acid were used in this assay.
e Estimated by HPLC. Compound 6 (18%) was detected.
f Reaction at 60°C.
g The carboxylic acid 10 (40%) was also obtained.

G. Gerona-Na6arro et al. / Tetrahedron Letters 44 (2003) 6145–6148
6147
14). Since starting b-lactams 4 and 5 were 2:1 S/R
mixtures of enantiomers, compounds 13 and 14 were
obtained as diastereoisomeric mixtures in approxi-
mately the same ratio.
(75%) and 7 (90%) (Scheme 1, Table 1). Alternatively,
the alcoholysis could be performed in a faster and more
productive way by reaction with the corresponding
alcohol in the presence of DBU, as exemplified in the
synthesis of compound 8 (Table 1, entries 3 and 4). The
hydrolysis with NaOH afforded the corresponding
diprotected Asp derivatives 9 and 10, with a free car-
boxylate group at the side chain. All compounds result-
ing from the opening of the b-lactam ring showed in the
1H NMR spectra the signal corresponding to the ure-
thane NH proton.25 In addition to that, a clear
deshielding in the chemical sifts of the CO groups of
the Asp derivatives with respect to these carbonyls in
the starting b-lactams was observed in the 13C NMR
spectra.25
The feasibility of the Phe-derived b-lactams opening to
produce orthogonally protected a-benzyl Asp and Asn
derivatives could be extended to other a-alkyl ana-
logues, just by using 2-azetidinones derived from other
amino acids as starting materials. Moreover, taking
into account that we have reported a general method
for the asymmetric synthesis of our amino acid-derived
b-lactams,28 the procedures described here could have a
widespread application to the generation of a-alkyl
Asp/Asn derivatives in enantiomerically pure form.
Encouraged by the good results of the reactions with
O-nucleophiles, we then studied the 2-azetidinone ring
opening by N-nucleophiles. Thus, the reaction of the
b-lactam derivative 4 with satd ammonia in MeOH
afforded Asn-derivative 11 in excellent yield (Table 1).
This compound showed similar NMR characteristics to
those previously indicated for the Asp derivatives
resulting from opening with O-nucleophiles. It is inter-
esting to note that dilute NH3/MeOH solution gave a
mixture of the expected compound 11 and the succin-
imide 12. Considering that the formation of succin-
imides from Asn derivatives under basic conditions is
sufficiently documented,26 the generation of aspartimide
12 could be explained by cyclization of the acyclic
derivative 11 in the reaction medium.
Acknowledgements
This work was supported by CICYT (SAF 2000-0147).
G.G.-N. thanks a predoctoral fellow from the Spanish
Ministry of Science and Technology.
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