A new selective synthesis of the Ile-allo-Thr-Gly tripeptide fragment of lysobactin.

Article abstract of DOI:10.1021/ol005659o

[formula: see text] trans-Aziridine-2-carboxylic acid derivatives are useful intermediates for the synthesis of threonine or allo-threonine through ring expansion and SN2 displacement, respectively. We describe here the preparation of the Ile-allo-Thr-Gly 11 fragment of Lysobactin via the aziridine 9 intermediate.

Full text of DOI:10.1021/ol005659o

ORGANIC
LETTERS
2000
Vol. 2, No. 8
1105-1107
A New Selective Synthesis of the
Ile-allo-Thr-Gly Tripeptide Fragment of
Lysobactin
Silvia Armaroli, Giuliana Cardillo,* Luca Gentilucci, Massimo Gianotti, and
Alessandra Tolomelli
Dipartimento di Chimica “G.Ciamician” and CSFM-CNR, UniVersita` di Bologna,
Via Selmi 2, 40126 Bologna, Italy
cardillo@ciam.unibo.it
Received February 14, 2000
ABSTRACT
trans-Aziridine-2-carboxylic acid derivatives are useful intermediates for the synthesis of threonine or allo-threonine through ring expansion
and SN2 displacement, respectively. We describe here the preparation of the Ile-allo-Thr-Gly 11 fragment of Lysobactin via the aziridine 9
intermediate.
Lysobactin1 1 was isolated from the fermentation of Lyso-
bacter sp. SC13,067 (ATCC 53042) and is a potent agent
against Gram-positive bacteria (in vitro). Its efficacy in vivo
was compared with that of the antibiotic Vancomycin.
Vancomycin and related antibiotics inhibit bacterial cell wall
biosynthesis by specific binding to D-alanyl-D-alanine cell
wall precursors. The structure of 1 (Figure 1) shows the
interesting presence of the glycine-allo-threonine-isoleucine
tripeptide sequence.
We report here our progress toward the synthesis of this
tripeptide fragment containing allo-threonine with the as-
signed (2S,3S) configuration. Our project starts from the idea
that the â-hydroxy-R-amino acids in 1 come with the
aziridine acyl derivative precursor. These activated aziridine
compounds give aziridine ring opening with an inversion of
configuration by a proper nucleophile.2 On the other hand,
the aziridine ring expansion reaction gives the corresponding
oxazoline as a protected form of the amino alcohol com-
pounds. This reaction occurs with retention of configuration
of the starting aziridine derivative stereocenters (Scheme 1).3
We explored both of these strategies, showing that a
threonine or allo-threonine dipeptide sequence may be
synthesized from a unique starting aziridine simply by
(1) (a) O’Sullivan, J.; McCullough, J. E.; Tymiak, A. A.; Kirsch, D. R.;
Trejo, W. H.; Principe P. A. J. Antibiot. 1988, 41, 1740-1744. (b) Tymiak,
A. A.; McCormick, T. J.; Unger, S. E. J. Org. Chem. 1989, 54, 1149-
1157.
(2) (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599-619. (b)
Legters, J.; Thijs, L.; Zwanenburg, B. Recl. TraV. Chim. Pays-Bas 1992,
111, 59-68. (d) Dauban, P.; Dubois, L.; Tran Huu Dau, M. E.; Dodd, R.
H. J. Org. Chem. 1995, 60, 2035-2043.
(3) (a) Hori, K.; Nishiguchi, T.; Nabeya, A. J. Org. Chem. 1997, 62,
3081-3088. (b) Ferraris, F.; Drury, W. J., III; Cox, C.; Lectka, T. J. Org.
Chem. 1998, 63, 4568-4569 and references therein.
Figure 1. Lysobactin.
10.1021/ol005659o CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/29/2000

constant (J ) 5.7 Hz) confirmed the trans relationship.7 The
hydrolysis of 4 was carried out in THF with 0.1 N HCl, and
this gave the ester (2′S,3′R)-5 in 90% yield. Nucleophilic
intramolecular displacement to the amide (2′S,3′R)-6 was
performed in toluene at reflux for 3 h. The O-acetate 7 was
easily prepared by treatment of 6 with acetic anhydride and
pyridine in CH2Cl2 (Scheme 2).8
Scheme 1. Reactivity of Activated Aziridines
This sequence leads to the preparation of an Ile-Thr
derivative. To obtain Ile-allo-Thr, an SN2 aziridine ring
opening is required. However, attempts to promote the ring
opening of aziridine 3 by treatment with CH3COOH failed
to give 4 preferentially. This demonstrates that the presence
of the chiral auxiliary strongly favors the aziridine to
oxazoline ring expansion.9 For this reason the correct
sequence containing (2S,3S)-allo-threonine was obtained by
removing the imidazolidinone chiral auxiliary at an earlier
stage of the sequence, as outlined in Scheme 3.
changing the steps of the synthetic sequences. The (2′S,3′R)
aziridine 2 was obtained as the major isomer from a two-
step sequence: 1,4-addition of O-benzylhydroxylamine to
the R,â-unsaturated crotonyl derivative followed by cycliza-
tion to the corresponding trans aziridine4 through the
intermediate enolate.5 The stereochemical result of the
reaction was controlled using (4S,5R)-1,5-dimethyl-4-
phenylimidazolidin-2-one as a chiral auxiliary. The synthesis
of the isoleucine-threonine derivative is outlined in Scheme
2. The acyl derivative (2S,3R)-36 was obtained in 90% yield
by treatment of 2 with N-BOC-isoleucine and DCC in
CH2Cl2. After purification by flash chromatography on silica
gel, compound 3 was converted to oxazoline (4S,5R)-4 in
the presence of BF3‚Et2O. The oxazoline H4-H5 coupling
Scheme 3. Synthesis of Derivative 9
Scheme 2. Synthesis of Dipeptide Derivatives 6 and 7
The introduction of a masked glycine was achieved by
treatment of 2 with neat allylamine10 at room temperature
(4) For the addition of NH2OBn, see: (a) Amoroso, R.; Cardillo, G.;
Sabatino, P.; Tomasini, C.; Trere`, A. J. Org. Chem. 1993, 58, 5615-5619.
For cyclization to trans aziridine, see: (c) Cardillo, G.; Casolari, S.;
Gentilucci, L.; Tomasini, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 1848-
1849. (d) Bongini, A.; Cardillo, G.; Gentilucci, L.; Tomasini, C. J. Org.
Chem. 1997, 62, 9148-9153.
(5) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T.
J. Am. Chem. Soc. 1990, 112, 8215-8216.
(6) For a review of aziridine-containing peptides, see: (a) Okawa, K.;
Nakajima, K. Biopolymers 1981, 20, 1811-1821. (b) Korn, A.; Rudolph-
Bo¨hner, S.; Moroder, L. Tetrahedron 1994, 50, 1717-1730.
(7) (a) Foglia, T. A.; Gregory, L. M.; Maerker, G. J. Org. Chem. 1970,
35, 3779-3785. (b) Pines, S. H.; Kozlowski, M. A.; Karady, S. J. Org.
Chem. 1969, 34, 1621-1627.
(8) Selected data for 5: 1H NMR (CDCl3) δ 0.74 (d, 3H, J ) 6.9 Hz);
0.79 (d, 3H, J ) 6.6 Hz); 0.80 (t, 3H, J ) 7.2 Hz); 0.97-1.34 (m, 2H);
1.31 (d, 3H, J ) 6.0 Hz); 1.45 (s, 9H); 1.62-1.88 (bm, 3H); 2.83 (s, 3H);
3.88-3.96 (m, 2H); 4.84 (d, 1H, J ) 3.3 Hz); 5.05 (d, 1H, J ) 8.4 Hz);
5.31 (d, 1H, J ) 9.0 Hz); 5.38 (dq, 1H, J ) 3.3, 6.0 Hz); 7.07-7.32 (m,
5H). 13C NMR (CDCl3) δ 11.5, 14.2, 14.9, 15.1, 25.1, 26.9, 28.4, 37.9,
54.2, 57.8, 59.2, 60.4, 79.4, 127.0, 128.3, 128.5, 135.9, 155.2, 155.3, 170.9,
171.1. [R]20 ) -46.2 (c ) 0.6, CHCl3). 6: 1H NMR (CDCl3) δ 0.80 (d,
D
3H, J ) 6.6 Hz); 0.88 (t, 3H, J ) 7.5 Hz); 0.89 (d, 3H, J ) 7.5 Hz);
1.03-1.31 (m, 2H); 1.19 (d, 3H, J ) 6.3 Hz); 1.41 (s, 9H); 1.75-1.93 (m,
1H); 2.83 (s, 3H); 3.91-3.98 (m, 1H); 3.98 (dq, 1H, J ) 6.6, 9.3 Hz); 4.33
(dq, 1H, J ) 2.1, 6.3 Hz); 5.05 (d, 1H, J ) 8.1 Hz); 5.34 (d, 1H, J ) 9.3
Hz); 5.95 (dd, 1H, J ) 2.1, 8.7 Hz); 6.67 (d, 1H, J ) 8.7 Hz); 7.13-7.37
(m, 5H). 13C NMR (CDCl3) δ 11.4, 15.1, 15.5, 19.5, 24.8, 28.2, 28.3, 37.3,
54.2, 55.7, 59.2, 59.4, 68.5, 79.8, 126.8, 128.3, 128.7, 136.1, 155.2, 169.9,
171.4, 171.5. [R]20 ) -45.0 (c ) 1, CHCl3).
D
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Org. Lett., Vol. 2, No. 8, 2000

for 4 h to give the allylamido derivative (2S,3R)-8 in 95%
yield. The coupling of compound 8 with N-BOC-isoleucine
was performed in CH2Cl2, and (2S,3R)-9 was obtained in
90% yield.
Scheme 4. Synthesis of Tripeptide 11
Ring opening of the (2S,3R)-aziridine derivative 9 was
performed in CH3COOH as reported in the literature.2b This
reaction proceeded through an SN2 mechanism, and the allo-
threonine acetate derivative (2S,3S)-10 was isolated in 95%
yield. Finally 10 was treated with KMnO4/CH3COOH11 in a
remarkably clean reaction to give (2S,3S)-11, which was
converted to its methyl ester derivative 12 with CH2N2
(Scheme 4). The 1H NMR and 13C NMR of both compounds
are consistent with their assigned structures.12
In conclusion, our synthetic protocol which starts from
the aziridine enabled us to prepare allo-Thr- and Thr-
(9) It is generally assumed that the ring expansion of N-acylaziridine
occurs via a carbocationic-like TS (ref 3a) or a carbocationic intermediate
(ref 3b) and is favored by the presence of Lewis acids.
containing sequences in a few steps and in a high yield. Since
five hydroxyamino acids in the Lysobactin backbone are
present in the syn or anti configuration,13 our results show a
reasonable and encouraging route toward the total synthesis
of the macrocyclic lactone.
Our semiempirical calculations suggest that the presence of the imidazolidin-
2-one substituent could be responsible for the accelerated expansion rate.
Indeed, the reactant adopts a preferential conformation in which the
endocyclic carbonylic oxygen points toward the aziridine C3′, thus
stabilizing the incipient positive charge. This model is in accord with our
previous experimental observations that aziridine 2-ester ring expansion is
much slower than that of aziridine 2-imide.
Acknowledgment. This work was supported by MURST
(60% and Cofin ‘98) and by the University of Bologna (funds
for selected topics “Sintesi e caratterizzazione di biomolecole
per la salute umana”).
(10) Davis, S. G.; Dixon, D. J. Synlett 1998, 963-964.
(11) Itani, H.; Uyeo, S. Synlett 1995, 213.
(12) Selected data for 11: 1H NMR (CDCl3) δ 0.91 (m, 6H); 1.20-
1.40 (m, 1H); 1.25 (m, 3H); 1.39 (s, 9H); 1.41-1.60 (m, 1H); 1.80-2.00
(m, 1H); 2.05 (s, 3H); 3.95-4.18 (m, 3H); 4.92-5.04 (m, 1H); 5.05-5.21
(m, 1H); 5.23-5.40 (d, 1H, J ) 7.6 Hz); 7.30-7.45 (m, 1H); 7.46-7.60
(m, 1H). 13C NMR (CDCl3) δ 11.8, 14.8, 17.0, 20.5, 24.7, 28.3, 33.9, 39.2,
Supporting Information Available: Full experimental
details and analytical data for all new compounds (3-12)
54.2, 59.7, 65.8, 79.0, 155.4, 163.7, 166.2, 166, 4, 181.5. [R]20 ) -22.0
D
1
(c ) 1.0, CHCl3).
and representative H NMR spectra of compounds 3, 4, 7,
(13) For an alternative method for the direct introduction of hy-
droxyamino acids starting from heterocyclic compounds, see: (a) Palomo,
C.; Aizpurua, J. M.; Ganboa, I.; Odriozola, B.; Maneiro, E.; Miranda, J. I.;
Urchegui, R. Chem. Commun. 1996, 161-162. (b) Palomo, C.; Cabre`, F.;
Ontoria, J. M. Tetrahedron Lett. 1992, 33, 4819-4822.
8, and 12. This material is available free of charge via the
Internet at http://pubs.acs.org.
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