Synthesis of optically pure threonine-containing dipeptides by regio- and stereo-controlled ring expansion of aziridine-2-imide derivatives

Article abstract of DOI:10.1039/a807063f

The regio- and stereo-selective ring expansion of chiral N-(α-amino acyl)aziridine-2-imides to oxazolines and subsequent ring opening to optically pure threonine-containing dipeptides with the desired stereochemistry is described.

Full text of DOI:10.1039/a807063f

Synthesis of optically pure threonine-containing dipeptides by regio- and
stereo-controlled ring expansion of aziridine-2-imide derivatives
Giuliana Cardillo,* Luca Gentilucci and Alessandra Tolomelli
Dipartimento di Chimica ‘G. Ciamician’, Università di Bologna and C.S.F.M, via Selmi 2, 40126 Bologna, Italy.
E-mail: Cardillo@ciam.unibo.it
Received (in Liverpool, UK) 8th September 1998, Accepted 3rd December 1998
H
The regio- and stereo-selective ring expansion of chiral N-(a-
O
O
O
N
amino acyl)aziridine-2-imides to oxazolines and subsequent
ring opening to optically pure threonine-containing dipep-
tides with the desired stereochemistry is described.
HO
R1
+
i
N
N
S
R
R2HN
Ph
1
b-Hydroxy a-amino acids are structural units present in a large
number of naturally occurring biologically active compounds.1
For instance, hexadepsipeptide antibiotic azinothricin,2 de-
psipeptides variapeptin and citropeptin,3 and the macrocyclic
lactone antiobiotic lysobactin4 contain in their sequence several
b-hydroxy-a-amino acids linked together.
>95%
R1
H
N
O
O
R2
O
O
N
N
O
N
O
The importance of these amino acids has stimulated the
development of numerous methods for their stereoselective
synthesis.5 Nevertheless a conceptually new strategy for the
preparation of non-proteogenic a-amino acid derivatives start-
ing from suitable heterocyclic compounds has been recently
investigated for direct use in peptide coupling reactions. Ring-
opening coupling reactions of enantiomerically pure 3-hydroxy
b-lactams with various (S)-amino acid esters to give the
corresponding dipeptides have been described by Ojima et al.,6
while access to non-proteogenic peptide fragments of lyso-
bactin from chiral azetidin-2-ones has been recently reported by
Palomo et al.7
We describe here a new and efficient strategy for the
synthesis of threonine-containing dipeptides starting from
enantiomerically pure aziridine-2-imides via a ring expansion to
oxazolines8 that occurs in a regio- and stereo-controlled
manner.9
ii
>90%
N
N
N
Ph
R2HN
R1
2
Ph
3
+
iii
95%
O
O
OH
O
O
OAc
R
N
N
iv
99%
N
N
S
HN
O
HN
O
Ph
Ph
R1
4
R1
5
R2HN
R2HN
a R1 = Pri, R2 = Ac
b R1 = Ph, R2 = Boc
Scheme 1 Reagents and conditions: i, DCC (1.1 equiv.), CH2Cl2–MeCN,
12 h, room temp.; ii, BF3·Et2O (1 equiv.), CH2Cl2, room temp.; iii, TsOH
(1.1 equiv.), MeOH–H2O, room temp.; iv, Ac2O (1.2 equiv.), pyridine (1.2
equiv.), CH2Cl2, 2 h, room temp.
Thus the enantiopure aziridine (2AR, 3AS)-110 was treated with
N-acetylleucine and DCC in CH2Cl2–MeCN giving compound
2a in 95% yield, which spontaneously converted into oxazoline-
4-imide 3a (Scheme 1), obtained in quantitative yield and
purified by flash chromatography. Hydrolysis of 3a performed
with TsOH in MeOH–H2O gave dipeptide 4a in almost
quantitative yield. The trans configuration of aziridine 2a was
retained in 3a as shown by the oxazoline coupling constant
value of H4 and H5 (JH4–H5 = 4.7 Hz; lit.,11 Jtrans = 4–7 Hz).
The regiochemistry of the aziridine ring expansion was easily
alanine and DCC to give 7. The ring expansion was performed
under the conditions reported for 2b and compound 8 was
finally isolated in good yield after acetylation. The 1H NMR and
13C NMR spectra confirmed the structure (Scheme 2).
H
1
1
established by H NMR analysis of 3a and confirmed by H
NMR decoupling experiments on 4a.
N
H
Boc
O
Ph
O
O
In a similar way, 2b was obtained by treatment of 1 with N-
Boc-phenylalanine and DCC. The ring expansion of 2b was
promoted by BF3·Et2O in the presence of trace water and
afforded at once the (S)-Phe-(2AR, 3AS)-Thr derivative 4b, which
is immediately treated with Ac2O to give 5.12 Under these acidic
conditions, fast ring opening of oxazoline 3b to 4b was
N
O
N
O
i
N
N
R
S
>95%
N
N
Ph
7
6
Ph
1
ii,iii
observed, 3b being detected in only trace amounts in the H
NMR spectrum of the crude reaction mixture.
O
O
OAc
These results show that (2R, 3S)-threonine can be easily
introduced in a polypeptide sequence. The design and synthesis
of modified peptides offers opportunities for drug preparation.
Among the modifications designed to obtain higher biological
activity and greater resistance to enzymatic hydrolysis, the
substitution of non-proteinogenic amino acids in a polypeptide
sequence is of current interest.
S
N
N
R
HN
O
Ph
8
Ph
BocHN
Scheme 2 Reagents and conditions: i, DCC (1.1 equiv.), CH2Cl2–MeCN,
12 h, room temp.; ii, BF3·Et2O (1 equiv.), CH2Cl2, room temp.; iii, Ac2O
(1.2 equiv.), pyridine (1.2 equiv.), CH2Cl2, 2 h, room temp.
In order to prepare the (2S, 3R)-threonine-containing dipep-
tide, the trans aziridine 610 was treated with N-Boc-phenyl-
Chem. Commun., 1999, 167–168
167

O
OH
Notes and references
O
1 A. Saeed and D. W. Young, Tetrahedron, 1992, 48, 2507 and references
cited therein; R. B. Herbert, B. Wilkinson, G. J. Ellames and K. E.
Kunec, J. Chem. Soc., Chem. Commun., 1993, 205.
2 H. Maehr, C. M. Liu, N. J. Pelleroni, J. Smallheer, L. Todaro, T. H.
Williams and J. F. Blount, J. Antibiot., 1986, 39, 17.
HO
i
N
NH
Ph
4a, 5b
+
90%
HN
O
9
R1
R2HN
ii
3 M. Nakagawa, Y. Hayakawa, K. Furihata and H. Seto, J. Antibiot.,
1990, 43, 477.
O
OH
>95%
4 J. O’Sullivan, J. E. McCullough, A. A. Tymiak, D. R. Kirsch, W. H.
Trejo and P. A. Principe, J. Antibiot., 1988, 41, 1740; T. Kato, H. Hinoo,
Y. Tervi, J. Kikuchi and J. Shoji, J. Antibiot., 1988, 41, 719.
5 H. Shao and M. Goodman, J. Org. Chem., 1996, 61, 2582; Williams, Z.
Zhang, F. Shao, P. J. Carroll and M. Joulliè, Tetrahedron, 1996, 52,
11673 and references cited therein; K. J. Hale, S. Manaviazar and V. M.
Delisser, Tetrahedron, 1994, 50, 9181; S. Kanemasa, T. Mori and A.
Tatsukawa, Tetrahedron Lett., 1993, 34, 8293; T. Sanuzaka, T.
Nagamitsu, H. Tanaka, S. Omura, P. A. Sprengler and A. B. Smith,
Tetrahedron Lett., 1993, 34, 4447; E. J. Corey, D.-H. Lee and S. Choi,
Tetrahedron Lett., 1992, 33, 6735.
MeO
9a [α]D –17.9 (c 0.7, CHCl3)
9b [α]D –11.4 (c 4, CHCl3)
10b [α]D –7.7 (c 5, CHCl3)
HN
R2HN
O
R1
10
a R1 = Pri, R2 = Ac
b R1 = Ph, R2 = Boc
Scheme 3 Reagents and conditions: i, LiOH (3 equiv.), H2O2 (4 equiv.),
THF–H2O, 2 h, 0 °C; ii, CH2N2.
6 I. Ojima, C. M. Sun and Y. H. Park, J. Org. Chem., 1994, 59, 1249; I.
Ojima, H. Wang, T. Wang and E. W. Ng, Tetrahedron Lett., 1998, 39,
923.
7 C. Palomo, J. M. Aizpurua, I. Gamboa, B. Odriozola, E. Maneiro, J. I.
Miranda and R. Urchegui, Chem. Commun., 1996, 161; C. Palomo, I.
Gamboa, B. Odriozola and A. K. Linden, Tetrahedron Lett., 1997, 38,
3093.
8 I. J. Burnstein, P. E. Fanta and B. S. Green, J. Org. Chem. 1970, 35,
4084; T. A. Foglia, L. M. Gregory and G. Maerkel, J. Org. Chem., 1970,
35, 3779; C. U. Pittman and S. P. McManus J. Org. Chem., 1970, 35,
1187; D. Haidukewych and A. I. Meyers, Tetrahedron Lett., 1972, 30,
3031; S. G. Bates and M. A. Varelas, Can. J. Chem., 1980, 58, 2562; J.
Legters, L. Thijs and B. Zwanenburg, Recl. Trav. Chim. Pays-Bas,
1992, 111, 16.
9 K. Hory, T. Nishiguchi and A. Nabeja, J. Org. Chem., 1997, 62, 3081;
G. Cardillo, L. Gentilucci, A. Tolomelli and C. Tomasini, Tetrahedron
Lett., 1997, 38, 6953.
Finally, to obtain the free dipeptide, 4a was submitted to non-
destructive removal of the chiral auxiliary under Evans’
conditions,13 by means of LiOOH in THF–H2O (Scheme 3).
After 2 h the N-acetyl-(S)-Leu-(2R, 3S)-Thr dipeptide 9a was
recovered in good yield. Longer reaction times should be
avoided; indeed, after 6 h the reaction mixture contained 10% of
epimerized product.
On the basis of these results, 5b was hydrolysed over 2 h
giving without any epimerization the N-Boc-(S)-Phe-(2R, 3S)-
Thr dipeptide 9b,14 which was essentially pure after work-up
according to analysis of the crude reaction mixture. Compound
9b was converted by means of CH2N2 into the corresponding
methyl ester 10b.15
In order to confirm the stereochemistry of the aziridine ring
expansion via an SNi mechanism for 2 and 7, an authentic
sample of dipeptide 8b was prepared from commercially
available (2R, 3S)-threonine and (S)-phenylalanine (Scheme 4).
10 G. Cardillo, S. Casolari, L. Gentilucci and C. Tomasini, Angew. Chem.,
Int. Ed. Engl., 1996, 35, 1848; A. Bongini, G. Cardillo, L Gentilucci and
C. Tomasini, J. Org. Chem., 1997, 62, 9148.
11 S. H. Pines, M. A. Kozlowski and S. Karady, J. Org. Chem., 1969, 34,
1621; D.-M. Gou, Y.-C. Liu and C.-S. Chen, J. Org. Chem., 1993, 58,
1287.
O
OH
O
12 Selected data for 5: dH(CDCl3) 0.80 (d, J 6.7, 3H, CH3CHCHPh), 1.20
(d, J 6.5, 3H, CH3CHOAc), 1.32 (s, 9H, But), 1.95 (s, 3H, COCH3), 2.88
(s, 3H, NCH3), 2.95–3.18 (m, 2H, CH2Ph), 4.00 (dq, J 6.7, 8.4, 1H,
CH3CHCHPh), 4.34–4.50 (m, 1H, CHCH2Ph), 4.88 (d, J 6.0, 1H,
HNBoc), 5.05 (d, J 8.4, 1H, CH3CHCHPh), 5.50 (dq, J 1.3, 6.5,
CHOAc), 6.08 (dd, J 1.3, 9.5, 1H, CHCHOAc), 6.65 (d, J 9.5, 1H,
HNCHCH), 7.02–7.46 (m, 10H, ArH); dC(CDCl3) 14.7, 20.8, 24.9,
25.6, 28.2, 33.9, 49.1, 54.3, 55.5, 59.9, 70.4, 77.8, 126.9, 128.2, 128.6,
129.2, 136.2, 136.3, 155.0, 155.4, 168.5, 170.5, 171.2.
13 J. R. Gage and D. A. Evans, Org. Synth., 1989, 68, 83.
14 Selected data for 9b: nmax/cm21 3300 br, 3050, 1720, 1700, 1660;
dH(CDCl3) 0.93 (d, J 6.0, CH3), 1.35 (s, 9H, But), 2.85–3.20 (m, 2H,
CH2Ph), 4.20–4.40 (m, 1H, CHOH), 4.40–4.67 (m, 2H, CHCHOH +
CHCH2Ph), 5.40 (d, J 6.0, 1H, HNBoc), 6.00–6.40 (m, 3H, OH +
HNCHCH + CO2H), 7.10–7.40 (m, 5H, ArH); dC(CDCl3) 19.3, 28.2,
38.9, 55.7, 57.4, 67.6, 80.1, 127.0, 128.6, 129.3, 136.4, 156.3, 172.2,
173.4; [a]D 211.4 (c 4, CHCl3).
i
ii
HO
Ph
NHBoc
MeO
+
10b
9b
60%
95%
NH2
Scheme 4 Reagents and conditions: i, DCC (1.1 equiv.), CH2Cl2–MeCN,
12 h, room temp.; ii, LiOH (2 equiv.), H2O2 (3 equiv.), THF–H2O, 1 h,
0 °C.
The (2R, 3S)-threonine methyl ester and N-Boc-(S)-phenyl-
alanine were coupled with DCC in CH2Cl2–MeCN and the
desired dipeptide derivative was obtained in satisfactory yield.
This compound was treated with LiOOH in THF–H2O13 and
afforded the corresponding carboxylic acid. Both 9b and 10b
showed H NMR and 13C NMR spectra which were identical,
1
and optical rotation values which were comparable, with the
authentic samples.
15 Selected data for 10b: nmax/cm21 3350, 3050, 1750, 1694, 1659, 1525;
dH(CDCl3) 1.00 (d, J 6.1, 3H, CH3), 1.32 (s, 9H, But), 2.95 (dd, J 6.7,
13.9, 1H, CH2Ph), 3.11 (dd, J 6.2, 13.9, 1H, CH2Ph), 3.67 (s, 3H,
CO2CH3), 4.20–4.32 (m, 1H, CHOH), 4.40–4.60 (m, 2H, CHCHOH +
CHCH2Ph), 5.40–5.58 (br s, 1H, HNBoc), 7.10–7.33 (m, 6H, ArH +
HNCHCH); dC(CDCl3) 19.5, 28.0, 33.6, 38.3, 52.2, 57.5, 67.2, 79.8,
126.5, 128.2, 129.1, 136.5 155.2, 171.2, 172.2; [a]D 27.7 (c 5,
CHCl3).
In conclusion, we have reported a new method that permits
the synthesis of b-hydroxy a-amino acids coupled with other a-
amino acids, starting from aziridine derivatives. Furthermore,
due to the observed retention of configuration in the ring
expansion of the starting aziridine, the stereochemistry of the
final dipeptide can be fixed by using the appropriate starting
material.
We thank the University of Bologna for funds for selected
research topics.
Communication 8/07063F
168
Chem. Commun., 1999, 167–168