Mixed sugar-nylon 14-, 28- and 42-membered ring macrocyclic lactams

Article abstract of DOI:10.1016/j.tetlet.2003.10.105

Hydrogenation of linear ω-azido-pentafluorophenyl esters from mixed oligomers of 6-amino-6-deoxy-D-galactonic acid (or 6-amino-6-deoxy-D-mannonic acid) and 6-aminohexanoic acid gives cyclic peptides containing 14-, 28- and 42-membered ring lactams. Hydrog

Full text of DOI:10.1016/j.tetlet.2003.10.105

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 163–166
Mixed sugar–nylon 14-, 28- and 42-membered ring
macrocyclic lactams
Benjamin A. Mayes,a Andrew R. Cowley,b Christopher W. G. Ansellc
and George W. J. Fleeta,*
aDyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
bChemical Crystallography Laboratory, Oxford University, 9 Parks Road, Oxford OX1 3QU, UK
cSmith & Nephew Research Centre, York Science Park, York YO10 5DF, UK
Received 23 September 2003; revised 10 October 2003; accepted 17 October 2003
Abstract—Hydrogenation of linear x-azido-pentafluorophenyl esters from mixed oligomers of 6-amino-6-deoxy-
D-galactonic acid
(or 6-amino-6-deoxy- -mannonic acid) and 6-aminohexanoic acid gives cyclic peptides containing 14-, 28- and 42-membered ring
D
lactams. Hydrogenation of a tetrameric peptide derived from e-amino acids gave a 28-membered ring lactam in 79% yield.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
2. Synthesis and cyclisations of mixed [gal-hex] oligomers
The preceding paper1 described unsuccessful attempts to
prepare fully hydroxylated versions of nylon 6, which
instead resulted in the high yield formation of up to 70-
membered rings by the cyclisation of oligomers derived
from e-amino acids. Thus the azido-galactono-ester 4
was converted into a series of linear homooligomers 1,
which on hydrogenation gave the corresponding mac-
rocyclic lactams 3 in very high yields; such macrocycles
may be viewed as members of a novel class of bioma-
terials, carbopeptoid–cyclodextrins (CPCD), which have
structural features common to both macrocyclic carbo-
hydrates and cyclic peptides.
The azidoester 42 was converted into the linear gal-hex
dimer 10 and tetramer 12 PFP esters of 6-amino-6-
deoxy-D-galactonic acid [gal] and 6-aminohexanoic acid
[hex] by standard peptide coupling methodology
(Scheme 1).
Thus the methyl ester 4 was treated with sodium
hydroxide in aqueous dioxane to give the corresponding
acid, which with methyl 6-aminohexanoate hydrochlo-
ride in the presence of diisopropylethylamine (DIPEA)
and O-(1H-benzotriazol-yl)-N,N,N0,N0-tetramethyluro-
nium tetrafluoroborate (TBTU) gave the linear gal-hex
dimer 9 in 91% yield. Hydrogenation of the azido ester 9
in methanol in the presence of palladium black gave the
corresponding amino ester, which was coupled with the
acid formed by hydrolysis of 9, with subsequent acti-
vation with DIPEA and TBTU to give the linear gal-hex
tetramer 11 in 68% yield. Further reactions of 9 and 11
with sodium hydroxide in aqueous dioxane, followed by
activation of the resulting carboxylic acid in dioxane by
EDCI and treatment with pentafluorophenol afforded
the gal-hex linear dimeric 10 and tetrameric 12 PFP
esters in 86% and 75% yields, respectively.
The cyclisation presumably occurs by intramolecular
cyclisation of intermediate amino pentafluorophenyl
(PFP) esters. Although the cyclisations are efficient for
the formation of homooligomers, each of which has the
stereochemistry of
D-galactonic acid, the full range of
structures that gives rise to efficient macrolactamisation
has not yet been established. This paper reports the
synthesis of oligomers composed of alternating 6-amino-
6-deoxyaldonic acid and 6-aminohexanoic acid units,
and their cyclisations to 14-, 28- and 42-membered rings.
Hydrogenation of the linear gal-hex dimer PFP ester 10
in the presence of palladium black in dioxane at a
concentration of 18 mg/mL gave a separable3 mixture of
the cyclic dimer 5, tetramer 8 and hexamer 7 in a ratio of
Keywords: cyclic peptide; cyclodextrin; sugar amino acid; macrocyclic
lactam; biopolymer.
* Corresponding author. Tel.: +44-1865-277386; fax: +44-1865-
277378; e-mail: george.fleet@chem.ox.ac.uk
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.105

164
B. A. Mayes et al. / Tetrahedron Letters 45 (2004) 163–166
O
O
N3
O
O
NH
O
OC6F5
(i)
H
N
O
O
O
O
O
O
O
O
O
O
n
1
2 n = 1,2,3,4
n+1
3 n = 1,2,3,4,7,9
O
OR
OR
O
RO
N3
6
NH
5
CO2Me
O
4
N
RO
RO
H
OR
3
O
O
NH
OR
OR
2
O
O
1
O
HN
4
HN
O
RO
gal-hex cyclic dimer 14 ring
(ii) (iii)
NH
OR
5 R,R = Me2C
OR
RO
HN
(vi)
O
OR
6 R = H
OR
RO
O
H
N
RO
(i)
O
OR
O
N3
O
NH
O
gal-hex cyclic hexamer 42 ring
O
O
7 R,R = Me2C
O
(ii) (v)
OR
2
OR
4
O
6
10 R = OC6F5
9 R = OMe
(i) (ii) (iv)
5
3
1
N
H
NH
OR
OR
H
N
O
OR
O
N3
O
O
O
NH
NH
O
O
O
O
O
OR
OR
NH
(i)
H
N
O
O
O
O
(ii) (v)
O
OR
OR
11 R = OMe
12 R = OC6F5
gal-hex cyclic tetramer 28 ring
8 R,R = Me2C
Scheme 1. Reagents and conditions: (i) H2, Pd black, dioxane, room temperature and pressure; (ii) NaOH, H2O, dioxane, then Amberlite IR-120 Hþ;
(iii) H2N(CH2)5COOHÆHCl, DIPEA, TBTU; (iv) DIPEA, TBTU; (v) C6F5OH, EDCI; (vi) Amberlyst-15, H2O, dioxane.
1:2:1 and a combined yield of 91%. It is possible that the
tetramer 8 (or the hexamer 7) might have been a
catenane structure; however hydrogenation of the tet-
ramer PFP ester 12 gave the same cyclic gal-hex tetramer
8 showing that this is a monocyclic structure. Removal
of the acetonides in 5 by treatment with Amberlyst-15
acidic resin gave the deprotected gal-hex cyclic dimer 6,4
the structure of which was firmly established5 by X-ray
crystallographic analysis (Fig. 1).
dimer 14 in 96% yield. (Scheme 2). Subsequent treat-
ment with dimethoxypropane in the presence of p-tolu-
enesulfonic acid (p-TSA) gave the fully protected dimer
19 in 90% yield.
Hydrogenation of the protected methyl ester 19 in
methanol in the presence of palladium black gave the
corresponding amino ester, which was coupled with the
acid formed by hydrolysis of 19, with subsequent acti-
vation with DIPEA and TBTU to give the linear man-
hex tetramer 23 in 90% yield. Hydrolysis of the man-hex
methyl esters 14, 19 and 23 by sodium hydroxide in
aqueous dioxane, followed by activation of the resulting
carboxylic acids in dioxane by EDCI and treatment with
pentafluorophenol gave the corresponding man-hex lin-
ear PFP esters 15, 20 and 24 in 64%, 98% and 90%
yields, respectively.
3. Synthesis and cyclisations of mixed [man-hex]
oligomers
The azido-mannono-lactone 136 was treated with methyl
6-aminohexanoate hydrochloride in the presence of
DIPEA to afford the partially protected linear man-hex

B. A. Mayes et al. / Tetrahedron Letters 45 (2004) 163–166
165
Reduction of the each of the PFP esters by hydrogena-
tion caused cyclooligomerisation to macrocycles. Thus
hydrogenation of the dimer 15 in dioxane at a concen-
tration of 16 mg/mL gave a separable mixture of the
partially protected 14-membered 16 (21% yield), 28-
membered 25 (37% yield) and 42-membered 21 (15%
yield) ring man-hex cyclic oligomers (73% combined
yield of cyclic materials). Treatment of 16 with acid
ion exchange resin in aqueous dioxane gave the fully
deprotected macrocyclic lactam 187 in quantitative
yield.
Hydrogenation of the fully protected man-hex dimer 20
in dioxane at a concentration of 10 mg/mL gave 17:26:22
in a ratio of approximately 1:3:1 and a combined yield
of 86%; these cyclic oligomers were more difficult to
separate by flash chromatography. Hydrogenation of
the linear man-hex tetrameric PFP ester 24 in dioxane at
a concentration of 1 mg/mL gave the same man-hex 28-
membered ring 26 in an isolated yield of 79%.
Figure 1. X-ray crystal structure of deprotected gal-hex dimer 6 with
crystallographic numbering.
O
OH
R1O
O
OR
N3
6
NH
NH
O
5
(i)
N3H2C
O
4
R2O
R2O
O
OR1
O
HO
3
2
O
O
HO
O
1
HN
14 R = Me
15 R = C6F5
(iv)
13
(ii) (iii)
O
+
man-hex cyclic dimer 14 ring
OR2 OR1
O
(v)
16 R1,R1 = Me2C; R2 = H
17 R1,R1 = R2,R2 = Me2C
18 R1 = R2 = H
N
(vii)
H
O
NH
OR2 OR1
O
O
HN
OR
N3
O
NH
R2O
R1O
O
OR2
OR1
NH
O
OR1
OR2
(ii) (iii)
O
O
(iv)
19 R = Me
20 R = C6F5
O
R1O
R2O
HN
O
H
N
O
+
(ii) (iv) (vi)
man-hex cyclic hexamer 42 ring
21 R1,R1 = Me2C; R2 = H
OR2 OR1
O
6
22 R1,R1 = R2,R2 = Me2C
5
3
1
N
H
4
2
NH
OR2 OR1
H
N
O
OR
O
N3
O
NH
NH
O
O
O
O
O
OR1 OR2 NH
O
O
(iv)
H
N
O
O
O
O
OR1 OR2
O
23 R = Me
24 R = C6F5
(ii) (iii)
man-hex cyclic tetramer 28 ring
25 R1,R1 = Me2C; R2 = H
26 R1,R1 = R2,R2 = Me2C
Scheme 2. Reagents and conditions: (i) H2N(CH2)5COOHÆHCl, DIPEA; (ii) NaOH, H2O, dioxane, then Amberlite IR-120 Hþ; (iii) C6F5OH, EDCI;
(iv) H2, Pd black, dioxane; (v) Me2C(OMe)2, p-TSA; (vi) DIPEA, TBTU; (vii) Amberlyst-15, H2O, dioxane.

166
B. A. Mayes et al. / Tetrahedron Letters 45 (2004) 163–166
0.16 · 0.18 · 0.40 mm. Crystal system: orthorhombic, space
4. Summary
group P 21 21 21. Unit-cell parameters: a ¼7:7898ð2Þ,
ꢀ
b ¼ 11:0897ð2Þ, c ¼ 15:6046ð4Þ A, volume ¼ 1348.03(5)
This paper shows that a series of 14-, 28- and 42-mem-
bered macrocyclic lactams may be formed in good yields
from linear oligomers derived from e-amino acids. The
preceding paper provided a specific example of a fully
hydroxylated system, which also underwent efficient
cyclisation; this work suggests that the construction of a
family of macrocycles with the structural characteristics
of both cyclodextrins and cyclic peptides will be rela-
tively easy and thus provide access to a novel new class
of biomaterials.8
3
3
ꢀ
A . Calculated density: 1.430 mg/m . X-ray data were
measured using a Nonius KappaCCD diffractometer
using graphite-monochromated Mo-Ka radiation,
ꢀ
k ¼ 0:71073 A. Data were collected using
x scans,
2h 6 55ꢁ. 10735 reflections measured, of which 1790
unique, Rint ¼ 0:028, 1586 reflections with I > 3rðIÞ used
in refinement. Absorption corrections were applied using
the multi-scan technique (transmission range 0.96, 0.98,
l ¼ 0:115). The structure was solved by direct methods
(SIR92). Full-matrix least-squares refinement on F was
carried out using the CRYSTALS program suite. 205
parameters included were included in the refinement:
Coordinates and anisotropic thermal parameters of non-
hydrogen atoms; coordinates and isotropic thermal pa-
rameters of OH and NH hydrogen atoms. Other hydrogen
atoms were positioned geometrically. After convergence,
R ¼ 0:0272, wR ¼ 0:0313, residual electron density (min,
References and Notes
1. Mayes, B. A.; Simon, L.; Watkin, D. J.; Ansell, C. W. G.;
Fleet, G. W. J. Tetrahedron Lett. 2003, 45. See: doi:10.1016/
j.tetlet.2003.10.103.
2. Long, D. D.; Stetz, R. J. E.; Nash, R. J.; Marquess, D. G.;
Lloyd, J. D.; Winters, A. L.; Fleet, G. W. J. J. Chem. Soc.,
Perkin Trans. 1 1999, 901–908.
À3
ꢀ
.
max) ¼ )0.17, 0.14 eA
6. Joseph, C. C.; Regeling, H.; Zwanenburg, B.; Chittenden,
G. J. F. Tetrahedron 2002, 58, 6907–6911.
7. Selected data for deprotected man-hex cyclic dimer 18:
3. Elution of products by gradient elution from 100% ethyl
acetate to 93%:7%, then 91%:9% ethyl acetate/methanol.
½aŠ25: )30.1 (c 0.95, H2O); mp > 220 ꢁC, needles contract
D
24
D
4. Selected data for deprotected gal-hex cyclic dimer 6: ½aŠ
and amalgamate into amorphous solid above 217 ꢁC; mmax
(thin film, Ge plate): 3307 cmÀ1 (br s, O–H, N–H),
1638 cmÀ1 (C@O, amides I); 1H NMR dH (500 MHz,
D2O): 1.13–1.23 (2H, m, H-9, H-90), 1.40–1.48 (1H, m, H-
8), 1.53–1.66 (3H, m, H-80, H-10, H-100), 2.30 (2H, t, J 6.2,
)22.0 (c 0.65, D2O); mp > 220 ꢁC; mmax (thin film, Ge plate):
3326 cmÀ1 (br s, O–H, N–H), 1643 cmÀ1 (C@O, amides I),
1550 cmÀ1 (C@O, amides II); 1H NMR dH (400 MHz,
D2O): 1.14 (2H, m, J 7.6, H-9, H-90), 1.39–1.49 (2H, m, H-
8, H-80), 1.56 (2H, a-quin, J 7.2, H-10, H-100), 2.14–2.77
H-11, H-110), 2.97 (1H, a-ddd, J7;7 13.5, J 6.1, J 3.5, H-7),
0
(2H, m, J 6.3, H-11, H-110), 3.16 (1H, dd, J1;1 13.3, J1;2 4.8,
3.08 (1H, dd, J1;1 14.6, J 3.0, H-1), 3.43 (1H, a-d, J3;2 9.6,
0
0
H-1), 3.21–3.32 (2H, m, H-7, H-70), 3.41–3.48 (2H, m, H-
10, H-3), 3.89 (1H, dd, J4;3 8.0, J4;5 5.1, H-4), 3.95 (1H, a-
dd, J 11.3, J2;1 4.8, H-2), 4.24 (1H, d, J5;4 5.1, H-5); 13C
NMR dC (100 MHz, D2O): 25.01 (C-9), 25.19 (C-10), 28.43
(C-8), 35.32 (C-11), 38.91 (C-7), 39.83 (C-1), 67.98 (C-2),
69.77 (C-3), 71.24 (C-4), 74.29 (C-5), 173.83, 177.64
(2 · CONH). MS m=z (ES-): 288.80 ([M)H]À, 100%);
HRMS: C12H21N2O6 ([M)H]À) calcd 289.1400, found
289.1393.
H-3), 3.63 (1H, a-ddd, J7 ;7 13.5, J 9.7, J 3.3, H-70), 3.75
0
0
(1H, a-dt, J2;3 9.6, J 2.3, H-2), 3.97 (1H, dd, J1 ;1 14.6, J 1.6,
H-10), 4.24 (1H, a-d, J4;5 3.2, H-4), 4.41 (1H, d, J5;4 3.2, H-
5); 13C NMR dC (125 MHz, D2O): 25.23 (C-9), 25.42 (C-
10), 28.69 (C-8), 35.61 (C-11), 38.86 (C-7), 41.30 (C-1),
67.55 (C-4), 68.49 (C-2), 70.52 (C-3), 77.27 (C-5), 174.19,
178.29 (2 · CONH). MS m=z (ES-): 289.14 ([M–H]À,
100%); HRMS: C12H21N2O6 ([M)H]À) calcd 289.1400,
found 289.1407.
5. Crystallographic data have been deposited with the
CCDC, reference no. CCDC 220310. Crystal size
8. A BBSRC CASE award with Smith & Nephew [to B.A.M.]
is gratefully acknowledged.