Efficient construction of the carbon skeleton of the novel polyoxazole-based cyclopeptide IB-01211 via a biomimetic macrocyclisation

Article abstract of DOI:10.1055/s-0029-1219180

An efficient construction of the entire carbon skeleton of the novel polyoxazole-based natural product IB-01211 was developed which featured a biomimetic macrocyclisation of an ω-amino acid tethered through two bisoxazole units as the key step. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1219180

LETTER
555
Efficient Construction of the Carbon Skeleton of the Novel Polyoxazole-Based
Cyclopeptide IB-01211 via a Biomimetic Macrocyclisation
C
onstructiono
h
f
the Carbon
i
Skelet
t
onof
a
a
Polyoxazo
l
le-BasedCyc
K
lopeptide . Chattopadhyay,* Sovan K Singha
Department of Chemistry, University of Kalyani, Kalyani 741235, India
Fax +91(33)25828282; E-mail: skchatto@yahoo.com
Received 9 November 2009
This paper is respectfully dedicated to Professor Gerald Pattenden in celebration of his 70th birthday
late stage of their biogenesis through a macrolactamisa-
Abstract: An efficient construction of the entire carbon skeleton of
the novel polyoxazole-based natural product IB-01211 was devel-
oped which featured a biomimetic macrocyclisation of an w-amino
acid tethered through two bisoxazole units as the key step.
tion reaction involving the NH2 functionality of a serine–
threonine–cysteine residue linked to an oxazole/thiazole
ring and a CO2H group linked to another such hetero-
cyclic unit, for example, the conversion of 5 into 7
(Scheme 1). This biogenetically patterned macrocyclisa-
tion proposal has found important applications in the sec-
ond-generation synthesis8 of the important lectin-binding
agent ulapualide A and in the synthesis of the important
telomerase inhibitor telomestatin.9 Herein, we wish to re-
port another fruitful application of this concept in contin-
uation of our ongoing work on the synthesis of polyazole-
based bioactive natural products.10
IB-01211 (2), isolated4 from the microorganism strain
ES7-008, is strongly cytotoxic11 to several cell lines. It has
a unique and unprecedented structure accommodating
four oxazole rings and one thiazole ring tethered with a
tripeptide containing a dehydroamino acid residue. The
total synthesis of IB-01211 as well as problems associated
with the construction of the macrocyclic ring of this natu-
ral product has been recently reported.12 We became inter-
ested in developing a general synthetic route to its all-
oxazole analogue 3 based on Pattenden’s biomimetic pro-
posal. The retrosynthetic strategy we adopted for the com-
pound 3 is depicted in Scheme 2, which left the key
fragments to be the bisoxazole amino alcohol 10, the
dipeptide 11, and the phenyl-substituted bisoxazole deriv-
ative 12. A convergent union of these fragments following
the synthetic direction was therefore pursued.
Key words: heterocycles, biomimetic, macrocyclisation, peptides,
oxazoles
Several contiguously linked macrocyclic oxazole/thia-
zole-based natural products, isolated mainly from marine
sources and/or microorganisms, have shown interesting
and useful levels of biological activity.1 This, in turn, has
generated considerable interest not only in the synthesis of
these challenging natural products but also in the design
and synthesis of their simpler analogues with a view to ob-
taining compounds of desired properties.2 YM-2163913
(1, Figure 1), IB-012114 (2), and telomestatin5 (4) are
good examples in these regards.
A major hurdle in the synthesis of such complex targets
has often been the crucial macrocyclisation step. Synthet-
ic efforts by several groups towards these and related cy-
clic peptides have revealed interesting developments of
several macrolactamisation protocols and problems asso-
ciated with such cyclisations, but development of alter-
nate macrocyclisation protocols have also been rewarding
in some instances.6 Several years ago, during the course of
their synthetic studies on the novel trisoxazole-based ma-
rine metabolite ulapualide, Pattenden speculated7 that per-
haps one of the oxazole or thiazole rings is formed at the
O
O
O
S
O
N
NH
O
N
O
N
O
N
HN
N
H
HN
N
N
N
N
O
Ph
O
N
N
O
NH
NH
N
O
O
O
O
O
N
N
N
O
N
N
N
O
O
N
O
S
O
O
X
Ph
1
2 X = S
3 X = O
4
Figure 1
SYNLETT 2010, No. 4, pp 0555–0558
0
1.
0
3.
2
0
1
0
Advanced online publication: 08.01.2010
DOI: 10.1055/s-0029-1219180; Art ID: D31909ST
© Georg Thieme Verlag Stuttgart · New York

556
S. K. Chattopadhyay, S. K. Singha
LETTER
X
X
X
N
N
N
N
heterocycle
formation
HX
macrocyclisation
HX
NH
NH2
X
O
N
N
HO2C
N
X
X
X
5 X = O, S
6 X = O, S
7 X = O, S
Scheme 1
O
H
N
O
H
N
N
O
N
H
O
O
H
HN
oxazole
formation
O
N
HN
N
O
N
O
N
O
N
O
N
Ph
H
N
Ph
O
N
O
N
N
O
O
O
O
OH
3
8
OH
O
H
N
O
HO
N
NH2
O
H
N
O
HN
H
N
O
amide-bond
formation
O
O
NHBoc
CO2Me
N
11
N
O
N
Ph
N
O
N
O
H2N
CO2H
N
Ph
O
N
H2N
O
CO2Me
10
OH
O
12
OH
9
Scheme 2
Fragment 10 was easily prepared by trifluoroacetic acid latter was then cleanly oxidized to the corresponding ke-
mediated global deprotection of the bisoxazole-oxazoli- toamide 19 using pyridinium chlorochromate (PCC) as
dine derivative 13 previously described by us.13 The crude the oxidant. The survival of the sensitive oxazolidine ring
TFA salt 14 thus obtained was used as such in the next during this transformation was a fortunate outcome; how-
step. Although the natural dipeptide residue 11 contained ever, this has not been documented previously, to the best
D-allo-isoleucine as the N-terminal amino acid, we opted of our knowledge. The construction of the second oxazole
to use the cheaper L-isoleucine as a replacement in our ex- ring from the latter was then attempted under Wipf’s
plorative studies. Thus, the bisoxazole amine 14 was cou- protocol15 using triphenylphosphine–iodine combination.
pled with easily obtainable Boc-L-Ile-L-Val-OH using the
Pleasingly, the reaction proceeded smoothly to provide
N-methylmorpholine–EDC–HOBt combination to deliver
the desired bisoxazole derivative 20, [a]D –72.6 (c 0.56,
the coupled product 15 (Scheme 3) in good yield and as a
MeOH), as a colourless solid, mp 118–119 °C, in an over-
all yield of 51% from 16 over three steps. The ester func-
tionality in compound 20 was then smoothly hydrolysed
to the corresponding carboxylic acid 21.
colourless solid. The free OH group in the latter was then
protected as its TBDPS ether under standard conditions to
provide 16, [a]D –37.5 (c 0.5, MeOH), also as a colourless
solid, mp 178–179 °C.
Having access to the desired key fragments, we then fo-
cused on their convergent union. Thus, the NBoc group in
The preparation of the second bisoxazole fragment 12 fol-
lowed from the monooxazole acid 17 (Scheme 4), also
the dipeptide-linked bisoxazole derivative 16 was depro-
previously reported by us.14 Thus, amide bond formation
tected using trifluoroacetic acid to give the corresponding
between 17 and racemic phenylserine methyl ester hydro-
crude amine as its TFA salt 22 (Scheme 5) in readiness for
peptide coupling with the bisoxazole acid 21 using the N-
methylmorpholine–EDC–HOBt combination. The cou-
pled product 23 was obtained as a colourless solid, mp
chloride using dicyclohexylcarbodiimide (DCC) as the
activating agent led to the b-hydroxy amide 18 as the ex-
pected diastereomeric mixture but in very good yield. The
Synlett 2010, No. 4, 555–558 © Thieme Stuttgart · New York

LETTER
Construction of the Carbon Skeleton of a Polyoxazole-Based Cyclopeptide
557
O
O
OH
O
NHBoc
O
N
N
NH2TFA
NH
O
O
N
Boc
O
Boc
i
ii
N
N
O
N
Boc
CO2H
ii
H
N
i
N
CO2Me
Ph
CO2H
N
N
O
O
O
HO
17
CO2Me
CO2Me
14
18
13
O
O
N
OR
O
H
N
N
Boc
N
Boc
N
NHBoc
iii
H
O
N
O
N
O
H
O
N
CO2Me
Ph
N
N
O
O
CO2R
O
O
19
Ph
CO2Me
20 R = Me
21 R = H
iv
15 R = H
16 R = TBDPS
iii
Scheme 4 Reagents and conditions: (i) PhSer-OMe·HCl, DCC,
HOBt, Et3N, CH2Cl2, 0 °C to r.t., 18 h, 84%; (ii)PCC, powdered MS
4 Å, CH2Cl2, r.t., 45 min, 82%; (iii) Ph3P, I2, Et3N, THF, –78 °C, 3 h,
75%; (iv) LiOH, THF–H2O (4:1), r.t., 1.5 h, 86%.
Scheme 3 Reagents and conditions: (i) 50% TFA in CH2Cl2, 0 °C
to r.t., 1.5 h; (ii) EDC·HCl, HOBt, NMM, CH2Cl2, 0 °C to r.t., 18 h,
76%; (iii) TBDPSCl, Et3N, DMAP (cat.), CH2Cl2, r.t., 18 h, 77%.
TBDPSO
O
TBDPSO
O
H
N
H
N
N
H
NH
N
H
NH2TFA
Ph
O
O
O
O
O
N
O
i
N
N
ii
16
N
N
O
O
N
Boc
CO2R
O
CO2Me
N
22
23 R = Me
24 R = H
iii
O
TBDPSO
O
TBDPSO
O
H
N
O
H
N
N
N
H
O
O
H
HN
N
iv
v
O
N
HN
N
O
N
O
O
N
O
N
O
Ph
Ph
O
N
H
O
N
CO2H
N
TFAH2N
O
O
OH
HO
25
26
OR
O
H
N
N
O
H
O
HN
N
N
N
vi
O
O
Ph
H
O
N
N
O
O
27 R = TBDPS
28 R = H
vii
Scheme 5 Reagents and conditions: (i) 50% TFA in CH2Cl2, 0 °C to r.t., 1.5 h; (ii) 21, EDC·HCl, HOBt, NMM, CH2Cl2, 0 °C to r.t., 24 h,
70%; (iii) LiOH, THF–H2O (4:1), r.t., 1.5 h, 90%; (iv) 50% TFA in CH2Cl2, 0 °C to r.t., 1.5 h; (v) DPPA, HOBt, DIEA, DMAP (cat.), DMF–
CH2Cl2 (1:1) (2.5 mmol), r.t., 36 h, 39% over two steps; (vi) MsCl, DBU, 0 °C to r.t., 4 h, 74%; (vii) n-Bu4N+F–, THF, 0 °C to r.t., 2 h, 89%.
Synlett 2010, No. 4, 555–558 © Thieme Stuttgart · New York

558
S. K. Chattopadhyay, S. K. Singha
LETTER
Chem. Int. Ed. 2003, 42, 4961. (g) Liu, P.; Panek, J. S.
96 °C, in 70% yield. The latter was then sequentially
deprotected at the two bisoxazole termini, that is, hydrol-
ysis of the methyl ester leading to the carboxylic acid 24
followed by TFA-mediated simultaneous removel of the
Boc group and cleavage of the oxazolidine ring in a one-
pot manner to provide the macrocyclisation precursor 25,
which was used as such in the next step. After some ex-
perimentation, it was found that macrocyclisation of 25
proceeded well using diphenylphosphoryl azide (DPPA)
and 1-hydroxybenzotriazole (HOBt) as activating agents
in the presence of diisopropylethylamine under high dilu-
tion (2.5 mmol) in a 1:1 mixture of DMF and dichlo-
romethane at room temperature. The cyclised product 26,
[a]D –17.6 (c 0.5, MeOH), was obtained as a colourless
solid, mp 118–119 °C, in an overall yield of 39% over two
steps from the carboxylic acid 24. The macrocyclic b-hy-
droxy amide 26 was then subjected to a two-step, one-pot
dehydration involving formation of the corresponding
mesylate followed by elimination to the corresponding
enamide 27 in good yield. Removal of the pendant TB-
DPS group from the latter was effected smoothly in the
presence of fluoride ion to provide compound 28 in very
good yield.16
J. Am. Chem. Soc. 2000, 122, 1235.
(3) Deeley, J.; Pattenden, G. Chem. Commun. 2005, 797.
(4) Kanoh, K.; Matsuo, Y.; Adachi, K.; Imagawa, H.;
Nishizawa, M.; Shizuri, Y. J. Antibiot. 2005, 58, 289.
(5) Shin-Ya, K.; Weirzba, K.; Matsuo, K.; Ohtani, T.; Yamada,
Y.; Furihata, K.; Hayakawa, Y.; Seto, H. J. J. Am. Chem.
Soc. 2001, 123, 1262.
(6) Wipf, P. Chem. Rev. 1995, 95, 2115.
(7) Chattopadhyay, S. K.; Pattenden, G. Synlett 1997, 1342.
(8) (a) Pattenden, G.; Ashweek, N. J.; Baker-Glenn, C. A. G.;
Walker, G. M.; Yee, J. G. K. Angew. Chem. Int. Ed. 2007,
46, 4359. (b) Pattenden, G.; Ashweek, N. J.; Baker-Glenn,
C. A. G.; Kempson, J.; Walker, G. M.; Yee, J. G. K. Org.
Biol. Chem. 2008, 6, 1478.
(9) (a) For related contemporaneous studies, see: Doi, T.;
Yoshida, M.; Shin-Ya, K.; Takahasi, T. Org. Lett. 2006, 8,
4165. (b) Deeley, J.; Bertram, A.; Pattenden, G. Org. Biol.
Chem. 2008, 6, 1994. (c) Marson, M. C.; Saadi, M. Org.
Biol. Chem. 2006, 4, 3892.
(10) Chattopadhyay, S. K.; Biswas, S. Tetrahedron Lett. 2006,
47, 7897.
(11) Romero, F.; Malet, L.; Canedo, L. M.; Cuevas, C.; Reyes, J.
WO 2005/000880 A2, 2005.
(12) (a) Hernández, D.; Vilar, G.; Riego, E.; Cañedo, L. M.;
Cuevas, C.; Albericio, F.; Álvarez, M. Org. Lett. 2007, 9,
809. (b) Hernández, D.; Riego, E.; Francesch, A.; Cuevas,
C.; Albericio, F.; Álvarez, M. Tetrahedron 2007, 63, 9862.
(c) Hernández, D.; Riego, E.; Albericio, F.; Álvarez, M. Eur.
J. Org. Chem. 2008, 3389.
(13) Chattopadhyay, S. K.; Biswas, S.; Ghosh, S. K. Synthesis
2008, 7897.
(14) Chattopadhyay, S. K.; Biswas, S.; Pal, B. K. Synthesis 2006,
1289.
In conclusion, we have developed, following Pattenden’s
biomimetic proposal, a concise synthetic route to the mac-
rocyclic core of a proposed analogue of the important an-
ticancer natural product IB-01211 with built-in
functionalities for further synthetic manipulations. The b-
hydroxy amide 26 and the enamide 27 may serve as ap-
propriate handles to install the fifth oxazole ring in view
of ample precedence17 of such transformations.
(15) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604.
(16) All new compounds reported here gave satisfactory
spectroscopic and/or analytical data.
The macrocyclic products 26–28 may also prove to be bi-
ologically relevant. The methodology developed may find
use in the synthesis of related compounds and/or design
and synthesis of modified IB-01211. Work will be contin-
ued in this laboratory along some of these directions.
Data for 27
Mp 144–146 °C. IR (KBr): 3367, 2927, 1683, 1652, 1515,
1259, 1114, 766 cm–1. 1H NMR (400 MHz, CDCl3): d = 9.46
(s, 1 H), 8.61 (d, J = 8.4 Hz, 1 H), 8.35 (s, 1 H), 8.27 (s, 1 H),
8.14 (s, 1 H), 8.13 (d, J = 7.2 Hz, 1 H), 7.64–7.62 (m, 2 H),
7.49–7.43 (m, 6 H), 7.40–7.38 (m, 4 H), 7.36–7.33 (m, 3 H),
6.88 (s, 1 H), 6.01 (dd, J = 6.8 Hz, 1 H), 5.97 (s, 1 H), 5.34–
5.28 (m, 1 H), 4.63 (dd, J = 8.0, 4.8 Hz, 1 H), 4.10 (dd
J = 9.2, 5.6 Hz, 1 H), 3.97–3.92 (m, 1 H), 3.73 (t J = 9.2 Hz,
1 H), 2.42–2.37 (m, 1 H), 1.90–1.87 (m, 1 H), 1.03–0.99 (m,
15 H), 0.90–0.86 (m, 2 H), 0.80 (d, J = 6.8 Hz, 3 H), 0.65 (t,
J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 171.7 (s),
169.9 (s), 164.5 (s), 160.3 (s), 159.1 (s), 158.6 (s), 154.6 (s),
152.1 (s), 151.6 (s), 141.8 (d), 139.3 (d), 139.1 (d), 137.3 (s),
135.0 (d), 134.9 (d), 132.7 (s), 132.6 (s), 132.2 (s), 131.8 (s),
130.4 (d), 130.3 (s), 129.9 (d), 129.8 (d), 129.5 (s), 128.5 (d),
128.3 (d), 127.8 (d), 127.7 (d), 126.0 (s), 105.2 (t), 64.7 (t),
59.8 (d), 56.4 (d), 49.3 (d), 38.2 (d), 29.2 (d), 26.3 (q), 24.7
(t), 19.8 (q), 18.7 (q), 18.3 (s), 14.9 (q), 11.1 (q). HRMS
(TOFMS ES+): m/z [M+ + Na] calcd for C51H54N8NaO9Si:
973.3681; found: 973.3682
Acknowledgment
Financial assistance from DST, New Delhi (Grant No SR/S1/OC-
35/2009) is gratefully acknowledged. One of us (S.K.S.) is thankful
to CSIR, New Delhi for a fellowship.
References and Notes
(1) For reviews see: (a) Pattenden, G. J. Heterocycl. Chem.
1992, 29, 607. (b) Faulkner, D. J. Nat. Prod. Rep. 2002, 29,
1; and earlier reports in the series. (c) Yeh, V. S. C.
Tetrahedron 2004, 60, 11995. (d) Bertram, A.; Pattenden,
G. Nat. Prod. Rep. 2007, 24, 18. (e) Hughes, R. A.; Moody,
C. J. Angew. Chem. Int. Ed. 2007, 46, 2.
(2) For some examples, see: (a) Gonzalez, M. A.; Pattenden, G.
Angew. Chem. Int. Ed. 2003, 42, 1255. (b) Krebs, O.;
Taylor, R. J. K. Org. Lett. 2005, 7, 1063. (c) Bagley, M. C.;
Chapaneri, K.; Dale, J. W.; Xiong, X.; Bower, J. J. Org.
Chem. 2005, 70, 1389. (d) Bagley, M. C.; Bashford, K. E.;
Hesketh, C. L.; Moody, C. J. J. Am. Chem. Soc. 2000, 122,
3301. (e) Mann, E.; Kessler, H. Org. Lett. 2003, 5, 4567.
(f) Burgett, A. W. G.; Li, Q.; Wei, Q.; Harran, P. G. Angew.
(17) (a) Chattopadhyay, S. K.; Kempson, J.; McNeil, A.;
Pattenden, G.; Reader, M.; Rippon, D. E.; Waite, D.
J. Chem. Soc., Perkin Trans. 1 2000, 2415. (b) Endo, N.;
Tsuboi, K.; Kim, R.; Yonezawa, Y.; Shin, C. Heterocycles
2003, 60, 1567.
Synlett 2010, No. 4, 555–558 © Thieme Stuttgart · New York