A short route to the macrocyclic core of biaryl ether-based cyclopeptides

Article abstract of DOI:10.1016/j.tetlet.2007.03.133

A new route based on an intramolecular Horner-Wadsworth-Emmons type olefination of amidophosphonates has been developed for the construction of a 17-membered macrocyclic scaffold related to some biologically important biaryl ether-based cyclic peptides.

Full text of DOI:10.1016/j.tetlet.2007.03.133

Tetrahedron Letters 48 (2007) 3655–3659
A short route to the macrocyclic core of biaryl ether-based
cyclopeptides
Shital K. Chattopadhyay,* Ayan Bandyopadhyay and Benoy K. Pal
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
Received 16 February 2007; revised 15 March 2007; accepted 22 March 2007
Available online 25 March 2007
Abstract—A new route based on an intramolecular Horner–Wadsworth–Emmons type olefination of amidophosphonates has been
developed for the construction of a 17-membered macrocyclic scaffold related to some biologically important biaryl ether-based cyc-
lic peptides.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Members belonging to the family of naturally occurring
biaryl ether-based cyclopeptides such as K-13 (1) and
OF4949’s (2) (Fig. 1) have proved to be exciting syn-
thetic targets1 over the past two decades, largely because
of their good biological activities and structural com-
plexity. Not surprisingly, non-natural biaryl ether-con-
taining macrocycles have also been prepared2 in the
quest for potential therapeutic agents and/or com-
pounds having altered bioactivity. Although a number
of macrocyclisation methodologies for the construction
of somewhat elusive biaryl ether-containing macrocyclic
structures of varying ring sizes have emerged during
these studies, newer methods for the construction of
such compounds continue to be developed.3 Of the var-
ious heterocyclisation routes, macrocyclisation through
biaryl ether bond formation involving oxidative phenol
coupling,4 Ullmann cyclisation5 or SNAr reactions6 has
been widely used. An elegant C–C bond forming macro-
cyclisation protocol involving Pd-catalysed cyclisation
of an organozinc derivative has recently been reported.7
Macrocycle formation through intramolecular Horner–
Wadsworth–Emmons (HWE) type olefination has
proved to be highly effective in many demanding situa-
tions over the years.8 Herein, we report a new route to
the 17-membered ring system of some biaryl ether-con-
taining cyclic peptides based on a HWE- type macro-
olefination of an amidophosphonate as the key step.
We envisioned that the macrocyclic model compound 3
(Scheme 1), related to the OF-4949 ring system, could
OR1
OH
O
O
O
O
H
H
H2N
N
HO2C
N
H
CO2H
NHAc
N
H
N
H
O
O
R2
CONH2
HO
2 OF-4949's
1 K-13
Figure 1.
Keywords: Olefination; Peptide; Biaryl; Macrocycle.
*
Corresponding author. Tel.: +91 33 25828750x305; fax: +91 33 25828282; e-mail: skchatto@yahoo.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.133

3656
S. K. Chattopadhyay et al. / Tetrahedron Letters 48 (2007) 3655–3659
O
R
O
O
H2
C=C
CHO
PO(OEt)2
O
O
O
H
H
H
N
N
N
CO2Me
CO2Me
N
N
H
CO2Me
N
H
H
O
O
R
O
R
3
4
5
amide bond
formation
O
O
PO(OEt)2
CO2Me
H2N
CHO
N
H
CO2H
R
6
7
Scheme 1.
possibly be derived from either substrate or reagent con-
trolled hydrogenation of the corresponding dehydro-
peptide 4 which, in turn, could be derived from
amidophosphonate-aldehyde 5 if the crucial intramole-
cular olefination could be effected. Compound 5 was
expected to be formed by condensation of the carboxylic
acid 6 and amine 7 through amide bond formation.
protected amino acids 12a–c, led to dipeptides 14a–c
in acceptable yields. Hydrogenolytic removal of the Z-
group in the latter compounds provided access to the
corresponding amines 7a–c which were used without
purification. Coupling of each of these amines with bi-
aryl carboxylic acid 6 separately, led to macrocyclisation
precursors 5a–c in moderate to good yields.
The synthetic sequence started from the known 3-
hydroxybenzaldehyde which on treatment with malonic
acid in refluxing pyridine afforded the known3e cinnamic
acid derivative 8 (Scheme 2) in excellent yield (91%). The
latter on esterification with acetyl chloride in methanol
delivered unsaturated ester 9, also in high yield. Cata-
lytic hydrogenation of 9 with H2 in the presence of
Pd–C (10%) in ethanol/acetic acid (19:1) provided satu-
rated ester 10 almost quantitatively. An Ullmann type
coupling between phenol 10 and 4-iodobenzaldehyde
proceeded well using 2,2,6,6-tetramethyl-3,5-heptanedi-
one (TMHD) as additive9 in the presence of cesium car-
bonate and CuBr to afford biaryl ether 11 in high yield
(89%). Hydrolysis of the ester functionality in the latter
under conventional conditions using lithium hydroxide
monohydrate in THF/water (5:1) liberated carboxylic
acid 6, uneventfully, in 94% yield.
With the key precursors in hand, we next focused on
the macrocyclisation step. A number of bases have been
used for intermolecular olefination of amidophospho-
nates with aromatic and aliphatic aldehydes. Notable
among these are KOBut, NaH, DBU and 1,1,3,3-tetra-
methylguanidine (TMG). We opted to evaluate some of
these conditions11 but using higher dilution and/or
elevated temperature. The results are summarised in
Table 1. Initial experiments with substrate 5a revealed
that the reaction proceeded poorly with previously suc-
cessful bases like DBU, KOBut or NaH under a range
of conditions. Similarly, use of TMG as a base did not
alter the fate of the reaction to any significant extent. In
most of these cases, unchanged starting material was
largely recovered. However, in some instances polar
unidentified by-products were also formed. Following
our earlier success12 with the Nicolaou conditions13
(K2CO3/18-crown-ether) in macrocycle construction,
we opted to employ those conditions to the current
effort.
Amide bond formation between Schmidt’s amin-
ophosphonate10 13 (Scheme 3) and the appropriate Z-
OH
OH
CO2H
i
OH
iv
iii
+
CO2H
CO2Me
CHO
CO2R
8, R = H
9, R = Me
10
ii
O
v
6
CHO
CO2Me
11
Scheme 2. Reagents and conditions: (i) pyridine, morpholine (cat.), reflux, 2 h, 91%; (ii) AcCl, MeOH, reflux, 4 h, 96%; (iii) H2, Pd–C, EtOH–AcOH
(19:1), rt, 48 h, 97%; (iv) 4-IC6H4CHO, CuBr, Cs2CO3, TMHD, NMP, 75 ꢁC, 16 h, 89%; (v) LiOH, THF–H2O (5:1), rt, 4 h, 94%.

S. K. Chattopadhyay et al. / Tetrahedron Letters 48 (2007) 3655–3659
3657
O
PO(OEt)2
CO2Me
PO(OEt)2
CO2Me
i
ZHN
CO2H
+
ZHN
N
H2N
R
H
R
13
14a, R = Bn, 67%
14b, R = CH3, 64%
14c, R = H, 61%
12a, R = Bn
12b, R = CH3
12c, R = H
O
O
PO(OEt)2
CO2Me
iii
ii
CHO
PO(OEt)2
H2N
N
O
H
H
R
N
N
CO2Me
H
O
R
7a, R = Bn
7b, R = CH3
7c, R = H
5a, R = Bn,64%
5b, R = CH3, 60%
5c, R = H, 56%
Scheme 3. Reagents and conditions: (i) DCC, CH2Cl2, ꢀ10 ꢁC to rt, 6 h; (ii) H2, Pd–C, MeOH, rt, 2 h; (iii) 6, DCC, HOBt, CH2Cl2, ꢀ10 ꢁC to rt,
12 h.
Table 1. Attempted macrocyclisation of 5a
Entry
Base
Solvent
Concentration
Temperature
Time (h)
% 4a
1
2
3
4
DBU
CH2Cl2
THF
THF
0.004
0.004
0.004
0.004
Reflux
12
24
24
24
8
11
0
KOBut
rt to 50 ꢁC
rt to reflux
Reflux
NaH
Me2NC(@NH)NMe2
THF
14
Pleasingly, when a solution of amidophosphonate 5a in
toluene was slowly added (via a syringe pump) to a solu-
tion of K2CO3 (6 equiv) and 18-crown-6 (12 equiv) in
toluene (0.001 M) at 80 ꢁC and then heated to reflux
for 20 h, conversion to the desired macrocycle 4a
(Scheme 4) took place in an acceptable 51% yield. Sim-
ilarly, substrates 5b–c were converted to cyclic dehydro-
peptides 4b–c.
the DPhe-residue was noticed when the solvent was
changed from CDCl3 (d 6.30) to DMSO-d6 (d 9.40) indi-
cating the formation of hydrogen bond in the latter sol-
vent.15 Moreover, the aromatic protons marked H in
macrocyclic structures 4a–c appeared around d 6.2
which seemed to be diagnostic16 of this kind of ring sys-
tem. The other spectral parameters were consistent with
the assigned structures.
Macrocyclic compounds 4a–c were obtained as colour-
less, amorphous, high melting solids.14 The stereochem-
ical integrity of the compound prepared was verified
from HPLC studies in different solvents and using vari-
ous columns including a chiral one, thereby indicating
that negligible or no racemisation had taken place dur-
ing macrocyclisation. The compounds displayed inter-
esting 1H NMR spectral properties in CDCl3 where
most of the peaks were obtained as broad singlets. Well
resolved spectra were obtained in DMSO-d6. A signifi-
cant change of the chemical shift of the NH proton of
Preliminary experiments revealed that dehydropeptide
4a underwent rapid hydrogenation to the corresponding
saturated compound 15 (Scheme 5) which was obtained
as an inseparable mixture of two diastereomers (3:1,
HPLC, 1H NMR). However, elucidation of the stereose-
lectivity of the hydrogenation reaction was not estab-
lished at this stage.
In conclusion, we have developed a concise convergent
synthesis of the 17-membered macrocyclic scaffold of
biologically important biaryl ether-based cyclic peptides
O
O
K2CO3 (6 eq.),
18-crown-6 (12 eq.)
H
CHO
O
O
PO(OEt)2
Toluene (0.001 M)
H
H
N
N
°
CO2Me
80-110 C, 20 h
N
N
CO2Me
H
H
O
R
O
R
4a, R = Bn, 51%
4b, R = CH3, 44%
4c, R = H, 42%
5a-c
Scheme 4.

3658
S. K. Chattopadhyay et al. / Tetrahedron Letters 48 (2007) 3655–3659
O
O
H2, Pd-C
methanol
92%
O
O
H
N
H
N
CO2Me
CO2Me
N
N
H
H
H
O
O
Ph
Ph
4a
15
Scheme 5.
5. Boger, D. L.; Yohannes, D. J. Am. Chem. Soc. 1991, 113,
1427.
utilising intramolecular olefination of an amidophosph-
onate-aldehyde. The methodology described here may
find application in the synthesis of other cyclic peptides
containing a DPhe-residue. It is well known17 that incor-
poration of a DPhe-residue in peptides confers resistance
to enzymatic degradation. Moreover, DPhe-residues in
cyclic peptides may introduce interesting conforma-
tional features relevant to drug design. Macrocyclic
compounds 4a–c may therefore find application in this
regard. Their utility in the synthesis of biaryl ether-
based natural products (and analogues thereof) through
stereo-controlled hydrogenation seems to be a possibil-
ity as well. The scaffold18 may also prove to provide
opportunities for the preparation of derivatised biaryl
ether-based cyclic peptides through well known trans-
formation reactions on the unsaturated system.19 Future
work in these directions will be pursued in our
laboratory.
6. (a) Pearson, A. J.; Bignan, G.; Zhang, P.; Chelliah, M. J.
Org. Chem. 1996, 61, 3940; (b) Janetka, J. W.; Rich, D. R.
J. Am. Chem. Soc. 1997, 119, 6488; (c) Beugelmans, R.;
Singh, G. P.; Bois-Choussy, M.; Chastanet, J.; Zhu, J. J.
Org. Chem. 1994, 59, 5535; (d) Bigot, A.; Tran Huu Dau,
M. E.; Zhu, J. J. Org. Chem. 1999, 64, 6283; (e)
Beugelmans, R.; Bigot, A.; Zhu, J. Tetrahedron Lett.
1994, 35, 7391.
7. Perez-Gonzalez, M.; Jackson, R. F. W. Chem. Commun.
2000, 2423.
8. For some recent applications, see: (a) Harvey, J. E.; Raw,
S. A.; Taylor, R. J. K. Tetrahedron Lett. 2003, 44, 7209;
(b) Mulzer, J.; Ohler, E. Angew. Chem., Int. Ed. 2001, 40,
3842; (c) Gonzalez, M. A.; Pattenden, G. Angew. Chem.,
Int. Ed. 2003, 42, 1255; (d) Yeung, K.-S.; Paterson, I.
Chem. Rev. 2005, 105, 4237; (e) O’Neil, G. W.; Philips, A.
J. J. Am. Chem. Soc. 2006, 128, 5340; (f) Seo, S.-Y.; Jung,
J.-K.; Paek, S.-M.; Lee, Y.-S.; Kim, S.-H.; Suh, Y.-G.
Tetrahedron Lett. 2006, 47, 6527.
9. Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.;
Volante, R. P.; Riedes, P. J. Org. Lett. 2002, 9, 1623.
10. Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984, 33.
11. (a) Schmidt, U.; Griesser, H.; Leitenberger, V.; Leiberkn-
echt, A.; Mangold, R.; Meyer, R.; Reidel, B. Synthesis
1992, 487; (b) Geyer, A.; Gege, C.; Schmidt, R. R. Angew.
Chem., Int. Ed. 2000, 39, 3245; (c) Zhang, J. Y.; Xiong, C.
Y.; Ying, J. F.; Wang, W.; Hruby, V. J. Org. Lett. 2003, 5,
3115; (d) Adamczyk, M.; Akireddy, S. R.; Reddy, R. E.
Org. Lett. 2001, 3, 3157.
Acknowledgements
We are thankful to the DST and CSIR, New Delhi, for
funds and fellowships.
References and notes
1. For reviews, see: (a) Rao, A. V. R.; Gurjar, M. K.; Reddy,
L.; Rao, A. S. Chem. Rev. 1995, 95, 2135; (b) Nicolaou, K.
C.; Boddy, C. N. C.; Brase, S.; Winssinger, N. Angew.
Chem., Int. Ed. 1999, 38, 2096; (c) Zhu, J. Synlett 1997,
133.
12. Chattopadhyay, S. K.; Pattenden, G. J. Chem. Soc.,
Perkin Trans. 1 2000, 2429.
13. (a) Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R. J. Am.
Chem. Soc. 1982, 104, 2030; (b) Aristoff, P. A. J. Org.
Chem. 1981, 46, 1954.
2. For a review, see: Fairlie, D. P.; Abbenante, G.; March, S.
R. Curr. Med. Chem. 1995, 2, 654; For some recent
reports, see: (a) Venkatraman, S.; Njoroge, F. G.; Girija-
vallabham, V. M.; Madison, V. S.; Yao, N. H.; Prongay,
A. N.; Butkiewicz, N.; Pichardo, J. J. Med. Chem. 2005,
48, 5088; (b) Janetka, J. W.; Raman, P.; Stayshur, K.;
Flentke, G. R.; Rich, D. H. J. Am. Chem. Soc. 1997, 119,
441.
3. (a) Cai, Q.; He, G.; Ma, D. J. Org. Chem. 2006, 71, 5268;
(b) Decicco, C. P.; Song, Y.; Evans, D. A. Org. Lett. 2001,
3, 1029; (c) Kohn, W. D.; Zhang, L.; Weigel, J. A. Org.
Lett. 2001, 3, 971; (d) Arnusch, C. J.; Pieters, R. J.
Tetrahedron Lett. 2004, 45, 4153; (e) Cristau, P.; Vors,
J.-P.; Zhu, J. Org. Lett. 2001, 3, 4079; (f) Cristau, P.; Vors,
J.-P.; Zhu, J. Tetrahedron Lett. 2003, 44, 5575; (g) West, C.
W.; Rich, D. E. Org. Lett. 1999, 1, 1819; (h) Pearson, A.
J.; Zhang, P.; Bignan, G. J. Org. Chem. 1997, 62, 4536.
4. (a) Evans, D. A.; Ellman, J. A.; DeVries, K. M. J. Am.
Chem. Soc. 1989, 111, 8912; (b) Suzuki, Y.; Nishiyama, S.;
Yamamura, S. Tetrahedron Lett. 1990, 31, 4053.
14. Typical procedure for the conversion 5a ! 4a: A solution of
phosphonate-aldehyde 5a (124 mg, 0.2 mmol) in dry
toluene (40 ml) was added slowly over 4 h to a solution
of K2CO3 (166 mg, 1.2 mmol) and 18-crown-6 (600 mg,
2.4 mmol) in dry toluene (160 ml) at 80 ꢁC. The mixture
was then heated to reflux for 16 h and then allowed to
warm to rt. It was then sequentially washed with HCl
(1 N, 2 · 25 ml), water (3 · 50 ml) and brine (25 ml) and
then dried (Na2SO4) and filtered. The filtrate was concen-
trated under reduced pressure to leave a viscous mass
which was purified by column chromatography over silica
gel using a mixture of chloroform and methanol (19:1) as
eluent to afford product 4a as a colourless crystalline solid
(48 mg, 51%).
Compound 4a: Mp: 278–280 ꢁC. [a]D ꢀ42 (c, 0.5 in
CHCl3 + MeOH, 3:1). IR (KBr): 3283, 1718, 1643, 1497,
1
1244 cmꢀ1. H NMR (400 MHz, DMSO-d6): d 9.56 (1H,
s), 7.85 (1H, d, J = 8.1 Hz,), 7.69 (1H, s), 7.34–7.10 (9H,
m), 6.96–6.84 (2H, m), 6.69 (1H, s), 6.24 (1H, s), 4.69 (1H,
br s), 3.77 (3H, s), 3.02–2.91 (2H, m), 2.71–2.40 (3H, m),

S. K. Chattopadhyay et al. / Tetrahedron Letters 48 (2007) 3655–3659
3659
2.12–2.05 (1H, m). 13C NMR (100 MHz, DMSO-d6): d
169.5 (s), 168.5 (s), 164.7 (s), 157.1 (s), 155.4 (s), 142.6 (s),
136.9 (d), 136.4 (d), 129.8 (d), 128.9 (d), 128.8 (d), 127.6
(d), 127.4 (d), 125.7 (d), 124.8 (d), 122.8 (s), 118.9 (s), 115.0
(d), 113.6 (d), 52.5 (d), 51.8 (q), 39.2 (t), 31.9 (t), 27.5 (t).
HRMS (TOF MS ES+): obsd 493.1715 (M+Na); calcd
493.1739 (C28H26N2O5+Na).
7.24 (1H, t, J = 7.9 Hz), 6.97–6.92 (3H, m), 6.86 (1H, d,
J = 7.8 Hz), 6.22 (1H, s), 3.79 (3H, s), 3.76 (2H, d,
J = 5.7 Hz), 2.84–2.81 (2H, m), 2.40–2.36 (2H, m). 13C
NMR (75 MHz, DMSO-d6): d 171.5, 165.2, 157.1, 155.6,
142.1, 134.6, 130.8, 129.5, 129.1, 128.8, 123.9, 123.3, 120.7,
116.3, 115.0, 68.1, 52.7, 42.1, 38.7. HRMS (TOF MS
ES+): obsd 381.1445 (M+H); calcd 381.1450
(C21H20N2O5+H).
Compound 4b: Mp: 284–286 ꢁC. [a]D ꢀ130 (c, 0.4 in
CHCl3 + MeOH, 3:1). IR (KBr): 3280, 1732, 1645, 1528,
15. Jain, R. M.; Rajashankar, K. R.; Ramakumar, S.;
Chauhan, V. S. J. Am. Chem. Soc. 1997, 119, 3205.
16. Boger, D. L.; Nomoto, Y.; Teegarden, B. R. J. Org. Chem.
1993, 58, 1425–1433.
17. English, M. L.; Stammer, C. H. Biochem. Biophys. Res.
Commun. 1978, 83, 1464.
18. For a recent review on amino acid derived macrocycles,
see: Gibson, S. E.; Lecci, C. Angew. Chem., Int. Ed. 2006,
45, 1364; For our earlier studies on macrocyclic dehydro-
peptide-based scaffolds, see: Chattopadhyay, S. K.;
Biswas, S. Tetrahedron Lett. 2006, 47, 7897.
1
1246 cmꢀ1. H NMR (300 MHz, DMSO-d6): d 9.39 (1H,
s), 7.82 (1H, d, J = 6.7 Hz), 7.66 (1H, s), 7.36–7.29 (3H,
m), 7.10 (1H, s), 6.98–6.89 (2H, m), 6.69 (1H, s), 6.27 (1H,
s), 4.48 (1H, br s), 3.77 (3H, s), 3.06 (1H, t, J = 12.1 Hz),
2.65–2.50 (2H, m), 2.25 (1H, br s), 1.16 (3H, d, J =
5.5 Hz). 13C NMR (100 MHz, DMSO-d6): d 170.2, 169.9,
165.2, 157.7, 155.9, 143.1, 136.5, 130.4, 129.4, 128.4, 125.2,
123.3, 119.5, 115.5, 114.3, 52.3, 47.2, 32.6, 28.3, 19.2.
HRMS (TOF MS ES+): obsd 417.1426 (M + Na); calcd
417.1426 (C22H22N2O5+Na).
Compound 4c: 1H NMR (300 MHz, DMSO-d6): d 8.94
(1H, s), 7.55 (1H, s), 7.48 (1H, s), 7.35 (2H, d, J = 8.2 Hz),
19. For a recent review, see: Bonquer, C.; Walenzyk, T.;
Konig, B. Synthesis 2006, 1.