Synthesis of Diverse Macrocyclic Peptidomimetics Utilizing Ring-Closing Metathesis and Solid-Phase Synthesis

Article abstract of DOI:10.1021/jo0352629

The synthesis of a range of highly functionalized peptidomimetic macrocycles has been accomplished using ring-closing metathesis and enyne tandem cross-metathesis-ring-closing metathesis reactions. This approach gives access to rigidified macrocycles mode

Full text of DOI:10.1021/jo0352629

Syn th esis of Diver se Ma cr ocyclic P ep tid om im etics Utilizin g
Rin g-Closin g Meta th esis a n d Solid -P h a se Syn th esis
Anthony G. M. Barrett,*,† Alan J . Hennessy,† Ronan Le Ve´zoue¨t,† Panayiotis A. Procopiou,*,‡
Peter W. Seale,‡ Stefan Stefaniak,† Richard J . Upton,‡ Andrew J . P. White,† and
David J . Williams†
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, U.K., and
GlaxoSmithKline, Department of Medicinal Chemistry, Gunnels Wood Road, Stevenage SG1 2NY, U.K.
agmb@imperial.ac.uk
Received August 29, 2003
The synthesis of a range of highly functionalized peptidomimetic macrocycles has been accomplished
using ring-closing metathesis and enyne tandem cross-metathesis-ring-closing metathesis reactions.
This approach gives access to rigidified macrocycles modeled on the structures of cyclic peptides
and designed to be biologically stable. The potential for peripheral functionalization of these
templates has been demonstrated using Diels-Alder reactions, palladium(0) coupling reactions,
and amide formation both in the solution phase and using polymer-supported syntheses.
In tr od u ction
should not be totally rigid, thus ensuring low entropy
while enabling some relaxation into binding conforma-
tions. Pendant groups should be attached to the template
to allow varied orientation in space. The assembly of the
ring system should be short (<10 steps), divergent to
enable combinatorial synthesis, and amenable to solid
supported synthesis for ease of handling of large numbers
of analogues. Computational analysis of the non-peptide-
based macrocycles of basic structures 1 and 2 (Figure 1)
revealed that the conformational rigidity imposed by the
aromatic rings and the trans alkene moiety should give
the desired receptor binding. We therefore envisioned
that these novel potential pharmacophores would provide
a basic scaffold for the facile attachment of diverse
peripheral functionalities in addition to the hydrogen
bond donor and acceptor units already present.
Research on site-specific mutation of proteins involved
in biologically important protein-protein interactions
shows that the key residues for binding are often non-
contiguous and grouped in areas of the molecules that
are 15-30 Å across. Molecules that can span such
distances usually contain long highly flexible chains
whose orientation to maximize binding is entropically
disfavored. Peptide chemistry and early combinatorial
chemistry have generally focused on the solid-phase
assembly of linear chains of building blocks. However,
the conformational restrictions imposed within cyclic
peptides make them useful probes for the investigation
of biologically important systems.1 Small cyclic peptides
containing four to six amino acids have indeed the ability
to display key pharmacophoric groups in well-defined
three-dimensional orientation. Although these peptides
are less susceptible to proteolysis, their linkages may still
be labile in vivo. Peptidomemetics are generally designed
with the aim of retaining or increasing the biological
activity of the parent peptide while reducing metabolic
degradation. The incorporation of all carbon bridging
units into cyclic peptidomemetics can infer increased
metabolic stability and conformational rigidity.2 We were
interested in producing novel small macrocyclic com-
pounds of 15-18 ring size by using other building blocks
besides R amino acids and other reactions besides amide
bond construction. The new desired pharmacophore
template should contain some rigidifying elements but
The use of the ring-closing metathesis reaction3 for the
elaboration of macrocyclic ring systems has been devel-
oped by Fu¨rstner4 and rapidly adopted by other groups.5
Such macrocyclization reactions are noted for their mild
reaction conditions, wide functional group tolerance, and
the preference for cyclization over intermolecular side
reactions.3-4 We have ourselves recently employed alkene
cross-metathesis and ring-closing metathesis for the
(2) (a) Gante, J . Angew. Chem., Int. Ed. Engl. 1994, 33, 1699. (b)
Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244.
(c) Miller, S. J .; Blackwell, H. E.; Grubbs, R. H. J . Am. Chem. Soc.
1996, 118, 9606. (d) Blackwell, H. E.; Sadowsky, J . D.; Howard, R. J .;
Sampson, J . N.; Chao, J . A.; Steinmetz, W. E.; O’Leary, D. J .; Grubbs,
R. H. J . Org. Chem. 2001, 66, 5291. (e) Schafmeister, C. E.; Po, J .;
Verdine, G. L. J . Am. Chem. Soc. 2000, 122, 5891. (f) Creighton, C. J .;
Reitz, A. B. Org. Lett. 2001, 3, 893.
(3) For recent reviews on alkene metathesis, see: (a) Connon, S. J .;
Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900. (b) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (c) Fu¨rstner, A. Angew.
Chem., Int. Ed. 2000, 39, 3012. (d) Grubbs, R. H.; Chang, S. Tetrahe-
dron 1998, 54, 4413. (e) Armstrong, S. K. J . Chem. Soc., Perkin Trans.
1 1998, 371. (f) Ivin, K. J . J . Mol. Catal. A 1998, 133, 1. (g) Randall,
M. L.; Snapper, M. L. J . Mol. Catal. A 1998, 133, 29. (h) Gibson, S. E.;
Keen, S. P. Top. Organomet. Chem. 1998, 1, 155. (i) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036.
† Imperial College London.
‡ GlaxoSmithKline.
(1) (a) Lambert, J . N.; Mitchell, J . P.; Roberts, K. D. J . Chem. Soc.,
Perkin Trans. 1 2001, 471. (b) Belvisi, L.; Bernardi, A.; Checchia, A.;
Manzoni, L.; Potenza, D.; Scolastico, C.; Castorina, M.; Cupelli, A.;
Giannini, G.; Carminati, P.; Pisano, C. Org. Lett. 2001, 3, 1001. (c)
Decicco, C. P.; Song, Y.; Evans, D. A. Org. Lett. 2001, 3, 1029. (d)
Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W. D.
Tetrahedron 1997, 53, 12789.
10.1021/jo0352629 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/15/2004
1028
J . Org. Chem. 2004, 69, 1028-1037

Synthesis of Diverse Macrocyclic Peptidomimetics
SCHEME 1. Retr osyn th etic An a lysis of
Ma cr ocycle 1
F IGURE 1. Target macrocyclic templates.
elaboration of delicate bioactive molecules such as â-lac-
tams,6 glycosphingolipids,7 macrocyclic coronanes,8 and
hydroxyvitamin D2 derivatives.9 Consequently, we viewed
macrocyclization by this method as crucial in our syn-
thetic planning. Herein, we report the synthesis of
macrocycles 1 and 2 and demonstrate the potential of the
enhancement of diversity of 2 by functionalization of the
diene, ester, and iodide groups using both solution-phase
and polymer-supported parallel synthesis.
SCHEME 2. Syn th esis of
Meta th esis-Ma cr ocycliza tion P r ecu r sor 3
(4) (a) Fu¨rstner, A.; Langemann, K. J . Org. Chem. 1996, 61, 3942.
(b) Fu¨rstner, A.; Langemann, K. J . Org. Chem. 1996, 61, 8746. (c)
Fu¨rstner, A.; Langemann, K. J . Am. Chem. Soc. 1997, 119, 9130. (d)
Fu¨rstner, A.; Mu¨ller, T. J . Org. Chem. 1998, 63, 424. (e) Fu¨rstner, A.;
Gastner, T.; Weintritt, H. J . Org. Chem. 1999, 64, 2361. (f) Fu¨rstner,
A.; Mu¨ller, T. J . Am. Chem. Soc. 1999, 121, 7814. (g) Fu¨rstner, A.;
Seidel, G.; Kindler, N. Tetrahedron 1999, 55, 8215. (h) Fu¨rstner, A.;
A¨ıssa, C.; Riveiros, R.; Ragot, J . Angew. Chem., Int. Ed. 2002, 41, 4763.
(i) Fu¨rstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2003, 42, 308. (j)
Fu¨rstner, A.; J eanjean, F.; Razon, P.; Wirtz, C.; Mynott, R. Chem. Eur.
J . 2003, 9, 320.
(5) For applications including cyclic peptoids, see: (a) Bertinato, P.;
Sorensen, E. J .; Meng, D.; Danishefsky, S. J . J . Org. Chem. 1996, 61,
8000. (b) Nicolaou, K. C.; King, N. P.; He, Y. Top. Organomet. Chem.
1998, 1, 73. (c) Hoveyda, A. H. Top. Organomet. Chem. 1998, 1, 105.
(d) Miller, S. J .; Blackwell, H. E.; Grubbs, R. H. J . Am. Chem. Soc.
1996, 118, 9606. (e) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.;
Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1997, 36, 166. (f) Magnier,
E.; Langlois, Y. Tetrahedron Lett. 1998, 39, 837. (g) Irie, O.; Samizu,
K.; Henry, J . R.; Weinreb, S. M. J . Org. Chem. 1999, 64, 587. (h) Mohr,
B.; Weck, M.; Sauvage, J .-P.; Grubbs, R. H. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1308. (i) J oe, D.; Overman, L. E. Tetrahedron Lett.
1997, 38, 8635. (j) Prabhakaran, E. N.; Rajesh, V.; Dubey, S.; Iqbal, J .
Tetrahedron Lett. 2001, 42, 339. (k) Saha, B.; Das, D.; Banerji, B.; Iqbal,
J . Tetrahedron Lett. 2002, 43, 6467. (l) Banerji, B.; Bhattacharya, M.;
Madhu, B. R.; Das, S. K.; Iqbal, J . Tetrahedron Lett. 2002, 43, 6473.
(m) Banerji, B.; Mallesham, B.; Kiran Kumar, S.; Kunwar, A. C.; Iqbal,
J . Tetrahedron Lett. 2002, 43, 6479. (n) Sastry, T. V. R. S.; Banerji,
B.; Kirankumar, S.; Kunwar, A. C.; Das, J .; Nandy, J . P.; Iqbal, J .
Tetrahedron Lett. 2002, 43, 7621. (o) Boruah, A.; Rao, I. N.; Nandy, J .
P.; Kiran Kumar, S.; Kunwar, A. C.; Iqbal, J . J . Org. Chem. 2003, 68,
5006.
(6) (a) Barrett, A. G. M.; Ahmed, M.; Baker, S. P.; Baugh, S. P. D.;
Braddock, D. C.; Procopiou, P. A.; White, A. J . P.; Williams, D. J . J .
Org. Chem. 2000, 65, 3716. (b) Barrett, A. G. M.; Baugh, S. P. D.;
Braddock, D. C.; Flack, K.; Gibson, V. C.; Giles, M. R.; Marshall, E.
L.; Procopiou, P. A.; White, A. J . P.; Williams, D. J . J . Org. Chem. 1998,
63, 7893. (c) Barrett, A. G. M.; Baugh, S. P. D.; Gibson, V. C.; Giles,
M. R.; Marshall, E. L.; Procopiou, P. A. Chem. Commun. 1997, 155.
(d) Barrett, A. G. M.; Baugh, S. P. D.; Gibson, V. C.; Giles, M. R.;
Marshall, E. L.; Procopiou, P. A. Chem. Commun. 1996, 2231.
(7) (a) Barrett, A. G. M.; Beall, J . C.; Braddock, D. C.; Flack, K.;
Gibson, V. C.; Salter, M. M. J . Org. Chem. 2000, 65, 6508. (b) Ahmed,
M.; Barrett, A. G. M.; Beall, J . C.; Braddock, D. C.; Flack, K.; Gibson,
V. C.; Procopiou, P. A.; Salter, M. M. Tetrahedron 1999, 55, 3219.
(8) Barrett, A. G. M.; Hamprecht, D.; J ames, R. A.; Ohkubo, M.;
Procopiou, P. A.; Toledo, M. A.; White, A. J . P.; Williams, D. J . J . Org.
Chem. 2001, 66, 2187.
Resu lts a n d Discu ssion
Syn th esis of Ma cr ocycles 1 a n d 2. We initially
sought to synthesize the macrocycle 1 using the retrosyn-
thetic plan outlined in Scheme 1. This route should be
flexible and allow for access to a diverse set of macrocyclic
compounds by simple variation in the amino acid and
sulfonamide units. We considered that macrocyclization
using a ring-closing metathesis reaction of diene 3 should
provide the target cyclic peptidomimetic 1. In turn, diene
3 should be available from amine 5 and acid chloride 6
via the amide 4 and N-alkylation.
The synthesis of racemic diene 3, which is outlined in
Scheme 2, utilized standard amino acid chemistry and
hydrogenation of an intermediate dehydro-R-amido ester.
Aldehyde 7 was condensed with acetic anhydride and
N-benzoylglycine to provide the oxazolone 8.10 Deacetyl-
(9) Ahmed, M.; Atkinson, C. E.; Barrett, A. G. M.; Malagu, K.;
Procopiou, P. A. Org. Lett. 2003, 5, 669.
(10) Cornforth, S. J .; Ming-Hui, D. J . Chem. Soc., Perkin Trans. 1
1991, 2183.
J . Org. Chem, Vol. 69, No. 4, 2004 1029

Barrett et al.
F IGURE 2. Catalysts employed for macrocyclization of 3.
SCHEME 3. Rin g-Closin g Meta th esis of Dien e 3
F IGURE 3. Projected late-stage diversification of scaffold 2.
SCHEME 4. Syn th esis of Ma cr ocyclic P ep toid 2
ation and methanolysis gave the corresponding dehydro-
R-amido ester, which was hydrogenated over palladium
on carbon and O-allylated to provide benzamide 10.
Deacylation of amide 10 by formation of the imino
chloride and imidate and hydrolysis11 gave the corre-
sponding primary amine. This was directly acylated
using the acid chloride 6 and N-alkylated using the
sulfonamide 1112 to produce the target diene 3.
With precursor 3 in hand, its macrocyclization using
the ruthenium catalysts 12 and 13 (Figure 2) under
various high dilution conditions was examined (Scheme
3).4,8 Using catalyst 12,13 the optimum procedure was
found to be the slow syringe pump additions of the
catalyst 12 to a solution of the diene 3 in dichloromethane
at reflux. Under these conditions, the macrocyclic alkene
1 was formed in 69% yield as a mixture of cis and trans
isomers (3:1). Using the second-generation Grubbs cata-
lyst 13,14 the macrocyclization was accomplished under
milder conditions and gave the macrocyclic amide 1
(51%), which was isolated solely as the trans isomer.
Furthermore, when the 3:1 mix of isomers was allowed
to further react with catalyst 13 (5 mol %), rapid and
total isomerization to the trans isomer was observed.
Such isomerization is consistent with reversible ring-
closing metathesis with this catalyst.15
The synthesis of the enyne 19 and its subsequent
macrocyclization reaction to provide the second macro-
cyclic peptoid 2 are outlined in Scheme 4. Racemic
o-tyrosine 14 was converted into the amine hydrochloride
16 by sequential esterification, Boc protection,16 and
O-allylation. Subsequent acylation using acid chloride 6
gave amide 17, which was N-alkylated using the sul-
fonamide 18 to provide the enyne 19. The requisite
sulfonamide reagent 18 was, in turn, synthesized from
2-propynylamine and 4-iodobenzenesulfonyl chloride.
We have exploited the use of enyne metathesis3a,17-19
for the preparation of a diverse range of 6-, 7-, and
8-membered mono-, bi-, and tricyclic â-lactams in the
past, and with precursor 19 in hand, we anticipated that
such a ring closing enyne metathesis should provide the
target macrocycle 2.6b,20 These studies on the key enyne
With the elaboration of the 16-membered macro-
cycle 1 successfully accomplished, attention was directed
toward the second target macrocycle 2, which would
provide a versatile template for further late struc-
tural variation at the three points of diversity shown in
Figure 3.
(11) (a) Burk, M. J .; Allen, J . G. J . Org. Chem. 1997, 62, 7054. (b)
Daehne, W. V.; Frederiksen, E.; Gundersen, E.; Lund, F.; Mørch, P.;
Petersen, H. J .; Roholt, K.; Tybring, L.; Godtfredsen, W. O. J . Med.
Chem. 1970, 13, 607. (c) Weissenburger, H. W. O.; Van der Hoeven,
M. G. Recl. Trav. Chim. Pays-Bas 1970, 1081.
(12) Sanghavi, N. M.; Parab, V. L.; Patravale, B. S.; Patel, M. N.
Synth. Commun. 1989, 19, 1499.
(13) (a) Schwab, P.; France, M. B.; Ziller, J . W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039. (b) Schwab, P.; Grubbs, R. H.;
Ziller, J . W. J . Am. Chem. Soc. 1996, 118, 100.
(14) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953. (b) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1,
1751.
(15) (a) Smith, A. B., III; Adams, C. M.; Kozmin, S. A. J . Am. Chem.
Soc. 2001, 123, 990. (b) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L. Org.
Lett. 2001, 3, 449. (c) Lee, C. W.; Grubbs, R. H. Org. Lett. 2000, 2,
2145.
(16) Curtis, N. R.; Kulagowski, J . J .; Leeson, P. D.; Mawer, I. M.;
Ridgill, M. P.; Rowley, M.; Grimwood, S.; Marshall, G. R. Bioorg. Med.
Chem. Lett. 1996, 6, 1145.
(17) For the first reports, see: (a) Katz, T. J .; Sivavec, T. M. J . Am.
Chem. Soc. 1985, 107, 737. (b) Sivavec, T. M.; Katz, T. J .; Chiang, M.
Y.; Yang, G. X.-Q. Organometallics 1989, 8, 1620.
1030 J . Org. Chem., Vol. 69, No. 4, 2004

Synthesis of Diverse Macrocyclic Peptidomimetics
TABLE 1. Op tim iza tion of th e Ta n d em En yn e
Meta th esis-Cr oss-Meta th esis Ma cr ocycliza tion To
P r ovid e 2a
entry catalyst solvent
T (°C) ethylene
% 23
% 2
1
2
3
4
5
6
7
8
9
12
12
12
21
20
20
20
20
20
PhMe
60
40
40
40
no
no
yes
no
0
0
0
0
0
0
<5
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
CH2Cl2
PhMe
CH2Cl2
CH2Cl2
(CH2Cl)2 40
(CH2Cl)2 40
<5
<5
0
60-80 no
reflux no
60
reflux yes
23
<5
<5
yes
10 (32)b
30
15
25
10
27
12
yes
yes
yes
no
yes
yes
25 (45)b
32
10c 20
11
12
13
14
22
13
13
13
22 (60)b
<5 (65)c
35d
CH2Cl2
(CH2Cl)2 23
(CH2Cl)2 40
40
<5
56 (78)e
44
30
a
Reaction time was 24 h, ethylene bubbling continued until 19
b
was fully consumed (TLC), 10% catalyst employed. Percent of
recovered starting material. c 1 equiv of Ti(Oi-Pr)4 added. 23
d
recycled once to give a further 22% of 2. e Overall yield.
F IGURE 5.
Much to our delight, complete consumption of enyne 19
was observed after only 4 h reaction at room temperature
using catalyst 13 (entries 12-14),14 after which time
ethylene addition was discontinued. After a further 24 h
reaction, the products triene 23 and diene 2 were
separated. The side product triene 23 was subsequently
recycled to afford a further amount of macrocyclic product
2 (78% yield after one recycle). Increasing the reaction
temperature had a deleterious effect on the yield, and
the conditions employed in entry 13 were therefore used
for the synthesis of diene 2 on a multigram scale.
Significantly, 2 was isolated as the E-isomer and none
of the cis alkene isomer was detected.
On the basis of these results, it is reasonable to suggest
that the formation of diene 2 proceeds via the interme-
diacy of triene 23. Intermediate 23 may have arisen
either from an initial crossed enyne metathesis reaction
between 19 and ethylene or from diene 25 and ring-
opening metathesis with ethylene (Figure 5). Interest-
ingly, none of the typical enyne product 25 was isolated.
For this reason, we favor the higher probability of macro-
cyclization taking place through the formation of carbene
24, which undergoes rapid metathesis with ethylene to
provide triene 23. A subsequent slower ring-closing meta-
thesis of the allyl ether residue with the diene moiety in
23 occurs to provide the macrocycle 2.28 The formation
of 1,3-dienes from alkynes has precedent,19b,26 as have
reactions that proceed via tandem ROM-RCM pro-
cesses.27 During the course of our studies, Shair and Lee
have reported similar macrocyclization protocols.29
F IGURE 4. Additional catalysts examined for macrocycliza-
tion of enyne 19.
macrocyclization19 using the ruthenium catalysts 12, 13,
and 20 and the boomerang supported catalysts 21 and
22 are summarized in Table 1 and Figure 4. The Grubbs
catalyst 12 or its boomerang equivalent 21 were almost
completely inactive in catalyzing the crucial macrocy-
clization reaction (entries 1-4).13,21 The addition of eth-
ylene22 proved beneficial for macrocyclization reactions
using the catalyst 2023 and led to efficient conversion of
enyne 19 to triene 23 and diene 2 (entries 5-9) while
the addition of the mild Lewis acid titanium tetraisopro-
poxide24 (entry 10) or the use of the polymer-supported
version of the catalyst 2225 (entry 11) had little effect.
(18) For reviews on enyne metathesis, see: (a) Poulsen, C. S.;
Madsen, R. Synthesis 2003, 1. (b) Mori, M. Top. Organomet. Chem.
1998, 1, 133.
(19) For early intermolecular applications, see: (a) Stragies, R.;
Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2519.
(b) Kinoshita, A.; Sakakibara, N.; Mori, M. J . Am. Chem. Soc. 1997,
119, 12388. (c) Schu¨rer, S. C.; Blechert, S. Synlett 1998, 167. For early
intramolecular applications, see: (d) Kinoshita, A.; Mori, M. Synlett
1994, 1020. (e) Hammer, K.; Undheim, K. Tetrahedron 1997, 53, 10603.
(f) Kinoshita, A.; Mori, M. J . Org. Chem. 1996, 61, 8356. (g) Kinoshita,
A.; Mori, M. Heterocycles 1997, 46, 1375. (h) Kim, S.-H.; Zuercher, W.
J .; Bowden, N. B.; Grubbs, R. H. J . Org. Chem. 1996, 61, 1073. (i)
Codesido, E. M.; Castedo, L.; Granja, J . R. Org. Lett. 2001, 3, 1483. (j)
Yao, Q. Org. Lett. 2001, 3, 2069.
(20) Barrett, A. G. M.; Baugh, S. P. D.; Braddock, D. C.; Flack, K.;
Gibson, V. C.; Procopiou, P. A. Chem. Commun. 1997, 1375.
(21) Ahmed, M.; Barrett, A. G. M.; Braddock, D. C.; Cramp, S. M.;
Procopiou, P. A. Tetrahedron Lett. 1999, 40, 8657.
(22) Mori, M.; Sakakibara, N.; Kinoshita, A. J . Org. Chem. 1998,
63, 6082.
(23) (a) Scholl, M.; Trnka, T. M.; Morgan, J . P.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 2247. (b) Huang, J .; Stevens, E. D.; Nolan,
S. P.; Petersen, J . L. J . Am. Chem. Soc. 1999, 121, 2674. (c) Fu¨rstner,
A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J .; Nolan, S. P. J . Org.
Chem. 2000, 65, 2204.
(24) Fu¨rstner, A.; Langemann, K. J . Am. Chem. Soc. 1997, 119,
9130.
(26) (a) Kinoshita, A.; Sakakibara, N.; Mori, M. Tetrahedron 1999,
55, 8155. (b) Smulik, J . A.; Diver S. T. Org. Lett. 2000, 2, 2271. (c)
Smulik, J . A.; Diver, S. T. J . Org. Chem. 2000, 65, 1788. (d) Lee, H.-
Y.; Kim, B. G.; Snapper, M. L. Org. Lett. 2003, 5, 1855.
(27) (a) Kitamura, T.; Mori, M. Org. Lett. 2001, 3, 1161. (b) Ru¨ckert,
A.; Eisele, D.; Blechert, S. Tetrahedron Lett. 2001, 42, 5245.
(28) (a) Cabrejas, L. M. M.; Rohrbach, S.; Wagner, D.; Kallen, J .;
Zenke, G.; Wagner, J . Angew. Chem., Int. Ed. Engl. 1999, 38, 2443.
(b) Wagner, J .; Cabrejas, L. M. M.; Grossmith, C. E.; Papageorgiou,
C.; Senia, F.; Wagner, D.; France, J .; Nolan, S. P. J . Org. Chem. 2000,
65, 9255.
(29) Layton, M. E.; Morales, C. A.; Shair, M. D. J . Am. Chem. Soc.
2002, 124, 773. Hansen, E. C.; Lee, D. J . Am. Chem. Soc. 2003, 125,
9582.
(25) Ahmed, M.; Arnauld, T.; Barrett, A. G. M.; Braddock, D. C.;
Procopiou, P. A. Synlett 2000, 1007.
J . Org. Chem, Vol. 69, No. 4, 2004 1031

Barrett et al.
rings, A and B, inclined by ca. 71°. The amide group is
rotated by ca. 20° out of the plane of ring A and the
olefinic group by ca. 63° out of that of ring B. A perhaps
unusual feature of the macrocycle geometry is the copla-
narity of the olefinic and vinylic groups [the torsional
twist about C(22)-C(23) is 179°]. This geometry, how-
ever, does not give rise to any apparent delocalization,
the C(22)-C(23) bond length being typical of a C(sp2)-
C(sp2) single bond and the overall pattern of bonding does
not differ significantly from that observed in other cyclic
systems where these two groups are appreciably rotated
with respect to each other.30 Although the amide and
olefinic groups are steeply inclined to each other (ca. 71°)
the distance from the amide N(10)-H hydrogen atom to
the C(21)dC(22) bond is too long for any N-H‚‚‚π
interaction [the shortest contact is to C(21) at 3.2 Å].
Indeed the only potential transannular interaction is an
N-H‚‚‚O hydrogen bond to O(19), but although the
N‚‚‚O distance of 2.99 Å is reasonable, the H‚‚‚O distance
(2.41 Å) is on the long side for any appreciable bonding
interaction.
F IGURE 6. NMR conformational studies of macrocycle 2.
With the macrocyclic template 2 accessible in sufficient
quantities, its further diversification using both solution-
and solid-phase chemistry was examined.
F u n ction a liza tion of Ma cr ocycle 2 in th e Solu tion
P h a se. As outlined in Figure 3, macrocycle 2 has three
key functional groups that are available for modification
and library synthesis: the diene, the ester, and the aryl
iodide. Diels-Alder reactions with the diene unit were
initially investigated (Scheme 5). Pleasingly, cycloaddi-
tion of diene 2 with N-phenylmaleimide 27 and tetra-
cyanoethylene provided adducts 28 (60%) and 31 (52%).
No apparent influence of the remote amino acid derived
chiral center was observed and both 28 and 31 were
obtained as 1:1 mixtures of endo-diastereoisomers. The
structures of these adducts were confirmed by 1- and 2-D
NMR studies. The aryl iodide functionality was appropri-
ate for palladium(0) catalyzed transformations. Thus, the
Diels-Alder adduct 28 was allowed to react under Suzuki
coupling31 with 3-nitrobenzeneboronic acid 29 to afford
the corresponding biphenyl 30 (76%). One of the diaste-
reoisomers of the adduct 30 was separated by chroma-
tography and subsequent crystallization and shown to
be the endo isomer by NOE analysis. Surprisingly,
although the Suzuki coupling reaction of iodide 28
proceeded uneventfully, the parent diene 2 failed to
undergo a similar coupling under a variety of conditions.
This was possibly due to binding of the diene unit to a
palladium(0) intermediate, thereby disfavoring catalytic
turnover. The ester group in macrocycle 2 was readily
transformed into the carboxylic acid 32 (87%) and
subsequently coupled to glycine methyl ester hydrochlo-
ride 35 to afford the dipeptide 33 (58%). The resultant
F IGURE 7. X-ray crystal structure of 26.
The constitution and conformation of the macrocyclic
product 2 in solution were confirmed by 2-D high field
(750 MHz) NMR studies (Figure 6). Hence, the observa-
tion of an ROE between 24Z-H and 22-H, but not to
21-H, as well as an NOE from 21-H to 25-H clearly
established the orientation of the double bond as the one
depicted in Figure 6. This orientation was expected due
to the steric interactions, which would have been involved
between 21-H and 24Z-H in the alternative orientation.
Many ROE’s, such as the transannular ROE observed
between 21-H and 4-H, can be used as restraints in
molecular modeling for generating preferred conforma-
tions. Furthermore, local regions of conformational pref-
erence could be identified, such as the coupling between
12′-H and 11-H (3J 11-12′ ) 2.5 Hz), indicating a preferred
gauche orientation between these two protons. Interest-
ingly, these NMR studies could not exclude the presence
of a given low percentage conformation in fast dynamic
exchange in solution. The cyclic nature of 2 combined
with the NMR restraints observed could be further
exploited to determine the possible low energy conforma-
tions of the macrocycle.
(30) For examples, see: (a) Hauptmann, H.; Mu¨hlbauer, G.; Walker,
N. P. C. Tetrahedron Lett. 1986, 27, 1315. (b) Ishihara, M.; Ohba, S.;
Saito, Y.; Shizuri, Y.; Yamaguchi, S.; Yamamura, S. Acta Crystallogr.
Sect. C 1987, 43, 2445. (c) Mori, M.; Okada, K.; Shimazaki, K.; Chuman,
T.; Kuwahara, S.; Kitahara, T.; Mori, K. J . Chem. Soc., Perkin Trans.
1 1990, 1769.
(31) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457. (b) Suzuki, A. J . Organomet. Chem. 1999, 576, 147. (c)
Miyaura, N. Advances in Metal-Organic Chemistry; Liebeskind, L.
S., Ed.; J AI: London, 1998; Vol. 6, p 187. (d) Suzuki, A. Metal Catalyzed
Cross-Coupling Reactions; Diederich, F., Stang, P. J ., Eds.; Wiley-
VCH: New York, 1998; Chapter 2. (e) Stanforth, S. P. Tetrahedron
1998, 54, 263.
The solid-state structure of 2 was determined from a
single-crystal X-ray study of the corresponding 4-ni-
trobenzyl ester 26 and is illustrated in Figure 7. The
central 17-membered macrocycle has a distinctly puck-
ered and self-filling conformation with its two phenyl
1032 J . Org. Chem., Vol. 69, No. 4, 2004

Synthesis of Diverse Macrocyclic Peptidomimetics
SCHEME 5. Diver sifica tion of th e Ma cr ocyclic Tem p la te in th e Solu tion P h a se
ester 33 was in turn saponified to provide 34, thereby
constituting a single amino acid extension of the macro-
cyclic scaffold and exploiting a further point of diversity.
Reduction of ester 2 to its corresponding alcohol 36 was
also readily carried out using lithium borohydride albeit
in modest unoptimized yield (45%). Having demonstrated
that all three key diversification reactions of the macro-
cyclic template 2 were possible, attention was directed
toward related solid-supported syntheses.
40, 41, and 43 in excellent yields and reasonable purities
(Figure 9). In this manner, cycloadducts 40, 41, and 43
Diver sifica tion of th e Ma cr ocycle 2 Usin g Solid -
Su p p or ted Syn th esis. Carboxylic acid 32 was im-
mobilized onto Wang resin using coupling conditions32
with 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole in the
presence of N-methylimidazole. This gave resin 37 with
a modest loading level (0.41 mmol/g) (Figure 8). In
F IGURE 8. Immobilization of the macrocyclic template on
solid support.
contrast, carbodiimide-coupling reactions proved ineffec-
tive as a method of attachment to the Wang resin,
presumably due to steric hindrance suppressing the
reactivity of the intermediate. Representative Diels-
Alder reactions were carried out on resin 37 using a 10-
fold excess of dienophile and subsequent mild cleavage
from the support using trifluoroacetic acid in dichlo-
romethane (1:9). This provided the Diels-Alder products
F IGURE 9. Diversification of the macrocyclic template by
solid-phase synthesis.
were obtained as 1:1 mixtures of diastereoisomers as
established by 1H NMR spectroscopy. As a representative
example of palladium(0)-catalyzed coupling of the aryl
iodide, a Sonogashira coupling reaction33 was successfully
undertaken. Thus, the resin 37 was allowed to react with
the dienophile N-phenylmaleimide followed by 2-propyn-
(32) Blankemeyer-Menge, B.; Nimtz, M.; Frank, R. Tetrahedron Lett.
1990, 31, 1701.
J . Org. Chem, Vol. 69, No. 4, 2004 1033

Barrett et al.
(MgSO4), and rotary evaporated to give a yellow solid which
was recrystallized from PhMe to give sulfonamide 1112 (6.7 g,
58%) as colorless needles: 1H NMR (300 MHz, CDCl3) δ 7.85
(d, J ) 8.5 Hz, 2H), 7.52 (d, J ) 8.5 Hz, 2H), 5.67-5.80 (m,
1H), 5.12-5.23 (m, 2H), 4.57 (br s, 1H), 3.62-3.67 (m, 2H).
NaH (7.5 mg, 0.19 mmol) was added to sulfonamide 11 (65
mg, 0.28 mmol) in dry DMF (1 mL) and the mixture was
stirred until homogeneous. Chloride 4 (78 mg, 0.19 mmol) in
DMF (2 mL) was added dropwise and stirring continued for
20 h. The mixture was poured into H2O (10 mL), extracted
with CH2Cl2 (20 mL), and the combined organic extracts were
rotary evaporated. The resultant oily residue was chromato-
graphed (hexanes/EtOAc 2:1) to yield amide 3 (76 mg, 66%)
as a colorless foam: Rf ) 0.34 (hexanes/EtOAc 1:1); IR 1740,
1-ol in the presence of Pd(PPh3)2Cl2 and copper(I) iodide.
Subsequent cleavage using trifluoroacetic acid gave
alkyne 42 in excellent overall yield.
The potential for further solid-phase diversification of
the macrocyclic template was demonstrated by converting
acid 32 into acid 34 and subsequently coupling the latter
to Wang resin to provide resin 38a . More conveniently,
acid 32 was directly linked to commercial preloaded
glycine-Wang resin through a peptide coupling reaction
using PyBop and HOBt, which gave resin 38b with a
superior loading.34 In the same way, the carboxylic acid
32 was immobilized on commercial RINK amide resin to
provide resin 39. Subsequent cleavage of resins 38b and
39 using trifluoroacetic acid gave acid 34 (65%) and
amide 44 (72%) in good yields and purities, indicating
that these resins are suitable for further solid-phase
synthesis.
1
1657, 1605 cm-1; H NMR (300 MHz, CDCl3) δ 7.79 (d, J )
8.5 Hz, 2H), 7.33-7.76 (m, 6H), 7.03-7.08 (m, 2H), 6.47-6.50
(m, 2H), 6.01-6.09 (m, 1H), 5.40-5.50 (m, 3H), 5.29 (dd, J )
10.5, 1.0 Hz, 1H), 5.04-5.11 (m, 2H), 4.86 (q, J ) 6.5 Hz, 1H),
4.59 (d, J ) 5.0 Hz, 2H), 4.37 (s, 2H), 3.79 (s, 3H), 3.76 (s,
3H), 3.20 (d, J ) 5.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
172.4, 166.7, 160.1, 157.4, 139.2, 138.8, 136.3, 134.4, 132.9,
131.62, 131.55, 129.5, 128.8, 128.6, 127.3, 126.4, 120.1, 117.8,
117.2, 105.3, 105.3, 100.1, 69.4, 55.4, 54.3, 52.3, 50.0, 49.8, 31.7;
MS (CI) m/z 630 (M + NH4)+, 613 (M + H)+; HRMS (FAB)
calcd for C31H34ClN2O7S (M + H)+ 613.1800, found 613.1795.
Con clu sion
In conclusion, we have demonstrated the power of ring-
closing metathesis in the synthesis of polyfunctional
macrocyclic peptoid alkenes and dienes. Both 16- and 17-
membered ring systems were prepared, respectively,
using a diene RCM and an enyne tandem CM-RCM
process. The diversification of diene 2 was accomplished
using solution and solid-phase synthesis and thereby
demonstrated the potential to prepare libraries of ana-
logues of this template.
Met h yl 17-((4-Ch lor op h en yl)su lfon yl)-9-m et h oxy-2-
o x o -12-o x a -3,17-d ia za t r ic y c lo (17.3.1.06 ,1 1 ]t r ie ic o s a -
1(23),6,8,10,14,19,21-h ep ta en e-4-ca r boxyla te (1). (a ) Syn -
th esis Usin g Ca ta lyst 12. Separate solutions of Grubbs
catalyst 12 (2.7 mg, 0.0003 mmol) in CH2Cl2 (3 mL) and diene
3 (50 mg, 0.82 mmol) in CH2Cl2 (3 mL) were added over 5 h
via syringe pumps to CH2Cl2 (30 mL) at reflux. Reflux was
maintained for an additional 24 h when the mixture was rotary
evaporated. The residue was chromatographed (hexanes/
EtOAc 1:1) to yield macrocycle 1 (33 mg, 69%) as a chromato-
graphically inseparable 3:1 mixture of trans and cis isomers
as a white solid. Data for major (trans) isomer: mp 131-135
Exp er im en ta l Section
Meth yl N-(3-(N-(2-P r op en -1-yl)(4-ch lor op h en yl)su lfon -
a m id om eth yl)ben zoyl)-O -m eth yl-2-(2-p r op en -1-yloxy)-
tyr osin a te (3). K2CO3 (33 mg, 0.24 mmol) and chloride 6 (34
µL, 0.24 mmol) were added to amine 5 (60 mg, 0.24 mmol) in
dry CH2Cl2 (6 mL). The mixture was stirred at room temper-
ature for 20 h, filtered through Celite, and rotary evaporated.
Chromatography (CH2Cl2/EtOAc 9:1) gave amide 4 (81 mg,
81%) as a colorless oil: Rf ) 0.51 (CH2Cl2/EtOAc 9:1); 1H NMR
(300 MHz, CDCl3) δ 7.38-7.74 (m, 4H), 7.05-7.10 (m, 2H),
6.46-6.49 (m, 2H), 6.00-6.09 (m, 1H), 5.54 (dd, J ) 17.3, 1.0
Hz, 1H), 5.30 (d, J ) 10.0 Hz, 1H), 4.87 (q, J ) 6.5 Hz, 1H),
4.57-4.61 (m, 4H), 3.80 (s, 3H), 3.77 (s, 3H), 3.21 (d, J ) 6.5
Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 172.3, 166.6, 160.1,
156.8, 137.9, 132.8, 131.7, 131.6, 128.9, 127.3, 127.0, 117.8,
117.3, 105.2, 100.1, 69.4, 55.4, 54.4, 52.3, 45.6, 31.6; MS (CI)
m/z 418 (M + H)+, 384, 379, 366, 313, 256; HRMS (CI) calcd
for C22H25ClNO5 (M + H)+ 418.1427, found 418.1421. The
crude amide 4 was used directly in the next step without
further purification. Allylamine (3.75 mL, 50 mmol) was added
to 4-ClC6H4SO2Cl (10.6 g, 50 mmol) and K2CO3 (6.91 g, 50
mmol) in CH2Cl2 (60 mL). After the mixture was stirred for 3
h, H2O (13 mL) and 10% aqueous HCl (25 mL) were added.
The organic phase was separated, successively washed with
10% aqueous HCl, saturated NaHCO3, and H2O, dried
°C; Rf ) 0.32 (hexanes/EtOAc 1:1); IR 1730, 1643 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 7.84 (d, J ) 8.5 Hz, 2H), 7.74 (d, J
) 8.0 Hz, 1H), 7.52-7.58 (m, 3H), 7.42-7.44 (m, 2H), 7.36 (d,
J ) 6.5 Hz, 1H), 7.06 (d, J ) 8.5 Hz, 1H), 6.45 (dd, J ) 8.5,
2.0 Hz, 1H), 6.35 (d, J ) 2.0 Hz, 1H), 5.46 (dt, J ) 15.5, 6.0
Hz, 1H), 5.80 (dt, J ) 15.5, 6.5 Hz, 1H), 4.74 (dt, J ) 9.5, 3.0
Hz, 1H), 4.58 (d, J ) 14.0 Hz, 1H), 4.45 (dd, J ) 12.0, 6.5 Hz,
1H), 4.31 (dd, J ) 13.0, 6.0 Hz, 1H), 4.40 (d, J ) 14.0 Hz, 1H),
3.80-3.88 (m, 1H), 3.76 (s, 3H), 3.74-3.76 (m, 1H), 3.70 (s,
3H), 3.17 (dd, J ) 14.0, 9.5 Hz, 1H), 3.07 (dd, J ) 14.0, 3.0
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 171.8, 167.7, 160.1,
156.8, 139.5, 135.1, 134.6, 132.5, 132.4, 130.8, 129.7, 129.5,
129.1, 128.6, 128.2, 128.1, 127.1, 117.4, 105.3, 99.5, 68.5, 55.6,
55.4, 52.4, 52.2, 50.4, 31.6; MS (CI) m/z 585 (M + H)+; HRMS
(CI) calcd for
C
29H30ClN2O7S (M + H)+ 585.1462, found
585.1473. (b) Syn th esis Usin g Ca ta lyst 13. Catalyst 13 (28
mg, 0.033 mmol) in CH2Cl2 (10 mL) was added to diene 3 (87
mg, 0.16 mmol) in CH2Cl2 (70 mL). After overnight stirring at
room temperature, the mixture was rotary evaporated and the
residue was chromatographed (hexanes/EtOAc 1:1) to yield
1
macrocycle 1 (49 mg, 51%) as a white solid. H and 13C NMR
spectra were consistent with the product 1 consisting solely
of the trans isomer. (c) Z to E Isom er iza tion of Ma cr ocycle
1 Usin g Ca ta lyst 13. Catalyst 13 (0.6 mg, 0.0007 mmol) in
CD2Cl2 (0.7 mL) was added to macrocycle 1 (E/Z ) 3:1) (8.5
mg, 0.015 mmol) in an NMR tube. 1H NMR spectra were
recorded periodically and complete isomerization to the trans
isomer was observed to have taken place after 2 h.
(33) (a) Sonogashira, K. In Metal Catalyzed Cross-Coupling Reac-
tions; Diederich, F., Stang, P. J ., Eds.; Wiley-VCH: New York, 1998;
Chapter 5. (b) Brandsma, L.; Vasilevsky, S. F.; Verkruijsse, H. D.
Application of Transition Metal Catalysts in Organic Synthesis;
Springer-Verlag: Berlin, 1998; Chapter 10. (c) Rossi, R.; Carpita, A.;
Bellina, F. Org. Prep. Proced. Int. 1995, 27, 127. (d) Sonogashira, K.
In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon:
New York, 1991; Vol. 3, Chapter 2.4.
(34) (a) Fre´rot, E.; Coste, J .; Pantaloni, A.; Dufour, M.-N.; J ouin, P.
Tetrahedron 1991, 47, 259. (b) Coste, J .; Le-Nguyen, D.; Castro, B.
Tetrahedron Lett. 1990, 31, 205. (c) Behrendt, R.; Renner, C.; Schenk,
M.; Wang, F.; Wachtveitl, J .; Oesterhelt, D.; Moroder, L. Angew. Chem.,
Int. Ed. 1999, 38, 2771. (d) Coste, J .; Fre´rot, E.; J ouin, P. J . Org. Chem.
1994, 59, 2437.
Meth yl N-(3-(N-(2-P r op yn -1-yl)(4-iod op h en yl)su lfon a -
m id om eth yl)ben zoyl)(2-(2-p r op en -1-yloxy)p h en yl)a la n i-
n a te (19). Using the same procedure as for the synthesis of
3, 19 (327 mg, 87%) was obtained as a colorless foam: Rf )
1
0.56 (hexanes/EtOAc 1:1); IR 1734, 1658 cm-1; H NMR (300
MHz, CDCl3) δ 7.90-7.93 (m, 2H), 7.60-7.68 (m, 4H), 7.51-
7.54 (m, 1H), 7.39-7.41 (m, 1H), 7.16-7.36 (m, 3H), 6.95-
1034 J . Org. Chem., Vol. 69, No. 4, 2004

Synthesis of Diverse Macrocyclic Peptidomimetics
6.97 (m, 2H), 6.01-6.10 (m, 1H), 5.41-5.48 (m, 1H), 5.26-
5.28 (m, 1H), 4.80-4.91 (m, 1H), 4.64-4.66 (m, 2H), 4.37 (s,
2H), 3.92 (s, 2H), 3.76 (s, 3H), 3.28 (d, J ) 6.5 Hz, 2H), 2.05 (t,
J ) 2.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 172.3, 166.7,
156.4, 138.4, 138.3, 135.1, 134.6, 133.0, 132.0, 131.3, 129.3,
129.0, 128.8, 127.5, 127.0, 125.1, 121.4, 117.7, 112.4, 100.5,
75.6, 74.9, 69.4, 54.3, 52.4, 49.7, 35.9, 32.2; MS (FAB) m/z 673
(M + H)+; HRMS (FAB) calcd for C30H30IN2O6S (M + H)+
673.0869, found 673.0858. Anal. Calcd for C30H29IN2O6S: C,
53.58; H, 4.35; N, 4.17. Found: C, 53.38; H, 4.45; N, 4.26.
Met h yl
(1S,24R,28S)-20-((4-Iod op h en yl)su lfon yl)-
13,25,27-tr ioxo-26-ph en yl-3-oxa-12,20,26-tr iazapen tacyclo-
[20.6.1.114,18.04,9.024,28]t r ia con t a -4,6,8,14(30),15,17,22(29)-
h ep ta en e-11-ca r boxyla te (28). N-Phenylmaleimide 27 (72
mg, 0.42 mmol) and diene 2 (190 mg, 0.28 mmol) in ClCH2-
CH2Cl (0.5 mL) were heated at 40 °C for 48 h. Rotary
evaporation and chromatography (hexanes/EtOAc 1:1) gave
imide 28 (140.7 mg, 60%), a 1:1 mixture of diastereoisomers,
as a white solid: mp 145-150 °C (hexanes-EtOAc); Rf ) 0.25
(hexanes/EtOAc 1:1); IR 1738, 1642 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.92-7.95 (m, 2H), 7.74-7.87 (m, 2H), 7.60 (d, J )
8.5 Hz, 1H), 7.56 (d, J ) 8.5 Hz, 1H), 7.35-7.50 (m, 5H), 7.16-
7.26 (m, 4H), 6.98-7.12 (m, 3H), 5.98 (br s, 0.5H), 5.78 (br s,
0.5 H), 5.15-5.18 (m, 0.5H), 4.41-4.64 (m, 1.5H), 4.27-4.38
(m, 1H), 4.00-4.12 (m, 1.5H), 3.73 (s, 1.5H), 3.70-3.73 (m,
0.5H), 3.67 (s, 1.5H), 3.30-3.40 (m, 4.5H), 3.14-3.27 (m, 1H),
3.04 (dd, J ) 14.0, 1.5 Hz, 0.5H), 2.85 (br s, 0.5H), 2.64 (d, J
) 15.5 Hz, 0.5H), 2.54 (d, J ) 15.0 Hz, 0.5H), 2.20 (br s, 0.5H),
1.80-1.85 (m, 0.5 H), 1.06-1.11 (m, 0.5H); 13C NMR (125 MHz,
CDCl3) δ 177.7, 177.6, 176.2, 176.1, 172.2, 171.2, 167.9, 166.6,
157.3, 156.8, 139.5, 138.7, 137.9, 136.9, 136.7, 136.5, 135.3,
134.6, 134.0, 132.7, 132.1, 131.9, 131.6, 131.5, 130.7, 130.0,
129.7, 129.6, 129.3, 129.2, 129.1, 128.92, 128.86, 128.75, 128.6,
128.5, 128.1, 127.0, 126.9, 126.3, 126.2, 123.3, 122.7, 100.4,
100.2, 117.5, 114.4, 73.4, 71.5, 56.0, 55.8, 54.1, 53.3, 53.1, 52.4,
52.2, 42.0, 41.7, 39.9, 37.3, 36.8, 32.6, 31.1, 26.8, 26.0; MS
(FAB) m/z 846 (M + H)+, 786, 663, 557, 551; HRMS (FAB)
calcd for C40H37IN3O8S (M + H)+ 846.1346, found 846.1381.
Meth yl 18-((4-Iod op h en yl)su lfon yl)-16-m eth ylid en e-2-
oxo-12-oxa -3,18-d ia za t r icyclo[18.3.1.06,11]t e t r a e icosa -
1(24),6,8,10,14,20,22-h ep ta en e-4-ca r boxyla te (2). Ethylene
was bubbled through catalyst 13 (52 mg, 0.060 mmol) in
ClCH2CH2Cl (40 mL). After 15 min, 19 (0.40 g, 0.60 mmol) in
ClCH2CH2Cl (40 mL) was added. Maintaining ethylene bub-
bling, the mixture was stirred for 4 h at room temperature
until enyne 19 was consumed (TLC). The ethylene bubbling
was stopped, the mixture stirred for a further 24 h and filtered
through silica. Rotary evaporation and chromatography (hex-
anes/EtOAc 2:1) gave 2 (228 mg, 56%) as a white solid and 23
(145 mg, 35%) as an oil. Triene 23 (145 mg, 0.21 mmol) in
ClCH2CH2Cl (10 mL) was allowed to react with catalyst 13
(18 mg, 0.021 mmol) in ClCH2CH2Cl (10 mL), and the mixture
was stirred under N2 for 24 h to afford a further amount of
macrocycle 2 (90 mg, 22%, 78% overall yield) after chroma-
tography. Triene 23: Rf ) 0.55 (hexanes/EtOAc 1:1); IR 1737,
1
1652, 1522 cm-1; H NMR (400 MHz, CDCl3) δ 7.82 (d, J )
8.5 Hz, 2H), 7.41-7.62 (m, 3H), 7.14-7.35 (m, 6H), 6.87-7.09
(m, 3H), 6.18 (dd, J ) 18.0, 11.0 Hz, 1H), 5.99-6.08 (m, 1H),
5.44 (d, J ) 1.5 Hz, 1H), 5.40 (d, J ) 1.5 Hz, 1H), 5.26-5.30
(m, 2H), 4.89-5.06 (m, 2H), 4.60 (dd, J ) 3.5, 1.0 Hz, 2H),
4.28-4.35 (m, 2H), 3.97 (d, J ) 15.5 Hz, 1H), 3.89 (d, J ) 15.5
Hz, 1H), 3.75 (s, 3H), 3.25 (d, J ) 7.0 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 172.3, 166.6, 156.5, 139.5, 139.1, 138.4, 136.5,
136.0, 133.9, 133.0, 131.4, 131.3, 128.7, 128.6, 128.5, 127.2,
126.2, 125.0, 121.3, 119.1, 117.7, 115.6, 112.2, 100.0, 69.3, 54.0,
52.3, 51.0, 49.6, 32.3; MS (FAB) m/z 701 (M + H)+, 400, 267;
HRMS (FAB) calcd for C32H34IN2O6S (M + H)+ 701.1182, found
701.1207. Diene 2: mp 119-122 °C (EtOAc); Rf ) 0.40
(hexanes/EtOAc 1:1); IR 1739, 1653, 1497 cm-1; 1H NMR (750
MHz, CDCl3) δ 7.89 (d, J ) 8.0 Hz, 2H), 7.59 (s, 1H), 7.56 (d,
J ) 8.0 Hz, 2H), 7.44 (d, J ) 6.5 Hz, 1H), 7.24-7.29 (m, 2H),
7.19 (dd, J ) 7.5, 2.0 Hz, 1H), 7.14-7.17 (m, 1H), 6.97 (t, J )
7.5 Hz, 1H), 6.93 (d, J ) 7.5 Hz, 1H), 6.55 (dt, J ) 16.0, 6.5
Hz, 1H), 6.19 (d, J ) 16.0 Hz, 1H), 5.18 (s, 1H), 5.11 (s, 1H),
4.76-4.81 (m, 1H), 4.51-4.53 (m, 2H), 4.21 (br d, J ) 13.5
Hz, 1H), 4.14 (d, J ) 13.5 Hz, 1H), 4.12 (br d, J ) 13.5 Hz,
1H), 3.84 (d, J ) 13.5 Hz, 1H), 3.69 (s, 3H), 3.33 (dd, J ) 14.5,
9.0 Hz, 1H), 3.30 (dd, J ) 14.5, 2.5 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 171.7, 168.4, 156.3, 139.2, 138.6, 137.2, 136.6,
135.0, 134.1, 131.8, 130.9, 128.8, 128.5, 128.3, 127.8, 126.5,
126.0, 125.4, 123.3, 121.5, 111.6, 100.6, 69.5, 55.7, 53.4, 52.4,
52.1, 32.12; MS (FAB) m/z 673 (M + H)+, 495, 371; HRMS
(FAB) calcd for C30H30IN2O6S (M + H)+ 673.0869, found
673.0870. Anal. Calcd for C30H29IN2O6S: C, 53.58; H, 4.35; N,
4.17. Found: C, 53.49; H, 4.17; N, 4.06. On a larger scale,
ethylene was bubbled through catalyst 13 (260 mg, 0.31 mmol)
in ClCH2CH2Cl (250 mL). After 25 min, 19 (3.50 g, 5.20 mmol)
in ClCH2CH2Cl (250 mL) was added. Maintaining ethylene
bubbling, the mixture was stirred for 5.5 h at room temper-
ature until enyne 19 was consumed (TLC). The ethylene
bubbling was stopped, and the mixture was stirred for a
further 24 h and filtered through silica. Rotary evaporation
and chromatography (hexanes/EtOAc 2:1) gave 2 (1.28 g, 37%)
as a white solid and 23 (1.74 g, 48%) as an oil. Triene 23 (1.74
g, 2.48 mmol) in ClCH2CH2Cl (100 mL) was allowed to react
with catalyst 13 (100 mg, 0.12 mmol) in ClCH2CH2Cl (100 mL),
and the mixture was stirred under N2 for 24 h to afford a
further amount of macrocycle 2 (870 mg, 25%, 62% overall
yield) after chromatography.
Meth yl (1S,24R,28S)-20-((3′-Nitr o-4-bip h en ylyl)su lfo-
n y l)-13,25,27-t r i o x o -26-p h e n y l-3-o x a -12,20,26-t r i -
a za p en ta cyclo[20.6.1.114,18.04,9.024,28]tr ia con ta -4,6,8,14(30),-
15,17,22(29)-h ep ta en e-11-ca r boxyla te (30). Iodide 28 (140.7
mg, 0.17 mmol), Pd(dppf)Cl2 (7 mg, 0.0083 mmol), K3PO4 (106
mg, 0.50 mmol) and 3-nitrophenylboronic acid 29 (33.6 mg,
0.18 mmol) in dry degassed DME (1.2 mL) were allowed to
react at room temperature for 24 h. H2O (5 mL) and CH2Cl2
(20 mL) were added, and the organic layer was separated,
dried (Na2SO4), and rotary evaporated. Chromatography (hex-
anes/EtOAc 1:1) gave imide 30 (103.0 mg, 76%), a 1:1 mixture
of diastereoisomers, as a white solid: mp 148-150 °C (hex-
anes-EtOAc); Rf ) 0.15 (hexanes/EtOAc 1:1); IR 1741, 1705,
1
1525 cm-1; H NMR (400 MHz, CDCl3) δ 8.49 (d, J ) 7.5 Hz,
1H), 8.27-8.30 (m, 1H), 7.95-8.03 (m, 3H), 7.81-7.86 (m, 3H),
7.75 (d, J ) 7.5 Hz, 0.5H), 7.66-7.71 (m, 1H), 7.53 (d, J ) 7.5
Hz, 0.5H), 7.36-7.50 (m, 4.5H), 7.17-7.32 (m, 4.5H), 7.08-
7.14 (m, 1H), 6.97-7.05 (m, 2H), 5.99 (br s, 0.5H), 5.81 (br s,
0.5H), 5.14-5.18 (m, 0.5H), 4.69-4.72 (m, 1H), 4.51-4.56 (m,
1H), 4.41 (t, J ) 10.5 Hz, 0.5H), 4.31 (dd, J ) 10.0, 3.0 Hz,
0.5H), 4.27 (d, J ) 9.5 Hz, 0.5H), 4.11-4.19 (m, 1H), 4.05 (d,
J ) 14.5 Hz, 0.5H), 3.79 (d, J ) 14.5 Hz, 0.5H), 3.73 (s, 1.5H),
3.67 (s, 1.5H), 3.53 (d, J ) 14.5 Hz, 0.5H), 3.42 (dd, J ) 14.0,
3.0 Hz, 0.5H), 3.28-3.29 (m, 2H), 3.14-3.25 (m, 1.5H), 3.04
(d, J ) 13.5 Hz, 0.5H), 2.87 (br s, 0.5H), 2.64 (d, J ) 15.5 Hz,
0.5H), 2.54 (d, J ) 14.5 Hz, 0.5H), 2.20 (br s, 0.5H), 1.80-
1.86 (m, 0.5H), 1.06-1.16 (m, 0.5H); 13C NMR (100 MHz,
CDCl3) δ 177.7, 177.6, 176.2, 176.1, 172.2, 171.2, 167.9, 166.7,
157.2, 156.8, 148.8, 143.2, 143.1, 140.9, 140.8, 139.7, 138.2,
137.0, 136.8, 136.4, 135.4, 134.5, 133.9, 133.24, 133.19, 132.7,
132.2, 131.9, 131.6, 131.5, 130.2, 130.1, 129.9, 129.7, 129.6,
129.3, 129.2, 129.1, 128.9, 128.8, 128.7, 128.4, 128.2, 128.1,
128.03, 127.99, 127.1, 127.0, 126.9, 126.3, 126.2, 123.3, 123.2,
122.7, 122.3, 117.7, 114.4, 73.4, 71.5, 56.1, 55.9, 54.1, 53.4, 53.0,
52.4, 52.2, 51.4, 42.0, 41.7, 39.9, 39.8, 37.3, 36.8, 32.6, 32.1,
26.8, 26.0; MS (FAB) m/z 841 (M + H)+, 663; HRMS (FAB)
calcd for C46H41N4O10S (M + H)+ 841.2543, found 841.2515.
Recrystallization from hexanes and EtOAc gave one diaste-
reoisomer of imide 30 (29 mg, 21%) as colorless crystals: mp
1
147-149 °C (hexanes-EtOAc); H NMR (500 MHz, CDCl3) δ
8.49 (t, J ) 2.0 Hz, 1H), 8.30 (ddd, J ) 8.0, 2.0, 1.0 Hz, 1H),
7.81-8.00 (m, 3H), 7.81-7.87 (m, 4H), 7.70 (t, J ) 8.0 Hz, 1H),
7.43-7.50 (m, 3H), 7.35-7.40 (m, 2H), 7.17-7.23 (m, 4H), 7.08
J . Org. Chem, Vol. 69, No. 4, 2004 1035

Barrett et al.
(dd, J ) 7.5, 1.5 Hz, 1H), 7.04 (d, J ) 7.5 Hz, 1H), 6.99 (t, J )
7.5 Hz, 1H), 6.00 (br s, 1H), 5.20 (m, 1H), 4.71 (d, J ) 14.5
Hz, 1H), 4.41 (t, J ) 10.5 Hz, 1H), 4.32 (dd, J ) 10.5, 3.0 Hz,
1H), 4.18 (d, J ) 13.5 Hz, 1H), 3.73 (d, J ) 14.5 Hz, 1H), 3.67
(s, 3H), 3.43 (dd, J ) 17.5, 3.0 Hz, 1H), 3.35 (d, J ) 13.5 Hz,
1H), 3.15-3.21 (m, 3H), 2.70 (d, J ) 15.5 Hz, 1H), 2.20 (br s,
1H), 1.06-1.16 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 177.7,
176.2, 171.2, 166.6, 157.3, 148.8, 143.2, 140.9, 138.7, 138.2,
137.0, 136.8, 134.0, 133.2, 132.7, 131.9, 131.5, 130.2, 130.0,
129.4, 129.1, 128.9, 128.8, 128.22, 128.19, 128.1, 127.1, 126.9,
126.3, 123.3, 122.3, 117.6, 73.4, 56.1, 54.1, 53.4, 52.1, 41.7, 39.9,
37.3, 32.6, 26.8.
successively with 1 M NaOH (10 mL), 1 M HCl (10 mL), and
H2O (10 mL), dried (Na2SO4), and rotary evaporated. The
product was chromatographed (hexanes/EtOAc 2:1) to give
ester 26 (35 mg, 52%) as a white solid: mp 120-122 °C
(hexanes-EtOAc); Rf ) 0.45 (hexanes/EtOAc 1:1); IR 1746,
1
1657, 1516 cm-1; H NMR (400 MHz, CDCl3) δ 8.17 (d, J )
8.5 Hz, 2H), 7.91 (d, J ) 8.5 Hz, 2H), 7.67 (d, J ) 8.0 Hz, 1H),
7.62-7.64 (m, 2H), 7.55 (d, J ) 8.0 Hz, 2H), 7.42 (d, J ) 8.5
Hz, 2H), 7.23-7.28 (m, 2H), 7.12 (t, J ) 6.0 Hz, 2H), 6.93 (d,
J ) 8.5 Hz, 1H), 6.82 (t, J ) 7.5 Hz, 1H), 6.63 (dt, J ) 16.0,
6.5 Hz, 1H), 6.11 (d, J ) 16.0 Hz, 1H), 5.04-5.30 (m, 4H),
4.82-4.87 (m, 1H), 4.51 (d, J ) 6.5 Hz, 2H), 4.12 (dd, J ) 7.0,
3.0 Hz, 2H), 3.99 (d, J ) 4.5 Hz, 2H), 3.29-3.49 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 170.9, 168.7, 156.2, 147.6, 142.9,
139.1, 138.7, 137.0, 136.8, 134.9, 134.4, 131.9, 130.7, 129.0,
128.8, 128.4, 128.3, 127.7, 126.3, 125.9, 125.1, 123.8, 123.5,
121.5, 111.6, 100.7, 69.8, 65.2, 56.1, 53.8, 52.5, 32.2; MS (FAB)
m/z 794 (M + H)+, 391; HRMS (FAB) calcd for C36H33IN3O8S
18-((4-Iod op h en yl)su lfon yl)-16-m eth ylid en e-2-oxo-12-
oxa -3,18-d ia za t r icyclo[18.3.1.06,11]t et r a eicosa -1(24),6,8,-
10,14,20,22-h eptaen e-4-car boxylic Acid (32). Aqueous LiOH
(1 M; 0.094 mL, 0.095 mmol) was added to ester 2 (58.1 mg,
0.086 mmol) in THF (1 mL). After 4 h at room temperature,
the mixture was neutralized with 1 M HCl and extracted with
CH2Cl2 (2 × 20 mL). The combined organic extracts were dried
(Na2SO4) and rotary evaporated to give carboxylic acid 32 (49.0
mg, 87%) as a white solid: mp 215-220 °C dec; IR 1722, 1671,
(M + H)+ 794.1033, found 794.1056. Anal. Calcd for C36H32
-
IN3O8S: C, 54.48; H, 4.06; N, 5.29. Found: C, 54.57; H, 3.97;
N, 5.16. Crystal data: C36H32N3O8SI‚0.5C4H8O2, M ) 837.7,
triclinic, P1h (no. 2), a ) 9.0425(14) Å, b ) 9.2131(10) Å, c )
23.544(3) Å, R ) 90.965(14)°, â ) 95.791(12)°, γ ) 95.601(14)°,
V ) 1941.4(4) Å3, Z ) 2, Dc ) 1.433 g cm-3, µ(Cu KR) ) 7.46
mm-1, T ) 183 K, colorless blocks; 5756 independent measured
reflections, F2 refinement, R1 ) 0.101, wR2 ) 0.254, 4132
independent observed absorption corrected reflections [|Fo| >
4σ(|Fo|), 2θmax ) 120°], 502 parameters.
1
1650, 1581 cm-1; H NMR (400 MHz, acetone-d6) δ 8.06 (d, J
) 8.5 Hz, 2H), 7.70-7.76 (m, 3H), 7.56-7.60 (m, 1H), 7.49 (d,
J ) 6.0 Hz, 1H), 7.20-7.32 (m, 4H), 7.07 (d, J ) 8.0 Hz, 1H),
6.94 (d, J ) 7.5 Hz, 1H), 6.63 (dt, J ) 16.0, 6.5 Hz, 1H), 6.24
(d, J ) 16.0 Hz, 1H), 5.34 (s, 1H), 5.11 (s, 1H), 4.52-4.68 (m,
3H), 4.20-4.34 (m, 2H), 4.06 (d, J ) 9.0 Hz, 2H), 3.33 (dd, J
) 14.0, 5.0 Hz, 1H), 3.25 (dd, J ) 14.0, 3.0 Hz, 1H); 13C NMR
(100 MHz, acetone-d6) δ 172.5, 168.4, 157.4, 140.7, 139.6, 138.8,
138.3, 136.0, 135.2, 132.5, 130.7, 130.1, 129.5, 128.8, 127.8,
127.0, 126.9, 126.7, 123.9, 122.0, 112.7, 101.0, 71.2, 56.6, 53.9,
52.9, 32.6; MS (FAB) m/z 659 (M + H)+, 391; HRMS (FAB)
calcd for C29H28IN2O6S (M + H)+ 659.0713, found 659.0733.
Anal. Calcd for C29H27IN2O6S: C, 52.90; H, 4.13; N, 4.25.
Found: C, 52.98; H, 4.02; N, 4.30.
Resin 37. 1-Methylimidazole (15 µL, 0.19 mmol) and
carboxylic acid 32 (30 mg, 0.046 mmol) in CH2Cl2 (0.5 mL)
were added to 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole
(14 mg, 0.047 mmol), and the resulting mixture was added to
Wang resin (26 mg, 0.58 mmol/g, 0.015 mmol). The mixture
was shaken under an argon atmosphere for 24 h, washed
alternately with CH2Cl2 (3×) and MeOH (3 ×), and dried
overnight at 40 °C in vacuo. The excess carboxylic acid could
be recovered from the washings by chromatography (CH2Cl2/
AcOH 1:4). The loading of resin 37 was determined by weight
increase to be approximately 0.41 mmol/g. A portion of the
starting carboxylic acid was cleaved from the resin by shaking
the beads in TFA in CH2Cl2 (1:9) for 10 min. The resin was
filtered off, and the filtrate was rotary evaporated to yield 32
(>95% recovered yield) with spectroscopic data identical to that
obtained for the starting material.
Meth yl N-((18-((4-Iodoph en yl)su lfon yl)-16-m eth yliden e-
2-oxo-12-oxa -3,18-d ia za t r icyclo[18.3.1.06,11]t et r a eicosa -
1(24),6,8,10,14,20,22-h eptaen -4-yl)car bon yl)glycin ate (33).
Et3N (5 µL, 0.037 mmol) was added to acid 32 (29 mg, 0.034
mmol) in CH2Cl2 (0.3 mL). After 15 min, isobutyl chloroformate
(5 µL, 0.037 mmol) in CH2Cl2 (0.1 mL) was added dropwise at
-15 °C, and the mixture was stirred at this temperature for
30 min. Et3N (6 µL, 0.041 mmol) and MeO2CCH2NH3Cl 35 (4.3
mg, 0.034 mmol) were successively added, and the reaction
mixture was allowed to warm to room temperature overnight.
H2O (1 mL) and CH2Cl2 (10 mL) were added, and the organic
layer was separated, dried (Na2SO4), and rotary evaporated.
The residual solid was chromatographed (hexanes/EtOAc 2:1)
to yield amide 33 (15 mg, 58%) as a white solid: mp 95-98
°C (hexanes-EtOAc); Rf ) 0.35 (hexanes/EtOAc 1:1); IR 1745,
(1S,24R,28S)-20-((4-Iod op h en yl)su lfon yl)-13,25,27-tr i-
o x o -2 6 -p h e n y l -3 -o x a -1 2 ,2 0 ,2 6 -t r i a z a p e n t a c y c l o -
[20.6.1.114,18.04,9.024,28]t r ia con t a -4,6,8,14(30),15,17,22(29)-
h ep ta en e-11-ca r boxylic Acid (40). A mixture of resin 37
(50.1 mg, 0.062 mmol) and N-phenylmaleimide 27 (107 mg,
0.62 mmol) in ClCH2CH2Cl (1.0 mL) was shaken at 40 °C for
48 h. The resin was filtered off, washed alternately with CH2-
Cl2 (3×) and MeOH (3×), and dried overnight at 40 °C in
vacuo. The carboxylic acid product was cleaved from the resin
by shaking the beads with TFA (0.2 mL) in CH2Cl2 (2 mL) for
10 min. The resin was filtered off, and the filtrate was rotary
evaporated to yield crude acid 40 (13 mg, 92%), a 1:1 mixture
of diastereoisomers, as a white solid: mp 190-198 °C dec; IR
1722, 1633 cm-1; 1H NMR (400 MHz, acetone-d6) δ 8.04-8.07
(m, 2H), 7.64-7.82 (m, 4H), 7.52-7.62 (m, 0.5H), 7.45-7.52
(m, 1H), 7.31-7.44 (m, 6H), 7.15-7.19 (m, 3.5H), 7.11 (d, J )
8.0 Hz, 0.5H), 6.98 (t, J ) 7.5 Hz, 0.5H), 6.31 (br s, 0.5H), 5.85
(br s, 0.5H), 4.97-5.00 (m, 0.5H), 4.69 (d, J ) 15.0 Hz, 0.5H),
4.60 (dd, J ) 10.5, 2.5 Hz, 0.5H), 4.41-4.56 (m, 1.5H), 4.31
(dd, J ) 9.5, 3.0 Hz, 0.5H), 4.25 (d, J ) 15.0 Hz, 0.5H), 4.16
(d, J ) 13.5 Hz, 0.5H), 4.10 (d, J ) 14.0 Hz, 0.5H), 3.88 (d, J
) 15.0 Hz, 0.5H), 3.36-3.56 (m, 3.5H), 3.21-3.33 (m, 1H), 3.11
(dd, J ) 13.5, 2.5 Hz, 1H), 2.44-2.60 (m, 1.5H), 1.94-2.31 (m,
1H), 1.08-1.14 (m, 0.5H); 13C NMR (125 MHz, acetone-d6) δ
178.9, 177.4, 173.0, 172.3, 167.55, 167.48, 167.1, 167.0, 158.43,
158.38, 141.3, 139.6, 139.5, 139.4, 138.6, 137.3, 136.5, 135.5,
135.4, 133.6, 132.9, 133.0, 132.4, 132.1, 131.7, 131.6, 129.9,
129.8, 129.7, 129.6, 129.5, 129.4, 129.2, 129.05, 129.00, 128.8,
1
1655, 1522 cm-1; H NMR (400 MHz, CDCl3) δ 7.88 (d, J )
8.5 Hz, 2H), 7.69 (d, J ) 7.5 Hz, 1H), 7.51-7.55 (m, 4H), 7.19-
7.29 (m, 4H), 6.91-6.97 (m, 3H), 6.51 (dt, J ) 16.0, 6.0 Hz,
1H), 6.18 (d, J ) 16.0 Hz, 1H), 5.18 (s, 1H), 5.15 (s, 1H), 4.65-
4.70 (m, 1H), 4.56 (dd, J ) 12.5, 6.0 Hz, 1H), 4.46 (dd, J )
12.5, 6.5 Hz, 1H), 4.21 (d, J ) 15.5 Hz, 1H), 3.93-4.06 (m,
5H), 3.69 (s, 1H), 3.43 (dd, J ) 14.0, 10.0 Hz, 1H), 3.18 (dd, J
) 14.0, 3.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 171.4, 170.0,
169.0, 156.2, 139.2, 138.6, 137.1, 136.7, 134.5, 133.6, 132.1,
131.4, 128.8, 128.6, 128.4, 127.8, 126.4, 125.9, 123.37, 123.36,
121.7, 111.7, 100.7, 69.6, 57.2, 53.2, 52.3, 52.1, 41.2, 31.6; MS
(FAB) m/z 730 (M + H)+, 641, 613; HRMS (FAB) calcd for
C
32H33IN3O7S (M + H)+ 730.1084, found 730.1117.
(4-Nitr op h en yl)m eth yl 18-((4-Iod op h en yl)su lfon yl)-
1 6 -m e t h y l i d e n e -2 -o x o -1 2 -o x a -3 ,1 8 -d i a z a t r i c y c l o -
[18.3.1.06 ,1 1 ]-t e t r a e i c o s a -1(24),6,8,10,14,20,22-h e p -
ta en e-4-ca r box-yla te (26). 1-Methylimidazole (13 µL, 0.16
mmol) was added to acid 32 (57 mg, 0.086 mmol) in CH2Cl2 (1
mL). Upon complete dissolution of 32, 1-(mesitylene-2-sulfo-
nyl)-3-nitro-1,2,4-triazole (25 mg, 0.084 mmol) and 4-nitroben-
zyl alcohol (8.6 mg, 0.056 mmol) were added. After 24 h,
CH2Cl2 (20 mL) was added, and the mixture was washed
1036 J . Org. Chem., Vol. 69, No. 4, 2004

Synthesis of Diverse Macrocyclic Peptidomimetics
128.7, 128.6, 128.5, 128.4, 128.3, 127.9, 127.74 127.71, 122.9,
118.0, 115.5, 100.6, 100.4, 74.4, 72.7, 56.9, 54.9, 54.7, 53.8, 53.5,
51.4, 42.9, 42.7, 41.01, 40.98, 38.0, 37.4, 32.9, 32.3, 27.5, 26.7;
MS (ES+) m/z 854 (M + Na)+, 832 (M + H)+.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
conditions and characterization data for 8, 9, methyl (Z)-2-
benzamido-3-(2-hydroxy-4-methoxyphenyl)propenoate, methyl
2-benzamido-3-(2-hydroxy-4-methoxyphenyl)propanoate, 10, 5,
methyl 3-(2-hydroxyphenyl)-2-aminopropanoate hydrochloride,
15, methyl 2-((tert-butyloxycarbonyl)amino)-3-(2-(2-propen-1-
yloxy)phenyl)propanoate, 16-18, 31, 34, 36, and 41-44.
Ack n ow led gm en t. We thank GlaxoSmithKline Re-
search Ltd. for support of our research and for the
generous endowment (to A.G.M.B.), the EPSRC for
grant support, the postdoctoral program of the DAAD
(German Academic Exchange Service) (to S.S.), the
Royal Society, and the Wolfson Foundation for a Royal
Society-Wolfson Research Merit Award (to A.G.M.B.)
and for establishing the Wolfson Centre for Organic
Chemistry in Medical Sciences at Imperial College
London.
1
Copies of H and 13C spectra for 1-3, 23, 28, 30, 31, 33, 34,
36, 40-44 and methyl 3-(2-(2-propen-1-yloxy)phenyl)-2-tert-
butyloxycarbonylaminopropanoate. COSY, ROESY, and HMQC
spectra for 2; NOESY, COSY, and HMQC spectra for 30; and
X-ray crystallographic data for 26. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O0352629
J . Org. Chem, Vol. 69, No. 4, 2004 1037