Skeletal diversity by allylation/RCM on Ugi four-component coupling reaction products

Article abstract of DOI:10.1016/j.tetlet.2006.04.098

Here, we report a diversity-oriented synthetic approach toward skeletally diverse, cyclized peptidomimetics with diverse appendages. Starting from α-(N-acylamino)amides with various appendages, 12 to 16-membered lactams with defined olefin geometry were s

Full text of DOI:10.1016/j.tetlet.2006.04.098

Tetrahedron Letters 47 (2006) 4763–4767
Skeletal diversity by allylation/RCM on Ugi four-component
coupling reaction products
Masato Oikawa,* Shinya Naito and Makoto Sasaki
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku University, Tsutsumidori-Amamiya,
Aoba-ku, Sendai 981-8555, Japan
Received 27 February 2006; revised 11 April 2006; accepted 14 April 2006
Available online 19 May 2006
Abstract—Here, we report a diversity-oriented synthetic approach toward skeletally diverse, cyclized peptidomimetics with diverse
appendages. Starting from a-(N-acylamino)amides with various appendages, 12 to 16-membered lactams with defined olefin geo-
metry were synthesized by a common synthetic sequence. We also synthesized the macrocycle in a liquid phase directed toward
a construction of the peptidomimetics library.
Ó 2006 Elsevier Ltd. All rights reserved.
Biologically functional small molecules play a central
role in the study of chemical biology and/or chemical
genetics.1 While useful molecules have been usually
found in natural resources, efforts have been also paid
in these studies to use a synthetic small molecules
library, which is readily accessible by diversity-oriented
organic synthesis (DOS).2 The major concern in DOS,
recently, is to develop an efficient methodology for
acquisition of skeletal diversity in the library construc-
tion employing a split-pool technology to raise not only
the quantity but also the quality of the small molecules
library.3–5
introduction of olefins, reactive in the cyclization step
after the Ugi reaction, which produces only the append-
age-based diversity; our approach thus enables realiza-
tion of a small molecules library with both skeletal
and appendage-based diversities.
The substrates used in this study were prepared by Ugi
four-component coupling reaction between amine, alde-
hyde, carboxylic acid, and isocyanide.12 As had been
already reported, the reaction proceeded quite smoothly
by employing 2,2,2-trifluoroethanol as a solvent,13 to
give a-(N-acylamino)amides in good to excellent yields
(Fig. 1). Another advantage of this solvent is that the
undesired transesterification between the ethyl ester
and 2,2,2-trifluoroethanol, which frequently takes place
when methanol is used as a solvent, was not observed at
all and the Ugi products were obtained quite cleanly.
One biologically important class of artificial small mole-
cules is peptidomimetics which mimic unique secondary
motifs of peptide, such as loop or turn structures, to
modulate the interactions at protein/receptor or pro-
tein/protein.6,7 Synthetic works on conformationally
constrained, cyclized peptidomimetics for reverse turn
motifs have been actively studied both in solution8 and
solid phases,7 and ring-closing metathesis (RCM) reac-
tion has been recently paid considerable attention for
the cyclization of peptides.9,10 However, there is no
report describing the acquisition of skeletal diversity
by DOS for these cyclized peptidomimetics. In this
letter, we report our approach toward this by RCM as
a key reaction starting from Ugi four-component cou-
pling reaction products.11 This is the first example for
With the desired a-(N-acylamino)amides 1–6 in hand,
we first explored the construction of 12-membered lac-
tam triamide (Scheme 1). As expected from our previous
study,5 alkylation of the amide 1 with allyl iodide was
smoothly effected by employing Cs2CO3 in DMF
(86%). The use of allyl bromide was much less effective
(70%). To the acrylamide moiety was then added allyl-
amine at 40 °C (83%), and the resultant secondary
amine was sulfonylated with TsCl in 100% yield to give
the diallylated precursor for metathesis cyclization.
Finally, by using 20 mol % of the second generation
Hoveyda–Grubbs catalyst (Fig. 2)14 at 80 °C in 1,2-
dichloroethane, the desired lactam triamide 7 was
obtained in 85% yield after 44 h with complete trans
*
Corresponding author. Tel./fax: +81 22 717 8827; e-mail: mao@
bios.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.098

4764
M. Oikawa et al. / Tetrahedron Letters 47 (2006) 4763–4767
Br
Br
Br
O
O
O
N
H
N
H
Br
N
H
O
N
O
N
O
N
Br
HN
Br
N
H
O
Br
Br
O
1 (92%)
2 (82%)
3 (87%)
Br
O
O
O
OEt
OEt
Br
N
H
N
H
N
H
O
N
O
O
N
O
Br
O
N
Br
NH
Br
N
H
O
O
Br
4 (86%)
5 (95%)
6 (95%)
Figure 1. Ugi four-component coupling products used in the present study. In parentheses are yields, and the colored moieties are common skeleton
for the Ugi product.
1
selectivity as judged from H NMR and LC–MS analy-
Br
ses.15 It should be noted that other acyl groups can be
introduced to the intermediary secondary amines gener-
ated by the conjugate addition of allylamine to gain the
appendage-based diversity.
O
N
N
O
a-d
Larger macrocycles were obtained by bisallylation stra-
tegy (Scheme 2). In these cases, the Ugi products 2–4
bearing two p-bromoanilides were treated with allyl
iodide and Cs2CO3 in DMF at rt to afford the diallylated,
metathesis precursors in 74–97% yields. Ring-closing
metathesis of these precursors proceeded at 60–83 °C
in moderate yields; 67% for 13-membered 8, 74% for
14-membered 9, and 71% for 15-membered 10, lactam
1
N
S
Br
O
O
Me
7 (trans/cis = >20 : 1)
Scheme 1. Reagents and conditions: (a) allyl iodide, Cs2CO3, DMF, rt,
1 h, 86%, (b) allylamine, ethanol, 40 °C, 36 h, 83%, (c) TsCl,
triethylamine, 1,2-dichloroethane, 0 °C, 30 min, 100%, (d) second
generation Hoveyda–Grubbs catalyst (20 mol %), 1,2-dichloroethane,
80 °C, 44 h, 85%.
Br
O
N
N
O
a, b
2
3
4
n
N
Br
O
N
N
Cl
Cl
Br
Ru
8 (from 2, n = 1, trans:cis = 1 : >20)
9 (from 3, n = 2, trans:cis = 1 : >20)
10 (from 4, n = 3, trans:cis = >20 : 1)
O
Scheme 2. Reagents and conditions: (a) allyl iodide, Cs2CO3, DMF, rt,
1.5 h, 86% from 2, 74% from 3, and 97% from 4, (b) second generation
Hoveyda–Grubbs catalyst (30 mol %), 1,2-dichloroethane, 67% for 8
(83 °C, 80 h), 74% for 9 (60 °C, 48 h), and 71% for 10 (60 °C, 42 h).
Figure 2. The second generation Hoveyda–Grubbs catalyst14 used in
the present study.

M. Oikawa et al. / Tetrahedron Letters 47 (2006) 4763–4767
4765
triamides with cis, cis, and trans geometries, respec-
O
O
tively.15 The size of the macrocycle with unique olefin
geometry can be thus easily controlled by the choice of
the dicarboxylic acid monoamide.
NH
O
N
O
a-c
Fifteen-membered lactam tetramide was constructed
from the Ugi product 5 bearing acrylamide and ethyl
ester functionalities (Scheme 3). Treatment of 5 with
allylamine in ethanol induced conjugate addition at rt,
which was followed by amidation at the ester moiety
at a higher temperature (50 °C) in one-pot operations,
furnishing the diallylated product in 66% yield. After
the secondary amine thus generated was again sulfonyl-
ated with TsCl (85%), the metathesis cyclization was
realized quite smoothly by employing 25 mol % of the
Hoveyda–Grubbs catalyst, to afford the 15-membered
lactam tetramide 11 with cis-olefin in good yield
(89%).15 Because the reactivity of the acrylamide and
ester functionalities toward allylamine is much different,
different amines can be introduced to these positions by
which different size of macrocycles would be accessible
by these reaction sequences.
6
HN
Br
N
Br
12 (trans/cis = 5 : 1)
Scheme 4. Reagents and conditions: (a) allyl iodide, Cs2CO3, DMF, rt,
24 h, 39%, (b) allylamine, ethanol, 40 °C, 36 h, 91%, (c) second
generation Hoveyda–Grubbs catalyst (20 mol %), 1,2-dichloroethane,
60 °C, 8 h, 62%.
onstration shows the usefulness of the incorporation of
the anilide into a polyamide as a r-element,3,16 different
appendages that pre-encode skeletal information, for the
selective chemical modification in order to gain the skel-
etal diversity.
The last example is the construction of 16-membered
tetramide from the Ugi product 6 (Scheme 4). Since 6
contains two amide protons, selective allylation of the
anilide functionality over the alkyl amide should be
achieved, and this was realized by the combination of
allyl iodide and Cs2CO3, as used in other cases for 1–
4, in low yield (39%) but with complete selectivity. Other
decomposed products were also detected but not charac-
terized. After amidation of the ethyl ester with allyl-
amine in 91% yield, the diallylated cyclization precursor
was treated with 20 mol % of the Hoveyda–Grubbs
catalyst at 60 °C to give the 16-membered tetramide 12
in acceptable yield (62%) and selectivity (trans/cis =
5:1).15 It should be also noted here that the selective
N-allylation of the anilide moiety in the presence of
two other monoalkyl amides was also possible in the
inversed-mode sequence, where amidation of the ester
moiety was done (99%) prior to N-allylation (42%),
for the synthesis of the metathesis substrate. This dem-
From the successful experiments shown above, the con-
struction of the small molecules library comprising the
skeletally diverse tri- and tetraamide macrocycles with
appendage diversity was then expected by the common
reaction sequence in the order of Ugi reaction, N-sulf-
onylation, 1,4-conjugate addition, amidation, N-acyl-
ation, and ring-closing metathesis. As a preliminary
study toward this goal, we examined the liquid-phase
synthesis of the 15-membered lactam tetramide on
poly(ethylene glycol) monomethyl ether (MPEG-OH)
of MW 5000.17 Among three linkers developed by us
for the high-throughput synthesis with the MPEG poly-
mer,18,19 a formylacetal linker19 was employed in the
present study because of the stability under alkaline con-
ditions. At first, 3-(2-hydroxyethoxy)benzaldehyde was
loaded onto the platform 13 (0.186 mmol/g) by using
iodine monochloride (Scheme 5). The polymer was
collected by the addition of diethyl ether in 100%
(weight-based recovery), and the conversion yield for
14 was determined to be also 100% from 1H NMR.
To the aldehyde 14 was successively effected the reaction
sequence including Ugi reaction, 1,4-conjugate addition,
amidation, N-sulfonylation, and ring-closing metathesis
to furnish the tetramide macrocycle 15 in 61% yield for
four steps. Finally, the small molecule was released from
the polymer on exposure to trifluoroacetic acid in
CH2Cl2 to give the 15-membered lactam tetramide 16
in 98% isolated yield with excellent olefin geometrical
selectivity (trans/cis = 1:>20).15 The purity of 16 was
found reasonable (44%) from LC–MS analysis.
O
NH
N
O
O
HN
a-c
5
O
O
N
Br
S
In summary, we have developed a new DOS process,
which features three types of introduction of allyl
groups to the Ugi four-component coupling reaction
products followed by RCM reaction, for skeletally
diverse cyclized peptidomimetics with diverse append-
ages. We also demonstrated the synthesis of the macro-
cycle in liquid phase. Work is in progress to construct
Me
11 (trans/cis = 1 : >20)
Scheme 3. Reagents and conditions: (a) allylamine, ethanol,
rt ! 50 °C, 36 h, 66%, (b) TsCl, triethylamine, 1,2-dichloroethane,
0 °C, 30 min, 85%, (c) second generation Hoveyda–Grubbs catalyst
(25 mol %), 1,2-dichloroethane, 60 °C, 20 h, 89%.

4766
M. Oikawa et al. / Tetrahedron Letters 47 (2006) 4763–4767
Opin. Chem. Biol. 2005, 9, 248–258; Wessjohann, L. A.;
O
a
SMe
Ruijter, E. Strategies for total and diversity-oriented
synthesis of natural product(-like) macrocycles. In Natural
Products Synthesis I: Targets Methods Concepts; Springer-
Verlag Berlin: Berlin, 2004; Vol. 243, pp 137–184; Arya,
P.; Joseph, R.; Gan, Z. H.; Rakic, B. Chem. Biol. 2005, 12,
163–180.
MPEG
O
O
O
CHO
MPEG
13
(0.186 mmol/g)
14
3. Burke, M. D.; Berger, E. M.; Schreiber, S. L. Science 2003,
302, 613–618; Burke, M. D.; Schreiber, S. L. Angew.
Chem. Int. Ed. 2004, 43, 46–58; Burke, M. D.; Berger, E.
M.; Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 14095–
14104.
4. For our efforts in this field, see: Oikawa, M.; Ikoma, M.;
Sasaki, M. Tetrahedron Lett. 2005, 46, 415–418.
5. Oikawa, M.; Ikoma, M.; Sasaki, M. Tetrahedron Lett.
2005, 46, 5863–5866.
6. Freidinger, R. M. Trends Pharmacol. Sci. 1989, 10, 270–
274; Kolter, T.; Klein, A.; Giannis, A. Angew. Chem. Int.
Ed. Engl. 1992, 31, 1391–1392; Nesloney, C. L.; Kelly, J.
W. Bioorg. Med. Chem. 1996, 4, 739–766; Gillespie, P.;
Cicariello, J.; Olson, G. L. Biopolymers 1997, 43, 191–217;
Freidinger, R. M. Curr. Opin. Chem. Biol. 1999, 3, 395–
406.
O
O
O
MPEG
O
NH
O
N
O
b-e
HN
N
S
O
15
O
Me
HO
O
7. Souers, A. J.; Ellman, J. A. Tetrahedron 2001, 57, 7431–
7448.
8. Gurrath, M.; Muller, G.; Kessler, H.; Aumailley, M.;
Timpl, R. Eur. J. Biochem. 1992, 210, 911–921; Schumann,
F.; Muller, A.; Koksch, M.; Muller, G.; Sewald, N. J. Am.
Chem. Soc. 2000, 122, 12009–12010.
O
NH
N
O
O
f
HN
9. Miller, S. J.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117,
5855–5856; Miller, S. J.; Blackwell, H. E.; Grubbs, R. H.
J. Am. Chem. Soc. 1996, 118, 9606–9614; Reichwein, J. F.;
Wels, B.; Kruijtzer, J. A. W.; Versluis, C.; Liskamp, R. M.
J. Angew. Chem. Int. Ed. 1999, 38, 3684–3687; Reichwein,
J. F.; Versluis, C.; Liskamp, R. M. J. J. Org. Chem. 2000,
65, 6187–6195; Bijani, C.; Varray, S.; Lazaro, R.; Marti-
nez, J.; Lamaty, F.; Kieffer, N. Tetrahedron Lett. 2002, 43,
3765–3767; Barrett, A. G. M.; Hennessy, A. J.; Vezouet,
R. L.; Procopiou, P. A.; Seale, P. W.; Stefaniak, S.;
Upton, R. J.; White, A. J. P.; Williams, D. J. J. Org.
Chem. 2004, 69, 1028–1037; Poirier, M.; Aubry, N.;
Boucher, C.; Ferland, J. M.; LaPlante, S.; Tsantrizos, Y.
S. J. Org. Chem. 2005, 70, 10765–10773; Kazmaier, U.;
Hebach, C.; Watzke, A.; Maier, S.; Mues, H.; Huch, V.
Org. Biomol. Chem. 2005, 3, 136–145.
N
S
16
(trans/cis = 1 : >20)
O
O
Me
Scheme 5. Reagents and conditions: (a) 3-(2-hydroxyethoxy)benz-
aldehyde, iodine monochloride, molecular sieves 4 A, CH2Cl2, 0 °C !
˚
rt, 80 min, 100%, (b) ethyl isocyanoacetate, acrylic acid, benzylamine,
CF3CH2OH, rt ! 50 °C, 72 h, 100%, (c) allylamine, CF3CH2OH,
ethanol, 50 °C, 20 h, 100%, (d) TsCl, triethylamine, CH2Cl2, 0 °C ! rt,
90 min, 61%, (e) second generation Hoveyda–Grubbs catalyst
(10 mol %), 1,2-dichloroethane, 60 °C, 35 h, 100%, (f) TFA/CH2Cl2
(3:7), rt, 4 h, 98% isolated yield, 44% purity. Yields were evaluated
from 1H spectra using a methyl group of the MPEG polymer as a
reference except for the step f.
10. For representatives for selective macrocyclic ring closure
by RCM, see: Furstner, A.; Langemann, K. J. Org. Chem.
1996, 61, 3942–3943; Lee, D.; Sello, J. K.; Schreiber, S. L.
J. Am. Chem. Soc. 1999, 121, 10648–10649; Lee, C. W.;
Grubbs, R. H. Org. Lett. 2000, 2, 2145–2147; Behbehani,
H.; Ibrahim, M. R.; Ibrahim, Y. A. Tetrahedron Lett.
2002, 43, 6421–6426; Deiters, A.; Martin, S. F. Chem. Rev.
2004, 104, 2199–2238.
the skeletally diverse peptidomimetics library by these
methodologies.
References and notes
11. For other reports on tandem Ugi/RCM reaction, see:
Hebach, C.; Kazmaier, U. Chem. Commun. 2003, 596–597;
Dietrich, S. A.; Banfi, L.; Basso, A.; Damonte, G.; Guanti,
G.; Riva, R. Org. Biomol. Chem. 2005, 3, 97–106.
12. Ugi, I. Angew. Chem. Int. Ed. Engl. 1959, 71, 386; Ugi, I.;
Steinbruckner, C. Angew. Chem. Int. Ed. Engl. 1960, 72,
267–268; Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000,
39, 3169–3210.
13. Kim, Y. B.; Choi, E. H.; Keum, G.; Kang, S. B.; Lee, D.
H.; Koh, H. Y.; Kim, Y. S. Org. Lett. 2001, 3, 4149–4152.
14. Purchased from Aldrich Co. (Catalog No. 569755):
Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda,
A. H. J. Am. Chem. Soc. 2000, 122, 8168–8179.
15. The geometrical selectivity in the RCM reaction is
generally controlled by the thermodynamic stability of
the macrocycle generated. Works are in progress toward
1. Schreiber, S. L. Bioorg. Med. Chem. 1998, 6, 1127–1152;
Crews, C. M.; Splittgerber, U. Trends Biochem. Sci. 1999,
24, 317–320; Stockwell, B. R. Trends Biotechnol. 2000, 18,
449–455; Stockwell, B. R. Nat. Rev. Genet. 2000, 1, 116–
125; Clemons, P. A.; Koehler, A. N.; Wagner, B. K.;
Sprigings, T. G.; Spring, D. R.; King, R. W.; Schreiber, S.
L.; Foley, M. A. Chem. Biol. 2001, 8, 1183–1195;
Blackwell, H. E.; Perez, L.; Stavenger, R. A.; Tallarico,
J. A.; Eatough, E. C.; Foley, M. A.; Schreiber, S. L. Chem.
Biol. 2001, 8, 1167–1182; Schreiber, S. L. Chem. Eng. News
2003, 81, 51–61.
2. Schreiber, S. L. Science 2000, 287, 1964–1969; Spring, D.
R. Org. Biomol. Chem. 2003, 1, 3867–3870; Liao, Y.; Hu,
Y. H.; Wu, H.; Zhu, Q.; Donovan, M.; Fathi, R.; Yang, Z.
Curr. Med. Chem. 2003, 10, 2285–2316; Tan, D. S. Nat.
Chem. Biol. 2005, 1, 74–84; Shang, S.; Tan, D. S. Curr.

M. Oikawa et al. / Tetrahedron Letters 47 (2006) 4763–4767
4767
the clear-cut explanation for these selectivities in our case
through library construction with the aid of computa-
tional support.
1917–1924, MPEG-OH of MW 5000 (average) was
purchased from Aldrich Co. (Catalog No. 20251-7).
18. Oikawa, M.; Ikoma, M.; Sasaki, M. Tetrahedron Lett.
2004, 45, 2371–2375; Oikawa, M.; Takeda, Y.; Sasaki, M.
Tetrahedron Lett. 2005, 46, 4667–4670.
16. Sello, J. K.; Andreana, P. R.; Lee, D. S.; Schreiber, S. L.
Org. Lett. 2003, 5, 4125–4127.
17. Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97, 489–
509; Wentworth, P.; Janda, K. D. Chem. Commun. 1999,
19. Oikawa, M.; Tanaka, T.; Kusumoto, S.; Sasaki, M.
Tetrahedron Lett. 2004, 45, 787–790.