ACS Combinatorial Science
Research Article
pentapeptide from the marine hydroid Gymnangium regae. J. Org.
Chem. 2004, 69, 3036−3042. (b) Balakrishnan, S.; Scheuermann, M.
J.; Zondlo, N. J. Arginine mimetics using α-guanidino acids:
Introduction of functional groups and stereochemistry adjacent to
recognition guanidiniums in peptides. ChemBioChem 2012, 13, 259−
270. (c) Balakrishnan, S.; Zhao, C.; Zondlo, N. J. Convergent and
stereospecific synthesis of molecules containing α-functionalized
guanidiniums via α-guanidino acids. J. Org. Chem. 2007, 72, 9834−
9837. (d) Suhs, T.; Burkhard, K. Synthesis of functionalized guanidino
amino acids. Chem.Eur. J. 2006, 12, 8150−8157. (e) Lal, B.;
Gangopadhyay, A. K. A practical synthesis of free and protected
guanidino acids from amino acids. Tetrahedron Lett. 1996, 37, 2483−
2486.
linkages. J. Chem. Soc. Chem. Commun. 1996, 22, 2509−2510. (b) Miel,
H.; Rault, S. Total deprotection of N,N′-bis(tert-butoxycarbonyl)-
guanidines using SnCl4. Tetrahedron Lett. 1997, 38, 7865−7866.
(c) Freeman, N. S.; Gilon, C. The use of tin(IV) chloride for mild and
selective Boc deprotection on TFA cleavable rink-amide MBHA resin.
Synlett 2009, 13, 2097−2100.
(28) A complex mixture of products was observed upon prolonged
exposure to Lewis acid.
(29) (a) Faucher, A.-M.; Bailey, M. D.; Beaulieu, P. L.; Brochu, C.;
Duceppe, J.-S.; Ferland, J.-M.; Ghiro, E.; Gorys, V.; Halmos, T.; Kawai,
S. H.; Poirier, M.; Simoneau, B.; Tsantrizos, Y. S.; Llinas-Brunet, M.
̀
Synthesis of BILN 2061, an HCV NS3 protease inhibitor with proven
antiviral effect in humans. Org. Lett. 2004, 6, 2901−2904.
(b) Dykhuizen, E. C.; May, J. F.; Tongpenyai, A.; Kiessling, L. L.
Inhibitors of UDP-galactopyranose mutase thwart mycobacterial
growth. J. Am. Chem. Soc. 2008, 130, 6706−6707.
(16) Terrett, N. K. Methods for the synthesis of macrocycle libraries
for drug discovery. Drug Discovery Today Technol. 2010, 7, e97−e104.
(17) Driggers, E. M.; Hale, S. P.; Lee, J.; Terrett, N. K. The
exploration of macrocycles for drug discoveryAn underexploited
structural class. Nat. Rev. Drug Discovery 2008, 7, 608−624.
(30) For the synthesis of macrocycles through ring-closing
metathesis, see the following general reviews: (a) 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. Ring-closing metathesis of olefinic
peptides: Design, synthesis, and structural characterization of macro-
cyclic helical peptides. J. Org. Chem. 2001, 66, 5291−5302.
(18) (a) Marsault, E.; Peterson, M. L. Macrocycles are great cycles:
Applications, opportunities, and challenges of synthetic macrocycles in
drug discovery. J. Med. Chem. 2011, 54, 1961−2004. (b) Cummings,
M. D.; Lin, T.-I.; Hu, L.; Tahri, A.; McGowan, D.; Amssoms, K.; Last,
S.; Devogelaere, B.; Rouan, M.-C.; Vijgen, L.; Berke, J. M.; Dehertogh,
P.; Fransen, E.; Cleiren, E.; van der Helm, L.; Fanning, G.; Van
Emelen, K.; Nyanguile, O.; Simmen, K.; Raboisson, P.; Venderville, S.
Structure-based macrocyclization yields hepatitis C virus NS5B
inhibitors with improved binding affinities and pharmacokinetic
properties. Angew. Chem., Int. Ed. 2012, 51, 4637−4640.
́
(b) Gradillas, A.; Perez-Castells, J. macrocyclization by ring-closing
metathesis in the total synthesis of natural products: Reaction
conditions and limitations. Angew. Chem., Int. Ed. 2006, 45, 6086−
6101. For RCM-based build/couple/pair strategies, see: (a) Dock-
endorff, C.; Nagiec, M. M.; Weïwer, M.; Buhrlage, S.; Ting, A.; Nag, P.
P.; Germain, A.; Kim, H.-J.; Youngsaye, W.; Scherer, C.; Bennion, M.;
Xue, L.; Stanton, B. Z.; Lewis, T. A.; MacPherson, L.; Palmer, M.;
Foley, M. A.; Perez, J. R.; Schreiber, S. L. Macrocyclic hedgehog
pathway inhibitors: Optimization of cellular activity and mode of
action studies. ACS Med. Chem. Lett. 2012, 3, 808−813. (b) Dandapani,
S.; Lowe, J. T.; Comer, E.; Marcaurelle, L. A. Diversity-oriented
synthesis of 13- to 18-membered macrolactams via ring-closing
metathesis. J. Org. Chem. 2011, 76, 8042−8048.
(19) Kim, K. S.; Qian, L. Improved method for the preparation of
guanidines. Tetrahedron Lett. 1993, 34, 7677−7680.
(20) (a) Nielsen, T. E.; Scheiber, S. L. Towards the optimal screening
collection: A synthesis strategy. Angew. Chem., Int. Ed. 2008, 47, 48−
56. (b) Isidro-Llobet, A.; Murillo, T.; Bello, P.; Cilibrizzi, A.;
Hodgkinson, J. T.; Galloway, W. R. J. D.; Bender, A.; Welch, M.;
Spring, D. R. Organic synthesis toward small-molecule probes and
drugs special feature. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6793−
6798. (c) Fitzgerald, M. E.; Mulrooney, C. A.; Duvall, J. R.; Wei, J.;
Suh, B.-C.; Akella, L. B.; Vrcic, A.; Marcaurelle, L. A. Build/couple/
pair strategy for the synthesis of stereochemically diverse macro-
lactams via head-to-tail cyclization. ACS. Comb. Sci. 2012, 14, 89−96.
(d) Serba, C.; Wissinger, N. Following the lead from nature: Divergent
pathways in natural product synthesis and diversity-oriented synthesis.
Eur. J. Org. Chem. 2013, 20, 4195−4214.
́
(31) (a) Baron, A.; Verdie, P.; Martinez, J.; Lamaty, F. cis-Apa: A
practical linker for the microwave-assisted preparation of cyclic
pseudopeptides via RCM cyclative cleavage. J. Org. Chem. 2001, 76,
766−772. (b) García-Aranda, M. I.; Marrero, P.; Gautier, B.; Martín-
Martínez, M.; Inguimbert, N.; Vidal, M.; García-Lop
́ ́
ez, M. T.; Jimenez,
M. A.; Gonzalez-Muniz, R.; Perez de Vega, M. J. Parallel solid-phase
́
́
̃
synthesis of a small library of linear and hydrocarbon-bridged
analogues of VEGF81−91: Potential biological tools for studying the
VEGF/VEGFR-1 interaction. Bioorg. Med. Chem. 2001, 19, 1978−
1986.
(21) (a) Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Facile and
efficient guanylation of amines using thioureas and Mukaiyama’s
reagent. J. Org. Chem. 1997, 62, 1540−1542. (b) Levallet, C.;
Lerpiniere, J.; Ko, S. Y. The HgCl2-promoted guanylation reaction:
The scope and limitations. Tetrahedron 1997, 53, 5291−5304.
(c) Dahmen, S.; Brase, S. A. Novel solid-phase synthesis of highly
̂
diverse guanidines: Reactions of primary amines attached to the T2*
linker. Org. Lett. 2000, 2, 3563−3565.
(32) Catalysts 29−33 are available from Strem. 29: Catalog number
44-0082. 30: Catalog number 44-7780. 31: Catalog number 44-7775.
32: Catalog number 44-0055. 33: Catalog number 44-7777.
(33) The main impurity in macrocycles 28{1−2} and 34{1−2}−
36{1−4} stems from unconverted 26{1−2} (typical 5−10%).
(22) Nefzi, A.; Arutyunyan, S.; Fenwick, J. E. Two-step Hantzsch-
based macrocyclization approach for the synthesis of thiazole-
containing cyclopeptides. J. Org. Chem. 2010, 75, 7939−7941.
(23) Bernatowicz, C. A.; Wu, Y.; Matsueda, G. R. 1H-Pyrazole-1-
carboxamidine hydrochloride an attractive reagent for guanylation of
amines and its application to peptide synthesis. J. Org. Chem. 1992, 57,
2497−2502.
(24) Drake, B.; Patek, M.; Lebl, M. A convenient preparation of
́
monosubstituted N,N′-Di(Boc)-protected guanidines. Synthesis 1994,
6, 579−582.
(25) Ohara, K.; Vasseur, J.-J.; Smietana, M. NIS-promoted
guanylation of amines. Tetrahedron Lett. 2009, 50, 1463−1465.
(26) Doi, T.; Hoshina, Y.; Mogi, H.; Yamada, Y.; Takahashi, T. Solid-
phase combinatorial synthesis of aeruginosin derivatives and their
biological evaluation. J. Comb. Chem. 2006, 8, 571−582.
(27) For the use of SnCl4 to remove the Boc group from thioamides,
consult (a) Frank, R.; Schutkowski, M. Extremely mild reagent for Boc
deprotection applicable to the synthesis of peptides with thioamide
G
dx.doi.org/10.1021/co400102v | ACS Comb. Sci. XXXX, XXX, XXX−XXX