Solid-phase synthesis of multiple classes of peptidomimetics from versatile resin-bound aldehyde intermediates

Article abstract of DOI:10.1021/ja069188y

A wide variety of highly substituted lactam containing peptidomimetic scaffolds are prepared by solid-phase synthesis from a single, versatile class of resin-bound aldehyde intermediates (1). These include monocyclics 3, bicyclics 4, tricyclics 5, and tet

Full text of DOI:10.1021/ja069188y

Published on Web 05/16/2007
Solid-Phase Synthesis of Multiple Classes of Peptidomimetics
from Versatile Resin-Bound Aldehyde Intermediates
William L. Scott,*,† Jacek G. Martynow, John C. Huffman, and
†
‡
,
†
Martin J. O’Donnell*
Contribution from the Department of Chemistry and Chemical Biology, Indiana UniVersity
Purdue UniVersity Indianapolis, Indianapolis, Indiana 46202-3274, and Department of
Chemistry, Indiana UniVersity, Bloomington, Indiana 47405-4001
Received December 21, 2006; E-mail: wscott@chem.iupui.edu
Abstract: A wide variety of highly substituted lactam containing peptidomimetic scaffolds are prepared by
solid-phase synthesis from a single, versatile class of resin-bound aldehyde intermediates (1). These include
monocyclics 3, bicyclics 4, tricyclics 5, and tetracyclics 6. The key intermediate 1 is readily synthesized
from resin-bound natural or unnatural R-amino acids. The synthetic procedures permit the construction of
a large diversity of substitution patterns for ready use in combinatorial chemistry. In every case, the release
of final products from resin is by a cyclitive cleavage process. Since this depends on successful completion
of multiple intermediate synthetic steps, the products are often quite pure, even though previous steps
involve only a filtration workup. The mild conditions for many of these synthetic procedures offer the promise
of using this chemistry in peptide fragment condensations to produce modified peptides, at either the
N-terminus or C-terminus, or as individually assembled peptide segments with a wide variety of
conformationally restricted peptidomimetic linkers at the point of juncture.
1
. Introduction
of the simplest ways of creating, in a small space, conforma-
tional constraints on amino acid side chains. They also increase
the enzymatic stability of the internal amide link, an important
aspect when converting small peptides, subject to ready
enzymatic hydrolysis, into “non-peptide” analogues that can
maintain activity under physiological conditions.
The substituted lactam scaffolds “A” and “B” are frequently
found in peptidomimetic structures.1 In the absence of the
secondary and tertiary structure imposed by extended peptide
sequences on local regions of a peptide or protein, they are one
-5
†
This article reports the preparation, via solid-phase synthesis,
of a wide variety of highly substituted lactam containing
Indiana University Purdue University Indianapolis.
Indiana University.
‡
(
1) Selected monographs and reviews related to peptidomimetics: (a) Hir-
schmann, R. Angew. Chem., Int. Ed. Engl. 1991, 30, 1278-1301. (b)
Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244-
(2) Early references and recent examples of R-amino-γ-lactams: (a) du-
Vigneaud, V.; Carpenter, F. H. The γ-Lactam of Benzylhomopenicilloic
Acid and Related Compounds. In The Chemistry of Penicillin; Clarke, H.
T., Johnson, J. R., Robinson, R., Eds.; Princeton University Press:
Princeton, NJ, 1949; pp 1004-1017. (b) Sheradsky, T.; Knobler, Y.;
Frankel, M. J. Org. Chem. 1961, 26, 1482-1487. (c) Knobler, Y.; Bonni,
E.; Sheradsky, T. J. Org. Chem. 1964, 29, 1229-1236. (d) Freidinger, R.
M.; Veber, D. F.; Perlow, D. S.; Brooks, J. R.; Saperstein, R. Science 1980,
210, 656-658. (e) Freidinger, R. M.; Perlow, D. S.; Veber, D. F. J. Org.
Chem. 1982, 47, 104-109. (f) Thorsett, E. D.; Harris, E. E.; Aster, S. D.;
Peterson, E. R.; Snyder, J. P.; Springer, J. P.; Hirshfield, J.; Tristram, E.
W.; Patchett, A. A.; Ulm, E. H.; Vassil, T. C. J. Med. Chem. 1986, 29,
251-260. (g) Kobayashi, S.; Bryant, L. L., Jr.; Tsukamoto, Y.; Saegusa,
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Gallicchio, S. N.; Williams, T. M. Tetrahedron Lett. 2000, 41, 1141-1145.
(i) Galaud, F.; Lubell, W. D. Biopolymers (Peptide Science) 2005, 80, 665-
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Tetrahedron 2005, 61, 5465-5473. (k) Mart ´ı n-Mart ´ı nez, M.; De la Figuera,
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Gonz a´ lez-Mu n˜ iz, R. J. Med. Chem. 2005, 48, 7667-7674.
(3) Recent examples of R-amino lactams with various other ring sizes (4, 6, 7,
8, 9, 10): (a) Hoffmann, T.; Waibel, R.; Gmeiner, P. J. Org. Chem. 2003,
68, 62-69. (b) Mandal, P. K.; Kaluarachchi, K. K.; Ogrin, D.; Bott, S. G.;
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Ma, S.-W.; Vanderah, T. W.; Lai, J.; Porreca, F.; Hruby, V. J. Tetrahedron
Lett. 2006, 47, 2233-2236. (g) Van Rompaey, K; Ballet, S.; T o¨ mb o¨ ly, C.;
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1
267. (c) Olson, G. L.; Bolin, D. R.; Bonner, M. P.; B o¨ s, M.; Cook, C.
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5
3, 12789-12854. (i) Halab, L.; Gosselin, F.; Lubell, W. D. Biopolymers
(
Peptide Science) 2000, 55, 101-122. (j) Hruby, V. J.; Balse, P. M. Curr.
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2
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10.1021/ja069188y CCC: $37.00 © 2007 American Chemical Society
J. AM. CHEM. SOC. 2007, 129, 7077-7088
9
7077

A R T I C L E S
Scott et al.
Scheme 1. Peptidomimetic Scaffolds Available from Versatile
Aldehyde Intermediates 1
peptidomimetic scaffolds based on A or B, including many cases
of an underrepresented class of derivatives in which the position
alpha to the amine and lactam carbonyl is functionalized (e.g.,
R1 in structure B). This is accomplished through the synthesis
and use of a remarkably stable and versatile class of resin-bound
6
aldehyde intermediates (1). The multipotent nature of 1 is
demonstrated by preparing a representative series of five
peptidomimetic scaffolds: lactones 2, lactams 3, bicyclics 4,
tricyclics 5, and tetracyclics 6 (Scheme 1). The importance of
the scaffolds formed from 1, well documented in the solution
literature, will be discussed in more detail in the appropriate
sections of this article. The simple synthetic procedures reported
permit a wide diversity of substitution patterns and are, in this
7
sense, combinatorial chemistry enabled. In every case, the
1
is prepared under achiral conditions and the resulting products
release of final products from resin is by a cyclitive cleavage
8
are racemic, which is compatible with their use at the beginning
stages of a discovery process. When 1 is combined, in sub-
sequent convergent syntheses, with chiral reagents, the diaster-
process. This removes the need for “resin-linker handles” that
remain on the products. Since cyclitive cleavage depends on
successful completion of multiple intermediate synthetic steps,
the products are often quite pure, even though previous steps
involve only a filtration workup.
With solid-phase based chemistry9,10 the multiple step
sequences described in this report are quickly carried out on a
micromole scale. Even peptidomimetic scaffold syntheses
requiring as many as 10 steps provide good overall yields. Resin
(
7) Selected combinatorial chemistry monographs and reviews: (a) A Practical
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Library Synthesis”.
(
4) Examples of simple R-alkyl-R-amino-γ-lactams: (a) Holladay, M, W.;
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Lett. 2003, 13, 2035-2040. (e) Scott, W. L.; Alsina, J.; Kennedy, J. H.;
O’Donnell, M. J. Org. Lett. 2004, 6, 1629-1632. (f) Kyei, A. S.;
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4
5, 8931-8934. (g) Raghavan, B.; Johnson, R. L. J. Org. Chem. 2006, 71,
2
151-2154.
(
5) Early references and recent examples of R-alkyl-R-amino-γ-lactams
containing a C-terminal R-amino acid residue (R-alkyl dipeptide mimet-
ics): (a) Freidinger, R. M. J. Org. Chem. 1985, 50, 3631-3633. (b)
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1
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(
f) Acton, J. J., III; Jones, A. B. Tetrahedron Lett. 1996, 37, 4319-4322.
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(
6) Selected reviews concerning the parent amino acid aldehyde (“aspartalde-
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2
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7078 J. AM. CHEM. SOC.
9
VOL. 129, NO. 22, 2007

Solid-Phase Synthesis of a Variety of Peptidomimetics
A R T I C L E S
Scheme 2. Synthesis of Aldehyde Intermediates 1
eomeric products are nonracemic. Finally, in the preparation
of the bicyclic scaffold 4, solid-phase chemistry allows forma-
tion of each of two stereoisomers through temperature controlled
sequential release in the final cyclitive cleavage.
in a variety of synthetic studies during the intervening years.13
Solid-Phase Unnatural Amino Acid and Peptide Synthesis
1
4
(UPS), an integrated technique that extends the scope of the
solution-phase chemistry to a general solid-phase synthesis of
unnatural R-amino acids, peptides, and peptidomimetics was
1
.1. Preparation of Versatile Aldehyde Intermediates 1.
1
4a
At the core of this report is the preparation and use of resin-
reported in 1996. This chemistry involves addition of three
steps to the normal Merrifield peptide synthesis in order to attach
an unnatural side chain to a resin-bound R-amino acid or
9
bound 1. The starting material is a standard Merrifield resin,
chosen for its versatility and low cost. The stability of the
polystyrene-based Merrifield resin to acids, non-nucleophilic
bases, and oxidation allows the use of all these conditions in
the course of the resin-bound chemistry. In addition, since all
(
11) Selected monographs and reviews related to R-amino acid synthesis and
utilization: (a) Amino Acids, Peptides and Proteins; Specialist Periodical
Reports, The Royal Society of Chemistry: London, 1969-2004; Vols.
1
-34. (b) Barrett, G. C. Chemistry and Biochemistry of the Amino Acids;
8
Chapman and Hall: London, 1985. (c) R-Amino Acid Synthesis; Symposium-
in-Print, O’Donnell, M. J., Ed. Tetrahedron 1988, 44, 5253-5614. (d)
Williams, R. M. In Synthesis of Optically ActiVe R-Amino Acids; Baldwin,
J. E., Ed.; Organic Chemistry Series; Pergamon Press: Oxford, 1989. (e)
Duthaler, R. O. Tetrahedron 1994, 50, 1539-1650. (f) Waldmann, H.
Synlett 1995, 133-141. (g) Studer, A. Synthesis 1996, 793-815. (h)
Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl.
scaffolds are released from resin by a cyclitive cleavage process
there is no need for alternative linkers to permit specialized
cleavage conditions. Scheme 2 outlines the syntheses of
aldehyde intermediates 1.
The intermediates are all made by ozonolysis of the R-allyl
substituted derivatives 11 derived from resin-bound natural or
unnatural R-amino acids 7 or 12.11 These, in turn, are synthe-
1
996, 35, 2708-2748. (i) Obrecht, D.; Altorfer, M.; Bohdal, U.; Daly, J.;
Huber, W.; Labhardt, A.; Lehmann, C.; M u¨ ller, K.; Ruffieux, R.; Sch o¨ n-
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(
j) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998,
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2
50. (l) Bouifraden, S. et al. Amino Acids 1999, 16, 345-379. (m) Gibson,
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(
o) Asymmetric Synthesis of NoVel Sterically Constrained Amino Acids;
1
2
benozphenone imine of glycine ethyl ester, reported in 1978.
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2
001, 57, 6329-6650. (p) N a´ jera, C. Synlett 2002, 1388-1403. (q) Park,
The benzophenone imines of glycine alkyl esters have been used
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Chem., Int. Ed. 2003, 42, 4290-4299. (s) Sagan, S.; Karoyan, P.; Lequin,
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(
9) (a) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149-2154. (b) Merrifield,
B. Science 1986, 232, 341-347. (c) Retrospective: Lerner, R. A. Science
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ski, K. Tetrahedron Lett. 1984, 25, 3651-3654. (d) Cationic, glycine
equivalent: O’Donnell, M. J.; Falmagne, J.-B. Tetrahedron Lett. 1985, 26,
699-702. (e) Acidity studies: O’Donnell, M. J.; Bennett, W. D.; Bruder,
W. A.; Jacobsen, W. N.; Knuth, K.; LeClef, B.; Polt, R. L.; Bordwell, F.
G.; Mrozack, S. R.; Cripe, T. A. J. Am. Chem. Soc. 1988, 110, 8520-
8525. (f) O-Alkylation by transesterification: O’Donnell, M. J.; Cook, G.
K.; Rusterholz, D. B. Synthesis 1991, 989-993. (g) N-Terminal C-selective
alkylation of dipeptides: O’Donnell, M. J.; Burkholder, T. P.; Khau, V.
V.; Roeske, R. W.; Tian, Z. Polish J. Chem. 1994, 68, 2477-2488. (h)
Cationic R-amino phosphonate equivalent: O’Donnell, M. J.; Lawley, L.
K.; Pushpavanam, P. B.; Burger, A.; Bordwell, F. G.; Zhang, X.-M.
Tetrahedron Lett. 1994, 35, 6421-6424.
2
006, 313, 57.
(
10) Selected monographs and reviews on solid-phase synthesis: (a) Lorsbach,
B. A.; Kurth, M. J. Chem. ReV. 1999, 99, 1549-1581. (b) Solid-Phase
Organic Synthesis; Burgess, K., Ed.; Wiley: New York, 2000. (c) Solid-
Phase Synthesis; Kates, S. A., Albericio, F., Eds.; Dekker: New York,
2000. (d) Seneci, P. Solid-Phase Synthesis and Combinatorial Technologies;
Wiley: New York, 2000. (e) Zaragoza, F. Organic Synthesis on Solid
Phase: Supports, Links, Reactions; Wiley: Chichester, U.K., 2000. (f)
Franz e´ n, R. G. J. Comb. Chem. 2000, 2, 195-214. (g) Solid-Phase Organic
Syntheses, Vol. 1. Czarnik, A. W., Ed.; Wiley: New York, 2001. (h)
Sammelson, R. E.; Kurth, M. J. Chem. ReV. 2001, 101, 137-202. (i) Gil,
C.; Knepper, K.; Br a¨ se, S. In Polymeric Materials in Organic Synthesis
and Catalysis; Buchmeiser, M. R., Ed.; Wiley-VCH: Weinheim, 2003; pp
1
37-199. (j) Ganesan, A. Mini-ReV. Med. Chem. 2006, 6, 3-10. (k) Cironi,
P.; Alvarez, M.; Albericio, F. Mini-ReV. Med. Chem. 2006, 6, 11-25. (l)
Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah, N.; Reddy, D. R. Mini-
ReV. Med. Chem. 2006, 6, 53-69.
J. AM. CHEM. SOC.
9
VOL. 129, NO. 22, 2007 7079

A R T I C L E S
Scott et al.
Figure 1. Seven aldehyde resins 1 used in the synthesis of peptidomimetic scaffolds 2-5.
peptide: (a) activation of the N-terminal residue by conversion
into a Schiff base (Scheme 2, 7 to 8, R1 * H; or 12 to 13); (b)
removal of the proton on the carbon R to the newly introduced
imine functionality and reaction of the resulting carbanion with
an electrophile (8 to 9, R1 * H; or 13 to 14); (c) removal of the
Schiff base activating group (9 to 10, R1 * H; or 14 to 10, R1
catalysts. Boron alkylation of a resin-bound glycine cation
equivalent derived from 13 yields various products often difficult
1
4f
to prepare from the anionic equivalents. All these routes
provide multiple means of introducing substituents into 7 or
12. This makes possible numerous variations on R1 in structure
1, expanding the potential combinatorial synthesis of arrays of
substituted target scaffolds 2-6 (Scheme 1).
)
H).
Alkylation of resin-bound starting materials 13 (derived from
2
. Results and Discussion
glycine) or 8 (prepared from an R-substituted R-amino acid)
In the current work, Merrifield-bound aldehyde precursor 10,
lead, respectively, to mono-1 or dialkylated products such
4a
14b
R1 ) H, was prepared from resin-bound glycine 12. For 10, R1
H (i.e., R,R-dialkyl R-amino acid derivatives), procedures
14c
as 14 or 9. Alkylations with activated and unactivated halides
*
are readily accomplished, and reactions with Michael acceptors
14b
from 7 to 10 previously reported for Wang resin were adapted
to Merrifield resin.
lead to various glutamic acid derivatives.14e Tandem dialkylation
1
5,16
For most of the R-substituted cases,
14d
from 13 also gives R,R-dialkylated R-amino acids. On-resin
commercially available resin-bound Boc-protected amino acid
derivatives of 7 were used as starting materials. The exception
was the resin-bound O-benzyl protected tyrosine starting mate-
rial (leading to 1f, see Figure 1), which was prepared from
chloromethylated Merrifield resin by conventional means.
Group R2 in 2-6 (Scheme 1) is envisioned as a key location
in scaffold derivatives for modifications of functionality inter-
enantioselective alkylations1 and Michael additions can be
4g
14j
accomplished using Cinchona alkaloid-derived phase-transfer
(
13) Reviews and selected solution-phase studies from the authors’ laboratory:
(a) O’Donnell, M. J. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
VCH: New York, 1993; Chapter 8, pp 389-411. (b) O’Donnell, M. J.;
Esikova, I. A.; Mi, A.; Shullenberger, D. F.; Wu, S. In Phase-Transfer
Catalysis: Mechanisms and Syntheses; Halpern, M. E., Ed.; ACS Sym-
posium Series 659; American Chemical Society: Washington, DC, 1997;
Chapter 10, pp 124-135. (c) O’Donnell, M. J. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; Chapter
(15) General review concerning the asymmetric synthesis of R,R-disubstituted
R-amino acids: Vogt, H.; Br a¨ se, S. Org. Biomol. Chem. 2007, 5, 406-
430.
1
0, pp 727-755. (d) O’ Donnell, M. J. Aldrichimica Acta 2001, 34, 3-15.
e) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506-517. (f) O’Donnell,
M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353-2355.
(
(16) Selected recent lead references for solution-phase asymmetric syntheses
of R,R-disubstituted R-amino acid derivatives by allylation reactions: (a)
Kuwano, R.; Ito, Y. J. Am. Chem. Soc. 1999, 121, 3236-3237. (b) Alezra,
V.; Bonin, M.; Chiaroni, A.; Micouin, L.; Riche, C.; Husson, H.-P.
Tetrahedron Lett. 2000, 41, 1737-1740. (c) Ding, K.; Ma, D. Tetrahedron
2001, 57, 6361-6366. (d) Solladi e´ -Cavallo, A.; Sedy, O.; Salisova, M.;
Schmitt, M. Eur. J. Org. Chem. 2002, 3042-3049. (e) Trost, B. M.; Dogra,
K. J. Am. Chem. Soc. 2002, 124, 7256-7257. (f) Nakoji, M.; Kanayama,
T.; Okino, T.; Takemoto, Y. J. Org. Chem. 2002, 67, 7418-7423. (g)
Kawabata, T.; Kawakami, S.-p.; Shimada, S.; Fuji, K. Tetrahedron 2003,
59, 965-974. (h) Koch, C.-J.; Simonyiov a´ , S.; Pabel, J.; K a¨ rtner, A.;
Polborn, K.; Wanner, K. T. Eur. J. Org. Chem. 2003, 1244-1263. (i)
Gardiner, J.; Abell, A. D. Tetrahedron Lett. 2003, 44, 4227-4230. (j) Trost,
B. M.; J a¨ kel, C.; Plietker, B. J. Am. Chem. Soc. 2003, 125, 4438-4439.
(k) Jew, S.-s.; Jeong, B.-S.; Lee, J.-H.; Yoo, M.-S.; Lee, Y.-J.; Park, B.-s.;
Kim, M. G.; Park, H.-g. J. Org. Chem. 2003, 68, 4514-4516. (l) Kanayama,
T.; Yoshida, K.; Miyabe, H.; Kimachi, T.; Takemoto, Y. J. Org. Chem.
2003, 68, 6197-6201. (m) Belokon, Y. N.; Bhave, D.; D’Addario, D.;
Groaz, E.; North, M.; Tagliazucca, V. Tetrahedron 2004, 60, 1849-1861.
(n) Gardiner, J.; Abell, A. D. Org. Biomol. Chem. 2004, 2, 2365-2370.
(o) Brunner, M.; Saarenketo, P.; Straub, T.; Rissanen, K.; Koskinen, A.
M. P. Eur. J. Org. Chem. 2004, 3879-3883. (p) Fukuta, Y.; Ohshima, T.;
Gnanadesikan, V.; Shibuguchi, T.; Nemoto, T.; Kisugi, T.; Okino, T.;
Shibasaki, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5433-5438. (q)
Harding, C. I.; Dixon, D. J.; Ley, S. V. Tetrahedron 2004, 60, 7679-
7692. (r) Rojas-Lima, S.; T e´ llez-Zenteno, O.; L o´ pez-Ruiz, H.; Loubet-
Gonz a´ lez, L.; Alvarez-Hernandez, A. Heterocycles 2005, 65, 59-75. (s)
Ooi, T.; Miki, T.; Maruoka, K. Org. Lett. 2005, 7, 191-193. (t) Lee, Y.-
J.; Lee, J.; Kim, M.-J.; Kim, T.-S.; Park, H.-g.; Jew, S.-s. Org. Lett. 2005,
7, 1557-1560. (u) Saghiyan, A. S.; Dadayan, S. A.; Petrosyan, S. G.;
Manasyan, L. L.; Geolchanyan, A. V.; Djamgaryan, S. M.; Andreasyan,
S. A.; Maleev, V. I.; Khrustalev, V. N. Tetrahedron: Asymmetry 2006,
17, 455-467. (v) Xu, P.-F.; Li, S.; Lu, T.-J.; Wu, C.-C.; Fan, B.; Golfis,
G. J. Org. Chem. 2006, 71, 4364-4373.
(
g) O’Donnell, M. J.; Chen, N.; Zhou, C.; Murray, A.; Kubiak, C. P.; Yang,
F.; Stanley, G. G. J. Org. Chem. 1997, 62, 3962-3975. (h) O’Donnell, M.
J.; Delgado, F.; Hostettler, C.; Schwesinger, R. Tetrahedron Lett. 1998,
3
F.; Zhou, C. J. Am. Chem. Soc. 2002, 124, 9348-9349. (j) O’Donnell, M.
J.; Cooper, J. T.; Mader, M. M. J. Am. Chem. Soc. 2003, 125, 2370-
9, 8775-8778. (i) O’Donnell, M. J.; Drew, M. D.; Cooper, J. T.; Delgado,
2
371. (k) Ramachandran, P. V.; Madhi, S.; Bland-Berry, L.; Reddy, M. V.
R.; O’Donnell, M. J. J. Am. Chem. Soc. 2005, 127, 13450-13451.
14) References from the authors’ laboratory concerning the solid-phase synthesis
of unnatural R-amino acids, peptides, and peptidomimetics: (a) O’Donnell,
M. J.; Zhou, C.; Scott, W. L. J. Am. Chem. Soc. 1996, 118, 6070-6071.
(
(
b) Scott, W. L.; Zhou, C.; Fang, Z.; O’Donnell, M. J. Tetrahedron Lett.
1
997, 38, 3695-3698. (c) O’Donnell, M. J.; Lugar, C. W.; Pottorf, R. S.;
Zhou, C.; Scott, W. L.; Cwi, C. L. Tetrahedron Lett. 1997, 38, 7163-
166. (d) Griffith, D. L.; O’Donnell, M. J.; Pottorf, R. S.; Scott, W. L.;
7
Porco, J. A., Jr. Tetrahedron Lett. 1997, 38, 8821-8824. (e) Dom ´ı nguez,
E.; O’Donnell, M. J.; Scott, W. L. Tetrahedron Lett. 1998, 39, 2167-
2
170. (f) O’Donnell, M. J.; Delgado, F.; Drew, M. D.; Pottorf, R. S.; Zhou,
C.; Scott, W. L. Tetrahedron Lett. 1999, 40, 5831-5835. (g) O’Donnell,
M. J.; Delgado, F.; Pottorf, R. S. Tetrahedron 1999, 55, 6347-6362. (h)
O’Donnell, M. J.; Drew, M. D.; Pottorf, R. S.; Scott, W. L. J. Comb. Chem.
2
000, 2, 172-181. (i) O’Donnell, M. J.; Scott, W. L. Unnatural Amino
Acid and Peptide Synthesis (UPS). In Peptides 2000; Martinez, J., Fehrentz,
J.-A., Eds.: EDK: Paris, 2001; pp 31-36. (j) O’Donnell, M. J.; Delgado,
F.; Dom ´ı nguez, E.; de Blas, J.; Scott, W. L. Tetrahedron: Asymmetry 2001,
1
2, 821-828. (k) Scott, W. L.; Delgado, F.; Lobb, K.; Pottorf, R. S.;
O’Donnell, M. J. Tetrahedron Lett. 2001, 42, 2073-2076. (l) Scott, W.
L.; O’Donnell, M. J.; Delgado, F.; Alsina, J. J. Org. Chem. 2002, 67, 2960-
2
969. (m) Scott, W. L.; Alsina, J.; O’Donnell, M. J. J. Comb. Chem. 2003,
, 684-692. (n) O’Donnell, M. J.; Alsina, J.; Scott, W. L. Tetrahedron
5
Lett. 2003, 44, 8403-8406. (o) Reference 4e. (p) Alsina, J.; Scott, W. L.;
O’Donnell, M. J. Tetrahedron Lett. 2005, 46, 3131-3135.
7080 J. AM. CHEM. SOC.
9
VOL. 129, NO. 22, 2007

Solid-Phase Synthesis of a Variety of Peptidomimetics
A R T I C L E S
Scheme 3. Characterization of Resin-Bound Olefins by
Methanolysis with NaOMe
Figure 2. Diol product from NaBH4 reduction of 1f.
oxidation. The procedure is straightforward and gives good
conversions, as determined by the yields and purities of products
1
9
subsequently produced. Figure 1 lists the resin-bound alde-
hydes 1 prepared and used in subsequent scaffold formation.
2
.1. Multiple Uses of Versatile Intermediates 1. 2.1.1.
Preparation of Lactones 2. One of the simplest scaffolds
2
0,21
available from 1 is lactone 2 (Scheme 1).
An example of
the biological significance of this scaffold is the N-acyl-L-
homoserine lactone signal molecule and its analogues used by
Gram-negative bacteria to activate quorum sensing.2 The
lactone scaffold synthesis, with representative examples, is
outlined in Scheme 4 (yields given here and in subsequent
schemes, figures, and tables are based on resin-bound R-amino
acids 7 and 12 and are for purified products). Since these
lactones required base and elevated temperature for the final
cyclitive cleavage, it was possible, after reduction and prior to
release, to wash away excess reagents and obtain, after cleavage,
crude products in 90 to 98% purity. Purification and complete
characterization of these lactones also substantiated the nature
of the resin-bound aldehyde intermediates 1.
Sodium cyanoborohydride22 was routinely used as a reducing
agent after observing, in one case (the reduction of 1f), that
NaBH4 led to the diol product 17 (Figure 2). 2-Amino-2-alkyl
substituted-1,4-butanediols such as 17 are highly functionalized
molecules, and this alternate synthetic pathway should afford
access to a variety of such derivatives from intermediates 1.
0f
acting with receptor binding or enzyme active sites. Often R2
fragments will be introduced from carboxylic acid starting
materials. Therefore initial work focused on producing amide
derivatives for R2 (with the exception of one sulfonamide) in
the final products. After hydrolyzing 9 or 14 to 10, the second
site of diversity, R2, was incorporated by reaction of 10 with
acid chlorides or a sulfonyl chloride. All the resulting resin-
bound R-substituted olefins 11 were characterized by cleavage
with methoxide to afford methyl esters 15 (Scheme 3).
1
7,18
Ozonolysis
of resin-bound substrates is still not a com-
monly used solid-phase reaction, even though it was first
reported more than 30 years ago as a means to form aldehydes.
There have been subsequent reports of ozonolyses of resin-
bound olefins, both to transform substrates and to cleave olefins
serving as linkers to resins. In the present study ozone generation
was calibrated to ensure complete reaction without over-
(
18) Selected ozonolyses on solid phase: (a) Fr e´ chet, J. M.; Schuerch, C.
Carbohyd. Res. 1972, 22, 399-412. (b) Sylvain, C.; Wagner, A.; Mios-
kowski, C. Tetrahedron Lett. 1997, 38, 1043-1044. (c) Pothion, C.; Paris,
M.; Heitz, A.; Rocheblave, L.; Rouch, F.; Fehrentz, J.-A.; Martinez, J.
Tetrahedron Lett. 1997, 38, 7749-7752. (d) Paris, M.; Heitz, A.; Guerlavais,
V.; Cristau, M.; Fehrentz, J.-A.; Martinez, J. Tetrahedron Lett. 1998, 39,
7
287-7290. (e) Panek, J. S.; Zhu, B. J. Am. Chem. Soc. 1997, 119, 12022-
12023. (f) Br a¨ se, S.; Dahmen, S.; Pfefferkorn, M. J. Comb. Chem. 2000,
(
17) Selected reviews of ozonolysis and early references and recent examples
of the ozonolyses of allylglycine-type systems in solution: (a) Review:
Berglund, R. A. Ozone. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; John Wiley: Chichester, U.K., 1995; Vol. 6, pp 3837-
2, 710-715. (g) For an alternative to ozonolysis (oxidation of diol to
aldehyde) on solid phase, see: Nielsen, T. E.; Meldal, M. Org. Lett. 2005,
7, 2695-2698.
(19) See Supporting Information for experimental details.
3
843. (b) Review: Van Ornum, S. G.; Champeau, R. M.; Pariza, R. Chem.
(20) Early references and recent examples of R-amino-γ-lactones (homoserine
lactones): (a) Baldwin, J. E.; North, M.; Flinn, A. Tetrahedron Lett. 1987,
28, 3167-3168. (b) Schwab, J. M.; Ray, T. Chem. Commun. 1988, 29-
31. (c) Baldwin, J. E.; North, M.; Flinn, A. Tetrahedron 1988, 44, 637-
642. (d) Son, J.-K.; Kalvin, D.; Woodard, R. W. Tetrahedron Lett. 1988,
29, 4045-4048. (e) Rolland-Fulcrand, V.; Rolland, M.; Roumestant, M.-
L.; Martinez, J. Eur. J. Org. Chem. 2004, 873-877. (f) Geske, G. D.;
Wezeman, R. J.; Siegel, A. P.; Blackwell, H. E. J. Am. Chem. Soc. 2005,
127, 12762-12763. (g) Annedi, S. C.; Biabani, F.; Poduch, E.; Mannargudi,
B. M.; Majumder, K.; Wei, L.; Khayat, R.; Tong, L.; Kotra, L. P. Bioorg.
Med. Chem. 2006, 14, 214-236.
ReV. 2006, 106, 2990-3001. (c) Moe, O. A.; Warner, D. T. J. Am. Chem.
Soc. 1952, 74, 2690-2691. (d) Kamber, M.; Just, G. Can. J. Chem. 1985,
6
3, 823-827. (e) Reference 5d. (f) Turner, N. J.; Whitesides, G. M. J.
Am. Chem. Soc. 1989, 111, 624-627. (g) Allen, N. E.; Boyd, D. B.;
Campbell, J. B.; Deeter, J. B.; Elzey, T. K.; Foster, B. J.; Hatfield, L. D.;
Hobbs, J. N., Jr.; Hornback, W. J.; Hunden, D. C.; Jones, N. D.; Kinnick,
M. D.; Morin, J. M., Jr.; Munroe, J. E.; Swartzendruber, J. K.; Vogt, D. G.
Tetrahedron 1989, 45, 1905-1928. (h) Sakaitani, M.; Ohfune, Y. J. Am.
Chem. Soc. 1990, 112, 1150-1158. (i) Tudor, D. W.; Lewis, T.; Robins,
D. J. Synthesis 1993, 1061-1062. (j) Di Fabio, R.; Alvaro, G.; Bertani,
B.; Giacobbe, S. Can. J. Chem. 2000, 78, 809-815. (k) Smith, A. B., III;
Liu, H.; Hirschmann, R. Org. Lett. 2000, 2, 2037-2040. (l) L u¨ sch, H.;
Uzar, H. C. Tetrahedron: Asymmetry 2000, 11, 4965-4973. (m) Wolfe,
S.; Ro, S.; Kim, C.-K.; Shi, Z. Can. J. Chem. 2001, 79, 1238-1258. (n)
Fuchi, N.; Doi, T.; Harada, T.; Urban, J.; Cao, B.; Kahn, M.; Takahashi,
T. Tetrahedron Lett. 2001, 42, 1305-1308. (o) Knapp, S.; Morriello, G.
J.; Nandan, S. R.; Emge, T. J.; Doss, G. A.; Mosley, R. T.; Chen, L. J.
Org. Chem. 2001, 66, 5822-5831. (p) Di Fabio, R.; Alvaro, G.; Bertani,
B.; Donati, D.; Giacobbe, S.; Marchioro, C.; Palma, C.; Lynn, S. M. J.
Org. Chem. 2002, 67, 7319-7328. (q) Reference 4c. (r) Duan, J. J.-W.;
Lu, Z.; Xue, C.-B.; He, X.; Seng, J. L.; Roderick, J. J.; Wasserman, Z. R.;
Liu, R.-Q.; Covington, M. B.; Magolda, R. L.; Newton, R. C.; Trzaskos,
J. M.; Decicco, C. P. Bioorg. Med. Chem. Lett. 2003, 13, 2035-2040. (s)
Wen, S.-J.; Yao, Z.-J. Org. Lett. 2004, 6, 2721-2724. (t) Ikeda, D.;
Kawatsura, M.; Uenishi, J. Tetrahedron Lett. 2005, 46, 6663-6666.
(21) Early references and recent examples of R-alkyl-R-amino-γ-lactones: (a)
Pedersen, M. L; Berkowitz, D. B. Tetrahedron Lett. 1992, 33, 7315-7318.
(b) Hayes, J. F.; Tavassoli, A.; Sweeney, J. B. Synlett 2000, 1208-1209.
(c) Reference 17k. (d) Berkowitz, D. B.; McFadden, J. M.; Sloss, M. K. J.
Org. Chem. 2000, 65, 2907-2918. (e) Kiuchi, M.; Adachi, K.; Kohara,
T.; Minoguchi, M.; Hanano, T.; Aoki, Y.; Mishina, T.; Arita, M.; Nakao,
N.; Ohtsuki, M.; Hoshino, Y.; Teshima, K.; Chiba, K.; Sasaki, S.; Fujita,
T. J. Med. Chem. 2000, 43, 2946-2961. (f) Torrente, S.; Alonso, R. Org.
Lett. 2001, 3, 1985-1987. (g) Ma, D.; Zhu, W. J. Org. Chem. 2001, 66,
348-350. (h) Mazal, C.; Jonas, J.; Z a´ k, Z. Tetrahedron 2002, 58, 2729-
2733. (i) Brouillette, W. J.; Bajpai, S. N.; Ali, S. M.; Velu, S. E.; Atigadda,
V. R.; Lommer, B. S.; Finley, J. B.; Luo, M.; Air, G. M. Bioorg. Med.
Chem. 2003, 11, 2739-2749. (j) Gasperi, T.; Loreto, M. A.; Tardella, P.
A.; Veri, E. Tetrahedron Lett. 2003, 44, 4953-4956. (k) Pihko, P. M.;
Pohjakallio, A. Synlett 2004, 2115-2118. (l) Reference 3e.
J. AM. CHEM. SOC.
9
VOL. 129, NO. 22, 2007 7081

A R T I C L E S
Scott et al.
Scheme 5. Synthetic Scheme for Syntheses of Lactams 3
Scheme 4. Representative Lactones Prepared through Reduction
and Cyclitive Cleavage
preferred solvent for NaBH(OAc)3 reductions is dichloroethane.
For reactions with aldehyde resins 1, NaBH3CN was used
because of its efficiency, solvent compatibility, and selectivity.
The chemoselectivity in reductions with NaBH3CN broadly
depends on solvent and pH, thus allowing a careful selection
of reducing capability versus tolerability toward diverse func-
tional groups. Acetic acid has been reported as the acidic
component in reductive aminations with sodium cyanoborohy-
dride performed on resin, as mixtures of NaBH3CN and acetic
2
5b,25e
acid, in either DMF or THF.
Interestingly, it was reported
that when THF was used as the solvent the presence of a small
amount of water did not negatively impact reductions,2 which
makes similar conditions an attractive choice for applications
in solid-phase chemistry. Ultimately, the best results were
achieved with NaBH3CN dissolved in a 0.3-0.5 M solution of
AcOH in dry THF, DMF, or mixtures of these two solvents,
depending on the solubility of the amine component.
5b
2
.1.2. Preparation of Lactams 3. As noted in the introduc-
tion, lactam scaffolds are a frequent theme in peptidomimetic
structures,1
-5
providing one of the simplest scaffolds for
Partial cyclitive cleavage often occurred during the room-
temperature reductive aminations. In the case of the reaction
between unreactive amines (aniline) and aldehyde resins with
R1 ) H, heating in toluene at 65-75 °C for 6-15 h was
necessary to optimize yields. For aldehyde resins with R1 )
alkyl, the optimal results were obtained after heating the
preformed reductive amination products in chlorobenzene, in
the presence of DIEA, at 80-85 °C for 18 h. These results may
reflect an interplay between the Thorpe-Ingold effect,26 the
lowered nucleophilicity of phenyl-substituted amines, and the
steric hindrance which the preformed amines encounter, to
varying degrees, upon the approach to the ester carbonyl
cleavage site. Following aqueous workup the lactams thus
formed were purified from any excess reagents or reduction
byproducts by chromatography and crystallization.19
recreating, in a small space, some of the conformational
constraints present in larger peptides or proteins. Early examples
are the Freidinger lactams23 3 (R1 ) H), which were developed
in the early 1980s. More recently a number of groups have
reported examples of 3 in which R1 is either hydrogen or a
variety of other substituents.1 In the present case, both
R-monosubstituted and R,R-disubstituted lactams 3 were pre-
pared by reductive amination of 1 with primary amines (R3-
NH2) and NaBH3CN to give intermediate 18, followed by
cyclitive cleavage (Scheme 5).
-5
Sodium cyanoborohydride and the alternative reducing agent
sodium triacetoxyborohydride have been used extensively in
2
2,24
reductive aminations of amines both in solution
and on solid
2
5
phase. Sodium triacetoxyborohydride is widely used for
reductive amination under mild conditions.24d,f However, the
2
.1.3. Multiple Site Variations on Lactam 3 Scaffold. For
(
22) (a) Borch, R. F; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971,
the lactam scaffold 3 the combinatorial potential of 1 was
exemplified by preparing a series of lactams in which R1, R2,
and R3 were varied. These cases are discussed in the following
sections.
9
3, 2897-2904. (b) Review: Hutchins, R. O.; Hutchins, M. K. Sodium
Cyanoborohydride. In Encyclopedia of Reagents for Organic Synhesis;
Paquette, L. A., Ed.; John Wiley: Chichester, U.K., 1995; Vol. 7, pp 4539-
4
542.
(
23) Reviews and early references to Freidinger lactams: (a) Reviews: references
o and 1u. (b) References 2d, 2e, and 5a.
1
(
24) Review and selected examples of solution-phase reductive aminations: (a)
Review: Baxter, E. W.; Reitz, A. B. in Organic Reactions; Overman, L.
E., Ed.; Wiley: New York, 2002; Vol. 59, Chapter 1, pp 1-697. (b)
Nutaitis, C. F.; Schultz, R. A.; Obaza, J.; Smith, F. X. J. Org. Chem. 1980,
(25) Selected examples of reductive aminations on solid phase: (a) Esser, C.
K.; Kevin, N. J.; Yates, N. A.; Chapman, K. T. Bioorg. Med. Chem. Lett.
1997, 7, 2639-2644. (b) Brown, E. G.; Nuss, J. M. Tetrahedron Lett. 1997,
38, 8457-8460. (c) Kung, P.-P.; Swayze, E. Tetrahedron Lett. 1999, 40,
5651-5654. (d) Jefferson, E. A.; Swayze, E. E. Tetrahedron Lett. 1999,
40, 7757-7760. (e) Forns, P.; Sevilla, S.; Erra, M.; Ortega, A.; Fern a´ ndez,
J.-C.; de la Figuera, N.; Fern a´ ndez-Forner, D.; Albericio, F. Tetrahedron
Lett. 2003, 44, 6907-6910.
4
5, 4606-4608. (c) Manescalchi, F.; Nardi, A. R.; Savoia, D. Tetrahedron
Lett. 1994, 35, 2775-2778. (d) Abdel-Magid, A. F.; Carson, K. G.; Harris,
B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849-
3
862. (e) Hannachi, J.-C.; Vidal, J.; Mulatier, J.-C.; Collet, A. J. Org. Chem.
2
004, 69, 2367-2373. (f) Chen, Z.; Kende, A. S.; Colson, A.-O.;
(26) (a) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915, 107,
1080-1106. (b) Jung, M. E.; Piizzi, G. Chem. ReV. 2005, 105, 1735-
1766.
Mendezandino, J. L; Ebetino, F. H.; Bush, R. D.; Hu, X. E. Synth. Commun.
2
006, 36, 473-479.
7082 J. AM. CHEM. SOC.
9
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Solid-Phase Synthesis of a Variety of Peptidomimetics
A R T I C L E S
Table 1. Amines (R3NH2) and Amides (R2) as Variables in the Reductive Amination/Cyclization Sequence to Lactams 3
a
Combined yield of two diasteroemers. b Isolated as a mixture of diastereomers. c Isolated yield of diastereomeric mixture as 1:1 complex with alanine
tert-butyl ester.
2.1.3.1. Amine Survey (R3NH2) in Lactam Formation. We
which afforded sulfonamide derivatives (3k-3o). These com-
first chose to survey five primary amines (R3NH2) for reaction
with a single aldehyde intermediate, 1a (R1 ) H, R2 )
pounds fall into a class of lactam sulfonamide derivatives with
5
l
known biological activity. For sulfonamide lactam 3o, the
acidity of the sulfonamide hydrogen led to formation of a one-
to-one complex of product with excess alanine tert-butyl ester,
which was isolated and characterized after chromatography.
4
-methylbenzoyl). These would probe the scope of amine
compatibility with the reduction/cyclitive cleavage conditions
in lactams where there was only monosubstitution R to the
lactam carbonyl. Simple phenethyl amine was used, along with
potentially more problematic amines. For example, 2-amino-
2.1.3.3. Preparation of R-Substituted Lactams (Variations
of R ). Finally, it was shown that R-disubstituted lactams (3,
1
1
-phenylethanol was chosen because it has polyfunctionality;
1
R * H) can be readily made by this reductive amination/
aniline is a less reactive amine; isopropyl amine is more
hindered; and alanine tert-butyl ester demonstrates the ability
to incorporate amino acids. The results of this survey are
summarized in Table 1, column 1.
cyclization route (Table 2). This highly functionalized, compact,
conformationally restricted peptidomimetic scaffold has been
1
-5
the focus of numerous studies.
An unstated driving force for earlier development of the resin-
As expected, a variety of conditions were required, but the
desired product was obtained in all cases. Starting from
commercial BocGly Merrifield resin, this eight-step reaction
sequence typically gave products in 30-50% overall purified
yield. When diastereomeric products were formed (as in 3b and
bound, R-disubstitution chemistry (reported in 1998 and shown
as part of Scheme 2, compounds 7 to 10) was to provide
synthetic access to the resin-bound olefin 10 required for
1
4b
multiple variations of R in peptidomimetic 3. This would allow,
1
through subsequent conversion to aldehyde 1, the synthesis of
3
e) they were in equal proportions. The lactam 3e is an example
multiple scaffolds with large variations in R (Scheme 5, R *
1
1
of a conformationally restricted peptidomimetic. Its synthesis
here provides an alternative to another solid-phase based route
we recently published to this important class of molecules.
H). Earlier attempts to make 10 by synthesizing, in solution,
an R-disubstituted protected R-amino acid precursor (e.g., Boc-
R-methyl-R-allylglycine), and then linking its carboxylate salt
to chloromethylated Merrifield resin, gave very poor conver-
sions. Presumably this was due to the hindrance to attack
imposed by the adjacent sterically encumbered quaternary
center. This was the primary reason for subsequently developing
a simple route to prepare these R,R-disubsituted R-amino acids
4
e
The long-term stability of aldehyde intermediates 1 is
noteworthy. As reported in the Supporting Information, various
derivatives of resin 1 (R1 ) H), stored for more than 12 years
at room temperature in a capped bottle (and not under an inert
atmosphere), gave, in all cases examined, the expected prod-
2
7
14b
ucts.
on-resin. Using this procedure, there is now access to multiple
R1 in 10, with these R1 groups, in turn, present in 7 either from
2
.1.3.2. Other Amides (R2) in Lactam Formation with
Amines R3NH2. These same amines were reacted with two other
amide derivatives of aldehyde 1 (R1 ) H: 1b and 1c), to give
an additional 10 lactams (Table 1, columns 2 and 3). The data
show that the synthetic sequence is compatible with other amide
substituents. A special case is the sulfonamide precursor (1c),
(
27) A direct comparison of new vs old resin was made by preparing five
compounds (3a-3d and 3h) from samples of resins 1a and 1b that were
over 12 years old. Additionally, 10 new compounds (3p-3y) were prepared
and fully characterized from aged resins 1h-1j (for full details see Table
1
, experimental procedures, and NMR spectra in the Supporting Informa-
tion).
J. AM. CHEM. SOC.
9
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A R T I C L E S
Scott et al.
Table 2. R-Substituted Lactams Available from 1 (R2 ) 4-MeC6H4-)
a
Isolated as a racemic mixture of diastereomers. b Isolated as a mixture of two diastereomers. c Combined yield of two isolated diastereomers.
natural R-amino acids or by introduction, on-resin, by previously
reported procedures.
mentary to the route reported here, it is limited to amine
containing substrates that can be remotely linked to resins (as
with the carboxylic acid of amino acids). In the present work
there is no requirement for this remote link since the amine
incorporation is an integral part of the final steps leading to
cyclitive cleavage.
14
With R-disubstituted 1 (R1 * H) available, it was now
possible to make intensively funtionalized scaffolds. The first
exemplification was in the synthesis of R-disubstituted mono-
cyclic lactams 3. It was gratifying that this could be ac-
complished as easily as in the monosubstituted cases, using the
same reductive amination/cyclization route (Scheme 5, R1 *
H). This was done, in a comprehensive fashion, with a series
of four R-disubstitued aldehyde intermediates (Figure 1) 1d-
The wide range of structures synthesized provided an
opportunity to observe some interesting effects of substituents
on the NMR chemical shifts of diastereomeric pairs of com-
pounds. Of particular note was the strong influence of a benzyl
1
1g (columns) and five different amines (rows), to make multiply
or a 4-benzyloxybenzyl R group in the R position of the
1
substituted γ-lactams (Table 2).
γ-lactam ring on the H NMR chemical shifts of methyl groups
The route proved to be very general and was compatible with
functionalized side chains R1, such as those present in the
protected tyrosine and lysine derivatives (see products 3fa-
when present in the R3 side chain. For example, a ∆ ) 0.4
ppm was found for the R-methyl protons in the alanine derived
compounds 3dd and 3fd, and a ∆ ) 0.25 ppm was observed
for the methyl protons in isopropylamine derived 3de and 3fe.
The observed differences of chemical shifts between two
diastereomers were similar in magnitude to the anisochrony of
isopropyl methyl groups in chiral molecules reported by
3
fe and 3ga-3ge), along with a combination of R3’s derived
from R3NH2. When R3NH2 is an amino acid (compounds 3dd,
ed, 3fd, and 3gd), it is possible to construct a series of
3
conformationally restricted dipeptidomimetics, in these cases
of the dipeptides (R,S)-Phe-(S)-Ala, (R,S)-Ala-(S)-Ala, (R,S)-
Tyr-(S)-Ala, and (R,S)-Lys-(S)-Ala, respectively. There are only
a limited number of published solution-phase routes to these
scaffolds. We recently published a general, alternative solid-
28a
1
others. Moreover, in the H NMR spectra of the 2-Cl-Z-lysine
derivatives 3ga-3ge, many signals showed some splitting or
line broadening, on the order of 1-2 Hz, which is attributable
to the slow exchange of rotamers of the urethane C-N bond in
4e
28b,28c
phase route which also makes them accessible. While comple-
the 2-Cl-Z group.
7084 J. AM. CHEM. SOC.
9
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Solid-Phase Synthesis of a Variety of Peptidomimetics
A R T I C L E S
Scheme 6. Selective Formation of Diastereomeric Bicyclics 4
through Controlled Release from Resin
analogous way, but from resin 1d, bicyclics 4 were prepared
by reaction with (R)-cysteine ethyl ester to form intermediate
thiazolidine 19 followed by cyclitive cleavage (Scheme 6). By
virtue of solid-phase methodology and a final cyclitive cleavage
step, this multistep synthesis (seven steps from starting resin
7
4
) directly provides high quality diastereomeric products 4a and
b in good overall yield.
Along with the high purities obtained directly by this solid-
phase synthesis, there are a number of interesting stereochemical
observations to report. First of all, this synthesis gave (pre-
dominantly) only two (4a and 4b) of the four diastereomers
possible. The stereochemistry was confirmed by X-ray structure
for 4a and NMR analysis for 4b. Second, 4a and 4b could be
released from the resin with temperature controlled selectivity.
2
.1.4. Preparation of Bicyclic γ-Lactams 4. There is a rich
history regarding the preparation and importance of bicyclic
scaffolds 4. In the 1940s they were considered analogues of
nature’s beautiful peptidomimetic, penicillin.2 Years later they
experienced a resurgence of interest, both as â-turn peptido-
mimetics and as conformationally restricted scaffolds for
a
The presence of two of the four diastereomers was not
surprising in light of the observation by others, in solution
chemistry, that, in spite of the mixture of thiazolidine diaster-
eomers presumably present in intermediate 19, the bicyclic
products formed with (R)-cysteine derivatives have predomi-
nantly the (S)-stereochemistry at the ring fusion. This is assumed
to be a function of either selective cyclization of one of the
two isomers in the thiazolidine precursor (which is equilibrating
under the reaction conditions) or subsequent equilibration of
the ring fusion to a more thermodynamically stable product.3
Of note in this current work is that it is possible to selectively
obtain each of the two diastereomers 4a and 4b using a
temperature regulated sequential cyclitive release. After the
initial reaction of 1d with (R)-cysteine ethyl ester the resin was
thoroughly washed. Heating at 60-75 °C then provided 4a in
high purity. Raising the temperature to 115 °C then released
increasing amounts of 4b (see Table 2 on page 56 of the
Supporting Information for full details of this experimental
observation).
analogues of both natural and synthetic molecules with a range
of biological activities.1
,29-31
There are many reports of solution-
phase syntheses of derivatives and analogues of bicyclic scaffold
3
0
4
, including those with non-hydrogen substitution at R1. There
31
is also a report of a synthesis on resin. The majority, both in
solution and on solid phase, rely on the formation of a
thiazolidine intermediate (paralleling an approach first reported
by duVigneaud, and then by Sheehan in his classic synthesis
of penicillin) through the reaction of â-amino thiols with the
solution equivalent of 1. This was followed by intramolecular
cyclization, through either attack of the thiazolidine nitrogen
on an ester link or attack on an activated carboxylic acid. In an
2a
32
0i
(
28) (a) Pourahmady, N.; Palaniswamy, V. A.; Eisenbraun, E. J. Org. Magn.
Reson. 1983, 21, 670-671. (b) Friebolin, H. Basic One- and Two-
Dimensional NMR Spectroscopy, 2nd ed.; VCH: New York, 1993; pp 287-
3
15. (c) See Supporting Information in: Jensen, K. J.; Alsina, J.; Songster,
M. F.; V a´ gner, J.; Albericio, F.; Barany, G. J. Am. Chem. Soc. 1998, 120,
441-5452.
29) Early references and recent examples of the formation of bicyclic
thiazolidine lactams 4 (R ) H) in solution: (a) Nagai, U.; Sato, K.
Tetrahedron Lett. 1985, 26, 647-650. (b) Nagai, U.; Sato, K.; Nakamura,
R.; Kato, R. Tetrahedron 1993, 49, 3577-3592. (c) Qiu, W.; Gu, X.;
Soloshonok, V. A.; Carducci, M. D.; Hruby, V. J. Tetrahedron Lett. 2001,
5
(
2.1.5. Preparation of Tricyclics 5 and Tetracyclics 6. Up
to this point a key feature in the use of 1 has been its conversion
into an amine intermediate (e.g., 18, Scheme 5, or 19, Scheme
4
2, 145-148. (d) Ndungu, J. M.; Gu, X.; Gross, D. E.; Cain, J. P.; Carducci,
6) that proceeds to form the final scaffold while simultaneously
M. D.; Hruby, V. J. Tetrahedron Lett. 2004, 45, 4139-4142.
(
30) Early references and recent examples of the formation of bicyclic
thiazolidine lactams 4 (R * H) in solution: (a) Baldwin, J. E.; Lee, V.;
Schofield, C. J. Heterocycles 1992, 34, 903-906. (b) Genin, M. J.; Johnson,
R. L. J. Am. Chem. Soc. 1992, 114, 8778-8783. (c) Genin, M. J.; Mishra,
R. K.; Johnson, R. L. J. Med. Chem. 1993, 36, 3481-3483. (d) Chalmers,
D. K.; Marshall, G. R. J. Am. Chem. Soc. 1995, 117, 5927-5937. (e)
Subasinghe, N. L.; Khalil, E. M.; Johnson, R. L. Tetrahedron Lett. 1997,
undergoing cyclitive cleavage from the resin. This overall
process is chemically efficient and produces samples that are
8
quite pure, since the cyclitive cleavage is unlikely to occur
from most resin impurities produced, either from incomplete
reaction or as side products at earlier steps.
3
8, 1317-1320. (f) Takeuchi, Y.; Marshall, G. R. J. Am. Chem. Soc. 1998,
1
20, 5363-5372. (g) Khalil, E. M.; Ojala, W. H.; Pradhan, A.; Nair, V.
The Pictet-Spengler reaction is a widely used approach for
the synthesis of amine containing cyclic structures, both in
D.; Gleason, W. B.; Mishra, R. K.; Johnson, R. L. J. Med. Chem. 1999,
4
2, 628-637. (h) Khalil, E. M.; Pradhan, A.; Ojala, W. H.; Gleason, W.
3
3
34
B.; Mishra, R. K.; Johnson, R. L. J. Med. Chem. 1999, 42, 2977-2987. (i)
Somu, R. V.; Johnson, R. L. J. Org. Chem. 2005, 70, 5954-5963.
31) Solid-phase synthesis of a bicyclic thiazolidine lactam: Johannesson, P.;
Erd e´ lyi, M.; Lindeberg, G.; Fr a¨ ndberg, P.-A.; Nyberg, F.; Karl e´ n, A.;
Hallberg, A. J. Med. Chem. 2004, 47, 6009-6019.
solution and on solid phase, from aldehyde precursors. It
offered another synthetic route from aldehyde 1 to a key amine
intermediate 20 and the opportunity to form highly function-
alized multicyclic lactam containing scaffolds through a sub-
sequent cyclitive cleavage process (Scheme 7). Again, solid-
(
(
32) Sheehan, J. C.; Henery-Logan, K. R. J. Am. Chem. Soc. 1957, 79, 1262-
1
263.
J. AM. CHEM. SOC.
9
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A R T I C L E S
Scott et al.
Scheme 7. Formation of Polycyclic Peptidomimetics from 1 via
Pictet-Spengler Reactions
Scheme 8. Formation of Tricyclic Scaffold from 1d
phase methodology with a final cyclitive cleavage step enabled
this multistep synthesis (seven steps from starting resin 7),
providing high quality products 5 or 6 in good overall yield.
This expanded scope and potential was demonstrated by
synthesizing the representative tricyclic 5 and tetracyclic 6
through amine intermediates 21 and 23 (Schemes 8 and 9,
respectively). To our knowledge there are no published ex-
amples, either in solution or through solid-phase synthesis, of
the R-amino, R-alkyl disubstituted lactam scaffolds exemplified
3
5
by 5 and 6. The formation of 5a and 5b, by reaction of 1d
with dopamine, proceeded uneventfully under very mild condi-
tions (Scheme 8).
The Pictet-Spengler was catalyzed by acetic acid, and the
cyclitive cleavage proceeded at room temperature. Due to the
oxidative instability, polarity, and acidity of the catechol
containing products, the mixture of diastereomers was im-
mediately converted to the bis-acetate derivatives 22a and 22b,
for chromatographic purification and characterization by NMR
(22a) and X-ray (22b) analysis.
As in the tricyclic case, the reaction took place uneventfully
under very mild conditions, with acetic acid catalysis, and the
cyclitive cleavage proceeded at room temperature. Products were
characterized by X-ray, LC/MS, and NMR analysis.
(
33) Review, early references, and recent examples of Pictet-Spengler reactions
in solution: (a) Review: Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95,
1
797-1842. (b) Review: Reference 1q. (c) Review: Larghi, E. L.;
Amongero, M.; Bracca, A. B. J.; Kaufman, T. S. ArkiVok 2005, 98-153.
(d) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030-2036.
In an analogous fashion, the use of 1 to form a tetracyclic
(
e) de la Figuera, N.; Rozas, I.; Garcia-L o´ pez, M. T.; Gonz a´ lez-Mu n˜ iz, R.
scaffold through the Pictet-Spengler intermediate was exempli-
fied by reacting 1d with 5-methoxytryptamine (Scheme 9) to
yield the highly substituted tetracyclic peptidomimetics 6a and
Chem. Commun. 1994, 613-614. (f) De la Figuera, N.; Alkorta, I.; Garc ´ı a-
L o´ pez, M. T.; Herranz, R.; Gonz a´ lez-Mu n˜ iz, R. Tetrahedron 1995, 51,
7841-7856. (g) Andreu, D.; Ruiz, S.; Carre n˜ o, C.; Alsina, J.; Albericio,
F.; Jim e´ nez, M. A.; de la Figuera, N.; Herranz, R.; Garc ´ı a-L o´ pez, M. T.;
Gonz a´ lez-Mu n˜ iz, R. J. Am. Chem. Soc. 1997, 119, 10579-10586. (h) de
la Figuera, N.; Mart ´ı n-Mart ´ı nez, M.; Herranz, R.; Garc ´ı a-L o´ pez, M. T.;
Latorre, M.; Cenarruzabeitia, E.; del R ´ı o, J.; Gonz a´ lez-Mu n˜ iz, R. Bioorg.
Med. Chem. Lett. 1999, 9, 43-48. (i) Mart ´ı n-Mart ´ı nez, M.; De la Figuera,
N.; Latorre, M.; Herranz, R.; Garc ´ı a-L o´ pez, M. T.; Cenarruzabeitia, E.;
Del R ´ı o, J.; Gonz a´ lez-Mu n˜ iz, R. J. Med. Chem. 2000, 43, 3770-3777. (j)
D’Alessio, S.; Gallina, C.; Gavuzzo, E.; Giordano, C.; Gorini, B.; Mazza,
F.; Paradisi, M. P.; Panini, G.; Pochetti, G. Eur. J. Med. Chem. 2001, 36,
6
b.
43-53. (k) Gonz a´ lez-Mu n˜ iz, R.; Mart ´ı n-Mart ´ı nez, M.; Granata, C.; de
Oliveira, E.; Santiveri, C. M.; Gonz a´ lez, C.; Frechilla, D.; Herranz, R.;
Garc ´ı a-L o´ pez, M. T.; Del R ´ı o, J.; Jim e´ nez, M. A.; Andreu, D. Bioorg. Med.
Chem. 2001, 9, 3173-3183. (l) Mart ´ı n-Mart ´ı nez, M.; Latorre, M.; Garc ´ı a-
L o´ pez, M. T.; Cenarruzabeitia, E.; Del R ´ı o, J.; Gonz a´ lez-Mu n˜ iz, R. Bioorg.
Med. Chem. Lett. 2002, 12, 109-112. (m) Stork, G.; Tang, P. C.; Casey,
M.; Goodman, B.; Toyota, M. J. Am. Chem. Soc. 2005, 127, 16255-16262.
7086 J. AM. CHEM. SOC.
9
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Solid-Phase Synthesis of a Variety of Peptidomimetics
A R T I C L E S
Scheme 9. Formation of Tetracyclic Scaffold from 1d
Scheme 10. Representative Synthesis of All Four Scaffolds from
a Common Intermediate 1d
3. Summary
A wide variety of highly substituted lactam containing
peptidomimetic scaffolds can now be prepared by solid-phase
synthesis from a single, versatile class of resin-bound aldehyde
intermediates (1). These include monocyclics 3, bicyclics 4,
tricyclics 5, and tetracyclics 6. Scheme 10 summarizes the power
of this general approach through the synthesis, in just two steps,
of each of these scaffolds from a representative common
intermediate 1d. The synthetic procedures permit the construc-
tion of a large diversity of substitution patterns for ready use in
combinatorial chemistry. In every case, the release of final
products from resin is by a cyclitive cleavage process. Since
this depends on successful completion of multiple intermediate
synthetic steps, the products are often quite pure, even though
previous steps involve only a filtration workup. Solid-phase
chemistry permits these multistep syntheses to be successfully
carried out on a micromole scale.
peptides, at either the N-terminus or C-terminus, or as individu-
ally assembled peptide segments with a wide variety of
conformationally restricted peptidomimetic linkers at the point
of juncture. For example, reductive aminations to lactams 3
(Scheme 5) could be done with the amine component R3 coming
from the N-terminus of a peptide in solution (N-terminal
modification), a peptide as the “amide” functionality R2 in
Scheme 5 (C-terminal modification), or peptides as components
of both R3 and R2 (segment condensation). Similarly, by a
process closely analogous to known peptide fragment condensa-
tion work, a peptide fragment possessing at its N-terminus a
cysteine residue could be reacted with 1 to create a bicyclic
lactam unit (analagous to the bicyclic lactam in structures 4,
Scheme 6) at the point of juncture. Finally, fragment and
segment condensations may be possible from 1 in which the
amide functionality is part of a peptide, and the other peptide
The mild conditions for many of these synthetic procedures
are noteworthy, as they offer the promise of using this chemistry
36
in peptide fragment condensations to produce modified
(
34) Review and selected examples of Pictet-Spengler reactions on solid
phase: (a) Review: Nielsen, T. E.; Diness, F.; Meldal, M. Curr. Opin.
Drug DiscoVery DeV. 2003, 6, 801-814. (b) Wang, H.; Ganesan, A. Org.
Lett. 1999, 1, 1647-1649. (c) Groth, T.; Meldal, M. J. Comb. Chem. 2001,
(36) Selected peptide fragment condensation reviews: (a) Benz, H. Synthesis
1994, 337-358. (b) Albericio, F.; Lloyd-Williams, P.; Giralt, E. Meth.
Enzymol. 1997, 289, 313-336. (c) Barlos, K.; Gatos, D. Biopolymers
(Peptide Science) 1999, 51, 266-278. (d) Borgia, J. A.; Fields, G. B. Trends
Biotechnol. 2000, 18, 243-251. (e) Dawson, P. E.; Kent, S. B. H. Ann.
ReV. Biochem. 2000, 69, 923-960. (f) Coltart, D. M. Tetrahedron 2000,
56, 3449-3491. (g) Okada, Y. Curr. Org. Chem. 2001, 5, 1-43. (h) Tam,
J. P.; Xu, J.; Eom, K. D. Biopolymers (Peptide Science) 2001, 60, 194-
205. (i) Nilsson, B. L.; Soellner, M. B.; Raines, R. T. Ann. ReV. Biophys.
Biomol. Struct. 2005, 34, 91-118. (j) Durek, T.; Becker, C. F. W. Biomol.
Eng. 2005, 22, 153-172. (k) Papas, S.; Strongvis, C.; Tsikaris, V. Curr.
Org. Chem. 2006, 10, 1727-1744.
3
, 45-63. (d) Orain, D.; Koch, G.; Giger, R. Chimia 2003, 57, 255-261.
(
e) Grimes, J. H., Jr.; Angell, Y. M.; Kohn, W. D. Tetrahedron Lett. 2003,
4
4, 3835-3838. (f) Kunda, B.; Sawant, D.; Chhabra, R. J. Comb. Chem.
2
005, 7, 317-321. (g) Danieli, B.; Giovanelli, P.; Lesma, G.; Passarella,
D.; Sacchetti, A.; Silvani, A. J. Comb. Chem. 2005, 7, 458-462. (h)
Nielsen, T. E.; Meldal, M. J. Comb. Chem. 2005, 7, 599-610. (i) Reference
18g. (j) Lee, S.-C.; Park, S. B. J. Comb. Chem. 2006, 8, 50-57. (k) Chang,
W.-J.; Kulkarni, M. V.; Sun, C.-M. J. Comb. Chem. 2006, 8, 141-144.
35) Based on SciFinder Scholar and Beilstein CrossFire searches of generic
scaffolds.
(
J. AM. CHEM. SOC.
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A R T I C L E S
Scott et al.
fragment (in solution) has, at its N-terminus, a residue (e.g.,
tryptophan) capable of undergoing a Pictet-Spengler reaction
preliminary studies in our laboratory indicated the feasibility
of synthesizing the monocyclic lactams through a reductive
amination, cyclitive cleavage process.
(Scheme 7).
Supporting Information Available: Full experimental details,
characterization data, and proton NMRs of all products are
provided. Crystallographic data are given for products 4a, 22b,
and 6a. This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment. Dedicated to the memory of Professor R.
9c
B. Merrifield. We gratefully acknowledge the financial support
of the National Institutes of Health (R01 GM028193) and the
Lilly Research Laboratories, along with their gift of resins
demonstrating the long-term stablility of key intermediates 1.
We also acknowledge the work of Dr. Jordi Alsina. His
JA069188Y
7088 J. AM. CHEM. SOC.
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VOL. 129, NO. 22, 2007