Solid-phase synthesis of amino- and carboxyl-functionalized unnatural α-amino acid amides

Article abstract of DOI:10.1021/ol901279v

Image Persented A new solid-phase synthesis efficiently incorporates three different substituents (from R¹-X, R²-CO₂H, and R³-NH₂) into a glycine-based peptidomimetic scaffold. The synthetic sequence

Full text of DOI:10.1021/ol901279v

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3558-3561
Solid-Phase Synthesis of Amino- and
Carboxyl-Functionalized Unnatural
r-Amino Acid Amides
William L. Scott,* Ziniu Zhou, Jacek G. Martynow, and Martin J. O’Donnell*
Department of Chemistry and Chemical Biology, Indiana UniVersity Purdue UniVersity
Indianapolis, Indianapolis, Indiana 46202-3274
wscott@iupui.edu; modonnel@iupui.edu
Received June 8, 2009
ABSTRACT
A new solid-phase synthesis efficiently incorporates three different substituents (from R1-X, R2-CO2H, and R3-NH2) into a glycine-based
peptidomimetic scaffold. The synthetic sequence is general and is typically accomplished in >50% overall isolated yield. Alkylating agents
with a range of reactivities and normal and branched primary amines give good results. Utility was demonstrated by the synthesis of a series
of protected phosphotyrosine mimetics.
The Distributed Drug Discovery (D3) project1,2 develops
methodology for the simple, economical synthesis of struc-
tural scaffolds commonly found in biologically active
molecules. The goal of D3 is to expedite the discovery of
drug leads for neglected diseases. It relies on solid-phase
chemistry, a critical component of which is the nature of
the linker used to join the substrate molecule to the solid
support.3 D3 has utilized various linkers to enable the solid-
phase synthesis of many derivatized scaffolds based on
R-monosubstituted and R,R-disubstituted resin-bound un-
natural amino acid intermediates.
Regardless of the linker, D3-type syntheses based on
derivatives of R-monosubstituted resin-bound unnatural
amino acids start from resin-bound glycine 1 and utilize an
activated benzophenone imine derivative 2. This proceeds,
depending on the linker, to acid 3 (from Wang),1b ester 4
(from Merrifield or Wang),2a,1c amide 5 (from Rink),4 or
ketone/aldehyde 6 (from Weinreb)5 (Scheme 1).
BAL (Backbone Amide Linker) resins3c,6 were developed
for peptide synthesis (Scheme 2). When amino acid amides
7 are made by conventional BAL chemistry, the naturally
occurring amino acids used are obtained commercially and
then attached to the BAL resin (9 to 10).
(1) (a) Scott, W. L.; O’Donnell, M. J. J. Comb. Chem. 2009, 11, 3–13.
(b) Scott, W. L.; Alsina, J.; Audu, C. O.; Babaev, E.; Cook, L.; Dage, J. L.;
Goodwin, L. A.; Martynow, J. G.; Matosiuk, D.; Royo, M.; Smith, J. G.;
Strong, A. T.; Wickizer, K.; Woerly, E. M.; Zhou, Z.; O’Donnell, M. J.
J. Comb. Chem. 2009, 11, 14–33. (c) Scott, W. L.; Audu, C. O.; Dage,
J. L.; Goodwin, L. A.; Martynow, J. G.; Platt, L. K; Smith, J. G.; Strong,
A. T.; Wickizer, K.; Woerly, E. M.; O’Donnell, M. J. J. Comb. Chem.
Our goal is to apply BAL methodology to the synthesis
of the fundamental peptidomimetic scaffold 7, now with the
2009, 11, 34–43
.
(2) For lead references concerning the solid-phase synthesis of unnatural
R-amino acids, peptides, and peptidomimetics from the authors’ laboratory,
see: (a) O’Donnell, M. J.; Zhou, C.; Scott, W. L. J. Am. Chem. Soc. 1996,
118, 6070–6071. (b) Scott, W. L.; Martynow, J. G.; Huffman, J. C.;
(4) Scott, W. L.; Delgado, F.; Lobb, K.; Pottorf, R. S.; O’Donnell, M. J.
Tetrahedron Lett. 2001, 42, 2073–2076.
O’Donnell, M. J. J. Am. Chem. Soc. 2007, 129, 7077–7088
.
(5) O’Donnell, M. J.; Drew, M. D.; Pottorf, R. S.; Scott, W. L. J. Comb.
Chem. 2000, 2, 172–181.
(3) (a) Guillier, F.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100, 2091–
2157. (b) Cironi, P.; Alvarez, M.; Albericio, F. Mini-ReV. Med. Chem. 2006,
6, 11–25. (c) Boas, U.; Brask, J.; Jensen, K. J. Chem. ReV. 2009, 109, 2092–
2118.
(6) (a) Jensen, K. J.; Alsina, J.; Songster, M. F.; Va´gner, J.; Albericio,
F.; Barany, G. J. Am. Chem. Soc. 1998, 120, 5441–5452. (b) Alsina, J.;
Albericio, F. Biopolymers 2003, 71, 454–477
.
10.1021/ol901279v CCC: $40.75
Published on Web 07/22/2009
 2009 American Chemical Society

Scheme 1
.
Synthesis of Unnatural R-Amino Acid Derivatives
from Resin-Bound Glycine 1
Scheme 3
.
Role of Imine Activating Group in Controlling
Mono- or Dialkylation Chemistry
precedence, we expected that initial model studies with
imines 15 and 16a would give the desired products 7 and
17, respectively (Scheme 4). Pilot alkylations of 15 with
benzyl bromide gave 7a (95% crude purity by LC/MS).
However, incomplete alkylation was observed with the less
reactive 1-iodooctane, which yielded 7g (28% crude purity
by LC/MS), and alkylation of the aldimine 16a with benzyl
bromide gave no dialkylated product 17 (R2 ) 4-NC-C6H4).
This lack of reactivity was unanticipated. The increased steric
environment imposed by the BAL linker likely alters the
acidity of 15 and 16a and/or the reactivity of the anion
obtained upon their deprotonation.
Scheme 2. Synthesis of Targets 7 by Conventional BAL
Chemistry
These preliminary studies suggested, however, that the
glycine aldimine 19 (Ar ) 3,4-Cl2C6H3) might provide the
required activation for complete monoalkylation to 16
without further undesired dialkylation (Scheme 5).
Alkylation of 19 with benzyl bromide and the base BTPP9
followed by acylation and cleavage provided clean monoalky-
lation to 7a (Scheme 5, Figure 1). No dialkyated product
was observed. As in the majority of our previous solid-phase
syntheses, the current products are racemic.10
To demonstrate the variety of substitutions possible at the
two more challenging scaffold positions, R1 and R3, twelve
products 7 were prepared exploring these variables with a
constant N-acylating agent (R2-CO2H ) 4-cyanobenzoic
acid) (Figure 1). Resin-bound 18 was prepared by reductive
amination of the aldehyde resin 8 with primary amines R3-
NH2 followed by coupling with FmocGly and deprotection.
18 was reacted with 3,4-dichlorobenzaldehyde to form 19.
potential to contain multiple variations of unnatural amino
acids. This paper reports a continuous solid-phase BAL-based
route that incorporates amines and the on-resin synthesis of
these unnatural amino acids. It requires an alternative
activated intermediate to the benzophenone imine 2 shown
in Scheme 1. Subsequent acylation with carboxylic acids and
final cleavage provides the N-acylated unnatural amino acid
amides 7.
(7) pKa (DMSO) of the ethyl ester starting materials and monomethylated
product: Ph2CdNCH2CO2Et, 18.7; Ph2CdNCH(Me)CO2Et, 22.8;
4-ClC6H4CHdNCH(Me)CO2Et, 19.2. See: (a) 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. (b) O’Donnell, M. J.; Delgado, F.; Hostettler, C.;
Schwesinger, R. Tetrahedron Lett. 1998, 39, 8775–8778.
A key premise in our solid-phase alkylation chemistry is
the ability to selectively monoalkylate the benzophenone
imines of glycine derivatives 2 to lead to products 3-6
(Scheme 1). This is based on our earlier solution-phase
studies,7 which predict that monoalkylation products 12
should be ∼104 less acidic than 2 as a result of A1,3 strain in
such products (Scheme 3). When R,R-dialkylation is required,
the ketimine in 2 is replaced with an aldimine (13),8 which
is not subject to the acid-weakening effect observed in 12.
On the basis of this extensive solution- and solid-phase
(8) (a) Scott, W. L.; Zhou, C.; Fang, Z.; O’Donnell, M. J. Tetrahedron
Lett. 1997, 38, 3695–3698. (b) Ten different aldehydes were previously
studied for the aldimine activating step.8a Since the 3,4-dichlorobenzaldehyde
imine gave the best results in this earlier case, this variable was not explored
in the current BAL imine-based work.
(9) BTPP ) tert-butylimino-tri(pyrrolidino)phosphorane.
(10) For a discussion, see footnotes 32-35 in ref 1b and associated text.
Org. Lett., Vol. 11, No. 16, 2009
3559

Scheme 4
.
Pilot BAL-Based Alkylations to Mono- and
Disubstituted Derivatives
Scheme 5
.
Synthetic Route to Secondary N-Acylated Unnatural
R-Amino Acid Amides
Figure 1. Survey of alkylating agents and amines for the preparation
of products 7. R2 ) 4-NC-C6H4. Yields of final products, after
chromatographic purification, were calculated on the basis of the
initial loading of the starting resin and are the overall yields for all
reaction steps starting from these resins.
n-propyl amine, and cyclohexylamine) illustrate compatibility
of this new procedure with normal and branched alkyl
amines.
As noted above (Scheme 4), initial pilot studies had
indicated reduced reactivity for BAL-based Schiff bases. To
probe the limitations this might impose with the new
activation procedure, more hindered benzylic alkylating
agents were examined (Figure 2, R1X ) 2-methylbenzyl
bromide, 2,6-dimethylbenzyl bromide, benzhydryl bromide,
and 9-bromofluorene). Ortho substitution, leading to 7m and
7n, did not appear to adversely affect reactivity. However,
the secondary halide benzhydryl bromide gave poor yields
of 7o and the more rigid and sterically demanding 9-bro-
mofluorene was problematic, yielding only trace amounts
(∼5% by LC/MS) of the crude product 7p.
The key alkylation of 19 to 16 was conducted at room
temperature with 10 equiv each of the alkylating agent and
the base BTPP. Hydrolysis, acylation, and resin cleavage to
7 followed standard procedures.1,2
Alkylating agents (R1-X) were used to represent an active
benzylic and allylic halide (benzyl bromide and allyl bro-
mide, respectively) as well as a less reactive halide (1-
iodooctane).11 The success with the latter halide is in marked
contrast with the poor conversion obtained in the earlier pilot
scale alkylation of 15 with 1-iodooctane to yield 7g. In
addition, a benzylic difluorophosphonate was used to prepare
products 7j-7l and demonstrate the syntheses of stable,
protected phosphotyrosine-containing peptidomimetics.12,13
In turn, the three primary amines R3-NH2 (benzylamine,
The all-solid-phase synthetic procedure reported here
incorporates three different substituents (from R1-X, R2-
(12) (a) Kumar, S.; Liang, F.; Lawrence, D. S.; Zhang, Z.-Y. Methods
2005, 35, 9–21. (b) Easty, D.; Gallagher, W.; Bennett, D. C. Curr. Cancer
Drug Targets 2006, 6, 519–532. (c) Heneberg, P. Curr. Med. Chem. 2009,
16, 706–733.
(13) Use of diethyl ((4-R-bromomethyl)phenyldifluoromethyl)phosphonate
to prepare protein tyrosine phosphatase (PTP) inhibitors:(a) Solas, D.; Hale,
R. L.; Patel, D. V. J. Org. Chem. 1996, 61, 1537–1539. (b) Liu, W.-Q.;
Roques, B. P.; Garbay, C. Tetrahedron Lett. 1997, 38, 1389–1392. (c) Liu,
W.-Q.; Vidal, M.; Olszowy, C.; Million, E.; Lenoir, C.; Dhoˆtel, H.; Garbay,
C. J. Med. Chem. 2004, 47, 1223–1233.
(11) For routes to a variety of R-side-chain functionalized R-amino acid
derivatives [-(CH2)n-G where G ) CN, OAc, SR, N3, NHR, NR2, NHAr,
alkyne, nitrogen heterocycle] via Schiff base derivatives of R-amino esters
and related compounds, see :(a) Scott, W. L.; O’Donnell, M. J.; Delgado,
F.; Alsina, J. J. Org. Chem. 2002, 67, 2960–2969. (b) Table 5 in ref 1b.
3560
Org. Lett., Vol. 11, No. 16, 2009

the complete sequence was examined with a variety of
alkylating agents R1-X and amines R3-NH2. Both reactive
and less reactive alkylating agents gave good results. Because
initial pilot studies indicated reduced reactivity for BAL-
based Schiff bases, more hindered alkylating agents were
probed. Some hindrance is tolerated, but bulky alkylating
agents were more problematic, with the sterically crowded
9-bromofluorene giving only a trace amount of product. Both
normal and branched primary amines are compatible with
the procedure. The syntheses of 7j, 7k, and 7l demonstrate
the ability to use this procedure to incorporate a stable
protected phosphotyrosine mimetic into a peptidomimetic
series.
Acknowledgment. We gratefully acknowledge the Na-
tional Institutes of Health (R01 GM028193), The National
Science Foundation (MRI CHE-0619254), and The Camile
and Henry Dreyfus Foundation for their financial support.
We thank Profs. J. R. McCarthy (IUPUI) and Z.-Y. Zhang
(Indiana University School of Medicine) for helpful discus-
sions.
Figure 2. Products 7m-7p from sterically demanding benzylic
halides. R2 ) 4-NC-C6H4.
CO2H, and R3-NH2) into the glycine-based peptidomimetic
scaffold 7. Utilizing simple Bill-Board solid-phase equip-
ment1 the 8-step sequence can typically be accomplished in
>50% overall isolated yield, providing a very efficient new
method to a wide variety of unnatural R-amino acid amides.
The reduced reactivity of benzophenone imine activated
intermediate 2 was overcome by utilizing aldimine activation
(e.g., 19) for the alkylation step. Clean monoalkylation was
observed at this critical stage. The scope and limitation of
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra of all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL901279V
Org. Lett., Vol. 11, No. 16, 2009
3561