Synthesis of C -propargylic esters of N-protected amino acids and peptides

Article abstract of DOI:10.1021/jo100537q

Figure presented Recent years have seen a huge surge of interest in the application of alkyne-derived motifs for so-called click chemistry. Given the critical importance of amino acids in organic synthesis as well as their myriad of applications in click chemistry it is interesting to note that the synthesis of C-propargyl derived amino acid esters has not been particularly well served. We report a convenient, straightforward, and high-yielding synthesis of structurally diverse C-propargyl-derived N-protected amino acid esters.

Full text of DOI:10.1021/jo100537q

pubs.acs.org/joc
Synthesis of C-Propargylic Esters of N-Protected
Amino Acids and Peptides
Sean P. Bew* and Glyn D. Hiatt-Gipson
School of Chemistry, University of East Anglia, Norwich,
NR4 7TJ, United Kingdom
s.bew@uea.ac.uk
FIGURE 1. Previously synthesized N-protected O-propargylic
R-amino acid esters.
Received March 21, 2010
SCHEME 1. Synthetic Routes to N-Cbz-β-aminoalanine Pro-
pargyl Ester 9
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochlor-
ide ($22 per gram), were low yielding, i.e., 14% for 6,4 required
long reaction times, i.e., 5 took 48 h to go to completion,5 or
employed DCC (dicyclohexylcarbodiimide), necessitating flash
chromatography for the efficient and complete removal of the
DCU (N,N0-dicyclohexylurea) byproduct, i.e., synthesis of 3
and 4 (Figure 1).6
Attempting the synthesis of ester 9 a solution of acid 7 was
warmed with propargyl alcohol 8 (Q = OH) and 10 mol %
tosic acid (Scheme 1). After 6 h an intractable brown tar had
formed. Subsequent analysis (1H NMR) indicated ∼10% of
ester 9 had formed but that this was embedded within a
complex unidentifiable mixture.
Recent years have seen a huge surge of interest in the
application of alkyne-derived motifs for so-called “click”
chemistry. Given the critical importance of amino acids in
organic synthesis as well as their myriad of applications in
“click” chemistry it is interesting to note that the synthesis
of C-propargyl derived amino acid esters has not been
particularly well served. We report a convenient, straight-
forward, and high-yielding synthesis of structurally
diverse C-propargyl-derived N-protected amino acid esters.
An alternative procedure was required. The O-propargy-
lation of R-amino carboxylic acids with use of propargyl
bromide and base has been reported with (S)-tyrosine and
(S)-aspartic acid.7 Reinvestigating the synthesis of ester 9 we
stirred acid 7 in dimethylformamide with propargyl bromide
and anhydrous potassium carbonate (1.2 equiv). After a
simple workup, i.e., dilute with aqueous citric acid, extract
with ethyl acetate, and filter through a Varian SPE cartridge
(NH2), an unoptimized 81% yield of ester 9 was afforded
that was pure enough (1H NMR indicated >95%) to be used
for a subsequent reaction.
With this result we set about investigating the scope of the
reaction with alternative N-protected R-amino acids. Both
aryl and alkyl side chain equipped R-amino acids such as
N-Cbz-(S)-phenylalanine and N-Bz leucine (entries A and B,
Table 1) afforded the corresponding propargyl esters 10 and
A search of SciFinder reveals that to date over 1700 papers
have been published on “click chemistry”. Critical to its
continued success and development is the ready availability
of structurally diverse alkyne (and azide) starting materials.
In an ongoing extension of a Trøger base project1 we
required an efficient, cheap, reliable, and straightforward
synthesis of structurally diverse N-protected R-amino acid
propargyl esters suited to “click” chemistry. Given the wide-
spread availability of structurally diverse natural and un-
natural amino acids and the extensive interest in “click”
chemistry we were surprised that a search on SciFinder
afforded a limited number of R-amino acid propargyl esters.
Furthermore upon closer inspection many of the proposed
syntheses employed elevated reaction temperatures, i.e., 70 °C,2
multistep reaction processes, i.e., synthesis of propargyl ester 3
from methyl ester 1 via acid 2,3 and the use of relatively
expensive reagents, i.e., synthesis of esters 5 and 6 utilized
(4) Sanda, F.; Araki, H.; Masuda, T. Macromolecules 2005, 38, 10605.
(5) Loethen, S.; Ooya, T.; Soo, C. H.; Yui, N.; Thompson, D. H.
Biomacromolecules 2006, 7, 2501.
(1) Bew, S. P.; Legentil, L.; Scholier, V.; Sharma, S. V. Chem. Commun.
2007, 389.
(2) Loeffler, L. J.; Sajadi, Z.; Hall, I. H. J. Med. Chem. 1977, 20, 1578.
(3) Werner, S.; Iyer, P. S.; Fodor, M. D.; Coleman, C. M.; Twining, L. A.;
Mitasev, B.; Brummond, K. M. J. Comb. Chem. 2006, 8, 370.
(6) Haridas, V.; Lal, K.; Sharma, Y. K.; Upreti, S. Org. Lett. 2008, 10,
1645. Brummond, K. M.; Mitasev, B. Org. Lett. 2004, 6, 2245.
(7) Sudhir, V. S.; Venkateswarlu, C.; Musthafa, O. T. M.; Sampath, S.;
Chandrasekaran, S. Eur. J. Org. Chem. 2009, 2120.Mandal, P. K.;McMurray,
J. S. J. Org. Chem. 2007, 72, 6599.
DOI: 10.1021/jo100537q
r
Published on Web 05/05/2010
J. Org. Chem. 2010, 75, 3897–3899 3897
2010 American Chemical Society

Bew and Hiatt-Gipson
JOCNote
TABLE 1. Examples of Structurally Diverse N-Protected O-Propargylic Amino Acid Esters and Peptides Synthesized in This Study
11 in 86% and 83% yields, respectively. Similarly the cyclic
R-amino acid N-Cbz-(S)-proline derived propargyl ester (12,
entry C) was returned in an excellent 95% yield and without
recourse to flash chromatography. The synthesis of propar-
gyl ester 13 derived from the doubly N-Cbz protected (S)-
lysine was achieved in a pleasing 85% yield (entry D), again
no column chromatography was required. Subjecting differ-
entially N,O-diprotected N-Cbz-(S)-serine-O-benzyl to pro-
pargylation afforded the desired ester 14 (Table 1, entry E,
81% yield) with both N-Cbz and O-benzyl protecting groups
remaining intact. Similarly the diprotected mono-O-benzyl
ester N-Cbz aspartic acid precursor afforded the correspond-
ing R-amino propargylic ester 15 in an 82% yield (entry F).
Incorporating an N-Boc protecting group within (S)-glu-
tamic acid, (S)-leucine, (S)-proline, and (S)-phenylalanine
afforded (Scheme 1) the expected N-Boc protected R-amino
acid propargylic esters 16-19 in 89%, 92%, 96%, and 91%
yields, respectively (entries G-J), without recourse to column
chromatography. Similarly incorporating an unnatural, aryl
containing R-amino acid, i.e., N-Boc-4-fluoro-(S)-phenylgly-
cine, afforded the corresponding propargylic ester 20 in a
pleasing 86% yield (entry K).
All attempts at transforming N-acetylglycine, N-Fmoc-
(S)-valine, N-Fmoc-(S)-phenylalanine, N-Fmoc-β-alanine,
or N-Fmoc-(S)-alanine into the corresponding propargylic
esters (not shown) employing the reaction conditions
outlined in Scheme 1 failed to return any of the desired
products. Seemingly the use of base labile N-protecting
groups resulted in their cleavage during the reaction
process.
3898 J. Org. Chem. Vol. 75, No. 11, 2010

Bew and Hiatt-Gipson
JOCNote
A particularly useful application would focus on the
ability to generate propargylic esters of dipeptides. With this
in mind we subjected the simple monoprotected N-Boc-gly
gly dipeptide to our standard propargylation reaction con-
ditions (Scheme 1). After a simple workup we were delighted
to isolate the desired propargyl ester of N-Boc-gly-gly (21) in
an unoptimised 67% yield (entry L, Table 1).
The application of our O-propargylation reaction to
R-amino acids that have heteroatoms embedded within
their side chains was deemed worthy of investigation.
Initiating this study we probed the O-propargylation of
N-Boc-(S)-methionine sulfone. The desired ester (22) was
afforded in an unoptimized but pleasing 71% yield (entry
M). Similarly incorporating imidazole equipped R-amino
acids such as 3-N-benzyl-R-N-Boc-(S)-histidine (entry N),
3-N-BOM-R-N-Boc-(S)-histidine (entry O) afforded the cor-
responding propargyl esters 23 and 24 in 41% and 43% yields,
respectively.
acids. With this in mind we took commercially available
(R)-3-(Boc-amino)-3-phenylpropionic acid and subjected it
to our standard conditions with propargyl bromide and
potassium carbonate in dimethylformamide. The corre-
sponding propargyl ester (27) was afforded as a white
powder in a 75% yield (entry R).
In summary, the efficient synthesis of C-propargylated
R-amino acids has been achieved by using very mild reaction
conditions that tolerate the majority of commonly used
amino acid protecting groups. Utilizing cheap reagents the
desired products are afforded, in the majority of cases, pure
enough to be employed as is, thus negating the cost and
environmental impact of purification. It is envisaged that
this protocol will be widely applicable, affording valuable
C-propargylated amino acids building blocks that should
find significant use in the synthetic chemistry community.
Experimental Section
The synthesis of (S)-serine derived propargylic ester 25 has
been previously reported; however, the yield was a very poor
14%.4 We felt our procedure may offer this potentially
valuable R-amino acid building block in a higher yield.
Consequently we were delighted that subjecting N-Boc-(S)-
serine to the reaction conditions outlined in Scheme 1 aff-
orded ester 25 in a significantly improved 65% yield (entry P).
The dansyl group is routinely employed as a fluorogenic
agent for the N-derivatization and analysis of R-amino acids
and peptides.8 Furthermore Borthwick et al. has demon-
strated that a series of N-dansyl-(S)-proline R-methylpyrro-
lidine-5,5-lactam derivatives display single-figure μM inhi-
bition of human cytomegalovirus (HCMV) protease.9 Thus
the ability to generate a N-dansyl-(S)-proline propargyl ester
26 may have significant applications in the spectroscopic
determination of amino acids or peptides as well as acting
as a valuable tool for probing biological systems. With this
in mind we subjected commercially available N-dansyl-(S)-
proline to our standard propargylic reaction conditions. We
were delighted that ester 26 (entry Q) was afforded in an 85%
yield and, similar to previous examples, the product was pure
enough to be used “as is”.
General Procedure. A flame-dried 25-mL round-bottomed
flask was charged with N-Cbz-(S)-proline (1 g, 4 mmol) and
anhydrous potassium carbonate (830 mg, 6 mmol) in DMF
(5 mL). The resulting suspension was stirred for 30 min under an
atmosphere of nitrogen. Propargyl bromide (80% in toluene,
710 mg, 6 mmol) was added and the reaction was stirred for 16 h
at ambient temperature. The resulting mixture was diluted with
water (5 mL), acidified with citric acid (1 mL), and extracted
with ethyl acetate (2 ꢀ 2 mL). The combined organic extracts
were washed with brine (2 mL), dried with magnesium sulfate,
and filtered through NH2 loaded silica. Solvent removal af-
forded 12 (1.1 g, 3.8 mmol) as a yellow oil in a 95% yield, with
the following physicochemical properties.
1H NMR (400 MHz, CDCl3) δ 7.23 (m, 5H, ArH), 5.03 (m,
2H, CH2(cbz)), 4.62 (m, 1H, CHH(yne)), 4.45 (s, 1H, CHH(yne)),
4.28 (m, 1H, RCH), 3.41 (m, 2H, δCH2), 2.41 (1H, CH(yne)), 2.12
(d, J = 7.42 Hz, 1H, βCHH), 1.85 (m, 3H, βCHH, γCH2); 13
C
NMR (75 MHz, CDCl3) δ 172.1, 171.9, 154.9, 154.2, 136.7,
136.6, 128.5, 128.4, 128.0, 127.9, 127.9, 127.8, 77.2, 75.3, 66.9,
66.9, 58.9, 58.6, 52.4, 52.3, 46.8, 46.3, 30.6, 29.6, 24.1, 23.3; FT-
IR (KBr neat) 3285, 2956, 2883, 1753, 1704, 1452, 1417, 1353,
1167; m/z [ES] M þ Na (found) 310.0, (calcd) 310.11; HRMS
(NSI) calcd for C16H21N2O4 305.1496, found 305.1496; [R]25
-80.3 (c 1.0, CHCl3).
D
Our study to date had focused on, in the majority of cases,
investigating N-protected R-amino acids derived from nat-
ural sources. Although we did not envisage any issues it was
thought prudent to establish that the procedure outlined in
Scheme 1 also worked for unnatural N-protected β-amino
Acknowledgment. The authors would like to acknowledge
the financial assistance of the University of East Anglia,
EPSRC and Chemistry Innovation. We would also like to
thank Librarion for providing us with some of the R-amino
acids used in this study.
(8) Lam, S. J. Chromatogr. Sci. 1984, 22, 416. Chen, Z. J. Chromatogr.
Libr. 2005, 70, 309. Takeuchi, T. J. Chromatogr. Libr. 2005, 70, 229.
(9) Borthwick, A. D.; Crame, A. J.; Ertl, P. F.; Exall, A. M.; Haley, T. M.;
Hart, G. J.; Mason, A. M.; Pennell, A. M. K.; Singh, O. M. P.; Weingarten,
G. G.; Woolven, J. M. J. Med. Chem. 2002, 45, 1. Borthwick, A. D.; Exall, A.
M.; Haley, T. M.; Jackson, D. L.; Mason, A. M.; Weingarten, G. G. Bioorg.
Med. Chem. Lett. 2002, 12, 1719.
Supporting Information Available: General experimental
methods, additional experimental procedures, and compound
characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 11, 2010 3899