Se -(9-fluorenylmethyl) selenoesters; Preparation, reactivity, and use as convenient synthons for selenoacids

Article abstract of DOI:10.1021/ol401677a

Se-(9-Fluorenylmethyl) selenoesters are readily prepared, stable precursors to selenocarboxylates, which they liberate on treatment with DBU. Fm selenoesters are compatible with the use of TFA for the removal of Boc groups and with simple peptide bond for

Full text of DOI:10.1021/ol401677a

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Se-(9-Fluorenylmethyl) Selenoesters;
Preparation, Reactivity, and Use as
Convenient Synthons for Selenoacids
†
Fabien Fecourt, Bernard Delpech, Oleg Melnyk, and David Crich*
†
‡
,§
ꢀ
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS,
1 Avenue de la Terrasse, 91190 Gif-sur-Yvette, France, CNRS UMR 8161,
Univ. Lille Nord de France, Institut Pasteur de Lille, 59021, Lille, France, and
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit,
Michigan 48202, United States
Dcrich@chem.wayne.edu
Received June 13, 2013
ABSTRACT
Se-(9-Fluorenylmethyl) selenoesters are readily prepared, stable precursors to selenocarboxylates, which they liberate on treatment with DBU.
Fm selenoesters are compatible with the use of TFA for the removal of Boc groups and with simple peptide bond forming reactions. Amino acid
derived selenocarboxylates condense directly with amines to give amides, react smoothly with isocyanates and isothiocyanates to give amides,
and couple with electron-deficient azides also to give amides.
In recent years, thioacids1 have featured prominently
in the search2 for improved methods for amide bond
formation because of (i) their increased acidity with respect
to the corresponding carboxylic acids; (ii) the greater
nucleophilicity of the thiocarboxylate with respect to the
carboxylate anion; and (iii) the increased reactivity of
derived thioestersoversimpleesterstowardamines. Amide
bond forming reactions based on the thioacid function
include (i) reaction with azides and in particular electron-
deficient azides;3 (ii) reaction with 2,4-dinitrobenzenesul-
fonamides and with other electron-deficient arenes in the
presence of amines;4 (iii) reaction with isocyanates, iso-
thiocyanates, and thiocarbamates;5 (iv) reaction with
isonitriles;6 and (v) direct reaction with amines in the
† Institut de Chimie des Substances Naturelles.
‡ Univ. Lille Nord de France.
§ Wayne State University.
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10.1021/ol401677a
XXXX American Chemical Society

presence of silver or copper salts, or other electrophiles.7
Selenoacids,8 with the more polarizable and more nucleo-
philic selenium atom,9 have the potential for even greater
reactivity in amide bond forming reactions, either as direct
precursors to amides or as precursors to reactive selenoe-
sters. Indeed, this potential has been recognized by several
groups, particularly with respect to the increased reactivity
of selenocarboxylates toward simple azides,10 and has
begun to be exploited in the native chemical ligation of
peptides.11 The potential of selenoacid chemistry is, how-
ever, limited by the instability of selenocarboxylates to-
ward aerobic oxidation and by the limited range of
methods developed to generate them in situ. Thus, seleno-
carboxylates are typically generated by the reaction of
metal (hydrogen) selenides with activated carboxylic acid
derivatives,10d,11a,12 reaction of trimethylsilyl selenocarbox-
ylates with the fluoride anion,12b,13 nucleophilic deacylation
of diacyl selenides10b,14 and diacyl diselenides,10c,15 or selena-
tion of carboxylic acids10a,16 with Woollins’ reagent.17 While
these methods have proved adequate for the synthesis of
simple selenocarboxylates, all suffer from problems asso-
ciated with the lack of functional group compatibility or
the use of unstable air-sensitive reagents.
By analogy with the generation of thiocarboxylates by
elimination from S-(9-fluorenylmethyl)4c or S-(2-
cyanoethyl)3l thiocarboxylates, we conceived that the use-
fulness of selenocarboxylates in synthesis would be ex-
panded by the availability of a general, clean method for
their generation in situ from a readily accessible, stable
derivative such as a Se-(9-fluorenylmethyl) selenocarbox-
ylate. Toward this end we prepared the yellow, crystalline,
and air-stable bis(9-fluorenylmethyl) diselenide 2 by reac-
tion of 9-fluorenylmethyl tosylate 1 with the reagent
generated in situ by the action of sodium borohydride on
metallic selenium (Scheme 1).
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Scheme 1. Preparation of Bis(9-fluorenylmethyl) Diselenide
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Various amino acid based Fm selenoesters were then
prepared by reduction of the diselenide 2 with sodium
borohydride in ethanolic THF followed by reaction with
N-Boc-protected aminoacyl N-hydroxysuccinimides
(Table 1). These Fm selenoesters were isolated as white
or off-white solids in good yield following chromatogra-
phy over silica gel.
Table 1. Preparation of Fluorenylmethyl Selenoestersa
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entry
product
% yield
1
2
3
4
5
Boc-Phe-SeFm (3)
Boc-D-Phe-SeFm (4)
Boc-Val-SeFm (5)
77
74
81
75
60
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Kanda, T.; Murai, T.; Ishihara, H. J. Chem. Soc., Chem. Commun. 1993,
277–278. (c) Koketsu, M.; Nada, F.; Hiramatsu, S.; Ishihara, H.
J. Chem. Soc., Perkin Trans. 1 2002, 737–740.
Boc-Ala-SeFm (6)
Boc-Asp-(γSeFm)-OBn (7)
a All AAs have the L-configuration unless otherwise indicated.
(13) Kawahara, Y.; Kato, S.; Kanda, T.; Murai, T. Bull. Chem. Soc.
Jpn. 1994, 67, 1881–1885.
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44b, 1519–1523.
Subsequent treatment with trifluoroacetic acid in di-
chloromethane, followed by evaporation and trituration
with ether, gave the corresponding ammonium salts as
white solids (Table 2). Coupling with a N-Boc-protected
amino acid with the aid of O-benzotriazolyl tetramethy-
luronium hexafluorophosphate (HBTU) in the presence of
diisopropylethylamine (DIEA) then afforded a series of
(15) Ishihara, H.; Muto, S.; Kato, S. Synthesis 1986, 128–130.
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~
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Boc Removal and Dipeptide Formation in the Presence of 9-Fluorenylmethyl Selenoestersa
entry
substrate
ammonium salt
% yield Boc-AA2-OH
dipeptide
% yield
1
2
3
4
5
Boc-Phe-SeFm (3)
Boc-D-Phe-SeFm (4)
Boc-Val-SeFm (5)
Boc-Ala-SeFm (6)
TFA Phe-SeFm (8)
94
90
95
94
91
Boc-Val-OH
Boc-Val-OH
Boc-Phe-OH
Boc-Phe-OH
Boc-Val-OH
Boc-Val-Phe-SeFm (13)
Boc-Val-D-Phe-SeFm (14)
Boc-Phe-Val-SeFm (15)
Boc-Phe-Ala-SeFm (16)
Boc-Val-Asp-(γSeFm)-OBn (17)
80
81
88
79
70
3
TFA
3 D-Phe-SeFm (9)
3
3
TFA Val-SeFm (10)
TFA Ala-SeFm (11)
Boc-Asp-(γSeFm)-OBn (7) TFA Asp-(γSeFm)-OBn (12)
3
a All AAs have the L-configuration unless otherwise indicated.
dipeptides in good yield (Table 2). The ability to remove
the Boc-protecting group in this manner and conduct a
subsequent peptide bond-forming reaction demonstrates
the stability of the selenoester function toward acidic con-
ditions and its reduced reactivity toward amines as com-
pared to standard activated amino acid esters, as is also ap-
parent from the recent solid-phase work of Durek et al.11b
Comparison of the 13C NMR spectra of the diastereomeric
dipeptidyl selenoesters 13 and 14 revealed the absence of
epimerization R- to the selenoester function in any of the
three steps reported in Tables 1 and 2.
and confirming the high reactivity of selenoesters toward
soft nucleophiles such as amines.18 Similar coupling reac-
tions were alsoobservedwithbenzylamine(Table 3). How-
ever, in light of the subsequently established reaction
of amines with selenocarboxylates (Table 4) we cannot
rule out the possibility of a two-stage mechanism for these
reactions.
The apparent direct reaction of the selenoesters with
basic amines was circumvented by the use of DBU as the
base as also reported by Namelikonda and Manetsch for
the analogous fluorenylmethyl thioesters.3k The so-formed
selenocarboxylates were not isolated but were immediately
exposed to reaction with amino acid methyl esters in DMF
at rt resulting in the formation of a series of dipeptides
(Table 4). Beyond the simple amino acid derivatives of
entries 1À3 of Table 4, entry 4 demonstrates application
of this chemistry to the side chain of aspartic acid, while entry
5 establishes viability at the dipeptide level. The direct reac-
tion of selenocarboxylates with amines to give amides in this
manner is reminiscent of the analogous reaction of thiocar-
boxylates with amines reported by Wang and Danishefsky,
and others, albeit they proceed in significantly better yield in
the absence of additives such as HOBT.7n,p We cannot rule
out the possibility of a mechanism involving oxidation to
the corresponding diacyl diselenides by extraneous air despite
our best efforts to the contrary. However, in view of the
Table 3. Reaction of Fluorenylmethyl Selenoesters with
Aminesa
entry
substrate
product
% yield
1
2
3
Boc-Phe-SeFm (3)
Boc-Phe-SeFm (3)
Boc-Val-SeFm (5)
Boc-Phe-NC5H10 (18)
Boc-Phe-NHBn (19)
Boc-Val-NHBn (20)
70
87
72
a All AAs have the L-configuration.
Attempted deprotection of the Fm selenoester 3 with
piperidine in DMF, as previously employed for the Fm
thioesters,4c resulted only in the displacement of selenoe-
ster function giving only the piperidyl amide 18 (Table 3)
Table 4. Formation of Selenocarboxylates and Their Reaction with Aminesa
entry
substrate
selenocarboxylateb
H-AA2OMe
product
% yield
1
2
3
4
5
Boc-Phe-SeFm (3)
Boc-Phe-SeÀ (21)
H-Val-OMe
H-Leu-OMe
H-D-Phe-OMe
H-Val-OMe
H-D-Phe-OMe
Boc-Phe-Val-OMe (25)
64
56
64
78
59
Boc-Val-SeFm (5)
Boc-Val-SeÀ (22)
Boc-Val-Leu-OMe (26)
Boc-Val-SeFm (5)
Boc-Val-SeÀ (22)
Boc-Asp-(γSeÀ)-OBn (23)
Boc-Phe-Val-SeÀ (24)
Boc-Val-D-Phe-OMe (27)
Boc-Asp-(γ-Val-OMe)-OBn (28)
Boc-Phe-Val-D-Phe-OMe (29)
Boc-Asp-(γSeFm)-OBn (7)
Boc-Phe-Val-SeFm (15)
a All AAs have the L-configuration unless otherwise indicated. b Selenocarboxylates were not isolated but used immediately in situ.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 5. Formation of Selenocarboxylates and Their Reaction with Various Electrophilesa
entry
substrate
selenocarboxylateb
electrophile
product
% yield
1
2
3
4
5
6
7
Boc-Val-SeFm (5)
Boc-Phe-SeFm (3)
Boc-Phe-SeFm (3)
Boc-Phe-SeFm (3)
Boc-Phe-SeFm (3)
Boc-Phe-SeFm (3)
Boc-Val-SeFm (5)
Boc-Val-SeÀ (22)
Boc-Phe-SeÀ (21)
Boc-Phe-SeÀ (21)
Boc-Phe-SeÀ (21)
Boc-Phe-SeÀ (21)
Boc-Phe-SeÀ (21)
Boc-Val-SeÀ (22)
PhCOCH2Br
Me2NpC6H4N3
MepC6H4SO2N3
PhCH2N3
Boc-Val-SeCH2COPh (30)
Boc-Phe-NHpC6H4NMe2 (31)
Boc-Phe-NHSO2pC6H4Me (32)
Boc-Phe-NHCH2Ph (19)
Boc-Phe-NHPh (33)
85
43
65
26
48
84
86
PhNdCdO
PhNdCdS
Boc-Phe-NHPh (33)
PhNdCdS
Boc-Val-NHPh (34)
a All AAs have the L-configuration. b Selenocarboxylates were not isolated but used immediately in situ.
acidity of hydrogen selenide (pKa1 3.89, pKa2 11.0) as
compared to that of hydrogen sulfide (pKa1 6.88, pKa2
14.15) we consider it likely that selenide (Se2À) is a viable
leaving group in this chemistry.
Overall, we demonstrate that Se-(9-fluorenylmethyl)
selenoesters are readily prepared, stable precursors to
selenocarboxylates, which they liberate on treatment with
DBU. The Fm selenoesters are compatible with the use of
TFA for the removal of Boc groups and with simple
peptide bond forming reactions. Amino acid derived sele-
nocarboxylates condense directly with amines to give
amides, react smoothly with isocyanates and isothiocya-
nates to give amides, and couple with electron-deficient
azides also to give amides.
Finally, we turned our attention to the reaction of the in
situ generated N-protected amino acyl selenocarboxylates
with other electrophiles (Table 5). Thus, as anticipated in
view of the precedent,10a,11a,12c selenocarboxylates are alky-
lated by a simple alkyl halide to give selenoesters (Table 5,
entry 1). N-Protected amino acyl selenocarboxylates react at
rt with azides to give amides (Table 5, entries 2À4), as has
been reported for simple selenocarboxylates,10 although at
least for the present examples the reaction is noticeably
more efficient with electron-deficient azides as is known
to be the case for thiocarboxylates.3g Finally, again analo-
gously with the thiocarboxylates,5a,d we demonstrate the
reaction of selenocarboxylates with isocyanates and iso-
thiocyanates to give amides (Table 5, entries 5À7).
Acknowledgment. We acknowledge financial support
from the ANR grant “click-unclick”.
Supporting Information Available. Experimental pro-
cedures and characterization data for all compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org.
(18) Chu, S.-H.; Mautner, H. G. J. Org. Chem. 1966, 31, 308–312.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX