General, Mild, and Metal-Free Synthesis of Phenyl Selenoesters from Anhydrides and Their Use in Peptide Synthesis

Article abstract of DOI:10.1021/acs.joc.7b00173

A mild, practical, and simple procedure for phenyl selenoesters synthesis from several anhydrides and diphenyl diselenide was developed. This transition-metal-free method provides a straightforward entry to storable Fmoc-amino acid selenoesters which are effective chemoselective acylating reagents. An application to oligopeptide synthesis was illustrated.

Full text of DOI:10.1021/acs.joc.7b00173

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Article
General, Mild, and Metal-Free Synthesis of Phenyl Selenoesters
from Anhydrides, and their Use in Peptide Synthesis
Andrea Temperini, Francesca Piazzolla, Lucio Minuti, Massimo Curini, and Carlo Siciliano
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00173 • Publication Date (Web): 17 Apr 2017
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General, Mild, and MetalꢀFree Synthesis of Phenyl Selenoesters from Anhydrides, and their
Use in Peptide Synthesis
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Andrea Temperini,*† Francesca Piazzolla,† Lucio Minuti,‡ Massimo Curini† and Carlo Siciliano,#
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†Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, 06123 Perugia,
Italy
‡ Dipartimento di Chimica, Biologia e Biotecnologie, Università di Perugia, Via Elce di Sotto 8,
06123 Perugia, Italy
# Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria,
Edificio Polifunzionale, 87030 Arcavacata di Rende, Cosenza, Italy
Dedicated to the memory of Prof. Alessandro Degl’Innocenti
andrea.temperini@unipg.it
Acylation
O
NaBH4, 40 °C
EtOAc, 30 min
AcOH, rt
O
PhSeSePh
R
SePh
X= OCOR, OiBu
R
X
Peptide Synthesis
ABSTRACT: A mild, practical and simple procedure for phenyl selenoesters synthesis from
several anhydrides and diphenyl diselenide was developed. This transition metalꢀfree method
provides a straightforward entry to storable Fmocꢀamino acid selenoesters which are effective
chemoselective acylating reagents. An application to oligopeptide synthesis was illustrated.
INTRODUCTION
Selenoesters1 have shown to be useful intermediates in synthetic organic chemistry as
precursors of acyl radicals,2 mild acyl transfer reagents3 and intermediate to access ketones.4 In
addition, selenoesters have attracted attention in material science5 and pharmaceutical science.6
Furthermore, in recent years, some peptide segment assembly strategies, based on native chemical
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ligation (NCL) with peptidylꢀselenoesters as acyl donors,7 have been investigated. Various synthetic
methods for the synthesis of selenoesters have been developed and they are usually based on the
reaction of acyl chloride with selenols,8 alkali metal selenolates,9 phenyltributyl stannyl selenides10
or phenylseleno trimethylsilane,11 as well as with selenolate anions generated in situ by reduction
of diselenides with transition metals.12 Additional methods, including reaction of carboxylic acids
with selenocyanates13 or phenylselenenyl chloride,14 alkylation of selenocarboxylates,15 oxidative
coupling of aldehydes with diphenyl diselenide16 and oxidative hydration of
(phenylseleno)acetylenes,17 have also been reported. However, many of the above cited methods
suffer from synthetic drawbacks due to the limited availability and air instability of selenium
containing precursors, unsatisfactory yields and limited to narrow substrate scope. Furthermore, the
methods reported are sometimes not attractive, as they can be environmentally unsafe due to harsh
reaction conditions and toxic catalysts and solvents. Thus, the development of a mild, efficient,
versatile and nonꢀmetalꢀmediated method for the synthesis of selenoester is desiderable.
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Considering our ongoing research into organoselenium chemistry18 we wish to report an account on
phenyl selenoesters synthesis from anhydrides. Despite some scattered reports on phenyl
selenoesters synthesis by reaction of alkali metal benzeneselenolates with symmetric anhydrides,19
the relevance of this method has not been fully explored. Thus, herein we propose a simple
experimental procedure to prepare phenyl selenoesters by reaction of diphenyl diselenide and
sodium borohydride in EtOAc, followed by anhydride addition. To date, there have been no reports
on reduction of diphenyl diselenide with sodium borohydride in EtOAc as solvent.
RESULTS AND DISCUSSION
Synthesis of Selenoesters from Anhydrides. We performed a set of experiments using
benzoic anhydride 2a as model substrate to determine the best reaction conditions (see Table S1 and
S2, Supporting Information). As a result, the model reaction was carried out with diphenyl
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diselenide 1a (1 equiv) and NaBH4 (2 equiv) at 40 °C in EtOAc for 30 minutes followed by glacial
acetic acid addition at room temperature (10 equiv). The treatment of the resulting mixture with
benzoic anhydride (2.1 equiv) at room temperature gave (5 h) selenoesters 3a in 94% isolated yield.
Using the optimized conditions, the scope of the reaction was extended to a wide range of aromatic
and aliphatic anhydrides (Table 1). All reactions were clean and efficient and the phenyl
selenoesters 3aꢀg were obtained in good to excellent yields. Notably, the reaction with diꢀtertꢀbutyl
dicarbonate generated the new selenocarbonate 3f in high yield. In this example, glacial acetic acid
was not added (Table 1, entry 6) Moreover, this method let us prepare for the first time the freeꢀ
amino selenoesters 3g (Table 1, entry 7) starting from isatoic anhydride.
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Table 1. Preparationa of phenyl selenoesters 3aꢀg from anhydrides 2
O
NaBH4, 40 °C
AcOH, rt
PhSeSePh
EtOAc, 30 min Anhydride 2
R
SePh
1a
3
Entry
1
Anhydride
t (h)
5
Product
Yield (%)b
O
O
O
94
O
SePh
2a
3a
O
NO2
O
O
NO2
O
SePh
2
24
86
NO2
3b
2b
O
O
O
O
O
O
O
3
4
5
8
90
88
89
O
2c
SePh
3c
O
14
18
O
2d
SePh
3d
O
O
SePh
2e
3e
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O
O
O
6
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18
23
92c
74
O
O
SePh
SePh
O
O
2f
3f
O
O
O
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N
O
NH2
H
3g
2g
a
Conditions: substrate 1a (1 mmol), NaBH4 (2 equiv), AcOH (10 equiv), anhydride 3 (2.1 equiv),
EtOAc (10 mL). b Yield of isolated product after chromatographic purification. c Glacial acetic acid
was not added.
As far as the diselenide is concerned, the influence of an electronꢀdonating or electronꢀ
withdrawing group, such as chloro and methoxy groups, on the aromatic ring of the diselenide was
also investigated (Scheme 1).
Scheme 1. Synthesis of two selenoesters using different diselenide moieties
OMe
O
Bz2O
20 h
NaBH4, EtOAc AcOH
p-(OMe)C6H5Se)2
rt, 30 min
40 °C, 30 min
Ph
Se
1b
4
86%
O
NaBH4, EtOAc
40 °C, 30 min
AcOH
Ac2O
20 h
o-(Cl)C6H5Se)2
rt, 30 min
Se
1c
5
82%
Cl
Both groups didn’t show a significant influence on the diselenide reduction and the nucleophilic
selenium reactivity. Very good yields of the expected selenoesters 4 and 5 were achieved.
Synthesis of Selenoesters from Carboxylic Acids. In order to access more easily a wide
library of selenoesters, we envisioned the use of carboxylic acids 6 instead of anhydrides 2 as
substrates. Accordingly, the starting acid was converted into the reactive anhydride intermediate
with iBuOCOCl and Nꢀmethylmorpholine (NMM), then the selenoesters were obtained by addition
of nucleophilic selenium species (Scheme 2). To the best of our knowledge, only three examples for
preparing selenoesters from mixed anhidrides have primarly focused on the use of readily oxidable
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benzenselenol3b or ethanolic sodium benzeneseleno(triethoxy)borate20a or by employing sodium
phenylselenide obtained from benzenselenol.20b
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7
8
Scheme 2. Synthesis of selenoesters from carboxylic acids
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1a,
NaBH4,EtOAc
O
O
O
O
i-BuOCOCl, NMM
40 °C, then AcOH
EtOAC, 30 min
0 °C
R
SePh
R
OH
rt, 13-16 h
R
O
O
3
6
In preliminary experiments it was found that the mixed anhydride intermediate, prepared from
phenylacetic acid 6a and 1.1 equiv. of Nꢀmethyl morpholine and 1.1 equiv. of isobutyl
chloroformate, was stable at 0 °C in EtOAc solution. The anhydrideꢀforming reaction appeared to
be complete in 30 minutes at 0°C. After addition of 1.2 equiv. of nucleophilic selenium species
(prepared as above) and overnight stirring at room temperature, the corresponding phenyl
selenoester 3h was obtained in a 70% yield. Higher amount of nucleophilic selenium species or
shorter reaction time diminished the product yield. A better yield (82%) of product 3h was
obtained when the reaction was carried out with a 10% in excess of mixed anhydride with respect to
the nucleophilic selenium species (Table 2). The use of the more powerful nucleophile sodium
benzeneselenolate, generated from reduction of diphenyl diselenide with sodium18a in a mixture of
DMF and THF, resulted in a 50% yield. With the optimized reaction conditions in hand, we
demonstrated the scope of our procedure for a variety of carboxylic acids. As shown in Table 2,
several functionalized aliphatic acids were smoothly converted into the corresponding phenyl
selenoesters in good to excellent yields.
Table 2. Substrate scope of phenyl selenoesters synthesisa from aliphatic carboxylic acids 6aꢀh
Entry Acida t (h)
16
Product
Yield (%)b
82
O
1
6a
Ph
SePh
3h
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O
2
3
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77
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6b
6c
SePh
3i
3j
O
SePh
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O
4
14
62
6d
SePh
SePh
O
3k
O
5
6
15
15
82
91
6e
6f
PhSe
3l
O
SePh
11
3m
O
O
7
8
13
15
79
61
6g
6h
SePh
SePh
PhSe
6
3n
O
H
N
O
3o
a Conditions: Acid 6 (2.2 equiv), iꢀBuOCOCl (2.2 equiv) and NMM (2.2 equiv) in EtOAC (10 mL)
30 min at 0 °C. Then a solution prepared from diphenyl diselenide (1 mmol), NaBH4 (2 equiv),
AcOH (10 equiv) in EtOAc (10 mL) was added. b Yield of isolated products after chromatographic
purification.
The procedure showed good functional group compatibility as amide, alkene, alkyne and
carbonyl groups were all tolerated under the reaction conditions employed. Notable are the good
yields of selenoesters 3j and 3k, which show diene and carbonyl reactive sites respectively.
Interestingly, the reaction occurred efficiently even with suberic acid (6g) giving the corresponding
diselenoester 3n in excellent yield. Interestingly, the preparation of selenoester 3l possessing a
second phenylseleno group on the alkyl chain was achieved. This group could quickly be displaced
by elimination or substitution3d to give variously substituted derivatives (see preparation of Nꢀ
acryloylꢀproline methyl ester in Supporting Information). To further extend the substrate scope of
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this method, reactions with aromatic and heteroaromatic carboxylic acids were examined (Table 3).
All the substrates produced the corresponding derivatives in very good yields.
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Table 3. Substrate scope of phenyl selenoesters synthesisa from aromatic and heteroaromatic
carboxylic acids 6iꢀo
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Entry Acida t (h)
Product
Yield (%)b
75
Cl
O
1
2
16
15
6i
6j
SePh
3p
O
70
80
SePh
O
3q
O
3
16
6k
SePh
3r
O
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5
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16
13
14
79
77
80
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6m
6n
O
SePh
SePh
SePh
3s
O
S
N
3t
O
3u
O
7
13
76
6o
SePh
N
3v
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a Conditions: Acid 6 (2.2 equiv), iꢀBuOCOCl (2.2 equiv) and NMM (2.2 equiv) in EtOAC (10 mL)
4
5
6
7
30 min at 0 °C. Then a solution prepared from diphenyl diselenide (1 mmol), NaBH4 (2 equiv),
AcOH (10 equiv) in EtOAc (10 mL) was added. Yield of isolated product after chromatographic
purification
b
8
9
The selenoester 3r was obtained in high yield despite the presence of a Michael acceptor group as
the conjugate double bond. Worthy of note is also the first synthesis of two nitrogenꢀcontaining
heterocyclic selenoesters 3u and 3v.
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Application to NꢀFmocꢀLꢀamino acids. The preparation of selenoester 3o from Lꢀ
pyroglutamic acid has inspired us to apply the above methodology to NꢀFmocꢀLꢀamino acids 7
(Table 4). Despite the many methods reported for the synthesis of selenoesters, examples of these
compounds from Cbzꢀ, Phthꢀ and Bocꢀprotected Lꢀamino acids are scarcely represented in literature.
In these reports, mixed anhydride derivatives of a restricted number of protected proteinogenic Lꢀ
amino acids were reacted with benzeneselenol3b,21 or benzeneseleno(trietoxy)borate.20,22 Recently,
Arora and coꢀworkers7c have reported the preparation of some phenyl selenoesters of NꢀFmocꢀLꢀ
amino acids by in situ Cꢀactivation with DCC, and their use in molecular biology studies. In view of
our previous observation, slight excesses (10% mol) of isobutyl chloroformate and NMM were
employed and the mixed anhydrideꢀforming reaction appeared to be complete in 30ꢀ40 minutes at
0 °C in EtOAc. Then 1.2 equiv. of nucleophilic selenium species (prepared as above) were added
and the reaction mixture was allowed to warm to room temperature. This procedure was applied to
the chemoselective and efficient preparation of various NꢀFmocꢀLꢀamino acid selenoesters 8 (Table
4).
Table 4. Results of the reaction of synthesis of NꢀFmocꢀLꢀamino acid selenoesters 8aꢀn
1a,
i-BuOCOCl
NMM, EtOAc
NaBH4
R
R
EtOAc, 40 °C
Fmoc
OH
Fmoc
SePh
N
H
N
H
30 min, 0 °C
then rt, AcOH
O
O
7
8
Entry NꢀFmocꢀLꢀamino acid
t (h)
Product
Yield (%)a
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1
2
FmocꢀGlyꢀOH
FmocꢀAlaꢀOH
14
15
16
15
14
15
16
17
16
15
FmocꢀGlyꢀSePh
FmocꢀAlaꢀSePh
FmocꢀValꢀSePh
FmocꢀLeuꢀSePh
FmocꢀPheꢀSePh
FmocꢀProꢀSePh
FmocꢀMetꢀSePh
FmocꢀTrpꢀSePh
FmocꢀGlnꢀSePh
FmocꢀCys(Trt)ꢀSePh
72b
84
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
3
FmocꢀValꢀOH
95
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4
FmocꢀLeuꢀOH
94
5
FmocꢀPheꢀOH
75b
91
6
FmocꢀProꢀOH
7
FmocꢀMetꢀOH
86b
85
7g
7h
7i
8g
8h
8i
8
FmocꢀTrpꢀOH
9
FmocꢀGlnꢀOH
95c
83d
82b
86
10
11
12
13
14
FmocꢀCys(Trt)ꢀOH
FmocꢀAsp(OtBu)ꢀOH
FmocꢀSer(OtBu)ꢀOH
FmocꢀLys(Boc)ꢀOH
FmocꢀTyr(OtBu)ꢀOH
7j
8j
14 FmocꢀAsp(OtBu)ꢀSePh
15 FmocꢀSer(OtBu)ꢀSePh
7k
7l
8k
8l
15
FmocꢀLys(Boc)ꢀSePh
86b
79b
7m
7n
8m
8n
16 FmocꢀTyr(OtBu)ꢀSePh
a Isolated yield. A mixture of EtOAc/THF was employed to dissolve the NꢀFmocꢀLꢀamino acid. c
A mixture of EtOAc/DMF was employed to dissolve the NꢀFmocꢀLꢀamino acid. THF was
employed to dissolve the NꢀFmocꢀLꢀamino acid.
b
d
Fourteen representative proteinogenic N-Fmocꢀprotected Lꢀamino acids 7aꢀn, also containing acidꢀ
labile protecting groups in the sideꢀchain, were conveniently transformed into the corresponding
crystalline phenyl selenoesters 8aꢀn in 72%ꢀ95% ranging yield. The structures of known 8aꢀc and
8f were confirmed by spectroscopic data in agreement with those already reported.7c The 13C NMR
spectra of compounds 8aꢀn showed the characteristic peak for the carbonyl carbon of the
selenoester moiety around 195 ppm. Selenoesters from NꢀFmoc(Pbf)ꢀLꢀarginine and NꢀFmoc(Trt)ꢀ
hystidine were not obtained under our reaction conditions. Interesting is the successful preparation
of selenoesters 8h and 8i from the unprotected NꢀFmocꢀLꢀtryptophan and NꢀFmocꢀLꢀglutamine,
respectively. The experimental conditions of the new procedure were found to be highly compatible
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with acidꢀlabile protections, as also proved by the transformation of NꢀBocꢀLꢀalanine 9 into the
known21 selenoester 10 in a 76% yield (Scheme 3).
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9
Scheme 3. Synthesis of acidꢀlabile NꢀBocꢀLꢀalanine selenoester 10
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Me
1a, NaBH4,EtOAc
40 °C, then AcOH
Me
i-BuOCOCl, NMM
Boc
OH
Boc
SePh
N
N
0 °C, EtOAC
rt,16 h
H
H
O
O
9
10
76%
Acylation Reactions. In view of the weakness of the carbonꢀselenium bond, selenoesters are
reactive intermediates which, after activation, can react with water or alcohols3c to give the
corresponding carboxylic acids or esters, respectively. Furthermore, selenoesters undergo
aminolysis much more rapidly3d than the thioacyl analogues as reported by Connors and Bender.23
Despite the recent exploitations in selenoestersꢀbased ligation approaches,7 there are no reports on
the regular use of selenoesters as acyl donors. Chemoselective acylation of amines is one of the
most basic reactions for the protection or activation of amino groups in organic and pharmaceutical
synthesis. A variety of reagents have been developed by devising a leaving group for the above
purpose and continuing efforts have been made in order to create an ideally chemoselective
reagent.24 It is reasonably assumed that our protocol allows the synthesis of a variety of selenoesters
which could successfully be employed as selective acylating agents under mild conditions. Thus,
the acylation of various amines 11 with 10% excess of some selenoesters of the type 3 (Table 5)
was carried out at room temperature and in different solvents to test the influence of the solvent too.
The results obtained are summarized in Table 5. All examined selenoesters served as excellent Nꢀ
acylating reagents of primary amines, amino alcohols, amino acids and amino esters.
Table 5. Acylation of amines and diamines with phenyl selenoesters 3
R1NH2
11
O
O
+ PhSeSePh
NHR1
R
SePh
solvent, rt
under air
R
3
1a
12
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Entry Selenoestera
Amine
t
Solvent
MeCN
Product
Yield
(%)b
(h)
NH2
O
NH2
1
2
97c
3h
H2N
Bn
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
12a
11a
11b
O
OH
OH
2
24
THF
84
3g
H2N
N
H
NH2
12b
O
3
4
14 MeCNd
81
81
3g
3k
H2N
CO2Me
N
H
NH2
CO2Me
11c
12c
NH2
O
NH2
3
MeCN
H2N
H2N
N
H
O
12d
11a
Ph
CO2H
5
6
24 EtOHd
85
96
O
3m
3u
Ph
N
H
12e
CO2H
11
11d
NH2
O
NH2
N
2
6
MeCN
DMF
H2N
N
H
12f
11a
11a
NH2
NH2
89e
94
Boc
7
8
3f
H2N
N
H
12g
O
H
H
24 EtOH
3g
N
Ph
N
Ph
N
H2N
H
NH2
11e
12h
H
O
H
N
Ph
9
3
MeCN
92
3h
N
Ph
H2N
Bn
N
H
11e
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5
6
7
8
9
12i
Ph
H2N
CO2Me
Ph
Ph
O
O
10
5
DMFd
86f
3n
N
CO2Me
N
MeO2C
6
H
H
11f
12j
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
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45
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47
48
49
50
51
52
53
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55
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57
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59
60
a
b
A 10% mol excess of selenoesters was employed.
Yield of isolated product after
c
d
e
chromatographic purification. 92% yield in THF or EtOAc after 4 h. DIPEA was added. The
same yield was obtained in MeCN. f An excess of aminoester was employed.
Reaction of selenoester 3h with 2ꢀaminobenzylamine 11a in THF or EtOAC gave, after 4 h, the
amide 12a in 92% yield. Solvent replacement with MeCN or DMF decrease reaction time to 2h
increasing the yield up to 97% with MeCN (Table 5, entry 1). Moreover, selenoesters can
selectively acylate an aliphatic amine in the presence of an aromatic one (Table 5, entries 1, 4, 6 and
7). In a competitive acylation experiment of a 1:1 mixture of benzylamine and aniline with 3c in
THF, only the acylated product of benzylamine was detected by GCꢀMS. Noteworthy, aromatic
amine such as aniline was not acylated even in DMF for two days. As depicted in Table 5, entry 2,
when both hydroxy and amino groups are present in the substrate as in 11b, acyltransfer only
occurred at the amino group. This result was largely supported by the use of EtOH as a compatible
solvent in acylation reactions (Table 5, entries 5 and 8). In a molecule with both primaryꢀ and
secondary amino groups such as Nꢀbenzylethaneꢀ1,2ꢀdiamine 11e, acyltransfer only occurred at the
primary amino group (Table 5, entries 8 and 9). We observed that this peculiar difference in
reactivity could be annulled by changing the solvent. Secondary amine such as piperidine was
slowly acylated (16 h) with 3a in 72% yield using DMF (see Figure S1, Supporting Information).
We checked that the solvent properties manage the acylation control of selenocarbonate 3f too. The
NꢀBoc derivative 12g was obtained when MeCN or DMF were used as reaction solvent (Table 6,
entry 7). Notably, compounds 12b, 12c and 12h, are anthranilamide derivatives which are found in
numerous drugs and drug candidates,25 whereas compounds 12f and 12h possessing three nitrogen
atoms with different acidꢀbase properties could be applied in chelation chemistry.26 In order to
evaluate their acylꢀtransfer potentiality, acylation of some amines with selenoesters 4 and 5 was
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also examined. We did not observe any influence of chloro and methoxy substituents on the leaving
group ability of the phenylseleno portion (see Figure S2, Supporting Information).
6
7
8
9
Based on these results, it seemed likely that selenoesters 8aꢀn and 10 might also serve as convenient
acylating species for the solution phase synthesis of oligopeptides. Despite its synthetic interest, the
formation of amide bonds between amino acidꢀderived selenoester intermediates and protected or
free C-terminal Lꢀamino acids and peptides has been scarcely reported.3b,3d,7c,21 Moreover,
racemization of activated amino acids is a critical concern in peptide synthesis.27 Previously, mixed
anhydride as intermediate in peptide synthesis, was proposed by Vaughan.28a However, this
approach suffer the drawback of lack of regioselectivity in the nucleophilic addition for one position
over the second one, then, a lot of coupling agents were developed.28b,c Thus, we decided to study
the preparation of some model dipeptides in order to evaluate the potential of selenoesters 8aꢀn as
stable reagents in peptide synthesis. Accordingly, when selenoesters 8cꢀe, 8k and 8n were reacted
with Lꢀamino acid, ester or amide 13 in the proper solvent at room temperature various dipeptides
14 were produced (Table 6).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 6. Solution phase synthesis of peptides employing selenoesters 8 as neutral acylating
agents
R1
13
R
R
H2N COR2
H
N
Fmoc
SePh
Fmoc
COR2 + PhSeSePh
N
N
DIPEA
Solvent, rt
under air
H
H
O
O
R1
14
1a
8
R2= OH, OMe, NH2
Entry Selenoester
Amine
t (h)
Amide
Yield (%)a
Solvent
Ph
H2N
CO2Me
1
90c
H
DMFb
1
8e
Fmoc
N
CO2Me
N
13a
H
O
14a
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5
6
H2N
CO2Me
20
65c
H
DMFb
Fmoc
N
2
CO2Me
8c
N
H
O
7
8
N
H
N
H
9
13b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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14b
Ph
2
HN
79c
90
MeCNb
3
4
8e
8e
Fmoc
N
N
H
CO2Me
O
14c
CO2Me
CO2Me
13c
H2N
CO2Me
Ph
5
H
DMFd
Fmoc
N
N
H
O
13d
14d
H2N
CO2H
13
H
N
DMFb
Fmoc
CO2H
Ph
5
6
79
96
8c
N
H
Ph
O
11d
14e
H2N
CO2H
16
DMFb
8d
H
N
Fmoc
CO2H
N
H
13e
O
14f
p-OtBuPh
H2N
CO2H
15
H
DMFb
7
8
9
78
94
73
8n
8k
10
13f
Fmoc
N
CO2H
N
H
O
14g
H2N
CONH2
CO2tBu
16
H
N
EtOHe
13g
Fmoc
CONH2
Ph
N
H
O
14h
Ph
6
O
O
H
MeCNf
H2N
Boc
N
N
H
CO2H
N
N
CO2H
H
H
O
16
15
a
b
c
Isolated yield. 2 equiv. of amino ester or amino acid were employed. The degree of
racemization was determined by HPLC analysis (for details and chromatograms, see Supporting
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Information). d 1.2 equiv. of amino ester was employed. e 1.4 equiv. of glycinamide was employed. f
4
5
1.4 equiv. of selenoester 10 was employed vs dipeptidyl acid 15.
Selenoesters 8e underwent complete conversion into dipeptide27f 14a in 24 h with Lꢀalanine methyl
ester hydrochloride and DIPEA in THF. The same reaction carried out in EtOAc was complete in
16 h. To further accelerate the coupling, we changed the solvent from EtOAc to MeCN providing
an additional boost (3 h) to the reaction time which, in DMF, was only 1 h (Table 6, entry 1). The
HPLC analysis of the dipeptide ester 14a synthesized in THF or in DMF showed practically the
absence of racemization under the applied reaction conditions (d.r. = 99.5:0.5, Figure S4,
Supporting Information). We also tested the coupling of selenoester 8c with Lꢀtryptophane methyl
ester hydrochloride (Table 6, entry 2) in DMF because, as reported elsewhere,27d amide bond
formation involving valine is relatively slow, thus producing mixtures of epimers. Notably, no
epimerization was observed by HPLC and NMR analysis of the isolated dipeptide after 20 h
reaction time (d.r. > 99.9:0.1, Figure S7, Supporting Information). The very low level of
epimerization observed agreed the one recently reported for similar couplings.7c Moreover, the
extent of epimerization was also measured for other difficult couplings,27d as in case of the reaction
of 8e with Lꢀproline methyl ester hydrochloride in DMF. Although the reaction went to
completeness in just 2 h, the expected dipeptide ester 14c (Table 6, entry 3) was obtained with a
minimum extent of racemization (d.r. = 98.3:1.7, Figure S10, Supporting Information). We also
evaluated the configurational stability of a selenoesters as (D)ꢀ8e (see Supporting Information). As
previously described, selenoesters undergo methanolysis in presence of anhydrous copper(II)
chloride in MeCN at room temperature.3d HPLC analysis on chiral stationary phase was used to
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
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24
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34
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59
60
examine the enantiomeric ratio of
NꢀFmocꢀDꢀphenylalanine methyl esters obtained by
methanolysis of a sample of (D)ꢀ8e stored at room temperature for six months and the same
compound obtained from a sample of (D)ꢀ8e stored at 0 °C for an identical period of time.
Chromatograms showed the absence of racemization in both cases, and the measured e.r. was
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comparable to the one of a N-FmocꢀDꢀphenylalanine methyl ester sample (e.r. > 99.9:0.1) obtained
from freshly prepared (D)ꢀ8e (Figures S14, S17, and S18, Supporting Information).
6
7
8
9
Further, we successfully synthesized the N-Fmocꢀdipeptidyl ester as 14d (Table 6, entry 4) and the
series of N-Fmocꢀdipeptidyl acids 14eꢀg (Table 6, entries 5ꢀ7,), as well as the N-Bocꢀtripeptidyl
acid 16 (Table 6, entry 9), by reacting selenoesters 8cꢀe and 8n with the corresponding amino ester,
amino acids or dipeptidyl acid, respectively. As expected, reaction of selenoester 8k with an excess
of glycinamide hydrochloride 13g and DIPEA in EtOH gave the N-Fmocꢀdipeptidyl amide 14h in
excellent yield. Under the usual experimental conditions, the homogeneous phase coupling
reactions occurred without detectable epimerization as observed by 1H and 13C NMR spectra.
In addition, we next checked whether this protocol could be extended to longer peptides. As a
proof of concept, a tripeptide synthesis was performed in the N→C direction. Accordingly, N-
Fmocꢀdipeptidyl acid 14e (Scheme 4) was transformed into the corresponding selenoester 17 which
was easily coupled to Lꢀalanine in DMF at room temperature to prepare the N-Fmocꢀprotected
tripeptide 18 in excellent yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. N→C solution phase synthesis of tripeptide 18 using selenoester as reactive
intermediate
1a, NaBH4,EtOAc
40 °C, then AcOH
H
i-BuOCOCl, NMM
14e
Fmoc
N
COSePh
Ph
N
0 °C, EtOAC
rt,18 h
H
O
17
67%
O
H
Alanine, DIPEA
Fmoc
N
DMF, rt, 20 h
under air
N
N
CO2H
H
H
O
18
91%
Ph
The potential application of our protocol for the solution synthesis of NꢀFmocꢀtripeptides via C→N
route was investigated. A linear approach was selected for the preparation of Fmocꢀtripeptide esters
19b, 19c and amide 19a (Scheme 5). Thus, chain extension from Nꢀterminus of Fmoc protected
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9
dipeptides 14a, 14d and 14h leading to tripeptides was undertaken. Selective removal of Fmocꢀ
protecting group with diethylamine in MeCN at room temperature gave the free amino dipeptide
intermediate which was immediately reacted with an excess of selenoesters 8a and 8e to furnish the
protected tripeptides 19aꢀc in good global yields.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. C→N solution phase synthesis of tripeptides using selenoesters as neutral acylating
agents
CO2tBu
O
1) Et2NH, MeCN
rt, 4 h
H
N
H
N
CONH2
14h
14a
Fmoc
Fmoc
N
H
8a
2) , DIPEA, EtOH
O
19a
89%
rt, 20 h, under air
Ph
O
1) Et2NH, MeCN
rt, 2 h
O
H
N
N
H
N
CO2Me
2) 8e, DIPEA, THF
rt, 14 h, under air
H
Ph
19b
75%
1) Et2NH, MeCN
rt, 4 h
O
H
N
14d
Fmoc
2) 8a, DIPEA, DMF
rt, 16 h, under air
N
H
N
H
CO2Me
O
19c
69%
Ph
Finally, in an effort to apply our protocol to the convergent synthesis of fully protected Leuꢀ
enkephalin29 pentapeptide 21, we studied the coupling of two fragments. The key step was the
preparation and the coupling of crude N-Fmocꢀdipeptidyl selenophenyl ester intermediate 20 with
the unprotected tripeptide intermediate obtained from 19c (Scheme 6). Thus, N-Fmocꢀdipeptide 14g
(Table 6) was converted, as for 14e (Scheme 4), into the corresponding selenoester 20 which was
directly employed for the successive reaction without purification. Removal of the Fmoc protecting
group from 19c furnished the corresponding free tripeptide intermediate which was reacted with a
slight excess of crude selenoester 20. The fully protected Leuꢀenkephalin 21 was obtained in 57%
global yield after purification and its structure was confirmed by MALDI ꢀMS/MS analysis (Figure
S20, Supporting Information).
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Scheme 6. Synthesis of pentapeptide 21 by 2+3 fragment condensation strategy using
selenoester as active intermediate
6
7
8
9
p-OtBuPh
1) i-BuOCOCl, NMM
0 °C, EtOAc
H
14g
Fmoc
N
COSePh
N
1a,
2)
NaBH4, EtOAc
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
40 °C, then AcOH
rt,15 h
O
20
19c + Et2NH, MeCN
rt, 4 h
Fmoc-Tyr-(OtBu)-Gly-Gly-Phe-Leu-OMe
then DMF, DIPEA, rt
14 h, under air
21
57%
CONCLUSIONS
In summary, herein we proposed a mild and easy procedure for the preparation of phenyl
selenoesters from anhydrides. The novelty of this protocol is mainly related to the use of EtOAc as
solvent and to the simplicity of the procedure that prevents the typical drawbacks of using volatile
benzeneselenol or transition metals. Phenyl selenoesters were tested as stable, mild and completely
chemoselective reagents in a series of acylation processes conducted under air, in which diphenyl
diselenide is the exclusive byproduct. The present protocol was extensively and successfully
applied to N-FmocꢀLꢀamino acids as substrates and the phenyl selenoesters obtained were utilized
as neutral acylating agents for the synthesis of dipeptide esters and acids. In this study, preliminary
investigations on the susceptibility to racemization were carried out; the results obtained allowed us
to synthesize tripeptides and the fully protected Leuꢀenkephalin pentapeptide. Thus, this procedure
represents a further valuable tool for the construction of the peptide bond. The extension of this
strategy to the synthesis of longer peptide targets and to solidꢀphase peptide synthesis is currently
under investigation.
EXPERIMENTAL SECTION
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General Information. Unless otherwise stated, all reactions were carried out using bench
solvents. All chemicals were of reagent grade and were used without further purification. All air
sensitive reactions were carried out under argon atmosphere. Chromatography was performed on
silica gel (Merck 60, 70ꢀ230 mesh), and analytical TLC was carried out on preꢀcoated silica gel
plates (Merck 60 F254, 0.25 mm) using UV light and 0.5% w/v potassium permanganate aqueous
solution(followed by gentle heating) for visualization. Melting points were measured on a hot plate
apparatus and are uncorrected. Proton magnetic resonance (1H NMR) spectra were recorded at 200
and 400 MHz. Carbon magnetic resonance (13C NMR) spectra were recorded at 50 and 100 MHz.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Unless otherwise specified CDCl3 was used as solvent and chemical shifts (δ) are reported in parts
per million (ppm). The NMR spectra were calibrated using the proton or carbon signals of residual,
nonꢀdeuterated solvents peak: δH 7.27 and δC77.0 for CDCl3, δH 2.50 and δC 39.5 for (CD3)2SO. 1H
NMR spectral data are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; and br, broadened), coupling constants, number of protons, assignments (where
possible). Coupling constant (J) are quoted in Hertz (Hz) to the nearest 0.1 Hz. Infrared (IR) spectra
were recorded on a diffuse reflectance sampling cell. Only significant absorption maxima (νmax) are
reported in wavenumbers (cmꢀ1). GCꢀMS analysis were obtained with a gas chromatograph (HPꢀ
5MS capillary column 29.0 m, ID 0.25, film 0.25 ꢀm) equipped with a mass selective detector at an
ionizing voltage of 70 eV; for the ions containing selenium only the peaks arising from seleniumꢀ80
isotope are given. Optical rotations were measured in a 50 mm cell using the Dꢀline of sodium at
the specified temperature. [α]D values are given in 10ꢀ1 deg cm2 gꢀ1; concentrations (c) are quoted in
g 100 mLꢀ1. HPLC analysis were performed on a HPLC system equipped with a UV/Vis detector
with chiral columns and solvents specified. All chromatograms were run at 25 °C. Combustion
analyses were carried out on an elemental analyzer. HRMS analyses were performed using a
MALDIꢀTOFꢀTOF analyzer equipped with an Nd:YLF Laser with λ = 345ꢀnm wavelength of <500
ps pulse length and p to 1000 Hz repetition rate, in reflectron positive mode with a mass accuracy of
3 ppm.
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The diselenides 1b and 1c were prepared as described in literature.30 Acid 6e was synthesized as
previously reported.31 LLꢀAlanylꢀphenylalanine 15 is previously known and commercially
available.32
9
General Procedure for the Synthesis of Selenoesters 3a-g from Anhydrides.
Diphenyl diselenide (0.32 g, 1 mmol) and sodium borohydride (76 mg, 2.0 mmol) were placed in an
ovenꢀdried roundꢀbottom flask under argon flow. EtOAc (10 mL) was added to the content of the
flask and the mixture was heated at 40 °C for 30ꢀ40 min yielding a white mixture after cooling to
room temperature. Glacial acetic acid (0.58 mL, 10 mmol) was added (caution, gas evolved) at
room temperature and after 30 min the resulting mixture was treated with 2.1 mmol of anhydride.
The progress of the reaction was monitored by TLC (5ꢀ24 h). After addition of water (10 mL) the
mixture was extracted with three 30 mL portions of EtOAc. The combined extracts were washed
with brine (10 mL), dried (MgSO4), filtrated and concentrated in vacuo. The residue was purified by
column chromatography on silica as specified below.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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Se-Phenyl benzenecarboselenoate (3a): According to general procedure the title compound was
obtained (0.50 g, 94% yield) using a diethyl etherꢀhexane mixture (2:98) as eluent. Spectral data
were in accordance with the literature.2a
Se-Phenyl 2-methyl-6-nitrobenzenecarboselenoate (3b): According to general procedure the
crude selenoester was purified by chromatography using an ethyl acetateꢀhexane mixture (1:9) as
eluent to give 3b (0.54 g, 84% yield): light yellow solid; mp 84–86 ºC; 1H NMR (200 MHz, CDCl3)
δ 7.96 (d, J = 8.0 Hz, 1H), 7.61ꢀ7.52 (m, 3H), 7.46 (d, J = 8.0 Hz, 1H), 7.42ꢀ7.33 (m, 3H), 2.50 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 194.9, 144.7, 136.5, 135.9 (2C), 135.6, 130.2, 129.5 (2C),
129.4, 129.0, 125.9, 121.9, 18.8; FTIR 3073, 1738, 1704, 1424, 1190, 865, 738 cmꢀ1; Anal. Calcd
for C14H11NO3Se: C, 52.51; H, 3.46; N, 4.37. Found: C, 52.33; H, 3.84; N, 4.15.
Se-Phenyl ethaneselenoate (3c): According to general procedure the title compound was
obtained (0.36 g, 90% yield) using a diethyl etherꢀhexane mixture (4:96) as eluent. Spectral data
were in accordance with the literature.33
Se-Phenyl propaneselenoate (3d): According to general procedure the title compound was
obtained (0.30 g, 88% yield) using a diethyl etherꢀhexane mixture (2:98) as eluent. Spectral data
were in accordance with the literature.12c
Se-Phenyl 2,2-dimethylpropaneselenoate (3e): According to general procedure the title
compound was obtained (0.43 g, 89% yield) using a diethyl etherꢀhexane mixture(2:98) as eluent.
Spectral data were in accordance with the literature.34
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O-(tert-Butyl) Se-phenyl selenocarbonate (3f): No acetic acid was added after reduction of
diphenyl diselenide with sodium borohydride. The product was purified by chromatography using a
diethyl etherꢀhexane mixture(1:99) as eluent to give 3f (0.48 g, 92%) as a light yellow oil; 1H NMR
(200 MHz, CDCl3) δ 7.72ꢀ7.62 (m, 2H), 7.48ꢀ7.35 (m, 3H), 1.59 (s, 9H); 13C NMR (50 MHz,
CDCl3) δ 164.7, 135.6 (2C), 129.0, (2C), 128.7, 126.7, 86.2, 28.1 (3C); FTIR 2980, 1728, 1370,
1105, 830, 740 cmꢀ1; EIMS (70 eV) m/z [M ꢀ 44]+ 214 (2), 157 (42), 77 (30), 57 (100), 51 (16).
Anal. Calcd for C11H14O2Se: C, 51.37; H, 5.49. Found: C, 51.19; H, 5.79.
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Se-Phenyl 2-aminobenzenecarboselenoate (3g): According to general procedure the organic
phase was concentrated to give a solid residue which was triturated with hexane (2x30 ml) to afford
3f (0.41 g, 74%): white solid; mp = 123ꢀ125 ºC; 1H NMR (200 MHz, CDCl3) δ 7.87 (dd, J = 8.3,
1.4 Hz, 1H), 7.68ꢀ7.56 (m, 2H), 7.53ꢀ7.38 (m, 3H), 7.32 (ddd, J = 8.4, 8.3, 1.4 Hz, 1H), 6.75 (ddd, J
= 8.4, 8.3, 1.1 Hz, 1H), 6.66 (dd, J = 8.3, 1.1Hz, 1H), 5.60 (br s, 2H); 13C NMR (100 MHz,
CDCl3) δ 193.9, 147.4, 136.8 (2C), 134.8, 131.2, 129.2 (2C), 129.0, 126.3, 119.4, 117.1, 116.7;
FTIR 3463, 3360, 1764, 1617, 1481, 1202, 889, 748 cmꢀ1; EIMS (70 eV) m/z M+ 277 (5), 120 (100),
157 (8), 92 (75), 77 (12), 65 (62). Anal. Calcd for C13H11NOSe: C, 56.53; H, 4.01; N, 5.07. Found:
C, 56.44; H, 4.35; N, 5.13.
Preparation of Selenoesters 4 and 5. 1,2ꢀbis(4ꢀMethoxyphenyl)diselenide 1b (0.15 g, 0.40
mmol) and sodium borohydride (31 mg, 0.8 mmol) were placed in an ovenꢀdried roundꢀbottom
flask under argon flow. EtOAc (6 mL) was added to the contents of the flask and the mixture was
heated at 40 °C for 30ꢀ40 min yielding a white mixture after cooling to room temperature. Glacial
acetic acid (0.23 mL, 4 mmol) was added (caution, gas evolved) at room temperature and after 30
min the resulting mixture was treated with benzoic anhydride (0.18 g, 0.82 mmol). After the
reaction was complete (15 h) water (10 mL) was added and the mixture extracted with three 20 mL
portions of EtOAc. The combined extracts were washed with brine (10 mL), dried (MgSO4),
filtrated and concentrated in vacuo. Purification of the residue by column chromatography on silica
gel using a diethyl etherꢀhexane mixture (8:92) as eluent gave Se-(4-methoxyphenyl)
benzenecarboselenoate (4) (0.20 g, 86% yield). Spectral data were in accordance with the
literature.35
In an ovenꢀdried roundꢀbottom flask, 1,2ꢀbis (2ꢀChlorophenyl)diselenide 1c (0.30 g, 0.79 mmol)
and sodium borohydride (60 mg, 1.6 mmol) were placed under argon flow. EtOAc (8 mL) was
added to the contents of the flask and the mixture was heated at 40 °C for 30ꢀ40 min yielding a
white mixture after cooling to room temperature. Glacial acetic acid (0.46 mL, 8 mmol) was added
(caution, gas evolved) at room temperature and after 30 min the resulting mixture was treated with
acetic anhydride (0.15 mL, 1.66 mmol). After the reaction was complete (20 h) water(10 mL) was
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added and the mixture extracted with three 20 mL portions of EtOAc. The combined extracts were
washed with brine (10 mL), dried (MgSO4), filtrated and concentrated in vacuo. After purification
by column chromatography on silica gel using a diethyl etherꢀhexane mixture (2:98) as eluent Se-
1
(2-chlorophenyl) ethaneselenoate (5) was obtained as a colorless oil (0.31 g, 82% yield). H NMR
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(200 MHz, CDCl3) δ 7.65 (dd, J = 7.4, 2.0 Hz, 1H), 7.53 (dd, J = 7.6, 1.6 Hz, 1H), 7.36 (dt, J = 7.6,
2.0 Hz, 1H), 7.27 (ddd, J = 7.6, 7.4, 1.6Hz, 1H), 2.5 (s, 3 H); 13C NMR (50 MHz, CDCl3) δ 194.6,
138.2, 138.0, 130.6 (2C), 129.8, 127.2, 33.8; FTIR 3060, 1731, 1450, 1096, 752 cmꢀ1; EIMS (70
eV) m/z M+ 234 (67), 192 (96), 156 (100), 129 (13), 112 (50), 75 (40), 50 (23). Anal. Calcd for
C8H7ClOSe: C, 41.14; H, 3.02; Found: C, 40.83; H, 3.35.
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General Procedure for the Synthesis of Selenoesters 3h-v from Acids. To a
solution of acid 6 (2.2 mmol) in EtOAc (10 mL) at 0 °C Nꢀmethylmorpholine (NMM 0.24 mL, 2.2
mmol) and isobutyl chloroformate (0.28 ml, 2.2 mmol) were added. The reaction mixture was
stirred at 0 °C for 40 min under argon atmosphere. Then, a fresh solution of nucleophilic selenium
species, prepared as described above by means of reaction of diphenyl diselenide (0.32 g, 1 mmol)
and sodium borohydride (76 mg, 2.0 mmol) in EtOAc (10 mL) at 40 °C an successive addition of
glacial acetic acid (0.58 mL, 10 mmol) at room temperature, was added directly in one portion
through a syringe allowing to reach room temperature gradually. The stirring was continued till the
completion of the reaction (13ꢀ16 h). The mixture was then poured into water (20 mL) and
extracted with EtOAc (3 x 30 mL). The organic layer was washed with brine (10 mL), dried over
sodium sulfate and evaporated. The reaction product was purified by column chromatography on
silica gel.
Se-Phenyl phenylethaneselenoate (3h): According to general procedure the title compound was
obtained (0.45 g, 82% yield) using a diethyl etherꢀhexane mixture (2:98) as eluent. Spectral data
were in accordance with the literature.17a
Se-Phenyl hept-6-yneselenoate (3i): According to general procedure the crude selenoester was
purified by chromatography using a diethyl etherꢀhexane mixture (4:96) as eluent to give 3i (0.40 g,
1
75%) as a light yellow oil; H NMR (200 MHz, CDCl3) δ 7.60ꢀ7.46 (m, 2H), 7.45ꢀ7.30 (m, 3H),
2.75 (t, J = 7.0 Hz, 1H), 2.25 (dt, J = 7.0, 2.6 Hz, 2H), 1.80 (t, J = 2.6 Hz, 2H), 1.90ꢀ1.75 (m, 2H),
1.67ꢀ1.50 (m, 2H); 13C NMR (50 MHz, CDCl3) δ 200.1, 135.8 (2C), 129.3 (2C), 128.9, 126.3, 83.6,
68.8, 46.8, 27.4, 24.3, 18.1; FTIR 3290, 2927, 1718, 1438, 956, 739 cmꢀ1; EIMS (70 eV) m/z M+
266 (3), 157 (25), 109 (69), 81 (100), 79 (72), 53 (37). Anal. Calcd for C13H14OSe: C, 58.87; H,
5.32. Found: C, 58.65; H, 5.66.
Se-Phenyl (2E,4E)-hexa-2,4-dieneselenoate (3j): According to general procedure the residue
was purified by chromatography using a diethyl etherꢀhexane mixture (4:96) as eluent to give 3j
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(0.37 g, 74% yield) as a light yellow oil; H NMR (200 MHz, CDCl3) δ 7.65ꢀ7.50 (m, 2H), 7.48ꢀ
7.26 (m, 3H), 7.20 (dd, J = 14.3, 9.4 Hz, 1H), 6.36ꢀ6.08 (m, 3H), 1.88 (d, J = 5.6 Hz, 3H); 13C NMR
(50 MHz, CDCl3) δ 190.7, 142.3, 141.7, 135.8 (2C), 129.6, 129.2 (2C), 128.8, 127.2, 125.3, 19.0;
FTIR 3025, 1689, 1635, 1590, 1438, 1322, 1114, 1008, 776, 738 cmꢀ1; EIMS (70 eV) m/z [Mꢀ95]+
157 (10), 95 (100), 77 (10), 67 (38). Anal. Calcd for C12H12OSe: C, 57.38; H, 4.82. Found: C,
57.19; H, 5.09.
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Se-Phenyl 4-oxopentaneselenoate (3k): According to general procedure crude selenoester was
purified by chromatography using an ethyl acetateꢀhexane mixture (1:9) as eluent to give 3k (0.32 g,
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62% yield) as an oil; H NMR (200 MHz, CDCl3) δ 7.58ꢀ7.48 (m, 2H), 7.44ꢀ7.30 (m, 3H), 2.99 (t,
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J = 6.2 Hz, 2H), 2.76 (t, J = 6.2 Hz, 2H), 2.20 (s, 3H); C NMR (50 MHz, CDCl3) δ 205.7, 199.3,
135.8 (2C), 129.3 (2C), 128.9, 126.0, 41.0, 37.7, 29.7; FTIR 3419, 3059, 1716, 1367, 1065, 848,
741 cmꢀ1;EIMS (70 eV) m/z M+ 256 (1), 157 (15), 99 (100), 77 (16), 71 (16). Anal. Calcd for
C11H12O2Se: C, 51.78; H, 4.74. Found: C, 51.57; H, 4.99.
Se-Phenyl 3-(phenylseleno)propaneselenoate (3l): Reaction was carried out with 0.6 equiv of
diphenyl diselenide, 1.0 equiv of 3ꢀ(phenylseleno)propanoic acid 6e and 1.1 equiv of isobutyl
chloroformate. The product was purified by chromatography using a diethyl etherꢀhexane mixture
(2:98) as eluent to give 3l (0.31 g, 82% yield) as a light yellow oil; 1H NMR (200 MHz, CDCl3) δ
7.62ꢀ7.48 (m, 4H), 7.42ꢀ7.28 (m, 6H), 3.21ꢀ3.02 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 199.1,
135.7 (2C), 133.3 (2C), 129.4 (2C), 129.2 (2C), 129.0, 128.8, 127.5, 126.0, 47.9, 21.3; FTIR 3419,
3059, 1716, 1367, 1065, 848, 741 cmꢀ1. Anal. Calcd for C15H14OSe2: C, 48.93; H, 3.83. Found: C,
48.65; H, 4.17.
Se-Phenyl tetradecaneselenoate (3m): Reaction was carried out with 0.6 equiv of diphenyl
diselenide, 1.0 equiv of myristic acid 6f and 1.1 equiv of isobutyl chloroformate and NMM. The
product was purified by chromatography using a diethyl etherꢀhexane mixture (2:98) as eluent to
give 3m (0.34 g, 91% yield) as a light yellow oil; 1H NMR (200 MHz, CDCl3) δ 7.60ꢀ7.45 (m, 2H),
7.43ꢀ7.30 (m, 3H), 2.71 (t, J = 7.3 Hz, 2H), 1.79ꢀ1.60 (m, 2H), 1.43ꢀ1.20 (m, 20H), 0.85 (t, J = 7.2
Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 200.4, 135.7 (2C), 129.3 (2C), 128.8, 126.5, 47.5, 31.9,
26.6 (2C), 29.3 (3C), 29.2 (2C), 28.8, 25.4, 22.7, 14.1; FTIR 2924, 2854, 1725, 735 cmꢀ1; EIMS (70
eV) m/z M+ 368 (1), 211 (100), 157 (30), 109 (20), 85 (35), 57 (53). Anal. Calcd for C20H32OSe: C,
65.38; H, 8.78. Found: C, 65.30; H, 9.09.
Se1,Se8ꢀDiphenyl octanebis(selenoate) (3n): Reaction was carried out with 1.2 equiv of
diphenyl diselenide, 1.0 equiv of suberic acid 6g and 2.2 equiv of isobutyl chloroformate and
NMM. The product was purified by chromatography using a diethyl etherꢀhexane mixture (5:95) as
eluent to give 3n (0.36 g, 79% yield): light yellow solid; mp = 47ꢀ48 ºC. 1H NMR (200 MHz,
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CDCl3) δ 7.60ꢀ7.47 (m, 4H), 7.45ꢀ7.32 (m, 6H), 2.72 (t, J = 7.2 Hz, 4H), 1.80ꢀ1.62 (m, 4H), 1.48ꢀ
1.32 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 200.2 (2C), 153.7 (4C),.129.3 (4C), 128.8 (2C), 126.3
(2C), 47.2 (2C), 28.3 (2C), 25.0 (2C); FTIR 3419, 3055, 2937, 1718, 1438, 953, 742 cmꢀ1. Anal.
Calcd for C20H22O2Se2: C, 53.11; H, 4.90. Found: C, 52.86; H, 5.15.
Se-Phenyl 5-oxopyrrolidine-2-carboselenoate (3o): According to general procedure the product
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was purified by chromatography using an ethyl acetateꢀhexane mixture (4:6) as eluent to give 3o
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(0.33 g, 61% yield): white solid; mp = 93–95 ºC; [α] 20 ꢀ121.72 (c 0.66, CHCl3); H NMR (200
D
MHz, CDCl3) δ 7.92 (br s, 1H), 7.54ꢀ7.28 (m, 5H), 4.42ꢀ4.25 (m, 1H), 2.72ꢀ2.20 (m, 4H); 13C NMR
(50 MHz, CDCl3) δ 204.5, 179.8, 135.8 (2C), 129,3 (2C), 129.0, 125.2, 65.1, 28.7, 25.5; FTIR 3244,
1725, 1670, 1273, 992, 880, 741 cmꢀ1; EIMS (70 eV) m/z [M ꢀ 14]+ 245 (10) 241 (68), 204 (40),
157 (100), 126 (81), 84 (21), 51 (40). Anal. Calcd for C11H11NO2Se: C, 49.27; H, 4.13; N, 5.22.
Found: C, 49.01; H, 4.39; N, 5.15.
Se-Phenyl 2-chlorobenzenecarboselenoate (3p): According to general procedure the title
compound was obtained (0.44 g, 75% yield) using a diethyl etherꢀhexane mixture (2:98) as eluent.
Spectral data were in accordance with the literature.12f
Se-Phenyl 4-methoxybenzenecarboselenoate (3q): According to general procedure the title
compound was obtained (0.41 g, 70% yield) using a diethyl etherꢀhexane mixture (5:95) as eluent.
Spectral data were in accordance with the literature.2a
Se-Phenyl (2E)-3-phenylprop-2-eneselenoate (3r): According to general procedure the title
compound was obtained (0.51 g, 80% yield) using a diethyl etherꢀhexane mixture (4:96) as eluent.
Spectral data were in accordance with the literature.14
Se-Phenyl furan-2-carboselenoate (3s): According to general procedure the title compound was
obtained (0.40 g, 79% yield) using a diethyl etherꢀhexane mixture (1:9) as eluent. Spectral data
were in accordance with the literature.16a
Se-Phenyl thiophene-2-carboselenoate (3t): According to general procedure the title compound
was obtained (0.42 g, 77% yield) using a diethyl etherꢀhexane mixture (4:96) as eluent. Spectral
data were in accordance with the literature.19
Se-Phenyl pyridine-2-carboselenoate (3u): According to general procedure the crude
selenoester was purified by chromatography using an ethyl acetateꢀhexane mixture (2:8) as eluent to
give 3u (0.43 g, 80% yield): white solid; mp = 103–105 ºC; 1H NMR (400 MHz, CDCl3) δ 8.74 (dt,
J = 4.7, 1.4 Hz, 1H), 7.89ꢀ7.83 (m, 2H), 7.69ꢀ7.50 (m, 3H), 7.49ꢀ7.34 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 196.7, 152.6, 149.3, 137.5, 136.2 (2C), 129.2 (2C), 128.8, 128.3, 126.7, 119.3; FTIR 3055,
1778, 1690, 1434, 1213, 995, 892, 790 cmꢀ1; EIMS (70 eV) m/z M+ 263 (15), 234 (12), 155 (63),
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106 (66), 78 (100), 51 (23). Anal. Calcd for C12H9NOSe: C, 54.98; H, 3.46; N, 5.34. Found: C,
54.84; H, 3.81; N, 5.25.
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Se-Phenyl quinoline-4-carboselenoate (3v): According to general procedure the crude product
was purified by chromatography using an ethyl acetateꢀhexane mixture (2:8) as eluent to give 3v
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(0.48 g, 76% yield): light yellow solid; mp = 73–75 ºC; H NMR (200 MHz, CDCl3) δ 9.08 (d, J =
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4.5 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 4.5 Hz, 1H), 7.81 (t, J =
8.4 Hz, 1H), 7.71ꢀ7.60 (m, 3H), 7.54ꢀ7.43 (m, 3H); 13C NMR (50 MHz, CDCl3) δ 195.2, 149.6,
148.7, 143.6, 135.9 (2C), 130.4, 129.7 (2C), 129.6, 129.5, 128.7, 126.1, 124.9, 121.9, 119.2; FTIR
3069, 1699, 1502, 1222, 1049, 892, 739 cmꢀ1; EIMS m/z M+ 313 (4), 156 (100), 128 (87), 101 (47),
75 (23). Anal. Calcd for C16H11NOSe: C, 61.55; H, 3.55; N, 4.49. Found: C, 61.40; H, 3.75; N, 4.35.
Typical Procedure for the Synthesis of Selenoesters from N-Fmoc-L-amino Acids
8a-n. To a solution of NꢀFmocꢀLꢀamino acid 7 (2.0 mmol) in EtOAc (16 mL) at 0 °C Nꢀ
methylmorpholine (NMM 0.24 mL, 2.2 mmol) and isobutyl chloroformate (0.28 ml, 2.2 mmol)
were added. A mixture of EtOAc/THF (1:1) was employed to dissolve NꢀFmocꢀLꢀGlyꢀOH, Nꢀ
FmocꢀLꢀPheꢀOH, NꢀFmocꢀLꢀAsp(OtBu)ꢀOH, NꢀFmocꢀLꢀMetꢀOH, NꢀFmocꢀLꢀLys(Boc)ꢀOH, and
NꢀFmocꢀLꢀTyr(OtBu)ꢀOH whereas NꢀFmocꢀLꢀGlnꢀOH was dissolved in a mixture of EtOAc/DMF
(2:1) and NꢀFmocꢀLꢀCys(Trt)ꢀOH in THF. The reaction mixture was stirred at 0 °C for 40 min
under argon atmosphere. Then, a fresh solution of nucleophilic selenium species, prepared as
described above by means of reaction of diphenyl diselenide (0.38 g, 1.2 mmol) and sodium
borohydride (92 mg, 2.4 mmol) in EtOAc (10 mL) at 40 °C an successive addition of glacial acetic
acid (0.68 mL, 12 mmol) at room temperature, was added directly in one portion through a syringe.
After the addition, the cloudy mixture was allowed to reach room temperature gradually. The
stirring continued till reaction completion (14ꢀ17 h). The mixture was then poured into water (20
mL) and extracted with EtOAc (3 x 30 mL). The organic layer was washed with brine (10 mL),
dried over sodium sulfate and evaporated. The reaction product was purified by column
chromatography on silica gel or the solid residue was triturated with hexane or diethyl ether and
filtrated to afford the pure crystalline product (1H and 13C NMR).
Se-Phenyl {[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethaneselenoate (8a): According to
general procedure the title compound was obtained as a white solid (0.63 g, 72% yield) after
column chromatography with dichloromethane as eluent: mp = 133–135 ºC. Spectra matches
previously reported data.7c
Se-Phenyl
(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propaneselenoate
(8b):
According to general procedure the residue was purified by chromatography using dichloromethane
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as eluent the give 8b (0.76 g, 84%) yield as a white solid: mp = 163–165 ºC; [α] 24 D ꢀ11.37 (c 0.52,
CHCl3). Spectra matches previously reported data.7c
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Se-Phenyl (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-methylbutaneselenoate (8c):
According to general procedure the title compound was obtained as a white solid (0.90 g, 92%
yield) using a hexaneꢀdichloromethane mixture (1:1) as eluent: mp = 140–142 ºC; [α] 24 D ꢀ41.33 (c
0.58, CHCl3). Spectra matches previously reported data.7c
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Se-Phenyl (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-methylpentaneselenoate (8d):
According to general procedure the organic solvent was removed to dryness and the residue was
triturated with hexane (2x20 ml). The solid was filtered to afford 8d (0.93 g, 94% yield): white
solid; mp = 133–135 ºC; [α] 20 D ꢀ35.20 (c 0.70, CHCl3). 1H NMR (200 MHz, CDCl3) δ 7.80 (d, J =
7.0 Hz, 2H), 7.70ꢀ7.56 (m, 2H), 7.52ꢀ7.28 (m, 9H), 5.12 (d, J = 9.1 Hz, 1H), 4.67 (dd, J = 10.6, 4.3
Hz, 1H), 4.57ꢀ4.41 (m, 2H), 4.28 (t, J = 6.8 Hz, 1H), 1.82ꢀ1.43 (m, 3H), 0.97 (d, J = 6.3 Hz, 3H),
0.92 (d, J = 6.3 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 204.1, 155.9, 143.7, 143.5, 141.3 (2C),
136.0 (2C), 129.3 (2C), 128.9, 127.7 (2C), 127.1 (2C), 125.8, 124.9 (2C), 120.2 (2C), 67.0, 62.3,
47.2, 40.8, 24.6, 23.0, 21.3; FTIR 3332, 2947, 1730, 1681, 1530, 1235, 1028, 737 cmꢀ1. Anal. Calcd
for C27H27NO3Se: C, 65.85; H, 5.53; N, 2.84. Found: C, 65.68; H, 5.89; N, 2.75.
Se-Phenyl (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-phenylpropaneselenoate (8e):
According to general procedure the organic solvent was removed to dryness and the residue was
triturated with hexane (2x30 ml). The solid was filtered to afford 8e (0.98 g, 93% Yield): light
yellow solid; mp = 170–172 ºC; [α]22 ꢀ86.74 (c 0.56, CHCl3); δH (200 MHz, CDCl3) 7.79 (d, J =
D
7.2 Hz, 2H), 7.69ꢀ7.25 (m, 14H), 7.24ꢀ7.11 (m, 2H), 5.18 (d, J = 9.4 Hz, 1H), 4.84ꢀ4.70 (m, 1H),
4.57ꢀ4.36 (m, 2H), 4.24 (t, J = 6.6 Hz, 1H), 3.29ꢀ3.00 (m, 2H); 13C NMR (50 MHz, CDCl3) δ 203.4,
155.7, 143.5 (2C), 141.2 (2C), 135.9 (2C), 135.1, 129.4 (2C), 129.3 (2C), 129.0, 128.8 (2C), 127.7
(2C), 127.3, 127.0 (2C), 125.7, 125.0 (2C), 120.0 (2C), 67.2, 64.0, 47.0, 37.5; FTIR 3342, 3065,
1720, 1695, 1528, 1248, 1045, 735 cmꢀ1. Anal. Calcd for C30H25NO3Se: C, 68.44; H, 4.79; N, 2.66.
Found: C, 68.19; H, 5.05; N, 2.56.
9H-Fluoren-9-ylmethyl
(2S)-2-[(phenylseleno)carbonyl]pyrrolidine-1-carboxylate
(8f):
According to general procedure the residue was purified by chromatography using dichloromethane
as eluent to give 8f (0.87 g, 91% yield); waxy solid, mp = 37–40 ºC; [α]22 D ꢀ87.41 (c 0.83, CHCl3);
Spectral data were in accordance with the literature.7c
Se-phenyl (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-(methylthio)butaneselenoate
(8g): According to general procedure the title compound was obtained as pale yellow solid (0.88 g,
86% yield) after column chromatography with dichloromethane as eluent: mp = 115–117 ºC; [α]24
D ꢀ35.78 (c 0.43, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.6 Hz, 2H), 7.73ꢀ7.61 (m, 2H),
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7.55ꢀ7.48 (m, 1H), 7.47ꢀ7.37 (m, 6H), 7.36 (t, J = 7.6 Hz, 2H), 5.63 (d, J = 8.8 Hz, 1H), 4.71ꢀ4.41
(m, 3H), 4.32 (t, J = 6.6 Hz, 1H), 2.68ꢀ2.49 (m, 2H), 2.31ꢀ2.19 (m, 1H), 2.12 (s, 3H), 2.03ꢀ1.90 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 203. 3, 155.9, 143.7, 143.5, 141.3 (2C), 135.9 (2C), 129.3 (2C),
129.0 (2C), 127.7 (2C), 127.1, 125.6, 124.9 (2C), 120.0 (2C), 67.1, 62.9, 47.2, 31.0, 29.9, 15.3;
FTIR 3286, 2915, 1708, 1690, 1532, 1255, 1053, 740 cmꢀ1. Anal. Calcd for C26H25NO3SSe: C,
61.17; H, 4.94; N, 2.74. Found: C, 60.98; H, 5.19; N, 2.66.
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Se-Phenyl
(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-(1H-indol-3-
yl)propaneselenoate (8h): According to general procedure the title compound was obtained (0.96 g,
85% yield) after chromatography using dichloromethane as eluent: white solid; mp = 180–183 ºC;
[α]24 D ꢀ97.92 (c 0.39, CHCl3); 1H NMR (200 MHz, CDCl3) δ 8.15 (s, 1H), 7.78 (d, J = 7.3 Hz, 2H),
7.58 (t, J = 7.4 Hz, 2H), 7.49ꢀ7.12 (m, 13H), 7.01 (s, 1H), 5.41 (d, J = 8.9 Hz, 1H), 4.93ꢀ4.75 (m,
1H), 4.55 (dd, J = 10.6, 6.8 Hz, 1H), 4.41 (dd, J = 10.6, 6.8 Hz, 1H), 4.23 (t, J = 6.8 Hz, 1H), 3.42
(dd, J = 14.6, 5.1 Hz, 1H), 3.30 (dd, J = 14.6, 5.1 Hz, 1H); 13C NMR δ (50 MHz, CDCl3) 204.4,
155.9, 143.7, 143.5, 141.2 (2C), 136.1, 136.0 (2C), 129.3 (2C), 129.0 (2C), 127.7 (2C), 127.4,
127.1 (2C), 125.9, 125.1 (2C), 123.3, 122.5, 120.0 (2C), 118.6, 11.4, 109.1, 67.3, 63.6, 47.1, 27.5;
FTIR 3473, 3425, 3332, 3054, 1722, 1695, 1532, 1249, 1047, 737 cmꢀ1. Anal. Calcd for
C32H26N2O3Se: C, 67.96; H, 4.63; N, 4.95. Found: C, 67.77; H, 4.95; N, 4.84.
Se-Phenyl (2S)-5-amino-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-5-oxopentaneselenoate
(8i): According to general procedure the organic solvent was removed to dryness and the residue
was triturated with diethyl ether (2x30 ml). The solid was filtered to afford 8i (0.96 g, 95% yield):
mp = 193–195 ºC; [α]20 ꢀ33.51 (c 0.77, DMF); 1H NMR (200 MHz, DMSOd6) δ 8.42 (d, J = 7.8
D
Hz, 1H), 7.89 (d, J = 7.4, 2H), 7.77 (d, J = 6.8 Hz, 2H), 7.50ꢀ7.21 (m, 10H), 6.82 (br s, 1H), 4.57ꢀ
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4.51 (m, 1H), 4.49ꢀ4.08 (m, 3H), 2.18 (t, J = 7.1 Hz, 2H), 2.10ꢀ1.70 (m, 2H); C NMR (50 MHz,
DMSOd6) δ 204.5, 172.2, 156.3, 143.7 (2C), 140.8 (2C), 135.8 (2C), 129.4 (2C), 128.8, 127.7 (2C),
127.2 (2C), 125.9, 125.3 (2C), 120.2, (2C), 66.0, 63.5, 46.7, 30.7, 26.2; FTIR 3446, 3300, 1720,
1699, 1654, 1544, 1201, 739 cmꢀ1. Anal. Calcd for C26H24N2O4Se: C, 61.54; H, 4.77; N, 5.52.
Found: C, 61.27; H, 5.13; N, 5.45.
Se-Phenyl (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-(tritylthio)propaneselenoate
(8j): According to general procedure the organic solvent was removed to dryness and the residue
was triturated with hexane (2x30 ml). The solid was filtered to afford 8j (1.20 g, 83% yield): pale
yellow solid; mp = 176–178 ºC; [α]24 D ꢀ17.74 (c 0.44, CHCl3); 1H NMR (200 MHz, CDCl3) δ7.74ꢀ
7.67 (m, 2H), 7.63ꢀ7.57 (m, 2H), 7.38ꢀ7.12 (m, 24H), 4.91 (d, J = 8.3 Hz, 1H), 4.57 (dd, J = 10.6,
6.5 Hz, 1H), 4.38 (dd, J = 10.6, 6.5 Hz, 1H), 4.21 (t, J = 6.5 Hz, 1H), 4.14 (dt, J = 8.3, 5.5 Hz, 1H),
2.70ꢀ2.55 (m, 2H); 13C NMR δ (50 MHz, CDCl3) 202.7, 155.8, 144.0 (3C), 143.7, 143.6, 141.4 (2C),
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135.9 (2C), 129.5 (6C), 129.3 (2C), 129.0, 128.2 (6C), 127.9, 127.8, 127.2 (2C), 127.1 (3C), 125.8,
125.1, 125.0, 120.1 (2C), 67.7, 67.1, 62.4, 47.2, 33.4; FTIR 3281, 3057, 1720, 1693, 1537, 1261,
1055, 1038, 741 cmꢀ1. Anal. Calcd for C43H35NO3SSe: C, 71.26; H, 4.87; N, 1.93.Found: C, 71.05;
H, 5.25; N, 1.75.
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tert-Butyl
(3S)-3-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxo-4-
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(phenylseleno)butanoate (8k): According to general procedure the title compound was obtained as
solid (0.66 g, 82% yield) using dichloromethane as eluent: mp = 93–95 ºC; [α]22 ꢀ8.29 (c 0.66,
D
CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.88ꢀ7.60 (m, 4H), 7.58ꢀ7.29 (m, 9H), 6.26 (d, J = 10.0 Hz,
1H, 4.82ꢀ4.60 (m, 2H), 4.41 (dd, J = 17.0, 6.6 Hz, 1H), 4.35 (t, J = 6.6 Hz, 1H), 3.08 (dd, J = 17.2,
4.8 Hz, 1H), 2.72 (dd, J = 17.2, 4.3 Hz, 1H), 1.50 (s, 9H); 13C NMR (50 MHz, CDCl3) δ 202.8,
170.0, 155.9, 143.6, 143.5, 141.3 (2C), 135.9 (2C), 129.2 (2C), 128.9, 127.7 (2C), 127.1 (2C),
125.9, 125.1, 125.0, 120.0, (2C), 82.3, 67.4, 59.9, 47.1, 37.1, 28.0 (3C); FTIR 3337, 2982, 1740,
1685, 1526, 1230, 1034, 741 cmꢀ1. Anal. Calcd for C29H29NO5Se: C, 63.27; H, 5.31; N, 2.54.
Found: C, 63.12; H, 5.58; N, 2.35.
Se-Phenyl (2S)-3-tert-butoxy-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propaneselenoate
(8l): According to general procedure the organic solvent was removed to dryness and the residue
was triturated with hexane (3x20 ml). The solid was filtered to afford 8l (0.90 g, 86% yield): white
solid; mp = 103–105 ºC; [α]20 D ꢀ32.11 (c 1.01, CHCl3); 1H NMR (200 MHz, CDCl3)δ 7.85ꢀ7.55 (m,
4H), 7.52ꢀ7.30 (m, 9H), 5.89 (d, J = 8.7 Hz, 1H), 4.67 (dd, J = 10.0, 6.1 Hz, 1H), 4.59ꢀ4.20 (m, 3H),
3.94 (dd, J = 9.1, 2.3 Hz, 1H), 3.56 (dd, J = 9.1, 3.6 Hz, 1H), 1.20 (s, 9H); 13C NMR (50 MHz,
CDCl3) δ 203.3, 156.2, 143.6 (2C), 141.3 (2C), 135.9 (2C), 129.3 (2C), 128.9, 127.8 (2C), 127.1
(2C), 126.2, 125.1, 125.0, 120.0, (2C), 73.8, 67.4, 63.4, 61.4, 47.2, 27.3 (3C); FTIR 3346, 2972,
1724, 1699, 1506, 1216, 1090, 736 cmꢀ1. Anal. Calcd for C28H29NO4Se: C, 64.36; H, 5.59; N, 2.68.
Found: C, 64.25; H, 5.95; N, 2.62.
Se-Phenyl
(2S)-6-[(tert-butoxycarbonyl)amino]-2-{[(9H-fluoren-9-
ylmethoxy)carbonyl]amino}hexaneselenoate (8m): According to general procedure the title
compound was obtained (1.07 g, 86% yield) using ethyl acetate/dichloromethane (5:95) as eluent:
white solid; mp = 115–116 ºC; [α]20 D ꢀ33.93 (c 0.36, CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.81ꢀ
7.52 (m, 4H), 7.50ꢀ7.20 (m, 9H), 5.72 (d, J = 8.5 Hz, 1H), 4.67 (dd, J = 10.2, 6.3 Hz, 1H), 4.58 (br s,
1H), 4.51ꢀ4.34 (m, 2H), 4.29 (t, J = 6.6 Hz, 1H), 3.28ꢀ3.01 (m, 2H), 2.06ꢀ1.65 (m, 2H), 1.64ꢀ1.30
(m, 4H), 1.50 (s, 9H); 13C NMR (50 MHz, CDCl3) δ 204.1, 175.4, 156.3, 143.8, 143, 6, 141.3 (2C),
135.9 (2C), 129.2 (2C), 128.9, 127.7 (2C), 127.1 (2C), 125.8, 125.1, 125.0, 120.0, (2C), 79.4, 67.1,
63.7, 47.2, 39.8, 31.0, 29.5, 28.4 (3C), 22.2; FTIR 3337, 2933, 1729, 1688, 1521, 1170, 739 cmꢀ1.
Anal. Calcd for C32H36N2O5Se: C, 63.31; H, 5.97; N, 4.61. Found: C, 63.14; H, 6.29; N, 4.56.
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ylmethoxy)carbonyl]amino}propaneselenoate (8n): According to general procedure the organic
solvent was removed to dryness and the residue was triturated with hexane (3x20 ml). The solid
was filtered to afford 8n (0.95 g, 79% yield): white solid; mp = 104–106 ºC; [α]20 D ꢀ71.94 (c 0.38,
CHCl3); ); 1H NMR (200 MHz, CDCl3) δ 7.77 (d, J = 7.5 Hz, 2H), 7.63ꢀ7.53 (m, 2H), 7.48ꢀ7.35 (m,
7H), 7.32 (d, J = 7.5 Hz, 2H), 7.05 (d, J = 8.4, 2H), 6.94 (d, J = 8.4 Hz, 2H), 5.18 (d, J = 8.6 Hz,
1H), 4.78ꢀ4.66 (m, 1H), 4.57ꢀ4.33 (m, 2H), 4.24 (t, J = 6.9 Hz, 1H), 3.20ꢀ2.99(m, 2H), 1.30 (s,
9H); 13C NMR (50 MHz, CDCl3) δ 203.5, 155.8, 154.7, 143.6, 143, 5, 141.3 (2C), 135.9 (2C),
129.8 (2C), 129.3 (2C), 129.0 127.8 (3C), 127.1 (2C), 125.8, 125.0 (2C), 124.4 (2C), 120.0, (2C),
78.5, 67.3, 64.1, 47.1, 37.0, 28.8 (3C); FTIR 3302, 2976, 1718, 1694, 1532, 1260, 1169, 1047, 739
cmꢀ1. Anal. Calcd for C34H33NO4Se: C, 68.22; H, 5.56; N, 2.36. Found: C, 67.97; H, 5.88; N, 2.31.
Synthesis of Selenoester 10. To a solution of NꢀBocꢀalanine 9 (0.76 g, 4.0 mmol) in
EtOAc (32 mL) at 0 °C Nꢀmethylmorpholine (NMM 0.49 mL, 4.4 mmol) and isobutyl
chloroformate (0.56 ml, 4.4 mmol) were added. The reaction mixture was stirred at 0 °C for 40 min
under argon atmosphere. Then, a fresh solution of nucleophilic selenium species, prepared as
described above from diphenyl diselenide (0.75 g, 2.4 mmol), sodium borohydride (0.19 g, 4.8
mmol) and glacial acetic acid (1.36 mL, 24 mmol) in EtOAc (20 mL), was added directly in one
portion through syringe allowing to reach room temperature gradually. After 16 h the mixture was
poured into water (40 mL) and extracted with EtOAc (3 x 40 mL). The organic layer was washed
with brine (10 mL), dried over sodium sulfate and evaporated and the residue was triturated with
hexane (3x20 ml). The suspension was filtered to afford Se-phenyl (2S)-2-[(tert-
butoxycarbonyl)amino]propaneselenoate (10) (0.99 g, 76% yield) as a white solid: mp = 122–124
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NMR (200 MHz, CDCl3) δ 7.55ꢀ7.32 (m, 5H), 5.04 (d, J = 7.6 Hz, 1H), 4.44 (quint, J = 7.6 Hz, 1H),
1.51(s, 9H), 1.40 (d, J = 7.5 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 204.7, 154.9, 135.9 (2C), 129.2
(2C), 128.8, 125.9, 80.6, 58.9, 28.3 (3C), 17.8; FTIR 3282, 2980, 1717, 1683, 1526, 1164, 902, 744
cmꢀ1. Anal. Calcd for C14H19NO3Se: C, 51.22; H, 5.83; N, 4.27. Found: C, 51.08; H, 6.15; N, 4.20.
Chemoselective Acylation of Amines: General Procedure. To a solution of Seꢀphenyl
selenocarboxylate 3 (1.1 mmol) in the appropriate solvent (8 mL) amine (1.00 mmol) was added
and the resulting mixture was stirred at room temperature open to the air. When amine salts or
amino acids were employed (amines 11c, 11d and 11f), 2.0 equiv of DIPEA were added. After
complete consumption of amine (2ꢀ24 h) the reaction mixture was evaporated. The residue was
chromatographed using a silica gel column and the amide 12 was obtained in a pure form. Notably
the diphenyl diselenide was also recovered in 70ꢀ84% yield.
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