Thioacetic acid/NaSH-mediated synthesis of N -protected amino thioacids and their utility in peptide synthesis

Article abstract of DOI:10.1021/jo402872p

Thioacids are recently gaining momentum due to their versatile reactivity. The reactivity of thioacids has been widely explored in the selective amide/peptide bond formation. Thioacids are generally synthesized from the reaction between activated carboxylic acids such as acid chlorides, active esters, etc., and Na₂S, H₂S, or NaSH. We sought to investigate whether the versatile reactivity of the thioacids can be tuned for the conversion of carboxylic acids into corresponding thioacids in the presence of NaSH. Herein, we report that thioacetic acid- and NaSH-mediated synthesis of N-protected amino thioacids from the corresponding N-protected amino acids, oxidative dimerization of thioacids, crystal conformations of thioacid oxidative dimers, and the utility of thioacids and oxidative dimers in peptide synthesis. Our results suggest that peptides can be synthesized without using standard coupling agents.

Full text of DOI:10.1021/jo402872p

Article
pubs.acs.org/joc
Thioacetic Acid/NaSH-Mediated Synthesis of N‑Protected Amino
Thioacids and Their Utility in Peptide Synthesis
Sachitanand M. Mali and Hosahudya N. Gopi*
Department of Chemistry, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pune 411 008, India
S
* Supporting Information
ABSTRACT: Thioacids are recently gaining momentum due to their versatile reactivity. The reactivity of thioacids has been
widely explored in the selective amide/peptide bond formation. Thioacids are generally synthesized from the reaction between
activated carboxylic acids such as acid chlorides, active esters, etc., and Na2S, H2S, or NaSH. We sought to investigate whether the
versatile reactivity of the thioacids can be tuned for the conversion of carboxylic acids into corresponding thioacids in the
presence of NaSH. Herein, we report that thioacetic acid- and NaSH-mediated synthesis of N-protected amino thioacids from
the corresponding N-protected amino acids, oxidative dimerization of thioacids, crystal conformations of thioacid oxidative
dimers, and the utility of thioacids and oxidative dimers in peptide synthesis. Our results suggest that peptides can be synthesized
without using standard coupling agents.
substitution using sulfur reagents such as NaSH, Na2S, Fm-SH
[(9H-fluoren-9-yl)methanethiol], etc. For the activation of free
carboxylic acids, various strategies including carbodiimides,
active esters, acid chlorides, etc. have been utilized. All these
activated carboxylic acid derivatives have also been practiced
directly in the synthesis of peptides/amides. In addition,
epimerization of the amino acids has been observed in the
direct transformation of carboxylic acids to the thioacids using
Lawesson’s reagent.30 Inspired by the versatile reactivity of
thioacids, thioesters, and disulfide and persulfide (R−S−S−H)
formation from sulfur, we anticipate that by tuning the reaction
conditions it may be possible to synthesize the α-amino
thioacids directly from α-amino acids in the presence of
thioacetic acid and NaSH (Scheme 1), which can be further
utilized for peptide synthesis either in the presence or absence
of metal salts and coupling additives. Herein, we are reporting
the thioacetic acid- and NaSH-mediated synthesis of N-
protected amino thioacids, oxidation of thioacids to the
INTRODUCTION
■
Sulfur in the form of thiols and thioacids plays a significant role
in biology. The formation of covalent disulfide (R−S−S−R)
bonds through the oxidation of thiols (R−SH) is a most
distinctive property of sulfur, and these disulfide bonds are
ubiquitous in nature. Further, the involvement of protein
thioacids as “sulfide” donors in the biosynthesis of thiamin,
thioquinolobactin, vitamin B1, and cysteine have been
reported.1−3 Wieland and colleagues in their preliminary
investigation reported the potential of α-amino thioacids as
acylating agents in the peptide synthesis as well as thioester
strategy in the chemical ligation.4 The versatile reactivity of
thioacids (RCOSH) with various functional groups such as
azides,5−8 isonitriles,9 sulfonamides,10 nitroso derivatives,11
isocyanates,12 dinitrofluorobenzene,13 aziridines,14,15 and thio-
carbamates16 has been recently demonstrated in the amide
bond formation. In addition, the affinity of the sulfur toward
the metals has also been exploited in the synthesis of peptides
using thioacids.17−20 Danishefsky and colleagues showed the
thioacid-mediated synthesis of peptides and glycopeptides in
the presence of coupling additive HOBt.21,22 Further, to
support thioacids as possible precursors in the synthesis of
polypeptides in primordial conditions, Orgel and colleagues
demonstrated the N-acylation and polypeptide synthesis using
thioacetic acid and α-amino thioacids, respectively, in the
presence of oxidizing agents.23,24 Due to the versatile chemistry
of N-protected amino thioacids, various protocols have been
developed for the synthesis of N-protected amino thioa-
cids.25−30 Most of these protocols involve the activation of
carboxylic acid functional group followed by the nucleophilic
Scheme 1. Thioacetic Acid and NaSH-Mediated Synthesis of
N-Protected α-Amino Thioacids Directly from the
Corresponding N-Protected α-Amino Acids
Received: September 5, 2013
Published: February 18, 2014
© 2014 American Chemical Society
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corresponding oxidative dimers, and their applications in
peptide synthesis. Using N-protected amino thioacids as well
as their oxidative dimers, various peptides were synthesized in
moderate to good yields in the presence and absence of metals,
respectively.
Table 1. Synthesis of N-Protected Amino Thioacid Oxidative
Dimers Starting from the Corresponding Amino Acids
RESULTS AND DISCUSSION
■
Boc-AA (1) Boc-AA-SH (2) Boc-AA-S-S-AA-Boc (3) yield (%)
To realize our hypothesis, the N-Boc-Ala (1a) was treated with
thioacetic acid and NaSH in THF. The reaction mixture was
subjected to the mass spectral analysis after stirring for ∼36 h at
room temperature. Instructively, the mass spectral results (see
the Supporting Inforamtion) suggested the partial conversion
of N-Boc-Ala (1a) to corresponding N-Boc-Ala-SH (2a). The
schematic representation of the reaction is shown in Scheme 2.
a
b
c
d
e
f
Boc-Ala
Boc-Leu
Boc-Phe
Boc-Val
Boc-Aib
Fmoc-Leu
Boc-Ala-SH
Boc-Lue-SH
Boc-Phe-SH
Boc-Val-SH
Boc-Aib-SH
Fmoc-Leu-SH
Boc-Ala-S-S-Ala-Boc
Boc-Leu-S-S-Leu-Boc
Boc-Phe-S-S-Phe-Boc
Boc-Val-S-S-Val-Boc
Boc-Aib-S-S-Aib-Boc
Fmoc-Leu-S-S-Leu-Fmoc
40
35
31
33
25
26
Scheme 2. Synthesis of Boc-Ala-SH from the Thioacetic Acid
and NaSH and Subsequent Oxidative Dimerization of N-
Boc-Ala-SH
Fmoc-protected amino acids was studied using Fmoc-Leu. The
thioacid oxidative dimer of Fmoc-Leu (3f) was isolated in
similar yields as that of Boc-amino acids. The results suggest
that this method is compatible for both N-Fmoc and N-Boc
protecting groups. We anticipate that the lower yields of the
oxidative dimers are probably due to the dissociation/
hydrolysis of thioacid disulfides during the aqueous workup
and column chromatography. To validate our assumption, the
solution of pure thioacid dimer 3d in THF was treated with
10% Na2CO3 solution. The TLC and mass spectral analyses
suggests (see Supporting Information) that dissociation of
thioacid dimer into corresponding N-protected amino acids and
thioacids, indicating the instability of thioacid oxidative dimers
in the aqueous solution.
Although the results were quite encouraging, we found it
difficult to separate the pure N-Boc-Ala-SH from the reaction
mixture as it is contaminated with unreacted Boc-Ala. We
anticipate that thioacids can be selectively separated from the
reaction mixture through the oxidative dimerization. In this
regard, the excess thioacetic acid was removed from the
reaction mixture through the evaporation under reduced
pressure. The crude reaction mixture containing both 1a and
2a, after the aqueous workup, was subjected to the iodine
mediated oxidation reaction31 in THF and water in a ratio of
4:1 (Scheme 2). The pure Boc-Ala thioacid dimer (3a) was
isolated after the aqueous workup and column purification with
40% yield. To further understand the necessity of thioacetic
acid and NaSH in the conversion of N-protected amino acids to
the corresponding thioacids, we performed two control
reactions, one without thioacetic acid and the other without
NaSH. The mass spectral analysis reveals that there is no
formation of N-protected amino thioacids in both the control
reactions, suggesting the requirement of thioacetic acid and
NaSH for the formation of N-protected amino thioacids. In
order to understand the role of solvents in the conversion of
carboxylic acids to corresponding thioacids, we carried out the
same experiment in DCM, EtOAc, MeOH, DMF, and THF;
however, we found better yields of thioacids in THF compared
to other solvents.
However, out of all the thioacid oxidative dimers in the Table
1, we were able to get the single crystals for 3a and 3e, and their
X-ray structures are shown in Figure 1. Analysis of the crystal
structures reveals that the disulfides adopted the gauche
conformation (g ≈ 60°) with a S−S bond distance of 2.03 Å.
The remarkable results of the thioacetic acid- and NaSH-
mediated conversion of a variety of N-protected amino acids to
the corresponding amino thioacids enable us to propose the
possible mechanism of the reaction. The schematic representa-
tion is shown in Scheme 3. Both Orgel23,24 and Danishef-
sky21,22 in their pioneering work proposed that diacyl disulfide
and thioacid persulfide are the probable intermediates in the
thioacid-mediated amide bond synthesis. We speculate that the
treatment of NaSH with the thioacetic acid may lead to the
formation of activated thioacetic acid persulfide A. The
persulfide formation may be facilitated by the open air
oxidation as the reactions were performed in the open flasks
and hydrated NaSH. The reaction between A and the N-Boc-
amino acid (1) leads to the formation of a mixed anhydride, C.
The in situ generated reactive mixed anhydride (C) further
reacted with NaSH to give thioacid 2. In addition, persulfide A
can also be expected from the reaction between oxidative dimer
(B) and NaSH. To confirm whether the mixed anhydride C
will undergo thionation reaction, we synthesized the mixed
anhydride by reacting Boc-Ala with acetic anhydride in the
presence of DIPEA (Scheme 4). The in situ generated mixed
anhydride was further treated with NaSH. After the aqueous
workup, the Boc-Ala-SH was isolated in 95% yield, suggesting
that mixed anhydride C is a competent intermediate in the
formation of N-protected amino thioacids. In a control reaction
under inert argon atmosphere, we observed drastic decrease in
the yield of N-protected thioacid (2a), indicating the
requirement of open air to facilitate the formation of A.
With these encouraging results, we subjected various other
Boc-amino acids (Table 1) including the sterically hindered
Boc-Aib (α-amino isobutyric acid) to the synthesis of
corresponding thioacids mediated by the thioacetic acid and
NaSH and subsequent oxidative dimerization. The list of N-
Boc-amino thioacid oxidative dimers synthesized using the
above protocol is given in Table 1. All N-Boc-thioacid oxidative
dimers (3a−e) were isolated after the column purification in
25−40% overall yield. The compatibility of the reaction with
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Figure 1. X-ray structures of 3a [(Boc-Ala-S)2] and 3e [(Boc-Aib-S)2].
and the products were isolated within 30 min. The list of
peptides synthesized using N-protected diacyl disulfides is given
in Table 2. Further, these coupling reactions also suggest that
Scheme 3. Mechanism of the Synthesis of α-Amino Thioacid
from α-Amino Acids Mediated by Thioacetic Acid and NaSH
Table 2. Peptides Synthesized from Diacyl Disulfides
no.
3
NH2-R1
peptides
yield (%)
P1
P2
P3
P4
P5
P6
P7
P8
P9
P10
P11
3a
3a
3b
3b
3c
3c
3c
3d
3e
3e
3f
H-Val-OMe
Boc-Ala-Val-OMe
75
86
84
70
74
76
81
73
65
74
84
H-Trp-OMe
Boc-Ala-Trp-OMe
H-Phe-Ala-OBn
H-Trp-Val-OMe
H-Val-OMe
Boc-Leu-Phe-Ala-OBn
Boc-Leu-Trp-Val-OMe
Boc-Phe-Val-OMe
Boc-Phe-D-Val-OMe
Boc-Phe-Ala-OMe
H-D-Val-OMe
H-Ala-OMe
H-Ala-Trp-OMe
H-Val-OMe
Boc-Val-Ala-Trp-OMe
Boc-Aib-Val-OMe
H-Trp-OMe
Boc-Aib-Trp-OMe
Fmoc-Leu-Ala-Leu-OMe
H-Ala-Leu-OMe
thioacid persulfide, a reactive intermediate after the first
coupling reaction, can undergo a coupling reaction with free
amines as postulated by Danishefsky and colleagues.21,22 As
both acyl groups in the diacyl disulfides are involved in the
acylation reactions, it requires 2 equiv of free amine to
complete the reaction. The dipeptides P1 and P2 were
synthesized by reacting 3a with methyl esters of valine and
tryptophan, respectively. The tripeptides P3 and P4 were
synthesized from 3b by reacting with benzyl and methyl esters
of the dipeptides Phe-Ala and Trp-Val, respectively. Further, 3c
was coupled with methyl esters of L-Val, D-Val, and Ala to give
dipeptides P5, P6, and P7, respectively. Similarly, tripeptide P8
was isolated from the reaction between 3d and the methyl ester
of dipeptide Ala-Trp. To ensure whether the sterically hindered
thioacid dimers can undergo peptide coupling reactions, we
subjected N-Boc-Aib thioacid dimer (3e) to the coupling
reaction with the methyl ester of valine as well as the methyl
ester of Trp to give dipeptides P9 and P10, respectively.
Peptide P11 was synthesized from the reaction between 3f and
the free dipeptide Ala-Leu methyl ester. All peptides (P1−P11)
were isolated in moderate to good yields and are given in Table
2. The only byproduct that we observed in the coupling
reaction is Sn (poly sulfur, n = 1, 2, 3, etc). Overall, these
findings signify that peptides can be synthesized without using
coupling reagents, additives and the activated carboxylic acids
of N-protected amino acids. Further, to understand the
racemization during the peptides synthesis, we coupled 3c
with the methyl ester of racemic mixture of ( )-Val and
subjected it to chiral HPLC analysis along with diastereomeric
dipeptides P5 and P6. The HPLC profiles of these peptides are
Scheme 4. Synthesis of Thioacids from in Situ Generated
Mixed Anhydrides
In order to understand whether these N-protected-thioacid
oxidative dimers can undergo coupling reactions with free
amino acid esters and peptides, we subjected them for the
coupling reactions with various amino esters in THF. The
schematic representation of the peptide synthesis is shown in
Scheme 5. Results reveal that all thioacid oxidative dimers
undergo coupling reactions with amines and peptides without
any additives. The coupling reactions were found to be rapid,
Scheme 5. Synthesis of Peptides from Diacyl Disulfides
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given in the Supporting Information. Single peaks were
observed for peptides P5 and P6 at tR 12.15 and 13.23 min
respectively, whereas the diastereomeric mixture obtained after
the coupling of 3c with ( ) Val methyl ester showed two peaks
at tR 12.20 and 13.28 min, corresponding to the individual P5
and P6, respectively. Analysis suggests that no racemization
during the synthesis of these dipeptides and it was further
thioacids and their utility in peptide synthesis. The N-protected
thioacids were selectively oxidized to the corresponding
thioacid oxidative dimers in the presence of unreacted N-
protected amino acids and showed their utility in peptide
synthesis. Though yields of these diacyl disulfides are low,
however, their coupling reactions were found to be very neat,
fast and high yielding in comparison with the copper sulfate
mediated synthesis of peptides from the corresponding
thioacids. We are presently investigating how to improve the
yields of the thioacid oxidative dimers and their utility in the
solid-phase peptide synthesis. The results presented here
suggest that peptides can be synthesized without using standard
coupling reagents. The involvement of the thioacetic acid in the
conversion of amino acids to the corresponding thioacids in the
presence of NaSH and the peptides coupling reactions from the
both thioacid oxidative dimers as well as thioacids indicate the
significant role of thioacids in the synthesis of polypeptide in
prebiotic era. Overall, the chemistry reported here may open
new opportunities to rethink the amide bond formation32in
both chemistry and biology.
1
supported by the H NMR.
Although the coupling reactions of thioacid oxidative dimers
were found to be mild and clean and required no additional
coupling agents, base, or additives; however, the major
remaining issue is the dissociation of thioacid dimers during
the aqueous workup. We hypothesized that instead of the
isolation of thioacid oxidative dimers we can selectively couple
the N-protected amino thioacids from the reaction mixture
(Scheme 1) containing carboxylic acids with free amines in the
presence of 30 mol % copper sulfate (CuSO4·5H2O). To
validate, we subjected the crude mixture containing unreacted
1a and thioacid 2a for the coupling reaction with benzylamine
in the presence of 30 mol % copper sulfate in methanol as
reported earlier (Scheme 6).19,20 The N-acylated product P12
EXPERIMENTAL SECTION
■
Scheme 6. Selective Amide Bond Formation from the Crude
Reaction Mixture Containing Unreacted Boc-Ala and Boc-
Ala-SH
General Information. All amino acids, thioacetic acid, N-
hydroxysuccinamide, di-tert-butyl dicarbonate, CuSO4·5H2O, NaSH,
and THF were used as commercially available. Column chromatog-
raphy was performed on silica gel (100−200 mesh). 1H and 13C NMR
were recorded on a 400 MHz instrument (100 MHz for 13C) using the
residual solvent signals as an internal reference. The chemical shifts (δ)
are reported in ppm, and coupling constants (J) are given in hertz. IR
spectra were recorded on an FT-IR spectrophotometer using KBr
pellets. High-resolution mass spectra were obtained from an ESI-TOF
MS spectrometer.
General Procedure for the Synthesis of N-Protected Amino
Thioacid Oxidative Dimers. In a 50 mL round-bottom (RB) flask
was dissolved N-protected amino acid (10 mmol) in 15 mL of dry
THF. This solution was then treated with NaSH (20 mmol) and
thioacetic acid (10 mmol) at room temperature. After the reaction
mixture was stirred for about 36 h in open air, the solvent was
evaporated under reduced pressure. The residue was diluted with
water (50 mL) and acidified with 5% HCl (pH ∼ 2). This aqueous
solution was extracted with ethyl acetate (30 mL × 3). The combined
organic layer was washed with brine, dried over anhydrous Na2SO4,
and evaporated under reduced pressure to give N-protected amino
thioacid which was used for oxidative dimerization without further
purification.
was isolated in 78% yield. The unreacted N-protected amino
acid was removed through aqueous workup. Motivated by this
result, we extend the same methodology for the synthesis of
peptides. Using this methodology, peptides P1, P2, P5, and P7
were synthesized and isolated in good yields. Along with these
peptides, we also synthesized dipeptides P13 and P14 and
isolated them in good yields after the column purification
(Table 3).
In comparison of thioacid dimers versus copper sulfate
mediated thioacid peptide coupling reactions, better yields were
observed in the case of thioacid dimer mediated coupling
reactions. Overall, these results indicate that peptides can be
synthesized through selective coupling of N-protected thioacids
in the presence of N-protected carboxylic acids.
The N-protected amino thioacid obtained from the above
procedure was dissolved in a THF/H2O (4:1, 20 mL/5 mL) solvent
mixture at room temperature. To this solution was added iodine (10
mmol). The reaction mixture was stirred for about 12 h. The solvent
was evaporated under reduced pressure. The residue was diluted with
water (40 mL) and extracted with ethyl acetate (30 mL × 3). The
CONCLUSION
In conclusion, we have demonstrated the potential of thioacetic
acid and NaSH in the synthesis of N-protected α-amino
■
Table 3. List of the Thioacid and Peptides Synthesized by Using NaSH and Thioacetic Acid
entry
thioacid
amine
peptide
yield (%)
1
2
3
4
5
6
Boc-Ala-SH
H2N-Val-OMe
H2N-Trp-OMe
H2N-Val-OMe
H2N-Ala-OMe
H2N-Trp-OMe
H2N-Ala-OMe
P1
P2
P5
P7
67
63
65
69
65
60
Boc-Ala-SH
Boc-Phe-SH
Boc-Phe-SH
Boc-Ser(OtBu)-SH
Cbz-Leu-SH
Boc-Ser(OtBu)-Trp-OMe (P13)
Cbz-Leu-Ala-OMe (P14)
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combined organic layer was washed with 10% aq Na2CO3 and brine
and dried over anhydrous Na2SO4. The combined organic layer was
evaporated under reduced pressure to give N-protected amino thioacid
dimer. The pure thioacid oxidative dimer was obtained after the silica
gel column purification using ethyl acetate and petroleum ether.
General Procedure for the Synthesis of Peptides Using N-
Protected Amino Thioacid Oxidative Dimers. The N-protected
amino thioacid oxidative dimer (0.5 mmol) was dissolved in dry THF
at room temperature. To this solution was added the methyl ester of
amino acid or N-terminal free peptide (1.5 mmol in ∼2 mL ethyl
acetate). The reaction mixture was stirred for about 30 min. After
completion of the reaction (as monitored by TLC), the reaction
mixture was diluted with ethyl acetate (50 mL) and washed with 5% aq
HCl, 10% Na2CO3, and brine. The organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure to give
crude peptide, which was purified by column chromatography using
ethyl acetate and petroleum ether.
Synthesis of Boc-Ala-SH by Using Boc-Ala-OH, NaSH, and
Acetic Anhydride. In a 50 mL RB flask, Boc-Ala-OH (0.945 g, 0.5
mmol) was dissolved in 7 mL of dry THF. To this solution was added
diisopropylethylamine (1 mmol). This reaction mixture was then
cooled to 0 °C prior to addition of acetic anhydride (0.510 g, 0.5
mmol) and stirred for another 30 min. The reaction mixture was
treated NaSH (0.308 g, 0.55 mmol) and stirred for another 4 h. After
completion of the reaction (indicated by mass spectra), the solvent
THF was evaporated and residue was treated with water (25 mL) and
acidified with 5% HCl to reach pH ∼ 2. This aqueous layer was then
extracted with ethyl acetate (20 mL × 3), washed with brine, dried
over anhydrous Na2SO4, and evaporated under reduced pressure to get
Boc-Ala-SH in 95% (0.974 g).
General Procedure for the Synthesis of Di/Tripeptides by
Using N-Protected Amino Thioacids and Copper Sulfate. The
N-protected amino thioacid (10 mmol) obtained by the above
procedure was dissolved in distilled methanol (10 mL). To this
solution was added the methyl ester of amino acid or N-terminal free
peptide (12 mmol) with stirring. This reaction mixture was treated
with 30 mol % of CuSO4·5H2O. After 5 min, the clean reaction
mixture was converted to a dark brown turbid solution indicating the
completion of the reaction (also monitored by TLC). The reaction
mixture was centrifuged, and the residue was further washed with
methanol. The combined methanol solution was evaporated under
reduced pressure. The residue was then dissolved in ethyl acetate (80
mL), washed with 10% aq Na2CO3, 5% aq HCl, and brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The
product was purified by column chromatography using ethyl acetate
and petroleum ether.
7.37−7.23 (m, 10H), 5.01 (br, 2H, 4.81 (br, 2H), 3.27−3.14 (m, 4H),
1.44 (s, 18H); 13C NMR (100 MHz; CDCl3) δ 196.1, 154.9, 135.0,
129.3, 128.8, 127.3, 80.9, 81.0, 61.0, 37.8, 28.1 HRMS (ESI) m/z calcd
for C28H36N2NaO S2 [M + Na]+ = 583.1912, obsd [M + Na]+
=
6
583.1919.
(S)-2-((tert-Butoxycarbonyl)amino)-3-methylbutanoic dithioper-
oxyanhydride [(Boc-Val-S)2] (3d): white powder (0.8 g, 33%); mp =
127−129 °C; [α]25 +18 (c 0.1, MeOH); UV (λmax) = 231 nm; IR ν
D
(cm−1) 3383, 2961, 1721, 1705, 1504, 1368, 1250, 1167, 1057, 1019;
1H NMR (400 MHz; CDCl3) δ 5.09 (d, J = 8 Hz, 2H), 4.42 (q, J = 4
Hz, 2H), 2.38−2.34 (m, 2H), 1.48 (s, 18H), 1.0 (dd, J = 8 Hz, 12H);
13C NMR (100 MHz, CDCl3) 195.9, 155.3, 80.8, 65.3, 31, 28.2, 19.1,
16.8; HRMS (ESI) m/z calcd for C20H36N2NaO6S2 [M + Na]+
=
487.1912, obsd [M + Na]+ = 487.1925.
2-((tert-Butoxycarbonyl)amino)-2-methylpropanoic dithioperox-
yanhydride [(Boc-Aib-S)2] (3e): white powder (0.54 g, 25%); mp =
167−169 °C; UV (λmax) = 231 nm; IR ν (cm−1) 3368, 2980, 2929,
1
1712, 1507, 1386, 1366, 1274, 1253, 1159, 970, 878, 828; H NMR
(400 MHz; CDCl3) δ 5.09 (br, 2H), 1.55 (s, 12H), 1.46 (s, 18H); 13
C
NMR (100 MHz, CDCl3) 198.3, 153.9, 80.6, 62.5, 28.2, 25.5; HRMS
(ESI) m/z calcd for C18H32N2NaO6S2 [M + Na]+ = 459.1599, obsd
[M + Na]+ = 459.1592.
2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-methylpenta-
noic dithioperoxyanhydride [(Fmoc-Leu-S-)2] (3f): white powder
(0.95 g, 26%); mp = 154−156 °C; [α]25 −14 (c 0.1, MeOH); UV
D
(λmax) = 212, 265, 289, 300 nm; IR ν (cm−1) = 3387, 2956, 2922,
1
2861, 1703, 1522, 1447, 1381, 1323, 1246, 1122, 1045, 738, 547; H
NMR (200 MHz, CDCl3) δ 7.77 (d, J = 8 Hz, 4H), 7.62 (t, J = 6 Hz,
4H), 7.44−7.31 (m, 8H), 5.21 (d, J = 8 Hz, 1H), 5.05 (d, J = 8 Hz,
1H), 4.67−4.42 (m, 6H), 4.25 (t, J = 6 Hz, 2H), 0.93 (dd, J = 6, 6 Hz,
12H); 13C NMR (100 MHz, CDCl3) 196.1, 155.6, 143.6, 141.3, 127.7,
127.1, 124.9, 120.0, 67.1, 60.4, 59.7, 59.4, 47.2, 41.0, 24.6, 23.0, 21.3;
HRMS (ESI) m/z calcd for C42H44N2O6S2 [M + Na]+ = 759.2538,
obsd [M + Na]+ = 759.2536.
Boc-Ala-Val-OMe (P1):33 white powder (0.226g, 75%); [α]25D −44
1
(c 0.1, MeOH); H NMR (400 MHz; CDCl3) δ 6.76 (d, J = 4, 1H),
5.09 (d, J = 8 Hz, 1H), 4.51 (dd, J = 8 Hz, 1H), 4.18 (br, 1H), 3.72 (s,
3H), 2.20−2.21 (m, 1H), 1.43 (s, 9H), 1.34 (d, J = 8 Hz, 3H), 0.90
(dd, J = 4 Hz, J = 8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 172.5,
172.2, 155.5, 80.0, 56.9, 52.0, 49.9, 31.1, 28.1, 18.8, 17.6; MALDI
TOF/TOF m/z calcd for C14H26N2NaO5 (M + Na) is 325.1739 obsd
325.1589.
Boc-Ala-Trp-OMe (P2): white powder (0.334 g, 86%); [α]25 −12
D
1
(c 0.1, MeOH); H NMR (400 MHz; CDCl3) δ 8.35 (d, J = 8 Hz,
1H), 7.52 (d, J = 8 Hz, 1H), 7.35 (d, J = 8 Hz, 1H), 7.18 (t, J = 8 Hz,
1H), 7.11 (t, J = 8 Hz, 1H), 7.01 (br, 1H), 6.63 (d, J = 8 Hz, 1H), 5.01
(br, 1H), 4.92−4.87 (m, 1H), 4.16−4.14 (m, 1H), 3.66 (s, 3H), 3.32
(d, J = 8 Hz, 2H), 1.41 (s, 9H), 1.29 (d, J = 8 Hz, 3H); 13C NMR (100
MHz, CDCl3) 172.3, 172.0, 136.0, 127.5, 123.0, 122.1, 119.5, 118.4,
111.2, 109.6, 80.0, 52.9, 52.3, 28.2, 27.5, 18.3; MALDI TOF/TOF m/z
calcd for C20H27N3NaO5 (M + Na) is 412.1848, obsd 412.1998.
(S)-2-((tert-Butoxycarbonyl)amino)propanoic dithioperoxyanhy-
dride [(Boc-Ala-S)2] (3a): white powder (0.82 g, 40%); mp = 123−125
°C; [α]25 +20 (c 0.1, MeOH); UV (λmax) = 231 nm; IR ν (cm−1)
D
3379, 2972, 1705, 1507, 1367, 1271, 1241, 1164, 1048, 1031, 965, 912;
1H NMR (400 MHz; CDCl3) δ 5.07 (d, J = 8 Hz, 2H), 4.54 (t, J = 6
Hz, 2H), 1.48 (s, 18H), 1.45 (d, J = 8 Hz, 6H); 13C NMR (100 MHz,
CDCl3) 199.6, 154.8, 80.9, 56.3, 28.2, 18.7; HRMS (ESI) m/z calcd
Boc-Leu-Phe-Ala-OBn (P3): white powder (0.452 g, 84%); [α]25
−36 (c 0.1, MeOH); H NMR (400 MHz; CDCl3) δ 7.38−7.32 (m,
D
1
for C16H28N2NaO6S2 [M + Na]+ = 431.1286, obsd [M + Na]+
431.1287.
=
5H), 7.25−7.17 (m, 5H), 6.71−6.69 and 6.67−6.65 (d, J = 8 Hz, 1H)
and (d, J = 8 Hz, 1H), 5.15 (s, 2H), 4.83 (d, J = 8 Hz, 1H), 4.69 (q, J =
8 Hz, J = 4 Hz, 1H), 4.56−4.49 (m, J = 8 Hz, 1H), 4.05 (br, 1H),
3.14−3.02 (m, 2H), 1.62−1.55 (m, 2H), 1.4 (s, 9H), 1.34 (d, J = 8 Hz,
3H), 0.90 (t, J = 8 Hz, 6H); 13C NMR (100 MHz, CDCl3) 172.3,
172.0, 170.1, 155.6, 136.3, 135.3, 129.2, 128.5, 128.3, 128.1, 126.9,
80.2, 67.0, 53.8, 48.2, 40.9, 37.8, 29.6, 28.2, 24.6, 22.9, 21.7, 17.9;
MALDI TOF/TOF m/z calcd for C30H41N3NaO6 (M + Na)
562.2893, obsd 562.3182.
(S)-2-((tert-Butoxycarbonyl)amino)-4-methylpentanoic dithio-
peroxyanhydride [(Boc-Leu-S)2] (3b): white powder (0.87 g, 35%);
mp = 106−108 °C; [α]25 +2 (c 0.1, MeOH); UV (λmax) = 231 nm;
D
IR ν (cm−1) 3395, 2973, 1719, 1701, 1495, 1393, 1366, 1235, 1162,
1
1052, 870; H NMR (400 MHz; CDCl3); δ 4.97 (d, J = 8, 2H), 4.51
(br, 2H), 1.74 (t, J = 6 Hz, 4H), 1.60−1.57 (m, 2H), 1.47 (s, 18H),
0.96 (dd, J = 8 Hz, 12H); 13C NMR (100 MHz, CDCl3); 196.7, 155.0,
80.8, 59.2, 41.0, 28.2, 24.6, 22.9, 21.4; HRMS (ESI) m/z calcd for
Boc-Leu-Trp-Val-OMe (P4):34 white powder (0.371 g, 70%); [α]25
−28 (c 0.1, MeOH); H NMR (400 MHz; CDCl3) δ 8.23 (br, 1H),
D
1
C22H40N2NaO6S2 [M + Na]+ = 515.2225, obsd [M + Na]+
515.2228.
=
7.71 (d, J = 8 Hz, 1H), 7.35 (d, J = 8 Hz, 1H), 7.20−7.11 (m, 3H),
6.88 (d, J = 8 Hz, 1H), 6.34 (d, J = 8 Hz, 1H), 4.83 (d, J = 8 Hz, 1H),
4.76 (br, 1H), 4.13 (q, J = 4 Hz, 1H), 4.13 (q, J = 8 Hz, 1H), 3.63 (s,
3H), 3.33 (dd, J = 8 Hz, J = 4 Hz, 1H), 3.15 (dd, J = 8 Hz, J = 4 Hz,
1H), 2.03−1.97 (m, 1H), 1.63 (t, J = 6 Hz, 2H), 1.39 (s, 9H), 0.91 (d,
J = 4 Hz, 6H), 0.77 (dd, J = 8 Hz, J = 8 Hz 6H); 13C NMR (100 MHz,
(S)-2-((tert-Butoxycarbonyl)amino)-3-phenylpropanoic dithio-
peroxyanhydride [(Boc-Phe-S-)2] (3c): white powder (0.868 g,
31%); mp = 137−139 °C; [α]25 −14 (c 0.1, MeOH); UV (λmax) =
D
209 and 252 nm; IR ν (cm−1) 3337, 2972, 2928, 1733, 1502, 1449,
1368, 1224, 1163,1053, 849, 750, 701; 1H NMR (400 MHz; CDCl3) δ
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Article
CDCl3) 171.9, 171.7, 171,2, 156.0, 136.0, 127.4, 123.3, 122.0, 119.4,
118.3, 111.3, 109.3, 80.2, 52.6, 52.3, 51.4,, 30.4, 28.2, 27.4, 24.5, 22.8,
17.3; MALDI TOF/TOF m/z calcd for C28H42N4NaO6 (M + Na) is
553.3002, obsd 553.3280.
127.4, 80.1, 50.2, 43.4, 28.3, 18.5; MALDI TOF/TOF m/z calcd for
C15H22N2O3 (M + Na) is 301.1528, obsd 301.1804.
Boc-Ser(OtBu)-Trp-OMe (P13): gummy (1.94 g, 65%); H NMR
1
(400 MHz; CDCl3) δ 8.331 (br, 1H), 7.55 (d, J = 8 Hz, 1H), 7.34 (d, J
= 8 Hz, 1H), 7.31 (br, 1H), 7.17 (t, J = 7.2 Hz, 1H), 7.11 (t, J = 6.8
Hz, 1H), 7.01 (d, J = 1 Hz, 1H), 5.42 (d, J = 5.2 Hz, 1H), 4.5 (m, 1H),
4.18 (br, 1H), 3.75 and 3.37 (dd, 2H), 3.30 (br, 2H), 3.63 (s, 3H),
1.42 (s, 9H), 1.11 (s, 9H); 13C NMR (100 MHz, CDCl3) 172.0, 170.3,
155.5, 136.1, 127.6, 123.0, 122.2, 119.6, 118.7, 111.3, 109.9, 80.0, 74.0,
61.8, 60.5, 54.2, 53.1, 52.3, 28.3, 27.3, 21.1, 14.3. MALDI TOF/TOF
m/z calcd for C24H35N3O6 (M + Na) 484.2424, obsd 484.2915.
Boc-Phe-Val-OMe (P5):35 white powder (0.279 g, 74%); [α]25
D
1
−18 (c 0.1, MeOH); H NMR (400 MHz; CDCl3) δ 7.35−7.26 (m,
5H), 6.45 (d, J = 8 Hz, 1H), 5.10 (br, 1H), 4.51 (q, J = 4 Hz, 1H), 4.4
(br, 1H), 3.74 (s, 3H), 3.12 (d, J = 8 Hz, 2H), 2.18−2.12 (m, 1H),
1.46 (s, 9H), 0.90 (dd, J =4 Hz, J = 8 Hz, 6H); 13C NMR (100 MHz;
CDCl3) δ 171.7, 171.1, 155.3, 136.5, 129.2, 128.5, 126.8, 80.1, 57.1,
55.7, 52.0, 37.9, 31.2, 28.1, 18.7, 17.6; MALDI TOF/TOF m/z calcd
for C20H30N2O5 (M + Na) 401.2052, obsd (M + Na) 401.2318.
Boc-Phe-DVal-OMe (P6):36 white powder (0.287 g, 76%); [α]25D +6
Cbz-Leu-Ala-OMe (P14):37 white powder (1.26 g, 60%); H NMR
1
(400 MHz; CDCl3) δ 7.35 (m, 5H), 6.62 (d, J = 5.6 Hz, 1H), 5.30 (d,
J = 8.4 Hz, 1H), 5.10 (s, 2H), 4.59−4.54 (m,1H), 4.26−4.20 (m,1H),
3.74 (s, 3H), 1.73−1.60 (m, 2H), 1.55−1.48 (m, 1H), 1.39 (d, J = 6.8
Hz, 3H), 0.94 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz; CDCl3)
173.1, 171.7, 156.1, 136.1, 128.5, 128.1, 128.0, 67.0, 53.3, 52,5, 48.0,
41.5, 24.6, 22.9, 22.0, 18.2; MALDI TOF/TOF m/z calcd for
C18H26N2O5 (M + Na) 373.1739, obsd 373.2563.
1
(c 0.1, MeOH); H NMR (400 MHz; CDCl3) δ 7.35−7.25 (m, 5H),
6.45 (d, J = 4 Hz, 1H), 5.06 (br, 1H), 4.51 (br, 1H), 4.45 (br, 1H),
3.75 (s, 3H), 3.12 (d, J = 8 Hz, 2H), 2.13−2.06 (m,, 1H), 1.46 (s, 9H),
0.83 (dd, J = 8 Hz, J = 8 Hz, 6H); 13C NMR (100 MHz; CDCl3) δ
171.9, 171.1, 155.3, 136.5, 129.2, 128.7, 126.9, 80.2, 57.0, 55.8, 52.1,
38.2, 31.0, 28.2, 18.7, 17.5; MALDI TOF/TOF m/z calcd for
C20H30N2O5 (M + Na) 401.2052, obsd (M + Na) 401.2291.
Crystal Structure Analysis of (Boc-Ala-S-)2 (3a). Crystals of (Boc-
Ala-CO-S-)2 were grown by slow evaporation of ethyl acetate/n-
hexane (40/60). A single crystal (0.12 × 0.07 × 0.04 mm) was
mounted in a loop with a small amount of the mother liquor. The X-
ray data were collected at 100 K using Mo Kα radiation (λ = 0.71073
Boc-Phe-Ala-OMe (P7): white powder (0.283 g, 81%); [α]25 −22
D
1
(c 0.1, MeOH); H NMR (400 MHz; CDCl3) δ 7.32−7.20 (m, 5H),
6.47 (d, J = 4 Hz, 1H), 5.03 (d, J = 8 Hz, 1H), 4.56−4.49 (m, 1H),
4.38−4.37 (m, 1H), 3.72 (s, 3H), 3.08 (t, J = 6 Hz, 2H), 1.41 (s, 9H),
1.35 (d, J = 8 Hz, 3H); 13C NMR (100 MHz; CDCl3) δ 172.8, 170.7,
155.3, 136.4, 129.3, 128.6, 126.9, 80.2, 55.5, 52.4, 48.0, 38.3, 28.2, 18.3;
MALDI TOF/TOF m/z calcd for C18H26N2O5 (M + Na) = 373.1739,
obsd (M + Na) 373.1906.
́
Å), ω-scans (2θ = 56.56°) for a total number of 3080 independent
reflections. Space group P2(1),2(1),2(1) a = 10.322(3) Å, b =
11.312(4) Å, c = 18.663(6) Å, α = 90.00°, β = 90°, γ = 90.00°, V =
2179.1(12) Å3, orthorhombic P, Z = 4 for chemical formula
C16H28N2O6S2, with one molecule in asymmetric unit; ρcalcd =1.245
g cm−3, μ = 0.275 mm−1, F(000) = 872, Rint = 0.1890. All non-
hydrogen atoms were refined anisotropically. The hydrogen atoms
were fixed geometrically in the idealized position and refined in the
final cycle of refinement as riding over the atoms to which they are
bonded. The final R value was 0.0684 (wR2 = 0.1170) for 3080
observed reflections (F0 ≥ 4σ(|F0|)) and 243 variables, S = 0.943. The
largest difference peak and hole were 0.284 and −0.341 e Å3,
respectively.
Boc-Val-Ala-Trp-OMe (P8): white powder (0.356 g, 73%); [α]25
−34 (c 0.1, MeOH); H NMR (400 MHz; CDCl3) δ 8.56 (br, 1H),
D
1
7.48 (d, J = 8 Hz, 1H), 7.33 (d, J = 8 Hz, 1H), 7.16 (t, J = 8 Hz, 1H),
7.09 (t, J = 8 Hz, 1H), 7.00 (br, 1H), 6.78 (d, J = 8 Hz, 1H), 6.69 (d, J
= 8 Hz, 1H), 5.12 (d, J = 8 Hz, 1H), 4.90−4.85 (m, 1H), 4.53−4.45
(m,1H), 3.94 (t, J = 8 Hz, 1H), 3.67 (s, 3H), 3.30 (d, J = 8 Hz, 2H),
2.06−2.00 (m, 1H), 1.45 (s, 9H), 1.32 (d, J = 8 Hz, 3H), 0.86 (dd, J =
8 Hz, J = 16 Hz, 6H); 13C NMR (100 MHz, CDCl3); 171.9, 171.8,
171.5, 136.0, 127.4, 123.3, 122.0, 119.4, 118.3, 111.3, 109.3, 80.2, 59.8,
52.8, 52.4, 48.6, 30.7, 29.6, 28.7, 19.1, 17.2; MALDI TOF/TOF m/z
calcd for C25H36N4NaO6 (M + Na) 511.2532, obsd 511.2528.
Boc-Aib-Val-OMe (P9): white powder (0.205 g, 65%); [α]25D −6 (c
0.1, MeOH); 1H NMR (400 MHz; CDCl3) δ 7.02 (br, 1H), 4.94 (br,
1H), 4.52 (q, J = 4 Hz, 1H), 3.71 (s, 3H), 2.19−2.13 (m, 1H), 1.51
and 1.47 (s, 6H), 1.43 (s, 9H), 0.92 (dd, J = 8 Hz, J = 4 Hz, 6H); 13C
NMR (100 MHz, CDCl3) 174.4, 172.4, 154.5, 80.1, 57.0, 56.8, 52.0,
31.1, 28.3, 28.2, 26.0, 18.9, 17.5; MALDI TOF/TOF m/z calcd for
C15H28N2NaO5 (M + Na) 339.1896, obsd 339.1841.
Crystal Structure Analysis of (Boc-Aib-S-)2 (3e). Crystals of (Boc-
Aib-CO-S-)2 were grown by slow evaporation of ethyl acetate/n-
hexane (40/60). A single crystal (0.1 × 0.06 × 0.03 mm) was mounted
in a loop with a small amount of the mother liquor. The X-ray data
were collected at 100 K temperature using Mo Kα radiation (λ =
́
0.71073 Å), ω-scans (2θ = 56.56°) for a total number of 6601
independent reflections. Space group Pca2(1), a = 23.375(11) Å, b =
9.575(4) Å, c = 10.580(5) Å, α = 90.00°, β = 90°, γ = 90.00°, V =
2368.1(19) Å3, orthorhombic P, Z = 4 for chemical formula
C18H32N2O6S2, with one molecule in asymmetric unit; ρcalcd = 1.225
g cm−3, μ = 0.258 mm−1, F(000) = 936, Rint = 0.0806. All non-
hydrogen atoms were refined anisotropically. The hydrogen atoms
were fixed geometrically in the idealized position and refined in the
final cycle of refinement as riding over the atoms to which they are
bonded. The final R value was 0.0386 (wR2 = 0.0680) for 6601
observed reflections (F0 ≥ 4σ(|F0|)) and 263 variables, S = 0.766. The
largest difference peak and hole were 0.205and −0.249 e Å3,
respectively.
Boc-Aib-Trp-OMe (P10): white powder (0.298 g, 74%); [α]25 +2
D
1
(c 0.1, MeOH); H NMR (400 MHz; CDCl3) δ 8.43 (br, 1H), 7.54
(d, J = 8 Hz, 1H), 7.34 (d, J = 4 Hz, 1H), 7.18−7.03 (m, 3H), 6.89 (br,
1H), 5.02 (d, J = 4 Hz, 1H), 4.91−4.85 (m, 1H), 3.63 (s, 3H), 3.36−
3.25 (m, 2H), 1.43 and 1.39 (s, 6H) and (s, 9H); 13C NMR (100
MHz, CDCl3) 174.4, 172.4, 154.5, 136.0, 127.4, 122.9, 121.9, 119.3,
118.4, 111.2, 109.7, 79.9, 56.6, 53.0, 52.2, 28.1, 27.6, 24.4; MALDI
TOF/TOF m/z calcd for C21H29N3NaO5 (M + Na) is 426.2005, obsd
426.1302.
Fmoc-Leu-Ala-Leu-OMe (P11): white powder (0.460 g, 84%);
[α]25D −50 (c 0.1, MeOH); 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J
= 8 Hz, 2H), 7.58 (d, J = 8 Hz, 2H), 7.39 (t, J = 6 Hz, 2H), 7.30 (t, J =
8 Hz, 2H), 6.77 (d, J = 16 Hz, 2H), 7.30 (t, J = 8 Hz, 2H), 6.77 (d, J =
16 Hz, 2H), 5.43 (d, J = 8 Hz, 1H), 4.56 (br, 2H), 4.47−4.34 (m, 2H),
4.20 (t, J = 6 Hz, 2H), 3.71 (s, 3H), 1.62−154 (m, 6H), 1.37 (d, J = 8
Hz, 3H), 0.92 (t, J = 6 Hz, 12H); 13C NMR (100 MHz, CDCl3) 173.1,
172.2, 171.7, 156.2, 143.7, 141.3, 127.7, 127.0, 125.0, 120.0, 67.0, 54.0,
52.3, 50.8, 48.7, 47.1, 41.7, 42.3, 29.7, 24.7, 24.6, 23.0, 21.8, 18.0;
MALDI TOF/TOF m/z calcd for C31H41N3NaO6 [M + Na]
574.2893, obsd 574.3691.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR, 13C NMR, and mass spectra of all compounds (3a−f,
and P1−P14) and crystallographic information for compounds
3a and 3e (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: hn.gopi@iiserpune.ac.in.
Notes
■
Boc-Ala-NHBn (P12):19 white solid (1.5 g, 78%); H NMR (400
1
MHz; CDCl3) δ 7.32−7.22 (m, 5H), 6.821 (br, 1H), 5.201 (br, 1H),
4.412 (br, 2H), 4.226 (br, 1H), 1.395 (s, 9H), 1.376−1.357 (d, 3H, J =
7.6 Hz); 13C NMR (100 MHz; CDCl3) 172.7, 155.6, 138.1, 128.7,
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank IISER Pune for financial support and S.M.M. is
thankful to CSIR, Government of India, for a Senior Research
Fellowship.
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