An amine protecting group deprotectable under nearly neutral oxidative conditions

Article abstract of DOI:10.3762/bjoc.14.149

The 1,3-dithiane-based dM-Dmoc group was studied for the protection of amino groups. Protection was achieved under mild conditions for aliphatic amines, and under highly reactive conditions for the less reactive arylamines. Moderate to excellent yields were obtained. Deprotection was performed by oxidation followed by treating with a weak base. The yields were good to excellent. The new amino protecting group offers a different dimension of orthogonality in reference to the commonly used amino protecting groups in terms of deprotection conditions. It is expected to allow a collection of transformations to be carried out on the protected substrates that are unattainable using any known protecting groups.

Full text of DOI:10.3762/bjoc.14.149

An amine protecting group deprotectable under nearly
neutral oxidative conditions
Shahien Shahsavari1, Chase McNamara1, Mark Sylvester1, Emily Bromley1,
Savannah Joslin1, Bao-Yuan Lu2 and Shiyue Fang*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1750–1757.
1Department of Chemistry, Michigan Technological University, 1400
Townsend Drive, Houghton, MI 49931, USA and 2Nalco Champion,
an Ecolab Company, 11177 S. Stadium Drive, Sugar Land, TX 77478,
USA
doi:10.3762/bjoc.14.149
Received: 16 March 2018
Accepted: 03 July 2018
Published: 13 July 2018
Email:
Shiyue Fang* - shifang@mtu.edu
Associate Editor: B. Stoltz
* Corresponding author
© 2018 Shahsavari et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
amine; carbamate; dM-Dmoc; oxidation; protecting group
Abstract
The 1,3-dithiane-based dM-Dmoc group was studied for the protection of amino groups. Protection was achieved under mild condi-
tions for aliphatic amines, and under highly reactive conditions for the less reactive arylamines. Moderate to excellent yields were
obtained. Deprotection was performed by oxidation followed by treating with a weak base. The yields were good to excellent. The
new amino protecting group offers a different dimension of orthogonality in reference to the commonly used amino protecting
groups in terms of deprotection conditions. It is expected to allow a collection of transformations to be carried out on the protected
substrates that are unattainable using any known protecting groups.
Introduction
In multistep organic synthesis, amino groups usually have to be dimension of orthogonality of amine protection in terms of
protected [1]. Protecting groups for the purpose mainly include deprotection conditions [13-17]. This group was deprotected
those deprotectable by acid (e.g., tert-butyloxycarbonyl (Boc) under oxidative conditions under which the commonly used
group) [2-4], base (e.g., 9-fluorenylmethyloxycarbonyl (Fmoc) Boc, Fmoc, benzyl and Teoc groups could potentially survive.
group and trifluoroacetyl group) [5-7], catalytic hydrogenation Oxidation was achieved by hydrogen peroxide in the presence
(e.g., benzyl group) [8], photoirradiation (e.g., 2-nitro- of an ammonium molybdate catalyst. Recently, we reported the
phenylethyl carbamate and 6-nitroveratryl carbamate) [9,10] use of the Dmoc group for amine protection in automated solid-
and fluoride (e.g., trimethylsilylethyloxycarbonyl (Teoc) group) phase oligodeoxynucleotide (ODN) synthesis [18]. For depro-
[11,12]. The 1,3-dithian-2-ylmethoxycarbonyl (Dmoc) group tection, we found that sodium periodate could effectively
first reported by Kunz and co-workers provides a different oxidize multiple Dmoc functions in the ODNs to achieve com-
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plete deprotection. Under these oxidative conditions, oxidation tions most suitable for the reaction were to react one equivalent
of the ODN was not observed. The mild deprotection condi- amine with one equivalent of 4 in the solvent THF using five
tions allowed us to introduce sensitive functionalities into equivalents of DIPEA as the base. At room temperature, the
ODNs, which are otherwise impossible or highly difficult to reaction could complete within eight hours.
achieve [18]. In addition, we also investigated the potential of
the dimethyl-1,3-dithian-2-ylmethyl (dM-Dim) group for or- After suitable conditions for protection of amines with
thogonal carboxylic acid protection [19]. To further explore the dM-Dmoc were identified, we investigated the substrate scope
use of the 1,3-dithiane function as protecting group in organic of the reaction. As shown in Table 1, primary aliphatic amines
synthesis, here we report the results of our studies on the use of including 3a–d gave good to excellent isolated yields of carba-
the dimethyl-1,3-dithian-2-ylmethoxycarbonyl (dM-Dmoc) mates 5a–d (Table 1, entries 1–4). Under these conditions, how-
group for amine protection (Scheme 1). Compared with the ever, secondary aliphatic amines could not react or could react
Dmoc group, the dM-Dmoc group is expected to be more stable but gave very low yields. We tried a variety of other conditions
under nucleophilic conditions, which will allow many transfor- such as deprotonating the amine followed by reacting with 4
mations including base hydrolysis of esters and amides, hydride and heating excess amine with 4 without any solvent but failed
reduction of carbonyl compounds, and a wide range of nucleo- to identify one that could afford useful yields. We also tried to
philic substitution reactions to be carried out without losing the use the optimized conditions for the protection of aliphatic pri-
protection. With Dmoc protection, such transformations would mary amines to protect arylamines, but found that arylamines
be unattainable or require fine tuning of reaction conditions to were not reactive enough for the reaction. Therefore, for
keep the protection. In addition, the side product 2 from depro- protecting arylamines, we used conditions for the formation of
tection of dM-Dmoc is less likely to act as a Michael acceptor hindered O-tert-alkyl N-arylcarbamates we reported earlier
to react with the amine product than 1 from deprotection of [20]. Treating one equivalent 3e with two equivalents LDA and
Dmoc due to its higher steric hindrance. Such side reactions one equivalent 4 in THF gave the desired arylamine dM-Dmoc
could be a serious issue in some situations [18].
carbamate 5e in synthetically useful yield (Table 1, entry 5).
Three additional arylamines were also tested, which include the
two heterocyclic arylamines 3g and 3h, all gave synthetically
Results and Discussion
To protect amines, compound 4 was prepared readily by useful yields of the aryl carbamate products 5f–h (Table 1,
reacting deprotonated 1,3-dithiane with acetone followed by entries 6–8). Finally, to investigate the suitability of the
treating with p-nitrophenylchloroformate (see experimental dM-Dmoc group for protecting amino acids, phenylalanine (3i)
section). The compound is stable, which allows easy purifica- was selected to react with 4 to give 5i (Table 1, entry 9). The
tion and storage. However, we expected that it could react with general conditions for aliphatic amine protection were used, but
amines under suitable conditions. Using benzylamine (3a) as due to the low solubility of 3i in THF, DMSO was used as the
the model substrate, we tested a variety of reaction conditions to solvent. Compound 5i was obtained in 80% isolated yield.
form the dM-Dmoc protected carbamate 5a (see Table 1 for
structures). These include using different solvents such as THF, For deprotection of dM-Dmoc protected amines, we used the
DCM, acetonitrile and toluene, and different bases such as conditions we developed earlier for the deprotection of Dmoc
DIPEA, pyridine and trimethylamine. We found that the condi- protected ODNs directly without making additional efforts to
Scheme 1: Dmoc and dM-Dmoc protection and deprotection of amines.
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Table 1: Protection of amines with dM-Dmoc and deprotection.a
entry
1
3
5 (yield)
3 (yield)
3a (76%)
3a
5a (92%)
5b (89%)
5c (72%)
5d (97%)
5e (46%)
5f (42%)
5g (57%)
5h (52%)
2
3
4
5
6
7
8
3b (54%)
3c (55%)
3d (88%)
3e (73%)
3f (64%)
3g (53%)
3h (48%)
3b
3c
3d
3e
3f
3g
3h
9
3i (41%)
3i
5i (80%)
aReaction conditions: For converting 3a–d to 5a–d, 3 (1 equiv), 4 (1 equiv), DIPEA (5 equiv), THF, rt, 8 h. For 3e–h to 5e–h, 3 (1 equiv), 4 (1 equiv),
LDA (2 equiv), THF, −78 °C to rt, 8 h. For 3i to 5i, 3i (1 equiv), 4 (1 equiv), DIPEA (5 equiv), DMSO, rt, 8 h. For 5 to 3, 5 (1 equiv), NaIO4 (10 equiv),
THF/H2O (v/v 1:1), rt, 12 h; then K2CO3 (10 equiv), MeOH (MeOH/H2O for 5i to 3i), rt, 1 h. Isolated yields were obtained in all cases except for 3i, for
which the yield was determined with RP-HPLC.
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evaluate other conditions [18]. These conditions could be supe- deprotonation of the carboxylic acid group by potassium
rior to reported conditions [13,15,17,21] because they do not carbonate, which made the starting material insoluble and
require transition metal catalysts or any special devices such as prevented deprotonation of H-2 in the oxidized 1,3-dithiane
an electrochemical cell. Therefore, the dM-Dmoc carbamates function. The problem was solved by using a solvent mixture of
were first oxidized with sodium periodate at room temperature. methanol and water. It is important to note that carrying out the
After removing the excess oxidizing agent and other inorganic deprotection reaction in one pot by performing the oxidation
salts by filtration, β-elimination to give the amine products was under basic conditions is not feasible. In theory, using the one
initiated with the weak base potassium carbonate at room tem- pot approach, once the sulfides in dM-Dmoc were oxidized,
perature. The products were then purified with flash column β-elimination would follow to give the desired amine products
chromatography. As shown in Table 1, the yields of the depro- directly. We tested the idea, and as expected, complex mixtures
tection ranged from 48% to 88%. Among them, 3a and 3d, were formed. Reasons for the observation include oxidation of
which are aliphatic amines, gave better yields (Table 1, entries 1 amine products by sodium periodate and its reduced products.
and 4). Compounds 3b and 3c are also aliphatic amines, but In addition, we also found that oxidation of sulfides by sodium
their yields were lower. This might be caused by evaporation periodate was significantly slower under basic conditions than
due to their low boiling points during work-up and purification. under neutral and acidic conditions.
The arylamines were obtained in lower yields (Table 1, entries
5–8) compared with the aliphatic ones. Among the four To demonstrate the feasibility of selective deprotection of
arylamine examples, 5g and 5h contained a pyridine ring, which dM-Dmoc protected amines in the presence of Boc protected
could be sensitive to oxidative conditions. However, it looked ones, compound 6 [22] was reacted with 4 under the general ali-
like that sodium periodate was benign to pyridine and some phatic amine protection conditions to give the Boc and
other nitrogen containing aromatic heterocycles [18]. The dM-Dmoc protected diamine 7 (Scheme 2). Selective removal
dM-Dmoc protected phenylalanine (5i) was deprotected under of dM-Dmoc was simply achieved under the general deprotec-
slightly different conditions (Table 1, entry 9). In the β-elimina- tion conditions without any fine tuning of conditions. The
tion step, when methanol was used as the solvent as in the desired Boc protected 6 was obtained in 80% isolated yield. To
general deprotection procedure, no reaction occurred even after demonstrate the orthogonality of dM-Dmoc and Fmoc protec-
stirring overnight. This might be caused by the more favoured tions, compound 9 was prepared (Scheme 2). Compound 4 was
Scheme 2: Selective deprotection of dM-Dmoc-, Boc- and Fmoc-protected amines.
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reacted with 1,2-bis(2-aminoethoxy)ethane to give 8, which was hexanes/EtOAc); IR (thin film) ν 3339, 2930, 1420 cm−1;
reacted with Fmoc-Cl to give the dM-Dmoc and Fmoc pro- 1H NMR (400 MHz, CDCl3) δ 1.32 (s, 6H), 1.73–1.85 (m, 1H),
tected diamine 9. We found that selective removal of Fmoc 2.00–2.07 (m, 1H), 2.41 (s, 1H), 2.78–2.90 (m, 4H), 4.10 (s,
from 9 to give 8 could be achieved under typical Fmoc depro- 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 25.9, 27.4, 30.9,
tection conditions involving piperidine. Selective removal of 61.0, 73.4 ppm; HRMS (ESI) m/z: [M + K]+ calcd for
dM-Dmoc was also simple; treating 9 under the standard C7H14OS2K, 217.0123; found, 217.0121.
dM-Dmoc deprotection conditions gave the Fmoc protected di-
amine 10 in 75% isolated yield (Scheme 2). The basic condi- 2-(1,3-Dithian-2-yl)propan-2-yl (4-nitrophenyl) carbonate
tions involving potassium carbonate used to induce β-elimina- (4): To a solution of 2-(1,3-dithian-2-yl)propan-2-ol (6.4 g,
tion of oxidized dM-Dmoc did not cause any loss of Fmoc 36 mmol, 1 equiv) and pyridine (2.9 mL, 54 mmol, 1.5 equiv)
protection.
in DCM (100 mL) was added p-nitrophenylchloroformate
(7.2 g, 36 mmol, 1 equiv) at rt under argon. After stirring for
8 h, the contents were poured into a separatory funnel and parti-
Conclusion
In summary, we have demonstrated that dM-Dmoc could serve tioned between EtOAc (40 mL) and H2O (80 mL). The aqueous
as a new protecting group for aliphatic and arylamines. This layer was extracted with DCM (50 mL × 2). The combined
group could be removed under nearly neutral oxidative condi- organic layer was dried over anhydrous Na2SO4, filtered and
tions, which are orthogonal to the commonly used conditions concentrated. Flash column chromatography (SiO2, 9:1
for deprotection of protected amines including acid, base, and hexanes/EtOAc) gave 4 as a white amorphous solid (10.0 g,
catalytic hydrogenation. Compared to Dmoc, dM-Dmoc has the 81%): TLC Rf = 0.4 (5:1 hexanes/EtOAc); IR (thin film)
advantage of being stable under a wide range of basic and ν 3083, 2981, 1713, 1592, 1522 cm−1; 1H NMR (400 MHz,
nucleophilic conditions. We expect that the new protecting CDCl3) δ 1.70 (s, 6H), 1.81–1.91 (m, 1H), 2.11–2.18 (m, 1H),
group will find wide applications in multistep organic synthesis. 2.92–2.95 (m, 4H), 4.98 (s, 1H), 7.38 (d, J = 9.2 Hz, 2H), 8.26
(d, J = 6.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 24.1,
Experimental
25.7, 30.8, 56.2, 86.9, 121.9, 125.1, 145.2, 150.0, 155.5 ppm;
General: All reactions were performed in oven-dried glassware HRMS (ESI) m/z: [M + K]+ calcd for C14H18O2S2K, 321.0385;
under an argon atmosphere using standard Schlenk techniques. found, 321.0404.
Reagents and solvents available from commercial sources were
used as received unless otherwise noted. THF and CH2Cl2 were General procedure for dM-Dmoc protection of aliphatic
dried using an Innovative Technology Pure-Solv™ system. amines – synthesis of carbamates 5a–d: To a solution of an
Acetone, pyridine, and diisopropylamine were distilled over amine (0.292 mmol, 1 equiv) and DIPEA (0.255 mL,
CaH2 under nitrogen. Thin-layer chromatography (TLC) was 1.46 mmol, 5 equiv) in dry THF (10 mL) was added 4 (0.100 g,
performed using Sigma-Aldrich TLC plates, silica gel 60F-254 0.292 mmol, 1 equiv) at rt under argon. After stirring for 8 h,
over glass support, 0.25 μm thickness. Flash column chromato- the reaction was quenched with sat. NH4Cl (15 mL). Organics
graphy was performed using SiliCycle silica gel, particle size were extracted with EtOAc (10 mL × 2). The extracts were
40–63 μm. 1H and 13C spectra were measured on Varian dried over anhydrous Na2SO4, filtered, and concentrated. The
UNITY INOVA spectrometer at 400 and 100 MHz, respective- carbamates 5a (column eluted with 3:1 hexanes/EtOAc; TLC
ly; chemical shifts (δ) were reported in reference to solvent Rf = 0.5, developed with 1:1 hexanes/EtOAc), 5b (6:1 hexanes/
peaks (residue CHCl3 at δ 7.24 ppm for 1H and CDCl3 at EtOAc; Rf = 0.5, 3:1 hexanes/EtOAc), 5c (6:1 hexanes/EtOAc;
δ 77.00 ppm for 13C).
Rf = 0.5, 3:1 hexanes/EtOAc), and 5d (9:1 hexanes/EtOAc;
Rf = 0.5, 6:1 hexanes/EtOAc) were purified with flash column
2-(1,3-Dithian-2-yl)propan-2-ol: To a solution of 1,3-dithiane chromatography (SiO2).
(5.0 g, 41.6 mmol) in dry THF (100 mL) was slowly added
n-BuLi (2.5 M in pentane, 15.7 mL, 41.6 mmol) at −78 °C 2-(1,3-Dithian-2-yl)propan-2-yl benzylcarbamate (5a):
under argon. After stirring for 30 min, freshly distilled acetone Colorless oil (0.084 g, 92%); IR (thin film) ν 3343, 3020, 2937,
(3.0 mL, 41.6 mmol) was added dropwise, and stirring was 1697, 1506, 1452 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.58 (s,
continued for 1 h. The reaction was quenched with sat. NH4Cl 6H), 1.75–1.84 (m, 1H), 2.04–2.09 (m, 1H), 2.81–2.92 (m, 4H),
(75 mL) and extracted with EtOAc (50 mL × 2). The extracts 4.30 (d, J = 5.88 Hz, 2H), 5.00 (brs, 1H), 5.09 (s, 1H),
were dried over anhydrous Na2SO4, filtered, and concentrated. 7.23–7.31 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3) δ 25.1,
The residue was purified by flash column chromatography 26.2, 31.2, 44.8, 57.6, 82.4, 127.5, 127.6, 128.7, 138.8, 155.3
(SiO2, 4:1 hexanes/EtOAc) to afford the title compound as a ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C15H21NO2S2Na,
white amorphous solid (6.24 g, 84%): TLC Rf = 0.3 (4:1 334.0911; found, 334.0905.
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2-(1,3-Dithian-2-yl)propan-2-yl butylcarbamate (5b): Pale 2-(1,3-Dithian-2-yl)propan-2-yl phenylcarbamate (5e):
yellow oil (0.072 g, 89%); IR (thin film) ν 3359, 2930, 1710, Brown oil (0.035 g, 46%); IR (thin film) ν 3359, 3002, 2927,
1516 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J = 7.24 Hz, 1780, 1592, 1487 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.43 (s,
3H), 1.27–1.36 (m, 2H), 1.43–1.45 (m, 2H), 1.54 (s, 6H), 6H), 1.68–1.77 (m, 1H), 2.02–2.08 (m, 1H), 2.80–2.91 (m, 4H),
1.75–1.82 (m, 1H), 2.02–2.08 (m, 1H), 2.79–2.92 (m, 4H), 5.09 (s, 1H), 7.21–7.33 (m, 4H) ppm; 13C NMR (100 MHz,
3.06–3.11 (m, 2H), 4.62 (brs, 1H), 5.04 (s, 1H) ppm; 13C NMR CDCl3) δ 24.6, 26.1, 31.1, 56.3, 85.3, 127.8, 128.2, 128.6,
(100 MHz, CDCl3) δ 13.9, 20.0, 25.1, 26.2, 31.2, 32.1, 40.6, 138.7, 151.0 ppm; HRMS (ESI) m/z: [M + K]+ calcd for
57.7, 81.9, 155.3 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C14H19NO2S2K, 336.0754; found, 336.0760.
C12H23NO2S2Na, 300.1068; found, 300.1056.
2-(1,3-Dithian-2-yl)propan-2-yl (4-nitrophenyl)carbamate
2-(1,3-Dithian-2-yl)propan-2-yl allylcarbamate (5c): Orange (5f): Brown oil (37 mg, 42%); IR (thin film) ν 3305, 3080,
solid (0.055 g, 72%). mp 67–68 °C; IR (thin film) ν 3343, 3080, 2971, 1732, 1620, 1595 cm−1; 1H NMR (400 MHz, CDCl3)
2940, 1707, 1516 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.54 (s, δ 1.65 (s, 6H), 1.78–1.85 (m, 1H), 2.08–2.12 (m, 1H),
6H), 1.70–1.81 (m, 1H), 1.99–2.08 (m, 1H), 2.79–2.91 (m, 4H), 2.85–2.92 (m, 4H), 5.02 (s, 1H), 6.95 (brs, 1H), 7.50 (d,
3.70–3.72 (m, 2H), 4.76 (brs, 1H), 5.05–5.08 (m, 2H), 5.17 (d, J = 9.2 Hz, 2H), 8.17 (d, J = 9.2 Hz, 2H) ppm; 13C NMR
J = 17.3 Hz, 1H), 5.74–5.84 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 25.1, 26.2, 31.3, 57.4, 84.6, 117.8, 125.3,
(100 MHz, CDCl3) δ 25.1, 26.2, 31.2, 43.2, 57.5, 82.2, 116.0, 143.0, 144.1, 151.2 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
134.7, 155.1 ppm; HRMS (ESI) m/z: [M + K]+ calcd for C14H18N2O4S2Na, 365.0605; found, 365.0610.
C11H19NO2S2K, 300.0494; found, 300.0496.
2-(1,3-Dithian-2-yl)propan-2-yl (pyridin-2-yl)carbamate
2-(1,3-Dithian-2-yl)propan-2-yl (2-((tert-butyldiphenylsilyl)- (5g): Pale brown oil (0.043 g, 57%); IR (thin film) ν 3184,
oxy)ethyl)carbamate (5d): Colorless oil (0.142 g, 97%); IR 2930, 1719, 1640, 1583 cm−1; 1H NMR (400 MHz, CDCl3)
(thin film) ν 3369, 3076, 2930, 1713, 1510, 1452 cm−1; δ 1.63 (s, 6H), 1.75–1.82 (m, 1H), 2.02–2.08 (m, 1H),
1H NMR (400 MHz, CDCl3) δ 1.04 (s, 9H), 1.57 (s, 6H), 2.80–2.88 (m, 4H), 5.14 (s, 1H), 6.90–6.92 (m, 1H), 7.61–7.65
1.74–1.83 (m, 1H), 2.04–2.11 (m, 1H), 2.82–2.92 (m, 4H), (m, 1H), 7.93 (d, J = 8.4 Hz, 1H), 8.33–8.35 (m, 1H), 9.70 (brs,
3.27–3.31 (m, 2H), 3.69–3.71 (m, 2H), 4.96 (brs, 1H), 5.07 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 25.3, 26.2, 31.3,
1H), 7.34–7.41 (m, 6H), 7.62–7.64 (m, 4H) ppm; 13C NMR 57.2, 83.5, 112.8, 118.4, 138.4, 147.8, 152.3, 152.5 ppm;
(100 MHz, CDCl3) δ 19.4, 25.1, 26.2, 27.0, 31.1, 43.1, 57.6, HRMS (ESI) m/z: [M + Na]+ calcd for C13H18N2O2S2Na,
63.2, 82.2, 127.7, 129.9, 133.5, 135.7, 155.3 ppm; HRMS (ESI) 321.0707; found, 321.0701.
m/z: [M + Na]+ calcd for C26H37NO3S2SiNa, 526.1882; found,
526.1875.
2-(1,3-Dithian-2-yl)propan-2-yl (pyridin-4-yl)carbamate
(5h): Orange oil (0.040 g, 52%); IR (thin film) ν 3170, 2950,
General procedure for dM-Dmoc protection of arylamines – 1719, 1636, 1580 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.63 (s,
synthesis of carbamates 5e–h: To a solution of diisopropyl- 6H), 1.76–1.84 (m, 1H), 2.06–2.12 (m, 1H), 2.84–2.91 (m, 4H),
amine (0.076 mL, 0.541 mmol, 2.1 equiv) in THF (10 mL) at 5.01 (s, 1H), 7.39 (d, J = 6.5 Hz, 2H), 7.55 (brs, 1H), 8.39 (d,
−78 °C under argon was added n-BuLi (2.5 M in pentane, J = 6.2 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 24.9,
0.206 mL, 0.514 mmol, 2 equiv). The mixture was stirred for 26.1, 31.3, 57.3, 84.5, 112.9, 146.8, 149.2, 151.3 ppm; HRMS
15 min. To the freshly prepared LDA solution was added an (ESI) m/z: [M + H]+ calcd for C13H18N2O2S2H, 299.0887;
amine (0.257 mmol, 1 equiv) in THF (50 mL) at −78 °C. After found, 299.0879.
stirring for 45 min, solid 4 (0.088 g, 0.257 mmol, 1 equiv) was
added to the amide solution at −78 °C under positive argon N-(((2-(1,3-Dithian-2-yl)propan-2-yl)oxy)carbonyl)-L-
pressure. The mixture was stirred for 8 h while warming to rt phenylalanine (5i): This compound was prepared following the
gradually. The reaction was quenched with sat. NH4Cl (15 mL) general procedure for dM-Dmoc protection of aliphatic amines
and extracted with EtOAc (10 mL × 2). The extracts were dried with slight modifications: DMSO instead of THF was used as
over anhydrous Na2SO4, filtered, and concentrated. The carba- the solvent. During work-up, 5% citric acid (instead of sat.
mates 5e (column eluted with 9:1 hexanes/EtOAc; TLC NH4Cl) and EtOAc were used for partition. Flash column chro-
Rf = 0.2, developed with 5:1 hexanes/EtOAc), 5f (6:1 hexanes/ matography (SiO2, 3:1:0.04 hexanes/EtOAc/AcOH) gave 5i as
EtOAc; Rf = 0.4, 3:1 hexanes/EtOAc), 5g (5:1 hexanes/EtOAc; a white foam after co-evaporation with toluene (80%): TLC
Rf = 0.5, 2:1 hexanes/EtOAc), and 5h (98:2 EtOAc/MeOH; Rf = 0.2 (1:1:0.02 hexanes/EtOAc/AcOH); IR (thin film)
Rf = 0.5, 9:1 EtOAc/MeOH) were purified with flash column ν 3331, 3035, 2933, 1715, 1497 cm−1; 1H NMR (400 MHz,
chromatography (SiO2).
CDCl3) two rotamers, δ 1.43 (s, 1.2H), 1.45 (s, 1.2H), 1.51 (s,
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1.8H), 1.55 (s, 1.8H), 1.74–1.79 (m, 1H), 2.03–2.07 (m, 1H), 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 25.1, 26.2, 28.6,
2.84–2.87 (m, 4H), 2.98–3.08 (m, 1H), 3.15–3.20 (m, 1H), 31.1, 40.7, 57.6, 70.4, 79.5, 82.2, 155.4, 156.2 ppm; HRMS
4.44–4.50 (m, 0.4H), 4.57–4.62 (m, 0.6H), 4.84 (s, 0.4H), 5.02 (ESI) m/z: [M + Na]+ calcd for C19H36N2O6S2Na, 475.1912;
(s, 0.6H), 5.17–5.18 (m, 1H), 6.47 (bs, 1H), 7.18–7.28 (m, 5H) found, 475.1898. Selective removal of dM-Dmoc in the pres-
ppm; 13C NMR (100 MHz, CDCl3) two rotamers, δ 24.8, 25.1, ence of Boc in 7 to give 6 was achieved following the general
26.2, 31.2, 38.1, 39.3, 54.6, 57.5, 83.2, 84.3, 127.2, 128.7, procedure for deprotection of dM-Dmoc protected amines. The
129.7, 135.8, 154.5, 155.6, 175.9, 176.3 ppm; HRMS (ESI) m/z: product was purified by flash column chromatography (SiO2,
[M − H]− calcd for C17H22NO4S2, 368.0996; found, 368.0987.
9.5:0.5 DCM/MeOH; TLC Rf = 0.4, 9:1 DCM/MeOH).
Isolated yield of 80% was obtained.
General procedure for deprotection of dM-Dmoc protected
amines: To a suspension of 5 (1 equiv) in THF/H2O (v/v 1:1) Selective deprotection of dM-Dmoc and Fmoc protected
was added NaIO4 (10 equiv) at rt. After stirring overnight, the amine: The dM-Dmoc and Fmoc protected diamine 9 was pre-
mixture was concentrated on a rotary evaporator. The residue pared from 1,2-bis(2-aminothoxy)ethane. Compound 8 was syn-
was dissolved in acetone (5% AcOH in acetone for 5i), and the thesized using the general procedure for dM-Dmoc protection
insoluble inorganic salts were removed by filtration. The filtrate of aliphatic amines and purified with flash column chromato-
was concentrated on a rotary evaporator. The residue (after graphy (SiO2, 9:0.5:0.5 DCM/MeOH/Et3N): Light yellow oil
co-evaporation with toluene for 5i) was suspended in methanol (64%); TLC Rf = 0.3 (9:1 DCM/MeOH); IR (thin film) ν 3359,
(dissolved in 1:1 methanol/H2O in the case of 5i). Finely 2937, 1713, 1519 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.51 (s,
ground K2CO3 (10 equiv) was added, and the mixture was 6H), 1.69–1.76 (m, 1H), 2.00–2.06 (m, 1H), 2.80–2.89 (m, 4H),
stirred at rt for 1 h. Insoluble salts were removed by filtration. 3.05 (bs, 2H), 3.25 (bs, 2H), 3.50 (t, J = 4.7 Hz, 4H), 3.56 (s,
The filtrate was concentrated on a rotary evaporator and puri- 4H) ppm, 5.00 (s, 1H), 5.44 (bs, 1H); 13C NMR (100 MHz,
fied via flash column chromatography (SiO2). All amine prod- CDCl3) δ 25.2, 26.3, 31.2, 40.7, 41.5, 57.7, 70.2, 70.3, 70.4,
ucts 3a–i were known and were indentified with TLC and 82.1, 155.3 ppm; HRMS (ESI) m/z: [M + H]+ calcd for
NMR. Chromatography and TLC information: 3a (column C14H28N2O4S2H, 353.1569; found, 353.1576. For the synthe-
eluted with 8.5:1:0.5 EtOAc/MeOH/Et3N; TLC Rf = 0.4, 9:1 sis of 9, compound 8 (0.225 g, 0.640 mmol, 1 equiv) in 1,4-
EtOAc/MeOH), 3b (8.5:1:0.5 EtOAc/MeOH/Et3N; Rf = 0.2, 9:1 dioxane (5 mL) and 15% Na2CO3 (5 mL) was reacted with
EtOAc/MeOH), 3c (8.5:1:0.5 EtOAc/MeOH/Et3N; Rf = 0.2, 9:1 Fmoc-Cl (0.402 g, 0.292 mmol, 1 equiv) at rt under argon. After
EtOAc/MeOH), 3d (9:0.5:0.5 EtOAc/MeOH/Et3N; Rf = 0.5, 9:1 8 h, the reaction mixture was diluted with EtOAc (50 mL), and
EtOAc/MeOH), 3e (9:1 hexanes/EtOAc; Rf = 0.2, 5:1 hexanes/ the organic and aqueous phases were separated. The former was
EtOAc), 3f (5:1 hexanes/EtOAc; Rf = 0.3, 3:1 hexanes/EtOAc), washed with water (25 mL), 5% citric acid (25 mL) and brine
3g (5:1 hexanes/EtOAc; Rf = 0.4, 2:1 hexanes/EtOAc), 3h (25 mL × 2), dried over anhydrous Na2SO4, filtered, and
(9.5:0.5 EtOAc/MeOH; Rf = 0.5, 9:1 EtOAc/MeOH), 3i concentrated to dryness. The residue was purified with flash
(Rf = 0.5, 3:1:1 n-BuOH/AcOH/H2O). Isolated yields were ob- column chromatography (SiO2, 1:1 hexanes/EtOAc): Light
tained for 3a–h (see Table 1). Yield of 3i was determined yellow oil (0.185 g, 50%); TLC Rf = 0.2 (1:1 hexanes/EtOAc);
to be 41% using RP-HPLC (column: C-18, 5 μm, 100 Å, IR (thin film) ν 3337, 3070, 2943, 1713, 1449 cm−1; 1H NMR
250 × 3.20 mm; solvent A: 0.1 M triethylammonium acetate, (400 MHz, CDCl3) δ 1.45 (s, 6H), 1.69–1.79 (m, 1H),
5% acetonitrile; solvent B: 90% acetonitrile; gradient: time, 2.00–2.04 (m, 1H), 2.77–2.85 (m, 1H), 3.26–3.29 (m, 2H),
0–60 min, solvent B, 0–45%; flow rate: 1 mL/min; detection: 3.36–3.37 (m, 2H), 3.49–3.53 (m, 4H), 3.56 (s, 4H), 4.17–4.20
UV 257 nm) by comparing with authentic sample.
(m, 1H), 4.37–4.38 (m, 2H), 5.02 (m, 1H), 5.16 (bs, 1H), 5.36
(bs, 1H), 7.27 (t, J = 7.4 Hz, 2H), 7.35 (t, J = 7.4 Hz, 2H), 7.56
Selective deprotection of dM-Dmoc protected amine in the (d, J = 6.7 Hz, 2H), 7.72 (d, J = 7.4 Hz, 2H) ppm; 13C NMR
presence of a Boc protected amine: Compound 6 was pre- (100 MHz, CDCl3) δ 25.2, 26.3, 31.2, 40.7, 41.2, 47.5, 57.7,
pared following a reported procedure [22]. The general proce- 68.8, 70.3, 70.5, 82.2, 120.1, 125.2, 127.1, 127.8, 141.4, 144.1,
dure for dM-Dmoc protection of aliphatic amines (i.e., the pro- 155.3, 156.6 ppm; HRMS (ESI) m/z: [M + H]+ calcd for
cedure for the synthesis of 5a–d) was used to covert 6 to 7. C29H38N2O6S2H, 575.2250; found, 575.2262. For selective
Compound 7 was purified with flash column chromatography removal of the Fmoc group of 9 to give 8, 9 (90 mg,
(SiO2, 1:1 hexanes/EtOAc): Colorless oil (55%); TLC Rf = 0.2 0.157 mmol, 1 equiv) in dry DCM (10 mL) was reacted with pi-
(1:1 hexanes/EtOAc); IR (thin film) ν 3356, 2933, 1707, 1690, peridine (2 mL) at rt under argon for 2 h. The reaction mixture
1510 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9H), 1.54 (s, was concentrated to dryness under reduced pressure. The
6H), 1.74–1.81 (m, 1H), 2.03–2.09 (m, 1H), 2.83–2.88 (m, 4H), residue was purified with flash column chromatography (SiO2,
3.28–3.32 (m, 4H), 3.50–3.53 (m, 4H), 3.57 (s, 4H), 5.04 (s, 9:0.5:0.5 DCM/MeOH/Et3N; TLC Rf = 0.3, 9:1 DCM/MeOH)
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11.Igarashi, J.; Kobayashi, Y. Tetrahedron Lett. 2005, 46, 6381–6384.
doi:10.1016/j.tetlet.2005.06.171
to give 8 as a light yellow oil (45 mg, 82%). For selective
removal of the dM-Dmoc group of 9 to give 10 [23], the general
procedure for deprotection of dM-Dmoc protected amines was
used. The product was purified with flash column chromato-
graphy (SiO2, 9:0.5:0.5 DCM/MeOH/Et3N, TLC Rf = 0.5, 8:1:1
DCM/MeOH/Et3N). An isolated yield of 75% was obtained.
12.Smith, A. B.; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc. 2001,
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Supporting Information
16.Kunz, H.; Barthels, R. Chem. Ber. 1982, 115, 833–845.
doi:10.1002/cber.19821150302
Supporting Information File 1
17.Waldmann, H.; Kunz, H. J. Org. Chem. 1988, 53, 4172–4175.
doi:10.1021/jo00253a003
Images of 1H and 13C NMR spectra of new compounds
including 5a–i and 7–9.
18.Lin, X.; Chen, J.; Shahsavari, S.; Green, N.; Goyal, D.; Fang, S.
Org. Lett. 2016, 18, 3870–3873. doi:10.1021/acs.orglett.6b01878
19.Shahsavari, S.; Wigstrom, T.; Gooding, J.; McNamara, C.; Fang, S.
Tetrahedron Lett. 2018, 59, 1763–1766.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-149-S1.pdf]
doi:10.1016/j.tetlet.2018.03.076
20.Shahsavari, S.; Gooding, J.; Wigstrom, T.; Fang, S. ChemistrySelect
2017, 2, 3959–3963. doi:10.1002/slct.201700364
21.Barnhurst, L. A.; Wan, Y.; Kutateladze, A. G. Org. Lett. 2000, 2,
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Acknowledgements
Financial support from NIH (R15GM109288), NSF
(CHE1111192), and PHF Graduate Assistantship (S.S.); the
assistance from D. W. Seppala (electronics), J. L. Lutz (NMR),
L. R. Mazzoleni (MS), M. Khaksari (MS), and A. Galerneau
(MS); and NSF equipment grants (CHE1048655, CHE9512455,
AGS1531454) are gratefully acknowledged.
22.Tang, W.; Fang, S. Tetrahedron Lett. 2008, 49, 6003–6006.
doi:10.1016/j.tetlet.2008.07.174
23.Koda, H.; Brazier, J. A.; Onishi, I.; Sasaki, S. Bioorg. Med. Chem.
2015, 23, 4583–4590. doi:10.1016/j.bmc.2015.05.056
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Shahien Shahsavari - https://orcid.org/0000-0001-7731-0785
Mark Sylvester - https://orcid.org/0000-0003-4472-7896
Emily Bromley - https://orcid.org/0000-0002-7160-7323
Savannah Joslin - https://orcid.org/0000-0002-2876-4032
Shiyue Fang - https://orcid.org/0000-0002-6523-7557
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