Hydrogenolytic cleavage of naphthylmethyl ethers in the presence of sulfides

Article abstract of DOI:10.1016/j.carres.2017.06.011

With the aid of a series of model thioether or thioglycoside containing polyols protected with combinations of benzyl ethers and 2-naphthylmethyl ethers it is demonstrated that the latter are readily cleaved selectively under hydrogenolytic conditions in the presence of the frequently catalyst-poisoning sulfides. These results suggest the possibility of employing 2-naphthylmethyl ethers in place of benzyl ethers in synthetic schemes when hydrogenolytic deprotection is anticipated in the presence of thioether type functionality.

Full text of DOI:10.1016/j.carres.2017.06.011

Accepted Manuscript
Hydrogenolytic cleavage of naphthylmethyl ethers in the presence of sulfides
Philip O. Adero, Dean R. Jarois, David Crich
PII:
S0008-6215(17)30388-9
10.1016/j.carres.2017.06.011
CAR 7408
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 29 May 2017
Revised Date: 19 June 2017
Accepted Date: 19 June 2017
Please cite this article as: P.O. Adero, D.R. Jarois, D. Crich, Hydrogenolytic cleavage of naphthylmethyl
ethers in the presence of sulfides, Carbohydrate Research (2017), doi: 10.1016/j.carres.2017.06.011.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Hydrogenolytic Cleavage of Naphthylmethyl Ethers in the Presence of Sulfides
Philip O Adero, Dean R Jarois, and David Crich*
Department of Chemistry, Wayne State University, 5101 Cass Avenue Detroit, MI 48202, USA
dcrich@chem.wayne.edu
Abstract. With the aid of a series of model thioether or thioglycoside containing polyols
protected with combinations of benzyl ethers and 2-naphthylmethyl ethers it is demonstrated that
the latter are readily cleaved selectively under hydrogenolytic conditions in the presence of the
frequently catalyst-poisoning sulfides. These results suggest the possibility of employing 2-
naphthylmethyl ethers in place of benzyl ethers in synthetic schemes when hydrogenolytic
deprotection is anticipated in the presence of thioether type functionality.
Keywords: Naphthylmethyl ethers, benzyl ethers, hydrogenolysis, thioethers, thioglycosides
1. Introduction.
Benzyl ethers are very widely employed as semi-permanent protecting groups in organic
chemistry and carbohydrate chemistry and are typically removed by hydrogenolysis at the end of
a synthetic sequence.1,2 However, quoting Kocienski “A typical cause of vexation in the catalytic
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hydrogenolysis of benzyl ethers is catalyst poisoning which can occur when the substrate
contains thioethers”.2 Such problems, which often go unreported, are widespread, can sometimes
be solved by recourse to large amounts of catalyst,3,4 and are frequently circumvented by recourse
to the far less convenient reductive cleavage of benzyl ethers with sodium in liquid ammonia or
related protocols.4-8 Confronted with such problems in our laboratory we were intrigued by the
possibility of employing 2-naphthylmethyl (Nap) ethers in place of benzyl ethers. 2-
Naphthylmethyl ethers have enjoyed widespread use and continuous refinement in carbohydrate
chemistry as surrogates for p-methoxybenzyl ethers since their introduction to the field by
Matta,9-14 because of their greater stability to Brønsted acids but comparable ease of removal
under oxidative condition with dichlorodicyanoquinone. However, it was the selective
hydrogenolytic removal of Nap ethers in presence of benzyl ethers initially reported by Spencer15
that suggested the possibility of their use as a possible remedy to the problem in hand. Here, we
report the synthesis of a series of compounds containing benzyl and Nap together with either
thioethers or thioglycosides and demonstrate that indeed the Nap ethers are removed selectively
under these conditions.
2. Results and discussion
An initial test substrate and a series of carbohydrate-based model compounds characterized by
the presence of a thioether or thioglycoside, multiple benzyl ethers and a 2-naphthylmethyl ether
were synthesized by standard means (Scheme 1). A peptide-based substrate was prepared as
described in Scheme 2.
2

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NaH,
NaH,
HO
ONap
BnO
ONap
S(CH2)2OH
S
S
BnBr
NapBr
2, 75%
3, 81%
1
HO
BnO
NapO
BnO
OBn
O
OBn
O
NaH,
BnO
BnO
NapBr
SPh
SPh
4
5, 77%
HO
BnO
ONap
O
ONap
O
TsOH
ONap
O
NaH,
BnBr
Ph
O
HO
BnO
O
BnO
BnO
BnO
MeOH
SPh
SPh
SPh
6
7, 89%
8, 88%
NapO
HO
BnO
OBn
O
OBn
O
OBn
O
BH3.THF
Yb(OTf)3
Ph
O
NaH,
BnO
BnO
O
StBu
StBu
StBu
BnO
BnO
NapBr
9
11, 72%
10, 94%
OBn
O
OBn
O
NaH,
NapO
BnO
HO
SPh
SPh
SPh
BnO
NapBr
OBn
13, 77%
OBn
12
ONap
O
OH
O
NaH,
BnO
BnO
BnO
BnO
SPh
NapBr
OBn
15, 81%
OBn
14
Scheme 1. Synthesis of Substrates for Hydrogenolysis.
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Scheme 2. Synthesis of a Peptide-Based Substrate.
After a brief survey of catalysts and conditions, hydrogenolysis over palladium hydroxide on
carbon in ethanolic ethyl acetate under the 3 atmospheres of hydrogen were found to be suitable
for cleavage of the naphthylmethyl ethers in good yield, with the solvent chosen so as to dissolve
the widest range of substrates and products. As reported in Table 1 under these conditions
naphthylmethyl ethers in variety of diverse steric environments could be removed in good to
excellent yield in the presence of one or more benzyl ethers and thioethers or thioglycosides.
Thus, the naphthylmethyl ether is cleanly removed in the presence of alkyl thioethers and
thioglycosides (Table 1, entries 1, 4, and 7) and in the presence of aryl thioglycosides, whether
axial or equatorial (Table 1, entries 2, 3, 5, and 6) always in the presence of one or more benzyl
ethers. Additionally, as demonstrated by the example of entry 7 (Table 1) the selective
hydrogenolysis may be affected in the presence of amide and carbamate groups.
4

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Table 1. Selective Hydrogenolysis of Naphthylmethyl Ethers in the Presence of Benzyl Ethers
and Thioethers or Thioglycosides.
Entry Substrate
Product
Time
(h)
%
Yield
1
2
12
72
HO
2
92
OBn
O
BnO
BnO
SPh
4
3
16
65
4
5
3
6
89
70
OBn
O
NapO
BnO
SPh
OBn
13
OH
O
6
2
88
BnO
BnO
SPh
OBn
14
5

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MeS
7
7
88
ONap
H
CO2Me
O
H
N
BocHN
N
H
H
OBn
O
23
3. Conclusion.
Nap ethers are cleaved by hydrogenolysis in the presence of benzyl ethers in compounds carrying
thioether or thioglycoside groups, thereby extending the possible uses of the Nap group. The
results also suggest that Nap ethers be considered as replacements for benzyl ethers in synthetic
schemes when global deprotection by hydrogenolysis is anticipated in the presence of thioethers
and thioglycosides, although we have yet to test this possibility.
4. Experimental section
4.1. General
All reactions were conducted under an atmosphere of nitrogen or argon. Extracts were dried over
sodium sulfate and chromatography was carried out over silica gel. Sephadex chromatography
was carried out over Sephadex C25. Specific rotations were measured on an automatic
polarimeter with a path length of 10 cm in chloroform solution unless otherwise stated. High-
resolution (HRMS) mass spectra were recorded in the electrospray mode using a time of flight
mass analyzer (ESI-TOF).
4.2.1 2-((2-(Naphthalen-2-ylmethoxy)ethyl)thio)ethanol (2).
To a suspension of sodium hydride (0.43 g, 10.9 mmol, 60% in mineral oil) in dry THF (30 mL),
under argon, cooled to 0 °C, was slowly added 2,2-thiodiethanol 1 (3.3 g, 27.15 mmol). The
6

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reaction mixture was stirred for 1 h before 2–(bromomethyl)naphthalene (2.0 g, 9.05 mmol) in
dry THF (20 mL) was added dropwise, and stirring continued for 5 h. The reaction mixture was
diluted with water (50 mL) and extracted diethyl ether (50 mL x 2). The organic layer was
washed with water and brine and dried over Na2SO4, and the solvent was evaporated under
reduced pressure. Chromatographic purification (hexane ethyl acetate 6:1-2:1) gave the title
1
compound 2 (1.78 g, 75%) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 7.87 – 7.76 (m,
4H), 7.53 – 7.43 (m, 3H), 4.71 (s, 2H), 3.71 (t, J = 6.0 Hz, 2H), 3.69 (t, J = 6.4 Hz, 2H), 2.78 (t, J
= 6.4 Hz, 2H). 2.76 (t, J = 6.0 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 135.3, 133.2, 133.0,
128.3, 127.9, 127.7, 126.6, 126.2, 126.0, 125.7, 73.3, 69.9, 60.8, 35.9, 31.6. ESIHRMS calcd for
C22H24O2SNa [M + Na]+, 385.0925; found; 385.0921.
4.2.2 2-(2-Naphthalen-2-ylmethoxy)ethyl 2-(benzyloxy)ethyl) sulfide (3)
A solution of 2 (1.2 g, 4.58 mmol) in dry DMF (22 mL) under argon, was cooled to 0 ˚C and
treated with NaH (0.27 g, 60% dispersion in mineral oil). The reaction mixture was stirred for 10
min before benzyl bromide (0.61 ml, 5.04 mmol) was added dropwise. The reaction mixture was
warmed to room temperature and stirred for 2 h before it was cooled to 0 ˚C and quenched with
MeOH (1 mL), and concentrated in vacuo. The concentrate was dissolved in ethyl acetate,
washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by
silica gel column chromatography (hexane-ethyl acetate (9:1)) to give the title compound (1.3 g,
81%) as a colorless oil. ;1H NMR (600 MHz, CDCl3) δ 7.85 – 7.81 (m, 3H), 7.80 – 7.76 (m, 1H),
7.51 – 7.43 (m, 3H), 7.36 – 7.31 (m, 4H), 7.30 – 7.26 (m, 1H), 4.69 (s, 2H), 4.51 (s, 2H), 3.69 (t,
J = 6.7 Hz, 2H), 3.65 (t, J = 6.7 Hz, 2H), 2.82 (t, J = 6.1 Hz, 2H), 2.80 (t, J = 6.1 Hz, 2H). 13C
NMR (151 MHz, CDCl3) δ 138.1, 135.6, 133.2, 133.0, 128.4, 128.2, 127.9, 127.8, 127.7, 127.6,
7

ACCEPTED MANUSCRIPT
126.4, 126.1, 125.9, 126.0, 73.1, 73.0, 70.0, 32.1, 32.1. ESIHRMS calcd for C22H24O2SNa [M +
Na]+, 375.1395; found; 375.1396.
4.2.3 Phenyl 2,3,4-tri-O-benzyl-6-O-(2-naphthyl)methyl-1-thio-α-D-mannopyranoside (5).
A solution of 416 (0.30 g, 0.57 mmol) in anhydrous DMF (6 mL), was cooled to 0 ˚C, treated with
NaH (60% dispersion in mineral oil, 33 mg,) under argon, and stirred for 20 min. A solution 2–
(bromomethyl) naphthalene (0.33 mg, 1.5 mmol,) in DMF (2 mL) was added slowly followed by
TBAI (40 mg, 0.11 mmol). The reaction mixture was stirred for 12 h, after which it was
quenched with methanol (0.2 mL) and water (10 mL). The mixture was extracted with ethyl
acetate, and the combined organic phase was washed with HCl (1 M), saturated NaHCO3, brine,
dried over Na2SO4, filtered and concentrated in vacuo. The resulting brown oil was purified by
silica chromatography, eluting with hexane-ethyl acetate (9:1) to give 5 (0.29 g, 74%) as a
1
colorless oil. [α]RT
+44 (c 0.24, CHCl3); H NMR (600 MHz, CDCl3) δ 7.83 – 7.80 (m, 1H),
D =
7.78 – 7.75 (m, 3H), 7.49 – 7.44 (m, 5H), 7.40 – 7.27 (m, 10H), 7.25 – 7.15 (m, 6H), 7.14 – 7.09
(m, 2H), 5.64 (d, J = 1.7 Hz, 1H), 4.91 (d, J = 10.7 Hz, 1H), 4.82 (d, J = 12.4 Hz, 1H), 4.75 (d, J
= 12.4 Hz, 1H), 4.66 (d, J = 12.4 Hz, 1H), 4.64 (d, J = 12.4 Hz, 1H), 4.62 (d, J = 11.7 Hz, z1H),
4.60 (d, J = 11.7 Hz, 1H), 4.52 (d, J = 10.7 Hz, 1H), 4.32 (ddd, J = 9.9, 5.1, 1.9 Hz, 1H), 4.10 (t,
J = 9.6 Hz, 1H), 4.02 (dd, J = 3.2, 1.7 Hz, 1H), 3.91 – 3.87 (m, 2H), 3.80 (dd, J = 10.9, 1.9 Hz,
13
1H). C NMR (151 MHz, CDCl3) δ 138.3, 138.2, 137.9, 135.8, 134.4, 133.2, 132.9, 131.6,
129.0, 128.4, 128.4, 128.3, 128.0, 127.9, 127.9, 127.8, 127.7, 127.7, 127.6, 127.4 126.4, 126.0,
125.9, 125.7, 85.8, 80.2, 76.3, 75.2, 75.0, 73.4, 72.8, 72.1, 71.9, 69.1. ESIHRMS calcd for
C44H42O5SNa [M + Na]+,705.2651; found; 705.2654.
4.2.4 Phenyl 3-O-benzyl-2-O-(2-naphthyl)methyl-1-thio-α-D-mannopyranoside (7).
8

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A solution of 617 (0.6 g, 1.02 mmol) in CHCl3-MeOH (4:1, 16 mL) was treated with p-TsOH
monohydrate (0.2 g, 1.02 mmol) and stirred under argon at room temperature for 2 h, after which,
it was quenched with triethylamine (0.2 mL) and concentrated. The residue was purified by flash
column chromatography over silica gel (hexane/ethyl acetate 1:1) to give 7 (0.44 g, 89%) as a
colorless oil. [α]RT +0.4 (c 0.55, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.83 – 7.79 (m, 1H),
D =
7.78 – 7.75 (m, 2H), 7.74 – 7.71 (m, 1H), 7.50 – 7.44 (m, 3H), 7.38 – 7.35 (m, 2H), 7.34 – 7.28
(m, 5H), 7.27 – 7.23 (m, 3H), 5.55 (d, J = 1.5 Hz, 1H), 4.82 (d, J = 12.3 Hz, 1H), 4.72 (d, J =
12.3 Hz, 1H), 4.57 (d, J = 11.7 Hz, 1H), 4.49 (d, J = 11.7 Hz, 1H), 4.16 (t, J = 9.1Hz 1H), 4.14 –
4.10 (m, 1H), 4.05 (dd, J = 3.0, 1.5 Hz, 1H), 3.92 – 3.80 (m, 2H), 3.71 (dd, J = 9.1, 3.0 Hz, 1H).
13C NMR (151 MHz, CDCl3) δ 137.7, 135.1, 133.8, 133.2, 133.1, 131.9, 129.1, 128.6 128.3,
128.0, 127.9, 127.9, 127.7, 127.7, 126.8, 126.2, 126.1, 125.9, 86.2, 79.6, 75.5, 73.3, 72.33, 71.8,
67.3, 62.7. ESIHRMS calcd for C30H30O5SNa [M + Na]+, 525.1712; found; 525.1719.
4.2.5 Phenyl 3,4,6-tri-O-benzyl-2-O-(2-naphthyl)methyl-1-thio-α-D-mannopyranoside (8).
To a solution of 7 (0.27 g, 0.54 mmol) in anhydrous DMF (2.6 mL) was added NaH (86 mg, 60%
dispersion in mineral oil) at -15 °C. After stirring for 5 min BnBr (0.15 mL, 1.23 mmol) was
added, and the mixture was warmed to room temperature and stirred for 6 h. The reaction mixture
was quenched with MeOH (0.4 mL, at 0 °C) and diluted with ethyl acetate, washed with water
and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified
by column chromatography on silica gel (hexane: ethyl acetate 9:1) to afford 8 as a colorless oil
(0.32 g, 88%). [α]RT +33 (c 0.42, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.85 – 7.81 (m, 1H),
D =
7.80 – 7.71 (m, 3H), 7.52 (dd, J = 8.4, 1.7 Hz, 1H), 7.50 – 7.46 (m, 2H), 7.44 – 7.41 (m, 2H),
7.37 – 7.27 (m, 12H), 7.23 (dt, J = 9.3, 7.3 Hz, 5H), 5.65 (d, J = 1.7 Hz, 1H), 4.95 (d, J = 10.8
Hz, 1H), 4.91 (d, J = 12.5 Hz, 1H), 4.81 (d, J = 12.5 Hz, 1H), 4.69 (d, J = 12.0 Hz, 1H), 4.65 (d,
9

ACCEPTED MANUSCRIPT
J = 11.7 Hz, 1H), 4.62 (d, J = 11.7 Hz, 1H), 4.58 (d, J = 10.8 Hz, 1H), 4.52 (d, J = 12.0 Hz, 1H),
4.31 (ddd, J = 9.9.6, 5.1, 1.9 Hz, 1H), 4.13 (t, J = 9.6 Hz, 1H), 4.07 (dd, J = 3.1, 1.7 Hz, 1H),
3.92 – 3.85 (m, 2H), 3.78 (dd, J = 9.6, 3.1 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ 138.4, 138.4,
138.2, 135.4, 134.4, 133.2, 133.0, 131.7, 129.0, 128.4, 128.4, 128.3, 128.2, 128.0, 128.0, 127.8,
127.8, 127.7, 127.6, 127.5, 127.4, 126.8, 126.1, 126.0, 126.0, 85.9, 80.2, 76.2, 75.2, 75.0, 73.3,
72.8, 72.2, 72.0, 69.2. ESIHRMS calcd for C44H42O5SNa [M + Na]+, 705.2651; found; 705.2654.
4.2.6 tert-Butyl 2,3,4-tri-O-benzyl-1-thio-β-D-mannopyranoside (10).
To a solution of 94 (130 mg, 0.25 mmol) in dry DCM (3 mL) was added BH3.THF (1.0 M in
THF, 1.3 mL, 1.25 mmol) under argon with stirring. After 10 mins yttrium (III)
trifluoromethanesulfonate (15.5mg, 0.025 mmol) was added and the reaction mixture was stirred
under argon at room temperature for 2 h. The reaction mixture was cooled to 0 ˚C, then
triethylamine (50 µL, 0.04 mmol) was added dropwise followed by slow addition of methanol
(100 µL). The solvent was removed under reduced pressure and the residue was taken up
methanol and then concentrated to give a residue, which was purified by flash column
chromatography on silica gel using hexane-ethyl acetate (4:1) as eluent. The product was
obtained as a light yellow oil (117 mg, 90 %). [α]RT -23 (c 1.78, CHCl3); 1H NMR (600 MHz,
D =
CDCl3) δ 7.59 – 7.04 (m, 15H), 4.94 (d, J = 11.3 Hz, 1H), 4.91 (d, J = 11.3 Hz, 1H), 4.79 (d, J =
10.9 Hz, 1H), 4.72 (d, J = 11.8 Hz, 1H), 4.67 (d, J = 11.8 Hz, 2H), 4.66 (d, J = 1.0 Hz, 1H), 4.64
(d, J = 10.9 Hz, 1H), 4.00 (dd, J = 3.0, 1.0 Hz, 1H), 3.90 (t, J = 9.5 Hz, 1H), 3.84 (dd, J = 11.9,
3.0 Hz, 1H), 3.40 – 3.33 (m, 1H), 1.36 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 138.3, 138.1,
128.4, 128.4, 128.2, 128.1, 128.1, 127.8, 127.7, 127.5, 127.4, 84.5, 82.3, 79.9, 78.5, 77.2, 77.0,
76.9, 75.3, 75.2, 74.9, 72.3, 62.7, 43.3, 31.6. ESIHRMS calcd for C31H38O5SNa [M + Na]+,
545.2338; found; 545.2341.
10

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4.2.7
(11).
tert-Butyl 2,3,4-tri-O-benzyl-6-O-(2-naphthyl)methyl-1-thio-β-D-mannopyranoside
This compound was synthesized from 10 by alkylation with sodium hydride and 2-
naphthylmethyl bromide, as described for compound 5, in 72% yield as a pale yellow oil. [α]RT
D =
1
-19.7 (c 0.62, CHCl3) H NMR (600 MHz, CDCl3) δ 7.83 – 7.68 (m, 4H), 7.54 – 7.38 (m, 5H),
7.33 – 7.12 (m, 13H), 4.93 (d, J = 11.5 Hz, 1H), 4.86 (d, J = 10.9 Hz, 1H) 4.84 (d, J = 11.5 Hz,
1H), 4.73 (d, J = 12.1 Hz, 1H), 4.71 (d, J = 12.1 Hz, 1H) 4.69 (d, J = 11.8 Hz, 1H), 4.66 (d, J =
1.0 Hz, 1H) 4.63 (d, J = 11.8 Hz, 1H), 4.55 (d, J = 10.9 Hz, 1H), 3.99 (dd, J = 3.1, 1.0 Hz, 1H),
3.88 (t, J = 9.5 Hz, 1H), 3.80 (dd, J = 10.8, 1.8 Hz, 1H), 3.72 (dd, J = 10.8, 6.5 Hz, 1H), 3.64 (dd,
J = 9.5, 3.0 Hz, 1H), 3.54 – 3.50 (m, 1H), 1.39 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 138.2,
138.2, 136.0, 132.9, 128.4, 128.2, 128.1, 128.0, 128.0, 127.9, 127.6, 127.6, 127.5, 127.4, 126.3,
125.9, 125.9, 125.6, 84.7, 82.1, 79.8, 78.2, 75.1, 75.0, 74.9, 73.4, 72.2, 69.9, 43.4, 31.7.
ESIHRMS calcd for C31H38O5SNa [M + Na]+, 685.2964; found; 685.2969.
4.2.8 Phenyl 2,3,6-tri-O-benzyl-4-O-(2-naphthyl)methyl-1-thio-β-D-glucopyranoside (13).
This compound was prepared in 77% yield by alkylation of 12 with sodium hydride and benzyl
bromide, as described for compound 5, and had spectral data consistent with the literature.18
4.2.9 Phenyl 2,3,4-tri-O-benzyl-6-O-(2-naphthyl)methyl-1-thio-β-D-glucopyranoside (15).
This compound was synthesized from 14, by alkylation with sodium hydride and 2-
naphthylmethyl bromide, as described for compound 5, in 81% yield as a colorless oil. [α]RT
D =
+3 (c 1.78, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.86 – 7.78 (m, 4H), 7.63 – 7.58 (m, 2H), 7.49
– 7.45 (m, 3H), 7.41 – 7.37 (m, 2H), 7.36 – 7.26 (m, 8H), 7.26 – 7.18 (m, 6H), 7.15 – 7.10 (m,
2H), 4.90 (d, J = 10.3 Hz, 2H), 4.85 (d, J = 10.9 Hz, 1H), 4.82 (d, J = 10.9 Hz, 1H), 4.77 (d, J =
11

ACCEPTED MANUSCRIPT
12.2 Hz, 1H), 4.74 (d, J = 10.2 Hz, 1H), 4.71 (d, J = 9.9 Hz, 1H), 4.69 (d, J = 7.7 Hz, 1H), 4.58
(d, J = 10.8 Hz, 1H), 3.83 (dd, J = 10.9, 1.9 Hz, 1H), 3.77 (d, J = 4.7 Hz, 1H), 3.72 (t, J = 8.9 Hz,
13
1H), 3.67 (t, J = 9.4 Hz, 1H), 3.57 – 3.50 (m, 2H). C NMR (151 MHz, CDCl3) δ 138.4, 138.0,
137.9, 135.7, 133.8, 133.3, 133.0, 131.9, 128.9, 128.4, 128.4, 128.4, 128.2, 128.1, 127.9, 127.9,
127.8, 127.8, 127.8, 127.7, 127.4, 126.4, 126.1, 125.8, 125.8, 87.5, 86.7, 80.8, 79.1, 77.8, 75.8,
75.4, 75.0, 73.5, 69.0. ESIHRMS calcd for C44H42O5SNa [M + Na]+, 705.2651; found; 705.2651.
4.2.10 N-(tert-Butoxycarbonyl)-O-(2-naphthyl)methyl-L-serine Methyl Ester (17).
A solution of N-Boc-L-serine 16 (2.1 g, 10.2 mmol) in anhydrous DMF (20 mL) was cooled to -
15 ˚C, treated with NaH (0.6 g, 10.5 mmol, 60% dispersion in mineral oil) under argon and
stirred for 30 min. A solution 2–(bromomethyl)naphthalene (2.26 mg, 10.24 mmol,) in DMF (5
mL) was slowly added followed by TBAI (0.36 g, 0.1 mmol). The reaction mixture was stirred
for 12 h, after which it was diluted with ethyl acetate (20 mL), poured into water, and extracted
with ethyl acetate. The organic layer was washed with HCl (0.5M), and water, dried (MgSO4)
and concentrated in vacuo. The residue (2.0 g) was dissolved in acetone (40 mL), cooled to 0 ˚C
and treated with K2CO3 (1.1 g, 8.6 mmol) followed by MeI (0.8 mL, 5.7 mmol). The reaction
mixture was warmed to room temperature and stirred for 10 h, then was filtered and diluted with
ethyl acetate, washed with Na2S2O5, water, brine and dried over Na2SO4, and concentrated in
vacuo. Purification by silica gel chromatography (hexane:ethyl acetate 85:15) gave the title
compound (2.2 g, 60%) as a colorless oil. [α]RTD = +12 (c 2.80, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 7.84 – 7.78 (m, 3H), 7.71 (s, 1H), 7.51 – 7.44 (m, 2H), 7.38 (dd, J = 8.5, 1.7 Hz, 1H),
5.42 (d, J = 8.8 Hz, 0H), 4.70 (d, J = 12.3 Hz, 1H), 4.63 (d, J = 12.3 Hz, 1H), 4.50 – 4.37 (m,
1H), 3.89 (dd, J = 9.4, 3.3 Hz, 1H), 3.73 (s, 3H), 3.71 (dd, J = 9.7, 3.7 Hz, 1H), 1.43 (s, 9H). 13C
NMR (151 MHz, CDCl3) δ 171.2, 155.4, 135.0, 133.2, 133.0, 128.2, 127.8, 127.7, 126.4, 126.2,
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126.0, 125.5, 80.0, 73.3, 70.0, 54.0, 52.4, 28.3. ESIHRMS calcd for C20H25NO5Na [M + Na]+,
382.1630; found; 382.1632.
4.2.11
N-(tert-Butoxycarbonyl)-(O-benzyl-L-serinyl)-O-(2-naphthyl)methyl)-L-serine
Methyl Ester (20).
A solution of 16 (175 mg, 0.49 mmol) in dichloromethane (5 mL) was treated with trifluoroacetic
acid (0.5 mL) at room temperature and stirred for 2 h. The volatiles were removed in vacuo, and
the residue taken up in ethyl acetate, washed with saturated aqueous Na2CO3, followed by brine.
The organic layer was dried over Na2SO4 and concentrated in vacuo to give the crude amine 18
(120 mg, 0.46 mmol) which was used without further purification. In a separate flask, a solution
of N-Boc-O-benzyl-L-serine 19 (155 mg, 0.52 mmol) in DMF (3 mL) was treated with HATU
(200 mg, 0.52 mmol) and DIPEA (0.3 mL) and stirred for 0.5 h at room temperature before 18
(120 mg, 0.46 mmol) was added and the resulting mixture was stirred for 3 h. The reaction
mixture was cooled to 0 ˚C and quenched with trimethylamine (100 µL), diluted with H2O (2
mL) and extracted with EtOAc (4 mL x 2). The organic layer was dried Na2SO4 and concentrated
in vacuo then purified by silica gel chromatography (hexane-ethyl acetate 2:1) to give 20 as a
colorless oil (77 mg, 69%). [α]RT +21 (c 0.90, CHCl3); 1H NMR (400 MHz, CD3OD) δ 7.83 –
D =
7.78 (m, 3H), 7.72 (br s, 1H), 7.48 – 7.43 (m, 2H), 7.38 (dd, J = 8.5, 1.7 Hz, 1H), 7.32 – 7.19 (m,
6H), 4.70 (t, J = 3.9 Hz, 1H), 4.64 (d, J = 12.2 Hz, 1H), 4.57 (d, J = 12.2 Hz, 1H), 4.50 (d., J =
12.0 Hz, 1H), 4.47 (d, J = 12.1 Hz, 1H), 4.38 (t, J = 5.4 Hz, 1H), 3.88 (dd, J = 9.8, 4.3 Hz, 1H),
3.75 – 3.68 (m, 3H), 3.67 (s, 3H), 1.42 (s, 9H). 13C NMR (101 MHz, CD3OD) δ 171.4, 170.3,
156.3, 137.8, 135.2, 133.3, 133.1, 128.0, 127.8, 127.7, 127.5, 127.4, 127.4, 127.3, 126.2, 125.8,
125.6, 125.4, 79.5, 72.8, 72.8, 72.7, 69.7, 69.1, 54.4, 52.8, 51.6, 27.3. ESIHRMS calcd for
C30H36N2O7Na [M + Na]+, 559.2420; found; 559.2421.
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4.1.2 N-(tert-Butoxycarbonyl)-L-methionyl)-(O-benzyl-L-serinyl)-(O-(2-naphthyl)methyl)-L-
serine Methyl Ester (23).
A solution of 20 (70 mg, 0.13 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic
acid (0.2 mL) at room temperature and stirred for 2 h. The volatiles were removed in vacuo and
the residue taken up in ethyl acetate, washed with saturated aqueous Na2CO3, followed by brine.
The organic layer was dried over Na2SO4 and concentrated in vacuo to give the crude amine 21
(57 mg, 0.13 mmol), which was used without further purification. In a separate flask a solution
of N-BOC-L-methionine 22 (42 mg, 0.17 mmol) in dry DMF (1 mL) was treated with HATU (65
mg, 0.17 mmol) and DIPEA (0.1 mL,) and stirred for 30 minutes at room temperature before 21
(57 mg, 0.13 mmol) was added. The reaction mixture was stirred for an additional 3 h, cooled to
0 ˚C, quenched with trimethylamine (50 µL), diluted with water (3 mL), and extracted with ethyl
acetate (2 mL × 3). The organic layers were washed with brine and dried over anhydrous Na2SO4,
then concentrated in vacuo. Chromatography over silica gel eluting with hexane-ethyl acetate
1
(2:1) gave the title compound (60 mg, 70%) as a colorless oil [α]RT
-3 (c 0.75, MeOH); H
D =
NMR (600 MHz, CD3OD) δ 7.81 – 7.75 (m, 3H), 7.70 (s, 1H), 7.47 – 7.40 (m, 2H), 7.39 – 7.34
(m, 1H), 7.30 – 7.17 (m, 5H), 4.72 – 4.66 (m, 2H), 4.65 – 4.60 (m, 1H), 4.59 – 4.53 (m, 2H), 4.50
(d, J = 11.8 Hz, 1H), 4.47 (d, J = 11.8 Hz, 1H), 4.41 (s, 1H), 4.25 – 4.18 (m, 1H), 2.55 – 2.39 (m,
2H), 2.09 – 1.95 (m, 4H), 1.91 – 1.78 (m, 1H), 1.38 (s, 9H). 13C NMR (151 MHz, CD3OD) δ
173.3, 170.4, 170.3, 156.5, 137.7, 135.2, 135.2, 133.3, 133.3, 133.1, 128.0, 127.8, 127.8, 127.5,
127.5, 127.4, 127.3, 126.2, 126.2, 125.8, 125.6, 125.4, 79.4, 72.9, 72.8, 72.8, 72.8, 69.4, 69.1,
69.0, 53.9, 53.7, 52.9, 52.9, 51.6, 31.4, 29.7, 3.4, 13.9. ESIHRMS calcd for C35H45N3O8SNa [M
+ Na]+, 690.2825; found; 690.2819.
4.3 General Hydrogenolysis Procedure.
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20% Pd(OH)2/C was dispersed in EtOAc-EtOH (40 mL/mmol, 1:2) under argon. The mixture
was degassed and stirred for 1 h under 3 atm of hydrogen before a solution of the substrate in
EtOH-EtOAc (2:1, 0.05M) was added. The reaction mixture was purged with hydrogen and
stirred at room temperature under a hydrogen atmosphere (3 atm) until complete by TLC. The
catalyst was removed by filtration through Celite and washed with EtOAc. The filtrate was
concentrated, and the resulting residue was purified by chromatography over silica gel eluting
with ethyl acetate/hexane mixtures to give the products.
4.4.1 2-((2-Benzyloxyethyl)thio) ethanol (24).
Compound 3 (10 mg, 0.028 mmol) was subjected to hydrogenolysis according to the standard
conditions using 20% Pd(OH)2 (40 mg, 0.056 mmols). After chromatography on silica gel
(hexane/ethyl acetate 2:1 ) the title compound was obtained as a colorless oil (4.3 mg, 72 %) with
spectral data identical to the literature.19
4.4.2
Phenyl 2,3,4-tri-O-benzyl-1-thio-α-D-mannopyranoside (4) by Selective
Hydrogenolysis of 5.
Compound 5 (10 mg, 0.015 mmol) was subjected to hydrogenolysis according to the standard
conditions using 20% Pd(OH)2 (15 mg, 0.022 mmol). After chromatography on silica gel
(hexane/ethyl acetate 4:1) the title compound was obtained as a colorless oil (7.1 mg, 92 %) with
spectral data identical to the above sample and to the literature.20
4.4.3 Phenyl 3,4,6-tri-O-benzyl-1-thio-α-D-mannopyranoside (25) by Selective
Hydrogenolysis of 8.
Compound 8 (11 mg, 0.016 mmol) was subjected to hydrogenolysis according to the standard
conditions using 20% Pd(OH)2 (22 mg, 0.032 mmol). After chromatography on silica gel
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(hexane/ethyl acetate 4:1) the title compound was obtained as a colorless oil (5.7 mg, 65 %) with
spectral data identical to the literature.21
4.4.4 S-tert-Butyl 2, 3, 4-tri-O-benzyl-1-thio-β-D-mannopyranoside (10) by Selective
Hydrogenolysis of 11.
Compound 11 (15 mg, 0.02 mmol) was subjected to hydrogenolysis according to the standard
conditions using 20% Pd(OH)2 (24 mg, 0.03 mmol). Chromatographic purification (hexane/ethyl
acetate 4:1) gave the title compound (10.5 mg, 89 %) as a colorless oil with spectral data identical
to the above sample.
4.4.5 Phenyl 2,3,6-tri-O-benzyl-1-thio-β-D-glucopyranoside (12) by Selective
Hydrogenolysis of 13.
Compound 13 (10 mg, 0.015 mmol) was subjected to hydrogenolysis according to the standard
conditions using 20% Pd(OH)2 (15 mg, 0.022 mmol). After chromatography on silica gel
(hexane/ethyl acetate 4:1) the title compound was obtained as a powder, (5.5 mg, 70 %) with
spectral data identical to the literature.22
4.4.6 Phenyl 2,3,4-tri-O-benzyl-1-thio-β-D-glucopyranoside (14) by Selective
Hydrogenolysis of 15.
Compound 15 (10 mg, 0.015 mmol) was subjected to hydrogenolysis according to the standard
conditions using 20% Pd(OH)2 (15 mg, 0.022 mmol). After chromatography on silica gel
(hexane/ethyl acetate 5:1) the title compound was obtained as a white powder, (7 mg, 88%) with
spectral data identical to the literature.23
4.4.7 N-(tert-Butoxycarbonyl)-L-methionyl)-(O-benzyl-L-serinyl-L-serine (26).
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The compound was synthesized from 23 (40 mg, 0.06 mmol) using the general hydrogenolysis
protocol in the form of a colorless oil (26 mg, 82%).1H NMR (600 MHz, CD3OD) δ 7.56 – 7.02
(m, 5H), 4.63 (t, J = 5.3 Hz, 1H), 4.58 – 4.49 (m, 3H), 4.22 – 4.14 (m, 1H), 3.91 – 3.85 (m, 1H),
3.81 – 3.76 (m, 2H), 3.74 – 3.71 (m, 1H), 3.71 (s, 3H), 2.61 – 2.47 (m, 2H), 2.08 – 2.01 (m, 4H),
1.89 – 1.82 (m, 1H), 1.41 (s, 9H). 13C NMR (151 MHz, CD3OD) δ 173.2, 170.5, 170.4, 156.6,
137.8, 128.0, 127.5, 127.3, 79.4, 72.9, 72.8, 69.3, 61.4, 61.4, 54.9, 54.8, 54.0, 53.8, 53.0, 51.4,
31.3, 29.7, 27.3, 13.8. ESIHRMS calcd for C24H37N3O8SNa [M + Na]+, 550.2199; found;
550.2195.
Acknowledgement. We thank the NIH (GM 62160) for support of this work, and acknowledge
support from the NSF (MRI-084043) for the purchase of the 600 MHz NMR spectrometer in the
Lumigen Instrument Center at Wayne State University.
References
(1)
Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; 3rd ed.;
Wiley: New York, 1999.
(2)
(3)
(4)
(5)
Kocienski, P. J. Protecting Groups; 3rd ed.; Thieme: Stuttgart, 2005.
Moreau, V.; Norrild, J. C.; Driguez, H. Carbohydr. Res. 1997, 300, 271.
Crich, D.; Li, H. J. Org. Chem. 2000, 65, 801.
Metha, S.; Jordan, K. L.; Weimar, T.; Kreis, U. C.; Batchelor, R. J.; Einstein, F.
W. B.; Pinto, B. M. Tetrahedron: Asymmetry 1994, 5, 2367.
(6)
(7)
Nitz, M.; Bundle, D. R. J. Org. Chem. 2001, 66, 8411.
Joe, M.; Sun, D.; Taha, H.; Completo, G. C.; Croudace, J. E.; Lammas, D. A.;
Besra, G. S.; Lowary, T. L. J. Am. Chem. Soc. 2006, 128, 5059.
17

ACCEPTED MANUSCRIPT
(8)
92, 230.
(9)
Collin, M.-P.; Hobbie, S. N.; Böttger, E. C.; Vasella, A. Helv. Chim. Acta 2009,
Xia, J.; Abbas, S. A.; Locke, R. D.; Piskorz, C. F.; L., A. J.; Matta, K. L.
Tetrahedron Lett. 2000, 41, 169.
(10) Liao, W.; D., L. R.; Matta, K. L. Chem. Commun. 2000, 369.
(11) Wright, J. A.; Yu, J.; Spencer, J. B. Tetrahedron Lett. 2001, 42, 4033.
(12) Volbeda, A. G.; Kistemaker, H. A. V.; Overkleeft, H. S.; van der Marel, G. A.;
Filippov, D. V.; Codée, J. D. C. J. Org. Chem. 2015, 80, 8796.
(13) Li, Y.; Roy, B.; Liu, X. Chem. Commun. 2011, 47, 8952.
(14) Lloyd, D.; Bylsma, M.; Bright, D. K.; Chen, X.; Bennett, C. S. J. Org. Chem.
2017, 82, 3926.
(15) Gaunt, M. J.; Yu, J.; Spencer, J. B. J. Org. Chem. 1998, 63, 4172.
(16) Waschke, D.; Leshch, Y.; Thimm, J.; Himmelreich, U.; Thiem, J. Eur. J. Org.
Chem. 2012, 948.
(17) Yajima, A.; Kawajiri, A.; Mori, A.; Katsuta, R.; Nukada, T. Tetrahedron Lett.
2014, 55, 4350.
(18) Herczeg, M.; Mezὅ, E.; Eszenyi, D.; Antus, S.; Borbás, A. Tetrahedron 2014, 70,
2919.
(19) Morellato-Castillo, L.; Acharya, P.; Combes, O.; Michiels, J.; Descours, A.;
Ramos, O. H. P.; Yang, Y.; Vanham, G.; Ariën, K. K.; Kwong, P. D.; Martin, L.; Kessler, P. J.
Med. Chem. 2013, 56, 5033.
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(20) Pothukanuri, S.; Winssinger, N. Org. Lett. 2007, 9, 2223.
(21) Zhang, Y.-M.; Brodzky, A.; Sinaӱ, P.; Sanint-Marcoux, G.; Perly, B. Tetrahedron:
Asymmetry 1995, 6, 1195.
(22) Motawia, M. S.; Olsen, C. E.; Enevoldsen, K.; Marcussen, J.; Moller, B. L.
Carbohydr. Res. 1995, 277, 109.
(23) He, X.; Chan, T. H. Synthesis 2006, 1645.
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•
•
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Hydrogenolytic cleavage in presence of thioglycosides
Selective hydrogenolysis
Deprotection of thioglycosides