Mild Method for 2-Naphthylmethyl Ether Protecting Group Removal Using a Combination of 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and β-Pinene

Article abstract of DOI:10.1021/acs.joc.7b00065

The use of a combination of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and β-pinene permits the removal of 2-naphthylmethyl (Nap) ether protecting groups on highly sensitive substrates. The reaction tolerates both acid and base sensitive protecting groups, and products are afforded in 68-96% yield. The utility of the method is demonstrated by the removal of the Nap protecting groups on highly sensitive 2,6-dideoxy-sugar disaccharides.

Full text of DOI:10.1021/acs.joc.7b00065

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Note
A Mild Method for 2-Naphthylmethyl Ether Protecting Group Removal Using a
Combination of 2,3-Dichloro5,6-dicyano-1,4-benzoquinone (DDQ) and #-Pinene
Dina Lloyd, Marissa Bylsma, Danielle K. Bright, Xizhao Chen, and Clay S Bennett
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00065 • Publication Date (Web): 10 Mar 2017
Downloaded from http://pubs.acs.org on March 10, 2017
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A Mild Method for 2-Naphthylmethyl Ether Protecting Group Removal Using a
Combination of 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and β-Pinene
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Dina Lloyd, Marissa Bylsma, Danielle K. Bright, Xizhao Chen, and Clay S.
Bennett*
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Department of Chemistry, Tufts University, Medford, MA 02155, USA.
clay.bennett@tufts.edu
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
ABSTRACT: The use of a combination of 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) and β-pinene permits the removal of 2-naphthylmethyl
(Nap) ether protecting groups on highly sensitive substrates. The reaction
tolerates both acid and base sensitive protecting groups, and products are
afforded in 68-96% yield. The utility of the method is demonstrated by the
removal of the Nap protecting groups on highly sensitive 2,6-dideoxy-sugar
disaccharides.
Like most other forms of chemical synthesis, carbohydrate chemistry relies
heavily on protecting groups. In addition to masking functional groups from
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reacting, protecting groups often play a role of both controlling selectivity in
traditional glycosylation reactions,1,2 and modulating the reactivity of coupling
partners through either "arming" or "disarming" effects.3 As a consequence,
when planning the synthesis of an oligosaccharide, it is often necessary to
carefully consider the nature of the protecting groups on every monosaccharide.
Typically, protecting groups in carbohydrate chemistry can be divided into two
groups; "permanent" protecting groups, such as benzyl ethers, which are
removed at the end of the synthesis, and "temporary" protecting groups, which
are removed during the course of the synthesis to unmask nucleophilic alcohols
for further coupling.4 Among the temporary protecting groups that have found
increased usage over the course of the past decade, the 2-naphthylmethyl (Nap)
protecting group has emerged as a particularly valuable addition to the chemist's
arsenal.5 Two factors give rise to the utility of this protecting group. First, it does
not significantly attenuate carbohydrate reactivity (it is not a disarmed protecting
group). Furthermore, it can be readily removed under a variety of conditions that
are orthogonal to benzyl ethers, including deprotection under oxidative6-8 and
acid-mediated conditions.9-11
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Given the versatility of the Nap protecting group, we sought to examine its
applicability as a temporary protecting group in our ongoing studies in 2-deoxy-
sugar oligosaccharide synthesis.12,13 Owing to the highly labile nature of deoxy-
sugars, we had to limit our studies to reactions that did not require the use of
strong acid. To this end, we studied the reaction of disaccharide 1 with DDQ in
the presence of CH2Cl2 and water under conditions described by Danishefsky
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and co-workers.14 In the absence of any additives, DDQ removed the Nap ether
to afford the deprotected disaccharide 2 in moderate yield (56%, Table 1, entry
1). Reasoning that the acidic 2,3-dichloro-5,6-dicyanohydroquinone byproduct of
the DDQ deprotection was causing product decomposition,15 we next looked at
the use of additives in the reaction. The use of the non-nucleophilic base tri-tert-
butyl pyrimidine (TTBP) did not improve the yield of the reaction (Table 1, entry
2), presumably due to the low pKa of the conjugate base of TTBP.16 The more
basic hindered amines, such as 2,6-di-tert-butyl-4-methylpyridine (DTBMP)
resulted in a slight increase in the yield of the desired product (Table 1, entry 3).
Surprisingly, 2,6-di-tert-butylpyridine (DTBP) resulted in greatly increased yields
of the desired product (Table 1 entry 4), despite the fact that this compound is
slightly less basic than DTBMP.17
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While the use of DTBP afforded the desired product in good yield, we
sought to further improve the yield and mildness of the reaction while avoiding
the use of expensive additives. To this end, we turned our attention to the use of
non-basic proton scavengers. Recently, Shen and coworkers described the use
of the strained alkene β-pinene as an alternative acid scavenger in glycosylations
where amine bases were problematic.18,19 Reasoning that we could take
advantage of this proton scavenger in our studies, we examined the outcome of
the reaction when β-pinene was used in place of an amine base. This approach
proved to be highly effective, and treating 1 with a combination of DDQ and β-
pinene led to the formation of the desired product 2 in 96% yield (Table 1, entry
5).20
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TABLE 1. Screen of Additives on DDQ-mediated Nap Ether Removal.
Having established the optimal conditions for Nap ether removal, we
turned our attention to examining the scope of the reaction, and its compatibility
with various common sugar protecting groups (Table 2). The synthesis of these
substrates were carried out under standard conditions as outlined in Scheme 1.
Benzylidene acetals are tolerated under the reaction conditions, although the
position of the ether seems to affect the yield (Table 2, entries 1 and 2).
Similarly, Nap ethers on ethyl or phenyl thioglycosides of both fucose and
rhamnose can be readily removed (Table 2, entries 5-7). The reaction tolerates
deoxy-sugars possessing sensitive β-linked anomeric 4-methoxyphenyl (PMP)
protecting groups (Table 2, entry 8). Omitting β-pinene from this latter reaction
led to both
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Table 2. Substrate Scope.
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Scheme 1. Synthesis of Substrates Used in this Study.
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reduced yield and anomerization of the PMP group to give predominantly α-
linked product (Table 2, entry 8). This latter result highlights the importance of
the use of scavangers in the deprotection of sensitive substrates. With less
sensitive substrates similar yields were obtained both in the presence and
absence of β-pinene (Table 2, entires 1, 3, 4, 6, and 7). Finally, the reaction
conditions also tolerated highly-sensitive glycal structures (Table 2, entries 9 and
10), although removal of an allylic Nap group proceeded in lower yield than the
corrosponding homoallylic Nap ether. Noteably, in the absence of β-pinene we
were only able to obtain the product in low (18%) yield along with significant
quantity of a byproduct. The NMR spectra of this product appeared to contain a
mixture of hemiacetal and aldehyde. In order to elucidate the identity of this
material, it was acetylated to afford the 2,3-anhydro sugar 32 in 60% yield over
two steps (Scheme 2). This latter result clearly demonstrates the advantage of
the use of β-pinene in the reaction.
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Scheme 2. Identification of Byproduct from the Reaction of 17 without β-
Pinene.
In conclusion, we have demonstrated that a combination of DDQ and β-
pinene permits the removal of Nap ethers under particularly mild conditions. The
reaction tolerates a number of highly sensitive substrates, and does not suffer
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from problems of in situ anomerization of the substrates observed when DDQ is
used alone. Given the mildness of these conditions, and the inexpensive nature
of β-pinene, we anticipate that these conditions will prove useful to chemists who
wish to use Nap ethers as protecting groups in all areas of synthetic chemistry.
EXPERIMENTAL SECTION
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General Considerations. All reactions were performed under inert argon
atmosphere, unless otherwise noted. Flash column chromatography was
performed on 230-400 mesh silica gel,. Analytical and preparative thin layer
chromatography was carried out on silica gel 60 F-254 plates. Products were
visualized using UV or by staining with 5% aqueous sulfuric acid or ceric
ammonium molybdate. NMR spectra were recorded on a NMR spectrometer at
500 MHz for 1H-NMR and 125 MHz for 13C-NMR. Chemical shifts are reported in
ppm relative to TMS (for 1H-NMR in CDCl3) or CDCl3 (for 13C-NMR in CDCl3). For
1H NMR spectra, data are reported as follows: δ shift, multiplicity [s = singlet, m =
multiplet, t = triplet, d = doublet, dd = doublet of doublets, td = triplet of doublets,
q = quartet, brs = broad singlet, coupling constants are reported in Hz. Low
resolution mass spectra (LRMS) were recorded using a ESI-MS with an
additional APCI source. High resolution mass spectra (HRMS) were obtained on
Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (FT-ICR-MS)
with direct analysis in real time (DART) ionization source. Optical rotations were
measured at 589 nm in a 5 cm cell at 24 °C. Solvents for reactions were dried
immediately prior to use. All other chemicals were purchased at the highest
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possible quality and used as received. Compounds 4,21 6,21 8,22 10,23 15,24 20,25
23,26 27,27 and 3025 were prepared according to literature methods
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Procedure A: General procedure Nap ether removal with β-pinene. To a
solution of 1 (0.59 mmol) and β-pinene (2.0 mmol) in DCM (58 mL) and H2O (2.9
mL), was added DDQ (1.1 mmol). The reaction was stirred at room temperature
under argon for 4 h and monitored by TLC. The reaction mixture was then diluted
with DCM (50 mL), and the organic layer was washed 3 times with 50 ml of 2M
NaOH. The pooled organic layers were washed with 100 ml of sat. NaHCO3,
dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified
by flash chromatography on silica gel (30% ethyl acetate in hexanes) to afford 2
(323 mg, 96%) as a white powder.
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Procedure B: General procedure Nap ether removal without β-pinene.
To a solution of 1 (0.59 mmol) in DCM (59 mL) and H2O (2.9 mL), was added
DDQ (1.1 mmol). The reaction was stirred at room temperature under argon for 4
h and monitored by TLC. The reaction mixture was then diluted with DCM (75
mL), and the organic layer was washed 3 times with 50 ml of 2M NaOH. The
pooled organic layers were washed with 50 ml of sat. NaHCO3, dried over
Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (30% ethyl acetate in hexanes) to afford 2 (183 mg,
54%) as a white powder.
p-methoxylphenyl
4-(4'-O-Benzyl-2',6'-dideoxy-β-D-arabino-
hexopyranosyl)-3-O-benzyl-2,6-dideoxy-β-D-arabino-hexopyranose (2). Mp: 151-
152 °C; [α] D 24 = – 30.0 (c 1.05, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.41–7.26
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(m, 10H), 6.97–6.91 (m, 2H), 6.84–6.78 (m, 2H), 4.95 (dd, J = 9.9, 2.0 Hz, 1H),
4.82–4.64 (m, 5H), 3.76 (s, 3H), 3.71–3.56 (m, 1H), 3.50–3.40 (m, 1H), 3.39–
3.25 (m, 2H), 2.99 (t, J = 8.9 Hz, 1H), 2.45 (ddd, J = 11.4, 6.3, 1.7 Hz, 1H), 2.26
(ddd, J = 13.7, 6.8, 1.7 Hz, 1H), 2.08 (d, J = 3.2 Hz, 1H), 1.88 (td, J = 12.1, 10.1
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Hz, 1H), 1.60 (td, J = 12.0, 9.8 Hz, 1H), 1.35 (t, J = 6.5 Hz, 6H); C NMR (125
MHz, CDCl3) δ 155.0, 151.2, 138.7, 138.2, 128.7, 128.4, 128.1, 127.9, 127.6,
127.5, 117.9, 114.5, 100.5, 98.5, 85.8, 82.5, 77.6, 75.2, 71.9, 71.6, 71.3, 71.0,
55.6, 39.3, 37.0, 18.5, 18.4; LRMS (ESI) m/z: [M + Na]+ Calcd for C33H40O8Na
587.26; Found 587.45; HRMS (DART) m/z: [M + NH4]+ Calcd for C33H44NO8
582.3061; Found 582.3058.
Methyl 3-O-benzyl-4,6-O-benzylidine-α-D-glucopyranoside (4). The title
compound was prepared according to procedure A using 3 (250 mg, 0.48 mmol)
and β-pinene (0.24 mL, 11.6 mmol) dissolved in DCM (48 mL) and H2O (22.4
mL) were treated with DDQ (220 mg, 0.97 mmol) for 4 h. The title compound was
purified by flash column chromatography on silica gel (20% ethyl acetate in
hexanes) to afford compound 4 (159 mg, 89%) as a white solid. The
spectroscopic data is in good agreement with previously reported data.21 1H NMR
(500 MHz, CDCl3) δ 7.52–7.46 (m, 2H), 7.43–7.27 (m, 8H), 5.58 (s, 1H), 4.97 (d,
J = 11.6 Hz, 1H), 4.82 (d, J = 3.8 Hz, 1H), 4.79 (d, J = 11.6 Hz, 1H), 4.30 (dd, J =
10.0, 4.6 Hz, 1H), 3.89–3.80 (m, 2H), 3.80–3.70 (m, 2H), 3.65 (t, J = 9.2 Hz, 1H),
3.46 (s, 3H), 2.29 (d, J = 7.4 Hz, 1H).
Methyl 3-O-benzyl-4,6-O-benzylidine-α-D-glucopyranoside (4). The title
compound was prepared according to procedure B using 3 (250 mg, 0.48 mmol)
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in DCM (48 mL) and H2O (2.4 mL), was added DDQ (220 mg, 0.97 mmol). The
title compound was purified by flash column chromatography on silica gel (20%
ethyl acetate in hexanes) to afford compound 4 (158 mg, 89%). The
spectroscopic data is in good agreement with previously reported data.21
Methyl 2-O-benzyl-4,6-O-benzylidine-α-D-glucopyranoside (6). The title
compound was prepared according to procedure A using 5 (234 mg, 0.45 mmol)
and β-pinene (0.24 mL, 1.5 mmol) dissolved in DCM (46 mL) and H2O (2.3 mL)
were treated with DDQ (206 mg, 0.9 mmol) for 4 h. The title compound was
purified by flash column chromatography on silica gel (20% ethyl acetate in
hexanes) to afford compound 6 (155 mg, 93%) as a white solid. The
spectroscopic data is in good agreement with previously reported data.21 1H NMR
(500 MHz, CDCl3) δ 7.52–7.44 (m, 2H), 7.42–7.28 (m, 8H), 5.52 (s, 1H), 4.79 (d,
J = 12.2 Hz, 1H), 4.71 (d, J = 12.2 Hz, 1H), 4.61 (d, J = 3.6 Hz, 1H), 4.26 (dd, J =
10.2, 4.8 Hz, 1H), 4.15 (td, J = 9.3, 2.2 Hz, 1H), 3.81 (td, J = 10.0, 4.8 Hz, 1H),
3.70 (t, J = 10.3 Hz, 1H), 3.53–3.43 (m, 2H), 3.38 (s, 3H), 2.55 (d, J = 2.2 Hz,
1H).
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Methyl 3-O-benzyl-4,6-O-benzylidine-β-D-glucopyranoside (8).The title
compound was prepared according to procedure A using 7 (100 mg, 0.19 mmol)
and β-pinene (0.10 mL, 0.64 mmol) dissolved in DCM (19 mL) and H2O (0.95
mL) were treated with DDQ (86 mg, 0.38 mmol) for 4 h. The title compound was
purified by flash column chromatography on silica gel (40% ethyl acetate in
hexanes) to afford compound 8 (63 mg, 86%) as a white solid. The spectroscopic
data is in good agreement with previously reported data.22 1H NMR (500 MHz,
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CDCl3) δ 7.52 – 7.46 (m, 2H), 7.44 – 7.26 (m, 8H), 5.58 (s, 1H), 4.98 (d, J = 11.6
Hz, 1H), 4.79 (d, J = 11.6 Hz, 1H), 4.40 – 4.31 (m, 2H), 3.81 (t, J = 10.3 Hz, 1H),
3.75 – 3.63 (m, 2H), 3.58 (s, 3H), 3.57 – 3.52 (m, 1H), 3.46 (ddd, J = 10.1, 8.8,
5.0 Hz, 1H), 2.43 (d, J = 2.2 Hz, 1H).
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Methyl 3-O-benzyl-4,6-O-benzylidine-β-D-glucopyranoside (8).The title
compound was prepared according to procedure B using 7 (100 mg, 0.19 mmol)
dissolved in DCM (19 mL) and H2O (0.95 mL) was treated with DDQ (86 mg,
0.38 mmol) for 3 h. The title compound was purified by flash column
chromatography on silica gel (40% ethyl acetate in hexanes) to afford compound
20 (62 mg, 85%) as a white solid. The spectroscopic data is in good agreement
with previously reported data.22 1H NMR (500 MHz, CDCl3) δ 7.52 – 7.46 (m, 2H),
7.44 – 7.26 (m, 8H), 5.58 (s, 1H), 4.98 (d, J = 11.6 Hz, 1H), 4.79 (d, J = 11.6 Hz,
1H), 4.40 – 4.31 (m, 2H), 3.81 (t, J = 10.3 Hz, 1H), 3.75 – 3.63 (m, 2H), 3.58 (s,
3H), 3.57 – 3.52 (m, 1H), 3.46 (ddd, J = 10.1, 8.8, 5.0 Hz, 1H), 2.43 (d, J = 2.2
Hz, 1H).
Methyl 3-O-benzyl-4,6-O-benzylidine-α-D-mannopyranoside (10).The title
compound was prepared according to procedure A using 9 (100 mg, 0.19 mmol)
and β-pinene (0.10 mL, 0.64 mmol) dissolved in DCM (19 mL) and H2O (0.95
mL) were treated with DDQ (86 mg, 0.38 mmol) for 4 h. The title compound was
purified by flash column chromatography on silica gel (40% ethyl acetate in
hexanes) to afford compound 10 (69 mg, 94%) as colorless oil. The
spectroscopic data is in good agreement with previously reported data.22 1H
NMR (500 MHz, CDCl3) δ 7.52 – 7.46 (m, 2H), 7.42 – 7.25 (m, 8H), 5.61 (s, 1H),
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4.84 (d, J = 11.8 Hz, 1H), 4.76 – 4.67 (m, 2H), 4.27 (dd, J = 9.7, 4.3 Hz, 1H),
4.10 (t, J = 9.3 Hz, 1H), 4.04 – 3.99 (m, 1H), 3.93 – 3.76 (m, 3H), 3.36 (s, 3H),
2.80 (d, J = 1.5 Hz, 1H).
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Methyl 3-O-benzyl-4,6-O-benzylidine-α-D-mannopyranoside (10).The title
compound was prepared according to procedure B using 9 (100 mg, 0.19 mmol)
dissolved in DCM (19 mL) and H2O (0.95 mL) was treated with DDQ (86 mg,
0.38 mmol) for 4 h. The title compound was purified by flash column
chromatography on silica gel (40% ethyl acetate in hexanes) to afford compound
10 (62 mg, 85%) as colorless oil. The spectroscopic data is in good agreement
with previously reported data.23 1H NMR (500 MHz, CDCl3) δ 7.52 – 7.46 (m, 2H),
7.42 – 7.25 (m, 8H), 5.61 (s, 1H), 4.84 (d, J = 11.8 Hz, 1H), 4.76 – 4.67 (m, 2H),
4.27 (dd, J = 9.7, 4.3 Hz, 1H), 4.10 (t, J = 9.3 Hz, 1H), 4.04 – 3.99 (m, 1H), 3.93
– 3.76 (m, 3H), 3.36 (s, 3H), 2.80 (d, J = 1.5 Hz, 1H).
Ethyl 6-Deoxy-4-O-benzyl-2-O-pivaloyl-1-thio-β-D-galactopyranoside (12).
The title compound was prepared according to procedure A using 11 (462.8 mg,
0.885 mmol) and β-pinene (0.47 mL, 3.03 mmol) dissolved in DCM (89 mL) and
H2O (4.4 mL) were treated with DDQ (400 mg, 1.77 mmol) for 5 h. The title
compound was purified by flash column chromatography on silica gel (5% ethyl
acetate in toluene) to afford compound 12 (251.4 mg, 74%) as a white solid. Mp:
144-145 °C; [α] D 24 = –8.4 (c = 1.14, CH2Cl2); 1H NMR (500 MHz, CDCl3): δ 7.37-
7.31 (m, 5H), 5.02 (t, J = 10.0 Hz, 1H), 4.83 (d, J = 11.7 Hz, 1H), 4.69 (d, J =
11.7 Hz, 1H), 4.37 (d, J = 10.0 Hz, 1H), 3.67-3.63 (m, 3H), 2.77-2.72 (m, 1H),
2.69-2.62 (m, 1H), 2.25 (d, J = 9.5 Hz, 1 H), 1.34 (d, J = 6.5 Hz, 3H), 1.25 (t, J =
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7.5 Hz, 3H), 1.23 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 178.5, 138.0, 128.6,
128.0, 127.9, 82.9, 80.1, 76.1, 75.0, 74.4, 71.1, 38.9, 27.1, 23.6, 17.3, 14.9;
LRMS (ESI) m/z: [M + Na]+ Calcd for C20H30O5SNa 405.17; Found 405.29;
HRMS (DART) m/z: [M + NH4]+ Calcd for C20H34NO5S 400.2152; Found
400.2144.
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Phenyl
6-Deoxy-3-O-benzyl-2-O-pivaloyl-1-thio-β-D-galactopyranoside
(14). The title compound was prepared according to procedure A using 13 (100
mg, 0.18 mmol) and β-pinene (0.09 mL, 0.60 mmol) dissolved in DCM (17 mL)
and H2O (1.9 mL) were treated with DDQ (79.5 mg, 0.35 mmol) for 2 h. The title
compound was purified by flash column chromatography on silica gel (5% to 10%
ethyl acetate in toluene) to afford compound 14 (60.7 mg, 80%) as an
amorphous solid. [α] D 24 = +5.5 (c = 0.95, CH2Cl2); 1H NMR (500 MHz, CDCl3): δ
7.50-7.48 (m, 2H), 7.34-7.26 (m, 8H), 5.23 (t, J = 9.8 Hz, 1H), 4.66-4.58 (m, 3H),
3.84 (t, J = 2.5 Hz, 1H), 3.62-3.57 (m, 2H), 2.38 (s, 1H), 1.40 (d, J = 6.5 Hz, 3H),
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1.24 (s, 9H); C NMR (125 MHz, CDCl3): δ 177.0, 137.4, 133.9, 132.2, 128.9,
128.7, 128.2, 127.8, 127.7, 86.9, 80.4, 74.5, 71.9, 69.2, 68.6, 38.9, 27.3, 16.9;
LRMS (ESI) m/z: [M + Na]+ Calcd for C24H30O5SNa 453.17; Found 453.36;
HRMS (DART) m/z: [M + NH4]+ Calcd for C24H34NO5S 448.2152; Found
448.2155.
Phenyl
6-Deoxy-3-O-benzyl-2-O-pivaloyl-1-thio-β-D-galactopyranoside
(14). The title compound was prepared according to procedure B using 13
(116.7 mg, 0.20 mmol) dissolved in DCM (20 mL) and H2O (2.2 mL) were treated
with DDQ (96.5 mg, 0.43 mmol) for 5 h. The title compound was purified by flash
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afford compound 14 (73.8 mg, 84%) as an amorphous solid. The spectroscopic
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data is in good agreement with data as shown above. H NMR (500 MHz,
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CDCl3): δ 7.50-7.48 (m, 2H), 7.34-7.26 (m, 8H), 5.23 (t, J = 9.5 Hz, 1H), 4.66-
4.58 (m, 3H), 3.84 (t, J = 2.5 Hz, 1H), 3.62-3.57 (m, 2H), 2.35 (s, 1H), 1.40 (d, J =
6.5 Hz, 3H), 1.24 (s, 9H).
Phenyl 6-Deoxy-3-O-benzyl-2-O-pivaloyl-1-thio-α-L-rhamnopyranose (16).
The title compound was prepared according to procedure A using 1524 (60.5 mg,
0.10 mmol) and β-pinene (0.06 mL, 0.36 mmol) dissolved in DCM (10.6 mL) and
H2O (0.53 mL) were treated with DDQ (48 mg, 0.212 mmol) for 4 h. The title
compound was purified by flash column chromatography on silica gel (5% ethyl
acetate in toluene) to afford compound 16 (30.9 mg, 68%) as a white solid. The
spectroscopic data is in good agreement with previously reported data.24 1H NMR
(500 MHz, CDCl3): δ 7.49-7.47 (m, 2H), 7.38-7.26 (m, 8H), 5.60 (s, 1H), 5.40 (s,
1H), 4.72 (d, J = 10.9 Hz, 1H), 4.42 (d, J = 10.9 Hz, 1H), 4.23-4.20 (m, 1H), 3.72
(dd, J = 2.4, 9.5 Hz, 1H), 3.62 (t, J = 9.2 Hz, 1H), 2.33 (s, 1H), 1.35 (d, J = 6.1
Hz, 3H), 1.21 (s, 9H).
Phenyl 6-Deoxy-3-O-benzyl-2-O-pivaloyl-1-thio-α-L-rhamnopyranose (16).
The title compound was prepared according to procedure B using 1524 (115.5
mg, 0.20 mmol) dissolved in DCM (20 mL) and H2O (2.2 mL) were treated with
DDQ (93.3 mg, 0.41 mmol) for 4 h. The title compound was purified by flash
column chromatography on silica gel (5% ethyl acetate in toluene) to afford
compound 16 (61.3 mg, 70%) as a white solid. The spectroscopic data is in good
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agreement with previously reported data.24 1H NMR (500 MHz, CDCl3): δ 7.49-
7.47 (m, 2H), 7.37-7.26 (m, 8H), 5.60 (s, 1H), 5.40 (s, 1H), 4.72 (d, J = 11.1 Hz,
1H), 4.42 (d, J = 11.1 Hz, 1H), 4.23-4.20 (m, 1H), 3.72 (dd, J = 2.4, 9.5 Hz, 1H),
3.62 (t, J = 9.2 Hz, 1H), 2.33 (s, 1H), 1.35 (d, J = 6.0 Hz, 3H), 1.21 (s, 9H).
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β-p-methoxylphenyl
3-O-Benzyl-2,6-Dideoxy-D-arabino-hexopyranose
(18). The title compound was prepared according to procedure A using 17 (1.5
g, 3.6 mmol) and β-pinene (1.9 mL, 12.3 mmol) dissolved in DCM (360 mL) and
H2O (18 mL) were treated with DDQ (1.6 g, 7.2 mmol) for 3 h. The title compound
was purified by flash column chromatography on silica gel (100%
dichloromethane then switched to 10% ethyl acetate in hexanes) to afford
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compound 18 (1.0 g, 90%) as a white solid. Mp: 68-69 °C; [α] D = –64.3 (c =
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0.97, CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.42 – 7.29 (m, 5H), 6.98–6.93 (m,
2H), 6.85–6.77 (m, 2H), 4.98 (dd, J = 9.8, 2.1 Hz, 1H), 4.72 (d, J = 11.6 Hz, 1H),
4.51 (d, J = 11.6 Hz, 1H), 3.76 (s, 3H), 3.52–3.37 (m, 2H), 3.34–3.26 (m, 1H),
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2.54–2.47 (m, 2H), 1.83 (td, J = 12.0, 9.9 Hz, 1H), 1.38 (d, J = 6.1 Hz, 3H); C
NMR (126 MHz, CDCl3) δ 155.2, 151.3, 138.0, 128.8, 128.1, 127.9, 118.0, 117.9,
98.6, 78.8, 75.6, 71.9, 71.1, 55.8, 36.0, 18.1; LRMS (ESI) m/z: [M + Na]+ Calcd
for C20H24O5Na 367.15; Found 367.16; HRMS (DART) m/z: [M + NH4]+ Calcd for
C20H28NO5 362.1962; Found 362.1947.
α-p-Methoxylphenyl-3-O-benzyl-2,6-dideoxy-D-arabino-hexopyranose
(18a).The title compound was prepared according to procedure B using 17 (825
mg, 1.9 mmol) dissolved in DCM (20 mL) and H2O (2 mL), was added DDQ (882
mg, 3.1 mmol). The reaction was stirred at room temperature under argon for 2 h
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and monitored by TLC. The reaction mixture was diluted with DCM (25 mL), and
the organic layer was washed 3 times with 2M NaOH. The pooled organic layers
were washed H2O, dried over Na2SO4, filtered and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel (20% ethyl
acetate in hexanes) to afford 18 (438 mg, 67% 5:1 α:β) as a white powder. Mp:
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84-85 °C; [α] D = +98.75 (c 1.28, CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.42–
7.27 (m, 5H), 6.98 (d, J = 12.2 Hz, 2H), 6.83 (d, J = 12.2 Hz, 2H), 5.50 (d, J =
3.7, 1.4 Hz, 1H), 4.74 (d, J = 11.5 Hz, 1H), 4.57 (d, J = 11.5 Hz, 1H), 3.95 (ddd, J
= 11.4, 8.9, 4.8 Hz, 1H), 3.83 (dq, J = 9.5, 6.2 Hz, 1H), 3.77 (s, 3H), 3.31 (td, J =
9.2, 2.1 Hz, 1H), 2.48 (dd, J = 13.0, 4.9, 1.5 Hz, 1H), 2.43 (d, J = 2.1 Hz, 1H),
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1.77 (ddd, J = 12.9, 11.4, 3.6 Hz, 1H), 1.26 (d, J = 6.2 Hz, 3H); C NMR (125
MHz, CDCl3) δ 154.9, 150.8, 138.4, 128.7, 128.0, 127.9, 117.9, 114.7, 96.8,
77.0, 76.2, 71.4, 68.4, 55.8, 35.1, 18.0; LRMS (ESI) m/z: [M + NH4]+ Calcd for
C20H28NO5 (M+NH4) 362.41; Found 362.18; HRMS (DART) m/z: [M + NH4]+
Calcd for C20H28NO5 362.1962; Found 362.1971.
3-O-Benzyl-6-deoxy-D-glucal (20). The title compound was prepared
according to procedure A using 19 (325 mg, 0.9 mmol) and β-pinene (0.8 mL, 3.6
mmol) dissolved in DCM (90 mL) and H2O (4.5 mL) were treated with DDQ (410
mg, 1.8 mmol) for 4 h. The title compound was purified by flash column
chromatography on silica gel (10% ethyl acetate in toluene) to afford compound
20 (180 mg, 91%) as colorless oil. The spectroscopic data is in good agreement
with previously reported data.25 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 4.4 Hz,
4H), 7.35–7.26 (m, 1H), 6.35 (dd, J = 6.2, 1.5 Hz, 1H), 4.85 (dd, J = 6.1, 2.2 Hz,
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1H), 4.71 (d, J = 11.7 Hz, 1H), 4.55 (d, J = 11.8 Hz, 1H), 4.05 (dt, J = 7.1, 1.9 Hz,
1H), 3.90 (dq, J = 9.2, 6.3 Hz, 1H), 3.62 (ddd, J = 9.3, 7.0, 3.6 Hz, 1H), 2.19 (d, J
= 3.6 Hz, 1H), 1.39 (d, J = 6.4 Hz, 3H).
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4-O-Benzyl-6-deoxy-D-glucal (22). The title compound was prepared
according to procedure A using 21 (250 mg, 0.69 mmol) and β-pinene (0.37 mL,
2.3 mmol) dissolved in DCM (58 mL) and H2O (2.9 mL) were treated with DDQ
(322 mg, 1.3 mmol) for 2 h. The title compound was purified by flash column
chromatography on silica gel (30% ethyl acetate in hexane) to afford compound
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22 (111mg, 73%) as a pink-white solid. Mp: 107-108 °C; [α] D = +10.9 (c 1.01,
CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.39–7.30 (m, 5H), 6.33-6.32 (dd, J = 6.0,
1.4 Hz, 1H), 4.82 (d, J = 11.6 Hz, 1H), 4.80 (d, J = 11.6 Hz, 1H), 4.70 (dd, J =
6.0, 2.3 Hz, 1H), 4.37–4.33 (m, 1H), 3.91 (dq, J = 9.6, 6.4 Hz, 1H), 3.28 (dd, J =
9.6, 6.9 Hz, 1H), 1.67 (d, J = 5.6 Hz, 1H), 1.41 (d, J = 6.4 Hz, 3H); 13C NMR (126
MHz, CDCl3) δ 144.7, 138.3, 128.6, 127.9, 103.1, 82.5, 74.3, 74.1, 70.0, 17.6;
HRMS (DART) m/z: [M - H]- Calcd for C13H15O3 219.1027; Found 219.1029.
Acetyl 4-O-Benzyl-6-deoxy-D-erythro-hex-2-enopyranoside (32). The title
compound was prepared according to procedure B using 21 (250 mg, 0.69
mmol) dissolved in DCM (58 mL) and H2O (2.9 mL) was treated with DDQ (322
mg, 1.3 mmol) for 2 h. The title compound was purified by flash column
chromatography on silica gel (30% ethyl acetate in hexane) to afford a white
solid. This solid was dissolved in pyridine (1.2 mL), and treated with 4-
dimethylaminopyridine (2 mg, 0.01 mmol) followed by dropwise addition of acetic
anhydride (0.05 mL, 0.58 mmol). After stirring for 3 h, the reaction mixture was
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concentrated in vacuo and azeotroped with toluene (2 x 25 mL). The title
compound was purified by flash column chromatography on silica gel (20% ethyl
acetate in hexane) to afford compound 32 (75 mg, 60% over 2 steps 10:1 α:β) as
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yellow oil. [α] D = +79.9 (c 1.07, CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.40 –
7.27 (m, 5H), 6.21 (s, 1H), 6.18 (d, J = 9.7 Hz, 1H), 5.78 (ddd, J = 10.3, 2.9, 1.9
Hz, 1H), 4.69 (d, J = 11.5 Hz, 1H), 4.57 (d, J = 11.5 Hz, 1H), 3.90 (dq, J = 9.0,
6.2 Hz, 1H), 3.73 (dq, J = 9.0, 1.7 Hz, 1H), 2.08 (s, 3H), 1.32 (d, J = 6.2 Hz, 3H);
13C NMR (126 MHz, CDCl3) δ 170.3, 137.9, 132.1, 128.6, 128.1, 128.0, 124.9,
88.9, 75.8, 71.5, 68.4, 21.4, 18.3; LRMS (ESI) m/z: [M + Na]+ Calcd for
C15H18NaO4 285.29; Found 285.09; HRMS (DART) m/z: [M - OAc]+ Calcd for
C13H15O2 203.1067; Found 203.1085.
Preparation of Substrates:
Methyl-2-O-(2-naphthylmethyl)-3-O-benzyl-4,6-O-benzylidene-α-D-
glucopyranoside (3). Sodium hydride (60% in mineral oil, 80 mg, 1.9 mmol) and
tetrabutylammonium iodide (48 mg, 0.13 mmol) were suspended in DMF (10
mL). The suspension was cooled to 0 °C and treated with a solution of 421 (250
mg, 0.67 mmol) in DMF (3 mL), while additional DMF (3 mL) was simultaneously
added. After the mixture was stirred for 10 min at 0 °C, 2-(bromomethyl)-
naphthalene (287 mg, 1.30 mmol) in 4 mL DMF was added dropwise to the
mixture and the reaction was then allowed to warm to room temperature. After
being stirred for 2 h, the reaction mixture was quenched with saturated aqueous
NH4Cl and extracted three times with diethyl ether. The pooled organic layers
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were washed with water and brine, and then dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash column chromatography
on silica gel (20% ethyl acetate in hexanes) to afford compound 3 (336 mg, 98%)
as a white solid. The spectroscopic data is in good agreement with previously
reported data.28 1H NMR (500 MHz, CDCl3) δ 7.86 – 7.74 (m, 4H), 7.54 – 7.44
(m, 5H), 7.44 – 7.27 (m, 8H), 5.55 (s, 1H), 5.02 (d, J = 12.3 Hz, 1H), 4.94 (d, J =
11.2 Hz, 1H), 4.87 (d, J = 11.8 Hz, 2H), 4.59 (d, J = 3.7 Hz, 1H), 4.25 (dd, J =
10.2, 4.9 Hz, 1H), 4.08 (t, J = 9.3 Hz, 1H), 3.83 (td, J = 10.0, 4.8 Hz, 1H), 3.69 (t,
J = 10.3 Hz, 1H), 3.64 – 3.56 (m, 2H), 3.41 (s, 3H).
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Methyl-2-O-benzyl-3-O-(2-naphthylmethyl)-4,6-O-benzylidene-α-D-
glucopyranoside (5). Sodium hydride (60% in mineral oil, 160 mg, 3.9 mmol) and
tetrabutylammonium iodide (96 mg, 0.26 mmol) were suspended in DMF (6 mL).
The suspension was cooled to 0 °C and treated with a solution of 621 (0.5 g, 1.3
mmol) in DMF (3 mL), while additional DMF (3 mL) was simultaneously added.
After the mixture was stirred for 10 min at 0 °C, 2-(bromomethyl)naphthalene
(574 mg, 2.6 mmol) in 3 mL DMF was added dropwise to the mixture and the
reaction was then allowed to warm to room temperature. After being stirred for 2
h, the reaction mixture was quenched with saturated aqueous NH4Cl and
extracted three times with diethyl ether. The pooled organic layers were washed
with water and brine, and then dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by flash column chromatography on silica gel
(10% ethyl acetate in hexanes) to afford compound 5 (656 mg, 98%) as a white
solid. The spectroscopic data is in good agreement with previously reported
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data.28 1H NMR (500 MHz, CDCl3) δ 7.84 – 7.74 (m, 3H), 7.73 – 7.67 (m, 1H),
7.54–7.26 (m, 13H), 5.57 (s, 1H), 5.07 (d, J = 11.6 Hz, 1H), 5.00 (d, J = 11.6 Hz,
1H), 4.88 (d, J = 12.1 Hz, 1H), 4.73 (d, J = 12.2 Hz, 1H), 4.61 (d, J = 3.7 Hz, 1H),
4.27 (dd, J = 10.2, 4.8 Hz, 1H), 4.10 (t, J = 9.3 Hz, 1H), 3.84 (td, J = 9.9, 4.8 Hz,
1H), 3.72 (t, J = 10.3 Hz, 1H), 3.64 (t, J = 9.4 Hz, 1H), 3.59 (dd, J = 9.3, 3.8 Hz,
1H), 3.41 (s, 3H).
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Ethyl-6-deoxy-3,4-O-isopropylidene-2-O-pivaloyl-1-thio-β-D-galactoside
(24). Synthesis of compound 24 was performed using procedures adapted from
Chan et al.29 A solution of 2326 (3.43 g, 13 mmol) in pyridine (21 mL) was cooled
to 0 °C and treated dropwise with pivaloyl chloride (8.5 mL, 69 mmol). The
reaction was then allowed to warm to room temperature and stirred overnight.
The mixture was then diluted with ethyl acetate, washed with dilute aqueous HCl
solution, saturated NaHCO3 solution, and brine. The organic layer was then dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (25% ethyl acetate in hexanes) to
afford compound 24 (4.46 g, 97%) as a white solid. Mp: 54-55 °C; [α] D 24 = +12.9
1
(c = 1.4, CH2Cl2); H NMR (500 MHz, CDCl3): δ 5.00 (dd, J = 10.2, 7.3 Hz, 1H),
4.32 (d, J = 10.2 Hz, 1H), 4.13 (dd, J = 7.2, 5.4Hz, 1H), 4.06 (dd, J = 5.3, 2.0 Hz,
1H), 3.87 (td, J = 6.5, 1.9 Hz, 1H), 2.76-2.69 (m, 1H), 2.68-2.62 (m, 1H), 1.57 (s,
3H), 1.42 (d, J = 6.5 Hz, 3H), 1.36 (s, 3H), 1.24 (d, J = 2.5 Hz, 3H), 1.23 (s, 9H);
13C NMR (125 MHz, CDCl3): δ 177.1, 110.1, 82.3, 76.8, 76.5, 72.7, 71.0, 38.7,
27.9, 26.5, 26.4, 23.6, 16.9, 14.8; LRMS (ESI) m/z: [M + Na]+ Calcd for
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C16H28O5SNa 355.16; Found 355.27; HRMS (DART) m/z: [M + NH4]+ Calcd for
C16H32NO5S 350.1996; Found 350.2002.
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Ethyl-6-deoxy-2-O-pivaloyl-1-thio-β-D-galactopyranoside (25). Synthesis
of compound 25 was performed using procedures adapted from van Boom et al.
26 A solution of 24 (2.79 g, 8.4 mmol) in acetic acid (41 mL) and water (10 mL)
was refluxed at 110 °C for 24 h. The reaction mixture was cooled to room
temperature. Upon cooling, the reaction was quenched with saturated NaHCO3
solution and extracted 3 times with CH2Cl2. The pooled organic layers were
washed with brine, dried over Na2SO4, filtered and concentrate in vacuo. The
residue was purified by flash column chromatography on silica gel (30% ethyl
acetate in hexanes) to afford compound 25 (1.56 g, 64%) as an amorphous solid.
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[α] D = –23.7 (c = 1.02, CH2Cl2); H NMR (500 MHz, CDCl3) δ 4.91 (t, J = 9.6
Hz, 1H), 4.41 (d, J = 10.0 Hz, 1H), 3.78 (ddd, J = 6.0, 3.5, 1.1 Hz, 1H), 3.72 –
3.63 (m, 2H), 2.96 (d, J = 7.5 Hz, 1H), 2.79 – 2.61 (m, 2H), 2.25 (d, J = 5.9 Hz,
1H), 1.37 (d, J = 6.5 Hz, 3H), 1.27 (t, J = 7.4 Hz, 3H), 1.25 (s, 9H); 13C NMR (125
MHz, CDCl3): δ 179.0, 82.9, 74.6, 74.2, 72.1, 71.4, 38.9, 27.1, 23.9, 16.6, 15.0;
LRMS (ESI) m/z: [M + Na]+ Calcd for C13H24O5SNa 315.12; Found 314.82;
HRMS (DART) m/z: [M + NH4]+ Calcd for C13H28NO5S 310.1683; Found
310.1693.
Ethyl-6-deoxy-3-O-(2-naphthylmethyl)-2-O-pivaloyl-1-thio-β-D-
galactopyranoside (26). Synthesis of compound 26 was performed using
procedures adapted from Takahashi et al.25 Compound 25 (1 g, 3.4 mmol) and
Bu2SnO (0.93 g, 3.7 mmol) were suspended in toluene (33 mL) at room
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temperature. The reaction mixture was stirred at reflux at 120 °C under Dean-
Stark conditions for 3 h, then cooled to room temperature. Tetrabutylammonium
iodide (0.25 g, 0.68 mmol) and 2-(bromomethyl)naphthylene (1.1 g, 5.1 mmol)
were added to the reaction mixture at room temperature. The reaction was
returned to reflux, stirred for 3 h, then allowed to cool to room temperature and
concentrated in vacuo. The crude residue was purified by flash column
chromatography on silica gel (20% to 30% ethyl acetate in hexanes) to afford
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compound 26 (680 mg, 46%) as an amorphous solid. [α] D = –20.8 (c = 1.06,
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CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.85 – 7.82 (m, 3H), 7.74 (s, 1H), 7.51 –
7.41 (m, 3H), 5.29 (t, J = 9.7 Hz, 1H), 4.80-4.79 (m, 2H), 4.33 (d, J = 10.0 Hz,
1H), 3.85 (s, 1H), 3.62 (dd, J = 9.4, 3.3 Hz, 1H), 3.58 (d, J = 6.3 Hz, 1H), 2.79-
13
2.64 (m, 2H), 2.43 (s, 1H), 1.36 (d, J = 6.5 Hz, 3H), 1.26 – 1.21 (m, 12H); C
NMR (125 MHz, CDCl3): δ 177.2, 134.9, 133.3, 133.2, 128.6, 128.0, 127.9,
126.6, 126.5, 126.3, 125.6, 83.2, 80.3, 74.6, 72.1, 69.4, 68.5, 38.9, 27.4, 23.4,
16.8, 14.9; LRMS (ESI) m/z: [M + Na]+ Calcd for C24H32O5SNa 455.19; Found
455.64; HRMS (DART) m/z: [M + NH4]+ Calcd for C24H36NO5S 450.2309; Found
450.2302.
Ethyl-6-Deoxy-4-O-benzyl-3-O-(2-naphthylmethyl)-2-O-pivaloyl-1-thio-β-D-
galactopyranoside (11). A solution of 26 (540 mg, 1.2 mmol), sodium hydride
(60% in mineral oil, 190 mg, 4.7 mmol) in DMF (8 mL) was cooled to 0 °C and
treated dropwise with benzyl bromide (0.29 mL, 2.4 mmol) and the reaction was
then allowed to warm to room temperature 1 h. The reaction mixture was
quenched with saturated aqueous NH4Cl solution. The reaction was diluted with
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Et2O and H2O, and extracted 3 times with Et2O. The pooled organic layers were
washed two times with H2O and brine, then dried over Na2SO4, filtered and
concentrate in vacuo. The residue was purified by flash column chromatography
on silica gel (10% to 15% ethyl acetate in hexanes) to afford compound 11
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(462.8 mg, 74%) as a white powder. Mp: 97-98 °C; [α] D = –4.0 (c = 0.97,
CH2Cl2); 1H NMR (500 MHz, CDCl3): δ 7.85-7.81 (m, 3H), 7.76 (s, 1H), 7.50-7.48
(m, 2H), 7.44-7.42 (m, 1H), 7.34-7.24 (m, 5H), 5.49 (t, J = 6.5 Hz, 1H), 5.00 (d, J
= 12.0 Hz, 1H), 4.79 (s, 2H), 4.68 (d, J = 11.5 Hz, 1H), 4.35 (d, J = 10.0 Hz, 1H),
3.67 (d, J = 2.7 Hz, 1H), 3.65 (s, 1H), 3.54 (q, J = 6.4 Hz, 1H), 2.79-2.72 (m, 1H),
2.71-2.64 (m, 1H), 1.25-1.22 (m, 15H); 13C NMR (125 MHz, CDCl3): δ 177.1,
138.7, 135.6, 133.4, 133.1, 128.4, 128.3, 128.2, 128.0, 127.9, 127.6, 126.4,
126.2, 126.1, 125.6, 83.5, 82.5, 76.1, 75.1, 74.5, 72.8, 69.3, 38.9, 27.4, 23.4,
17.4, 14.9; LRMS (ESI) m/z: [M + Na]+ Calcd for C31H38SO5Na 545.23; Found
545.35; HRMS (DART) m/z: [M + NH4]+ Calcd for C31H42NSO5 540.2778; Found
540.2783.
Phenyl-6-deoxy-2-O-pivaloyl-1-thio-β-D-galactopyranoside (28). Synthesis
of compound 28 was performed using procedures adapted from van Boom et
al.26 A solution of 2727 (1.92 g, 5.0 mmol) in acetic acid (24 mL) and water (6 mL)
was refluxed at 110 °C for 2 h. The reaction mixture was then allowed to cool to
room temperature. Upon cooling, the solution was diluted with CH2Cl2. The
mixture was washed with saturated NaHCO3 solution, brine, dried over Na2SO4,
filtered and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (50% ethyl acetate in hexanes) to afford compound
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28 (1.64 g, 96%) as a white powder. Mp: 149-150 °C; [α] D = –11.0 (c = 1.22,
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CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.53 – 7.45 (m, 2H), 7.36 – 7.28 (m, 3H),
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4.88 (t, J = 9.6 Hz, 1H), 4.64 (d, J = 10.1 Hz, 1H), 3.77 (ddd, J = 6.1, 3.4, 1.0 Hz,
1H), 3.74 – 3.64 (m, 2H), 2.97 (d, J = 7.5 Hz, 1H), 2.15 (d, J = 6.1 Hz, 1H), 1.39
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(d, J = 6.5 Hz, 3H), 1.28 (s, 9H); C NMR (125 MHz, CDCl3): δ 179.0, 133.2,
132.5, 129.1, 128.1, 86.2, 74.6, 74.5, 72.1, 71.4, 39.1, 27.3, 16.8; LRMS (ESI)
m/z: [M + Na]+ Calcd for C17H24O5SNa 363.12; Found 363.27; HRMS (DART)
m/z: [M + NH4]+ Calcd for C17H28NO5S 358.1683; Found 358.1682.
Phenyl-6-deoxy-3-O-benzyl-2-O-pivaloyl-1-thio-β-D-galactopyranoside
(14). Synthesis of 14 was performed using procedures adapted from Takahashi
et al.25 Compound 28 (250 mg, 0.74 mmol) and Bu2SnO (200 mg, 0.81 mmol)
were suspended in toluene (7 mL) at room temperature. The reaction mixture
was stirred at reflux at 130 °C under Dean-Stark conditions for 3 h, then cooled
to room temperature. Tetrabutylammonium iodide (54.3 mg, 0.15 mmol) and
benzyl bromide (0.13 mL, 1.1 mmol) were added to the reaction mixture at room
temperature. The reaction was returned to reflux, stirred for 3 h, then the reaction
mixture was allowed to cool to room temperature and concentrated in vacuo. The
crude product was purified by flash column chromatography on silica gel (30%
ethyl acetate in hexanes) to afford 14 (287.5 mg, 91%) as an amorphous solid.
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[α] D = +5.5 (c = 0.95, CH2Cl2); H NMR (500 MHz, CDCl3): δ 7.50-7.48 (m,
2H), 7.34-7.26 (m, 8H), 5.23 (t, J = 9.8 Hz, 1H), 4.66-4.58 (m, 3H), 3.84 (t, J =
2.5 Hz, 1H), 3.62-3.57 (m, 2H), 2.38 (s, 1H), 1.40 (d, J = 6.5 Hz, 3H), 1.24 (s,
9H); 13C NMR (125 MHz, CDCl3): δ 177.0, 137.4, 133.9, 132.2, 128.9, 128.7,
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128.2, 127.8, 127.7, 86.9, 80.4, 74.5, 71.9, 69.2, 68.6, 38.9, 27.3, 16.9; LRMS
(ESI) m/z: [M + Na]+ Calcd for C24H30O5SNa 453.17; Found 453.36; HRMS
(DART) m/z: [M + NH4]+ Calcd for C24H34NO5S 448.2152; Found 448.2155.
Phenyl-6-deoxy-4-O-(2-naphthylmethyl)-3-O-benzyl-2-O-pivaloyl-1-thio-β-
D-galactopyranoside (13). A solution of 14 (1.6 g, 3.7 mmol) and sodium hydride
(60% in mineral oil, 0.46 g, 11 mmol) in DMF (8.6 mL) was cooled to 0 °C and
treated with 2-(bromomethyl)naphthylene (1.6 g, 7.5 mmol) and then the reaction
was allowed to warm to room temperature. After being stirred overnight, the
reaction mixture was quenched using saturated NH4Cl aqueous solution. The
reaction was diluted with Et2O and H2O and extracted 3 times with Et2O. The
pooled organic layer was washed two times with H2O then washed with brine.
The pooled organic layers were dried over Na2SO4, filtered and concentrate in
vacuo. The residue was purified by column chromatography on silica gel (100%
toluene) to afford compound 13 (1.97 g, 91%) as a white powder. Mp: 86-87 °C;
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[α] D = +4.4 (c = 1.29, CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.82 – 7.75 (m,
3H), 7.67 (s, 1H), 7.50 – 7.45 (m, 5H), 7.35 – 7.30 (m, 5H), 7.26 – 7.17 (m, 3H),
5.51 (t, J = 9.8 Hz, 1H), 5.11 (d, J = 11.9 Hz, 1H), 4.82 (d, J = 11.9 Hz, 1H), 4.69
– 4.59 (m, 3H), 3.68 (d, J = 2.8 Hz, 1H), 3.64 (dd, J = 9.6, 2.7 Hz, 1H), 3.56 (q, J
= 6.9 Hz, 1H), 1.27 (d, J = 6.3 Hz, 3H), 1.24 (s, 9H); 13C NMR (125 MHz, CDCl3):
δ 176.8, 137.9, 135.9, 134.3, 133.1, 133.0, 131.8, 131.5, 128.7, 128.5, 127.9,
127.8, 127.7, 127.6, 127.4, 126.9, 126.5, 125.9, 125.8, 87.1, 82.6, 75.4, 74.9,
74.3, 72.7, 69.3, 38.8, 27.2, 17.4; LRMS (ESI) m/z: [M + Na]+ Calcd for
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C35H38O5SNa 593.23; Found 593.36; HRMS (DART) m/z: [M + NH4]+ Calcd for
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C35H42NO5S 588.2778; Found 588.2785.
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3-O-Benzyl-4-O-(2-naphthylmethyl)-6-deoxy-D-glucal (19).
Sodium
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hydride (60% by weight, 1 g, 27 mmol) and tetrabutylammonium iodide (664 mg,
1.8 mmol) were suspended in DMF (38 mL). The suspension was cooled to 0 °C
and treated with a solution of 2025 (2 g, 9.0 mmol) in DMF (15 mL), while
additional DMF (15 mL) was simultaneously added. After the mixture was stirred
for 10 min at 0 °C, 2-(bromomethyl)naphthalene (3.9 g, 18 mmol) in 10 mL DMF
was added dropwise to the mixture and the reaction was then allowed to warm to
room temperature. After being stirred for 2 h, the reaction mixture was quenched
with saturated aqueous NH4Cl and extracted three times with diethyl ether. The
pooled organic layers were washed with water and brine, and then dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (2% ethyl acetate in hexanes) to afford
compound 19 (2.9 g, 90%) as a white powder. Mp: 60-61 °C; [α] D 24 = –40.1 (c =
1.32, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.87–7.78 (m, 3H), 7.75 (s, 1H), 7.47
(ht, J = 5.3, 2.5 Hz, 3H), 7.34 (dt, J = 6.9, 2.1 Hz, 3H), 7.32–7.22 (m, 2H), 6.37
(d, J = 6.0 Hz, 1H), 5.03 (dd, J = 11.9, 4.1 Hz, 1H), 4.91–4.83 (m, 2H), 4.67 (dt, J
= 12.3, 2.9 Hz, 1H), 4.58 (dd, J = 11.6, 1.9 Hz, 1H), 4.26 (dd, J = 6.9, 2.9, 2.3 Hz,
1H), 4.04–3.94 (m, 1H), 3.54 (ddd, J = 8.7, 6.4, 1.9 Hz, 1H), 1.40 (dd, J = 6.4, 1.9
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 144.9, 138.5, 135.8, 133.4, 133.1, 128.5,
128.3, 128.0, 127.9, 127.8, 127.7, 126.8, 126.2, 126.1, 126.0, 100.2, 79.5, 76.6,
74.2, 74.1, 70.6, 17.7; LRMS (ESI) m/z: [M + NH4]+ Calcd for C24H28NO3 378.45;
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Found 378.02; HRMS (DART) m/z: [M + NH4]+ Calcd for C24H28NO3 378.2064;
Found 378.2076.
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3-O-(2-Naphthylmethyl)-4-O-benzyl-6-deoxy-D-glucal (21). Sodium
hydride (60% in mineral oil, 738 mg, 18 mmol) and tetrabutylammonium iodide
(679 mg, 1.8 mmol) were suspended in DMF (42 mL). The suspension was
cooled to 0 °C and treated with a solution of 2925 (2.5 g, 9.2 mmol) in DMF (10
mL), while additional DMF (10 mL) was simultaneously added. After the mixture
was stirred for 10 min at 0 °C, benzyl bromide (2.1 mL, 18 mmol) was added
dropwise to the mixture and the reaction was then allowed to warm to room
temperature. After being stirred for 3 h, the reaction mixture was quenched with
saturated aqueous NH4Cl and extracted three times with diethyl ether. The
pooled organic layers were washed with water and brine, and then dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (2% ethyl acetate in hexanes) afforded
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compound 21 (2.8g, 87%) as an amorphous solid: [α] D 24 = –54.4 (c = 1.14,
CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.90–7.67 (m, 4H), 7.57–7.37 (m, 3H),
7.37–7.17 (m, 5H), 6.37 (d, J = 6.1, 1.4 Hz, 1H), 4.98–4.83 (m, 2H), 4.82 (d, J =
12.0 Hz, 1H), 4.76–4.69 (m, 2H), 4.27 (dd, J = 6.6, 1.4 Hz, 1H), 3.96 (dq, J = 9.1,
6.5 Hz, 1H), 3.52 (dd, J = 9.0, 6.5 Hz, 1H), 1.39 (d, J = 6.4 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 144.9, 138.3, 136.0, 133.0, , 128.4, 128.2, 128.1, 128.0,
127.9, 127.8, 126.5, 126.5, 126.2, 126.0, 125.9, 100.3, 79.7, 76.6, 74.1, 70.8,
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; LRMS (ESI) m/z: [M + Na]+ Calcd for C24H24O3Na 383.16; Found 383.18;
HRMS (DART) m/z: [M + NH4]+ Calcd for C24H28NO3 378.2064; Found 378.2059.
3-O-Benzyl-4-O-(2-naphthylmethyl)-2,6-dideoxy-D-arabino-hexopyranose
(30). Synthesis of compound 30 was performed using procedures adapted from
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Blumenstein et al.30 To a solution of 19 (1.5 g, 5.2 mmol) in THF (20 ml), Ph3 HBr
.
(361 mg, 1.0 mmol) was added to the reaction and allowed to stir at room
temperature. After 10 min, H2O (0.47 ml, 26 mmol) was added to the reaction.
The reaction was stirred for 4 h. The reaction was quenched with saturated,
aqueous NaHCO3, diluted with ethyl acetate and water, and extracted 3 times
with ethyl acetate. The pooled organic layer was washed with H2O, brine, and
dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified
by flash column chromatography on silica gel (25% ethyl acetate in hexanes) to
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afford compound 30 (1.8 g, 94%) as a white powder. Mp: 150-151 °C; [α] D
=
+14.8 (c = 1.05, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.86–7.74 (m, 4H), 7.51 –
7.42 (m, 3H), 7.39–7.25 (m, 5H), 5.35 (d, J = 3.7 Hz, 1H), 5.11 (d, J = 11.2 Hz,
1H), 4.82 (d, J = 10.8 Hz, 1H), 4.73–4.63 (m, 2H), 4.09–3.97 (m, 2H), 3.20 (dd, J
= 19.2, 0.9 Hz, 1H), 2.38–2.30 (m, 2H), 1.70 (ddd, J = 13.2, 11.2, 3.6, 2.2 Hz,
1H), 1.30 (d, J = 6.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 138.7, 136.1, 133.39,
133.0, 128.6, 128.5, 128.2, 128.1, 128.0, 127.8, 127.77, 127.76, 127.7, 126.8,
126.7, 126.2, 126.1, 126.0, 125.9, 93.9, 92.1, 84.4, 83.5, 79.1, 76.9, 75.3, 75.28,
71.9, 71.6, 71.6, 67.5, 53.5, 38.5, 35.9, 18.4, 18.38; LRMS (ESI) m/z: [M + Na]+
Calcd for C24H26O4Na 401.17; Found 401.19; HRMS (DART) m/z: [M + NH4]+
Calcd for C24H30NO4 396.2169; Found 396.2157.
ACS Paragon Plus Environment