Notepubs.acs.org/joc

Formal Total Synthesis of L‑Ossamine via Decarboxylative
Functionalization Using Visible-Light-Mediated Photoredox Catalysis
in a Flow System
Shinsuke Inuki,† Keisuke Sato,† Takahide Fukuyama,‡ Ilhyong Ryu,‡ and Yukari Fujimoto*,††Graduate School of Science and Technology, Keio University, Yokohama, Kanagawa 223-8522, Japan
Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan‡S Supporting Information*

ABSTRACT: A formal total synthesis of L-ossamine was achieved. The key feature of the synthesis was the decarboxylative
functionalization of a threonine derivative using visible-light-mediated photoredox catalysis. This reaction was implemented in a
ﬂow reactor, allowing for the eﬃcient conversion to the desired product.

Dbulb. Visible-light-mediated decarboxylative functionalizationsof carboxylic acids and their derivatives present a promising
approach to new carbon−carbon or carbon−heteroatom bondformation.10 Oda and co-workers developed the photosensitized decarboxylative Michael addition of N-(acyloxy)phthalimides using Ru(bpy)3Cl2.11 MacMillan et al. reported anumber of decarboxylative functionalization reactions ofcarboxylic acids using photoredox catalysis.12 Recently, wedeveloped a decarboxylative benzoyloxylation of β-hydroxyamino acids in the presence of Ru(bpy)3Cl2 and benzoylperoxide (BzO)2.13 We focused on the visible-light-mediateddecarboxylative Michael addition of carboxylic acids12c andexpected that this type of transformation reaction of threonine
derivatives could provide ready access to the deoxyaminosugar,
ossamine. Furthermore, in order to enhance the visible-lightmediated photoredox catalysis, we planned to implement a
continuous ﬂow reactor.14 Recently, several groups reported
implementing the photoredox reactions in a ﬂow system,14b,15
which enabled eﬃcient conversions mainly by improving
irradiation of the reaction mixture as compared to batchprocessing.
The synthetic strategy for achieving L-ossamine is illustrated
in Scheme 1. The visible-light-mediated photoredox reaction of
the threonine derivative 1 and acrylic acid ester derivative 2 was
expected to enable carbon homologation and provide thefunctionalized 1,2-amino alcohol 3 for the synthesis ofossamine. This reaction proceeded through an α-amino radical
intermediate A, which could be generated from the threonine
derivative 1 via visible-light-mediated decarboxylation. The

eoxyaminosugar motifs occur in a number of biologically
active natural products and pharmaceuticals, including
aminoglycosides, macrolides, or anthracyclines, which playfundamental roles in regulating numerous biological processes.1
The development of eﬃcient methods for synthesizing
deoxyaminosugars is an important issue in the ﬁeld of organic
synthesis.2 A deoxyaminosugar, ossamine,3 is contained inossamycin4 derived from the bacterial species Streptomyces
hygroscopicus (Figure 1), which inhibits oxidative phosphor-

Figure 1. Structures of ossamycin and ossamine.

ylation by targeting the mitochondrial FOF1 ATP synthase.5
Ossamine and its analogues have been the target of synthetic
studies,6 and some groups have accomplished the total
synthesis of ossamine.3,7 Several groups have also reported
the total synthesis of epi-ossamine (forosamine).8
Visible-light-mediated photoredox reactions employing transition-metal complexes have received considerable attention inrecent years.9 These types of reactions enable mild and eﬃcienttransformations using a commercially available household light© 2016 American Chemical Society

Received: October 18, 2016
Published: December 20, 2016
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DOI: 10.1021/acs.joc.6b02531
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Scheme 1. Synthetic Strategy toward L-Ossamine via Decarboxylative Functionalization Using Visible-Light-Mediated
Photoredox Catalysis in a Flow System

Table 1. Initial Studies and Reaction Optimization

entryasubRphotoredox catalyst (mol %)

1
2
3
4
5
6
7
8
9
10
11
12e

5a
5a
5a
5a
5a
5a
5a
5b
5c
5d
5a
5a

Boc
Boc
Boc
Boc
Boc
Boc
Boc
CO2Me
Z
Troc
Boc
Boc

Ru(bpy)3Cl2·6H2O (1)Ir(ppy)3 (1)Ir[dF(CF3)ppy]2(dtbpy)PF6 (1)Ir[dF(CF3)ppy]2(dtbpy)PF6 (1)Ir[dF(CF3)ppy]2(dtbpy)PF6 (1)Ir[dF(CF3)ppy]2(dtbpy)PF6 (1)Ir[dF(CF3)ppy]2(dtbpy)PF6 (2)Ir[dF(CF3)ppy]2(dtbpy)PF6 (2)Ir[dF(CF3)ppy]2(dtbpy)PF6 (2)Ir[dF(CF3)ppy]2(dtbpy)PF6 (2)Ir[dF(CF3)ppy]2(dtbpy)PF6 (2)Ir[dF(CF3)ppy]2(dtbpy)PF6 (2)additive

solventyieldb,c (%)

H2O (10 equiv)
H2O (10 equiv)

DMF
DMF
DMF
EtOH
MeCN
dioxane
DMF
DMF
DMF
DMF
DMF
DMF

ND
ND
50 (41)ND
21
2273 (62)47(27)
39 (12)85 (79)62 (50)

drd

81:19

73:27
77:23
79:21
85:15
72:28
78:22
78:22

a

Reaction conditions: 0.1 mmol of substrate, 2.0 equiv of ethyl acrylate, 1.5 equiv of base, 1 or 2 mol % of photoredox catalyst at room temperature
with irradiation from a 6.5 W LED light bulb. bYields were determined by 1H NMR analysis. Yields of the isolated products are given in parentheses.
c
ND = not detected. dDetermined by 1H NMR analysis. eK2HPO4 was used instead of Cs2CO3. bpy = 2,2′-bipyridine; ppy = 2-phenylpyridine;dF(CF3)ppy = 2-(2,4-diﬂuorophenyl)-5-(triﬂuoromethyl)pyridine; dtbpy = 4,4′-di-tert-butyl-2,2′-bipyridine.

yield to 73% (entry 7). The use of N-CO2Me,17 Z, and Troc
derivatives (5b−d) decreased the yields of the desired products(entries 8−10). The addition of H2O produced the desired
product in 85% yield (entry 11). Recently, Overman et al.
reported that the presence of H2O improved the photoredox
reaction of oxalate salts.18 The use of K2HPO4 as a base
(optimal conditions, as reported by MacMillan et al.) was not
eﬀective (entry 12).12c
With optimized conditions in hand (Table 1, entries 7 and11), we next examined decarboxylative functionalizations of
threonine derivatives 719 and 8,20 which were easily preparedfrom D-threonine (Table 2). The reaction of oxazolizinone
derivative 7a under the optimized conditions (Table 1, entry 7)
gave a trace amount of the desired product (entry 1).
Introduction of a Boc group to the nitrogen atom provided
the desired product in low yield (entry 2). Next, the treatmentof Z-protected derivative 8a under the same conditions gave thedesired products 10a in low yields (entry 3). Changing fromthe Z to the Boc group enhanced the yield of desired product10b (70%) as a 65:35 diastereomixture (entry 4). The NMR
spectral data of major diastereomer were in agreement withthose reported by Pak et al.,21 which indicated that the majorintermediate A could react with acrylic acid derivatives 2 to givethe desired 1,2-amino alcohol 3, which could be converted to Lossamine through lactonization, reduction, and dimethylation.
It should be noted that in previous synthetic studies ofossamine the threonine-derived carboxylic acid 1 was converted
to compound 3 in at least four steps (esteriﬁcation of the
carboxylic acid 1, reduction to aldehyde, homologation, andreduction of the resulting oleﬁn),6 but this synthetic routeenables the direct introduction of C3 units at a 1,2 amino
alcohol under mild conditions.
Initially, we investigated model studies of a visible lightmediated photoredox reaction of the β-hydroxy amino acidderivatives 5a−d (Table 1). Treatment of 5a16 and ethyl
acrylate with 1 mol % Ru(bpy)3Cl2·6H2O or Ir(ppy)3 as aphotoredox catalyst, along with Cs2CO3 in DMF underirradiation with visible light, did not aﬀord the desired product.
Next, referring to MacMillan’s report,12c we used Ir[dF(CF3)ppy]2(dtbpy)PF6 as a photoredox catalyst to give the desired
product 6a in 50% yield as a 81:19 diastereomixture (entry 3).
Changing the solvent from DMF to EtOH, MeCN, or dioxane
did not enhance the yield of the desired product. Increased
loading of the photoredox catalyst (2 mol %) improved the1249

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Table 2. Decarboxylative Functionalization of Threonine Derivatives

entrya

sub

R1

1
2
3
4
5

7a
7b
8a
8b
8b

H
Boc

R2

solvent

time (h)products

yieldb (%)

drc

Z
Boc
Boc

DMF
DMF
DMF
DMF
DMF/H2O (10:1)

42
48
43
45
47

9a
9b
10a
10b
10b

trace
20
14
70
50

60:40
65:35
61:39

a

Reaction conditions: 0.1 mmol of substrate, 2.0 equiv of methyl acrylate, 1.5 equiv of base, 2 mol % of photoredox catalyst at room temperature
with irradiation from a 6.5 W LED light bulb. bIsolated yields. cDetermined by 1H NMR analysis. dF(CF3)ppy = 2-(2,4-diﬂuorophenyl)-5(triﬂuoromethyl)pyridine; dtbpy = 4,4′-di-tert-butyl-2,2′-bipyridine.

diastereomer had the trans-conﬁguration. In order to increase
the eﬃciency of the reaction and conduct it on a larger scale, weplanned to apply this reaction to continuous ﬂow chemistry.
The optimized conditions described above (Table 1, entries 7
and 11) were heterogeneous, which is unsuitable for the ﬂow
reactor. Therefore, the reaction conditions were modiﬁed tohomogenize the reaction mixture. When DMF/H2O (10:1) wasused as a solvent, the reaction mixture was dissolved, and thedesired product 10b was obtained in 50% yield (entry 5). Next,
we performed the reaction using continuous ﬂow reactor as
shown in Scheme 2 and Figure 2. The ﬂow reaction in 4 hunder acidic conditions gave the diastereomixture of the lactone
116b (63% yield), which was diﬃcult to separate. Removal of
the isopropylidene group, separation of the resulting 1,2-amino
alcohol, and lactonization thus aﬀorded the desired lactone 11.
The lactone 11 was converted into the corresponding Zprotected lactone 12 by treatment with TFA, followed by ZCl
and Et3N. Reduction of the lactone with DIBAL-H and theformation of ethyl acetal provided 14. Finally, removal of the Zgroup using Pd(OH)2 and hydrogen led to the amine 15, theenantiomer of which, ent-15, has been described by Voelter et
al. where the conversion from ent-15 to D-ossamine wasreported.7b The conversion of 14 to an acetyl amide derivative
16 was carried out for spectral analysis (eq 1). The NMR
spectral data agreed well with the data reported for ent-16.7b

Scheme 2. Continuous Flow Decarboxylative
Functionalization of Threonine Derivatives

In conclusion, we accomplished the formal total synthesis of
the deoxyaminosugar L-ossamine starting from threonine. Thissynthetic route features the visible-light-mediated decarboxylative functionalization of β-hydroxy amino acids, whichallowed direct access to the core structure of thedeoxyaminosugar from the threonine derivative. Implementation of this reaction in the continuous ﬂow reactor improved
the eﬃciency of the photoredox catalysis reaction.

■

residence time under irradiation of a 48 W LED lamp using a 3
mL reactor provided full conversion of the starting material tothe desired product 10b in 80% yield (50% yield in 47 h inbatch, Table 2, entry 5). Using the photo ﬂow reactor could
allow the enhancement of irradiation per unit volume to havesigniﬁcant eﬀects on the photoredox reaction course.
With the requisite carbon framework 10b in hand, we next
examined the conversion to L-ossamine (Scheme 3). Removalof the isopropylidene group with the simultaneous lactonization

EXPERIMENTAL SECTION

General Methods. All moisture-sensitive reactions were performed using syringe−septum cap techniques under an argon
atmosphere, and all glassware was dried in an oven at 80 °C for 2 hprior to use. Reactions at −78 °C employed a CO2−MeOH bath.
Analytical thin-layer chromatography (TLC) was performed on silica
gel 60 F254 plates (0.25 mm thickness). For ﬂash chromatography,
silica gel 60 N [spherical neutral (40−50 μm)] was employed. Melting
points were measured by a hot-stage melting point apparatus
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Figure 2. (a) Flow reactor for photoreactions (2 mm width, 0.5 mm depth, 3 m length, MiChS Co., Ltd.). (b) Flow reactor setup for the visiblelight-mediated decarboxylative functionalization.

Scheme 3. Formal Total Synthesis of L-Ossamineand dried over Na2SO4. The ﬁltrate was concentrated under reducedpressure to give an oily residue, which was puriﬁed by ﬂash
chromatography over silica gel with n-hexane−EtOAc (6:1) to give
6a as a colorless oil (25.9 mg, 79% yield, dr = 78:22). The ratio of thediastereomer were determined by 1H NMR analysis. 6a: 1H NMR(400 MHz, CDCl3) δ 5.06 (s, 1H), 4.20 (dd, J = 8.3, 6.3 Hz, 1H), 4.12
(q, J = 7.2 Hz, 2H), 3.92−3.87 (m, 1H), 3.74 (dd, J = 8.3, 2.4 Hz, 1H),
2.24−2.14 (m, 2H), 2.22−2.05 (m, 2H), 1.48 (s, 9H), 1.24 (t, J = 7.2
Hz, 3H), 0.93 (s, 9H); 13C NMR (400 MHz, CDCl3) δ 173.3, 151.9,
93.7, 79.8, 74.7, 62.5, 51.4, 29.7, 28.1 (3C), 28.0, 27.0, 26.5 (3C), 20.0;
HRMS (ESI) (m/z) calcd for C17H31NNaO5 [M + Na]+ 352.2094,
found 352.2103.
Benzyl (5S)-4-(3-Methoxy-3-oxopropyl)-2,2,5-trimethyloxazolidine-3-carboxylate (10a). By a procedure identical with that
described for synthesis of 6a from 5a (Table 1, entry 7), thecarboxylic acid 8a (27.9 mg, 0.10 mmol) and methyl acrylate (17.9μmol, 0.20 mmol) were converted into 10a as a colorless oil (4.7 mg,
14% yield, dr = 60:40). The ratio of the diastereomer was determinedby 1H NMR analysis: 1H NMR of major isomer (400 MHz, CDCl3) δ
7.38−7.30 (m, 5H), 5.14 (s, 2H), 4.00−3.93 (m, 1H), 3.72−3.60 (m,1H), 3.57 (s, 3H), 2.49−2.20 (m, 2H), 2.16−1.89 (m, 2H), 1.68−1.45(m, 6H), 1.31 (d, J = 6.3 Hz, 3H); 1H NMR of minor isomer (400
MHz, CDCl3) δ 7.38−7.30 (m, 5H), 5.19 (d, J = 12.6 Hz, 1H), 5.01
(d, J = 12.6 Hz, 1H), 4.25−4.18 (m, 1H), 4.00−3.88 (m, 1H), 3.67 (s,3H), 2.49−2.20 (m, 2H), 2.16−1.89 (m, 2H), 1.68−1.45 (m, 6H),
1.27 (d, J = 6.3 Hz, 3H); 13C NMR of major isomer (400 MHz,CDCl3) δ 173.5, 152.4, 136.3, 128.5 (2C), 128.1(2C), 128.0, 93.2,
75.3, 66.7, 62.4, 51.4, 30.7, 27.0, 24.8, 23.5, 20.3; HRMS (ESI) (m/z)
calcd for C18H25NNaO5 [M + Na]+ 358.1625, found 358.1620.
tert-Butyl (5S)-4-(3-Methoxy-3-oxopropyl)-2,2,5-trimethyloxazolidine-3-carboxylate (10b). By a procedure identical with that
described for the synthesis of 6a from 5a (Table 1, entry 7), thecarboxylic acid 8b (25.9 mg, 0.10 mmol) and methyl acrylate (17.9μmol, 0.20 mmol) were converted into 10b as a colorless oil (21.1 mg,
70% yield, dr = 65:35). The ratio of the diastereomers was determinedby 1H NMR analysis: 1H NMR of major isomer (400 MHz, CDCl3) δ
3.98−3.90 (m, 1H), 3.68 (s, 3H), 3.58−3.42 (m, 1H), 2.39−2.28 (m,2H), 2.12−1.97 (m, 2H), 1.60 (s, 3H), 1.53−1.44 (m, 12H), 1.31 (d, J(uncorrected). Optical rotations were measured with a polarimeter. All
NMR spectral data were recorded on an NMR spectrometer for 1H(400 MHz) and 13C (100 MHz). Chemical shifts are reported in δ(ppm) relative to TMS in CDCl3 as internal standard (1H NMR) or
the residual CHCl3 signal (13C NMR). 1H NMR spectra are tabulated
as follows: chemical shift, multiplicity (b = broad, s = singlet, d =doublet, t = triplet, q = quartet, m = multiplet), number of protons,
and coupling constant(s). Exact mass (HRMS) spectra were recordedon an electronspray ionization quadrupole time-of-ﬂight (ESI-QTOF)
mass spectrometer. Microﬂow photoredox reactions were carried out
by using a photoreactor, MiChS L (2 mm width, 0.5 mm depth, 3 mlength, MiChS Co., Ltd.).
General Procedure for Visible-Light-Mediated Decarboxylative Functionalization: tert-Butyl (2R)-2-tert-Butyl-4-(3-ethoxy3-oxopropyl)oxazolidine-3-carboxylate (6a). Decarboxylative
Functionalization Reaction (Table 1, Entry 7). To a dried Pyrex
tube equipped with a stir bar were added 5a (27.3 mg, 0.10 mmol),Ir[dF(CF3)ppy]2(dtbpy)PF6 (2.24 mg, 2.0 μmol), and Cs2CO3 (48.9
mg, 0.15 mmol). After the vial was sealed, evacuated, and backﬁlledwith argon, DMF (3.3 mL) and ethyl acrylate (21.8 μmol, 0.20 mmol)
were added to the vial. The reaction was stirred and irradiated withtwo 6.5 W LED bulbs until complete consumption of carboxylic acid5a. The mixture was diluted with saturated NaHCO3 aq. The wholewas extracted twice with Et2O. The extract was washed with saturated
NaHCO3 aq and H2O and dried over Na2SO4. The ﬁltrate wasconcentrated under reduced pressure to give an oily residue, which was
puriﬁed by ﬂash chromatography over silica gel with n-hexane−EtOAc(6:1) to give 6a as a colorless oil (20.3 mg, 62% yield, dr = 77:23). The
ratio of the diastereomer were determined by 1H NMR analysis.
Decarboxylative Functionalization Reaction in the Presence ofH2O (Table 1, Entry 11). To a dried Pyrex tube equipped with a stir
bar were added 5a (27.3 mg, 0.10 mmol), Ir[dF(CF3)ppy]2(dtbpy)PF6(2.24 mg, 2.0 μmol), and Cs2CO3 (48.9 mg, 0.15 mmol). After the vial
was sealed, evacuated, and backﬁlled with argon, DMF (3.3 mL), H2O(18 μL), and ethyl acrylate (21.8 μmol, 0.20 mmol) were added to thevial. The reaction was stirred and irradiated with two 6.5 W LED bulbs
until complete consumption of carboxylic acid 5a. The mixture wasdiluted with saturated NaHCO3 aq. The whole was extracted twicewith Et2O. The extract was washed with saturated NaHCO3 aq., H2O
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4.24−4.15 (m, 1H), 3.71−3.41 (m, 4H), 2.39−2.28 (m, 2H), 2.12−
1.97 (m, 2H), 1.59−1.44 (m, 15H), 1.25 (d, J = 6.3 Hz, 3H); 13C
NMR of major isomer (400 MHz, CDCl3) δ 173.3, 151.9, 93.7, 79.8,
74.7, 62.5, 51.4, 29.7, 28.1 (3C), 28.0, 27.0, 26.5, 20.0; HRMS (ESI)(m/z) calcd for C15H27NNaO5 [M + Na]+ 324.1781, found 324.1775.
All spectral data were in agreement with those reported for ent-10b by
Pak et al.21
General Procedure for Visible-Light-Mediated Decarboxylative Functionalization Using a Flow System. To a dried roundbottom ﬂask equipped with a stir bar were added 8b (117 mg, 0.45mmol), Ir[dF(CF3)ppy]2(dtbpy)PF6 (10.2 mg, 9.0 μmol), andCs2CO3 (222 mg, 0.68 mmol). After the ﬂask was sealed, evacuated,and backﬁlled with argon, DMF (13.6 mL), H2O (1.36 mL), andmethyl acrylate (81.4 μmol, 0.90 mmol) were added to the ﬂask. The
mixture was pumped into a ﬂow reactor (2 mm width, 0.5 mm depth,
3 m length, MiChS Co., Ltd.) at room temperature by a syringe pumpat a ﬂow rate of 0.75 mL/h (residence time: 4.0 h) and irradiated witha 48 W LED bulb. The product stream was collected into an
Erlenmeyer ﬂask. The mixture was collected for 6 mL in total, anddiluted with saturated NaHCO3 aq. The whole was extracted twicewith Et2O. The extract was washed with saturated NaHCO3 aq andH2O and dried over Na2SO4. The ﬁltrate was concentrated under
reduced pressure to give an oily residue, which was puriﬁed by ﬂash
chromatography over silica gel with n-hexane−EtOAc (6:1) to give
10b as colorless oil. The ratio of the diastereomers was determined by
1
H NMR analysis.
tert-Butyl [(2S,3S)-2-Methyl-6-oxotetrahydro-2H-pyran-3-yl] Carbamate (11). One-Step Process. To a stirred solution of 10b (42.7
mg, 0.14 mmol) in benzene (1.0 mL) was added acetic acid (0.50 mL)
at 100 °C. After being stirred for 24.0 h at the same temperature, themixture was concentrated under reduced pressure to give an oily
residue, which was puriﬁed by ﬂash chromatography over silica gelwith n-hexane−EtOAc (2:1) to give 11 as a colorless oil (20.3 mg,
63% yield, 62:38 diastereomixture). All spectral data were inagreement with those reported by Nishiyama et al.6b
Two-Step Process. To a stirred solution of 10b (37.5 mg, 0.12mmol) in MeOH was added CSA (2.9 mg, 12 μmol) at room
temperature. After being stirred for 2.0 h at the same temperature, themixture was quenched with H2O. The whole was extracted twice with
Et2O. The combined organic layers were washed with saturated
NaHCO3 aq and dried over Na2SO4. The ﬁltrate was concentrated
under reduced pressure to give an oily residue, which was puriﬁed byﬂash chromatography over silica gel with n-hexane−EtOAc (2:1) togive the 1,2-amino alcohol as a colorless oil (24.6 mg, 76% yield,
diasteromixture). The pure diastereomer of amino alcohol was isolated
by ﬂash chromatography over silica gel with n-hexane−EtOAc (2:1).
To a stirred solution of the above pure diastereomer of amino alcohol(71.0 mg, 0.27 mmol) in benzene (2.0 mL) was added acetic acid (1.0mL) at 100 °C. After being stirred for 16.5 h at the same temperature,
the mixture was concentrated under reduced pressure to give an oily
residue, which was puriﬁed by ﬂash chromatography over silica gelwith n-hexane−EtOAc (3:2) to give 11 as a colorless oil (66.7 mg,
quant.).
Benzyl [(2S,3S)-2-Methyl-6-oxotetrahydro-2H-pyran-3-yl] Carbamate (12). To a stirred solution of 11 (48.8 mg, 0.213 mmol) in
CH2Cl2 (1.6 mL) at 0 °C was added triﬂuoroacetic acid (0.40 mL),and the mixture was stirred for 2.0 h at room temperature. The
mixture was concentrated under reduced pressure, and the residue wasdissolved in THF (2 mL). To the solution at 0 °C were added ZCl(33.8 μL, 0.234 mmol) and dropwise Et3N (75.7 μL, 0.533 mmol).
After being stirred for 13.0 h at room temperature, the mixture wasquenched with saturated NaHCO3 aq. The whole was extracted twicewith Et2O. The combined organic layers were washed with saturated
NaHCO3 aq and dried over Na2SO4. The ﬁltrate was concentrated
under reduced pressure to give an oily residue, which was puriﬁed byﬂash chromatography over silica gel with n-hexane−EtOAc (1:1) togive 12 as colorless oil (40.9 mg, 73% yield): [α]28D −32.1 (c 1.74,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.37−7.28 (m, 5H), 5.88 (d,J = 8.8 Hz, 1H), 5.10 (s, 2H), 4.51−4.43 (m, 1H), 4.07 (m, 1H),

2.57−2.44 (m, 2H), 2.21−2.08 (m, 1H), 1.97−1.87 (m,1H), 1.30 (d, J= 6.3 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 171.5, 156.3, 136.2,
128.3 (2C), 128.0, 127.7 (2C), 77.2, 66.7, 47.0, 25.8, 25.3, 16.8;
HRMS (ESI) (m/z) calcd for C14H17NNaO4 [M + Na]+ 286.1050,
found 286.1052.
Benzyl [(2S,3S)-6-Hydroxy-2-methyltetrahydro-2H-pyran-3-yl]
Carbamate (13). To a stirred solution of 12 (40.9 mg, 0.155mmol) in CH2Cl2 (2 mL) was added DIBAL-H in n-hexane (1.03 M;
202 μL, 0.208 mmol) at −78 °C. After being stirred for 1.0 h at thistemperature, the mixture was quenched with MeOH and saturated
Rochelle salt aq. After being stirred for 5.5 h at room temperature, thewhole was extracted twice with CH2Cl2. The combined organic layers
were dried over Na2SO4, and the ﬁltrated was concentrated under
reduced pressure to give an oily residue, which was puriﬁed by ﬂash
chromatography over silica gel with n-hexane−EtOAc (1:1) to give 13
as a colorless oil (35.4 mg, 86% yield, 62:38 anomeric mixture): [α]28D−7.58 (c 1.03, CHCl3); 1H NMR (400 MHz, CDCl3) of majoranomer δ 7.39−7.29 (m, 5H), 5.53 (d, J = 9.3 Hz, 1H), 5.11 (s, 2H),
4.82−4.74 (m, 1H), 3.77−3.71 (m, 2H), 2.13−1.95 (m, 2H), 1.85−
1.67 (m, 2H), 1.19 (d, J = 6.3 Hz, 3H); 1H NMR (400 MHz, CDCl3)of minor anomer: δ 7.39−7.25 (m, 5H), 5.32 (d, J = 9.3 Hz, 1H),
5.23−5.12 (m, 1H), 5.11 (s, 2H), 4.37−4.31 (m, 1H), 3.70−3.63 (m,1H), 1.84−1.66 (m, 2H), 1.52−1.39 (m, 2H), 1.11 (d, J = 6.3 Hz,3H); 13C NMR (400 MHz, CDCl3) of major anomer δ 156.2, 136.5,
128.5 (2C), 128.0 (2C), 127.9, 96.3, 73.2, 66.6, 47.8, 27.9, 23.3, 17.6;
13
C NMR (400 MHz, CDCl3) of minor anomer: δ 156.2, 136.4, 128.5(2C), 128.1 (2C), 127.9, 91.5, 66.7, 65.3, 48.7, 27.3, 24.2, 17.5; HRMS
(ESI) (m/z) calcd for C14H19NNaO4 [M + Na]+ 288.1206, found288.1207.
Benzyl [(2S,3S)-6-Ethoxy-2-methyltetrahydro-2H-pyran-3-yl] Carbamate (14). To a stirred solution of 13 (42.09 mg, 0.159 mmol) in
EtOH (2.6 mL) was added p-toluenesulfonic acid monohydrate (3.02
mg, 15.9 μmol) at room temperature. After being stirred for 3.0 h at 70°C, the mixture was quenched with H2O. The whole was extracted
twice with Et2O. The combined organic layers were washed withsaturated NaHCO3 aq and dried over Na2SO4. The ﬁltrate wasconcentrated under reduced pressure to give an oily residue, which was
puriﬁed by ﬂash chromatography over silica gel with n-hexane−EtOAc(3:1) to give 14 as colorless oil (30.0 mg, 64% yield, 65:35 anomericmixture): 1H NMR (400 MHz, CDCl3) of major anomer δ 7.39−7.25(m, 5H), 5.26 (d, J = 9.3 Hz, 1H), 5.11 (s, 2H), 4.79−4.73 (m, 1H),
4.12−4.05 (m, 1H), 3.72−3.63 (m, 2H), 3.48−3.40 (m, 1H), 2.09−
1.91 (m, 2H), 1.79−1.65 (m, 2H), 1.27−1.14 (m, 3H), 1.10 (d, J = 6.3
Hz, 3H); 1H NMR (400 MHz, CDCl3) of minor anomer δ 7.39−7.25(m, 5H), 5.33 (d, J = 9.3 Hz, 1H), 5.10 (s, 2H), 4.46−4.41 (m, 1H),
3.98−3.90 (m, 1H), 3.72−3.65 (m, 2H), 3.55−3.47 (m, 1H), 1.79−
1.66 (m, 2H), 1.62−1.46 (m, 2H), 1.27−1.15 (m, 3H), 1.20−1.15 (m,3H); 13C NMR (400 MHz, CDCl3) of major anomer δ 156.2, 136.5,
128.5 (2C), 128.0 (2C), 127.7, 96.8, 66.7, 65.0, 62.6, 48.8, 28.1, 24.1,
17.5, 15.1; 13C NMR (400 MHz, CDCl3) of minor anomer δ 156.2,
136.6, 128.4 (2C), 128.1 (2C), 127.9, 101.9, 72,9, 66.5, 64.3, 48.1,
26.1, 24.3, 17.5, 15.1; HRMS (ESI) (m/z) calcd for C16H23NNaO4 [M+ Na]+ 316.1519, found 316.1522.
(2S,3S)-6-Ethoxy-2-methyltetrahydro-2H-pyran-3-amine−Hydrogen p-Toluenesulfonate (15). To a stirred solution of 14 (30.0 mg,
0.102 mmol) in EtOH (1 mL) was added Pd(OH)2/C (20% on
charcoal, 6.00 mg, 8.55 μmol) at room temperature. After being stirred
for 14.0 h under a H2 atmosphere (3 bar) at the same temperature, themixture was ﬁltered through a Celite pad, and the ﬁltrate wasconcentrated in vacuo. The residue was taken up in Et2O and treatedwith an ethereal solution of p-toluenesulfonic acid, and the mixture
was ﬁltered to give 15 as a white amorphous solid (17.96 mg, 53%
yield, 63:37 anomeric mixture): mp 125−126 °C [lit.7b mp 145−146°C (the anomeric ratio was not shown in the literature)]; 1H NMR(400 MHz, CDCl3) of major anomer δ 7.75 (d, J = 8.3 Hz, 2H), 7.13
(d, J = 8.3 Hz, 2H), 4.67−4.63 (m, 1H), 4.02−3.95 (m, 1H), 3.66−
3.56 (m, 1H), 3.43−3.33 (m, 1H), 3.26 (m, 1H), 2.35 (s, 3H), 2.07−
1.87 (m, 2H), 1.45−1.37 (m, 2H), 1.21−1.12 (m, 6H); 1H NMR (400
MHz, CDCl3) of minor anomer δ 7.75 (d, J = 8.3 Hz, 2H), 7.13 (d, J =8.3 Hz, 2H), 4.43−4.38 (m, 1H), 3.91−3.82 (m, 1H), 3.71−3.61 (m,1252

DOI: 10.1021/acs.joc.6b02531
J. Org. Chem. 2017, 82, 1248−1253

Note

The Journal of Organic Chemistry1H), 3.52−3.43 (m, 2H), 3.29 (m, 1H), 2.35 (s, 3H), 1.79−1.64 (m,2H), 1.63−1.54 (m, 2H), 1.25 (d, J = 6.3 Hz, 3H), 1.21−1.12 (m,3H); 13C NMR (400 MHz, CDCl3) of major anomer: δ 141.6, 140.2,
128.8 (2C), 126.1 (2C), 96.4, 63.2, 62.6, 49.4, 22.9, 22.1, 21.3, 17.2,
15.2; 13C NMR (400 MHz, CDCl3) of minor anomer δ 141.6, 140.2,
128.8 (2C), 126.1 (2C), 101.6, 71.3, 63.7, 48.6, 25.8, 25.0, 21.3, 17.2,
15.0; HRMS (ESI) (m/z) calcd for C8H17NNaO2 [M + Na]+
182.1151, found 182.1150.
N-[(2S,3S)-6-Ethoxy-2-methyltetrahydro-2H-pyran-3-yl]acetamide (16). To a stirred solution of 14 (25.6 mg, 87.3 μmol) in
EtOH (1 mL) was added Pd(OH)2/C (20% on charcoal, 5.10 mg,
7.27 μmol) at room temperature. After being stirred for 18.0 h under a
H2 atmosphere (3 bar) at the same temperature, the mixture wasﬁltered through a Celite pad, and the ﬁltrate was concentrated under
reduced pressure to give a crude amine, which was used without
further puriﬁcation. To a stirred solution of the above amine inpyridine (0.40 mL) was added acetic anhydride (0.20 mL) at room
temperature. After being stirred for 20.0 h at the same temperature,
the mixture was diluted with CH2Cl2, washed with 1 M HCl, H2O,
saturated NaHCO3 aq, and brine, and dried over Na2SO4. The ﬁltrate
was concentrated in vacuo to give 16 as a white amorphous solid (5.25
mg, 21% yield, 58:42 anomeric mixture): mp 113−114 °C [lit.7b mp
150−151 °C (the anomeric ratio was not shown in the literature)]; 1H
NMR (400 MHz, CDCl3) of major anomer δ 4.83−4.76 (m, 1H),
4.14−4.06 (m, 1H), 3.96−3.91 (m, 1H), 3.73−3.64 (m, 1H), 3.48−
3.41 (m, 1H), 2.04 (s, 3H), 1.79−1.56 (m, 4H), 1.28−1.18 (m, 3H),
1.08 (d, J = 6.3 Hz, 3H); 1H NMR (400 MHz, CDCl3) of minor
anomer δ 4.48−4.42 (m, 1H), 4.00−3.94 (m, 1H), 3.93−3.88 (m,1H), 3.72−3.66 (m, 1H), 3.60−3.51 (m, 1H), 2.01(s, 3H), 1.79−1.56(m, 4H), 1.28−1.18 (m, 3H), 1.17 (d, J = 6.3 Hz, 3H); 13C NMR (400
MHz, CDCl3) of major anomer δ 169.8, 96.8, 65.0, 64.5, 46.9, 24.5,
23.8, 23.5, 17.6, 15.1; 13C NMR (400 MHz, CDCl3) of minor anomer
δ 169.8, 102.7, 72.9, 62.7, 46.3, 27.8, 26.3, 23.4, 17.6, 15.1; HRMS
(ESI) (m/z) calcd for C10H19NNaO3 [M + Na]+ 224.1257, found224.1254.

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ASSOCIATED CONTENT

S Supporting Information*

The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b02531.

■

NMR spectra for all new compounds (PDF)

AUTHOR INFORMATION

Corresponding Author*E-mail: fujimotoy@chem.keio.ac.jp.
ORCID

Yukari Fujimoto: 0000-0001-5320-3192
Notes

The authors declare no competing ﬁnancial interest.

■

ACKNOWLEDGMENTS
This research was ﬁnancially supported by grants from theGrant-in-Aid for Scientiﬁc Research (Nos. JP26282211,
JP26102732, JP26882036, JP16H01162, and JP16K16638),
the Mizutani Foundation for Glycoscience, and the Nagase
Science Technology Foundation and Protein Research
Foundation. We thank Prof. K. Suenaga for assistance inmeasuring the chiroptical data.

■

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Tetrahedron Lett. 1969, 10, 1181.
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DOI: 10.1021/acs.joc.6b02531
J. Org. Chem. 2017, 82, 1248−1253