Chemical synthesis of 1-deoxy-L-fructose and L-sorbose through carbonyl translocation

Article abstract of DOI:10.1002/ejoc.201403196

Two rare sugars - 1-deoxy-L-fructose and L-sorbose - were synthesized from inexpensive starting materials by a carbonyl translocation method developed in our laboratory. Reduction of a known starting compound gave a 1,5-diol derivative. Selective protecti

Full text of DOI:10.1002/ejoc.201403196

Job/Unit: O43196
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Date: 21-11-14 11:28:13
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FULL PAPER
DOI: 10.1002/ejoc.201403196
Chemical Synthesis of 1-Deoxy-
L
-fructose and
L-Sorbose Through Carbonyl
Translocation
Hsin-Pei Wu,[a] Nai-Yun Hsu,[a] Tai-Ni Lu,[a] and Che-Chien Chang*[a]
Keywords: Synthetic methods / Carbohydrates / Deoxysugars / Rare sugars
Two rare sugars – 1-deoxy-
L-fructose and
L-sorbose – were
from the known starting material in five steps and in a total
synthesized from inexpensive starting materials by a carb- yield of 42%. This approach represents the first report of a
onyl translocation method developed in our laboratory. Re-
duction of a known starting compound gave a 1,5-diol deriv-
ative. Selective protection of the corresponding primary
alcohol and oxidation of the secondary alcohol provided the
chemical synthesis of 1-deoxy-
was applied to convert inexpensive
which was prepared in five steps from a known starting ma-
terial in a total yield of 55%. The synthetic methods repre-
L
-fructose. A similar strategy
D
-glucose into -sorbose,
L
desired product in acyclic, protected form. Subsequent de- sent a complementary method to biological approaches for
protection resulted in the production of 1-deoxy-
L-fructose
the synthesis of vitamin C.
masked carbonyl carbon (anomeric carbon) of the sugar
has to be reduced to give a diol derivative. Selective protec-
tion of the corresponding primary alcohol, oxidation of the
secondary alcohol, and subsequent deprotection affords the
desired rare sugars.
Introduction
Deoxysugars, an important class of carbohydrates, occur
widely in nature. They are found in liposaccharides, glyco-
proteins, and glycolipids on bacterial cell surfaces.[1] 2-
Deoxy-d-ribose is, of course, a component of DNA. Syn-
thesis[2] of its l-configured counterpart, 2-deoxy-l-ribose, is
important because it is used in studies involving nucleic acid
recognition[3] and antitumor agents.[4] A number of syn-
thetic and biochemical methods for preparing rare deoxy-
sugars have been developed.[5] However, most involve con-
siderable labor or the use of expensive starting materials
and reagents,[6] thus making them poorly amenable for use
in an industrial production process. Hence, a general and
practical method for the synthesis of rare sugars from
inexpensive starting materials would be highly desirable.
A synthetic methodology for preparation of the rare 2-
deoxy-l-ribose through carbonyl translocation has recently
been developed in this laboratory.[2a] The method is based
on a radical process involving carbonyl translocation and
represents an alternative and efficient approach to the syn-
thesis of rare 2-deoxy-l-sugars from inexpensive starting
materials: namely, d-sugars. However, to prepare other rare
non-deoxysugars by this carbonyl translocation process, a
new synthetic approach that does not involve the use of the
radical process was needed. A schematic representation of
a highly efficient and simple method involving carbonyl
translocation for the synthesis of rare sugars is shown in
Scheme 1. To achieve such a carbonyl translocation, the
Scheme 1. A new synthetic method involving carbonyl trans-
location.
Here we report on the synthesis of two examples – 1-
deoxy-l-fructose and l-sorbose – by this new synthetic
methodology.
1-Deoxy-d-fructose has been shown to serve as a poten-
tial metabolic inhibitor and an antimetabolite.[7] Its synthe-
sis from d-arabinose was successfully developed by Fleet
and co-workers.[7b] Although the same strategy could also
be applied to prepare 1-deoxy-l-fructose from l-arabinose,
an alternative synthetic approach for an efficient synthesis
of 1-deoxy-l-fructose could lead to the development of
additional potential inhibitors. The current methods for
[a] Department of Chemistry, Fu Jen Catholic University,
New Taipei City, Taiwan, 24205, R.O.C
E-mail: 080686@mail.fju.edu.tw
http://140.136.176.3/joom/data/eng/Faculty/C-C%20Chang.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403196.
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H.-P. Wu, N.-Y. Hsu, T.-N. Lu, C.-C. Chang
FULL PAPER
preparing 1-deoxy-l-fructose involve biochemical pro- The methodology represents the first report of a chemical
cedures,[8] and although the synthesis involves a fermenta- synthesis of 1-deoxy-l-fructose. The overall synthesis
tion step, the process also involves the use of toxic Raney avoided the need for expensive reagents and would be
nickel.
l-Sorbose is the starting material for the bioproduction
amenable for use in an industrial process.
The carbonyl translocation methodology was also
of vitamin C. The current industrial processes for preparing applied to the synthesis of l-sorbose, the synthesis of which
l-sorbose are based on bioproduction with use of d-sorbitol from an inexpensive d-glucose derivative is shown in
as the starting material.[9] From an industrial point of view, Scheme 3. The synthesis started from the known intermedi-
the main problem associated with this process is the sub- ate 6, which was prepared in two steps from commercial
strate concentration [10–20% (w/v)], which limits the effi- available methyl d-glucopyranoside.[17] Reduction of 6 with
ciency of production. Therefore, the development of a LAH afforded 1,5-diol derivative 7,[12] and selective protec-
chemical process for the production of l-sorbose would be tion with a trityl group gave compound 8.[18] An oxidation
desirable.[10] By our new methodology, 1-deoxy-l-fructose reaction provided the acyclic l-sorbose derivative 9,[18] and
and l-sorbose were prepared from inexpensive l-rhamnose two deprotection steps resulted in the production of l-
and d-glucose, respectively, as starting materials.
sorbose. The l-sorbose was thus obtained from the known
intermediate 6 in five synthetic steps in a total yield of
55%.[19] Current industrial production of l-sorbose relies
on biosynthesis, whereas here a complementary and
efficient chemical synthesis has been successfully explored.
This simple and inexpensive method provides an alternative
and potentially useful industrial process for the synthesis of
vitamin C.
Results and Discussion
The synthesis of 1-deoxy-l-fructose is shown in
Scheme 2. The synthesis started from the known intermedi-
ate 1, which was readily prepared in three steps from com-
mercially available l-rhamnose.[11] LAH reduction[12] gave
the 1,5-diol derivative 2, and selective protection of the pri-
mary hydroxy group with a trityl group[13] generated com-
pound 3. A Swern oxidation[14] of the remaining secondary
hydroxy group produced 4, an acyclic and protected form
of 1-deoxy-l-fructose. Removal of the trityl group by treat-
ment with formic acid in a diethyl ether solution[15] gave
the 1-deoxy-l-fructose derivative 5 in the pyranose form.
Benzyl-protected 1-deoxy-l-fructose derivative 5 may also
be used as a convenient synthon for further synthetic
manipulation. Finally, removal of the benzyl groups under
high-pressure conditions (50 psi) successfully afforded 1-
deoxy-l-fructose.
Scheme 3. Reagents and conditions: (a) LiAlH4, THF, 0 °C to room
temp., 16 h, 95%; (b) TrCl, DMAP, DBU, toluene/CH2Cl2 (1:2,
v/v), 60 °C, 2 d, 84%; (c) (COCl)2, DMSO, NEt3, CH2Cl2, –78 °C,
1 h, 94%; (d) HCO2H/diethyl ether (1:1, v/v), room temp., 15 min,
77%; (e) Pd/C, H2, EtOH, 50 psi, 24 h, 95%.
Conclusions
A new synthetic methodology based on carbonyl trans-
location without the need for a radical process has been
successfully developed and allows conversion of inexpensive
starting materials into rare sugars. No expensive reagents
or harsh conditions were required for the synthesis. 1-
Deoxy-l-fructose was prepared from the known intermedi-
ate 1 in five steps in a total yield of 42% (or eight steps from
l-rhamnose). This represents the first report of a chemical
synthesis of 1-deoxy-l-fructose in which no toxic reagents
are used. Meanwhile, l-sorbose was synthesized from the
known intermediate 6 in five steps in a total yield of 55%
Scheme 2. Reagents and conditions: (a) LiAlH4, THF, 0 °C to r.t.,
16 h, 80%; (b) TrCl, DMAP, DBU, toluene/CH2Cl2 (1:2, v/v),
60 °C, 2 d, 79%; (c) (COCl)2, DMSO, NEt3, CH2Cl2, –78 °C, 1 h,
87%; (d) HCO2H/diethyl ether (1:1, v/v), room temp., 2 h, 95%;
(e) Pd/C, H2, EtOH, 50 psi, 24 h, 80%.
1-Deoxy-l-fructose was thus prepared from the known (or seven steps from methyl d-glucopyranoside). The syn-
intermediate 1 in five steps and in a total yield of 42%.[16] thesis of l-sorbose represents a complementary chemical
2
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Chemical Synthesis of 1-Deoxy-l-fructose and l-Sorbose
The reaction mixture was stirred at 60 °C for 2 d and then worked
up by addition of water. The resulting mixture was extracted with
CH2Cl2 (60 mLϫ3). The combined organic layers was washed with
brine (50 mL), dried with MgSO4, filtered, and concentrated to give
a crude product, which was purified by flash chromatography with
EtOAc/hexanes 2:8 as eluent to give a white solid (1.23 g, 79%),
m.p. 71.5–73.4 °C. [α]2D4 = –32.17 (c = 1.00, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.58–7.45 (m, 6 H), 7.44–7.29 (m, 22 H),
7.14–7.06 (m, 2 H), 4.85 (d, J = 11.7 Hz, 1 H), 4.67–4.47 (m, 5 H),
4.08–3.94 (m, 2 H), 3.89 (td, J = 5.6, 2.9 Hz, 1 H), 3.64 (dd, J =
10.5, 2.9 Hz, 1 H), 3.57 (dd, J = 5.6, 4.2 Hz, 1 H), 3.45 (dd, J =
10.5, 5.6 Hz, 1 H), 2.57 (s, 1 H, OH), 1.24 (d, J = 6.3 Hz, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.0 (s), 138.4 (s),
138.3 (s), 138.1 (s), 128.8 (d), 128.3 (d), 128.3 (d), 128.2 (d), 128.0
(d), 127.7 (d), 127.6 (d), 127.5 (d), 126.9 (d), 86.9 (s), 82.2 (d), 79.1
(d), 78.5 (d), 73.6 (t), 73.4 (t), 72.6 (t), 67.5 (d), 63.2 (t), 19.5
method to the bioproduction of l-sorbose. This efficient
and inexpensive method provides an alternative and poten-
tial industrial process for the synthesis of vitamin C.
Furthermore, this new synthetic approach is sufficiently ge-
neral and efficient that many other rare sugars could also
be prepared from inexpensive starting materials. Such stud-
ies are currently underway.
Experimental Section
General: 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra
were recorded with a Bruker Avance 300 MHz instrument. NMR
spectra were recorded in CDCl3, CD3OD, or D2O. Chloroform (δ
1
= 7.26 ppm in H NMR; δ = 77.0 ppm in 13C NMR), methanol (δ
1
= 3.31 ppm in H NMR; δ = 49.00 ppm in 13C NMR), and D2O
(q) ppm. IR (neat): ν = 3464 (OH), 3087, 3062, 3031, 2932, 2878,
˜
(acetone as internal standards, δ = 2.22 ppm in 1H NMR; δ =
30.9 ppm in 13C NMR) were used as internal standards, respec-
tively. Splitting patterns are reported as follows: s: singlet, d: doub-
let, t: triplet, q: quartet, m: multiplet. Coupling constants (J) are
reported in Hz. IR spectra were recorded with a Perkin–Elmer
Spectrum 100 FT-IR spectrometer and are reported in cm–1. High-
resolution mass spectrometry (HRMS) was recorded with a
Shimadzu LCMS-IT-TOF spectrometer (ESI-MS). Optical rota-
tions were measured with a Horiba SEPA-300 Digital polarimeter.
TLC (Merck Art. 60 F254, 0.25 mm) precoated sheets were used.
Reaction products were isolated by flash chromatography per-
formed on Merck Art. Geduran Si 60 (0.040–0.063 mm) silica gel,
yields of products refer to chromatographically purified products
unless otherwise stated. THF and toluene were distilled over traces
of sodium metal with use of benzophenone as indicator under N2.
Dichloromethane, DMSO, DBU, and triethylamine were dried with
CaH2 and then distilled. Ethanol was dried with magnesium and
iodine and then distilled. Formic acid was distilled before use. All
reactions were performed under a blanket of N2 or Ar.
1959, 1813, 1598, 1494, 1450, 1395, 1329, 1217, 1181, 1155, 1089,
1069, 1029, 1003, 900, 850, 759, 698, 668, 643, 633, 617, 606 cm–1.
HRMS (ESI): calcd. for C46H46NaO5 [M + Na]+ 701.3243; found
701.3245.
2,3,4-O-Tribenzyl-1-O-trityl-L-fructitol (4): A solution of DMSO
(63.9 μL, 0.10 mmol) in CH2Cl2 (0.15 mL) was added dropwise at
–78 °C to a solution of oxalyl chloride (65 μL, 0.75 mmol) in
CH2Cl2 (0.15 mL), and the reaction mixture was then stirred for
30 min followed by addition of a solution of 3 (69.3 mg, 0.10 mmol)
in CH2Cl2 (0.55 mL) at the same temperature. The resulting mix-
ture was stirred for another 30 min, then quenched by dropwise
addition of Et3N (0.21 mL, 1.5 mmol) in CH2Cl2 (0.15 mL) at
–78 °C, and allowed to warm up gradually to room temp. The mix-
ture was diluted with CH2Cl2 (10 mL), washed with water (3 mL)
and brine (3 mL), dried with MgSO4, filtered, and concentrated to
give a crude product, which was purified by flash chromatography
with EtOAc/hexanes 15:85 as eluent to give a yellow oil (59 mg,
87%). [α]2D4 = –48.46 (c = 1.03, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.54–7.44 (m, 6 H), 7.40–7.15 (m, 22 H), 6.92 (dd, J
= 7.2, 1.8 Hz, 2 H), 4.76 (d, J = 11.4 Hz, 1 H), 4.55 (d, J = 11.4 Hz,
1 H), 4.45–4.35 (m, 3 H), 4.32–4.23 (one d at 4.29, J = 3.0 Hz, 1
H, overlapped with one t at 4.26, J = 4.9 Hz, 1 H), 4.18 (d, J =
3.6 Hz, 1 H), 3.88–3.79 (m, 1 H), 3.71 (dd, J = 10.5, 8.7 Hz, 1 H),
3.25 (dd, J = 10.5, 3.7 Hz, 1 H), 2.14 (s, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 211.1 (s), 143.9 (s), 138.3 (s), 137.7 (s), 137.3
(s), 128.8 (d), 128.4 (d), 128.3 (d), 128.2 (d), 128.1 (d), 128.0 (d),
127.9 (d), 127.8 (d), 127.6 (d), 127.4 (d), 127.3 (d), 127.0 (d), 86.7
(s), 86.1 (d), 79.6 (d), 77.9 (d), 74.4 (t), 73.5 (t), 71.9 (t), 62.0 (t),
2,3,4-O-Tribenzyl-L-rhamnitol (2): LAH (39.7 mg) was added to a
solution of 1 (0.13 g, 0.31 mmol) in THF (3.0 mL). The reaction
mixture was stirred for 16 h at room temp. After the reaction was
completed, water (49 μL) was added, 5 min later NaOH(aq.) (15%,
49 μL) was added, and 5 min later water (98 μL) was added, and
the mixture was then stirred for another 20 min. A white precipitate
formed, and the reaction mixture was then filtered and washed with
diethyl ether. The filtrate was concentrated to give a crude product,
which was purified by flash chromatography with EtOAc/hexanes
1:1 as eluent to give a white solid (0.11 g, 80%), m.p. 64.9–66.9 °C.
27.6 (q) ppm. IR (neat): ν = 3088, 3063, 3023, 2875, 2776, 2403,
˜
[α]2D4 = –7.70 (c = 1.29, CHCl3). H NMR (300 MHz, CDCl3): δ =
1
2315, 1958, 1881, 1812, 1710 (C=O), 1598, 1493, 1448, 1396, 1353,
1332, 1260, 1217, 1184, 1154, 1087, 1074, 1028, 943, 900, 847, 750,
697, 668, 643, 632, 603 cm–1. HRMS (ESI): calcd. for C46H44NaO5
[M + Na]+ 699.3087; found 699.3088.
7.55–7.20 (m, 15 H), 4.81–4.71 (two d overlapped at 4.78 and 4.74,
J = 11.4 Hz, 2 H), 4.70–4.56 (m, 3 H), 4.49 (d, J = 11.4 Hz, 1 H),
4.06 (q, J = 5.7 Hz, 1 H), 4.00–3.90 (m, 2 H), 3.89–3.80 (m, 1 H),
3.74 (q, J = 4.5 Hz, 1 H), 3.51 (dd, J = 5.7, 3.9 Hz, 1 H), 2.71 (d,
J = 5.3 Hz, 1 H, OH), 2.48 (t, J = 5.3 Hz, 1 H, OH), 1.26 (d, J =
6.3 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 137.9
(s), 137.8 (s), 128.4 (d), 128.3 (d), 128.1 (d), 127.8 (d), 127.7 (d),
82.1 (d), 79.5 (d), 78.4 (d), 74.0 (t), 73.4 (t), 71.8 (t), 67.3 (d), 60.4
2,3,4-Tri-O-benzyl-1-deoxy-L-fructose (5): Formic acid (0.66 mL)
was added to a solution of 4 (90 mg, 0.13 mmol) in diethyl ether
(0.66 mL). The reaction mixture was stirred at room temp. for 2 h.
The solution was diluted with diethyl ether and neutralized with
NaHCO3(aq.) until the pH was 7. The resulting mixture was washed
with water (10 mLϫ3) and brine (10 mL), dried with MgSO4, fil-
tered, and concentrated to give a crude product, which was purified
by flash chromatography with EtOAc/hexanes 3:7 as eluent to give
a yellow oil (55 mg, 95%). A mixture of anomers in a ratio of 1.4:1
(t), 19.6 (q) ppm. IR (neat): ν = 3440 (OH), 3089, 3066, 3012, 2936,
˜
2880, 2403, 2316, 1953, 1879, 1812, 1606, 1587, 1497, 1454, 1396,
1329, 1216, 1062, 1028, 917, 882, 849, 697, 667, 615 cm–1. HRMS
(ESI): calcd. for C27H32KO5 [M + K]+ 475.1887; found 475.1816.
1
2,3,4-O-Tribenzyl-1-O-trityl-
L
-rhamnitol (3): DBU (0.62 mL,
was obtained. Due to difficulties in H and 13C NMR analysis, we
4.12 mmol), a catalytic amount of DMAP (28.0 mg, 0.23 mmol), can only provide the following data. [α]2D4 = +47.29 (c = 0.6,
and TrCl (0.96 g, 3.44 mmol) were added to a solution of 2 (1.00 g,
2.29 mmol) in a co-solvent system (CH2Cl2/toluene 2:1, 22.0 mL). Hmajor+minor), 5.63 (s, 1 H, Hminor), 5.02 (d, J = 10.8 Hz, 1.4 H,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.45–7.15 (m, 36 H,
Eur. J. Org. Chem. 0000, 0–0
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H.-P. Wu, N.-Y. Hsu, T.-N. Lu, C.-C. Chang
Hmajor), 4.80 (d, J = 12.3 Hz, 2.4 H, Hmajor+minor), 4.71 (d, J = 2.12 mmol) in a co-solvent system (CH2Cl2/toluene 2:1, 21.0 mL).
FULL PAPER
10.8 Hz, overlapped with d at 4.69, J = 12.6 Hz, 3.4 H), 4.64–4.56
(m, 4.2 H), 4.52 (d, J = 12.0 Hz, 2 H, Hminor), 4.48–4.40 (m, 2.4
The reaction mixture was stirred at 60 °C for 2 d and then worked
up by addition of water (20 mL). The resulting mixture was ex-
H), 4.07–3.88 (m, 3.4 H), 3.87–3.69 (m, overlapped with d at 3.82, tracted with CH2Cl2 (70 mLϫ3). The combined organic layers was
J = 7.5 Hz, 8.4 H), 3.40 (d, J = 3.3 Hz, 1 H, Hminor), 2.69 (br. s, 1
H, Hminor, OH), 1.47 (s, 4.2 H, Hmajor), 1.34 (s, 3 H, Hminor) ppm.
13C NMR (75 MHz, CDCl3, mixture): δ = 138.4, (s), 138.2 (s),
washed with brine (70 mL), dried with MgSO4, filtered, and con-
centrated to give a crude product, which was purified by flash
chromatography with EtOAc/hexanes 2:8 as eluent to give a pale
138.1 (s), 137.3 (s), 137.1 (s), 128.6 (d), 128.5 (d), 128.4 (d), 128.2 yellow oil (1.40 g, 84%). [α]2D5 = +10.83 (c = 13.84, CHCl3). 1H
(d), 128.1 (d), 127.9 (d), 127.8 (d), 127.6 (d), 97.9 (s, anomeric car-
bon, major), 97.1 (s, anomeric carbon, minor), 79.8 (d), 79.1 (d),
77.3 (d), 75.8 (t), 74.6 (d), 74.1 (t), 73.4 (t), 72.9 (d), 71.8 (t), 71.6
NMR (300 MHz, CDCl3): δ = 7.49–7.41 (m, 6 H), 7.40–7.19 (m,
27 H), 7.09–7.02 (m, 2 H), 4.72 (d, J = 10.5 Hz, 2 H), 4.66 (d, J =
11.7 Hz, 1 H), 4.60 (d, J = 11.7 Hz, 1 H), 4.52 (d, J = 12.9 Hz, 1
(d), 71.6 (t), 71.2 (t), 60.8 (t), 57.6 (t), 26.6 (q), 24.3 (q) ppm. IR H), 4.48 (d, J = 12.9 Hz, 1 H), 4.40 (d, J = 11.4 Hz, 1 H), 4.18 (d,
(neat): ν = 3443 (OH), 3088, 3064, 3031, 2987, 2877, 2247, 1956, J = 11.4 Hz, 1 H), 4.10 (t, J = 4.2 Hz, 1 H), 3.94 (br. d, J = 4.2 Hz,
˜
1879, 1813, 1724, 1606, 1586, 1497, 1454, 1425, 1397, 1373, 1351,
2 H), 3.69–3.55 (m, overlapped with one d at 3.59, J = 3.9 Hz, 3
1309, 1259, 1235, 1206, 1177, 1092, 1064, 1027, 948, 910, 876, 838, H), 3.47 (dd, J = 10.5, 3.3 Hz, 1 H), 3.24 (dd, J = 10.3, 5.0 Hz, 1
815, 697, 648, 617 cm–1. HRMS (ESI): calcd. for C27H30NaO5 [M H), 2.93 (d, J = 3.9 Hz, 1 H, OH) ppm. 13C NMR (75 MHz,
+ Na]+ 457.1991; found 457.2000.
1-Deoxy-
CDCl3): δ = 143.9 (s), 138.4 (s), 138.2 (s), 138.1 (s), 128.7 (d), 128.4
(d), 128.3 (d), 128.2 (d), 128.1 (d), 128.0 (d), 127.8 (d), 127.6 (d),
127.5 (d), 127.4 (d), 126.9 (d), 86.7 (d), 79.1 (d), 78.5 (d), 77.6 (d),
74.3 (t), 73.3 (t), 73.1 (t), 73.0 (t), 71.2 (t), 70.7 (d), 63.0 (t) ppm.
L
-fructose: Compound 5 (84.6 mg, 0.19 mmol) and Pd/C
(25 wt.-% 21.2 mg) were added to a flask containing 2 mL of EtOH
(2.0 mL). The air inside the metal reaction vessel was removed by
vacuum and replaced with H2 gas, with the pressure of the reaction
kept at 50 psi. The reaction mixture was stirred at room temp. for
24 h. After TLC analysis indicated that starting material had been
consumed completely, the reaction mixture was filtered and con-
centrated to give a crude product, which was purified by flash
chromatography with CH2Cl2/MeOH 4:1 as eluent to give a color-
IR (neat): ν = 3654, 3571 (OH), 3086, 3059, 3029, 2865, 2315, 2244,
˜
1956, 1877, 1811, 1596, 1491, 1449, 1397, 1352, 1313, 1250, 1211,
1183, 1154, 1065, 1027, 1001, 944, 899, 846, 816, 763, 732, 695,
631 cm–1. HRMS (ESI): calcd. for C53H52NaO6 [M + Na]+
807.3662; found 807.3656.
1,3,4,5-O-Tetrabenzyl-6-O-trityl-L A solution of
-sorbose (9):[18]
less liquid (25.6 mg, 80%). Due to difficulty of H and 13C NMR
analysis, we can only provide the following data.
1
DMSO (45 μL, 0.63 mmol) in CH2Cl2 (0.3 mL) was added drop-
wise at –78 °C to a solution of oxalyl chloride (46 μL, 0.53 mmol)
in CH2Cl2 (0.3 mL) and the reaction mixture was then stirred for
30 min, followed by addition of a solution of 8 (0.16 g, 0.21 mmol)
in CH2Cl2 (1.2 mL) at the same temperature. The resulting mixture
was stirred for another 30 min, then quenched by dropwise ad-
dition of Et3N (0.15 mL, 1.05 mmol) in CH2Cl2 (0.3 mL) at –78 °C,
and allowed to warm up gradually to room temp. The mixture was
diluted with CH2Cl2 (30 mL), washed with water (10 mL) and brine
(10 mL), dried with MgSO4, filtered, and concentrated to give a
crude product, which was purified by flash chromatography with
EtOAc/hexanes 15:85 as eluent to give a yellow oil (0.15 g, 94%).
Note: Comparison of our 1H and 13C spectra with the literature
data (ref.,[7b] spectra obtained from Prof. Fleet and Dr. Wormald,
University of Oxford) is shown in the Supporting Information.
[α]2D6 = +81.43 (c = 0.85, H2O). Lit.: [α]2D0 = +85.5 (c = 1.4, H2O)
was reported in ref.;[8b] for the enantiomer 1-deoxy-d-fructose,
[α]2D1 = –80.5 (c = 1.0, H2O) was reported in ref.[7b] HRMS (ESI):
calcd. for C6H12NaO5 [M + Na]+ 187.0583; found 187.0580.
2,3,4,6-O-Tetrabenzyl-D
-glucitol (7):[12] LAH (0.29 g, 7.55 mmol)
was added at 0 °C to a solution of 6 (1.20 g, 2.20 mmol) in THF
(14.6 mL). The reaction mixture was stirred for 16 h at room temp.
After the reaction was complete by TLC analysis, water (354 μL)
was added, 5 min later NaOH(aq.) (15%, 354 μL) was added, and
5 min later further water (709 μL) was added, and the mixture was
continuously stirred for another 20 min. A white precipitate
formed, and the reaction mixture was then filtered and washed with
diethyl ether. The filtrate was concentrated to give a colorless liquid
1
[α]2D6 = –5.32 (c = 7.10, CHCl3). H NMR (300 MHz, CDCl3): δ =
7.49–7.40 (m, 5 H), 7.38–7.18 (m, 26 H), 7.16–7.11 (m, 2 H), 7.05–
7.00 (m, 2 H), 4.65 (d, J = 12.0 Hz, 2 H), 4.56 (d, J = 11.3 Hz, 1
H), 4.44 (d, J = 11.3 Hz, 1 H), 4.36 (d, J = 12.0 Hz, 1 H), 4.30 (d,
J = 11.7 Hz, 1 H), 4.27 (d, J = 11.1 Hz, 1 H), 4.19 (dd, J = 6.6,
6.0 Hz, 1 H), 4.14 (d, J = 8.7 Hz, 2 H), 4.01 (d, J = 3.9 Hz, 1 H),
3.97–3.87 (m, overlapped with one d at 3.95, J = 11.4 Hz, 2 H),
3.47 (dd, J = 10.3, 3.6 Hz, 1 H), 3.14 (dd, J = 10.3, 5.1 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 207.4 (s, C=O), 143.8
(s), 138.3 (s), 137.8 (s), 137.4 (s), 136.9 (s), 128.7 (d), 128.3 (d),
128.2 (d), 128.1 (d), 128.0 (d), 127.8 (d), 127.7 (d), 127.6 (d), 127.0
(d), 86.7 (s), 82.7 (d), 79.9 (d), 78.7 (d), 74.6 (t), 74.3 (t), 73.6 (t),
(1.19 g, 95%), which was pure enough for the next step. [α]2D6
=
1
+14.55 (c = 3.87, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.40–
7.17 (m, 20 H), 4.73 (d, J = 11.4 Hz, 2 H), 4.67 (d, J = 10.5 Hz, 1
H), 4.65 (d, J = 13.7 Hz, 1 H), 4.59 (d, J = 13.7 Hz, 1 H), 4.57 (d,
J = 10.5 Hz, 1 H), 4.52 (d, J = 11.4 Hz, 2 H), 4.10–4.00 (m, 1 H),
3.91 (dd, J = 6.3, 3.0 Hz, 1 H), 3.85–3.69 (m, 3 H), 3.65 (d, J =
4.8 Hz, 2 H), 3.62–3.51 (m, 1 H), 3.00 (d, J = 5.6 Hz, 1 H, OH),
2.18 (t, J = 5.6 Hz, 1 H, OH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 138.1 (s), 138.0 (s), 137.8 (s), 128.4 (d), 128.1 (d), 128.0 (d),
127.9 (d), 127.8 (d), 127.7 (d), 79.5 (d), 79.1 (d), 77.4 (d), 74.5 (t),
73.2 (t), 62.8 (t) ppm. IR (neat): ν = 3086, 3060, 3030, 2935, 2866,
˜
1957, 1878, 1812, 1730 (C=O), 1597, 1493, 1450, 1397, 1334, 1249,
1211, 1176, 1154, 1154, 1109, 1069, 1046, 1027, 1002, 945, 901,
808, 763, 735, 695, 632 cm–1. HRMS (ESI): calcd. for C53H50NaO6
[M + Na]+ 805.3505; found 805.3500.
73.2 (t), 73.1 (t), 71.1 (t), 70.7 (d), 61.8 (t) ppm. IR (neat): ν = 3438
˜
1,3,4,5-O-Tetrabenzyl-L
-sorbose (10):[6] Formic acid (0.35 mL) was
(OH), 3089, 3063, 3030, 2874, 2334, 1954, 1878, 1812, 1606, 1586,
1496, 1453, 1425, 1397, 1355, 1308, 1237, 1208, 1086, 1065, 1027,
911, 819, 732, 695, 600 cm–1. HRMS (ESI): calcd. for C34H39O6
[M + H]+ 543.2747; found 543.2741.
added to a solution of 9 (57.4 mg, 0.07 mmol) in diethyl ether
(0.35 mL). The reaction mixture was stirred at room temp. for
15 min. The solution was diluted with diethyl ether (10 mL) and
then neutralized with NaHCO3(aq.) until the pH was 7. The organic
2,3,4,6-O-Tetrabenzyl-1-O-trityl-
3.18 mmol), a catalytic amount of DMAP (25.9 mg, 0.21 mmol), with MgSO4, filtered, and concentrated to give a crude product,
and TrCl (0.89 g, 3.18 mmol) were added to a solution of 7 (1.15 g, which was purified by flash chromatography with EtOAc/hexanes
D
-gluctiol (8):[18] DBU (0.48 mL, layer was then washed with water (10 mL) and brine (10 mL), dried
4
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Job/Unit: O43196
/KAP1
Date: 21-11-14 11:28:13
Pages: 6
Chemical Synthesis of 1-Deoxy-l-fructose and l-Sorbose
25:75 as eluent to give a yellow oil (31 mg, 77%). [α]2D6 = –17.33 (c
= 2.45, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.38–7.22 (m,18
H), 7.20–7.15 (m, 2 H), 4.97 (d, J = 10.7 Hz, 1 H), 4.86 (d, J =
10.5 Hz, 1 H), 4.83 (d, J = 10.5 Hz, 1 H), 4.72 (d, J = 11.7 Hz, 1
H), 4.62 (d, J = 11.7 Hz, 1 H), 4.58–4.44 (m, 3 H), 3.95 (t, J =
9.3 Hz, 1 H), 3.81–3.69 (m,2 H), 3.69–3.55 (m, 1 H), 3.48 (d, J =
9.3 Hz, 1 H), 3.40 (d, J = 9.3 Hz, 1 H), 3.30 (d, J = 11.7 Hz, over-
lapped with s at 3.28, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
138.6 (s), 138.2 (s), 137.7 (s), 137.3 (s), 128.4 (d), 128.3 (d), 128.2
(d), 128.0 (d), 127.9 (d), 127.8 (d), 127.6 (d), 97.4 (s, anomeric C),
82.7 (d), 78.6 (d), 78.4 (d), 75.7 (t), 75.6 (t), 73.7 (t), 71.8 (t), 61.0
[3] D. D’Alonzo, A. Guaragna, G. Palumbo, Chem. Biodiversity
2001, 8, 373–413.
[4] a) S. B. Pai, S.-H. Liu, Y.-L. Zhu, C. K. Chu, Y.-C. Cheng,
Antimicrob. Agents Chemother. 1996, 40, 380–386; b) C. K.
Chu, T. W. Ma, K. Shanmuganathan, C. G. Wang, Y. J. Xiang,
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[5] R. M. de Lederkremer, C. Marino, Adv. Carbohydr. Chem. Bio-
chem. 2008, 61, 143–216.
[6] For related examples: samarium diiodide (SmI2) was used in
the synthesis of ketohexopyranoses from aldohexopyranoses;
please see: a) M. Adinolfi, G. Barone, A. Iadonisi, Tetrahedron
Lett. 1998, 39, 7405–7406; b) M. Adinolfi, A. Iadonisi, L.
Mangoni, Tetrahedron Lett. 1996, 37, 5987–5988.
[7] a) L. D. Williams Jr., L. M. William, Biochemistry 1976, 15,
4506–4512; b) N. A. Jones, S. F. Jenkinson, R. Soengas, M.
Fanefjord, M. R. Wormald, R. A. Dwek, G. P. Kiran, R. De-
vendar, G. Takata, K. Morimoro, K. Izumori, G. W. J. Fleet,
Tetrahedron: Asymmetry 2007, 18, 774–786.
[8] a) P. Gullapalli, A. Yoshihara, K. Morimoto, R. Devendar, K.
Akimitsu, S. F. Jenkinson, G. W. J. Fleet, K. Izumori, Tetrahe-
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vendar, A. Yoshihara, K. Morimoto, G. Takata, G. W. J. Fleet,
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[9] P. D. Wulf, W. Soetaert, E. J. Vandamme, Biotechnol. Bioeng.
2000, 69, 339–343.
(t) ppm. IR (neat): ν = 3429 (OH), 3088, 3063, 3030, 2873, 1953,
˜
1877, 1812, 1725, 1605, 1586, 1542, 1496, 1453, 1361, 1331, 1308,
1253, 1206, 1157, 1072, 1027, 902, 842, 818, 734, 695, 605 cm–1.
HRMS (ESI): calcd. for C34H36KO6 [M + K]+ 579.2149; found
579.2123.
L-Sorbose: Compound 10 (0.15 g, 0.28 mmol) and Pd/C (25 wt.-%
38.0 mg) were added to a flask containing 2.8 mL of EtOH
(2.8 mL). The air inside the metal reaction vessel was removed by
vacuum and replaced with H2 gas, with the pressure of the reaction
kept at 50 psi. The reaction mixture was stirred at room temp. for
24 h. After TLC analysis indicated that starting material had been
consumed completely, the reaction mixture was filtered, and then
concentrated to give a white solid (48 mg, 95%). Due to difficulty
of 1H and 13C NMR analysis, we can only provide the following
data.
[10] a) W. R. Sullivan, J. Am. Chem. Soc. 1945, 67, 837–840; b) K.
Gätzi, T. Reichstein, Helv. Chim. Acta 1938, 21, 186–195.
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[12] T. Wennekes, R. J. B. H. N. van den Berg, W. Donker, G. A.
van der Marel, A. Strijland, J. M. F. G. Aerts, H. S. Overkleeft,
J. Org. Chem. 2007, 72, 1088–1097.
1
Note: Comparisons of our H and 13C spectra with reference spec-
tra (sample obtained from TCI Chemicals) are shown in the Sup-
porting Information, m.p. 164.1–166.2 °C. [α]2D6 = –37.69 (c = 1.53,
H2O). Lit.: [α]2D7 = –42.8 (c = 4, H2O) and [α]1D9 = –42.9Ϯ2 (c =
1.6, H2O) were reported in ref.[10a] and ref.[10b] HRMS (ESI): calcd.
for C6H12NaO6 [M + Na]+ 203.0532; found 203.0529.
[13] a) I. M. Pinilla, M. B. Martínes, J. A. Galbis, Carbohydr. Res.
2003, 338, 549–555; b) Y. Wang, A. J. Bennet, Org. Biomol.
Chem. 2007, 5, 1731–1738.
Acknowledgments
[14] K. Omura, D. Swerm, Tetrahedron 1978, 34, 1651–1660.
[15] M. Bessodes, D. Komiotis, K. Antonakis, Tetrahedron Lett.
1986, 27, 579–580.
The work was generously supported by the Ministry of Science
and Technology, Taiwan and the Department of Chemistry, Fu Jen
Catholic University. C. C. C. is very grateful to Prof. George W. J.
Fleet (Department of Chemistry, University of Oxford) and Dr.
Mark R. Wormald (Department of Biochemistry, University of Ox-
ford) for kindly providing spectra of 1-deoxy-d-fructose for com-
parison. C. C. C. also thanks Prof. Milton S. Feather (Department
of Biochemistry, University of Missouri) for preliminary dis-
cussions and English language polishing. H. P. W. thanks the De-
partment of Chemistry for a Master’s Student research award.
[16] Specific rotation of 1-deoxy-l-fructose obtained by our meth-
odology is [α]2D6 = +81.43 (c = 0.85, H2O). [α]2D0 = +85.5 (c =
1.4, H2O) is reported in ref.[8b]; for the enantiomeric 1-deoxy-
d-fructose, [α]2D1 = –80.5 (c = 1.0, H2O) is reported in ref.[7b]
.
[17] a) I. Damager, C. E. Olsen, B. L. Møller, M. S. Motawia, Car-
bohydr. Res. 1999, 320, 19–30; b) D. J. Hardick, D. W. Hutchin-
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6285–6296.
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2008, 343, 1675–1692; b) Y. Rabinsohn, H. G. Fletcher, J. Org.
Chem. 1967, 32, 3452–3457.
[1] D. A. Johnson, H. W. Liu, Curr. Opin. Chem. Biol. 1998, 2,
642–649.
[2] a) N.-Y. Hsu, C.-C. Chang, Eur. J. Org. Chem. 2013, 658–661;
b) Q. Ji, M. Pang, J. Han, S. Feng, X. Zhang, Y. Ma, J. Meng,
Synlett 2006, 15, 2498–2500; c) B. H. Cho, J. H. Kim, H. B.
Jeon, K. S. Kim, Tetrahedron 2005, 61, 4341–4346.
[19] Specific rotation of l-sorbose obtained by our methodology is
[α]2D4 = –37.69 (c = 1.53, H2O). [α]2D7 = –42.8 (c = 4, H2O) and
[α]1D9 = –42.9Ϯ2 (c = 1.6, H2O) are reported in ref.[10a,10b]
.
Received: September 10, 2014
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
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5

Job/Unit: O43196
/KAP1
Date: 21-11-14 11:28:13
Pages: 6
H.-P. Wu, N.-Y. Hsu, T.-N. Lu, C.-C. Chang
FULL PAPER
Unusual Sugars
Two rare sugars – 1-deoxy-l-fructose and
l-sorbose – were synthesized from inexpen-
sive starting materials by a carbonyl trans-
location method.
H.-P. Wu, N.-Y. Hsu, T.-N. Lu,
C.-C. Chang* .................................... 1–6
Chemical Synthesis of 1-Deoxy-l-fructose
and l-Sorbose Through Carbonyl Trans-
location
Keywords: Synthetic methods
/ Carbo-
hydrates / Deoxysugars / Rare sugars
6
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