Fluorinated and Conformationally Fixed Derivatives of l -HomoDMDP: Synthesis and Glycosidase Inhibition

Article abstract of DOI:10.1021/acs.joc.5b00571

Fluorinated and conformationally fixed derivatives of L-homoDMDP, i.e., 2,5-dideoxy-2,5-imino-DL-glycero-L-manno-heptitol, have been synthesized from D-xylose-derived cyclic nitrone 10 with oxazolidinone 19 or 28 and oxazinanone 22 or 32 as key intermedia

Full text of DOI:10.1021/acs.joc.5b00571

Article
pubs.acs.org/joc
Fluorinated and Conformationally Fixed Derivatives of
L‑HomoDMDP: Synthesis and Glycosidase Inhibition
Yi-Xian Li,† Yousuke Shimada,‡ Isao Adachi,‡ Atsushi Kato,*,‡ Yue-Mei Jia,† George W. J. Fleet,§,⊥
Min Xiao,∥ and Chu-Yi Yu*,†,⊥
†Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
‡Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
§Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
∥State Key Laboratory of Microbial Technology and National Glycoengineering Research Center, Shandong University, Jinan 250100,
China
⊥National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, China
S
* Supporting Information
ABSTRACT: Fluorinated and conformationally fixed deriva-
tives of L-homoDMDP, i.e., 2,5-dideoxy-2,5-imino-DL-glycero-L-
manno-heptitol, have been synthesized from D-xylose-derived
cyclic nitrone 10 with oxazolidinone 19 or 28 and oxazinanone
22 or 32 as key intermediates. An evaluation of glycosidase
inhibition showed replacement of the C-6 hydroxyl groups with
fluoride in L-homoDMDP and its C-6 epimer did not have a
significant influence on α-glucosidase inhibition by these iminosugars, while replacement of an amino group with a cyclic
carbamate group in most conformationally fixed derivatives led to a sharp decrease in the level of glycosidase inhibition, revealing
the importance of the free amino group in interaction of enzymes with these molecules.
activities and selectivities.44−48 In previous studies,38 we have
INTRODUCTION
■
set out an initial examination of the structure−activity
relationship of L-DMDP and L-homoDMDP (Figure 1) and
found the C-3 hydroxyl group of these compounds played an
important role in interaction with enzymes, and fluorination of
the C-3 hydroxyl led to a sharp decrease in the level of
2,5-Dideoxy-2,5-imino-D-mannitol (DMDP)1−5 was first iso-
lated from leaves of Derris eliptica (Leguminosae) in 19761 and
soon recognized as the parent structure for a series of
subsequently isolated iminosugars, including 1,4-dideoxy-1,4-
imino-D-arabinitol (D-AB1),3,6−8 homoDMDP,9−11 7-deoxy-
homoDMDP,5,9 6-C-alkyl derivatives of DMDP,5,12 austral-
ine,13 and alexine.14 DMDP and its derivatives were found to
exhibit attractive biological activities,15−19 such as glycosidase
inhibition,3,9,10,20−27 and as anti-HIV21,26,28−30 and anticancer
agents,31−34 that thus made them important research targets for
the past four decades. Moreover, the synthetic enantiomers of
some naturally occurring iminosugars are more potent
glycosidase inhibitors than the natural products them-
selves.25,35−37 For example, L-DMDP (1) exhibited α-
glucosidase inhibitory activities more potent and specific than
those of the natural product DMDP.36−38 Similar biological
activities were also found for the related L-AB120,35 and L-
homoDMDP (3).38 Thus, the L-enantiomers are also likely to
provide potential new chemotherapeutic agents. Structure−
activity relationship studies of these compounds will help in the
evaluation of the potential of this type of molecules.
glycosidase inhibition (2 and 4). Combining the results of Stutz
̈
et al.,40 we can establish that hydroxyls of the iminosugar core
should remain intact to prevent weakening of glycosidase
Figure 1. L-DMDP, L-homoDMDP, australine, and their fluorinated
analogues.
Fluorine is one of the most efficient and useful tools in
structure−activity relationship study.38−43 Introduction of
fluorine into a lead compound or veterinary drug will not
only help in understanding the docking mode of the molecule
and enzyme but also afford derivatives with modified biological
Received: March 13, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00571
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Article
inhibition. In our recent study,49 C-7 fluorination of australine
(6) considerably enhanced the potency of its inhibition against
α-glucosidase. This enriches the few examples in which the
fluorination of a hydroxy group increases rather than greatly
decreases the level of inhibition. The results prompted us to
study the effects of substitution of the side chain hydroxyl
groups in DMDP derivatives with fluoride; this modification
should not interfere with interaction of the iminosugar core and
its acceptor. It is therefore clear that L-homoDMDP is a good
candidate for such studies. Thus, in this work, we report the
synthesis of L-homoDMDP derivatives with the C-6 or C-7
hydroxyls substituted with fluoride (7 and 8) and examine their
glycosidase inhibition.
Because the NEt2 groups were found in the initial reaction
intermediates of 11 and DAST, we tentatively assumed that
DAST preferentially reacted with the primary hydroxyl group in
11 to furnish intermediate 16 (Scheme 3). On one hand, attack
of fluoride at the C-7 leaving group would afford product 12,
which would continue to react with another equivalent of
DAST to give intermediate 17. The carbonyl in the Cbz group
then attacked the C-6 leaving group in SN2 mode, resulting in
an inversion of the C-6 configuration from the S-configuration
in 11 to the R-configuration in 14. On the other hand, the C-6
hydroxyl in 16 could attack the C-7 leaving group, affording
epoxide 18,54,55 which would form intermediate 12 by attack of
fluoride56 or oxazolidinone 19 via intramolecular 5-exo-tet
opening of the epoxide and give product 14 by reaction with
another equivalent of DAST. Notably, cyclic sulfite 20 is also
considered to be a possible intermediate in the reaction, though
no report of the formation of the cyclic derivative by diols and
DAST has been published.
In view of the low yield of the reaction and inability to
achieve C-6 fluorinated product 7, another reaction route must
be designed. Bicyclic derivatives such as 19 are no doubt good
candidates. Synthetic methods for this type of carbamate have
been well-documented in the literature.57−61 Herein, the
synthesis was based on our previously reported procedures;38,62
treatment of 9 with sodium hydride at room temperature
provided oxazolidinone 19 and oxazinanone 22 in 82% total
yield (Scheme 4). By the same procedures, bicyclic derivatives
28 and 32 were obtained from 11 in 85% total yield (Scheme
5).
Fluorination of oxazolidinones 19 and 28 afforded
compounds 14 and 29, respectively, both in moderate yields.
Low yields of the reaction may be attributed to the formation of
side products with an Et2N group (detected by NMR
characterization), which failed to be converted to the target
fluorination product 14 or 29 by further reaction. Subsequent
hydrogenolysis of the four oxazolidinones resulted in products
21, 30, 15, and 31, respectively (Schemes 4 and 5). The C-5
configuration of oxazolidinone 31 was confirmed as S by a
NOESY experiment that showed strong H4 and H5 correlation.
While oxazinanones 22 and 32 were reacted with DAST,
fluorination gave anticipated products 23 and 33 together with
elimination products 24 and 34, respectively. The C-5
configurations of 23 and 33 were determined via their
hydrogenation products 25 and 35. The C-5 configuration of
compound 35 was determined to be R through NOESY
experiments because a strong interaction of H-4 and H-5 was
observed. Accordingly, the C-5 configuration of product 25 was
determined to be S. Therefore, fluorination of 22 and 32 had
been finished in usual SN2 pattern.
Hydrolysis of oxazinanones 33 and 23 provided amines 36
and 26, respectively, which were then debenzylated to give the
target products, 6-deoxy-6-fluorinated-L-homoDMDP (7) and
its C-6 epimer 27. Surprisingly, while the same hydrolysis
procedures were applied for fluorinated oxazolidinones 14 and
29, decomposition of the starting materials was observed.
Various bases, including KOH and K2CO3, and different
reaction temperatures were tried, but no positive result was
achieved.
Retrosynthesis showed that the cyclic nitrone50,51 10 derived
from D-xylose52,53 is a good starting material for compounds 7
and 8 (Scheme 1). Because of the steric hindrance of N-Cbz,
Scheme 1. Retrosynthesis of Fluorinated L-HomoDMDP
Analogues from Cyclic Nitrones
the C-6 and C-7 hydroxyls of intermediate 9 may show
different reactivity while reacting with fluorination reagents,
thus affording the desired C-6 and C-7 fluorinated derivatives.
RESULTS AND DISCUSSION
■
Synthesis of C-6 and C-7 Fluorinated Derivatives of L-
HomoDMDP. Key intermediate 9 and its C-6 epimer 11 were
prepared by previously reported procedures.38 Reaction of 11
with diethylaminosulfur trifluoride (DAST) in the presence of
pyridine was overall slow, and some intermediates clearly
involving the Et2N group were detected by NMR character-
ization. Continuing stirring of the solution for several days
resulted in conversion of the intermediates to fluorinated
oxazolidinone 14 in 39% yield finally, together with some
unidentified side products. To determine its C-5 configuration,
14 was hydrogenated under routine conditions to afford
debenzylated product 15 (Scheme 2). The C-5 configuration of
15 was then determined to be the R-configuration through
NOESY experiments because a strong interaction of H-4 and
H-6 was observed. The result indicated that inversion of the
configuration at position C-6 of 11 had occurred during the
fluorination procedure.
Scheme 2. Synthesis of Fluorinated and Conformationally
Fixed Analogues of L-HomoDMDP
Glycosidase Inhibition. Compounds 7, 15, 21, 25, 27, 30,
31, and 35 were assayed as potential inhibitors of a range of
glycosidases, and the results are summarized in Table 1.
L-HomoDMDP (3) and 6-epi-L-homoDMDP showed potent
and moderate inhibition of rat intestinal sucrase (IC50 values of
B
DOI: 10.1021/acs.joc.5b00571
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Article
Scheme 3. Possible Mechanism for Formation of Oxazolidinone 14
Scheme 4. Preparation of L-HomoDMDP Derivatives from 9
Scheme 5. Preparation of L-HomoDMDP Derivatives from 11
5.5 and 64 μM, respectively).38 6-Deoxy-6-fluorinated-L-
homoDMDP (7) showed a slightly decreased level of inhibition
of rice α-glucosidase (IC50 = 82 μM), while its C-6 epimer 27
had slightly stronger inhibition of the same enzyme (IC50 = 59
μM). Conformationally fixed fluorinated L-homoDMDP
derivatives showed obvious decreases in inhibitory activity,
C
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Article
Table 1. Concentrations of Iminosugars Giving 50% Inhibition of Various Glycosidases
IC50 (μM)
a
a
enzyme
α-glucosidase
3
6-epi-3
7
27
25
35
21
30
31
15
b
c
yeast
NI (8%)
NI (7%)
ND
NI (2%)
NI (6%)
NI (5%)
NI (0%)
356
NI (0%)
NI (3%)
ND
NI (26%) NI (48%) NI (9%)
ND ND NI (32%)
d
Aspergillus niger
ND
NI (14%) NI (0%)
rice
28
29
328
82
59
NI (39%) NI (42%) NI (29%) NI (44%) NI (13%) 23
NI (31%) 240 NI (40%) 305 NI (23%) 89
rat intestinal
maltase
163
162
255
rat intestinal
sucrase
5.5
64
ND
ND
ND
ND
ND
ND
ND
ND
β-glucosidase
almond
NI (14%)
NI (4%)
NI (7%)
NI (0%)
NI (0%)
NI (9%)
NI (10%) NI (39%) NI (17%) NI (11%) NI (19%) 533.5
bovine liver
NI (17%) NI (6%)
NI (6%) NI (1%)
NI (24%) NI (1%)
NI (5%)
NI (1%)
NI (5%)
NI (4%)
NI (0%)
NI (2%)
NI (3%)
NI (6%)
NI (42%) NI (0%)
NI (0%)
NI (0%)
NI (6%)
NI (0%)
NI (12%) NI (7%)
596 NI (32%)
NI (32%) NI (19%)
α-galactosidase
coffee bean
β-galactosidase
bovine liver
α-mannosidase
jack beans
β-mannosidase
NI (4%)
NI (9%)
NI (1%)
NI (0%)
NI (1%)
NI (9%)
NI (1%)
NI (7%)
NI (4%)
NI (3%)
NI (4%)
NI (0%)
NI (0%)
290 NI (0%)
NI (35%) NI (0%)
NI (10%) NI (1%)
NI (1%)
NI (0%)
NI (9%)
NI (2%)
NI (0%)
NI (4%)
NI (0%)
NI (1%)
NI (2%)
NI (0%)
NI (0%)
NI (0%)
snail
NI (0%)
NI (40%) NI (12%) NI (1%)
NI (15%) NI (0%)
α-L-fucosidase
bovine kidney
trehalase
porcine kidney
NI (31%) NI (0%)
NI (12%) NI (2%)
NI (6%)
NI (0%)
NI (0%)
NI (2%)
NI (2%)
NI (0%)
NI (0%)
NI (0%)
NI (0%)
NI (4%)
NI (6%)
NI (12%)
amyloglucosidase
A. niger
NI (6%)
NI (6%)
NI (4%)
NI (3%)
α-L-rhamnosidase
Pandanus
decumbens
NI (14%) NI (25%) NI (7%)
NI (25%) NI (1%)
a
b
c
d
Taken from ref 38. NI, no inhibition (<50% inhibition at 1000 μM). Numbers in parentheses are inhibition percents at 1000 μM. ND, not
determined.
compound 15 being an exception. Oxazolidinone 15 exhibited
weak inhibition of β-glucosidase and inhibition of rice α-
glucosidase (IC50 = 23 μM) similar to that of L-homoDMDP
(3). Compounds 31 and 35 also showed weak inhibition of
coffee bean α-galactosidase (IC50 values of 596 and 290 μM,
respectively).
Therefore, replacement of the C-6 hydroxyl group with
fluoride did not cause a significant decrease in the level of
glycosidase inhibition, which indicated that the C-6 hydroxyl
group played an unimportant role in interaction with enzymes.
For most oxazolidinone and oxazinanone derivatives, sub-
stitution of the cyclic carbamate group with an amino group
sharply decreased the level of glycosidase inhibition of the
derivatives, which showed that the free amino group in these
molecules may play an important role in interaction with
enzymes. This result is consistent with previous re-
ports59−61,63,64 that N-acylated iminosugars are almost always
much weaker inhibitors of glycosidases than the parent
iminosugars.
found to have similar glycosidase inhibitory activities with L-
homoDMDP. This indicates that the C-6 hydroxyl groups in L-
homoDMDP-related molecules do not have an important effect
in their interaction with enzymes; the study also confirms that
the corresponding carbamates are in general much weaker
inhibitors than their amine analogues. The biological studies
reported are valuable for the design of DMDP-related lead
compounds.
EXPERIMENTAL SECTION
■
General Methods. All reagents were used as received from
commercial sources without further purification or prepared as
described in the literature. Tetrahydrofuran was dried over 4 Å
molecular sieve. Dichloromethane was distilled from CaH2 immedi-
ately before being used. Analytical TLC was performed with 0.20 mm
silica gel 60F plates with a 254 nm fluorescent indicator. TLC plates
were visualized by ultraviolet light or by treatment with a spray of
Pancaldi reagent [(NH4)6MoO4, Ce(SO4)2, H2SO4, and H2O] or a
0.5% solution of KMnO4 in acetone. Chromatographic purification of
products was conducted by flash column chromatography on silica gel
(200−300 mesh). Acidic ion exchange chromatography was performed
on Dowex 50WX8-400 resin, H+ form. Melting points were measured
with an electrothermal melting point apparatus and are uncorrected.
Polarimetry was determined using a polarimeter with concentrations
(c) given in grams per 100 mL. Infrared spectra were obtained from a
FT-IR spectrometer. 1H, 13C, and 19F NMR spectra were recorded on
a magnetic resonance spectrometer (1H at 300 or 600 MHz, 13C at 75
or 150 MHz, and 19F at 376 or 565 MHz) using CDCl3 (with TMS as
an internal standard), MeOD, or D2O (with H2O as an internal
standard) as a solvent. High-resolution mass spectra (HRMS) were
recorded on a LTQ/FT linear ion trap mass spectrometer.
CONCLUSIONS
■
In summary, fluorinated and conformationally fixed derivatives
of L-homoDMDP have been prepared from nitrone-derived
oxazolidinones and oxazinanones. Glycosidase assays showed
that C-6 fluorinated derivatives 7 and 27 exhibited glycosidase
inhibition similar to that of L-homoDMDP and its C-6 epimer.
Conformationally fixed derivatives 21, 25, 30, 31, and 35
showed a sharp decrease in the level of or disappearance of
glycosidase inhibition, while oxazolidinone derivative 15 was
D
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Article
Material and Methods for the Enzyme Inhibition Assay. With
rat intestinal maltase and sucrase as exceptions, other enzymes were
purchased from Sigma-Aldrich Chemical Co. (St. Louis, MO). Brush
border membranes prepared from rat small intestine according to the
method of Kessler et al.65 were assayed at pH 6.8 for rat intestinal
maltase and sucrase using maltose and sucrose. The released D-glucose
was determined colorimetrically using the Glucose CII-test (Wako
Pure Chemical Ind., Osaka, Japan). Other glycosidase activities were
determined using an appropriate p-nitrophenyl glycoside as a substrate
in a buffer solution at the optimal pH value of each enzyme. The
reaction was stopped by adding 400 mM Na2CO3. The released p-
nitrophenol was measured spectrometrically at 400 nm.
General Procedures for the Synthesis of Oxazolidinone 19
or 28 and Oxazinanone 22 or 32. To a solution of diol 9 or 11 (1
equiv) in THF was added NaH (60%, 6 equiv) and the mixture stirred
at room temperature overnight. An aqueous NH4Cl solution was
added, and the solution was extracted three times with EtOAc. The
combined organic phases were dried over MgSO4 and concentrated in
vacuo. The crude product was purified by flash column chromatog-
raphy (silica gel, 5:1 petroleum ether/EtOAc) to give anticipated
oxazolidinone 19 or 28 and oxazinanone 22 or 32. Data for 19
(Lit.62): light yellow syrup, 0.28 g, 24% yield from 9 (1.40 g, 2.35
mmol); [α]D20 −1.9 (c 1.04 in CH2Cl2); νmax 3439 m, 3031 w, 2867 m,
1759 vs, 1454 m, 1365 m, 1209 m, 1071 s, 739 s, 699 s cm−1; δH (300
MHz, CDCl3) 7.37−7.23 (15H, m, PhCH2O), 4.73−4.42 (7H, m,
PhCH2O), 4.26 (1H, t, J = 4.2 Hz), 4.21−4.16 (1H, m), 4.13−4.08
(1H, m), 4.01 (1H, t, J = 7.8 Hz), 3.79−3.67 (2H, m), 3.57 (2H, d, J =
5.7 Hz); δC (75 MHz, CDCl3) 160.4, 137.8, 137.4, 137.2, 128.6, 128.5,
128.2, 128.1, 127.9, 127.8, 127.5, 86.2, 81.9, 76.1, 73.4, 72.4, 72.2, 70.0,
63.4, 62.5, 60.7.
and then washed three times with MeOH. The filtrate was
concentrated in vacuo, affording target compound 21 or 30. Data
for 21: light yellow syrup, 59.8 mg, 89% yield from 19 (0.15 g, 0.31
mmol); [α]D20 −26.9 (c 0.67 in MeOH); νmax 3358 m, 2935 w, 1735 s,
1654 w, 1401 m, 1231 m, 1108 s, 1035 vs cm−1; δH (300 MHz, D2O)
4.93 (1H, td, J = 6.9, 3.3 Hz), 4.16 (1H, dd, J = 9.0, 7.2 Hz), 4.08 (1H,
t, J = 6.6 Hz), 4.04 (1H, d, J = 8.7 Hz), 4.00 (1H, dd, J = 9.3, 3.6 Hz),
3.92 (1H, dd, J = 12.6, 9.6 Hz), 3.82 (1H, dd, J = 12.0, 3.9 Hz), 3.69
(1H, dd, J = 12.0, 5.4 Hz), 3.62−3.57 (1H, m); δC (75 MHz, D2O)
162.0, 78.2, 77.4, 73.6, 63.6, 62.0, 60.7, 59.7; δC (Dept-135, 75 MHz,
D2O) positive, 78.2, 77.4, 73.6, 63.6, 62.0; negative, 60.7, 59.7;
HRMS(ESI) calcd for C8H14NO6+ [M + H]+ m/z 220.0816, found m/
z 220.0814.
Data for 30: light yellow syrup, 12.3 mg, 90% yield from 28 (30.4
20
mg, 0.06 mmol); [α]D 0 (c 0.18 in MeOH); νmax 3355 m, 2932 w,
1735 s, 1381 m, 1241 m, 1098 s, 1046 vs cm−1; δH (300 MHz, D2O)
4.76 (1H, t, J = 4.5 Hz), 4.11 (1H, t, J = 6.2 Hz), 3.04 (1H, t, J = 7.4
Hz), 3.89 (1H, dd, J = 12.9, 3.0 Hz), 3.82−3.75 (2H, m), 3.73−3.69
(2H, m), 3.67−3.61 (1H, m); δC (75 MHz, D2O) 162.5, 80.4, 78.5,
77.8, 64.7, 62.9, 62.2, 60.7; δC (Dept-135, 75 MHz, D2O) positive,
80.4, 78.5, 77.8, 64.7, 62.9; negative, 62.2, 60.7; HRMS(ESI) calcd for
+
C8H14NO6 [M + H]+ m/z 220.0816, found m/z 220.0816.
General Fluorination Procedures for the Synthesis of
Oxazolidinone 14 or 29 and Oxazinanone 23 or 33. To a
solution of DAST (1.2 equiv) and pyridine (6 equiv) in dichloro-
methane was added the solution of oxazolidinone 19 or 28 and
oxazinanone 22 or 32 in dichloromethane at 0 °C. The reaction
mixture was stirred overnight at room temperature when TLC showed
completion of the reaction. The reaction mixture was quenched with
an aqueous NaHCO3 solution and extracted three times with EtOAc.
The combined organic phases were dried over MgSO4 and
concentrated in vacuo. The crude product was purified by flash
column chromatography (silica gel, 5:1 petroleum ether/EtOAc) to
give anticipated fluorinated oxazolidinone 14 or 29 and oxazinanone
23 (accompanied by side product 24) or 33 (accompanied by side
product 34). Data for 14: yellow syrup, 69.8 mg, 58% yield from 19
Data for 22 (Lit.38): light yellow solid, 0.67 g, 58% yield from 9
(1.40 g, 2.35 mmol); mp 72−74 °C; [α]D20 +19.1 (c 3.24 in CH2Cl2);
νmax 3063 w, 3031 w, 2867 m, 1673 vs, 1457 w, 1454 m, 1434 m, 1363
m, 1260 w, 1089 s cm−1; δH (300 MHz, CDCl3) 7.25−7.17 (15H, m,
PhCH2O), 4.65−4.35 (6H, m, PhCH2O), 4.23−4.18 (1H, m, H2),
4.10−4.05 (2H, m, H3 and H6), 3.99−3.93 (1H, m, H4), 3.79 (1H, t,
J = 10.1 Hz, H6), 3.73−3.66 (m, 1H, H5), 3.58 (dd, 1H, J = 9.6, 6.9
Hz, H1), 3.51 (dd, 1H, J = 9.6, 4.5 Hz, H1), 3.44 (dd, 1H, J = 8.4, 5.7
Hz, H4a); δC (75 MHz, CDCl3) 152.6, 138.0, 137.9, 137.7, 128.5,
128.0, 127.9, 127.8, 86.9, 82.8, 73.3, 72.1, 71.8, 69.9, 68.2, 65.7, 64.5,
63.0.
20
(0.12 g, 0.25 mmol); [α]D +2.4 (c 0.85 in CH2Cl2); νmax 3033 w,
2866 m, 1764 vs, 1362 m, 1211 m, 1101 s, 743 m, 702 m cm−1; δH
(300 MHz, CDCl3) 7.34−7.22 (15H, m, PhCH2O), 4.84−4.72 (1H,
m, H5), 4.66−4.32 (8H, m, H6 and PhCH2O), 4.24 (1H, t, J = 3.5 Hz,
H3), 4.14 (1H, dd, J = 8.4, 5.4 Hz, H4), 4.08−3.99 (2H, m, H1 and
H4a), 3.61−3.56 (2H, m, H1 and H2); δC (75 MHz, CDCl3) 159.6
(OCO), 137.7, 137.3, 137.1, 128.6, 128.5, 128.2, 128.1, 127.9, 127.8
(Ph), 86.1 (C3), 82.0 (C4), 80.5 (d, J = 173.3 Hz, C6), 73.8 (d, J =
21.4 Hz, C5), 73.4 (C1), 72.4, 72.2, 69.9 (PhCH2O), 62.9 (d, J = 4.8
Hz, C4a), 62.4 (C2); δC (Dept-135, 75 MHz, CDCl3) positive, 128.6,
128.5, 128.2, 128.1, 127.9, 127.8, 86.1, 82.0, 73.8, 62.9, 62.4; negative,
80.5, 73.4, 72.4, 72.2, 69.9; HRMS(ESI) calcd for C29H31FNO5+ [M +
H]+ m/z 492.2181, found m/z 492.2181.
Data for 28 (Lit.62): light yellow syrup, 0.58 g, 28% yield from 11
20
(2.50 g, 4.19 mmol); [α]D +16.7 (c 0.48 in CH2Cl2); νmax 3437 w,
3031 w, 2867 m, 1756 s, 1454 m, 1366 m, 1252 m, 1216 m, 1104 s,
1063 s, 739 m, 698 m cm−1; δH (300 MHz; CDCl3) 7.34−7.23 (15H,
m, PhCH2O), 4.67−4.44 (6H, m, PhCH2O), 4.33 (1H, q, J = 4.2 Hz),
4.22 (1H, t, J = 3.3 Hz), 4.16−4.11 (1H, m), 3.90 (1H, dd, J = 6.0, 3.9
Hz), 3.77 (1H, t, J = 5.4 Hz), 3.69 (1H, dd, J = 12.3, 3.6 Hz), 3.61−
3.50 (3H, m); δC (75 MHz, CDCl3) 160.4, 137.9, 137.5, 137.3, 128.6,
128.5, 128.4, 128.2, 127.9, 127.8, 127.7, 87.9, 85.5, 80.2, 73.3, 72.5,
72.0, 69.4, 64.0, 63.4, 62.5.
Data for 29: light yellow syrup, 0.23 g, 56% yield from 28 (0.41 g,
20
0.84 mmol); [α]D +11.8 (c 3.21 in CH2Cl2); νmax 3063 w, 3032 w,
2866 w, 1765 m, 1454 m, 1365 m, 1253 m, 1217 m, 1099 s, 1062 s,
1028 m, 739 m, 699 m cm−1; δH (300 MHz, CDCl3) 7.27−7.12 (15H,
m, PhCH2O), 4.51 (2H, dd, J = 12.0, 3.3 Hz, PhCH2O), 4.44 (2H, s,
PhCH2O), 4.36 (3H, dd, J = 11.7, 6.6 Hz, PhCH2O and H6), 4.31−
4.28 (1H, m, H6), 4.26−4.20 (1H, m, H5), 4.17−4.10 (1H, m, H3),
4.08−4.04 (1H, m, H2), 3.81 (1H, dd, J = 6.0, 4.2 Hz, H4), 3.67 (1H,
dd, J = 6.3, 3.9 Hz, H4a), 3.47 (2H, d, J = 5.7 Hz, H1); δC (75 MHz,
CDCl3) 160.0 (OCO), 137.9, 137.5, 137.4, 128.7, 128.5, 128.3,
128.2, 128.0, 127.9, 127.8, 127.7 (Ph), 87.9 (C4), 85.5 (C3), 82.4 (d, J
= 175.2 Hz, C6), 77.2 (d, J = 20.7 Hz, C5), 73.3, 72.6, 72.1
(PhCH2O), 69.5 (C1), 63.5 (d, J = 5.4 Hz, C4a), 62.7 (C2); δC (Dept-
135, 75 MHz, CDCl3) positive, 128.7, 128.6, 128.5, 128.3, 128.0,
127.9, 127.8, 127.7, 87.9, 85.5, 77.2, 63.5, 62.7; negative, 82.4, 73.3,
Data for 32: white solid, 1.16 g, 57% yield from 11 (2.50 g, 4.19
mmol); mp 136−138 °C; [α]D −5.6 (c 1.08 in CH2Cl2); νmax 3331
20
m, 2902 m, 2869 m, 1652 s, 1475 m, 1454 m, 1365 m, 1112 s, 1028 m,
735 m, 695 m cm−1; δH (300 MHz, CDCl3) 7.32−7.22 (15H, m,
PhCH2O), 4.69−4.41 (6H, m, PhCH2O), 4.33−4.23 (3H, m), 4.16−
4.12 (2H, m), 4.01 (1H, s), 3.79 (1H, dd, J = 9.9, 5.1 Hz), 3.68 (1H,
dd, J = 7.5, 2.7 Hz), 3.54 (1H, dd, J = 9.6, 3.0 Hz), 2.88 (1H, d, J =
18.3 Hz); δC (75 MHz, CDCl3) 151.8, 138.1, 137.9, 137.7, 128.5,
128.4, 128.0, 127.9, 127.7, 82.6, 81.8, 73.3, 72.8, 72.2, 71.1, 68.5, 64.1,
62.3, 60.5; δC (Dept-135, 75 MHz, CDCl3) positive, 128.5, 128.4,
128.0, 127.9, 127.7, 82.6, 81.8, 64.1, 62.3, 60.5; negative, 73.3, 72.8,
72.2, 71.1, 68.5; HRMS(ESI) calcd for C29H31NO6Na+ [M + Na]+ m/
z 512.2044, found m/z 512.2050.
+
72.6, 72.1, 69.5; HRMS(ESI) calcd for C29H31FNO5 [M + H]+ m/z
General Procedures for Hydrogenation of Oxazolidinone 19
or 28. Oxazolidinone 19 or 28 (1 equiv) was dissolved in methanol,
followed by 10% Pd/C (20 wt %) and 2 N HCl. The suspension was
stirred under a hydrogen atmosphere for 24−48 h when TLC showed
completion of the reaction. Hydrogen was then replaced with nitrogen,
and the catalyst was removed from the reaction mixture by filtration
492.2181, found m/z 492.2177.
Data for 23: light yellow solid, 0.21 g, 65% yield from 22 (0.32 g,
0.65 mmol); mp 75−77 °C; [α]D20 −1.9 (c 1.07 in CH2Cl2); νmax 3032
w, 2868 m, 1707 vs, 1460 m, 1429 m, 1361 m,1277 m, 1105 vs, 744 m,
700 m cm−1; δH (300 MHz, CDCl3) 7.24−7.11 (15H, m, PhCH2O),
E
DOI: 10.1021/acs.joc.5b00571
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
4.71 (1H, d, JH,F = 44.1 Hz, H5), 4.60−4.34 (7H, m, H3 and
PhCH2O), 4.23 (1H, t, J = 5.1 Hz, H4), 4.18−4.14 (1.5H, m, H2 and
H6), 4.04−3.94 (1.5H, m, H2 and H6), 3.78 (1H, dd, J = 9.9, 3.9 Hz,
H1), 3.63 (1H, dd, J = 28.8, 8.4 Hz, H4a), 3.47 (1H, d, J = 8.1 Hz,
H1); δC (75 MHz, CDCl3) 150.4 (OCO), 138.0, 137.8, 137.7,
128.6, 128.5, 128.1, 128.0, 127.9, 127.8 (Ph), 82.6 (C3), 82.1 (d, J =
5.5 Hz, C4), 80.1 (d, J = 182.3 Hz, C5), 73.4, 73.0, 72.6 (PhCH2O),
68.9 (C1), 67.9 (d, J = 20.7 Hz, C6), 62.3 (C2), 62.2 (d, J = 19.7 Hz,
C4a); δC (Dept-135, 75 MHz, CDCl3) positive, 128.6, 128.5, 128.1,
128.0, 127.9, 127.8, 82.6, 82.1, 80.1, 62.3, 62.2; negative, 73.4, 73.0,
(376 MHz, D2O) δ −231.0 (dt, J = 71.4, 22.6 Hz, 1F); HRMS(ESI)
calcd for C8H13FNO5+ [M + H]+ m/z 222.0772, found m/z 222.0773.
Data for 31: yellow syrup, 11.8 mg, 87% yield from 29 (30.0 mg,
0.06 mmol); [α]D20 0 (c 0.18 in MeOH); νmax 3355 m, 1753 m, 1736
m, 1410 m, 1243 m, 1092 s, 1045 s cm−1; δH (600 MHz, MeOD) 4.77
(1H, ddd, J = 22.8, 7.2, 4.2 Hz, H5), 4.70 (0.5H, dd, J = 10.8, 3.0 Hz,
H6), 4.64−4.60 (1H, m, H6), 4.53 (0.5H, dd, J = 10.8, 4.8 Hz, H6),
4.14 (1H, t, J = 5.4 Hz, H3), 3.90 (1H, t, J = 6.3 Hz, H4), 3.76 (1H,
dd, J = 11.4, 4.2 Hz, H1), 3.70−3.67 (2H, m, H1 and H4a), 3.62 (1H,
dd, J = 9.6, 4.8 Hz, H2); δC (75 MHz, D2O) 162.1 (OCO), 83.1 (d,
J = 169.7 Hz, C6), 78.3 (C3), 78.2 (d, J = 16.2 Hz, C5), 77.8 (C4),
64.7 (C2), 62.1 (d, J = 6.2 Hz, C4a), 60.6 (C1); δC (Dept-135, 75
MHz, D2O) positive, 78.3, 78.2, 77.8, 64.7, 62.0; negative, 83.1, 60.6;
19F NMR (565 MHz, D2O) δ −232.7 (s, 1F); HRMS(ESI) calcd for
C8H12FNO5Na+ [M + Na]+ m/z 244.0592, found m/z 244.0590.
Data for 25: yellow syrup, 32.7 mg, 88% yield from 23 (82.6 mg,
+
72.6, 68.9, 67.9; HRMS(ESI) calcd for C29H31FNO5 [M + H]+ m/z
492.2181, found m/z 492.2179.
Data for side product 24: yellow syrup, 0.08 g, 26% yield from 22
20
(0.32 g, 0.65 mmol); [α]D −15.3 (c 1.05 in CH2Cl2); νmax 3322 w,
3033 m, 2870 m, 1726 vs, 1419 m, 1361 m, 1266 m, 1214 m, 1102 vs,
742 m, 703 m cm−1; δH (300 MHz, CDCl3) 7.20−7.06 (15H, m,
PhCH2O), 6.20 (1H, dd, J = 6.3, 2.3 Hz, H6), 5.02 (1H, dd, J = 6.3,
1.7 Hz, H5), 4.58−4.36 (6H, m, PhCH2O), 4.14−3.99 (3H, m, H2,
H3 and H4a), 3.77 (1H, dd, J = 9.0, 2.0 Hz, H4), 3.67 (1H, dd, J = 9.6,
2.0 Hz, H1), 3.51 (1H, dd, J = 9.3, 3.0 Hz, H1); δC (75 MHz, CDCl3)
148.4 (OCO), 139.8 (C6), 138.0, 137.9, 137.8, 137.7, 137.6, 128.6,
128.5, 128.3, 128.1, 128.0, 127.9, 127.7 (Ph), 102.0 (C5), 88.4 (C4),
83.2 (C3), 73.5, 72.7, 72.4 (PhCH2O), 69.2 (C1), 62.5 (C4a), 58.6
(C2); δC (Dept-135, 75 MHz, CDCl3) positive, 139.8, 128.6, 128.5,
128.3, 128.1, 128.0, 127.9, 127.7, 102.0, 88.4, 83.2, 62.5, 58.6; negative,
73.5, 72.7, 72.4, 69.2; HRMS(ESI) calcd for C29H29NO5Na+ [M +
Na]+ m/z 494.1938, found m/z 494.1946.
20
0.17 mmol); [α]D −9.8 (c 0.82 in MeOH); νmax 3335 s, 2949 m,
1676 vs, 1471 m, 1439 m, 1335 m, 1300 m, 1224 m, 1065 m cm−1; δH
(600 MHz, D2O) 5.28 (1H, d, JH,F = 46.8 Hz, H5), 4.67 (1H, t, J =
11.7 Hz, H6), 4.50 (1H, dd, J = 38.4, 13.2 Hz, H6), 4.21−4.14 (2H, m,
H3 and H4), 4.04 (1H, dd, J = 12.0, 3.0 Hz, H1), 3.79−3.75 (2H, m,
H1 and H4a), 3.72 (1H, dd, J = 6.6, 3.0 Hz, H2); δC (150 MHz, D2O)
153.5 (OCO), 79.7 (d, J = 178.2 Hz, C5), 74.4 (C3), 73.0 (d, J =
6.2 Hz, C4), 68.9 (d, J = 20.1 Hz, C6), 63.8 (C2), 62.1(d, J = 19.8 Hz,
C4a), 59.0 (C1); δC (Dept-135, 75 MHz, D2O) positive, 79.5, 74.2,
72.8, 63.6, 61.9; negative, 68.7, 58.8; 19F NMR (376 MHz, D2O) δ
−208.1 (dd, J = 75.2 Hz, 37.6 Hz, 1F); HRMS(ESI) calcd for
+
C8H13FNO5 [M + H]+ m/z 222.0772, found m/z 222.0773.
Data for 33: yellow syrup, 0.24 g, 49% yield from 32 (0.49 g, 1.00
20
mmol); [α]D +33.3 (c 0.24 in CH2Cl2); νmax 3032 w, 2920 m, 1713
Data for 35: yellow syrup, 21.0 mg, 82% yield from 33 (57.0 mg,
vs, 1424 m, 1360 m, 1258 m, 1100 s, 743 m, 700 m cm−1; δH (300
MHz, CDCl3) 7.30−7.18 (15H, m, PhCH2O), 4.71 (0.5H, dd, J =
10.5, 6.2 Hz, H5), 4.58−4.37 (6.5H, m, H5 and PhCH2O), 4.22−4.11
(4H, m, H2, H3 and H6), 3.84 (1H, dd, J = 7.2, 4.1 Hz, H4), 3.77−
3.63 (2H, m, H1 and H4a), 3.58−3.54 (1H, m, H1); δC (75 MHz,
CDCl3) 151.4 (OCO), 137.8, 137.3, 137.2, 128.5, 128.4, 128.1,
128.0, 127.9, 127.8, 127.7 (Ph), 85.8 (C4), 84.6 (d, J = 178.5 Hz, C5),
82.8 (C3), 73.4, 72.2, 72.1 (PhCH2O), 68.5 (C1), 66.4 (d, J = 26.8 Hz,
C6), 63.4 (d, J = 27.5 Hz, C4a), 62.7 (C2); δC (Dept-135, 75 MHz,
CDCl3) positive, 128.6, 128.5, 128.1, 128.0, 127.9, 127.8, 127.7, 85.8,
84.6, 82.8, 63.4, 62.7; negative, 73.4, 72.2, 72.1, 68.5, 66.4;
20
0.12 mmol); [α]D +82.9 (c 0.56 in MeOH); νmax 3342 s, 2937 m,
1685 vs, 1440 m, 1358 m, 1057 m cm−1; δH (600 MHz, D2O) 5.12
(1H, ddd, JH,F = 48.6, 9.0, 4.8 Hz, H5), 4.48−4.40 (2H, m, H6), 4.16
(1H, t, J = 7.2 Hz, H3), 4.02−3.96 (2H, m, H1 and H4), 3.79 (1H, dd,
J = 12.6, 3.0 Hz, H1), 3.75−3.69 (2H, m, H2 and H4a); δC (150 MHz,
D2O) 154.4 (OCO), 84.7 (d, J = 173.4 Hz, C5), 77.3 (C4), 75.3
(C3), 66.5 (d, J = 25.2 Hz, C6), 64.2 (C2), 62.8 (d, J = 26.7 Hz, C4a),
59.6 (C1); δC (Dept-135, 75 MHz, D2O) positive, 84.5, 77.1, 75.1,
64.1, 62.6; negative, 66.4, 59.5; 19F NMR (376 MHz, D2O) δ −194.1
to −194.3 (m, 1F); HRMS(ESI) calcd for C8H13FNO5+ [M + H]+ m/
z 222.0772, found m/z 222.0773.
+
HRMS(ESI) calcd for C29H31FNO5 [M + H]+ m/z 492.2181,
General Hydrolysis Procedures for the Synthesis of Amine
26 or 36. To the solution of fluorinated oxazinanone 23 or 33 (1
equiv) in a 2:1 MeOH/H2O solvent was added KOH (8.8 equiv) and
the mixture refluxed overnight. After TLC showed completion of the
reaction, water was added, and then the mixture was extracted three
times with EtOAc. The combined organic phases were dried over
MgSO4 and concentrated in vacuo. The crude product was purified by
flash column chromatography (silica gel, 1:1 petroleum ether/EtOAc)
to give anticipated hydrolysis product 26 or 36. Data for 26: light
yellow solid, 0.15 g, 83% yield from 23 (0.19 g, 0.39 mmol); mp 51−
53 °C; [α]D20 −22.0 (c 0.55 in CH2Cl2); νmax 3336 w, 3031 w, 2865 m,
1496 w, 1454 m, 1363 w, 1098 s, 1028 m, 738 s, 698 s cm−1; δH (300
MHz, CDCl3) 7.31−7.19 (15H, m, PhCH2O), 4.61−4.43 (7H, m, H6
and PhCH2O), 4.03 (1H, t, J = 2.1 Hz, H3), 3.96 (1H, t, J = 4.4 Hz,
H4), 3.82 (1H, t, J = 4.4 Hz, H7), 3.74 (1H, dd, J = 9.6 Hz, H7), 3.53
(2H, s, br, NH and OH), 3.49 (2H, d, J = 5.4 Hz, H1), 3.42−3.32 (2H,
m, H2 and H5); δC (75 MHz, CDCl3) 138.0, 137.7, 128.6, 128.5,
128.0, 127.9 (Ph), 93.2 (d, JC,F = 174.2 Hz, C6), 85.7 (d, J = 4.7 Hz,
C4), 85.2 (C3), 73.3, 72.3, 72.0 (PhCH2O), 69.6 (C1), 63.2 (d, J =
22.3 Hz, C7), 62.5 (d, J = 19.3 Hz, C5), 61.7 (C2); δC (Dept-135, 75
MHz, CDCl3) positive, 128.6, 128.5, 128.0, 127.9, 93.2, 85.7, 85.2,
62.5, 61.7; negative, 73.3, 72.3, 72.1, 69.6, 63.2; HRMS(ESI) calcd for
found m/z 492.2162.
Data for side product 34: yellow syrup, 0.15 g, 32% yield from 32
(0.49 g, 1.00 mmol); [α]D +6.9 (c 0.29 in CH2Cl2); νmax 2924 m,
20
1715 vs, 1457 m, 1202 m, 1098 vs, 742 m, 701 m cm−1; δH (300 MHz,
CDCl3) 7.37−7.21 (15H, m, PhCH2O), 5.06 (1H, s, H5), 4.93−4.80
(2H, m, H6), 4.62−4.37 (8H, m, H2, H3 and PhCH2O), 4.18 (1H, s,
H4), 3.84 (1H, dd, J = 9.3, 4.5 Hz, H1), 3.67−3.61 (1H, m, H1); δC
(75 MHz, CDCl3) 151.1 (OCO), 139.4 (C4a), 138.0, 137.2, 137.1,
128.6, 128.5, 128.4, 128.0, 127.7 (Ph), 96.0 (C5), 81.1, 80.3 (C3 and
C4), 73.2, 71.4, 71.1 (PhCH2O), 67.8, 67.3 (C1 and C6), 63.0 (C2);
δC (Dept-135, 75 MHz, CDCl3) positive, 128.6, 128.5, 128.4, 128.0,
127.7, 96.0, 81.1, 80.3, 63.0; negative, 73.2, 71.4, 71.1, 67.8, 67.3;
+
HRMS(ESI) calcd for C29H30NO5 [M + H]+ m/z 472.2118, found
m/z 472.2127.
Synthesis of Fluorinated Oxazolidinone 15 or 31 and
Oxazinanone 25 or 35. Hydrogenation of 14, 29, and oxazinanone
23 or 33 was performed according to the general hydrogenation
procedures to give products 15, 31, and oxazinanone 25 or 35. Data
for 15: yellow syrup, 16.5 mg, 91% yield from 14 (40.5 mg, 0.08
mmol); [α]D20 −12.3 (c 0.82 in MeOH); νmax 3356 s, 2933 m, 1740 vs,
1400 m, 1233 m, 1111 m, 1044 m, 774 m cm−1; δH (600 MHz, D2O)
5.08 (1H, dt, J = 24.0, 3.9 Hz, H5), 4.93 (0.5H, dd, J = 11.4, 2.1 Hz,
H6), 4.88−4.84 (1.5H, m, H6), 4.15 (1H, t, J = 8.1 Hz, H3), 4.10−
4.07 (2H, m, H4 and H4a), 3.81 (1H, dd, J = 12.0, 3.6 Hz, H1), 3.69
(1H, dd, J = 12.0, 5.4 Hz, H1), 3.59 (1H, dd, J = 9.0, 5.4 Hz, H2); δC
(75 MHz, D2O) 161.6 (OCO), 80.8 (d, J = 168.6 Hz, C6), 78.1
(C3), 75.1 (d, J = 18.6 Hz, C5), 73.7 (d, J = 2.9 Hz, C4), 63.5 (C2),
61.6 (d, J = 4.8 Hz, C4a), 60.6 (C1); δC (Dept-135, 75 MHz, D2O)
positive, 78.1, 75.1, 73.7, 63.5, 61.6; negative, 80.8, 60.6; 19F NMR
+
C28H33FNO4 [M + H]+ m/z 466.2388, found m/z 466.2386.
Data for 36: yellow syrup, 83.5 mg, 88% yield from 33 (0.10 g, 0.20
20
mmol); [α]D −46.2 (c 0.13 in CH2Cl2); νmax 3342 w, 3030 w, 2864
m, 1496 w, 1454 m, 1364 w, 1096 s, 1028 m, 737 s, 698 s cm−1; δH
(300 MHz, CDCl3) 7.34−7.24 (15H, m, PhCH2O), 4.60−4.41 (7H,
m, H6 and PhCH2O), 4.12 (1H, t, J = 2.7 Hz, H3), 3.97 (1H, dd, J =
5.4, 3.3 Hz, H4), 3.87 (1H, t, J = 4.4 Hz, H7), 3.81 (1H, d, J = 4.8 Hz,
H7), 3.51 (2H, d, J = 5.1 Hz, H1), 3.48−3.40 (1H, m, H5), 3.28 (1H,
F
DOI: 10.1021/acs.joc.5b00571
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
dd, J = 9.9, 4.8 Hz, H2), 3.15 (1H, s, br, OH); δC (75 MHz, CDCl3)
137.94, 137.92, 137.8, 128.5, 127.93, 127.90, 127.86, 127.84, 127.78
(Ph), 90.9 (d, JC,F = 172.3 Hz, C6), 86.1 (C4), 85.6 (C3), 73.2, 72.1,
71.7 (PhCH2O), 69.0 (C1), 64.3 (d, J = 25.0 Hz, C5), 63.7 (d, J = 24.2
Hz, C7), 62.3 (C2); δC (Dept-135, 75 MHz, CDCl3) positive, 128.5
127.94, 127.90, 127.86, 127.84, 127.78, 90.9, 86.1, 85.6, 64.3, 62.3;
negative, 73.2, 72.1, 71.7, 68.9, 63.7; HRMS(ESI) calcd for
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+
6-Deoxy-6-fluorinated-L-homoDMDP (7) and Its C-6 Epimer,
27. Hydrogenation of 36 and 26 was conducted according to the
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(100 mL) and then 1 N NH4OH (50 mL), affording 6-deoxy-6-
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[α]D20 −22.5 (c 1.51 in MeOH); νmax 3335 vs, 2929 m, 1413 m, 1053 s
cm−1; δH (300 MHz, D2O) 4.78 (1H, ddd, JH,F = 49.2 Hz, JH,H = 9.9
Hz, JH,H = 5.1 Hz, H6), 4.05 (1H, t, J = 7.8 Hz, H4), 3.96−3.90 (2H,
m, H1 and H3), 3.84 (1H, d, J = 5.1 Hz, H1), 3.82−3.69 (2H, m, H7),
3.22 (1H, ddd, J = 21.9, 8.1, 4.8 Hz, H5), 3.10−3.04 (1H, m, H2); 19F
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+
HRMS(ESI) calcd for C7H15FNO4 [M + H]+ m/z 196.0980, found
m/z 196.0980.
Data for 7: yellow syrup, 29.0 mg, 89% yield from 36 (77.6 mg, 0.17
mmol); [α]D20 −27.5 (c 1.38 in MeOH); νmax 3390 vs, 2928 m, 1726
m, 1568 s, 1421 m, 1096 m cm−1; δH (300 MHz, D2O) 4.63 (1H, ddd,
JH,F = 49.8 Hz, JH,H = 9.6 Hz, JH,H = 5.1 Hz, H6), 4.12 (1H, t, J = 7.2
Hz, H4), 3.87−3.82 (2H, m, H1 and H3), 3.76 (1H, d, J = 4.2 Hz,
H1), 3.73−3.61 (2H, m, H7), 3.16 (1H, ddd, J = 18.6, 7.2, 5.7 Hz,
H5), 3.00−2.94 (1H, m, H2); δC (75 MHz, D2O) 95.2 (d, JC,F = 171.6
Hz, C6), 77.4 (d, J = 8.5 Hz, C4), 77.3 (C3), 61.7 (C2), 61.3 (d, J =
20.2 Hz, C7), 60.9 (C1), 59.6 (d, J = 20.9 Hz, C5); δC (Dept-135, 75
MHz, D2O) positive, 95.2, 77.4, 77.3, 61.7, 59.6; negative, 61.3, 60.9;
19F NMR (376 MHz, D2O) δ −200.3 (t, J = 69.6 Hz, 1F);
+
HRMS(ESI) calcd for C7H15FNO4 [M + H]+ m/z 196.0980, found
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m/z 196.0981.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR, 13C NMR, and 19F NMR spectra and infrared spectra
of intermediates and products. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/acs.joc.5b00571.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: yucy@iccas.ac.cn.
*E-mail: kato@med.u-toyama.ac.jp.
■
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial support from the National Basic Research Program of
China (2012CB822101), the National Natural Science
Foundation of China (21202173 and 21272240), National
Science and Technology Major Projects for “Major New Drugs
Innovation and Development” (2013ZX09508104), the Devel-
opment Fund for Collaborative Innovation Center of
Glycoscience of Shandong University, and the National
Engineering Research Center for Carbohydrate Synthesis of
Jiangxi Normal University is gratefully acknowledged. This
work was also supported in part by an Emeritus Research
Fellowship (G.W.J.F.) and a Grant-in-Aid for Scientific
Research (C) (26460143) (A.K.) from the Japanese Society
for the Promotion of Science (JSPS).
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