L-DMDP, l-homoDMDP and their C-3 fluorinated derivatives: Synthesis and glycosidase-inhibition

Article abstract of DOI:10.1039/c0ob01063d

l-DMDP and l-homoDMDP, the enantiomers of naturally occurring DMDP and homoDMDP have been synthesized from d-xylose derived cyclic nitrone 9. Their 3-deoxy-3-fluorinated analogues were also obtained from polyhydroxylated fluorinated cyclic nitrone 10, whi

Full text of DOI:10.1039/c0ob01063d

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PAPER
L-DMDP, L-homoDMDP and their C-3 fluorinated derivatives: synthesis and
glycosidase-inhibition†
Yi-Xian Li,a,e Mu-Hua Huang,a Yukiko Yamashita,b Atsushi Kato,b Yue-Mei Jia,a Wu-Bao Wang,a
George W. J. Fleet,c Robert J. Nashd and Chu-Yi Yu*a
Received 23rd November 2010, Accepted 8th February 2011
DOI: 10.1039/c0ob01063d
L-DMDP and L-homoDMDP, the enantiomers of naturally occurring DMDP and homoDMDP have
been synthesized from D-xylose derived cyclic nitrone 9. Their 3-deoxy-3-fluorinated analogues were
also obtained from polyhydroxylated fluorinated cyclic nitrone 10, which was prepared from fluorinated
sugar 12 in seven steps. Bioactivities of these iminosugars against various glycosidases were evaluated.
While L-DMDP and L-homoDMDP are potent inhibitors of a-glucosidases, a sharp decrease of
inhibition was found when the C-3 hydroxyl group of these compounds was replaced by fluoride, which
showed the great importance of the C-3 hydroxyl in their interaction with enzymes.
Introduction
Naturally occuring polyhydroxylated pyrrolidines1 such as DMDP
12–3 and related homoDMDP 24–6 (Fig. 1) are potent inhibitors of
some glycosidases with mild inhibition of others. Interestingly, the
synthetic L-enantiomer of DMDP 3 was found to be an even more
powerful and specific a-glucosidase inhibitor than the natural
product.7 Similar interesting biological activities were also found
with other D- and L- iminosugars, such as the natural DAB and
the synthetic enantiomer LAB, the natural (-)-steviamine and its
enantiomer (+)-steviamine.8 Though no substantive explanation
was given for the experimental results, it provided a promising
new direction for pharmaceutical chemistry. In order to find
more selective and better glycosidase inhibitors on the basis of
our previous study of L-iminosugars,7 we have synthesized the
Fig.
1
DMDP, homoDMDP, their enantiomers and 3-deoxy-3-
fluorinated analogues.
enantiomers of DMDP, homoDMDP and their C-3 fluorinated
derivatives (3–6) and examined their glycosidase inhibition.
While fluoride and hydroxyl groups are chemical isosteres,9 the
incorporation of fluorine or a fluorinated group often furnishes
molecules with unique properties that can not be attained by any
other elements. Introduction of fluorine into pharmaceutical and
veterinary drugs to enhance their pharmacological properties has
become almost standard practice. We are interested in a synthesis
and biological activity study of fluorinated L-DMDP derivatives
with one or more hydroxyl groups replaced by fluoride, thus to
further enhance biological performance of this type of molecules
and discover relationship between structure and activities as
glycosidases inhibitors.
Since Stu¨tz et al.10 reported the replacement of the C6 hydroxyl
group of DMDP by a fluoro atom or methoxyl group led to a 10 or
102-fold reduction of inhibition of glycosidases, the C6 hydroxyl
group was believed to be important for interactions of DMDP
with the enzyme. The results drove us to consider the possibility
of pursuing DMDP derivatives in which the hydroxyl group of
C-3 or C-4 is substituted by fluoride which will not interfere
with the hydrogen-bond interaction of the C6 hydroxyl group
and its acceptor. 3-Deoxy-3-fluoro-L-DMDP (4) and 3-deoxy-
3-fluoro-L- homoDMDP (6) are thus synthesized and evaluated
aBeijing National Laboratory for Molecular Science (BNLMS), CAS Key
Laboratory of Molecular Recognition and Function, Institute of Chemistry,
Chinese Academy of Sciences, Beijing, 100191, China. E-mail: yucy@
iccas.ac.cn
bDepartment of Hospital Pharmacy, University of Toyama, 2630, Sugitani,
Toyama, 930-0194, Japan
cChemistry Research Laboratory, Department of Chemistry, University of
Oxford, Mansfield Road, Oxford, UK, OX1 3TA
dPhytoquest Limited, IBERS, Plas Gogerddan, Aberystwyth, Ceredigion,
Wales, UK, SY23 3EB
eGraduate University of The Chinese Academy of Sciences, Beijing, 100049,
China
† Electronic supplementary information (ESI) available: Characterization
data (1H, 13C and 19F NMR spectra) of the fluorinated intermediates and
products. See DOI: 10.1039/c0ob01063d
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against various glycosidases together with L-DMDP (3) and L-
homoDMDP (5).
Retrosynthesis (Scheme 1) for compounds 3–6 showed that
the cyclic nitrone11 9 derived from D-xylose is a good starting
material for 3 and 5, while fluorinated analogues 4 and 6 can
be synthesized effeciently from fluorinated nitrone 10 with a
Grignard addition reaction and dihydroxylation as the key steps.
According to the retrosynthetic analysis, we started the synthesis
from preparation of the fluorinated nitrone 10. Nitrone 9 was
synthesized in hundreds of grams via the reported procedure.11–12
Scheme 2 Synthesis of fluorinated nitrone 10. Reagents and conditions: a)
BnBr, 60% NaH, THF, RT; b) conc. HCl, EtOH, 40 ◦C, 63% for two steps;
c) BnBr, 60% NaH, THF, 40 ◦C, 85%; d) 1 N HCl, dioxane, 80 ◦C, 79%;
e) NH2OTBS, PPTs, anhydrous MgSO4, dry toluene, reflux, 98%; f) MsCl,
pyridine, DCM, 96%; g) TBAF, THF, 0 ◦C, 15 min, then NH2OH·HCl,
NaHCO3, 65 ◦C, 68%.
Two repetitions of the process provided product 15 in 79% total
yield.
15 was converted to the target cyclic nitrone 10 in three steps.
Thus, 15 was refluxed with NH2OTBS in dry toluene in the
presence of anhydrous MgSO4 and catalytic amount of pyridinium
p-toluenesulfonate (PPTs) to give the ring-opening product 16 in
quantitative yield. The free hydroxyl group in 16 was esterified
with mesyl chloride with two equivalents of pyridine to afford
methanesulfonate 17; heating or excess base caused eliminati◦on
to form 18. Removal of the TBS group of 17 by TBAF at 0 C
gave the unprotected oxime which on further treatment with two
equivalents of NH2OH at 65 ◦C for 48 h afforded the target
cyclic nitrone 10 together with unreacted oxime. Reaction of the
recovered oxime with more hydroxylamine gave conversion to
nitrone 10 in 68% total yield. Treatment of the silyl ether 17
with TBAF at higher temperature19,24–25 gave lower yield of 10
(45% optimum yield). The cyclic nitrone 10 was a stable light
yellow syrup and could be stored under cold conditions for several
months.
Scheme
1
Retrosynthesis of L-DMDP, L-homoDMDP and their
3-deoxy-3-fluorinated analogues from cyclic nitrones.
There are generally two strategies to prepare fluorinated imi-
nosuars. That is, introducing fluoride into an existed iminosugar
unit13 or preparing fluorinated iminosugars from a fluoride-
containing segment such as fluorinated amino acid or sugar.14 As
a special class of compounds, fluorinated nitrones or N-oxides
were originally developed in the form of pyridine N-oxide,15
quinoline N-oxide, isoquinoline N-oxide,16 pyrroline N-oxide,17
and pyrrolinone N-oxide.18 Though many fluorinated nitrones or
N-oxides have already been well documented in the literature,
no fluorinated polyhydroxylated cyclic nitrone with one or more
hydroxyl groups replaced by fluoride has been reported previously.
Results and discussion
Synthesis of L-DMDP (3), L-homoDMDP (5), and their
3-deoxy-3-fluorinated analogues (4 and 6)
Synthesis of fluorinated nitrone (10)
The key intermediate nitrone 10 was synthesized via the reported
methods11–12,19 with slight modifications, starting from fluorinated
sugar 11 which could be prepared on a large scale from diacetone
glucose (Scheme 2).21
The execution of the synthesis of L-DMDP (3), L-homoDMDP (5),
and their 3-deoxy-3-fluorinated analogues (4 and 6) is depicted in
Scheme 3.
Starting from cyclic nitrone 9 or 10, the key intermediate
compounds 19 or 20 were obtained in excellent yields by nu-
cleophilic addition of vinyl magnesium chloride with nitrone
9 or 10, respectively, according to the reported method.19–20
Reduction of hydroxylamine 19 or 20 by Zn–Cu(OAc)2-AcOH26
or Fe–Cu(OAc)2-AcOH gave the corresponding amine 21 or
22, respectively, which was treated with CbzCl in weak basic
conditions to afford N-Cbz derivative 7 or 8, all in excellent yields.
L-DMDP (3) and L-homoDMDP (5) were then synthesized from
7, and their 3-deoxy-3-fluorinated analogues (4 and 6) from 8.
To synthesize L-DMDP (3) and L-homoDMDP (5),
dihydroxylation27 of compound 7 afforded a mixture of two
separable epimeric diols 23a and 23b in 91% yield with poor
diastereoselectivity (23a : 23b = 53 : 47). In order to determine the
Selective hydrolysis of the 5,6-acetonide, followed by oxidation
and reduction gave compound 12 in 88% yield.22–23 The alcohol
12 was then treated with benzyl bromide/NaH to furnish the
C-5 hydroxyl protected sugar, of which the 1,2-O-isopropylidene
group was then hydrolyzed with hydrochloric acid in ethanol to
directly provide ethyl glycoside 13 as a mixture of a/b isomers
(a/b = 56 : 44). 13 was then benzylated to afford the dibenzylated
compound 14 as a yellow syrup, which was hydrolyzed in routine
acidic conditions24 to give 15. The hydrolysis process was slow
and incomplete, with some 14 remaining even after refluxing the
reaction mixture at 100 ◦C for 24 h. However, such prolonged
heating caused decompostion, so that the reaction was stopped at
an appropriate stage and the starting material 14 was recovered.
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Scheme 3 Synthesis of L-DMDP, L-homoDMDP and their 3-deoxy-3-fluorinated analogues. Reagents and conditions: a) CH2 CHMgCl, THF, 0 ◦C -
RT; b) Zn (for 19) or Fe (for 20), Cu(OAc)2, AcOH, RT; c) CbzCl, NaHCO3, THF/H2O, RT; d) OsO4, NMO, acetone, RT; e) 10% Pd/C, 6 N HCl, H2,
MeOH, RT; f) NaIO4, EtOH/H2O, RT; g) NaBH4, EtOH, RT.
C-6 configuration of the side-chain in 23a and 23b, compound 23a
was treated with NaOH-MeOH at room temperature to form its
bicyclic derivative 31 in 82% yield (Scheme 4). The C-4 configu-
ration in compound 31 was then determined as R-configuration
through NOESY experiments since a strong interaction of H-4
and H-5 was observed. Therefore, the C-6 configuration of the
side-chain in 23a was determined as R-configuration, and the
C-6 configuration of the side-chain in 23b as S-configuration.
Subsequent hydrogenolysis of 23a or 23b gave L-homoDMDP
5 or its C-6 epimer 25, respectively, in high yield. The diol side-
24b were determined as R- and S-configuration, respectively.
Subsequent hydrogenolysis of 24a or 24b afforded 3-deoxy-3-
fluoro-L-homoDMDP 6 or its C-6 epimer 26, respectively, in high
yield. Oxidation of the diol side-chain of 24 (mixture of 24a and
24b) by NaIO4 formed aldehyde 28, which was directly reduced
by NaBH4 without further purification to afford 30. Further
hydrogenolysis of 30 gave 3-deoxy-3-fluoro-L-DMDP 4 in 94%
yield.
Evaluation against various glycosidases of L-DMDP (3),
L-homoDMDP (5), 6-epi-L-homoDMDP (25), and their
3-deoxy-3-fluorinated analogues (4, 6 and 26)
23
chain of 23 (mixture of 23a and 23b) was oxidized by NaIO4 to
form aldehyde 27, which was directly reduced by NaBH4 without
further purification to afford 29. Further hydrogenolysis of 29 led
1
to L-DMDP 3. H NMR and 13C NMR spectra of compounds
Compounds 3–6 together with 25 and 26 were assayed as potential
inhibitors of a range of glycosidases, the results are summarized
in Table 1.
3 and 5 are identical to those reported for natural DMDP 1 and
homoDMDP 2 with optical rotation [3:[a]2D0 -51.8 (c 0.97 in H2O);
5:[a]2D0 -40.0 (c 0.15 in H2O)] opposite to those of natural products
[1: [a]2D0 +56.4 (c 7 in H2O);2 2: [a]D25 +31.5 (c 0.44 in H2O)4].
L-DMDP (3)7 and L-homoDMDP (5) showed potent inhibition
of a-glucosidase (IC50 0.83 mM and 5.5 mM, respectively, against
rat intestinal sucrase) and 6-epi-L- homoDMDP (25) was a
moderate inhibitor of a-glucosidase (IC50 64 mM against rat
intestinal sucrase). However, their C-3 fluorinated analogues 4,
6 and 26 showed virtually no inhibition of the tested enzymes,
except compound 4 showed weak inhibition of a-glucosidase (IC50
809 mM against rat intestinal sucrase) and trehalase from porcine
kidney (IC50 494 mM). Therefore, the replacement of the C-3
hydroxyl group with a fluoro atom in either 3 or 5 has caused loss
of glycosidase inhibitory activity, which indicates the importance
of the C-3 hydroxyl group in the interaction between enzymes
and these molecules. The biological study results observed herein
might be valuable for further structure–activity studies on the
DMDP-related iminosugars.
Scheme 4 NOESY interaction in 31 and 32.
The 3-deoxy-3-fluorinated analogues, compounds 4 and 6, were
synthesized through the generally similar procedures to those for
the synthesis of 3 and 5. Thus, dihydroxylation of compound
8 gave a mixture of two separable epimeric diols 24a and 24b
in 89% isolated yield with poor diastereoselectivity (24a : 24b =
61 : 39). The C-6 configuration of the side-chain in 24a and 24b
was determined by NOESY experiments of the configuration-
retained bicyclic derivative 32 which was made through treatment
of 24a with NaOH-MeOH at room temperature in 76% yield
(Scheme 4). The C-6 configuration of the side-chain in 24a and
Conclusion
In summary, we have developed a simple and efficient method for
the synthesis of L-DMDP and L-homoDMDP via the chemistry
of sugar-derived cyclic nitrones. L-DMDP (3), L-homoDMDP
(5) and its C-6 epimer 25 have been synthesized smoothly from
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Table 1 Concentration of iminosugars giving 50% inhibition of various glycosidases
IC50 (mM)
Enzyme
3
4
5
6
25
26
a-Glucosidase
Yeast
Rice
Rat intestinal maltase
Rat intestinal isomaltase
Rat intestinal sucrase
b-Glucosidase
Almond
NIa (23.3%)b
1.5
1.8
0.76
0.83
NI (3.7%)
NI (20.5%)
NI (19.1%)
NI (20.0%)
809
NI (8.2%)
28
29
112
5.5
NI (2.8%)
NI (0.1%)
NI (0.1%)
NI (0%)
NI (7.3%)
328
163
161
64
NI (2.4%)
NI (0%)
NI (1.2%)
NI (10.1%)
NI (20.4%)
NI (13.1%)
NI (10.6%)
NI (12.4%)
NI (0.7%)
NI (7.5%)
NI (5.1%)
NI (0.7%)
NI (14.0%)
NI (6.7%)
NI (3.9%)
NI (1.7%)
NI (9.5%)
NI (3.4%)
NI (7.1%)
NI (1.5%)
NI (0.2%)
NI (5.6%)
NI (6.7%)
NI (4.9%)
C. saccharolyticum
Bovine liver
a-Galactosidase
Coffee beans
Human lysosome
b-Galactosidase
Bovine liver
Rat intestinal lactase
a-Mannosidase
Jack beans
b-Mannosidase
Helix pomatia
a-L-Fucosidase
Bovine kidney
Trehalase
NI (8.7%)
NI (4.4%)
NI (6.8%)
NI (5.6%)
NI (4.4%)
NI (2.5%)
NI (1.1%)
NI (3.1%)
NI (4.1%)
NI (3.7%)
NI (14.2%)
NI (3.9%)
NI (2.8%)
NI (19.7%)
NI (9.8%)
NI (12.2%)
NI (9.1%)
NI (42.2%)
NI (10.7%)
NI (0%)
NI (3.0%)
NI (12.0%)
NI (5.6%)
NI (6.8%)
NI (0.5%)
NI (0%)
NI (0%)
179
NI (43.6%)
NI (0%)
NI (0%)
494
NI (1.1%)
NI (0%)
NI (39.3%)
NI (0%)
NI (4.0%)
NI (0%)
NI (2.4%)
NI (0%)
NI (1.2%)
NI (9.1%)
NI (0.6%)
NI (6.9%)
NI (0%)
NI (0.3%)
NI (11.9%)
NI (5.5%)
NI (6.3%)
NI (0.3%)
NI (9.1%)
NI (0%)
Porcine kidney
Amyloglucosidase
A. niger
a-L-Rhamnosidase
P. decumbens
NI (6.2%)
NI (0%)
NI (0%)
NI (27.2%)
NI (0%)
NI (0%)
NI (0.3%)
NI (1.3%)
a NI: No inhibition (less than 50% inhibition at 1000 mM). b ( ◊ ◊ ◊ ): inhibition % at 1000 mM.
the readily available sugar-derived cyclic nitrones 9 in excellent
overall yields; while their C-3 fluorinated derivatives, i.e., 3-deoxy-
3-fluoro-L-DMDP (4), 3-deoxy-3-fluoro-L-homoDMDP (6) and
its C-6 epimer 26 have been synthesized in excellent overall yields
from the fluorinated cyclic nitrone 10 which was prepared from
the readily available fluorosugar 11. Compounds 3–6, 25 and
26 were assayed against a range of various glycosidases, which
showed that L-DMDP (3) and L-homoDMDP (5) were potent
inhibitors of a-glucosidase, while their C-3 fluorinated analogues
showed no inhibition of the tested glycosidases. This indicates
that the C-3 hydroxyl in DMDP-related molecules may play an
important role in their interaction with enzymes. These results
might be vaulable for further structure–activity studies of the
DMDP-related iminosugars and for design and synthesis of more
potent and selective glycosidase inhibitors.
purification of products was carried out by flash column chro-
matography on silica gel (200–300 mesh). Acidic ion exchange
chromatography was performed on Amberlite IR-120 (H+) or
Dowex 50WX8-400, H+ form. Melting points were determined
using an electrothermal melting point apparatus. Melting points
are uncorrected. Infrared spectra were recorded on a JASCO
FT/IR-480 plus Fourier transform spectrometer. NMR spectra
were measured in CDCl3 (with TMS as internal standard) or
D2O on a Bruker AV300, AV400 or AV600 magnetic resonance
spectrometer (1H at 300 MHz or 600 MHz, 13C at 75 MHz,
19F at 376 MHz). High-resolution mass spectra (HRMS) were
recorded on a Thermo Scientific LTQ/FT mass spectrometer or
a GCT mass spectrometer mass spectrometer. Polarimetry was
carried out using an Optical ActivityAA-10R polarimeter and
the measurements were made at the sodium D-line with a 0.5 dm
pathlength cell. Concentrations (c) are given in gram per 100 mL.
Experimental
3-Deoxy-3-fluoro-1,2-O-isopropylidene-a-D-xylofuranose (12)
Material and methods
To a solution of 11 (10.3 g, 39.3 mmol) in THF (50 mL) was
added 1 N HCl (5 mL), and stirred at room temperature overnight.
Aqueous NaOH was used to neutralize the acid, solvent and
water was removed under vacuum. The residue was dissolved
in MeOH (50 mL), aqueous NaIO4 (8.4 g, 39.4 mmol/10 mL
water) was added at room temperature, many white particles
appeared. The solid was filtered 1 h later, washed with EA and
MeOH, the filtrate was then concentrated under reduced pressure
to give an aldehyde as light yellow syrup. The aldehyde was
All reagents were used as received from commercial sources with-
out further purification or prepared as described in the literature.
Tetrahydrofuran was distilled from sodium and benzophenone
immediately before use. Analytical TLC was performed with
0.20 mm silica gel 60F plates with 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,
H2O) or a 0.5% solution of KMnO4 in acetone. Chromatographic
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dissolved in EtOH (100 mL) again and cooled to 0 ◦C, NaBH4
(1.5 g, 40.5 mmol) was added in several batches, obvious heat was
observed. The suspension was stirred for 0.5 h and quenched by
aqueous NH4Cl, solvent was then removed under vacuum. The
residue was washed by EtOAc for several times, the filtrate was
concentrated and purified by flash column chromatography (silica
gel, petroleum ether/EtOAc 5 : 1) to give 12 (6.6 g, 87%) as a light
yellow oil. [a]D20 -17.1 (c 1.06 in CH2Cl2); nmax/cm-1 3438 m, 2985
w, 1656 w, 1381 m, 1217 m, 164 m, 1079 s, 1021 s; dH (300 MHz;
CDCl3) 5.91 (1H, d, J = 3.7 Hz, H1), 4.92 (1H, dd, JH,F = 50.2 Hz,
JH,H = 1.7 Hz, H3), 4.62 (1H, dd, J = 11.1 Hz, 3.7 Hz, H2), 4.25
(1H, ddd, J = 30.1 Hz, 6.0 Hz, 4.1 Hz, H4), 3.77 (2H, d, J =
6.1 Hz, H5), 3.40 (1H, s, br, OH), 1.42, 1.25 (3H each, s, CMe2);
(300 MHz; CDCl3) 7.33–7.25 (10H, m, PhCH2O), 5.13–4.88 (2H,
m, H1 and H3), 4.67–4.52 (4H, m, PhCH2O), 4.48–4.38 (1H, m,
H4), 4.16–4.05 (1H, m, H2), 3.82–3.44 (4H, m, H5 and CH2CH3),
1.25–1.15 (3H, m, CH2CH3); dC (75 MHz; CDCl3) 138.1, 137.4,
137.2, 128.6, 128.5, 128.3, 128.1, 127.8 (Ph), 106.4, 101.1, 99.8
(C1), 96.4 (d, JC,F = 185.3 Hz, C3), 93.7 (d, JC,F = 186.8 Hz, C3),
86.3 (d, J = 26.3 Hz, C2), 83.5 (d, J = 24.0 Hz, C2), 80.0 (d, J =
20.3 Hz, C4), 75.9 (d, J = 20.3 Hz, C4), 73.6, 73.5, 72.7, 72.4
(PhCH2O), 68.4, 68.0 (C5), 63.9, 63.8 (CH2CH3), 15.2 (CH2CH3);
dC (Dept-135; 75 MHz; CDCl3) positive, 128.5, 128.3, 128.1, 127.8,
106.4, 101.1, 99.8, 96.4, 93.7, 86.3, 83.5, 80.0, 75.9, 15.2; negative,
73.6, 73.5, 72.7, 72.4, 68.4, 68.0, 63.9, 63.8; HRMS(ESI) calcd for
C21H25FO4Na+ [M+Na]+ 383.1629, found 383.1622.
dC (75 MHz; CDCl3) 111.3 (CMe2), 103.8 (C1), 93.0 (d, JC,F
=
3-Deoxy-3-fluoro-2,5-di-O-benzyl-D-xylofuranose (15)
182.0 Hz, C3), 81.7 (d, J = 32.3 Hz, C2), 79.5 (d, J = 18.8 Hz, C4),
58.2 (d, J = 9.8 Hz, C5), 25.6, 25.2 (CMe2); dC (Dept-135; 75 MHz;
CDCl3) positive, 103.8, 93.0, 81.7, 79.5, 25.6, 25.2; negative, 58.2.
[lit.22
dH (250 MHz; CDCl3) 5.91 (1H, d, J = 3.8 Hz, H1), 4.92 (1H,
dd, JH,F = 50.4 Hz, JH,H = 2.3 Hz, H3), 4.62 (1H, dd, J = 11.1 Hz,
3.8 Hz, H2), 4.28 (1H, m, H4), 3.82 (2H, m, H5), 1.41, 1.25 (3H
each, s, CMe2)]
To a solution of l4 (14.5 g, 40.3 mmol) in dioxane (100 mL) was
added 1 N HCl (50 mL), and stirred at 90 ◦C overnight. The
solution was concentrated under reduced pressure and neutralized
by aqueous NaHCO3, then extracted with EtOAc (3 ¥ 50 mL),
dried over Na2SO4, and concentrated again to get a dark brown
oil, which was purified by flash column chromatography (silica gel,
petroleum ether/EtOAc 20 : 1 to 5 : 1) to furnish 10.3 g light yellow
syrup (15), and 0.4 g starting material (14), 79% yield. 15: nmax/cm-1
3380 s, 2929 m, 1454 w, 1046 s, 741 m, 698 m; dH (300 MHz; CDCl3)
7.29–7.23 (10H, m, PhCH2O), 5.46 (0.5H, d, J = 3.9 Hz, H1b),
5.30 (0.5H, s, H1a), 5.12–4.91 (1H, m, H3), 4.58–4.33 (5H, m, H4
and PhCH2O), 4.09–3.99 (1H, m, H2), 3.75–3.62 (2H, m, H5); dC
(75 MHz; CDCl3) 138.0, 137.7, 137.2, 136.7, 128.8, 128.6, 128.5,
128.4, 128.1, 128.0, 127.9, 127.8 (Ph), 101.5 (d, J = 10.8 Hz, C1),
96.1 (d, J = 12.0 Hz, C1), 94.7 (d, JC,F = 185.0 Hz, C3), 94.3
(d, JC,F = 186.3 Hz, C3), 87.0 (d, J = 24.2 Hz, C2), 81.6 (d, J =
26.8 Hz, C2), 79.6 (d, J = 19.9 Hz, C4), 77.6 (d, J = 32.0 Hz, C4),
73.7, 73.6, 73.3, 72.2 (PhCH2O), 68.1 (d, J = 10.1 Hz, C5), 67.3 (d,
J = 11.3 Hz, C5); dC (Dept-135; 75 MHz; CDCl3) positive, 128.8,
128.6, 128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 101.5, 96.1, 94.7,
94.3, 87.0, 81.6, 79.6, 77.6; negative, 73.7, 73.6, 73.3, 72.2, 68.1,
67.3; HRMS(ESI) calcd for C19H21FNO4Na+ [M+Na]+ 355.1316,
found 355.1304.
3-Deoxy-3-fluoro-1-O-ethyl-5-O-benzyl-D-xylofuranose (13)
To a suspension of NaH (6.2 g, 60%, 0.16 mol) in THF (100 mL)
was added dropwise a solution of 12 (19.8 g, 0.10 mol) in THF
(50 mL). BnBr (12.4 mL, 0.10 mol) was added dropwise 10 min
later. After TLC showed completion of the reaction, the sus-
pension was poured into iced saturated aqueous NH4Cl solution
carefully, and extracted with EtOAc (2 ¥ 50 mL), EtOAc phases
were combined and concentrated. The crude benzylation product
was stirred with EtOH (200 mL) and conc. HCl (10 mL) at 40 ◦C
overnight. The solution was concentrated under reduced pressure
and neutralized by aqueous NaHCO3, the solution was extracted
with EtOAc (3 ¥ 50 mL), dried over Na2SO4, concentrated again,
and then purified by flash column chromatography (silica gel,
petroleum ether/EtOAc 20 : 1 to 5 : 1) to get compound 13 (17.6 g,
63%) as a mixture of a and b isomers (a/b = 56 : 44), yellow oil.
13: nmax/cm-1 3434 m, 2977 m, 2925 m, 1720 w, 1496 w, 1453 m,
1371 m, 1091 s, 1048 s, 741 m, 699 m; dH (300 MHz; CDCl3) 7.34–
7.27 (5H, m, PhCH2O), 5.18–4.74 (2H, m, H1 and H3), 4.64–4.51
(2H, m, PhCH2O), 4.42–4.21 (2H, m, H2 and H4), 3.77–3.47 (4H,
m, H5 and CH2CH3), 3.13–3.07 (1H, m, OH), 1.26–1.15 (3H, m,
CH2CH3); dC (75 MHz; CDCl3) 137.9, 137.8, 128.6, 128.4, 128.1,
127.9, 127.8, 127.7 (Ph), 108.1, 100.5 (C1), 97.2 (d, JC,F = 183.0 Hz,
C3), 95.4 (d, JC,F = 186.8 Hz, C3), 80.1 (d, J = 19.5 Hz, C2), 78.9
(d, J = 26.3 Hz, C2), 77.2 (d, J = 19.5 Hz, C4), 76.4 (d, J =
28.5 Hz, C4), 73.8, 73.6, 73.5 (PhCH2O), 68.6, 68.5 (C5), 64.6,
63.7 (CH2CH3), 15.1 (CH2CH3); dC (Dept-135; 75 MHz; CDCl3)
positive, 128.6, 128.4, 128.2, 128.1, 127.9, 127.8, 127.7, 108.1,
100.5, 97.2, 95.4, 80.1, 78.9, 77.2, 76.4, 15.1; negative, 73.8, 73.6,
73.5, 68.6, 68.5, 64.6, 63.7; HRMS(ESI) calcd for C14H19FNO4Na+
[M+Na]+ 293.1160, found 293.1162.
(2S,3S,4S)-2,5-Di-O-benzyl-3-fluoro-4-hydroxypentanal
O-(tert-butyldimethylsilyl) oxime (16)
The well-protected 3-deoxy-3-fluoro-D-xylofuranose 15 (0.3 g,
0.9 mmol) was dissolved in toluene (10 mL), NH2OTBS (0.3 g,
2.0 mmol), anhydrous MgSO4 and catalytic amount of PPTs was
followed. The mixture was immediately transferred to a 100 ◦C oil
bath and stirred for 0.5 h. After cooling to room temperature, the
solution was washed with water twice and dried over MgSO4, then
evaporated to get a red oil, which was purified by flash column
chromatography (silica gel, petroleum ether/EtOAc 15 : 1) to give
16 (0.4 g, 98%) as a light yellow oil. It’s a mixture with E/Z ratio
as 76 : 24. 16: nmax/cm-1 3454 m, 3033 m, 2929 s, 2858 s, 1496 m,
1455 m, 1362 m, 1253 s, 1114 s, 1028 m, 931 s, 839 s, 785 m, 735 m,
697 s; dH (300 MHz; CDCl3) 7.63 (0.77H, d, J = 7.8 Hz, H1, E),
7.36–7.30 (10H, m, PhCH2O), 7.06 (0.23H, d, J = 6.1 Hz, H1, Z),
3-Deoxy-3-fluoro-1-O-ethyl-2,5-di-O-benzyl-D-xylofuranose (14)
Similar benzylation procedures to 12 were performed on 13 (13.1 g,
48.5 mmol) to afford 14 (14.8 g, 85%) as light yellow oil. 14:
n
4.68–4.37 (4H, m, PhCH2O), 4.67 (1H, dt, JH,F = 46.8 Hz, JH,H =
3.9 Hz, H3), 4.28 (1H, dq, J = 22.8 Hz, 7.8 Hz, H2), 4.13–4.03
(1H, m, H4), 3.58–3.44 (2H, m, H5), 3.15 (0.22H, d, J = 3.3 Hz,
OH, Z), 2.88 (0.78H, d, J = 3.6 Hz, OH, E), 0.99 (6.79H, s, t-Bu,
max/cm-1 3347 m, 3064 m, 3033 m, 2977 s, 2927 s, 1725 m, 1604
w, 1496 m, 1454 s, 1372 s, 1206 m, 1111 vs, 747 s, 699 s; dH
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E), 0.94 (2.21H, s, t-Bu, Z), 0.24 (4.72H, s, CH3, E), 0.21 (1.28H, s,
CH3, Z); dC (75 MHz; CDCl3) 153.2 (d, J = 5.6 Hz, C1, Z), 151.5
(d, J = 6.6 Hz, C1, E), 137.8, 137.7, 136.9, 128.6, 128.5, 128.4,
128.3, 128.2, 128.1, 127.9, 127.8 (Ph), 92.7 (d, JC,F = 180.7 Hz,
C3, E), 91.8 (d, JC,F = 180.8 Hz, C3, Z), 75.7 (d, J = 19.7 Hz,
C2, E), 73.6, 72.4 (PhCH2O), 71.9 (d, J = 21.0 Hz, C2, Z), 71.0
(PhCH2O), 69.9 (d, J = 19.8 Hz, C4), 69.8 (d, J = 6.0 Hz, C5),
69.5 (d, J = 6.1 Hz, C5), 26.1 (d, J = 8.4 Hz, t-Bu, E), 18.2 (d,
J = 9.8 Hz, t-Bu, Z), -5.2 (d, J = 6.5 Hz, CH3); dC (Dept-135;
75 MHz; CDCl3) positive, 153.2, 151.5, 128.6, 128.5, 128.4, 128.3,
128.1, 127.9, 127.8, 92.7, 91.8, 75.7, 71.9, 69.9, 26.1, 18.2, -5.2;
negative, 73.6, 72.4, 71.0, 69.8, 69.5; Found: C, 65.47; H, 7.70; N,
3.12. C25H36NO4FSi requires C, 65.04; H, 7.86; N, 3.03%.
66.0 (d, J = 21.0 Hz, C2), 38.5 (d, J = 2.3 Hz, OMs); dC (Dept-135;
75 MHz; CDCl3) positive, 129.2, 129.0, 128.7, 128.3, 128.1, 89.1,
77.6, 66.0, 38.5; negative, 73.7, 72.9, 67.9; HRMS(ESI) calcd for
C20H22FNO5SNa+ [M+Na]+ 430.1095, found 430.1097.
(3S,4S,5R)-3-(Benzyloxy)-5-((benzyloxy)methyl)-4-fluoro-
pyrrole-1-oxide (10)
17 (23.7 g, 44.0 mmol) was dissolved in THF (100 mL) and cooled
to 0–5 ◦C. TBAF (12.3 g, 47.1 mmol) was added in several batches
and stirred for 15 min, then poured into water (200 mL). EtOAc
(3 ¥ 50 mL) was used to extract the solution, then organic phases
were combined and directly concentrated under reduced pressure
to give the oxime intermediate. The intermediate was dissolved
in EtOH (100 mL) and water (25 mL), NH2OH·HCl (5.9 g,
85.5 mmol) and NaHCO3 (7.9 g, 94.1 mmol) was followed. The
mixture was stirred at 60 ◦C for 48 h, EtOH was then removed
in vacuo. The residue was extracted with EtOAc (3 ¥ 50 mL),
dried over MgSO4, then purified by flash column chromatography
(silica gel, petroleum ether/EtOAc 5 : 1 to 2 : 1) to afford pure 10
as yellow oil and recover part of 17 which was recycled once to
get altogether 9.9 g nitrone 10, 68% yield. 10: [a]2D0 +24 (c 0.67 in
CH2Cl2); nmax/cm-1 3367 m, 3032 w, 2922 m, 2867 m, 1656 w, 1580
m, 1453 m, 1361 m, 1094 s, 1028 s, 740 m, 698 m; dH (300 MHz;
CDCl3) 7.25–7.16 (10H, m, PhCH2O), 6.89 (1H, s, H2), 5.22 (1H,
d, JH,F = 52.5 Hz, H4), 4.66 (1H, d, J = 21.6 Hz, H3), 4.61–4.42
(4H, m, PhCH2O), 4.10–4.01 (2H, m, H5 and H6), 3.77–3.73 (1H,
m, H6), 2.87 (1H, s, H2O); dC (75 MHz; CDCl3) 137.4, 136.7 (Ph),
133.2 (C2), 128.7, 128.5, 128.3, 128.0, 127.9, 127.6, 127.5, 127.0
(Ph), 93.1 (d, JC,F = 185.3 Hz, C4), 81.7 (d, J = 28.5 Hz, C3), 77.3
(d, J = 26.3 Hz, C5), 73.5, 72.0 (PhCH2O), 65.0 (d, J = 5.3 Hz,
C6); dC (Dept-135; 75 MHz; CDCl3) positive, 133.2, 128.7, 128.5,
128.3, 128.0, 127.9, 127.6, 127.0, 93.1, 81.7, 77.3; negative, 73.5,
72.0, 65.0; 19F NMR (376 MHz, CDCl3) d -182.2 (t, J = 24.4 Hz,
1F); HRMS(ESI) calcd for C19H21FNO3+ [M+H]+ 330.1500, found
330.1494.
(2S,3S,4S)-2,5-Di-O-benzyl-3-fluoro-4-(methanesulfonate)
pentanal O-(tert-butyldimethylsilyl) oxime (17)
The mixture 16 (0.41 g, 0.9 mmol) was dissolved in DCM (5 mL),
with Et3N (0.24 mL, 1.7 mmol) as base, MsCl (0.07 mL, 0.9 mmol)
was added dropwise at 0–5 ◦C, then stirred overnight at room
temperature, TLC showed completion of the reaction. It was
washed with 1 N HCl twice and then water for 3 times. DCM
phase was concentrated under reduced pressure to get dark red
oil. It was purified by flash column chromatography (silica gel,
petroleum ether/EtOAc 15 : 1) to give a yellow syrup 17 (0.46 g,
96%) also as a mixture of E/Z isomers. 17: nmax/cm-1 3032 w, 2955
m, 2930 m, 2858 m, 1497 w, 1472 m, 1455 m, 1362 s, 1254 m,
1178 s, 1120 m, 1027 m, 930 s, 839 s, 788 m, 740 m, 699 m; dH
(300 MHz; CDCl3) 7.66 (0.79H, d, J = 7.5 Hz, H1, E), 7.42–7.28
(10H, m, PhCH2O), 7.11 (0.21H, d, J = 5.4 Hz, H1, Z), 5.12–5.04
(1H, m, H4), 4.88 (0.79H, dd, JH,F = 47.1 Hz, JH,H = 2.4 Hz, H3),
4.86 (0.21H, dd, JH,F = 47.4 Hz, JH,H = 2.4 Hz, H3), 4.63–4.13 (5H,
m, PhCH2O and H2), 3.72–3.67 (1H, m, H5), 3.40 (1H, dd, J =
11.4 Hz, 3.6 Hz, H5), 3.32 (0.51H, s, OMs, Z), 3.05 (2.49H, s,
OMs, E), 1.05 (7.58H, s, t-Bu, E), 0.99 (2.42H, s, t-Bu, Z), 0.30
(4.37H, s, CH3, E), 0.26 (1.63H, s, CH3, Z); dC (75 MHz; CDCl3)
152.7 (d, J = 5.3 Hz, C1, Z), 151.0 (d, J = 6.0 Hz, C1, E), 137.1,
136.4, 136.2, 128.9, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0 (Ph),
93.3 (d, JC,F = 182.3 Hz, C3, E), 92.0 (d, JC,F = 179.3 Hz, C3, Z),
80.5 (d, J = 21.0 Hz, C4, Z), 80.1 (d, J = 20.3 Hz, C4, E), 73.6, 73.5
(PhCH2O), 73.3 (d, J = 17.3 Hz, C2, E), 71.9, 70.7 (PhCH2O), 69.5
(d, J = 18.0 Hz, C2, Z), 68.4 (d, J = 7.5 Hz, C5), 38.9 (OMs, Z),
38.4 (OMs, E), 26.1, 25.8 (t-Bu), -5.2, -5.3 (CH3); dC (Dept-135;
75 MHz; CDCl3) positive, 152.7, 151.0, 128.9, 128.6, 128.5, 128.4,
128.3, 128.1, 128.0, 93.3, 92.0, 80.5, 80.1, 73.3, 69.5, 38.9, 38.4,
26.1, 25.8, -5.2, -5.3; negative, 73.6, 73.5, 71.9, 70.7, 68.4.
General procedures for synthesis of hydroxylamine 19 and 20
Nitrone 9 or 10 (1 eq)◦was dissolved in dry THF, purged with
argon and cooled to 0 C, vinyl magnesium chloride (1.6 M, 2.5
eq) was injected by a syringe slowly to maintain the system below
10 ◦C. The reaction was quenched by aqueous NH4Cl 5 min later,
and extracted with EtOAc twice. The combined EtOAc phases
were dried over MgSO4 and concentrated in vacuo. The crude
product was purified by flash column chromatography (silica gel,
petroleum ether/EtOAc 5 : 1) to give anticipated product 19 or 20.
◦
19: white solid, 81% yield. mp 74–75 C; [a]2D0 +28.9 (c 0.83
(2S,3S,4S)-2,5-Di-O-benzyl-3-fluoro-4-(methanesulfonate)
pentanenitrile (18)
in CHCl3); nmax/cm-1 3258 w, 3031 w, 2865 m, 1497 w, 1454 m,
1362 w, 1206 w, 1096 s; dH (300 MHz; CDCl3) 7.35–7.25 (15H, m,
PhCH2O), 6.04 (1H, ddd, J = 17.4 Hz, 10.9 Hz, 8.1 Hz), 5.32 (1H,
dd, J = 17.4 Hz, 1.8 Hz), 5.27 (1H, dd, J = 11.5 Hz, 1.8 Hz), 4.58–
4.44 (6H, m), 3.97 (1H, t, J = 3.4 Hz), 3.91 (1H, dd, J = 5.3 Hz, 3.0
Hz), 3.79 (1H, dd, J = 7.5 Hz, 6.0 Hz), 3.75 (1H, dd, J = 9.6 Hz, 6.0
Hz), 3.64 (1H, dd, J = 9.6 Hz, 8.9 Hz), 3.52 (1H, dd, J = 8.9 Hz,
5.6 Hz); dC (75 MHz; CDCl3) 138.1, 138.0, 135.4, 128.4, 128.3,
127.9, 127.8, 127.7, 127.6, 119.4, 86.0, 83.8, 73.4, 72.9, 71.9, 71.7,
69.7, 67.9 [conforms to NMR of its enantiomer20]; HRMS(ESI)
18: yellow oil, side product in synthesis of 17 under excess base or
heating. [a]D20 +58.8 (c 1.23 in CH2Cl2); nmax/cm-1 3033 w, 2875 w,
1495 w, 1455 m, 1362 s, 1178 s, 1124 m, 972 m, 932 m, 810 m, 748 m,
700 m; dH (300 MHz; CDCl3) 7.37–7.20 (10H, m, PhCH2O), 5.04–
4.94 (1.5H, m, H4 and H3), 4.83–4.79 (1.5H, m, H3 and H2), 4.45–
4.27 (4H, m, PhCH2O), 3.72–3.48 (2H, m, H5), 3.02 (3H, s, OMs);
dC (75 MHz; CDCl3) 136.8, 134.5, 129.2, 129.0, 128.7, 128.3, 128.1
(Ph), 114.5 (d, J = 4.5 Hz, CN), 89.1 (d, JC,F = 188.3 Hz, C3), 77.6
(d, J = 19.5 Hz, C4), 73.7, 72.9 (PhCH2O), 67.9 (d, J = 6.8 Hz, C5),
+
calcd for C28H31NO4 [M+H]+ 446.2331, found 446.2325.
3410 | Org. Biomol. Chem., 2011, 9, 3405–3414
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20: yellow syrup, 89% yield. [a]2D0 0 (c 1.06 in CH2Cl2); nmax/cm-1
3269 m, 3064 m, 3031 m, 2867 m, 1645 w, 1496 m, 1454 m, 1363
m, 1099 vs, 1028 s, 993 m, 738 s, 698 s; dH (300 MHz; CDCl3)
7.31–7.25 (10H, m, PhCH2O), 7.13 (1H, s, NOH), 5.97 (1H, ddd,
J = 17.7 Hz, 10.2 Hz, 8.1 Hz, H7), 5.31 (1H, d, J = 16.8 Hz, H8),
General procedures for synthesis of N-Cbz protected acetal 7 and 8
The crude amine 21 or 22 (1 eq) was dissolved in THF, followed
by NaHCO3 solid (3 eq) and water, then CbzCl (1.2 eq) was
added in one batch and stirred at RT for 1 h. Water was added,
the mixture was then extracted with EtOAc twice, the combined
organic phases were dried over MgSO4 and concentrated under
reduced pressure, then purified by flash column chromatography
(silica gel, petroleum ether/EtOAc 6 : 1) to give 7 or 8.
5.27 (1H, d, J = 9.9 Hz, H8), 5.04 (1H, dt, JH,F = 53.7 Hz, JH,H
=
2.9 Hz, H4), 4.68–4.48 (4H, m, PhCH2O), 4.05 (1H, ddd, J =
22.5 Hz, 6.6 Hz, 2.4 Hz, H3), 3.79–3.59 (4H, m, H2, H5 and H6);
dC (75 MHz; CDCl3) 137.9, 137.5 (Ph), 134.9 (C7), 128.7, 128.6,
128.5, 128.2, 127.9, 127.8, 127.7, 127.6, 127.5 (Ph), 119.9 (C8), 97.9
(d, JC,F = 183.8 Hz, C4), 85.1 (d, J = 24.0 Hz, C3), 73.4 (PhCH2O),
72.8 (d, J = 5.3 Hz, C2), 72.2 (PhCH2O), 70.1 (d, J = 23.3 Hz, C5),
66.9 (d, J = 5.3 Hz, C6); dC (Dept-135; 75 MHz; CDCl3) positive,
134.9, 128.7, 128.6, 128.5, 128.2, 127.9, 127.8, 127.7, 127.6, 127.5,
97.9, 85.1, 72.8, 70.1; negative, 119.9, 73.3, 72.2, 66.9; Found: C,
70.07; H, 6.74; N, 3.99. C21H24FNO3 requires C, 70.57; H, 6.77; N,
3.92%.
7: colorless syrup, 95% yield. [a]2D0 +5.4 (c 0.74 in CHCl3);
n
max/cm-1 1701 vs; dH (300 MHz; CDCl3) 7.27–7.09 (20H, m), 5.79
(1H, m), 5.21–4.92 (4H, m), 4.55 (1H, dd, J = 10.7 Hz, 8.6 Hz),
4.46–4.20 (7H, m), 4.15–4.10 (2H, m), 3.95 (0.5H, dd, J = 8.5 Hz,
4.3 Hz), 3.77 (1H, d, J = 2.5 Hz), 3.66 (0.5H, dd, J = 9.6 Hz, 4.3 Hz),
3.43 (1H, t, J = 9.6 Hz); dC (75 MHz; CDCl3) 155.1, 138.6, 137.8,
136.7, 136.6, 128.6, 128.5, 128.3, 128.1, 127.9, 127.6, 116.4, 86.9,
82.8, 73.1, 71.4, 71.0, 67.9, 67.0, 66.4, 63.2; HRMS(ESI) calcd for
C36H38NO5 [M+H]+ 564.2744, found 564.2745; C36H37NNaO5
+
+
[M+Na]+ 586.2564, found 586.2577.
8: light yellow syrup, 91% yield. [a]2D0 +12.0 (c 1.00 in CH2Cl2);
General procedures for synthesis of amine 21 and 22
n
max/cm-1 3032 w, 2827 w, 1705 s, 1495 w, 1454 m, 1407 s, 1351
Copper(II) acetate (0.1 eq) was added to a suspension of activated
zinc (10 eq) or iron powder (10 eq, used as received) in acetic
acid, and the mixture was stirred at 30 ◦C for 1 h until copper
colour disappeared. A solution of hydroxylamine 19 or 20 (1 eq)
in acetic acid was added, and the reaction mixture was stirred
s, 1261 w, 1215 m, 1095 s, 1028 m, 925 m, 797 w, 769 w, 738 s,
697 m; dH (300 MHz; CDCl3) 7.21–7.15 (15H, m, PhCH2O and
PhCH2OC O), 5.64 (1H, t, J = 7.8 Hz, H7), 5.18–4.92 (5H, m,
H4, H8 and PhCH2OC O), 4.55–4.25 (6H, m, PhCH2O, H5 and
H6), 3.96–3.63 (2H, m, H3 and H6), 3.44 (1H, dd, J = 18.3 Hz,
9.0 Hz, H2); dC (75 MHz; CDCl3) 153.7, 152.9 (C O), 137.1,
136.8, 135.9, 135.3 (Ph), 134.5, 134.0 (C7), 127.5, 127.4, 127.3,
127.2, 127.1, 127.0, 126.7, 126.6 (Ph), 116.2, 115.7 (C8), 94.4 (d,
JC,F = 180.0 Hz, C4), 93.3 (d, JC,F = 180.8 Hz, C4), 84.7 (d, J =
26.3 Hz, C3), 84.0 (d, J = 26.3 Hz, C3), 72.1, 70.8 (PhCH2O), 66.5
(d, J = 10.5 Hz, C6), 66.0 (PhCH2OC O), 65.7 (d, J = 9.8 Hz,
C6), 65.4 (d, J = 6.8 Hz, C2), 62.5 (d, J = 22.5 Hz, C5), 62.0 (d,
J = 21.8 Hz, C5); dC (Dept-135; 75 MHz; CDCl3) positive, 134.5,
134.0, 127.5, 127.4, 127.3, 127.2, 127.1, 127.0, 126.6, 94.4, 93.3,
84.7, 84.0, 65.4, 62.5, 62.0; negative, 116.2, 115.7, 72.1, 70.8, 66.5,
66.0, 65.7; Found: C, 72.49; H, 6.46; N, 2.84. C29H30FNO4 requires
C, 73.24; H, 6.36; N, 2.95%.
◦
at 30 C overnight. Solvent was removed in vacuum, the residue
was neutralized by aqueous NaHCO3 and washed with EtOAc for
three times. The resulting filtrate was extracted with EtOAc, then
organic layers were combined, dried over MgSO4 and concentrated
under reduced pressure. Part of the crude product was purified by
flash column chromatography (silica gel, petroleum ether/EtOAc
3 : 1) to give the target product (21 or 22) for NMR and yield
calculation. The remaining product was directly used in the next
step.
21: yellow syrup, 97% yield. [a]2D0 -13.8 (c 0.15 in CHCl3);
n
max/cm-1 3324 w, 3030 w, 2861 m, 1497 w, 1454 m, 1363 w, 1095
s; dH (300 MHz; CDCl3) 7.38–7.15 (15H, m), 5.84 (1H, ddd, J =
17.3 Hz, 10.1 Hz, 7.2 Hz), 5.18 (1H, d, J = 17.7 Hz), 5.03 (1H, d, J =
10.3 Hz), 4.53–4.41 (6H, m), 3.82–3.76 (2H, m), 3.59 (1H, dd, J =
7.0 Hz, 6.4 Hz), 3.45–3.41 (2H, m), 3.34 (1H, dd, J = 10.0 Hz, 4.6
Hz), 2.06 (1H, br); dC (75 MHz; CDCl3) 137.7, 137.2, 137.1, 127.4,
127.3, 126.8, 126.7, 126.6, 115.1, 88.2, 84.9, 72.2, 71.0, 70.8, 69.8,
General procedures for synthesis of diol 23 and 24
N-Cbz protected acetal 7 or 8 (1 eq) was dissolved in acetone,
followed by 60 v% aqueous NMO (10 eq) and 0.5 wt% aqueous
OsO4 (0.01 eq) solution. Caution! The mixture was stirred at RT for
four days. Saturated aqueous NaHSO3 was added and stirred for
1 h, then extracted with EtOAc for three times, organic phases were
combined, dried over MgSO4 and concentrated in vacuum, then
purified by flash column chromatography (silica gel, petroleum
ether/EtOAc 1 : 1) to give separable diol 23a and 23b (23a/23b =
53/47, 91% total yield) or 24a and 24b (24a/24b = 61/39, 89%
total yield).
+
63.4, 60.3; HRMS(ESI) calcd for C28H32NO3 [M+H]+ 430.2377,
found 430.2378.
22: yellow syrup, 96% yield. [a]2D0 -11.1 (c 0.18 in CH2Cl2);
n
max/cm-1 3031 w, 2864 m, 1642 w, 1496 w, 1453 m, 1366 m, 1097
vs, 1027 m, 738 s, 698 s; dH (300 MHz; CDCl3) 7.33–7.24 (10H,
m, PhCH2O), 5.87 (1H, ddd, J = 17.1 Hz, 10.2 Hz, 6.9 Hz, H7),
5.26 (1H, d, J = 17.1 Hz, H8), 5.13 (1H, d, J = 10.2 Hz, H8),
4.92 (1H, dt, JH,F = 53.7 Hz, JH,H = 3.5 Hz, H4), 4.68–4.55 (4H,
m, PhCH2O), 3.93 (1H, ddd, J = 20.1 Hz, 5.7 Hz, 3.6 Hz, H3),
3.69 (1H, t, J = 6.3 Hz, H2), 3.58–3.48 (3H, m, H5 and H6); dC
(75 MHz; CDCl3) 138.0 (C7), 137.9, 137.7, 128.5, 128.4, 127.8,
127.7 (Ph), 116.4 (C8), 99.0 (d, JC,F = 182.3 Hz, C4), 88.0 (d, J =
22.5 Hz, C3), 73.3, 72.2 (PhCH2O), 69.7 (d, J = 6.0 Hz, C6), 64.0
(d, J = 6.0 Hz, C2), 61.3 (d, J = 24.0 Hz, C5); dC (Dept-135;
75 MHz; CDCl3) positive, 138.0, 128.5, 128.4, 127.8, 127.7, 99.0,
88.0, 64.0, 61.3; negative, 116.4, 73.3, 72.2, 69.7; HRMS(ESI) calcd
23a: colorless syrup, 48% yield. [a]2D0 +37.0 (c 1.20 in CHCl3);
n
max/cm-1 3432 s, 3032 w, 2938 w, 1681 vs, 1497 w, 1454 m, 1415
m, 1213 w, 1073 vs; dH (300 MHz; CDCl3) 7.39–7.23 (20H, m),
5.16 (2H, s), 4.56 (2H, d, J = 12.1 Hz), 4.48 (2H, d, J = 11.8 Hz),
4.42 (2H, d, J = 12.1 Hz), 4.30 (1H, s), 4.23 (1H, s), 4.16 (1H, dd,
J = 10.4 Hz, 3.9 Hz), 4.06 (1H, br, d, J = 6.7 Hz), 3.94 (1H, br,
s), 3.81 (1H, dd, J = 8.8 Hz, 4.1 Hz), 3.59 (1H, m), 3.53 (1H, dd,
J = 10.4 Hz, 8.9 Hz), 3.56 (1H, br, s); dC (75 MHz; CDCl3) 156.2,
+
for C21H25FNO2 [M+H]+ 342.1864, found 342.1864.
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©

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5: light yellow syrup, 83% yield. [a]2D0 -40.0 (c 0.15 in H2O) [lit.4
[a]D25 +31.5 (c 0.44 in H2O) for its enantiomer]; nmax/cm-1 3228 s,
2941 w, 1106 w, 1061 w; dH (300 MHz; D2O) 4.00 (1H, t, J = 7.1
Hz), 3.78 (1H, t, J = 7.5 Hz), 3.70 (1H, dd, J = 6.8 Hz, 3.4 Hz),
3.69–3.61 (2H, m), 3.55 (1H, dd, J = 11.7 Hz, 6.0 Hz), 3.52 (1H,
dd, 1H, J = 11.6 Hz, 6.8 Hz), 2.97–2.95 (1H, m), 2.92 (1H, dd,
J = 7.2 Hz, 5.5 Hz); dC (75 MHz; D2O) 77.9, 77.8, 72.9, 63.4, 61.8,
61.6, 61.4; dC (Dept-135; 75 MHz; D2O) positive, 77.9, 77.8, 72.8,
138.1, 137.5, 135.9, 128.6, 128.5, 128.4, 128.3, 128.0, 127.9, 127.8,
127.7, 127.6, 82.8, 82.6, 73.1, 71.4, 71.3, 71.0, 68.2, 67.7, 66.3, 63.6,
62.8; dC (Dept-135; 75 MHz; CDCl3) positive, 128.6, 128.5, 128.4,
128.3, 128.0, 127.9, 127.8, 127.7, 127.6, 82.8, 82.5, 71.0, 66.2, 63.6;
negative, 73.1, 71.4, 71.3, 68.2, 67.7, 62.8; HRMS(ESI) calcd for
C36H40NO7 [M+H]+ 598.2799, found 598.2812.
+
23b: colorless syrup, 43% yield. [a]2D0 +35.4 (c 0.91 in CHCl3);
n
max/cm-1 3125 vs, 1760 m, 1454 w, 1401 vs, 1097 m; HRMS(ESI)
calcd for C36H40NO7 [M+H]+ 598.2799, found 598.2797.
+
+
61.8, 61.4; negative, 63.3, 61.6; HRMS(ESI) calcd for C7H16NO5
24a: light yellow syrup, 54% yield. [a]2D0 +57.4 (c 0.98 in CH2Cl2);
[M+H]+ 194.1023, found 194.1028.
◦
n
max/cm-1 3429 m, 3032 m, 2939 m, 1701 s, 1496 w, 1454 m, 1415 s,
25: light yellow solid, 94% yield. mp 118–120 C; [a]2D0 -35.1
(c 0.97 in H2O); nmax/cm-1 3317 vs, 2918 m, 1412 m, 1046 s; dH
(300 MHz; D2O) 3.86 (1H, t, J = 7.5 Hz), 3.78–3.66 (2H, m),
3.63–3.46 (4H, m), 2.99 (1H, dd, J = 10.5 Hz, 6.6 Hz), 2.89 (1H, t,
1H, J = 6.5 Hz) [1H NMR accords with that of its enantiomer5];
dC (75 MHz; D2O) 77.5, 77.2, 71.1, 63.3, 61.8, 61.5; dC (Dept-
135; 75 MHz; D2O) positive, 77.5, 77.2, 71.1, 61.5; negative, 63.3,
1350 s, 1211 w, 1093 s, 1029 m, 998 m, 739 m, 698 s; dH (300 MHz;
CDCl3) 7.21–7.09 (15H, m, PhCH2O and PhCH2OC O), 5.14–
4.94 (3H, m, H3 and PhCH2OC O), 4.51–4.03 (7H, m, PhCH2O,
H4, H5 and H6), 3.89 (1H, s, H2), 3.66 (1H, t, J = 4.4 Hz, H7),
3.56 (1H, d, J = 11.1 Hz, H1), 3.43 (2H, t, J = 9.6 Hz, H1 and
H7), 2.96 (1H, s, OH); dC (75 MHz; CDCl3) 157.0 (C O), 137.9,
137.2, 135.8, 128.7, 128.6, 128.5, 128.3, 128.0, 127.9, 127.8, 127.7
(Ph), 95.1 (d, JC,F = 179.3 Hz, C3), 81.5 (d, J = 28.5 Hz, C4), 73.5
(C6), 73.2, 71.7 (PhCH2O), 68.1 (PhCH2OC O), 67.3 (C5), 67.1
(C1), 64.2 (C7), 63.7 (d, J = 21.8 Hz, C2); dC (Dept-135; 75 MHz;
CDCl3) positive, 128.7, 128.6, 128.5, 128.3, 128.1, 127.9, 127.8,
127.7, 95.1, 81.5, 73.4, 67.3, 63.7; negative, 73.2, 71.7, 68.1, 67.1,
64.2; HRMS(ESI) calcd for C29H32FNO6Na+ [M+Na]+ 532.2106,
found 532.2105.
61.8; HRMS(ESI) calcd for C7H16NO5 [M+H]+ 194.1023, found
+
194.1023.
6: yellow syrup, 89% yield. [a]2D0 -35.6 (c 1.13 in MeOH);
n
max/cm-1 3344 vs, 2934 m, 1409 m, 1040 s; dH (300 MHz; D2O)
4.69 (1H, dt, JH,F = 49.8 Hz, JH,H = 4.8 Hz, H3), 4.12 (1H, ddd, J =
21.9 Hz, 7.5 Hz, 5.1 Hz, H4), 3.69–3.63 (1H, m, H6), 3.60–3.41
(4H, m, H1 and H7), 3.24 (1H, ddd, J = 19.2 Hz, 11.1 Hz, 5.4 Hz,
H2), 2.89 (1H, dd, J = 7.2 Hz, 5.7 Hz, H5); dC (75 MHz; D2O)
99.6 (d, JC,F = 180.8 Hz, C3), 76.5 (d, J = 24.0 Hz, C4), 71.0 (C6),
63.3 (C7), 62.2 (d, J = 6.8 Hz, C5), 61.1 (d, J = 4.5 Hz, C1), 60.7
(d, J = 22.5 Hz, C2); dC (Dept-135; 75 MHz; D2O) positive, 99.6,
76.5, 71.0, 62.2, 60.7; negative, 63.3, 61.1; HRMS(ESI) calcd for
24b: light yellow syrup, 35% yield. [a]2D0 +45.1 (c 1.02 in CH2Cl2);
n
max/cm-1 3435 m, 3063 w, 3032 m, 2943 m, 1685 s, 1496 m, 1454
s, 1415 s, 1349 s, 1211 m, 1095 s, 999 m, 913 m, 771 m, 739 m,
698 m; dH (300 MHz; CDCl3) 7.19–7.04 (15H, m, PhCH2O and
PhCH2OC O), 5.09 (1H, d, JH,F = 49.2 Hz, H3), 4.97 (2H, s,
PhCH2OC O), 4.49–4.19 (5H, m, PhCH2O and H4), 4.08 (1H,
ddd, J = 23.4 Hz, 9.9 Hz, 3.6 Hz, H2), 3.93 (1H, d, J = 5.7 Hz, H6),
3.84 (1H, s, OH), 3.65 (1H, dt, J = 8.4 Hz, 3.9 Hz, H1), 3.51–3.35
(4H, m, H1, H5 and H7); dC (75 MHz; CDCl3) 156.3 (C O),
137.9, 137.4, 135.8, 128.8, 128.7, 128.6, 128.5, 128.3, 128.1, 128.0,
127.9, 127.8, 127.7, 127.5 (Ph), 95.7 (d, JC,F = 180.0 Hz, C3), 82.8
(d, J = 26.3 Hz, C4), 73.2, 71.7 (PhCH2O), 71.0 (d, J = 5.3 Hz,
C5), 68.0 (PhCH2OC O), 67.2 (d, J = 9.8 Hz, C1), 65.3 (C6),
64.0 (d, J = 22.5 Hz, C2), 62.6 (C7); dC (Dept-135; 75 MHz;
CDCl3) positive, 128.8, 128.6, 128.5, 128.3, 128.2, 128.0, 127.9,
127.8, 127.7, 95.7, 82.8, 71.0, 65.3, 64.0; negative, 73.2, 71.7, 68.0,
67.2, 62.6; Found: C, 67.80; H, 6.38; N, 2.81. C29H32FNO6 requires
C, 68.35; H, 6.33; N, 2.75%.
C7H15FNO4 [M+H]+ 196.0980, found 196.0980.
+
26: yellow syrup, 85% yield. [a]2D0 -15.3 (c 1.18 in MeOH);
n
max/cm-1 3337 vs, 2934 m, 1410 m, 1041 s; dH (300 MHz; D2O)
4.72 (1H, dt, JH,F = 53.1 Hz, JH,H = 4.1 Hz, H3), 4.25 (1H, ddd,
J = 21.6 Hz, 6.3 Hz, 4.2 Hz, H4), 3.65–3.44 (5H, m, H1, H6 and
H7), 3.26 (1H, ddd, J = 19.5 Hz, 10.2 Hz, 5.7 Hz, H2), 2.93 (1H,
t, J = 6.2 Hz, H5); dC (75 MHz; D2O) 100.0 (d, JC,F = 180.0 Hz,
C3), 76.5 (d, J = 24.8 Hz, C4), 72.1 (C6), 63.3 (C7), 62.7 (d, J =
6.0 Hz, C5), 61.5 (d, J = 23.3 Hz, C2), 60.6 (d, J = 6.0 Hz, C1); dC
(Dept-135; 75 MHz; D2O) positive, 100.0, 76.5, 72.1, 62.8, 61.5;
negative, 63.3, 60.6; HRMS(ESI) calcd for C7H15FNO4 [M+H]+
+
196.0980, found 196.0979.
General procedures for synthesis of aldehyde 27 and 28
The diol mixture of 23 or 24 (1 eq) was dissolved in MeOH,
aqueous NaIO4 (1 eq) was added at room temperature, many white
particles appeared. TLC showed completion of the reaction 1 h
later, particles were filtered, washed with EtOAc and MeOH, the
filtrate was then concentrated under reduced pressure to give the
aldehyde 27 or 28.
General procedures for synthesis of L-homoDMDP (5), its C-3
fluorinated derivative (6) and their C-6 epimers (25 and 26)
The N-Cbz protected diol 23a, 23b, 24a or 24b (1 eq) was dissolved
in methanol, followed by 10% Pd/C (20 wt%) and 6 N HCl. The
suspension was stirred under hydrogen atmosphere for 48–60 h,
and TLC showed completion of the reaction. Hydrogen was then
replaced by nitrogen, catalyst was filtered, and the filtrate was
concentrated in vacuo. The residue was neutralized with conc.
NH3 and concentrated again. The residue was then purified by
an acidic ion exchanger column (Dowex 5W¥8-400, H+ form,
Aldrich, column size: 1.3 ¥ 14 cm), eluting with distilled water
(100 mL) and then 1 N NH4OH (50 mL), affording the target
compound 5, 25, 6 or 26.
27: light yellow syrup, 98% yield. [a]2D0 +57.0 (c 1.20 in CHCl3);
n
max/cm-1 3032 w, 2867 w, 1706 vs, 1454 m, 1409 s, 1350 s, 1207 m,
1096 s; dH (300 MHz; CDCl3) 9.46 (0.5H, d, J = 1.5 Hz, CHO),
9.37 (0.5H, d, J = 1.8 Hz, CHO), 7.38–7.18 (20H, m, PhCH2O),
5.24–5.06 (2H, m), 4.70–4.30 (8H, m), 4.18 (1H, s), 4.07 (1H, d,
J = 4.5 Hz), 3.87 (1H, ddd, J = 66.6 Hz, 9.0 Hz, 4.5 Hz), 3.65–3.57
(1H, m); dC (75 MHz; CDCl3) 200.3, 200.1, 155.5, 155.3, 138.3,
138.1, 137.0, 136.8, 136.1, 135.9, 128.6, 128.5, 128.4, 128.1, 128.0,
127.9, 127.8, 127.7, 127.6, 84.6, 83.4, 81.2, 79.8, 73.2, 73.1, 71.8,
3412 | Org. Biomol. Chem., 2011, 9, 3405–3414
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71.1, 70.9, 68.2, 67.7, 67.6, 67.5, 63.5, 63.2; HRMS(ESI) calcd for
negative, 73.3, 71.9, 67.7, 67.5, 62.3, 60.8; HRMS(ESI) calcd for
+
+
C35H36NO6 [M+H]+ 566.2537, found 566.2518.
C28H31FNO5 [M+H]+ 480.2181, found 480.2161.
28: light yellow syrup, 99% yield. [a]2D0 +57.1 (c 0.49 in CH2Cl2);
n
max/cm-1 3447 w, 3033 w, 2871 w, 1708 s, 1453 m, 1411 s, 1351
General procedures for synthesis of L-DMDP (3) and its C-3
fluorinated analogue (4)
s, 1207 m, 1097 s, 990 m, 741 m, 698 m; dH (300 MHz; CDCl3)
9.35 (1H, d, J = 27.9 Hz, HC O), 7.26–7.15 (15H, m, PhCH2O
and PhCH2OC O), 5.20–4.98 (3H, m, H3 and PhCH2OC O),
4.59–4.23 (6H, m, PhCH2O, H1 and H4), 4.07 (1H, d, J =
11.1 Hz, H5), 3.98–3.84 (1H, m, H1), 3.70–3.45 (1H, m, H2);
dC (75 MHz; CDCl3) 198.9 (d, J = 8.3 Hz, HC O), 155.0, 154.1
(PhCH2OC O), 137.9, 137.7, 136.3, 135.8, 135.6, 128.5, 128.4,
128.3, 128.2, 127.9, 127.8, 127.7 (Ph), 94.6 (d, J = 179.3 Hz, C3),
93.4 (d, J = 178.5 Hz, C3), 83.3 (d, J = 30.8 Hz, C4), 82.3 (d,
J = 30.8 Hz, C4), 73.3, 72.2 (PhCH2O), 70.8 (C5), 67.9, 67.8
(PhCH2OC O), 67.1 (d, J = 9.8 Hz, C1), 66.4 (d, J = 9.8 Hz,
C1), 63.8 (d, J = 21.8 Hz, C2), 63.3 (d, J = 21.8 Hz, C2); dC (Dept-
135; 75 MHz; CDCl3) positive, 198.9, 128.7, 128.5, 128.4, 128.3,
128.2, 127.9, 127.8, 127.7, 94.6, 93.4, 83.3, 82.3, 70.8, 63.8, 63.3;
negative, 73.3, 72.2, 67.9, 67.8, 67.1, 66.4; HRMS(ESI) calcd for
C28H28FNO5Na+ [M+Na]+ 500.1844, found 500.1854.
The N-Cbz protected alcohol 29 or 30 (1 eq) was dissolved in
methanol, followed by 10% Pd/C (20 wt%) and 6 N HCl, the
suspension was stirred under hydrogen atmosphere for 48–72 h.
TLC showed completion of the reaction. Hydrogen was then
replaced by nitrogen, catalyst was filtered, and the filtrate was
concentrated in vacuo. The residue was neutralized with conc.
NH3 and concentrated again. The residue was then purified by
an acidic ion exchanger column (Dowex 5W¥8-400, H+ form,
Aldrich, column size: 1.3 ¥ 14 cm), eluting with distilled water
(100 mL) and then 1 N NH4OH (50 mL), affording the target
compound 3 or 4.
◦
3: light yellow solid, 92% yield. mp 108–110 C; [a]2D0 -51.8 (c
0.97 in H2O) [lit.7 mp 116–117 ◦C (MeOH); [a]2D3 -52.7 (c 0.28 in
H2O)]; dH (300 MHz; D2O) 3.93 (2H, d, J = 6.3 Hz, H3 and H4),
3.76–3.71 (4H, m, H6), 3.42 (2H, s, H2 and H5); dC (75 MHz;
D2O) 74.0, 62.2, 57.7; dC (Dept-135; 75 MHz; D2O) positive, 74.1,
62.3; negative, 57.7.
General procedures for synthesis of alcohol 29 and 30
4: yellow syrup, 94% yield. [a]2D0 -40.2 (c 1.00 in MeOH);
The solution of aldehyde 27 or 28 (1 eq) in EtOH was cooled by an
ice-water bath, and NaBH4 (1.1 eq) was added in several batches,
obvious heat can be observed. The suspension was stirred for 1 h
and quenched by aqueous NH4Cl, EtOH and water was removed
in vacuo, the residue was washed by EtOAc several times and salt
was filtered. The filtrate was concentrated in vacuo to give alcohol
29 or 30.
n
max/cm-1 3321 s, 2933 m, 1424 m, 1045 s; dH (300 MHz; D2O)
4.72 (1H, dt, JH,F = 54.0 Hz, JH,H = 4.5 Hz, H3), 4.07 (1H, ddd, J =
21.0 Hz, 6.6 Hz, 4.5 Hz, H4), 3.64–3.51 (4H, m, H1 and H6), 3.26
(1H, ddd, J = 20.7 Hz, 11.1 Hz, 6.0 Hz, H2), 3.01 (1H, dd, J =
11.7 Hz, 5.7 Hz, H5); dC (75 MHz; D2O) 100.0 (d, JC,F = 180.8 Hz,
C3), 76.5 (d, J = 23.2 Hz, C4), 62.4 (d, J = 6.0 Hz, C5), 61.4, 61.2
(C1 and C6), 60.8 (C2); dC (Dept-135; 75 MHz; D2O) positive,
100.0, 76.5, 62.4, 60.8; negative, 61.4, 61.2; HRMS(ESI) calcd for
29: light yellow syrup, 78% yield. [a]2D0 +24.0 (c 0.50 in CHCl3);
n
max/cm-1 3445 m, 3031 m, 2923 m, 1760 m, 1698 s, 1496 m, 1454
C6H13FNO3 [M+H]+ 166.0874, found 166.0873.
+
m, 1410 m, 1349 m, 1209 m, 1094 vs, 736 m, 697 m; dH (300 MHz;
CDCl3) 7.23–7.10 (20H, m, PhCH2O), 5.02 (2H, dd, J = 36.9 Hz,
12.3 Hz, PhCH2OC O), 4.56–4.24 (6H, m, PhCH2O), 4.08 (1H,
d, J = 14.7 Hz), 4.00 (1H, s), 3.91 (1H, s), 3.80 (3H, s), 3.62 (1H, dd,
J = 9.0 Hz, 4.2 Hz), 3.43 (1H, t, J = 9.3 Hz); dC (75 MHz; CDCl3)
155.7, 154.7, 138.4, 138.1, 137.4, 137.3, 137.0, 136.3, 136.2, 128.6,
128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.6, 85.3, 84.2, 81.7,
80.6, 73.1, 71.4, 71.3, 68.4, 67.6, 67.5, 67.3, 66.8, 65.4, 63.7, 63.6,
63.4, 62.0; dC (Dept-135; 75 MHz; CDCl3) positive, 128.6, 128.4,
128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.6, 85.3, 84.2, 81.7,
80.6, 66.8, 65.4, 63.4; negative, 73.1, 71.4, 71.3, 68.4, 67.6, 67.5,
67.3, 63.7, 62.0.
General procedures for synthesis of 31 and 32 for NOESY
determination of diol 23 and 24
To a solution of diol 23a or 24a (1 eq) in MeOH was added NaOH
(10 eq) and stirred at room temperature overnight. Water was
added and the solution was extracted with EtOAc twice, organic
phases were combined and concentrated under reduced pressure,
then directly purified by preparative plate to get bicyclic product
31 or 32.
31: light yellow syrup, 82% yield. [a]2D0 +15.4 (c 1.02 in CHCl3);
30: light yellow syrup, 86% yield. [a]2D0 +24.9 (c 0.89 in CH2Cl2);
n
max/cm-1 3063 w, 3031 w, 2867 m, 1673 vs, 1457 w, 1454 m, 1434
n
max/cm-1 3447 w, 3032 w, 2937 w, 1764 w, 1703 s, 1497 w, 1454 m,
m, 1363 m, 1260 w, 1089 s; dH (600 MHz; CDCl3) 7.27–7.17 (15H,
m, PhCH2O), 4.56 (2H, s, PhCH2O), 4.48 (1H, d, J = 11.9 Hz,
PhCH2O), 4.44 (1H, d, J = 11.6 Hz, PhCH2O), 4.42 (1H, d, J =
12.0 Hz, PhCH2O), 4.38 (1H, d, J = 11.6 Hz, PhCH2O), 4.16–
4.14 (1H, m, H7), 4.12 (1H, dd, J = 3.8 Hz, 3.3 Hz, H6), 4.09
(1H, dd, J = 10.5 Hz, 4.6 Hz, H3), 3.89 (1H, dd, J = 6.7 Hz,
4.4 Hz, H5), 3.82 (1H, t, J = 10.2 Hz, H3), 3.74–3.71 (m, 1H, H4),
3.64 (dd, 1H, J = 9.5 Hz, 6.4 Hz, H9), 3.53 (dd, 1H, J = 9.6 Hz,
3.7 Hz, H9), 3.42 (dd, 1H, J = 7.9 Hz, 7.5 Hz, H4a), 2.61 (br s,
1H, OH); dC (75 MHz; CDCl3) 150.6, 136.9, 136.5, 127.6, 127.5,
127.4, 127.0, 126.9, 126.7, 86.0, 81.9, 72.3, 71.1, 68.2, 67.5, 64.5,
1413 s, 1350 m, 1096 s, 1028 m, 739 m, 698 m; dH (300 MHz; CDCl3)
7.42–7.38 (15H, m, PhCH2O and PhCH2OC O), 5.46–5.14 (3H,
m, H3 and PhCH2OC O), 4.76–4.52 (4H, m, PhCH2O), 4.48–
4.05 (5H, m, H1, H4 and H6), 3.85–3.65 (2H, m, H2 and H5);
dC (75 MHz; CDCl3) 155.5, 154.5 (PhCH2OC O), 138.3, 138.0,
137.5, 137.3, 136.3, 136.1, 128.8, 128.6, 128.4, 128.3, 128.1, 128.0,
127.8, 127.7 (Ph), 95.3 (d, JC,F = 179.3 Hz, C3), 94.8 (d, JC,F
=
177.8 Hz, C3), 82.9 (d, J = 26.3 Hz, C4), 82.7 (d, J = 27.0 Hz, C4),
73.3, 71.9 (PhCH2O), 67.7 (PhCH2OC O), 67.5 (d, J = 5.3 Hz,
C1), 66.4, 65.1 (C5), 63.6 (d, J = 22.5 Hz, C2), 62.3, 60.8 (C6); dC
(Dept-135; 75 MHz; CDCl3) positive, 128.8, 128.6, 128.4, 128.3,
128.1, 128.0, 127.8, 127.7, 95.3, 94.8, 82.9, 82.7, 66.4, 65.1, 63.6;
63.7, 61.7; HRMS(ESI) calcd for C29H32NO6 [M+H]+ 490.2224,
+
found 490.2226.
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32: light yellow solid, 76% yield. mp 84–86 C; [a]2D0 -31.6 (c
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0.38 in CH2Cl2); nmax/cm-1 3353 m, 3032 w, 2922 m, 1682 s, 1471
m, 1437 m, 1361 w, 1280 m, 1100 s, 1029 m, 998 m, 740 m, 698 m;
H (600 MHz; CDCl3) 7.39–7.30 (10H, m, PhCH2O), 5.31 (1H, dt,
JH,F = 55.8 Hz, JH,H = 4.8 Hz, H6), 4.84–4.54 (4H, m, PhCH2O),
4.42 (1H, ddd, J = 21.6 Hz, 9.0 Hz, 5.4 Hz, H5), 4.35 (1H, dd,
J = 12.0 Hz, 2.4 Hz, H3), 4.23 (1H, d, J = 12.0 Hz, H3), 4.18
(1H, dt, J = 27.0 Hz, 3.6 Hz, H7), 4.05 (1H, s, H4), 3.92 (1H, dd,
J = 10.2 Hz, 3.6 Hz, H9), 3.76–3.72 (2H, m, H4a and H9), 2.93
(1H, d, J = 7.2 Hz, OH); HRMS(ESI) calcd for C22H24FNO5Na+
[M+Na]+ 424.1531, found 424.1534.
d
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Acknowledgements
This work is supported by The National Basic Research Program
of China (No. 2009CB526511 and No. 2011CB808603), The
Ministry of Science and Technology and the Ministry of Health
of the P.R. China (No. 2009ZX09501-006), and The Chinese
Academy of Sciences.
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3414 | Org. Biomol. Chem., 2011, 9, 3405–3414
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The Royal Society of Chemistry 2011
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