General intermediates for the synthesis of 6-C-alkylated DMDP-related natural products

Article abstract of DOI:10.3390/molecules18066723

Protected L-homoDMDP en-8 and its C-6 epimer en-7 were prepared through two different pathways starting from the vinylpyrrolidine en-9. Based on the NMR and X-ray analysis, the stereochemistry of homoDMDP at C-6 was confirmed to be consistent with reported data. Compounds en-7 and en-8 are general intermediates for the synthesis of a series of 6-C-alkylated DMDP-related natural products, such as broussonetine G, homoDMDP-7-O-apioside, homoDMDP-7-O-β-D-xyloside and so on.

Full text of DOI:10.3390/molecules18066723

Molecules 2013, 18, 6723-6733; doi:10.3390/molecules18066723
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
General Intermediates for the Synthesis of 6-C-Alkylated
DMDP-Related Natural Products
Mu-Hua Huang 1,2, Yi-Xian Li 1, Yue-Mei Jia 1 and Chu-Yi Yu 1,*
1
Beijing National Laboratory for Molecular Science (BNLMS),
CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100191, China
2
School of Materials Science and Engineering, Beijing Institute of Technology,
Beijing 100081, China
* Author to whom correspondence should be addressed; E-Mail: yucy@iccas.ac.cn.
Received: 8 May 2013; in revised form: 24 May 2013 / Accepted: 27 May 2013 /
Published: 7 June 2013
Abstract: Protected L-homoDMDP en-8 and its C-6 epimer en-7 were prepared through
two different pathways starting from the vinylpyrrolidine en-9. Based on the NMR and
X-ray analysis, the stereochemistry of homoDMDP at C-6 was confirmed to be consistent
with reported data. Compounds en-7 and en-8 are general intermediates for the synthesis of
a series of 6-C-alkylated DMDP-related natural products, such as broussonetine G,
homoDMDP-7-O-apioside, homoDMDP-7-O-β-D-xyloside and so on.
Keywords: homo-DMDP; broussonetine G; homoDMDP-7-O-apioside; glycosidase
inhibitors; cyclic nitrones
1. Introduction
The naturally occurring polyhydroxylated alkaloid (2R,3R,4R,5R)-2,5-dihydroxymethyl-3,4-
dihydroxypyrrolidine (DMDP, 1, Figure 1) [1] has become a key iminosugar in the field of glycosidase
inhibitors [2–4]. 6-C-Butyl-DMDP (2, Figure 1) [5] and broussonetine G (3, Figure 1) [6–8] represent a
class of 6-C-alkyl-DMDP natural products with high β-glycosidase inhibitory properties. Another 6-C-
alkyl-DMDP example is 2,5-dideoxy-2,5-imino-glycero-D,L-manno-heptitol (homo-DMDP, 4, Figure 1),
which was synthesized by the Wong group [9] in 1995 before it was isolated in 1997 [10] from
Hyacinthaceae plants. In addition, 7-O-glycosylated homoDMDP natural products such as

Molecules 2013, 18
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homoDMDP-7-O-apioside (5, Figure 1) and homoDMDP-7-O-β-D-xyloside (6, Figure 1), isolated
from bluebell, also showed very highly selective glycosidase inhibition properties [11]. Interestingly,
the stereochemistry at C-6 of the above mentioned 6-C-alkyl-DMDP natural products was not reported
upon their isolation owing to limitations on NMR analysis due to the scarce amounts of substance
available from natural sources. An unambiguous stereochemistry elucidation of the homoDMDP-related
natural products is needed for establishing the structure-activity relationships of these compounds in medicinal
chemistry, and a collective synthesis of these natural products based on a common intermediate would
be of great significance [12] for speeding up the chemical biology study of these fascinating molecules.
Figure 1. DMDP, homoDMDP and 6-C-alkyl-DMDP natural products.
OH
H
N
OH
H
N
HO
H
N
HO
O
HO
*
6
OH
6
5
O
2
3
H
H
H
4
OH
HO
HO
OH
HO
OH
Broussonetine G
DMDP
1
6-C-Butyl-DMDP
2
3
OH
HO
O
OH
OH
OH
7
OH
O
O
H
6
O
HO
OH
OH
H
N
OH
H
N
HO
HO
N
2
3
*
*
5
OH
H
4
H
H
HO
OH
HO
OH
HO
OH
homoDMDP
4
homoDMDP-7-O-β-
HomoDMDP-7-O-apioside
D-xylopyranoside
5
6
In recent years, some of the synthetic L-enantiomers of iminosugars, were found to be even more
powerful and specific glycosidase inhibitors than the natural products, e.g., L-DMDP vs. DMDP [13],
(+)-steviamine vs. natural (-)-steviamine [14]. These experimental results provided a promising new
direction for pharmaceutical chemistry. However, a substantive explanation for this fact requires more
information about the stereochemistry of the relevant compounds. In order to promote research on
iminosugars, our group has developed a powerful strategy for the synthesis of DMDP-related natural
products or analogues via cyclic nitrone intermediates [15], which has led to easy access to a series of
DMDP-related iminosugars [13,14,16–21], as well as glycosidase inhibitors.
Although Wong et al. had indicated the absolute configuration of homoDMDP to be
(2R,3R,4R,5R,6S) based on their enantiospecific synthesis of a series of five-membered iminosugars [22],
no direct experimental proof was available until our group reported the synthesis of
L-homoDMDP [19]. There, we disclosed the stereochemistry of L-homoDMDP determined by
analyzing the 2D-NMR of an oxazinone intermediate, a conformation-locked L-homoDMDP. In this
article, we report a further confirmation of L-homoDMDP’s stereochemistry based on X-ray and 2D-NMR
analysis of its oxazolidinone derivatives. In addition, both epimers of protected L-homoDMDP at C-6

Molecules 2013, 18
6725
were obtained readily, which are common intermediates for enantiomers of 6-C-alkyl-DMDP natural
products such as homoDMDP-7-O-apioside and homoDMDP-7-O-β-D-xyloside.
2. Results and Discussion
6-C-Alkyl-DMDP iminosugars have attracted lots of attention, and several syntheses are available
in the literature [7,22]. However, these syntheses are either tedious or the method was only suitable for
a specific compound. In order to solve the material supply problem and speed up the study of
glycosidase inhibition, a practical synthesis of this family of natural products is in great demand. In
this regard, the collective synthesis strategy [12] relying on an advanced common intermediate
provides a good opportunity. In addition, a full assignment of the stereochemistry of 6-C-alkyl-DMDP
iminosugars requires both epimers.
Taking homo-DMDP-7-O-apioside and homo-DMDP-7-O-β-D-xylopyranoside as examples, we
envisioned that it is necessary to obtain both C-6 epimers 7 and 8, which could be reached from the
same intermediate 9 (Scheme 1). Furthermore, conformation-locked molecules 7 and 8 are very good
intermediates for stereochemistry assignment based on 2D-NMR analysis, and all the isomers or
intermediates represent interesting medicinal chemistry targets. From a retrosynthesis point of view,
homoDMDP-related natural products 5 and 6 could be synthesized via glycosylation of alcohol 7 or 8,
which could be accessed from all-trans substituted pyrrolidine 9 by alkene oxidation. Based on the
well-developed chemistry of highly stereoselective addition of organometallic reagents to cyclic
nitrones [23–25], pyrrolidine 9 could be prepared on a large scale with extreme purity.
Scheme 1. Synthesis of en-7.
Cbz
N
I
BnO
BnO
BnO
BnO
H
N
AgNO3
I2
O
Acetonitrile
57%
Acetonitrile
84%
BnO
OBn
O
en-9
ONO2
OH
O
BnO
BnO
H
N
H
Zn / NH4Ac
BnO
BnO
BnO
BnO
O
O
N
MeOH
92%
O
12
en-7
With grams of vinyl-containing pyrrolidine en-9 [19] in hand, the synthesis of en-7 and en-8 was
attempted (Scheme 1). The terminal alkene en-9 was treated with iodine in acetonitrile, and the
oxazolidinone 11 was obtained in 57% yield, with structure supported by its IR data (νmax 1,762 cm−1)
and 13C-NMR spectrum (δ 159.98 ppm). Its relative configuration was studied by its NOESY spectrum
1
based on the full assignment of all protons through H-NMR and 2D-NMR (COSY, HMBC). The
strong correlations observed between H-3/H-1 as well as H-5/H-1 revealed that H-1,H-3 and H-5 were
on the underside of the pyrrolidine ring (Figure 2), while the strong correlations between H-2/H-4

Molecules 2013, 18
6726
showed they were on the same side. i.e., the pyrrolidine was all-trans substituted, which was consistent
with the previous results reported by our group. The correlations between H-5/H-1 as well as H-5/H-7
showed the C(7)H2I was on the upper side of the oxazolidinone ring. Furthermore, the above
determination of relative as well as absolute configuration of the oxazolidinone 11 was unambiguously
confirmed to be (2S,3S,4S,5R,6S) by X-ray diffraction [26]. The treatment of iodide 11 by silver nitrate
followed by reductive hydrolysis [27] furnished the alcohol en-7 in a total yield of 77% over two steps.
Since during these two steps the stereocenters have not been touched, the streochemistry of en-7 was
determined to be (2S,3S,4S,5S,6S).
Figure 2. Stereochemistry elucidation of 11 by NOESY and X-ray analysis.
α,β
H-1
H-3
H-2
H-5
H-6
H-4
α
H-7
β
H-7
H
CH2I
6
BnO
7
5
H
4
CH2OBn
(H-7,H-5)
1
H
O
N
3
BnO
H
2
O
H
(H-1, H-5)
11
(H-1, H-3)
(H-2,H-4)
11
In the course of the synthesis of L-homoDMDP, we were delighted to find that the major product 13
(Scheme 2) obtained from dihydroxylation on terminal alkene en-9 was the right diastereomer for
L-homoDMDP, which was prepared by the hydrogenation on diol 13 to remove the protecting groups.
The stereochemistry of L-homoDMDP was confirmed to be (2S,3S,4S,5S,6R) based on a conformation-
locked oxazinone intermediate [19]. In order to provide more evidence for the stereochemistry
confirmation of homoDMDP, as well as common intermediates in the collective synthesis of
homoDMDP-related pyrrolidine natural products, we decided to make the correseponding
oxazolidinone derivatives. The diol 13 was selectively protected as trityl ether 14, the secondary alcohol
14 was then treated with alkaline solution, and the oxazolidinone 15 was obtained in 69% yield over two
steps. After treatment of trityl ether 15 with mineral acid, the alcohol en-8 was obtained in 85% yield
(Scheme 2). Conformation of the oxazolidinone structure was supported by its IR data (νmax 1,758 cm−1)
and 13C-NMR spectrum (δ 160.03 ppm).

Molecules 2013, 18
6727
Scheme 2. Synthesis of en-8.
Cbz
N
OTr
OH
Cbz
N
OH
OH
Cbz
N
BnO
BnO
BnO
BnO
TrCl
Py.
ref 19
H
H
BnO
OBn
BnO
OBn
OBn
90%
en-9
14
13
OH
OTr
BnO
BnO
BnO
BnO
BnO
H
N
H(R)
NaOH
HCl
MeOH
O
O
N
MeOH
85%
77%
O
O
BnO
15
en-8
Similarly, the relative configuration of alcohol en-8 was assigned unambiguously through NOESY
spectrum (Figure 3). The strong correlations observed between H-3/H-1, H-5/H-1, as well as H-5/H-3
revealed H-1, H-3 and H-5 were on the upper side of the pyrrolidine ring, i.e., the pyrrolidine was
all-trans-substituted. The correlations between H-7/H-4 showed the C(7)H2OH was on the underside
of the oxazolidinone ring. Based on the above analysis as well as comparison with en-7, the
stereochemistry of en-8 was deduced to be (2S,3S,4S,5S,6R), and the configuration of homoDMDP
was determined as (2R,3R,4R,5R,6S), which was consistent with reported data [19].
Figure 3. Stereochemistry elucidation of en-8 by NOESY.
H-5
α,β
H-1
H-6
H-3
H-4
α,β
H-7
H-2
H
H
6
BnO
5
H
(H-3,H-1
(H-5,H-1)
4
CH2OBn
7
1
CH2OH
O
O
N
3
BnO
H
2
H
en-8
OH
BnO
(H-7,H-4)
(H-1,H-5)
H
(R)
(H-5,H-3)
BnO
O
N
O
BnO
en-8

Molecules 2013, 18
6728
With both C-6 epimers en-7 and en-8 in hand, the syntheses of the enantiomers of homo-DMDP-7-
O-apioside and homo-DMDP-7-O-β-D-xylopyranoside by glycosylation of en-7 and en-8 were on the
right course. In addition, iodide 11 represents an ideal intermediate for the total synthesis of
enantiomers of 6-C-alkyl-DMDP natural products such as L-6-C-butyl-DMDP and (+)-broussonetine
G. For the total synthesis of the natural 6-C-alkyl-DMDP pyrrolidines, we are currently working on the
synthesis of cyclic nitrone 10. The relevant results will be reported in due course.
3. Experimental
3.1. General
All reagents were used as received from commercial sources without further purification or
prepared as described in the literature. Tetrahydrofuran was distilled from sodium and benzophenone
immediately before use. Reaction mixtures were stirred using Teflon-coated magnetic stir bars.
Analytical TLC was performed with 0.20 mm silica gel 60F plates with 254 nm fluorescent indicator.
Plates were visualized by ultraviolet light and treatment with Pancaldi reagent [(NH4)6MoO4,
Ce(SO4)2, H2SO4, H2O] or 0.5% ninhydrin in acetone stain, followed by gentle heating. Chromatographic
purification of products was carried out by flash chromatography on silica gel (230–400 mesh) as well
as on the 001 × 7 (732#) strong acid styrene cation exchange resin (Tianjin Kermel Chemical Reagent
Development Center, Tianjin, China). Melting points were determined using an Electrothermal melting
point apparatus. Both melting points and boiling 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 and AV600 magnetic resonance
spectrometers. Chemical shifts (δ) are reported in ppm, and coupling constants (J) are in Hz. The
following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet. High-resolution mass spectra (HRMS) were recorded on an APEXII
FT-ICR (SIMS) mass spectrometer. Polarimetry was carried out using an Optical Activity AA-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. Single-crystal X-ray diffraction was collected on a
Rigaku RAPID-AUTO diffractometer.
(1S,5S,6S,7S,7aR)-6,7-bis(Benzyloxy)-5-((benzyloxy)methyl)-tetrahydro-1-(iodomethyl)pyrrolo[1,2-c]
oxazol-3(1H)-one (11). To a solution of alkene en-9 (0.22 g, 0.39 mmol) in acetonitrile (3 mL), iodine
(0.36 g, 1.4 mmol) was slowly added, and the resulting purple mixture was stirred at r.t. for 3.5 h. The
reaction was then quenched by adding sat. aqueous Na2S2O3, and extracted with EtOAc. The combined
organic extracts were dried over anhydrous Na2SO4, concentrated, the residue was purified by FCC
(silica gel, eluted with 10%–20% EtOAc in petroleum ether) to give the title oxazolidinone 11 as a
colorless crystalline product (0.13 g, yield 57%). IR（KBr, cm−1)1,767 (vs), 1,455 (w), 1,362 (w),
1,213 (w), 1,100 (w). [α]2D5 = +55.8° (c 0.86, CHCl3). H-NMR (CDCl3, 600 MHz): δ (ppm)
1
7.35–7.25 (m, 15H), 4.64–4.44 (m, 6H), 4.37–4.34 (m, 1H), 4.22 (t, 1H, J = 2.7 Hz), 4.17 (t, 1H,
J = 6.6 Hz), 3.90 (dd, 1H, J = 3.8 and 5.5 Hz), 3.71 (t, 1H, J = 4.3 Hz), 3.59–3.53 (m, 2H), 3.28 (dd,
13
1H, J = 4.3 and 10.4 Hz), 3.18 (dd, 1H, J = 8.3 and 10.1 Hz). C-NMR (CDCl3, 75 MHz): δ (ppm)
160.00, 137.84, 137.36, 137.30, 128.64, 128.51, 128.45, 128.21, 127.96, 127.91, 127.78, 127.70,

Molecules 2013, 18
6729
87.55, 84.99, 78.26, 73.30, 72.74, 71.94, 69.32, 68.12, 62.76, 5.90. DEPT-135 (CDCl3, 75 MHz) δ
(ppm): Positive: 128.64, 128.51, 128.45, 128.22, 127.96, 127.91, 127.78, 127.70, 87.55, 84.98, 78.26,
68.11, 62.75; Negative: 73.30, 72.74, 71.94, 69.32, 5.91. FTICR-MS m/z: 600.1243 [M+H]+
(C29H31NO5I+ requires 600.1241).
(1S,5S,6S,7S,7aR)-6,7-bis(Benzyloxy)-5-((benzyloxy)methyl)-tetrahydro-1-(O-nitroate-methyl)pyrrolo[1,2-c]
oxazol-3(1H)-one (12). To a solution of iodide 11 (0.21 g, 0.35 mmol) in acetonitrile (6 mL) silver
nitrate (0.18 g, 1.0 mmol) was added, the resulting reaction mixture was heated to reflux for 40 h. The
resulting solid was filtered off, the filtrates was concentrated, the residue was purified by FCC (silica
gel, eluted with 10-30% EtOAc in petroleum ether) to give the nitrate 12 (0.16 g, 84% yield) as
colorless syrup. IR (KBr, cm−1)：2,864 (w), 1,765 (vs), 1,638 (s), 1,279 (s), 1,096 (m), 739 (m), 698 (m).
[α]2D5 = +22.1° (c 1.0, CHCl3). H-NMR (CDCl3, 300 MHz): δ (ppm) 7.36–7.19 (m, 15H), 4.69–4.36
1
(m, 9H), 4.28 (t, 1H, J = 3.3 Hz), 4.15 (d, 1H, J = 2.9 Hz), 3.90 (dd, 1H, J = 4.0 and 6.0 Hz), 3.68 (d,
1H, J = 6.1 Hz), 3.58 (d, 2H, J = 5.4 Hz). 13C-NMR (CDCl3, 75 MHz): δ (ppm) 159.30, 137.75,
137.24, 128.78, 128.55, 128.48, 128.43, 128.07, 127.98, 127.93, 127.85, 127.71, 87.66, 85.30, 74.76,
73.35, 72.80, 72.18, 71.88, 69.43, 64.31, 62.69. DEPT-135 (CDCl3, 75 MHz) δ (ppm): Positive:
128.78, 128.55, 128.48, 128.06, 127.99, 127.93, 127.85, 127.71, 87.65, 85.30, 74.76, 64.30, 62.69;
+
Negative: 73.35, 72.80, 72.18, 71.88, 69.42. FTICR-MS m/z: 535.2079 [M+H]+ (C29H31N2O8 requires
535.2075).
(1S,5S,6S,7S,7aS)-6,7-bis(Benzyloxy)-5-((benzyloxy)methyl)-tetrahydro-1-(hydroxymethyl)pyrrolo[1,2-c]
oxazol-3(1H)-one (en-7). To a suspension of nitrate 12 (0.10 g, 0.19 mmol) and ammonium acetate
(0.08 g, 1 mmol) in MeOH (5 mL) was added zinc powder (0.11 g, 1 mmol). The resulting mixture
was stirred at r. t. The solvents were removed in vacuo, the residue was purified via FCC (silica gel,
eluted with 10%–40% EtOAc in petroleum ether) to give the alcohol en-7 (87 mg, yield 92%) as a
colorless syrup. IR (KBr, cm−1): 3,443 (w), 3,062 (vw), 3,031 (w), 2,928 (w), 2,867 (w), 1,758 (vs),
1,101 (m), 1,070 (m). [α]2D5 = +14.2° (c 1.1, CHCl3). H-NMR (CDCl3, 300 MHz): δ (ppm) 7.31–7.14
1
(m, 15H), 4.31 (dd, 1H, J = 4.0 and 4.5 Hz), 4.22 (t, 1H, J = 3.0 Hz), 4.18–4.09 (m, 1H), 3.88 (dd, 1H,
13
J = 3.9 and 5.9 Hz), 3.76–3.66 (m, 2H), 3.63–3.49 (m, 3H), 1.96 (t, 1H, J = 6.5 Hz, OH). C-NMR
(CDCl3, 75 MHz): δ (ppm) 160.24, 137.85, 137.43, 137.32, 128.65, 128.49, 128.44, 128.20, 127.94,
127.80, 127.77, 127.70, 87.89, 85.51, 80.05, 73.28, 72.50, 72.01, 69.40, 63.96, 63.55, 62.46.
DEPT-135 (CDCl3, 75 MHz) δ (ppm) Positive: 128.65, 128.49, 128.44, 128.21, 127.95, 127.80,
127.77, 127.70, 87.88, 85.50, 80.06, 63.95, 62.46; Negative: 73.27, 72.50, 72.01, 69.39, 63.54.
FTICR-MS m/z: 490.2228 [M+H]+ (C29H32NO6+ requires 490.2224).
(2S,3S,4S,5S)-Benzyl 3,4-bis(benzyloxy)-2-((benzyloxy) methyl)-5-((R)-1,2-dihydroxyethyl)pyrrolidine-
1-carboxylate (14). To a solution of diol (0.22 g, 0.4 mmol) in DCM (3 mL) was added pyrridine
(1 mL) and trityl chloride (0.22 g, 0.8 mmol). The resulting reaction mixture was stirred at r.t. for 14 h.
The solvents were removed in vacuo, the residue was dissolved in EtOAc and HCl (1 N). After
extraction, the combined organics were dried over anhydrous Na2SO4, concentrated, the residue was
purified by FCC (silica gel, elutedwith 10%–30% EtOAc in petroleum ether) to give the trityl ether 14
(0.28 g, yield 90%). IR (KBr, cm−1):3,435 (s), 1,702 (vs), 1,075 (vs). [α]D25 = +64.8° (c 1.3, CHCl3).

Molecules 2013, 18
6730
1H-NMR (CDCl3, 300 MHz): δ (ppm) 7.56–7.03 (m, 35H), 5.36–5.14 (m, 2H), 4.80 (brs, 0.5 H),
4.69–4.07 (m, 11H), 3.90 (brs, 0.5 H), 3.85 (dd, 1H, J = 4.1 and 8.9 Hz), 3.63–3.54 (m, 1H), 3.51–3.41
13
(m, 1H), 3.06 (t, 0.5H, J = 8.8 Hz), 2.92 (t, 0.5H, J = 8.9 Hz). C-NMR (CDCl3, 75 MHz): δ (ppm)
154.67, 154.50, 143.83, 143.70, 138.42, 138.16, 137.55, 137.41, 136.44, 136.24, 128.80, 128.66,
128.61, 128.39, 128.23, 128.00, 127.89, 127.68, 127.62, 127.57, 127.35, 127.26, 127.08, 127.05,
86.99, 86.90, 82.09, 81.62, 81.41, 80.68, 73.16, 73.09, 71.51, 71.42, 68.77, 68.60, 67.52, 67.45, 67.34,
67.17, 66.70, 65.97, 65.74, 63.35, 63.06. DEPT-135 (CDCl3, 300 MHz): δ (ppm) positive 128.79,
128.66, 128.61, 128.39, 128.33, 128.18, 128.13, 128.00, 127.89, 127.61, 127.57, 127.35, 127.26,
127.08, 82.09, 81.62, 81.41, 80.68, 68.77, 67.52, 67.30, 66.70, 63.35, 63.05. negative 73.16, 73.09,
71.51, 71.42, 68.60, 67.44, 67.34, 67.16, 65.97, 65.74. FTICR-MS m/z: 840.3904 [M+H]+
+
+
(C55H54NO7 requires 862.3895); 862.3728 [M+Na]+ (C55H53NNaO7 requires 862.3714).
(1R,5S,6S,7S,7aS)-6,7-bis(Benzyloxy)-5-((benzyloxy)methyl)-tetrahydro-1(hydroxymethyl)pyrrolo[1,2-c]
-oxazol-3(1H)-one (en-8). To a solution of alcohol 14 (64 mg, 0.0076 mmol) in MeOH (3 mL) was
added KOH (80 mg, 1.5 mmol).The resulting reaction mixture was stirred at r.t. for 10 min, and then
quenched by adding HCl (1 N, 5 mL). The mixture was extracted with EtOAc, the combined organics
were dried over anhydrous Na2SO4, concentrated, and the residue was purified by FCC (silica gel,
eluted with 10% EtOAc in petroleum ether) to give the oxazolidinone 15 (43 mg, yield 77%) as a
colorless oil. IR (KBr, cm−1): 3,061 (w), 3,031 (w), 1,762 (vs), 1,494 (w), 1,450 (w), 1,364 (w), 1,211
(w), 1,093 (m). [α]2D5 = +2.9° (c 0.69 , CHCl3). H-NMR (CDCl3, 600 MHz): δ (ppm) 7.37 (d, 6H,
1
ArH), 7.26–7.13 (m, 20H, ArH), 7.09 (d, 2H, J = 5.2 Hz, ArH), 6.91 (d, 2H, J = 6.9 Hz, ArH), 4.74
(dd, 1H, J = 6.2 and 12.7 Hz, H-1), 4.46 (ABQ, 2H, J = 12.0 Hz, PhCH2O), 4.37 (d, 1H, J = 11.8 Hz,
PhCH2O), 4.23 (d, 1H, J = 11.8 Hz, PhCH2O), 4.24 (d, 1H, J = 11.2 Hz, PhCH2O), 4.06 (d, 1H,
J = 11.1 Hz, PhCH2O), 4.08-4.05 (m, 2H, H-5 and H-6), 3.93 (t, 1H, J = 7.2 Hz, H-7a), 3.87 (dd, 1H,
J = 3.6 and 6.4 Hz, H-7), 3.50 (d, 2H, J = 5.7 Hz H-9), 3.38 (dd, 1H, J = 6.3 and 10.5 Hz, H-8), 3.28
(dd, 1H, J = 4.4 and 10.5 Hz, H-8). 13C-NMR (CDCl3, 75 MHz): δ (ppm) 160.07, 143.27, 137.81,
137.41, 137.30, 137.41, 137.30, 128.64, 128.41, 128.33, 127.97, 127.80, 127.75, 127.67, 127.46,
127.24, 87.31, 85.84, 83.19, 77.44, 76.59, 75.29, 73.28, 72.24, 71.66, 69.63, 64.09, 62.67, 62.37.
+
FTICR-MS m/z: 732.3309 [M+H]+ (C48H46NO6 requires 732.3319).
(1R,5S,6S,7S,7aS)-6,7-bis(Benzyloxy)-5-((benzyloxy)methyl)-tetrahydro-1(hydroxymethyl)pyrrolo[1,2-c]
-oxazol-3(1H)-one (en-8). To a solution of oxazolidinone 15 (102 mg, 0.014 mmol) in MeOH
(5 mL) was added 5 drops of concentrated HCl, the reaction mixture was stirred at r.t. for 10 mins.
TLC revealed the complete disappearance of starting material, the reaction was quenched by adding
sat. aqueous NaHCO3. The mixture was extracted with EtOAc, the combined organics were dried over
anhydrous Na2SO4, concentrated, the residue was purified by FCC (silica gel, eluted with 10%–50%
EtOAc in petroleum ether) to give the oxazolidinone en-8 (58 mg, yield 85%) as a colorless syrup. IR
(KBr, cm−1) 3,442 (w), 3,062 (vw), 3,031 (vw), 2,868 (w), 1,758 (vs), 1,497 (vw), 1,454 (w), 1,364
(w), 1,209 (w), 1,071 (m). [α]2D5 = –5.1° (c 1.9, CHCl3); H-NMR (CDCl3, 600 MHz): δ (ppm)
1
7.35–7.24 (m, 15H), 4.71 (dd, 1H, J = 5.9 and 13.6 Hz), 4.63 (d, 1H, J = 11.4 Hz), 4.59 (d, 1H,
J = 12.0 Hz), 4.59 (d, 1H, J = 11.5 Hz), 4.53 (d, 2H, J = 12.4 Hz), 4.43 (d, 1H, J = 11.6 Hz), 4.27 (dd,
1H, J = 3.8 and 4.5 Hz), 4.18 (dd, 1H, J = 4.8 and 8.0 Hz), 4.11 (dd, 1H, J = 5.0 and 8.7 Hz), 4.02

Molecules 2013, 18
6731
13
(t, 1H, J = 7.9 Hz), 3.78–3.70 (m, 2H), 3.60–3.55 (m, 2H), 2.23 (t, 1H, J = 6.6 Hz, OH). C-NMR
(CDCl3, 75 MHz): δ (ppm) 160.03, 137.69, 137.24, 136.78, 128.56, 128.50, 128.33, 128.28, 128.06,
127.89, 127.78, 86.14, 81.47, 75.35, 73.41, 72.36, 72.28, 70.23, 63.11, 62.59, 60.74. DEPT-135
(CDCl3, 75 MHz): δ (ppm) positive 128.56, 128.50, 128.33, 128.28, 128.06, 127.89, 127.78, 86.14,
81.47, 75.35, 63.11, 62.59; negative 73.41, 72.36, 72.29, 70.23, 60.74. FTICR-MS m/z: 490.2230
+
[M+H]+ (C29H32NO6 requires 490.2224).
4. Conclusions
In summary, the access to both C-6 epimers of protected L-homoDMDP was achieved with high
efficiency. The (6S)-epimer en-7 was prepared in 44% overall yield from vinylpyrrolidine en-9 using
the iodolactonization as a key step. The (6R)-epimer en-8 was synthesized in 59% overall yield from
the known diol 13 through a 3-step-sequence-regioselective tritylation of diol 13, lactonization to give
oxazolidinone and acidic hydrolysis of the trityl ether. The stereochemistry confirmation of
L-homoDMDP was achieved through 2D-NMR and X-ray data based on the bicyclic oxazolidinone
intermediate en-8. This work will lead to the collective synthesis of homoDMDP-related natural
products and their analogues, and potentially to the unambigous disclosure of their stereochemistry.
Supplementary Materials
1H and 13C-NMR spectra of compounds en-7 and en-8 were available free of charge.
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/18/6/6723/s1.
Acknowledgments
This work is supported by The National Basic Research Program of China (No. 2012CB822101 and
No. 2011CB808603), The National Natural Science Foundation of China (No. 21272240 and
No. 21202008), The Chinese Academy of Sciences, and Excellent Young Scholars Research Fund of
Beijing Institute of Technology.
Conflict of Interest
The authors declare no conflict of interest.
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Sample Availability: Not available.
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