A versatile approach to N-alkylated 1,4-dideoxy-1,4-imino-d-arabinitols and 1,4-dideoxy-1,4-imino-l-xylitols

Article abstract of DOI:10.1021/jo1020322

A versatile and concise synthesis of N-alkylated 1,4-dideoxy-1,4-imino-d- arabinitol and 1,4-dideoxy-1,4-imino-l-xylitol derivatives is described. These were prepared using pseudohemiketal lactams as key intermediates, which in turn were obtained from suc

Full text of DOI:10.1021/jo1020322

ARTICLE
pubs.acs.org/joc
A Versatile Approach to N-Alkylated 1,4-Dideoxy-1,
4-imino-D-arabinitols and 1,4-Dideoxy-1,4-imino-L-xylitols
Guan-Nan Wang, Lin Yang, Li-He Zhang, and Xin-Shan Ye*
State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University,
Xue Yuan Road No. 38, Beijing 100191, China
S Supporting Information
b
ABSTRACT: A versatile and concise synthesis of N-alkylated
1,4-dideoxy-1,4-imino-D-arabinitol and 1,4-dideoxy-1,4-imino-
L-xylitol derivatives is described. These were prepared using
pseudohemiketal lactams as key intermediates, which in turn
were obtained from sucrose. The key intermediates were
prepared by a diastereospecific tandem reaction which facili-
tated the introduction of various substituents on the nitrogen
atom of the iminosugars.
’ INTRODUCTION
Iminosugars, widespread in plants and microorganisms, are
carbohydrate mimetics in which the endocyclic oxygen is re-
placed by nitrogen.1 These kinds of compounds raise many
synthetic challenges and open the way to treat a wide range of
diseases, including diabetes,2,3 viral infections,4,5 tumor meta-
stasis,6 and lysosomal storage disorders.7 Two iminosugar-based
drugs have been approved: N-hydroxyethyldeoxynojirimycin (N-
hydroxyethyl DNJ, Miglitol, Figure 1) in 1996 for the treatment
of type II diabetes, and N-butyl-deoxynojirimycin (NB-DNJ,
Miglustat, Figure 1) in 2003 as the first oral treatment for
Gaucher disease, a severe lysosomal storage disorder. Both of
Figure 1. Structures of some iminosugars.
them are N-alkylated iminosugars. N-Alkylated iminosugars
However, more efficient approaches to prepare this type of com-
pounds are still needed. On the other hand, since many imino-
sugars have better activities after N-alkylation, the N-alkylated
DAB 1 and 1,4-dideoxy-1,4-imino-L-xylitol derivatives could be
more active in vivo. In fact, some N-alkylated DAB 1 analogues
are also naturally occurring compounds. For example, the N-
hydroxyethylated derivative of DAB 1 (N-hydroxyethyl DAB 1)
(Figure 1) was isolated from the seeds of African legume
Angylocalyx pynaertii.23 However, the preparation of these N-
alkylated iminosugars has not been explored widely to date.
Previously, we reported a concise, one-pot tandem reaction
starting from the sugar lactones which provided a facile and
efficient approach to construct the N-alkylated sugar lactams.24
On the basis of these findings, we wanted to explore the
synthesis of naturally occurring DAB 1 and 1,4-dideoxy-1,4-
imino-L-xylitol as well as their N-alkylated derivatives. Herein,
we describe a short and versatile route to these types of
iminosugars using the same lactam, which was prepared from
sucrose, as an intermediate.
also show antiviral activities. For instance, the long alkyl-chain
compound N-nonyl-DNJ (NN-DNJ, Figure 1) can block the
HCV ion channel p7.8,9 Compared to the parent iminosugars,
the N-alkylated structures tend to exhibit better biological
activities in vivo, partially due to the improvement of lipophi-
licity of the compounds, and sometimes because the alkylated
chains contribute additional binding to the pocket of the
receptor.
1,4-Dideoxy-1,4-imino-D-arabinitol (known as DAB 1, Figure 1),
isolated from two types of leguminose plants, Arachniodes
standishii10 and Angylocalyx boutiqueanus,11 was shown to be a
good inhibitor with a broad inhibitory spectrum toward mam-
malian glycosidases such as ER R-glucosidase II, Golgi R-man-
nosidase I/II, intestinal isomaltase, and trehalase.12,13 In primary
rat hepatocytes, DAB 1 was found to be one of the most potent
inhibitors of basal- and glucagon-stimulated glycogenolysis ever
reported14 and also one of the most powerful anti-HIV agents.15
1,4-Dideoxy-1,4-imino-L-xylitol (Figure 1)16,17 as the epimer of
DAB 1 was also proven to be a potential glycosidase inhibitor.18
Because of their dazzling activities, several synthetic strategies
have been developed to prepare these valuable compounds
from both carbohydrate18-20 and noncarbohydrate sources.21,22
Received: October 13, 2010
Published: March 04, 2011
r
2011 American Chemical Society
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Scheme 1. Synthesis of Compounds 6a-e from Sucrose 1a
a Im = imidazole.
Scheme 2. Proposed Mechanism for the Formation of Compound 6 from Compound 4
Scheme 3. Switchable Conversion Paths of Compound 6
Table 1. Preparation of N-Substituted 1,4-Dideoxy-1,
4-imino-L-Xylitols
R1, R2
product 9
product 10
’ RESULTS AND DISCUSSION
entry
The structural resemblance makes fructose a potentially good
parent structure for DAB 1 and its epimer. However, because of
the presence of two primary hydroxyl groups and anomerization,
it is difficult to obtain a single protected isomer of fructofurano-
side with a defined anomeric configuration. The method origin-
ally reported by Richardson et al.25 and improved by Madsen
et al.26 gave us a solution to this problem and allowed us to
choose inexpensive sucrose (1) as the starting material. Hence,
following the reported procedure, sucrose (1) was converted to a
fructose derivative in which the two primary hydroxyl groups
were differentiated and one primary hydroxyl group, together
with the 3-hydroxyl group, was selectively protected with an
isopropylidene group, yielding the R-methyl fructofuranoside 2.
The remaining primary hydroxyl group of compound 2 was
1
2
3
4
5
R1 = R2= (CH2)8CH3
R1 = R2= (CH2)3CH3
R1 = R2= (CH2)6OH
R1 = R2= CH2CH2OH
R1 = PMB, R2 = H
9a, 94%
9b, 95%
9c, 87%
9d, 96%
9e, 95%
10a, 98%
10b, 95%
10c, 97%
10d, 95%
10e, 97%
substituted by an iodine atom to give the iodide 3; subsequent
elimination and benzylation gave compound 4 in 45-70% yields.
The yield was lower (45-55%) when this reaction was carried
out on a scale greater than 500 mg. Therefore, an alternative
stepwise procedure, especially more suitable for a larger scale,
was also attempted for the preparation of compound 4. In this
case, the iodide 3 was treated with benzyl trichloroacetimidate
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Table 2. Preparation of N-Substituted DAB 1
entry
R1, R2
product 11
product 12
product 13
1
2
3
4
R1 = R2 = (CH2)8CH3
R1 = R2 = (CH2)3CH3
R1 = CH2CH2OBn, R2 = CH2CH2OH
R1 = PMB, R2 = H
11a, 91%
11b, 84%
11c, 94%
11d, 74%
12a, 95%
12b, 96%
12c, 98%
12d, 75%a
13a, 98%
13b, 97%
13c, 98%
13d, 97%
a LiAlH4 was used instead of BH3 THF.
3
under acidic conditions to protect the hydroxyl group; this was
followed by a base-promoted elimination of hydrogen iodide,
affording compound 4 in 68% overall yield from 3 (Scheme 1).
With compound 4 in hand, the key one-pot tandem reaction
was next explored. The sequence began with ozonolysis, followed
by a tandem reaction with various amines. In fact, we first tried
the reaction with amines using a typical Lewis acid-catalyzed
reductive amination procedure (from compound 4 to 60 via
intermediate 7, Scheme 2). However, the reductive amination of
amine ketone was much more difficult than that of amine alde-
hyde in our previous work;24 most of the alkylamine did not react
with the lactone 7. Only allylamine provided the reductive
amination product in 20% yield as a diastereomeric mixture. When
acetic acid was used as catalyst, compound 6 instead of com-
pound 60 was isolated in moderate yield. Subsequent experi-
ments showed that the reaction is acid-catalyzed ester-amide
exchange followed by nucleophilic cyclization and that the use of
the reducing reagent NaCNBH3 is not necessary. To increase the
reaction yield, a series of acids including both Lewis acids such as
ZnCl2 and AlCl3 and protonic acids such as trifluoroacetic acid
and toluene sulfonic acid (p-TsOH) were also checked, and p-
TsOH gave the best result. Meanwhile, it was noticed that 1,
3-isopropylidene group was partially hydrolyzed during the
p-TsOH-catalyzed reaction; methanol was replaced by ethanol as
the solvent to overcome this problem. A series of N-substituted
iminosugar precursors 6a-e were then prepared in high yields by
the one-pot tandem reaction with the cis-1,3-dioxane product as
the sole diastereomer (Scheme 1). The mechanism to form
pseudohemiketal lactam 6 from lactone 7 was proposed as the
following: the lactone ring-opening attacked by amine gave
intermediate 8, and the subsequent intramolecular nucleophilic
addition of newly formed amide to the ketone led to the forma-
tion of compound 6 (Scheme 2). Theoretically, the nucleophilic
addition should result in a pair of diastereomers. However,
probably due to the ring strain, the nucleophilic addition tended
to selectively take the direction to form less strain ring, which was
cis-1,3-dioxane isomer.
hydroxyl group in pseudohemiketal provides an opportunity for
making both L-xylo- and D-arabino family of iminosugars.
The unique structure of compounds 6a-e made it possible for
further conversion to get the L or D family of N-alkylated imino-
sugars, respectively (Scheme 3). For path a, the carbonyl group of
lactam and hydroxyl group in pseudohemiketal were both redu-
ced. When LiAlH4 was used as the reducing reagent and heated in
the presence of compound 6 in refluxing THF, high yields were
obtained for the compounds bearing N-nonyl or N-butyl chains;
however, the yields were poor for the compounds with N-PMB
or N-hydroxylethyl chains, since the benzyloxy group of C-2 was
easily eliminated to afford R,β-unsaturated lactams in these cases.
The elimination was avoided by using the alane reagent (3:1
LiAlH4/AlCl3)27 as the reductant; when the reaction was per-
formed at -78 °C, compounds 9a-e were isolated in high yields.
The protective groups were smoothly removed by hydrogeno-
lysis and hydrolysis, providing the target compounds 10a-e in
the form of HCl salts (Table 1).
When we took the other path (path b in Scheme 3) to prepare
N-substituted DAB 1, the 1,3-isopropylidene group in com-
pound 6 was first removed to provide a diastereomeric mixture
of R and β anomers (1:1 ratio). The subsequent BF3 OEt2-
3
mediated reductive dehydroxylation of the diastereomeric mix-
ture using the modified procedure originally reported by the
Huang group,22,28 led to the D-arabino-1,4-lactam 11a-d as the
sole isolated diastereoisomer in high overall yields (Table 2). It
was found that the purity of BF3 OEt2 is essential in order to
3
have a high yield, so it was freshly distilled from CaH2 under
reduced pressure before use.
The stereochemistry of compounds 11a-d deserved further
investigation. The best way to confirm the stereochemistry of the
hydroxylmethyl group was to make both diastereoisomers and
compare them. For the BF3 OEt2-mediated reaction, when com-
3
pound 6b reacted with untreated BF3 OEt2 and triethylsilane, it
3
provided both D-arabino-1,4-lactam 11b and L-xylono-1,4-lactam
14b (Scheme 4). The vicinal coupling constants (J3,4 > 6.0 Hz for
3,4-cis diastereomers and J3,4 < 4.4 Hz for 3,4-trans diastereo-
mers) are commonly used to determine the 3,4-relative stereo-
chemistry of γ-lactams.29,30 However, the configurations of com-
pounds 11b and 14b could not be determined by this empirical
rule, since they have very similar vicinal coupling constants (com-
pound 11b, J3,4-trans = 6.0 Hz; compound 14b, J3,4-cis = 7.0 Hz).
The assigned stereochemistry was supported by NOESY experi-
Generally, the syntheses of N-substituted iminosugars starting
from commercially available sugars involve the following steps:
introduction of an amino functionality in the sugar skeleton,
subsequent aminocyclization to generate the imino ring, and
finally, at least one more step to introduce the side chain on the
nitrogen atom. In contrast, our approach combined amination,
cyclization, and installation of N-substituents in one step. Fur-
thermore, it should be noted that this tandem reaction is a strain-
controlled diastereospecific reaction, and the newly formed
1
ments after confirmation of the proton assignment by H-1H
COSY experiments and also further confirmed by converting a
series of compounds 11 to compounds 13. As shown in Figure 2,
H-2/H-4 and H-3/H-5 have a long-distance correlation in
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Scheme 4. Reductive Dehydroxylation with Untreated BF3 OEt2
3
’ EXPERIMENTAL SECTION
Methyl 6-Deoxy-1,3-O-isopropylidene-r-D-xylulohex-5,6-
enofuranoside (4). Method 1. Sodium hydride (60% in mineral oil,
160 mg, 4.0 mmol) was added to the solution of methyl 6-deoxy-6-iodo-
1,3-O-isopropylidene-R-D-fructofuranoside 326 (344 mg, 1.0 mmol) in
dry DMF at 0 °C under argon atmosphere. The mixture was stirred for
15 min, and then benzyl bromide (0.24 mL, 2.0 mmol) was added
dropwise. After being stirred for 5 h at 0 °C, the mixture was poured into
ice-water and extracted with ethyl acetate. The organic layer was dried
with Na2SO4, filtered, and evaporated to dryness. The residue was
purified by column chromatography on silica gel (petroleum ether-
ethyl acetate, 15:1 to 12:1 containing 1% Et3N) to yield compound 4 as
an oil (210 mg, 69%): Rf = 0.65 (petroleum ether-ethyl acetate, 3:1).
Method 2. Trifluoromethanesulfonic acid (50.0 μL) was added to a
stirred solution of methyl 6-deoxy-6-iodo-1,3-O-isopropylidene-R-D-
fructofuranoside 3 (1.0 g, 2.9 mmol), benzyl trichloroacetimidate32
(2.2 g, 8.7 mmol), and activated 4 Å molecular sieves (powder) in
dichloromethane (20 mL) and cyclohexane (40 mL) at 0 °C under
argon atmosphere. The solution became light pink. When the color
faded away, trifluoromethanesulfonic acid (30.0 μL) was added again
until the reaction was completely finished (monitored by TLC). The
reaction was quenched by sodium bicarbonate aqueous solution. The
reaction mixture was filtered through a pad of Celite, and the filter cake
was washed by dichloromethane (10 mL ꢀ 3). The combined organic
phase was washed with brine, dried (Na2SO4), and concentrated. The
residue was purified by column chromatography on silica gel (petroleum
ether-ethyl acetate, 10:1) to afford compound 5 as a syrup (908 mg,
72%): Rf = 0.75 (petroleum ether--ethyl acetate, 3:1).
Sodium hydride (60% in mineral oil, 336 mg, 8.4 mmol) was added to
a stirred solution of compound 5 (908 mg, 2.1 mmol) in DMF (50 mL)
at 0 °C. After being stirred for 4 h, the mixture was poured into ice-
water and extracted with ethyl acetate. The organic layer was dried with
Na2SO4, filtered, and evaporated to dryness. The residue was purified by
column chromatography on silica gel (petroleum ether-ethyl acetate,
15:1 to 12:1 containing 1% Et3N) to yield compound 4 as an oil (608 mg,
95%): Rf = 0.65 (petroleum ether-ethyl acetate, 3:1); 1H NMR
(300 MHz, CDCl3) δ 1.34 (s, 3H), 1.42 (s, 3H), 3.36 (s, 3H), 3.85 (d, J =
12.2 Hz, 1H), 3.94 (d, J = 12.2 Hz, 1H), 4.15 (s, 1H), 4.24 (s, 1H), 4.29
(dd, J = 1.2, 2.4 Hz, 1H), 4.61-4.71 (m, 3H), 7.25-7.38 (m, 5H); 13C
NMR (75 MHz, CDCl3) δ 21.1, 26.3, 49.6, 62.08, 62.12, 71.3, 77.3, 81.7,
88.0, 99.2, 104.2, 127.8, 127.9, 128.4, 137.5, 160.1; HRMS calcd for
C17H22O5Na [M þ Na]þ 329.1359, found 329.1361.
Figure 2. Selective NOE enhancements in NOE experiments.
compound 11b, which suggests that the lactam has the D-arabino
stereochemistry (which is 3,4-trans diastereomer), while in com-
pound 14b H-2/H-5 has a long-distance correlation and H-3/H-
4 has a stronger correlation than that in compound 11b, which
suggests that the lactam 14b has the L-xylono stereochemistry
(which is the 3,4-cis diastereomer).
Subsequently, the carbonyl groups of lactams 11a-d were
reduced by BH3 THF or LiAlH4 to obtain compounds 12a-d
3
(Table 2). The product was generated from the product-BH3
adduct by stirring in methanol for 24-48 h. However, the adduct
of N-PMB compound 12d and BH3 was too tight to release the
product 12d efficiently by stirring in methanol. Therefore, in this
case, LiAlH4 was used as reductant instead of BH3 THF. It should
3
be noticed that the unprotected hydroxyl group in N-hydro-
xylethyl lactam 6d made the reductive reaction very complicated.
Therefore, compound 6d0 instead of compound 6d was used to
prepare N-hydroxylethyl DAB 1 (compound 13c). The ami-
noethanol was selectively O-benzylated using benzyl chloride
before the reaction with lactone 7 to afford the desired lactam
6d0.31 Finally, compounds 12a-d were subjected to catalytic
hydrogenolysis to afford DAB 1 and its N-substituted derivatives
in nearly quantitative yield. The spectroscopic data of com-
pounds 10e (1,4-dideoxy-1,4-imino-L-xylitol) and 13d (DAB 1)
coincided with those reported in the literatures,19,22 which further
confirmed the stereochemistry assigned to compounds 11 and
14 by the NOESY experiments.
’ CONCLUSION
In summary, we have developed a versatile and concise
approach to the synthesis of N-alkylated 1,4-dideoxy-1,4-imino-
D-arabinitol and 1,4-dideoxy-1,4-imino-L-xylitol derivatives start-
ing from sucrose. The key reaction included the tandem trans-
formation from exoglycal to pseudohemiketal lactams, which
combined ozonolysis, amination, cyclization, and installation of
N-substituents in one pot and in a diastereospecific manner. On
the basis of the key lactam intermediates, a series of five-mem-
bered iminosugar analogues were prepared efficiently. The dis-
closed approach will facilitate construction of various N-alkylated
1,4-dideoxy-1,4-imino-D-arabinitol and 1,4-dideoxy-1,4-imino-L-
xylitol derivatives as well as other related iminosugars with biolo-
gical importance.
(4aS,7S,7aS)-7-Benzyloxytetrahydro-4a-methoxy-2,2-
dimethylfuro[3,2-d][1,3]dioxin-6-one (7). A solution of com-
pound 4 (2.0 g, 6.5 mmol) in MeOH (50 mL) at -78 °C was bubbled
with O3 until the solution became pale blue. The solution was stirred at
-78 °C for 3 min and then bubbled with N2 until the solution became
colorless. Methyl sulfide (1.0 mL) was added, and the mixture was
stirred at -78 °C for 2 h. The solution was warmed to room temperature
and concentrated under reduced pressure to provide lactone 7 (2.0 g,
100%) as a colorless oil, which was stable at -20 °C for several months:
1
Rf = 0.60 (petroleum ether-ethyl acetate, 3:1); H NMR (300 MHz,
CDCl3) δ 1.33 (s, 3H), 1.41 (s, 3H), 3.44 (s, 3H), 3.82 (d, J = 12.5 Hz,
1H), 4.02 (s, 1H), 4.04 (d, J = 12.5 Hz, 1H), 4.14 (s, 1H), 4.74 (d, J =
11.9 Hz, 1H), 4.92 (d, J = 11.9 Hz, 1H), 7.26-7.41 (m, 5H); 13C NMR
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(75 MHz, CDCl3) δ 21.9, 25.3, 50.5, 61.1, 72.8, 75.1, 78.2, 100.3, 104.4,
128.2, 128.3, 128.5, 136.3, 172.3; HRMS calcd for C16H20O6Na [M þ
Na]þ 331.1152, found 331.1147.
J = 11.7 Hz, 1H), 4.88 (d, J = 11.7 Hz, 1H), 7.29-7.39 (m, 5H); 13
C
NMR (75 MHz, CDCl3) δ 20.6, 27.0, 41.9, 60.8, 62.8, 73.0, 74.3,
79.7, 84.9, 99.5, 128.2, 128.3, 128.5, 136.6, 172.4. ESI-MS 360 [M þ
Naþ]. Anal. Calcd for C17H23NO6: C, 60.52; H, 6.87; N, 4.15.
Found: C, 60.38; H, 6.77; N, 4.07.
General Procedure for the Synthesis of N-Substituted
Lactams 6a-e. Amine (NH2R1, 1.3 mmol) and toluenesulfonic acid
(5.6 mg, 64.9 μmol) were added to a stirred solution of lactone 7
(200 mg, 0.65 mmol) in absolute ethyl alcohol (40 mL) at room
temperature. The mixture was allowed to stir for 12-24 h (monitored
by TLC) followed by quenching with saturated NaHCO3 aqueous
solution. After removal of the solvent, the product mixture was
dissolved in ethyl acetate (80 mL) and washed with brine (20 mL ꢀ
2). The organic phase was dried (Na2SO4), filtered, and concentrated.
The residue was purified by column chromatography on silica gel to
provide the products 6a-e.
(4aR,7S,7aS)-7-Benzyloxytetrahydro-4a-hydroxy-2,2-di-
methyl-5-nonyl[1,3]dioxino[5,4-b]pyrrol-6(4H)-one (6a):
yield 83%; white foam after column chromatography (petroleum
ether-ethyl acetate, 8:1 containing 1% Et3N); Rf = 0.55 (petroleum
ether-ethyl acetate, 3:1); IR νmax (KBr)/cm-1: 3379, 3065, 3032,
2993, 2927, 2856, 1685, 1497, 1457, 1427, 1377, 1341, 1272, 1226,
1203, 1158, 1099, 957, 859, 738, 700, 612, 519; 1H NMR (300 MHz,
CDCl3) δ 0.88 (t, J = 6.6 Hz, 3H) 1.26-1.32 (m, 15H), 1.48 (s, 3H),
1.62 (brs, 2H), 2.94 (s, 1H), 3.21-3.38 (m, 2H), 3.81 (s, 1H), 3.90 (s,
2H), 4.04 (s, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.89 (d, J = 11.4 Hz, 1H),
7.32-7.37 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 14.1, 19.8, 22.7,
27.1, 27.6, 28.9, 29.3, 29.5, 31.8, 39.0, 61.7, 72.8, 74.3, 79.4, 84.9, 98.9,
128.2, 128.3, 128.5, 136.7, 171.8; ESI-MS 420 [M þ Hþ]. Anal. Calcd
for C24H37NO5: C, 68.71; H, 8.89; N, 3.34; Found: C, 68.63; H, 8.94;
N, 3.29.
(4aR,7S,7aS)-7-Benzyloxy-5-(2-benzyloxyethyl)tetrahydro-
4a-hydroxy-2,2-dimethyl[1,3]dioxino[5,4-b]pyrrol-6(4H)-one
(6d0). Compound 6d0 was prepared by lactone 7 and 2-(benzyloxy)
ethanamine31 as general procedure for the synthesis of N-substituted
lactams: yield 92%, colorless oil after column chromatography (petroleum
ether-ethyl acetate, 3:1 containing 0.5% Et3N); Rf = 0.30 (petroleum
ether-ethyl acetate, 2:3); 1H NMR (300 MHz, CDCl3) δ 1.28 (s, 3H),
1.44 (s, 3H), 3.10-3.19 (m, 1H), 3.56-3.61 (m, 1H), 3.68 (dt, J = 3.0,
9.9 Hz, 1H), 3.78-3.96 (m, 4H), 4.08 (s, 1H), 4.48-4.59 (ABq, J = 11.4
Hz, 2H), 4.75 (d, J = 12.0 Hz, 1H), 4.89 (d, J = 12.0 Hz, 1H), 7.25-7.41
(m, 10H); 13C NMR (75 MHz, CDCl3) δ 21.2, 26.3, 39.3, 64.0, 67.7,
72.6, 73.5, 74.6, 79.8, 85.1, 99.6, 127.8, 128.1, 128.3, 128.5, 136.4, 137.1,
171.9; HRMS calcd for C24H29NO6Na [M þ Naþ] 450.1887f ound
450.1890.
(4aR,7S,7aS)-5-(4-Methoxybenzyl)-7-benzyloxytetrahydro-
4a-hydroxy-2,2-dimethyl[1,3]dioxino[5,4-b]pyrrol-6(4H)-one
(6e): yield 90%; white amorphous solid after column chromatography
(petroleum ether-ethyl acetate, 3:1 containing 0.5% Et3N); Rf = 0.55
(petroleum ether-ethyl acetate, 1:1); 1H NMR (300 MHz, CDCl3) δ
1.24 (s, 3H), 1.42 (s, 3H), 3.00 (s, 1H), 3.69 (s, 2H), 3.77 (s, 3H), 3.93 (s,
1H), 4.05 (s, 1H), 4.32 (d, J =15.4 Hz, 1H), 4.64 (d, J =15.4Hz, 1H), 4.75
(d, J = 11.4 Hz, 1H), 4.92 (d, J = 11.4 Hz, 1H), 6.82 (d, J = 8.1 Hz, 2H),
7.23-7.35 (m, 7H); 13C NMR (75 MHz, CDCl3) δ 20.5, 26.8, 41.8, 55.2,
62.7, 72.9, 74.9, 79.3, 86.0, 99.3, 113.8, 128.2, 128.3, 128.5, 129.0, 129.2,
136.7, 158.9, 171.8; ESI-MS: 413 [M þ Naþ]. Anal. Calcd for C23H27-
NO6: C, 66.81; H, 6.58; N, 3.56. Found: C, 66.89; H, 6.50; N, 3.34.
(4aS,7R,7aR)-7-Benzyloxyhexahydro-2,2-dimethyl-5-nonyl
[1,3]dioxino[5,4-b]pyrrole (9a). Preparation of Alane. A cooled
(0 °C) solution of anhydrous AlC13 (13.3 mg, 0.1 mmol) was added to
anhydrous THF (5 mL) via syringe under a static argon atmosphere. The
resulting clear and colorless solution was allowed to stir at 0 °C for 5 min,
and lithium aluminum hydride (12 mg, 0.3 mmol) was added. Bubbling
was observed. The resulting clear and colorless solution was allowed to
warm to room temperature and stir for 20 min to give a solution of alane
(0.4 mmol).
To a stirred, cooled (-78 °C) solution of alane (0.4 mmol) in dry
THF (5 mL) was added a solution of lactam 6a (42 mg, 0.1 mmol) in dry
THF (5 mL) under an argon atmosphere. The mixture was allowed to
stir for 45 min at -78 °C, then warmed to room temperature over
20 min, and stirred for additional 15 min. The mixture was recooled to
0 °C and quenched with by careful addition of 0.5 N NaOH aqueous
solution (30 μL). The precipitate was filtered off and washed with
dichloromethane (5 mL ꢀ 3). The solvent was evaporated in vacuo, and
the residue was dissolved in dichloromethane (30 mL). This solution
was washed with brine (10 mL). The organic layer was dried (MgSO4),
filtered, and concentrated. The residue was purified by column chro-
matography (petroleum ether-ethyl acetate, 6:1 containing 0.5% Et3N)
to provide 9a (36.7 mg, 94%) as a colorless oil: Rf = 0.45 (petroleum
ether-ethyl acetate, 2:1); 1H NMR (300 MHz, CDCl3) δ 0.88 (t, J =
6.9 Hz, 3H), 1.26 (s, 12H), 1.37 (s, 3H), 1.39 (s, 3H), 1.44 (m, 2H),
2.20-2.30 (m, 2H), 2.49-2.58 (m, 1H), 2.67 (dd, J = 5.7, 12.0 Hz, 1H),
3.45 (dd, J = 6.3, 9.3 Hz, 1H), 3.66 (dd, J = 6.6, 11.4 Hz, 1H), 3.89 (dd,
J = 5.7, 11.4 Hz, 1H), 4.05 (dt, J = 1.8, 6.9 Hz, 1H), 4.20 (dd, J = 2.4,
6.0 Hz, 1H), 4.55 (ABq, J = 11.7 Hz, 2H), 7.28-7.35 (m, 5H); 13C
NMR (75 MHz, CDCl3) δ 14.1, 22.1, 22.7, 26.4, 27.6, 28.2, 29.3, 29.5,
31.9, 55.4, 57.2, 61.4, 62.5, 71.9, 75.8, 83.1, 98.9, 127.8, 128.4, 138.0;
HRMS calcd for C24H40NO3 [M þ Hþ] 390.3003, found 390.3001.
(4aS,7R,7aR)-7-Benzyloxy-5-butylhexahydro-2,2-dimethyl
[1,3]dioxino[5,4-b]pyrrole (9b). Compound 9b was prepared from
(4aR,7S,7aS)-7-Benzyloxytetrahydro-4a-hydroxy-2,2-di-
methyl-5-butyl[1,3]dioxino[5,4-b]pyrrol-6(4H)-one (6b): yield
81%; colorless oil after column chromatography (petroleum ether-
ethyl acetate, 6:1 containing 1% Et3N); Rf = 0.3 (petroleum ether-ethyl
acetate, 2:1); IR νmax (KBr)/cm-1 3369, 3064, 3031, 2959, 2934, 2873,
1686, 1497, 1455, 1428, 1377, 1334, 1271, 1226, 1201, 1164, 1096, 937,
1
858, 738, 700, 611, 519; H NMR (300 MHz, CDCl3) δ 0.94 (t, J =
7.5 Hz, 3H), 1.31 (s, 3H), 1.26-1.42 (m, 2H), 1.47 (s, 3H), 1.52-1.66
(m, 2H), 3.22 (brs, 1H, OH), 3.27-3.34 (m, 2H), 3.83 (s, 1H), 3.89 (s,
2H), 4.04 (s, 1H), 4.72 (d, J = 11.4 Hz, 1H), 4.88 (d, J = 11.4 Hz, 1H),
7.27-7.37 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 13.7, 20.0, 20.2,
27.4, 30.9, 38.7, 61.9, 72.8, 74.4, 79.4, 85.0, 99.0, 128.1, 128.2, 128.5,
136.7, 171.7; ESI-MS 372 [M þ Naþ]. Anal. Calcd for C19H27NO5: C,
65.31; H, 7.79; N, 4.01. Found: C, 65.04; H, 7.58; N, 3.84.
(4aR,7S,7aS)-7-Benzyloxytetrahydro-4a-hydroxy-5-(6-hy-
droxyhexyl)-2,2-dimethyl[1,3]dioxino[5,4-b]pyrrol-6(4H)-one
(6c): yield 72%; colorless oil after column chromatography (petroleum
ether-ethyl acetate, 1:1 to 1:2 containing 0.5% Et3N); Rf = 0.2 (petroleum
ether-ethyl acetate-methanol, 10:10:1); IR νmax (KBr)/cm-1: 3393,
3064, 3032, 2989, 2935, 2861, 1687, 1496, 1455, 1427, 1377, 1272,
1
1225, 1152, 1097, 962, 930, 857, 740, 700, 612, 520; H NMR (300
MHz, CDCl3) δ 1.31 (s, 3H, CH3), 1.36-1.68 (m, 8H), 1.48 (s, 3H), 1.95
(brs, 1H), 3.21-3.37 (m, 2H), 3.57 (t, J = 6.3 Hz, 3H), 3.82-3.92 (m,
3H), 4.04 (s, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.90 (d, J = 11.4 Hz, 1H),
7.31-7.37 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 20.2, 25.1, 26.5, 27.2,
28.7, 32.3, 38.7, 62.2, 62.5, 73.0, 74.7, 79.6, 85.3, 99.1, 128.2, 128.3, 128.5,
136.6, 171.8; ESI-MS 416 [M þ Naþ]. Anal. Calcd for C21H31NO6: C,
64.10; H, 7.94; N, 3.56. Found: C, 63.86; H, 7.70; N, 3.36.
(4aR,7S,7aS)-7-Benzyloxytetrahydro-4a-hydroxy-5-(2-hy-
droxyethyl)-2,2-dimethyl[1,3]dioxino[5,4-b]pyrrol-6(4H)-
one (6d): yield 89%; colorless oil after column chromatography
(petroleum ether-ethyl acetate, 1:1.5 to 1:2 containing 1% Et3N);
1
Rf = 0.2 (petroleum ether-ethyl acetate-methanol, 10:15:2); H
NMR (300 MHz, CDCl3) δ 1.31 (s, 3H), 1.47 (s, 3H), 3.18-3.27 (m,
1H), 3.65-3.79 (m, 4H), 3.87-3.90 (m, 3H), 4.10 (s, 1H), 4.74 (d,
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ARTICLE
compound 6b as described in the preparation of compound 9a, yielding
9b as a colorless oil (95% yield): Rf = 0.35 (petroleum ether-ethyl
acetate, 2:1); 1H NMR (300 MHz, CDCl3) δ 0.90 (t, J = 7.2 Hz, 3H,
CH3), 1.25-1.48 (m, 10H), 2.20-2.31 (m, 2H), 2.50-2.57 (m, 1H),
2.67 (dd, J = 6.3, 12.3 Hz, 1H), 3.45 (dd, J = 6.6, 9.3 Hz, 1H), 3.66 (dd, J
= 6.6, 11.4 Hz, 1H), 3.89 (dd, J = 6.0, 11.4 Hz, 1H), 4.05 (dt, J = 2.3, 6.9
Hz, 1H), 4.20 (dd, J = 2.3, 6.0 Hz, 1H), 4.50-4.61 (ABq, J = 11.7 Hz,
2H), 7.26-7.35 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 14.0, 20.7,
22.1, 26.4, 30.4, 55.0, 57.2, 61.3, 62.5, 71.9, 75.9, 83.1, 98.9, 127.7, 127.8,
128.4, 138.0; HRMS calcd for C19H30NO3 [M þ Hþ] 320.2220, found
320.2219.
58.3, 59.1, 70.9, 74.2, 75.7; HRMS calcd for C14H30NO3 [M þ Hþ]
260.2220, found 260.2222.
1,4-Dideoxy-l,4-(butylimino)-L-xylitol (10b). Compound 10b
was prepared from compound 9b as described in the preparation of
compound 10a, yielding 10b (95% yield, in the form of HCl salt) as a
colorless oil: IR vmax(KBr)/cm-1 3357, 2961, 2876, 2697, 1634, 1462,
1415, 1305, 1258, 1116, 1085, 1057, 991, 783, 737, 584, 478; 1H NMR
(300 MHz, D2O) δ 0.74 (t, J = 7.2 Hz, 3H), 1.14-1.23 (m, 2H), 1.49-
1.57 (m, 2H), 2.96-3.06 (m, 1H), 3.10 (d, J = 12.9 Hz, 1H), 3.29-3.39
(m, 1H), 3.65-3.67 (m, 1H), 3.76 (dd, J = 4.2, 12.9 Hz, 1H), 3.85-3.90
(m, 2H), 4.16-4.18 (m, 2H); 13C NMR (75 MHz, D2O) δ 13.3, 19.8,
27.3, 57.4, 58.1, 59.1, 70.9, 74.2, 75.72; HRMS calcd for C9H20NO3 [M
þ Hþ] 190.1438, found 190.1443.
6-((4aS,7R,7aR)-7-Benzyloxytetrahydro-2,2-dimethyl[1,3]
dioxino[5,4-b]pyrrol-5(6H)-yl)hexan-1-ol (9c). Compound 9c
was prepared from compound 6c as described in the preparation of
compound 9a, yielding 9c (87% yield) after column chromatography
(petroleum ether-ethyl acetate, 1:1 containing 0.5% Et3N): Rf = 0.3
1,4-Dideoxy-l,4-(6-hydroxyhexylimino)-L-xylitol (10c). Com-
pound 10c was prepared from compound 9c as described in the
preparation of compound 10a, yielding 10c (97% yield, in the form of
HCl salt) as a colorless oil: IR νmax (KBr)/cm-1 3332, 3047, 2939, 2862,
1641, 1407, 1083, 1055, 727, 600; 1H NMR (300 MHz, D2O) δ 1.21 (m,
4H), 1.34-1.38 (m, 2H), 1.59 (m, 2H), 2.97-3.03 (m, 1H), 3.10 (d, J =
13.1 Hz, 1H), 3.30-3.42 (m, 3H), 3.67 (m, 1H), 3.77 (dd, J = 4.2,
13.1 Hz, 1H), 3.85-3.92 (m, 2H), 4.16-4.18 (m, 2H); 13C NMR (75
MHz, D2O) δ 25.0, 25.3, 26.0, 31.5, 57.4, 58.2, 59.1, 62.1, 70.9, 74.2,
75.7; HRMS calcd for C11H24NO4 [M þ Hþ] 234.1700, found
234.1701.
1,4-Dideoxy-l,4-(2-hydroxyethylimino)-L-xylitol (10d). Com-
pound 10d was prepared from compound 9d as described in the prepara-
tion of compound 10a, yielding 10d (95% yield, in the form of HCl salt) as a
colorless oil: IR νmax (KBr)/cm-1 3418, 2956, 1635, 1441, 1406, 1312,
1257, 1094, 1047, 593; 1H NMR (300 MHz, D2O) δ 3.22-3.30 (m, 2H),
3.53-3.61 (m, 1H), 3.77-3.88 (m, 4H), 3.92-3.94 (m, 2H), 4.22-4.26
(m, 2H); 13C NMR (75 MHz, D2O) δ 57.1, 57.4, 59.5, 60.2, 71.7, 74.6,
75.5; HRMS calcd for C7H16NO4 [M þ Hþ] 178.1074, found 178.1078.
1,4-Dideoxy-l,4-imino-L-xylitol (10e). Compound 10e was pre-
pared from compound 9e as described in the preparation of compound
10a, yielding 10e (97% yield, in the form of HCl salt) as a colorless oil: IR
νmax (KBr)/cm-1 3421, 2935, 1635, 1407, 1316, 1049, 987, 780, 609; 1H
NMR (300 MHz, D2O) δ 2.90 (d, J = 12.8 Hz, 1H), 3.32 (dd, J = 4.5, 12.8
Hz, 1H), 3.46-3.51 (m, 1H), 3.63 (dd, J = 7.8, 11.6 Hz, 1H), 3.76 (dd, J =
5.7, 11.6 Hz, 1H), 4.06-4.07 (m, 1H), 4.12-4.13 (m, 1H); 13C NMR
(75MHz, D2O)δ 51.1, 58.9, 62.7, 75.8, 76.0;HRMScalcdfor C5H12NO3
[M þ Hþ] 134.0812, found 134.0815; [R]D29 -2.9 (c 0.17, H2O) [lit19.
[R]2D0 -4.3 (c 0.38, H2O)].
(3S,4R,5R)-3-Benzyloxy-4-hydroxy-5-(hydroxymethyl)-1-
nonylpyrrolidin-2-one (11a). Dowex 50 Hþ resin was added to the
solution of lactam 6a (45 mg, 0.11 mmol) in methanol (8 mL) at room
temperature. The mixture was alowed to stir slowly for 24 h. The resin
was then filtered off, and the filtrate was concentrated to afford the
product with the isopropylidene group removed as a diastereomeric
mixture, which was used in the next step without further purification. To
the cooled (-78 °C) solution of diastereomeric mixture in dry
dichloromethane (10 mL) were added under argon atmosphere triethyl-
silane (140 μL, 0.88 mmol) and freshly distilled boron trifluoride
etherate (34 μL, 0.275 mmol). After being stirred at -78 °C for 8 h,
the mixture continued to stir for 8 h at room temperature. The reaction
was quenched with saturated sodium bicarbonate aqueous solution
(1.0 mL) and extracted with dichloromethane (3 ꢀ 10 mL). The
combined extracts were dried (Na2SO4), filtered, and concentrated in
vacuo. The residue was purified by column chromatography (petroleum
ether- ethyl acetate, 1:1) on silica gel to provide the compound 11a
(35.3 mg, 91% yield over two steps) as a white amorphous solid: Rf =
0.65 (petroleum ether-ethyl acetate-methanol, 5:5:2); IR νmax (KBr)/
cm-1 3402, 2926, 2855, 1669, 1459, 1376, 1336, 1262, 1097, 1076, 802,
737, 698, 607, 473; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 6.9 Hz,
3H), 1.25 (s, 12H), 1.44-1.49 (m, 2H), 2.55 (brs, 1H), 2.84-2.93
1
(petroleum ether-ethyl acetate/methanol, 10:10:1); H NMR (300
MHz, CDCl3) δ 1.32-1.48 (m, 10H), 1.50-1.58 (m, 4H), 2.20-2.31
(m, 2H), 2.52-2.61 (m, 1H), 2.65 (dd, J = 6.0, 11.7 Hz, 1H), 3.46 (dd,
J = 6.3, 9.6 Hz, 1H), 3.61-3.70 (m, 3H), 3.90 (dd, J = 5.4, 11.7 Hz, 1H),
4.04 (dt, J = 2.4, 6.9 Hz, 1H), 4.20 (dd, J = 2.4, 6.0 Hz, 1H), 4.50-4.60
(ABq, J = 11.7 Hz, 2H), 7.26-7.36 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ 21.8, 25.4, 26.5, 27.2, 28.1, 32.6, 55.1, 57.2, 61.2, 62.3, 62.8,
71.8, 75.7, 83.1, 98.9, 127.8, 128.4, 138.0; HRMS calcd for C21H34NO4
[M þ Hþ] 364.2482, found 364.2487.
2-((4aS,7R,7aR)-7-Benzyloxytetrahydro-2,2-dimethyl[1,3]
dioxino[5,4-b]pyrrol-5(6H)-yl)ethanol (9d). Compound 9d was
prepared from compound 6d as described in the preparation of
compound 9a, yielding 9d (96% yield) without chromatography: Rf =
1
0.25 (petroleum ether-ethyl acetate-methanol, 10:10:1); H NMR
(300 MHz, CDCl3) δ 1.36 (s, 3H), 1.41 (s, 3H), 2.42 (dd, J = 5.4,
10.2 Hz, 1H), 2.57 (td, J = 3.5, 12.9 Hz, 2H), 2.79-2.87 (m, 2H), 3.51-
3.57 (m, 2H), 3.59 (dd, J = 3.5, 9.3 Hz, 1H), 3.66-3.73 (m, 1H), 3.91-
4.01 (m, 2H), 4.25 (dd, J = 1.5, 5.1 Hz, 1H), 4.51-4.60 (ABq, J = 11.7
Hz, 2H), 7.29-7.38 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 21.1, 27.2,
56.0, 57.1, 59.6, 60.5, 60.9, 71.7, 75.1, 82.9, 98.5, 127.7, 127.8, 128.4,
137.8; HRMS calcd for C17H26NO4 [M þ Hþ] 308.1856, found
308.1856.
(4aS,7R,7aR)-5-(4-Methoxybenzyl)-7-benzyloxyhexahydro-
2,2-dimethyl[1,3]dioxino[5,4-b]pyrrole (9e). Compound 9e was
prepared from compound 6e as described in the preparation of compound
9a, yielding 9e (95% yield) after column chromatography (petroleum
ether-ethyl acetate, 5:1): Rf = 0.55 (petroleum ether-ethyl acetate, 1:1);
1H NMR (300 MHz, CDCl3) δ 1.35 (s, 3H), 1.36 (s, 3H), 2.30 (t, J =
8.4 Hz, 1H), 2.79 (dd, J = 6.3, 12.6 Hz, 1H), 3.30 (t, J = 8.1 Hz, 1H), 3.46-
3.62 (m, 4H), 3.79 (s, 3H), 4.05 (t, J= 6.9 Hz, 1H), 4.19 (d, J= 5.7 Hz, 1H),
4.47-4.58 (ABq, J = 11.7 Hz, 2H), 6.83 (d, J = 7.8 Hz, 2H), 7.19-7.32 (m,
7H); 13C NMR (75 MHz, CDCl3) δ 22.4, 26.1, 55.2, 57.1, 58.4, 61.3, 62.0,
71.9, 76.1, 82.8, 99.1, 113.6, 127.7, 127.8, 128.4, 130.2, 130.3, 138.0, 158.9;
HRMS calcd for C23H30NO4 [M þ Hþ] 384.2169, found 384.2162.
1,4-Dideoxy-l,4-(nonylimino)-L-xylitol (10a). A methanolic
solution (4 mL) of compound 9a (39 mg, 0.10 mmol) was adjusted
to pH = 2 with 2 N HCl and stirred at rt in the presence of 10% Pd/C
(5 mg) under 4 atm hydrogen pressure for 48 h. The catalyst was then
removed by filtration through Celite, and the filtrate was concen-
trated. The residue was subjected to a C-18 reversed-phase column
chromatography (eluent: H2O) to give compound 10a (29 mg, 98%
yield, in the form of HCl salt) as a colorless oil: IR νmax (KBr)/cm-1
3326, 2927, 2855, 2685, 1680, 1640, 1465, 1377, 1264, 1091, 1057,
784, 724, 599, 479; 1H NMR (400 MHz, D2O) δ 0.79 (t, J = 6.8 Hz,
3H), 1.21-1.28 (m, 12H), 1.69 (brs, 2H), 3.09-3.16 (m, 1H), 3.21
(d, J = 13.2 Hz, 1H), 3.4-3.49 (m, 1H), 3.77 (m, 1H), 3.89 (dd, J =
4.0, 13.2 Hz, 1H), 3.94-4.03 (m, 2H), 4.30 (m, 2H); 13C NMR
(75 MHz, D2O) δ 13.9, 22.6, 25.4, 26.2, 28.6, 28.87, 28.93, 31.6, 57.4,
2006
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ARTICLE
(m, 2H), 3.31-3.36 (m, 1H), 3.62-3.72 (m, 1H), 3.77 (brs, 2H), 4.04
(d, J = 6.0 Hz, 1H), 4.18 (t, J = 6.0 Hz, 1H), 4.78 (d, J = 11.7 Hz, 1H),
5.10 (d, J = 11.7 Hz, 1H), 7.29-7.42 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ 14.1, 22.7, 26.8, 27.3, 29.2, 29.3, 29.5, 31.8, 40.2, 59.5, 61.7,
72.8, 73.2, 81.8, 128.1, 128.3, 128.5, 137.5, 171.0; HRMS calcd for
C21H34NO4 [M þ Hþ] 364.2482, found 364.2489.
on silica gel to provide compound 12a (36.5 mg, 95%) as a colorless oil:
Rf = 0.25 (petroleum ether-ethyl acetate-methanol, 5:5:1); 1H NMR
(500 MHz, CD3OD) δ 0.89 (t, J = 7.0 Hz, 3H), 1.28-1.30 (m, 12H),
1.49-1.53 (m, 2H), 2.26-2.32 (m, 1H), 2.44 (m, 1H), 2.62 (dd, J = 6.0,
11.0 Hz, 1H), 2.83-2.89 (m, 1H), 3.18-3.21 (m, 1H), 3.64 (dd, J = 5.0,
11.0 Hz, 1H), 3.70 (dd, J = 5.5, 11.0 Hz, 1H), 3.84 (td, J = 2.5, 6.5 Hz,
1H), 4.07 (dd, J = 2.5, 5.5 Hz, 1H), 4.53 (d, J = 11.5 Hz, 1H), 4.59 (d, J =
11.5 Hz, 1H), 7.24-7.36 (m, 5H); 13C NMR (125 MHz, CD3OD) δ
14.4, 23.7, 28.6, 28.7, 30.4, 30.6, 30.7, 33.1, 56.8, 58.3, 62.4, 72.2, 74.4,
78.6, 84.9, 128.6, 128.9, 129.3, 139.6; HRMS calcd for C21H36NO3
[M þ Hþ] 350.2690, found 350.2692.
(3S,4R,5R)-3-Benzyloxy-4-hydroxy-5-(hydroxymethyl)-1-
butylpyrrolidin-2-one (11b). Compound 11b was prepared from
compound 6b as described in the preparation of compound 11a, yielding
11b (84% yield) as a white amorphous solid: Rf = 0.55 (petroleum
ether-ethyl acetate-methanol, 5:5:2); IR νmax (KBr)/cm-1 3395, 3064,
3032, 2959, 2930, 2873, 1682, 1458, 1378, 1345, 1282, 1214, 1155, 1101,
1028, 981, 787, 740, 699, 605, 514; 1H NMR (500 MHz, CDCl3, after
D2O shake) δ 0.92 (t, J = 7.5 Hz, 3H, CH3), 1.26-1.35 (m, 2H,
CH2CH3), 1.39-1.55 (m, 2H, NCH2CH2), 2.40 (m, 1H, OH-5), 2.69
(d, J = 4.0 Hz, 1H, OH-3), 2.88-2.94 (m, 1H, NCH2 ꢀ 1), 3.33-3.36
(m, 1H, H-4), 3.65-3.71 (m, 1H, NCH2 ꢀ 1), 3.74-3.81 (m, 2H, H-5),
4.04 (d, J = 6.0 Hz, 1H, H-2), 4.16-4.19 (td, J = 4.0, 6.0 Hz, 1H, H-3),
4.78 (d, J = 11.5 Hz, 1H, PhCH2 ꢀ 1), 5.10 (d, J = 11.5 Hz, 1H, PhCH2
ꢀ 1), 7.29-7.42 (m, 5H, Ph); deuterium exchange 1H NMR (500 MHz,
CDCl3 containing 2 drops of D2O) δ 0.91 (t, J = 7.5 Hz, 3H, CH3),
1.26-1.34 (m, 2H, CH2CH3), 1.38-1.54 (m, 2H, NCH2CH2), 2.87-
2.93 (m, 1H, NCH2 ꢀ 1), 3.31-3.34 (m, 1H, H-4), 3.65-3.71 (m, 1H,
NCH2 ꢀ 1), 3.75-3.78 (m, 2H, H-5), 4.05 (d, J = 6.0 Hz, 1H, H-2), 4.17
(t, J = 6.0 Hz, 1H, H-3), 4.78 (d, J = 11.5 Hz, 1H, PhCH2 ꢀ 1), 5.10 (d,
J = 11.5 Hz, 1H, PhCH2 ꢀ 1), 7.28-7.42 (m, 5H, Ph); 13C NMR (75
MHz, CDCl3) δ 13.7, 20.0, 29.3, 39.8, 59.5, 61.7, 72.8, 73.2, 81.7, 128.1,
128.3, 128.5, 137.5, 171.0; HRMS calcd for C16H24NO4 [M þ Hþ]
294.1700, found, 294.1699.
The methanolic solution (4 mL) of compound 12a (36.5 mg,
0.10 mmol) was stirred at room temperature in the presence of 10%
Pd/C (5 mg) under 4 atm of hydrogen pressure for 48 h. The catalyst
was then removed by filtration through Celite, and the filtrate was
concentrated. The residue was subjected to a C-18 reversed-phase
column chromatography (methanol-water, 1:1) to give 13a (25.4 mg,
98%) as a colorless oil: IR νmax (KBr)/cm-1 3347, 2926, 2855, 2694,
1640, 1466, 1381, 1257, 1068, 1019, 895, 721, 605; 1H NMR (300 MHz,
CD3OD) δ 0.89 (t, J = 7.2 Hz, 3H), 1.30-1.37 (m, 12H), 1.75 (m, 2H),
3.08-3.24 (m, 1H), 3.39-3.49 (m, 3H), 3.58 (d, J = 11.7 Hz, 1H),
3.80-4.02 (m, 3H), 4.19 (m, 1H); 13C NMR (75 MHz, D2O) δ 13.9,
22.6, 25.3, 26.2, 28.6, 28.9, 31.7, 57.4, 58.3, 59.1, 70.9, 74.2, 75.7; HRMS
calcd for C14H30NO3 [M þ Hþ] 260.2220, found 260.2215.
1,4-Dideoxy-l,4-(butylimino)-D-arabinitol (13b). Compound
12b was prepared from compound 11b as described in the preparation
of compound 12a, Rf = 0.15 (petroleum ether-ethyl acetate-methanol,
5:5:3). After concentration, without chromatography, catalytic hydro-
genolysis was conducted to 12b as described in the preparation of
compound 13a, yielding 13b (93% yield over two steps) as a colorless
oil: IR νmax (KBr)/cm-1 3356, 2962, 2876, 2711, 1639, 1465, 1410,
1346, 1258, 1078, 1017, 906, 739, 572; 1H NMR (300 MHz, CD3OD) δ
0.98 (t, J = 7.2 Hz, 3H), 1.37-1.44 (m, 2H), 1.74 (m, 2H), 3.10-3.15
(m, 1H), 3.43-3.61 (m, 4H), 3.87-4.03 (m, 3H), 4.20 (brs, 1H); 13C
NMR (75 MHz, CD3OD) δ 13.9, 20.9, 28.3, 58.7, 60.7, 60.9, 75.7, 77.7,
78.5; HRMS calcd for C9H20NO3 [M þ Hþ] 190.1438, found 190.1442.
1,4-Dideoxy-l,4-(2-hydroxyethylimino)-D-arabinitol (13c).
Compound 12c was prepared from compound 11c as described in the
preparation of compound 12a, yielding 12c as a colorless oil: Rf = 0.65
(petroleum ether-ethyl acetate-methanol, 5:5:1); 1H NMR (300
MHz, CDCl3) δ 1.99 (brs, 2H), 2.53-2.62 (m, 2H), 2.83 (dd, J =
6.9, 10.8 Hz, 1H), 2.95-3.04 (m, 1H), 3.26 (dd, J = 2.7, 10.8 Hz, 1H),
3.55 (t, J = 5.7 Hz, 2H), 3.65-3.75 (m, 2H), 3.87-3.91 (m, 1H), 4.23
(dd, J = 3.6, 5,7 Hz, 1H), 4.52-4.57 (m, 4H), 7.29-7.35 (m, 10H); 13C
NMR (75 MHz, CDCl3) δ 53.2, 57.6, 59.5, 68.7, 71.3, 71.4, 73.2, 83.2,
127.7, 127.8, 128.4, 138.0; HRMS calcd for C21H28NO4 [M þ Hþ]
358.2013, found 358.2017. Compound 13c was prepared from com-
pound 12c as described in the preparation of compound 13a, yielding
13c (96% yield over two steps) as a colorless oil: IR νmax (KBr)/cm-1
3357, 2935, 1611, 1408, 1265, 1072, 892, 655, 613; 1H NMR (400 MHz,
D2O) δ 2.58-2.62 (m, 2H), 2.81 (m, 1H), 2.97-3.05 (m, 2H), 3.56-
3.64 (m, 4H), 3.81-3.83 (m, 1H), 4.01 (t J = 2.8 Hz, 1H); 13C NMR
(100 MHz, D2O) δ 59.3, 61.5, 63.1, 75.3, 77.9, 81.0; HRMS calcd for
C7H16NO4 [M þ Hþ] 178.1074, found 178.1078.
(3S,4R,5R)-3-Benzyloxy-1-(2-(benzyloxy)ethyl)-4-hydro-
xy-5-(hydroxymethyl)pyrrolidin-2-one (11c). Compound 11c
was prepared from compound 6d0 as described in the preparation of
compound 11a, yielding 11c (94% yield) as a colorless oil: Rf = 0.30
(petroleum ether-ethyl acetate-methanol, 5:5:2); IR νmax (KBr)/cm-1
3404, 3064, 3031, 2924, 2854, 1678, 1496, 1457, 1357, 1333, 1264, 1204,
1
1151, 1085, 1045, 1028, 908, 806, 738, 698, 607, 531, 460; H NMR
(300 MHz, CDCl3) δ 2.90 (brs, 1H), 3.18-3.28 (m, 2H), 3.53-3.62
(m, 3H), 3.81-3.94 (m, 3H), 4.07 (d, J = 6.9 Hz, 1H), 4.31-4.32 (m,
1H), 4.43-4.55 (ABq, J = 11.4 Hz, 2H), 4.79 (d, J = 11.7 Hz, 1H), 5.08
(d, J = 11.7 Hz, 1H), 7.29-7.44 (m, 10H); 13C NMR (75 MHz, CDCl3)
δ 41.9, 58.0, 63.6, 68.5, 71.9, 72.7, 73.6, 82.0, 127.9, 128.2, 128.3, 128.5,
128.6, 136.5, 137.8, 172.3; HRMS calcd for C21H26NO5 [M þ Hþ]
372.1805, found 372.1806.
(3S,4R,5R)-1-(4-Methoxybenzyl)-3-(benzyloxy)-4-hydro-
xy-5-(hydroxymethyl)pyrrolidin-2-one (11d). Compound 11d
was prepared from compound 6e as described in the preparation of
compound 11a, yielding 11d (74% yield) as a white amorphous solid: Rf
1
= 0.30 (petroleum ether-ethyl acetate-methanol, 5:5:2); H NMR
(300 MHz, CDCl3) δ 2.26 (brs, 1H), 2.87 (d, J = 3.9 Hz, 1H), 3.16-
3.21 (m, 2H), 3.67 (m, 2H), 3.77 (s, 3H), 4.09-4.14 (m, 2H), 4.20-
4.25 (m, 1H), 4.73 (d, J = 15.0 Hz, 1H), 4.80 (d, J = 11.7 Hz, 1H), 5.11
(d, J = 11.7 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H),
7.29-7.43 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 43.7, 55.3, 59.0,
61.8, 72.7, 72.9, 77.2, 81.8, 114.3, 128.0, 128.1, 128.3, 128.5, 129.2, 137.5,
159.2, 171.4; HRMS calcd for C20H24NO5 [M þ Hþ] 358.1649, found
358.1642.
(2R,3R,4R)-1-(4-Methoxybenzyl)-4-benzyloxy-2-(hydroxy-
methyl)pyrrolidin-3-ol (12d). A mixture of 11d (46 mg, 0.13
mmol) and LiAlH4 (31 mg, 0.78 mmol) in THF (10 mL) was heated
to reflux for 16 h. The mixture was cooled to 0 °C, treated with H2O
dropwise (60 μL), and stirred at room temperature until the gray
powder completely turned to white. The solids were filtered off and
washed with ethyl acetate (20 mL). After evaporation of the filtrate, the
residue was subjected to column chromatography (petroleum ether-
ethyl acetate 1:1) to afford 12d (33 mg, 75% yield) as a white amorphous
solid: Rf = 0.35 (petroleum ether-ethyl acetate-methanol, 5:5:1); 1H
1,4-Dideoxy-l,4-(nonylimino)-D-arabinitol (13a). BH3 THF
3
(1M, 0.44 mL, 0.44 mmol) was added dropwise to the solution of lactam
11a (40 mg, 0.11 mmol) in anhydrous THF (10 mL) at 0 °C, and after
being stirred for 20 min at room temperature, the mixture was heated
under reflux for 4 h. The mixture was cooled to 0 °C, treated with methanol
dropwise (5 mL), and allowed to stir for 36 h at room temperature. The
mixture was concentrated in vacuo. The residue was purified by column
chromatography (petroleum ether-ethyl acetate-methanol, 10:10:1)
2007
dx.doi.org/10.1021/jo1020322 |J. Org. Chem. 2011, 76, 2001–2009

The Journal of Organic Chemistry
ARTICLE
NMR (300 MHz, CDCl3) δ 2.66-2.77 (m, 2H), 3.06 (dd, J = 2.1,
11.1 Hz, 1H), 3.40 (d, J = 12.9 Hz, 1H), 3.46-3.56 (m, 2H), 3.71-3.86
(m, 6H), 3.94 (d, J = 12.9 Hz, 1H), 4.29 (dd, J = 3.0, 5.1 Hz, 1H), 4.46-
4.55 (m, 2H), 6.85 (d, J = 8.4 Hz, 2H), 7.19-7.34 (m, 7H); 13C NMR
(75 MHz, CDCl3) δ 55.4, 56.2, 57.5, 59.3, 71.3, 71.7, 77.9, 82.6, 113.8,
127.8, 128.4, 129.0, 130.2, 137.8, 159.0; HRMS calcd for C20H26NO4
[M þ Hþ] 344.1856, found 344.1851.
’ ACKNOWLEDGMENT
This work was financially supported by the National Natural
Science Foundation of China (Grant No. 90713010) and a grant
(2009ZX09501-011) from the Ministry of Science and Technol-
ogy of China.
1,4-Dideoxy-l,4-imino-D-arabinitol Hydrochloride (DAB
1 HCl) (13d). Compound 13d was prepared from compound 12d as
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0 °C, the resulting mixture was evaporated in vacuo, and further
evaporation under high vacuo gave DAB 1 in the form of hydrochloride
salt: IR vmax(KBr)/cm-1 3424, 3381, 3286, 3030, 2972, 2943, 2764,
1632, 1578, 1450, 1399, 1378, 1360, 1326, 1301, 1261, 1216, 1167, 1110,
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: xinshan@bjmu.edu.cn.
2008
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dx.doi.org/10.1021/jo1020322 |J. Org. Chem. 2011, 76, 2001–2009