A flexible approach to azasugars: asymmetric total syntheses of (+)-castanospermine, (+)-7-deoxy-6-epi-castanospermine, and (+)-1-epi- castanospermine

Article abstract of DOI:10.1002/chem.200903490

The asymmetric total synthesis of natural azasugars (+)-castanospermine, (+)-7-deoxy-6-epI-castanospermine, and synthetic (+)-1-epi-castanospermine has been accomplished in nine to ten steps from a common chiral building block (S)-8. The method features a powerful chiral relay strategy consisting of a highly diastereoselective vinylogous Mukaiyama-type reaction with either chiral or achiral aldehydes (≥ 95% de; de = diastereomeric excess) and a diastereodivergent reduction of tetramic acids, which allows formation of three continuous stereogenic centers with high diastereo-selectivities. The method also provides a flexible access to structural arrays of 5-(α-hydroxyalkyl) tetramic acids, such as 17/34, and 5-(α-hydroxyalkyl)-4-hydroxyl-2- pyrrolidinones, such as 18 and 25/35 a. The method constitutes the first realization of the challenging chiral synthons A and D and thus of the conceptually attractive retrosynthetic analysis shown in Scheme 1 in a highly enantioselective manner.

Full text of DOI:10.1002/chem.200903490

FULL PAPER
DOI: 10.1002/chem.200903490
A Flexible Approach to Azasugars: Asymmetric Total Syntheses of
(+)-Castanospermine, (+)-7-Deoxy-6-epi-castanospermine,
and (+)-1-epi-Castanospermine
Gang Liu, Tian-Jun Wu, Yuan-Ping Ruan, and Pei-Qiang Huang*[a]
Abstract: The asymmetric total synthe-
sis of natural azasugars (+)-castano-
spermine, (+)-7-deoxy-6-epi-castano-
spermine, and synthetic (+)-1-epi-cas-
tanospermine has been accomplished
in nine to ten steps from a common
chiral building block (S)-8. The method
features a powerful chiral relay strat-
egy consisting of a highly diastereose-
lective vinylogous Mukaiyama-type re-
action with either chiral or achiral al-
dehydes (ꢀ95% de; de=diastereo-
meric excess) and a diastereodivergent
reduction of tetramic acids, which
allows formation of three continuous
stereogenic centers with high diastereo-
selectivities. The method also provides
a flexible access to structural arrays of
5-(a-hydroxyalkyl)tetramic acids, such
as 17/34, and 5-(a-hydroxyalkyl)-4-hy-
droxyl-2-pyrrolidinones, such as 18 and
25/35a. The method constitutes the
first realization of the challenging
chiral synthons A and D and thus of
the conceptually attractive retrosyn-
thetic analysis shown in Scheme 1 in a
highly enantioselective manner.
Keywords: alkaloids · asymmetric
synthesis · Mukaiyama-type reac-
tion
· natural products · total
synthesis
Introduction
Polyhydroxylated pyrrolidine, piperidine, pyrrolizidine, and
indolizidine alkaloids, also known as azasugars, are an im-
portant class of sugar mimetic that exhibit important bioac-
tivity.[1] Among them, castanospermine (1), an alkaloid[2]
first isolated from the seeds of Castanospermum australe
and then from the dried pod of Alexa leiopetala, has attract-
ed considerable attention. As a powerful inhibitor of a- and
b-glucosidases,[3] castanospermine (1) shows considerable
potential as an antiviral agent in the treatment of HIV,[4]
hepatitis C,[5] and HSV-1[6] infections. Castanospermine and
its stereoisomers also have potential use in the inhibition of
the progression of multiple sclerosis,[7] angiogenesis,
cancer,[8] and diabetes.[9] MBI-3253 (celgosivir, 6-O-butanoyl
castanospermine) (2), in combination with peginterferon 2b
alone (double combination therapy) or also with ribavirin
(triple combination therapy) are under Phase II clinical
trials for the treatment of patients with chronic HCV.[10–12]
Several stereoisomers of castanospermine have also been
isolated from natural sources.[13] The synthetic 1-epi-castano-
spermine (3)[14] was suggested to possess anti-HIV activity,
and thus is a valuable synthetic target for full evaluation of
its biological activity. In addition, 7-deoxy-6-epi-castanosper-
mine (4) was isolated from the seeds of Castanospermum
australe.[15] At the same time, these alkaloids provide a natu-
ral platform for exploring new synthetic methodologies.[16]
Numerous imaginative strategies have been developed for
the enantioselective synthesis of castanospermine[16] and
their stereoisomers.[14,17] However, novel, efficient, and flexi-
[a] G. Liu, Dr. T.-J. Wu, Prof. Y.-P. Ruan, Prof. Dr. P.-Q. Huang
Department of Chemistry and The Key Laboratory
for Chemical Biology of Fujian Province,
College of Chemistry and Chemical Engineering
Xiamen University, Xiamen
Fujian 361005 (P. R. China)
Fax : (+86)592-2186400
E-mail: pqhuang@xmu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903490.
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ble methods are still in high demand because of both the
high biological and pharmaceutical potential of this class of
compounds and the continuing discovery of new azasugars,
such as hyacinthacine B4 (5),[18] from natural sources. A con-
ceptually attractive strategy for a general approach to azasu-
gars, such as castanospermine (1), 1-epi-castanospermine
(3), 7-deoxy-6-epi-castanospermine (4), and hyacinthacine
B4 (5), is illustrated retrosynthetically in Scheme 1. The
By starting from this building block, a highly diastereoselec-
tive and C-5 regioselective alkylation method was estab-
lished for the synthesis of 5-alkyltetramic acid derivatives 9.
Further elaboration of compounds 9 to 5-alkyl-4-hydroxyl-2-
pyrrolidinones 11 via the corresponding 5-alkyltetramic
acids 10 validated compound 8 as a synthetic equivalent of
chiral synthons D and A.[26] More recently, we reported pre-
liminary results on the highly diastereoselective C-5 a-hy-
droxyalkylation of 8 and application of this method to the
asymmetric synthesis of 3.[28] We now report full details of
this work. In addition, we also describe the asymmetric syn-
thesis of 1, an extension of the highly diastereoselective C-5
a-hydroxyalkylation of tetramic acid derivative 8 to achiral
aldehydes, and the application of the latter method to the
asymmetric synthesis of 4.
Results and Discussion
Our initial efforts have been devoted to the exploration of
the use of vinylogous enolate 12, generated[29] in situ from
tetramic acid derivative 8. Disappointedly, although the al-
kylation of this enolate shows excellent diastereoselectiv-
ity,[26] its reaction with iso-butanal gave compound 13a as a
mixture of four diastereomers in only modest selectivity
with a ratio of 2:4:27:67 (Scheme 3).
Scheme 1. Retrosynthetic analysis of polyhydroxylated alkaloids (azasu-
gars). P=protecting group.
practical realization of this approach in a highly enantio-
and diastereoselective manner has been hampered by the
nonavailability of suitable synthetic methodology allowing
the generation and/or stereoselective reaction of carbanions
B/C corresponding to chiral synthon A.[19–21] The challenges
associated with the chiral-synthon-A-based methodology are
manifold, they include quick proton exchange of the carban-
ion B,[21] b-elimination of the carbanion C,[22] low stereose-
[23]
ꢁ
lective C C bond formation
and access to the enantio-
meric form of carbanions B/C.[19a,b]
In connection with a program aimed at the synthesis of 5-
alkylteramic acids and 5-alkyltetramates, which are also key
structural features found in many bioactive natural prod-
ucts,[24,25] we have been engaged in the development of
enantiomerically pure tetramic acid derivative 8 as a syn-
thetic equivalent of tetramic acid synthon D and 4-hydroxyl-
2-pyrrolidinone 5-carbanionic synthon A (Scheme 2).[26,27]
Scheme 3. Reaction of vinylogous enolate 12 with iso-butanal. HMPA=
hexamethylphosphoramide.
In light of the widespread use of 2-[(tert-butyldimethylACHTUNGTRENNUNGsi-
ACHUTNGERNlNUG yl)AHCTUNGTRENNoUGN xy]pyrrole (14a) (TBS=tert-butyldimethylsilyl; Boc=
tert-butoxycarbonyl) by Casiraghi and co-workers[30a,b,31] and
its chiral version 14b by Royer and co-workers,[30c,31] as well
as 2-trimethylsilyloxy-4-methoxypyrrole (14c) (TMS=trime-
thylsilyl)[19f,g,29] in vinylogous aldol reactions, we turned our
attention to the exploration of the use of the silyl dienol
Scheme 2. Demonstration of compound 8 as a synthetic equivalent of
chiral synthons A and D. PMB=p-methoxylbenzyl.
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A Flexible Approach to Azasugars
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ether 14d.[31] However, successive treatment of compound 8
with reagent system TBSOTf/2,6-lutidine and an aldehyde
led only to the recovery of starting material. Thus vinylo-
gous TMS-enol ether 14e was chosen as a synthetic equiva-
lent of the vinylogous enolate 12.
To begin the synthesis of 3, 4-O-(4-methoxybenzyl)-2,3-
bisACHTUNGTRENNUNG(O-benzyl)-l-threose (15) was prepared according to a
Scheme 5. Possible transition states.
known procedure (cf. the Supporting Information). The vi-
nylogous silyl enol ether 14e was prepared in situ from tet-
ramic acid derivative 8 by treatment with LDA in THF at
ꢁ788C for 1 h and trapping the resultant vinylogous enolate
12 with trimethylsilyl chloride. Without isolation, the vinylo-
gous silyl enol ether 14e was allowed to react, in the pres-
ence of tin tetrachloride at ꢁ788C, with 15 for 3.5 h
(Scheme 4). To our delight, the desired a-hydroxyalkylated
TMS-enol ether 14e is blocked by the substituent of the
chiral auxiliary. Thus an aldehyde approaches 14e from the
si face. Next, formation of a six-membered transition state
favors the approach of the aldehyde by the re face (TS1)
leading to the erythro (anti)-product. The reaction of 14e
with aldehyde 15 differs from examples reported by Casira-
ghi both in its stereoselection and also in the reaction condi-
tions used (THF at ꢁ788C vs. diethyl ether at ꢁ858C).
The stage was now set for the synthesis of 3. Compound
16 was treated with HCl (10% in THF) at 308C to give tet-
ramic acid 17 (Scheme 6). In the presence of AcOH, reduc-
Scheme 4. Diastereoselective vinylogous Mukaiyama-type reaction of
14e with chiral aldehyde 15. LDA=lithium diisopropylamide.
product 16 was obtained as the sole product in 60% yield.
1
Both the H and 13C NMR spectra of the product are quite
complex, showing a mixture in a 2.2:1 ratio. Since HPLC
analysis showed only one product in 99% de (de=diastereo-
meric excess), we assumed that the complex peaks appear-
1
ing in both the H and 13C NMR spectra of 16 are rotameric
in nature, owing to slow rotation of the chiral auxiliary. To
1
confirm this interpretation, H NMR spectra of 16 were re-
corded in [D6]DMSO at 20 and 958C, respectively. The
peaks from the minor isomer disappeared at 958C, and re-
appeared when the temperature returned to 208C. These
NMR spectroscopic experiments showed that the aldol
products observed in the NMR spectra are rotamers rather
than diastereomers, in agreement with our previous observa-
tions.[26] This was confirmed at a later stage (16!18). A ste-
reochemical assignment was also carried out at a later stage
(vide infra), which revealed that the newly formed stereo-
centers are erythro (anti) and the relationship with the adja-
cent stereocenter is threo (syn).
Thus the vinylogous Mukaiyama-type reaction between
14e and 15 established the correct configurations at C-8a
and C-8 required for the synthesis of castanospermine and
its C-1 epimer. This stereoselection can be rationalized by
transition-state TS1, which is favored over TS2 (Scheme 5).
In transition-state TS1 or TS2, the re face of the vinylogous
Scheme 6. Synthesis of indolizidinone 23. CAN=ammonium cerium(IV)
nitrate; TsCl=p-toluenesulfonyl chloride; py=pyridine.
[32]
tion of this crude tetramic acid with NaBH4
at ꢁ10 to
58C for 9 h gave diol 18 as the sole diastereomer as judged
by 1H NMR spectroscopic analysis.
The two hydroxyl groups in compound 18 were protected
(NaH, BnBr, nBu4NI) to afford the desired bisbenzylated
product 19 in 72% yield. Treatment of compound 19 with I2
in refluxing methanol[33] resulted in the selective cleavage of
the O-PMB group and furnished primary alcohol 20 in 76%
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P.-Q. Huang et al.
yield. Tosylation of alcohol 20 (pTsCl/py) produced tosylate
21 in 96% yield. Cleavage of the N-PMB group under Yosh-
imura conditions[34] (CAN, MeCN/H2O 9:1, 5 h, RT) gave
the desired lactam 22 in 85% yield. Cyclization of 22 was
undertaken by treatment with nBuLi in THF at ꢁ788C for
0.5 h, then overnight at RT. The desired indolizidinone 23
was obtained in 84% yield.
The relative stereochemistry of 23 was established first by
1
1H-1H COSY and H-13C HMQC experiments to identify the
signals of each proton and then by NOESY experiments.
These experiments showed that the vinylogous Mukaiyama-
type reaction on 14e led predominately to the erythro (anti)-
isomer 16, and that reduction (17!18) established the 4,6-
threo (syn)-stereochemistry.[32]
Subsequent reduction of lactam 23 with borane dimethyl
sulfide complex (BH3·SMe2, THF, RT, 15 h) proceeded
smoothly to give indolizidine 24 in 92% yield (Scheme 7).
Scheme 7. Synthesis of 1-epi-castanospermine (3).
Scheme 8. Synthesis of (+)-castanospermine (1). DMAP=4-dimethyl-
AHCTUNGTREGaNNUN minopyridine.
Finally, cleavage of the four benzyl groups in 24 was accom-
plished by 10% Pd/C-catalyzed transfer hydrogenation to
give 1-epi-castanospermine (3) in quantitative yield. The
physical and spectral data of the synthetic material ([a]2D2 =
+3.8 (c=0.54 in MeOH); lit.[14] [a]D25 =+3.8 (c=0.5 in
MeOH); for the antipode: [a]2D2 =ꢁ4 (c=1.2 in MeOH);
[a]2D2 =ꢁ3.1 (c=1.86 in MeOH)) are consistent with those
reported.[14]
Next we turned our attention to the asymmetric synthesis
of (+)-castanospermine (1). Reduction of tetramic acid de-
rivative 17 with sodium borohydride (NaBH4) at ꢁ308C
yielded hydroxyl lactams 18 and 25 in a ratio of 1:7 in a
combined yield of 70% (Scheme 8). Such cis diastereoselec-
tivity is generally observed in the reduction of tetramic
acids.[35]
The stereochemical outcome of the reduction of 17 with
NaBH4 in HOAc/CH2Cl2 can be rationalized by Evansꢁ di-
rected-reduction model.[32] Compound 17 provides a singular
situation merging an alicyclic–cyclic b-hydroxy ketone
system, the hydroxyl group directed intramolecular hydride
delivery via the transition state TS3 leads to 1,3-syn-diol 18
(Scheme 9), which is in contrast to results seen with simple
alicyclic systems.[32]
Scheme 9. Proposed stereochemical course.
the monobenzylated product 26 was obtained in 85% yield.
This difference is attributable to the steric hindrance of cis-
25. To tackle this problem, an alternative approach was de-
vised. Thus after chemoselective cleavage of O-PMB by re-
fluxing an I2-containing methanolic solution[33] of 25, the
triol 27, obtained in 77% yield, was trisacetylated to give
28. Treatment of the resulting trisACTHUNTGRNEUNG(acetate) with ceric ammo-
nium nitrate in MeCN/H2O (9:1, v/v) at RT gave lactam 29
in 88% yield. One-pot conversion of lactam 29 to trihy-
For the bisbenzylation of 25, the conditions used in the
synthesis of 1-epi-castanospermine (18!19) were used, but
N
ACHTUNGTRENpNGNU yrrolidine 30 was achieved by reduction with borane
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lowed by treating the resulting borane–pyrrolidine complex
with 6m HCl at RT for 30 min, which with concomitant tris-
deacetylation gave pyrrolidine 30 in 63% yield. The key cyc-
lization of trihydroxylated pyrrolidine derivative 30 was per-
formed by treatment with PPh3/CCl4/NEt3 in DMF.[36] After
1 h reaction at RT in the dark, indolizidine 31 was formed in
70% yield. It is noteworthy that the foregoing modifications
relative to the procedures developed for 1-epi-castanosper-
mine were one step shorter.
with aldehyde 33 gave product 13g as the sole diastereomer
in 65% yield (Scheme 10). Treatment of 13g with a 10%
HCl in THF at 308C afforded tetramic acid derivative 34,
which without further purification, was reduced with NaBH4
Finally, bisdebenzylation of 31 was achieved by catalytic
transfer hydrogenolysis (HCO2H, 10% Pd/C, MeOH, RT,
4 h). Filtration of the reaction mixture through ion-exchange
resin Dowex 1ꢂ8–100 afforded (+)-castanospermine (1) in
87% yield. The physical ([a]2D0 =+77.5 (c=0.3 in H2O);
lit.[2a] [a]D24 =+79.7 (c=0.93 in H2O)) and spectral data of
the synthetic material are consistent with those reported.[2a]
To develop a more general vinylogous Mukaiyama-type
reaction based on tetramic acid derivative 8, we next exam-
ined the coupling of the vinylogous silyl enol ether 14e, gen-
erated in situ from derivative 8, with achiral aldehydes. The
results are summarized in Table 1. As can be seen, the a-hy-
droxyalkylation of 8 with achiral aldehydes (Table 1, en-
Scheme 10. Vinylogous Mukaiyama-type reaction with aldehyde 33 and
subsequent transformations.
Table 1. Results for the vinylogous Mukaiyama-type reaction of the vi-
nylogous silyl enol ether 14e derived from 8 with achiral aldehydes.
(THF, H2O) at ꢁ788C to give diols 35a and 35b in 10:1
ratio in a combined yield of 60% (Scheme 10).
The stereochemistry of the major diastereomer (35a) was
deduced from the triol 36, which was obtained by treating
35a with iodine in refluxing methanol (Scheme 11). The rel-
ative stereochemistry of 36 was established by single-crystal
X-ray diffraction analysis (Figure 1).
Entry
Aldehyde
Product
Yield [%][a]
de[b]
97
99
97
97
95
1
2
3
4
5
iPrCHO
nPrCHO
nC5H11CHO
nC6H13CHO
cHexCHO
13a
13b
13c
13d
13e
84
85
77
77
78
6
13 f
69
>99
7
13g
65
>99
Scheme 11. Synthesis of the triol 36.
[a] Isolated yield. [b] de determined by HPLC analysis.
Although triol 36 could serve as an intermediate for the
synthesis of 4, its high polarity and low solubility led us to
protect the hydroxyl groups by benzylation (NaH, BnBr,
nBu4NI, THF). As in the case of 25, the monobenzylated
tries 1–7) gave, in each case, only one major (13) of the four
possible diastereomers in excellent diastereoselectivity.
These results support the proposed mechanism shown in
Scheme 5, namely, stereoselection of the vinylogous Mu-
kaiyama-type reaction is governed by the chiral auxiliary
and not by the chiral aldehyde.
With the dual aims of confirming the stereochemistry of
the vinylogous Mukaiyama-type reaction based on tetramic
acid derivative 8, and of demonstrating the synthetic value
of the method, the synthesis of the azasugar 4[15,37] was un-
dertaken. For this purpose, the required aldehyde 33 was
synthesized from the known (S)-butanetriol 32 (cf. the Sup-
porting Information). By using our previously established
methods, the condensation of the tetramic acid derivative 8
1
product 37 was obtained in 85% yield and its H-13C HMBC
spectrum showed the benzyl group was located at the C-4
hydroxyl group. The amide 40 was obtained by successive
iodine-mediated selective cleavage of the O-PMB (I2,
MeOH, reflux),[33] bisacetylation (Ac2O, NEt3, DMAP,
CH2Cl2), and cleavage of the N-PMB with CAN in a mix-
ture of MeCN/H2O (9:1). Treatment of a THF solution of
amide 40 with borane–dimethylsulfide complex at reflux re-
sulted in concomitant reduction of the amide group and
cleavage of the two acetyl groups to give product 41 in 71%
yield, isolated after the hydrochloride salt formation. Treat-
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P.-Q. Huang et al.
Conclusion
Chiral nonracemic tetramic acid derivative 8 has been
shown to be a suitable practical equivalent of synthons A
and D, made by a highly diastereoselective, vinylogous Mu-
kaiyama-type reaction with chiral nonracemic aldehydes. On
the basis of this method, diastereo-divergent syntheses of
(+)-1-epi-castanospermine (3) and (+)-castanospermine (1)
have been achieved in ten and nine steps, in 14.7 and 13.9%
overall yields, respectively, from the key building block 8.
The power of the synthon-A-based method has been further
demonstrated by its vinylogous Mukaiyama-type reaction
with achiral aldehydes and its application in the asymmetric
synthesis of 7-deoxy-6-epi-castanospermine (4), achieved in
ten steps with 7.8% overall yield. Tetramic acid derivative 8
thus provides, via silyl dienol ether 14e formed in situ, the
first platform for the highly diastereo- and enantioselective
synthesis of structural arrays of 5-(a-hydroxyalkyl)tetramic
acids, such as 17/34, 5-(a-hydroxyalkyl) 4-hydroxyl-2-pyrroli-
dinones, such as 18, and 25/35a with two or three continuous
chiral centers (Scheme 13). This constitutes the first practi-
cal fulfillment in a highly enantioselective manner of the
conceptually attractive retrosynthetic analysis set out in
Scheme 1.
Figure 1. X-ray crystallographic structure of compound 36.[38]
ment of amino-diol 41 with a mixture of triphenylphos-
phine/carbon tetrachloride/triethylamine in DMF produced
the desired indolizidine 42 in 75% yield (Scheme 12). Final-
ly, the indolizidine 42 was converted into 7-deoxy-6-epi-cas-
tanospermine (4) in 80% yield by bisdebenzylation (10%
Pd/C, HCO2H, MeOH) and chromatographic separation by
using an ion-exchange resin Dowex 1ꢂ8–100. The physical
and spectral data of the synthetic material ([a]2D0 =+17.1
(c=0.6 in MeOH); lit.[15] [a]2D6 =+18.3 (c=0.712 in MeOH))
are consistent with those reported.[15]
Scheme 13. Tetramic acid derivative 8 as a versatile chiral building block
for the enantio- and diastereoselective construction of hydroxylated N-
containing heterocycles. TMSOTf=trimethylsilyl trifluoromethanesulfo-
nate.
Experimental Section
General: Melting points were uncorrected. IR spectra were measured by
using film KBr pellet techniques. 1H NMR spectra were recorded in
CDCl3 with tetramethylsilane as an internal standard. Chemical shifts are
expressed in d (ppm) units downfield from TMS. Silica gel (300–400
mesh) was used for flash column chromatography, eluting (unless other-
wise stated) with ethyl acetate/petroleum ether (PE) (60–908C) mixture.
Ether and THF were distilled over sodium benzophenone ketyl under
N2. Dichloromethane was distilled over calcium hydride under N2.
Typical procedure for the vinylogous Mukaiyama-type reactions of vinyl-
ogous silyl enol ether 14e, generated in situ from 8, with chiral, achiral,
and a-achiral aliphatic aldehydes: LDA (0.41 mmol in 3 mL of THF) was
added dropwise over 5 min to a solution of tetramic acid derivative 8
Scheme 12. Synthesis of 7-deoxy-6-epi-castanospermine (4).
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A Flexible Approach to Azasugars
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(100 mg, 0.27 mmol) in anhydrous THF (3 mL) and HMPA (0.23 mL,
1.35 mmol) at ꢁ788C, and the resultant mixture was stirred for 1 h at
ꢁ788C. TMSCl (0.09 mL, 0.67 mmol) was added at ꢁ788C and the mix-
ture was allowed to warm to ꢁ108C followed by stirring for 2 h. The mix-
ture was re-cooled to ꢁ788C, and aldehyde 15 (170 mg, 0.4 mmol) and
SnCl4 (0.4 mL, 0.81 mmol, 2m in CH2Cl2) were successively added. The
mixture was stirred at ꢁ788C for 3.5 h and then quenched with saturated
NaHCO3 solution (5 mL). The resulting mixture was extracted with
CH2Cl2 (3ꢂ15 mL). The organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash column chromatography on silica
gel eluting with EtOAc/PE 1:2 to give (R)-1-(4-methoxybenzyl)-5-
[(1R,2S,3S)-4-(4-methoxybenzyloxy)-2,3-bis(benzyloxy)-1-hydroxybutyl]-
4-[(S)-2-(3-methoxypentan-3-yl)pyrrolidin-1-yl]-1H-pyrrol-2(5H)one (16)
(128 mg, 60%) as a colorless oil. de=>99% (determined by HPLC anal-
ysis); [a]2D0 =+45.4 (c=2.3 in CHCl3); 1H NMR (400 MHz, CDCl3, two
rotamers, M/m 2.2:1): d=0.60–0.70 (m, 6H; rotamer m), 0.72–0.84 (m,
6H; rotamer M), 1.05–1.91 (m, 8H), 2.66 (s, 1H), 3.00 (s, 1H), 3.05–3.20
(m, 1H), 3.45–3.74 (m, 6H), 3.75 (s, 3H), 3.78 (s, 3H), 4.02–4.07 (m, 1H),
4.08–4.17 (m, 1H), 4.22 (d, J=14.7 Hz, 1H; rotamer m), 4.30 (d, J=
14.7 Hz, 1H; rotamer M), 4.33–4.77 (m, 6H; two rotamers), 4.83 (s, 1H;
rotamer m), 5.02 (s, 1H; rotamer M), 5.20 (d, J=14.7 Hz, 1H; rotamer
M), 5.31 (d, J=14.7 Hz, 1H; rotamer m), 6.79 (d, J=8.7 Hz, 2H), 6.85
(d, J=8.4 Hz, 2H), 7.13–7.36 ppm (m, 14H); 13C NMR (100 MHz,
CDCl3, two rotamers): d=7.8, 8.8, 24.5, 24.7, 25.6, 26.5, 44.8, 50.5, 52.0,
55.1, 55.2, 63.5, 66.8, 67.8, 71.8, 72.9, 73.1, 73.5, 74.4, 79.0, 81.5, 95.3,
113.7, 113.8, 127.7, 127.8, 128.1, 128.3, 128.4, 129.1, 129.6, 130.0, 130.7,
137.8, 137.9, 158.6, 159.3, 164.8, 174.0 ppm; IR (KBr): n˜ =2934, 1634,
1591, 1513, 1245, 1034 cmꢁ1; MS (ESI): m/z (%): 793 (100) [M+H]+;
HRMS (ESI): m/z: calcd for C48H61N2O8 +H+: 793.4428; found:
793.4419.
analysis); [a]2D0 =+26.5 (c=1.5 in CHCl3); 1H NMR (400 MHz, CDCl3):
d=0.79–0.89 (m, 9H), 1.12–2.11 (m, 16H), 3.17 (s, 3H), 3.20–3.33 (m,
2H), 3.62–3.68 (m, 1H), 3.78 (s, 3H), 3.85–3.92 (m, 1H), 4.10 (s, 1H),
4.33 (d, J=14.8 Hz, 1H), 4.96 (s, 1H), 4.98 (d, J=14.8 Hz, 1H), 6.81–6.83
(m, 2H), 7.21–7.23 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=7.8,
8.5, 14.0, 22.5, 24.7, 25.0, 25.8, 25.9, 26.4, 29.7, 31.9, 44.7, 50.0, 52.3, 55.2,
65.9, 66.0, 73.9, 81.5, 94.2, 113.9, 129.7, 130.8, 158.7, 164.7, 174.1 ppm; IR
(KBr): n˜ =3334, 2934, 1638, 1591, 1513, 1385, 1248 cmꢁ1; MS (ESI): m/z
(%): 495 (100) [M+Na]+, 473 (60) [M+H]+; elemental analysis calcd
(%) for C28H44N2O4: C 71.15, H 9.38, N 5.93; found: C 70.93, H 9.78, N
5.72.
(5R)-4-[(S)-2-(1-Methoxy-1-ethylpropyl)pyrrolidin-1-yl]-5-[(S)-1-hy-
ACHUTNGRENUdNG roxyCAHUTNGTRENhNNGU eptyl]-1-(4-methoxybenzyl)-2,5-dihydro-1H-2-azol-one (13d): By
following the typical procedure, the reaction of tetramic acid derivative 8
(159 mg, 0.43 mmol) with n-heptanal (172 mL, 1.28 mmol) gave com-
pound 13d (160 mg, yield: 77%) as a colorless oil. de=97% (determined
1
by HPLC analysis); [a]2D0 =+23.7 (c=1.4 in CHCl3); H NMR (400 MHz,
CDCl3): d=0.79–0.89 (m, 9H), 1.10–2.11 (m, 18H), 3.17 (s, 1H), 3.20–
3.33 (m, 2H), 3.62–3.70 (m, 1H), 3.77 (s, 3H), 3.85–3.92 (m, 1H), 4.10 (s,
1H), 4.34 (d, J=14.8 Hz, 1H), 4.96 (s, 1H), 4.98 (d, J=14.8 Hz, 1H),
6.81–6.83 (m, 2H), 7.22 ppm (d, J=8.5 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d=7.8, 8.5, 14.0, 22.6, 24.7, 25.0, 25.8, 26.2, 26.4, 29.4, 29.8, 31.7,
44.7, 50.0, 52.4, 55.2, 66.0, 73.9, 81.5, 94.2, 113.9, 129.7, 130.8, 158.7, 164.7,
174 ppm; IR (KBr): n˜ =3361, 2930, 1634, 1587, 1513, 1389, 1245 cmꢁ1; MS
(ESI): m/z (%): 509 (80) [M+Na]+, 487 (100) [M+H]+; elemental analy-
sis calcd (%) for C29H46N2O4: C 71.57, H 9.53, N 5.76; found: C 71.94, H
9.91, N 5.58.
(5R)-4-[(S)-2-(1-Methoxy-1-ethylpropyl)pyrrolidin-1-yl]-5-[(S)-cyclo-
ACHUTNGRENUNhG exylACHTUGNTREN(NUGN hydroxyl)methyl]-1-(4-methoxybenzyl)-2,5-dihydro-1H-2-azolone
(13e): By following the typical procedure, the reaction of tetramic acid
derivative 8 (142 mg, 0.38 mmol) with cyclohexanecarbaldehyde (138 mL,
1.15 mmol) gave compound 13e (143 mg, yield: 78%) as a colorless oil.
de=95% (determined by HPLC analysis); [a]2D0 =+59.4 (c=3.2 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=0.79–0.89 (m, 6H,), 1.05–1.95
(m, 19H), 2.49 (s, 1H), 3.10–3.15 (m, 1H), 3.17 (s, 1H), 3.20–3.30 (m,
1H), 3.65–3.72 (m, 2H), 3.77 (s, 3H), 4.08 (s, 1H), 4.15 (d, J=14.9 Hz,
1H), 5.01 (s, 1H), 5.10 (d, J=14.9 Hz, 1H), 6.81–6.83 (m, 2H), 7.17–
7.19 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=7.8, 8.6, 24.7, 25.1,
25.9, 26.2, 26.3, 26.5, 27.6, 31.4, 38.9, 44.6, 50.1, 53.1, 55.2, 64.3, 66.1, 81.6,
95.5, 113.8, 129.6, 130.5, 158.9, 166.0, 174.0 ppm; IR (KBr): n˜ =3342,
(5R)-4-[(S)-2-(1-Methoxy-1-ethylpropyl)pyrrolidin-1-yl]-5-[(S)-1-hy-
droxy-2-methypropyl]-1-(4-methoxybenzyl)-2,5-dihydro-1H-2-azolone
(13a): By following the typical procedure, the reaction of tetramic acid
derivative 8 (100 mg, 0.27 mmol) with iPrCHO (73 mL, 0.81 mmol) gave
13a (101 mg, 84%) as a colorless oil. de=97% (determined by HPLC
analysis); [a]2D0 =+50.2 (c=3.0 in CHCl3); 1H NMR (400 MHz, CDCl3):
d=0.70–1.01 (m, 12H), 1.33–1.97 (m, 9H), 2.50–2.80 (m, 1H), 3.17 (s,
3H), 3.22–3.33 (m, 1H), 3.64–3.73 (m, 2H), 3.78 (s, 3H), 4.05–4.10 (m,
1H), 4.10–4.19 (d, J=14.9 Hz, 1H), 5.02 (s, 1H), 5.14 (d, J=14.9 Hz,
1H), 6.79–6.81 (m, 2H), 7.17–7.19 ppm (m, 2H); 13C NMR (100 MHz,
CDCl3): d=7.9, 8.6, 17.7, 21.0, 24.8, 25.1, 26.0, 26.3, 29.3, 29.7, 44.7, 50.1,
53.1, 55.2, 64.6, 66.2, 76.7, 81.6, 95.3, 113.9, 129.6, 130.5, 158.7, 166.1,
2930, 1638, 1587, 1245, 1034 cmꢁ1
; MS (ESI): m/z (%): 507 (100)
[M+Na]+, 485 (50) [M+H]+; elemental analysis calcd (%) for
C29H44N2O4: C 71.87, H 9.15, N 5.78; found: C 71.34, H 9.13, N 5.41.
174.1 ppm; IR (KBr): n˜ =3323, 2965, 1638, 1587, 1513, 1245, 1034 cmꢁ1
;
(5R)-4-[(S)-2-(1-Methoxy-1-ethylpropyl)pyrrolidin-1-yl]-5-[(S)-1-hy-
droxy-3-tert-butyldimethylsilanoxypropyl]-1-(4-methoxy-benzyl)-2,5-dihy-
dro-1H-2-azolone (13 f): By following the typical procedure, the reaction
of tetramic acid derivative 8 (156 mg, 0.42 mmol) with 3-(tert-butyldime-
thylsilyloxy)propanal (237 mg, 1.26 mmol) gave compound 13 f (162 mg,
69%) as a colorless wax solild. de=>99% (determined by HPLC analy-
sis); [a]2D0 =+35.9 (c=2.9 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
0.08 (s, 3H), 0.09 (s, 3H), 0.77–0.85 (m, 6H), 0.90 (s, 9H), 1.33–1.98 (m,
10H), 3.14 (s, 1H), 3.20–3.35 (m, 2H), 3.62–3.74 (m, 2H), 3.78 (s, 3H),
3.88–3.96 (m, 1H), 3.98 (s, 1H), 4.09 (s, 1H), 4.19 (d, J=9.8 Hz, 1H),
4.30 (d, J=14.5 Hz, 1H), 4.97 (s, 1H), 5.14 (d, J=14.5 Hz, 1H), 6.81–6.83
(m, 2H), 7.24–7.26 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=ꢁ6.0,
ꢁ5.9, 7.5, 8.1, 17.7, 24.5, 24.7, 25.5, 25.6, 26.0, 30.5, 44.0, 49.4, 51.8, 54.8,
62.9, 64.0, 65.7, 74.4, 81.0, 93.8, 113.4, 129.6, 130.5, 158.2, 164.0,
MS (ESI): m/z (%): 467 (100) [M+Na+], 445 (70) [M+H]+; elemental
analysis calcd (%) for C26H40N2O4: C 70.24, H 9.07, N 6.30; found: C
69.96, H 9.41, N 6.07.
(5R)-4-[(S)-2-(1-Methoxy-1-ethylpropyl)pyrrolidin-1-yl]-5-[(S)-1-hy-
droxy-1-propyl]-1-(4-methoxybenzyl)-2,5-dihydro-1H-2-azolone
(13b):
By following the typical procedure, the reaction of tetramic acid deriva-
tive 8 (91 mg, 0.24 mmol) with n-butanal (66 mL, 0.73 mmol) gave com-
pound 13b (91 mg, 85%) as a colorless oil. de=99% (determined by
HPLC analysis); [a]2D0 =+18.6 (c=1.2 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=0.78–0.92 (m, 9H), 1.12–2.08 (m, 12H), 3.15 (s, 3H), 3.19–
3.33 (m, 2H), 3.64–3.73 (m, 1H), 3.78 (s, 3H), 3.85–3.94 (m, 1H), 4.10 (s,
1H), 4.33 (d, J=14.8 Hz, 1H), 4.99 (s, 1H), 5.01 (d, J=14.8 Hz, 1H),
6.79–6.81 (m, 2H), 7.17–7.19 ppm (m, 2H); 13C NMR (100 MHz, CDCl3):
d=7.8, 8.5, 14.1, 19.4, 24.8, 25.0, 25.8, 26.4, 31.9, 44.7, 50.0, 52.3, 55.2,
65.9, 66.0, 73.6, 81.5, 94.3, 113.9, 129.7, 130.8, 158.7, 164.7, 174.2 ppm; IR
(KBr): n˜ =3350, 2934, 1634, 1591, 1509, 1377, 1241 cmꢁ1; MS (ESI): m/z
(%): 467 (50) [M+Na+], 445 (100) [M+H]+; elemental analysis calcd
(%) for C26H40N2O4: C 70.24, H 9.07, N 6.30; found: C 69.97, H 9.45, N
6.00.
173.5 ppm; IR (KBr): n˜ =3346, 2930, 1638, 1587, 1513, 1245, 1093 cmꢁ1
;
MS (ESI): m/z (%) 583 (83) [M+Na]+, 561 (100) [M+H]+; elemental
analysis calcd (%) for C31H52N2O5Si: C 66.39, H 9.35, N 4.99; found: C
69.79, H 9.75, N 5.05.
(R)-1-(4-Methoxybenzyl)-5-[(1S,3S)-4-(4-methoxybenzyloxy)-3-(benzyl-
AHCTUNGTERGoNNUN xy)-1-hydroxybutyl]-4-[(S)-2-(3-methoxypentan-3-yl)-pyrrolidin-1-yl]-
(5R)-4-[(S)-2-(1-Methoxy-1-ethylpropyl)pyrrolidin-1-yl]-5-[(S)-1-hy-
ACHTUNGTRENNUNGdroxyACHTUNGTRENNUNGhexyl]-1-(4-methoxybenzyl)-2,5-dihydro-1H-2-azolone (13c): By
following the typical procedure, the reaction of tetramic acid derivative 8
(117 mg, 0.31 mmol) with n-hexanal (114 mL, 0.94 mmol) gave compound
13c (113 mg, 77%) as a colorless oil. de=97% (determined by HPLC
1H-pyrrol-2(5H)one (13g): By following the typical procedure, the reac-
tion of tetramic acid derivative 8 (379 mg, 1.02 mmol) with aldehyde 33
(383 mg, 1.22 mmol) gave compound 13g (454 mg, 65%) as a colorless
oil. de=>99% (determined by HPLC analysis); [a]2D0 =+17.6 (c=1.0 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=0.68–0.83 (m, 6H), 1.20–1.99
Chem. Eur. J. 2010, 16, 5755 – 5768
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5761

P.-Q. Huang et al.
(m, 10H), 2.98 (s, 3H), 3.14–3.31 (m, 2H), 3.47 (dd, J=10.0, 4.4 Hz, 1H),
3.52 (dd, J=10.0, 5.6 Hz, 1H), 3.57 (dd, J=7.9, 5.0 Hz, 1H), 3.72 (s, 3H),
3.78 (s, 3H), 3.80–3.90 (m, 1H), 4.12–4.16 (m, 1H), 4.22–4.29 (m, 1H),
4.30 (d, J=14.7 Hz, 1H), 4.45 (s, 1H), 4.50 (d, J=11.5 Hz, 1H), 4.61 (d,
J=11.4 Hz, 1H), 4.89 (s, 1H), 5.06 (d, J=14.6 Hz, 1H), 6.74–6.80 (m,
2H), 6.84–6.89 (m, 2H), 7.10–7.45 ppm (m, 9H); 13C NMR (CDCl3,
100 MHz): d=7.7, 8.6, 24.2, 24.8, 25.6, 26.5, 32.0, 44.4, 50.3, 52.0, 55.1,
55.2, 65.1, 66.3, 69.7, 72.2, 72.6, 73.0, 75.4, 81.4, 93.6, 113.7, 113.8, 127.7,
127.8, 128.3, 128.4, 129.2, 129.4, 129.5, 129.7, 129.9, 130.7, 138.4, 158.5,
159.2, 164.6, 174.0 ppm; IR (KBr): n˜ =3432, 2949, 1634, 1590, 1501, 1248,
1100 cmꢁ1; MS (ESI): m/z (%): 709 (100) [M+Na]+; elemental analysis
calcd (%) for C41H54N2O7: C 71.69, H 7.92, N 4.08, O 16.31; found: C
71.57, H 7.62, N 4.17.
127.8, 127.9 128.1, 128.2, 128.3, 128.4, 128.5, 128.6, 128.9, 129.1, 129.3,
129.5, 129.9, 137.7, 137.8, 138.1, 18.2, 158.8, 159.2, 173.8 ppm; IR (KBr):
n˜ =2922, 1688, 1610, 1509, 1451, 1245, 1093 cmꢁ1; MS (ESI): m/z (%): 844
(100) [M+Na]+; elemental analysis calcd (%) for C52H55NO8: C 76.07, H
6.74, N 1.83; found: C 76.07, H 7.14, N 1.82.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
was added to a methanolic solution (2 mL) of compound 19 (346 mg,
0.42 mmol) at 708C. After the mixture had been stirred at 708C for 96 h,
the reaction was quenched with saturated Na2S2O3 solution. The metha-
nol was removed under reduced pressure and the aqueous phase was ex-
tracted with Et2O (3ꢂ5 mL). The combined organic layers were separat-
ed, washed with brine, dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel eluting with EtOAc/PE 1:2 to give
compound 20 (225 mg, 76%) as a colorless oil. [a]2D0 =ꢁ13.5 (c=1.7 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=2.52 (d, J=17.2 Hz, 1H), 2.84
(dd, J=17.2, 5.2 Hz, 1H), 3.38 (dd, J=8.8, 4.3 Hz, 1H), 3.55–3.61 (m,
2H), 3.64–3.72 (m, 3H), 3.75 (s, 3H), 4.05 (d, J=8.5 Hz, 1H), 4.22 (d, J=
6.5 Hz, 1H), 4.27 (d, J=12.0 Hz, 1H), 4.33 (d, J=11.0 Hz, 1H), 4.36 (d,
J=12.0 Hz, 1H), 4.43 (d, J=13.0 Hz, 2H), 4.48 (d, J=12.5 Hz, 2H), 4.67
(d, J=11.0 Hz, 1H), 4.72 (d, J=16.5 Hz, 1H), 4.74 (d, J=11.0 Hz, 1H),
6.77 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 7.10–7.38 ppm (m,
20H); 13C NMR (125 MHz, CDCl3): d=38.2, 43.1, 55.2, 60.8, 65.7, 69.9,
71.9, 72.4, 74.9, 75.0, 76.0, 78.0, 79.7, 114.0, 127.6, 127.7, 127.8, 127.9,
128.0, 128.1, 128.3, 128.4, 128.5, 128.6, 128.9, 137.5, 137.6, 137.7, 158.9;
(S)-1-(4-Methyoxybenzyl)-5-[(1R,2S,3S)-4-(4-methyoxybenzyl-oxy)-2,3-
bis(benzyloxy)-1-hydroxybutyl]pyrrolidine-2,4-dione (17): A solution of
10% HCl (20 mL) was added to a THF (50 mL) solution of compound
16 (650 mg, 0.82 mmol). After the mixture had been stirred at 308C for
48 h, the mixture was extracted with ethyl acetate (3ꢂ15 mL) and the
combined extracts were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure to give the
crude tetramic acid derivative 17 as a colorless oil, which was used in the
next step without further purification.
ACHTUNGTRENNUNG
NaBH4 (80 mg, 2.1 mmol) was added portionwise to a solution of the
crude tetramic acid derivative 17 (446 mg, 0.70 mmol) in a mixed solvent
system CH2Cl2 (10 mL)/AcOH (1 mL) at ꢁ258C. The mixture was stirred
at ꢁ108C for 9 h and quenched with a cooled saturated solution of
NaHCO3 (5 mL). The resulting mixture was extracted with CH2Cl2 (3ꢂ
10 mL). The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica gel
eluting with EtOAc/PE 1:1 to give 18 as a colorless solid and (375 mg,
84%) as a single diastereomer. M.p. 252–2548C (EtOAc/PE); [a]2D0 =+
173.7 ppm; IR (KBr): n˜ =3408, 2930, 1669, 1513, 1459, 1248, 1093 cmꢁ1
;
MS (ESI): m/z (%): 724 (35) [M+Na]+, 702 (100) [M+H]+; HRMS
(ESI): m/z: calcd for C44H47NO7 +H+: 702.3431; found: 702.3417.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
dine (0.15 mL, 1.6 mmol), a solution of pTsCl (91 mg, 0.48 mmol) in an-
hydrous CH2Cl2 (0.5 mL), and DMAP (cat.) were added successively to a
solution of compound 20 (225 mg, 0.32 mmol) in anhydrous CH2Cl2
(1 mL) at ꢁ88C. After the mixture had been stirred at ꢁ88C for 30 h, the
mixture was diluted with CH2Cl2 (4 mL) and water, and the aqueous
phase was extracted with CH2Cl2 (3ꢂ3 mL). The combined organic
phases were washed successively with 1m HCl and brine (1 mL), dried
over anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash column chromatographic purifica-
tion on silica gel eluting with EtOAc/PE 1:2 to give compound 21
1
1.2 (c=0.9 in CHCl3); H NMR (400 MHz, CDCl3): d=1.88 (s, 1H), 2.26
(dd, J=17.4, 2.0 Hz, 1H), 2.73 (brs, 1H), 2.78 (dd, J=17.4, 6.5 Hz, 1H),
3.25–3.32 (m, 1H), 3.45 (s, 1H), 3.52 (d, J=6.4, 4.6 Hz, 1H), 3.60 (d, J=
10.5, 3.4 Hz, 1H), 3.75 (s, 3H), 3.79 (s, 3H), 3.81–3.84 (m, 2H), 3.86 (d,
J=15.4 Hz, 1H), 4.30 (d, J=11.6 Hz, 1H), 4.36 (d, J=11.6 Hz, 1H),
4.38–4.42 (m, 1H), 4.43 (d, J=11.5 Hz, 2H), 4.61 (d, J=11.5 Hz, 1H),
4.64 (d, J=11.5 Hz, 1H), 4.92 (d, J=15.4 Hz, 1H), 6.81 (m, 2H), 6.87 (m,
2H), 7.10 (m, 2H), 7.18–7.38 ppm (m, 12H); 13C NMR (100 MHz,
CDCl3): d=40.4, 43.3, 55.3, 65.3, 67.8, 68.4, 68.5, 73.2, 73.8, 80.8, 113.9,
114.1, 128.1, 128.3, 128.7, 129.1, 129.4, 129.7, 137.4, 159.0, 159.4,
1
(263 mg, 96%) as a colorless oil. [a]2D0 =ꢁ8.3 (c=1.1 in CHCl3); H NMR
(400 MHz, CDCl3): d=2.41 (s, 3H), 2.50 (d, J=17.3 Hz, 1H), 2.80 (dd,
J=17.3, 6.4 Hz, 1H), 3.49 (dd, J=7.6, 4.0 Hz, 1H), 3.58 (s, 1H), 3.65 (d,
J=15.2 Hz, 1H), 3.67–3.73 (m, 1H), 3.75 (s, 3H), 3.98 (d, J=6.8 Hz,
1H), 4.05 (dd, J=10.4, 6.4 Hz, 1H), 4.15 (dd, J=10.4, 4.4 Hz, 1H), 4.23–
4.31 (m, 4H), 4.34 (d, J=11.2 Hz, 1H), 4.43 (d, J=11.6, 1H), 4.45 (d, J=
11.6 Hz, 1H), 4.58 (d, J=10.8 Hz, 1H), 4.62 (d, J=11.2 Hz, 1H), 4.72 (d,
J=15.2 Hz, 1H), 6.63 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 7.05–
7.36 (m, 22H), 7.60 ppm (d, J=8.4 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d=21.6, 38.1, 43.4, 55.2, 66.0, 69.3, 70.2, 72.6, 72.9, 74.7, 74.8,
75.6, 765, 78.8, 114.1, 127.6, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.4,
128.5, 128.6, 129.0, 129.9, 132.5, 137.4, 137.5, 137.6, 144.9, 158.9,
173.9 ppm; IR (KBr): n˜ =3378, 2961, 1699, 1510, 1386, 1245, 1036 cmꢁ1
;
MS (ESI): m/z (%): 642 (100) [M+H]+; HRMS (ESI): m/z: calcd for
C38H44NO8 +H+: 642.3067; found: 642.3054.
ACHTUNGTRENNUNG
(60% in mineral oil, 26 mg, 0.65 mmol) was added to a solution of com-
pound 18 (375 mg, 0.59 mmol) in anhydrous THF (20 mL) at ꢁ208C.
After H2 evolution had ceased (10 min), benzyl bromide (0.7 mL,
5.9 mmol) and tetrabutylammonium iodide (22 mg, 0.06 mmol) were
added. The mixture was stirred at RT for 3 days. The reaction was
quenched with H2O (1 mL) at 08C and the mixture was extracted with
Et2O (3ꢂ5 mL). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatography on
silica gel eluting with EtOAc/PE 1:2 to give compound 19 (346 mg, 72%)
as a colorless oil. [a]2D0 =+4.5 (c=1.5 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=2.46 (d, J=17.3 Hz, 1H), 2.81 (dd, J=17.3, 6.4 Hz, 1H),
3.51–3.65 (m, 6H), 3.70 (s, 3H), 3.77 (s, 3H), 4.03 (dd, J=8.4, 1.0 Hz,
1H), 4.21 (d, J=6.2 Hz, 1H), 4.23–4.33 (m, 6H), 4.37 (d, J=12.0 Hz,
1H), 4.44 (d, J=11.5 Hz, 1H), 4.53 (d, J=12.0 Hz, 1H), 4.64 (d, J=
10.8 Hz, 1H), 4.71 (d, J=11.5 Hz, 1H), 6.67 (d, J=8.6 Hz, 2H), 6.79 (d,
J=8.6 Hz, 2H), 6.98 (d, J=8.6 Hz, 2H), 7.12–7.35 ppm (m, 22H);
13C NMR (125 MHz, CDCl3): d=38.4, 43.1, 55.1, 55.2, 65.6, 68.8, 70.1,
72.3, 72.7, 73.0, 74.9, 75.0, 76.0, 77.8, 79.5, 113.7, 113.8, 113.9, 127.4, 127.6,
173.6 ppm; IR (KBr): n˜ =2926, 1688, 1517, 1365, 1248, 1178, 1089 cmꢁ1
;
MS (ESI): m/z (%): 878 (60) [M+Na]+, 856 (100) [M+H]+; elemental
analysis calcd (%) for C51H53NO9S: C 71.56, H 6.24, N 1.64; found: C
71.51, H 6.62, N 1.70.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
was added to a solution of compound 21 (263 mg, 0.31 mmol) in CH3CN
(36 mL) and H2O (4 mL), and the mixture was stirred at RT for 3 h. The
reaction was diluted with H2O (30 mL) and extracted with EtOAc (3ꢂ
25 mL). The combined organic layers were washed successively with a sa-
turated aqueous solution of sodium bicarbonate (5 mL) and brine
(5 mL), then dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column chro-
matography on silica gel eluting with EtOAc/PE 2:1 to give compound
22 (192 mg, 85%) as a colorless oil. [a]2D0 =ꢁ25.9 (c=1.0 in CHCl3);
5762
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 5755 – 5768

A Flexible Approach to Azasugars
FULL PAPER
1
1H NMR (400 MHz, CDCl3): d=2.25 (dd, J=17.2, 2.4 Hz, 1H), 2.41 (s,
3H), 2.43 (dd, J=17.2, 6.8 Hz, 1H), 3.30–3.40 (m, 2H), 3.52 (dd, J=6.0,
2.8 Hz, 1H), 3.85 (m, 1H), 4.00 (d, J=6.8 Hz, 1H), 4.10–4.15 (m, 2H),
4.30–4.42 (m, 5H), 4.50 (d, J=11.6 Hz, 1H), 4.56 (d, J=11.2 Hz, 1H),
4.63 (d, J=11.6 Hz, 1H), 5.30 (brs, 1H), 7.11–7.36 (m, 22H), 7.70 ppm
(d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=21.7, 37.0, 64.7,
68.9, 70.6, 72.1, 74.4, 75.0, 75.3, 77.8, 127.7, 127.8, 128.0, 128.1, 128.2,
128.3, 128.4, 128.5, 128.6, 128.7, 129.9, 132.6, 137.2 137.6, 145.1,
+3.8 (c=0.5 in MeOH) (lit.[14] [a]2D5 =+3.8 (c=0.5 in MeOH)); H NMR
(400 MHz, CD3OD): d=1.55–1.65 (m, 1H), 2.10–2.26 (m, 3H), 2.61 (q,
J=9.2 Hz, 1H), 2.89 (t, J=8.8 Hz, 1H), 3.02 (dd, J=11.2, 4.8 Hz, 1H),
3.10 (t, J=8.6 Hz, 1H), 3.15–3.23 (m, 1H), 3.47 (ddd, J=10.8, 9.2, 5.2 Hz,
1H), 4.08–4.15 ppm (m, 1H); 13C NMR (100 MHz, CD3OD): d=33.9,
52.5, 56.2, 70.9, 74.3, 74.7, 74.9, 80.2 ppm; IR (KBr): n˜ =3390, 2910, 1643,
1161, 1124, 1090 cmꢁ1; MS (ESI): m/z (%): 212 (60) [M+Na]+, 190 (100)
[M+H]+; HRMS (ESI): m/z: calcd for C8H16NO4 +H+: 190.1079; found:
190.1074.
175.1 ppm; IR (KBr): n˜ =3405, 2918, 1700, 1455, 1365, 1175, 1093 cmꢁ1
;
MS (ESI): m/z (%): 758 (90) [M+Na]+, 736 (100) [M+H]+; elemental
analysis calcd (%) for C43H45NO8S: C 70.18, H 6.16, N 1.90; found: C
70.09, H, 6.56, N 1.98.
AHCTUNGTERG(NNUN 4S,5R)-1-(4-Methoxybenzyl)-5-[(1R,2S,3S)-4-(4-methoxybenzyl-oxy)-2,3-
bis(benzyloxy)-1-hydroxybutyl]-4-hydroxy-pyrrolidin-2-one (25): NaBH4
(29 mg, 0.77 mmol) was added to a methanolic solution (5 mL) of the
crude tetramic acid derivative 17 (163 mg, 0.26 mmol) at ꢁ308C. After
the mixture had been stirred for 40 min, the reaction was quenched with
a saturated aqueous solution of NaHCO3 (3 mL). The resulting mixture
was extracted with CH2Cl2 (3ꢂ10 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel eluting with EtOAc/PE 2:1 to give
two diastereoisomers 25 (102 mg, 61%; colorless oil) and 18 (14 mg, 9%;
colorless oil) in a ratio of 7:1. Compound 25: [a]2D0 =+40 (c=1.6 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=2.47 (dd, J=17.3, 3.2 Hz, 1H),
2.57 (dd, J=17.3, 7.0 Hz, 1H), 3.28 (dd, J=5.5, 2.5 Hz, 1H), 3.60 (dd, J=
10.9, 4.9 Hz, 1H), 3.65–3.85 (m, 3H), 3.73 (s, 3H), 3.80 (s, 3H), 3.84 (d,
J=15 Hz, 1H), 3.90–3.96 (m, 1H), 4.23–4.36 (m, 3H), 4.41 (d, J=
11.0 Hz, 1H), 4.43 (d, J=11.6 Hz, 1H), 4.49 (d, J=11.6, 1H), 4.53 (d, J=
11.7 Hz, 1H), 4.70 (d, J=11.7 Hz, 1H), 4.77 (d, J=11.0 Hz, 1H), 5.10 (d,
J=15.0 Hz, 1H), 6.72 (m, 2H), 6.87–6.89 (m, 2H), 7.02–7.04 (m, 2H),
7.15–7.36 ppm (m, 10H); 13C NMR (100 MHz, CDCl3): d=40.0, 43.2,
55.1, 55.2, 62.0, 67.5, 68.9, 72.7, 73.2, 74.4, 78.5, 80.1, 113.8, 114.1, 127.7,
127.8, 127.9, 128.2, 128.4 (2C), 128.7, 129.2, 129.3, 129.9, 136.8, 138.1,
159.0, 159.3, 173.3 ppm; IR (KBr): n˜ =3378, 2925, 1699, 1611, 1515, 1457,
1245, 1178, 1071 cmꢁ1; MS (ESI): m/z (%): 642 (100) [M+H]+; HRMS
(ESI): m/z: calcd for C38H43NO8 +H+: 642.3061; found: 642.3055.
(1R,6S,7R,8R,8aR)-1,6,7,8-Tetrakis(benzyloxy)hexahydro-indolizidin-
3(5H)one (23): nBuLi (0.18 mL, 0.29 mmol, 1.6m in pentane) was added
to a solution of compound 22 (192 mg, 0.26 mmol) in anhydrous THF
(5 mL) at ꢁ788C. The mixture was stirred at ꢁ788C for 30 min, slowly
warmed to RT, and then stirred overnight. The reaction was quenched
with H2O (2 mL) and extracted with Et2O (3ꢂ5 mL). The organic layer
was washed with brine, dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel eluting with EtOAc/PE 1:2 to give
compound 23 (124 mg, 84%) as a colorless solid. M.p. 96–988C (EtOAc/
PE); [a]2D0 =+41.8 (c=1.0 in CHCl3); 1H NMR (500 MHz, CDCl3): d=
2.46 (d, J=18.0 Hz, 1H), 2.54 (dd, J=18.0, 7.5 Hz, 1H), 2.62 (t, J=
11.5 Hz, 1H), 3.03 (t, J=9.5 Hz, 1H), 3.40–3.46 (m, 1H), 3.44 (d, J=
10.0 Hz, 1H), 3.66 (t, J=8.7 Hz, 1H), 3.77 (d, J=7.5 Hz, 1H), 4.39 (d,
J=12.0 Hz, 1H), 4.45 (dd, J=13.0, 5.5 Hz, 1H), 4.51 (d, J=12.0 Hz, 1H),
4.61 (d, J=11.5 Hz, 1H), 4.66 (d, J=11.5 Hz, 1H), 4.72 (d, J=11.5 Hz,
1H), 4.83 (d, J=11.0 Hz, 1H), 4.94 (d, J=11.5 Hz, 1H), 5.02 (d, J=
11.0 Hz, 1H), 7.20–7.38 ppm (m, 20H); 13C NMR (125 MHz, CDCl3): d=
37.4, 41.0, 66.0, 70.7, 72.8, 73.0, 75.2, 75.9, 77.8, 78.8, 86.5, 127.5, 127.7,
127.8, 127.9, 128.0, 128.2, 128.4, 128.5, 137.5, 137.6, 137.7, 138.3,
171.3 ppm; IR (KBr): n˜ =2923, 1698, 1454, 1092, 1069 cmꢁ1; MS (ESI):
m/z (%): 586 (100) [M+Na]+, 564 (60) [M+H]+; HRMS: m/z: calcd for
C36H38NO5 +H+: 564.2750; found: 564.2737.
AHCTUNGTERG(NNUN 4S,5S)-1-(4-Methoxybenzyl)-5-[(1R,2S,3S)-4-(4-methoxybenzyl-oxy)-2,3-
(1R,6S,7R,8R,8aR)-1,6,7,8-Tetrakis(benzyloxy)octahydroindolizidine
(24): BH3·Me2S (40 mL, 0.68 mmol) was added to a cooled (08C) solution
of compound 23 (22 mg, 0.04 mmol) in dry THF (3 mL). The mixture was
stirred at RT for 15 h and then quenched with water (2 mL) at 08C. The
resulting mixture was stirred at 608C for 3 h and then extracted with
CH2Cl2 (3ꢂ4 mL). The combined organic layers were dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel eluting
with EtOAc/PE 1:5 to give compound 24 (20 mg, 92%) as a colorless
solid. M.p. 103–1058C (EtOAc/PE); [a]2D0 =+6.4 (c=1.6 in CHCl3);
1H NMR (400 MHz, CDCl3): d=1.77–1.85 (m, 1H), 2.00–2.12 (m, 1H),
2.20 (t, J=10.4 Hz, 1H), 2.30 (dd, J=9.6, 5.2 Hz, 1H), 2.51 (dd, J=17.6,
8.8 Hz, 1H), 2.86 (t, J=8.0 Hz, 1H), 3.20 (dd, J=10.8, 5.4 Hz, 1H), 3.40
(t, J=9.2 Hz, 1H), 3.55 (t, J=4.8 Hz, 1H), 3.62–3.71 (m, 1H), 3.86–3.94
(m, 1H), 4.42 (s, 2H), 4.63 (d, J=11.6 Hz, 1H), 4.67 (d, J=11.6 Hz, 1H),
4.70 (d, J=11.2 Hz, 1H), 4.82 (d, J=10.8 Hz, 1H), 4.86 (d, J=11.2 Hz,
1H), 4.92 (d, J=10.8 Hz, 1H), 6.80 (d, J=8.4 Hz, 2H), 7.20–7.33 ppm
(m, 20H); 13C NMR (100 MHz, CDCl3): d=31.4, 51.6, 53.8, 71.4, 72.1,
72.9, 74.4, 75.7, 79.3, 81.7, 82.1, 87.6, 127.3, 127.4, 127.5, 127.6, 127.7,
127.8, 127.9, 128.0, 128.2, 128.3, 128.4, 138.4, 138.5, 138.8, 138.9 ppm; IR
(KBr): n˜ =2926, 2854, 2799, 1613, 1352, 1097 cmꢁ1; MS (ESI): m/z (%):
550 (100) [M+H]+; HRMS: m/z: calcd for C36H40NO4 +H+: 550.2957;
found: 550.2946.
bis(benzyloxy)-1-hydroxybutyl]-4-(benzyloxy)-pyrrolidin-2-one (26): NaH
(60% in mineral oil, 16 mg, 0.39 mmol) was added in one portion to a so-
lution of compound 25 (115 mg, 0.18 mmol) in anhydrous THF (10 mL)
at ꢁ208C. After H2 evolution had ceased (10 min), benzyl bromide
(0.11 mL, 0.9 mmol) and a catalytic amount of tetrabutylammonium
iodide were added. The mixture was warmed to RT and stirred for
3 days. The reaction was quenched with H2O (2 mL) at 08C and the re-
sulting mixture was extracted with Et2O (3ꢂ5 mL). The combined organ-
ic layers were washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel eluting with EtOAc/PE 1:2 to
give compound 26 (112 mg, yield: 85%) as a colorless oil. [a]2D0 =+40
(c=1.6 in CHCl3); 1H NMR (400 MHz, CDCl3): d=2.37 (dd, J=17.0,
6.0 Hz, 1H), 2.58 (dd, J=17.0, 1.8 Hz, 1H), 3.34 (dd, J=10.3, 6.2 Hz,
1H), 3.56 (dd, J=5.3, 3.0 Hz, 1H), 3.61 (dd, J=10.3, 3.2 Hz, 1H), 3.64–
3.76 (m, 3H), 3.71 (s, 3H), 3.79 (s, 3H), 3.91 (d, J=15.0 Hz, 1H), 4.08 (d,
J=11.0 Hz, 1H), 4.14–4.22 (m, 2H), 4.26 (d, J=11.5 Hz, 1H), 4.32 (d,
J=11.5 Hz, 1H), 4.36 (d, J=11.0 Hz, 1H), 4.37 (d, J=12.0 Hz, 1H), 4.53
(d, J=12.0 Hz, 1H), 4.56 (d, J=11.4 Hz, 1H), 4.60 (d, J=11.4 Hz, 1H),
5.20 (d, J=15.0 Hz, 1H), 6.71–6.77 (m, 2H), 6.82–6.87 (m, 2H), 7.36–
7.04 ppm (m, 19H); 13C NMR (100 MHz, CDCl3): d=37.2, 43.2, 55.1,
55.2, 60.6, 69.5, 70.1, 71.3, 72.2, 72.9, 74.2, 75.8, 77.9, 79.9, 113.7, 114.0,
127.7 (2C), 128.1, 128.2 (2C), 128.3, 128.5, 128.6, 129.2, 129.4, 130.2,
136.5, 138.0, 138.2, 158.9, 159.1, 172.8 ppm; IR (KBr): n˜ =3508, 2925,
2861, 1700, 1614, 1511, 1249, 1081, 1037 cmꢁ1; MS (ESI): m/z (%): 732
(100) [M+H]+; HRMS (ESI): m/z: calcd for C45H49NO8 +H+: 732.3536;
found: 732.3541.
(1R,6S,7R,8R,8aR)-Octahydroindolizine-1,6,7,8-tetraol
(1-epi-castano-
spermine) (3): HCOOH (0.25 mL) was added to a mixture of compound
24 (15 mg, 0.02 mmol), 10% Pd/C (80 mg), and MeOH (2 mL) under an
argon atmosphere. The suspension was stirred for 2 h and then filtered
through a pad of Celite. The filter cake was washed several times with
MeOH and then concentrated under reduced pressure. The residual
syrup was dissolved in ethanol and stirred with Dowex 1ꢂ8–100 ion-ex-
change resin (80 mg) for 6 h. The mixture was filtered through Celite and
the resulting filtrate was concentrated under reduced pressure to give 1-
AHCTUNGTERG(NNUN 4S,5R)-5-[(1R,2S,3S)-2,3-Bis(benzyloxy)-1,4-dihydroxybutyl]-1-(4-me-
thoxybenzyl)-4-hydroxypyrrolidin-2-one (27): Iodine (100 mg, 0.39 mmol)
was added to a methanolic solution (5 mL) of compound 25 (263 mg,
0.14 mmol). After the mixture had been stirred at 708C for 96 h, the re-
action was quenched with saturated Na2S2O3 solution. The methanol was
removed under reduced pressure and the aqueous phase was extracted
epi-castanospermine (3) (5.2 mg, quantitative) as a colorless oil. [a]D20
=
Chem. Eur. J. 2010, 16, 5755 – 5768
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5763

P.-Q. Huang et al.
with EtOAc (3ꢂ10 mL). The organic layer was dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel eluting with
EtOAc/PE 5:1 to afford compound 27 (165 mg, 77%) as a colorless oil.
[a]2D0 =ꢁ85.4 (c=1.2 in CHCl3); 1H NMR (400 MHz, CDCl3): d=2.46
(dd, J=17.3, 2.5 Hz, 1H), 2.57 (dd, J=17.3, 6.8 Hz, 1H), 3.04–3.14 (m,
1H), 3.25 (dd, J=5.3, 2.7 Hz, 1H), 3.61 (dd, J=5.4, 2.6 Hz, 1H), 3.74 (s,
3H), 3.76–3.83 (m, 2H), 3.88–3.83 (m, 1H), 3.87 (d, J=15.0 Hz, 1H),
4.17 (d, J=8.2 Hz, 1H), 4.28 (d, J=3.4 Hz, 1H), 4.29–4.36 (m, 1H), 4.38–
4.44 (m, 1H), 4.43 (d, J=11.1 Hz, 1H), 4.51 (d, J=11.6 Hz, 1H), 4.70 (d,
J=11.6 Hz, 1H), 4.74 (d, J=11.0 Hz, 1H), 5.15 (d, J=15.0 Hz, 1H),
6.71–6.78 (m, 2H), 7.06–7.11 (m, 2H), 7.17–7.39 ppm (m, 10H);
13C NMR (100 MHz, CDCl3): d=33.9, 43.2, 55.2, 59.6, 62.4, 67.5, 67.9,
72.1, 73.9, 77.6. 79.6, 114.1, 127.8, 128.0 (2C), 128.3, 128.5, 128.6, 128.8,
129.4, 136.4, 137.8, 159.0, 173.4 ppm; IR (KBr): n˜ =3430, 2931, 2871,
1673, 1512, 1453, 1246, 1074, 1028 cmꢁ1; MS (ESI): m/z (%): 522 (100)
[M+H]+; HRMS (ESI): m/z: calcd for C30H35NO7 +H+: 522.2486; found:
522.2480.
pound 29 (80 mg, 0.15 mmol) in dry THF (4 mL) at 08C. The reaction
was heated at reflux for 10 h and quenched carefully with MeOH (2 mL)
at 08C. The mixture was concentrated under reduced pressure. The resi-
due was dissolved in MeOH (3 mL) and then 6n HCl (0.5 mL) was
added. The resulting mixture was stirred at RT for 30 min and then con-
centrated. The residue was dissolved in H2O, passed through a column of
ion-exchange resin (Dowex 1ꢂ8–100, OHꢁ form) eluting with water
(20 mL). The eluent was concentrated under reduced pressure and puri-
fied by flash column chromatography on silica gel eluting with CH2Cl2/
MeOH 10:1 to afford compound 33 (37 mg, 63%) as a colorless oil.
[a]2D0 =+26.5 (c=1.0 in CHCl3); 1H NMR (400 MHz, CD3OD): d=1.73–
1.82 (m, 1H), 1.84–1.94 (m, 1H), 2.73 (ddd, J=10.8, 9.5, 4.0 Hz, 1H),
2.97 (dd, J=8.5, 3.5 Hz, 1H), 3.06 (td, Jt =8.1, Jd =10.8 Hz, 1H), 3.74
(dd, J=6.1, 2.2 Hz, 1H), 3.78 (dt, Jd =2.4, Jt =5.8 Hz, 1H), 3.81–3.90 (m,
2H), 3.96 (dd, J=8.5, 2.1 Hz, 1H), 4.33–4.37 (m, 1H), 4.63 (d, J=
11.5 Hz, 1H), 4.68 (d, J=11.5 Hz, 1H), 4.75 (d, J=11.2 Hz, 1H), 4.78 (d,
J=11.2 Hz, 1H), 7.24–7.43 ppm (m, 10H); 13C NMR (100 MHz,
CD3OD): d=35.5, 45.1, 61.7, 65.6, 70.2, 73.0, 73.7, 75.1, 80.0, 81.4, 128.7,
128.9, 129.3, 129.4, 129.5, 129.6, 140.0, 140.1 ppm; IR (KBr): n˜ =3400,
ACHTUNGTRENNUNG(4S,5R)-5-[(1R,2S,3S)-2,3-Bis(benzyloxy)-1,4-diacetoxybutyl]-1-(4-me-
2930, 1635, 1450, 1395, 1060 cmꢁ1
; MS (ESI): m/z (%): 388 (100)
thoxybenzyl)-4-acetoxypyrrolidin-2-one (28): Ac2O (0.12 mL, 1.3 mmol),
Et3N (0.18 mL, 1.3 mmol), and a catalytic amount of DMAP were succes-
sively added to an ice-bath-cooled solution of compound 27 (137 mg,
0.26 mmol) in CH2Cl2 (10 mL). The mixture was stirred at RT overnight
and then quenched with a saturated aqueous solution of NaHCO3 (5 mL)
at 08C. The organic layer was separated and the aqueous layer was ex-
tracted with CH2Cl2 (3ꢂ8 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash column chromatography on silica
gel eluting with EtOAc/PE 1:1 to afford compound 28 (148 mg, 87%) as
a colorless oil. [a]2D0 =ꢁ21.7 (c=2.0 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=1.97 (s, 3H), 2.01 (s, 3H), 2.04 (s, 3H), 2.50 (dd, J=16.7,
8.1 Hz, 1H), 2.80 (dd, J=16.7, 8.5 Hz, 1H), 3.69 (td, Jt =4.1, Jd =7.1 Hz,
1H), 3.74 (s, 3H), 3.79 (d, J=15.2 Hz, 1H), 3.88 (dd, J=7.7, 2.0 Hz, 1H),
3.93 (dd, J=11.7, 7.0 Hz, 1H), 4.06 (dd, J=7.7, 3.7 Hz, 1H), 4.30 (dd, J=
11.7, 4.3 Hz, 1H), 4.38 (d, J=12.0 Hz, 1H), 4.51 (d, J=12.0 Hz, 1H),
4.56 (s, 2H), 5.10 (d, J=15.2 Hz, 1H), 5.31 (q, J=8.2 Hz, 1H), 5.71 (dd,
J=7.7, 2.0 Hz, 1H), 6.72–6.78 (m, 2H), 7.01–7.06 (m, 2H), 7.11–7.19 (m,
2H), 7.27–7.38 ppm (m, 8H); 13C NMR (100 MHz, CDCl3): d=20.8, 20.9,
21.1, 37.4, 43.2, 55.2, 57.9, 63.3, 67.8, 70.8, 72.0, 74.0, 75.6, 114.2, 127.5,
127.8, 127.9, 128.0, 128.4, 128.5, 129.2, 137.3, 137.4, 159.1, 169.6, 169.8,
170.3, 170.9 ppm; IR (KBr): n˜ =2936, 1743, 1698, 1513, 1370, 1229, 1075,
1038 cmꢁ1; MS (ESI): m/z (%): 648 (100) [M+H]+; HRMS (ESI): m/z:
calcd for C36H41NO10 +H+: 648.2803; found: 648.2800.
[M+H]+; HRMS: m/z: calcd for C22H29NO5 +H+: 388.2124; found:
388.2127.
(1S,6S,7S,8R,8aR)-6,7-Bis(benzyloxy)octahydroindolizine-1,8-diol (31):
Triphenylphosphine (68 mg, 0.26 mmol), dry carbon tetrachloride (25 mL,
0.26 mmol), and freshly distilled triethylamine (36 mL, 0.26 mmol) were
added to a solution of compound 30 (50 mg, 0.13 mmol) in dry DMF
(2 mL). The mixture was stirred in the dark at RT for 1 h and then
quenched with methanol (1 mL). After the mixture had been stirred for
30 min, the solvent was removed under reduced pressure. The residue
was purified by flash column chromatography on silica gel eluting with
CH2Cl2/MeOH 10:1 to afford compound 31 (33 mg, 70%) as a colorless
oil. [a]2D0 =+64 (c=1.1 in CHCl3); 1H NMR (400 MHz, CDCl3): d=1.77
(dddd, J=13.7, 8.6, 8.4, 1.8 Hz, 1H), 1.89 (dd, J=9.5, 4.3 Hz, 1H), 2.02
(dd, J=10.4, 10.4 Hz, 1H), 2.08 (brs, 1H), 2.13 (dd, J=17.6, 8.8 Hz, 1H),
2.24 (dddd, J=13.6, 9.1, 7.1, 2.2 Hz, 1H), 2.50 (s, 1H), 3.10 (dt, Jt =8.9,
Jd =2.1 Hz, 1H), 3.32 (dd, J=10.6, 5.1 Hz, 1H), 3.39 (t, J=8.9 Hz, 1H),
3.68–3.76 (m, 2H), 4.30–4.38 (m, 1H), 4.66 (s, 2H), 4.73 (d, J=11.5 Hz,
1H), 5.04 (d, J=11.5 Hz, 1H), 7.27–7.39 ppm (m, 10H); 13C NMR
(100 MHz, CDCl3): d=33.8, 52.0, 54.4, 69.2, 70.6, 71.5, 72.6, 75.1, 79.1,
86.6, 127.7, 127.8, 127.9, 128.4, 128.6, 138.2, 138.8 ppm; IR (KBr): n˜ =
3364, 2998, 2940, 2875, 1660, 1100, 1079 cmꢁ1; MS (ESI): m/z (%): 370
(100) [M+H]+; HRMS: m/z: calcd for C22H27NO4 +H+: 370.2013; found:
370.2013.
5-(2,3-Bisbenzyloxy-1,4-diacetoxy-butyl)-4-acetoxypyrrolidin-2-one (29):
CAN (729 mg, 1.33 mmol) was added to a solution of compound 28
(172 mg, 0.27 mmol) in a mixed solvent system CH3CN/H2O (v/v 9:1,
27 mL). The mixture was stirred at RT for 5 h and then diluted with H2O
(10 mL). The mixture was extracted with EtOAc (4ꢂ15 mL). The com-
bined organic phases were washed successively with a saturated aqueous
solution of NaHCO3 and brine, dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel eluting with EtOAc/PE 1:1 to
afford compound 29 (123 mg, 88%) as a colorless oil. [a]2D0 =+31.1 (c=
(1S,6S,7R,8R,8aR)-Octahydroindolizine-1,6,7,8-tetraol (castanospermine)
(1): HCOOH (0.2 mL) was added to a mixture of compound 31 (28 mg,
0.076 mmol) and 10% Pd/C (40 mg) in MeOH (5 mL) under an argon at-
mosphere. The suspension was stirred for 4 h and then filtered through a
short pad of Celite. The filtrate was concentrated under reduced pressure
and the residue was dissolved in water and passed through a column of
ion-exchange resin (Dowex 1ꢂ8–100, OHꢁ form) eluting with water
(30 mL). The eluent was concentrated under reduced pressure to give
castanospermine (1) (13 mg, 87%) as a colorless solid. M.p. 209–2108C
(MeOH/Et2O); [a]D20 =+77.5 (c=0.3 in H2O) (lit.[2a] [a]2D4 =+79.7 (c=
0.93 in H2O)); 1H NMR (400 MHz, D2O): d=1.71 (dddd, J=13.9, 8.7,
8.7, 1.8 Hz, 1H), 2.02 (dd, J=9.9, 4.3 Hz, 1H), 2.06 (t, J=10.8 Hz, 1H),
2.21 (q, J=9.2 Hz, 1H), 2.33 (dddd, J=13.9, 9.3, 7.3, 2.2 Hz, 1H), 3.08
(ddd, J=9.2, 9.1, 2.2 Hz, 1H), 3.18 (dd, J=10.8, 5.1 Hz, 1H), 3.32 (t, J=
9.1 Hz, 1H), 3.56–3.65 (m, 2H), 4.41 ppm (ddd, J=6.8, 4.4, 1.8 Hz 1H);
13C NMR (100 MHz, D2O): d=32.5, 51.4, 55.2, 68.8, 69.4, 69.9, 71.2,
78.8 ppm; IR (KBr): n˜ =3389, 2915, 1648, 1155, 1117, 1070 cmꢁ1; MS
(ESI): m/z (%): 190 (100) [M+H]+; HRMS (ESI): m/z: calcd for
C8H15NO4 +H+: 190.1074; found: 190.1074.
1
1.0 in CHCl3); H NMR (400 MHz, CDCl3): d=1.96 (s, 3H), 1.98 (s, 3H),
2.00 (s, 3H), 2.15 (d, J=17.6 Hz, 1H), 2.36 (dd, J=17.6, 5.7 Hz, 1H),
3.61 (dd, J=3.7, 3.0 Hz, 1H), 3.78 (dt, Jd =2.7, Jt =6.2 Hz, 1H), 3.83 (dd,
J=10.3, 4.5 Hz, 1H), 4.04 (dd, J=11.4, 6.5 Hz, 1H), 4.24 (dd, J=11.4,
5.3 Hz, 1H), 4.33–4.37 (m, 1H), 4.49 (d, J=11.6 Hz, 1H), 4.61 (d, J=
11.7 Hz, 1H), 4.74 (d, J=11.7 Hz, 1H), 4.78 (d, J=11.6 Hz, 1H), 5.22
(dd, J=10.3, 4.0 Hz, 1H), 5.29 (t, J=5.0 Hz, 1H), 6.17 (s, 1H), 7.27–
7.41 ppm (m, 10H); 13C NMR (100 MHz, CDCl3): d=20.6, 20.7, 20.8,
37.7, 56.9. 62.5, 66.4, 68.9, 73.0, 73.3, 74.7, 75.6, 128.1, 128.3, 128.4, 128.6
(2C), 128.9, 136.5, 136.9, 169.4, 170.0, 170.4, 174.2 ppm; IR (KBr): n˜ =
3225, 2920, 1740, 1703, 1370, 1230, 1100, 1035 cmꢁ1; MS (ESI): m/z (%):
528 (100) [M+H]+; HRMS: m/z: calcd for C28H33NO9 +H+: 528.2228;
found: 528.2226.
AHCTUNGTERG(NNUN 4S,5S)-1-(4-Methoxybenzyl)-5-[(1S,3S)-4-(4-methoxybenzyloxy)-3-(ben-
zyloxy)-1-hydroxybutyl]-4-hydroxypyrrolidin-2-one (35a): A solution of
10% HCl (20 mL) was added to a solution of compound 13g (647 mg,
0.94 mmol) in THF (50 mL). The mixture was stirred at 308C for 48 h
and extracted with ethyl acetate (3ꢂ20 mL). The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, filtered,
ACHTUNGTRENNUNG
5764
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 5755 – 5768

A Flexible Approach to Azasugars
FULL PAPER
and concentrated under reduced pressure. The residue was dissolved in
THF (15 mL) and cooled to ꢁ788C, NaBH4 (108 mg, 2.83 mmol) was
added one portion, then H2O (1 mL) was added slowly over 3 min. After
the mixture had been stirred for 30 min, the reaction was quenched with
a saturated aqueous solution of NaHCO3 (5 mL). The resulting mixture
was extracted with EtOAc (3ꢂ10 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel eluting with EtOAc/PE 5:1 to give
compound 35a (275 mg, 54.4%; colorless oil) and 35b (28 mg, 5.5%; col-
orless oil). Compound 35a: [a]2D0 =ꢁ47 (c=2.1 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=1.66 (ddd, J=14.0, 9.2, 2.3 Hz, 1H), 2.00 (ddd, J=
14.0, 10.4, 2.9 Hz, 1H), 2.47 (dd, J=17.1, 1.5 Hz, 1H), 2.57 (dd, J=17.1,
5.8 Hz, 1H), 3.22 (dd, J=4.9, 2.9 Hz, 1H), 3.47–3.58 (m, 2H), 3.74 (s,
3H), 3.79 (s, 3H), 3.82–3.95 (m, 1H), 4.03 (d, J=15.0 Hz, 1H), 4.27–4.36
(m, 1H), 4.42–4.57 (m, 5H), 4.70 (d, J=11.4 Hz, 1H), 5.01 (d, J=
15.0 Hz, 1H), 6.70–6.78 (m, 2H), 6.84–6.90 (m, 2H), 7.02–7.08 (m, 2H),
7.16–7.45 ppm (m, 7H). 13C NMR (CDCl3, 100 MHz): d=35.9, 41.8, 43.5,
55.2 (2C), 63.3, 66.3, 67.7, 71.9, 72.5, 73.1, 75.1, 113.8, 114.2, 127.7, 127.9,
128.2, 128.4, 129.1, 129.3. 130.0, 138.4, 159.0, 159.2, 174.4 ppm; IR (KBr):
n˜ =3366, 2934, 2860, 1665, 1611, 1516, 1453, 1246, 1175, 1071 cmꢁ1; MS
(ESI): m/z (100): 558 [M+Na]+; elemental analysis calcd (%) for
C31H37NO7: C 69.51, H 6.96, N 2.62, O 20.91; found: C 69.73, H 7.14, N
2.91.
After the mixture had been stirred for 30 min, BnBr (0.83 mL,
6.92 mmol) and Bu4NI (cat. amount) were added. The reaction was
stirred at RT for 15 h and then quenched with saturated NH4Cl solution
(5 mL) at 08C. The aqueous phase was extracted with EtOAc (3ꢂ
10 mL). The combined organic phases were dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel eluting with
EtOAc/PE 1:1 to afford compound 37 (735 mg, 85%) as a colorless oil.
[a]2D0 =ꢁ2.1 (c=2.5 in CHCl3); 1H NMR (400 MHz, CDCl3): d=1.57
(ddd, J=13.8, 9.8, 2.9 Hz, 1H), 1.75 (ddd, J=13.8, 9.7, 2.3 Hz, 1H), 2.47
(dd, J=17.1, 6.0 Hz, 1H), 2.65 (dd, J=17.1, 1.9 Hz, 1H), 3.24 (d, J=
10.2 Hz, 1H, D2O exchangeable), 3.35 (dd, J=5.5, 3.3 Hz, 1H), 3.44–3.49
(m, 2H), 3.73 (s, 3H), 3.78 (s, 3H), 3.84–3.91 (m, 1H), 3.94 (d, J=
14.9 Hz, 1H), 4.19 (tt, J=10.1, 2.9 Hz, 1H), 4.28 (dt, Jt =5.8, Jd =2.3 Hz,
1H), 4.32 (d, J=11.2 Hz, 1H), 4.45 (d, J=11.2 Hz, 1H), 4.46 (s, 2H),
4.54 (d, J=11.2 Hz, 1H), 4.69 (d, J=11.3 Hz, 1H), 5.23 (d, J=14.9 Hz,
1H), 6.69–6.75 (m, 2H), 6.84–6.88 (m, 2H), 7.01–7.11 (m, 2H), 7.16–
7.40 ppm (m, 12H); 13C NMR (CDCl3, 100 MHz): d=36.5, 37.0, 43.3,
55.1, 55.2, 62.7, 66.1, 71.4, 72.1, 72.6, 72.9, 74.9, 75.3, 113.7, 114.0, 127.5,
127.8, 128.1, 128.3 (2C), 128.6, 129.2, 129.3, 130.2, 136.3, 138.6, 158.8,
159.1, 172.8 ppm; IR (KBr): n˜ =3506, 2929, 2863, 1696, 1610, 1509, 1248,
1084, 1034 cmꢁ1; MS (ESI): m/z (%): 648 (100) [M+Na]+; HRMS (ESI):
m/z: calcd for C38H43NO7 +H+: 626.3118; found: 626.3138.
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG(4R,5S)-1-(4-Methoxybenzyl)-5-[(1S,3S)-4-(4-methoxybenzyloxy)-3-(ben-
zyloxy)-1-hydroxybutyl]-4-hydroxypyrrolidin-2-one (35b): [a]2D0 =ꢁ29.1
(c=1.1 in CHCl3); 1H NMR (400 MHz, CDCl3): d=1.58 (ddd, J=14.2,
8.8, 3.4 Hz, 1H), 1.72 (ddd, J=14.2, 9.6, 3.0 Hz, 1H), 2.25 (dd, J=17.5,
1.6 Hz, 1H), 2.76 (dd, J=17.5, 6.9 Hz, 1H), 2.80 (brs, 1H, D2O ex-
changeable), 3.17–3.20 (m, 1H), 3.22 (brs, 1H, D2O exchangeable), 3.44–
3.55 (m, 2H), 3.72 (s, 3H), 3.69–3.77 (m, 1H), 3.78 (s, 3H), 3.99 (d, J=
14.3 Hz, 1H), 3.98–4.06 (m, 1H), 4.31 (m, 1H), 4.37 (d, J=11.5 Hz), 4.44
(s, 2H), 4.64 (d, J=11.5 Hz, 1H), 4.84 (d, J=15.0 Hz, 1H), 6.74–6.82 (m,
2H), 6.84–6.89 (m, 2H), 7.08–7.17 (m, 2H), 7.18–7.39 ppm (m, 5H);
13C NMR (CDCl3, 100 MHz): d=33.4, 41.3, 43.6, 55.2 (2C), 65.0, 71.1,
71.8, 72.2, 73.0, 75.1, 113.8, 114.1, 127.8, 127.9, 128.2, 128.4, 129.2, 129.3,
129.9, 138.2, 158.9, 159.2, 174.0 ppm; IR (KBr): n˜ =3392, 2933, 1669,
1610, 1513, 1455, 1244, 1081, 1027 cmꢁ1; MS (ESI): m/z (%): 558 (100)
[M+Na]+; elemental analysis calcd (%) for C31H37NO7: C 69.51, H 6.96,
N 2.62, O 20.91; found: C 69.32, H 7.03, N 2.81.
a
0.54 mmol). After the mixture had been stirred at 708C for 96 h, the re-
action was quenched with saturated Na2S2O3 solution. The methanol was
removed under reduced pressure and the aqueous phase was extracted
with EtOAc (3ꢂ10 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica gel
eluting with CH2Cl2/MeOH (10:1) to afford compound 38 (225.6 mg,
83%) as a colorless solid. M.p. 183–1858C (EtOAc); [a]2D0 =ꢁ2.7 (c=2.3
1
in CHCl3); H NMR (400 MHz, CDCl3): d=1.60–1.75 (m, 2H), 2.15 (brs,
1H, D2O exchangeable), 2.50 (dd, J=17.1, 6.0 Hz, 1H), 2.67 (dd, J=
17.1, 1.8 Hz, 1H), 3.32 (brs, 1H, D2O exchangeable), 3.36 (dd, J=5.5,
3.4 Hz, 1H), 3.44–3.57 (m, 1H), 3.74 (s, 3H3), 3.70–3.83 (m, 2H), 3.96 (d,
J=14.9 Hz, 1H), 4.22–4.11 (m, 1H), 4.31 (dt, Jt =5.9, Jd =2.5 Hz, 1H),
4.35 (d, J=11.2 Hz, 1H2), 4.51 (d, J=11.3 Hz, 1H), 4.57 (d, J=11.2 Hz,
1H), 4.62 (d, J=11.3 Hz, 1H), 5.23 (d, J=14.9 Hz, 1H), 6.67–6.81 (m,
2H), 7.04–7.11 (m, 2H), 7.21–7.44 ppm (m, 10H); 13C NMR (CDCl3,
100 MHz): d=36.0, 37.0, 43.4, 55.2, 62.8, 64.2, 66.3, 71.5, 72.4, 74.9, 114.0,
127.8 (2C), 128.2 (2C), 128.5, 128.7, 129.3, 136.2, 138.2, 158.9, 172.8 ppm;
IR (KBr): n˜ =3451, 2933, 1664, 1516, 1450, 1244, 1069, 1026 cmꢁ1; MS
(ESI): m/z (%): 528 (100) [M+Na]+; HRMS (ESI): m/z: calcd for
C30H35NO6 +H+: 506.2543; found: 528.2425.
ACHTUNGTRENNUNG
a
0.47 mmol). After the mixture had been stirred at 708C for 96 h, the re-
action was quenched with saturated Na2S2O3 solution. The methanol was
removed under reduced pressure and the aqueous phase was extracted
with EtOAc (3ꢂ10 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel eluting
with CH2Cl2/MeOH 10:1 to afford compound 36 (157 mg, 81%) as a col-
orless solid. M.p. 169–1708C (MeOH); [a]2D0 =ꢁ43.5 (c=1.0 in MeOH);
1H NMR (400 MHz, CD3OD): d=1.60 (ddd, J=14.2, 10.2, 2.8 Hz, 1H),
1.90 (ddd, J=14.2, 10.0, 2.5 Hz, 1H), 2.35 (ddd, J=17.1, 2.4, 0.9 Hz, 1H),
2.60 (dd, J=17.1, 6.0 Hz, 1H), 3.29 (dd, J=5.1, 3.0 Hz, 1H), 3.54 (dd, J=
11.6, 4.8 Hz, 1H), 3.64 (dd, J=11.6, 4.5 Hz, 1H), 3.68 (s, 3H), 3.74 (ddt,
Jt =6.9, Jd =4.6, 2.5 Hz, 1H), 3.93 (d, J=15.0 Hz, 1H), 4.21 (td, Jd =10.0,
Jt =2.8 Hz, 1H), 4.42 (d, J=11.1 Hz, 1H), 4.53 (dt, Jt =5.9, Jd =2.3 Hz,
1H), 4.70 (d, J=11.1 Hz, 1H), 5.10 (d, J=15.0 Hz, 1H), 6.68–6.73 (m,
2H), 6.97–7.03 (m, 2H), 7.17–7.47 ppm (m, 5H); 13C NMR (CD3OD,
100 MHz): d=37.2, 42.4, 44.3, 55.7, 64.6, 65.1, 67.5, 68.5, 73.5, 78.6, 115.2,
128.7, 129.1, 129.2, 129.4, 130.2, 140.2, 160.6, 176.6 ppm; IR (KBr): n˜ =
3369, 2934, 1661, 1459, 1248, 1077, 1042 cmꢁ1; MS (ESI): m/z (%): 438
(100) [M+Na]+; elemental analysis calcd (%) for C23H29NO6: C 66.49, H
7.04, N 3.37, O 23.10; found: 66.13, H 7.24, N 3.30.
ACHUTNGRENUN(G 4S,5R)-5-[(1S,3S)-3-Benzyloxy-1,4-bisACHTUNGTNER(NUGN acetoxy)butyl]-1-(4-methoxyben-
zyl)-4-benzyloxypyrrolidin-2-one (39): DMAP (cat. amount), Ac2O
(0.21 mL, 2.2 mmol), and Et3N (0.30 mL, 2.2 mmol) were added succes-
sively to an ice-bath-cooled solution of compound 38 (363 mg,
0.72 mmol) in CH2Cl2 (20 mL). The mixture was stirred at RT overnight
and quenched with a saturated aqueous solution of NaHCO3 (5 mL) at
08C. The organic layer was separated and the aqueous layer was extract-
ed with CH2Cl2 (3ꢂ5 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica gel
eluting with EtOAc/PE 1:1 to afford compound 39 as a colorless oil
(417 mg, 85%). [a]2D0 =ꢁ39.2 (c=1.7 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=1.82–1.96 (m, 2H), 2.02 (s, 3H), 2.04 (s, 3H), 2.51–2.60 (m,
1H), 2.64 (dd, J=16.7, 8.7 Hz, 1H), 3.57–3.67 (m, 1H), 3.76 (s, 3H), 3.78
(dd, J=8.3, 1.4 Hz, 1H), 3.84 (d, J=14.8 Hz, 1H), 4.04 (dd, J=11.7,
5.2 Hz, 1H), 4.20–4.31 (m, 2H), 4.43 (d, J=11.2 Hz, 1H), 4.51 (d, J=
12.0 Hz, 1H), 4.58 (d, J=12.0 Hz, 1H), 4.60 (d, J=11.2 Hz, 1H), 5.19 (d,
J=14.8 Hz, 1H), 5.64–5.71 (m, 1H), 6.74–6.81 (m, 2H), 6.98–7.09 (m,
2H), 7.20–7.36 ppm (m, 10H); 13C NMR (CDCl3, 100 MHz): d=20.8,
21.2, 32.9, 37.2, 44.2, 55.2, , 60.8, 65.6, 70.2, 72.1, 72.2, 72.7, 73.3, 114.1,
127.4, 127.7, 127.8, 128.06, 128.1, 128.3, 128.4, 128.5, 129.2, 137.2, 138.0,
159.1, 170.2, 170.7, 172.0 ppm; IR (KBr): n˜ =1738, 1692, 1513, 1252, 1200,
ACHTUNGTRENNUNG(4S,5S)-1-(4-Methoxybenzyl)-5-[(1S,3S)-4-(4-methoxybenzyloxy)-3-(ben-
zyloxy)-1-hydroxybutyl]-4-(benzyloxy)pyrrolidin-2-one (37): Compound
35a (740 mg, 1.38 mmol) in THF (3 mL) was added to a suspension of
NaH (60% in mineral oil, 117 mg, 2.9 mmol) in THF (15 mL) at ꢁ308C.
Chem. Eur. J. 2010, 16, 5755 – 5768
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5765

P.-Q. Huang et al.
1026 cmꢁ1; MS (ESI): m/z (%): 590 (100) [M+Na]+; HRMS (ESI): m/z:
calcd for C30H35NO6 +H+: 590.2754; found: 590.2777.
1349, 1131, 1065 cmꢁ1; MS (ESI): m/z (%): 354 (100) [M+H]+; HRMS
(ESI): m/z: calcd for C22H27NO3 +H+: 354.2069; found: 354.2086.
(+)-7-Deoxy-6-epi-castanospermine (4): HCOOH (0.3 mL) was added to
a suspension of compound 42 (25 mg, 0.07 mmol), 10% Pd/C (20 mg),
and MeOH (2 mL) under an argon atmosphere. The suspension was
stirred for 4 h and then filtered through a pad of Celite. The filtrate was
concentrated under reduced pressure. The residue was dissolved in water
and passed through a column of ion-exchange resin (Dowex 1ꢂ8–100,
OHꢁ form) and eluted with water (20 mL). The eluent was concentrated
under reduced pressure to give 4 (10 mg, yield: 80%) as a colorless oil.
[a]2D0 =+17.1 (c=0.6 in MeOH) (lit.[15] [a]2D6 =+18.3 (c=0.712 in
MeOH)); 1H NMR (400 MHz, CD3OD): d=1.35 (ddd, J=13.2, 11.5,
3.0 Hz, 1H), 1.62 (dd, J=9.3, 4.0 Hz, 1H), 1.64–1.72 (m, 1H), 2.02–2.19
(m, 4H), 3.02 (td, Jd =11.6, Jt =2.2 Hz, 1H), 3.07–3.13 (m, 1H), 3.96–4.01
(m, 1H), 4.07 (ddd, J=11.45, 9.30, 4.86 Hz, 1H), 4.29–4.33 ppm (m, 1H);
13C NMR (100 MHz, CD3OD): d=33.6, 40.8, 53.5, 58.9, 63.9, 67.7, 71.7,
75.4 ppm; IR (KBr): n˜ =3395, 2923, 1648, 1164, 1120, 1070 cmꢁ1; MS
(ESI): m/z (%): 174 (100) [M+H]+; HRMS (ESI): m/z: calcd for
C8H15NO3 +Na+: 196.0950; found: 196.0941.
ACHTUNGTRENNUNG(4S,5R)-5-[(1S,3S)-3-Benzyloxy-1,4-bisACHTUNGTRNE(NUGN acetoxy)butyl]-4-benzyl-oxypyrro-
lidin-2-one (40): CAN (1.62 g, 2.95 mmol) was added to a solution of 39
(350 mg, 0.59 mmol) in a mixed solvent system CH3CN/H2O (v/v 9: 1,
60 mL). The mixture was stirred at RT for 5 h and then diluted with H2O
(10 mL). The mixture was extracted with EtOAc (4ꢂ15 mL). The com-
bined organic phases were washed successively with a saturated aqueous
solution of NaHCO3 (5 mL) and brine (3 mL), dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel eluting with
EtOAc/PE 2:1 to afford compound 40 (239 mg, 86%) as a colorless oil.
[a]2D0 =ꢁ24.5 (c=1.5 in CHCl3); 1H NMR (400 MHz, CDCl3): d=1.88
(ddd, J=14.5, 10.0, 3.0 Hz, 1H), 1.98 (s, 1H, 3H), 2.02 (s, 1H, 3H), 2.02–
2.09 (m, 1H), 2.45 (dd, J=17.1, 5.7 Hz, 1H), 2.52 (dd, J=17.1, 7.5 Hz,
1H), 3.65 (dtd, Jd =7.7, 3.1, Jt =4.6 Hz, 1H), 4.00–4.09 (m, 2H), 4.24 (dd,
J=11.7, 4.4 Hz, 1H), 4.41 (td, Jd =7.3, Jt =6.1 Hz, 1H), 4.45 (d, J=
11.3 Hz, 1H), 4.51 (d, J=11.8 Hz, 1H), 4.55 (d, J=11.8 Hz, 1H), 4.61 (d,
J=11.3 Hz, 1H), 5.42–5.48 (m, 1H), 6.18 (s, 1H), 7.20–7.39 ppm (m,
10H); 13C NMR (CDCl3, 100 MHz): d=20.8, 21.0, 32.8, 36.6, 59.7, 65.4,
70.7, 72.0 (2C), 73.2, 74.2, 127.6, 127.7, 127.8, 128.1, 128.3, 128.4, 137.1,
137.8, 170.3, 170.8, 175.0 ppm; IR (KBr): n˜ =3217, 2925, 1736, 1699, 1368,
1232, 1096, 1037 cmꢁ1; MS (ESI): m/z (%): 492 (100) [M+Na]+; HRMS
(ESI): m/z: calcd for C26H31NO7 +H+: 470.2179; found: 470.2189.
Acknowledgements
The authors are grateful to the NSF of China (20832005) and the Nation-
al Basic Research Program (973 Program) of China (grant no.
2010CB833200) for financial support.
ACHTUNGTRENNUNG(1S,3S)-3-(Benzyloxy)-1-[(2S,3S)-3-(benzyloxy)pyrrolidin-2-yl]butane-1,4-
diol (41): BH3·SMe2 (0.36 mL, 3.8 mmol) was added to a solution of com-
pound 40 (178 mg, 0.38 mmol) in dry THF (5 mL) at 08C. The reaction
was heated at 608C for 10 h and then quenched with MeOH (2 mL) at
08C. The mixture was concentrated under reduced pressure. The residue
was dissolved in MeOH (3 mL) and 6n HCl (0.5 mL) was added. After
the mixture had been stirred at RT for 30 min, the volatile solvent was
removed under reduced pressure. The residue was dissolved in H2O and
passed through a column of ion-exchange resin (Dowex 1ꢂ8–100, OHꢁ
form) eluting with water (40 mL). The eluent was concentrated under re-
duced pressure and purified by flash column chromatography on silica
gel eluting with CH2Cl2/MeOH (10: 1) to afford pyrrolidine 41 (127 mg,
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71%) as
a
colorless oil. [a]D20 =+33.8 (c=1.1 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=1.65 (ddd, J=14.6, 10.1, 4.6 Hz, 1H), 1.84–1.97
(m, 2H), 2.01 (dddd, J=13.6, 7.8, 5.4, 2.2 Hz, 1H), 2.33 (brs, 3H, D2O
exchangeable), 2.80 (dd, J=5.4, 4.8 Hz, 1H), 2.90 (ddd, J=11.1, 8.8,
5.4 Hz, 1H), 3.20 (ddd, J=11.1, 7.9, 6.8 Hz, 1H), 3.56 (dd, J=11.3,
4.3 Hz, 1H), 3.74–3.83 (m, 2H), 4.07 (ddd, J=10.0, 5.6, 2.3 Hz, 1H), 4.21
(dt, Jt =4.9, Jd =2.2 Hz, 1H), 4.36 (d, J=11.5 Hz, 1H), 4.59 (d, J=
11.5 Hz, 1H), 4.60 (s, 2H), 7.26–7.38 ppm (m, 10H); 13C NMR (100 MHz,
CDCl3): d=31.5, 37.9. 44.5, 64.5, 66.7, 68.4, 70.8, 72.1, 77.4, 81.0, 127.7,
127.8 (2C), 127.9 (2C), 128.1, 128.4 (2C), 128.6 (2C), 137.4, 138.4 ppm;
IR (KBr): n˜ =3397, 2926, 1637, 1454, 1392, 1065 cmꢁ1; MS (ESI): m/z
(%): 372 (100) [M+H]+; HRMS (ESI): m/z: calcd for C22H29NO4 +H+:
372.2175; found: 372.2188.
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with CH2Cl2/MeOH 20:1 to afford indolizidinol 42 (48 mg, 75%) as a col-
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orless oil. [a]2D0 =+64.7 (c=0.9 in CHCl3); H NMR (400 MHz, CD3OD):
d=1.35 (ddd, J=13.4, 11.4, 3.3 Hz, 1H), 1.78 (dd, J=9.3, 4.7 Hz, 1H),
1.85–2.14 (m, 4H), 2.35 (dddd, J=13.3, 4.7, 2.7, 2.1 Hz, 1H), 3.11 (t, J=
7.9 Hz, 1H), 3.26 (td, Jd =12.1, Jt =1.9 Hz, 1H), 3.73–3.78 (m, 1H), 4.17–
4.29 (m, 2H; H-1), 4.49 (d, J=12.2 Hz, 1H), 4.54 (d, J=11.8 Hz, 1H),
4.59 (d, J=12.2 Hz, 1H), 4.61 (d, J=11.8 Hz, 1H), 7.19–7.44 ppm (m,
10H); 13C NMR (100 MHz, CD3OD): d=30.7, 38.7, 54.5, 56.2, 64.4, 71.5,
72.3, 74.7, 75.4, 79.0, 128.4, 128.5, 128.8 (2C), 128.9 (2C), 129.2 (2C),
129.3 (2C), 140.2, 140.4 ppm; IR (KBr): n˜ =3389, 2918, 2859, 2797, 1614,
5766
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A Flexible Approach to Azasugars
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Received: December 20, 2009
Published online: April 8, 2010
5768
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Chem. Eur. J. 2010, 16, 5755 – 5768