Asymmetric syntheses of 1-deoxy-6,8a-di-epi-castanospermine and 1-deoxy-6-epi-castanospermine

Article abstract of DOI:10.1021/jo300309z

Asymmetric syntheses of both 1-deoxy-6,8a-di-epi-castanospermine and 1-deoxy-6-epi-castanospermine, polyhydroxylated indolizidine alkaloids that act as selective glycosidase inhibitors, have been accomplished in seven steps. The key feature of our unique syntheses includes the stereoselective introduction of the C-3 and C-4 hydroxyl groups utilizing the aza-Claisen rearrangement-induced ring expansion of 1-acyl-2-alkoxyvinyl pyrrolidine and a substrate-controlled stereoselective transannulation of the resulting azoninone intermediate.

Full text of DOI:10.1021/jo300309z

Note
pubs.acs.org/joc
Asymmetric Syntheses of 1-Deoxy-6,8a-di-epi-castanospermine and
1-Deoxy-6-epi-castanospermine
Hwayoung Yun, Jongmin Kim, Jaehoon Sim, Sujin Lee, Young Taek Han, Dong-Jo Chang, Dae-Duk Kim,
and Young-Ger Suh*
College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea
S
* Supporting Information
ABSTRACT: Asymmetric syntheses of both 1-deoxy-6,8a-di-
epi-castanospermine and 1-deoxy-6-epi-castanospermine, poly-
hydroxylated indolizidine alkaloids that act as selective
glycosidase inhibitors, have been accomplished in seven
steps. The key feature of our unique syntheses includes the
stereoselective introduction of the C-3 and C-4 hydroxyl
groups utilizing the aza-Claisen rearrangement-induced ring expansion of 1-acyl-2-alkoxyvinyl pyrrolidine and a substrate-
controlled stereoselective transannulation of the resulting azoninone intermediate.
ver the past half century, studies on glycosidase inhibitors
have been part of promising new drug-development
deoxycastanospermines 1 and 2 have been reported.5 The
major challenge in their synthesis involved the elaboration of
the four contiguous stereocenters that are compactly arranged.
In this regard, these iminosugars have been considered as
attractive targets in terms of both synthetic and medicinal
chemistry.6
We have reported systematic studies on the ACR-induced
stereoselective ring-expansions of lactams of various ring sizes
and synthetic applications of this method.7 However, there is a
limit in synthetic application of the stereoselective ring-
expansion of 5-membered azacycles. Our previous studies on
the ACR-induced stereoselective ring-expansions of the 5-
membered azacycles to yield the corresponding 9-membered
lactams revealed that the mixed internal olefin geometries of
the desired azoninone products consistently hindered the use of
our synthetic strategy for the production of indolizidine
alkaloids.7c Fortunately, we were able to overcome this poor
olefin-geometry selectivity by using a substituent-controlled and
microwave-assisted ACR of 1-acyl-2-alkoxyvinylpyrrolidine.
Our unified synthetic strategy for the 1-deoxycastanosper-
mines 1 and 2 is outlined in Scheme 1. The final alkaloid
O
programs.1 Since nojirimycin, a natural glycosidase inhibitor,
was isolated from a Streptomyces strain in 1966,2 significant
work on glycosidase inhibitors has been performed.1 Glyco-
sidase inhibitors exhibit diverse biological activities and have
many types of beneficial effects, including anticancer,
antidiabetic, antiobesity, antiviral, fungicidal, and insecticidal.1
Among these glycosidase inhibitors, natural and non-natural
polyhydroxylated indolizidine alkaloids, which structurally
mimic bioactive carbohydrates, have attracted a great interest
because of their potential to serve as pharmaceutical lead
compounds (Figure 1).3 In particular, castanospermine, a
Scheme 1. Retrosynthetic Analysis
Figure 1. Polyhydroxylated indolizidines.
highly hydroxylated indolizidine alkaloid, inhibits many types of
α- and β-D-glucosidases.4 The selectivity and potency of the
inhibition of glycosidases can be altered by modifying the five
stereocenters.
1-Deoxy-6,8a-di-epi-castanospermine 1 is known to be a
potent inhibitor of α-L-fucosidase, and 1-deoxy-6-epi-castano-
spermine 2 was shown to be an inhibitor of lysosomal α-
mannosidase in a competitive manner.4 Despite the excellent
biological activities of these compounds, few syntheses of 1-
products 1 and 2 are accessible from the azoninones 3 and 4
bearing (Z)- or (E)-olefins via substrate-controlled stereo-
selective transannulations. The 9-membered lactams 3 and 4
Received: February 11, 2012
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
Note
can be stereoselectively constructed through a ring-expansion
ACR of the N-acyl-α-alkoxyvinylpyrrolidines 5 and 6.7 The
appropriate aza-Claisen precursor could be obtained by the
selective formation of the (E)- or (Z)-silyl enol ether7d,8
followed by a facile amidation with the protected glycolic acid
8. The change in the olefin-geometry of the ACR precursor
effectively provides stereochemical diversity of the azoninone
intermediate through the corresponding substrate-induced
transition state.7 The optically active aldehyde 7 was expected
to be derived from commercially available L-proline.9
of the synthetic product were consistent with those of the
reported product.5a,f
The synthesis of 1-deoxy-6-epi-castanospermine 2 com-
menced with the stereoselective preparation of the (Z)-
silyloxyvinyl pyrrolidine 12 from aldehyde 7 (Scheme 3). The
Scheme 3. Synthesis of 1-Deoxy-6-epi-castanospermine 2
The synthesis of 1-deoxy-6,8a-di-epi-castanospermine 1
(Scheme 2) commenced with the preparation of the (E)-silyl
Scheme 2. Synthesis of 1-Deoxy-6,8a-di-epi-castanospermine
1
treatment of aldehyde 7 with TBSCl in the presence of NaH
provided largely the (Z)-silyl enol ether 12 (>7:1),8b,c which
was separable from the (E)-stereoisomer by chromatography.
Selective Boc-deprotection of 12 with TMSOTf in the presence
of 2,6-lutidine and the subsequent amidation of the resulting
amine with acid 8 afforded the ACR precursor 6. Unfortunately,
our initial attempts to achieve the ACR of 6 under a variety of
previously used ACR conditions7 were not successful. However,
this reluctant ACR of 6 proceeded under microwave-assisted
conditions.13 Only azoninone 4 (J = 16.8 Hz) with an internal
(E)-olefin was obtained, although the yield was not satisfactory.
The reaction seemed to proceed through a chairlike transition
state, and the low yield is likely due to the instability of the (Z)-
silyl enol ether under the ACR conditions. Again, the
stereoselective transannulation of 414 by Oxone treatment
provided the corresponding indolizidine 13,11 which was then
subjected to acetylation of the three hydroxyl groups. The
global reduction of 14 with LAH afforded 1-deoxy-6-epi-
castanospermine 2. The synthetic product proved to be
identical in all respects with the authentic alkaloid.5a,b
In conclusion, we have achieved the highly concise syntheses
of 1-deoxy-6,8a-di-epi-castanospermine 1 (13% overall yield)
and 1-deoxy-6-epi-castanospermine 2 (4% overall yield) in only
seven steps from the known aldehyde 7. The key features of our
syntheses include the stereoselective construction of the
indolizidine backbone with the two silyloxy groups utilizing
the ACR-induced ring-expansion of the (E)- and (Z)-1-acyl-2-
alkoxyvinylpyrrolidines and the stereoselective transannulation
of the resulting azoninone. It should be noted that the
azoninone bearing an internal (E)-olefin could be prepared by
microwave-accelerated ACR of the labile N-acyl-(Z)-silylox-
yvinylpyrrolidine. Our syntheses seem to be quite efficient in
terms of excellent asymmetric induction, high versatility, low
number of steps and simple manipulations. Considering a
variety of approaches for triggering the transannular reaction,
our synthetic route can also be widely applicable to the
syntheses of other highly functionalized indolizidine alkaloids.
enol ether 9 (>20:1) by a reaction of aldehyde 79 with DBU in
the presence of TBSCl.7d,8a Selective Boc-deprotection of 9
with TMSOTf and 2,6-lutidine followed by the amidation of
the resulting amine with 8 afforded the ACR precursor 5. With
the desired amide 5 in hand, we executed the ACR of 5 under
our standard ACR conditions.7 Azoninone 3 bearing an internal
(Z)-olefin and two sec-alcohol units was stereoselectively
obtained in high yield. The coupling constant between the
two olefinic protons of 3 (J = 11.7 Hz) was indicative of a cis-
relationship. The selective production of the desired product as
a single diastereomer was likely due to the ACR of 5 only
through a boatlike transition state induced by the two bulky
silyloxy substituents, which preferentially occupied pseudoe-
quatorial positions. To the best of our knowledge, the
stereoselective formation of azoninone via an amide enolate-
induced ACR has not been reported previously.10 After
extensive attempts to perform the pivotal transannular ring-
contraction of lactam 3 under various conditions, we finally
obtained indolizidine 10 through the effective Oxone-induced
transannulation11 of 3 and the concomitant TBS-deprotection.
We did not observe any regio- or diastereomers. The exclusive
formation of the desired isomer is explained by the initial
epoxide formation, which spontaneously underwent the regio-
and stereoselective ring-opening by the amide nitrogen. The
exposure of triol 10 to Ac2O and the global reduction of the
resulting amide 11 with LAH produced 1-deoxy-6,8a-di-epi-
castanospermine 1.12 Because the amide reduction of triol 10
did not proceed under various conditions, protection of the
triols as acetates was inevitable. The physical and spectral data
B
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Note
+ H+); HR-MS (FAB+) calcd for C20H42NO3Si2 (M + H+) 400.2703,
found 400.2702.
EXPERIMENTAL SECTION
■
Unless noted otherwise, all starting materials and reagents were
obtained from commercial suppliers and were used without further
purification. Tetrahydrofuran was distilled from sodium benzophenone
ketyl. Dichloromethane, triethylamine and pyridine were freshly
distilled from calcium hydride. All solvents used for routine isolation
of products and chromatography were reagent grade and glass distilled.
Reaction flasks were dried at 100 °C. Air- and moisture-sensitive
reactions were performed under argon atmosphere. Flash column
chromatography was performed using silica gel of 230−400 mesh with
the indicated solvents. Thin-layer chromatography was performed
using 0.25 mm silica gel plates. Optical rotations were measured with a
digital polarimeter at ambient temperature using 100 mm cell of 2 mL
capacity. Infrared spectra were recorded on a FT-IR spectrometer.
(3S,4S,Z)-3,4-Bis(tert-butyldimethylsilyloxy)-3,4,8,9-tetrahy-
dro-1H-azonin-2(7H)-one (3). To a solution of the amide 5 (1.53 g,
3.83 mmol) in toluene (60 mL) was added lithium bis(trimethylsilyl)-
amide (11.5 mL, 11.5 mmol, 1.0 M in hexanes) at 120 °C. After
stirring for 15 h at the same temperature, the reaction mixture was
quenched with H2O at ambient temperature. The aqueous layer was
extracted with EtOAc (2 × 70 mL) and the combined organic layers
were dried over MgSO4 and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (EtOAc: n-
hexane =1: 10) to afford 1.01 g (66%) of the azoninone 3 as white
solid: mp 81−83 °C; [α]2D6 −10.1 (c 1.01, MeOH); FT-IR (thin film,
1
neat) νmax 3409, 2954, 2930, 2858, 1686, 1515, 1472, 1362 cm−1; H
NMR (CD3OD, 400 MHz) δ 6.89 (d, 1H, J = 11.2 Hz), 5.53 (m, 1H),
5.27 (dd, 1H, J = 11.6, 6.7 Hz), 4.57 (d, 1H, J = 6.4 Hz), 4.20 (s, 1H),
4.03 (m, 1H), 3.03 (m, 1H), 2.00−1.82 (m, 2H), 1.73 (m, 2H), 0.92
(s, 18H), 0.15 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H); 13C
NMR (CD3OD, 100 MHz) δ 177.9, 135.0, 131.9, 81.3, 76.2, 41.3,
31.9, 27.3, 27.3, 27.3, 27.1, 27.1, 27.1, 27.0, 20.0, 20.0, −3.6, −3.7,
−3.7, −4.1; LR-MS (FAB+) m/z 400 (M + H+); HR-MS (FAB+)
calcd for C20H42NO3Si2 (M + H+) 400.2703, found 400.2715.
(6S,7S,8R,8aS)-6,7,8-Trihydroxyhexahydroindolizin-5(1H)-
one (10). To a solution of the azoninone 3 (897 mg, 2.24 mmol) in
MeOH (30 mL) and H2O (10 mL) were added Oxone (3.44 g, 11.2
mmol) at ambient temperature. After being stirred for 60 h at the same
temperature, the reaction mixture was concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(MeOH/CH2Cl2 = 1: 10) to afford 264 mg (63%) of the triol 10 as
colorless and foamy solid: [α]2D6 −83.1 (c 1.04, MeOH); FT-IR (thin
film, neat) νmax 3378, 2889, 1623, 1484, 1326 cm−1; 1H NMR
(CD3OD, 500 MHz) δ 4.18 (d, 1H, J = 3.7 Hz), 4.13 (d, 1H, J = 4.2
Hz), 4.02 (dd, 1H, J = 4.6, 2.6 Hz), 3.90 (m, 1H), 3.42 (dd, 2H, J =
8.8, 5.5 Hz), 2.04−1.87 (m, 2H), 1.95−1.79 (m, 2H); 13C NMR
(CD3OD, 125 MHz) δ 172.3, 72.9, 69.6, 69.6, 60.6, 46.7, 28.1, 24.3;
LR-MS (FAB+) m/z 188 (M + H+); HR-MS (FAB+) calcd for
C8H14NO4 (M + H+) 188.0923, found 188.0911.
1
Mass spectra were obtained with a GC−MS instrument. The H and
13C NMR spectra were recorded on 300, 400, or 500 MHz
spectrometers as solutions in the indicated solvent. Chemical shifts
are expressed in parts per million (ppm, δ) downfield from
tetramethylsilane and are referenced to the deuterated solvent
(CHCl3). 1H NMR data were reported in the order of chemical
shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad and/or multiple resonance), number of protons,
and coupling constant in hertz (Hz).
(S,E)-tert-Butyl 2-(2-(tert-Butyldimethylsilyloxy)vinyl)-
pyrrolidine-1-carboxylate (9). To a solution of the aldehyde 7
(1.17 g, 5.49 mmol) in CH2Cl2 (50 mL) were added TBSCl (2.23 g,
14.8 mmol, ca. 10%) and DBU (8.2 mL, 54.9 mmol) at ambient
temperature. After being stirred for 12 h at 40 °C, the reaction mixture
was quenched with saturated aqueous NaHCO3 and then extracted
with CH2Cl2 (2 × 60 mL). The combined organic layers were dried
over MgSO4 and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (EtOAc/n-hexane =1: 10)
to afford 1.58 g (88%) of the (E)-silyl enol ether 9 as a colorless oil:
[α]2D4 −7.10 (c 1.00, CHCl3); FT-IR (thin film, neat) νmax 2958, 2931,
2884, 2859, 1698, 1663, 1473, 1391, 1364 cm−1; H NMR (CDCl3,
1
300 MHz) δ 6.31 (brs, 1H), 4.86 (dd, 1H, J = 11.8, 8.0 Hz), 4.16 (brs,
1H), 3.29 (brs, 2H), 1.99−1.71 (m, 2H), 1.85−1.54 (m, 2H), 1.40 (s,
9H), 0.87 (s, 9H), 0.09 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 154.4,
142.0, 112.0, 78.7, 55.2, 45.8, 32.9, 28.5, 28.5, 28.5, 25.6, 25.6 25.6,
22.9, 18.2, −5.3, −5.3; LR-MS (FAB+) m/z 328 (M + H+); HR-MS
(FAB+) calcd for C17H34NO3Si (M + H+) 328.2308, found 328.2316.
(S,E)-2-(tert-Butyldimethylsilyloxy)-1-(2-(2-(tert-
butyldimethylsilyloxy)vinyl)pyrrolidin-1-yl)ethanone (5). To a
solution of the (E)-silyl enol ether 9 (100 mg, 305 μmol) in CH2Cl2
(10 mL) were added 2,6-lutidine (71 μL, 610 μmol) and TMSOTf (83
μL, 458 μmol) at 0 °C. After being stirred for 1 h at ambient
temperature, the reaction mixture was quenched with MeOH and then
concentrated in vacuo. This crude mixture was used for the next step
without further purification. To a solution of the crude amine and the
acid 8 (87.2 mg, 458 μmol) in CH2Cl2 (5 mL) were added 1-
hydroxybenzotriazole hydrate (45.4 mg, 336 μmol), 4-methylmorpho-
line (74 μL, 671 μmol), and EDCI (87.8 mg, 458 μmol) at ambient
temperature. After being stirred for 14 h at the same temperature, the
reaction mixture was quenched with H2O. The aqueous layer was
extracted with CH2Cl2 (2 × 10 mL), and the combined organic layers
were dried over MgSO4 and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (EtOAc/n-
hexane = 1:5) to afford 73.1 mg (60%) of the amide 5 as white solid:
mp 62−64 °C; [α]2D5 −23.5 (c 1.03, MeOH); FT-IR (thin film, neat)
(6S,7S,8R,8aS)-5-Oxooctahydroindolizine-6,7,8-triyl Triace-
tate (11). To a solution of the triol 10 (264 mg, 1.41 mmol) in
pyridine (30 mL) was added acetic anhydride (1.3 mL, 14.1 mmol) at
ambient temperature. After stirring for 12 h at the same temperature,
the reaction mixture was concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (EtOAc: n-
hexane =1: 3 to 1: 1) to afford 313 mg (71%) of the triacetate 11 as a
pale yellow oil: [α]2D6 −130 (c 1.05, CHCl3); FT-IR (thin film, neat)
1
νmax 3481, 2977, 2939, 2891, 1754, 1662, 1459, 1372, 1332 cm−1; H
NMR (CDCl3, 400 MHz) δ 5.55 (m, 1H), 5.46 (m, 1H), 5.30 (m,
1H), 3.91 (d, 1H, J = 10.7 Hz), 3.52 (m, 2H), 2.11 (s, 3H), 2.07 (s,
6H), 2.00−1.84 (m, 2H), 1.88−1.46 (m, 2H); 13C NMR (CDCl3, 100
MHz) δ 169.8, 169.2, 169.2, 163.3, 67.5, 66.3, 66.2, 57.2, 44.6, 27.1,
22.1, 20.6, 20.6, 20.5; LR-MS (FAB+) m/z 314 (M + H+); HR-MS
(FAB+) calcd for C14H20NO7 (M + H+) 314.1240, found 314.1241.
1-Deoxy-6,8a-di-epi-castanospermine (1). To a solution of
lithium aluminum hydride (157 mg, 4.15 mmol) in THF (10 mL) was
slowly added a solution of the triacetate 11 (130 mg, 415 μmol) in
THF (10 mL) at 0 °C. After being for 12 h at 60 °C, the reaction
mixture was quenched with H2O and NaOH (10%). The resulting
mixture was dried over MgSO4 at 0 °C and filtered under reduced
pressure. The organic layer was concentrated in vacuo, and the residue
was purified by flash column chromatography on silica gel (MeOH/
CH2Cl2 = 1:10) to afford 61.8 mg (86%) of 1-deoxy-6,8a-di-epi-
castanospermine 1 as a colorless solid: mp 127−129 °C; [α]2D5 23.3 (c
0.950, MeOH); FT-IR (thin film, neat) νmax 3365, 2922, 2822, 1647,
1464 cm−1; 1H NMR (D2O, 500 MHz) δ 3.92 (m, 1H), 3.83 (s, 2H),
3.00 (m, 1H), 2.97 (m, 1H), 2.71 (m, 1H), 2.42 (m, 2H), 1.80−1.69
(m, 2H), 1.74−1.57 (m, 2H); 13C NMR (D2O, 100 MHz) δ 72.2,
69.6, 66.5, 64.8, 55.0, 53.2, 24.4, 22.6; LR-MS (FAB+) m/z 174 (M +
H+); HR-MS (FAB+) calcd for C8H16NO3 (M + H+) 174.1130, found
174.1130.
νmax 2954, 2930, 2885, 2858, 1666, 1471, 1425, 1362, 1338 cm−1; H
1
NMR (CD3OD, 400 MHz, mixture of rotamers) δ 6.45 (m, 1H), 6.47
(m), 4.96 (dd, 1H, J = 11.9, 8.5 Hz), 4.87 (dd), 4.41 (m, 1H), 4.54
(m), 4.24 (s, 2H), 4.33 (m), 3.50−3.41 (m, 2H), 3.56−3.48 (m),
2.05−1.83 (m, 2H), 2.16−2.07 (m), 1.91−1.74 (m, 2H), 1.69−1.66
(m), 0.92 (m, 18H), 0.16 (s, 3H), 0.13 (s, 3H), 0.11 (m, 6H); 13C
NMR (CD3OD, 75 MHz, mixture of rotamers) δ 172.9/172.0, 144.8/
145.3, 112.9/112.3, 64.8/65.4, 57.4/57.7, 48.2/47.3, 36.0/33.2, 27.2/
27.2, 27.2/27.2, 27.2/27.2, 26.9/29.9, 26.9/26.9, 26.9/26.9, 23.4/25.8,
20.2/20.1, 19.9, −4.3, −4.3, −4.4, −4.4; LR-MS (FAB+) m/z 400 (M
C
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The Journal of Organic Chemistry
Note
(S,Z)-tert-Butyl 2-(2-(tert-Butyldimethylsilyloxy)vinyl)-
pyrrolidine-1-carboxylate (12). To a solution of sodium hydride
(940 mg, 23.5 mmol, 60% dispersion in paraffin liquid) in THF (10
mL) was slowly added a solution of the aldehyde 7 (833 mg, 3.91
mmol) in THF (30 mL) and TBSCl (2.95 g, 19.6 mmol) at −78 °C.
After being stirred for 1 h at ambient temperature, the reaction mixture
was quenched with H2O and then extracted with EtOAc (2 × 20 mL).
The combined organic layers were dried over MgSO4 and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc/n-hexane = 1:10) to afford 1.06
g (83%) of the (Z)-silyl enol ether 12 as a colorless oil: [α]2D3 33.5 (c
1.00, CHCl3); FT-IR (thin film, neat) νmax 3037, 2957, 2930, 2884,
2859, 2712, 1698, 1657, 1473, 1462, 1392, 1364, 1343, 1321 cm−1; 1H
NMR (CDCl3, 300 MHz) δ 6.07 (d, 1H, J = 5.7 Hz), 4.62 (m, 1H),
4.46 (brs, 1H), 3.33 (m, 2H), 2.08−1.77 (m, 2H), 1.80 (m, 2H), 1.40
(s, 9H), 0.89 (s, 9H), 0.09 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ
154.6, 137.7, 113.4, 78.6, 52.6, 46.1, 33.5, 28.5, 28.5, 28.5, 25.5, 25.5
25.5, 23.6, 18.2, −5.3, −5.6; LR-MS (FAB+) m/z 328 (M + H+); HR-
MS (FAB+) calcd for C17H34NO3Si (M + H+) 328.2308, found
328.2303.
(6S,7S,8R,8aR)-6,7,8-Trihydroxyhexahydroindolizin-5(1H)-
one (13). To a solution of the azoninone 4 (104 mg, 260 μmol) in
MeOH (6 mL) and H2O (2 mL) was added Oxone (400 mg, 1.30
mmol) at ambient temperature. After being stirred for 24 h at the same
temperature, the reaction mixture was concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(MeOH/CH2Cl2 = 1:10) to afford 28.7 mg (59%) of the triol 13 as
pale yellow solid: mp 78−80 °C; [α]2D2 16.3 (c 1.10, MeOH); FT-IR
(thin film, neat) νmax 3384, 2975, 2919, 2886, 1652, 1480, 1461, 1391,
1340 cm−1; 1H NMR (CD3OD, 500 MHz) δ 4.21 (d, 1H, J = 3.8 Hz),
3.90 (t, 1H, J = 3.8 Hz), 3.53 (m, 1H), 3.49 (m, 1H), 3.44−3.34 (m,
2H), 2.37−1.93 (m, 2H), 1.89−1.71 (m, 2H); 13C NMR (CD3OD, 75
MHz) δ 171.8, 77.6, 77.0, 71.6, 62.7, 47.1, 33.7, 24.8; LR-MS (FAB+)
m/z 188 (M + H+); HR-MS (FAB+) calcd for C8H14NO4 (M + H+)
188.0923, found 188.0921.
(6S,7S,8R,8aR)-5-Oxooctahydroindolizine-6,7,8-triyl Triace-
tate (14). To a solution of the triol 13 (70.0 mg, 374 μmol) in
pyridine (10 mL) was added acetic anhydride (0.3 mL, 3.74 mmol) at
ambient temperature. After stirring for 13 h at the same temperature,
the reaction mixture was concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (EtOAc/n-
hexane = 1:3 to 1:1) to afford 91.4 mg (78%) of the triacetate 14 as a
pale yellow oil: [α]2D4 21.9 (c 1.31, CHCl3); FT-IR (thin film, neat)
νmax 3482, 2956, 2888, 1751, 1692, 1447, 1371 cm−1; 1H NMR
(CDCl3, 300 MHz) δ 5.49 (d, 1H, J = 4.0 Hz), 5.38 (t, 1H, J = 3.5
Hz), 4.83 (dd, 1H, J = 8.0, 3.0 Hz), 3.58 (m, 2H), 3.50 (m, 1H), 2.27−
1.91 (m, 2H), 2.14 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H), 1.81 (m, 2H);
13C NMR (CDCl3, 75 MHz) δ 169.9, 169.5, 169.5, 163.1, 73.9, 72.1,
(S,Z)-2-(tert-Butyldimethylsilyloxy)-1-(2-(2-(tert-
butyldimethylsilyloxy)vinyl)pyrrolidin-1-yl)ethanone (6). To a
solution of the (Z)-silyl enol ether 12 (1.53 g, 4.67 mmol) in CH2Cl2
(30 mL) were added 2,6-lutidine (1.1 mL, 9.34 mmol) and TMSOTf
(1.3 mL, 7.01 mmol) at 0 °C. After being stirred for 2 h at ambient
temperature, the reaction mixture was quenched with MeOH and then
concentrated in vacuo. This crude mixture was used for next step
without further purification. To a solution of the crude amine and the
acid 8 (1.33 g, 7.01 mmol) in CH2Cl2 (50 mL) were added 1-
hydroxybenzotriazole hydrate (695 mg, 5.14 mmol), 4-methylmorpho-
line (1.1 mL, 10.3 mmol), and EDCI (1.34 g, 7.01 mmol) at ambient
temperature. After being stirred for 18 h at the same temperature, the
reaction mixture was quenched with H2O. The aqueous layer was
extracted with CH2Cl2 (2 × 60 mL), and the combined organic layers
were dried over MgSO4 and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (EtOAc/n-
hexane = 1:5) to afford 1.12 g (60%) of the amide 6 as a colorless oil:
[α]2D0 90.2 (c 0.100, MeOH); FT-IR (thin film, neat) νmax 2954, 2930,
68.3, 58.2, 45.2, 31.9, 22.9, 20.8, 20.7, 20.6; LR-MS (FAB+) m/z 314
(M + H+); HR-MS (FAB+) calcd for C14H20NO7 (M + H+) 314.1240,
found 314.1237.
1-Deoxy-6-epi-castanospermine (2). To a solution of lithium
aluminum hydride (41.4 mg, 1.09 mmol) in THF (5 mL) was added a
solution of the triacetate 14 (34.0 mg, 109 μmol) in THF (5 mL) at 0
°C. After being stirred for 8 h at 60 °C, the reaction mixture was
quenched with H2O and NaOH (10%). The resulting mixture was
dried over MgSO4 at 0 °C and filtered under reduced pressure. The
organic layer was concentrated in vacuo and the residue was purified
by flash column chromatography on silica gel (MeOH/CH2Cl2
=
1
2885, 2857, 1667, 1650, 1462, 1426, 1342 cm−1; H NMR (CD3OD,
1:10) to afford 15.5 mg (82%) of 1-deoxy-6-epi-castanospermine 2 as a
colorless solid: mp 123−125 °C; [α]2D3 −25.2 (c 0.250, MeOH); FT-IR
(thin film, neat) νmax 3364, 2924, 2853, 2809, 1745, 1660, 1648, 1567,
1412, 1339 cm−1; 1H NMR (D2O, 400 MHz) δ 3.96 (brs, 1H), 3.49 (t,
1H, J = 9.1 Hz), 3.43 (dd, 1H, J = 9.5, 3.5 Hz), 3.04 (dd, 1H, J = 12.7,
2.4 Hz), 2.93 (m, 1H), 2.26 (d, 1H, J = 12.6 Hz), 2.17 (q, 1H, J = 9.2
Hz), 1.97 (m, 2H), 1.75 (m, 2H), 1.50 (m, 1H); 13C NMR (D2O, 75
MHz) δ 75.9, 73.6, 69.8, 68.4, 55.8, 53.9, 28.2, 21.8; LR-MS (FAB+)
m/z 174 (M + H+); HR-MS (FAB+) calcd for C8H16NO3 (M + H+)
174.1130, found 174.1128.
400 MHz) δ 6.33 (d, 1H, J = 5.6 Hz), 4.56 (dd, 1H, J = 9.1, 5.8 Hz),
4.32 (s, 2H), 3.47 (m, 2H), 2.15 (m, 1H), 2.00−1.81 (m, 2H), 1.93−
1.74 (m, 2H), 0.96 (s, 9H), 0.91 (s, 9H), 0.19 (s, 6H), 0.09 (s, 6H);
13C NMR (CD3OD, 75 MHz) δ 172.8, 141.6, 112.4, 64.3, 53.5, 48.0,
35.7, 27.2, 27.2, 27.2, 26.9, 26.9, 26.9, 24.0, 20.2, 19.9, −4.2, −4.3,
−4.3, −4.6; LR-MS (FAB+) m/z 400 (M + H+); HR-MS (FAB+)
calcd for C20H42NO3Si2 (M + H+) 400.2703, found 400.2702.
(3S,4S,E)-3,4-Bis(tert-butyldimethylsilyloxy)-3,4,8,9-tetrahy-
dro-1H-azonin-2(7H)-one (4). To a solution of the amide 6 (56.6
mg, 142 μmol) in benzene (60 mL) was added lithium
diisopropylamide (142 μL, 284 μmol, 2.0 M in THF). The reaction
mixture and a magnetic bar were sealed in the reaction vessel of a
Discover monomode microwave apparatus (CEM) and irradiated for
1.5 h at 150 °C. The reaction mixture was quenched with H2O at
ambient temperature. The aqueous layer was extracted with EtOAc (2
× 70 mL), and the combined organic layers were dried over MgSO4
and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc/n-hexane = 1:10) to afford 11.9
mg (21%) of the azoninone 4 as a pale yellow oil: [α]2D1 20.2 (c 0.825,
CHCl3); FT-IR (thin film, neat) νmax 3428, 3394, 2953, 2928, 2857,
2739, 2710, 1736, 1686, 1651, 1514, 1470, 1409, 1389, 1362, 1344
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ygsuh@snu.ac.kr.
■
Notes
1
cm−1; H NMR (CDCl3, 300 MHz) δ 6.07 (d, 1H, J = 8.4 Hz), 5.55
The authors declare no competing financial interest.
(m, 1H), 5.44 (dd, 1H, J = 16.8, 8.1 Hz), 4.26 (dd, 1H, J = 8.3, 3.2
Hz), 4.15 (d, 1H, J = 3.3 Hz), 3.72−2.93 (m, 2H), 2.20 (m, 2H),
1.94−1.50 (m, 2H), 0.89 (s, 9H), 0.86 (s, 9H), 0.12 (s, 3H), 0.06 (s,
3H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (C6D6, 75 MHz) δ 175.0,
131.8, 131.1, 79.6, 77.5, 40.0, 29.3, 28.1, 26.3, 26.3, 26.3, 25.9, 25.9,
25.9, 18.6, 18.5, −4.3, −4.4, −4.4, −5.4; LR-MS (FAB+) m/z 400 (M
+ H+); HR-MS (FAB+) calcd for C20H42NO3Si2 (M + H+) 400.2703,
found 400.2701.
ACKNOWLEDGMENTS
■
This work was supported by a National Research Foundation of
Korea (NRF) grant funded by the Korean government
(MEST) (No. 20100028431) and a National Research
Foundation of Korea Grant funded by the Korean government
(MEST) (NRF-C1ABA001-2010-0020428).
D
dx.doi.org/10.1021/jo300309z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
namic isomers. We might have not identified the kinetic isomer of 4
because of the rapid conformational relaxation under the harsh
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dx.doi.org/10.1021/jo300309z | J. Org. Chem. XXXX, XXX, XXX−XXX