Epimerization of C5 of an: N -hydroxypyrrolidine in the synthesis of swainsonine related iminosugars

Article abstract of DOI:10.1039/c6ob00531d

Epimerization of C5 of an N-hydroxypyrrolidine ring by regioselective oxidation to a nitrone followed by diastereoselective reduction provides a new approach to the synthesis of swainsonine and related compounds. The only protection in the synthesis of the potent mannosidase inhibitor DIM (1,4-dideoxy-1,4-imino-d-mannitol) was the acetonation of d-mannose.

Full text of DOI:10.1039/c6ob00531d

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Epimerization of C5 of an N-hydroxypyrrolidine in
the synthesis of swainsonine related iminosugars†
Cite this: DOI: 10.1039/c6ob00531d
Bao-Chen Qian,a,e Akiko Kamori,b Kyoko Kinami,b Atsushi Kato,*b Yi-Xian Li,a
George W. J. Fleetc,d and Chu-Yi Yu*a,d
Received 10th March 2016,
Accepted 14th April 2016
Epimerization of C5 of an N-hydroxypyrrolidine ring by regioselective oxidation to a nitrone followed by
diastereoselective reduction provides a new approach to the synthesis of swainsonine and related com-
pounds. The only protection in the synthesis of the potent mannosidase inhibitor DIM (1,4-dideoxy-1,4-
imino-D-mannitol) was the acetonation of D-mannose.
DOI: 10.1039/c6ob00531d
www.rsc.org/obc
dase II,8 and may be useful in the treatment of cancer and
Introduction
other diseases.9 There are many syntheses of swainsonine(1)10
The biological properties of iminosugars, especially their and its analogues11 such as 8a-epi-swainsonine (2)10e,12
glycosidase inhibition, make them attractive synthetic targets.1 (Fig. 1). 1,4-Dideoxy-1,4-imino-D-mannitol (DIM, 3),13 the pyr-
Mannosidase inhibitors have potential in the treatment of rolidine equivalent of mannofuranose, is almost as potent an
many diseases, including cancer, HCV and HIV.2 Polyhydroxy- inhibitor of α-mannosidase as is swainsonine. The synthesis of
lated indolizidine alkaloids, conformationally restricted pyrrol- swainsonine from mannose requires the introduction of nitro-
idine equivalents of furanoses, are
a
subclass of gen with retention at C4 of mannose; in all previous syntheses,
iminosugars.3 Swainsonine (1) (Fig. 1), first isolated from the this has been done before the formation of the pyrrolidine
fungal plant pathogen Rhizoctonia leguminicola4 in 1973 and ring. In the context of our interest in iminosugars,14 we have
later from Swainsona canescens5 and other sources,6 is a potent developed a novel approach which provides the first example
inhibitor of lysosomal α-mannosidase4b,7 and Golgi mannosi- in which the stereochemistry is adjusted after the formation of
the pyrrolidine ring. In particular, this provides a short syn-
thesis of DIM with only acetonide protection; subsequent
manipulation allows access to other targets. There are many
advantages in the use of sugar-derived cyclic nitrones as start-
ing materials for the aim of developing an efficient and flexible
synthesis of DIM (3), swainsonine (1) and related compounds.
The synthesis of swainsonine (1) and DIM (3) is outlined in
Fig. 2. The pyrrolidine ring in the cyclic nitrone 10, available
on a large scale in 43% yield from D-mannose, requires inver-
sion at C5 for the construction of swainsonineand DIM. Repla-
Fig. 1 Swainsonine and related compounds.
cement of 10 with cyclic nitrones derived from various other
sugars as starting materials would provide a diverse synthesis
of iminosugars via similiar synthetic routes. Sugar-derived
cyclic nitrones can be prepared on multi-gram scales from
almost any aldose and have proven to be effective building
blocks for the synthesis of iminosugars.14a–c,15 Furthermore,
the nitrone functionality in the pyrrolidine ring can undergo a
variety of chemical reactions which provides the possibility of
diverse construction of the pyrrolidine ring with various sub-
stituents and stereochemistries.
The key steps of the synthesis involve epimerization of C5
of the nitrone 10: (i) regioselective oxidation of N-hydroxypyrrol-
idine (9) to nitrone (8), followed by (ii) diastereoselective
reduction of nitrone (8) to N-hydroxypyrrolidine (7).16
aBeijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of
Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China. E-mail: yucy@iccas.ac.cn
bDepartment of Hospital Pharmacy, University of Toyama, 2630 Sugitani,
Toyama 930-0194, Japan. E-mail: kato@med.u-toyama.ac.jp
cChemistry Research Laboratory, Department of Chemistry, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, UK
dNational Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal
University, Nanchang 330022, PR China
eUniversity of Chinese Academy of Sciences, Beijing 100049, China
†Electronic supplementary information (ESI) available: Copies of 1H, 13C and 2D
NMR spectra, data of crystal structure and results of the bioassay. CCDC
1455389. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c6ob00531d
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Scheme 1 Reagents and conditions: (a) NaBH4, MeOH, 0 °C, 89%; (b)
MnO2, CH2Cl2, rt, 95% total yield.
amine in hand, we explored an efficient and regioselective oxi-
dation method for the transformation of 9 to the desired cyclic
nitrone 8. After several attempts with different oxidation
methods and conditions, oxidation of 9 with MnO2 at room
temperature was optimal, yielding the expected nitrone 8
together with nitrone 10 in high total yield (95%) with accept-
able regioselectivity (a ratio of 8/10 = 3 : 1).14c,18
The next task was the reduction of nitrone 8 into the
desired pyrrolidine. Catalytic hydrogenation was first
attempted for the reduction of nitrone 8 and was expected to
give the pyrrolidine 11 smoothly. However, Pd-catalyzed hydro-
genation of 8 unexpectedly resulted in a complicated mixture
of products, especially when the reaction was conducted on
gram-scale. Accordingly nitrone 8 was treated with NaBH4 in
methanol at 0 °C, which afforded manno-pyrrolidine hydroxyl-
amine 7 in excellent yield (94%) and high diastereoselectivity.
Manno-7 was the only product; none of the epimeric talo-9 was
formed (Scheme 2).
Fig. 2 Retrosynthesis of swainsonine.
Reduction of 7 followed by deprotection gives DIM (3) in
which the only protecting step was the acetonation of
mannose. Selective deprotection and homologation of the side
chain of the pyrrolidine 6, and subsequent chemical manipu-
lations provide access to swainsonine. The syntheses of 8a-epi-
swainsonine (2) and its equivalent monocyclic pyrrolidine ana-
logue 22 are also reported. The side-by-side comparison of
glycosidase inhibition of swainsonine (1) and its epimer 2 with
those of their monocyclic equivalents, DIM (3) and its epimer
22, was studied.
Reduction of 7 with zinc powder and Cu(OAc)2 in acetic
acid and subsequent installation of Cbz protecting group gave
the fully protected pyrrolidine 12 in good total yield (89%).
Selective cleavage of the side-chain acetonide (Scheme 2)
exposed the 6,7-diol for further regio-selective modification.
The acetonide on the side-chain was selectively removed by 1%
H2SO4-MeOH system19 at room temperature to afford diol 1320
together with tetrahydroxylated pyrrolidine 14 in moderate
yield (52% and 6.5%, respectively). The structure of 14 was
confirmed by X-ray crystallographic analysis (Fig. 3, and
Results and discussion
The starting polyhydroxylated cyclic nitrone 10 was prepared ESI†).21 Finally, Pd-catalyzed hydrogenation of 14 produced
according to the reported method from D-mannose in six steps DIM (3) in 88% yield.
with an overall yield of 43%.17 In comparison with swainso-
Homologation of the side-chain of diol 13 required the
nine (1), it can be seen that nitrone 10 bears all stereocenters selective exposure of the primary hydroxyl group (Scheme 2).
of swainsonine (1) except that at C5 position, which is corre- Thus, the primary hydroxyl group was first selectively protected
lated to the C8a position of swainsonine. Therefore, inversion by TBS group and then the secondary hydroxyl group was
of the configuration at C5 of nitrone 10 is necessary for the etherified with chloromethylmethylether to give 6 in good
construction of the bicyclic indolizidine skeleton of swainso- yield (76% in two steps). Selective cleavage of the TBS protect-
nine (1) with the correct C8a configuration. The synthesis ing group gave the free primary alcohol 15. The usual
started with the reduction of nitrone 10 (Scheme 1). Reduction methods, i.e. TBAF and KF, for the selective removal of TBS
of nitrone 10 with NaBH4 at 0 °C in methanol resulted in the protection resulted in the formation of bicyclic compound 16
formation of hydroxylamine 9 in 89% yield. With the hydroxyl- (Table 1). The unexpectedly easy formation of the bicyclic
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compound 16 may be due to the relatively strong basic reaction
conditions. It was necessary to use neutral or weak acidic
reagents. Olah’s reagent [pyridinium poly(hydrogen fluoride)]
with 6 gave the desired alcohol 15 in good yield.22
Subsequent oxidation of the alcohol 15 with Dess–Martin
periodinane gave the aldehyde which was used directly in the
Wittig olefination with methyl 2-(triphenylphosphoranylidene)
acetate to afford the unsaturated ester 5. After being separated
from triphenylphosphine oxide by recrystallization, crude 5
was used in the next step without further purification. The
catalytic hydrogenation and cyclization of 5 were performed in
a one-pot reaction; the cyclization gave the δ-lactam 17 after
Scheme 2 Reagents and conditions: (a) NaBH4, MeOH, 0 °C, 94%; (b)
Zn, Cu(OAc)2, AcOH, rt; (c) CbzCl, NaHCO3, THF–H2O (20 : 1), 89% for 2
steps; (d) 1% H2SO4(w/w), MeOH, rt, 52% for 13; (e) Pd/C, H2, MeOH,
88%; (f) TBSCl, Et3N, CH2Cl2; (g) MOMCl, DIPEA, CH2Cl2, 0 °C to rt, 76%
in 2 steps.
Scheme 3 Reagents and conditions: (a) DMP (Dess–Martin periodi-
nane), NaHCO3, CH2Cl2, rt; (b) Ph3P = CHCO2Me, toluene, reflux; (c) Pd/
C, H2, MeOH then K2CO3, 79% in 3 steps; (d) 3 N HCl, MeOH, 97%; (e)
LiAlH4, THF, reflux; (f) 3 N HCl, MeOH, 74% in 2 steps.
Fig. 3 X-Ray crystal structure of 14.
Table 1 Conditions for selective deprotection of 6
Reagent
Temperature (°C)
Product
Yield (%)
TBAF
TBAF
0
rt
0
16
16
16
15
97
92
86
91
KF
Olah’s reagenta
rt
Scheme 4 Reagents and Conditions (a) Zn, Cu(OAc)2, AcOH, rt; (b)
CbzCl, NaHCO3, THF–H2O (20 : 1), 87% in 2 steps; (c) 1% H2SO4(w/w),
MeOH, rt, 69% for 20; (d) Pd/C, H2, MeOH, 81%.
a Olah’s reagent = pyridinium poly(hydrogen fluoride).
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the addition of potassium carbonate in excellent total yield
(79% in three steps). Removal of the acetonide and methoxy-
methyl protecting groups provided the polyhydroxylated
δ-lactam 18 in 97% yield. Then, reduction of δ-lactam 17 with
LiAlH4 yielded the tertiary amine 4 together with impurities
which were difficult to remove. Accordingly, crude 4 was
treated directly with HCl–MeOH solution to give the target
final product swainsonine (1). Purification of the crude
product with acidic ion exchange resin produced pure swainso-
nine (1) in 74% yield in two steps. Thus, swainsonine (1) was
synthesized starting from cyclic nitrone 10 with an overall
yield of 12.5%. The structure of swainsonine (1) was confirmed
by spectroscopic data and its relative configuration was further
confirmed by NOESY experiment of 18 (see ESI†) (Scheme 3).
The synthesis of 8a-epi-swainsonine (2) was achieved via a
similar route (Scheme 4). Hydroxylamine 9, obtained from the
reduction of nitrone 10, was treated with zinc powder and
cupric acetate monohydrate to give secondary cyclic amine,
which was then protected with Cbz group to give 19 in 87%
yield (two steps). Selective cleavage of the side-chain acetonide
afforded 5,6-diol 20 in 69% yield together with the by-product
21 (with a ratio of 20/21 = 15 : 1). Removal of protecting group of
21 gave pyrrolidine iminosugar 22,23 the C5-talo epimer of DIM.
Diol 20 was selectively protected with TBS and MOM
groups respectively to yield 23 in 79% total yield in two steps
Scheme 5 Reagents and Conditions: (a) TBSCl, Et3N, CH2Cl2; (b)
MOMCl, DIPEA, CH2Cl2, 0 °C to rt, 79% in 2 steps; (c) TBAF, THF, 97%; (d)
DMP, NaHCO3, CH2Cl2, rt; (e) Ph3P = CHCO2Me, toluene, reflux; (f) Pd/
C, H2, MeOH, 63% in 3 steps; (g) 3 N HCl, MeOH, 99%; (h) LiAlH4, THF,
reflux, 92%; (i) 3 N HCl, MeOH, 94%.
Table 2 The glycosidase inhibition of swainsonine (1), DIM (3) and related compounds (2, 18, 22 and 26)
IC50 (μM)
Enzyme
α-Glucosidase
Yeast
NIa (0.3%)b
NI (45.3%)
NI (42.9%)
NI (5.4%)
NI (0%)
NI (6.8%)
NI (13.4%)
NI (3.7%)
NI (17.4%)
NI (5.6%)
NI (3.4%)
NI (4.2%)
68
NI (4.9%)
NI (17%)
NI (28.1%)
Rice
NI (38.7%)
NI (31.6%)
Rat intestinal maltase
β-Glucosidase
Almond
NI (1.2%)
NI (30.3%)
NI (6.6%)
595
NI (0%)
NI (36.8%)
NI (6.2%)
NI (0%)
NI (20.2%)
NI (20.5%)
NI (40.8%)
NI (37.2%)
Bovine liver
α-Galactosidase
Coffee beans
β-Galactosidase
Bovine liver
α-Mannosidase
Jack bean
NI (1.8%)
546
NI (0%)
491
NI (0%)
1000
NI (0%)
NI (17.9%)
625
NI (35.7%)
NI (46.8%)
3.9
NI (7.4%)
NI (14.6%)
213
0.73
NI (3.8%)
NI (0%)
NI (2.4%)
NI (2.9%)
NI (0%)
NI (0%)
71
β-Mannosidase
Snail
NI (0%)
NI (0%)
NI (4.3%)
NI (9.3%)
NI (4.9%)
NI (0%)
NI (16.3%)
NI (4.8%)
NI (0%)
NI (26.1%)
NI (2.2%)
NI (8.3%)
NI (3.9%)
NI (0%)
NI (3.6%)
NI (6.4%)
NI (33.2%)
NI (2.8%)
NI (0%)
NI (1.2%)
NI (29.4%)
NI (9.6%)
NI (3.8%)
NI (1.6%)
α-L-Fucosidase
Bovine kidney
α,α-Trehalase
Porcine kidney
Amyloglucosidase
Aspergillus niger
α-L-Rhamnosidase
Penicillium decumbens
β-Glucuronidase
E. coli
NI (19.1%)
NI (0.7%)
NI (6.5%)
NI (11.5%)
NI (0%)
NI (17.7%)
NI (0%)
NI (0.4%)
NI (13.8%)
542
NI (22.3%)
NI (0%)
NI (23.8%)
Bovine liver
a NI: no inhibition (less than 50% inhibition at 1000 μM). b ( ): inhibition at 1000 μM.
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(Scheme 5). As in the synthesis of swainsonine (1), cleavage Analytical TLC was performed with 0.20 mm silica gel 60F
of TBS group was then performed. In contrast to the plates with 254 nm fluorescent indicator. TLC plates were visu-
synthesis of swainsonine (1), the TBS group was removed alized by ultraviolet light or by treatment with a spray of Pan-
easily with TBAF to give the alcohol 24 in 97% yield; base caldi reagent {(NH4)6MoO4, Ce(SO4)2, H2SO4, H2O}.
induced closure to a lactam did not occur in the epimeric Chromatographic purification of products was carried out by
series.
flash column chromatography on silica gel (230–400 mesh).
Homologation of the side-chain of 24 and the subsequent Acidic ion exchange chromatography was performed on
hydrogenation gave the key intermediate 25 in 63% yield Amberlite IR-120 (H+) or Dowex 50 W × 8–400, H+ form.
(three steps). Treatment of 25 with HCl–MeOH solution pro- Melting points were determined using an electrothermal
duced polyhydroxylated δ-lactam 26 in quantitative yield. The melting point apparatus. Infrared spectra were recorded on an
reduction of 25 with LiAlH4 gave the precursor of 8a-epi-swain- FT-IR spectrometer. NMR spectra were recorded on magnetic
sonine 27 in 92% yield. The indolizidine 27 could be purified resonance spectrometers (1H at 300 MHz, 400 MHz or
easily. Finally, acidic hydrolysis of 27 with HCl–MeOH solution 500 MHz, 13C at 75 MHz, 100 MHz or 125 MHz) in CDCl3
provided 8a-epi-swainsonine (2) as a white solid in 94% yield.
(with TMS as internal standard), D2O or CD3OD. Chemical
The fully-deprotected iminosugars prepared were evaluated shifts (δ) are reported in ppm, and coupling constants (J) are
against a number of glycosidases (Table 2, for complete results in Hz. High resolution mass spectra (HRMS) were recorded on
of bioassay, see ESI†). For the first time a side by side compari- an LTQ/FT linear ion trap mass spectrometer. Polarimetry
son of swainsonine (1) and its 8a-epimer 2 and of each with measurements were made at the sodium D-line with a 0.5 dm
their pyrrolidine equivalents of the parent manno- and talo-fur- path length cell. Concentrations (c) are given in gram per
anoses is presented. 8a-epi-Swainsonine (2) is also α-manno- 100 mL.
sidase inhibitor, though the inhibition potency was about 100-
fold lower than that of swainsonine (1). DIM (3) is comparable D-talitol (9). Sodium borohydride (3.1 g, 80 mmol) was added
potent inhibitor against Jack bean mannosidase (IC50 to a solution of nitrone 10 (5 g, 20 mmol) in methanol in
N-Hydroxyl-2,3,5,6-di-O-isopropylidene-1,4-dideoxy-1,4-imino-
=
3.9 μM), whereas it also showed moderate inhibition against small portions at 0 °C. The mixture was stirred for 2 hours at
yeast α-glucosidase and E. coli β-glucuronidase, with IC50 the same temperature then the reaction was quenched with
values 68 and 542 μM, respectively. 4-epi-DIM (22) is a much saturated NH4Cl and the methanol was removed in vacuo. The
weaker inhibitor of Jack bean mannosidase (IC50 = 213 μM) residue was redissolved in water (15 mL) and extracted with
than DIM (3).24 Amide 18 showed no inhibition of α-manno- EtOAc (10 mL × 3). The combined organic layers were dried
sidase but was a weak inhibition of bovine liver β-glucosidase with MgSO4 and concentrated. The white crystalline product
(IC50 = 595 μM) and β-galactosidase (IC50 = 491 μM). In con- (4.3 g, 89%) was then employed for the next step without
trast, 26 did not show inhibition against these enzymes but further purification 9: m.p. 83–85 °C: [α]2D0 = −29 (c = 1.0,
showed weak inhibition against Jack bean mannosidase (IC50 CH2Cl2); IR (thin film, cm−1) 3419, 2986, 2938, 1373, 1210,
= 625 μM).
1059, 850; 1H NMR (300 MHz, CDCl3) δ 4.75 (q, J = 5.9 Hz, 1H),
4.43 (dd, J = 6.7, 5.4 Hz, 1H), 4.30 (q, J = 6.5 Hz, 1H), 4.10 (dd,
J = 8.4, 6.5 Hz, 1H), 3.94 (dd, J = 8.4, 6.4 Hz, 1H), 3.62 (dd, J =
11.9, 5.9 Hz, 1H), 3.18–3.13 (m, 2H), 1.67 (br, 1H), 1.53 (s, 3H),
1.46 (s, 3H), 1.37 (s, 3H), 1.32 (s, 3H); 13C NMR (75 MHz,
Conclusions
In summary, inversion of C5 in a pyrrolidine provides a new CDCl3) δ 114.1, 109.6, 80.8, 78.5, 75.5, 75.2, 66.3, 63.7, 27.2,
strategy for the synthesis of iminosugars such as swainsonine 26.6, 25.3, 24.8; HRMS calcd for [C12H21NO5H+] 260.1492,
(1) starting from sugar-derived cyclic nitrone 10. Swainsonine found 260.1491.
(1) was synthesized in 12 steps with overall yield of 12.5%.
(3R,4S)-5-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3,4-O-isopropyl-
Additionally, swainsonine related compounds (2, 3, 18, 22 and idene-3,4-dihydroxy-3,4-dihydro-2H-pyrrole 1-oxide (8). Active
26) were also synthesized. This synthetic approach provides a manganese dioxide (2.4 g, 28 mmol) was added to a solution
versatile approach to the synthesis of compounds related to of 9 (3.5 g, 13.5 mmol) in CH2Cl2 (30 mL). The suspension
swainsonine (1), which will be valuable for future study of the liquid was stirred for 48 hours at room temperature. Then the
structure–activity relationship (SAR) of swainsonine-related mixture was filtered through a celite pad and the residue was
compounds.
washed with CH2Cl2. The eluent was concentrated and the
residue was purified by column chromatography with CH2Cl2
to give 8 (2.5 g, 72%) and EtOAc/petroleum ether (1 : 1) to give
10 (0.8g, 23%)as white crystals. 8: m.p. 92–95 °C; [α]2D0 = +16
(c = 0.5, CH2Cl2); IR (thin film, cm−1) 2988, 2350, 1599, 1374,
Experimental
General methods
1
1207, 1038, 852, 699; H NMR (300 MHz, CDCl3) δ 5.37 (d, J =
All reagents were obtained commercially or prepared as 6.5 Hz, 1H), 5.16–5.11 (m, 1H), 4.88–4.84 (m, 1H), 4.45 (dd, J =
described in the literature. Reactions sensitive to moisture 9.0, 7.2 Hz, 1H), 4.21–4.14 (m, 2H), 4.11–4.05 (m, 1H), 1.51 (s,
were carried out under an inert atmosphere (Ar). Reactions 3H), 1.48 (s, 3H), 1.4 3 (s, 3H), 1.41 (s, 3H); 13C NMR (125 MHz,
were stirred using Teflon-coated magnetic stirring bars. CDCl3) δ 145.0, 112.3, 110.4, 81.0, 71.8, 71.3, 68.3, 66.8, 27.1,
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26.0, 25.5, 24.8; HRMS calcd for [C12H19NO5Na+] 280.1155, to a solution of 12 (5.1 g, 13.5 mmol) in methanol (25 mL) at
found 280.1151. room temperature, the mixture was stirred overnight. The reac-
N-Hydroxyl-2,3,5,6-di-O-isopropylidene-1,4-dideoxy-1,4-imino- tion was neutralized with aqueous NaHCO3 and methanol was
D-mannitol (7). Sodium borohydride (1.1 g, 29 mmol) was removed in vacuo. The residue was extracted with EtOAc
added to a solution of 8 (1.8 g, 0.7 mmol) in methanol in (15 mL × 3) and the combined organic layers were dried
small portions at 0 °C. The mixture was stirred for 2 hours at (MgSO4). The residue was purified by column chromatography
the same temperature, then the reaction was quenched with with EtOAc/petroleum ether (1 : 3) to give 13 (2.4 g, 52%) and
saturated NH4Cl and the methanol was removed in vacuo. The 14 (0.3 g, 6.5%) as clear oil. 13 [α]2D0 = −30 (c = 1.0, CH2Cl2); IR
residue was redissolved in water (5 mL) and extracted with (thin film, cm−1) 3447, 2940, 1670, 1685, 1419, 1212, 1084,
1
EtOAc (5 mL × 3). The combined organic layers were dried 869; H NMR (300 MHz, CDCl3) δ 7.39–7.28 (m, 5H), 5.14 (d,
with MgSO4 and concentrated. The product (1.7 g, 94%) was J = 12.3 Hz, 1H), 5.09 (d, J = 12.3 Hz, 1H), 4.90 (dd, J = 6.8 Hz,
employed for the next step without further purification as 1H), 4.76 (ddd, J = 11.8, 7.0, 4.7 Hz, 1H), 4.19 (dd, J = 7.5 Hz,
white crystal.7: m.p. 79–83 °C; [α]2D0 = −70 (c = 1.0, CH2Cl2); IR 1H), 4.04 (dd, J = 10.7, 7.0 Hz, 1H), 3.97–3.83 (m, 1H),
(thin film, cm−1) 3183, 2988, 2939, 2877, 1701, 1380, 1211, 3.77–3.64 (m, 2H), 3.59 (dt, J = 12.2, 3.9 Hz, 1H), 3.47 (br, 1H),
1104, 1064, 849; 1H NMR (300 MHz, CDCl3) δ 6.22 (s, 1H), 4.72 3.29 (dd, J = 12.5, 4.6 Hz, 1H), 1.54 (s, 3H), 1.35 (s, 3H); 13C
(dd, J = 6.6, 5.2 Hz, 1H), 4.64 (dd, J = 6.6, 4.8 Hz, 1H), 4.39 (q, NMR (75 MHz, CDCl3) δ 155.6, 135.9, 128.6, 128.4, 128.2,
J = 6.4 Hz, 1H), 4.20 (dd, J = 8.5, 6.5 Hz, 1H), 4.11 (dd, J = 8.5, 113.9, 80.0, 78.2, 76.7, 71.1, 67.8, 63.3, 59.9, 50.6, 26.3, 24.8;
6.1 Hz, 1H), 3.52 (d, J = 11.1 Hz, 1H), 2.75 (dd, J = 11.3, 4.8 Hz, HRMS calcd for [C17H23NO6Na+] 360.1418, found 360.1413;
1H), 2.71 (dd, J = 7.8, 5.1 Hz, 1H), 1.45 (s, 3H), 1.44 (s, 3H), 14 [α]2D0 = −42 (c = 1.0, CH2Cl2); IR (thin film, cm−1) 3348,
1.41 (s, 3H), 1.30 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 110.5, 2940, 1682, 1417, 1357, 1211, 1102, 890; 1H NMR (400 MHz,
108.3, 77.7, 74.9, 74.3, 72.0, 67.7, 63.3, 26.8, 25.6, 25.5, 23.9; CD3OD) δ 7.44–7.26 (m, 5H), 5.15 (s, 2H), 4.38 (dd, J = 6.8, 4.8
HRMS calcd for [C12H21NO5H+] 260.1492, found 260.1492.
Hz, 1H), 4.31–4.28 (m, 1H), 4.11 (q, J = 4.6 Hz, 1H), 4.01–3.99
N-Benzyloxycarbonyl-2,3,5,6-di-O-isopropylidene-1,4-dideoxy- (m, 1H), 3.71–3.65 (m, 3H), 3.37–3.33 (m, 1H); 13C NMR
1,4-imino-D-mannitol (12). Zinc powder (15.6 g, 23.4 mol) and (125 MHz, CD3OD) δ 156.2, 155.7, 136.6, 128.2, 127.8, 127.5,
cupric acetate monohydrate (0.38 g, 23.4 mmol) were added to 73.1, 72.9, 72.4, 71.9, 70.2, 69.4, 66.9, 63.4, 60.1, 59.8, 52.0,
acetic acid (15 mL); the reaction mixture was stirred for 15 min 51.5; HRMS calcd for [C14H19NO6Na+] 320.1105, found
at room temperature and turned brown. Then the substrate 7 320.1100.
(3.9 g, 14.4 mmol) in acetic acid was added and the mixture
1,4-Dideoxy-1,4-imino-D-mannitol (3). 15 mg of 10% Pd/C
was stirred overnight at room temperature. The acetic acid was was added to a solution of 14 (45 mg, 0.15 mmol) in methanol,
removed in vacuo and the residue was washed with EtOAc then the mixture was stirred under the atmosphere of H2 at
(10 mL × 3). Then the eluent was washed with aqueous room temperature for 24 hours and filtered through a celite
NaHCO3 solution and the water phase was extracted with pad. Removal of methanol gave 3 (21 mg, 88%) as yellow oil.
EtOAc (5 mL × 3). The combined organic layers were dried [α]2D0 = −26 (c = 1.0, CH2Cl2); IR (thin film, cm−1) 2941, 2833,
with MgSO4 and concentrated. The residue was redissolved in 1659, 1448, 1131, 1026; 1H NMR (500 MHz, D2O) δ 4.24 (dt, J =
THF (25 mL) and water (1 mL). To the mixture was added 8.2, 4.2 Hz, 1H), 4.12 (t, J = 3.8 Hz, 1H), 3.77 (ddd, J = 9.3, 6.5,
NaHCO3 (2.2 g, 25.9 mmol) at room temperature, then CbzCl 2.9 Hz, 1H), 3.66 (dd, J = 12.0, 2.9 Hz, 1H), 3.47 (dd, J = 12.0,
(3.1 mL, 22 mmol) was added slowly. The mixture was stirred 6.5 Hz, 1H), 3.08 (dd, J = 11.2, 8.0 Hz, 1H), 3.03 (dd, J = 9.4, 3.5
overnight. The reaction was quenched with saturated NH4Cl Hz, 1H), 2.68 (dd, J = 11.2, 8.5 Hz, 1H); 13C NMR (125 MHz,
and extracted with EtOAc (10 mL × 3). The combined organic D2O) δ 72.1, 71.4, 70.2, 63.6, 60.7, 48.4; HRMS calcd for
layers were dried with MgSO4 and concentrated. The residue [C6H13NO4H+] 164.0917, found 164.0917.
was purified by column chromatography with EtOAc/
N-Benzyloxycarbonyl-2,3-O-isopropylidene-5-O-methoxylmethyl-
petroleum ether (1 : 20) to give 12 (5.1 g, 89%) as clear oil. 12: 6-O-tert-butyldimethylsilyl-1,4-dideoxy-1,4-imino-D-mannitol (6).
[α]2D0 = −26 (c = 1.0, CH2Cl2); IR (thin film, cm−1) 2986, 1707, Triethylamine (2 mL, 28 mmol) and tert-butyldimethylsilyl
1412, 1370, 1211, 1060, 858; 1H NMR (300 MHz, CDCl3) δ chloride (3.8 g, 26 mmol) were added to a solution of 13 (4.8 g,
7.37–7.26 (m, 5H), 5.13 (d, J = 12.3 Hz, 1H), 5.08 (d, J = 12.3 14.2 mmol) in CH2Cl2 (15 mL) in small portions. The mixture
Hz, 1H), 4.78 (dd, J = 6.1 Hz, 1H), 4.66 (ddd, J = 10.6 6.4, 4.0 was stirred at room temperature for 7 hours. The reaction was
Hz, 1H), 4.59–4.52 (m, 1H), 4.09 (dd, J = 8.8, 6.1 Hz, 1H), quenched with saturated NH4Cl and extracted with EtOAc
4.01–3.94 (m, 2H), 3.77 (dd, J = 12.6, 6.1 Hz, 1H), 3.50 (dd, J = (5 mL × 3). The combined organic layers were dried with
12.7, 3.7 Hz, 1H), 1.48 (s, 3H), 1.40 (s, 3H), 1.37 (s, 3H), 1.35 (s, MgSO4 and concentrated. Then the residue was redissolved in
3H). 13C NMR (75 MHz, CDCl3) δ 155.1, 136.3, 128.5, 128.1, dry CH2Cl2 To the mixture was added N,N-diisopropyl-
128.0, 113.1, 109.0, 80.0, 77.9, 74.4, 67.8, 67.3, 62.7, 52.1, 26.8, ethylamine (4.4 mL, 25 mmol) at 0 °C under argon, and then
26.5, 25.4, 24.9; HRMS calcd for [C20H27NO6Na+] 400.1731, chloromethyl methyl ether (1.5 mL, 20 mmol) was added
found 400.1727.
dropwisely. The mixture was allowed to warm to room temp-
N-Benzyloxycarbonyl-2,3-O-isopropylidene-1,4-dideoxy-1,4- erature and stirred for 48 hours. The reaction was quenched
imino-D-mannitol (13) and N-Benzyloxycarbonyl-1,4-dideoxy- with saturated NH4Cl and extracted with EtOAc (10 mL × 3).
1,4-imino-D-mannitol (14). 1% (w/w) H2SO4 (15 mL) was added The combined organic layers were dried with MgSO4 and con-
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centrated. The residue was purified by column chromato- ture overnight. Then the reaction was concentrated in vacuo,
graphy with EtOAc/petroleum ether (1 : 10) to give 6 (5.4 g, redissolved in water and extracted with EtOAc (5 mL × 3). The
76%) as clear oil. [α]2D0 = −14 (c = 0.5, CH2Cl2); IR (thin film combined organic layers were dried with MgSO4 and concen-
1
cm−1) 2932, 1706, 1417, 1251, 1212, 1089, 1038, 838; H NMR trated. The residue was purified by column chromatography
(300 MHz, CDCl3) δ 7.35–7.29 (m, 5H), 5.12 (s, 2H), 4.83 (t, J = with EtOAc/petroleum ether (1 : 1) to give amide 17 (135 mg,
6.8 Hz, 1H), 4.71–4.62 (m, 3H), 4.22 (dd, J = 6.6, 5.3 Hz, 1H), 72%) as clear oil. [α]2D0 = +22 (c = 0.5, CH2Cl2); IR (thin film
4.19–4.11 (m, 1H), 4.02 (dd, J = 11.7, 7.4 Hz, 1H), 3.85–3.78 (m, cm−1) 2939, 1652, 1451, 1379, 1212, 1156, 1098; 1H NMR
2H), 3.33 (s, 3H), 3.32–3.25 (m, 1H), 1.53 (s, 3H), 1.32 (s, 3H), (300 MHz, CDCl3) δ 4.76 (d, J = 6.8 Hz, 1H), 4.74–4.65 (m, 3H),
0.87 (s, 9H), 0.02 (s, 6H).13C NMR (75 MHz, CDCl3) δ 154.8, 4.16 (d, J = 13.5 Hz, 1H), 4.12–4.01 (m, 1H), 3.38 (s, 3H), 3.33
136.6, 128.6, 128.2, 113.8, 97.6, 80.0, 78.0, 77.8, 67.3, 64.3, (dd, J = 7.9, 2.8 Hz, 1H), 3.05 (dd, J = 13.6, 3.7 Hz, 1H),
60.5, 55.8, 51.4, 26.8, 26.0, 25.2, 18.3, −5.3, −5.4; HRMS calcd 2.52–2.41 (m, 1H), 2.41–2.27 (m, 1H), 2.20–2.14 (m, 1H),
for [C25H41NO7SiNa+] 518.2545, found 518.2541.
1.90–1.81 (m, 1H), 1.37 (s, 3H), 1.29 (s, 3H). 13C NMR (75 MHz,
N-Benzyloxycarbonyl-2,3-O-isopropylidene-5-O-methoxylmethyl- CDCl3) δ 168.6, 112.0, 95.9, 79.8, 77.6, 70.3, 65.3, 55.6, 50.6,
1,4-dideoxy-1,4-imino-D-mannitol (15). Excess Olah’s reagent 29.5, 27.7, 26.6, 24.8; HRMS calcd for [C13H21NO5H+]
was added to a solution of 6 (4 g, 8 mmol) in THF. The 272.1493, found 272.1488.
mixture was stirred at room temperature for 2 hours. The reac-
5-Oxo-D-swainsonine (18). Hydrochloric acid (3 N, 2 mL) was
tion was quenched with saturated NaHCO3 and extracted with added to a solution of 17 (54 mg, 0.2 mmol) in methanol. The
EtOAc (10 mL × 3). The combined organic layers were dried mixture was stirred at room temperature for 2 hours. Removal
with MgSO4 and concentrated in vacuo. The residue was puri- of solvent gave 18 (35 mg, 97%) as yellow gel. 18: [α]2D0 = −16
fied by column chromatography with EtOAc/petroleum ether (c = 0.25, CH2Cl2); IR (thin film cm−1) 3359, 2933, 1061, 1488,
(1 : 5) to give 15 (2.7 g, 91%) as clear oil. 15: [α]D20 = −56 (c = 0.5, 1415, 1267, 1110, 1046, 808; 1H NMR (500 MHz, D2O) δ
CH2Cl2); IR (thin film cm−1) 3462, 2939, 1702, 1418, 1212, 4.47–4.43 (m, 1H), 4.27 (d, J = 2.6 Hz, 1H), 4.03–3.98 (m, 1H),
1088, 1038, 866; 1H NMR (300 MHz, CDCl3) δ 7.75–7.09 (m, 3.72 (dd, J = 11.7, 9.0 Hz, 1H), 3.45 (d, J = 9.1 Hz, 1H), 3.20 (dd,
5H), 5.14 (d, J = 12.3 Hz, 1H), 5.07 (d, J = 12.3 Hz, 1H), 4.85 (t, J = 11.2, 9.5 Hz, 1H), 2.52–2.38 (m, 2H), 2.12–2.09 (m, 1H),
J = 6.6 Hz, 1H), 4.76 (dt, J = 7.01, 6.9 Hz, 1H),4.68 (d, J = 6.9 1.87–1.78 (m, 1H). 13C NMR (125 MHz, D2O) δ 171.6, 70.3,
Hz, 1H), 4.63 (q, J = 6.9 Hz, 1H), 4.28 (dd, J = 8.8, 6.9 Hz, 1H), 69.2, 65.7, 63.2, 48.3, 28.8, 28.1; HRMS calcd for [C8H13NO4H+]
4.11 (dd, J = 12.0, 7.5 Hz, 1H), 3.97 (s, 1H), 3.83 (dt, J = 8.9, 2.6 188.0917, found 188.0917.
Hz, 1H), 3.74 (dd, J = 11.7 Hz, 1H), 3.59 (dt, J = 12.8, 3.5 Hz,
Swainsonine (1). Lithium aluminium hydride (80 mg,
1H), 3.43 (s, 3H), 3.09 (dd, J = 12.0, 7.0 Hz, 1H), 1.50 (s, 3H), 2 mmol) was added to solution of amide 18 (120 mg,
1.32 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 155.9, 136.0, 128.7, 0.73 mmol) in dry THF. The reaction mixture was refluxed for
128.4, 128.2, 113.6, 97.6, 80.0, 77.9, 67.9, 62.4, 59.3, 55.9, 51.0, 4 hours. To the mixture were subsequently added water
27.3, 25.4; HRMS calcd for [C19H27NO7Na+] 404.1680, found (0.08 mL), 15% (w/w) NaOH (0.08 mL) and water (0.24 mL) and
404.1678.
white solid occurred. The mixture was filtered to separate the
1,2-O-Isopropylidene-8-O-methoxylmethyl-5-oxo-D-swainsonine solid and washed with CH2Cl2. The eluent was dried with
(17). Sodium hydrogen carbonate (0.17 g, 2.34 mmol) was MgSO4 and concentrated. The residue was chromatographed
added to a solution of DMP (0.69 g, 1.56 mmol) in dry CH2Cl2. on silica gel with EtOAc–PE (1 : 3) to give 4 which was then dis-
The mixture was stirred at room temperature for 15 minutes solved in methanol. To a solution of 4 in methanol was added
and 15 (0.3 g, 0.78 mmol) in 2 mL of dry CH2Cl2 was added 2 mL of 3 N HCl. The mixture was stirred at room temperature
dropwisly. The mixture was stirred at room temperature for for 20 minutes. The reaction was concentrated and the residue
2 hours. The product and substrate cannot be separated by was subjected to an ion exchange column (DOWEX 50 W × 8,
TLC. To this suspension was added 3 mL of saturated 100–200 mesh) eluted with 6 N ammonia solution. Removal of
Na2S2O3. The mixture was stirred and became clear. Then solvent gave 1 (56 mg, 74%) as white solid. 1: mp 141–143 °C
5 mL of saturated NH4Cl was added and the mixture was (lit.4b mp 144–145 °C); [α]2D5 = −81.9 (c = 1.05, MeOH) [lit.4b
extracted with EtOAc (3 × 10 mL). The combined organic layers [α]2D0 = −87.2 (c 2.1, MeOH)]; IR (KBr cm−1) 3359, 2928, 1661,
1
were dried with MgSO4 and concentrated. The residue was dis- 1447, 1327, 1215, 1142, 1084, 1027; H NMR (500 MHz, D2O) δ
sovled in dry toluene (15 mL) and methyl 3-(triphenylphos- 4.42–4.35 (m, 1H), 4.29 (dd, J = 5.7, 3.6 Hz, 1H), 3.83 (dt, J =
phoranylidene)propanoate (0.31 g, 0.94 mmol) was added. 10.7, 4.6 Hz, 1H), 2.99–2.94 (m, 2H), 2.67 (dd, J = 10.9,8.25 Hz,
The mixture was refluxed under argon for 1 hour. The mixture 1H), 2.14–2.02 (m, 3H), 1.76 (d, J = 13.8 Hz, 1H), 1.55 (qt, J =
was concentrated and the residue was recrystallized with Et2O 5.7, 3.6 Hz, 1H), 1.31–1.23 (m, 1H); [lit.5 (90 MHz, D2O, ref.
to separate Ph3PO. Then the solvent was removed and the DSS) 4.42–4.17(m, 2H), 3.79(ddd, J = 9–10, 10, 4–5 Hz, 1H),
residue was dissolved in MeOH. To the mixture under argon 2.85(m, 2H), 2.50 (dd, J = 11, 6 Hz, 1H), 2.13–0.94 (m, 6H);
was added 30 mg of 10% Pd/C. The reaction was stirred under lit.4b (89.55 MHz, D2O, ref. DSS) 4.44–4.18 (m, 2H), 3.80 (ddd,
the atmosphere of H2 at room temperature for 24 hours, fil- 1H), 2.89 (dd, 2H), 2.53 (dd, 1H), 2.14–0.98 (m, 6H)]; 13C NMR
tered through a celite pad, and concentrated in vacuo. The (125 MHz, D2O) δ 72.29, 69.08, 68.53, 65.66, 59.90, 51.22,
residue was redissolved in methanol (5 mL) and K2CO3 31.85, 22.54; [lit.5 (D2O, ref. MeOH) 72.55, 69.42, 68.74, 66.07,
(30 mg) was added. The mixture was stirred at room tempera- 60.38, 51.33, 32.16, 22.89; lit.4b (22.5 MHz, D2O, ref. MeOH)
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72.56, 69.42, 68.77, 66.06, 60.38, 51.38, 32.21, 22.89]; HRMS 127.5, 74.0, 72.5, 70.1, 67.1, 65.8, 63.4; HRMS calcd for
calcd for [C8H15NO3H+] 174.1125, found 174.1127.
[C14H19NO6Na+] 320.1105, found 320.1101.
N-Benzyloxycarbonyl-2,3,5,6-di-O-isopropylidene-1,4-dideoxy-
1,4-Dideoxy-1,4-imino-D-talitol (22). 10% Pd/C (15 mg) was
1,4-imino-D-talitol (19). Zinc powder (10 g, 0.15 mmol) and added to a solution of 21 (25 mg, 0.08 mmol) in methanol,
cupric acetate monohydrate (0.3 g, 0.15 mmol) were added to then the mixture was stirred under the atmosphere of H2 at
acetic acid (15 mL), the mixture was stirred for 15 min at room room temperature for 24 hours and filtered through a celite
temperature and turned into brown. Then the substrate 7 (4 g, pad. Removal of methanol gave 22 (11 mg, 81%) as yellow oil.
15 mmol) in acetic acid was added and the mixture was stirred [α]2D0 = −54 (c = 0.4, CH2Cl2); IR (thin film cm−1) 2930, 1671,
overnight at room temperature. The acetic acid was removed 1445, 1329, 1126, 1003; 1H NMR (400 MHz, D2O) δ 4.14 (dd, J =
under vacuum and the residue was washed with EtOAc (10 mL 7.7, 4.7 Hz, 1H), 3.98 (dd, J = 8.2, 4.9 Hz, 1H), 3.85–3.76 (m,
× 3). Then the eluent was washed with aqueous NaHCO3 solu- 1H), 3.65 (dd, J = 11.8, 3.9 Hz, 1H), 3.55 (dd, J = 11.8, 7.0 Hz,
tion and the water phase was extracted with EtOAc (5 mL × 3). 1H), 3.21 (dd, J = 12.6, 4.8 Hz, 1H), 3.08 (dd, J = 8.2, 4.2 Hz,
The combined organic layer was dried over MgSO4 and concen- 1H), 2.90 (dd, J = 12.6, 2.8 Hz, 1H); [lit.23e 1H NMR (D2O) δ 3.95
trated. The residue was redissolved in THF (25 mL) and water (dt, H-2, 1H), 3.78 (dd, H-3, J2,3 = 5.2 Hz, 1H), 3.62 (m, H-5,
(1 mL). To the mixture was added NaHCO3 (2.5 g, 30 mmol) at 1H), 3.57 (dd, H-6′, J5,6′ = 4.1 Hz, 1H), 3.40 (dd, H-6, J6,6′ = 11.8
room temperature, then CbzCl (3.1 mL, 22 mmol) was added Hz, J5,6 = 7.7 Hz, 1H), 3.02 (dd, H-1′, J1′,2 = 5.1 Hz, 1H), 2.78
slowly. The mixture was stirred overnight. The reaction was (dd, H-4, J3,4 = 7.9 Hz, J4,5 = 4.2 Hz, 1H), 2.62 (dd, H-1, J1,1′
=
quenched with saturated NH4Cl and extracted with EtOAc 12.5 Hz, J1,2 = 3.4 Hz, 1H)]; 13C NMR (100 MHz, D2O) δ 72.8,
(10 mL × 3). The combined organic layers were dried with 70.5, 70.0, 63.7, 62.1, 50.1; HRMS calcd for [C6H13NO4H+]
MgSO4 and concentrated. The residue was purified by column 164.0917, found 164.0914.
chromatography with EtOAc/petroleum ether (1 : 20) to give 19
N-Benzyloxycarbonyl-2,3-O-isopropylidene-5-O-methoxylmethyl-
(23).
(4.9 g, 82%) as clear oil. [α]2D5 = +76 (c = 1.00, CH2Cl2); IR (thin 6-O-tert-butyldimethylsilyl-1,4-dideoxy-1,4-imino-D-talitol
film cm−1) 2986, 1703, 1455, 1213, 1118, 1060, 872; 1H NMR Triethylamine (3.7 mL, 26 mmol) and tert-butyldimethylsilyl
(300 MHz, CDCl3) δ 7.38–7.29 (m, 5H), 5.23–5.10 (m, 2H), chloride (3 g, 20 mmol) were added to a solution of 20 (4.5 g,
4.80–4.70 (m, 2H), 4.32–4.17 (m, 2H), 4.06–3.99 (m, 1H), 13 mmol) in CH2Cl2 (5 mL) in small portions. The mixture was
3.95–3.86 (m, 1H), 3.76 (t, J = 8.3 Hz, 0.5H), 3.63–3.52 (m, stirred at room temperature for 7 hours. The reaction was
1.5H), 1.38 (s, 3H), 1.33–1.30 (m, 9H); 13C NMR (75 MHz, quenched with saturated NH4Cl and extracted with EtOAc
CDCl3) δ 156.0, 155.3, 136.8, 136.4, 128.5–126.9, 111.6, 109.1, (5 mL × 3). The combined organic layers were dried with
109.0, 83.4, 82.8, 80.2, 79.5, 77.7, 77.5, 67.3, 67.1, 66.0, 65.9, MgSO4 and concentrated. Then the residue was redissolved in
63.9, 63.6, 54.4, 54.3, 26.9, 26.0, 25.5, 25.4, 24.8; HRMS calcd dry CH2Cl2. To the mixture was added N,N-diisopropyl-
for [C20H27NO6Na+] 400.1731, found 400.1728.
ethylamine (4.4 mL, 25 mmol) at 0 °C under argon, and then
N-Benzyloxycarbonyl-2,3,-O-isopropylidene-1,4-dideoxy-1,4- chloromethyl methyl ether (1.5 mL, 20 mmol) was added
imino-D-talitol (20) and N-benzyloxycarbonyl-1,4-dideoxy-1,4- dropwisely. The mixture was allowed to warm to room temp-
imino-D-talitol (21). 1% (w/w) H2SO4 was add to a solution of erature and stirred for 48 hours. The reaction was quenched
19 (3 g, 8.9 mmol) in methanol (15 mL) at room temperature, with saturated NH4Cl and extracted with EtOAc (10 mL × 3).
the mixture was stirred overnight. The reaction was neutralized The combined organic layers were dried with MgSO4 and con-
with aqueous NaHCO3 and methanol was removed in vacuo. centrated. The residue was purified by column chromato-
The residue was extracted with EtOAc (15 mL × 3) and the com- graphy with EtOAc/petroleum ether (1 : 10) to give 23 (5.2 g,
bined organic layers were dried (MgSO4). The residue was puri- 79%) as clear oil. 23: [α]2D0 = +8 (c = 0.5, CH2Cl2); IR (thin film
1
fied by column chromatography with EtOAc/petroleum ether cm−1) 2932, 1706, 1458, 1418, 1213, 1121, 1032, 838; H NMR
(1 : 3) to give 20 (1.8 g, 69%) and 21 (0.11 g, 4.6%) as clear oil. (300 MHz, CDCl3) δ 7.35–7.26 (m, 5H), 5.14 (s, 2H), 4.91 (d, J =
20: [α]2D0 = +54 (c = 1.0, CH2Cl2); IR (thin film cm−1) 3423, 2986, 6.0 Hz, 1H), 4.82 (d, J = 6.7 Hz, 0.5H), 4.76 (d, J = 6.8 Hz, 0.5H),
2940, 1682, 1425, 1214, 1126, 1063, 699; 1H NMR (300 MHz, 4.73 (d, J = 5.6 Hz, 1H), 4.66 (dd, J = 6.6 Hz, 0.5H), 4.60 (dd, J =
CDCl3) δ 7.43–7.27 (m, 5H), 5.18 (s, 2H), 4.80–4.74 (m, 2H), 6.7 Hz, 0.5H), 4.28 (dd, J = 12.0, 4.5 Hz, 1H), 4.00–3.88 (m,
4.33 (d, J = 1.6 Hz, 1H), 4.03–3.93 (m, 1H), 3.91 (d, J = 12.4 Hz, 1H), 3.81–3.76 (m, 1H), 3.69 (dd, J = 11.4, 3.3 Hz, 1H),
1H), 3.70–3.65 (m, 1H), 3.58 (dd, J = 12.3, 4.8 Hz, 2H), 3.62–3.45 (m, 2H), 3.36 (d, J = 13.0 Hz, 3H), 1.39 (s, 3H), 1.30
3.52–3.48 (m, 1H), 2.06 (d, J = 4.5 Hz, 1H), 1.41 (s, 3H), 1.31 (s, (s, 3H), 0.87 (d, J = 5.6 Hz, 9H), 0.07–0.01 (m, 6H); 13C NMR
3H); 13C NMR (75 MHz, CDCl3) δ 156.8, 136.4, 128.5, 128.1, (100 MHz, CDCl3) δ 155.2, 155.1, 136.9, 136.6, 128.5, 128.0,
127.5, 111.5, 83.1, 79.9, 73.5, 67.5, 65.0, 63.3, 54.3, 26.9, 24.8; 127.9, 127.8, 127.7, 111.3, 111.3, 96.9, 96.5, 82.8, 82.2, 80.1,
HRMS calcd for [C17H23NO6Na+] 360.1418, found 360.1414. 21: 79.4, 77.8, 76.7, 67.2, 66.9, 65.3, 65.1, 63.9, 63.4, 55.9, 55.9,
[α]2D0 = +18 (c = 1.0, MeOH); IR (thin film cm−1) 3335, 2940, 53.7, 53.5, 26.9, 26.8, 25.9, 25.8, 24.8, 24.7, 18.3, −5.4, −5.5,
1682, 1417, 1357, 1101, 698; 1H NMR (300 MHz, CD3OD) δ −5.57, −5.6; HRMS calcd for [C25H41NO7SiNa+] 518.2545,
7.39–7.32 (m, 5H), 5.15 (m, 2H), 4.41 (dd, J = 10.6, 6.1 Hz, 1H), found 518.2540.
4.16 (dd, J = 4.2, 2.5 Hz, 1H), 3.95–3.91 (m, 1H), 3.79 (dt, J =
N-Benzyloxycarbonyl-2,3-O-isopropylidene-5-O-methoxylmethyl-
5.9, 2.9 Hz, 1H), 3.89–3.48 (m, 4H), 3.43–3.32 (m, 1H); 13C 1,4-dideoxy-1,4-imino-D-talitol (24). Tetrabutylammonium fluor-
NMR (125 MHz, CD3OD) δ 157.2, 136.7, 128.1, 127.9, 127.7, ide trihydrate (2.8 g, 8.9 mmol) was added to a solution of 23
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(4 g, 8 mmol) in THF. The mixture was stirred at room temp- mixture was stirred at room temperature for 2 hours. Removal
erature for 30 minutes. The reaction was quenched with satu- of solvent gave 26 (37 mg, 99%) as yellow gel. [α]2D0 = −56 (c =
rated NH4Cl and extracted with EtOAc (10 mL × 3). The 0.5, MeOH); IR (thin film cm−1) 3354, 2946, 1605, 1487, 1416,
combined organic layers were dried with MgSO4 and concen- 1266, 1110, 1046; 1H NMR (300 MHz, D2O) δ 4.26–4.24 (m,
trated in vacuo. The residue was purified by column chromato- 1H), 4.22 (t, J = 4.3 Hz, 1H), 4.02 (dd, J = 10.1, 4.2 Hz, 1H),
graphy with EtOAc/petroleum ether (1 : 5) to give 24 (2.9 g, 3.61–3.54 (m, 2H), 3.37 (d, J = 14.0 Hz, 1H), 2.37–2.32 (m, 2H),
97%) as oil. [α]2D0 = +66 (c = 0.75, CH2Cl2); IR (thin film cm−1
)
2.08–1.96 (m, 1H), 1.95–1.84 (m, 1H). 13C NMR (75 MHz, D2O)
2940, 1701, 1678, 1423, 1212, 1128, 1051, 869; 1H NMR δ 172.3, 70.5, 67.9, 62.6, 61.0, 51.5, 26.6, 25.4; HRMS calcd for
(300 MHz, CDCl3) δ 7.42–7.27 (m, 5H), 5.23–5.14 (m, 2H), [C8H13NO4H+] 188.0917, found 188.0918.
4.79–4.72 (m, 1H), 4.70 (d, J = 6.0 Hz, 1H), 4.60 (dd, J = 11.8,
1,2-O-Isopropylidene-8-O-methoxylmethyl-8a-epi-D-swainsonine
6.7 Hz, 2H), 4.49 (d, J = 1.9 Hz, 1H), 4.17 (dd, J = 9.7, 5.1 Hz, (27). Lithium aluminium hydride (0.16 g, 4 mmol) was added
1H), 3.89 (d, J = 12.4 Hz, 1H), 3.89–3.83 (m, 1H), 3.76–3.62 (m, to solution of amide 25 (0.4 g, 1.5 mmol) in dry THF. The reac-
1H), 3.55 (dd, J = 12.3, 5.0 Hz, 1H), 3.46–3.36 (m, 1H), 3.35 (s, tion mixture was refluxed for 4 hours. To the mixture were sub-
3H), 1.40 (s, 3H), 1.31 (s, 3H); 13C NMR (75 MHz, CDCl3) δ sequently added water (0.16 mL), 15% (w/w) NaOH and water
156.7, 136.4, 128.5, 128.1, 127.6, 111.5, 96.9, 83.0, 80.9, 80.1, (0.48 mL) and white solid occurred. The mixture was filtered to
67.5, 64.2, 60.7, 55.9, 54.3, 26.9, 24.8; HRMS calcd for separate the solid and washed with CH2Cl2. The eluent was
[C19H27NO7Na+] 404.1680, found 404.1677.
dried with MgSO4 and concentrated. The residue was purified
1,2-O-Isopropylidene-8-O-methoxylmethyl-5-oxo-8a-epi-D-swain- by column chromatography with EtOAc/petroleum ether (1 : 3)
sonine (25). Sodium hydrogen carbonate was added (0.29 g, to give 27 (0.35 g, 92%) as yellow oil. [α]2D0 = −36 (c = 0.5,
3.5 mmol) to a solution of DMP (1.03 g, 2.3 mmol) in dry CH2Cl2); IR (thin film cm−1) 2985, 2937, 1668, 1444, 1380,
CH2Cl2. The mixture was stirred at room temperature for 1209, 1040; 1H NMR (300 MHz, CDCl3) δ 4.78–4.63 (m, 3H),
15 minutes and 24 (0.5 g, 1.3 mmol) in 2 mL of dry CH2Cl2 4.59 (t, J = 6.3 Hz, 1H), 3.98 (s, 1H), 3.45 (dd, J = 8.8, 6.3 Hz,
was added dropwisly. The mixture was stirred at room temp- 1H), 3.39 (s, 3H), 2.99 (d, J = 10.4 Hz, 1H), 2.28 (dd, J = 9.1, 4.5
erature for 2 hours. The product and substrate cannot be sep- Hz, 1H), 2.22–2.09 (m, 2H), 2.03 (d, J = 14.1 Hz, 1H), 1.89–1.74
arated by TLC. To this suspension was added 3 mL of (m, 1H), 1.49 (s, 3H), 1.41 (m, 2H), 1.32 (s, 3H). 13C NMR
saturated Na2S2O3. The mixture was stirred and became clear. (75 MHz, CDCl3) δ 113.8, 96.1, 79.6, 77.6, 71.4, 70.5, 60.5, 55.8,
Then 5 mL of saturated NH4Cl was added and the mixture was 52.4, 28.1, 27.3, 25.3, 19.7; HRMS calcd for [C13H23NO4H+]
extracted with EtOAc (3 × 10 mL). The combined organic layers 258.1700, found 258.1697.
were dried with MgSO4 and concentrated. The residue was
8a-epi-Swainsonine (2). Hydrochloric acid (3 N, 2 mL) was
redissolved in dry toluene (15 mL) and methyl 3-(triphenylphos- added to a solution of 27 (51 mg, 0.2 mmol) in methanol. The
phoranylidene)propanoate (0.5 g, 1.5 mmol) was added. The mixture was stirred at room temperature for 20 minutes.
mixture was refluxed under argon for 1 hour. The mixture was Removal of solvent and work-up with acidic ion exchange
concentrated and the residue was recrystallized with Et2O to column (DOWEX 50 W × 8, 100–200 mesh) gave 2 (32 mg,
separate Ph3PO. Then the solvent was removed and the residue 94%) as white solid. m.p. 112–115 °C [lit.12e mp 117–119 °C];
was dissolved in MeOH. To the mixture under argon was [α]2D0 = −66 (c = 0.5, MeOH) [lit.12e [α]2D1 −63 (c 0.95, MeOH)]; IR
1
added 30 mg of 10% Pd/C. The reaction was stirred under (thin film cm-1) 3355, 2928, 1661, 1446, 1328, 1124; H NMR
atmosphere of H2 at room temperature for 24 hours, filtered (500 MHz, D2O, ref. MeOH) δ 4.25–4.12 (m, 2H), 3.97 (dd, J =
through a celite pad, and concentrated in vacuo. The residue 9.4, 6.7 Hz, 1H), 3.56 (dd, J = 11.2, 6.7 Hz, 1H), 3.18–3.03 (m,
was redissolved in methanol (5 mL) and K2CO3 (30 mg) was 1H), 2.47 (d, J = 9.2 Hz, 1H), 2.42 (d, J = 5.0 Hz, 1H), 2.41–2.35
added. The mixture was stirred at room temperature overnight. (m, 1H), 1.99–1.88 (m, 1H), 1.85–1.75 (m, 1H), 1.68–1.51 (m,
Then the reaction was concentrated in vacuo, redissolved in 2H); [lit.12e (600 MHz, D2O, ref CD3OD) δ 4.32 (q, J = 6.6 Hz,
water and extracted with EtOAc (5 mL × 3). The combined 1H), 4.10 (m, 1H), 3.91 (dd, J = 9.0, 6.6 Hz, 1H), 3.39 (dd, J =
organic layers were dried with MgSO4 and concentrated. The 10.2, 6.6 Hz, 1H), 2.95 (dd, J = 10.2, 1.8 Hz, 1H), 2.14 (dd, J =
residue was purified by column chromatography with EtOAc/ 10.2, 6.6 Hz, 1H), 2.10 (m, 2H), 1.87–1.90 (m, 1H), 1.69–1.77
petroleum ether (1 : 1) to give amide 25 (197 mg, 63%) as clear (m, 1H), 1.50–1.58 (m, 2H) ]; 13C NMR (125 MHz, D2O, ref.
oil. [α]2D0 = −44 (c = 0.5, CH2Cl2); IR (thin film cm−1) 3443, MeOH) δ 69.2, 69.15, 66.5, 62.8, 59.9, 52.6, 29.4, 18.7; [lit.12e
2938, 1641, 1459, 1376, 1216, 1151, 1085, 1033; 1H NMR (150 MHz, D2O, ref. CD3OD) δ 70.7, 70.5, 67.7, 64.4, 61.4, 53.4,
(300 MHz, CDCl3) δ 4.78–4.74 (m, 2H), 4.71–4.66 (m, 2H), 30.9, 20.1]; HRMS calcd for [C8H15NO3H+] 174.1125, found
4.18–4.12 (m, 2H), 3.57 (dd, J = 6.3, 2.6 Hz, 1H), 3.48 (dd, J = 174.1126.
13.9, 1.2 Hz, 1H), 3.41 (s, 3H), 2.44–2.35 (m, 2H), 2.25–2.22 (m,
1H), 1.86–1.74 (m, 1H), 1.53 (s, 3H), 1.37 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 168.6, 113.3, 95.5, 79.5, 76.6, 68.0, 66.6,
Acknowledgements
56.0, 49.5, 28.0, 26.5, 25.8, 25.2; HRMS calcd for
[C13H21NO5H+] 272.1492, found 272.1495.
We thank the Ministry of Science and Technology of
5-Oxo-8a-epi-D-swainsonine (26). Hydrochloric acid (3 N, P. R. China (no. 2012CB822101), the National Natural Science
2 mL) to a solution of 25 (54 mg, 0.2 mmol) in methanol. The Foundation of China (no. 21272240, 21202173), National
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Science and Technology Major Projects for “Major New Drugs 10 For review of synthesis of swainsonine, see: (a) A. El Nemr,
Innovation and Development” (2013ZX09508104), and the
Chinese Academy of Sciences for financial support. This work
was supported in part by a Grant-in-Aid for Scientific Research
(C) (no. 26460143) (AK) from the Japanese Society for the
Promotion of Science (JSPS) and a Leverhulme research fellow-
ship (GWJF).
Tetrahedron, 2000, 56, 8579–8629. For representative
methods for the synthesis of (−)-swainsonine, see:
(b) S. P. Chavan, L. B. Khairnar, K. P. Pawar, P. N. Chavan
and S. A. Kawale, RSC Adv., 2015, 5, 50580–50590;
(c) X.-G. Wang, A.-E. Wang and P.-Q. Huang, Chin. Chem.
Lett., 2014, 25, 193–196; (d) P. Singh, S. K. Manna and
G. Panda, Tetrahedron, 2014, 70, 1363–1374; (e) A. A. Ansari
and Y. D. Vankar, RSC Adv., 2014, 4, 12555–12567;
(f) Q. R. Li, G. R. Dong, S. J. Park, Y. R. Hong, I. S. Kim and
Y. H. Jung, Eur. J. Org. Chem., 2013, 4427–4433;
(g) V. Dhand, J. A. Draper, J. Moore and R. Britton, Org.
Lett., 2013, 15, 1914–1917; (h) D. J. Wardrop and
E. G. Bowen, Org. Lett., 2011, 13, 2376–2379; (i) Y.-S. Tian,
J.-E. Joo, B.-S. Kong, V.-T. Pham, K.-Y. Lee and W.-H. Ham,
J. Org. Chem., 2009, 74, 3962–3965; ( j) P. K. Sharma,
R. N. Shah and J. P. Carver, Org. Process Res. Dev., 2008, 12,
831–836; (k) H. Guo and G. A. O’Doherty, Tetrahedron,
2008, 64, 304–313; (l) H. Guo and G. A. O’Doherty, Org.
Lett., 2006, 8, 1609–1612; (m) J. Ceccon, A. E. Greene and
J.-F. Poisson, Org. Lett., 2006, 8, 4739–4742; (n) R. Martín,
C. Murruzzu, M. A. Pericàs and A. Riera, J. Org. Chem.,
2005, 70, 2325–2328; (o) L. Song, E. N. Duesler and
P. S. Mariano, J. Org. Chem., 2004, 69, 7284–7293;
(p) K. B. Lindsay and S. G. Pyne, Aust. J. Chem., 2004, 57,
669–672; (q) K. B. Lindsay and S. G. Pyne, J. Org. Chem.,
2002, 67, 7774–7780; (r) N. Buschmann, A. Rückert and
S. Blechert, J. Org. Chem., 2002, 67, 4325–4329;
(s) B. M. Trost and D. E. Patterson, Chem. – Eur. J., 1999, 5,
3279–3284; (t) W. H. Pearson and E. J. Hembre, J. Org.
Chem., 1996, 61, 7217–7221; (u) S. A. Miller and
A. R. Chamberlin, J. Am. Chem. Soc., 1990, 112, 8100–8112;
(v) R. B. Bennett, J. R. Choi, W. D. Montgomery and
J. K. Cha, J. Am. Chem. Soc., 1989, 111, 2580–2582;
(w) J. M. Dener, D. J. Hart and S. Ramesh, J. Org. Chem.,
1988, 53, 6022–6030; (x) T. Suami, K.-i. Tadano and
Y. Iimura, Carbohydr. Res., 1985, 136, 67–75; (y) T. Suami,
K.-i. Tadano and Y. Iimura, Chem. Lett., 1984, 13, 513–516;
(z) G. W. J. Fleet, M. J. Gough and P. W. Smith, Tetrahedron
Lett., 1984, 25, 1853–1856; (aa) M. H. Ali, L. Hough and
A. C. Richardson, J. Chem. Soc., Chem. Commun., 1984,
447–448.
Notes and references
1 (a) N. Asano, R. J. Nash, R. J. Molyneux and
G. W. J. Fleet, Tetrahedron: Asymmetry, 2000, 11, 1645–
1680; (b) R. J. Nash, A. Kato, C.-Y. Yu and G. W. J. Fleet,
Future Med. Chem., 2011, 3, 1513–1521; (c) R. Zelli,
J.-F. Longevial, P. Dumy and A. Marra, New J. Chem.,
2015, 39, 5050–5074.
2 (a) A. J. Thompson, R. J. Williams, Z. Hakki, D. S. Alonzi,
T. Wennekes, T. M. Gloster, K. Songsrirote, J. E. Thomas-
Oates, T. M. Wrodnigg, J. Spreitz, A. E. Stütz, T. D. Butters,
S. J. Williams and G. J. Davies, Proc. Natl. Acad. Sci. U. S. A.,
2012, 109, 781–786; (b) M. Damme, W. Morelle, B. Schmidt,
C. Andersson, J. Fogh, J.-C. Michalski and T. Lübke, Mol.
Cell Biol., 2010, 30, 273–283; (c) Y.-Y. Zhao, M. Takahashi,
J.-G. Gu, E. Miyoshi, A. Matsumoto, S. Kitazume and
N. Taniguchi, Cancer Sci., 2008, 99, 1304–1310.
3 (a) I. S. Kim and Y. H. Jung, Heterocycles, 2011, 83, 2489–
2507; (b) J. P. Michael, Nat. Pro. Rep., 2004, 21, 625–649.
4 (a) F. P. Guengerich, S. J. DiMari and H. P. Broquist, J. Am.
Chem. Soc., 1973, 95, 2055–2056; (b) M. J. Schneider,
F. S. Ungemach, H. P. Broquist and T. M. Harris, Tetra-
hedron, 1983, 39, 29–32.
5 S. M. Colegate, P. R. Dorling and C. R. Huxtable,
Aust. J. Chem., 1979, 32, 2257–2264.
6 (a) M. Hino, O. Nakayama, Y. Tsurumi, A. Kimiko,
S. Toshihiro, T. Hiroshi, K. Masanobu, A. Hatsuo and
I. Hiroshi, J. Antibiot., 1985, 38, 926–935; (b) R. J. Molyneux
and L. F. James, Science, 1982, 216, 190–191; (c) D. S. Grum,
D. Cook, D. Baucom, I. W. Mott, D. R. Gardner, R. Creamer
and J. G. Allen, J. Nat. Prod., 2013, 76, 1984–1988.
7 Y.-F. Liao, A. Lal and K. W. Moremen, J. Biol. Chem., 1996,
271, 28348–28358.
8 (a) A. D. Elbein, R. Solf, P. R. Dorling and K. Vosbeck, Proc. 11 For recent synthesis of swainsonine related conpounds,
Natl. Acad. Sci. U. S. A., 1981, 78, 7393–7397;
(b) G. P. Kaushal, T. Szumilo, I. Pastuszak and A. D. Elbein,
Biochemistry, 1990, 29, 2168–2176; (c) I. Pastuszak,
G. P. Kaushal, K. A. Wall, Y. T. Pan, A. Sturm and
A. D. Elbein, Glycobiology, 1990, 1, 71–82.
see: (a) L. Wu, P. Chen and G. Liu, Org. Lett., 2016, 18, 960–
963; (b) C.-M. Si, Z.-Y. Mao, H.-Q. Dong, Z.-T. Du, B.-G. Wei
and G.-Q. Lin, J. Org. Chem., 2015, 80, 5824–5833;
(c) P. Rajasekaran, A. A. Ansari and Y. D. Vankar,
Eur. J. Org. Chem., 2015, 2902–2913.
9 (a) T. Kino, N. Inamura, K. Nakahara, S. Kiyoto, T. Goto, 12 (a) H.-K. Zhang, S.-Q. Xu, J.-J. Zhuang, J.-L. Ye and
T. Hiroshi, K. Masanobu, A. Hatsuo and I. Hiroshi, J. Anti-
biot., 1985, 38, 936–940; (b) S. L. White, K. Schweitzer,
M. J. Humphries and K. Olden, Biochem. Biophys. Res.
Commun., 1988, 150, 615–625; (c) M. Yagita and E. Saksela,
Scand. J. Immunol., 1990, 31, 275–282; (d) P. E. Shaheen,
W. Stadler, P. Elson, J. Knox, E. Winquist and
R. M. Bukowski, Invest. New Drugs, 2005, 23, 577–581.
P.-Q. Huang, Tetrahedron, 2012, 68, 6656–6664;
(b) X.-L. Wang, W.-F. Huang, X.-S. Lei, B.-G. Wei and
G.-Q. Lin, Tetrahedron, 2011, 67, 4919–4923; (c) J. A. Coral,
H. Guo, M. Shan and G. A. O’Doherty, Heterocycles, 2009,
79, 521–529; (d) J. Bi and V. K. Aggarwal, Chem. Commun.,
2008, 120–122; (e) J. N. Abrams, R. S. Babu, H. Guo, D. Le,
J. Le, J. M. Osbourn and G. A. O’Doherty, J. Org. Chem.,
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2016

View Article Online
Organic & Biomolecular Chemistry
Paper
2008, 73, 1935–1940; (f) B. Dudot, L. Micouin, I. Baussanne
and J. Royer, Synthesis, 1999, 688–694; (g) G. E. Keck and
D. R. Romer, J. Org. Chem., 1993, 58, 6083–6089;
(h) Y. G. Kim and J. K. Cha, Tetrahedron Lett., 1989, 30,
5721–5724; (i) K.-i. Tadano, Y. Hotta, M. Morita, T. Suami,
3414; (m) X.-G. Hu, B. Bartholomew, R. J. Nash,
F. X. Wilson, G. W. J. Fleet, S. Nakagawa, A. Kato, Y.-M. Jia,
R. v. Well and C.-Y. Yu, Org. Lett., 2010, 12, 2562–2565;
(n) C.-Y. Yu and M.-H. Huang, Org. Lett., 2006, 8, 3021–
3024.
B. Winchester and I. C. di Bello, Bull. Chem. Soc. Jpn., 1987, 15 (a) R. Lahiri, A. A. Ansari and Y. D. Vankar, Chem. Soc. Rev.,
60, 3667–3671; ( j) K.-i. Tadano, Y. Hotta, M. Morita,
T. Suami, B. Winchester and I. C. di Bello, Chem. Lett.,
1986, 15, 2105–2108.
2013, 42, 5102–5118; (b) J. Boisson, A. Thomasset,
E. Racine, P. Cividino, T. Banchelin Sainte-Luce,
J.-F. Poisson, J.-B. Behr and S. Py, Org. Lett., 2015, 17, 3662–
3665; (c) G. D’Adamio, C. Parmeggiani, A. Goti,
A. J. Moreno-Vargas, E. Moreno-Clavijo, I. Robina and
F. Cardona, Org. Biomol. Chem., 2014, 12, 6250–6266;
(d) R. Lahiri, A. Palanivel, S. A. Kulkarni and Y. D. Vankar,
J. Org. Chem., 2014, 79, 10786–10800; (e) D. A. MacKenzie,
A. R. Sherratt, M. Chigrinova, A. J. Kell and J. P. Pezacki,
Chem. Commun., 2015, 51, 12501–12504; (f) M. Malinowski,
T. Rowicki, P. Guzik, M. Gryszel, S. Lapczynski,
M. Wielechowska, K. Czerwinska, I. Madura and W. Sas,
Org. Biomol. Chem., 2016, 14, 470–482.
13 (a) D. Díez, M. T. Benéitez, M. J. Gil, R. F. Moro,
I. S. Marcos, N. M. Garrido, P. Basabe and J. G. Urones, Syn-
thesis, 2005, 565–568; (b) R. Badorrey, C. Cativiela,
M. a. D. Díaz-de-Villegas, R. Díez and J. A. Gálvez, Tetra-
hedron Lett., 2004, 45, 719–722; (c) F.-M. Kieß,
P. Poggendorf, S. Picasso and V. Jager, Chem. Commun.,
1998, 119–120; (d) M.-J. Blanco and F. J. Sardina, J. Org.
Chem., 1996, 61, 4748–4755; (e) N. M. Carpenter,
G. W. J. Fleet, I. Cenci di Bello, B. Winchester, L. E. Fellows
and R. J. Nash, Tetrahedron Lett., 1989, 30, 7261–7264;
(f) H. Setoi, H. Kayakiri, H. Takeno and M. Hashimoto, 16 P. Merino, I. Delso, T. Tejero, F. Cardona, M. Marradi,
Chem. Pharm. Bull., 1987, 35, 3995–3999; (g) B. P. Bashyal,
G. W. J. Fleet, M. J. Gough and P. W. Smith, Tetrahedron,
E. Faggi, C. Parmeggiani and A. Goti, Eur. J. Org. Chem.,
2008, 2929–2947.
1987, 43, 3083–3093; (h) G. W. J. Fleet, P. W. Smith, 17 (a) W.-B. Wang, M.-H. Huang, Y.-X. Li, P.-X. Rui, X.-G. Hu,
S. V. Evans and L. E. Fellows, J. Chem. Soc., Chem.
Commun., 1984, 1240–1241.
14 (a) Y.-X. Li, K. Kinami, Y. Hirokami, A. Kato, J.-K. Su,
Y.-M. Jia, G. W. J. Fleet and C.-Y. Yu, Org. Biomol. Chem.,
W. Zhang, J.-K. Su, Z.-L. Zhang, J.-S. Zhu, W.-H. Xu,
X.-Q. Xie, Y.-M. Jia and C.-Y. Yu, Synlett, 2010, 488–492;
(b) O. Tamura, A. Toyao and H. Ishibashi, Synlett, 2002,
1344–1346.
2016, 14, 2249–2263; (b) Y.-X. Li, R. Iwaki, A. Kato, Y.-M. Jia, 18 I. Delso, T. Tejero, A. Goti and P. Merino, J. Org. Chem.,
G. W. J. Fleet, X. Zhao, M. Xiao and C.-Y. Yu, Eur. J. Org. 2011, 76, 4139–4143.
Chem., 2016, 1429–1438; (c) Y.-X. Li, Y. Shimada, K. Sato, 19 G. M. J. Lenagh-Snow, N. Araujo, S. F. Jenkinson,
A. Kato, W. Zhang, Y.-M. Jia, G. W. J. Fleet, M. Xiao and
C.-Y. Yu, Org. Lett., 2015, 17, 716–719; (d) Y.-X. Li,
Y. Shimada, I. Adachi, A. Kato, Y.-M. Jia, G. W. J. Fleet,
C. Rutherford, S. Nakagawa, A. Kato, C.-Y. Yu,
A. C. Weymouth-Wilson and G. W. J. Fleet, Org. Lett., 2011,
13, 5834–5837.
M. Xiao and C.-Y. Yu, J. Org. Chem., 2015, 80, 5151–5158; 20 H. Setoi, H. Kayakiri, H. Takeno and M. Hashimoto, Chem.
(e) A. Kato, Z.-L. Zhang, H.-Y. Wang, Y.-M. Jia, C.-Y. Yu, Pharm. Bull., 1987, 35, 3995–3999.
K. Kinami, Y. Hirokami, Y. Tsuji, I. Adachi, R. J. Nash, 21 The crystal structure of compound 14 has been deposited
G. W. J. Fleet, J. Koseki, I. Nakagome and S. Hirono, J. Org.
Chem., 2015, 80, 4501–4515; (f) J.-S. Zhu, S. Nakagawa,
W. Chen, I. Adachi, Y.-M. Jia, X.-G. Hu, G. W. J. Fleet,
at the Cambridge Crystallographic Data Centre and allo-
cated the deposition number CCDC 1455389. See the ESI†
for the details.
F. X. Wilson, T. Nitoda, G. Horne, R. van Well, A. Kato and 22 (a) K. C. Nicolaou, S. P. Seitz, M. R. Pavia and N. A. Petasis,
C.-Y. Yu, J. Org. Chem., 2013, 78, 10298–10309;
(g) W.-B. Zhao, S. Nakagawa, A. Kato, I. Adachi, Y.-M. Jia,
X.-G. Hu, G. W. J. Fleet, F. X. Wilson, G. Horne,
J. Org. Chem., 1979, 44, 4011–4013; (b) S. Masamune,
L. D. L. Lu, W. P. Jackson, T. Kaiho and T. Toyoda, J. Am.
Chem. Soc., 1982, 104, 5523–5526.
A. Yoshihara, K. Izumori and C.-Y. Yu, J. Org. Chem., 2013, 23 (a) S. K. Chattopadhyay and J. P. Mukherjee, Synthesis,
78, 3208–3221; (h) H. Zhao, A. Kato, K. Sato, Y.-M. Jia and
C.-Y. Yu, J. Org. Chem., 2013, 78, 7896–7902; (i) W.-Y. Xu,
R. Iwaki, Y.-M. Jia, W. Zhang, A. Kato and C.-Y. Yu, Org.
Biomol. Chem., 2013, 11, 4622–4639; ( j) Z.-L. Zhang,
S. Nakagawa, A. Kato, Y.-M. Jia, X.-G. Hu and C.-Y. Yu, Org.
Biomol. Chem., 2011, 9, 7713–7719; (k) W. Zhang, K. Sato,
A. Kato, Y.-M. Jia, X.-G. Hu, F. X. Wilson, R. van Well,
G. Horne, G. W. J. Fleet, R. J. Nash and C.-Y. Yu, Org. Lett.,
2014, 2481–2488; (b) B. Chandrasekhar, A. Madhan and
B. V. Rao, Tetrahedron, 2007, 63, 8746–8751; (c) R. Badorrey,
C. Cativiela, M. D. Díaz-de-Villegas, R. Díez and
J. A. Gálvez, Synlett, 2005, 1734–1736; (d) J. G. Buchanan,
K. W. Lumbard, R. J. Sturgeon, D. K. Thompson and
R. H. Wightman, J. Chem. Soc., Perkin Trans. 1, 1990, 699–
706; (e) G. W. J. Fleet, J. C. Son, D. S. C. Green, I. C. di Bello
and B. Winchester, Tetrahedron, 1988, 44, 2649–2655.
2011, 13, 4414–4417; (l) Y.-X. Li, M.-H. Huang, 24 B. Winchester, S. al Daher, N. C. Carpenter, I. Cenci di
Y. Yamashita, A. Kato, Y.-M. Jia, W.-B. Wang, G. W. J. Fleet,
R. J. Nash and C.-Y. Yu, Org. Biomol. Chem., 2011, 9, 3405–
Bello, S. S. Choi, A. J. Fairbanks and G. W. J. Fleet, Biochem.
J., 1993, 290, 743–749.
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