Efficient and stereodivergent syntheses of D- and L-fagomines and their analogues

Article abstract of DOI:10.1002/ejoc.200800796

The syntheses of D- and L-fagomines 1, 4, 5 and 6 and their isomers from starting D-glycals have been achieved. The syntheses involve elaboration of common amino alcohol precursors obtained from 2-deoxy-1-amino sugar derivatives. The key steps in the synt

Full text of DOI:10.1002/ejoc.200800796

FULL PAPER
DOI: 10.1002/ejoc.200800796
Efficient and Stereodivergent Syntheses of
Analogues
D
- and -Fagomines and Their
L
Nitee Kumari,[a] B. Gopal Reddy,[a] and Yashwant D. Vankar*[a]
Keywords: Carbohydrates / Azasugars / Enzymes / Inhibitors / Fagomines / Total synthesis / Hydroazidation
The syntheses of
isomers from starting
theses involve elaboration of common amino alcohol precur-
sors obtained from 2-deoxy-1-amino sugar derivatives. The
D
- and
L
-fagomines 1, 4, 5 and 6 and their
key steps in the syntheses are intramolecular reductive amin-
ation and intramolecular N-heterocyclization.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
D-glycals have been achieved. The syn-
Introduction
Polyhydroxyated piperidines (azasugars) containing a ni-
trogen atom in place of the ring oxygen atom of a sugar
moiety have been a subject of great synthetic interest be-
cause of their remarkable biological activity as glycosidase
inhibitors.[1,2] Since glycosidases are involved in numerous
fundamental biological processes, azasugars have been
shown to be effective therapeutic agents for the treatment
of a wide range of diseases, including diabetes,[3] viral infec-
tion,[4] tumour metastasis[5] and lysosomal storage disor-
der.[6] In addition, some azasugars have also been reported
to inhibit enzymes such as glycosyltransferases,[7] glycogen
phosphorylases,[8] a sugar nucleotide mutase,[9] nucleoside
processing enzyme[10] and metalloproteinases.[11] These im-
portant developments in the fields of bio-organic and me-
dicinal chemistry, with direct potential for therapeutic ap-
plications, have led to many synthetic approaches towards
naturally occurring azasugars and structurally modified an-
alogues.[1,2]
1,2-Dideoxy-azasugars represent a small but an impor-
tant class of glycosidase inhibitors.[12] Fagomine (1,
Scheme 1), a member of this family, was isolated from the
seeds of Japanese buckwheat Fagopyrum esculentum aus-
trale Moench[13] and also from the seeds of Castanosper-
mum australe (Leguminosae).[14] Recently, isomers of fago-
mine such as 2 and 3 have been isolated from the leaves and
roots of the legume Xanthocersis zambesiaca.[1e,15]
Scheme 1.
for mammalian α-glucosidase and ß-galactosidase, as well
as for lysosomal α-galactosidase A in Fabry lymphoblasts.
Several syntheses of -fagomine (1), both from carbo-
hydrate[18] and from non-carbohydrate precursors,[19] have
been reported in the literature. However, syntheses of fago-
mine isomers such as 2 and 3 have been reported much
more rarely.[19f] Most synthetic efforts have been directed
towards the synthesis of fagomines possessing the naturally
occurring  configuration; only Shipman and co-workers
were able to produce the -configured fagomine dia-
stereomer as a by-product,[18d] whereas Passacantilli and
co-workers[20] reported the synthesis of 1,2-dideoxy--aza-
sugars from -glycal derivatives.
In continuation of our efforts directed towards the syn-
thesis of new glycosidase inhibitors from carbohydrate de-
rivatives,[21] here we report short and efficient syntheses of
- and -fagomines and their epimers by two methodologies
newly developed in our laboratory[22,23] for the preparation
of 2-deoxy-1-amino sugar derivatives from -glycals.
Further, fagomine (1) has been reported to have a potent
antihyperglycemic effect in streptozocin-induced diabetic
mice and in potentiation of glucose-induced insulin se-
cretion.[16] Another recent report[17] also found 4-epi-fago-
mine (4) to be a potent glycosidase inhibitor, particularly
Results and Discussion
The two approaches towards fagomines and their ana-
logues are based on the introduction of amino functionali-
ties into -glycals, followed by ring-opening to cleave the
C–O bonds, and finally cyclizations to make C–N bonds.
Our retrosynthetic analysis is outlined in Scheme 2.
[a] Department of Chemistry, Indian Institute of Technology
Kanpur,
Kanpur 208016, India
Fax: +91-512-259-7436
E-mail: vankar@iitk.ac.in
160
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Efficient, Stereodivergent Syntheses of Fagomines and Analogues
Scheme 2.
In the first approach, we introduced amino groups as mixture did not matter, because the reduction with LiAlH4
described in a recent report[22] from our laboratory to make in the next step led to the loss of the asymmetric centre.
vicinal chloroacetamide sugar derivatives from -glycals. Thus, reduction of these 2-deoxy-1-amino sugar derivatives
3,4,6-Tri-O-benzyl--glucal, on treatment with silver ni- 11a and 11b with LiAlH4 gave the ring-opened amino
trate/oxalyl chloride in acetonitrile, thus gave a dia- alcohols 13a and 13b (Scheme 4), respectively. Oxidation of
stereomeric mixture (1:1) of the corresponding chloroacta- the free hydroxy groups in 13a and 13b with pyridinium
mide derivative 7a (Scheme 3) in 80% yield, whereas in the chlorochromate (PCC) in CH2Cl2 easily provided the de-
case of 3,4,6-tri-O-benzyl--galactal the product 7b was sired ketones 14a and 14b in 90% and 88% yields, respec-
formed in 15:1 diastereomeric ratio, also in 80% yield. The tively. Reductive amination and debenzylation of ketones
amide functionalities in chloroacetamides 7a and 7b were 14a and 14b under H2 (50 psi) in MeOH in the presence of
unmasked to provide the corresponding free amines 8a and Pd/C (10%) afforded the desired fagomine (1, 80:20 dia-
8b, respectively, under mild acidic conditions as described stereomeric ratio) and 4-epi-fagomine (4, 85:25 dia-
in our reported procedure.[22] The resulting crude amines stereomeric ratio), respectively, each in a single step.
were protected as benzyl carbamates 9a and 9b, which after
For the synthesis of -fagomine (5) and 4-epi--fagomine
dechlorination under radical conditions[24] afforded the 2- (6), the free amines in 8a and 8b were protected as tert-
deoxy-1-amino sugar derivatives 11a and 11b, respectively butyl carbamates to give 10a and 10b (Scheme 3), followed
(Scheme 3). Interestingly, 11b was found to exist in only one by radical dechlorination to form 2-deoxy-1-amino deriva-
anomeric form (β-anomer), whereas 11a was found to be a tives 12a and 12b, respectively. These amino compounds
1:1 anomeric mixture. The formation of 11a as an anomeric 12a and 12b, under ring-opening reaction conditions similar
Scheme 3.
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161

N. Kumari, B. G. Reddy, Y. D. Vankar
FULL PAPER
duction of the azido sugars 17a and 17b with LiAlH4
(2 equiv.) in ether at reflux afforded the corresponding
amino alcohols 18a and 18b, respectively. The primary
–NH2 groups were protected as –NHNos moieties to give
19a and 19b, which was followed by benzylation with BnBr
in the presence of K2CO3 as a base to give tertiary amines
20a and 20b, respectively.
Oxidation of the free hydroxy groups in 20a and 20b with
IBX gave the corresponding ketones 21a and 21b in 99%
and 85% yields, respectively. Removal of the nosyl groups
in 21a and 21b with PhSH/K2CO3 in acetonitrile[26] gave
the secondary amines 22a and 22b, which were unstable on
silica gel columns, so we proceeded further without purifi-
cation. Intramolecular reductive amination of the crude
amino ketones 22a and 22b with NaBH(OAc)3 afforded the
corresponding cyclized products 23a and 23b, respectively,
as single stereoisomers. Finally, removal of the benzyl
groups in 23a and 23b by hydrogenolysis with 20%
Pd(OH)2/C in THF under H2 pressure at room temperature
afforded fagomine (1) and 3-epi-fagomine (4), respectively.
The spectroscopic data for 1 and 4 were found to be in
agreement with the reported data.[19]
We have also synthesized -fagomine (5) and 4-epi--fag-
omine (6) from compounds 19a and 19b, respectively, via
intermediates 25a and 25b as shown in Scheme 7. Thus, 19a
and 19b were treated with PPh3 and diisopropyl azadicar-
boxylate (DIAD) for intramolecular SN2-type cyclization,
under typical Mitsunobu conditions, to afford the cyclized
products 24a and 24b, respectively, in good yields. Removal
of the nosyl groups was carried out with PhSH/K2CO3 to
give 25a and 25b, respectively.
Scheme 4.
to those used in the cases of 11a and 11b, gave amino
alcohols 15a and 15b (Scheme 5), respectively, upon treat-
ment with LiAlH4. The free hydroxy groups of amino
alcohols 15a and 15b were mesylated with MsCl/Et3N, fol-
lowed by intramolecular N-heterocyclization. This was ac-
complished by the removal of their Boc groups in
CF3COOH/dichloromethane, followed by K2CO3-induced
intramolecular SN2 cyclization,[25] leading to the targets 25a
and 25b (Scheme 5). The spectroscopic data for compounds
25a and 25b were in accordance with the literature data.[20]
The removal of the benzyl ethers in 25a and 25b was carried
The inhibitory activities of fagomine isomers 5 and 6
out with Pd(OH)2 in MeOH to afford fully deprotected - were tested against a few glycosidases,[27] and the results are
fagomine (5) and 4-epi--fagomine (6) in 80% and 85% shown in Table 1. Compound 5 was found to show moder-
yields, respectively.
ate inhibition of β-glucosidase, α-galactosidase and β-galac-
In our second approach directed towards the synthesis tosidase, whereas it showed no inhibition of α-glucosidase
of 1 and 4, we again followed a methodology developed in and α-mannosidase. On the other hand, compound 6
our laboratory for easy access to 2-deoxy-1-azido sugars showed no inhibition of α-glucosidase, β-glucosidase and α-
from -glycals,[23] using TMSONO2 and TMSN3 in aceto- mannosidase, but reasonable inhibition of α-galactosidase
nitrile for the synthesis of 17a and 17b (Scheme 6). Re- and β-galactosidase at 0.8 m concentration.
Scheme 5.
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Efficient, Stereodivergent Syntheses of Fagomines and Analogues
Scheme 6.
Conclusions
In conclusion, we have developed two synthetic strategies
for fagomine and its analogues involving the use of 2-de-
oxy-1-amino sugar derivatives obtained from -glycals by
methods developed in our laboratory for choloroamidation
and hydroazidation. A concise sequence of ring-opening
and cyclization reactions then allowed us to prepare both
- and -fagomine and their analogues in few steps. The
strategy based on hydroazidation of glycals is more efficient
for the synthesis of -fagomine and its derivatives, whereas
the strategy based on choloroamidation of glycals is more
effective for the synthesis of -fagomine and derivatives.
Experimental Section
General: Infrared spectra were recorded on a Bruker FT/IR Vec-
tor 22 spectrophotometer. 1H and 13C NMR spectra were recorded
on JEOL LA-400 and JEOL ECX-500 spectrometers in CDCl3
with tetramethylsilane as the internal standard. The mass spectra
were recorded on a Waters HAB213 Q Tof Premier Micromass
spectrometer and a Microscopic II triple Quadrupole mass spec-
trometer. Rotation values were recorded on an Autopol II auto-
matic polarimeter at the wavelength of the sodium -line (589 nm)
at 25 °C. Column chromatography was performed on silica gel
(100–200 mesh), and thin-layer chromatography (TLC) was per-
formed on silica gel plates made with grade G silica gel obtained
from s.d.fine-chem Ltd., Mumbai. Melting points were determined
with a Fischer–John melting point apparatus. All solvents and
common reagents were purified by established procedures.
Scheme 7.
Table 1. IC50 values for compounds 5 and 6.
Enzymes
5
NI[a]
5.8 m
0.6 m
0.67 m
NI[a]
6
α-Glucosidase (rice)
NI[a]
β-Glucosidase (almonds)
α-Galactosidase (coffee beans)
β-Galactosidase (bovine liver)
α-Mannosidase (jack beans)
NI[a]
0.9 m
0.77 m
NI[a]
Starting Material: All starting materials 7a, 7b, 8a, 8b, 17a and 17b
[a] NI: no inhibition at Ͻ1.0 m concentration; inhibition studies
were carried out at optimal pH of the enzymes and at 37 °C.
were prepared by the reported procedures.[22,23]
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163

N. Kumari, B. G. Reddy, Y. D. Vankar
FULL PAPER
Benzyl (4S,5R,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-3-chloro- (Cquat, Ph), 128.49, 128.47, 128.44, 128.40, 128.32,128.29, 128.24,
tetrahydro-2H-pyran-2-ylcarbamate (9a): Benzyl chloroformate 128.13, 127.95, 127.91, 127.89, 127.86, 127.80, 127.72, 127.69,
(CbzCl) (0.54 g, 3.19 mmol) and saturated aq. NaHCO3 solution 127.65,127.62, 127.5 (Ph), 85.9, 82.8, 80.7, 78.2, 76.7, 76.5, 76.1,
(5 mL) were added at room temperature to a mixture of chlo-
roamine 8a (1 g, 2.13 mmol) and EtOAc (7 mL). The reaction mix-
ture was stirred for 2.5–3 h until the reaction was complete (TLC
monitoring). The organic layer was separated, and the aqueous
layer was extracted with more EtOAc (2ϫ10 mL). Conventional
workup, followed by column chromatographic purification, gave a
1:1 mixture of two diastereomers; yield 90% (1.16 g), liquid, Rf =
0.50 (hexane/ethyl acetate, 8:2). 1H NMR (500 MHz, CDCl3, 1:1
mixture of diastereomers): δ = 7.13–7.41 (m, 20 H) 6.01–6.03 (d, J
= 9.5 Hz, 1 H, NHCbz, isomer A), 5.80–5.81 (d, J = 8.5 Hz, 1 H,
NHCbz, isomer B), 5.25–5.27 (d, J = 10 Hz, 1 H, 1-H, isomer A),
4.45–5.19 (m, 13 H, 6ϫCH2Ph, both isomers, 1-H, isomer B), 4.36
(br. s, 1 H, 6Ј-H, isomer A), 3.98–4.01 (t, J = 9 Hz, 1 H, 5-H,
isomer A), 3.65–3.85 (8 H, 2-H, 3-H, 6-H, isomer B, 2-H, 3-H, 5-
H, 6-H, 6Ј-H, isomer A), 3.55–3.61 (m, 2 H, 4-H, both iso-
mers) ppm. 13C NMR (100 MHz, CDCl3, mixture of dia-
75.2, 74.9, 73.5, 73.2, 71.2, 68.4, 67.9, 67.3, 67.2, 61.7, 61.1,
33.1 ppm. IR (CH Cl ): ν
= 1726, 3343 cm–1. MS/ESI: [M +
˜
max
2
2
Na]+ calcd. 590.2519; found 590.2513.
Benzyl
(2R,4R,5R,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-
tetrahydro-2H-pyran-2-ylcarbamate (11b): The same experimental
procedure as used for converting compound 9a to give compound
11a was followed; yield 75% (353 mg), viscous liquid, Rf = 0.50
(hexane/ethyl acetate, 8:2), [α]2D5 = –18.2 (c = 61, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 7.25–7.37 (m, 20 H), 5.46 (d, J = 9.8 Hz,
1 H), 5.04–5.14 (q, J = 12.2 Hz, 2 H), 4.95–5.03 (m, 1 H), 4.90 (d,
J = 11.7 Hz, 1 H), 4.53–4.64 (m, 3 H), 4.38–4.45 (q, J = 11.7 Hz,
2 H), 3.89 (br. s, 1 H), 3.56–3.63 (m, 4 H), 1.97–2.01 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 155.2 (N–C=O), 138.78, 138.12,
137.99, 136.15 (Cquat, Ph), 128.47, 128.37, 128.19, 127.9, 127.7,
127.5, 127.3 (Ph), 78.7, 77.6, 75.2, 74.5, 73.5, 71.6, 70.4, 68.5, 66.9,
32.6 ppm. IR (CH Cl : ν
= 1725, 3345 cm–1. MS/ESI: [M +
˜
max
2
2
stereomers): δ = 156.2 (N–C=O), 138.1, 137.9, 137.3, 135.9 (Cquat
,
Na]+ calcd. 590.2519; found 590.2512.
Ph), 128.49, 128.47, 128.44, 128.40, 128.32,128.29, 128.24, 128.13,
127.95, 127.91, 127.89, 127.86, 127.80, 127.72, 127.69,
127.65,127.62, 127.5 (Ph), 85.9, 82.8, 80.7, 78.2, 76.7, 76.5, 76.1,
75.2, 74.9, 73.5, 73.2, 71.2, 68.4, 67.9, 67.3, 67.2, 61.7, 61.1 ppm.
Benzyl
(3R,4R)-3,4,6-Tris(benzyloxy)-5-hydroxyhexylcarbamate
(13a): A solution of compound 11a (300 mg, 0. 53 mmol) in THF
(3 mL) was added dropwise at 0 °C to a suspension of LiAlH4
(40.3 mg, 1.06 mmol) in dry THF (5 mL). The reaction mixture
was stirred for 2 h at room temperature. The reaction mixture was
cooled to 0 °C and quenched with EtOAc and water, followed by
NaOH (1 ). The resulting white precipitate was removed by fil-
tration through a celite pad, and the filtrate was extracted with
ethyl acetate (2ϫ50 mL). The organic layer was washed with brine
and dried with Na2SO4, and the solvent was removed to provide
the ring-opened product, which was purified by column chromatog-
raphy; yield 95%, viscous liquid Rf = 0.50 (hexane/ethyl acetate,
6:4), [α]2D5 = +26.9 (c = 1.05, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 7.21–7.36 (m, 20 H), 5.06 (s, 2 H) 4.43–4.69 (m, 7 H),
3.96 (m, 1 H), 3.65–3.67 (m, 4 H), 3.14–3.17 (m, 3 H), 1.77–1.84
(m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.2 (N–C=O),
138.03, 137.93, 137.49, 136.63 (Cquat, Ph) 128.50, 12845, 128.40,
128.15, 128.02, 127.88, 127.72, 126.93 (Ph), 73.6, 73.5, 72.7, 71.1,
IR (CH Cl ): ν
= 1731, 3327 cm–1. MS/ESI: [M + Na]+ calcd.
˜
max
2
2
624.2129; found 624.2131.
Benzyl (2R,3R,4S,5S,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-
3-chloro-tetrahydro-2H-pyran-2-ylcarbamate (9b): The same experi-
mental procedure as used to obtain compound 9a from 8a was
followed; yield 80% (1.03 g), viscous liquid, Rf = 0.50 (hexane/ethyl
acetate, 8:2), [α]2D5 = +20.8 (c = 1.88, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 7.23–7.39 (m, 20 H), 5.65 (d, J = 9.8 Hz, 1 H), 5.13
(s, 2 H), 5.003 (t, J = 9.52 Hz, 1 H, 1-H), 4.84 (d, J = 11.5 Hz, 1
H), 4.66 (d, J = 11.0 Hz, 2 H), 4.61 (d, J = 11.0 Hz, 1 H), 4.34–
4.43 (q, J = 11.9 Hz, 2 H), 4.11 (t, J = 9.8 Hz, 1 H, 2-H), 3.97 (br.
s, 1 H, 4-H), 3.68–3.72 (m, 1 H, 6Ј-H), 3.51–3.54 (m, 3 H, 3-H, 5-
H, 6-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.5 (N–C=O),
138.13, 137.7, 137.48, 136.01 (Cquat, Ph), 128.43, 128.27, 128.24,
128.1, 127.95, 127.89, 127.81, 127.71, 127.56, 127.0 (Ph), 83.1, 74.9,
70.7, 66.5, 65.8, 38.2, 30.1 ppm. IR (CH Cl ): ν = 1715,
˜
max
2
2
74.8, 73.4, 73.2, 67.8, 67.2, 65.2, 59.8 ppm. IR (CH Cl ): ν =
˜
max
2
2
3425 cm–1. MS/ESI: [M + Na]+ calcd. 592.2675; found 592.2670.
1725, 3345 cm–1. MS/ESI: [M + Na]+ calcd. 624.2129; found
Benzyl (3R,4S)-3,4,6-Ttris(benzyloxy)-5-hydroxyhexylcarbamate
624.2130.
(13b): The same experimental procedure as used for converting
compound 11a to 13a was followed; yield 90% (363 mg), viscous
liquid Rf = 0.50 (hexane/ethyl acetate, 6:4), [α]2D5 = +26.9 (c = 1.05,
Benzyl
(4R,5S,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)tetra-
hydro-2H-pyran-2-ylcarbamate (11a): Tributyltin chloride (35.1 mg,
0.11 mmol), sodium cyanoborohydride (60.9 mg, 0.82 mmol) and
AIBN (5 mg) were added to a solution of the chloro derivative 9a
(500 mg, 0.83 mmol) in tBuOH (10 mL) in a dry, round-bottomed
flask. The suspension was heated at reflux for 2 h, and after com-
pletion of the reaction (TLC monitoring) the reaction mixture was
concentrated in vacuo, water was added, and extraction was carried
out with EtOAc (3ϫ10 mL). The organic layer was then washed
with NH4OH solution (2%) followed by brine. The organic layer
was dried with anhydrous sodium sulfate and concentrated in
vacuo to provide crude dechlorinated product, which was purified
by column chromatography; yield 82%, liquid Rf = 0.50 (hexane/
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.19–7.28 (m, 20 H),
5.02 (s, 2 H) 4.44–4.69 (m, 7 H), 3.96 (br. s, 1 H), 3.65 (m, 2 H),
3.45–3.47 (m, 2 H), 3.19 (m ppm. 2 H), 2.23 (br. s, 1 H), 1.75–1.77
(m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.3, 137.9 (m),
128.1 (m), 77.8, 74.02, 73.5, 72.5, 70.9, 69.8, 66.5, 38.2,30.6 ppm.
IR (CH Cl ): ν
= 1710, 3420 cm–1. MS/ESI: [M + Na]+ calcd.
˜
max
2
2
592.2675; found 592.2669.
Benzyl (3R,4S)-3,4,6-Tris(benzyloxy)-5-oxohexylcarbamate (14a):
Pyridinium chlorochromate (400 mg, 1.8 mmol) was added to a
stirred mixture of compound 13a (500 mg, 0.88 mmol) and molecu-
ethyl acetate, 8:2). 1H NMR (500 MHz, CDCl3, 1:1 mixture of dia- lar sieves (4 Å, 100 mg) in CH2Cl2 (10 mL), in an ice/salt bath.
stereomers): δ = 7.32–7.16 (m, 20 H), 5.50 (d, J = 9.5 Hz, 1 H,
NHCbz, isomer A), 5.45 (d, J = 8.5 Hz, 1 H, NHCbz, isomer B),
Dichloromethane was then poured into the mixture after it had
been stirred for 10 h at room temperature. The resulting mixture
5.14 (br. s, 4 H), 5.02–5.07 (br., 1 H, 1-H, isomer A), 4.58–4.65 (m, was filtered through celite, and the solvent was evaporated. The
13 H, 6ϫCH2Ph, both isomers, 1-H, isomer B), 3.84–4.17 (m, 4 residue was purified by column chromatography; yield 90%
H, both isomers), 3.54–3.73 (m, 6 H, both isomers), 1.95–2.00 (m, (448 mg), viscous liquid, Rf = 0.50 (hexane/ethyl acetate, 9:1),
1
4 H, both isomers) ppm. 13C NMR (100 MHz, CDCl3, mixture of
[α]2D5 = –13.3 (c = 00.30, CH2Cl2). H NMR (400 MHz, CDCl3): δ
diastereomers): δ = 156.0 (N–C=O), 138.1, 137.9, 137.2, 136.8 = 7.21–7.36 (m, 20 H), 5.06 (s, 2 H), 4.39–4.64 (m, 7 H), 4.27 (s, 2
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Efficient, Stereodivergent Syntheses of Fagomines and Analogues
H), 4.05–4.06 (d, J = 3.68 Hz, 1 H), 3.96 (m, 1 H), 3.65 (m, 1 H),
3.08–3.11 (m, 2 H), 1.73–1.75 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 207.9, 156.2, 137.34, 137.1, 136.67 (Cquat, Ph), 128.6,
4.04 (t, J = 9.5 Hz, 1 H), 3.97 (m, 1 H), 3.68–3.72 (m, 1 H), 3.54–
3.58 (m, 3 H), 1.40 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 154.6, 138.21, 137.71, 137.47 (Cquat, Ph), 128.43, 128.21, 127.98,
128.5, 128.41, 128.03, 127.9 (Ph), 83.7, 73.5, 74.4, 73.8, 73.4, 72.8, 127.93, 127.8, 127.7 (Ph), 83.2, 82.8, 80.5, 74.8, 73.4, 73.1, 67.7,
66.7, 37.7, 30.5 ppm. IR (CH Cl ): ν
= 1723, 3350 cm–1. MS/ 59.9, 28.2 ppm. IR (CH Cl ): νmax = 1725, 3345 cm–1. MS/ESI: [M
˜
˜
2
2
max
2
2
ESI: [M + Na]+ calcd. 590.2519; found 590.2517.
+ Na]+ calcd. 590.2285; found 590.2288.
Benzyl (3R,4R)-3,4,6-Tris(benzyloxy)-5-oxohexylcarbamate (14b): tert-Butyl (4R,5S,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)tetra-
The same experimental procedure as used for converting com-
pound 13a to 14a was followed; yield 88% (438 mg), viscous liquid,
Rf = 0.50 (hexane/ethyl acetate, 9:1), [α]2D5 = +15.0 (c = 1, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.26–7.36 (m, 20 H), 5.06 (s, 2
hydro-2H-pyran-2-ylcarbamate (12a): The same experimental pro-
cedure as used for 11a from 9a was followed; yield 80%, 182 mg,
liquid, Rf = 0.50 (hexane/ethyl acetate, 8:2), H NMR (500 MHz,
1
CDCl3) (1:1 mixture of diastereomers) δ = 7.16–7.32 (m, 15 H, Ar-
H), 4.76–4.79 (m, 1 H), 4.45–4.61 (m, 6 H), 4.31 (s, 2 H), 4.17 (d, H), 5.25 (br., 1 H), 4.94 (br., 1 H), 4.86 (d, J = 9.5 Hz, 1 H), 4.34–
J = 3.44 Hz, 1 H), 3.85–3.88 (m, 1 H), 3.17–3.28 (m, 2 H), 1.59– 4.66 (m, 13 H), 4.17 (br., 1 H), 3.84–4.05 (m, 3 H), 3.46–3.73 (m,
1.88 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 207.5, 161.2, 5 H), 2.23–2.26 (m, 2 H), 1.95 (m, 2 H), 1.44 (s, 9 H, tert-butyl),
137.5, 137.42, 136.8 (Cquat, Ph) 128.55, 128.46, 128.15, 128.00 (Ph), 1.42 (s, 9 H, tert-butyl) ppm. 13C NMR (100 MHz, CDCl3, 1:1 mix-
83.7, 78.2, 74.2, 73.3, 73.2, 72.5, 66.5, 37.8, 30.5 ppm. IR (CH2Cl2): ture of diastereomers): δ = 154.6, 154.2 (N–C=O), 138.15, 137.88,
ν
max = 1723, 3350 cm–1. MS/ESI: [M + Na]+ calcd. 590.2519; found
137.3 (Cquat, Ph), 128.46, 128.3, 128.27, 128.23, 128.19, 127.94,
127.92, 127.86, 127.79, 127.7,127.61, 127.45 (Ph), 86.1, 80.7, 78.2,
77.2, 76.5, 76.1, 75.2, 74.9, 73.5, 73.4, 73.2, 71.2, 68.5, 68.1, 61.5,
˜
590.2514.
(2R,3R,4R)-2-(Hydroxymethyl)piperidine-3,4-diol (1): Pd/C (10%,
150 mg) was added to a solution of the oxidized product 14a
(300 mg, 0.53 mmol) in MeOH (50 mL). The reaction mixture was
shaken under hydrogen (50 psi) for 24 h at room temperature. After
removal of the catalyst by filtration through neutralized and deacti-
vated Al2O3, the solvent was evaporated under reduced pressure.
-Fagomine (1) was afforded as a mixture of two diastereoisomers
in a ratio of 80:20.
61.2, 33.3, 28.2 ppm. IR (CH Cl ): ν
= 1726, 3343 cm–1. MS/
˜
max
2
2
ESI: [M + Na]+ calcd. 556.2675; found 556.2677.
tert-Butyl (2R,4R,5R,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-
tetrahydro-2H-pyran-2-ylcarbamate (12b): The same experimental
procedure as used for 11a from 9a was followed; yield 78%, viscous
liquid, Rf = 0.50 (hexane/ethyl acetate, 8:2), [α]2D5 = –11.4 (c = 3.5,
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.25–7.33 (m, 15 H),
5.17–5.19 (d, J = 10.6 Hz, 1 H), 4.39–4.92 (m, 7 H), 3.89 (br. s, 1
(2R,3S,4R)-2-(Hydroxymethyl)piperidine-3,4-diol (4): The same ex-
perimental procedure as used for converting compound 14a into
1 was followed. The product was obtained as a mixture of two
diastereoisomers in a ratio of 85:15.
H), 3.57–3.63 (m, 4 H), 1.95–1.99 (m, 2 H) 1.42 (s, 9 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 154.5, 138.86, 138.16, 138.02 (Cquat
,
Ph), 128.46, 128.36, 128.16, 127.9, 127.69, 127.46, 127.3 (Ph), 80.2,
78.4, 77.7, 75.1, 74.4, 73.4, 71.7, 70.4, 68.5, 32.7, 28.3 ppm. IR
tert-Butyl
(4S,5R,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-3-
(CH Cl ): ν
= 1718, 3340 cm–1. MS/ESI: [M + Na]+ calcd.
˜
max
2
2
chlorotetrahydro-2H-pyran-2-ylcarbamate (10a): Boc2O (1.1 g,
5.05 mmol) and saturated aq. NaHCO3 solution (10 mL) were
added at room temperature to a solution of a mixture of chlo-
roamines 8a (2 g, 4.23 mmol in 15 mL EtOAc). The reaction mix-
ture was stirred for 2.5–3 h to complete the reaction (TLC monitor-
ing). The organic layer was separated, and the aqueous layer was
extracted with more EtOAc (2ϫ10 mL). Conventional workup fol-
lowed by column chromatographic purification gave a 1:1 mixture
of two diastereomers; yield 90% (2.18 g), liquid, Rf = 0.50 (hexane/
ethyl acetate, 8:2). 1H NMR (500 MHz, CDCl3, 1:1 mixture of dia-
stereomers): δ = 7.13–7.41 (m, 15 H, Ar-H), 5.72–5.74 (d, J =
10 Hz, 1 H, 1-H, isomer A), 5.35–5.364 (d, J = 9.5 Hz, 1 H, 1-H,
isomer B), 5.17–5.18 (d, J = 10 Hz, 1 H, 1-H, isomer A), 4.47–4.99
(m, 13 H, 6ϫOCH2Ph, both isomers, 1-H, isomer B), 4.37–4.38
(d, J = 2.5 Hz, 1 H, 6-H, isomer B), 3.98–4.01 (t, J = 9 Hz, 1 H,
5-H, isomer B), 3.65–3.85 (m, 8 H, 2-H, 3-H, 6Ј-H, isomer A, 2-
H, 3-H, 5-H, 6-H, 6Ј-H, isomer B), 3.53–3.58 (m, 2 H, 4-H, both
556.2675; found 556.2675.
tert-Butyl (3R,4R)-3,4,5-Tris(benzyloxy)-5-hydroxyhexylcarbamate
(15a): The same experimental procedure as used for 13a from 11a
was followed; yield 95% (384 mg), viscous liquid, Rf = 0.50 (hex-
ane/ethyl acetate, 6:4), [α]2D5 = +19.2 (c = 1.04, CH2Cl2). H NMR
1
(400 MHz, CDCl3): δ = 7.24–7.35 (m, 15 H), 4.46–4.68 (m, 7 H),
3.96–3.98 (m, 1 H), 3.65–3.83 (m, 4 H), 3.11–3.18 (m. 3 H), 1.74–
1.82 (m, 2 H), 1.43 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 155.9, 138.05, 137.97, 137.54 (Cquat, Ph), 128.48, 128.38, 128.14,
128.02, 127.88, 127.68 (Ph), 79.2, 73.6, 73.5, 72.7, 71.1, 70.8, 37.8,
29.7, 28.4 ppm. IR (CH Cl ): ν
= 3306, 1730, 1533 cm–1. MS/
˜
max
2
2
ESI: [M + Na]+ calcd. 558.2832; found 558.2834.
tert-Butyl(3R,4S)-3,4,6-tris(benzyloxy)-5-hydroxyhexylcarbamate
(15b): The same experimental procedure as used for 13a from 11a
was followed; yield 90% (364 mg), Rf = 0.3 (hexane/ethyl acetate,
6:4), [α]2D5 = +2.2 (c = 1.35, CH2Cl2). 1H NMR (400 MHz, CDCl3):
isomers), 1.50 (s, 9 H, tert-butyl, isomer B), 1.48 (s, 9 H, tert-butyl, δ = 7.25–7.33 (m, 15 H), 4.47–4.76 (m, 7 H), 3.92–3.96 (dt, J = 5.7,
isomer A) ppm. 13C NMR (100 MHz, CDCl3, 1:1 mixture of dia-
3.4 Hz, 1 H), 3.68–3.73 (m, 2 H, 3-H), 3.52 (m, 2 H), 3.18 (t, J =
6.5 Hz, 2 H), 2.61 (br. s, 1 H), 1.77–1.82 (dd, J = 12.4, 6.36 Hz, 2
stereomers): δ = 154.6, 154.2 (N–C=O), 138.15, 137.88, 137.3
(Cquat, Ph), 128.46, 128.3, 128.27, 128.23, 128.19, 127.94, 127.92, H), 1.42 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.3,
127.86, 127.79, 127.7,127.61, 127.45 (Ph), 86.1, 80.7, 78.2, 77.2,
76.5, 76.1, 75.2, 74.9, 73.5, 73.4, 73.2, 71.2, 68.5, 68.1, 61.5, 61.2,
137.9, 137.64, 137.5 (Cquat, Ph) 127.8–127.4 (m, Ph), 78.0, 77.9,
73.9, 73.4, 72.5, 70.9, 69.9, 37.8, 30.7, 28.4 ppm. IR (CH Cl ): ν
˜
max
2
2
28.2 ppm. IR (CH Cl ): ν
= 1726, 3343 cm–1. MS/ESI: [M +
˜
max
= 3440, 1705 cm–1. MS/ESI: [M + Na]+ calcd. 558.2832; found
2
2
Na]+ calcd.; 590.2285; found 590.2288.
558.2834.
tert-Butyl (2R,3R,4S,5S,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymeth- (3S,4R)-1,3,4-Tris(benzyloxy)-6-(tert-butoxycarbonylamino)hexan-
yl)-3-chlorotetrahydro-2H-pyran-2-ylcarbamate (10b): The same ex-
perimental procedure as used for 10a from 8a was followed; yield
2-yl Methanesulfonate (16a): Alcohol 15a (200 mg, 0.37 mmol) was
dissolved in dry DCM (2 mL), and the mixture was cooled to 0 °C
with an ice bath. Triethylamine (74.7 mg, 0.74 mmol) and 4-(di-
80% (1.95 g), liquid, Rf = 0.50 (hexane/ethyl acetate, 8:2), [α]2D5
=
+48.9 (c = 1.125, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.25– methylamino)pyridine (0.2 mmol) were added, followed by slow ad-
7.45 (m, 15 H), 5.28–5.29 (d, J = 9.6 Hz, 1 H), 4.39–5.22 (m, 7 H), dition of MsCl (63.3 mg, 0.56 mmol). The reaction mixture was
Eur. J. Org. Chem. 2009, 160–169
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
165

N. Kumari, B. G. Reddy, Y. D. Vankar
FULL PAPER
stirred for 1 h at 0 °C to complete the reaction (TLC monitoring)
(Cquat, Ph), 128.29, 128.25, 128.00, 127.75, 127.58, 127.38 (Ph),
78.1, 73.5, 73.4, 71.4, 71.1, 70.9, 70.7, 54.7, 39.7, 29.5 ppm. IR
and was then quenched by addition of saturated aq. NaHCO3 solu-
tion (10 mL), and the mixture was extracted with CH2Cl2 (CH Cl ): ν
= 3340, 1685, 1100 cm–1. MSESI: [M + H]+ calcd.
˜
max
2
2
(3ϫ25 mL). The organic layer was washed with brine and dried
with anhydrous sodium sulfate. Concentration of the organic layer
on a rotary evaporator gave a crude product, which was purified
through column chromatography; yield 95% (217 mg), viscous li-
quid, Rf = 0.50 (hexane/ethyl acetate, 6:4), [α]2D5 = +28.6 (c = 00.35,
418.2382; found 418.2383.
(2R,3R,4R)-6-Amino-1,3,4-tris(benzyloxy)hexan-2-ol (18a): A solu-
tion of compound 17a (200 mg, 0.435 mmol) in diethyl ether
(3 mL) was added dropwise at 0 °C to a suspension of LiAlH4
(41 mg, 1.10 mmol) in dry ether (5 mL). The reaction mixture was
slowly brought to room temperature and was then heated at reflux
for 2 h. The reaction mixture was cooled to 0 °C and quenched
with EtOAc and water, followed by NaOH (1 ). The resulting
white precipitate was removed by filtration through a celite pad
and the filtrate was extracted with ethyl acetate (2ϫ50 mL). The
organic layer was washed with brine and dried with Na2SO4, and
the solvent was removed to provide the crude amino alcohol 18a,
which was subjected to subsequent reaction without any further
purification.
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.26–7.37 (m, 15 H),
4.98–4.99 (m, 1 H), 4.42–4.77 (m, 7 H), 3.83–3.95 (m, 3 H), 3.53–
3.56 (m, 1 H), 3.07–3.10 (m, 2 H), 3.01 (s, 3 H), 1.51–1.75 (m, 2
H), 1.43 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.8,
137.7, 137.65 (Cquat, Ph), 127.93–128.49 (m, Ph), 82.9, 79.9, 74.3,
73.4, 72.7, 69.0, 38.4, 37.6, 30.6, 28.4 ppm. IR (CH Cl ): ν =
˜
max
2
2
3424, 1710, 1362 cm–1. MSESI: [M + Na]+ calcd. 636.2607; found
636.2600.
(3R,4R)-1,3,4-Tris(benzyloxy)-6-(tert-butoxycarbonylamino)hexan-
2-yl Methanesulfonate (16b): The same experimental procedure as
used for 16a from 15a was followed; yield 98% (198 mg). Rf = 0.4
(hexane/ethyl acetate, 7:3), [α]2D5 = +8.6 (c = 2.68, CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 7.25–7.33 (m, 15 H), 4.79–4.82 (m,
2 H), 4.44–4.63 (m, 6 H), 3.95–3.97 (m, 1 H), 3.67–3.71 (m, 3 H),
3.18 (m, 2 H), 2.89 (s, 3 H), 1.77–1.82 (m, 2 H), 1.41 (s, 9 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 155.9, 137.79, 137.72, 137.21
(Cquat, Ph), 128.44, 127.99, 127.87 (Ph), 81.6, 79.2, 78.9, 78.4, 74.4,
(2R,3S,4R)-6-Amino-1,3,4-tris(benzyloxy)hexan-2-ol (18b): The
same experimental procedure as used for 18a from 17a was fol-
lowed.
4-Nitro-N-[(3R,4R)-3,4,6-tris(benzyloxy)-5-oxohexyl]benzenesulfon-
amide (19a): Pyridine (41 µL, 0.506 mmol) and p-nitrobenzenesul-
fonyl chloride (111 mg, 0.505 mmol) were added at 20 °C to a
stirred solution of amino alcohol 18a (200 mg, 0.459 mmol) in
CH2Cl2 (4 mL). The mixture was stirred for 1 h and extracted with
CH2Cl2 (2ϫ15 mL), and the organic layer was washed with water
and brine and dried with anhydrous Na2SO4. The concentrated
crude product was purified by column chromatography to give
compound 19a; yield 96 % (259 mg), viscous liquid, (over two
steps), [α]2D5 = +23.0 (c = 1, CH2Cl2). 1H NMR (400 MHz, CDCl3):
δ = 8.19–8.22 (m, 2 H), 7.80–7.83 (m, 2 H), 7.19–7.36 (m, 15), 4.90
(t, J = 6.1 Hz, 1 H), 4.38–4.63 (m, 6 H), 3.90 (br. s, 1 H), 3.58–
3.73 (m, 4 H), 3.04 (br. s, 1 H), 2.88–3.00 (m, 2 H), 1.72–1.86 (m,
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 149.7, 145.7, 137.79,
137.65, 137.37 (Cquat, Ph), 128.58, 128.46, 128.40, 12832, 128.16,
128.07, 128.05, 127.97, 127.89, 127.79 (Ph), 77.7, 76.6, 73.7, 73.4,
73.5, 71.9, 69.4, 38.4, 37.4, 30.1, 28.4 ppm. IR (CH Cl ): ν =
˜
max
2
2
3425, 1711 cm–1. MSES+: [M + H]+ calcd. 614.2788; found
614.2786.
(2S,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)piperidine (25a):
Trifluoroacetic acid (0.08 mL, 1.05 mmol) was added dropwise over
5 min, with stirring at 0 °C, to a solution of mesylate 16a (253 mg,
0.41 mmol) in dry DCM (4 mL). The reaction mixture was then
immediately warmed to room temperature and was stirred for
45 min, after which it was again cooled to 0 °C and diluted with
CH2Cl2 (10 mL). K2CO3 solution (2 , 5 mL) was added carefully.
This mixture was partitioned, and the aqueous phase was extracted
with DCM (5 mLϫ4). The combined organic phase was dried with
anhydrous K2CO3 and was filtered through celite. The solvents
were removed on a rotary evaporator. The residues were then dis-
solved in CH3CN (15 mL), and K2CO3 (283 mg, 2.05 mmol) was
added in two portions over 2 h. After the mixture had been stirred
for 12 h it was gradually heated up to 70 °C over 3 h. The consump-
tion of primary amine was confirmed by TLC, and the mixture was
filtered through celite and concentrated in vacuo to give the crude
cyclized product, which was purified by column chromatography;
yield 65% (111 mg), viscous liquid, (over two steps) Rf = 0.30 (hex-
72.6, 70.9, 70.5, 40.4, 30.1 ppm. IR (CH Cl ): ν = 3286, 1730,
˜
max
2
2
1529 cm–1. MS ES+: m/z = 643 [M + Na]+. C33H36N2O8S {643.20
[M + Na]+}: C 63.85, H 5.85, N 4.51, S 5.17; found C 63.90, H
5.91, N 4.55, S 5.09.
4-Nitro-N-[(3R,4S)-3,4,6-tris(benzyloxy)-5-hydroxyhexyl]benzene-
sulfonamide (19b): The same experimental procedure as used for
19a from 18a was followed; yield 94% (253 mg, over two steps),
viscous liquid, [α]2D5 = –1.5 (c = 2, CH2Cl2). H NMR (400 MHz,
1
CDCl3): δ = 8.20–8.23 (m, 2 H), 7.80–7.83 (m, 2 H), 7.22–7.35 (m,
15 H), 5.12–5.17 (dd, J = 15.4, 4.9 Hz, 1 H), 4.38–4.70 (m, 6 H),
3.81 (d, J = 3.4 Hz, 1 H), 3.68–3.72 (m, 2 H), 3.45–3.51 (m, 2 H),
3.00–3.12 (m, 1 H), 2.29–2.99 (m, 1 H), 2.27 (br. s, 1 H), 1.79–1.84
(br. dd, J = 12.4, 6.1 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 149.7, 145.7, 137.59, 137.51 (Cquat, Ph), 128.66, 128.49, 128.45,
128.11, 128.03, 127.93, 127.9, 124.19 (Ph), 78.6, 78.1, 74.3, 73.4,
1
ane/ethyl acetate 2:8), [α]2D5 = –11.75 (c = 1.7, CH2Cl2). H NMR
(400 MHz, CDCl3): δ = 7.10–7.29 (m, 15 H), 5.01 (br., 1 H), 4.41–
4.63 (m, 6 H), 3.43–3.67 (m, 5 H, 3-H), 2.95–3.02 (m, 2 H), 1.70–
1.99 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.21,
137.93 (Cquat, Ph), 128.37, 128.32, 128.01, 127.76, 127.63, 127.4
(Ph), 82.9, 73.3, 72.8, 72.5, 71.4, 70.9, 69.4, 54.1, 39.8, 29.6,
72.1, 70.9, 69.9, 40.4, 30.0 ppm. IR (CH Cl ): ν = 3306, 1730,
˜
max
2
2
25.1 ppm. IR (CH Cl ): νmax = 3424, 1710, 1362 cm–1. MS/ESI: [M
1533 cm–1. MS ES+: m/z = 643 [M + Na]+. C33H36N2O8S {643.20
[M + Na]+}: C 63.85, H 5.85, N 4.51, S 5.17; found C 63.89, H
5.88, N 4.57, S, 5.21.
˜
2
2
+ H]+ calcd. 418.2382; found 418.2383.
(2S,3S,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)piperidine (25b):
The same experimental procedure as for procuring compound 25a
from 16a was followed; yield 70% (120 mg), (over two steps), vis-
cous liquid, Rf = 0.30 (hexane/ethyl acetate 2:8), [α]2D5 = –46.75 (c
N-Benzyl-4-nitro-N-[(3R,4R)-3,4,6-tris(benzyloxy)-5-hydroxyhexyl]-
benzenesulfonamide (20a): K2CO3 (167 mg, 1.209 mmol) and benzyl
bromide (53 µL, 0.445 mmol) were added at 20 °C to a stirred solu-
= 1.6, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.23–7.37 (m, tion of sulfonamide 19a (250 mg, 0.403 mmol) in DMF (4 mL).
15 H), 4.34–4.68 (m, 6 H), 3.95 (br. s, 1 H), 3.73 (m, 1 H) 3.60 (m, The mixture was stirred for a further 1 h and after completion of
1 H), 3.34–3.38 (m, 2 H), 2.76 –3.02 (m, 3 H), 1.45–1.98 (m, 2
the reaction it was extracted with diethyl ether (2ϫ20 mL), washed
with water and brine, and dried with Na2SO4. The organic layer
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.89, 138.3, 131.33
166
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Eur. J. Org. Chem. 2009, 160–169

Efficient, Stereodivergent Syntheses of Fagomines and Analogues
was concentrated to provide a crude product, which was purified
by column chromatography to give compound 19a; yield 95 %,
271 mg, viscous liquid, [α]2D5 = +12.0 (c = 1, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 8.18–8.21 (m, 2 H, Ar-H), 7.81–7.83 (m, 2
H, Ar-H), 7.16–7.36 (m, 20 H, Ar-H), 4.24–4.57 (m, 8 H,
4ϫCH2Ph), 3.82 (br. s, 1 H, 1Ј-H), 3.51–3.61 (m, 4 H, 6-H, 6Ј-H,
(2S,3R,4R)-1-Benzyl-3,4-bis(benzyloxy)-2-(benzyloxymethyl)piper-
idine (23a): K2CO3 (116 mg, 0.846 mmol) and thiophenol (35 µL,
0.338 mmol) were added at 23 °C to a stirred solution of compound
21a (200 mg, 0.282 mmol) in dry CH3CN (4 mL). The reaction
mixture was stirred for 5 h, and after completion of the reaction
the mixture was extracted with ethyl acetate (2ϫ15 mL). The or-
3-H, 4-H), 3.14 (br. t, J = 7.5 Hz, 2 H, –OH and 5-H), 2.96 (br. s, ganic phase was washed with water and brine, dried with anhydrous
1 H, 1-H), 1.61–1.78 (m, 2 H, 2-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 149.7, 145.6, 137.93, 137.89, 137.62, 135.33 (Cquat
Ph), 128.69, 128.37, 128.33, 128.17, 128.12, 127.95, 127.86, 127.81,
Na2SO4 and concentrated under reduced pressure (avoiding heat-
ing) to give the unstable amino derivative 22a. The amino derivative
was subjected to subsequent reaction without any further purifica-
,
127.73, 124.21 (Ph), 77.6, 76.6, 73.47, 73.43, 72.3, 70.9, 70.4, 51.8, tion. Amino derivative 22a was hence dissolved in 1,2-dichloroe-
45.1, 29.0 ppm. IR (CH Cl ): ν
= 3452, 1747, 1530 cm–1. MS
˜
max
thane (3 mL), the reaction mixture was cooled to –35 °C, and anhy-
drous Na2SO4 (134 mg, 1.12 mmol), glacial acetic acid (97 µL,
1.70 mmol) and NaBH(OAc)3 (90 mg, 0.423 mmol) were added.
The stirring was continued for 24 h at the same temperature, and
the suspension was filtered, the solvent was evaporated, and the
residue was purified by chromatotron (ethyl acetate/hexane/0.2%
Et3N) to give compound 23a; yield 74% (106 mg), oil (over two
steps), [α]2D5 = –10.0 (c = 0.6, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 7.19–7.36 (m, 20 H), 4.93 (d, J = 11.0 Hz, 1 H), 4.56–
4.66 (q, J = 11.7 Hz, 2 H), 4.52 (d, J = 11.0 Hz, 1 H), 4.47 (br. s,
2 H), 4.11 (br. d, J = 13.4 Hz, 1 H), 3.77–3.84 (m, 2 H), 3.42–3.48
(ddd, J = 13.2, 8.3, 4.8 Hz, 1 H), 3.35 (br. d, J = 13.4 Hz, 1 H),
2.80 (br. d, J = 11.9 Hz, 1 H), 2.41 (br. d, J = 8.3 Hz, 1 H), 1.93–
2.03 (m, 2 H), 1.59–1.60 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 138.91, 138.2 (Cquat, Ph), 129.13, 128.32, 128.28,
128.12, 128.00, 127.96, 127.62, 127.53, 127.46, 127.4, 126.84 (Ph),
82.0, 79.1, 74.9, 73.2, 71.1, 67.2, 65.1, 57.1, 49.2, 28.6 ppm. MS
ES+: m/z = 508 [M + H]+; C34H37NO3 {508.28 [M + H]+}: C 80.44,
H 7.35, N 2.76; found C 80.48, H 7.41, N 2.78.
2
2
ES+: m/z = 733 [M + Na]+. C40H42N2O8S {733.25[M + Na]+}: C
67.59, H 5.96, N 3.94, S 4.51; found C 67.62, H 5.91, N 3.99, S
4.53.
N-Benzyl-4-nitro-N-[(3R,4S)-3,4,6-tris(benzyloxy)-5-hydroxyhexyl]-
benzenesulfonamide (20b): The same experimental procedure as
used for converting 19a to 20a was followed; yield 98% (280 mg),
viscous liquid, [α]2D5 = –4.34 (c = 1.1, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 8.19–8.22 (m, 2 H) ppm. 7.83–7.87 (m, 2 H), 7.19–
7.7.34 (m, 20 H), 4.12–4.62 (m, 8 H), 3.73–3.77 (m, 1 H), 3.51–3.6
(m, 2 H), 3.41–3.47 (br. d, J = 5.36 Hz, 1 H), 3.20–3.30 (m, 2 H),
2.67 (br. s, 1 H), 1.70–1.77 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 149.7, 145.5, 137.88, 135.51 (Cquat, Ph), 128.74, 128.42,
128.35, 128.25, 128.15, 127.89, 127.84, 127.80, 124.25 (Ph), 78.8,
74.0, 73.4, 72.1, 70.9, 69.7, 52.1, 45.2, 29.5 ppm. IR (CH Cl ): ν
˜
max
2
2
= 3309, 1746, 1532 cm–1. MS ES+: m/z = 733 [M + Na]+.
C40H42N2O8S {733.25 [M + Na]+}: C 67.59, H 5.96, N 3.94, S 4.51;
found C 67.64, H 5.99, N 3.98, S 4.54.
N-Benzyl-4-nitro-N-[(3R,4S)-3,4,6-tris(benzyloxy)-5-oxohexyl]ben-
zenesulfonamide (21a): IBX (1-hydroxy-1,2-benziodoxol-3(1H)-one
1-oxide, 2-iodoxybenzoic acid, 283 mg, 1.014 mmol) was added at
room temperature to a stirred solution of alcohol 20a (240 mg,
0.338 mmol) in acetone (4 mL). The mixture was heated at reflux
at 80 °C for 2.5 h, and after completion of reaction (TLC monitor-
ing) it was cooled to room temperature and filtered through a sin-
tered funnel. Evaporation of the filtrate gave a crude product,
which was purified by column chromatography to give compound
21a; yield 98%, 234 mg, viscous liquid, [α]2D5 = –13.0 (c = 1,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 8.19–8.21 (m, 2 H),
7.80–7.82 (m, 2 H), 7.12–7.32 (m, 20 H), 4.18–4.53 (m, 10 H), 3.95
(d, J = 4.1 Hz, 1 H), 3.66–3.69 (dd, J = 10.4, 5.3 Hz, 1 H), 3.10–
3.15 (m, 2 H), 1.57–1.75 (m, 2 H) ppm. 13C NMR (100 MHz,
(2S,3S,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-1-benzylpiper-
idine (23b): The same experimental procedure as used for the syn-
thesis of 23a from 21a was followed; yield 70 % (100 mg), oil,
1
[α]2D5 = –5.33 (c = 0.75, CH2Cl2). H NMR (400 MHz, CDCl3): δ
= 7.21–7.34 (20 H), 4.94 (d, J = 11.0 Hz, 1 H), 4.56–4.67 (q, J =
11.9 Hz, 2 H), 4.51 (d, J = 11.0 Hz, 1 H), 4.48 (br. s, 2 H), 4.10 (d,
J = 13.6 Hz, 1 H), 3.77–3.84 (m, 2 H), 3.60 (t, J = 8.8 Hz, 1 H),
3.39–3.48 (m, 1 H), 3.33 (d, J = 13.6 Hz, 1 H), 2.77–2.82 (dt, J =
11.7, 7.3, 3.4 Hz, 1 H), 2.37–2.41 (dt, J = 9.0, 5.6, 3.0 Hz, 1 H),
1.93–2.03 (m, 2 H, 2Ј-H), 1.51–1.61 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 138.89, 138.20 (Cquat, Ph), 129.1, 128.32,
128.29, 128.12, 128.00, 127.96, 127.62, 127.53, 127.46, 127.4,
126.81 (Ph), 82.02, 79.11, 76.61, 74.9, 73.22, 71.18, 67.26, 65.14,
57.18, 49.26, 28.67 ppm. MS ES+: m/z = 508 [M + H]+; C34H37NO3
{508.28 [M + H]+}: C 80.44, H 7.35, N 2.76; found C 80.46, H
7.39, N 2.73.
CDCl3): δ = 207.3, 149.7, 145.3, 137.3, 137.0, 136.6, 135.3, (Cquat
,
Ph), 128.7, 128.47, 128.38, 128.29, 128.25, 128.14, 128.11, 127.89,
127.84, 127.77, 124.2 (Ph), 83.5, 76.6, 74.1, 73.5, 73.2, 72.2, 52.1,
44.8, 29.2 ppm. IR (CH Cl ): νmax = 1730, 1529 cm–1. MS ES+: m/z
˜
2
2
(2R,3R,4R)-2-(Hydroxymethyl)piperidine-3,4-diol (1): Pd/C (10%,
150 mg) was added to a solution of 23a (300 mg, 0.53 mmol) in
MeOH (50 mL). The reaction mixture was shaken under hydrogen
(50 psi) for 24 h at room temperature. After removal of the catalyst
by filtration through neutralized and deactivated Al2O3, the solvent
was evaporated under reduced pressure. -Fagomine (1) was af-
forded as a pale brown solid; yield 80% (62 mg), [α]2D5 = +20.4 (c
= 731 [M + Na]+. C40H40N2O8S {731.24 [M + Na]+}: C 67.78, H
5.69, N 3.95, S 4.52; found C 67.85, H 5.77, N 3.93, S 4.55.
N-Benzyl-4-nitro-N-[(3R,4R)-3,4,6-tris(benzyloxy)-5-oxohexyl]ben-
zenesulfonamide (21b): The same experimental procedure as used
for 21a was followed; yield 99% (236 mg), viscous liquid, [α]2D5
=
1
–5.7 (c = 0.70, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 8.22–
8.24 (m, 2 H), 7.8–7.87 (m, 2 H), 7.16–7.34 (m, 20 H), 4.15–4.52
(m, 8 H), 4.01–4.02 (d, J = 3.6 Hz, 1 H), 3.70–3.72 (m, 1 H), 2.20–
2.24 (m, 2 H), 1.60–1.74 (m, 2 H) ppm. 13C NMR (100 MHz,
1
= 1.0 in H2O), H NMR (400 MHz, D2O): δ = 3.76 (dd, J = 11.8,
3.0 Hz, 1 H), 3.73 (dd, J = 11.8, 6.5 Hz, 1 H), 3.56 (ddd, J = 11.5,
9.0, 5.0 Hz, 1 H), 3.35 (t, J = 9.5 Hz, 1 H), 3.25–3.27 (m, 1 H),
2.89–2.96 (m, 2 H), 2.01 (m, 1 H), 1.53–1.43 (m, 1 H) ppm. 13C
NMR (125 MHz, D2O): δ = 70.8, 69.9, 60.2, 58.1, 41.9, 28.9 ppm.
CDCl3): δ = 207.4, 149.7, 145.5, 137.5, 137.0, 136.9, 135.4, (Cquat
,
Ph), 128.77, 128.54, 128.48, 128.40, 128.38, 128.26, 128.18, 128.15,
127.98, 127.88, 127.82, 127.79 (Ph), 83.5, 74.1, 73.3, 73.1, 72.1,
52.1, 44.8, 29.1 ppm. IR (CH Cl ): ν
= 1729, 1530 cm–1. MS
˜
max
(2R,3S,4R)-2-(Hydroxymethyl)piperidine-3,4-diol (4): The same
procedure as used for converting 23a to 1 was followed; yield 86%
(67 mg), [α]2D5 = +10.4 (c = 1.4 in H2O), 1H NMR (500 MHz, D2O):
δ = 3.90 (s, 1 H, 3-H), 3.69–3.77 (m, 2 H), 3.58–3.61 (m, 1 H), 3.01
2
2
ES+: m/z = 731 [M + Na]+. C40H40N2O8S {731.24 [M + Na]+}: C
67.78, H 5.69, N 3.95, S 4.52; found C 67.83, H 5.73, N 3.99, S
4.54.
Eur. J. Org. Chem. 2009, 160–169
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
167

N. Kumari, B. G. Reddy, Y. D. Vankar
FULL PAPER
(m, 1 H), 2.85–2.89 (m, 1 H), 2.67–2.75 (m, 2 H), 2.51 (m, 1 H), H) ppm. 13C NMR (125 MHz, D2O): δ = 70.9, 69.8, 60.0, 57.8,
1.63–1.84 (m, 2 H) ppm. 13C NMR (125 MHz, D2O): δ = 69.3, 41.8, 28.9 ppm.
68.7, 62.8, 59.9, 46.8, 25.6 ppm.
(2S,3S,4R)-2-(Hydroxymethyl)piperidine-3,4-diol (6): The same pro-
cedure as used for 5 was followed; yield 85% (46 mg), [α]2D5 = –8.0
(2S,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-1-(4-nitrophen-
ylsulfonyl)piperidine (24a): PPh3 (101 mg, 0.386 mmol) and di-
isopropyl azodicarboxylate (76 µL, 0.386 mmol) were added at
room temperature to a stirred solution of compound 19a (200 mg,
0.322 mmol) in dry toluene (3 mL). The reaction mixture was
stirred for a further 2 h and after completion of reaction (TLC
monitoring), solvent was evaporated and the crude product was
purified by column chromatography to give compound 24a; yield
83% (161 mg), viscous liquid, [α]2D5 = –11.76 (c = 0.85, CH2Cl2).
1
(c = 0.5 in MeOH). H NMR (500 MHz, D2O): δ = 3.96 (ddd, J
= 5.1, 4.5, 2.5 Hz, 1 H), 3.80 (dd, J = 12.6, 5.6 Hz, 1 H), 3.78 (dd,
J = 11.5, 5.0 Hz, 1 H), 3.72 (dd, J = 11.5, 5.0 Hz, 1 H), 3.56 (m, 1
H), 3.18–3.16 (m, 1 H), 3.05–3.01 (m, 1 H), 1.82–1.67 (m, 2
H) ppm. 13C NMR (125 MHz, D2O): δ = 70.3, 67.9, 60.8, 57.8,
38.8, 28.9 ppm.
1H NMR (400 MHz, CDCl3): δ = 17.84–8.03 (m, 4 H), 7.11–7.36 Acknowledgments
(m, 15 H), 4.59–4.78 (m, 4 H), 4.48–4.52 (br. dd, J = 10.5, 6.1 Hz,
1 H), 4.32–4.35 (2ϫd, J = 11.7 Hz, 2 H), 3.75–3.82 (dd, J = 13.8,
4.8 Hz, 1 H), 3.64–3.73 (m, 3 H), 3.53–3.57 (dd, J = 9.5, 6.1 Hz, 1
H), 3.05–3.12 (dt, J = 13.6, 2.6 Hz, 1 H), 1.97–2.04 (m, 1 H), 1.48–
1.57 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 149.5, 146.7,
138.4, 137.9, 137.4 (Cquat, Ph), 128.49, 128.39, 128.36, 128.22,
127.91, 127.84, 127.69, 127.59, 127.52, 123.86 (Ph), 80.1, 76.2, 73.3,
We thank the Department of Science and Technology, New Delhi,
for financial support to Y. D. V. in the form of a Ramanna Fellow-
ship (Grant No. SR/S1/RFOC-04/2006). N. K. thanks the Univer-
sity Grants Commitee (UGC), New Delhi for a senior research
fellowship.
73.2, 72.4, 66.0, 55.7, 40.0, 31.1 ppm. IR (CH Cl ): ν = 1722,
˜
max
2
2
1529 cm–1. MS: ES+: m/z = 620 [M + NH4]+; C33H34N2O7S {620.24
[M + NH4]+}: C 65.76, H 5.69, N 4.65, S 5.32; found C 65.80, H
5.73, N 4.68, S 5.34.
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(2S,3S,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-1-(4-nitrophen-
ylsulfonyl)piperidine (24b): The same procedure as used for 24a was
followed. Viscous liquid; yield 94%, (176 mg), [α]2D5 = +59.13 (c =
1.15, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.21–7.93 (19 H),
4.48–4.62 (br. dd, J = 11.0, 4.6 Hz, 1 H), 4.40–4.49 (m, 6 H), 3.95
(br. d, J = 2.2 Hz, 1 H), 3.74 (br. d, J = 14.4 Hz, 1 H), 3.53–3.67
(m, 3 H, 3-H), 3.16–3.24 (br. dt, J = 14.3, 3.0 Hz, 1 H), 1.71–1.78
(m, 1 H), 1.61 (br. d, J = 8.8 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 149.4, 146.3, 138.0, 137.8, 137.4 (Cquat, Ph), 128.51,
128.41, 128.39, 128.32, 128.11, 127.98, 127.94, 127.65, 127.32,
123.631 (Ph), 74.4, 73.4, 72.8, 72.6, 70.3, 69.0, 57.6, 41.5, 24.8 ppm.
IR (CH Cl ): ν
= 1743, 1529 cm–1. MS ES+: m/z = 620 [M +
˜
max
2
2
NH4]+; C33H34N2O7S {620.24 [M + NH4]+}: C 65.76, H 5.69, N
4.65, S 5.32; found C 65.78, H 5.75, N 4.69, S 5.35.
(2S,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)piperidine (25a):
K2CO3 (170 mg, 1.21 mmol) and benzyl bromide (55 µL,
0.46 mmol) were added at 20 °C to a stirred solution of sulfon-
amide 24a (250 mg, 0.415 mmol) in DMF (4 mL). The mixture was
stirred for a further 1 h and after completion of the reaction it was
extracted with diethyl ether (2ϫ20 mL) and washed with water and
brine, and dried with Na2SO4. The organic layer was concentrated
to provide a crude product, which was purified by column
chromatography to give compound 25a; yield 89% (154 mg).
(2S,3S,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)piperidine (25b):
The same experimental procedure as used for 25b from 24a was
followed; yield 91% (157 mg).
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(150 mg) was added to a solution of 25a (150 mg, 1.02 mmol) in
MeOH (20 mL). The reaction mixture was shaken under hydrogen
(50 psi) for 24 h at room temperature. After removal of the catalyst
by filtration through neutralized and deactivated Al2O3, the solvent
was evaporated under reduced pressure. -Fagomine (5) was af-
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= 0.5 in MeOH), 1H NMR (500 MHz, D2O): δ = 3.87 (dd, J =
12.5, 3.2 Hz, 1 H), 3.73 (dd, J = 12.6, 5.6 Hz, 1 H), 3.65 (ddd, J =
11.5, 9.0,5.0 Hz, 1 H), 3.33 (t, J = 6.5 Hz, 1 H), 3.18–3.16 (m, 1
H), 3.07–3.02 (m, 2 H), 2.074–1.97 (m, 1 H), 1.64–1.62 (m, 1
168
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Received: August 14, 2008
Published Online: November 25, 2008
Eur. J. Org. Chem. 2009, 160–169
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