Organocatalyzed synthesis of (-)-4-epi-fagomine and the corresponding pipecolic acids

Article abstract of DOI:10.1016/j.tet.2015.07.036

The enantioselective synthesis of 4-epi-fagomine was accomplished starting from dioxanone and Cbz-protected benyzlamine, in 4 steps, with 18% overall yield. The key feature of this synthetic approach is the tactical combination of reactions: organocatalyz

Full text of DOI:10.1016/j.tet.2015.07.036

Accepted Manuscript
Organocatalyzed synthesis of (-)-4-epi-fagomine and the corresponding pipecolic
acids
Jasna Marjanovic, Zorana Ferjancic, Radomir N. Saicic
PII:
S0040-4020(15)01073-X
10.1016/j.tet.2015.07.036
TET 26981
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 May 2015
Revised Date: 24 June 2015
Accepted Date: 13 July 2015
Please cite this article as: Marjanovic J, Ferjancic Z, Saicic RN, Organocatalyzed synthesis of (-)-4-epi-
fagomine and the corresponding pipecolic acids, Tetrahedron (2015), doi: 10.1016/j.tet.2015.07.036.
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Organocatalytic synthesis of (-)-4-epi-
fagomine and the corresponding pipecolic
acids
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Jasna Marjanovic, Zorana Ferjancic and Radomir N. Saicic

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Tetrahedron
journal homepage: www.elsevier.com
Organocatalyzed synthesis of (-)-4-epi-fagomine and the corresponding pipecolic
acids
Jasna Marjanovicb , Zorana Ferjancica, and Radomir N. Saicica,
aFaculty of Chemistry, University of Belgrade, Studentski trg 16, POB 51, 11158 Belgrade, Serbia
bInnovative Centre, Faculty of Chemistry, Studentski trg 16, Belgrade
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The enantioselective synthesis of 4-epi-fagomine was accomplished starting from dioxanone and
Cbz-protected benyzlamine, in 4 steps, with 18% overall yield. The key feature of this synthetic
approach is the tactical combination of reactions: organocatalyzed aldolization/reductive
amination, which allows for a quick formation of heterocyclic rings with defined absolute
configuration of all stereogenic centers. Two hydroxypipecolic acids and a reduced fagomine
analogue were also synthesized.
Available online
Dedicated to Professor Sam Zard, on the occasion of
his 60th birthday.
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Organocatalysis
Iminosugars
Fagomine
Pipecolic acids
Glycolipid storage disorders
lysosomal glucosylceramidase (GAB-2),4 and to suppress the
level of cytokines, which are associated with inflammation and
diabetes.5 The corresponding pipecolic acids, such as 3-
hydroxypipecolic acid (3), are constituents of several natural
products with important biological activity, as well as
intermediates in the syntheses of biologically active compounds;
for these reasons, they have attracted considerable attention from
synthetic chemists.6 Therefore, we set out to develop efficient
syntheses of these compounds.
1. Introduction
Iminosugars (also known as polyhydroxylated alkaloids or
iminocyclitols) are a class of compounds that allow for selective
inhibition of sugar-processing enzymes. This property offers a
wide range of therapeutic applications, such as in the fight
against diabetes, cancer, HIV, obesity, and viral and prion
infections.1 The malfunctions of one glycosidase enzyme result in
a relatively rare glycolipid storage disorder, known as Fabry
disease.2 This is a disorder of glycosphingolipid metabolism
caused by the deficiency of lysosomal α-galactosidase, which
results in deposition of excess globotriaosylceramide in blood
vessels and other organs, with life-threatening consequences.
Counterintuitively, glycosidase inhibitors could help in treating
diseases resulting from glucosidase deficiency (from the
deficiency of these enzymes): at subinhibitory concentrations,
some iminosugars stabilize the proper folding of the mutated
enzyme (the active site-specific-chaperone effect), thus allowing
its transport out of the endoplasmatic reticulum and enhancing its
glycolytic activity several times.3 1-Deoxy-galactonojirimycin
(1) was found to be the most active compound for this purpose;
however, the 1,2-dideoxy-derivative 2, also known as 4-epi-
fagomine, was also found to have considerable α-galactosidase A
Figure 1. 1-deoxygalactonojirimycin (1), 4-epi-fagomine (2) and (-)-cis-
(2S,3R)-3-hydroxypipecolic acid (3).
Several syntheses of 4-epi-fagomine have been reported, most
of which use the chiron approach. Chattopadhyay and
collaborators prepared the compound from
D-glucose (14 steps,
inhibiting activity. In addition, it was found to inhibit non-
0.3% overall yield); in addition to 4-epi-fagomine, they also
———
Corresponding author. Tel.: +381-11-333-6658; fax: +381-11-328-2537; e-mail: zferjan@chem.bg.ac.rs
Corresponding author. Tel.: +381-11-328-2537; fax: +381-11-328-2537; e-mail: rsaicic@chem.bg.ac.rs

2
Tetrahedron
ACCEPTED MANUSCRIPT
prepared the corresponding pipecolic acid.5 Takahata, Kato and
coworkers synthesized a series of fagomine-type analogues
(including 4-epi-fagomine), starting from the Garner aldehyde
(12 steps, 9% yield).7 Aerts, Overkleeft and coworkers prepared a
series of deoxynojirimycine derivatives, where 4-epi-fagomine
was obtained from the Garner aldehyde (7 steps, yield not
indicated).4,8 Fan and coworkers prepared 4-epi-fagomine by the
isomerisation of fagomine (experimental details not provided).3b
Upon exposure of aldol 7 to a hydrogen atmosphere in the
presence of palladium on charcoal, double deprotection followed
by the reductive amination afforded piperidine derivative 8
(78%). Acid-catalyzed deprotection of the dioxane unit then
completed the shortest synthesis of 4-epi-fagomine (2), so far (4
steps, 16% overall yield).
With piperidine derivative 8 in hand, we turned our attention
towards the synthesis of pipecolic acids (Scheme 2). Protection
of amine was followed by the acid-catalyzed rearrangement of
dioxane 9 into thermodynamically more stable dioxolane 10. The
primary hydroxyl group was sequentially oxidized, first with
DMP to the aldehyde, and then to the carboxylate 11 by Pinnick-
Lindgren oxidation. Acid-catalyzed removal of the dioxolane in
11, followed by reductive decarboxybenzylation of 12, gave
pipecolic acid 13.
Vankar and collaborators prepared fagomine analogues of both L-
and
D-series; 4-epi-fagomine was prepared from tri-O-benzyl-
galactal (7 steps, 28% overall yield).9 The most efficient
synthesis of 4-epi-fagomine, so far, is reported by Timmer,
Stocker and collaborators: starting from 2-deoxygalactose, the
target compound was obtained in 6 steps and with 60% overall
yield.10
2. Results and discussion
We designed a catalytic asymmetric synthesis of 4-epi-
fagomine (ent-2), that hinges on a tactical combination of
reactions: organocatalyzed aldolization/reductive amination,
which allows for a rapid access to heterocyclic systems with
defined absolute configuration of all stereogenic centers. The
synthesis starts from achiral, commercially available small
molecules, so both enantiomers of the target compound could be
obtained by a proper choice of a chiral organocatalyst ((R)- or
(S)-proline). Recently, we have demonstrated the feasibility of
this approach in total syntheses of natural products (+)-
swainsonine11 and hyacinthacine derivatives.12 Some time ago,
Joglar, Clapes and coworkers have reported a conceptually
similar, two-step synthesis of fagomine, starting from
dihydroxyacetone and a β-aminopropanal derivative.13 In their
Scheme 2. Synthesis of pipecolic acid 13. Reagents and conditions: a)
CbzCl, Et3N, CH2Cl2, 0 °C to rt, 24 h, 86%; b) p-TsOH (0.15 equiv), acetone,
rt, 24 h, 65%; c) i) DMP (2 equiv), CH2Cl2, 30 min; ii) NaClO2,
NaH2PO4•H2O, H2O2, CH3CN, 0 ° to rt, 3 h, 77% over two steps; d) 3M HCl,
MeOH, rt, 2.5 h, 64%; e) H2, Pd/C, EtOH, 1 h, 93%.
synthesis the aldolization step was catalyzed by
D-fructose-6-
phosphate aldolase, and has resulted in syn-stereochemistry of
the product, characteristic for chemoenzymatic aldolizations.
Our synthesis commenced with hetero-Michael addition of the
commercially available carbamate 4 to acrolein (41%; Scheme
1).14 The resulting adduct 5 was then submitted to the (S)-
proline-organocatalyzed aldol reaction15 with dioxanone (6).16
The reaction could be performed in either DMF or DMSO, where
the use of DMF as a solvent gave slightly higher yield (60%).
However, we prefered the reaction in DMSO, for the reason of
the superior purity of the product 7 (50-52%), which was
obtained with complete diastereoselectivity (i.e., exclusively
anti-isomer). The only side-product of the reaction was the
product of self-addition of dioxanone, which is easily separable
by chromatography.
Carbamate 9 could also be converted into a more interesting
synthetic target, namely 3-hydroxypipecolic acid (ent-3; Scheme
3). To this end, the corresponding xanthate was submitted to
Barton-McCombie deoxygenation with hypophosphorous acid, as
a
convenient reducing agent. After the acid-catalyzed
deprotection of dioxane 14, the resulting diol 15 could be
selectively oxidized to acid 16 by a sequence of reactions
involving PIDA oxidation followed by the Pinnick-Lindgren
oxidation. Alternatively, hydrogenolytic deprotection of
carbamate 15 yielded (-)-4-deoxyfagomine 17.
Scheme 3. Synthesis of pipecolic acid ent-3 and deoxyazasugar 17.
Reagents and conditions: a) NaH, CS2, THF, MeI, rt, 30 min, 80% ; b)
H3PO2, Et3N, AIBN (cat.), 1,4-dioxane, reflux, 30 min, 77%; c) 3M HCl,
MeOH, rt, 1 h, 72%; d) TEMPO (cat.), PIDA, CH2Cl2, rt, 3 h,; e) NaClO2,
NaH2PO4•H2O, 30% H2O2, -10 °C to rt, 3 h, 45% from 15; f) H2, 10% Pd/C,
EtOH, 1 h, 90%; g) H2, 10% Pd/C, EtOH, 2 h, 95%.
Scheme 1. Synthesis of 4-epi-fagomine ent-2. Reagents and conditions: a)
acrolein (10 equiv), CSA (20 mol %), CH2Cl2, 0 ° to rt, 3 h, 41%; b) 6 (1.5
equiv), (S)-Proline (30 mol %), DMF (or DMSO with 5 equiv of H2O), 4 °C,
24 h, 60% (52% in DMSO); c) H2, 10% Pd/C, EtOH, 2 h, 78%; d) 3M HCl,
MeOH, reflux, 4 h, 92%.

3
dried over anh. MgSO4 and concentrated under reduced
ACCEPTED MANUSCRIPT
pressure. Purification of the crude product by dry-flash
chromatography (SiO2; eluent: toluene/EtOAc = 85/15) afforded
the title aldol 7 (335.8 mg, 60%) as a pale yellow viscous oil.
Method B: Dioxanone 6 (390 mg, 3.00 mmol) and water
(180.0 ꢀL, 10.00 mmol) were added to a cold (0 °C) solution of
aldehyde 5 (601 mg, 2.02 mmol) and proline (66 mg, 0.57 mmol,
30 mol %) in DMSO (7.8 mL), and the mixture was vigorously
stirred for 24 h at 4 ºC. The reaction was quenched by addition of
brine followed by extraction with EtOAc. The aqueous phase was
extracted with EtOAc (3 × 15 mL). The combined organic extract
was dried over anh. MgSO4, filtered and concentrated under
reduced pressure. Purification of the crude product by dry-flash
chromatography (SiO2; eluent: toluene/EtOAc = 85/15) afforded
the title aldol 7 (864.2 mg, 52%) as a pale yellow viscous oil.
[α]D -85.6 (c 1.00, CHCl3); H NMR (500 MHz, DMSO-d6, 65
ºC) δ 7.39–7.19 (m, 10H), 5.13 (s, 2H), 4.68 (bd, J=5.3 Hz, 1H),
4.47 (s, 2H), 4.23 (d, J=3.8 Hz, 1H), 4.20 (d, J=17.2 Hz, 1H),
3.95 (d, J=16.8 Hz, 1H), 3.89–3.83 (m, 1H), 3.40–3.24 (m, 2H),
1.80–1.65 (m, 2H), 1.39 (s, 3H), 1.37 (s, 3H); 13C NMR (126
MHz, DMSO-d6, 65 ºC) δ 207.6 (C), 155.4 (C), 137.9 (C), 136.7
(C), 128.1 (CH), 128.0 (CH), 127.4 (CH), 127.1 (CH), 126.9
(CH), 126.7 (CH), 99.7 (C), 77.8 (CH), 67.0 (CH), 66.4 (CH2),
66.0 (CH2), 49.7 (CH2), 43.6 (CH2), 30.2 (CH2), 24.3 (CH3), 22.8
(CH3); IR (ATR) v 3448, 2987, 2939, 1742, 1698, 1423, 1226,
1088, 736, 700 cm-1; HRMS (ESI) for C24H30NO6 [M+H]+
calculated: 428.2068; found: 428.2059.
3. Conclusions
To summarize, enantioselective syntheses of 4-epi-fagomine
(ent-2), cis-3-hydroxypipecolic acid (13), as well as their two 4-
deoxy analogues (17 and ent-3), are described. These syntheses
rely on the organocatalyzed aldol addition/reductive amination
reaction cascade, which allows for the efficient, stereocontrolled
formation of functionalized nitrogen heterocycles.
4. Experimental
4.1. General methods
20
1
All chromatographic separations were performed on silica gel,
10–18 µm, 60 Å (dry-flash), 100–200 µm 60 Å (column
chromatography), ICN Biomedicals, 60 (0.063-0.200 mm)
(column chromatography), Merck and ion exchange column
chromatography (acidic resin DOWEX 50WX8-100). Standard
techniques were used for the purification of reagents and
solvents. Petroleum ether (PE) refers to the fraction boiling at
70–72 °C. NMR spectra were recorded on Bruker Avance III 500
(1H NMR at 500 MHz, 13C NMR at 126 MHz). Chemical shifts
are expressed in ppm (δ) using TMS as the internal standard. IR
spectra were recorded on a Nicolet 6700 FT instrument, and are
expressed in cm–1. Mass spectra were obtained on Agilent
technologies 6210 TOF LC/MS instrument (LC: series 1200) and
LTQ Orbitrap XL hybrid FTMS (Thermo Scientific). Melting
points were determined on a Electrothermal apparatus and are
uncorrected. Optical rotations were determined on a Rudolph
Research Analytical AUTOPOL IV Automatic Polarimeter.
4.4. (4aS,8S,8aR)-2,2-Dimethylhexahydro-4H-
[1,3]dioxino[5,4-b]pyridin-8-ol (8)
A mixture of aldol 7 (58.5 mg, 0.14 mmol) and 10% Pd/C
(30.3 mg, 0.03 mmol) in ethanol (14.0 mL) was stirred for 2 h
under a hydrogen atmosphere (5 bar). The mixture was filtered
and concentrated under reduced pressure. Purification of the
4.2. Benzylbenzyl(3-oxopropyl)carbamate (5)14
Freshly distilled acrolein (7.0 mL, 104.81 mmol) was added
with stirring to
benzylbenzylcarbamate
residue
by
column
chromatography
(SiO2;
eluent:
a
cold (0 °C) solution of N-
(2.5 g, 10.36 mmol) and (+)-
dichloromethane/methanol = 1/1) afforded compound 8 (20.0
20
4
mg, 78%) as a white solid. mp 128-130 ºC; [α]D -45.3 (c 1.00,
MeOH); 1H NMR (500 MHz, MeOD) δ 4.17 (dd, J=12.2, 2.3 Hz,
1H), 4.12–4.11 (m, 1H), 3.66 (dd, J=12.2, 1.6 Hz, 1H), 3.61
(ddd, J=11.8, 4.8, 3.1 Hz, 1H), 3.11 (ddd, J=13.8, 4.4, 2.1 Hz,
1H), 2.59 (td, J=13.3, 3.0 Hz, 1H), 2.44–2.41 (m, 1H), 1.76 (ddd,
J=24.7, 12.6, 4.4 Hz, 1H), 1.63–1.56 (m, 1H), 1.49 (s, 3H), 1.41
(s, 3H); 13C NMR (126 MHz, MeOD) δ 100.5 (C), 70.7 (CH),
70.0 (CH), 65.2 (CH2), 52.8 (CH), 44.7 (CH2), 30.0 (CH2), 30.0
(CH3), 19.0 (CH3); IR (ATR) v 3366, 2991, 2943, 1458, 1381,
1198, 1057, 971, 837 cm-1; HRMS (ESI) for C9H18NO3 [M+H]+
calculated: 188.1281; found: 188.1283.
camphorsulfonic acid (0.5 g, 2.15 mmol, 20 mol %) in
dichloromethane (10 mL). After 20 min cooling bath was
removed and the reaction mixture was stirred for an additional
3.5 h at room temperature. The reaction mixture was diluted with
dichloromethane and washed with sat. aq. NaHCO3 (10 mL). The
organic extract was concentrated in vacuo, diluted with Et2O (20
mL), washed with water, dried over anh. MgSO4 and
concentrated. Purification of the residue by dry-flash
chromatography (SiO2; eluent: petroleum ether/EtOAc = 8/2)
1
afforded aldehyde 5 (1.3 g, 41 %) as a colorless liquid. H NMR
(500 MHz, DMSO-d6, 65 ºC): δ 9.64 (t, J=1.7 Hz, 1H), 7.38–7.22
(m, 10H), 5.15 (s, 2H), 4.50 (s, 2H), 3.55 (t, J=6.8 Hz, 2H), 2.65
(td, J=6.8, 1.7 Hz, 2H); 13C NMR (126 MHz, DMSO-d6, 65 ºC):
δ 201.0 (CH), 155.3 (C), 137.7 (C), 136.6 (C), 128.1 (CH), 128.0
(CH), 127.4 (CH), 127.2 (CH), 127.0 (CH), 126.8 (CH), 66.3
(CH2), 50.1 (CH2), 42.1 (CH2), 40.6 (CH2); IR (ATR) v 3063,
3032, 2950, 1670, 1473, 1422, 1238, 1123, 737, 700 cm-1;
HRMS (ESI) for C18H20NO3 [M+H]+ calculated: 298.1443; found:
298.1429.
4.5. (2S,3R,4S)-2-(Hydroxymethyl)piperidine-3,4-diol (ent-4-
epi-fagomine) (ent-2)
A solution of amine 13 (27.7 mg, 0.15 mmol) in solvent mixture
methanol/3M HCl (5.7 mL, v/v= 2/1) was stirred and heated to
reflux for 4 h. After the volatiles were removed under reduced
pressure, the residue was purified by ion exchange column
chromatography (acidic resin DOWEX 50WX8-100), to give the
title compound ent-2 (20.1 mg, 92%) as a white solid. mp 219-
20
221 ºC, [lit.17 mp 220-222 ºC]; [α]D -15.5 (c 1.00, H2O), [lit.17
4.3. Benzylbenzyl((S)-3-((S)-2,2-dimethyl-5-oxo-1,3-dioxan-4-
yl)-3-hydroxypropyl)carbamate (7)
20
1
[α]D -10.4 (c 1.02, H2O)]; H NMR (500 MHz, D2O) δ 3.93–
3.91 (m, 1H), 3.75 (ddd, J=11.0, 6.1, 2.9 Hz, 1H), 3.65 (ddd,
J=18.0, 11.5, 6.7 Hz, 2H), 3.13–3.05 (m, 1H), 2.75 (td, J=6.7, 1.5
Hz, 1H), 2.66–2.58 (m, 1H), 1.75–1.65 (m, 2H); 13C NMR (126
MHz, D2O) δ 72.5 (CH), 70.3 (CH), 64.3 (CH2), 61.7 (CH), 45.5
(CH2), 30.0 (CH2); IR (ATR) v 3355, 2938, 1446, 1358, 1057,
Method A: A solution of dioxanone 6 (250 mg, 1.92 mmol),
aldehyde 5 (389 mg, 1.31 mmol) and (S)-proline (48 mg, 0.42
mmol, 30 mol %) in DMF (3.4 mL) was stirred overnight at 4 ºC.
The reaction mixture was diluted with water, extracted with
EtOAc, the combined organic extract was washed with water,

4
Tetrahedron
1025, 805 cm-1; HRMS (ESI) for C6H14NO3 [M+H]+ calculated:
reduced pressure. The residue was further used without
ACCEPTED MANUSCRIPT
148.0968; found: 148.0972.
purification.
To a stirred solution of the crude aldehyde (obtained from 10
(96.7 mg, 0.30 mmol)) in CH3CN (2.1 mL) was added a solution
of NaH2PO4•H2O (8.2 mg, 0.06 mmol) in H2O (0.4 mL) and 30%
H2O2 (45.0 ꢀL, 0.57 mmol).5 The mixture was cooled to 0°C, and
NaClO2 (45.0 mg, 0.50 mmol) in H2O (0.9 mL) was added
dropwise over a period of 30 minutes. The reaction mixture was
stirred at 15 °C. After 3 h, the reaction was quenched by the
addition of a small amount of Na2SO4 (50.0 mg) and extracted
with EtOAc (3 × 5 mL). Evaporation of the solvent followed by
column chromatography of the residue (SiO2; eluent:
dichloromethane/methanol = 95/5) afforded compound 11 (77.7
4.6. (4aS,8S,8aR)-Benzyl 8-hydroxy-2,2-dimethyltetrahydro-
4H-[1,3]dioxino[5,4-b]pyridine-5(4aH)-carboxylate (9)
Benzyl chloroformate (104.7 mg, 0.61 mmol) was added
dropwise (over a period of 20 min) to a cold (0 °C) solution of
amine 8 (104.5 mg, 0.56 mmol) and triethyl amine (75.6 mg,
0.75 mmol) in dichloromethane (0.6 mL). The reaction was
warmed to room temperature and stirred overnight, then diluted
with water (10 mL). The mixture was extracted with
dichloromethane (3 × 20 mL), and the combined organic extract
was washed with sat. aq. NaHCO3 (2 × 20 mL), brine (20 mL),
dried over anh. MgSO4, filtered and concentrated under reduced
pressure. Purification of the residue by column chromatography
(SiO2; eluent: dichloromethane/methanol = 95/5) afforded the
title compound 9 (154.3 mg, 86%) as a colorless viscous oil.
20
mg, 77% over two steps) as a white solid. mp 45-47 °C; [α]D
1
+15.5 (c 1.00, CHCl3); H NMR (500 MHz, DMSO-d6, 65 ºC) δ
7.40–7.26 (m, 5H), 5.12–5.01 (m, 2H), 4.66 (dd, J=6.9, 5.2 Hz,
1H), 4.42–4.34 (m, 2H), 3.74 (bd, J=12.2 Hz, 1H), 3.25 (bs, 1H),
1.75–1.64 (m, 2H), 1.38 (s, 3H), 1.27 (s, 3H); 13C NMR (126
MHz, DMSO-d6, 65 ºC) δ 169.9 (C), 154.9 (C), 136.5 (C), 128.0
(CH), 127.3 (CH), 127.0 (CH), 106.8 (C), 71.5 (CH), 69.8 (CH),
66.0 (CH2), 54.6 (CH), 36.1 (CH2), 29.1 (CH2), 26.2 (CH3), 23.9
(CH3); IR (ATR) v 3741, 2988, 2936, 1702, 1422, 1259, 1214,
1040, 738 cm-1; HRMS (ESI) for C17H20NO6 [M-H]- calculated:
334.1296; found: 334.1309.
20
1
[α]D +106.1 (c 1.00, CHCl3); H NMR (500 MHz, DMSO-d6,
65 ºC) δ 7.40–7.29 (m, 5H), 5.08 (dd, J=21.7, 12.6 Hz, 2H), 4.52
(d, J=5.8 Hz, 1H), 4.18 (dd, J=4.4, 2.3 Hz, 1H), 3.98 (dd, J=12.0,
4.0 Hz, 1H), 3.87 (ddd, J=13.0, 9.0, 2.0 Hz, 1H), 3.73 (dd,
J=12.3, 3.4 Hz, 1H), 3.67 (dd, J=8.0, 4.0 Hz, 1H), 3.60 (tdd,
J=8.5, 5.8, 2.3 Hz, 1H), 3.53 (ddd, J=13.1, 9.8, 7.5 Hz, 1H), 2.02
(ddd, J=18.3, 12.8, 9.1 Hz, 1H), 1.60–1.50 (m, 1H), 1.40 (s, 3H),
1.33 (s, 3H); 13C NMR (126 MHz, DMSO-d6, 65 ºC) δ 154.5 (C),
136.6 (C), 128.0 (CH), 127.4 (CH), 127.2 (CH), 97.8 (C), 67.7
(CH), 65.9 (CH2), 65.5 (CH), 61.4 (CH2), 48.9 (CH), 38.2 (CH2),
27.8 (CH3), 27.4 (CH2), 19.7 (CH3); IR (ATR) v 3440, 2988,
2936, 1695, 1424, 1381, 1262, 1075, 771, 700 cm-1; HRMS (ESI)
for C17H24NO5 [M+H]+ calculated: 322.1649; found: 322.1647.
4.9. (2R,3R,4S)-1-(Benzyloxycarbonyl)-3,4-
dihydroxypiperidine-2-carboxylic acid (12)
A solution of compound 11 (93.5 mg, 0.28 mmol) in solvent
mixture methanol/3M HCl (12.6 mL, v/v = 2/1) was stirred at
room temperature for 2 h. After the volatiles were removed under
reduced pressure, the residue was purified by column
chromatography (SiO2; eluent: dichloromethane/methanol = 9/1),
to give the title compound 12 (53.1 mg, 64%) as a colorless,
4.7. (3aR,4S,7aS)-Benzyl 4-(hydroxymethyl)-2,2-
dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-
carboxylate (10)
20
1
viscous oil. [α]D +40.8 (c 0.7, MeOH); H NMR (500 MHz,
DMSO-d6, 65 ºC) δ 7.38–7.27 (m, 5H), 5.08 (s, 2H), 4.47 (bs,
1H), 3.84 (bs, 1H), 3.78–3.62 (m, 2H), 3.30 (bs, 1H), 1.69–1.54
(m, 2H); 13C NMR (126 MHz, DMSO-d6, 65 ºC) δ 172.6 (C),
155.1 (C), 136.8 (C), 128.0 (CH), 127.3 (CH), 127.0 (CH), 69.5
(CH), 66.7 (CH), 65.9 (CH2), 55.1 (CH), 35.0 (CH2), 30.3 (CH2);
IR (ATR) v 3371, 2951, 1678, 1610, 1413, 1154, 746, 603 cm-1;
HRMS (ESI) for C14H18NO6 [M+H]+ calculated: 296.1134; found:
296.1123.
pTsOH•H2O (14.0 mg, 0.07 mmol) was added to a solution of
alcohol 9 (153.7 mg, 0.48 mmol) in acetone (6.9 mL), and the
mixture was stirred at room temperature for 24 h. The reaction
mixture was treated with triethylamine (14.6 mg, 0.14 mmol) and
concentrated under reduced pressure. The residue was purified by
column chromatography (SiO2; eluent: petroleum ether/EtOAc =
6/4), to afford alcohol 10 (99.9 mg, 65%) as a colorless viscous
oil. [α]D20 +29.4 (c 1.00, CHCl3); 1H NMR (500 MHz, DMSO-d6,
65 ºC) δ 7.39–7.28 (m, 5H), 5.09 (s, 2H), 4.42 (dd, J=6.8, 5.8 Hz,
1H), 4.33–4.28 (m, 2H), 4.07 (dd, J=12.8, 6.8 Hz, 1H), 3.74–3.65
(m, 2H), 3.53 (ddd, J=13.1, 6.4, 5.0 Hz, 1H), 3.29 (ddd, J=13.2,
9.2, 4.1 Hz, 1H), 1.88–1.80 (m, 1H), 1.76–1.69 (m, 1H), 1.37 (d,
J=0.5 Hz, 3H), 1.28 (d, J=0.5 Hz, 3H); 13C NMR (126 MHz,
DMSO-d6, 65 ºC) δ 155.3 (C), 136.8 (C), 128.0 (CH), 127.3
(CH), 127.0 (CH), 107.0 (C), 71.4 (CH), 70.3 (CH2), 65.9 (CH2),
59.6 (CH), 54.2 (CH), 36.9 (CH2), 27.3 (CH2), 26.0 (CH3), 24.3
(CH3); IR (ATR) v 3462, 2985, 2936, 1697, 1418, 1256, 1212,
1063, 869, 700 cm-1; HRMS (ESI) for C17H24NO5 [M+H]+
calculated: 322.1649; found: 322.1647.
4.10. (2R,3R,4S)-3,4-Dihydroxypiperidine-2-carboxylic acid
(3,4-Dihydroxypipecolic Acid) (13)
A suspension of 12 (21.9 mg, 0.07 mmol) and 10% Pd/C (5.3
mg, 0.005 mmol) in methanol (1.5 mL) was stirred under a
hydrogen atmosphere (1 bar) for 2 h at room temperature. The
reaction mixture was filtered through celite, concentrated under
reduced pressure and purified by column chromatography (SiO2;
eluent: EtOAc/EtOH/H2O = 4/4/2), to give the title compound 13
(11.1 mg, 93%) as a white solid. mp 240-242 ºC, [lit.5 for ent-13
20
25
mp 245-247 ºC]; [α]D +6.8 (c 0.65, H2O), [lit.5 [α]D +7.5 (c
4.8. (3aR,4R,7aS)-5-(Benzyloxycarbonyl)-2,2-
dimethylhexahydro-[1,3]dioxolo[4,5-c]pyridine-4-carboxylic
acid (11)
1
2.10, H2O)]; H NMR (500 MHz, D2O) δ 4.43–4.40 (m, 1H),
3.97 (ddd, J=11.5, 5.2, 2.8 Hz, 1H), 3.75 (d, J=1.6 Hz, 1H), 3.46
(ddd, J=13.1, 4.6, 2.3 Hz, 1H), 3.05 (td, J=13.2, 3.8 Hz, 1H),
2.07–1.90 (m, 2H); 13C NMR (126 MHz, D2O) δ 171.6 (C), 67.8
(CH), 67.5 (CH), 61.9 (CH), 41.2 (CH2), 23.6 (CH2); IR (ATR) v
3395, 3313, 3109, 2957, 2926, 2856, 1732, 1458, 1269, 1074 cm-
1; HRMS (ESI) for C6H12NO4 [M+H]+ calculated: 162.0761;
found: 162.0758.
Dess-Martin’s periodinane (268 mg, 0.63 mmol) was added to
a
solution of alcohol 10 (96.7 mg, 0.30 mmol) in
dichloromethane (3.0 mL) and the reaction mixture was stirred at
room temperature for 30 min. The reaction mixture was diluted
with dichloromethane, washed with 5% Na2S2O3 and sat. aq.
NaHCO3, dried over anh. MgSO4, filtered and concentrated under

5
4.11. (4aS,8aS)-Benzyl 2,2-dimethyltetrahydro-4H-
[1,3]dioxino[5,4-b]pyridine-5(4aH)-carboxylate (14)
128.0 (CH), 127.7 (CH), 69.2 (CH), 67.4 (CH2), 59.1 (CH2),
ACCEPTED MANUSCRIPT
56.6 (CH), 39.8 (CH2), 28.3 (CH2), 23.6 (CH2); IR (ATR) v 3394,
2936, 1675, 1432, 1258, 1074, 999, 738, 699 cm-1; HRMS (ESI)
for C14H20NO4 [M+H]+ calculated: 266.1387; found: 266.1383.
To a solution of compound 8 (62.0 mg, 0.19 mmol) in THF
(0.2 mL) was added sodium hydride (12.0 mg, 0.50 mmol) under
an argon atmosphere. After stirring for 15 minutes at room
temperature, carbon disulfide (0.3 mL, 5.10 mmol) was added,
followed after 0.5 h by iodomethane (65 ꢀL, 1.04 mmol). The
resulting solution was stirred for 30 minutes and the reaction was
quenched by addition of water. The mixture was extracted with
EtOAc, the extract was washed with wather, dried over anh.
MgSO4, filtered and concentrated under reduced pressure. The
residue was purified by column chromatography (SiO2; eluent:
petroleum ether/EtOAc = 85/15), to give the xanthate (63.5 mg,
4.13. (2R,3S)-1-(Benzyloxycarbonyl)-3-hydroxypiperidine-2-
carboxylic acid (16)
A solution of compound 15 (52.0 mg, 0.20 mmol),
(diacetoxy)iodobenzene (71.6 mg, 0.22 mmol) and TEMPO (8.0
mg, 0.05 mmol, 25 mol%) in abs. dichloromethane (3.4 mL) was
stirred at room temperature for 3 h, under an argon atmosphere.20
The reaction was quenched by the addition of sat. aq. Na2S2O3
(5mL) and stirred for 30 min. The mixture was extracted with
dichloromethane (3 × 20 mL) and the combined organic extract
was dried over anh. MgSO4, filtered and concentrated under
reduced pressure. The residue was used without further
purification.
To a stirred solution of crude aldehyde (obtained from 15
(52.0 mg, 0.20 mmol)) in acetonitrile (1.1 mL) was added the
solution of NaH2PO4•H2O (6.1 mg, 0.04 mmol) in water (0.3
mL) and 30% H2O2 (40.0 ꢀL, 0.51 mmol). The mixture was
stirred and cooled at -10 °C, NaClO2 (31.2 mg, 0.34 mmol) in
water (0.6 mL) was added dropwise over 30 min, the reaction
mixture was then stirred at 15 °C. After 3 h, the reaction was
quenched by addition of a small amount of Na2SO3 (11.3 mg) and
acidified with 10% aq HC1 (5 mL). The organic layer was
separated, aqueous layer was extracted with EtOAc (4 × 5 mL),
the combined organic extract was evaporated, and the residue
was dissolved in 10% aq. NaHCO3 (15 mL). The bicarbonate
layer was washed with EtOAc (15 mL) and then made acidic to
pH 2 and extracted with EtOAc (3 × 15 mL). The organic extract
was dried over anh. MgSO4, filtered and concentrated under
reduced pressure. The residue was purified by column
chromatography (SiO2; eluent: dichloromethane/methanol = 8/2),
to give 24.7 mg (45% over two steps) of the title compound 16,
as a colorless viscous oil. [α]D20 +13.4 (c 0.42, CH2Cl2), [lit.19 ent
20
80%) as a pale yellow viscous oil. [α]D +41.8 (c 1.00, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.39–7.30 (m, 5H), 5.60 (td,
J=8.8, 2.3 Hz, 1H), 5.12 (q, J=12.3 Hz, 2H), 4.56 (dd, J=4.1, 2.2
Hz, 1H), 4.18–4.09 (m, 1H), 4.04 (dd, J=12.2, 3.6 Hz, 1H), 3.96–
3.83 (m, 2H), 3.79–3.69 (m, 1H), 2.56 (s, 3H), 2.49–2.40 (m,
1H), 1.94–1.82 (m, 1H), 1.44 (s, 3H), 1.42 (s, 3H); 13C NMR
(126 MHz, CDCl3) δ 215.6 (C), 155.2 (C), 136.3 (C), 128.6
(CH), 128.1 (CH), 128.0 (CH), 99.1 (C), 78.0 (CH), 67.4 (CH2),
65.3 (CH), 62.2 (CH2), 49.1 (CH), 38.3 (CH2), 27.9 (CH3), 24.5
(CH2), 20.0 (CH3), 19.1 (CH3); IR (ATR) v 2989, 2940, 1670,
1422, 1220, 1058, 980, 736, 700 cm-1; HRMS (ESI) for
C19H25NO5S2Na [M+Na]+ calculated: 434.1066; found: 434.1055.
AIBN (74 mg; 0.45 mmol) was added to a refluxing solution
of xanthate (412 mg, 1.00 mmol), hypophosphorous acid (0.56
mL of the 50% aqueous solution, 5.12 mmol) and triethylamine
(0.8 mL, 5.73 mmol) in dioxane (9.1 mL) and the reaction
mixture was stirred for 30 minutes at room temperature.18 Upon
completion, the reaction mixture was diluted with
dichloromethane (20 mL) and washed with water. The organic
extract was dried over anh. MgSO4, filtered and concentrated
under reduced pressure. Purification by column chromatography
(SiO2; eluent: petroleum ether/EtOAc = 85/15), afforded the title
compound 14 (236.8 mg,77%) as a colorless oil. [α]D20 +128.7 (c
1.00, CHCl3); 1H NMR (500 MHz, DMSO-d6, 65 ºC) δ 7.40–7.28
(m, 5H), 5.09 (q, J=12.6 Hz, 2H), 4.24–4.19 (m, 1H), 3.92 (dd,
J=12.1, 4.3 Hz, 1H), 3.85 (ddd, J=10.0, 6.8, 2.8 Hz, 1H), 3.77
(dd, J=12.1, 4.1 Hz 1H), 3.70 (q, J=4.4 Hz, 1H), 3.39 (ddd,
J=13.1, 10.0, 6.8 Hz, 1H), 1.82–1.75 (m, 1H), 1.68–1.59 (m, 2H),
1.58–1.49 (m, 1H), 1.38 (d, J=0.5 Hz, 3H), 1.32 (d, J=0.5 Hz,
3H); 13C NMR (126 MHz, DMSO-d6, 65 ºC) δ 154.6 (C), 136.7
(C), 128.0 (CH), 127.4 (CH), 127.1 (CH), 97.6 (C), 65.9 (CH2),
63.7 (CH), 61.0 (CH2), 49.0 (CH), 37.9 (CH2), 27.7 (CH3), 23.3
(CH2), 20.5 (CH3), 18.0 (CH2); IR (ATR) v 2989, 2941, 2874,
1699, 1423, 1379, 1232, 1033, 768, 699 cm-1; HRMS (ESI) for
C17H23NO4Na [M+Na]+ calculated: 328.1519; found: 328.1525.
25
1
[α]D -13.9 (c 0.42, CH2Cl2)]; H NMR (500 MHz, CDCl3) δ
7.39–7.28 (m, 5H), 7.25–6.60 (bs, 1H), 5.20–5.12 (m, 2H), 5.12–
4.98 (m, 1H), 4.10–3.94 (m, 1H), 3.92–3.83 (m, 1H), 2.98–2.74
(m, 1H), 2.06–1.96 (m, 1H), 1.77–1.66 (m, 1H), 1.58–1.43 (m,
2H); 13C NMR (126 MHz, CDCl3) δ 172.2 (C), 156.7 (C), 135.8
(C), 128.5 (CH), 128.2 (CH), 127.8 (CH), 68.6 (CH), 68.1 (CH2),
57.6 (CH), 40.8 (CH2), 29.6 (CH2), 23.4 (CH2); IR (ATR) v 3336,
2952, 2869, 1702, 1423, 1260, 1155, 975, 751, 699 cm-1; HRMS
(ESI) for C14H17NO5Na [M+Na]+ calculated: 302.0999; found:
302.0996.
4.14. (2R,3S)-3-Hydroxypiperidine-2-carboxylic acid (3-
hydroxypipecolic acid, ent-3)
4.12. (2S,3S)-Benzyl 3-hydroxy-2-(hydroxymethyl)piperidine-
1-carboxylate (15)
A suspension of compound 16 (13.2 mg, 0.05 mmol) and 10%
Pd/C (2.0 mg, 0.002 mmol) in methanol (0.7 mL) was stirred for
1 h under a hydrogen atmosphere (1 bar). The reaction mixture
was filtered through celite, concentrated under reduced pressure
and purified by column chromatography (SiO2; eluent:
EtOAc/EtOH/H2O = 4/4/2), to give the title compound ent-3 (6.1
A solution of amine 14 (220.0 mg, 0.72 mmol) in solvent
mixture methanol/3M HCl (31.5 mL, v/v= 2/1) was stirred at
room temperature for 1 h. After the volatiles were removed under
reduced pressure, the residue was purified by column
chromatography (SiO2; eluent: dichloromethane/methanol =
95/5), to give the title compound 15 (137.6 mg, 72%) as a
20
mg, 90%) as a colorless, viscous oil. [α]D +48.3 (c 0.3, H2O),
27
1
[lit.21 [α]D +51.0 (c 0.75, H2O)]; H NMR (500 MHz, D2O) δ
4.56–4.51 (m, 1H), 3.70 (d, J=1.8 Hz, 1H), 3.47–3.41 (m, 1H),
3.08–2.99 (m, 1H), 2.08–1.95 (m, 2H), 1.86–1.72 (m, 2H); 13C
NMR (126 MHz, D2O): δ 172.3 (C), 64.1 (CH), 62.2 (CH), 43.6
(CH2), 28.7 (CH2), 15.8 (CH2); IR (ATR) v 3060, 2928, 2856,
1630, 1405, 1254, 1113, 998, 735 cm-1; HRMS (ESI) for
C6H12NO3 [M+H]+ calculated: 146.0812; found: 146.0809.
colorless viscous oil. [α]D +20.3 (c 1.00, CH2Cl2), [lit.19 ent
20
[α]D25 +6.24 (c 0.25, H2O)]; 1H NMR (500 MHz, CDCl3 + drop of
D2O) δ 7.39–7.28 (m, 5H), 5.12 (d, J=2.4 Hz, 2H), 4.52–4.43 (m,
1H), 4.16–4.07 (m, 1H), 3.97–3.84 (m, 2H), 3.82–3.73 (m, 1H),
3.44 (bs, 1H), 2.92 (bs, 1H), 1.87–1.80 (m, 1H), 1.75–1.68 (m,
1H), 1.62 (ddd, J=23.9, 12.4, 4.0 Hz, 1H), 1.53–1.41 (m, 1H);
13C NMR (126 MHz, CDCl3) δ 156.1 (C), 136.4 (C), 128.5 (CH),

6
Tetrahedron
4.15. (2S,3S)-2-(Hydroxymethyl)piperidin-3-ol (17)
ACCEPTED MANUSCRIPT
8. 8 Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H. Org. Lett. 2003,
5, 2527.
A suspension of 15 (12.9 mg, 0.05 mmol) and 10% Pd/C (3.2
9. 9 Kumari, N.; Gopal Reddy, B.; Vankar, Y. D. Eur. J. Org. Chem.
2009, 160.
mg, 0.003 mmol) in methanol (0.7 mL) was stirred for 2 h under
a hydrogen atmosphere (1 bar). The reaction mixture was filtered
through celite, concentrated under reduced pressure and purified
by ion exchange column chromatography (acidic resin DOWEX
50WX8-100), to give the title compound 17 (6.1 mg, 95%), as a
10. 10 Corkran, H. M.; Munneke, S.; Dangerfield, E. M.; Stocker, B.
L.; Timmer, M. S. M. J. Org. Chem. 2013, 78, 9791.
11
11.
Trajkovic, M.; Balanac, V.; Ferjancic, Z.; Saicic, R. N. RSC
Adv. 2014, 4 (96), 53722.
12. 12 Marjanovic, J.; Divjakovic, V.; Matovic, R.; Ferjancic, Z.;
Saicic, R. N. Eur. J. Org. Chem. 2013, 5555.
20
pale yellow, viscous oil. [α]D +13.3 (c 0.60, H2O), ), [lit.19 ent
[α]D25 -13.2 (c 2.51, H2O)], [α]D20 +10.8 (c 0.38, MeOH), ), [lit.22
[α]D28 +10.8 (c 0.50, MeOH)]; 1H NMR (500 MHz, D2O) δ 4.03–
3.99 (m, 1H), 3.67 (ddd, J=19.0, 11.5, 6.7 Hz, 2H), 3.15–3.08 (m,
1H), 2.90 (ddd, J=11.1, 7.2, 3.6 Hz, 1H), 2.72 (td, J=12.4, 3.2
Hz, 1H), 1.93–1.86 (m, 1H), 1.82–1.68 (m, 2H), 1.60–1.53 (m,
1H); 13C NMR (126 MHz, D2O) δ 64.4 (CH), 61.4 (CH2), 59.5
(CH), 44.3 (CH2), 29.7 (CH2), 18.9 (CH2); IR (ATR) v 3308,
2937, 2863, 1596, 1440, 1099, 1037, 993, 734 cm-1.
13. 13 Castillo, J. A.; Calveras, J.; Casas, J.; Mitjans, M.; Vinardell, M.
P.; Parella, T.; Inoue, T.; Sprenger, G. A.; Joglar, J.; Clapes, P.
Org. Lett. 2006, 8, 6067.
14. 14 Pohjakallio, A.; Pihko, P. M. Chem. Eur. J. 2009, 15, 3960.
Alternatively, aldehyde 5 can be prepared from commercially
available benzyl-3-butenyl amine, via a
benzyloxycarbonylation/ozonolysis sequence, in 80% yield:
Brands, K. M. J.; Meekel, A. A. P.; Pandit, U. K. Tetrahedron
1991, 47, 2005.
15. 15For selected review articles on enamine organocatalyzed aldol
reactions, see: (a) Notz, W.; Tanaka, F.; Barbas, C. F. III, Acc.
Chem. Res. 2004, 37, 580; (b) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471; (c) Geary, L.
M.; Hultin, P. G. Tetrahedron: Asymmetry 2009, 20, 131; (d)
Heravi, M. M.; Asadi, S. Tetrahedron: Asymmetry 2012, 23, 1431;
(e) Bisai, V.; Bisai, A.; Singh, V. K. Tetrahedron 2012, 68, 4541.
16. 16 For the first examples of organocatalyzed aldol reactions with
dioxanone, see: (a) Suri, J. T.; Ramachary, D. B.; Barbas, C. F., III
Org. Lett. 2005, 7, 1383. (b) Enders, D.; Grondal, C. Angew.
Chem. Int. Ed. 2005, 44, 1210. (c) Ibrahem, I.; Cordova, A.
Tetrahedron Lett. 2005, 46, 3363.
Acknowledgments
This work was supported by the Serbian Ministry of
Education, Science and Technological Development (project No.
172027) and the Serbian Academy of Sciences and Arts (Proj.
No. F193. The authors gratefully acknowledge the support of the
humanitarian foundation “Hrast” and the support of Dr. Ivan
Trifunovic. The authors acknowledge the support of the FP7
RegPot project FCUB ERA GA No. 256716. The EC does not
share responsability for the content of the article.
17. 17 Kato, A.; Miyauchi S.; Kato, N.; Nash, R. J.; Yoshimura, Y.;
Nakagome, I.; Hirono, S.; Takahata, H.; Adachi, I. Bioorg. Med.
Chem. 2011, 19, 3558.
18. 18 Maslak, V.; Matovic, R.; Saicic, R. N. Tetrahedron. 2004, 60,
8957.
Supplementary Material
19. 19 Kalamkar, N. B.; Kasture, V. M.; Dhaval, D. D. J. Org. Chem.
2008, 73, 3619.
Copies of NMR spectra for all compounds are available as the
electronic version at: http://XXXXX.
20. 20 Meister, A. C.; Nieger, M.; Bräse, S. Chem. Eur. J. 2013, 19,
10836.
21. 21 Yoshimura, Y.; Ohara, C.; Imahori, T.; Saito, Y.; Kato, A.;
Miyauchi, S.; Adachi, I.; Takahata, H. Bioorg. Med. Chem. 2008,
16, 8273.
References and notes
22. 22 Kim, I. S.; Oh, J. S.; Zee, O. P.; Jung, Y. H. Tetrahedron, 2007,
63, 2622.
1. 1 (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645; (b) Watson, A. A.; Fleet,
G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J. Phytochemistry
2001, 56, 265; (c) Iminosugars: From Synthesis to Therapeutic
Applications; P. Compain, O. R. Martin Eds.; Wiley: Chichester,
2007; (d) Nash, R. J.; Kato, A.; Yu, C.-Y.; Fleet, G. W. J. Future
Med. Chem. 2011, 3, 1513; (e) Li, J.; Browning, S.; Mahal, S. P.;
Oelschlegel, A. M.; Weissmann, C. Science 2010, 327, 869; (e)
Lahiri, R.; Ansari, A. A.; Vankar, Y. D. Chem. Soc. Rev. 2013, 42,
5102.
2. 2 (a) Butters, T. D.; Dwaek, R. A.; Platt, F. M. Chem. Rev. 2000,
100, 4683; (b) Kolter, T.; Sandhoff, K. Angew. Chem. Int. Ed.
1999, 38, 1532.
3. 3 (a) Fan, J.-Q.; Ishii, S.; Asano, N.; Suzuki, Y. Nature Med. 1999,
5, 112; (b) Asano, N.; Ishii, S.; Kizu, H.; Ikeda, K.; Yasuda, K.;
Kato, A.; Martin, O. R.; Fan, J.-Q. Eur. J. Biochem. 2000, 267,
4179.
4. 4 van den Berg, R. J. B. H. N.; Wennekes, T.; Ghisaidoobe, A.;
Donker-Koopman, W. E. Strijland, A.; Boot, R. G.; van. der
Marel, G. A.; Aerts, J. M. F. G.; Overkleeft, H. S. ACS Med.
Chem. Lett. 2011, 2, 519.
5. 5 Ajish Kumar, K. S.; Rathee, J. S.; Subramanian, M.;
Chattopadhyay, S. J. Org. Chem. 2013, 78, 7406.
6. 6 For a review article on syntheses of 3-hydroxypipecolic acids,
see: Cochi, A.; Pardo, D. G.; Cossy, J. Eur. J. Org. Chem. 2013,
809.
7. 7 (a) Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H.; Kato, A.;
Adachi, I. J. Org. Chem. 2003, 68, 3606; (b) Kato, A.; Miyauchi,
S.; Kato, N.; Nash, R. J.; Yoshimura, Y.; Nakagome, I.; Hirono,
S.; Takahata, H.; Adachi, I. Bioorg. Med. Chem. 2011, 19, 3558.

ACCEPTED MANUSCRIPT
H
N
H
N
H
N
HO2C
HO
HO
HO
HO
HO
OH
OH
OH
1
2
3
1-deoxygalactonojirimycin (+)-4-epi-fagomine 3-hydroxypipecolic acid

ACCEPTED MANUSCRIPT
O
OH
Bn
N
Cbz
CHO
b
a
Cbz
N
NH
Bn
O
O
Cbz
60%
41%
Bn
7
4
5
c
78%
O
H
N
H
N
d
HO
O
O
O
92%
HO
ent-2
4-epi-fagomine
O
OH
OH
6
8
dioxanone

ACCEPTED MANUSCRIPT
Cbz
Cbz
N
H
N
N
b
HO
a
O
O
65%
86%
O
O
O
O
OH
OH
10
8
9
c
77%
Cbz
Cbz
H
N
HO2C
N
HO2C
HO
HO2C
HO
N
e
d
93%
64%
O
O
11
OH
13
OH
12

ACCEPTED MANUSCRIPT
Cbz
N
Cbz
N
Cbz
N
c
a, b
O
O
HO
72%
62%
O
O
HO
15
OH
9
14
g
95%
d, e
45%
Cbz
N
H
N
H
HO2C
HO
HO2C
HO
N
f
HO
HO
90%
ent-3
17
16

ACCEPTED MANUSCRIPT
Supporting information
Organocatalyzed synthesis of (-)-4-epi-fagomine and the corresponding
pipecolic acids
Jasna Marjanovicb , Zorana Ferjancica,* and Radomir N. Saicica,*
aFaculty of Chemistry, University of Belgrade, Studentski trg 16, POB 51, 11158 Belgrade, Serbia
bInnovative Centre, Faculty of Chemistry, Studentski trg 16, Belgrade
Table of contents
NMR spectra of compound 5 ........................................................................................................................................... S2
NMR spectra of compound 7 ........................................................................................................................................... S3
NMR spectra of compound 8............................................................................................................................................ S4
NMR spectra of compound ent-2 ................................................................................................................................... S5
NMR spectra of compound 9 ........................................................................................................................................... S6
NMR spectra of compound 10 ........................................................................................................................................ S7
NMR spectra of compound 11 ........................................................................................................................................ S8
NMR spectra of compound 12.......................................................................................................................................... S9
NMR spectra of compound 13 ...................................................................................................................................... S10
NMR spectra of compound xanthate .......................................................................................................................... S11
NMR spectra of compound 14 ...................................................................................................................................... S12
NMR spectra of compound 15........................................................................................................................................ S13
NMR spectra of compound 16 ...................................................................................................................................... S14
NMR spectra of compound ent-3 ................................................................................................................................. S15
NMR spectra of compound 17 ...................................................................................................................................... S16
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