A practical approach to Dideoxy-1,4- and 1,5-iminopentitols from protected sugar hemiacetals

Article abstract of DOI:10.1016/j.carres.2019.107855

The convenient and straightforward preparation of dideoxy-1,4- and 1,5-iminopentitol derivatives from protected sugar hemiacetals by way of N-tert-butanesulfinyl glycosylamines and open-chain aminoalditols is reported. The synthetic procedure is a method of choice for the making of these important scaffolds of biological interest.

Full text of DOI:10.1016/j.carres.2019.107855

Journal Pre-proof
A practical approach to Dideoxy-1,4- and 1,5-iminopentitols from protected sugar
hemiacetals
Justyna Jaszczyk, Sizhe Li, Chloé Cocaud, Cyril Nicolas, Olivier R. Martin
PII:
S0008-6215(19)30428-8
DOI:
https://doi.org/10.1016/j.carres.2019.107855
CAR 107855
Reference:
To appear in: Carbohydrate Research
Received Date: 19 July 2019
Revised Date: 17 October 2019
Accepted Date: 21 October 2019
Please cite this article as: J. Jaszczyk, S. Li, Chloé. Cocaud, C. Nicolas, O.R. Martin, A practical
approach to Dideoxy-1,4- and 1,5-iminopentitols from protected sugar hemiacetals, Carbohydrate
Research (2019), doi: https://doi.org/10.1016/j.carres.2019.107855.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Ltd.

CARBOHYDRATE RESEARCH Manuscript
NOTE
A Practical Approach to Dideoxy-1,4- and 1,5-iminopentitols from
Protected Sugar Hemiacetals.
Justyna Jaszczyk, Sizhe Li, Chloé Cocaud, Cyril Nicolas*, Olivier R. Martin**
Institut de Chimie Organique et Analytique (ICOA), UMR 7311, Université d’Orléans et CNRS, Rue
de Chartres, BP 6759, 45067 Orléans cedex 2, France.
E-mail addresses: cyril.nicolas@univ-orleans.fr (C. Nicolas), olivier.martin@univ-orleans.fr (O.R.
Martin).
Fax: +33(02)38417281.
Abstract
The convenient and straightforward preparation of dideoxy-1,4- and 1,5-iminopentitol
derivatives from protected sugar hemiacetals by way of N-tert-butanesulfinyl glycosylamines
and open-chain aminoalditols is reported. The synthetic procedure is a method of choice for
the making of these important scaffolds of biological interest.
Keywords
Sugar
Hemiacetals;
N-tert-butanesulfinyl
glycosylamines;
aminoalditols;
Dideoxyiminopentitols
1. Introduction
Polyhydroxylated pyrrolidines and piperidines known as 1,4- and 1,5-dideoxyiminosugars
have been known as natural products since the discovery of fagomine (1,2-
dideoxynojirimycin, Figure 1) and moranoline in the 1970’s [1,2]. The name ‘moranoline’
was later abandoned and 1-deoxynojirimycin (DNJ) preferred. A large diversity of 1-
deoxyiminosugars was found a posteriori in microorganisms and plants [e.g., DMDP (2,5-
dihydroxymethyl-3,4-dihydroxypyrrolidine also known as 2,5-dideoxy-2,5-imino-
D-
mannitol), Figure 1] [3] and many new structures synthesized [4]. The biological studies on

these compounds revealed their remarkable properties as inhibitors of glycosidases, as well as
of other carbohydrate-processing enzymes [5]. When protonated, they mimic charge and
shape of the cationic intermediates generated in the glycosidase catalyzed reactions. As such,
these sugar analogues have considerable therapeutic potential and three 1,5-dideoxy-1,5-
iminohexitol derivatives have now been commercialized as drugs (Figure 1). N-[2-
hydroxyethyl]-1-deoxynojirimycin (miglitol) to treat diabetes mellitus type 2, N-butyl-
deoxynojirimycin (miglustat) to act towards type I Gaucher disease and progressive
neurologic manifestations of Niemann-Pick disease type
C
(NP-C) and 1-
deoxygalactonojirimycin (migalastat) for the treatment of Fabry disease [6‒11].
Figure 1. Natural 1-deoxyiminosugars and derivatives used as drugs.
A diversity of synthetic methodologies have been developed to access 1-
deoxyiminosugars in the piperidine and pyrrolidine series, most often from sugars as starting
materials [12], [13‒17]. Such methods include for example, from protected, reducing aldo-
furanoses or –pyranoses, double oxidation-double reductive amination sequences [18‒20] or
reduction, double mesylation and double SN2 reactions [21]. Also from aldonolactones,
formation of an open-chain amide, cyclization by oxidation and reductive amination to
generate a lactam and reduction of the carbonyl group [22,23] has proven to be a convenient
method. Remarkably, all these synthetic routes appear to be methods of choice although
manipulation of the oxo-intermediates is commonly quite challenging and double reductive
amination protocols give typically moderate overall yields (~ 50%) over long reaction times
(48 h). Of relevance to our work is the method of Buchanan and Wrightman who reported the
synthesis of a 2,3,5-tri-O-benzyliminoxylitol by a three-step procedure via an open chain
oxime [24]. The technique consisting in forming a glycosylamine and reacting it with a
nucleophile to generate an open-chain aminoalditol has been used mostly with C-
nucleophiles to reach eventually 1-C-susbtituted iminoalditol compounds in the pyrrolidine
and piperidine series [17]. The in situ or stepwise reductive amination of sugar hemiacetals

with amines by way of a glycosylamine, followed by the activation of the free OH group and
cyclisation was reported by a few authors [25], [26,27] as an approach to 1-deoxyiminosugars
but remained limited to few examples and their generality was not demonstrated.
Furthermore, the reaction sequences involved generally long periods of time (usually ≥ 16 h)
and/or low temperatures, the iminosugar compounds being obtained in their N-protected
form; thus requiring an additional step for deprotection.
As shown in our previous work, N-tert-butanesulfinyl glycosylamines are highly efficient
aldose imine surrogates and their reactions with organometallic nucleophiles have led to a
diversity of 1-C-substituted iminoalditols derivatives [28,29]. On this basis, a short, general
and convenient synthetic route to 1-deoxyiminoalditols using hydride as the nucleophile was
envisaged (Figure 2).
Figure 2. Synthetic plan from protected Hemiacetals.
Combined with the cyclisation of the resulting open-chain aminoalditols, the route should
lead in very few steps and short reaction times to protected or deprotected cyclic
iminopentitols. We report in this note the implementation of the methodology.
2. Results and Discussion
Starting from known tri-O-benzyl pentofuranoses (1a, 1b), that were respectively obtained
from L-xylose and D-arabinose, formation of the sulfinyl glycosylamines of type 2 was
executed under conditions improved from the ones we previously described [28,29]. Thus,
using Ti(OEt)4 as the promoter and commercial (R)-(+)-2-methyl-2-propanesulfinamide ((R)-
3, 2 equiv.) [30] in dry toluene, compounds (SR)-2a (83%) and (SR)-2b (86%) could be
isolated in excellent yields after 1.5 h at 110 °C. Addition of NaBH4 (4 equiv.) was then
performed in toluene at room temperature (ca. 20 °C) with the D-arabinofuranosylamine (SR)-
2b to obtain compound (SR)-4b in good yield (84%, 72% over 2 steps) after a reaction time of
20 h. Alternatively, for the synthetic utility of the proposed study, the glycosylamines were
not isolated. Instead, following general procedure A (G.P. A), step (1) was carried out, and
the crude reaction mixture was directly treated with NaBH4 (4 equiv.) at 110 °C for 1 h to

afford the corresponding iminoalditols ((SR)-4a and (SR)-4b) in high yields (e.g., 76 and 74%
respectively over the two-step sequence).
Of note, the reaction sequence could also be realized using the (S)-(‒)-chiral sulfinyl
auxiliary. Heating under microwave irradiation (i.e., 110 °C for 1.5 h) could also be achieved
in step (1) to form the sulfinyl glycosylamines in comparable yields with that under standard
heating. Subsequent reduction at 110 °C for 1 h could then be carried out at the bench, with
no improvement of the reaction sequence yield (Scheme 1). Notably, synthesis of the
aminoalditol compounds 4 could not be fully accomplished under microwave irradiation as a
dramatic yield decrease was observed for the reduction step (e.g., 58% for (SR)-4b). The free
OH position was next activated as a mesylate, and the crude mesylate treated with t-BuOK (0
°C or 20 °C, 0.5-1.5 h) to perform the cyclization, thus giving pyrrolidine derivatives (SR)-5a
and (SR)-5b in moderate yields (66‒69%).
Scheme 1. Reactions of pentofuranose hemiacetals. General Procedure A (G.P. A): step (1), then
addition of NaBH4 (4 eq.), 110 °C, 1 h (compound 2 not isolated); General Procedure B (G.P. B): step
(3) and (5) (use of crude 5).
The sulfinyl group was cleaved by simple treatment with acidic methanol to give 6a and
6b in good yield (93%) [28]. Once again, the two reactions could be completed in a single
sequence. The sulfinyl group could be cleaved from the intermediate mesylate, which was not
isolated and subsequently cyclized upon acidification and neutralisation of the reaction
mixture with a basic anion exchange resin (step (3) and (5), general procedure B or G.P. B),
thus giving directly 6a and 6b from (SR)-4a and (SR)-4b in 72 and 70% yield respectively

[29]. Starting from
1,4-imino- -arabinitol 6a, and from
-xylitol derivative 6b was obtained, both resulting from an inversion of configuration at C-4
upon ring closure. Compound 6a was then deprotected by hydrogenolysis to afford the
known -DAB 7a as its hydrochloride salt [22].
L-xylofuranose derivative 1a [31], the sequence gave the O-benzylated
D
D
-arabinofuranose 1b [32], the corresponding 1,4-imino-
L
D
The scope of the reactions was then extended and the same sequence was applied to a tri-
O-benzylated pentopyranose, with the goal of forming a 1,5-dideoxy-1,5-iminopentitol
derivative. 3,4,5-Trihydroxypiperidines and their N- and O-alkylated and arylated synthetic
derivatives have been shown exhibiting outstanding array of biological activities and
promising potential in the area of antibacterial, anti-inflammatory and antiviral agents [33].
Scheme 2. Reaction of a
L-lyxopyranose hemiacetal. Procedure C (P. C): Step (1), then evaporation
of the solvent and step (2) carried out.
The known tri-O-benzyl-
lyxose. Reaction with Ellman's (R)-tert-butanesulfinamide [30] was performed at 110 °C to
give the desired glycosylamine (SR)-9 readily (Scheme 2). The -lyxopyranosylamine
L-lyxopyranose 8 [34] was thus prepared in three steps from L-
L
derivative was not soluble in toluene. It could be isolated (77%) and characterized.
Importantly, heating under µW irradiation was mandatory to allow formation of (SR)-9 in
good yield over a short period of time [35]. Afterwards, the toluene was evaporated and the
crude compound (SR)-9 was reduced to the corresponding aminopentitol derivative (SR)-10
(64%) upon addition of NaBH4 (4 equiv.) in EtOH at 80 °C for 2 h (49% over two steps).
Step (1) and (2) could obviously be performed without isolation of (SR)-9 to give (SR)-10 in
good overall yield (56%, procedure C (P. C)). The open-chain compound was thereafter

cyclized by way of the mesylate under the conditions described for the pyrrolidines (G.P. B),
thus affording the 1,5-dideoxy-1,5-imino-L-lyxitol 11 in moderate yield (44%).
3. Conclusion
We have reported in this note a brief synthesis of protected or free 1,4-imino or 1,5-
iminopentitol derivatives using a sulfinyl glycosylamine as an aldose imine equivalent.
Reduction of the latent imine provides an open-chain aminoalditol, which can be readily
cyclized by an internal SN2 process. This method will be applicable to a large diversity of
pentose hemiacetals to prepare the corresponding cyclic iminoalditols in moderate to good
overall yields in a convenient and straightforward manner. Although the use of a chiral
sulfinyl group is required for the proposed study, it is important to note that (R)- and (S)-2-
methyl-2-propanesulfinamides are inexpensive and readily to prepare [30]. Furthermore, the
sulfinylamino function has optimal properties to allow implementation of this methodology:
stable glycosylamine and open-chain intermediates, favourable reactivity of the latent N-
sulfinyl imine, and ready deprotection of the nitrogen atom, thus providing the possibility of
post-functionalisation of this endocyclic atom.
4. Experimental section
4.1. General remarks
Unless otherwise stated, all reagents were purchased from commercial suppliers and used
as received. Toluene (puriss. p.a., ACS reagent, ≥ 99.7% (GC)) and THF (99.9% GC) with
2,6-di-tert-butyl-4-methylphenol (250 mg/L) as stabilizer were purified by passage through a
column containing activated alumina under nitrogen pressure (Dry Solvent Station GT S100,
GlassTechnology, Geneva, CH). Dichloromethane (99.99% GC) was distilled from calcium
hydride (CaH2) and used as solvent in reactions under anhydrous conditions. Methanol
(anhydrous, 99.8%) and N,N-dimethylformamide (anhydrous, 99.8%) were purchased from
Sigma-Aldrich. MS 4 Å was activated by drying in an oven at 500 °C (48 h). It was then
allowed to reach room temperature (ca. 20 °C) and kept over CaCl2 in a desiccator prior to
use. Amberlite® IRA-400 was prepared in its OH‾ form by passing 1M KOH until the
effluent is free from chloride ions, then washed with distilled H2O until neutral and MeOH.
Microwave activation was performed in sealed vessel, using a Biotage Initiator system. The
following setting was used: Normal absorption level, Fixed Hold Time: on, Power: 100 Watt,
Hold time: 90 minutes, Temperature: 110 °C. The internal temperature was measured by an
IR-sensor. NMR spectra were recorded at 298 K with a Bruker Avance III HD nanobay 400

MHz spectrometer equipped with a BBO probe. The structures of the new compounds were
assigned with the aid of 1 D [1H NMR, 13C NMR, Distortionless Enhancement by
Polarization Transfer (DEPT)] and 2 D Correlation Spectroscopy [(1H−1H COSY and 1H−13C
1
Heteronuclear Single Quantum Coherence (HSQC)] experiments. H NMR (400 MHz)
chemical shift values are listed in parts per million (ppm). Tetramethylsilane (TMS) was used
as an internal standard, or alternatively, spectra were calibrated using the signals of the
corresponding non-deuterated solvent. Data are reported as follows: chemical shift (ppm on
the δ scale), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet and m = multiplet),
13
coupling constant Ј (Hz), and integration. C NMR (101 MHz) chemical shifts are given in
ppm. Spectra were calibrated using the corresponding non-deuterated solvent or TMS as an
internal standard. NMR primary data should be processed by MestReNova. High-resolution
mass spectra were recorded with a Brucker maXis ESI qTOF ultrahigh-resolution mass
spectrometer coupled to a Dionex Ultimate 3000 RSLC system (FR2708, Orléans). MS data
were acquired in positive mode and were processed using Data Analysis 4.4 software
(Bruker). Infrared spectra were recorded with a Thermo Scientific Nicolet IS10 FTIR
spectrometer using diamond ATR golden gate sampling and are reported in wave numbers
(cm–1). Specific optical rotations were measured with a JASCO P-2000 digital polarimeter, in
a thermostated (20 °C) 1 dm long cell with high-pressure sodium lamp and are reported as
follow: [α]DT [solvent, c (g/100 mL)]. Analytical thin-layer chromatography (TLC) was
performed with Merck Silica Gel 60 F254 precoated plates. Visualization of the developed
chromatogram was performed under ultraviolet light (254 nm) and on staining by immersion
in aqueous, acidic ceric ammonium molybdate followed by charring at 150 °C. Flash
chromatography was performed in air on Silica Gel 60 (230–400 mesh) with petroleum ether
(PE, bp 40–65 °C) and ethyl acetate as eluents, unless otherwise stated. Organic solutions
were concentrated under reduced pressure with a Buchi rotary evaporator.
4.2. General procedures
4.2.1. General procedure for the preparation of 1-N-tert-butanesulfinylamino-1-deoxy-
pentitol derivatives of type 4a and 4b from protected sugar hemiacetals (1a, 1b) (G.P. A).
A single-necked flask equipped with a reflux condenser and an argon inlet system was
charged with related tri-O-benzyl-pentofuranose, 4 Å activated molecular sieves (0.4 g per
mmol of substrate) and (S)- or (R)-2-methyl-2-propanesulfinamide (2.0 equiv.). Dry toluene
(4 mL per mmol of substrate) was inserted and the mixture was stirred for 5 min at room

temperature (~20 °C). Titanium(IV) ethoxide (Ti(OEt)4, 1.5 equiv.) was then added and the
reaction mixture was stirred at 110 °C until no more starting material was observed by TLC
(generally, 1.5 h). The content was next allowed to reach 20 °C and NaBH4 (4.0 equiv.) was
o
added. The resulting suspension was stirred at 110 C until no more sulfinyl glycosylamine
intermediate remained in the reaction mixture (1 h). The suspension was then allowed to cool
down to room temperature and sat. aqueous NaCl was added. The mixture was stirred at 20
°C for 10 min and the precipitate and molecular sieves were filtered through a pad of celite®.
The cake was rinsed (EtOAc) and the aqueous layer was discarded. The organic phase was
washed (sat. aq. NH4Cl), dried over MgSO4, filtered through a cotton plug and concentrated
in vacuo. The crude product was purified through column chromatography (SiO2, PE:EtOAc)
to provide the 1-N-tert-butanesulfinylamino-1-deoxy-pentitol derivative.
4.2.2. General procedure for the Synthesis of 1,4-Dideoxy-1,4-iminopentitol derivatives of
type 6a and 6b and 1,5-Dideoxy-1,5-imino-
butanesulfinylamino-1-deoxy-pentitols (G.P. B).
L-lyxitol 11, from corresponding N-tert-
To a solution of compound 4 in anhydrous CH2Cl2 (0.08
M), under argon atmosphere,
were added Et3N (2.2 equiv.) and MsCl (2.0 equiv.) and the reaction mixture was stirred at
room temperature until no more starting material was present (30−60 min). The mixture was
then diluted (CH2Cl2) and the organic phase was washed with aq. NH4Cl. The aqueous phase
was extracted 3× with CH2Cl2 and the combined organic phases were dried over MgSO4. The
solvent was evaporated at the evaporator to give the crude mesylated intermediate which was
used in the next cyclization step without further purification.
A single-necked flask under argon atmosphere was charged with AcCl (5 equiv., 0.4
M)
and dry MeOH and the mixture was stirred at 20 °C for 30 min (solution A). Another flask
under argon atmosphere (flask B) was charged with dry MeOH and crude mesylated
intermediate (0.4
M), and solution A was added through syringe to flask B. The reaction
mixture was stirred for 1 h; Amberlite IRA-400 (OH– form) ion-exchange resin was then
added until pH 8. The mixture was stirred further for 1 h at the same temperature and the
suspension was filtered through a cotton plug. The solvents were evaporated under reduced
pressure and the residue was purified by chromatography to provide compound 6a, 6b or 11
in good yield.
4.3. Synthesis of Compounds 4-7 and 9-11.
4.3.1. 2,3,5-Tri-O-benzyl-1-[(SR)-N-tert-butanesulfinylamino]-1-deoxy-L-xylitol (SR)-4a.

Compound (SR)-4a was synthesized according to G.P. A, and isolated as a colorless oil
1
(1.9 g, 76%). Rf 0.2 (SiO2, PE:EtOAc 1:1) H NMR (400 MHz, CDCl3/TMS): δ 7.36–7.21
(overlapped, 15 H, HAr), 4.78–4.38 (overlapped, 6 H, OCH2Ph), 4.00–3.87 (overlapped, 2 H,
H-4, H-2), 3.70 (dd, J = 6.1, 2.2 Hz, 1 H, H-3), 3.60–3.43 (overlapped, 3 H, H-1a, H-5a, NH),
3.39 (dd, J = 9.3, 6.4 Hz, 1 H, H-5b), 3.27 (dt, J = 12.7, 6.2 Hz, 1 H, H-1b), 2.48 (d, J = 7.5
13
Hz, 1 H, OH), 1.16 (s, 9 H, tBu) ppm. C NMR (101 MHz, CDCl3/TMS): δ 138.0 (C, CAr),
138.0 (C, CAr), 137.9 (C, CAr), 128.5–127.7 (CH, CHAr), 79.3 (CH, C-2), 77.3 (CH, C-3),
74.3 (CH2, OCH2Ph), 73.3 (CH2, OCH2Ph), 72.8 (CH2, OCH2Ph), 71.3 (CH2, C-5), 68.9 (CH,
C-4), 55.8 (C, tBu), 45.7 (CH2, C-1), 22.6 (CH3, tBu) ppm. HRMS (ESI): calcd. for
C30H40NO5S [M+H+] 526.2627; found 526.2621.
4.3.2. 2,3,5-tri-O-benzyl-(SR)-N-tert-butanesulfinyl-1,4-dideoxy-1,4-imino-D-arabinitol (SR)-
5a.
To a solution of compound (SR)-4a (200 mg, 0.38 mmol) in anhydrous CH2Cl2 (5 mL),
under argon atmosphere were added triethylamine (113 µL, 0.84 mmol) and MsCl (59 µL,
0.76 mmol) and the reaction mixture was stirred at room temperature for 1 h. The mixture
was diluted by addition of CH2Cl2 (20 mL) and the organic solution was washed with
saturated aq. NaCl (30 mL). Next, the aqueous phase was extracted with CH2Cl2 (2 × 20 mL)
and combined organic phases were dried over MgSO4 and filtered over a cotton plug. Solvent
removal through rotary evaporation gave the crude mesylated intermediate which was used
for the cyclisation step without further purification.
To a solution of the just generated mesylated intermediate in anhydrous THF (5 mL) under
argon atmosphere was added t-BuOK (85 mg, 0.76 mmol) and the reaction mixture was
stirred at 20 °C for 30 min. Saturated aq. NH4Cl (10 mL) was then added and the mixture was
extracted with EtOAc (3 × 15 mL). Next, the combined organic phases were washed with
saturated aq. NaCl (20 mL), dried over MgSO4, filtered over a cotton plug and concentrated
under vacuum. The crude product was purified by flash chromatography (SiO2, PE : EtOAc
2:1) to give (SR)-5a (132 mg, 69%) as colorless oil. Rf 0.32 (SiO2, PE:EtOAc 2:1). [α]D20 −9.6
(c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3/TMS): δ 7.37–7.20 (overlapped, 15 H, HAr), 4.60
(s, 2 H, OCH2Ph), 4.51–4.40 (overlapped, 4 H, OCH2Ph), 4.08–3.97 (overlapped, 3 H, H-1a,
H-2, H-3), 3.86–3.77 (m, 1 H, H-4), 3.57–3.46 (m, 2 H, H-5), 2.79 (dd, J = 10.2, 4.3 Hz, 1 H,
13
H-1b), 1.15 (s, 9 H, tBu) ppm. C NMR (101 MHz, CDCl3/TMS): δ 138.2 (C, CAr), 138.1
(C, CAr), 137.9 (C, CAr), 128.5−127.6 (CH, CHAr), 83.1 (CH, C-2 or C-3), 82.1 (CH, C-3 or
C-2), 73.1 (CH2, OCH2Ph), 72.1 (CH2, OCH2Ph), 71.6 (CH2, OCH2Ph), 71.2 (CH2, C-5),

68.26 (CH, C-4), 57.6 (C, tBu), 44.8 (CH2, C-1), 23.6 (CH3, tBu) ppm. IR (neat): 3021
(C−H), 2929 (C−H), 2857 (C−H), 1714, 1451 (C=C), 1064 (C−O), 739 (C−H), 694 (C−H)
cm–1. HRMS (ESI): calcd. for C30H38NO4S [M+H+] 508.2522; found: 508.2519.
4.3.3. 2,3,5-Tri-O-benzyl-1,4-dideoxy-1,4-imino-D-arabinitol 6a.
Compound 6a was synthesized from imino-L-xylitol (SR)-4a according to G.P. B. It was
isolated as a colorless oil (110 mg, 72%). Rf 0.45 (SiO2, CH2Cl2:MeOH 15:1). NMR data are
20
1
consistent with that of the literature [22]. [α]D −1.0 (c 1.0, CHCl3); H NMR (400 MHz,
CDCl3/TMS): δ 7.31–7.21 (overlapped, 15 H, HAr), 4.59–4.39 (overlapped, 6 H, OCH2Ph),
4.05–3.97 (m, 1 H, H-2), 3.87 (dd, J = 4.8, 1.9 Hz, 1 H, H-3), 3.61 (dd, J = 9.5, 5.1 Hz, 1 H,
H-5a), 3.55 (dd, J = 9.5, 5.6 Hz, 1 H, H-5b), 3.24 (q, J = 4.8 Hz, 1 H, H-4), 3.09 (d, J = 3.6
13
Hz, 2 H, H-1), 2.24 (br s, 1 H, NH) ppm. C NMR (101 MHz, CDCl3/TMS): δ 138.3 (C,
CAr), 138.2 (C, CAr), 138.2 (C, CAr), 128.4–127.6 (CH, CHAr), 85.8 (CH, C-3), 84.6 (CH, C-
2), 73.2 (CH2, OCH2Ph), 71.9 (CH2, OCH2Ph), 71.1 (CH2, OCH2Ph), 70.4 (CH2, C-5), 64.2
(CH, C-4), 51.1 (CH2, C-1) ppm. IR (neat): 3034 (C−H), 2917 (C−H), 2863 (C−H), 1739,
1451 (C=C), 1087 (C−O), 736 (C−H), 688 (C−H) cm–1. HRMS (ESI): calcd. for C26H30NO3
[M+H+] 404.2226; found: 404.2218.
Alternatively, it could be prepared by removal of the chiral sulfinyl auxiliary from imino-
D-arabinitol 5a.
In a 2-mL single-necked round-bottomed flask under argon atmosphere was inserted AcCl
(17 µL, 0.24 mmol) and dry MeOH (0.5 mL) and the solution was stirred at 20 °C for 30 min
(solution A). In parallel, another 2-mL flask under argon atmosphere was charged with
imino-D-arabinitol (SR)-5a (30 mg, 0.06 mmol) and solution A was added through syringe.
The reaction mixture was stirred for 15 min and neutralized by addition of resin Amberlite
IRA-400 (OH– form) until pH 8. The solution was filtered through a cotton plug and
concentrated under vacuum to afford 6a in good yield (23 mg, 93%).
4.3.4. 1,4-Dideoxy-1,4-imino-D-arabinitol 7a.HCl.
A vigorously stirred suspension of 6a (70 mg, 0.173 mmol), 20% Pd(OH)2−C (40 mg),
and aq. HCl (1 N, 0.6 mmol, 600 µL) in iPrOH (5 mL) was degassed under vacuum and
saturated with hydrogen (3x). The reaction mixture was stirred at 20 °C for 48 h under
hydrogen atmosphere (balloon of H2). The mixture was filtered over a pad of celite® and the
solid residue was rinsed with MeOH. The solvents were evaporated under reduced pressure to

give 7a.HCl as colorless syrup in quantitative yield (29 mg). Characterization data are
20
consistent with those reported in the literature [22]. [α]D +24.5 (c 0.47, H2O); (Lit [α]D
+27.27 (c 0.47, D2O)). 1H NMR (400 MHz, D2O): δ 4.37–4.31 (m, 1 H, H-2), 4.15–4.06 (m,
1 H, H-3), 3.96 (dd, J = 12.2, 4.6 Hz, 1 H, H-5), 3.84 (dd, J = 12.2, 8.2 Hz, 1 H, H-5), 3.67–
13
3.54 (overlapped, 2 H, H-4, H-1a), 3.37 (d, J = 12.6 Hz, 1 H, H-1b) ppm. C NMR (101
MHz, D2O): δ 75.6 (CH, C-3), 74.2 (CH, C-2), 66.6 (CH, C-4), 58.9 (CH2, C-5), 50.0 (CH2,
C-1) ppm. HRMS (ESI): calcd. for C5H12NO3 [M+H+] 134.0817; found: 134.0812.
4.3.5. 2,3,5-Tri-O-benzyl-1-[(SR)-N-tert-butanesulfinylamino]-1-deoxy-D-arabinitol (SR)-4b.
The title compound was synthesized according to G.P. A to afford (SR)-4b as yellowish
20
1
syrup (277 mg, 74%). Rf 0.1 (SiO2, PE:EtOAc 5:5). [α]D –34.5 (c 0.78, CHCl3). H NMR
(400 MHz, CDCl3/TMS): δ 7.39–7.22 (overlapped, 15H, HAr), 4.70–4.48 (overlapped, 6 H, 3
× OCH2Ph), 4.02–3.94 (br m, 1 H, H-4), 3.92–3.86 (m, 1 H, H-2), 3.71–3.59 (overlapped, 3
H, H-3, H-5a, H-5b), 3.46–3.25 (overlapped, 3 H, H-1a, H-1b, NH), 2.92 (br s, 1 H, OH),
1.13 (s, 9 H, tBu) ppm. 13C NMR (101 MHz, CDCl3/TMS): δ 138.1 (C, CAr), 138.0 (C, CAr),
137.8 (C, CAr), 128.7–127.9 (CH, CHAr), 79.4 (CH, C-2), 77.4 (CH, C-3), 73.7 (CH2,
OCH2Ph), 73.6 (CH2, OCH2Ph), 73.3 (CH2, OCH2Ph), 71.2 (CH2, C-5), 70.7 (CH, C-4), 55.9
(C, tBu), 45.6 (CH2, C-1), 22.7 (CH3, tBu) ppm. IR (neat): 3309 (O−H), 3062 (C−H), 3030
(C−H), 2865 (C−H), 1454 (C=C), 1068 (C−O), 735 (C−H), 697 (C−H) cm–1. HRMS (ESI):
calcd. for C30H40NO5S [M+H+] 526.2622; found 526.2622.
Alternatively, it could be prepared by reduction of the isolated glycosylamine derived
from 1b, compound 2b [29].
An oven-dried 5-mL single-necked round-bottomed flask was charged with compound
(SR)-2b (50 mg, 95 µmol) and flushed with argon. Dry THF (0.5 mL) was inserted (syringe)
and NaBH4 (7 mg, 0.19 mol) was added in one portion. The reaction mixture was then
allowed to stir at 20 °C for 20 h under argon atmosphere. The mixture was quenched by the
addition of aq. NH4Cl (10 mL), and it was extracted twice with EtOAc (2 × 10 mL). The
combined organic phases were dried (Na2SO4), filtered through a cotton plug and the solvents
were evaporated under reduced pressure. The crude product was purified by column
chromatography (SiO2, PE:EtOAc 5:5 to 3:7) to afford
mg, 84%).
D-arabinitol (SR)-4b in good yield (42
4.3.6. 2,3,5-Tri-O-benzyl-(SR)-N-tert-butanesulfinyl-1,4-dideoxy-1,4-imino-L-xylitol (SR)-5b.

To a solution of compound (SR)-4b (96 mg, 0.18 mmol) in anhydrous CH2Cl2 (3.5 mL), in
the presence of 4Å MS, under argon atmosphere were added Et3N (100 µL, 0.73 mmol) and
MsCl (57 µL, 0.73 mmol) and the reaction mixture was stirred at 20 °C for 30 min. The
molecular sieves were filtered through Celite®, the cake rinsed with CH2Cl2 and the organic
solution washed with aq. NH4Cl (10 mL). Next, the aqueous phase was extracted once with
CH2Cl2, combined organic phases were dried over MgSO4 and filtered over a cotton plug.
Solvent evaporation gave the crude mesylated intermediate which was used in the cyclisation
step without further purification.
To a solution of the just generated mesylated intermediate in anhydrous THF (3.5 mL)
under argon atmosphere was added t-BuOK (40 mg, 0.36 mmol) and the reaction mixture
was stirred at 0 °C for 1 h. Extra t-BuOK (20 mg, 0.18 mmol) was added and stirring was
pursued for another 30 min. Aqueous NH4Cl (10 mL) was then added and the mixture was
extracted twice with EtOAc (2 × 5 mL). The combined organic phases were then washed with
saturated aq. NaCl, dried over MgSO4, filtered over a cotton plug and concentrated under
vacuum. The crude product was purified by flash chromatography (SiO2, PE:EtOAc 7:3) to
give (SR)-5b (60 mg, 66%) as a pale yellow oil.
20
1
Rf 0.4 (SiO2, PE:EtOAc 7:3). [α]D –36.1 (c 1.06, CHCl3). H NMR (400 MHz,
CDCl3/TMS): δ 7.40–7.19 (overlapped, 15 H, HAr), 4.64–4.42 (overlapped, 6 H, OCH2Ph),
4.17 (dt, J = 6.9, 4.3 Hz, 1 H, H-2), 4.06 (dd, J = 6.0, 4.6 Hz, 1 H, H-3), 4.01–3.94 (m, 1 H,
H-4), 3.87 (dd, J = 11.5, 6.9 Hz, 1 H, H-1a), 3.74 (d, J = 4.8 Hz, 2 H, H-5), 3.02 (dd, J =
11.5, 3.7 Hz, 1 H, H-1b), 1.16 (s, 9 H, tBu) ppm. 13C NMR (101 MHz, CDCl3/TMS): δ 138.3
(C, CAr), 138.1 (C, CAr), 138.1 (C, CAr), 128.4−127.5 (CH, CHAr), 83.2 (CH, C-3), 81.5 (CH,
C-2), 73.5 (CH2, OCH2Ph), 72.5 (CH2, OCH2Ph), 71.8 (CH2, OCH2Ph), 68.2 (CH2, C-5),
59.7 (CH, C-4), 57.7 (C, tBu), 51.2 (CH2, C-1), 23.1 (CH3, tBu) ppm. IR (neat): ν = 3029
(C−H), 2924 (C−H), 2865 (C−H), 1454 (C=C), 1362, 1074 (C−O), 1028 (C−N), 753 (C−H)
cm-1. HRMS (ESI): calcd. for C30H38NO4S [M+H+] 508.2516; found: 508.2515.
4.3.7. 2,3,5-Tri-O-benzyl-1,4-dideoxy-1,4-imino-L-xylitol 6b.
The titled compound was synthesized from (SR)-4b according to G.P. B to afford 6b as a
20
yellow oil (51 mg, 70 %). Rf 0.4 (SiO2, CH2Cl2:MeOH 9:1). [α]D +7.9 (c 0.96, CHCl3). 1H
NMR (400 MHz, CDCl3/TMS): δ 7.39–7.20 (overlapped, 15 H, HAr), 4.60–4.42 (overlapped,
6 H, 3 × OCH2Ph), 4.05–3.93 (overlapped, 2 H, H-2, H-3), 3.73–3.69 (m, 1 H, H-5a), 3.66–
3.58 (m, 1 H, H-5b), 3.49 (dd, J = 11.5, 5.5 Hz, 1 H, H-4), 3.35 (dd, J = 11.8, 5.6 Hz, 1 H, H-

1a), 2.90 (d, J = 12.0 Hz, 1 H, H-1b), 2.25 (br s, 1 H, NH) ppm. 13C NMR (101 MHz,
CDCl3/TMS): δ 138.5 (C, CAr), 138.3 (C, CAr), 138.2 (C, CAr), 128.5−127.7 (CH, CHAr), 83.2
(CH, C-2 or C-3), 82.9 (CH, C-3 or C-2), 73.5 (CH2, OCH2Ph), 71.9 (CH2, OCH2Ph), 71.5
(CH2, OCH2Ph), 69.3 (CH2, C-5), 60.5 (CH, C-4), 50.9 (CH2, C-1) ppm. IR (neat): 3062
(C−H), 3029 (C−H), 2914 (C−H), 2861 (C−H), 1453 (C=C), 1094 (C−O), 1027 (C−N), 735
(C−H), 697 (C−H) cm−1. HRMS (ESI): calcd. for C26H30NO3 [M+H+] 404.2220; found:
404.2220.
Alternatively, compound 6b could be obtained from imino-L-xylitol 5b.
In a 10-mL single-necked round-bottomed flask under argon atmosphere was inserted
AcCl (37 µL, 0.52 mmol) and dry MeOH (3.0 mL) and the solution was stirred at 20 °C for
30 min (solution A). In parallel, another 10-mL flask under argon atmosphere was charged
with imino-L-xylitol (SR)-5b (53 mg, 0.104 mmol) and solution A was added through syringe.
The reaction mixture was stirred for 15 min and neutralized by addition of resin Amberlite
IRA-400 (OH– form) until pH 8. The solution was filtered through a cotton plug and
concentrated under vacuum to afford 6b in good yield (39 mg, 93%).
4.3.8. 2,3,4-tri-O-benzyl-(SR)-N-tert-butanesulfinyl-α/β-L-lyxopyranosylamine (SR)-9.
A 5-mL microwave vial under argon atmosphere was charged with 2,3,4-tri-O-benzyl-
L-
lyxopyranose (0.5 g, 1.19 mmol) 8 [34], 4 Å activated molecular sieves (0.5 g), (R)-(+)-2-
methyl-2-propanesulfinamide (0.288 g, 2.38 mmol) and a microwave magnetic stir bar. Dry
toluene (5 mL) was inserted and the mixture was stirred during 10 min at 20 °C. Ti(OEt)4
(0.41 g, 1.78 mmol) was added, the vial was sealed and the reaction mixture was heated at
110 °C for 1.5 h under microwave irradiation. After cooling to room temperature, the cap was
removed and the brown solution was diluted (CH2Cl2, 50 mL). Brine was added (50 mL) and
the mixture was stirred for 5 min. Molecular sieves and the precipitate were filtered over
celite and the cake was rinsed with CH2Cl2 (3 × 20 mL). The phases were separated and the
aqueous phase was extracted twice with CH2Cl2 (2 × 20 mL). The combined organic layers
were then dried over MgSO4, filtered over a cotton plug and evaporated under reduced
pressure. The crude compound product was purified by column chromatography (SiO2,
EtOAc : PE, 1:1) to provide (SR)-9 as yellow oil (0.48 g, 77%). Mixture of anomers ca. 8:2,
1
not assigned. Rf 0.38 (SiO2, EtOAc : PE, 1:1). H NMR (400 MHz, CDCl3/TMS): δ 7.40–
7.19 (overlapped, 15 H, HAr), 5.64 (br s, 0.7 H, NH maj.), 5.05 (br d, J = 7.8 Hz, 0.8 H, H-1
maj.), 4.97 (dd, J = 8.0, 5.4 Hz, 0.2 H, H-1 min.), 4.70–4.42 (overlapped, 6 H, OCH2Ph

maj., OCH2Ph min.), 4.07 (dd, J = 12.8, 2.0 Hz, 0.8 H, H-5b maj.), 3.94 (t, J = 3.2 Hz, 0.8 H,
H-2 maj.), 3.90–3.75 (overlapped, 1.6 H, H-2 min., H-5a min., H-5b min., H-3 maj.), 3.72–
3.65 (m, 0.8 H, H-4 maj.), 3.63–3.50 (overlapped, 1.2 H, H-5a maj., H-3 min., H-4 min., NH
min.), 1.18 (s, 1.8 H, tBu min.), 1.08 (s, 7.6 H, tBu maj.) ppm. 13C NMR (101 MHz,
CDCl3/TMS): δ 138.2 (C, CAr min.), 138.0 (C, CAr maj.), 138.0 (C, CAr min.), 137.9 (C, CAr
maj.), 137.8 (C, CAr min.), 137.6 (C, CAr maj.), 128.5 (CH, CHAr min.), 128.5–127.7 (CH,
CHAr min., CHAr maj.), 82.9 (CH, C-1 maj.), 82.6 (CH, C-1 min.), 77.3 (CH, C-3 maj.), 76.2
(CH, C-3 min.), 74.8 (CH, C-4 min.), 74.7 (CH, C-4 maj.), 73.9 (CH2, OCH2Ph maj.), 73.5
(CH, C-2 maj.), 73.4 (CH, C-2 min.), 73.0 (CH2, OCH2Ph min.), 71.7 (CH2, OCH2Ph maj.),
71.7 (CH2, OCH2Ph maj.), 71.5 (CH2, OCH2Ph min.), 71.5 (CH2, OCH2Ph min.), 64.0 (CH2,
C-5 min.), 58.7 (CH2, C-5 maj.), 56.1 (C, tBu maj.), 55.9 (C, tBu min.), 22.4 (CH3, tBu maj.),
22.4 (CH3, tBu min.) ppm. HRMS (ESI): calcd. for C30H38NO5S [M+H+] 524.2471; found
524.2465.
4.3.9. 2,3,4-Tri-O-benzyl-1-(SR)-N-tert-butanesulfinylamino-1-deoxy-L-lyxitol (SR)-10.
Procedure C (P. C). A 5-mL microwave vial under argon atmosphere was charged with
2,3,4-Tri-O-benzyl- - lyxopyranose 8 [34] (0.1 g, 0.24 mmol), 4 Å activated molecular sieves
L
(0.2 g), (R)-(+)-2-methyl-2-propanesulfinamide (58 mg, 0.48 mmol) and a microwave
magnetic stir bar. Dry toluene (2 mL) was inserted and the mixture was stirred during 10 min
at 20 °C. Ti(OEt)4 (82 mg, 0.36 mmol) was added, the vial was sealed and the reaction
mixture was heated at 110 °C for 1.5 h under microwave irradiation. After cooling to room
temperature, the cap was removed and the solvent was evaporated under reduced pressure
(septum pierced by a needle).
The crude 2,3,4-tri-O-benzyl-(SR)-N-tert-butanesulfinyl-α/β-L-lyxopyranosylamine (SR)-9
was then dissolved by adding 5 mL of absolute ethanol, the mixture was flushed with argon
and NaBH4 (36 mg, 0.95 mmol) was added. The reaction mixture was subsequently heated at
80 °C under argon atmosphere, until no more of the sulfinyl intermediate was observed (2 h).
Next, the suspension was allowed to cool down to room temperature and the solvent was
evaporated. The residue was dissolved in CH2Cl2 (20 mL) and molecular sieves were
eliminated by filtration through a cotton plug. The organic phase was washed with sat. aq.
NH4Cl (20 mL) and the aqueous phase was extracted 3× with CH2Cl2 (3 × 10 mL). Combined
organic layers were dried over MgSO4, filtered over a cotton plug and the solvent was
evaporated under reduced pressure. The crude product was purified by column

chromatography (SiO2, PE : EtOAc 1:2 to 1:3) to afford the titled compound (SR)-10 in 56%
20
yield (ca. 71 mg). Rf 0.25 (SiO2, PE:EtOAc 1:2). [α]D −59.4 (c 1.5, CHCl3); 1H NMR (400
MHz, CDCl3/TMS): δ 7.39–7.23 (overlapped, 15 H, HAr), 4.77–4.49 (overlapped, 6 H,
OCH2Ph), 3.93–3.86 (dd, J = 5.2, 3.8 Hz, 1 H, H-3), 3.85-3.76 (overlapped, 2 H, H-2, H-5a),
3.75–3.63 (overlapped, 3 H, H-4, H-5b, NH), 3.52–3.29 (m, 2 H, H-1), 2.45 (t, J = 6.1 Hz, 1
H, OH), 1.08 (s, 9 H, tBu) ppm. 1H NMR (400 MHz, Benzene-d6): δ 7.22–7.14 (overlapped,
6 H, HAr), 7.03–6.92 (overlapped, 9 H, HAr), 4.58–4.31 (overlapped, 6 H, OCH2Ph), 3.94 (t, J
= 6.3 Hz, 1 H, OH), 3.87 (dd, J = 5.5, 3.8 Hz, 1 H, H-2), 3.83 (q, J = 5.0 Hz, 1 H, , H-3),
3.72–3.62 (m, 2 H, H-5), 3.56 (q, J = 4.9 Hz, 1 H, H-4), 3.44–3.30 (m, 2 H, H-1), 0.80 (s, 9
13
H, tBu) ppm. C NMR (101 MHz, CDCl3/TMS) δ 138.1 (C, CAr), 138.1 (C, CAr), 137.8 (C,
CAr), 128.6–127.9 (CH, CHAr) 79.8 (CH), 79.4 (CH), 79.4 (CH), 74.2 (CH2, OCH2Ph), 72.7
(CH2, OCH2Ph), 72.1 (CH2, OCH2Ph), 61.2 (CH2, C-5), 55.7 (C, tBu), 45.6 (CH2, C-1), 22.6
13
(CH3, tBu) ppm. C NMR (101 MHz, Benzene-d6) δ 139.3 (C, CAr), 139.2 (C, CAr), 138.9
(C, CAr), 128.7–127.8 (CH, CHAr) 80.8 (CH, C-4), 80.6 (CH, C-2), 79.4 (CH, C-3), 77.8 (CH,
CHCl3), 74.7 (CH2, OCH2Ph), 72.9 (CH2, OCH2Ph), 72.1 (CH2, OCH2Ph), 61.5 (CH2, C-5),
55.6 (C, tBu), 45.7 (CH2, C-1), 22.7 (CH3, tBu) ppm. IR (neat): 3392 (O−H), 3031 (C−H),
2930 (C−H), 2876 (C−H), 1707, 1454 (C=C), 1043 (C−O), 736 (C−H), 691 (C−H) cm–1.
HRMS (ESI): calcd for C30H40NO5S [M+H+]: 526.2627; found: 526.2632.
Alternatively, compound (SR)-10 could be obtained from the reduction of isolated 2,3,4-
tri-O-benzyl-(SR)-N-tert-butanesulfinyl-α/β-L-lyxopyranosylamine (SR)-9.
An oven-dried 5-mL single-necked round-bottomed flask under argon atmosphere, was
charged with compound (SR)-9 (90 mg, 0.17 mmol), and absolute ethanol (5 mL). NaBH4 (26
mg, 0.69 mmol) was then added, portionwise, and the reaction mixture was stirred at 80 °C
for 2 h. The suspension was allowed to cool down to room temperature and the solvent was
removed by rotary evaporation. The crude residue was dissolved in EtOAc (20 mL) and the
organic phase was washed with sat. brine (20 mL). Next, the aqueous layer was discarded and
the organic phase was dried (MgSO4), filtered over a cotton plug and evaporated under
reduced pressure. The crude product was purified by column chromatography (SiO2,
PE:EtOAc 1:2 to 1:3) to provide compound (SR)-10 in moderate yield (58 mg, 64%).
4.3.10. 2,3,4-Tri-O-benzyl-1,5-dideoxy-1,5-imino-L-lyxitol 11.
Compound 11 was synthesized from amino-
L-lyxitol (SR)-10 according to G.P. B. It was
isolated as a colorless syrup (18 mg, 44% over two steps) after purification by

chromatography (SiO2, CH2Cl2:MeOH 100:1 to 30/1). Rf 0.4 (SiO2, CH2Cl2:MeOH 15:1).
[α]D20 +33.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3/TMS): δ 7.43–7.22 (overlapped, 15
H, HAr), 4.77–4.53 (overlapped, 6 H, 3 × OCH2Ph), 3.79–3.68 (overlapped, 2 H), 3.61 (br d, J
= 5.3 Hz, 1 H), 3.13 (br dd, J = 13.4, 2.8 Hz, 1 H, H-5a or H-1a), 3.05 (dd, J = 13.6, 6.0 Hz, 1
H, H-1a or H-5a), 2.64 (br d, J = 13.8 Hz, 1 H, H-1b or H-5b), 2.57 (br dd, J = 13.6, 7.3 Hz, 1
H, H-5b or H-1b) ppm. 13C NMR (101 MHz, CDCl3/TMS): δ 138.9 (C, CAr), 138.7 (C, CAr),
138.7 (C, CAr), 128.4−127.5 (CH, CHAr), 79.8 (CH), 76.6 (CH), 74.7 (CH), 72.5 (CH2,
OCH2Ph), 72.4 (CH2, OCH2Ph), 71.4 (CH2, OCH2Ph), 47.7 (CH2, C-5), 46.8 (CH2, C-1)
ppm. IR (neat): 3310 (N−H), 3028 (C−H), 2923 (C−H), 2866 (C−H), 1717, 1448 (C=C),
1097 (C−O), 729 (C−H), 694 (C−H) cm–1. HRMS (ESI): calcd. for C26H30NO3 [M+H+]
404.2226; found: 404.2218.
Notes.
The authors declare no conflicts of interest.
Ackowledgments.
The authors thank the Centre National de la Recherche Scientifique (CNRS), Labex SynOrg
(ANR-11-LABX-0029) and the MENRT program for support of this work.
References.
[1] M. Koyama, S. Sakamura, The Structure of a New Piperidine Derivative from Buckwheat Seeds
(Fagopyrum esculentum Moench), Agric. Biol. Chem. 38 (1974) 1111‒1112.
[2] M. Yagi, T. Kouno, Y. Aoyagi, H. Murai, The Structure of Moranoline, a Piperidine Alkaloid
from Morus Species, Nippon Nogei Kagaku Kaishi 50 (1976) 571‒572.
[3] M.S.J. Simmonds, G.C. Kite, E.A. Porter, Taxonomic Distribution of Iminosugars in Plants and
Their Biological Activities, in Iminosugars as Glycosidase Inhibitors, A.E. Stuetz Ed., Wiley-VCH,
Weinheim, 1999, pp. 8‒30.
[4] P. Compain, O.R. Martin, Iminosugars, from synthesis to therapeutic applications, Wiley,
Chichester, 2007.
[5] N. Asano, Naturally occurring iminosugars and related alkaloids: structure, activity and
applications, in ref. [4], pp. 7‒24.
[6] G. Horne, F.X. Wilson, J. Tinsley, D.H. Williams, R. Storer, Iminosugars past, present and future:
medicines for tomorrow, Drug Discov. Today 16 (2011) 107‒118.

[7] N. Asano, Iminosugars: The Potential of Carbohydrate Analogs, in Carbohydrate Chemistry: State
of the Art and Challenges for Drug Development; L. Cipolla, Ed.; Imperial College Press: London,
UK, 2016; pp. 279–301.
[8] A. Wadood, M. Ghufran, A. Khan, S.S. Azam, M. Jelani, R. Uddin, Selective glycosidase
inhibitors: A patent review (2012‒present), Int. J. Biol. Macromol. 111 (2018) 82‒91.
[9] J. Stirnemann, N. Belmatoug, F. Camou, C. Serratrice, R. Froissart, C. Caillaud, T. Levade, L.
Astudillo, J. Serratrice, A. Brassier, C. Rose, T. Billette de Villemeur, M.G. Berger, A Review of
Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int. J. Mol. Sci. 18 (2017)
441‒470.
[10] K.A. Lyseng-Williamson, Miglustat: A Review of Its Use in Niemann-Pick Disease Type C,
Drugs 74 (2014) 61‒74.
[11] E.H. McCafferty, L.J. Scott, Migalastat: A Review in Fabry Disease, Drugs 79 (2019) 543‒554.
[12] For a non-exhaustive list of pertinent publications, reviews see ref [13‒17].
[13] B. Laferla, L. Cipolla, F. Nicotra, General strategies for the synthesis of iminosugars and new
approaches towards iminosugar libraries, in Ref. [4], pp 25‒62.
[14] P. Compain, V. Chagnault, O.R. Martin, Tactics and strategies for the synthesis of iminosugar C-
glycosides: a review, Tetrahedron: Asymmetry 20 (2009) 672‒711.
[15] B.L. Stocker, E.M. Dangerfield, A.L. Win-Mason, G.W. Haslett, M.S.M. Timmer, Recent
Developments in the Synthesis of Pyrrolidine-Containing Iminosugars, Eur. J. Org. Chem. (2010)
1615‒1637.
[16] D. Hernández, A. Boto, Nucleoside Analogues: Synthesis and Biological Properties of
Azanucleoside Derivatives, Eur. J. Org. Chem. (2014) 2201‒2220.
[17] C. Nicolas, O.R. Martin, Glycoside Mimics from Glycosylamines: Recent Progress, Molecules
(2018) 1612‒1641.
[18] C.R.R. Matos, R.S.C. Lopes, C.C. Lopes, Synthesis of 1-Deoxynojirimycin and N-Butyl-1-
deoxynojirimycin, Synthesis (1999) 571–573.
[19] T. Wennekes, B. Lang, M. Leeman, G.A. van der Marel, E. Smits, M. Weber, J. van Wiltenburg,
M. Wolberg, J.M.F.G. Aerts, H.S. Overkleeft, Large-Scale Synthesis of the Glucosylceramide
Synthase Inhibitor N-[5-(Adamantan-1-yl-methoxy)-pentyl]-1-deoxynojirimycin, Org. Proc. Res.
Dev. 12 (2008) 414‒423.

[20] E.W. Baxter, A.B. Reitz, Expeditious Synthesis of Aza sugars by the Double Reductive
Amination of Dicarbonyl Sugars, J. Org. Chem. 59 (1994) 3175‒3185.
[21] See for ex: C. Wang, D.A. Kuntz, T. Hamlet, L. Sim, D.R. Rose, B.M. Pinto, Synthesis,
enzymatic activity, and X-ray crystallography of an unusual class of amino acids, Bioorg. Med.
Chem. 14 (2006) 8332‒8340.
[22] H.S. Overkleeft, J. van Wiltenburg, U.K. Pandit, A facile transformation of Sugar Lactones to
Azasugars, Tetrahedron 50 (1994) 4215–4224.
[23] D. Hazelard, M.L. Lepage, J.P. Schneider, M.M. Pichon, P. Compain, F. Massicot, Large-Scale
Synthesis of 2,3,4,6-Tetra-O-Benzyl-1-Deoxynojirimycin, Carbohydrate Chemistry: Proven Synthetic
Methods, C. Vogel, P. Murphy Eds, CRC Press, 2017, Vol. 4 pp. 293‒303.
[24] J.G. Buchanan, K.W. Lumbard, R.J. Sturgeon, D.K. Thompson, R.H. Wightman, Potential
glycosidase inhibitors: synthesis of 1,4-dideoxy-1,4-imino derivatives of
D-glucitol,
D- and
L-xylitol,
D
- and -allitol, - and -talitol, and -gulitol, J. Chem. Soc. Perkin Trans. 1 (1990) 699
L
D
L
D
‒
706.
[25] Q. Meng, M. Hesse, A new synthesis of (2S,3R,4R)-2-(hydroxymethyl)pyrrolidine-3,4-diol,
Helv. Chim. Acta 74 (1991) 445 450.
‒
[26] R.R. France, I. Cumpstey, T.D. Butters, A.J. Fairbanks, M.R. Wormald, Fluorescence labelling
of carbohydrates with 2-aminobenzamide (2AB), Tetrahedron Asymmetry 11 (2000) 4985 4994.
‒
[27] Process for Production of Deoxygalactonojirimycin derivatives PCT Patent Appl.
WO2004/054975, Oxford Glycosciences.
[28] C. Cocaud, C. Nicolas, A. Bayle, T. Poisson, X. Pannecoucke, O.R. Martin, Synthesis and
Reactivity of N-tert-butanesulfinyl glycosylamines, Eur. J. Org. Chem. (2015) 4330‒4334.
[29] C. Cocaud, C. Nicolas, T. Poisson, X. Pannecoucke, C.Y. Legault, O.R. Martin, Tunable
Approach for the Stereoselective Synthesis of 1 C Diethylphosphono(difluoromethyl) Iminosugars
as Glycosyl Phosphate Mimics, J. Org. Chem. 82 (2017) 2753‒2763.
[30] M.T. Robak, M.A. Herbage, J.A. Ellman, Synthesis and Applications of tert-Butanesulfinamide,
Chem. Rev. 110 (2010), 3600‒3740.
[31] J.-B. Behr, A. Erard, G. Guillerm, A Facile and Rapid Route to a New Series of Pyrrolizidines
Structurally Related to (1)-Alexine and (1)-Australine, Eur. J. Org. Chem. (2002) 1256‒1262.
[32] J. Zeng, S. Vedachalam, S. Xiang, X.-W. Liu, Direct C-Glycosylation of Organotrifluoroborates
with Glycosyl Fluorides and Its Application to the Total Synthesis of (+)-Varitriol, Org. Lett. 13
(2011) 42‒45.

[33] K. Prichard, D. Campkin, N. O’Brien, A. Kato, G.W.J. Fleet, Biological activities of 3,4,5-
trihydroxypiperidines and their N- and O-derivatives, Chem. Biol. Drug Des. 92 (2018) 1171‒1197.
[34] M.S. Schmidt, V. Wittman, Stereoselective synthesis of 1,10-linked α-L-lyxopyranosyl β-D-
glucopyranoside, the proposed biosynthetic precursor of the FG ring system of avilamycins,
Carbohydr. Res. 343 (2008) 1612‒1623
[35] N-tert-butanesulfinyl-pentopyranosylamines are much prone to hydrolysis than their furanosyl
counterparts. They are typically obtained in moderate yields (ca. 45%) through treatment of protected
pentopyranose hemiacetals with compounds of type 3 (2 equiv.), Ti(OEt)4 (1.5 equiv.), MS (4Å) in
toluene at 70 °C for 48 h; see ref. [17] and [28,29].
Graphical abstract.

Highlights
● Short, general and convenient method
● Synthesis of dideoxy-1,4- and 1,5-iminopentitols from protected sugar hemiacetals
● Use of a sulfinyl glycosylamine as an aldose imine equivalent
● Moderate to good overall yields (24-55%) obtained through two reaction sequences of 2.5 and
3.5 h

Declaration of interests
X The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
£ The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
Cyril Nicolas, the 17th of October 2019