Stereodivergent synthesis of piperidine iminosugars 1-deoxy-D-nojirimycin and 1-deoxy-D-altronojirimycin

Article abstract of DOI:10.1016/j.tet.2020.131837

A stereodivergent approach for producing piperidine iminosugars has been developed employing a common optically active precursor. The key steps of the synthetic pathway are the double diastereoselection in the asymmetric dihydroxylation of the suitable ch

Full text of DOI:10.1016/j.tet.2020.131837

Tetrahedron 79 (2021) 131837
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereodivergent synthesis of piperidine iminosugars 1-deoxy-D-
nojirimycin and 1-deoxy-D-altronojirimycin
, b, **,
Martina De Angelis a
1, Carla Sappino a, Emanuela Mandic a, Marianna D’Alessio a,
Maria Grazia De Dominicis a, Sara Sannino a, Ludovica Primitivo a b, Paolo Mencarelli a,
,
Alessandra Ricelli b, Giuliana Righi b
, *, 1
a “Sapienza” University of Rome, Dep. Chemistry, P.le A. Moro 5 - 00185 Roma, Italy
b CNR-IBPM,“Sapienza” University of Rome, Dep. Chemistry, P.le A. Moro 5 - 00185 Rome, Italy
a r t i c l e i n f o
A B S T R A C T
Article history:
A stereodivergent approach for producing piperidine iminosugars has been developed employing a
common optically active precursor. The key steps of the synthetic pathway are the double diaster-
eoselection in the asymmetric dihydroxylation of the suitable chiral vinyl epoxy ester and the regio- and
stereospecific opening of the epoxide ring with azide. The synthesis of two piperidine iminosugars, 1-
deoxy-D-altronojirimycin and 1-deoxy-D-nojirimycin, was achieved by two related routes.
© 2020 Elsevier Ltd. All rights reserved.
Received 13 August 2020
Received in revised form
27 November 2020
Accepted 29 November 2020
Available online 3 December 2020
Keywords:
Stereodivergent synthesis
Asymmetric dihydroxylation
Iminosugars
1-deoxy-D-nojirimycin
1-deoxy-D-altronojirimycin
1. Introduction
diseases, from viral infections to tumoral metastases.3 Nowadays,
some piperidine azasugar derivatives are currently in the market:
Polyhydroxylated piperidines, pyrrolidines, pyrrolizidines,
indolizidines and nortropanes, also known as azasugars or imino-
sugars, are widespread in plants and microorganisms. Their dis-
covery dates back to 1965, when nojirimycin was isolated from
Streptomyces and its biological properties were disclosed. This
discovery triggered an enormous amount of interest in the isolation
and synthesis of many other iminosugars, and subsequent inves-
tigation of their biological activity.1
As structural analogues of traditional carbohydrates where the
endocyclic oxygen is replaced by a nitrogen atom, their most
valuable property is the ability to inhibit glycosidase and glyco-
syltransferase enzymes by mimicking the corresponding natural
carbohydrate substrates.2 Therefore these sugar mimics have
tremendous therapeutic potential for treating a vast array of
two different derivatives of 1-deoxynojirimycin: miglitol (Glyset®),
a drug for treating type II diabetes mellitus,4 and miglustat
(Zavesca®) used for the treatment of Gaucher disease5 and the 1-
deoxygalactonojirimycin (migalastat-Galafold™)6, a drug for the
treatment of Fabry disease,7 a rare genetic disorder.
Their low natural abundance has led to an increasing interest in
their synthesis. Most of the syntheses reported to date make use of
carbohydrates as precursors, due to their structural similarity.8
Fewer syntheses start from linear molecules, and those often
make use of the dihydroxylation reaction to generate new stereo-
centers.9 Recently, we reported
a study on double stereo-
differentiation in the asymmetric dihydroxylation (AD) of optically
active olefins.10
As already described by other authors,11,12 the intrinsic diaster-
eoselection of the substrate, due to its capability to interact with
osmium tetroxide, and the chiral ligand effect can be combined in
order to exalt the intrinsic stereofacial preference of the reaction
(matched conditions) or even to override it, thereby obtaining the
naturally less favoured product as the major one (mismatched
conditions).13 In our studies, among the tested cases, the most
* Corresponding author. (G. Righi).
** Corresponding author. “Sapienza” University of Rome, Dep. Chemistry, P.le A.
Moro 5 - 00185 Roma, Italy. (M. De Angelis);
E-mail addresses: m.deangelis@uniroma1.it (M. De Angelis), giuliana.righi@cnr.it
(G. Righi).
1
interesting results were obtained on trans a,b-unsaturated epoxy
These authors contributed equally
https://doi.org/10.1016/j.tet.2020.131837
0040-4020/© 2020 Elsevier Ltd. All rights reserved.

M. De Angelis, C. Sappino, E. Mandic et al.
Tetrahedron 79 (2021) 131837
Table 1
Cinchona ligands catalyzed AD reaction.
.
a) OsO4 (5%), NMO, acetone/H2O 8:1, ligand
Ligand
7a/7ba
1
2
3
4
5
6
7
-
60:40
90:10
23:77
>95:5
14:86
88:12
50:50
(DHQD)2PHAL
(DHQ)2PHAL
(DHQD)2AQN
(DHQ)2AQN
(DHQD)2PYR
(DHQ)2PYR
matched
mismatched
matched
mismatched
matched
Figure 1. Piperidine Iminosugars
esters, which were successfully converted in the corresponding
diols, through a matched or mismatched pathway, depending on
the ligand used, with a considerable diastereomeric control (>80%).
The molecules obtained, containing four adjacent stereogenic
centers, could be further elaborated giving access to amino poly-
alcoholic fragments, common motifs in many natural occurring and
biologically active compounds, such as iminosugars.
a
Chromatographically inseparable mixtures. The ratio has been calculated by
of the ester moiety on the 1H NMR spectra
integration of the signals of the CHOH in
a
of the crude mixture. The correct stereochemistry was assigned comparing the data
of the final iminosugar with those reported in the literature16
diastereoselection: using the dihydroquinidine derivatives it was
possible to greatly increase the diastereomeric ratio in favour of the
natural diastereomer (matched reaction), whereas the dihy-
droquinine ones were able to override intrinsic diastereofacial
preference (mismatched reaction) with very good d.r. This result is
noteworthy because the enhancement, as well as the natural ster-
eoselectivity inversion in AD, depending on the employed ligand, is
not easily achievable on any chiral olefin.17 In particular, the better
results were obtained using anthraquinone core ligands (entry 4
and 5). Therefore, (DHQD)2AQN was the ligand of choice for route b
(towards the 1-deoxy-D-altronojirimycin) and (DHQ)2AQN that for
route a (towards the 1-deoxy-D-nojirimycin) (Scheme 2). The
inseparable mixtures of diols, obtained from the AD of 7 catalyzed
by the appropriate ligand, (DHQD)2AQN and (DHQ)2AQN, were
separately subjected to the same synthetic pathway until the
compounds 10 and 14.
We have previously reported the preparation of 1-
deoxyaltronojirimycin14 exploiting the intrinsic diastereoselection
of the dihydroxylation of optically active trans
a,b-unsaturated
epoxy ester 7, without considering the ligand’s effect on the dia-
stereocontrol of the reaction, which was still being studied. The
synthetic pathway was the same as that described in route a of
scheme 2, except for the selectivity obtained in the AD of 7,
significantly enhanced in the approach here described (from 60:40
to >95:5, Table 1).
2. Results and discussions
Here, we report a stereodivergent synthesis, which, starting
from the a,b-unsaturated epoxy ester 7, allows preparation of 1-
deoxynojirimycin or 1-deoxyaltronojirimycin simply by changing
the ligand used in the asymmetric dihydroxylation reaction of the
double bond of 7.
Compound 7 was prepared from a suitable optically active 2,3-
epoxy alcohol 5, easily obtained from the commercially available
fumaric acid monoethyl ester 1,15 which was first transformed in
the (E)-ethyl 4-hydroxybut-2-enoate 2 by using BH3$DMS. After
converting 2 in the corresponding tert-butyldiphenylsilyl ether 3,
the DIBAL reduction furnished 4, finally subjected to the Sharpless
asymmetric epoxidation (AE) to give the epoxy alcohol 5. The
oxidation to aldehyde of 5, followed by a Horner-Emmons reaction,
In order to provide good regioselectivity in the further azidolysis
and protect the diolic moieties, the different mixtures of diols (7a/
7b 14:86, route b and 7a/7b >95:5, route a) in the corresponding
acetonides were transformed.18 The subsequent azidolysis of the
epoxide ring was performed on the diastereomeric acetonide
mixtures. The use of the system NaN3/NH4Cl in methanol at 70 ꢀC19
enabled the regioselective attack of C-5 (Scheme 2) and the chro-
matographic purification of the crudes allowed separation of the
major diastereoisomer (9 or 13) from the minor one. The hindered
alcoholic moiety of 9 and 13 was efficiently protected as tert-
buthyldimethylsilyl ether employing tert-buthyldimethylsilyl
ether triflate/2,6 lutidine20 to produce 10 and 14. The reduction of
azide moiety and subsequent ring closure on the azido alcohol 10
was accomplished smoothly in a one-pot reaction by treatment
with triphenylphosphine and water to produce the lactam 11’. It
turned into 11 through a spontaneous cleavage of the acetonide
ring, probably caused by the trans bycyclic system tension. The
subsequent amide reduction was carried out using
boraneedimethyl sulfide to generate the corresponding piperidine
12. Unfortunately, the same one-pot sequence failed on the azido
alcohol 14. Indeed, in these conditions only the reduction product
19 was isolated, and all the attempts to transform it in the lactam 20
afforded the corresponding trans
a,b-unsaturated epoxy ester 7,
substrate of choice for the dihydroxylation reaction (Scheme 1).
As observed previously, the dihydroxylation reaction without
chiral ligand on substrate 7 led to a poor diastereomeric ratio
(60:40). Considering that sometimes one ligand gives excellent
results in the matched case, unlike its pseudoenantiomer in the
mismatched case, we decided to perform the AD on substrate 7
using the most common second-generation Cinchona alkaloids
(Table 1).
As expected, the ligand effect added to that of the stereogenic
center, gave in all cases (except for entry 7)
a double
failed (Scheme 3)21-2.3
.
According to the Staudinger reaction mechanism, it was hy-
pothesized that the rate-determining step of the reaction is the
nucleophilic intramolecular attack on the carbonyl leading to in-
termediates 22 and 24 (Scheme 4).
In order to find out whether the observed difference in behav-
iour between the ring closures of the two diastereoisomers was
related to the different stabilities of 22 and 24, Molecular Orbital
Scheme 1. Preparation of epoxy ester 7
2

M. De Angelis, C. Sappino, E. Mandic et al.
Tetrahedron 79 (2021) 131837
Scheme 5. Simplified model of piperidine ring closure
Scheme 6. Attempts to form lactam 20
models of reagents 21 and 23. Modeling of the actual reagents 21
and 23 and of the actual intermediates 22 and 24 was not carried
out because the MO calculations were extremely slow (see Scheme
6).
The computational results indicated that compounds 25 and 19
have almost the same relative stabilities, 19 being more stable than
25 by just 0.13 kcal/mol. To the contrary, the stabilities of 26 and 28
are very different, the former being more stable by 7.79 kcal/mol. As
hypothesized above, the ring closure of the two diastereoisomers is
the rate-determing step of the reaction. In this step, the high energy
intermediates 22 and 24 are formed. Therefore, according to the
Hammond postulate, the transition state should have energy and
structure similar to the intermediate. At this point, it is possible to
estimate the relative energies of the two transition states by
assuming that only 50% of the energy difference between the in-
termediates is found in the transition states. Consequently, the
transition state for the process leading to 26 will be more stable
than that leading to 28, by 3.90 kcal/mol. Also, by taking into ac-
count the small energy difference (0.13 kcal/mol) between reagents
Scheme 2. Stereodivergent synthesis of 1-deoxy-D-nojirimycin and 1-deoxy-D-altro-
nojirimycin starting from epoxy ester 7
25 and 19, the difference between the two activation energies (DEa)
is 4.03 kcal/mol. This energy difference can be translated, by using
the Arrhenius equation, into a reactivity ratio k25/k19 ¼ 903. In
other words, the ring closure reaction leading from 19 to 28 is about
one thousand times slower than that leading from 25 to 26. This
result seems to clarify why the azido alcohol 14, when treated with
triphenylphosphine, does not undergo the ring closure reaction
that should lead to compound 20.
Scheme 3. Attempts to form lactam 20
Hypothesizing that the presence of the acetonide ring could
make lactamization more difficult, after several unsuccessful at-
tempts at protecting the diol moiety as disilyl ether, the selective
acetonide cleavage was performed. This step was not trivial, and
24
after numerous trials the use of TFA in CH2Cl2 allowed us to
obtain the desired diol 29 in satisfactory yield, together with a
small amount of desilylated byproducts. However, here too, the
lactam formation was not observed and the one-pot sequence on
the azide diol 29 furnished a complex mixture of inseparable
products.
Considering that removal of acetonide is not sufficient to allow
ring closure, the related problem may be ascribed to the steric
hindrance in the lactam 20 (see Fig. 1). In fact, as shown in figure 2,
in the lactam 20 the hydroxyl groups would occupy pseudoaxial
positions. To the contrary, in the easily formed lactam 11 the hy-
droxyl groups are in the more stable pseudoequatorial positions. To
overcome the ring tension issues of the lactam 20 it was necessary
Scheme 4. Intramolecular cyclization of 21 and 23 intermediates
(MO) calculations have been carried out (see Supporting Informa-
tion for computational details) on the simplified intermediates 26
and 28 (Scheme 5). The same calculations were also computed with
regard to compounds 25 and 19, which were chosen as simplified
3

M. De Angelis, C. Sappino, E. Mandic et al.
Tetrahedron 79 (2021) 131837
provides access to different piperidine iminosugars. Halide opening
of the oxirane and subsequent substitution with azide could lead,
e.g., to 1-deoxy-galactonojirimycin or 1-deoxy-ido-nojirimycin.
Studies pursuing these possibilities are ongoing in our laboratories.
4. Experimental section
General. Organic solvents and reagents were purchased and
used without further purification unless otherwise stated. Re-
actions were monitored by thin-layer chromatography (TLC) car-
ried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV
light (254 nm) and visualisation was achieved by inspection under
short-wave UV light (Mineralight UVG 11 254 nm) followed by
staining with phosphomolybdic acid dip [polyphosphomolybdic
acid (5 g), ethanol (100 mL)] or ninhydrin dip [ninhydrin (5g),
sulfuric acid (5 mL), n-butanol (100mL)] and heating. Low tem-
perature reactions were performed in a Haake EK 101cryostat using
anacetone bath. Unless otherwise stated, reactions were carried out
under standard atmosphere. 1H and 13C NMR spectra were recorded
using a Varian Mercury 300 (1H, 300 MHz; 13C, 75 MHz), Bruker
300 (1H, 300 MHz; 13C, 75 MHz) and Bruker 400 (1H, 400 MHz; 13C,
100 MHz) instruments. Residual solvent peaks were used as in-
ternal references: chloroform (1H, d 7.26 ppm; 13C,
acetone (1H, 2.05 ppm; 13C,
30.83 ppm) and deuterium oxide
(1H,
4.79 ppm). Chemical shifts ( ) are reported in parts per
d 77.00 ppm),
d
d
d
d
million (ppm) relative to the internal standard and coupling con-
stant (J) in Hz. Splitting patterns are designated as s, singlet; br s,
broad singlet; d, doublet; br d, broad doublet; dd, doublet of dou-
blets; ddd, doublet of doublet of doublets; t, triplet; q, quartet; m,
multiplet. Unless otherwise stated, all spectra are registered in
deuterated chloroform. Optical rotations were measured with a
Jasco Mod. DIP-370 polarimeter with a cell pathway length of 10
cm; solution concentrations are reported in grams per 100 mL. All
chromatographic purifications were performed using forced flow
on flash silica gel (Kiesegel 200e400 mesh from E. Merck, Ger-
many). All procedures are referred to 1 mmol and the yields to
isolated and spectroscopically homogeneous compounds.
Elemental analyses for C, H and N were performed on an EA 1110
CHNS-O instrument. All procedures are referred to 1 mmol and the
yields to isolated and spectroscopically homogeneous compounds.
Synthetic Details. Compound 230, 431, 532, 628, and 713 are
known.
General Procedure A: Dihydroxylation Reaction. To a solution
of 1 mmol of 7 in 9 mL of acetone/water (8:1) were added 2 mmol
(270 mg) of NMO, ligand (DHQD)2AQN or (DHQ)2AQN, (0.15 mmol)
and 0.63 mL of a 2.5% solution of OsO4 in tert-butanol (0.05 mmol of
OsO4). The mixture was left stirring overnight at room temperature.
The reaction was then quenched with 5 mL of a saturated solution
of Na2S2O3 and the mixture left stirring for 1 h before transfer into a
separating funnel. The aqueous layer was extracted with 10 mL of
ethyl acetate, the combined organic layers dried over Na2SO4 and
the solvent removed under reduced pressure.
Figure 2. a) 3D model of lactam 11 b) 3D model of lactam 20
to employ a SN2 type strategy to achieve the piperidine ring, the
same one we developed.14
The one pot transformation of the azide 14 to N-(t-butox-
ycarbonyl)amine 15 was carried out for this purpose. The high
yielding reduction of the ester moiety of 15 to alcohol 16 was
performed with NaBH4 in THF/H2O 10:1 and, after functionalization
of the alcoholic group as methanesulfonate, the closure of the
piperidine ring was conducted with potassium tert-butoxide,25
resulting in a good yield of protected 1-deoxy-D-altronojirimycin
(Scheme 2). Finally, treating 12 and 18 with 37% HCl aq. in methanol
at 70ꢀC,26 the 1-deoxy-D-nojirimycin and the (þ)-1-deoxy-D-
altronojirimycin were obtained as hydrochlorides in nearly quan-
titative yield. The iminosugars’ physical data are consistent with
those reported in the literature for the same compounds.27,28,29
3. Conclusions
In summary, the enantioselective stereodivergent approach for
producing the piperidine iminosugars 1-deoxy-D-nojirimycin and
1-deoxy-D-altronojirimycin has been developed starting from a
common suitable chiral vinyl epoxy ester through the double dia-
stereoselective asymmetric dihydroxylation as the key step. Using
Cinchona alkaloids derivatives as chiral ligands in the AD reaction,
in particular (DHQD)2AQN and (DHQ)2AQN, we have achieved both
the matched and the mismatched pathway with excellent results.
Further elaborations of the diastereomeric diols allowed isolation
of the azido alcohols 10 and 14 as pure compounds, which, when
submitted to different ring closure conditions, led to the synthesis
of the two target iminosugars.
General Procedure B: Diol protection as acetonide. 1 mmol of
diols mixture (7aþ7b) was dissolved in 2 ml of dichloromethane
and
2 ml of 2,2-dimethoxypropane and 0.047 g of 4-
toluenesulphonic acid were added and the mixture stirred at
room temperature. until completion (24 h, TLC monitoring). The
solvent was evaporated in vacuo and the mixture was dissolved in
ethyl acetate, washed with brine and NaHCO3 saturated solution
until pH 7. The combined organic layers were dried over anhydrous
Na2SO4 and the solvent evaporated in vacuo. The crude, used
without purification.
Note the wide applicability of the proposed approach that,
simply by suitably choosing the chiral ligand in the two asymmetric
reactions (AE and AD) or the nucleophile in the epoxy ring opening,
General Procedure C: Azidolysis Epoxide Ring. 1 mmol of 8a
and 8b mixture was dissolved in 10 mL of MeOH and NaN3 (5 mmol,
0.325 g) and NH4Cl (2 mmol, 0.107 g) were added and the mixture
4

M. De Angelis, C. Sappino, E. Mandic et al.
Tetrahedron 79 (2021) 131837
was left stirring at 70ꢀC until complete consumption of the sub-
strate (12 h, TLC monitoring). The mixture was filtered, concen-
trated in vacuo and the residue diluted with ethyl acetate and
washed with brine. The organic layer was dried over Na2SO4 and
after filtration the solvent evaporated under vacuum. The crude
was purified by flash chromatography on silica gel (hexane/ethyl
acetate 8:2).
General Procedure D: Hydoxyl Group Protection as Silyl
Ether. In a two-neck flask under argon atmosphere 1 mmol of 9 or
13 was dissolved in 6 mL of anhydrous dichloromethane, and 2
mmol of 2,6-lutidine and 3 mmol of TBSOTf were added and the
mixture stirred at room temperature. until completion (12 h, TLC
monitoring). The reaction was quenched with water, the two
phases were separated, and the aqueous layer was extracted twice
with dichloromethane, and the combined organic layers were
washed with brine and NaHCO3 saturated solution until pH 7. The
combined organic layers were dried over Na2SO4 and after filtration
the solvent evaporated in vacuo. The crude was purified by flash
chromatography on silica gel (hexane/ethyl acetate 95:5).
General Procedure E: Reduction with PPh3. To a solution of
azido derivative 10 or 14 (1 mmol) in THF (3 mL) was added tri-
phenylphosphine (1 mmol, 223 mg) in one portion at 0 ꢀC. After
stirring at 0 ꢀC for 10 min, the reaction mixture was warmed to
room temperature and stirred for 48 h. Water (20 mL) was added.
After stirring at room temperature for an additional 12 h, the re-
action mixture was concentrated to dryness. The crude was purified
by flash chromatography on silica gel (hexane/ethyl acetate 95:5).
General Procedure F: Total Deprotection. To piperidine de-
rivatives 12 or 18 (1mmol) in MeOH (1 mL) was added HCl (37%, 1
mL) and the resultant mixture was stirred at 70 ꢀC until complete
consumption of the substrate (TLC monitoring). After cooling to
room temperature, the mixture was diluted with EtOH (0.5 mL) and
CH3CN (5 mL) followed by removal of the solvents. The residual oil
was purified by flash chromatography (CHCl3eMeOH 1:1) to give
the known iminosugars as hydrochlorides.
using a solvent mixture hexane/ethyl acetate 98:2 to produce the
product as a yellow oil (5.93 g). Yield 58% from 1.
1H NMR (300 MHz, CDCl3)
d: 7.72-7.66 (4H, m, Ar), 7.47-7.37 (6H,
m, Ar), 7.02 (1 H, dt, J 15.5, 3.4 Hz, CH¼CHCOOEt), 6.32 (1H, dt, J
15.5, 2.2 Hz, CH¼CHCOOEt), 4.38 (2H, dd, J 3.4, 2.3 Hz CH2OTBDPS),
4.25 (2H, q, J 7.1 Hz, COOCH2CH3), 1.33 (3H, t, J 7.1 Hz, COOCH2CH3),
1.11 (9H, s, C(CH3)3).13C NMR (75 MHz, CDCl3)
d: 166.8, 146.9, 135.5,
133.1, 130.0, 127.9, 119.8, 63.0, 60.4, 26.9, 19.4, 14.4. C22H28O3Si
(368.5): Calcd: 71.7, H 7.6 %. Found: C 71.7, H 7.7 %.
(E)-4-((tert-butyldiphenylsilyl)oxy)but-2-en-1-ol
4 In a three
neck flask equipped with a dropping funnel under argon atmo-
sphere, 16.09 mmol (5.93 g) of ester 3 were dissolved in 160.9 mL of
dry THF and the reaction mixture was cooled at -40ꢀC. 32.9 mL of a
25% solution of DIBAL in toluen (48.27 mmol of DIBAL) were added
dropwise and the mixture was left stirring at -40ꢀC for 12 hours
(TLC monitoring). 110 mL of a saturated solution of Rochelle salt
(sodium potassium tartrate tetrahydrate) were added at 0ꢀC and
stirred for 8 hours. THF was evaporated in vacuo, the mixture was
transferred into a separative funnel with AcOEt and the aqueous
layer was extracted four times with AcOEt. The combined organic
layers were dried over Na2SO4 and after filtration the solvent
evaporated in vacuo. The crude was purified by flash chromatog-
raphy on silica gel (hexane/ethyl acetate 9:1) giving the product 4
(4.31 g). Yield 82%
1H NMR (400 MHz, CDCl3)
d:7.73e7.65 (4H, m, Ar), 7.46-7.34
(6H, m, Ar), 5.97-5.87 (1H, m, CH2CH¼CH CH2), 5.84-5.74 (1H, m,
CH2CH¼CH CH2), 4.25-4.23 (2H, m, TBDPSOCH2), 4.16-4.14 (2H, m,
CHCH2OH), 1.74 (1H, bs, OH), 1.09 (9H, s, C(CH3)3). 13C NMR (100
MHz, CDCl3)
26.9, 19.3.
d: 135.6, 133.7, 130.6, 129.8, 129.0, 127.8, 63.9, 63.2,
((2S,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)oxiran-2-yl)
methanol 5 In a three-neck flask equipped with a dropping funnel
under argon atmosphere, 1.32 g of activated powdered 4Å molec-
ular sieves were dissolved in 74.5 mL of dry CH2Cl2. The flask was
cooled to -20 ꢀC. 0.41 mL (2.37 mmol) of (þ)-Diethyl L-tartrate, 0.59
mL (1.98 mmol) of Titanium(IV) isopropoxide. The reaction mixture
was stirred at -20 ꢀC as 4.81 mL of a tert-Butyl hydroperoxide so-
lution 5.5 M in decane (26.38 mmol of t-BuOOH) were added
through the addition funnel at a moderate rate (over ca. 5 min). The
resulting mixture was stirred at -20 ꢀC for 30 min. Allylic alcohol 4
(4.31 g, 13.19 mmol,), dissolved in 5.68 mL of CH2C12, was then
added dropwise through the same addition funnel over a period of
5 min, being careful to maintain the reaction temperature between
-20 and -15 ꢀC. The reaction mixture was left stirring for 8 hours
(TLC monitoring). A freshly prepared solution of 9.21 g of ferrous
sulfate heptahydrate and 8.68 g of tartaric acid in a total volume of
55.1 mL of deionized water is cooled to ca. 0 ꢀC, by means of an ice
water bath. The epoxidation reaction mixture was allowed to warm
to ca. 0 ꢀC and then was slowly poured into a beaker containing the
precooled stirring ferrous sulfate solution (external cooling is not
essential during or after this addition). The two-phase mixture was
stirred for 5-10 min and then transferred into a separatory funnel.
The phases were separated and the aqueous phase was extracted
with ether. The combined organic layers were treated with 2.8 mL
of a precooled (0 ꢀC) solution of 30% NaOH (w/v) in saturated brine.
The two-phase mixture was stirred vigorously for 1 h at 0 ꢀC.
Following transfer to a separatory funnel and dilution with water,
the phases were separated and the aqueous layer was extracted
with ether. The combined organic layers were dried over sodium
sulfate, filtered, and concentrated. The crude was purified by flash
(E)-ethyl 4-hydroxybut-2-enoate 2 In a two-neck flask under
argon atmosphere 27.75 mmol (4.00 g) of fumaric acid monoethyl
ester 1 were dissolved in 14 mL of anhydrous THF and 27.75 mmol
(2.6 mL) of BH3$DMS were slowly added at -40ꢀC. The mixture was
stirred at -40ꢀC for 1 h, then warmed to room temperature and
stirred until completion (TLC monitoring). The reaction mixture
was cooled at 0ꢀC, quenched with 17 mL of water and 6.66 g of
K2CO3 and stirred for 15 min. THF was evaporated in vacuo, the
mixture was transferred into a separative funnel with AcOEt and
the aqueous layer was extracted three times with AcOEt. The
combined organic layers were dried over Na2SO4 and after filtration
the solvent evaporated in vacuo. The crude, used without purifi-
cation, was subjected to protection of the alcoholic moiety as silyl
ether. 1H NMR (400 MHz, CDCl3)
d 6.97 (1H, dtd J 15.7, 4.0, 1.7 Hz,
CH¼CHCOOEt), 6.03 (1H, ddd, J 15.7, 3.8, 2.1 Hz, CH¼CHCOOEt),
4.27 (2H, bs, CH2OH), 4.16-4.11 (2H, m, COOCH2CH3), 3.1 (1H, bs,
OH), 1.23 (3H, td, J 7.1, 1.5 Hz, COOCH2CH3); 13C NMR (75 MHz,
CDCl3)
d: 166.8, 147.4, 120.0, 61.6, 60.5, 14.2.
(E)-Ethyl 4-[(tert-butyldiphenylsilyl)oxy]but-2-enoate
3
In a
round bottom flask the alcohol 2 was dissolved in 37.4 mL of CH2Cl2
and 41.6 mmol (10.7 mL) of tert-buthyldiphenylsilyl chloride, and
2.78 mmol (0.39 mg) of 4-(dimethylamino)pyridine (DMAP) and
19.3 mL of triethylamine were added. The mixture was stirred at
room temperature for 12 hours (TLC monitoring). The reaction
mixture was transferred into a separative funnel, HCl 0.1N was
added, and the layers separated three times with CH2Cl2. The
combined organic layers were washed with brine and then dried
over Na2SO4. The solvent was evaporated in vacuo to leave the
crude, which was purified by flash chromatography on silica gel
chromatography on silica gel (hexane/ethyl acetate 6:4) affording
23
epoxy alcohol 5 in 87% yield (3.93 g). [
a]
¼ -13.8ꢀ (c 5.4, CHCl3).
D
1H NMR (300 MHz CDCl3)
d
: 7.71-7.68 (4H, m, Ar), 7.45-7.40 (6H, m,
5

M. De Angelis, C. Sappino, E. Mandic et al.
Tetrahedron 79 (2021) 131837
Ar), 3.95-3.88 (2H, m, CH2OH), 3.79 (1H, dd, J 12.3, 4.3 Hz,
TBDPSOCHaHb), 3.62 (1H, dd, J 12.5, 4.3 Hz, TBDPSOCHaHb), 3.21-
3.16 (1H, m, OCHCH2OH), 3.13-3.08 (1H, m, TBSPSOCH2CHO), 2.18
CHOH-CHOH, OH), 3.80-3.70 (5H, m, CH2OTBDPS, COOCH3), 3.37
(bs, 1H, OH), 3.33-3.29 (1H, m, CHep), 3.20 (dd, 1H, J 5,0, 1,8 Hz,
CHep), 1.08 (9H, s, CH3).13C NMR (75 MHz, CDCl3)
d: 173.2; 135.6;
135.5, 133.2, 133.1, 129.8, 127.8; 71.7; 71.4; 63.3; 57.3; 55.0; 52.7;
26.8; 19.2.
(1H, bs, OH), 1.07 (9H, s, C(CH3)3). 13C NMR (75 MHz, CDCl3)
135.7, 135.6, 133.3, 129.9, 127.9, 63.3, 61.4, 55.9, 55.8, 26.7, 19.2.
(2R,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)oxirane-2-
d:
(4R,5S)-Methyl 5-[(1R,2R)-2-azido-3-(tert-butyldiphenylsilyl)oxy-
carbaldehyde 6 In a round bottom flask 11.48 mmol (3.93 g) of epoxy
alcohol 5 were dissolved in 11.5 mL of CH2C12. 1.15 mmol (179 mg)
of TEMPO (2,2,6,6-Tetramethylpiperidinyloxy), and 12.63 mmol
(4.07 g) of DIAB (Iodobenzene I,I-diacetate) were added. The
mixture was stirred at room temperature for 2 hours (TLC moni-
toring). The reaction mixture was transferred into a separative
funnel with CH2Cl2 and washed with a saturated solution of
Na2S2O3. The aqueous layer was extracted three times with CH2Cl2,
the combined organic layers were washed with brine and then
dried over Na2SO4. The solvent was evaporated in vacuo and the
crude was used without chromatographic purification. 1H NMR
1-hydroxypropyl]-2,2-dimethyl-1,3-dioxolane-4-carboxylate
9 and
(4S,5R)-Methyl-5-((1R,2R)-2-azido-3-[(tert-butyldiphenylsilyl)oxy-1-
hydroxypropyl]-2,2-dimethyl-1,3-dioxolane-4-carboxylate 13. Diols
mixture (7a:7b > 95:5, 7b:7a 86:14) was subjected to diols pro-
tection reaction as acetonide according to General Procedure B.
The crude, used without purification, was subjected to azidolysis of
the epoxy ring according to General Procedure C to give 9 (55%
23
from 7, 2.42 g) and 13 (61% from 7, 2.69 g) as yellow oils. 9: [
-25.2ꢀ (c 3.1, CHCl3); IR (neat)
2010, 1720, 1209, 1154; 1H NMR (400 MHz CDCl3)
a
]
¼
D
n
cm-1 3470, 3074, 3050, 2940, 2869,
: 7.74-7.72 (4H,
d
m, Ar), 7.46-7.40 (6H, m, Ar), 4.58 (1H, d, J 7.7 Hz, OCHCOOCH3), 4.43
(1H, d, J 7.7, CHOCHOCOOCH3), 4.09 (1H, dd, J 10.8, 3.0 Hz,
OCHaHbCHN3), 3.95 (1H, dd, J 10.8, 6.1 Hz, OCHaHbCHN3), 3.81-3.71
(4H, m, COOCH3, CHOH), 3.49-3.41 (1H, m, CHN3), 2.29 (1H, bd, J 9.5
Hz, OH) 1.49 (3H, s, CH3CCH3), 1.47 (3H, s, CH3CCH3), 1.11 (9H, s,
(300 MHz, CDCl3)
d: 9.14 (1H, d, J 6.1 Hz, CHO), 7.83-7.70 (4H, m,
Ar), 7.55-7.45 (6H, m, Ar), 3.99 (1H, dd, J 12.2, 1.9 Hz, TBDPSOCH2
-
CHOCH), 3.90 (1H, dd, J 12.2, 4.3 Hz, TBDPSOCH2CHOCH), 3.52-3.42
(2H, m, TBDPSOCH2CHO), 1.16 (9H, s, C(CH3)3); 13C NMR (75 MHz,
CDCl3)
19.3.
d: 198.2, 137.5, 135.6, 130.3, 130.0, 127.9, 61.9, 56.6, 56.2, 26.7,
C(CH3)3); 13C NMR (100 MHz, CDCl3)
d: 171.3, 136.0, 136.0, 133.1,
(E)-methyl
3-((2S,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)
133.1, 130.3, 130.2, 128.2, 128.1, 112.0, 78.3, 75.4, 68.9, 65.2, 64.6,
oxiran-2-yl)acrylate 7 In a round bottom flask aldehyde 6 was dis-
solved in 29.4 mL of THF. 12.97 mmol (311 mg) of LiOH and 12.97
mmol (2.36 g) of TMPA (trimethylphosphonoacetate) were added.
The mixture was stirred at room temperature for 12 hours (TLC
monitoring). A saturated solution of NH4Cl was added and the
mixture was left stirring for 10 minutes. THF was evaporated in
vacuo and the mixture was transferred into a separative funnel
with AcOEt. The reaction mixture was transferred in a separative
funnel, the phases are separated and the aqueous phase is extracted
with AcOEt. the combined organic layers were washed with brine
and then dried over Na2SO4. The solvent was evaporated in vacuo
52.9, 27.1, 27.0, 26.0,19.5. C25H32N3O6Si (498.6): Calcd: C 60.2, H 6.5,
23
N 8.4 %. Found: C 60.3, H 6.7, N 8.7 %. 13: [
IR (neat)
1154; 1H NMR (300 MHz CDCl3)
(6H, m, Ar), 4.55 (1H, d, J 6.6 Hz, OCHCOOCH3), 4.42 (1H, dd, J 6.6,
4.4 Hz, CHOCHOCOOCH3), 4.04 (1H, dd, 10.9, 3.3 Hz,
a]
¼ -9.6ꢀ (c 1.1, CHCl3);
D
n
cm-1 3475, 3065, 3050, 2940, 2858, 2095, 1730, 1209,
d: 7.73-7.69 (4H, m, Ar), 7.44-7.41
J
OCHaHbCHN3), 3.92 (1H, dd, J 10.9, 6.1 Hz, OCHaHbCHN3), 3.87 (1H,
dd, J 7.9, 4.4 Hz, CHOH), 3.83 (3H, s, COOCH3), 3.63 (1H, ddd, J1¼J2 7,
3.3 Hz, CHN3), 2.62 (1H, d, J 4.0 Hz, OH) 1.45 (3H, s, CH3CCH3), 1.41
(3H, s, CH3CCH3), 1.09 (9H, s, C(CH3)3); 13C NMR (75 MHz, CDCl3)
d:
171.8, 135.6, 129.9 127.8, 111.4, 79.2, 75.0, 70.4, 64.5, 63.4, 52.7, 26.8,
26.7, 25.4, 19.1. C25H32N3O6Si (498.6): Calcd: C 60.2, H 6.5, N 8.4 %.
Found: C 60.4, H 6.6, N 8.7 %.
and the crude was purified by flash chromatography on silica gel
23
(hexane/ethyl acetate 98:2). Yield 77% from 5 (3.50 g). [
a
]
¼ -9.2ꢀ
D
(c 3.8, CHCl3). 1H NMR (300 MHz, CDCl3)
d
: 7.76-7.63 (4H, m, Ar),
7.47-7.36 (6H, m, Ar), 6.69 (1H, dd, J 15.7, 7.1 Hz, CH¼CHCOOCH3),
6.13 (1H, d,
15.7 Hz, CH¼CHCOOCH3), 3.87-3.83 (2H, m,
(4R,5R)-Methyl 5-[(5R,6R)-6-azido-2,2,3,3,10,10-hexamethyl-
9,9-diphenyl-4,8-dioxa-3,9-disilaundecan-5-yl]-2,2-dimethyl-1,3-
dioxolane-4-carboxylate 10 and (4S,5S)-Methyl-5-[(5R,6R)-6-
azido-2,2,3,3,10,10-hexamethyl-9,9-diphenyl-4,8-dioxa-3,9-
disilaundecan-5-yl]-2,2-dimethyl-1,3-dioxolane-4-carboxylate 14.
Compounds 9 and 13 were subjected to hydroxyl group pro-
tection as silyl ether according to General Procedure D to give 10
(76% from 9, 2.32 g) and 14 (76% from 13, 2.57 g) as yellow oils. 10:
J
TBDPSOCH2), 3.76 (3H, s, COOCH3), 3.38 (1H, dd, J 7.1, 1.4 Hz,
OCHCH¼CH), 3.12-3.06 (1H, m, CHOCHCH¼CH), 1.07 (9H, s,
C(CH3)3); 13C NMR (75 MHz, CDCl3)
d: 166.0, 144.4, 135.6, 135.5,
133.0, 132.9, 129.9, 127.8, 123.5, 62.9, 60.9, 53.8, 51.7, 26.7, 19.2.
(2R,3R)-Methyl 3-{(2S,3S)-3-[(tert-butyldiphenylsilyl) oxymethyl]
oxiran-2-yl}-2,3-dihydroxypropanoate 7A and (2S,3S)-Methyl 3-
{(2S,3S)-3-[(tert-butyldiphenylsilyl) oxymethyl]oxiran-2-yl}-2,3-
dihydroxypropanoate 7B.
Compound 7 was subjected to asymmetric dihydroxylation re-
action according to General Procedure A. Diols 7a and 7b are ob-
tained as chromatographically inseparable mixtures. The ratio has
[
a
]
23D¼ -28.2ꢀ (c 3.7, CHCl3); IR (neat)
n
cm-1 3038, 2935, 2860,
: 7.74-7.66 (4H,
2116, 1755, 1201, 1150; 1H NMR (300 MHz CDCl3)
d
m, Ar), 7.50-7.35 (6H, m, Ar), 4.44 (1H, d, J 7.5 Hz, OCHCOOCH3), 4.28
(1H, dd, J 7.5, 3.6 Hz, CHOCHOCOOCH3), 4.04 (1H, dd, J 10.3, 3.1 Hz,
OCHaHbCHN3), 3.87-3.63 (6H, m, OCHaHbCHN3, COOCH3, CHN3,
CHOTBS), 1.40 (6H, s, CH3CCH3), 1.10 (9H, s, (CH3)2SiC(CH3)3), 0.77
(9H, s, Ph2SiC(CH3)3), 0.04 (3H, s, CH3SiCH3), -0.07 (3H, s,
been calculated by integration of the signals of the CHOH in
a of the
ester moiety on the 1H NMR spectra of the crude mixture. 7b (data
given for the inseparable mixture 7b/7a 86:14): 1H NMR (300 MHz,
CH3SiCH3); 13C NMR (75 MHz, CDCl3)
d: 171.2, 135.6, 133.0, 132.9,
129.8, 127.7, 111.1, 80.1, 74.9, 72.0, 66.1, 65.2, 52.5, 26.7, 26.6, 25.8,
CDCl3) d: 7.68-7.66 (4H, m, Ar), 7.43-7.37 (6H, m, Ar), 4.26 (1H, d, J
2,3 Hz, CHOH-COOMe), 3.97-3.91 (1H, d, J 3,1 Hz, CHOH-CHOH),
25.7, 19.1, 18.1, -4.3, -4.6. C32H49N3O6Si2 (627.9): Calcd: C 61.2, H 7.9,
3.83-3.68 (7H, m, CH2OTBDPS, COOCH3, OH, OH), 3.18-3.11 (2H, m,
CHep), 1.05 (9H, s, CH3).13C NMR (100 MHz, CDCl3)
d: 172.9; 135.6;
134.8; 129.8, 129.6. 127.8, 127.7; 72.4; 70.2; 63.1; 55.6; 55.0; 53.1;
23
N 6.7 %. Found: C 61.4, H 8.0, N 6.9 %. 14: [
CHCl3); IR (neat)
NMR (300 MHz CDCl3)
a
]
¼ -11.3ꢀ (c 2.3,
D
n
cm-1 3042, 2928, 2860, 2110, 1755, 1210, 1150; 1H
d
: 7.71-7.70 (4H, m, Ar), 7.45-7.36 (6H, m,
26.7; 19.6. 7a (data given for the inseparable mixture 7a/7b
Ar), 4.56 (1H, d, J 6.7 Hz, OCHCOOCH3), 4.48 (1H, dd, J 6.7, 2.7 Hz,
CHOCHOCOOCH3), 3.93-3.62 (7H, m, OCHaHbCHN3, OCHaHbCHN3,
COOCH3, CHN3, CHOTBS), 1.47 (3H, s, CH3CCH3), 1.39 (3H, s,
90:10):1H NMR (300 MHz, CDCl3)
d: 7.72-7.70 (4H, m, Ar), 7.44-7.37
(6H, m, Ar), 4.38 (1H, d, J 3,5 Hz, CHOH-COOMe), 4.00-3.93 (2H, m,
6

M. De Angelis, C. Sappino, E. Mandic et al.
Tetrahedron 79 (2021) 131837
known iminosugar as hydrochloride (90% yield, 383 mg). 1H NMR
CH3CCH3), 1.10 (9H, s, (CH3)2SiC(CH3)3), 0.79 (9H, s, Ph2SiC(CH3)3),
0.06 (3H, s, CH3SiCH3), -0.09 (3H, s, CH3SiCH3); 13C NMR (75 MHz,
(400 MHz D2O) d: 3.99 (1H, dd, J 12.7, 3.1 Hz, C6HaHb), 3.91 (1H, dd, J
12.7, 5.1 Hz, C6HaHb) 3.82 (1H, ddd, J 11.9, 9.3, 5.1 Hz, C2HOH), 3.64
(1H, dd, J1¼J2¼9.3 Hz, C4HOH), 3.59-3.51 (2H, m, C1HaHb, C3HOH),
3.25 (1H, ddd, J 9.3, 5.1, 3.1 Hz, C5HNH) 3.01 (1H, dd, J1¼J2¼11.9 Hz,
CDCl3) d: 171.9, 135.6, 132.9, 129.8, 127.8, 110.7, 79.1, 74.5, 71.3, 66.2,
65.0, 52.4, 26.7, 26.6, 25.7, 25.2, 19.1, 17.9, -4.3, -4.5. C32H49N3O6Si2
(627.9): Calcd: C 61.2, H 7.9, N 6.7 %. Found: C 61.4, H 8.0, N 6.9 %.
(3R,4R,5R,6R)-5-(tert-Butyldimethylsilyl)oxy-6-[(tert-butyldi-
C1HaHb); 13C NMR (100 MHz, D2O)
d: 76.4, 68.0, 67.2, 60.2 (C-6),
phenylsilyl)oxymethyl]-3,4-dihydroxypiperidin-2-one
11
and
25
57.9 (C-5), 46.1 (C-1).33,34 mp¼ 201-203 ꢀC; [
a]
¼ þ38.8ꢀ (c 0.7,
D
(4S,5S)-Methyl 5-[(5R,6R)-6-amino-2,2,3,3,10,10-hexamethyl-9,9-
diphenyl-4,8-dioxa-3,9-disilaundecan-5-yl]-2,2-dimethyl-1,3-
dioxolane-4-carboxylate 19. The azido derivatives 10 and 14 were
subjected to the azide reduction reaction with PPh3 according to
General Procedure E to give 11 as colorless oil, yield 85% (1.66 g),
and 19 as yellow oil, yield 78% (1.92 g). (The cleavage of acetonide
H2O), (lit.35 mp: 200-202 ꢀC; [
a
]
23D¼ þ36.9ꢀ (c 1.1, H2O));
C6H14ClNO4 (199.6): Calcd: C 36.1; H 7.1; N 7.0 %. Found C 36.4; H
7.4; N 7.4 %. (2S,3S,4R,5R)-Methyl 5-azido-4-[(tert-butyldime-
thylsilyl)oxy]-6-[(tert-butyldiphenylsilyl)oxy]-2,3-
dihydroxyhexanoate 29.
TFA (14.7 mL) was added to a cooled (0ꢀC) solution of 14 (4.10
mmol) in CH2Cl2 (131 mL) and the mixture was left stirring at 0ꢀC
until completion (TLC monitoring). The reaction mixture was
diluted with CH2Cl2, and the organic layer was washed with a
saturated aqueous solution of NaHCO3 and brine, dried over Na2SO4
and concentrated. The crude was purified by flash chromatography
on silica gel using a solvent mixture hexane/ethyl acetate 80:20
ring in compound 11 occurred spontaneously, see Supporting Info.).
23
11: [
a
]
¼ -17.1ꢀ (c 1.1, CHCl3) IR (neat)
n
cm-1 3463, 3285, 3073,
D
3038, 1690, 1460, 1250, 1150 1H NMR (400 MHz CDCl3)
d: 7.68-7.57
(4H, m, Ar), 7.50-7.32 (6H, m, Ar), 6.07 (1 H, bs NH), 3.91-3.84 (2H,
m, C6HaHb, C2HOH), 3.73 (1H, dd, J1¼J2¼8.6 Hz, C3HOH), 3.59 (1H,
dd J1¼J2¼8.6 Hz, C4HOTBS), 3.53 (1H, dd, J1¼J2¼8.8 C6-HaHb), 3.43-
3,36 (1 H, m, C5HNH), 3.27 (1 H, bs, OH), 1.06 (9H, s,
(CH3)2SiC(CH3)3), 0.74 (9H, s, Ph2SiC(CH3)3), 0.09 (3H, s, CH3SiCH3),
affording 29 in 52% yield (1.25 g). IR (neat)
n
cm-1 3080, 2980, 2870,
: 7.71- 7.66 (4H,
2100, 1710, 1250, 1150; 1H NMR (400 MHz CDCl3)
d
m, Ar), 7.47-7.37 (6H, m, Ar), 4.39 (1H, d, J 0.9 Hz, CHOHCO), 4.00-
-0.12 (3H, s, CH3SiCH3); 13C NMR (100 MHz, CDCl3)
d:171.1, 135.5,
3.92 (2H, m, CHOH, CHOTBS), 3.91-3.84 (2H, m, CHN3, OCHaHb)
135.4, 132.6, 130.1, 130.0, 128.0, 127.9, 74.4, 70.9, 70.4, 65.1, 58.3,
26.8, 25.7,19.2,18.1, -3.8, -5.1. C28H43NO5Si2 (529.8): Calcd: C 63.5, H
3.84-3.76 (4H, m, OCHaHb, OCH3), 1.07 (9H, s, (CH3)2SiC(CH3)3),
-0.85 (9H, s, (Ph2SiC(CH3)3), -0.09 (6H, s, CH3SiCH3). 13C NMR (100
8.2, N 2.6 %. Found: C 63.6, H 8.3, N 2.9 %. 19: IR (neat)
n
cm-1 3400,
: 7.68-7.63
3070, 2855, 1750, 1252, 1150; 1H NMR (400 MHz CDCl3)
d
MHz, CDCl3)
72.4, 70.0, 67.2, 63.6, 53.0, 26.8, 26.0, 19.2, 18.2, -4.0, -5.1.
29H45N3O6Si2 (587.85): Calcd: C 59.25, H 7.7, N 7.15 %. Found: C
d 174.4, 135.8, 135.7, 133.0, 132.9, 130.0, 128.0, 72.5,
(4H, m, Ar), 7.45-7.34 (6H, m, Ar), 4.55 (2H, m, CHOCHOCOOCH3),
3.94-3.92 (1H, m, CHOTBS), 3.81-3.73 (4H, OCHaHbCHN3, COOCH3,
CHN3,), 3.56 (1H, dd, J110.0, J2 8.2, OCHaHbCHN3), 3.10 (1H, dt, J 8.1, J
5.2 Hz, CHNH2) 1.44 (3H, s, CH3CCH3), 1.36 (3H, s, CH3CCH3), 1.08
(9H, s, (CH3)2SiC(CH3)3), 0.83 (9H, s, Ph2SiC(CH3)3), 0.07 (3H, s,
CH3SiCH3), -0.04 (3H, s, CH3SiCH3); 13C NMR (100 MHz, CDCl3)
d:
172.6, 135.9, 135.9, 133.8, 133.7, 130.0, 128.0, 110.3, 79.2, 74.9, 73.0,
66.2, 56.6, 52.5, 27.2, 26.8, 26.2, 25.5, 19.6, 18.3, -3.8, -4.2.
C
59.5, H 7.8, N 7.3 %.
(4S,5S)-Methyl
5-[(5R,6R)-6-(((tert-butyldiphenylsilyl)oxy)
methyl)-2,2,3,3,10,10-hexamethyl-8-oxo-4,9-dioxa-7-aza-3-
silaundecan-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate 15. 4.10
mmol (2.57 g) of 14 were dissolved in 8.2 mL of ethyl acetate and
4.51 mmol (984 mg) of (Boc)2O were added, and the mixture was
left stirring under H2 atmosphere (1 atm) at room temperature
until completion (6 h, TLC monitoring). The reaction mixture was
filtered through a pad of celite and the solvent was evaporated in
vacuo. The product was used without chromatographic purifica-
C
32H51NO6Si2 (601.9): Calcd: C 63.85, H 8.5, N 2.3 %. Found: C 64.0,
H 8.7, N 2.5 %.
(3S,4R,5R,6R)-5-[(tert-Butyldimethylsilyl)oxy-6-(tert-butyldiphe-
nylsilyl)oxymethyl]-piperidine-3,4-diol 12. To a solution of 11 (3.14
mmol) in dry THF (13.6 mL) was added BH3.DMS (12.56 mmol, 1.1
mL) at 0 ꢀC. After stirring under nitrogen at room temperature until
complete consumption of the substrate (TLC monitoring), the re-
action was quenched by cautiously adding methanol until gas
evolution ceased. Additional methanol was added and the solvents
were evaporated. The residue was dissolved in methanol and 2 N
HCl was added to the solution. The mixture was refluxed for 10 min
and, after cooling, the solution was evaporated and the pH was
adjusted to 11e12 with a 15% sol of NH4OH. The solution was
evaporated and the residue purified by flash chromatography on
silica gel (CHCl3/CH3OH 98:2) to afford 12 as colorless oil (1.10 g).
tion. Yellow oil. 1H NMR (400 MHz, CDCl3)
d: 7.66-7.62 (4H, m, Ar),
7.42-7.33 (6H, m, Ar), 5.31 (1H, d, J 8.2 Hz, NH), 4.71 (1H, d, J 5.8 Hz,
CHOCOOCH3), 4.45 (1H, dd, J1 5.8, J2 2.9 Hz, CHOCHOCOOCH3), 4.35
(1H, dd, J1¼J2¼2.9 Hz, CHOTBS), 4.21-4.15 (1H, m, CHNHBoc), 3.77-
3.61 (5H, m, OCHaHbCHNHBoc, COOCH3), 1.47 (3H, s, CH3CCH3)
1.30-1.24 (12H, m, NHCOC(CH3)3), 1.03 (9H, s, Ph2SiC(CH3)3) 0.80
(9H, s, Ph2SiC(CH3)3), CH3OSi, 0.05 (3H, s, CH3OSi), 0.04 (3H, s,
CH3OSi). 13C NMR (75 MHz, CDCl3)
d: 173.1,155.7, 135.9,135.0, 133.4,
130.0, 129.9, 128.0, 127.9, 110.9, 80.0, 75.2, 72.2, 63.6, 63.2, 54.9,
52.7, 28.6, 27.1, 26.8, 26.0, 25.3, 19.4, 18.2, -4.2, -4.4.
tert-Butyl {(5R,6R)-5-[(4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-
1,3-dioxolan-4-yl]-2,2,3,3,10,10-hexamethyl-9,9-diphenyl-4,8-dioxa-
3,9-disilaundecan-6-yl}carbamate 16. 15 was dissolved in a solution
of THF/H2O 41 mL/4.1 mL and 12.3 mmol (465 mg) of NaBH4 were
added; the mixture was left stirring for four hours (TLC moni-
toring). 61.5 mL of water were added to the reaction mixture and it
was subsequently transferred into a separative funnel, the layers
separated, and the aqueous one extracted three times with ethyl
acetate. The combined organic layers were washed with brine and
NaHCO3 until pH 7, then dried over Na2SO4. The solvent was
evaporated in vacuo to leave the crude, which was purified by flash
Yield: 68%. IR (neat)
n
cm-1 3358, 3068, 2953, 2864, 1460, 1250,
: 7.65-7.61 (4H, m, Ar), 7.42-7.37
1105; 1H NMR (400 MHz CDCl3)
d
(6H, m, Ar), 3.93 (1H, dd, J 9.7, 3.0 Hz, C6HaHb), 3.53 (2H, m, C6HaHb,
C2HOH), 3.22 (3H, m, C1HaHbNH, C3HOH, C4HOTBS,), 2.64 (1H,
ddd, J 11.3, 8.4, 2.9 Hz, C5HNH), 2.56 (1H, dd, J1¼J2¼10 Hz, C1HaHb),
1.07 (9H, s, (CH3)2SiC(CH3)3), 0.71 (9H, s, (Ph2SiC(CH3)3), 0.03 (3H, s,
CH3SiCH3), -0.21 (3H, s, CH3SiCH3); 13C NMR (100 MHz, CDCl3)
d:
135.6, 135.5, 133.2, 129.7, 127.7, 80.1, 73.6, 71.4, 65.3, 62.2, 49.6, 26.9,
25.8, 19.3, 18.0, -3.7, -4.9. C28H45NO4Si2 (518.8): Calcd: C 65.2, H 8.8,
N 2.7 %. Found: C 65.4, H 9.0, N 2.9 %.
chromatography on silica gel using a solvent mixture hexane/ethyl
23
acetate 95:5. Yellow oil, 85% yield from 14 (2.35 g). [
a
]
¼ -8.2ꢀ (c
D
1-Deoxy-D-nojirimycin. Compound 12 was subjected to a total
deprotection reaction according to General Procedure F to give the
1.4, CHCl3) IR (neat)
n
cm-1 3450, 3312, 3060, 2960, 1662, 1423,1112
7

M. De Angelis, C. Sappino, E. Mandic et al.
Tetrahedron 79 (2021) 131837
1H NMR (300 MHz CDCl3)
Ar), 4.72 (1H, d, 8.12 Hz, CHNHBoc), 4.13-3.55 (9H,
d: 7.78-7.55 (4H, m, Ar), 7.54-7.30 (6H, m,
1H NMR (400 MHz D2O)
d
: 4.14-4.10 (1H, m, C4HOH), 4.03-3.94 (2H,
J
m
m, C2HOH, C3HOH), 3.92 (1H, dd, J 3.4, 12.7 Hz, C6HaHb), 3.79 (1H,
CH2CHNHBocCHOTBSCHOCHOCH2OH), 3.15 (1H, br s, CH2OH),
1.50-1.30 (15H, m, CH3CCH3, NHCOC(CH3)3), 1.07 (9H, s,
dd, J 6.8, 12.7 Hz, C6HaHb), 3.39- 3.30 (2H, m, C5HNH, C1HaHb), 3.18
(1H, dd, J 2.6 13.4 Hz, C1HaHb); 13C NMR (100 MHz, D2O)
d: 68.4 (C-
4), 66.2 (C-2), 63.6 (C-3), 58.1 (C-6), 55.8 (C-5), 43.9 (C-1).37,38
Ph2SiC(CH3)3), 0.79 (9H
CH3CH3SiC(CH3)3), 0.02 (3H, s, CH3CH3SiC(CH3)3). 13C NMR (75
MHz, C3D6O) : 156.9, 135.7, 135.0, 130.0, 129.4, 128.0, 127.7, 108.7,
s
(CH3)2SiC(CH3)3, 0.08 (3H,
s
C6H14ClNO4 (199.6): Calcd: C 36.1; H 7.1; N 7.0 %. Found C 36.4; H
25
7.3; N 7.4 %. Mp 102-104ꢀC, (lit.39103-105ꢀC); [
a
]
¼ þ34.1ꢀ (c 1.7,
D
d
25
MeOH), (lit40. [
a]
D þ33.2 (c 0.5, MeOH)).
79.1, 78.6, 77.9, 73.0, 64.0, 63.4, 55.6, 30.1, 28.0, 26.8, 26.6, 26.4, 25.7,
19.1, -4.4, -4.7. C36H59NO7Si2 (674.0): Calcd: C 64.15; H 8.8, N 2.1 %.
Found C 64.3; H 9.0, N 2.2 %.
Declaration of competing interest
(4R,5S)-5-{[(5R,6R)-6-(tert-Butyldiphenylsilyloxymethyl)-
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.
2,2,3,3,10,10-hexamethyl-8-oxo-4,9-dioxa-7-aza-3-silaundecan-5-
yl]-2,2-dimethyl-1,3-dioxolan-4-yl}methyl methanesulfonate 17. In a
two-neck round bottom flask, under argon atmosphere, 3.49 mmol
of 16 was dissolved in 104.7 mL of anhydrous CH2Cl2, and 4.19
mmol (0.32 mL) of MsCl, 6.98 mmol (0.97 mL) of Et3N, and 0.03
mmol (0.004 g) of DMAP were subsequently added; the mixture
was left stirring at room temperature until completion (6 h, TLC
monitoring). The mixture was transferred into a separative funnel,
water and ice were added, the layers were separated, and the
organic one was washed with HCl 2N and brine until pH 7, then
dried over Na2SO4. The solvent was evaporated in vacuo to produce
the crude that was used without purification. Pale yellow oil. 1H
Acknowledgments
We thank Regione Lazio for its financial support.
References
1) N. Asano, R.J. Nash, R.J. Molyneux, G.W.J. Fleet, Sugar-mimic glycosidase in-
hibitors: natural occurrence, biological activity and prospects for therapeutic
application, Tetrahedron:Asymmetry 11 (2000) 1645e1680.
NMR (300 MHz CDCl3) d: 7.68-7.59 (4H, m, Ar), 7.45-7.31(6H, m, Ar),
2) Y. Ichikawa, Y. Igarashi, M. Ichikawa, Y. Suhara, 1-N-Iminosugars: Potent and
Selective Inhibitors of
3007e3018.
[3] (a) P. Compain, O.R. Martin, Iminosugars: From Synthesis to Therapeutic Ap-
plications, Wiley Chichester, 2007;
a-Glycosidases, J. Am. Chem. Soc. 120 (1998)
4.54 (1H, d, J 8.22 Hz, CHNHBoc), 4.24-3.53 (8H, m CH2CHNHBoc-
CHOTBSCHOCHOCH2OMs), 3.02 (3H, s, CH2OSO2CH3), 1.46 (3H, s,
CH3CCH3), 1.43-1.40 (12H, m, CH3CCH3, NHCOC(CH3)3), 1.04 (9H, s,
(b) B. G. Iminosugars Winchester, from botanical curiosities to licensed drugs,
Tetrahedron: Asymm. 20 (2009) 645e651;
(c) O.P. Bande, V.H. Jadhav, V.G. Puranik, D.D. Dhavale, M. Lombardo, Stereo-
controlled approach to pyrrolidine iminosugar C-glycosides and 1,4-dideoxy-
1,4-imino-l-allitol using a d-mannose-derived cyclic nitrone, Tetrahedron Lett
50 (2009) 6906e6908.
Ph2SiC(CH3)3), 0.80 (9H
CH3CH3SiC(CH3)3), 0.037 (3H, s, CH3CH3SiC(CH3)3). 13C NMR (75
MHz, CDCl3) : 155.4, 135.5, 133.1, 129.7, 127.7, 127.6, 127.6, 110.1,
s (CH3)2SiC(CH3)3), 0.053 (3H, s,
d
79.5, 77.2, 73.0, 70.3, 62.6, 55.2, 45.9, 37.5, 28.3, 27.0, 26.8, 26.7, 25.8,
20.9, 19.1, 17.9, -4.2, -4.4.
[4] Fattorusso, E.; Scafati O. T. Modern Alkaloids, Wiley-VCH: New York, 2008,
111-133.
(2R,3R,4S,5R)-tert-butyl-3-[(tert-Butyldimethylsilyl)oxy]-2-
{[(tert-butyldiphenylsilyl)oxy]methyl}-4,5-dihydroxypiperidine-1-
carboxylate 18. In a two-neck round bottom flask, under argon at-
mosphere, compound 17 was dissolved in 69.8 mL of anhydrous
THF and 6.98 mmol (783 mg) of tBuOK were added at 0ꢀC and the
mixture was left stirring at room temperature until completion (8
h, TLC monitoring). 5 mL of saturated solution of NH4Cl were added
to the reaction flask, the mixture was left stirring for 5 minutes, and
was was transferred into a separative funnel. The layers were
separated, the aqueous one extracted twice with CH2Cl2. The
combined organic layers were dried over Na2SO4 and the solvent
was evaporated in vacuo. The crude was purified by chromatog-
raphy on silica gel using a solvent mixture hexane/ethyl acetate
95:5. Yellow oil. Yield 64% from 16 (1.38 g).
5) T. Cox, R. Lachmann, C. Hollak, J. Aerts, S. van Weely, M. Hrebícek, F. Platt,
T. Butters, R. Dwek, C. Moyses, I. Gow, D. Elstein, A. Zimran, Novel oral treat-
ment of Gaucher’s disease with N-butyldeoxynojirimycin (OGT 918) to
decrease substrate biosynthesis, The Lancet 355 (2000) 1481e1485.
6) A. Markham, Migalastat: First Global Approval, Drugs 76 (2016) 1147e1152.
7) R. Schiffmann, Handbook of Clinical Neurology, Fabry disease 132 (2015)
231e248.
€
[8] (a) U.M. Lindstrom, P. Somfai, Asymmetric synthesis of (þ)-1-
deoxynojirimycin, Tetrahedron Lett 39 (1998) 7173e7176;
(b) T. Wennekes, A.J. Meijer, A.K. Groen, R.G. Boot, J.E. Groener, M. van Eijk,
R. Ottenhoff, N. Bijl, K. Ghauharali, H. Song, T.J. O’Shea, H. Liu, N. Yew,
D. Copeland, R.J. van den Berg, G.A. van der Marel, H.S. Overkleeft, J. Aerts,
M Dual-Action Lipophilic Iminosugar Improves Glycemic Control in Obese
Rodents by Reduction of Visceral Glycosphingolipids and Buffering of Carbo-
hydrate Assimilation, J. Med. Chem. 53 (2010) 689e698;
(c) G. Pandey, D. Grahacharya, K.S. Shashidhara, M.I. Khanb, G. Vedavati,
V. Puranikc, G. Synthesis of polyfunctional quinolizidine alkaloids: develop-
ment towards selective glycosidase inhibitors, Org.Biomol.Chem. 7 (2009)
3300e3307;
The room temperature NMR of 18 was complicated by the ex-
23
(d) P. Compain, O.R. Martin, E. Gallienne, Oulaïdi, F. 1-C-Alkyl imino-d-xylitol
and -l-arabinitol derivatives obtained via nucleophilic addition to pentose-
derived N-tert-butanesulfinyl imines: sugar- versus chiral auxiliary-induced
stereoselectivity, Tetrahedron: Asymmetry 22 (2011) 609e612.
istence of carbamate rotamers.36
[
a]
¼ -13.3ꢀ (c 1.1, CHCl3). IR
D
(neat)
NMR (300 MHz CDCl3)
n
cm-1 3458, 3065, 2953, 2864, 1660, 1465, 1250, 1110; 1H
d
: 7.69-7.59 (4H, m, Ar), 7.50-7.35 (6H, m,
[9] (a) C. Ribes, E. Falomir, M. Carda, J.A. Marco, Stereoselective Synthesis of the
Ar), 4.68-4.07 (3H, m, C2H, C3H, C4H), 3.83- 3.52 (3H, m, C6Hb,
C5H, C1Ha), 3.50-3.27 (1H, m,C6Hb), 2.62-2.44 (1H, m, C1Hb), 1.45-
1.40 (9H, m, NHCOC(CH3)3), 1.06 (9H, s, Ph2SiC(CH3)3), 0.94-0.88
Glycosidase Inhibitor Australine through
a One-Pot, Double-Cyclization
Strategy, Org. Lett. 9 (2007) 77e80;
(b) P. Somfai, P. Marchand, S. Torsell, U.L. Lindstrom, Asymmetric synthesis of
(þ)-1-deoxynojirimycin and (þ)-castanospermine, Tetrahedron 59 (2003)
1293e1299;
(c) K. Savaspun, C.W.G. Au, S.G. Pyne, Total Synthesis of Hyacinthacines B3, B4,
and B5 and Purported Hyacinthacine B7, 7-epi-Hyacinthacine B7, and 7a-epi-
(9H, m, (CH3)2SiC(CH3)3), 0.20-0.13 (6H, m, CH3CH3SiC(CH3)133.
NMR (75 MHz CDCl3) : 154.9,154.6,135.6,135.5, 135.4, 133.0, 132.7,
C
d
Hyacinthacine B3 from
4569e4581.
a Common Precursor, J. Org. Chem. 79 (2014)
129.9, 127.9, 127.8, 80.1, 79.8, 73.6, 73.3, 70.1, 69.9, 68.2, 67-9 61.4,
60.3, 59.6, 58.0, 44.6, 43.9, 28.3, 26.8, 25.7, 21.0, 19.1, 18.0, 14.2, -4.6,
-4.9. C33H53NO6Si2 (615.3): Calcd: C 64.35; H 8.7, N 2.3 %. Found C
64.6; H 8.9, N 2.5 %.
1-Deoxy-D-altronojirimycin. Compound 18 was subjected to a
total deprotection reaction according to General Procedure F to
give the known iminosugar as hydrochloride (92% yield, 407 mg).
10) G. Righi, P. Bovicelli, I. Tirotta, C. Sappino, E. Mandic’, Double Stereo-
differentiation in the Asymmetric Dihydroxylation of Optically Active Olefins,
Chirality 28 (2016) 387e393.
11) S. Masamune, W. Choy, J.S. Petersen, L.R. Sita, Double Asymmetric Synthesis
and a New Strategy for Stereochemical Control in Organic Synthesis, Angew.
Chem. Int. Ed. Engl. 24 (1985) 1e30.
12) K. Morikawar, K.B. Sharpless, Double diastereoselection in asymmetric
8

M. De Angelis, C. Sappino, E. Mandic et al.
Tetrahedron 79 (2021) 131837
dihydroxylation, Tetrahedron Lett 34 (1993) 5575e5578.
1293e1299.
13) (a) H.C. Kolb, M.S. Van Nieuwenhze, K.B. Sharpless, Catalytic Asymmetric
Dihydroxylation, Chem. Rev. 94 (1994) 2483e2547.
14) G. Righi, E. Mandic’, I. Tirotta, G.M.C. Naponiello, C. Sappino, C. Marucci,
27) S.H. Park, J.Y. Kim, J.S. Kim, C. Jung, D.K. Song, W.H. Ham, 1, 3-Oxazine as a
chiral building block used in the total synthesis of (þ)-1-deoxynojirimycin and
(2R, 5R)-dihydroxymethyl-(3R, 4R)-dihydroxypyrrolidine, Tetrahedron:
Asymmetry 26 (2015) 657e661.
28) V.H. Jadhav, O. Bande, V.G. Puranik, D.D. Dhavale, Synthesis of azepane and
nojirimycin iminosugars: the Sharpless asymmetric epoxidation of d-glucose-
derived allyl alcohol and highly regioselective epoxide ring opening using
sodium azide, Tetrahedron: Asymmetry 21 (2010) 163e170.
29) S.K. Bagal, S.G. Davies, J.A. Lee, P.M. Roberts, P.M. Scott, J.E. Thomson, Syntheses
of the Enantiomers of 1-Deoxynojirimycin and 1-Deoxyaltronojirimycin via
Chemo- and Diastereoselective Olefinic Oxidation of Unsaturated Amines,
J. Org. Chem. 75 (2010) 8133e8146, and references therein.
30) S. Kobayashi, A. Ando, H. Kuroda, S. Ejima, A. Masuyama, I. Ryu, Rapid access to
6-bromo-5,7-dihydroxyphthalide 5-methyl ether by a CuBr2-mediated multi-
step reaction: concise total syntheses of hericenone J and 50-deoxohericenone
C (hericene A), Tetrahedron 67 (2011) 9087e9092.
M.
Tomei,
P.
Bovicelli,
Stereoselective
synthesis
of
(þ)-1-
deoxyaltronojirimycin, Nat. Prod. Res. 30 (2016) 1655e1660.
[15] This preparation of 5 was a slight improvement compared to that already
reported in ref. 14
[16] (a) A.M.C.H. van den Nieuwendijk, R.J.B.H.N. van den Berg, M. Ruben,
M.D. Witte, J. Brussee, R.G. Boot, G.A. van der Marel, J.M.F.G. Aerts,
H.S. Overkleeft, Synthesis of Eight 1-Deoxynojirimycin Isomers from a Single
Chiral Cyanohydrin, Eur. J. Org. Chem 18 (2012) 3437e3446;
(b) O.V. Singh, H. Han, A general methodology for the asymmetric synthesis of
1-deoxyiminosugars, Tetrahedron. Lett. 44 (2003) 2387e2391.
[17] (a) N. Moitessier, B. Maigret, F. Chreꢀtien, Y. Chapleur, Molecular Dynamics-
ased Models Explain the Unexpected Diastereoselectivity of the Sharpless
Asymmetric Dihydroxylation of Allyl D-Xylosides, Eur. J. Org. Chem. (2000)
995e1005;
31) S. Shuto, I. Sugimoto, H. Abe, A. Matsuda, Mechanistic Study of the Ring-
Enlargement Reaction of (3-Oxa-2-silacyclopentyl)methyl Radicals into 4-
(b) R.A. Fernandes, P. Kumar, Double stereodifferentiation in asymmetric
dihydroxylation: application to the first diastereoselective synthesis of L-xylo-
[2R,3S,4S]-C18-phytosphingosine, Tetrahedron Lett 41 (2000) 10309e10312;
(c) M. De Angelis, L. Primitivo, C. Lucarini, S. Agostinelli, C. Sappino, A. Ricelli,
G. Righi, Stereocontrolled total synthesis of iminosugar 1,4-dideoxy-1,4-
imino-D-iditol, Carb. Res. 492 (2020) 108028.
Oxa-3-silacyclohexyl Radicals. Evidence for
a Pentavalent Silicon-Bridging
Radical Transition State in 1,2-Rearrangement Reactions of
b-Silyl Radicals,
J. Am. Chem. Soc. 122 (2000) 1343e1351.
32) J.M. Escudier, M. Baltas, L. Gorrichon, Diastereoface differentiation in addition
of lithium enolates to chiral
a, b-epoxyaldehydes, Tetrahedron 49 (1993)
18) S.A. Hermitage, A. Murphy, P. Nielsen, S.M. Roberts, An efficient protocol for
the stereoselective dihydroxylation of ene-ester systems, Tetrahedron 54
(1998) 13185e13202.
19) C.H. Beherens, K.B. Sharpless, Selective transformations of 2,3-epoxy alcohols
and related derivatives. Strategies for nucleophilic attack at carbon-3 or car-
bon-2, J. Org. Chem. 50 (1985) 5696e5704.
20) E.J. Corey, H. Cho, C. Rücker, D.H. Hua, Studies with trialkylsilyltriflates: new
syntheses and applications, Tetrahedron Lett 22 (1981) 3455e3458.
21) H.E. Purkey, K. Robarge, J. Chen, Z. Chen, L.B. Corson, C.Z. Ding, A.G. Dipasquale,
H. Zhang, A. Zhou, Cell active hydroxylactam inhibitors of human lactate de-
hydrogenase with oral bioavailability in mice, ACS Med Chem Lett 7 (2016)
896e901.
5253e5266.
33) S.-H. Park, J.-Y. Kim, J.-S. Kim, C. Jung, D.-K. Song, W.-H. Ham, 1,3-Oxazine as a
chiral building block used in the total synthesisof (þ)-1-deoxynojirimycin and
(2R,5R)-dihydroxymethyl-(3R,4R)-dihydroxypyrrolidine, Tetrahedron:Asym-
metry 26 (2015) 657e661.
34) V.H. Jadhav, O.P. Bande, V.G. Puranik, D.D. Dhavale, V.H. Jadhav, O.P. Bande,
V.G. Puranik, D.D. Dhavale, Tetrahedron:Asymmetry 21 (2010) 163e170.
35) D. Best, C. Wang, A.C. Weymouth-Wilson, R.A. Clarkson, F.X. Wilson, R.J. Nash,
S. Miyauchi, A. Kato, G.W.J. Fleet, Looking glass inhibitors: scalable syntheses of
DNJ, DMDP, and (3R)-3-hydroxy-l-bulgecinine from d-glucuronolactone and of
l-DNJ, l-DMDP, and (3S)-3-hydroxy-d-bulgecinine from l-glucuronolactone.
DMDP inhibits
b-glucosidases and
b-galactosidases whereas l-DMDP is
a
22) A. Karanfil, B. Balta, M. Eskici, A [3þ3] cyclization strategy for asymmetric
synthesis of alkyl substituted piperidine-2-ones using 1,2-cyclic sulfamidates:
a formal synthesis of (S)-coniine from l-norvaline, Tetrahedron 68 (2012)
10218e10229.
potent and specific inhibitor of
(2010) 311e319.
36) D. Wang, W.A. Nugent, 2-Deoxyribose as a Rich Source of Chiral 5-Carbon
Building Blocks, J. Org. Chem. 72 (2007) 7307e7312.
a-glucosidases, Tetrahedron: Asymmetry 21
23) J. Van Ameijde, G. Horne, M.R. Wormald, R.A. Dwek, R.J. Nash, P. Wyn Jones,
E.L. Evinson, G.W.J. Fleet, Isolation synthesis and glycosidase inhibition profile
of 3-epi-casuarine, Tetrahedron: Asymmetry (2006) 2702e2712.
24) H.-J. Lin, A.K. Adak, L.V.R. Reddy, S.H. Prof Wu, C.-C. Prof Lin, Total Synthesis of
an Immunomodulatory Phosphoglycolipid from Thermophilic Bacteria, Chem.
Eur. J. 19 (2013) 7989e7998.
37) A.M.C.H. van den Nieuwendijk, R.J.B.H.N. van den Berg, M. Ruben, M.D. Witte,
J. Brussee, R.G. Boot, G.A. van der Marel, J.M.F.G. Aerts, H.S. Overkleeft, Syn-
thesis of Eight 1-Deoxynojirimycin Isomers from a Single ChiralCyanohydrin,
Eur. J. Org. Chem (2012) 3437e3446.
38) O.V. Singh, H. Han, A general methodology for the asymmetric synthesis of1-
deoxyiminosugars, Tetrahedron Lett 44 (2003) 2387e2391.
25) B. Wang, R.-H. Liu, Stereospecific, Flexible and Redox-Economic Asymmetric
Synthesis of cis- and trans-3-Hydroxypipecolic Acids and -Analogs, Eur. J. Org.
Chem. 17 (2009) 2845e2851.
39) N. Ikota, J. Hirano, R. Gamage, H. Nakagawa, H. Hama-Inaba, Improved syn-
thesis of 1-deoxynojirimycin and facile synthesis of its stereoisomers from (S)-
pyroglutamic acid derivative, Heterocycles 46 (1997) 637e644.
40) O.V. Singh, H. Han, A general methodology for the asymmetric synthesis of 1-
deoxyiminosugars, Tetrahedron Lett 44 (2003) 2387e2391.
€
26) P. Somfai, P. Marchand, S. Torsell, U.M. Lindstrom, Asymmetric synthesis of
(þ)-1-deoxynojirimycin and (þ)-castanospermine, Tetrahedron 59 (2003)
9