Stereocontrolled total synthesis of iminosugar 1,4-dideoxy-1,4-imino-D-iditol

Article abstract of DOI:10.1016/j.carres.2020.108028

The first stereocontrolled total synthesis of iminosugar 1,4-dideoxy-1,4-imino-D-iditol is described. The key step in our approach was the double diastereoselection in the asymmetric dihydroxylation (AD) of suitable optically active olefin, the chiral vin

Full text of DOI:10.1016/j.carres.2020.108028

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Stereocontrolled total synthesis of iminosugar 1,4-dideoxy-1,4-imino-D-iditol
Martina De Angelis, Ludovica Primitivo, Claudia Lucarini, Sonia Agostinelli, Carla
Sappino, Alessandra Ricelli, Giuliana Righi
PII:
S0008-6215(20)30143-9
DOI:
https://doi.org/10.1016/j.carres.2020.108028
CAR 108028
Reference:
To appear in: Carbohydrate Research
Received Date: 3 March 2020
Revised Date: 27 April 2020
Accepted Date: 28 April 2020
Please cite this article as: 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, Carbohydrate
Research (2020), doi: https://doi.org/10.1016/j.carres.2020.108028.
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Stereocontrolled total synthesis of iminosugar 1,4-dideoxy-1,4-imino-D-iditol
Martina De Angelis,b,* Ludovica Primitivo,b Claudia Lucarini,b Sonia Agostinelli,b Carla Sappino,b
Alessandra Ricelli,a Giuliana Righi a,*
a CNR-IBPM, “Sapienza” University of Rome, Dep. Chemistry, P.le A. Moro 5, 00185, Rome, Italy
b “Sapienza” University of Rome, Dep. Chemistry, P.le A. Moro 5, 00185, Roma, Italy
*
These authors contributed equally to this work
m.deangelis@uniroma1.it
giuliana.righi@cnr.it
Abstract: The first stereocontrolled total synthesis of iminosugar 1,4-dideoxy-1,4-imino-D-iditol is
described. The key step in our approach was the double diastereoselection in the asymmetric
dihydroxylation (AD) of suitable optically active olefin, the chiral vinyl azido alcohol 9. Performing
the AD using the most common Cinchona alkaloids as ligands enabled us to identify the ligand of
choice for the stereodivergent synthesis of 1,4-dideoxy-1,4-imino-D-iditol and 1,4-dideoxy-1,4-
imino-D-galactitol. These type of iminosugars, both natural and unnatural, are intensively studied
for their promising chemotherapeutic properties against viral infections, diabetes, cancer, and
tuberculosis.
Keywords: iminosugars; 1,4-dideoxy-1,4-imino-D-iditol; 1,4-dideoxy-1,4-imino-D-galactitol;
asymmetric dihydroxylation.
1. Introduction
Iminosugars, carbohydrate analogues in which the endocyclic oxygen is replaced by a nitrogen
atom, are nowadays one of the most attractive class of sugar mimics because of their high
glycosidase and glycosyltransferase inhibitor activity and hence their therapeutic potential in a vast
array of diseases, such as diabetes, glycosphingolipid storage disorders, and viral infections (HIV,
hepatitis B and C...) [1].
Among iminosugars, several five-membered pyrrolidine compounds are selective inhibitors of
α-
and
β-glucosidases.
For
example,
the
(2R,5R)-bis(dihydroxymethyl)-(3R,4R)-
dihydroxypyrrolidine, DMDP [2], the first pyrrolidine iminosugar discovered and isolated in 1976
from Derris elliptica [3], displays strong inhibition on glycosidases I and antiviral activity [4]. The
1-deoxy derivative of D-arabinosimine (DAB-1), isolated in 1985 from Angylocalyx boutiqueanus

[5], is a potent inhibitor of glycogen phosphorylase and is under study as a treatment for Type II
diabetes and preventative of HIV replication. Its diastereoisomer, LAB-1, is a strong intestinal α-
glucosidase inhibitor and a powerful anti-AIDS agent. The C-5 epimer of DMDP, 2,5-dideoxy-2,5-
imino-D-glucitol (DGDP), recently isolated from traditional Thai folk medicine “Non tai yak”
(Stemona tuberosa) [6], exhibited broad-spectrum inhibition against α- and β-glucosidases and α-
mannosidases.
Figure 1
The 1,4-dideoxy-1,4-imino hexitols, are not only potent glycosidase inhibitors[7], but also
promising inhibitors of mycobacterial galactan biosynthesis, probably by means of their inhibition
of the mycobacterial UDP-Gal mutase. In particular, the 1,4-dideoxy-1,4-imino-D-galactitol
(DMDG) is the first known inhibitor of E. coli K12 UDP-Gal mutase and mycobacterial galactan
biosynthesis [8,9,10]. This activity may have therapeutic potential for the treatment of
mycobacterial infections such as tuberculosis and leprosy, diseases that have become currently
public health concerns one more due to the recent reappearance of multiresistances against most
existing treatments.
2. Results and discussion
In our previous work we described the total synthesis of the pyrrolidine alkaloids 1,4-dideoxy-
1,4-imino-D-galactitol and its diastereoisomer 1,4-dideoxy-1,4-imino-D-glucitol, exploiting as key
steps two different regio- and stereoselective nucleophilic openings of a suitable chiral vinyl
epoxide and subsequent double diastereoselection in the asymmetric dihydroxylation (AD). [11]
As already reported by us, using (DHQ)2PHAL as chiral ligand in the AD of the optically
active vinyl azido alcohols 9 and 17, we obtained an increase of the natural diastereoselection,

achieving almost exclusively the diols A and C. Instead, the use of (DHQD)2PHAL increased the
production of the unnatural diols B and D, but was not able to reverse the diasteroisomeric ratio.
With the purpose of enhancing the amount of diols B and D, precursor of the iminosugars 1,4-
dideoxy-1,4-imino-D-iditol and 1,4-dideoxy-1,4-imino-D-altritol respectively, in this work we
performed the AD on substrates 9 and 17 using all the most common second generation Cinchona
alkaloids, to test their influence on the diastereoselectivity.
Azido alcohols 9 and 17 were prepared from cis 2-butene-1,4-diol 1 after careful selection of the
suitable protecting group: the Sharpless asymmetric epoxidation on monobenzyl ethers 2 and 10 led
to the corresponding epoxides 5 and 13 with moderate yields and enantiomeric excess, while on the
tert-butyldimethylsilyl ethers 3 and 11 it never gave reproducible results. Finally, the protection as
tert-butyldiphenylsilyl ethers (4 and 12) allowed us to obtain the optically active epoxides 7 and 15
in very good yields and excellent enantiomeric excess (Scheme 1).
Scheme 1. a) NaH, TBDPSCl (or TBDMSCl), THF, 0°C to rt, nearly quantitative yield; b) Ti(O-i-Pr)4, (+)-DET, t-
BuOOH, CH2Cl2, -20°C, 7 87% and 15 89%; c) TEMPO, IBDA, CH2Cl2, rt,; d) LiOH, TMPA, THF, reflux, (8 75%
from 7 and 16 77% from 15); e) TMSN3, BF3∙OEt2, CH2Cl2, rt; f) TBSOTf, 2,6-lutidine, CH2Cl2, rt, (9 74% from 8 and
17 73% from 16).
The subsequent oxidation to aldehyde of epoxy alcohols 7 and 15, followed by a Horner-
Emmons reaction, afforded the corresponding trans α,β-unsaturated epoxy esters 8 and 16. The
heterocyclic ring was then subjected to a regio and stereocontrolled nucleophilic opening using the
BF3/TMSN3 system to give the target vinyl azido alcohols 9 and 17.
Table 1. Asymmetric dihydroxylation of vinyl azido alcohols 9 and 17

Entry
Ligand
//
A/B
C/D
75:25
>95:5
70:30
81:19
84:16
>95:5
50:50
90:10
>95:5
75:25
>95:5
80:20
>95.5
75:25
1
2
3
4
5
6
7
(DHQ)2PHAL
(DHQD)2PHAL
(DHQ)2Pyr
(DHQD)2Pyr
(DHQ)2AQN
(DHQD)2AQN
As shown in Table 1, all the dihydroquinin-derived ligands (DHQ) lead almost exclusively to
the diastereoisomers A and C (matched case), which also remain predominant also with the use of
the dihydroquinidine-derived ligands (DHQD).
Despite not being able to overturn the diastereomeric ratio, a larger amount of the
diastereoisomer B (mismatched case) was obtained by using (DHQD)2AQN in the dihydroxylation
of the syn azido alcohol 9, giving an equimolar mixture of the two diastereoisomeric triols.
The diastereomeric ratio was determined by integration of the two methyl signals on silicon
(two singlets at about 0.02 and -0.13ppm) of the TBSO group of each diastereoisomer on the 1H
NMR spectra of the crude mixture.

Fig. 2. Comparison between the signals of the two methyls on the silicon of the hydroxylation
products of 9 (A + B): a) without ligand; b) with (DHQ)2AQN; c) with (DHQD)2AQN.
The diastereomeric ratio obtained in the last case is to be considered a convenient way to
achieve at the same time 1,4-dideoxy-1,4-imino-D-galactitol [8,9] and 1,4-dideoxy-1,4-imino-D-
iditol (an inhibitor of α-L-fucosidase and α-D-arabinosidase) [12], employing the azidotriol B as
the common precursor and by exploiting the same synthetic route until the separation of the two
diastereoisomers in the final steps of the synthesis. For this purpose, following a sequence of steps
already performed, the inseparable mixture of A and B was subjected to the one-pot reduction of the
azide moiety and subsequent ring closure using triphenylphosphine to obtain an inseparable mixture
of the polar lactams 18 and 19 (Scheme 2) [13]. Fortunately, the monosilylation of the lactams 18
and 19, obtained treating the mixture with t-butyldimethylsilyl chloride in the presence of
imidazole, enabled separation of the protected lactams 20 and 21 as single diastereomers. In both
diastereoisomers the hydroxyl group in α to the carbonyl was selectively silylated, as proven
through the corresponding acetyl derivatives.
A borane–dimethyl sulfide reduction in refluxing THF[14], followed by a work-up sufficiently
acidic to remove the silyl protecting groups (HCl 37% in MeOH), enabled us to synthesize 1,4-
dideoxy-1,4-imino-D-galactitol and its diastereoisomer 1,4-dideoxy-1,4-imino-D-iditol as
hydrochlorides in excellent yield, with analytical data in accordance with those previously
published[11,15].

Scheme 2. a) PPh3, THF dry, rt; b) TBDMSCl, imidazole, THF dry, reflux, (20 27% from 9 and 21 28% from 9); c)
BH3-SMe2, THF dry, rt; then HCl (37%), MeOH, 70 °C.
3. Conclusion
In conclusion, after testing the influence of different ligands on the diastereoselectivity in the
asymmetric dihydroxylation of the suitable chiral vinyl azido alcohol, we reported the first total
synthesis of the pyrrolidine iminosugar 1,4-dideoxy-1,4-imino-D-iditol.
Contrary to the expectations raised by our previous work, no Cinchona ligand was able to
reverse the stereochemistry of the AD reaction. In fact, after testing the influence of different
ligands on the diastereoselectivity of the AD, only the use of (DHQD)2AQN furnished an equimolar
mixture of the two diastereoisomeric triols. However, this result is to be considered a convenient
strategy to realise the first total synthesis of the pyrrolidine iminosugar 1,4-dideoxy-1,4-imino-D-
iditol, in addition of 1,4-dideoxy-1,4-imino-D-galactitol, with a total satisfactory yield (11%), by
exploiting a single synthetic route until the final separation of the diastereoisomers through a simple
monosilylation of the corresponding lactams.
4. Experimental section
4.1. General methods

Organic solvents and reagents were purchased and used without further purification unless
otherwise stated. Reactions were monitored by thin-layer chromatography (TLC) carried out on
0.25 mm E. Merck silica gel plates (60F-254) using UV light (254 nm) and visualization 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
temperature reactions were performed in a Haake EK 101cryostat using an acetone bath. Unless
1
13
otherwise stated, reactions were carried out under standard atmosphere. H and C NMR spectra
13
were recorded using a Varian Mercury 300 (1H, 300 MHz; C, 75 MHz), Bruker 300 (1H, 300
13
13
MHz; C, 75 MHz) and Bruker 400 (1H, 400 MHz; C, 100 MHz) instruments. Residual solvent
peaks were used as internal references: chloroform (1H, d 7.26 ppm; 13C, δ 77.00 ppm), acetone (1H,
13
δ 2.05 ppm; C, δ 30.83 ppm) and deuterium oxide (1H, δ 4.79 ppm;). Chemical shifts (δ) are
reported in parts per million (ppm) relative to the internal standard and coupling constant (J) in Hz.
Splitting patterns are designated as s, singlet; br s, broad singlet; d, doublet; br d, broad doublet; dd,
doublet of doublets; 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 200–400 mesh from E. Merck, Germany). 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.
Compound 3 [16], 4 [17], 5 [18], 6 [14], 7 [19], 8 [11], 9 [18], 10 [20], 11 [19], 12 [21], 13 [22], 14
[23], 15 [11], 16 [21], are known.
4.2 (E,4R,5S)-Methyl 4-azido-5-(t-butyldimethylsilyloxy)-6-(t-butyldiphenylsilyloxy)hex-2-enoate
(17). To a stirred solution of 16 (1 mmol) in dry CH2Cl2 (3 mL) were added TMSN3 (1 mmol, 115
mg, 0.13 mL) and BF3•OEt (2 mmol, 283 mg, 0.25 mL) dropwise and the mixture left stirring at
room temperature. After complete consumption of the substrate (12 h, TLC monitoring), the
mixture was diluted with CH2Cl2 and washed with aq NaHCO3 and brine until pH 7. The organic
layer was dried over Na2SO4 and after filtration the solvent evaporated under vacuum. The crude,

used without purification, was subjected to the hydroxyl group protection as silyl ether. In a two
neck flask under argon atmosphere the azido alcohol was dissolved in 6 ml of CH2Cl2 and 2 mmol
(214 mg, 0.23 mL) of 2,6-lutidine and 3 mmol (793 mg, 0.69 mL) of tert-butyldimethylsilyl triflate
were added and the mixture stirred at r.t. until completion (12 h, TLC monitoring). The reaction was
quenched with water, then the two phases were separated and the aqueous layer was extracted twice
with CH2Cl2, 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 vacuum. The crude was purified by flash chromatography on silica gel (hexane/ethyl
acetate 90:10) to afford 17 (74% from 8).
1H NMR (300 MHz, CDCl3) δ: 7.75-7.66 (m, 4H, Ar), 7.50-7.27 (m, 6H, Ar), 6.98 (dd, 1H, J =
15.7, 7.3 Hz,CH=CHCOOCH3 ), 6.13 (d, 1H, J = 15.7 Hz, CH=CHCOOCH ), 4.45-4.36 (m, 1H,
CHN3), 3.90-3.80 (m, 1H, CHOTBS), 3.78 (s, 3H, COOCH3), 3.65-3.53 (m, 2H, CHaOTBDPS,
CHbOTBDPS), 1.08 (s, 9H, C(CH3)3), 0.86 (s, 9H, C(CH3)3), 0.06 (s, 3H, SiCH3), -0.07 (s, 3H,
13
SiCH3). C NMR (75 MHz, CDCl3) δ: 166.0; 141.4; 135.5; 132.9; 132.8; 129.9; 129.9; 127.8;
127.8;124.5; 74.6; 64.4; 51.7; 26.8; 25.7; 19.2; 18.0; -4.7; -5.0. C29H43N3O4Si2 (553.28): C 62.89, H
7.83, N 7.59; found C 62.91, H 7.85, N 7.63.
4.3
(2R,3S,4R,5S)-Methyl
4-azido-5-(t-butyldimethylsilyloxy)-6-(t-butyldiphenylsilyloxy)-2,3-
dihydroxyhexanoate A [11] and (2S,3R,4R,5S)-Methyl 4-azido-5-(t-butyldimethylsilyloxy)-6-(t-
butyldiphenylsilyloxy)-2,3-dihydroxyhexanoate B (mixture 50:50). To a solution of 1 mmol of 9 in 9
mL of acetone/water (8:1) were added 2 mmol (270 mg) of NMO, ligand (DHQD)2AQN (0.15
mmol, 129 mg) and 0.05 mmol of OsO4 (0.63 mL of a 2.5% solution of OsO4 in tert-butanol).) The
mixture left stirring overnight at room temperature. The reaction was then quenched with 5 mL
Na2S2O3 saturated solution, the mixture left stirring for 1 h and then transferred in a separating
funnel. The aqueous layer was extracted with 10 mL of EtOAc, the combined organic layers dried
over Na2SO4 and the solvent removed under reduced pressure. The product was used without
chromatographic purification.
1H NMR (400 MHz, CDCl3) δ: 7.70-7.64 (m, 8H, Ar), 7.47-7.33 (m, 12H), 4.52 (d 1H, J =1.3 Hz,
CHOH A), 4.50 (d 1H, J = 1.3 Hz, CHOH B), 4.28-4.22 (m 2H, CHOH B, CHOTBS B) 4.20-4.11
(m, 3H, CHOH A, CHOTBS A, OH), 3.96 (bs, 1H, OH) 3.83-3.80 (m, 2H, CHaHbOTBDPS A,
CHaHbOTBDPS B) 3.73 (s, 3H, OCH3 A), 3.72 (s, 3H, OCH3 B), 3.70-3.57 (m, 4H,
CHaHbOTBDPS A, CHN3 A, CHaHbOTBDPS B, CHN3 B), 1.04 (s, 18H, (CH3)3C A, (CH3)3C B),
0.82 (s, 9H, (CH3)3C A), 0.81 (s, 9H, (CH3)3C B), 0.01 (s, 3H, CH3 A), -0.06 (s, 3H, CH3 B), -0.13
13
(s, 3H, CH3 A), -0.17 (s, 3H, CH3 B). C NMR (100 MHz, CDCl3) δ 173.9, 173.3, 135.8, 135.7,

133.2, 133.2, 133.0, 133.0, 130.0, 130.0, 127.9, 72.8, 72.2, 71.7, 71.4, 71.1, 71.0, 70.5, 64.6, 64.6,
64.3, 62.0, 53.0, 52.9, 26.9, 25.8, 25.7, 19.2, 18.1, 18.0, 14.3, 12.1, -4.1, -4.6, -5.2, -5.2.
4.4
(1’S,3R,4S,5R)-5-[1’-(t-Butyldimethylsilyloxy)-2’-(t-butyldiphenylsilyloxy)-ethyl]-3,4-
dihydroxypyrrolidin-2-one (18) and (1’S,3S,4R,5R)-5-[1’-(t-Butyldimethylsilyloxy)-2’-(t-
butyldiphenylsilyloxy)-ethyl]-3,4-dihydroxypyrrolidin-2-one (19)
To a solution of the inseparable mixture of diols
A and B (1 mmol) in THF (3 mL) was
added triphenylphosphine (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 then added. After stirring at room temperature for an additional 12 h, the
reaction mixture was concentrated to dryness. The crude was purified by flash
chromatography on silica gel (hexane/ethyl acetate 80:20) to give an inseparable mixture of
the polar lactams 18 and 19
.
1H NMR (400 MHz, CDCl3) δ: 7.70-7.62 (m, 8H, Ar), 7.47-7.33 (m, 12H, Ar), 5.98 (bs, 1H, NH
18), 5.85 (bs, 1H, NH 19), 4.95 (bs, 1H, OH 18), 4.77-4.53 (m, 2H, OH 18, OH 19), 4.53-4.40 (m,
2H, CHOH 19), 4.37 (d, 1H, J = 7.8 Hz, CHOH 18), 4.16 (dd, 1H, J1=J2=7.8 Hz, CHOH 18), 4.13-
4.07 (m, 1H, CHOH 19), 3.93 (m, 1H, CHOTBS 19) 3.80-3.57 (m, 5H, CHOTBS 18,
CHaHbOTBDPS 18, CHaHbOTBDPS 19), 3.54-3.42 (m, 2H, CHNH 18, CHNH 19), 1.06 (s, 9H,
(CH3)3C 18), 1.05 (s, 9H, (CH3)3C 19), 0.82 (s, 9H, (CH3)3C 18), 0.75 (s, 9H, (CH3)3C 19), -0.01 (s,
13
3H, CH3 19), -0.05 (s, 3H, CH3 18), -0.16 (s, 3H, CH3 19), -0.24 (s, 3H, CH3 18). C NMR (100
MHz, CDCl3) δ: 173.5, 135.7, 135.6, 135.6, 130.2, 130.1, 130.1, 130.0, 128.1, 128.0, 76.6, 76.1,
75.3, 71.6, 69.0, 66.9, 65.2, 60.1, 56.0, 27.0, 26.9, 25.8, 25.8, 19.2, 19.1, 18.0, 17.9, -4.3, -4.4, -4.6,
-5.0
4.5
(1’S,3R,4S,5R)-5-[1’(tert-Butyl-dimethyl-silyloxy)-2’-(tert-butyl-diphenyl-silyloxy)-ethyl] -3-
(tert-butyl-dimethyl-silyloxy)-4-hydroxypyrrolidin-2-one (20) and (1’S,3S,4R,5R)-5-[1’-(tert-Butyl-
dimethyl-silyloxy)-2’-(tert-butyl-diphenyl-silyloxy)-ethyl]-3-(tert-butyl-dimethyl-silyloxy)-4-
hydroxypyrrolidin-2-one (21)
In a two neck flask under argon atmosphere 1 mmol of lactam was dissolved in 6 ml of dry THF.
2,2 mmol of imidazole (150 mg) and 1,1 mmol (166 mg) of tert-butyldimethylsilyl chloride were
added and the mixture stirred at reflux temperature until completion (12 h, TLC monitoring). The
THF was evaporated, the reaction mixture was dissolved in CH2Cl2 and washed with HCl 1M, then
with NaHCO3 saturated solution and finally with brine. The organic layer was dried over Na2SO4

and after filtration the solvent evaporated in vacuum. The crude was purified by flash
chromatography on silica gel (hexane/ethyl acetate 85:15).
1
20: yield 27% from 17; H NMR (400 MHz, CDCl3) δ: 7.70-7.60 (m, 4H, Ar), 7.53-7.37 (m, 6H),
5.55 (bs, 1H, NH), 4.33 (d, 1H, J = 7.9 Hz CHOTBS), 4.15 (dd, 1H, J = 7.9, 7.0 Hz, CHOH), 3.69
(dd, 1H, J = 10.9, 8.6 Hz, CHaOTBDPS), 3,60 (dd, 1H, J = 10.9, 3.7 Hz, CHbOTBDPS), 3.51 (td,
1H, J = 8.6, 3.7 Hz, CHOTBS), 3.30 (dd, 1H, J = 8.6, 7.0 Hz, CHNH), 1.07 (s, 9H, (CH3)3C), 0.96
(s, 9H, (CH3)3C), 0.75 (s, 9H, (CH3)3C), 0.22 (s, 3H, CH3 C), 0.19 (s, 3H, CH3 C), -0.12 (s, 3H, CH3
C), -0.40 (s, 3H, CH3 C). 13C NMR (100 MHz, CDCl3) δ: 172.7, 135.8, 135.6, 132.0, 132.0, 130.6,
130.4, 128.3, 128.2, 77.3, 76.7, 74.5, 66.7, 62.1, 26.9, 25.9, 25.7, 19.2, 18.5, 17.9, -4.3, -4.6, -4.9, -
5.0. C34H57NO5Si3 (643.35): C 63.40, H 8.92, N 2.17; found C 63.70, H 9.36, N 2.03.
21: yield 28% from 17;1H NMR (400 MHz, CDCl3) δ: 7.67-7.60 (m, 4H, Ar), 7.51-7.38 (m, 6H),
5.44 (bs, 1H, NH), 4.36 (dd, 1H, J = 6.5, 5.0 Hz, CHOH), 4.21 (d, 1H, J = 5.0 Hz, CHOTBS), 4.04
(dt, 1H, J = 8.8, 4.4 Hz, CHOTBS), 3,86 (dd, 1H, J = 6.5, 4.4 Hz, CHNH), 3.66 (dd, 1H, J = 10.4,
4.2 Hz, CHaOTBDPS), 3.48 (dd, 1H, J = 10.4, 8.8 Hz, CHbOTBDPS), 1.07 (s, 9H, (CH3)3C), 0.93
(s, 9H, (CH3)3C), 0.78 (s, 9H, (CH3)3C), 0.17 (s, 3H, CH3 C), 0.16 (s, 3H, CH3 C), 0.02 (s, 3H, CH3
C), -0.14 (s, 3H, CH3 C). 13C NMR (100 MHz, CDCl3) δ: 174.3, 135.9, 135.8, 132.6, 132.5, 130.6,
130.5, 128.4, 128.3, 128.2, 76.6, 76.0, 70.5, 65.7, 58.4, 27.1, 26.1, 26.0, 19.4, 18.6, 18.1, -4.1, -4.1,
-4.2, -4.7. C34H57NO5Si3 (643.35): C 63.40, H 8.92, N 2.17; found C 63.78, H 9.31, N 2.00.
4.6
(1’S,3R,4S,5R)-5-[1’(tert-Butyl-dimethyl-silyloxy)-2’-(tert-butyl-diphenyl-silyloxy)-ethyl] -3-
(tert-butyl-dimethyl-silyloxy)-4-acetoxypyrrolidin-2-one 22 (acetyl derivative of 20) and
(1’S,3S,4R,5R)-5-[1’-(tert-Butyl-dimethyl-silyloxy)-2’-(tert-butyl-diphenyl-silyloxy)-ethyl]-3-(tert-
butyl-dimethyl-silyloxy)-4-acetoxypyrrolidin-2-one 23 (acetyl derivative of 21)
1 mmol of substrate (20 or 21) was dissolved in 1 ml of pyridine and 0.5 ml of acetic anhydride was
added. The mixture left stirring overnight at room temperature. The reaction mixture was
transferred in a separating funnel with ethyl acetate and washed with HCl 2M. 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. The product was analyzed without chromatographic
purification.
1
22: H NMR (400 MHz, CDCl3) δ: 7.71-7.55 (m, 4H, Ar), 7.51-7.35 (m, 6H), 5.85 (bs, 1H, NH),
5.21 (dd, 1H, J1=J2= 4.5 Hz, CHOAc), 4.29 (d, 1H, J = 4.5 Hz CHOTBS), 3.91 (m, 1H, CHOTBS),
3,60 (m, 2H, CHNH, CHaOTBDPS), 3.54 (dd, 1H, J1 = 11.0 J2 = 5.7 Hz, CHbOTBDPS), 2.06 (s,
3H, COCH3) 1.05 (s, 9H, (CH3)3C), 0.89 (s, 9H, (CH3)3C), 0.84 (s, 9H, (CH3)3C), 0.16 (s, 3H, CH3
C), 0.13 (s, 3H, CH3 C), -0.06 (s, 3H, CH3 C), -0.12 (s, 3H, CH3 C).

1
23: H NMR (400 MHz, CDCl3) δ: 7.65-7.56 (m, 4H, Ar), 7.49-7.35 (m, 6H), 5.63 (bs, 1H, NH),
5.31 (dd, 1H, J1=J2=7.8 Hz, CHOAc), 4.51 (d, 1H, J = 7.8 Hz, CHOTBS), 4.18 (m, 1H, CHOTBS),
3.62-3.55 (m, 2H, CHNH, CHaOTBDPS), 3.45-3.66 (m, 1H, CHbOTBDPS), 2.12 (s, 3H, COCH3)
1.05 (s, 9H, (CH3)3C), 0.88 (s, 9H, (CH3)3C), 0.79 (s, 9H, (CH3)3C), 0.15 (s, 3H, CH3 C), 0.09 (s,
3H, CH3 C), -0.02 (s, 3H, CH3 C), -0.20 (s, 3H, CH3 C).
As is widely known, the acetylation of a secondary alcoholic function results in a deshielding of
about 1.1 ppm of the CHOAc signal compared to the original CHOH one. By comparing the 1H
NMR of 20 and 21 with the respective acetyl derivatives 22 and 23, it is possible to observe the
expected deshielding for two dd systems, from 4.15 ppm of 20 to 5.21 ppm of 22 and from 4.36
ppm of 21 to 5.31 of 23, respectively. The multiplicity of the deshielded systems is consistent with
the CHOH in C-3 position, thus proving that the hydroxyl groups in α to the carbonyl, which have
doublet multiplicity, were selectively silylated for both 20 and 21.
4.7 1,4-dideoxy-1,4-imino-D-iditol hydrochloride [12, 15]
.
To a solution of 21 (1 mmol) in dry THF (4.34 mL) was added BH3 DMS (5 mmol, 0.15 mL) at 0
°C. The reaction mixture was stirred under nitrogen at reflux temperature for 5 hours and then at
room temperature until complete consumption of the substrate (TLC monitoring); the reaction was
quenched by cautiously adding 1,5 ml of HCl 1M. The mixture was refluxed for 2 hours and after
cooling, was concentrated to dryness. The mixture was coevaporated 4 times with a solution of
MeOH/HCl 37% (1:1). The product was washed 3 times with hexane removing the supernatant and
the solid residue was crystallized from MeOH/H2O 90:10 affording 1,4-dideoxy-1,4-imino-D-
iditol·HCl salt as white crystals (85%). mp = 154-156 °C; (lit [15] mp=157-158 °C). αD= + 3.2 (c=
1.5, H2O); (lit [15] αD= +3.7, c= 3, H2O).
1H NMR (400 MHz, CDCl3) δ:4.31 (bd, 1H, J = 3.9 Hz, H-2), 4.20 (bd, 1H, J = 2.5 Hz, H-3), 4.04
(ddd, 1H, J = 8.5, 4.8, 3.3 Hz, H-5), 3.75-3.66 (m, 2H, H-4 + H-6), 3.58-3.55 (m, 2H, H-6’+ H-5),
3.19 (bd, 1H, J = 13.1 Hz, H-5’) . 13C NMR (100 MHz, CDCl3) δ:75.0, 74.4, 68.3, 63.5, 63.3, 50.5.
C6H14ClNO4 (199.06): C 36.10, H 7.07, N 7.02; found C 36.14, H 7.11, N 6.98. C6H14ClNO4
(199.06): C 36.10, H 7.07, N 7.02; found C 36.14, H 7.11, N 6.98.
4.8
1,4-dideoxy-1,4-imino-D-galactitol hydrochloride [8, 9, 10]
Following the same procedure already described for 1,4-dideoxy-1,4-imino-D-iditol·HCl salt, after
crystallization from MeOH/H2O 90:10, 1,4-dideoxy-1,4-imino-D-galactitol·HCl salt) was obtained
as white crystals (81%). mp = 100-103 °C; (lit [11] mp=100-102 °C). αD= -23 (c= 1.5, H2O); (lit
[11] αD= -22, c= 1,5, H2O)

1H NMR (400 MHz, D2O) δ: 4.24 (1H, dt, J = 5.0, 3.2 Hz, H-2), 4.08 (1H, br t, J = 3.5 Hz, H-3),
3.93-3.88 (1H, m, H-5), 3.69 (1H, dd, J = 12.2, 3.6 Hz, H-6), 3.58 (1H, dd, J = 12.2, 4.9 Hz, H-6’),
13
3.49-3.43 (2H, m, H-4+H-1), 3.25 (1H, dd, J = 12.4, 3.2 Hz, H-1’). C NMR (100 MHz, D2O) δ:
76.5, 74.5, 69.1, 66.7, 63.3, 49.9. C6H14ClNO4 (199.06): C 36.10, H 7.07, N 7.02; found C 36.13, H
7.09, N 6.99.
Acknowledgments
We thank CNR-Regione Lazio project (DCM.AD003.014) for partial financial support.
Reference
[1] (a) P. Compain,; O.R. Martin, Iminosugars: From Synthesis to Therapeutic Applications; Wiley: Chichester,
2007, https://doi.org/10.1002/9780470517437.ch1 (b) B.G. Winchester, Iminosugars: from botanical
curiosities
to
licensed
drugs,
Tetrahedron:
Asymm.
20
(2009)
645-651,
https://doi.org/10.1016/j.tetasy.2009.02.048 (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) 6906-6908,
https://doi.org/10.1016/j.tetlet.2009.09.139.
[2] T.M Wrodnigg, From Liana to a Glycotechnology Tool, 25 Years of 2,5-Imino-2,5-dideoxy-imino-D-mannitol
(DMDP), Monatshefte für Chemie 133 (2002) 393-426.
[3] A.Welter, J. Jadot, G. Dardenne, M. Marlier, J. Casimir, 2,5-Dihydroxymethyl 3,4-dihydroxypyrrolidine dans les
feuilles de Derris elliptica, Phytochemistry 15 (1976) 747-749, https://doi.org/10.1016/S0031-9422(00)94435-2.
[4] S.V. Evans, L.E. Fellows, T.K.M. Shing, G.W. Fleet, Glycosidase inhibition by plant alkaloids which are structural
analogues of monosaccharides, Phytochemistry 24 (1985) 1953-1955, https://doi.org/10.1016/S0031-
9422(00)83099-X.
[5] R.J. Nash, E.A. Bell, J.M. Williams, 2-Hydroxymethyl-3,4-dihydroxypyrrolidine in fruits of Angylocalyx
boutiqueanus, Phytochemistry 24 (1985) 1620-1622.
[6] Review: 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,
https://doi.org/10.1002/ejoc.200901320.
[7] T. Yamashita, K. Yasuda, H. Kizu, Y. Kameda, A.A. Watson, R. Nash, New Polyhydroxylated Pyrrolidine,
Piperidine, and Pyrrolizidine Alkaloids from Scilla sibirica, J. Nat. Prod, 65 (2002), , 1875-1881,
https://doi.org/10.1021/np020296h.
[8] R.E. Lee, M.D. Smith, R.J. Nash, R.C. Griffiths, M. McNeil, R.K. Grewal, W. Yan, G.S. Besra, P.J.Brennan, G.J.W.
Fleet, Inhibition of UDP-Gal Mutase and Mycobacterial Galactan Biosynthesis by Pyrrolidine Analogues of
Galactofuranose Tetrahedron Lett 38. (1997) 6733-6736, https://doi.org/10.1016/S0040-4039(97)01539-6.
[9] S. Desvergnes, V. Desvergnes, O.R. Martin, K. Itoh, H. Liucand, S. Py, Stereoselective synthesis of β-1-C-
substituted 1,4-dideoxy-1,4-imino-d-galactitols and evaluation as UDP-galactopyranose mutase inhibitors, Bioorg.
Med. Chem. 15 (2007) 6443–6449, https://doi.org/10.1016/j.bmc.2007.06.059.
[10] L. Guazzelli, F. D'Andrea, S. Sartini, F. Giorgelli, G. Confini, L. Quattrini, I. Piano, C. Gargini, C. La Motta,
Synthesis and investigation of polyhydroxylated pyrrolidine derivatives as novel chemotypes showing dual activity
as glucosidase and aldose reductase inhibitors Bioorganic Chemistry 92 (2019), 103298,
https://doi.org/10.1016/j.bioorg.2019.103298.
[11] G. Righi, E. Mandic, C. Sappino, E. Dema, P. Bovicelli, Asymmetric routes toward polyhydroxylated pyrrolidines:
Synthesis of 1,4-dideoxy-1,4-imino-d-galactitol and 1,4-dideoxy-1,4-imino-d-glucitol Carb. Res, 435 (2016) 100-
105, https://doi.org/10.1016/j.carres.2016.09.018.
[12] a) S. Katsuhiko, N. Tatsuto, K.Osamu, 3,4-Dihydroxypyrrolidine as Glycosidase Inhibitor, Curr. Top. Med.
Chem. 9 (2009) 34-57. https://doi.org/10.2174/156802609787354315 b) I. Lundt, R. Madsen, S.A. Daher, B.
Winchester, Deoxyiminoalditols from aldonolactones. III. Preparation of 1,4-dideoxy-1,4-imino-L-gulitol. -

Evaluation of 1,4-dideoxy-1,4-iminohexitols as glycosidase inhibitors Tetrahedron, 50 (1994) 7513-7520,
https://doi.org/10.1016/S0040-4020(01)90479-X.
[13] H. Sun,K.A. Abboud, N.A. Horenstein, A new route into hexahydro-cyclopenta[b]pyrrole-cis-3a,6-diols. Synthesis
of constrained bicyclic analogues of pyrrolidine azasugars, Tetrahedron 61 (2005) 10462–10469,
https://doi.org/10.1016/j.tet.2005.08.055.
[14] R. Fu, Y. Du, Z.-Y. Li,W.-X. Xu, P.Q. Huang, Asymmetric syntheses of 6-deoxyfagomin, d-
deoxyrhamnojirimycin,
and
d-rhamnono-1,5-lactam,
Tetrahedron
65
(2009)
9765–9771,
https://doi.org/10.1016/j.tet.2009.09.083.
[15] a) I. Lundt, R. Madsen, Deoxyiminoalditols from Aldonolactones; II. Preparation of 1,4-Dideoxy-1,4-
iminohexitols with D- and L-Galacto and D- and L-Ido Configuration: Potential Glycosidase Inhibitors, Synthesis 7
(1993) 720-724, DOI: 10.1055/s-1993-25928.
[16] H. Takamura, T. Kikuchi, K. Iwamoto, E. Nakao, N. Harada, T. Otsu, N. Endo, Y.-W. Guo, I. Kadota, Unified
Total Synthesis, Stereostructural Elucidation, and Biological Evaluation of Sarcophytonolides, J. Org. Chem. 83
(2018) 11028 – 11056, https://doi.org/10.1021/acs.joc.8b01634.
[17] W.R. Roush, J.A. Straub, M.S. van Nieuwenhze, A stereochemically general synthesis of 2-deoxyhexoses via the
asymmetric allylboration of 2,3-epoxy aldehydes, J. Org. Chem, 56 (1991) 1636-1648,
https://doi.org/10.1021/jo00004a053.
[18] K. Ueda, Y. Okado, K. Shigetomi, M. Ubukata, Novel autophagy modulators: Design and synthesis of (+)-
epogymnolactam analogues and structure-activity relationship, Bioorg. & Med. Chem. 26 (2018) 5159 – 5168,
https://doi.org/10.1016/j.bmc.2018.09.013.
[19] J.M. Escudier, M. Baltas, L. Gorrichon, Diastereoface differentiation in addition of lithium enolates to chiral α,β-
epoxyaldehydes, Tetrahedron 49 (1993), 5253-5266, https://doi.org/10.1016/S0040-4020(01)82375-9.
[20] G. Righi, G. Pescatore, F. Bonadies, C. Bonini, A study on the chelation control in the regioselective opening of
2,3-bifunctionalized epoxides, Tetrahedron 57 (2001) 5649-5656, https://doi.org/10.1016/S0040-4020(01)00492-6.
[21] G. Righi, E. Mandic’, I. Tirotta, G.C.M. Naponiello, C. Sappino, C. Marucci, M. Tomei, P. Bovicelli,
Stereoselective synthesis of (+)-1-deoxyaltronojirimycin, Nat. Prod. Res 30. (2016) 1655-1660,
https://doi.org/10.1080/14786419.2015.1131983.
[22] Y. Gao, R.M. Hanson, J.M. Klunder, S.Y. Ko, H. Masamune, K.B. Sharpless, Catalytic asymmetric epoxidation
and kinetic resolution: modified procedures including in situ derivatization, J. Am. Chem. Soc. 109 (1987) 5765-
5780, https://doi.org/10.1021/ja00253a032.
[23] B. Wölfl, G. Mata, A. Fürstner, Total Synthesis of Callyspongiolide, Part 2: The Ynoate Metathesis/cis Reduction
Strategy, Chemistry - A European Journal 25 (2019) 255-259, https://doi.org/10.1002/chem.201804988.

The first stereocontrolled total synthesis of iminosugar 1,4-dideoxy-1,4-imino-D-iditol is described.
The key step was the asymmetric dihydroxylation (AD) of suitable optically active vinyl azido
alcohol. In particular using (DHQD)2AQN as chiral ligand it was possible to realise the
stereodivergent synthesis of 1,4-dideoxy-1,4-imino-D-iditol and 1,4-dideoxy-1,4-imino-D-
galactitol,
iminosugars with promising chemotherapeutic properties.

Declaration of interests
☒ 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: