Stereoselective synthesis of (+)-1-deoxyaltronojirimycin

Article abstract of DOI:10.1080/14786419.2015.1131983

A stereocontrolled, facile and high-yield approach for producing (+)-altroDNJ, has been developed starting from the inexpensive commercial cis 2-butene-1,4-diol. Sharpless epoxidation and a subsequent dihydroxylation were used for the introduction of all

Full text of DOI:10.1080/14786419.2015.1131983

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
Stereoselective synthesis of (+)-1-
deoxyaltronojirimycin
Giuliana Righi, Emanuela Mandic’, Ilaria Tirotta, Gaia Clara Mercedes
Naponiello, Carla Sappino, Cristina Marucci, Michela Tomei & Paolo Bovicelli
To cite this article: Giuliana Righi, Emanuela Mandic’, Ilaria Tirotta, Gaia Clara Mercedes
Naponiello, Carla Sappino, Cristina Marucci, Michela Tomei & Paolo Bovicelli (2016):
Stereoselective synthesis of (+)-1-deoxyaltronojirimycin, Natural Product Research, DOI:
10.1080/14786419.2015.1131983
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Date: 23 March 2016, At: 18:04

Natural Product research, 2016
http://dx.doi.org/10.1080/14786419.2015.1131983
Stereoselective synthesis of (+)-1-deoxyaltronojirimycin
Giuliana Righia, Emanuela Mandic’b‡, Ilaria Tirottab, Gaia Clara Mercedes Naponiellob,
Carla Sappinob, Cristina Maruccib, Michela Tomeib and Paolo Bovicellia
b
adepartment of chemistry, cNr-IBPM, sapienza university of rome, rome, Italy; department of chemistry,
sapienza university of rome, rome, Italy
ARTICLE HISTORY
ABSTRACT
received 24 July 2015
accepted 3 december 2015
A stereocontrolled, facile and high-yield approach for producing
(+)-altroDNJ, has been developed starting from the inexpensive
commercial cis 2-butene-1,4-diol. Sharpless epoxidation and a
subsequent dihydroxylation were used for the introduction of all
stereocentres; finally, the ring closure under basic conditions afforded
the piperidine heterocycle.
KEYWORDS
Iminosugar; stereoselective
synthesis; heterocycles;
dihydroxylation;
1-deoxyaltronojirimycin
HCl
H
OH
COOMe
N
O
HO
HO
O
HO
OH
TBDPSO
TBDPSO
COOCH3
OH
OH
OH
(+)-1-deoxyaltronojirimycin
hydrochloride
1. Introduction
Iminosugars, carbohydrate analogues in which the endocyclic oxygen is replaced by a nitro-
gen atom, are nowadays 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 (e.g. HIV, hepatitis B and C) (Compain & Martin 2007).
Usually the main problem is the lack of selectivity towards the target enzyme, causing
several adverse effects. In order to increase the binding affinity to a particular substrate,
many studies have been carried out and several different substitution patterns have been
designed and tested. The understanding of the complicated metabolism of glycoconjugates
is a challenge for modern medicine and will allow to design iminosugars specific for a par-
ticular molecular target.
Two different derivatives of 1-deoxynojirimicin are currently in the market: miglitol
(Glyset®), a drug for treating type II diabetes mellitus (Fattorusso & Scafati 2008) and miglustat
(Zavesca®) used for the treatment of Gaucher desease (Cox et al. 2000) (Figure 1).
CONTACT Giuliana righi
giuliana.righi@cnr.it
‡this author contributed equally to this work.
supplemental data for this article can be accessed at http://dx.doi.org/10.1080/14786419.2015.1131983.
© 2016 taylor & Francis

2
G. RIGHI ET Al.
Figure 1. 1-deoxynojirimycin and several of its derivatives.
Herein we wish to describe a new route to (+)-1-deoxyaltronojirimycin, a nojirimicin
analogue having altrose stereochemistry (Figure 1), isolated from Angylocalyxpynaertii
(leguminosae) (Asano et al. 2001) and endowed with modest glycosidase inhibition activ-
ity (Kato et al. 2005)
2. Results and discussions
Some of the already reported syntheses of deoxynojirimycin and its various isomers (Compain
& Martin 2007) employ chiral pool as starting material: carbohydrates as D-glucose derived
(Dhavale et al. 2004), amino acids as the Garner aldehyde (Karjalainen & Koskinen 2011;
Singh et al. 2014) or pyroglutamic acid (Ikota et al. 1997).
Other approaches are based on total synthesis starting from open chain precursors,
achieving the goal through chemoenzymatic methods (van den Nieuwendijk et al. 2012;
Soler et al. 2014), or through racemic resolution (Bagal et al. 2010) or asymmetric reaction
such as asymmetric dihydroxylation (Somfai et al. 2003) or asymmetric aminohydroxylation
(Singh & Han 2003; Chacko & Ramapanicker 2015).
Our approach, based on both our experience on stereo and regiocontrolled opening of
oxirane ring (Antonioletti et al. 2000; Righi et al. 2011) and the results we recently obtained
on dihydroxylation reaction of optically active trans α,β-unsaturated epoxy esters (Righi et
al. 2012), starts from a suitable optically active 2,3-epoxy alcohol 2, easily obtained from the
commercially available cis 2-butene-1,4-diol (Roush et al. 1991).
The oxidation to aldehyde of epoxy alcohol 2 followed by a Horner–Emmons reaction
afforded the corresponding trans α,β-unsaturated epoxy ester 4, substrate of choice for the
dihydroxylation reaction (Scheme 1).
Osmium-catalysed dihydroxylation of 4 provided a diastereomeric mixture (60:40 dr)
of chromatographically inseparable epoxy diols 5A and 5B in nearly quantitative yield
(VanRheenen et al. 1976, Scheme 2). The ratio has been calculated by integration of the
1
signals of the CHOH in α of the ester moiety on the H NMR spectra of the crude mixture.
The correct stereochemistry was assigned comparing the data of the final iminosugar with
those reported in literature (Singh & Han 2003; van den Nieuwendijk et al. 2012).
In order to protect the diolic moieties and to achieve a simpler separation, the mixture
of 5A and 5B was transformed in the corresponding acetonides (Hermitage et al.1998).
Unfortunately, also 6A and 6B proved to be extremely difficult to separate and consequently
the subsequent opening with azide of the epoxide ring was performed on the diastereomeric
mixture.

NATURAl PRODUCT RESEARCH
3
Scheme 1. (a)teMPo (2,2,6,6-tetramethylpiperidinyloxy), IBda (iodobenzene I,I-diacetate), ch2cl2, rt, 2 h;
(b) lioh, tMPa (trimethylphosphonoacetate), thF, 70 °c, 77% from 2.
Scheme 2. (a) oso4, NMo(N-methylmorpholine-N-oxide), acetone/h2o 8:1, rt, >95% (60:40 dr).
Scheme 3. (a) dMP (2,2-dimethoxypropane), ptsoh, acetone, rt; (b) NaN3, Nh4cl, Meoh, 70 °c, 58%
7A + 7B from 4, 31% of isolated 7A).
The regioselectivity of the attack is hardly predictable, as the epoxide ring is functionalised
with two ether moieties. However, the use of the system NaN3/NH4Cl in methanol at 70 °C
(Behrens et al. 1985) led exclusively to the attack on C-5 (Scheme 3).
After this reaction, the major diastereomer 7A was isolated via chromatographic puri-
fication, while 7B was obtained only as mixture with 7A. Consequently, from this step the
synthesis was carried out only from 7A.
Hydrogenation of azido derivative 7A in the presence of ditert-buthyldicarbonate afforded
carbamate 8. The free alcoholic moiety was then protected as tert-buthyldimethylsilyl ether
in 80% yield from 7A, followed by the nearly quantitative reduction of the ester to alcohol 10.
After mesylation of the just obtained alcoholic function, the ring closure was accomplished
with potassium tert-butoxide (Wang & liu 2009), giving the totally protected (+)-1-deoxyal-
tronojirimicin 12 in good yield (Scheme 4).
Finally, the total deprotection was achieved by treatment with 37% HCl aq. in methanol at
70 °C (Somfai et al. 2003), affording the (+)-1-deoxyaltronojirimicin in nearly quantitative
yield (Scheme 5).

4
G. RIGHI ET Al.
Scheme 4. (a) h2, Pd/c 10%, (Boc)2o, acoet, rt, 1 atm; (b) tBdMsotf (tert-butyldimethylsilyltrifluorom
ethanesulfonate), 2,6-lutidine, ch2cl2, rt, 80% from 7A; (c) NaBh4, thF/h2o 10:1, 0 °c, rt, 94%; (d) Mscl,
et3N, dMaP, ch2cl2, rt; (e) t-BuoK, thF, 0 °c, rt, 62% from 10.
Scheme 5. (a) 37% hcl aq, Meoh, 70 °c, 92% yield.
3. Conclusions
In summary, through stereocontrolled, facile and high-yield reactions, we have developed
a new approach for producing (+)-altroDNJ hydrochloride starting from the inexpensive
commercial cis 2-butene-1,4-diol. Moreover, even if the number of steps is comparable to
that of some already reported syntheses, in our sequence only few chromatographic puri-
fications were required, making the route accessible and efficient.
It is noteworthy that, the regio and stereoselective control of the key steps allows achieve-
ment of the enantiomer (−)-1-deoxyaltronojirimicin simply using (−)-DET instead of (+)-DET
in the Sharpless asymmetric epoxidation, following the same synthetic pathway.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by the MIUR (Ministry of Universityand Research – Rome) [grant number
PRIN 2010–2011: Design and stereoselective synthesis of compounds active towards proteic targets
involved in viral and tumoural pathologies]; MIUR in the framework of the [grant number Flagship
Project NanoMAX].

NATURAl PRODUCT RESEARCH
5
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