Synthesis of 1-deoxy-l-gulonojirimycin and 1-deoxy-l-talonojirimycin

Article abstract of DOI:10.1016/j.tetlet.2009.02.111

De novo synthesis of noncompetitive glycosidase inhibitors l-gulo-DNJ and l-talo-DNJ has been achieved in 9-10 steps starting from Garner's aldehyde. Key to the success of this procedure was the construction of the 2,3-unsaturated piperidine 14, which syn

Full text of DOI:10.1016/j.tetlet.2009.02.111

Tetrahedron Letters 50 (2009) 2045–2047
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Synthesis of 1-deoxy-L-gulonojirimycin and 1-deoxy-L-talonojirimycin
*
Annalisa Guaragna, Daniele D’Alonzo , Concetta Paolella, Giovanni Palumbo
Dipartimento di Chimica Organica e Biochimica, Università di Napoli Federico II, via Cinthia, 4 I-80126 Napoli, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
De novo synthesis of noncompetitive glycosidase inhibitors L-gulo-DNJ and L-talo-DNJ has been achieved
Received 16 December 2008
Revised 5 February 2009
Accepted 10 February 2009
Available online 21 February 2009
in 9–10 steps starting from Garner’s aldehyde. Key to the success of this procedure was the construction
of the 2,3-unsaturated piperidine 14, which syn dihydroxylation under Kishi’s and Donohoe’s conditions
led to the desired iminosugars.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
L
-Iminosugars
Polyhydroxylated piperidines
Glycosidase inhibitors
Dihydroxylation
Iminosugars (sugar analogues having the endocyclic oxygen re-
placed with nitrogen) undoubtedly represent one of the most
attractive classes of carbohydrate mimetics.1 The great deal of
attention developed around iminosugars lies in their powerful
inhibitory aptitude towards carbohydrate processing enzymes,
that is, glycosidases2 and glycosyltransferases.3 As these enzymes
are involved in a plethora of key biochemical events, such as diges-
tion, lysosomal catabolism of glycoconjugates and post-transla-
tional glycoprotein processing, the significant inhibitory
properties of iminosugars, such as deoxynojirimycin (DNJ, 1,
Fig. 1) and its derivatives, make them excellent candidates for
medical intervention, ranging from antidiabetics4 and antivirals5
to agents devoted to the treatment of genetic disorders.6 In search
of such molecules, considerable efforts have been devoted to the
synthesis of -DNJ (ent-1) (Fig. 1) and its congeners.
In spite of the great amount of routes leading to one or some
piperidines, just a few of them can claim to be applied to the con-
struction of most
-epimers.12 In this context, in a previous report
we had developed a general procedure13 for the synthesis of 1-
deoxy- -iminopyranoses by a non-carbohydrate-based route; as
proof of it, iminosugars belonging to -manno-, -altro- and -allo-
configuration (2–4, Fig. 2) were prepared in high yields and stere-
oselective fashion. In order to widen this strategy, access to -gul-
oDNJ (5) and -taloDNJ (6) (Fig. 2) has been examined in this Letter.
L
L
-
L
L
L
L
L
L
L
We began our synthesis with the coupling reaction of enol thi-
oether14 7 with the Garner’s aldehyde 8 in the presence of BuLi at
ꢀ78 °C (Scheme 1), to achieve a mixture of diastereomers 9 (syn/
for new, more efficient and selective inhibitors,
rently represent a significant breakthrough,7 especially regarding
glycosidase inhibition. Deep interference by -iminosugars has
been found against
-glycosidases8 (i.e., fucosidases and rhamno-
sidases), this behaviour being related to their structural similarity
with the natural substrates ( -fucose and -rhamnose) of the corre-
sponding enzymes. Remarkably, activity has also been extended to
glycosidases belonging to -series, often displaying considerably
selective as well as potent inhibition.9 Recent studies into the ac-
tion mechanism of -glycosidase inhibition have revealed that
some -iminosugars, especially pyrrolidines, are able to mimic
the conformation of natural -hexose substrates, by virtue of their
high structural flexibility.10 On the other hand, activity of the more
L-iminosugars cur-
anti, dr = 1:9) in good overall yield (72%). As already noticed,13
a
L
preference for the anti-adduct was found in anhydrous Et2O, as a
consequence of the poorly ionised nature of the organolithium
intermediate.15 On the other hand, no reversal stereoselection
was observed in other solvents (such as THF) or after addition of
several chelating16 catalysts [ZnBr2,Ti(O-i-Pr)4, Cp2TiCl2]. Thus, in
L
L
L
D
D
L
H
N
H
N
D
HO
HO
OH
OH
OH HO
rigid L-piperidines has been justified invoking a noncompetitive
mode of action.7,11 Driven by the intriguing therapeutic potential
OH
1
DNJ
OH
1
ent-
L-DNJ
mirror
* Corresponding author. Tel./fax: +39 081 674119.
E-mail address: dandalonzo@unina.it (D. D’Alonzo).
Figure 1. Deoxynojirimycin (1) and its enantiomer L-DNJ (2).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.111

2046
A. Guaragna et al. / Tetrahedron Letters 50 (2009) 2045–2047
H
N
H
N
H
N
S
NHBoc
OAc
1.80% AcOH, 50°C
2. Ac2O, Py, rt
HO
HO
HO
HO
HO
HO
S
syn-9
90% o.y.
OH
OH
OH
OAc
RO
OH
OH
OH
11 R = MPM
12 R = H
4
3
DDQ, CH2Cl2/H2O
rt, 95%
2
L
-altro-DNJ
L
-allo-DNJ
L
-manno-DNJ
H
N
Ag2O, TsCl
THF, 40 °C
H
N
68%
HO
HO
HO
OH
OH
HO
L
Boc
N
Boc
N
Ra-Ni
OH
OH
AcO
AcO
EtOH, 0°C
6
AcO
AcO
5
-talo-DNJ
S
L
-
-DNJ
gulo
68%
S
13
Figure 2. L-Iminosugars.
14
order to selectively obtain the adduct syn-9 (which is the suitable
precursor for -gulo and -taloDNJ synthesis), an oxidation/reduc-
Boc
Ra-Ni excess
EtOH, rt
N
L
L
AcO
AcO
tion procedure17 was preferred. sec-Alcohols 9 were treated with
in situ-generated PDC and Ac2O in CH2Cl2 at room temperature,
affording ketone 10 (Scheme 1). Then, reduction of 10 with sodium
borohydride proceeded with full stereoselectivity, giving alcohol
syn-9 as the only diastereomer (73% yield over two steps).
Next, alcohol syn-9 was converted into its diacetate 11 by oxa-
zolidine ring opening (80% aq AcOH) and subsequent acetylation
(90% o.y.) (Scheme 2). MPM group removal (DDQ) of 11 furnished
the primary alcohol 12 in very good yield (95%). Tosylation of pri-
mary hydroxyl group (Ag2O/TsCl) followed by in situ intramolecu-
lar attack on tosylate intermediate18 by the amino group gave
piperidine 13 (68% yield). Finally, removal of dithioethylene bridge
of 13 (Raney-Ni) led to olefin 14 (68% yield). As previously reported
for similar substrates,13,19 when the desulfurisation reaction was
carried out with a Raney-Ni excess (or for prolonged reaction
times), the over-reduction product was obtained in a satisfying
83% yield, affording the 1,2,3-trideoxy iminosugar derivative 15
(Scheme 2).
83%
15
Scheme 2. Preparation of unsaturated L-piperidine 14.
Kishi's
osmylation
14
R = Ac
RO
NBoc
RO
Donohoe's
osmylation
16 R = H
Scheme 3. Prevision of the stereoselective outcome of dihydroxylation reaction
under Kishi’s or Donohoe’s conditions.
starting from the deprotected allylic alcohol 16, using the Dono-
hoe’s conditions22 (OsO4/TMEDA), which usually take place as a
consequence of the hydrogen bond formation between the allylic
OH group of 16 and the incoming OsO4 reagent (Scheme 3).
Thus, treatment of the diacetate 14 with OsO4/NMO in t-BuOH/
acetone followed by acetylation of the crude residue afforded
With the key unsaturated piperidine 14 in our hand, access to
desired iminosugars was planned by an appropriate choice of the
conditions for double-bond syn dihydroxylation (Scheme 3). Partic-
ularly, osmylation under Kishi’s conditions20 (OsO4/NMO) (which
is driven by steric factors) is expected to occur from the less hin-
dered face of the olefin,21 leading to the iminosugar with
configuration. On the other hand, since access to
L-gulo-
exclusively the L-guloDNJ derivative 17. Exposure of 17 to refluxing
L
-taloDNJ is ham-
aq 6 N HCl furnished the pure 1-deoxy-
an excellent 91% yield (Scheme 4).
L
-gulonojirimycin (5)23 in
pered by the difficulty to carry out osmylation from the same side
of the allylic acetoxy group, synthesis of the latter was envisaged,
Subsequently, acetyl groups of olefin 14 were removed under
common Zemplén conditions, affording diol 16. The latter was then
treated with stoichiometric OsO4 and TMEDA in CH2Cl2 at ꢀ78 °C,
BocN
O
OHC
S
S BocN
OH
1. OsO4/NMO
t-BuOH/Acetone
2. Ac2O/Py
Boc
N
8
O
S
S
H
AcO
AcO
14
BuLi, Et 2O, -78 °C
72% yield
MPMO
7
MPMO
OAc
83% o.y.
9
OAc
syn/anti = 1:9
[ref. 13]
17
CrO3/Py, Ac 2O
80%
CH2Cl2 yield
.HCl
H
6M aq HCl
reflux
N
HO
S BocN
91%
OH
HO
S
BocN
OH
O
S
OH
O
S
NaBH4, MeOH
5.
O
HCl
MPMO
91% yield
10
MPMO
L-gulo-DNJ
syn
-9
Scheme 4. Osmylation of 14 under Kishi’s conditions.
Scheme 1. Synthesis of sec-alcohol syn-9.

A. Guaragna et al. / Tetrahedron Letters 50 (2009) 2045–2047
2047
tured that entry of OsO4/TMEDA is hampered by the presence of
t-butoxycarbonyl group in the 5HN conformation, and by the axi-
ally oriented C-6 methylene group when 16 adopts the NH5 confor-
mation (Scheme 6).
Boc
N
RO
RO
MeONa/MeOH 14 R = Ac
In summary, in this Letter, we have outlined a synthetic path for
16 R = H
quant.
the preparation of non-naturally occurring
oDNJ (6). Studies aimed to obtain the remaining deoxyiminopyra-
noses belonging to -series by anti-dihydroxylation reactions of
L-guloDNJ (5) and L-tal-
OsO4/TMEDA
flash
CH2Cl2 chromatography
L
56%
38%
olefins 14 and 16 are ongoing and will be published in due course.
Boc
N
Boc
N
References and notes
HO
HO
HO
HO
1. Compain, P.; Martin, O. R. Iminosugars—From Synthesis to Therapeutic
Applications; John Wiley & Sons Ltd: West Sussex England, 2007.
2. Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515–553.
3. (a) Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001, 9, 3077–3092; (b)
Compain, P.; Martin, O. R. Curr. Top. Med. Chem. 2003, 3, 541–560.
4. Asano, N. Glycobiology 2003, 13, 93R–104R.
O
O
Os
N
O
O
O
Os
O
N
N
O
O
18
N
19
5. Pavlovic, D.; Neville, D. C.; Argaud, O.; Blumberg, B.; Dwek, R. A.; Fischer, W. B.;
Zitzmann, N. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 6104–6108.
6. (a) Butters, T. D.; Dwek, R. A.; Platt, F. M. Glycobiology 2005, 15, 43R–52R; (b)
Butters, T. D. Curr. Opin. Chem. Biol. 2007, 11, 412–418.
quant.
quant.
aq 6N HCl
aq 6N HCl
7. D’Alonzo, D.; Guaragna, A.; Palumbo, G. Curr. Med. Chem. 2009, 16, 473–505.
8. (a) Wu, C.-Y.; Chang, C.-F.; Chen, J. S.-Y.; Wong, C.-H.; Lin, C.-H. Angew. Chem.,
Int. Ed. 2003, 42, 4661–4664; (b) Chang, C.-F.; Ho, C.-W.; Wu, C.-Y.; Chao, T.-A.;
Wong, C.-H.; Lin, C.-H. Chem. Biol. 2004, 11, 1301–1306.
9. See, for example: Yu, C.-Y.; Asano, N.; Ikeda, K.; Wang, M.-X.; Butters, T. D.;
Wormald, M. R.; Dwek, R. A.; Winters, A. L.; Nash, R. J.; Fleet, G. W. J. Chem.
Commun. 2004, 1936–1937.
10. Carmona, A. T.; Popowycz, F.; Gerber-Lemaire, S.; Rodríguez-García, E.; Schütz,
C.; Vogel, P.; Robina, I. Bioorg. Med. Chem. 2003, 11, 4897–4911.
11. Asano, N.; Ikeda, K.; Yu, L.; Kato, A.; Takebayashi, K.; Adachi, I.; Kato, I.; Ouchi,
H.; Takahata, H.; Fleet, G. W. J. Tetrahedron: Asymmetry 2005, 16, 223–229.
12. Kato, A.; Kato, N.; Kano, E.; Adachi, I.; Ikeda, K.; Yu, L.; Okamoto, T.; Banba, Y.;
Ouchi, H.; Takahata, H.; Asano, N. J. Med. Chem. 2005, 48, 2036–2044.
13. Guaragna, A.; D’Errico, S.; D’Alonzo, D.; Pedatella, S.; Palumbo, G. Org. Lett.
2007, 9, 3473–3476.
H
H
HCl
HCl
N
N
HO
HO
HO
HO
OH
OH
OH
5.HCl
OH
6 .HCl
L-talo-DNJ
L-gulo-DNJ
Scheme 5. Osmylation of 14 under Donohoe’s conditions.
14. Guaragna, A.; Pedatella, S.; Palumbo, G. In e-Encyclopedia of Reagents for Organic
Synthesis (e-EROS); Paquette, L. A., Ed.; John Wiley & Sons: New York, US, 2008.
15. Maercker, A.; Roberts, J. D. J. Am. Chem. Soc. 1966, 88, 1742–1759.
16. Liang, X.; Andersch, J.; Bols, M. J. Chem. Soc., Perkin Trans. 1 2001, 2136–2157.
17. Okamoto, N.; Hara, O.; Makino, K.; Hamada, Y. J. Org. Chem. 2002, 67, 9210–
9215.
18. The presence of tosylate intermediate has been ascertained as it can be easily
isolated by common chromatographic purification techniques.
19. D’Alonzo, D.; Guaragna, A.; Napolitano, C.; Palumbo, G. J. Org. Chem. 2008, 73,
5636–5639.
5HN
O
O
O
HO
H
NH5
N
N
O
O
H
O
O
O
O
O
O
Os
Os
O
HO
20. Cha, J. K.; No-Soo, K. Chem. Rev. 1995, 95, 1761–1795.
21. See, for example: Guaragna, A.; Napolitano, C.; D’Alonzo, D.; Pedatella, S.;
Palumbo, G. Org. Lett. 2006, 8, 4863–4866.
N
O
O
N
N
N
22. Donohoe, T. J. Synlett 2002, 1223–1232.
ꢀ2.5 (c 0.5 MeOH); 1H NMR (500 MHz, D2O) d
Scheme 6. Proposed NH5 and 5HN conformers for olefin 16.
23. Data for compound 5ꢁHCl: ½a D
ꢂ
3.13 (t, J = 12.2 Hz, 1H), 3.31 (dd, J = 4.8, 12.2 Hz, 1H), 3.55–3.59 (ddd, J = 1.5,
4.4, 9.3 Hz, 1H), 3.82 (dd, J = 9.3, 12.2 Hz, 1H), 3.91 (dd, J = 4.4, 12.2 Hz, 1H),
4.07 (dd, J = 3.0, 4.8 Hz, 1H), 4.16 (dd, J = 1.5, 4.8 Hz, 1H), 4.26 (ddd, J = 3.0, 4.9,
11.7 Hz, 1H). 13C NMR (125 MHz, D2O) d 42.4, 55.5, 59.0, 62.6, 67.2, 68.5. Anal.
Calcd for C6H13NO4: C, 44.16; H, 8.03; N, 8.58. Found: C, 43.89; H, 7.87; N, 8.70.
24. Donohoe, T. J.; Blades, K.; Moore, P. R.; Waring, M. J.; Winter, J. J. G.; Helliwell,
M.; Newcombe, N. J.; Stemp, G. J. Org. Chem. 2002, 67, 7946–7956.
affording a mixture of L-gulo- and L-taloDNJ derivatives 18 and 19
(dr = 6:4), which can be separated by flash chromatography
(CHCl3/MeOH, 8:2). Hydrolysis of osmate esters 18 and 19 along
with removal of N-Boc protection using aq 6 N HCl24 furnished
+22.0 (c 0.5 MeOH); 1H NMR (400 MHz, D2O) d
deoxy-
a very good 93% overall yield (Scheme 5).
L-gulonojirimycin (5) and deoxy-L
-talonojirimycin (6)25 in
25. Data for compound 6ꢁHCl: ½a D
ꢂ
3.10 (dd, J = 1.6, 13.6 Hz, 1H), 3.24 (dt, J = 1.8, 6.7 Hz, 1H), 3.35 (dd, J = 2.8,
13.6 Hz, 1H), 3.65–3.74 (m, 3H), 3.99–4.04 (m, 1H), 4.02–4.08 (m, 1H). 13C NMR
(100 MHz, D2O) d 50.4, 61.1, 62.5, 68.7, 69.2, 69.9. Anal. Calcd for C6H13NO4: C,
44.16; H, 8.03; N, 8.58. Found: C, 44.45; H, 8.10; N, 8.39.
In our opinion, the low level of selectivity observed above could
be due to the difficulty in the access of the incoming OsO4/TMEDA
complex to the syn face of allylic alcohol 16. Indeed, even though
NMR data suggest that olefin 16 exists as a mixture of conformers
(presumably corresponding to NH5 and 5HN),26 it can be conjec-
26. 1H NMR (500 MHz, CD3OD) d 1.47 (s, 4.5H), 1.48 (s, 4.5H), 3.47–3.60 (m, 1H),
3.51 (br t, J = 10.8 Hz, 1H), 3.81 (br dd, J = 11.2, 3.3 Hz, 1H), 4.09–4.12 (m, 0.5H),
4.15–4.18 (m, 0.5H), 4.40 (br s, 1H), 4.54 (br s, 1H), 5.63 (br d, J = 10.2 Hz, 1H),
5.64–5.75 (m, 1H).