Synthesis of 1,2- trans -2-Acetamido-2-deoxyhomoiminosugars

Article abstract of DOI:10.1021/ol502929h

The first synthesis of 1,2-trans-homoiminosugars devised as mimics of I-d-GlcNAc and I-d-ManNAc is described. Key steps include a regioselective azidolysis of a cyclic sulfite and a I-amino alcohol skeletal rearrangement applied to a polyhydroxylated azep

Full text of DOI:10.1021/ol502929h

Letter
pubs.acs.org/OrgLett
Synthesis of 1,2-trans-2-Acetamido-2-deoxyhomoiminosugars
Yves Bleriot,*,† Anh Tuan Tran,‡ Giuseppe Prencipe,‡ Yerri Jagadeesh,† Nicolas Auberger,† Sha Zhu,‡
́
Charles Gauthier,† Yongmin Zhang,‡ Jerome Desire,† Isao Adachi,§ Atsushi Kato,§
́
̂
́
́
and Matthieu Sollogoub*,‡
†Glycochemistry Group of “Organic Synthesis” Team, Universite
́ ̂
de Poitiers, UMR-CNRS 7285 IC2MP, Bat. B28, 4 rue Michel
Brunet, TSA 51106, 86073 Poitiers Cedex 9, France
‡Sorbonne Universites
́
, UPMC Univ Paris 06, Institut Universitaire de France, UMR-CNRS 8232, IPCM, LabEx MiChem, F-75005
Paris, France
§Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
S
* Supporting Information
ABSTRACT: The first synthesis of 1,2-trans-homoiminosu-
gars devised as mimics of β-D-GlcNAc and α-D-ManNAc is
described. Key steps include a regioselective azidolysis of a
cyclic sulfite and a β-amino alcohol skeletal rearrangement
applied to a polyhydroxylated azepane. The β-D-GlcNAc
derivative has been coupled to serine to deliver an iminosugar
C-amino acid. The two homoiminosugars demonstrate moderate glycosidase inhibition.
lycosidase inhibitors are enjoying much interest as they
selectivity, have mainly focused on the functionalization of the
G
find applications in an increasing number of therapies.1
endocyclic nitrogen,16 the ring hydroxyl groups,17 or the
acetamido group.18 Introduction of a stereochemically defined
and chemically stable pseudoanomeric substituent cis to the C-2
substituent of the piperidine ring has been achieved and could
constitute a promising alternative.19 We would like to report
herein, and in parallel to our previous paper, a synthetic
strategy allowing access to the complementary 1,2-trans homo-
2-acetamido-1,2-dideoxy iminosugars, illustrated by the syn-
thesis of β-homo-2-acetamido-1,2-dideoxynojirimycin (β-
HNJNAc, 11) and α-homo-2-acetamido-1,2-dideoxy-mannojir-
imycin (α-HMJNAc, 12) (Figure 1).
Hexosaminidases that trim N-acetyl-β-D-glucosamine (GlcNAc)
from glycoconjugates are of high therapeutic interest, being
involved in several human pathologies including allergy,2
osteoarthritis,3 Parkinson’s4 and Alzheimer’s5 diseases. Imino-
sugars, i.e. sugars analogues in which the endocyclic oxygen has
been replaced by nitrogen, constitute the most promising class
of glycosidase inhibitors. Among the most potent β-
hexosaminidase inhibitors, we can mention the naturally
occurring pochonicine (1),6 siastatin B (2),7 nagstatin (3),8
the synthetic pyrrolidines LABNAc (4),9 ADMDP-acetamide
(5),10 polyhydroxylated proline amide 6,11 azepane (7),12 and
piperidines such as IFGNAc (8),13 DNJNAc (9),14 and
DGJNAc (10)15 (Figure 1). Introduction of structural diversity
in compounds 9 and 10, to possibly increase their potency and
The ring isomerization of seven-membered polyhydroxylated
azacycles constitutes one strategy among many others to
generate new or known piperidine iminosugars.20 This
transformation, based on a β-aminoalcohol rearrangement,21
requires a free alcohol at the β position and exploits the
anchimeric assistance of the nitrogen. Access to 1,2-trans 2-
acetamido-2-deoxy-homoiminosugars using this approach re-
quires the preliminary trans introduction of OH and N3
functionalities at the respective β and γ positions of the
azepane ring. Epoxide azidolysis appears to be a suitable route
toward this goal. Epoxidation of known azacycloheptene 13
(see our previous paper) was thus studied (Scheme 1). While
m-CPBA-, oxone-, or H2O2-mediated oxidation gave dis-
appointing results, the procedure developed by Shi22 furnished
the 3R,4R epoxide 14 in an acceptable 54% yield. The
stereochemistry of the oxirane ring in 14 was established by
comparing the 1H NMR coupling constants for the protons H-
3, H-4, and H-5 that matched those obtained for the
Received: October 3, 2014
Published: October 20, 2014
Figure 1. Structure of iminosugars 1−12.
© 2014 American Chemical Society
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Organic Letters
Letter
Scheme 1. Synthesis of Azido Alcohols 16−19
Table 1. Dihydroxylation of Azacycloheptene 13
24:25
a
entry
conditions
ratio
1
2
3
4
5
6
7
OsO4, acetone/H2O
α-AD-mix, t-BuOH/H2O
2:1
1.5:1
2.5:1
2.9:1
1:1.4
1:1.5
1:1.9
b
modified SAD, 0.05 equiv of ligand I, t-BuOH/H2O
b
modified SAD, 0.2 equiv of ligand I, tBuOH/H2O
β-AD-mix, t-BuOH/H2O
b
modified SAD, 0.05 equiv of ligand II, t-BuOH/H2O
b
modified SAD, 0.2 equiv of ligand II, t-BuOH/H2O
a
The ratio of diols 24/25 was determined by 1H NMR by integrating
b
the protons of the Boc group. Ligand I = [(DHQ)2PHAL]; ligand II
= [(DHQD)2PHAL].
these diols were found to be difficult to separate on a large
scale, the mixture of diols obtained after dihydroxylation was
directly treated with thionyl chloride and Et3N to furnish the
separable sulfites 26 and 27 in an excellent 92% yield (Scheme
2). Because of the presence of a stereogenic sulfur atom, 26 and
27 were both obtained as a mixture of diastereoisomers that
were not separated and directly used in the next step.
corresponding N-Cbz epoxide derivative.24 Additionally, a
NOESY experiment supported a cis relationship for the H-4
and H-5 protons. In parallel, oxirane-mediated epoxidation
using CF3COCH3 furnished the diastereomeric 3S,4S epoxide
15 (51%) along with epoxide 14 (29%). Azidolysis of 14 using
NaN3 and NH4Cl in DMF/H2O at 90 °C afforded the required
trans azido alcohol 16 as the minor product (32%) along with
its regioisomer 17 (57%). Similar treatment of epoxide 15
furnished the azido alcohol 18 (52%) along with its regioisomer
19 (40%). Because of the presence of rotamers, the
stereochemistry of azido alcohols 16−19 was difficult to
elucidate by NMR. Their firm structure assignment was
achieved via their deprotection with TFA followed by
hydrogenolysis (H2, Pd/C, AcOH) to give the known
Scheme 2. Synthesis of Cyclic Sulfites 26 and 27
With the synthesis of β-HNJNAc (11) in mind, we took
advantage of the cyclic sulfite 27 to study its azidolysis (Scheme
3).28 Treatment of 27 with LiN3 (20% solution in water) at 130
°C provided the desired azido alcohol 16 (57%). A significant
amount of diol 25 (25%) was also recovered probably arising
from cyclic sulfite hydrolysis. Switching to neat NaN3 at 130 °C
furnished the required azido alcohol 16 in 80% yield (42% from
13) along with its regioisomer 17 (9%). Removal of the Boc
group in 16 with TFA followed by N-benzylation furnished the
N-benzyl azepane 28 (82% over two steps), which was
characterized by a large coupling constant between the trans
H-3 and H-4 protons (J = 9.5 Hz) and NOE contacts between
H-3 and H-5 and between H-4 and H-6. The β-amino alcohol
rearrangement of 28 under Mitsunobu conditions proved
unsatisfactory, affording the piperidine 29 in low yield. Use of
TFAA29 was beneficial as it furnished piperidine 29 in excellent
yield (93%) after ester hydrolysis. For this transformation, we
propose a mechanism (Scheme 4) in which the free alcohol in
28 is activated as its trifluoroacetate ester 30 and displaced by
the endocyclic nitrogen, generating a fused piperidine−
aziridinium ion 31. The released trifluoroacetate ion then
attacks the methylene carbon of the aziridinium ion and
displaces the ammonium group to furnish the piperidine 29
1
tetrahydroxylated aminoazepanes 20−23, the H NMR data
for which were in good agreement with the literature.23b The
observed regioselectivities for the azidolysis step are similar to
those reported in the case of a N-Cbz protecting group.23 While
the well-established Furst−Plattner principle24 of trans diaxial
̈
epoxide ring-opening usually furnishes major diastereoisomers
in the case of piperidines,25 the azepane ring flexibility can be
invoked here to explain the lack of regiocontrol during
azidolysis. On the basis of the disappointing results above
(17% yield for azido alcohol 16 and 26% yield for azido alcohol
18 from compound 13), we concluded that a second round of
optimization would be necessary to achieve synthetically useful
yields. We anticipated that protection of the corresponding 3,4-
cis diols as their cyclic sulfites26 could provide the synthetic
equivalent of an epoxide, possibly allowing the regioselective
introduction of an azide at the γ position. To this end, several
asymmetric dihydroxylation conditions were applied to 13 in
order to improve the modest level of diastereoselectivity
obtained in the case of OsO4-mediated dihydroxylation (Table
1).
1
The best conversion and diastereoselectivities were obtained
with the modified Sharpless asymmetric dihydroxylation (SAD)
method27 using AD-mix α and β, respectively, with 0.2 equiv of
ligand (entries 4 and 7) that afforded the bottom-face diol 24
and the top-face diol 25 in 65% and 58% yields, respectively. As
after ester hydrolysis. H NMR analysis of 29 (J1,2 = 10.0 Hz,
J3,4 = J4,5 = 8.0 Hz) confirmed its β-D-gluco configuration.
Conversion of the azide functionality into an acetamide under
standard conditions (PPh3, THF/H2O then Ac2O, py) gave the
crystalline diacetylated derivative 32 (61%), the crystal
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Organic Letters
Letter
To further exemplify our methodology, we synthesized a
mannose analogue, namely the α-homo-2-acetamido-1,2-
dideoxymannojirimycin (α-HMJNAc, 12). Azidolysis of the
cyclic sulfite 26 under the conditions depicted above furnished
the azido alcohol 18 in 45% yield (27% from 13) along with its
regioisomer 19 (46%). Replacement of the Boc group by the
electron-donating benzyl group yielded azepane 36, as
characterized by a small coupling constant between the cis H-
4 and H-5 protons (J = 1.5 Hz) and a correlation in the COSY
spectrum between H-3 and the free OH. Treatment of 36 with
TFAA in toluene at 110 °C yielded the piperidine 37 in 80%
yield after ester hydrolysis. Introduction of the acetamide group
in 37 uneventfully provided piperidine 38 in 83% yield. O-
Deacetylation followed by hydrogenolysis under mild acidic
conditions yielded the target α-HMJNAc 12. The trans
relationship between the NHAc function and the pseudoano-
meric CH2OH group is confirmed by a NOESY cross-
correlation between H-2 and H-7 (Scheme 5). NMR analysis
Scheme 3. Synthesis of β-HNJNAc 11 and Conjugate 35
Scheme 5. Synthesis of α-HMJNAc 12
Scheme 4. Proposed Mechanism for the Formation of
Piperidine 29 from 28
indicated that, in CD3OD, β-HNJNAc (11) adopts a β-glucose-
4
like C1-type conformation (J2,3 = 10.1 Hz, J3,4 = 8.8 Hz, J4,5
=
1
9.7 Hz) and α-HMJNAc (12) an inverted C4 chair (J2,3 = 3.5
Hz, J3,4 = 3.5 Hz, J4,5 = 3.5 Hz and H-6/H-1 NOESY cross-
correlation).
structure of which was solved (Figure 2). O-Deacetylation with
Et3N in MeOH followed by hydrogenolysis under mild acidic
The β-HNJNAc (11) and α-HMJNAc (12) were assayed on
a panel of β-N-acetylhexosaminidases from human placenta,
bovine kidney, HL-60, Jack bean, and Aspergillus oryzae and α-
N-acetylgalactosaminidase from chicken liver (Table 2).
Surprisingly, β-HNJNAc (11) is only a moderate inhibitor of
Table 2. Concentration (in μM) of Iminosugars 11 and 12
Giving 50% Inhibition of Various Glycosidases (IC50)
Figure 2. X-ray crystallography of compound 32 (CCDC 1015486).
enzyme
11
12
β-N-acetylhexosaminidase
human placenta
conditions furnished the target β-HNJNAc 11 (Scheme 3).30
To demonstrate the potential of these derivatives as
“iminosugar C-glycosyl donors”, homoiminosugar 29 was
coupled to the serine precursor 3331 to yield the corresponding
iminosugar amino acid precursor 34 after functional group
interconversion from azide to acetamide. Hydrogenolysis
followed by ester hydrolysis provided the homoiminosugar
amino acid 35 (Scheme 3).
72
302
624
394
95
bovine kidney
65
88
HL-60
Jack bean
41
a
Aspergillus oryzae
α-N-acetylgalactosaminidase chicken liver
NI
NI
NI
NI
a
NI: no inhibition (less than 50% inhibition at 1000 μM).
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Letter
Am. Chem. Soc. 2009, 131, 5390−5392. (c) Mondon, M.; Hur, S.;
β-N-acetylhexosaminidases. As expected, α-HMJNAc (12),
which displays a different configuration for two hydroxyl
groups compared to the parent gluco-configured substrate, is a
poor inhibitor of these enzymes.
In summary, the first synthesis of 1,2-trans homoiminosugars
derived from GlcNAc and ManNAc bearing a pseudoanomeric
CH2OH group is reported exploiting a β-amino alcohol
rearrangement applied to a seven-membered iminosugar. Use
of a cyclic sulfite derivative as an epoxide equivalent and its
azidolysis proved beneficial to access the azepane precursor
necessary for the ring-contraction step. This work has produced
novel structures that could be used as probes in the field of β-
N-acetylhexosaminidases.
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ASSOCIATED CONTENT
* Supporting Information
■
S
(b) Steiner, A. J.; Schitter, G.; Stutz, A. E.; Wrodnigg, T. M.; Tarling,
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C. A.; Withers, S. G.; Mahuran, D. J.; Tropak, M. B. Tetrahedron:
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AUTHOR INFORMATION
Corresponding Authors
■
(18) Stubbs, K. A.; Bacik, J.-P.; Perley-Robsertson, G. E.; Whitworth,
G. E.; Gloster, T. M.; Vocadlo, D. J.; Mark, B. L. ChemBioChem 2013,
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*E-mail: yves.bleriot@univ-poitiers.fr.
*E-mail: matthieu.sollogoub@upmc.fr.
Notes
(19) During the revision of this manuscript, the group of Wong
reported the synthesis of iminosugar C-glycoside analogues of α-D-
GlcNAc-1-phosphate; see Hsu, C.-H.; Schelwies, M.; Enck, S.; Huang,
L.-Y.; Huang, S.-H.; Chang, Y.-F.; Cheng, T.-J. R.; Cheng, W.-C.;
Wong, C.-H. J. Org. Chem. 2014, 79, 8629−8637.
The authors declare no competing financial interest.
(20) (a) Poitout, L.; Le Merrer, Y.; Depezay, J.-C. Tetrahedron Lett.
1996, 37, 1613−1616. (b) Bagal, S. K.; Davies, S. G.; Lee, J. A.;
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ACKNOWLEDGMENTS
■
Support for this research was provided by the Sanfilippo
Foundation Switzerland, Dorphan, and “Vaincre les Maladies
Lysosomales“. We thank Dr. Matthew Young, University of
Oxford, for proofreading this manuscript.
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