A new and short synthesis of naturally occurring 1-deoxy-l-gulonojirimycin from tri-O-benzyl-d-glucal

Article abstract of DOI:10.1016/j.tetlet.2010.08.049

A new and short synthesis of naturally occurring 1-deoxy-l-gulonojirimycin from tri-O-benzyl-d-glucal, via a regioselective intramolecular cyclization of an amino triol intermediate, is described. Its absolute configuration was deduced from the single crystal X-ray analysis of compound 11.

Full text of DOI:10.1016/j.tetlet.2010.08.049

Tetrahedron Letters 51 (2010) 5574–5576
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new and short synthesis of naturally occurring 1-deoxy-L-gulonojirimycin
from tri-O-benzyl-D-glucal
⇑
Muthupandian Ganesan, Namakkal G. Ramesh
Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi 110016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and short synthesis of naturally occurring 1-deoxy-L-gulonojirimycin from tri-O-benzyl-D-glucal,
Received 21 July 2010
Revised 13 August 2010
Accepted 17 August 2010
Available online 20 August 2010
via a regioselective intramolecular cyclization of an amino triol intermediate, is described. Its absolute
configuration was deduced from the single crystal X-ray analysis of compound 11.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
L-Azasugars
1-Deoxy- -gulonojirimycin
L
Regioselective cyclization
Glycosidase inhibitors
Since the isolation of nojirimycin 1 (NJ) (Fig. 1) as the first natu-
rally occurring polyhydroxylated alkaloid,1 syntheses of natural
polyhydroxylated piperidines (azasugars or iminosugars) and their
unnatural analogues continue to receive a great deal of attention
due to their ability to selectively inhibit different types of enzymes
of medicinal interest such as glycosyltransferases and glycosidases.2
OH
OH
OH
HO
OH
OH
HO
HO
OH
OH
HO
HO
OH
OH
N
H
N
H
N
1
2
3
1-deoxynojirimycin
Glyset ®
nojirimycin
Though NJ was found to be a potent inhibitor of a- and b-glucosi-
dases, 1-deoxynojirimycin 2 (DNJ), the stable analogue of NJ was
found to be a more potent inhibitor than NJ itself.3 As inhibitors of
glycosidases, azasugars are thus expected to have therapeutic appli-
cations in the treatment of a variety of carbohydrate-mediated dis-
orders such as diabetes, viral infections, HIV, hepatitis, cancer
metastasis, and Gaucher’s disease.4 Over the years, extensive re-
search work has been carried out on the synthesis and inhibition
OH
OH
OH
HO
OH
OH
HO
OH
OH
HO
OH
N
N
H
N
H
OH
-
4
6
5
Zavesca®
1-deoxy-
D
-
1-deoxy-
L
gulonojirimycin
gulonojirimycin
studies of
D-iminosugars, as most of the naturally occurring DNJ ana-
-family.1,2,4,5 Successful development of synthetic
Figure 1. Representative examples of azasugars.
logues belong to
D
six-membered-azasugar based clinical drugs such as GlysetÒ 3 and
ZavescaÒ 4 (Fig. 1) represent significant research breakthrough in
of the capsular polysaccharide isolated from Streptococcus pneumo-
this area.5 Recent studies reveal that
L
-DNJ and its analogues, though
-sugars, also display significant
-glycosidases through a non-competi-
tive mode of action against these enzymes.6 In view of this, there
has been an upsurge in research related to the synthesis of -DNJ
and its congeners. In this context, 1-deoxy- -gulonojirimycin 6
-gulo-DNJ) (Fig. 1) represents a rare example of naturally occurring
DNJ analogue belonging to the -family. It was first collected as an
niae type 12F.7
L
-gulo-DNJ 6, is also a constituent entity of a novel
disaccharide, 7-O-b- -glucopyranosyl- -homonojirimycin, a potent
inhibitor of -gulo-DNJ 6 was first iso-
-glucosidase and trehalase.8
do not mimic the conformation of
inhibition activities against
D
D
a
D
a
L
lated as a free base in 2001 from the extract of the bark Angylocalyx
L
pynaertii along with a plethora of other DNJ analogues.9 However,
L
it was initially identified as D-gulo-DNJ 5 and not L-gulo-DNJ 6. In
(L
2005, the correct stereochemistry was established through asym-
metric synthesis. Comparison of the specific rotation of the naturally
occurring compound with that of the synthetic one revealed that the
L
amorphous hydroacetate in 1982 during degradative sugar analysis
naturally occurring compound was indeed
found to be a highly specific inhibitor of
L
-gulo-DNJ.6b,10,11 It was
-fucosidase with a Ki
value of 14 l L
m.6b Several syntheses of -gulo-DNJ6b,7,11,12 and
a
-L
⇑
Corresponding author. Tel.: +91 11 26596584; fax: +91 11 26581102.
E-mail address: ramesh@chemistry.iitd.ac.in (N.G. Ramesh).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.049

M. Ganesan, N. G. Ramesh / Tetrahedron Letters 51 (2010) 5574–5576
5575
D
-gulo-DNJ6b,10,13 even prior to its isolation, have been reported.
Most of the syntheses reported so far for L-gulo-DNJ utilize D-su-
gar-derived starting materials.7,12 A couple of asymmetric syntheses
arealsoavailable.6b,11 Amongthecarbohydrate-basedroutes, except
for a lone low-yielding indirect example,7 glycals have hardly been
used as starting materials for the synthesis of L-gulo-DNJ despite
their ready availability. In continuation of our research work on
the transformation of glycals into novel azasugars and other biolog-
ically important compounds,14 we had recently accomplished a new
and short synthesis of naturally occurring
available tri-O-benzyl- -glucal 7 which we report herein.
Our synthesis relied on the use of amino diol 8,14d prepared in
three-steps from tri-O-benzyl- -glucal 7, as a convenient starting
L-gulo-DNJ from readily
D
D
material (Scheme 1). Protection of the hydroxyl functional groups
of 8 as their TBS ethers afforded compound 9 in high yield.15
Deprotection of the benzyl groups of compound 9 was carefully
carried out with hydrogen in the presence of 10% Pd on charcoal
to give the triol 10 in 85% yield.16 It should be noted that exposure
of compound 9 toward hydrogenation reaction for a longer time
led to the deprotection of the TBS ethers also.17 Next, we attempted
a regioselective intramolecular cyclization of the amino triol inter-
Figure 2. Single crystal X-ray structure of compound 11. Hydrogens (except those
in the piperidine ring) are omitted for clarity.
mediate 10 to obtain the protected 1-deoxy-L-gulonojirimycin 11.
It was expected that, upon intramolecular cyclization, compound
10 would preferentially form the six-membered ring to afford
compound 11. Thus, amino triol 10 when subjected to an intramo-
uration of 2R,3R,4R,5S (numbering as per parent 1-deoxynojirimy-
cin 2).
lecular cyclization under Mitsunobu condition underwent
a
In conclusion, we have reported a new and a short synthesis of
smooth cyclization reaction to afford a single product in just
20 min. Upon careful analysis of 1H and 13C NMR spectral data,
its structure was identified to be the expected product 11.18 The
formation of the six-membered ring as well as the absolute config-
uration of 11 as 2R,3R,4R,5S (numbering as per parent 1-deoxynoj-
irimycin 2) could be inferred from the single crystal X-ray analysis
of compound 11 (Fig. 2).19 This is the first report on the single crys-
naturally occurring 1-deoxy-
L-gulonojirimycin from readily avail-
able tri-O-benzyl- -glucal under very mild reaction conditions in
D
a high overall yield. The methodology is simple to carry out and
amenable for large-scale preparations. We have also deduced the
absolute configuration of naturally occurring 1-deoxy-L-gulonojir-
imycin from the single crystal X-ray analysis of compound 11.
tal X-ray structure of L-gulo-DNJ derivative. Subsequently, depro-
Acknowledgments
tection of the TBS and tosyl groups was carried out in a two-step
one-pot fashion. Exposure of compound 11 to 0.1 M solution of
TBAF led to a facile deprotection of the TBS groups to afford com-
pound 12, which without any work-up and/or purification was
subjected to detosylation reaction under Birch condition to get
The authors thank the Department of Science and Technology,
New Delhi, India for the financial support and Mr. Nem Singh for
his help with the single crystal X-ray analysis. The authors thank
the DST-FIST and IITD for funding of the single crystal X-ray dif-
fraction facility at IITD.
L
-gulo-DNJ 6 as a viscous liquid. For characterization purpose,
-gulo-DNJ 6 was converted into its hydrochloride salt by acidificat-
L
ion with hydrochloric acid in methanol.20 The specific rotation
Supplementary data
{½a 3D1
ꢀ
ꢁ 2:3 (c 0.6, MeOH)} and spectral data of
L-gulo-DNJ.HCl
(6ꢂHCl) were found to be identical with the literature values re-
Supplementary data (experimental procedure, spectral data and
copies of 1H and 13C NMR spectra of all new compounds and crys-
tallographic data of compound 11) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2010.08.049.
ported by D’Alonzo and co-workers {[
a
]
D ꢁ 2.5 (c 0.5, MeOH)}.11
Our synthesis along with the single crystal X-ray structure of com-
pound 11 thus unambiguously proves that the naturally occurring
gulo-DNJ indeed belongs to the
L-family and has an absolute config-
References and notes
1. Inouye, S.; Tsuruoka, T.; Niida, T. J. Antibiot. 1966, 19, 288–292.
2. For reviews on piperidine azasugars, see: Afarinkia, K.; Bahar, A. Tetrahedron:
Asymmetry 2005, 16, 1239–1287; Pearson, M. S. M.; Mathé-Allainmat, M.;
Fargeas, V.; Lebreton, J. Eur. J. Org. Chem. 2005, 2159–2191; Asano, N.; Oseki, K.;
Kizu, H.; Matsui, K. J. Med. Chem. 1994, 37, 3701–3706.
3. Newbrun, E.; Hoover, C. I.; Walker, G. J. Arch. Oral Biol. 1983, 28, 531–536.
4. Compain, P.; Martin, O. R. Iminosugars—From Synthesis to Therapeutic
Applications; John Wiley & Sons Ltd: West Sussex England, 2007.
5. Winchester, B. G. Tetrahedron: Asymmetry 2009, 20, 645–651. and references
cited therein.
6. (a) D’Alonzo, D.; Guaragna, A.; Palumbo, G. Curr. Med. Chem. 2009, 16, 473–505;
(b) 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; (c)
Meyers, A. I.; Andres, C. J.; Resek, J. E.; Woodall, C. C.; McLaughlin, M. A.; Lee, P.
H.; Price, D. A. Tetrahedron 1999, 55, 8931–8952.
OBn
OBn
OBn
O
OTBS
BnO
BnO
OH
BnO
BnO
Ref. 14d
BnO
BnO
a
c
OH
NHTs
OTBS
NHTs
9
8
7
b
OH
3
OH
OH
OTBS
OTBS
NHTs
RO
OH
OR
HO
OH
3
2
4
2
4
e
HO
1N5
1N5
OH
HO
H.HCl
Ts
10
R = TBS, 11
6.HCl
d
R = H, 12 (not isolated)
7. Leontein, K.; Lindberg, B.; Lönngren, J. Acta Chem. Scand., Ser. B 1982, 36, 515–
518.
8. (a) Ikeda, K.; Takahashi, M.; Nishida, M.; Miyauchi, M.; Kizu, H.; Kameda, Y.;
Arisawa, M.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J.; Asano, N. Carbohydr. Res.
2000, 323, 73–80; (b) Kyosseva, S. V.; Kyossev, Z. N.; Elbein, A. D. Arch. Biochem.
Biophys. 1995, 316, 821–826.
Scheme 1. Synthesis of 1-deoxy- -gulonojirimycin from tri-O-benzyl-D-glucal.
L
Reagents and conditions: (a) TBSCl, Imd, DMF, rt, 1 h, 82%; (b) 10% Pd/C, MeOH,
42 °C, 40 min, 85%; (c) Ph3P, DEAD, THF, 0 °C to rt, 20 min, 90%; (d) 1.0 M, TBAF in
THF, rt, 10 min; (e) (i) Na–liq. NH3, THF, ꢁ78 °C, 3 h; (ii) HCl, MeOH, rt, 10 min, 75%
(from 11).

5576
M. Ganesan, N. G. Ramesh / Tetrahedron Letters 51 (2010) 5574–5576
9. Asano, N.; Yasuda, K.; Kizu, H.; Kato, A.; Fan, J.-Q.; Nash, R. J.; Fleet, G. W. J.;
Molyneux, R. J. Eur. J. Biochem. 2001, 268, 35–41; Asano, N.; Ishii, S.; Kizu, H.;
Ikeda, K.; Yasuda, K.; Kato, A.; Martin, O. R.; Fan, J.-Q. Eur. J. Biochem. 2000, 267,
4179–4186.
10. Pyun, S.-J.; Lee, K.-Y.; Oh, C.-Y.; Joo, J.-E.; Cheon, S.-H.; Ham, W.-H. Tetrahedron
2005, 61, 1413–1416.
1H), 4.24 (m, 1H), 4.09 (br d, J = 7.5 Hz, 1H), 3.77 (br d, J = 7.5 Hz, 1H), 3.68 (dd,
J = 9.6, 5.4 Hz, 1H), 3.56–3.50 (m, 2H), 3.38 (t, J = 9.3 Hz, 1H), 3.28 (dd, J = 9.6,
4.8 Hz, 1H), 2.41 (s, 3H), 0.98 (s, 9H), 0.83 (s, 9H), 0.17 (s, 3H), 0.14 (s, 3H),
ꢁ0.06 (s, 3H), ꢁ0.07 (s, 3H); 13C NMR (300 MHz, CDCl3) d 143.1, 139.1, 139.0,
138.6, 138.3, 129.6 (2ꢃ-C), 128.3 (4ꢃ-C), 128.1 (2ꢃ-C), 127.9 (2ꢃ-C), 127.7
(4ꢃ-C), 127.6, 127.5, 127.2, 126.9 (2ꢃ-C), 82.7, 75.9, 75.2, 74.8, 73.3, 72.6, 71.5,
61.9, 56.4, 25.9 (3ꢃ-C), 25.8 (3ꢃ-C), 21.4, 18.1 (2ꢃ-C), ꢁ4.5, ꢁ4.8, ꢁ5.6, ꢁ5.7;
HRMS (ESI) calcd for C46H67NO7SSi2Na [M+Na]+ 856.4075, found: 856.4061.
11. Guaragna, A.; D’Alonzo, D.; Paolella, C.; Palumbo, G. Tetrahedron Lett. 2009, 50,
2045–2047.
12. For synthesis of 1-deoxy-
L-gulonojirimycin, see: (a) Wei, B.-G.; Chen, J.; Huang,
16. Data for 10: ½a D33
ꢀ
ꢁ 2:2 (c 0.76, CHCl3); vmax (KBr)/cmꢁ1: 3426, 2081, 1636,
P.-Q. Tetrahedron 2006, 62, 190–198; (b) Ostrowski, J.; Altenbach, H.-J.;
Wischnat, R.; Brauer, D. J. Eur. J. Org. Chem. 2003, 1104–1110; (c) Joseph, C.
C.; Regeling, H.; Zwanenburg, B.; Chittenden, G. J. F. Carbohydr. Res. 2002, 337,
1083–1087; (d) Le Merrer, Y.; Sanière, M.; McCort, I.; Dupuy, C.; Depezay, J.-C.
Tetrahedron Lett. 2001, 42, 2661–2663; (e) Davis, B. G.; Hull, A.; Smith, C.; Nash,
R. J.; Watson, A. A.; Winkler, D. A.; Griffiths, R. C.; Fleet, G. W. J. Tetrahedron:
Asymmetry 1998, 9, 2947–2960; (f) Le Merrer, Y.; Poitout, L.; Depezay, J.-C.;
Dosbaa, I.; Geoffroy, S.; Foglietti, M.-J. Bioorg. Med. Chem. 1997, 5, 519–533; (g)
Poitout, L.; Le Merrer, Y.; Depezay, J.-C. Tetrahedron Lett. 1996, 37, 1609–1612;
(h) Poitout, L.; Le Merrer, Y.; Depezay, J.-C. Tetrahedron Lett. 1996, 37, 1613–
1616; (i) Park, K. H. Bull. Korean Chem. Soc. 1995, 16, 985–988; (j) Legler, G.;
Stütz, A. E.; Immich, H. Carbohydr. Res. 1995, 272, 17–30; (k) Lohray, B. B.;
Jayamma, Y.; Chatterjee, M. J. Org. Chem. 1995, 60, 5958–5960; (l) Poitout, L.; Le
Merrer, Y.; Depezay, J.-C. Tetrahedron Lett. 1994, 35, 3293–3296; (m) Baxter, E.
V.; Reitz, A. B. J. Org. Chem. 1994, 59, 3175–3185; (n) Legler, G.; Julich, E.
Carbohydr. Res. 1984, 128, 61–72.
1415, 1256, 1159, 1090, and 666; 1H NMR (300 MHz, CDCl3)
d 7.67 (d,
J = 7.8 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H), 5.19 (d, J = 7.8 Hz, exchangeable with
D2O, 1H), 3.83 (br m, 1H), 3.66–3.54 (m, 3H), 3.49–3.46 (m, 2H), 3.39–3.30 (m,
1H), 3.25 (s, 1H), 3.05–2.99 (m, exchangeable with D2O, 2H), 2.3 (s, CH3 and an
exchangeable proton, 4H), 0.78 (s, 9H), 0.73 (s, 9H), 0.002 (s, 6H), ꢁ0.12 (s, 3H),
ꢁ0.11 (s, 3H); 13C NMR (300 MHz, CDCl3) d 143.8, 137.0, 129.8 (2ꢃ-C), 127.2
(2ꢃ-C), 72.1, 71.9, 68.3, 63.9, 62.2, 57.2, 25.8 (6ꢃ-C), 21.5, 18.2, 17.9, ꢁ4.7,
ꢁ4.9, ꢁ5.7 (2ꢃ-C); HRMS (ESI) calcd for C25H49NO7SSi2Na [M+Na]+ 586.2666,
found 586.2675.
17. For Pd/C catalyzed deprotection of silyl ethers, see: Kim, S.; Jacobo, S. M.;
Chang, C.-T.; Bellone, S.; Powell, W. S.; Rokach, J. Tetrahedron Lett. 2004, 45,
1973–1976; Ikawa, T.; Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron 2004, 60,
6901–6911.
18. Data for 11: ½a D28
ꢀ
ꢁ 22:0 (c 0.41, CHCl3); vmax (KBr)/cmꢁ1: 3518, 3444, 3277,
2930, 2856, 1757, 1698, 1595, 1575, 1470, 1399, 1310, 1253, 1192, 1157, 1098,
1037, 953, 837, 787, 715, 686, 634, 559, 467, and 429; 1H NMR (300 MHz,
CDCl3) d 7.78 (d, J = 7.2 Hz, 2H), 7.28 (d, J = 7.2 Hz, 2H), 4.06–3.84 (m, 7H), 3.55
(d, J = 13.5 Hz, 1H), 3.03 (s, exchangeable with D2O, 1H), 2.43 (s, 3H), 2.17 (s,
exchangeable with D2O, 1H), 0.94 (s, 9H), 0.84 (s, 9H), 0.15 (s, 6H), 0.015 (s,
3H), ꢁ0.03 (s, 3H); 13C NMR (300 MHz, CDCl3) d 143.3, 137.9, 129.6 (2ꢃ-C),
127.3 (2ꢃ-C), 71.7, 69.5, 69.2, 61. 3, 56.0, 48.1, 25.9 (3ꢃ-C), 25.8 (3ꢃ-C), 21.5,
18.3, 18.0, ꢁ4.5, ꢁ4.9, ꢁ5.7, ꢁ5.9; HRMS (ESI) calcd for C25H48NO7SSi2 [M+H]+
546.2741, found 546.2730.
13. For synthesis of 1-deoxy-D-gulonojirimycin, see: Non-carbohydrate based
synthesis: (a) Ruiz, M.; Ruanova, T. M.; Blanco, O.; Núñez, F.; Pato, C.; Ojea,
V. J. Org. Chem. 2008, 73, 2240–2255; (b) Amat, M.; Huguet, M.; Llor, N.; Bassas,
O.; Gómez, A. M.; Bosch, J.; Badia, J.; Baldoma, L.; Aguilar, J. Tetrahedron Lett.
2004, 45, 5355–5358; (c) Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H. Org.
Lett. 2003, 5, 2527–2529; (d) Singh, O. V.; Han, H. Tetrahedron Lett. 2003, 44,
2387–2391; (e) Ruiz, M.; Ojea, V.; Ruanova, T. M.; Quintela, J. M. Tetrahedron:
Asymmetry 2002, 13, 795–799; (f) Haukaas, M. H.; O’Doherty, G. A. Org. Lett.
2001, 3, 401–404; (g) Liao, L.-X.; Wang, Z.-M.; Zhang, H.-X.; Zhou, W.-S.
Tetrahedron: Asymmetry 1999, 10, 3649–3657; Carbohydrate based synthesis:
Ghosh, S.; Shashidhar, J.; Dutta, S. K. Tetrahedron Lett. 2006, 47, 6041–6044.
14. (a) Ganesan, M.; Madhukarrao, R. V.; Ramesh, N. G. Org. Biomol. Chem. 2010, 8,
1527–1530; (b) Kumar, V.; Ramesh, N. G. Org. Biomol. Chem. 2007, 5, 3847–
3858; (c) Kumar, V.; Ramesh, N. G. Chem. Commun. 2006, 4952–4954; (d)
Kumar, V.; Ramesh, N. G. Tetrahedron 2006, 62, 1877–1885.
19. The crystallographic data for the structure 11 in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC-782793. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033; e-mail: deposit@cam.ac.uk.
20. Data for 6.HCl: ½a D31
ꢀ
ꢁ 2:3 (c 0.6, MeOH) [lit.11
[
a
]
D ꢁ 2.5 (c 0.5, MeOH) and for
its D [a]D + 2.6 (c 1.6, MeOH)]; v
-enantiomer13d max (KBr)/cmꢁ1: 3134 (br), 2332,
2135, 1597, 1409, 1343, 1119, 974, 733, 619, and 470; 1H NMR (300 MHz, D2O)
d 4.17–4.12 (m, 1H), 4.03–4.01 (m, 1H), 3.96 (br m, 1H), 3.80 (dd, J = 12, 4.8 Hz,
1H), 3.72 (m, 1H), 3.45–3.40 (m, 1H), 3.21(dd, J = 12.0, 4.8 Hz, 1H), 3.02 (t,
J = 11.7 Hz, 1H); 13C NMR (300 MHz, D2O) d 68.4, 67.1, 62.5, 58.8, 55.3, 42.2
[lit.11 13C NMR (125 MHz, D2O) d 68.5, 67.2, 62.6, 59.0, 55.5, 42.4]; HRMS (ESI)
calcd for C6H14NO4 [M+H]+ 164.0923, found 164.0924.
15. Data for 9: ½a 3D3 max (KBr)/cmꢁ1: 3283, 3062, 3032, 2857,
þ 4:3 (c 0.62, CHCl3); v
ꢀ
1952, 1744, 1598, 1334, 1251, 1158, 839, 777, 740, 700, 668, 606, 554, 460, and
403; 1H NMR (300 MHz, CDCl3) d 7.72 (d, J = 8.1 Hz, 2H), 7.40–7.22 (m, 17H),
4.96 (d, J = 9.3 Hz, exchangeable with D2O, 1H), 4.87 (d, J = 10.8 Hz, 1H), 4.70 (d,
J = 11.1 Hz, 1H), 4.63 (d, J = 11.1 Hz, 1H), 4.61–4.53 (m, 2H), 4.48 (d, J = 10.8 Hz,