Eight stereoisomers of homonojirimycin from d -mannose

Article abstract of DOI:10.1021/ol3005744

Although there are 32 6-azidoheptitols, there are only 16 homonojirimycin (HNJ) stereoisomers. Two epimeric azidoalditols derived from d-mannose allow the synthesis in water of eight stereoisomers of HNJ.

Full text of DOI:10.1021/ol3005744

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2050–2053
Eight Stereoisomers of Homonojirimycin
from D-Mannose
Gabriel M. J. Lenagh-Snow,† Sarah F. Jenkinson,†,‡ Scott J. Newberry,† Atsushi Kato,§
Shinpei Nakagawa,§ Isao Adachi,§ Mark R. Wormald,‡ Akihide Yoshihara,
Kenji Morimoto, Kazuya Akimitsu,^ Ken Izumori, ,^ and George W. J. Fleet*,†,‡
Chemistry Research Laboratory, Department of Chemistry, University of Oxford,
Mansfield Road, OX1 3TA, U.K., Oxford Glycobiology Institute, University of Oxford,
South Parks Road, Oxford, OX1 3QU, U.K., Department of Hospital Pharmacy, University
of Toyama, Toyama 930-0194, Japan, Rare Sugar Research Center, Kagawa University,
2393 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0795, Japan, and Faculty of Agriculture,
Kagawa University, 2393 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0795, Japan
george.fleet@chem.ox.ac.uk
Received March 6, 2012
ABSTRACT
Although there are 32 6-azidoheptitols, there are only 16 homonojirimycin (HNJ) stereoisomers. Two epimeric azidoalditols derived from
D-mannose allow the synthesis in water of eight stereoisomers of HNJ.
Homonojirimycin (HNJ) 1 is a seven carbon imino-
sugar1 which was made2 before it was recognized as a
natural product from Omphalea diandra (Euphorbiaceae).3
Many of the stereoisomers of HNJ, as well as corresponding
glycosides, have subsequently been isolated from a wide
range of plants4 and synthesized by many different routes.5
† Chemistry Research Laboratory, Department of Chemistry, University of
Oxford.
‡ Oxford Glycobiology Institute, University of Oxford.
§ University of Toyama.
(4) (a) Asano, N.; Nishida, M.; Kizu, H.; Matsui, K.; Watson, A. A.;
Nash, R. J. J. Nat. Prod. 1997, 60, 98–101. (b) Kim, H. S.; Kim, Y. H.;
Hong, Y. S.; Paek, N. S.; Lee, H. S.; Kim, T. H.; Kim, K. W.; Lee, J. J.
Planta Medica 1999, 65, 437–439. (c) Asano, N.; Kato, A.; Miyauchi,
M.; Kizu, H.; Kameda, Y.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J.
J. Nat. Prod. 1998, 61, 625–628. (d) Ikeda, K.; Takahashi, M.; Nishida, M.;
Miyauchi, M.; Kizu, H.; Kameda, Y.; Arisawa, M.; Watson, A. A.;
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(e) Kato, A.; Kato, N.; Adachi, I.; Hollinshead, J.; Fleet, G. W. J.;
Kuriyama, C.; Ikeda, K.; Asano, N.; Nash, R. J. J. Nat. Prod. 2007, 70,
993–997. Kite, G. C.; Hoffmann, P.; Lees, D. C.; Wurdack, K. J.; Gillespie,
L. J. Biochem. Systematics Ecol. 2005, 33, 1183–1186.
Rare Sugar Research Center, Kagawa University.
^ Faculty of Agriculture, Kagawa University.
(1) (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645–1680. (b) Watson, A. A.; Fleet,
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Creemer, L. J.; Daniel, J. K.; King, C. H. R.; Liu, P. S. J. Org. Chem.
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r
10.1021/ol3005744
Published on Web 04/03/2012
2012 American Chemical Society

This paper describes the synthesis of eight (2ꢀ9) of the 15
diastereomers of HNJ from D-mannose by a divergent
biotechnological strategy in water that depends on the
isomerization of monosaccharides by the techniques of
Izumoring [Scheme 1].6
the azidoketoses 12/13 with their C3 epimers 14/15. Hy-
drogenation of each of the four azidoketoses by Raney
nickel resulted in reduction of the azide to the correspond-
ing amine which underwent intramolecular reductive
amination to give two epimeric HNJs.
Chain extension and functional group manipulation
allowed the conversion of D-mannose to the two epimeric
6-azido-heptitols 10/11 in which all the chiral centers are
preserved. Gluconobacter thailandicus specifically recog-
nizes a terminal diol stereochemical motif with an R,R
configuration adjacent to the terminal carbon and thus
allowed the oxidation of 10/11 to the azidoketoses 12/13.
D-Tagatose-3-epimerase (DTE) is a promiscuous enzyme
that epimerizes C3 of a ketose; there is no ketose so far
reported that is not a substrate for DTE. DTE equilibrated
The seven carbon lactone diacetonide 16, which may be
prepared on a scale up to 10 kg by a Kiliani reaction on
diacetone mannose,7 is a key intermediate for the synthesis
of the epimeric 6-azido-heptitols 10/11 [Scheme 2]. Ester-
ification of the free alcohol in 16 with triflic anhydride af-
forded the crystalline triflate 17; reaction of 17 with sodium
azide in DMF resulted in nucleophilic substitution with
retention to give 19 in an overall yield of 80% for the two
steps.8 The all cis-azide 19 is more stable than the epimeric
azidolactone 18;9 it was not possible to readily isolate 18
from reaction of 17 with sodium azide. Reduction of the
base-sensitive azidolactone 19 with DIBALH in dichloro-
methane gave the lactol 2010 [93% yield] which on further
reduction with sodium borohydride in methanol afforded
the protected diol 21 [96% yield]. Removal of the acetonides
in 21 by acid hydrolysis with Dowex in water gave the azido-
Scheme 1. Summary of Synthesis of HNJ Stereoisomers
25
heptitol 10 [mp136ꢀ138 ꢀC, [R]D þ10.9 (c1.0, H2O)] in an
overall yield of 69% from 16. For the epimer 11, the lactone
16 was reduced by THF/borane to give the lactol 22 [88%
yield] in which the anomeric hydroxyl group was protected
as the corresponding TBDMS ether 23 [79%]. Esterification
of the hydroxyl group at C2 of 23 with triflic anhydride gave
the triflate 24 [75%] which, with sodium azide in DMF,
resulted in nucleophilic substitution with inversion to give
25 [71%]. Removal of the silyl ether and diacetonide groups
in 25 by aqueous trifluoroacetic acid gave the unprotected
lactols 26; reduction of 26 with sodium borohydride in water
25
gave the azidoheptitol 11 [mp 159ꢀ160 ꢀC, [R]D ꢀ8.5
(c 1.0, H2O)] in an overall yield of 27% from 16.
Oxidation of the (R,R) stereochemical motif adjacent to
the terminal carbon in the epimeric azidoheptitols 10 and
11 by Gluconobacter thailandicus gave complete conver-
25
sion to the azidoketoses 12 {[R]D þ21.7 (c 0.4, H2O)} and
25
13 {[R]D þ25.7 (c 1.0, H2O)} respectively [Scheme 3].
Scheme 2. Synthesis of Azidoheptitols
Org. Lett., Vol. 14, No. 8, 2012
2051

Reaction of DTE with 12 caused equilibration with the
25
C3 epimer 14 {[R]D þ31.0 (c 0.7, H2O)} in a ratio of
25
Scheme 3. Biotechnological Synthesis of HNJ Stereoisomers
64:36. Similarly DTE caused equilibration of 13 with 15
{[R]D þ22.3 (c 1.0, H2O)}.
Each of the azidoketoses is predominantly an equilib-
rium mixture of the R and β furanose anomers,11 with very
minor amounts (<2%) of other forms [Figure 1]. As
shown in Figure 2, 12 exists in an R:β ratio of 1.0:4.6, 14
Figure 2. 1H NMR spectra of azidoketoses (500 MHz) in D2O:
(a) 12, (b) 14, (c) 13, (d) 15. Full NMR analysis is reported in
Supporting Information.
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I.; Fleet, G. W. J.; di Bello, I. C.; Winchester, B. Tetrahedron Lett. 1989, 30,
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Tetrahedron 1992, 48, 10191–10200. (d) Bruce, I.; Fleet, G. W. J.; di Bello,
I. C.; Winchester, B. Tetrahedron 1992, 48, 10191–10200. (e) Holt, K. E.;
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Figure 1. Ratio of anomers of azidoketoses.
2052
Org. Lett., Vol. 14, No. 8, 2012

Table 1. Properties of HNJ Diastereomersa
a a-t = apparent triplet; a-dt = apparent double triplet.
in an R:β ratio of 1.9:1.0, 13 in an R:β ratio of 4.0:1.0, and
15 in an R:β ratio of 1.0:1.75.
The stereoselectivity in the cyclic reductive aminations
may be rationalized by the arguments of Wong;12 greater
selectivity was found with synergy in steric hindrance and
torsional strain, withthe least selectivity where these effects
were opposed. The crude reaction mixtures were separated
by ion exchange chromatography by a combination of
Hydrogenation of the azidoketoses in the presence of
Raney nickel in each case caused reduction of the azide to
the corresponding amine, followed by intramolecular
amination to give iminoheptitols; examination of the crude
product from the reduction showed the clean formation of
two iminosugars. The reduction of azidoketoses 12 [to 2
and 3] and 14 [to 6 and 7] showed no stereoselectivity in the
reduction of the intermediate imine. In contrast, hydro-
genation of 13 gave 4 together with 5 in a 20:1 ratio. A
similar highly stereoselective reduction of 15 gave 8 and 9
in a ratio of 15:1.
þ
Dowex 1 ꢁ 2 (OHꢀ form) and Amberlite CG-50(NH4
form) to afford six iminoheptitols for which the properties
are reported in Table 1. It was not possible to obtain pure
samples of iminoheptitols 5 and 9 formed as the minor
products from the hydrogenation of 13 and 15, respec-
tively; further investigations for the separation of the
iminoheptitols is in progress.
In summary, biotechnological syntheses of eight stereo-
isomers of HNJ from D-mannose are described; a similar
sequence from D-glucose, which should provide the other
eight stereoisomers, is under investigation.
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Acknowledgment. This work was supported by the
Program for Promotion of Basic and Applied Re-
searches for Innovations in Bio-oriented Industry and
Grant-in-Aid for Scientific Research (C) (No: 23590127)
from the Japanese Society for the Promotion of Science
(JSPS).
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data. This material is
available free of charge via the Internet at http://pubs.
acs.org.
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The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
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