A rapid synthesis of hexofuranose-like iminosugars using ring-closing metathesis

Article abstract of DOI:10.1021/ol051232b

(Chemical Equation Presented) Two new 1-N-iminosugars have been prepared as hexofuranose analogues in an efficient manner by an RCM-based route. Both 3,4-disubstituted pyrrolidines display moderate inhibitory activity against Mycobacterium smegmatis galac

Full text of DOI:10.1021/ol051232b

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3521-3523
A Rapid Synthesis of Hexofuranose-like
Iminosugars Using Ring-Closing
Metathesis
Sylvaine Cren, Claire Wilson, and Neil R. Thomas*
School of Chemistry, Centre for Biomolecular Sciences, UniVersity of Nottingham,
UniVersity Park, Nottingham NG7 2RD, United Kingdom
neil.thomas@nottingham.ac.uk
Received May 25, 2005
ABSTRACT
Two new 1-N-iminosugars have been prepared as hexofuranose analogues in an efficient manner by an RCM-based route. Both 3,4-disubstituted
pyrrolidines display moderate inhibitory activity against Mycobacterium smegmatis galactan biosynthesis.
Iminosugars have generated continued interest because of
their potential therapeutic applications and use as mechanistic
probes. Iminosugars are potent inhibitors of glycosidases,
but they also inhibit glycosyltransferases.1 Previously, we
reported (()-(3S,4R)-4-[(1R)-1,2-dihydroxyethyl]pyrrolidin-
3-ol as a moderate inhibitor of UDP-Galf transferase, a key
enzyme involved in mycobacterial galactan biosynthesis.2
Mycobacteria are pathogens responsible for several human
diseases, including tuberculosis (TB) and leprosy. Every year,
TB kills ∼3 million people worldwide, and there is an urgent
need for new and effective anti-TB drugs.3
There are various synthetic approaches to iminosugars,
most of them starting from carbohydrate templates. However,
many of these require a large number of steps, including
extensive protecting group manipulations, lead to low overall
yields, and are dependent on the availability of a suitable
starting sugar. An alternative strategy is to construct the
desired carbon skeleton first and then add the appropriate
oxygenation in a stereocontrolled manner as described here.
RCM (ring-closing metathesis) has been used for the
synthesis of iminosugars in a growing number of examples.4
The key RCM reaction is usually performed using ruthenium
complexes 1 or 2.5
Here we report the enantioselective synthesis of iminosugar
(3R,4S)-4-[(1R)-1,2-dihydroxyethyl]pyrrolidin-3-ol (3) and
its diastereoisomer (3S,4R)-4-[(1R)-1,2-dihydroxyethyl]pyr-
rolidin-3-ol (25), isomers of our previously reported trans-
ferase inhibitor,2 using RCM to form the key five-membered
ring core.
(4) (a) For a review on the synthesis of piperidine and pyrrolidine natural
alkaloids with RCM, see: Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem.
2003, 3693. (b) For selected examples, see: Huwe, C. M.; Blechert, S.
Synthesis 1997, 61. Singh, O. V.; Han, H. Tetrahedron Lett. 2003, 44, 2387.
Guanti, G.; Riva, R. Tetrahedron Lett. 2003, 44, 357. Hongqing, L., Ble´riot,
Y.; Chantereau, C.; Mallet, J.-M.; Sollogoub, M.; Zhang, Y.; Rodr´ıguez-
Garc´ıa, E.; Vogel, P.; Jime´nez-Barbero, J.; Sinay¨, P. Org. Biomol. Chem.
2004, 2, 1492.
(1) (a) For a review on iminosugars as glycosidase inhibitors, see:
Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. ReV. 2002, 102,
515. (b) For a review on iminosugars as glycosyltransferase inhibitors,
see: Compain, P.; Martin, O. R. Curr. Top. Med. Chem. 2003, 3, 541.
(2) Cren, S.; Gurcha, S. S.; Blake, A. J.; Besra, G. S.; Thomas, N. R.
Org. Biomol. Chem. 2004, 2, 2418.
(5) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039. (b) Scholl, M.; Ding, S.; Lee, C. W.;
Grubbs, R. H. Org. Lett. 1999, 1, 953.
(3) WHO website: http://www.who.int/tb/en.
10.1021/ol051232b CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/15/2005

The retrosynthetic analysis of iminosugar 3 is shown in
Scheme 1. 1,2-Diol and amine protection leads to the
Displacement of the mesylate with N-benzyl-allylamine
gave the diene 18 in a moderate yield (55%). The precursor
of the RCM reaction was then reacted with ruthenium
complex 1, but no reaction was observed even at elevated
temperatures. The diene was then subjected to RCM using
the more reactive ruthenium complex 2 in dichloromethane,
and a single product was isolated, which was identified as
the pyrrole 19. Not only did this indicate that RCM had taken
place, it also suggested that the catalyst had brought about
alkene isomerization and dehydrogenation. Neither a change
of the reaction solvent to toluene nor an adjustment of the
reaction temperature led to a change in the reaction outcome;
in every instance the pyrrole was the only product ever
isolated.
Scheme 1
protected pyrrolidine 4. Retrosynthetic dehydration of the
alcohol affords the alkene 5, which can then be disconnected
to the diene 6. Cleavage of the allylamine and further
functional group interconversion gives the ketone 8 via the
alkene 7. The key reaction in our route would be formation
of the pyrroline 5 via the RCM reaction of diene 6, which
would afford a trisubstituted double bond with the stereo-
chemistry of the C-1′ carbon atom, R to the double bond
already established.
A synthesis of chiral synthon 8 from L-(S)-erythrulose has
been described by Vandewalle.6 However, L-(S)-erythrulose
is no longer commercially available. An alternative route to
ketone 8 is the oxidative cleavage of L-ascorbic acid, a
method first reported by Jung and Shaw.7 Using this
approach, L-ascorbic acid 9 was converted into the diol 12
following the procedure devised by Abushanab et al.8
Selective protection of the primary hydroxyl group followed
by oxidation of the secondary hydroxyl group gave the
ketone 14 in good overall yield (41%).
Scheme 3
There are only a few reports of pyrrole formation during
RCM.9 Most of them mention pyrrole formation as a side
reaction of the RCM reaction. However, Verpoort and co-
workers recently developed a general pyrrole synthesis using
a tandem Grubbs’ carbene-RuCl3 catalytic system; they
assumed that RuCl3 was responsible for the pyrrole
formation.9d They also noticed that amines bearing an
electron-withdrawing group on the nitrogen atom did not
dehydrogenate to the pyrrole, but gave the corresponding
pyrrolines. This suggests that the basicity of the nitrogen
atom plays an important role in the dehydrogenation.
Nevertheless, there is one example in the literature where
the RCM reaction (with 1 in dichloromethane at reflux) of
an N-Boc-protected amine gave, after purification, a mixture
of the expected pyrroline and the corresponding pyrrole.9b
In our case, we observed total conversion of the diene 18
into the pyrrole 19 in the presence of 2 (1 mol % in
dichloromethane or toluene).
Scheme 2
In light of these results, we next decided to synthesize
the N-Boc-protected diene 21 and subject it to the RCM
reaction (Scheme 4). Treatment of the mesylate 17 with
allylamine and subsequent protection afforded the RCM
precursor 21 in good yield (90%). This precursor was then
subjected to RCM using ruthenium complex 2 in dichlo-
romethane; the reaction was complete in 36 h (microwave
(6) De Wilde, H.; De Clercq, P.; Vandewalle, M. Tetrahedron Lett. 1987,
28, 4757.
(7) Jung, M. E.; Shaw, T. J. J. Am. Chem. Soc. 1980, 102, 6304.
(8) Abushanab, E.; Bessodes, M.; Antonakis, K. Tetrahedron Lett. 1984,
25, 3841.
(9) (a) Evans, P.; Grigg, R.; Monteith, M. Tetrahedron Lett. 1999, 40,
5247. (b) Bujard, M.; Briot, A.; Gouverneur, V.; Mioskowski, C. Tetra-
hedron Lett. 1999, 40, 8785. (c) Yang, C.; Murray, W. V.; Wilson, L. J.
Tetrahedron Lett. 2003, 44, 1783. (d) Dieltiens, N.; Stevens, C. V.; De
Vos, D.; Allaert, B.; Drozdzak, R.; Verpoort, F. Tetrahedron Lett. 2004,
45, 8995. (e) Yang, Q.; Xiao, W.-J.; Yu, Z. Org. Lett. 2005, 7, 871.
Ketone 14 was then converted into the corresponding
alkene 15 using Wittig chemistry, and cleavage of the silyl
ether afforded the allylic alcohol 16. Activation of the alcohol
then gave the mesylate 17 in quantitative yield.
3522
Org. Lett., Vol. 7, No. 16, 2005

Iminosugars 3 and 25 were tested against Mycobacterium
smegmatis galactan biosynthesis using the cell-free assay
involving both UDP-Galp mutase and UDP-Galf transferase
developed by Besra and co-workers.12 Both iminosugars
exhibited weak activity. When compared to the results
obtained for the corresponding racemic mixtures,2 the
inhibition was better with the enantiopure iminosugars
indicating these were the more active components of the
racemate (Table 1).
Scheme 4
accelerated RCM10 was also investigated and resulted in
shorter reaction times ∼20 min at 100 °C). Significantly,
none of the pyrrole was detected, and the desired pyrroline
22 was obtained in quantitative yield and in 90% overall
yield from the mesylate 17.
Table 1. Inhibition of M. smegmatis Galactan Biosynthesis
compound (8 mM)
(()-25
(()-3
25
3
The hydroboration of 22 was now performed using a slight
excess of BH3‚THF and afforded a mixture of diastereoiso-
meric alcohols 23 and 24 in a 1.7:1 ratio (Scheme 5). The
% inhibition
59
40
72
85
Surprisingly, iminosugar 3, bearing the L-galacto config-
uration (by analogy with the natural substrate, D-galacto-
furanose) was the most active of the two diastereoisomers
tested. Stereochemical subtleties in the inhibition of carbo-
hydrate-processing enzymes by iminosugars has recently
been discussed,13 but overall the recognition process remains
unpredictable.
Scheme 5
In summary, we have developed an efficient synthesis of
iminosugars with the formation of the five-membered core
by ring-closing metathesis as a key step. To our knowledge,
this constitutes the first example of an iminosugar synthesis
utilizing the RCM with the stereochemistry at C-1′ already
set up. This route allows rapid access to 3,4-disubstituted
pyrrolidines14 and could be applied to the synthesis of a range
of new iminosugars.
two diastereoisomers were separated by column chromatog-
raphy; the less polar compound 23 was obtained as a
crystalline solid, and subsequent recrystallization from n-
hexane gave crystals suitable for X-ray analysis (Figure 1).11
Acknowledgment. We thank the University of
Nottingham for financial support and Professor G. S. Besra
(School of Biosciences, University of Birmingham, U.K.)
for assistance with the galactan biosynthesis assays.
Supporting Information Available: Experimental pro-
cedures along with spectroscopic and other data in CIF
format for compounds 3 and 12-25. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL051232B
(11) The crystallographic data (excluding structure factors) for compound
23 have been deposited (CCDC 272229) with the Cambridge Crystal-
lographic Data Centre. Copies of the data can be obtained, free of charge,
upon application to the CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK
(fax, +44 (0)1223 336033; e-mail, deposit@ccdc.cam.ac.uk).
(12) Pathak, A. K.; Pathak, V.; Seitz, L.; Maddry, J. A.; Gurcha, S. S.;
Besra, G. S.; Suling, W. J.; Reynolds, R. C. Bioorg. Med. Chem. 2001, 9,
3129.
Figure 1. X-ray crystal structure of compound 23.
Both alcohols 23 and 24 were converted into iminosugars
25 and 3, respectively, by removal of the protecting groups
with aqueous 1 M HCl.
(13) 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.
(14) Synthesis of a diastereoisomer (3R,4S)-4-[(1S)-1,2-dihydroxyethyl]-
pyrrolidin-3-ol from D-xylose has been reported: Filichev, V. V.; Brandt,
M.; Pedersen, E. B. Carbohydr. Res. 2001, 333, 115.
(10) For a selected example, see: Yang, C.; Murray, W. V.; Wilson, L.
J. Tetrahedron Lett. 2003, 44, 1783.
Org. Lett., Vol. 7, No. 16, 2005
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