Novel cyclic sugar imines: carbohydrate mimics and easily elaborated scaffolds for aza-sugars.

Article abstract of DOI:10.1021/ol016970o

[reaction: see text] Representative simple or polyhydroxylated, pyrrolidine (e.g, DRAM) or piperidine (e.g., DNJ) imines not only are potential carbohydrate-processing enzyme inhibitors that may be formed as regioisomeric variants but also are scaffolds that may be rapidly elaborated to diversely functionalized aza-sugars through highly diastereoselective organometallic additions.

Full text of DOI:10.1021/ol016970o

ORGANIC
LETTERS
2002
Vol. 4, No. 1
103-106
Novel Cyclic Sugar Imines:
Carbohydrate Mimics and Easily
Elaborated Scaffolds for Aza-Sugars
Benjamin G. Davis,*,†,‡ Michael A. T. Maughan,‡ Timothy M. Chapman,†,‡
Renaud Villard,‡ and Steve Courtney§
Dyson Perrins Laboratory, UniVersity of Oxford, South Parks Road,
Oxford OX1 3QY, U.K. and Oxford Glycosciences Ltd., The Forum, 86 Milton Park,
Abingdon, Oxfordshire OX14 4RY, U.K.
ben.daVis@chem.ox.ac.uk
Received October 29, 2001
ABSTRACT
Representative simple or polyhydroxylated, pyrrolidine (e.g, DRAM) or piperidine (e.g., DNJ) imines not only are potential carbohydrate-
processing enzyme inhibitors that may be formed as regioisomeric variants but also are scaffolds that may be rapidly elaborated to diversely
functionalized aza-sugars through highly diastereoselective organometallic additions.
Polyhydroxylated nitrogen heterocycle aza-sugars may be
considered to be mimics of sugars in which the ring oxygen
has been substituted for a nitrogen atom.1 The often potent
inhibitory activity of many of these compounds toward
carbohydrate-processing enzymes has suggested their use in
a wide range of potential therapeutic strategies including the
treatment of viral infections,2 cancer,3 diabetes,4 tuberculosis,5
lysosomal storage diseases,6 and parasitic protozoa.7 More-
over, aza-sugar transition state analogues have proved
themselves to be invaluable tools in the study of the
mechanism of action of carbohydrate-processing enzymes.8
We have chosen to investigate two structural motifs that may
offer generally enhanced inhibitory potency in aza-sugars:
(i) CdN unsaturation and (ii) additional hydrophobic sub-
stituents.
† Dyson Perrins Laboratory.
‡ Department of Chemistry, University of Durham, South Road, Durham
DH1 3LE, U.K.
§ Oxford Glycosciences Ltd.
(1) (a) Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2, 199. (b)
O’Hagan, D. Nat. Prod. Rep. 1997, 14, 637. (c) Stu¨tz, A. E. Iminosugars
as Glycosidase Inhibitors; Wiley: Weinheim, 1999. (d) Asano, N.; Nash,
R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11,
1645.
(2) (a) Karpas, A.; Fleet, G. W. J.; Dwek, R. A.; Petursson, S.;
Namgoong, S. K.; Ramsden, N. G.; Jacob, G. S.; Rademacher, T. W. Proc.
Natl. Acad. Sci., U.S.A. 1988, 85, 9229. (b) Block, T. M.; Xu, X. L.; Platt,
F. M.; Foster, G. R.; Gerlich, W. H.; Blumberg, B. S.;. Dwek, R. A. Proc.
Natl. Acad. Sci., U.S.A. 1994, 91, 2235.
(3) Goss, P. E.; Baker, M. A.; Carver J. P.; Dennis, J. W. Clin. Cancer
Res. 1995, 1, 935.
(4) Watson, K. A.; Mitchell, E. P.; Johnson, L. N.; Son, J. C.; Bichard,
C. J. F.; Orchard, M. G.; Fleet, G. W. J.; Oikonomakos, N. G.; Leonidas,
D. D.; Kontou, M.; Papageorgiou, A. C. Biochemistry 1994, 33, 5745.
Remarkably, despite their direct resemblance to the
putative flattened transition states or intermediates of car-
(5) (a) Davis, B. G.; Brandstetter, T. W.; Hackett, L.; Winchester, B.
G.; Nash, R. J.; Watson, A. A.; Griffiths, R. C.; Smith, C.; Fleet, G. W. J.;
Tetrahedron 1999, 55, 4489. (b) Shilvock, J. P.; Wheatley, J. R.; Nash, R.
J.; Watson, A. A.; Griffiths, R. C.; Butters, T. D.; Muller, M.; Watkin, D.
J.; Winkler, D. A.; Fleet, G. W. J. J. Chem. Soc., Perkin Trans. 1 1999,
2735.
10.1021/ol016970o CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/08/2001

bohydrate-processing enzyme mechanisms and their potential
to act as suicide inhibitors, few sugar imines are known. In
the few cases that sugar imines have been synthesized they
have shown enhanced inhibitory properties over their fully
reduced counterparts.9 Indeed, nectrisine (FR-900483) 1
isolated from Nectria lucida is a known potent R-manno-
sidase and glucosidase inhibitor.10 The introduction of
hydrophobic aromatic or alkyl groups has also given rise to
novel sugar mimetics with enhanced potency (through
interaction with hydrophobic protein residue side chains) and
bioavailability (through altered membrane permeability) in
carbohydrate-processing systems.11 Typically the synthesis
of sugar mimetics bearing such additional substituents often
requires their introduction at an early stage in the synthesis;
however the synthesis of diverse arrays of aza-sugars would
ideally involve the elaboration of a late stage intermediate.
To address this problem and with the aim of creating libraries
for high throughput screening, we set ourselves the goal of
developing just such a late stage diversification. As our
synthetic strategy we have successfully combined (i) regio-
selective CdN imine formation with (ii) the irreversible
addition of organometallics to these late stage cyclic imine
intermediates (Scheme 1).
Remarkably, although the irreversible addition of orga-
nometallics to acyclic imines has been widely exploited,13
its application to cyclic imines has been scarce.14 Indeed,
such additions to polyhydroxylated imines have to date been
limited solely to iminoribitol 2. These elegant studies15 have
highlighted the synthetic potential of this method through
the addition of a variety of nucleophiles to 2 that allowed
the preparation of “immucillin” nucleoside analogues as
potential antimalarials.7 However the generality of this
methodology and in particular the scope of the imine
electrophile is unexplored. This communication reveals the
wide scope of this methodology, including its application to
the elaboration of 3 to prepare nectrisine analogues, the
elaboration of known model glycosidase inhibitors 1-deoxy-
nojirimycin (4, DNJ)16 and 1,4-deoxy-1,4-imino-L-rhamnitol
(5, DRAM),17 and the first examples of such additions to
cyclic ketimines.
To probe the breadth of (i) imines that could be synthe-
sized and (ii) the imine addition methodology we chose imine
targets 10, 11, 15, 18, 21, 22, 25 and 26 (Scheme 2). Simple
piperidinoimines 10 and 11 were readily prepared by
elimination of HCl with diazabicycloundecene (DBU) from
their corresponding N-chloro derivatives 8 and 9, which were
themselves prepared using N-chlorosuccinimide (NCS) in
Et2O. Polyhydroxylated sugar imines 15, 18, 21, 22, 25, and
26 were prepared in three contrasting ways to illustrate ready
preparation from different sources.
Scheme 1a
First, to illustrate the construction of a complete aza-sugar
motif from an unfunctionalized scaffold, racemic dihydroxy
iminothreitol 15 was prepared from 3-pyrroline 12 in seven
steps. Thus, N-protection, epoxidation,18 and hydrolysis gave
trans-diol 13,19 which after protecting group manipulation
afforded protected amine 14 in 36% overall yield. Chlorina-
tion of 14 using NCS followed by elimination with diaza-
bicycloundecene (DBU) gave target iminothreitol 15. The
(10) (a) Hibata, T.; Nakayama, O.; Tsurumi, Y.; Okuhara, M.; Terano
H. Ohsaka, M. J. Antibiot. 1988, 41, 296. (b) Kim, Y. J.; Takatsuki, A.;
Kogoshi, N.; Kitahara, T. Tetrahedron 1999, 55, 8353.
a Strategic stages: (i) regioselective imine formation; (ii) ir-
reversible addition of R1M, R2M, ....
(11) For representative examples, see: (a) Platt, F. M.; Neises, G. R.;
Karlsson, G. B.; Dwek R. A.; Butters, T. D. J. Biol. Chem. 1994, 269,
27108. (b) Murray, B. W.; Takayama, S.; Schultz J.; Wong C.-H.
Biochemistry 1996, 35, 11183. (c) Bleriot, Y.; Veighey, C. R.; Smelt, K.
H.; Cadefau, J.; Stalmans, W.; Biggadike, K.; Lane, A. L.; Mu¨ller, M.;
Watkins, D. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 1996, 7, 2761. (d)
Butters, T. D.; van den Broek, L. A. G. M.; Fleet, G. W. J.; Kru¨lle, T. M.;
Wormald, M. R.; Dwek, R. A.; Platt, F. M. Tetrahedron: Asymmetry 2000,
11, 113.
(12) Some of this work was first presented at the 2nd EuroConference
on Carbohydrates in Drug Research, Estoril, Portugal, Sept 14-17, 2000.
(13) (a) Volkmann, R. A. In ComprehensiVe Organic Synthesis: Addi-
tions to C-X π bonds, Part 1; Schreiber, S. L., Ed.; Pergamon: Oxford,
1991; pp 355-396. (b) Bloch, R. Chem. ReV. 1998, 98, 1407. (c) Kobaysahi,
S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
(14) Elegant Strecker-type additions of cyanide to cyclic imines have
been reported but due to their reversible nature rely on product stability for
stereocontrol. See ref 9a for a prime example.
(15) (a) Evans, G. B.; Furneaux, R. H.; Gainsford, G. J.; Schramm V.
L.; Tyler, P. C. Tetrahedron 2000, 56, 3053. (b) Furneaux, R. H.; Limberg,
G.; Tyler P. C.; Schramm, V. L. Tetrahedron 1997, 53, 2915. (c) Horenstein,
B. A.; Zabinski R. F.; Schramm, V. L. Tetrahedron Lett. 1993, 34, 7213.
(16) Inouye, S.; Tsurouka, T.; Ito, T.; Niida, T. Tetrahedron 1968, 24,
2125.
(17) Davis, B.; Bell, A. A.; Nash, R. J.; Watson, A. A.; Griffiths, R. C.;
Jones, M. G.; Smith, C.; Fleet, G. W. J. Tetrahedron Lett. 1996, 37, 8565.
(18) Li, Q.; Wang, W.; Berst, K. B.; Claiborne A.; Hasvold, L. Bioorg.
Med. Chem. Lett. 1998, 8, 1953.
Thus, this Letter describes the synthesis of novel sugar
imines of double utility not only as attractive inhibitor targets
in their own right but also as scaffolds that may be readily
and diversely elaborated. In this way we have been able to
construct sugar mimics bearing one or both of two structural
elements of potentially enhanced potency: (i) endocyclic Cd
N unsaturation and (ii) a hydrophobic group.12
(6) Fan, J. Q.; Ishii, S.; Asano N.; Suzuki, Y. Nat. Med. 1999, 5, 112.
(7) (a) Li, C. M.; Tyler, P. C.; Furneaux, R. H.;. Kicska, G.; Xu, Y. M.;
Grubmeyer, C.; Girvin, M. E.; Schramm, V. L. Nat. Struct. Biol. 1999, 6,
582. (b) Miles, R. W.; Tyler, P. C.; Evans, G. B.; Furneaux, R. H.; Parkin,
D. W.; Schramm, V. L. Biochemistry 1999, 38, 13147.
(8) (a) Sinnott, M. L. Chem. ReV. 1990, 90, 1171. (b) Legler, G. AdV.
Carbohydr. Chem. Biochem. 1990, 48, 319 (c) Stu¨tz, A. E. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1926 (d) Heightman T. D.; Vasella, A. T. Angew.
Chem., Intl Ed. 1999, 38, 750.
(9) (a) Takayama, S.; Martin, R.; Wu, J. Y.; Laslo, K.; Siuzdak, G.;
Wong, C.-H. J. Am. Chem. Soc. 1997, 119, 8146. (b) Wong, C.-H.;
Provencher, L.; Porco, J. A.; Jung, S. H.; Wang, Y. F.; Chen, L. R.; Wang
R.; Steensma, D. H. J. Org. Chem. 1995, 60, 1492.
(19) Huang H.; Wong, C.-H. J. Org. Chem. 1995, 60, 3100.
104
Org. Lett., Vol. 4, No. 1, 2002

elimination method also allowed the synthesis of the two
nectrisine analogues 25 and protected 5-methyl-5-deoxy-
nectrisine 26 from iminothreitol 23.21
Scheme 2a
With a representative selection of aldimine or ketimine,
pyrrolidino- or piperidino-, simple or polyhydroxylated
substrates 10, 11, 15, 18, and 21 in hand, we investigated
the introduction of hydrophobic substituents through organo-
metallic addition (Table 1).22 Simple imines 10 and 11
Table 1. Results of Organometallic Additions to Cyclic Imines
a Reagents and conditions: (i) NCS, Et2O, 70%, 75%, 96%, 97%,
93% from 6, 7, 14, 19, 23; (ii) DBU, DCM for 11, 77% from 7;
DBU, THF, 67%, 90%, 52% for 15, 21, 25; (iii) ZCl, 3 M, NaOH
(aq), toluene, 97%; (iv) mCPBA, DCM, 46%; (v) 2 M H2SO4 (aq),
Et2O, 96%; (vi) TBDMSOTf, py, DCM, 92% for 14, 61% for 18;
(vii) H2, Pd-C, MeOH, 92%; (viii) see ref 20, 36% from 16; (ix)
PPh3, DCM, 0 °C, 96%; (x) LiTMP, THF, 90%, 83% for 22, 26.
presence of an imine CdN bond was confirmed by charac-
teristic IR (υmax 1645 cm-1), 1H NMR (δH (CDCl3) 7.44 (d,
1H, J2,3 2.8 Hz)), and 13C NMR (δC 169.0) resonances.
Second, as an alternative strategy for the preparation of sugar
imines we utilized a Staudinger aza-Wittig cyclization.
Iminorhamnitol 18 was prepared from protected azidolactol
17, which was itself prepared from parent carbohydrate
L-rhamnose 16 in six steps.20 Thus, treatment of 17 with
solid-supported PPh3 led to intramolecular imine formation.
Protection of the secondary alcohol gave 18 in 57% overall
yield. Finally, we elaborated commercially available aza-
sugar arcehtype tetra-Bn-DNJ 19 and were pleased to
discover that through the appropriate choice of conditions
the regioselectivity of the elimination of 20 could be
controlled. Thus, treatment of 20 with DBU afforded
ketimine 21, whereas elimination with lithium tetramethyl-
piperidide (LiTMP) gave aldimine 22. This adaptable
a Conditions unless stated otherwise: Et2O, rt. b THF, rt. c Et2O, dioxane,
rt. d Product stereochemistry established by NOESY NMR at >98% de
unless stated otherwise. e Yield over two steps from chloramine. f 72% de.
reacted sluggishly with a variety of organometallics in only
moderate yield. Interestingly, under the conditions of the
Grignard reaction, dimerization products were obtained
alongside the expected addition products.23 However, we
were delighted to observe that the addition methodology
(21) Compound 23 is in fact a product of the novel addition reactions
described below (see Table 1).
(22) This range of imines allowed us to successfully demonstrate
representative additions to both aldimines 10, 15, 18 and ketimines 11, 21.
Additions to other aldimines 22, 26 and ketimine 25 are now underway.
(23) Tentatively characterized as addition product of exocyclic enamine
tautomer of 10 to 10 itself, which was catalyzed by Mg salts; the synthetic
utility of this dimerization is currently being explored.
(20) Davis, B. G.; Nash, R. J.; Watson, A. A.; Smith C.; Fleet, G. W. J.
Tetrahedron 1999, 55, 4801.
Org. Lett., Vol. 4, No. 1, 2002
105

could be applied to ketimines; reaction of BnMgCl with 11
gave the corresponding adduct 28 in a moderate 39% yield,
which to the best of our knowledge is the first such addition
to a cyclic ketimine. The reactions of polyhydroxylated
imines 15, 18, and 21 with nucleophiles were more efficient,
proceeded more rapidly than for the corresponding simple
imines 10 and 11, and were compatible with a variety of
protecting groups (Bn, TBDMS, isopropylidene). Moreover,
in all cases good to excellent diastereoselectivities were
observed in a sense consistent with steric approach control,
which only drifted from >98% de for delivery of the small
methyl substituent to 15 to give 29. It should be noted that
even hindered imines such as 21 are effective reactants using
this strategy and provided another rare example of an addition
to cyclic ketimines. Best yields were obtained with 18, and
this may be due to an inherently greater stability of this fused
[4.4.0] bicyclic system. This is supported by the recovery
of 18 as the balance of mass in its reaction (based on
recovered starting material reaction yield of 32 was 97%)
and by the isolation of pyridine elimination products and
benzyl alcohol as side products in reactions of less rigid 21.
Scheme 3a
a Reagents and conditions: (i) NCS, Et2O then DBU, 59%, 79%
for 15, 34; (ii) 25-50% TFA (aq); 63%, 34% for 35, 36; (iii)
PhMgBr, Et2O, 44%.
well with alternative synthetic routes. For example, we
successfully synthesized protected 5-methyl-5-deoxy-nec-
trisine (26) in 10 steps and 12% overall yield, which
compares favorably to the synthesis of the only similar
analogue 5-deoxynectrisine (16 steps, 10% yield).10 The
mechanism of these useful organometallic additions is
unclear. Interestingly, side products consistent with both
radical and polar additions have been isolated, and further
investigation of the mechanism is in progress. Testing of
the novel aza-sugars synthesized here and their deprotection
products for biological activity, including the inhibition of
carbohydrate-processing enzymes, is underway, the results
of which will be presented in due course.
In summary, we have successfully demonstrated that both
sugar-derived imines and diversely functionalized aza-sugars,
as potential carbohydrate-processing enzyme inhibitors, may
be rapidly synthesized as a representative range of simple
or polyhydroxylated, pyrrolidine or piperidine scaffolds by
regioselective imine formation and highly diastereoselective
irreversible addition. A wide variety of novel aza-sugars have
been prepared in this way including aromatic, alkyl, and Cd
N functionalized analogues of deoxynojirimycin (DNJ), 1,4-
imino-L-rhamnitol (DRAM), and nectrisine. This ready
elaboration of known and commercially available aza-sugar
scaffolds lends itself well to the rapid development of aza-
sugar libraries through parallel synthesis methods (Scheme
1) and hence to structure-activity relationship studies.
Scheme 3 illustrates that different advantageous CdN or
hydrophobic motifs may be sequentially installed, e.g., into
15, 30, and 34, at each stage in routes that may generate
potential inhibitors, e.g., 35 and 36, at each such iterative
stage.24 Although in some cases the efficiencies of additions
are only modest, the overall yield of this strategy compares
Acknowledgment. We thank the EPSRC (R.V.) and
Oxford Glycosciences for funding (M.A.T.M., T.M.C.);
David Scopes and Phil Hay for useful discussions; and the
EPSRC for access to the Mass Spectrometry Service at
Swansea, the Chemical Database Service at Daresbury, and
for the award of CNAA (M.A.T.M.) and quota (T.M.C.)
studentships.
Supporting Information Available: Experimental pro-
cedures and characterization. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL016970O
(24) Other complementary methods exist for creating potentially elec-
trohphilic azomethine carbons, e.g., nitrones or acyl immoniums, However,
these require additional steps to both introduce and remove additional
functionality.
106
Org. Lett., Vol. 4, No. 1, 2002