Proc Indian Natn Sci Acad, @ Printed
71,,
A, Nos. 3&4, May & July 2005, pp. 137-t53
in India.
1-I'T.IMINOSUGARS: A CREATIVE CHEMICAL DESIGN FOR TRANSTTION STATE ANALOGUES OF GLYCOSIDASE
INHIBITORS GANESH PANDE,Y*, SHRINIVAS G DUMBRE AND MANMOHAN KAPUR Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune-411008 (India) (Received 03 May 2005; Accepted 19 July 2005) Understanding of the reaction mechanisms of glycosidases, structure and activity correlation has led to design, synthesis and evaluation of several potent glycosidase inhibitors. Azasugars or 1-N-iminosugars are a creative chemical design for transition state analogues of carbohydrate mimetics-based glycosyl transferase inhibitors. This review focuses
on the development and synthesis of various 1-N-iminosugars that shows significant biological activity.
Key Words: 1-N-lminosugars, Glycosidase inhibitors
1 Introduction Azasugars (polyhydroxylated pyrrolidines and piperidines) represent an interesting class of glycosidase inhibitors and are widely recognized as potential therapeutics for the treatment of interalia diabetes, cancer, and viral infections. The biological activity of these glycomimetics comes from the conformational resemblance to natural sugars, by the protonation of the ring nitrogen at physiological pH, which mimics the developing charge of an intermediate oxocarbonium ion during glycosidic bond cleavage of a glycoside (i.e. enzyme) Enzymes are one
of the four major classes of nature's biopolymers, playing a fundamental role in life's processes. In particular, glycosidases and glycosyl transferases are ubiquitous macromolecules, which catalyze glycosyl group transfer reactions that assemble, trim and shape bioactive glycoprotein and glycolipid conjugates. Overall, these processes involve cleavage of the glycosidic bond linking a sugar's anomeric carbon with an oligo or polysaccharide or a nucleoside diphosphate group. The liberated glycosyl group is further transferred to water (by glycosidases) or to some other nucleophilic acceptor (by transferases) (Fig.
1).
A primary
classification
of
glycosidases can be
done based on, a) The position *E -mail
:
of the glycosidic
[email protected]; Fax: +9 l-20-25902624; Tel: +91-20-25902324.
bond that is cleaved by the enzyma Exoglycosidases remove sugars one at a time, from the non-reducing
end of an oligo or polysaccharide and are involved and glycogen, the processing of eucaryotic glycoproteins, the biosynthesis and modification of glycosphingolipids and the catabolism of peptidoglycans and other glycoconjugates. Endoglycosidases cleave interior
in the breakdown of starch
glycosidic bonds within polysaccharides and are involved in the catabolism and clearance of the aged glycoproteins. These enzymes also catalyze the alteration of bacterial and plant cell walls as well as the hydrolysis of highly insoluble structural polysaccharides like chitin and cellulose.
Ro-Vt_R. t1)
-9!-1t.' Oligo/ R"=
H4- Ro-\d*oH
Po'Ysaccaride
(2)
1
R"= Nucleoside drphosphate grouq
I
I
Glvcosvl trans{erase
ll
no-\li9\*r.ru (3)
Nu = Nuteophitic acceptor
Fig.1
b) Glycosidases are more rigorously classified based on the stereochemistry of the anomeric glycosidic bond that they cleave. Enzymes catalyzing the cleavage of a d-glycosidic bond are termed as riglycosidases while those cleaving a d-glycosidic bond are termed as A-glycosidases. Depicted in Scheme 1 is a typical glycosidase reaction mechanism. d-Glycosidases (axial glycoside bond)
GANESH PANDEY er a/.
138
A. a -Glycosidase reaction (axial glycoside bond)
I
\\\ no\
r"'
o
|--\\
Protonation
Tv e"a,me
oH)
(4)
o-R
B. b-Glycosidase reaction
|+n,o {
(equtorial glycoside bond)
II
rro- * \-_r I oH \^
( N noL
?n .on
\lI9LL6 oH fl Proionationl HO \ / I
oH
_o
by enzyme
r
!)vo.'["
I '
\....'>o, ,o-.T\
oH \oH
:. (i)""
(10)
(6)
Ll
I lH
I
\-\,oH-oa .)
Ho\-
L
,r,N
First intermidiate
Scheme
are generally believed to act through an E2 type elimination mechanism during which a positively charged aglyssn (the leaving group) and the lone pair of the ring oxygen are positioned antiperiplanar, cooperatively facilitating the glycosidic bond cleavage reaction.l In the case of the A-glycosidase (equatorial glycoside bond) reaction, if the enzyme proceeds via an E2 type mechanism, similar to that of the d-glycosidases, the protonated substrate 6 has to go through a highly strained intermediate 7 that may not favor further reaction. Therefore, in the case of a d-glycosidase reaction, the positively charged aglycon leaves via an E1 like mechanism, involving the glycosyl cation 8, further stabilized by the ring oxygen to give 9. Thus, as seen in Scheme 1, although the final reaction intermediate in both the reaction mechanisms is the same flattened, half chair oxocarbenium ion 9, the first intermediate in the case of d-glycosidase reaction differs with respect to the position of charge development. Glycosidases are also classified on the basis of the stereochemical outcome of the newly formed anomeric bond. The enzymatic cleavage of the glycosidic bond liberates a sugar hemiacetal with either the same configuration as the substrate (retention) or less cornmonly, the opposite
1
configuration (inversion). Based on this criterion or inverting glycosidases. Any chemical entity that is capable of mimicking either the charge or shape (or both) of the substrate or that of any of the transition states, can act as a reversible inhibitor of that particular glycosidase. These entities are termed as glycosidase inhibitors. glycosidases are classified as retaining
2 Inhibitors of Glycosidases Historically, the first glycosidase inhibitors were the
families of the monosaccharide-derived
d-
aldonolactones (such as D-gluconolactone 1,1-),2 and glycosyl amines (1-amino-1-deoxy pyranoses such as D-glucosyl amine l2).3 (Fig. 2) Although, lacking long-term stability in aqueous solution, these families of compounds typically display competitive inhibition against glycosidases
o
HO
Ho-\-o-rNH' ll
,roH
uo"
OH ({ 1}
f
"oH OH
(121
Fig. 2
1-N-IMINOSUGARS:
A
CREATIVE CHEMICAT DESIGN
t39
whose substrates they most closely resemble. Ever
(b) The aminocyclitols like trehazolin, acarbose,
since the pioneering work by Paulsen on sugar analogues with basic nitrogen instead of oxygen
mannostatins and allosamidins. (c) Entities incorporating a nitrogen in more than one position, including the one in the ring, e.g.; Nagstatins, Siastatins, etc. Several comprehensive reviews and accounts on glycosidases and glycosidase inhibitors have been published, covering various subsections of the
in the ring (also called the azasugars or iminosugars)a
and the discovery of such a natural product (nojirimycin 17)5, over three dozen naturally occurring iminosugars have been identified and many additional analogues and horologes have been synthesized, opening a dynamic research area.
A wide variety of structural motifs
characterize
glycosidase inhibitors. Prominent amongst them are:
(a) The nitrogen heterocycles incorporating four to seven membered rings as well as bicyclics like pyrrolizidines, indolizidines and nortropanes. Inhibitor
field.6 These "sugar-shaped alkaloids"
are
widespread in plants and microorganismsT and are believed to bind to the active site of the glycosidases by closely mimicking the charge and shape of the transition state of the glycosidic cleavage reaction. Some of the natural and synthetic glycosidase inhibitors are being depicted below in the tabular
form. Activity
Source
(only the most inhibited enzymes are being listed)
(L) Four Membered Rings OH
Ho..
A-o* l-l LNH
Synthetic compund.s
Inhibits amyloglucosidase from Rhizous mold. (K, = 7.6 mM, ICru = 4.0 mM)8
Isolated from leaves of Derris elliptica.e
Inhibits a-glucosidase from Bacillus stearothermophillus.(K, = 0.03 mM at pH 6.8)10' Inhibits trehalase from corynebacterium W. GC, =
(13) 1,3-dideoxy-1,3-im ino-L-xylitol
(2) Five Membered Rings H
N-
Ho1 ) -o* .\ HO1ra1 OH DMDP:
0.35 mM)
1ob
(2R,3R,4R,5R)Bis(hydroxymethyl)-Cihydroxy pyrrolidine
Isolated from fruits of
HO
HOs)
OH
An gy lo c alux
b
outiqe anu s.1'
Inhibits a-glucosidase from yeast. (IC,n = 0.18 mM at PH 6.8). ''z
(1
DAB 1: 1.4-dideoxy-1,4-imino-Darabinitol
uo1-Nr\ \/ -.-1 HO OH
Isolated from culture broth of
fiingts Nectria lidica.t3
(16)
Inhibits a-glucosidase from yeast. 1a 0C- = 0.08 mM).
Nectricine (3)
Six membered Rings CH.OH l'
HO,rAt, ll
Ho'-fon 6H 117l
Nojirimycin
Isolated ftom Streptomyes roseochromogenes.s
Inhibits A-glucosidase from Aspergillus wentii. (K,= 0.07 l.tM at pH 5'0) Inhibits d-glucosidase from 1s sweet almond. (4 = 0.9 pM at pH 5.0).
t40
GANESH PANDEY e/ a/. CH,OH l'
Ho..rAr.rH
lt
uo/-tr: OH
First synthesized.a Later was isolated from roots of Mulberv ttees-16
(18)
Inhibits 6-glucosidase from rice. (K, = 0.01 pM at pft 6.0) 16 Inhibits 6-glucosidase from Bacillus stearothermophilus (K = 0.44 at pH 6.8). 10
1-deoxynojirimycin (Moranoline)
CH"OH
Ho"
t'
rA*, Ir
HOv
Isolated from seeds of
Inhibits r7-galactosidase from rat intestine.
F agopyrum E sculentum.ls
(IC, =
Isolated from Streptomyces
Inhibits d-glucuronidase from bovine liver (ICro = 16 lt}d)."^ Inhibits N-acetyl neuraminidase from streptococcas. (IC.n = 29 ltM)."o
15
4M at pH
5.8).
1'q
e)
(1
Fagomine
COOH
Ho\-\ tl
Hot\-t-NH :
NHAc
verticillus var. Quantum.2o
(20)
Siastatin B
CH,OH
unl' ,'"a(-N\
I l- /-l cooH Ho/----'-'N :
Isolated from Streptomyces Amakusaesis.22
Inhibits N-Ac-d-glucosamindine from bovine kidney (IC,o = g.g1 pM at pH 5.0;. z:"'r Also inhibits i/-Acd-glucosamidine from hog kidney (!{, = 0.011 7zM at pH 4.5).""
Synthetic molecule.2a
Inhibits ui-glucosidase from Bacillus stearothermophilus
NHAc l21l
Nagstatin
(4) Seven Membered Rings
HO OH 1i Ho' ( YoH \,i
(K, = 4.8 pM at pH 6.8).'o'
H (22) (3S,4R,5R,6s)-3.4.5.6tetrahydroxyazepane
(5) Pyrrolizidines
HO.OH -J-{
Ho{l) \-NJ HoHri
1ze1
Isolated from Alexa leiopetala
(plate
S).'zs"
Isolated from the seeds ol C a stano sp ermum Au s tr a I ae.26
HO
pgH2i 12ay
Austraiine
Inhibits amyloglucosidase from aspergillus niger. (ICso = 6 pM at pH 5.0).'zsb
Inhibits amyloglucosidase from aspergillus niger.
(K, =
7
ttM).'u
1.N-IMINOSUGARS:
A
t47
CREATIVE CHEMICAL DESIGN
(6) Indolizidines OH
Isolated from the seeds of
HO
Castanospermum Australae.2T
Inhibits 6-glucosidase from rice (K, = 0.015 plM).'zs' Inhibits sucrase from cacogreen coffee beans cell line'
(K, = o.o02a pM at pH 8.0)''*
HO Castanospermine
LI 9H
C[]o,
Inhibits amyloglucosidase from aspergillus niger (K,= 2.0 at pH 5.0).30
Isolated from Astralagus lentiginous.2e
(26)
Lentiginosine
H?H9H /',,'.I--\
Isolated from legumes of
(-'{,-/ o'
Swainson
Canescens.3l
(27)
Swansonine
Inhibits ri-mannosidase from human liver lysosomal (Ki = 0.07 mM at pH 4.0).3tu Inhibits d-manrrosidase from humanliver, golgi II (ICs0 = 0.04 lM at pH 5.7)."o
(7) Nortropanes
Hq
PH
(r*\-o,
Calystegia sepium.33
Inhibits d-glucosidase fuom Caldocellum saccharolyticum. (K, = 12 pM, lCro = 37 l.tM).to
Isolated from M. bombYsis,
Inhibits d-glucosidase from sweet almonds.
Isolated from root cultures of
\J) (28)
Calystegine A3
'o'* PH
(\Lo,
*oV.o*
M.
alba.3s
(K = 0.4s pM, tC,o = 0.82
ttM).=a
(2s)
Calystegine
3
C1
Biological Significance Inhibitors
of
with very advanced malignancies showed that
Glycosidase
The tremendous potential of glycosidase inhibitors
in studying the biological functions oligosaccharides has resulted
in
of
opening up new
avenues in glycobiology.36 The capability of polyhydroxy alkaloids to disrupt the general cellular function of glycoprotein processing promises therapeutic potential for the treatment of various carbohydrate related disorders. Investigation of these alkaloids for therapeutic potential has so far concentrated on three major disease states i.e., for treatment of cancer and inhibition of metastatis, as anti-diabetic drugs and for antiviral activities. Swainsonine (27) has received particular attention as an anti-metastatic agent. Clinical trials in humans
lysosomal 6-mannosidase and Golgi mannosidase II were inhibited and some improvement in clinical status occurred.3' Castanospermine (25) has also been reported to suppress the metastasis in the mice but experiments with this alkaloid have not been as extensive as those with swainsonine.3s Castanospermine and l"-deoxynojirimycin (18) have been shown to be capable of suppressing the infectivity of a number of retroviruses, including the HIV responsible for AIDS.3e" This effect is a
consequence
of disruption of
glycoprotein
processing enzyme resulting in the changes of the structure of the glycoprotein coat of the virus. Cellular recognition of the host is, thus, prevented and syncytum formation is suppressed. To reduce
142
GANESH PANDEY e/ a/.
water-solubility (causative of rapid excretion), 6O-butyryl castanospermine and N-butyldeoxynojirimycin have been synthesized and both these compounds have undergone clinical trials against AIDS in humans, either alone or in combination with AZT.3eb Another structural modification of deoxynojirimycin, the I'rhydroxyethyl derivative, miglitol, an inhibitor of rf-glucosidase, has been clinically evaluated and released as an antidiabetic drug in insulin and noninsulin dependent diabetes. The alkaloid was shown to potently inhibit glucose induced insulin release and also suppressed the islet rf-glucoside hydrolase activity, thus, controlling postglycemia.ao Another glycosidase inhibitor, voglibose, a synthetic derivative of valiolamine is also being marketed as an anti-diabetic.T Acarbose, a naturally occuffing glycosidase inhibitor, has also been used as an antidiabetic agent.T The ability of polyhydroxy alkaloid glycosidase inhibitors to prevent cellular recognition has resulted in their evaluation for clinical situations where suppression of an immune response is desirable. Thus, ln vivo experiments have shown that castanospermine can be used as an immunosuppressive drug; promoting heart and renal
allograft survival in rats.al Glycosidase inhibitors are also showing tremendous promise as new therapeutics for lysosomal storage diseases like Gaucher's disease and Fabry disease.T
4
Development of l-N-iminosugars as Glycosidase Inhibitors An important element of enzymatic catalysis is the ability of an enzyme to lower the energy of the transition state for the reaction it catalyses. The only real evidence for this theory is the fact that stable compounds that resembles the transition state, transition state analogues, are competitive inhibitors of that particular enzyme.6' These understanding have led to a keen interest in recent years for designing compounds that in terms of polarity and shape resemble the transition state of glycosidic cleavage or formation to create potent, selective errzyme inhibitors. As depicted below, (Scheme 2) therc are three important reaction intermediates 31, 32, and 33 depending upon the position of the charge buildup during the glycoside hydrolysis. It was observed that a compound that could resemble any of the intermediates 3L-33 should be an inhibitor of the respective glycosidases.
Ho1-o-ro-* uof I
Iu.] lt
A
] no-\-o'.-o:n
,*
Hof iLOH]
'or-r
OH
(30)
-RQH
I
'oH
+ROH I
(31)
ol
,o^ro)
r-ro-\-o'-o
ll Hof
I
'on
oH
"o/)/ oHl
OH
l
(33)
{32)
Scheme 2
There are a number of compounds that fulfill this criterion. One group of compounds belongs to the nojirimycin class. These compounds resemble monosaccharides but the ring oxygen has been replaced with a nitrogen atom. Thus, if protonated at the basic nitrogen atom, these compounds become the analogues of 33. Glucosamidines6u are a group of glycosidase inhibitors, designed by Ganem and co-workers that resemble 33. Another group of glycosidase inhibitors belongs to the glycosyl amine class, which upon protonation, resemble 31. Acarbose and similar compounds when protonated at nitrogen, also resemble intermediate 3L. Until the last decade, no glycosidase inhibitor that was an analogue of 32 was known. It was long interpreted that 32 was insignificant in the glycoside cleavage process and in many theoretical discussions of glycosidic cleavage, 32 was indeed, ignored at the expense of 33. In 1.991, Reymond and coworkers reported isolating a catalytic antibody, (using transition state analogue 35 as a hapten) that could catalyse the hydrolysis of a tetrahydropyranyl
ether, a simple model of a glycosidic bond.a2 Compound 35 was considered an analogue of a carbocation at the anomeric center and in principle, an analogue of ion 32, except for the lack of hydroxyl groups. Antibody
z-O---OH
tl\/
Hzo
+Ho1/-R
(36)
. \-^l,.{> (
(37)
o]" I l- I ro'f 'ou lloHl
_t
_.r-'
[ro^f
I
L
(32)
..1
Scheme 3
This report suggested that analogues of 32 could be good transition state analogues of glycoside cleavage and since 32 was a significant transition
1.N-IMINOSUGARS:
A
in the case of a
Isogalactofagomine (40) was designed and synthesized by Ichikawa and coworkers and was found to inhibit d-galactosidase in the nanomolar range (Aspergillus oryzae, K, = 4.1 nM at pH 6.8).4 Isofucofagomine (41) was simultaneously synthesized by the groups of Bols and Ichikawa and was an extremely potent inhibitor of 6fucosidases (bovine liver, ICro = 26 ltM),os (human placenta, K, = 6.4 l.t}ld).ou Isoglucuronofagomine (42) was also designed and synthesized by the group of Ichikawa and exhibited nanomolar inhibition of d-glucuronidase (bovine liveg K - 79 nM at pH 5.0).4? Noeuromycin (43), the 2- hydroxy analogue of isofagomine was designed and synthesized by Bols and coworkers and was found to be a better mimic of D-glucose as compared to isofagomine and inhibited glucosidases in thp nanomolar range; (d-glucosidase rom sweet almonds, K, = 69 nM), (rf-glucosidase from yeast, K, = 22 rM).ot The high inhibitory activity towards ri-glucosidase was attributed to the 2-hydroxy group. In a similar manner, D-galactonoeuromycin (44) and L-fuconoeuromycin (45) were synthesized and both exhibited nanomolar inhibition of the respective glycosidases.a8 Also notable is the compound 46 (5hydroxy isofagomine), the N-alkyl derivatives of which (butyl and octyl) were found to be inhibitors
d-glycosidase reaction; analogues of this would be good inhibitors of dglycosidases. This finding led to a spurt of activity state
of creative chemical design of anomer selective dglycosidase inhibitors led by the groups of Bols,a3 Ichikawa52 and Nishimura.6e This new class of designed molecules was termed as 1-azasugar or
L-N-iminosugar class of glycosidase inhibitors. The first 1-N-iminosugar synthesized was the D-glucose type 1-N-iminosugar, isofagomine (38) (named after natural product fagomine). Designed by Bols and co-workers,a3 this molecule was nearly a perfect mimic of D-glucose and as expected, turned out to be an extremely potent inhibitor of d-glucosidase (sweet almonds, K, = 0.11 LtM).
no^1oyor
Ho-YNH t_ HOY .)
no"
OH
f
"oH OH
(38)
(3e)
lsofagomine
D-Glucose Fig.
3
Subsequently, extremely potent and selective
d-glycosidase inhibitors (1-Azasugars) were designed and synthesized. The most prominent amongst them are depicted below (Fig. a). CH?OH
HO\-ltl ,o/-*' (40)
lsogalactofagomine
-/'rl .\ v
HO'
HO,
-NH
(421
lsofucofagomine
lsog lucu ronofagomine
CH,OH
-,\
HO,\YNH
-^/'v.NH rrv i
9H,
HO,,
ll
OH (43)
,\
ll
HoA-l'lH
(41)
HO..,\
ll
cooH
QHs
HO,.
CH,OH HO..
a)rvx
.( HO'
Y
OH (45)
OH (441
Noeuromycin
D-Galacto
L-Fuco
noeuromycin
noeuromycin
OH
(o' HO,
_\
ll ,o&N-n (46) (a) R =
CaHe (b) R = CsH17
t43
CREATIVE CHEMICAL DESIGN
COOH
CH,OH
*o'A**
HO, ,( -L.NH Ir
*orl-...,-il*
noy'--rvn
(47)
(48)
D-Glucurono azafagornine
Azafagomine
R=H:s-hydroxy lsofagomine
Fig. 4
CH"
r" Ho".\** Ir
uo'\''-NH (4e)
L-Fuco
azafagomine
GANESH PANDEY er a/.
of glycolipid biosynthesis.4e l/-Butyl-5-hydroxy isofagomine (46a) inhibited 50% of phorbol ester (TPA)-induced differentiation of HL-60 cells at 0.5 mM. It also inhibits 40 7o of UDP glucose: Nacylsphingosine glucosyltransferase (from rat brain) activity at 5 mM. N-Octyl-5-hydroxy isofagomine (a6b) inhibits 50 Vo of the same enzyme activity at 1mM. Bols and co-workers also
designed
azafagomine (a7) which mimicked the transition states of both d- as well as d- glycosidase reaction.so"
This compound along with the D-glucurono (aS) and L-fuco (49) analogs when compared with the isofagomines and noeuromycins, exhibited slightly
poorer inhibitory properties for the respective glycosidases.5ob
Driven by the promising biological activities and contiguous functionalities, these designed piperidines have been in the limelight for synthetic organic chemists. The foregoing section would focus on some of the notable synthetic approaches
Approach IIsl Recently, isofagomine has been synthesized from 56 via a much shorter route (five steps from 56, in abott 30% yield); by albeit with extremely poor diastereoselectivity (dr = a 2:I).
ll-o\/oBn tto 9oit
f
-o-oan lo-v'olr
attt
b
l)t 1:
loH (57)
OH (56)
/OvOBn
r r c /-o-1oBn o,ruffior-r .-._- o,njlJ--1oa" AcO
_
OAc (59)
(58)
(a-oH :b-oH =
Scheme 5
OH
NO2 OH
(56)
(60)
=
a
5.6.2 Bols' Approach5T Bols and co-workers published a short threestep synthesis of 5-hydroxy isofagomine starting from 128 that in turn was derived from D-Mannose in three steps.
no-\.o--oH u"\ I " / 1"r
OBn _t>
ror
'-' .
/l-rt"'r ){ b'
H
Xot
OH
-ot
o ll^ -!- .UH)a>f""
(b) 'o' {%' "+ ll NH HCI Hoy'\-
(12e)
(128)
(46)
Scheme 22 Reagents and conditions: (a) NaIOo, MeOH-HrO (1:1), 2 h, 0 'c, 93o/o; (b) (i) NH3, H', 37 atm, 5Va pdlc' MeOH' 67%; (1i)
.-O-r.0Bn
HCl, HrO, MeOH, 50-55 "C, 2 h, 1,00 Vo.
IIb BocHN-.,.(,Ao, ---->
(43)
:
5.6.3 Ganem's Approachss The approach of Ganem and co-workers was
OH {122]-
of selective Fowler reductions as the key step. The synthesis utilized nine steps and had an overall yield of 49%. The enantioselectivity was a maderate 837o. based upon the use
Scheme 20
Reagents and conditions: (a) H2, PdlC, TEA, MeOH then (Boc)ro, TEA, (dr = a 2:1), chromatographic separation, 44%; (b) H,, Pd/C, EtOH, then HCl, H,O, 98Vo.
gH
ri^/-co2cHr Ho\-4v-co2cH3 ssleps I i I I
5.6 Approaches towards S-hydroxy Isofagomine
l\
Scheme
B
b
Ichikawa and co-workers first designed and synthesized 5-hydroxy isofagomine (46) in eight steps starting from 123 that was derived from Dmannose.
a
-N-
N
6orrr,
c02Ph
{741
5.6.1 lchikawa's Approachae
HO!---.J'CO2CH3 L I"OH tl t130)
{7s) QH
HO\
---\ /COOH 1tl T oH 'N'
c
(46i
H
(131)
Scheme 23 Reagent and conditions: (a) OsOo, NMO, 81%; (b)L\OIH,95Va;
(c) (i) HMDS-py, 110 "C; (ii) LAH, rIIF,83%.
x"]. .X. o-r-*oH
Yo*
-r--'
(123)
/ X,^ xl *oio*orn ,b4 O-
\/
\
o
Hofflo-o,ooa"
tt LOBn
LOBn
llzal
{125)
5.7 Miscellarxeous 5.7.1
An approach towards the Synthesis of
5-
epi-isofagomine5s -oH
N,-L?to.-?l*oan
d -\_z
(127\
I
LOBn
'-
"o. ll-l-o' *o/*N' (46)
Scheme 21 Reagents and conditions: (a) AgrO, BnBr, KI, DMF, rt. 10 h, 85Vo; (b) (i) 70Eo AcOH, rt, overnight, 80Vo; (ii) NaIO,, MeOHHrO, 0 "C, 30 min; (iii) NaBHo, rt, overnight, 84Vo; (c) (i) (CF3SO,),O, DCM, py, -40 "C, to 0 "C, 30 min; (ii) NaN., DMF, 80 "C, overnight,94To over two steps; (d) 60 Vo TFA, rt, overnight, 83%; (e) (i) 20 % Pd(OH),, H,, aq. HCl, pH = 3; (ii) Dowex 50w-x8 [H.] eluted with 5vo NH,oH, 957a.
Kazmaier and co-workers synthesized S-epiisofagomine (61) in seventeen steps with an overall yield of 9Vo from 132 utilizing an asymmetric chelate-controlled enolate Claisen rearrangement as the key step. 5.7.2 An Approach towards 5-hydroxy-5-epiisofagominesad
Pandey et
isofagomine
al.
synthesized 5-hydroxy-5-epi-
83 from 82.
5-hydroxy-5-epi-
isofagomine showed inhibition for b-glycosidase (37 "C, pH 6.0), K, = 96 mM.
1-,^T-IMINOSUGARS:
t-^^ A*"''t-.
OH OH llb
\r'\//I
CREATIVE CHEMICAL DESIGN
,U, b \/ +Y
I
o
(134I
(133) OTBDPS
a +"*-Y
{1421
{1411
HO,.
e
{1 37)
+. o\-/\ tt uo'
t-lCt
(84)
I
t
(143)
-.-\
tl
(136)
ll+ -..NHBoc TBDpSO-
I
QH:
)
g6/--t'lt-l
oBn
\
OTBDPS
9Bn rr-
ur-4r
QH:
/ I
/ \or(-N.rn
^_o BocHN ll
OH
-t-o
149
OTBDPS
\z-)
OTBDPS
A
q
?Bn
''
)-o
O--.\
tl -
-NHBoc
(138)
?Bn
tt-
Scheme 26 Reagents and conditions: (a) (i) TsCl, Py, DCM, rt, 24 h,95%; (iD PhCHTNHCHJMS, CsrCOr, TBAI, CH3CN. Reflux, 72 h, 58Vo; (b) hn, DCN, 2-PrOH, 2 h 55Va; (c) Pd(OH),, on C, HCL, MeOH, H,, 1atm, 28 h, quant.
rr?gr
6 Piperidine Triols as Glycosidase Inhibitors Ho\-^)' + h [-f 'N' H.HCI (61)
Scheme 24 Reagents and conditions: (a) (i) NaH, BnBr, DMF,90ok; (li) TFA, HrOl MeOH, 89%; (iii)TBDPSC1, py, DCM, t0% DMAP, 86Vo; (b) DCC, llVo DMAP, Boc-Gly-OH, 99Vo; (c) LDA, ZnCl, THF, -78 'C, 89Vo; (d) (D NMM, CICOOR, THF; (ii) 2mercaptopyridine-N-oxide sodium salt; (iii) r-BuSH, hn,70%; (e) (i) AD-mix-b, /-BuoH, H,O, 88%; (ii) DMP, TsOH, Acetone, 9a%; (fl TBAF, TIIF, 97ok; (g) (i) (CF3So,),o, py, DCM; (ii) HCl, dioxane; (iii) NaHCO,, 50 "C, dioxane-wates 49%; (h) (l)
TMSI, DCM; (ii) HCl, MeOH; (iii) Dowex 50W-X8, 57%.
-o'
|
tol\ ' o -^-.'N
vo .1"t .^ =oy'..- nn (82) bn
(140)
.oA
b>
nv,. ,\
:rOH
I
..^.^ HU
-NH.HCr (83)
Scheme 25 Reagents and conditions: (a) (i) OsOo, NMO, py , acetone-water
(9:1), from 0 'C to rt,24 h, 95% ; (ii) Pd(OH),. H,, EtOH, 65 psi, 6 h, 90%; (b) HCl, MeOH, rt, 4 h, quant.
Dale and co-workers systematically studied the inhibition of sweet almond d-glucosidase by a wide variety of normal and deoxy sugars. While the stereochemical configurations of individual ring hydroxyls were important, removing the C-6
hydroxymethyl substituent altogether had remarkably little effect on enzyme substrate This suryrising finding led Ganem and co-workers to postulate that stereochemically simpler or nor-analogues of deoxynojirimycin L8 may also be good inhibitors of glycosidases. Along with the gluco- analog 144, Ganem and interactions.6o
co-workers prepared and studied the galactose- 145 and mannose- analogs 146 of des(hydroxymethyl) deoxynojirimycin and found that these molecules were almost as potent glycosidase inhibitors as their
parent deoxynojirimycins6l (Fig. 5). gH
HO'
HO
,(
isofagomine
des(hydroxymethyl) deoxygalactonojiri mycin
des(hydroxymethyl) deoxynojirimycin
5ad
Pandey et al. synthesized 5'-deoxy-5-epiisofagomine (84) from (141), which showed inhibition for b-glycosidase (37 'C, pH 6.0), K = 30 mM.
In addition to these
approaches towards 1-Niminosugars, Mehta and coworkers have published
an approach for Isofagomine analogs utilizing a Diels-Alder cycloaddition approach.seu Various groups, including those of Bols5eb'" and Horenstein,5ed have synthesized many other structural analogs of these molecules, but these have not been covered here.
I
-NH
(145)
(1441
5.7.i An Approach towards 5'-deoxy-5-epi-
OH
.,"\--\ uAl
HOr_--\ LI ( .NH
QH
QH
HO
HO,.
^ f't ..^/\ -NH
HO'
__\ .\ -NH (147l
(146) des(hydroxymelhyl) deoxymannojirimycin
des(hydroxymethyl) deoxyallonojjrimycin
Fig.
5
Five years later, Kusano and co-workers isolated
triols 144, 145 and 147 from Eupatorium fortunei TURZ and showed that these triols were active components of the extracts of this plant, used in traditional Chinese and Japanese folk medicine as a diuretic, antipyretic, emmenagogue and antidiabetic agent.62
GANESH PANDEY e/ al
150
These structural analogues of the parent deoxynojirimycin can also beconsidered as 1-Niminosugar type glycosidase inhibitors although they do not resemble any of the existing pyranose sugars. Not many syntheses of these molecules are known. We shall concentrate specifically only on the reported syntheses of these molecules and
7.3 Lundt's Approachqa Lundt and co-workers derived 3,4,5-piperidine
triols from aldonolactones. Ho) B'oH oH
(}" OH
t -
Ganem and co-workers synthesized 144, 145 and 146, utilizing their strategy of reductive opening of bromopyranose sugars. --_-----
TsO^ l----t..-
12"-V"b-V ,
OBn O
o--\-
oBn
\ r17t)
:*
Nr_-1
-\
$72t
cbzHN
O- -\
11741 simirarry
O--\
lrrq
V
oH
OH (1471
9*9-o-----=_
