Polycyclitols - Novel conduritol and carbasugar hybrids as new glycosidase inhibitors

581

Polycyclitols — Novel conduritol and carbasugar

hybrids as new glycosidase inhibitors¹

Goverdhan Mehta and Senaiar S. Ramesh

Abstract: A family of novel carbasugar analogues (bicyclitols) based on cis-hydrindane and cis-decalin frameworks has

been conceptualized. These novel entities can be regarded as conduritol and carbasugar hybrids. Syntheses of these

polyhydroxylated entities have been achieved in stereo- and regioselective manners, starting from the readily available

Diels–Alder adducts of 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopentadiene and appropriate dienophiles like

cyclopentadiene or p-benzoquinone, that embody a masked 7-ketonorbornenone moiety. Thermally induced chelotropic

elimination of CO from the appropriately functionalized 7-ketonorbornenone derivatives to deliver annulated bicyclic

1,3-cyclohexadiene derivatives was the key step in this synthetic endeavor. Further oxy-functionalization of the 1,3-

cyclohexadiene moiety delivered the targeted polycyclitols. A preliminary investigation of the glycosidase inhibitory

potency of these bicyclitols, identified compounds 18 and 54 as potent and selective inhibitors of α-glucosidase (yeast).

Key words: carbasugar, conduritol, glycomimics, glycosidase inhibitors.

Résumé : On a conceptualisé une nouvelle famille d’analogues de carbasucres (bicyclitols) reposant sur des squelettes

de cis-hydrindane et de cis-décaline. Ces nouvelles entités peuvent être considérées comme des hybrides du conduritol

et des carbasucres. Des synthèses de ces entités polyhydroxylées ont été réalisées de façons stéréo- et régiosélectives à

partir d’adduits de Diels–Alder facilement accessibles du 5,5-diméthoxy-1,2,3,4-tétrachlorocyclopentadiène et de diéno-

philes appropriés, tels le cyclopentadiène ou la p-benzoquinone, qui comportent une portion 7-cétonorbornénone

marquée. L’étape clé de ces synthèses implique une élimination chélotropique thermiquement induite de CO à partir

des dérivés fonctionnalisés d’une façon appropriée de la 7-cétonorbornénone qui permet d’obtenir les dérivés cyclo-

hexa-1,3-diènes bicycliques annelés. Une oxy-fonctionnalisation subséquente de la portion cyclohexa-1,3-diène conduit

aux polycyclitols recherchés. Une étude préliminaire du pouvoir inhibiteur de la glycosidase de ces bicyclitols a permis

d’identifier les composés 18 et 54 comme actifs et comme inhibiteurs sélectifs de l’α-glucosidase (levure).

Mots clés : carbasucre, conduritol, glycomimique, inhibiteurs de la glycosidas.

[Traduit par la Rédaction] Mehta and Ramesh 594

Introduction

oxygen atom of a monosaccahride by a carbon (carbasugar,

1) or nitrogen atom (azasugar, 2). The lack of a glycosidic

linkage in these entities, which otherwise resemble the

monosaccharides in shape, size, and functionalization, ren-

ders them hydrolytically stable. In this context, a range of

carbasugars, azasugars, and their analogues, with diverse

functionalization and stereochemical features have been de-

vised, and their glycosidase inhibitory activities evaluated

(1, 2). Additionally, conduritols 3 (1,2,3,4-tetrahydroxy-5-

cyclohexenes) and their various derivatives have also at-

tracted attention because of their glycosidase inhibitory

properties (3). Several bicyclic and tricyclic conduritol vari-

ants like 4 and 5 have also been synthesized and evaluated

for their efficacy against various glycosidases (4).

Glycosidases and related enzymes are crucial in many bi-

ological processes that are vital for the normal functioning

of cells. Hence, inhibitors of these carbohydrate-processing

enzymes have received increased attention in the past few

decades from a synthetic as well as a biological activity per-

spective. These pursuits have been largely fuelled by the re-

alization of their potential as therapeutic agents for the

treatment of a variety of carbohydrate-mediated diseases like

diabetes, cancer, AIDS, and viral infections (1, 2). The basic

premise for the design of glycosidase inhibitors has been to

generate transition state mimics by replacing the endocyclic

Received 30 November 2004. Published on the NRC

Research Press Web site at http://canjchem.nrc.ca on 7 June

2005.

Naturally occurring alkaloids like 1-deoxynojirimycin (6)

can be regarded as simple azasugar analogues of ^D-glucose

and have been found to be potent inhibitors of α- and β-

Dedicated in appreciation of the many notable contributions

of Professor Howard Alper to chemistry.

OH

G. Mehta²and S.S. Ramesh. Department of Organic

Chemistry, Indian Institute of Science, Bangalore 560012,

India.

OH

HO

OH

X

OH

¹This article is part of a Special Issue dedicated to Professor

Howard Alper.

OH

1 X = CH₂

2 X = NH

5

4

3

²Corresponding author (e-mail: gm@orgchem.iisc.ernet.in).

Can. J. Chem. 83: 581–594 (2005)

doi: 10.1139/V05-032

582

Can. J. Chem. Vol. 83, 2005

Scheme 1. Retrosynthetic analysis of 11 and 12.

oxyfunctionalization

glucosidases. Besides nojirimycins, several other mono- and

bicyclic alkaloids based on polyhydroxylated pyrrolidine,

piperidine, pyrrolizidine, indolizidine, and quinolizidine

frameworks have also been identified as carbohydrate mim-

ics. Typical examples include bicyclic pyrrolizidine alkaloid

alexine 7, indolizidine alkaloid castanospermine 8, and

quinolizidine alkaloid 9 (5).

OH

OP

HO

OH

OP

n

OH

OP

HO

OH

HO

H

N

H

N

H

N

HO

14

HO

11 n = 1

12 n = 2

NH

OH

CH₂OH

OH

HO

6

7

8

9

decarbonylation

OR

Spurred by the heightened interest in the design of potent

inhibitors of glycosidases and inspired by the structures of

bicyclic alkaloids 7–9, we have conceived of a new family

of polyhydroxylated diquinanes 10, hydrindanes 11, and

decalins 12, collectively termed as “polycyclitols”, as poten-

tial glycomimics (6, 7). Among these bicyclitols, 11 and 12

can be considered as ring-annulated carbasugar entities and

more interestingly, the decalin polyol 12 can be regarded as

a hydrid of two carbasugars A and B (see bold portions in

13a and 13b). The presence of the additional hydroxyl

groups on the annulus, it is presumed, may provide addi-

tional binding points for these analogues at the receptor site.

The effect of annulation on the biological profile of bio-

molecules can be profound, as seen in the case of the natural

glycosidase inhibitors, deoxynojirimycin 6 and castanosper-

mine 8. The former, a nitrogen analogue of glucose, inhibits

yeast α-glucosidase, but is inactive against almond β-

glucosidase. On the other hand 8, a ring-annulated analogue

of 6, is a potent inhibitor of β-glucosidase, but exhibited no

inhibition against yeast α-glucosidase (5). The bicyclitols 11

and 12 conceptualized here have a similar structural relation-

ship to carbasugars as castanospermine 8 has to deoxyno-

jirimycin 6. Indeed, these bicyclitols can be visualized as the

carbon analogues of castanospermine 8 and other bicyclic al-

kaloids exhibiting glycosidase activity. Alternatively, these

novel bicyclic entities can be regarded as annulated con-

duritol, with 12 being a hybrid of two conduritols with

shared, common ring junction carbon atoms.

RO

O

H

n

OP

F

n

PO

15

(P= protecting group, R = alkyl)

oxyfunctionalization

Alder adducts, following fairly general and flexible synthetic

sequences. We also report on the glycosidase inhibitory ac-

tivity of the newly synthesized polycyclitols, two of which

have exhibited an impressive and selective inhibition of

yeast α-glucosidase.

Results and discussions

Retrosynthetic analysis

A general retrosynthetic analysis for accessing hydrindane

11 and decalin 12 based bicyclitols is depicted in Scheme 1.

It was visualized that the hydroxyl group pattern on the six-

membered ring could be generated through oxyfunctionali-

zation of diene 14 (n = 1, 2), which in turn could be ob-

tained by the thermal or photochemical decarbonylation of

the 7-ketonorbornyl moiety in 15. The precursor tricyclic ke-

tones 15 (n = 1, 2) are readily obtainable via Diels–Alder

cycloaddition between 5,5-dimethoxy-1,2,3,4-tetrachloro-

cyclopentadiene and an appropriate cyclic dienophile

(Scheme 1).

OH OH

OH

HO

OH

HO

OH

HO

OH

Thus, tricyclic precursors 16 and 17 were obtained via a

Diels–Alder reaction between 5,5-dimethoxy-1,2,3,4-tetra-

chlorocyclopentadiene and cyclopentadiene or p-benzo-

quinone, respectively. While the tricyclic endo-adduct 16

was to serve as the starting point for the hydrindane based

polyols 11 (see bold portion), the benzoquinone derived

Diels–Alder endo-adduct 17 was chosen as the starting ma-

terial for the decalin based polyols 12 (bold portion)

(Scheme 2). The main advantage in the choice of endo-

adducts 16 and 17 as our basic launching pad was that their

tricyclic framework built on a norbornyl matrix confers on

them a topological bias towards exo-selectivity. This built-in

facial bias in 16 and 17 was, therefore, expected to ensure

stereoselective operations, particularly oxyfunctionalization

maneuvers. The foregoing retrosynthetic analysis provided

HO

OH

12

OH

11

10

OH OH

HO

OH

HO

OH

A

B

HO

OH

13a

OH

13b

Herein, we report the stereo- and regioselective synthesis

of the newly conceptualized polyhydroxylated carbocyclic

entities, with as many as nine (in 11) and 10 (in 12)

stereogenic centers, starting from readily available Diels–

Mehta and Ramesh

583

Scheme 3. Reagents and conditions: (a) toluene, reflux, 24 h,

Scheme 2.

70%; (b) Mn(OAc)₃, AcOH, 70 °C, 1 h, 64%; (c) OsO₄(1 mol%),

NMMO, Me₂CO–H₂O–t-BuOH (5:5:2), rt, 12 h, 80%; (d) Na,

liq. NH₃, THF, EtOH, –33 °C, 30 min, 72%; (e) Ac₂O, pyridine,

DMAP, CH₂Cl₂, rt, 2 h, 88%; (f) Amberlyst-15, acetone, rt, 1 h,

89%; (g) C₆H₅NO₂, heat, 160 °C, 2 h, 50%; (h) OsO₄(1 mol%),

NMMO, Me₂CO–H₂O–t-BuOH (5:5:2), rt, 48 h, 88%; (i) aq.

NaOH, rt, 1 h, 60%.

OH

OMe

Cl

OH

MeO

Cl

HO

H

OH

Cl

OH

11

16

OCH₃

H₃CO

Cl

H₃CO

Cl

OCH₃

Cl

OMe

Cl

MeO

Cl

HO

OH

Cl

H

HO

OH

H

O

a

Cl

H

Cl

16

Cl

O

OH OH

12

b

17

OCH₃

Cl

OCH₃

Cl

H₃CO

Cl

H₃CO

Cl

the road map for the synthesis of the targeted new family of

bicyclitols.

H

c

Synthesis of hydrindane based bicyclitols

OH

Cl

The synthesis of the first galacto-configured cis-

hydrindane-based polyol 18, emanated from the tricyclic

Diels–Alder adduct 16, obtained by the [4 + 2] cycloaddition

of 5,5,-dimethoxy-1,2,3,4-tetrachlorocyclopentadiene and

cyclopentadiene (Scheme 3) (8). Adduct 16 was subjected to

allylic oxidation, using in-situ-generated Mn(OAc)₃, to de-

liver the exo-acetate derivative 19 (Scheme 3) (9). The exo-

acetate 19 was subjected to dihydroxylation following the

Upjohn catalytic OsO₄–NMMO protocol (10) to generate

diol 20, which on reductive dehalogenation (21) followed

by acetylation furnished the C_s-symmetric triacetate 22

(Scheme 3) (8a). All three acetate functionalities in 22 were

cis disposed, owing to the exo-propensity of the topology of

the endo-fused system 19.

AcO

19

20

d

OCH₃

H₃CO

H

e

H

OH

OAc

AcO

O

21

22

The tricyclic 7-ketal derivative 22 upon exposure to

Amberlyst-15 in moist acetone, resulted in ketal depro-

tection and furnished the 7-ketonorbornenone derivative 23

(Scheme 3). As contemplated earlier, decarbonylation in 23

through thermal activation by heating in nitrobenzene

(~160 °C) furnished the C_s-symmetric cyclohexa-1,3-diene

derivative 24 in moderate yield (Scheme 3) (11). The cyclic

1,3-diene moiety in 24 was subjected to exhaustive dihy-

droxylation employing the catalytic OsO₄–NMMO protocol

(10) to furnish a single tetrahydroxy-triacetate 25, which

was devoid of any symmetry. Loss of symmetry during the

double dihydroxylation reaction on the diene secured the

stereochemistry of 25, which required the two hydroxyl-

ations on diene 24 to occur from the exo- and endo-faces, re-

spectively, of the cis-hydrindane (Scheme 3). Mild base

hydrolysis of triacetate 25 gave the targeted heptahydroxy

bicyclitol 18, an annulated 5a-carbagalactose derivative.

The synthesis of diastereomeric cis-hydrindane-based car-

basugar analogue 26 started from the readily available endo-

tricyclic enone 27. Enone 27 was obtained following the

protocol reported by Schuda et al. (12) involving [4 + 2]

dimerization of the ethylene ketal of 2,4-cyclopentadienone

and chemoselective deketalization. Enone 27 was converted

to endo-allylic alcohol 28 via DIBAL-H reduction from the

exo-face and the norbornene double bond was protected

f

OAc

H

g

OAc

H

AcO

24

23

h

OH

OAc

OH

H

HO

i

4

7

OAc

OH

1

H

OH

25

18

through intramolecular bromoetherification to give 29

(Scheme 4). The cyclopentene double bond in 29 was

stereoselectively dihydroxylated and the resulting cis-diol 30

was protected as acetonide 31. The norbornene double bond

584

Can. J. Chem. Vol. 83, 2005

Scheme 4. Reagents and conditions: (a) DIBAL-H (1 mol/L in

hexane), CH₂Cl₂, –78 °C, 15 min, 90%; (b) NBS, CH₂Cl₂, rt,

3 h, 80%; (c) OsO₄(1 mol%), NMMO, Me₂CO–H₂O–t-BuOH,

(5:5:2), rt, 12 h, 82%; (d) Amberlyst-15, acetone, 4 Å molecular

sieves, rt, 3 h, 95%; (e) Zn dust, AcOH, MeOH, rt, 4 h, 85%;

(f) Amberlyst-15, acetone, reflux, 3 h, 81%; (g) C₆H₅NO₂,

160 °C, 4 h, 67%; (h) OsO₄(1 mol%), NMMO, Me₂CO–H₂O–t-

BuOH (5:5:2), rt, 48 h, 83%; (i) 30% CF₃COOH, rt, 30 min,

89%.

was now unmasked with Zn metal to render 32 (Scheme 4)

(8a). The ketal moiety in 32 was carefully deprotected in the

presence of Amberlyst-15 to furnish the crystalline 7-

norbornenone derivative 33 (Scheme 4). Tricyclic ketone 33,

on heating in nitrobenzene (160 °C), quite readily converted

to the 1,3-cyclohexadiene derivative 34 through extrusion of

CO (11). At this point, it was recognized that diene 34 was

well suited for generating stereochemically diverse oxygena-

tion patterns through appropriate sequencing of the oxy-

functionalization protocol.

O

Towards this end, the cis-hydrindane diene 34 was sub-

jected to exhaustive dihydroxylation under catalytic OsO₄

conditions to furnish the pentahydroxy compound 35

(Scheme 4). The stereochemical assignment for 35 followed

from an incisive analysis of the spectral data in analogy with

that of compound 25. In addition, it is expected that the di-

recting influence of the free α-hydroxyl group at the peri po-

sition in diene 34 would lead to the preferred stereostructure

of 35. Mild acid hydrolysis of the acetonide protecting group

in 35 furnished the targeted heptahydroxylated hydrindane

26, which was an epimer of 18 at C1. Polyol 26, like 18,

embodies a 5a-carbagalactose moiety, with the hydroxylated

carbocyclic annulation spanning the C_5a-C₆atoms of the

carbasugar (Scheme 4).

O

H

a

H

HO

O

27

28

b

O

Br

H

c

In another stereochemical variation in the hydroxylation

pattern on the hydrindane framework, [4 + 2] cycloaddition

of singlet oxygen (¹O₂) was effected on 34 to deliver endo-

peroxide 36 as the sole product in good yield with the addi-

tion of ¹O₂to 34 from the preferred convex face of the

molecule (Scheme 5) (13). The peroxide linkage in 36 was

cleanly cleaved with lithium aluminum hydride to yield the

1,4-diol derivative 37 and further dihydroxylated under the

standard catalytic OsO₄conditions to give a 3:1 mixture of

tetrols 38 and 39, respectively. All attempts to separate the

mixture of tetrols at this stage were unsuccessful. At this

point, we reasoned that one of the stereoisomers from the

dihydroxylation should have the hydroxyl groups in an all

cis orientation while the other diastereomer would have a

trans–syn–trans arrangement of the hydroxyl groups on the

six-membered ring. Hence, it was reasoned that the protec-

tion of the hydroxyl groups in the mixture of 38 and 39 as

the corresponding acetonides, would result in the formation

of a tris-acetonide derivative in the case of 38 and a bis-

acetonide in the case of 39 and would thus be rendered ame-

nable to separation. Consequently, the mixture of 38 and 39

was treated with Amberlyst-15 in acetone medium to fur-

nish, as anticipated, tris-acetonide 40 and bis-acetonide 41,

respectively, which were then readily separable by column

chromatography (Scheme 5). The major isomer 40 originates

from dihydroxylation of 37 from the syn-face of allylic alco-

hols, an outcome that is in conflict with Kishi’s rule (14) for

dihydroxylation of allylic alcohols. The stereochemical out-

come in this case can be attributed to the overwhelming

topological preference of the cis-hydrindane moiety in 37

to react from the less-hindered, convex face to yield syn-

dihydroxylated 38 as the major product. The acetonide de-

protection in 40 and 41 in the presence of 30% trifluoroacetic

acid cleanly furnished the diastereomeric heptahydroxylated

hydrindanes 42 and 43, respectively (Scheme 5). The

bicyclic carbasugar analogues 42 and 43 correspond to the

OH

O

29

30

d

O

Br

H

e

O

HO

O

31

32

f

O

H

g

H

O

OH

HO

O

34

33

h

HO

O

OH

H

HO

i

O

OH

HO

H

OH

HO

35

26

Mehta and Ramesh

585

Scheme 5. Reagents and conditions: (a) O₂, hν, methylene blue,

CHCl₃, 20 °C, 8 h, 90%; (b) LiAlH₄, THF, rt, 1 h, 54%;

(c) OsO₄(1 mol%), NMMO, Me₂CO–H₂O–t-BuOH (5:5:2), rt,

1 h; (d) Amberlyst-15, acetone, 4 Å molecular sieves, followed

by silica gel separation (62% for 40 and 21% for 41); (e) 30%

CF₃COOH, 92% for 42, and 88% for 43.

Scheme 6. Reagents and conditions: (a) toluene, reflux, 24 h,

83%; (b) NaBH₄, CeCl₃·7H₂O, MeOH, 0 °C, 10 min, 69%;

(c) MsCl, pyridine, DMAP, CH₂Cl₂, rt, 24 h, 72%; (d) NaI,

C₂H₅COCH₃, reflux, 8 h, 80%; (e) OsO₄(1 mol%), NMMO,

Me₂CO–H₂O–t-BuOH (5:5:2), rt, 48 h, 66%; (f) Amberlyst-15,

acetone, 4 Å molecular sieves, rt, 3 h, 75%; (g) Na, liq. NH₃,

THF, EtOH, –33 °C, 30 min, 49%; (h) Amberlyst-15, acetone, rt,

2 h, 98%; (i) C₆H₅NO₂, 160 °C, 4 h, 63%; (j) OsO₄(1 mol%),

NMMO, Me₂CO–H₂O–t-BuOH (5:5:2), rt, 48 h, 85%; (k) 30%

CF₃COOH, rt, 30 min, 95%.

O

HO

O

H

b

a

H

O

34

O

OMe

MeO

O

MeO OMe

H

HO

O

OH

Cl

HO

Cl

H

O

37

a

36

Cl

H

Cl

c

Cl

17

Cl

O

b

HO

O

H

HO

OMe

Cl

OMe

Cl

MeO

Cl

O

+

I

d

H

OR

H

Cl

I

H

OH

Cl

HO

Cl

MsO

47

(1:3)

39

38

RO

45 R = H

46 R = Ms

d

c

OMe

MeO

Cl

OMe

Cl

MeO

Cl

HO

O

e

H

O

H

Cl

OH

O

H

O

H

Cl

O

Cl

O

Cl

HO

48

44

O

OH

O

f

41

40

OMe

Cl

OMe

H

MeO

Cl

MeO

e

H

O

H

O

g

OH

O

OH

O

H

HO

Cl

OH

Cl

OH

H

HO

50

OH

49

h

H

OH

O

OH

HO

OH

42

H

43

O

H

i

OH

H

α-allopyranose and α-mannopyranose configurations, respec-

O

tively.

O

OH

HO

51

52

O

Synthesis of cis-decalin-based bicyclitols

j

The synthetic venture towards cis-decalin-based carbas-

ugar analogues of type 12 emanated from the readily avail-

able Diels–Alder adduct 17 of 5,5-dimethoxy-1,2,3,4-

tetrachlorocyclopentadiene and p-benzoquinone (Scheme 6)

(15). Tricyclic quinone 17 was elaborated to the symmetrical

tricyclic diene 44 essentially following a literature procedure

(16). Adduct 17 was subjected to Luche reduction (NaBH₄-

CeCl₃·7H₂O) (17) to give endo,endo-diol 45 and was further

HO

OH

HO

OH

H

HO

OH

HO

O

k

HO

H

HO

OH

54

53

586

Can. J. Chem. Vol. 83, 2005

Scheme 7. Reagents and conditions: (a) OsO₄(1 mol%),

NMMO, Me₂CO–H₂O–t-BuOH (5:5:2), rt, 1.5 h, 75%;

(b) Amberlyst-15, acetone, 4 Å molecular sieves, rt, 1 h, 82%;

(c) Na, liq. NH₃, THF, EtOH, –33 °C, 40 min, 88%;

(d) Amberlyst-15, acetone, rt, 2 h, 95%; (e) C₆H₅NO₂, 160 °C,

3 h, 43%; (f) OsO₄(1 mol%), NMMO, Me₂CO–H₂O–t-BuOH

(5:5:2), rt, 48 h, 73%; (g) 30% CF₃COOH, rt, 30 min, 90%.

converted to dimesylate 46, and NaI-mediated 1,4-

elimination (via 47) in 46 led to the desired C_s-symmetric

tricyclic diene 44 (Scheme 6). Exhaustive catalytic-OsO₄-

mediated dihydroxylation on tricyclic diene 44 furnished

1

tetrol 48 (Scheme 6). The symmetrical nature of the H and

¹³C NMR spectra of 48 indicated an all cis relationship of

the hydroxyl groups, which implied that the double

dihydroxylation occurred from the exo-face of the tricyclic

diene. Acetonide protection of the vicinal hydroxyl groups

in tetrol 48 resulted in selective formation of the symmetri-

cal monoacetonide 49 (Scheme 6). Acetonide 49 was sub-

jected to reductive dechlorination in Na – liquid ammonia

milieu to give the symmetrical olefin 50 in a modest yield

(Scheme 6). The ketal deprotection in 50 proceeded quite

uneventfully to furnish the crystalline 7-norbornenone deriv-

ative 51 in quantitative yield (Scheme 6). As contemplated

earlier, thermally induced decarbonylation in tricyclic

ketone 51 led to the C_s-symmetric bicyclic cyclohexadiene

derivative 52 (11).

OMe

Cl

OMe

Cl

MeO

Cl

MeO

Cl

H

OH

a

H

Cl

HO

45

HO

55

OH

b

OMe

Cl

OMe

MeO

Cl

MeO

Bicyclic diene 52 was subjected to exhaustive dihydroxyl-

ation employing catalytic OsO₄to stereoselectively furnish

the hexahydroxylated decalin 53 as a single diastereomer

(Scheme 6). The stereochemical assignments for 53 were

done on the basis of loss of symmetry (NMR) during

dihydroxylation and in analogy with earlier observations for

compound 25 (see Scheme 3). The acetonide protection in

53 was relieved by exposure to 30% trifluoroacetic acid to

deliver the targeted octahydroxylated decalin based

carbasugar analogue 54. Bicyclitol 54 can be regarded as

embodying an α-carbagalactopyranose configuration on a

cis-decalin framework (Scheme 6).

H

O

H

c

OH

O

H

Cl

O

HO

57

O

56

d

O

OH

H

O

H

e

To generate stereochemical variations of hydroxyl groups

on the decalin framework, tricyclic endo,endo-diol 45 was

dihydroxylated stereoselectively to furnish tetrol 55

(Scheme 7). Dihydroxylation in 55 occurred exclusively

from the convex face because of the exo-propensity of the

tricyclic system built on a norbornyl scaffold, and the struc-

ture of 55 was secured on the basis of symmetry (C_s) re-

OH

O

H

O

OH

59

HO

58

O

f

vealed by its H and ¹³C NMR spectra. The cis-diol moiety

1

HO

OH

HO

OH

in 55 was protected using Amberlyst-15 in acetone medium

to furnish acetonide 56. Reductive dechlorination in 56 un-

der Birch reduction conditions delivered the C_s-symmetric

olefin 57 (Scheme 7). The ketal moiety in 57 was next

deprotected to unmask the carbonyl group and furnish nor-

bornenone derivative 58 (Scheme 7). On thermal activation,

tricyclic ketone 58 underwent smooth decarbonylation to

furnish the C_s-symmetric bicyclic cyclohexadiene derivative

59 (Scheme 7) (11). Bicyclic diene 59 was diastereomeric

with 52 (Scheme 6), and hence the protocol adopted earlier

for the elaboration of 52 could be extended to diene 59 for

the realization of the targeted octahydroxy polyol.

H

HO

OH

O

g

O

H

60

61

With the availability of the designer polycyclitols 18, 26,

42, 43, 54, and 61, our attention was turned towards the

evaluation of their efficacy as glycosidase inhibitors.

The 1,3-cyclohexadiene moiety in 59 was double

dihydroxylated (OsO₄–NMMO) to furnish the hexahydroxyl-

ated cis-decalin derivative 60, which was devoid of any sym-

metry as indicated by its NMR (¹H and ¹³C) spectral

analysis. Hence, as observed in the case of 25 and 53 (vide

supra), the two sequential dihydroxylations on the diene

moiety had occurred from opposite faces, thereby generating

a cis–trans–cis arrangement of the hydroxyl groups in 60

(Scheme 7). The acetonide deprotection in 60 delivered

octahydroxylated decalin 61, a diastereomeric sibling of 54.

Glycosidase inhibitory potencies of bicyclitols

Evaluation of the glycosidase inhibitory activity of the

newly synthesized bicyclitols 18, 26, 42, 43, 54, and 61 was

carried out against various commercially available glyco-

sidases, α-glucosidase (yeast), β-glucosidase (sweet almond),

α-galactosidase (green coffee beans), β-galactosidase (Esche-

richia coli), α-mannnosidase (jack bean) and β-mannnosidase

(snail acetone powder), using their corresponding ortho- or

para-nitrophenylglycosides at the optimum pH and tempera-

ture for each enzyme (see Experimental) (18). All assays

Mehta and Ramesh

587

were done up to 1 mmol/L concentration of the polyols.

Gratifyingly, the decalin-based carbasugar analogue 54 ex-

hibited an impressive inhibition of yeast α-glucosidase, with

an inhibition constant K_i= 12 µmol/L (cf. K_i= 25 µmol/L

for deoxynojirimycin). However, the same compound 54 did

not show any significant inhibitory activity against almond

β-glucosidase up to 1 mmol/L concentration, thus highlight-

ing the selectivity of 54 towards α-glucosidase. To our fur-

ther delight, the hydrindane-based polyol 18 exhibited a

moderate and selective inhibition of yeast α-glucosidase

(K_i= 84 µmol/L) but, like 54, was totally inert to the almond

β-glucosidase. Both these compounds failed to elicit any in-

hibition of the galactosidases and mannosidases. The other

polyols 26, 42, 43, and 61 failed to exhibit any significant

(<1 mmol/L) inhibitory activity against the glycosidases ex-

amined. The lack of inhibitory activity of polyols 26, 42, 43,

and 61 when compared with their diastereomeric siblings 18

and 54, which inhibited α-glucosidase, brings forth the effect

of subtle variations in the stereochemical dispositions of the

hydroxyl groups on their inhibitory potency against the car-

bohydrate processing enzymes. At present, the precise rea-

sons for the selective affinity of 18 and 54 against α-

glucosidase and the effect of subtle stereochemical varia-

tions on their inhibitory activity is not clear and remains a

matter that still tickles our curiosity. Further investigations

will hopefully illuminate this puzzling observation.

1106 CHN analyzer. Silica gel from Acme (100–200 mesh

particle size) was used for column chromatography. All

moisture- and air-sensitive reactions were performed under

an argon atmosphere with dry, freshly distilled solvents

under anhydrous conditions using standard syringe–septum

techniques. Yields reported are of isolated materials judged

homogeneous by thin layer chromatography (TLC) and

NMR. All solvent extracts were washed with water/brine as

appropriate and dried over anhydr. Na₂SO₄before removal

of the solvent on a rotary evaporator under reduced pressure.

The glycosidase enzymes and their corresponding substrates

(ortho- or para-nitrophenolates) were purchased from the

Sigma Chemical Company, USA.

1,7,8,9-Tetrachloro-10,10-dimethoxy-

tricyclo[5.2.1.0^2,6]deca-4,8-dien-3-ylacetate (19)

Cyclopentadiene (12 g, 0.18 mol) was added to a solution

of 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopentadiene (50 g,

0.18 mol) in dry toluene (80 mL) and the resulting solution

was refluxed for 24 h. Excess solvent was distilled off from

the reaction mixture and the residue obtained was distilled

under reduced pressure (130–140 °C/5 torr, 1 torr =

133.3224 Pa) to yield adduct 16 (41.6 g, 70%). To a solution

of the Mn(OAc)₂·H₂O (10.8 g, 44 mmol) in AcOH (40 mL)

was added Ac₂O (14 mL) and the mixture was refluxed for

20 min. Solid KMnO₄(1.74 g, 10.1 mmol) was carefully

added and the resulting mixture was refluxed for an addi-

tional 30 min. After cooling to 70 °C, adduct 16 (12 g,

36.4 mmol) and KBr (720 mg, 6 mmol) were added and the

reaction mixture was stirred at the same temperature until

complete consumption of the starting material. The reaction

mixture was cooled to room temperature and filtered through

a Celite pad. The filtrate was extracted with hexane (3 ×

100 mL) and the residue obtained after the usual work-up,

was chromatographically purified on a silica gel column (5%

ethyl acetate – hexane) to afford the exo-acetate 19 (9 g,

64%), mp 111 to 112 °C (lit. value (8a) mp 110 °C). IR

(Nujol, cm^–1): 1740.

Conclusion

We have delineated a relatively short and fairly general

synthetic access to novel bicyclic carbasugar analogues

based on cis-decalin and cis-hydridane frameworks with as

many as eight to seven hydroxyl groups, respectively. The

synthetic approaches leading to secured stereochemistry at

all the stereogenic centers (nine in 11 and 10 in 12) in the

bicyclitols are notable for their simplicity and stereoselecti-

vity. The decalin-based polyol 54 and hydrindane bicyclitol

18 exhibited significant and selective inhibition of yeast α-

glucosidase.

10,10-Dimethoxy-3,5-di(acetyloxy)tricyclo[5.2.1.0^2,6]dec-

8-en-4-yl acetate (22)

Experimental section

To the solution of exo-acetate 19 (4 g, 10.3 mmol) in

acetone–water–t-BuOH (5:5:1, 25 mL), OsO₄(26 mg, 1 mol%),

and 50% aq. NMMO solution (2.65 mL, 11.3 mmol) were

added sequentially. The pale yellow reaction mixture was

stirred at room temperature for 12 h prior to quenching of

the reaction by addition of solid NaHSO₃(1 g). The

resulting mixture was filtered through a Celite pad and the

filtrate was concentrated under reduced pressure to give a

residue, which on chromatographic purification on a silica

gel column furnished diol 20 (3.5 g, 80%). The solution of

diol 20 (2.2 g, 5.2 mmol) in dry THF (25 mL) and absolute

EtOH (10 mL) was added to freshly distilled liquid ammonia

(250 mL) and to this solution, freshly cut pieces of sodium

(1 g) were carefully added, until the blue color of the solu-

tion persisted. The reaction mixture was stirred for 15 min,

prior to quenching the reaction with solid NH₄Cl (1 g). Am-

monia was allowed to evaporate overnight, the residue ob-

tained was diluted with ice-cooled water (100 mL) and

extracted with ethyl acetate (3 × 100 mL). The usual work-

up and evaporation of volatiles under reduced pressure fur-

General

Melting points were recorded on a Büchi B-540 apparatus

and are uncorrected. IR spectra were recorded on JASCO

1

FT-IR 410 spectrometer. H NMR spectra were recorded on

a JEOL JNM-LA 300 or a Bruker AMX 400 or a Bruker

DRX 500 instrument in CDCl₃solutions, unless otherwise

stated. Chemical shifts are reported with respect to

1

tetramethylsilane (Me₄Si) as the internal standard (for H

NMR) and the central line (77.0 ppm) of CDCl₃(for ¹³C

NMR). The chemical shifts are expressed in parts per mil-

lion (δ) downfield from Me₄Si. The standard abbreviations s,

d, t, q, and m refer to singlet, doublet, triplet, quartet, and

multiplet, respectively. Coupling constants (J), whenever

discernible, have been reported in Hz. Low resolution mass

spectra (LR-MS) were recorded either on a Shimadzu GC–

MS-QP 5050A spectrometer (EI or CI mode) or on a Q-TOF

Micromass mass spectrometer. High resolution mass spectra

(HR-MS) were recorded on a Q-TOF Micromass mass spec-

trometer. Elemental analyses were obtained on a Carlo Erba

588

Can. J. Chem. Vol. 83, 2005

nished a residue (21) that was dissolved in dry pyridine

(10 mL), then Ac₂O (1 mL) and catalytic DMAP (100 mg)

were added. The reaction mixture was stirred at room tem-

perature for 2 h before diluting with water. The reaction

mixture was extracted with CH₂Cl₂(3 × 60 mL) and after

the usual work-up was purified by silica gel column chroma-

tography (20% ethyl acetate – hexane) to furnish triacetate

22 (1.2 g, 64%), mp 140–142 °C. IR (Nujol, cm^–1): 1725.

D₂O) δ: 174.2 (COCH₃), 174.1 (COCH₃), 173.2 (COCH₃),

75.0, 74.7, 71.7, 71.1, 70.0, 69.0, 68.6, 45.6 (CH_bridgehead),

43.5 (CH_bridgehead), 20.9 (COCH₃), 20.8 (COCH₃), 20.5

(COCH₃). Anal. calcd. for C₁₅H₂₂O₁₀: C 49.72, H 6.12;

found: C 49.53, H 6.52.

Bicyclitol 18

Tetrol 25 (22 mg, 0.061 mmol) was stirred with aq. NaOH

(0.5 mol/L, 200 µL) at room temperature for 1 h and the

volatiles were removed under reduced pressure. The residue

obtained was dissolved in double distilled water and the

solution was filtered with Dowex cation-exchange resin

(50 W × 8, H⁺form). The filtrate was concentrated to fur-

3,4,5-Tri(acetyloxy)tricyclo[5.2.1.0^2,6]dec-8-en-10-one (23)

A solution of ketal 22 (200 mg, 0.543 mmol) in moist ac-

etone (8 mL) was stirred with Amberlyst-15 (~30 mg) at

room temperature for 1 h. The resin was filtered through a

cotton plug and the filtrate was concentrated to give a resi-

due, which was subjected to chromatography on a silica gel

column (15% ethyl acetate – hexane) to furnish ketone 23

(155 mg, 89%). IR (Nujol, cm^–1): 3036, 1778, 1743. ¹H

NMR (300 MHz, CDCl₃) δ: 6.69 (t, J = 2.4 Hz, 2H), 5.37 (t,

J = 3.4 Hz, 1H), 4.55–4.49 (m, 2H), 3.16–3.13 (m, 2H),

2.98–2.96 (m, 2H), 2.14 (s, 3H), 2.05 (s, 6H). LR-MS (CI)

m/z: 323 [M⁺+ 1]. Anal. calcd. for C₁₆H₁₈O₇: C 59.62, H

5.63; found: C 59.66, H 5.69.

1

nish 18 (8 mg, 60%). H NMR (300 MHz, D₂O) δ: 4.13 (t,

J = 4.3 Hz, 1H), 3.98–3.85 (m, 4H), 3.73 (dd, J = 7.3,

4.0 Hz, 1H), 3.61 (dd, J = 7.6, 2.8 Hz, 1H), 2.21–2.08 (m,

2H). ¹³C NMR (100 MHz, D₂O) δ: 76.4 (CHOH), 75.0 (CHOH),

74.6 (CHOH), 74.4 (CHOH), 73.1 (CHOH), 71.9 (CHOH),

71.8 (CHOH), 48.3 (CH_bridgehead), 47.2 (CH_bridgehead). LR-MS

(CI) m/z: 237 [M⁺+ 1]. Anal. calcd. for C₉H₁₆O₇: C 45.76,

H 6.83; found: C 45.84, H 6.79.

(2R*,3R*,7S*,8R*,9S*)-5,5-Dimethylspiro[dihy-

1,3-Di(acetyloxy)-2,3,3a,4,5,7a-hexahydro-1H-2-indenyl

acetate (24)

dro[1,3]dioxolane]-2,13-4,6-dioxatetra-

cyclo[8.2.1.0^2,9.0^3,7]tridecen-8-ol (32)

Ketone 23 (85 mg, 0.264 mmol) was heated to 160 °C in

nitrobenzene solvent (2 mL) for 2 h. The reaction mixture

was cooled to 80 °C and the nitrobenzene was distilled un-

der reduced pressure. The residue obtained was chromato-

graphed on a silica gel column (10% ethyl acetate – hexane)

to deliver the crystalline cyclohexadiene triacetate 24

(39 mg, 50%), mp 198.6–199.9 °C. IR (Nujol, cm^–1): 1740.

¹H NMR (300 MHz, CDCl₃) δ: 5.88–5.84 (m, 2H, C=CH),

5.70–5.66 (m, 2H, C=CH), 5.25 (t, J = 4.5 Hz, 1H, CHOAc),

5.09–5.05 (m, 2H, CHOAc), 3.10 (br s, 2H), 2.09 (s, 3H,

COCH₃), 2.07 (s, 6H, COCH₃). ¹³C NMR (75 MHz, CDCl₃)

δ: 170.1 (2C, COCH₃), 170.0 (COCH₃), 124.7 (2C, C=CH),

122.4 (2C, C=CH), 78.0 (2C, CHOAc), 69.5 (CHOAc), 38.9

(2C, CH_bridgehead), 20.7 (2C, COCH₃), 20.6 (COCH₃). LR-

MS (EI, 70 eV) m/z: 252 [M⁺– Ac + 1]. Anal. calcd. for

C₁₅H₁₈O₆: C 61.22, H 6.16; found: C 61.70, H 6.42.

To a magnetically stirred solution of alcohol 28 (8) (2 g,

9.7 mmol) in CH₂Cl₂(20 mL), NBS (2.1 g, 11.6 mmol) was

added in one portion at room temperature and the resulting

suspension was stirred for 3 h. Upon complete consumption

of the starting material (TLC), the reaction mixture was di-

luted with CH₂Cl₂(80 mL) and water (50 mL). Following

the usual work-up, subsequent evaporation of the solvent

gave a residue, which on chromatographic purification on a

silica gel column furnished 29 (2.2 g, 80%). Osmium tetroxide

(16 mg, 1 mol%) and 50% aq. NMMO (2.28 mL,

9.75 mmol) was added to a solution of bromoether 29

(1.85 g, 6.5 mmol) in an acetone–water–t-BuOH (5:5:2, 25 mL)

solvent system, and the resulting pale yellow reaction mix-

ture was stirred at room temperature for 12 h. The reaction

mixture was cooled to ice-bath temperature, diluted with

ethyl acetate (70 mL), and the osmate ester was hydrolyzed

by addition of solid NaHSO₃(500 mg). The solution was fil-

tered through a Celite pad and the filtrate was concentrated

under reduced pressure to furnish the crude diol 30 (1.76 g).

The crude diol 30 was dissolved in dry acetone (20 mL) and

Amberlyst-15 (300 mg) and powdered molecular sieves (1 g)

were added. The reaction mixture was stirred for 3 h at room

temperature and then was filtered through a Celite pad. The

filtrate obtained on complete removal of the solvent was

chromatographed on a silica gel column to furnish acetonide

31 (1.76 g, 75%). To a solution of bromoether 31 (1 g,

2.78 mmol) in MeOH (15 mL), acetic acid (0.1 mL) and Zn

dust (550 mg, 8.34 m atom) were added sequentially at room

temperature and the resulting suspension was stirred for 4 h.

The reaction mixture was filtered through a Celite pad and

the filtrate was concentrated under reduced pressure. The

residue obtained was diluted with CH₂Cl₂(60 mL) and evap-

oration of the solvent furnished a residue, which on purifica-

tion on a silica gel column gave alcohol 32 (660 mg, 85%),

mp 96 to 97 °C (lit. value (8a) mp 98 °C). IR (Nujol, cm^–1):

3400.

1,3-Di(acetyloxy)-4,5,6,7-tetrahydroxyperhydro-2-indenyl

acetate (25)

To a solution of diene 24 (35 mg, 0.119 mmol) in

acetone–water–t-BuOH (5:5:2,

2 mL), catalytic OsO₄

(0.3 mg, 1 mol%) and 50% aq. NMMO (83 µL, 0.357 mmol)

were sequentially added at 0 °C. The resulting pale yellow

reaction mixture was stirred at room temperature for 48 h.

The reaction was cooled to 0 °C, prior to quenching by addi-

tion of solid NaHSO₃(10 mg). The resulting mixture was di-

luted with ethyl acetate (15 mL), filtered through Celite, and

the filtrate was concentrated under reduced pressure. The

residue obtained was subjected to silica gel column chroma-

tography (5% methanol – ethyl acetate) to afford tetrol 25

(38 mg, 88%). IR (Nujol, cm^–1): 3290, 1743. ¹H NMR

(300 MHz, D₂O) δ: 5.38 (t, J = 6.3 Hz, 1H), 5.27 (dd, J =

6.3, 1.8 Hz, 1H), 5.08 (t, J = 6.9 Hz, 1H), 3.97 (br s, 1H),

3.90 (t, J = 3.9 Hz, 1H), 3.78 (dd, J = 7.8, 3.6 Hz, 1H), 3.66

(dd, J = 8.1, 3 Hz, 1H), 2.52 (m, 1H), 2.40 (br s, 1H), 1.99

(s, 6H, COCH₃), 1.95 (s, 3H, COCH₃). ¹³C NMR (75 MHz,

Mehta and Ramesh

589

4.06 (m, 1H), 3.98–3.93 (m, 2H), 3.69–3.58 (m, 2H), 2.59–

2.51 (m, 1H, H_bridgehead), 2.41–2.37 (m, 1H, H_bridgehead), 1.32

(s, 3H), 1.20 (s, 3H). ¹³C NMR (75 MHz, D₂O) δ: 111.0

(C_q), 87.9 (CH_acetonide), 83.0 (CH_acetonide), 77.1 (CHOH),

70.5, 70.4, 70.3, 69.2, 45.8, 45.6, 25.8 (C_bridgehead), 23.4

(C_bridgehead). LR-MS (EI, 70 eV) m/z: 258 [M⁺– H₂O].

(2R*,3R*,7S*,8R*,9S*)-8-Hydroxy-5,5-dimethyl-4,6-

dioxatetracyclo[8.2.1.0^2,9.0^3,7]tridec-11-en-13-one (33)

Ketal 32 (350 mg, 1.24 mmol) was stirred with

Amberlyst-15 (~50 mg) in moist acetone (10 mL), under re-

flux for 3 h. Upon complete consumption of the starting ma-

terial, the reaction mixture was cooled, diluted with acetone

(25 mL), and the resin was filtered through a cotton plug.

The filtrate was concentrated under reduced pressure and the

residue obtained was chromatographed on a silica gel col-

umn (30% ethyl acetate – hexane) to give ketone 33

(237 mg, 81%), mp 179 to 180 °C. IR (Nujol, cm^–1): 1771.

¹H NMR (300 MHz, CDCl₃) δ: 6.64 (m, 1H), 6.48 (m, 1H),

4.36 (dd, J = 9.3, 5.4 Hz, 1H), 4.10 (d, J = 5.4 Hz, 1H), 4.03

(t, J = 5.4 Hz, 1H), 3.20 (dt, J = 8.7, 3.9 Hz, 1H), 3.14–2.95

(m, 3H), 1.44 (s, 3H), 1.23 (s, 3H). ¹³C NMR (75 MHz,

CDCl₃) δ: 200.1 (C=O), 135.2 (C=CH), 130.3 (C=CH),

110.8 (C_q), 89.4 (CH_acetonide), 82.0 (CH_acetonide), 81.3

(CHOH), 49.2, 49.0 (CH), 47.1 (CH), 44.4 (CH), 27.9

(CH_3acetonide), 25.3 (CH_3acetonide). LR-MS (EI, 70 eV) m/z:

237 [M⁺+ 1]. Anal. calcd. for C₁₃H₁₆O₄: C 66.09, H 6.83;

found: C 66.46, H 7.22.

Bicyclitol 26

Acetonide 35 (25 mg, 0.09 mmol) was stirred in 30%

trifluoroacetic acid (1 mL) at room temperature for 30 min

until all the starting material had been consumed. The

volatiles were removed under reduced pressure to furnish

1

polyol 26 (19 mg, 89%). H NMR (300 MHz, D₂O) δ: 4.19–

4.15 (m, 1H), 4.01–3.81 (m, 4H), 3.68–3.64 (m, 1H), 3.61–

3.56 (m, 1H), 2.40–2.33 (m, 1H), 2.13–2.07 (m, 1H). ¹³C

NMR (75 MHz, D₂O) δ: 77.9, 77.2, 73.6, 72.9, 72.3, 68.4,

67.4, 45.9, 41.8. LR-MS (CI) m/z: 237 [M⁺+ 1]. Anal.

calcd. for C₉H₁₆O₇: C 45.76, H 6.83; found: C 45.88, H

7.32.

(2S*,3R*,7S*,8R*,9R*)-5,5-Dimethyl-4,6,11,12-

tetraoxatetracyclo[8.2.2.0^2,9.0^3,7]tetradec-13-en-8-ol (36)

A slow stream of oxygen gas was bubbled through a solu-

tion of diene 34 (60 mg, 0.288 mmol) in chloroform (6 mL),

contained in a specially designed reaction flask with an

outer water jacket, in the presene of methylene blue (~5 mg)

as the sensitizer and under irradiation from a 500 W tung-

sten lamp. The temperature of the reaction mixture was

maintained at 20 °C by circulating cold water through the

outer jacket of the reaction flask. Upon complete consump-

tion of the starting material (TLC, 8 h), the solvent was

evaporated under reduced pressure. The residue obtained

was chromatographed over a silica gel column (20% ethyl

acetate – hexane) to furnish the endo-peroxide 36 (62 mg,

(3aR*,3bS*,7aR*,8R*,8aS*)-2,2-Dimethyl-3b,7a,8,8a-

tetrahydro-3aH-indeno[1,2-d][1,3]dioxol-8-ol (34)

A solution of ketone 33 (220 mg, 0.932 mmol) in

nitrobenzene (6 mL) solvent was heated, with vigorous stir-

ring, to 160 °C and reacted for 4 h. Upon complete con-

sumption of the starting material (TLC), the reaction mixture

was cooled to 80 °C and the solvent was distilled off under

reduced pressure. The resulting dark brown residue was

charged on the silica gel column and chromatographed (25%

ethyl acetate – hexane) to give diene 34 (130 mg, 67%) as a

white solid, mp 190.6–191.2 °C. IR (Nujol, cm^–1): 3470. H

1

NMR (300 MHz, CDCl₃) δ: 6.17 (dd, J = 9.9, 5.1 Hz, 1H,

C= CH), 5.80 (dd, J = 9.9, 4.8 Hz, 2H, C= CH), 5.72–5.70

(m, 1H), 4.74 (d, J = 6.0 Hz, 1H, H_acetonide), 4.45 (d, J =

6 Hz, 1H, H_acetonide), 4.03 (br s, 1H, CHOH), 3.08–3.05 (m,

2H, H_bridgehead), 2.26 (d, J = 2.4 Hz, 1H, H_bridgehead), 1.42 (s,

3H), 1.31 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ: 129.2

(C=CH), 127.6 (C=CH), 123.3 (C=CH), 122.9 (C=CH),

110.4 (C_q), 87.3 (CH_acetonide), 83.9 (CH_acetonide), 79.6

(CHOH), 45.3 (CH), 39.6 (CH), 26.8 (CH_3bridgehead), 24.3

(CH_3bridgehead). LR-MS (EI, 70 eV) m/z: 208 [M⁺]. Anal.

calcd. for C₁₂H₁₆O₃: C 69.21, H 7.74; found: C 68.88, H

7.52.

1

90%). IR (KBr, cm^–1): 3445. H NMR (300 MHz, CDCl₃) δ:

6.78 (m, 1H, C=CH), 6.59 (m, 1H, C=CH), 4.85–4.80 (m,

2H, H_peroxy), 4.36 (dd, J = 9.0, 5.2 Hz, 1H, H_acetonide), 4.17 (t,

J = 5.2 Hz, 1H, H_acetonide), 4.11 (d, J = 6.0 Hz, 1H), 3.33 (dt,

J = 8.7, 4.0 Hz, 1H, H_bridgehead), 3.08 (dd, J = 8.7, 5.2 Hz,

1H), 1.47 (s, 3H, CH₃), 1.26 (s, 3H, CH₃). ¹³C NMR

(75 MHz, CDCl₃) δ: 135.3 (C=CH), 130.2 (C=CH), 111.7

(C_q), 88.0, 80.9, 79.9, 70.9 (CH_peroxy), 70.8 (CH_peroxy), 44.5,

44.0, 27.8, 25.2. LR-MS (CI) m/z: 241 [M⁺+ 1]. Anal. calcd.

for C₁₂H₁₆O₅: C 59.99, H 6.71; found: C 60.21, H 6.83.

(3aR*,3bR*,4R*,7S*,7aS*,8R*,8aS*)-2,2-Dimethyl-

3b,4,7,7a,8,8a-hexahydro-3aH-indeno[1,2-d][1,3]dioxole-

4,7,8-triol (37)

(3aR*,3bR*,4S*,5S*,6S*,7S*,7aS*,8R*,8aS*)-2,2-

Dimethylperhydroindeno[1,2-d][1,3]dioxole-4,5,6,7,8-

pentaol (35)

LiAlH₄(12 mg, 0.312 mmol) was added to a solution of

the endo-peroxide 36 (50 mg, 0.208 mmol) in dry THF

(6 mL) at 0 °C under an atmosphere of N₂. The resulting

suspension was stirred at room temperature for 1 h, before

quenching the reaction by careful addition of ethyl acetate

(15 mL) followed by addition of a cold, satd. Na₂SO₄solu-

tion (2 mL). After dilution with ethyl acetate, the aluminium

salts were filtered through a Celite pad. Evaporation of the

solvent under reduced pressure, after the usual work-up,

gave a residue that was chromatographed over a silica gel

column (60% ethyl acetate – hexane) to furnish the 1,4-diol

37 (27 mg, 54%), mp 210 to 211 °C. IR (Nujol, cm^–1): 3444.

¹H NMR (300 MHz, CDCl₃) δ: 5.69 (br s, 2H, C=CH), 4.71

To a solution of diene 34 (45 mg, 0.216 mmol) in an

acetone–water–t-BuOH (5:5:2, 4 mL) solvent system, cata-

lytic OsO₄(1 mol%, 0.5 mg) and 50% aq. NMMO (151 µL,

0.648 mmol) were added at 0 °C. The resulting pale yellow

reaction mixture was stirred at room temperature for 48 h,

before diluting with ethyl acetate (10 mL) and quenching

with solid NaHSO₃(10 mg). The resulting mixture was fil-

tered through a Celite pad and the filtrate was concentrated

under reduced pressure. The residue was subjected to silica

gel column chromatography (5% methanol – ethyl acetate)

1

to afford pentaol 35 (49 mg, 83%). H NMR (300 MHz,

D₂O) δ: 4.70–4.65 (m, 1H), 4.35 (dd, J = 6.0, 1.8 Hz, 1H),

590

Can. J. Chem. Vol. 83, 2005

(d, J = 5.7 Hz, 1H), 4.42 (d, J = 5.7 Hz, 1H), 4.13 (br s, 1H),

4.07 (d, J = 4.8 Hz, 1H), 3.81 (d, J = 7.8 Hz, 1H), 2.36 (m,

1H), 1.90 (t, J = 8.4 Hz, 1H), 1.33 (s, 3H), 1.22 (s, 3H). ¹³C

NMR (75 MHz, CDCl₃) δ: 133.6 (C=CH), 129.9 (C=CH),

111.5 (C_q), 86.0, 83.2, 77.7, 66.5, 62.5, 46.3, 46.1, 25.7,

23.5. LR-MS (CI) m/z: 243 [M⁺+ 1]. Anal. calcd. for

C₁₂H₁₈O₅: C 59.49, H 7.49; found: C 59.63, H 7.52.

30 min. Upon complete consumption of the starting mate-

rial, the volatiles were removed under reduced pressure to

afford 42 (21 mg, 92%). H NMR (300 MHz, D₂O) δ: 4.03

(dd, J = 6.9, 4.5 Hz, 1H), 3.89–3.85 (m, 2H), 3.74–3.70 (m,

3H), 3.62 (dd, J = 6.6, 3 Hz, 1H), 2.46 (dd, J= 14.4, 6.9 Hz,

1H), 2.11 (dd, J = 12.3, 6.9 Hz, 1H). ¹³C NMR (75 MHz,

D₂O) δ: 78.9, 77.6, 72.7, 72.2, 71.5, 70.8, 70.1, 47.5, 41.0.

LR-MS (CI) m/z: 237 [M⁺+ 1]. Anal. calcd. for C₉H₁₆O₇: C

45.76, H 6.83; found: C 45.53, H 6.79.

1

(3aR*,3bR*,4S*,5S*,6R*,7R*,7aS*,8R*,8aS*)-2,2-Dimethyl-

perhydroindeno[1,2-d][1,3]dioxole-4,5,6,7,8-pentaol (38)

and (3aR*,3bR*,4S*,5R*,6S*,7R*,7aS*,8R*,8aS*)-2,2-

dimethylperhydroindeno[1,2-d][1,3]dioxole-4,5,6,7,8-

pentaol (39)

Bicyclitol 43

Bisacetonide 41 (10 mg, 0.032 mmol) was treated with

30% trifluoroacetic acid (150 µL) and the resulting biphasic

mixture was stirred vigorously at room temperature for

30 min. The volatiles were removed under reduced pressure

To a solution of diol 37 (55 mg, 0.227 mmol) in an

acetone–water–t-BuOH (5:5:2, 5mL) solvent system, cata-

lytic OsO₄(0.6 mg, 1 mol%), and 50% aq. NMMO (64 µL,

0.272 mmol) were added sequentially at 0 °C and the result-

ing mixture was stirred at room temperature for 1 h. The re-

action was quenched by addition of solid NaHSO₃(10 mg),

diluted with ethyl acetate (15 mL), and filtered through a

Celite pad. The filtrate was concentrated under reduced pres-

1

to furnish 43 (7 mg, 88%). H NMR (300 MHz, D₂O) δ:

4.10 (t, 1H, J = 5.7 Hz), 4.00 (t, 1H, J = 5.4 Hz), 3.86 (t, J =

5.4 Hz, 1H), 3.83 (dd, J = 14, 7.2 Hz, 1H), 3.75–3.70 (m,

1H), 3.66–3.61 (m, 2H), 2.36 (dd, J = 15, 6.9 Hz, 1H), 1.93

(dd, J = 14.4, 6.9 Hz, 1H). ¹³C NMR (75 MHz, D₂O) δ:

77.8, 77.1, 74.0, 73.2, 72.3, 72.0, 68.8, 48.6, 44.2. LR-MS

(CI) m/z: 237 [M⁺+ 1]. Anal. calcd. for C₉H₁₆O₇: C 45.76,

H 6.83; found: C 45.77, H 6.98.

1

sure to yield a residue, whose H NMR spectrum was found

to be a mixture of diastereomers 38 and 39 (60 mg) in a 3:1

ratio. However, their chromatographic separation was unsuc-

cessful and the mixture was used as such for the next step.

(2R*,3S*,6R*,7S*)-1,8,9,10-Tetrachloro-11,11-di-

methoxytricyclo[6.2.1.0^2,7]undeca-4,9-diene-3,6-diol (45)

To a solution of 1,2,3,4-tetrachloro-5,5-dimethoxycyclo-

pentadiene (63 mL, 0.36 mol) in dry toluene (300 mL), p-

benzoquinone (40 g, 0.37 mol) was added and the resulting

solution was refluxed for 24 h. Excess solvent was distilled

off under reduced pressure and the residue obtained was

recrystallized from hexane to furnish adduct 17 (110 g,

83%). Adduct 17 (10 g, 26.8 mmol) was dissolved in dry

MeOH (150 mL) and to this solution at 0 °C under an inert

atmosphere, CeCl₃·7H₂O (1 g, 10 mol%) and NaBH₄(2 g,

53.6 mmol) were added in sequential portions. The resulting

solution was stirred at the same temperature for 10 min until

the starting material was completely consumed. The reaction

mixture was diluted with ethyl acetate (150 mL) and

quenched by the addition of water (80 mL). The organic

layer was separated and after the usual work-up furnished

residue 45 (6.9 g, 69%), mp 162 to 163 °C (lit. value (16)

mp 167 to 168 °C). IR (Nujol, cm^–1): 3450.

(3aR*,3bS*,6aS*,6bS*,6R*,9aS*,10R*,10aR*,10bR*)-

2,2,5,5,8,8-Hexamethylperhydrodi[1,3]dioxolo-[4′,5′:1,

2:4′,5′:6,7]indeno[4,5-d][1,3]dioxole-10-ol (40) and

(3aR*,3bR*,4S*,4aR*,7aS*,8R*,8aR*,9R*,9aS*)-2,2,6,6-

tetramethylperhydro[1,3]dioxolo[4′,5′:1,2]indeno[5,6-

d][1,3]dioxole-4,8,9-triol (41)

The solution of mixture of 38 and 39 (60 mg) in dry ace-

tone (10 mL) was treated sequentially with Amberlyst-15

resin (~5 mg) and 4 Å molecular sieves (~30 mg) and the re-

sulting mixture was stirred at room temperature for 3 h. The

reaction mixture was filtered through a Celite pad and the

filtrate was concentrated under reduced pressure. The resi-

due obtained was charged on a silica gel column and

chromatographed with a 10% ethyl acetate – hexane solvent

system to furnish trisacetonide 40 (48 mg, 62%). Further

elution of the column with 30% ethyl acetate –hexane gave

bisacetonide 41 (14 mg, 21%). Compound 40: mp 210 to

211 °C. IR (Nujol, cm^–1): 3361. ¹H NMR (300 MHz,

CDCl₃) δ: 4.75 (d, J = 6.0 Hz, 1H), 4.42 (dd, J = 9.6,

5.1 Hz, 2H), 4.36 (dd, J = 13.5, 5.1 Hz, 1H), 4.28 (dd, J =

6.9, 4.5 Hz, 1H), 4.08 (d, J = 5.1 Hz, 1H), 3.93 (t, J =

6.9 Hz, 1H), 2.64–2.55 (m, 2H), 1.53 (s, 3H), 1.51 (s, 3H),

1.41 (s, 3H), 1.37 (s, 3H), 1.35 (s, 3H), 1.26 (s, 3H). LR-MS

(EI, 70 eV) m/z: 356 [M⁺]. Compound 41: mp 190 to

191 °C. IR (Nujol, cm^–1): 3372. ¹H NMR (300 MHz,

CDCl₃) δ: 4.74 (br d, J = 5.1 Hz, 1H), 4.49 (d, J = 5.1 Hz,

1H), 4.41 (br d, J = 5.4 Hz, 1H), 4.15–4.10 (m, 2H), 4.02–

3.96 (m, 1H), 3.73 (dd, J = 12.3, 6.9 Hz, 1H), 2.53–2.50 (m,

2H), 1.51 (s, 3H), 1.43 (s, 3H), 1.34 (s, 3H), and 1.30 (s,

3H). LR-MS (EI, 70 eV) m/z: 317 [M⁺+ 1].

(2R*,7S*)-1,8,9,10-Tetrachloro-11,11-

dimethoxytricyclo[6.2.1.0^2,7]undeca-3,5,9-triene (44)

To a magnetically stirred solution of diol 45 (5 g,

13.3 mmol) in dry CH₂Cl₂(25 mL), triethylamine (5.6 mL,

39.9 mmol), DMAP (162 mg, 10 mol%), and methanesul-

phonyl chloride (2.5 mL, 29.2 mmol) were added sequen-

tially at 0 °C under an inert atmosphere and the resulting

solution was stirred at room temperature for a further 24 h.

The reaction mixture was diluted with CH₂Cl₂(50 mL) prior

to quenching the reaction by adding water (30 mL). The or-

ganic layer was separated and the aqueous layer was ex-

tracted with CH₂Cl₂(3 × 60 mL). The residue obtained by

the usual work-up was subjected to chromatographic purifi-

cation on a silica gel column (35% ethyl acetate – hexane) to

furnish dimesylate 46 (5.1 g, 72%). Dimesylate 46 (8.4 g,

15.7 mmol) was dissolved in 2-butanone (60 mL) and so-

Bicyclitol 42

Trisacetonide 40 (35 mg, 0.098 mmol) was stirred with

30% trifluoroacetic acid (500 µL) at room temperature for

Mehta and Ramesh

591

dium iodide (8.2 g, 54.9 mmol) was added to this solution.

The dark brown solution was then refluxed for 8 h. The re-

action mixture was cooled to ice bath temperature and di-

luted with diethylether (100 mL) and water (80 mL). The

usual work-up and evaporation of the solvent under reduced

pressure gave a residue, which on purification on a silica gel

column (hexane) furnished the tricyclic diene 44 (4.3 g,

80%), mp 162 to 163 °C (lit. value (16) mp 167 to 168 °C).

aq. satd. NH₄Cl solution (50 mL) and water (100 mL) were

added to the resulting residue, which was subsequently ex-

tracted with ethyl acetate (3 × 200 mL). Removal of the

volatiles, followed by purification of the residue by silica gel

column chromatography (50% ethyl acetate – hexane) gave

the dechlorinated product 50 (3.4 g, 49%), mp 173–175 °C.

1

IR (Nujol, cm^–1): 3460, 3380. H NMR (300 MHz, CDCl₃)

δ: 6.93 (s, 2H, C=CH), 4.38 (s, 2H), 3.24 (s, 3H), 3.17 (s,

5H), 3.05 (s, 2H), 2.60–2.50 (m, 2H), 1.91 (s, 1H), 1.88 (s,

1H), 1.53 (s, 3H), 1.35 (s, 3H). ¹³C NMR (75 MHz, CDCl₃)

δ: 133.8 (2C, C=CH), 118.9 (C_q), 110.0 (C_q), 76.6 (2C,

(2R*,3S*,4S*,5R*,6R*,7S*)-1,8,9,10-Tetrachloro-11,11-

dimethoxytricyclo[6.2.1.0^2,7]undec-9-ene-3,4,5,6-tetraol

(48)

C

_acetonide), 68.8 (2C, CHOH), 52.0 (OCH₃), 50.0 (OCH₃),

46.8 (2C, CH), 40.4 (2C, CH), 25.9 (CH), 24.0 (CH). LR-

MS (EI, 70 eV) m/z: 312 [M⁺]. Anal. calcd. for C₁₆H₂₄O₆: C

61.52, H 7.74; found: C 61.83, H 7.90.

A solution of diene 44 (1.2 g, 3.51 mmol) in an acetone–

water–t-BuOH solvent system (5:5:2, 50 mL) was treated se-

quentially with catalytic OsO₄(8 mg, 1 mol%) and 50% aq.

NMMO (2.5 mL, 10.53 mmol). The resulting pale yellow

solution was stirred vigorously at room temperature for 48 h,

during which all the starting material was consumed (TLC).

The reaction was quenched by addition of solid NaHSO₃

(500 mg), diluted with ethyl acetate (100 mL), and filtered

through a Celite pad. The filtrate was concentrated under

reduced pressure to give a residue, which was chromato-

graphed on a silica gel column (70% ethyl acetate – hexane)

to furnish tetrol 48 (950 mg, 66%). IR (Nujol, cm^–1): 3430.

¹H NMR (300 MHz, CDCl₃) δ: 3.76 (br s, 2H), 3.66 (br s,

2H), 3.63 (s, 3H), 3.56 (s, 3H), 3.14 (m, 2H). ¹³C NMR

(75 MHz, CDCl₃) δ: 129.7 (2C, C=CCl), 111.7 (C_q), 70.7

(2C, CHOH), 68.0 (2C, CHOH), 52.8 (2C, C-Cl), 52.5 (2C,

OMe), 51.8 (2C, CH). LR-MS (EI, 70 eV) m/z: 410 [M⁺+ 1].

(2R*,3R*,4R*,8S*,9S*,10S*)-3,9-Dihydroxy-6,6-dimethyl-

5,7-dioxatetracyclo[9.2.1.0^2,10.0^4,8]tetradec-12-en-14-one

(51)

A solution of ketal 50 (1 g, 3.20 mmol) in moist acetone

(40 mL) was stirred with Amberlyst-15 (~150 mg) at room

temperature for 2 h. Upon complete consumption of the

starting material, the reaction mixture was filtered through a

cotton plug. The filtrate on concentration gave a solid resi-

due, which on purification by chromatography over a short

silica gel column (50% ethyl acetate – hexane) afforded

ketone 51 (834 mg, 98%), mp 213–215 °C. IR (Nujol, cm^–1):

3270, 1777.

(3aR*,4R*,4aS*,8aR*,9S*,9aS*)-2,2-Dimethyl-

3a,4,4a,8a,9,9a-hexahydronaphtho[2,3-d][1,3]dioxole-4,9-

diol (52)

(2R*,3S*,4S*,8R*,9R*,10S*)-1,11,12,13-Tetrachloro-

14,14-dimethoxy-6,6-dimethyl-5,7-dioxatetra-

cyclo[9.2.1.0^2,10.0^4,8]tetradec-12-ene-3,9-diol (49)

A solution of ketone 51 (300 mg, 1.13 mmol) in nitro-

benzene (15 mL) was heated, with vigorous stirring, at

160 °C for 4 h. Upon complete consumption of the starting

material (TLC), the reaction mixture was cooled to 80 °C

and the solvent was distilled off under reduced pressure. The

residue left behind was chromatographed over a silica gel

column (30% ethyl acetate – hexane) to furnish diene 52

(169 mg, 63%) as a colorless solid, mp 189 to 190 °C. IR

Tetrol 48 (950 mg, 2.32 mmol) was stirred with

Amberlyst-15 (~100 mg) and 4 Å molecular sieves (500 mg)

in dry acetone (30 mL) at room temperature for 3 h. Upon

complete consumption of the starting material, the reaction

mixture was filtered through a Celite pad. The filtrate was

concentrated under reduced pressure to give a residue, which

was chromatographed over a short silica gel column (25%

ethyl acetate – hexane) to afford acetonide 49 (783 mg,

75%), mp 180.1–181.4 °C. IR (Nujol, cm^–1): 3346. ¹H NMR

(300 MHz, CDCl₃) δ: 4.44 (s, 2H), 3.63 (s, 3H), 3.59 (s,

3H), 3.11–3.01 (m, 2H), 2.29 (d, J = 6.6 Hz, 2H), 1.57 (s,

3H), 1.37 (s, 3H). LR-MS (EI, 70 eV) m/z: 451 [M⁺+ 1].

Anal. calcd. for C₁₆H₂₀O₆Cl₄: C 42.69, H 4.48; found: C

42.84, H 4.80.

1

(KBr, cm^–1): 3356. H NMR (300 MHz, CDCl₃) δ: 5.87–

5.83 (m, 2H, C=CH), 5.65–5.61 (m, 2H, C=CH), 4.42–4.40

(m, 2H, H_acetonide), 3.74 (br s, 2H, CHOH), 3.00–2.98 (m,

2H, OH), 2.70–2.67 (m, 2H), 1.55 (s, 3H), 1.40 (s, 3H). ¹³C

NMR (75 MHz, CDCl₃) δ: 125.8 (2C, C=CH), 122.6 (2C,

C=CH), 109.3 (C_q), 74.8 (2C, C_acetonide), 69.0 (2C, CHOH),

35.4 (2C, CH), 26.0 (CH), 24.4 (CH). LR-MS (EI, 70 eV)

m/z: 239 [M⁺+ 1]. Anal. calcd. for C₁₃H₁₈O₄: C 65.53, H

7.61; found: C 65.90, H 7.72.

(2R*,3R*,4R*,8S*,9S*,10S*)-14,14-Dimethoxy-6,6-

dimethyl-5,7-dioxatetracyclo[9.2.1.0^2,10.0^4,8]tetradec-12-

ene-3,9-diol (50)

(3aR*,4R*,4aR*,5S*,6S*,7S*,8S*,8aS*,9S*,9aS*)-2,2-

Dimethylperhydronaphtho[2,3-d][1,3]dioxole-4,5,6,7,8,9-

hexol (53)

Diene 52 (25 mg, 0.105 mmol) was treated sequentially

with catalytic amounts of OsO₄(0.2 mg, 1 mol%) and 50%

aq. NMMO (54 µL, 0.231 mmol) in an acetone–water–t-

BuOH solvent system (5:5:2, 5 mL) at 0 °C and the resulting

pale yellow reaction mixture was stirred at room temperature

for 48 h. The reaction mixture was cooled to 0 °C and di-

luted with ethyl acetate (20 mL) prior to quenching with

Liquid ammonia (300 mL) was distilled into a 250 mL

three-necked round-bottomed flask equipped with a con-

denser, KOH guard tube, and septum. Acetonide 49 (10 g,

22.22 mmol) in dry THF (40 mL) and absolute EtOH

(40 mL) were added to the flask. Small pieces of freshly cut

sodium were introduced into the reaction mixture with stir-

ring at –33 °C until the blue color persisted. The mixture

was stirred for 30 min and solid NH₄Cl (1 g) was added.

The excess ammonia was allowed to evaporate, and a cold

592

Can. J. Chem. Vol. 83, 2005

solid NaHSO₃(10 mg). The mixture was filtered through a

Celite pad and the filtrate was concentrated. The residue

thus obtained was chromatographed over a silica gel column

(8% methanol – ethyl acetate) to furnish hexol 53 (27 mg,

ica gel column (6% ethyl acetate – hexane) to afford ace-

tonide 56 (675 mg, 82%), mp 210–212 °C. IR (KBr, cm^–1):

1

3260. H NMR (300 MHz, CDCl₃) δ: 4.43 (s, 2H, H_acetonide),

4.29 (br s, 2H, CHOH), 3.79 (s, 3H, OCH₃), 3.57 (s, 3H,

OCH₃), 3.04 (s, 2H, H_bridgehead), 1.45 (s, 3H), 1.34 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ: 129.4 (2C, C=CCl), 114.7

(C_q), 108.4 (C_q), 76.7 (2C, C_acetonide), 75.6 (2C, C-Cl), 65.1

(2C, CHOH), 53.1 (OCH₃), 51.7 (OCH₃), 46.3 (2C, CH),

26.1 (CH_3acetonide), 23.3 (CH_3acetonide). LR-MS (EI, 70 eV)

m/z: 451 [M⁺+ 1]. Anal. calcd. for C₁₆H₂₀O₄Cl₆: C 42.69, H

4.48; found: C 43.04, H 4.62.

1

85%). IR (Nujol, cm^–1): 3350. H NMR (300 MHz, D₂O) δ:

4.46–4.43 (m, 1H), 4.35–4.31 (m, 1H), 4.13–4.11 (br t, J =

3.3 Hz, 1H), 3.97 (br dd, J = 6.6, 2.7 Hz, 1H), 3.92 (br s,

1H), 3.85 (br dd, J = 12.0, 3.0 Hz, 1H), 3.71 (br dd, J = 8.7,

2.1 Hz, 1H), 3.64–3.61 (m, 1H), 2.21 (m, 1H), 2.06 (m, 1H),

1.39 (s, 3H), 1.26 (s, 3H). ¹³C NMR (75 MHz, D₂O) δ:

111.1 (C_q), 77.9, 76.6, 72.8, 71.3, 70.9, 70.7, 68.4, 66.2,

40.0 (CH), 38.9 (CH), 26.2, 24.9. LR-MS (EI, 70 eV) m/z:

289 [M⁺– H₂O + 1]. Anal. calcd. for C₁₃H₂₂O₈: C 50.97, H

7.24; found: C 50.63, H 7.52.

(2R*,3R*,4R*,8S*,9R*,10S*)-14,14-Dimethoxy-6,6-

dimethyl-5,7-dioxatetracyclo[9.2.1.0^2,10.0^4,8]tetradec-12-

ene-3,9-diol (57)

Bicyclitol 54

Liquid ammonia (100 mL) was distilled into a three-

necked round-bottomed flask equipped with a Dewar con-

denser, KOH guard tube, and septum. The solution of

acetonide 56 (1 g, 2.22 mmol) in dry THF (10 mL) and ab-

solute EtOH (5 mL) was added to the reaction flask. Small

pieces of freshly cut sodium were introduced, with stirring,

into the resulting mixture until the blue color of the solution

persisted. The mixture was stirred for 40 min and quenched

by addition of solid NH₄Cl (~1 g). The excess ammonia was

allowed to evaporate and the residue obtained was diluted

with cold aq. satd. NH₄Cl solution (20 mL) and water

(50 mL). The residue, resulting from the usual work-up, was

purified by silica gel column chromatography (70% ethyl ac-

etate – hexane) to furnish the olefin diol 57 (610 mg, 88%),

Acetonide 53 (20 mg, 0.065 mmol) was stirred vigorously

with 30% trifluoroacetic acid (800 µL) at room temperature

for 30 min. The volatiles were removed under reduced pres-

1

sure to furnish 54 (16 mg, 95%). H NMR (300 MHz, D₂O)

δ: 4.19 (br s, 1H), 4.00 (br s, 1H), 3.96–3.81 (series of m,

4H), 3.75–3.60 (m, 2H), 2.22–2.18 (m, 2H). ¹³C NMR

(75 MHz, D₂O) δ: 77.0, 76.7, 76.0, 74.2, 73.2, 71.2 (3C),

43.1 (CH), 40.5 (CH). LR-MS (EI, 70 eV) m/z: 264 [M⁺– 2].

Anal. calcd. for C₁₀H₁₈O₈: C 45.11, H 6.81; found: C 45.32,

H 7.01.

(2R*,3S*,4S*,5R*,6S*,7S*)-1,8,9,10-Tetrachloro-11,11-

dimethoxytricyclo[6.2.1.0^2,7]undec-9-ene-3,4,5,6-tetrol

(55)

1

mp 200–202 °C. IR (Nujol, cm^–1): 3420, 1260. H NMR

(300 MHz, CDCl₃) δ: 6.17 (t, 2H, J = 3.0 Hz, C=CH), 3.94

(br s, 2H, H_acetonide), 3.32 (s, 3H, OCH₃), 3.13 (br s, 3H,

OCH₃), 3.04 (br s, 2H, CHOH), 2.92 (s, 2H), 1.65 (s, 2H),

1.44 (s, 3H), 1.30 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ:

132.0 (2C, C=CH), 119.4 (C_q), 108.4 (C_q), 78.5 (2C,

A solution of diol 45 (1 g, 2.66 mmol) in acetone–water–

t-BuOH (5:5:2, 15 mL) was treated sequentially with OsO₄

(7 mg, 1 mol%) and 50% aq. NMMO (747 µL, 3.19 mmol)

at 0 °C. The resulting pale yellow reaction mixture was

stirred at room temperature for 1.5 h, at which point all the

starting material had been consumed (TLC). The reaction

mixture was cooled to 0 °C and quenched by the addition of

solid NaHSO₃(500 mg). The mixture was filtered through a

Celite pad and the filtrate was concentrated under reduced

pressure. The residue obtained was chromatographed over a

silica gel column (30% ethyl acetate – hexane) to furnish 55

(817 mg, 75%). IR (Nujol, cm^–1): 3420, 3315, 3245. ¹H

NMR (300 MHz, DMSO) δ: 3.83 (br s, 4H), 3.50 (s, 3H),

3.43 (s, 3H), 3.00 (s, 2H). ¹³C NMR (75 MHz, DMSO) δ:

128.7 (2C, C=CCl), 114.6 (C_q), 77.1 (2C, C-Cl), 68.4 (2C,

CHOH), 67.3 (2C, CHOH), 52.4 (OCH₃), 51.5 (OCH₃), 46.2

(2C, CH). LR-MS (EI, 70 eV) m/z: 374 [M⁺– Cl + 1]. Anal.

calcd. for C₁₃H₁₆Cl₄O₄: C 38.08, H 3.93; found: C 37.88, H

3.88.

C

_acetonide), 71.4 (2C, CHOH), 52.0 (2C, OCH₃), 49.8 (2C),

46.7 (2C), 26.7 (CH_3acetonide)), 23.0. LR-MS (EI, 70 eV) m/z:

312 [M⁺]. Anal. calcd. for C₁₆H₂₄O₆: C 61.52, H 7.74;

found: C 61.90, H 7.52.

(2R*,3R*,4R*,8S*,9R*,10S*)-3,9-Dihydroxy-6,6-

dimethyl-5,7-dioxatetracyclo[9.2.1.0^2,10.0^4,8]tetradec-12-

en-14-one (58)

Ketal 57 (220 mg, 0.705 mmol) was dissolved in moist

acetone (20 mL) and stirred with Amberlyst-15 resin

(~50 mg) for 2 h, when all the starting material had been

consumed (TLC). The reaction mixture was filtered through

a Celite pad and the filtrate was concentrated under reduced

pressure to give a solid residue, which was chromatographed

over a silica gel column (50% ethyl acetate – hexane) to fur-

nish the 7-ketonorbornene 58 (178 mg, 95%), mp 220–

221.5 °C. IR (KBr, cm^–1): 3443, 1778.

(2R*,3R*,4S*,8R*,9R*,10S*)-1,11,12,13-Tetrachloro-

14,14-dimethoxy-6,6-dimethyl-5,7-dioxatetra-

cyclo[9.2.1.0^2,10.0^4,8]tetradec-12-ene-3,9-diol (56)

To a solution of tetrol 55 (750 mg, 1.829 mmol) in dry ac-

etone (25 mL), Amberlyst-15 (~100 mg) and 4 Å molecular

sieve powder (250 mg) were added sequentially and the re-

sulting mixture was stirred at room temperature for 1 h.

Upon complete consumption of the starting material (TLC),

the reaction mixture was filtered through a Celite pad and

the filtrate was concentrated under reduced pressure to give

a solid residue. The residue was chromatographed over a sil-

(3aR*,4S*,4aS*,8aR*,9R*,9aS*)-2,2-Dimethyl-

3a,4,4a,8a,9,9a-hexahydronaphtho[2,3-d][1,3]dioxole-4,9-

diol (59)

A solution of ketone 58 (90 mg, 0.338 mmol) in nitro-

benzene (10 mL) was heated to 160 °C, with vigorous stir-

ring, for 3 h. Upon complete consumption of the starting

material (TLC), the reaction mixture was cooled to 80 °C

and the solvent was distilled off under reduced pressure. The

Mehta and Ramesh

593

resulting residue was subjected to silica gel column chroma-

tography (30% ethyl acetate – hexane) to afford diene 59

(35 mg, 43%), mp 188.5–190 °C. IR (KBr, cm^–1): 3321,

3034. H NMR (300 MHz, CDCl₃) δ: 5.97–5.94 (m, 2H,

C=CH), 5.54–5.50 (m, 2H, C=CH), 4.50–4.49 (m, 2H,

3.2.1.25) from snail acetone powder. The substrates for the

glycosidase were the corresponding ortho- or para-nitro-

phenylglycosides. The α-glucosidase (0.135 units/mL)³was

assayed using p-nitophenyl-α-^D-glucopyranoside (2.53 mmol/L)

as the substrate at pH 6.8 (100 mmol/L phosphate

buffer) at 37 °C, while β-glucosidase (0.133 units/mL)

was assayed using p-nitrophenyl-β-^D-glucopyranoside

(2.57 mmol/L) as the substrate at pH 5.0 (10 mmol/L acetate

buffer) at 37 °C. The potency of α-galactosidase (0.1 units/mL)

and β-galactosidase (0.91 units/mL) was studied using

p-nitrophenyl-α-^D-galactopyranoside (2.12 mmol/L) and o-

nitrophenyl-β-^D-galactopyranoside (2.34 mmol/L) as sub-

strate at pH 6.5 (100 mmol/L phosphate buffer) and pH 7.3

(100 mmol/L phosphate buffer) at 25 and 37 °C, respec-

tively. The assay involving α-mannosidase (0.116 units/mL)

was carried out using p-nitrophenyl-α-^D-mannopyranoside

(2.01 µmol/L) as substrate at pH 4.5 (10 mmol/L acetate

buffer) at 25 °C, while β-mannosidase (0.125 units/mL) was

assayed using p-nitrophenyl-α-^D-mannopyranoside (2.15 mmol/L)

as substrate at pH 4 (10 mmol/L acetate buffer) at 25 °C.

Typical assays were carried out in 1.5 mL disposable

Eppendorf tubes, with the reaction volume being maintained

at 200 µL. The mixture of enzyme and potential inhibitor in

the optimum buffer medium was preincubated for 5 min and

the reaction was initiated by adding the corresponding sub-

strate solution (prepared in double-distilled water) to the re-

action mixture. After incubation for 30 min at the optimum

temperature for the enzyme, the reaction was quenched by

addition of 800 µL of Na₂CO₃buffer (400 mmol/L) solution.

The enzyme activity was determined by measuring the ab-

sorption of the nitrophenolate ion released at 400 nm (in the

case of p-nitrophenol) or 410 nm (in the case of o-

nitrophenol). In the control experiments, the inhibitor was

replaced by a corresponding buffer solution. The K_iwas cal-

culated using the Lineweaver–Burk plot.

1

H

_acetonide), 3.86 (br s, 2H), 3.53 (d, J = 6.9 Hz, 2H), 3.20

(br s, 2H, H_bridgehead), 1.46 (s, 3H), 1.37 (s, 3H). ¹³C NMR

(75 MHz, CDCl₃) δ: 125.8 (2C, C=CH), 123.8 (2C, C=CH),

108.6 (C_q), 74.9 (2C, C_acetonide), 69.7 (2C, CHOH), 32.4

(2C), 26.6 (CH_3acetonide), 24.0 (CH_3acetonide). LR-MS (EI,

70 eV) m/z: 239 [M⁺+ 1]. Anal. calcd. for C₁₃H₁₈O₄: C

65.53, H 7.61; found: C 65.90, H 7.52.

(3aR*,4S*,4aR*,5S*,6S*,7S*,8S*,8aS*,9R*,9aS*)-2,2-

Dimethylperhydronaphtho[2,3-d][1,3]dioxole-4,5,6,7,8,9-

hexol (60)

To a solution of diene 59 (25 mg, 0.105 mmol) in

acetone–water–t-BuOH (5:5:2, 6 mL), catalytic amounts of

OsO₄(0.5 mg, 1 mol%) and 50% aq. NMMO (75 µL,

0.315 mmol) were sequentially added at 0 °C. The resulting

pale yellow reaction mixture was stirred at room temperature

for 48 h. The reaction mixture was cooled to 0 °C prior to

quenching with solid NaHSO₃(15 mg). The resulting mix-

ture was diluted with ethyl acetate (20 mL), filtered through

Celite, and the filtrate was concentrated under reduced pres-

sure. The residue was subjected to silica gel column chroma-

tography (10% methanol – ethyl acetate) to afford hexol 60

1

(23 mg, 73%). IR (Nujol, cm^–1): 3460. H NMR (300 MHz,

D₂O) δ: 4.27 (d, J = 3 Hz, 1H), 4.20 (dd, J = 8.4, 5.4 Hz,

1H), 4.14 (dd, J = 5.1, 1.2 Hz, 1H), 4.03 (t, J = 3 Hz, 1H),

3.97–3.92 (m, 1H), 3.86 (dd, J = 10.2, 3.6 Hz, 1H), 3.79 (dd,

J = 8.4, 5.4 Hz, 1H), 3.52 (dd, J = 10.2, 3.3 Hz, 1H), 2.54–

2.20 (m, 2H), 1.39 (s, 3H), 1.26 (s, 3H). ¹³C NMR (75 MHz,

D₂O) δ: 110.5 (C_q), 80.1 (CH_acetonide), 78.3 (CH_acetonide),

72.7, 72.3, 72.0, 71.5, 67.4, 66.4, 41.9 (CH_bridgehead), 39.3

(CH_bridgehead), 28.6, 26.6. LR-MS (EI, 70 eV) m/z: 306 [M⁺].

Anal. calcd. for C₁₃H₂₂O₈: C 50.97, H 7.24; found: C 50.90,

H 7.51.

Acknowledgements

We thank the Chemical Biology Unit of the Jawaharlal

Nehru Centre for Advanced Scientific Research for financial

support. High field NMR data reported here were obtained

through the help of S.I.F at the Indian Institute of Science

(IISc). S.S.R. thanks the Council of Scientific and Industrial

Research (CSIR), India, for the award of a Research Fellow-

ship. We appreciate the help of Dr. Utpal Tatu, Department

of Biochemistry, in performing enzymatic assays.

Bicyclitol 61

Acetonide hexol 60 (14 mg, 0.046 mmol) was stirred vig-

orously with 30% TFA (500 µL) at room temperature for

30 min. The volatiles were removed under reduced pressure

1

to furnish 61 (11 mg, 90%). H NMR (300 MHz, D₂O) δ:

4.06 (m, 1H), 3.93 (dd, J = 10.5, 3.0 Hz, 1H), 3.87 (br s,

1H), 3.81 (m, 1H), 3.75 (t, J = 3.9 Hz, 1H), 3.73 (t, J =

3.0 Hz, 1H), 3.68 (t, J = 3.3 Hz, 1H), 3.52 (dd, J = 10.5,

3.0 Hz, 1H), 2.35 (dt, J = 6.6, 2.7 Hz, 1H), 2.28 (m, 1H).

¹³C NMR (75 MHz, D₂O) δ: 73.6, 72.8, 71.3, 70.7, 70.4,

69.3, 69.1, 67.4, 40.2, 38.4. LR-MS (CI) m/z: 266 [M⁺].

Anal. calcd. for C₁₀H₁₈O₈: C 45.11, H 6.81; found: C 45.45,

H 7.12.

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General procedure for enzymatic assays

The enzymes assayed were α-glucosidase (EC 3.2.1.20)

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Article Doi

Polycyclitols - Novel conduritol and carbasugar hybrids as new glycosidase inhibitors

DOI: 10.1139/v05-032

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