Synthesis and α-Glucosidase and α-Amylase Inhibitory Activity Evaluation of Azido- and Aminocyclitols

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FULL PAPER

DOI: 10.1002/ejoc.201402762

Synthesis and α-Glucosidase and α-Amylase Inhibitory Activity Evaluation of

Azido- and Aminocyclitols

Gökay Aydin,^[a]Khamis Ally,^[a]Fatih Aktas,^[a]Ertan Sahin,^[b]Arif Baran,*^[a]and

¸

Metin Balci*^[c]

Keywords: Synthetic methods / Carbocycles / Cyclitols / Carbasugars / Amines / Biological activity

For the synthesis of some azido- and aminocyclitols, (3aR-

S,7aSR)-1,3,3a,7a-tetrahydroisobenzofuran was used as the

starting material. For further functionalization of the diene

unit, the diene was subjected to epoxidation reactions to give

mono- and bisepoxides depending on the amount of m-chlo-

roperbenzoic acid used. The ring-opening of the epoxide

functionality with NaN₃resulted in the formation of mono-

and bisazido cyclitols. The tetrahydrofuran ring was opened

amino- and bisaminocyclitol derivatives. The inhibitory ef-

fects of 20 compounds against α-glucosidase and α-amylase

were tested. The results indicated that some of these com-

pounds seem to have good inhibitory activity against α-

glucosidase, and low inhibitory activity against α-amylase.

Furthermore, it was demonstrated that the number and posi-

tion of azides, amines, and hydroxy groups appeared to play

an important role in determining the inhibitory potency of

in an acid-catalysed reaction with sulfamic acid. The re- these compounds.

duction of azide groups to give amines provided various

amine (3), and their analogues,^[3d]were first isolated as frag-

Introduction

ments of the pseudooligosaccharide validamycin A (1), and

were found to have inhibitory activity against certain

glycosidases (Figure 1).^[4]Valiolamine (4) was shown to be

a more potent α-glycosidase inhibitor than valienamine and

validamine against porcine intestinal sucrase, maltase, and

isomaltase.^[5]Voglibose (5),^[6,3d]an unnatural aminocyclitol,

is also an α-glycosidase inhibitor that is used for lowering

post-prandial blood glucose levels in people with diabetes

mellitus. In this context, some glycosidase inhibitors con-

taining an aminocyclitol structure have recently appeared

on the market. In recent years, significant efforts have been

made to develop synthetic methods directed not only

Aminocyclitols are substructures of many biologically

active natural products, including aminoglycoside-type anti-

biotics. They are a privileged class of structures for drug

development, and they are expected to act as carbohydrate

mimics, which can be developed as inhibitors of glycosid-

ases.^[1]The introduction of an amine group into a carbo-

hydrate-like structure can result in modified biological ac-

tivity. Carbasugars, formed by replacing the ring-oxygen

atom in monosaccharides, are thought to be more potent

drug candidates than natural sugars since the lack of an

endocyclic oxygen leads to enhanced hydrolytic stability.^[2]

Because of their close structural relationship with sugars,

aminocyclitols may also be regarded as aminocarbasu-

gars.^[3]

Natural aminocyclitols are secondary metabolites found

as structural subunits in some complex natural products,

such as validamycins (1), a family of antibiotics isolated

from the fermentation culture of Streptomyces hygros-

copicus.^[2]Aminocyclitols such as valienamine (2), valid-

[a] Department of Chemistry, Sakarya University,

54100 Sakarya, Turkey

E-mail: abaran@sakarya.edu.tr

www.sakarya.edu.tr

[b] Department of Chemistry, Atatürk University,

25240 Erzurum, Turkey

[c] Department of Chemistry, Middle East Technical University,

06800 Ankara, Turkey

E-mail: mbalci@metu.edu.tr

http://ww w .metu.edu.tr/~mbalci

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201402762.

Figure 1. Structures of some aminocyclitols.

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G. Aydin, K. Ally, F. Aktas¸, E. S¸ahin, A. Baran, M. Balci

FULL PAPER

towards the total synthesis of natural aminocyclitols, but position from the back side, forming the trans ring-opened

also towards the design of structural analogues with im- product 9. On the other hand, the nucleophile also attacks

proved or new biological properties. The synthesis of the double bond from the same face as the epoxide by an

aminocyclitols has attracted the attention of synthetic S_N2’ mechanism to form 8. The configuration of diol 11a

1

chemists.^[1b]Therefore, we were inspired to work on the de- was confirmed by H NMR spectroscopy. The proton 4-H

velopment of new methods for the synthesis of aminocycli- appears as a doublet of doublets with coupling constants

tol derivatives. Recently, we reported the synthesis of of J_4,3a= 11.1 and J_4,5= 8.2 Hz, which clearly supports the

various carbasugars.^[7]In this paper, we report the synthesis trans relationship of protons 4-H and 5-H, and also of 4-H

of some aminocarbasugars from a simple starting material, and 3a-H. This stereochemistry is consistent with the ring-

and the biological activities of the products.

opening mechanism.

For the synthesis of aminocyclitol derivatives, compound

9 was treated with m-CPBA (1 equiv.) in dichloromethane,

which gave two epoxides, 14 and 15, in 77 and 5% yields

(Scheme 2). For characterization of the structures, the

major product (i.e., 14) was transformed into diacetate 17.

Removal of the chlorobenzoate group from 14 with ammo-

nia in methanol gave diol 16, which was easily converted

into the corresponding epoxydiacetate (i.e., 17). Further-

more, the chlorobenzoate in 15 was also ammonolysed to

give the corresponding diol (i.e., 18), in order to compare

the structures of 16 and 18. Acetylation of 14 in the pres-

ence of acetic anhydride and pyridine gave 19.

Results and Discussion

Diene 6 was synthesized in five steps, starting with the

addition of maleic anhydride to in-situ-generated buta-

diene.^[7b,9]Reduction of the anhydride^[8]functionality fol-

lowed by addition of bromine and subsequent elimination

of HBr gave diene 6, which was used for the synthesis of

various aminocyclitols.

Diene 6 was treated with m-chloroperbenzoic acid (m-

CPBA; 1.2 equiv.) in dichloromethane to give two regioiso-

mers 8 and 9 in 41 and 22% yields, respectively (Scheme 1).

The structures of 8 and 9 were determined with the help of

The structures of 16 and 18 were assigned based on their

1D (¹H and ¹³C) and 2D (COSY, HSQC, and HMBC) ¹H NMR spectra and geometry optimization calculations

NMR spectra. For further characterization of the struc- (DFT, B3LYP at 6-31+G* level). The resonance signals of

tures, compounds 8 and 9 were first ammonolysed in meth- 3-H in 16 appear as a triplet at δ = 3.98 ppm with a cou-

anol to give 10 and 11a, followed by acetylation to give the pling constant of 8.5 Hz, whereas the 3-H proton in 18 res-

corresponding acetates (i.e., 12 and 11b). Comparison of onates as a doublet of doublets at δ = 3.32 ppm with cou-

the spectroscopic data of 10 and 12 with those of com- pling constants of J_3,3a= 10.5 Hz and J_3,2= 8.5 Hz. These

pounds obtained by photooxygenation of diene 6 followed values support the trans relationship of 3-H and 2-H as well

by cleavage of the peroxide linkage in 13 and acetylation as 3-H and 3a-H in both 16 and 18. For the assignment of

confirmed the positions of the substituents and the configu- the configuration of the epoxide rings, the dihedral angles

rations of the hydroxy group and the chlorobenzoate in between the vicinal protons 1a-H and 2-H and between the

8.^[7c]We suggest the following mechanism for the formation vicinal protons 6b-H and 6a-H were calculated. The dihe-

of isomers 8 and 9. m-Chloroperbenzoic acid (m-CPBA) dral angles found are given in Table 1. The measured cou-

attacks the double bond in 6 from the sterically less pling constants J_1a,2= 1.2 Hz and J_6a,6b= 4.1 Hz (J_1a,6b

=

crowded exo side to give monoepoxide 7, which undergoes 4.4 Hz, coupling constant between the epoxide protons) for

a ring-opening reaction under the reaction conditions 18 and the coupling constants J_1a,2= J_6a,6b≈ 0.0 Hz for 18

(Scheme 1). The epoxide ring formed is then attacked by m- are in good agreement with the dihedral angles determined

chlorobenzoic acid (m-ClC₆H₄CO) at the more active allylic by DFT calculations.

Scheme 1. Reaction of diene 6 with m-CPBA.

2

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Azido- and Aminocyclitols

Scheme 2. Synthesis of epoxydiols 16 and 18.

Table 1. Geometry-optimized structures and relevant dihedral H and the proton 7a-H. The resonance signal of 7-H ap-

angles and coupling constants of 16 and 18.

pears as a triplet at 3.79 with coupling constants of J_7,6

=

J_7,7a= 10.3 Hz, which clearly supports the trans relation-

ship of 7-H and 7a-H, and of 7-H and 6-H. These values

clearly show that the azide anion prefers to attack the epox-

ide ring from the back side, and from the less crowded side,

as expected, to form 20. Removal of the acetate groups

from 20 followed by hydrogenation of the azide function-

ality provided aminotriol 22.

Sulfamic acid^[10]was used as an efficient catalyst in acetic

anhydride to promote the acetolysis reaction of the tetra-

hydrofuran ring. Reaction of sulfamic acid with triacetate

20 at reflux temperature of a mixture of acetic acid and

acetic anhydride (1:1) gave the desired pentaacetate (i.e.,

23), which was characterized spectroscopically. Pentaacetate

23 was submitted to ammonolysis followed by hydrogen-

ation to give the desired aminopentaol (i.e., 25). The confi-

guration at all the carbon atoms was preserved, since the

reaction took place at the methylene carbon atoms of the

tetrahydrofuran ring.

We then turned our attention to the epoxide-ring-open-

ing reaction of 17. Epoxide opening with NaN₃in ethanol

followed by acetylation resulted in the formation of a single

product, 20 (Scheme 3). First we determined the position

of the azide functionality by using NMR spectroscopic data

In the second part of this work we turned our attention

(COSY, HSQC, and HMBC). The COSY spectra of 20 and to the synthesis of other isomeric aminocyclitol derivatives

21 showed strong correlations between the azido proton 7- starting from compound 8, which was obtained as the

Scheme 3. Synthesis of aminotriol 22 and aminopentaol 25.

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Scheme 4. Synthesis of epoxy diacetate 27.

major isomer from the reaction of diene 6 with m-chloro-

perbenzoic acid (Scheme 1). The reaction of 8 with m-

CPBA (1.2 equiv.) gave epoxide 26a as the sole product

(Scheme 4). The alcohol in 26a was acetylated to give 26b

for further characterization of the structure. Removal of the

chlorobenzoate group in 26a followed by acetylation re-

sulted in the formation of symmetrical diacetate 27. The

spectroscopic data of 27 exactly matched those of the prod-

uct obtained by photooxygenation of diene 6 followed by

cleavage of the peroxide linkage and then acetylation.^[7b]

The exclusive formation of 26a as a single isomer can again

be explained by the cis-directing effect of the neighbouring

hydroxy group, as discussed above.

Next we tried the epoxide-ring-opening reaction of

epoxydiacetate 27 using NaN₃in ethanol. As shown in

Scheme 5, the reaction was complete within 12 h under re-

flux conditions. The desired azidoalcohol was acetylated to

give azidotriacetate 31 as the major product in 69% yield,

and its isomer 30 was formed as the minor product in 2%

yield. Again, the position of the azide functionality in 31

was determined from its COSY spectrum. The resonance

signal of 7-H appears as a doublet of doublets with cou-

pling constants of J_7,6= 10.6 and J_7,7a= 10.5 Hz, which

clearly supports the trans relationship of 7-H and 6-H and

Scheme 5. Synthesis of aminotriol 33 and aminopentaol 36.

of 7-H and 7a-H. On the other hand, the proton 6-H (next compound 36, azidotriacetate 34 was first hydrolysed to the

to the azido group) resonates as a triplet with coupling con- corresponding azidopentaol (i.e., 35), which was easily con-

stants of J_6,5= J_6,7= 10.5 Hz, which indicates that 6-H also verted into 36 in high yield by hydrogenation.

has a trans relationship to both neighbouring protons, 5-H

In the last part of this work, the results obtained from

and 7-H. All these findings indicate a trans ring-opening of the reaction of monoepoxides 17 and 27 enabled us to de-

the epoxide ring in 27. After detailed NMR spectral studies, velop this approach further and synthesize diaminocyclitol

a cis configuration was assigned to the protons 5-H and 6- derivatives. We successfully treated diene 6 with m-CPBA

H in the minor product (i.e., 30). Finally, azidotriacetate 31 (2.5 equiv.) and obtained the desired bisepoxides (i.e., 37

was submitted to a hydrolysis reaction with ammonia in and 38) with, respectively, trans and cis relative configura-

methanol followed by hydrogenation to give aminotriol 33. tions for the two epoxides (Scheme 6), as well as ring-open-

The sulfamic acid catalysed ring-opening reaction of 31 ing products 14 and 26a. cis-Bisepoxide 38 was identified

in the presence of acetic anhydride resulted in the formation by comparison of its spectroscopic data with those of the

of azidopentaacetate 34. Detailed spectral analysis of 34 compound obtained by photooxygenation of diene 6 fol-

indicated that the configurations of the carbon atoms did lowed by CoTPP (tetraphenylporphyrinatocobalt) catalysed

not change during the tetrahydrofuran-ring-opening reac- rearrangement.^[7d]The unsymmetrical structure of 37 was

tion. The structure of 34 was further confirmed by X-ray confirmed by the presence of eight signals in its ¹³C NMR

crystal structure analysis (Figure 2). To synthesize target spectrum.

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Having obtained these promising bisepoxides (i.e., 37 and

38), first we treated the symmetrical cis-bisepoxide (i.e., 38)

with NaN₃, and then acetylated the products to give two

separable compounds, 39 and 40, in 6 and 71% yields,

respectively (Scheme 7). The ¹H NMR spectrum of 40

showed that it was a symmetrical compound containing two

azide functionalities. X-ray analysis of diazido compound

40 confirmed the cis-configuration of the azides and the

trans configuration of the azides and the acetates (Figure 3).

The minor product (i.e., 39) was formed by nucleophilic at-

tack of ethanol, which was used as solvent. Ammonolysis

of 40 gave 41, which was easily converted into diaminodiol

42 by catalytic reduction.

Figure 2. The X-ray crystal structure of 34.

Figure 3. The X-ray crystal structure of 40.

For the synthesis of diaminotetrol 45, diazidodiacetate

40 was first submitted to a tetrahydrofuran-ring-opening re-

action using sulfamic acid in the presence of acetic an-

hydride to give 43, which was converted into 45 using

straightforward methods as described above (Scheme 7).

We then investigated the ring-opening reaction of trans-

bisepoxide 37. The reaction of 37 with NaN₃in ethanol

followed by acetylation provided two ring-opened products,

Scheme 6. Reaction of diene 6 with m-CPBA (2.5 equiv.). Synthesis

of bisepoxides 37 and 38.

Scheme 7. Synthesis of diaminodiol 42 and diaminotetrol 45 starting from cis-bisepoxide 38.

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Scheme 8. Synthesis of diaminodiol 49 and diaminotetrol 52 starting from trans-bisepoxide 37.

47 and 46, in 78 and 7% yields, respectively (Scheme 8).

Under the established optimized conditions, azido di-

The spectroscopic data indicated the formation of an epox- acetate 47 was easily converted into diaminodiol 49, and

ide-ring-opened product 47 and the incorporation of two also into 52 following cleavage of the tetrahydrofuran ring

azide functionalities into the molecule. The positions of the with sulfamic acid.

azides were determined with the help of the COSY spec-

trum. The configurations of the azides were established by

Inhibition Assay

measuring the corresponding coupling constants between

the relevant protons. The azido proton 7-H, next to the

tetrahydrofuran ring, resonates at δ = 3.87 ppm as a triplet

with coupling constants of J_7,6= J_7,7a= 10.2 Hz, indicating

a trans relationship between 6-H and 7-H and also between

7-H and 7a-H. Furthermore, the small coupling between 5-

H and 6-H, J_5,6= 2.9 Hz, shows the cis configuration of

these protons. If we bring all these findings together, we can

assign a trans-cis-trans relationship to the substituents in

47.

For the formation of compound 47, we suggest the fol-

lowing ring-opening mechanism. According to the Fürst–

Plattner rule,^[11]opening of cyclohexene epoxides generally

proceeds in such a fashion that the trans-diaxial rather than

the trans-diequatorial product is obtained. The isomer with

diaxial substituents is favoured because the transition state

is chair-like rather than boat-like. Therefore the azide anion

prefers to first attack the epoxide ring with a cis configura-

tion relative to the tetrahydrofuran ring, at C-2a, to give

intermediate 53 (Scheme 9). Then the second azide anion

attacks mono-epoxide 53 at the C-1a carbon atom to give

ring-opened product 47, whose configuration is completely

in agreement with our NMR spectral findings. We assigned

the same configuration to 46, which was formed as a side-

product from the reaction of ethanol as a nucleophile in the

epoxide-ring-opening reaction.

α-Glucosidase and α-amylase inhibitors are used for

treatment of type 2 diabetes mellitus, a metabolic disorder

characterized by high blood glucose.^[12]α-Glucosidase and

α-amylase are enzymes that hydrolyse the α-glycosidic

bonds of polysaccharides such as starch and glycogen,

yielding glucose and maltose. Therefore, inhibition of these

enzymes is important in the treatment of diabetes mellitus,

cancer, and HIV infections.^[13–15]In recent years, these in-

hibitors, which reduce blood-glucose levels, have been ex-

ploited intensively. There are oral antidiabetic drugs pro-

duced by the pharmacetical industry like acarbose, miglitol,

and voglibose.^[16,17]These drugs are sugar derivatives that

mimic sugar structures.^[18]

The inhibitory activities of the synthesized compounds

were evaluated in vitro against α-glucosidase from Sac-

charomyces cerevisia and Bacillus sp. α-amylase. The en-

zyme inhibition values of all compounds were also com-

pared with the inhibition values of acarbose. The inhibitory

profile of α-glucosidase was determined based on the enzy-

matic cleavage of p-nitrophenyl α-d-glucopyranoside to re-

lease p-nitrophenol.^[19]α-Amylase activity was assayed by

monitoring the maltose produced from starch by the DNS

(3,5-dinitrosalicylic acid) method.

Azidotriol 21 did not inhibit α-glucosidase or α-amylase.

However, 22 and 25 did inhibit these enzymes (Table 2).

Compound 24 inhibited α-glucosidase. We compared these

values with IC₅₀values determined previously for acarbose

against α-glucosidase (1.05Ϯ0.04 mm) and α-amylase

(0.071Ϯ0.006 mm). These values show that 22 and 25 are

potent inhibitors of α-glucosidase and α-amylase, with IC₅₀

values of 4.33Ϯ0.06 and 3.86Ϯ0.14 mm for α-glucosidase,

and 3.22Ϯ0.21 and 2.75Ϯ0.24 mm for α-amylase, respec-

tively. In the next group, we changed the position of the

Scheme 9. Suggested mechanism for the formation of 47.

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Azido- and Aminocyclitols

azido and amino functionalities, and observed that 32 we examined the inhibitory potency of the diols and epoxy-

(Table 2) is a good inhibitor of α-glucosidase but a weak diols (i.e., 10, 11a, 18, and 29), and we found that com-

inhibitor of α-amylase. On the other hand, 33 and 35 were pounds 11a and 18a showed inhibition of α-glucosidase,

good inhibitors of α-glucosidase. Next, we examined the and 29 of α-amylase (Table 4).

inhibitory abilities of compounds with two azido or amino

functionalities connected to adjacent carbon atoms, as in

41, 42, 44, and 45 (Table 3). Compounds 41 and 45 did not

Table 3. Inhibition of α-glucosidase and α-amylase by 41, 42, 44,

45, 48, 49, 51, and 52.

show any inhibition of α-amylase, but there was remarkable

inhibition of α-glucosidase for compounds 41, 42, 44, and

45. In particular, 44 and 45 were very potent inhibitors of

α-glucosidase (1.97Ϯ0.15 and 1.84Ϯ0.005 mm). Upon

changing the position of the azido and amino functionali-

ties, as in 48, 49, 51, and 52, we observed similar effects.

All of these compounds showed inhibition of α-glucosidase,

except compound 49. Diazidotetrol 51 showed strong inhi-

bition of α-glucosidase (2.09Ϯ0.11 mm), and diaminodiol

49 showed strong inhibition of α-amylase (Table 3). Finally,

Table 2. Inhibition of α-glucosidase and α-amylase by 21, 22, 24,

25, 32, 33, 35, 36, and acarbose.

[a] IC₅₀is the concentration of inhibitor at which α-amylase or α-

glucosidase was inhibited by 50%; n.i.: no inhibition, n.t.: not

tested. * The values with asterisks in a column are statistically sig-

nificant (p Ͻ 0.05).

Conclusions

In summary, we have achieved the synthesis of various

isomeric aminocyclitols starting from tetrahydroisobenzof-

uran 6. The complex stereochemistry was introduced by

epoxidation of the diene followed by epoxide-ring-opening

reactions with NaN₃. Reduction of the azido functionalities

and cleavage of the tetrahydrofuran ring with sulfamic acid

gave various mono- and diaminocyclitol derivatives. The in-

[a] IC₅₀is the concentration of inhibitor at which α-amylase or α-

hibitory effects of 20 compounds against α-glucosidase and

glucosidase was inhibited by 50%; n.i.: no inhibition, n.t.: not

α-amylase were tested. The results indicated that com-

pounds 11a, 18, 44, 45, 48, and 51 seem to have good in-

tested. * The values with asterisks in a column are statistically sig-

nificant (p Ͻ 0.05).

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dichloromethane to give white crystals (2.64 g, 22%). R_f(EtOAc/

hexane, 1:4): 0.38, m.p. 114–116 °C. H NMR (300 MHz, CDCl₃):

Table 4. Inhibition of α-glucosidase and α-amylase by 10, 11a, 18,

and 29.

1

δ = 8.03 (br. t, J = 1.8 Hz, 1 H, arom.), 7.95 (dt, J = 7.9, 1.2 Hz,

1 H, arom.), 7.55 (ddd, J = 7.9, 2.1, 1.2 Hz, 1 H, arom.), 7.40 (t, J

= 7.9 Hz, arom.), 5.79 (ddd, A part of AB system, J_6,7= 9.9, J =

3.7, 2.3 Hz, 1 H, 6-H or 7-H), 5.65 (dt, B part of AB system, J_6,7

= 9.9, J = 1.7 Hz, 1 H, 6-H or 7-H), 5.52 (dq, J_5,4= 8.5, J_5,6= J_5,7

= J_5,3a= 1.6 Hz, 1 H, 5-H), 4.14 (dd, A part of AB system, J =

9.1, 2.1 Hz, 1 H, CH₂), 4.02 (t, J = 8.5 Hz, 1 H, CH₂), 3.91 (dd, B

part of AB system, J = 9.1, 5.7 Hz, 1 H, CH₂), 3.86 (dd, J_4,5

=

10.8, J_4,3a= 10.8 Hz, 1 H, 4-H), 3.51 (t, J = 8.5 Hz, 1 H, CH₂),

3.07–2.97 (m, 1 H, 3a-H or 7a-H), 2.61 (br. s, 1 H, OH), 2.51

(dddd, J_3a,4= 10.8, J = 6.9, 5.8, 2.1 Hz, 1 H, 3a-H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 166.0, 135.0, 133.6, 131.8, 130.04, 130.02,

129.0, 128.1, 126.4, 76.5, 72.3, 71.4, 70.05, 44.0, 41.0 ppm. IR

(KBr): ν = 3381, 2943, 2888, 1716, 1574, 1426, 1327, 1273, 1252,

˜

1118, 1081, 892 cm^–1. C₁₅H₁₅ClO₄(294.73): calcd. C 61.13, H 5.13;

found C 61.35, H 5.26.

(3aRS,4SR,7RS,7aSR)-7-Hydroxy-1,3,3a,4,7,7a-hexahydroiso-

benzofuran-4-yl 3-Chlorobenzoate (8): Compound 8 was isolated as

the second fraction as a colourless liquid (4.92 g, 41%). R_f(EtOAc/

1

hexane, 1:4): 0.34. H NMR (300 MHz, CDCl₃): δ = 8.01 (br. d, J

= 1.7 Hz, 1 H, arom.), 7.92 (ddd, J = 7.6, 1.7, 1.4 Hz, 1 H, arom.),

7.54 (ddd, J = 8.0, 1.7, 1.4 Hz, 1 H, arom.), 7.39 (t, J = 8.0 Hz, 1

H, arom.), 6.30 (dt, A part of AB system, J_5,6= 10.3, J_5,4= 2.3 Hz,

1 H, 5-H), 5.85 (dt, B part of AB system, J_6,5= 10.3, J_6,7= 2.3 Hz,

1 H, 6-H), 5.29–5.32 (m, 1 H, 4-H), 4.13 (dq, J_7,7a= 7.0, 2.1 Hz, 1

H, 7-H), 4.05 (dd, J_3,3Ј= 8.5, J_3,3a= 7.6 Hz, 1 H, 3-H), 3.92 (dd,

A part of AB system, J_1,1Ј= 8.8, J_1,7a= 5.9 Hz, 1 H, 1-H), 3.9 (dd,

B part of AB system, J_1,1Ј= 8.8, J_1Ј,7a= 4.1 Hz, 1 H, 1Ј-H), 3.65

(dd, J_3,3Ј= 8.5, J_3Ј,3a= 7.6 Hz, 1 H, 3Ј-H), 2.70 (dq, J = 4.6, 7.6 Hz,

1 H, 3a-H), 2.44–2.37 (m, 1 H, 7a-H), 2.40–2.25 (br. s, 1 H, OH)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 165.2, 134.8, 134.3, 133.5,

[a] IC₅₀is the concentration of inhibitor at which α-amylase or α-

glucosidase was inhibited by 50%; n.i.: no inhibition, n.t.: not

tested. * The values with asterisks in a column are statistically sig-

nificant (p Ͻ 0.05).

hibitory activity against α-glucosidase, and none of the syn-

thesized compounds showed good inhibitory activity

against α-amylase, except for 29 and 49, compared to acar-

bose. Furthermore, the study demonstrated that both the

number and position of azide, amine, and hydroxy groups 131.9, 130.0, 129.9, 128.1, 126.5, 71.9, 71.0, 68.7, 66.3, 44.1,

42.3 ppm. IR (KBr): ν = 3406, 2937, 2866, 1717, 1575, 1476, 1427,

˜

appears to play an important role in determining the inhibi-

tory potency of the compound against α-glucosidase and α-

amylase. Furthermore, we noted that the ring-opening of

the tetrahydrofuran moiety results in an increased activity.

These results may be used for the development of new drugs

for the treatment of diseases like hyperglycemia and diabe-

tes mellitus.

1287, 1252, 1127, 1083, 1045 cm^–1. C₁₅H₁₅ClO₄(294.73): calcd. C

61.13, H 5.13; found C 61.35, H 5.21.

General Procedure for the Hydrolysis of Benzoates and Acetates:

The esters (1.0–3.0 mmol) were dissolved in absolute methanol (15–

50 mL) in a flask. NH_3(g)was passed through the solution for 1.5 h.

The reaction flask was closed with a stopper, and the mixture was

stirred for 12 h at room temperature. After completion of the reac-

tion, the solvent and the acetamide by-product were removed under

reduced pressure to give the corresponding alcohols.

Experimental Section

(3aRS,4SR,7RS,7aSR)-1,3,3a,4,7,7a-Hexahydroisobenzofuran-4,7-

diol (10): Benzoate 8 (0.25 g, 0.85 mmol) was ammonolysed as de-

scribed above to give 10 (0.121 g, 92%) as a colourless, viscous oil.

¹H NMR (300 MHz, D₂O): δ = 5.61 (br. s, 2 H), 4.6 (br. s, 2 H,

DOH), 3.80 (br. d, J = 4.4 Hz, 2 H), 3.72 (dd, J = 8.5, 6.5 Hz, 2

H), 3.48 (dd, J = 8.5, 4.8 Hz, 2 H), 2.18 (dt, J = 12.3, 7.0 Hz, 2 H)

ppm. ¹³C NMR (75 MHz, D₂O): δ = 130.5, 71.1, 65.1, 43.5 ppm.

C₈H₁₂O₃(156.18): calcd. C 61.52, H 7.74; found C 61.63, H 7.68.

Reaction of (3aRS,7aSR)-1,3,3a,7a-Tetrahydroisobenzofuran (6)

with m-CPBA. General Procedure for Epoxidation: Diene 6 (5.00 g,

40.93 mmol) was dissolved in dichloromethane (250 mL), and m-

CPBA (75%; 11.30 g, 49.11 mmol, 1.2 equiv.) was added at 0 °C.

The reaction mixture was stirred was stirred magnetically at 0 °C

for 2 h. After completion of the reaction, NaHSO₃(50% aq.;

100 mL) was added, and the mixture was stirred for 30 min. The

organic layer was separated and washed with saturated NaHCO₃

(2ϫ 300 mL), brine (2ϫ 300 mL), and water (4ϫ 400 mL), and

dried (Na₂SO₄). The solvent was removed under reduced pressure,

and the residue (8.8 g, 73%) was purified by chromatography on

silica gel (50 g) eluting with EtOAc/hexane (1:4) to give two separa-

ble fractions containing 8 and 9. The mixed fraction was submitted

again to column chromatography.

General Procedure for the Acetylation of Hydroxy Groups: The

alcohol (1.0–5.0 mmol) was dissolved in pyridine (1–5 mL) and ace-

tic anhydride (0.5–2 mL), and the mixture was stirred magnetically

at room temp. for 12 h. Dichloromethane (50–100 mL) was added,

and the solution was stirred for 5 min. Then ice-cold HCl (5% aq.;

50 mL) was added, and the mixture was stirred at room tempera-

ture for a while. The organic layer was washed with saturated

NaHCO₃(2 ϫ 50 mL) and water (3 ϫ 100 mL), and dried with

(3aSR,4SR,5SR,7aRS)-4-Hydroxy-1,3,3a,4,5,7a-hexahydroiso-

benzofuran-5-yl 3-Chlorobenzoate (9): Compound 9 was isolated as

the first fraction as a white powder that was crystallized from Na₂SO₄. The solvent was evaporated, and the residue was filtered

8

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Azido- and Aminocyclitols

through a short column (silica gel, eluting with EtOAc/hexane) to

give the corresponding acetates.

hexane (1:3) to give colourless crystals (0.29 g, 5%). R_f(EtOAc/

hexane, 1:3): 0.36, m.p. 170–172 °C. H NMR (300 MHz, CDCl₃/

1

C₆D, :1:1): δ = 7.99 (t, J = 1.8 Hz, 1 H, arom.), 7.81 (dt, J = 7.9,

6

(3aRS,4SR,7RS,7aSR)-1,3,3a,4,7,7a-Hexahydroisobenzofuran-4,7-

diyl Diacetate (12): Diol 10 (0.19 g, 1.22 mmol) was dissolved in

pyridine (3 mL) and acetic anhydride (3.5 mL), and the solution

was stirred magnetically at room temperature for 12 h as described

above to give diacetate 12 (0.25 g, 86%) as a colourless viscous oil.

¹H NMR (300 MHz, CDCl₃): δ = 5.85 (br. s, 2 H), 5.13 (br. d, J

= 3.8 Hz, 2 H), 3.95 (dd, J = 8.5, 6.4 Hz, 2 H), 3.67 (dd, J = 8.5,

5.3 Hz, 2 H), 2.51 (dt, J = 12.0, 6.7 Hz, 2 H), 2.09 (br. s, 6 H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 170.9, 128.9, 71.1, 67.6, 41.2,

21.4 ppm.

1.6 Hz, 1 H, arom.), 7.28 (ddd, J = 8.2, 2.2, 1.1 Hz, 1 H, arom.),

7.05 (t, J = 8.0 Hz, 1 H, arom.), 4.98 (d, J = 8.5 Hz, 1 H, 2-H),

3.99 (br. d, A part of AB system, J = 9.1 Hz, 1 H, 4-H), 3.77 (t, J

= 8.7 Hz, 1 H, 6-H), 3.50 (dd, B part of AB system, J = 9.1, 5.3 Hz,

1 H, 4Ј-H), 3.42 (t, J = 9.1 Hz, 2 H, 3-H, 6Ј-H), 2.96 (d, J = 3.1 Hz,

1 H, 1a-H or 6b-H), 2.74 (br. d, J = 3.1 Hz, 1 H, 1a-H or 6b-H),

2.67 (br. q, J = 9.1 Hz, 1 H, 6a-H), 1.93–1.86 (m, 1 H, 3a-H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 165.3, 135.0, 133.9, 131.3, 130.2,

130.1, 128.2, 74.4, 70.7, 68.8, 68.4, 55.3, 52.8, 40.8, 39.2 ppm. IR

(KBr): ν = 3401, 2942, 2887, 1716, 1575, 1475, 1312, 1291, 1246,

˜

1089, 1031 cm^–1. C₁₅H₁₅ClO₅(310.73): calcd. C 57.98, H 4.87;

found C 57.93, H 5.01.

(3aSR,4SR,5SR,7aRS)-1,3,3a,4,5,7a-Hexahydroisobenzofuran-4,5-

diol (11a): Benzoate 9 (0.64 g, 2.07 mmol) was ammonolysed as

described above to give 11a (0.312 g, 92%) as a colourless, viscous

(1aSR,2RS,3SR,3aSR,6aRS,6bSR)-3-Hydroxyoctahydrooxireno-

[2,3-e]isobenzofuran-2-yl 3-Chlorobenzoate (14): Compound 14 was

isolated as the second fraction as a colourless liquid (4.5 g, 76%).

R_f(EtOAc/hexane, 1:3): 0.32. ¹H NMR (300 MHz, CDCl₃): δ =

8.09 (m, 1 H, arom.), 7.49 (dm, J = 8.0 Hz, 1 H, arom.), 7.57 (ddd,

J = 8.0, 2.0, 1.0 Hz, 1 H, arom.), 7.42 (t, J = 7.6 Hz, 1 H, arom.),

5.31 (br. d, J_2,3= 9.1 Hz, 1 H, 2-H), 4.06 (t, J = 8.5 Hz, 1 H, 6-

H), 3.99 (dd, J_3,3a= 11.0, J_3,2= 8.9 Hz, 1 H, 3-H), 3.95–3.88 (m,

3 H, 3Ј-H, 6-H, 6Ј-H), 3.58 (br. d, J = 4.1 Hz, 1 H, 1a-H), 3.37 (br.

t, J = 4.1 Hz, 1 H, 6b-H), 2.85 (dq, J = 9.1, 4.1 Hz, 1 H, 6a-H),

2.39–2.29 (m, 1 H, 3a-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

165.9, 134.9, 133.7, 131.5, 130.13, 130.08, 128.2, 76.3, 71.7, 69.7,

1

oil. H NMR (300 MHz, D₂O): δ = 5.59 (ddd, A part of AB sys-

tem, J_7,6= 10.0, J_7,7a= 3.5, J_7,5= 2.1 Hz, 1 H, 7-H), 5.49 (dt, J_6,7

= 10.0, J_6,5= J_6,7a= 1.6 Hz, 1 H, 6-H), 4.62 (s, 2 H, DOH), 3.99

(dq, J_5,4= 8.2, J = 2.1 Hz, 1 H, 5-H), 3.91 (dd, A part of AB

system, J = 9.2, 2.2 Hz, 1 H, CH₂), 3.82 (t, J = 8.6 Hz, 1 H, CH₂),

3.76 (dd, B part of AB system, J = 9.2, 6.0 Hz, 1 H, CH₂), 3.30 (t,

J = 8.6 Hz, 1 H, CH₂), 3.25 (dd, J_4,3a= 11.1, J_4,5= 8.2 Hz, 1 H,

4-H), 2.83–2.94 (m,1 H, 7a-H), 2.34–2.25 (dddd, J = 10.3, 7.9, 5.9,

2.0 Hz, 1 H, 3a-H) ppm. ¹³C NMR (75 MHz, D₂O): δ = 129.8,

126.9, 72.4, 72.1, 71.7, 70.8, 43.3, 40.6 ppm. IR (KBr): ν = 3383,

˜

3030, 2929, 2869, 1719, 1426, 1286, 1252, 1069, 896, 748 cm^–1

.

C₈H₁₂O₃(156.18): calcd. C 61.52, H 7.74; found C 61.42, H 7.71.

68.9, 55.9, 53.4, 44.9, 38.1 ppm. IR (KBr): ν = 3427, 2938, 2859,

˜

1717, 1574, 1427, 1289, 1254, 1127, 1072, 1003, 910 cm^–1

.

(3aSR,4SR,5SR,7aRS)-1,3,3a,4,5,7a-Hexahydroisobenzofuran-4,5-

diyl Diacetate (11b): Diol 11a (0.54 g, 3.46 mmol) was dissolved in

pyridine (1 mL) and acetic anhydride (1.5 mL), and the resulting

solution was stirred magnetically at room temperature for 12 h as

described above to give diacetate 11b (0.72 g, 87%) as a colourless

C₁₅H₁₅ClO₅(310.73): calcd. C 57.98, H 4.87; found C 57.57, H

4.79.

(1aRS,2RS,3SR,3aSR,6aRS,6bRS)-3-Acetoxyoctahydroxyocta-

hydrooxireno[2,3-e]isobenzofuran-2-yl 3-Chlorobenzoate (15b):

Hydroxybenzoate 15a (0.13 g, 0.42 mmol) was acetylated as de-

1

viscous oil. H NMR (300 MHz, CDCl₃): δ = 5.74 (dt, J_4,5= 10.0,

J_3,4= 2.0 Hz, 1 H, 7-H), 5.55 (dd, J_6,7= 10.0, J_6,5= J_6,7a= 1.5 Hz,

1 H, 6-H), 5.38 (dt, J_1,6= 8.2, J_5,6= 1.6 Hz, 1 H), 5.09 (dd, J_4,3a

= 10.3, J_4,5= 8.2 Hz, 1 H, 4-H), 3.98 (t, J = 8.3 Hz, 1 H, 1-H),

3.82 (dd, A part of AB system, J = 9.4, 6.4 Hz, 1 H, 3-H), 3.74

(dd, B part of AB system, J = 9.4, 2.8 Hz, 1 H, 3Ј-H), 3.50 (t, J =

8.2 Hz, 1 H, 1Ј-H), 2.97 (m, 1 H, 7a-H), 2.61–2.52 (dddd, J = 10.6,

8.5, 6.2, 2.9 Hz, 1 H, 3a-H), 2.02 (s, 3 H, OMe), 2.01 (s, 3 H, OMe)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 170.9, 170.7, 128.6, 126.5,

1

scribed above to give 15b (0.13 g, 88%) as a colourless liquid. H

NMR (300 MHz, CDCl₃): δ = 8.01 (t, J = 1.4 Hz, 1 H), 7.90 (dt,

J = 7.6, 1.2 Hz, 1 H, arom.), 7.55 (ddd, J = 8.0, 2.2, 1.2 Hz, 1 H,

arom.), 7.39 (t, J = 8.0 Hz, 1 H, arom.), 5.22–5.11 (m, 2 H), 4.16

(t, J = 8.8 Hz, 1 H), 3.83 (dd, J = 9.9, 8.8 Hz, 1 H), 3.78–3.73 (m,

2 H), 3.29 (d, A part of AB system, J = 3.0 Hz, 1 H, epoxide), 3.22

(br. d, B part of AB system, J = 3.0 Hz, 1 H, epoxide), 3.12 (br. q,

J = 9.7 Hz, 1 H), 2.34–2.26 (m, 1 H), 1.99 (s, 3 H, COCH₃) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 170.6, 164.8, 135.0, 133.8, 131.2,

130.2, 130.1, 128.1, 72.4, 70.3, 69.1, 68.4, 55.6, 52.3, 39.9, 39.0,

72.3, 71.7, 71.2, 70.7, 41.8, 40.7, 21.3, 21.2 ppm. IR (KBr): ν =

˜

2939, 2871, 1736, 1569, 1487, 1477, 1429, 1368, 1241, 1220, 1071,

1029, 974, 958, 919, 901, 760, 725, 642 cm^–1. C₁₂H₁₆O₅(240.26):

calcd. C 59.99, H 6.71; found C 59.67, H 6.75.

21.1 ppm. IR (KBr): ν = 2941, 2872, 1725, 1575, 1473, 1428, 1371,

˜

1289, 1253, 1222, 1125, 1075, 1033, 934, 900, 814, 747, 674 cm^–1.

C₁₇H₁₇ClO₆(352.77): calcd. C 57.88, H 4.86; found C 58.13, H

4.68.

Reaction of Hydroxybenzoate 9 with m-Chloroperbenzoic Acid: A

solution of 9 (5.60 g, 19.0 mmol) in dichloromethane (200 mL) was

cooled to 0 °C, and m-chloroperbenzoic acid (75 %; 5.25 g,

22.8 mmol, 1.2 equiv.) was added. The resulting mixture was stirred

magnetically at room temp. for 48 h. The progress of the reaction

was monitored by ¹H NMR spectroscopy. At the end of this period,

NaHSO₃(50 % aq.; 300 mL) was added, and the mixture was

stirred for a further 30 min at room temp. The mixture was ex-

tracted with dichloromethane (500 mL), and the combined organic

layers were washed with saturated NaHCO₃(2ϫ 300 mL), brine

(2ϫ 200 mL), and water (4ϫ 500 mL), and dried (Na₂SO₄), and

concentrated under reduced pressure. The crude material was puri-

fied by column chromatography on silica (60 g) with ethyl acetate/

hexane (1:4).

(1aSR,2RS,3SR,3aSR,6aRS,6bSR)-Octahydrooxireno[2,3-e]iso-

benzofuran-2,3-diol (18): Epoxybenzoate 15a (0.15 g, 0.483 mmol)

was ammonolysed with NH₃in MeOH as described above to give

1

epoxy diol 18 (70 mg, 84%) as a colourless viscous oil. H NMR

(300 MHz, CDCl₃): δ = 4.12 (d, J = 9.1 Hz, 1 H, 4-H, 6-H), 4.06

(t, J = 9.0 Hz, 1 H, 4-H, 6-H), 3.74–3.66 (m, 3 H, 4-H, 6-H, 2-H),

3.32 (dd, J = 10.5, J = 8.5 Hz, 1 H, 3-H), 3.23 (d, J_1,6b= 3.5 Hz,

1 H, 1-H or 6b-H), 3.13 (br. d, J_1,6b= 3.5 Hz, 1 H, 1-H or 6b-H),

3.00 (br. q, J = 8.7 Hz, 1 H, 6a-H), 2.07–2.00 (m, 1 H, 3a-H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 71.5, 71.1, 71.0, 68.8, 57.3, 52.9,

40.9, 39.5 ppm. IR (KBr): ν = 3308, 2934, 2890, 1670, 1567, 1319,

˜

1252, 1121, 1061, 1032, 975, 917, 889, 877, 816, 648 cm^–1. C₈H₁₂O₄

(172.18): calcd. C 55.81, H 7.02; found C 55.96, H 7.28.

(1aRS,2RS,3SR,3aSR,6aRS,6bRS)-3-Hydroxyoctahydrooxireno-

[2,3-e]isobenzofuran-2-yl 3-Chlorobenzoate (15a): Compound 15a

was isolated as the first fraction, and was crystallized from EtOAc/

(1aSR,2RS,3SR,3aSR,6aRS,6bSR)-3-Acetoxyoctahydrooxireno-

[2,3-e]-isobenzofuran-2-yl 3-Chlorobenzoate (19): A solution of hy-

Eur. J. Org. Chem. 0000, 0–0

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G. Aydin, K. Ally, F. Aktas¸, E. S¸ahin, A. Baran, M. Balci

FULL PAPER

droxybenzoate 14 (1.25 g, 4.02 mmol) in pyridine (3 mL) and acetic

anhydride (3.5 mL) was stirred magnetically at room temp. for 12 h (75 MHz, CD₃OD): δ = 72.1, 71.2, 70.7, 69.3, 58.4, 52.9, 44.9,

2.15 (dddd, J = 10.9, 9.1, 6.0, 2.7 Hz, 1 H, 3a-H) ppm. ¹³C NMR

as described above to give 19 (1.23 g, 87%) as colourless crystals,

38.2 ppm. IR (KBr): ν = 3319, 2971.14, 2945, 2861, 1739, 1471,

˜

crystallized from ethyl acetate, m.p. 129–131 °C. ¹H NMR

1432, 1380, 1356, 1218, 1127, 1062, 1040, 921, 883 cm^–1. C₈H₁₂O₄

(300 MHz, CDCl₃): δ = 8.03 (dd, J = 2.4, 1.8 Hz, 1 H, arom.), 7.93 (172.18): calcd. C 55.81, H 7.02; found C 56.03, H 6.98.

(dt, J = 7.7, 1.5 Hz, 1 H, arom.), 7.55 (ddd, J = 8.2, 1.3, 1.0 Hz, 1

(3aSR,4SR,5RS,6SR,7RS,7aSR)-7-Azidooctahydroisobenzofuran-

H, arom.), 7.39 (t, J = 8.0 Hz, 1 H, arom.), 5.44 (m, 2 H, 2-H, 3-

4,5,6-triyl Triacetate (20): Diacetate 17 (2.8 g, 10.93 mmol) was dis-

H), 4.11 (t, J = 8.6 Hz, 1 H, 6-H), 3.86 (t, J = 8.6 Hz, 1 H, 6Ј-H),

solved in absolute ethanol (60 mL). Sodium azide (0.92 g,

10.92 mmol, 1.3 equiv.) was added to the solution. The reaction

mixture was heated at reflux for 24 h. The reaction mixture was

3.85 (dd, J = 9.5, 6.7 Hz, 1 H, 4-H), 3.63 (dd, J = 9.6, 3.8 Hz, 1

H, 4Ј-H), 3.60 (br. d, J = 4.0 Hz, 1 H, 1a-H), 3.37 (t, J = 4.4 Hz,

1 H, 6b-H), 2.89 (dq, J = 3.5, 8.5 Hz, 1 H, 6a-H), 2.52–242 (m, 1

cooled to room temperature, then the solid was removed by fil-

1

H, 3a-H), 1.93 (s, 3 H, COMe) ppm. H NMR (300 MHz, C₆D₆):

tration, and the ethanol was evaporated under reduced pressure.

δ = 8.02 (dd, J = 1.8 Hz, 1 H, arom.), 7.93 (br. d, J = 7.6 Hz, 1 H,

Without any further purification, the resulting residue was dis-

solved in pyridine (6 mL) and acetic anhydride (8.5 mL). The reac-

tion mixture was stirred magnetically at room temp. for 24 h. After

usual work-up as described above, the residue was purified by

arom.), 7.00 (ddd, J = 7.9, 2.1, 1.0 Hz, 1 H, arom.), 6.67 (t, J =

8.2 Hz, 1 H, arom.), 5.66 (br. t, J = 9.7 Hz, 1 H, 3-H), 5.27 (br. d,

J = 9.3 Hz, 1 H, 2-H), 3.72 (t, J = 7.9 Hz, 1 H, CH₂), 3.67–3.58

(m, 2 H, CH₂), 3.51 (dd, J = 9.4, 5.9 Hz, 1 H, CH₂), 3.16 (br. d, J

chromatography on a silica gel column (40 g) eluting with hexane/

= 4.1 Hz, 1 H, 1a-H), 2.51 (br. t, J = 4.1 Hz, 1 H, 6b-H), 2.01–1.87

ethyl acetate (6:1) to give azido triacetate 20 (2.52 g, 68 %) as

colourless crystals, crystallized from EtOAc/hexane (1:2), m.p. 112–

114 °C. ¹H NMR (300 MHz, CDCl₃): δ = 5.34–5.31 (m, 1 H, 5-H),

5.15 (dd, J_6,7= 10.3, J_6,5= 3.3 Hz, 1 H, 6-H), 5.05 (m, 1 H, 4-H),

4.03 (d, J = 9.4 Hz, 1 H, CH₂), 3.96 (t, J = 8.2 Hz, 1 H, CH₂), 3.88

(dd, J = 9.7, 8.8 Hz, 1 H, CH₂), 3.79 (t, J_7,6= J_7,7a= 10.3 Hz, 1

H, 7-H), 3.75 (dd, J = 9.2, 4.8 Hz, 1 H, CH₂), 2.57 (br. q, J =

8.5 Hz, 1 H, 3a-H), 2.30–2.21 (m, 1 H, 7a-H), 2.09 (s, 6 H, OMe),

2.05 (s, 3 H, OMe) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 170.1,

169.6, 169.3, 71.7, 71.5, 69.6, 68.1, 67.8, 58.2, 42.5, 42.4, 21.2, 21.1,

(m, 2 H, 6a-H, 3a-H), 1.46 (s, 3 H, COMe) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 170.3, 170.4, 135.0, 133.8, 131.2, 130.2 (2

C), 128.2, 73.7, 71.6, 70.4, 69.8, 55.8, 53.0, 42.9, 38.5, 21.1 ppm.

¹³C NMR (75 MHz, C₆D₆): δ = 169.5, 165.0, 134.9, 133.3, 131.6,

130.1 (2 C), 128.0, 73.9, 71.0, 70.2, 69.3, 55.5, 52.5, 42.8, 38.1,

20.1 ppm. IR (KBr): ν = 2936, 2870, 1742, 1721, 1576, 1429, 1371,

˜

1287, 1257, 1230, 1126, 1073, 1038, 926 cm^–1. C₁₇H₁₇ClO₆(352.77):

calcd. C 57.88, H 4.86; found C 58.01, H 4.54.

(1aSR,2RS,3SR,3aSR,6aRS,6bSR)-Octahydrooxireno[2,3-e]iso-

benzofuran-2,3-diyl Diacetate (17): Acetylbenzoate 19 (3.0 g,

8.50 mmol) was dissolved in absolute methanol (50 mL) in a flask

(100 mL). NH_3(g)was passed through the reaction mixture for

1.5 h. The reaction flask was closed with a stopper, and the mixture

was stirred for 12 h. Then the methanol was evaporated.

20.9 ppm. IR (KBr): ν = 2972, 2937, 2897, 2112, 1742, 1430, 1369,

˜

1237, 1210, 1078, 1056, 1027 cm^–1. C₁₄H₁₉N₃O₇(341.32): calcd. C

49.27, H 5.61, N 12.31; found C 49.05, H 5.68, N 12.48.

(3aSR,4SR,5RS,6SR,7RS,7aSR)-7-Azido-octahydroisobenzofuran-

4,5,6-triol (21): Azido triacetate 20 (0.80 g, 2.34 mmol) was

ammonolysed with NH₃in absolute MeOH as described above to

give azidotriol 21 (0.47 g, 93%) as cubic crystals, crystallized from

Without any additional purification, the residue was dissolved in

pyridine (4 mL) and acetic anhydride (4.5 mL). The resulting mix-

ture was stirred magnetically at room temp. for 12 h. The reaction

mixture was worked up as described above. The residue was puri-

fied by chromatography on a silica gel column (24 g) eluting with

hexane/ethyl acetate (2:1) to give diacetate 17 (1.89 g, 87 %) as

1

ethanol, m.p. 191–193 °C. H NMR (300 MHz, D₂O): δ = 4.53 (s,

3 H, DOH), 3.82–3.62 (m, 7 H), 3.51 (t, J_7,6= J_7,7a= 8.4 Hz, 1 H,

7-H), 2.35–2.13 (m, 2 H, 3a-H and 7a-H) ppm. ¹³C NMR

(75 MHz, D₂O): δ = 72.7, 71.0, 70.6, 69.1, 68.1, 60.7, 43.8,

41.7 ppm. IR (KBr): ν = 3420, 3342, 3295, 2921, 2903, 2889, 2086,

˜

colourless crystals, crystallized from EtOAc/hexane (1:4), m.p. 100–

1411, 1239, 1058, 1034, 918, 894 cm^–1. C₈H₁₃N₃O₄(215.21): calcd.

C 44.65, H 6.09, N 19.53; found C 44.47, H 6.18, N 19.71.

1

102 °C. H NMR (300 MHz, CDCl₃/C₆D₆, 1:3): δ = 5.35 (t, J_3,2

=

J_3,3a= 9.4 Hz, 1 H, 3-H), 5.06 (dd, J_2,3= 9.4, J_2,1a= 1.2 Hz, 1 H,

3-H), 3.62–3.47 (m, 4 H, CH₂), 3.02 (dd, J_1a,6b= 4.4, J_1a,2= 1.2 Hz,

1 H, 1a-H), 2.50 (dd, J_6b,1a= 4.4, J_6b,6a= 3.4 Hz, 1 H, 6b-H), 2.05–

1.91 (m, 1 H, 6a-H), 1.89–1.79 (m, 1 H, 3a-H) ppm. ¹H NMR

(300 MHz, CDCl₃): δ = 5.3–5.19 (m, 2 H, 3-H, 2-H), 4.08 (t, J =

8.5 Hz, 1 H, CH₂), 3.83 (d, J = 8.8 Hz, 1 H, CH₂), 3.80 (dd, J =

10.4, 1.8 Hz, CH₂), 3.60 (dd, J = 10.4, 4.1 Hz, 1 H, CH₂), 3.46 (d,

J = 4.4 Hz, 1 H, 1a-H), 3.31 (t, J = 3.8 Hz, 1 H, 6b-H) ppm. ¹³C

NMR (75 MHz, CDCl₃/C₆D₆, 1:3): δ = 170.4, 169.5, 72.2, 71.2,

(3aSR,4SR,5RS,6SR,7RS,7aSR)-7-Amino-octahydroisobenzofuran-

4,5,6-triol (22): General Procedure for Hydrogenation: A solution of

azidotriol 21 (0.46 g, 2.14 mmol) in absolute methanol (15 mL) was

flushed with hydrogen gas (the air in the solvent was removed un-

der vacuum, and then the flask was filled with hydrogen gas; this

process was repeated three times) and then Pd (10% on activated

carbon; 25 mg) was added. The resulting mixture was stirred at

room temp. for 12 h under the hydrogen atmosphere. The catalyst

was removed by filtration. The solvent was removed, then the resi-

due was filtered through a short silica gel column eluting with

methanol. Aminotriol 22 (0.36 g, 89%) was obtained as a brown

70.6, 69.3, 55.5, 52.3, 42.9, 38.1, 20.3 (2 C) ppm. IR (KBr): ν =

˜

2971, 2940, 2875, 1734, 1435, 1369, 1218, 1076, 1034, 918,

884 cm^–1. C₁₂H₁₆O₆(256.25): calcd. C 56.24, H 6.29; found C

56.47, H 6.13.

1

liquid. H NMR (300 MHz, D₂O): δ = 3.75–3.79 (m, 2 H), 3.71–

3.66 (m, 4 H), 3.59–3.56 (dm, J = 7.4 Hz, 1 H, 6-H), 2.81 (t, J_7,6

= J_7,7a= 7.4 Hz, 1 H, 7-H), 2.30–2.21 (m, 1 H, 3a-H), 2.13 (quintet,

J = 6.7 Hz, 1 H, 7a-H) ppm. ¹³C NMR (75 MHz, D₂O): δ = 72.9,

(1aRS,2RS,3SR,3aSR,6aRS,6bSR)-Octahydrooxireno[2,3-e]iso-

benzofuran-2,3-diol (16): Diacetate 17 (0.40 g, 1.56 mmol) was am-

monolysed with NH₃in MeOH as described above to give diol

16 (0.25 g, 93%) as colourless crystals, crystallized from absolute

72.2, 70.6, 69.6, 68.7, 49.1, 43.6, 43.5 ppm. IR (KBr): ν = 3337,

˜

3286, 2886, 1739, 1595, 1366, 1268, 1229, 1204, 1055, 954,

876 cm^–1. C₈H₁₅NO₄(189.21): calcd. C 50.78, H 7.99, N 7.40;

found C 50.55, H 8.14, N 7.65.

1

ethanol, m.p. 151–153 °C. H NMR (300 MHz, CD₃OD): δ = 4.9

(s, 2 H, OH), 3.98 (t, J_3,2= J_3,3a= 8.5 Hz, 1 H, 3a-H), 3.83 (dd, J

= 8.1, 2.9 Hz, 1 H, CH₂), 3.78–3.71 (m, 3 H), 3.46 (dd, J = 10.8,

9.0 Hz, 1 H, CH₂), 3.36 (dd, J = 4.4, 1.2 Hz, 1 H, 1a-H), 3.28 (dd,

J = 4.4, 4.1 Hz, 1 H, 6b-H), 2.80 (dq, J = 9.0, 4.1 Hz, 1 H, 6a-H),

(1SR,2RS,3SR,4SR,5SR,6RS)-4,5-Bis(acetoxymethyl)-6-azido-

cyclohexane-1,2,3-triyl Triacetate (23): General Procedure for Tetra-

10

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Azido- and Aminocyclitols

hydrofuran Ring-Opening with Sulfamic Acid: Azido triacetate 22

(1.4 g, 4.10 mmol) was dissolved in Ac₂O/AcOH (1:1; 10 mL), and

sulfamic acid (40 mg) was added at room temperature. The mixture

3.44 (d, B part of AB system, J = 5.0 Hz, 1 H, 6a-H), 3.28 (br. s,

1 H, OH), 2.58–2.68 (m, 1 H, 2a-H), 2.49–2.39 (m, 1 H, 5a-H)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 165.3, 134.9, 133.8, 131.4,

was heated at reflux temperature for 24 h. The mixture was then 130.1, 130.0, 128.2, 73.4, 72.4, 72.3, 69.6, 56.5, 54.2, 42.7,

cooled to room temperature, and HCl (5% aq.; 50 mL) was added.

The mixture was extracted with ethyl acetate (350 mL). The organic

39.9 ppm. IR (KBr): ν = 3300, 2950, 2870, 2853, 1723, 1705, 1576,

˜

1428, 1288, 1264, 1252, 1126, 1074, 1043, 904 cm^–1. C₁₅H₁₅ClO₅

phase was washed with saturated NaHCO₃(2ϫ 100 mL) and water (310.73): calcd. C 57.98, H 4.87; found C 57.75, H 4.73.

(2ϫ 300 mL), and dried (MgSO₄). The solvent was removed under

reduced pressure, and the residue was purified on a short column

(1aSR,2SR,2aSR,5aRS,6RS,6aRS)-6-Acetoxyoctahydrooxireno-

[2,3-f]isobenzofuran-2-yl 3-Chlorobenzoate (26b): Hydroxybenzoate

of silica gel (20 g) eluting with dichloromethane to give pentaacet-

26a (4.6 g, 14.80 mmol) was dissolved in pyridine (6 mL) and acetic

1

ate 23 (1.52 g, 84%) as a pale yellow liquid as the sole product. H

anhydride (7.5 mL), and acetylated as described above to give 26b

NMR (300 MHz, C₆D₆): δ = 5.58 (t, J = 3.9 Hz, 1 H, 2-H), 5.37

(4.33 g, 83%) as colourless crystals, crystallized from diethyl ether,

(dd, J_1,6= 9.1, J_1,2= 3.6 Hz, 1 H, 1-H), 5.33 (t, J_3,4= J_3,2= 4.4 Hz,

m.p. 185–187 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.04 (t, J =

1 H, 3-H), 4.20 (dd, J = 11.5, 6.8 Hz, 1 H, CH₂), 4.13–4.07 (m, 2

1.7 Hz, 1 H, arom.), 7.95 (dt, J = 8.0, 1.5 Hz, 1 H, arom), 7.56

H, CH₂), 4.02 (dd, J = 10.6, 7.0 Hz, 1 H, CH₂), 3.63 (dd, J_6,5

=

(ddd, J = 8.0, 2.0, 1.2 Hz, 1 H, arom.), 7.41 (t, J = 8.0 Hz, 1 H,

arom.), 5.31 (d, J = 8.5 Hz, 1 H, 2-H), 5.11 (d, J = 8.5 Hz, 1 H, 6-

H), 3.89 (dd, A part of AB system, J = 9.1, 4.7 Hz, 1 H, 3-H or 5-

H), 3.86 (dd, A part of AB system, J = 9.2, 4.8 Hz, 1 H, 3-H or 5-

H), 3.68 (dd, B part of AB system, J = 9.2, 5.0 Hz, 1 H, 3Ј-H or

5Ј-H), 3.65 (dd, B part of AB system, J = 9.1, 5.0 Hz, 1 H, 3Ј-H

or 5Ј-H), 3.55 (d, J = 5.2 Hz, 1 H, 1a-H or 6a-H), 3.49 (d, J =

5.2 Hz, 1 H, 1a-H or 6a-H), 2.75–2.59 (m, 2 H, 2a-H, 5a-H), 2.14

(s, 3 H, COMe) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 171.0,

165.2, 134.9, 133.8, 131.3, 130.1 (2 C), 128.2, 73.1, 72.2 (2 C), 72.0,

10.4, J_6,1= 9.1 Hz, 1 H, 6-H), 2.40–2.31 (m, 1 H, 4-H), 2.15 (ddd,

J = 10.5, 7.0, 5.3 Hz, 1 H, 5-H), 1.68 (s, 3 H, COMe), 1.64 (s, 3 H,

COMe), 1.62 (s, 6 H, COMe), 1.61 (s, 3 H, COMe) ppm. ¹³C NMR

(75 MHz, C₆D₆): δ = 169.9, 169.7, 169.2, 168.74, 168.66, 72.5, 69.4,

68.3, 62.5, 61.3, 58.0, 38.8, 37.8, 20.2, 20.13, 20.09, 20.0, 19.9 ppm.

IR (KBr): ν = 2971, 2108, 1738, 1680, 1433, 1368, 1217, 1038,

˜

905 cm^–1. C₁₈H₂₅N₃O₁₀(443.41): calcd. C 48.76, H 5.68, N 9.48;

found C 48.91, H 5.81, N 9.37.

(1SR,2RS,3SR,4RS,5SR,6SR)-4-Azido-5,6-bis(hydroxymethyl)-

cyclohexane-1,2,3-triol (24): Pentacetate 23 (0.8 g, 1.80 mmol) was

ammonolysed with NH₃in absolute MeOH as described above to

give pentaol 24 (0.38 g, 90%) as a viscous oil. ¹H NMR (300 MHz,

D₂O): δ = 4.65 (s, 5 H, DOH), 3.71 (t, J = 2.2 Hz, 1 H), 3.68–3.54

(m, 7 H), 1.91 (m, 2 H) ppm. ¹³C NMR (75 MHz, D₂O): δ = 72.3,

53.8, 53.7, 39.8, 39.7, 21.3 ppm. IR (KBr): ν = 3025, 2965, 2882,

˜

1732, 1721, 1576, 1477, 1296, 1230, 1073, 1028, 921, 888 cm^–1

.

C₁₇H₁₇ClO₆(352.77): calcd. C 57.88, H 4.86; found C 57.79, H

4.74.

(1aRS,2RS,2aRS,5aSR,6SR,6aRS)-Octahydrooxireno[2,3-f]iso-

benzofuran-2,6-diyl Diacetate (27): Epoxybenzoate 26b (3.0 g,

8.50 mmol) was ammonolysed with NH₃in MeOH as described

above. The crude product was then reacetylated as described above

to give symmetrical epoxydiacetate 27 (1.68 g, 77%) as colourless

crystals, crystallized from EtOAc, m.p. 162–164 °C. ¹H NMR

(300 MHz, CDCl₃): δ = 5.03 (quasi d, J = 7.9 Hz, 2 H, 2-H, 6-H),

3.83 (dd, A part of AB system, J = 9.2, 6.7 Hz, 2 H, 3-H, 5-H),

3.59 (dd, B part of AB system, J = 9.2, 4.7 Hz, 2 H, 3Ј-H, 5Ј-H),

3.42 (s, 2 H, 1-H, 6a-H), 2.51–2.56 (m, 2 H, 3a-H, 5a-H), 2.11 (s,

6 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 171.0, 72.2, 72.0, 53.7,

71.7, 70.7, 61.9, 60.6, 60.0, 43.0, 39.9 ppm. IR (KBr): ν = 3295,

˜

2897, 2104, 1660, 1611, 1395, 1255, 1089, 1044, 1003, 934 cm^–1.

C₈H₁₅N₃O₅(233.22): calcd. C 41.20, H 6.48, N 18.02; found C

41.39, H 6.17, N 18.37.

(1SR,2RS,3SR,4RS,5SR,6SR)-4-Amino-5,6-bis(hydroxymethyl)-

cyclohexane-1,2,3-triol (25): A mixture of pentaol 24 (0.33 g,

1.41 mmol) and Pd (10% on activated carbon; 26 mg) in absolute

methanol (50 mL) was stirred, and hydrogen was bubbled through

the solution. The mixture was stirred under hydrogen as described

above for the synthesis of 22 to give compound 25 (0.28 g, 95%)

39.6, 21.3 ppm. IR (KBr): ν = 2996, 2962, 2870, 1720, 1381, 1368,

˜

1

as a pale yellow viscous oil. H NMR (300 MHz, D₂O): δ = 4.65

1242, 1159, 1058, 1030, 986 cm^–1. C₁₂H₁₆O₆(256.25): calcd. C

56.24, H 6.29; found C 55.85, H 6.48.

(s, 7 H, DOH), 3.78 (t, J = 4.4 Hz, 1 H, 4-H), 3.74–3.62 (m, 3 H),

3.58–3.51 (m, 3 H), 2.98 (t, J = 7.6 Hz, 1 H), 1.93–1.81 (m, 2 H)

ppm. ¹³C NMR (75 MHz, D₂O): δ = 72.5, 72.0, 70.8, 61.4, 60.2,

(3aSR,4SR,5SR,6SR,7RS,7aRS)-6-Azido-octahydroisobenzofuran-

4,5,7-triyl Triacetate (30) and (3aSR,4SR,5RS,6SR,7RS,7aRS)-6-

Azido-octahydroisobenzofuran-4,5,7-triyl Triacetate (31): Epoxydi-

acetate 27 (6.4 g, 24.98 mmol) was dissolved in absolute ethanol

(150 mL). Sodium azide (2.11 g, 32.46 mmol) was added to the

solution. The reaction mixture was heated at reflux overnight, then

it was cooled to room temperature, and the solvent was removed

under reduced pressure. The residue was filtered through a short

silica gel column, eluting with EtOAc.

51.3, 42.7, 41.0 ppm. IR (KBr): ν = 3290, 2894, 2471, 1739, 1567,

˜

1383, 1217, 1036, 1004 cm^–1. C₈H₁₇NO₅(207.23): calcd. C 46.37,

H 8.27, N 6.76; found C 46.20, H 8.41, N 6.45.

(1aRS,2RS,2aRS,5aSR,6SR,6aSR)-6-Hydroxyoctahydrooxireno-

[2,3-f]isobenzofuran-2-yl 3-Chlorobenzoate (26a): A solution of m-

chloroperbenzoic acid (75 %; 1.49 g, 7.24 mmol, 1.2 equiv.) was

added to a solution of hydroxybenzoate 8 (1.6 g, 5.43 mmol) in

dichloromethane (100 mL) at 0 °C. The resulting mixture was

stirred magnetically overnight at room temp. The reaction was

worked up as described above. The residue was purified by column

chromatography on silica gel (15 g) eluting with dichloromethane

to give epoxybenzoate 26a (1.30 g, 77%) as colourless crystals, crys-

tallized from EtOAc, m.p. 121–123 °C. ¹H NMR (300 MHz,

CDCl₃): δ = 7.99 (br. s, 1 H, arom.), 7.91 (br. d, J = 7.6 Hz, 1 H,

arom.), 7.52 (dt, A part of AB system, J = 8.0, 1.0 Hz, 1 H, arom.),

7.37 (t, B part of AB system, J = 8.0 Hz, 1 H, arom.), 5.24 (d, J_2,2a

= 8.2 Hz, 1 H, 2-H), 3.96 (br. d, J_6,5a= 8.7 Hz, 1 H, 6-H), 3.77–

3.89 (m, 3 H, 5-H, 5Ј-H, 3-H), 3.66 (dd, J_3,3Ј= 9.1, J_3,2a= 5.0 Hz,

After evaporation of the ethyl acetate, without any additional puri-

fication, the residue was dissolved in pyridine (12 mL) and acetic

anhydride (15 mL), and the mixture was stirred magnetically at

room temp. for 24 h. The reaction mixture was worked up as de-

scribed above. The residue was purified by chromatography on a

silica gel (60 g) column eluting with hexane/EtOAc (2:1) to give

two compounds 30 and 31.

Compound 30 was isolated as the first fraction. A pure sample of

30 was obtained after repeated column chromatography (0.17 g,

2%), as white crystals, crystallized from EtOAc, m.p. 196–198 °C.

1 H, 3-H), 3.51 (d, A part of AB system, J = 5.0 Hz, 1 H, 1a-H), ¹H NMR (300 MHz, C₆D₆): δ = 5.39 (dd, J = 6.5, 3.5 Hz, 1 H, 5-

Eur. J. Org. Chem. 0000, 0–0

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Job/Unit: O42762

/KAP1

Date: 22-09-14 11:12:00

Pages: 16

G. Aydin, K. Ally, F. Aktas¸, E. S¸ahin, A. Baran, M. Balci

FULL PAPER

H), 5.25–5.30 (m, 2 H, 4-H, 7-H), 3.90 (dd, J = 8.8, 5.0 Hz, 1 H,

1-H or 3-H), 3.74 (dd, J = 8.6, 6.3 Hz, 1 H, 1-H or 3-H), 3.57 (dd,

3.8 Hz, 1 H, CH₂), 3.82 (br. t, J = 10.3 Hz, 1 H, 3-H), 2.56–2.47

(m, 1 H, 5-H), 2.42–2.33 (m, 1 H, 6-H), 2.14 (s, 3 H, COMe), 2.12

J = 7.6, 3.2 Hz, 1 H, 6-H), 3.51 (t, J = 8.0 Hz, 1 H, 1Ј-H or 3Ј-H), (s, 6 H, COMe), 2.05 (s, 3 H, COMe), 2.01 (s, 3 H, COMe) ppm.

3.45 (dd, J = 8.8, 6.8 Hz, 1 H, 1Ј-H or 3Ј-H), 2.16 (quintet, J = ¹³C NMR (75 MHz, CDCl₃): δ = 170.7, 170.5, 170.0, 169.9, 169.7,

7.0 Hz, 1 H, 3a-H or 7a-H), 2.05–1.96 (dt, 1 H, 3a-H or 7a-H),

70.7, 70.3, 70.1, 63.2, 61.7, 61.4, 39.5, 37.3, 21.2, 21.1, 21.0, 20.94,

1.62 (s, 3 H, COMe), 1.54 (s, 3 H, COMe), 1.48 (s, 3 H, COMe) 20.9 ppm. IR (KBr): ν = 2976, 2938, 2110, 1735, 1432, 1367, 1212,

˜

ppm. ¹³C NMR (75 MHz, C₆D₆): δ = 169.1, 169.0, 168.6, 71.5, 1031, 921 cm^–1. C₁₈H₂₅N₃O₁₀(443.41): calcd. C 48.76, H 5.68, N

69.4, 69.0, 68.9, 67.7, 61.1, 43.0, 42.9, 20.2, 20.1, 19.8 ppm. IR 9.48; found C 48.41, H 5.44, N 9.60.

(KBr): ν = 2989, 2953, 2901, 2880, 2116, 1736, 1426, 1371, 1230,

˜

(1SR,2RS,3SR,4RS,5RS,6SR)-3-Azido-5,6-bis(hydroxymethyl)-

cyclohexane-1,2,4-triol (35): Azidopentaacetate 34 (0.78 g,

1.76 mmol) was ammonolysed with NH₃in MeOH as described

above to give 35 (0.37 g, 90 %) as a brown liquid. ¹H NMR

(300 MHz, D₂O): δ = 4.65 (s, 5 H, DOH), 4.08–3.98 (m, 1 H), 3.74

(dd, J = 11.7, 4.7 Hz, 1 H), 3.59–3.52 (m, 2 H), 3.50–3.30 (m, 4

H), 2.13–2.00 (m, 2 H) ppm. ¹³C NMR (75 MHz, D₂O): δ = 70.8,

1218, 1068, 1031, 978 cm^–1. C₁₄H₁₉N₃O₇(341.32): calcd. C 49.27,

H 5.61, N 12.13; found C 48.42, H 5.93, N 12.07.

Compound 31 was isolated as the second fraction (5.94 g, 69%)

as white crystals, crystallized from hexane/EtOAc (1:3), m.p. 124–

126 °C. ¹H NMR (300 MHz, C₆D₆): δ = 5.37 (t, J_4,3a= J_4,5

=

2.9 Hz, 1 H, 4-H), 5.12 (dd, J_7,6= 10.6, J_7,7a= 10.5 Hz, 1 H, 7-H),

4.93 (dd, J_5,6= 10.5, J_5,4= 2.9 Hz, 5-H), 3.81 (t, J_6,5= J_6,7

=

70.3, 70.2, 68.8, 60.6, 58.6, 43.1, 40.2 ppm. IR (KBr): ν = 3307,

˜

10.5 Hz, 1 H, 6-H), 3.78 (d, J = 8.8 Hz, 1 H, 1-H or 3-H), 3.33 (t,

J = 9.4 Hz, 1 H, 1-H or 3-H), 3.21 (dd, J = 9.1, 4.0 Hz, 1Ј-H or

3Ј-H), 3.12 (t, J = 9.1 Hz, 1 H, 1Ј-H or 3Ј-H), 2.03–1.91 (m, 2 H,

3a-H, 7a-H), 1.69 (s, 6 H, COMe), 1.64 (s, 3 H, COMe) ppm. ¹³C

NMR (75 MHz, C₆D₆): δ = 169.3, 169.1, 169.0, 71.5, 70.5, 70.4,

2900, 2105, 1738, 1655, 1416, 1352, 1255, 1059, 1015, 956 cm^–1.

C₈H₁₅N₃O₅(233.22): calcd. C 41.20, H 6.48, N 18.02; found C

41.43, H 6.77, N 17.68.

(1SR,2RS,3SR,4RS,5RS,6SR)-3-Amino-5,6-bis(hydroxymethyl)-

cyclohexane-1,2,4-triol (36): Azidopentaol 35 (0.36 g, 1.54 mmol)

was hydrogenated with Pd (10% on activated carbon; 25 mg) as

described above to give aminopentaol 36 (0.29 g, 81%) as a brown

viscous oil. ¹H NMR (300 MHz, D₂O): δ = 4.68 (s, 7 H, DOH),

3.91 (t, J = 2.6 Hz, 1 H, 1-H), 3.70 (dd, J = 11.4, 5.0 Hz, 1 H,

CH₂), 3.58–3.47 (m, 2 H), 3.35–3.26 (m, 2 H), 3.18 (t, J = 10.3 Hz,

1 H), 2.74 (t, J = 10.0 Hz, 1 H, 3-H), 2.08–2.03 (m, 1 H, 5-H),

1.99–1.89 (m, 1 H, 6-H) ppm. ¹³C NMR (75 MHz, D₂O): δ = 71.1,

67.3, 66.8, 62.2, 42.9, 42.4, 20.27, 20.25, 20.1 ppm. IR (KBr): ν =

˜

2940, 2904, 2109, 1738, 1435, 1370, 1209, 1070, 1028, 931 cm^–1.

C₁₄H₁₉N₃O₇(341.32): calcd. C 49.27, H 5.61, N 12.31; found C

49.16, H 5.75, N 12.49.

(3aRS,4RS,5SR,6RS,7SR,7aSR)-6-Azidooctahydroisobenzofuran-

4,5,7-triol (32): Azidotriacetate 31 (0.8 g, 2.34 mmol) was ammono-

lysed with NH₃in MeOH as described above to give 32 (0.46 g,

91%) as a brown viscous oil. ¹H NMR (300 MHz, D₂O): δ = 3.90–

3.85 (m, 2 H), 3.81 (t, J = 9.8 Hz, 1 H), 3.63 (dd, J = 9.1, 4.4 Hz,

1 H), 3.61–3.45 (m, 2 H, 1-H or 3-H), 3.29 (dd, J = 11.0, 8.6 Hz,

1 H, 1-H or 3-H), 3.24–3.17 (m, 1 H, 3-H or 7-H), 2.63–2.53 (m,

1 H, 3a-H or 7a-H), 2.20 (ddd, J = 10.5, 6.4, 4.2 Hz, 1 H, 3a-H or

7a-H) ppm. ¹³C NMR (75 MHz, D₂O): δ = 71.32, 71.25, 70.2, 67.6,

70.7, 70.0, 60.6, 58.6, 56.1, 43.2, 40.1 ppm. IR (KBr): ν = 3273,

˜

2916, 1575, 1355, 1013, 879 cm^–1. C₈H₁₇NO₅(207.23): calcd. C

46.37, H 8.27, N 6.76; found C 46.05, H 8.54, N 6.52.

(1aRS,1bRS,2aRS,2bRS,5aSR,5bRS)-Octahydrobis(oxireno)[2,3-

e:2Ј,3Ј-g]isobenzofuran (37) and (1aRS,1bSR,2aSR,2bSR,

5aRS,5bRS)-Octahydrobis(oxireno)[2,3-e:2Ј,3Ј-g]isobenzofuran (38):

A solution of m-chloroperbenzoic acid (37.67 g, 163.99 mmol,

75%) was added to a solution of (3aR,7aS)-1,3,3a,7a-tetrahydro-

isobenzofuran (6; 8.0 g, 65.5 mmol) in dichloromethane (500 mL)

at 0 °C. The resulting mixture was stirred magnetically at room

temp. for 48 h. The reaction mixture was worked up as described

above. The crude product mixture (14.5 g) was separated by column

chromatography on silica gel (70 g) eluting with hexane/EtOAc

(4:1). Some mixed fractions were repurified by chromatography.

Four compounds were isolated in the following order.

67.5, 66.6, 44.2, 42.9 ppm. IR (KBr): ν = 3341, 2937, 2884, 2105,

˜

1726, 1667, 1615, 1566, 1376, 1257, 1089, 1039, 909 cm^–1

.

C₈H₁₃N₃O₄(215.21): calcd. C 44.65, H 6.09, N 19.53; found C

44.30, H 6.28, N 19.31.

(3aSR,4SR,5RS,6SR,7RS,7aRS)-6-Amino-octahydroisobenzofuran-

4,5,7-triol (33): Azidotriol 32 (0.42 g, 1.94 mmol) was hydrogenated

with Pd (10% on activated carbon; 30 mg) as described above to

give 33 (0.310 g, 84%) as a white powder, crystallized from from

1

ethanol, m.p. 266–268 °C. H NMR (300 MHz, D₂O): δ = 4.63 (s,

DOH), 3.92–3.84 (m, 3 H, 4-H, 1-H, 3-H), 3.67 (dd, J = 8.8,

4.4 Hz, 1 H, 1-H or 3-H), 3.6–3.36 (m, 2 H, 5-H and 1-H or 3-H),

3.35 (d, J = 8.8 Hz, 1 H, 7-H), 3.09 (t, J = 10.0 Hz, 1 H, 7-H), 2.84

(t, J = 10.0 Hz, 1 H, 6-H), 2.65–2.56 (m, 1 H, 3a-H), 2.17 (m, 1 H,

7a-H) ppm. ¹³C NMR (75 MHz, D₂O): δ = 72.4, 71.7, 71.5, 67.9,

Compound 37 was isolated as the first fraction (5.73 g, 57%) as a

pale yellow liquid. H NMR (300 MHz, CDCl₃): δ = 4.05 (dd, J =

8.8, 7.3 Hz, 1 H, CH₂), 3.96–3.90 (m, 2 H, CH), 3.92 (t, J = 8.2 Hz,

1 H), 3.56 (dd, J = 10.2, 7.6 Hz, 1 H), 3.47–3.45 (m, 2 H, epoxide),

3.11–3.08 (m, 2 H, epoxide), 2.80 (dq, J = 10.5, 2.0 Hz, 1 H, CH),

2.63–2.55 (m, 1 H, CH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

1

67.6, 54.1, 44.3, 42.8 ppm. IR (KBr): ν = 3443, 3352, 3280, 3165,

˜

2927, 2897, 2881, 1741, 1582, 1395, 1358, 1263, 1218, 1089, 1035,

914, 888 cm^–1. C₈H₁₅NO₄(189.21): calcd. C 50.78, H 7.99, N 7.40;

found C 50.96, H 8.23, N 7.52.

71.8, 70.5, 54.3, 52.4, 51.4, 50.8, 37.4, 35.3 ppm. IR (KBr): ν =

˜

2917, 2871, 2850, 1726, 1457, 1437, 1368, 1239, 1175, 1121, 1084,

1021, 988, 945, 905, 859, 841, 769, 718, 657 cm^–1. C₈H₁₀O₃

(154.17): calcd. C 62.33, H 6.54; found C 62.10, H 6.83.

(1SR,2RS,3SR,4RS,5RS,6SR)-5,6-Bis(acetoxymethyl)-3-azido-

cyclohexane-1,2,4-triyl Triacetate (34): Sulfamic acid (40 mg) was

added to a stirred solution of 31 (1.3 g, 3.81 mmol) in Ac₂O/AcOH

(1:1; 10 mL) at room temperature. The mixture was heated at reflux

temperature for 24 h, as described above for the synthesis of 23, to

give azidopentaacetate 34 (1.22 g, 72%) as colourless cubic crystals,

crystallized from EtOAc, m.p. 167–169 °C. ¹H NMR (300 MHz,

Compound 38 was isolated as the second product (1.00 g, 10%) as

a colourless liquid.^[7d]Compound 14 was isolated as the third frac-

tion (2.30 g, 11%). Compound 26a was isolated as the fourth frac-

tion (1.60 g, 10%).

(3aRS,4RS,5SR,6SR,7SR,7aSR)-5-Azido-6-ethoxyoctahydroiso-

CDCl₃): δ = 5.42 (t, J_1,2= J_1,6= 3.1 Hz, 1 H, 1-H), 5.18 (dd, J_4,5benzofuran-4,7-diyl Diacetate (39) and (3aRS,4RS,5RS,6SR,

= 11.7, J_4,3= 10.0 Hz, 1 H, 4-H), 5.05 (dd, J_2,3= 10.8, J_2,1

3.1 Hz, 1 H, 2-H), 4.27–4.15 (m, 3 H, CH₂), 3.98 (dd, J = 11.8,

=

7SR,7aSR)-5,6-Diazidooctahydroisobenzofuran-4,7-diyl Diacetate

(40): cis-Bisepoxide 38 (2.4 g, 15.57 mmol) was dissolved in abso-

12

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Azido- and Aminocyclitols

lute ethanol (75 mL). Sodium azide (2.52 g, 38.76 mmol) was added

to the solution. The reaction mixture was heated at reflux for 24 h.

The solvent was evaporated, and the residue was filtered through

a short silica gel column with ethyl acetate.

1254, 1229, 1059, 917, 809 cm^–1. C₈H₁₆N₂O₃(188.23): calcd. C

51.05, H 8.57, N 14.88; found C 51.32, H 8.72, N 14.70.

(1RS,2RS,3SR,4SR,5SR,6RS)-2,3-Bis(acetoxymethyl)-5,6-diazido-

cyclohexane-1,4-diyl Diacetate (43): Sulfamic acid (40 mg) was

added to a stirred solution of diazidodiacetate 40 (1.65 g,

5.09 mmol) in Ac₂O/AcOH (1:1; 10 mL) at room temperature. The

mixture was heated at reflux temperature for 24 h as described

above to give 43 (1.56 g, 72%) as colourless cubic crystals, crys-

tallized from EtOAc, m.p. 93–95 °C. ¹H NMR (300 MHz, CDCl₃):

δ = 5.29 (br. t, J = 6.1 Hz, 2 H, 1-H, 4-H), 4.31 (dd, J = 11.7,

6.8 Hz, 2 H, CH₂), 4.11 (dd, J = 11.7, 4.7 Hz, 2 H, CH₂), 3.93 (br.

d, J = 5.6 Hz, 2 H, 5-H, 6-H), 2.46–2.41 (m, 2 H, 2-H, 3-H), 2.13

(s, 6 H, COMe), 2.06 (s, 6 H, COMe) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 170.8, 169.7, 69.3, 62.6, 61.8, 21.2, 21.1 ppm. IR

Without any additional purification, the residue was dissolved in

pyridine (5 mL) and acetic anhydride (6 mL), and the mixture was

stirred magnetically at room temp. for 12 h. At the end of this

period, dichloromethane (200 mL) was added, and the mixture was

stirred for 5 min. The mixture was quenched with cold HCl (5%

aq.; 100 mL), then neutralized with NaHCO₃(300 mL), washed

with water (3ϫ 400 mL), and dried with Na₂SO₄. The solvents

were evaporated, and the residue (4.8 g) was loaded onto a on silica

gel (60 g) column and eluted with hexane/EtOAc (4:1). After re-

peated column chromatography, two ring-opened products 39 and

40 were isolated.

(KBr): ν = 2989, 2108, 1736, 1702, 1496, 1470, 1429, 1370, 1217,

˜

1027, 915 cm^–1. C₁₆H₂₂N₆O₈(426.39): calcd. C 45.07, H 5.20, N

19.71; found C 45.35, H 5.33, N 19.9.

Compound 39 was isolated as the first fraction (0.32 g, 6%) as a

pale yellow solid, m.p. 86–88 °C. ¹H NMR (300 MHz, CDCl₃/

C₆D₆, 1:1): δ = 5.46 (dd, J_4,5= 10.3, J_4,3a= 9.0 Hz, 1 H, 4-H), 5.03

(dd, J = 3.5, 2.6 Hz, 1 H, 7-H), 3.91 (dd, J = 9.8, 8.0 Hz, 1 H, 1-

H), 3.84 (br. dd, J = 9.0, 1.6 Hz, 1 H, 3-H), 3.73 (dd, J = 8.8,

8.0 Hz, 1 H, 1Ј-H), 3.61 (dt, J = 2.9, 1.8 Hz, 1 H, 6-H), 3.56 (dd,

J = 8.8, 5.0 Hz, 1 H, 3Ј-H), 3.39 (q, J = 7.0 Hz, 2 H, CH₂), 3.27

(dd, J_5,4= 10.3, J_5,6= 2.9 Hz, 1 H, 5-H), 2.35–2.27 (m, 1 H, 7a-

H), 2.23–2.15 (m, 1 H, 3a-H), 1.88 (s, 3 H), 1.77 (s, 3 H), 1.01 (t,

J = 7.0 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃/C₆D₆, 1:1): δ =

169.9, 169.3, 79.3, 70.5, 69.2, 68.2, 67.1, 66.9, 60.7, 43.2, 42.8, 20.7,

(1RS,2RS,3SR,4SR,5SR,6RS)-2,3-Diazido-5,6-bis(hydroxymethyl)-

cyclohexane-1,4-diol (44): Diazidotetraacetate 43 (0.45 g,

1.06 mmol) was ammonolysed with NH₃in absolute MeOH as de-

1

scribed above to give 44 (0.25 g, 92%) as a brown viscous oil. H

NMR (300 MHz, D₂O): δ = 4.61 (s, DOH), 3.83–3.79 (m, 4 H),

3.66–3.53 (m, 4 H), 2.09–1.99 (m, 2 H) ppm. ¹³C NMR (75 MHz,

D O): δ = 68.0, 64.6, 59.7, 42.5 ppm. IR (KBr): ν = 3276, 2875,

˜

2

2094, 1731, 1661, 1611, 1248, 1047, 1019, 881, 785 cm^–1

.

C₈H₁₄N₆O₄(258.24): calcd. C 37.21, H 5.46, N 32.54; found C

37.47, H 5.59, N 32.27.

20.6, 15.2 ppm. IR (KBr): ν = 2983, 2940, 2914, 2102, 1736, 1434,

˜

1375, 1227, 1218, 1107, 1096, 1062, 1030, 935, 887 cm^–1

.

(1RS,2RS,3SR,4SR,5SR,6RS)-2,3-Diamino-5,6-bis(hydroxymeth-

yl)cyclohexane-1,4-diol (45): Diaminotetrol 44 (0.32 g, 1.24 mmol)

was hydrogenated with Pd (10% on activated carbon; 20 mg) in

absolute methanol (50 mL) as described above to give 45 (0.23 g,

90%) as a pale brown, viscous oil. ¹H NMR (300 MHz, D₂O): δ =

3.72 (dd, J = 11.7, 3.8 Hz, 2 H, CH₂), 3.62 (br. t, J = 5.2 Hz, 2 H,

1-H, 4-H), 3.47 (dd, J = 11.7, 5.5 Hz, 2 H, CH₂), 2.97 (d, J =

5.0 Hz, 1 H, 2-H, 3-H), 2.00–1.92 (dt, 2 H, 5-H, 6-H) ppm. ¹³C

NMR (75 MHz, D₂O): δ = 72.0, 60.2, 53.6, 42.7 ppm. IR (KBr): ν˜

= 3277, 2889, 1586, 1438, 1378, 998, 936 cm^–1. C₈H₁₈N₂O₄

(206.24): calcd. C 46.59, H 8.80, N 13.58; found C 46.69, H 8.94,

N 13.65.

C₁₄H₂₁N₃O₆(327.34): calcd. C 51.37, H 6.47, N 12.84; found C

51.21, H 6.69, N 12.51.

Compound 40 was isolated as the second product (3.57 g, 71%) as

1

colourless crystals, crystallized from EtOAc, m.p. 149–151 °C. H

NMR (300 MHz, CDCl₃/C₆D₆, 2:1): δ = 5.08 (br. t, J = 5.3 Hz, 2

H, 4-H, 7-H), 3.77 (dd, J = 8.5, 5.3 Hz, 2 H, 1-H, 3-H), 3.70 (br.

d, J = 5.5 Hz, 2 H, 5-H, 6-H), 3.63–3.57 (m, 2 H, 1Ј-H, 3Ј-H),

2.26–2.22 (m, 2 H, 3a-H, 7a-H), 1.92 (s, 6 H, COMe) ppm. ¹³C

NMR (75 MHz, CDCl₃/C₆D₆, 2:1): δ = 169.6, 68.2, 69.1, 62.2, 43.0,

20.9 ppm. IR (KBr): ν = 2971, 2912, 2873, 2148, 2111, 1740, 1428,

˜

1371, 1303, 1262, 1216, 1067, 1039, 1023, 921 cm^–1. C₁₂H₁₆N₆O₅

(324.30): calcd. C 44.44, H 4.97, N 25.91; found C 44.16, H 5.18,

N 26.24.

(3aSR,4SR,5RS,6SR,7RS,7aSR)-7-Azido-5-ethoxyoctahydroiso-

benzofuran-4,6-diyl Diacetate (46) and (3aSR,4SR,5RS,6SR,

7RS,7aSR)-5,7-Diazidooctahydroisobenzofuran-4,6-diyl Diacetate

(47): trans-Bisepoxide 37 (2.2 g, 14.27 mmol) was dissolved in abso-

lute ethanol (75 mL). Sodium azide (2.30 g, 35.38 mmol) was

added, and the resulting reaction mixture was heated at reflux for

22 h. The solvent was evaporated, and the residue was filtered

through a short silica gel column with ethyl acetate.

(3aRS,4RS,5RS,6SR,7SR,7aSR)-5,6-Diazido-octahydroisobenzo-

furan-4,7-diol (41): Diazidodiacetate 40 (0.72 g, 2.22 mmol) was

ammonolysed with NH₃in absolute MeOH as described above to

1

give 41 (0.48 g, 90%) as a brown viscous oil. H NMR (300 MHz,

CDCl₃): δ = 3.87 (d, J = 6.0 Hz, 2 H, 4-H, 7-H), 3.83–3.69 (m, 6

H, 5-H, 6-H, 1-H, 3-H), 2.41–2.31 (m, 2 H, 3a-H, 7a-H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 69.6, 67.4, 64.1, 44.1 ppm. IR (KBr):

Without any additional purification, the residue was esterified as

described above. The crude residue was purified by chromatog-

raphy on a silica gel column (37 g) eluting with hexane/EtOAc

(10:1) to give two products 46 and 47.

ν = 3344, 2971, 2885, 2101, 1737, 1664, 1615, 1373, 1255, 1050,

˜

910, 882 cm^–1. C₈H₁₂N₆O₃(240.22): calcd. C 40.00, H 5.04, N

34.98; found C 39.87, H 5.01, N 35.34.

(3aRS,4RS,5RS,6SR,7SR,7aSR)-5,6-Diamino-octahydroisobenzo-

Compound 46 was isolated as the first fraction (0.32 g, 7%) as a

furan-4,7-diol (42): Diazidodiol (0.63 g, 2.62 mmol) was hydroge- colourless liquid. ¹H NMR (300 MHz, C₆D₆): δ = 5.22 (dd, J =

nated with Pd (10% on activated carbon powder; 30 mg) in abso-

lute methanol (50 mL) as described above to give diaminodiol 42

(0.42 g, 85%) as colourless crystals, crystallized from ethanol, m.p.

10.5, 2.9 Hz, 1 H, 4-H), 50.3 (dd, J = 3.3, 2.1 Hz, 1 H, 6-H), 3.98–

3.88 (m, 3 H), 3.77 (dt, J = 3.6, 1.2 Hz, 1 H, 5-H), 3.63 (dd, J =

9.7, 8.2 Hz, 1 H, CH₂O), 3.41 (dd, J = 9.0, 4.6 Hz, 1 H, CH₂O),

213–215 °C. ¹H NMR (300 MHz, D₂O): δ = 3.82–3.72 (m, 4 H, 3.24–3.13 (m, 2 H, OCH₂), 2.01–2.0 (m, 1 H, 7a-H), 1.92–1.85 (m,

CH₂), 3.48 (br. t, J = 6.2 Hz, 2 H, 4-H, 7-H), 2.94 (br. d, J =

1 H, 3a-H), 1.68 (s, 3 H, COCH₃), 1.58 (s, 3 H, COCH₃), 0.82 (t,

6.2 Hz, 2 H, 5-H, 6-H), 2.38–2.28 (m, 2 H, 3a-H, 7a-H) ppm. ¹³C J = 6.4 Hz, CH₃) ppm. ¹³C NMR (75 MHz, C₆D₆): δ = 169.7,

NMR (75 MHz, D O): δ = 70.6, 70.3, 54.4, 44.2 ppm. IR (KBr): ν

= 3380, 3072, 2959, 2932, 2889, 2874, 1628, 1599, 1565, 1468, 1359,

169.1, 76.9, 73.6, 71.3, 58.8, 42.6, 42.5, 20.3, 15.2 ppm. IR (KBr):

ν = 2976, 2940, 2879, 2101, 1739, 1487, 1433, 1372, 1223, 1109,

˜

2

˜

Eur. J. Org. Chem. 0000, 0–0

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Date: 22-09-14 11:12:00

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G. Aydin, K. Ally, F. Aktas¸, E. S¸ahin, A. Baran, M. Balci

FULL PAPER

1068, 1052, 1026, 966, 948, 900 cm^–1. C₁₄H₂₁N₃O₆(327.34): calcd. (KBr): ν = 3325, 2917, 2899, 2097, 1711, 1659, 1421, 1251, 1135,

˜

C 51.37, H 6.47, N 12.84; found C 51.55, H 6.58, N 12.50.

1089, 1021, 1002, 969, 930 cm^–1. C₈H₁₄N₆O₄(258.24): calcd. C

37.21, H 5.46, N 32.54; found C 37.38, H 5.64, N 32.79.

Compound 47 was isolated as the second fraction (3.61 g, 78%) as

colourless crystals, crystallized from EtOAc/hexane (1:3), m.p. 153–

155 °C. ¹H NMR (300 MHz, CDCl₃): δ = 5.22 (dd, J_6,7= 10.2, J_6,5

= 2.9 Hz, 1 H, 6-H), 5.03 (br. t, J_4,5= J_4,3a= 3.2 Hz, 1 H, 4-H),

4.06 (dd, J_6,5= 2.9, J_5,4= 3.6 Hz, 1 H, 5-H), 4.02–3.88 (m, 2 H,

CH₂), 3.87 (t, J_7,6= J_7,7a= 10.2 Hz, 1 H, 7-H), 3.76 (dd, J = 9.1,

5.0 Hz, CH₂), 2.56–2.46 (m, 1 H, 3a-H), 2.28–2.18 (m, 1 H, 3a-H),

2.18 (s, 3 H, COMe), 2.11 (s, 3 H, COMe) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 170.1, 169.7, 73.3, 71.3, 68.8, 68.3, 61.2,

(1SR,2RS,3SR,4RS,5SR,6SR)-2,4-Diamino-5,6-bis(hydroxymeth-

yl)cyclohexane-1,3-diol (52): Diazidotetrol 51 (0.56 g, 2.17 mmol)

was hydrogenated with Pd (10% on activated carbon; 24 mg) in

absolute methanol (45 mL) as described above to give diamino-

tetrol 52 (0.39 g, 88%) as a brown viscous oil. ¹H NMR (300 MHz,

D₂O): δ = 3.79–3.42 (m, 10 H), 3.17 (t, J = 5.0 Hz, 1 H), 3.02 (dd,

J = 7.6, 3.8 Hz, 1 H), 2.10–1.92 (m, 2 H) ppm. ¹³C NMR (75 MHz,

D₂O): δ = 72.1, 71.1, 61.3, 60.5, 54.0, 52.8, 42.3, 41.9 ppm. IR

58.3, 42.6, 42.5, 21.2, 20.9 ppm. IR (KBr): ν = 2943, 2879, 2101,

˜

(KBr):

ν =

˜

3271, 2920, 2900, 1555, 1405, 1018, 758 cm^–1.

1748, 1488, 1432, 1371, 1327, 1215, 1067, 1045, 1025, 900 cm^–1.

C₁₂H₁₆N₆O₅(324.30): calcd. C 44.44, H 4.97, N 25.91; found C

44.15, H 4.64, N 26.13.

C₈H₁₈N₂O₄(206.24): calcd. C 46.59, H 8.80, N 13.58; found C

47.72, H 8.62, N 13.85.

α-Glucosidase Inhibition Assay: A partially modified method de-

scribed by Pierre et al.^[19]was used for the α-glucosidase inhibition

assay. The inhibitory activities of the compounds were determined

by a spectrophotometric assay of the α-glucosidase with the p-

nitrophenyl glucoside in the presence of the synthesized com-

pounds. The residual hydrolytic activity of the glucosidase towards

the p-nitrophenyl glucoside substrate was measured spectromet-

rically (Shimadzu UV/Vis spectrophotometer). An assay mixture

containing the α-glucosidase enzyme (0.1 U/mL) in sodium phos-

phate buffer (67 mm, pH 6.8) and inhibitor (0.2–1.6 mg/mL) were

preincubated for 3 min, 200 rpm at 37 °C, and the absorbance was

recorded at 400 nm. The reaction was initiated by the addition of p-

nitrophenyl α-d-glucopyranoside (substrate, 500 μm; 10 μL). After

incubating the mixture for 1 min at 37 °C, the reaction was stopped

by the addition of sodium carbonate (1 m aq.; 100 μL), and the p-

nitrophenolate formed was recorded at 400 nm.

(3aSR,4SR,5RS,6SR,7RS,7aSR)-5,7-Diazido-octahydroisobenzo-

furan-4,6-diol (48): Diazidodiacetate 47 (0.64 g, 1.97 mmol) was

ammonolysed with NH₃in absolute MeOH as described above to

give diazidodiol 48 (0.44 g, 93%) as colourless crystals, crystallized

from ethanol, m.p. 138–140 °C. ¹H NMR (300 MHz, D₂O): δ =

4.60 (s, 2 H, DOH), 4.02 (dd, J = 7.7, 3.6 Hz, 1 H, CH), 3.91–3.83

(m, 3 H), 3.80–3.71 (m, 3 H), 3.62 (t, J = 7.0 Hz, 1 H, 7-H), 2.4–

2.29 (m, 2 H, CH) ppm. ¹³C NMR (75 MHz, D₂O): δ = 70.9, 70.3,

69.4, 67.2, 65.3, 60.5, 44.0, 41.8 ppm. IR (KBr): ν = 3352, 2967,

˜

2945, 2925, 2900, 2097, 1664, 1614, 1490, 1451, 1374, 1343, 1253,

1150, 1093, 1050, 1023, 1003, 923, 885 cm^–1. C₈H₁₂N₆O₃(240.22):

calcd. C 40.00, H 5.04; found C 40.32, H 5.36.

(3aSR,4SR,5RS,6SR,7RS,7aSR)-5,7-Diaminooctahydroisobenzo-

furan-4,6-diol (49): Diazidodiol 48 (0.26 g, 1.08 mmol) was hydro-

genated with Pd (10 % on activated carbon; 24 mg) in absolute

methanol (50 mL) as described above to give diaminodiol 49

1

(0.17 g, 83%) as a pale brown liquid. H NMR (300 MHz, D₂O):

α-Amylase Inhibition Assay: α-Amylase solution (1 U/mL; 200 μL)

in sodium phosphate buffer (20 mm, pH 6.9), NaCl (0.006 m), and

inhibitor (0.2–1.6 mg/mL) were mixed. After incubation at 25 °C

for 3 min at 200 rpm, starch solution [0.25% w/v in sodium phos-

phate buffer (20 mm, pH 6.9); 400 μL] was added. After 5 min at

200 rpm, the reaction was stopped by the addition of DNS [3,5-

dinitrosalicylic acid; 1% in NaOH (0.4 m)], and the mixture was

boiled for 5 min. After boiling, the mixture was diluted with dis-

tilled water (10 mL) and its absorbance was measured at 540 nm.

δ = 3.89–3.71 (m, 5 H), 3.46 (t, J = 9.6 Hz, 1 H), 2.98 (t, J =

4.1 Hz, 1 H), 2.85 (dd, J = 9.7, 3.8 Hz, 1 H), 2.37–2.19 (m, 2 H,

CH) ppm. ¹³C NMR (75 MHz, D₂O): δ = 74.3, 71.1, 69.9, 69.6,

53.1, 49.9, 44.5, 43.5 ppm. IR (KBr): ν = 3281, 2924, 2874, 1729,

˜

1571, 1462, 1375, 1344, 1268, 1203, 1051, 915, 882 cm^–1

.

C₈H₁₆N₂O₃(188.23): calcd. C 51.05, H 8.57, N 34.98, N 14.88;

found C 51.42, H 8.29, N 15.

(1SR,2RS,3SR,4SR,5SR,6RS)-4,5-Bis(acetoxymethyl)-2,6-diazido-

cyclohexane-1,3-diyl Diacetate (50): Sulfamic acid (40 mg) was

added to a stirred solution of diazidodiacetate 47 (1.70 g,

5.24 mmol) in Ac₂O/AcOH (1:1; 10 mL) at room temperature. The

mixture was then heated at reflux temperature for 24 h as described

above to give 50 (1.66 g, 74%) as a colourless viscous oil. ¹H NMR

(300 MHz, CDCl₃): δ = 5.25 (t, J = 5.3 Hz, 1 H), 5.18 (dd, J = 8.2,

3.8 Hz, 1 H), 4.33–4.20 (m, 3 H), 4.14 (dd, J = 11.7, 6.7 Hz, 1 H),

3.99 (m, 1 H), 3.96 (t, J = 8.7 Hz, 1 H), 2.45–2.35 (m, 1 H), 2.33–

2.23 (m, 1 H), 2.16 (s, 3 H, COCH₃), 2.12 (s, 3 H, COCH₃), 2.08

(s, 3 H, COCH₃), 2.05 (s, 3 H, COCH₃) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 170.8, 170.7, 169.9, 169.7, 73.7, 69.5, 62.5, 61.8, 60.7,

Determination of IC₅₀Values and Statistical Analysis: To obtain

IC₅₀values, the sample was diluted to various concentrations (0.2,

0.4, 0.8, 1.0, and 1.2 mg/mL) and used in the enzyme assay pro-

cedures described above. The IC₅₀values were determined from

plots of percentage inhibition vs. inhibitor concentration, and cal-

culated by logarithmic regression analysis. IC₅₀is defined as the

concentration of compound that inhibits 50% of the activity of the

enzyme. Both positive and negative controls were run. Acarbose

was used as positive control. All experiments were carried out in

triplicate, and results are given as meanϮSEM (standard error of

the mean).

57.9, 39.0, 38.1, 21.2, 21.0 (2 C), 20.9 ppm. IR (KBr): ν = 2971,

˜

2105, 1738, 1432, 1368, 1217, 1036, 903 cm^–1. C₁₆H₂₂N₆O₈

(426.39): calcd. C 45.07, H 5.20, N 19.71; found C 45.34, H 5.51,

N 19.96.

X-ray Structure Determination: CCDC-997223 (for 34) and -997011

(for 40) contain the supplementary crystallographic data for this

paper. These data can be obtained free of charge from The Cam-

bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/

data_request/cif.

(1SR,2RS,3SR,4RS,5SR,6SR)-2,4-Diazido-5,6-bis(hydroxymeth-

yl)cyclohexane-1,3-diol (51): Diazidotetraacetate 50 (0.46 g,

1.08 mmol) was ammonolysed with NH₃in absolute MeOH as de-

scribed above to give diazidotetrol 51 (0.25 g, 90%) as a brown

viscous oil. ¹H NMR (300 MHz, D₂O): δ = 3.93–3.90 (m, 2 H),

Supporting Information (see footnote on the first page of this arti-

cle): 1D and 2D ¹H and ¹³C NMR spectra for all new compounds,

3.73–3.57 (m, 6 H), 2.03–1.94 (m, 2 H) ppm. ¹³C NMR (75 MHz, X-ray structural analysis for 34 and 40, and Cartesian coordinates

D₂O): δ = 71.2, 68.1, 65.6, 61.7, 60.03, 59.6, 43.1, 40.1 ppm. IR for DFT structures for 16 and 18.

14

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Azido- and Aminocyclitols

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The authors are indebted to the Scientific and Technological Re-

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Received: June 16, 2014

Eur. J. Org. Chem. 0000, 0–0

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Date: 22-09-14 11:12:00

Pages: 16

G. Aydin, K. Ally, F. Aktas¸, E. S¸ahin, A. Baran, M. Balci

FULL PAPER

Amino-Substituted Carbasugars

Aminocyclitols are found in many natural

products with remarkable biological activi-

ties. The synthesis of various amino-substi-

tuted carbasugars and their inhibitory ef-

fects against α-glucosidase and α-amylase

are discussed.

G. Aydin, K. Ally, F. Aktas¸, E. S¸ahin,

A. Baran,* M. Balci* ...................... 1–16

Synthesis and α-Glucosidase and α-Amyl-

ase Inhibitory Activity Evaluation of

Azido- and Aminocyclitols

Keywords: Synthetic methods

/ Carbo-

cycles / Cyclitols / Carbasugars / Amines /

Biological activity

16

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Article Doi

Synthesis and α-Glucosidase and α-Amylase Inhibitory Activity Evaluation of Azido- and Aminocyclitols

DOI: 10.1002/ejoc.201402762

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Article abstract of DOI:10.1002/ejoc.201402762

Full text of DOI:10.1002/ejoc.201402762

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