Synthesis of 1-glycosyl derivatives of benzocamalexin

1-Glycosyl Derivatives of Benzocamalexin

1657

SYNTHESIS OF 1-GLYCOSYL DERIVATIVES OF BENZOCAMALEXIN

b

Martin HUMENÍK^a1,*, Milan DZURILLA^a2, Peter KUTSCHY^a3, Eva SOLČÁNIOVÁ ,

c1

c2

Vladimir KOVÁČIK and Slávka BEKEŠOVÁ

a

Institute of Chemical Sciences, Faculty of Science, P. J. Šafárik University, Moyzesova 11,

041 67 Košice, Slovak Republic; e-mail: mhumenik@yahoo.com, dzurilla@kosice.upjs.sk,

kutschy@kosice.upjs.sk

Institute of Chemistry, Faculty of Natural Sciences, Comenius University, Mlynská dolina CH-2,

842 15 Bratislava, Slovak Republic; e-mail: solcaniova@fns.uniba.sk

Institute of Chemistry, Slovak Academy of Sciences, Dúbravská cesta 9, 842 38 Bratislava,

1

2

3

b

c

1

2

Slovak Republic; e-mail: chemkov@savba.sk, chembeke@savba.sk

Received May 25, 2004

Accepted July 12, 2004

Th e lin ear syn th esis of 1-(β-D-glucopyran osyl)-, 1-(β-D-galactopyran osyl)-, 1-(β-D-m an n o-

pyran osyl)- an d 1-(β-D-ribofuran osyl)ben zocam alexin was elaborated from in dolin e as a

startin g com poun d an d correspon din g pen taacetylh exoses or 1-O-acetyl-2,3,5-tri-O-ben zoyl-

D-ribose as suitable glycosyl don ors.

Keyw ord s: In dole; Glycosides; Nucleosides; Ph ytoalexin s; Cam alexin ; Ben zocam alexin ;

Natural products; Plan t h orm on es; Alkaloids.

Th e syn th esis of in dole N-glycosides appeared to be of a great im portan ce

after isolation of in dole n ucleoside an tibiotics such as rebeccam ycin ¹,

staurosporin ², n eosidom ycin ³an d SF-2140 ^3b–3d,4. In addition , in dole

nucleosides are the targets for synthesis of new compounds with attractive bio-

logical effects⁵.

Ben zocam alexin 2 is a sim ple an alog of cam alexin 1 wh ich is a un ique

represen tative of ph ytoalexin s biosyn th esized by a few wild crucifers e.g.

Camelina sativa an d Arabidopsis thaliana⁶. Cam alexin exh ibits an tifun gal ac-

tivities again st Alternaria brassicae Cladosporium sp. or Alternaria

brassicicola^6a,6ban d a sign ifican t cytotoxic activity again st h um an breast

can cer cell lin e SKBr3 ⁷. Ph ytoalexin s form a part of th e in duced ch em ical

defen ce of plan ts in respon se to several form s of stress, in cludin g m icrobial

attack⁸. Syn th esis of ben zocam alexin was reported^9,10; h owever, its biologi-

cal activity was n ot exam in ed because of its poor solubility in aqueous m e-

dium ¹⁰. In accord with our in terest in th e syn th esis of n ucleoside an alogs

derived from in dole ph ytoalexin s, we h ave also studied th e syn th esis of

Collect. Czech. Chem. Commun. (Vol. 69) (2004)

doi:10.1135/cccc20041657

1658

Humeník, Dzurilla, Kutschy, Solčániová, Kováčik, Bekešová:

1-glycosyl derivatives of ben zocam alexin . Sin ce a good m eth od of en h an c-

in g water solubility of poorly soluble in doles is th e preparation of corre-

spon din g N-glycosides^5e, th e en h an ced solubility of ben zocam alexin

N-glycosides com pared with ben zocam alexin itself is also expected.

6

5

7

4

7a

S

3a

¹S

N

2

N³

4

3

3a

5

6

2

N

H

1

2

7a

1

N

H

7

Th e m ain goal of th e presen t work was th e syn th esis of four

1-glycosylben zocam alexin s derived from D-glucose, D-galactose, D-m an n ose

an d D-ribose. We decided for a lin ear approach , usin g th e so-called

in dolin e-in dole m eth od¹¹, wh ich offers th e possibility to take advan tage of

en h an ced n ucleoph ilicity of in dolin e in com parison with th e less

n ucleoph ilic in dole rin g. High reactivity of in dolin e facilitates its reaction

with eith er un protected sacch arides or th eir peracetylated, com m ercially

an d syn th etically easily accessible derivatives^11,12

.

Preparation of startin g in dolin e N-glycosides 4a–4d (Sch em e 1) derived

from h exoses was perform ed usin g im proved described syn th eses¹³. Usin g

m eth an ol in stead of eth an ol an d also em ployin g colum n ch rom atograph y

for purification of th e prepared com poun ds in stead of recrystallization al-

lowed us to prepare correspon din g 1-glycosylin dolin es in h igh er yields – 4a

(85%), 4b (69%) as well as m ixture of an om ers 4c an d 4d (77%) in stead of

th e described 74% (4a), 58% (4b) an d 26% (m ixture of an om ers 4c an d 4d ).

In th e previous work^13c, form ation of two an om ers 4c an d 4d was de-

scribed; h owever, th e an om ers were n ot separated an d th eir ratio was n ot

1

given . In our case, H NMR spectrum of th e reaction m ixture after work-up

revealed th e ratio of 4c:4d = 1.65:1, deduced from in tegrated in ten sities of

th e sign als assign ed to an om eric proton s. After several un successful at-

tem pts to separate an om ers 4c an d 4d , it appeared th at com plete separation

by flash ch rom atograph y is n ot possible because of fast epim erization of 4c

an d 4d on silica gel. An yway, pure 4c an d 4d were obtain ed in low yields

by flash ch rom atograph y an d subjected to detailed ¹H NMR an d ¹³C NMR

an alyses in cludin g HH COSY, HMQC an d NOE differen ce experim en ts. In

th e case of 1-(β-ribofuran osyl)in dolin e 4e (Sch em e 1) th e use of startin g

1,2,3,5-tetra-O-acetyl-D-ribofuran ose did n ot seem advan tageous sin ce its

reaction with in dolin e was described to produce on ly 1-acetylin dolin e as

Collect. Czech. Chem. Commun. (Vol. 69) (2004)

1-Glycosyl Derivatives of Benzocamalexin

1659

sole product¹¹. In con trast, th e form ation of N-glycosidic bon d could be

ach ieved by th e reaction of 1-O-acetyl-2,3,5-tri-O-ben zoyl-D-ribofuran ose

(10d , Sch em e 1) with in dolin e, as reported^13b. Alth ough com poun d 10d

can be obtain ed in a th ree-step procedure in 96% yield¹⁴, its reaction with

in dolin e in eth an ol was described to afford on ly 45% yield of

1-ribofuran osylin dolin e derivative 4e ^13b(Sch em e 1). We h ave foun d th at a

ch an ge of th e solven t can sign ifican tly im prove th e yield of desired product

4e. Th e best yield (84%) was obtain ed in ch loroform after reflux for 24 h

(Table I, en try 4).

After preparation of 1-glycosylin dolin es 4a–4e, our syn th esis con tin ued

with furth er aglycon tran sform ation s. Oxidation of in dolin e N-glycosides

with 2,3-dich loro-5,6-dicyan o-1,4-ben zoquin on e (DDQ) was carried out un -

13c

der sim ilar con dition s as publish ed for 4a ^13b,13d, 4b

an d 4e ^13b. In all

cases usin g toluen e as a solven t at room tem perature in stead of boilin g m-xy-

len e^13b–13dprovided com parable yields of 5a (87%), 5e (76%) an d im proved

th e yield of 5b (85%) com pared with th e publish ed 48% ^13c. Oxidation of a

m ixture of 1-(α-m an n opyran osyl)- 4c an d 1-(β-m an n opyran osyl)in dolin e

4d provided a m ixture of both 1-m an n opyran osylin doles 5c an d 5d in th e

ratio α:β = 1.3:1 an d an overall yield of 74% after work-up. Th e previously

n ot described 1-m an n opyran osylin doles appeared m ore stable th an

in dolin es 4c an d 4d an d th eir separation by colum n ch rom atograph y af-

forded com poun ds 5c (42%) an d 5d (32%).

Th e m ixture of in doles 5c an d 5d is en rich ed in β-an om er com pared to

in dolin es 4c an d 4d . To explain th is fact oxidation s of isolated com poun d

4c an d 4d was perform ed. Com poun d 4c afforded a 2:1 m ixture of 5c an d

5d wh ereas com poun d 4d gave th e sole product 5d . Hen ce α-an om er 4c ap-

peared to be less stable durin g th e oxidation reaction , presum ably because

of a deh ydrogen ation un der th e effect of DDQ usually accom pan ied by

TABLE I

In fluen ce of solven t on th e yield of ribosylation in th e reaction of in dolin e with 10d

En try

Solven t

Reaction tim e, h

Yield, %

1

2

3

4

EtOH

6.5

8

45

26

54

84

MeOH

CH₂Cl₂

CHCl₃

48

24

Collect. Czech. Chem. Commun. (Vol. 69) (2004)

1660

Humeník, Dzurilla, Kutschy, Solčániová, Kováčik, Bekešová:

an om erization ¹¹. In stability of α-an om er 4c was observed also durin g NMR

m easurem en t. ¹H NMR spectrum taken after dissolution sh owed th e pres-

en ce of a sin gle com poun d. After som e tim e required for HH COSY, HMQC

an d NOE m easurem en ts, ca. 20% of β-an om er 4d was presen t. Durin g th e

sam e NMR m easurem en ts with pure 4d , n o sign als of α-an om er appeared in

spectra. Th e epim erization of α-an om er 4c in CDCl₃solution is proposed

via acid catalyzed rin g open in g an d subsequen t cyclization ¹¹proceeded to

th e th erm odyn am ically m ore stable β-isom er 4b. On th e basis of th ese ob-

servation s, 4c could be design ated as a kin etic an d 4b as a th erm odyn am ic

product in th e in dolin e glycosidation reaction (Sch em e 1).

1.POCl₃,DMF

15 min, 0 °C

10a-10d

DDQ

2. 90 °C

72-95%

MeOH, AcOH

rt,

69-85%

toluene, rt,

74-78%

N

H

Gl

3

4a-4e

5a-5e

O

K₂CO₃or

CH₃ONa

MeOH,

36% HCl

S

N

NH₂

MeOH, rt

78-99%

N

7

Gl

SH

6a-6e

N

73-94%

Gl

Sach

8a-8e

9a-9e

Substituents Gl and Sach:

10a-10d:

a: R¹, R³= OAc

R², R⁴= H

b: R¹, R⁴= OAc

R², R³= H

c: R², R³= OAc

R¹, R⁴= H

R¹

¹R¹

OAc

R⁴

R

R²

O

R¹

O

R³

AcO

R¹

b

a

c

OAc

10a-10c

R¹

O

R¹

O

R¹

BzO

OAc

O

d

R²

OBz

O

10d

Gl: R¹= OAc

R²= OBz

Sach: R¹, R²= OH

e

R²R²

SCHEME 1

Collect. Czech. Chem. Commun. (Vol. 69) (2004)

1-Glycosyl Derivatives of Benzocamalexin

1661

Th e prepared in doles 5a–5e were subjected to th e Vilsm eier reaction ac-

cordin g to th e described preparation of 1-(2,3,4,6-tetra-O-acetyl-

β-D-glucopyran osyl)in dole-3-carbaldeh yde¹⁵(6a). Usin g th e sam e con di-

tion s, aldeh ydes 6a (83%), 6b (72%), 6c (85%), 6d (77%) an d 6e (95%) were

obtain ed in good to excellen t yields. Durin g th e Vilsm eier form ylation fur-

th er epim erization of in doles 5c an d 5d was n ot observed. Th e prepared

in dole-3-carbaldeh ydes are key in term ediates with reactive aldeh yde

groups, wh ich allow furth er fun ction al tran sform ation s. Th e reaction of al-

deh ydes an d keton es with suitably substituted 2-am in oben zen eth iols pro-

vides a wide ran ge of ben zoth iazoles. Previous works used th is reaction for

preparation of un substituted⁹an d 1-substituted¹⁰ben zocam alexin s. We ex-

ten ded th is m eth od in to th e area of 1-glycosides.

Cyclocon den sation of in dole-3-carbaldeh ydes 6b –6e with 2-am in o-

ben zen eth iol (7) in m eth an ol in th e presen ce of a catalytic am oun t of 36%

aqueous HCl afforded, after 15 m in at room tem perature (6a required reflux

for 30 m in ), good yields of ben zocam alexin s 8a (83%), 8b (94%), 8c (81%),

8d (73%) an d 8e (81%) (Sch em e 1).

Appropriate ben zocam alexin derivatives for biological screen in g were af-

forded by fin al deprotection . Th is was ach ieved by treatm en t of

peracetylated com poun ds 8a–8d with a catalytic am oun t of powdered

K₂CO₃in m eth an ol¹⁴at room tem perature for 1–4 h . Th is efficien t

deprotection afforded n ew, to date n ot described 1-glycopyran osyl-

ben zocam alexin s 9a (99%), 9b (96%), 9c (93%) an d 9d (91%) in excellen t

yields. Th e rem oval of ben zoyl groups of 8e with 0.1 M solution of sodium

m eth oxide in dry m eth an ol¹⁶afforded 1-(β-ribofuran osyl)ben zocam alexin

9e (78%) (Sch em e 1).

Th e structure of th e prepared n ucleoside an alogs was con firm ed by spec-

tral m eth ods. In ¹H an d ¹³C NMR spectra, th e sign als were assign ed on th e

basis of 2D H-H COSY an d HMQC h eterocorrelated spectra. Th e β-an om eric

con figuration of n ew glucopyran osyl 8a, 9a an d n ew galactopyran osyl de-

rivatives 6b–9b (Sch em e 1) was con firm ed by vicin al trans-diaxial couplin g

con stan ts J(1,2) = 9.0–11.9 Hz.

In startin g m an n opyran osides 4c an d 4d , th e an om eric con figuration was

determ in ed in literature^13con ly on th e basis of couplin g con stan ts of

an om eric proton s. Th e data publish ed for H-1′ of α-an om er are δ 4.89 ppm ,

d, J(1,2) ≈ 1 Hz an d th ose for β-an om er are δ 4.78 ppm , d, J(1,2) = 2.4 Hz. In

our opin ion th e values of couplin g con stan ts are too close to m ake a reli-

able assign m en t. Th erefore we perform ed NOE experim en ts with 4c an d 4d

(Fig. 1). In th e case of 4d , th e irradiation of an om eric proton H-1′ m arkedly

in creased th e in ten sity of sign als H-5′ (14.3%) an d th e opposite irradiation

Collect. Czech. Chem. Commun. (Vol. 69) (2004)

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Humeník, Dzurilla, Kutschy, Solčániová, Kováčik, Bekešová:

of H-5′ resulted in in creased in ten sity of th e H-1′ sign al (11.8%). Th e ob-

served NOE between H-5′ an d H-1′ eviden ces th eir cis-diaxial orien tation of

H-1′ an d H-5′ an d th us con firm s th e β-an om eric con figuration of 4d . NOE

experim en ts perform ed with com poun d 4c revealed n o in teraction between

H-1′ an d H-5′ con trary to th e previous case. Irradiation of th e H-5′ sign al in -

creased on ly th e in ten sity of th e H-3′ sign al (5.8%) related to th eir

cis-diaxial orien tation . Irradiation of H-1′ en h an ced on ly sign als of H-2′

(4.8%) related to th eir proxim ity an d H-7 (4.5%) but again with n o in flu-

en ce on th e H-5′ sign al. Th e absen ce of th ese in teraction s, so rem arkable in

th e previous case, in dicates th at H-1′ an d H-5′ are on th e opposite sides of

th e m an n opyran osyl rin g an d 4c h as α-an om eric con figuration .

1

Th e results are opposite to th ose presen ted in th e literature^13can d our H

NMR spectra of 4c an d 4d do n ot correspon d with th e publish ed on es. New

data for th e H-1′ sh ift of α-an om er 4c are δ 4.79 ppm , d, J(1,2) = 2.2 Hz an d

for β-an om er 4d δ 4.91 ppm , J(1,2) = 1.1 Hz. Con sequen tly, th e correct as-

sign m en t of α- an d β-con figuration for com poun ds 4c an d 4d is opposite.

Reliable determ in ation of con figuration of 4c an d 4d on th e basis of NOE

experim en ts allowed us to apply couplin g con stan ts of an om eric proton s

also to oth er syn th esized m an n opyran osides. Th us com poun ds 5c–9c,

sh owin g couplin g con stan ts J(1,2) = 2.2–3.6 Hz, were assign ed as α-an om ers

wh ereas com poun ds 5d –9d with J(1,2) = 0–1.1 Hz were assign ed as

β-an om ers. Th is con clusion was con firm ed by NOE experim en ts with α-8c,

J(1,2) = 3.5 Hz an d β-8d , J(1,2) = 1.1 Hz (Fig. 2).

In th e case of ribofuran osides th e syn th esis started from described

β-an om ers of 4e an d 5e ^13b. Sin ce durin g th e syn th etic path from 4e to 9e

n o epim erization was observed, th e prepared com poun ds 6e, 8e an d 9e

sh ould possess β-con figuration . Th is presum ption arose from th e sim ilarity

FIG. 1

NOE en h an cem en ts in com poun ds 4c an d 4d

Collect. Czech. Chem. Commun. (Vol. 69) (2004)

1-Glycosyl Derivatives of Benzocamalexin

1663

of couplin g con stan ts of an om eric proton s, wh ich vary with in 4.4–5.8 Hz.

Th e predicted β-an om eric con figuration of 1-ribofuran osylben zocam alexin

8e was con firm ed by NOE experim en ts wh ich disclosed in teraction be-

tween H-1′ an d H-4′ (Fig. 3).

FIG. 2

NOE en h an cem en ts in com poun ds 8c an d 8d

FIG. 3

NOE en h an cem en ts in com poun d 8e

Collect. Czech. Chem. Commun. (Vol. 69) (2004)

1664

Humeník, Dzurilla, Kutschy, Solčániová, Kováčik, Bekešová:

Durin g determ in ation of an om eric con figuration by NOE experim en ts,

addition al NOEs were observed, wh ich can be exploited for description s of

aglycon con form ation in sacch aride m oieties.

Th e irradiation of an om eric proton H-1′ of 4d m arkedly in creased th e in -

ten sity of sign al H-7 (12.4%). Th is spatial proxim ity of h ydrogen s in dicates

th e con form ation al position of th e in dolin e skeleton relative to th e

m an n opyran osyl rin g as depicted in Fig. 1. In th e oth er α-an om er, 4c, th e

observed in teraction between H-3′ an d H-2 (4.6%), H-2′ an d H-2 (5.3%) an d

H′-2 (5.6%) as well as H-1′ an d H-7 (4.8%) allow us to propose th e orien ta-

tion of th e in dolin e skeleton with th e ben zen e rin g directed to th e side of

th e m an n opyran osyl rin g oxygen atom (Fig. 1).

NOE effects in m an n opyran osylben zocam alexin 8c revealed stron g in ter-

action s between H-2 an d H-2′ or H-3′ wh ereas in th e case of 8d between

H-1′ an d H-7. Th ese results in dicate con form ation al orien tation of ben zo-

cam alexin m oieties as sh own in Fig. 2.

Fin ally in th e case of 8e, stron g in teraction s between H-1′ an d H-2 or H-7

(Fig. 3) in dicate spatial proxim ity of th ese h ydrogen s. On th is basis th e

con form ation al orien tation of ben zocam alexin aglycon relative to th e

sacch aride rin g could n ot be determ in ed.

As prim ary in vitro screen in g for growth in h ibition an d cytotoxicity,

com poun ds 9a–9e were subm itted to NCI (Nation al Can cer In stitute,

Beth esda, U.S.A.) an d evaluated for th eir cytotoxic poten cy on th ree h um an

cell lin es, such as NCI-H460 lun g can cer, MCF7 breast can cer an d SF-268

gliom a. A com poun d is con sidered active wh en it reduces th e growth of

an y of th e cell lin es to 32% or less an d it is th en passed on for evaluation in

th e full pan el of sixty cell lin es. Com poun ds 9c an d 9e were active in th is

test. Th e pan el of sixty h um an tum our cell lin es is organ ized in to subpan els

represen tin g leukaem ia, m elan om a an d can cers of lun g, colon , kidn ey,

ovary, breast, prostate an d cen tral n ervous system . Th e test com poun ds

were dissolved in DMSO an d evaluated usin g five con cen tration s at ten -fold

dilution s, th e h igh est bein g 10^–4m ol l^–1an d th e oth ers 10^–5–10^–8m ol l^–1.

Th ey did n ot sh ow a level of activity sufficien t to en ter th e subsequen t in

vivo step.

Th e syn th esis of five n ovel, to date n ot described 1-glycosylben zo-

cam alexin s was accom plish ed by usin g th e in dolin e-in dole m eth od, wh ich

allowed to evaluate th eir an tican cer effect depen din g on differen t

sacch aride m oieties. Bin din g of aglycon with β-D-ribose or α-D-m an n ose

outlin ed th e m ain m otifs of 1-glycosylben zocam alexin s suitable for furth er

studies in order to im prove th eir biological activity.

Collect. Czech. Chem. Commun. (Vol. 69) (2004)

1-Glycosyl Derivatives of Benzocamalexin

1665

EXPERIMENTAL

¹H an d ¹³C NMR spectra were m easured on a Varian Gem in i 2000 NMR spectrom eter operat-

13

in g at 300 MHz for ¹H an d at 75 MHz for

C, usin g tetram eth ylsilan e as an in tern al stan -

dard. Ch em ical sh ifts (δ) are reported in ppm , down field from tetram eth ylsilan e, couplin g

con stan ts (J) in Hz. Th e assign m en t of proton an d carbon atom sign als is based on HH

COSY, HMQC spectra an d NOE differen ce spectra of com poun ds 4c, 4d , 8c, 8d , 8e an d 9e.

Microan alyses were perform ed with a Perkin –Elm er, Model 2400 an alyzer. Th e EI m ass spec-

tra were recorded on a Fin igan SSQ 700 spectrom eter at ion ization en ergy 70 eV, wh ereas

MALDI-TOF m ass spectra were m easured on a MALDI IV (Sh im adzu, Kratos An alytical)

in stru m en t. For MALDI m easu rem en ts th e an alyzed sam ples were dissolved in an aceto-

n itrile–water m ixture (1:1). Th e Matrix, 2,5-dih ydroxyben zoic acid (DHB), was dissolved in

th e sam e m ixture. Solution s of a sam ple an d th e m atrix were m ixed in th e ratio 1:10. After

dryin g on target, th e sam ples were bom barded with a 3 n s dose (100 doses) of a n itrogen la-

ser (λ 337 n m ). Ion acceleration voltage was 5 kV. Th e reaction course was m on itored by

th in layer ch rom atograph y usin g Silufol plates (Kavalier®). Th e preparative colum n ch ro-

m atograp h y (flash ch rom atograp h y) was p erform ed on Kieselgel Merck Typ e 9385,

230–400 m esh .

Peracetylation of D-glucose, D-galactose an d D-m an n ose was accom plish ed by a classic re-

action in pyridin e/Ac₂O an d a m ixture of an om ers was used for subsequen t reaction s.

1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyran osyl)in dolin e (4a)

Peracetylated β-D-glucose (5.0 g, 12.80 m m ol) was dissolved in m eth an ol (100 m l). In dolin e

(3.05 g, 2.87 m l, 25.60 m m ol) an d acetic acid (5 m l) were added to th e solution an d th e re-

action m ixture was stirred at room tem perature for 24 h . Th e precipitated product was fil-

tered off an d recrystallized from m eth an ol. Yield 4.89 g (85%), lit.^13c74%; C₂₂H₂₇NO₉

(449.5); wh ite crystals; m .p. 117–118 °C (m eth an ol), lit.^13c119–120 °C.

1-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyran osyl)in dolin e (4b)

Peracetylated β-D-galactose (1.83 g, 4.69 m m ol) was dissolved in 10 m l of m eth an ol an d to

th e solution were added in dolin e (1.39 g, 1.32 m l, 11.72 m m ol) an d acetic acid (1.7 m l).

Th e reaction m ixture was stirred at room tem perature for 24 h , con cen trated un der reduced

pressure an d residue was subjected to colum n ch rom atograph y (cycloh exan e–eth yl acetate

3:1). Yield 1.44 g (69%), lit.^13c58%; C₂₂H₂₇NO₉(449.5); wh ite crystals; m .p. 110–112 °C

(m eth an ol), lit.^13c109–110 °C.

1-(2,3,4,6-Tetra-O-acetyl-α-D-m an n opyran osyl)in dolin e (4c) an d

1-(2,3,4,6-Tetra-O-acetyl-β-D-m an n opyran osyl)in dolin e (4d )

Com poun ds 4c an d 4d were prepared accordin g to th e procedure for syn th esis of 4b. Yield

77% as a m ixture of an om ers with α:β ratio 1.65:1, lit.^13c26%. Sam ples of 4c an d 4d for de-

tailed NMR ch aracterization were prepared by addition al colum n ch rom atograph y (cyclo-

h exan e–eth yl acetate 5:1) yieldin g 4a (29%) 4b (14%) an d m ixture of 4a an d 4b (34%).

Compound 4c: For C₂₂H₂₇NO₉(449.5) calculated: 58.79% C, 6.06% H, 3.12% N; foun d:

58.89% C, 6.21% H, 3.23% N; wh ite solid; m .p. 92–95 °C (m eth an ol). ¹H NMR (300 MHz,

CDCl₃): 2.05 s, 3 H (CH₃); 2.06 s, 3 H (CH₃); 2.09 s, 3 H (CH₃); 2.18 s, 3 H (CH₃); 2.97–3.15 m ,

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Humeník, Dzurilla, Kutschy, Solčániová, Kováčik, Bekešová:

2 H (H-3, H′-3); 3.31 q, 1 H, J(2,2′) = J(2,3) = J(2,3′) = 8.3 (H-2); 3.81 dt, 1 H, J(2,2′) = J(2,3) =

8.3, J(2,3′) = 3.0 (H′-2); 4.18 dd, 1 H, J(6′,6′′) = 11.5, J(5′,6′) = 1.9 (H-6′); 4.25 m , 1 H (H-5′);

4.32 dd, 1 H, J(6′,6′′) = 11.3, J(5′,6′′) = 6.0 (H′-6′); 4.79 d, 1 H, J(1′,2′) = 2.2 (H-1′); 5.31–5.39 m ,

1 H (H-3′, H-4′); 5.57 t, 1 H, J(2′,3′) = 2.5, J(1′,2′) = 2.2 (H-2′); 6.75 td, 1 H, J = 5.9, 1.9 (H-5);

7.05–7.14 m , 3 H (H-4, H-5, H-6). ¹³C NMR (75 MHz, CDCl₃): 21.02, 21.08, 21.20 (CH₃CO);

29.14 (CH₂aglycon ); 50.21 (NCH₂aglycon ); 62.64 (C-6′); 66.31 (C-4′); 68.73 (C-2′); 69.30

(C-5′); 70.28 (C-3′); 87.08 (C-1′); 111.31 (C-7); 120.72 (C-5); 124.51 (C-6); 127.69 (C-4);

130.57 (C-3a); 150.66 (C-7a); 169.85, 170.33, 170.68, 170.82 (CH₃CO). Differen ce NOE spectra

(CDCl₃): irradiated at δ 4.79 (H-1′) en h an ced sign als (H-2′, 4.8%), (H-7, 4.5%); irradiated at

δ 5.57 (H-2′) en h an ced sign als (H-1′, 7.4%), (H-2, 5.3%), (H′-2, 5.6%); irrad iated at δ

5.31–5.39 (H-3′ an d H-4′) en h an ced sign als (H-5′, 5.6%), (H-2, 4.6%); irradiated at δ 4.25

(H-5′) en h an ced sign als (H-3′, 5.8%). MS MALDI-TOF, m/z (%): 488 [M + K]⁺(6), 472 [M +

Na]⁺(52), 450 [M + H]⁺(100).

Compound 4d : For C₂₂H₂₇NO₉(449.5) calculated: 58.79% C, 6.06% H, 3.12% N; foun d:

58.91% C, 6.15% H, 3.04% N; wh ite solid; m .p. 130–139 °C (m eth an ol). ¹H NMR (300 MHz,

CDCl₃): 2.00 s, 3 H (CH₃); 2.05 s, 3 H (CH₃); 2.07 s, 3 H (CH₃); 2.21 s, 3 H (CH₃); 2.90–3.07

m , 2 H (H-3, H′-3); 3.34 ddd, 1 H, J(2,2′) = 9.2, J(2,3) = 9.2, J(2,3′) = 6.7 (H-2); 3.60 q, 1 H,

J(2,2′) = J(2′,3) = J(2′,3′) = 8.7 (H′-2); 3.82 ddd, 1 H, J(4′,5′) = 9.4, J(5′,6′) = 6.2, J(5′,6′′) = 2.7

(H-5′); 4.15 dd, 1 H, J(6′,6′′) = 12.1, J(5′,6′) = 2.7 (H-6′); 4.26 dd, 1 H, J(6′,6′′) = 12.1, J(5′,6′′)

= 6.2 (H′-6′); 4.91 d, 1 H, J(1′,2′) = 1.1 (H-1′); 5.13 dd, 1 H, J(3′,4′) = 10.1, J(2′,3′) = 3.1 (H-3′);

5.27 t, 1 H, J(3′,4′) = 10.1, J(4′,5′) = 10.0 (H-4′); 5.65 dd, 1 H, J(2′,3′) = 3.1, J(1′,2′) = 1.1

(H-2′); 6.62 d, 1 H, J(6,7) = 7.8 (H-7); 6.75 t, 1 H, J(4,5) = J(5,6) = 7.31 (H-5); 7.04–7.09 m ,

2 H (H-4, H-6). ¹³C NMR (75 MHz, CDCl₃): 20.86, 20.98, 21.01, 21.44 (CH₃CO); 29.03 (CH₂

aglycon ); 48.40 (NCH₂aglycon ); 63.08 (C-6′); 66.44 (C-4′); 69.86 (C-2′); 72.63 (C-3′); 74.30

(C-5′); 85.15 (C-1′); 108.85 (C-7); 119.88 (C-5); 124.81 (C-6); 127.37 (C-4); 139.83 (C-3a);

150.07 (C-7a); 169.85, 170.23, 170.38, 170.78 (CH₃CO). Differen ce NOE spectra (CDCl₃): ir-

radiated at δ 4.91 (H-1′) en h an ced sign als (H-2′, 11.0%), (H-5′, 14.3%), (H-7, 12.4%);

irradiated at δ 5.65 (H-2′) en h an ced sign als (H-1′, 6.8%), (H-3′, 7.9%), (H-2, 3.4%); irradiated

at δ 5.13 (H-3′) en h an ced sign als (H-2′, 9.4%), (H-5′, 6.6%); irradiated at δ 5.27 (H-4′) en -

h an ced sign als (H-2′, 2.5%), (H-5′, 4.5%), (H-6′, 2.4%); irradiated at δ 3.82 (H-5′) en h an ced

sign als (H-1′, 11.8%), (H-3′, 6.0%), (H-4′, 3.0%); MS MALDI-TOF, m/z (%): 488 [M + K]⁺(18),

472 [M + Na]⁺(73), 450 [M + H]⁺(100).

1-(2,3,5-Tri-O-ben zoyl-β-D-ribofuran osyl)in dolin e (4e)

1-O-Acetyl-2,3,5-tri-O-ben zoyl-β-D-ribofuran ose (12; 2.58 g, 5.07 m m ol) was dissolved in

CH₂Cl₂(80 m l). In dolin e (2.84 m l, 3.02 g, 25.3 m m ol) an d a catalytic am oun t of AcOH

(3.1 m l) were added to th e solution an d th e reaction m ixture was refluxed for 24 h . Sin ce

TLC sh owed full con sum ption of startin g sacch aride 12, th e reaction m ixture was wash ed

with 1 M aqueous HCl an d a saturated solution of aqueous NaHCO₃, th e organ ic layer was

dried with an h ydrous Na₂SO₄an d evaporated un der reduced pressure. Th e residue was sub-

jected to colum n ch rom atograph y (ben zen e–eth yl acetate 70:1). Yield 2.40 g (84%), lit.^13b

45%; C₃₄H₂₉NO₇(563.6); wh ite foam . ¹H NMR spectrum was iden tical with th at of th e com -

poun d prepared accordin g to th e procedure described in literature^13b

.

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1-Glycosyl Derivatives of Benzocamalexin

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1-(2,3,4,6-Tetra-O-acetyl-α-D-m an n opyran osyl)-1H-in dole (5c) an d

1-(2,3,4,6-Tetra-O-acetyl-β-D-m an n opyran osyl)-1H-in dole (5d )

A m ixture of an om ers 4c an d 4d (0.38 g 0.845 m m ol) was dissolved in dry toluen e (3 m l).

DDQ was dissolved in 3 m l of toluen e an d, with in 15 m in , was added dropwise to th e

m ixture. Th e reaction m ixture was stirred at room tem perature for 2 h , diluted with toluen e

(10 m l) an d wash ed with 4% aqueous solution of K₂CO₃(2×). Th e organ ic layer was dried

with an h ydrous Na₂SO₄an d toluen e was evaporated on a vacuum evaporator. Th e residue

was subjected to colum n ch rom atograph y (cycloh exan e–eth yl acetate 5:1). Both an om ers

were obtain ed in yields 42% (5c) an d 32% (5d ).

Compound 5c: For C₂₂H₂₅NO₉(447.4) calculated: 59.06% C, 5.63% H, 3.13% N; foun d:

59.19% C, 5.60% H, 3.06% N; wh ite foam . ¹H NMR (300 MHz, CDCl₃): 2.03 s, 3 H (CH₃);

2.05 s, 3 H (CH₃); 2.11 s, 3 H (CH₃); 2.17 s, 3 H (CH₃); 3.68 m , 1 H (H-5′); 4.06 dd, 1 H,

J(6′,6′′) = 12.3, J(5′,6′) = 2.6 (H-6′); 4.33 dd, 1 H, J(6′,6′′) = 12.3, J(5′,6′′) = 6.3 (H′-6′); 5.40 t,

1 H, J(3′,4′) = J(4′,5′) = 8.9 (H-4′); 5.50 dd, 1 H, J(3′,4′) = 8.9, J(2′,3′) = 3.2 (H-3′); 5.97 d, 1 H,

J(1′,2′) = 2.7 (H-1′); 6.06 t, 1 H, J(2′,3′) = 3.2, J(1′,2′) = 2.7 (H-2′); 6.63 d, 1 H, J = 3.34 (H-3);

7.15–7.26 m , 2 H; 7.48 d, 1 H, J = 3.42 an d 7.62 d, 2 H, J = 8.5 (H arom .). ¹³C NMR (75 MHz,

CDCl₃): 20.74 (CH₃CO); 61.63 (C-6′); 65.92, 67.66, 70.18, 70.75 (C-2′–C-5′); 82.09 (C-1′);

104.57, 111.79, 121.10, 122.72, 124.99, 129.19, 136.64 (C arom .); 169.56, 169.84, 170.48,

170.60 (CH₃CO). MS MALDI-TOF, m/z (%): 486 [M + K]⁺(100), 470 [M + Na]⁺(54), 448 [M +

H]⁺(7).

Compound 5d : For C₂₂H₂₅NO₉(447.4) calculated: 59.06% C, 5.63% H, 3.13% N; foun d:

59.21% C, 5.55% H, 3.01% N; wh ite foam . ¹H NMR (300 MHz, CDCl₃): 1.99 s, 3 H (CH₃);

2.02 s, 3 H (CH₃); 2.09 s, 3 H (CH₃); 2.10 s, 3 H (CH₃); 3.95 m , 1 H (H-5′); 4.23 d, 1 H,

J(6′,6′′) = 12.3 (H-6′); 4.33 dd, 1 H, J(6′,6′′) = 12.3, J(5′,6′′) = 5.7 (H′-6′); 5.32 dd, 1 H, J(3′,4′)

= 10.0, J(2′,3′) = 3.0 (H-3′); 5.57 t, 1 H, J(3′,4′) = J(4′,5′) = 10.0 (H-4′); 5.57 d, 1 H, J(2′,3′) =

3.0 (H-2′); 5.84 s, 1 H (H-1′); 6.52 d, 1 H, J(2,3) = 3.3 (H-3); 7.13 t, 1 H, J = 7.4; 7.19–7.24 m ,

2 H; 7.41 d, 1 H, J = 8.2 an d 7.59 d, 1 H, J = 7.7 (H arom .). ¹³C NMR (75 MHz, CDCl₃):

20.60, 20.76 (CH₃CO); 62.62 (C-6′); 65.59, 69.54, 71.40, 75.39 (C-2′–C-5′); 82.32 (C-1′);

103.42, 109.92, 120.57, 121.19, 122.23, 125.1, 128.76, 135.26 (C arom .); 169.49, 169.72,

170.08, 170.70 (CH₃CO). MS MALDI-TOF, m/z (%): 486 [M + K]⁺(50), 470 [M + Na]⁺(100),

448 [M + H]⁺(19).

1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyran osyl)-1H-in dole (5a)

Product 5a was prepared accordin g to procedure for syn th esis of m an n opyran osylin dolin es

5c an d 5d . Yield 87%, lit.^13c78%; C₂₂H₂₅NO₉(447.4); wh ite crystals; m .p. 146–149 °C

(m eth an ol), lit.^13c148–149 °C.

1′-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyran osyl)-1H-in dole (5b)

Com poun d 5b was prepared accordin g to th e procedure for syn th esis of m an n opyran osyl-

in dolin es 5c an d 5d . Yield 85%, lit.^13c48%; C₂₂H₂₅NO₉(447.4); wh ite crystals; m .p.

129–131 °C (m eth an ol), lit.^13c128–129 °C.

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Humeník, Dzurilla, Kutschy, Solčániová, Kováčik, Bekešová:

1-(2,3,5-Tri-O-ben zoyl-β-D-ribofuran osyl)-1H-in dole (5e)

Com poun d 5e was prepared accordin g to th e procedure for syn th esis of m an n o-

pyran osylin dolin es 5c an d 5d . Yield 76%, lit.^13c78%; C₃₄H₂₇NO₇(561.6); wh ite foam .

Vilsm eier Reaction for Preparation of Aldeh ydes 6a–6e

New 1-glycosylin dole-3-carbaldeh ydes 6b–6e were prepared applyin g procedure reported for

preparation of glucosylin dole-3-carbaldeh yde 6a ¹⁵. 1-Glycosylin doles 5a–5e (2.7 m ol) were

dissolved in dry DMF an d th e solution was cooled to 0 °C. A solution of POCl₃(0.7 m l) in

dry DMF (2.3 m l) was prepared at 0 °C an d added dropwise to th e ice-cooled solution of

1-glycosylin dole. Th e reaction m ixture was stirred at 0 °C for 15 m in an d at 80–90 °C for

2 h . Sin ce th e startin g m aterial was con sum ed, th e reaction m ixture was cooled to room

tem perature an d poured in to a m ixture of crush ed ice an d water. Th e water solution was

carefully n eutralized with 4% aqueous solution of K₂CO₃an d th e precipitated product was

filtered off an d wash ed with water.

1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyran osyl)-1H-in dole-3-carbaldeh yde (6a)

Yield 83%, lit.¹⁵84%; C₂₃H₂₅NO₁₀(475.5); wh ite crystals; m .p. 203–205 °C (m eth an ol), lit.¹⁵

203–204 °C.

1-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyran osyl)-1H-in dole-3-carbaldeh yde (6b)

Yield 72%. For C₂₃H₂₅NO₁₀(475.5) calculated: 58.10% C, 5.30% H, 2.95% N; foun d: 58.03% C,

5.09% H, 2.79% N; wh ite crystals; m .p . 205–206 °C (d ich lorom eth an e–cycloh exan e).

¹H NMR (300 MHz, CDCl₃): 1.68 s, 3 H (CH₃); 2.01 s, 3 H (CH₃); 2.03 s, 3 H (CH₃); 2.27 s, 3 H

(CH₃); 4.18–4.27 m , 3 H (H-5′, H-6′, H′-6′); 5.31 dd, 1 H, J(2′,3′) = 9.9 J(3′,4′) = 3.1 (H-3′);

5.58 d, 1 H, J(3′,4′) = 3.1 (H-4′); 5.61 d, 1 H, J(1′,2′) = 9.5 (H-1′); 5.70 t, 1 H, J(1′,2′) = 9.5,

J(2′,3′) = 9.9 (H-2′); 7.31–7.39 m , 2 H; 7.50 d, 1 H, J = 7.3; 7.93 s, 1 H an d 8.31 d, 1 H, J =

6.7 (H arom .); 10.06 s, 1 H (CHO). ¹³C NMR (75 MHz, CDCl₃): 20.12, 20.56, 20.68 an d

20.76 (CH₃CO); 61.38 (C-6′); 67.11, 68.30, 71.11, 73.96 (C-2′–C-5′); 84.04 (C-1′); 110.25,

120.06, 122.55, 123.65, 124.60, 125.35, 135.52, 136.87 (C arom .); 168.72, 170.01, 170.42

(CH₃CO); 185.16 (CHO). EI MS, m/z (%): 475 [M]⁺(6), 331 (20), 169 (35), 144 (11), 109 (21),

43 (8).

1-(2,3,4,6-Tetra-O-acetyl-α-D-m an n opyran osyl)-1H-in dole-3-carbaldeh yde (6c)

Yield 85%. For C₂₃H₂₅NO₁₀(475.5) calculated: 58.10% C, 5.30% H, 2.95% N; foun d: 58.29% C,

5.35% H, 3.10% N; wh ite crystals; m .p. 143–144 °C (dich lorom eth an e–cycloh exan e).

¹H NMR (300 MHz, CDCl₃): 2.00 s, 3 H (CH₃); 2.09 s, 6 H (2 × CH₃); 2.16 s, 3 H (CH₃); 3.79 m ,

1 H (H-5′); 4.06 d, 1 H, J(6′,6′′) = 12.3 (H-6′); 4.52 dd, 1 H, J(6′,6′′) = 12.3, J(5′,6′′) = 7.4

(H′-6′); 5.36 t, 1 H, J(3′,4′) = J(4′,5′) = 7.5 (H-4′); 5.41 d, 1 H, J(3′,4′) = 7.5 (H-3′); 6.02 d, 1 H,

J(1′,2′) = 2.5 (H-1′); 6.04 t, 1 H, J(1′,2′) = J(2′,3′) = 2.5 (H-2′); 7.35 m , 2 H; 7.63 d, 1 H, J =

6.8; 8.08 s, 1 H an d 8.32 m , 1 H (H arom .); 10.08 s, 1 H (CHO). ¹³C NMR (75 MHz, CDCl₃):

20.68 (CH₃CO); 61.03 (C-6′); 65.97, 67.00, 69.54, 72.47 (C-2′–C-5′); 81.36 (C-1′); 112.03,

120.31, 122.45, 123.90, 124.86, 125.45, 135.77, 137.33 (C arom .); 169.42, 169.55, 170.32,

170.53 (CH₃CO); 185.16 (CHO). MS MALDI-TOF, m/z (%): 514 [M + K]⁺(10), 498 [M + Na]⁺

(85), 476 [M + H]⁺(100).

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1-(2,3,4,6-Tetra-O-acetyl-β-D-m an n opyran osyl)-1H-in dole-3-carbaldeh yde (6d )

Yield 77%. For C₂₃H₂₅NO₁₀(475.5) calculated: 58.10% C, 5.30% H, 2.95% N; foun d: 58.19% C,

5.48% H, 2.81% N; wh ite solid; m .p. 73–75 °C (dich lorom eth an e–cycloh exan e). ¹H NMR

(300 MHz, CDCl₃): 2.02 s, 6 H (2 × CH₃); 2.13 6 H (2 × CH₃); 4.03 m , 1 H (H-5′); 4.23 d, 1 H,

J(6′,6′′) = 11.9 (H-6′); 4.39 dd, 1 H, J(6′,6′′) = 11.9, J(5′,6′′) = 6.1 (H′-6′); 5.38 m , 2 H (H-3′,

H-4′); 5.63 s, 1 H (H-2′); 5.94 s, 1 H (H-1′); 7.95–7.41 m , 2 H; 7.95 s, 1 H an d 8.31 m , 1 H

(H arom .); 10.06 s, 1 H (CHO). ¹³C NMR (75 MHz, CDCl₃): 20.55, 20.72, 20.78 (CH₃CO);

62.39 (C-6′); 65.19, 68.64, 70.00, 75.88 (C-2′–C-5′); 82.25 (C-1′); 109.91, 119.55, 122.47,

123.69, 124.65, 125.12, 135.70, 135.85 (C arom .); 169.15, 169.61, 170.03, 170.60 (CH₃CO);

184.90 (CHO). MS MALDI-TOF, m/z (%): 514 [M + K]⁺(32), 498 [M + Na]⁺(100), 476 [M +

H]⁺(12).

1-(2,3,5-Tri-O-ben zoyl-β-D-ribofuran osyl)-1H-in dole-3-carbaldeh yde (6e)

Yield 95%. For C₃₅H₂₇NO₈(589.6) calculated: 71.30% C, 4.62% H, 2.38% N; foun d: 71.52% C,

4.33% H, 2.69% N; white solid; m .p. 80–83 °C (m ethanol). ¹H NMR (300 MHz, CDCl₃): 4.72 dd,

1 H, J(5′,5′′) = 12.1, J(4′,5′) = 3.1 (H-5′); 4.77 m , 1 H (H-4′); 4.98 dd, 1 H, J(5′,5′′) = 12.1,

J(4′,5′′) = 2.7 (H′-5′); 5.98–6.03 m , 2 H (H-3′, H-2′); 6.45 d, 1 H, J(1′,2′) = 4.4 (H-1′); 7.28–7.63

bm , 12 H (H arom .); 7.97 d, 5 H, J = 9.15; 8.13 d, 2 H, J = 7.62 an d 8.29 d, 1 H, J = 7.1

(H arom .); 9.71 s, 1 H (CHO). ¹³C NMR (75 MHz, CDCl₃): 63.16 (C-5′); 70.97, 74.60, 80.57

(C-4′–C-2′); 88.13 (C-1′); 110.45, 119.92, 122.60, 123.68, 124.71, 125.69, 128.66, 128.89,

129.28, 129.86, 133.89, 133.98, 134.88, 136.62 (C arom .); 165.04, 165.34, 166.15 (CH₃CO);

185.03 (CHO). EI MS, m/z (%): 561 [M]⁺(8), 445 (17), 201 (22), 105 (100), 77 (27).

1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyran osyl)-3-(1,3-ben zoth iazol-2-yl)-1H-in dole (8a)

1-Glucopyran osylin dole-3-carbaldeh yde 6a (1.0 g, 2.10 m m ol) was dissolved in m eth an ol

(8 m l). 2-Am in oben zen eth iol (0.26 g, 0.22 m l, 2.10 m m ol) an d 1 drop of 36% HCl were

added to th e solution . Th e reaction m ixture was refluxed for 30 m in an d cooled to 0 °C. Th e

precipitated product was filtered off an d recrystallized form m eth an ol. Yield 1.01 g (83%).

For C₂₉H₂₈N₂O₉S (580.6) calculated: 59.99% C, 4.86% H, 4.82% N; foun d: 60.21% C, 4.98% H,

4.69% N; wh ite crystals; m .p. 228–230 °C (m eth an ol). ¹H NMR (300 MHz, CDCl₃): 1.68 s, 3 H

(CH₃); 2.03 s, 3 H (CH₃); 2.09 s, 3 H (CH₃); 2.10 s, 3 H (CH₃); 4.05 m , 1 H (H-5′); 4.19 dd, 1 H,

J(6′,6′′) = 12.5, J(5′,6′) = 2.5 (H-6′); 4.34 dd, 1 H, J(6′,6′′) = 12.5, J(5′,6′′) = 4.9 (H′-6′); 5.33 t, 1 H,

J = 9.6; 5.48 t, 1 H, J = 9.3 an d 5.58 t, 1 H, J = 9.1 (H-2′–H-4′); 5.71 d, 1 H, J(1′,2′) = 8.9

(H-1′); 7.33–7.39 m , 3 H; 7.46–7.52 m , 2 H; 7.89 d, 1 H, J = 8.0; 8.06 d, 2 H, J = 8.3 an d

8.48 m , 1 H (H arom .). ¹³C NMR (75 MHz, CDCl₃): 20.11, 20.63, 20.78 (CH₃CO); 61.86

(C-6′); 68.05, 70.75, 73.16, 75.08 (C-2′–C-5′); 83.65 (C-1′); 110.35, 113.57, 121.37, 121.96,

122.40, 122.72, 123.91, 124.62, 126.06, 126.23, 126.76, 133.75, 136.66, 153.80, 162.11

(C arom .); 168.69, 169.41, 170.18, 170.65 (CH₃CO). EI MS, m/z (%): 580 [M]⁺(5), 331 (5),

250 (42), 169 (38), 109 (25), 43 (100).

1-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyran osyl)-3-(1,3-ben zoth iazol-2-yl)-1H-in dole (8b)

1-Galactopyran osylin dole-3-carbaldeh yde 6b (0.388 g, 0.789 m m ol) was dissolved in m eth -

an ol (5 m l) an d 2-am in oben zen eth iol ( 0.197 g, 0.168 m l, 1.57 m m ol) an d 1 drop of 36% HCl

were added. Th e reaction m ixture was stirred at room tem perature for 15 m in , n eutralized

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Humeník, Dzurilla, Kutschy, Solčániová, Kováčik, Bekešová:

with several drops of 28% aqueous solution of NH₄OH, con cen trated un der reduced pressure

an d th e residue was subjected to colum n ch rom atograph y (cycloh exan e–eth yl acetate 1:1).

Yield 0.450 g (94%). For C₂₉H₂₈N₂O₉S (580.6) calculated: 59.99% C, 4.86% H, 4.82% N;

foun d: 59.82% C, 4.64% H, 5.08% N; wh ite crystals; m .p. 169–170 °C (m eth an ol). ¹H NMR

(300 MHz, CDCl₃): 1.69 s, 3 H (CH₃); 2.02 s, 3 H (CH₃); 2.05 s, 3 H (CH₃); 2.32 s, 3 H (CH₃);

4.18–4.27 m , 3 H (H-5′, H-6′, H′-6′); 5.31 dd, 1 H, J(2′,3′) = 9.6, J(3′,4′) = 3.1 (H-3′); 5.60 d,

1 H, J(3′,4′) = 3.1 (H-4′); 5.64 d, 1 H, J(1′,2′) = 9.2 (H-1′); 5.77 t, 1 H, J(1′,2′) = 9.2, J(2′,3′) =

9.6 (H-2′); 7.33–7.39 m , 3 H; 7.49 t, 1 H, J = 8.0; 7.57 m , 1 H; 7.89 d, 1 H, J = 7.9; 8.07 d,

1 H, J = 8.1; 8.13 bs, 1 H an d 8.44 m , 1 H (H arom .). ¹³C NMR (75 MHz, CDCl₃): 20.19,

20.60, 20.71, 20.87 (CH₃CO); 61.86 (C-6′); 67.21, 68.22, 71.32, 73.84 (C-2′–C-5′); 84.38

(C-1′); 110.60, 113.18, 121.38, 121.76, 122.27, 122.67, 123.83, 124.59, 126.06, 126.28,

127.21, 133.72, 136.59, 153.11, 162.25 (C arom .); 168.70, 170.06, 170.16, 170.45 (CH₃CO).

EI MS, m/z (%): 580 [M]⁺(9), 331 (3), 250 (50), 169 (43), 109 (35), 43 (100).

1-(2,3,4,6-Tetra-O-acetyl-α-D-m an n opyran osyl)-3-(1,3-ben zoth iazol-2-yl)-1H-in dole (8c)

Com poun d 8c was prepared accordin g to th e procedure for syn th esis of 1-galactopyran osyl-

ben zocam alexin 8b. Yield 81%. For C₂₉H₂₈N₂O₉S (580.6) calculated: 59.99% C, 4.86% H,

4.82% N; foun d: 60.12% C, 4.71% H, 4.98% N; wh ite crystals; m .p. 133–135 °C (m eth an ol).

¹H NMR (300 MHz, CDCl₃): 2.04 s, 3 H (CH₃); 2.09 s, 3 H (CH₃); 2.15 s, 3 H (CH₃); 2.18 s, 3 H

(CH₃); 3.80 m 1 H, (H-5′); 4.09 dd, 1 H, J(6′,6′′) = 12.5, J(5′,6′) = 2.6 (H-6′); 4.49 dd, 1 H,

J(6′,6′′) = 12.5 J(5′,6′′) = 6.7 (H′-6′); 5.40 t, 1 H, J(3′,4′) = J(4′,5′) = 8.3 (H-4′); 5.54 dd, 1 H,

J(3′,4′) = 8.4, J(2′,3′) = 3.2 (H-3′); 6.07 d, 1 H, J(1′,2′) = 3.5 (H-1′); 6.11 t, 1 H, J(1′,2′) = 3.5,

J(2′,3′) = 3.3 (H-2′); 7.32–7.42 bm , 3 H (H-5, H-6, H-5′′); 7.48 dt, 1 H, J(6′′,7′′) = 8.0, J = 1.4

(H-6′′); 7.69 m , 1 H (H-7); 7.89 d, 1 H, J(4′′,5′′) = 8.4 (H-4′′); 8.07 d, 1 H, J(6′′,7′′) = 8.0

(H-7′′); 8.23 s, 1 H (H-2); 8.56 m , 1 H (H-4). ¹³C NMR (75 MHz, CDCl₃): 20.91, 20.95, 20.97,

20.98 (CH₃CO); 61.52 (C-6′); 66.09 (C-4′); 67.58 (C-2′); 70.07 (C-3′); 72.06 (C-5′); 81.85

(C-1′); 112.20 (C-7); 114.17 (C-3); 121.50 (C-4′′); 122.13 (C-4); 122.79 (C-7′′); 123.03 (C-5);

124.26 (C-6); 124.71 (C-5′′); 126.19 (C-6′′); 126.34 (C-3a); 126.82 (C-2); 134.09 (C-7′′a);

137.33 (C-7a); 154.25 (C-3′′a); 162.02 (C-2′′); 169.61, 169.78, 170.60, 170.63 (CH₃CO). Dif-

feren ce NOE spectra (CDCl₃): irradiated at δ 6.07 (H-1′) en h an ced sign als (H-2, 9.0%), (H-7,

5.7%); irradiated at δ 6.11 (H-2′) en h an ced sign als (H-3′, 1.3%), (H-2, 9.0%), (H-7, 5.9%);

irradiated at δ 5.54 (H-3′) en h an ced sign als (H-5′, 7.7%), (H-2, 13.7%); irradiated at δ 5.40

(H-4′) en h an ced sign als (H-5′, 5.2%), (H-2, 5.9%); irradiated at δ 3.80 (H-5′) en h an ced sig-

n als (H-3′, 4.9%), (H-4′, 4.9%), (H-6′, 0.9%). EI MS, m/z (%): 580 [M]⁺(5), 331 (3), 250 (30),

169 (27), 109 (25), 43 (100).

1-(2,3,4,6-Tetra-O-acetyl-β-D-m an n opyran osyl)-3-(1,3-ben zoth iazol-2-yl)-1H-in dole (8d )

Com poun d 8d was prepared accordin g to th e procedure for syn th esis of 1-galactopyran osyl-

ben zocam alexin 8b. Yield 73%. For C₂₉H₂₈N₂O₉S (580.6) calculated: 59.99% C, 4.86% H,

4.82% N; foun d: 60.09% C, 4.66% H, 4.75% N; wh ite crystals; m .p. 188–189 °C (m eth an ol).

¹H NMR (300 MHz, CDCl₃): 2.00 s, 3 H (CH₃); 2.04 s, 3 H (CH₃); 2.11 s, 3 H (CH₃); 2.13 s, 3 H

(CH₃); 4.02 m , 1 H (H-5′); 4.28 dd, 1 H, J(6′,6′′) = 12.3, J(5′,6′) = 2.2 (H-6′); 4.39 dd, 1 H,

J(6′,6′′) = 12.3, J(5′,6′′) = 6.1 (H′-6′); 5.36 dd, 1 H, J(3′,4′) = 10.0, J(2′,3′) = 3.0 (H-3′); 5.45 t, 1 H,

J(3′,4′) = J(4′,5′) = 10.0 (H-4′); 5.61 dd, 1 H, J(1′,2′) = 1.1, J(2′,3′) = 3.3 (H-2′); 5.94 d, 1 H,

J(1′,2′) = 1.1 (H-1′); 7.31–7.38 bm , 3 H (H-5, H-6, H-5′′); 7.42–7.50 bm , 2 H (H-7, H-6′′); 7.88

d, 1 H, J(4′′,5′′) = 8.1 (H-4′′); 8.04 d, 1 H, J(6′′,7′′) = 8.1 (H-7′′); 8.07 s, 1 H (H-2); 8.48 m , 1 H

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(H-4). ¹³C NMR (75 MHz, CDCl₃): 20.81, 20.91, 20.98, 21.07 (CH₃CO); 62.76 (C-6′); 65.57

(C-4′); 69.19 (C-2′); 71.32 (C-3′); 75.99 (C-5′); 82.31 (C-1′); 110.06 (C-7); 113.086 (C-3);

121.43 (C-4′′); 122.05 (C-4); 122.59 (C-7′′); 122.70 (C-5); 123.89 (C-6); 124.58 (C-5′′); 125.81

(C-3a); 126.24 (C-6′′); 127.34 (C-2); 133.95 (C-7′′a); 135.68 (C-7′a); 154.14 (C-3′′a); 162.24

(C-2′′); 169.47, 169.74, 170.14, 170.78 (CH₃CO). Differen ce NOE spectra (CDCl₃): irradiated

at δ 5.94 (H-1′) en h an ced sign als (H-2′, 3.7%), (H-3′, 3.0%), (H-5′, 11.2%), (H-7, 12.9%),

(H-2, 4.6%); irradiated at δ 5.61 (H-2′) en h an ced sign als (H-1′, 4.0%), (H-2, 2.6%), (H-7,

2.2%); irradiated at δ 5.45 (H-4′) en h an ced sign als (H-5′, 6.5%), (H-2, 2.7%), (H-7, 3.3%); ir-

radiated at δ 4.02 (H-5′) en h an ced sign als (H-1′, 9.2%), (H-3′, 6.9%), (H-4′, 4.0%). EI MS, m/z

(%): 580 [M]⁺(7), 250 (42), 169 (28), 109 (28), 43 (100).

1-(2,3,5-Tri-O-ben zoyl-β-D-ribofuran osyl)-3-(1,3-ben zoth iazol-2-yl)-1H-in dole (8e)

Yield 81%. For C₄₁H₃₀N₂O₇S (694.8) calculated: 70.88% C, 4.35% H, 4.03% N; foun d:

71.06% C, 4.59% H, 3.92% N; pale yellow crystals; m .p. 167–168 °C (m eth an ol). ¹H NMR

(300 MHz, CDCl₃): 4.77 dd, 1 H, J(5′,5′′) = 12.2, J(4′,5′) = 3.2 (H-5′); 4.84 m , 1 H (H-4′); 4.93

dd, 1 H, J(5′,5′′) = 12.2, J(4′,5′′) = 2.6 (H′-5′); 6.02 t, 1 H, J(2′,3′) = J(3′,4′) = 5.7 (H-3′); 6.06 t,

1 H, J(2′,3′) = 5.7, J(1′,2′) = 5.5 (H-2′); 6.51 d, 1 H, J(1′,2′) = 5.5 (H-1′); 7.22–7.59 bm , 13 H

(H arom .); 7.65 d, 1 H, J = 8.2 (H-7); 7.82 d, 1 H, J = 7.8 (H-4′′); 7.94–8.00 m , 5 H (H-7′′ an d

4 H of OBz); 8.10 s, 1 H (H-2); 8.15–8.18 m , 2 H (OBz); 8.47 d, 1 H, J = 7.7 (H-4). ¹³C NMR

(75 MHz, CDCl₃): 63.92 (C-5′); 71.50 (C-3′); 74.64 (C-2′); 80.66 (C-4′); 88.11 (C-1′); 110.58

(C-7); 113.85 (C-3); 121.36 (C-4′′); 122.12 (C-4); 122.63 (C-7′′); 122.70 (C-5); 124.00 (C-6);

124.49 (C-5′′); 126.06 (C-2); 126.10 (C-6′′); 126.53 (C-3a); 128.71, 128.72, 128.91, 129.50,

129.97, 130.00, 133.59, 133.91 (OBz); 134.16 (C-7′′a); 136.61(C-7a); 154.10 (C-3′′a); 162.18

(C-2′′); 165.16, 165.44, 165.40 (CH₃CO). Differen ce NOE spectra (CDCl₃): irradiated at δ 6.51

(H-1′) en h an ced sign als (H-2′ an d H-3′, 5.7%), (H-4′, 6.2%), (H-2, 8.0%), (H-7, 14.0%); irradi-

ated at δ 6.06 (H-2′ an d H-3′) en h an ced sign als (H-1′, 4.8%), (H-4′, 3.2%), (H-5′, 4.3%),

(H′-5′, 3.3%); irradiated at δ 4.84 (H-4′) en h an ced sign als (H-1′, 4.0%), (H-2′ an d H-3′, 7.0%).

EI MS, m/z (%): 694 [M]⁺(4), 445 (16), 249 (16), 201 (29), 105 (100) 77 (23).

1-(β-D-Glucopyran osyl)-3-(1,3-ben zoth iazol-2-yl)-1H-in dole (9a)

1-Glucopyran osylben zocam alexin 8a (0.1 g, 0.172 m m ol) was dissolved in 20 m l of dry

m eth an ol an d a catalytic am oun t of fin e powdered K₂CO₃(2.5 m g, 0.0172 m m ol) was

added. Th e reaction m ixture was stirred for 4 h , filtered th rough a sh ort colum n of silica gel

an d evaporated to dryn ess. Th e residue was recrystallized from a m ixture of m eth an ol–dieth yl

eth er. Yield 0.07 g (99%). For C₂₁H₂₀N₂O₅S (412.5) calculated: 61.15% C, 4.89% H, 6.79% N;

foun d: 61.31% C, 5.13% H, 6.92% N; pale yellow solid; m .p. >300 °C decom position (m eth -

an ol–dieth yl eth er). ¹H NMR (300 MHz, DMSO-d₆): 3.41 t, 1 H, J = 9.0; 3.50 d, 1 H, J = 8.7;

3.56 m , 2 H; 3.75 m , 1 H an d 3.89 t, 1 H, J = 8.9 (H sacch aride, H-2′–H-6′); 4.14 bs, 4 H

(CD₃COOD exch an geable, 4 × OH); 5.59 d, 1 H, J = 9.0 (H-1′); 7.30–7.34 bm , 2 H; 7.39 td, 1

H, J = 8.0, 1.2; 7.50 td, 1 H, J = 8.2, 1.2; 7.74 m , 1 H; 8.00 d, 1 H, J = 8.1; 8.06 d, 1 H, J = 7.5;

8.37 s, 1 H an d 8.45 m , 1 H (H arom .). ¹³C NMR (75 MHz, DMSO-d₆): 60.98 (C-6′); 69.84,

71.87, 77.41, 79.63 (C-2′–C-5′); 85.23 (C-1′); 110.62, 111.97, 120.96, 121.64, 121.74, 123.03, 124.45,

125.22, 126.21, 129.53, 133.11, 136.90, 153.54, 162.38 (C arom .). MS MALDI-TOF, m/z (%):

435 [M + Na]⁺(54), 413 [M + H]⁺(79).

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1-(β-D-Galactopyran osyl)-3-(1,3-ben zoth iazol-2-yl)-1H-in dole (9b)

Com poun d 9b was prepared accordin g to th e procedure for syn th esis of 1-glucopyran osyl-

ben zocam alexin 9a. Yield 96%. For C₂₁H₂₀N₂O₅S (412.5) calculated: 61.15% C, 4.89% H,

6.79% N; foun d: 61.28% C, 4.67% H, 6.69% N; pale yellow solid; m .p. >300 °C decom posi-

tion (m eth an ol–dieth yl eth er). ¹H NMR (300 MHz, DMSO-d₆): 3.58 m , 3 H; 3.76 t, 1 H, J =

5.9; 3.84 d, 1 H, J = 2.4 an d 4.17 t, 1 H, J = 9.1 (H sacch aride, H-2′–H-6′); 4.64 bs, 2 H

(CD₃COOD exch an geable, 2 × OH); 5.08 bs, 1 H (CD₃COOD exch an geable, OH); 5.28 bs, 1 H

(CD₃COOD exch an geable, OH); 5.49 d, 1 H, J = 8.7 (H-1′); 7.28–7.34 bm , 2 H; 7.38 td, 1 H, J =

7.5, 0.6; 7.50 td, 1 H, J = 8.1, 1.1; 7.81 m , 1 H; 7.99 d, 1 H, J = 8.1; 8.08 d, 1 H, J = 7.5; 8.38 s,

1 H an d 8.42 m , 1 H (H arom .). ¹³C NMR (75 MHz, DMSO-d₆): 60.62 (C-6′); 68.62, 69.11,

74.05, 78.07 (C-2′–C-5′); 86.55 (C-1′); 110.34, 112.42, 120.97, 121.63, 121.68, 121.74, 122.92,

124.47, 125.36, 126.25, 130.07, 133.06, 136.55, 153.67, 162.35 (C arom .). MS MALDI-TOF,

m/z (%): 435 [M + Na]⁺(89), 413 [M + H]⁺(69).

1-(α-D-Man n opyran osyl)-3-(1,3-ben zoth iazol-2-yl)-1H-in dole (9c)

Com poun d 9c was prepared accordin g to th e procedure for syn th esis of 1-glucopyran osyl-

ben zocam alexin 9a. Yield 93%. For C₂₁H₂₀N₂O₅S (412.5) calculated: 61.15% C, 4.89% H,

6.79% N; foun d: 61.38% C, 5.11% H, 6.99% N; pale yellow solid; m .p. >300 °C decom posi-

tion (m eth an ol–dieth yl eth er). ¹H NMR (300 MHz, DMSO-d₆): 3.67 m , 1 H; 3.79 m , 2 H;

3.99 m , 2 H; 4.42 bs, 4 H (CD₃COOD exch an geable, 4 × OH); 4.45 t, 1 H, J = 8.7 (H

sacch aride, H-2′–H-6′); 5.49 d, 1 H, J = 2.8 (H-1′); 7.23–7.41 bm , 3 H; 7.53 m , 1 H; 7.80 m , 1 H;

8.01 d, 1 H, J = 7.8; 8.06 d, 1 H, J = 7.8; 8.36 s, 1 H an d 8.43 m , 1 H (H arom .). ¹³C NMR

(75 MHz, DMSO-d₆): 60.58 (C-6′); 66.74, 69.83, 72.23, 80.56 (C-2′–C-5′); 80.70 (C-1′);

110.73, 112.89, 121.37, 121.62, 121.73, 123.41, 124.89, 125.83, 126.68, 130.29, 133.53,

137.29, 154.11, 162.84 (C arom .). MS MALDI-TOF, m/z (%): 435 [M + Na]⁺(56), 413 [M +

H]⁺(100).

1-(β-D-Man n opyran osyl)-3-(1,3-ben zoth iazol-2-yl)-1H-in dole (9d )

Com poun d 9c was prepared accordin g to th e procedure for syn th esis of 1-glucopyran osyl-

ben zocam alexin 9a. Yield 91%. For C₂₁H₂₀N₂O₅S (412.5) calculated: 61.15% C, 4.89% H,

6.79% N; foun d: 61.25% C, 5.20% H, 7.05% N; pale yellow solid; m .p. >300 °C decom posi-

tion (m eth an ol–dieth yl eth er). ¹H NMR (300 MHz, DMSO-d₆): 3.53 m , 1 H; 3.55–3.63 bm ,

2 H; 3.73 dd, 1 H, J = 9.2, 3.2; 3.79 t, 1 H, J = 11.4 an d 3.96, dd, 1 H, J = 7.5, 2.0

(H sacch aride, H-2′–H-6′); 4.01 bs, 4 H (CD₃COOD exch an geable, 4 × OH); 5.96 s, 1 H (H-1′);

7.28–7.41 bm , 3 H; 7.51 m , 1 H; 7.75 m , 1 H; 7.99 d, 1 H, J = 7.8; 8.05 d, 1 H, J = 7.2;

8.42 m , 1 H an d 8.51 s, 1 H (H arom .). ¹³C NMR (75 MHz, DMSO-d₆): 61.15 (C-6′); 66.47,

70.55, 73.54, 80.36 (C-2′–C-5′); 82.37 (C-1′); 109.98, 111.32, 120.76, 121.59, 121.68, 121.74,

122.90, 124.27, 124.44, 126.24, 130.54, 132.94, 136.17, 153.64, 162.39 (C arom.). MS MALDI-TOF,

m/z (%): 435 [M + Na]⁺(71), 413 [M + H]⁺(100).

1-(β-D-Ribofuran osyl)-3-(1,3-ben zoth iazol-2-yl)-1H-in dole (9e)

Com poun d 8e (0.690 g, 0.993 m m ol) was dissolved in dry m eth an ol (20 m l) an d 1 M solu-

tion of sodium m eth oxide in dry m eth an ol (7 m l) was added dropwise. Th e reaction m ix-

ture was stirred at room tem perature overn igh t, n eutralized with Am berlite IR 120 (H⁺) an d

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1-Glycosyl Derivatives of Benzocamalexin

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filtered th rough silica gel. Meth an ol was evaporated un der reduced pressure an d th e residue

was recrystallized from m ixture m eth an ol–dieth yl eth er. Yield 0.295 (78%). For

₂₀H₁₈N₂O₄S (382.4) calculated: 62.81% C, 4.74% H, 7.33% N; foun d: 63.08% C, 4.55% H,

a

g

C

7.48% N; pale yellow solid; m .p. 284–286 °C (m eth an ol–dieth yl eth er). ¹H NMR (300 MHz,

DMSO-d₆): 3.66 dd, 1 H, J(5′,5′′) = 11.9, J(4′,5′) = 3.4 (H-5′); 3.75 dd, 1 H, J(5′,5′′) = 11.9,

J(4′,5′′) = 3.3 (H′-5′); 4.05 m , 1 H; 4.16 t, 1 H, J(2′,3′) = 4.3 (H-3′); 4.37 t, 1 H, J = 5.5 (H-2′);

4.60–5.80 bs, 3 H (D₂O exch an geable, 3 × OH); 6.0 d, 1 H, J(1′,2′) = 5.8, 7.33–7.44 bm , 3 H

(H-6′′, H-6, H-5); 7.54 t, 1 H, J = 8.2 (H-5′′); 7.77 m , 1 H (H-7); 8.02 d, 1 H, J = 7.9 (H-4′′);

8.08 d, 1 H, J = 7.7 (H-7′′); 8.43 m , 1 H (H-4); 8.56 s, 1 H (H-2). ¹³C NMR (75 MHz,

DMSO-d₆): 61.47 (C-5′); 70.41 (C-3′); 74.77 (C-2′); 85.54 (C-4′); 89.45 (C-1′); 111.39 (C-7);

111.80 (C-3); 121.43 (C-4′′); 122.25 (C-4); 122.32 (C-7′′); 122.62 (C-5); 123.92 (C-6); 125.15

(C-5′′); 125.71 (C-3a); 126.90 (C-6′′); 128.80 (C-2); 133.50 (C-7′′a); 136.95 (C-7a); 153.93

(C-3′′a); 162.85 (C-2′′). MS MALDI-TOF, m/z (%): 405 [M + Na]⁺(28), 383 [M + H]⁺(100).

We thank the Grant Agency for Science, Slovak Republic for financial support of this work (grant

No. 1/9246/02) and we are grateful to NCI (National Cancer Institute, Bethesda, U.S.A.) for evalua-

tion of cytotoxic potency of our compounds on human cell lines.

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Lett . 1985 , 26 , 4011; b) Kaneko T., Clardy J., Wong. H., Okamoto T. K.: Tetrahedron Lett .

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Article Doi

Synthesis of 1-glycosyl derivatives of benzocamalexin

DOI: 10.1135/cccc20041657

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