Ali 2014 Tetrahedron-Letters

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Isolation, characterization, and NMR spectroscopic data of indole

and oxindole alkaloids from Mitragyna speciosa

Zulfiqar Ali a, Hatice Demiray a,c, Ikhlas A. Khan a,b,

a National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, USAb Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, University, MS 38677, USAc Ege University, Faculty of Science, Biology Department, Izmir 35100, Turkey

a r t i c l e i n f o

Article history:

Received 19 September 2013

Revised 4 November 2013

Accepted 10 November 2013

Available online 16 November 2013

Keywords:

Mitragyna speciosa

Rubiaceae

Indole/oxindole

7b-Hydroxy-7H-mitraciliatine

Isospeciofoleine

a b s t r a c t

A newindole alkaloid, 7b-hydroxy-7H-mitraciliatine (1) and a new oxindole alkaloid, isospeciofoleine (2)

together with nine known alkaloids were isolated from Mitragyna speciosaand characterized by NMR, CD,

and MS spectroscopic data analyses. The 1H and 13C NMR spectroscopic data of isospeciofoline (3), isorot-

undifoline (4), paynantheine (5), and 3-isopaynantheine (6) were also reported for the first time.

2013 Elsevier Ltd. All rights reserved.

Mitragyna speciosa Korth (Rubiaceae), endemic to tropicalSoutheast Asia, has opium-like effects and coca-like stimulancy.

Traditionally, M. speciosa has been used as a remedy to cure diar-

rhea, cough, muscular pain and fatigue. M. speciosa is also fre-

quently used by drug addicts seeking relief during opioid

withdrawal stage.14 A number of chemical and pharmacological

studies have been carried out on this plant and many indole and

oxindole alkaloids have been reported.1 The present phytochemical

study on M. speciosa leaves, aimed at the discovery of alkaloids

with interesting skeletons, resulted in the isolation of 11 indole

and oxindole alkaloids including two previously undiscovered

compounds. Structure elucidation of these alkaloids was achieved

by NMR, CD, and MS spectroscopic data analyses. The structures

of16 are shown inFigure 1.

An alkaloid enriched fraction from the methanol extract of theleaves of M. speciosa5 was fractionated using silica gel

(2200 1.500) column chromatography (CC) with gradients of CHCl3/

MeOH into 16 fractions (Frs. 116). Frs. 24 were combined (2.7 g)

and subjected to CC [silica gel (3600 100), hexanes/acetone/NH4OH,

(208:90:1)] to isolate mitragynine (1.7 g). Fr. 5 (2.4 g) was divided

into nine subfractions (Frs. 5A5I) using CC [silica gel (40 00 1.500),

hexanes/acetone, (7:3)]. Corynoxine B (14 mg) was purified from

fraction 5E (501 mg) along with an impure material (Fr. 5EA) by

CC [silica gel (3500 0.7500), hexanes/acetone/NH4OH, (208:90:1)].

Compound5 (108 mg) was obtained as an upper band from pre-parative thin layer chromatography (PTLC) [silica gel plate

(0.5 mm), hexanes/acetone/NH4OH, (208:90:1)] of fraction 5EA.

The contents of the lower band were applied to PTLC [silica gel

plate (0.5 mm), CHCl3/EtOAc (7:3)], followed by reverse phased

HPLC [C-18 silica, MeOH/H2O, 65:35] to purify compounds 2

0040-4039/$ - see front matter 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.tetlet.2013.11.031

Corresponding author. Tel.: +1 662 9157821; fax: +1 662 9157989.

E-mail addresses:[email protected](Z. Ali),[email protected](I.A. Khan).

N N

OMeMeO

O

OMe

H

OH

7-Hydroxy-7H-mitraciliatine (1)

NH

N

OMeMeO

O

H

O

OH

NH

N

OMeMeO

O

OMe

H

NH

N

OMeMeO

O

OMe

H

NH

N

OMeMeO

O

H

O

OH

Paynantheine (5) 3-Isopaynantheine (6)

Isospeciofoline (3),Isospeciofoleine (2)

1

23

4

5

6

789

10

11

1213

14 15

16

17

1819

20

21

22

1 2

3

4

5

6

789

10

11

1213

14 15

16

17

18

19

20

21

22

Isorotundifoline (4)

NH

N

OMeMeO

O

H

O

OH

Figure 1. Structures of alkaloids 16.

Tetrahedron Letters 55 (2014) 369372

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Tetrahedron Letters

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(2 mg),3 (11 mg), and4 (77 mg). Speciogynine (45 mg) was puri-

fied by PTLC [silica gel plate (0.5 mm), hexanes/acetone/NH4OH,

(208:90:1)] of fraction 5I. Speciociliatine (650 mg) and corynoxine

(44 mg) were obtained from fractions 7 and 8 by CC [silica gel

(3600 100), CHCl3/MeOH (49:1)] followed by PTLC [silica gel plate

(0.5 mm), hexanes/acetone/NH4OH, (180:120:1)]. Compound 6

(28 mg) was obtained from fraction 8 by CC [silica gel (40

0.75), hexanes/acetone/NH4OH, (180:120:1)] and compound 1

(17 mg) was purified from fractions 10 and 11 (138 mg) by PTLC

[silica gel plate (0.5 mm), CHCl3/MeOH/NH4OH, (28:15:1)].Compound 16 was obtained as a yellow solid (a22D 149.0 (c

0.13, MeOH)). The molecular formula of compound1 was inferred

to be C23H30N2O5 from a protonated ion [M+H]+ atm/z415.2224 in

the HR-ESI-ToF-MS (calcd for C23H31N2O5, 415.2233). The UV spec-

trum showed absorptions at 291, 240, and 220 nm. The IR spec-

trum exhibited absorption due to conjugated ester carbonyl

function at 1700 cm1. The 13C NMR spectrum exhibited 23 reso-

nances which were differentiated as four methyl, five methylene,

seven methine, and seven quaternary carbons. The characteristic

resonances for three methoxy groups [dH/dC 3.83 (s)/55.5

(9-OCH3), 3.81 (s)/61.6 (17-OCH3), and 3.69 (s)/51.4 (22-OCH3)],

a primary methyl [dH/dC 0.71 (t,J= 7.2 Hz)/11.2 (CH3-18)], an oxy-

genated olefinic bond in conjugation with the oxo group [dH/dC

7.34 (s)/160.1 (CH-17) and dC 112.1 (C-16)], and an iminic quater-nary carbon [dC182.9 (C-2)] were found in the

1H and/or 13C NMR

spectra. The resonances for a 1,2,3-trisubstituted phenyl ring with

an ABC spin system [dH/dC 6.70 (br d, J= 8.0 Hz)/108.8 (CH-10),

7.27 (t, J= 8.0 Hz)/130.6 (CH-11), 7.21 (br d, J= 8.0 Hz)/114.3

(CH-12), dC126.5 (C-8), 155.9 (C-9), and 154.6 (C-13)] and an oxy-

genated quaternary carbon [dC82.1 (C-7)] along with five aliphatic

methylenes and three aliphatic methines were also observed. The1H and 13C NMR data (See Tables 1 and 2) were assigned with

the help of HSQC, 1H1H COSY, and HMBC (Fig. 2) spectra. NMR

data analyses showed that1 had the same planer structure as that

of 7-hydroxyspeciocilliatine.7 Literature reports indicated that the13C NMR resonances of an ethyl group were the key to determining

the configuration at C-20. The reported 13C NMR resonances of the

ethyl group are dC

18.920.5 (C-19) and dC

12.613.3 (C-18) for

C-20 S anddC 24.224.4 (C-19) and dC 11.211.3 (C-18) for C-20

R.7,8 Based on the chemical shifts of C-20 ethyl group [dC 24.2

(C-19) and dC 11.2 (C-18)], the configuration at C-20 in 1 was as-

signed to beR. The CD spectrum of1 (Fig. 3) showed negative cot-

ton effects at 316, 272 and 216 nm and found to be partially

comparable to that of 7-hydroxyspeciociliatine, for which negative

cotton effects at 307 and 256 nm and positive cotton effect at

230 nm were reported.7 The reverse cotton effects at lower absor-

bance could be due to the opposite configurations at C-20 in1and

7-hydroxyspeciociliatine. 7 Consequently, the structure of 7b-hy-

droxy-7H-mitraciliatine (1) was established as shown in Figure 1.Compound29 was obtained as a yellow solid (a27D 38 (c0.05,

MeOH)). The molecular formula of compound 2 was inferred to

be C22H26N2O5 from a protonated ion [M+H]+ atm/z399.1913 in

the HR-ESI-ToF-MS (calcd for C22H27N2O5, 399.1920). The UV spec-

trum showed absorptions at 290, 239, and 220 nm. The absorp-

tions in the IR spectrum at 1623 and 1706 cm1 supported the

amide carbonyl and conjugated ester carbonyl functions. The 13C

NMR spectrum displayed 22 resonances, which were differentiated

as two methyl, five methylene, eight methine, and seven quater-

nary carbons. The 1H and/or 13C NMR spectra of2 showed charac-

teristic resonances for two methoxy groups [dH/dC 3.70 (s)/61.4

(17-OCH3) and 3.59 (s)/51.0 (22-OCH3)], an oxygenated olefinic

bond adjacent to an oxo group [dH/dC 7.20 (s)/159.7 (CH-17) and

dC 111.3 (C-16)], and an external double bond [dH/dC 5.50 (dt,J= 18.0, 10.8 Hz)/138.5 (CH-19), 4.98 (br d, J= 18.0 Hz) and 4.95

(br d, J= 10.8 Hz)/116.2 (CH2-18)], a 1,2,3-trisubstituted phenyl

ring [dH/dC 6.57 (br d, J= 8.5 Hz)/111.6 (CH-10), 7.06 (t,

J= 8.5 Hz)/129.4 (CH-11), 6.41 (br d, J= 8.5 Hz)/101.0 (CH-12), dC116.6 (C-8), 154.4 (C-9), and 140.6 (C-13)], a conjugated ester car-

bonyl carbon [dC 168.2 (C-22)], and an amide carbonyl carbon [dC179.2 (C-2)]. The 1H and 13C NMR data assignment (See Tables 1

and 2) was done by analyses of the HSQC, 1H1H COSY, and HMBC

(Fig. 2) spectra. When the NMR spectroscopic data of2 were com-

pared with those of isospeciofoline (3), the resonances for an ethyl

group were found missing in 2 showing instead for an external

double bond. The sharp signals at dH 11.86 and dH 11.74 in the1H NMR spectra of2 and3 indicated a non-acidic phenol because

of intramolecular hydrogen bonding between C-9 hydroxyl and

lone pair of N-4 (Fig. 4), which ultimately supported the S

Table 11H NMR spectroscopic dataa for compounds 16 (500 MHz, d in ppm, CDCl3)

No. 1 2 3 4 5 6

dH, mult. (Jin Hz) dH, mult. (Jin Hz) dH, mult. (Jin Hz) dH, mult. (Jin Hz) dH, mult. (Jin Hz) dH, mult. (Jin Hz)

3 4.24, d (5.5) 2.69, br d (11.4) 2.61, br d (11.3) 3.01, dd (12.0, 2.9) 3.23, br d (10.7) 4.44, br s

5 3.51, br t (14.1)

2.70, br d (14.1)

3.42, br t (9.8)

2.61

3.42, t d (9.0, 2.5)

2.58, br t (9.0)

3.35, t d (9.1, 3.0)

2.61, m

3.07

2.57, d t (11.0, 5.6)

3.22

6 2.49, br d (14.1)

2.01, t d (14.1, 4.1)

2.43, br t (12.1)

2.18

2.43, br t (10.3)

2.21

2.35, ddd (13.7, 10.7, 3.2)

2.06, d t (13.2, 8.5)

3.17, m

2.99

3.18

2.84, br d (14.5)10 6.70, br d (8.0) 6.57, br d (8.5) 6.60, br d (8.0) 6.46, br d (7.9) 6.45, br d (7.9) 6.47, br d (7.9)

11 7.27, t (8.0) 7.06, t (8.5) 7.08, t (8.0) 6.97, t (7.9) 6.99, t (7.9) 7.02, t (7.9)

12 7.21, br d (8.0) 6.41, br d (8.5) 6.43, br d (8.0) 6.31, br d (7.9) 6.87, br d (7.9) 6.95, br d (7.9)

14 2.37, t d (13.1, 5.9)

2.09

1.69

1.38

2.14

1.26

1.43, t d (13.1, 12.3, 6.7)

1.35, br d (13.5)

2.09, q (12.1)

1.96, d t (12.6, 3.3)

2.45, t d (13.6, 5.7)

1.99, br d (13.6)

15 3.03, br t (11.9) 2.61 2.92, d t (13.1, 2.8) 3.21, t (6.3) 2.75, t d (11.8, 3.8) 2.36, br t (12.5)

17 7.34, s 7.20, s 7.32, s 7.32, s 7.33, s 7.26, s

18 0.71, t (7.2) 4.98, br d (18.0)

4.95, br d (10.8)

0.90, t (7.0) 0.77, t (7.4) 5.00, dd (17.2, 2.0)

4.96, dd (10.3, 2.0)

4.91, br d (17.8)

4.83, br d (9.8)

19 1.30, m

0.87, m

5.50, dt (18.0, 10.8) 1.66

1.26

1.14 5.58, ddd (17.9, 10.3, 8.0) 5.34, dt (17.8, 9.8)

20 2.03 2.90, m 1.64 1.84, dp (12.5, 6.9) 3.04 2.95, p (8.2)

21 2.44, br d (10.6)

2.06

3.21, br d (10.2)

2.13, t (11.0)

3.32, br d (11.9)

2.36, br d (11.9)

2.96, dd (11.3, 4.8)

2.83, t (11.3)

3.02, br d (10.1)

2.27, br t (11.2)

2.63, br d (7.5)

9-OMe 3.83, s 3.86, s 3.88, s

17-OMe 3.81, s 3.70, s 3.64, s 3.72, s 3.75, s 3.72, s

22-OMe 3.69, s 3.59, s 3.60, s 3.59, s 3.70, s 3.65, sNH 9.01, s 8.67, s 9.09, s 8.18, s 8.19, s

OH 11.86, s 11.74, s

a Overlapped.

370 Z. Ali et al. / Tetrahedron Letters 55 (2014) 369372


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configuration at C-7.10 Furthermore, the comparative analyses of

the CD spectra of2 and isospeciofoline (3)10 supported theR, S,S,

and S, absolute configurations at C-3, C-7, C-15, and C-20, respectively,

due to the positive cotton effects at 293, 243, and 214 nm and negative

cotton effect at 262 nm (Fig. 3). Finally the structure of 2 was

elucidated as shown inFigure 1and named as isospeciofoleine.

Compounds 36were identified as isospeciofoline (3), isorotun-

difoline (4), paynantheine (5), and 3-isopaynantheine (6) by anal-

yses of their NMR, mass, and CD spectroscopic data and were

found to be reported previously from Mitragyna species.1014

Herein the

1

H and

13

C NMR data of36 are also reported firsttime. Five other known alkaloids were identified as speciogynine,

speciociliatine, corynoxine, corynoxine B, and mitragynine by com-

paring their NMR spectroscopic data with those previously

reported.7,8

Acknowledgments

The authors are thankful for support from The United States

Food and Drug Administration (Grant No. U01-FD004246-01). We

are also grateful to Dr. Bharathi Avula for mass data analyses.

Supplementary data

Supplementary data (general experimental procedures and

1

Hand 13C NMR spectra of1 and2) associated with this article can

1 2

N N

OMeMeO

O

OMeOH

NH

N

OMeMeO

O

OH

O

Figure 2. HMBC (?) and COSY ( ) correlations of1 and 2.

Table 213C NMR spectroscopic data for compounds 16(125 MHz, d in ppm, CDCl3)

No. 1 2 3 4 5 6

dC, mult. dC, mult. dC, mult. dC, mult. dC, mult. dC, mult.

2 182.9, C 179.2, C 180.1, C 179.9, C 133.1, C 130.8, C

3 54.4, CH 68.5, CH 70.5, CH 63.6, CH 60.0, CH 53.9, CH

5 48.8, CH2 53.0, CH2 53.6, CH2 53.4, CH2 53.0, CH2 51.4, CH26 35.3, CH2 34.0, CH2 33.6, CH2 33.7, CH2 23.8, CH2 19.0, CH2

7 82.1, C 56.9, C 57.0, C 57.2, C 107.5, C 107.6, C8 126.5, C 116.6, C 117.0, C 116.6, C 117.4, C 117.9, C

9 155.9, C 154.4, C 154.3, C 154.3, C 154.4, C 154.3, C

10 108.8, CH 111.6, CH 111.5, CH 111.4, CH 99.6, CH 99.5, CH

11 130.6, CH 129.4, CH 129.2, CH 129.3, CH 121.7, CH 121.8, CH

12 114.3, CH 101.0, CH 101.4, CH 101.1, CH 104.4, CH 104.6, CH

13 154.6, C 140.6, C 141.0, C 141.1, C 137.5, C 137.2, C

14 28.2, CH2 28.9, CH2 25.2, CH2 31.4, CH2 33.3, CH2 31.1, CH215 33.7, CH 37.1, CH 38.3, CH 30.9, CH 38.7a, CH 33.9a, CH

16 112.1, C 111.3, C 110.7, C 110.8, C 111.7a, C 111.6, C

17 160.1, CH 159.7, CH 160.6, CH 159.6, CH 159.9, CH 159.7, CH

18 11.2, CH3 116.2, CH2 12.7, CH3 12.1, CH3 115.4, CH2 115.2, CH219 24.2, CH2 138.5, CH 18.8, CH2 24.0, CH2 139.4, CH 139.5, CH

20 39.5, CH 41.8, CH 39.6, CH 38.8, CH 42.7, CH 43.0, CH

21 51.2, CH2 57.3, CH2 54.5, CH2 52.9, CH2 61.3, CH2 51.0, CH222 169.0, C 168.2, C 168.8, C 169.4, C 169.0a, C 168.8, C

9-OMe 55.5, CH3 55.3, CH3 55.2, CH3

17-OMe 61.6, CH3 61.4, CH3 61.3, CH3 61.1, CH3 61.5, CH3 61.4, CH322-OMe 51.4, CH3 51.0, CH3 51.2, CH3 51.5, CH3 51.3, CH3 51.2, CH3

a Broad signal.

Figure 3. CD spectra of1, 2, and3.

Figure 4. Intramolecular hydrogen bonding in compounds 2 and 3.

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be found, in the online version, at http://dx.doi.org/10.1016/

j.tetlet.2013.11.031.

References and notes

1. Takayama, H.Chem. Pharm. Bull.2004, 52, 916928.2. Jansen, K. L.; Prast, C. J.J Psychoactive Drugs 1988, 20, 455457.3. Khor, B.-S.; Amar, J. M. F.; Adenan, M. I.; Shu-Chien, A. C. PLoS One 2011, 6,

e28340.4. Adkins, J. E.; Boyer, E. W.; McCurdy, C. R.Curr. Top. Med. Chem. 2011,11, 1165

1175.

5. An alkaloid enriched fraction (3.7 g) wasobtained by usual acid base treatment

of the methanolic extract (70 g) of the leaves of Mitragyna speciosa (550 g)(Voucher No. 12433).

6. 7b-Hydroxy-7H-mitraciliatine (1).Yellow powder;a22D 149.0 (c0.13, MeOH);UV (MeOH) kmaxnm (loge): 291 (3.37), 240 (3.80), 220 (3.99); IR cm

1: 3491,

1700, 1631, 1593, 1485, 1434, 1270, 1244, 1133, 1107, 1074, 1006; CD (MeOH)

kmaxnm (De): 216 (1.70), 272 (3.49), 316 (1.86);1H NMR: seeTable 1; 13C

NMR: seeTable 2; HR-ESI-ToF-MSm/z: 415.2224 [M+H]+, (calcd 415.2233 forC23H31N2O5).

7. Kitajima, M.;Misawa, K.; Kogure, N.; Said, I. M.; Horie, S.; Hatori, Y.; Murayama,

T.; Takayama, H. J. Nat. Med. 2006, 60, 2835.8. Sakakibara, I.; Takahashi, H.; Terabayashi, S.; Yuzurihara, M.; Kubo, M.; Ishige,

A.; Higuchi, M.; Komatsu, Y.; Okada, M.; Maruno, M.; Biqiang, C.; Jiang, H. X.

Phytomedicine1998, 5, 8386.9. Isospeciofoleine (2).Yellow powder;a27D 38.0 (c0.05, MeOH); UV (MeOH) kmax

nm (loge): 290 (3.18), 239 (3.86), 220 (4.08); IR cm1: 3300, 1706, 1623, 1481,1432, 1279, 1236, 1205, 1145, 1138, 1107; CD (MeOH) kmax nm (De): 214

(8.13), 243 (1.41), 216 (1.21), 293 (0.93); 1H NMR: seeTable 1; 13C NMR: seeTable 2; HR-ESI-ToF-MS m/z: 399.1913 [M+H]+, (calcd 399.1920 forC22H27N2O5).

10. Hemingway, S. R.; Houghton, P. J.; Phillipson, J. D.; Shellard, E. J.Phytochemistry1975, 14, 557563.

11. Shellard, E. J.; Houghton, P. J.; Resha, M. Planta Med.1978, 34, 253263.12. Shellard, E. J.; Houghton, P. J.; Resha, M. Planta Med.1978, 34, 2636.13. Shellard, E. J.; Lala, P. K. Planta Med. 1978, 33, 6369.14. Beckett, A. H.; Shellard, E. J.; Phillipson, J. D.; Lee, C. M. Planta Med. 1966, 14,

277288.

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Ali 2014 Tetrahedron-Letters