Betuligenol derivative with growth inhibition and antifeedant activity

Article abstract of DOI:10.1016/j.bmcl.2004.01.040

The title chiral amine, 3-(4-methoxyphenyl)-1-methylpropylamine 5 has been synthesized from naturally abundant betuligenol 1 in three steps and also in good yield. Furthermore, the versatile intermediate 3 could be manipulated for the preparation of chiral disulphide 7. The amine derivative 5 prepared from (-)-betuligenol showed significant growth inhibition and antifeedant activity.

Full text of DOI:10.1016/j.bmcl.2004.01.040

Bioorganic & Medicinal Chemistry Letters 14 (2004) 1729–1731
Betuligenol derivative with growth inhibition and
antifeedant activity§
Sunil K. Chattopadhyay,* Sachin Srivastava, Koneni V. Sashidhara, Arun K. Tripathi,
Asish K. Bhattacharya and Arvind S. Negi
Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow-226 015, India
Received 14 November 2003; revised 17 January 2004; accepted 19 January 2004
Abstract—The title chiral amine, 3-(4-methoxyphenyl)-1-methylpropylamine 5 has been synthesized fromnaturally abundant
betuligenol 1 in three steps and also in good yield. Furthermore, the versatile intermediate 3 could be manipulated for the preparation
of chiral disulphide 7. The amine derivative 5 prepared from( À)-betuligenol showed significant growth inhibition and antifeedant activity.
# 2004 Elsevier Ltd. All rights reserved.
We have been working1À5 on different parts of Taxus
wallichiana collected fromdifferent parts of India for
the isolation of paclitaxel=(taxol1), its important ana-
logues and precursor 10-deacetyl baccatin III. During
the course of this investigation, we have isolated a
major compound from the leaves of Taxus wallichiana
collected fromKashmir, India, which was identified as
(+)-betuligenol 1.6 We have also isolated (À)-betuloside
and its aglycone (À)-betuligenol fromthe leaves of the
same plant collected from Himachal Pradesh, India.
The absolute configuration at the chiral centre in the
aglycone portion of (À)-betuloside has been found to be
R by X-ray diffraction studies.7 As 1 could be isolated
with a yield of 0.2–0.4% fromthe leaves of T. wall-
ichiana and its chemistry has never been studied; we
have studied its chemistry to prepare some of its inter-
esting derivatives for potential biological activity.
The reaction of (+)-betuligenol 1, [a]2D3 +16ꢀ (c 1,
MeOH), with 48% HBr at 80 ꢀC cleanly produced its
phenolic bromo derivative 2 with a yield of 70%. The
above derivative 2 was then converted into its methyl
ether 3 with dimethyl sulphate in refluxing acetone. As
depicted in Scheme 1, the derivative 3 was found to be a
Scheme 1. Reagents and conditions: (i) HBr (48% aq.), 80 ꢀC, 6 h, 70%; (ii) Me2SO4, K2CO3, acetone, reflux, 4 h, 85%; (iii) NaN3, DMF, 70 ꢀC, 6 h,
80%; (iv) Pd–C (10%), EtOH, H2, rt, overnight, 80%; (v) KSCN, DMF, 60 ꢀC, 4 h, 75%; (vi) LAH, THF, reflux, 8 h, 70%.
Keywords: Taxus wallichiana; Betuligenol; Chiral amine; Synthesis; Antifeedant activity.
§CIMAP Communication No.: 99-87J
* Corresponding author. Tel.: +91-522-2717436; fax: +91-522-2342666; e-mail: sk.chattopadhyay@cimap.res.in
0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.01.040

1730
S. K. Chattopadhyay et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1729–1731
versatile intermediate as it can be manipulated for the
preparation of both chiral amine 5 and disulphide 7
analogues of (+)-betuligenol 1 in good yields.
Acknowledgements
The authors are grateful to the Director, CIMAP,
Lucknow for providing the necessary facilities. The
authors are grateful to the referee for his valuable
comments.
The bromo derivative 3 was converted into the chiral
amine 5 in a two steps reaction sequence which includes
reaction of 3 with sodiumazide in DMF at 60 ꢀC to
formthe azide 4 in 85% yield which was then converted
into the amine 5 through catalytic hydrogenation in
presence of Pd/C in an excellent yield.
References and notes
1. Chattopadhyay, S. K.; Sharma, R. P.; Appendino, G.;
Gariboldi, P. Phytochemistry 1995, 39, 869.
2. Chattopadhyay, S. K.; Sharma, R. P. Phytochemistry
1995, 39, 935.
3. Chattopadhyay, S. K.; Saha, G. C.; Sharma, R. P.;
Kumar, S.; Roy, R. Phytochemistry 1996, 42, 787.
4. Banerjee, S.; Upadhyay, N.; Kukreja, A. K.; Ahuja, P. S.;
Kumar, S.; Saha, G. C.; Sharma, R. P.; Chattopadhyay,
S. K. Planta Medica 1996, 62, 329.
5. Chattopadhyay, S. K.; Kulshrestha, M.; Saha, G. C.;
Sharma, R. P.; Jain, S. P.; Kumar, S. Planta Medica 1996,
62, 482.
6. Chattopadhyay, S. K., Unpublished results; see also:
Rojatkar, S. R.; Sawaikar, D. D.; Sinha, B.; Ravin-
dranathan, T.; Nagasampagi, B. A. Phytochemistry 1995,
39, 259.
7. Parmar, V. S.; Vardhan, A.; Taneja, P.; Sinha, R.; Pat-
naik, G. K.; Tripathi, S. C.; Ball, P. M.; Larsen, S. J.
Chem. Soc., Perkin Trans. 1 1991, 2687.
8. Folkins, P. L.; Harpp, D. N. J. Org. Chem. 1992, 57, 2013.
9. Chattopadhyay, S. K.; Tripathi, V. K.; Thakur, R. S.;
Sharma, R. P.; Jain, S. P. Indian J. Chem. 1994, 33B, 409.
10. Tewari, R. K.; Prakash, O.; Singh, O. P. Bulletin of Ento-
mology 1989, 30, 195.
Following another sequence of reactions the same reac-
tive bromo intermediate 3 was converted into a dis-
ulphide 7 by first treating it with potassiumthiocyanate
to formthe thiocyanate compound 6 which was then
reduced with LiAlH4 at 60 ꢀC to formthe disulphide 7
in 70% yield. The LiAlH4 reduction of the thiocyanate
6 under the reaction condition directly gave the di-
sulphide 7 instead of a thiol (SH) product as evidenced
by mass spectral data. Also, the LiAlH4 reduction
product of thiocyanate 6 remained unchanged under
the condition of disulphide formation in presence of
iodine.8
It is worth mentioning that we have also isolated9 the
(À)-betuligenol which is the optical isomer of (+)-
betuligenol 1 fromthe needles of T. wallichiana. (À)-
Betuligenol has also been converted into amorphous
solid, (+)-(R)-3-(4-methoxyphenyl)-1-methylpropyla-
mine, [a]2D3 +8.0ꢀ (c 1, MeOH) following the same
sequence of reactions as described in Scheme 1.
(À)-Betuligenol was not found to be active in bioassay
studies as a growth inhibitor or an antifeedant. But the
amine derivative (R)-5 prepared from( À)-betuligenol
showed significant activity as a growth inhibitor and
antifeedant against 4th instar larvae of Spilarctia obli-
qua Walker (Bihar hairy caterpillar) (Table 1). This
insect attacks more than twenty cash crops like lentil,
mint and coleus etc.10À14 In conclusion, we have devel-
oped a synthetic sequence through which both the chiral
precursors of dobutamine, that is, (S)- as well as (R)-3-
(4-methoxyphenyl)-1-methylpropylamine 5 could be
readily synthesized fromthe naturally abundant (+)-
betuligenol 1 as well as (À)-betuligenol in good yield.
Further, we have demonstrated the versatility of inter-
mediate 3 as it can easily be manipulated for the
synthesis of both chiral amine 5 and disulphide 7
analogues of betuligenol.
11. Khattak, S. U.; Jabbar, A.; Hussain, N. Pakistan Journal
of Zoology 1991, 23, 297.
12. Selected physical data: 3: colourless oil, [a]2D3 À8.40ꢀ (c 1,
MeOH), 1H NMR (300 MHz, CDCl3) d 7.10 (d, J=8.1
Hz, 2H, ArH), 6.82 (d, J=8.1 Hz, 2H, ArH), 4.04 (m, 1H,
H-2), 3.77 (s, 3H, OCH3), 2.75 (m, 2H, H-4), 2.01 (m, 2H,
H-3), 1.71 (d, J=6.6 Hz, 3H, 1-CH3), EI–MS m/z 242
(M+), 244 (M++2); 4: colourless oil, [a]2D3 À1.30ꢀ (c 1,
MeOH), IR (Neat, cmÀ1) 2101, 1613, 1513, 1461, 1247,
1
1179, 1037, 928, H NMR (300 MHz, CDCl3) d 7.15 (d,
J=7.7 Hz, 2H, ArH), 6.83 (d, J=7.1 Hz, 2H, ArH), 3.79
(s, 3H, OCH3), 3.41 (m, 1H, H-2), 2.62 (m, 2H, H-4), 1.75
(m, 2H, H-3), 1.27 (d, J=6.4 Hz, 3H, 1-CH3); 5: colour-
less solid, mp 96–98 ꢀC (acetone–hexane), [a]2D3 À0.50ꢀ (c
1
1, MeOH), H NMR (300 MHz, CDCl3+D2O) d 7.10 (d,
J=8.7 Hz, 2H, ArH), 6.83 (d, J=8.7 Hz, 2H, ArH), 3.79
(s, 3H, OCH3), 2.83 (m, 1H, H-2), 2.55 (m, 2H, H-4), 1.55
(m, 2H, H-3), 1.10 (d, J=6.6 Hz, 3H, 1-CH3); EI–MS m/z
179 (M+), 162, 147, 121, 44; 6: colourless oil, [a]2D3 +0.06ꢀ
(c 1, MeOH), IR (neat, cmÀ1) 2900, 2155, 1610, 1580,
1
1510, 1460, 1242, H NMR (300 MHz, CDCl3) d 7.45 (d,
J=8.4 Hz, 2H, ArH), 6.84 (d, J=8.4 Hz, 2H, ArH), 3.79
(s, 3H, OCH3), 3.40 (m, 1H, H-2), 2.90 (m, 2H, H-4), 2.30
(m, 2H, H-3), 1.80 (d, J=6.9 Hz, 3H, 1-CH3); EI-MS m/z
221 (M+), 121; 7: colourless oil, [a]2D3 À5.0ꢀ (c 1, MeOH),
1H NMR (300 MHz, CDCl3) d 7.10 (d, J=8.4 Hz, 4H,
ArH), 6.82 (d, J=8.4 Hz, 4H, ArH), 3.78 (s, 6H, OCH3),
2.8 (m, 4H, H-3), 2.65 (m, 4H, H-4), 1.74–2.0 (m, 2ÂH,
H-3), 1.32 (d, J=6.6 Hz, 2Â3H, 1-CH3), ES–MS m/z 408
(M++ NH+4 ).
Table 1.
Compd
Concentration
(ppm)
% Feeding
deterrency
% Growth
inhibition
(R)-5
1000
2000
3000
4000
5000
1000
5
32.0
40.0
64.0
82.0
100.0
100.0
—
48.0
59.0
72.0
100.0
128.0
—
13. Insect bioassay: Antifeedant and growth inhibitory assays
were carried out with larvae of polyphagus pest insect
Spilarctia obliqua (Noctuidae, Lepidoptera). The larvae
were froma laboratory colony reared on artificial diet
Azadirachtin
Diflubenzuron
100.0

S. K. Chattopadhyay et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1729–1731
1731
under controlled conditions at 26 ꢀC.14 Antifeedant and
growth inhibitory studies were conducted with pre-
weighed broth instar larvae (n=30 for each treatment)
that were kept on a diet containing compounds and their
derivatives under study. After 24 h, number of faecal
produced were counted and % feeding-deterrency was
analyzed.15 The same experiment was continued for next
48 h. Weight of the insect larvae was taken daily. Weight
gain or loss data was used to analyze % growth inhibi-
tion.16 Azadirachtin fromneemtree and diflubenzuron,
which were used as a positive control, were obtained from
SIGMA Chemicals Company, USA. Solvent acetone was
used in negative control.
14. Tripathi, A. K.; Jain, D. C. Phytotherapy Research 1991,
5, 139.
15. Bentley, M. D.; Leonard, D. E.; Stoddard, W. F.; Zalkov,
L. H. Annals of Entomological Society of America 1984,
77, 393.
16. Scriber, F. M.; Slansky, F., Jr. Annual Review of Ento-
mology 1981, 26, 183.