M. Koteswara Reddy et al. / Tetrahedron Letters 52 (2011) 6537–6540
6539
limido-1,2,3-triazolo-forskolin (5a) in its IR showed broad peak at
3458 cmꢀ1 due to OH groups. The peaks at 1735 cmꢀ1, 1708 cmꢀ1
and 1685 cmꢀ1 are due to ketone, ester and amide carbonyls,
respectively. In the 1H NMR of 5a, the triazole ring proton appeared
at d 7.43 as a singlet, and the aromatic protons at d 7.71(dd,
CH3
O
CH3
CH3
H 13
H
CH3
OH 11
2
H
12
15
1
14
8
O
O
H
10
9
H
H
CH3
4
5H6
3
7
H3C
J = 5.2 Hz, J = 2.8 Hz, H-300,600),
d 7.83(dd, J = 5.2 Hz, J = 2.8 Hz,
OH
H
O
H
O
H
H-400,500), the phthalimide N–CH2 at d 4.38 (t, J = 6.8 Hz), and other
3 CH2 groups are at d 3.73 (t, J = 6.8 Hz), d 1.95(m), d 1.75(m) and
H2C
C
C
40-OCH2 as ABq at
d 4.68 (d, J = 12.0 Hz) and d 4.42 (d,
H
13
J = 12.0 Hz). In C NMR of 5a, triazole carbons C-40 and C-50 ap-
peared at d 146.9 and d 122.4, the carbon signal assignments in
the phthalimide and N(CH2)4 are as follows d 168.1(C@O), C-500,C-
400 at d 133.8, C-300a,C-600a at d 132.1 and C-300,C-600 at d 123.1,
49.3 (100-CH2), 36.8 (10-CH2), 27.3 (10-CH2-CH2), 23.9 (100-CH2-
CH2). In the DIPMS of (5a), the quasimolecular ion [M+H]+ peak ap-
peared at m/z 693 and 715[M+Na]+.
Figure 1. NOESY of 1-O-propargyl forskolin (2).
H3C
O
CH3
1-O-propargyl-6-O-acetyl-7-deacetyl forskolin (3) on reaction
with different alkyl azides (4a–g) in the presence of CuSO4ꢂ5H2O
and sodium ascorbate in water/t-butanol (1:1) medium gave 1,4-
disubstituted triazolo-6-O-acetyl-7-deacetyl-forskolins (6a–g) in
quantitative yields (Scheme 1). These are characterized by IR, 1H
NMR, 13C NMR and MS. N-Butyl-phthalimido-1,2,3-triazolo-6-acet-
yl-7-deacetyl-1,4-disubstituted-forskolin (6a). In its IR showed
peaks at 3445 cmꢀ1 (OH), 1728 cmꢀ1(CO, ester), 1715 cmꢀ1(CO, ke-
tone) and 1690 cmꢀ1 (CO, amide). In the 1H NMR of 6a the triazole
ring proton appeared at d 7.43 as a singlet, the pthalimide protons
appeared as d 7.84 (d, J = 5.6 Hz, H-500,H-400), d 7.72 (d, J = 5.6 Hz, H-
600,H-300), N–CH2 at d 4.39 (t, J = 6.8 Hz) and CH2 X 3 are at d 3.73 (t,
J = 6.8 Hz), 1.94(m), 1.74(m) and OCH2 as ABq at d 4.70 (d,
J = 12.0 Hz), d 4.44 (d, J = 12.0 Hz). In 13C NMR of 6a the carbon sig-
nal assignments for the phthalimido triazole moiety are as follows
d 147.1(C-40), d 122.4(C-50), d 168.1(CO), d 133.9(C-500, C-400), d
132.1(C-3a, C-6a) d 123.2(C-600, C-300). The DIPMS of 6a, the quasi-
molecular ion [M+H]+ peak appeared at m/z 693.
Propargylation of forskolin afforded 1-O-propargyl forskolin (2)
and 1-O-propargyl-6-O-acetyl-7-deacetyl forskolin (3). Since 1,2,3-
triazole moiety is considered to be bioisosteric to amide, several
novel 1,4-disubstituted-triazolo-forskolins (5a–g) and 1,4-disub-
stituted-triazolo-6-O-acetyl-7-deacetyl forskolins (6a–g) were
synthesized adopting the click reaction conditions. These ana-
logues are expected to have AC isoform selectivity and increased
water solubility.
H3C
O
CH3
O
H
13
H
CH3
1
11
H
2
1O2
14
8 H
OH
H
10
9
H
H3C4
6 OH
5
H
3
7
O
H
H
H
H2C
C
C
H
Figure 2. NOESY of 1-O-propargyl-6-O-acetyl-7-deacetyl forskolin (3).
showed NOE with 4a-CH3 at d 0.98, 10a-CH3 at d 1.41 and 8a-CH3 at
d 1.58 indicating its axial location. This OCOCH3 must be at 6a to
exhibit the NOE mentioned above. The presence of OCOCH3 at 6 ax-
ial position is due to a 1,2-shift from the 7e-OCOCH3 of forskolin.9
To confirm the 1,2-shift of 7e-OCOCH3 in the formation of com-
pound 3, its NOESY was compared with 2 and forskolin (1). In for-
skolin (1) and 2 7e-OCOCH3 did not show NOE with the any CH3
where as the OCOCH3 of compound 3 showed NOE with three
CH3 groups at d 0.98, d 1.41 and 1.58 indicating that OCOCH3 group
in compound 3 (Fig. 2) being located in the axial position at C-6.
Acetyl group has shifted from C-7 to 6-OH via a cyclic intermediate
under the basic conditions of the reaction (Scheme 2). Compound 3
is 1-O-propargyl-6-O-acetyl-7-deacetyl forskolin, a regioisomer of
2, arising from the acetate rearrangement. In 13C NMR of 3, the
OCH2 propargyl moiety appeared at d 56.1, the C„CH at d 75.6
and the C„CH at d 75.1. The HRMS [ESI] of compound 3, the
[M+Na] showed the peak at m/z at 471.2364.
Acknowledgements
1-O-propargyl-forskolin (2) and 1-O-propargyl-6-O-acetyl-7-
deacetyl forskolin (3) have the terminal alkyne moiety as a substi-
tuent. Reactions of alkyl azides (4a–g) with terminal alkynes under
click reaction conditions with Cu(I) catalyst system afford regiose-
lectively 1,4-disubstituted-1,2,3-triazoles.24 The alkyl azides were
synthesized by the reaction of alkyl bromides with sodium azide
in DMSO and H2O as per literature method.26
This work has been funded by the AP-Netherlands Biotechnol-
ogy Project during 2005–2009 in a programme to give value addi-
tion to Indian Medicinal Plants by providing technology for their
chemical processing. Authors thank the Chairman of the AP-Neth-
erlands Biotechnology Program, Dr. M.V. Rao and Coordinator, Dr.
G. Pakki Reddy for their support and encouragement.
1-O-Propargyl-forskolin (2) on reaction with different substi-
tuted azides (4a–g) in the presence of CuSO4ꢂ5H2O and sodium
ascorbate in water/t-butanol (1:1) medium gave 1,4-disubstituted
triazolo forskolins (5a–g) in quantitative yields (Scheme 1). These
are characterized by IR, 1H NMR, 13C NMR and MS. N-Butyl-phtha-
Supplementary data
Supplementary data associated with this article can be found, in
References and notes
O
O
1. Shah, V.; Bhat, S. V.; Bajwa, B. D.; Dornauer, H.; De Souza, N. J. Planta Med. 1980,
39, 183–185.
2. (a) Bhat, S. V.; Bajwa, B. D.; Dornauer, H.; De Souza, N. J.; Fehlhaber, H. W.
Tetrahedron Lett. 1977, 18, 1669–1672; (b) Bhat, S. V.; Dohadwalla, A. N.; Balbir,
N. K. D.; Bajwa, B. S.; Dornauer, H.; de Souza, N. J. J. Med. Chem. 1983, 26, 486–
492.
O
CH3
O
O
6
O
CH3
OH
O
CH3
O
6
6
7
7
7
3. (a) Onda, T.; Hashimoto, Y.; Nagai, M.; Kuramochi, H.; Saito, S.; Yamazaki, H.;
Toya, Y.; Sakai, I.; Homey, C. J.; Nishikawa, K.; Ishikawa, Y. J. Biol. Chem. 2001,
Scheme 2. Mechanism for the migration of acetyl group from 7 to 6 position of
forskolin.