First synthesis of 1,9-dideoxyforskolin from ptychantin A

Article abstract of DOI:10.1016/S0040-4039(03)00236-3

1,9-Dideoxyforskolin 2 has been synthesized starting from ptychantin A 3.

Full text of DOI:10.1016/S0040-4039(03)00236-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2305–2306
First synthesis of 1,9-dideoxyforskolin from ptychantin A
Hisahiro Hagiwara,a,* Fumihide Takeuchi,a Takashi Hoshi,b Toshio Suzuki,b Toshihiro Hashimotoc
and Yoshinori Asakawac
aGraduate School of Science and Technology, Niigata University, 8050, 2-nocho, Ikarashi, Niigata 950-2181, Japan
bFaculty of Engineering, Niigata University, 8050, 2-nocho, Ikarashi, Niigata 950-2181, Japan
cFaculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
Received 24 December 2002; revised 23 January 2003; accepted 27 January 2003
Abstract—1,9-Dideoxyforskolin 2 has been synthesized starting from ptychantin A 3. © 2003 Elsevier Science Ltd. All rights
reserved.
During the course of investigation of antihypertensive
and cardioactive substances in nature, de Souza et al.
isolated several labdane diterpenoids1 from Coleus
forskohlii, which has been used as a folk medicine in
India. One major constituent, forskolin 1 (Fig. 1)
showed significant blood pressure lowering properties.2
In addition, a wide variety of biological activities were
observed by raising the level of cAMP and, as a result,
activating protein kinase. Due to such activities, more
than 1,500 citations dealing with the physiological
found to inhibit glucose transports in rats adipocytes in
micromolar range.4 The activity is expected to treat
some diseases (Alzheimer, diabetes, cancer) caused by
abnormal glucose uptake.5
Alternatively, five new labdane diterpenoids have been
isolated from liverwort Ptychanthus striatus.6 All of
them have closely related structures to forskolins,
although antihypertensive activities have not yet been
found in these compounds. The major constituent,
ptycanthin A 3 easily available in large quantity
(0.45%) from the liverwort, would be a good starting
material for syntheses of forskolin and its derivatives.
properties of forskolin
1 appeared in Chemical
Abstracts in 2001. The physiological importance in
addition to the highly oxygenated structure of forskolin
1 stimulated the interest of synthetic organic chemists
and there has been a surge of synthetic studies.3
Recent results of synthetic study as well as the impor-
tance of physiological activity of 1,9-dideoxyfoskolin 27
prompted us to report synthesis of 2 from ptychantin A
3 which is described in Scheme 1. One major problem
in the present synthesis was selective transformation of
a hydroxy and three acetoxy groups, especially selective
oxidation at C-11, by discriminating the subtle differ-
ence in the environment around each functional group.
One other major constituent, 1,9-dideoxyforskolin 2,
was not potent in antihypertensive activity. However,
attention was recently focused on 2 because it has been
Selective hydrolysis of the 6-acetoxy group by potas-
sium hydroxide proceeded quantitatively owing to the
highly congested nature of the acetoxy group at C-6 to
give diol 4 whose 6,7-diol moieties were protected as an
acetonide in 91% yield by 2,2-dimethoxypropane. The
resulting acetonide 5 was reduced with lithium alu-
minumhydride to provide diol 6 in 97% yield. After
several attempts, selective oxidation of the hydroxyl
group at C-11 was fortunately accomplished by PCC to
give ketone 7 in 71% yield. The densely substituted
nature of the b-face of 6 may allow such selective
oxidation of the a-equatorial hydroxy group at C-11.
Figure 1.
Keywords: 1,9-dideoxyforskolin; ptychantin A; labdane; forskolin.
* Corresponding author. Tel./fax: +81-25-262-7368; e-mail:
hagiwara@gs.niigata-u.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00236-3

2306
H. Hagiwara et al. / Tetrahedron Letters 44 (2003) 2305–2306
Then, in order to remove the hydroxyl group at C-1,
the alcohol 7 was transformed into thiocarbonylimida-
zolide 8a by solid-state reaction,8 thiocarbonylformate
8b or xanthate 8c by conventional procedure in 82, 54
or 33% yield, respectively. Radical cleavage of 8a, 8b or
8c with n-tributyltinhydride in the presence of AIBN
furnished 9 in 83, 41 or 72% yield respectively. Hydrol-
ysis of the acetonide 9 proceeded very slowly but
quantitatively by dilute HClO4 to give diol 10. Finally,
selective acetylation of the less hindered hydroxy group
at C-6 of the diol 10 completed the synthesis of 1,9-
dideoxyforskolin 2 in 86% yield. The spectral data of
the synthetic 2 were identical with those of natural 2
{[h]2D5 −89.2, lit.1 −89.4} kindly supplied by Dr. Rosner.
In summary, we have completed the first synthesis of
1,9-dideoxyforskolin 2 in 37% overall yield in eight
steps from ptychantin A 3. Since ptychantins are avail-
able in large quantity, present protocol offers enough
supply of physiologically potent compounds.
Acknowledgements
We thank Dr. M. Rosner, Aventis Pharma, for provid-
ing spectral data of 1,9-dideoxyforskolin 2. Thanks are
also due to Shorai Foundation for Science and Tech-
nology for partial financial support.
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Scheme 1. Reagents, conditions and yields: (i) KOH/MeOH,
rt, 13 h, 100%; (ii) 2,2-dimethoxypropane, PTSA, rt, 91%; (iii)
LAH, Et2O, rt, 2.5 h, 97%; (iv) PCC/AcONa, CH2Cl2, rt, 3 h,
71%; (v) thiocarbonyldiimidazolide, DMAP, 2 h, 82% for 8a;
phenylchlorothionoformate, DMAP, CHCl3, reflux, 23 h,
54% for 8b; n-BuLi/CS2/MeI, THF, 0°C, 4 h, 33% for 8c; (vi)
AlBN/n-Bu3SnH, toluene, 100–120°C, 30–45 min, 83% from
8a, 41% from 8b, 72% from 8c; (vii) 10% HClO4/THF (1:2),
rt, 7 days, 100%; (viii) Ac2O/Pyr./DMAP, 0°C, 1 h, 86%.