Expedient construction of the ziegler intermediate useful for the synthesis of forskolin via consecutive rearrangements

Article abstract of DOI:10.1021/ol902133q

"Chemical Equation Presented" The Ziegler Intermediate, useful for the total synthesis of forskolin, was synthesized in 10 reaction steps starting from commercially available a-lonone. This highly efficient synthesis relies on the success of two consecuti

Full text of DOI:10.1021/ol902133q

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5442-5444
Expedient Construction of the Ziegler
Intermediate Useful for the Synthesis of
Forskolin via Consecutive
Rearrangements
Heping Ye,†,‡ Gang Deng,† Jun Liu,*,‡ and Fayang G. Qiu*,†
Laboratory of Molecular Engineering and Laboratory of Natural Product Synthesis,
Guangzhou Institute of Biomedicine and Health, The Chinese Academy of Sciences,
Guangzhou 510663, China, and Department of Chemistry, Wuhan UniVersity of
Science and Technology, Wuhan 430070, China
qiu_fayang@gibh.ac.cn
Received September 16, 2009
ABSTRACT
The Ziegler intermediate, useful for the total synthesis of forskolin, was synthesized in 10 reaction steps starting from commercially available
r-ionone. This highly efficient synthesis relies on the success of two consecutive highly regio- and stereoselective rearrangements. The
current synthesis has not only established an efficient synthetic route to access the Ziegler intermediate but it has also paved a way to the
structural optimization of forskolin.
The Ayurvedic herb Coleus forskohlii, a member of the mint
family growing in the subtropical areas in India, Burma, and
Thailand, has been utilized as a traditional folk medicine to
treat disorders of the digestive organs.1 Forskolin (l) (Figure
1), a highly oxygenated labdane diterpene isolated in 1977
from the roots of C. forskohlii2 by a research group from
Hoechst, India, has been shown to have therapeutic potential
against glaucoma, congestive heart failure, bronchial asthmas,
Figure 1. Chemical structures of forskolin (1) and the Ziegler
intermediate 2.
† Guangzhou Institute of Biomedicine and Health.
‡ Wuhan University of Science and Technology.
etc.3 In addition, forskolin, together with a few other
congeners, is a unique and potent stimulator of the enzyme
adenylate cyclase in various tissues.4 For example, it has
been shown to be effective for lowering blood pressure,
(1) (a) Kogler, H.; Fehlohaber, H.-W. Magn. Reson. Chem. 1991, 29,
993–998. (b) For a review on forskolin, see: Colombo, M. I.; Zinczuk, J.;
Ruveda, E. A. Tetrahedron 1992, 48, 963–1037.
(2) (a) Bhat, S. V.; Bajwa, B. S.; Dornauer, H.; de Souza, N. J.;
Fehlhaber, H.-W. Tetrahedron Lett. 1977, 1669–1672. (b) Paulus, E. F. Z.
Krisallogr. 1980, 152, 239–245; 153, 43-49. (c) Bhat, S. V.; Bajwa,
Dornauer, B. S. H.; de Souza, N. J. J. Chem. Soc., Perkin Trans. 1 1982,
76, 7–771.
(3) Seamon, K. B. Annu. Rep. Med. Chem. 1984, 19, 293–301.
10.1021/ol902133q CCC: $40.75
Published on Web 10/30/2009
 2009 American Chemical Society

inhibiting platelet aggregation, improving heart function, and
possibly increasing nitric oxide levels.5 Further, it has been
used as a standard when a lipolytic agent is examined.6
Owing to its broad range of physiological activities and
unique structural features, forskolin has been the subject of
many synthetic efforts.7 So far, four different total syntheses
of this highly challenging target have been completed,8 and
the first three have proceeded through the intermediacy of
lactone (2), first synthesized9 by the Ziegler group. Conse-
quently, this advanced intermediate has emerged as a highly
attractive target for substantial synthetic investigation.10
We have been interested in designing efficient synthetic
strategies. In a previous paper, we proposed a standard to
gauge the efficiency of synthetic strategies.11 According to
that standard, we started to work on the synthesis of
intermediate 2 and the retrosynthetic analysis is shown in
Scheme 1.
synthetic strategy, which is the main point of this paper.
Subsequent conversion of 3 into 2 is also known.
As shown in Scheme 2, chemoselective epoxidation of
R-ionone provided (95%) the desired epoxide intermediate,
Scheme 2. Synthesis of the Ziegler Intermediate
Scheme 1. Retrosynthetic Analysis of the Ziegler Intermediate
treatment of which with sodium methoxide produced inter-
mediate 5 in 81% yield. Upon reaction with diketene,
intermediate 5 was converted into an acetoacetyl ester (90%),
which afforded intermediate 6 after treatment with a mixture
of anhydrous potassium carbonate-cesium carbonate (4:1
mol ratio) in refluxing acetonitrile in 48% yield. We had
some difficulty in optimizing the reaction yield to what was
reported in the literature, though the effort of optimization
is still being continued. Chemoselective oxidation of 6 with
m-CPBA led to the formation of epoxide 4 in 80% yield.
The key reaction of this synthesis was designed to proceed
through the following sequence:
After a brief literature comparison, we have found that
some of the key intermediates in our synthetic design are
known, though the transformations that we plan to use are
different. R-Ionone is a commercial material which may be
converted into intermediate 4 in five steps as documented
in the literature. While transformation of 4 into 3 is
established, it takes six reaction steps. Thus, there is still
considerable room to enhance the efficiency of the entire
Regio- and stereoselective addition of tosylhydrazine to
the epoxide was catalyzed by TsOH. The newly formed
hydrazine derivative decomposed under the reaction condi-
(4) (a) Seamon, K. B.; Daly, J. W. AdV. Cyclic Nucleotide Res. 1986,
20, 1–150, and references cited therein. (b) Bhat, S. V.; Dohadwalla, A. N.;
Bajwa, B. S.; Dadkar, N. K.; Dornauer, H.; De Souza, N. J. J. Med. Chem.
1983, 26, 486–492. (c) Khandelwal, Y.; Rajeshwari, K.; Rajagopalan, R.;
Swamy, L.; Dohadwalla, A. N.; de Souza, N. J.; Rupp, R. H. J. Med. Chem.
1988, 31, 1872–1879.
(8) (a) Ziegler, F. E.; Jaynes, B. H.; Saindane, M. T. J. Am. Chem. Soc.
1987, 109, 8115–8116. (b) Hashimoto, S.; Sakata, S.; Sonegawa, M.;
Ikegami, S. J. Am. Chem. Soc. 1988, 110, 3670–3672. (c) Corey, E. J.;
Jardine, P. D. S.; Rohloff, J. C. J. Am. Chem. Soc. 1988, 110, 3672–3673.
(d) Delpech, B.; Calvo, D.; Lett, R. Tetrahedron Lett. 1996, 37, 1015–
1018; 1019-1022.
(5) (a) Dubey, M. P.; Srimal, R. C.; Nityanand, S.; Dhawan, B. N. J.
Ethnopharmacol. 1981, 3, 1–13. (b) Rola-Pleszczinski, M.; Thivierge, M.;
Alami, N.; Muller, E.; de Brum-Fernandes, A. J.; Pleszczynski, R.-M. J. Biol.
Chem. 1993, 268, 17457–17462. (c) Roth, D. M.; Bayat, H.; Drumm, J. D.;
Gao, M. H.; Swaney, J. S.; Ander, A.; Hammond, H. K. Circulation 2002,
105, 1989–1994. (d) Zhang, X. P.; Tada, H.; Wang, Z.; Hintze, T. H.
Arterioscler. Thromb. Vasc. Biol. 2002, 22, 1273–1278.
(9) (a) Ziegler, F. E.; Jaynes, B. H.; Saindane, M. T. Tetrahedron Lett.
1985, 26, 3307–3310. (b) Ziegler, F. E.; Jaynes, B. H. Tetrahedron Lett.
1988, 29, 2031–2032.
(6) (a) Morimoto, C.; Kameda, K.; Tsujita, T.; Okuda, H. J. Lipid Res.
2001, 42, 120–127. (b) Lofgren, P.; Hoffstedt, J.; Ryden, M.; Thorne, A.;
Holm, C.; Wahrenberg, H.; Arner, P. J. Clin. Endocrinol. Metab. 2002,
87, 764–771. (c) Imbeault, P.; Prud’homme, D.; Tremblay, A.; Despres,
J. P.; Mauriege, P. J. Clin. Endocrinol. Metab. 2000, 85, 2455–2462. (d)
Imbeault, P.; Tremblay, A.; Despres, J. P.; Mauriege, P. Eur. J. Clin. InVest.
2000, 30, 290–296.
(10) For other syntheses of the Ziegler intermediate, see: (a) Colombo,
M. I.; Somoza, C.; Zinczuk, J.; Bacigaluppo, J. A.; Ru´veda, E. A.
Tetrahedron Lett. 1990, 31, 39–42. (b) Colombo, M. I.; Zinczuk, J.;
Bacigaluppo, J. A.; Somoza, C.; Ru´veda, E. A. J. Org. Chem., 1990, 55,
5631–5639. (c) Preite, M. D.; Ru´veda, E. A. Synth. Commun. 1994, 24,
2809–2825. (d) Leclaire, M.; Pericaud, F.; Lallemand, J. Y. J. Chem. Soc.,
Chem. Commun. 1995, 1333–1334. (e) Leclaire, M.; Levet, R.; Pericaud,
F.; Ricard, L.; Lallemand, J. Y. Tetrahedron 1996, 52, 7703–7718.
(11) Qiu, F. Can. J. Chem. 2008, 86, 903–906.
(7) For reviews on forskolin synthesis, see: (a) Reference 1b. (b) Bhat,
S. V. Prog. Chem. Org. Nat. Prod. 1993, 62, l–74. (c) He, H.-M.; Wu,
Y.-L. Youji Huaxue 1991, 11, l–12.
Org. Lett., Vol. 11, No. 23, 2009
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tions, leading to a diimine derivative. The latter was unstable
and underwent an electrocyclic reaction to afford intermediate
3′ (Scheme 3). The stereochemistry of the bridgehead
hydrogen depends on that of the imine derivative.
Scheme 4
.
Possible Mechanism of the 1,3-Rearrangement
Leading to Intermediate 3
Scheme 3
.
Mechanistic Rationale of the Stereocontrolled
Hydrogen Atom Transfer
Oxidation of 3 with m-CPBA afforded the epoxide
intermediate, 7, in 59% yield. Without optimization, the latter
was treated with KOH in methanol to furnish the desired
diol 8, which was converted into the Ziegler intermediate
upon treatment with a catalytic amount of toluenesulfonic
acid and dimethoxypropane in 69% overall yield from
intermediate 7. The spectroscopic data of the final product
are in full agreement with those reported.
Although this paper describes a racemic synthesis of the
Ziegler intermediate, an asymmetric synthesis may be
achieved by using chiral 6, which is readily accessible
through a known procedure.12
Although intermediate 3′ was the initially desired product
from the rearrangement, during the course of the reaction, a
small amount of a new product was detected and was
identified to be 3. We believed that intermediate 3 was
produced from the hydroxyl rearrangement of 3′ under the
reaction conditions. Much to our delight, when it was treated
with an aqueous sulfuric acid solution (1%), 3′ was converted
into 3 in high yield. A possible mechanism of this rear-
rangement is proposed as shown in Scheme 4.
The driving force for this rearrangement to occur is
perhaps due to the strain release from 3′ to 3 and the
thermodynamic stability difference of the carbon-carbon
double bond between 3′ and 3. The stereochemistry of the
hydroxyl group was identified by comparison of its spec-
troscopic data with those reported and by conversion of 3
into the Ziegler intermediate, whose spectroscopic data were
in full agreement with those reported in the literature. The
reason for such an outcome to occur is perhaps due to the
difference in the torsional strain of the developing transition
state to form 3 as is compared to its epimer 3a.
In summary, we have achieved an efficient synthesis of
the Ziegler intermediate. Conversion of this intermediate into
forskolin is under way and will be presented for publication
in due course.
Acknowledgment. This work was supported by a grant
from GIBH.
Supporting Information Available: Experimental pro-
1
cedures, analytical data, and copies of H and 13C NMR
spectra for 2-4 and 7. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL902133Q
Based on the above analysis, conversion of 3′ into 3 was
achieved when the reaction mixture from the first step was
treated with dilute sulfuric acid prior to purification.
(12) Lallemand, J. Y.; Leclaire, M.; Levet, R.; Aranda, G. Tetrahedron:
Asymmetry 1993, 4, 1775–1778.
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