Progress toward the total synthesis of ingenol: construction of the complete carbocyclic skeleton.

Article abstract of DOI:10.1021/ol015855a

[reaction: see text] The complete carbocyclic skeleton of ingenol is assembled via a route that employs ring-closing metathesis (RCM) to close the strained "inside-outside" BC ring system (i.e., 24 --> 25).

Full text of DOI:10.1021/ol015855a

ORGANIC
LETTERS
2001
Vol. 3, No. 10
1563-1566
Progress toward the Total Synthesis of
Ingenol: Construction of the Complete
Carbocyclic Skeleton
Haifeng Tang, Naeem Yusuff, and John L. Wood*
Sterling Chemistry Laboratory, Department of Chemistry, Yale UniVersity,
New HaVen, Connecticut 06520-8107
john.wood@yale.edu
Received March 15, 2001
ABSTRACT
The complete carbocyclic skeleton of ingenol is assembled via a route that employs ring-closing metathesis (RCM) to close the strained
“inside-outside” BC ring system (i.e., 24 f 25).
Ingenol (1, Scheme 1), isolated and characterized by the
Hecker group in 1968,1 has attracted considerable interest
from both the chemical and biological communities. Like
the phorbol esters, various ingenol esters have been shown
to mimic diacylglycerol and function as PKC activators.2
Furthermore, many possess potent tumor promoting,3 anti-
leukemic,4 and anti-HIV5 properties. Hence, efficient syn-
thetic access to these natural products and various synthetic
analogues will promote the development of new therapeutic
agents. However, despite the efforts of many groups, a
complete total synthesis of 1 has yet to be reported.
While the high degree of oxygenation, notably the cis-
triol, represents a formidable synthetic challenge, the most
imposing obstacle is construction of the highly strained
“inside-outside” BC ring system. Successful approaches to
the BC ring junction have generally relied upon fragmenta-
tion and rearrangement strategies,6,7 while attempts at direct
alkylations to construct the trans bridgehead all resulted in
cis stereochemistry.8 To date, synthesis of the complete
ingenol tetracyclic carbon skeleton has only been achieved
by Funk and co-workers.7 In addition, very elegant work
from the Winkler group has led to several ingenol analogues
Scheme 1
(1) Hecker, E. Cancer Res. 1968, 28, 2338.
(2) Hasler, C. M.; Acs, G.; Blumberg, P. Cancer Res. 1992, 52, 202.
(3) Hecker, E. Pure Appl. Chem. 1977, 49, 1423-1431.
(4) Kupchan, S. M.; Uchida, I.; Branfman, A. R.; Dailey, R. G.; Fei, B.
Y. Science 1976, 191, 571.
(5) Fujiwara, M.; Ijichi, K.; Tokuhisa, K.; Katsuura, K.; Shigeta, S.;
Konno, K. Antimicrob. Agents Chemother. 1996, 40(1), 271-273.
(6) (a) Winkler, J. D.; Henegar, K. E. J. Am. Chem. Soc. 1987, 109,
2850. (b) Rigby, J. H.; Claire, V. S.; Cuisiat, S. V.; Heeg, M. J. J. Org.
Chem. 1996, 61, 7992. (c) Tanino, K.; Kuwajima, I.; Nakamura, T.; Matsui,
T. J. Org. Chem. 1997, 62, 3032.
(7) (a) Funk, R. L.; Olmstead, T. A.; Parvez, M. J. Am. Chem. Soc. 1988,
110, 3298. (b) Funk, R.; Olmstead, T. A.; Parvez, M.; Stallman, J. B. J.
Org. Chem. 1993, 58, 5873.
10.1021/ol015855a CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/06/2001

containing both the inside-outside BC ring junction and the
cis-triol functionality.9
present in 6a and 6b, both esters were similarly advanced
with the hope of obtaining this information from later
intermediates. Ester 6a was alkylated with allyl bromide to
provide enol ether 7, which upon heating smoothly under-
went Claisen rearrangement to furnish 8 as a single diaste-
reomer. Heating a dichloromethane solution of 8 and 10 mol
% Grubbs’s catalyst (4) to reflux provided ring-closed
product 9 in good yield. Reduction of 9 furnished diol 10,
the structure of which was established by single-crystal X-ray
analysis. Inspection of the crystal structure revealed that 10
contained the undesired “outside-outside” stereochemistry;
thus, rigorously establishing the relative stereochemistry of
6a and 8.
Next, we focused our efforts on advancing the remaining
diastereomer 6b. Since studies of three-component reactions
on cyclic enones have shown that the electrophile is typically
trapped trans to the nucleophile,15 we were confident that
compound 6b possessed the correct stereochemistry to
furnish the desired RCM precursor 3. Unlike 6a, alkylation
of 6b gave rise exclusively to C-alkylated product 3 (Scheme
3). Unfortunately, all attempts to construct the BC ring
system using RCM on substrate 3 were unsuccessful.
In contemplating a synthesis of the BC ring system, we
became intrigued by the notion of establishing the trans
relationship between C(8) and C(10) on a cyclic precursor
(e.g., 3, Scheme 1) and subsequently closing the B ring via
a robust cyclization protocol like ring-closing metathesis
(RCM).10-12 Specifically, we were curious if application of
the RCM protocol to diene 3 would furnish the strained
inside-outside bicycle 2.13 While this work was in progress,
a similar metathesis strategy to the ABC ring system was
reported by Kigoshi.14
To explore this hypothesis, 3-carene was advanced to
cycloheptenone 5 following the procedure of Funk (Scheme
2).7a Treatment of 5 with lithium dimethyl cuprate followed
Scheme 2
Scheme 3
Having established that diene 3 was not a suitable
precursor to the BC ring system, computational studies were
performed to identify a more viable cyclization substrate.
Conformational searches16 of potential candidates using the
Merck Molecular Force Field (MMFF)17 suggested that
inclusion of the A ring would facilitate construction of the
inside-outside BC ring system.18 To explore this prediction,
we initiated an approach to 12 wherein a Diels-Alder
reaction between exo-olefin 14 and cyclopentadiene (15) was
envisioned to simultaneously introduce the A ring and the
functionality needed for the RCM chemistry (Scheme 4).
(10) (a) Grubbs, R. H.; Fu, G. C. J. Am. Chem. Soc. 1992, 114, 5426.
(b) Grubbs, R. H.; Schwab, P.; France, M. B.; Ziller, J. W. Angew. Chem.,
Int. Ed. Engl. 1995, 34(18), 2039.
(11) (a) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.;
Dimare, M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875. (b) Bazan,
G. C.; Oskam, J. H.; Cho, H.-N.; Park, L. Y.; Schrock, R. R. J. Am. Chem.
Soc. 1991, 113, 6899.
(12) For a recent review, see: Armstrong, S. K. J. Chem. Soc., Perkin
Trans. 1 1998, 371.
by trapping of the resulting enolate with allyl iodide gave
rise to â-keto esters 6a and 6b as a 1:1.2 mixture of
diastereomers. Uncertain of the relative stereochemistry
(13) For an application of RCM to a different inside-outside system,
see: Krafft, M. E.; Cheung, Y.-Y.; Juliano-Capucao, C. A. Synthesis 2000,
1020.
(14) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett.
2000, 41, 3927.
(15) Boeckman, R. K. J. Org. Chem. 1973, 38, 4450.
(16) Calculations were performed using Spartan Version 5.1, Wavefunc-
tion Inc. 18401 Von Karman Ave. Suite 370, Irvine, CA 92612.
(17) Halgren, T. A. J. Comput. Chem. 1996, 17, 490.
(8) (a) Paquette, L. A.; Ross, R. J.; Springer, J. P. J. Am. Chem. Soc.
1988, 110, 6192. ( b) Mehta, G.; Pathak, V. P. J. Chem. Soc., Chem.
Commun. 1987, 876. (c) Harmata, M.; Elahmad, S.; Barnes, C. L.
Tetrahedron lett. 1995, 36, 1397. (d) Rigby, J. H.; Cuisiat, S. V. J. Org.
Chem. 1993, 58, 6286. (e) Rigby, J. H.; Rege, S. D.; Sandanayaka, V. P.;
Kirova, M. J. Org. Chem. 1996, 61, 842.
(9) Winkler, J. D.; Sanghee, K.; Harrison, S.; Lewin, N. E.; Blumberg,
P. M. J. Am. Chem. Soc. 1999, 121, 296.
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Org. Lett., Vol. 3, No. 10, 2001

that boron trifluoride diethyl etherate effectively catalyzed
the Diels-Alder reaction between 14 and cyclopentadiene
(15) to provide a ternary mixture of diastereomers (20a,b,c)
in a ratio of 20:8:1, respectively. We were delighted to find
that the major constituent 20a possessed the desired stereo-
chemistry.23 Alkylation of 20a with allyl bromide furnished
13, the precursor for the tandem ROM-RCM. Upon exposure
of 13 to various ROM-RCM conditions under an atmosphere
of ethylene, only ring-opening metathesis was observed,
thereby providing triene 12 in excellent yield. Further
exposure of this triene to various RCM conditions did not
result in the desired product but rather regenerated nor-
bornene 13 as the only isolable product in 8% yield.
Scheme 4
In an effort to prevent reversion to 13, efforts focused on
masking the C(2) olefin prior to attempted RCM. To this
end, ring-opening metathesis of 20a under an atmosphere
of ethylene gave rise to diene 22 in excellent yield (Scheme
6). Regioselective dihydroxylation of the C(2) olefin followed
Scheme 6
Thus, tandem ring-opening ring-closing metathesis (ROM-
RCM) of 13 would furnish the tetracyclic ingenol skeleton
11.19
Studies commenced with known â-keto ester 16 (Scheme
5),7a,20 which was converted to the corresponding ketal 17.21,22
Scheme 5
by oxidative cleavage provided the corresponding aldehyde,
which was protected to afford acetal 23. Alkylation of 23
proceeded smoothly to afford RCM precursor 24. Gratify-
ingly, following careful optimization, exposure of 24 to 4
(four additions of 20 mol % 4 every 45 min) in refluxing
toluene led to the elusive inside-outside ring system 25.
Dihydroxylation of 25 followed by esterification with p-
bromobenzoyl chloride delivered dibenzoate 27, the structure
of which was confirmed by single-crystal X-ray analysis
(Figure 1).
Reduction of 17 followed by hydrolysis of the ketal delivered
alcohol 18 in near quantitative yield. Acetylation of the
alcohol followed by subsequent elimination furnished exo-
olefin 14. After considerable experimentation, it was found
Org. Lett., Vol. 3, No. 10, 2001
1565

Current efforts are directed toward developing a more
efficient approach to 24 and advancing 25 to 1; progress
along these lines will be reported in due course.
Acknowledgment. We are pleased to acknowledge the
support of this investigation by Bristol-Myers Squibb,
Yamanouchi, Pfizer, Merck and the Camille and Henry
Dreyfus Foundation for a Teacher-Scholar Award. J.L.W.
is a fellow of the Alfred P. Sloan Foundation.
Supporting Information Available: Experimental pro-
cedures and spectral data pertaining to all new compounds
and crystallographic data for 10, 17, 21, and 27. This material
is available free of charge via the Internet at http://pubs.acs.org.
Figure 1. Crystal structure of 27 (benzoates removed for clarity).
OL015855A
In conclusion, the carbocyclic skeleton of ingenol has been
successfully constructed using ring-closing metathesis. In
addition, the A and B rings in 25 have the appropriate
functionality to allow for elaboration to the natural product.
(20) â-keto ester 16 is actually isolated from a mixture of four
diastereomers produced using the literature procedure (See ref 7a). However,
it was subsequently discovered that the corresponding ketals were more
readily separated. Thus, the diastereomeric mixture was carried forward
on a preparative scale.
(18) A conformational search of precursor 3 illustrated that the two
internal olefinic carbons are oriented 4.2 Å away from each other. With
the installation of the A ring, the C ring conformation was dramatically
twisted at quaternary center C(8), imparting a dihedral angle between C(8)-
C(7) and C(10)-C(4) of 79.9°. Furthermore, the distance between the two
internal olefinic carbons was reduced to 3.8 Å.
(21) The ketals were separated by silica gel chromatography. Four
diastereomeric ketals were eluted in the ratio of 43:23:18:16. Only the major
diastereomer 17 was advanced.
(22) The stereochemistry of 17 was unambiguously determined by X-ray
crystallography.
(23) Ozonolysis of the major diastereomer 20a gave rise to a crystalline
compound 21, the structure of which was established by X-ray crystal-
lography. For spectral data pertaining to 20b and 20c, see Supporting
Information.
(19) (a) Blechert, S.; Stragies, R. Synlett 1998, 169. (b) Schrock, R. R.;
Hoveyda, A. H.; Weatherhead, G. S.; Ford, J. G.; Alexanian, E. J. J. Am.
Chem. Soc. 2000, 122, 1828.
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Org. Lett., Vol. 3, No. 10, 2001