Synthetic studies toward 13-Oxyingenol: Construction of the fully substituted tetracyclic compound

Article abstract of DOI:10.1021/ol103151k

Chemical equations presented. 13-Oxyingenol and its derivatives have high levels of anti-HIV activity. A fully substituted tetracyclic skeleton of 13-oxyingenol is constructed by using spiro-cyclization and ring-closing olefin metathesis as key steps.

Full text of DOI:10.1021/ol103151k

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2160–2163
Synthetic Studies toward 13-Oxyingenol:
Construction of the Fully Substituted
Tetracyclic Compound
Takayuki Ohyoshi,† Yamato Miyazawa, Kenta Aoki, Satomi Ohmura, Yuki Asuma,
Ichiro Hayakawa, and Hideo Kigoshi*
Department of Chemistry, Graduate School of Pure and Applied Sciences,
University of Tsukuba, Tennodai, Tsukuba 305-8571, Japan
kigoshi@chem.tsukuba.ac.jp
Received December 27, 2010
ABSTRACT
13-Oxyingenol and its derivatives have high levels of anti-HIV activity. A fully substituted tetracyclic skeleton of 13-oxyingenol is constructed by
using spiro-cyclization and ring-closing olefin metathesis as key steps.
13-Oxyingenol (1)1 and ingenol (3) are diterpenoids
isolated from the plants of Euphorbia sp. The main struc-
tural features of ingenols are a highly strained insideÀout-
side bicyclic ring system and a high degree of oxygenation
(Figure 1). They and their analogues showed strong bioac-
tivity against protein kinase C activation and anti-HIV
activity.2 In particular, 13-oxyingenol derivatives such as
RD4-2138 (2) have strong anti-HIV activity. The unique
† Research fellow of the Japan Society for the Promotion of Science
(JSPS).
(1) Uemura, D.; Ohwaki, H.; Hirata, Y.; Chen, Y.-P.; Hsu, H.-Y.
Figure 1. Structures of ingenol, 13-oxyingenol, and 13-oxyin-
genol derivative.
Tetrahedron Lett. 1974, 24, 2529.
(2) Fujiwara, M.; Okamato, M.; Ijichi, K.; Tokuhisa, K.; Hanasaki,
Y.; Katuura, K.; Uemura, D.; Shigeta, S.; Konno, K.; Yokota, T; Baba,
M. Arch. Virol. 1998, 143, 2003.
(3) Review: (a) Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387.
(b) Kuwajima, I; Tanino, K. Chem. Rev. 2005, 105, 4661. (c) Cha, J. K.;
Epstein, O. L. Tetrahedron 2006, 62, 1329.
(4) Total synthesis of ingenol: (a) Winkler, J. D.; Rouse, M. B.;
Greaney, M. F.; Harrison, S. J.; Jean, Y. T. J. Am. Chem. Soc. 2002,
124, 9726. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.;
Nakamura, T; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003,
125, 1498. (c) Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.;
Greene, B.; Yusuff, N.; Wood, J. L. J. Am. Chem. Soc. 2004, 126,
16300.
(5) Successful construction of insideÀoutside skeleton: (a) Funk,
R. L.; Olmstead, T. A.; Parvez, M. J. Am. Chem. Soc. 1988, 110, 3298.
(b) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett.
2000, 41, 3927. (c) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F.
Org. Lett. 2002, 4, 799. (d) Epstein, O. L.; Cha, J. K. Angew. Chem., Int.
Ed. 2005, 44, 121.
structures of ingenol derivatives, along with their
potent biological activity, have made them attrac-
tive targets for synthesis. Although several total synth-
eses and synthetic studies of 3 have been reported,3À5
the total synthesis of 1 has not been reported thus
far. In 2004, we achieved the formal synthesis of
optically active ingenol by using ring-closing
metathesis.6 This synthesis provides the first synthetic
access to optically active ingenol. In 2007, we reported
the construction of the insideÀoutside framework
of 13-oxyingenol by using intramolecular radical
(6) Watanabe, K.; Suzuki, Y.; Aoki, K.; Sakakura, A.; Suenaga, K.;
Kigoshi, H. J. Org. Chem. 2004, 69, 7802.
r
10.1021/ol103151k
Published on Web 03/29/2011
2011 American Chemical Society

cyclization and ring-closing metathesis.7 We describe
herein an improved synthetic route to the 13-oxyin-
genol skeleton.
of Funk’s keto ester 9 stereoselectively (Scheme 2).5a How-
ever, in the case of 13-oxyingenol, the methyl group was
introduced from the β face of enones 11 and 12 exclusively,
possibly because of the steric hindrance of the C-13 sub-
stituent. Therefore, we plannedthesynthesisof desired keto
ester 16 by hydrogenating seven-membered enone 15,
where hydrogen could be introduced from the β face of
15 because of the above-mentioned steric hindrance.
Our new retrosynthetic analysis of 13-oxyingenol (1) is
shown in Scheme 3. We planned toconstruct the B ring of 1
bya ring-opening reaction of epoxide 17. Epoxide17might
be obtained from triene 18 by regio- and stereoselective
dihydroxylation and epoxidation. The insideÀoutside
ABC ring system could be synthesized by intramolecular
spiro-cyclization of 20 and the ring-closing olefin metath-
esis reaction of 19. In this work, we decided to introduce a
hydroxy group at C-2, which we utilized for the introduc-
tion of the requisite functional group at the A ring.
Chloride 20 can be prepared from keto ester 16.
Scheme 1. Our Previous Synthesis of the Pentacyclic Carbon
Framework of 13-Oxyingenol
Scheme 3. Retrosynthetic Analysis of 13-Oxyingenol
The outline of our previous synthesis of the pentacyclic
carbon framework of 13-oxyingenol is shown in Scheme 1.
This strategy had a serious problem: the silicon-tether
group in compound 7 could not be successfully cleaved
by HF py, TBAF, or Tamao oxidation.8 Thus, we could
3
not yet introduce a methyl group at C-11 into the insi-
deÀoutside framework.
Scheme 2. Synthetic Strategy of 13-Oxyingenol
The starting point for this work was the construction of
keto ester 16. Therefore, we attempted to introduce
the methyl group at C-11 in seven-membered enone 21,
an intermediate in our previous synthesis,7,9 by using
1,3-dipolar cycloaddition and subsequent thermolysis
(Scheme 4).10 Treatment of 21with diazomethane afforded
the cycloadduct 22,11 which was thermolyzed in toluene to
givethe desiredenone 15 in 91% yield. A plausible reaction
mechanism of the thermolysis of 22 to 15 is illustrated in
Scheme 5. Stereoselective hydrogenation of 15 occurred
from the opposite side against the OTBS group to afford
the keto ester 16 as the desired diastereomer at C-11. The
stereochemistry of C-11 in 16 was confirmed by the
NOESY correlation between H-11 and the methyl group
On the other hand, in the synthetic study of ingenol by
Funk, the methyl group can be introduced from the R face
(9) Hayakawa, I.; Miyazawa, Y.; Ohyoshi, T.; Asuma, Y.; Aoki, K.;
Kigoshi, H. Synthesis 2011, 769.
(10) (a) Van Auken, T. V.; Rinehart, K. L. J. Am. Chem. Soc. 1962,
84, 3736. (b) Srikrishna, A.; Hemamalini, P. Indian J. Chem. 1990, 29,
242.
(11) X-ray crystallographic analysis of cycloadduct 22 is shown in
the SI.
(7) Hayakawa, I.; Asuma, Y.; Ohyoshi, T.; Aoki, K.; Kigoshi, H.
Tetrahedron Lett. 2007, 48, 6221.
(8) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics
1983, 2, 1694.
Org. Lett., Vol. 13, No. 9, 2011
2161

removal of the primary TBS group in 25a gave an allylic
alcohol, which was converted into chloride 20a, a precur-
sor for intramolecular spiro-cyclization. The alkylated
compound 24b was also converted into 25b and 25c, which
were separated by silica gel chromatography. Compounds
25b and 25c were converted into the corresponding chlor-
ides 20b and 20c in the same manner, respectively. The
stereochemistry of C-10in25b was determinedbythe NOE
correlation between H-10 and H-14.
Scheme 4. Syntheses of Alkylated Compounds 24a and 24b
Scheme 6. Syntheses of Chlorides 20aÀc, Precursors of Intra-
molecular Spiro-Cyclization
Scheme 5. Plausible Reaction Mechanism of Thermolysis of
Cycloadduct 22
of the cyclopropane part. 16 was alkylated with iodide
2312 to give alkylated compounds 24a and 24b, which
were the diastereomers of the secondary hydroxy group
at C-2. The stereochemistry of C-2 in 24a and 24b was
1
determined by the H NMR analysis of corresponding
spiro ketone 26a and 26b, respectively (Table 1 and
Supporting Information (SI)).
Table 1 summarizes the attempts at the intramolecular
spiro-cyclization of chlorides 20aÀc. In our previous
reports,6,7 similar intramolecular spiro-cyclization was
carried out by Et3CONa in boiling xylene. In entries 1, 3,
and 5, we examined cyclization under these conditions.
The spiro-cyclization of 20a afforded the desired spiro
ketone 26a (5%) and the undesired seven-membered ether
27a (5%) (entry 1). Also, the spiro-cyclization of 20b gave
similar results to that of 20a (desired 26b = 11%, un-
desired 27b = 11%) (entry 3). Treatment of 20c with
Et3CONa gave the desired 26b (57%) as the sole product
(entry 5). These results indicated that the stereochemistry
of the C-2 and C-10 positions in spiro-cyclization precur-
sors 20aÀc is an important factor in the yield of this
cyclization. The desired spiro ketones 26a and 26b are
obtained from the thermodynamic enolate. Therefore, 20a
in toluene was heated from room temperature to the
boiling point in 20 min to give the desired 26a in 86%
yield (entry 2). However, treatment of 20b under the same
conditions gave only the undesired 27b (entry 4). On the
other hand, treatment of 20c under the same conditions
gave the desired 26b, but the yield was low (33%) (entry 6).
Although we could not convert 20b into the desired spiro
ketone under these conditions, the epimerization of the
C-10 position in 25b by using t-BuOK afforded 25c, which
was converted into 26b through 20c (Scheme 7). The
Table 1. Study of Intramolecular Spiro-Cyclization
entry chloride solvent
temp
reflux
yield
1
2
3
4
5
6
20a
20a
20b
20b
20c
20c
xylene
26a = 5%, 27a = 5%
toluene rt to reflux 26a = 86%
xylene reflux 26b = 11%, 27b = 11%
toluene rt to reflux 27b = 42%
xylene reflux 26b = 57%
toluene rt to reflux 26b = 33%
The syntheses of precursors for intramolecular spiro-
cyclization are illustrated in Scheme 6. The methoxycar-
bonyl group of 24a was removed by heating with lithium
iodide to afford ketone 25a, which was obtained as a 3:1
inseparable mixture of C-10 diastereomers.13 Selective
(12) Iodide 23 was prepared from commercially available β-hydroxy-γ-
butyrolactone. The detailed synthetic procedures for 23 are given in the SI.
(13) Elsinger, F. Org. Synth., Coll. Vol. V. 1973, 76.
2162
Org. Lett., Vol. 13, No. 9, 2011

triflate 32, which was transformed into triene 18 by the
Negishi coupling.16 Regio- and stereoselective dihydroxyla-
tion of 18 with a stoichiometric amount of OsO4 gave diol
33, and the resulting secondary hydroxy group in 33 was
protected by a benzoyl group to afford allyl alcohol 34.
Epoxidation of 34 by using t-BuOOH and VO(acac)2 gave
epoxy alcohol 17. This epoxydation proceeded regio- and
stereoselectively. The benzoyl group of 17 was transformed
into p-bromobenzoate 35, and the stereochemistry of 35 was
determined by X-ray crystallographic analysis (Figure 2).
Scheme 7. Epimerization of C-10 Position in Compound 25b
stereochemistry of spiro ketone 26b was determined by the
NOE correlation between H-11 and allylic H-4 (see SI).
The stereoselectivity of this spiro-cyclization can be ex-
plained by our previous proposed transition state model.6
Alkylation of 26b byLDA and iodide 28gavethe desired
ketone 19 as the sole product (Scheme 8). The ring-closing
olefin metathesis of 19 with the second-generation Hovey-
daÀGrubbs catalyst14 gave tetracyclic ketone 29 in quan-
titative yield. The stereochemistry of 29 was determined by
NOESY correlations (see SI). Thus, we achieved the
construction of an insideÀoutside framework of 13-oxyin-
genol. The MPM group in 29 was removed, and the
resulting hydroxy group was oxidized by DessÀMartin
periodinane to afford diketone 30. Spiro-ketone 26a was
converted into 30 in the same manner.
Figure 2. X-ray crystallographic structure of 35.
Next, we attempted to construct an A ring of 13-oxyin-
genol (1) (Scheme 9). Diketone 30 was oxidized to enone 31
by ItoÀSaegusa oxidation.15 31 was converted into enol
In conclusion, we have achieved the synthesis of the fully
substituted tetracyclic skeleton of 13-oxyingenol by using
intramolecular spiro-cyclization and ring-closing olefin
metathesis as key steps. The construction of the A ring
part was established by using the C-2 hydroxy group. As a
preliminary work, we attempted the ring-opening reaction
of epoxide 17 to construct the allylic alcohol part of the B
ring under acidic, basic, or radical conditions. However,
the desired ring-opening compound could not be obtained.
A further approach toward the synthesis of 13-oxyingenol
is currently underway in our group.
Scheme 8. Synthesis of Diketone 30
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology
(MEXT), Japan; a grant from the Uehara Memorial
Foundation; and a grant from the Suntory Institute for
Bioorganic Research (SUNBOR GRANT). We would
like tothank Profs. Akira Sekiguchi and Masaaki Ichinohe
(University of Tsukuba) for the X-ray crystallographic
analysis and helpful discussions. We are grateful to Dr.
Kosuke Namba (Hokkaido University) for his useful
information on the 1,3-dipolar cycloaddition.
Scheme 9. Synthesis of Epoxy Alcohol 17
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Negishi, E.;King, A. O.;Okukado, N. J. Org. Chem. 1977, 42, 1821.
(14) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168.
(15) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
Org. Lett., Vol. 13, No. 9, 2011
2163