A formal synthesis of antimalarial diterpenoid 7,20-diisocyanoadociane

Article abstract of DOI:10.1246/cl.2011.246

A formal synthesis of antimalarial diterpenoid 7,20-diisocyanoadociane, isolated from marine sponge Adocia sp., was achieved. The authors synthesized Corey's synthetic intermediate 2 for 7,20-diisocyanoadociane. This synthesis involves the synthesis of a perhydropyrene derivative using a sequential isomerizationintramolecular DielsAlder reaction as the key step.

Full text of DOI:10.1246/cl.2011.246

doi:10.1246/cl.2011.246
246
Published on the web February 5, 2011
A Formal Synthesis of Antimalarial Diterpenoid 7,20-Diisocyanoadociane
Hiroaki Miyaoka,*1 Yusuke Okubo,1 Makiko Muroi,1 Hidemichi Mitome,2 and Etsuko Kawashima1
1School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392
2Faculty of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578
(Received December 13, 2010; CL-101051; E-mail: miyaokah@toyaku.ac.jp)
A
formal synthesis of antimalarial diterpenoid 7,20-
NC
O
H
H
H
diisocyanoadociane, isolated from marine sponge Adocia sp.,
was achieved. The authors synthesized Corey’s synthetic
intermediate 2 for 7,20-diisocyanoadociane. This synthesis
involves the synthesis of a perhydropyrene derivative using a
sequential isomerization-intramolecular Diels-Alder reaction as
the key step.
7
7
H
H
H
H
H
O
20
CN
20 H
H
H
1
H
2
7,20-diisocyanoadociane (1)
Figure 1. Structures of 7,20-diisocyanoadociane (1) and Corey’s
synthetic intermediate 2.
7,20-Diisocyanoadociane (1) is a marine diterpenoid iso-
lated from a marine sponge of the genus Adocia collected in
Australia, on the Great Barrier Reef.1 7,20-Diisocyanoado-
ciane (1) has a unique all-trans-perhydropyrene ring system
(Figure 1). The relative configuration of 1 was demonstrated by
single-crystal X-ray analysis1 and the absolute configuration of 1
was determined by its total synthesis by Corey.2 7,20-Diisocya-
noadociane strongly inhibits proliferation of the malaria parasite
Plasmodium falciparum.3-5 The biological activity and unique
structural features prompted the synthetic chemists to undertake
its preparation.6 Total synthesis of 1 using the intramolecular
Diels-Alder reaction by Corey2 and formal synthesis of 1 using
the intramolecular Michael reaction by Mander7 have been
reported. The authors achieved the synthesis of Corey’s
synthetic intermediate 2 via the construction of all-trans-
perhydropyrene derivative by the sequential isomerization-
intramolecular Diels-Alder reaction as the key step.
1) DIBAH
CH2Cl2
-78 °C
O
LDA, HMPA
THF, -78 °C
O
BnO
O
O
O
then
2) BnOH
p-TsOH
Ph-H, reflux
98% (2 steps)
Br
79%
TBSO
BnO
3
5
4
1) BH3
THF, 0 °C
NaOH
TBSO
HO
1) H2, Pd(OH)2,
AcOEt, 86%
2)
MgBr
H2O2, 86%
2) TBSCl
imidazole
DMF, 97%
O
Et2O
0 °C, 99%
HO
6
7
OTBS
OH
1) TrCl
pyridine
90%
1) NaH
DMSO
TsO
cis-Decalin 11 was synthesized from (S)-4-methyltetrahy-
dro-2H-pyran-2-one (3)8 (Scheme 1). Lactone 3 was treated with
LDA in the presence of HMPA followed by allyl bromide to
give trans-lactone 4 as a sole product in 79% yield. Lactone 4
was reduced to the hemiacetal with DIBAH and treatment with
benzyl alcohol and p-TsOH gave benzyl acetal 5 as a
diastereomeric mixture (3:2). Hydroboration-oxidation of the
terminal olefin in 5 provided the primary alcohol, and protection
of the hydroxy group as a TBS ether afforded TBS ether 6.
Following deprotection of the benzyl acetal in 6 by hydro-
genolysis, the resulting hemiacetal was treated with allylmag-
nesium bromide to afford diol 7 as a diastereomeric mixture
(5:3). The hemiacetal did not react with the Wittig reagent or
Horner-Wadsworth-Emmons reagent, the hemiacetal was re-
covered. The primary hydroxy group in diol 7 was protected as
a Tr ether and the secondary hydroxy group was converted to
tosylate 8. Treatment of tosylate 8 with NaH in DMSO resulted
in elimination of tosylate to give (E)-diene and deprotection
of TBS with TBAF gave alcohol 9. Oxidation of alcohol 9
with IBX gave the aldehyde and subsequent vinylation with
vinylmagnesium chloride afforded allylic alcohol 10. Allylic
alcohol 10 was oxidized with IBX in DMSO via the spontaneous
endo-selective intramolecular Diels-Alder reaction of the
generated enone to afford cis-decalin 11 as a sole product in
74% yield.9
2) TBAF, THF
84% (2 steps)
2) TsCl, DMAP
Et3N
CH2Cl2
89%
TrO
TrO
8
9
OH
O
1) IBX
H
H
DMSO
IBX
DMSO, THF
THF, 92%
H
H
74%
2)
MgCl
THF, 0 °C
88%
TrO
TrO
10
11
Scheme 1. Synthesis of cis-decalin 11.
Construction of the perhydropyrene skeleton was performed
by a sequential isomerization-intramolecular Diels-Alder reac-
tion (Scheme 2). The ketone in cis-decalin 11 was reduced with
NaBH4 and the resulting secondary hydroxy group was
protected to give TBS ether 12 as a diastereomeric mixture.
The Tr group in 12 was deprotected by treatment with Et2AlCl to
give the primary alcohol, which was then oxidized with IBX to
afford aldehyde 13. Aldehyde 13 was treated with the Horner-
Wadsworth-Emmons reagent 1410 and LHMDS in the presence
of HMPA to give (E,E)-¡,¢,£,¤-unsaturated ester 15 in 81%
yield (E,E:E,Z = 21:1). Unsaturated ester 15 was reduced with
Chem. Lett. 2011, 40, 246-247
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

247
O
H
OTBS
H
O
H
O
H
1) Et2AlCl
CH2Cl2
97%
1) NaBH4
MeOH
H
H
H
H
H
H
H
H
HO
0 °C, 99%
IBX
H
H
H
H 11
H
H
OHC
2) TBSOTf
2,6-lutidine
CH2Cl2
2) IBX
DMSO, THF
92%
DMSO
THF
72%
H
H
TrO
TrO
0 °C, 93%
11
12
20a
19a
MeO2C
OTBS
H
TBAF
THF, 67%
OTBS
O
H
H
P(OEt)2
O
H
O
14
H
H
H
H
H
1) H2, Pd-C
AcOEt
MeO2C
LHMDS, HMPA
THF, -78 °C, 81%
H
H
H
H
H
11
O
O
OHC
15
2) NaOMe
15
H
H
H
13
MeOH, THF
OTBS
H
15
70% (2 steps)
H
1) TrCl, pyridine
2) TBAF, THF, 50 °C
H
2
21a
OH
LiAlH4
Ref. 2
MsOH, Ph-Cl
100 °C, 50%
Et2O, 0 °C
95%
3) IBX
DMSO,THF
78% (3 steps)
7,20-diisocyanoadociane (1)
H
O
H
O
H
15
16
O
O
H
1) IBX
DMSO
THF
H
H
HO
H
H
H11
H
H
11
O
OTr
OTr
DBU, BHT
8
H
H
H
H
H
2) TBAF
THF
11% (2 steps)
H
H
1
mesitylene
220 °C, 82%
1
H
H
H
H
H
21b
19b
18
17
O
H
O
H
H
H
Scheme 3. Formal synthesis of 7,20-diisocyanoadociane.
HO
HO
Et2AlCl
H
H
H
H
H
+
achived by treatment with methanesulfonic acid (MsOH) in
chlorobenzene at 100 °C to give diketone 21a as a major product
(21a:21b = 25:4) in 50% yield. Diketone 21a was hydrogenated
and isomerized at C-15 to afford all-trans-perhydropyrene
derivative 2, which was Corey’s synthetic intermediate.2 Spectral
CH2Cl2
63%
H
H
H
H
19a
(19a : 19b = 5 : 6)
19b
25
data and sign of the optical rotation of synthetic 2, ½¡ꢀD +13.0
Scheme 2. Synthesis of perhydropyrene derivative 19.
(c 0.91, CHCl3), were identical with those of Corey’s inter-
23
mediate, ½¡ꢀD +7.5 (c 2.5, CHCl3), ca. 60% ee.2 Therefore the
LiAlH4 to allylic alcohol 16, whose hydroxy group was
protected as a Tr ether. The TBS group was removed by
treatment with TBAF and the resulting secondary alcohol was
oxidized with IBX to give ketone 17. Ketone 17 is a substrate of
the sequential isomerization-intramolecular Diels-Alder reac-
tion as the key step. When ketone 17 was heated in the presence
of DBU and BHT in mesitylene at 220 °C, an intramolecular
Diels-Alder reaction following isomerization at C-8 occurred to
afford a diastereomeric mixture of perhydropyrene derivative 18
(exo:endo = 5:6) in 82% yield. This sequential reaction did not
occur in the absence of DBU. This is the first example of a
sequential isomerization-intramolecular Diels-Alder reaction in
the presence of a base. Since chromatographic separation of the
exo/endo mixture of 18 was difficult, the mixture was subjected
to deprotection of the Tr group by treatment with Et2AlCl which
then allowed for chromatographic separation to provide exo-
adduct 19a and endo-adduct 19b (19a:19b = 5:6), respectively.
Corey’s synthetic intermediate was synthesized from per-
hydropyrene derivatives 19a and 19b (Scheme 3). Alcohol 19a
was oxidized by IBX to give aldehyde 20a, which was then
deformylated11 and isomerized at C-11 by treatment with TBAF
to afford diketone 21a. On the other hand, conversion of alcohol
19b to enone 21a via isomerization at C-1 was examined.
Alcohol 19b was converted to diketone 21b by similar methods
via the aldehyde. Isomerization of C-1 in diketone 21b was
formal synthesis of 7,20-diisocyanoadociane was achieved.12
References and Notes
1
J. T. Baker, R. J. Wells, W. E. Oberhänsli, G. B. Hawes, J. Am. Chem.
Soc. 1976, 98, 4010.
2
3
E. J. Corey, P. A. Magriotis, J. Am. Chem. Soc. 1987, 109, 287.
A. D. Wright, G. M. König, C. Angerhofer, P. Greenidge, A. Linden,
R. Desqueyroux-Faundez, J. Nat. Prod. 1996, 59, 710.
4
5
A. D. Wright, H. Wang, M. Gurrath, G. M. König, G. Kocak, G.
Neumann, P. Loria, M. Foley, L. Tilley, J. Med. Chem. 2001, 44, 873.
Reviews of antimalarial isocyano-containg compounds: E. Fattorusso,
O. Taglialatela-Scafati, Mar. Drugs 2009, 7, 130.
6
7
8
9
I. Mancini, G. Guella, A. Defant, Mini Rev. Med. Chem. 2008, 8, 1265.
K. A. Fairweather, L. N. Mander, Org. Lett. 2006, 8, 3395.
C. J. Francis, J. B. Jones, J. Chem. Soc., Chem. Commun. 1984, 579.
Similar stereoselective intramolecular Diels-Alder reactions have been
reported, see: a) R. D. White, G. F. Keaney, C. D. Slown, J. L. Wood,
Org. Lett. 2004, 6, 1123. b) H. Miyaoka, H. Shida, N. Yamada, H.
Mitome, Y. Yamada, Tetrahedron Lett. 2002, 43, 2227. c) R. D. White,
J. L. Wood, Org. Lett. 2001, 3, 1825. d) K. Takasu, R. Katagiri, Y.
Tanaka, M. Toyota, H.-S. Kim, Y. Wataya, M. Ihara, Heterocycles
2001, 54, 607. e) K. A. Parker, J. G. Farmar, J. Org. Chem. 1986, 51,
4023. f) T. Kitahara, H. Kurata, T. Matsuoka, K. Mori, Tetrahedron
1985, 41, 5475. g) D. F. Taber, B. P. Gunn, J. Am. Chem. Soc. 1979,
101, 3992.
10 E. J. Corey, B. W. Erickson, J. Org. Chem. 1974, 39, 821.
11 C. Kuroda, A. Murase, H. Suzuki, T. Endo, S. Anzai, Bull. Chem. Soc.
Jpn. 1998, 71, 1639.
12 Supporting Information is available electronically on the CSJ-Journal
Web site, http://www.csj.jp/journals/chem-lett/index.html.
Chem. Lett. 2011, 40, 246-247
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/