Total synthesis of marine diterpenoid kalihinene X

Article abstract of DOI:10.1016/S0040-4039(02)00212-5

Total synthesis of marine diterpenoid kalihinene X was achieved. This total synthesis involves regioselective coupling reaction of carbanion of alkyl sulfone with epoxyalcohol and construction of cis-decalin ring by intramolecular Diels-Alder reaction. The absolute configuration of kalihinene X could be determined by this total synthesis.

Full text of DOI:10.1016/S0040-4039(02)00212-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2227–2230
Total synthesis of marine diterpenoid kalihinene X
Hiroaki Miyaoka, Hiroshi Shida, Naohito Yamada, Hidemichi Mitome and Yasuji Yamada*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 17 December 2001; revised 21 January 2002; accepted 25 January 2002
Abstract—Total synthesis of marine diterpenoid kalihinene X was achieved. This total synthesis involves regioselective coupling
reaction of carbanion of alkyl sulfone with epoxyalcohol and construction of cis-decalin ring by intramolecular Diels–Alder
reaction. The absolute configuration of kalihinene X could be determined by this total synthesis. © 2002 Published by Elsevier
Science Ltd.
Kalihinane-type diterpenoid possessing cis- or trans-
decalin and tetrahydropyran or tetrahydrofuran as its
fundamental skeleton, is a highly functionalized marine
diterpenoid, bearing isocyano, isothiocyanato, for-
mamide, hydroxy and/or chlorine groups.1–15 Most
kalihinane-type diterpenoids exhibit antimicrobial,1–3
antifungal,1–3,5,7 cytotoxic,5 anthelmintic,4,6 anti-
fouling10–13 and antimalarial15 activity. Kalihinene X
(1), isolated from the Japanese marine sponge,
Acanthella cavernosa, by Fusetani in 1995, is a kalihi-
nane-type diterpene formamide having cis-decalin and
chlorinated tetrahydropyran moieties.10 The relative
configuration of kalihinene X (1) was determined by
NOESY though its absolute configuration remains to
be elucidated. Kalihinene X (1) inhibits the attachment
and metamorphosis of cyprid larvae of the barnacle,
Balanus amphitrite with EC50 of 0.49 mg/mL, while no
toxicity is found at this concentration. The total synthe-
sis of kalihinane-type diterpenoid has not been reported
to date.16 Consequently, the present study was under-
taken to determine the absolute configuration of kalihi-
nene X and establish a method for the total synthesis of
kalihinene X. This synthesis was achieved through
regio-selective alkylation of alkyl sulfone to epoxide
and intramolecular Diels–Alder reaction as key steps,
as discussed in the following.
NHCHO
H
O
O
10
H
H
A
10
1
RO
10
H
6
H
H
H
7
6
RO
H
O
11
O
O
O
14
Cl
kalihinene X (1)
Cl
B
C
Cl
Cl
OH
O
RO
H
HO
SO2Ph
OH
+
RO
SO2Ph
F
14
OR
OR
D
E
Scheme 1. Synthetic strategy for kalihinene X (1).
Keywords: biologically active compounds; marine metabolites; terpenes and terpenoids.
* Corresponding author. Tel.: +81-426-76-3046; fax: +81-426-76-3069; e-mail: yamaday@ps.toyaku.ac.jp
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00212-5

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H. Miyaoka et al. / Tetrahedron Letters 43 (2002) 2227–2230
Our synthetic strategy is presented in Scheme 1. We
decided to utilize the key intermediate A, capable of
being transformed into kalihinene X (1) via diastereose-
lective introduction of methyl and formamido groups at
C-10 position. cis-Decalin A may likely be formed by
intramolecular Diels–Alder reaction of trienone B
which would be obtainable from compound C in the
construction of enone and dienen. It was considered
that compound C could be produced from compound
D by removal of phenylsulfonyl group, chlorination at
C-14 and construction of tetrahydropyran moiety and
that compound D could be synthesized by a regioselec-
tive epoxide-opening reaction of carbanion of sulfone F
with epoxide E.
secondary hydroxy group, as TBDPS ether. Selective
methanolysis of TBS ether afforded allylic alcohol.
Epoxidation of the allylic alcohol according to Sharp-
less procedure18 gave epoxide 3 as a diastereomeric
mixture (10:1).19 Regioselective coupling reaction of an
anion of sulfone 420 with epoxyalcohol 3 was effectively
carried out to produce coupling product 5.21 The
phenylsulfonyl group of 5 was removed by treatment
with NaꢀHg in MeOH and two hydroxy groups were
protected as acetate to give diacetate 6, [a]2D2 –17.4° (c
0.81, CHCl3).22 The TBDPS group in 6 was removed by
treatment with TBAF to give allylic alcohol. A solution
of the allylic alcohol in CCl4 was refluxed in the pres-
ence of Ph3P to afford allylic chloride 7 as the sole
product. Reductive removal of acetate was carried out
by treatment with DIBAL-H to give diol, the selective
protection of whose primary hydroxy group as pivalate
gave alcohol 8. Alcohol 8 was subsequently treated with
Hg(OAc)2 in THF–H2O (3:1) and then reductively
The synthesis of kalihinene X (1) was conducted start-
ing from known (E,R)-3,7-dimethylocta-2,7-diene-1,6-
diol17 (2) (97% ee) (Scheme 2). The primary hydroxy
group in diol 2 was protected as TBS ether and the
SO2Ph
OH
O
a
b
HO
HO
BnO
H
OH
OTBDPS
OTBDPS
OH
2
3
5
BnO
SO2Ph
4
OAc
OAc
e
c
d
BnO
BnO
H
H
Cl
OTBDPS
OAc
OAc
7
6
OTBS
BnO
H
OH
H
PivO
g
h
f
PivO
BnO
O
H
OPiv
O
Cl
8
Cl
9
10
Cl
O
H
OH
CN
H
H
H
H
H
H
j
i
k
1
O
O
O
Cl
Cl
Cl
11
12
13
Scheme 2. Reagents and conditions: (a) (1) TBSꢀCl, Et3N, DMAP, CH2ClCH2Cl, rt, (2) TBDPSꢀCl, imidazole, DMF, rt, (3)
n
,
PPTS, MeOH, rt, 83% (three steps), (4) tBuOOH, (−)-DIPT, Ti(OiPr)4, 4 A MS, CH2Cl2, −20°C, 95%; (b) 4, BuLi, THF, −78°C
to rt; (c) (1) NaꢀHg, Na2HPO4, MeOH, rt, 89% (two steps), (2) Ac2O, pyridine, DMAP, 60°C, 82%; (d) (1) TBAF, AcOH–THF,
60°C, quant., (2) CCl4, Ph3P, reflux, 86%; (e) (1) DIBAL-H, toluene, −78°C, (2) PivꢀCl, pyridine, rt, 78% (two steps); (f) (1)
Hg(OAc)2, THF/H2O (3:1), rt, (2) NaBH4, MeOH–KOH aq., 41% (two steps); (g) (1) H2, PdꢀC, EtOH, 94%, (2) Dess–Martin
periodinane, CH2Cl2, rt, 93%, (3) vinyl magnesium bromide, THF, 0°C, 89%, (4) TBSꢀCl, imidazole, DMF, rt, 96%; (h) (1)
n
DIBAL-H, toluene, −78°C, 90%, (2) Dess–Martin periodinane, CH2Cl2, rt, (3) CH2ꢁC(CH3)CH2P(O)Ph2, BuLi, HMPA, THF,
t
−78°C to rt, (4) TBAF, THF, rt, 75% (three steps); (i) Dess–Martin periodinane, CH2Cl2, rt, 93%; (j) (1) TsCH2NC, BuOK,
DME/tBuOH (5:1), 0°C to rt, 96%, (2) KHMDS, MeI, toluene, rt, 83%; (k) (1) DIBAL-H, toluene, −78°C, 91%, (2) NaClO2,
2-methyl-2-butene, NaH2PO4, tBuOH/H2O (4:1), (3) DPPA, Et3N, toluene, rt to 100°C, (4) DIBAL-H, toluene, −78°C, 63% (three
steps).

H. Miyaoka et al. / Tetrahedron Letters 43 (2002) 2227–2230
2229
demercurated with NaBH4,23 giving tetrahydropyran 9,
[h]2D2 –13.4° (c 0.71, CHCl3). Compound 9 was con-
verted to TBS ether 10 in four steps: (1) removal of Bn
group by hydrogenolysis to give primary alcohol, (2)
oxidation of the hydroxy group with Dess–Martin
periodinane24 to give aldehyde, (3) vinylation with vinyl
magnesium bromide to give a secondary alcohol as a
diastereomeric mixture (1:1) and (4) protection of the
hydroxy group as TBS ester. TBS ether 10 was con-
verted to allylic alcohol 11 as follows: (1) reductive
removal of pivaloyl group with DIBAL-H to give pri-
mary alcohol, (2) oxidation of the hydroxy group with
Dess–Martin periodinane24 to produce aldehyde, (3)
reaction of 2-methyl-2-propenyldiphenylphosphine
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product.26 Ketone 12 was treated with tosylmethyl iso-
cyanide (TsCH2NC)27 and tBuOK in DME–tBuOH
(5:1) to produce nitrile as a diastereomeric mixture (1:1)
at the cyano group. Without separation of the
diastereomers, methylation at C-10 was conducted with
KHMDS then CH3I to afford compound 13 along with
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DIBAL-H gave aldehyde and subsequent oxidation
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acid. Treatment of this carboxylic acid with
diphenylphosphoryl azide (DPPA)28 and Et3N afforded
isocyanate and reduction with DIBAL-H led to kalihi-
nene X (1), [h]2D7 +24.4° (c 0.34, CHCl3). Spectral data
and sign of optical rotation of synthetic kalihinene X
(1) were identical with those of natural kalihinene X,
[h]2D3 +26.7° (c 0.31, CHCl3).10 The absolute configura-
tion of kalihinene X was clearly shown to be 1 from the
present synthesis.
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A has been
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19. The mixture of epoxide 3 and its diastereomer was not
separable.
20. Sulfone
4 was prepared by oxidation of 3-benzyl-
oxypropyl phenyl sulfide29 with OXONE®30 in MeOH–
H2O (1:1).
Acknowledgements
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from diastereomer of epoxide 3, was purified.
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The authors express their appreciation to Professor
Nobuhiro Fusetani, The University of Tokyo, and Dr.
Hiroshi Hirota, RIKEN (The Institute of Physical and
Chemical Research), for providing the NMR spectral
data of natural kalihinene X. This work was supported
by a Grant-in-Aid for Scientific Research from Ministry
of Education, Culture, Sports, Science and Technology
of Japan.
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