Total synthesis of antimalarial diterpenoid (+)-kalihinol A

Article abstract of DOI:10.1039/c1cc16468f

Total synthesis of antimalarial diterpenoid (+)-kalihinol A, isolated from marine sponge Acanthella sp., is achieved. This total synthesis involves regioselective alkylation of an epoxide, construction of a tetrahydropyran ring by iodo-etherification, construction of a cis-decalin ring by intramolecular Diels-Alder reaction, isomerization of cis-decalin to trans-decalin, and subsequent functionalization of the trans-decalin ring.

Full text of DOI:10.1039/c1cc16468f

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COMMUNICATION
Total synthesis of antimalarial diterpenoid (+)-kalihinol Aw
Hiroaki Miyaoka,* Yasunori Abe, Nobuaki Sekiya, Hidemichi Mitome and
Etsuko Kawashima
Received 18th October 2011, Accepted 21st November 2011
DOI: 10.1039/c1cc16468f
Total synthesis of antimalarial diterpenoid (+)-kalihinol A,
isolated from marine sponge Acanthella sp., is achieved. This
total synthesis involves regioselective alkylation of an epoxide,
construction of a tetrahydropyran ring by iodo-etherification,
construction of a cis-decalin ring by intramolecular Diels–Alder
reaction, isomerization of cis-decalin to trans-decalin, and
subsequent functionalization of the trans-decalin ring.
and isocyano groups at C-10 and transformation of the azido
group at C-5 to an isocyano group. trans-Decalin A is obtained
by diastereoselective introduction of hydroxy and azido groups
and isomerization of cis-decalin B to trans-decalin. cis-Decalin B
may likely be formed by intramolecular Diels–Alder reaction of
triene C, which would be obtained from tetrahydropyran D by
the construction of diene and dienophile. Tetrahydropyran D is
obtained from compound E by introduction of a chlorine atom
with the inversion of stereochemistry at C-14 and formation of
the tetrahydropyran ring using iodo-etherification. Compound E
is obtained by regioselective alkylation of epoxyalcohol G using
Grignard reagent F.
Various terpene isocyanides have been isolated from marine
invertebrates and many of these are of considerable interest from
the standpoint of their respective biological activities.1 Kalihinol
A (1), isolated from the marine sponge Acanthella sp. by Scheuer
and co-workers in 1984, is a richly functional diterpenoid
possessing isocyano, hydroxy, tetrahydropyranyl and chlorine
moieties. The relative configuration of kalihinol A (1) was
demonstrated by X-ray analysis.2 The absolute configuration of
1 was determined using CD exciton chirality methods by the
authors.3 Since kalihinol A was first isolated, more than forty
different kalihinane-type diterpenoids, possessing isocyano,
isothiocyano and/or formamido moieties, have been isolated and
identified from marine sponges.4a–4i Kalihinane-type diterpenoids
have demonstrated extensive biological activities including anti-
microbial,2,4a,4b,4i antifungal,2,4a,4b,4d cytotoxic,4d anthelmintic4c
and antifouling4e–4g activities. Kalihinol A is particularly noted
for its antimalarial activity against Plasmodium falciparum
(EC50 1.2 Â 10À9 M) and possesses a remarkable selective index
(SI 317), defined as the ratio of FM3A cell cytotoxicity to
P. falciparum.4h The total syntheses of two kalihinane-type diter-
penoids were reported. The authors reported the total synthesis of
(+)-kalihinene X possessing a cis-decalin ring system.5 Wood and
co-workers reported the synthesis of (Æ)-kalihinol C possessing a
tetrahydrofuranyl ring.6 The authors achieved the first total
synthesis of (+)-kalihinol A by construction of a tetrahydropyran
ring via iodo-etherification and a cis-decalin ring via an intra-
molecular Diels–Alder cycloaddition reaction as key steps.
Our synthetic strategy is presented in Scheme 1. (+)-Kalihinol
A is synthesized from trans-decalin A by transduction of methyl
Scheme 1 Synthetic strategy for kalihinol A.
cis-Decalin 10 was synthesized from (E,R)-3,7-dimethylocta-
2,7-diene-1,6-diol (2)7 (97% ee) (Scheme 2). The primary
hydroxy group in diol 2 was protected as a TBS ether and
the secondary hydroxy group was protected as a TBDPS ether.
Selective deprotection of the TBS group by treatment with PPTS
in MeOH afforded the allylic alcohol in 83% yield (3 steps).
School of Pharmacy, Tokyo University of Pharmacy and
Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
E-mail: miyaokah@toyaku.ac.jp; Fax: +81 42 676 3073;
Tel: +81 42 676 3080
w Electronic supplementary information (ESI) available: Experimental
procedures and characterisation for new compounds. See DOI:
10.1039/c1cc16468f
c
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Chem. Commun., 2012, 48, 901–903 901

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alcohol as a diastereomeric mixture (1 : 1) in 99% yield,
and subsequent protection of the hydroxy group using TBSCl
to give TBS ether 8 in 99% yield. The pivaloyl group in 8 was
removed using DIBAH to give the primary alcohol in 97% yield,
oxidized using Dess–Martin periodinane to give the aldehyde,
and subsequently treated with CH2QC(CH3)CH2P(O)Ph2 with
BuLi in the presence of HMPA to afford triene 9 in 78% yield
(2 steps).12 Deprotection of the TBS group in triene 9 gave the
allylic alcohol in 96% yield, which was then oxidized with
Dess–Martin periodinane to facilitate, via endo-selective intra-
molecular Diels–Alder reaction, in the spontaneous formation
of cis-decalin 10 as a sole product in 99% yield.13
Epoxidation of ketone 10 using mCPBA in the presence of
Na2HPO4 generated a mixture of desired a-epoxide 11a and its
diastereomer b-epoxide 11b (11a : 11b = 1 : 3) in 95% yield
(Fig. 1). Furthermore, when other epoxidation reagents
(magnesium monoperoxyphthalate, DMDO) were used, the
desired a-epoxide 11a was obtained as a minor product. The
relative configuration of a-epoxide in 11a was confirmed by
X-ray crystallographic analysis. In an effort to obtain a-epoxide
as a major product, the oxygenated functional group at C-10 in
10 was used.
Ketone 10 was reduced with NaBH4 to afford the b-alcohol
as a major product in 95% yield (b-OH : a-OH = 5 : 1)
(Scheme 3). The hydroxy group in the b-alcohol was protected
as a TBS ether in quantitative yield. Epoxidation of the TBS
ether was achieved using mCPBA in the presence of Na2HPO4
to give the desired a-epoxide 12 as a sole product in 99% yield.
Deprotection of the TBS group in a-epoxide 12 was achieved
by treatment with TBAF to afford the secondary alcohol in
93% yield, which was then oxidized using 2-iodoxybenzoic
acid (IBX) in THF–DMSO to give the ketone in 95% yield.14
The ketone was treated with NaN3 in the presence of NH4Cl
to give trans-decalin 13 and cis-decalin 14 (13 : 14 = 2 : 1) in
95% yield. Following separation of these compounds, cis-decalin
14 was treated with tBuOK in EtOH to afford a mixture of trans-
decalin 13 and cis-decalin 14 (13 : 14 = 3 : 2) in 99% yield.
trans-Decalin 13 was treated with 2-(methylsulfonyl)benzo-
thiazole15 and LiHMDS to give exo-olefine 15 in 88% yield
(Scheme 4). When using the Wittig reagent (Ph3P+CH3IÀ and
BuLi), exo-olefine 15 (24% yield) and the epoxide (24% yield)
were obtained, and trans-decalin 13 (22%) was recovered.
Scheme 2 Reagents and conditions: (a) TBSCl; (b) TBDPSCl; (c) PPTS,
83% (3 steps); (d) D-(À)-DET, TBHP, Ti(OiPr)4, 95%; (e) 4, CuI, 94%;
(f) Ac2O, DMAP, Py, 82%; (g) TBAF, 95%; (h) CCl3COCCl3, PPh3,
90%; (i) DIBAH; (j) PivCl, Py, 78% (2 steps); (k) IDCP; (l) Bu3SnH,
Et3B, 72% (2 steps); (m) H2, Pd/C, 99%; (n) Dess–Martin periodinane,
98%; (o) CH2QCHMgBr, 99%; (p) TBSCl, 99%; (q) DIBAH, 97%;
(r) Dess–Martin periodinane; (s) CH2QC(CH3)CH2P(O)Ph2, BuLi,
78% (2 steps); (t) TBAF, 96%; (u) Dess–Martin periodinane, 99%.
Sharpless asymmetric epoxidation of the aforementioned allylic
alcohol afforded epoxyalcohol 3 in 95% yield (87% de).
Regioselective nucleophilic alkylation of epoxyalcohol 3 with
Grignard reagent 48 in the presence of CuI afforded diol 5 in
94% yield as a sole product. The two hydroxy groups in 5 were
acetylated with Ac2O and DMAP in pyridine to give the
diacetate in 82% yield. The TBDPS group was deprotected by
treatment with TBAF in the presence of AcOH to afford the
allylic alcohol in 95% yield. The allylic alcohol was treated with
CCl3COCCl3 and Ph3P to give allylic chloride 6 in 90% yield
with concomitant inversion of the stereochemical configuration
at C-14.9 Although the allylic alcohol was converted into allylic
chloride 6 by treatment with Ph3P in CCl4 under reflux, the
reproducibility of the reaction was invariably poor. The two
acetyl groups in 6 were removed with DIBAH to give the diol,
the primary hydroxy group of which was protected to give the
mono pivalate in 78% yield (2 steps). Intramolecular iodo-
etherification of the mono pivalate was achieved by treatment
with iodonium di-sym-collidine perchlorate (IDCP)10 to give
iodotetrahydropyran, which was dehalogenated by Bu3SnH and
Et3B to afford tetrahydropyran 7 in 72% yield (2 steps).
Although tetrahydropyran 7 was also obtained by intramolecular
alkoxymercuration (1. Hg(OAc)2, THF–H2O, 2. NaBH4,
MeOH–KOH aq.), the chemical yield was low (41% yield).
The Bn group in tetrahydropyran 5 was removed by hydro-
genolysis to give the primary alcohol in 99% yield, oxidized
using Dess–Martin periodinane11 to give the aldehyde in 98%
yield, vinylated using vinyl magnesium bromide to the secondary
Fig. 1 Epoxidation of cis-decalin 10 and ORTEP drawing of epoxide 11a.
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902 Chem. Commun., 2012, 48, 901–903
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with LiBHEt3 to afford tosylamide 17 in 83% yield. Deprotection
of the tosyl group with lithium naphthalenide18 in 17 afforded the
diamine, which upon formylation with acetic formic anhydride
and subsequent dehydration with TsCl and pyridine19 gave
(+)-kalihinol A (1) in 74% yield (3 steps). The spectral data
and sign of the optical rotation of synthetic (+)-kalihinol A,
[a]D25 +12.4 (c 0.64, CHCl3), were identical with those of natural
kalihinol A, [a]D +16.0 (c 1.0, CHCl3).2 Hence, the first total
synthesis of (+)-kalihinol A was achieved.
Notes and references
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Scheme 3 Reagents and conditions: (a) NaBH4, 95%; (b) TBSCl,
quant.; (c) mCPBA, 99%; (d) TBAF, 93%; (e) IBX, 95%; (f) NaN3,
4 (a) A. Patra, C. W. J. Chang, P. J. Scheuer, G. D. Van Duyne,
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a sole product in 46% yield.16 The relative configuration of
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6H2O17 to give the amine (84% yield), which was then treated
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Scheme 4 Reagents and conditions: (a) 2-(methylsulfonyl)benzothiazole,
LiHMDS, 88%; (b) PhIQNTs, Cu(OTf)2, 46%; (c) NaBH4, NiCl2Á6H2O,
84%; (d) LiBHEt3, 83%; (e) Li, naphthalene; (f) acetic formic anhydride;
(g) TsCl, Py, 74% (3 steps).
´
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Chem. Commun., 2012, 48, 901–903 903