Asymmetric total synthesis of halicholactone

Article abstract of DOI:10.1016/S0040-4039(00)00434-2

The total synthesis of halicholactone by using the chirality of (diene)Fe(CO)₃ complexes was reported. The key steps of the synthesis include catalytic asymmetric alkylation, regio- and stereoselective phenylsulfenylation, regio- and stereoselective cyclopropanation and formation of a nine-membered lactone by ring-closing metathesis. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00434-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3653–3656
Asymmetric total synthesis of halicholactone
Yoshiji Takemoto,a,∗ Yasutaka Baba,b Goutum Saha,b,† Syusuke Nakao,b Chuzo Iwata,b
Tetsuaki Tanaka b,∗ and Toshiro Ibuka a,‡
aGraduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
bGraduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
Received 18 February 2000; revised 6 March 2000; accepted 10 March 2000
Abstract
The total synthesis of halicholactone by using the chirality of (diene)Fe(CO)3 complexes was reported. The
key steps of the synthesis include catalytic asymmetric alkylation, regio- and stereoselective phenylsulfenylation,
regio- and stereoselective cyclopropanation and formation of a nine-membered lactone by ring-closing metathesis.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: iron and compounds; cyclopropanation; ring-closing metathesis; total synthesis; halicholactone.
The marine metabolites, halicholactone 1a and neohalicholactone 1b, were isolated from the marine
sponge Halichondoria okadai by the Yamada group as lipoxygenase inhibitors in 1989.1 The absolute
stereochemistry of 1a and 1b, (8S,9R,11R,12R,15R), was established by Wills and co-workers through
their first total synthesis.2 These compounds possess a number of unusual structural features, including
a nine-membered lactone, trans-disubstituted cyclopropane ring, and bis-allylic alcohol. Although the
formal total synthesis of 1a was also reported by Datta and Mohapatr in 1997,3 the stereoselective
construction of the stereogenic centers of C-9 to C-12 still remained to be solved. Accordingly, we
planned a stereoselective asymmetric synthesis of 1a using the chirality of (diene)Fe(CO)3.4
To this end, our synthetic approach was initiated with the chiral Fe(CO)3 complex 6, prepared
from the dialdehyde Fe(CO)3 complex 7 by the catalytic asymmetric alkylation that we had already
reported.5 Stereoselective introduction of the hydroxy and phenylsulfenyl groups using the chirality of a
(diene)Fe(CO)3 complex (6→5) was followed by 1,3-migration of a sulfoxide, giving the triol derivative
4. Regio- and stereoselective cyclopropanation by the modified Simmons–Smith reaction of 4 and the
nine-membered lactone formation by the ring-closing metathesis of 2 produced the aimed natural product
1a (Scheme 1). We report here the stereoselective total synthesis of halicholactone 1a using the chiral
(diene)Fe(CO)3 complex 6.
∗
Corresponding author. E-mail: takemoto@pharm.kyoto-u.ac.jp (Y. Takemoto)
Current address: Claude Pepper Institute, Florida Institute of Technology, Melbourne, FL 32901, USA.
Deceased January 20, 2000.
†
‡
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00434-2
tetl 16714

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Scheme 1.
We initiated this study with the elongation and functionalization of the TBS-ether 8, which was
prepared from 6 in the usual manner. Successive subjection of 8 to Horner–Emmons reaction and DIBAL-
H reduction gave the allylic alcohol 10 in 97% yield. The dihydroxylation of 10 with OsO4 proceeded
stereoselectively to afford the triol 11 as an inseparable diastereoisomeric mixture in a 9:1 ratio (detected
from 500 MHz 1H NMR).6 The regioselective protection of three hydroxyl groups of 11 with PivCl and
TBSOTf gave 12a and 12b, respectively. Furthermore, the diols 12a and 12b were converted into the bis-
chloroacetoxy compounds 13a and 13b, respectively. At this stage, the diastereoisomers contaminated
in 13a and 13b were separated by silica gel column chromatography (Scheme 2). The stereochemistry
of 13b was unambiguously determined by X-ray crystallographic analysis. We next examined the first
key step, that is, stereoselective introduction of a phenylsulfanyl group by nucleophilic substitution.7
Treatment of the diol 12b with TMSSPh and Sc(OTf)3 in CH2Cl2 at room temperature provided the
undesired product 14 as the sole product. However, the reaction of 13a, bearing a more reactive leaving
group, with Me2AlSPh8 gave the desired phenylsulfide 5 regio- and stereoselectively.
Scheme 2. Conditions: (a) TBSOTf, pyridine, 0°C, 100%; (b) (EtO)2P(O)CH2CO2Et, NaH, THF, 0°C, 99%; (c) DIBAL-H,
CH2Cl2, −78°C, 97%; (d) (i) OsO4, Py, −20°C; (ii) sat. aq. NaHSO3, 94%; (e) PivCl, Py, CH2Cl2, 0°C to rt, 97%; (f) TBSOTf,
pyridine, 0°C, 56% (89% based on the consumed 11); (g) (ClCH2CO)2O, DMAP, CH2Cl2, 13a: 89%, 13b: 81%; (h) TMSSPh,
Sc(OTf)3, CH2Cl2, −78°C to rt (62%); (i) Me2AlSPh, CH2Cl2, −78°C, 69%
To next investigate the second key step, that is, the regio- and stereoselective Simmons–Smith reaction,
14 was transformed into the alcohol 4 (Scheme 3). After decomplexation of 14 with CAN (ceric(IV)
ammonium nitrate), successive treatment of the resulting sulfide 15 with m-CPBA and P(OMe)3 in
refluxing MeOH furnished the allylic alcohol 17 in good yield. We presumed that the group-selectivity of
the two olefins in 17 and diastereomeric face-selectivity of the C3–C4 double bond could be controlled
by the hydroxyl group of C2.9 After 17 was converted into the requisite product 4 by the usual
protection–deprotection protocol, the reaction of 4 with 2.5 equiv. of Et2Zn and 3.0 equiv. of CH2I2

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in CH2Cl2 at −20°C, as expected, provided the desired mono-cyclopropanated product 3 in 68% yield
as a single product (11% recovered of 4). The homoallylic alcohol 21a was synthesized from 3 by the
following sequence: removal of the pivaloyl group with MeLi, cleavage of a 1,2-diol with Pb(OAc)4, and
introduction of an allyl group.10 Although this manipulation gave the undesired product 21b along with
21a, 21b was easily converted into 21a via the standard Mitsunobu protocol.
Scheme 3. Conditions: (a) CAN, K2CO3, MeCN, −30°C, 97%; (b) m-CPBA, CH2Cl2, −78°C, 95%; (c) P(OMe)3, MeOH,
75°C, 88%; (d) SEMCl, i-Pr2NEt, n-Bu4NI, CH2Cl2, 100%; (e) DIBAL-H, CH2Cl2, −78°C, 91%; (f) PivCl, Py-CH2Cl2, 0°C to
rt, 64% (85% based on the consumed 19); (g) Et2Zn, CH2I2, CH2Cl2, −20°C, 69% (77% based on the consumed 4); (h) MeLi,
Et2O, 0°C, 90%; (i) (i) Pb(OAc)4, Na2CO3, CH2Cl2, −40°C (68%); (ii) tetraallyltin, Sc(OTf)3, CH3CN; (j) (i) DIAD, AcOH,
PPh3, THF; (ii) NaH, MeOH, 60% (70% based on the consumed 21b)
The final task was formation of a nine-membered lactone possessing a (Z)-olefin. Although the
esterification of 21a with 5-hexenoic acid and the ring-closing metathesis (RCM) of the resulting
product with Grubbs’ catalyst 2611 gave the desired lactone, removal of the protecting group resulted
in only decomposed products due to the instability of the cyclopropane and lactone units to the reaction
conditions (Scheme 4). The problem was finally overcome by the replacement of the protecting group
of 21a from the TBS and SEM group to an acetyl group. Namely, the diacetate 2, prepared from 21a
in five steps, was exposed to the RCM conditions with 26 in the presence of Ti(Oi-Pr)412, giving rise to
the desired Z-isomer 27 in 72% yield along with the corresponding dimer (11%). The total synthesis of
halicholactone 1a was completed by methanolysis of two acetyl groups, and the obtained product 1a was
identical (1H NMR, 13C NMR, IR, MASS and [α]D) in all respects to the reported data of the natural
halicholactone 1a.
Scheme 4. Conditions: (a) Ethyl vinyl ether, PPTS, CH2Cl2, 90%; (b) TBAF, MS 4 Å, 85°C, DMPU, 64%; (c) Ac2O, Et3N,
DMAP, CH2Cl2, 88%; (d) PPTS, t-BuOH, 69% (71% based on the consumed 24); (e) 5-hexenoic acid, DCC, DMAP, CH2Cl2,
82%; (f) 26, Ti(Oi-Pr)4, CH2Cl2 (0.1 mM), reflux, 72%; (g) K2CO3, MeOH, 61%
In summary, we have achieved the asymmetric total synthesis of halicholactone 1a from the chiral
(diene)Fe(CO)3 complex 6 via regio- and stereoselective phenylsulfenylation and cyclopropanation as
well as formation of a nine-membered lactone by the ring-closing metathesis.

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Acknowledgements
This article is dedicated to the memory of Professor Toshiro Ibuka. This work was supported in part by
The Japan Health Sciences Foundation, Suzuken Memorial Foundation and Grant-in-Aid for Scientific
Research (C) from the Ministry of Education, Science, Sports, and Culture, Japan.
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