Stereoselective total synthesis of muconin

Article abstract of DOI:10.1016/S0040-4020(03)00135-2

An antitumor acetogenin, muconin, was synthesized through a coupling reaction of a THF-THP segment and a terminal butenolide. The key reactions include successive ether-ring formation reaction under acidic and basic conditions or one-pot double cyclization promoted by TBAF and stereoselective reduction of acyclic ketones adjacent to the 2,6-cis THP with Zn(BH₄)₂.

Full text of DOI:10.1016/S0040-4020(03)00135-2

Tetrahedron 59 (2003) 1627–1638
Stereoselective total synthesis of muconin
b
a,b
Shunya Takahashi,a Akemi Kubota and Tadashi Nakata
,
*
aRIKEN (The Institute of Physical and Chemical Research), Hirosawa 2-1, Wako-shi, Saitama 351-0198, Japan
bGraduate School of Science and Engineering, Saitama University, Saitama, Saitama 338-8570, Japan
Received 6 January 2003; revised 24 January 2003; accepted 24 January 2003
Abstract—An antitumor acetogenin, muconin, was synthesized through a coupling reaction of a THF–THP segment and a terminal
butenolide. The key reactions include successive ether-ring formation reaction under acidic and basic conditions or one-pot double
cyclization promoted by TBAF and stereoselective reduction of acyclic ketones adjacent to the 2,6-cis THP with Zn(BH4)2. q 2003 Elsevier
Science Ltd. All rights reserved.
1. Introduction
potent and selective in vitro cytotoxicity to MCF-7 (breast
cancer) and PACA-2 in a panel of six human solid tumor
cell lines. Recently, we have been engaged in synthetic
studies on the THP-acetogenins, resulting in the total
synthesis of mucocin6 and jimenezin.7 As part of our
continuing studies in this field, we describe herein the
details of the total synthesis8 of 1 in a stereocontrolled
manner.9
Annonaceous acetogenins are a relatively new class of
natural products that have a wide range of biological
activities such as cytotoxic, antitumor, antimicrobial,
antimalarial, antifeedant, pesticidal and immunosuppressive
effects.1 They are characterized by the presence of one to
three tetrahydrofuran (THF) rings in the center of a long
alkyl chain with a butenolide moiety at the end, and
classified into three types according to the number of THF
rings and their connection patterns, i.e. the adjacent bis-
THF, nonadjacent bis-THF, and mono-THF. Their struc-
tural diversity and remarkable biological activities have
attracted much attention of synthetic organic chemists, and
this has consequently stimulated synthetic efforts.2
2. Results and discussion
Our synthetic strategy directed toward 1 was based on a
convergent process which involves a Pd-catalyzed cross-
coupling reaction of the THF–THP segment 2 and a vinyl
iodide 3,6e,10 as illustrated in Scheme 1. Disconnection of
the acetylene unit and cleavage of the THF ring in 2 lead to a
THP derivative 4, which would be synthesized from an
epoxy alcohol 5 through a 6-exo cyclization and stereo-
inversion at the C-8 position. For effective inversion, we
planned to utilize a stereoselective reduction of an acyclic
ketone adjacent to the 2,6-cis THP ring. The usefulness of
the method has been already demonstrated in our total
synthesis of mucocin6a,d and jimenezin.7
Recently, acetogenins have been discovered that also bear a
tetrahydropyran (THP) ring additional to the usual THF
rings.3,4 A representative member of that group is muconin
(1),5 which was isolated from the leaves of Rollinia mucosa
(Jacq.) Baill. (Annonaceae) by McLaughlin et al. in 1996
(Fig. 1). Muconin (1) is structurally related to the cytotoxic
acetogenin, jimenezin, differing remarkably in the stereo-
relationship of the THP and THF rings and bearing no
hydroxyl group on the THP ring. Compound 1 showed
Figure 1.
Keywords: annonaceous acetogenin; antitumor agent; muconin; Zn(BH4)2 reduction.
*
Corresponding author. Fax: þ81-48-462-4666; e-mail: shunyat@riken.go.jp
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00135-2

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S. Takahashi et al. / Tetrahedron 59 (2003) 1627–1638
Scheme 1. Retrosynthetic scheme of muconin (1).
Scheme 2. (a) LiAlH4, THF, 08C; (b) p-TsCl, pyridine, 08C; (c) NaCN, DMSO, rt ,608C; (d) DIBAL, CH2Cl2, 2788C; (e) (EtO)2P(O)CH2CO2Et, NaH, THF,
08C; (f) D-DET, Ti(Oi-Pr)4, t-BuO2H, MS4A, CH2Cl2, 2238C; (g) TBDPSCl, imidazole, DMF–CH2Cl2, rt; (h) AD-mix b, MeSO2NH2, t-BuOH–H2O, 08C;
(i) CSA, CH2Cl2, rt, then MeOH, conc., and (MeO)2CMe2–CH2Cl2, rt.
Scheme 3. (a) Dess–Martin periodinane, NaHCO3, CH2Cl2, rt; (b) Zn(BH4)2, Et2O, 2108C; (c) p-TsCl, DMAP, Et3N, CH2Cl2, 08C ,rt; (d) AcOH–H2O, rt;
(e) NaOMe, MeOH, rt ,508C; (f) (MeO)2CMe2, CSA, CH2Cl2, rt; (g) MOMBr, i-Pr2NEt, CH2Cl2, rt; (h) BzCl, pyridine, CH2Cl2, 220 ,58C, and then MsCl,
220 ,08C; (i) aq. NaOH, MeOH–THF, 220 ,58C; (j) lithium (trimethylsilyl)acetylide, BF3·Et2O, THF, 2788C; (k) K2CO3, MeOH, rt.

S. Takahashi et al. / Tetrahedron 59 (2003) 1627–1638
1629
at a later stage (vide infra). Upon treatment of 5 with
d-camphorsulfonic acid (CSA) in CH2Cl2, 6-exo cyclization
occurred to produce a THP derivative 11 in 86% yield. From
a practical point of view, isolation after the following
hydroxy protection was found to be more efficient. Hence,
after completion of the cyclization, the reaction mixture was
treated with methanol in order to hydrolyze the TBDPS
ether, concentrated in vacuo and then reacted with 2,2-
dimethoxypropane in CH2Cl2 in one pot to give a
diacetonide 12 in 85% overall yield. In the 1H NMR spectra
of 12, the signals corresponding to the protons of H-3 and 7
were observed at 3.30 ppm (ddd, J3,4¼11, J2,3¼6.7,
Figure 2.
Synthesis began from reduction of an unsaturated ester 6,
which was prepared by Keinan and Sinha’s procedure
(Scheme 2).11 The resulting alcohol was subjected to
tosylation to afford the corresponding tosylate. Treatment
of this with sodium cyanide gave a nitrile 7 in 84% overall
yield from 6. The nitrile 7 was converted into an allyl
alcohol 8 by the following sequence: (1) reduction of the
nitrile function with DIBAL, (2) Wittig reaction, (3) DIBAL
reduction of ester carbonyl (85% overall yield). Installation
of the requisite oxygen function into the carbon backbone
was accomplished by the Sharpless protocol.12 Initially, 8
was epoxidized with Ti(Oi-Pr)4 and t-BuO2H in the
presence of D-diethyl tartrate to give an epoxide 9 in 91%
yield. The optical purity was determined to be .94% e.e. by
0
J3,4 ¼1.9 Hz) and 3.21 ppm (1H, ddd, J6,7¼11, J7,8¼6.3,
0
J6 ,7¼1.9 Hz), respectively. The large coupling constant of
two protons indicates that the compound 12 has the desired
THP ring system. Furthermore, the optical purity of 12 was
determined to be .98% e.e. by the 1H NMR analyses of the
corresponding MTPA esters.
The alcohol 12 was oxidized with Dess–Martin periodinane
to give a ketone 13, which was reduced with Zn(BH4)213 in
ether (Scheme 3). As expected, the reduction at 210 , 08C
proceeded stereoselectively to afford a 93:7 mixture of the
desired b-alcohol and its epimer 14 in 98% yield; the
reaction at low temperature (2788C) slightly decreased
the selectivity (b/a¼ca 90/10, ,96%). The similar results
(b/a¼93/7, ,98%) were also obtained when CH2Cl2 was
employed as a solvent. This high stereoselectivity would be
explained by the a-chelation as shown in Figure 2. As
1
the H NMR analyses of the corresponding MTPA esters.
After silylation with chloro t-butyldiphenylsilane and
imidazole, the resulting silylether 10 reacted with AD-mix
b in the presence of methanesulfonamide (2.0 equiv.) in
t-BuOH–water to give the tetraol 5 in almost quantitative
yield. Although this compound included a trace amount of
the diastereomers, the undesired isomers could be separated
Scheme 4. (a) CSA, CH2Cl2, rt, and then (MeO)2CMe2, rt; (b) p-TsCl, DMAP, Et3N, CH2Cl2, rt; (c) TBAF, THF, rt; (d) Dess–Martin periodinane, NaHCO3,
CH2Cl2, rt; (e) Zn(BH4)2, Et2O, 2108C; (f) AcOH–H2O, rt ,508C; (g) TBAF, THF, rt ,508C; (h) n-BuLi, MOMCl, THF, 2238C,rt; (i) See Scheme 3.

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S. Takahashi et al. / Tetrahedron 59 (2003) 1627–1638
Scheme 5. (a) (Ph3P)2PdCl2, CuI, Et3N, rt; (b) (Ph3P)3RhCl, H2, benzene–EtOH, rt; (c) 10% HCl–MeOH, CH2Cl2, rt.
separation of these isomers was found to be difficult at this
stage, 14 was transformed into the corresponding tosylate 15
by treatment with p-toluenesulfonyl chloride (TsCl) and
triethylamine (Et3N) in the presence of N,N-dimethyl-
aminopyridine (DMAP). Acidic hydrolysis of 15 afforded a
C-8 epimeric mixture of tetraols 4a (97% yield). Formation
of the second ether-ring was achieved by heating 4a with
sodium methoxide (8.4 equiv.) in methanol at rt ,508C, and
subsequent isopropylidenation provided a mixture of
cyclized products, from which the desired bicyclic ether
16 was isolated in 78% yield after chromatography on silica
gel. In addition, a minor isomer 17 was also obtained, which
could be quite useful for preparation of pharmacologically
important analogues of 1. The remaining task was
introduction of an ethynyl group through a stereoinversion
at the C-2 position in 16. Prior to the transformation, the 12-
hydroxyl group in 16 was protected as a methoxymethyl
(MOM) ether (MOMBr, N,N-diisopropylethylamine), and
subsequent hydrolysis of 18 gave a diol 19 in 89% yield.
Successive treatment of 19 with benzoyl chloride and
methanesulfonyl chloride in pyridine provided a mesyl
benzoate. Exposure of this to alkaline conditions led to an
oxirane formation to give 20 in 83% yield from 19. The
epoxide 20 reacted with lithium trimethylsilylacetylide in
the presence of BF3·E2O to produce a terminal acetylene 2
in 97% yield after de-silylation (potassium carbonate,
MeOH).
analyses revealed that each compound consisted of an
unseparable mixture of two carbinols† and that a minor
component of the low polar substance was identical with the
starting alcohol 21. Based on the a-chelation mechanism of
Zn(BH4)2 reduction, we estimated that the major component
of the low polar substance should be the desired 2R,8S-
isomer and tentatively assigned the structure of the low
polar substance and the high polar one to be 26 and 27,
respectively. This assumption was confirmed by chemical
transformation into the known compounds (vide infra).‡ The
low polar substance 26 was tosylated, and the resulting
ditosylate 28 was hydrolyzed to afford a diol 4b in good
yield. Double cyclization of 4b into a tricyclic system was
performed by treatment of 4b with TBAF at rt ,508C,
giving a 8,11-trans THF derivative 29 and the correspond-
ing cis isomer 30 in 65 and 8% yield, respectively. Each
isomer was easily separated by chromatography on silica
gel. Methoxymethylation (n-BuLi, MOMCl) of the trans
isomer 29 furnished the key intermediate 20, from which
preparation of the left half segment 2 has been already
established. This new route was quite simple and required
only 9 steps§ from 5 for preparation of 2 (cf. 13 steps in the
previous Scheme).
Having completed the stereoselective synthesis of the left-
half segment 2, we turned to the final steps of the synthesis
(Scheme 5). The acetylene 2 was coupled with the g-lactone
3 in the presence of (PPh3)2PdCl2 and CuI in triethylamine14
at rt to afford an enyne 31 in 79% yield. This underwent
regioselective reduction with Wilkinson’s catalyst to give a
partially protected muconin 32, in which all protecting
groups were subsequently cleaved by hydrogen chloride in
methanol–CH2Cl2 to give muconin (1). The spectroscopic
and physical properties of 1 were identical those of natural
1.
Furthermore, we have also developed an alternative route
for short-step synthesis of 2 (Scheme 4). Initially, the epoxy
tetraol 5 was transformed into the corresponding acetonide
21 in 86% yield according to the one-pot sequence. After
tosylation of 21, the resulting ditosylate 22 was employed to
an SN2 reaction. Attempts for the simultaneous inversion at
the C-2, and 8 positions of 22 under several conditions (e. g.
NaOBz or CsOAc in the presence of 18-Crown-6 in toluene,
HMPA and so on) gave unsatisfactory results, while
treatment of 22 with n-tetrabutylammonium fluoride
(TBAF) at rt caused an intramolecular etherification, giving
a terminal epoxide 23 in 57% yield along with a
hydroxytosylate 24 (15%). These results prompted us to
conduct an intramolecular double ether-cyclization as
follows. In order to prepare the substrate needed for such
cyclization, the two hydroxyl groups in 21 was simul-
taneously oxidized to afford a diketone 25 in 95% yield.
Zn(BH4)2 reduction of 25 in Et2O gave two products, which
were separated into a low polar (Rf value 0.38 on silica gel
HPTLC, with 2:1 Et2O–hexane) substance (85%) and a
high polar compound (13%) with Rf value 0.27 by
chromatography on silica gel. The 1H- and 13C NMR
In summary, we have succeeded in a convergent synthesis
of 1 via successive ether-ring formation reaction under
acidic and basic conditions or one-pot double cyclization
promoted by TBAF and stereoselective reduction of acyclic
ketones as the key steps.
†
The isomer ratio was 89/11 (for 26) or 56/44 (for 27). The major
constituent of 27 was estimated to be an 8b-alcohol by comparison with
the 1H NMR data (the chemical shifts and splitting pattern of H-7) of 26;
see, Section 3.
‡
Desilylation (TBAF, THF), isopropylidenation and Dess–Martin
oxidation of 26 afforded 13 in high yield. Compound 27 could be taken
back to the starting diketone 25 by the oxidation.
This synthesis proceeded in 18% overall yield. On the other hand, the
§
previous procedure resulted in 45% overall yield.

S. Takahashi et al. / Tetrahedron 59 (2003) 1627–1638
1631
3. Experimental
3.1. General procedures
concentrated to give an aldehyde (17.2 g). To a stirred
suspension of NaH (60% oil suspension, 3.21 g, 80.3 mmol)
in THF (150 ml) was added dropwise triethyl phosphono-
acetate (18.0 g, 80.3 mmol) at 08C, and the mixture was
stirred at 08C for 1 h. To this solution was added a solution
of the above aldehyde (17.2 g) in THF (50 ml) at 08C and
the mixture was stirred at 08C for 1 h. After addition of
water, the mixture was extracted with ether. The extracts
were washed successively with water and brine, dried, and
concentrated. The residue was passed through a short
column of silica gel {hexane–hexane-EtOAc (50:1)} to
give an unsaturated ester (19.5 g). To a stirred solution of
the ester (19.5 g) in CH2Cl2 (300 ml) was added dropwise a
0.93 M hexane solution of DIBAL (134 ml, 0.12 mol) at
2788C. After stirring at 2788C for 2.5 h, the mixture was
quenched with i-PrOH (34 ml) and water (34 ml) at 2788C
and returned to rt. After addition of silica gel, the resulting
mixture was stirred for 1 h, diluted with EtOAc, filtered
through a pad of celite, and concentrated. Chromatography
on silica gel with hexane–EtOAc (10:1) as the eluent
yielded 8 (15.9 g, 85% from 7) as a colorless oil. IR (CHCl3)
Melting points were determined using a Yanaco MP-500
apparatus and are uncorrected. Optical rotations were
measured with a JASCO DIP-370 polarimeter. IR spectra
were recorded with a JASCO VALOR-III spectro-
photometer. 1H NMR spectra were recorded at 270 or
400 MHz with JEOL EX-270 or JNM-a 400 spectrometers,
using tetramethylsilane as the internal standard. Column
chromatography was performed on Kanto silica gel 60N
(spherical, neutral; 40–100 mm). Merck precoated silica gel
60 F254 plates, 0.25 mm thickness, was used for analytical
thin-layer chromatography. The solvent extracts were dried
with magnesium sulfate, and the solutions were evaporated
under diminished pressure at 40–428C.
3.1.1. (E,E)-5,9-Docosadienonitrile (7). To a stirred
suspension of LiAlH4 (1.07 g, 28.2 mmol) in THF (40 ml)
was added dropwise a solution of 6 (10.3 g, 29.3 mmol) in
THF (10 ml) at 08C, and the mixture was stirred at 08C ,rt
for 12 h. At 08C, water (1.0 ml), 15% NaOH solution
(1.0 ml) and water (3.0 ml) was added sequentially to
produce a heterogeneous mixture, which was stirred at
08C,rt for 1 h. The resulting mixture was filtered through a
pad of celite and MgSO4, and concentrated to give a dienol
as a crystalline solid (8.74 g, 97%).
1
3300–3200, 2918, 1472, 1461, 1082, 962, 907 cm21; H
NMR (400 MHz, CDCl3): d 0.88 (3H, t, J¼6.3 Hz), 1.22–
1.48 (22H, m), 1.94–2.07 (10H, m), 4.05–4.13 (2H, brd),
5.34–5.44 (4H, m), 5.63 (1H, ddd, J¼15, 5.3, 4.8 Hz), 5.69
(1H, ddd, J¼15, 6.3, 6.3 Hz); 13C NMR (100 MHz, CDCl3):
d 14.2, 22.8, 29.0, 29.3, 29.4, 29.6, 29.7, 29.8, 31.8, 32.0,
32.1, 32.7, 32.8, 63.9, 128.9, 129.5, 129.9, 130.2, 130.7,
133.2.
To a stirred solution of the above dienol (21.5 g, 69.7 mmol)
in pyridine (150 ml) was added p-TsCl (17.4 g, 91.2 mmol)
at 08C, and the mixture was stirred at the same temperature
for 16 h. After addition of ice-water, the resulting mixture
was stirred for 10 h, and then extracted with ether. The
extracts were washed successively with cold HCl solution,
water, sat. NaHCO3 solution, water, brine, dried, and
concentrated. The residue was dissolved in dimethyl-
sulfoxide (50 ml) and sodium cyanide (5.2 g, 0.11 mol)
was added to the solution. The mixture was stirred at rt for
12 h and 608C for 4 h, and then poured into ice-water. The
resulting mixture was extracted with ether. The extracts
were washed with water, brine, dried, and concentrated.
Chromatography on silica gel with hexane–hexane-EtOAc
(20:1) gave 7 (19.3 g, 87%) as a colorless oil. IR (neat)
Anal. Found: C, 82.67; H, 12.81. Calcd for C24H44O: C,
82.69; H, 12.72.
3.1.3. (E,E,2R,3R)-2,3-Oxido-7,11-tetracosadien-1-ol (9).
D-(2)-Diethyltartrate (1.01 g, 4.30 mmol) and Ti(Oi-Pr)4
(0.93 ml, 3.16 mmol) was added sequentially to a suspen-
sion of 8 (1.00 g, 2.87 mmol) and MS 4A (1.5 g) in CH2Cl2
(22 ml) at 2238C, and the mixture was stirred at the same
temperature for 20 min. A 5.2 M isooctane solution of
t-BuO2H (0.86 ml) was added, and the mixture was stirred
at 2238C for 18 h. After addition of dimethylsulfide (2 ml)
and sat. Na2SO4 solution, the resulting mixture was stirred
at the same temperature for 1 h, allowed to warm to rt over
1 h, and then extracted with EtOAc. The extracts were
washed with brine, dried, and concentrated. Chromato-
graphy on silica gel with hexane–EtOAc (10:1–4:1) as the
eluent yielded 9 (953 mg, 91%) as an amorphous powder.
[a]2D3¼þ16.9 (c 0.69, CHCl3); IR (KBr) 3280, 3157, 2918,
1
2925, 2247, 1460, 1458, 967 cm21; H NMR (400 MHz,
CDCl3): d 0.88 (3H, t, J¼6.3 Hz), 1.22–1.38 (20H, m), 1.70
(1H, dd, J¼15.4, 7.2 Hz), 1.72 (1H, dd, J¼15, 6.8 Hz), 1.96
(2H, m), 2.05 (4H, brs), 2.14 (2H, m), 2.31 (2H, t, J¼
7.3 Hz), 5.28–5.54 (4H, m); 13C NMR (100 MHz, CDCl3):
d 14.2, 16.3, 22.8, 25.2, 29.3, 29.4, 29.6, 29.7, 29.8, 31.3,
32.0, 32.6, 32.7, 119.5, 127.4, 129.2, 130.9, 132.9.
1460, 1041, 992, 963, 878 cm21 1H NMR (400 MHz,
;
CDCl3): d 0.88 (3H, t, J¼6.3 Hz), 1.22–1.35 (20H, m),
1.45–1.60 (4H, m), 1.85–2.05 (9H, m), 2.90–2.96 (2H, m),
3.61 (1H, ddd, J¼13, 6.8, 4.4 Hz), 3.90 (1H, ddd, J¼13, 5.3,
2.4 Hz), 5.32–5.46 (4H, m); 13C NMR (100 MHz, CDCl3):
d 14.2, 22.8, 25.9, 29.3, 29.4, 29.6, 29.7, 29.8, 31.0, 32.0,
32.3, 32.6, 32.7, 32.8, 129.4, 129.5, 130.5, 130.7; HRMS
calcd for C24H44O2Na [MþNa]þ 387.3239, found
387.3231.
Anal. Found: C, 83.01; H, 12.52; N, 4.29. Calcd for
C22H39N: C, 83.21; H, 12.38; N, 4.41.
3.1.2. (E,E,E)-2,7,11-Tetracosatrien-1-ol (8). To a stirred
solution of 7 (17.0 g, 53.5 mmol) in CH2Cl2 (150 ml) was
added dropwise a 0.93 M hexane solution of DIBAL (75 ml,
69.9 mmol) at 2788C. After stirring at 2788C for 1.5 h, the
mixture was quenched with i-PrOH (19 ml) and water
(19 ml) at 2788C and returned to rt. After addition of silica
gel, the resulting mixture was stirred for 1 h, diluted with
EtOAc and filtered through a pad of celite. The filtrate was
Anal. Found: C, 79.10; H, 12.25. Calcd for C24H44O2: C,
79.06; H, 12.16.
3.1.4. (E,E,2R,3R)-1-t-Butyldiphenylsilyloxy-7,11-tetra-
cosadien-2,3-oxido (10). To a stirred solution of 9

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S. Takahashi et al. / Tetrahedron 59 (2003) 1627–1638
(824 mg, 2.26 mmol) and imidazole (462 mg, 6.78 mmol)
in DMF–CH2Cl2 (4:1, 20 ml) was added TBDPSCl
(0.65 ml, 2.49 mmol) at 08C, and the mixture was stirred
at 08C ,rt for 12 h, poured into ice-water. The resulting
mixture was stirred for 1 h and extracted with ether. The
extracts were washed successively with cold HCl solution,
water, sat. NaHCO3 solution, water, brine, dried and
concentrated. Chromatography on silica gel with hexane–
EtOAc (50:1–30:1) as the eluent afforded 10 (1.33 g, 98%)
as a colorless oil. [a]D22¼þ10.9 (c 0.25, CHCl3); IR (neat)
yielded 12 (171 mg, 85%) as a colorless oil. [a]2D5¼þ27.8 (c
;
856 cm21 1H NMR (400 MHz, CDCl3): d 0.87 (3H, t,
0.24, CHCl3); IR (neat) 3490, 2926, 1251, 1214, 1073,
J¼6.8 Hz), 1.22–1.82 (31H, m), 1.35 (3H, s), 1.36 (6H, s),
1.39 (3H, s), 1.89–1.93 (1H, m), 2.72 (1H, brs), 3.21 (1H,
ddd, J¼11, 6.3, 1.9 Hz), 3.30 (1H, ddd, J¼11, 6.7, 1.9 Hz),
3.45 (1H, brq, J¼6.3 Hz), 3.59 (2H, m), 3.87 (1H, dd,
J¼7.2, 5.8 Hz), 3.95 (1H, dd, J¼12, 6.3 Hz), 4.30 (1H, dd,
J¼8.3, 6.3 Hz); 13C NMR (100 MHz, CDCl3): d 14.2, 22.6,
22.7, 25.3, 26.2, 26.7, 27.2, 27.3, 27.4, 27.8, 29.1, 29.4,
29.6, 29.7, 29.8, 31.9, 32.9, 66.8, 73.6, 78.1, 78.7, 80.7,
80.8, 80.9, 107.7, 109.2; HRMS calcd for C30H57O6
[MþH]þ 513.4155, found 513.4150.
1
2926, 1464, 1428, 1113, 967 cm21; H NMR (400 MHz,
CDCl3): d 0.90 (3H, t, J¼6.8 Hz), 1.08 (9H, s), 1.25–1.63
(24H, m), 1.94–2.10 (8H, m), 2.80 (1H, m), 2.91 (1H, m),
3.75 (1H, dd, J¼12, 4.3 Hz), 3.79 (1H, dd, J¼12, 3.8 Hz),
5.38–5.48 (4H, m), 7.38–7.48 (6H, m), 7.70 (4H, brd,
J¼7.2 Hz); 13C NMR (100 MHz, CDCl3): d 14.2, 19.3,
22.8, 25.9, 26.8, 29.3, 29.4, 29.6, 29.7, 29.8, 31.1, 32.0,
32.3, 32.7, 32.8, 56.3, 58.5, 64.3, 127.6, 129.5, 129.6, 129.7,
130.4, 130.7, 133.2, 135.4.
Anal. Found: C, 70.19; H, 11.21. Calcd for C30H56O6: C,
70.27; H, 11.01.
3.1.7. (2R,3S,7R,11R,12R)-1,2:11,12-(Diisopropylidene-
dioxy)-3,7-oxido-8-tetracosanone (13). To a stirred mix-
ture of 12 (24.0 mg, 0.05 mmol) and a trace amount of
NaHCO3 in CH2Cl2 (0.5 ml) was added Dess–Martin
periodinane (33.0 mg, 0.08 mmol) at rt. The resulting
suspension was stirred at the same temperature for 6 h,
diluted with sat. NaHCO3/Na2S2O3 solution, and then
extracted with ether. The extracts were washed successively
with water, brine, dried, and concentrated to give 13
(27 mg), which was employed to the next step without
further purification. An analytical sample was prepared by
chromatography on silica gel {hexane–EtOAc (4:1)}.
Colorless oil; [a]2D3¼þ58.5 (c 0.62, CHCl3); IR (neat)
2926, 1719, 1379, 1369, 1250, 1215, 1098, 1070,
Anal. Found: C, 79.27; H, 10.50. Calcd for C40H62O2Si: C,
79.67; H, 10.36.
3.1.5. (2R,3R,7R,8R,11R,12R)-1-t-Butyldiphenylsilyloxy-
2,3-oxido-7,8,11,12-tetracosanetetraol (5). To a stirred
suspension of AD-mix b (4.72 g) and methanesulfonamide
(0.32 g, 3.34 mmol) in t-BuOH-water (1:1, 20 ml) was
added dropwise 10 (0.94 g, 1.56 mmol) at 08C, and the
mixture was vigorously stirred at the same temperature for
14 h. After quenching with Na2S2O3 (2.9 g), the reaction
mixture was gradually warmed to rt over 1.5 h with stirring,
and then concentrated. The residue was diluted with water
and CH2Cl2, and then extracted with EtOAc. The extracts
were washed successively with brine, dried and concen-
trated. The residue was passed through a short column of
silica gel {hexane-EtOAc (1:1)–EtOAc} to afford 5 (1.03 g,
99%) as an amorphous solid, which contained a trace
amount of methanesulfonamide. This compound was
employed to the next step without further purification. IR
1
1044 cm21; H NMR (400 MHz, CDCl3): d 0.86 (3H, t,
J¼6.8 Hz), 1.22–1.96 (30H, m), 1.35 (9H, s), 1.40 (3H, s),
2.67 (1H, ddd, J¼18.7, 8.7, 6.8 Hz), 2.76 (1H, ddd, J¼18.7,
9.1, 5.7 Hz), 3.33 (1H, ddd, J¼11, 6.8, 2.0 Hz), 3.52–3.61
(2H, m), 3.82 (1H, dd, J¼12, 2.4 Hz), 3.93–3.99 (2H, m),
4.07 (1H, m); 13C NMR (100 MHz, CDCl3): d 14.2, 22.8,
25.5, 26.0, 26.1, 26.8, 27.3, 27.4, 27.9, 28.0, 29.4, 29.6,
29.7, 29.8, 31.9, 32.9, 34.5, 66.9, 78.1, 78.6, 80.0, 80.9,
82.8, 209.9; HRMS calcd for C30H54O6Na [MþNa]þ
533.3818, found 533.3815.
(KBr) 3280, 3157, 2918, 1460, 1143, 1114, 963, 878 cm21
;
1H NMR (400 MHz, CD2Cl2): d 0.88 (3H, t, J¼6.8 Hz),
1.05 (9H, s), 1.22–1.70 (32H, m), 2.23 (1H, d, J¼4.8 Hz),
2.43 (1H, d, J¼4.4 Hz), 2.80 (1H, m), 2.90 (1H, m), 3.21
(1H, brs), 3.30 (1H, brs), 3.33–3.43 (4H, m), 3.69 (1H, dd,
J¼12, 4.8 Hz), 3.81 (1H, dd, J¼12, 3.4 Hz), 7.38–7.43 (6H,
m), 7.66–7.68 (4H, m); 13C NMR (100 MHz, CD2Cl2): d
14.3, 19.5, 22.8, 23.1, 26.1, 27.0, 29.8, 30.0, 30.1, 30.6,
30.7, 31.9, 32.3, 33.6, 34.1, 56.4, 58.7, 64.7, 74.8, 74.9,
75.0, 127.9, 129.9, 133.6, 135.7; HRMS calcd for C40H66-
O6SiNa [MþNa]þ 693.4526, found 693.4516.
Anal. Found: C, 70.58; H, 10.69. Calcd for C30H54O6: C,
70.55; H, 10.66.
3.1.8. (2R,3S,7R,8RS,11R,12R)-1,2:11,12-(Diisopropyl-
idenedioxy)-3,7-oxido-8-tetracosanol (14). To a stirred
solution of the above ketone 13 (27 mg, ca 0.05 mmol) in
ether (0.4 ml) was added dropwise a 0.14 M solution of
Zn(BH4)2 (2.0 ml) in ether at 2108C, and the mixture was
stirred at the same temperature for 0.5 h. After quenching
with sat. NH4Cl solution, the resulting mixture was dried
over MgSO4, filtered through a pad of celite, and
concentrated. Chromatography on silica gel with hexane–
EtOAc (4:1) as the eluent gave 14 (23.6 mg, 98%) as a
stereoisomeric mixture (b/a¼ca 93/7 by 1H NMR analysis).
Colorless oil; IR (neat) 3477, 2926, 1251, 1215, 1068, 1046,
3.1.6. (2R,3S,7R,8R,11R,12R)-1,2:11,12-(Diisopropyl-
idenedioxy)-3,7-oxido-8-tetracosanol (12). A mixture of
5 (265 mg, 0.39 mmol) and d-camphorsulfonic acid (60 mg,
0.26 mmol) in CH2Cl2 (5 ml) was stirred at rt for 2 h,
concentrated, and then diluted with methanol (3 ml). The
mixture was stirred at rt for 18 h, concentrated, co-evapo-
rated with benzene, and then diluted with 2,2-dimethoxy-
propane–CH2Cl2 (1:2, 3 ml). The resulting mixture was
stirred at rt for 5 h, and then diluted with ether. The ethereal
solution was washed successively with sat. NaHCO3
solution, water, brine, dried, and concentrated. Chromato-
graphy on silica gel with hexane–EtOAc (4:1) as the eluent
856 cm21 1H NMR (400 MHz, CDCl3): d 0.87 (3H, t,
;
J¼6.8 Hz), 1.22–2.20 (45H, m), 3.21 (0.07H, ddd, J¼11,
6.3, 1.9 Hz), 3.25–3.35 (1.93H, m), 3.45 (0.07H, brq,
J¼6.3 Hz), 3.55–3.63 (2.93H, m), 3.87–3.98 (2H, m),
4.01–4.30 (1H, m); 13C NMR (100 MHz, CDCl3): d 14.2,
22.6, 22.7, 25.3, 26.2, 26.8, 27.2, 27.3, 27.4, 28.3, 29.1,

S. Takahashi et al. / Tetrahedron 59 (2003) 1627–1638
1633
29.2, 29.3, 29.4, 29.6, 29.7, 29.8, 31.9, 32.8, 32.9, 66.8,
67.0, 73.5, 73.6, 78.1, 78.2, 78.7, 78.9, 80.4, 80.7, 80.8,
80.9, 81.1, 81.2, 107.8, 109.2; HRMS calcd for C30H56O6Na
[MþNa]þ 535.3975, found 535.3969.
Dowex 50W X-8 (Hþ) resin. The suspension was filtered,
concentrated, and diluted with 2,2-dimethoxypropane–
CH2Cl2 (1:10, 12 ml). To a stirred mixture was added
d-camphorsulfonic acid (40 mg, 0.17 mmol), and the
mixture was stirred at rt for 0.5 h, diluted with ether, and
then washed successively with sat. NaHCO3 solution, water,
brine, dried, and concentrated. Chromatography on silica
gel with hexane–ether (3:1) as the eluent yielded 16
(145 mg, 48% from 15), and a mixture of 16 and 17, which
was separated by preparative TLC {hexane–EtOAc (4:1), 3
developments}to afford more additional 16 (88 mg, 30%)
and 17 (17 mg, 6%).
Anal. Found: C, 70.24; H, 11.03. Calcd for C30H56O6: C,
70.27; H, 11.01.
3.1.9. (2R,3S,7R,8RS,11R,12R)-1,2:11,12-(Diisopropyl-
idenedioxy)-3,7-oxido-8-tetracosanol p-toluenesulfonate
(15). To a stirred mixture of 14 (23.6 mg, 0.05 mmol), N,N-
dimethylaminopyridine (6.1 mg, 0.05 mmol) and triethyl-
amine (50ml) in CH2Cl2 (0.3 ml) was added p-toluene-
sulfonyl chloride (19.0 mg, 0.10 mmol) at 08C, and then the
mixture was stirred at 08C,rt for 12 h. After addition of ice-
water, the resulting mixture was extracted with ether. The
extracts were washed successively with cold HCl solution,
water, sat. NaHCO3 solution, water, brine, dried and
concentrated. Chromatography on silica gel with hexane–
EtOAc (10:1) as the eluent gave 15 (29.7 mg, 97%) as a
colorless oil. IR (neat) 2927, 1601, 1368, 1189, 1177, 1096,
1072, 921 cm21; 1H NMR (400 MHz, CDCl3): d 0.87 (3H,
t, J¼6.8 Hz), 1.22–1.90 (44H, m), 2.40 (0.21H, s), 2.44
(2.79H, s), 3.09–3.19 (1H, m), 3.35–3.51 (3H, m), 3.59–
3.64 (1H, m), 3.73–3.79 (1H, m), 3.88–3.93 (1H, m), 4.52
(0.93H, ddd, J¼8.7, 4.3, 3.9 Hz), 4.58 (0.07H, m), 7.31 (2H,
d, J¼7.8 Hz), 7.77 (2H, d, J¼8.3 Hz); 13C NMR (100 MHz,
CDCl3): d 14.1, 21.6, 22.4, 22.6, 22.7, 25.3, 26.2, 26.4, 26.7,
26.8, 27.3, 27.8, 28.0, 28.2, 28.6, 29.3, 29.4, 29.5, 29.6,
29.7, 29.8, 31.9, 32.8, 67.0, 67.1, 77.8, 77.9, 78.9, 79.1,
80.2, 80.6, 80.8, 80.9, 85.1, 85.2, 107.7, 109.0, 127.6, 129.3,
129.4, 134.7, 144.1; HRMS calcd for C37H62O8SNa
[MþNa]þ 689.4063, found 689.4083.
16; colorless oil; [a]D25¼þ17.8 (c 0.23, CHCl3); IR (neat)
3480, 2925, 1251, 1210, 1075, 852 cm21 1H NMR
;
(400 MHz, CDCl3): d 0.87 (3H, t, J¼6.8 Hz), 1.22–1.97
(32H, m), 1.35 (3H, s), 1.41 (3H, s), 2.45 (1H, brs), 3.25–
3.31 (2H, m), 3.37 (1H, brq, J¼6.5 Hz), 3.79 (1H, dd,
J¼7.9, 6.5 Hz), 3.85 (1H, ddd, J¼7.9, 5.8, 5.6 Hz), 3.91–
4.04 (3H, m); 13C NMR (100 MHz, CDCl3): d 14.2, 22.8,
22.9, 25.4, 25.7, 26.8, 27.3, 28.0, 28.3, 28.4, 29.4, 29.7,
29.8, 31.9, 33.5, 66.9, 74.1, 78.3. 78.6, 80.2, 81.1, 82.7,
109.1; HRMS calcd for C27H51O5 [MþH]þ 455.3737,
found 455.3738.
Anal. Found: C, 71.06; H, 11.26. Calcd for C27H50O5: C,
71.32 H, 11.08.
17; amorphous solid; [a]2D1¼20.48 (c 0.42, CHCl3); IR
(CHCl3) 3426, 2919, 1263, 1097, 1046, 848 cm21; 1H NMR
(400 MHz, CDCl3): d 0.87 (3H, t, J¼6.8 Hz), 1.22–2.01
(32H, m), 1.33 (3H, s), 1.39 (3H, s), 2.70 (1H, d, J¼6.7 Hz),
3.28 (1H, ddd, J¼11, 6.8, 1.5 Hz), 3.30 (1H, m), 3.45 (1H,
ddd, J¼11, 4.9, 2.0 Hz), 3.81–3.91 (3H, m), 4.08 (1H, ddd,
J¼10, 8.7, 8.2 Hz); 13C NMR (100 MHz, CDCl3): d 14.2,
22.8, 25.3, 25.9, 26.6, 26.8, 28.2, 28.4, 28.5, 29.4, 29.7,
29.8, 31.9, 34.6, 67.5, 74.8, 78.1, 78.9, 79.2, 82.1, 82.2,
109.0; HRMS calcd for C27H51O5 [MþH]þ 455.3737,
found 455.3744.
Anal. Found: C, 66.66; H, 9.51; S, 5.14. Calcd for
C37H62O8S: C, 66.63; H, 9.37; S, 4.81.
3.1.10. (2R,3S,7R,8RS,11R,12R)-3,7-Oxido-8-(p-toluene-
sulfonyloxy)-1,2,11,12-tetracosanetetraol (4a). A solution
of 15 (441 mg, 0.66 mmol) in AcOH–water (7:1, 12 ml)
was stirred at rt for 24 h, concentrated, and then co-evapo-
rated with toluene (£5) to give 4a (387 mg, quant.), which
was employed to the next step without further purification.
An analytical sample was prepared by preparative TLC
{CHCl3–MeOH (10:1), 2 developments}. Colorless oil; IR
(neat) 3409, 2926, 1566, 1457, 1367, 1188, 1176, 1096,
Anal. Found: C, 71.23; H, 11.07. Calcd for C27H50O5: C,
71.32 H, 11.08.
3.1.12. (2R,3S,7R,8R,11R,12R)-1,2-(Isopropylidene-
dioxy)-12-(methoxymethoxy)-3,7:8,11-dioxidotetra-
cosane (18). To a stirred mixture of 16 (462 mg, 1.02 mmol)
and N,N-diisopropylethylamine (0.71 ml, 4.06 mmol) in
CH2Cl2 (2.0 ml) was added dropwise bromomethyl methyl
ether (0.17 ml, 2.03 mmol) at 08C. The mixture was stirred
at rt for 12 h, and then poured into ice–water. The resulting
mixture was extracted with ether. The extracts were washed
successively with cold HCl solution, water, sat. NaHCO3
solution, water, brine, dried and concentrated. Chromato-
graphy on silica gel with hexane–ethyl acetate (10:1) as the
eluent yielded 18 (462 mg, 91%) as a colorless oil.
[a]2D2¼þ33.2 (c 0.40, CHCl3); IR (neat) 2925, 1210, 1150,
920 cm21 1H NMR (400 MHz, CDCl3): d 0.88 (3H, t,
;
J¼6.8 Hz), 1.10–2.00 (32H, m), 2.43 (3H, s), 3.18–3.31
(5H, m), 3.33–3.55 (3H, m), 3.57–3.82 (3H, m), 4.50–4.65
(1H, m), 7.32 (2H, d, J¼8.2 Hz), 7.77 (1H, d, J¼8.2 Hz);
13C NMR (100 MHz, CDCl3): d 14.2, 21.7, 22.7, 22.8, 25.6,
25.8, 26.2, 26.6, 26.8, 26.9, 27.0, 28.3, 29.4, 29.6, 29.8,
31.9, 33.1, 33.5, 62.9, 74.0, 77.5, 79.3, 84.7, 127.6, 129.6,
134.2, 144.5; HRMS calcd for C31H54O8SNa [MþNa]þ
609.3437, found 609.3420.
1
3.1.11. (2R,3S,7R,8R,11R,12R)-1,2-(Isopropylidene-
dioxy)-3,7:8,11-dioxido-12-tetracosanol (16) and
(2R,3S,7R,8S,11R,12R)-1,2-(isopropylidenedioxy)-
3,7:8,11-dioxido-12-tetracosanol (17). A mixture of the
above tetraol 4a (387 mg, 0.66 mmol) and sodium
methoxide (300 mg, 5.55 mmol) in methanol (1.5 ml) was
stirred at rt for 1 h and 508C for 5 h, and then treated with
1100, 1076, 1040 cm21; H NMR (400 MHz, CDCl3): d
0.86 (3H, t, J¼6.8 Hz), 1.23–1.95 (32H, m), 1.33 (3H, s),
1.39 (3H, s), 3.26–3.26 (2H, m), 3.38 (3H, s), 3.40–3.47
(1H, m), 3.82–4.03 (5H, m), 4.65, 4.82 (2H, each d,
J¼6.8 Hz); 13C NMR (100 MHz, CD2Cl2): d 14.2, 22.7,
22.9, 25.5, 25.6, 26.8, 27.3, 28.3, 28.4, 29.4, 29.7, 29.9,
31.2, 31.9, 55.7, 67.1, 71.4, 78.4, 78.6, 79.4, 80.0, 80.9,

1634
S. Takahashi et al. / Tetrahedron 59 (2003) 1627–1638
81.7, 96.5, 108.9; HRMS calcd for C29H54O6Na [MþNa]þ
(1H, m), 3.24 (1H, ddd, J¼11, 3.9, 2.0 Hz), 3.31 (1H, ddd,
J¼11, 4.9, 2.0 Hz), 3.91 (1H, m), 4.02 (1H, m), 4.68, 4.82
(2H, each d, J¼6.8 Hz); 13C NMR (100 MHz, CD2Cl2): d
14.3, 23.1, 23.3, 25.9, 27.3, 27.9, 28.4, 28.7, 29.8, 30.0,
30.1, 30.3, 31.5, 32.4, 44.0, 54.5, 55.8, 78.7, 80.2, 80.3,
81.6, 81.9, 97.0; HRMS calcd for C26H48O5Na [MþNa]þ
463.3399, found 463.3405.
521.3818, found 521.3835.
Anal. Found: C, 70.24; H, 11.05. Calcd for C29H54O6: C,
69.84; H, 10.91.
3.1.13. (2R,3S,7R,8R,11R,12R)-12-(Methoxymethoxy)-
3,7:8,11-dioxido-1,2-tetracosanediol (19). A solution of
18 (371 mg, 0.74 mmol) in AcOH–water (10:1, 3.3 ml) was
stirred at rt for 12 h, concentrated, and then co-evaporated
with toluene (£5). Chromatography on silica gel with
hexane–EtOAc (1:1)–EtOAc as the eluent yielded 19
(334 mg, 98%) as a colorless oil. [a]2D0¼þ28.3 (c 0.50,
Anal. Found: C, 70.87; H, 11.10. Calcd for C26H48O5: C,
70.87; H, 10.98.
3.1.15. (4S,5S,9R,10R,13R,14R)-14-(Methoxymethoxy)-
a stirred
5,9:10,13-dioxido-1-hexacosyn-4-ol (2). To
CHCl3); IR (neat) 3420, 2925, 1149, 1087, 1039, 918 cm21
;
solution of trimethylsilylacetylene (0.2 ml, 1.42 mmol) in
THF (1.5 ml) was added dropwise a 1.59 M solution of
n-butyllithium in hexane (0.84 ml, 1.34 mmol) at 2788C,
and the mixture was stirred at the same temperature for 1 h.
A solution of 20 (194 mg, 0.44 mmol) in THF (0.6 ml) and
BF3·Et2O (0.17 ml, 1.34 mmol) was added sequentially to
the above solution at 2788C. The mixture was stirred at the
same temperature for 2 h, poured into sat. NH4Cl solution,
and extracted with ether. The extracts were washed
successively with water, brine, dried, concentrated, and
passed through a short column of silica gel {hexane–EtOAc
(10:1–4:1)} to give a syrup (232 mg). A mixture of the
syrup (232 mg) and potassium carbonate (31 mg) in
methanol (2.0 ml) was stirred at rt for 5 h, and then
concentrated. The residue was purified by chromatography
on silica gel {hexane–EtOAc (10:1–4:1)} to give 2
(199 mg, 97%) as a colorless oil. [a]2D3¼þ39.4 (c 0.40,
CHCl3); IR (neat) 3449, 3314, 2924, 2120, 1101, 1084,
1039, 918 cm21; 1H NMR (400 MHz, CDCl3): d 0.87 (3H,
t, J¼6.8 Hz), 1.22–1.75 (29H, m), 1.86–1.94 (3H, m), 1.99
(1H, t, J¼2.4 Hz), 2.38 (1H, ddd, J¼17, 5.9, 2.4 Hz), 2.48
(1H, ddd, J¼17, 5.9, 2.4 Hz), 3.33 (1H, ddd, J¼11, 5.9,
2.0 Hz), 3.35–3.48 (2H, m), 3.38 (3H, s), 3.59 (1H, dd,
J¼11, 5.9 Hz), 3.89 (1H, ddd, J¼7.3, 6.3, 5.8 Hz), 3.96 (1H,
ddd, J¼8.3, 6.4, 6.3 Hz), 4.66, 4.81 (2H, each d, J¼6.8 Hz);
13C NMR (100 MHz, CDCl3): d 14.1, 22.6, 22.8, 23.0, 25.5,
26.9, 27.0, 27.7, 28.4, 29.3, 29.5, 29.6, 29.8, 31.1, 31.9,
69.9, 72.4, 78.8, 79.4, 80.0, 80.9, 81.0, 81.8, 96.5; HRMS
calcd for C28H50O5Na [MþNa]þ 489.3556, found
489.3551.
1H NMR (400 MHz, CDCl3): d 0.87 (3H, t, J¼6.8 Hz),
1.20–1.74 (29H, m), 1.88–1.96 (3H, m), 2.80 (2H, brs),
3.28 (1H, ddd, J¼11, 5.4, 1.5 Hz), 3.38 (3H, s), 3.42–3.49
(2H, m), 3.54 (1H, dd, J¼9.3, 4.9 Hz), 3.67 (1H, dd,
J¼11.7, 3.9 Hz), 3.76 (1H, dd, J¼11.7, 4.9 Hz), 3.84 (1H,
ddd, J¼8.3, 5.8, 5.8 Hz), 3.96 (1H, ddd, J¼8.3, 7.3, 6.4 Hz),
4.66, 4.80 (2H, each d, J¼6.8 Hz); 13C NMR (100 MHz,
CDCl3): d 14.2, 22.7, 22.9, 25.5, 27.3, 27.4, 28.1, 28.5,
29.4, 29.6, 29.7, 29.8, 29.9, 31.0, 31.2, 31.9, 55.8,
63.8, 73.6, 79.6, 80.1, 80.3, 81.2, 81.8, 96.6; HRMS
calcd for C26H50O6Na [MþNa]þ 481.3505, found
481.3534.
3.1.14. (2S,3S,7R,8R,11R,12R)-12-(Methoxymethoxy)-
1,2:3,7:8,11-trioxido-tetracosane (20). From 19. To a
stirred solution of 19 (179 mg, 0.39 mmol) in pyridine
(1.5 ml) was added dropwise a solution of benzoyl chloride
(55 ml, 0.47 mmol) in CH2Cl2 (0.4 ml) at 2208C, and the
mixture was stirred at 220 to 58C for 12 h. Methanesulfonyl
chloride (70 ml, 0.90 mmol) was added at 2208C, and the
mixture was stirred at 220 to 08C for 7 h, then poured into
ice–water. The resulting mixture was extracted with ether.
The extracts were washed successively with cold HCl
solution, water, sat. NaHCO3 solution, water, brine, dried
and concentrated to give a syrup (271 mg). To a stirred
solution of the syrup (271 mg) in THF–methanol (1:1,
1.6 ml) was added a 4 M solution of NaOH (0.2 ml) at
2208C. The mixture was stirred at 220 to 58C for 17 h,
diluted with CH2Cl2, and washed successively with water,
brine, dried, and concentrated. Chromatography on silica
gel with hexane–EtOAc (10:1–4:1) as the eluent yielded 20
(143 mg, 83% from 19).
Anal. Found: C, 72.37; H, 10.89. Calcd for C28H50O5: C,
72.06; H, 10.80.
From 29. To a stirred solution of 29 (49.4 mg, 0.12 mmol)
in THF (0.5 ml) was added dropwise a 1.6 M hexane
solution of n-BuLi (0.1 ml, 0.16 mmol) at 2238C, and the
mixture was stirred at 2238C for 15 min. Chloromethyl
methyl ether (12 ml, 0.16 mmol) was added, and the mixture
was stirred at 2238C ,rt for 18 h. After quenching with sat.
NH4Cl solution, the resulting mixture was extracted with
ether. The extracts were washed successively with water,
brine, dried and concentrated. Chromatography on silica gel
{hexane–EtOAC (4:1)} followed by purification by pre-
parative TLC {hexane–EtOAc (2:1), 3 developments}
yielded 20 (22.0 mg, 40%). Colorless oil; [a]2D3¼þ24.3 (c
1.07, CHCl3); IR (neat) 2925, 1150, 1105, 1089, 1040,
3.1.16. (2R,3S,7R,8R,11R,12R)-1-t-Butyldiphenylsilyl-
oxy-11,12-(isopropylidenedioxy)-3,7-oxido-2,8-tetra-
cosanediol (21). To a stirred solution of 5 (240 mg,
0.36 mmol) in CH2Cl2 (4.5 ml) was added d-camphorsul-
fonic acid (54 mg, 0.23 mmol) at rt, and the mixture was
stirred at rt for 3 h. 2,2-Dimethoxypropane (0.1 ml) was
added and stirring was further continued for 3.5 h. After
addition of triethylamine, the resulting mixture was
concentrated. Chromatography on silica gel with hexane–
EtOAc (4:1–2:1) as the eluent yielded 21 (226 mg, 89%) as
a colorless oil. [a]2D3¼þ15.5 (c 0.96, CHCl3); IR (neat)
3441, 2928, 1428, 1239, 1113, 1087, 1048 cm21; 1H NMR
(400 MHz, CDCl3): d 0.88 (3H, t, J¼6.8 Hz), 1.07 (9H, s),
1.22–1.93 (35H, m), 1.34 (3H, s), 2.47 (1H, brs), 2.58 (1H,
brs), 3.17 (1H, ddd, J¼11, 6.3, 2.0 Hz, H-7), 3.37 (1H, ddd,
J¼11, 6.3, 2.0 Hz, H-3), 3.42 (1H, m, H-8), 3.55–3.62 (2H,
918 cm21 1H NMR (400 MHz, CDCl3): d 0.87 (3H, t,
;
J¼6.8 Hz), 1.23–1.95 (32H, m), 2.67 (1H, dd, J¼4.9,
2.9 Hz), 2.74 (1H, t, J¼4.9 Hz), 1.81–1.91 (1H, m), 3.00

S. Takahashi et al. / Tetrahedron 59 (2003) 1627–1638
1635
m, H-11, 12), 3.65 (1H, m, H-2), 3.72 (1H, dd, J¼10,
6.3 Hz, H-1), 3.77 (1H, dd, J¼10, 4.4 Hz, H-10), 7.38–7.45
(6H, m), 7.65 (4H, brd, J¼7.8 Hz); 13C NMR (100 MHz,
CDCl3): d 14.2, 19.4, 22.8, 26.2, 26.9, 27.0, 27.2, 27.3, 27.4,
28.7, 29.1, 29.4, 29.6, 29.7, 29.9, 31.9, 32.9, 64.7, 73.7,
74.1, 77.8, 80.7, 80.8, 80.9, 107.8, 127.7, 128.2, 129.7,
132.9, 135.4.
Anal. Found: C, 67.07; H, 9.39; S, 5.43. Calcd for
C34H56O7S: C, 67.07; H, 9.27; S, 5.27.
24; colorless oil; [a]D23¼þ20.9 (c 0.22, CHCl3); IR (neat)
3546, 2927, 1599, 1457, 1366, 1189, 1177, 1096, 920 cm21
;
1H NMR (400 MHz, CDCl3): d 0.88 (3H, t, J¼6.8 Hz),
1.20–1.90 (32H, m), 1.29 (3H, s), 1.33 (3H, s), 2.40 (1H, t,
J¼6.3 Hz), 2.44 (3H, s), 2.45 (3H, s), 3.38–3.48 (3H, m),
3.55 (1H, ddd, J¼11, 6.8, 1.9 Hz), 3.67 (1H, ddd, J¼13, 6.8,
2.9 Hz), 3.77 (1H, ddd, J¼13, 6.3, 4.4 Hz), 4.37 (1H, dd,
J¼6.7, 3.4 Hz), 4.54 (1H, dd, J¼7.2, 4.8 Hz), 7.33 (4H, m),
7.72 (4H, m); 13C NMR (100 MHz, CDCl3): d 14.2, 21.7,
21.8, 22.6, 22.8, 26.1, 26.2, 26.8, 27.2, 27.3, 27.5, 27.9,
29.4, 29.6, 29.7, 29.8, 31.9, 32.8, 61.4, 76.3, 77.9, 80.1,
80.7, 83.7, 84.1, 107.9, 127.6, 127.8, 129.6, 129.8, 133.6,
134.3, 144.5; HRMS calcd for C41H64O10S2Na [MþNa]þ
803.3839, found 803.3830.
Anal. Found: C, 72.67; H, 10.09. Calcd for C43H70O6Si: C,
72.63; H, 9.92.
3.1.17. (2R,3S,7R,8R,11R,12R)-1-t-Butyldiphenylsilyl-
oxy-11,12-(isopropylidenedioxy)-3,7-oxido-2,8-tetra-
cosanediol di-p-toluenesulfonate (22). Treatment of 21
(143 mg, 0.21 mmol) as described for preparation of 15
yielded 22 (149 mg), which was employed to the next step
without further purification. An analytical sample was
prepared by chromatography on silica gel {hexane–EtOAc
(4:1)}. Colorless oil; [a]2D3¼þ7.7 (c 0.97, CHCl3); IR (neat)
3072, 2928, 1599, 1463, 1428, 1367, 1189, 1177, 1113,
1097, 915 cm21; 1H NMR (400 MHz, CDCl3): d 0.88 (3H,
t, J¼6.8 Hz), 1.00 (9H, s), 1.20–1.83 (32H, m), 1.31 (3H, s),
1.34 (3H, s), 2.37 (3H, s), 2.40 (3H, s), 3.37–3.43 (3H, m),
3.58 (1H, dd, J¼11, 3.9 Hz), 3.63 (1H, m), 3.66 (1H, dd,
J¼11, 3.8 Hz), 4.39 (1H, dd, J¼9.6, 4.3 Hz), 4.54 (1H, dd,
J¼10.7, 6.2 Hz), 7.22 (2H, d, J¼8.2 Hz), 7.23 (2H, d,
J¼8.7 Hz), 7.37–7.43 (6H, m), 7.55–7.59 (4H, m), 7.71
(2H, d, J¼8.7 Hz), 7.72 (2H, d, J¼8.2 Hz); 13C NMR
(100 MHz, CDCl3): d 14.1, 19.2, 21.5, 21.6, 22.5, 22.7,
25.6, 26.1, 26.4, 26.7, 27.2, 27.3, 28.3, 29.3, 29.5, 29.6,
29.8, 31.9, 32.8, 61.8, 75.5, 77.4, 80.4, 81.0, 83.6, 83.7,
107.9, 127.7, 127.8, 127.9, 129.5, 129.6, 129.7, 129.8,
132.9, 133.0, 134.3, 134.4, 135.4, 135.6, 144.3, 144.4;
HRMS calcd for C57H82O10SiS2Na [MþNa]þ 1041.5016,
found 1041.5010.
3.1.19. (3S,7R,11R,12R)-1-t-Butyldiphenylsilyloxy-11,12-
(isopropylidenedioxy)-3,7-oxido-2,8-tetracosanedione
(25). Treatment of 21 (136.1 mg, 0.19 mmol) as described
for preparation of 13 yielded 25 (149 mg), which was
employed to the next step without further purification. An
analytical sample was prepared by chromatography on silica
gel {hexane–EtOAc (4:1)}. Colorless oil; [a]2D3¼þ15.3 (c
0.74, CHCl3); IR (neat) 3070, 2928, 1740, 1720, 1428,
1378, 1367, 1240, 1205, 1113, 1110, 1045 cm21; 1H NMR
(400 MHz, CDCl3): d 0.88 (3H, t, J¼6.8 Hz), 1.11 (9H, s),
1.20–1.94 (30H, m), 1.33 (3H, s), 1.34 (3H, s), 2.61 (1H,
ddd, J¼19.3, 7.8, 7.3 Hz), 2.66 (1H, ddd, J¼19.3, 8.7,
5.3 Hz), 3.50–3.60 (2H, m), 3.75 (1H, brd, J¼11.6 Hz),
3.95 (1H, brd, J¼11.6 Hz), 4.61 (1H, brd, J¼18.8 Hz), 4.65
(1H, brd, J¼18.8 Hz), 7.37–7.46 (6H, m), 7.65–7.67 (4H,
m); 13C NMR (100 MHz, CDCl3): d 14.2, 19.4, 22.7, 25.9,
26.1, 26.8, 27.3, 27.4, 29.4, 29.6, 29.7, 29.8, 32.0, 32.8,
34.4, 67.1, 79.9, 81.1, 81.5, 82.6, 107.8, 127.6, 129.7, 132.7,
135.4, 205.9, 209.2.
3.1.18. (2S,3S,7R,8R,11R,12R)-11,12-(Isopropylidene-
dioxy)-1,2:3,7-dioxido-8-tetracosanol p-toluenesulfonate
(23) and (2R,3S,7R,8R,11R,12R)-11,12-(isopropylidene-
dioxy)-3,7-oxido-2,8-di-p-toluenesulfonyloxy-1-tetra-
cosanol (24). To a stirred solution of 22 (103 mg,
0.10 mmol) in THF (0.5 ml) was added a 1.0 M THF
solution of TBAF (0.12 ml, 0.12 mmol) at rt, and the
mixture was stirred at rt for 2d, then concentrated. The
residue was passed through a short column of silica gel
{hexane–EtOAc (4:1)} and then purified by preparative
TLC {hexane–EtOAc (4:1)} to give 23 (35.1 mg, 57%),
and 24 (11.5 mg, 15%).
Anal. Found: C, 72.94; H, 9.49. Calcd for C43H66O6Si: C,
73.04; H, 9.41.
3.1.20. (2R,3S,7R,8RS,11R,12R)-1-t-Butyldiphenylsilyl-
oxy-11,12-(isopropylidenedioxy)-3,7-oxido-2,8-tetra-
cosanediol (26) and (2S,3S,7R,8RS,11R,12R)-1-t-
butyldiphenylsilyloxy-11,12-(isopropylidenedioxy)-3,7-
oxido-2,8-tetracosanediol (27). Treatment of the above
ketone 25 (149 mg, ca 0.19 mmol) as described for
preparation of 14 yielded 26 (117 mg, 85%) as a C-8
epimeric mixture (b/a¼ca 89/11 by 1H NMR analysis)
and 27 (17 mg, 13%) as a C-8 epimeric mixture (b/a¼ca
56/44).
23; colorless oil; [a]D24¼þ29.6 (c 0.51, CHCl3); IR (neat)
1
2927, 1599, 1457, 1366, 1188, 1176, 1096, 914 cm21; H
NMR (400 MHz, CDCl3): d 0.87 (3H, t, J¼6.8 Hz), 1.20–
1.92 (32H, m), 1.31 (3H, s), 1.33 (3H, s), 2.40 (3H, s), 2.58
(1H, dd, J¼4.9, 2.5 Hz), 2.71 (1H, t, J¼4.9 Hz), 2.88 (1H,
ddd, J¼7.3, 4.9, 2.5 Hz), 3.10 (1H, ddd, J¼11, 5.8, 2.0 Hz),
3.38–3.45 (2H, m), 3.51 (1H, ddd, J¼11, 4.9, 1.9 Hz), 3.55
(1H, ddd, J¼11, 6.8, 1.9 Hz), 4.77 (1H, dd, J¼8.7, 4.7 Hz),
7.31 (2H, d, J¼7.8 Hz), 7.81 (2H, d, J¼8.2 Hz); 13C NMR
(100 MHz, CDCl3): d 14.2, 21.7, 22.6, 22.7, 25.4, 26.2,
26.6, 27.2, 27.3, 28.4, 29.4, 29.5, 29.6, 29.7, 29.8, 31.9,
32.8, 43.8, 54.0, 77.2, 78.7, 80.4, 80.9, 83.8, 107.8, 127.8,
129.4, 134.2, 144.2; HRMS calcd for C34H56O7SNa
[MþNa]þ 631.3644, found 631.3638.
26; colorless oil; IR (neat) 3449, 3072, 2928, 1597, 1428,
1377, 1367, 1239, 1219, 1113, 1087, 1048 cm21; 1H NMR
(400 MHz, CDCl3): d 0.88 (3H, t, J¼6.8 Hz), 1.07 (9H, s),
1.22–1.94 (38H, m), 2.40 (2H, brs), 3.17 (0.11H, ddd,
J¼11.7, 6.3, 1.8 Hz, H-7minor), 3.23 (0.89H, ddd, J¼12, 3.3,
2.0 Hz, H-7major), 3.36–3.46 (1H, m), 3.52–3.81 (5H, m),
7.37–7.46 (6H, m), 7.65–7.67 (4H, m); 13C NMR
(100 MHz, CDCl3): d 14.2, 19.4, 22.8, 25.5, 26.0, 26.2,
26.9, 27.0, 27.2, 27.3, 27.4, 28.7, 29.1, 29.4, 29.6, 29.7,
29.9, 32.0, 32.9, 64.4, 64.7, 73.5, 73.7, 74.0, 74.1, 77.8,
80.4, 80.7, 80.8, 80.9, 81.1, 81.2, 107.8, 127.6, 127.7, 129.7,

1636
S. Takahashi et al. / Tetrahedron 59 (2003) 1627–1638
132.9, 133.0, 135.4; HRMS calcd for C43H70O6SiNa
[MþNa]þ 733.4839, found 733.4854.
residue was passed through a short column of silica gel
{hexane–EtOAc (10:1–4:1)} to give 4b (387 mg,
0.66 mmol), which was dissolved in THF (1 ml). A 1.0 M
THF solution of TBAF (0.2 ml, 0.2 mmol) was added to the
solution, and the mixture was stirred at rt for 24 h and at
508C for 3 h, and then concentrated. Chromatography on
silica gel with hexane–EtOAc (10:1–4:1) as the eluent
yielded 29 (22.1 mg, 59% from 26), and a mixture of 29 and
30, which was separated by preparative TLC {hexane–
EtOAc (1:1)} to afford more additional 29 (2.4 mg, 6%) and
30 (3.1 mg, 8%).
Anal. Found: C, 72.69; H, 10.09. Calcd for C43H70O6Si: C,
72.63; H, 9.92.
27; colorless oil; IR (neat) 3400, 3060, 2929, 1597, 1428,
1377, 1367, 1239, 1219, 1113, 1066, 1044 cm21; 1H NMR
(400 MHz, CDCl3): d 0.88 (3H, t, J¼6.8 Hz), 1.06 (9H, s),
1.22–1.94 (32H, m), 1.37 (3H, s), 1.38 (3H, s), 2.26 (2H,
brs), 3.23 (0.44H, ddd, J¼11.7, 5.9, 1.8 Hz, H-7minor), 3.30
(0.56H, ddd, J¼11.8, 3.5, 1.8 Hz, H-7major), 3.45–3.65
(4H, m), 3.66–3.76 (2H, m), 7.37–7.46 (6H, m), 7.65–7.67
(4H, m); 13C NMR (100 MHz, CDCl3): d 14.2, 19.3, 22.7,
22.9, 24.8, 26.2, 26.9, 27.1, 27.3, 27.4, 28.7, 29.2, 29.4,
29.5, 29.6, 29.7, 29.8, 31.9, 32.8, 32.9, 64.3, 64.4, 73.4,
73.6, 74.4, 80.5, 80.7, 80.8, 80.9, 81.0, 81.2, 96.0, 107.7,
127.5, 127.6, 129.5, 129.6, 133.1, 133.2, 135.3; HRMS
calcd for C43H70O6SiNa [MþNa]þ 733.4839, found
733.4855.
29; colorless oil; [a]D24¼þ8.0 (c 0.41, CHCl3); IR (neat)
1
3475, 2925, 1467, 1441, 1087, 1047, 904 cm21; H NMR
(400 MHz, CDCl3): d 0.87 (3H, t, J¼6.8 Hz), 1.22–2.00
(33H, m), 2.66 (1H, dd, J¼4.8, 2.5 Hz), 2.76 (1H, t,
J¼4.8 Hz), 3.02 (1H, m), 3.22 (1H, ddd, J¼11.2, 7.3,
1.9 Hz), 3.31 (1H, ddd, J¼11.2, 6.8, 1.5 Hz), 3.36 (1H, dd,
J¼6.8, 5.8 Hz), 3.81 (1H, ddd, J¼6.8, 6.8, 6.3 Hz), 3.89
(1H, ddd, J¼8.3, 5.8, 5.8 Hz); 13C NMR (100 MHz,
CDCl3): d 14.1, 22.7, 22.8, 25.6, 26.7, 27.3, 28.2, 28.3,
29.3, 29.5, 29.6, 29.7, 31.9, 33.2, 43.8, 54.1, 74.0, 77.8.
79.9, 80.9, 82.8; HRMS calcd for C24H44O4Na [MþNa]þ
419.3137, found 419.3126.
Anal. Found: C, 72.55; H, 10.08. Calcd for C43H70O6Si: C,
72.63; H, 9.92.
3.1.21. (2R,3S,7R,8RS,11R,12R)-1-t-Butyldiphenylsilyl-
oxy-11,12-(isopropylidenedioxy)-3,7-oxido-2,8-tetra-
cosanediol di-p-toluenesulfonate (28). To a stirred mixture
of 26 (67.2 mg, 0.09 mmol), N,N-dimethylaminopyridine
(23.1 mg, 0.19 mmol) and triethylamine (0.2 ml) in CH2Cl2
(1.0 ml) was added p-toluenesulfonyl chloride (54 mg,
0.28 mmol) at rt, and then the mixture was stirred at rt for
12 h. More p-toluenesulfonyl chloride (27 mg, 0.14 mmol)
was added, and stirring was further continued for 10 h. After
addition of ice–water, the resulting mixture was vigorously
stirred for 30 min and then extracted with ether. The extracts
were washed successively with cold HCl solution, water,
sat. NaHCO3 solution, water, brine, dried, and concentrated.
The residue was passed through a short column of silica gel
{hexane–EtOAc (10:1–4:1)} to give 28 (99.0 mg), which
was employed to the next step without further purification.
Analytical sample was prepared by preparative TLC
{hexane–EtOAc (4:1)}. Colorless oil; IR (neat) 3070,
Anal. Found: C, 72.50; H, 11.24. Calcd for C24H44O4: C,
72.68 H, 11.18.
30; white solid; mp 63–658C; [a]2D1¼26.7 (c 0.62, CHCl3);
IR (CHCl3) 3401, 2920, 1465, 1095, 1077, 1064, 1051,
1
902 cm21; H NMR (400 MHz, CD2Cl2): d 0.87 (3H, t,
J¼6.8 Hz), 1.22–1.98 (32H, m), 2.59 (1H, dd, J¼5.4,
2.9 Hz), 2.66 (1H, brs), 2.70 (1H, t, J¼5.4 Hz), 2.91 (1H,
m), 3.15 (1H, ddd, J¼11.1, 5.8, 1.9 Hz), 3.31 (1H, m), 3.38
(1H, ddd, J¼11.2, 6.3, 1.9 Hz), 3.76 (1H, dd, J¼6.2,
5.4 Hz), 3.84 (1H, ddd, J¼6.8, 6.8, 4.3 Hz); 13C NMR
(100 MHz, CD2Cl2): d 14.4, 23.1, 23.2, 26.3, 27.1, 27.9,
28.1, 28.5, 29.8, 30.1, 30.2, 32.4, 34.7, 43.9, 54.4, 74.5,
78.8. 79.6, 82.2, 82.9.
Anal. Found: C, 72.59; H, 11.17. Calcd for C24H44O4: C,
72.68 H, 11.18.
3050, 2929, 2927, 1599, 1367, 1189, 1177, 1113, 920 cm21
;
1H NMR (400 MHz, CDCl3): d 0.87 (3H, t, J¼6.8 Hz), 0.99
(9H, s), 1.22–1.84 (38H, m), 2.37, 2.38, 2.39, 2.40 (total
6H, each s), 3.18–3.25 (1H, m), 3.38–3.70 (5H, m), 4.05
(0.89H, m), 4.35 (0.89H, m), 4.38 (0.11H, m), 4.34 (0.11H,
m), 7.19–7.21 (2H, m), 7.30–7.58 (10H, m), 7.65–7.74
(2H, m); 13C NMR (100 MHz, CDCl3): d 14.2, 19.3, 21.6,
21.7, 22.4, 22.5, 22.7, 25.3, 25.6, 26.2, 26.8, 27.3, 27.4,
29.1, 29.4, 29.6, 29.7, 29.9, 32.0, 32.9, 61.5, 61.8, 74.4,
75.5, 78.3, 80.4, 80.7, 81.0, 81.1, 83.3, 83.6, 83.7, 85.2,
107.8, 127.6, 129.2, 129.4, 129.5, 129.6, 132.7, 132.9,
134.2, 134.4, 134.7, 135.3, 135.4, 144.2, 144.3; HRMS
calcd for C57H82O10SiS2Na [MþNa]þ 1041.5016, found
1041.5020.
3.1.23. Butenolide (31). To a stirred solution of 2 (57.5 mg,
0.12 mmol) and 3 (114 mg, 0.20 mmol) in Et3N (2 ml) were
added (Ph3P)2PdCl2 (9.1 mg, 0.01 mmol) and CuI (7.3 mg,
0.04 mmol) at rt, and the reaction mixture was stirred at rt
for 2 h, poured into ice–water. The resulting mixture was
extracted wtih EtOAc. The extracts were washed succes-
sively with cold HCl solution, water, sat. NaHCO3 solution,
water, brine, dried, concentrated. Chromatography on silica
gel with hexane–EtOAc (10:1–4:1–1:1) as the eluent
yielded an enyne 31 (87.2 mg, 79%) as a colorless oil. IR
(neat) 3464, 2927, 1758, 1428, 1104, 1081, 1032 cm21; 1H
NMR (400 MHz, CDCl3) of ca 3/1 of an isomeric mixture: d
0.87 (3H, t, J¼6.8 Hz), 1.04 (9H, s), 1.21–2.04 (37H, m),
1.31 (3H, d, J¼6.8 Hz), 2.18–2.60 (4H, m), 3.28–3.60 (4H,
m), 3.39 (3H, s), 3.86–4.06 (3H, m), 4.65, 4.66, 4.81, 4.83
(total 2H, each d, J¼6.8 Hz), 4.88 (1H, qd, J¼6.8, 1.5 Hz),
5.30 (0.74H, brd, J¼16.1 Hz), 5.33 (0.26H, brd,
J¼10.7 Hz), 5.51 (0.26H, ddd, J¼10.7, 7.8, 7.3 Hz), 5.82
(0.74H, ddd, J¼16.1, 7.3, 6.8 Hz), 6.88 (0.74H, brd,
J¼1.5 Hz), 6.92 (0.26H, brd, J¼1.5 Hz), 7.35–7.44 (6H,
3.1.22. (2S,3S,7R,8R,11R,12R)-1,2:3,7:8,11-Trioxido-12-
tetracosanol (29) and (2S,3S,7R,8S,11R,12R)-1,2:
3,7:8,11-trioxido-12-tetracosanol (30). A solution of the
above ditosylate 28 (99.0 mg, 0.66 mmol) in AcOH–water
(20:1, 2.1 ml) was stirred at rt for 3d and then at 508C for
6 h, concentrated, and then co-evaporated with toluene. The

S. Takahashi et al. / Tetrahedron 59 (2003) 1627–1638
1637
m), 7.62–7.67 (4H, m); 13C NMR (100 MHz, CDCl3): d
14.1, 18.9, 19.3, 22.6, 22.8, 23.9, 25.5, 26.9, 27.7, 28.3,
28.4, 29.3, 29.6, 29.8, 31.1, 31.7, 31.9, 35.2, 55.7, 71.1,
72.7, 78.8, 79.1, 79.4, 80.0, 80.6, 80.9, 81.8, 84.9, 96.5,
109.6, 110.0, 127.6, 129.7, 130.3, 133.8, 135.8, 141.8,
142.8, 151.4, 173.8; HRMS calcd for C55H82O8SiNa
[MþNa]þ 921.5677, found 921.5691.
spectral measurements, and Dr T. Chihara and his
collaborators in RIKEN for the elemental analyses.
References
1. For reviews see: (a) Rupprecht, J. K.; Hui, Y.-H.; McLaughlin,
J. L. J. Nat. Prod. 1990, 53, 237–278. (b) Fang, X.-P.; Rieser,
M. J.; Gu, Z.-M.; Zhao, G.-X.; McLaughlin, J. L. Phytochem.
Anal. 1993, 4, 27–67. (c) Gu, Z.-M.; Zhao, G.-X.; Oberlies,
N. H.; Zeng, L.; McLaughlin, J. L. Recent Advances in
Phytochemistry; Plenum Press: New York, 1995; Vol. 29. pp
249–310. (d) Koert, U. Synthesis 1995, 115–132. (e) Hoppe,
R.; Scharf, H.-D. Synthesis 1995, 1447–1464. (f) Figadere, B.
Acc. Chem. Res. 1995, 28, 359–365. (g) Zafra-Polo, M. C.;
Gonzalez, M. C.; Estornell, E.; Sahpaz, S.; Cortes, D.
Phytochemistry 1996, 42, 253–271. (h) Zeng, L.; Ye, Q.;
Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.; McLaughlin, J. L.
Nat. Prod. Rep. 1996, 13, 275–306. (i) Zafra-Polo, M. C.;
Figadere, B.; Gallardo, T.; Tormo, J. R.; Cortes, D.
Phytochemistry 1998, 48, 1087–1117. (j) Alali, F. Q.; Liu,
X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504–540, and
references cited therein.
3.1.24. Muconin 4-O-(t-butyldiphenylsilyl)-22-O-(meth-
oxymethyl) diether (32). A mixture of 31 (41.3 mg,
46 mmol) and tris(triphenylphosphine)rhodium chloride
(21.0 mg, 23 mmol) in benzene–ethanol (4:1, 0.75 ml)
was stirred at rt for 7 h under hydrogen atmosphere, and
concentrated. The residue was purified by chromatography
on silica gel {hexane–EtOAc (10:1–4:1–2:1)} to give 32
(35.5 mg, 85%) as a colorless oil. [a]2D2¼þ2.7 (c 0.70,
CHCl3); IR (neat) 2927, 1759, 1460, 1321, 1210, 1104,
1077, 1030 cm21; 1H NMR (400 MHz, CDCl3): d 0.87 (3H,
t, J¼6.8 Hz), 1.03 (9H, s), 1.10–1.76 (46H, m), 1.31 (3H, d,
J¼6.8 Hz), 2.37–2.46 (2H, m), 3.14 (1H, ddd, J¼11, 6.8,
1.9 Hz), 3.30 (1H, ddd, J¼11, 5.3, 1.9 Hz), 3.38 (1H, m),
3.39 (3H, s), 3.46 (1H, m), 3.89 (1H, ddd, J¼7.8, 5.9,
5.9 Hz), 3.95–4.04 (2H, m), 4.66, 4.82 (2H, each d,
J¼6.8 Hz), 4.88 (1H, qd, J¼6.8, 1.5 Hz), 6.91 (1H, m),
7.34–7.42 (6H, m), 7.62–7.67 (4H, m); 13C NMR
(100 MHz, CDCl3): d 14.1, 18.9, 19.3, 22.6, 22.9, 24.8,
25.3, 25.5, 26.9, 27.1, 27.8, 28.4, 29.3, 29.4, 29.6, 29.8,
31.1, 31.7, 31.9, 32.5, 36.3, 71.7, 74.2, 77.4, 79.4, 79.9,
80.8, 81.1, 81.8, 96.6, 127.5, 129.6, 130.6, 134.1, 135.8,
151.1, 173.9; HRMS calcd for C55H88O8SiNa [MþNa]þ
927.6146, found 927.6149.
2. For recent total synthesis see: (a) Harcken, C.; Bruckner, R.
New J. Chem. 2001, 40–54. (b) Hu, T.-S.; Yu, Q.; Wu, Y.-L.;
Wu, Y. J. Org. Chem. 2001, 66, 853–861. (c) Maezaki, N.;
Kojima, N.; Sakamoto, A.; Iwata, C.; Tanaka, T. Org. Lett.
2001, 3, 429–432. (d) Burke, S. D.; Jiang, L. Org. Lett. 2001,
3, 1953–1955. (e) Dixon, D. J.; Ley, S. V.; Reynolds, D. J.
Chem. Eur. J. 2002, 8, 1621–1636. (f) Makabe, H.; Hattori,
Y.; Tanaka, A.; Oritani, T. Org. Lett. 2002, 4, 1083–1085, and
references cited therein.
Anal. Found: C, 72.88; H, 9.54. Calcd for C55H88O8Si: C,
72.96; H, 9.80.
3. Shi, G.; Alfonso, D.; Fatope, M. O.; Zeng, L.; Gu, Z.-M.;
Zhao, G-X.; He, K.; MacDougal, J. M.; McLaughlin, J. L.
J. Am. Chem. Soc. 1995, 117, 10409–10410.
3.1.25. Muconin (1). To a stirred solution of 32 (8.9 mg,
9.8 mmol) in CH2Cl2–MeOH (2:1, 0.9 ml) was added a
10% HCl solution in MeOH (0.3 ml) at rt, and the mixture
was stirred at rt for 1 day. After addition of NaHCO3, the
resulting mixture was filtered through a pad of celite, and
then concentrated. The residue was purified by preparative
TLC (EtOAc, 3 developments) to afford 1. (4.8 mg, 78%) as
a white powder. [a]2D3¼þ12.9 (c 0.21, CHCl3); IR (KBr)
3441, 2923, 1755, 1464, 1073, 1050, 1027 cm21; 1H NMR
(400 MHz, CDCl3): d 0.87 (3H, t, J¼6.8 Hz), 1.20–2.00
(46H, m), 1.43 (3H, d, J¼6.8 Hz), 2.30–2.62 (3H, m), 2.38
(1H, dd, J¼15.1, 8.2 Hz), 2.51 (1H, ddd, J¼15.1, 2.0,
1.5 Hz), 3.16 (1H, m), 3.30 (1H, m), 3.37 (1H, m), 3.42 (1H,
m), 3.80 (1H, m), 3.84 (1H, m), 3.88 (1H, m), 5.05 (1H, qd,
J¼6.8, 1.0 Hz), 7.18 (1H, brs); 13C NMR (100 MHz,
CDCl3): d 14.1, 19.1, 22.7, 22.9, 25.2, 25.5, 25.6, 27.0,
27.1, 28.3, 29.3, 29.4, 29.6, 29.7, 31.9, 32.4, 33.3, 37.3,
69.9, 74.0, 74.1, 78.0, 80.9, 81.3, 82.9, 131.1, 151.8, 174.6;
HRMS (FAB) calcd for C37H66O7Na 645.4706, found
645.4714.
4. Chavez, D.; Acevedo, L. A.; Mata, R. J. Nat. Prod. 1998, 61,
419–421.
5. Shi, G.; Kozlowski, J. F.; Schwedler, J. T.; Wood, K. V.;
MacDougal, J. M.; McLaughlin, J. L. J. Org. Chem. 1996, 61,
7988–7989.
6. (a) Takahashi, S.; Nakata, T. Tetrahedron Lett. 1999, 40,
723–726. (b) Takahashi, S.; Nakata, T. Tetrahedron Lett.
1999, 40, 727–730. (c) Takahashi, S.; Fujisawa, K.; Sakairi,
N.; Nakata, T. Heterocycles 2000, 53, 1361–1370.
(d) Takahashi, S.; Nakata, T. J. Org. Chem. 2002, 67,
5739–5752. (e) Takahashi, S.; Kuboto, A.; Nakata, T.
Angew. Chem. Int. Ed. 2002, 41, 4751–4754.
7. Takahashi, S.; Maeda, K.; Hirota, S.; Nakata, T. Org. Lett.
1999, 1, 2025–2028.
8. (a) Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem.
1998, 63, 4876–4877. (b) Yang, W-Q.; Kitahara, T. Tetra-
hedron Lett. 1999, 40, 7827–7830. (c) Yang, W-Q.; Kitahara,
T. Tetrahedron 2000, 56, 1451–1461.
9. Preliminary communication, Takahashi, S.; Kubota, A.;
Nakata, T. Tetrahedron Lett. 2002, 43, 8661–8664.
10. This compound was prepared from the corresponding
aldehyde through a vinyl iodide formation.15 For an
alternative synthesis of the aldehyde, see: Sinha, S. C.;
Sinha, A.; Sinha, S. C.; Keinan, E. J. Am. Chem. Soc. 1997,
119, 12014–12015.
Acknowledgements
We are grateful to Dr J. L. Mclaughlin (Purdue University)
for providing us copies of the NMR spectra of natural
muconin. We also thank Ms K. Harata (RIKEN) for mass
11. Sinha, S. C.; Keinan, E. J. Am. Chem. Soc. 1993, 115,
4891–4892.

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12. (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109,
5765–5780. (b) Kolb, H. C.; VanNieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547.
13. Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338–344.
14. Hoye, T. R.; Ye, Z. J. Am. Chem. Soc. 1996, 118, 1801–1802.
15. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408–7410.