A new approach to the synthesis of cyclic ethers via the intermolecular allylation of α-acetoxy ethers and ring-closing metathesis

Article abstract of DOI:10.1016/j.tet.2004.05.045

A concise synthesis of the isolaurepinnacin skeleton 6 was achieved via the intermolecular allylation of the α-acetoxy ether 3 followed by ring-closing metathesis. This methodology was successfully applied to the convergent synthesis of the oxocene 15, an advanced synthetic intermediate for the total synthesis of laurencin.

Full text of DOI:10.1016/j.tet.2004.05.045

Tetrahedron 60 (2004) 7361–7365
A new approach to the synthesis of cyclic ethers via the
intermolecular allylation of a-acetoxy ethers
and ring-closing metathesis
b
b
,
Isao Kadota,a Hiroshi Uyehara and Yoshinori Yamamoto
,
*
*
aResearch and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
bDepartment of Chemistry, Graduate School of Science, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan
Received 17 March 2004; revised 17 May 2004; accepted 19 May 2004
Available online 7 June 2004
This paper is dedicated to Professor R. H. Grubbs on the occasion of his receipt of the 2003 Tetrahedron Prize
Abstract—A concise synthesis of the isolaurepinnacin skeleton 6 was achieved via the intermolecular allylation of the a-acetoxy ether 3
followed by ring-closing metathesis. This methodology was successfully applied to the convergent synthesis of the oxocene 15, an advanced
synthetic intermediate for the total synthesis of laurencin.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
eight-membered ring ethers by the intermolecular allylation
of a-acetoxy ethers and ring-closing metathesis.
Red algae and marine organisms which feed on Laurencia
species have produced a variety of medium ring ethers such
as isolaurepinnacin,1 laurencin,2 and obtusenyne3 (Fig. 1).
The unique structural features of these C15 metabolites have
attracted the attention of synthetic chemists, and a number
of strategies have been investigated.4
2. Results and discussion
For an initial study, we examined the synthesis of the seven-
membered cyclic ether 6 as shown in Scheme 1.8 Reaction
of the homoallylic alcohol 19 with butyryl chloride and
pyridine gave 2 in 99% yield. The ester 2 was then subjected
to the Rychnovsky acetylation. Partial reduction of 2 with
DIBAL-H followed by trapping of the resulting aluminium
hemiacetal with acetic anhydride/pyridine/DMAP afforded
the a-acetoxy ether 3 in 78% yield.10 Treatment of 3 with
allyltributyltin and BF3·OEt2 gave the allylated product 4 as
a 1:1 mixture of diastereoisomers in 85% yield.11 Finally,
the diene 4 obtained was subjected to ring-closing
metathesis.12 Thus, treatment of 4 with the first generation
We recently developed a convergent method for the
synthesis of polycyclic ether frameworks by the intra-
molecular allylation of a-acetoxy ether and ring-closing
metathesis.5 It was thought that the intermolecular version
of this methodology would provide an efficient route to the
construction of medium ring ethers. Crimmins et al. have
reported similar approaches via asymmetric aldol- or
alkylation followed by ring-closing metathesis.6,7 In this
paper, we wish to report concise syntheses of seven- and
Figure 1. Representative marine medium ring ethers.
Keywords: Polycyclic ether; Allylation; RCM; Lewis acid; Marine natural product.
*
Corresponding authors. Tel.: þ81-22-217-6581; fax: þ81-22-217-6784; e-mail addresses: yoshi@yamamoto1.chem.tohoku.ac.jp;
ikadota@mail.tains.tohoku.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.045

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I. Kadota et al. / Tetrahedron 60 (2004) 7361–7365
Scheme 1. Reagents and conditions: (a) C3H7COCl, pyridine, CH2Cl2,
0 8C, 99%; (b) DIBAL-H, CH2Cl2, 278 8C, then Ac2O, pyridine, DMAP,
278 8C to rt, 78%; (c) allyltributyltin, BF3·OEt2, CH2Cl2, 0 8C to rt, 85%;
(d) 5, CH2Cl2, 35 8C, 100%.
Scheme 3. Reagents and conditions: (a) (i) AgNO3, KOH, MeOH–H2O,
0 8C; (ii) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt, then 9 DMAP,
toluene, rt, 94%; (b) (i) DDQ, NaHCO3, CH2–Cl2–H2O, 0 8C, 91%;
(ii) TIPSOTf, 2,6-lutidine, CH2Cl2, rt. 89%; (c) DIBAL-H, CH2Cl2,
278 8C, then (CH2ClCO)2O, pyridine, DMAP, 278 8C to rt, 78%;
(d) allyltributyltin, BF3·OEt2, CH2Cl2, 278 8C, 64%; (e) 5, CH2Cl2,
35 8C, 99%.
Grubbs catalyst 513 provided the oxepene 6, corresponding
to the isolaurepinnacin skeleton, in quantitative yield.
Although the target molecule 6 was obtained as a mixture
of diastereoisomers, the methodology employed allowed us
to construct the seven-membered cyclic ether 6 in only four
steps from the known alcohol 1.
Encouraged by this result, we next examined the synthesis
of eight-membered cyclic ether using the methodology
described above. Scheme 2 illustrates the preparation of the
alcohol segment 9. Reduction of 714 with LiBH4 gave the
alcohol 8 in 94% yield. Swern oxidation of 8 followed by
Grignard reaction in the presence of ZnBr2 afforded 9 as the
sole product in 86% yield.15
Figure 2. NOE experiment on the acetate 16.
3. Conclusion
We have developed a new method for the construction of
medium ring ethers via the intermolecular allylation of
a-acetoxy ethers and ring-closing metathesis. The result
described here demonstrates the efficiency and applicability
of this methodology, and further studies towards the total
synthesis of marine cyclic ethers having a medium ring are
in progress.
Scheme 2. Reagents and conditions: (a) LiBH4, MeOH, 0 8C, 94%; (b) (i)
(COCl)2, DMSO, CH2Cl2, 278 8C, then Et3N; (ii) EtMgBr, ZnBr2, ether,
0 8C, 86%.
Oxidation of the known aldehyde 1016 with Ag2O generated
from AgNO3 and KOH in situ gave the corresponding
carboxylic acid, which was subjected to the Yamaguchi
esterification with the alcohol 9 obtained above, providing
the ester 11 in 94% yield (Scheme 3).17 Removal of the
PMB group of 11 with DDQ followed by protection with
TIPS group gave 12 in 81% overall yield.18 The modified
Rychnovsky acetylation afforded the a-chloroacetoxy ether
13 in 78% yield.19 Allylation of 13 using allyltributyltin/
BF3·OEt2 gave 14 with high stereoselectivity (.95:5) in
64% yield.20 Finally, the diene 14 was subjected to the ring-
closing metathesis to provide 15 in 99% yield. The oxocene
15 is an advanced synthetic intermediate for the total
synthesis of laurencin.
4. Experimental
4.1. General
All reactions involving air- and/or moisture-sensitive
materials were carried out under argon with dry solvents
purchased from Wako or Kanto chemicals. On workup,
extracts were dried over MgSO4. Reactions were monitored
by thin-layer chromatography carried out on 0.25 mm
Merck silica gel plates (60F-254). Column chromatography
was performed with Kanto Chemical silica gel (60N,
spherical, neutral, particle size 0.100–0.210 mm). Yields
refer to chromatographically and spectroscopically homo-
geneous materials.
The a,a0-cis stereochemistry of 15 was unambiguously
determined by NOE experiment on the acetate derivative 16
as shown in Figure 2.
4.1.1. Ester 2. To a solution of 1 (1.76 g, 11.2 mmol) in

I. Kadota et al. / Tetrahedron 60 (2004) 7361–7365
7363
CH2Cl2 (110 mL) at 0 8C were added pyridine (1.82 mL,
22.5 mmol) and butyryl chloride (1.39 mL, 13.4 mmol).
After stirring for 1 h at the same temperature, the mixture
was diluted with ether, then washed with saturated NaHCO3
and brine. Concentration and chromatography (hexane/
EtOAc, 20:1) gave 2 (2.49 g, 99%): oil; Rf¼0.68 (hexane/
was added LiBH4 (0.12 g, 5.36 mmol), and the mixture was
stirred for 1.5 h at the same temperature. The mixture was
quenched with aqueous NaOH (10%, 40 mL) and extracted
with EtOAc. The organic layer was washed with brine.
Concentration and chromatography (hexane/AcOEt¼2:1)
gave 8 (0.94 g, 94%): oil; Rf¼0.35 (hexane/AcOEt¼2:1);
[a]2D3¼214.1 (c 0.94, CHCl3); IR (neat) 3600–3200,
1
EtOAc, 4:1); IR (neat) 1738 cm21; H NMR (300 MHz,
CDCl3) d 5.75 (dddd, J¼17.1, 9.9, 7.2, 7.2 Hz, 1H), 5.10–
5.00 (m, 2H), 4.93 (quint, J¼6.3 Hz, 1H), 2.34–2.24 (m,
2H), 2.26 (t, J¼7.3 Hz, 2H), 1.73–1.52 (m, 4H), 1.34–1.20
(m, 8H), 0.95 (t, J¼7.3 Hz, 3H), 0.88 (t, J¼7.0 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 173.2, 133.8, 117.4, 72.9, 38.6,
36.4, 33.5, 31.6, 29.0, 25.2, 22.5, 18.5, 13.9, 13.3. Anal.
calcd for C14H26O2: C, 74.29; H, 11.60. Found: C, 73.90; H,
11.52.
1612 cm21 1H NMR (400 MHz, CDCl3) d 7.27 (d,
;
J¼8.5 Hz, 2H), 6.89 (d, J¼8.5 Hz, 2H), 5.81 (ddd, J¼
17.1, 7.1, 2.9 Hz, 1H), 5.14–5.07 (m, 2H), 4.59 (d, J¼
11.2 Hz, 1H), 4.47 (d, J¼11.2 Hz, 1H), 3.81 (s, 3H), 3.68–
3.50 (m, 3H), 2.41–2.26 (m, 2H), 1.94 (m, 1H); 13C NMR
(100 MHz, CDCl3); d 158.6, 133.5, 129.8, 128.8, 117.0,
113.4, 78.4, 70.9, 63.8, 55.1, 35.3.; HRMS (ESI), calcd for
C13H18O3Na (MþNa): 245.1148. Found: 245.1154.
4.1.2. a-Acetoxy ether 3. To a solution of 2 (0.57 g,
2.52 mmol) in CH2Cl2 (15 mL) at 278 8C was added
DIBAL-H (0.93 M in hexane, 5.0 mL, 5.04 mmol), and the
mixture was stirred for 1 h at the same temperature. To the
mixture, acetic anhydride (1.43 mL, 15.1 mmol), DMAP
(0.61 g, 5.04 mmol) in CH2Cl2 (8 mL), and pyridine
(0.62 mL, 7.5 mmol) were added. After stirring for 24 h at
278 8C, the mixture was allowed to warm to room
temperature. The mixture was diluted with ether, then
washed with saturated potassium sodium tatrate, saturated
NaHCO3, and brine. Concentration and chromatography
(hexane/EtOAc, 40:1 containing 1% Et3N) gave 3 (0.53 g,
78%) as a mixture of diastereomers: oil; Rf¼0.57 (hexane/
4.1.6. Alcohol 9. To a solution of DMSO (0.95 mL,
13.4 mmol) in CH2Cl2 (40 mL) at 278 8C was added
(COCl)2 (0.95 mL, 10.9 mmol), and the mixture was stirred
for 15 min at the same temperature. A solution of 8 (1.35 g,
6.07 mmol) in CH2Cl2 (20 mL) was introduced to the
resulting mixture. After stirring for additional 15 min, Et3N
(4.2 mL, 30.4 mmol) was added, and the mixture was
allowed to warm to room temperature. The reaction mixture
was diluted with ether, then washed with water and brine.
After concentration, the residual crude aldehyde was used
for next reaction without purification.
To a stirring mixture of anhydrous zinc bromide (1.5 g,
6.70 mmol) in ether (30 mL) at 0 8C were added the alcohol
obtained above in ether (30 mL) and EtMgBr (1.0 M in
ether, 36 mL, 36 mmol). After stirring for 2 h at the same
temperature, the mixture was quenched with saturated
NH4Cl and extracted with ether. The organic layer was
washed with saturated NaHCO3 and brine. Concentration
and chromatography (hexane/AcOEt¼2:1) gave 9 (1.3 g,
86%): oil; Rf¼0.57 (hexane/AcOEt¼2:1); [a]2D1¼217.4 (c
1
EtOAc 20:1); IR (neat) 1737 cm21; H NMR (400 MHz,
C6D6) d 6.18–6.03 (m, 1H), 5.97–5.73 (m, 1H), 5.09–4.92
(m, 2H), 3.73–3.68 (m, 1H), 2.37–2.18 (m, 2H), 1.76 (s,
1.5H), 1.73 (s, 1.5H), 1.69–1.23 (m, 14H), 0.90–0.81 (m,
6H); HRMS (ESI), calcd for C16H29O3Na (MþNa):
293.2093. Found: 293.2043.
4.1.3. Diene 4. To a solution of 3 (0.19 g, 0.71 mmol) in
CH2Cl2 (7 mL) at 0 8C were added allyltributyltin (0.45 mL,
1.42 mmol) and BF3·OEt2 (1.0 M in CH2Cl2, 1.42 mL,
1.42 mmol). After stirring for 3 h at room temperature, the
mixture was diluted with ether, then washed with saturated
NaHCO3 and brine. Concentration and chromatography
(hexane/EtOAc, 20:1) gave 4 (2.49 g, 85%) as a 1:1 mixture
of diastereoisomers: colorless oil; Rf¼0.45 (hexane/EtOAc
10:1); IR (neat) 1640 cm21; 1H NMR (400 MHz, CDCl3) d
5.80–5.68 (m, 2H), 5.03–4.82 (m, 4H), 3.40–3.22 (m, 2H),
2.22–2.00 (m, 4H), 1.54–1.00 (m, 14H), 0.89–0.78 (m,
6H); HRMS (EI), calcd for C17H32O (Mþ): 252.2453.
Found: 252.2464.
1
0.99, CHCl3); IR (neat) 3600–3200, 1463 cm21; H NMR
(400 MHz, CDCl3) d 7.25 (d, J¼8.5 Hz, 2H), 6.87 (d,
J¼8.5 Hz, 2H), 5.85 (ddd, J¼16.3, 10.0, 7.1 Hz, 1H), 5.15–
5.06 (m, 2H), 4.62 (d, J¼11.0 Hz, 1H), 4.41 (d, J¼11.0 Hz,
1H), 3.79 (s, 3H), 3.44 (ddd, J¼13.4, 5.1, 5.1 Hz, 1H), 3.32
(dd, J¼11.1, 5.5 Hz, 1H), 2.49–2.29 (m, 3H), 1.60–1.38
(m, 2H), 0.95 (t, J¼7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3); d 159.1, 134.3, 130.4, 129.3, 117.2, 113.7, 80.8,
73.7, 71.8, 55.2, 34.9, 26.2, 10.1; HRMS (ESI), calcd for
C15H22O3Na (MþNa): 273.1461. Found: 273.1467.
4.1.7. Ester 11. To a solution of 10 (2.29 g, 8.06 mmol) in
methanol (80 mL) at 0 8C were added KOH (6.78 g,
120 mmol) in water (40 mL) and AgNO3 (13.7 g,
80.6 mmol) in water (40 mL). After stirring for 20 min at
the same temperature, the insoluble material was filtered off
through a Celite pad. The filtrate was acidified by 10%
H2SO4 and extracted with EtOAc. The organic layer was
washed with brine and concentrated to give the crude
carboxylic acid which was used for next reaction without
purification.
4.1.4. Oxepene 6. To a solution of 4 (40 mg, 0.16 mmol) in
CH2Cl2 (16 mL) was added 5 (26 mg, 32 mmol). After
stirring for 4 h at 35 8C, the mixture was concentrated and
purified by silica gel column chromatography (hexane/
EtOAc, 10:1) to give 6 (38 mg, 100%): colorless oil;
Rf¼0.56 (hexane/EtOAc 10:1); IR (neat) 2930, 1460 cm21
;
1H NMR (400 MHz, CDCl3) d 5.74–5.64 (m, 2H), 3.98–
3.94 (m, 1H), 3.30–3.25 (m, 1H), 2.37–2.03 (m, 4H), 1.60–
1.28 (m, 14H), 0.93–0.87 (m, 6H); HRMS (EI), calcd for
C15H28O (Mþ): 224.2140. Found: 224.2130.
To a solution of the carboxylic acid obtained above in THF
(80 mL) were added Et3N (1.12 mL, 8.06 mmol) and 2,4,6-
trichlorobenzoyl chloride (1.26 mL, 8.06 mmol). After
stirring for overnight, the mixture was concentrated under
4.1.5. Alcohol 8. To a solution of 7 (1.77 g, 4.47 mmol) and
methanol (0.22 mL, 5.36 mmol) in ether (45 mL) at 0 8C

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reduced pressures and diluted with toluene (80 mL). A
solution of 9 (437 mg, 1.05 mmol) and DMAP (4.0 g,
32.2 mmol) in toluene (80 mL) was added, and the mixture
was stirred for 3 h at room temperature. The mixture was
diluted with ether, then washed with aqueous NH4Cl, water,
and brine. Concentration and chromatography (hexane/
EtOAc, 10:1) gave 11 (2.76 g, 77%): oil; Rf¼0.69 (hexane/
AcOEt¼2:1); [a]1D9¼217.4 (c 0.97, CHCl3); IR (neat)
acetoxy ether 13 which was used for next reaction without
purification.
To a solution of 13 obtained above in CH2Cl2 (6 mL) at
278 8C were added allyltributyltin (0.96 mL, 3.10 mmol)
and BF3·OEt2 (1.0 M in CH2Cl2, 1.8 mL, 1.8 mmol). After
stirring for 3 h at room temperature, the mixture was
quenched with Et3N, diluted with ether, then washed with
saturated NaHCO3 and brine. Concentration and
chromathography (hexane/ether, 10:1) gave 14 (230 mg,
64%): oil; Rf¼0.46 (hexane/AcOEt¼10:1); [a]2D4¼þ1.0 (c
1
1744 cm21; H NMR (400 MHz, CDCl3) d 7.33–7.23 (m,
12H), 6.83 (d, J¼8.8 Hz, 2H), 5.82 (dddd, J¼17.1, 10.0, 7.1,
7.1 Hz, 1H), 5.11–4.95 (m, 2H), 4.68 (d, J¼11.5 Hz, 1H),
4.58–4.40 (m, 4H), 4.32 (d, J¼11.5 Hz), 4.16 (dd, J¼10.7,
6.1 Hz, 1H), 3.75 (s, 3H), 3.66–3.54 (m, 3H), 3.50 (dd,
J¼10.7, 6.1 Hz, 1H), 2.29 (dd, J¼6.8, 6.3 Hz, 2H), 2.18–
1.95 (m, 2H), 1.74–1.53 (m, 2H), 0.86 (t, 3H)HH; 13C NMR
(100 MHz, CDCl3) d 172.3, 159.0, 138.2, 137.4, 134.9,
134.3, 132.3, 130.2, 129.2, 128.2, 128.0, 127.9, 127.6,
127.4, 117.2, 113.6, 78.1, 75.9, 74.9, 72.9, 72.3, 71.6, 65.8,
55.2, 34.4, 33.2, 22.6, 10.1; HRMS (ESI), calcd for
C33H40O6Na (MþNa): 555.2723. Found: 555.2705.
1
1.36, CH3Cl); IR (neat) 1641 cm21; H NMR (400 MHz,
CDCl3) d 7.34–7.22 (m, 10H), 5.96–5.79 (m, 2H), 5.10–
4.99 (m, 4H), 4.69 (d, J¼11.8 Hz, 1H), 4.49 (d, J¼11.8 Hz,
1H), 4.45 (d, J¼10.2 Hz, 1H), 4.42 (d, J¼8.0 Hz, 1H), 3.95
(dt, J¼8.3, 3.5 Hz, 1H), 3.71–3.67 (m, 1H), 3.62–3.55 (m,
3H), 3.47 (dt, J¼9.3, 3.2 Hz, 1H), 2.47–2.06 (m, 4H),
1.93–1.70 (m, 5H), 1.43–1.35 (m, 2H), 1.07–1.00 (m,
21H); 13C NMR (100 MHz, CDCl3) d 138.7, 138.4, 136.8,
135.4, 128.1, 128.0, 127.4, 127.3, 127.2, 117.0, 116.0, 84.2,
80.6, 72.7, 72.2, 67.1, 36.2, 36.0, 31.1, 21.8, 18.2, 12.8,
11.7; HRMS (ESI), calcd for C37H58O4SiNa (MþNa):
617.4002. Found: 617.3997.
4.1.8. TIPS Ether 12. To a solution of 11 (16.8 mg,
38 mmol) in CH2Cl2 (0.4 mL) at 0 8C were added
saturated NaHCO3 (40 mL) and DDQ (31 mg, 0.13 mmol).
After stirring for 5 h at the same temperature, the
mixture was diluted with ether, then washed with saturated
NaHCO3 and brine. Concentration and chromatography
(hexane/EtOAc, 4:1) gave the corresponding alcohol
(11 mg, 91%).
4.1.10. Oxocene 15. To a mixture of 14 (179 mg,
0.303 mmol) in CH2Cl2 (60 mL) was added 5 (24 mg,
30 mmol). After stirring for 4 h at 35 8C, the mixture was
concentrated and purified by silica gel column chromato-
graphy (hexane/EtOAc, 10:1) to give 15 (170 mg, 99%): oil;
Rf¼0.33 (hexane/AcOEt, 10:1); [a]2D1¼215.7 (c 1.09,
1
To a solution of the alcohol obtained (9.3 mg, 29 mmol) in
CH2Cl2 (1 mL) at 0 8C were added 2,6-lutidine (7 mL,
58 mmol) and TIPSOTf (11 mL, 41 mmol). After stirring for
4.5 h at room temperature, the mixture was quenched with
MeOH, diluted with ether, then washed with water and
brine. Concentration and chromatography (hexane/EtOAc,
10:1) gave 12 (12 mg, 89%): oil; Rf¼0.63 (hexane/
AcOEt¼4:1); [a]2D4¼214.3 (c 1.43, CHCl3); IR (neat)
CH3Cl); IR (neat) 3027, 1454 cm21; H NMR (400 MHz,
CDCl3) d 7.37–7.24 (m, 10H), 5.82–5.65 (m, 2H), 4.81 (d,
J¼11.5 Hz, 1H), 4.59 (d, J¼11.5 Hz, 1H), 4.48 (d,
J¼11.9 Hz, 1H), 4.42 (d, J¼11.9 Hz, 1H), 3.91 (ddd,
J¼8.8, 5.0, 2.0 Hz, 1H), 3.77–3.73 (m, 1H), 3.58 (t,
J¼7.2 Hz, 2H), 3.38–3.32 (m, 1H), 3.28 (dd, J¼10.0,
2.6 Hz), 2.84–2.76 (m, 1H), 2.60–2.52 (m, 1H), 2.27–2.21
(m, 1H), 2.13 (dd, J¼13.9, 8.3 Hz, 1H), 1.82 (q, J¼6.2 Hz,
2H), 1.78–1.39 (m, 2H), 1.13–0.87 (m, 21H), 0.90 (t,
J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 139.0,
138.5, 130.0, 129.2, 128.2, 128.1, 127.6, 127.4, 127.3, 84.7,
84.3, 79.3, 76.0, 73.0, 72.8, 67.4, 33.9, 32.9, 29.5, 26.1,
18.4, 18.3, 13.2, 12.8, 11.2; HRMS (ESI), calcd for
C35H54O4SiNa (MþNa): 589.3689. Found: 589.3684.
1
1747 cm21; H NMR (400 MHz, CDCl3) d 7.36–7.23 (m,
10H), 5.85 (dddd, J¼17.1, 10.0, 7.1, 7.1 Hz, 1H), 5.10–5.00
(m, 2H), 4.88 (ddd, J¼9.3, 3.7, 3.7 Hz, 1H), 4.73 (d,
J¼11.5 Hz, 1H), 4.48 (d, J¼12.0 Hz, 1H), 4.42 (d,
J¼12.0 Hz, 1H), 4.37 (d, J¼11.5 Hz, 1H), 4.15 (dd,
J¼9.0, 3.9 Hz, 1H), 3.97 (dd, J¼10.3, 5.9 Hz, 1H), 3.69–
3.54 (m, 2H), 2.38–1.94 (m, 3H), 1.80 (ddd, J¼14.6, 7.6,
3.3 Hz, 1H), 1.75–1.50 (m, 2H), 1.16 (m, 21H), 0.89 (t,
J¼7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 172.3,
134.8, 128.3, 128.2, 127.9, 127.7, 127.6, 127.5, 117.1, 78.2,
75.1, 73.0, 72.4, 72.2, 65.9, 37.7, 33.3, 21.7, 18.2, 15.4,
12.8, 10.4; HRMS (ESI), calcd for C34H52O5SiNa (MþNa):
591.3482. Found: 591.3476.
4.1.11. Acetate 16. Lithium wire (2.3 mg, 330 mmol) was
cut into small pieces and added to 10 mL of liquid ammonia
at 278 8C, and the mixture was stirried for 10 min at the
same temperature. To the resulting deep blue mixture, a
solution of 15 (19 mg, 33 mmol) was introduced. After
stirring for 20 min, the mixture was quenched with a 1:1
mixture of methanol and saturated NH4Cl. The mixture was
extracted with ether, and the organic layer was washed with
brine. Concentration and chromathography (hexane/EtOAc,
2:1) gave the corresponding diol (12.8 mg, 100%).
4.1.9. Diene 14. To a solution of 12 (345 mg, 0.61 mmol) in
CH2Cl2 (3 mL) at 278 8C was added DIBAL-H (0.93 M in
hexane, 1.30 mL, 1.21 mmol), and the mixture was stirred
for 0.5 h at the same temperature. To the mixture, pyridine
(0.15 mL, 1.83 mmol), DMAP (148 mg, 1.21 mmol) in
CH2Cl2 (1.5 mL), and (CH2ClCO)2O (626 mg, 3.66 mmol)
in CH2Cl2 (1.5 mL) were added. After stirring for 1 h at
278 8C, the mixture was allowed to warm to room
temperature. The mixture was diluted with ether, then
washed with saturated potassium sodium tatrate, saturated
NaHCO3, and brine. Concentration gave the crude a-chloro-
To a solution of the diol obtained (7.5 mg, 19.4 mmol) in
CH2Cl2 (0.5 mL) were added Ac2O (11 mL, 116 mmol),
pyridine (9.4 mL, 116 mmol), and DMAP (a catalytic
amount). After stirring for 16 h, the mixture was concen-
trated and subjected to a column chromatography (hexane/
EtOAc, 10:1 to 4:1) to give 16 (9 mg, 100%): oil; Rf¼0.77
(hexane/AcOEt, 2:1); [a]2D5¼212.0 (c 0.40, CH3Cl); IR

I. Kadota et al. / Tetrahedron 60 (2004) 7361–7365
7365
(neat) 2925, 1742 cm21 1H NMR (500 MHz, C6D6) d
;
7548–7549. (b) Crimmins, M. T.; Choy, A. L. J. Am. Chem.
Soc. 1999, 121, 5653–5660. (c) Ref. 4j.
5.61–5.50 (m, 2H), 5.02 (ddd, J¼9.5, 3.4 Hz, 1H), 4.21–
4.01 (m, 2H), 3.79 (ddd, J¼11.0, 4.9, 2.4 Hz, 1H), 3.34 (dd,
J¼10.5, 3.4 Hz), 3.26–3.22 (m, 1H), 2.84–2.76 (m, 2H),
2.37–1.65 (m, 6H), 1.74 (s, 3H), 1.69 (s, 3H), 1.12–0.94
(m, 21H), 0.96 (t, J¼7.4 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 169.8, 129.6, 129.3, 84.2, 82.5, 76.7, 73.9, 61.0,
34.2, 28.8, 26.5, 20.8, 18.7, 18.6, 18.5, 13.6, 11.1; HRMS
(ESI), calcd for C25H46O6SiNa (MþNa): 493.2961. Found:
493.2991.
7. For a recent review of the synthesis of cyclic ethers via ring-
closing metathesis, see: Yet, L. Chem. Rev. 2000, 2963–3007.
8. For the stereoselective synthesis of 6, see: Berger, D.;
Overman, L. E. Synlett 1992, 811–813.
9. Katzenellenbogen, J. A.; Lenox, R. S. J. Org. Chem. 1973, 38,
326–335.
10. (a) Dahanukar, V. H.; Rychnovsky, S. D. J. Org. Chem. 1996,
61, 8317–8320. (b) Kopecky, D. J.; Rychnovsky, S. D. J. Org.
Chem. 2000, 65, 191–198. (c) Kopecky, D. J.; Rychnovsky,
S. D. Org. Synth. 2003, 80, 177–183.
11. For the intermolecular allylation of a-acetoxy ethers, see
Ref. 9a.
Acknowledgements
12. For recent reviews on ring-closing metathesis, see: (a) Grubbs,
R.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446–452.
(b) Schmalz, H.-G. Angew. Chem., Int. Ed. Engl. 1995, 34,
1833–1835. (c) Schuster, M.; Blechert, S. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2036–2056. (d) Grubbs, R.; Chang, S.
Tetrahedron 1998, 54, 4413–4450. (e) Armstrong, S. K.
J. Chem. Soc., Perkin Trans. 1 1998, 371–388.
This work was financially supported by the Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
References and notes
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18. In a preliminary experiment, compound A, having a PMB
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BF3·OEt2. Unexpectedly, the acetal derivative B was produced
via the intramolecular attack of the PMB ether moiety to the
resulting oxocarbenium ion. To avoid this undesired reaction,
the electron-donating PMB group was replaced by a TIPS
group at this stage.
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Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 11893–11899.
20. The reaction of the epimeric substrate C gave the diastereo-
isomer D, selectively (ca. 4:1). These results suggest that the
stereoselectivity of the allylation is controlled by the
stereochemistry at the b-position.
5. Kadota, I.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am.
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