Enzymatic desymmetrization of 1,1′-methylenedi[(1R,1′S,3R, 3′S,5S,5′R)-3-hydroxy-8-oxabicyclo[3.2.1]oct-6-ene-1-yl]: Novel precursors of long chain polyketides

Article abstract of DOI:10.1016/j.tetasy.2005.05.038

meso-1,1′-Methylenedi[(1R,1′S,3R,3′S,5S,5′R) -3-hydroxy-8-oxabicyclo[3.2.1]oct-6-ene-1-yl] 14 obtained through the [4+3]-cycloaddition of 2,2′-methylenedifuran to oxyallyl cation, followed by reduction, has been desymmetrized by means of a lipase catalyze

Full text of DOI:10.1016/j.tetasy.2005.05.038

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2277–2283
Enzymatic desymmetrization of 1,10-methylenedi-
[(1R,10S,3R,30S,5S,50R)-3-hydroxy-8-oxabicyclo[3.2.1]-
oct-6-ene-1-yl]: novel precursors of long chain polyketides
*
´
Gerald Coste and Sandrine Gerber-Lemaire
´ ´
Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Federale de Lausanne, BCH,
CH-1015 Lausanne, Switzerland
Received 2 May 2005; accepted 25 May 2005
Available online 29 June 2005
Abstract—meso-1,10-Methylenedi[(1R,10S,3R,30S,5S,50R)-3-hydroxy-8-oxabicyclo[3.2.1]oct-6-ene-1-yl] 14 obtained through the
[4+3]-cycloaddition of 2,20-methylenedifuran to oxyallyl cation, followed by reduction, has been desymmetrized by means of a lipase
catalyzed transesterification to afford (1S,3S,5S)-1-{[(1R,3R,5R)-3-hydroxy-8-oxabicyclo[3.2.1]oct-6-en-yl]methyl}-8-oxabi-
cyclo[3.2.1]oct-6-en-3-yl acetate (À)-15 (89% ee). This compound was transformed into aromatic ester derivatives for establishing
the absolute configuration.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
long-chain polyketides bearing unsymmetrical functions
at the terminal positions, which can be further trans-
formed into long chain 1,3-polyol fragments 12. In order
to generate more stereoisomeric 15-carbon polyketides it
would be of high interest to achieve desymmetrization of
the meso bicyclic adduct 2 in order to apply our double-
ring opening pathway. Herein, we report a lipase-cata-
lyzed transesterification for the desymmetrization8 of
diol 14, readily obtained through the stereoselective
reduction of 2 in the presence of K-selectride.
Polyketides (1,3-polyoxo, 1,3-polyols, aldols) are
amongst a great variety of natural products of biological
interest1 with several approaches for their syntheses
already having been proposed.2 Vogel et al. have devel-
oped a noniterative, asymmetric synthesis of fifteen-
carbon polyketides, starting from the readily available
2,20-methylenedifuran 1. A double [4+3]-cycloaddition
of halogenated 2-oxyallyl cations to 1 generates, after
reductive work-up, a 55:45 mixture of diketones 2 and
3 (60% yield), which can be readily separated (Scheme
1).3 Various pentadecan-1,3,5,7,9,11,13,15-octols were
prepared from meso-2, using a late desymmetrization
of diolefin 4 by means of the Sharpless asymmetric
dihydroxylation.4 It was reported that threo-3 can be
converted into the enantiomerically pure diacetate (+)-
8 and diol (À)-7,5 and we have shown that they can be
transformed in a few steps into enantiomerically pure,
long-chain polyketides,6 and polyfunctional 1,7-dioxa-
spiro[5.5]undecanes7 as well. This efficient strategy is
based on the double ozonolysis of dialkene (À)-9 fol-
lowed by the diastereoselective reduction of the resulting
b-hydroxyketone intermediate to give rapid access to
2. Results and discussion
Desymmetrization of diol 14 was attempted in the pres-
ence of several commercially available lipases (Scheme 2,
Table 1), using vinyl acetate as solvent. Lipases from
Pseudomonas fluorescens, Pseudomonas cepacia, Asper-
gillus niger, Aspergillus orizae and Rizopus orizae were
uneffective in catalyzing the transesterification of 14 (en-
tries 1–5). Lipase from Candida rugosa afforded a low
conversion into the desired monoacetate (À)-15 with
an enantiomeric excess of 76%. Finally, lipase from Can-
dida cylindracea afforded the monoacetate (À)-15 with
enantiomeric excesses ranging from 80% to 89%. The
best results were obtained at 40 ꢁC (10 h of reaction,
4000 U/mmol, 44% yield, 54% recovered starting diol).
Elevation of the temperature (entry 10) or increasing
*
Corresponding author. Tel.: +41 21 693 93 72; fax: +41 21 693 93
55; e-mail: sandrine.gerber@epfl.ch
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.05.038

2278
G. Coste, S. Gerber-Lemaire / Tetrahedron: Asymmetry 16 (2005) 2277–2283
+
ref. 5
O
ref. 3
O
O
O
O
O
O
O
O
O
O
O
+
O
O
1
OAc
OH
OAc
OH
(+)-8
(–)-threo-3
meso-2
(-)-7
ref. 4
OH
OH
OP
OP
PO
AD-mix β
PO
OAc
OAc
OAc
(-)-5, ee = 98%
OAc
meso-4
PO
*
*
*
*
OH OP OH OH OH OH OP OH
OH OH OH OP OH
ref. 6
ref. 7
12
11
OBOM
OH
P = BOM
BOMO
(+)-8
OH
O
OR
OR
O
R = H, (-)-9
R = TES, (-)-10
HO
OH OH
EtS SEt
(+)-13
Scheme 1.
oxybenzoate) (+)-17 derived from (À)-15 through a
sequence involving transformations that do not modify
the initial stereogenic centers (Scheme 3). Esterification
of the free secondary alcohol in the presence of para-
methoxybenzoyl chloride, followed by treatment with
BCl3 at 0 ꢁC, protection of the resulting diol and reduc-
tive dechlorination (Bu3SnH, AIBN) of the dichlorodiol
intermediate, afforded derivative (+)-17, bearing para-
methoxybenzoate chromophores. The complementary
enantiomer was similarly obtained after introduction
of a pivaloyl moiety on (À)-15 and selective hydrolysis
of the acetate at the C(30) position.
K-selectride
O
O
O
O
-78 to 25 C
OH
98%
OH
O
O
meso-14
meso-2
lipase
OAc
O
O
OAc
OH
(-)-15
Scheme 2.
A circular dichroism (CD) spectrum of (+)-17 (Fig. 1)
double Cotton effect (De267 = +6,
the amount of enzyme (entry 8) resulted in a loss of
enantioselectivity. With the addition of cosolvents, such
as toluene or chloroform, the transesterification did not
occur (data not shown).
showed
a
De241 = À2), which results from the exciton coupling
between the two aromatic chromophores at C(40) and
C(60) to produce a positive couplet.9 This result was
expected for all possible conformations of (+)-17
(Scheme 3) and is consistent with the fact that the point
of inflexion of the CD curve is close to k = 257 nm, the
The absolute configuration of monoacetate (À)-15 was
determined by circular dichroism of tris(para-meth-
Table 1. Lipase catalyzed transesterification of 14
Entrya
Lipase
U mmolÀ1
Yield (À)-15 (%)
No reaction
eeb (%)
Yield (%), 14
T (ꢁC)
1
2
3
4
5
6
7
8
9
10
Pseudomonas fluorescens
Pseudomonas cepacia
Aspergillus niger
4800
14,400
3000
4800
4800
4800
4000
5800
4000
4000
25
25
25
25
25
25
25
25
40
60
No reaction
No reaction
Aspergillus orizae
Rizopus orizae
No reaction
No reaction
Candida rugosa
17
44
34
44
40
76
85
80
89
81
56
46
46
54
38
Candida cylindracea
Candida cylindracea
Candida cylindracea
Candida cylindracea
a Assays were performed in 0.08 M of the solvent in vinyl acetate at 50 mg scale. Yields were calculated after isolation by flash chromatography.
b Determined by 1H NMR of MosherÕs ester.

G. Coste, S. Gerber-Lemaire / Tetrahedron: Asymmetry 16 (2005) 2277–2283
2279
1. BCl3, 0°C
PMBzO
OPMBz
2. PMBzCl, pyridine, DMAP cat.
PMBzCl, pyridine
O
O
(-)-15
3. Bu3SnH, AIBN cat., 80°C
DMAP cat.
85%
OPMBz
(+)-17
OAc
70%
OAc
OPMBz
16
1. PMBzCl, pyridine, DMAP cat.
2. BCl3, 0°C
PMBzO
OPMBz
1. PivCl, pyridine, DMAP cat.
O
O
(-)-15
2. K2CO3, MeOH
3. PMBzCl, pyridine, DMAP cat.
4. Bu3SnH, AIBN cat., 80°C
OPiv
OPMBz
55%
OH
OPiv
22%
(-)-19
(+)-18
OP
H
PO
H
OP
H
H
OP
H
OP
H
H
PO
OP
PO
P = PMBz
(+)-17 (λmax = 257 nm)
(-)-19 (λmax = 257 nm)
PO
OP
H
OP
OP
H
H
H
PO
H
H
H
H
OP
OP
PO
Scheme 3.
plet, as expected for all possible conformations of this
derivative. In this case, the point of inflexion of the
CD curve is also close to k = 255 nm, the wavelength
of maximum absorption in the UV spectrum. These data
allowed the establishment of the (1R,40S,6R,60S)- and
the (1S,40R,6S,60R)-configurations of (+)-17 and (À)-
19, respectively, and thus the (1S,10R,3S,30R,5S,50R)-
configuration of monoacetate (À)-15.
9
6
(+)-17
(-)-19
3
∆ε
0
-3
-6
220
240
260
280
300
This result was finally confirmed by X-ray crystallogra-
phy of the (1S)-camphanoyl ester derivative of (À)-15
(Fig. 2).10
[nm]
Figure 1. CD spectra of (+)-17 and (À)-19 in MeCN.
wavelength of maximum absorption in the UV spec-
trum. Furthermore, the circular dichroism (CD) spec-
trum of (À)-19 (Fig. 1) showed a double Cotton effect
(De264 = À4.5, De246 = +3.2) to produce a negative cou-
3. Conclusion
We have demonstrated that meso-14, readily obtained
from bicyclo adduct meso-2, can be desymmetrized at
an early stage of its conversion into long-chain poly-
ketides, affording (1S,3S,5S)-1-{[(1R,3R,5R)-3-hydroxy-
8-oxabicyclo[3.2.1]oct-6-en-1-yl]methyl}-8-oxabicyclo[3.2.1]-
oct-6-en-3-yl acetate (À)-15 with 89% ee. This new
derivative can be further transformed in order to intro-
duce different functionalities on the two cycloheptene
rings to provide new potential precursors of unsymmet-
rical long-chain polyketides.
4. Experimental
4.1. General
Commercial reagents (Fluka, Aldrich) were used without
purification. Solvents were filtered prior to use (Innova-
tive Technology). Solutions after reactions and extrac-
tions were evaporated in a rotatory evaporator under
reduced pressure. Liquid/solid flash chromatography
Figure 2. X-ray diffraction analysis of (À)-20.

2280
G. Coste, S. Gerber-Lemaire / Tetrahedron: Asymmetry 16 (2005) 2277–2283
23
405
23
435
23
577
(FC): columns of silica gel (0.040–0.63 mm, Merck No.
9385 silica gel 60, 240–400 mesh). TLC for reaction mon-
itoring: Merck silica gel 60F254 plates; detection by UV
light; Pancaldi reagent [(NH4)6MoO4, Ce(SO4)2,
H2SO4, H2O]. IR spectra: Perkin–Elmer-1420 spectro-
meter. 1H NMR spectra: Bruker-ARX-400 spectrometer
(400 MHz); d(H) in ppm relative to the solventÕs residual
1H signal [CHCl3, d(H) 7.27] as internal reference; all 1H
assignments were confirmed by 2D-COSY-45. 13C NMR
spectra: same instrument as above (100.6 MHz); d(C) in
ppm relative to solventÕs C-signal [CDCl3, d(C) 77.0] as
internal reference; coupling constants J in hertz. MAL-
DI-TOF mass spectra were obtained from the Swiss
Institute of Technology Mass Spectral Facility. Elemen-
tal analyses: Ilse Beetz, D-96301 Kronach, Germany.
Circular dichroism spectra were recorded on a JOBIN
YVON MARK VI using cubic quartz cell (length
0.1 cm) and calibrated with D-(+)-camphorsulfonic acid.
(76 mg, 54%). ½aŠ ¼ À20, ½aŠ ¼ À19, ½aŠ ¼ À9,
23
½aŠ ¼ À8 (c 0.46, CHCl3). UV (CH3CN): kmax
589
(e) = 262, 228 (1624, 1363 dm3 molÀ1 cmÀ1) nm.
IR (film): 3450, 3075, 2940, 1345, 1255, 1225, 1030, 745,
700 cmÀ1. 1H NMR (400 MHz, CDCl3): d = 6.49 (1H, d,
3J = 5.9 Hz, H-70), 6.36 (1H, dd, 3J = 5.9, 1.6 Hz, H-60),
3
3
6.15 (1H, d, J = 6.0 Hz, H-7), 6.11 (1H, dd, J = 6.0,
3
1.3 Hz, H-6), 5.05 (1H, t, J = 5.8 Hz, H-3), 4.78 (1H,
br s, H-50), 4.76 (1H, br s, H-5), 3.97 (1H, m, H-30),
2.25 (1H, d, 3J = 10.4 Hz, OH–C-30), 2.21–2.02
(2H, 2m, H-4exo, H-40exo), 2.07 (1H, d, 2J = 15.3 Hz,
H-2exo), 2.00 (1H, d, J = 12.1 Hz, H-20exo), 1.98 (3H, s,
2
2
CH3(OAc)), 1.95 (2H, 2d, AB, J = 14.5 Hz, H-8), 1.91
(1H, d, 2J = 12.1, H-2e0 ndo), 1.72 (1H, d, 2J = 15.3
2
H-2endo), 1.68, 1.57 (2H, 2d, J = 15.7, 10.6 Hz, H-4endo
,
H-40endo) ppm. 13C NMR (100 MHz, CDCl3): d = 170.4
1
0
0
(s, C@O), 138.8 (d, C7 , JC,H = 168), 134.6 (d, C6 ,
1JC,H = 169), 136.5 (d, C7, JC,H = 178), 132.5 (d, C6,
1
1
0
JC,H = 170), 84.3 (s, C1 ), 83.6 (s, C1), 77.9 (d, C5 ),
0
4.2. General procedure for the oxa-bridge opening and
protection as p-methoxybenzoates
1
77.8 (d, C5), 67.2 (d, C3 , JC,H = 161), 65.6 (d, C3,
0
1
1
JC,H = 142), 44.4 (t, C8, JC,H = 123), 41.9 (d, C2 ,
0
1
To a solution of the substrate (50–200 mg) in CH2Cl2
(2–8 mL) at 0 ꢁC was added dropwise a 1 M solution
of BCl3 in CH2Cl2 (3 equiv). After stirring for 30 min
at 0 ꢁC, the mixture was poured into an aqueous satu-
rated solution of NaHCO3 (15 mL) and extracted with
CH2Cl2 (3 · 15 mL). The combined organic extracts
were dried over MgSO4 and concentrated in vacuo.
The residue was taken up in pyridine (3–5 mL) and trea-
ted with a catalytic amount of DMAP and p-meth-
oxybenzoyl chloride (3 equiv). The resulting mixture
was stirred at room temperature for 12 h. The sol-
vent was evaporated under reduced pressure. The resi-
due was taken up in an aqueous saturated solution of
NaHCO3 (10 mL) and extracted with DCM (3 · 10
mL). The combined organic layers were dried over MgSO4
and concentrated in vacuo. The residue was purified by
flash chromatography (30% AcOEt in pentane).
1JC,H = 129), 38.0 (t, C2, JC,H = 129), 31.7 (t, C4,
1
1
0
JC,H = 127), 35.5 (t, C4 , JC,H = 125), 21.5 (q, CH3-
(OAc), 1JC,H = 127) ppm. MALDI-TOF: 329.46
(M+Na). Anal. Calcd for C17H22O5 (306.36): C, 66.65;
H, 7.24. Found C, 66.02; H, 7.28.
4.3.2. Data for (1R,6R)-6-(acetyloxy)-4-({(4S,6S)-
4,6-bis[(4-methoxybenzoyl)oxy]cyclohept-1-en-yl}meth-
yl)-cyclohept-3-en-1-yl
4-methoxybenzoate
(+)-17.
23
405
23
435
23
577
23
589
½aŠ ¼ þ154, ½aŠ ¼ þ116, ½aŠ ¼ þ50, ½aŠ ¼ þ44
(c 0.47, CHCl3). UV (CH3CN): kmax (e) = 273,
266, 257 (34,000, 32,300, 34,880 dm3 molÀ1 cmÀ1) nm.
IR (film): 3410, 2960, 2840, 1730, 1710, 1700, 1605,
1510, 1255, 1165, 1100, 1030, 850, 770, 695 cmÀ1. H
1
NMR (400 MHz, CDCl3): 8.05–7.95 (m, 6H arom),
6.94–6.88 (m, 6H arom), 5.62 (1H, t, J = 6.3 Hz, H-
3
3
20), 5.53 (H, t, J = 6.5 Hz, H-3), 5.31 (2H, m, H-40,
H-1), 5.21, 5.02 (2H, 2m, H-6, H-60), 3.85 (9H, s,
4.3. General procedure for the dechlorination
3OMe), 2.70 (2H, AB, 2J = 14.2 Hz, H-8), 2.37, 2.19
3
(2 · 2H, 2t, J = 5.6, 5.1 Hz, H-7, H-50), 2.55 (2H, m,
To a solution of the substrate (100 mg) in toluene
(0.5 mL) were added Bu3SnH (3 equiv) and a catalytic
amount of AIBN. The mixture was stirred for 3 h at
80 ꢁC. The solution was then diluted with CH3CN
(10 mL) and extracted with pentane (3 · 10 mL). The
solution was concentrated in vacuo and the residue
was purified by flash chromatography (30% AcOEt in
pentane).
H-30), 2.63–2.47 (2H, m, H-2), 2.63–2.52 (4H, m, H-5,
H-70), 1.99 (3H, s, CH3(OAc)) ppm. 13C NMR
(100 MHz, CDCl3): d = 170.2 (s, C@O(Ac)), 165.4,
165.3 (2s, 3C@ O(PMBz)), 163.3, 163.2 (2s, Carom),
0
137.6, 137.2 (2s, C1 , C4), 131.6, 131.5 (2d, Carom
,
1JC,H = 161,
162),
123.5,
123.4
(2d,
C3, JC,H = 150.3), 122.9, 122.8, 122.7 (3s, Carom),
C2 ,
0
1
0
113.6, 113.5 (2d, Carom), 69.0, 68.9 (2d, C4 , C1,
1
1
JC,H = 147), 68.4, 68.2 (2d, C6, C6 , JC,H = 148), 55.4,
0
1
55.3 (q, 3OMe, JC,H = 144), 50.5 (t, C3 , C2,
0
4.3.1.
(1S,3S,5S)-1-{[(1R,3R,5R)-3-Hydroxy-8-oxabi-
1
1
JC,H = 122), 41.7, 41.5 (2t, C5 , C7, JC,H = 118, 125),
0
cyclo[3.2.1]oct-6-en-1-yl]methyl}-8-oxabicyclo[3.2.1]oct-6-
en-3-yl acetate (À)-15. To a solution of diol 14
(140 mg, 0.530 mmol) in vinyl acetate (6.6 mL) at
1
36.4 (t, C8, JC,H = 124), 32.4, 32.1 (2t, C7 , C5,
0
1JC,H = 128, 127), 21.2 (q, CH3(OAc), JC,H = 129)
1
40 ꢁC was added lipase from C. cylindracea (2 U mgÀ1
,
ppm. MALDI-TOF: 735.32 (M+Na), 751.28 (M+K).
Anal. Calcd for C41H44O11 (712.78): C, 69.09; H, 6.22.
Found C, 69.07; H, 6.36.
4000 U mmolÀ1, 1.06 g). The resulting suspension was
stirred at 40 ꢁC for 10 h. The mixture was filtered
through a pad of Celiteꢂ. Removal of the solvent under
reduced pressure and purification of the residue was
done by flash chromatography (3–10% methanol in
CH2Cl2) afforded (À)-15 as a pale yellow oil (71 mg,
44%) and starting diol 14 as a pale yellow solid
4.3.3.
(1R,3R,5R)-1-{[(1S,3S,5S)-3-Hydroxy-8-oxabi-
cyclo[3.2.1]oct-6-en-1-yl]methyl}-8-oxabicyclo[3.2.1]oct-
6-en-3-yl 2,2-dimethylpropanoate (+)-18. To a solution
of alcohol (À)-15 (710 mg, 0.232 mmol) in CH2Cl2/pyr-

G. Coste, S. Gerber-Lemaire / Tetrahedron: Asymmetry 16 (2005) 2277–2283
2281
1
162), 123.4, 123.1 (2d, C2 , C3, JC,H = 150), 122.9,
0
idine (3/1, 8 mL) was added pivaloyl chloride (430 lL,
0.348 mmol). The resulting mixture was stirred at
25 ꢁC for 12 h. The mixture was poured into an aqueous
saturated solution of NaHCO3 (15 mL) and extracted
with CH2Cl2 (3 · 15mL). The combined organic layers
were dried over MgSO4 and concentrated in vacuo.
Purification of the residue by flash chromatography
(2% methanol in CH2Cl2) afforded a pivaloate interme-
diate as a colourless oil (615 mg, 68%). A solution of this
intermediate (465 mg, 0.119 mmol) in methanol (6 mL)
was treated with K2CO3 (250 mg, 0.179 mmol) for 12 h
at 25 ꢁC. The mixture was poured into an aqueous satu-
rated solution of NaHCO3 (10 mL) and extracted with
AcOEt (3 · 10mL). The combined organic layers were
dried over MgSO4 and concentrated in vacuo. Purifica-
tion of the residue by flash chromatography (2% metha-
nol in CH2Cl2) afforded (+)-18 as a white solid (338 mg,
1
122.8 (2s, Carom), 113.6, 113.5 (2d, Carom, JC,H = 160,
1
159), 69.1, 68.8 (2d, C4 , C1, JC,H = 147, 148), 68.6,
0
1
68.0 (2d, C6, C6 , JC,H = 146, 148), 55.4 (q, 3OMe,
0
1
1
JC,H = 144), 50.6 (t, C2, C3 , JC,H = 122), 41.7, 41.4
0
1
1
(2t, C5 , C7, JC,H = 134), 32.6 (t, C8, JC,H = 127), 38.7
0
1
(s, C(Me)3), 36.4, 36.0 (2t, C7 , C5, JC,H = 128, 127),
0
1
26.8 (q, CH3(Piv), JC,H = 127) ppm. MALDI-TOF:
777.74 (M+Na), 793.72 (M+K). Anal. Calcd for
C44H50O11 (754.34): C, 70.01; H, 6.68. Found C,
70.10; H, 6.70.
4.3.5. Mosher’s ester of (À)-15. (1R,3R,5R)-1-
{[(1S,3S,5S)-3-(Acetyloxy)-8-oxabicyclo[3.2.1]oct-6-en-
1-yl]methyl}-8-oxabicyclo[3.2.1]oct-6-en-3-yl (2S)-3,3,3-
trifluoro-2-methoxy-2-phenylpropanoate. To a solution
of (À)-15 (10 mg, 0.033 mmol) in dichloromethane
(0.5 mL) were added DMAP (2.5 mg, 0.020 mmol), pyr-
idine (10 lL) and (1S)-(À)-a-methoxy-a-(trifluoro-
methyl)-phenylacetyl chloride (7 lL, 0.036 mmol). The
resulting mixture was stirred at room temperature for
12 h. The mixture was poured into an aqueous saturated
solution of NaHCO3 (3 mL) and extracted with CH2Cl2
(3 · 3mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. Purification of the
residue by flash chromatography (3% methanol in
23
23
23
81%). PF = 95 ꢁC. ½aŠ ¼ þ23, ½aŠ ¼ þ20, ½aŠ
¼
405
435
577
23
589
þ10, ½aŠ ¼ þ8 (c 0.49, CHCl3). UV (CH3CN): kmax
(e) = 228 (221 dm3 molÀ1 cmÀ1) nm. IR (KBr): 3590,
2941, 1720, 1655, 1560, 1460, 1290, 1165, 1030,
1
670 cmÀ1. H NMR (400 MHz, CDCl3): d = 6.47 (1H,
3
3
d, J = 5.9 Hz, H-70), 6.35 (1H, d, J = 5.9 Hz, H-60),
6.16 (1H, d, 3J = 5.7 Hz, H-7), 6.11 (1H, d, 3J =
5.7 Hz, H-6), 5.03 (1H, t, J = 5.7 Hz, H-3), 4.76 (2H,
3
br s, H-5, H-50), 3.96 (1H, m, H-30), 2.25 (1H, d,
3J = 10.2 Hz, OH-C-30), 2.16 (2H, 2dt, 2J = 14.7,
CH2Cl2) afforded a colourless oil (9 mg, 96%).
½aŠ ¼ À55, ½aŠ ¼ À45, ½aŠ ¼ À24, ½aŠ ¼ À26 (c
23 23 23 23
577
3J = 4.7 Hz, H-4exo, H-40exo), 2.07 (2H, m, H-2exo
,
405
435
589
H-20exo), 2.03 (2H, AB, J = 15.0 Hz, H-8), 1.91 (1H, d,
2J = 14.6 Hz, H-20endo), 1.67 (1H, d, 2J = 14.8 Hz, H-
0.65, CHCl3). UV (CH3CN): kmax (e) = 230, 261 (1088,
2
666 dm3 molÀ1 cmÀ1) nm. IR (film): 2920, 1730, 1680,
2endo), 1.67, 1.52 (2H, 2d, 2J = 14.7 Hz, H-4endo
,
1454, 1360, 1255, 1185, 1120, 1030, 700 cmÀ1 1H
.
H-40endo), 1.14 (9H, s, Me3(Piv)) ppm. 13C NMR
NMR (400 MHz, CDCl3): d = 7.50–7.46, 7.43–7.37
3
0
(100 MHz, CDCl3): d = 177.4 (s, C@O), 138.8 (d, C7 ,
(5Harom, 2m), 6.16 (1H, d, J = 6.0 Hz, H-60), 6.11
1
1
JC,H = 169), 136.5 (d, C7, JC,H = 179), 134.6 (d, C6 ,
3
(1H, dd, J = 6.0, 1.6 Hz, H-70), 5.85 (2H, s, H-6, H-
0
1
3
1JC,H = 170), 132.4 (d, C6, JC,H = 170), 84.3, 83.8 (2s,
7), 5.30, 5.03 (2H, 2t, J = 5.1, 5.3 Hz, H-30, H-3), 4.72
3
0
0
0
C1, C1 ), 78.0, 77.9 (2d, C5, C5 ), 66.7 (d, C3 ,
(2H, d, J = 3.0 Hz, H-5, H-50), 3.50 (3H, s, OMe),
1JC,H = 162), 65.6 (d, C3, JC,H = 142), 44.4 (t, C8,
2.23 (1H, ddd, J = 15.2, J = 5.1, 4.0 Hz, H-40exo), 2.14
1
2
3
(1H, ddd, 2J = 15.0, 3J = 5.3, 4.1 Hz, H-4exo), 1.61,
1
1
JC,H = 123.2), 41.9 (d, C2 , JC,H = 129), 38.7 (s,
0
1
2
ÀC(Me)3), 38.1 (t, C2, JC,H = 129), 35.6 (t, C4,
1.55 (2H, 2d, J = 15.2, 15.0 Hz, H-40endo, H-4endo), 2.13
1
1
0
JC,H = 127), 31.7 (t, C4 , JC,H = 125), 27.0 (q, 3CH3,
(1H, dd, 2J = 15.2, 3J = 6.0 Hz, H-2e0 xo), 2.01 (2H, d,
2
1JC,H = 127) ppm. MALDI-TOF: 371.5 (M+Na). Anal.
Calcd for C20H28O5 (348.43): C, 68.94; H, 8.10. Found
C, 68.97; H, 8.03.
2J = 15.0, H-2exo), 1.75, 1.71 (2H, 2d, J = 15.2, 15.0,
H-20endo, H-2endo), 1.98 (2H, AB, 2J = 15.0 Hz, H-8),
1.97 (3H, s, CH3(OAc)) ppm. 13C NMR (100 MHz,
CDCl3): 170.4 (s, C@O(OAc)), 165.5 (s, C@O), 136.5
1
1
0 0
(d, C7 , JC,H = 166), 136.3 (d, C7 , JC,H = 166), 132.3
4.3.4. Data for (1S,6S)-4-({(4R,6R)-4,6-bis[(4-meth-
oxybenzoyl)oxy]cyclohept-1-en-1-yl}methyl)-6-[(2,2-di-
methylpropanoyl)oxy]cyclohept-3-en-1-yl 4-methoxybenzo-
1
(d, C6 , JC,H = 171), 131.9 (d, C6, JC,H = 178), 129.5,
1
0
128.4, 127.3 (3d, Carom
(s, CF3), 121.9 (s, C(CF3)), 83.7, 83.6 (2s, C1 , C1),
,
1JC,H = 160, 159, 160), 124.8
23
23
23
0
ate (À)-19. ½aŠ ¼ À116, ½aŠ ¼ À88, ½aŠ ¼ À35
405
435
589
1
77.7, 77.4 (2d, C5 , C5), 70.0 (2d, C3, C3 , JC,H = 152,
0
0
(c 0.55, CHCl3). UV (CH3CN): kmax (e) = 272, 267, 256
(34,000, 32,700, 36,885 dm3 molÀ1 cmÀ1) nm. IR (film):
2955, 1710, 1605, 1510, 1255, 1165, 1100, 1030, 845,
1
145), 55.2 (q, OMe, JC,H = 129), 44.1 (t, C8,
1
1
JC,H = 124), 38.0, 37.3 (2t, C2 , C2, JC,H = 127, 127),
0
1
1
770, 695 cmÀ1. H NMR (400 MHz, CDCl3): d = 8.06–
31.6, 31.5 (2t, C4 , C4, JC,H = 128), 21.5 (q, CH3(OAc),
1JC,H = 129) ppm. 19F NMR (376.5 Hz, CDCl3):
À71.69 ppm. MALDI-TOF: 545.68 (M+Na). Anal.
Calcd for C27H29F3O7 (522.51): C, 62.06; H, 5.59.
Found C, 61.49; H, 5.64.
0
7.94 (6H arom, m), 6.94–6.87 (6H arom, m), 5.59, 5.45
3
(2H, 2t, J = 6.6, 6.9 Hz, H-20, H-3), 5.32 (2H, m, H-1,
H-40), 5.18–5.01 (2H, 2m, H-6, H-60), 3.86, 3.83 (9H,
2s, 3OMe), 2.87, 2.67 (2H, 2d, 2J = 14.4 Hz, H-8),
2.64–2.40 (4H, m, H-5, H-70), 2.57–2.37 (2H, m, H-2),
2.47–2.43, 2.38–2.35 (4H, 2m, H-7, H-50), 2.38–2.35,
2.22–2.20 (4H, 2m, H-7, H-50), 2.35 (2H, m, H-30),
1.18 (9H, s, 3CH3) ppm. 13C NMR (100 MHz, CDCl3):
d = 177.6 (s, C@O(Piv)), 165.5, 165.4 (2s, 3C@
O(PMBz)), 163.4, 163.3 (3s, Carom), 137.6, 137.5 (2s,
0
4.3.6. (1R,3R,5R)-1-{[(1S,3S,5S)-3-(Acetyloxy)-8-oxabi-
cyclo[3.2.1]oct-6-en-1-yl]methyl}-8-oxabicyclo[3.2.1]-oct-
6-en-3-yl 4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]hept-
ane-1-carboxylate (À)-20. To a solution of (À)-15
(21 mg, 0.068 mmol) in dichloromethane (1 mL) were
added DMAP (2.5 mg, 0.020 mmol), pyridine (100 lL)
C1 , C4), 131.6, 131.5 (3d, Carom,
1JC,H = 162, 161,

2282
G. Coste, S. Gerber-Lemaire / Tetrahedron: Asymmetry 16 (2005) 2277–2283
2. For recent papers, see, for example: McGarvey, G. J.;
Mathys, J. A.; Wilson, K. J. Tetrahedron Lett. 2000, 41,
6011–6015; Greer, P. B.; Donaldson, W. A. Tetrahedron
Lett. 2000, 41, 3801–3803; Wender, P. A.; Lippa, B.
and (1S)-(À)-camphanic chloride (23 mg, 0.103 mmol).
The resulting mixture was stirred at 25 ꢁC for 12 h.
The mixture was poured into an aqueous saturated solu-
tion of NaHCO3 (3 mL) and extracted with CH2Cl2
(3 · 3mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. Purification of the
residue by flash chromatography (3% methanol in
CH2Cl2) afforded (À)-20 as a colourless oil (34 mg,
´
Tetrahedron Lett. 2000, 41, 1007–1011; Kiegiel, J.; Jozwik,
J.; Wozniak, K.; Jurczak, J. Tetrahedron Lett. 2000, 41,
4959–4963; Barrett, A. G. M.; Braddock, D. C.; de Koning,
P. D.; White, A. J. P.; Williams, D. J. J. Org. Chem. 2000,
65, 375–380; Sarraf, S. T.; Leighton, J. L. Org. Lett. 2000,
2, 1209–1212; Zacuto, M. J.; Leighton, J. L. J. Am. Chem.
Soc. 2000, 122, 8587–8688; Kiyoota, S. I.; Hena, M. A.;
Yabukami, T.; Murai, K.; Goto, F. Tetrahedron Lett. 2000,
41, 7511–7516; Bouzbouz, S.; Cossy, J. Org. Lett. 2000, 2,
3975–3977; Org. Lett. 2000, 2, 501–504; Trieselmann, T.;
Hoffmann, R. W. Org. Lett. 2000, 2, 1209–1212; Paterson,
I.; Collett, L. A. Tetrahedron Lett. 2001, 42, 1187–1191;
Hunter, T. J.; OÕDoherty, G. A. Org. Lett. 2001, 3, 1049–
1052; Sinz, C. J.; Rychnovsky, S. D. Angew. Chem., Int. Ed.
2001, 40, 3224–3227; Kopecky, D. J.; Rychnovsky, S. D.
J. Am. Chem. Soc. 2001, 123, 8420–8421; Burova, S. A.;
McDonald, F. E. J. Am. Chem. Soc. 2002, 124, 8188–8189;
Schneider, C.; Tolksdorf, F.; Rehfeuter, M. Synlett 2002,
2098–2100; Sheperd, J. N.; Myles, D. C. Org. Lett. 2003,
1027–1030; Paterson, I.; Florence, G. J. Eur. J. Org. Chem.
2003, 2193–2208; Zacuto, M. J.; OÕMalley, S. J.; Leighton,
J . L.Tetrahedron 2003, 59, 8889–8900; Della, M. C.;
Maulucci, N.; De Riccardis, F.; Izzo, I. Tetrahedron:
Asymmetry 2003, 14, 3371–3378; Smith, A. B., III; Pitram,
S. M.; Boldi, A. M.; Gaunt, M. J.; Sfouggatakis, C.; Moser,
W. H. J. Am. Chem. Soc. 2005, 125, 14435–14445; Turks,
M.; Fonquerne, F.; Vogel, P. Org. Lett. 2004, 6, 1053–1056;
Fader, L. D.; Carreira, E. M. Org. Lett. 2004, 6, 2485–
2488; Wessjohann, L. A.; Wild, H.; Schrekker, H. S.
Tetrahedron Lett. 2004, 45, 9073–9078; Paterson, I.;
Delgado, O.; Florence, G. J.; Lyothier, I.; OÕBrien, M.;
Scott, J. P.; Sereinig, N. J. Org. Chem. 2005, 70, 150–160;
Smith, A. B., III; Walsh, S. P.; Frohn, M.; Duffey, M. O.
Org. Lett. 2005, 7, 139–142; Vogel, P.; Gerber-Lemaire, S.;
Carmona, A. T.; Meilert, K. T.; Schwenter, M. E. Pure
Appl. Chem. 2005, 77, 131–137; De Vicente, J.; Betzemeier,
B.; Rychnovsky, S. D. Org. Lett. 2005, 7, 1853–1856;
Lohse-Fraefel, N.; Carreira, E. M. Org. Lett. 2005, 7,
2011–2014.
96%). This oil crystallized as a white solid in pen-
23
tane (3 mL) at 4 ꢁC. PF: 162 ꢁC. ½aŠ ¼ À8,
405
23
435
23
589
½aŠ ¼ À6, ½aŠ ¼ À3 (c 0.24, CHCl3). UV (CH3CN):
kmax (e) = 228 (1216 dm3 molÀ1 cmÀ1) nm. IR (KBr):
2960, 2845, 1715, 1700, 1610, 1505, 1420, 1290, 1160,
1120, 1035, 845, 770, 670 cmÀ1. H NMR (400 MHz,
1
3
CDCl3): 6.19 (1H, d, H7 , J = 5.9 Hz, H-7 ), 6.15 (2H,
0
0
d, J = 5.9 Hz, H-60, H-700), 6.09 (1H, dd, 3J = 5.9,
3
3
1.0 Hz, H-600), 5.22 (1H, t, J = 5.9 Hz, H-30), 5.03
3
(1H, t, J = 5.7 Hz, H-3 ), 4.75 (1H, br s, H5 ), 4.71
00
0
00
(1H, br s, H5 ), 2.37, 2.11 (2H, 2m, H-6exo,00H-6endo),
2.22 (1H, m, H-4e0 xo), 2.16–2.14 0(0 1H, m, H-4exo), 2.12,
2.08 (2H, 2m, H-2e0 xo
,
H-2exo), 2.00 (2H, 2d,
2J = 14.7 Hz, H-80), 1.97 (3H, s, CH3(OAc)), 1.91, 1.68
(2H, 2m, H-5endo, H-5exo), 1.76, 1.71 (2H, 2dd, 2J =
15.2, 14.8 Hz, H-2e0 ndo, H-200 ), 1.60, 1.55 (2H, 2d, J =
2
endo
00
, H-4 ), 1.11, 1.03, 0.93
endo
15.5, 15.2 Hz, H-4e0 ndo
(3 · 3H, 3s, 3CH3) ppm. 13C NMR (100 MHz, CDCl3):
d = 178.1 (s, C@O(camphanoyl)), 170.4 (s, C@O), 166.6
1
0
00
(s, C@O), 136.6 (d, C7 , JC,H = 171), 136.5 (d, C7 ,
1
1
1
JC,H = 171), 132.5 (d, C6 , JC,H = 170), 132.3 (d, C6 ,
0
00
0
JC,H = 170), 90.9 (s, C7), 83.7, 83.6 (2s, C1 , C1 ), 77.7,
0
1
77.4 (2d, C5 , C5 ), 68.8 (d, C3 , JC,H = 146), 67.2 (d,
0
00
0
1
C3 , JC,H = 151), 54.8, 54.1 (2s, C1, C4), 44.2 (t, C8 ,
00
0
1
1
JC,H = 124), 38.0, 37.9 (2t, C2 , C2 , JC,H = 129), 31.7
0
00
1
(2t, C4 , C4 , JC,H = 128), 30.4 (t, C6, JC,H = 128),
1
0
00
1
28.9 (t, C5, JC,H = 136), 21.4 (q, CH3(OAc), JC,H
1
=
1
129), 16.9 (2q, 2CH3–C7, JC,H = 127), 9.6 (q, CH3–C4,
1JC,H = 127) ppm. MALDI-TOF: 509.65 (M+Na).
Anal. Calcd for C27H34O8 (486.55): C, 66.65; H, 7.04.
Found C, 66.65; H, 7.16.
3. Meilert, K. M.; Schwenter, M. E.; Shatz, Y.; Dubbaka,
S. R.; Vogel, P. J. Org. Chem. 2003, 68, 2964.
4. Schwenter, M. E.; Vogel, P. Chem. Eur. J. 2000, 6, 4091–
4103; Schwenter, M. E.; Vogel, P. J. Org. Chem. 2001, 66,
7869–7872.
Acknowledgements
This work was supported by the Swiss National Foun-
dation (Grant No. 200020-100028/1). We thank Dr.
Rosario Scopelitti for the X-ray analysis and Mr. Mar-
tial Rey, Mr. Mandal Bhubaneswar and Mr. Francisco
Sepu`lveda for technical help.
´
5. Csaky, A. G.; Vogel, P. Tetrahedron: Asymmetry 2000, 11,
¨
4935–4944.
6. Gerber-Lemaire, S.; Vogel, P. Eur. J. Org. Chem. 2003,
2959–2963.
7. Gerber-Lemaire, S.; Vogel, P. Eur. J. Org. Chem. 2004,
5040–5046.
References
´
8. For recent papers on desymmetrization, see: Garcıa-
1. Omura, S.; Tanaka, H. Macrolide Antibiotics: Chemistry,
Biology and Practise; Academic Press: New York, 1984;
Rychnovsky, S. D.; Griesgraber, G.; Schlegel, R. J. Am.
Chem. Soc. 1995, 117, 197–210; Richardson, T. I.;
Rychnovsky, S. D. J. Org. Chem. 1996, 61, 4219–4231;
Lipschutz, B. H.; Ullman, B.; Lindsley, C.; Recchi, S.;
Buzard, D. J.; Dickson, D. J. Org. Chem. 1998, 63, 6092–
6093; Pawlak, J.; Sowinski, P. P.; Borowski, E.; Garibaldi,
P. J. Antibiot. 1995, 48, 1034–1038; McGarvey, G. J.;
Mathys, J. A.; Wilson, K. J.; Overly, K. O.; Buonova, P.
T.; Spours, P. G. J. Am. Chem. Soc. 1995, 60, 7778–7790;
Mukhopadhyay, T.; Vijayakumar, E. K. S.; Nadkarni, S.
R.; Fehlhaber, H. W.; Kogler, H.; Petry, S. J. Antibiot.
1998, 57, 582–585.
Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev. 2005,
105, 313–354, and references cited therein; Hegemann, K.;
Fro¨hlich, R.; Haufe, G. Eur. J. Org. Chem. 2004, 2181–
2192; Trost, B. M.; Mino, T. J. Am. Chem. Soc. 2003, 125,
2410–2411; Marchionni, C.; Vogel, P. Helv. Chim. Acta
2001, 84, 431–472; Marchionni, C.; Meilert, K.; Vogel, P.;
Schenk, K. Synlett 2000, 1111–1114; Vogel, P. Curr. Org.
Chem. 1998, 2, 255–280; Dienes, Z.; Vogel, P. J. Org.
Chem. 1996, 61, 6958–6970; Ancerewicz, J.; Vogel, P.;
Schenk, K. Helv. Chim. Acta 1996, 79, 1415–1427;
Ancerewicz, J.; Vogel, P. Helv. Chim. Acta 1996, 79,
1393–1414; Marchionni, C.; Vogel, P.; Roversi, P. Tetra-
hedron Lett. 1996, 37, 4149–4152; Dienes, Z.; Vogel, P.
Bioorg. Med. Chem. Lett. 1995, 5, 547–550; Dienes, Z.;

G. Coste, S. Gerber-Lemaire / Tetrahedron: Asymmetry 16 (2005) 2277–2283
2283
Antonsson, T.; Vogel, P. Tetrahedron Lett. 1993, 34, 1013–
1016; Antonsson, T.; Vogel, P. Tetrahedron Lett. 1990, 31,
89–92.
10. Crystallographic data (excluding structure factors) for the
structure herein have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion number CCDC 270615. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK.
9. Harada, N.; Nakanishi, K. Circular Dichroic Spectroscopy
Exciton Coupling in Organic Chemistry; University Science
Books: Hill Valley, CA, 1983.