Total synthesis of a novel macrotetrolide

Article abstract of DOI:10.1016/j.tet.2008.09.038

The total synthesis of a novel macrotetrolide, an isobutyl nonactin analog, has been achieved in 15% yield by coupling both enantiomers of the corresponding nonactic acid analogs followed by macrolactonization. These building blocks were prepared starting from β-ketoester in nine steps and 34% overall yield, in an efficient and highly stereoselective sequence. The key steps of the strategy are asymmetric hydrogenation, chelation-controlled allylation, intramolecular haloetherification of bishomoallylic ether presenting a trisubstituted double bond deactivated by an ester, and finally a stereoselective reduction of α-bromoester.

Full text of DOI:10.1016/j.tet.2008.09.038

Tetrahedron 64 (2008) 11296–11303
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of a novel macrotetrolide
,
Ludovic Coutable a, Karim Adil b, Christine Saluzzo a
*
a UCO2M, UMR 6011, Universite´ du Maine, Avenue O. Messiaen, 72085 Le Mans Cedex 09, France
b LdOF, UMR 6010, Universite´ du Maine, Avenue O. Messiaen, 72085 Le Mans Cedex 09, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 May 2008
Received in revised form 7 September 2008
Accepted 10 September 2008
Available online 24 September 2008
The total synthesis of a novel macrotetrolide, an isobutyl nonactin analog, has been achieved in 15% yield
by coupling both enantiomers of the corresponding nonactic acid analogs followed by macro-
lactonization. These building blocks were prepared starting from
b-ketoester in nine steps and 34%
overall yield, in an efficient and highly stereoselective sequence. The key steps of the strategy are
asymmetric hydrogenation, chelation-controlled allylation, intramolecular haloetherification of bisho-
moallylic ether presenting a trisubstituted double bond deactivated by an ester, and finally a stereo-
selective reduction of a-bromoester.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Macrotetrolides, and in particular nactins (Fig. 1), display a wide
range of biological activities,1 such as antimicrobial, insecticidal,
antifungal, and immunosuppressive. The total synthesis of nonactin
1, the lowest homolog of the nactin family, has been achieved by six
groups2 and to our knowledge, only one synthesis of a non-natural
2.1. Synthesis of nonactic acid analogs
Our synthesis (Scheme 2) started with the catalytic asym-
metric reduction of 5-methyl-3-oxo-hexanoic acid ethyl ester 10.
Hydrogenation5 of 10 with RuCl2[(R)-BINAP] afforded (3R)-3-
hydroxyester 11 in 96% yield and 97% ee.6 Protection of the
secondary alcohol 11 with benzyl-2,2,2-trichloroacetimidate in
nonactin analog (macrotetrolide a
) has been reported.3
These macrolactones are composed of both enantiomers of
nonactic, homononactic or bishomononactic acids. It has been
shown that the bigger the alkyl groups size (R1–R4), the better the
antimicrobial and antifungal activities.1 The latter are correlated to
the ability of such a compound to complex cations. It is the reason
why nonactin is also used for the preparation of ion selective
electrodes.4
the presence of triflic acid7 yielded the
b-benzyloxyester 12
(85%), which was then reduced to aldehyde 13 (90%) with
DIBAL-H at ꢀ78 ꢁC in ether.8 The introduction of the second
(+)
R1
O
(-)
Herein, we report an efficient and highly stereoselective syn-
thesis of a novel synthetic nonactin analog. A general retrosynthetic
analysis is presented in Scheme 1.
O
O
O
O
O
O
R4
O
O
O
O
R2
Coupling of (þ) and (ꢀ)-nonactic acid analogs A, followed by
macrolactonization, would lead to the macrotetrolide. The (þ) and
(ꢀ)-nonactic acid analogs A could be prepared using the same
strategy; only the formation of (ꢀ)-A is depicted in Scheme 1. We
(+)
(-)
R3
O
R1
R2
R3
R4
Me Me Me Me
Me Me Me Et
nonactin (1)
monactin (2)
dinactin (3)
trinactin (4)
tetranactin (5)
macrotetrolide α (6)
OH
envisaged its synthesis from a-bromo-THF B via a radical-mediated
Me Et
Me Et
Me Et
Et
Et
Et
Et
reduction. The cis-THF B could be built from the bishomoallylic
ether C using a diastereoselective haloetherification. This ether C
could be synthesized via a double bond homologation sequence
from homoallylic alcohol D. The latter could be obtained by a ster-
Et
Et
i-Pr i-Pr i-Pr i-Pr
CO2H
R
O
eoselective allylation of the aldehyde E, easily accessible from
ketoester F.
b-
(+)-nonactic acid (7)
R = Me
R = Et
(+)-homononactic acid (8)
(+)-bishomononactic acid (9) R = i-Pr
* Corresponding author. Tel.: þ33 2 43 83 33 37; fax: þ33 2 43 83 39 02.
E-mail address: christine.saluzzo@univ-lemans.fr (C. Saluzzo).
Figure 1. Structures of naturally occurring macrotetrolides, macrotetrolide
monomer precursor acids.
a and the
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.038

L. Coutable et al. / Tetrahedron 64 (2008) 11296–11303
11297
yield and as a single diastereoisomer (determined by 1H NMR
spectroscopy).
O
R
R
O
O
O
O
O
O
O
R
O
O
R
(+)-A
(-)-A
Finally, a radical-mediated reduction of a-bromo-THF 18 using
O
O
(Me3Si)3SiH and AIBN, at ꢀ25 ꢁC in toluene and under UV irradia-
tion, gave the desired protected nonactic acid analog 19 in 85%
yield. Analysis of the crude reaction mixture by 1H NMR spectros-
copy indicated that the diastereoisomeric excess (86%) was in favor
of the 1,2-anti product.14 These results are consistent with Guin-
don’s ones.15
OBn
OBn
CO2Et
CO2Et
R
R
O
O
(-)-A
B
Br
The synthesis of the (þ)-19 enantiomer was performed in the
OBn OH
OBn
same way, starting from the b-ketoester 10, which was hydroge-
nated in methanol at 50 ꢁC under 50 bar in the presence of
RuCl2[(S)-BINAP]. The overall yield was similar to that obtained for
the synthesis of compound (ꢀ)-19.
R
R
R
R
OP
D
C
CO2Et
OBn O
O
O
H
OEt
2.2. Determination of the absolute and relative
configurations
E
F
Scheme 1. Synthetic plan.
Alcohol (R)-11 has already been formed by asymmetric re-
stereocenter was achieved via 1,3-asymmetric induction. Chela-
tion-controlled allylation9 of
-benzyloxyaldehyde 13, promoted
duction of b-ketoester 10 with Saccharomyces cerevisiae and has
b
been reported to present an optical rotation of þ10.3 (c 8.0,
CHCl3).6a By asymmetric hydrogenation of 10 in the presence of
RuCl2[(R)-BINAP] catalyst, we measured for alcohol 11 an optical
rotation of ꢀ12.9 (c 8.0, CHCl3). According to the quadrant rule,16
we expected the formation of the (R)-enantiomer. In order to
confirm this hypothesis, a chemical transformation of the ethyl
by TiCl4, led to product 14 with excellent yield and diaster-
eoselectivity (anti:syn¼98:2, determined by GC analysis of the
crude mixture and after purification). Alcohol 14 (96% dr) was
therefore converted to its 2,6-dichlorobenzylether (DCB) 15 (97%,
detected as a single isomer by NMR spectroscopy after purifi-
cation), since Rychnovsky and Bartlett10 and more recently
White et al.11 observed a highly stereoselective haloetherification
with this protecting group for the synthesis of cis-2,5-di-
substituted tetrahydrofuran. The terminal alkene 15 was trans-
formed into primary alcohol 16 (90%) via a highly regioselective
sequence of hydroboration/oxidation with 9-BBN/H2O2/NaOAc.12
The Swern oxidation of this primary alcohol 16 was followed by
in situ Wittig reaction13 to give a 97:3 (E:Z) mixture of isomeric
products from which the major (E)-bishomoallylic ether 17 was
isolated in 69% yield after column chromatography.
ester 11 to acid 20 was performed (Scheme 3). The optical rotation
20
for compound 20 ([
a]
¼ꢀ13.9 (c 1.05, CHCl3)) was consistent with
D
the (R)-enantiomer; the value for the (S)-20 enantiomer (99% ee)
being þ14.2 (c 1.2, CHCl3).17
The absolute configuration of 11 was also determined by appli-
cation of the modified Mosher’s method.18 Alcohol 11 was treated
with (S)- and (R)-2-methoxy-2-phenyl-2-(trifluoromethyl)acetic
acid (MTPA) to give, respectively, the (S)- and (R)-MTPA derivatives
(21a and 21b). The calculation of the DdS–R values clearly established
the absolute configuration of C-3 as R (Scheme 3).
Our first attempts at electrophilic cyclization of compound 17
with iodine in acetonitrile, according to Bartlett,10 were un-
successful. However, with iodine monobromide or bromine, the
Relative configurations of the stereocenters were confirmed by
crystallographic analysis of the dinitrobenzoate derivative 22,
obtained from compound 19 via subsequent debenzylation
and esterification with 3,5-dinitrobenzoic acid (Scheme 4 and
Fig. 2).
formation of
a-halo-cis-THF occurred. The best results were
obtained with bromine. Bromo-cis-THF 18 was obtained in 90%
NH
H2 (50 bar)
RuCl2[(R)-BINAP]
OH
O
OBn O
OBn O
O
O
BnO CCl3
DIBAL-H
i-Bu
OEt
i-Bu
OEt
i-Bu
OEt
i-Bu
H
MeOH, 50 °C
96%, 97% ee
Et2O, -78 °C
90%
TfOH, Et2O
0 °C to r.t.
85%
10
11
12
13
TiCl4
quant.
Sn(n-Bu)3
CH2Cl2, -78 °C
Cl
1. 9-BBN, THF, r.t.
2. H2O2, NaOAc
Br
OBn ODCB
OBn ODCB
OBn OH
Cl
OH
i-Bu
i-Bu
i-Bu
NaH, n-Bu4NI, DMF, r.t.
90%
15
14
16
97%
anti:syn = 98:2
1. Swern oxidation
69% (2 steps)
2. Ph3P=C(Me)CO2Et, CH2Cl2, r.t.
(Me3Si)3SiH, AIBN
toluene, -25 °C
OBn ODCB
OBn
O
OBn
O
Br2
i-Bu
CO Et
i-Bu
OEt
i-Bu
OEt
CH2Cl2, -78 °C
90%
UV lamp (366 nm)
anti:syn = 93:7
O
O
2
17
19
18
Br
(85% yield of pure 1,2-anti 19)
Scheme 2. Synthesis of nonactic acid analog.

11298
L. Coutable et al. / Tetrahedron 64 (2008) 11296–11303
OH
O
OH
O
28). For the preparation of the linear tetramer, esterification be-
1 N NaOH
0 °C to r.t.
tween compounds 27 and 28 was performed under Yamaguchi
et al. conditions.21 After desilylation, hydrogenolysis, subsequent
intramolecular modified Yamaguchi procedure22 furnished the
isobutyl analog of nonactin 32. The latter was obtained in 15%
overall yield starting from (þ) and (ꢀ)-19.
i-Bu
OEt
i-Bu
OH
11
20
(S)-MTPA or
(R)-MTPA
DCC, DMAP
CH2Cl2, r.t.
MTPA
+0.07
+0.14
+0.08
3. Conclusion
O
O
OR
3
O
-0.06
O
i-Bu
OEt
We have reported a total stereoselective synthesis of protected
nonactic acid analog 19 from b-ketoester 10, in nine steps and 34%
overall yield. The key steps of this synthesis sequence were the
asymmetric hydrogenation, the allylation reaction, a cis-cyclo
bromoetherification followed by a radical-mediated dehalogena-
tion; all the reactions being highly stereocontrolled.
-0.05
-0.04
+0.09
+0.07
-0.06
21a R = (S)-MTPA
21b R = (R)-MTPA
Δδ
values (ppm)
S-R
Scheme 3. Determination of the absolute configuration.
The two protected enantiomers (þ)-19 and (ꢀ)-19, analogs of
nonactic acid, were submitted to esterification then macro-
lactonization in order to produce the isobutyl analog of nonactin 32
in 15% overall yield.
OBn
O
i-Bu
OEt
O2N
O
19
NO2
4. Experimental
4.1. General
1. H2, Pd/C, MeOH, r.t.
2. 3,5-dinitrobenzoic acid
DCC, DMAP, CH2Cl2
0 °C to r.t.
O
O
CO2Et
i-Bu
64%
O
All commercial materials were used without further purification
unless otherwise noted. Et2O and THF were distilled over sodium
benzophenone ketyl. Dichloromethane, toluene, DMF, and DMSO
were distilled from calcium hydride. All reactions were performed
under a dry argon atmosphere in oven-dried glassware. Flash
22
Scheme 4. Determination of the relative configurations.
2.3. Synthesis of the macrotetrolide
chromatography was performed on Merck silica gel (40–63 mm).
Analytical thin-layer chromatography was carried out on Merck
silica gel 60F254. Optical rotations were measured with a Perkin
Elmer 343 polarimeter at the sodium D line with a 1-dm path
length, 1-mL cell. NMR spectra were recorded on a Bruker AC400
and are referenced to TMS as internal standard. IR spectra were
recorded on a Nicolet Avatar 370 DTGS infrared spectrometer. El-
emental analyses were performed by the Service de Microanalyse
de l’Institut de Chimie des Substances Naturelles, Gif-sur-Yvette.
High-resolution mass spectra were recorded on a Waters Micro-
massÒ GCT PremierÔ. Chiral GC was performed on an HP 6890 with
We applied (ꢀ)-19 and (þ)-19 in the synthesis of the corre-
sponding nonactin analog. For that, it was necessary to deprotect
selectively a terminal carbonyl function in the presence of a non-
terminal one. It is the reason why the ethyl ester (ꢀ)-19 was
transformed into its corresponding 2-trimethylsilylethyl ester 25
(TMSE) (Scheme 5), which gave easily the acid in the presence of
tetrabutylammonium fluoride (TBAF).19 Thus, saponification with
KOH in MeOH/H2O,14 esterification with 2-trimethylsilylethanol in
the presence of diisopropylcarbodiimide (DIC) and DMAP20 fol-
lowed by hydrogenolysis of the benzyl ether function afforded the
hydroxyester 25 in 60% yield (three steps) (Scheme 5). As for
the ester (þ)-19, it was hydrolyzed with KOH in MeOH/H2O to yield
the corresponding acid (þ)-23, which was then submitted to es-
terification with the hydroxyester 25 in the presence of DCC and
DMAP. The resulting dimer 26, formed in 73% yield, was then di-
vided into two parts. The first aliquot was treated with TBAF in
order to generate the acid function (compound 27) and the second
one with hydrogen to lead to the free hydroxyl group (compound
He as carrier gas and using an Rt-
bDEX cstÔ column (30 m, 0.5 mm
id, 0.25 m df). Radical-mediated reactions were carried out using
m
a Hamamatsu UV Spot Light Source (200W type L8222-01).
4.2. Ethyl 3-hydroxy-5-methylhexanoate (11)
(R)-BINAP (53 mg, 0.084 mmol) and [(benzene)RuCl2]2 (20 mg,
0.04 mmol) were dissolved in degassed DMF (1.4 mL) under argon.
The reaction was heated to 100 ꢁC for 10 min. After cooling to 50 ꢁC,
the solvent was removed under vacuum to give the catalyst as an
orange-red solid. This catalyst (5 mg) was dissolved in a degassed
solution of b-ketoester 10 (1.72 g, 10.0 mmol) in MeOH (1.5 mL).
The mixture was transferred to an autoclave, which was purged
three times with hydrogen. The mixture was stirred overnight at
50 ꢁC under a pressure of 50 bar. After carefully venting the hy-
drogen at room temperature, the solvent was removed and the
residue dissolved in Et2O. The ether solution was filtered through
a pad of silica gel. Evaporation of the solvent gave the pure
b
-hydroxyester 11 as
a
colorless oil (1.67 g, 96%). (3R)-11:
20
[a
]
]
¼ꢀ12.9 (c 8.0, CHCl3). With (S)-BINAP, (3S)-11 was obtained:
D
20
D
[a
¼þ13.3 (c 8.0, CHCl3).
4.3. Ethyl 3-(benzyloxy)-5-methylhexanoate (12)
To a stirred solution of
b-hydroxyester 11 (870 mg, 5.00 mmol)
Figure 2. ORTEP drawing of 22.
and benzyl-2,2,2-trichloroacetimidate (2.53 g, 10.0 mmol) in Et2O

L. Coutable et al. / Tetrahedron 64 (2008) 11296–11303
11299
OBn
OBn
CO2Et
CO2Et
i-Bu
i-Bu
O
O
90%
(+)-19
(-)-19
1. KOH, MeOH/H2O
KOH, MeOH/H2O
0 °C to r.t.
OH
OBn
0 °C to r.t. [(-)-23, 88%]
CO2TMSE
CO2H
i-Bu
i-Bu
2. Me3SiCH2CH2OH, DIC, DMAP
CH2Cl2, 0 °C to r.t. (24, 72%)
3. H2, Pd/C, MeOH, r.t. (95%)
O
O
25
(+)-23
DCC, DMAP
73%
O
CH2Cl2, -10 °C to r.t.
OBn
i-Bu
CO2TMSE
H2, Pd/C
TBAF, THF
r.t.
90%
i-Bu
O
26
O
O
MeOH, r.t.
quant.
OH
O
i-Bu
OBn
O
i-Bu
CO2TMSE
CO2H
i-Bu
O
28
i-Bu
O
27
O
O
O
O
1. TCBCl, Et3N, THF, r.t.
2. DMAP, CH2Cl2, r.t.
90%
O
OBn
O
i-Bu
i-Bu
O
i-Bu
CO2TMSE
i-Bu
O
O
29
O
O
O
O
O
O
i-Bu
1. TBAF, THF, r.t. (30, 96%)
O
O
O
i-Bu
O
2. H2, Pd/C, MeOH, r.t. (31, 72%)
O
O
3. TCBCl, DMAP, 4A ms
CH2Cl2, r.t. (60%)
O
i-Bu
O
O
O
32
O
i-Bu
Scheme 5. Synthesis of the macrotetrolide.
(10 mL) was added, at room temperature, trifluoromethanesulfonic
acid (44 L, 0.50 mmol). The mixture was stirred overnight and
concentrated. The residue was taken up with cyclohexane and the
crystalline trichloroacetamide removed by filtration. The filtrate
was washed with brine, dried (MgSO4), and concentrated. The
crude mixture was purified by flash chromatography (cyclohexane/
CDCl3)
d
0.91 (d, 3H, J¼6.5 Hz), 0.92 (d, 3H, J¼6.5 Hz), 1.32 (ddd, 1H,
m
J¼13.8, 7.6, 5.7 Hz),1.66 (ddd,1H, J¼13.8, 7.5, 6.3 Hz),1.7–1.8 (m,1H),
2.59 (ddd, 1H, J¼16.2, 5.1, 2.0 Hz), 2.67 (ddd, 1H, J¼16.2, 6.5, 2.6 Hz),
3.9–4.1 (m, 1H), 4.53 (d, 1H, J¼11.3 Hz), 4.54 (d, 1H, J¼11.3 Hz), 7.2–
7.4 (m, 5H), 9.82 (dd, 1H, J¼2.6, 2.0 Hz); 13C NMR (100 MHz, CDCl3)
d
22.3, 22.8, 24.4, 43.8, 48.4, 71.0, 72.6, 127.5, 127.6, 128.2, 138.0,
AcOEt, 95/5) to give the
b
a
-benzyloxyester 12 as a colorless oil
201.4; IR (film) 3089, 3064, 3031, 2956, 2928, 2870, 2726,1951,1875,
1724,1604,1497,1467,1454,1386,1367,1354,1308,1244, 1207,1171,
1142,1096,1069,1028, 737, 698. Anal. Calcd for C14H20O2: C, 76.33; H,
9.15. Found: C, 76.38; H, 9.05.
20
(1.12 g, 85%). (3R)-12:
[
]
D
¼þ10.0 (c 1.0, CHCl3); (3S)-12:
20
[
a]
¼ꢀ8.9 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d 0.89 (d, 3H,
D
J¼6.6 Hz), 0.91 (d, 3H, J¼6.6 Hz),1.25 (t, 3H, J¼7.2 Hz), 1.29 (ddd, 1H,
J¼13.9, 8.1, 5.0 Hz), 1.60 (ddd, 1H, J¼13.9, 8.0, 5.8 Hz), 1.7–1.9 (m,
1H), 2.46 (dd, 1H, J¼15.0, 5.7 Hz), 2.62 (dd, 1H, J¼15.0, 6.8 Hz), 3.9–
4.0 (m, 1H), 4.14 (q, 1H, J¼7.2 Hz), 4.15 (q, 1H, J¼7.2 Hz), 4.51 (d, 1H,
J¼11.3 Hz), 4.58 (d, 1H, J¼11.3 Hz), 7.2–7.4 (m, 5H); 13C NMR
4.5. 6-(Benzyloxy)-8-methylnon-1-en-4-ol (14)
To a stirred solution of
b-benzyloxyaldehyde 13 (980 mg,
(100 MHz, CDCl3)
d 14.1, 22.2, 23.1, 24.5, 40.2, 44.1, 60.3, 71.4, 74.4,
4.45 mmol) in CH2Cl2 (45 mL) was added, at ꢀ78 ꢁC, TiCl4 (freshly
127.5, 127.7, 128.2, 138.4, 171.7; IR (film) 3089, 3065, 3031, 2956,
2870, 1950, 1877, 1736, 1603, 1496, 1466, 1454, 1368, 1307, 1240,
1179, 1096, 1069, 1029, 735, 697. Anal. Calcd for C16H24O3: C, 72.69;
H, 9.15. Found: C, 72.73; H, 9.27.
distilled over copper, 488 mL, 4.45 mmol). After 2 min, allyl-
tributyltin (1.65 mL, 5.34 mmol) was added dropwise and stirring
was continued at ꢀ78 ꢁC for at least 30 min. Upon complete con-
sumption of aldehyde, the reaction mixture was quenched with
saturated aqueous NH4Cl solution and the temperature allowed to
warm up to room temperature. The aqueous phase was separated
and extracted twice with CH2Cl2. The combined organic extracts
were washed with brine, dried (MgSO4), and concentrated. The
residue was purified by flash chromatography (cyclohexane/AcOEt,
4.4. 3-(Benzyloxy)-5-methylhexanal (13)
To a stirred solution of b-benzyloxyester 12 (793 mg, 3.00 mmol)
in Et2O (6 mL) was added dropwise, at ꢀ78 ꢁC, a 1 M solution of
DIBAL in toluene (4.2 mL, 4.2 mmol), and stirring was continued at
ꢀ78 ꢁC for at least 1 h. Upon complete consumption of ester, the
reaction mixture was quenched with a 2 N hydrochloric acid solu-
tion (12 mL) and the temperature allowed to warm up to room
temperature. The aqueous phase was separated and extracted twice
with Et2O. The combined organic extracts were washed with brine,
dried (MgSO4) and concentrated. The residue was purified by flash
95/5) to give the alcohol 14 as a colorless oil (1.17 g, quantitative
20
yield, 96% dr). (4R,6R)-14: [
a]
¼ꢀ25.6 (c 2.0, CHCl3); (4S,6S)-14:
D
20
[a
]
¼þ24.0 (c 2.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d 0.90 (d, 6H,
D
J¼6.3 Hz), 1.2–1.4 (m, 1H), 1.58 (ddd, 1H, J¼14.7, 6.5, 2.4 Hz), 1.6–1.8
(m, 2H), 1.76 (ddd, 1H, J¼14.7, 9.6, 3.5 Hz), 2.2–2.3 (m, 2H), 2.88 (d,
J¼3.0 Hz), 3.78 (m, 1H), 3.9–4.1 (m, 1H), 4.56 (s, 2H), 5.09 (dm, 1H,
J¼10.5 Hz), 5.10 (dm, 1H, J¼16.8 Hz), 5.83 (ddt, 1H, J¼16.8, 10.5,
chromatography (cyclohexane/AcOEt, 9/1) to give the
b
-benzylox-
¼þ4.10 (c
7.1 Hz), 7.2–7.4 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 22.8, 22.9, 24.7,
20
yaldehyde 13 as a colorless oil (596 mg, 90%). (3R)-13: [
a
]
39.4, 42.2, 42.9, 67.7, 71.1, 75.5, 117.4, 127.7, 127.9 (2C), 128.4 (2C),
134.9,138.3; IR (film) 3443, 3067, 3031, 2955, 2928, 2869,1948,1826,
D
20
24.9, CHCl3); (3S)-13: [
a]
¼ꢀ1.8 (c 10.0, CHCl3); 1H NMR (400 MHz,
D

11300
L. Coutable et al. / Tetrahedron 64 (2008) 11296–11303
1641,1605,1497,1467,1454,1433,1385,1366,1308,1246,1207,1170,
1147, 1090, 1068, 1028, 997, 914, 868, 845, 816, 735, 697. Anal. Calcd
for C17H26O2: C, 77.82; H, 9.99. Found: C, 77.77; H, 9.94.
22.4 mmol), and the resulting mixture was stirred for 30 min. Sub-
sequently, a solution of alcohol 16 (3.52 g, 8.00 mmol) in CH2Cl2
(30 mL) was added over 5 min giving a white precipitate. After
stirring at ꢀ78 ꢁC for 10 min, Et3N (5.40 mL, 38.9 mmol) was
added. After 15 min, the reaction mixture was allowed to warm
up to 0 ꢁC and stirred for 1 h. Then, (carbethoxyethylidene)-
triphenylphosphorane (4.35 g, 12.0 mmol) was added at 0 ꢁC, and
the resultant mixture stirred at room temperature overnight. The
reaction mixture was diluted with Et2O (80 mL), washed twice with
H2O, brine, then dried (MgSO4), and concentrated. The residue was
taken up with cyclohexane, filtered, and concentrated. Purification
by flash chromatography (cyclohexane/AcOEt, 95/5) gave the pure
4.6. 6-(Benzyloxy)-4-(2,6-dichlorobenzyloxy)-8-
methylnon-1-ene (15)
To a suspension of NaH (60% dispersion in mineral oil, 64 mg,
1.60 mmol) in DMF (6.5 mL) was added, at 0 ꢁC, a solution of alcohol
14 (210 mg, 0.80 mmol) in DMF (0.7 mL). The mixture was stirred
for 20 min at 0 ꢁC, and a solution of 2,6-dichlorobenzyl bromide
(395 mg, 1.60 mmol) in DMF (1.3 mL) was added slowly, followed
by Bu4NI (59 mg, 0.16 mmol) at 0 ꢁC. The resulting mixture was
stirred overnight at room temperature, then quenched with satu-
rated aqueous NH4Cl solution, and diluted with Et2O. The aqueous
phase was separated and the organic layer was washed with H2O
and brine, dried (MgSO4), and concentrated. The residue was pu-
rified by flash chromatography (cyclohexane/AcOEt, 95/5) to give
(E)-bishomoallylic ether 17 as
a colorless oil (2.86 g, 69%).
20
20
(2E,6R,8R)-17: [
a]
¼ꢀ28.9 (c 1.1, CHCl3); (2E,6S,8S)-17: [
a
]
¼þ31.0
D
D
(c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3)
d
0.90 (d, 3H, J¼6.6 Hz), 0.91
(d, 3H, J¼6.6 Hz), 1.2–1.4 (m, 1H), 1.30 (t, 3H, J¼7.1 Hz), 1.5–1.7 (m,
2H), 1.6–1.8 (m, 4H), 1.84 (s, 3H), 2.2–2.4 (m, 2H), 3.6–3.8 (m, 2H),
4.19 (q, 2H, J¼7.1 Hz), 4.27 (d, 1H, J¼11.3 Hz), 4.49 (d, 1H, J¼11.3 Hz),
4.72 (d, 1H, J¼10.4 Hz), 4.78 (d, 1H, J¼10.4 Hz), 6.77 (tm, 1H,
J¼7.4 Hz), 7.14 (dd, 1H, J¼8.5, 7.5 Hz), 7.2–7.4 (m, 7H); 13C NMR
the product 15 as a colorless oil (328 mg, 97%). (4R,6R)-15:
20
[
a]
¼ꢀ54.4 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3)
d 0.88 (d, 3H,
D
J¼6.5 Hz), 0.89 (d, 3H, J¼6.5 Hz), 1.26 (ddd, 1H, J¼13.6, 6.8, 6.8 Hz),
1.53 (ddd, 1H, J¼13.6, 6.7, 6.7 Hz), 1.6–1.7 (m, 2H), 1.6–1.8 (m, 1H),
2.4–2.5 (m, 2H), 3.69 (m, 1H), 3.7–3.8 (m, 1H), 4.23 (d, 1H,
J¼11.3 Hz), 4.46 (d, 1H, J¼11.3 Hz), 4.73 (d, 1H, J¼10.5 Hz), 4.84 (d,
1H, J¼10.5 Hz), 5.08 (dm, 1H, J¼10.1 Hz), 5.11 (dm, 1H, J¼17.1 Hz),
5.88 (ddt, 1H, J¼17.1, 10.1, 7.1 Hz), 7.12 (dd, 1H, J¼8.5, 7.6 Hz), 7.2–7.4
(100 MHz, CDCl3) d 12.3, 14.3, 22.9, 23.1, 24.0, 24.6, 32.7, 40.4, 43.9,
60.3, 65.1, 70.8, 74.8, 75.3, 121.4, 127.3, 127.6 (2C), 128.0, 128.2–128.4
(4C),129.8,133.7,136.8 (2C),138.9,141.8,168.1; IR (film) 3088, 3064,
3030, 2954, 2928, 2869, 1947, 1865, 1712, 1650, 1582, 1564, 1496,
1466,1454,1437,1386,1366,1273,1261,1196,1135,1094,1075,1029,
993, 918, 855, 826, 779, 767, 736, 697. Anal. Calcd for C29H38Cl2O4: C,
66.79; H, 7.34. Found: C, 66.77; H, 7.25.
(m, 7H); 13C NMR (100 MHz, CDCl3)
d 22.9, 23.1, 24.6, 38.3, 40.5,
43.9, 65.1, 70.8, 74.7, 75.1, 117.3, 127.3, 127.5 (2C), 128.2–128.3 (4C),
129.8, 133.8, 134.4, 136.8 (2C), 139.1; IR (film) 3067, 3030, 2954,
2868, 1945, 1864, 1722, 1640, 1582, 1564, 1496, 1467, 1454, 1437,
1385, 1365, 1306, 1247, 1198, 1147, 1094, 1065, 1028, 994, 914, 853,
826, 778, 767, 733, 697; HRMS (CIþ, methane) m/z [MþH]þ Calcd for
C24H31Cl2O2: 421.1701, found: 421.1696.
4.9. Ethyl 2-{5-[2-(benzyloxy)-4-methylpentyl]tetrahydro-
furan-2-yl}-2-bromopropanoate (18)
To
a stirred solution of bishomoallylic ether 17 (2.86 g,
5.49 mmol) in CH2Cl2 (275 mL) was added slowly, at ꢀ78 ꢁC, a 1.0 M
solution of Br2 in CH2Cl2 (freshly prepared, 7.70 mL, 7.70 mmol).
The resulting brown solution was stirred in the dark at ꢀ78 ꢁC.
After complete consumption of starting material (z1 h), the re-
action mixture was quenched by the addition of saturated aqueous
Na2S2O3 solution and diluted with Et2O. The aqueous phase was
separated and extracted twice with Et2O. The combined organic
extracts were washed with brine, dried (MgSO4), and concentrated.
The residue was purified by flash chromatography (cyclohexane/
4.7. 6-(Benzyloxy)-4-(2,6-dichlorobenzyloxy)-8-
methylnonan-1-ol (16)
To a stirred solution of 15 (1.85 g, 4.41 mmol) in THF (20 mL) was
added dropwise, at 0 ꢁC, a 0.5 M solution of 9-BBN in THF (26.4 mL,
13.2 mmol). The mixture was stirred at 0 ꢁC for 1 h and at room
temperature overnight. The reaction mixture was cooled to 0 ꢁC,
EtOH (3.9 mL), saturated aqueous NaOAc (13.4 mL), and 30% H2O2
(4.3 mL) were added in that order; stirring was continued at 0 ꢁC for
1 h and at room temperature for 5 h. The mixture was diluted with
Et2O (150 mL), washed twice with H2O, saturated aqueous NaHCO3
solution, saturated aqueous NH4Cl solution, dried (MgSO4), and
concentrated. The residue was purified by flash chromatography
AcOEt, 95/5) to give the a-bromotetrahydrofuran 18 as a colorless
20
oil (2.18 g, 90%). (2S,3S,6R,8R)-18: [
a
]
¼ꢀ26.4 (c 1.0, CHCl3);
D
20
(2R,3R,6S,8S)-18: [
CDCl3)
a]
¼þ25.3 (c 1.0, CHCl3); 1H NMR (400 MHz,
D
d
0.88 (d, 6H, J¼6.6 Hz), 1.26 (ddd, 1H, J¼13.6, 7.3, 6.2 Hz),
1.29 (t, 3H, J¼7.1 Hz), 1.4–1.6 (m, 2H), 1.6–1.8 (m, 3H), 1.84 (s, 3H),
1.9–2.1 (m, 2H), 2.0–2.2 (m, 1H), 3.5–3.7 (m, 1H), 4.11 (m, 1H), 4.24
(q, 2H, J¼7.1 Hz), 4.42 (dd,1H, J¼8.0, 5.6 Hz), 4.51 (s, 2H), 7.2–7.4 (m,
(cyclohexane/AcOEt, 8/2) to give the alcohol 16 as a colorless oil
20
(1.76 g, 90%). (4R,6R)-16: [
a]
¼ꢀ47.2 (c 1.0, CHCl3); (4S,6S)-16:
5H); 13C NMR (100 MHz, CDCl3)
d 13.8, 22.6, 22.7, 22.8, 24.5, 28.3,
D
20
[
a]
¼þ40.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d
0.90 (d, 3H,
31.9, 41.0, 44.2, 61.8, 61.9, 71.3, 75.1, 78.0, 81.9, 127.3, 127.7 (2C),
128.1 (2C), 138.8, 170.3; IR (film) 3088, 3064, 3030, 2955, 2869,
1949, 1875, 1739, 1604, 1460, 1366, 1263, 1213, 1173, 1070, 963, 910,
862, 806, 735, 698. Anal. Calcd for C22H33BrO4: C, 59.86; H, 7.54.
Found: C, 59.88; H, 7.52.
D
J¼6.6 Hz), 0.90 (d, 3H, J¼6.6 Hz), 1.27 (ddd, 1H, J¼13.7, 6.7, 6.7 Hz),
1.5–1.8 (m, 9H), 3.6–3.7 (m, 3H), 3.7–3.8 (m, 1H), 4.26 (d, 1H,
J¼11.3 Hz), 4.49 (d,1H, J¼11.3 Hz), 4.73 (d,1H, J¼10.4 Hz), 4.79 (d,1H,
J¼10.4 Hz), 7.14 (dd, 1H, J¼8.5, 7.6 Hz), 7.2–7.4 (m, 7H); 13C NMR
(100 MHz, CDCl3)
d 22.9, 23.1, 24.6, 27.9, 30.2, 40.3, 43.8, 63.0, 65.1,
70.8, 74.9, 75.6,127.3,127.6 (2C),128.2–128.4 (4C),129.8,133.7,136.8
(2C),138.9; IR (film) 3404, 3088, 3064, 3030, 2951, 2924, 2868,1946,
1865,1806,1582,1564,1496,1468,1454,1436,1385,1365,1247,1197,
1171, 1146, 1094, 1059, 993, 854, 826, 778, 767, 733, 697. Anal. Calcd
for C24H32Cl2O3: C, 65.60; H, 7.34. Found: C, 65.54; H, 7.31.
4.10. Ethyl 2-{5-[2-(benzyloxy)-4-methylpentyl]-
tetrahydrofuran-2-yl}propanoate (19)
To a stirred and degassed solution of a-bromotetrahydrofuran
18 (221 mg, 0.50 mmol) and AIBN (12 mg, 0.08 mmol) in dry
toluene (5 mL) was added dropwise, at ꢀ25 ꢁC, (Me3Si)3SiH
4.8. Ethyl 8-(benzyloxy)-6-(2,6-dichlorobenzyloxy)-2,10-
dimethylundec-2-enoate (17)
(233 mL, 0.75 mmol). The reaction mixture was irradiated for
1.5 h with an UV lamp (366 nm) and then concentrated. The
residue was taken up with cyclohexane (5 mL) and treated with
a 1 M solution of TBAF in THF (1.25 mL, 1.25 mmol) for 5 min at
room temperature. After filtration of the mixture through
To a stirred solution of oxalyl chloride (1.51 mL, 17.6 mmol) in
CH2Cl2 (120 mL) was added dropwise, at ꢀ78 ꢁC, DMSO (1.59 mL,

L. Coutable et al. / Tetrahedron 64 (2008) 11296–11303
11301
a short pad of silica gel and solvent removal, a residue was
obtained and subsequently purified by flash chromatography
(cyclohexane/AcOEt, 9/1) to yield, as a colorless oil, the major
then concentrated. The residue was taken up with Et2O, filtered,
and concentrated. Flash chromatography (cyclohexane/AcOEt, 95/
5) afforded the 3,5-dinitrobenzoate ester 22 as white crystals
20
isomer 19 (153 mg, 85%). (2S,3S,6R,8R)-19: [
a
]
D
¼ꢀ9.30 (c 1.0,
(30 mg, 64%). Mp 48–50 ꢁC. 1H NMR (400 MHz, CDCl3)
d 0.96 (d, 6H,
20
CHCl3); (2R,3R,6S,8S)-19: [
(400 MHz, CDCl3)
a
]
D
¼þ10.5 (c 1.0, CHCl3); 1H NMR
J¼6.5 Hz), 1.08 (d, 3H, J¼7.0 Hz), 1.26 (t, 3H, J¼7.1 Hz), 1.4–1.7 (m,
4H), 1.75 (ddd, 1H, J¼13.7, 8.2, 5.8 Hz), 1.8–2.1 (m, 4H), 2.45 (dq, 1H,
J¼8.2, 7.0 Hz), 3.9–4.1 (m, 2H), 4.13 (q, 2H, J¼7.1 Hz), 5.4–5.5 (m,
d
0.88 (d, 3H, J¼6.5 Hz), 0.90 (d, 3H, J¼6.5 Hz),
1.11 (d, 3H, J¼7.0 Hz), 1.26 (t, 3H, J¼7.1 Hz), 1.27 (ddd, 1H, J¼13.6,
7.5, 5.9 Hz), 1.4–1.8 (m, 6H), 1.9–2.1 (m, 2H), 2.50 (dq, 1H, J¼8.2,
7.0 Hz), 3.5–3.7 (m, 1H), 4.0–4.1 (m, 2H), 4.15 (q, 1H, J¼7.1 Hz),
4.15 (q, 1H, J¼7.1 Hz), 4.51 (d, 1H, J¼11.3 Hz), 4.53 (d, 1H,
1H), 9.1–9.3 (m, 3H); 13C NMR (100 MHz, CDCl3)
d 13.3, 14.2, 22.3,
22.9, 24.8, 28.4, 31.4, 41.0, 43.8, 45.5, 60.3, 74.3, 75.8, 80.7, 122.1,
129.4 (2C), 134.5, 148.6 (2C), 162.0, 174.7; IR (film) 3105, 2959, 2873,
1731, 1629, 1598, 1548, 1462, 1345, 1277, 1172, 1075, 921, 825, 773,
730, 722; HRMS (FI) m/z [M]þ Calcd for C22H30N2O9: 466.1951,
found: 466.1949.
J¼11.3 Hz), 7.2–7.4 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 13.3,
14.2, 22.7, 23.0, 24.6, 28.6, 31.5, 41.8, 44.5, 45.6, 60.2, 71.6, 75.4,
76.5, 80.3, 127.3, 127.8 (2C), 128.2 (2C), 139.0, 174.9; IR (film)
3088, 3064, 3030, 2954, 2870, 1948, 1876, 1732, 1604, 1497, 1455,
1368, 1332, 1300, 1259, 1188, 1157, 1067, 1029, 952, 905, 862,
806, 736, 698. Anal. Calcd for C22H34O4: C, 72.89; H, 9.45. Found:
C, 72.68; H, 9.43.
Crystallographic data for 22: C22H30N2O9, M¼466.48, mono-
clinic, space group C21, a¼44.604(9) Å, b¼5.648(5) Å, c¼9.899(2) Å,
a
¼90ꢁ,
b
¼93.07(2)ꢁ,
g
¼90ꢁ, V¼2490.2(16) Å3, T¼293(2) K, Z¼4,
d¼1.236 g/cm3. A single crystal was used for measurement on
a Siemens AED2 four-circle diffractometer equipped with a graph-
4.11. (3R)-3-Hydroxy-5-methylhexanoic acid (20)
ite monochromatized Mo Ka1
(
l¼0.71073 Å). The crystal structure
was solved by direct methods using SHELX-97 and successive re-
finements and difference Fourier maps using SHELXL-97 program.
The location of the hydrogen atoms was performed by applying the
geometrical constraints using AFIX and DFIX option in SHELXL-97
program. Crystallographic data have been deposited in the Cam-
bridge Crystallographic Data Centre (deposition number CCDC
688312). Copies of the data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ,
UK; fax: þ44 1223 336 033 or deposit@ccdc.cam.ac.uk].
A solution of ester 11 (105 mg, 0.60 mmol) in 1 N NaOH
(3 mL) was stirred at 0 ꢁC, then allowed to warm up to room
temperature and stirred overnight. The reaction mixture was
washed with ether, the aqueous layer was acidified with dilute
HCl to pHz1, and then extracted twice with AcOEt. The organic
layer was washed with brine, dried (MgSO4), and concentrated
to give the acid 20 as a white solid (77 mg, 88%). (3R)-20:
20
[
a]
¼ꢀ13.9 (c 1.05, CHCl3).
D
4.12. Preparation of the (S)- and (R)-MTPA esters
(21a and 21b)
4.14. 2-{5-[2-(Benzyloxy)-4-methylpentyl]tetrahydrofuran-2-
yl}propanoic acid (23)
To a stirred solution of alcohol 11 (44 mg, 0.25 mmol) and DMAP
(7 mg, 0.06 mmol) in CH2Cl2 (2.5 mL) were added slowly, at 0 ꢁC,
(S)-MTPA (70 mg, 0.30 mmol) and DDC (62 mg, 0.30 mmol). The
mixture was allowed to warm up to room temperature and stirred
overnight, then concentrated. The residue was taken up with Et2O,
filtered, and concentrated. Flash chromatography (cyclohexane/
AcOEt, 9/1) afforded the (S)-MTPA ester derivative 21a as a colorless
oil (62 mg, 63%). Through a similar procedure, the (R)-MTPA ester
derivative 21b was obtained as a colorless oil (59 mg, 60%) from 11
(44 mg, 0.25 mmol) using (R)-MTPA.
To a stirred solution of ester 19 (290 mg, 0.80 mmol) in MeOH
(24 mL) was added dropwise, at 0 ꢁC, a 1 M aqueous solution of
KOH (24.0 mL, 24.0 mmol). The mixture was allowed to warm up
to room temperature and stirred overnight, then cooled to 0 ꢁC. It
was diluted with Et2O (25 mL) and brine (10 mL), then acidified
with a 2 M aqueous solution of HCl to pHw1. The aqueous phase
was separated and extracted twice with Et2O. The combined or-
ganic extracts were washed with brine, dried (MgSO4), and
concentrated. The residue was purified by flash chromatography
(S)-MTPA ester derivative (21a): 1H NMR (400 MHz, CDCl3)
(cyclohexane/AcOEt, 8/2þAcOH, 1%) to give the acid 23 as a col-
20
d
0.93 (d, 3H, J¼6.5 Hz), 0.95 (d, 3H, J¼6.5 Hz), 1.20 (t, 3H, J¼7.2 Hz),
orless oil (240 mg, 90%). (2S,3S,6R,8R)-23: [
a
]
D
¼ꢀ25.1 (c 1.0,
20
1.45 (ddd, 1H, J¼13.5, 7.8, 5.2 Hz), 1.5–1.7 (m, 1H), 1.70 (ddd, 1H,
J¼13.5, 8.0, 5.9 Hz), 2.55 (dd, 1H, J¼15.9, 5.3 Hz), 2.63 (dd, 1H,
J¼15.9, 7.6 Hz), 4.06 (q, 2H, J¼7.2 Hz), 5.54 (dddd, 1H, J¼7.8, 7.8, 5.3,
5.3 Hz).
CHCl3); (2R,3R,6S,8S)-23: [
(400 MHz, CDCl3)
a
]
¼þ26.0 (c 1.0, CHCl3); 1H NMR
D
d
0.88 (d, 3H, J¼6.6 Hz), 0.89 (d, 3H, J¼6.6 Hz),
1.16 (d, 3H, J¼7.1 Hz), 1.28 (ddd, 1H, J¼13.6, 7.3, 6.6 Hz), 1.5–1.8
(m, 5H), 1.55 (ddd, 1H, J¼13.6, 6.8, 6.8 Hz), 1.9–2.1 (m, 2H), 2.52
(dq, 1H, J¼8.1, 7.1 Hz), 3.5–3.7 (m, 1H), 3.9–4.1 (m, 1H), 4.0–4.2
(m, 1H), 4.51 (d, 1H, J¼11.4 Hz), 4.54 (d, 1H, J¼11.4 Hz), 7.2–7.4 (m,
(R)-MTPAesterderivative (21b): 1H NMR (400 MHz, CDCl3)
d 0.85
(d, 3H, J¼6.5 Hz), 0.88 (d, 3H, J¼6.5 Hz), 1.24 (t, 3H, J¼7.2 Hz), 1.36
(ddd, 1H, J¼13.6, 8.3, 5.0 Hz), 1.4–1.6 (m, 1H), 1.63 (ddd, 1H, J¼13.6,
8.3, 5.4 Hz), 2.60 (dd,1H, J¼15.8, 5.1 Hz), 2.69 (dd,1H, J¼15.8, 7.6 Hz),
4.12 (q, 2H, J¼7.2 Hz), 5.54 (dddd, 1H, J¼8.3, 8.3, 5.1, 5.1 Hz).
5H); 13C NMR (100 MHz, CDCl3)
d 13.1, 22.8, 22.9, 24.5, 28.8, 31.4,
41.6, 44.2, 45.2, 71.3, 75.2, 76.9, 79.9, 127.4, 127.9 (2C), 128.2 (2C),
138.8, 179.7; IR (film) 3700–2200, 3088, 3064, 3030, 2957, 1949,
1866, 1806, 1716, 1605, 1587, 1497, 1464, 1420, 1384, 1366, 1328,
1290, 1227, 1170, 1144, 1070, 1028, 951, 898, 849, 736, 698. Anal.
Calcd for C20H30O4: C, 71.82; H, 9.04. Found: C, 71.71; H, 9.01.
4.13. Ethyl 2-(5-{2-[3,5-dinitrobenzyloxy]-4-
methylpentyl}tetrahydrofuran-2-yl)propanoate (22)
A mixture of the ether 19 (110 mg, 0.30 mmol) and 10% palla-
dium on charcoal (64 mg) in MeOH (3 mL) was stirred for 4 h at
room temperature under H2 (1 atm). The solid was filtered off and
washed with AcOEt. The filtrate was evaporated under reduced
pressure. To a solution of this crude alcohol (27 mg, 0.10 mmol),
3,5-dinitrobenzoic acid (25 mg, 0.12 mmol), and DMAP (24 mg,
0.20 mmol) in CH2Cl2 (1 mL) was added slowly, at 0 ꢁC, a solution of
DCC (23 mg, 0.11 mmol) in CH2Cl2 (0.5 mL). The mixture was
allowed to warm up to room temperature and stirred overnight,
4.15. (2S,3S,6R,8R)-2-(Trimethylsilyl)ethyl 2-{5-[2-
(benzyloxy)-4-methylpentyl]tetrahydrofuran-2-
yl}propanoate (24)
To a stirred solution of acid (ꢀ)-23 (257 mg, 0.77 mmol), DMAP
(9 mg, 0.08 mmol), and 2-(trimethylsilyl)ethanol (122 mL,
0.85 mmol) in CH2Cl2 (4 mL) was added dropwise, at 0 ꢁC, DIC
(132 L, 0.85 mmol). The mixture was allowed to warm up to room
temperature and stirred overnight, then concentrated. The residue
m

11302
L. Coutable et al. / Tetrahedron 64 (2008) 11296–11303
was taken up with Et2O (7 mL), filtered, and concentrated. Flash
chromatography (cyclohexane/AcOEt, 95/5) afforded the ester 24 as
(5 mL). The phases were separated and the organic layer was
dried (MgSO4) and concentrated. The residue was purified by
20
a colorless oil (241 mg, 72%). [
a
]
¼ꢀ6.0 (c 1.0, CHCl3); 1H NMR
flash chromatography (cyclohexane/AcOEt, 8/2þAcOH, 1%) to
D
20
(400 MHz, CDCl3)
d
0.0–0.1 (m, 9H), 0.88 (d, 3H, J¼6.5 Hz), 0.90 (d,
give the acid 27 as a colorless oil (106 mg, 90%). [
a
]
¼þ9.6 (c
D
3H, J¼6.5 Hz), 0.9–1.1 (m, 2H), 1.11 (d, 3H, J¼7.0 Hz), 1.27 (ddd, 1H,
J¼13.6, 7.5, 5.8 Hz), 1.4–1.8 (m, 5H), 1.53 (ddd, 1H, J¼13.6, 6.8,
6.8 Hz), 1.9–2.1 (m, 2H), 2.50 (dq, 1H, J¼8.2, 7.0 Hz), 3.6–3.7 (m, 1H),
3.9–4.1 (m, 2H), 4.1–4.2 (m, 2H), 4.50 (d, 1H, J¼11.2 Hz), 4.54 (d, 1H,
1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d 0.88, 0.89, 0.90, 0.90
(4d, 12H, J1¼J2¼J3¼J4¼6.6 Hz), 1.10, 1.12 (2d, 6H, J1¼J2¼7.1 Hz),
1.26 (ddd, 1H, J¼13.6, 7.5, 5.9 Hz), 1.35 (ddd, 1H, J¼13.8, 8.3,
4.8 Hz), 1.4–1.9 (m, 12H), 1.9–2.1 (m, 4H), 2.47 (dq, 1H, J¼8.3,
7.1 Hz), 2.51 (dq, 1H, J¼8.2, 7.1 Hz), 3.5–3.7 (m, 1H), 3.9–4.1 (m,
4H), 4.51 (s, 2H), 5.0–5.1 (m, 1H), 7.2–7.4 (m, 5H); 13C NMR
J¼11.2 Hz), 7.2–7.4 (m, 5H); 13C NMR (100 MHz, CDCl3)
d
ꢀ1.6 (3C),
13.3, 17.3, 22.8, 23.1, 24.6, 28.5, 31.5, 41.8, 44.5, 45.7, 62.4, 71.6, 75.4,
76.5, 80.2, 127.3, 127.8 (2C), 128.2 (2C), 139.0, 175.0; IR (film) 3089,
3064, 3030, 2954, 2869, 1945, 1865, 1735, 1606, 1497, 1455, 1384,
1365, 1332, 1250, 1163, 1068, 1029, 938, 859, 838, 735, 697. Anal.
Calcd for C25H42O4Si: C, 69.08; H, 9.74. Found: C, 68.81; H, 9.53.
(100 MHz, CDCl3)
d 13.0, 13.2, 22.1, 22.8, 23.0, 23.0, 24.5, 24.5,
28.3, 28.6, 31.2, 31.5, 41.2, 41.6, 43.6, 44.3, 44.9, 45.6, 70.8, 71.4,
75.4, 76.5, 76.9, 79.9, 80.0, 127.3, 127.7 (2C), 128.2 (2C), 138.8,
174.4, 179.1; IR (film) 3700–2200, 3089, 3064, 3030, 2953, 2870,
1949, 1873, 1732, 1714, 1497, 1463, 1456, 1418, 1384, 1367, 1260,
1192, 1169, 1142, 1068, 1029, 950, 902, 849, 736, 698. Anal. Calcd
for C33H52O7: C, 70.68; H, 9.35. Found: C, 70.66; H, 9.32.
4.16. (2S,3S,6R,8R)-2-(Trimethylsilyl)ethyl 2-[5-(2-hydroxy-4-
methylpentyl)tetrahydrofuran-2-yl]propanoate (25)
A mixture of the ether 24 (228 mg, 0.52 mmol) and 10% palla-
dium on charcoal (110 mg) in MeOH (6 mL) was stirred overnight at
room temperature under H2 (1 atm). The solid was filtered off and
washed with AcOEt. The filtrate was evaporated under reduced
pressure. The residue was purified by flash chromatography (cy-
4.19. Dimer 28
A mixture of the ether 26 (123 mg, 0.19 mmol) and 10% palla-
dium on charcoal (40 mg) in MeOH (2 mL) was stirred overnight at
room temperature under H2 (1 atm). The solid was filtered off and
washed with AcOEt. The filtrate was evaporated under reduced
pressure. The residue was purified by flash chromatography (cy-
clohexane/AcOEt, 8/2) to give the alcohol 25 as a colorless oil
20
(171 mg, 95%). [
CDCl3)
a
]
¼þ20.0 (c 1.0, CHCl3); 1H NMR (400 MHz,
D
d
0.0–0.1 (m, 9H), 0.89 (d, 3H, J¼6.6 Hz), 0.89 (d, 3H,
clohexane/AcOEt, 7/3) to give the alcohol 28 as a colorless oil
¼þ0.4 (c 1.0, CHCl3); 1H NMR (400 MHz,
20
J¼6.6 Hz), 0.9–1.1 (m, 2H), 1.10 (d, 3H, J¼7.0 Hz), 1.18 (ddd, 1H,
J¼13.6, 8.3, 4.7 Hz), 1.45 (ddd, 1H, J¼13.6, 8.7, 5.8 Hz), 1.5–1.8 (m,
5H), 1.9–2.1 (m, 2H), 2.49 (dq, 1H, J¼8.2, 7.0 Hz), 2.74 (br s, 1H), 3.8–
4.0 (m, 1H), 3.9–4.1 (m, 1H), 4.1–4.2 (m, 3H); 13C NMR (100 MHz,
(108 mg, 100%). [
CDCl3)
a
]
D
d
0.0–0.1 (m, 9H), 0.86, 0.88, 0.89 (3d, respectively, 3H, 3H,
6H, J1¼J2¼J3¼6.6 Hz), 0.9–1.1 (m, 2H), 1.07, 1.08 (2d, 6H,
J1¼J2¼7.0 Hz), 1.17 (ddd, 1H, J¼13.2, 8.2, 4.9 Hz), 1.34 (ddd, 1H,
J¼13.4, 8.3, 4.5 Hz), 1.4–1.8 (m, 12H), 1.8–2.0 (m, 4H), 2.47 (dq, 1H,
J¼8.0, 7.0 Hz), 2.49 (dq, 1H, J¼8.0, 7.0 Hz), 2.72 (br s,1H), 3.8–3.9 (m,
2H), 3.9–4.1 (m, 2H), 4.0–4.2 (m, 3H), 4.9–5.1 (m, 1H); 13C NMR
CDCl3)
d
ꢀ1.6 (3C), 13.3, 17.2, 22.2, 23.2, 24.5, 28.6, 30.7, 41.7, 45.3,
46.3, 62.6, 66.9, 77.1, 80.9, 174.8; IR (film) 3443, 2957, 2870, 1732,
1464, 1413, 1384, 1367, 1334, 1251, 1216, 1164, 1116, 1066, 938, 858,
838, 762, 694. Anal. Calcd for C18H36O4Si: C, 62.74; H, 10.53. Found:
C, 62.44; H, 10.44.
(100 MHz, CDCl3)
d
ꢀ1.5 (3C), 13.1, 13.2, 17.2, 22.1, 22.3, 23.1, 23.2,
24.5, 24.5, 28.2, 28.5, 30.7, 31.4, 41.3, 41.6, 43.8, 45.3, 45.4, 46.4, 62.4,
66.9, 71.3, 76.5, 77.0, 80.1, 80.7, 174.2, 174.9; IR (film) 3520, 2956,
2870, 1732, 1464, 1384, 1368, 1336, 1251, 1189, 1167, 1062, 946, 901,
860, 838, 762, 694. Anal. Calcd for C31H58O7Si: C, 65.22; H, 10.24.
Found: C, 65.41; H, 10.41.
4.17. Dimer 26
To a stirred solution of acid (þ)-23 (139 mg, 0.42 mmol), alcohol
25 (143 mg, 0.42 mmol), and DMAP (13 mg, 0.10 mmol) in CH2Cl2
(2 mL) was added slowly, at ꢀ10 ꢁC, a solution of DCC (90 mg,
0.44 mmol) in CH2Cl2 (0.4 mL). The mixture was allowed to warm
up to room temperature and stirred overnight, then concentrated.
The residue was taken up with Et2O, filtered, and concentrated.
4.20. Tetramer 29
To a solution of acid 27 (116 mg, 0.20 mmol) and Et3N (64
0.46 mmol) in THF (2.4 mL) was added, at room temperature, 2,4,6-
trichlorobenzoyl chloride (53 L, 0.34 mmol). The mixture was
mL,
Flash chromatography (cyclohexane/AcOEt, 9/1) afforded the dimer
m
20
26 as a colorless oil (196 mg, 72%). [
a
]
¼þ15.3 (c 0.8, CHCl3); 1H
stirred at room temperature for 2 h. The white precipitate was fil-
tered off under argon and washed with THF. The filtrate was
evaporated under reduced pressure. The residue was diluted with
CH2Cl2 (7 mL) and DMAP (73 mg, 0.60 mmol) was added at room
temperature, followed by a solution of the alcohol 28 (92 mg,
0.16 mmol) in CH2Cl2 (2 mL). The resulting mixture was stirred
overnight at room temperature, then quenched by adding a satu-
rated solution of NH4Cl. The aqueous layer was extracted twice with
CH2Cl2 and the combined organic extracts were dried (MgSO4) and
concentrated. The residue was purified by flash chromatography
D
NMR (400 MHz, CDCl3)
d
0.0–0.1 (m, 9H), 0.87, 0.89, 0.90 (3d, re-
spectively, 3H, 6H, 3H, J1¼J2¼J3¼6.6 Hz), 0.9–1.1 (m, 2H), 1.07, 1.09
(2d, 6H, J1¼J2¼7.1 Hz), 1.27 (ddd, 1H, J¼13.5, 7.4, 5.9 Hz), 1.37 (ddd,
1H, J¼13.5, 8.3, 4.6 Hz), 1.4–1.9 (m, 12H), 1.8–2.1 (m, 4H), 2.47 (dq,
1H, J¼7.9, 7.1 Hz), 2.50 (dq, 1H, J¼7.8, 7.1 Hz), 3.5–3.7 (m, 1H), 3.8–
3.9 (m,1H), 3.9–4.1 (m, 3H), 4.1–4.2 (m, 2H), 4.51 (s, 2H), 4.9–5.1 (m,
1H), 7.2–7.4 (m, 5H); 13C NMR (100 MHz, CDCl3)
d
ꢀ1.5 (3C), 13.1
(2C), 17.3, 22.2, 22.8, 23.1 (2C), 24.5, 24.6, 28.3 (2C), 31.4, 31.6, 41.3,
41.7, 43.8, 44.4, 45.3, 45.6, 62.5, 71.1, 71.5, 75.4, 76.4, 76.7, 80.0, 80.1,
127.3, 127.8 (2C), 128.2 (2C), 139.0, 174.3, 174.9; IR (film) 3087, 3063,
3030, 2956, 2872, 1946, 1866, 1737, 1606, 1496, 1462, 1382, 1366,
1333, 1252, 1188, 1165, 1065, 943, 901, 859, 838, 738, 697. Anal.
Calcd for C38H64O7Si: C, 69.05; H, 9.76. Found: C, 69.36; H, 9.99.
(CH2Cl2/AcOEt, 9/1 then CH2Cl2/MeOH, 98/2) to give the tetramer
29 as a colorless oil (161 mg, 90%). [
NMR (400 MHz, CDCl3)
20
a
]
¼þ7.8 (c 1.0, CHCl3); 1H
D
d
0.0–0.1 (m, 9H), 0.87, 0.89, 0.90 (3d, re-
spectively, 9H, 9H, 6H, J1¼J2¼J3¼6.6 Hz), 0.9–1.1 (m, 2H), 1.05, 1.06,
1.08, 1.09 (4d, 12H, J1¼J2¼J3¼J4¼7.1 Hz), 1.1–1.4 (m, 4H), 1.4–2.0 (m,
32H), 2.4–2.6 (m, 4H), 3.5–3.7 (m, 1H), 3.7–3.9 (m, 3H), 3.9–4.1 (m,
5H), 4.1–4.2 (m, 2H), 4.50 (s, 2H), 4.9–5.1 (m, 3H), 7.2–7.4 (m, 5H);
4.18. Dimer 27
To a solution of the ester 26 (139 mg, 0.21 mmol) in THF
13C NMR (100 MHz, CDCl3)
d
ꢀ1.6 (3C), 12.7, 12.8, 13.0 (2C),17.1, 22.1,
(1 mL) was added, at 0 ꢁC, a 1 M solution of TBAF in THF (630
m
L,
22.2, 22.2, 22.8, 23.0, 23.0, 23.0, 23.0, 24.4 (3C), 24.5, 27.9, 28.0, 28.2
(2C), 31.3, 31.4 (2C), 31.5, 41.1, 41.1, 41.2, 41.6, 43.7 (3C), 44.3, 45.1,
45.1, 45.3, 45.6, 62.3, 70.8, 70.9, 71.0, 71.4, 75.3, 76.3, 76.5, 76.5, 76.6,
0.63 mmol). The mixture was stirred at 0 ꢁC for 2 h and at room
temperature overnight, then diluted with Et2O (5 mL) and brine

L. Coutable et al. / Tetrahedron 64 (2008) 11296–11303
11303
79.6, 79.7, 79.8, 80.0, 127.2, 127.6 (2C), 128.1 (2C), 138.8, 174.0, 174.1,
174.1, 174.8; IR (film) 3088, 3064, 3030, 2955, 2871, 1946, 1864,
1732, 1497, 1463, 1378, 1368, 1337, 1251, 1189, 1167, 1062, 945, 903,
859, 838, 736, 697. Anal. Calcd for C64H108O13Si: C, 69.03; H, 9.78.
Found: C, 68.93; H, 9.73.
was stirred at the same temperature overnight, then the solids
were filtered off and washed with CH2Cl2. The filtrate was washed
with dilute HCl, aqueous NaHCO3, and brine before being dried
(MgSO4). After removal of the solvent, the residue was chromato-
graphed (cyclohexane/AcOEt, 7/3) to give the macrotetrolide 32 as
20
a colorless oil (45 mg, 60%). [
a
]
¼0.0 (c 1.0, CHCl3); 1H NMR
D
4.21. Tetramer 30
(400 MHz, CDCl3) d 0.88, 0.90 (2d, respectively, 12H, 12H,
J1¼J2¼6.6 Hz), 1.07 (d, 12H, J¼7.0 Hz), 1.31 (ddd, 4H, J¼13.6, 8.2,
4.9 Hz), 1.4–1.7 (m, 16H), 1.69 (ddd, 4H, J¼13.7, 6.8, 6.8 Hz), 1.77
(ddd, 4H, J¼13.7, 6.5, 5.8 Hz), 1.8–2.0 (m, 4H), 1.9–2.1 (m, 4H), 2.56
(dq, 4H, J¼7.2, 7.0 Hz), 3.82 (dddd, 4H, J¼6.7, 6.7, 6.7, 6.7 Hz), 4.04
(ddd, 4H, J¼7.2, 7.2, 7.0 Hz), 4.98 (dddd, 4H, J¼7.8, 7.8, 5.4, 5.4 Hz);
To a solution of the ester 29 (155 mg, 0.14 mmol) in THF (1.5 mL)
was added, at 0 ꢁC, a 1 M solution of TBAF in THF (418
mL,
0.42 mmol). The mixture was stirred at 0 ꢁC for 2 h and at room
temperature overnight, then diluted with Et2O (5 mL) and brine
(5 mL). The phases were separated and the organic layer was dried
(MgSO4) and concentrated. The residue was purified by flash
13C NMR (100 MHz, CDCl3)
d 12.5 (4C), 22.3 (4C), 23.0 (4C), 24.6
(4C), 27.8 (4C), 31.3 (4C), 40.8 (4C), 43.6 (4C), 44.6 (4C), 70.6 (4C),
76.1 (4C), 79.6 (4C), 174.4 (4C); IR (film) 2956, 2871, 1732, 1463,
1369, 1337, 1264, 1191, 1166, 1141, 1059; HRMS (FD) m/z [M]þ Calcd
for C52H88O12: 904.6276, found: 904.6335.
chromatography (cyclohexane/AcOEt, 8/2þAcOH, 1%) to give the
20
acid 30 as a colorless oil (135 mg, 96%). [
a]
¼þ8.2 (c 1.0, CHCl3); 1H
D
NMR (400 MHz, CDCl3) d 0.87, 0.88, 0.89, 0.89 (4d, respectively, 9H,
3H, 9H, 3H, J1¼J2¼J3¼J4¼6.7 Hz), 1.05, 1.07, 1.09 (3d, 9H,
J1¼J2¼J3¼7.1 Hz), 1.14 (d, 3H, J¼7.1 Hz), 1.1–1.4 (m, 4H), 1.4–2.1 (m,
32H), 2.4–2.6 (m, 4H), 3.5–3.7 (m, 1H), 3.7–3.9 (m, 2H), 3.9–4.1 (m,
6H), 4.50 (s, 2H), 4.9–5.1 (m, 3H), 7.2–7.4 (m, 5H); 13C NMR
Acknowledgements
The authors thank the CNRS for financial support and the
(100 MHz, CDCl3)
d 12.7, 13.0, 13.0 (2C), 22.0, 22.2 (2C), 22.8, 23.0,
`
Ministere de la Recherche for L.C. graduate fellowship.
23.0, 23.0, 23.0, 24.4 (3C), 24.5, 27.9, 28.1, 28.2, 28.7, 31.2, 31.3, 31.4,
31.5, 41.1, 41.1 (2C), 41.6, 43.6, 43.7 (2C), 44.3, 44.8, 45.1, 45.2, 45.6,
70.7, 70.9, 70.9, 71.4, 75.4, 76.4, 76.5, 76.5, 76.9, 79.6, 79.8, 79.9 (2C),
127.3, 127.7 (2C), 128.2 (2C), 138.8, 174.1, 174.2, 174.3, 178.3; IR (film)
3700–2200, 3089, 3064, 3030, 2955, 2871, 1732, 1463, 1368, 1261,
1191, 1168, 1142, 1063, 1029, 946, 904, 736, 698. Anal. Calcd for
C59H96O13: C, 69.93; H, 9.55. Found: C, 69.72; H, 9.29.
References and notes
ˇ
ꢀ
1. Zizka, Z. Folia Microbiol. 1998, 43, 7.
2. (a) Gerlach, H.; Oertle, K.; Thalmann, A.; Servi, S. Helv. Chim. Acta 1975, 58,
2036; (b) Schmidt, U.; Gombos, J.; Haslinger, E.; Zak, H. Chem. Ber. 1976, 109,
2628; (c) Bartlett, P. A.; Meadows, J. D.; Ottow, E. J. Am. Chem. Soc. 1984, 106,
5304; (d) Fleming, I.; Ghosh, S. K. J. Chem. Soc., Chem. Commun. 1994, 2287; (e)
Lee, J. Y.; Kim, B. H. Tetrahedron 1996, 52, 571; (f) Wu, Y.; Sun, Y.-P. Org. Lett.
2006, 8, 2831 For a comprehensive review, see: (g) Fleming, I.; Ghosh, S. K. Stud.
Nat. Prod. Chem. 1996, 18, 229.
3. Hanadate, T.; Kiyota, H.; Oritani, T. Biosci. Biotechnol. Biochem. 2001, 65, 2118.
4. (a) Bu¨hlmann, P.; Pretsch, E.; Bakker, E. Chem. Rev. 1998, 98, 1593; (b) Garcia, C.
A. B.; Ju´ nior, L. R.; Neto, G. O. J. Pharm. Biomed. Anal. 2003, 31, 11.
5. (a) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi, H.;
Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856; (b) Noyori, R.; Ohkuma, T.
Angew. Chem., Int. Ed. 2001, 40, 40.
6. (a) Baraldi, P. T.; Zarbin, P. H. G.; Vieira, P. C.; Correa, A. G. Tetrahedron: Asym-
metry 2002, 13, 621; (b) Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. M. Tetra-
hedron 2004, 60, 7345.
7. Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett. 1988, 29, 4139.
8. Enders, D.; von Berg, S.; Jandeleit, B. Org. Synth., Coll. Vol. 10 2004, 66; Org.
Synth. 2002, 78, 177.
9. Keck, G. E.; Castellino, S.; Wiley, M. R. J. Org. Chem. 1986, 51, 5480 and references
therein.
10. Rychnovsky, S. D.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103, 3963.
11. White, J. D.; Wang, G.; Quaranta, L. Org. Lett. 2003, 5, 4109.
12. Suenaga, K.; Araki, K.; Sengoku, T.; Uemura, D. Org. Lett. 2001, 3, 527.
13. Guindon, Y.; Soucy, F.; Yoakim, C.; Ogilvie, W. W.; Plamondon, L. J. Org. Chem.
2001, 66, 8992.
14. Miura, A.; Kiyota, H.; Kuwahara, S. Tetrahedron 2005, 61, 1061.
15. Guindon, Y.; Lavalle´e, J.-F.; Boisvert, L.; Chabot, C.; Delorme, D.; Yoakim, C.; Hall,
D.; Lemieux, R.; Simoneau, B. Tetrahedron Lett. 1991, 32, 27.
16. Shimizu, H.; Nagasaki, I.; Saito, T. Tetrahedron 2005, 61, 5405.
17. Duthaler, R. O.; Herold, P.; Lottenbach, W.; Oertle, K.; Riediker, M. Angew. Chem.,
Int. Ed. Engl. 1989, 28, 495.
4.22. Tetramer 31
A mixture of the ether 30 (125 mg, 0.12 mmol) and 10% palla-
dium on charcoal (30 mg) in MeOH (1.5 mL) was stirred for 4 h at
room temperature under H2 (1 atm). The solid was filtered off and
washed with AcOEt. The filtrate was evaporated under reduced
pressure. The residue was purified by flash chromatography (cy-
clohexane/AcOEt, 1/1 then cyclohexane/AcOEt, 1/2þAcOH, 1%) to
ˆ
20
give the hydroxy acid 31 as a colorless oil (82 mg, 72%). [
a
]
D
¼ꢀ11.0
(c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3)
d 0.86, 0.88, 0.88, 0.89 (4d,
respectively, 9H, 6H, 3H, 6H, J1¼J2¼J3¼J4¼6.7 Hz), 1.05, 1.06, 1.08
(3d, 9H, J1¼J2¼J3¼7.1 Hz), 1.13 (d, 3H, J¼7.1 Hz), 1.18 (ddd, 1H,
J¼13.6, 8.6, 3.2 Hz), 1.2–1.4 (m, 3H), 1.4–2.1 (m, 32H), 2.4–2.6 (m,
4H), 3.7–4.1 (m, 8H), 4.1–4.2 (m, 1H), 4.9–5.1 (m, 3H); 13C NMR
(100 MHz, CDCl3)
d 12.7, 13.0, 13.0, 13.2, 22.0, 22.1, 22.2, 22.3, 23.0
(2C), 23.0, 23.2, 24.5 (4C), 27.9, 28.1, 28.4, 28.6, 30.7, 31.2, 31.3, 31.4,
41.1, 41.1 (2C), 41.6, 43.7, 43.7, 43.7, 44.9, 45.1, 45.2, 45.4, 46.3, 66.9,
70.8, 70.9, 71.0, 76.4, 76.5, 76.8, 76.9, 79.7, 79.9, 79.9, 80.7, 174.2,
174.2, 174.4, 178.3; IR (film) 3700–2200, 2955, 2870, 1732, 1464,
1367, 1261, 1192, 1167, 1067, 902, 737, 696. Anal. Calcd for
C52H90O13$0.54H2O: C, 66.94; H, 9.72. Found: C, 66.94; H, 9.45.
18. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991,
113, 4092.
4.23. Macrotetrolide 32
19. Sieber, P. Helv. Chim. Acta 1977, 60, 2711; Gerlach, H. Helv. Chim. Acta 1977, 60,
3039.
20. Bourne, G. T.; Horwell, D. C.; Pritchard, M. C. Tetrahedron 1991, 47, 4763.
21. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989.
To a mixture of hydroxy acid 31 (77 mg, 0.08 mmol), DMAP
(69 mg, 0.57 mmol), and powered/activated molecular sieves (4 Å,
2.12 g) in CH2Cl2 (40 mL) was added slowly, at room temperature,
2,4,6-trichlorobenzoyl chloride (22
mL, 0.14 mmol). The mixture
22. Hikota, M.; Sakurai, Y.; Horita, K.; Yonemitsu, O. Tetrahedron Lett. 1990, 31, 6367.