The asymmetric total synthesis of cinbotolide: A revision of the original structure

Article abstract of DOI:10.1021/jo501471m

The structure 3,4-dihydroxy-2,4,6,8-tetramethyldec-8-enolide (1) was assigned to a metabolite of Botrytis cinerea, but the spectra of several synthetic analogues had significant differences from that of 1. Examination of the constituents of a B. cinerea mutant that overproduces polyketides gave sufficient quantities of 1, now named cinbotolide, for chemical transformations. These led to a revised γ-butyrolactone structure for the metabolite. This structure has been confirmed by an asymmetric total synthesis, which also established its absolute configuration.

Full text of DOI:10.1021/jo501471m

Article
pubs.acs.org/joc
The Asymmetric Total Synthesis of Cinbotolide: A Revision of the
Original Structure
†
†
chez, James R . Hanson,‡
†
Jose
́
Manuel Botubol, María Jesus
́
Duran
́
-Pen
̃
a, Antonio J. Macías-San
́
†
,†
Isidro G. Collado, and Rosario Hernan
́
dez-Galan*
́
†
Departamento de Química Organ
iz, 11510 Puerto Real, Cad
Department of Chemistry, University of Sussex, Brighton, Sussex, BN1 9QJ, United Kingdom
́
ica, Facultad de Ciencias, Instituto de Biomolec
́
ulas, Campus Universitario Rio San Pedro s/n,
Universidad de Cad
‡
́
́
iz, Spain
*
S Supporting Information
ABSTRACT: The structure 3,4-dihydroxy-2,4,6,8-tetramethyldec-8-enolide
1) was assigned to a metabolite of Botrytis cinerea, but the spectra of several
(
synthetic analogues had significant differences from that of 1. Examination of
the constituents of a B. cinerea mutant that overproduces polyketides gave
sufficient quantities of 1, now named cinbotolide, for chemical trans-
formations. These led to a revised γ-butyrolactone structure for the
metabolite. This structure has been confirmed by an asymmetric total
synthesis, which also established its absolute configuration.
INTRODUCTION
Botrytis cinerea is a well-known phytopathogen that forms a
damaging gray mold on a large number of commercial crops.
HMBC heteronuclear correlations. However, in the light of our
■
synthetic work with the analogues, a significant observation was
the absence of a three-bond through-oxygen HMBC correlation
for the OCOCH system in the natural product. This
led us to consider an alternative γ-butyrolactone structure 3 for
1
Numerous metabolites have been isolated from this fungu-
2
−4
s. Among these 1 was a polyketide for which the structure5
8
3
,4-dihydroxy-2,4,6,8-tetramethyldec-8-enolide was proposed.
cinbotolide. This lactone might arise by a biosynthetic ring
However, 11-membered lactones are rare, and there are only a
few examples that have been found in nature.
In the context of our interest in the metabolites of B. cinerea,
we have recently attempted to verify the structure of 1 by
means of a total synthesis. We obtained several analogues of
this structure, among them the (Z)-isomer 2 containing a
MOM protecting group (Figure 1). However, the spectroscopic
closure of a putative hydroxy-acid precursor involving the
nucleophilic attack of a hydroxyl group at C-4 on the terminal
carboxylic acid. The γ-butyrolactone would be thermodynami-
cally more stable than the 11-membered lactone.
6
RESULTS AND DISCUSSION
■
Acetylation of cinbotolide 1 under standard conditions
quantitatively afforded a diacetate 4 (Scheme 1). The chemical
shifted observed for signals assigned to H-10 and the HMBC
correlation between the signals assigned to H-10 and H-3 and
those assigned to the carbonyl groups of the acetates indicated
that the free hydroxyl groups were located at C-3 and C-10
(
Figure 2) and are incompatible with the original structure. The
Figure 1. Structures of compounds 1 and 2.
IR spectrum of the diacetate had carbonyl absorption at 1775
and 1740 cm− corresponding to the presence of a γ-
butyrolactone and acetate esters. Although cinbotolide itself
had IR absorption at 1748 cm which is rather low for a γ-
butyrolactone, this might be affected by hydrogen bonding
from the hydroxyl group at C-3. Treatment of cinbotolide
with p-bromobenzoyl chloride gave a mono-p-bromobenzoate
5
1
data of these analogues had significant differences from those
reported for the natural product, which suggested that its
−1
7
,8
structure should be revised. In the literature there are a
9
−15
number of precedents for corrections
medium-sized lactones.
to the structures of
16
The study of a mutant of B. cinerea, bcbot4, which
overproduces polyketides including this metabolite, which we
have now named cinbotolide, gave sufficient material for us to
carry out simple chemical transformations to clarify its
structure. The carbon framework of cinbotolide had been
and di-p-bromobenzoate 6 (Scheme 1) for which similar IR
and results were obtained (Scheme 1).
Received: July 2, 2014
5
unequivocally established on the basis of the HSQC and
©
XXXX American Chemical Society
A
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The Journal of Organic Chemistry
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Scheme 1. Synthesis of Compounds 4−7
Scheme 2. Retrosynthetic Route for the Synthesis of 3
asymmetric aldol reaction and lactonization, would then
provide, separately, both C-6 epimers of cinbotolide.
First the carboxylic acid 10 was prepared following the
synthetic route shown in Scheme 3 using the inexpensive
Scheme 3. Synthesis of Carboxylic Acid 10
Figure 2. Key HMBC and NOE correlations for 4.
geraniol as a starting material. The hydroxyl group of geraniol
was protected using MOMCl to afford compound 11 which
was then subjected to a chemoselective epoxidation with m-
CPBA at low temperature to give the epoxide 12 in 83% yield.
This compound was transformed into the intermediate
In the NMR spectra of compound 4, there were NOE
interactions between H-2, H-3 and C4-Me (Figure 2) that
supported the relative configuration of the ring as 2R*,3S*,4S*.
17
Riguera’s variable-temperature NMR method was used to
determine the absolute configuration at C-3. Esterification of
compound 5 with (R)-MPA ((R)-methoxyphenylacetic acid)
afforded compound 7 in 76% yield. The variable-temperature
carboxylic acid 10 by HIO hydrolysis of the epoxide followed
4
by the subsequent cleavage of the diol, to generate the aldehyde
13. Further oxidation with Jones’s reagent gave 10 in an overall
1
1 2
T T
H NMR analysis of 7 revealed a negative Δδ value for H-5′
yield of 82% from 12.
and a positive value for the C2-Me (Figure 3), which indicated
The enantioselective methylation of the carboxylic acid 10 in
which the primary alcohol was protected as its benzyl ether, has
been previously described by Zhou et al. in the synthesis of
1
8
(
−)-kazusamycin A. Following this procedure, compound 10
was converted to the amide 14 using the oxazolidinone (S)-15
in 78% yield (Scheme 4). Enantioselective methylation with
18−20
21
MeI afforded
compound 9 in 74% yield and 92% de.
1 2
T T
Figure 3. Chemical shifts differences, Δδ
C), for H-5a′ and C2-Me protons.
(T = 25 °C, T = −60
This produced the “S” stereochemistry for the methyl group at
C-6 according to the empirical rule generally accepted.
1
2
19
°
Reductive cleavage of the oxazolidinone with NaBH gave
4
the alcohol 16 in 93% yield. This was subjected to a one-pot
oxidation/olefination using the TEMPO-BAIB system and
a S-configuration for C-3. Together with the NOE effects
observed for compound 4, this supports the absolute
configuration for the ring as 2R,3S,4S, but leaves the
configuration at C-6 undetermined.
In order to confirm the new γ-butyrolactone structure for
cinbotolide and establish the absolute configuration of the
methyl group in the side chain we have carried out an
asymmetric total synthesis of both epimers at C-6. A
retrosynthetic analysis of both C-6 epimers of cinbotolide is
shown in Scheme 2. In this approach the stereochemistry of the
methyl group at C-6 can be effectively controlled through an
amidation of the carboxylic acid 10 using a suitable chiral
auxiliary and subsequent methylation. Conversion of this
compound 9 into the aldehyde 8, followed by an anti
22
(carbethoxyethylidene)triphenyl phosphorane to stereoselec-
tively produce the ester 17 in good yield. Reduction of the ester
group with DIBAL and subsequent Sharpless asymmetric
2
3−25
epoxidation with (−)-DIT
afforded the epoxide 19a in
21
78% yield and 80% de. Reductive cleavage of the latter with
LiAlH gave rise to the diol 20a with the correct stereo-
4
chemistry at the C-4 position of the natural product. Sequential
protection of the primary and tertiary hydroxyl groups with
TBS and MOM respectively followed by desilylation and
oxidation with PCC, afforded the aldehyde 8a in good overall
yield (Scheme 4).
Condensation of the aldehyde 8a with the appropriate
oxazolidinone (Scheme 5) by the procedure reported by
B
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Article
Scheme 4. Preparation of Aldehyde 8a
1
Scheme 5. Synthesis of 3a
Table 1. H NMR Spectroscopic Differences between 3a and
3
a
entry
protons
3a
3
1
2
3
4
5
6
7
H-5a
H-5b
6-Me
H-7a
H-7b
H-10a
H-10b
1.70 (dd, J 14.5, 3.5)
1.64 (dd, J 14.5, 8.5)
1.00 (d, J 6.5)
1.93−1.85 (m)
1.55 (dd, J 15.8, 8.0)
0.96 (d, J 6.2)
2.01 (dd, J 13.5, 7.0)
1.96 (dd, J 13.5, 7.0)
4.16 (d, J 7.0)
2.15 (dd, J 12.2, 5.2)
1.93−1.85 (m)
4.17 (dd, J 12.0, 7.0)
4.12 (dd, J 12.0, 7.0)
a
δH in ppm, J in Hz.
2
6,27
Evans,
afforded via methanolysis of the silyloxy derivative,
21
Scheme 6. Synthesis of Compound 3b
the anti-aldol product 24a in 67% yield and 95% de. Finally,
although several sets of conditions were examined for the
removal of the MOM protecting groups, the γ-butyrolactone 3a
was only obtained in low yield when the deprotection was
28
carried out using p-TsOH in methanol.
Efforts to improve the yield in the deprotection/lactonization
reaction were not continued because this lactone showed slight
differences in its NMR data when compared to those reported
for cinbotolide. This applied especially to the H-5 and H-7
protons resonances while the H-10 protons appeared as a two-
proton doublet while in cinbotolide they were resolved into two
separate doublet of doublets (Table 1).
At this point, we carried out the synthesis of the
corresponding epimer at C-6 following a similar synthetic
strategy to that described in Schemes 4 and 5. The adduct ent-9
was prepared in good yield and de from the carboxylic acid 10
by amidation with (R)-15 and enantioselective methylation
1
9
with MeI. Compound ent-9 was converted to compound 24b
in good overall yield following the route outlined in Scheme 6.
In order to confirm the absolute stereochemistry of the alcohol
group at C-3, we carried out different attempts to obtain the
MPA or MPTA ester in the hydroxyl group at C-3 for the
C
dx.doi.org/10.1021/jo501471m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
synthesized compounds 24a,b. All of them were unsuccessful
indicating an important steric congestion around C3. At this
point, methanolysis of the oxazolidinone group by treatment
with sodium methoxide, yielded the methyl ester 26b (Scheme
coated with silica gel with fluorescent indicator (254 nm), 0.25 mm
thick. Specific rotations were determined with a digital polarimeter.
Infrared spectra were recorded on a FT-IR spectrophotometer and
peak position reported in wavenumbers (cm ). H and C NMR
measurements were recorded on 400, 500, and 600 MHz
−1
1
13
6
). Although, the MPA ester could not be obtained again, the
spectrometers with SiMe as the internal reference. Chemical shifts
4
relative anti stereochemistry of the aldol adduct 24b was
are reported in parts per million (ppm) and were referenced to CDCl3
determined according to the method of Heathcock on the ester
(
δH 7.25, δC 77.0), CD Cl (δ 5.32, δC 54.0), C D (δ 7.16, δC
2 2 H 6 6 H
2
9
2
6b. Different reaction conditions were then evaluated in
1
28.4) and acetone-d (δH 2.09, δC 29.0). NMR assignments were
6
order to increase the yield in the deprotection of the MOM
made using a combination of 1D and 2D techniques. Multiplicities are
described using the following abbreviations: s = singlet, d = doublet, t
= triplet, q = quarter; quint = quintuplet; sext = sextuplet; m =
multiplet, br = broad. High-resolution mass spectroscopy (HRMS)
was recorded with a double-focusing magnetic sector mass
spectrometer in positive ion mode, or in a QTOF mass spectrometer
in positive ion electrospray mode at 20 V cone voltage or in positive
ion APCI mode.
30
ethers and subsequent lactonization. When PPTS in refluxing
t-BuOH was used, the γ-butyrolactone 3b was obtained in 65%
yield. The spectroscopic data for compound 3b were identical
5
with those reported for cinbotolide. Since the optical rotation
of the natural product had not been reported previously, the
synthetic lactone was converted to its diacetate whose optical
rotation showed the same sign and magnitude as 4 (−10.3°, c =
Acetylation of Natural Product 1. Pyridine (2 drops) was added
to a solution of natural product 1 (3.0 mg, 0.01 mmol) in acetic
anhydride (0.5 mL) at 0 °C and stirred at room temperature for 18 h.
Then, cyclohexane was added (2 mL), and the solvent was evaporated
under reduced pressure. This procedure was repeated three times to
give quantitatively (3R,4S,5S,2′R,4′E)-4-acetoxy-5-(6-acetoxy-2,4-di-
methylhex-4-enyl)-3,5-dimethyl-4,5-dihydrofuran-2(3H)-one (4) (3.4
mg, 100%). Yellow oil: [α]D20 −10.3° (c 0.30, CHCl ); IR (film) ν
0
.30, CHCl ).
3
Additionally the absolute configuration of alcohol group at
C-3, was confirmed by esterification of 3a and 3b with (R)-
MPA afforded compounds 27a and 27b respectively. The
1
Riguera variable-temperature H NMR analysis of both
1
7
1 2
T T
compounds indicated a negative Δδ
value for H-5′ and
3
max
a positive value for the C2-Me (Scheme 7), which confirmed an
S-configuration for C-3. NOE experiments supported the
absolute configuration for the carbons C2−C4 as 2R,3S,4S.
−
1 1
2
945, 1775, 1740, 1455, 1374, 1223, 1087, 1022, 990, 939 cm ; H
NMR (400 MHz, C D ) δ 5.36 (t, J = 6.8 Hz, 1H), 4.97 (d, J = 5.8 Hz,
6
6
1
1
H), 4.58 (d, J = 6.8 Hz, 2H), 2.32 (dq, J = 6.8, 5.8 Hz, 1H), 2.14 (m,
H), 1.71 (s, 3H), 1.68−1.61 (m, 3H), 1.59 (s, 3H), 1.48 (s, 3H), 1.26
Scheme 7. Synthesis of Compounds 27a,b and Chemical
(dd, J = 14.0, 5.2 Hz, 1H), 0.99 (d, J = 6.8 Hz, 3H), 0.82 (s, 3H), 0.69
T
1
T
2
13
Shifts Differences, Δδ
(T = 25 °C, T = −80 °C), for H-
(d, J = 6.0 Hz, 3H); C NMR (100 MHz, C D ) δ 175.2, 170.1, 169.2,
1
2
6 6
5
a′ and C2-Me Protons
140.2, 121.5, 85.0, 77.0, 61.0, 48.1, 41.0, 38.5, 26.5, 22.6, 21.1, 20.5,
+
+
1
9.8, 16.0, 8.8; HRMS (ESI ) calcd for C H O Na [M + Na]
18 28 6
3
63.1784, found 363.1795.
p-Bromobenzoylation of 3. To a stirred solution of 3 (4.0 mg,
0
.016 mmol) in dry pyridine (0.8 mL) were added p-bromobenzoyl
chloride (14.0 mg, 0.064 mmol) and DMAP (20.0 mg, 0.031 mmol).
The reaction mixture was stirred at room temperature for 12 h and was
then neutralized by addition of 1 N HCl. The mixture was extracted
with CH Cl (3 × 5 mL), washed with H O (10 mL), dried over
2
2
2
anhydrous Na SO , filtered, and evaporated under reduced pressure to
2
4
give a crude product that was purified by silica gel column
chromatography. Elution with petroleum ether:ethyl acetate (80:20)
yielded the compound 5 (1.8 mg, 26%) and 6 (4.6 mg, 48%).
(
3R,4S,5S,2′R,4′E)-5-[6-(p-Bromobenzoyloxy)-2,4-dimethyl-
hex-4-enoyl]-4-hydroxy-3,5-dimehtyldihydrofuran-2(3H)-one
(
5). Amorphous solid: [α]D20 +4.3° (c 0.1, CH OH); IR (film) υ
542, 2925, 1772, 1718, 1589, 1456, 1100, 1011, 757 cm ; H NMR
3
max
−1 1
3
CONCLUSIONS
■
(500 MHz, CD COCD ) δ 7.94 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.8
Hz, 2H), 5.50 (tq, J = 6.8, 1.2 Hz, 1H), 4.85 (d, J = 6.8, 2H), 4.44 (d, J
= 5.6 Hz, OH), 4.13 (t, J = 5.6 Hz, 1H), 3.04 (dq, J = 7.2, 5.6 Hz, 1H),
3 3
The synthesis of the derivatives 4−7 of cinbotolide have led us
to correct the previously published structure to that of the γ-
butyrolactone 3b. This structure has been confirmed by an
asymmetric total synthesis of the two possible epimers at C-6
involving a 16-step synthetic sequence from geraniol. This has
established the absolute stereochemistry of cinbotolide as
2
.35 (dd, J = 13.2, 5.2 Hz, 1H), 1.99 (m, 1H), 1.85 (dd, J = 13.2, 9.3
Hz, 1H), 1.83 (dd, J = 14.4, 6.2 Hz, 1H), 1.79 (d, J = 1.2 Hz, 3H), 1.70
(
(
dd, J = 14.4, 6.4 Hz, 1H), 1.38 (s, 3H), 1.14 (d, J = 7.2 Hz, 3H), 0.94
d, J = 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl ) δ 178.1, 166.1,
3
1
4
42.5, 132.8 (2C), 132.1 (2C), 130.7, 128.2, 121.1, 88.1, 76.6, 62.5,
2
R,3S,4S,6R.
+
9.0, 42.0, 40.6, 27.5, 23.0, 21.3, 16.4, 9.0; HRMS (APCI ) calcd for
+
C H O BrNa [M + Na] 461.0940, found 461.0933.
21
27
5
EXPERIMENTAL SECTION
General Experimental Methods. Unless otherwise noted,
materials and reagents were obtained from commercial suppliers and
were used without further purification. Dichloromethane, ethyl acetate
■
(3R,4S,5S,2′R,4′E)-4-(p-Bromobenzoyloxy)-5-[6-(p-bromo-
benzoyloxy)-2,4-dimethylhex-4-enoyl]-3,5-dimehtyldihydro-
2
0
furan-2(3H)-one (6). Amorphous solid: [α]
CHCl ); IR (film) υmax 2925, 1771, 1718, 1590, 1458, 1268, 1172,
1099, 1011, 757; H NMR (500 MHz, CD
−12.5° (c 0.24,
D
3
1
and triethylamine were freshly distilled from CaH and tetrahydrofur-
COCD ) δ 8.00 (d, J = 8.8
3 3
2
an was dried over sodium and benzophenone and freshly distilled
before use. Air- and moisture-sensitive reactions were performed under
an argon atmosphere. Purification by semipreparative and analytical
HPLC was performed, respectively, with 250 mm × 10 mm (10 μm
particles) and 250 mm × 4 mm (5 μm particles) columns using a
differential refractometer detector. Silica gel was used for column
chromatography. TLC analyses were performed on aluminum plates
Hz, 2Harom), 7.92 (d, J = 8.8 Hz, 2Harom), 7.75 (d, J = 8.8 Hz,
2Harom), 7.70 (d, J = 8.8 Hz, 2Harom), 5.67 (d, J = 5.8, 1H), 5.44 (tq,
J = 6.8, 1.2 Hz, 1H), 4.85 (dd, J = 12.1, 6.8 Hz, 1H), 4.81 (dd, J = 12.1,
6.8 Hz, 1H), 3.48 (dq, J = 7.2, 5.8 Hz, 1H), 2.24 (dd, J = 12.5, 5.5 Hz,
1H), 2.01 (m, 1H), 1.90−1.84 (m, 2H), 1.77 (d, J = 1.2 Hz, 3H), 1.64
(dd, J = 14.5, 6.7 Hz, 1H), 1.29 (s, 3H), 1.08 (d, J = 7.2 Hz, 3H), 0.82
(d, J = 6.4 Hz, 3H); 13C NMR (125 MHz, CD COCD ) δ 176.6,
3
3
D
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Article
1
1
2
66.1, 165.3, 142.1, 133.1 (2C), 132.8 (2C), 132.3 (2C), 132.1 (2C),
30.7, 129.3, 129.2, 128.2, 121.4, 86.9, 79.0, 62.4, 48.9, 41.7, 39.6, 27.4,
Preparation of (E)-6-(Methoxymethoxy)-4-methylhex-4-enal
(13). A solution of HIO (7260.2 mg, 31.5 mmol) in water (28 mL)
4
+
3.3, 21.5, 16.4, 9.2; HRMS (ESI ) calcd for C H O NaBr [M +
was added to (±)-(E)-6,7-epoxy-1-(methoxymethoxy)-3,7-dimethy-
locta-2,6-diene (12) (6134.7 mg, 28.7 mmol) dissolved in THF (48
mL) at 0 °C and stirred for 20 min. Then, brine was added (35 mL),
and the layers were separated, and the aqueous layer was extracted
with ethyl acetate (3 × 80 mL). The combined organic solution was
washed with saturated sodium bicarbonate (100 mL) and brine (100
mL), dried over anhydrous sodium sulfate and filtered. The solvent
was evaporated under reduced pressure to give quantitatively the
aldehyde 13 (4930.7 mg, 100%), which was used without chromato-
graphic purification. Colorless oil: IR (film) νmax 3433, 2936, 2727,
28
30
6
2
+
Na] 643.0307, found 643.0306.
Preparation of (3R,4S,5S,2′R,4′E)-5-[6-(p-Bromobenzoyloxy)-
2
,4-dimethylhex-4-enoyl]-4-((R)-methoxyphenylacetoxy)-3,5-
dimehtyldihydrofuran-2(3H)-one (7). A mixture of N-(3-
(
dimethylamino)propyl)-N′-ethylcarbodiimide (EDCI) (2.2 mg, 10.2
μmol), N,N′-DMAP (0.18 mg, 1.36 μmol) and (−)-(R)-α-methoxy-α-
phenylacetic acid (MPA) (1.5 mg, 8.16 mmol) in dry CH Cl (0.3
2
2
mL) was stirred for 10 min. To the resulting mixture was added the
compound 5 (3.0 mg, 6.8 μmol) in CH Cl (0.2 mL). After stirring for
1
mL). The crude was sequentially washed with H O (2 mL), twice with
saturated sodium bicarbonate solution (20 mL), H O (2 mL), dried
over anhydrous sodium sulfate, filtered and evaporated under reduced
2
2
−1 1
8 h, the reaction mixture was evaporated and then added Et O (5
1724, 1442, 1387, 1150, 1101, 1040, 920 cm ; H NMR (500 MHz,
CDCl ) δ 9.77 (t, J = 1.4 Hz, 1H), 5.37 (tq, J = 6.8, 1.2 Hz, 1H), 4.61
2
2
3
(s, 2H), 4.06 (d, J = 6.8 Hz, 2H), 3.36 (s, 3H), 2.56 (dt, J = 7.6, 1.4
2
Hz, 2H), 2.36 (t, J = 7.6 Hz, 2H), 1.69 (s, 3H); 13C NMR (100 MHz,
20
pressure to give ester 7 (3.03 mg, 76% yield). Amorphous solid: [α]D
12.5° (c 0.24, CHCl ); IR (film) υ 2925, 1771, 1718, 1590, 1458,
CDCl ) δ 201.9, 138.6, 121.3, 95.6, 63.5, 55.2, 41.8, 31.5, 16.5; HRMS
3
+
+
(
ESI ) calcd for C H O Na [M + Na] 195.0997, found 195.0990.
−
1
9 16 3
3
max
1
Preparation of (E)-6-(Methoxymethoxy)-4-methylhex-4-
268, 1172, 1099, 1011, 757; H NMR (500 MHz, CD Cl ) δ 7.89 (d,
2 2
enoic acid (10). The above aldehyde 13 (5333.0 mg, 31.0 mmol)
was dissolved in acetone (92 mL) and Jones reagent (2.7 M) was
added dropwise at 0 °C until the solution remained orange. The
organic phase was diluted with ethyl acetate (400 mL) and washed
with water (200 mL) until pH = 3. A final washed with brine, dried
J = 8.8 Hz, 2Harom), 7.58 (d, J = 8.8 Hz, 2Harom), 7.41−7.33 (m,
5H), 5.44 (tq, J = 7.0, 1.2 Hz, 1H), 5.27 (d, J = 5.8, 1H), 4.85 (d, J =
7.0 Hz, 1H), 4.76 (s, 1H), 3.40 (s, 3H), 2.91 (dq, J = 7.3, 5.8 Hz, 1H),
2.26 (dd, J = 13.3, 5.3 Hz, 1H), 1.89 (m, 1H), 1.79 (d, J = 1.2 Hz, 3H),
1.78 (dd, J = 13.2, 8.8 Hz, 1H), 1.63 (dd, J = 14.6, 6.2 Hz, 1H), 1.44
over NaSO and evaporation of the solvent under reduced pressure
4
(
(
s, 3H), 1.33 (dd, J = 14.6, 6.0 Hz, 1H), 0.81 (d, J = 6.6 Hz, 3H), 0.71
d, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CD Cl ) δ 176.0, 169.8,
gave the acid 10 (4411.1 mg, 81.9%), which was used without
chromatographic purification for the next step. Colorless oil: IR (film)
2
2
1
1
2
+
65.7, 141.2, 136.0, 131.7 (2C), 131.1 (2C), 129.7, 129.1, 128.7 (2C),
27.8, 127.3 (2C), 120.4, 86.0, 82.6, 77.6, 62.0, 57.4, 47.7, 40.9, 38.6,
6.4, 22.7, 20.6, 16.1, 7.8; HRMS (ESI ) calcd for C H O NaBr [M
−1
ν
3385, 2945, 1734, 1442, 1387, 1206, 1151, 1102, 1036, 946 cm ;
max
1
+
H NMR (500 MHz, CDCl ) δ 5.34 (tq, J = 6.8, 1.4 Hz, 1H), 4.58 (s,
3
30
35
7
+
2H), 4.03 (d, J = 6.8 Hz, 2H), 3.33 (s, 3H), 2.44 (m, 2H), 2.32 (t, J =
Na] 609.1464, found 609.1473.
7
1
.6 Hz, 2H), 1.66 (s, 3H); 13C NMR (125 MHz, CDCl ) δ 178.4,
3
Preparation of (E)-1-(Methoxymethoxy)-3,7-dimethylocta-
,6-diene (11). Chloromethyl methyl ether (MOMCl) (8.2 mL,
09.1 mmol) was added slowly to a mixture stirred of geraniol (8 g,
1.9 mmol), N,N′-diisopropylethylamine (20 mL, 114.3 mmol), N,N′-
+
38.7, 120.9, 95.3, 63.4, 55.1, 33.9, 32.3, 16.2; HRMS (ESI ) calcd for
2
1
5
+
C H O [M + H] 189.1127, found 189.1118.
9
17
4
Preparation of (4S,4′E)-4-Benzyl-3-[6-(methoxymethoxy)-4-
methylhex-4-enoyl]oxazolidin-2-one (14). A round-bottom flask
was flame-dried and charged with (E)-6-(methoxymethoxy)-4-
dimethylaminepyridine (1269 mg, 10.4 mmol) in dry CH Cl (250
2
2
mL) at 0 °C under an argon atmosphere, and the mixture was allowed
to warm to room temperature stirring for 2 h. Then, saturated
ammonium chloride solution (100 mL) and CH Cl (30 mL) were
added, the layers were separated, and the aqueous layer was extracted
twice with CH Cl (30 mL). The combined organic solution was
washed with 1 N HCl (300 mL), saturated sodium bicarbonate (300
mL), twice with brine (300 mL), dried over anhydrous sodium sulfate
and filtered. The solvent was evaporated under reduced pressure to
give a crude product which was purified by silica gel column
chromatography. Elution with petroleum ether:ethyl acetate (95:5)
yielded the compound 11 (9430.5 mg, 91.7%) as a yellow oil.
Spectroscopic data of compound 11 were identical to those described
methylhex-4-enoic acid (10) (2477.4 mg, 13.2 mmol) and Et N (2.0
3
mL, 14.5 mmol) in dry THF (17.4 mL), and cooled at −78 °C. Then,
pivaloyl chloride (1.6 mL, 13.2 mmol) was added dropwise, and the
mixture was stirred at −78 °C for 10 min, and 0 °C for 30 min. In a
separated flame-dried round-bottom flask charged with argon, a
solution of (4S)-benzyloxazolidin-2-one ((S)-15) (2354.1 mg, 13.3
mmol) in dry THF at −78 °C was added n-BuLi (2.5 M solution in
Hexane, 5.3 mL, 13.3 mmol). The chelated oxazolidinone was
2
2
2
2
transferred via cannula to the solution of acid/Et N/PivCl at −78 °C,
3
and the reaction mixture was allowed to warm to 0 °C. The reaction
was stirred for 1 h, and was quenched with aqueous solution of
ammonium chloride (50 mL). Then, the layers were separated, and the
aqueous layer was extracted with ethyl acetate (3 × 80 mL). The
combined organic solution was dried over anhydrous sodium sulfate
and filtered. The solvent was evaporated under reduced pressure to
give a crude product which was purified by silica gel column
chromatography. Elution with petroleum ether:ethyl acetate (75:25)
31
in the literature.
Preparation of (± )-(E)-6,7-Epoxy-1-(methoxymethoxy)-3,7-
dimethylocta-2,6-diene (12). A solution of m-CPBA (7010.4 mg,
3
1.3 mmol) in CH Cl (59.6 mL) was added at −20 °C to a solution
2
2
of (E)-1-(methoxymethoxy)-3,7-dimethylocta-2,6-diene (11) (6194.7
mg, 31.3 mmol) in CH Cl2 (128 mL). Once the reaction was
20
2
yielded the compound 14 (3580.4 mg, 78.3%). Colorless oil: [α]D
completed (30 min.), a solution of 1 M NaOH was added (120 mL),
and the mixture was allowed to warm to room temperature. Then, the
layers were separated, and the aqueous layer was extracted twice with
CH Cl (180 mL). The combined organic solution was washed with
brine (300 mL), dried over anhydrous sodium sulfate and filtered. The
solvent was evaporated under reduced pressure to give a crude product
which was purified by silica gel column chromatography. Elution with
petroleum ether:ethyl acetate (90:10) yielded the epoxide 12 (5562.3
+
1
7
45.1° (c 0.61, CHCl ); IR (film) ν 2926, 1782, 1702, 1453, 1353,
3
max
−1
1
213, 1148, 1104, 1047, 921 cm ; H NMR (400 MHz, CDCl ) δ
3
.32−7.24 (m, 3H), 7.20−7.18 (m, 2H), 5.42 (tq, J = 6.8, 1.2 Hz, 1H),
4.65 (ddt, J = 9.6, 7.4, 3.4 Hz, 1H), 4.60 (s, 2H), 4.19 (dd, J = 9.2, 7.4
Hz, 1H), 4.15 (dd, J = 9.2, 3.4 Hz, 1H), 4.07 (d, J = 6.8 Hz, 2H), 3.35
2
2
(
s, 3H), 3.28 (dd, J = 13.4, 3.4 Hz, 1H), 3.11 (ddd, J = 16.0, 8.2, 6.8
Hz, 1H), 3.03 (ddd, J = 16.0, 8.2, 6.8 Hz, 1H), 2.76 (dd, J = 13.4, 9.6
13
Hz, 1H), 2.42 (dd, J = 8.2, 6.8 Hz, 2H), 1.73 (s, 3H); C NMR (100
mg, 83.1%). Colorless oil: IR (film) ν 2929, 1451, 1379, 1250, 1149,
max
MHz, CDCl ) δ 172.6, 153.4, 138.8, 135.2, 129.4 (2C), 128.9 (2C),
3
−1 1
1
6
2
1
102, 1040, 922 cm ; H NMR (500 MHz, CDCl ) δ 5.39 (tq, J =
3
127.3 (d, Carom), 121.3, 95.6, 66.2, 63.5, 55.2, 55.1, 37.9, 33.9, 33.7,
+
+
.8, 1.2 Hz, 1H), 4.62 (s, 2H), 4.06 (d, J = 6.8 Hz, 2H), 3.36 (s, 3H),
.70 (t, J = 6.2 Hz, 1H), 2.21 (dt, J = 14.4, 7.6 Hz, 1H), 2.13 (dt, J =
4.4, 7.6 Hz, 1H), 1.69 (s, 3H), 1.68−1.63 (m, 2H), 1.29 (s, 3H), 1.24
1
6.5; HRMS (ESI ) calcd for C H NO Na [M + Na] 370.1630,
19 25 5
found 370.1620.
Preparation of (4S,2′S,4′E)-4-Benzyl-3-[6-(methoxyme-
thoxy)-2,4-dimethylhex-4-enoyl]oxazolidin-2-one (9). A solu-
tion of NaN(SiMe ) (1.0 M solution in THF, 5.6 mL, 5.6 mmol) was
(
s, 3H); 13C NMR (125 MHz, CDCl ) δ 139.9, 120.8, 95.6, 64.0, 63.6,
3
+
5
8.4, 55.2, 36.2, 27.2, 24.8, 18.7, 16.4; HRMS (ESI ) calcd for
3
2
+
C H O [M + H] 215.1647, found 215.1634.
added dropwise at −78° to a solution of (S,E)-4-benzyl-3-[6-
1
2
22
3
E
dx.doi.org/10.1021/jo501471m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
(
methoxymethoxy)-4-methylhex-4-enoyl]oxazolidin-2-one (14)
1762.9 mg, 5.1 mmol) in dry THF (12.7 mL) and stirred for 1 h
Preparation of (S,2E,6E)-8-(Methoxymethoxy)-2,4,6-trime-
thylocta-2,6-dien-1-ol (18). Diisobutylaluminum hydride (DI-
at the same temperature. Iodomethane (1.7 mL, 25.4 mmol) was
added, and the reaction was monitored by TLC at −78 °C (5 h).
Then, an aqueous solution of ammonioum chloride (50 mL) was
added (25 mL), and the mixture was allowed to warm to room
temperature. The layers were separated, and the aqueous layer was
extracted with ethyl acetate (3 × 40 mL). The combined organic
solution was washed with brine (80 mL), dried over anhydrous sodium
sulfate and filtered. The solvent was evaporated under reduced
pressure to give a crude product which was purified by silica gel
column chromatography. Elution with petroleum ether:ethyl acetate
BALH) (7.8 mL of a solution 1.0 M in CH
slowly added to a solution of (S,2E,6E)-ethyl 8-(methoxymethoxy)-
,4,6-trimethylocta-2,6-dienoate ((E)-17) (958.7 mg, 3.55 mmol) in
dry CH Cl (11.1 mL) and cooled at −78 °C. The reaction was stirred
2 2
Cl , 7.8 mmol) was
2
2
2
for 1 h at the same temperature and quenched with ethyl acetate (20
mL). Then, a saturated solution of Rochelle’s salt (20 mL) was added,
and the mixture was allowed to warm to room temperature while
maintaining vigorous stirring for a further hour. The aqueous phase
was extracted with ethyl acetate (3 × 50 mL), and the combined
organic solutions were washed with brine (80 mL), dried over
anhydrous sodium sulfate and filtered. Evaporation of the solvent
under reduced pressure rendered a crude product that was purified by
silica gel column chromatography. Elution with petroleum ether:ethyl
acetate (70:30) yielded (S,2E,6E)-8-(methoxymethoxy)-2,4,6-trime-
(
75:25) yielded the compound 9 (1394.8 mg, 74%, 92% de). Colorless
20
oil: [α]D +52.1° (c 0.92, CHCl ); IR (film) ν 2932, 1779, 1699,
1
MHz, CDCl ) δ 7.31−7.24 (m, 3H), 7.20−7.18 (m, 2H), 5.36 (tq, J =
3
max
−1 1
456, 1382, 1349, 1209, 1148, 1102, 1041, 969 cm ; H NMR (400
3
20
thylocta-2,6-dien-1-ol (18) (616.0 mg, 76.1%). Colorless oil: [α]D
6
(
1
.4, 1.2 Hz, 1H), 4.61 (ddt, J = 9.6, 7.4, 3.2 Hz, 1H), 4.57 (s, 2H), 4.15
dd, J = 9.0, 7.4 Hz, 1H), 4.11 (dd, J = 9.0, 3.2 Hz, 1H), 4.04 (dd, J =
1.6, 6.4 Hz, 1H), 4.00 (dd, J = 11.6, 6.4 Hz, 1H), 3.95 (sext, J = 7.0
Hz, 1H), 3.32 (s, 3H), 3.22 (dd, J = 13.4, 3.2 Hz, 1H), 2.74 (dd, J =
−
14.0° (c 0.36, CHCl ); IR (film) ν 3427, 2927, 1645, 1451, 1383,
3
max
−
1 1
1
5
1
214, 1149, 1098, 1038, 921 cm ; H NMR (400 MHz, CDCl ) δ
3
.26 (t, J = 6.8 Hz, 1H), 5.12 (d, J = 8.8 Hz, 1H), 4.59 (d, J = 6.8 Hz,
H), 4.57 (d, J = 6.8 Hz, 1H), 4.07 (dd, J = 11.4, 6.8 Hz, 1H), 3.99
1
7
3.4, 9.6 Hz, 1H), 2.46 (dd, J = 13.3, 7.0 Hz, 1H), 2.08 (dd, J = 13.5,
.0 Hz, 1H), 1.67 (s, 3H), 1.17 (d, J = 7.0 Hz, 3H); 13C NMR (100
(dd, J = 11.7, 6.8 Hz, 1H), 3.93 (s, 2H), 3.34 (s, 3H), 2.70 (s, OH),
.57 (dsext, J = 8.8, 7.2 Hz, 1H), 1.99 (dd, J = 13.4, 7.2 Hz, 1H), 1.93
2
MHz, CDCl ) δ 176.7, 153.0, 137.6, 135.2, 129.3 (2C), 128.8 (2C),
1
HRMS (ESI ) calcd for C H NO Na [M + Na] 384.1787, found
3
3
13
(dd, J = 13.4, 7.2 Hz, 1H), 1.63 (s, 6H), 0.91 (d, J = 7.2 Hz, 3H);
C
27.2, 122.9, 95.4, 66.0, 63.4, 55.3, 55.1, 43.2, 37.8, 35.5, 16.8, 16.2;
+
+
NMR (100 MHz, CDCl
3
) δ 139.3, 133.6, 132.3, 121.9, 95.2, 69.1, 63.5,
20
27
5
+
5
5.1, 47.5, 30.1, 20.5, 16.3, 13.7; HRMS (ESI ) calcd for C H O Na
1
3
24
3
84.1786.
+
[
M + Na] 251.1623, found 251.1614.
Preparation of (S,E)-6-(Methoxymethoxy)-2,4-dimethylhex-
Preparation of (2R,3R,4S,6E)-2,3-Epoxy-8-(methoxyme-
4
-en-1-ol (16). NaBH (1044.9 mg, 28.2 mmol) was added at 0 °C to
4
thoxy)-2,4,6-trimethyloct-6-en-1-ol (19a). Ti(i-OPr) (titanium-
4
a stirred solution of (4S,2′S,4′E)-4-benzyl-3-[6-(methoxymethoxy)-
2
(
IV) isopropoxide, 0.57 mL, 1.94 mmol) was added at −25 °C to a
,4-dimethylhex-4-enoyl]oxazolidin-2-one (9) (2549.7 mg, 7.1 mmol)
solution of (−)-DIT ((−)-diisopropyl D-tartrate, 538 mg, 2.3 mmol) in
dry CH Cl (13.9 mL) under an argon atmosphere. The mixture was
in a mixture 4:1 THF:H O (35.2 mL). When TLC monitoring
2
2
2
indicated the completion of the reaction (12 h), 1 N HCl was added
until pH = 7. Layers were separated, and the aqueous layer was
extracted with two portions of ethyl acetate (15 mL). The combined
organic solution was washed with brine (30 mL), dried over anhydrous
sodium sulfate and filtered. Solvent was evaporated under reduced
pressure at 0 °C to give a crude product which was purified by silica
gel column chromatography. Elution with petroleum ether:ethyl
acetate (70:30) yielded the alcohol 16 (1239.3 mg, 93.4%). Colorless
oil: [α]D −5.1° (c 0.23, CHCl ); IR (film) ν 3420, 2927, 1667,
1
CDCl ) δ 5.30 (t, J = 6.8 Hz, 1H), 4.56 (s, 2H), 4.03 (dd, J = 12.0, 6.8
Hz, 1H), 4.00 (dd, J = 12.0, 6.8 Hz, 1H), 3.40 (dd, J = 10.6, 5.4 Hz,
stirred for 20 min and then, a solution of (S,2E,6E)-8-(methox-
ymethoxy)-2,4,6-trimethylocta-2,6-dien-1-ol (18) (551.8 mg, 2.4
mmol) in dry CH Cl (5.7 mL) was added slowly stirring for 20
2
2
min. Finally, TBHP (5.0−6.0 M solution in nonane, 0.9 mL, 4.84
mmol) was added slowly. When TLC monitoring indicated the
completion of the reaction (2 h), diethyl ether (2 mL) and a saturated
Na SO solution (2 mL) were added, and the mixture was allowed to
2
4
warm to room temperature, stirred for an additional hour, filtered with
2
0
3
max
Et O (250 mL) through Celite, and the solvent evaporated. The crude
2
−
1 1
453, 1383, 1215, 1149, 1100, 1042, 921 cm ; H NMR (500 MHz,
was redissolved in diethyl ether (5 mL) and a solution of NaOH (153
mg) in brine (5 mL) was added at 0 °C. The mixture was stirred
vigorously for 2 h, and the aqueous layer was separated and extracted
with three portions of ethyl acetate (15 mL). The combined organic
solution was washed with brine (20 mL), dried over anhydrous sodium
sulfate and filtered. Evaporation of the solvent gave a crude product
that was purified by silica gel column chromatography. Elution with
3
1
H), 3.34 (dd, J = 10.6, 5.4 Hz, 1H), 3.31 (s, 3H), 2.26 (s, OH), 2.10
13
(
m, 1H), 1.78 (m, 2H), 1.62 (s, 3H), 0.81 (d, J = 6.4 Hz, 3H);
C
NMR (125 MHz, CDCl ) δ 139.3, 121.9, 95.3, 67.8, 63.5, 55.0, 43.8,
3
2
3
+
+
3.4, 16.4, 16.1; HRMS (ESI ) calcd for C H O Na [M + Na]
10 20 3
11.1310, found 211.1301.
Preparation of (S,2E,6E)-Ethyl 8-(methoxymethoxy)-2,4,6-
petroleum ether:ethyl acetate (70:30) yielded the alcohol 19a (432.6
20
mg, 77.8%, 80% de). Colorless oil: [α]D −7.8° (c 0.14, CHCl ); IR
3
trimethylocta-2,6-dienoate ((E)-17). TEMPO (207.3 mg, 1.3
mmol) and BAIB (4.6 g, 14.3 mmol) were added at 0 °C to a
solution of (S,E)-6-(methoxymethoxy)-2,4-dimethylhex-4-en-1-ol (16)
−1
(
film) νmax 3450, 2936, 1639, 1447, 1382, 1147, 1096, 1038, 922 cm ;
H NMR (500 MHz, CDCl ) δ 5.37 (tq, J = 7.0, 1.2 Hz, 1H), 4.62 (s,
1
3
2
H), 4.09 (dd, J = 11.5, 7.0 Hz, 1H), 4.00 (dd, J = 11.5, 7.0 Hz, 1H),
(
1224.1 mg, 6.5 mmol) in dry CH Cl (19.4 mL), and the mixture was
2 2
3
.58 (d, J = 12.0 Hz, 1H), 3.53 (d, J = 12.0 Hz, 1H), 3.36 (s, 3H), 2.67
stirred for 4 h. Then, (carbethoxyethylidene)triphenylphosphorane
5.0 g, 13.0 mmol) was added, and the solution was stirred for a
(d, J = 9.5 Hz, 1H), 2.05 (dd, J = 13.4, 8.3 Hz, 1H), 2.00 (dd, J = 13.4,
(
6
=
6
.9 Hz, 1H), 1.66 (s, 3H), 1.68−1.59 (m, 1H), 1.25 (s, 3H), 1.06 (d, J
further 12 h at 40 °C. The solvent was removed under reduced
pressure, and the residue was purified by silica gel column
chromatography. Elution with petroleum ether:ethyl acetate (94:6)
13
6.6 Hz, 3H); C NMR (125 MHz, CDCl ) δ 138.2, 122.6, 95.8,
3
+
6.3, 66.1, 63.6, 61.9, 55.3, 44.4, 30.5, 18.0, 16.5, 14.8; HRMS (ESI )
+
calcd for C H O [M + H] 245.1753, found 245.1741.
13
25
4
yielded the ester (E)-17 (1495.6 mg, 85.2%). Colorless oil: [α]D20
Preparation of (2S,4S,6E)-8-(Methoxymethoxy)-2,4,6-trime-
+
1
5.4° (c 0.94, CHCl ); IR (film) νmax 2932, 1711, 1649, 1452, 1367,
thyloct-6-ene-1,2-diol (20a). LiAlH (4.0 M solution in THF, 1.0
3
4
−1 1
254, 1207, 1149, 1102, 1039, 921, 750 cm ; H NMR (400 MHz,
mL, 3.9 mmol) was added slowly at 0 °C to a solution of
(2R,3R,4S,6E)-2,3-epoxy-8-(methoxymethoxy)-2,4,6-trimethyloct-6-
en-1-ol (19a) (432.6 mg, 1.8 mmol) in THF (11.2 mL) under inert
atmosphere. The mixture was allowed to warm to room temperature
and when TLC monitoring indicated the completion of the reaction
(12 h), the mixture was recooled at 0 °C and water (5 mL) and HCl
1N (2 mL) were added slowly until pH = 3. The layers were separated,
and the aqueous layer was extracted with two portions of ethyl acetate
(15 mL). The combined organic solution was washed with brine (30
CDCl ) δ 6.52 (dq, J = 9.8, 1.4 Hz, 1H), 5.32 (tq, J = 6.8, 1.2 Hz, 1H),
4
3
.59 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 4.04 (d, J = 6.8 Hz, 2H), 3.34
(
s, 3H), 2.68 (dsext, J = 9.8, 6.8 Hz, 1H), 2.07 (dd, J = 13.6, 6.8 Hz,
1
3
H), 2.03 (dd, J = 13.6, 6.8 Hz, 1H), 1.81 (d, J = 1.4 Hz, 3H), 1.64 (s,
H), 1.27 (t, J = 7.1 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl ) δ 168.3, 147.2, 138.3, 126.4, 122.5, 95.3, 63.4, 60.4,
5
C H O Na [M + Na] 293.1729, found 293.1723.
3
+
5.1, 46.5, 31.4, 19.5, 16.4, 14.2, 12.4; HRMS (ESI ) calcd for
+
1
5
26
4
F
dx.doi.org/10.1021/jo501471m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mL), dried over anhydrous sodium sulfate, filtered, and the solvent was
evaporated under reduced pressure to give diol 20a (407.9 mg,
oil: [α] 20 +6.8° (c 0.35, CHCl ); IR (film) ν 3457, 2930, 1644,
1460, 1382, 1146, 1095, 1031, 919 cm ; H NMR (400 MHz,
D
3
max
−1
1
9
3.5%), which was used in the next step without further purification.
CDCl ) δ 5.32 (t, J = 6.8 Hz, 1H), 4.68 (s, 2H), 4.62 (s, 2H), 4.07 (d,
3
20
Colorless oil: [α]D −1.0° (c 0.11, CHCl ); IR (film) ν 3418, 2929,
J = 6.8, Hz, 2H), 3.44 (dd, J = 12.0, 6.2 Hz, 1H), 3.41 (s, 3H), 3.37 (s,
3H), 3.35 (dd, J = 12.0, 8.0 Hz, 1H), 3.26 (dd, J = 8.0, 6.2 Hz, OH),
2.05 (dd, J = 16.2, 9.6 Hz, 1H), 1.88−1.80 (m, 2H), 1.64 (s, 3H), 1.43
(dd, J = 14.8, 6.8 Hz, 1H), 1.37 (dd, J = 14.8, 3.8 Hz, 1H), 1.19 (s,
3
max
−1 1
1
644, 1456, 1381, 1149, 1100, 1038, 923 cm ; H NMR (400 MHz,
CDCl ) δ 5.33 (tq, J = 7.0, 1.2 Hz, 1H), 4.61 (s, 2H), 4.08 (dd, J =
3
1
1
1
1
1.5, 7.0 Hz, 1H), 4.04 (dd, J = 11.5, 7.0 Hz, 1H), 3.41 (d, J = 10.8 Hz,
H), 3.36 (s, 3H), 3.32 (d, J = 10.8 Hz, 1H), 1.99 (dd, J = 13.2, 7.2 Hz,
H), 1.87 (dd, J = 13.2, 6.8 Hz, 1H), 1.85−1.75 (m, 1H), 1.65 (s, 3H),
.47 (dd, J = 14.4, 3.3 Hz, 1H), 1.26 (dd, J = 14.4, 7.8 Hz, 1H), 1.15
3H), 0.90 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl ) δ 139.3,
3
122.4, 95.5, 90.8, 80.0, 68.9, 63.6, 55.4, 55.2, 49.4, 42.3, 26.2, 21.4,
+
+
20.3, 16.1; HRMS (ESI ) calcd for C H O Na [M + Na] 313.1991,
15
30
5
(
s, 3H), 0.95 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl ) δ
found 313.2006.
3
1
39.7, 122.2, 95.5, 73.2, 70.1, 63.5, 55.2, 49.3, 44.6, 26.6, 23.4, 22.0,
Preparation of (2S,4S,6E)-2,8-Bis(methoxymethoxy)-2,4,6-
trimethyloct-6-enal (8a). Alcohol 23a (115.5 mg, 0.40 mmol) was
dissolved in CH Cl (1 mL) and then added dropwise to a suspension
+
+
1
6.2; HRMS (ESI ) calcd for C H O Na [M + Na] 269.1729,
13 26 4
found 269.1740.
2
2
Preparation of (2S,4S,6E)-1-(tert-Butyldimethylsilyloxy)-8-
of PCC (87.7 mg, 0.6 mmol) and powdered 4 Å molecular sieves
175.4 mg) in CH Cl (2 mL) at 0 °C. The reaction was stirred
(methoxymethoxy)-2,4,6-trimethyloct-6-en-2-ol (21a). A solu-
(
2
2
tion of tert-butylchlorodimethylsilane (501.4 mg, 2.76 mmol) in dry
THF (1.7 mL) was added to a solution of imidazole (1257.8 mg, 18.4
mmol) and (2S,4S,6E)-8-(methoxymethoxy)-2,4,6-trimethyloct-6-ene-
vigorously at 0 °C for 2 h, diethyl ether (6 mL) was then added, and
the mixture was stirred for an additional 1 h. The suspension was
filtered over a silica gel pad (petroleum ether:ethyl acetate, 80:20, 300
mL). The solvent was evaporated under reduced pressure at 0 °C to
give the aldehyde 8a (98.6 mg, 86%) that was used immediately in the
1
,2-diol (20a) (566.5 mg, 2.3 mmol) in dry THF (3.2 mL) at 0 °C
under an argon atmosphere. The mixture was allowed to warm to
room temperature and when TLC monitoring indicated the
completion of the reaction (1.5 h), were added brine (5 mL). The
organic layer was washed three times with brine (5 mL), dried over
anhydrous sodium sulfate, filtered, and the solvent evaporated under
reduced pressure. The crude product was purified by silica gel column
chromatography. Elution with petroleum ether:ethyl acetate (92:8)0
yielded the compound 21a (672 mg, 81.2%). Colorless oil: [α]D2
20
next step. Colorless oil: [α]D −9.7° (c 0.32, CHCl ); IR (film) ν
3
max
−1
1
2
928, 1732, 1455, 1378, 1148, 1104, 1036, 918 cm ; H NMR (400
MHz, CDCl ) δ 9.56 (s, 1H), 5.32 (t, J = 6.8 Hz, 1H), 4.68 (s, 1H),
3
4
.65 (d, J = 7.4 Hz, 1H), 4.62 (s, 2H), 4.06 (d, J = 6.8, Hz, 2H), 3.40
(
2
8
s, 3H), 3.36 (s, 3H), 2.01 (dd, J = 16.4, 10.0 Hz, 1H), 1.92−1.82 (m,
H), 1.64 (s, 3H), 1.62 (dd, J = 14.6, 3.6 Hz, 1H), 1.49 (dd, J = 14.6,
13
.0 Hz, 1H), 1.29 (s, 3H), 0.86 (d, J = 6.0 Hz, 3H); C NMR (100
+
1.2° (c 1.4, CHCl ); IR (film) ν 3466, 2929, 1644, 1454, 1385,
3
max
MHz, CDCl ) δ 203.9, 138.9, 122.7, 95.5, 92.0, 82.8, 63.5, 55.8, 55.2,
−1
1
3
1
255, 1149, 1098, 1038, 837 cm ; H NMR (400 MHz, CDCl ) δ
+
3
4
[
8.8, 42.6, 26.0, 21.4, 18.6, 16.1; HRMS (ESI ) calcd for C H O Na
M + Na] 311.1834, found 311.1840.
15 28 5
5
.31 (t, J = 7.0 Hz, 1H), 4.62 (s, 2H), 4.07 (d, J = 7.0, Hz, 2H), 3.37
+
(
d, J = 9.4, Hz, 1H), 3.36 (s, 3H), 3.32 (d, J = 9.4, Hz, 1H), 2.28 (s,
Preparation of (4S,2′R,3′S,4′S,6′S,8′E)-4-Benzyl-3-[3-hy-
OH), 2.03 (dd, J = 16.2, 9.8 Hz, 1H), 1.88−1.81 (m, 2H), 1.64 (s,
droxy-4,8-bis(methoxymethoxy)-2,4,6,8-tetramethyldec-8-
3
1
H), 1.36 (dd, J = 14.4, 3.4 Hz, 1H), 1.27 (dd, J = 14.3, 7.4 Hz, 1H),
eneyl]oxazolidin-2-one (24a). (+)-(4S)-4-Benzyl-3-propionyloxa-
.12 (s, 3H), 0.94 (d, J = 6.2 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H); 13
C
zolidin-2-one (114.6 mg, 0.49 mmol) was treated with MgCl (23.8
2
NMR (100 MHz, CDCl ) δ 139.6, 122.1, 95.4, 72.7, 70.9, 63.6, 55.2,
3
mg, 0.24 mmol), NaSbF (50.7 mg, 0.20 mmol) and triethylamine
6
4
9.4, 44.7, 26.5, 25.9 (3C), 23.5, 21.6, 18.3, 16.1, −5.5 (2C); HRMS
(0.15 mL, 1.1 mmol) in ethyl acetate (1 mL) and stirred for 10 min at
+
+
(
ESI ) calcd for C H O NaSi [M + Na] 383.2594, found 383.2599.
19 40 4
room temperature. Then, aldehyde 8a (170.0 mg, 0.59 mmol)
dissolved in ethyl acetate (0.5 mL) and chlorotrimethylsilane (0.1 mL,
Preparation of (2S,4S,6E)-1-(tert-Butyldimethylsilyloxy)-2,8-
bis(methoxymethoxy)-2,4,6-trimethyloct-6-ene (22a).
2S,4S,6E)-1-(tert-Butyldimethylsilyloxy)-8-(methoxymethoxy)-2,4,6-
trimethyloct-6-en-2-ol (21a) (651.6 mg, 1.81 mmol) was converted to
2S,4S,6E)-1-(tert-butyldimethylsilyloxy)-2,8-bis(methoxymethoxy)-
,4,6-trimethyloct-6-ene (22a) (694.9 mg, 95%) following the
0
.79 mmol) were added sequentially and stirred for 36 h. The orange
(
slurry was pushed through a pad of silica with Et O (200 mL), and the
2
solvent removed under reduced pressure. The residue was dissolved in
dry methanol (40 mL) and trifluoroacetic acid (0.05 mL, 0.65 mmol)
was added at 0 °C. The mixture was stirred for 15 min and solvent was
evaporated under reduced pressure to obtain a crude product which
was purified by silica gel column chromatography. Elution with
(
2
methodology described above for the synthesis of (E)-1-(methox-
ymethoxy)-3,7-dimethylocta-2,6-diene (11) but using 5 equiv of
DIPEA and 3.5 equiv of MOMCl. Colorless oil: [α]D20 +3.4° (c 0.51,
CHCl ); IR (film) ν 2929, 2858, 1463, 1384, 1253, 1148, 1104,
petroleum ether:ethyl acetate (80:20) yielded the compound 24a
3
max
20
−
1
1
(205.4 mg, 66.7%, 95% de). Colorless oil: [α]
D
+9.2° (c 0.12,
1
037, 919, 838, 778 cm ; H NMR (500 MHz, CDCl ) δ 5.31 (t, J =
3
CHCl ); IR (film) ν 3457, 2930, 1782, 1673, 1453, 1384, 1209,
3
max
7
.0 Hz, 1H), 4.73 (d, J = 7.5, Hz, 1H), 4.70 (d, J = 7.5, Hz, 1H), 4.62
−1 1
1
3
7
1
147, 1106, 1030, 920 cm ; H NMR (400 MHz, CDCl ) δ 7.34−7−
3
(
=
s, 2H), 4.06 (d, J = 7.0, Hz, 2H), 3.48 (d, J = 9.8, Hz, 1H), 3.44 (d, J
9.8, Hz, 1H), 3.36 (s, 3H), 3.34 (s, 3H), 2.11 (dd, J = 11.8, 4.2 Hz,
0 (m, 2H), 7.27−7.22 (m, 3H), 5.29 (t, J = 7.0 Hz, 1H), 4.68 (d, J =
.4 Hz, 1H), 4.65 (d, J = 7.4 Hz, 1H), 4.60 (s, 2H), 4.68−4.58 (m,
H), 4.37 (d, J = 9.4, Hz, OH), 4.34 (dq, J = 7.2, 2.8 Hz, 1H), 4.12 (m,
1
1
0
1
H), 1.87−1.75 (m, 2H), 1.64 (s, 3H), 1.47 (dd, J = 15.0, 3.8 Hz, 1H),
.35 (dd, J = 15.0, 7.0 Hz, 1H), 1.19 (s, 3H), 0.89 (d, J = 6.0 Hz, 3H),
.87 (s, 9H), 0.02 (s, 6H); 13C NMR (125 MHz, CDCl ) δ 139.8,
22.0, 95.4, 91.2, 79.0, 68.9, 63.5, 55.3, 55.1, 49.3, 42.8, 26.0, 25.8
2H), 4.05 (d, J = 7.0, Hz, 2H), 3.58 (dd, J = 9.4, 2.8 Hz, 1H), 3.44 (dd,
J = 13.4, 3.4 Hz, 1H), 3.34 (s, 3H), 3.29 (s, 3H), 2.57 (dd, J = 13.4,
10.8 Hz, 1H), 2.14 (m, 1H), 1.90 (dd, J = 13.4, 3.0 Hz, 1H), 1.86−
1.76 (m, 2H), 1.64 (s, 3H), 1.38−1.35 (m, 1H), 1.37 (d, J = 7.2 Hz,
3
+
(
3C), 21.4, 21.3, 18.2, 16.0, −5.6 (2C); HRMS (ESI ) calcd for
+
C H O Si [M-OMe] 373.2774, found 373.2774.
2
0
41
4
3
H),1.33 (s, 3H), 0.88 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz,
Preparation of (2S,4S,6E)-2,8-Bis(methoxymethoxy)-2,4,6-
trimethyloct-6-en-1-ol (23a). Tetrabutylammonium fluoride
TBAF, 1.0 M solution, 2.4 mL, 2.4 mmol) was added slowly to a
solution stirred of (2S,4S,6E)-1-(tert-butyldimethylsilyloxy)-2,8-bis-
methoxymethoxy)-2,4,6-trimethyloct-6-ene (22a) (694.9 mg, 1.72
CDCl ) δ 178.3, 152.9, 139.6, 135.5, 129.3 (2C), 129.0 (2C), 127.3,
3
(
122.1, 95.4, 90.9, 81.8, 80.9, 65.8, 63.5, 55.6, 55.3, 55.1, 49.5, 43.2,
+
38.0, 34.6, 26.7, 21.5, 21.3, 17.9, 16.1; HRMS (ESI ) calcd for
+
(
C
28
H43NO
8
Na [M + Na] 544.2886, found 544.2898.
mmol) in dry tetrahydrofuran (16.8 mL) under an argon atmosphere.
When TLC monitoring indicated the completion of the reaction (3 h),
the mixture was washed three times with brine (10 mL), dried over
anhydrous sodium sulfate and filtered. The solvent was evaporated
under reduced pressure to give a crude product which was purified by
silica gel column chromatography. Elution with petroleum ether:ethyl
acetate (75:25) yielded the alcohol 23a (470.7 mg; 94.4%). Colorless
Deprotection of Compound 24a. To a solution of compound
24a (41.3 mg, 0.079 mmol) in MeOH (1 mL) was added p-TsOH (3
mg, 0.016 mmol), and the resulting solution was stirred overnight. The
MeOH was evaporated, and the resulting crude was redissolved in
EtOAc (5 mL), washed with H O (2 mL), dried over Na SO , and
2
2
4
filtered. Evaporation of the solvent gave a crude product that was
purified by silica gel column chromatography. Elution with petroleum
G
dx.doi.org/10.1021/jo501471m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
ether:ethyl acetate (70:30) yielded the lactones 25a (10.9 mg, 45.9%)
and 3a (4.3 mg, 21.3%).
2,4-dimethylhex-4-en-1-ol (ent-16) (982.4 mg, 5.22 mmol) was
converted to (R,2E,6E)-ethyl 8-(methoxymethoxy)-2,4,6-trimethyloc-
ta-2,6-dienoate (ent-17) (1312.2 mg, 93%) following the methodology
(
3R,4S,5S,2′S,4′E)-4-Hydroxy-5-(6-(methoxymethoxy)-2,4-di-
methylhex-4-enyl)-3,5-dimethyl-4,5-dihydrofuran-2(3H)-one
described above for the synthesis of ester 17 from 16. Colorless oil:
(
25a). Colorless oil: [α]D20 +4.2° (c 0.13, CHCl ); IR (film) ν
430, 2928, 1751, 1456, 1382, 1213, 1149, 1098, 1035, 937 cm ; H
20
3
max
[α]D −5.4° (c 0.29, CHCl ).
3
−1
1
3
Preparation of (R,2E,6E)-8-(Methoxymethoxy)-2,4,6-trime-
thylocta-2,6-dien-1-ol (ent-18). (R,2E,6E)-Ethyl 8-(methoxyme-
thoxy)-2,4,6-trimethylocta-2,6-dienoate (ent-17) (1375.3 mg, 5.10
mmol) was converted to (R,2E,6E)-8-(methoxymethoxy)-2,4,6-
trimethylocta-2,6-dien-1-ol (ent-18) (872.2, 75.1%) following the
methodology described above for the synthesis of alcohol 18 from
17. Colorless oil: [α]D20 +14.0° (c 0.26, CHCl3).
NMR (500 MHz, CDCl ) δ 5.35 (t, J = 6.8 Hz, 1H), 4.64 (d, J = 6.6
3
Hz, 1H), 4.62 (d, J = 6.6 Hz, 1H), 4.09 (d, J = 6.8 Hz, 2H), 4.00 (d, J
=
5.4 Hz, 1H), 3.37 (s, 3H), 2.92 (dq, J = 7.2, 5.4 Hz, 1H), 1.99 (m,
1
H), 1.92−1.83 (m, 2H), 1.70 (dd, J = 14.6, 3.3 Hz, 1H), 1.66 (s, 3H),
1
.61 (dd, J = 14.6, 9.1 Hz, 1H), 1.32 (s, 3H), 1.24 (d, J = 7.2 Hz, 3H),
1
.00 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl ) δ 177.3, 138.9,
3
1
1
22.9, 95.6, 87.4, 76.6, 63.9, 55.2, 49.0, 40.5, 39.7, 26.6, 22.5, 21.2,
Preparation of (2R,3R,4R,6E)-2,3-Epoxy-8-(methoxyme-
thoxy)-2,4,6-trimethyloct-6-en-1-ol (19b). (R,2E,6E)-8-(Methox-
ymethoxy)-2,4,6-trimethylocta-2,6-dien-1-ol (ent-18) (861.6 mg, 3.78
mmol) was converted to (2R,3R,4R,6E)-2,3-epoxy-8-(methoxyme-
thoxy)-2,4,6-trimethyloct-6-en-1-ol (19b) (718.0 mg, 77.9% yield, 80%
+
+
6.3, 8.3; HRMS (ESI ) calcd for C H O Na [M + Na] 323.1834,
16 28 5
found 323.1831.
(
3R,4S,5S,2′S,4′E)-4-Hydroxy-5-(6-hydroxy-2,4-dimethylhex-
4
-enyl)-3,5-dimethyl-4,5-dihydrofuran-2(3H)-one (3a). Color-
20
less oil: [α]D −4.8° (c 0.10, CHCl ); IR (film) ν 3430, 2921,
748, 1455, 1351, 1218, 1092, 1015, 938 cm ; H NMR (500 MHz,
3
max
de) following the methodology described above for the synthesis of
−1 1
1
20
epoxy 19a from 18. Colorless oil: [α]D +14.3° (c 0.15, CHCl ); IR
3
CDCl ) δ 5.42 (t, J = 7.0 Hz, 1H), 4.16 (d, J = 7.0 Hz, 2H), 4.02 (d, J
−1
3
(film) ν 3446, 2936, 1646, 1454, 1385, 1216, 1149, 1042, 923 cm ;
H NMR (500 MHz, CDCl ) δ 5.40 (t, J = 6.8 Hz, 1H), 4.62 (s, 2H),
max
=
5.5 Hz, 1H), 2.93 (dq, J = 7.2, 5.5 Hz, 1H), 2.01 (dd, J = 13.5, 7.0
Hz, 1H), 1.96 (dd, J = 13.5, 7.0 Hz, 1H), 1.92−1.86 (m, 1H), 1.70
dd, J = 14.5, 3.5 Hz, 1H), 1.66 (s, 3H), 1.64 (dd, J = 14.5, 8.5 Hz,
1
3
4.09 (d, J = 6.8 Hz, 2H), 3.66 (dd, J = 12.5, 4.5 Hz, 1H), 3.56 (dd, J =
12.5, 8.5 Hz, 1H), 3.37 (s, 3H), 2.75 (d, J = 9.2 Hz, 1H), 2.38 (dd, J =
14.0, 4.8 Hz, 1H), 1.98 (dd, J = 14.0, 9.2 Hz, 1H), 1.79 (dd, J = 8.5, 4.5
(
1
H), 1.33 (s, 3H), 1.24 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.5 Hz, 3H);
1
3
C NMR (125 MHz, CDCl ) δ 177.7, 138.1, 125.7, 87.4, 76.6, 59.3,
3
Hz, OH), 1.67 (s, 3H), 1.60 (dtq, J = 9.2, 6.8, 4.8 Hz, 1H), 1.29 (s,
+
4
8.9, 40.6, 39.7, 26.6, 22.4, 21.1, 16.2, 8.3; HRMS (ESI ) calcd for
13
3
H), 0.87 (d, J = 6.8 Hz, 3H); C NMR (125 MHz, CDCl ) δ 138.4,
+
3
C H O [M-H O] 239.1647, found 239.1640.
1
4
23
3
2
122.6, 95.5, 65.4, 64.7, 63.6, 60.8, 55.2, 45.1, 31.0, 16.3, 15.6, 14.3;
Preparation of (3R,4S,5S,2′S,4′E)-5-[6-((R)-Methoxyphenyla-
+
+
HRMS (ESI ) calcd for C H O Na [M + Na] 267.1572, found
13
24
4
cetoxy)-2,4-dimethylhex-4-enoyl]-4-((R)-methoxyphenylace-
toxy)-3,5-dimethyldihydrofuran-2(3H)-one (27a).
2
67.1563.
Preparation of (2S,4R,6E)-8-(Methoxymethoxy)-2,4,6-trime-
(
3
3R,4S,5S,2′S,4′E)-4-Hydroxy-5-(6-hydroxy-2,4-dimethylhex-4-enyl)-
thyloct-6-ene-1,2-diol (20b). (2R,3R,4R,6E)-2,3-Epoxy-8-(methox-
ymethoxy)-2,4,6-trimethyloct-6-en-1-ol (19b) (718.0 mg, 2.94 mmol)
was converted to (2S,4R,6E)-8-(methoxymethoxy)-2,4,6-trimethyloct-
,5-dimethyl-4,5-dihydrofuran-2(3H)-one (3a) (0.7 mg, 2.7 μmol)
was converted to compound 27a (1.2 mg, 80.0%) following the
methodology described above for the synthesis of 7 from 5.
Amorphous solid: [α]D20 −35.7° (c 0.1, CHCl ); IR (film) υ
6
-ene-1,2-diol (20b) (712.5 mg, 98.4%) following the methodology
3
max
described above for the synthesis of diol 20a from 19a. Colorless oil:
1
2
927, 1771, 1720, 1453, 1265, 1190, 1105, 1021, 757; H NMR
20
[
1
α]D −0.6° (c 0.19, CHCl ); IR (film) ν 3418, 2929, 1647, 1455,
3
max
(600 MHz, CD Cl ) δ 7.34−7.23 (m, 10H), 5.15 (d, J = 6.0, 1H), 5.06
(t, J = 7.0 Hz, 1H), 4.67 (s, 1H), 4.64 (s, 1H), 4.51 (dd, J = 12.0, 7.2
2
2
−1
1
385, 1214, 1148, 1104, 1037, 922 cm ; H NMR (500 MHz,
CDCl ) δ 5.34 (t, J = 6.8 Hz, 1H), 4.62 (s, 2H), 4.09 (dd, J = 12.0, 7.4
3
Hz, 1H), 4.45 (dd, J = 12.0, 7.2 Hz, 1H), 3.33 (s, 3H), 3.31 (s, 3H),
Hz, 1H), 4.05 (dd, J = 12.0, 6.8 Hz, 1H), 3.40 (d, J = 11.0 Hz, 1H),
2
.80 (dq, J = 7.5, 6.5 Hz, 1H), 1.95 (m, 1H), 1.81 (dd, J = 13.0, 8.5 Hz,
H), 1.71 (m, 2H), 1.54 (s, 3H), 1.26 (s, 3H), 1.20 (dd, J = 13.0, 7.5
3
.37 (d, J = 11.0 Hz, 1H), 3.36 (s, 3H), 2.18 (s, OH), 2.08 (dd, J =
12.0, 5.8 Hz, 1H), 1.96 (s, OH), 1.89−1.81 (m, 2H), 1.66 (s, 3H),
.55 (dd, J = 14.4, 3.6 Hz, 1H), 1.23 (dd, J = 14.4, 6.4 Hz, 1H), 1.17
1
13
Hz, 1H) 0.82 (d, J = 6.1 Hz, 3H), 0.68 (d, J = 7.2 Hz, 3H); C NMR
1
(
125 MHz, CD Cl ) δ 176.2, 170.7, 169.5, 140.3, 136.3, 135.7, 128.83,
2 2
13
(s, 3H), 0.93 (d, J = 6.4 Hz, 3H); C NMR (125 MHz, CDCl ) δ
3
1
7
28.77, 128.5 (2C), 128.3, 128.2, 127.0 (4C), 120.5, 86.4, 82.5, 82.3,
7.4, 61.0, 56.9, 56.8, 48.6, 40.2, 37.9, 26.4, 23.1, 20.3, 16.0, 7.9;
1
40.0, 122.2, 95.5, 73.1, 70.5, 63.6, 55.2, 49.2, 44.7, 26.3, 23.8, 22.3,
+
H O
Na [M + Na]+ 269.1729,
26 4
+
+
16.2; HRMS (ESI ) calcd for C13
found 269.1731.
HRMS (ESI ) calcd for C H O Na [M + Na] 575.2621, found
32
40
8
5
75.2617.
Preparation of (2S,4R,6E)-1-(tert-Butyldimethylsilyloxy)-8-
methoxymethoxy)-2,4,6-trimethyloct-6-en-2-ol (21b).
Preparation of (4R,4′E)-4-Benzyl-3-[6-(methoxymethoxy)-4-
(
methylhex-4-eneyl]oxazolidin-2-one (ent-14). (E)-6-(Methoxy-
methoxy)-4-methylhex-4-enoic acid (10) (2385.7 mg, 12.7 mmol) was
converted to (4R,4′E)-4-benzyl-3-[6-(methoxymethoxy)-4-methylhex-
(
(
2S,4R,6E)-8-(Methoxymethoxy)-2,4,6-trimethyloct-6-ene-1,2-diol
20b) (712.5 mg, 2.90 mmol) was converted to (2S,4R,6E)-1-(tert-
butyldimethylsilyloxy)-8-(methoxymethoxy)-2,4,6-trimethyloct-6-en-
4
-enoyl]oxazolidin-2-one (ent-14) (3214.5 mg, 73.1%) following the
2
-ol (21b) (852.0 mg, 81.6%) following the methodology described
methodology described above for the synthesis of 14 from 10.
2
0
Colorless oil: [α]D20 −45.1° (c 0.31, CHCl ).
above for the synthesis of 21a from 20a. Colorless oil: [α]D −1.9° (c
0
1
3
.17, CHCl ); IR (film) ν 3466, 2928, 1645, 1454, 1383, 1251,
3 max
Preparation of (4R,2′R,4′E)-4-Benzyl-3-[6-(methoxyme-
−1 1
147, 1096, 1035, 832 cm ; H NMR (400 MHz, CDCl ) δ 5.32 (t, J
thoxy)-2,4-dimethylhex-4-enoyl]oxazolidin-2-one (ent-9).
3
=
6.8 Hz, 1H), 4.62 (s, 2H), 4.07 (d, J = 6.8, Hz, 2H), 3.38 (d, J = 9.2,
Hz, 1H), 3.36 (s, 3H), 3.33 (d, J = 9.2, Hz, 1H), 2.28 (s, OH), 2.16
dd, J = 11.8, 4.6 Hz, 1H), 1.88−1.78 (m, 2H), 1.65 (s, 3H), 1.50 (dd,
J = 14.4, 4.4 Hz, 1H), 1.21 (dd, J = 14.4, 6.6 Hz, 1H), 1.12 (s, 3H),
.90 (s, 9H), 0.89 (d, J = 6.0 Hz, 3H), 0.05 (s, 6H); 13C NMR (100
MHz, CDCl ) δ 139.9, 122.0, 95.4, 72.6, 70.8, 63.6, 55.2, 49.2, 44.9,
(
4R,4′E)-4-Benzyl-3-[6-(methoxymethoxy)-4-methylhex-4-enoyl]-
oxazolidin-2-one (ent-14) (3112.2 mg, 8.97 mmol) was converted to
(
(
4R,2′R,4′E)-4-benzyl-3-[6-(methoxymethoxy)-2,4-dimethylhex-4-
enoyl]oxazolidin-2-one (ent-9) (2396.07 mg, 72% yield, 92% de.)
following the methodology described above for the synthesis of 9 from
1
0
4. Colorless oil: [α]D20 −52.3° (c 0.22, CHCl ).
3
3
+
2
6.4, 25.9 (3C), 23.8, 21.9, 18.3, 16.1, −5.5, −5.5; HRMS (ESI ) calcd
Preparation of (R,E)-6-(Methoxymethoxy)-2,4-dimethylhex-
+
4
-en-1-ol (ent-16). (4R,2′R,4′E)-4-Benzyl-3-[6-(methoxymethoxy)-
for C19H O SiNa [M + Na] 383.2594, found 383.2600.
40 4
2
,4-dimethylhex-4-enoyl]oxazolidin-2-one (ent-9) (2086.4 mg, 5.78
mmol) was converted to (R,E)-6-(methoxymethoxy)-2,4-dimethylhex-
-en-1-ol (ent-16) (999.7 mg, 92%) following the methodology
Preparation of (2S,4R,6E)-1-(tert-Butyldimethylsilyloxy)-2,8-
bis(methoxymethoxy)-2,4,6-trimethyloct-6-ene (22b).
(2S,4R,6E)-1-(tert-Butyldimethylsilyloxy)-8-(methoxy−methoxy)-
2,4,6-trimethyloct-6-en-2-ol (21b) (852.0 mg, 2.37 mmol) was
converted to (2S,4R,6E)-1-(tert-butyldimethylsilyloxy)-2,8-bis-
(methoxymethoxy)-2,4,6-trimethyloct-6-ene (22b) (950.0 mg,
99.4%) following the methodology described above for the synthesis
4
described above for the synthesis of alcohol 16 from 9. Colorless oil:
[
α]D20 +5.1° (c 0.53, CHCl3).
Preparation of (R,2E,6E)-Ethyl 8-(methoxymethoxy)-2,4,6-
trimethylocta-2,6-dienoate (ent-17). (R,E)-6-(Methoxymethoxy)-
H
dx.doi.org/10.1021/jo501471m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
of 22a from 21a. Colorless oil: [α] 20 +3.5° (c 0.47, CHCl ); IR (film)
thoxy)-2,4,6,8-tetramethyldec-8-enoyl]oxazolidin-2-one (24b) (8 mg,
D
3
νmax 2929, 2857, 1458, 1380, 1256, 1147, 1101, 1037, 919, 836, 775
0.015 mmol) was dissolved in dry CH Cl under argon atmosphere
2
2
−1 1
cm ; H NMR (400 MHz, CDCl ) δ 5.32 (t, J = 6.8 Hz, 1H), 4.72 (s,
(0.6 mL). A solution of sodium methoxide (0.5 M solution in MeOH,
0.03 mL, 0.015 mmol) was added, and the reaction was stirred at 0 °C
for 5 min. The reaction was quenched with saturated ammonium
chloride (0.5 mL) and CH Cl was added (3 mL). The organic layer
3
2
3
1
1
H), 4.62 (s, 2H), 4.07 (d, J = 6.8, Hz, 2H), 3.51 (d, J = 10.0, Hz, 1H),
.45 (d, J = 10.0, Hz, 1H), 3.36 (s, 3H), 3.34 (s, 3H), 2.15 (dd, J =
2.8, 5.0 Hz, 1H), 1.89−1.80 (m, 1H), 1.78 (dd, J = 12.8, 9.2 Hz, 1H),
.64 (s, 3H), 1.54 (dd, J = 14.6, 4.2 Hz, 1H), 1.31 (dd, J = 14.6, 6.6
2
2
was washed with brine (1 mL), dried over anhydrous sodium sulfate
and filtered. The solvent was evaporated under reduced pressure to
give the ester 26b (1.8 mg, 32%). Colorless oil: [α]D20 −51.8° (c 0.1,
CHCl ); IR (film) ν 3439, 2921, 1731, 1455, 1380, 1211, 1034, 746
13
Hz, 1H), 1.20 (s, 3H), 0.88 (m, 12H), 0.03 (s, 6H); C NMR (100
MHz, CDCl ) δ 139.8, 121.9, 95.4, 91.2, 79.0, 68.7, 63.6, 55.3, 55.2,
3
4
9.3, 43.2, 26.0, 25.9 (3C), 21.8, 21.4, 18.2, 16.1, −5.5 (2C); HRMS
3
max
+
+
−1 1
(
ESI ) calcd for C H O NaSi [M + Na] 427.2856, found 427.2851.
cm ; H NMR (500 MHz, CDCl ) δ 5.32 (t, J = 6.5 Hz, 1H), 4.64 (d,
21
44
5
3
Preparation of (2S,4R,6E)-2,8-Bis(methoxymethoxy)-2,4,6-
J = 7.5, Hz, 1H), 4.63 (d, J = 7.5, Hz, 1H), 4.61 (s, 2H), 4.07 (d, J =
6.5, Hz, 2H), 3.71 (d, J = 9.5 Hz, OH), 3.67 (s, 3H), 3.44 (dd, J = 9.5,
2.5 Hz, 1H), 3.36 (s, 3H), 3.32 (s, 3H), 2.77 (dq, J = 7.5, 2.5 Hz, 1H),
2.10 (dd, J = 13.0, 6.0 Hz, 1H), 1.82 (dd, J = 13.0, 8.5 Hz, 1H), 1.72−
1.64 (m, 2H), 1.63 (s, 3H), 1.49 (dd, J = 13.0, 3.5 Hz, 1H), 1.32 (d, J
= 7.5 Hz, 3H), 1.25 (s, 3H), 0.91 (d, J = 6.0 Hz, 3H); 13C NMR (125
trimethyloct-6-en-1-ol (23b). (2S,4R,6E)-1-(tert-Butyldimethylsily-
loxy)-2,8-bis(methoxymethoxy)-2,4,6-trimethyl oct-6-ene (22b)
(
(
9
950.0 mg, 2.35 mmol) was converted to (2S,4R,6E)-2,8-bis-
methoxymethoxy)-2,4,6-trimethyloct-6-en-1-ol (23b) (626.8 mg,
2%) following the methodology described above for the synthesis
2
0
of 22a from 23a. Colorless oil: [α]D +9.8° (c 0.75, CHCl ); IR (film)
max
MHz, CDCl ) δ 176.9, 139.4, 122.4, 95.4, 91.1, 81.3, 79.2, 63.5, 55.5,
3
3
−
1
+
ν
3473, 2928, 1645, 1449, 1384, 1212, 1147, 1093, 1032, 918 cm ;
55.2, 51.5, 49.4, 42.5, 38.7, 26.6, 21.6, 20.2, 17.0, 16.1; HRMS (ESI )
1
+
H NMR (500 MHz, CDCl ) δ 5.32 (t, J = 6.8 Hz, 1H), 4.69 (d, J =
calcd for C H O Na [M + Na] 399.2359, found 399.2351.
3
19 36
7
7
.5 Hz, 1H), 4.65 (d, J = 7.5 Hz, 1H), 4.62 (s, 2H), 4.07 (d, J = 6.8,
Deprotection of Compound 24b with PPTS. A solution of
pyridinium p-toluenesulfonate (PPTS, 31.1 mg, 0.12 mmol) in t-
BuOH (2 mL) was added to a solution of (4S,2′R,3′S,4′S,6′R,8′E)-4-
benzyl-3-[3-hydroxy-4,8-bis(methoxymethoxy)-2,4,6,8-tetramethyldec-
8-enoyl]oxazolidin-2-one (24b) (29.4 mg, 0.06 mmol) at 80 °C and
stirred for 12 h. Then, saturated sodium bicarbonate (1 mL) was
added and stirred for 10 min. Water (3 mL) and ethyl acetate (10 mL)
were added, and the aqueous layer was separated and extracted with
three portions of ethyl acetate (10 mL). The combined organic
solution was washed with brine (10 mL), dried over anhydrous sodium
sulfate and filtered. Evaporation of the solvent gave a crude product
that was purified by silica gel column chromatography. Elution with
petroleum ether:ethyl acetate (60:40) yielded the lactones 25b (3.7
mg, 23%) and 3b (8.8 mg, 65%).
Hz, 2H), 3.45 (dd, J = 12.5, 6.5, Hz, 1H), 3.40 (s, 3H), 3.37 (s, 3H),
3
.35 (dd, J = 12.5, 8.0 Hz, 1H), 3.26 (dd, J = 8.0, 6.5 Hz, OH), 2.12
(
(
dd, J = 17.5, 10.0 Hz, 1H), 1.86−1.78 (m, 2H), 1.63 (s, 3H), 1.60
dd, J = 14.6, 4.0 Hz, 1H), 1.23 (dd, J = 14.6, 6.0 Hz, 1H), 1.20 (s,
3
1
2
H), 0.90 (d, J = 6.0 Hz, 3H); 13C NMR (125 MHz, CDCl ) δ 139.6,
3
22.3, 95.5, 90.7, 79.9, 68.7, 63.5, 55.4, 55.2, 49.1, 42.7, 26.0, 21.9,
+
+
0.4, 16.1; HRMS (ESI ) calcd for C H O Na [M + Na] 313.1991,
15 30 5
found 313.1990.
Preparation of (2S,4R,6E)-2,8-Bis(methoxymethoxy)-2,4,6-
trimethyloct-6-enal (8b). (2S,4R,6E)-2,8-Bis(methoxymethoxy)-
2
converted to (2S,4R,6E)-2,8-bis(methoxymethoxy)-2,4,6-trimethy-
loct-6-enal (8b) (171.0 mg, 89.5%) following the methodology
described above for the synthesis of 8a from 23a. Colorless oil: [α]D
−
1
,4,6-trimethyloct-6-en-1-ol (23b) (192.3 mg, 0.66 mmol) was
20
(3R,4S,5S,2′R,4′E)-4-Hydroxy-5-(6-(methoxymethoxy)-2,4-di-
12.0° (c 0.42, CHCl ); IR (film) ν 2928, 2720, 1732, 1455, 1378,
methylhex-4-enyl)-3,5-dimethyl-4,5-dihydrofuran-2(3H)-one
3
max
−1
1
20
215, 1148, 1103, 1038, 919 cm ; H NMR (500 MHz, CDCl ) δ
(25b). Colorless oil: [α]
D
−2.8° (c 0.16, CHCl ); IR (film) νmax
3
3
−
1 1
9
.53 (s, 1H), 5.32 (t, J = 7.0 Hz, 1H), 4.76 (d, J = 7.0 Hz, 1H), 4.62 (d,
3443, 2940, 1750, 1456, 1383, 1215, 1147, 1099, 1037, 934 cm ; H
NMR (500 MHz, CDCl ) δ 5.33 (t, J = 6.8 Hz, 1H), 4.61 (s, 2H), 4.08
J = 7.0 Hz, 1H), 4.61 (s, 2H), 4.07 (d, J = 7.0, Hz, 2H), 3.39 (s, 3H),
3
3
.36 (s, 3H), 2.07 (dd, J = 16.4, 10.0 Hz, 1H), 1.86−1.78 (m, 2H),
(dd, J = 11.6, 6.8 Hz, 1H), 4.05 (dd, J = 11.6, 6.8 Hz, 1H), 4.01 (d, J =
5.4 Hz, 1H), 3.36 (s, 3H), 2.93 (dq, J = 7.2, 5.4 Hz, 1H), 2.15 (dd, J =
12.1, 4.9 Hz, 1H), 1.92−1.84 (m, 3H), 1.66 (s, 3H), 1.56 (dd, J = 14.1,
1
.69 (dd, J = 14.8, 4.2 Hz, 1H), 1.62 (s, 3H), 1.44 (dd, J = 14.8, 7.0
13
Hz, 1H), 1.30 (s, 3H), 0.87 (d, J = 6.5 Hz, 3H); C NMR (125 MHz,
CDCl ) δ 203.5, 139.0, 122.6, 95.5, 91.9, 82.6, 63.5, 55.8, 55.2, 48.8,
4
6.4 Hz, 1H), 1.34 (s, 3H), 1.22 (d, J = 7.2 Hz, 3H), 0.95 (d, J = 6.2 Hz,
3
+
13
2.6, 26.1, 21.3, 18.2, 16.0; HRMS (ESI ) calcd for C H O Na [M +
3H); C NMR (125 MHz, CDCl
3
) δ 177.6, 139.4, 122.4, 95.4, 87.7,
15
28
5
+
Na] 311.1834, found 311.1837.
76.4, 63.7, 55.2, 48.4, 40.4, 40.0, 26.6, 22.9, 21.4, 16.2, 8.3; HRMS
+
+
Preparation of (4S,2′R,3′S,4′S,6′R,8′E)-4-Benzyl-3-[3-hy-
droxy-4,8-bis(methoxymethoxy)-2,4,6,8-tetramethyldec-8-
enoyl]oxazolidin-2-one (24b). (2S,4R,6E)-2,8-Bis(methoxymeth-
oxy)-2,4,6-trimethyloct-6-enal (8b) (170.0 mg, 0.59 mmol) was
converted to (4S,2′R,3′S,4′S,6′R,8′E)-4-benzyl-3-[3-hydroxy-4,8-bis-
(ESI ) calcd for C H O Na [M + Na] 323.1834, found 323.1834.
16 28 5
(3R,4S,5S,2′R,4′E)-4-Hydroxy-5-(6-hydroxy-2,4-dimethylhex-
4-enyl)-3,5-dimethyl-4,5-dihydrofuran-2(3H)-one (3b). Color-
less oil: [α]D20 −2.5° (c 0.2, CHCl ); IR (film) ν
3433, 2931,
3
max
−1 1
1742, 1451, 1361, 1210, 1090, 1018, 936 cm ; H NMR (500 MHz,
(
methoxymethoxy)-2,4,6,8-tetra-methyldec-8-enoyl]oxazolidin-2-one
CDCl ) δ 5.41 (t, J = 7.0 Hz, 1H), 4.17 (dd, J = 12.0, 7.0 Hz, 1H),
3
(24b) (223.5 mg, 72.5% yield, 95% de) following the methodology
4.12 (dd, J = 12.0, 7.0 Hz, 1H), 4.03 (d, J = 5.5 Hz, 1H), 2.94 (dq, J =
7.2, 5.5 Hz, 1H), 2.15 (dd, J = 12.2, 5.2 Hz, 1H), 1.93−1.85 (m, 3H),
20
described above for the synthesis of 24a from 8a. Colorless oil: [α]D
+
1
5.5° (c 0.27, CHCl ); IR (film) νmax 3457, 2930, 1781, 1673, 1460,
1.66 (s, 3H), 1.55 (dd, J = 15.8, 8.0 Hz, 1H), 1.35 (s, 3H), 1.24 (d, J =
3
−1
1
13
384, 1208, 1147, 1105, 1030, 919 cm ; H NMR (500 MHz,
7.5 Hz, 3H), 0.96 (d, J = 6.2 Hz, 3H); C NMR (125 MHz, CDCl ) δ
3
CDCl ) δ 7.36−7−32 (m, 2H), 7.29−7.24 (m, 3H), 5.33 (t, J = 6.8
177.6, 138.4, 125.4, 87.6, 76.5, 59.3, 48.3, 40.4, 40.0, 26.6, 22.8, 21.5,
3
+
+
Hz, 1H), 4.66−4.59 (m, 5H), 4.36 (dq, J = 7.2, 2.6 Hz, 1H), 4.14 (m,
16.2, 8.3; HRMS (ESI ) calcd for C H O Na [M + Na] 279.1572,
14 24 4
2
H), 4.07 (d, J = 6.8, Hz, 2H), 3.61 (br s, 1H), 3.45 (dd, J = 13.2, 3.0
found 279.1563.
Hz, 1H), 3.37 (s, 3H), 3.30 (s, 3H), 2.60 (dd, J = 13.2, 10.8 Hz, 1H),
.16 (dd, J = 13.0, 5.2 Hz, 1H), 1.83 (dd, J = 13.0, 9.0 Hz, 1H), 1.78
dd, J = 13.0, 6.0 Hz, 1H), 1.74−1.69 (m, 1H), 1.65 (s, 3H), 1.54 (dd,
J = 13.0, 4.0 Hz, 1H), 1.38 (d, J = 7.2 Hz, 3H), 1.32 (s, 3H), 0.92 (d, J
6.4 Hz, 3H); 13C NMR (125 MHz, CDCl ) δ 178.3, 152.9, 139.5,
Preparation of (3R,4S,5S,2′R,4′E)-5-[6-((R)-Methoxyphenyla-
cetoxy)-2,4-dimethylhex-4-enoyl]-4-((R)-methoxyphenylace-
toxy)-3,5-dimehtyldihydrofuran-2(3H)-one (27b).
(3R,4S,5S,2′R,4′E)-4-Hydroxy-5-(6-hydroxy-2,4-dimethylhex-4-enyl)-
3,5-dimethyl-4,5-dihydrofuran-2(3H)-one (3b) (1.2 mg, 4.7 μmol)
was converted to compound 27b (2.2 mg, 86.0%) following the
2
(
=
3
1
35.5, 129.3 (2C), 129.0 (2C), 127.3, 122.3, 95.4, 90.8, 81.8, 81.0,
6
1
5.8, 63.5, 55.6, 55.2, 55.1, 49.4, 42.4, 38.0, 34.6, 26.7, 21.6, 20.9, 17.9,
methodology described above for the synthesis of 7 from 5.
+
+
20
6.1; HRMS (ESI ) calcd for C H NO Na [M + Na] 544.2886,
Amorphous solid: [α]
D
−47.5° (c 0.13, CHCl ); IR (film) υmax
3
28
43
8
1
found 544.2901.
2925, 1770, 1723, 1453, 1253, 1172, 1108, 1023, 759; H NMR (600
MHz, CD Cl ) δ 7.33−7.27 (m, 10H), 5.18 (d, J = 6.0, 1H), 5.16 (t, J
= 7.0 Hz, 1H), 4.69 (s, 1H), 4.61 (s, 1H), 4.51 (d, J = 6.6 Hz, 1H),
3.33 (s, 3H), 3.31 (s, 3H), 2.81 (dq, J = 7.2, 5.9 Hz, 1H), 2.11 (dd, J =
Preparation of (2R,3S,4S,6R,8E)-Allyl 3-hydroxy-4,10-bis-
methoxymethoxy)-2,4,6,8-tetramethylnon-8-enoate (26b).
2
2
(
(
4S,2′R,3′S,4′S,6′R,8′E)-4-Benzyl-3-[3-hydroxy-4,8-bis(methoxy me-
I
dx.doi.org/10.1021/jo501471m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
3.2, 4.8 Hz, 1H), 1.73 (m, 1H), 1.59 (s, 3H), 1.58 (m, 1H), 1.48 (dd,
(16) Searles, S.; Tamres, M.; Barrow, G. B. J. Am. Chem. Soc. 1953,
75, 71−73.
J = 14.4, 6.6 Hz, 1H), 1.33 (s, 3H), 1.28 (m, 1H), 0.65 (d, J = 7.2 Hz,
3
1
1
5
H), 0.62 (d, J = 6.6 Hz, 3H); 13C NMR (125 MHz, CDCl ) δ 176.2,
(17) Latypov, S. K.; Seco, J. M.; Quinoa, E.; Riguera, R. J. Am. Chem.
Soc. 1998, 120, 877−882.
3
70.6, 169.8, 141.3, 136.3, 135.6, 129.2, 128.8 (2C), 128.7, 128.6 (2C),
27.23 (2C), 127.21 (2C), 119.9, 86.0, 82.6, 82.5, 77.6, 61.9, 57.4,
7.3, 47.5 40.9, 38.5, 26.3, 22.7, 20.6, 16.1, 7.8; HRMS (ESI ) calcd for
(18) Zhou, S.; Chen, H.; Liao, W.; Che, S.-H.; Li, G.; Ando, R.;
Kuwajima, I. Tetrahedron Lett. 2005, 46, 6341−6344.
(19) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
+
+
C H O Na [M + Na] 575.2621, found 575.2619.
3
2
40
8
1
(
04, 1737−1739.
20) Takano, D.; Nagamitsu, T.; Ui, H.; Shiomi, K.; Yamaguchi, Y.;
ASSOCIATED CONTENT
■
Masuma, I.; Omura, S. Org. Lett. 2001, 3, 2289−2291.
*
S
Supporting Information
1
(
21) Diasteroisomeric excess was valuated by H NMR.
22) Vatel
Copies of H and 13C NMR spectra for all new compounds
appearing in the schemes, 2D NMR of 3a, 3b and 4−7 as well
as NOE spectra of 3a, 3b and 4. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
(
̀
e, J. M. Tetrahedron Lett. 2006, 47, 715−718.
(23) Pfenninger, A. Synthesis 1986, 2, 89−116.
(24) Johnson, R. A.; Sharpless, K. B. In Comprehensive Organic
Synthesis; Trost, B. M., Flemings, I., Eds.; Pergamon Press: New York,
1
(
(
991; Vol 7, pp 389−436.
25) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1−300.
AUTHOR INFORMATION
■
*
26) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am.
Corresponding Author
E-mail: rosario.hernandez@uca.es.
Chem. Soc. 2002, 124, 393.
(27) May, A. E.; Connell, N. T.; Dahlmann, H. A.; Hoye, T. R. Synlett
2
(
2
(
4
(
010, 13, 1984−1986.
28) Boehlow, T. R.; J Harburn, J. J.; Spilling, C. D. J. Org. Chem.
001, 66, 3111−3118.
29) Heathcock, C. H.; Pirrung, M. C.; Sohn, J. E. J. Org. Chem. 1979,
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(
This research was supported by grants from MINECO
AGL2012-39798-C02-01) and Junta de Andalucia (P07-
FQM-02689). J. M. Botubol is grateful to the Junta de
Andalucia for his research fellowship. We gratefully acknowl-
edge Dr. Muriel Viaud from the UMR BIOGER, INRA
́
(
1
(France) for supplying B. cinerea mutants. Use of NMR and
mass spectrometry facilities at the SCCYT of the University of
Cad
́
iz is acknowledged.
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