Concise route to defined stereoisomers of the hydroxy acid of the chondramides

Article abstract of DOI:10.1016/j.tet.2008.04.109

The use of Kobayashi vinylogous aldol reaction in the reaction with acetaldehyde led to anti-aldol product 11. After reductive removal of the chiral auxiliary, the primary alcohol was converted to the allyliodide 14. This compound could be engaged in an Evans alkylation reaction, leading eventually to hydroxy acid 19. Inclusion of a Mitsunobu inversion reaction on the sequence starting with ent-11 led to hydroxy ester 30, featuring a 6,7-syn-configuration. These hydroxy acids should help to elucidate the correct stereostructure of the chondramide depsipeptides.

Full text of DOI:10.1016/j.tet.2008.04.109

Tetrahedron 64 (2008) 6263–6269
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journal homepage: www.elsevier.com/locate/tet
Concise route to defined stereoisomers of the hydroxy acid of the chondramides
*
Anke Schmauder, Sven Mu¨ller, Martin E. Maier
Institut fu¨r Organische Chemie, Universita¨t Tu¨bingen, Auf der Morgenstelle 18, 72076 Tu¨bingen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of Kobayashi vinylogous aldol reaction in the reaction with acetaldehyde led to anti-aldol
product 11. After reductive removal of the chiral auxiliary, the primary alcohol was converted to the
allyliodide 14. This compound could be engaged in an Evans alkylation reaction, leading eventually to
hydroxy acid 19. Inclusion of a Mitsunobu inversion reaction on the sequence starting with ent-11 led to
hydroxy ester 30, featuring a 6,7-syn-configuration. These hydroxy acids should help to elucidate the
correct stereostructure of the chondramide depsipeptides.
Received 21 March 2008
Received in revised form 25 April 2008
Accepted 28 April 2008
Available online 30 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Since the stereochemistryof jasplakinolide is known, a numberof
syntheses have appeared for the natural product10 as well as the
Screening of the fermentation broth of the myxobacteria
Chondromyces crocatus led to the isolation of four antifungal and
cytostatic depsipeptides, the chondramides A–D (1–4) (Fig. 1).1,2
They are comprised of a tripeptide subunit and a 7-hydroxy-
trimethyloctenoic acid. The tripeptide sector consists of an alanine
u
-hydroxy acid.10,11 On the other hand, for the chondramide just the
constitution was published.1b Due to the structural similarity to
jasplakinolide, structure 3 for chondramide C was proposed by
Ghosh et al.12 However, this seems not to be correct.13 We became
interested in the chondramides as lead structure for targeting the
actin of certain species.14 One major reason for choosing the chon-
followed by a N-methyl-tryptophan and a
b-tyrosine. In two of the
chondramides, the tryptophan is chlorinated in the 2-position. The
dramides is the fact that the u-hydroxyacid7 as a straight polyketide
b
a
-tyrosine unit of chondramides A and B additionally contains an
-methoxy substituent. The chondramides are similar to some
should be much more easier to synthesize than the jasplakinolide
hydroxyacid6. Thisfactalsostimulatedthedesignofsimpleranalogs
of acid 6.15 Typicalroutes to acid6 are based on aldehyde 8. Extension
is done either by reaction with 2-propenyl-magnesium bromide
followed by Claisen rearrangement or by the sequence Wittig re-
action, conversion to an allylic halide, and asymmetric alkylation.10,11
Since the preparation of 8 already requires a number of steps, the
synthesis of hydroxyacid6 in large amounts is cumbersome. In order
to delineate the stereostructure of the chondramides, we designed
an aldol approach that would allow the facile preparation of various
stereoisomers of 7. In this paper we describe the realization of this
goal by employing a vinylogous aldol reaction.16,17
cyclodepsipeptides that have been isolated from marine sponges.
These macrocycles include jasplakinolide3 (5), the geodiamolides,4
neosiphoniamolide,5 and the seragamides.6
All these marine depsipeptides, except for the chondramides,
share the same polyketide
difference between the chondramide and jasplakinolide
u
-hydroxy acid (6) (Fig. 2). The major
-hydroxy
u
acid is a putative acetyl versus lactoyl starter unit for the bio-
synthesis of the polyketide part.7 Accordingly, the macrocycle of
jasplakinolide has a ring size of 19, whereas the chondramides
consist of a smaller, 18-membered ring. Both hydroxy acids, 6 and 7,
feature non-bonded interactions that restrict the conformation of
the polyketide part but should also govern the conformation of the
whole macrocyclic system. Thus, one can identify a syn-pentane
and a 1,3-allylic interaction.8 Even though one would expect dif-
ferent shapes for jasplakinolide and the chondramides,9 they show
similar biological activity. These depsipeptides interfere with the
microfilament fibers of the cytoskeleton. Thus, they exert their
cytostatic effect by inducing actin polymerization.
2. Results
Our target was a hydroxy ester so that in the synthesis of the
depsipeptide, the ester bond to the tripeptide sector would be
formed first. The macrocyclic ring would then be closed by the
formation of an amide bond. Deprotonation and silylation of the
unsaturated imide 9 gave the vinylketene silyl N,O-acetal 10
(Scheme 1).16 Reaction of 10 with distilled acetaldehyde (2 equiv) in
presence of TiCl4 (1 equiv) in CH2Cl2 at ꢀ80 ꢁC provided a good
yield of the anti-aldol adduct 11, probably via transition state A
(Scheme 1). Following silylation of the hydroxyl function with
tBuPh2SiCl (TBDPSCl), the chiral auxiliary was removed from 12 by
* Corresponding author. Tel.: þ49 7071 2975247; fax: þ49 7071 295137.
E-mail address: martin.e.maier@uni-tuebingen.de (M.E. Maier).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.109

6264
A. Schmauder et al. / Tetrahedron 64 (2008) 6263–6269
OH
OH
O
O
H
N
H
N
N
N
R1
O
N
N
O
H
H
O
O
O
O
6
R2
6
Me
Me
H
H
N
N
O
O
R2
H
R1
OMe
proposed by Ghosh for 3
Chondramide A (1)
Chondramide B (2)
Chondramide C (3)
Chondramide D (4)
OH
OMe Cl
H
H
H
Cl
O
H
N
Br
N
O
H
N
O
O
Me
H
N
Jasplakinolide (5)
O
Figure 1. Structures of the chondramides and of jasplakinolide (5).
O
O
O
O
TBSO
1. NaN(SiMe3)2
THF, –80 °C
TiCl4
CH2Cl2
H
N
O
N
N
O
vinylogous
aldol
alkylation
2. TBSCl
–80 °C
(71%)
OP
8
O
9
10
OH
H
HO2C
HO2C
O
O
OTBDPS
O
OH
O
OH
6
7
TBDPSCl, imidaz.
CH2Cl2, 0 °C (96%)
O
N
O
1,3-allylic interaction
syn-pentane interaction
hydroxy acid of jasplakinolide
12
11
Figure 2. The
chemistry of 7 reflects the Ghosh proposal.
u-hydroxy acids of jasplakinolide and the chondramides. The stereo-
OTBDPS OH
OTBDPS
I
NaBH4, THF/H2O
0 to RT (89%)
(PhO)3P+Me I–
DMF, 0 °C
13
14
O
O
reduction with sodium borohydride in aqueous THF.18 This pro-
vided the allylic alcohol 13. The subsequent conversion of 13 to the
corresponding allylic iodide turned out to be non-trivial and many
reagents gave 14 only in moderate yield. However, methyl-
triphenoxyphosphonium iodide gave rise to allylic iodide 14 in
good yield.19,20 Since the double bond of 14 can undergo isomeri-
zation during flash chromatography, iodide 14 was used crude for
the subsequent alkylation of propionyloxazolidinone21 15. Using
standard conditions, that is, deprotonation of 15 with NaN(SiMe3)2
in THF followed by addition of iodide 14 furnished compound 16 in
71% yield based on alcohol 13. Hydrolysis of the carboxylic acid
derivative 16 led to the OH-protected acid 17. Esterification of the
acid with tBuOH under Yamaguchi conditions22 gave ester 18.
Finally, cleavage of the silyl ether using TBAF provided hydroxy
ester 19, suitable for esterification with the tripeptide fragment of
the chondramides.
N
O
15
O
OTBDPS
O
H2O2, LiOH
Bn
NaN(SiMe3)2, THF
–80 °C (71%, 2 steps)
N
O
THF/H2O (74%)
16
Bn
OTBDPS
OTBDPS
Cl3C6H2COCl
CO2H
CO2tBu
tBuOH, DMAP
toluene (91%)
17
18
aldol via:
TiCl4
H
OH
O
Me
Me
TBAF, THF, 50 °C
(82%)
CO2tBu
H
Me
19
A
Y
OTBS
In a related manner the vinylogous aldol reaction with acetal-
dehyde was carried out with ent-10 providing the aldol product ent-
11 (74% yield) (Scheme 2). Access tothe 6,7-syn-diastereomer should
be possible by Mitsunobu inversion.23 This was demonstrated on
aldol product ent-11 using benzoic acid. However, this also might be
possible by reaction of a hydroxy ester such as 19 or ent-19 with the
tripeptide acid. In the case of ent-11 we obtained the benzoate 20.
Reductive removal of the chiral auxiliary delivered allylic alcohol 21.
Scheme 1. Synthesis of the 6,7-anti-hydroxy ester 19 by vinylogous aldol reaction.
To be on the safe side the benzoate was replaced by a robust silyl
protecting group. This was achieved in a simple four-step sequence
consisting of benzoate cleavage under basic conditions, selective
pivaloylation of the primary alcohol to give 23, silylation of the
secondary hydroxyl group, and reductive removal of the pivaloyl

A. Schmauder et al. / Tetrahedron 64 (2008) 6263–6269
6265
group using DIBAL-H leading to alcohol 25. Using the same sequence
of steps as shown before (cf. Scheme 1), the allylic alcohol 25 could
be transformed to the 6,7-syn-hydroxy ester 30 via a sequence of
iodination to 26, asymmetric alkylation with 15 providing 27 (77%,
two steps), saponification (84%) to the acid 28, esterification with
tBuOH (90%) yielding ester 29, and cleavage of the silyl ether.
with electron spray ionization (ESI). Analytical LC–MS: HP 1100
Series connected with an ESI MS detector Agilent G1946C; positive
mode with fragmentor voltage of 40 eV; column: Nucleosil 100-5,
C-18 HD, 5
m
m, 70ꢂ3 mm Machery-Nagel; eluent: NaCl solution
(5 mM)/acetonitrile; gradient: 0–10–15–17–20 min with 20–80–
80–99–99% acetonitrile; flow rate: 0.5 mL minꢀ1. Flash chromatog-
raphy: J. T. Baker silica gel 43–60 mm. Thin-layer chromatography:
Machery-Nagel Polygram Sil G/UV254. Perkin–Elmer 341 Polarim-
eter, Na-lamp, 589 nm, 1 dm cuvette, 25 ꢁC. Solvents were distilled
prior to use; petroleum ether with a boiling range of 40–60 ꢁC was
used. Reactions were generally run under a nitrogen atmosphere.
O
O
TBSO
OH
O
TiCl4, CH2Cl2
N
O
N
O
–80 °C, (74%)
O
ent-10
ent-11
4.1.1. (4S)-3-((10E,30E)-10-{[tert-Butyl(dimethyl)silyl]oxy}-20-
H
methyl-10,30-pentadienyl)-4-isopropyl-1,3-oxazolidin-2-one (10)16
To a stirred solution of acylated oxazolidinone 9 (8.00 g,
35.5 mmol) in THF (380 mL) was added dropwise NaN(SiMe3)2
(9.8 g, 53.3 mmol), dissolved in THF (60 mL) at ꢀ80 ꢁC. After
90 min, tBuMe2SiCl (TBSCl, 16.1 g, 106.5 mmol) in THF (80 mL) was
added and the mixture was stirred for 30 min. The reaction mixture
was treated with saturated NH4Cl solution (100 mL) and allowed to
warm to room temperature. The aqueous layer was extracted with
ethyl acetate (2ꢂ200 mL). The combined organic layers were
washed with water (100 mL) and saturated NaCl solution (100 mL),
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography (petroleum ether/EtOAc, 7:1)
O
OBz
O
OBz
OH
NaBH4, THF
0 °C (87%)
PhCO2H, Ph3P
N
O
DEAD, toluene
0 °C (75%)
20
21
OH
OH
OH
OPiv
NaOH
PivCl, Py
MeOH, RT
(74%)
CH2Cl2 (82%)
22
TBDPSO
23
OPiv
TBDPSCl, imidaz.
DIBAL-H
CH2Cl2, 0 °C (99%)
to give ketene acetal 10 (11.12 g, 92%) as a colorless oil. Rf¼0.33 (pe-
CH2Cl2, –80 °C
ꢀ55.6 (c 1.00, CH2Cl2); 1H NMR
20
(92%)
24
troleum ether/EtOAc, 7:1); [a]
D
O
O
(400 MHz, CDCl3):
d
[ppm]¼0.13, 0.18 (2s, 3H each, Si(CH3)2C(CH3)3),
N
O
15
OTBDPS OH
0.91 (d, J¼6.9 Hz, 6H, CH(CH3)2), 0.96 (s, 9H, Si(CH3)2C(CH3)3), 1.73–
1.79 (m, 6H, 20-CH3, 50-H),1.85–2.00 (m,1H, CH(CH3)2), 3.92–4.04 (m,
1H, 4-H), 4.11(dd,J¼8.4,8.4 Hz,1H, 5-H), 4.30(dd,J¼8.8,8.8 Hz,1H, 5-
H), 5.62 (qd, J¼15.4, 6.7 Hz,1H, 40-H), 6.19 (d, J¼15.5 Hz, 1H, 30-H); 13C
OTBDPS
I
(PhO)3P+Me I–
DMF, 0 °C
Bn
NaN(SiMe3)2, THF
–80 °C (77%, 2 steps)
25
26
NMR (100 MHz, CDCl3):
d
[ppm]¼ꢀ4.9, ꢀ4.3 (Si(CH3)2C(CH3)3), 12.3
(20-CH3),16.3 (CH(CH3)2),18.0 (Si(CH3)2C(CH3)3),18.3 (CH(CH3)2),18.8
(C-50), 25.6 (Si(CH3)2C(CH3)3), 29.3 (CH(CH3)2), 59.4 (C-4), 64.4 (C-5),
115.0 (C-20), 124.3 (C-40), 128.1 (C-30), 134.7 (CO), 155.9 (CO); HMRS
(ESI): [MþNa]þ calcd for C18H33NO3Si 362.2122, found 362.2121.
O
OTBDPS
O
OTBDPS
H2O2, LiOH
CO2H
N
O
THF/H2O (84%)
27
Bn
28
OTBDPS
4.1.2. (4S)-3-[(20E,40S,50R)-50-Hydroxy-20,40-dimethyl-20-hexenoyl]-
4-isopropyl-1,3-oxazolidin-2-one (11)
Cl3C6H2COCl
TBAF, THF, 50 °C
(87%)
CO2tBu
tBuOH, DMAP
toluene (90%)
To a stirred solution of acetaldehyde (0.91 mL, 16.04 mmol) in
CH2Cl2 (40 mL) at ꢀ80 ꢁC were added a 1.0 M solution of TiCl4 in
CH2Cl2 (8.02 mL, 8.02 mmol) and a solution of oxazolidinone 10
(2.72 g, 8.02 mmol) in CH2Cl2 (40 mL) dropwise resulting in a color
change from yellow to red. After stirring for 16 h at ꢀ80 ꢁC, the
reaction mixture was quenched with pyridine (5 mL). Saturated
Rochelle salt solution (15 mL) and saturated NaHCO3 (15 mL) so-
lution were added and the mixture was allowed to warm to room
temperature The aqueous layer was extracted with ethyl acetate
(2ꢂ50 mL). The combined organic layers were washed with water
and saturated NaCl solution, dried over Na2SO4, filtered, and con-
centrated in vacuo. The residue was purified by flash chromatog-
raphy (petroleum ether/EtOAc, 2:1) to give alcohol 11 (1.53 g, 71%)
29
OH
CO2tBu
30
Scheme 2. Synthesis of the hydroxy ester 30 via ent-11 followed by Mitsunobu in-
version at C7.
3. Conclusion
We could illustrate a very concise strategy to stereoisomers of the
7-hydroxy acid of the chondramides. Work is now in progress to
prepare the corresponding chondramide derivatives in order to de-
lineate the correct stereostructure of the chondramides. The advan-
tageoftheapproachisthatgramamountsoftheacidscanbeprepared.
as a colorless solid; mp 53 ꢁC. Rf¼0.28 (petroleum ether/EtOAc,
20
2:1); [
d
a
]
þ2.5 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3):
D
[ppm]¼0.89 (d, J¼6.9 Hz, 3H, CH(CH3)2), 0.90 (d, J¼6.9 Hz, 3H,
CH(CH3)2), 0.95 (d, J¼6.6 Hz, 3H, 40-CH3), 1.22 (d, J¼6.1 Hz, 3H,
60-H), 1.92 (d, J¼1.5 Hz, 3H, 20-CH3), 2.25–2.36 (m, 1H, CH(CH3)2),
2.41–2.52 (m, 1H, 40-H), 3.21 (d, J¼2.0 Hz, 1H, OH), 3.44–3.53 (m,
1H, 50-H), 4.16 (dd, J¼9.0, 5.7 Hz, 1H, 5-H), 4.31 (dd, J¼9.0, 9.0 Hz,
1H, 5-H), 4.55 (ddd, J¼10.2, 5.6, 4.6 Hz, 1H, 4-H), 5.74–5.80 (m, 1H,
4. Experimental
4.1. General
1H and 13C NMR: Bruker Avance 400, spectra were recorded at
295 K either in CDCl3 or in acetone-d6. Chemical shifts are cali-
brated with respect to the residual proton and carbon resonance of
(dH 7.25 ppm, dC 77.0 ppm); acetone-d6 (dH
2.40 ppm, dC 29.8 ppm). HRMS (FT-ICR): Bruker Daltonic APEX 2
30-H); 13C NMR (100 MHz, CDCl3):
d
[ppm]¼13.9 (20-CH3), 15.2
(CH(CH3)2), 16.1 (40-CH3), 17.8 (CH(CH3)2), 20.0 (C-60), 28.4
(CH(CH3)2), 41.9 (C-40), 58.0 (C-4), 63.4 (C-5), 71.6 (C-50), 131.2
(C-20), 142.1 (C-30), 154.5 (CO), 171.5 (CO); HMRS (ESI): [MþNa]þ
calcd for C14H23NO4 292.15193, found 292.15191.
the solvent: CDCl3

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A. Schmauder et al. / Tetrahedron 64 (2008) 6263–6269
4.1.3. (4S)-3-((20E,40S,50R)-50-{[tert-Butyl(diphenyl)silyl]oxy}-20,40-
dimethyl-20-hexenoyl)-4-isopropyl-1,3-oxazolidin-2-one (12)
Si(Ph)2C(CH3)3), 1.60 (d, J¼1.3 Hz, 3H, 2-CH3), 2.36–2.48 (m, 1H, 4-
H), 3.80–3.89 (m,1H, 5-H), 3.97–4.05 (m, 2H,1-H), 5.67 (d, J¼9.7 Hz,
1H, 3-H), 7.37–7.50 (m, 6H, Har), 7.66–7.76 (m, 4H, Har); 13C NMR
To a stirred solution of aldol product 11 (1.53 g, 5.70 mmol) in
CH2Cl2 (25 mL) at 0 ꢁC were added imidazole (1.16 g, 17.09 mmol)
and a catalytic amount of DMAP. The mixture was stirred for 10 min
before TBDPSCl (2.96 mL, 11.39 mmol) was added. The mixture was
allowed to warm to room temperature. After stirring for 20 h, the
reaction mixture was quenched with water and the aqueous layer
was extracted with CH2Cl2 (2ꢂ30 mL). The combined organic layers
were dried over NaSO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (petroleum ether/
(100 MHz, acetone-d6):
d
[ppm]¼15.4 (C-1), 15.6 (4-CH3), 17.3 (2-
CH3), 19.9 (Si(Ph)2C(CH3)3), 20.2 (C-6), 27.4 (Si(Ph)2C(CH3)3), 40.7
(C-4), 73.3 (C-5), 128.4 (Car), 128.5 (Car), 130.4 (Car), 130.6 (Car), 132.8
(C-3), 134.2 (Car), 134.7 (Car), 135.3 (C-2), 136.6 (Car).
4.1.6. (4R)-4-Benzyl-3-((20S,40E,60S,70R)-70-{[tert-butyl-
(diphenyl)silyl]oxy}-20,40,60-trimethyloct-40-enoyl)-1,3-oxazolidin-
2-one (16)
EtOAc, 7:1) to afford silyl ether 12 (2.78 g, 96%) as a colorless oil.
To a stirred solution of NaN(SiMe3)2 (2.78 g, 15.18 mmol) in THF
(20 mL) was added (4R)-4-benzyl-3-propionyl-1,3-oxazolidin-2-
one21 (15) (3.22 g, 13.8 mmol) in THF (7 mL) at ꢀ80 ꢁC. After 1 h,
iodide 14 (2.27 g crude, about 4.6 mmol) in THF (3 mL) was added
and the reaction mixture was allowed to warm to ꢀ50 ꢁC. After
stirring the reaction mixture at this temperature for 18 h, the
mixture was quenched with saturated NH4Cl solution (10 mL) and
allowed to warm to room temperature. The layers were separated
and the aqueous layer was extracted with CH2Cl2 (2ꢂ40 mL). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography (petroleum ether/EtOAc, 7:1) to give oxazolidi-
20
Rf¼0.37 (petroleum ether/EtOAc, 7:1); [
a
]
þ8.0 (c 1.00, CH2Cl2);
D
1H NMR (400 MHz, CDCl3):
d
[ppm]¼0.89 (d, J¼6.6 Hz, 3H,
CH(CH3)2), 0.90 (d, J¼6.8 Hz, 3H, CH(CH3)2), 1.01–1.08 (m, 15H,
Si(Ph)2C(CH3)3, 40-CH3, 60-H), 1.69 (d, J¼1.3 Hz, 3H, 20-CH3), 2.30–
2.40 (m, 1H, CH(CH3)2), 2.48–2.57 (m, 1H, 40-H), 3.87 (qd, J¼9.7,
3.6 Hz, 1H, 50-H), 4.15 (dd, J¼8.9, 5.6 Hz, 1H, 5-H), 4.29 (dd, J¼8.9,
8.9 Hz, 1H, 5-H), 4.50 (ddd, J¼9.7, 5.3, 4.5 Hz, 1H, 4-H), 6.02–6.07
(m, 1H, 30-H), 7.31–7.44 (m, 6H, Har), 7.64–7.74 (m, 4H, Har); 13C
NMR (100 MHz, CDCl3):
d
[ppm]¼13.4 (20-CH3), 15.0 (CH(CH3)2),
15.0 (40-CH3), 17.8 (CH(CH3)2), 19.4 (Si(Ph)2C(CH3)3), 20.3 (C-60),
27.0 (Si(Ph)2C(CH3)3), 28.2 (CH(CH3)2), 39.9 (C-40), 58.2 (C-4), 63.3
(C-5), 72.0 (C-50),127.4 (Car), 127.6 (Car), 129.4 (Car),129.6 (Car),130.9
(C-20), 134.0 (Car), 134.6 (Car), 135.9 (Car), 141.0 (C-30), 153.5 (CO),
172.0 (CO); HMRS (ESI): [MþNa]þ calcd for C30H41NO4Si 530.26971,
found 530.26963.
none 16 (1.954 g, 71% over two steps) as a colorless oil. Rf¼0.21
20
(petroleum ether/EtOAc, 7:1); [
a
]
D
ꢀ33.8 (c 1.00, CH2Cl2); 1H NMR
(400 MHz, CDCl3):
d
[ppm]¼1.04 (d, J¼6.6 Hz, 6H, 80-H, 60-CH3), 1.13
(s, 9H, Si(Ph)2C(CH3)3), 1.15 (d, J¼6.6 Hz, 3H, 20-CH3), 1.49 (s, 3H, 40-
CH3), 2.05 (dd, J¼13.0, 8.4 Hz, 1H, 30-H), 2.44–2.52 (m, 1H, 60-H),
2.56 (dd, J¼13.2, 6.1 Hz, 1H, 30-H), 2.75 (dd, J¼13.2, 9.9 Hz, 1H,
CH2Ph), 3.32 (dd, J¼13.2, 3.1 Hz, 1H, CH2Ph), 3.79–3.87 (m, 1H, 70-
H), 3.94–4.04 (m, 1H, 20-H), 4.18–4.27 (m, 2H, 5-H), 4.70–4.78 (m,
1H, 4-H), 5.18 (d, J¼9.4, 1H, 50-H), 7.23–7.26 (m, 1H, Har), 7.42 (m,
10H, Har), 7.75 (m, 4H, Har); 13C NMR (100 MHz, CDCl3):
4.1.4. (2E,4S,5R)-5-{[tert-Butyl(diphenyl)silyl]oxy}-2,4-dimethyl-2-
hexen-1-ol (13)
To a stirred solution of oxazolidinone 12 (2.86 g, 5.63 mmol) in
THF (66 mL) at 0 ꢁC was added NaBH4 (1.07 g, 28.15 mmol) in H2O
(33 mL). The reaction mixture was allowed to warm to room
temperature and stirred for 6 h, before the reaction mixture was
quenched with saturated NH4Cl solution (200 mL). The aqueous
layer was extracted with CH2Cl2 (2ꢂ40 mL). The combined or-
ganic layers were dried over Na2SO4, filtered, and concentrated in
vacuo. The crude product was purified by flash chromatography
d
[ppm]¼15.3 (40-CH3), 15.5 (60-CH3), 16.2 (20-CH3), 19.4 (C-8,
Si(Ph)2C(CH3)3), 27.0 (Si(Ph)2C(CH3)3), 35.6 (C-20), 38.1 (CH2Ph),
39.3 (C-60), 44.1 (C-30), 55.3 (C-4), 65.9 (C-5), 72.4 (C-70), 127.3 (Car),
127.3 (Car), 127.5 (Car), 128.9 (Car), 129.3 (Car), 129.4 (Car), 129.5 (Car),
130.4 (C-50), 132.2 (Car), 134.3 (C-40), 134.9 (Car), 135.3 (Car), 135.9
(Car), 153.1 (CO), 177.1 (CO); HMRS (ESI): [MþNa]þ calcd for
(petroleum ether/EtOAc, 6:1) to afford alcohol 13 (1.92 g, 89%) as
20
a colorless oil. Rf¼0.28 (petroleum ether/EtOAc, 6:1); [
a]
ꢀ1.2 (c
C37H47NO4Si 620.31666, found 620.31640.
D
1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
[ppm]¼0.96 (d,
J¼6.9 Hz, 3H, 4-CH3), 0.99 (d, J¼6.1 Hz, 3H, 6-H), 1.05 (s, 9H,
Si(Ph)2C(CH3)3), 1.14 (br s, 1H, OH), 1.45 (d, J¼1.3 Hz, 3H, 2-CH3),
2.40–2.51 (m, 1H, 4-H), 3.71–3.79 (m, 1H, 5-H), 3.92 (br s, 2H, 1-
H), 5.20–5.25 (m, 1H, 3-H), 7.31–7.49 (m, 6H, Har), 7.64–7.72 (m,
4.1.7. (2S,4E,6S,7R)-7-{[tert-Butyl(diphenyl)silyl]oxy}-2,4,6-
trimethyloct-4-enoic acid (17)
To a solution of oxazolidinone 16 (1.95 g, 3.27 mmol) in THF
(35 mL) was added H2O2 (30% in water, 1.34 mL, 13.07 mmol) at
0 ꢁC, followed by the addition of a solution of LiOH$H2O (0.274 g,
6.54 mmol) in water (17 mL). The reaction mixture was allowed to
warm to room temperature and after stirring for 15 h, saturated
Na2S2O3 solution (5 mL) and saturated NaHCO3 solution (5 mL)
were added. The aqueous layer was extracted with CH2Cl2
(2ꢂ20 mL) and the combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. Flash chromatography
(petroleum ether/EtOAc, 5:1) of the residue provided acid 17
4H, Har); 13C NMR (100 MHz, CDCl3):
d
[ppm]¼13.7 (2-CH3), 15.4
(4-CH3), 19.4 (Si(Ph)2C(CH3)3), 19.6 (C-6), 27.0 (Si(Ph)2C(CH3)3),
39.2 (C-4), 69.0 (C-1), 72.6 (C-5), 127.4 (Car), 127.5 (Car), 129.0 (C-
3), 129.4 (Car), 129.5 (Car), 134.4 (C-2), 134.7 (Car), 134.8 (Car), 135.9
(Car); HMRS (ESI): [MþNa]þ calcd for C24H34O2Si 405.22203,
found 405.22214.
4.1.5. (2E,4S,5R)-5-{[tert-Butyl(diphenyl)silyl]oxy}-2,4-dimethyl-1-
iodo-2-hexene (14)
(1.13 g, 79%) as a colorless oil. Rf¼0.24 (petroleum ether/EtOAc,
20
To a stirred solution of alcohol 13 (1.76 g, 4.60 mmol) in DMF
(6 mL) at 0 ꢁC was added methyltriphenoxyphosphonium iodide
(2.55 g, 5.64 mmol) in DMF (5 mL) dropwise. The reaction mixture
was allowed to warm to room temperature and stirred for 30 min.
The reaction mixture was diluted with hexane (70 mL) and the
organic layer was washed with cold aqueous 1 N NaOH (2ꢂ15 mL)
and water (2ꢂ15 mL). The organic layer was dried over Na2SO4,
filtered, and concentrated in vacuo to afford iodide 14 (2.32 g,
crude) as yellow oil. The crude product was used for the next re-
action without further purification. Rf¼0.38 (petroleum ether/
5:1); [
d
a
]
ꢀ15.8 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3):
D
[ppm]¼0.95 (d, J¼6.4 Hz, 6H, 8-H, 6-CH3), 1.06 (s, 9H,
Si(Ph)2C(CH3)3), 1.08 (d, J¼6.9 Hz, 3H, 2-CH3), 1.36 (s, 3H, 4-CH3),
2.01 (dd, J¼13.6, 8.0 Hz, 1H, 3-H), 2.29–2.45 (m, 2H, 3-H, 6-H), 2.51–
2.62 (m, 1H, 2-H), 3.71–3.80 (m, 1H, 7-H), 5.07 (d, J¼9.4 Hz, 1H, 5-
H), 7.31–7.45 (m, 6H, Har), 7.64–7.74 (m, 4H, Har); 13C NMR
(100 MHz, CDCl3):
d
[ppm]¼15.4 (6-CH3),15.7 (4-CH3),16.2 (2-CH3),
19.4 (Si(Ph)2C(CH3)3), 19.5 (C-8), 27.0 (Si(Ph)2C(CH3)3), 37.8 (C-2),
39.4 (C-6), 43.8 (C-3), 72.5 (C-7), 127.4 (Car), 127.5 (Car), 129.4 (Car),
129.5 (Car), 130.3 (C-5), 131.8 (C-4), 134.3 (Car), 134.9 (Car), 135.9
(Car), 136.0 (Car), 183.1 (CO); HMRS (ESI): [MþNa]þ calcd for
EtOAc, 40:1); 1H NMR (400 MHz, acetone-d6):
J¼7.1 Hz, 3H, 4-CH3), 0.99 (d, J¼6.4 Hz, 3H, 6-H), 1.06 (s, 9H,
d
[ppm]¼0.97 (d,
C27H38O3Si 461.24824, found 461.24824.

A. Schmauder et al. / Tetrahedron 64 (2008) 6263–6269
6267
4.1.8. tert-Butyl (2S,4E,6S,7R)-7-{[tert-butyl(diphenyl)silyl]oxy}-
2,4,6-trimethyloct-4-enoate (18)
(CH(CH3)2, C-60), 28.2 (CH(CH3)2), 38.3 (C-40), 58.2 (C-4), 63.4 (C-5),
74.4 (C-50), 128.3 (Car), 129.6 (Car), 130.6 (Car), 131.8 (C-20), 132.8
(Car), 138.4 (C-30), 153.5 (CO), 166.0 (CO), 171.7 (CO); HMRS (ESI):
[MþNa]þ calcd for C21H27NO5 396.17814, found 396.17804.
To a stirred solution of acid 17 (0.237 g, 0.54 mmol) in toluene
(5 mL) were added Et3N (0.225 mL, 1.62 mmol) and 2,4,6-tri-
chlorobenzoyl chloride (0.085 mL, 0.54 mmol). After 30 min, tBuOH
(0.103 mL, 1.08 mmol) and DMAP (0.264 g, 2.16 mmol) were added
and the mixture was stirred for 1 h at room temperature. The re-
action mixture was quenched with saturated NaHCO3 solution
(5 mL) and the aqueous layer was extracted with EtOAc (2ꢂ10 mL).
The combined organic layers were dried over NaSO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography (petroleum ether/EtOAc, 30:1) to afford ester 18
4.1.11. (2E,4R,5R)-5-(Benzoyloxy)-2,4-dimethyl-2-hexen-1-ol (21)
To a stirred solution of acylated oxazolidinone 20 (4.72 g,
12.63 mmol) in THF (140 mL) was added NaBH4 (2.39 g, 63.1 mmol)
in water (70 mL) at 0 ꢁC. The reaction mixture was warmed to room
temperature and after stirring for 3 h, it was treated with saturated
NH4Cl solution (40 mL). The aqueous layer was extracted with
CH2Cl2 (2ꢂ80 mL) and the combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography (petroleum ether/EtOAc, 4:1) to
(0.242 g, 91%) as a colorless oil. Rf¼0.28 (petroleum ether/EtOAc,
20
30:1); [
d
a
]
ꢀ11.9 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3):
D
[ppm]¼0.95 (d, J¼6.1 Hz, 3H, 8-H), 0.97 (d, J¼6.9 Hz, 3H, 6-CH3),
afford primary alcohol 21 (2.74 g, 87%) as a colorless oil. Rf¼0.23
20
1.01 (d, J¼6.9 Hz, 3H, 2-CH3), 1.06 (s, 9H, Si(Ph)2C(CH3)3), 1.35 (d,
J¼1.0 Hz, 3H, 4-CH3), 1.41 (s, 9H, C(CH3)3), 1.94 (dd, J¼13.5, 7.5 Hz,
1H, 3-H), 2.29 (dd, J¼13.5, 7.4 Hz, 1H, 3-H), 2.35–2.48 (m, 2H, 2-H,
6-H), 3.70–3.80 (m, 1H, 7-H), 5.03 (d, J¼9.4 Hz, 1H, 5-H), 7.32–7.44
(m, 6H, Har), 7.64–7.73 (m, 4H, Har); 13C NMR (100 MHz, CDCl3):
(petroleum ether/EtOAc, 4:1); [
a
]
ꢀ25.1 (c 1.00, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3):
d
[ppm]¼1.04 (d, J¼6.9 Hz, 3H, 4-CH3), 1.28 (d,
J¼6.4 Hz, 3H, 6-H), 1.49 (br s,1H, OH), 1.69 (d, J¼1.02 Hz, 3H, 2-CH3),
2.70–2.82 (m, 1H, 4-H), 4.01 (s, 2H, 1-H), 4.96–5.05 (m, 1H, 5-H),
5.27–5.34 (m, 1H, 3-H), 7.43 (t, J¼7.6 Hz, 2H, Har), 7.54 (t, J¼7.4 Hz,
1H, Har), 8.02 (m, 2H, Har); 13C NMR (100 MHz, CDCl3):
d
[ppm]¼15.3 (6-CH3), 15.7 (4-CH3), 16.8 (2-CH3), 19.3 (C-8), 19.4
(Si(Ph)2C(CH3)3), 27.0 (Si(Ph)2C(CH3)3), 28.1 (C(CH3)3), 38.8 (C-6),
39.2 (C-2), 44.2 (C-3), 72.5 (C-7), 79.2 (C(CH3)3), 127.3 (Car), 127.5
(Car), 129.3 (Car), 129.3 (Car), 129.5 (Car), 129.6 (C-5), 132.5 (C-4),
134.4 (Car), 135.0 (Car), 135.9 (Car), 175.9 (CO); HMRS (ESI): [MþNa]þ
calcd for C31H46O3Si 517.31084, found 517.31077.
d
[ppm]¼14.1 (2-CH3), 16.8 (4-CH3), 17.6 (C-6), 37.3 (C-4), 68.7 (C-1),
75.0 (C-5), 127.1 (C-3), 128.3 (Car), 129.5 (Car), 130.7 (Car), 132.8 (Car),
135.8 (C-2), 166.2 (CO); HMRS (ESI): [MþNa]þ calcd for C15H20O3
271.13047, found 271.13061.
4.1.12. (2E,4R,5R)-2,4-Dimethyl-2-hexene-1,5-diol (22)
4.1.9. tert-Butyl (2S,4E,6S,7R)-7-hydroxy-2,4,6-trimethyloct-4-
enoate (19)
To a stirred solution of silyl ether 18 (0.23 g, 0.46 mmol) in THF
(5 mL) was added Bu4NF$3H2O (TBAF, 0.58 g, 1.84 mmol) and the
mixture was stirred for 14 h at 55 ꢁC. Thereafter, the solvent was
removed in vacuo and flash chromatography (petroleum ether/
To a stirred solution of benzoate 21 (2.67 g, 10.74 mmol) in
MeOH (180 mL), NaOH (2.15 g, 53.68 mmol) was added at 0 ꢁC. The
reaction mixture was allowed to warm to room temperature, and
after 20 h the solution was concentrated in vacuo. The residue was
diluted with water and extracted with CH2Cl2 (2ꢂ50 mL). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
EtOAc, 6:1) of the residue provided hydroxy ester 19 (0.097 g, 82%)
20
as a colorless oil. Rf¼0.23 (petroleum ether/EtOAc, 6:1); [
a
]
D
ꢀ37.6
chromatography (CH2Cl2/MeOH, 15:1) to give diol 22 (1.15 g, 74%)
20
(c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
[ppm]¼0.89 (d,
as a colorless oil. Rf¼0.16 (CH2Cl2/MeOH, 15:1); [
a]
þ26.7 (c 1.00,
D
J¼6.9 Hz, 3H, 6-CH3), 1.05 (d, J¼6.9 Hz, 3H, 2-CH3), 1.13 (d, J¼6.1 Hz,
3H, 8-H), 1.40 (s, 9H, C(CH3)3), 1.63 (d, J¼0.8 Hz, 3H, 4-CH3), 1.78 (s,
1H, OH), 2.03 (dd, J¼13.9, 6.7 Hz,1H, 3-H), 2.25–2.38 (m, 2H, 3-H, 6-
H), 2.45–2.55 (m, 1H, 2-H), 3.39–3.48 (m, 1H, 7-H), 4.98 (d,
CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
[ppm]¼0.96 (d, J¼6.6 Hz, 3H,
4-CH3), 1.11 (d, J¼6.4 Hz, 3H, 6-H), 1.67 (d, J¼1.0 Hz, 3H, 2-CH3),
1.94 (br s, 1H, OH), 2.17 (br s, 1H, OH), 2.41–2.53 (m, 1H, 4-H), 3.57–
3.68 (m, 1H, H-5), 3.97 (s, 2H, 1-H), 5.22–5.30 (m, 1H, 3-H); 13C
J¼9.7 Hz, 1H, 5-H); 13C NMR (100 MHz, CDCl3):
d
[ppm]¼16.7
NMR (100 MHz, CDCl3):
d
[ppm]¼14.1 (2-CH3), 16.2 (4-CH3), 20.1
(4-CH3), 16.8 (6-CH3), 17.0 (2-CH3), 20.0 (C-8), 28.0 (C(CH3)3), 38.9
(C-2), 40.6 (C-6), 43.8 (C-3), 71.7 (C-7), 79.9 (C(CH3)3), 129.0 (C-5),
135.3 (C-4), 175.7 (CO); HMRS (ESI): [MþNa]þ calcd for C15H28O3
279.19307, found 279.19305.
(C-6), 39.2 (C-4), 68.6 (C-1), 71.8 (C-5), 127.7 (C-3), 135.7 (C-2);
HMRS (ESI): [MþNa]þ calcd for C8H16O2 167.10425, found
167.10417.
4.1.13. (20E,40R,50R)-50-Hydroxy-20,40-dimethyl-20-hexenyl
pivalate (23)
4.1.10. (4R)-3((20E,40R,50R)-50-(Benzoyloxy)-20,40-dimethyl-20-
hexenoyl)-4-isopropyl-1,3-oxazolidin-2-one (20)
To a stirred solution of diol 22 (0.19 g, 1.35 mmol) in CH2Cl2
(5 mL) and pyridine (1.09 mL, 13.45 mmol) was added pivaloyl
chloride (0.17 mL, 1.35 mmol) dropwise at 0 ꢁC, followed by stirring
the reaction mixture for 1 h. Then, water was added and the layers
were separated. The aqueous layer was extracted with EtOAc
(2ꢂ20 mL). The combined organic layers were washed with 1 N HCl
(10 mL), saturated NaHCO3 solution (10 mL), and saturated NaCl
solution (10 mL), then dried over Na2SO4, filtered, and concentrated
in vacuo. The crude product was purified by flash chromatography
To a stirred solution of Ph3P (9.07 g, 34.89 mmol) and benzoic
acid (6.34 g, 51.88 mmol) in toluene (120 mL) was added DEAD
(40% in toluene, 17.44 mL, 38.05 mmol) at 0 ꢁC. Then a solution of
alcohol ent-11 (2.33 g, 8.65 mmol) in toluene (20 mL) was added
dropwise and the reaction mixture was allowed to warm to room
temperature. After stirring for 16 h, the reaction mixture was
concentrated in vacuo and the residue purified by flash chroma-
tography (petroleum ether/EtOAc, 5:1) to give benzoate 20 (2.42 g,
75%) as a colorless solid; mp 74.9 ꢁC. Rf¼0.22 (petroleum ether/
(petroleum ether/EtOAc, 5:1) to afford pivalate 23 (0.31 g, 82%) as
20
20
EtOAc, 5:1); [
d
a]
ꢀ48.7 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3):
a colorless oil. Rf¼0.18 (petroleum ether/EtOAc, 5:1); [
a]
þ25.8 (c
D
D
[ppm]¼0.89 (d, J¼7.4 Hz, 3H, CH(CH3)2), 0.91 (d, J¼7.6 Hz, 3H,
1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
[ppm]¼0.97 (d,
CH(CH3)2),1.08 (d, J¼6.6 Hz, 3H, 40-CH3),1.36 (d, J¼6.4 Hz, 3H, 60-H),
1.93 (d, J¼1.3 Hz, 3H, 20-CH3), 2.30–2.43 (m, 1H, CH(CH3)2), 2.81–
2.93 (m, 1H, 40-H), 4.17 (dd, J¼8.9, 5.3 Hz, 1H, 5-H), 4.30 (dd, J¼8.8,
8.8 Hz, 1H, 5-H), 4.46–4.52 (m, 1H, 4-H), 5.01–5.10 (m, 1H, 50-H),
5.80–5.88 (m, 1H, 30-H), 7.42 (t, J¼7.6 Hz, 2H, Har), 7.54 (t, J¼7.4 Hz,
1H, Har), 8.02–8.08 (m, 2H, Har); 13C NMR (100 MHz, CDCl3):
J¼6.6 Hz, 3H, 40-CH3), 1.10 (d, J¼6.4 Hz, 3H, 60-H), 1.18 (s, 9H,
C(CH3)3), 1.60–1.66 (m, 4H, 20-CH3, OH), 2.37–2.48 (m, 1H, 40-H),
3.53–6.63 (m, 1H, 50-H), 4.37–4.48 (m, 2H, 10-H), 5.22–5.29 (m, 1H,
30-H); 13C NMR (100 MHz, CDCl3):
d
[ppm]¼14.2 (20-CH3), 16.4
(40-CH3), 20.5 (C-60), 27.2 (C(CH3)3), 38.8 (C(CH3)3), 39.6 (C-40), 69.7
(C-10), 71.8 (C-50), 130.7 (C-30), 131.1 (C-20), 178.3 (CO); HMRS (ESI):
[MþNa]þ calcd for C13H24O3 251.16177, found 251.16176.
d
[ppm]¼14.0 (20-CH3), 15.0 (CH(CH3)2), 16.1 (20-CH3), 17.8

6268
A. Schmauder et al. / Tetrahedron 64 (2008) 6263–6269
4.1.14. (20E,40R,50R)-50-{[tert-Butyl(diphenyl)silyl]oxy}-20,40-
dimethyl-20-hexenyl pivalate (24)
4.1.17. (4R)-4-Benzyl-3-((20S,40E,60R,70R)-70-{[tert-butyl(diphenyl)-
silyl]oxy}-20,40,60-trimethyl-40-octenoyl)-1,3-oxazolidin-2-one (27)
To a stirred solution of NaN(SiMe3)2 (2.82 g, 15.36 mmol) in THF
(20 mL) was added (4R)-4-benzyl-3-propionyl-1,3-oxazolidin-2-
one21 (15) (3.26 g, 13.97 mmol) in THF (7 mL) at ꢀ80 ꢁC. After 1 h,
iodide 26 (2.29 g crude, about 4.66 mmol) in THF (3 mL) was added
and the reaction mixture was allowed to warm to ꢀ50 ꢁC. After
stirring the reaction mixture at this temperature for 18 h, it was
quenched with saturated NH4Cl solution (10 mL) and allowed to
warm to room temperature. The layers were separated and the
aqueous layer was extracted with CH2Cl2 (2ꢂ40 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated in
vacuo. The crude product was purified by flash chromatography
(petroleum ether/EtOAc, 7:1) to give oxazolidinone 27 (2.14 g, 77%
To a stirred solution of alcohol 23 (1.17 g, 5.12 mmol) in CH2Cl2
(50 mL) at 0 ꢁC were added imidazole (1.05 g, 15.35 mmol) and
a catalytic amount of DMAP. The mixture was stirred for 10 min,
before TBDPSCl (2.66 mL, 10.23 mmol) was added. The mixture was
allowed to warm to room temperature and after 20 h the reaction
mixture was quenched with water. The aqueous layer was extracted
with CH2Cl2 (2ꢂ30 mL) and the combined organic layers were dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (petroleum ether/EtOAc, 30:1) to
afford pivalate 24 (2.362 g, 99%) as a colorless oil. Rf¼0.20 (petro-
20
leum ether/EtOAc, 30:1); [
a]
þ3.3 (c 1.00, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3):
d
[ppm]¼0.96 (d, J¼6.9 Hz, 6H, 40-CH3, 60-H),1.04
(s, 9H, Si(Ph)2C(CH3)3),1.19 (s, 9H, C(CH3)3),1.60 (d, J¼1.02 Hz, 3H, 20-
H), 2.39–2.52 (m,1H, 40-H), 3.68–3.78 (m,1H, 50-H), 4.41 (s, 2H,10-H),
5.31–5.37 (m, 1H, 30-H), 7.32–7.45 (m, 6H, Har), 7.63–7.72 (m, 4H,
over two steps) as a colorless solid; mp 115.8 ꢁC. Rf¼0.36 (petroleum
20
ether/EtOAc, 7:1); [
a]
ꢀ23.8 (c 1.00, CH2Cl2); 1H NMR (400 MHz,
D
CDCl3):
d
[ppm]¼1.00 (d, J¼1.8 Hz, 3H, 60-CH3),1.02 (d, J¼2.3 Hz, 3H,
Har); 13C NMR (100 MHz, CDCl3):
d
[ppm]¼14.2 (20-CH3), 16.3 (40-
80-H), 1.10 (s, 9H, Si(Ph)2C(CH3)3), 1.14 (d, J¼6.6 Hz, 3H, 20-CH3), 1.68
(s, 3H, 40-CH3), 2.02 (dd, J¼13.4, 9.0 Hz, 1H, 30-H), 2.38–2.61 (m, 1H,
60-H, 30-H), 2.71 (dd, J¼13.2, 9.9 Hz, 1H, CH2Ph), 3.32 (dd, J¼13.4,
3.2 Hz, 1H, CH2Ph), 3.70–3.82 (m, 1H, 70-H), 3.88–4.02 (m, 1H, 20-H),
4.14–4.27 (m, 2H, 5-H), 4.64–4.77 (m,1H, 4-H), 5.16 (d, J¼9.7 Hz,1H,
50-H), 7.21–2.24 (m, 1H, Har), 7.29–7.49 (m, 10H, Har), 7.69–7.77 (m,
CH3), 19.4 (Si(Ph)2C(CH3)3), 20.7 (C-60), 27.0 (Si(Ph)2C(CH3)3), 27.2
(C(CH3)3), 38.8 (C(CH3)3), 39.9 (C-40), 70.1 (C-10), 73.4 (C-50), 127.3
(Car), 127.5 (Car), 129.4 (Car), 129.5 (Car), 129.9 (C-20), 132.2 (C-30),
134.2 (Car), 135.0 (Car), 135.9 (Car), 178.3 (CO); HMRS (ESI): [MþNa]þ
calcd for C29H42O3Si 489.27954, found 489.27941.
4H, Har); 13C NMR (100 MHz, CDCl3):
d
[ppm]¼15.8 (40-CH3), 16.1
4.1.15. (2E,4R,5R)-5-{[tert-Butyl(diphenyl)silyl]oxy}-2,4-dimethyl-
2-hexen-1-ol (25)
(60-CH3), 17.0 (20-CH3), 19.4 (Si(Ph)2C(CH3)3), 21.1 (C-8), 27.1
(Si(Ph)2C(CH3)3), 35.7 (C-20), 38.0 (CH2Ph), 40.5 (C-60), 43.5 (C-30),
55.4 (C-4), 66.0 (C-5), 73.7 (C-70), 127.3 (Car), 127.4 (Car), 128.9 (Car),
129.3(Car),129.4 (Car),129.4(Car),131.1 (C-50),131.3(Car),134.3(C-40),
135.1 (Car),135.4 (Car),135.9 (Car),153.0 (CO),177.1 (CO); HMRS (ESI):
[MþNa]þ calcd for C37H47NO4Si 620.31666, found 620.31677.
To a stirred solution of pivalate 24 (2.36 g, 5.06 mmol) in CH2Cl2
(70 mL) at ꢀ80 ꢁC was added DIBAL-H (1 M in hexane, 12.65 mL,
12.65 mmol) in a dropwise fashion. After 1 h, the reaction mixture
was quenched with saturated Rochelle salt solution (20 mL), allowed
to warm to room temperature, and stirred vigorously for 1 h. The
aqueous layer was extracted with CH2Cl2 (2ꢂ30 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated in
vacuo. Flash chromatography (petroleum ether/EtOAc, 6:1) provided
4.1.18. (2S,4E,6R,7R)-7-{[tert-Butyl(diphenyl)silyl]oxy}-2,4,6-
trimethyloct-4-enoic acid (28)
To a solution of oxazolidinone 27 (2.04 g, 3.41 mmol) in THF
(35 mL) was added H2O2 (30% in water, 1.39 mL, 13.65 mmol) at
0 ꢁC, followed by the addition of a solution of LiOH$H2O (0.286 g,
6.82 mmol) in water (17 mL). The reaction mixture was allowed to
warm to room temperature and after stirring for 15 h, saturated
Na2S2O3 solution (5 mL) and saturated NaHCO3 solution (5 mL)
were added. The aqueous layer was extracted with CH2Cl2
(2ꢂ20 mL). The combined organic layers were dried over Na2SO4,
filtered, and concentrated in vacuo. Flash chromatography (petro-
alcohol 25 (1.79 g, 92%) as a colorless oil. Rf¼0.26 (petroleum ether/
20
EtOAc, 6:1); [
d
a
]
ꢀ3.8 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3):
D
[ppm]¼0.98 (d, J¼6.9 Hz, 3H, 4-CH3), 0.99 (d, J¼6.4 Hz, 3H, 6-H),
1.06 (s, 9H, Si(Ph)2C(CH3)3), 1.19 (br s, 1H, OH), 1.60 (s, 3H, 2-CH3),
2.38–2.50 (m, 1H, 4-H), 3.70–3.79 (m, 1H, 5-H), 3.93 (d, J¼5.9 Hz, 2H,
1-H), 5.25–5.31 (m,1H, 3-H), 7.32–7.46 (m, 6H, Har), 7.60–7.76 (m, 4H,
Har); 13C NMR (100 MHz, CDCl3):
d
[ppm]¼14.0 (2-CH3),16.2 (4-CH3),
19.4 (Si(Ph)2C(CH3)3), 21.1 (C-6), 27.1 (Si(Ph)2C(CH3)3), 39.8(C-4), 69.0
(C-1), 73.4 (C-5), 127.3 (Car), 127.4 (Car), 129.4 (C-3), 129.4 (Car), 129.5
(Car),134.2 (Car),134.3 (Car),134.9 (C-2),136.0 (Car),136.0 (Car); HMRS
(ESI): [MþNa]þ calcd for C24H34O2Si 405.2203, found 405.22237.
leum ether/EtOAc, 5:1) of the residue provided acid 28 (1.26 g, 84%)
20
as a colorless oil. Rf¼0.27 (petroleum ether/EtOAc, 5:1); [
a
]
þ4.7
D
(c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
[ppm]¼0.95 (d,
J¼6.4 Hz, 6H, 8-H, 6-CH3), 1.05 (s, 9H, Si(Ph)2C(CH3)3), 1.07 (d,
J¼7.1 Hz, 3H, 2-CH3), 1.57 (s, 3H, 4-CH3), 1.99 (dd, J¼13.5, 8.4 Hz, 1H,
3-H), 2.31–2.47 (m, 2H, 3-H, 6-H), 2.52–2.64 (m,1H, 2-H), 3.64–3.73
(m, 1H, 7-H), 5.05 (d, J¼9.4 Hz, 1H, 5-H), 7.31–7.45 (m, 6H, Har),
4.1.16. (2E,4S,5R)-5-{[tert-Butyl(diphenyl)silyl]oxy}-2,4-dimethyl-
1-iodo-2-hexene (26)
To a stirred solution of alcohol 25 (1.78 g, 4.66 mmol) in DMF
(3 mL) at 0 ꢁC was added methyltriphenoxyphosphonium iodide
(2.58 g, 5.59 mmol) in DMF (3 mL) dropwise. The reaction mixture
was allowed to warm to room temperature and stirred for 30 min.
The mixture was diluted with hexane (70 mL) and thenwashed with
cold aqueous 1 N NaOH (2ꢂ15 mL) and with water (2ꢂ15 mL). The
organic layer was dried over Na2SO4, filtered, and concentrated in
vacuo to afford iodide 26 (2.33 g, crude) as a yellow oil. This crude
product was used for the next reaction without further purification.
Rf¼0.38 (petroleum ether/EtOAc, 40:1); 1H NMR (400 MHz, acetone-
7.63–7.73 (m, 4H, Har); 13C NMR (100 MHz, CDCl3):
d
[ppm]¼16.1
(6-CH3), 16.1 (4-CH3), 17.1 (2-CH3), 19.4 (Si(Ph)2C(CH3)3), 21.1 (C-8),
27.1 (Si(Ph)2C(CH3)3), 37.6 (C-2), 40.6 (C-6), 43.6 (C-3), 73.8 (C-7),
127.3 (Car), 127.4 (Car), 129.3 (Car), 129.4 (Car), 131.0 (C-5), 131.1 (C-4),
134.3 (Car), 135.1 (Car), 135.9 (Car), 136.0 (Car), 183.0 (CO); HMRS
(ESI): [MþNa]þ calcd for C27H38O3Si 461.24824, found 461.24845.
4.1.19. tert-Butyl (2S,4E,6R,7R)-7-{[tert-butyl(diphenyl)silyl]oxy}-
2,4,6-trimethyloct-4-enoate (29)
d6):
d
[ppm]¼0.93 (d, J¼6.6 Hz, 3H, 4-CH3), 0.98 (d, J¼6.4 Hz, 3H,
To a stirred solution of acid 28 (1.20 g, 2.74 mmol) in
6-H), 1.05 (s, 9H, Si(Ph)2C(CH3)3), 1.74 (d, J¼1.0 Hz, 3H, 2-CH3), 2.38–
2.51 (m,1H, 4-H), 3.74–3.85 (m,1H, 5-H), 3.97–4.06 (m, 2H,1-H), 5.66
(d, J¼9.9 Hz, 1H, 3-H), 7.35–7.49 (m, 6H, Har), 7.68–7.75 (m, 4H, Har);
toluene (24 mL) were added Et3N (1.14 mL, 8.21 mmol) and
2,4,6-trichlorobenzoyl chloride (0.43 mL, 2.74 mmol). After 30 min,
tBuOH (0.52 mL, 5.47 mmol) and DMAP (1.34 g, 10.94 mmol) were
added and the mixture was stirred for 1 h at room temperature. The
reaction mixture was quenched with saturated NaHCO3 solution
(10 mL) and the aqueous layer was extracted with EtOAc
(2ꢂ40 mL). The combined organic layers were dried over Na2SO4,
13C NMR (100 MHz, acetone-d6):
d
[ppm]¼15.9 (C-1), 15.9 (4-CH3),
17.5 (2-CH3), 19.9 (Si(Ph)2C(CH3)3), 21.0 (C-6), 27.5 (Si(Ph)2C(CH3)3),
41.4 (C-4), 74.1 (C-5), 128.4 (Car), 128.5 (Car), 130.4 (Car), 130.6 (Car),
133.3 (C-3),133.6 (Car),134.7 (Car),135.5 (C-2),136.6 (Car),136.7 (Car).

A. Schmauder et al. / Tetrahedron 64 (2008) 6263–6269
6269
filtered, and concentrated in vacuo. The crude product was purified
References and notes
by flash chromatography (petroleum ether/EtOAc, 30:1) to afford
1. (a) Kunze, B.; Jansen, R.; Sasse, F.; Ho¨fle, G.; Reichenbach, H. J. Antibiot. 1995, 48,
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ester 29 (1.23 g, 90%) as a colorless oil. Rf¼0.31 (petroleum ether/
20
EtOAc, 30:1); [
d
a
]
D
þ3.1 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3):
[ppm]¼0.95 (d, J¼6.9 Hz, 3H, 8-H, 6-CH3), 1.02 (d, J¼7.1 Hz, 3H, 2-
2. For recent reviews, covering depsipeptides, see: (a) Hamada, Y.; Shioiri, T. Chem.
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CH3), 1.05 (s, 9H, Si(Ph)2C(CH3)3), 1.41 (s, 9H, C(CH3)3), 1.55 (s, 3H,
4-CH3),1.91 (dd, J¼13.7, 7.9 Hz,1H, 3-H), 2.33 (dd, J¼13.7, 6.6 Hz,1H,
3-H), 2.37–2.49 (m, 2H, 2-H, 6-H), 3.62–3.71 (m, 1H, 7-H), 5.03 (d,
J¼9.4 Hz,1H, 5-H), 7.30–7.45 (m, 6H, Har), 7.63–7.73 (m, 4H, Har); 13
C
NMR (100 MHz, CDCl3):
d
[ppm]¼16.4 (6-CH3),16.6 (4-CH3),17.0 (2-
CH3), 19.4 (Si(Ph)2C(CH3)3), 21.2 (C-8), 27.1 (Si(Ph)2C(CH3)3), 28.1
(C(CH3)3), 38.6 (C-6), 40.5 (C-2), 43.4 (C-3), 73.8 (C-7), 79.7 (C(CH3)3),
127.3 (Car),127.4 (Car),129.3 (Car),129.4 (Car),130.1 (C-5),131.8 (C-4),
134.3 (Car),135.1 (Car),136.0 (Car),136.0 (Car),176.1 (CO); HMRS (ESI):
[MþNa]þ calcd for C31H46O3Si 517.31084, found 517.31041.
6. Tanaka, C.; Tanaka, J.; Bolland, R. F.; Marriott, G.; Higa, T. Tetrahedron 2006, 62,
3536–3542.
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4.1.20. tert-Butyl (2S,4E,6R,7R)-7-hydroxy-2,4,6-trimethyloct-4-
enoate (30)
To a stirred solution of silyl ether 29 (1.18 g, 2.39 mmol) in THF
(25 mL) was added Bu4NF$3H2O (TBAF, 1.51 g, 4.79 mmol) and the
mixture was stirred for 14 h at 55 ꢁC. The solvent was removed in
vacuo and flash chromatography (petroleum ether/EtOAc, 6:1) of
8. (a) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1860; (b) Hoffmann, R. W. Angew.
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2779–2790.
10. (a) Grieco, P. A.; Hon, Y. S.; Perez-Medrano, A. J. Am. Chem. Soc. 1988, 110,
1630–1631; (b) Chu, K. S.; Negrete, G. R.; Konopelski, J. P. J. Org. Chem. 1991,
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the residue provided hydroxy ester 30 (0.534 g, 87%) as a colorless
20
oil. Rf¼0.18 (petroleum ether/EtOAc, 6:1); [
a]
þ19.1 (c 1.00,
D
CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
[ppm]¼0.95 (d, J¼6.6 Hz, 3H,
6-CH3), 1.04 (d, J¼6.9 Hz, 3H, 2-CH3), 1.10 (d, J¼6.4 Hz, 3H, 8-H), 1.41
(s, 9H, C(CH3)3), 1.53 (br s, 1H, OH), 1.62 (d, J¼1.27 Hz, 3H, 4-CH3),
1.97 (dd, J¼13.9, 6.7 Hz, 1H, 3-H), 2.35 (dd, J¼13.7, 7.4 Hz, 1H, 3-H),
2.39–2.53 (m, 2H, 6-H, 2-H), 3.53–3.62 (m, 1H, 7-H), 4.96–5.04 (m,
1H, 5-H); 13C NMR (100 MHz, CDCl3):
d
[ppm]¼16.4 (4-CH3), 16.7
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(6-CH3), 16.9 (2-CH3), 20.3 (C-8), 28.1 (C(CH3)3), 38.8 (C-2), 39.7 (C-
6), 43.9 (C-3), 72.0 (C-7), 79.9 (C(CH3)3), 128.8 (C-5), 133.8 (C-4),
175.8 (CO); HMRS (ESI): [MþNa]þ calcd for C15H28O3 279.19307,
found 279.19315.
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Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft
(grant Ma 1012/13-2), the NIH, and the Fonds der Chemischen
Industrie is gratefully acknowledged. We thank Graeme Nicholson
(Institute of Organic Chemistry) for measuring the HRMS spectra.
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Giannousis, P. J. Org. Chem. 1999, 64, 1750–1753.
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Supplementary data
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Procedures for ent-10 and ent-11, copies of NMR spectra. Sup-
plementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2008.04.109.