A chemoenzymatic approach to the stereocontrolled synthesis of the C1-C11 fragment of (+)-peloruside A

Article abstract of DOI:10.1002/ejoc.201000369

A highly efficient and diastereoselective synthesis of the C1C11 fragment of the marine natural product (+)-peloruside A has been developed. Through enzymatic desymmetrization of diethyl 3-hydroxyglutarate with lipase B from Candida antarctica a large-sca

Full text of DOI:10.1002/ejoc.201000369

FULL PAPER
DOI: 10.1002/ejoc.201000369
A Chemoenzymatic Approach to the Stereocontrolled Synthesis of the C1–C11
fragment of (+)-Peloruside A
Heike Schönherr,[a] Jan Mollitor,[a] and Christoph Schneider*[a]
Keywords: Natural products / Total synthesis / Antitumor agents / Enzymatic desymmetrization / Aldol reactions /
Diastereoselectivity
A highly efficient and diastereoselective synthesis of the C1–
C11 fragment of the marine natural product (+)-peloruside A
has been developed. Through enzymatic desymmetrization
of diethyl 3-hydroxyglutarate with lipase B from Candida
antarctica a large-scale access to enantiomerically highly
enriched starting material was achieved. Subsequent stereo-
generating key steps utilized in the synthesis were a
Sharpless asymmetric dihydroxylation and a doubly dia-
stereoselective Mukaiyama aldol reaction to set up the
stereogenic centers at C2, C3, C5, C7 and C8 with correct
absolute configuration.
dihydropyranone ring ahead of the macrolactonization, the
Ghosh and Evans syntheses featured a macrolactonization
of the seco acid of the natural product followed by an acid-
catalyzed lactol formation in the final step. Our retrosyn-
thetic analysis of peloruside A is based upon an aldol cou-
pling of methyl ketone 3 (C12–C19 fragment) and aldehyde
4 (C1–C11 fragment) similar to what Evans reported in his
synthesis.[10] For the synthesis of aldehyde 4 we anticipated
that a Mukaiyama aldol reaction of the trimethylsilyl enol
ether of α-benzyloxy ketone 6 with aldehyde 5 should give
rise to the required 7,8-anti-stereochemistry with the ter-
minal alkene easily being converted into the aldehyde moi-
ety (Scheme 1).
Introduction
The macrolide (+)-peloruside A (1) was isolated from the
New Zealand marine sponge Mycale hentscheli in 2000 by
Northcote and co-workers.[1] It features a 16-membered
macrocyclic lactone with an embedded lactol ring, 10 chiral
centers, multiple hydroxy and methoxy groups in either 1,2-
or 1,3-arrangements, and a side chain with a Z-configured
trisubstituted alkene moiety. It was shown to display potent
antitumor activity against P388 murine leukemia cells with
an IC50 value of 10 ng/mL.[2] Studies have demonstrated
that peloruside A like paclitaxel (Taxol®) exhibits microtu-
bule-stabilizing activity and arrests cells in the G2-M phase
of the cell cycle. It was also reported that peloruside A is
less susceptible than paclitaxel to MDR-cell lines and is
also potent in Taxol® resistant cells on the basis of a dif-
ferent, non-taxoid binding site of tubulin.[3–5] These aspects
underline the impact of peloruside A as a new antitumor
agent with significant clinical potential. Given the signifi-
cant biological activity, the low natural abundance and the
synthetically challenging structure of the natural product
peloruside A has attracted large attention among synthetic
research groups worldwide.[6–16]
The first total synthesis of peloruside A (1) by de
Brabander et al. established the absolute stereochemistry of
(+)-peloruside A.[17] Thus far, three more total syntheses
have been published by Taylor, Ghosh, and Evans and their
respective co-workers.[18–20] Whereas in the Brabander and
Taylor syntheses the pyran was assembled in the form of a
[a] Institut für Organische Chemie, Universität Leipzig,
Johannisallee 29, 04103 Leipzig, Germany
Fax: +49-341-9736599
E-mail: schneider@chemie.uni-leipzig.de
Scheme 1. Retrosynthetic analysis of (+)-peloruside A 1.
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Stereocontrolled Synthesis of a Peloruside A Fragment
For a large-scale synthesis of aldehyde 5 we envisioned upon acidification without any chromatographic purifica-
as the first step a chemoenzymatic desymmetrization reac- tion necessary (Scheme 3). Chemoselective reduction of the
tion of diethyl 3-hydroxyglutarate (7) to furnish mono acid acid in the presence of the ester was accomplished using
8 with the first chiral center established in high optical pu- borane dimethylsulfide complex.[25] After 12 h alcohol 11
rity. Desymmetrization reactions of prochiral molecules are was obtained in excellent yield without further purification.
particularly attractive for the synthesis of small chiral com- Mild IBX-oxidation proved to be the method of choice for
pounds especially when conducted in a catalytic manner. oxidizing 11 to the corresponding aldehyde 12 which was
The enzyme lipase B from the yeast Candida antarctica is isolated in quantitative yield after aqueous extraction of
known to catalyze esterifications, ester hydrolyses and acyl- DMSO used as solvent.[26] Again no chromatographic puri-
transfer reactions. Immobilized on an acrylate resin it toler- fication was necessary at this stage. Horner–Wadsworth–
ates temperatures of up to 70 °C[21,22] and a variety of or- Emmons reaction of aldehyde 12 with trimethyl phos-
ganic solvents[23] and reactions can easily be run on large phonoacetate and tetramethylguanidine as base furnished
scales. Furthermore dialkyl 3-hydroxyglutarates are excel- α,β-unsaturated methyl ester 13 in good yield and as pure
lent substrates for such hydrolytic desymmetrization reac- E-isomer after 12 h at –78 °CǞr.t. (Scheme 3).
tions with lipases. This might be due to additional hydrogen
bonding between the hydroxy group and an acceptor in the
binding pocket of the enzyme. Jacobsen et al. previously
determined the enantioselectivity of similar enzymatic hy-
drolyses and was also able to establish the absolute configu-
ration of the newly formed chiral center by co-crystalli-
zation of the acid with (R)-phenylethylamine.[24]
Results and Discussion
Synthesis of the C1–C7 Aldehyde 5
In the first step of the synthesis diethyl 3-hydroxyglutar-
ate (7) was treated with immobilized lipase B from Candida
antarctica (Novozym 435, enzyme loading 10 000 U/g). The
reaction was completed within 45 min in a buffer solution
with pH = 7 at room temperature. The enzyme was removed
by filtration and could be used several times after storage
in dichloromethane. The highly pure mono acid 8 was iso-
lated in 30–50 g batches with yields of typically 95% after
Scheme 3. Synthesis of α,β-unsaturated methyl ester 13.
a simple acid-base wash (Scheme 2). No further purification
was necessary. In order to determine the enantioselectivity
of the hydrolysis mono acid 8 was converted into the corre-
sponding benzyl ester the enantiomeric excess of which was
(E)-Enoate 13 was now ideally suited to install the re-
quired 2,3-syn-dioxygenation of the natural product via a
Sharpless asymmetric dihydroxylation. High yields and
measured through HPLC-analysis on a chiral stationary
enantioselectivities were achieved with a fortified AD-mix
phase.
comprising 1 mol-% K2OsO2(OH)4 as osmium source,
5 mol-% (DHQD)2PHAL as chiral ligand, K3[Fe(CN)6] as
co-oxidant, and methanesulfonamide as additive to facili-
tate osmate ester hydrolysis in a two-phase system of tert-
butanol and water.[27] A buffered system with K2CO3 and
Scheme 2. Enzymatic hydrolysis of diethyl 3-hydroxyglutarate 7.
NaHCO3 proved advantageous to avoid strong basic condi-
tions and retroaldol reaction of the product. After chroma-
The free hydroxy group of 8 was subsequently protected tographic purification syn-diol 14 was isolated as a single
as a TBS ether. Because the competing formation of the diastereomer in 89% yield. The minor enantiomer from the
silyl ester could not be avoided, two equivalents of TBSCl enzymatic hydrolysis was at this stage easily separated as a
and imidazole as base were employed to furnish the bissilyl- diastereomer by chromatography. The additional ester
ated compound 9. Crude 9 was then treated with K2CO3 in group in 14 was used advantageously to distinguish between
a 1:1:2 mixture of MeOH/H2O/THF to hydrolyze the silyl the 2- and 3-hydroxy groups as the 3-hydroxy group had to
ester and yield acid 10 in 90% yield over two steps. Large- be chemoselectively converted into a methyl ether. For this
scale purification of 10 proved to be very simple as the po- purpose syn-diol 14 was treated with para-toluenesulfonic
tassium carboxylate of 10 separated as an ionic liquid be- acid to effect a size-selective lactonization and formation of
tween the organic und aqueous phase during the extraction lactone 15 in good yield. The 2-hydroxy group was now
which was easily isolated and furnished very clean product easily protected as a TBDPS ether using TBDPSCl and
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H. Schönherr, J. Mollitor, C. Schneider
FULL PAPER
Scheme 4. Synthesis of lactone 16.
Scheme 5. Synthesis of aldehyde 5.
imidazole (Scheme 4). For the subsequent steps this very was methylated using Meerwein salt and proton sponge.[28]
bulky protecting group provided significant steric shielding Weinreb amide 18 was again chemoselectively reduced to
of the adjacent ester and helped to differentiate between the furnish aldehyde 5 in excellent yields (Scheme 5).[29]
ester and lactone moiety.
To access the C1–C7 aldehyde 5 for the doubly diastereo-
Doubly Diastereoselective Mukaiyama Aldol Reaction
selective Mukaiyama aldol reaction lactone 16 was transfer-
red into Weinreb amide 17 in quantitative yield. This amid-
In order to install the C7- and C8-stereogenic centers of
ation proceeded chemoselectively under lactone ring-open- peloruside A with the desired anti configuration we envi-
ing without attack at the methyl ester. The 3-hydroxy group sioned a substrate-controlled Mukaiyama aldol reaction of
Scheme 6. Mukaiyama aldol reaction of silyl enol ether 19 and aldehyde 5.
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Stereocontrolled Synthesis of a Peloruside A Fragment
the silyl enol ether of α-benzyloxy ketone 6 with the C1–C7- mation. 13C NMR spectroscopic analysis of the acetonide
aldehyde 5. Pagenkopf and co-workers had reported quite methyl signals and the quaternary carbon according to the
a similar carbon–carbon formation in their synthesis of a method developed by Rychnovsky[34] clearly revealed the
fragment of peloruside A.[30] In addition, various Lewis 5,7-anti configuration (Scheme 7).Likewise, the 7,8-anti
acid-catalyzed additions of silyl nucleophiles towards β-sil- configuration was secured through syn-diastereoselective re-
yloxy aldehydes have been shown to proceed with remarka- duction of the 9-keto group with Zn(BH4)2 and subsequent
bly high 1,3-anti-diastereoselectivities.[31–33] Based upon this formation of the corresponding 7,9-syn-diol acetonide 23
precedence we investigated a number of Lewis acids (e.g. which can be deduced from the characteristic 13C chemical
MeAlCl2, TiCl4, SnCl4, MgBr2·OEt2) as mediators for the shifts. The 7,8-relative configuration was now easily as-
reaction of silyl enol ether 19 and aldehyde 5 and eventually signed based upon the characteristic trans-diaxial coupling
3
3
found BF3·OEt2 optimal. When silyl enol ether 19 and alde- constants JH7-H8 = 9.0 Hz and JH8-H9 = 9.0 Hz placing
hyde 5 were treated with 1.3 equiv. of BF3·OEt2 in dichloro- the 7,8,9-substituents in this chair in equatorial positions
methane at –78 °C, complete conversion was observed (Scheme 7). The configuration of the minor diastereomer
within 1 h and two diastereomers were isolated through col- 21 has not been so rigorously assigned, but on the basis of
umn chromatography in a combined yield of 85% and a almost identical coupling constants 3JH7-H8 = 4.4 Hz for 20
ratio of 5:1. Fortunately, pure diastereomer 20 with the cor- and 4.7 Hz for 21 we assume a 7,8-anti configuration in
rect 5,7-anti-7,8-anti configuration was easily separated both stereoisomers.
from the minor diastereomer 21 in 70% yield by
chromatography (Scheme 6).
Synthesis of Aldehyde 4
Stereochemical Proof
The final steps of the synthesis of the C1–C11 aldehyde
4 commenced with the methylation of the 7-OH group with
Meerwein salt in the presence of proton sponge which pro-
ceeded in almost quantitative yield. The terminal double
bond was then converted into the aldehyde moiety in high
yield by a sequential dihydroxylation and oxidative cleavage
of the resulting diol (Scheme 8).
To verify the 5,7-anti configuration of major dia-
stereomer 20 it was converted into 5,7-anti-diol acetonide
22 through selective 5-OH-desilylation and acetonide for-
Conclusions
An efficient and convergent synthesis of the C1–C11
fragment of (+)-peloruside A has been developed. Aldehyde
4 containing the stereocenters at C2, C3, C5, C7, and C8
with the correct absolute configuration was synthesized in
an overall yield of 28% in 15 steps (longest linear sequence).
The enzymatic desymmetrization of diethyl 3-hydroxyglut-
arate in the first step of the sequence allowed the prepara-
tion of large amounts of highly enantiomerically enriched
starting material in up to 50 g scale. A Sharpless dihydrox-
ylation and a substrate-controlled aldol coupling intro-
duced the chiral centers at C2 and C3 and C7 and C8,
respectively. The C1–C11 fragment 4 of (+)-peloruside A
Scheme 7. Stereochemical proof of the 5,7-anti-7,8-anti configura-
tion of aldol product 20.
Scheme 8. Synthesis of aldehyde 4.
Eur. J. Org. Chem. 2010, 3908–3918
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H. Schönherr, J. Mollitor, C. Schneider
FULL PAPER
(R)-1-Benzyl 5-Ethyl 3-Hydroxypentanedioate: Carbonyldiimid-
azole (115 mg, 0.710 mmol, 1.05 equiv.) was added to a solution of
hydroxy acid 8 (120 mg, 0.680 mmol, 1 equiv.) in dichloromethane
(15 mL). After the CO2 evolution was finished a solution of imid-
azole (4 mg, 0.03 mmol, 4 mol-%) and sodium (1 mg, 0.04 mmol,
6 mol-%) in THF (1 mL) was added. The blue solution was stirred
at room temp. for 1 h. 1  HCl (10 mL) was added and the aqueous
phase was extracted with diethyl ether (3ϫ30 mL). The combined
organic layers were dried with MgSO4, filtered, and the solvent
was evaporated in vacuo. The residue was purified by flash column
chromatography over silica gel (1:80 w/w) using a mixture of petro-
leum ether and ethyl acetate [3:2 (v/v)] as an eluent. The title com-
pound was obtained as a colorless oil (125 mg, 69%). Rf = 0.61
(PE/EtOAc, 1:1). ee = 90%. Enantiomeric assay: Chiralcel OD, iso-
cratic (n-hexane/iPrOH, 95:5, flow 0.5 mL/min) λmax = 204 nm, t1
prepared as described above closely resembles a building
block which Evans successfully converted into the natural
product in his synthesis of (+)-peloruside A.[20]
Experimental Section
General: All reactions were carried out with magnetic stirring under
argon. Dry solvents were distilled from the indicated drying agents:
dichloromethane (CaH2), tetrahydrofuran (K), N,N-dimethylform-
amide (CaH2). Acetonitrile and chloroform were obtained from
VWR in HPLC quality (HiPerSolvCHROMANORM). Diethyl
ether (E), hexane (Hex) and petroleum ether (PE) for chromatog-
raphy were technical grade and distilled from KOH. Ethyl acetate
(EE) was distilled from CaCl2. All reactions were monitored by
thin-layer chromatography (TLC) on precoated silica gel 60 F254
plates (Merck KGaA); spots were visualized by treatment with a
solution of vanillin (0.5 g), conc. acetic acid (10 mL), and conc.
H2SO4 (5 mL) in methanol (90 mL), or with a solution of KMnO4
(3.0 g), K2CO3 (20 g), and acetic acid (0.25 mL) in water (300 mL),
or a solution of phosphomolybdic acid hydrate (1.0 g) in ethanol
(50 mL). Flash column chromatography was performed using
Merck silica gel 60 230–400 mesh (0.040–0.063 mm). Triethylamine
and diisopropylethylamine were distilled from CaH2. All other
chemicals were used as received from commercial suppliers. 1H and
13C NMR spectra were recorded with Varian Gemini 200 and 2000
(200 MHz), Varian Gemini 300 BB (300 MHz) and with Bruker
Avance DRX 400 (400 MHz) spectrometers. Chemical shifts are
reported relative to tetramethylsilane as internal standard or the
residual solvent signals [chloroform: δ (13C) = 77.16 ppm]. Melting
points were determined on a Boetius heating table. Elemental
analyses were obtained from the microanalytical laboratory of the
Dept. of Chemistry at the University of Leipzig. IR spectra were
obtained with a FTIR spectrometer (Genesis ATI, Mattson/
Unicam). ESI mass spectra were recorded on a Bruker APEX II
FT-ICR (high resolution) and on a Bruker ESQUIRE. Optical ro-
tations were measured using a Schmidt & Haensch Polartronic D
polarimeter. HPLC analyses were performed on a JASCO MD-
2010 plus instrument with a chiral stationary phase column (Chi-
ralcel OD purchased from Daicel Chemical Industries, Ltd.).
1
= 21.1 min, t2 = 28.8 min. H NMR (300 MHz, CDCl3): δ = 1.27
3
(t, JH,H = 7.0 Hz, 3 H, CH2CH3), 2.65–2.79 (m, 4 H, 2-CH2, 4-
3
CH2), 4.18 (q, JH,H = 7.0 Hz, 2 H, CH2CH3), 4.46–4.56 (m, 1 H,
3-CH), 5.16 (s, 2 H, CH2Ph), 7.30–7.42 (m, 5 H, Ph-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.13 (CH2CH3), 41.45 (4-CH2),
41.83 (2-CH2), 61.56 (CH2CH3), 64.88 (3-CH), 66.43 (OCH2Ph),
127.0, 127.6, 128.4, 135.9 (Ph-C), 173.3 (1-COOEt), 174.7 (5-CO-
OBn) ppm. MS (ESI): m/z (%) = 289 [M + Na]+. C14H18O5 (29)
[266].
(S)-3-(tert-Butyldimethylsilyloxy)-5-ethoxy-5-oxopentanoic Acid
(10): Imidazole (12.6 g, 185 mmol, 2.0 equiv.) was added to a solu-
tion of hydroxy acid 8 (16.3 g, 92.8 mmol, 1 equiv.) in dichloro-
methane (150 mL). At room temp. tert-butyldimethylsilyl chloride
(TBSCl) (32.0 g, 212 mmol, 2.3 equiv.) and a small amount of 4-
(dimethylamino)pyridine (DMAP) were added. A white precipi-
tation was observed. The solution was stirred for 24 h at room
temp. Water (100 mL) was added and the mixture was acidified
with 0.5  HCl (20 mL). The aqueous phase was saturated with
NaCl and extracted with diethyl ether (4ϫ50 mL). The combined
organic layers were dried with MgSO4, filtered, and the solvent was
evaporated in vacuo. The crude product 9 was used directly in the
next reaction. It was dissolved in a mixture of MeOH/H2O/THF,
1:1:2 (140 mL). K2CO3 (64.0 g, 463 mmol, 5 equiv.) was added and
the suspension was stirred for 2 h at room temp. The mixture was
diluted with water until the solution was clear and PE (150 mL)
was added. Three phases were formed and the middle phase was
separated from the organic and the aqueous phase. It was acidified
with 0.5  HCl (pH 2). The aqueous phase was extracted with di-
ethyl ether (3ϫ100 mL). The combined organic layers were dried
with MgSO4, filtered, and the solvent was evaporated in vacuo. The
title compound 10 was obtained as a colorless oil without further
purification (24.5 g, 90%). Rf = 0.60 (EtOAc). [α]2D2 = 2.8 (c = 3.96,
(S)-5-Ethoxy-3-hydroxy-5-oxopentanoic Acid (8): Lipase B from
Candida antarctica (7.07 g, enzyme loading 10000 U/g) was added
to a solution of diethyl 3-hydroxyglutarate (40.2 g, 0.20 mol) in
phosphate buffer (280 mL, pH 7). The solution was stirred for 1 h
at room temp. After completion of the reaction the immobilized
enzyme was filtered off and washed with dichloromethane
(200 mL). The filtrate was acidified to pH 2 by adding 1  HCl.
The aqueous phase was saturated with NaCl and extracted with
ethyl acetate (5ϫ150 mL). The combined organic layers were dried
with MgSO4, filtered, and the solvent was evaporated in vacuo. The
title compound 7 was obtained as a colorless oil without further
purification (33.3 g, 96%). Rf = 0.17 (PE/EtOAc, 1:1). [α]2D2 = +1.7
(c = 11.5, acetone); ref.[24] +1.8 (c = 11.5, acetone). 1H NMR
1
acetone). H NMR (300 MHz, CDCl3): δ = 0.08 (s, 3 H, SiCH3),
0.09 (s, 3 H, SiCH3), 0.85 [s, 9 H, C(CH3)3], 1.26 (t, 3JH,H = 7.0 Hz,
3
3
3 H, CH2CH3), 2.58 (dd, JH,H = 12.0, JH,H = 6.0 Hz, 2 H, 4-
2
3
CHaHb), 2.63 (dd, JH,H = 7.5, JH,H = 6.0 Hz, 2 H, 2-CHaЈHbЈ),
3
4.13 (q, JH,H = 6.0 Hz, 2 H, CH2CH3), 4.48–4.59 (m, 1 H, 3-CH)
ppm. 13C NMR (100 MHz, CDCl3): δ = –4.85 (SiCH3), –4.81
(SiCH3), 14.27 (CH2CH3),17.99 [C(CH3)3], 25.74 [C(CH3)3], 42.39
(2-CH2), 42.56 (4-CH2), 60.70 (3-CH), 66.22 (CH2CH3), 171.1 (1-
3
(300 MHz, CDCl3): δ = 1.26 (t, JH,H = 7.0 Hz, 3 H, CH2CH3),
COOEt), 177.3 (5-COOH) ppm. IR (film): ν = 2957, 2931, 2858,
˜
3
2.51–2.67 (m, 4 H, 2-CH2, 4-CH2), 4.16 (q, JH,H = 7.0 Hz, 2 H,
1737, 1714, 1473, 1464, 1378, 1257, 1202, 1157, 1095, 1051, 1028,
971, 940, 916, 838, 812, 779, 735 cm–1. MS (ESI): m/z = 313 [M +
Na]+. C13H26O5Si (290.43): calcd. C 53.76, H 9.02, O 27.54; found
C 53.40, H 8.89, O 27.50.
CH2CH3), 4.42–4.52 (m, 1 H, 3-CH), 7.60 (s, 1 H, COOH) ppm.
13C NMR (75 MHz, CDCl3): δ = 14.23 (CH2CH3), 40.57 (2-CH2),
40.65 (4-CH2), 61.14 (CH2CH3), 64.72 (3-CH), 172.1 (1-COOEt),
177.7 (5-COOH) ppm. IR (film): ν = 2985, 1728, 1405, 1377, 1275,
˜
1196, 1094, 1038, 876, 607 cm–1. MS (ESI): m/z (%) = 199 [M +
Ethyl (S)-3-(tert-Butyldimethylsilyloxy)-5-hydroxypentanoate (11):
A solution of carboxylic acid 10 (20.0 g, 69.0 mmol, 1 equiv.) in
Na]+. C7H12O5 (17) [176].
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Stereocontrolled Synthesis of a Peloruside A Fragment
THF (200 mL) was cooled to –25 °C. BH3·SMe2 (7.80 g, 100 mmol,
1.5 equiv.) was added slowly at this temperature via syringe. The
solution was stirred at room temp. for 12 h. A mixture of H2O and
AcOH (1:1, 30 mL) was added and the solvent was evaporated in
vacuo. The residue was given in a saturated solution of NaHCO3
3JH,H = 6.0 Hz, 2 H, CH2CH3), 4.22–4.35 (m, 1 H, 5-CH), 5.86 (d,
3
3
3JH,H = 15.5 Hz, 1 H, 2-CH=CH), 6.94 (dt, JH,H = 15.5, JH,H
=
7.5 Hz, 1 H, 3-CH=CH) ppm. 13C NMR (50 MHz, CDCl3): δ =
–4.77 (SiCH3), –4.51 (SiCH3), 14.30 (CH2CH3),18.09 [C(CH3)3],
25.82 [C(CH3)3], 40.38 (4-CH2), 42.54 (6-CH2), 51.59 (OCH3),
(150 mL). The aqueous phase was extracted with ethyl acetate 60.61 (CH2CH3), 68.39 (5-CH), 123.85 (2-CH=CH), 144.9 (3-
(3 ϫ 150 mL). The combined organic layers were dried with
MgSO4, filtered, and the solvent was evaporated in vacuo. The title
compound 11 was obtained as a pale yellow oil without further
purification (18.5 g, 97%). Rf = 0.25 (PE/Et2O, 1:1). [α]2D2 = +11.7
(c = 9.99, acetone). 1H NMR (300 MHz, CDCl3): δ = = 0.09 (s,
CH=CH), 166.8 (1-COOMe), 171.3 (7-COOEt) ppm. IR (film): ν
˜
= 3434, 2954, 2930, 2897, 2857, 2256, 1731, 1659, 1473, 1463, 1437,
1377, 1327, 1257, 1177, 1087, 1036, 991, 917, 838, 811, 778, 734
cm–1. UV/Vis (CH3CN): λmax [lg(ε)] = 213 nm (3.73). HRMS-ESI:
m/z = [M + Na]+ calcd. for C16H30O5Si: 353.17602; found
353.17521. C16H30O5Si (330.19): calcd. C 58.15, H 9.15, O 24.21;
3
6 H, SiCH3), 0.88 [s, 9 H, C(CH3)3], 1.26 (t, JH,H = 7.0 Hz, 3 H,
CH2CH3), 1.69–1.93 (m, 2 H, 4-CH2), 2.16 (, 1 H, OH), 2.47–2.62 found C 53.12, H 9.20, O 23.80.
3
(m, 2 H, 2-CH2), 4.12 (q, JH,H = 7.0 Hz, 2 H, CH2CH3), 4.32–
7-Ethyl 1-Methyl (2S,3R,5S)-5-(tert-Butyldimethylsilyloxy)-2,3-di-
4.40 (m, 1 H, 3-CH) ppm. 13C NMR (100 MHz, CDCl3): δ = –4.81
(SiCH3), 14.26 (CH2CH3),17.98 [C(CH3)3], 25.72 [C(CH3)3], 38.99
(4-CH2), 42.48 (2-CH2), 60.58 (CH2CH3), 68.25 (3-CH), 171.6 (1-
hydroxyheptanedioate (14): A solution of K3[Fe(CN)6] (28.0 g,
85.1 mmol, 3.5 equiv.), K2CO3 (11.8 g, 85.1 mmol, 3.5 equiv.) and
NaHCO3 (9.20 g, 110 mmol, 4.4 equiv.) in 150 mL water was pre-
pared. (DHQD)2PHAL (940 mg, 1.22 mmol, 0.05 equiv.) dissolved
in tBuOH (150 mL) was added. K2OsO4·2H2O (90 mg, 0.24 mmol,
0.01 equiv.) was added to the two-phase system and it was stirred
at room temp. for 1 h. The mixture was cooled to 0 °C and com-
pound 13 (8.00 g, 24.3 mmol, 1 equiv.) and methanesulfonamide
COOEt) ppm. IR (film): ν = 3457, 2956, 2930, 2896, 2857, 1337,
˜
1473, 1464, 1377, 1311, 1256, 1165, 1092, 1028, 940, 837, 812, 777,
708, 663 cm–1. MS (ESI): m/z = 299 [M + Na]+. C13H28O4Si
(276.18): calcd. C 56.48, H 10.21, O 23.15; found C 56.66, H 10.48,
O 23.38.
Ethyl (S)-3-(tert-Butyldimethylsilyloxy)-5-oxopentanoate (12): A (3.00 g, 31.6 mmol, 1.3 equiv.) were added. The solution was stirred
solution of IBX (28.0 mg, 100 mmol, 1.55 equiv.) in DMSO at 0 °C for 21 h. The reaction was stopped by the addition of
(200 mL) was prepared. A solution of alcolhol 11 (17.8 g, Na2SO3 (20.4 g, 162 mmol, 6.5 equiv.) and water (400 mL). After
64.6 mmol, 1 equiv.) in DMSO (50 mL) was added and the re-
sulting solution was stirred at room temp. for 12 h. Water was
added (300 mL) and the white precipitate was filtered off. The fil-
trate was extracted with diethyl ether (5ϫ75 mL). The combined
organic layers were dried with MgSO4, filtered, and the solvent was
evaporated in vacuo. The title compound 12 was obtained as a
colorless oil without further purification (17.5 g, 99%). Rf = 0.57
(PE/Et2O, 1:1). [α]2D2 = +8.2 (c = 10.10, acetone). 1H NMR
stirring for 30 min the mixture was diluted with ethyl acetate
(400 mL). The aqueous phase was extracted with ethyl acetate
(5ϫ75 mL). The combined organic layers were dried with MgSO4,
filtered, and the solvent was evaporated in vacuo. The residue was
purified by flash column chromatography over silica gel (1:100
w/w) using a mixture of petroleum ether and ethyl acetate [2:1
(v/v)] as an eluent. The title compound 14 was obtained as a color-
less viscous oil (8.31 g, 94%). Rf = 0.51 (PE/EtOAc, 1:1). [α]2D2
=
(300 MHz, CDCl3): δ = 0.06 (s, 6 H, SiCH3), 0.83 [s, 9 H, C(CH3) +10.5 (c = 2.85, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.08
3
3
3], 1.24 (t, JH,H = 7.0 Hz, 3 H, CH2CH3), 2.52 (dd, JH,H = 6.0,
(s, 3 H, SiCH3), 0.09 (s, 3 H, SiCH3), 0.88 [s, 9 H, C(CH3)3], 1.25
3JH,H = 1.5 Hz, 2 H, 2-CH2), 2.61–2.66 (m, 2 H, 4-CH2), 4.11 (q, (t, 3JH,H = 7.0 Hz, 3 H, CH2CH3), 1.84–1.89 (m, 2 H, 4-CH2), 2.55
3JH,H = 7.5 Hz, 2 H, CH2CH3), 4.58–4.64 (m, 1 H, 3-CH), 9.78 (t,
(dd, JH,H = 6.5, JH,H = 3.0 Hz, 2 H, 6-CHaHb), 3.81 (s, 3 H,
3
3
3JH,H = 2.0 Hz, 1 H, CHO) ppm. 13C NMR (100 MHz, CDCl3): δ OCH3), 4.11 (q, 3JH,H = 6.0 Hz, 2 H, CH2CH3), 4.07–4.15 (m, 4 H,
= –4.73 (SiCH3), –4.69 (SiCH3), 14.26 (CH2CH3),17.99 [C(CH3)3], CH2-CH3, 2-CH, 3-CH), 4.31–4.40 (m, 1 H, 5-CH) ppm. 13C NMR
25.74 [C(CH3)3], 42.74 (2-CH2), 50.96 (4-CH2), 60.70 (3-CH), 65.11 (100 MHz, CDCl3): δ = –4.62 (SiCH3), –4.48 (SiCH3), 14.29
(CH CH ), 170.9 (1-COOEt), 207.0 (5-CHO) ppm. IR (film): ν =
(CH2CH3),18.01 [C(CH3)3], 25.82 [C(CH3)3], 40.56 (4-CH2), 42.83
(6-CH2), 52.87 (OCH3), 60.69 (CH2CH3), 68.15 (5-CH), 70.32 (2-
CH), 73.84 (3-CH), 171.5 (7-COOEt), 173.7 (1-COOMe) ppm. IR
˜
2
3
3344, 2956, 2930, 2897, 2858, 1737, 1473, 1464, 1378, 1312, 1257,
1174, 1096, 1028, 940, 838, 812, 778 cm–1. MS (ESI): m/z = 297
[M + Na]+. C13H28O4Si (274.16): calcd. C 56.90, H 9.55, O 23.32;
found C 56.55, H 9.50, O 23.00.
(film): ν = 3466, 2955, 2930, 2897, 2857, 1739, 1473, 1463, 1439,
˜
1385, 1256, 1163, 1088, 1032, 969, 837, 811, 778 cm–1. UV/Vis
(CH3CN): λmax [lg (ε)] = 206 nm (2.91). HRMS-ESI: m/z =
[M + Na]+ calcd. for C16H32O7Si: 387.18150; found 387.18080,
[2M + Na]+ calcd. 751.37323; found 751.37295. C16H32O7Si
(364.19): calcd. C 52.72, H 8.85, O 30.73; found C 52.60, H 9.22,
O 30.26.
7-Ethyl 1-Methyl (S,E)-5-(tert-Butyldimethylsilyloxy)hept-2-ene-
dioate (13): A solution of aldehyde 12 (13.0 g, 47.4 mmol, 1 equiv.)
and trimethyl phosphonoacetate (10.4 g, 57.0 mmol, 1.2 equiv.) in
THF (200 mL) was cooled to –78 °C. Tetramethylguanidine
(6.55 g, 57.0 mmol, 1.2 equiv.) was added and the solution was
stirred 30 min at this temperature. The yellow reaction mixture was
warmed to room temp. overnight whilst stirring. It was diluted with
water (200 mL) and 1  HCl was added until a clear solution re-
sulted. The aqueous phase was extracted with diethyl ether
Methyl (S)-2-[(2R,4S)-4-(tert-Butyldimethylsilyloxy)-6-oxotetra-
hydro-2H-pyran-2-yl]-2-hydroxyacetate (15): To a solution of diol
14 (8.31 g, 22.9 mmol, 1 equiv.) in dichloromethane (200 mL) was
added p-toluenesulfonic acid (50 mg, 0.23 mmol, 0.01 equiv.). The
(5ϫ75 mL). The combined organic layers were dried with MgSO4, solution was stirred 24 h at room temp. The solvent was evaporated
filtered, and the solvent was evaporated in vacuo. The residue was
purified by flash column chromatography over silica gel (1:80 w/w)
using a mixture of petroleum ether and diethyl ether [4:1 (v/v)] as
an eluent. The title compound 13 was obtained as a colorless oil
(15.6 g, 81%). Rf = 0.74 (PE/Et2O, 1:1). [α]2D2 = +23.6 (c = 10.05,
in vacuo. The residue was purified by flash column chromatog-
raphy over silica gel (1:50 w/w) using a mixture of petroleum ether
and ethyl acetate [1:1 (v/v)] as an eluent. The title compound 15
was obtained as a colorless waxy solid (7.53 g, 90%). Rf = 0.50
(PE/EtOAc, 2:1); m.p. 54–56 °C. [α]2D2 = +13.5 (c = 9.95, acetone).
1H NMR (400 MHz, CDCl3): δ = 0.08 (s, 6 H, SiCH3), 0.89 [s, 9
1
acetone). H NMR (300 MHz, CDCl3): δ = 0.06 (s, 6 H, SiCH3),
3
0.86 [s, 9 H, C(CH3)3], 1.25 (t, JH,H = 7.0 Hz, 3 H, CH2CH3), H, C(CH3)3], 1.78–1.86 (m, 1 H, 4-CHaHb), 2.10–2.20 (m, 1 H, 4-
3
2.35–2.52 (m, 4 H, 6-CH2, 4-CH2), 3.72 (s, 3 H, OCH3), 4.11 (q, CHaHb), 2.57 (d, JH,H = 3.5 Hz, 2 H, 6-CH2), 3.09 (s, 1 H, OH),
Eur. J. Org. Chem. 2010, 3908–3918
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3913

H. Schönherr, J. Mollitor, C. Schneider
FULL PAPER
3.87 (s, 3 H, OCH3), 4.13 (d, JH,H = 3.5 Hz, 1 H, CHOH), 4.38–
3
0.02 (s, 3 H, SiCH3), 0.03 (s, 3 H, SiCH3), 0.85 [s, 9 H, C(CH3)3],
3
4.43 (m, 1 H, 5-CH), 4.99–5.06 (m, 1 H, 3-CH) ppm. 13C NMR 1.11 [s, 9 H, C(CH3)3], 1.66–1.76 (m, 2 H, 4-CH2), 2.57 (dd, JH,H
3
3
(100 MHz, CDCl3): δ = –4.77 (SiCH3), –4.73 (SiCH3), 18.13 = 15.0, JH,H = 5.5 Hz, 1 H, 6-CHaHb), 2.75 (dd, JH,H = 15.0,
[C(CH3)3], 25.83 [C(CH3)3], 32.35 (4-CH2), 39.27 (6-CH2), 53.42
3JH,H = 6.5 Hz, 1 H, 6-CHaHb), 2.91 (d, 3JH,H = 5.0 Hz, 1 H, OH),
(OCH3), 63.61 (5-CH), 72.22 (3-CH), 76.36 (2-CH), 169.3 (7- 3.16 (s, 3 H, NCH3), 3.41 (s, 3 H, OCH3), 3.68 (s, 3 H, NOCH3),
3
COOR), 172.1 (1-COOMe) ppm. IR (film): ν = 3447, 2956, 28.57,
3.98–4.02 (m, 1 H, 3-CH), 4.17 (d, JH,H = 4.0 Hz, 1 H, 2-CH),
˜
3
1736, 1473, 1444, 1389, 1360, 1252, 1163, 1133, 1112, 1083, 1061,
1032, 1006, 993, 958, 926, 886, 838, 811, 776, 743, 710, 685, 656,
537 cm–1. UV/Vis (CH3CN): λmax [lg(ε)] = 272 nm (3.66). HRMS-
ESI: m/z = [M + Na]+ calcd. for C14H26O6Si: 341.13963; found
341.13904. C14H26O6Si (318.15): calcd. C 52.80, H 8.23, O 30.15;
found C 53.02, H 8.66, O 29.70.
4.42 (p, JH,H = 6.0 Hz, 1 H, 5-CH), 7.33–7.42 (m, 6 H, Ph-H),
7.61–7.68 (m, 4 H, Ph-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
–4.71 (SiCH3), –4.62 (SiCH3), 18.07 [C(CH3)3], 19.67 [C(CH3)3],
25.95 [C(CH3)3], 27.12 [C(CH3)3], 32.05 (NCH3), 39.64 (6-CH2),
40.60 (4-CH2), 51.63 (OCH3), 61.48 (NOCH3), 67.73 (5-CH), 70.65
(3-CH), 76.20 (2-CH), 127.6, 127.8, 130.0, 130.1, 132.9, 136.0,
136.2 (Ph-C), 171.9 (1-COOMe), 172.4 (7-CONR2), 173.7 ppm. IR
Methyl (S)-2-[(2R,4S)-4-(tert-Butyldimethylsilyloxy)-6-oxotetra-
hydro-2H-pyran-2-yl]-2-(tert-butyldiphenylsilyloxy)acetate (16): To
a solution of lactone 15 (7.00 g, 22.0 mmol, 1 equiv.) and imidazole
(2.50 g, 33.0 mmol, 1.5 equiv.) in dichloromethane (150 mL) was
added tert-butyldiphenylsilyl chloride (TBDPSCl) (10.0 g,
33.0 mmol, 1.5 equiv.) and a small amount of 4-(dimethylamino)-
pyridine (DMAP). After stirring for 24 h at room temp. water
(100 mL) and 1  HCl (20 mL) were added. The aqueous phase
was extracted with diethyl ether (4ϫ50 mL). The combined or-
ganic layers were dried with MgSO4, filtered, and the solvent was
evaporated in vacuo. The residue was purified by flash column
chromatography over silica gel (1:50 w/w) using a mixture of petro-
leum ether and ethyl acetate [5:1 (v/v)] as an eluent. The title com-
pound 16 was obtained as a colorless oil (12.1 g, 99%). Rf = 0.42
(PE/EtOAc, 5:1). [α]2D2 = +4.6 (c = 1.53, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 0.04 (s, 3 H, SiCH3), 0.06 (s, 3 H, SiCH3),
0.86 [s, 9 H, C(CH3)3], 1.09 [2, 9 H, C(CH3)3], 1.74–1.81 (m, 1 H,
(film): ν = 3469, 3071, 3047, 2999, 2931, 2858, 1747, 1613, 1588,
˜
1514, 1428, 1390, 1362, 1336, 1302, 1249, 1109, 937, 822, 743, 704,
614, 508, 487 cm–1. UV/Vis (CH3CN): λmax [lg(ε)] = 223 nm (3.65).
MS (ESI): m/z = 618 [M + H]+, 640 [M + Na]+, 656 [M + K]+.
C32H51NO7Si2 (617.32): calcd. C 62.20, H 8.32, O 18.12; found C
61.76, H 8.56, O 17.88.
Methyl (2S,3R,5S)-5-(tert-Butyldimethylsilyloxy)-2-(tert-butyl-
diphenylsilyloxy)-3-methoxy-7-[methoxy(methyl)amino]-7-oxo-
heptanoate (18): To a solution of Weinreb amide 17 (5.00 g,
8.18 mmol, 1 equiv.) in dichloromethane (300 mL) was added mo-
lecular sieves and the solution was cooled to –5 °C. Proton sponge
(5.25 g, 24.5 mmol, 3 equiv.) was added and the mixture was stirred
until the solid was dissolved. Meerwein salt (3.63 g, 24.5 mmol,
3 equiv.) was added and the solution was stirred for 6 h at –5 °C.
The reaction mixture was diluted with ethyl acetate (100 mL) and
the white precipitation was filtered of through Celite 545. The resi-
due was washed with ethyl acetate (50 mL). The filtrate was washed
with a saturated solution of CuSO4 (4ϫ 50 mL) and water (50 mL).
The organic layer was dried with MgSO4, filtered, and the solvent
was evaporated in vacuo. The residue was purified by flash column
chromatography over silica gel (1:50 w/w) using a mixture of petro-
leum ether and ethyl acetate [2:1 (v/v)] as an eluent. The title com-
pound 18 was obtained as a colorless oil, which crystallized on
3
4-CHaHb), 1.88–1.97 (m, 1 H, 4-CHaHb), 2.54 (d, JH,H = 3.5 Hz,
3
2 H, 6-CH2), 3.47 (s, 3 H, OCH3), 4.30 (d, JH,H = 3.0 Hz, 1 H,
3
CHOTBS), 4.36 (d, JH,H = 4.0 Hz, 1 H, CHOTBDPS), 4.94 (dt,
3
3JH,H = 11.5, JH,H = 3.5 Hz, 1 H, 3-CH), 7.36–7.46 (m, 6 H, Ph-
H), 7.62–7.70 (m, 4 H, Ph-H) ppm. 13C NMR (75 MHz, CDCl3):
δ = –4.86 (SiCH3), –4.84 (SiCH3), 18.02 [C(CH3)3], 19.66 [C(CH3)
3], 25.75 [C(CH3)3], 26.95 [C(CH3)3], 31.60 (4-CH2), 39.38 (6-CH2),
51.86 (OCH3), 63.44 (5-CH), 73.87 (2-CH), 76.65 (3-CH), 127.8,
127.9, 130.2, 130.3, 132.8, 133.1, 135.9, 136.1 (Ph-C)169.0 (7-
storage at –10 °C (4.41 g, 85%). Rf = 0.51 (PE/EtOAc, 2:1). [α]2D2
=
1
19.7 (c = 0.71, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.01 (s,
3 H, SiCH3), 0.03 (s, 3 H, SiCH3), 0.85 [s, 9 H, C(CH3)3], 1.10 [s,
9 H, C(CH3)3], 1.66–1.72 (m, 1 H, 4-CHaHb), 1.79–1.85 (m, 1 H,
COOR), 170.6 (1-COOMe) ppm. IR (film): ν = 3072, 3001, 2932,
˜
2855, 1744, 1611, 1589, 1517, 1428, 1388, 1303, 1251, 1152, 1113,
1069, 1029, 934, 822, 746, 701, 602, 506, 489 cm–1. UV/Vis
(CH3CN): λmax [lg (ε)] = 222 nm (3.76), 227 nm (3.75), 271 nm
(3.22). MS (ESI): m/z = 579 [M + Na]+. C30H44O6Si2 (556.27):
calcd. C 64.71, H 7.96, O 17.24; found C 64.60, H 8.35, O 17.53.
3
4-CHaHb), 2.38 (dd, 3JH,H = 15.0, JH,H = 4.0 Hz, 1 H, 6-CHaHb),
2.74–2.82 (m, 1 H, 6-CHaHb), 3.16 (s, 3 H, NCH3), 3.30 (s, 3 H,
OCH3), 3.41 (s, 3 H, COOCH3), 3.49–3.55 (m, 1 H, 3-CH), 3.67 (s,
3
3 H, NOCH3), 4.31 (d, JH,H = 4.5 Hz, 1 H, 2-CH), 4.31–4.41 (m,
1 H, 5-CH), 7.35–7.43 (m, 6 H, Ph-H), 7.63–7.67 (m, 4 H, Ph-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = –4.77 (SiCH3), –4.57
(SiCH3), 18.07 [C(CH3)3], 19.47 [C(CH3)3], 25.97 [C(CH3)3], 27.17
[C(CH3)3], 32.15 (NCH3), 38.39 (4-CH2), 40.60 (6-CH2), 51.63
(COOCH3), 58.10 (OCH3), 61.35 (NOCH3), 67.08 (5-CH), 73.83
(2-CH), 79.82 (3-CH), 127.6, 127.8, 130.0, 130.1, 132.9, 136.0,
136.2 (Ph-C), 171.9 (1-COOMe), 172.4 (7-CONR2), 173.7 ppm. IR
Methyl (2S,3R,5S)-5-(tert-Butyldimethylsilyloxy)-2-(tert butyldi-
phenylsilyloxy)-3-hydroxy-7-[methoxy(methyl)amino]-7-oxohepta-
noate (17): A solution of N,O-dimethylhydroxylamine hydrochlo-
ride (1.05 g, 10.8 mmol, 3 equiv.) in dichloromethane (15 mL) was
cooled to –78 °C. A solution of trimethylaluminium (5.40 mL,
10.8 mmol, 3 equiv.) in hexane (2 ) was added slowly. After stir-
ring at room temp. for 12 h the mixture was cooled to –78 °C and
a solution of lactone 16 (2.00 g, 3.60 mmol, 1 equiv.) in dichloro-
methane (10 mL) was added dropwise. The solution was warmed
to room temp. and stirred for 4 h. At 0 °C a saturated aqueous
solution of sodium potassium tartrate (50 mL) was added. The sus-
pension was stirred until a clear solution was formed. The aqueous
phase was extracted with dichloromethane (3ϫ70 mL). The com-
bined organic layers were washed with 1  HCl, dried with MgSO4,
filtered, and the solvent was evaporated in vacuo. The title com-
pound 17 was obtained as a colorless oil in quantitative yield with-
out further purification (2.20 g, 100%). Rf = 0.33 (PE/EtOAc, 1:1).
(film): ν = 3429, 3075, 2978, 2933, 2836, 1728, 1641, 1613, 1587,
˜
1514, 1464, 1441, 1392, 1367, 1302, 1249, 1158, 1087, 1036, 997,
955, 917, 822, 760 cm–1. UV/Vis (CH3CN): λmax [lg(ε)] = 215 nm
(2.69). MS (ESI): m/z = 654 [M + Na]+. C33H53NO7Si2 (631.34):
calcd. C 62.72, H 8.45, O 17.72; found C 63.09, H 8.68,
O 17.29.
Methyl (2S,3R,5S)-5-(tert-Butyldimethylsilyloxy)-2-(tert-butyldi-
phenylsilyloxy)-3-methoxy-7-oxoheptanoate (5): A solution of Wein-
reb amide 18 (1.00 g, 1.58 mmol, 1 equiv.) in THF (70 mL) was
cooled to –78 °C. A solution of iBu2AlH (3.16 mL, 3.16 mmol,
2 equiv.) in hexane (1 ) was added dropwise. The reaction mixture
was stirred for 2 h at –78 °C. A mixture of MeOH/H2O, 1:10
1
[α]2D2 = –17.4 (c = 1.32, CHCl3). H NMR (400 MHz, CDCl3): δ =
3914
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3908–3918

Stereocontrolled Synthesis of a Peloruside A Fragment
(50 mL) was added and the solution was warmed to room temp.
1  HCl was added until the solution was clear. The aqueous phase
was saturated with NaCl and extracted with diethyl ether
(4ϫ50 mL). The combined organic layers were dried with MgSO4,
filtered, and the solvent was evaporated in vacuo. The residue was
purified by flash column chromatography over silica gel (1:30 w/w)
using a mixture of petroleum ether and ethyl acetate [5:1 (v/v)] as
an eluent. The title compound 5 was obtained as a colorless oil
(0.90 g, 99%). Rf = 0.71 (PE/EtOAc, 1:1). [α]2D2 = 14.4 (c = 1.67,
CHCl3). 1H NMR (200 MHz, CDCl3): δ = 0.02 (s, 6 H, SiCH3),
0.85 [s, 9 H, C(CH3)3], 1.10 [s, 9 H, C(CH3)3], 1.70–1.79 (m, 2 H,
title compound 6 was obtained as a colorless oil in quantitative
yield without further purification (110 mg, 99%). Rf = 0.42 (PE/E
5:1). 1H NMR (200 MHz, CDCl3): δ = 1.23 (s, 6 H, CH3), 4.28 (m,
3
2 H, CH2OBn), 4.56 (s, 2 H, OCH2Ph), 5.14 (d, JH,H = 17.0 Hz,
1 H, CH2=CH), 5.15 (d, 3JH,H = 11.0 Hz, 1 H, CH2=CH), 5.89 (dd,
3
3JH,H = 11.0, JH,H = 17.0 Hz, 1 H, CH2=CH), 7.28–7.35 (m, 5 H,
Ph-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.55 (CH3), 49.40
[C(CH3)2], 71.10 (OCH2-Ph), 73.17 (CH2OBn), 115.0 (CH2=CH),
127.9, 128.0, 128.5, 137.5 (Ph-C), 141.7 (CH=CH2), 209.1 (C=O)
ppm. IR (film): ν = 3433, 2976, 1723, 1453, 1383, 1275, 1121, 1027,
˜
924, 746, 714, 699, 651 cm–1. UV/Vis (CH3CN): λmax [lg (ε)] =
4-CH2), 2.45–2.50 (m, 2 H, 6-CH2), 3.25 (s, 3 H, OCH3), 3.46 (s, 206 nm (4.57), 264 nm (4.28). MS (ESI): m/z = 241 [M + Na]+, 459
3 H, COOCH3), 3.42–3.48 (m, 1 H, 3-CH), 4.24 (m, 1 H, 5-CH), [2M + Na]+, 463 [2M + Na]+. C14H18O2 (218.13).
3
4.33 (d, JH,H = 4.5 Hz, 1 H, 2-CH), 7.26–7.42 (m, 6 H, Ph-H),
7.63–7.67 (m, 4 H, Ph-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
–4.69 (SiCH3), –4.11 (SiCH3), 18.07 [C(CH3)3], 19.51 [C(CH3)3],
25.90 [C(CH3)3], 27.08 [C(CH3)3], 37.73 (4-CH2), 50.56 (6-CH2),
51.62 (COOCH3), 57.85 (OCH3), 65.61 (5-CH), 73.17 (2-CH),
79.48 (3-CH), 127.8, 127.9, 130.1, 130.2, 132.8, 133.0, 135.9, 136.2
(Ph-C), 171.6 (1-COOMe), 202.3 (7-CHO), 173.7 ppm. IR (film):
Methyl (2S,3R,5R,7R,8R)-8-(Benzyloxy)-5-(tert-butyldimethyl-
silyloxy)-2-(tert-butyldiphenylsilyloxy)-7-hydroxy-3-methoxy-
10,10-dimethyl-9-oxododec-11-enoate (20): To a solution of ketone
6 (267 mg, 1.22 mmol, 1.1 equiv.) in THF (5 mL) at –78 °C trimeth-
ylsilyl chloride (1.56 mL, 12.0 mmol, 10 equiv.), trimethylamine
(1.71 mL, 12.0 mmol, 10 equiv.) and a solution of LiHMDS (1 
in THF) (2.44 mL, 2.44 mmol, 2 equiv.) were added. The solution
was stirred for 20 min at –78 °C. Trimethylsilyl chloride (780 µL,
6.00 mmol, 5 equiv.), trimethylamine (860 µL, 6.00 mmol, 5 equiv.)
and a solution of LiHMDS (1  in THF) (4.16 mL, 4.16 mmol,
3.4 equiv.) were added. The solution was stirred for 1 h at –78 °C.
After complete conversion of 6 (TLC monitoring PE/E, 4:1,
5% NEt3) pH 7 buffer (2 mL) and water (2 mL) were added. The
mixture was warmed to room temp. The aqueous phase was ex-
tracted with diethyl ether (4ϫ10 mL). The combined organic layers
were washed with brine (10 mL), dried with MgSO4, filtered, and
the solvent was evaporated in vacuo. The residue was purified by
flash column chromatography over silica gel (1:30 w/w) using a
mixture of petroleum ether and diethyl ether [6:1 (v/v), 5% NEt3]
as an eluent. The silyl enol ether 19 was obtained as colorless oil in
quantitative yield. Compound 19 was dissolved in dichloromethane
(2 mL) and added to a solution of aldehyde 5 (631 mg, 1.10 mmol,
1 equiv.) in dichloromethane (5 mL) at –78 °C. BF3·OEt2
(0.420 mL, 1.59 mmol, 1.4 equiv.) was added dropwise at this tem-
perature. The solution was stirred for 1 h. After adding pH 7 buffer
(10 mL) the mixture was warmed to room temp. The aqueous
phase was extracted with diethyl ether (4ϫ10 mL). The combined
organic layers were dried with MgSO4, filtered, and the solvent
was evaporated in vacuo. The residue was purified by flash column
chromatography over silica gel (1:100 w/w) using mixtures of petro-
leum ether and diethyl ether [first 6:1, then 4:1 (v/v)] as an eluent.
The title compound 20 was obtained as a colorless oil (618 mg,
70%). Rf = 0.11 (PE/E 5:1). [α]2D2 = 26.1 (c = 0.92, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 0.02 (s, 3 H, SiCH3), 0.05 (s, 3 H,
SiCH3), 0.87 [s, 9 H, C(CH3)3], 1.10 [s, 9 H, C(CH3)3], 1.23 [s, 3 H,
C(CH3)2], 1.24 [s, 3 H, C(CH3)2], 1.50–1.79 (m, 4 H, 4-CH2, 6-
CH2), 3.23 (s, 3 H, OCH3), 3.41 (s, 3 H, COOCH3), 3.46 (mc, 1 H,
ν = 3465, 3072, 3000, 2932, 2858, 1743, 1613, 1588, 1514, 1428,
˜
1384, 1301, 1248, 1150, 1113, 1068, 1033, 936, 822, 744, 703, 604,
508, 488 cm–1. UV/Vis (CH3CN): λmax [lg(ε)] = 218 nm (3.97). MS
(ESI): m/z = 595 [M + Na]+. C31H48O6Si2 (572.30): calcd. C 64.99,
H 8.45, O 16.67; found C 65.27, H 8.76, O 16.39.
1-(Benzyloxy)-3,3-dimethylpent-4-en-2-ol: To a solution of α-benz-
yloxy acetaldehyde (1.00 g, 6.66 mmol, 1 equiv.) and prenyl bro-
mide (1.04 g, 6.99 mmol, 1.05 equiv.) in DMF (15 mL) were added
SnCl2·2H2O (2.25 g, 9.99 mmol, 1.5 equiv.) and NaI (1.50 g,
9.99 mmol, 1.5 equiv.). The suspension was stirred at room temp.
for 5 h. An exothermic reaction and a yellow color of the solution
could be observed. A solution of NH4Cl in water (8 mL, 30%) and
a solution of KF in water (8 mL, 30%) were added. The aqueous
phase was extracted with diethyl ether (4ϫ15 mL). The combined
organic layers were washed with brine (10 mL), dried with MgSO4,
filtered, and the solvent was evaporated in vacuo. The residue was
purified by flash column chromatography over silica gel (1:50 w/w)
using a mixture of n-pentane and diethyl ether [3:1 (v/v)] as an
eluent. The title compound 20 was obtained as a colorless liquid
(1.32 g, 90%). Rf = 0.62 (PE/E, 1:1). 1H NMR (200 MHz, CDCl3):
δ = 1.04 (s, 3 H, CH3), 1.05 (s, 3 H, CH3), 2.42 (s, 1 H, OH), 3.36
(t, 3JH,H = 10.0 Hz, 1 H, CHOH), 3.58 (m, 2 H, CH2OBn), 4.54 (s,
3
2 H, OCH2Ph), 5.00 (d, JH,H = 17.5 Hz, 1 H, CH2=CH), 5.02 (d,
3
3
3JH,H = 10.0 Hz, 1 H, CH2=CH), 5.88 (dd, JH,H = 10.0, JH,H
=
17.5 Hz, 1 H, CH2=CH), 7.29–7.38 (m, 5 H, Ph-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 22.94 (CH3), 23.56 (CH3), 39.91 [C(CH3)2],
71.67 (OCH2-Ph), 73.48 (CH2OBn), 76.64 (CHOH), 112.7
(CH2=CH), 127.8, 127.9, 128.6, 138.2 (Ph-C), 144.9 (CH=CH2)
ppm. IR (film): ν = 3463, 2964, 2929, 2869, 1497, 1453, 1383, 1204,
˜
1114, 1087, 1006, 912, 698, 613 cm–1. UV/Vis (CH3CN): λmax [lg(ε)]
= 206 nm (4.03), 252 nm (2.65). MS (ESI): m/z = 243 [M + Na]+,
463 [2M + Na]+. C14H20O2 (220.15).
3
3-CH), 4.02 (mc, 1 H, 5-CH), 4.16 (mc, 1 H, 7-CH), 4.27 (d, JH,H
3
= 4.5 Hz, 1 H, 2-CH), 4.38 (d, JH,H = 4.5 Hz, 1 H, 8-CH), 4.43
3
3
1-(Benzyloxy)-3,3-dimethylpent-4-en-2-one (6): To a solution of
pyridinium chlorochromate (PCC) (147 mg, 0.680 mmol,
1.5 equiv.) in dichloromethane (10 mL) was added a solution of 1-
(benzyloxy)-3,3-dimethylpent-4-en-2-ol (110 mg, 0.450 mmol,
1 equiv.) in dichloromethane (2 mL). The orange color of the solu-
tion turned to dark brown. After 12 h stirring at room temp. an-
other equivalent of PCC (100 mg) was added. The solution was
stirred for 2 h, diluted with diethyl ether and separated from the
black precipitation by decantation. The residue was washed with
diethyl ether (2ϫ10 mL). The combined organic layers were fil-
tered over silica gel and the solvent was evaporated in vacuo. The
(d, JH,H = 11.5 Hz, 1 H, OCH2Ph), 4.55 (d, JH,H = 11.5 Hz, 1 H,
OCH2Ph), 5.16 (d, 3JH,H = 17.5 Hz, 1 H, CH2=CH), 5.17 (d, 3JH,H
= 10.5 Hz, 1 H, CH2=CH), 5.96 (dd, 3JH,H = 17.5, 3JH,H = 10.5 Hz,
1 H, CH=CH2), 7.37 (m, 11 H, Ph-H), 7.64 (m, 4 H, Ph-H) ppm.
13C NMR (100 MHz, CDCl3): δ = –4.72 (SiCH3), –4.48 (SiCH3),
18.05 [C(CH3)3], 19.51 [C(CH3)3], 23.52 [C(CH3)2], 23.93 [C(CH3)
2], 25.98 [C(CH3)3], 27.09 [C(CH3)3], 37.07 (4-CH2), 37.18 (6-CH2),
50.58 [C(CH3)2], 51.51 (COOCH3), 58.15 (3-OCH3), 67.97 (5-CH),
68.83 (7-CH), 72.45 (OCH2Ph), 73.97 (2-CH), 79.57 (3-CH), 83.08
(8-CH), 114.9 (12-CH2=CH), 127.6, 127.8, 127.9, 128.0, 130.0,
132.9, 133.0, 135.9, 136.2, 137.9 (Ph-C), 141.9 (11-CH=CH2), 171.6
Eur. J. Org. Chem. 2010, 3908–3918
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3915

H. Schönherr, J. Mollitor, C. Schneider
FULL PAPER
(1-COOMe), 211.1 (9-C=O) ppm. IR (film): ν = 3479, 2928, 2857, 290 µmol, 10 equiv.) and catalytic amounts of camphorsulfonic
˜
1752, 1714, 1463, 1428, 1257, 1113, 837, 739, 702, 507 cm–1. UV/
Vis (CH3CN): λmax [lg(ε)] = 202 nm (4.60), 271 nm (4.68), 336 nm solution was stirred for 6 h. A saturated aqueous solution of
acid (0.5 mg, 3.0 µmol, 10 mol-%) were added at room temp. The
(2.48). MS (ESI): m/z = 813 [M + Na]+, 829 [M + K]+. HRMS-
ESI: m/z = [M + Na]+ calcd. for C45H66O8Si2 (790.43): 813.41884;
found 813.41860, [2M + Na]+ calcd. 1603.84847; found
1603.84724.
NaHCO3 (2 mL) and ethyl ether (4 mL) were added. The aqueous
phase was extracted with diethyl ether (3ϫ5 mL). The combined
organic layers were dried with MgSO4, filtered, and the solvent
was evaporated in vacuo. The residue was purified by flash column
chromatography over silica gel (1:80 w/w) using a mixture of hex-
ane and diethyl ether [2:1 (v/v), 2% NEt3] as an eluent. The title
compound 23 was obtained as a colorless oil (16 mg, 30%). Rf =
0.71 (Hex/E, 1:3, 5% NEt3). [α]2D2 = 19.9 (c = 1.60, CHCl3). 1H
NMR (400 MHz, [D8]toluene): δ = 0.16 (s, 3 H, SiCH3), 0.17 (s,
3 H, SiCH3), 1.01 [s, 9 H, C(CH3)3], 1.15 [s, 3 H, 10-C(CH3)2], 1.17
[s, 3 H, 10-C(CH3)2], 1.21 [s, 9 H, C(CH3)3], 1.43 [s, 3 H, OOC-
(CH3)a], 1.48 [s, 3 H, OOC(CH3)b], 1.76–1.80 (m, 1 H, 6-CHaCHb),
1.94–1.99 (m, 2 H, 6-CHaCHb, 4-CHaCHb), 2.10–2.20 (m, 1 H, 4-
Isopropylidene Acetal (22): To a solution of aldol product 20
(62 mg, 78 µmol, 1 equiv.) in ACN (5 mL) in a Teflon® vessel was
added a aqueous solution of HF (48%, 33 µL, 780 µmol, 10 equiv.)
at –5 °C. The solution was stirred for 10 h at –5 °C. HF (10 equiv.)
was added after every two hours. The reaction was stopped by add-
ing a saturated solution of NaHCO3 in water (5 mL). The aqueous
phase was extracted with dichloromethane (4ϫ5 mL). The com-
bined organic layers were dried with MgSO4, filtered, and the sol-
vent was evaporated in vacuo. The crude diol was dissolved in ace-
tone (2 mL) and 2,2-dimethoxypropane (114 µL, 900 µmol,
11.5 equiv.) and catalytic amounts of camphorsulfonic acid
(2.1 mg, 9.0 µmol, 10 mol-%) were added at room temp. The solu-
tion was stirred for 6 h. A saturated aqueous solution of NaHCO3
(2 mL) and ethyl ether (4 mL) were added. The aqueous phase was
extracted with diethyl ether (3ϫ5 mL). The combined organic lay-
ers were dried with MgSO4, filtered, and the solvent was evapo-
rated in vacuo. The residue was purified by flash column
chromatography over silica gel (1:80 w/w) using a mixture of hex-
ane and diethyl ether [1:1 (v/v), 2% NEt3] as an eluent. The title
compound 22 was obtained as a colorless oil (16 mg, 29%). Rf =
0.58 (Hex/E, 1:1, 5% NEt3). [α]2D2 = 21.3 (c = 1.59, CHCl3). 1H
NMR (400 MHz, [D8]toluene): δ = 1.19 [s, 18 H, SiC(CH3)3, 10-
C(CH3)2, OOC(CH3)a], 1.25 [s, 3 H, OOC(CH3)b], 1.66–1.73 (m,
1 H, 6-CHaCHb), 1.88–1.95 (m, 1 H, 4-CHaCHb), 2.00–2.21 (m,
2 H, 4-CHaCHb, 6-CHaCHb), 3.14 (s, 3 H, OCH3), 3.17 (s, 3 H,
COOCH3), 3.68 (mc, 1 H, 3-CH), 3.97 (mc, 1 H, 5-CH), 4.32–4.37
3
CHaCHb), 2.99–3.10 (t, JH,H = 9.0 Hz, 1 H, 8-CH), 3.14 (s, 3 H,
3
OCH3), 3.27 (s, 3 H, COOCH3), 3.61 (d, JH,H = 9.0 Hz, 1 H, 9-
CH), 3.67 (mc, 1 H, 3-CH), 4.11 (mc, 1 H, 7-CH), 4.30 (mc, 1 H, 5-
3
3
CH), 4.41 (d, JH,H = 11.5 Hz, 1 H, OCH2Ph), 4.48 (d, JH,H
=
3
4.5 Hz, 1 H, 2-CH), 4.55 (d, JH,H = 11.5 Hz, 1 H, OCH2Ph), 4.89
(d, JH,H = 11.0 Hz, 1 H, 12-CH2=CH), 5.01 (d, JH,H = 17.5 Hz,
3
3
3
3
1 H, 12-CH2=CH), 6.11 (dd, JH,H = 17.5, JH,H = 11.0 Hz, 1 H,
11-CH=CH2), 7.19 (m, 11 H, Ph-H), 7.77 (m, 4 H, Ph-H) ppm. 13
C
NMR (100 MHz, [D8]toluene): δ = –4.26 (SiCH3), –3.51 (SiCH3),
19.63 [OOC(CH3)a], 20.14 [C(CH3)3], 20.32 [10-C(CH3)2], 22.18
[C(CH3)3], 25.74 [10-C(CH3)2], 26.20 [C(CH3)3], 27.22 [C(CH3)3],
29.87 [OOC(CH3)b], 40.11 (6-CH2), 40.48 [10-C(CH3)2], 42.12 (4-
CH2), 50.80 (COOCH3), 58.39 (OCH3), 66.31 (5-CH), 70.87 (7-
CH), 72.55 (OCH2Ph), 74.69 (2-CH), 77.37 (9-CH), 79.10 (3-CH),
80.41 (8-CH), 98.07 [OOC(CH3)2], 110.1 (12-CH2=CH), 127.4,
127.8, 128.0, 128.4, 130.1, 136.2, 136.5 (Ph-C), 146.1 (11-
CH=CH ), 171.3 (1-COOMe) ppm. IR (film): ν = 2931, 2858,
˜
2
1753, 1472, 1462, 1428, 1381, 1252, 1204, 1169, 1111, 1029, 836,
787, 701, 613, 507 cm–1. UV/Vis (CH3CN): λmax [lg(ε)] = 209 nm
(4.49), 264 nm (3.00). MS (ESI): m/z = 855 [M + Na]+. HRMS-
ESI: m/z = [M + Na]+ calcd. for C48H72O8Si2 (832.48): 855.46612;
found 855.46581.
3
(m, 2 H, 7/8-CH), 4.34 (s, 2 H, OCH2Ph), 4.50 (d, JH,H = 5.0 Hz,
3
1 H, 2-CH), 4.98 (d, JH,H = 17.0 Hz, 1 H, 12-CH2=CH), 4.99 (d,
3
3
3JH,H = 11.0 Hz, 1 H, 12-CH2=CH), 5.93 (dd, JH,H = 17.5, JH,H
= 10.5 Hz, 1 H, 11-CH=CH2), 7.28 (m, 10 H, Ph-H), 7.80 (m, 5 H,
Ph-H) ppm. 13C NMR (100 MHz, [D8]toluene): δ = 19.51
[SiC(CH3)3], 24.90 [10-C(CH3)2], 25.67 [OOC(CH3)a], 25.80
[OOC(CH3)b], 28.25 [SiC(CH3)3], 35.21 (4-CH2), 37.14 (6-CH2),
51.56 [10-C(CH3)2], 51.85 (COOCH3), 58.52 (OCH3), 65.13 (7-
CH), 69.26 (5-CH), 73.57 (OCH2Ph), 75.18 (2-CH), 79.21 (3-CH),
82.91 (8-CH), 101.6 [OOC(CH3)2], 115.1 (12-CH2=CH), 128.9,
129.0, 131.0, 131.1, 134.7, 137.5, 138.5 (Ph-C), 143.8 (11-
Methyl (2S,3R,5R,7R,8R)-8-(Benzyloxy)-5-(tert-butyldimethyl-
silyloxy)-2-(tert-butyldiphenylsilyloxy)-3,7-dimethoxy-10,10-di-
methyl-9-oxododec-11-enoate (24): To a solution of aldol product
20 (191 mg, 0.240 mmol, 1 equiv.) in dichloromethane (8 mL) was
added molecular sieves at –5 °C. Proton sponge (155 mg,
0.720 mmol, 3 equiv.) was added and the mixture was stirred until
the solid was dissolved. Meerwein salt (107 mg, 0.720 mmol,
3 equiv.) was added and the solution was stirred for 3 h at –5 °C.
The reaction mixture was diluted with ethyl acetate (10 mL) and
the white precipitation was filtered of through Celite 545. The resi-
due was washed with ethyl acetate (5 mL). The filtrate was washed
with a saturated solution of CuSO4 (4ϫ 10 mL) and water (5 mL).
The organic layer was dried with MgSO4, filtered, and the solvent
was evaporated in vacuo. The residue was purified by flash column
chromatography over silica gel (1:50 w/w) using a mixture of petro-
leum ether and diethyl ether [5:1 (v/v)] as an eluent. The title com-
CH=CH ), 172.2 (1-COOMe), 210.5 (9-C=O) ppm. IR (film): ν =
˜
2
2932, 1751, 1715, 1428, 1382, 1224, 1113, 1027, 788, 702, 506 cm–1.
UV/Vis (CH3CN): λmax [lg(ε)] = 209 nm (4.28), 261 nm (2.38). MS
(ESI): m/z = 739 [M + Na]+. HRMS-ESI: m/z = [M + Na]+ calcd.
for C42H56O8Si (716.37): 739.36367; found 739.36293.
Isopropylidene Acetal (23): To a solution of aldol product 20
(50 mg, 63 µmol, 1 equiv.) in dichloromethane (2 mL) was added a
[35]
solution of freshly prepaired Zn(BH4)2
in ethyl ether (0.4 )
(290 µL, 95.0 µmol, 1.5 equiv.) at –78 °C. The solution was stirred
for 3 h at –78 °C. A saturated aqueous solution of NH4Cl (1 mL)
was added and the mixture was warmed to room temp. The aque- pound 24 was obtained as a colorless oil (192 mg, 99%). Rf = 0.23
1
ous phase was extracted with dichloromethane (4 ϫ 5 mL). The (PE/E, 4:1). [α]2D2 = 17.6 (c = 1.48, CHCl3). H NMR (400 MHz,
combined organic layers were washed with a saturated aqueous
solution of NaHCO3 (5 mL) and water (5 mL), dried with MgSO4,
filtered, and the solvent was evaporated in vacuo. The residue was
purified by flash column chromatography over silica gel (1:80 w/w)
using a mixture of hexane and diethyl ether [3:1 (v/v)] as an eluent.
The diol was obtained as colorless oil, 23 mg (46%). It was dis-
solved in acetone (2 mL) and 2,2-dimethoxypropane (36.0 µL,
CDCl3): δ = 0.03 (s, 3 H, SiCH3), 0.04 (s, 3 H, SiCH3), 0.87 [s, 9 H,
C(CH3)3], 1.10 [s, 9 H, C(CH3)3], 1.21 [s, 3 H, C(CH3)2], 1.23 [s,
3 H, C(CH3)2], 1.38–1.91 (m, 4 H, 4-CH2, 6-CH2), 3.24 (s, 3 H, 3-
OCH3), 3.27 (s, 3 H, 7-OCH3), 3.40 (s, 3 H, COOCH3), 3.39–3.48
(m, 1 H, 3-CH), 3.72–3.83 (m, 1 H, 7-CH), 4.01 (mc, 1 H, 5-CH),
4.25 (d, 3JH,H = 4.5 Hz, 1 H, 2-CH), 4.39 (d, 3JH,H = 12.0 Hz, 1 H,
3
3
OCH2Ph), 4.58 (d, JH,H = 12.0 Hz, 1 H, OCH2Ph), 4.61 (d, JH,H
3916
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3908–3918

Stereocontrolled Synthesis of a Peloruside A Fragment
3
= 3.0 Hz, 1 H, 8-CH), 5.15 (d, JH,H = 17.5 Hz, 1 H, CH2=CH),
Acknowledgments
3
3
5.16 (d, JH,H = 11.0 Hz, 1 H, CH2=CH), 5.96 (dd, JH,H = 17.5,
3JH,H = 11.0 Hz, 1 H, CH=CH2), 7.37 (m, 11 H, Ph-H), 7.64 (m, 4
H, Ph-H) ppm. 13C NMR (100 MHz, CDCl3): δ = –4.42 (SiCH3),
–3.77 (SiCH3), 18.11 [C(CH3)3], 19.49 [C(CH3)3], 23.51 [C(CH3)2],
24.33 [C(CH3)2], 26.14 [C(CH3)3], 27.12 [C(CH3)3], 37.07 (4-CH2),
39.45 (6-CH2), 50.50 [C(CH3)2], 51.43 (COOCH3), 57.02 (7-OCH3),
58.52 (3-OCH3), 66.30 (5-CH), 71.89 (OCH2Ph), 74.35 (2-CH),
77.20 (7-CH), 79.28 (3-CH), 79.89 (8-CH), 115.1 (12-CH2=CH),
127.6, 127.8, 127.8, 128.0, 128.4, 129.9, 130.0, 133.1, 133.1, 136.0,
136.2, 138.0 (Ph-C), 142.0 (11-CH=CH2), 171.7 (1-COOMe), 210.6
Generous financial support from the Deutsche Forschungsgemein-
schaft (DFG) (Schn 441/5-2) is most gratefully acknowledged. We
also thank Michael Riedel for early studies and Wacker AG for the
donation of chlorosilanes.
[1] L. M. West, P. T. Northcote, C. N. Battershill, J. Org. Chem.
2000, 65, 445–449.
[2] K. A. Hood, L. M. West, B. Rouwe, P. T. Northcote, M. V.
Berridge, S. J. Wakefield, J. H. Miller, Cancer Res. 2002, 62,
3356–3360.
[3] T. N. Gaitanos, R. M. Buey, J. F. Diaz, P. T. Northcote, P. Tees-
dale-Spittle, J. M. Andreu, J. H. Miller, Cancer Res. 2004, 64,
5063–5067.
(9-C=O) ppm. IR (film): ν = 2931, 2857, 1753, 1715, 1471, 1428,
˜
1113, 1055, 836, 740, 702, 506 cm–1. UV/Vis (CH3CN): λmax [lg(ε)]
= 205 nm (4.51), 210 nm (4.47), 259 nm (3.13). MS (ESI): m/z =
827 [M + Na]+ . HRMS-ESI: m/z = [M + Na]+ calcd. for
C46H68O8Si2 (804.45): 827.43449; found 827.43495.
[4] J. H. Miller, B. Rouwe, T. N. Gaitanos, K. A. Hood, K. P.
Crume, B. T. Baeckstroem, A. C. La Flamme, M. V. Berridge,
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Methyl (2S,3R,5R,7R,8R)-8-(Benzyloxy)-5-(tert-butyldimethyl-
silyloxy)-2-(tert-butyldiphenylsilyloxy)-3,7-dimethoxy-10,10-di-
methyl-9,11-dioxoundecanoate (4): To a solution of olefin 24
(560 mg, 0.690 mmol, 1 equiv.) in acetone (8 mL), water (1 mL) and
tert-butanol (0.1 mL) were added an aqueous solution (4%) of
OsO4 (1.1 mL, 0.170 mmol, 0.25 equiv.) and N-methylmorpholine
N-oxide (98.0 mg, 0.830 mmol, 1.2 equiv.) at room temp. The solu-
tion was stirred at room temp. for 4 h. An aqueous solution (0.5 )
of Na2S2O3 (5 mL) was added and the mixture was stirred for
30 min. The aqueous phase was extracted with ethyl acetate
(4ϫ10 mL). The combined organic layers were washed with water
(10 mL) and brine (10 mL), dried with MgSO4, filtered, and the
solvent was evaporated in vacuo. The crude diol was dissolved in
a mixture of THF and water (10 mL, 4:1). Sodium periodate
(298 mg, 1.39 mmol, 2 equiv.) was added at room temp. and the
solution was stirred for 18 h. Water (10 mL) and ethyl acetate
(5 mL) were added. The aqueous phase was extracted with ethyl
acetate (4ϫ10 mL). The combined organic layers were washed
with water (10 mL) and brine (10 mL), dried with MgSO4, filtered,
and the solvent was evaporated in vacuo. The residue was purified
by flash column chromatography over silica gel (1:50 w/w) using
mixtures of petroleum ether and diethyl ether [5:1 (v/v)] as an elu-
ent. The title compound 4 was obtained as a colorless oil (512 mg,
91%). Rf = 0.41 (PE/E, 3:1). [α]2D2 = 34.9 (c = 0.86, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 0.04 (s, 3 H, SiCH3), 0.08 (s, 3 H,
SiCH3), 0.91 [s, 9 H, C(CH3)3], 1.09 [s, 9 H, C(CH3)3], 1.20 [s, 3 H,
C(CH3)2], 1.29 [s, 3 H, C(CH3)2], 1.27–1.30 (m, 1 H, 6-CHaCHb),
[7] A. B. Smith III, J. M. Cox, N. Furuichi, C. S. Kenesky, J.
Zheng, O. Atasoylu, W. M. Wuest, Org. Lett. 2008, 10, 5501–
5504.
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3
3
1.66–1.71 (m, 2 H, 4-CH2), 1.90 (ddd, JH,H = 14.0, JH,H = 10.5,
4JH,H = 2.0 Hz, 1 H, 6-CHaCHb), 3.24 (s, 3 H, 3-OCH3), 3.39 (s,
3 H, 7-OCH3), 3.40 (s, 3 H, COOCH3), 3.45–3.49 (m, 1 H, 3-CH),
3
3.93–3.96 (m, 1 H, 7-CH), 4.03 (mc, 1 H, 5-CH), 4.25 (d, JH,H
=
3
2.5 Hz, 1 H, 8-CH), 4.28 (d, JH,H = 4.5 Hz, 1 H, 2-CH), 4.41 (d,
3JH,H = 11.0 Hz, 1 H, OCH2Ph), 4.78 (d, JH,H = 11.0 Hz, 1 H,
3
OCH2Ph), 7.34 (m, 11 H, Ph-H), 7.65 (m, 4 H, Ph-H), 9.45 (s, 1 H,
11-CHO) ppm. 13C NMR (100 MHz, CDCl3): δ = –4.53 (SiCH3),
–3.58 (SiCH3), 18.17 [C(CH3)3], 19.49 [C(CH3)3], 19.88 [C(CH3)2],
20.31 [C(CH3)2], 26.13 [C(CH3)3], 27.10 [C(CH3)3], 38.66 (4-CH2),
39.04 (6-CH2), 51.45 (COOCH3), 57.57 (7-OCH3), 57.81 [C(CH3)
2], 58.40 (3-OCH3), 66.33 (5-CH), 73.57 (OCH2Ph), 74.16 (2-CH),
79.98 (7-CH), 80.00 (3-CH), 81.89 (8-CH), 127.6, 127.8, 128.1,
128.3, 128.6, 129.9, 130.0, 133.0, 133.1, 135.9, 136.2, 137.2 (Ph-C),
171.7 (1-COOMe), 199.9 (11-CHO), 208.9 (9-C=O) ppm. IR (film):
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ν = 2931, 2857, 1727, 1706, 1509, 1462, 1428, 1249, 1114, 1008,
˜
837, 788, 703, 507 cm–1. UV/Vis (CH3CN): λmax [lg(ε)] = 206 nm
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Eur. J. Org. Chem. 2010, 3908–3918
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3917

H. Schönherr, J. Mollitor, C. Schneider
FULL PAPER
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Received: March 17, 2010
Published Online: May 21, 2010
3918
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3908–3918