Asymmetric synthesis of the C1-C13 fragment of the marine metabolite bistramide K

Article abstract of DOI:10.1002/ejoc.201000881

A synthetic study on the construction of the C1-C13 fragment of bistramide K is described. This unit differs from other members of the bistramide family, which are equipped with a pyran structure at C6-C11. In bistramide K, the linear C1-C13 portion conta

Full text of DOI:10.1002/ejoc.201000881

FULL PAPER
DOI: 10.1002/ejoc.201000881
Asymmetric Synthesis of the C1–C13 Fragment of the Marine Metabolite
Bistramide K
Claude Bauder*[a]
Keywords: Asymmetric synthesis / Chiral auxiliary / Diastereoselectivity / Natural products / Olefination
A synthetic study on the construction of the C1–C13 frag-
ment of bistramide K is described. This unit differs from other
members of the bistramide family, which are equipped with
a pyran structure at C6–C11. In bistramide K, the linear C1–
C13 portion contains three stereogenic centers as well as two
supplementary (E)-olefin positions. The key step in the syn-
thesis was the elaboration of the (E)-olefin C6–C7 by using a
Julia–Kocienski reaction between aldehyde 4 and benzo-
thiazolesulfone 15.
analysis to be acyclic.[5] Complementary chiroptical mea-
surements allowed the total synthesis of bistramide C[6] and
then of bistramide A[7] as well as of some of their sub-struc-
ture fragments[8] or isomeric analogues.[8g] The relative and
absolute configuration of some portions of bistramide D
were also described.[8h] Subsequently, X-ray crystallo-
graphic structures of the bistramide A–actin complex[9a]
and bistramide D[9b] were simultaneously reported.
Introduction
Bistramides A–D and K constitute a unique class of natural
bioactive substances extracted essentially from the marine
ascidian Lissoclinum bistratum Sluiter. Bistramide A has
been isolated in New Caledonia[1] and in Australia,[2] and
this was followed by the isolation of four additional bis-
tramides (B, C, D and K).[3] More recently, bistramide A, D,
and a novel member, named 39-oxobistramide K, have also
During the last decade, bistramide A and its analogues
been isolated in Madagascar from the marine invertebrate have been intensively studied because of their antiprolifera-
tunicate Trididemnum cyclops Michaelsen.[4] The framework tive activities,[4,8g,10a–10d] and these compounds provide a
of bistramide A was elucidated by NMR spectroscopic novel source of actin inhibitors for use in anticancer ther-
Scheme 1. Retrosynthetic analysis of the C1–C13 fragment of bistramide K.
[a] Laboratoire de Chimie Biomimétique des Métaux de
Transition, Institut de Chimie, UMR CNRS 7177, Université
de Strasbourg,
apy. However, bistramide D, and especially bistramide K,
were reported to be less toxic in vivo compared to their
congeners.[10e–10h] We report herein a convergent and en-
antioselective synthesis of the C1–C13 fragment of bis-
tramide K. This compound differs from all the other mem-
bers of the bistramide family in that the tetrahydropyran
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E-mail: cbauder@chimie.u-strasbg.fr
Supporting information for this article is available on the
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C. Bauder
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subunit (C6–C11) is substituted by an unsaturated, linear of this chiral center was considered to be (R), based on a
1
moiety (Scheme 1). With the exception of bistramide C, comparison of the H NMR spectra of the (R)- and (S)-
which has an oxo group at C39, the C14–C40 fragment is Mosher’s ester derivatives. After protection of the free al-
common to all the bistramides and has been widely re- lylic alcohol function of 1a as its tert-butyldimethylsilyl
ported in the literature.
(TBS) ether, the chiral auxiliary was reductively removed
with lithium borohydride. The resulting primary alcohol 3
was oxidized according to the Parikh–Doering protocol[14]
to afford the volatile aldehyde 4 in good yield (91%).[15]
This latter aldehyde was then subjected to (E)-olefination
Results and Discussion
The retrosynthetic analysis depicted in Scheme 1 illus- with an appropriate precursor of C7–C13. For this cou-
trates the route that was envisaged. The two subunits, alde- pling, we investigated several options.
hyde C1–C6 and the anion of the C7–C13 segment, could
Initially, a Horner–Wadsworth–Emmons (HWE) reac-
be connected by an (E)-olefination strategy. The synthesis tion was attempted for the synthesis of the C1–C13 segment
began with the preparation of aldehyde 4 (Scheme 2). Intro- between oxo phosphonate 7 and aldehyde 4 (Scheme 3).
duction of the chiral center at C4 was achieved by using the The preparation of this oxo phosphonate was initiated by
Evans aldol reaction.[11] Treatment of the chiral auxiliary an aldol reaction between the boron enolate of chiral (R)-
(4R)-3-acetyl-4-benzyloxazolidin-2-one derivative with di- 2-benzyl-3-propionyl-2-oxazolidinone and 3-benzyloxypro-
butylboron triflate (Bu2BOTf) and triethylamine in dichlo- panal, again using the convenient Evans aldol chemistry to
romethane, followed by reaction with crotonaldehyde, pro- introduce the syn stereochemistry at C9–C11. As expected,
vided the aldol product in 70% yield as a mixture of two the aldol reaction gave exclusively the syn-selective aldol ad-
epimers [anti/syn (75:25)].
duct 5 in 79% yield.[16] Removal of the chiral auxiliary with
Fortunately, the major product was the expected oxazol- magnesium methoxide afforded the corresponding ester 6a
idinone 1a, which was isolated as a crystalline compound in good yield. This ester was then homologated with the
from its diastereomer by column chromatography.[12] The anion of dimethyl methylphosphonate in modest yield, fol-
chirality of the newly formed center at C4 of the major lowed by silylation to provide the desired protected phos-
product 1a was determined by using the empirical Mosher’s phonate 7. The same treatment with the silylated ester 6b
ester method.[13] Consequently, the absolute configuration to generate phosphonate 7 was unsuccessful in our hands.
Scheme 2. Reagents and conditions: (a) Bu2BOTf, Et3N, CH2Cl2, –78 to 0 °C, (E)-MeC=CCHO, 70% (75:25 for 1a/1b,respectively); (b)
TBSCl, DMF, imdazole, 98%; (c) LiBH4, MeOH, THF, 82%; (d) Py·SO3, Et3N, DMSO, CH2Cl2, 91%.
Scheme 3. Reagents and conditions: (e) Bu2BOTf, Et3N, CH2Cl2, –78 to 0 °C, BnOCH2CH2CHO, 79%; (f) Mg, MeOH, 71% for 6a and
then TBSOTf, DIPEA, CH2Cl2, 86% for 6b; (g) BuLi, (MeO)2P(O)Me, THF, 43% then TBSOTf, DIPEA, CH2Cl2, 63%; (h) NaH, 4,
THF, 37%.
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Partial Synthesis of Bistramide K
The use of a range of classical HWE coupling conditions ing the coupling of iodide 11 with sulfide 16 an unexpected
(base and solvent) were investigated to obtain the (E)-enone by-product was observed that was fully characterized as
8.[17] The best results were observed with sodium hydride in methyl sulfide 14a (ca. 15–20%).[24] To obtain olefin 17, the
tetrahydrofuran (THF), albeit in modest yield (37%). α-lithiated sulfone derived from 15 was treated with alde-
Moreover, various attempts by using reported procedures hyde 4 in the presence of lithium hexamethyldisilazide
to reduce the carbonyl component of the α,β-unsaturated (LHMDS) at low temperature (–70 °C); the condensation
carbonyl function to afford a methylene group, either failed was conducted under the Barbier conditions in order to li-
or gave inseparable mixtures. Because of the modest yields, mit self-condensation of sulfone 15.
and to avoid the need for this carbonyl reduction, we turned
The olefination to adduct 17 proceeded smoothly in
to the preparation of phosphonate 12[18] and sulfone 13, good yield (81%) as a mixture of (E) and (Z) isomers (ratio
which are both available from the iodide 11 (Scheme 4). In 1:1), which was easily separated by preparative thin layer
these cases, the coupling of phosphonate 12 with aldehyde chromatography on plates impregnated with a solution of
4 afforded a complex reaction mixture,[19] whereas the clas- silver nitrate.[25] The two isomers [(E) and (Z)] were fully
sical Julia–Lythgoe olefination[20] by using sulfonate 13 led characterized by NMR spectroscopy at high field
to major degradation and by-products.
(600 MHz). Finally, the synthesis was achieved by debenz-
Finally, modified Julia–Lythgoe–Kocienski ole- ylating the (E) isomer 17 under the conditions of dissolved
a
fination[21] by using benzothiazolesulfone 15 and aldehyde metal reduction (Na/NH3) in 68.7%. During this debenz-
4 was successful for the preparation of olefin 17 (Scheme 5). ylation a mixture of two regioisomers formed, which was
The sulfone 15 was obtained by homologation of iodide 11 easily separated to afford the desired C1–C13 fragment 18
with metallated 2-methylthiobenzothiazole (16), which was of bistramide K. The second product formed as a result of
readily prepared from 2-benzothiazolethiol,[22] followed by migration of the silyl group at C11 towards the free alcohol
clean molybdate-mediated oxidation.[23] Surprisingly, dur- function at C13.
Scheme 4. Reagents and conditions: (i) TBSCl, DMF, imidazole, 92%; (j) LiBH4, MeOH, THF, 82%; (k) Ph3P, I2, imidazole, Et2O/
MeCN, 87%; (l) for 12: (MeO)2P(O)Me, BuLi, HMPA, THF, –78 °C, 63%; for 13: PhSO2Me, BuLi, THF, 0 °C, 67%; for 15: BT-SMe
(16) (BT = benzothiazolyl), LDA, HMPA, THF, 70.5% then EtOH, (NH4)6Mo7O24·4H2O, H2O2, 0 °C, 73 %.
Scheme 5. Julia–Kocienski olefination. Reagents and conditions: LHMDS (2.3 equiv.), –78 °C, 2 h, 81 % [(E)/(Z) 1:1]; debenzylation was
performed with Na in liquid ammonia.
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C. Bauder
FULL PAPER
crude product was first filtered through silica gel (EtOAc/hexane,
1:9) before being purified by flash chromatography on a silica gel
Conclusions
The first stereoselective synthesis of the C1–C13 unit of column (EtOAc/cyclohexane, 3:7). The two diastereomers 1a and
1b were separated in 70% combined yield as white solids (75:25;
3.36 g and 1.11g, respectively). Rf = 0.31 (1a), 0.22 (1b) (EtOAc/
cyclohexane, 2:3). The absolute configurations at C-4 in compound
1a was further verified by the Mosher ester analysis.[13] See the
Supporting Information for analyses, assignments and ∆δ values.
White crystals. M.p. 79 °C. [α]D = –35.0 (c = 1.35, CHCl3) {ref.[12]
[α]D = –35.3 (c = 0.54, CHCl3)}. C16H19NO4 (289.33): calcd. C
66.42, H 6.62, N 4.84; found C 66.53, H 6.67, N 4.51. 1H NMR
the natural marine compound bistramide K has been ac-
complished. The present studies have shown that the key
step was a satisfactory Julia–Kocienski olefination between
aldehyde 4 and benzothiazolesulfone 15. The two isomers
[(E) and (Z)] were easily separated on silica gel impregnated
with silver nitrate. The last debenzylation step completed
the formation of alcohol 18, which can be considered as a
precursor for further peptidic coupling with the well-de-
scribed C14–C40 fragment common to all the bistramides.
(300 MHz, CDCl3): δ = 7.37–7.18 (m, 5 H, Ph), 5.78 (ddq, J2-3
=
15.4, J2-1 = 6.3, J2-4 = 1 Hz, 1 H, 2-H), 5.58 (ddq, J3-2 = 15.4, J3-4
= 6.5, J3-1 = 1.5 Hz, 1 H, 3-H), 4.70 (m, X part of ABX system, 1
H, 4Ј-H), 4.59 (m, 1 H, 4-H), 4.20 (m, AB part of a degenerate
ABX system, 2 H, 5Ј-H), 3.17 (AB part of an ABX system, J5a-5b
= 17.3, J5a-4 = 8.6, J5b-4 = 3.7, ∆ν = 34 Hz, 2 H, 5-H), 3.04 (AB
part of an ABX system, J6Јa-6Јb = 13.5, J6Јa-4Ј = 9.4, J6Јb-4Ј = 3.4,
∆ν = 153 Hz, 2 H, 6Ј-H), 2.94 (d, J = 3.7 Hz, 1 H, OH), 1.74 (ddd,
J1-2 = 6.4, J1-3 = 1.3, J1-4 = 0.7 Hz, 3 H, 1-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 172.3 (CO), 153.4 (CO), 135.1 (Cq arom.),
131.8 (C-3), 129.4 (CH arom.), 129.0 (CH arom.), 127.6 (C-2),
127.5 (CH arom.), 68.8 (C-4), 66.3 (C-5), 55.1 (C-4Ј), 42.7 (C-5Ј),
37.8 (C-6Ј), 17.7 (Me) ppm.
Experimental Section
General Information: All solvents were purified according to stan-
dard methods. Reactions were carried out in flame-dried glassware
under argon, unless otherwise noted, and were monitored by thin
layer chromatography (TLC) with 0.25 mm Merck pre-coated silica
gel plates. Spots were detected under UV irradiation (254 nm) and/
or by staining with acidic ceric ammonium molybdate, unless
otherwise noted. Flash chromatographic purifications were per-
formed with silica gel 60 (particle size 0.040–0.063 mm) supplied
by Merck, Geduran. Yields refer to chromatographically and spec-
troscopically pure compounds, unless otherwise stated. All the
NMR spectra (1H, 13C, COSY, NOESY, HMQC as well as HSQC)
were measured with Bruker AV300, AV400, AV500 or AV600 spec-
trometers by using an internal deuterium lock at ambient tempera-
ture. If not otherwise noted, CDCl3 (δ = 7.26 ppm relative to resid-
ual CHCl3) was used as solvent for all NMR experiments. Multi-
plicities are described by using the following abbreviations: s = sin-
glet, d = doublet, t = triplet, q = quartet, m = multiplet, br. =
broad, and ABX = ABX system. For NMR assignments, please
refer to the atom numbering in the schemes; the oxazolidine posi-
tions are labelled with a prime; the benzyl position is labelled as
6Ј; Bzt is benzothiazolyl. Chemical shifts are given in ppm, and
coupling constants are presented in Hz. 13C NMR spectra were
calibrated from the central triplet peak (δ = 77.0 ppm) of CDCl3.
Optical rotations [α]D were recorded with a Polarimeter Model 341
(Perkin–Elmer) at a wavelength of 589 nm in a 10 cm quartz cu-
vette and are reported as follows: [α]D, concentration (c in g/
100 mL) and solvent. Elemental analyses were measured at the Ser-
vice de microanalyse of the University Louis Pasteur of Strasbourg
(France). Mass spectra (ESI-MS) were obtained with a microTOF
instrument (Bruker Daltonics, Bremen, Germany).
(–)-(R)-4-Benzyl-3-[(S,E)-3-hydroxyhex-4-enoyl]-1,3-oxazolidin-2-
one (1b): White crystals. M.p. 72 °C. [α]D = –76.3 (c = 0.085,
CHCl3). C16H19NO4 (289.33): calcd. C 66.42, H 6.62, N 4.84;
1
found C 66.42, H 6.78, N 4.62. H NMR (300 MHz, CDCl3): δ =
7.37–7.20 (m, 5 H, Ph), 5.79 (ddq, J2-3 = 15.3, J2-1 = 6.4, J2-4
=
1 Hz, 1 H, 2-H), 5.58 (ddq, J3-2 = 15.4, J3-4 = 6.5, J3-1 = 1.5 Hz, 1
H, 3-H), 4.69 (m, X part of ABX system, 1 H, 4Ј-H), 4.63 (m, 1
H, 4-H), 4.20 (m, AB part of a degenerate ABX system, 2 H, 5Ј-
H), 3.16 (AB part of an ABX system, J5a-5b = 17.3, J5a-4 = 8.5, J5b-
= 3.6, ∆ν = 29 Hz, 2 H, 5-H), 3.04 (AB part of an ABX system,
4
J6Јa-6Јb = 13.4, J6Јa-4Ј = 9.6, J6Јb-4Ј = 3.4, ∆ν = 162 Hz, 2 H, 6Ј-H),
2.81 (br. s, 1 H, OH), 1.72 (ddd, J1-2 = 6.5, J1-3 = 1.3, J1-4 = 0.8 Hz,
3 H, 1-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.1 (CO), 153.4
(CO), 135.0 (Cq arom.), 131.8 (C-3), 129.4 (CH arom.), 129.0 (CH
arom.), 127.6 (C-2), 127.5 (CH arom.), 68.7 (C-4), 66.3 (C-5), 55.1
(C-4Ј), 42.7 (C-5Ј), 37.9 (C-6Ј), 17.7 (Me) ppm.
(–)-(R)-4-Benzyl-3-[(R,E)-3-(tert-butyldimethylsilyloxy)hex-4-en-
oyl]-1,3-oxazolidin-2-one (2): To a solution of 1a (1.553 g,
5.37 mmol, 1 equiv.) in anhydrous DMF (5 mL), were successively
added a solution of tert-butyldimethylsilyl chloride (1.21 g,
1.5 equiv.) in anhydrous DMF (5 mL) and a solution of imidazole
(731 mg, 2 equiv.) in anhydrous DMF (5 mL). The reaction mixture
was stirred at room temp. for 2 h and then quenched with water
(10 mL) and diluted with diethyl ether (10 mL). The aqueous layer
was extracted with diethyl ether (3ϫ 10 mL), and the combined
organic layers were washed with water (5 ϫ 10 mL), brine
(10ϽmL), dried (Na2SO4), and filtered. The solvents were evapo-
rated under reduced pressure, and the crude product was purified
by chromatography on a silica gel column (EtOAc/cyclohexane,
1:9) to afford 2 (2.12 g; 98%) as a white solid, which could be
recrystallized from hexane. White crystals. M.p. 65 °C. [α]D = –37.4
(c = 0.85, CHCl3). C22H33NO4Si (403.59): calcd. C 65.47, H 8.24,
N 3.47; found C 65.65, H 8.27, N 3.45. 1H NMR (300 MHz,
(–)-(R)-4-Benzyl-3-[(R,E)-3-hydroxyhex-4-enoyl]-1,3-oxazolidin-2-
one (1a): A solution of Bu2BOTf (1  in CH2Cl2, 24.4 mL,
1.1 equiv.), followed by NEt3 (3.7 mL, 1.2 equiv.) was added drop-
wise at –78 °C to a solution of (R)-3-acetyl-4-benzyl-1,3-oxazol-
idin-2-one (4.86 g, 18.4 mmol, 1 equiv.) dissolved in anhydrous
CH2Cl2 (40 mL). After 15 min, the mixture was stirred at 0 °C for
1 h, and then crotonaldehyde (1.85 mL, 1 equiv.) was slowly added
at –78 °C. The reaction was continued at 0 °C for 2 h and at room
temp. for a further 1 h before being quenched slowly at 0 °C by
successive addition of a buffer solution (pH = 7, 25 mL) and H2O2/
CDCl3): δ = 7.36–7.20 (m, 5 H, Ph), 5.66 (ddq, J2-3 = 15.4, J2-1
=
MeOH (10:40 mL). Satd. aq. NaHCO3 (80 mL) was finally added, 6.2, J2-4 = 0.7 Hz, 1 H, 2-H), 5.51 (ddq, J3-2 = 15.3, J3-4 = 6.9, J3-
and the resulting biphasic mixture was carefully stirred for 10 min.
The aqueous layer was extracted with CH2Cl2 (2ϫ 60 mL), and
the combined organic layers were washed with brine, dried with
Na2SO4, filtered and concentrated under reduced pressure. The
= 1.5 Hz, 1 H, 3-H), 4.66 (m, 2 H, 4Ј-H, 4-H), 4.16 (m, AB part
1
of a degenerate ABX system, 2 H, 5Ј-H), 3.01 (AB part of an ABX
system, J6Јa-6Јb = 13.4, J6Јa-4Ј = 9.6, J6Јb-4Ј = 3.2, ∆ν = 172 Hz, 2 H,
6Ј-H), 3.16 (AB part of an ABX system, J5a-5b = 15.9, J5a-4 = 7.7,
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Partial Synthesis of Bistramide K
J5b-4 = 5.1, ∆ν = 72 Hz, 2 H, 5-H), 1.67 (dd, J1-2 = 6.2, J1-3
=
(20 mL) was added dropwise at –75 °C to the mixture. After 3 h at
–35 °C to 0 °C, the mixture was brought to –5 °C and the reaction
1.4 Hz, 3 H, 1-H), 0.87 (s, 9 H, tBuSi), 0.06 (s, 3 H, MeSi), 0.05 (s,
3 H, MeSi) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.5 (CO), quenched successively with a phosphate buffer solution (pH = 7,
153.3 (CO), 135.3 (Cq arom.), 133.5 (C-3), 129.4 (CH arom.), 128.9
26 mL) and H2O2/MeOH (10:40 mL). Stirring was continued for
(CH arom.), 127.3 (C-2), 126.2 (CH arom.), 69.9 (C-4), 66.0 (C-5), 20 min, then the reaction mixture was diluted with CH2Cl2 (40 mL)
55.1 (C-4Ј), 44.4 (C-5Ј), 37.8 (C-6Ј), 25.8 [C(CH3)3Si], 18.1 [C(Me)3- and satd. NaHCO3 (40 mL). The aqueous layer was extracted with
Si], 17.5 (Me), –4.3 (MeSi), –4.9 (MeSi) ppm.
CH2Cl2 (3 ϫ 40 mL), and the combined organic extracts were
washed with brine, dried (MgSO4), filtered, and concentrated under
reduced pressure. The crude product was purified by chromatog-
raphy on silica gel to give pure (–)-5 (7.12 g, 79%) as a colorless
viscous oil. [α]D = –48.2 (c = 0.95, CHCl3) [ref.[16] [α]D = –52.7 (c
= 0.9, CHCl3)]. C23H27NO5 (397.47): calcd. C 69.50, H 6.85, N
3.52; found C 70.33, H 7.33, N 3.29. 1H NMR (300 MHz, CDCl3):
δ = 7.37–7.19 (m, 10 H, 2 Ph), 4.68 (m, X part of an ABX system,
1 H, 4Ј-H), 4.51 (s, 2 H, OCH2Bn), 4.17 (m, 3 H, 5Ј-H, 11-H), 3.82
(dq, J9-10 = 7.0, J9-11 = 3.8 Hz, 1 H, 9-H), 3.68 (m, 2 H, 13-H),
3.30 (d, J = 2.4 Hz, 1 H, OH), 3.01 (AB part of an ABX system,
J6Јa-6Јb = 13.5, J6Јa-4Ј = 9.5, J6Јb-4Ј = 3.5, ∆ν = 151 Hz, 2 H, 6Ј-H),
1.82 (m, 2 H, 12-H), 1.28 (d, J10-9 = 7.0 Hz, 3 H, 10-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 176.7 (CO), 153.1 (CO), 138.1 (Cq
arom.), 135.2 (Cq arom.), 129.5 (CH arom.), 129.0 (CH arom.),
128.4 (CH arom.), 127.7 (2 CH arom.), 127.4 (CH arom.), 73.3
(CH2O), 70.4 (CHO), 68.4 (CH2O), 66.2 (CH2O), 55.3 (CH), 42.6
(CH), 37.7 (CH2), 33.7 (CH2), 11.1 (Me) ppm.
(+)-(3R,4E)-3-(tert-Butyldimethylsilyloxy)hex-4-en-1-ol (3): Meth-
anol (1 mL, 4 equiv.) followed by a solution of lithium borohydride
(2  in THF, 14.8 mL, 4.98 equiv.) were slowly added at –78 °C to
a solution of 2 (2.4 g, 5.95 mmol, 1 equiv.) in anhydrous THF
(33 mL). After stirring at 0 °C for 4 h the reaction mixture was
cautiously poured into a mixture of Et2O/water (120:50 mL), and
stirring was continued for 10 min. The aqueous layer was extracted
with diethyl ether (3ϫ 25 mL), and the combined organic layers
were washed with brine, dried (Na2SO4) and concentrated under
reduced pressure. The resulting residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:2) to give (+)-3
(1.121 g, 81.8%) as a colorless liquid. [α]D = +23.8 (c = 1.02,
CHCl3) {ref.[15] [α]D = –19.3 (c = 1.63, CHCl3)}. 1H NMR
(300 MHz, CDCl3): δ = 5.60 (ddq, J2-3 = 15.3, J2-1 = 7.0, J2-4
0.8 Hz, 1 H, 2-H), 5.46 (ddq, J3-2 = 15.3, J3-4 = 6.6, J3-1 = 1.4 Hz,
1 H, 3-H), 4.35 (m, 1 H, 4-H), 3.80 (m, 1 H, 6a-H), 3.72 (m, 1 H,
6b-H), 2.58 (br. s, 1 H, OH), 1.74 (m, 2 H, 5-H), 1.68 (dd, J1-2
=
=
(–)-Methyl (2R,3S)-5-(Benzyloxy)-3-hydroxy-2-methylpentanoate
(6a): To a solution of (–)-5 (1.203 g, 0.00303 mol) in MeOH
(25 mL) at 0 °C, was added Mg(OMe)2 (4 equiv., 291 mg of Mg in
25 mL of MeOH). After 30 min, the reaction was quenched with
satd. aq. NH4Cl (25 mL), and HCl (20%) was added until pH = 6.
The mixture was diluted with water (40 mL), and the aqueous layer
was extracted with EtOAc (3ϫ 20 mL), dried (MgSO4), filtered,
and concentrated under reduced pressure. The crude product was
purified by chromatography on silica gel to give (–)-6a (0.545 g,
71.3%) as a yellow liquid. [α]D = –8.7 (c = 1.08, CHCl3). C14H20O4
(252.313): calcd. C 66.65, H 7.99; found C 66.47, H 8.06. 1H NMR
(200 MHz, CDCl3): δ = 7.4–7.3 (m, 5 H, Ph), 4.52 (s, 2 H,
OCH2Bn), 4.2–4.0 (m, 1 H, 11-H), 3.8–3.6 (m, 2 H, 13-H), 3.70 (s,
6.2, J1-3 = 1.3 Hz, 3 H, 1-H), 0.89 (s, 9 H, tBuSi), 0.07 (s, 3 H,
MeSi), 0.04 (s, 3 H, MeSi) ppm. 13C NMR (75 MHz, CDCl3): δ =
133.7 (C-3), 125.7 (C-2), 73.5 (C-4), 60.5 (C-6), 39.3 (C-5), 25.8
[C(CH3)3Si], 18.1 [C(Me)3Si], 17.6 (Me), –4.2 (MeSi), –4.9 (MeSi)
ppm.
(+)-(3R,4E)-3-(tert-Butyldimethylsilyloxy)hex-4-enal (4): To the
alcohol (+)-3 (450 mg, 1.96 mmol, 1 equiv.), dissolved in anhydrous
CH2Cl2 (10 mL), were successively added at 0 °C, DMSO (3.2 mL),
NEt3 (1.9 mL; 7 equiv.), and pyridine–sulfur trioxide (Py·SO3;
0.854 g, 4.4 equiv.). The reaction mixture was warmed to room
temp. until all starting material had disappeared (TLC). After
about 2 h, the reaction mixture was diluted with diethyl ether
(30 mL) and added to water (50 mL). The organic layer was then
washed with water (11ϫ 15 mL), brine (10 mL), dried (MgSO4),
and filtered. The volatile solvents were completely removed, and
the residue was purified by silica gel chromatography to afford (+)-
4 (0.405 g, 91%) as a colorless liquid. [α]D = +15.3 (c = 1.02,
CHCl3) {ref.[15] [α]D = +14.0 (c = 2.0, CHCl3)}. C12H24O2Si
(228.409): calcd. C 63.10, H 10.59; found C 62.60, H 10.48. 1H
NMR (300 MHz, CDCl3): δ = 9.76 (dd, J6-5a = 2.8, J6-5b = 2.3 Hz,
1 H, 6-H), 5.65 (ddq, J2-3 = 15.3, J2-1 = 6.3, J2-4 = 0.9 Hz, 1 H, 2-
H), 5.47 (ddq, J3-2 = 15.3, J3-4 = 5.5, J3-1 = 1.5 Hz, 1 H, 3-H), 4.59
(m, 1 H, 4-H), 2.58 (ddd, J5a-5b = 15.5, J5a-4 = 7.0, J5a-6 = 2.9 Hz,
1 H, 5a-H), 2.47 (ddd, J5b-5a = 15.6, J5b-4 = 5.0, J5b-6 = 2.3 Hz, 1
H, 5b-H), 1.68 (ddd, J1-2 = 6.3, J1-3 = 1.4, J1-4 = 0.7 Hz, 3 H, 1-
H), 0.86 (s, 9 H, tBuSi), 0.05 (s, 3 H, MeSi), 0.03 (s, 3 H, MeSi)
ppm. 13C NMR (75 MHz, CDCl3): δ = 202.1 (CO), 133.1 (C-3),
126.3 (C-2), 69.4 (C-4), 51.6 (C-5), 25.7 [C(CH3)3Si], 18.1 [C(Me)3-
Si], 17.5 (Me), –4.2 (MeSi), –4.9 (MeSi) ppm.
3 H, MeO), 3.23 (d, JOH-11 = 3.4 Hz, 1 H, OH), 2.56 (qd, J9-10
=
7.2, J9-11 = 4.9 Hz, 1 H, 9-H), 1.8–1.7 (m, 2 H, 12-H), 1.21 (d, J10-
= 7.1 Hz, 3 H, 10-H) ppm. 13C NMR (50 MHz, CDCl3): δ =
9
176.6 (CO), 138.5 (Cq arom.), 129.1 (CH arom.), 128.3 (CH arom.),
74.0 (CH2Ph), 71.8 (CHOH), 69.3 (CH2), 52.4 (MeO), 45.5 (C-9),
34.4 (C-12), 12.2 (C-10) ppm.
(–)-Methyl (2R,3S)-5-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)-2-
methylpentanoate (6b): Compound (–)-6a (279 mg, 1.1 mmol,
1 equiv.) was diluted with anhydrous CH2Cl2 (22 mL). Disopropyl-
ethylamine (DIPEA, 0.77 mL, 4.42 mmol, 4 equiv.) followed by
tert-butyldimethylsilyl triflate (0.76 mL, 3.32 mmol, 3 equiv.) were
successively added, and the solution was stirred at room temp. for
2 h. The reaction was quenched with water (15 mL) and diluted
with diethyl ether (20 mL). The aqueous layer was extracted with
diethyl ether (3ϫ 20 mL), and the combined organic extracts were
washed with brine (20 mL), dried with MgSO4, filtered, and con-
centrated under reduced pressure. The residue was purified by
chromatography on silica gel to obtain the silylated final compound
(–)-6b (345 mg, 86%) as a colorless liquid. [α]D = –19.7 (c = 0.97,
CHCl3). C20H34O4Si (366.577): calcd. C 65.53, H 9.35; found C
(–)-(R)-4-Benzyl-3-[(2R,3S)-5-(benzyloxy)-3-hydroxy-2-methylpen-
tanoyl]-1,3-oxazolidin-2-one (5): (R)-2-Benzyl-3-propionyl-1,3-ox-
azolidin-2-one (5.3 g, 0.0227 mol, 1 equiv.) was dissolved in anhy-
drous CH2Cl2 (70 mL) at –50 °C, and a solution of Bu2BOTf (1 
in CH2Cl2, 28.4 mL, 1.25 equiv.) was slowly added (30 min). To
the light-purple solution was added NEt3 (3.94 mL, 0.0284 mol,
1.25 equiv.) at –35 °C, during which time a yellow color appeared.
The reaction mixture was then stirred at 0 °C for 20 min; then 3-
benzyloxy-1-propanal (4.67 g, 0.028 mol, 1.25 equiv.) in CH2Cl2
1
65.56, H 8.95. H NMR (200 MHz, CDCl3): δ = 7.4–7.3 (m, 5 H,
Ph), 4.52 and 4.45 (AB system, JAB = 12.1, ∆ν = 7.6 Hz, 1 H,
OCH2Ph), 4.19 (m, 1 H, 11-H), 3.65 (s, 3 H, MeO), 3.51 (t, J13-12
= 6.4 Hz, 2 H, 13-H), 2.57 (qd, J9-10 = 7, J9-11 = 4.5 Hz, 1 H, 9-
H), 1.82 (dt, J12-11 = J12-13 = 6.4 Hz, 2 H, 12-H), 1.12 (d, J = 7 Hz,
3 H, 10-H), 0.85 [s, 9 H, SiC(CH3)3], 0.04 [s, 3 H, Si(CH3)2], 0.01
Eur. J. Org. Chem. 2010, 6207–6216
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6211

C. Bauder
FULL PAPER
[s, 3 H, Si(CH3)2] ppm. 13C NMR (50 MHz, CDCl3): δ = 176.0
(CO), 139.1 (Cq arom.), 129.0 (CH arom.), 128.3 (CH arom.), 128.2
(CH arom.), 73.6 (CH2), 71.3 (CHOH), 67.4 (CH2), 52.1 (MeO),
portion of THF (0.5 mL) was used to rinse all the phosphonate.
The mixture was stirred for 1 h, during which time the mixture
turned yellow. A solution of the silylated aldehyde (+)-4 (41 mg,
45.6 (CH), 35.5 (CH2), 26.4 [SiC(CH3)3], 18.7 [SiC(CH3)3], 11.9 0.179 mmol, 1 equiv.) in anhydrous THF (0.5 mL) was then added
(CH3), –3.4 (SiCH3), –4.1 (SiCH3) ppm.
dropwise at –60 °C, and stirring was continued for 75 min. The
reaction was quenched with satd. aq. NH4Cl (5 mL) and diluted
with water (5 mL) and EtOAc (5 mL). The aqueous layer was ex-
tracted with EtOAc (3ϫ 10 mL), and the combined organic ex-
tracts were dried with Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by chromatography on
silica gel (EtOAc/hexane, 1:6) to yield the desired product 8 (50 mg,
37.5%) as a yellow liquid. H NMR (200 MHz, CDCl3): δ = 7.32
(m, 5 H, Ph), 6.77 (td, J6-7 = 15.7, J6-5 = 7.4 Hz, 1 H, 6-H), 6.19
(td, J7-6 = 15.7, J7-5 = 1.3 Hz, 1 H, 6-H), 5.56 (ddq, J2-3 = 15.3, J2-
(–)-Dimethyl (3R,4S)-6-(Benzyloxy)-4-(tert-butyldimethylsilyloxy)-
3-methyl-2-oxohexylphosphonate (7): To a solution of dimethyl
methylphosphonate (0.35 mL, 0.0033 mol, 3.4 equiv.) in THF
(3 mL) at –78 °C was added nBuLi (1.5  in hexane, 2 mL, 0.0030
mol, 3.1 equiv.). After 1 h, a solution of (–)-6a (0.243 g, 0.000963
mol) in THF (3 mL) was slowly added at –75 °C. The reaction mix-
ture was stirred for 2.5 h and then hydrolyzed with satd. aq. NH4Cl
(2 mL) and water (5 mL). The aqueous layer was acidified to pH
= 2 with 20% HCl and extracted with CH2Cl2 (3ϫ 5 mL). The
combined organic extracts were washed with brine (5 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure. The
crude product was purified by chromatography on silica gel to af-
ford the precursor of compound 7 (0.144 g, 43.2%). Yellow viscous
oil. [α]D = –33.1 (c = 0.49, CHCl3). C16H25O6P (344.347): calcd. C
55.81, H 7.32; found C 55.97, H 7.48. 1H NMR (200 MHz,
CDCl3): δ = 7.4–7.3 (m, 5 H, Ph), 4.52 (s, 2 H, OCH2Bn), 4.2–4.1
(m, 1 H, 11-H), 3.78 (d, JH-P = 11.3 Hz, 3 H, MeO), 3.77 (d, JH-P
= 11.3 Hz, 3 H, MeO), 3.8–3.6 (m, 2 H, 13-H), 3.59 (d, J = 2.7 Hz,
1 H, OH), 3.35, 3.25, 3.23 and 3.15 (AB system coupled with P,
JAB = 14, JH-P = 23, ∆ν = 12 Hz, 1 H, 7-H), 2.88 (qd, J9-10 = 7,
1
= 6.3, J2-4 = 0.9 Hz, 1 H, 2-H), 5.40 (ddq, J3-2 = 15.3, J3-4 = 6.6,
1
J3-1 = 1.5 Hz, 1 H, 3-H), 4.48 and 4.44 (AB system, J3-1 = 1.5, ∆ν
= 7.4 Hz, 2 H, CH2Ph), 4.12 (m, 2 H, 4-H, 11-H), 3.52 (m, 2 H,
13-H), 2.88 (dq, J9-10 = 6.9, J = 12.0 Hz, 1 H, 9-H), 2.32 (m, 2 H,
5-H), 1.76 (m, 2 H, 12-H), 1.66 (ddd, J1-2 = 6.4, J1-3 = 1.4, J1-4
=
0.7 Hz, 3 H, 1-H), 1.07 (d, J10-9 = 6.9 Hz, 3 H, 10-H), 0.87 (s, 18
H, 2 tBuSi), 0.034 (s, 3 H, MeSi), 0.027 (s, 9 H, 2 MeSi), 0.010 (s,
3 H, MeSi) ppm. 13C NMR (50 MHz, CDCl3): δ = 198.1 (CO),
143.3, 138.4, 133.7, 131.4, 128.3, 127.6, 127.5, 125.9, 72.8, 72.5,
71.0, 66.6, 49.5, 41.6, 35.0, 31.9, 29.7, 29.3, 25.9, 25.8, 22.7, 18.1,
18.0, 17.5, 14.1, 12.7, –4.3, –4.4, –4.5, –4.8 ppm.
J9-11 = 4 Hz, 1 H, 9-H), 1.8–1.6 (m, 2 H, 12-H), 1.12 (d, J = 7 Hz, (–)-(R)-4-Benzyl-3-[(2R,3S)-5-(benzyloxy)-3-(tert-butyldimethylsil-
3 H, 10-H) ppm. 13C NMR (50 MHz, CDCl3): δ = 205.9 (d, JC-P
= 6 Hz, CO), 138.5 (Cq arom.), 129.1 (CH arom.), 128.4 (CH
arom.), 128.3 (CH arom.), 74.0 (CH2), 71.4 (CHOH), 69.5 (CH2),
53.8 (d, JC-P = 6 Hz, MeO), 53.6 (d, JC-P = 6 Hz, MeO), 53.2 (d,
yloxy)-2-methylpentanoyl]-1,3-oxazolidin-2-one (9): The oxazolid-
inone (–)-5 (967 mg, 2.4 mmol, 1 equiv.) and imidazole (498 mg,
3 equiv.) were dissolved in anhydrous DMF (10 mL). tert-Butyldi-
methylsilyl chloride (1.47 g, 4 equiv.) was added at 0 °C, and the
JC-P = 2 Hz, CHMe), 41.1 (d, JC-P = 128 Hz, PCH2), 34.0 (CH2), reaction mixture was stirred at room temp. overnight. Water
10.9 (CH3) ppm. To a chilled (0 °C) solution of the above phos-
phonate alcohol (0.183 g, 0.531 mmol) in CH2Cl2 (15 mL) were
added DIPEA (0.25 mL, 2.7 equiv.) and TBSOTf (0.30 mL,
2.4 equiv.). The mixture was stirred at room temp. for 4 h, and then
the reaction was slowly quenched at 0 °C with cold water (8 mL).
The mixture was well stirred at ambient temperature for 0.5 h. The
organic extract was washed with water (3ϫ 10 mL), brine (3 mL),
dried (MgSO4), filtered, and concentrated under reduced pressure
to leave an orange oil. Purification of this crude product was car-
ried out by filtration through a pad of silica gel, eluting with Ac-
OEt/cyclohexane (1:1) to give the desired compound 7 (154 mg,
63.2%) as a colorless oil. [α]D = –80.6 (c = 0.97, CHCl3).
C22H39O6PSi (458.611): calcd. C 57.62, H 8.57; found C 57.24, H
8.49. 31P NMR (121.49 MHz, CDCl3): δ = 24.4 ppm. 1H NMR
(300 MHz, CDCl3): δ = 7.32 (m, 5 H, Ph), 4.50 and 4.43 (AB sys-
tem, JAB = 11.8, ∆ν = 6.9 Hz, 2 H, OCH2Bn), 4.04 (m, 1 H, 11-
H), 3.75 (d, JH-P = 11.3 Hz, 3 H, MeO), 3.74 (d, JH-P = 11.3 Hz, 3
(20 mL) and diethyl ether (20 mL) were added, and vigorous stir-
ring was continued for 30 min. The organic layer was washed with
water (30 mL), brine (20 mL), dried (Na2SO4), filtered, and concen-
trated under reduced pressure to yield the silylated compound (–)-
9 (1.143 g, 92%) as a white solid, which needed no further purifica-
tion. A sample was purified by column chromatography on silica
gel for analysis. M.p. 92 °C. [α]D = –69.1 (c = 1.12, CHCl3).
C29H41NO5Si (511.74): calcd. C 68.07, H 8.08, N 2.74; found C
68.21, H 8.13, N 2.57. 1H NMR (300 MHz, CDCl3): δ = 7.35–7.17
(m, 10 H, 2 Ph), 4.50 (m, X part of an ABX system, 1 H, 4Ј-H),
4.47 (A part of an AB system, JAB = 11.7, ∆ν = 11 Hz, 1 H,
OCH2Ph), 4.42 (B part of an AB system, JBA = 11.7, ∆ν = 11 Hz,
1 H, OCH2Ph), 4.17 (dt, J11-9 = 6.7, J11-12 = 5.0 Hz, 1 H, 11-H),
3.90 (AB part of an ABX system, J5Јa-5Јb = 9.1, J5Јa-4Ј = 8.1, J5Јb-4Ј
= 2.1, ∆ν = 80 Hz, 2 H, 5Ј-H), 3.88 (dq, J9-10 = J9-11 = 6.8 Hz, 1
H, 9-H), 3.57 (m, 2 H, 13-H), 2.97 (AB part of an ABX system,
J6Јa-6Јb = 13.3, J6Јa-4Ј = 9.6, J6Јb-4Ј = 3.3, ∆ν = 155 Hz, 2 H, 6Ј-H),
H, MeO), 3.56–3.38 (m, 3 H, 7a-H and 13-H), 3.09–2.97 (m, 2 H, 1.91 (m, 2 H, 12-H), 1.24 (d, J10-9 = 6.9 Hz, 3 H, 10-Me), 0.87 (s,
7b-H and 9-H), 1.85–1.72 (m, 1 H, 12a-H), 1.61–1.49 (m, 1 H, 12b- 9 H, tBuSi), 0.04 (s, 3 H, MeSi), 0.03 (s, 3 H, MeSi) ppm. 13C
H), 1.05 (d, J10-9 = 6.9 Hz, 3 H, 10-H), 0.88 [s, 9 H, SiC(CH3)3],
NMR (75 MHz, CDCl3): δ = 175.4 (CO), 152.9 (CO), 138.6 (Cq
arom.), 135.4 (Cq arom.), 129.4 (CH arom.), 128.9 (CH arom.),
0.08 [s, 3 H, Si(CH3)2], 0.05 [s, 3 H, Si(CH3)2] ppm. 13C NMR
(75 MHz, CDCl3): δ = 205.3 (d, JC-P = 6.8 Hz, CO), 138.9 (Cq 128.3 (CH arom.), 127.6 (CH arom.), 127.4 (CH arom.), 127.3 (CH
arom.), 129.0 (CH arom.), 128.3 (CH arom.), 128.2 (CH arom.), arom.), 72.8 (CH2), 70.9 (CH), 66.3 (CH2), 65.7 (CH2), 55.4 (CH),
73.6 (OCH2Ph), 71.7 (C-11), 67.0 (C-13), 53.6 (d, JC-P = 6.8 Hz,
MeO), 53.5 (d, JC-P = 6.8 Hz, MeO), 53.2 (s, C-9), 42.1 (d, JC-P
43.1 (CH), 37.7 (CH2), 35.1 (CH2), 25.8 [(CH3)3CSi], 18.0 [(CH3)3-
CSi], 13.7 (CH3), –4.7 (MeSi), –4.4 (MeSi) ppm.
=
128.8 Hz, CH2), 34.7 (C-12), 26.5 [SiC(CH3)3], 18.7 [SiC(CH3)3],
12.8 (CH3), –3.8 (SiCH3), –4.1 (SiCH3) ppm.
(–)-(2S,3S)-5-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)-2-methyl-
pentan-1-ol (10): To a solution of the oxazolidinone 9 (0.66 g,
1.25mmol, 1 equiv.) in anhydrous THF (7 mL) at 0 °C, were added
MeOH (0.15 mL) and LiBH4 (2  in THF, 2.4 mL, 3.2 equiv.). The
reaction mixture was stirred at 0 °C, and the temperature was grad-
ually raised to ambient during 6 h. When TLC monitoring (EtOAc/
cyclohexane, 2:3) showed that no more starting material had re-
(5S,6R,11R,E)-5-[2-(Benzyloxy)ethyl]-2,2,3,3,6,13,13,14,14-nona-
methyl-11-[(E)-prop-1-enyl]-4,12-dioxa-3,13-disilapentadec-8-en-7-
one (8): The silylated phosphonate 7 (114 mg, 0.249 mmol,
1.39 equiv.) was added at room temp. to a suspension of NaH
(6 mg, 0.261 mmol, 1.4 equiv.) in anhydrous THF (1 mL). A further
6212
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6207–6216

Partial Synthesis of Bistramide K
mained, the solution was slowly poured into a mixture of diethyl
ether (50 mL) and water (50 mL). A solution of 20% HCl (15 mL)
was added to bring the aqueous layer to pH = 1. The organic layer
was separated after stirring for 10 min, and the aqueous layer was
extracted with Et2O (3 ϫ 20 mL). The combined extracts were
EtOAc (10 mL); the reaction was quenched by addition of satd. aq.
NH4Cl (4 mL) followed by water (1 mL). The aqueous layer was
acidified with HCl (10%, 1.5 mL) to pH = 2 and extracted with
EtOAc (10 mL). The combined organic extracts were washed with
water (2ϫ 10 mL), brine (5 mL), dried (Na2SO4), filtered, and con-
washed with satd. aq. NaCl (10 mL), dried (Na2SO4), filtered, and centrated under reduced pressure. The crude residue was purified
concentrated under reduced pressure at ambient temperature to
leave a white liquid. Purification of this crude residue by flash
chromatography (EtOAc/cyclohexane, 2:3 then 4:1 to isolate the
chiral auxiliary) afforded 10 (362 mg, 82%) as a colorless liquid.
[α]D = –11.6 (c = 0.99, CHCl3) {ref.[26] [α]D = –8.5 (c = 0.3,
by silica gel column chromatography (EtOAc) to afford pure 12
(156 mg, 63%) as a light-yellow liquid. [α]D = –20.2 (c = 1.0,
CHCl3). C22H41O5PSi (444.617): calcd. C 59.43, H 9.29; found C
1
58.73, H 9.28. 31P NMR (121.49 MHz, CDCl3): δ = 36.5 ppm. H
NMR (300 MHz, CDCl3): δ = 7.36–7.24 (m, 5 H, Ph), 4.50 (A part
of an AB system, JAB = 12, ∆ν = 12 Hz, 1 H, OCH2Ph), 4.44 (B
CHCl3)}. C19H34O3Si (338.56): calcd. C 67.41, H 10.12; found C
1
67.53, H 10.18. H NMR (300 MHz, CDCl3): δ = 7.38–7.26 (m, 5 part of an AB system, JBA = 12, ∆ν = 12 Hz, 1 H, OCH2Ph), 3.74
H, Ph), 4.52 (A part of an AB system, JAB = 12, ∆ν = 14 Hz, 1 H,
OCH2Ph), 4.46 (B part of an AB system, JBA = 12, ∆ν = 14 Hz, 1
H, OCH2Ph), 3.96 (ddd, J = 7.8, J = 4.8, J = 3.3 Hz, 1 H, 11-
H), 3.69 (A part of an ABX system, JAB = 10.7, JAX = 8.7 Hz, 1
(m, 1 H, 11-H), 3.72 (d, JHP = 10.7 Hz, 6 H, MeO), 3.49 (t, J13-12
= 6.6 Hz, 2 H, 13-H), 1.9–1.2 (m, 7 H, 7-H, 8-H, 9-H and 12-H),
0.87 (s, 9 H, tBuSi), 0.76 (d, J = 6.8 Hz, 3 H, 10-H), 0.03 (s, 3 H,
MeSi), 0.02 (s, 3 H, MeSi) ppm. 13C NMR (75 MHz, CDCl3): δ =
3
3
3
H, 8a-H), 3.53 (m, 3 H, 8b-H, 13-H), 2.52 (br. s, 1 H, OH), 1.98 138.5 (Cq arom.), 128.3 (CH arom.), 127.6 (CH arom.), 127.5 (CH
(m, 1 H, 9-H), 1.81 (m, 1 H, 12-H), 0.89 (s, 9 H, tBuSi), 0.81 (d, arom.), 72.9 (OCH2Ph), 72.4 (C-11), 67.3 (C-13), 52.3 (d, JCP
=
J10-2 = 7.1 Hz, 3 H, 10-H), 0.10 (s, 3 H, MeSi), 0.06 (s, 3 H, MeSi)
6.8 Hz, MeO), 39.5 (d, JCP = 16.7 Hz, C-9), 32.9 (C-12), 25.9
ppm. 13C NMR (75 MHz, CDCl3): δ = 138.4 (Cq arom.), 128.4 [C(CH3)3Si], 24.4 (d, JCP = 5.0 Hz, C-8), 23.2 (d, JCP = 140.8 Hz,
(CH arom.), 127.7 (CH arom.), 127.6 (CH arom.), 72.9 (OCH2Ph), C-7), 18.1 [C(Me)3Si], 14.4 (C-10), –4.4 (MeSi), –4.5 (MeSi) ppm.
72.8 (CHOTBS), 67.1 (CH2OBn), 65.8 (C-8, CH2O), 39.9 (C-9,
(–)-[(3S,4S)-1-(Benzyloxy)-4-methyl-6-(phenylsulfonyl)hex-3-yloxy]-
CH), 32.3 (C-12, CH2), 25.8 [C(CH3)3Si], 18.0 [C(Me)3Si], 12.4 (C-
(tert-butyl)dimethylsilane (13): A solution of nBuLi (1.45  in hex-
10), –4.4 (MeSi), –4.7 (MeSi) ppm.
ane, 4.35 equiv.) was added at 0 °C to a solution of the appropriate
(+)-[(2R,3S)-5-(Benzyloxy)-1-iodo-2-methylpent-3-yloxy](tert-but-
yl)dimethylsilane (11): Alcohol 10 (457 mg, 1.35 mmol, 1 equiv.)
was dissolved under argon in a mixture of anhydrous diethyl ether
(12 mL) and anhydrous acetonitrile (3 mL). Imidazole (219 mg,
2.3 equiv.), triphenylphosphane (386 mg, 1.1 equiv.) and iodine
sulfone (842 mg, 4.3 equiv.), dissolved in anhydrous THF (14 mL).
Stirring was continued at room temp. for 40 min, then a solution
of 11 (560 mg, 1.25 mmol, 1 equiv.) in anhydrous THF (6 mL) was
added dropwise at 0 °C. The mixture was stirred at ambient tem-
perature for 2.5 h and then poured into water (10 mL) and satd.
(394 mg, 1.1 equiv.) were then successively added. The solution, aq. NH4Cl (10 mL). The organic layer was diluted with Et2O
which turned rapidly red-brown, was stirred at ambient tempera-
ture for 3 h. The reaction was then quenched by adding satd. aq.
sodium bisulfite (6 mL). Stirring was continued for 15 min, and the
mixture was diluted with water (20 mL) and diethyl ether (15 mL).
The aqueous layer was extracted with Et2O (3ϫ 20 mL), and the
combined organic extracts were washed with water (20 mL), brine
(10 mL), dried (MgSO4) and filtered. The solvents were evaporated
under reduced pressure, and the crude product was purified by
chromatography on silica gel (EtOAc/cyclohexane, 3:7) to yield the
pure product 11 (526 mg; 86.9%) as a colorless liquid. [α]D = +1.57
(c = 1.02, CHCl3). C19H33IO2Si (448.46): calcd. C 50.89, H 7.42;
(50 mL), and the aqueous layer was acidified with HCl (20 %,
13.5 mL) until pH = 6. The aqueous layer was extracted with Et2O
(15 mL), and the combined organic extracts were washed with
water (40 mL), brine (15 mL), dried (MgSO4), filtered, and concen-
trated under reduced pressure. The crude residue was purified by
silica gel column chromatography (EtOAc/cyclohexane, 2:8) to af-
ford pure 13 (399 mg, 67%) as a light-yellow oil. [α]D = –23.4 (c =
1.32, CHCl3). C26H40O4SSi (476.745): calcd. C 65.50, H 8.46;
1
found C 65.43, H 8.61. H NMR (300 MHz, CDCl3): δ = 7.9–7.5
(m, 5 H, PhSO2), 7.35–7.25 (m, 5 H, PhCH2), 4.52 (A part of an
AB system, JAB = 12, ∆ν = 14 Hz, 1 H, OCH2Ph), 4.46 (B part of
an AB system, JBA = 12, ∆ν = 14 Hz, 1 H, OCH2Ph), 3.7–3.6 (m,
1
found C 50.94, H 7.55. H NMR (300 MHz, CDCl3): δ = 7.4–7.3
(m, 5 H, Ph), 4.51 (A part of an AB system, JAB = 11.7, ∆ν = 1 H, 11-H), 3.45 (dd, J7-8a = J7-8b = 5.8 Hz, 2 H, 7-H), 3.18–3.02
11 Hz, 1 H, OCH2Ph), 4.46 (B part of an AB system, JBA = 11.7,
∆ν = 11 Hz, 1 H, OCH2Ph), 3.89 (ddd, J = 7.0, 5.7, 3.3 Hz, 1 H,
11-H), 3.49 (t, J = 6.7 Hz, 2 H, 13-H), 3.18 (AB part of an ABX
(m, 2 H, 13-H), 1.9–1.8 (m, 1 H, 12a-H), 1.7–1.6 (m, 1 H, 8a-H),
1.6–1.4 (m, 3 H, 8b-H, 9-H, 12b-H), 0.81 (d, J10-9 = 6.6 Hz, 3 H,
10-H), 0.77 (s, 9 H, tBuSi), 0.02 (s, 3 H, MeSi), 0.07 (s, 3 H, MeSi)
system, JAB = 9.6, JAX = 5.6, JBX = 8.1, ∆ν = 110 Hz, 2 H, 8-H), ppm. 13C NMR (75 MHz, CDCl3): δ = 139.1 (Cq arom., PhSO2),
1.9–1.8 (m, X part of an ABX system, 1 H, 9-H), 1.8–1.7 (m, 2 H,
138.4 (Cq arom., OBn), 133.6 (CH arom.), 129.3 (CH arom.), 128.4
12-H), 0.99 (d, J10-9 = 6.6 Hz, 3 H, 10-H), 0.88 (s, 9 H, tBuSi), 0.08 (CH arom., OBn), 128.1 (CH arom.), 127.7 (CH arom., OBn),
(s, 3 H, MeSi), 0.05 (s, 3 H, MeSi) ppm. 13C NMR (75 MHz,
CDCl3): δ = 138.4 (Cq arom.), 128.4 (CH arom.), 127.6 (CH
127.6 (CH arom., OBn), 73.0 (OCH2Ph), 72.4 (C-11), 67.1 (CH2),
55.3 (CH2), 37.7 (C-9), 32.8 (CH2), 25.8 [C(CH3)3Si], 25.3 (CH2),
arom.), 127.5 (CH arom.), 73.0 (OCH2Ph), 71.7 (CH), 66.9 (CH2), 18.0 [C(Me)3Si], 14.6 (C-10), –4.4 (MeSi), –4.5 (MeSi) ppm.
41.8 (CH), 33.6 (CH2), 25.9 [C(CH3)3Si], 18.1 [C(Me)3Si], 15.1
(Me), 12.1 (CH2), –4.4 (2 MeSi) ppm.
(–)-2-[(3S,4S)-6-(Benzyloxy)-4-(tert-butyldimethylsilyloxy)-3-meth-
ylhexylthio]benzo[d]thiazole (14): A solution of 15 (326 mg,
(–)-Dimethyl (3S,4S)-6-(Benzyloxy)-4-(tert-butyldimethylsilyloxy)-
1.79 mmol, 4 equiv.) in THF (3 mL) was added dropwise at –70 °C
3-methylhexylphosphonate (12): A solution of nBuLi (1.45  in hex- to a solution of LDA (4.4 equiv.) in THF (4 mL). The temperature
ane, 4.29 equiv.) was added at –73 °C to a solution of dimethyl
methylphosphonate (0.3 mL, 4.95 equiv.), dissolved in anhydrous
THF (3 mL). Stirring was continued at the same temperature for
1 h before the addition of a solution of 11 (251 mg, 0.56 mmol) in
anhydrous THF (2 mL), and HMPA (2.5 equiv.). The mixture was
stirred from –70 °C to –15 °C for 1.5 h and then diluted with
was kept below –70 °C during the addition. The resulting yellow-
orange solution was stirred at –70 °C for 1 h, then a mixture of
the iodide 11 (203 mg, 0.452 mmol) and HMPA (0.25 mL) in THF
(4 mL) was added dropwise to the lithiated 2-methylthiobenzothia-
zole. After stirring at –70 °C for 1.5 h, the mixture was diluted with
EtOAc (20 mL) and the reaction quenched with satd. aq. NH4Cl
Eur. J. Org. Chem. 2010, 6207–6216
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6213

C. Bauder
FULL PAPER
(5 mL), water (5 mL), and HCl (10%, 4 mL, to pH = 1). The or-
ganic extract was washed with water (3ϫ 15 mL), brine (8 mL),
dried (Na2SO4), filtered, and concentrated under reduced pressure
to give an orange oil. Purification of this crude material by column
chromatography on silica gel afforded the desired product 14
(160 mg; 70.5%) as a yellow oil and a second less polar product
identified as the unexpected thiol 14a (pale-yellow oil). [α]D = –25.4
(c = 2.5, CHCl3). C27H39NO2S2Si (501.819): calcd. C 64.62, H 7.83,
N 2.79; found C 64.90, H 8.19, N 2.46. 1H NMR (300 MHz,
CDCl3): δ = 7.87 (d, J = 7.7 Hz, 2 H, Bzt), 7.75 (d, J = 8.1 Hz, 2
H, Bzt), 7.41 (td, J = 15.3, J = 1.3 Hz, 1 H, Bzt), 7.35–7.26 (m, 5
H, Ar), 4.52 and 4.46 (AB system, JAB = 11.7, ∆ν = 13 Hz, 2 H,
OCH2Ph), 3.79 (m, 1 H, 11-H), 3.52 (t, J = 6.6 Hz, 2 H, 13-H),
3.46 (m, 1 H, 8a-H), 3.32 (m, 1 H, 8b-H), 2.06 (m, 1 H, 7a-H),
1.77 (m, 1 H, 9-H), 1.73 (m, 2 H, 12-H), 1.62 (m, 1 H, 7b-H), 0.94
(d, J10-9 = 6.8 Hz, 3 H, 10-H), 0.86 (s, 9 H, tBuSi), –0.06 (s, 3 H,
MeSi), –0.04 (s, 3 H, MeSi) ppm. 13C NMR (75 MHz, CDCl3): δ
= 167.3 (Cq arom.), 153.4 (Cq arom.), 138.5 (Cq arom.), 135.2 (Cq
arom.), 128.4 (CH arom.), 127.7 (CH arom.), 127.5 (CH arom.),
126.0 (CH arom.), 124.1 (CH arom.), 121.5 (CH arom.), 121.0 (CH
arom.), 73.0 (OCH2Ph), 72.6 (C-11), 67.4 (C-13), 37.9 (C-9), 32.8
(C-12), 32.1 (C-8), 31.4 (C-7), 25.9 [C(CH3)3Si], 18.1 [C(Me)3Si],
14.8 (C-10), –4.2 (MeSi), –4.5 (MeSi) ppm.
125.5 (CH arom.), 122.3 (CH arom.), 73.0 (OCH2Ph), 72.4 (C-11),
67.1 (C-13), 53.8 (C-7), 37.9 (C-9), 32.6 (C-12), 25.8 [C(CH3)3Si],
24.8 (C-8), 17.9 [C(Me)3Si], 14.8 (C-10), –4.4 (MeSi), –4.6 (MeSi)
ppm.
2-(Methylthio)benzo[d]thiazole (16): Synthesized according the lit-
erature.[27] Amber solid. 1H NMR (300 MHz, CDCl3): δ = 7.87 (d,
J = 7.7 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 7.71 (td, J = 7.1, 1.3 Hz,
1 H), 7.28 (td, J = 7.9, 1.3 Hz, 1 H), 2.79 (s, 3 H, Me) ppm. 13C
NMR (75 MHz, CDCl3): δ = 168.1 (Cq arom.), 153.3 (Cq arom.),
135.1 (Cq arom.), 126.1 (CH arom.), 124.1 (CH arom.), 121.4 (CH
arom.), 120.9 (CH arom.), 15.9 (MeS) ppm.
Preparation of Compound 17: A solution of LHMDS (1  in THF,
0.55 mL, 2.3 equiv.) was added dropwise at –72 °C to a solution
of benzothiazolyl sulfone 15 (126 mg, 0.236 mmol) and aldehyde 4
(58 mg, 1.7 equiv.) in THF (8 mL). The resulting yellow solution
was stirred from –72 °C to –10 °C for 2 h, then diluted with EtOAc
(10 mL), and the reaction quenched with satd. aq. NH4Cl (4 mL)
followed by water (4 mL) and aq. HCl (10%, 1 mL) until pH = 4.
The organic layer was washed with water (2ϫ 10 mL), brine and
dried with Na2SO4. Evaporation of the solvents under reduced
pressure gave an orange oil, which was purified by column
chromatography on silica gel (EtOAc/cyclohexane, 3:7) to afford a
light-yellow liquid of 17 (105 mg, 81.3%) as a mixture of (E)/(Z)
olefins (ratio 1:1). The two isomers were easily separated on a pre-
parative thin layer plate impregnated with silver nitrate in MeCN
(1 g/5 mL); elution with EtOAc/cyclohexane (5:95; products visual-
ized with KMnO4) afforded the (E) olefin (Rf = 0.6) and (Z) olefin
(Rf = 0.4). Each olefin was assigned by 2D NMR spectroscopic
analyses at high field (600 MHz).
(–)-[(3S,4S)-1-(Benzyloxy)-4-methyl-6-(methylthio)hex-3-yloxy]-
(tert-butyl)dimethylsilane (14a): Yellow oil. [α]D = –21 (c = 1,
CHCl3). C21H38O2SSi (382.675): calcd. C 65.91, H 10.01; found C
1
65.52, H 10.20. H NMR (300 MHz, CDCl3): δ = 7.35–7.26 (m, 5
H, Ar), 4.52 and 4.46 (AB system, JAB = 11.9 Hz, ∆ν = 13 Hz, 2
H, OCH2Ph), 3.93–3.88 (m, 1 H, 11-H), 3.50 (t, J13-2 = 6.6 Hz, 1
H, 13-H), 2.48 (AB part of an ABX system, JAB = 12.5 Hz, JAX
=
(–)-(3S,4S,6E,9R,10E)-1-(Benzyloxy)-3,9-bis(tert-butyldimethylsil-
yloxy)-4-methyldodeca-6,10-diene [17, (E) Isomer]: Light-yellow oil.
9.0 Hz, JBX = 5.1 Hz, ∆ν = 95 Hz, 2 H, 8-H), 2.06 (s, 3 H, MeS),
1.85–1.64 (m, 3 H, 9-H and 12-H), 0.96 (d, J10-9 = 6.8 Hz, 3 H, 10-
H), 0.89 (s, 9 H, tBuSi), 0.06 (s, 3 H, MeSi), 0.05 (s, 3 H, MeSi)
ppm. 13C NMR (75 MHz, CDCl3): δ = 138.5 (Cq arom.), 128.4
(CH arom.), 127.6 (CH arom.), 127.5 (CH arom.), 73.0 (OCH2Ph),
71.5 (C-11), 67.4 (C-13), 38.0 (C-9), 37.7 (C-8), 33.6 (C-12), 25.9
[C(CH3)3Si], 18.1 [C(Me)3Si], 15.9 (MeS), 14.1 (C-10), –4.3 (MeSi),
–4.4 (MeSi) ppm.
[α]D
C32H58NaO3Si2 [M + Na]+ 569.381; found 569.374. 1H NMR
(600 MHz, CDCl3): δ = 7.36–7.26 (m, 5 H, Ph), 5.57 (dq, J2-3
= –11.9 (c = 0.66, CHCl3). MS (ESI): calcd. for
=
15.3, J2-1 = 6.4 Hz, 1 H, 2-H), 5.33 (ddq, J3-2 = 15.3, J3-4 = 6.4,
J3-1 = 1.5 Hz, 1 H, 3-H), 5.4–5.3 (m, 2 H, 6-H and 7-H), 4.53 and
4.49 (AB system, JAB = 6, ∆ν = 10.7 Hz, 2 H, OCH2Ph), 4.02 (td,
J4-5 = J4-3 = 6.4 Hz, 1 H, 4-H), 3.75 (dt, J = 7.9, 4.0 Hz, 1 H, 11-
H), 3.49 (m, 2 H, 13-H), 2.24 (m, 1 H, 8a-H), 2.15 (m, 2 H, 5-H),
1.73 (m, 2 H, 12-H), 1.68 (d, J1-2 = 6.6 Hz, 3 H, 1-H), 1.67 (m, 1
H, 8b-H), 1.54 (m, 1 H, 9-H), 0.90 (s, 9 H, tBuSi), 0.89 (s, 9 H,
tBuSi), 0.82 (d, J10-9 = 6.6 Hz, 3 H, 10-H), –0.054 (s, 3 H, MeSi),
–0.051 (s, 3 H, MeSi), –0.04 (s, 3 H, MeSi), –0.03 (s, 3 H, MeSi)
ppm. 13C NMR (75 MHz, CDCl3): δ = 138.6 (Cq arom.), 134.5 (C-
3), 131.7 (C-6 or C-7), 128.3 (CH arom.), 127.7 (CH arom.), 127.6
(CH arom.), 127.5 (C-6 or C-7), 124.9 (C-2), 73.8 (C-4), 72.9
(OCH2Ph), 72.8 (C-11), 67.6 (C-13), 42.0 (C-5), 39.0 (C-9), 35.1
(C-8), 33.0 (C-12), 29.7 (fatty grease CH2), 25.9 [C(CH3)3Si], 18.3
[C(Me)3Si], 18.1 [C(Me)3Si], 17.6 (C-1), 14.4 (C-10), –4.27 (MeSi),
–4.33 (MeSi), –4.5 (MeSi), –4.7 (MeSi) ppm.
(–)-2-[(3S,4S)-6-(Benzyloxy)-4-(tert-butyldimethylsilyloxy)-3-meth-
ylhexylsulfonyl]benzo[d]thiazole (15): A solution of ammonium
molybdate (7 mg, 4.2% mol-equiv.) in water (0.3 mL) and hydrogen
peroxide (30% in water, 0.2 mL, 13 equiv.) was added dropwise to
a precooled (0 °C) solution of the previous sulfide 14 (67 mg,
0.133 mmol) in EtOH (1 mL). The yellow mixture was stirred at
room temp. for 21 h, then EtOAc (5 mL) and satd. aq. NaCl (1 mL)
were added before evoparation of the solvents under reduced pres-
sure. Water (5 mL) and EtOAc (10 mL) were added to the resulting
solid. The organic layer was washed with water (3ϫ 5 mL), brine
(2 mL), dried (Na2SO4), filtered, and concentrated under reduced
pressure to leave a yellow liquid. Purification by column
chromatography on silica gel (EtOAc/cyclohexane, 3:7) furnished
15 (48 mg, 67.3%) as a colorless oil. [α]D = –15.1 (c = 1.55, CHCl3).
C27H39NO4S2Si (533.818): calcd. C 60.75, H 7.36, N 2.62; found C
(–)-(3S,4S,6Z,9R,10E)-1-(Benzyloxy)-3,9-bis(tert-butyldimethylsil-
yloxy)-4-methyldodeca-6,10-diene [17, (Z) Isomer]: Yellow oil. [α]D
= –15 (c = 0.42, CHCl3). MS (ESI): calcd. for C32H58NaO3Si2 [M
+ Na]+ 569.381; found 569.4. 1H NMR (600 MHz, CDCl3): δ =
7.36–7.26 (m, 5 H, Ph), 5.56 (dq, J2-3 = 15.2, J2-1 = 6.4 Hz, 1 H,
1
61.06, H 7.66, N 2.19. H NMR (300 MHz, CDCl3): δ = 8.21 (d,
J = 9.1 Hz, 1 H, Bzt), 8.01 (d, J = 7.3 Hz, 1 H, Bzt), 7.66–7.55 (m,
2 H, Bzt), 7.36–7.27 (m, 5 H, Ph), 4.48 and 4.42 (AB system, JAB
= 11.7, ∆ν = 14.7 Hz, 2 H, OCH2Ph), 3.77 (m, 1 H, 11-H), 3.54 (t, 2-H), 5.5–5.40 (m, 3 H, 3-H, 6-H and 7-H), 4.53 and 4.49 (AB
J = 7.8 Hz, 7-H), 3.46 (t, J = 6.5 Hz, 13-H), 2.04 (m, 1 H, 8a-H), system, JAB = 6, ∆ν = 11.1 Hz, 2 H, OCH2Ph), 4.06 (td, J4-5
=
1.76–1.55 (m, 4 H, 8b-H, 9-H and 12-H), 0.86 (d, J10-9 = 6.6 Hz, 3
H, 10-H), 0.74 (s, 9 H, tBuSi), –0.02 (s, 3 H, MeSi), –0.05 (s, 3 H,
J4-3 = 6.5 Hz, 1 H, 4-H), 3.77 (dt, J = 8.0, 4.2 Hz, 1 H, 11-H), 3.53
(m, 2 H, 13-H), 2.23 (m, 1 H, 5a-H), 2.15 (m, 2 H, 5b-H and 8a-
MeSi) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.8 (Cq arom.), H), 1.84 (m, 1 H, 8b-H), 1.74 (m, 1 H, 12a-H), 1.68 (d, J1-2
=
152.8 (Cq arom.), 138.4 (Cq arom.), 136.8 (Cq arom.), 128.4 (CH 6.6 Hz, 3 H, 1-H), 1.66 (m, 1 H, 12b-H), 1.54 (m, 1 H, 9-H), 0.91
arom.), 128.0 (CH arom.), 127.7 (CH arom.), 127.6 (CH arom.), (s, 9 H, tBuSi), 0.90 (s, 9 H, tBuSi), 0.84 (d, J10-9 = 6.9 Hz, 3 H,
6214
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6207–6216

Partial Synthesis of Bistramide K
10-H), –0.06 (s, 3 H, MeSi), –0.054 (s, 3 H, MeSi), –0.048 (s, 3 H,
MeSi), –0.04 (s, 3 H, MeSi) ppm. 13C NMR (75 MHz, CDCl3): δ
= 138.6 (Cq arom.), 134.5 (C-3), 130.3 (C-6 or C-7), 128.3 (CH
arom.), 127.6 (CH arom.), 127.4 (CH arom.), 126.5 (C-6 or C-7),
124.9 (C-2), 73.5 (C-4), 72.9 (OCH2Ph), 72.8 (C-11), 67.6 (C-13),
39.2 (C-9), 36.5 (C-5), 33.1 (C-12), 29.7 (C-8), 25.9 [C(CH3)3Si],
18.3 [C(Me)3Si], 18.1 [C(Me)3Si], 17.6 (C-1), 14.5 (C-10), –4.30 (2
MeSi), –4.5 (MeSi), –4.7 (MeSi) ppm.
Acknowledgments
C. B. is grateful to Dr. Dominique Mandon and Prof. Remy Louis
for their encouragement.
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0.060 mmol) in anhydrous THF (1 mL) was added dropwise to a
dark-blue condensed liquid ammonia solution (ca. 4 mL) at –78 °C
containing sodium metal (18 mg, 13 equiv.). After 10 min, solid
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Ireland, C. Debitus, J. Nat. Prod. 1994, 57, 1336–1345; f) J.
Pusset, B. Maillere, C. Debitus, J. Nat. Toxins 1996, 5, 1–6; g)
H. L. Sings, K. L. Rinehart, J. Ind. Microbiol. 1996, 17, 385–
396; h) S. Siavoshian, C. Jacquot, J. F. Biard, G. Briand, C.
Roussakis, Anticancer Res. 1999, 19, 5361–5365.
15.2, J2-1 = 6.2, J2-4 = 0.8 Hz, 1 H, 2-H), 5.45–5.36 (m, 3 H, 3-H,
6-H and 7-H), 4.03 (td, J4-5 = J4-3 = 7.0 Hz, 1 H, 4-H), 3.89 (m, 1
H, 13a-H), 3.80 (m, 1 H, 13b-H), 3.73 (m, 1 H, 11-H), 3.15 (m, 1
H, OH), 2.17 (m, 3 H, 5-H and 8a-H), 1.84 (m, 1 H, 8b-H), 1.69
(m, 2 H, 12-H), 1.66 (d, J1-2 = 6.8 Hz, 3 H, 1-H), 1.54 (m, 1 H, 9-
H), 0.90 (s, 9 H, tBuSi), 0.89 (d, J10-9 = 9.3 Hz, 3 H, 10-H), 0.88
(s, 9 H, tBuSi), 0.08 (s, 6 H, 2 MeSi), 0.03 (s, 3 H, MeSi), 0.01 (s,
3 H, MeSi) ppm. 13C NMR (125 MHz, CDCl3): δ = 134.5 (C-3),
131.2 (C-6 or C-7), 128.1 (C-6 or C-7), 124.9 (C-2), 77.3 (residue
of CHCl3), 75.2 (C-11), 73.8 (C-4), 63.2 (C-13), 42.0 (C-5), 39.0 (C-
9), 36.4 (C-8), 35.6 (C-12), 29.7 (fatty grease CH2), 25.9 [2 C(CH3)3-
Si], 18.3 [C(Me)3Si], 18.2 [C(Me)3Si], 17.6 (C-1), 14.0 (C-10), –4.3
(MeSi), –4.7 (MeSi), –5.5 (2 MeSi) ppm.
(–)-(3S,4S,6E,9R,10E)-1,9-Bis(tert-butyldimethylsilyloxy)-4-methyl-
dodeca-6,10-dien-1-ol (18b): Colorless oil. [α]D = –13.2 (c = 0.45,
CHCl3). MS (ESI): calcd. for C25H52NaO3Si2 [M + Na]+ 479.3347;
found 479.334. 1H NMR (500 MHz, CDCl3): δ = 5.53 (qdd, J2-3
=
15.3, J2-1 = 6.3, J2-4 = 0.8 Hz, 1 H, 2-H), 5.41 (qdd, J3-2 = 15.4,
J3-4 = 6.3, J3-1 = 1.3 Hz, 1 H, 3-H), 5.38 (m, 2 H, 6-H and 7-H),
4.02 (td, J4-5 = J4-3 = 6.8 Hz, 1 H, 4-H), 3.76 (m, 1 H, 11-H), 3.73
(m, 2 H, 13-H), 2.29 (m, 1 H, 8a-H), 2.17 (m, 2 H, 5-H), 1.97 (br.
s, 1 H, OH), 1.72–1.60 (m, 4 H, 8b-H, 9-H and 12-H), 1.66 (d,
J1-2 = 6.8 Hz, 3 H, 1-H), 0.90 (s, 9 H, tBuSi), 0.88 (s, 9 H, tBuSi),
0.83 (d, J10-9 = 6.6 Hz, 3 H, 10-H), –0.09 (11-OSiMe), –0.07 (11-
OSiMe), –0.03 (4-OSiMe), –0.01 (4-OSiMe) ppm. 13C NMR
(125 MHz, CDCl3): δ = 134.5 (C-3), 131.2 (C-6 or C-7), 128.0 (C-
6 or C-7), 124.9 (C-2), 77.2 (residue of CHCl3), 74.9 (C-11), 73.7
(C-4), 60.8 (C-13), 42.0 (C-5), 38.9 (C-9), 34.5 (C-8 or C-12), 34.3
(C-8 or C-12), 29.7 (fatty grease CH2), 25.9 [2 C(CH3)3Si], 18.3
[C(Me)3Si], 18.0 [C(Me)3Si], 17.6 (C-1), 15.2 (C-10), –4.3 (2 MeSi),
–4.5 (MeSi), –4.7 (MeSi) ppm.
[11] D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981,
103, 2127–2129.
[12] Recently, this product was synthesized in a two-step procedure
in 38% yield starting from (chloroacetyl)oxazolidinone. When
we applied this method, we observed the formation of the diene
product, probably due to elimination of the hydroxy group in
the acidic medium: S. J. B. Son, M.-H. Hwang, W. Lee, D.-H.
Lee, Org. Lett. 2007, 9, 3897–3900.
[13] J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512–519.
[14] J. R. Parikh, W. E. Doering, J. Am. Chem. Soc. 1967, 89, 5505–
5507.
Supporting Information (see footnote on the first page of this arti-
cle): Complete spectroscopic and analytical data including copies
of NMR spectra for all compounds.
Eur. J. Org. Chem. 2010, 6207–6216
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6215

C. Bauder
FULL PAPER
[15] We observed the opposite optical rotation sign for compound
3 {[α]D = +23.8 (c = 1.02, CHCl3)} compared with that in the
literature {[α]D = –19.3 (c = 1.63, CHCl3}: E.-M. Moffatt, E. J.
Thomas, Tetrahedron 1999, 55, 3723–3734. However, compari-
son of the optical rotation of our aldehyde 4 {[α]D = +15.3 (c
= 1.02, CHCl3)} with the published data {[α]D = +14.0 (c =
2.0, CHCl3)} as well as our analysis on the Mosher’s ester de-
rivative of compound 1 (the precursor of 3 and 4) verified the
correct absolute stereochemistry and high optical purity for
compounds 3 and 4: I. Paterson, S. P. Wren, Soc. Chem. 1993,
1790–1792.
[16] The optical rotation for 5 {[α]D = –48.2 (c = 0.95, CHCl3)} is
in agreement with the literature value {[α]D = –52.7 (c = 0.9,
CHCl3)}: G. Pattenden, N. J. Ashweek, C. A. G. Baker-Glenn,
J. Kempson, G. M. Walker, J. G. K. Yee, Org. Biomol. Chem.
2008, 6, 1478–1497.
[22] A. R. Katritzky, J. M. Aurrecoechea, L. M. Vazquez de Mig-
uel, J. Chem. Soc. Perkin Trans. 1 1987, 769–774.
[23] H. S. Schultz, H. B. Freyermuth, S. R. Buc, J. Org. Chem. 1963,
28, 1140–1142.
[24] Analytical data for the by-product 14a: Yellow oil. [α]D = –21
(c = 1, CHCl3). C21H38O2SSi (382.675): calcd. C 65.91, H
1
10.01; found C 65.52, H 10.20. H NMR (300 MHz, CDCl3):
δ = 7.35–7.26 (m, 5 H, Ar), 4.52 and 4.46 (AB system, JAB
=
11.9 Hz, ∆ν = 13 Hz, 2 H, OCH2Ph), 3.93–3.88 (m, 1 H, 11-
H), 3.50 (t, J13-2 = 6.6 Hz, 1 H, 13-H), 2.48 (AB part of an
ABX system, JAB = 12.5 Hz, JAX = 9.0 Hz, JBX = 5.1 Hz, ∆ν
= 95 Hz, 2 H, 8-H), 2.06 (s, 3 H, MeS), 1.85–1.64 (m, 3 H, 9-
H and 12-H), 0.96 (d, J10-9 = 6.8 Hz, 3 H, 10-H), 0.89 (s, 9 H,
tBuSi), 0.06 (s, 3 H, MeSi), 0.05 (s, 3 H, MeSi) ppm. 13C NMR
(75 MHz, CDCl3): δ = 138.5 (Cq arom.), 128.4 (CH arom.),
127.6 (CH arom.), 127.5 (CH arom.), 73.0 (OCH2Ph), 71.5 (C-
11), 67.4 (C-13), 38.0 (C-9), 37.7 (C-8), 33.6 (C-12), 25.9
[C(CH3)3Si], 18.1 [C(Me)3Si], 15.9 (MeS), 14.1 (C-10), –4.3
(MeSi), –4.4 (MeSi) ppm.
[17] Only the (E)-olefination product was detected. Spectral data
for enone 8 are given in the Experimental Section.
[18] The preparation of phosphonate 12 required the addition of
HMPA. Indeed, the reaction did not exceed 5–10% without
HMPA even at room temp. for 24 h.
[25] The (E)/(Z) isomer mixture could not be separated by standard
column chromatographic purification. Thus, we successfully
adopted a described protocol using silica gel impregnated with
AgNO3 (1 g/5 mL in MeCN). The elution was performed with
EtOAc/cyclohexane (5:95). For more details, see: a) C. M. Wil-
liams, L. N. Mander, Tetrahedron 2001, 57, 425–447; b) T.-S.
Li, J.-T. Li, H.-Z. Li, J. Chromatogr. A 1995, 715, 372–375.
[26] H. Tian, X. Jiao, P. Xie, X. Liang, Tetrahedron Lett. 2005, 46,
8579–8581
[19] NMR spectral analyses (1H, 13C and 31P) of the crude material
indicated that addition of phosphonate 12 to the aldehyde 4
did actually occur but without elimination to produce the ole-
fination adduct.
[20] M. Julia, J.-M. Paris, Tetrahedron Lett. 1973, 14, 4833–4836.
[21] a) P. J. Kocienski, B. Lythgoe, S. Ruston, J. Chem. Soc. Perkin
Trans. 1 1978, 829–834; b) P. J. Kocienski, B. Lythgoe, S. Rus-
ton, J. Chem. Soc. Perkin Trans. 1 1979, 1290–1293; c) P. R.
Blakemore, W. J. Cole, P. J. Kocienski, A. Morley, Synlett 1998,
26–28; d) P. R. Blakemore, J. Chem. Soc. Perkin Trans. 1 2002,
2563–2585; e) C. Aïssa, Eur. J. Org. Chem. 2009, 1831–1844.
[27] L. Bethge, D. V. Jarikote, O. Seitz, Bioorg. Med. Chem. 2008,
16, 114–125
Received: June 18, 2010
Published Online: September 22, 2010
6216
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6207–6216