Asymmetric synthesis of a highly functionalized enantioenriched system close to thapsigargin framework

Article abstract of DOI:10.1039/c2ob26194d

A straightforward approach to a highly functionalized enantioenriched bicyclo[5.3.0]decadienone system close to the thapsigargin framework has been achieved. The developed synthetic route involves two main stages: installation of the chains on either side of the quaternary center at C7 starting from a central enantiopure epoxide and formation of the bicyclic octahydroazulene through subsequent Pauson-Khand annelation.

Full text of DOI:10.1039/c2ob26194d

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PAPER
Asymmetric synthesis of a highly functionalized enantioenriched system close
to thapsigargin framework†
Aurélien Tap,a Morgan Jouanneau,b Gilles Galvani,a Geoffroy Sorin,a Marie-Isabelle Lannou,a
Jean-Pierre Férézoub and Janick Ardisson*a
Received 29th February 2012, Accepted 6th August 2012
DOI: 10.1039/c2ob26194d
A straightforward approach to a highly functionalized enantioenriched bicyclo[5.3.0]decadienone system
close to the thapsigargin framework has been achieved. The developed synthetic route involves two main
stages: installation of the chains on either side of the quaternary center at C7 starting from a central
enantiopure epoxide and formation of the bicyclic octahydroazulene through subsequent Pauson–Khand
annelation.
Introduction
In recent years, research on natural sesquiterpene lactones has
fostered a renewed interest. These lactones are promising candi-
dates in cancer drug discovery and their activities position them
as lead compounds in clinical trials.1
Thapsigargin (Tg) 1 is a highly oxygenated sesquiterpene
lactone belonging to the 6,12-guaianolide family, isolated from
the Mediterranean plant species Thapsia (Apiaceae).2 This com-
pound presents a challenging complex chemical structure,
including a polyoxygenated 5-7-5 tricyclic core possessing eight
stereogenic centres and functionalized with five different ester
groups (Fig. 1). Tg is a very potent inhibitor of the endo/sarco-
plasmic calcium ATPase (SERCA).3,4 Tg derivatives are cur-
rently under clinical trials for treatment of prostate cancer.
Two main challenges emerge for Tg total synthesis: (i) the
construction of the 5,7-fused bicyclic core, (ii) the installation of
Scheme 1 Synthetic strategy to Tg 1 and 8-desoxy dienone 7.
the dense array of functional groups present throughout the
cyclic system. Remarkably, the Ley group succeeded in the first
and unique total synthesis of Tg5 as well as in the elaboration of
Fig. 1 Thapsigargin (Tg) 1.
a pivotal scaffold allowing access to unnatural analogues,6 by
means of a key diene ring closure metathesis step. A few other
aFaculté de Pharmacie, CNRS UMR 8638, Université Paris Descartes,
4 avenue de l’Observatoire, 75270 Paris Cedex 06, France.
efforts have led to alternative interesting approaches, through
either an efficient domino metathetic route (Kaliappan)7 or a
E-mail: janick.ardisson@parisdescartes.fr; Tel: +33 (0) 1 53 73 97 54
photochemical rearrangement (Massanet).8
bLCPSN, ICMMO, CNRS UMR 8182, Bâtiment 410, Université
Paris-Sud-11, 15 rue Georges Clemenceau, F-91405 Orsay Cedex,
France. Tel: +33 (0)1 69 1576 30
Our general strategy for the synthesis of Tg 1 relies on two
key points (Scheme 1). The stereocontrolled installation of the
functionalities on either side of the C7 tertiary alcohol is envi-
sioned at the beginning of the synthesis, through the addition of
†Electronic supplementary information (ESI) available: Experimental
procedures, spectral data, copies of 1H NMR and 13C NMR spectra of
new compounds. See DOI: 10.1039/c2ob26194d
8140 | Org. Biomol. Chem., 2012, 10, 8140–8146
This journal is © The Royal Society of Chemistry 2012

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side arms to the pivotal 7-centered (R)-epoxide 2,9 to deliver
intermediate 3. Then, Rh(I)-catalyzed allenic Pauson–Khand
(A.P.K.) reaction, should allow the construction of bicyclo[5.3.0]-
decadienone 4, chosen as an advanced precursor of Tg 1.10,11
To validate the above strategy, we decided to synthesize the
enantioenriched 8-desoxy dienone 7, structurally close to
dienone 4. As for Tg 1, the synthetic route will start from (R)-
epoxide 2, however, with a reduced number of steps. Bicyclic
dienone 7 should be accessible from regiocontrolled epoxide
opening through propargylation,12 followed by successive alky-
nylation13 and A.P.K. reaction,10,11 via intermediates 5 and 6.
We report here the results of this chemical validation study.14
Results and discussion
The synthesis began with the formation of the known
(R)-epoxide 10 available by means of an asymmetric Sharpless
epoxidation reaction of monoprotected allylic diol 9 with
L-(+)-diethyl tartrate [L-(+)-DET], in 75% yield and up to
90% ee (Scheme 2).9a Trityl (Tr) ether 9 was readily prepared in
three steps from commercial phosphonate 8.15,16
The ensuing nucleophilic opening of the epoxide moiety with
propargylmagnesium bromide proceeded in high yield to deliver
the terminal alkyne 11.12,17,18 The latter was then converted into
the corresponding PMB acetal before subsequent formylation of
the triple bond and protection of the incipient primary hydroxyl
group to give the fully protected intermediate 12 bearing ortho-
gonally protected hydroxyl functions.
Scheme 3 Synthesis of allenyne 17.
The synthesis was continued by installing the side chain at
C4–C5 (Scheme 3). Reduction of acetal 12 with DIBAL-H in
CH2Cl2 at low temperature provided the required primary
alcohol 13 as the main product in 61% yield along with the cor-
responding regioisomeric tertiary alcohol 14 which was separ-
ated by flash chromatography (12% yield).19 Then, the expected
(6S) alcohol 15 was obtained through a four-step sequence. Oxi-
dation of alcohol 13 to the corresponding aldehyde using Dess–
Martin conditions20 followed by nucleophilic addition of propy-
nyl magnesium bromide afforded a 1 : 1 mixture of the two epi-
meric propargylic alcohols 15. Successive oxidation reaction20
and reduction of the resulting ynone with (R)-Corey–Bakshi–
Shibata [(R)-CBS] reagent delivered the desired (6S) alcohol 15
in 78% yield and a d.r. of 90 : 10.13b,c,21 The absolute
Scheme 4 Synthesis of bicyclo[5.3.0]decadienone 18.
configuration of the (S)-C6 centre of secondary alcohol 15 was
confirmed through the synthesis of the corresponding (R)- and
(S)-α-methoxyphenylacetic acid (MPA) esters.18
Subsequent protection of the C6 hydroxyl function of (6S)-15
with a methoxymethyl (MOM) group and selective cleavage of
the TBS ether at C2 allowed isolation of propargyl alcohol 16 as
a single isomer after flash chromatography purification.
Finally, conversion of alcohol 16 into the allenyl precursor 17
of P.K.R. annelation was achieved in a two-step sequence: treat-
ment with methanesulfonyl chloride and subsequent SN2′ reac-
tion with methyl cyanocuprate.10
With allenyne 17 in hand, the feasibility of allene Pauson–
Khand cyclocarbonylation10,11 was then investigated under
various conditions.21 Allenyl compound 17 was first treated with
in situ prepared [Rh(CO)(dppp)2Cl] – 10 mol% of [Rh(Cl)-
(cod)]2 and 50 mol% of 1,3-bis(diphenylphosphino)propane –
under CO atmosphere in refluxing toluene for 5 hours, to
produce the bicyclo[5.3.0] derivative 18 in 76% yield
(Scheme 4).10 Conditions involving the use of 10 mol% of com-
mercially available [Rh(CO)2Cl]2 in toluene at 90 °C for 5 hours
under a CO atmosphere were also tested and led to 18 in 80%
yield;11 these latter conditions were preferred for simplicity’s
sake.
Scheme 2 Synthesis of silyl propargyl ether 12.
This journal is © The Royal Society of Chemistry 2012
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methoxy-α-(trifluoromethyl)phenyl acetic acid [(–)-MTPA], fol-
lowed by 1H NMR analysis (400 MHz; CDCl3): ratio of integrals
of CHa doublets at δ 2.73 and 2.79 corresponds to up to 95 : 5.
Conclusion
In summary, we report here preliminary studies towards a new
approach of the synthesis of the highly functionalized bicyclo-
[5.3.0]decadienone ring system of thapsigargin, starting from the
C7-centered enantiopure epoxide 10 easily accessible by means
of an asymmetric Sharpless epoxidation. Around the pivotal
starting block 10 is then articulated the stereocontrolled
implementation of the different substituents leading to the inter-
mediate allenyne 17, precursor of the P.K.R. double annelation
reaction. The synthetic sequence used to prepare the desired 5-7
bicyclic dienone 18 allows high and reproducible yields and
selectivities.
(2S)-2-(Trityloxymethyl)hex-5-yne-1,2-diol (11). A mixture of
magnesium turnings (4.74 g, 195 mmol), mercury(II) chloride
(269 mg, 0.99 mmol) and a single crystal of iodide in freshly
distilled diethyl ether (100 mL) was carefully treated with pro-
pargyl bromide (80% in toluene, 10.5 mL, 97.4 mmol) dissolved
in freshly distilled diethyl ether (40 mL). After the reaction had
started, the mixture was cooled to 0 °C and the rest of the propar-
gyl bromide solution was added within 1 hour. After being
cooled at 0 °C for an additional hour the reaction mixture was
warmed to room temperature and stirred for another hour.
Epoxide 10 (3.75 g, 10.8 mmol) was dissolved in anhydrous
THF and cooled to −78 °C. Under vigorous stirring, this sol-
ution was treated with freshly prepared propargylmagnesium
bromide (84 mL, 10.84 mmol) very slowly within 1 hour and
the mixture was slowly warmed to room temperature. After
3 hours the reaction was quenched with saturated aqueous
NH4Cl. The solution was extracted with diethyl ether (3×). The
combined extracts were dried (MgSO4) and concentrated in
vacuo. The crude residue was purified by flash chromatography
on silica gel (pentane/ethyl acetate 80 : 20 to 75 : 25) to yield the
expected diol 11 (4 g, 95%) as a colorless oil. [α]2D2 −9.6 (c 1.5
in CHCl3); νmax/cm−1 3418, 3296, 3061, 2929, 1491, 1449,
1224, 1074, 766, 708; δH (400 MHz; CDCl3): 7.28–7.44 (15 H,
m), 3.61 (1 H, d, J = 11.5 Hz), 3.50 (1 H, d, J = 11.5 Hz), 3.20
(1 H, d, J = 9.3 Hz), 3.12 (1 H, d, J = 9.3 Hz), 2.66 (1 H, s),
2.22–2.15 (2 H, m), 1.92 (1 H, t, J = 2.6 Hz), 1.81–1.76 (2 H,
m), 1.56 (1 H, s); δC (100 MHz; CDCl3): 143.4, 128.6, 128.0,
127.3, 87.0, 84.6, 73.6, 68.5, 66.5, 66.2, 33.3, 12.4; m/z
409.1770 (MNa+, C26H26NaO3 requires 409.1779).
Application of the present approach to the total synthesis of
thapsigargin 1 is currently in progress in our laboratories.
Experimental section
General remarks
All commercially available reagents and solvents (Fluka,
Aldrich, Acros, Fisher) were used without further purification.
For reactions requiring anhydrous conditions, commercial dry
solvents were directly used (Fluka, Aldrich) or freshly distilled
prior to use (THF and Et2O over sodium/benzophenone system,
DCM and DMSO over calcium hydride and MeOH and EtOH
over magnesium). Unless otherwise noted, experiments were
carried out under argon. Reactions were monitored by TLC
(Merck silica gel 60 F254 plates) with detection by use of UV
light (254 nm and 366 nm) or a phosphomolybdic acid solution
in EtOH (5%) followed by heating at 100–110 °C. Purifications
were performed by flash chromatography on silica gel (Merck
1
silica gel 60, 40–63 μm). H NMR spectra were recorded with
Bruker AVANCE 300 and AVANCE 400 spectrometers at 300
and 400 MHz, respectively. Chemical shifts are given in ppm
(4S)-tert-Butyl{5-[2-(4-methoxyphenyl)-4-(trityloxymethyl)-
1,3-dioxolan-4-yl)pent-2-ynyloxy}dimethylsilane (12). Diol 11
(4.31 g, 11.2 mmol) was dissolved in dry CH2Cl2 (8 mL) before
addition, at room temperature, of p-anisaldehyde dimethylacetal
(3.8 mL, 22.3 mmol) and PPTS (280 mg, 1.12 mmol). The
mixture was stirred at room temperature for 2 hours and the
solvent removed under reduced pressure. The crude product was
dissolved in CH2Cl2 before addition of a small quantity of PPTS
and a drop of water. The mixture was stirred for 30 min then
quenched with an aqueous saturated solution of NaHCO3 and
extracted with CH2Cl2 (3×), the organic layers were combined,
washed with brine, dried over MgSO4 and the solvent removed
under reduced pressure. The crude residue was dissolved in an
anhydrous mixture of THF/MeOH (50 : 2.5 mL). Sodium boro-
hydride (633 mg, 16.7 mmol) was added at 0 °C. The mixture
was stirred 30 min at 0 °C, quenched with an aqueous saturated
solution of NH4Cl and extracted with CH2Cl2 (3×); the organic
layers were combined, washed with brine, dried over MgSO4
and the solvent removed under reduced pressure. The crude
residue was purified by flash chromatography on silica gel
(pentane/ethyl acetate 90 : 10) to afford (4S)-4-(but-3-ynyl)-2-(4-
methoxyphenyl)-4-(trityloxymethyl)-1,3-dioxolanes, (4.2 g,
75%, unseparated 1.3 : 1 mixture of diastereomers) as a colorless
oil. νmax/cm−1 3292, 2934, 2293, 1615, 1517, 1448, 1375, 1250,
1072, 1033, 918, 834, 748, 704; m/z 527.2205 (MNa+,
1
relative to the residual H solvent signal (CDCl3: δ = 7.26 ppm)
1
as the internal reference. H NMR assignments were confirmed
by 2D COSY spectra. The given multiplicities reflect apparent
signal patterns. 13C NMR spectra were recorded with the same
instruments as above at 100 MHz. Chemical shifts are given in
ppm relative to the residual 13C solvent signal (CDCl3: δ =
77.0 ppm). 13C NMR assignments were confirmed by 2D HSQC
spectra. Coupling constants (J) are given in Hz for all NMR
spectroscopic data. Melting points were measured with a Büchi
510 apparatus and are uncorrected. IR spectra were recorded
with a Perkin Elmer Spectrum 65 FT-IR spectrometer. Mass
spectra were recorded with the following instruments: ESI-MS:
Waters ZQ 2000 spectrometer and ESI-TOF-HRMS: Waters
LCT Premier spectrometer.
2-Triphenylmethoxymethyl-2-propenol
9 was synthesized
according to a reported procedure, starting from ethyl 2-(triphe-
nylmethoxymethyl)propenoate.15
(2R)-[2-(Triphenylmethoxymethyl)oxiran-2-yl]methan-1-ol (10).
Sharpless epoxidation of 13 was carried out according to Kang
procedure from 2-triphenylmethoxymethyl-2-propenol 9.9a [α]D22
−20.0 (c 1.5 in CHCl3) (lit., −19.5 (c 1.5 in CHCl3). Determi-
nation of ee via Mosher ester synthesis from (R)-(+)-α-methoxy-
α-(trifluoromethyl)phenylacetic acid [(+)-MTPA] or (S)-(–)-α-
8142 | Org. Biomol. Chem., 2012, 10, 8140–8146
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C34H32NaO4 requires 527.2198). Major diastereomer: δH
(400 MHz; CDCl3): 7.55–7.28 (17 H, m), 6.96 (2 H, d, J = 8.6),
5.88 (1 H, s), 4.07 (1 H, d, J = 8.5), 3.98 (1H, d, J = 8.5 Hz),
3.84 (3 H, s), 3.32 (1 H, d, J = 9.6 Hz), 3.26 (1 H, d, J =
9.6 Hz), 2.31–2.27 (1 H, m), 2.19–2.06 (3 H, m), 1.95 (2 H, t, J
= 2.7 Hz); δC (100 MHz; CDCl3): 160.5, 143.6, 128.7, 128.1,
128.0, 127.8, 127.1, 113.8, 103.9, 86.8, 84.2, 81.9, 72.0, 68.3,
65.7, 55.2, 34.9, 13.0. Minor diastereomer: δH (400 MHz;
CDCl3): 7.55–7.28 (17 H, m), 6.99 (2 H, d, J = 8.6 Hz), 5.86
(1 H, s), 4.20 (1 H, d, J = 8.6 Hz), 3.88 (1H, d, J = 8.6 Hz), 3.82
(3 H, s), 3.23 (2 H, s), 2.31–2.27 (1 H, m), 2.19–2.06 (3 H, m),
1.98 (2 H, t, J = 2.7 Hz); δC (100 MHz; CDCl3): 160.4, 143.5,
128.7, 128.1, 128.0, 127.8, 127.1, 113.6, 103.8, 86.6, 84.2, 81.9,
72.8, 68.4, 65.5, 55.2, 33.9, 13.0.
A solution of n-BuLi (1.6 M in hexane, 1.1 mL, 1.75 mmol)
was added slowly to a stirred solution of the precedent
1.3 : 1 mixture of (4S)-4-(but-3-ynyl)-2-(4-methoxyphenyl)-4-
(trityloxymethyl)-1,3-dioxolanes (680 mg, 1.35 mmol) in anhy-
drous THF (3 mL), at −78 °C. The reaction mixture was stirred
for 1 hour at −78 °C before addition of depolymerized parafor-
maldehyde (obtained by heating the polymer) (400 mg,
13.5 mmol). The reaction mixture was stirred for 10 min at
−78 °C and then 30 min at room temperature. The mixture was
quenched with an aqueous saturated solution of NH4Cl and
extracted with Et2O (3×); the organic layers were combined,
washed with brine, dried over MgSO4; then the solvent was
removed under reduced pressure. The crude oil was purified by
flash chromatography on silica gel (pentane/ethyl acetate 80 : 20
to 70 : 30) to afford the expected primary alcohol, (4S)-5-[2-(4-
methoxyphenyl)-4-(trityloxymethyl)-1,3-dioxolan-4-yl]pent-2-
yn-1-ol, (513 mg, 71%, 1.3 : 1 mixture of diastereomers), as a
colorless oil. νmax/cm−1 3519, 2943, 2253, 1615, 1518, 1448,
1375, 1250, 1072, 1034, 918, 834, 749, 710; m/z 557.2310
(MNa+, C35H34NaO5 requires 557.2304). Major diastereomer:
δH (400 MHz; CDCl3): 7.50–7.23 (17 H, m), 6.93 (2 H, d, J =
8.7 Hz), 5.83 (1 H, s), 4.20 (2 H, s), 4.03 (1 H, d, J = 8.5 Hz),
3.93 (1 H, d, J = 8.5 Hz), 3.82 (s, 3H), 3.24 (1 H, d, J = 9.6 Hz),
3.20 (1 H, d, J = 9.6 Hz), 2.32–2.19 (2 H, m), 2.12–1.93 (3 H,
m); δC (100 MHz; CDCl3): 160.5, 143.6, 128.7, 128.2, 128.1,
127.9, 127.1, 113.8, 103.9, 86.8, 86.1, 82.0, 78.4, 72.1, 65.7,
55.3, 51.4, 35.0, 13.3. Minor diastereomer: δH (400 MHz;
CDCl3): 7.50–7.23 (17 H, m), 6.85 (2 H, d, J = 8.7 Hz), 5.80
(1 H, s), 4.22 (2 H, s), 4.16 (1 H, d, J = 8.6 Hz), 3.82 (1 H, d,
J = 8.6 Hz), 3.80 (3 H, s), 3.16 (2 H, s), 2.32–2.19 (2 H, m),
2.12–1.93 (3 H, m); δC (100 MHz; CDCl3): 160.5, 143.6, 128.7,
128.2, 128.1, 127.9, 127.1, 113.7, 103.8, 86.8, 86.1, 82.0, 78.4,
72.9, 65.5, 55.3, 51.4, 34.0, 13.3.
777, 703; m/z 671 (MNa+); m/z 671.3188 (MNa+,
C41H48NaO5Si requires 671.3169). Major diastereomer: δH
(400 MHz; CDCl3): 7.49–7.25 (17 H, m), 6.91 (2 H, d, J =
8.7 Hz), 5.81 (1H s,), 4.27 (2 H, s), 4.01 (1 H, d, J = 8.5 Hz),
3.90 (1 H, d, J = 8.5 Hz), 3.82 (3 H, s), 3.22 (1 H, d, J =
9.6 Hz), 3.15 (1 H, d, J = 9.6 Hz), 2.30–2.20 (2 H, m),
2.09–2.00 (2 H, m), 0.91 (9 H, s), 0.11 (6 H, s); δC (100 MHz;
CDCl3): 160.5, 143.6, 128.7, 128.2, 128.1, 127.9, 127.1, 113.8,
103.9, 86.8, 84.9, 82.0, 78.8, 72.1, 65.7, 55.3, 51.9, 35.1, 34.0,
25.9 13.4, −5.1. Minor diastereomer: δH (400 MHz; CDCl3):
7.49–7.25 (17 H, m), 6.85 (2 H, d, J = 8.6 Hz), 5.80 (1 H, s),
4.29 (2 H, s), 4.13 (1 H, d, J = 8.6 Hz), 3.83 (1 H, d, J =
8.6 Hz), 3.80 (3 H, s), 3.16 (2 H, s), 2.30–2.20 (2 H, m),
2.09–2.00 (2 H, m), 0.92 (9 H, s), 0.12 (6 H, s); δC (100 MHz;
CDCl3): 160.5, 143.6, 128.7, 128.2, 128.1, 127.9, 127.1, 113.7,
103.9, 86.8, 84.9, 82.0, 78.8, 72.8, 65.6, 55.3, 51.9, 35.1, 34.0,
25.9 13.4, −5.1.
(2R)-7-(tert-Butyldimethylsilyloxy)-2-(4-methoxybenzyloxy)-2-
(trityloxymethyl)hept-5-yn-1-ol (13) and (2R)-7-(tert-butyldi-
methylsilyloxy)-1-(4-methoxybenzyloxy)-2-(trityloxymethyl)hept-
5-yn-2-ol (14). DIBAL-H (1.1 M in cyclohexane, 4.2 mL,
4.67 mmol) was added at −78 °C over 3.5 h to a stirred solution
of the PMP acetal 12 (605 mg, 0.934 mmol) in anhydrous
CH2Cl2 (10 mL). The mixture was stirred for 1 hour at −78 °C,
quenched with an aqueous solution of NaOH 4 M and extracted
with CH2Cl2 (3×); the organic layers were combined, washed
with brine, dried over MgSO4 and the solvent removed under
reduced pressure. The crude residue was purified by flash chrom-
atography on silica gel (pentane/ethyl acetate 98 : 2 to 95 : 5) to
yield in order of elution the required primary alcohol 13,
(370 mg, 61%) and the secondary alcohol 14 (73 mg, 12%) as
colorless oils. 13: [α]2D2 −5.9 (c 1.0 in CHCl3); νmax/cm−1 3476,
2929, 2857, 1613, 1514, 1249, 1076, 836, 777, 707; δH
(400 MHz; CDCl3): 7.46–7.17 (17 H, m), 6.82 (2 H, d, J =
8.7 Hz), 4.36 (1 H, d, J = 10.5 Hz), 4.32 (1 H, d, J = 10.5 Hz),
4.27 (2 H, s), 3.79 (3 H, s), 3.74 (2 H, d, J = 6.9 Hz), 3.31 (1 H,
d, J = 9.6 Hz), 3.07 (1 H, d, J = 9.6 Hz), 2.21–2.18 (1 H, m),
2.09–1.92 (3 H, m), 1.87 (1 H, t, J = 6.9 Hz), 0.91 (9 H, s), 0.11
(6 H, s); δC (100 MHz; CDCl3): 159.1, 143.5, 130.6, 129.1,
128.7, 127.9, 127.1, 113.8, 86.8, 85.2, 78.7, 78.6, 63.9, 63.7,
63.6, 55.3, 51.9, 29.9, 25.9, 12.4, −5.1; m/z 673.3318 (MNa+,
C41H50NaO5Si requires 673.3325). 14: [α]2D2 +1.9 (c 0.62 in
CHCl3); νmax/cm−1 3554, 2928, 1514, 1449, 1249, 835, 775; δH
(400 MHz; CDCl3): 7.42–7.18 (17 H, m), 6.86 (2 H, d, J = 8.6
Hz), 4.47 (2 H, s), 4.25 (2 H, s), 3.81 (3 H, s), 3.58 (1 H, d, J =
9.0 Hz), 3.47 (1H, d, J = 9.0 Hz), 3.14 (1 H, d, J = 8.8 Hz), 3.04
(1 H, d, J = 8.8 Hz), 2.47 (1H, s), 2.19–2.05 (2 H, m), 1.84 (1H,
d, J = 8.3 Hz), 1.81 (1H, d, J = 8.3 Hz), 0.90 (9 H, s), 0.10 (6 H,
s); m/z 673.3337 (MNa+, C41H50NaO5Si requires 673.3325).
TBDMSCl (558 mg, 3.71 mmol) and imidazole (526 mg,
7.73 mmol) were successively added to a stirred solution of the
precedent mixture of alcohols (1.65 g, 3.09 mmol) in anhydrous
CH2Cl2 (20 mL), at room temperature. The mixture was stirred
for 1 hour at room temperature, quenched with an aqueous satu-
rated solution of NH4Cl and extracted with CH2Cl2 (3×); the
organic layers were combined, washed with brine, dried over
MgSO4 and the solvent removed under reduced pressure. The
crude residue was purified by flash chromatography on silica gel
(pentane/ethyl acetate 98 : 2 to 95 : 5) to yield the expected ether
12 (1.9 g, 95%, 1.3 : 1 mixture of diastereomers), as a colorless
oil. νmax/cm−1 2928, 2856, 1615, 1517, 1448, 1249, 1071, 834,
(4S,5S)-10-(tert-Butyldimethylsilyloxy)-5-(4-methoxybenzyloxy)-
5-(trityloxymethyl)deca-2,8-diyn-4-ol (6S-15). Dess–Martin reagent
(509 mg, 1.2 mmol) was added to a stirred solution of 13
(520 mg, 0.8 mmol) in anhydrous CH2Cl2 (13 mL) at room
temperature. The mixture was stirred for 45 min at room temp-
erature and quenched with an aqueous solution of Na2S2O3 and
extracted with CH2Cl2 (3×); the organic layers were combined,
washed with brine, dried over MgSO4 and the solvent removed
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under reduced pressure. A solution of propynyl magnesium
bromide (0.5 M in THF, 8.0 mmol, 16 mL) was added to a
stirred solution of the precedent crude aldehyde in anhydrous
THF (1 mL) at −78 °C. The mixture was warmed to room temp-
erature and stirred for 2 hours. The reaction was quenched with
an aqueous solution of NH4Cl and extracted with Et2O (3×); the
organic layers were combined, washed with brine, dried over
MgSO4 and the solvent removed under reduced pressure. The
crude residue was purified by flash chromatography on silica gel
(pentane/ethyl acetate 90 : 10) to afford the secondary alcohol 15
as a 1 : 1 mixture of epimers (396 mg, 72%, yellow oil). Dess–
Martin reagent (492 mg, 1.16 mmol) was then added to a stirred
solution of the latter alcohol (396 mg, 0.58 mmol) in anhydrous
CH2Cl2 (10 mL) at room temperature. The mixture was stirred
for 1 hour at room temperature, then quenched with an aqueous
solution of Na2S2O3 and extracted with CH2Cl2 (3×); the
organic layers were combined, washed with brine, dried over
MgSO4 and the solvent removed under reduced pressure. The
crude residue was purified by flash chromatography on silica gel
(pentane/ethyl acetate 98 : 2 to 95 : 5) to afford pure (5S)-10-
(tert-butyldimethylsilyloxy)-5-(4-methoxybenzyloxy)-5-(trityl-
oxymethyl)deca-2,8-diyn-4-one, (360 mg, 90%) as a yellow oil.
[α]D22 −8.7 (c 1.0 in CHCl3); νmax/cm−1 2929, 2857, 2218, 1675,
1515, 1250, 1079, 837, 707; δH (400 MHz; CDCl3): 7.44–7.22
(17 H, m), 6.83 (2 H, d, J = 8.7 Hz), 4.34 (1 H, d, J = 10.2 Hz),
4.27 (2 H, s), 4.20 (1 H, d, J = 10.2 Hz), 3.79 (3 H, s), 3.52 (1
H, d, J = 9.5 Hz), 3.25 (d, 1H, J = 9.5 Hz), 2.35–2.13 (2 H, m),
2.01 (3H, s), 1.86–1.92 (2 H, m), 0.91 (9 H, s), 0.11 (6 H, s); δC
(100 MHz; CDCl3): 189.5, 159.1, 143.1, 130.0, 129.1, 128.8,
127.8, 127.1, 113.7, 92.8, 86.7, 85.0, 84.5, 79.0, 78.9, 66.0,
63.2, 55.3, 51.9, 29.5, 25.9, 12.3, 4.38, −5.09; m/z 709.3333
(MNa+, C44H50NaO5Si requires 709.3325).
BH3–Me2S (221 μL, 2.33 mmol) and (R)-Corey–Bakshi–
Shibata [(R)-CBS)] reagent (1 M in toluene, 0.93 mL,
0.93 mmol) were successively added to a stirred solution of the
preceding ketone (320 mg, 0.466 mmol) in anhydrous THF
(4 mL) at −30 °C. The mixture was stirred at −30 °C for 1 hour
and quenched slowly with EtOH and then with water. The
aqueous layer was extracted with Et2O (3×). The organic layers
were combined, washed with brine, dried over MgSO4 and the
solvent removed under reduced pressure. The crude residue was
purified by flash chromatography on silica gel (pentane–ethyl
acetate 90 : 10) to give (6S)-15 (250 mg, 78%, d.r. 90 : 10), as a
colorless oil. νmax/cm−1 3529, 2928, 1613, 1514, 1449, 1249,
1075, 836, 777, 746, 707; δH (400 MHz; CDCl3): 7.48–7.16
(17 H, m), 6.83 (2 H, d, J = 8.6 Hz), 4.81 (1 H, dq, J = 5.8,
2.0 Hz), 4.41 (1 H, d, J = 10.5 Hz), 4.30 (1 H, d, J = 10.5 Hz),
4.29 (2 H, s), 3.79 (3 H, s), 3.41 (1 H, d, J = 9.8 Hz), 3.22 (1 H,
d, J = 9.8 Hz), 2.90 (1 H, d, J = 5.8 Hz), 2.35–2.06 (4 H, m),
1.86 (3 H, d, J = 2 Hz), 0.93 (9 H, s), 0.13 (6 H, s); δC
(100 MHz; CDCl3): 159.1, 143.2, 130.5, 129.2, 128.8, 127.9,
127.2, 113.7, 87.2, 85.4, 83.2, 79.5, 78.6, 77.2, 65.9, 64.6, 63.7,
55.3, 52.0, 30.0, 25.9, 12.9, 3.8, −5.1; m/z 711.3490 (MNa+,
C44H52NaO5Si requires 711.3482).
anhydrous CH2Cl2 (2 mL) at 0 °C. The mixture was stirred at
room temperature for 4 hours and quenched with water. The
aqueous layers were extracted with CH2Cl2 (3×). The organic
layers were combined, washed with brine, dried over MgSO4
and the solvent removed under reduced pressure. The crude
residue was purified by flash chromatography on silica gel
(pentane/ethyl acetate 90 : 10) to yield the required pure MOM
ether, (5S,6S)-6-(4-methoxybenzyloxy)-13,13,14,14-tetramethyl-
5-(prop-1-ynyl)-6-(trityloxymethyl)-2,4,12-trioxa-13-silapenta-
dec-9-yne, (170 mg, 80%, single diastereomer) as a colorless oil.
[α]D22 +33.4 (c 1.0 in CHCl3); νmax/cm−1 2931, 1810, 1071, 905,
727, 648; δH (400 MHz; CDCl3): 7.48–7.18 (17 H, m), 6.82
(2 H, d, J = 8.6 Hz), 4.93 (1 H, d, J = 6.6 Hz), 4.73 (1 H, q, J =
2.0 Hz), 4.59 (1 H, d, J = 6.6 Hz), 4.48 (2 H, s), 4.28 (2 H, s),
3.79 (3 H, s), 3.41 (1 H, d, J = 9.9 Hz), 3.35 (3 H, s), 3.33 (1 H,
d, J = 9.9 Hz), 2.31–2.06 (4 H, m), 1.82 (3 H, d, J = 2 Hz), 0.91
(9 H, s), 0.12 (6 H, s); δC (100 MHz; CDCl3): 158.7, 143.6,
131.6, 128.9, 128.6, 127.7, 127.0, 113.5, 94.6, 88.0, 85.7, 83.9,
79.8, 78.3, 75.3, 69.2, 65.0, 63.9, 56.1, 55.3, 52.0, 31.0, 25.9,
12.9, 3.7, −5.1; m/z 755.3753 (MNa+, C46H56NaO6Si requires
755.3744).
A molar solution of HF.Py (1.65 mL, 1.64 mmol) was added
to a solution of the preceding silyl ether (60 mg, 0.082 mmol) in
anhydrous THF (0.6 mL) at 0 °C. The mixture was stirred at
0 °C for 10 min, warmed to room temperature, then stirred for
1 hour. The reaction was quenched with an aqueous solution of
NaHCO3 and extracted with Et2O (3×). The organic layers were
combined, washed with brine, dried over MgSO4 and the solvent
removed under reduced pressure. The crude residue was purified
by flash chromatography on silica gel (pentane–ethyl acetate
90 : 10) to afford pure 16 (47 mg, 93%) as a colorless oil. [α]D22
+34.9 (c 1.0 in CHCl3); νmax/cm−1 2950, 1510, 1451, 1247,
1033, 755, 706; δH (400 MHz; CDCl3): 7.49–7.18 (17 H, m),
6.81 (2 H, d, J = 8.6 Hz), 4.93 (1 H, d, J = 6.6 Hz), 4.79 (1 H,
q, J = 2.1 Hz), 4.58 (1 H, d, J = 6.6 Hz), 4.49 (2 H, s), 4.19
(2 H, s), 3.79 (3 H, s), 3.38 (1 H, d, J = 8.8 Hz), 3.33 (3 H, s),
3.33 (1 H, d, J = 8.8 Hz), 2.33–2.02 (5 H, m), 1.82 (3 H, d, J =
2.1 Hz); δC (100 MHz; CDCl3): 158.7, 143.6, 131.5, 128.9,
128.5, 127.7, 127.0, 113.5, 94.5, 85.7, 83.9, 79.8, 78.3, 75.3,
69.2, 65.0, 63.9, 56.1, 55.3, 52.0, 31.0, 25.9, 12.9, 3.7, −5.1;
m/z 641.2868 (MNa+, C40H42NaO6 requires 641.2879).
(((S)-2-(4-Methoxybenzyloxy)-2-((S)-1-(methoxymethoxy)but-2-
ynyl)-5-methylhepta-5,6-dienyloxy)methanetriyl)tribenzene (17).
NEt3 (11.6 μL, 0.084 mmol) and MsCl (6.5 μL, 0.084 mmol)
were successively added to a solution of the primary alcohol 16
(47 mg, 0.076 mmol) in anhydrous CH2Cl2 (0.5 mL), at 0 °C,
then the solution was stirred for 1 hour at room temperature. The
mixture was quenched with an aqueous solution of NH4Cl and
extracted with CH2Cl2 (3×). The organic layers were combined,
washed with brine, dried over MgSO4 and the solvent removed
under reduced pressure. The residue was passed through a short
pad of silica gel to afford crude mesylate. To a solution of CuCN
(27 mg, 0.304 mmol) and anhydrous LiCl (26 mg, 0.608 mmol)
in THF (0.3 mL) was gradually added MeLi (1.6 M in Et2O,
0.2 mL, 0.304 mmol) at −78 °C. Then the reaction mixture was
warmed to −20 °C, and the solids dissolved at this temperature.
The reaction mixture was cooled to −78 °C again, and the crude
mesylate was added to the reaction mixture which was further
(6S,7S)-6-(4-Methoxybenzyloxy)-7-(methoxymethoxy)-6-(trityl-
oxymethyl)deca-2,8-diyn-1-ol (16). DIPEA (50 μL, 0.64 mmol)
and MOMCl (130 μL, 0.728 mmol) were successively added to
a solution of alcohol (6S)-15 (200 mg, 0.291 mmol) in
8144 | Org. Biomol. Chem., 2012, 10, 8140–8146
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stirred for 1h30 at this temperature. The reaction mixture was
quenched by addition of saturated aqueous NH4Cl and extracted
with Et2O (5×). The organic layers were combined, washed with
brine, dried over MgSO4 and the solvent removed under reduced
pressure. The crude residue was purified by flash chromato-
graphy on silica gel (pentane/ethyl acetate 98 : 2) to afford pure
allene 17 (35 mg, 75% over 2 steps) as a colorless oil. [α]D22
+50.9 (c 1.0 in CHCl3); νmax/cm−1 2931, 1514, 1248, 1096,
1033, 704; δH (400 MHz; CDCl3): 7.49–7.21 (17 H, m), 6.81
(2 H, d, J = 8.6 Hz), 4.93 (1 H, d, J = 6.6 Hz), 4.71 (1 H, q, J =
2.1 Hz), 4.60 (2 H, m), 4.58 (1 H, d, J = 6.6 Hz), 4.51 (2 H, s),
3.79 (3 H, s), 3.37 (1 H, d, J = 9.9 Hz), 3.36 (1 H, d, J =
9.9 Hz), 3.32 (3 H, s), 2.14–1.94 (3 H, m), 1.82 (3 H, d, J =
2.1 Hz), 1.77–1.72 (1 H, m), 1.64 (3 H, t, J = 3.0 Hz); δC
(100 MHz; CDCl3): 205.8, 158.7, 143.9, 131.9, 129.2, 129.0,
128.8, 127.7, 127.0, 113.6, 99.0, 94.6, 86.7, 83.7, 80.5, 75.6,
74.7, 69.7, 65.1, 64.0, 56.2, 55.3, 29.5, 26.6, 19.2, 3.9; m/z
639.3110 (MNa+, C41H44NaO5 requires 639.3086).
0.140 mmol), DMAP (4.0 mg, 0.035 mmol) and DCC (29 mg,
0.140 mmol) were successively added to a solution of diol 11
(45 mg, 0.116 mmol in anhydrous CH2Cl2 (1.5 mL), at room
temperature. The mixture was stirred for 20 min and was filtered
over a pad of celite. The solvent was removed under reduced
pressure.18 δH (400 MHz; CDCl3): 7.40–7.25 (20 H, m), 4.72
(1 H, s), 4.26 (1 H, d, J = 11.2 Hz), 4.19 (1 H, d, J = 11.2 Hz),
3.38 (3 H, s), 3.06 (1 H, d, J = 9.2 Hz), 2.99 (1 H, d, J =
9.2 Hz), 2.06–1.97 (2 H, m), 1.86 (1 H, t, J = 2.6 Hz),
1.75–1.65 (2 H, m).
(S)-((S)-2-Hydroxy-2-(trityloxymethyl)pent-4-ynyl) 2-methoxy-
2-phenylacetate. (S)-(+)-α-Methoxyphenylacetic acid (29 mg,
0.178 mmol), DMAP (5.0 mg, 0.044 mmol) and DCC (37 mg,
0.178 mmol) were successively added to a solution of diol 11
(57 mg, 0.148 mmol) in anhydrous CH2Cl2 (1.5 mL), at room
temperature. The mixture was stirred for 20 min and was filtered
over a pad of celite. The solvent was removed under reduced
pressure.18 δH (400 MHz; CDCl3): 7.41–7.24 (20 H, m), 4.67
(1 H, s), 4.20 (2 H, s), 3.38 (3 H, s), 3.03 (3H, s), 1.99–1.91
(2 H, m), 1.83 (1 H, t, J = 2.6 Hz), 1.63–1.47 (2 H, m).
(4S,5S)-5-(4-Methoxybenzyloxy)-4-(methoxymethoxy)-3,8-
dimethyl-5-(trityloxymethyl)-4,5,6,7-tetrahydroazulen-2(1H)-one
(18). Protocol 1: Allene 17 (17 mg, 0.028 mmol) was dissolved
in anhydrous toluene (0.3 mL) and the solution was evacuated
and charged with Ar three times and with CO three times; then
[RhCl(cod)]2 (1.4 mg, 0.0028 mmol) and 1,3-bis(diphenylphos-
phino)propane (5.8 mg, 0.014 mmol) were added. The mixture
was refluxed under CO balloon (1 atm) for 5 h. Most of the
solvent was evaporated in vacuo and the resulting concentrated
mixture was filtered through a pad of celite (washings with
ether). The combined filtrates were evaporated in vacuo. The
crude residue was purified by flash chromatography on silica gel
(pentane/ethyl acetate 80 : 20) to yield the title ketone 18
(13.7 mg, 76%) as a colorless oil.
Protocol 2: Allene 17 (13 mg, 0.021 mmol) was dissolved in
anhydrous toluene (0.3 mL) and the solution was evacuated and
charged with argon three times, then with CO three times before
addition of [Rh(CO)2Cl]2 (0.8 mg, 0.002 mmol). The mixture
was heated at 90 °C under CO balloon (1 atm) for 5 h. Most of
the solvent was evaporated in vacuo and the concentrated
mixture filtered through a pad of celite (washings with ether).
The combined filtrates were evaporated in vacuo and the crude
residue purified by flash chromatography on silica gel (pentane–
ethyl acetate 80 : 20) to yield 18 (10.3 mg, 80%) as a colorless
oil. [α]2D2 +36.8 (c 1.0 in CHCl3); νmax/cm−1 2924, 2852, 1694,
1611, 1513, 1449, 1247, 1149, 1097, 1033, 706; δH (400 MHz;
CDCl3): 7.48–7.20 (17 H, m), 6.87 (2 H, d, J = 8.7), 5.18 (1 H,
s), 4.79 (1 H, d, J = 6.7 Hz), 4.60 (1 H, d, J = 11.2 Hz), 4.58
(1 H, d, J = 11.2 Hz), 4.55 (1 H, d, J = 6.7 Hz), 3.81 (3 H, s),
3.30 (1 H, d, J = 10.3 Hz), 3.26 (3 H, s), 3.06 (1 H, d, J =
10.3 Hz), 2.86–2.79 (1 H, d, J = 20.8 Hz), 2.63–2.56 (1 H, d,
J = 20.8 Hz), 2.38–2.29 (1 H, m), 2.05–1.93 (1 H, m),
1.88–1.78 (2 H, m), 1.78 (3 H, s), 1.67 (3 H, s); δC (100 MHz;
CDCl3): 205.4, 160.4, 158.7, 143.2, 141.7, 135.1, 131.7, 129.1,
128.7, 128.2, 127.7, 127.0, 113.6, 95.9, 86.7, 80.4, 75.6, 64.9,
55.3, 40.3, 31.2, 30.3, 23.9, 8.71; m/z 667.3030 (MNa+,
C42H44NaO6 requires 667.3036).
(R)-((4S,5S)-10-(tert-Butyldimethylsilyloxy)-5-(4-methoxy-
benzyloxy)-5-(trityloxymethyl)deca-2,8-diyn-4-yl) 2-methoxy-2-
phenylacetate. (R)-(–)-α-Methoxyphenylacetic acid (5.6 mg,
0.034 mmol), DMAP (1.0 mg, 0.0083 mmol) and DCC (7 mg,
0.034 mmol) were successively added to a solution of alcohol
(6S)-15 (19 mg, 0.028 mmol) in anhydrous CH2Cl2 (1 mL), at
room temperature. The mixture was stirred for 20 min and was
filtered over a pad of celite. The solvent was removed under
reduced pressure.18 δH (400 MHz; CDCl3): 7.48–7.14 (22 H, m),
6.76 (2 H, d, J = 8.7 Hz), 6.00 (1 H, q, J = 2.2 Hz), 4.65 (1 H,
s), 4.26 (2 H, s), 4.21 (2 H, s), 3.78 (3 H, s), 3.34 (3 H, s), 3.30
(1 H, d, J = 9.9 Hz), 3.18 (1 H, d, J = 9.9 Hz), 2.17–1.96 (4 H,
m), 1.70 (3 H, d, J = 2.2 Hz), 0.90 (9 H, s), 0.11 (6 H, s).
(S)-((4S,5S)-10-(tert-Butyldimethylsilyloxy)-5-(4-methoxy-
benzyloxy)-5-(trityloxymethyl)deca-2,8-diyn-4-yl) 2-methoxy-2-
phenylacetate. (S)-(+)-α-Methoxyphenylacetic acid (5.7 mg,
0.035 mmol), DMAP (1.0 mg, 0.0087 mmol) and DCC (7 mg,
0.035 mmol) were successively added to a solution of alcohol
(6S)-15 (20 mg, 0.029 mmol) in anhydrous CH2Cl2 (1 mL), at
room temperature. The mixture was stirred for 20 min and was
filtered over a pad of celite. The solvent was removed under
reduced pressure.18 δH (400 MHz; CDCl3): 7.48–7.14 (22 H, m),
6.76 (2 H, d, J = 8.7 Hz), 6.04 (1 H, q, J = 2.2 Hz), 4.79 (1 H,
s), 4.25 (2 H, s), 4.09 (2 H, s), 3.78 (3 H, s), 3.35 (3 H, s), 3.20
(2 H, s), 2.21–2.02 (4 H, m), 1.78 (3 H, d, J = 2.2 Hz), 0.91
(9 H, s), 0.11 (6 H, s).
Acknowledgements
A. T. and M. J. thank ANR for doctoral fellowships (ANR
Thaser 2010). We thank Elise Prost for assistance with NMR
experiments.
Notes and references
(R)-((S)-2-Hydroxy-2-(trityloxymethyl)pent-4-ynyl) 2-methoxy-
2-phenylacetate. (R)-(–)-α-Methoxyphenylacetic acid (23 mg,
1 A. Ghantous, H. Gali-Muhtasib, H. Vuorela, N. A. Saliba and
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This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8140–8146 | 8145

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chromatography and TBDPS (tert-butyldiphenylsilyl) ether led to signifi-
cant lower yields than trityl ether (45% versus 75%) when subjected to
Sharpless epoxidation.
17 The ee (90%) and absolute configuration of 11 have been confirmed
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phenylacetic acid (MPA) esters, proving the absence of Payne
rearrangement.
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19 This modest regioselectivity is surprising but consistent with several lit-
erature results. Comparable (or even worse) regioselectivities were
reported when the primary alcohol function of similar acetal core was
protected by
a sterically bulky group (for instance TBDPS).
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20 D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155.
21 Recently, at the time when the present study was in progress in our lab-
oratories, Brummond described the synthesis of racemic 6,12-guaianolide
systems relatively close to our targets using an A.P.K. strategy11d
.
8146 | Org. Biomol. Chem., 2012, 10, 8140–8146
This journal is © The Royal Society of Chemistry 2012