A concise approach for the synthesis of bitungolides: Total syntheses of (-)-bitungolide B & e

Article abstract of DOI:10.1039/c4ob00250d

The first total synthesis of (-)-bitungolide B and a second-generation total synthesis of (-)-bitungolide E are described. The cornerstone of the approach comprises a convergent and flexible route involving Brown crotylation, highly diastereoselective sub

Full text of DOI:10.1039/c4ob00250d

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A concise approach for the synthesis of
bitungolides: total syntheses of (−)-bitungolide
B & E†
Cite this: Org. Biomol. Chem., 2014,
12, 4002
K. Mahender Reddy, J. Shashidhar and Subhash Ghosh*
The first total synthesis of (−)-bitungolide B and a second-generation total synthesis of (−)-bitungolide E
are described. The cornerstone of the approach comprises a convergent and flexible route involving
Brown crotylation, highly diastereoselective substrate controlled Paterson anti-aldol reaction, hydroxyl-
directed 1,3-syn/anti reduction, Barton–McCombie deoxygenation and RCM reactions. Via this route,
a common intermediate 13 is readily accessible for the synthesis of the family of bitungolides A–E and
franklinolides A–C.
Received 3rd February 2014,
Accepted 25th March 2014
DOI: 10.1039/c4ob00250d
www.rsc.org/obc
Introduction
Marine organisms have produced a wide range of biologically
active and structurally complex secondary metabolites. Bitun-
golides A–F are new examples of such secondary metabolites
isolated from an Indonesian sponge Theonella cf. swinhoei by
Tanaka et al. in 2002 (Fig. 1).1
Bitungolides comprise a complex structure and a unique
family of polyketides that display cytotoxic activity against 3Y1
rat normal fibroblast cells and also inhibit the dual specificity
phosphatase VHR. The structure of bitungolides B–F were
assigned by inference from the single crystal X-ray analysis of
bitungolide A; however, the absolute stereochemistry of bitun-
golide E and bitungolide F was confirmed through their total
synthesis by us and others.2,3 Recently Zhang et al. reported
the isolation of three phosphodiester derivatives of bitungo-
lides A, B and D called franklinolides A–C from an Australian
sponge sample CMB-01989.4 Franklinolides displayed cytotoxi-
city against a human brain cancer cell line. This phosphodi-
ester engenders the potent cytotoxic activity in franklinolides.
Bitungolides have attracted considerable attention from both
the synthetic and pharmacological communities, due to their
intriguing structure and potent cytotoxic activities. So far one
total synthesis of (−)-bitungolide E2b and three total syntheses
of (−)-bitungolide F2a,3 have been achieved. However to date
no total syntheses of bitungolides A–D or the phosphodiester
derivatives of bitungolides A, B and D, franklinolides A–C,
Fig. 1 Structure of (+)-bitungolides, franklinolides.
have been reported. Fascinated by the complex architecture as
well as the interesting biological profile of the bitungolides
and franklinolides, we wanted to develop a synthetic strategy
by which all the congeners of bitungolides A–E and franklino-
lides A–C could be synthesized. In this article we report the
total synthesis of (−)-bitungolides B and E via common key
intermediate 13.
Fine Chemicals Laboratory, CSIR-Indian Institute of Chemical Technology,
Results and discussion
Hyderabad-500 007, India. E-mail: subhash@iict.res.in; Fax: +91-40-27191604;
Tel: +91-40-27191609
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra. See DOI: 10.1039/c4ob00250d
Structural inspection of bitungolide B and bitungolide E
revealed that they possess similar structural features except for
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Scheme 1 Retrosynthetic analysis of (−)-bitungolide B and E.
the aromatic ring attached to the E,E-diene unit. In the case of known procedure, provided the desired β-hydroxy ketone 18 in
bitungolide B the phenyl ring contains chlorine and hydroxyl 85% yield, with a diastereomeric ratio of (20 : 1). In order to fix
groups whereas in the case of bitungolide E it is a simple the C5 stereocenter in the final molecule, hydroxyl ketone 18
phenyl ring. Thus retrosynthetically (−)-bitungolide B and was subjected to hydroxy-directed 1,3-syn reduction (Table 1)
(−)-bitungolide E could be derived from the α,β-unsaturated with Et2BOMe10 and NaBH4 in THF–MeOH (5 : 1), at −78 °C
δ-lactones 9a and 9b (Scheme 1) via desilylation followed by (entry 1). However to our surprise, the reduction of the ketone
Evans–Saksena reduction. The α,β-unsaturated δ-lactones 9a did not proceed at all. On the other hand reduction with
11
and 9b would be accessible through ring-closing metathesis of Zn(BH4)2 provided the reduced product but the yield and
bis-olefinic compounds 10a and 10b respectively. The bis- selectivity were very poor (entry 2). Gratifyingly we found cate-
olefinic compounds 10a and 10b might be obtained via DDQ- cholborane,12 in THF, at −78 °C to −20 °C, reduced hydroxy
mediated allylic alcohol oxidation, concomitant PMB deprotec- ketone 18 to 1,3-syn diol 19 (entry 3) with good yield (86%) and
tion of 11a and 11b followed by acrylation of the resulting high selectivity (95% de). The 1,3-syn relationship was con-
hydroxy keto compounds. The E,E-diene unit in 11a and 11b firmed via the Rychnovsky method.13a,b DDQ-mediated
could be introduced through the addition of ene-yne com- rearrangement of the PMB ether14 afforded secondary alcohol
pounds 12a and 12b to an aldehyde obtained from alcohol 13 20, which on deoxygenation under Barton–McCombie con-
followed by Red-Al reduction of the resulting propargyl ditions15 yielded the deoxy compound 21 in 90% yield over
alcohols. Common intermediate 13 could be obtained by two steps. Regioselective opening of the p-methoxybenzylidene
means of substrate-controlled Paterson anti-aldol reaction acetal with DIBAL-H16 from the less hindered side afforded
between aldehyde 14 and ketone 15.
primary alcohol 22 in 90% yield. Oxidation of the primary
Synthesis of common intermediate alcohol 13 started from alcohol 22 furnished an aldehyde, which on Julia–Kocienski
known compound 16 (Scheme 2).5 Oxidation of alcohol 16 olefination17 with 25 gave olefinic compound 23. Selective TBS
furnished an aldehyde, which on Grignard reaction with deprotection of 23 provided common intermediate 13. The
EtMgBr followed by hydrogenolysis of the benzyl ether gave a overall sequence proceeded in 14 steps from 16 with an overall
diol. Subsequent selective protection of the primary hydroxyl yield of 27.8%. Thus, this highly functionalised core 13, which
as the PMB ether6 followed by Dess–Martin periodinane oxi- is a common moiety present in (−)-bitungolides A–E and
dation7 of the secondary alcohol afforded ketone 15. The franklinolides A–C, can be accessed in multi-gram quantities
highly diastereoselective addition of the boron enolate gen- via a set of high yielding chemical transformations. Finally
erated from ketone 15 under Paterson conditions8 to known Parikh–Doering oxidation18 of 13 completed the synthesis of
aldehyde 149 prepared from aldehyde 17 according to the aldehyde fragment 24.
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Scheme 2 Synthesis of the common intermediate 13. Reagents and conditions: (1) (a) DMP, CH2Cl2, 0 °C, 2 h; (b) EtMgBr, THF, 0 °C, 2 h; (c) H2, Pd/C,
MeOH, rt, 1 h; (d) PMBCl, NaH, DMF 0 °C, 3 h; (e) DMP, CH2Cl2, 0 °C, 2 h, 72% over five steps; (2) (c-C6H11)2BCl, Et3N, Et2O, 0 °C, 2 h, then 14,
−78 °C to −20 °C, 14 h, 85%; (3) catecholborane THF, −78 °C to −20 °C, 12 h, 86%; (4) DDQ, 4 Å, MS, CH2Cl2, −10 °C, 2 h, 90%; (5) (a) NaHMDS, CS2
MeI, THF, −78 °C, 2 h; (b) nBu3SnH, AIBN, 120 °C, 1 h, 90% over two steps; (6) DIBAL-H, CH2Cl2, −40 °C to −10 °C, 2 h, 90%; (7) (a) SO3·Py, Et3N,
CH2Cl2–DMSO (0.9 : 1.0), 0 °C 1.5 h, (b) 25, NaHMDS, THF, −78 °C to rt, 18 h, 78% over two steps; (8) HF·Py, THF, 0 °C to rt, 20 h, 93%; (9) SO3·Py,
Et3N, CH2Cl2–DMSO (0.9 : 1.0), 0 °C, 1.5 h, quantitative.
Table 1 Different reagents and conditions screened for the reduction of the C5 ketone
Entry
Conditions
Time
24 h
6 h
Temperature
–78 °C
Result
1
Et2B-OMe (1.2 eq.), NaBH4 (1.2 eq.)
THF–MeOH (5 : 1)
Zn(BH4)2 (0.2 M in Et2O, 10 eq.), CH2Cl2
No reaction, starting material recovered
2a
–40 °C
40% yield based on recovered starting
material, 80% de
3
Catecholborane (1 M, 10 eq.), THF
12 h
–78 °C to −20 °C
86% yield, 95% de
a In Zn(BH4)2 reaction a considerable amount of diol was complexed with Zn salts; stirring with silica gel in EtOAc for 5 h led to decomplexation
and recovery of the required diol compound.
Synthesis of ene-yne fragment 12a is depicted in Scheme 3. on Red-Al reduction23 followed by DDQ-mediated one pot oxi-
Protection of the commercially available known aldehyde 26 as dation of the resulting allylic alcohol24 and PMB-deprotection
the TBS ether followed by Horner–Wadsworth–Emmons olefi- afforded the E,E-diene compound 30 in 60% yield over three
nation19 yielded α,β-unsaturated ester 27, which on DIBAL-H steps.
reduction afforded allylic alcohol 28. DMP oxidation of allylic
Next, acylation of 30 was carried out with acryloyl chloride
alcohol 28 furnished an aldehyde 29. Initial attempts to make to give the bis-olefinic compound 10a in 85% yield. Ring-
alkyne 12a from aldehyde 29 by Corey–Fuchs reaction20 or by closing metathesis25 of bis-olefinic compound 10a afforded
Ohira–Bestmann protocol21 did not yield satisfactory results. 9a. TBS deprotection of 9a gave β-hydroxy ketone 31, which on
On the other hand, aldehyde 29 via Colvin rearrangement22 in Evans–Saksena reduction26 furnished (−)-bitungolide B (7).
the presence of TMSCHN2, LDA in THF at reflux temperature, Similar to our previous observations, during the syntheses of
provided the desired ene-yne 12a in 75% yield over two steps.
other bitungolides E and F2, the spectral data of 7 were identi-
After achieving the fragments aldehyde 24 and ene-yne 12a, cal with those reported for the natural product except for the
the final synthesis of (−)-bitungolide B was planned by assem- specific rotation which was comparable in magnitude but
bling the fragments as depicted in Scheme 4. Addition of the opposite in sign {[α]2D5 = –44.3 (c 0.3, CHCl3); lit.1 [α]D27 = +42
anion generated from compound 12a to the aldehyde 24 (c 4.2, CHCl3)}. (−)-Bitungolide E (Scheme 5) was synthesized
yielded a diastereomeric mixture of propargylic alcohols which from aldehyde 24 and ene-yne 12b via the same sequence as
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Scheme 3 Synthesis of ene-yne fragment 12a. Reagents and conditions: (1) (a) TBSCl, imidazole, THF, 0 °C, 2 h; (b) NaH, THF, −78 °C 1 h 89% over
two steps; (2) DIBAL-H, CH2Cl2, −78 °C to 0 °C, 1 h, 93%; (3) DMP, CH2Cl2, 0 °C, 2 h; (4) TMSCH2N2, LDA THF, −78 °C, 1 h then reflux for 3 h, 75%
over two steps.
Scheme 4 Synthesis of (−)-bitungolide B. Reagents and conditions: (1) (a) 12a, nBuLi, THF, −78 °C, 2 h; (b) Red-Al, THF, 0 °C, 1 h; (c) DDQ, CHCl3,
buffer, 0 °C, 1 h, 60% over three steps; (2) Acryloyl chloride, Et3N, CH2Cl2, 0 °C, 2 h, 85%; (3) Grubbs 1st generation catalyst, CH2Cl2, 40 °C, 20 h,
85%; (4) HF–Py, CH3CN, rt, 48 h, 80%; (5) Me4NHB(OAc)3, acetone–AcOH (1 : 1), −25 °C, 3 h, 78%.
Scheme 5 Synthesis of (−)-bitungolide E. Reagents and conditions: (1) (a) 12b, n-BuLi, −78 °C, then aldehyde 24, 45 min; (b) Red-Al, dry THF, 0 °C
to rt, 1 h; (c) DDQ, CHCl3 pH 7 buffer (20 : 1), 0 °C, 10 min, 46% over 4 steps; (2) acryloyl chloride, Et3N, CH2Cl2, 0 °C to rt, 1 h, 79%; (3) G-1 catalyst,
CH2Cl2, reflux, 20 h, 80%; (4) HF–Py complex, CH3CN, 0 °C to rt, 15 h, 88%; (5) Me4NBH(OAc)3, CH3CN–AcOH (1 : 1), −20 °C, 3 h, 84%.
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used for the synthesis of (−)-bitungolide B with an overall yield obtained aldehyde was purified by column chromatography,
of 6.0% This entails a longest linear sequence of 21 steps, and was used in the next step without further characterization.
in comparison with our first generation synthesis2b of
To a stirred solution of the above crude aldehyde in THF
(−)-bitungolide E which was achieved in 26 steps with an (120 mL) was added EtMgBr (123 mL, 1 M in THF, 123 mmol)
overall yield of 2.5%.
at 0 °C under N2 atmosphere and the mixture was stirred for
45 min. The reaction was quenched with water (20 mL) and
diluted with EtOAc (200 mL). The layers were separated and
the aqueous phase was further extracted with EtOAc (2 ×
100 mL). The combined organic extracts were washed with
Conclusion
In conclusion we have achieved the first total synthesis of brine (10 mL), dried over Na2SO4, and concentrated under
(−)-bitungolide B (22 longest linear sequence from 16, 7.5%), vacuum to afford a diastereomeric mixture of alcohols which
and the second generation total synthesis of (−)-bitungolide E was used directly for the next reaction.
(22 longest linear sequence, 5.97%). The common intermedi-
ate 13 for bitungolides and potent cytotoxic franklinolides was (100 mL) was added Pd/C (1 g) and it was subjected to hydro-
synthesized via highly diastereoselective substrate controlled genation under atmospheric pressure using H2-filled
To this crude diastereomeric mixture of alcohols in EtOAc
a
anti-aldol reaction as a key step in multigram quantities. This balloon. After 2 h, the reaction mixture was filtered through a
strategy developed here is highly convergent and can be used short pad of celite and the filter cake was washed with EtOAc.
for the synthesis of other congeners of bitungolides, franklino- The filtrate and washings were combined and concentrated
lides and their analogs for biological studies. Presently we are under vacuum to afford the crude 1,3-diols, which were used
working in that direction.
directly in the next reaction.
To a stirred solution of the above crude diol in DMF
(200 mL) was added NaH (1.4 g, 33.99 mmol) at rt under N2
atmosphere. After 75 min of stirring at rt, PMBCl (4.6 mL,
33.99 mmol) was added very slowly to the reaction mixture and
stirred for another 30 min. Then the reaction mixture was
Experimental section
General experimental methods
All the reactions were performed under nitrogen or argon quenched with saturated NH4Cl (5 mL) and extracted with
atmosphere in oven-dried glass apparatus under magnetic stir- EtOAc (200 mL). The organic extract was washed with brine
ring. Anhydrous solvents were dried and distilled by standard (15 mL), dried over Na2SO4, and concentrated under vacuum
methods. Commercially available reagents were used without to afford a diastereomeric mixture of secondary alcohols,
further purification unless otherwise noted. Column chrom- which was used directly in the next step.
atography was carried out using silica gel (60–120 or
To a stirred solution of the above crude secondary alcohol
100–200 mesh) packed in glass columns. 1H NMR and 13C in anhydrous CH2Cl2 (85 mL) was added Dess–Martin periodi-
NMR were recorded in CDCl3 solvent on 300 MHz, 400 MHz, nane (13 g, 30.93 mmol) at 0 °C under N2 atmosphere and the
500 MHz and 75 MHz, 100 MHz, 125 MHz spectrometers, mixture was stirred for 45 min at rt. Then the reaction mixture
respectively, using TMS as an internal standard. Chemical was quenched with saturated aqueous NaHCO3 (15 mL) and
shifts are measured as ppm values relative to internal CHCl3 saturated Na2S2O3 (15 mL) and extracted with EtOAc (2 ×
1
δ 7.26 or TMS δ 0.0 for H NMR and CHCl3 δ 77 for 13C NMR. 250 mL). The combined organic extracts were washed with
In 1H NMR the multiplicity is defined as: s = singlet; d = brine (15 mL), dried over Na2SO4, filtered and concentrated
doublet; t = triplet; q = quartet; dd = doublet of doublets; ddd in vacuo. The crude residue was purified by column chromato-
= doublet of double of doublets; dt = doublet of triplets; m = graphy (SiO2, 5% EtOAc–hexane) to afford 15 (5.5 g, 72% over
multiplet; brs = broad singlet. Optical rotation values were five steps) as a colourless oil. Rf 0.6 (10% EtOAc in hexanes);
recorded on a Horiba sepa 300 polarimeter using a 2 mL cell [α]2D5 = –16.42 (c 2.1 in CHCl3); IR (neat): νmax 2965, 2868, 1710,
with a 10 mm path length. FTIR spectra were recorded on an 1512, 1460, 1246, 1174, 1088, 1033, 819 cm−1 1H NMR
;
Alpha (Bruker) infrared spectrophotometer. High resolution (500 MHz, CDCl3) δ = 7.2 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.6 Hz,
mass spectra (HRMS) [ESI+] were obtained using either a TOF 2H), 4.39 (ABq, J = 12.6 Hz, 2H), 3.79 (s, 3H), 3.57 (dd, J = 8.9,
or a double focusing spectrometer.
8.7 Hz, 1H), 3.46 (dd, J = 9.0, 5.2 Hz, 1H), 2.76 (m, 1H),
Synthesis of (R)-4-((4-methoxybenzyloxy)methyl)hexan-3-one 2.56–2.40 (m, 2H), 1.60 (dq, J = 15.2, 7.6 Hz, 1H), 1.44 (dq, J =
(15). To a stirred solution of 16 (6 g, 30.93 mmol) in anhy- 14.9, 7.4 Hz, 1H), 1.03 (t, J = 7.3 Hz, 3H), 0.85 (t, J = 7.4 Hz,
drous CH2Cl2 (100 mL) was added Dess–Martin periodinane 3H). 13C NMR (125 MHz, CDCl3) δ 213.9, 159.1, 130.2, 129.1
(13 g, 30.93 mmol) at 0 °C under N2 atmosphere and the (2C), 113.7 (2C), 72.8, 70.9, 55.2, 53.5, 36.6, 21.8, 11.7, 7.4.
moxture was stirred for 45 min at room temperature. The reac- HRMS (ESI) m/z [M + Na]+ calcd for C15H22O3Na 273.1461,
tion mixture was quenched with saturated aqueous NaHCO3 found 273.1459.
(15 mL), saturated aqueous Na2S2O3 (15 mL) and extracted with
Synthesis of (3R,5R,6R,7R,8S)-8,10-bis(tert-butyldimethyl-
EtOAc (2 × 250 mL). The combined organic extracts were silyloxy)-6-hydroxy-3-((4-methoxybenzyloxy)methyl)-5,7-dimethyl
washed with water (20 mL), brine (20 mL), dried over Na2SO4 decan-4-one (18). To a solution of chlorodicyclohexylborane
and concentrated under vacuum, which gave the aldehyde. The (13.9 mL, 13.9 mmol) in anhydrous ether (30 mL) at −78 °C
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were added dropwise triethylamine (2.4 mL, 16.75 mmol) fol-
(2R,3S,4R,5S)-5,7-Bis(tert-butyldimethylsilyloxy)-2-((4S,5R)-5-
lowed by ketone 15 (2.4 g, 9.31 mmol) in ether (15 mL) via ethyl-2-(4-methoxyphenyl)-1,3-dioxan-4-yl)-4-methylheptan-3-ol
cannula. The milky mixture was stirred at 0 °C for 2.5 h. Then (20). To a solution of 19 (2.5 g, 4.08 mmol) in CH2Cl2 contain-
the solution was again cooled to −78 °C before slow addition ing 4 Å MS (3.2 g) was treated with DDQ (1.4 g, 6.12 mmol) at
of aldehyde 14 (5 g, 13.97 mmol) in anhydrous ether (15 mL) −10 °C. After stirring for 2 h at the same temperature, the reac-
via cannula and the resulting solution was stirred for 2 h at tion was quenched with saturated aqueous NaHCO3 solution
the same temperature. Then the reaction mixture was kept at (10 mL) and extracted with EtOAc (2 × 100 mL). The organic
−25 °C overnight and after that it was stirred at 0 °C for extract was washed with water (2 × 10 mL), brine (10 mL),
30 min and monitored by TLC. After completion of the reac- dried over Na2SO4, filtered and concentrated in vacuo. The
tion, it was quenched successively with MeOH (26 mL), pH = 7 residue was purified by column chromatography (SiO2, 5–6%
buffer (26 mL), H2O2 (50%) (26 mL) and it was stirred for EtOAc–hexane) to afford 20 (2.2 g, 90%) as a colourless liquid.
another 30 min at room temperature and extracted with EtOAc Rf 0.6 (10% EtOAc–hexanes); [α]2D5 = +35.5 (c 0.45 in CHCl3); IR
(2 × 100 mL). The combined organic extracts were washed (neat): νmax 3522, 2955, 2930, 2855, 1741, 1517, 1464, 1250,
sequentially with water (20 mL), brine (20 mL) and dried over 1086, 834, 775 cm−1; 1H NMR (500 MHz, CDCl3) δ = 7.31 (d, J =
Na2SO4. The organic extracts were concentrated under vacuum 8.9 Hz, 2H), 6.83 (d, J = 7.9 Hz, 2H), 5.44 (s, 1H), 4.28 (d, J =
and the residue was purified by column chromatography (SiO2, 10.8 Hz, 1H), 3.90 (m, 1H), 3.85–3.81 (m, 3H), 3.80 (s, 3H),
60–120 mesh, 7% EtOAc–hexane) to afford 18 (4.76 g, 85%) as 3.71–3.59 (m, 2H), 3.56 (brs, OH), 1.97– 1.85 (m, 2H), 1.75 (m,
a colorless oil. Rf 0.5 (10% EtOAc in hexanes); [α]2D5 = –4.6 (c 3.0 1H), 1.70–1.64 (m, 2H), 1.57 (m, 1H), 1.39 (m, 1H), 1.04 (t, J =
in CHCl3); IR (neat): νmax 3481 (br), 2930, 2858, 1711, 1513, 6.9 Hz, 3H), 0.9 (s, 9H), 0.88 (s, 9H), 0.83 (d, J = 6.9 Hz, 3H),
1463, 1251, 1092, 1035, 1007, 836, 776 cm−1
;
1H NMR 0.75 (d, J = 6.9 Hz, 3H), 0.05 (s, 6H), 0.03 (s, 6H). 13C NMR
(300 MHz, CDCl3) δ = 7.21 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 8.9 (75 MHz, CDCl3) δ 160, 130.8, 127.3 (2C), 113.7 (2C), 102.1,
Hz, 2H), 4.41 (ABq, J = 10.8 Hz, 2H), 4.16 (d, J = 9.8 Hz, 1H), 86.9, 73.8, 72.3, 69.6, 59.5, 55.3, 39.4, 37.4, 37.12, 37.05, 25.99
3.99 (m, 1H), 3.80 (s, 3H), 3.51–3.68 (m, 4H), 3.41 (brs, OH), (3C), 25.96 (3C), 18.3, 18.1, 16.6, 12.0, 11.4, 9.4, −4.4, −4.8,
2.88 (m, 1H), 2.82 (m, 1H), 1.94–1.80 (m, 2H), 1.75–1.63 (m, −5.3 (2C). HRMS (ESI) m/z [M + Na]+ calcd for C33H62NaO6Si2
2H), 1.43 (m, 1H), 0.98 (d, J = 6.9 Hz, 3H), 0.92–0.86 (m, 24H), 633.3977, found 633.3979.
0.09 (s, 6H), 0.04 (s, 3H), 0.03 (s, 3H). 13C NMR (75 MHz,
(5S)-5-((2R,4R)-4-((4R,5R)-5-Ethyl-2-(4-methoxyphenyl)-1,3-
CDCl3) δ 216.7, 159.1, 130.3, 129.1 (2C), 113.7 (2C), 75.3, 72.9, dioxan-4-yl)pentan-2-yl)-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-
72.8, 70.3, 59.6, 55.2, 54.2, 49.3, 37.5, 35.7, 25.9 (6C), 21.1, 3,9-disilaundecane (21). To a stirred solution of 20 (2 g,
18.2, 17.9, 12.8, 11.8, 10.6, −4.4, −4.8, −5.4, −5.5. HRMS (ESI) 3.28 mmol) in anhydrous THF (15 mL) at −78 °C was added
m/z [M + Na]+ calcd for C33H62NaO6Si2 633.3977, found 1 M NaHMDS (32.8 mL, 32.8 mmol) and the reaction mixture
633.3985.
was stirred at the same temperature for 30 min. CS2 (4 mL,
Synthesis of (3R,4S,5S,6S,7R,8S)-8,10-bis(tert-butyldimethyl- 65.6 mmol) was added to that solution and stirred for 30 min
silyloxy)-3-((4-methoxybenzyloxy)methyl)-5,7-dimethyldecane- at −78 °C. Then MeI (6.2 mL, 98.4 mmol) was added to that
4,6-diol (19). A stirred solution of compound 18 (4 g, reaction mixture and stirred for 15 min at the same tempera-
6.55 mmol) in THF (50 mL) at −40 °C was treated with cate- ture. It was quenched by addition of H2O (5 mL) and extracted
cholborane (65 mL, 1 M in THF, 65.0 mmol). After stirring for with EtOAc (2 × 50 mL). The organic extract was washed with
12 h at −40 °C the reaction mixture was quenched with MeOH water (10 mL), brine (10 mL), dried over (Na2SO4), filtered and
and extracted with EtOAc (2 × 100 mL). The organic extract was concentrated under vacuum to afford the methyl xanthate
washed with 3 N NaOH (2 × 50 mL), followed by water (20 mL), derivative, which was used immediately in the next step
brine (20 mL), dried over Na2SO4 and concentrated under without further purification.
vacuum. The residue was purified by column chromatography
The crude methyl xanthate derivative, Bu3SnH (5 mL) and a
(SiO2, 10% EtOAc–hexanes) to afford 19 (3.4 g, 86%) as a color- catalytic amount of AIBN (0.4 g, 0.32 mmol) were taken in a
less oil. Rf 0.4 (10% EtOAc in hexanes); [α]2D5 = –9.3 (c 1.7 in round bottomed flask and the mixture was heated at 120 °C
CHCl3); IR (neat): νmax 3619 (br), 3422 (br), 2954, 2932, 2859, for 1 h. It was then quenched with H2O (5 mL). The reaction
1513, 1464, 1250, 1089, 1037, 1006, 834, 775 cm−1 1H NMR mixture was extracted with EtOAc (2 × 30 mL). The combined
;
(300 MHz, CDCl3) δ = 7.28 (d, J = 9.0 Hz, 2H), 6.87 (d, J = organic extracts were washed with water (5 mL), brine (5 mL),
8.3 Hz, 2H), 4.47 (ABq, J = 11.3 Hz, 2H), 4.04–3.95 (m, 2H), dried over Na2SO4, filtered and concentrated under vacuum.
3.85 (dd, J = 9.0, 1.5 Hz, 1H), 3.80 (s, 3H), 3.69–3.48 (m, 4H), The residue was purified by column chromatography (SiO2 3%
1.92–1.65 (m, 5H), 1.50 (m, 1H), 1.32 (m, 1H), 1.01 (d, J = EtOAc–hexane) to afford 21 (1.7 g, 90% over two steps) as a col-
6.8 Hz, 3H), 0.93 (t, J = 6.8 Hz, 3H), 0.89 (s, 18H), 0.68 (d, J = orless liquid. Rf 0.5 (5% EtOAc in hexanes); [α]2D5 = +26.3 (c 1.1
6.8 Hz, 3H), 0.1 (s, 6H), 0.04 (s, 3H), 0.03 (s, 3H). 13C NMR in CHCl3); IR (neat): νmax 2956, 2933, 2856, 1516, 1464, 1250,
(75 MHz, CDCl3) δ 159.0, 130.9, 129.1 (2C), 113.6 (2C), 77.3, 1093, 833, 775 cm−1; 1H NMR (300 MHz, CDCl3) δ = 7.39 (d, J =
76.9, 75.9, 72.9, 71.5, 59.5, 55.2, 42.7, 37.8, 37.7, 36.1, 25.86 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.43 (s, 1H), 4.28 (m, 1H),
(3C), 25.80 (3C), 18.2, 17.9, 17.6, 12.8, 12.7, 11.1, −4.5, −4.9, 3.88 (m, 1H), 3.80 (s, 3H), 3.73–3.57 (m, 3H), 3.41 (m, 1H),
−5.4, −5.5. HRMS (ESI) m/z [M + H]+ calcd for C33H65O6Si2 1.75–1.44 (m, 3H), 1.38–1.15 (m, 6H), 0.98 (t, J = 7.5 Hz, 3H),
613.4314, found 613.4315.
0.94–0.81 (m, 21H), 0.78 (d, J = 6.8 Hz, 3H), 0.03 (s, 12H).
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13C NMR (75 MHz, CDCl3) δ 159.6, 131.8, 127.1 (2C), 113.4 23 (0.54 g, 78% over two steps) as yellow oil. Rf 0.3 (5% EtOAc
(2C), 101.5, 85.6, 73.7, 69.3, 60.5, 55.2, 37.2, 35.95, 35.89, 35.6, in hexanes); [α]2D2 = −12.64 (c 1.15, CHCl3). IR (neat): νmax 2960,
31.6, 25.95 (3C), 25.91 (3C), 18.3, 18.1, 16.3, 14.1, 14, 12, −4.4, 2921, 2823, 1564, 1411, 1248 and 1034 cm−1 1H NMR
;
−4.5, −5.25, −5.29. HRMS (ESI) m/z [M + Na]+ calcd for (500 MHz, CDCl3) δ = 7.27 (d, J = 7.8 Hz, 2H), 6.86 (d, J = 8 Hz,
C33H62NaO5Si2 617.4028, found 617.4032. 2H), 5.54 (dt, J = 17.0, 10.1 Hz, 1H), 5.04 (dd, J = 10.0, 2.0 Hz,
(2R,3R,4R,6R,7S)-7,9-Bis(tert-Butyldimethylsilyloxy)-2-ethyl- 1H), 4.99 (dd, J = 17.0, 2.0 Hz, 1H), 4.51 (ABq, J = 11.0 Hz, 2H),
3-(4-methoxybenzyloxy)-4,6-dimethylnonan-1-ol (22). To 3.80 (s, 3H), 3.68 (m, 1H), 3.65–3.58 (m, 2H), 3.09 (dd, J = 7.0,
a
solution of 21 (1 g, 1.68 mmol) in anhydrous CH2Cl2 (10 mL) 4.0 Hz, 1H), 2.17 (m, 1H), 1.82–1.74 (m, 2H), 1.64–1.54 (m,
at −40 °C, DIBAL-H (6.8 mL, 1.0 M in toluene, 6.72 mmol) was 2H), 1.31–1.18 (m, 3H), 1.12 (m, 1H), 0.94 (d, J = 7 Hz, 3H),
added dropwise and stirred at that temperature for 2 h. The 0.89 (s, 9H), 0.88 (s, 9H), 0.83 (t, J = 8 Hz, 3H), 0.78 (d, J = 7 Hz,
reaction was then quenched by slow addition of anhydrous 3H), 0.04 (s, 6H), 0.03 (s, 3H), 0.02 (s, 3H). 13C NMR (75 MHz,
MeOH (0.5 mL), followed by saturated sodium potassium tar- CDCl3) δ 158.9, 140.2, 131.3, 129.0 (2C), 115.9, 113.6 (2C), 87.7,
trate solution. The reaction mixture was stirred (∼2 h) until 74.9, 73.7, 60.6, 55.2, 49.6, 36.0, 35.2, 33.3, 33.2, 25.96 (3C),
two clear layers separated. The organic layer was separated out 25.9(3C), 22.9, 18.3, 18.1, 17.3, 13.5, 11.8, −4.4, −4.6, −5.3(2C).
and the aqueous layer was extracted with EtOAc (2 × 50 mL). HRMS(ESIMS) m/z [M
The combined organic extracts were washed sequentially with 615.4240, found: 615.4238.
water (10 mL), brine (10 mL), dried over Na2SO4, filtered and (3S,4R,6R,7R,8R)-3-(tert-Butyldimethylsilyloxy)-8-ethyl-7-(4-
+
Na]+: calcd for C34H64O4NaSi2
concentrated under vacuum. The residue was purified by methoxybenzyloxy)-4,6-dimethyldec-9-en-1-ol (13). To the solu-
column chromatography (SiO2 12% EtOAc–hexane) to afford tion of 23 (0.3 g, 0.50 mmol) in anhydrous THF (3.5 mL) in a
22 (0.9 g, 90%) as a colorless liquid. Rf 0.3 (15% EtOAc in polypropylene vial, was added HF–py complex (40%, 0.06 mL)
hexanes); [α]2D5 = –4.35 (c 0.85 in CHCl3); IR (neat): νmax 3442, at 0 °C. The reaction mixture was slowly warmed to rt and
2928, 2857, 1514, 1464, 1384, 1250, 1090, 1040, 943, 835, stirred for 20 h. Then it was cautiously poured into saturated
1
775 cm−1; H NMR (300 MHz, CDCl3) δ = 7.25 (d, J = 8.5 Hz, NaHCO3 solution and stirred for 30 min. Then both the layers
2H), 6.86 (d, J = 8.5 Hz, 2H), 4.52 (ABq, J = 10.7 Hz, 2H), 3.80 were separated and the aqueous layer was further extracted
(s, 3H), 3.74–3.58 (m, 5H), 3.37 (dd, J = 6.4, 3.5 Hz, 1H), 2.02 with EtOAc (2 × 20 mL). The combined organic layers were
(brs, 1H), 1.85 (m, 1H), 1.75–1.47 (m, 5H), 1.37–1.19 (m, 3H), washed with saturated CuSO4 (20 mL), water (10 mL), brine
0.97–0.81 (m, 27H), 0.04 (brs, 12H). 13C NMR (75 MHz, CDCl3) (10 mL) and dried over Na2SO4. The solvent was evaporated
δ 159.1, 130.8, 129.3 (2C), 113.7 (2C), 85.8, 73.8, 73.5, 63.6, under vacuum. The residue was purified by column chromato-
60.3, 55.2, 44.0, 36.0, 35.4, 35.3, 32.7, 25.94 (3C), 25.89 (3C), graphy (SiO2, 18% EtOAc–hexanes) to afford 13 (220 mg, 93%
18.8, 18.3, 18.1, 16.7, 13.7, 12.5, −4.4, −4.5, −5.3, −5.4. HRMS yield) as a colourless viscous liquid. Rf 0.2 (10% EtOAc in
(ESI) m/z [M + Na]+ calcd for C33H64NaO5Si2 619.4184, found hexanes); [α]D22 = +6.21 (c 1.00, CHCl3). IR (neat): νmax 3542 (br),
619.4186.
2938, 2867, 1524, 1474, 1364, 1270, 1090, 953, 845, 775 cm−1
(S)-5-((2R,4R,5R,6R)-6-Ethyl-5-(4-Methoxybenzyloxy)-4-methyl- 1H NMR (500 MHz, CDCl3) δ 7.26 (d, J = 8.5 Hz, 2H), 6.87 (d,
oct-7-en-2-yl)-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-di- J = 8.5 Hz, 2H), 5.54 (dt, J = 17.0, 10.0 Hz, 1H), 5.06 (dd, J =
silaundecane (23). To a stirred solution of the alcohol 22 10.0, 1.7 Hz, 1H), 5.0 (dd, J = 17.2, 1.7 Hz, 1H), 4.51 (ABq, J =
(0.7 g, 1.17 mmol) in anhydrous CH2Cl2 (5 mL) at 0 °C, anhy- 11.0 Hz, 2H), 3.80 (s, 3H), 3.75–3.65 (m, 3H), 3.10 (dd, J = 7.7,
drous DMSO (4 mL), Et3N (0.9 mL, 5.85 mmol) and SO3–py 3.4 Hz, 1H), 2.17 (m, 1H), 1.85–1.73 (m, 2H), 1.71–1.57 (m,
complex (0.93 g, 5.85 mmol) were added sequentially under N2 3H), 1.29–1.18 (m, 2H), 1.12 (m, 1H), 0.95 (d, J = 6.8 Hz,
atmosphere and was stirred for 1 h. Saturated aqueous NH4Cl 3H), 0.89 (s, 9H), 0.84 (t, J = 7.7 Hz, 3H), 0.78 (d, J = 6.8 Hz,
(5 mL) was added and extracted with EtOAc (2 × 30 mL). The 3H), 0.08 (s, 3H), 0.06 (s, 3H). 13C NMR (CDCl3, 75 MHz):
combined organic extracts were washed with water (5 mL), δ 159.0, 140.0, 131.1, 129.1 (2C), 116.0, 113.6 (2C), 87.6,
brine (5 mL), and dried over anhydrous Na2SO4. Evaporation 76.3, 75.1, 61.0, 55.2, 49.7, 35.9, 33.6, 33.4, 33.2, 25.8
of the solvent furnished the crude aldehyde, which was passed (3C), 22.8, 17.9, 17.4, 12.8, 11.7, −4.3, −4.7. HRMS (ESI) m/z
through a short pad of silica gel and used as such for the next [M
+
Na]+ calcd for C28H50O4NaSi 501.3376, found:
reaction.
To the stirred solution of sulfone (0.78 g, 3.51 mmol) in
501.3373.
(E)-Ethyl
3-(3-(tert-butyldimethylsilyloxy)-2-chlorophenyl)-
THF (12 mL) at −78 °C was added NaHMDS (2.3 mL, 1 M in acrylate (27). To a stirred solution of commercially available
THF, 2.34 mmol) under an argon atmosphere. After 26 (2 g, 12.7 mmol) in anhydrous THF (80 mL) at 0 °C were
30 minutes the crude aldehyde in THF (6 mL) was added at added imidazole (2 g, 29.2 mmol) and TBSCl (2.5 g,
−78 °C to the reaction mixture. The reaction mixture was 16.99 mmol) sequentially under N2 atmosphere. After 2 h of
gradually warmed to room temperature and stirred for 18 h. stirring at rt, the reaction mixture was quenched with saturated
Then the reaction was quenched with water (5 mL) and NH4Cl (15 mL) and extracted with EtOAc (2 × 100 mL). The
extracted with EtOAc (2 × 50 mL). The combined organic combined organic extract was washed with brine (15 mL),
extract was washed with brine (10 mL), dried over Na2SO4, and dried over Na2SO4, filtered and concentrated under vacuum.
concentrated under vacuum. The residue was purified by The residue was used immediately in the next reaction without
column chromatography (SiO2, 3% EtOAc–hexanes) to afford further purification.
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To a stirred solution of NaH (0.76 g, 19.5 mmol) in THF under reduced pressure and purification of the residue on a
(60 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (4.3 g, silica gel column gave an aldehyde which was used directly for
19.5 mmol) at 0 °C under N2 atmosphere and stirred for the next reaction.
45 min. Then the reaction mixture was cooled to −78 °C and
To a solution of diisopropylamine (0.4 mL, 2.82 mmol) in
to that was added the above crude 3-(tert-butyldimethylsilyl- anhydrous THF (8 mL) was added n-butyllithium (1.6 M in
oxy)-2-chlorobenzaldehyde in THF (20 mL) via cannula. After hexane, 1.8 mL 2.82 mmol) at −78 °C and the mixture was
30 min, the reaction mixture was quenched with saturated stirred for 30 min. TMSCHN2 (2 M in hexanes, 1.4 mL,
NH4Cl (10 mL) solution and allowed to attain room tempera- 2.82 mmol) was added to the reaction mixture and stirred for
ture. The reaction mixture was extracted with EtOAc (2 × another 30 min. A solution of crude aldehyde prepared above
100 mL). The combined organic extract was washed with brine in THF (15 mL) was then added to the reaction mixture and
(15 mL), dried over Na2SO4 and concentrated under vacuum. stirred for 1 h at −78° C and 3 h at reflux temperature. Cold
The residue was purified by column chromatography (SiO2, 4% water (10 mL) was added and extracted with ether (2 × 50 mL).
EtOAc–hexanes) to afford 27 (3.8 g, 89% yield) as a yellow The combined organic extracts were washed with water
viscous liquid. Rf 0.5 (10% EtOAc in hexanes); IR (neat): νmax (10 mL), brine (10 mL), dried over Na2SO4 and concentrated
2955, 2859, 1737, 1695, 1573, 1464, 1291, 1237, 1045, 990, 831, under vacuum. The residue was purified by column chromato-
780 cm−1 1H NMR (500 MHz, CDCl3) δ = 8.11 (d, J = 16 Hz, graphy (SiO2, 1% EtOAc–hexanes) to afford 12a (0.514 g, 75%
;
1H), 7.23 (dd, J = 7.7, 1.0 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.91 yield over two steps) as a clear yellow oil. Rf 0.5 (5% EtOAc in
(dd, J = 7.7, 1.0 Hz, 1H), 6.40 (d, J = 16 Hz, 1H), 4.28 (q, J = hexanes); IR (neat): νmax 2930, 2857, 1570, 1466, 1288, 1253,
1
7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H), 1.04 (s, 9H), 0.23 (s, 6H). 998, 838, 781, 681 cm−1; H NMR (500 MHz, CDCl3) δ = 7.47
13C NMR (75 MHz, CDCl3) δ 166.5, 152.1, 141, 134.3, 126.9, (d, J = 16.1 Hz, 1H), 7.14 (dd, J = 7.9, 1.5 Hz, 1H), 7.09 (t, J =
121.5, 120.8, 120, 126.6, 60.6, 25.6 (3C), 19.3, 14.3, −4.4 (2C). 7.9 Hz, 1H), 6.84 (dd, J = 7.9, 1.5 Hz, 1H), 6.1 (dd, J = 16.3,
HRMS (ESI) m/z [M + H]+ calcd for C17H26O3ClSi 341.1334, 2.3 Hz, 1H), 3.1 (d, J = 2.3 Hz, 1H), 1.04 (s, 9H), 0.23 (s, 6H).
found 341.1313.
13C NMR (75 MHz, CDCl3) δ 152, 139.6, 135.6, 126.8, 125.1,
(E)-3-(3-(tert-Butyldimethylsilyloxy)-2-chlorophenyl)prop-2- 120.4, 118.7, 109.5, 82.6, 79.8, 25.6 (3C), 18.3, −4.4 (2C); MS
en-1-ol (28). To a solution of 27 (1.5 g, 4.41 mmol) in anhy- (EI) m/z 292 (M +). Anal. Calcd for C16H21ClOSi: C, 65.62;
drous CH2Cl2 (35 mL) at −78 °C was added DIBAL-H (1.0 M in H, 7.23; found: C, 64.97; H, 7.39.
toluene, 11 mL, 11.0 mmol) and the mixture was stirred at that
temperature for 15 min. Then the reaction mixture was slowly (tert-butyldimethylsilyloxy)-2-chlorophenyl)-12-ethyl-11-hydroxy-
warmed to 0 °C and stirred for 1 h. The reaction was then 8,10-dimethyltetradeca-1,3,13-trien-5-one (30). To stirred
(1E,3E,7S,8R,10R,11R,12R)-7-(tert-Butyldimethylsilyloxy)-1-(3-
a
quenched by slow addition of a few drops MeOH followed by solution of the alcohol 13 (0.170 g, 0.35 mmol) in anhydrous
saturated aqueous sodium potassium tartrate solution. The CH2Cl2 (5 mL) at 0 °C, anhydrous DMSO (4 mL), Et3N
reaction mixture was stirred (∼2 h) until two clear layers separ- (0.25 mL, 1.78 mmol) and SO3–Py complex (0.283 g,
ated and was then extracted with EtOAc (2 × 50 mL). The com- 1.78 mmol) were added sequentially under N2 atmosphere and
bined organic extract was washed with water (5 mL), brine the mixture was stirred for 45 min. Saturated aqueous NH4Cl
(5 mL), dried over Na2SO4, filtered and concentrated under (5 mL) was added and extracted with EtOAc (2 × 30 mL). The
vacuum. The residue was purified by column chromatography combined organic extracts were washed with water (5 mL),
(SiO2, 10% EtOAc–hexanes) to afford 28 (1.17 g, 93% yield) as a brine (5 mL), and dried over anhydrous Na2SO4. Evaporation
colorless liquid. Rf 0.2 (10% EtOAc in hexanes); IR (neat): νmax of the solvent furnished the crude aldehyde, which was passed
3338, 2930, 2858, 1570, 1466, 1288, 1254, 1020, 841, 782, through a short pad of silica gel and used as such for the next
680 cm−1
;
1H NMR (500 MHz, CDCl3) δ = 7.13 (dd, J = 7.7, reaction.
A solution of 12a (91.0 mg, 0.71 mmol) in anhydrous THF
1.0 Hz, 1H), 7.05 (t, J = 7.9 Hz, 1H), 7.0 (td, J = 16.2, 1.0 Hz,
1H), 6.79 (dd, J = 7.9, 1.3 Hz, 1H), 6.3 (td, J = 15.8, 5.6 Hz, 1H), (3 mL) at −78 °C was treated with n-BuLi (1.6 M in hexane,
4.33 (dd, J = 5.6, 1.5 Hz, 2H), 1.04 (s, 9H), 0.23 (s, 6H). 13C 0.44 mL, 0.71 mmol) and stirred for 40 min. A solution of the
NMR (75 MHz, CDCl3) δ 151.7, 136.5, 131.4, 127.5, 126.6, aldehyde prepared above in anhydrous THF (3 mL) was added
124.8, 119.4, 119.2, 63.4, 25.6 (3C), 18.3, −4.4 (2C). HRMS (ESI) to the reaction mixture and stirred for 1 h. The reaction
m/z [M + Na]+ calcd for C15H23O2ClNaSi 321.1048, found mixture was then quenched with saturated aqueous NH4Cl
321.1044.
(5 mL) solution at 0 °C and extracted with EtOAc (2 × 40 mL).
(E)-(3-(But-1-en-3-ynyl)-2-chlorophenoxy)(tert-butyl)dimethyl- The combined organic extracts were washed with water (5 mL)
silane (12a). To a solution of the alcohol 28 (0.7 g, 2.35 mmol) brine (5 mL) and dried over Na2SO4. Evaporation of the solvent
in anhydrous CH2Cl2 (10 mL) at 0 °C was added Dess–Martin under reduced pressure and purification of the residue via
periodinane (1.5 g, 3.45 mmol) under N2 atmosphere and the column chromatography (SiO2, 7% EtOAc–hexanes) afforded a
mixture was stirred for 45 min at rt. Saturated NaHCO3 mixture of diastereomeric alcohols (0.23 g, 88% yield), which
(10 mL) and saturated Na2S2O3 (10 mL) were added to the reac- were used directly for the next reaction.
tion mixture and extracted with EtOAc (2 × 50 mL). The com-
To a solution of the above diastereomeric mixture of alco-
bined organic extracts were washed with water (10 mL), brine hols (0.23 g, 0.308 mmol) in anhydrous THF (5 mL) at 0 °C
(10 mL) and dried over Na2SO4. Evaporation of the solvent was added Red-Al (3.46 M in toluene, 0.24 mL, 0.83 mmol)
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and the mixture was stirred at rt for 1 h. The reaction mixture (m, 1H), 1.94–1.73 (m, 2H), 1.06–0.98 (m, 13H), 0.91–0.76 (m,
was then quenched with MeOH (2 mL) and saturated aqueous 18H), 0.23 (s, 6H), 0.04 (s, 3H), 0.02 (s, 3H). 13C NMR (75 MHz,
potassium sodium tartrate solution (5 mL) at 0 °C. The reac- CDCl3) δ 199.9, 166.3, 152.2, 142.7, 138.0, 137.5, 135.6, 131.7,
tion mixture was allowed to stir at rt until two layers separated 130.7, 129.1, 128.6, 126.8, 125.8, 120.6, 119.3, 117.2, 80.0, 74.0,
and it was extracted with EtOAc (2 × 40 mL). The combined 48.1, 43.8, 36.4, 32.1, 31.6, 25.9 (3C), 25.6 (3C), 23.0, 18.3, 18.0,
organic extracts were washed with water (5 mL), brine (5 mL), 16.7, 13.7, 11.4, −4.3, −4.5, −4.7. HRMS (ESI) m/z [M + H]+
dried over Na2SO4, and concentrated under vacuum. Purifi- calcd for C39H64O5ClSi2 703.3975, found 703.3980.
cation of the residue by column chromatography (SiO2, 6%
EtOAc–hexanes) afforded the diene compound as a mixture of 11-(3-(tert-butyldimethylsilyloxy)-2-chlorophenyl)-4-methyl-7-
diastereomers (0.195 g, 85% yield). oxoundeca-8,10-dien-2-yl)-5-ethyl-5,6-dihydro-2H-pyran-2-one
(5R,6R)-6-((2R,4R,5S,8E,10E)-5-(tert-Butyldimethylsilyloxy)-
To a stirred solution of the mixture of dienes (40.0 mg, (9a). A solution of 10a (50 mg, 0.071 mmol) in anhydrous
0.066 mmol) in CHCl3 and pH = 7 phosphate buffer (20 : 1, CH2Cl2 (26 mL) was degassed and Grubbs’ first generation
4 mL) at 0 °C, DDQ (30 mg, 0.13 mmol) was added and stirred catalyst (10 mg, 0.0071 mmol) was added under nitrogen
for 1 h at 0 °C. The reaction was then quenched with saturated atmosphere. The resulting pale purple solution was heated to
aqueous NaHCO3 (5 mL) solution and extracted with EtOAc reflux (50 °C) for 20 h. The solvent was evaporated under
(2 × 20 mL). The combined organic extracts were washed with vacuum and the crude residue was purified by column chrom-
water (5 mL), brine (5 mL), dried over Na2SO4 and concen- atography (SiO2, 15% EtOAc–hexanes) to give 9a (40 mg, 85%
trated under vacuum. The residue was purified by column yield) as a clear oil. Rf 0.4 (10% EtOAc in hexanes); [α]2D5 = –45.4
chromatography (SiO2, 12% EtOAc–hexanes) to afford 30 (c 0.5 in CHCl3); IR (neat): νmax 3100, 2917, 2750, 1186, 1013,
1
(135 mg, 60% yield over four steps) as a clear oil. Rf 0.4 (10% and 1094, 835, 775 cm−1; H NMR (500 MHz, CDCl3) δ = 7.41
EtOAc in hexanes); [α]2D5 = –5.3 (c 0.8 in CHCl3); IR (neat): νmax (d, J = 16.0 Hz, 1H), 7.35 (dd, J = 16.0, 11.0 Hz, 1H), 7.24 (m,
3412 (br), 2970, 2860, 2361, 1676, 1526, 1463, 1190, 845, 1H), 7.14–7.04 (m, 2H), 6.88–6.81 (m, 2H), 6.31 (d, J = 15 Hz,
1
775 cm−1; H NMR (500 MHz, CDCl3) δ = 7.41 (d, J = 15.3 Hz, 1H), 6.04 (d, J = 10 Hz, 1H), 4.14 (m, 1H), 3.94 (dd, J = 11.0,
1H), 7.36–7.23 (m, 2H), 7.12 (t, J = 8 Hz, 1H), 6.87–6.80 (m, 3.0 Hz, 1H), 2.86 (dd, J = 15.0, 8.0 Hz, 1H), 2.46 (dd, J = 15.0,
2H), 6.30 (d, J = 15.3 Hz, 1H), 5.52 (dt, J = 17.7, 10.5 Hz, 1H), 3.0 Hz, 1H), 2.35 (m, 1H), 1.9 (m, 1H), 1.78–1.46 (m, 5H), 1.04
5.09 (dd, J = 10.2, 1.6 Hz, 1H), 5.02 (dd, J = 17.7, 1.6 Hz, 1H), (s, 9H), 0.97 (t, J = 8.0 Hz, 3H), 0.9–0.82 (m, 15H), 0.24 (s, 6H),
4.15 (m, 1H), 3.29 (m, 1H), 2.83 (m, 1H), 2.48 (dd, J = 14.5, 0.06 (s, 3H), 0.03 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 200,
4.0 Hz, 1H), 2.06 (m, 1H), 1.81–1.61 (m, 3H), 1.36–1.08 (m, 164.8, 150.9, 142.7, 138.4, 137.4, 131.7, 130.8, 129.1, 128.7,
3H), 1.04 (s, 9H), 0.92 (d, J = 6.4 Hz, 3H), 0.89–0.84 (m, 15H), 126.7, 120.9, 120.5, 119.3, 84.7, 73.7, 42.9, 36.7, 36.4, 35.7,
0.24 (s, 6H), 0.05 (s, 3H), 0.02 (s, 3H). 13C NMR (75 MHz, 31.5, 25.8(3C), 25.6(3C), 23.7, 18.0, 14.7, 14.0, 13.3, 11.0, −4.3
CDCl3) δ 200, 152.1, 142.7, 140.9, 139.2, 137.4, 135.7, 131.6, (2C), −4.7 (2C). HRMS (ESI) m/z [M + H]+ calcd C37H60O5ClSi2
129.1, 126.8, 120.5, 119.3, 116.4, 79.0, 74.1, 49.6, 43.6, 36.4, 674.3589, found 674.3586.
32.7, 31.3, 25.8(3C), 25.6(3C), 22.6, 18.3, 18.0, 16.9, 13.9, 11.5,
−4.4, −4.6, −4.7(2C). HRMS (ESI) m/z [M + Na]+ calcd for 5-hydroxy-4-methyl-7-oxoundeca-8,10-dien-2-yl)-5-ethyl-5,6-
C36H61O4ClNaSi2 671.3694, found 671.3697. dihydro-2H-pyran-2-one (31). To a solution of 9a (20 mg,
(5R,6R)-6-((2R,4R,5S,8E,10E)-11-(2-Chloro-3-hydroxyphenyl)-
(3R,4R,5R,7R,8S,11E,13E)-8-(tert-Butyldimethylsilyloxy)-14-(3- 0.0296 mmol) in anhydrous CH3CN (3 mL) in a polypropylene
(tert-butyldimethylsilyloxy)-2-chlorophenyl)-3-ethyl-5,7-dimethyl- vial was added HF–Py complex (70%, 2.20 µl) at 0 °C. The reac-
10-oxotetradeca-1,11,13-trien-4-yl acrylate (10a). To a stirred tion was slowly warmed to rt and stirred for 48 h. After com-
solution of 30 (80 mg, 0.123 mmol) in anhydrous CH2Cl2 pletion of the reaction, it was cautiously poured into aqueous
(3 mL) at 0 °C, Et3N (0.05 mL, 0.369 mmol) and acryloyl chlor- NaHCO3 (5 mL) solution and stirred for 30 min and extracted
ide (0.01 mL, 0.246 mmol) were added sequentially under with EtOAc (2 × 10 mL). The combined organic extracts were
nitrogen atmosphere and the mixture was stirred at the same washed with saturated CuSO4 (5 mL) solution, water (5 mL),
temperature for 2 h. Then it was quenched with water (2 mL) brine (5 mL), dried over Na2SO4, filtered and concentrated
and extracted with EtOAc (2 × 30 mL). The organic extract was under vacuum. The residue was purified by column chromato-
washed with saturated NaHCO3 (5 mL), brine (5 mL), dried graphy (SiO2, 24% EtOAc in hexanes) to afford 31 (10.5 mg,
over Na2SO4, filtered and concentrated under vacuum. The 80% yield) as colourless oil. Rf 0.5 (40% EtOAc in hexanes);
residue was purified by column chromatography (SiO2, 7% [α]2D5 = –91.3 (c 0.3 in CHCl3); IR (neat): νmax 3403 (br), 3300
EtOAc–hexanes) provided 10a (73 mg, 85% yield) as a colorless (br), 2917, 2850, 1246, 1093, 1034, 835, 775 cm−1 1H NMR
;
oil. Rf 0.6 (10% EtOAc in hexanes); [α]2D5 = –11.2 (c 0.7 in (300 MHz, CDCl3) δ = 7.41 (dd, J = 15.2, 11.0 Hz, 1H), 7.35 (d,
CHCl3); IR (neat): νmax 2970, 2890, 2361, 1646, 1516, 1463, J = 15.2 Hz, 1H), 7.25–7.16 (m, 2H), 7.11–6.96 (m, 2H), 6.88
1
1190, 840, 774 cm−1; H NMR (300 MHz, CDCl3) δ = 7.44–7.23 (dd, J = 15.9, 11.0 Hz, 1H), 6.32 (d, J = 15.9 Hz, 1H), 6.05 (d, J =
(m, 2H), 7.12 (m, 1H), 6.89–6.80 (m, 2H), 6.41 (dd, J = 17.3, 9.8 Hz, 1H), 3.98 (dd, J = 9.6, 2.0 Hz, 1H), 3.94 (m, 1H),
1.6 Hz, 1H), 6.31 (d, J = 15.8 Hz, 1H), 6.15 (dd, J = 17.3, 10.5 2.87–2.67 (m, 2H), 2.40–2.28 (m, 2H), 1.95 (m, 1H), 1.62 (m,
Hz, 1H), 5.83 (dd, J = 9.8, 1.5 Hz, 1H), 5.46 (m, 1H), 5.14–5.0 4H), 0.93 (m, 9H). 13C NMR (75 MHz, CDCl3) δ 201.4, 165.0,
(m, 2H), 4.91 (dd, J = 9.0, 3.0 Hz, 1H), 4.16–4.07 (m, 2H), 2.83 151.2, 143.0, 138.8, 137.2, 136.0, 130.7, 129.3, 127.7, 127.6,
(dd, J = 15.1, 8.3 Hz, 1H), 2.47 (dd, J = 15.1, 3.7 Hz, 1H), 2.27 120.8, 118.6, 116.4, 84.9, 72.1, 42.4, 36.6, 35.4, 35.0, 31.1, 20.1,
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14.3, 13.9, 11.0. HRMS (ESI) m/z [M + H]+ calcd for C25H32O5Cl thesized as a clear oil from 32 (40 mg, 0.082 mmol) via the
447.1938, found 447.1935. same procedure as described for the synthesis of 10a. Rf = 0.50
(5R,6R)-6-((2R,4R,5S,7S,8E,10E)-11-(2-Chloro-3-hydroxyphenyl)- (SiO2, 8% EtOAc–hexanes); [α]2D5 = +93.84 (c 0.18, CHCl3); IR
5,7-dihydroxy-4-methylundeca-8,10-dien-2-yl)-5-ethyl-5,6-dihydro- (neat): νmax 2928, 2855, 1720, 1648, 1616, 1580, 1460, 1260,
2H-pyran-2-one, {(−)-bitungolide B} (7). To a solution of 31 1192, and 1066 cm−1; 1H NMR (CDCl3, 300 MHz) δ = 7.53–7.44
(8 mg, 0.018 mmol) in anhydrous CH3CN (1.5 mL) at −30 °C (m, 2H), 7.43–7.30 (m, 4H), 7.04–6.78 (m, 2H), 6.44 (dd, J =
were added Me4NBH(OAc)3 (19.7 mg, 0.075 mmol) and glacial 17.2, 1.6 Hz, 1H), 6.30 (d, J = 15.6 Hz, 1H), 6.14 (dd, J = 17.2,
AcOH (1.5 mL) sequentially. The temperature of the reaction 9.9 Hz, 1H), 5.84 (dd, J = 9.9, 1.6 Hz, 2H), 5.46 (ddd, J = 17.2,
was slowly raised to −20 °C, and stirring was continued at this 9.8, 9.0 Hz, 1H), 5.11 (dd, J = 10.7, 2.5 Hz, 1H), 4.96 (m, 1H),
temperature for 3 h. Then the reaction mixture was quenched 4.12 (m, 1H), 2.82 (dd, J = 14.8, 8.2 Hz, 1H), 2.46 (dd, J = 14.8,
with saturated potassium sodium tartrate (2 mL) at 0 °C and 4.1 Hz, 1H), 2.25 (m, 1H), 1.80 (m, 1H), 1.66–1.35 (m, 5H),
stirred at rt for 1 h. The reaction mixture was extracted with 0.91–0.75 (m, 18H), 0.04 (s, 3H), −0.04 (s, 3H); 13C NMR
EtOAc (3 × 5 mL). The combined organic extracts were washed (CDCl3, 75 MHz): δ 200.0, 166.3, 142.9, 141.4, 137.9, 136.0,
with saturated aqueous NaHCO3 (2 mL), water (2 mL), brine 130.8, 130.7, 129.1, 128.8, 128.5, 127.2, 126.7, 117.2, 80.0, 74.0,
(2 mL), dried over Na2SO4, filtered and concentrated under 48.0, 43.9, 36.3, 32.0, 31.6, 25.8, 23.0, 18.0, 16.6, 13.6, 11.4,
vacuum. The residue was purified by column chromatography −4.7, −4.6; HRMS (ESI) m/z calcd for C33H50O4NaSi [M + Na]+:
(SiO2, 40% EtOAc–hexanes) to afford 7 (6 mg, 78% yield) as a 561.3376, found: 561.3369.
white amorphous solid. Rf 0.5 (60% EtOAc in hexanes); [α]D25
– 44.3 (c 0.3 in CHCl3); IR (neat): νmax 3403 (br), 3380 (br), methyl-7-oxo-11-phenylundeca-8,10-dien-2-yl)-5-ethyl-5,6-
2917, 2850, 1701, 1246, 1093, 1034, 830 cm−1 1H NMR dihydro-2H-pyran-2-one (9b). Compound 9b (18 mg, 80%
=
(5R,6R)-6-((2R,4R,5S,8E,10E)-5-(tert-Butyldimethylsilyloxy)-4-
;
(500 MHz, CDCl3) δ = 7.16 (m, 1H), 7.14 (m, 1H), 7.07 (dd, J = yield) was synthesized as a clear oil from 10b (25 mg,
9.8, 6.7 Hz, 1H), 6.90 (m, 1H), 6.88 (d, J = 15.3 Hz, 1H), 6.78 0.046 mmol) via the same procedure as described for the syn-
(dd, J = 14.8, 9.8 Hz, 1H), 6.52 (ddd, J = 15.8, 9.9, 1.9 Hz, 1H), thesis of compound 9a. Rf = 0.43 (SiO2, 15% EtOAc–hexanes);
6.05 (d, J = 9.8 Hz, 1H), 5.96 (dd, J = 15.3, 5.9 Hz, 1H), 5.66 [α]2D5 = −112.20 (c 0.14, CHCl3); IR (neat): νmax 2926, 2855, 1722,
(brs, OH), 4.61 (m, 1H), 3.97 (dd, J = 10.8, 2.9 Hz, 1H), 3.79 (m, 1616, 1589, 1461, 1382, 1250, and 1062 cm−1; 1H NMR (CDCl3,
1H), 2.68 (brs, OH), 2.43 (brs, OH), 2.36 (m, 1H), 1.95 (m, 1H), 300 MHz): δ 7.53–7.42 (m, 2H), 7.42–7.27 (m, 4H), 7.08 (dd, J =
1.84–1.66 (m, 5H), 1.5 (m, 1H), 1.20 (ddd, J = 12.8, 10.8, 1.9 Hz, 9.8, 6.0 Hz, 1H), 7.02–6.82 (m, 2H), 6.29 (d, J = 15.1 Hz, 1H),
1H), 0.96 (t, J = 7.9 Hz, 3H), 0.91 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 6.05 (d, J = 9.8 Hz, 1H), 4.14 (m, 1H), 3.94 (dd, J = 9.8, 3.0 Hz,
6.9 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 164.8, 151.6, 151.1, 1H), 2.85 (dd, J = 14.3, 8.3 Hz, 1H), 2.44 (dd, J = 14.3, 3.0 Hz,
137.8, 135.8, 131.3, 129.9, 128.0, 127.5, 120.9, 119.1, 118.1, 1H), 2.34 (m, 1H), 1.97–1.43 (m, 6H), 0.97 (t, J = 7.3 Hz, 3H),
114.7, 85.0, 73.4, 70.3, 38.8, 36.7, 36.1, 35.2, 31.0, 20.1, 14.7, 0.95 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H), 0.84 (s, 9H),
14.6, 11.0. HRMS (ESI) m/z [M + Na]+: calcd for C25H33O5ClNa 0.05 (s, 3H), −0.04 (s, 3H); 13C NMR (CDCl3, 75 MHz):
471.1908, found 471.1912.
δ 200.0, 164.8, 150.9, 142.9, 141.2, 136.1, 130.9, 129.0,
(1E,3E,7S,8R,10R,11R,12R)-7-(tert-Butyldimethylsilyloxy)-12- 128.7, 127.2, 126.8, 120.9, 84.7, 73.7, 42.9, 36.7, 36.4,
ethyl-11-hydroxy-8,10-dimethyl-1-phenyltetradeca-1,3,13-trien- 35.7, 31.4, 25.8, 22.6, 17.9, 14.6, 13.3, 10.9, −4.7; HRMS (ESI)
5-one (32). Compound 32 (50 mg, 45% over four steps) was m/z calcd for C31H46O4NaSi [M + Na]+: 533.3630, found:
synthesized as a clear oil from 12b (91.0 mg, 0.71 mmol) and 533.3638.
aldehyde 24 (150 mg, 0.30 mmol) by following the same pro-
(5R,6R)-5-Ethyl-6-((2R,4R,5S,8E,10E)-5-hydroxy-4-methyl-7-
cedure as described for the synthesis of compound 30. Rf 0.27 oxo-11-phenylundeca-8,10-dien-2-yl)-5,6-dihydro-2H-pyran-2-
(SiO2, 10% EtOAc–hexanes); [α]2D5 = +42.61 (c 0.21, CHCl3); IR one (33). Compound 33 (9.5 mg, 88% yield) was synthesized
(neat): νmax 3400 (br), 2925, 2855, 1515, 1587, 1461, 1252, and as a clear oil from 9b (14 mg, 0.027 mmol) by following the
1
1066 cm−1; H NMR (CDCl3, 300 MHz): δ = 7.25–7.43 (m, 2H), same procedure as described for compound 31. Rf = 0.32 (SiO2,
7.41–7.27 (m, 4H), 7.01–6.82 (m, 2H), 6.30 (d, J = 15.5 Hz, 1H), 20% EtOAc–hexanes); [α]2D5 = −180 (c 0.14, CHCl3); IR (neat):
5.51 (ddd, J = 17.1, 10.4, 9.2 Hz, 1H), 5.09 (dd, J = 10.4, 2.0 Hz, νmax 3474(br), 2924, 2868, 1715, 1615, 1585, 1458, 1382, 1252
1H), 5.03 (dd, J = 10.4, 2.0 Hz, 1H) 4.14 (dt, J = 8.3, 3.7 Hz, 1H), and 1060 cm−1 1H NMR (CDCl3, 500 MHz): δ 7.51–7.43 (m,
;
3.28 (dd, J = 7.9, 3.7 Hz, 1H), 2.81 (dd, J = 14.5, 8.3 Hz, 1H), 2H), 7.42–7.28 (m, 4H), 7.05 (dd, J = 9.8, 6.8 Hz, 1H), 7.01 (d,
2.46 (dd, J = 14.5, 3.7 Hz, 1H), 2.06 (m, 1H), 1.85–1.58 (m, 6H), J = 15.7 Hz, 1H), 6.87 (dd, J = 14.7, 10.8 Hz, 1H), 6.27 (d, J =
0.91 (d, J = 6.8 Hz, 3H), 0.89–0.84 (m, 15H), 0.04 (s, 3H), −0.04 15.7 Hz, 1H), 6.04 (d, J = 9.8 Hz, 1H), 3.96 (dd, J = 10.8, 2.9 Hz,
(s, 3H); 13C NMR (CDCl3, 75 MHz) δ 200.0, 142.9, 141.3, 139.2, 1H), 3.92 (m, 1H), 2.82 (dd, J = 16.7, 2.0 Hz, 1H), 2.66 (dd, J =
136.0, 130.8, 129.1, 128.8, 127.2, 126.7, 116.4, 79.0, 74.1, 49.7, 16.7, 9.8 Hz, 1H), 2.34 (m, 1H), 1.95 (m, 1H), 1.84–1.66 (m,
43.8, 36.4, 32.7, 31.3, 25.8, 22.6, 18.0, 17.0, 13.8, 11.6, −4.6, 3H), 1.65–1.47 (m, 2H), 1.00 (t, J = 7.8 Hz, 3H), 0.95 (d, J =
−4.7; HRMS (ESI) m/z calcd for C30H48O3NaSi [M + Na]+: 5.9 Hz, 0.95 (d, J = 5.9 Hz, 3H), 0.91 (d, J = 5.9 Hz, 3H); 13C
507.3270, found: 507.3272.
NMR (CDCl3, 150 MHz): δ 201.7, 165.1, 151.3, 143.8, 142.3,
(3R,4R,5R,7R,8S,11E,13E)-8-(tert-Butyldimethylsilyloxy)-3- 135.8, 129.6, 129.4, 128.9, 127.4, 126.4, 121.0, 85.0, 72.3, 42.3,
ethyl-5,7-dimethyl-10-oxo-14-phenyltetradeca-1,11,13-trien-4-yl 36.7, 35.0, 31.2, 20.2, 14.5, 14.1, 13.7, 10.8; HRMS (ESI) m/z
acrylate (10b). Compound 10b (34 mg, 79% yield) was syn- calcd for C25H32O4Na [M + Na]+: 419.2198, found: 419.2197.
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(5R,6R)-6-((2R,4R,5S,7S,8E,10E)-5,7-Dihydroxy-4-methyl-11-
8 (a) C. J. Cowden and I. Paterson, Org. React., 1997, 51, 1;
(b) I. Paterson, K. Ashton, R. Britton and H. Knust, Org.
Lett., 2003, 5, 963.
9 J. D. White, J. Hong and L. A. Robarge, J. Org. Chem., 1999,
64, 6206.
phenylundeca-8,10-dien-2-yl)-5-ethyl-5,6-dihydro-2H-pyran-2-
one, {(−)-bitungolide E} (8). Compound 8 (5 mg, 84% yield)
was synthesized as a clear oil from 33 (7 mg, 0.0176) via the
same procedure as described for the synthesis of 7. Rf = 0.46
(SiO2, 40% EtOAc–hexanes); [α]2D5 = −104.82 (c 0.2, CHCl3); IR 10 K. Chen, G. E. Hardtmann, K. Prasad, O. Repic and
(neat): νmax 3404 (br), 2960, 2924, 2855, 1713, 1459, 1384,
M. J. Shapiro, Tetrahedron Lett., 1987, 28, 155.
1
1258, and 1059 cm−1; H NMR (CDCl3, 500 MHz): δ 7.39 (br d, 11 F. Arikan, J. Li and D. Menche, Org. Lett., 2008, 10, 3521.
J = 7.3 Hz, 2H), 7.31 (t, J = 7.3 Hz, 2H), 7.22 (br t, J = 7.3 Hz, 12 (a) D. A. Evans and A. H. Hoveyda, J. Org. Chem., 1990, 55,
1H), 7.08 (dd, J = 9.5, 6.6 Hz, 1H), 6.78 (dd, J = 15.4, 10.3 Hz,
1H), 6.56 (br d, J = 15.4 Hz, 1H), 6.46 (dd, J = 15.4, 10.3 Hz,
5190; (b) I. Paterson, C. Watson, K. S. Yeung, P. A. Wallace
and R. A. Ward, J. Org. Chem., 1997, 62, 452.
1H), 6.04 (d, J = 9.6 Hz, 1H), 5.90 (dd, J = 15.4, 5.9 Hz, 1H), 13 (a) D. J. Skalitzky and S. D. Rychnovsky, Tetrahedron Lett.,
4.61 (m, 1H), 3.97 (dd, J = 10.3, 2.9 Hz, 1H), 3.80 (m, 1H), 2.36
(m, 1H), 1.95 (m, 1H), 1.84–1.76 (m, 2H), 1.72–1.68 (m, 3H),
1.49 (m, 1H), 1.20 (m, 1H), 0.96 (t, J = 7.4 Hz, 3H), 0.91 (d, J =
6.6 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3,
75 MHz): δ 164.9, 151.2, 137.2, 136.1, 132.6, 130.3, 128.6,
128.2, 127.5, 126.3, 120.9, 85.0, 73.3, 70.4, 38.8, 36.7, 36.1,
35.2, 31.0, 20.1, 14.7, 14.6, 11.0; HRMS (ESI) m/z calcd for
C25H34O4Na [M + Na]+: 421.2354, found: 421.2349.
1990, 31, 945; (b) In the 13C NMR spectra of 19a the two
methyls of the acetonide groups appeared at δ 19.8 and
30.0. The ketal carbon appeared at δ 97.2. Hence they have
a syn relationship.
14 Y. Oikawa, T. Yoshioka and O. Yonemitsu, Tetrahedron
Lett., 1982, 23, 889.
Acknowledgements
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K. M. R. thanks CSIR, New Delhi for
a
research
fellowship. S. G. is thankful to the Council of Scientific and
Industrial Research for funding under the ORIGIN programme
of the 12th five year plan.
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4012 | Org. Biomol. Chem., 2014, 12, 4002–4012
This journal is © The Royal Society of Chemistry 2014