Olefin cross-metathesis: Studies towards the total synthesis of (+)-bitungolide F

Article abstract of DOI:10.1002/hlca.201300326

A stereoselective synthesis of (5S,6S)-6-[(2S,5S,7R,8E,10E)-5-(benzyloxy)- 7-{[(tert-butyl)dimethylsilyl]oxy}-11-phenylundeca-8,10-dien-2-yl]-5-ethyl-5, 6-dihydro-2H-pyran-2-one (=(+)-9-O-benzyl-11-O-[(tert-butyl)dimethylsilyl] bitungolide F) is reported. The strategy involves Gilman reaction, olefin cross-metathesis, and Horner-Wadsworth-Emmons olefination as key steps. Copyright

Full text of DOI:10.1002/hlca.201300326

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Helvetica Chimica Acta – Vol. 97 (2014)
Olefin Cross-Metathesis: Studies towards the Total Synthesis of (þ)-
Bitungolide F
by Gandrath Dayaker* and Palakodety Radha Krishna*
D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division CSIR-Indian Institute of
Chemical Technology, Hyderabad, 500007, India (phone: þ 91-40-27193158; fax: þ 91-40-27160387; e-
mail: dayaker.gandrath@gmail.com)
A stereoselective synthesis of (5S,6S)-6-[(2S,5S,7R,8E,10E)-5-(benzyloxy)-7-{[(tert-butyl)dimethyl-
silyl]oxy}-11-phenylundeca-8,10-dien-2-yl]-5-ethyl-5,6-dihydro-2H-pyran-2-one (¼(þ)-9-O-benzyl-11-
O-[(tert-butyl)dimethylsilyl]bitungolide F) is reported. The strategy involves Gilman reaction, olefin
cross-metathesis, and HornerꢀWadsworthꢀEmmons olefination as key steps.
Introduction. – Bitungolides A – F are a,b-unsaturated d-lactones, isolated from
Theonella swinhoei by Tanaka and co-workers, and they show remarkable phosphatase
inhibition. When bitungolides were assayed against 3Y1 rat normal fibroblast cells, a
cytotoxic effect was observed at a concentration of 10 mg/ml [1a]. The structures of
bitungolides were elucidated by Tanaka through X-ray crystallography, following the
spectroscopic assignments. Structurally, all bitungolides (Fig.) contain one aromatic
ring, two conjugated olefinic C¼C bonds, 1,3-dihydroxy- and 1,3-dimethyl-substituted
stereogenic centres in the side chain, and an Et-substituted stereogenic center in the
lactone ring as common functionalities. Bitungolides have structures similar to those of
franklinolides [1b] (Fig.).
Bitungolide F possesses interesting biological activities as well as a unique
structural complexity; these features prompted substantial synthetic efforts towards
the total synthesis of (þ)-bitungolide F (1). Previously, three total syntheses of
(ꢀ)-bitungolide F and one synthesis of (ꢀ)-bitungolide E have been reported [2].
Herein, we report the first synthesis of the core skeleton of 1 by a convergent strategy
that features Gilman reaction, more importantly, an olefin cross-metathesis reaction
between two diversely substituted olefins, acid-catalyzed cyclization to access an a,b-
unsaturated d-lactone, and HornerꢀWadsworthꢀEmmons olefination to generate the
diene functionality.
Results and Discussion. – The retrosynthetic analysis of 1 is depicted in Scheme 1.
The target compound 1 was envisioned to be formed from aldehyde 2 and phosphonate
3 through the LiOH-mediated HornerꢀWadsworthꢀEmmons olefination. The alde-
hyde 2, in turn, could be synthesized from intermediate 4 by acid-catalyzed cyclization
and functional-group transformations. The ester 4 could be derived from cross-
metathesis product 5 on hydrogenation, silyl deprotection, oxidation, and (Z)-selective
Wittig reaction. Olefin 5, in turn, may be derived from the coupling of olefinic
ꢀ 2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Figure. Structures of some bitungolides and franklinolides
fragments 6 and 7 by an olefin cross-metathesis protocol. One of the olefins, 7, could be
prepared from the epoxide 8 via epoxide ring opening under Gilman conditions,
protection of the ensuing secondary alcohol as its 4-methoxybenzyl (PMB) ether, and
C1-Wittig olefination. The epoxide 8 was prepared from known triol 9, and the key
fragment 6 was obtained from a,b-unsaturated ester 10 via functional-group trans-
formations.
The synthesis of 7 (Scheme 2) started from the known triol 9 [3]. Oxidative
cleavage of triol 9 with NaIO4 in CH2Cl2 gave the corresponding aldehyde, which, on
t
Wittig olefination, afforded the a,b-unsaturated ester 11 [4]. Subsequently, BuPh2Si
(TBDPS) protection of 11 and reduction of the a,b-unsaturated ester 12 with DIBAL-
H afforded allylic alcohol 13. Sharpless asymmetric epoxidation [5] of 13 gave epoxy
alcohol 8. The Gilman reaction unambiguously led to Me substitution [6]. Thus, the
regioselective ring-opening reaction of epoxy alcohol 8 with Me2CuLi in Et2O, followed
by the treatment of the crude product with NaIO4 in CH2Cl2 to eliminate the minor 1,2-
diol product, led to the required 1,3-diol 14 as a pure product. It is pertinent to mention
that the Et group played a major role in defining the regioselective epoxide ring-
opening. Protection of the diol 14 as its 4-methoxybenzylidene acetal and subsequent
reductive opening of the acetal with DIBAL-H afforded the primary alcohol 15. Then,
oxidation of 15 under Swern conditions [7] gave the aldehyde, which, on Wittig
homologation [8], furnished the fragment 7 in 80% yield.
The synthesis of olefin fragment 6 commenced from the known a,b-unsaturated
ester 10 (Scheme 3) [9]. The ester was subjected to reduction with DIBAL-H in CH2Cl2
to furnish allylic alcohol 16, which, on Sharpless asymmetric epoxidation [5], gave
epoxy alcohol 17 (cf. [10]). Treatment of 17 under conventional conditions gave the
epoxy chloride quantitatively, which was treated with Na in Et2O to afford allylic

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Scheme 1. Retrosynthetic Analysis. TBDPS, tBuPh2Si; PMB, 4-Methoxybenzyl.
alcohol 18 [10]. Protection of the OH group as its Bn ether under conventional
conditions gave olefin 6 [11].
To access the functionalized C10 intermediate 5, we envisaged a cross-metathesis
reaction [12] as the conjunctive protocol for the union of two equally complex moieties
(Scheme 4). The reason for invoking this reaction is twofold: our earlier experience
[12f][12g] on its use in natural-product synthesis and the challenge this reaction poses
when two highly substituted complex synthons are the reactants. Accordingly, in order
to optimize the cross-metathesis product 5, various reaction conditions were evaluated.
The results are compiled in the Table. Amongst all, Grubbs second-generation catalyst
Gr-II; (10 mol-%)-mediated metathesis reaction between olefin 7 (1 equiv.) and allylic

Helvetica Chimica Acta – Vol. 97 (2014)
871
Scheme 2
a) 1. NaIO4, sat. NaHCO3, CH2Cl2, 08 to r.t.; 2. Ph3P¼CHCOOEt, CH2Cl2, 08 to r.t., 75%. b) tBuPh2SiCl
(TBDPSCl), 1H-imidazole, CH2Cl2, r.t.; 95%. c) Diisobutylaluminium hydride (DIBAL-H), CH2Cl2,
ꢀ 788 to 08; 98%; d) (ꢀ)-Diisopropyl d-tartrate ((ꢀ)-DIPT), Ti(OiPr)4, cumene hydroperoxide (CHP),
CH2Cl2, ꢀ 208; 90%. e) 1. Me2CuLi, Et2O, ꢀ 208; 2. NaIO4, sat. NaHCO3, CH2Cl2, 08 to r.t., 85%. f) 1.
Anisaldehyde dimethyl acetal, TsOH, CH2Cl2, 96%; 2. DIBAL-H, CH2Cl2, 08, 78%. g) 1. (COCl)2,
DMSO, Et3N, CH2Cl2, ꢀ 788; 2. MePPh3þIꢀ, tBuOK, THF, ꢀ 58 to 08; 80%.
Scheme 3
a) DIBAL-H, CH2Cl2, 0 8, 81%. b) (ꢀ)-DIPT, Ti(OiPr)4, CHP, CH2Cl2, ꢀ 208; 90%. c) 1. Ph3P, NaHCO3,
CCl4, reflux; 2. Na/Et2O, 08 to r.t., 82%. d) NaH, BnBr, THF, 08 to r.t., 85%.
alcohol 6 (1.5 equiv.) in CH2Cl2 (0.4m) at 458 afforded 5 (in an optimum yield of 47%
1
(E)/(Z) 90 :10; Entry 4). The H-NMR spectrum of 5 revealed the absence terminal
olefinic H-atoms in both fragments, and at the same time the appearance of two new
olefinic H-atom signals at d(H) 5.68 (dd, J ¼ 8.2, 15.6) and 5.20 ppm (dd, J ¼ 8.2, 15.6)
indicated the formation of the cross-metathesis product.
Since the geometry of the C¼C is inconsequential, reduction (PtO2/NaHCO3/
AcOEt) yielded the saturated compound 19. Then, silyl deprotection gave the primary
alcohol 20, which, upon Swern oxidation, followed by (Z)-selective Wittig olefination
[13] with the potassium salt of bis(2,2,2-trifluroethyl) [(methoxycarbonyl)methyl]
phosponate, under phase-transfer conditions at ꢀ 78 to 08 afforded (Z)-olefin 4 (66%)
along with 8% of the (E)-olefin. Then, deprotection of the PMB ether gave the

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Helvetica Chimica Acta – Vol. 97 (2014)
Scheme 4
a) Grubbs II, 10 mol-%, CH2Cl2, reflux, 47%. b) PtO2, NaHCO3, AcOEt, r.t., 93%. c) Bu4NF, THF, r.t.,
94%. d) 1. (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ 788; 2. (F3CCH2O)2POCH2COOMe, Potassium
bis(trimethylsilyl)amine (KHMDS), THF, ꢀ 788 to 08; 66%. e) 2,3-Dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ), CH2Cl2/H2O 19 :1; 87%. f) TsOH, benzene, r.t., 80%. g) 1. (tert-Butyl)dimethylsilyl
trifluoromethanesulfonate (TBDMSOTf), 2,6-lutidine, CH2Cl2, ꢀ 108, 82%; 2. HF · Pyridine, THF,
08 – r.t., 68%. h) 1. DessꢀMartin Periodinane (DMP), NaHCO3, CH2Cl2, 08 to r.t.; 2. 3, LiOH, THF,
44%. i) TiCl4, CH2Cl2, 08 and ꢀ 408 to 08, or BBr3, CH2Cl2, ꢀ 408 to 08, or Li naphthalenide, THF, ꢀ 208.
j) HF/Py, THF, 08 to r.t.; 50%.

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873
Table. Cross-Metathesis Reaction between 6 and 7 Yielding 5
Entry
6/7 [equiv.]
Cat. (10 mol-%)
Solvent
Time [h]
Yield of 5 [%]
1
2
3
4
5
6
7
1 : 1
1 : 1
Gr-I
Gr-II
Gr-II
Gr-II
Gr-II
Gr-II
Hoveyda Gr-I
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CH2Cl2
24
24
24
48
24
24
24
10
29
35
47
40
32
0
1.5 : 1
1.5 : 1
1 : 1.5
1.5 : 1
1.5 : 1
corresponding hydroxy ester 21, which, on acid-catalyzed lactonisation with concom-
itant deprotection of the isopropylidene group, furnished the diol 22 [13b][14].
t
Diol 22 was silylated (Scheme 4) as its BuMe2Si (TBS) ether (TBSOTf/2,6-
lutidine/CH2Cl2/ ꢀ 108/20 min), and followed by selective monodeprotection [15] of the
primary silyl group in the presence of HF · pyridine in THF at 08 to room temperature
affording the primary alcohol 23. The primary OH group of 23 was oxidized with
DessꢀMartin periodinane [16] to give aldehyde 2, which, after passing through a short
pad of silica gel and without any further characterization, was used for the next
reaction. Thus, 2, on LiOH-mediated HornerꢀWadsworthꢀEmmons olefination
[17][2a] with diethyl cinnamylphosphonate (3, prepared by refluxing (EtO)3P and
cinnamyl bromide) in THF at reflux temperature for 12 h, furnished the (E)-olefin 24
(44%) along with traces of the (Z)-isomer. Next task was the removal of both silyl and
Bn protecting groups in 24. Initially, a one-pot deprotection of both groups was
attempted, i.e., the acid-catalyzed deprotection using TiCl4 (Scheme 4). During this
reaction, a total consumption of starting material was observed. The EI-MS of the
crude product displayed the mass peaks at m/z 383 ([M ꢀ H]þ) and 384 (Mþ),
1
supporting the expected product formation. However, H-NMR was not clean after
purification. Hence, we decided to use alternate reaction conditions and attempted
BBr3-mediated one-pot deblocking strategy [18] (Scheme 4). Unfortunately, these
reaction conditions proved too drastic and resulted in total decomposition of the
starting material. Later, a stepwise deprotection was planned; first, the removal of the
Bn group, followed by that of the silyl group. Accordingly, when Li napthalenide [19] in
THF was used, no expected product was formed, although total consumption of starting
material was observed. Alternatively, when the silyl group was removed first under
conventional conditions, the expected product 25 was formed albeit in moderate yield
(50%), but the removal of the 9-O-Bn group remained elusive as ever even under
different Lewis acid conditions (like TiCl4 or BCl3) or under reductive conditions.
Though Bn removal was reported under certain conditions such as CrCl2/LiI [20a] in
aqueous AcOEt or according to some other protocols [20b], herein the removal of
9-O-Bn proved difficult due to the sensitivity of the skeleton. Since all the above
conditions proved futile, the synthetic route was abandoned.
Conclusions. – The synthesis of (5S,6S)-6-[(2S,5S,7R,8E,10E)-5-(benzyloxy)-7-
{[(tert-butyl)dimethylsilyl]oxy}-11-phenylundeca-8,10-dien-2-yl]-5-ethyl-5,6-dihydro-
2H-pyran-2-one (9-O-benzyl-11-O-[(tert-butyl)dimethylsilyl]bitungolide F) containing

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Helvetica Chimica Acta – Vol. 97 (2014)
five stereogenic centers and two conjugated (E)-C¼C was achieved involving cross-
metathesis reaction as the key step.
One of the authors (G. D.) thanks the UGC, New Delhi, for the research fellowship.
Experimental Part
General. Solvents were dried over standard drying agents and freshly distilled prior to use. Chemicals
were purchased and used without further purification. Org. solns. were dried (anh. Na2SO4) and
concentrated below 408 in vacuo. Column chromatography (CC): silica gel (SiO2; 60 – 120 mesh). Optical
rotations: JASCO DIP 300 digital polarimeter at 258. IR Spectra: Perkin-Elmer IR-683 spectropho-
1
tometer with NaCl optics. H- (200, 300, and 500 MHz) and 13C-NMR (50, 75, and 100 MHz) spectra:
Varian Gemini FT-200 MHz, Bruker Avance 300 MHz, and Bruker Avance 500 MHz spectrometers with
TMS as internal standard for solns. in CDCl3; J values in Hz. MS: CEC-21-11013 or Finnigan Mat 1210
double-focusing mass spectrometers operating at a direct inlet system or LC/MSD Trap SL (Agilent
Technologies). The software ACD/Name Version 1.0, developed by M/s Advanced Chemistry Develop-
ment Inc., Toronto, Canada, assisted nomenclature used in the Exper. Part.
Ethyl (2E,4R)-4-(Hydroxymethyl)hex-2-enoate (11). To a stirred soln. of 9 [3] (3.70 g, 27.61 mmol)
in CH2Cl2 (40 ml) were added NaIO4 (9.2 g, 43.0 mmol) and sat. aq. NaHCO3 (1.5 ml) at 08, the mixture
was stirred at r.t. for 10 h, then filtered through a Na2SO4 pad, washed with CH2Cl2 (30 ml), CH2Cl2 was
evaporated, and the crude aldehyde was used as such for the next step.
To a soln. of the aldehyde (2.70 g, 26.47 mmol) in CH2Cl2 (30 ml) was added ethyl (triphenyl-l5-
phosphanylidene)acetate (13.91 g, 31.76 mmol) at 08. The mixture was stirred at r.t. for 3 h, then CH2Cl2
was evaporated, and the residue was purified by CC (SiO2; AcOEt/hexane 1:4) to furnish 11 (3.55 g,
75% yield for two steps). Colorless liquid. [a]2D5 ¼ ꢀ35.1 (c ¼ 2.5, CHCl3). IR (neat): 3400, 1700, 1610,
1
1290. H-NMR (200 MHz): 6.74 (dd, J ¼ 8.8, 15.4, 1 H); 5.87 (d, J ¼ 16.6, 1 H); 4.19 (q, J ¼ 7.3, 2 H);
3.68 – 3.54 (m, 2 H); 2.39 – 2.18 (m, 1 H); 1.68 – 1.38 (m, 2 H); 1.30 (t, J ¼ 7.3, 3 H); 0.92 (t, J ¼ 7.3, 3 H).
13C-NMR (75 MHz): 166.7; 150.3; 123.0; 64.7; 60.4; 46.8; 23.0; 14.0; 11.4. EI-MS: 172 (Mþ). Anal. calc.
for C9H16O3 (172.22): C 62.77, H 9.36; found: C 62.75, H 9.35. These data are consistent with those
reported in [4].
Ethyl (2E,4R)-4-({[(tert-Butyl)diphenylsilyl]oxy}methyl)hex-2-enoate (12). To a cooled soln. of 11
(3.2 g, 18.60 mmol) and 1H-imidazole (3.79 g, 55.80 mmol) in CH2Cl2 (30 ml) was slowly added
TBDPSCl (5.35 ml, 20.46 mmol) at 08. The mixture was warmed to r.t. and stirred for 3 h, the reaction
was quenched with aq. HCl (1n, 30 ml), and the layers separated. The org. phase was washed with brine
(100 ml), dried (Na2SO4), filtered, and concentrated to afford 12 (7.20 g, 95%) after CC (SiO2; AcOEt/
hexane 4 :96). White syrupy liquid. [a]2D5 ¼ þ0.32 (c ¼ 1.3, CHCl3). IR (neat): 1750, 1610, 1210. 1H-NMR
(300 MHz): 7.63 – 7.57 (m, 4 H); 7.41 – 7.29 (m, 6 H); 6.78 (dd, J ¼ 8.3, 15.8, 1 H); 5.79 (d, J ¼ 14.3, 1 H);
4.18 (q, J ¼ 6.7, 2 H); 3.59 (dd, J ¼ 2.2, 6.0, 2 H); 2.33 – 2.21 (m, 1 H); 1.67 – 1.55 (m, 1 H); 1.45 – 1.31 (m,
1 H); 1.11 (t, J ¼ 6.7, 3 H); 1.03 (s, 9 H); 0.86 (t, J ¼ 6.7, 3 H). 13C-NMR (100 MHz): 166.4; 150.3; 135.4;
133.4; 129.5; 127.5; 122.2; 66.0; 60.1; 46.8; 26.8; 23.2; 19.4; 14.3; 11.5. HR-ESI-MS: 433.2190 ([M þ Na]þ,
C25H34NaO3Siþ; calc. 433.2175).
(2E,4R)-4-({[(tert-Butyl)diphenylsilyl]oxy}methyl)hex-2-en-1-ol (13). To a stirred soln. of 12 (7.00 g,
17.07 mmol) in anh. CH2Cl2 (70 ml), DIBAL-H (34.14 ml, 34.14 mmol, 1m soln. in hexane) was added at
ꢀ 108, and the mixture was stirred at 08 for 2 h. Then, MeOH (3 ml) was added, to the mixture at 08 and
stirred for 10 min. Next, sat. aq. soln. of sodium potassium tartarate (10 ml) was added, and after 10 min
MeOH was evaporated. The residue was diluted with H2O (40 ml) and extracted with CH2Cl2 (2 ꢁ
100 ml). The combined org. layers were washed with brine (100 ml), dried (Na2SO4), concentrated,
and the residue was purified by CC (SiO2; AcOEt/hexane 10 :90) to afford 13 (6.15 g, 98%). Colorless
syrup. [a]2D5 ¼ ꢀ24.7 (c ¼ 1.2, CHCl3). IR (neat): 3420, 3110, 1590, 1200. 1H-NMR (200 MHz): 7.66 – 7.56
(m, 4 H); 7.41 – 7.28 (m, 6 H); 5.71 – 5.35 (m, 2 H); 4.04 (d, J ¼ 5.4, 2 H); 3.57 (d, J ¼ 6.3, 2 H); 2.20 – 2.00
(m, 1 H); 1.67 – 1.50 (m, 3 H); 1.03 (s, 9 H); 0.84 (t, J ¼ 7.8, 3 H). 13C-NMR (100 MHz): 135.5; 134.2;

Helvetica Chimica Acta – Vol. 97 (2014)
875
133.8; 130.2; 129.5; 127.5; 66.9; 63.8; 46.6; 26.8; 23.6; 19.2; 11.5. HR-ESI-MS: 391.2062 ([M þ Na]þ,
C23H32NaO2Siþ; calc. 391.2069).
3,4-Anhydro-1-O-[(tert-butyl)diphenylsilyl]-2-deoxy-2-ethyl-l-arabinitol (8). To a suspension of
thoroughly dried molecular sieves (MS) (4 ꢂ, 5 g) in anh. CH2Cl2 (60 ml) was added (ꢀ)-DIPT (2.30 g in
10 ml CH2Cl2, 9.82 mmol), followed by slow addition of Ti(OiPr)4 (2.40 ml, 8.45 mmol) at ꢀ 208. After
stirring for 30 min, cumene hydroperoxide (CHP; 2.94 ml, 19.68 mmol) was slowly added, and the
resulting soln. was stirred at ꢀ 208 for a further 30 min. Allylic alcohol 13 (6.1 g, 16.50 mmol) in CH2Cl2
(20 ml) was then added, and the mixture was stirred at ꢀ 208 for 3 h, then warmed up to 08, and an aq.
basic soln. (3m NaOH/brine 3 :7, 30 ml) was added. After stirring for 1 h, the mixture was filtered through
a pad of Celite, and the pad was further washed with CH2Cl2. The filtrate was concentrated and purified
by flash CC (SiO2; AcOEt/hexane 20 :80) to afford 8 (5.7 g, 90%) Colorless oil. [a]2D5 ¼ þ37.14 (c ¼ 3.7,
CHCl3). IR (neat): 3415, 3010, 1240, 1140. 1H-NMR (200 MHz): 7.70 – 7.53 (m, 4 H); 7.43 – 7.30 (m, 6 H);
3.83 (d, J ¼ 1.7, 1 H); 3.72 – 3.49 (m, 3 H); 2.98 – 2.85 (m, 2 H); 1.63 – 1.14 (m, 3 H); 1.04 (s, 9 H); 0.91 (t,
J ¼ 7.3, 3 H). 13C-NMR (100 MHz): 135.4; 133.5; 129.6; 127.6; 64.1; 61.7; 58.3; 58.0; 45.3; 26.7; 22.1; 19.0;
11.4. HR-ESI-MS: 407.2010 ([M þ Na]þ, C23H32NaO3Siþ; calc. 407.2018).
1-O-[(tert-Butyl)diphenylsilyl]-2,4-dideoxy-2-ethyl-4-methyl-l-arabinitol (14). To a stirred mixture
of CuI (11.88 g, 62.40 mmol) in anh. Et2O (100 ml), MeLi (78 ml, 124.80 mmol, 1.6m soln. in hexane) was
added within 30 min at 08. The yellow color of the mixture turned to colorless, and stirring was continued
for 0.5 h. A soln. of 8 (4.80 g, 12.48 mmol) in anh. Et2O (20 ml) was added at ꢀ 208, and the mixture was
stirred for 20 h at the same temp. The reaction was quenched with aq. NH4Cl (60 ml) and NH3 solns.
(60 ml) at 08, and the mixture was allowed to be stirred for 15 min. Org. layer was separated, and the aq.
layer was extracted with AcOEt (2 ꢁ 100 ml). The combined org. layers were washed with H2O (2 ꢁ
100 ml) and brine (100 ml), dried (Na2SO4), and concentrated under reduced pressure. The crude
product was treated with NaIO4 in CH2Cl2 for 10 h at r.t., then purified by CC (SiO2; AcOEt/hexane,
23 :77) to afford 14 (4.25 g, 85%). Colorless liquid. [a]2D5 ¼ þ30.62 (c ¼ 2.65, CHCl3). IR (neat): 3450,
1
3090, 1240, 1140. H-NMR (300 MHz): 7.67 – 7.61 (m, 4 H); 7.45 – 7.34 (m, 6 H); 3.84 – 3.76 (m, 3 H);
3.72 – 3.55 (m, 2 H); 1.98 – 1.84 (m, 1 H); 1.65 – 1.42 (m, 2 H); 1.37 – 1.31 (m, 1 H); 1.06 (s, 9 H); 0.78 (t,
J ¼ 7.5, 3 H); 0.72 (d, J ¼ 7.5, 3 H). 13C-NMR (75 MHz): 135.6; 132.6; 129.9; 127.7; 81.7; 68.8; 66.3; 43.5;
37.2; 26.8; 19.1; 15.9; 13.7; 12.1. HR-ESI-MS: 423.2315 ([M þ Na]þ, C24H36NaO3Siþ; calc. 423.2331).
1-O-[(tert-Butyl)diphenylsilyl]-2,4-dideoxy-2-ethyl-3,5-O-(4-methoxybenzylidene)-4-methyl-l-ara-
binitol. To a soln. of 14 (3.80 g, 9.50 mmol) in anh. CH2Cl2 (30 ml) were added p-anisaldehyde dimethyl
acetal (1.79 ml, 10.45 mmol) and cat. TsOH at r.t. After 2 h at r.t., anh. MeOH (1 ml) was added, and the
soln. was stirred for 5 min, and then cooled to 08. A sat. aq. soln. of NaHCO3 (10 ml) and H2O (30 ml)
were added. The mixture was extracted with CH2Cl2 (2 ꢁ 60 ml), the extracts were washed with brine
(70 ml), dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by
CC (SiO2; AcOEt/hexane 3 :97) to afford the cyclic acetal (4.7 g, 96%). Colorless oil. [a]2D5 ¼ þ59.0 (c ¼
1.0, CHCl3). IR (neat): 3070, 2900, 1260, 1140. 1H-NMR (300 MHz): 7.66 – 7.55 (m, 4 H); 7.39 – 7.16 (m,
8 H); 6.79 (d, J ¼ 8.3, 2 H); 5.32 (s, 1 H); 4.07 (dd, J ¼ 4.5, 10.5, 1 H); 3.86 – 3.60 (m, 7 H); 2.11 – 2.00 (m,
1 H); 1.81 – 1.70 (m, 1 H); 1.66 – 1.49 (m, 1 H); 1.28 – 1.10 (m, 1 H); 1.04 (s, 9 H); 0.75 (t, J ¼ 6.7, 3 H); 0.72
(d, J ¼ 6.7, 3 H). 13C-NMR (75 MHz): 135.5; 133.0; 129.5; 129.4; 127.5; 127.3; 113.3; 100.9; 81.5; 73.3; 62.8;
55.2; 43.3; 30.1; 29.6; 26.8; 18.0; 12.9; 12.3. HR-ESI-MS: 541.2758 ([M þ Na]þ, C32H42NaO4Siþ; calc.
541.2750).
1-O-[(tert-Butyl)diphenylsilyl]-2,4-dideoxy-2-ethyl-3-O-(4-methoxybenzyl)-4-methyl-l-arabinitol
(15). DIBAL-H (9.55 ml, 1m soln. in hexane, 9.55 mmol) was added to a soln. of the cyclic acetal (4.50 g,
8.68 mmol) in CH2Cl2 (40 ml) at ꢀ 208, and the temp. was raised to 08. After 3 h, MeOH (3 ml) was
added to the mixture at 08, and the mixture was stirred for 10 min. Sat. aq. soln. of sodium potassium
tartrate (10 ml) was added, and after 10 min MeOH was evaporated. The mixture was diluted with H2O
(30 ml) and extracted with CH2Cl2 (2 ꢁ 60 ml). The org. layer was washed with brine (60 ml), dried
(Na2SO4), and concentrated in vacuo. The crude product was purified by CC (SiO2; AcOEt/hexane
10 :90) to afford 15 (3.50 g, 78%). Colorless liquid. [a]2D5 ¼ þ7.70 (c ¼ 1.5, CHCl3). IR (neat): 3400, 3100,
1200, 1140. 1H-NMR (200 MHz): 7.64 – 7.60 (m, 4 H); 7.42 – 7.60 (m, 6 H); 7.11 (d, J ¼ 8.0, 2 H); 6.76 (d,
J ¼ 8.8, 2 H); 4.50 – 4.40 (m, 2 H); 3.77 (s, 3 H); 3.72 – 3.54 (m, 5 H); 1.96 – 1.77 (m, 1 H); 1.60 – 1.40 (m,
2 H); 1.32 – 1.13 (m, 1 H); 1.07 (s, 9 H); 0.88 (t, J ¼ 7.3, 3 H); 0.77 (d, J ¼ 6.7, 3 H). 13C-NMR (75 MHz):

876
Helvetica Chimica Acta – Vol. 97 (2014)
135.5; 133.1; 131.2; 129.6; 129.3; 127.6; 113.8; 84.2; 74.8; 66.8; 63.7; 55.2; 45.7; 37.8; 26.9; 18.7; 15.2; 12.6.
HR-ESI-MS: 543.2899 ([M þ Na]þ, C32H44NaO4Siþ; calc. 543.2907).
(tert-Butyl)({(2S,3S,4S)-2-ethyl-3-[(4-methoxybenzyl)oxy]-4-methylhex-5-en-1-yl}oxy)diphenylsi-
lane (7). A soln. of oxalyl chloride (0.57 ml, 6.63 mmol) and CH2Cl2 (15 ml) at ꢀ 788 was treated with
DMSO (1.03 ml, 13.26 mmol). After 15 min, a soln. of 15 (2.30 g, 4.42 mmol) in CH2Cl2 (10 ml) was
added dropwise. After 1 h, Et3N (3.69 ml, 26.52 mmol) was added dropwise, and the mixture was warmed
to ꢀ 308. Then, it was diluted with CH2Cl2 (20 ml), warmed to r.t., and washed sequentially with H2O
(25 ml), sat. aq. NH4Cl (20 ml), H2O (25 ml), and brine (25 ml). The org. layer was dried (Na2SO4),
filtered, and concentrated in vacuo to afford aldehyde (2.30 g, 99% crude) as a clear, colorless oil. This
was used without further purification.
To a soln. of (methylidene)triphenylphosphonium iodide (4.72 g, 13.32 mmol) in anh. THF (25 ml),
tBuOK (1.24 g, 11.10 mmol) was added at ꢀ 58, and the mixture was stirred for 3 h at 08. The aldehyde
(2.30 g, 4.40 mmol) in anh. THF (10 ml) was added at 08, and the mixture was stirred for 3 h. The reaction
was quenched with sat. NH4Cl (20 ml) soln., org. layer was separated, and the aq. layer was extracted with
Et2O (2 ꢁ 60 ml). The combined org. layers were washed with brine (20 ml), dried (Na2SO4), and
concentrated to give a crude residue, which was purified by CC (SiO2; AcOEt/hexane 2 :98) to afford 7
(1.82 g, 80% over two steps). Colorless syrup. [a]2D5 ¼ þ40.97 (c ¼ 2.2, CHCl3). IR (neat): 3100, 1610,
1190, 1140. 1H-NMR (200 MHz): 7.69 – 7.55 (m, 4 H); 7.42 – 7.26 (m, 6 H); 7.17 (d, J ¼ 8.8, 2 H); 6.79 (d,
J ¼ 8.8, 2 H); 5.98 (m, 1 H); 5.00 – 4.51 (m, 2 H); 4.45 – 4.30 (m, 2 H); 3.77 (s, 3 H); 3.61 (d, J ¼ 5.1, 2 H);
3.50 (t, J ¼ 5.1, 1 H); 2.48 – 2.27 (m, 1 H); 1.69 – 1.43 (m, 2 H); 1.33 – 1.24 (m, 1 H); 1.06 (s, 9 H); 0.98 (t,
J ¼ 6.6, 3 H); 0.76 (d, J ¼ 6.6, 3 H). 13C-NMR (75 MHz): 158.9; 141.7; 135.6; 133.8; 131.4; 129.6; 129.1;
127.5; 114.1; 113.5; 82.7; 74.4; 62.9; 55.2; 45.2; 40.9; 26.9; 19.2; 18.7; 17.6; 12.2. HR-ESI-MS: 539.2947
([M þ Na]þ, C33H44NaO3Siþ; calc. 539.2957).
(2E)-4-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]but-2-en-1-ol (16). To a stirred soln. of 10 (6.82 g,
34.1 mmol) in anh. CH2Cl2 (20 ml), DIBAL-H (68.2 ml, 68.2 mmol, 1m soln. in hexane) was added at 08,
and the mixture was stirred at the same temp. for 2 h. MeOH (2 ml) was added to the mixture at 08 and
stirred for 10 min., sat. aq. soln. of sodium potassium tartrate (5 ml) was added, and, after 10 min, MeOH
was evaporated. The residue was diluted with H2O (20 ml) and extracted with CH2Cl2 (2 ꢁ 25 ml). The
combined org. layers were washed with brine (10 ml), dried (Na2SO4), concentrated, and the residue was
purified by CC (SiO2; AcOEt/hexane 2 :8) to afford 16 (4.75 g, 81%). Colorless syrup. [a]2D5 ¼ þ42.0 (c ¼
0.50). IR (neat): 3400, 1610, 1220, 1160. 1H-NMR (300 MHz): 5.79 – 5.58 (m, 2 H); 4.18 – 4.06 (m, 3 H);
3.98 (dd, J ¼ 6.0, 8.3, 1 H), 3.80 (dd, J ¼ 6.0, 8.3, 1 H), 2.41 – 2.21 (m, 2 H); 1.73 – 1.51 (br. s, 1 H); 1.38 (s,
3 H); 1.31 (s, 3 H). 13C-NMR (75 MHz): 132.1; 127.1; 108.9; 75.1; 68.7; 63.1; 36.4; 26.7; 25.4. EI-MS: 172
(Mþ). Anal. calc. for C9H16O3 (172.22): C 62.77, H 9.36; found: C 62.79, H 9.34. Spectroscopic data are
consistent with those reported in [10].
4,5-Anhydro-3-deoxy-1,2-O-(1-methylethylidene)-d-xylo-hexitol (17). To a suspension of thoroughly
dried MS (4 ꢂ, 3.0 g) in anh. CH2Cl2 (60 ml) was added (ꢀ)-DIPT (0.59 ml, 2.52 mmol), followed by slow
addition of Ti(OiPr)4 (0.37 ml, 1.26 mmol) at ꢀ 208. After stirring for 30 min, CHP (1.94 ml, 12.60 mmol)
was slowly added, and the mixture was stirred at ꢀ 208 for a further 30 min. Allylic alcohol 16 (4.3 g,
25.00 mmol) in CH2Cl2 (20 ml) was then added, and the mixture was stirred at ꢀ 208 for 12 h, then
warmed up to 08, and an aq. basic soln. (3m NaOH/brine 3 :7, 100 ml) was added. After stirring for 1 h,
the mixture was filtered through a pad of Celite, and the pad was further washed with CH2Cl2. The filtrate
was concentrated and purified by flash CC (SiO2; AcOEt/hexane 25 :75) to afford 17 (4.23 g, 90%).
Colorless oil. [a]2D5 ¼ þ79.92 (c ¼ 0.85, CHCl3). IR (neat): 3410, 1200, 1110. 1H-NMR (200 MHz): 4.31 –
4.14 (m, 1 H); 4.05 (dd, J ¼ 5.4, 7.8, 1 H); 3.83 (dd, J ¼ 2.3, 12.5, 1 H); 3.66 – 3.48 (m, 2 H); 3.09 – 2.99 (m,
1 H); 2.91 – 2.87 (m, 1 H); 2.03 – 1.83 (m, 1 H); 1.69 – 1.50 (m, 1 H); 1.38 (s, 3 H); 1.34 (s, 3 H). 13C-NMR
(75 MHz): 108.9; 73.3; 69.1; 61.4; 58.6; 52.9; 36.3; 26.7; 25.4. EI-MS: 188 (Mþ). Anal. calc. for C9H16O4
(188.22): C 57.43, H 8.57; found: C 57.45, H 8.59. Spectroscopic data are consistent with those reported in
[10].
(2R)-1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]but-3-en-2-ol (18). To a stirred soln. of 17 (4.0 g,
21.27 mmol) in anh. CCl4 (25 ml), Ph3P (11.1 g, 42.55 mmol) and NaHCO3 (0.178 g, 2.17 mmol) were
added, and the mixture was heated reflux for 4 h. CCl4 was evaporated under reduced pressure, and the

Helvetica Chimica Acta – Vol. 97 (2014)
877
residue was purified by CC (SiO2; AcOEt/hexane, 0.5 :9.5) to afford epoxy chloride quantitatively as a
colorless syrup.
A soln. of epoxy chloride (4.30 g, 20.87 mmol) in anh. Et2O (15 ml) was added dropwise to a stirred
suspension of freshly prepared Na sand (0.96 g, 41.7 mmol) in anh. Et2O (20 ml) under N2 at r.t. during
20 min. After complete addition, the mixture was stirred for further 8 h. Then, the reaction was carefully
quenched with MeOH (10 ml) at 08, and the mixture was diluted with brine (5 ml), dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified by CC (SiO2; AcOEt/hexane 2 :8) to give
18 (3.0 g, 82% over two steps). Colorless syrup. [a]2D5 ¼ ꢀ25.84 (c ¼ 1.1, CHCl3). IR (neat): 3420, 3010,
1
1610, 1220, 1110. H-NMR (300 MHz): 5.92 – 5.80 (m, 1 H); 5.33 – 5.06 (m, 2 H); 4.37 – 4.20 (m, 2 H);
4.03 (dd, J ¼ 6.0, 8.3, 1 H); 3.53 (t, J ¼ 7.5, 1 H); 2.36 – 2.10 (br. s, 1 H); 1.85 – 1.62 (m, 2 H); 1.39 (s, 3 H);
1.33 (s, 3 H). 13C-NMR (75 MHz): 140.5; 114.3; 108.8; 73.2; 69.8; 69.4; 39.8; 26.8; 25.6. EI-MS: 172 (Mþ).
Anal. calc. for C9H16O3 (172.22): C 62.77, H 9.36; found: C 62.76, H 9.33. Spectroscopic data are
consistent with reported ones [12].
(4R)-4-[(2R)-2-(Benzyloxy)but-3-en-1-yl]-2,2-dimethyl-1,3-dioxolane (6). To a cooled (08) suspen-
sion of NaH (0.837 g, 34.8 mmol, 60% (w/w) dispersion in paraffin oil) in THF (15 ml), a soln. of 18
(3.0 g, 17.4 mmol) in THF (10 ml) was added dropwise. After 15 min, BnBr (3.28 g, 17.4 mmol) was
added dropwise at 08 and stirred for 6 h at r.t. The reaction was quenched with sat. aq. NH4Cl soln.
(30 ml), and the mixture was extracted with AcOEt (2 ꢁ 100 ml). The combined org. layers were washed
with H2O (100 ml) and brine (50 ml), dried (Na2SO4), and evaporated. The crude product was purified
by CC (SiO2; AcOEt/hexane, 1:9) to afford 6 (3.87 g, 85%). Light-yellow syrup. [a]2D5 ¼ þ59.81 (c ¼ 0.9,
CHCl3). IR (neat): 2990, 1610, 1190, 1100. 1H-NMR (300 MHz): 7.37 – 7.17 (m, 5 H); 5.85 – 5.65 (m, 1 H);
5.28 – 5.15 (m, 2 H); 4.60 – 4.10 (m, 3 H); 4.05 – 3.80 (m, 2 H); 3.47 (t, J ¼ 7.8, 1 H); 1.75 (t, J ¼ 6.2, 2 H);
1.35 (s, 3 H); 1.31 (s, 3 H). 13C-NMR (75 MHz): 138.5; 138.0; 128.3; 127.7; 127.4; 117.4; 108.3; 77.7; 73.3;
70.4; 69.9; 40.0; 26.9; 25.8. HR-ESI-MS: 285.1458 ([M þ Na]þ, C16H22NaO3þ ; calc. 285.1467). Spectro-
scopic data are consistent with those reported in [11].
({(2S,3S,4S,5E,7R)-7-(Benzyloxy)-8-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-ethyl-3-[(4-methoxy-
benzyl)oxy]-4-methyloct-5-en-1-yl}oxy)(tert-butyl)diphenylsilane (5). To a soln. of 7 (0.882 g,
1.71 mmol) in anh. CH2Cl2 (0.4m) were added 6 (0.673 g, 2.57 mmol) and Grubbs II catalyst (10 mol-
%) under N2 at r.t., then temp. was raised to reflux, and the mixture was stirred for 48 h. The mixture was
directly adsorbed on SiO2 to perform the CC (SiO2; AcOEt/hexane 4 :96) to afford 5 (0.60 g, 47%).
Colorless syrup. [a]2D5 ¼ þ32.99 (c ¼ 2.0, CHCl3). IR (neat): 3010, 2940, 1610, 1190, 1100. 1H-NMR
(200 MHz): 7.73 – 7.54 (m, 4 H); 7.49 – 7.08 (m, 13 H); 6.78 (d, J ¼ 8.5, 2 H); 5.68 (dd, J ¼ 8.2, 15.6, 1 H);
5.20 (dd, J ¼ 8.2, 15.6, 1 H); 4.57 – 4.37 (m, 4 H); 4.30 – 4.09 (m, 2 H); 3.94 (dd, J ¼ 5.8, 7.8, 1 H); 3.76 (s,
3 H); 3.61 – 3.45 (m, 2 H); 3.39 (t, J ¼ 7.8, 1 H); 2.50 – 2.29 (m, 1 H); 1.67 – 1.24 (m, 14 H); 1.07 (s, 9 H);
0.78 (t, J ¼ 7.0, 3 H). 13C-NMR (75 MHz): 158.5; 139.0; 136.8; 135.3; 133.5; 131.1; 129.6; 129.3; 128.6;
127.9; 127.4; 127.3; 127.1; 113.3; 108.5; 82.5; 76.3; 74.3; 73.1; 69.7; 69.6; 62.5; 54.9; 45.3; 39.9; 39.6; 29.2;
26.6; 25.5; 19.0; 18.6; 18.3; 12.0. HR-ESI-MS: 773.4215 ([M þ Na]þ, C47H62NaO6Siþ; calc. 773.4213).
({(2S,3S,4S,7S)-7-(Benzyloxy)-8-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-ethyl-3-[(4-methoxybenzyl)-
oxy]-4-methyloctyl}oxy)(tert-butyl)diphenylsilane (19). To a stirred soln. of 5 (1.4 g, 1.86 mmol) in
AcOEt (6 ml), a cat. amount of PtO2 was added, and the mixture was stirred for 8 h at r.t. under H2. The
mixture was filtered through a pad of Celite; and the filtrate was concentrated under reduced pressure
and adsorbed on SiO2 for the CC (SiO2; AcOEt/hexane 4 :96) to furnish 19 (1.30 g, 93%). Colorless
1
syrup. [a]2D5 ¼ þ23.95 (c ¼ 0.35, CHCl3). IR (neat): 3020, 2990, 1290, 1120. H-NMR (200 MHz): 7.62 –
7.59 (m, 4 H); 7.36 – 7.23 (m, 11 H); 7.13 (d, J ¼ 8.2, 2 H); 6.75 (d, J ¼ 8.2, 2 H); 4.57 – 4.32 (m, 4 H);
4.29 – 4.07 (m, 1 H); 4.03 – 3.89 (m, 1 H); 3.75 (s, 3 H); 3.62 – 3.38 (m, 5 H); 1.17 – 1.08 (m, 16 H); 1.07 (s,
9 H); 0.85 (d, J ¼ 6.6, 3 H); 0.74 (t, J ¼ 7.4, 3 H). 13C-NMR (75 MHz): 135.6; 133.2; 130.9; 129.6; 129.0;
128.3; 127.8; 127.6; 127.5; 113.6; 108.3; 83.2; 76.9; 74.7; 73.7; 71.5; 70.1; 63.6; 55.2; 44.9; 39.5; 39.0; 36.1;
32.0; 27.0; 25.9; 19.3; 19.0; 18.4; 16.7; 12.6. HR-ESI-MS: 775.4386 ([M þ Na]þ, C47H64NaO6Siþ; calc.
775.4370).
(2S,3S,4S,7S)-7-(Benzyloxy)-8-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-ethyl-3-[(4-methoxybenzyl)-
oxy]-4-methyloctan-1-ol (20). To a soln. of 19 (1.25 g, 1.66 mmol) in anh. THF (10 ml), Bu4NF (2 ml,
1.99 mmol, 1m soln. in THF) was added at 08 under N2 atmosphere, and the mixture was stirred for 12 h at
r.t. THF was evaporated to furnish a crude residue, which was purified by CC (SiO2; AcOEt/hexane

878
Helvetica Chimica Acta – Vol. 97 (2014)
16 :84) to afford 20 (0.80 g, 94%). Colorless syrup. [a]2D5 ¼ þ27.9 (c ¼ 0.4, CHCl3). IR (neat): 3400, 3010,
1
2920, 1190, 1100. H-NMR (200 MHz): 7.32 – 7.23 (m, 5 H); 7.18 (d, J ¼ 8.3, 2 H); 6.75 (d, J ¼ 8.3, 2 H);
4.58 – 4.41 (m, 4 H); 4.22 – 4.00 (m, 1 H); 3.98 (dd, J ¼ 6.0, 7.9, 1 H); 3.75 (s, 3 H); 3.67 – 3.56 (m, 3 H);
3.44 (t, J ¼ 7.9, 1 H); 3.34 (dd, J ¼ 2.6, 6.7, 1 H); 1.78 – 1.62 (m, 8 H); 1.53 – 1.43 (m, 2 H); 1.36 (s, 3 H); 1.30
(s, 3 H); 0.88 (m, 6 H). 13C-NMR (75 MHz): 130.7; 129.2; 128.2; 127.7; 127.4; 113.7; 108.3; 84.3; 76.7; 73.8;
73.5; 71.4; 69.9; 63.4; 55.1; 44.0; 38.9; 35.6; 32.0; 27.6; 26.9; 25.7; 18.7; 16.7; 12.5. HR-ESI-MS: 537.3184
([M þ Na]þ, C31H46NaOþ6 ; calc. 537.3192).
Methyl (2Z,4S,5S,6S,9S)-9-(Benzyloxy)-10-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-ethyl-5-[(4-me-
thoxybenzyl)oxy]-6-methyldec-2-enoate (4). To a stirred soln. of oxalyl chloride (0.20 ml, 2.33 mmol)
in CH2Cl2 (7 ml) at ꢀ 788, DMSO (0.36 ml, 4.66 mmol) was added. After 15 min, a soln. of 20 (0.80 g,
1.55 mmol) in CH2Cl2 (5 ml) was added dropwise. After 1 h, Et3N (1.30 ml, 9.32 mmol) was added
dropwise, and the mixture was warmed to ꢀ 308. It was diluted with CH2Cl2 (15 ml), warmed to r.t., and
washed sequentially with H2O (20 ml) and brine (20 ml). The org. layer was dried (Na2SO4), filtered, and
concentrated in vacuo to afford 0.80 g (99% crude yield) of aldehyde as a light yellow syrup. This was
used as such for further reaction.
To a stirred soln. of (F3CCH2O)2POCH2COOMe (0.66 ml, 3.12 mmol), 18-crown-6 (2.46 g,
9.36 mmol) in anh. THF (8 ml) was added KHMDS (5.86 ml, 2.93 mmol, 0.5m soln. in toluene) at
ꢀ 788, and the temp. was raised to 08, and the mixture was stirred for further 30 min. To the mixture,
aldehyde (0.80 g, 1.55 mmol) dissolved in THF (5 ml) was added at ꢀ 788. The mixture was stirred for 2 h
at ꢀ 788, then temp. was gradually increased to 08 in 6 h. Later, the reaction was quenched with aq.
NH4Cl (10 ml), and the mixture was extracted with AcOEt (2 ꢁ 30 ml). The combined org. layers were
washed with brine (1 ꢁ 30 ml), dried (Na2SO4), and concentrated, and the residue was purified by CC
(SiO2; AcOEt/hexane 6 :94) to give 4 (0.58 g, 66%). Colorless syrup. [a]2D5 ¼ þ118.3 (c ¼ 0.5, CHCl3). IR
1
(neat): 3030, 2910, 1740, 1220. H-NMR (200 MHz): 7.26 – 7.20 (m, 5 H); 7.14 (d, J ¼ 8.4, 2 H); 6.78 (d,
J ¼ 8.8, 2 H); 6.07 (t, J ¼ 11.3, 1 H); 5.79 (d, J ¼ 11.3, 1 H); 4.61 – 4.33 (m, 4 H); 4.26 – 4.08 (m, 1 H); 3.96
(dd, J ¼ 5.8, 7.7, 1 H); 3.76 (s, 3 H); 3.67 (s, 3 H); 3.60 – 3.49 (m, 1 H); 3.42 (t, J ¼ 7.7, 1 H); 3.12 (t, J ¼ 5.5,
1 H); 1.78 – 1.56 (m, 6 H); 1.40 – 1.15 (m, 10 H); 0.94 (d, J ¼ 6.6, 3 H); 0.82 (d, J ¼ 7.3, 3 H). 13C-NMR
(75 MHz): 166.6; 152.9; 128.5; 128.0; 127.8; 121.0; 120.1; 113.7; 108.2; 87.4; 76.8; 74.8; 73.6; 71.4; 70.0;
55.2; 51.0; 42.5; 38.9; 36.8; 32.2; 27.3; 27.0; 25.8; 22.1; 16.6; 11.7. HR-ESI-MS: 591.3285 ([M þ Na]þ,
C34H48NaOþ7 ; calc. 591.3298).
Methyl (2Z,4S,5S,6S,9S)-9-(Benzyloxy)-10-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-ethyl-5-hydroxy-
6-methyldec-2-enoate (21). To a stirred soln. of 4 (0.56 g, 0.984 mmol) in CH2Cl2/H2O 19 :1 (8 ml) was
added DDQ (0.16 g, 1.18 mmol) at 08, and the mixture was stirred at r.t. for 20 min. Then, sat. aq.
NaHCO3 (8 ml) was added, the mixture was and extracted with CH2Cl2 (2 ꢁ 20 ml), the combined org.
layers were washed with H2O (20 ml) and brine (10 ml), dried (Na2SO4), concentrated, and the crude
residue was purified by CC (SiO2; AcOEt/hexane 12 :88) to afford 21 (0.385 g, 87%). Colorless syrup
1
[a]2D5 ¼ þ198.0 (c ¼ 1.4, CHCl3). IR (neat): 3400, 3030, 1720, 1220. H-NMR (200 MHz): 7.56 – 7.15 (m,
5 H); 6.05 (t, J ¼ 11.3, 1 H); 5.80 (d, J ¼ 11.8, 1 H); 4.56 – 4.50 (m, 2 H); 4.28 – 4.07 (m, 1 H); 3.97 (dd, J ¼
5.8, 8.0, 1 H); 3.66 (s, 3 H); 3.62 – 3.49 (m, 1 H); 3.43 (t, J ¼ 7.7, 1 H); 3.29 (t, J ¼ 5.5, 1 H); 1.86 – 1.17 (m,
17 H); 0.93 (d, J ¼ 6.6, 3 H); 0.84 (t, J ¼ 7.3, 3 H). 13C-NMR (75 MHz): 166.8; 152.3; 128.3; 127.8; 127.4;
120.9; 120.1; 108.4; 84.2; 79.2; 76.8; 73.6; 71.4; 70.0; 51.0; 42.9; 38.6; 36.7; 31.6; 27.2; 26.9; 22.0; 16.6; 11.5.
HR-ESI-MS: 471.2741 ([M þ Na]þ, C26H40NaOþ6 ; calc. 471.2723).
(5R,6R)-6-[(2S,5S,7R)-5-(Benzyloxy)-7,8-dihydroxyoctan-2-yl]-5-ethyl-5,6-dihydro-2H-pyran-2-
one (22). To a soln. of 21 (0.30 g, 0.66 mmol) in benzene (3 ml) was added cat. TsOH at r.t., and the was
stirred for 3 h. The mixture was treated with Et3N, and the solvent was removed under reduced pressure,
and the residue was adsorbed on SiO2 for CC (SiO2; AcOEt/hexane 60 :40) to afford 22 (0.20 g, 80%).
Colorless syrup. [a]2D5 ¼ þ272.2 (c ¼ 0.3, CHCl3). IR (neat): 3410, 2990, 1700, 1210, 1100. 1H-NMR
(500 MHz): 7.27 – 7.19 (m, 5 H); 6.99 (dd, J ¼ 6.7, 9.6, 1 H); 5.98 (d, J ¼ 9.6, 1 H); 4.61 – 4.40 (m, 2 H);
3.93 – 3.91 (m, 2 H); 3.71 – 3.65 (m, 1 H); 3.52 (dd, J ¼ 3.3, 10.6, 1 H); 3.38 (dd, J ¼ 6.7, 11.1, 1 H); 2.42 (br.
s, 2 H); 2.26 – 2.23 (m, 1 H); 1.89 – 1.36 (m, 7 H); 1.23 – 1.18 (m, 2 H); 0.89 (t, J ¼ 7.7, 3 H); 0.82 (d, J ¼ 6.7,
3 H). 13C-NMR (75 MHz): 164.8; 151.1; 138.5; 128.3; 127.8; 127.6; 120.7; 84.2; 76.9; 71.4; 69.1; 66.8; 36.4;
33.6; 30.5; 28.1; 20.0; 14.8; 10.8. HR-ESI-MS: 399.2140 ([M þ Na]þ, C22H32NaO5þ ; calc. 399.2147).

Helvetica Chimica Acta – Vol. 97 (2014)
879
(5R,6R)-6-[(2S,5S,7R)-5-(Benzyloxy)-7,8-bis{[(tert-butyl)dimethylsilyl]oxy}octan-2-yl]-5-ethyl-5,6-
dihydro-2H-pyran-2-one. A soln. of 22 (0.16 g, 0.42 mmol), 2,6-lutidine (0.29 ml, 2.54 mmol), and (tert-
butyl)dimethylsilyl trifluoromethanesulfonate (TBDMSOTf; 0.214 ml, 0.93 mmol) was stirred at ꢀ 108
for 20 min under N2, the reaction was quenched with sat. NaHCO3 (5 ml), and the mixture was extracted
with CH2Cl2 (2 ꢁ 15 ml). The org. layer was washed with sat. CuSO4 soln. (2 ꢁ 15 ml), brine (1 ꢁ 15 ml),
dried (Na2SO4), concentrated and the residue was purified by CC (AcOEt/hexane, 6 :94) to give the title
compound (0.210 g, 82%). Colorless syrup. [a]D25 ¼ þ232.60 (c ¼ 1.5, CHCl3). IR (neat): 3020, 2990, 1720,
1190. 1H-NMR (500 MHz): 7.35 – 7.19 (m, 5 H); 7.02 (dd, J ¼ 6.1, 9.2, 1 H); 6.04 (d, J ¼ 9.7, 1 H); 4.61 –
4.42 (m, 2 H); 3.98 (dd, J ¼ 2.5, 10.2, 1 H); 3.90 – 3.81 (m, 1 H); 3.68 – 3.59 (m, 1 H); 3.56 – 3.38 (m,
2 H); 2.34 – 2.24 (m, 1 H); 2.00 – 1.20 (m, 9 H); 0.98 (t, J ¼ 7.1, 3 H); 0.90 – 0.88 (m, 21 H); 0.05 – 0.04 (m,
12 H). 13C-NMR (75 MHz): 165.1; 150.9; 138.2; 128.2; 127.5; 127.2; 120.9; 84.3; 76.1; 70.7; 70.3; 67.9; 39.8;
36.5; 33.6; 31.3; 27.9; 25.9; 20.0; 18.4; 17.1; 14.8; 10.9; ꢀ 3.9; ꢀ 4.7; ꢀ 5.3. HR-ESI-MS: 627.3868 ([M þ
Na]þ, C34H60NaO5Siþ2 ; calc. 627.3877).
(5R,6R)-6-[(2S,5S,7R)-5-(Benzyloxy)-7-{[tert-butyl(dimethyl)silyl]oxy}-8-hydroxyoctan-2-yl]-5-
ethyl-5,6-dihydro-2H-pyran-2-one (23). A soln. of the compound (0.20 g, 0.33 mmol) obtained in the
previous step in anh. THF (2 ml) were added HF · pyridine (41 ml) at 08, and the mixture was stirred at r.t.
for 12 h. Later, the mixture was poured into sat. NaHCO3 soln. (10 ml), extracted with AcOEt (2 ꢁ
30 ml), org. layer was washed with sat. CuSO4 soln. (2 ꢁ 15 ml) and brine (1 ꢁ 15 ml), dried (Na2SO4),
concentrated, and the residue was purified by CC (SiO2; AcOEt/hexane 20 :80) to give 23 (0.11 g, 68%).
Colorless syrup. [a]2D5 ¼ þ230.36 (c ¼ 1.5, CHCl3). IR (neat): 3410, 3020, 2980, 1720, 1190. 1H-NMR
(500 MHz): 7.36 – 7.24 (m, 5 H); 7.06 (dd, J ¼ 6.3, 9.7, 1 H); 6.03 (d, J ¼ 9.7, 1 H); 4.60 – 4.44 (m, 2 H); 4.00
(dd, J ¼ 2.9, 10.2, 1 H); 3.96 – 3.88 (m, 1 H); 3.65 – 3.41 (m, 3 H); 2.37 – 2.27 (m, 1 H); 1.99 – 1.23 (m, 9 H);
0.96 (t, J ¼ 7.8, 3 H); 0.92 – 0.85 (m, 12 H); 0.07 (s, 6 H). 13C-NMR (75 MHz): 164.7; 150.9; 138.7; 128.3;
127.6; 127.4; 120.8; 84.2; 76.1; 70.4; 67.0; 39.5; 36.5; 33.6; 30.7; 27.7; 25.8; 20.0; 18.0; 16.5; 14.9; 10.9; ꢀ 4.3;
ꢀ 4.5. HR-ESI-MS: 513.3031 ([M þ Na]þ, C28H46NaO5Siþ; calc. 513.3012).
(5R,6R)-6-[(2S,5S,7R,8E,10E)-5-(Benzyloxy)-7-{[(tert-butyl)dimethylsilyl]oxy}-11-phenylundeca-
8,10-dien-2-yl]-5-ethyl-5,6-dihydro-2H-pyran-2-one (24). To a stirred soln. of 23 (0.05 g, 0.102 mmol) in
anh. CH2Cl2 (2 ml) were added NaHCO3 (0.017 g, 0.204 mmol) and DessꢀMartin periodinane (0.052 g,
0.122 mmol) at 08 under N2, and the mixture was stirred at r.t. for 1 h. Then, the reaction was quenched
with 1:1 mixture of sat. aq. soln. of Na2S2O3 and NaHCO3 (3 ml), the mixture was extracted with CH2Cl2
(2 ꢁ 15 ml), and the combined org. layers were washed with H2O (15 ml), brine (10 ml), dried (Na2SO4),
and concentrated, and the crude residue was purified by flash CC (SiO2; AcOEt/hexane 10 :90) to afford
2 (42 mg, 84%). Colorless syrup. Without further characterization, the aldehyde was used as such for next
step.
To the evacuated MS in a round bottomed flask and aldehyde (0.042 g, 0.086 mmol) in THF (1.5 ml)
were added 3 (0.065 g, 0.258 mmol) and LiOH · H2O (0.061 g, 0.258 mmol) under N2, and the mixture was
heated at reflux for 12 h. The mixture was filtered through SiO2 and washed with Et2O (20 ml). The org.
layer was dried (Na2SO4) and concentrated, and the residue was purified by CC (SiO2; AcOEt/hexane
7:93) to give the Wittig product (0.022 g, 44%). Colorless syrup. [a]2D5 ¼ þ79.7 (c ¼ 0.3, CHCl3). IR
1
(neat): 3010, 2980, 1730, 1610, 1190. H-NMR (500 MHz): 7.43 – 7.17 (m, 10 H); 7.06 (dd, J ¼ 6.4, 9.7,
1 H); 6.73 (dd, J ¼ 10.1, 14.9, 1 H); 6.50 (d, J ¼ 15.7, 1 H); 6.29 (dd, J ¼ 10.5, 14.9, 1 H); 6.04 (d, J ¼ 9.7,
1 H); 5.78 (dd, J ¼ 6.8, 14.9, 1 H); 4.61 – 4.38 (m, 3 H); 4.00 (dd, J ¼ 2.8, 10.5, 1 H); 3.69 – 3.60 (m, 1 H);
2.37 – 2.24 (m, 1 H); 2.06 – 1.91 (m, 1 H); 1.89 – 1.38 (m, 8 H); 0.98 – 0.84 (m, 15 H); 0.06 (s, 3 H); 0.03 (s,
3 H). 13C-NMR (75 MHz): 164.1; 150.9; 137.8; 131.9; 129.6; 128.5; 128.3; 128.0; 127.7; 126.2; 122.9; 120.9;
84.3; 76.0; 71.7; 50.0; 43.8; 39.7; 37.2; 33.6; 29.6; 27.8; 25.9; 21.0; 14.8; 11.0; ꢀ 3.7; ꢀ 4.7. HR-ESI-MS:
611.3527 ([M þ Na]þ, C37H52NaO4Siþ; calc. 611.3533).
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Received August 28, 2013