The First Stereoselective Total Synthesis of (-)-Synrotolide

Article abstract of DOI:10.1002/ejoc.201301215

The first stereoselective total synthesis of (-)-synrotolide has been realized by two different approaches, both starting from (S)-ethyl lactate. Both strategies used stereo- and regioselective epoxide opening with a nucleophile, aldehyde alkyne coupling and ring-closing metathesis as key steps. Judicious choice of reagents (CeCl₃·7H₂O and H₂SiF₆) for the chemoselective removal of protecting groups delivered the target molecule. The first stereoselective total synthesis of (-)-synrotolide has been accomplished by two different approaches starting from commercially available (S)-ethyl lactate. Both strategies used epoxide opening with hydroxide ion, aldehyde alkyne coupling, and ring-closing metathesis as the key steps. Crucially, chemoselective deprotection of the protecting groups delivered the target molecule.

Full text of DOI:10.1002/ejoc.201301215

FULL PAPER
DOI: 10.1002/ejoc.201301215
The First Stereoselective Total Synthesis of (–)-Synrotolide
Gowravaram Sabitha,*[a] Allu Senkara Rao,[a] AnkiReddy Sandeep,[a] and Jhillu S. Yadav[a]
Keywords: Total synthesis / Natural products / Cross-coupling / Cerium / Protecting groups
The first stereoselective total synthesis of (–)-synrotolide has
been realized by two different approaches, both starting from
(S)-ethyl lactate. Both strategies used stereo- and regioselec-
tive epoxide opening with a nucleophile, aldehyde alkyne
coupling and ring-closing metathesis as key steps. Judicious
choice of reagents (CeCl3·7H2O and H2SiF6) for the chemo-
selective removal of protecting groups delivered the target
molecule.
ranging from cytotoxicity against human tumor cells to an-
tibacterial and/or antifungal activity.[8] To the best of our
knowledge, the total synthesis of synrotolide (1) has not
been reported to date. However, two syntheses[9] on a syn-
thetic derivative of synrotolide, synrotolide diacetate have
been reported. In a continuation of our efforts toward the
synthesis of δ-lactone-containing natural products,[10] in
this communication, we wish to report the first stereoselec-
tive synthesis of synrotolide (1) by using two novel strate-
gies, both starting from commercially available (S)-ethyl
lactate.
Introduction
Natural products possessing the 5,6-dihydro-2H-pyran-2-
one (α,β-unsaturated δ-lactone) structural motif are well-
known for their broad range of biological properties such
as insect growth inhibition, antitumor, antibacterial, anti-
fungal, and immunosuppressive properties.[1] Synrotolide
(1)[2] belongs to this α,β-unsaturated δ-lactone class and
was isolated from the leaves of Syncolostemon rotundifolius.
Spectroscopic as well as X-ray analysis was used to deter-
mine the absolute stereochemistry of synrotolide as 6R-
[3R,6S-(diacetyloxy)-4R,5S-(dihydroxy)-1-heptenyl]-5,6-di-
The retrosynthetic analysis for synrotolide 1 by two ap-
hydro-2H-pyran-2-one. Other related members isolated proaches is depicted in Scheme 1. Synrotolide 1 synthesis
from different species include spicigerolide (2),[3] hyptolide was envisioned by chemoselective deprotection of protect-
(3),[4] anamarine (4),[5] synargentolide A (5),[6] and synparv- ing groups in lactones 7a and 7b. These two lactones could
olide (6)[7] (Figure 1), which possess an array of properties be generated from homoallylic alcohols 8a and 8b by acryl-
Figure 1. Synrotolide type pyranone polyacetates.
[a] Natural Products Chemistry Division, CSIR – Indian Institute
of Chemical Technology,
oylation followed by ring-closing metathesis (RCM) reac-
tion. The key intermediates 8a and 8b could be obtained by
two synthetic strategies involving an aldehyde and alkyne
coupling reaction. Aldehydes 9 and 11 were prepared from
(S)-ethyl lactate.
Hyderabad, A.P. 500007, India
E-mail: gowravaramsr@yahoo.com
sabitha@iict.res.in
www.iictindia.org
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301215.
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G. Sabitha, A. S. Rao, A. Sandeep, J. S. Yadav
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Scheme 1. Retrosynthetic analysis.
removed by using tetrabutylammonium fluoride (TBAF),
HF-Py, trifluoroacetic acid (TFA) and TiCl4. Thus, the free
triols in 17 were silylated by using TBSCl (3 equiv.) to af-
ford fully protected tetrol compound 18. The selective de-
protection of the primary silicon protecting group was
achieved by using p-toluenesulfonic acid (PTSA) in MeOH
at –15 °C to provide free alcohol 19 in 85% yield. Oxidation
of the alcohol afforded aldehyde 9, which was used for the
next reaction without further purification.
Results and Discussion
The first approach for the synthesis of synrotolide 1 started
from PMB-protected alcohol 13, which was prepared from
(S)-ethyl lactate by following
a reported procedure
(Scheme 2).[11] Oxidation of alcohol 13 provided the alde-
hyde, which was then subjected to Wittig olefination for the
homologation of the chain by using a stabilized ylide,
Ph3P=CHCOOEt to give α,β-unsaturated ester 14. The es-
ter group was reduced with diisobutylaluminum hydride
As expected, 1-tert-butyldimethylsilyloxy-2-propyne (10)
(DIBAL-H) in CH2Cl2 to give alcohol 15. The Sharpless reacted with crude aldehyde 9 to afford anti-20 as the major
epoxidation[12] of allyl alcohol 15 with l-(+)-DIPT and isomer (93:7 dr) (Scheme 3).[15] The newly generated hy-
TBHP afforded epoxy alcohol 16 (97:3 dr).[13] To generate droxyl group was acetylated to give monoacetate com-
the chiral center at C4Ј, nucleophilic epoxide ring opening pound 21. Oxidative removal of the PMB group delivered
was conducted with hydroxide ions. The stereo- and re- free hydroxy compound 22, which was acetylated to give
gioselective epoxide ring opening of 2,3-epoxy alcohol 16 23. Deprotection of the primary TBS group was ac-
by using 0.5 n NaOH in H2O/tBuOH (5:1)[12] at 70 °C for complished by using PTSA in MeOH at –15 °C for 30 min
15 h thus provided PMB-protected tetrol 17 (94:6 dr).[14] to provide propargylic alcohol 24. 2-Iodoxybenzoic acid
Here, the selection of protecting groups would play a crucial (IBX) mediated oxidation of the alcohol produced the alde-
role, because reported attempts[9] to deprotect the acetonide hyde, which was subjected to stereoselective allylation with
group in the presence of two OAc groups under different (+)-(Ipc)2B-allyl[16] to provide the expected homoallylic
conditions were not fruitful at the last stage. To this end, alcohol 8a (dr 97:3)[17] in good yield (81%). Acrylation of
we chose silyl and MOM protecting groups in the first and alcohol 8a with acryloyl chloride followed by RCM[18] in
second approach, respectively, assuming that they could be the presence of the second-generation Grubbs’ ruthenium
Scheme 2. Synthesis of aldehyde 9.
456
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The First Stereoselective Total Synthesis of (–)-Synrotolide
Scheme 3. Synthesis of synrotolide 1 (approach 1).
catalyst (10mol-%) afforded lactone 26. Partial hydrogena- oxidized to aldehyde 11, which was used for the next reac-
tion of the triple bond to the Z-olefin with Lindlar’s cata- tion without further purification.
lyst afforded 7a in 93% yield. Attempts to deprotect the
With aldehyde 11 in hand, coupling with alkyne unit 12
TBS groups by using TBAF and HF-Py in tetrahydrofuran was planned. The coupling partner, alkyne fragment 12 was
(THF) failed to give the expected molecule 1. However, we prepared from 3-butyn-1-ol by following the procedure re-
were successful in selective removal of the TBS groups in ported recently by us.[20] Lithiated alkyne 12 reacted with
the presence of two OAc groups. The desilylation was aldehyde 11 to afford alcohol 30a as a mixture of dia-
achieved by the action of H2SiF6 (20–25% in H2O)[19] in stereomers (80:20 dr),[21] which, without separation, was
acetonitrile (CH3CN) to give synrotolide 1 in 93% yield, converted in 94% yield into keto compound 30b by using
the spectroscopic data of which were identical to those of Dess–Martin periodinane (DMP) in CH2Cl2. Ketone 30b
the natural product.
was stereoselectively reduced to the chiral propargyl alcohol
The second approach to the target compound was based 30 in 89% yield by using (R)-2-methyl-CBS-oxazaborolid-
on selective removal of MOM protecting groups. Therefore, ine with the required stereoselectivity (9:1 dr)[21] (Scheme 5).
we planned to synthesize bis-MOM protected aldehyde 11 The newly generated hydroxy group was acetylated with
(Scheme 4).
acetic anhydride to form monoacetate 31. Removal of the
PMB-protected tetrol compound 17, which was prepared PMB group and subsequent acetylation of the resulting
from (S)-ethyl lactate (see Scheme 2), was used as the pre- alcohol 32 provided 33 as described in the first approach.
cursor. Tetrol 17, on treatment with TBSCl and imidazole, Cleavage of the silicon protecting group with TBAF re-
was monosilylated to afford 27 in 93% yield. Further reac- sulted in the formation of homoallylic alcohol 8b as re-
tion with chloromethyl methyl ether (MOMCl) and N,N- ported in Scheme 3. We then assembled the pyranone ring
diisopropylethylamine (DIPEA) in dichloromethane, pro- to give 35 by acryloylation of 8b followed by RCM reaction.
vided the fully protected compound 28, desilylation of Partial hydrogenation of the triple bond to the Z-olefin
which afforded the free alcohol 29. This free alcohol was with Lindlar’s catalyst afforded 7b in 93% yield. The final
Scheme 4. Synthesis of aldehyde 11.
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G. Sabitha, A. S. Rao, A. Sandeep, J. S. Yadav
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Scheme 5. Synthesis of synrotolide 1 (approach 2).
stage of the synthesis required selective deprotection of used stereo- and regioselective epoxide opening with a nu-
MOM groups, which proved to be challenging. Use of cleophile, aldehyde alkyne coupling and RCM reactions as
Lewis acids such as TFA or TiCl4 for deprotection of the the key steps.
MOM groups in the presence of two OAc groups resulted
in decomposition of the starting material. Fortunately, the
Experimental Section
use of CeCl3·7H2O in refluxing CH3CN/MeOH (1:1)[22] de-
livered the desired target molecule, synrotolide 1 in 71%
yield. Deprotection of the MOM groups was also success-
ful, as reported in the first approach, by the action of
H2SiF6 in CH3CN to give synrotolide 1 in 89% yield. Spec-
troscopic data for synthetic 1 matched the reported data for
the natural product in all regards.
General: All reactions were performed under an inert atmosphere.
All glassware used for reactions were oven/flame-dried. Anhydrous
solvents were distilled prior to use: THF from Na and benzo-
phenone; CH2Cl2 from CaH2; MeOH from Mg cake. Commercial
reagents were used without purification. Column chromatography
was carried out by using silica gel (60–120 mesh). Analytical thin-
layer chromatography (TLC) was run on silica gel 60 F254 pre-
coated plates (250 μm thickness). Optical rotations [α]2D5 were mea-
sured with an Anton Paar MCP-200 polarimeter and the concen-
tration c is given in g/100 mL. Infrared spectra were recorded in
CHCl3/KBr (as mentioned) with a Thermo Nicolet Nexus 670
spectrometer and are reported in wave numbers (cm–1). Mass spec-
troscopic data were obtained with MS (EI) ESI, HRMS mass spec-
trometers Quattro Micro Waters. High-resolution mass spectra
(HRMS) [ESI+] were obtained with either a TOF or a double fo-
Conclusions
We have successfully achieved the first total synthesis of
natural product (–)-synrotolide (1) by two different ap-
proaches. The main feature of the synthesis is the chemose-
lective removal of TBS and MOM protecting groups in the
last stage by using CeCl3·7H2O and H2SiF6. Both strategies cusing spectrometer Orbitrap Exactive (Thermo Scientific, Ger-
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The First Stereoselective Total Synthesis of (–)-Synrotolide
1
many). H NMR spectra were recorded at 300, 400, 500 and 13C
20.06 mmol), and the mixture was stirred for 30 min. To this reac-
tion mixture, allyl alcohol 15 (4.05 g, 18.24 mmol) followed, after
an interval of 30 min, by TBHP (5 m in toluene, 18.24 mL,
91.20 mmol) were added and stirring was continued until comple-
tion of the reaction (8 h). The reaction mixture was warmed to
0 °C, filtered through Celite, and the filtrate was quenched with
water (20 mL), and 15 % aqueous NaOH solution (8 mL), and
stirred vigorously for 1 h. The biphasic solution was separated and
the aqueous layer was extracted with CH2Cl2 (2ϫ 50 mL). The
combined organic extracts were dried with anhydrous Na2SO4 and
concentrated under vacuum. The crude residue was purified by col-
umn chromatography (hexane/EtOAc, 7:3) to afford pure epoxide
16 (3.95 g, 91%) as a colorless oil. [α]2D5 = –16.8 (c = 1.2, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.25 (d, J = 8.6 Hz, 2 H), 6.87
(d, J = 8.6 Hz, 2 H), 4.51 (s, 2 H), 3.87 (dd, J = 12.6, 2.7 Hz, 1 H),
3.80 (s, 3 H), 3.59 (dd, J = 12.6, 4.4 Hz, 1 H), 3.49–3.44 (m, 1 H),
3.12–3.09 (m, 1 H), 2.95 (dd, J = 5.1, 2.2 Hz, 1 H), 1.27 (d, J =
6.4 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 159.0, 130.2,
NMR spectra at 75, 125 MHz with Avance-300, Avance-500, and
Inova-400 spectrometers in CDCl3 solution unless otherwise men-
tioned; chemical shifts are given in ppm downfield from tetrameth-
ylsilane and coupling constants (J) are reported in Hertz [Hz]. The
following abbreviations are used to designate signal multiplicity: s
= singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
br = broad. The diastereomeric purity was determined by HPLC
analysis.
(S,E)-Ethyl 4-[(4-Methoxybenzyl)oxy]pent-2-enoate (14): A solution
of oxalyl chloride (4.30 mL, 51.02 mmol) in freshly distilled CH2Cl2
(80 mL) was cooled to –78 °C, and anhydrous DMSO (7.04 mL,
102.04 mmol) in CH2Cl2 (20 mL) was added dropwise. The mixture
was stirred for 15 min at –78 °C, then alcohol 13 (5 g, 25.51 mmol)
in CH2Cl2 (20 mL) was added dropwise. The reaction was stirred
for 30 min at –78 °C then triethylamine (neat, 21.1 mL,
153.04 mmol) was added dropwise. The mixture was stirred for
30 min at –78 °C, then ethoxycarbonylmethylene triphenylphos-
phorane (13.27 g, 38.26 mmol) was added at same temperature, and
the reaction mixture was stirred for 4 h (until room temp.); then it
was transferred to a separatory funnel and washed with H2O
(50 mL), 1 n HCl (50 mL), saturated sodium hydrogen carbonate
(50 mL), then brine (50 mL). Each wash was back-extracted with
CH2Cl2 (2ϫ 50 mL). The combined organic layers were dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography (hexane/
EtOAc, 9:1) to afford 14 (5.85 g, 87% yield from two steps) as a
colorless oil. [α]2D5 = –40.0 (c = 0.90, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.26 (d, J = 8.3 Hz, 2 H), 6.93–6.84 (m, 1 H), 6.88 (d,
J = 8.3 Hz, 2 H), 6.01 (dd, J = 15.8, 1.5 Hz, 1 H), 4.51 (d, J =
12.0 Hz, 1 H), 4.36 (d, J = 12.0 Hz, 1 H), 4.22 (q, J = 6.7 Hz, 2
H), 4.17–4.05 (m, 1 H), 3.81 (s, 3 H), 1.34–1.28 (m, 5 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 166.2, 159.1, 149.2, 130.0, 129.1,
129.0, 113.6, 73.7, 70.9, 61.3, 57.7, 55.1, 17.4 ppm. IR (neat): ν =
˜
3445.3, 2976.3, 2928.9, 1611.8, 1513.0, 1461.6, 1247.9, 1087.8,
1033.7, 821.7, 768.9 cm–1. MS (ESI): m/z = 261 [M + Na]+.
(2R,3R,4S)-4-[(4-Methoxybenzyl)oxy]pentane-1,2,3-triol (17): A
solution of epoxy alcohol 16 (3.75 g, 15.75 mmol) in a mixture of
0.5 n NaOH in H2O/tBuOH (5:1) (75 mL) was stirred for 15 h at
70 °C. Upon completion of the reaction (indicated by TLC), the
mixture was extracted with EtOAc (4ϫ 30 mL), and the organic
extracts were washed with brine (20 mL) and dried with anhydrous
Na2SO4. After evaporation of the solvent, the residue was purified
by column chromatography (3:7, hexane/EtOAc) to furnish triol 17
(2.90 g, 72%) as a colorless liquid. [α]2D5 = + 41.14 (c = 0.70,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 7.25 (d, J = 8.6 Hz, 2
H), 6.89 (d, J = 8.6 Hz, 2 H), 4.60 (d, J = 11.1 Hz, 1 H), 4.40 (d,
J = 11.1 Hz, 1 H), 3.81 (s, 3 H), 3.81–3.66 (m, 5 H), 2.97 (d, J =
2.6 Hz, 1 H), 2.53 (d, J = 3.3 Hz, 1 H), 1.30 (d, J = 5.8 Hz, 3
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 159.3, 129.8, 129.4,
121.1, 113.7, 73.4, 70.2, 60.3, 55.1, 20.5, 14.1 ppm. IR (neat): ν =
˜
2979.1, 1718.7, 1611.8, 1513.4, 1299.0, 1250.0, 1177.2, 1034.7,
113.9, 76.2, 74.0, 72.2, 70.4, 63.8, 55.2, 14.8 ppm. IR (neat): ν =
˜
823.5, 771.8 cm–1. MS (ESI): m/z = 287 [M + Na]+.
3405.8, 2934.1, 1612.4, 1513.4, 1460.7, 1248.1, 1072.2, 1033.6,
823.5 cm–1. MS (ESI): m/z = 279 [M + Na]+. HRMS (ESI): m/z
calcd. for C13H20O5Na [M + Na]+ 279.12029; found 279.11944.
(S,E)-4-[(4-Methoxybenzyl)oxy]pent-2-en-1-ol (15): DIBAL-H
(34.70 mL, 41.66 mmol) was added to a stirred solution of ester 14
(5.50 g, 20.83 mmol) in CH2Cl2 (85 mL) at 0 °C and the mixture
was stirred at the same temperature for 1 h. After monitoring with
TLC, the reaction was quenched with aq. MeOH (5 mL) at 0 °C.
Then a saturated solution of sodium potassium tartrate (35 mL)
was added, and the mixture was extracted with CH2Cl2 (3ϫ
50 mL). The organic layer was washed with brine (2ϫ 40 mL) and
H2O (2ϫ 40 mL) and the combined organic layer was dried with
anhydrous Na2SO4, concentrated under vacuum and the crude
alcohol was purified by column chromatography (hexane/EtOAc,
7:3) to afford 15 (4.16 g, 90% yield) as a colorless oil. [α]2D5 = –27.8
(5S,6R)-6-[(tert-Butyldimethylsilyl)oxy]-5-{(S)-1-[(4-methoxybenz-
yl)oxy]ethyl}-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaun-
decane (18): To an ice-bath cooled solution of triol 17 (0.90 g,
3.51 mmol) and imidazole (1.43 g, 21.09 mmol) in a mixture of an-
hydrous CH2Cl2 (10 mL) and DMF (10 mL) was added a solution
of TBSCl (1.69 g, 3.83 mmol) in anhydrous CH2Cl2 (3 mL). The
mixture was stirred at room temp. for 24 h, then diluted with water
(20 mL) and extracted with diethyl ether (3ϫ 20 mL). The com-
bined organic phases were washed with brine (20 mL) and dried
with anhydrous Na2SO4. The solvent was removed under reduced
pressure and the residue was purified by column chromatography
(hexane/EtOAc, 3:97) to give 18 (1.80 g, 86%) as a colorless oil.
1
(c = 0.90, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.19 (d, J =
7.9 Hz, 2 H), 6.81 (d, J = 7.9 Hz, 2 H), 5.80–5.73 (m, 1 H), 5.62
(dd, J = 15.8, 7.9 Hz, 1 H), 4.45 (d, J = 11.8 Hz, 2 H), 4.29 (d, J
= 11.8 Hz, 2 H), 4.12 (dd, J = 4.9, 0.9 Hz, 2 H), 3.94–3.87 (m, 1
H), 3.78 (s, 3 H), 1.25 (d, J = 5.9 Hz, 3 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 158.9, 134.2, 133.3, 130.8, 129.1, 113.6, 74.7, 69.6,
1
[α]2D5 = + 16.8 (c = 0.20, CHCl3). H NMR (300 MHz, CDCl3): δ
= 7.25 (d, J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6 Hz, 2 H), 4.43 (ABq,
J = 20.2, 11.1 Hz, 2 H), 3.80 (s, 3 H), 3.81–3.61 (m, 4 H), 3.50 (dd,
J = 11.7, 7.7 Hz, 1 H), 1.15 (d, J = 5.8 Hz, 3 H), 0.89 (s, 18 H), 0.85
(s, 9 H), 0.09–0.01 (m, 18 H) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 158.8, 131.0, 129.1, 113.5, 76.8, 75.9, 75.1, 70.4, 65.4, 55.2, 26.1,
26.0, 18.4, 18.3, 18.2, 15.4, –4.1, –4.2, –4.4, –4.7, –5.2, –5.3 ppm.
62.8, 55.2, 21.3 ppm. IR (neat): ν = 3426.4, 2971.9, 1612.1, 1512.8,
˜
1460.5, 1247.2, 1075.6, 1032.6, 820.5 cm–1. MS (ESI): m/z = 241
[M + NH3]+.
IR (neat): ν = 2954.3, 2930.4, 2856.8, 1249.6, 1093.0, 1038.0, 832.3,
˜
((2S,3S)-3-{(S)-1-[(4-Methoxybenzyl)oxy]ethyl}oxiran-2-yl)meth-
anol (16): To a freshly flame-dried double-necked round-bottomed
flask equipped with activated molecular sieves (4 Å, ca. 7 g) and
anhydrous CH2Cl2 (80 mL) at –20 °C were added Ti(OiPr)4
744.0 cm–1. MS (ESI): m/z = 621 [M + Na]+. HRMS (ESI): m/z
calcd. for C31H63O5NaSi3 [M + Na]+ 599.39778; found 599.39658.
(2R,3S,4S)-2,3-Bis[(tert-butyldimethylsilyl)oxy]-4-[(4-methoxy-
(5.34 mL, 18.24 mmol) and l-(+)-diisopropyl tartrate (4.69 g, benzyl)oxy]pentan-1-ol (19): To an ice-salt bath cooled solution of
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G. Sabitha, A. S. Rao, A. Sandeep, J. S. Yadav
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tri-TBS ether 18 (1.75 g, 2.92 mmol) in MeOH (20 mL), was added
PTSA (0.27 g, 1.46 mmol) as a solid. The reaction mixture was
stirred at –15 °C for 30 min, then the reaction was quenched with
(5S,6R,7R)-6-[(tert-Butyldimethylsilyl)oxy]-5-{(S)-1-[(4-methoxy-
benzyl)oxy]ethyl}-2,2,3,3,12,12,13,13-octamethyl-4,11-dioxa-3,12-
disilatetradec-8-yn-7-yl Acetate (21): Anhydrous Et3N (0.63 mL,
solid NaHCO3 (2 g) and filtered. The filtrate was concentrated un- 4.60 mmol), Ac2O (0.236 mL, 2.30 mmol), and DMAP (5 mg) were
der reduced pressure and the crude product was purified by column
chromatography (hexane/EtOAc, 85:15) to afford primary alcohol
19 (1.2 g, 85%) as a colorless oil. [α]2D5 = +24.8 (c = 0.20, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.25 (d, J = 8.6 Hz, 2 H), 6.86
(d, J = 8.6 Hz, 2 H), 4.50 (d, J = 11.4 Hz, 1 H), 4.44 (d, J =
added to a solution of alcohol 20 (1.0 g, 1.533 mmol) in anhydrous
CH2Cl2 (20 mL) at room temp. under a nitrogen atmosphere. The
mixture was stirred at room temp. for 30 min, then the reaction
was quenched with saturated NaHCO3 (10 mL). The organic layer
was extracted with CH2Cl2 (2ϫ 10 mL) and the combined organic
11.4 Hz, 1 H), 3.80 (s, 3 H), 3.82–3.78 (m, 1 H), 3.75–3.71 (m, 1 layers were dried with Na2SO4. The solvent was removed under
H), 3.68–3.62 (m, 3 H), 1.16 (d, J = 6.4 Hz, 3 H), 0.90 (s, 9 H),
0.87 (s, 9 H), 0.11 (s, 3 H), 0.09 (s, 3 H), 0.08 (s, 3 H), 0.04 (s, 3
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 158.9, 130.5, 129.1,
reduced pressure, and the mixture was purified by column
chromatography (hexane/EtOAc, 90:10) to afford 21 (0.987 g, 93%)
as a colorless liquid. [α]2D5 = –13.2 (c = 0.76, CHCl3). 1H NMR
113.6, 76.9, 75.4, 73.4, 70.6, 63.4, 55.1, 25.9, 25.8, 18.2, 18.0, 14.7, (300 MHz, CDCl3): δ = 7.25 (d, J = 8.4 Hz, 2 H), 6.86 (d, J =
–4.3, –4.5, –4.6, –4.7 ppm. IR (neat): ν = 3449.8, 2954.8, 2930.9, 8.4 Hz, 2 H), 5.79–5.75 (m, 1 H), 4.54–4.27 (m, 5 H), 3.91 (dd, J
˜
2856.9, 1513.3, 1465.8, 1250.3, 1091.3, 1037.5, 834.0, 775.7 cm–1.
MS (ESI): m/z = 485 [M + H]+. HRMS (ESI): m/z calcd. for
C25H49O5Si2 [M + H]+ 485.31130; found 485.31062.
= 7.7, 2.2 Hz, 1 H), 3.80 (s, 3 H), 3.68–3.60 (m, 1 H), 2.06 (s, 3 H),
1.08 (d, J = 6.4 Hz, 3 H), 0.91 (s, 9 H), 0.90 (s, 9 H), 0.89 (s, 9 H),
0.15–0.07 (m, 18 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 169.1,
158.8, 129.5, 129.1, 113.5, 79.8, 79.2, 75.0, 74.9, 74.2, 70.0, 66.8,
55.2, 51.6, 26.1, 25.9, 25.7, 21.0, 18.3, 18.2, 12.9, –3.7, –4.0, –4.7,
(5S,6R,7R)-6-[(tert-Butyldimethylsilyl)oxy]-5-{(S)-1-[(4-methoxy-
benzyl)oxy]ethyl}-2,2,3,3,12,12,13,13-octamethyl-4,11-dioxa-3,12-
disilatetradec-8-yn-7-ol (20): A solution of oxalyl chloride (0.31 mL,
3.71 mmol) in freshly distilled CH2Cl2 (10 mL) was cooled to
–78 °C, and anhydrous DMSO (0.58 mL, 7.43 mmol) in CH2Cl2
(2 mL) was added dropwise. The mixture was stirred for 15 min at
–78 °C, then alcohol 19 (0.90 g, 1.85 mmol) in CH2Cl2 (2 mL) was
added dropwise. The reaction was stirred for 1.5 h at –78 °C then
triethylamine (neat, 1.54 mL, 11.15 mmol) was added dropwise.
The mixture was stirred for 30 min at –78 °C then 30 min at 0 °C,
then transferred to a separatory funnel and washed with H2O
(10 mL), 1 n HCl (10 mL), saturated sodium hydrogen carbonate
(10 mL), then brine (10 mL). Each wash was back-extracted with
CH2Cl2 (2ϫ20 mL). The combined organic layers were dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was passed through a short silica plug with 100%
CH2Cl2, concentrated under reduced pressure, and then crude alde-
hyde 9 (0.86 g, 96%, yellow oil) was immediately subjected to the
next reaction without further purification.
–5.0, –5.1, –5.2 ppm. IR (neat): ν = 2954.9, 2931.1, 2857.4, 1768.0,
˜
1513.4, 1466.2, 1251.1, 1224.8, 1093.0, 1032.0, 836.7, 775.6 cm–1.
MS (ESI): m/z = 712 [M + Na]+. HRMS (ESI): m/z calcd. for
C36H70O7NaSi3 [M + Na]+ 712.44546; found 712.44514.
(5S,6R,7R)-6-[(tert-Butyldimethylsilyl)oxy]-5-[(S)-1-hydroxyethyl]-
2,2,3,3,12,12,13,13-octamethyl-4,11-dioxa-3,12-disilatetradec-8-yn-
7-yl Acetate (22): To an ice-bath cooled solution of 21 (0.95 g,
1.36 mmol) in aq. CH2Cl2 (20 mL; CH2Cl2/buffer (pH 7), 9:1),
DDQ (0.34 g, 1.50 mmol) was added and the reaction mixture was
stirred for 1 h at 0 °C. The reaction mixture was washed with 5%
aq. NaHCO3 solution (15 mL), the layers were separated and the
aqueous layer was extracted with CH2Cl2 (2ϫ 10 mL). The com-
bined organic extracts were washed with water, dried with anhy-
drous Na2SO4, and concentrated in vacuo. The crude product was
purified by column chromatography (hexane/EtOAc, 90:10) to af-
ford alcohol 22 (0.695 g, 89%) as a liquid. [α]2D5 = –29.50 (c = 0.68,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 5.69–5.67 (m, 1 H), 4.34
(d, J = 1.6 Hz, 2 H), 4.06–3.99 (m, 1 H), 3.76–3.72 (m, 2 H), 2.09
(s, 3 H), 1.16 (d, J = 6.4 Hz, 3 H), 0.92 (s, 18 H), 0.89 (s, 9 H),
0.19 (s, 3 H), 0.16 (s, 3 H), 0.13 (s, 3 H), 0.10 (s, 9 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 169.1, 85.9, 79.3, 76.9, 76.2, 66.7,
51.6, 26.0, 25.9, 25.7, 20.9, 18.3, 18.2, 17.3, –4.0, –4.2, –4.3, –4.5,
nBuLi (2.5 m in hexanes, 1.06 mL, 2.67 mmol) was added to a solu-
tion of alkyne 10 (0.454 g, 2.67 mmol) in THF (10 mL) at –78 °C.
After stirring for 5 min, the reaction mixture was warmed to –20 °C
and stirred for 30 min. The mixture was cooled back to –78 °C and
a solution of crude aldehyde 9 (0.86 g, 1.784 mmol) in THF (5 mL)
was added dropwise. The resulting mixture was stirred for 2 h at
–78 °C, then the mixture was poured onto saturated aqueous
NH4Cl solution (20 mL) and extracted with EtOAc (3ϫ 10 mL).
The combined organic extracts were washed with brine (20 mL),
dried with Na2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography (90:10, hexane/
–5.2 ppm. IR (neat): ν = 3455.1, 2955.4, 2931.5, 2858.0, 1748,
˜
1466.7, 1367.6, 1253.7, 1092.4, 1022.1, 836.0, 776.3 cm–1. MS
(ESI): m/z = 592 [M + Na]+. HRMS (ESI): m/z calcd. for
C28H62O6NaSi3 [M + Na]+ 592.38794; found 592.38680.
(2S,3S,4R,5R)-3,4,8-Tris[(tert-butyldimethylsilyl)oxy]oct-6-yne-2,5-
diyl Diacetate (23): Anhydrous Et3N (0.47 mL, 3.39 mmol), Ac2O
(0.173 mL, 1.69 mmol), and DMAP (5 mg) were added to a solu-
EtOAc) to afford 20 (1.10 g, 91% yield over 2 steps) as almost tion of alcohol 22 (0.65 g, 1.13 mmol) in anhydrous CH2Cl2
completely a single diastereomer (93:7 dr) as a colorless liquid.
(20 mL) at room temp. under a nitrogen atmosphere. The mixture
was stirred at room temp. for 30 min. The reaction was quenched
1
[α]2D5 = –11.5 (c = 0.50, CHCl3). H NMR (500 MHz, CDCl3): δ =
7.26 (d, J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6 Hz, 2 H), 4.56–4.39 (m, with saturated NaHCO3 (10 mL) and the organic layer was ex-
3 H), 4.38–4.28 (m, 2 H), 3.91–3.83 (m, 1 H), 3.79 (s, 3 H), 3.76 (t, tracted with CH2Cl2 (2ϫ 10 mL). The combined organic layers
J = 6.1 Hz, 1 H), 3.43 (d, J = 6.1 Hz, 1 H), 1.18 (d, J = 6.2 Hz, 3 were dried with Na2SO4, the solvent was removed under reduced
H), 0.90 (s, 9 H), 0.89 (s, 18 H), 0.13 (s, 3 H), 0.12 (s, 3 H), 0.10 pressure, and the mixture was purified by column chromatography
(s, 3 H), 0.09 (s, 3 H), 0.08 (s, 3 H), 0.06 (s, 3 H) ppm. 13C NMR (hexane/EtOAc, 95:5) to afford 23 (0.64 g, 92%) as a colorless li-
(CDCl3, 125 MHz): δ = 159.1, 130.0, 129.5, 113.6, 84.5, 84.1, 77.7,
76.8, 74.9, 70.7, 65.1, 55.1, 51.7, 26.0, 25.9, 25.8, 18.2, 18.1, 15.3,
quid. [α]2D5 = –24.4 (c = 0.50, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 5.73 (d, J = 1.8 Hz, 1 H), 5.27 (qd, J = 6.4, 1.8 Hz, 1 H), 4.34
–4.4, –5.1, –5.2 ppm; IR (neat): ν = 3448.4, 2930.9, 2857.4, 1513.5, (d, J = 1.5 Hz, 2 H), 3.86 (dd, J = 8.1, 1.7 Hz, 1 H), 3.63 (dd, J =
˜
1250.8, 1088.7, 835.6, 773.2 cm–1. MS (ESI): m/z = 670 [M + Na]+. 8.1, 2.4 Hz, 1 H), 2.09 (s, 3 H), 2.04 (s, 3 H), 1.16 (d, J = 6.4 Hz,
HRMS (ESI): m/z calcd. for C34H68O6NaSi3 [M + Na]+ 670.43489; 3 H), 0.93 (s, 18 H), 0.88 (s, 9 H), 0.17 (s, 3 H), 0.15 (s, 3 H), 0.14
found 670.43418.
(s, 3 H), 0.11 (s, 3 H), 0.09 (s, 6 H) ppm. 13C NMR (CDCl3,
460
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 455–465

The First Stereoselective Total Synthesis of (–)-Synrotolide
75 MHz): δ = 169.8, 169.1, 86.0, 78.7, 74.9, 74.8, 71.0, 66.6, 51.6,
26.0, 25.9, 25.7, 21.3, 20.9, 18.3, 18.2, 12.8, –4.0, –4.1, –4.7, –4.8,
(0.073 mL, 0.830 mmol) was added dropwise under N2 to a solu-
tion of alcohol 8a (0.30 g, 0.553 mmol) and Et3N (0.220 mL,
1.66 mmol) in CH2Cl2 (10 mL). The mixture was stirred at 0 °C for
–5.2, –5.3 ppm. IR (neat): ν = 2955.4, 2931.8, 2858.2, 1746.3,
˜
1467.3, 1369.1, 1253.0, 1224.7, 1156.6, 1089.5, 1027.9, 835.8, 1 h. Upon completion, the mixture was poured into brine (2 mL)
777.8 cm–1. MS (ESI): m/z = 634 [M + Na]+. HRMS (ESI): m/z
and extracted with CH2Cl2 (2ϫ 10 mL). The organic phase was
washed with 1M aq. HCl, dried with anhydrous Na2SO4, and con-
centrated. The crude product was purified by column chromatog-
raphy (hexane/EtOAc, 95:5) to afford the corresponding acrylic es-
ter 25 (0.275 g, 84%) as a colorless oil. [α]2D5 = –35.0 (c = 0.72,
CHCl3); 1H NMR (500 MHz, CDCl3): δ = 6.41 (dd, J = 17.1,
1.1 Hz, 1 H), 6.09 (dd, J = 17.3, 10.3 Hz, 1 H), 5.89–5.74 (m, 3 H),
5.60–5.52 (m, 1 H), 5.27 (qd, J = 6.4, 1.7 Hz, 1 H), 5.20–5.07 (m,
2 H), 3.83 (dd, J = 8.4, 1.7 Hz, 1 H), 3.62 (dd, J = 8.6, 2.0 Hz, 1
H), 2.60–2.51 (m, 2 H), 2.09 (s, 3 H), 2.05 (s, 3 H), 1.15 (d, J =
6.4 Hz, 3 H), 0.92 (s, 18 H), 0.15 (s, 3 H), 0.14 (s, 3 H), 0.13 (s, 3
H), 0.10 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 169.8,
169.1, 164.7, 132.0, 131.3, 127.9, 118.7, 84.3, 80.1, 74.7, 70.9, 66.4,
63.0, 39.0, 25.9, 25.8, 21.3, 21.0, 18.3, 12.5, –4.0, –4.8, –4.9 ppm.
calcd. for C30H64O7NaSi3 [M + Na]+ 634.39851; found 634.39795.
(2S,3S,4R,5R)-3,4-Bis[(tert-butyldimethylsilyl)oxy]-8-hydroxyoct-
6-yne-2,5-diyl Diacetate (24): To an ice-bath cooled solution of the
tri-TBS ether 23 (0.60 g, 0.974 mmol) in MeOH (10 mL) was added
PTSA (0.089 g, 0.487 mmol) as a solid. The reaction mixture was
stirred at –15 °C for 30 min, then the reaction was quenched with
solid NaHCO3 (1 g) and filtered. The filtrate was concentrated un-
der reduced pressure and the crude product was purified by column
chromatography (hexane/EtOAc, 85:15) to afford primary alcohol
24 (0.44 g, 91%) as a colorless oil. [α]2D5 = –21.7 (c = 0.60, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 5.71–5.69 (m, 1 H), 5.28 (qd, J
= 6.2, 2.1 Hz, 1 H), 4.33–4.26 (m, 2 H), 3.87 (dd, J = 7.9, 2.1 Hz,
1 H), 3.68 (dd, J = 7.7, 2.5 Hz, 1 H), 2.01 (s, 3 H), 2.06 (s, 3 H),
1.18 (d, J = 6.4 Hz, 3 H), 0.94 (s, 9 H), 0.93 (s, 9 H), 0.17 (s, 3 H),
0.15 (s, 3 H), 0.14 (s, 3 H), 0.12 (s, 3 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 170.0, 169.3, 85.7, 80.0, 74.9, 74.8, 71.1, 66.5, 50.9,
25.9, 25.8, 21.3, 20.9, 18.3, 12.9, –4.1, –4.2, –4.6, –4.8 ppm. IR
IR (neat): ν = 2987.5, 2934.5, 1736.6, 1374.8, 1231.6, 1180.4,
˜
1064.2, 1023.4, 983.1 cm–1. MS (ESI): m/z = 614 [M + Na]+.
HRMS (ESI): m/z calcd. for C30H64O8NaSi2 [M + Na]+ 614.35390;
found 614.35304.
(neat): ν = 3453.7, 2932.7, 2858.5, 1745.7, 1370.0, 1253.4, 1225.2,
˜
(2S,3S,4R,5R)-3,4-Bis[(tert-butyldimethylsilyl)oxy]-7-[(R)-6-oxo-
3,6-dihydro-2H-pyran-2-yl]hept-6-yne-2,5-diyl Diacetate (26): A
solution of Grubbs’ second-generation catalyst (G-II; 0.033 g,
0.0419 mmol, 10 mol-%) in CH2Cl2 (10 mL) was added dropwise
1155.4, 1116.5, 1028.5, 834.4, 774.9 cm–1. MS (ESI): m/z = 520 [M
+ Na]+. HRMS (ESI): m/z calcd. for C24H50O7NaSi2 [M + Na]+
520.31203; found 520.31014.
(2S,3S,4R,5R,8R)-3,4-Bis[(tert-butyldimethylsilyl)oxy]-8-hydroxy- to a solution of acrylic ester 25 (0.250 g, 0.419 mmol) in CH2Cl2
undec-10-en-6-yne-2,5-diyl Diacetate (8a): To an ice-cooled solution
of IBX (0.34 g, 1.195 mmol) in DMSO (0.27 mL, 3.98 mmol) and
CH2Cl2 (5 mL), was added a solution of alcohol 24 (0.40 g,
0.79 mmol) in CH2Cl2 (5 mL). The mixture was stirred at room
temp. for 2 h and then filtered through a Celite pad and washed
with Et2O (30 mL). The combined organic filtrates were washed
with H2O (2ϫ 10 mL) and brine (10 mL), dried (Na2SO4), and
concentrated in vacuo. The crude aldehyde (0.358 g, 90%, yellow
oil) was immediately subjected to the next reaction without further
purification.
(60 mL) at room temp., and stirring was continued for 5 h while
heating to reflux. The solvent was evaporated and the crude prod-
uct was purified by column chromatography (hexane/EtOAc, 75:25)
to give lactone 26 (0.219 g, 92%) as a pale-yellow oil. [α]2D5 = –19.50
1
(c = 0.70, CHCl3). H NMR (500 MHz, CDCl3): δ = 6.86 (dt, J =
9.9, 4.4 Hz, 1 H), 6.07 (dt, J = 9.9, 1.8 Hz, 1 H), 5.75 (dd, J = 2.2,
1.6 Hz, 1 H), 5.28–5.22 (m, 2 H), 3.81 (dd, J = 8.3, 1.9 Hz, 1 H),
3.65 (dd, J = 8.3, 2.2 Hz, 1 H), 2.72–2.58 (m, 2 H), 2.10 (s, 3 H),
2.06 (s, 3 H), 1.16 (d, J = 6.5 Hz, 3 H), 0.94 (s, 9 H), 0.93 (s, 9 H),
0.15 (s, 3 H), 0.14 (s, 6 H), 0.11 (s, 3 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 169.7, 169.2, 161.9, 143.6, 121.2, 82.4, 80.7, 77.9,
74.7, 68.2, 66.5, 62.2, 29.6, 25.9, 25.8, 20.9, 20.5, 17.5, 18.3, –4.1,
To a solution of (+)-IPC2B(allyl) (1.0 m in pentane, 0.86 mL,
0.860 mmol) in Et2O (10 mL) at –100 °C, a solution of the above
crude aldehyde (0.358, 0.717 mmol) in Et2O (5 mL) was added
slowly. The mixture was stirred at –100 °C for 2 h and then warmed
to 0 °C. The reaction was quenched by dropwise addition of H2O
(15 mL), then the mixture was diluted with Et2O (20 mL) and the
layers were separated. The aqueous layer was extracted with Et2O
(2ϫ 10 mL) and the combined organic layers were washed with
brine, dried with anhydrous Na2SO4, filtered, and concentrated.
The crude reaction mixture was further purified by column
chromatography (hexane/EtOAc, 95:5) to give homoallyl alcohol
8a (0.345 g, 81% over 2 steps) as a clear liquid. [α]2D5 = –18.6 (c =
0.90, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 5.95–5.79 (m, 1
H), 5.74–5.70 (m, 1 H), 5.29 (qd, J = 6.6, 1.8 Hz, 1 H), 5.22–5.12
(m, 2 H), 4.49–4.40 (m, 1 H), 3.86 (dd, J = 8.3, 1.8 Hz, 1 H), 3.64
(dd, J = 8.3, 2.2 Hz, 1 H), 2.42–2.32 (m, 2 H), 2.10 (s, 3 H), 2.06
(s, 3 H), 1.13 (d, J = 7.3 Hz, 3 H), 0.93 (s, 9 H), 0.92 (s, 9 H), 0.17
(s, 3 H), 0.16 (s, 3 H), 0.15 (s, 3 H), 0.12 (s, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 170.0, 169.3, 132.9, 118.8, 88.0, 79.2, 74.8,
74.7, 71.0, 66.6, 61.4, 41.8, 25.9, 25.8, 21.4, 21.0, 18.3, 12.6, –4.0,
–4.2, –4.6, –4.8 ppm. IR (neat): ν = 2988.3, 2937.4, 1736.8, 1376.0,
˜
1244.1, 1058.1, 863.8 cm–1. MS (ESI): m/z = 586 [M + Na]+.
HRMS (ESI): m/z calcd. for C28H52O8NaSi2 [M + Na]+ 586.32260;
found 586.32146.
(2S,3S,4R,5R,Z)-3,4-Bis[(tert-butyldimethylsilyl)oxy]-7-(6-oxo-
3,6-dihydro-2H-pyran-2-yl)hept-6-ene-2,5-diyl Diacetate (7a): To a
solution of 26 (0.20 g, 0.352 mmol) in EtOAc (5 mL), one drop of
quinoline and Lindlar’s catalyst (Pd/BaSO4 ) (0.0035 g,
0.0352 mmol, 10 mol-%) were added and the mixture was stirred at
room temp. under H2 for 15 min. After completion of the reaction,
the reaction mixture was filtered and the solvent was removed un-
der reduced pressure. The crude product was purified by column
chromatography (hexane/EtOAc, 75:25) to afford 26 (0.186 g, 93%)
as a colorless liquid. [α]2D5 = –20.10 (c = 0.80, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 6.94–6.85 (m, 1 H), 6.09–6.03 (m, 1 H),
5.86 (ddd, J = 8.8, 8.0, 0.6 Hz, 1 H), 5.63 (ddd, J = 10.4, 9.3,
0.9 Hz, 1 H), 5.50–5.38 (m, 2 H), 4.49–4.85 (m, 1 H), 4.33–4.16 (m,
2 H), 2.45–2.40 (m, 2 H), 2.09 (s, 3 H), 2.06 (s, 3 H), 1.35 (d, J =
6.1 Hz, 3 H), 0.94 (s, 18 H), 0.14 (s, 3 H), 0.13 (s, 6 H), 0.11 (s, 3
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 170.2, 169.5, 165.1,
143.8, 132.4, 128.4, 122.3, 77.8, 75.1, 71.3, 66.8, 30.0, 26.3, 26.2,
–4.1, –4.7, –4.9 ppm. IR (neat): ν = 3430.8, 2932.4, 2858.7, 1744.9,
˜
1341.4, 1253.4, 1225.3, 1155.9, 1118.6, 1031.8, 834.2, 776.4 cm–1.
MS (ESI): m/z = 496 [M + Na]+.
(2S,3S,4R,5R,8R)-8-(Acryloyloxy)-3,4-bis[(tert-butyldimethylsilyl)- 21.8, 21.4, 18.7, 17.1, –3.6, –4.3, –4.5 ppm. IR (neat): ν = 1737.4,
˜
oxy]undec-10-en-6-yne-2,5-diyl Diacetate (25): Acryloyl chloride
1376.8, 1244.8, 1058.4, 817.1 cm–1. MS (ESI): m/z = 588
Eur. J. Org. Chem. 2014, 455–465
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
461

G. Sabitha, A. S. Rao, A. Sandeep, J. S. Yadav
FULL PAPER
[M + Na]+. HRMS (ESI): m/z calcd. for C28H54O8NaSi2
anhydrous THF (20 mL) was added TBAF (1M in THF, 4.56 mL,
4.56 mmol) dropwise at 0 °C, and the mixture was stirred for
30 min. H2O (5 mL) was added, and the mixture was extracted with
EtOAc. The organic extracts were washed with brine and dried
with anhydrous Na2SO4. After evaporation of the solvent, the resi-
due was purified by column chromatography (hexane/EtOAc, 7:3)
[M + Na]+ 588.32362; found 588.32446.
(2S,3R,4S,5R,Z)-3,4-Dihydroxy-7-(6-oxo-3,6-dihydro-2H-pyran-2-
yl)hept-6-ene-2,5-diyl Diacetate (1): To a solution of 7a (4.0 mg,
0.0047 mmol) in MeCN (1 mL) was added fluorosilicic acid
(H2SiF6; 20–25 wt.-% in water, 0.1 mL). After 2 d stirring at room
temp., the mixture was filtered through a Celite pad and concen-
trated under reduced pressure. Purification by column chromatog-
raphy gave synrotolide 1 (2.0 mg, 90%). [α]2D5 = –24.8 (c = 0.20,
MeOH). 1H NMR (500 MHz, [D6]DMSO): δ = 7.10–7.02 (m, 1
H), 6.00–5.95 (m, 1 H), 5.82 (dd, J = 11.1, 8.8 Hz, 1 H), 5.72 (dd,
J = 10.8, 10.5 Hz, 1 H), 5.64–5.58 (m, 1 H), 5.38 (d, J = 5.9 Hz, 1
H), 5.34–5.26 (m, 1 H), 5.04 (d, J = 5.9 Hz, 1 H), 5.05–5.00 (m, 1
H), 3.54–3.46 (m, 1 H), 3.35–3.29 (m, 1 H), 2.45–2.34 (m, 2 H),
2.01 (s, 3 H), 1.99 (s, 3 H), 1.09 (d, J = 6.4 Hz, 3 H) ppm. 13C
NMR ([D6]DMSO, 125 MHz): δ = 169.8, 169.5, 163.3, 147.1,
131.9, 126.8, 120.1, 73.9, 71.3, 71.1, 71.0, 70.0, 29.5, 21.1, 20.7,
to furnish alcohol 29 (1.35 g, 95%) as a colorless liquid. [α]2D5
=
+29.40 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.26
(d, J = 9.0 Hz, 2 H), 6.87 (d, J = 9.0 Hz, 2 H), 4.80 (d, J = 6.7 Hz,
1 H), 4.74 (d, J = 6.0 Hz, 1 H), 4.73 (d, J = 6.0 Hz, 1 H), 4.65 (d,
J = 6.7 Hz, 1 H), 4.50 (ABq, J = 11.3, 2.3 Hz, 2 H), 3.88–3.83 (m,
1 H), 3.80 (s, 3 H), 3.81–3.66 (m, 4 H), 3.41 (s, 3 H), 3.39 (s, 3 H),
1.24 (d, J = 6.7 Hz, 3 H), ppm. 13C NMR (CDCl3, 125 MHz): δ =
159.1, 130.3, 129.1, 113.7, 97.4, 96.5, 79.7, 78.9, 74.6, 70.5, 62.0,
56.1, 55.7, 55.2, 15.0 ppm. IR (neat): ν = 3453.6, 2933.5, 1611.6,
˜
1513.3, 1248.3, 1202.4, 1030.7, 917.8, 822.7 cm–1. MS (ESI): m/z =
367 [M + Na]+. HRMS (ESI): m/z calcd. for C17H28O7Na [M +
Na]+ 367.17272; found 367.17140.
12.8 ppm. IR (neat): ν = 3449.4, 2921.7, 1739.3, 1642.9, 1377.7,
˜
1258.8, 1022.4 cm–1. MS (ESI): m/z = 365 [M + Na]+. HRMS
(ESI): m/z calcd. for C16H22O8Na [M + Na]+ 365.12069; found
365.12034.
(5S,6S,10R)-10-Allyl-5-{(S)-1-[(4-methoxybenzyl)oxy]ethyl}-6-
(methoxymethoxy)-12,12,13,13-tetramethyl-2,4,11-trioxa-12-sila-
tetradec-8-yn-7-one (30b): A solution of oxalyl chloride (0.44 mL,
5.23 mmol) in freshly distilled CH2Cl2 (10 mL) was cooled to
–78 °C, and anhydrous DMSO (0.74 mL, 10.40 mmol) in CH2Cl2
(2 mL) was added dropwise. The mixture was stirred for 15 min at
–78 °C, then alcohol 29 (0.90 g, 2.61 mmol) in CH2Cl2 (2 mL) was
added dropwise. The reaction was stirred for 1.5 h at –78 °C, then
triethylamine (neat, 2.17 mL, 15.69 mmol) was added dropwise.
The mixture was stirred for 30 min at –78 °C then for 30 min at
0 °C, then transferred to a separatory funnel and washed with H2O
(10 mL), 1 n HCl (10 mL), saturated sodium hydrogen carbonate
(10 mL), then brine (10 mL). Each wash was back-extracted with
CH2Cl2 (2ϫ 20 mL). The combined organic layers were dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was passed through a short silica plug with 100%
CH2Cl2, concentrated under reduced pressure, and then crude alde-
hyde 11 (0.89 g, 95%, yellow oil) was immediately subjected to the
next reaction without further purification.
(2R,3R,4S)-1-[(tert-Butyldimethylsilyl)oxy]-4-[(4-methoxybenzyl)-
oxy]pentane-2,3-diol (27): To a stirred solution of triol 17 (1.25 g,
4.88 mmol) in CH2Cl2 (30 mL), imidazole (0.66 g, 9.84 mmol) was
added at 0 °C and the mixture was stirred for 15 min. tert-Butyl
dimethyl silyl chloride (0.73 g, 4.88 mmol) was added at 0 °C and
the mixture was stirred for 1 h. Upon completion of the reaction
(indicated by TLC), the reaction mixture was concentrated under
reduced pressure and purified by chromatography (hexane/EtOAc,
8:2) to give 27 (1.68, 93%) as a colorless liquid. [α]2D5 = +22.0 (c =
1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.25 (d, J = 8.6 Hz,
2 H), 6.88 (d, J = 8.6 Hz, 2 H), 4.57 (d, J = 11.1 Hz, 1 H), 4.41 (d,
J = 11.1 Hz, 1 H), 3.80 (s, 3 H), 3.81–3.62 (m, 5 H), 1.28 (d, J =
6.1 Hz, 3 H), 0.90 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 159.3, 129.8, 129.4, 113.9, 76.2, 74.0,
72.2, 70.4, 63.8, 55.2, 14.8 ppm. IR (neat): ν = 3452.1, 2931.3,
˜
2858.0, 1612.8, 1513.6, 1465.1, 1250.6, 1078.9, 1037.9, 836.1,
778.3 cm–1. MS (ESI): m/z = 393 [M + Na]+. HRMS (ESI): m/z
calcd. for C19H34O5NaSi [M + Na]+ 393.20677; found 393.20516.
nBuLi (2.5 m in hexanes, 1.36 mL, 3.4 mmol) was added to a solu-
tion of alkyne 12 (0.65 g, 3.10 mmol) in THF (10 mL) at –78 °C.
After stirring for 1 h at –78 °C, a solution of aldehyde 11 (0.89 g,
2.58 mmol) in THF (8 mL) was added dropwise. The resulting mix-
ture was stirred for 2 h at –78 °C, then poured onto saturated aque-
ous NH4Cl solution (20 mL) and extracted with EtOAc (3 ϫ
30 mL). The combined organic extracts were washed with brine
(20 mL), dried with Na2SO4, and concentrated under reduced pres-
sure to afford the crude product 30a (1.08 g, 82% over 2 steps) as
a mixture of non-separable diastereoisomers (80:20 dr) as an oil.
The crude aldehyde 30a was immediately subjected to the next reac-
tion without further purification.
(5S,6R)-5-{(S)-1-[(4-Methoxybenzyl)oxy]ethyl}-6-(methoxymeth-
oxy)-9,9,10,10-tetramethyl-2,4,8-trioxa-9-silaundecane (28): To diol
27 (1.65 g, 4.45 mmol) in anhydrous CH2Cl2 (30 mL) at 0 °C, were
successively added DIPEA (3.81 mL, 22.29 mmol), catalytic
DMAP and MOMCl (1.10 mL, 13.35 mmol). The mixture was
stirred for 4 h at room temp., then the reaction was quenched by
adding water (20 mL) and the mixture was extracted with CH2Cl2
(2ϫ 25 mL). The organic extracts were washed with brine (20 mL),
dried with anhydrous Na2SO4, and concentrated under vacuo to
remove the solvent. The crude material was purified by column
chromatography (hexane/EtOAc, 9:1) to afford the pure product 28
(1.94 g, 95%) as an oil. [α]2D5 = –13.00 (c = 0.40, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.26 (d, J = 9.0 Hz, 2 H), 6.86 (d, J =
9.0 Hz, 2 H), 4.82–4.65 (m, 4 H), 4.48 (ABq, J = 11.3, 4.3 Hz, 2
H), 3.88–3.69 (m, 5 H), 3.80 (s, 3 H), 3.39 (s, 3 H), 3.35 (s, 3 H),
1.25 (d, J = 6.0 Hz, 3 H), 0.89 (s, 9 H), 0.04 (s, 6 H), 0.07 ppm.
13C NMR (CDCl3, 125 MHz): δ = 158.9, 130.7, 129.0, 113.6, 96.9,
96.5, 78.3, 78.1, 74.6, 70.2, 63.5, 55.9, 55.6, 55.1, 25.8, 18.2, 15.3,
Dess–Martin periodinane (0.88 g, 2.09 mmol) and NaHCO3
(0.20 g, 2.28 mmol) were added to alcohol 30a (1.05 g, 1.90 mmol)
in CH2Cl2 (20 mL) at 0 °C. After stirring for 30 min, the reaction
was warmed to 25 °C for 1 h. After 30 min, the reaction was diluted
with hexanes and filtered through Celite. The filtrate was concen-
trated in vacuo and the residue was purified by silica gel
chromatography (hexane/EtOAc, 9:1) to afford ketone 30b (0.98 g,
94%) as a colorless liquid. [α]2D5 = –19.8 (c = 0.50, CHCl3). 1H
NMR (500 MHz, CDCl3): δ = 7.24 (d, J = 8.6 Hz, 2 H), 6.85 (d,
J = 8.6 Hz, 2 H), 5.85–5.76 (m, 1 H), 5.15–5.08 (m, 2 H), 4.79 (d,
J = 6.7 Hz, 1 H), 4.74 (ABq, J = 8.2, 6.7 Hz, 2 H), 4.70 (d, J =
–5.3, –5.4 ppm. IR (neat): ν = 2930.7, 2856.3, 1613.2, 1513.4,
˜
1465.8, 1249.8, 1101.9, 1033.5, 836.6, 774.4 cm–1. MS (ESI): m/z =
481 [M + Na]+.
(2R,3S,4S)-4-[(4-Methoxybenzyl)oxy]-2,3-bis(methoxymeth- 6.7 Hz, 1 H), 4.48–4.36 (m, 4 H), 4.13 (dd, J = 7.4, 3.3 Hz, 1 H),
oxy)pentan-1-ol (29): To a solution of 28 (1.90 g, 4.14 mmol) in 3.79 (s, 3 H), 3.78–3.72 (m, 1 H), 3.40 (s, 3 H), 3.39 (s, 3 H), 2.43–
462
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 455–465

The First Stereoselective Total Synthesis of (–)-Synrotolide
2.39 (m, 2 H), 1.21 (d, J = 6.2 Hz, 3 H), 0.89 (s, 9 H), 0.12 (s, 3
H), 0.08 (s, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 184.7,
158.8, 132.9, 130.5, 129.2, 118.3, 113.4, 96.3, 96.2, 82.1, 81.2, 80.0,
(5S,6R,7R,10R)-10-Allyl-5-[(S)-1-hydroxyethyl]-6-(methoxymeth-
oxy)-12,12,13,13-tetramethyl-2,4,11-trioxa-12-silatetradec-8-yn-7-yl
Acetate (32): To an ice-bath cooled solution of 31 (0.75 g,
73.2, 70.5, 62.6, 56.1, 55.9, 55.1, 42.2, 25.6, 18.0, 16.3 ppm. IR 1.26 mmol) in aq. CH2Cl2 (20 mL; CH2Cl2/buffer (pH 7), 9:1),
(neat): ν = 2933.4, 2895.5, 1683.4, 1613.2, 1513.7, 1250.1, 1149.7,
DDQ (0.31 g, 1.38 mmol) was added and the reaction mixture was
stirred for 1 h at 0 °C. The reaction mixture was washed with 5%
aq. NaHCO3 solution (10 mL), the layers were separated, and the
aqueous layer was extracted with CH2Cl2 (2ϫ 10 mL). The com-
bined organic extracts were washed with water, dried with anhy-
drous Na2SO4, and concentrated in vacuo. The crude product was
purified by column chromatography (hexane/EtOAc, 80:20) to af-
ford alcohol 32 (0.53 g, 90%) as a liquid. [α]2D5 = –8.6 (c = 0.50,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 5.87–5.77 (m, 1 H), 5.75
(dd, J = 3.9, 1.8 Hz, 1 H), 5.14–5.07 (m, 2 H), 4.98 (d, J = 6.8 Hz,
1 H), 4.73 (d, J = 6.8 Hz, 1 H), 4.67 (d, J = 6.8 Hz, 1 H), 4.60 (d,
J = 6.8 Hz, 1 H), 4.40 (td, J = 6.4, 1.6 Hz, 1 H), 4.07–4.00 (m, 1
H), 3.81 (dd, J = 7.0, 4.1 Hz, 1 H), 3.68 (dd, J = 7.0, 3.5 Hz, 1 H),
3.44 (s, 3 H), 3.42 (s, 3 H), 2.84 (br. s, 1 H), 2.43–2.39 (m, 2 H),
2.11 (s, 3 H), 1.25 (d, J = 6.5 Hz, 3 H), 0.89 (s, 9 H), 0.11 (s, 3 H),
0.09 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 169.6, 133.5,
117.9, 98.3, 97.9, 88.3, 83.8, 79.6, 78.5, 66.5, 63.5, 62.6, 56.4, 56.2,
˜
1100.0, 1034.1, 918.8, 836.1, 778.9 cm–1. MS (ESI): m/z = 573 [M
+ Na]+. HRMS (ESI): m/z calcd. for C29H46O8NaSi [M + Na]+
573.28542; found 573.28269.
(5S,6R,7R,10R)-10-Allyl-5-{(S)-1-[(4-methoxybenzyl)oxy]ethyl}-6-
(methoxymethoxy)-12,12,13,13-tetramethyl-2,4,11-trioxa-12-sila-
tetradec-8-yn-7-ol (30): To a stirred solution of R-CBS catalyst (1M
in toluene, 0.17 mL, 0.17 mmol) in THF (5 mL), BH3·DMS (2M
in THF, 0.97 mL, 1.95 mmol) was added at 0 °C and the mixture
was stirred for 0.5 h. The mixture was cooled to –78 °C, then a
concentrated solution of keto compound 30b (0.98 g, 1.77 mmol)
in THF (0.5 mL) was added, and the mixture was stirred for 8 h at
–78 °C. The mixture was quenched with MeOH (1 mL) at –78 °C
and warmed to room temp., then the solvent was removed under
reduced pressure and the residue was purified by column
chromatography (hexane/EtOAc, 9:1) to afford the pure product 30
(0.87 g, 89%) as an oil. [α]2D5 = +5.5 (c = 0.40, CHCl3); H NMR
1
42.7, 25.6, 20.8, 18.1, 17.5, –4.6, –5.1 ppm. IR (neat): ν = 3445.5,
˜
2931.6, 1594.8, 1458.7, 1420.6, 1119.3, 1033.5, 768.7 cm–1. MS
(ESI): m/z = 497 [M + Na]+. HRMS (ESI): m/z calcd. for
C23H42O8NaSi [M + Na]+ 497.25412; found 497.25057.
(300 MHz, CDCl3): δ = 7.26 (d, J = 8.6 Hz, 2 H), 6.87 (d, J =
8.6 Hz, 2 H), 5.95–5.78 (m, 1 H), 5.16–5.04 (m, 2 H), 4.89 (d, J =
6.7 Hz, 1 H), 4.83 (d, J = 6.2 Hz, 1 H), 4.78 (d, J = 6.2 Hz, 1 H),
4.74–4.67 (m, 1 H), 4.69 (d, J = 6.7 Hz, 1 H), 4.49 (s, 3 H), 4.47–
4.39 (m, 1 H), 4.04 (dd, J = 6.9, 3.2 Hz, 1 H), 3.87–3.76 (m, 1 H),
3.80 (s, 3 H), 3.67 (dd, J = 6.9, 3.2 Hz, 1 H), 3.52 (d, J = 7.3 Hz,
1 H), 3.42 (s, 3 H), 3.34 (s, 3 H), 2.46–2.39 (m, 2 H), 1.24 (d, J =
6.2 Hz, 3 H), 0.89 (s, 9 H), 0.13 (s, 3 H), 0.10 (s, 3 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 159.0, 133.8, 130.5, 129.0, 117.7,
113.6, 97.8, 97.6, 86.9, 82.9, 79.9, 78.4, 74.4, 70.2, 62.7, 62.5, 56.4,
(2S,3S,4R,5R,8R)-8-[(tert-Butyldimethylsilyl)oxy]-3,4-bis(meth-
oxymethoxy)undec-10-en-6-yne-2,5-diyl Diacetate (33): Anhydrous
Et3N (0.43 mL, 3.16 mmol), Ac2O (0.16 mL, 1.58 mmol), and
DMAP (5 mg) were added to a solution of alcohol 32 (0.5 g,
1.05 mmol) in anhydrous CH2Cl2 (20 mL) at room temp. under a
nitrogen atmosphere. The mixture was stirred at room temp. for
30 min, then the reaction was quenched with saturated NaHCO3
(15 mL). The organic layer was extracted with CH2Cl2 (2ϫ 10 mL)
and the combined organic layers were dried with Na2SO4. The sol-
vent was removed under reduced pressure and the mixture was
purified by column chromatography (hexane/EtOAc, 90:10) to af-
ford 33 (0.51 g, 94%) as a liquid. [α]2D5 = +13.7 (c = 0.70, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 5.88–5.78 (m, 1 H), 5.62 (dd, J
= 5.6, 1.6 Hz, 1 H), 5.25–5.20 (m, 1 H), 5.14–5.07 (m, 2 H), 4.89
(d, J = 6.8 Hz, 1 H), 4.73 (d, J = 6.8 Hz, 1 H), 4.71 (d, J = 6.7 Hz,
1 H), 4.68 (d, J = 6.7 Hz, 1 H), 4.41 (td, J = 6.4, 1.6 Hz, 1 H), 3.94
(t, J = 4.8 Hz, 1 H), 3.87–3.83 (m, 1 H), 3.42 (s, 3 H), 3.39 (s, 3
H), 2.44–2.40 (m, 2 H), 2.09 (s, 3 H), 2.07 (s, 3 H), 1.30 (d, J =
6.4 Hz, 3 H), 0.89 (s, 9 H), 0.11 (s, 3 H), 0.09 (s, 3 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 169.8, 169.4, 133.6, 117.7, 97.6, 96.8,
88.5, 80.9, 78.1, 78.0, 70.1, 63.8, 62.6, 56.2, 42.7, 25.7, 21.2, 20.8,
56.1, 55.2, 43.0, 25.6, 18.1, 14.4, –4.5, –5.1 ppm. IR (neat): ν =
˜
3451.5, 2932.5, 1513.4, 1249.2, 1149.5, 1098.2, 1032.0, 834.0,
774.9 cm–1. MS (ESI): m/z = 575 [M + Na]+. HRMS (ESI): m/z
calcd. for C29H48O8NaSi [M + Na]+ 575.30107; found 575.29788.
(5S,6R,7R,10R)-10-Allyl-5-{(S)-1-[(4-methoxybenzyl)oxy]ethyl}-
6-(methoxymethoxy)-12,12,13,13-tetramethyl-2,4,11-trioxa-12-sila-
tetradec-8-yn-7-yl Acetate (31): Anhydrous Et3N (0.47 mL,
3.44 mmol), Ac2O (0.21 mL, 2.06 mmol), and DMAP (5 mg) were
added to a solution of alcohol 30 (0.76 g, 1.37 mmol) in anhydrous
CH2Cl2 (20 mL) at room temp. under a nitrogen atmosphere and
the mixture was stirred at room temp. for 30 min. The reaction
mixture was quenched with saturated NaHCO3, the organic layer
was extracted with CH2Cl2 (2ϫ 20 mL), and the combined organic
layers were dried with Na2SO4. The solvent was removed under
reduced pressure, and the mixture was purified by column
chromatography (hexane/EtOAc, 9:1) to afford pure product 31
15.1, –4.6, –5.1 ppm. IR (neat): ν = 2934.5, 2896.8, 1746.9, 1468.2,
˜
1372.4, 1236.0, 1152.8, 1082.0, 1032.0, 921.4, 838.6, 779.4 cm–1
.
MS (ESI): m/z = 539 [M + Na]+. HRMS (ESI): m/z calcd. for
1
(0.77 g, 95%) as an oil. [α]2D5 = +20.6 (c = 0.50, CHCl3). H NMR
C25H44O9NaSi [M + Na]+ 539.26468; found 539.26129.
(500 MHz, CDCl3): δ = 7.28 (d, J = 8.6 Hz, 2 H), 6.87 (d, J =
8.6 Hz, 2 H), 5.86–5.76 (m, 1 H), 5.67 (dd, J = 5.6, 1.8 Hz, 1 H), (2S,3S,4R,5R,8R)-8-Hydroxy-3,4-bis(methoxymethoxy)undec-10-
5.12–5.05 (m, 2 H), 4.87 (d, J = 6.7 Hz, 1 H), 4.76–4.71 (m, 3 H), en-6-yne-2,5-diyl Diacetate (8b): To a solution of 33 (0.5 g,
4.49 (s, 2 H), 4.38 (td, J = 6.4, 1.6 Hz, 1 H), 3.98–3.95 (m, 1 H), 0.96 mmol) in anhydrous THF (10 mL), was added TBAF (1M in
3.92–3.88 (m, 1 H), 3.88–3.83 (m, 1 H), 3.80 (s, 3 H), 3.37 (s, 3 H),
THF, 1.06 mL, 1.06 mmol) dropwise at 0 °C, and the mixture was
3.35 (s, 3 H), 2.41–2.37 (m, 2 H), 2.10 (s, 3 H), 1.25 (d, J = 6.2 Hz, stirred for 30 min. H2O (2 mL) was added, and the mixture was
3 H), 0.88 (s, 9 H), 0.10 (s, 3 H), 0.07 (s, 3 H) ppm. 13C NMR extracted with EtOAc. The organic extracts were washed with brine
(CDCl3, 75 MHz): δ = 169.5, 158.9, 133.6, 130.6, 129.1, 117.7, and dried with anhydrous Na2SO4. After evaporation of the sol-
113.6, 97.6, 97.0, 88.1, 79.9, 78.5, 78.0, 74.2, 70.3, 64.1, 62.6, 56.2, vent, the residue was purified by column chromatography (hexane/
56.0, 55.2, 42.8, 25.6, 18.1, 15.1, –4.5, –5.1 ppm. IR (neat): ν =
EtOAc, 7:3) to furnish alcohol 8b (0.36 g, 93%) as a colorless li-
˜
2933.1, 2857.2, 1748.2, 1616.1, 1513.7, 1247.8, 1247.3, 1094.4, quid. [α]2D5 = +18.7 (c = 0.80, CHCl3). 1H NMR (500 MHz,
1030.1, 835.2, 774.4 cm–1. MS (ESI): m/z = 617 [M + Na]+. HRMS
(ESI): m/z calcd. for C31H50O9NaSi [M + Na]+ 617.31163; found
617.30869.
CDCl3): δ = 5.95–5.78 (m, 1 H), 5.62 (dd, J = 7.1, 1.7 Hz, 1 H),
5.33–5.11 (m, 3 H), 4.80 (d, J = 6.7 Hz, 1 H), 4.75–4.65 (m, 2 H),
4.49–4.39 (m, 1 H), 4.04–3.98 (m, 1 H), 3.96–3.89 (m, 1 H), 3.42
Eur. J. Org. Chem. 2014, 455–465
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
463

G. Sabitha, A. S. Rao, A. Sandeep, J. S. Yadav
FULL PAPER
(s, 3 H), 3.41 (s, 3 H), 3.06–3.01 (m, 1 H), 2.49–2.41 (m, 2 H), 2.11 1 H), 5.30–5.18 (m, 2 H), 4.86 (d, J = 6.8 Hz, 1 H), 4.73 (d, J =
(s, 3 H), 2.08 (s, 3 H), 1.32 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR 6.9 Hz, 1 H), 4.72 (d, J = 6.8 Hz, 1 H), 4.70 (d, J = 6.9 Hz, 1 H),
(CDCl3, 75 MHz): δ = 170.3, 169.5, 132.9, 118.5, 97.3, 96.2, 88.3,
80.1, 78.1, 77.8, 70.2, 63.7, 61.4, 56.4, 56.1, 41.6, 21.3, 20.9,
3.92–3.85 (m, 2 H), 3.42 (s, 3 H), 3.40 (s, 3 H), 2.70–2.65 (m, 2 H),
2.13 (s, 3 H), 2.09 (s, 3 H), 1.29 (d, J = 6.4 Hz, 3 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 169.9, 169.3, 162.2, 143.8, 132.6,
127.8, 122.3, 97.3, 96.6, 77.6, 77.5, 69.9, 66.5, 63.0, 56.0, 29.4, 21.0,
15.9 ppm. IR (neat): ν = 3450.4, 2938.0, 1742.2, 1640.0, 1372.8,
˜
1232.4, 1150.7, 1027.0, 919.3, 760.3 cm–1. MS (ESI): m/z = 425 [M
+ Na]+. HRMS (ESI): m/z calcd. for C19H30O9Na [M + Na]+
425.17820; found 425.17538.
20.6, 15.0 ppm. MS (ESI): m/z = 453 [M + Na]+. IR (neat): ν =
˜
2988.3, 1737.4, 1376.8, 1244.8, 1058.4, 864.2, 817.1 cm–1. MS
(ESI): m/z = 453 [M + Na]+.
(2S,3S,4R,5R,8R)-8-(Acryloyloxy)-3,4-bis(methoxymethoxy)undec-
10-en-6-yne-2,5-diyl Diacetate (34): Acryloyl chloride (0.08 mL,
3.17 mmol) was added dropwise under N2 to a solution of 8b
(0.30 g, 0.76 mmol) and Et3N (0.31 mL, 2.23 mmol) in CH2Cl2
(10 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 h. Upon
completion of reaction, the mixture was poured into brine (2 mL)
and extracted with CH2Cl2 (2ϫ 10 mL). The organic phase was
dried with anhydrous Na2SO4, and concentrated. The crude prod-
uct was purified by column chromatography (EtOAc/hexane, 10%)
to afford the corresponding acrylic ester 34 (0.29 g, 86%) as a col-
orless oil. [α]2D5 = +56.3 (c = 0.60, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 6.44 (dd, J = 17.1, 1.3 Hz, 1 H), 6.12 (dd, J = 17.1,
10.3 Hz, 1 H), 5.87 (dd, J = 10.3, 1.3 Hz, 1 H), 5.84–5.73 (m, 1 H),
5.63 (dd, J = 5.2, 1.5 Hz, 1 H), 5.51 (td, J = 6.2, 1.3 Hz, 1 H),
5.29–5.10 (m, 3 H), 4.86 (d, J = 6.7 Hz, 1 H), 4.76–4.65 (m, 3 H),
3.96–3.83 (m, 2 H), 3.42 (s, 3 H), 3.38 (s, 3 H), 2.61–2.51 (m, 2 H),
2.11 (s, 3 H), 2.07 (s, 3 H), 1.30 (d, J = 6.4 Hz, 3 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 169.9, 169.4, 164.7, 131.8, 131.5,
127.8, 118.9, 97.6, 96.9, 84.0, 81.1, 78.1, 77.9, 70.1, 63.5, 63.1, 56.3,
(2S,3R,4S,5R,Z)-3,4-Dihydroxy-7-[(R)-6-oxo-3,6-dihydro-2H-
pyran-2-yl]hept-6-ene-2,5-diyl Diacetate (1): To a stirred solution of
7b (0.020 g, 0.046 mmol) in a mixture of MeOH (5 mL) and MeCN
(5 mL) was added CeCl3·7H2O (0.173 g, 0.465 mmol). After stir-
ring for 24 h at reflux temperature (reaction followed by TLC), the
mixture was filtered through Celite and the solvent was removed
under reduced pressure. The crude product was purified by column
chromatography (hexane/EtOAc, 2:8) to afford synrotolide 1
(0.011 g, 71%) as a colorless viscous oil. To a solution of 7b (0.02 g,
0.046 mmol) in MeCN (2 mL) was added fluorosilicic acid (H2SiF6;
20–25 wt.-% in water, 0.2 mL) and the mixture was stirred at room
temp. for 3 d. After completion of the reaction, the mixture was
filtered through Celite and the solvent was removed under reduced
pressure. The crude product was purified by column chromatog-
raphy (hexane/EtOAc, 2:8) to afford synrotolide 1 (0.014 g, 89%)
as a colorless viscous oil. [α]2D5 = –24.8 (c = 0.20, MeOH). 1H NMR
(500 MHz, [D6]DMSO): δ = 7.10–7.02 (m, 1 H), 6.00–5.95 (m, 1
H), 5.82 (dd, J = 11.1, 8.8 Hz, 1 H), 5.72 (dd, J = 10.8, 10.5 Hz, 1
H), 5.64–5.58 (m, 1 H), 5.38 (d, J = 5.9 Hz, 1 H), 5.34–5.26 (m, 1
H), 5.04 (d, J = 5.9 Hz, 1 H), 5.05–5.00 (m, 1 H), 3.54–3.46 (m, 1
H), 3.35–3.29 (m, 1 H), 2.45–2.34 (m, 2 H), 2.01 (s, 3 H), 1.99 (s,
3 H), 1.09 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR ([D6]DMSO,
125 MHz): δ = 169.8, 169.5, 163.3, 147.1, 131.9, 126.8, 120.1, 73.9,
38.7, 21.2, 20.9, 14.9 ppm. IR (neat): ν = 2936.5, 1730.9, 1609.7,
˜
1513.5, 1250.0, 1151.8, 1106.7, 1032.5, 920.5, 825.7 cm–1. MS
(ESI): m/z = 479 [M + Na]+.
(2S,3S,4R,5R)-3,4-Bis(methoxymethoxy)-7-[(R)-6-oxo-3,6-dihydro-
2H-pyran-2-yl]hept-6-yne-2,5-diyl Diacetate (35): A solution of
Grubbs’ second-generation catalyst (G-II; 0.021 g, 0.027 mmol,
10 mol-%) in CH2Cl2 (10 mL) was added dropwise to a solution of
34 (0.25 g, 0.548 mmol) in CH2Cl2 (60 mL) at room temp., and
stirring was continued for 5 h with heating to reflux. The solvent
was evaporated and the crude product was purified by silica gel
column chromatography (hexane/EtOAc, 7:3) to give lactone 35
(0.216 g, 91%) as a pale-yellow oil. [α]2D5 = +45.7 (c = 0.70, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 6.89 (dt, J = 10.0, 4.3 Hz, 1 H),
6.08 (dt, J = 9.8, 1.7 Hz, 1 H), 5.64 (dd, J = 5.6, 1.5 Hz, 1 H),
5.27–5.18 (m, 2 H), 4.84 (d, J = 6.9 Hz, 1 H), 4.73 (d, J = 6.9 Hz,
1 H), 4.72 (d, J = 6.7 Hz, 1 H), 4.69 (d, J = 6.7 Hz, 1 H), 3.93–
3.86 (m, 2 H), 3.42 (s, 3 H), 3.40 (s, 3 H), 2.72–2.65 (m, 2 H), 2.12
(s, 3 H), 2.08 (s, 3 H), 1.30 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 170.1, 169.5, 162.4, 144.1, 122.5, 97.5, 96.9,
82.7, 81.9, 77.9, 77.8, 70.2, 66.8, 63.2, 56.3, 29.7, 21.3, 20.8,
71.3, 71.1, 71.0, 70.0, 29.5, 21.1, 20.7, 12.8 ppm. IR (neat): ν =
˜
3449.4, 2921.7, 1739.3, 1642.9, 1377.7, 1258.8, 1022.4 cm–1. MS
(ESI): m/z = 365 [M + Na]+. HRMS (ESI): m/z calcd. for
C16H22O8Na [M + Na]+ 365.12069; found 365.12034.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra of all compounds.
Acknowledgments
A. S. R. and A. S. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi for the award of fellowships.
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(2S,3S,4R,5R,Z)-3,4-Bis(methoxymethoxy)-7-[(R)-6-oxo-3,6-di-
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1
less liquid. [α]2D5 = +21.6 (c = 0.90, CHCl3). H NMR (300 MHz,
CDCl3): δ = 6.92–6.86 (m, 1 H), 6.09 (dt, J = 9.6, 1.6 Hz, 1 H),
5.92–5.84 (m, 1 H), 5.62 (dd, J = 4.8, 1.3 Hz, 1 H), 5.51–5.39 (m,
464
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 455–465

The First Stereoselective Total Synthesis of (–)-Synrotolide
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Received: August 12, 2013
Published Online: November 7, 2013
Eur. J. Org. Chem. 2014, 455–465
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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