Stereoselective Total Synthesis of Obolactone via Prins Cyclization

Article abstract of DOI:10.1055/s-0029-1219227

The total synthesis of a pyrone natural product obolactone has been accomplished using Prins cyclization as the key step.

Full text of DOI:10.1055/s-0029-1219227

PAPER
1171
Stereoselective Total Synthesis of Obolactone via Prins Cyclization
Total
S
ynthesis of
o
O
bolactone wravaram Sabitha,* M. Nagendra Prasad, K. Shankaraiah, Jhillu S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: gowravaramsr@yahoo.com
Received 23 November 2009; revised 10 December 2009
O
O
Abstract: The total synthesis of a pyrone natural product obolac-
tone has been accomplished using Prins cyclization as the key step.
O
Key words: obolactone, natural product, Prins, aldol, ring-closing
metathesis
O
obolactone (1)
Figure 1
Chiral lactones are constituents of many naturally occur-
ring compounds and interest in their chemistry continues
unabated because of their usefulness as biologically active
agents. These molecules exert powerful effects on many
cell functions, making them useful tools for understanding
life processes and for treating life-threatening diseases.
One a-pyrone, obolactone (1; Figure 1) was isolated as
pale-yellow crystals from the fruits and trunk bark of
Cryptocarya obovata, which is found at Yen Chau, Son
La Province in the north of Hanoi, Vietnam.1 The relative
configuration of obolactone was deduced by spectroscop-
ic and X-ray crystallographic analyses and the absolute
stereochemistry was established by circular dichroism.
Obolactone (1) displayed significant cytotoxic activity
against the KB cell line, with an IC50 value of 3mM.
products.3 In a continuation of our interest in the Prins
reaction4 and its further extension to the syntheses of new
molecules,5 we now report a stereoselective synthesis of
obolactone by fixing its 1,3-syn diol system through the
Prins reaction.
In our retrosynthetic analysis (Scheme 1), we envisaged
that the target molecule 1 could be prepared by aldol con-
densation of 3 with 4, followed by ring-closing metathesis
(RCM) as reported earlier.2 Compound 3 could be made
from homoallyl alcohol 7 and 3-benzyloxypropion-
aldehyde (8) through the Prins reaction.
The synthesis started with the known chiral homoallyl al-
cohol 7 (Scheme 2). Prins cyclization of 7 with aldehyde
8, in the presence of trifluoroacetic acid, followed by hy-
drolysis of the trifluoroacetate gave trisubstituted pyran 6.
Protection of two the hydroxy groups as their TBS ethers
using TBDMSCl furnished the TBS-protected compound
9. Subsequent deprotection of the benzyl group and repro-
So far, and to the best of our knowledge, there is only one
report2 on the synthesis of this natural product. Our inter-
est in the total synthesis of 1 arose because of its unique
and interesting structural architecture. The Prins cycliza-
tion has emerged as a powerful synthetic tool for the con-
struction of substituted tetrahydropyran rings of natural
O
O
O
O
O
OH
O
O
O
2
1
O
O
O
TBDPSO
O
+
HO
I
4
3
O
OTHP
5
OH
CHO
HO
+
OBn
OH
7
HO
O
6
OBn
8
Scheme 1 Retrosynthetic analysis
SYNTHESIS 2010, No. 7, pp 1171–1175
x
x
.
x
x
.2
0
1
0
Advanced online publication: 20.01.2010
DOI: 10.1055/s-0029-1219227; Art ID: Z24909SS
© Georg Thieme Verlag Stuttgart · New York

1172
G. Sabitha et al.
PAPER
tection as its THP ether 11 was undertaken to facilitate its the starting material in hand, the stage was set to achieve
selective removal in the presence of other functional the target molecule as reported earlier.2
groups in later synthetic steps. Next, deprotection of the
Oxidation of the alcohol using 2-iodoxybenzoic acid
TBS groups, followed by tosylation of the primary hy-
(IBX) in dimethyl sulfoxide furnished the corresponding
droxy group of compound 12 with 1.1 equivalents of tosyl
aldehyde, which was condensed without isolation with
benzalacetone 4 to give alcohol 17.
chloride in the presence of triethylamine in dichloro-
methane, produced the corresponding primary tosylate
13. Treatment of the tosylate with sodium iodide in reflux-
Oxidation afforded the diketone 2, which was treated with
HF (40% aq solution) in acetonitrile at 45 °C for three
hours to remove the TBDPS group and induce cyclization
to the conjugated-pyrone ring in one-pot, to furnish hy-
dropyranone 18. Finally, RCM reaction using Grubbs’
catalyst under reflux conditions afforded the target mole-
cule obolactone 1 in 92% yield. The spectral data of the fi-
nal product was in good agreement with those reported for
the natural product.
ing acetone gave the corresponding iodo compound 14.
The secondary alcohol of compound 14 was inverted6 us-
ing acrylic acid, diethyl azodicarboxylate (DEAD) and
triphenylphosphane (Ph3P) under standard Mitsunobu7
conditions to yield the desired compound 5 which, on re-
ductive ring-opening using zinc in ethanol, furnished di-
ene 15 with chiral centers of the required configuration.
The hydroxy group was protected as its TBDPS ether and
removal of THP group yielded a known precursor 3. With
OH
a
b
CHO
HO
+
HO
OBn
O
6
OBn
OH
7
8
OTBS
OR
O
f
d
TBSO
RO
O
OR
OTHP
9 R = Bn
11 R = TBDMS
c
e
10 R = H
12 R = H
O
OH
OH
O
O
h
g
TsO
I
I
O
OTHP
OTHP
O
OTHP
13
14
5
O
O
TBDPSO
O
OR
l
i
O
k
HO
THPO
3
15 R = H
j
16 R = TBDPS
O
O
O
OH OR
O
O
O
OR
O
m
17 R = TBDPS
2 R = TBDPS
O
O
O
O
O
O
o
n
O
O
1
18
Scheme 2 Reagents and conditions: (a) (i) TFA, CH2Cl2, 3 h; (ii) K2CO3, MeOH, 0.5 h, r.t., 56% (over 2 steps); (b) TBDMSCl, imidazole,
CH2Cl2, 0 °C, 1 h, 90%; (c) Pd/C, H2, EtOAc, r.t., 92%; (d) 2,3-dihydropyran (DHP), PPTS, CH2Cl2, 0 °C, 0.5 h, 88%; (e) TBAF, THF, 0 °C,
2 h, 94%; (f) Et3N, TsCl, CH2Cl2, 0 °C to r.t., 3 h, 86%; (g) NaI, acetone, reflux, 24 h, 90%; (h) DEAD, Ph3P, acrylic acid, –78 °C to r.t., 0.5 h,
61%; (i) unactivated Zn, EtOH, reflux, 1 h, 75%; (j) TBDPSCl, imidazole, CH2Cl2, 0 °C to r.t., 97%; (k) NH4Cl, MeOH, reflux, 6 h, 89%; (l)
(i) IBX, DMSO, CH2Cl2, 0 °C, 85%; (ii) LDA, benzalacetone 4, THF, –78 °C, 60%; (m) IBX, DMSO, CH2Cl2, 0 °C, 78%; (n) HF (40% aq),
MeCN, 45 °C, 85%; (o) Grubbs II catalyst, CH2Cl2, reflux, 92%.
Synthesis 2010, No. 7, 1171–1175 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Obolactone
1173
1H NMR (300 MHz, CDCl3): d = 7.32–7.19 (m, 5 H), 4.46 (s, 2 H),
3.83–3.67 (m, 1 H), 3.66–3.38 (m, 5 H), 1.88–1.64 (m, 2 H), 1.50–
1.36 (m, 2 H), 1.26–1.05 (m, 2 H), 0.88 (s, 9 H), 0.87 (s, 9 H), 0.04
(s, 2 H).
13C NMR (75 MHz, CDCl3): d = 138.2, 128.3, 127.6, 75.9, 72.8,
72.7, 67.5, 66.5, 65.5, 40.9, 36.6, 35.9.
In conclusion, the total synthesis of obolactone has been
achieved in a stereocontrolled manner by the creation of
two chiral centers through the Prins reaction.
Reactions were conducted under N2 in anhydrous solvents and mon-
itored by TLC. Yields refer to chromatographically and spectro-
scopically (1H and 13C NMR) homogeneous material. Air-sensitive
reagents were transferred by syringe or double-ended needle. Evap-
oration of solvents was performed under reduced pressure on a
MS (EI): m/z = 495 [M + H]+.
1
Büchi rotary evaporator. H and 13C NMR spectra of samples in
2-{(2S,4S,6S)-4-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-6-[(1-{tert-
butyl}-1,1-dimethylsilyl)oxymethyl]tetrahydro-2H-2-pyranyl}-
1-ethanol (10)
To a stirred solution of 9 (10 g, 20.2 mmol) in EtOAc (80 mL), was
added 10% Pd/C (0.5 g, 0.47 mmol). The mixture was stirred under
H2 for 12 h and then filtered through Celite. The filtrate was concen-
trated under reduced pressure and the residue was purified by chro-
matography on silica gel (EtOAc–hexane, 3:7) to yield 10.
CDCl3 were recorded on Varian FT-200 MHz (Gemini) or Bruker
UXNMR FT-300 MHz (Avance) spectrometers. Chemical shifts
(d) are reported relative to TMS (d = 0.0 ppm) as an internal stan-
dard. MS (EI, 70 eV) were recorded with an LC-MSD (Agilent
Technologies) spectrometer. Column chromatography was per-
formed on silica gel (60–120 mesh) supplied by Acme Chemical
Co., India. TLC was performed on Merck 60 F-254 silica gel plates,
which were visualized under UV light. Optical rotations were mea-
sured with a JASCO DIP-370 polarimeter. n-Hexane (bp 60–80 °C)
was used.
25
Yield: 7.52 g (92%); colorless gummy liquid; [a]D +47 (c 1,
CHCl3).
IR (KBr): 3615, 3020, 2956, 1472, 1216, 759, 668 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.87–3.70 (m, 3 H), 3.69–3.78 (m,
4 H), 2.93 (br s, 1 H), 1.90–1.56 (m, 4 H), 1.41–1.11 (m, 2 H), 0.89
(s, 9 H), 0.87 (s, 9 H), 0.06 (s, 6 H), 0.05 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 76.5, 68.3, 66.2, 61.7, 41.6, 37.7,
37.4, 25.8, 25.7, 18.2, 18.0, –4.5, –5.4.
(2S,4S,6S)-2-[2-(Benzyloxy)ethyl]-6-(hydroxymethyl)tetrahy-
dro-2H-4-pyranol (6)
TFA (75 mL, 980.2 mmol) was added slowly to a solution of 7 (5 g,
49.01 mmol) and (benzyloxy)propanal (8; 20.0 g, 122 mmol) in
CH2Cl2 (90 mL) at 25 °C under N2. The mixture was stirred for 3 h
then sat. NaHCO3 (300 mL) was added, and the pH was adjusted to
>7 by addition of Et3N. The aqueous layer was extracted with
CH2Cl2 (4 × 80 mL) and the combined organic phase was concen-
trated. The residue was dissolved in MeOH (100 mL) and stirred
with K2CO3 (15 g) for 30 min. MeOH was then evaporated and H2O
(60 mL) was added. The mixture was extracted with CH2Cl2 (3 × 60
mL), and the combined organic layers were dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (EtOAc–hexane, 1:1)
to afford 6.
MS (EI): m/z = 405 [M + H]+.
tert-Butyl-{(2S,4S,6S)-2-[(1-{tert-butyl}-1,1-dimethylsilyl)oxy-
methyl]-6-[2-(tetrahydro-2H-2-pyranyloxy)ethyl]tetrahydro-
2H-4-pyranyloxy}dimethylsilane (11)
To a stirred solution of alcohol 10 (7.4 g, 18.2 mmol) and PPTS (50
mg, 0.2 mmol) in anhydrous CH2Cl2 (60 mL), was added DHP (2.48
mL, 27.4 mmol) dropwise at 0 °C. After completion of the reaction
(indicated by TLC), the reaction mixture was quenched with
NaHCO3 (0.2 g) and CH2Cl2 was removed under reduced pressure.
The crude reaction mass was subjected to silica gel column chroma-
tography (EtOAc–hexane, 2:8) to yield 11.
Yield: 7.8 g (88%); colorless liquid; [a]D25 +23 (c 1, CHCl3).
IR (KBr): 2882, 1340, 1215, 1047, 835, 757 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.57–4.51 (m, 1 H), 3.87–3.60 (m,
4 H), 3.51–3.24 (m, 5 H), 1.89–1.46 (m, 10 H), 1.31–1.04 (m, 2 H),
0.89 (s, 9 H), 0.87 (s, 9 H), 0.05 (s, 12 H).
13C NMR (75 MHz, CDCl3): d = 99.2, 76.2, 72.5, 68.8, 66.3, 63.8,
61.9, 41.8, 38.3, 36.1, 30.7, 25.8, 25.7, 25.4, 19.4, 18.4, 18.1, –4.5,
–5.2.
25
Yield: 7.3 g (56%); colorless gummy liquid; [a]D –13 (c 0.04,
CHCl3).
IR (KBr): 3410, 2922, 2854, 1736, 1453, 1368, 1244, 1096, 1029,
742, 699 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.36–7.17 (m, 5 H), 4.47 (q,
J = 12.5, 14.7 Hz, 2 H), 4.02–3.66 (m, 1 H), 3.66–3.30 (m, 6 H),
1.98–1.59 (m, 3 H), 1.57–1.30 (m, 3 H), 1.28–1.06 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 138.2, 128.3, 127.6, 75.9, 72.8,
72.7, 67.5, 66.5, 65.5, 40.9, 36.6, 35.9.
MS (EI): m/z = 289 [M + Na]+.
MS (EI): m/z = 511 [M + Na]+.
{(2S,4S,6S)-2-[2-(Benzyloxy)ethyl]-6-[(1-{tert-butyl}-1,1-di-
methylsilyl)oxymethyl]tetrahydro-2H-4-pyranyl}oxy(tert-bu-
tyl)dimethylsilane (9)
(2S,4S,6S)-2-(Hydroxymethyl)-6-[2-(tetrahydro-2H-2-pyranyl-
oxy)ethyl]tetrahydro-2H-4-pyranol (12)
To a stirred solution of alcohol 6 (7 g, 26.2 mmol) and imidazole
(5.3 g, 78.6 mmol) in anhydrous CH2Cl2 (60 mL), was added
TBDMSCl (8.6 g, 57.64 mmol) portion-wise at 0 °C. The reaction
mixture was stirred at the same temperature for 4 h and then
quenched with sat. aq NH4Cl (30 mL) and extracted with CH2Cl2
(3 × 50 mL). The organic layer was separated and the aqueous layer
was extracted with additional CH2Cl2 (2 × 30 mL). The combined
organic layers were washed with H2O (60 mL) and brine (30 mL),
and dried over anhydrous Na2SO4. The solvent was removed in vac-
uo and the residue was purified by silica gel column chromatogra-
phy (EtOAc–hexane, 2:8) to afford 9.
To a solution of 11 (7.5 g, 15.3 mmol) in THF (50 mL), was added
TBAF (33.7 mL, 33.7 mmol, 1.0 M in THF) at 0 °C. The reaction
mixture was stirred for 6 h and then diluted with H2O (20 mL) and
extracted with EtOAc (3 × 50 mL). The organic layer was washed
with H2O (40 mL) and brine (20 mL), dried over Na2SO4, and con-
centrated under reduced pressure. The crude product was purified
by column chromatography on silica gel (EtOAc–hexane, 1:1) to
give 12.
25
Yield: 3.74 g (94%); colorless gummy liquid; [a]D –9 (c 1.2,
CHCl3).
IR (KBr): 3520, 2931, 1368, 1221, 1098, 1029, 739, 687 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.57–4.52 (m, 1 H), 3.92–3.78 (m,
3 H), 3.62–3.41 (m, 6 H), 2.97–2.87 (br s, 1 H), 1.90–1.61 (m, 6 H),
1.60–1.41 (m, 4 H), 1.32–1.12 (m, 2 H).
25
Yield: 11.7 g (90%); colorless gummy liquid; [a]D +61 (c 0.5,
CHCl3).
IR (KBr): 2952, 2928, 1472, 1254, 1112, 1074, 836, 775 cm–1.
Synthesis 2010, No. 7, 1171–1175 © Thieme Stuttgart · New York

1174
G. Sabitha et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 98.7, 75.9, 72.5, 67.8, 65.8, 63.4,
62.4, 41.1, 36.7, 35.8, 30.7, 25.3, 19.6.
MS (EI): m/z = 447 [M + Na]+.
(1R)-1-[(2S)-2-Hydroxy-4-(tetrahydro-2H-2-pyranyloxy)bu-
tyl]-3-butenyl Acrylate (15)
MS (EI): m/z 283 [M + Na]+.
To a solution of 5 (2.5 g, 5.89 mmol) in EtOH (30 mL), commercial
Zn dust (5.58 g, 88.35 mmol) was added. The mixture was heated at
reflux until the reaction was complete (indicated by TLC). The re-
action mass was cooled to r.t. and filtered through Celite. The fil-
trate was concentrated under reduced pressure and the residue was
purified by silica gel column chromatography (EtOAc–hexane, 3:7)
to afford 15.
Yield: 1.31 g (75%); colorless liquid; [a]D25 –33 (c 1.5, CHCl3).
IR (KBr): 3412, 2984, 1718, 1400, 1098, 704 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.45–6.33 (m, 1 H), 6.17–6.01 (m,
1 H), 5.90–5.71 (m, 2 H), 5.25–5.02 (m, 3 H), 4.56 (m, 1 H), 3.92–
3.67 (m, 3 H), 3.56–3.37 (m, 2 H), 2.47–2.31 (m, 2 H), 1.99–1.83
(m, 2 H), 1.80–1.43 (m, 8 H).
(2S,4S,6S)-4-Hydroxy-6-[2-(tetrahydro-2H-2-pyranyloxy)eth-
yl]tetrahydro-2H-2-pyranylmethyl 4-Methyl-1-benzene-
sulfonate (13)
To a solution of 12 (3.6 g, 13.4 mmol) in anhydrous CH2Cl2 (25
mL), Et3N (20.05 mL, 14.7 mmol) was added at 0 °C. 4-Methylben-
zenesulfonyl chloride (2.79 g, 14.7 mmol) was then added portion-
wise over 1 h. The mixture was allowed to warm to r.t., stirred for 3
h then treated with aq 1 N HCl (20 mL) and extracted with CH2Cl2
(2 × 40 mL). The organic layers were washed with sat. NaHCO3 (20
mL) and H2O (20 mL). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography
(EtOAc–hexane, 3:7) to give 13.
Yield: 4.93 g (86%); colorless liquid; [a]D25 –39 (c 1, CHCl3).
IR (KBr): 3617, 2977, 1617, 1519, 1371, 1215, 1176, 1033, 757 cm–1.
13C NMR (75 MHz, CDCl3): d = 165.8, 133.3, 130.7, 128.6, 118.2,
98.6, 71.2, 68.6, 65.8, 62.3, 41.9, 38.6, 36.1, 30.5, 25.3, 19.4.
MS (EI): m/z = 321 [M + Na]+.
1H NMR (400 MHz, CDCl3): d = 7.79–7.58 (m, 2 H), 7.44–7.28 (m,
2 H), 4.44–4.36 (m, 1 H), 4.17–3.89 (m, 2 H), 3.88–3.49 (m, 5 H),
3.45–3.29 (m, 2 H), 2.45 (s, 3 H), 1.86–1.59 (m, 5 H), 1.55–1.36
(m, 5 H), 1.21–1.04 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 144.7, 132.8, 129.7, 127.9, 98.4,
72.7, 71.8, 67.5, 63.7, 63.3, 62.0, 40.7, 36.8, 35.8, 30.8, 25.4, 21.6,
19.5.
(1R)-1-{(2S)-2-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-4-(tetrahy-
dro-2H-2-pyranyloxy)butyl}-3-butenyl Acrylate (16)
To a stirred solution of alcohol 15 (1.3 g, 4.35 mmol) and imidazole
(0.59 g, 8.7 mmol) in anhydrous CH2Cl2 (20 mL), was added
TBDPSCl (1.39 mL, 5.22 mmol) dropwise at 0 °C. The reaction
mixture was stirred at the same temperature for 6 h. After comple-
tion of the reaction (indicated by TLC), the solvent was removed
under reduced pressure. The crude reaction mass was purified by
silica gel column chromatography (EtOAc–hexane, 2:8) to afford
16.
Yield: 2.2 g (97%); colorless liquid; [a]D25 –46 (c 1, CHCl3).
IR (KBr): 3515, 2936, 1726, 1429, 1280, 1109, 1066, 709 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.68 (d, J = 6.4 Hz, 4 H), 7.36–
7.46 (m, 6 H), 6.19 (dd, J = 9.2, 1.2 Hz, 1 H), 5.89 (dd, J = 17.2,
10.0 Hz, 2 H), 5.73 (dd, J = 10.6, 1.4 Hz, 1 H), 5.54–5.61 (m, 1 H),
4.94–5.00 (m, 3 H), 3.97–4.00 (m, 1 H), 3.68–3.74 (m, 2 H), 2.15
(dd, J = 12.2, 6.2 Hz, 2 H), 2.01 (s, 1 H), 1.66–1.92 (m, 4 H), 1.06
(s, 9 H).
MS (EI): m/z = 437 [M + Na]+.
(2S,4S,6S)-2-(Iodomethyl)-6-[2-(tetrahydro-2H-2-pyranyl-
oxy)ethyl]tetrahydro-2H-4-pyranol (14)
To a solution of 13 (4.8 g, 11.6 mmol) in acetone (60 mL), NaI (17.3
g, 115.8 mmol) was added and the mixture was heated at reflux for
6 h. After completion of the reaction (indicated by TLC), acetone
was removed under reduced pressure. The reaction mass was puri-
fied by chromatography on silica gel (EtOAc–hexane, 2:8) to afford
14.
Yield: 3.8 g (90%); colorless liquid.
IR (KBr): 3572, 2852, 1450, 1344, 1097, 745, 682 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.64–4.59 (m, 1 H), 3.96–3.78 (m,
4 H), 3.71–3.39 (m, 3 H), 3.20 (d, J = 6.2 Hz, 2 H), 2.71 (br s, 1 H),
1.98–1.46 (m, 8 H), 1.38–1.14 (m, 4 H).
MS (EI): m/z = 559 [M + Na]+.
(1R)-1-{(2S)-2-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-4-hydroxy-
butyl}-3-butenyl Acrylate (3)
MS (EI): m/z = 393 [M + Na]+.
To the THP ether 16 (2.1 g, 3.9 mmol) in MeOH (20 mL), commer-
cial NH4Cl (0.24 g, 4.68 mmol) was added and the mixture was
heated at reflux for 4 h. MeOH was removed and the residue was
diluted with H2O (15 mL) and extracted with Et2O (3 × 25 mL). The
combined organic extracts were dried over anhydrous Na2SO4.
Evaporation of solvent under reduced pressure followed by silica
gel column chromatography (EtOAc–hexane, 4:6) furnished THP
cleaved product 3.
(2S,4R,6S)-2-(Iodomethyl)-6-[2-(tetrahydro-2H-2-pyranyl-
oxy)ethyl]tetrahydro-2H-4-pyranyl Acrylate (5)
To a stirred solution of 14 (3.7 g, 9.9 mmol) in toluene (60 mL), was
added Ph3P (3.09 g, 11.8 mmol) and acrylic acid (0.81 mL, 11.8
mmol). The mixture was cooled to –78 °C, and DEAD (4.98 mL,
31.68 mmol) was added slowly. The mixture was slowly brought to
–20 °C and stirred for 1 h. After completion of the reaction (moni-
tored by TLC), toluene was removed under reduced pressure. The
crude reaction mass was purified by column chromatography
(EtOAc–hexane, 1:9) to give 6.
Yield: 2.58 (61%); colorless liquid; [a]D25 –3 (c 1.4, CHCl3).
IR (KBr): 2926, 1728, 1631, 1425, 1193, 1028, 809, 760 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.42 (dd, J = 17.3, 1.5 Hz, 1 H),
6.13 (dd, J = 17.3, 10.5 Hz, 1 H), 5.84 (dd, J = 10.5, 1.5 Hz, 1 H),
5.29–5.26 (m, 1 H), 4.79–4.66 (m, 1 H), 4.21–4.10 (m, 2 H), 3.92–
3.74 (m, 2 H), 3.69–3.40 (m, 2 H), 3.27 (d, J = 6.7 Hz, 2 H), 2.02–
1.86 (m, 2 H), 1.67–1.45 (m, 6 H), 1.41–1.10 (m, 4 H).
Yield: 1.57 g (89%); colorless liquid; [a]D25 –22 (c 1.1, CHCl3).
IR (KBr): 3450, 2892, 1725, 1436, 1178, 1054, 722 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.67–7.37 (m, 10 H), 6.18 (dd,
J = 9.2, 1.3 Hz, 1 H), 5.90 (dd, J = 17.3, 10.2 Hz, 1 H), 5.74 (dd,
J = 10.5, 1.5 Hz, 1 H), 5.62–5.53 (m, 1 H), 5.1–4.92 (m, 3 H), 4.1–
3.97 (m, 1 H), 3.75–3.70 (m, 2 H), 2.14 (dd, J = 12.3, 6.3 Hz, 2 H),
1.62–1.95 (m, 4 H), 1.05 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 165.5, 135.8, 136.0, 133.7, 133.3,
133.1, 130.7, 129.9, 128.5, 127.7, 127.6, 118.2, 70.5, 69.0, 59.5,
40.3, 39.1, 37.5, 26.9, 19.3.
13C NMR (75 MHz, CDCl3): d = 165.4, 132.9, 127.9, 98.5, 74.6,
72.5, 69.9, 63.7, 62.1, 37.0, 35.9, 30.6, 29.6, 25.4, 19.6, 8.4.
MS (EI): m/z = 475 [M + Na]+.
Synthesis 2010, No. 7, 1171–1175 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Obolactone
1175
(1R,3R,8E)-1-Allyl-3-[1-(tert-butyl)-1,1-diphenylsilyl]oxy-5,7-
dioxo-9-phenyl-8-nonenyl Acrylate (2)
(m, 1 H), 2.57–2.43 (m, 4 H), 2.40–2.28 (m, 1 H), 2.08–2.0 (m,
1 H).
To an ice-cooled solution of 2-iodoxybenzoic acid (1.38 g, 4.9
mmol) in DMSO (1.4 mL, 19.8 mmol), was added a solution of al-
cohol 3 (1.5 g, 3.3 mmol) in anhydrous CH2Cl2 (20 mL). The mix-
ture was stirred at r.t. for 2 h and then filtered through a Celite pad
and washed with Et2O (2 × 10 mL). The combined organic filtrates
were washed with H2O (15 mL) and brine (15 mL), dried over an-
hydrous Na2SO4, and concentrated in vacuo. The crude product was
purified by column chromatography to afford the aldehyde as a vis-
cous liquid (1.26 g, 85%), which was used directly for the next re-
action.
13C NMR (75 MHz, CDCl3): d = 192.6, 168.1, 165.3, 137.3, 135.0,
132.7, 131.2, 129.5, 128.9, 128.3, 127.5, 121.3, 118.6, 106.3, 76.4,
69.9, 41.5, 38.6, 38.2.
MS (EI): m/z = 339 [M + H]+.
(2R)-2-[(2R)-6-Oxo-3,6-dihydro-2H-2-pyranyl]methyl-6-[(E)-2-
phenyl-1-ethenyl]-3,4-dihydro-2H-4-pyranone (1)
A solution of 18 (0.12 g, 0.35 mmol) in CH2Cl2 (30 mL), was first
bubbled through with nitrogen, after which Grubbs type II catalyst
(0.03 g, 0.035 mmol) was added in one portion and the mixture was
heated at reflux under nitrogen at 50 °C for 4 h. After cooling to r.t.
the solvent was removed under reduced pressure. The crude mixture
was purified by silica gel column chromatography (EtOAc–hexane,
80:20) to give obolactone 1.
To a stirred solution of diisopropylamine (0.44 mL, 3.1 mmol) in
anhydrous THF (10 mL) at 0 °C under N2, was added n-BuLi (1.8
mL, 1.6 M in hexane) dropwise. The mixture was stirred for 30 min
at 0 °C, cooled to –78 °C, and then a solution of benzal acetone 4
(0.4 g, 2.7 mmol) in anhydrous THF (3 mL) was added dropwise.
After stirring for 45 min at –78 °C, the mixture was transferred by
syringe into a stirred and cooled (–78 °C) solution of aldehyde (1.2
g, 2.66 mmol) in THF (10 mL). The resulting mixture was allowed
to stir for 45 min at –78 °C and then quenched with sat. NH4Cl
(5 mL). The mixture was then diluted with EtOAc (10 mL), and the
layers were separated. The aqueous phase was extracted with
EtOAc (2 × 15 mL) and the combined organic phases were washed
with brine (2 × 5 mL), dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (EtOAc–hexane, 2:8) to yield alcohol 17 (0.95 g,
60%). This alcohol 17 (0.6 g, 1.01 mmol) was subjected to oxida-
tion using IBX and DMSO using the procedure described above for
compound 3, to yield ketone 2.
Yield: 0.1 (92%); light-yellow solid; [a]D25 +252 (c 1.2, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.56–7.45 (m, 2 H), 7.42–7.32 (m,
4 H), 6.98–6.89 (m, 1 H), 6.55 (dd, J = 16.1, 2.4 Hz, 1 H), 6.09 (dt,
J = 9.7, 1.6 Hz, 1 H), 5.53 (s, 1 H), 4.81–4.69 (m, 2 H), 2.63 (dd,
J = 17.0, 12.1 Hz, 1 H), 2.56 (dd, J = 17.0, 4.6 Hz, 1 H), 2.54–2.45
(m, 3 H), 2.15–2.04 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 192.2, 168.0, 163.7, 144.8, 137.5,
135.1, 129.7, 129.0, 127.7, 121.6, 121.2, 106.3, 75.7, 74.5, 41.3,
39.4, 29.2.
IR (KBr): 2924, 2852, 1718, 1654, 1625, 1578, 1400, 1342, 1248,
754, 669 cm–1.
MS (EI): m/z = 311 [M + H]+.
Yield: 0.46 g (78%); light-yellow foam.
IR (KBr): 2894, 1720, 1645, 1427, 1215, 1080, 758, 669 cm–1.
References
1H NMR (300 MHz, CDCl3): d = 7.74–7.30 (m, 16 H), 6.39–6.23
(m, 2 H), 5.99 (dd, J = 17.2, 10.3 Hz, 1 H), 5.76 (dd, J = 10.3,
1.2 Hz, 1 H), 5.67–5.60 (m, 1 H), 5.44 (s, 1 H), 5.13–5.17 (m, 1 H),
4.94–5.00 (m, 2 H), 4.21–4.27 (m, 1 H), 2.56 (t, J = 6.3 Hz, 2 H),
2.14–2.24 (m, 2 H), 1.80–1.87 (m, 2 H), 1.06 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 197.9, 177.0, 165.4, 139.5, 135.8,
135.1, 133.8, 133.4, 133.1, 130.6, 129.8, 129.7, 129.0, 128.5, 127.7,
127.5, 122.8, 117.9, 102.0, 70.1, 68.2, 47.2, 40.6, 38.5, 26.8, 19.1.
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MS (EI): m/z = 617 [M + Na]+.
(1R)-1-{(2R)-4-Oxo-6-[(E)-2-phenyl-1-ethenyl]-3,4-dihydro-
2H-2-pyranylmethyl}-3-butenyl Acrylate (18)
To a stirred solution of 2 (0.3 g, 0.35 mmol) in MeCN (10 mL), was
added HF (1 mL, 40% aq) at r.t. The reaction mixture was heated to
45 °C over 3 h and then quenched by addition of sat. NaHCO3
(6 mL). The resulting mixture was extracted with EtOAc (2 × 15
mL), and the combined organic layers were washed with brine
(2 × 4 mL), dried over Na2SO4, and concentrated under reduced
pressure. The residue was subjected to silica gel column chromatog-
raphy (EtOAc–hexane, 4:6) to give cyclized compound 18.
25
Yield: 0.145 g (85%); light-yellow foam; [a]D +155 (c 0.5,
CHCl3).
IR (KBr): 3020, 2976, 1719, 1654, 1566, 1420, 1215, 1046, 760,
669 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.57–7.46 (m, 2 H), 7.42–7.29 (m,
4 H), 6.53 (dd, J = 15.8, 2.4 Hz, 1 H), 6.42 (dd, J = 17.3, 1.4 Hz,
1 H), 6.12 (ddd, J = 17.3, 10.5, 2.2 Hz, 1 H), 5.86–5.14 (m, 2 H),
5.51 (s, 1 H), 5.34–5.25 (m, 1 H), 5.21–5.11 (m, 2 H), 4.65–4.53
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(7) Mitsunobu, O. Synthesis 1981, 1.
Synthesis 2010, No. 7, 1171–1175 © Thieme Stuttgart · New York