Concise asymmetric total synthesis of obolactone

Article abstract of DOI:10.1021/jo060028e

The first efficient asymmetric synthesis of obolactone 1 has been accomplished in 11 steps and with a 15% overall yield in which Brown's enantioselective allylation reactions and ring-closing metathesis reaction are key steps.

Full text of DOI:10.1021/jo060028e

asymmetric allylation from the commercially available starting
material aldehyde 2.
Concise Asymmetric Total Synthesis of
Obolactone
The synthesis of obolactone 1 commenced from 3-(O-TBS)-
propionaldehyde 2 (Scheme 2). Brown and Racherla’s asym-
metric allyl addition2 to aldehyde 2 gave (R)-homoallylic alcohol
33 in 85% yield with 92% ee.4 After the protection of 3 as its
tert-butyldiphenylsilyl ether 4, the vinyl group was cleaved
oxidatively to yield aldehyde 5. A second asymmetric allyl
addition to this aldehyde furnished a syn (3R,5R) product, 6,
accompanied by a small quantity of its anti diastereomer (dr,
94:6), which was removed chromatographically. Treatment of
6 with acryloyl chloride gave the corresponding acrylate 7, the
precursor of the unsaturated lactone ring. Selective deprotection
of the TBS of 7 under acidic conditions converted into alcohol
8, which was oxidized to aldehyde 9 under standard Swern
conditions.5
Jiyong Zhang,† Yang Li,† Wenkuan Wang,†
Xuegong She,*,†,‡ and Xinfu Pan*,†
Department of Chemistry, State Key Laboratory of Applied
Organic Chemistry, Lanzhou UniVersity, Lanzhou 730000,
People’s Republic of China, and State Key Laboratory for Oxo
Synthesis and SelectiVe Oxidation, Lanzhou Institute of
Chemical Physics, Chinese Academy of Sciences, Lanzhou
730000, People’s Republic of China
shexg@lzu.edu.cn
ReceiVed January 5, 2006
The optical purity of compound 6 is described in Scheme 3.
The ratio of (R)-4/(S)-4 is 96:4, which means that the ratio of
(i + ii)/(iii + iv) is 96:4. Compound i and iv are syn
diastereomers, while ii and iii are anti diastereomers. The anti
diastereomers (ii and iii) have been removed by column
chromatography, and the amount of iv is very little, so the
optically active compound 6 has been obtained.
As shown in Scheme 4, condensation of 4-phenyl-3-buten-
2-one 10 with aldehyde 9 gave alcohol 11 in a moderate yield.
Oxidation of 11 using the Dess-Martin reagent6 afforded the
diketone 12. The next stage required the removal of the TBDPS
to generate a â-diketo alcohol and then cyclization to the
conjugated γ-pyrone ring. Upon treatment of 12 with HF (40%
aq solution) in CH3CN7 at 45 °C for 3 h, the cleavage of the
TBDPS ether, and the cyclization was achieved in a one-pot
reaction to furnish hydropyranone 13 in excellent overall yield.
Compared with the procedure that employs HF‚pyridine, fol-
lowed by acidic conditions to construct conjugated γ-pyrone
rings,8 this method features milder conditions, a shorter reaction
time, and a more convenient operation. Next, the formation of
the unsaturated R-pyrone was achieved by RCM.9 Treatment
of 13 with the second-generation Grubbs catalyst, 14, in
refluxing CH2Cl2 afforded the desired lactone 1 in 90% yield.
The analytical and spectral data were in agreement with those
previously reported in the literature for obolactone.1
The first efficient asymmetric synthesis of obolactone 1 has
been accomplished in 11 steps and with a 15% overall yield
in which Brown’s enantioselective allylation reactions and
ring-closing metathesis reaction are key steps.
Obolactone (1) was isolated by Gue´ritte and co-workers from
Cryptocarya oboVata,1 a plant collected in northern Vietnam.
The plant is a tropical tree of the cinnamon family and was
found to possess a medium cytotoxicity on human nasopha-
ryngeal carcinoma KB cells. This natural product displays
significant cytotoxic activity against the KB cell line with an
IC50 value of 3 µM. The relative configuration of obolactone
was determined by X-ray crystallographic analysis; absolute
stereochemistry was assigned by circular dichroism. Structurally,
obolactone consists of dihydro forms of R- and γ-pyrones
containing a 2′R,6R absolute configuration. The known and
potential biological activity of obolactone, along with its
interesting molecular architecture, stimulated our synthetic
interest in this target. Herein we report the first asymmetric
synthesis of obolactone 1 utilizing a concise and efficient
strategy.
Our envisioned retrosynthetic analysis for the preparation of
obolactone is depicted in Scheme 1. The target molecule is
anticipated to be derived from the unsaturated ester 13 via a
ring-closing metathesis (RCM) reaction. The opening of the
conjugated γ-pyrone ring led to diketone 12, which could be
achieved by the aldol reaction of aldehyde 9 with ketone 10.
The aldehyde 9 is easily available in three steps from alcohol
6. In this strategy, both of the stereocenters are introduced by
In summary, a concise and efficient asymmetric total synthesis
of the pyrone natural product obolactone 1 has been achieved
using Brown’s enantioselective allylation reactions and RCM
(2) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
(3) (a) White, J. D.; Blakemore, P. R.; Browder, C. C.; Hong, J.; Lincoln,
C. M.; Nagornyy, P. A.; Robarge, L. A.; Wardrop, D. J. J. Am. Chem. Soc.
2001, 123, 8593. (b) Paterson, I.; Wallace, D. J.; Gibson, K. R. Tetrahedron
Lett. 1997, 38, 8911.
(4) The enantiomeric purity of compound 3 was determined by a chiral
HPLC analysis of its Mosher ester, using Chiralcel OD (from Daicel
Chemical Industries, Ltd.) and pure hexane as the eluent, 0.5 mL/min.
(5) Mancuso, A. J.; Huang, S -L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
(6) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(7) Newton, R. F. T.; Reynolds, D. P. Tetrahedron Lett. 1979, 41, 3981.
(8) Wender, P. A.; Koehler, M. F. T.; Sendzik, M. Org. Lett. 2003, 5,
4549.
(9) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. (b) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J.
Am. Chem. Soc. 2000, 122, 3783. (c) Trnka, T.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18.
† Lanzhou University.
‡ Chinese Academy of Sciences.
(1) Dumonter, V.; Hung, N. V,; Adeline, M.-T.; Riche, C.; Chiaroni,
A.; Se´venet, T.; Gue´ritte, F. J. Nat. Prod. 2004, 67, 858.
10.1021/jo060028e CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/10/2006
2918
J. Org. Chem. 2006, 71, 2918-2921

SCHEME 1. Retrosynthetic Analysis of Obolactone
SCHEME 2a
a Reagents and conditions: (a) (+)-Ipc2BOMe, CH2dCHCH2MgBr, Et2O, -100 °C, 85%, 92% ee; (b) TBDPSCl, imidazole, DMF, rt, 96%; (c) OsO4,
NMO, then NaIO4, 3:1 THF-H2O, rt, 84%; (d) (+)-Ipc2BOMe, CH2dCHCH2MgBr, Et2O, -100 °C, 67%, dr 94:6; (e) acryloyl chloride, Et3N, CH2Cl2, 0
°C, 94%; (f) TsOH, 20:1 THF-H2O, rt, 89%; (g) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 88%.
SCHEME 3
reaction as the key steps. Both of the stereocenters were
established facilely and with high selectively, and the R- and
γ-pyrone rings were constructed easily with this strategy. The
synthesis consists of 11 steps, starting from commercially
available aldehyde 2 in 15% overall yield.
Experimental Section
(3R)-1-[(tert-Butyldimethylsilyl)oxyl]hex-5-en-3-ol (3). A solu-
tion of (+)-Ipc2BOMe (10.88 g, 34.4 mmol) in dry Et2O (100 mL)
at 0 °C under Ar was treated dropwise with allylmagnesium bromide
(32 mL, 1.0 M in Et2O, 32 mmol). After 5 min, the reaction mixture
J. Org. Chem, Vol. 71, No. 7, 2006 2919

SCHEME 4a
a Reagents and conditions: (a) LDA, THF, then 9, -78 °C, 63%; (b) Dess-Martin periodinane, CH2Cl2, rt, 87%; (c) HF (40% aq), CH3CN, 45 °C, 89%;
(d) Grubbs catalyst 2nd generation 14, CH2Cl2, reflux, 90%.
was allowed to warm to room temperature and was stirred for 30
min to give a white suspension. The suspension was cooled to 0
°C and allowed to settle for another 30 min. The supernatant was
transferred via a syringe equipped with a filter into a 250-mL three-
neck flask and cooled to -100 °C. A solution of aldehyde 2 (3.96
g, 21.1 mmol) in dry Et2O (50 mL) was added dropwise to the
cooled solution of the borane over 1 h. Upon completion of the
addition, the reaction mixture was stirred at -100 °C for an
additional 4 h and was then quenched with 2 M aq NaOH (25 mL)
and 30 wt % aq H2O2 (10 mL). The resulting mixture was stirred
at room temperature overnight. The layers were separated, and the
aqueous phase was extracted with Et2O (3 × 50 mL). The combined
organic extracts were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by column
chromatography (hexanes/EtOAc, 20:1) to give alcohol 3 (3.37 g,
was quenched with H2O (20 mL), and the layers were separated.
The aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The
combined organic phases were washed with brine, dried (Na2SO4),
and concentrated in vacuo. The residue was purified by column
chromatography (hexanes/EtOAc, 25:1) to give aldehyde 9 (634
mg, 88%) as a colorless oil: [R]25D -8° (c 1.0, CHCl3); IR (KBr)
1
2930, 2857, 1727, 1723, 1405, 1269, 1192, 1108, 819, 704; H
NMR (300 MHz, CDCl3) δ 1.04 (s, 9H), 1.80-1.90 (m, 2H), 2.16-
2.20 (m, 2H), 2.52 (ddd, J ) 16.1, 6.3, 3.0 Hz, 1H), 2.59 (ddd, J
) 15.3, 5.1, 1.5 Hz, 1H), 4.23-4.27 (m, 1H), 4.94-5.06 (m, 3H),
5.55-5.64 (m, 1H), 5.76 (dd, J ) 10.4, 1.7 Hz, 1H), 5.93 (dd, J )
17.3, 10.4 Hz, 1H), 6.24 (dd, J ) 17.4 Hz, 1.5 Hz, 1H), 7.35-
7.46 (m, 6H), 7.63-7.67 (m, 4H), 9.65 (t, J ) 2.1 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 19.2, 26.9, 38.8, 40.8, 49.7, 66.4, 70.0,
118.2, 127.7, 128.3, 129.9, 130.8, 132.8, 133.2, 133.5, 135.8, 165.5,
201.5; HRMS (m/z) calcd for C27H34O4SiNa, 473.2124 [M + Na]+;
found, 473.2113.
85%) as a colorless oil: [R]25 +9° (c 2.40, CHCl3); IR (KBr)
D
1
3414, 3065, 2954, 2926, 2855, 1710, 1275, 1100 cm-1; H NMR
(300 MHz, CDCl3) δ 0.07 (s, 6H), 0.89 (s, 9H), 1.63-1.69 (m,
2H), 2.22-2.27 (m, 2H), 3.40 (s, 1H), 3.76-3.92 (m, 3H), 5.06-
5.13 (m, 2H), 5.79-5.88 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
-5.6, 18.0, 25.7, 37.7, 41.9, 62.5, 71.1, 117.1, 134.9; HRMS (m/
z) calcd for C12H26O2Si [M]+, 230.1702; found, 230.1698. An HPLC
analysis of the Mosher ester derived from the product indicated
that the allylation proceeded with 92% ee.
Diketone 12. To a solution of diisopropylamine (0.22 mL, 1.55
mmol) in dry THF (4 mL) at 0 °C under Ar was added n-BuLi
(0.60 mL, 1.48 mmol, 2.48 M in hexane) dropwise. The mixture
was stirred for 30 min at 0 °C, cooled to -78 °C, and then a solution
of unsaturated ketone 10 (196 mg, 1.34 mmol) in dry 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 9 (576 mg, 1.28 mmol) in THF (4 mL).
The resulting mixture was allowed to stir for 45 min at -78 °C
and was then quenched with saturated NH4Cl. The mixture was
then diluted with Et2O, and the layers were separated. The aqueous
phase was extracted with Et2O (3 × 20 mL). The combined organic
phases were washed with brine, dried (Na2SO4), and concentrated
in vacuo. The residue was purified by column chromatography
(hexanes/EtOAc, 8:1) to give â-keto alcohol 11 (481 mg, 63%),
which is an inconsequential mixture of diastereomers.
To a stirred solution of the diastereomeric mixture of â-keto
alcohol 11 (361 mg, 0.61 mmol) in dry CH2Cl2 (10 mL) was added
Dess-Martin periodinane (360 mg, 0.85 mmol) in one portion. The
mixture was stirred for 1 h at room temperature and quenched with
a 1:1 mixture of saturated NaS2O3 and saturated NaHCO3 (10 mL).
The resulting mixture was diluted with CH2Cl2 (15 mL), and the
layers were separated. The aqueous phase was extracted with CH2-
Cl2 (3 × 10 mL). The combined organic phases were washed with
brine, dried (Na2SO4), and concentrated in vacuo. The residue was
purified by column chromatography (hexanes/EtOAc, 20:1) to give
compound 12 (315 mg, 87%) as a pale yellow foam: [R]25D +51°
(c 2.10, CHCl3); IR (KBr) 2932, 1721, 1638, 1587, 1429, 1272,
1195, 1108, 1077, 971, 703 cm-1; 1H NMR (300 MHz, CDCl3) δ
1.06 (s, 9H), 1.81-1.88 (m, 2H), 2.15-2.23 (m, 2H), 2.56 (t, J )
6.5 Hz), 4.22-4.28 (m, 1H), 4.94-5.01 (m, 2H), 5.14-5.18 (m,
1H), 5.45 (s, 1H), 5.63 (ddt, J ) 17.2 Hz, 10.1, 7.1 Hz, 1H), 5.77
(3S,5R)-1-[(tert-Butyldimethylsilyl)oxyl]-3-[(tert-butyldiphe-
nyl)oxyl]oct-7-ene-5-ol (6). Aldehyde 5 (2.37 g, 5.04 mmol) was
subjected to the same asymmetric allylation sequence as described
above for alcohol 3. Workup was performed as described above,
and column chromatography (hexanes/EtOAc, 30:1) afforded
alcohol 6 (1.73 g, 67%, 94:6 dr) as a colorless oil: [R]25 +2° (c
D
1.60, CHCl3); IR (KBr) 3442, 2954, 2931, 2858, 1468, 1428, 1254,
1
1108, 837, 704 cm-1; H NMR (300 MHz, CDCl3) δ -0.05 (s,
6H), 0.82 (s, 9H), 1.06 (s, 9H), 1.59-1.78 (m, 4H), 2.08-2.13
(m, 2H), 2.62 (s, 1H), 3.45 (dt, J ) 10.1, 6.4 Hz, 1H), 3.57 (dt, J
) 10.5, 6.4 Hz, 1H), 3.84-3.85 (m, 1H), 4.08-4.16 (m, 1H), 5.02-
5.07 (m, 2H), 5.74 (ddt, J ) 15.9, 10.2, 7.1 Hz, 1H), 7.36-7.46
(m, 6H), 7.68-7.73 (m, 4H); 13C NMR (75 MHz, CDCl3) δ -5.5,
18.2, 19.3, 25.9, 27.0, 39.8, 42.1, 42.9, 59.8, 68.8, 71.0, 117.6,
127.5, 127.6, 129.6, 129.7, 133.8, 134.2, 134.8, 135.8; HRMS (m/
z) calcd for C30H48O3Si2, 512.3142 [M]+; found, 512.3150.
(3R,5R)-3-[(tert-Butyldiphenyl)oxyl]oct-7-enal-5-yl Acrylate
(9). To a solution of oxalyl chloride (305 mg, 2.40 mmol) in dry
CH2Cl2 (15 mL) at -78 °C was added dropwise dry DMSO (374
mg, 4.80 mmol) in CH2Cl2 (10 mL). After stirring at -78 °C for
10 min, alcohol 8 (723 mg, 1.60 mmol) in CH2Cl2 (5 mL) was
added dropwise. The resultant cloudy mixture was stirred at -78
°C for 30 min, and then Et3N (0.80 mL, 5.76 mmol) was added
slowly and stirred at the same temperature for 30 min, allowing
the reaction mixture to warm to room temperature. The reaction
2920 J. Org. Chem., Vol. 71, No. 7, 2006

(dd, J ) 10.2, 1.2 Hz, 1H), 5.98 (dd, J ) 17.3, 10.4 Hz, 1H), 6.29
(dd, J ) 17.3, 1.3 Hz, 1H), 6.37 (d, J ) 15.9 Hz, 1H), 7.34-7.46
(m, 10H), 7.51-7.54 (m, 1H), 7.56 (d, J ) 15.9 Hz, 1H), 7.65-
7.72 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 19.2, 26.9, 38.7, 40.6,
47.2, 68.1, 70.2, 101.9, 118.0, 122.8, 127.6, 127.6, 127.9, 128.6,
128.9, 129.7, 129.7, 129.9, 130.5, 133.0, 133.5, 133.8, 135.0, 135.9,
139.6, 165.5, 176.9, 197.7; HRMS (m/z) calcd for C37H42O5SiNa,
617.2700 [M + Na]+; found, 617.2694.
reaction mixture was heated to reflux and stirred for 6 h. The solvent
was then evaporated, and the residue was purified by column
chromatography (CH2Cl2/MeOH, 50:1) to give obolactone 1 (33
mg, 90%) as a pale yellow solid: mp 116-118 °C; [R]25 +243°
D
(c 1.35, CHCl3); IR (KBr) 2923, 1719, 1655, 1624, 1575, 1564,
1398, 1344, 1245, 1029, 969, 812, 757 cm-1; 1H NMR (400 MHz,
CDCl3) δ 2.09 (dt, J ) 14.7, 5.0 Hz, 1H) 2.48-2.53 (m, 3H), 2.55
(dd, J ) 16.8, 4.5 Hz, 1H), 2.62 (dd, J ) 16.8, 12.2 Hz, 1H), 4.73-
4.80 (m, 2H), 5.54 (s, 1H), 6.09 (dt, J ) 9.8, 1.8 Hz, 1H), 6.55
(dd, J ) 16.0, 2.4 Hz, 1H), 6.95 (dt, J ) 9.9, 3.9 Hz, 1H), 7.39 (d,
J ) 16.0 Hz, 1H), 7.34-7.41 (m, 3H), 7.53-7.55 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 29.4, 39.3, 41.2, 74.5, 75.6, 106.3, 121.1,
121.5, 127.7, 128.9, 129.7, 135.0, 137.5, 144.7, 163.6, 167.9, 192.3;
HRMS (m/z) calcd for C19H19O4, 311.1278 [M + H]+; found,
311.1276.
Compound 13. To a stirred solution of compound 12 (216 mg,
0.36 mmol) in MeCN (10 mL) was added HF (0.5 mL, 40% aq) at
room temperature. The reaction was heated to 45 °C over 3 h and
then quenched by the addition of saturated NaHCO3. The resulting
mixture was extracted with EtOAc (3 × 20 mL), and the combined
organic phases were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by column
chromatography (hexanes/EtOAc, 5:1) to give compound 13 (109
mg, 89%) as a pale yellow foam: [R]25 +163° (c 0.60, CHCl3);
Acknowledgment. We are grateful for the generous financial
support by the Special Doctorial Program Funds of the Ministry
of Education of China (20040730008), NSFC (QT program, No.
20572037), the key grant project of the Chinese Ministry of
Education (No. 105169), and Gansu Science Foundation (3ZS051-
A25-004).
D
IR (KBr) 2924, 1721, 1661, 1627, 1574, 1404, 1195, 1024, 985,
1
810 cm-1; H NMR (300 MHz, CDCl3) δ 2.04 (dt, J ) 14.7, 5.1
Hz, 1H), 2.34 (dt, J ) 14.7, 7.8 Hz, 1H) 2.47-2.55 (m, 2H), 4.58-
4.63 (m, 1H), 5.13-5.19 (m, 2H), 5.28-5.32 (m, 1H), 5.52 (s,
1H), 5.75-5.85 (m, 1H), 5.83 (dd, J ) 10.1, 1.2 Hz, 1H), 6.13
(ddd, J ) 17.3, 10.3, 2.1 Hz, 1H), 6.42 (dd, J ) 17.3, 1.3 Hz, 1H),
6.53 (dd, J ) 15.9, 2.2 Hz, 1H), 7.30-7.41 (m, 3H), 7.38 (d, J )
15.9 Hz), 7.48-7.52 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 38.1,
38.6, 41.4, 70.0, 76.3, 106.2, 118.7, 121.3, 127.6, 128.3, 128.8,
129.6, 131.3, 132.7, 135.0, 137.2, 165.4, 168.0, 192.6; HRMS (m/
z) calcd for C21H23O4, 339.1591 [M + H]+; found, 339.1595.
Obolactone (1). To a solution of 13 (40 mg, 0.12 mmol) in
degassed CH2Cl2 (12 mL) at room temperature was added the
second-generation Grubbs catalyst, 14, (10 mg, 0.012 mmol). The
Supporting Information Available: Spectroscopic data and full
experimental procedures for compounds 4, 5, 7, and 8; 1H and 13
C
NMR spectra for compounds 3-9, 12, 13, and obolactone 1; HPLC
spectra; and the standard report of the Mosher ester derived from
compound 3. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO060028E
J. Org. Chem, Vol. 71, No. 7, 2006 2921