Total synthesis of (-)-bitungolide F and determination of its absolute stereochemistry

Article abstract of DOI:10.1021/jo7023152

(Chemical Equation Presented) A highly convergent total synthesis of bitungolide F leading to the assignment of its absolute stereochemistry is described. The key steps include a Horner-Wadsworth-Emmons olefination to construct the C7-C8 bond, a Wittig reaction to introduce the conjugate E,E-olefinic moiety in the molecule, and finally a ring-closing metathesis reaction to construct the six-membered α,β-unsaturated δ-lactone of the molecule. Modified Evans's syn-aldol reaction, using Crimmins's protocol, was used to install the stereochemistries at the C4 and C5 centers. The stereochemistry at C9 was introduced by means of hydroxy-directed reduction of the C9 keto using Evans's protocol.

Full text of DOI:10.1021/jo7023152

Total Synthesis of (-)-Bitungolide F and
Determination of Its Absolute Stereochemistry
Subhash Ghosh,* Soma Uday Kumar, and J. Shashidhar
Indian Institute of Chemical Technology, Hyderabad 500 007,
India
FIGURE 1. Structures of bitungolides.
subhash@iict.res.in
Upon inspection of the structure of bitungolide F, we
suggested (Scheme 1) that a Wittig reaction between aldehyde
8 and the carbanion obtained from 7 could install the conjugated
(E,E)-diene in the molecule. Aldehyde 8 could be obtained by
means of ring-closing metathesis of the diene 9, which in turn
could be obtained from 11 via 10 using stereoselective hydroxy-
directed reduction of the C9 keto of 11 using Evans’s protocol.
We expected that compound 11 could be obtained through
Horner-Wadsworth-Emmons reaction between the ketophos-
phonate 12 and the aldehyde 13, which in turn could be
synthesized from the known aldehyde 14 using a modified
Evans’s syn-aldol reaction.
ReceiVed October 29, 2007
Thus our synthesis commenced (Scheme 2) with the addition
of (Z)-enolate, generated from 16, using Crimmins’s protocol4
to the known aldehyde 145 to give 17 with excellent diastereo-
selectivity (98:2 dr). Separation of the diastereomers by standard
silica gel column chromatography gave the required 17 in 96%
yield. Reductive removal of the chiral auxiliary from 17 with
A highly convergent total synthesis of bitungolide F leading
to the assignment of its absolute stereochemistry is described.
The key steps include a Horner-Wadsworth-Emmons
olefination to construct the C7-C8 bond, a Wittig reaction
to introduce the conjugate E,E-olefinic moiety in the
molecule, and finally a ring-closing metathesis reaction to
construct the six-membered R,â-unsaturated δ-lactone of the
molecule. Modified Evans’s syn-aldol reaction, using Crim-
mins’s protocol, was used to install the stereochemistries at
the C4 and C5 centers. The stereochemistry at C9 was
introduced by means of hydroxy-directed reduction of the
C9 keto using Evans’s protocol.
6
LiBH4 in ether furnished the 1,3-diol compound 18 in 90%
yield, which was protected as a p-methoxybenzylidine acetal
19 in 94% yield using the dimethyl acetal of p-methoxyben-
zaldehyde and a catalytic amount of CSA in CH2Cl2.7 Com-
pound 19 was converted to the aldehyde 13 in two steps. TBDPS
deprotection of 19 with TBAF gave primary alcohol 20, which
was oxidized with Dess-Martin periodinane8 to give the
required aldehyde 13.9
Synthesis of the ketophosphonate 12 (Scheme 3) started from
the known diol compound 22, which was prepared easily from
(-)-malic acid (21) according to reported procedures.10a,b
Selective protection of the primary hydroxy group as TBDPS
ether and secondary hydroxy group as TES ether gave the
compound 24,10c which on treatment with lithiated methyldim-
ethyl phosphonate afforded ketophosphonate 12 in 81% yield.
Having both the fragments 12 and 13 in hand, the stage was
set for their crucial coupling via Horner-Wadsworth-Emmons
reaction.11 Thus the reaction between the aldehyde 13 and the
Among the marine organisms, marine sponges are considered
to be one of the most important sources of pharmacologically
active compounds.1 Theonella swinhoei is one such marine
sponge which produced a wide range of interesting biologically
active compounds having fascinating structures.2 As a result,
sponges of the T. swinhoei family have attracted considerable
attention of natural product chemists, synthetic organic chemists,
as well as biologists over the years. In 2002, Tanaka et al.
isolated a series of unique polyketides, bitungolide A-F (1-
6),3 from the Indonesian sponge Theonella cf. swinhoei (Figure
1). The structure of bitungolide A (1) was established by X-ray
and the rest of the family by spectroscopic correlation. These
compounds showed cytotoxic effects against 3Y1 rat normal
fibroblast cells and inhibit dual-specificity phosphatase VHR.
Due to their interesting biological activities and unique structural
features, we became interested in the total synthesis of bitun-
golides. In this paper, we report the first asymmetric total
synthesis of bitungolide F along with its absolute stereochem-
istry.
(4) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org.
Chem. 2001, 66, 894-902.
(5) Roush, W. R.; Hoong, L. K.; Palmer, M. A. J.; Straub, J. A.;
Palkowitz, A. D. J. Org. Chem. 1990, 55, 4117-4126.
(6) Penning, T. P.; Djuric, S. W.; Haack, R. A.; Kailash, V. J.; Miyashiro,
J. M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20, 307-312.
(7) Kloosterman, M.; Slaghek, T.; Hermans, J. P. G.; VanBoom, J. H.;
Recl, J. R. Neth. Chem. Soc. 1984, 103, 335-341.
(8) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(9) Kirkham, J. E. D.; Lee, V.; Baldwin, J. E. Chem. Commun. 2006,
2863-2865.
(10) (a) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T.
Tetrahedron 1992, 48, 4067-4086. (b) Boukouvalas, J.; Fortier, G.; Radu,
I.-I. J. Org. Chem. 1998, 63, 916-917. (c) Ishikawa, Y.; Nishiyama, S.
Tetrahedron Lett. 2004, 45, 351-354.
(11) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-
2186.
(1) Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1-49.
(2) (a) Carmely, S.; Kashman, Y. Tetrahedron Lett. 1985, 26, 511-514.
(b) Kobayashi, M.; Tanaka, J.; Katori, T.; Matsuura, M.; Yamashita, M.;
Kitagawa, I. Chem. Pharm. Bull. 1990, 38, 2409-2418.
(3) Sirirath, S.; Tanaka, J.; Ohtani, I. I.; Ichiba, T.; Rachmat, R.; Ueda,
K.; Usui, T.; Osada, H.; Higa, T. J. Nat. Prod. 2002, 65, 1820-1823.
10.1021/jo7023152 CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/18/2008
1582
J. Org. Chem. 2008, 73, 1582-1585

SCHEME 1. Retrosynthetic Analysis of Bitungolide F (6)
SCHEME 4. Coupling of Aldehyde 13 with the
Ketophosphonate 12 and Completion of the Synthesisa
SCHEME 2. Synthesis of Aldehyde 13a
a Reagents and conditions: (i) LiCl, DIPEA, rt, 30 min, then 13, 12 h,
98%; (ii) Pd/C, EtOAc, NH4OAc (cat.), rt, 2 h, 95%; (iii) CSA (cat.),
CH2Cl2/MeOH (4:1), 0 °C, 10 min, 87%; (iv) Me4NBH(OAc)3, AcOH/
acetone (1:1), -20 °C, 10 h, 92%; (v) TBAF, THF, 0 °C to rt, 12 h, 95%;
(vi) TBSCl, Et3N, DMAP (cat.), CH2Cl2, 0 °C to rt, 2 h, 87%; (vii) TIPSOTf,
2,6-lutidine, CH2Cl2, 0 °C, 0.5 h, 95%; (viii) DIBAL-H, CH2Cl2, -40 to 0
°C, 2 h, 92%; (ix) (a) Dess-Martin periodinane, NaHCO3, CH2Cl2, 0 °C
to rt, 30 min, (b) PPh3dCH2, ether, 0 °C, 10 min, 96% over two steps; (x)
DDQ, CHCl3/pH 7 buffer (20:1), 0 °C to rt, 30 min, 91%; (xi) acryloyl
chloride, Et3N, 0 °C to rt, 30 min, 65%; (xii) 10 mol % of Grubbs’s first-
generation catalyst, CH2Cl2, 50 °C, 24 h, 85% (based on recovered SM);
(xiii) CSA (cat.), CH2Cl2/MeOH (4:1), 0 °C, 24 h, 80%; (xiv) DMP,
NaHCO3, CH2Cl2, 0 °C to rt, 2 h, 91%; (xv) 7, NaHMDS, THF, 0 °C, 20
min, then 8, rt, 2 h, 52%; (xvi) HF/Py, THF, rt, 24 h, 71%.
a Reagents and conditions: (i) 16, TiCl4, (-)-sparteine, 0 °C, CH2Cl2,
20 min then 14, 0 °C, 10 min, 96%; (ii) LiBH4, Et2O, cat. H2O, 0 °C, 90%;
(iii) PMP-acetal, CSA (cat.), CH2Cl2, 0 °C to rt, 12 h, 94%; (iv) TBAF,
THF, 0 °C, 12 h, 91%; (v) Dess-Martin periodinane, NaHCO3, CH2Cl2, 0
°C to rt, 1 h, 90%.
SCHEME 3. Synthesis of Ketophosphonate 12a
Stereoselective hydroxy-directed 1,3-anti-reduction of the keto
group following Evans’s protocol13 using [Me4NBH(OAc)3] in
AcOH/acetone (1:1) at -20 °C for 10 h afforded 1,3-anti-diol
compound 27 in 97% yield with excellent diastereoselectivity
(>20:1 in favor of anti). Separation of the minor isomer by
standard silica gel chromatography afforded pure 27 (92% yield),
which on routine protecting group manipulations furnished
compound 10. Reductive opening of the PMP-acetal of 10 with
DIBAL- H14 in CH2Cl2 at 0 °C from the less hindered side gave
the primary alcohol 30, which on oxidation followed by Wittig
reaction with Ph3PdCH2 in ether at 0 °C afforded compound
31 in 88% yield over three steps. PMB deprotection with DDQ15
under buffer conditions furnished secondary alcohol 32 in 91%
yield, which on acylation with acryloyl chloride gave the
a Reagents and conditions: (i) TBDPSCl, Et3N, cat. DMAP CH2Cl2, 0
°C to rt, 2 h, 98%; (ii) TESCl, Et3N, DMAP (cat.), CH2Cl2, 0 °C to rt, 2 h,
81%; (iii) n-BuLi, MePO(OMe)2, THF, -78 °C to rt, 81%.
ketophosphonate 12 (Scheme 4) using LiCl and DIPEA in
acetonitrile afforded compound 25 in 98% yield. Reduction of
the double bond under hydrogenation conditions using Pd-C
as a catalyst in the presence of a catalytic amount of ammonium
acetate in EtOAc at room temperature afforded keto compound
26.12 For the hydroxy-directed stereoselective reduction of the
C9 keto functionality, it was necessary to remove the TES
protection group, and its selective deprotection in the presence
of primary TBDPS was achieved using a catalytic amount of
CSA in CH2Cl2-MeOH (4:1) at 0 °C to give 11 in 87% yield.
(13) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
(14) Seiichi, T.; Masashi, A.; Seiji, S.; Kunio, O. Chem. Lett. 1983, 1593.
(15) Wipf, P.; Graham, T. H. J. Am. Chem. Soc. 2004, 126, 15346-
15347.
(12) Sajiki, H. Tetrahedron Lett. 1995, 36, 3465-3468.
J. Org. Chem, Vol. 73, No. 4, 2008 1583

bisolefinic compound 9. Ring-closing metathesis reaction16 of
9 with Grubbs’s first-generation catalyst furnished six-membered
R,â-unsaturated δ-lactone 33 in 85% yield (based on recovered
starting material). Selective deprotection of the TBS group using
catalytic CSA in CH2Cl2/MeOH (4:1) at 0 °C for 24 h afforded
the primary alcohol 34, which on oxidation with DMP gave
aldehyde 8. Crucial Wittig olefination between the aldehyde 8
and the carbanion obtained from 717 smoothly afforded the
desired (E,E)-diene 35 (3J12-13 ) 15.5 Hz) as the only isolable
product in 52% yield. Finally, deprotection of the TIPS
protecting groups using HF‚Py in THF furnished bitungolide F
in 71% yield, whose spectral data (1H and 13C) were in good
agreement with the literature value. The specific rotation of
synthetic bitungolide F ([R]25D ) -42.8, c ) 0.035, CHCl3) is
(dd, J ) 4.7, 10.1 Hz, 1H), 3.51-3.36 (m, 3H), 2.92-2.55 (m,
3H), 1.95-1.73 (m, 1H), 1.53-1.20 (m, 2H), 1.01 (s, 9H), 0.99-
0.95 (m, 3H), 0.85-0.73 (m, 12H), 0.43 (q, J ) 7.1 Hz, 6H); 13C
NMR (CDCl3, 75 MHz) δ 199.1, 159.8, 150.1, 135.5, 133.4, 131.2,
130.7, 129.6, 127.6 127.2, 113.5, 101.6, 83.6, 69.5, 69.1, 67.7, 55.2,
45.1, 37.5, 36.9, 26.8, 19.2, 16.2, 14.2, 11.9, 6.7, 4.7; HRMS
(ESIMS) calcd for C43H62O6NaSi2 [M + Na]+ 753.3982, found
753.4005.
(2S,4S,6S)-1-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-6-[(4S,5S)-
5-ethyl-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]heptane-2,4-diol (27).
A solution of compound 11 (515 mg, 0.83 mmol) in acetone/AcOH
(1:1, 4 mL) was cooled to -20 °C, and then Me4NBH(OAc)3 was
added (548 mg, 2.08 mmol) to it and stirred at the same temperature
for 10 h. The reaction was monitored by TLC. After disappearance
of the starting material, the reaction mixture was quenched with a
saturated aqueous solution of sodium potassium tartarate and stirred
at room temperature for 0.5 h, then diluted with EtOAc (30 mL).
The organic layer was washed with NaHCO3 (2 × 10 mL), water
(15 mL), and brine (15 mL), dried (Na2SO4), and concentrated in
vacuo. Column chromatography (SiO2, 20-25% EtOAc in petro-
leum ether eluant) gave pure compound 27 (502 mg, 97%) as
comparable in magnitude to that of natural bitungolide F ([R]25
D
) +43.0, c ) 0.85, CHCl3) but of opposite sign. Therefore,
the absolute stereochemistry of the natural bitungolide F is the
enantiomer of 6, and the absolute configuration of the stereo-
centers is (4S,5S,6S,9S,11R).
In conclusion, we have achieved the first asymmetric total
synthesis of (-)-bitungolide F in a convergent fashion and
established the absolute stereochemistry of the natural product.
Currently, we are working on the total synthesis of other
bitungolides, which will be reported in due course.
colorless syrup: [R]27 ) +11.38 (c 1.2, CHCl3); IR (neat) νmax
D
3750, 2930, 2361, 1516, 1462, 1248, 826, 772 cm-1; H NMR
1
(CDCl3,3 00 MHz) δ 7.69-7.63 (m, 4H), 7.44-7.36 (m, 8H), 6.87
(d, J ) 9.0 Hz, 2H), 5.44 (s, 1H), 4.28 (m, 1H), 4.06-3.96 (m,
1H), 3.91-3.83 (m, 2H), 3.77 (s, 3H), 3.64 (dd, J ) 4.5, 9.8 Hz,
1H), 3.58-3.46 (m, 2H), 1.87-1.72 (m, 4H), 1.65-1.30 (m, 6H),
1.07 (s, 9H), 1.00 (t, J ) 7.6 Hz, 3H), 0.84 (d, J ) 6.8 Hz, 3H);
13C NMR (CDCl3, 75 MHz) δ 159.8, 135.4, 133.1, 131.5, 129.7,
127.8, 127.2, 113.5, 101.8, 84.9, 69.3, 68.9, 67.8, 55.1, 38.9, 37.1,
34.5, 33.5, 29.7, 28.9, 26.7, 19.1, 16.2, 14.4, 11.9; HRMS (ESIMS)
calcd for C37H52O6NaSi [M + Na]+ 643.3430, found 643.3429.
Experimental Section
(2S,5E,7S)-1-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-7-[(4S,5S)-
5-ethyl-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]-2-[(1,1,1-triethyl-
silyl)oxy]-5-octen-4-one (25). To a solution of compound 20 (3.26
g, 10.5 mmol) in CH2Cl2 (35 mL) were added NaHCO3 (2.98 g,
21.0 mmol) and Dess-Martin periodinane (DMP) (6.68 g, 15.75
mmol). The reaction mixture was stirred for 1 h at room temperature
under nitrogen atmosphere. Saturated Na2S2O3 (25 mL) and
NaHCO3 (25 mL) were then added, and the biphasic mixture was
stirred for 15 min and extracted with 50% EtOAc in petroleum
ether (2 × 100 mL). The combined organic phase was washed with
water (75 mL) and brine (75 mL), dried (Na2SO4), and concentrated
in vacuo. The aldehyde 13 (Rf ) 0.64, 10% EtOAc in petroleum
ether), thus obtained, was directly used after flash chromatography
(3.2 g, 99%) for the next reaction without further characterization.
To a stirred solution of 12 (8.98 g, 15.75 mmol) in dry CH3CN
were added LiCl (668 mg, 15.75 mmol) and DIPEA (28.0 mL,
157.5 mmol) sequentially at room temperature. After 30 min,
aldehyde 13 (3.2 g, 10.3 mmol in CH3CN) was added to the reaction
mixture under nitrogen atmosphere. The resulting mixture was
stirred at room temperature for 12 h. CH3CN was evaporated on a
rotary evaporator, and the residue was diluted with EtOAc (200
mL) and washed with a saturated aqueous solution of NH4Cl (50
mL), water (50 mL), and brine (50 mL), dried (Na2SO4), and
concentrated in vacuo. Purification by column chromatography
(SiO2, 12-15% EtOAc in petroleum ether) afforded pure compound
25 (7.79 g, 98%) as colorless oil: [R]22D ) +28.33 (c 3.65, CHCl3);
(5S,6S)-6-(1S,3S,5S)-6-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-1-
methyl-3,5-di[(1,1,1-triisopropylsilyl)oxy]hexyl-5-ethyl-5,6-dihy-
dro-2H-2-pyranone (33). A solution of compound 9 (172 mg,
0.233 mmol) in dry degassed CH2Cl2 was treated with Grubbs’s
first generation catalyst (18.9 mg, 0.023 mmol) at room temperature
under nitrogen atmosphere. The resulting pale purple color solution
was heated to reflux (ca. 50 °C) for 24 h. The solvent was
evaporated in vacuo. Purification of the crude residue by column
chromatography (SiO2, 7-9% EtOAc in petroleum ether eluant)
gave pure compound 33 (113 mg, 85% based on recovered starting
material) as clear oil: [R]27 ) -68.7 (c 2.25, CHCl3); IR (neat)
D
νmax 2927, 2864, 2337, 1724, 1462, 1252, 1217, 1058, 761, 675
1
cm-1; H NMR (CDCl3, 400 MHz) δ 7.01 (dd, J ) 6.4, 9.7 Hz,
1H), 6.01 (d, J ) 9.7 Hz, 1H), 3.95 (dd, J ) 3.1, 7.3 Hz, 1H),
3.90-3.78 (m, 2H), 3.59 (dd, J ) 4.4, 9.9 Hz, 1H), 3.48 (dd, J )
6.0, 9.9 Hz, 1H), 2.28 (m, 1H), 1.99-1.78 (m, 3H), 1.74-1.59
(m, 3H), 1.58-1.44 (m, 3H), 1.08-1.01 (m, 42H), 0.97 (t, J ) 7.4
Hz, 3H), 0.90-0.85 (m, 12H), 0.04 (s, 6H); 13C NMR (CDCl3,
100 MHz) δ 164.7, 150.7, 121.1, 84.3, 71.4, 70.3, 68.1, 43.7, 36.7,
34.6, 33.9, 27.7, 25.9, 20.1, 18.3, 18.2, 14.8, 12.8, 12.7, 11.0, -5.5;
HRMS (ESIMS) calcd for C39H80O5NaSi3 [M + Na]+ 735.5211,
found 735.5201.
(5S,6S)-5-Ethyl-6-(1S,3S,5S,6E,8E)-1-methyl-9-phenyl-3,5-di-
[(1,1,1-triisopropylsilyl)oxy]-6,8-nonadienyl-5,6-dihydro-2H-2-
pyranone (35). To a solution of compound 34 (7 mg, 0.012 mmol)
in CH2Cl2 (1 mL) were added NaHCO3 (3.3 mg, 0.023 mmol) and
Dess-Martin periodinane (DMP) (7.5 mg, 0.017 mmol). The
reaction mixture was stirred for 1 h at room temperature under
nitrogen atmosphere. Saturated Na2S2O3 (1 mL) and NaHCO3 (0.2
mL) were then added, and the biphasic mixture was stirred for 15
min and extracted with 40% EtOAc in petroleum ether (2 × 10
mL). The combined organic phase was washed with water (5 mL)
and brine (5 mL), dried (Na2SO4), and concentrated in vacuo to
yield the aldehyde 8 (6 mg, 91%) which was directly carried to
the next step without further purification or characterization. To a
solution of compound 7 (30 mg, 0.12 mmol) in dry THF (3 mL)
IR (neat) νmax 2956, 2877, 1670, 1462, 1247, 1113, 741, 703 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.66-7.54 (m, 4H), 7.40-7.25 (m,
6H), 7.02-6.72 (m, 4H), 6.12 (dd, J ) 7.8, 16.4 Hz, 1H), 5.36 (m,
2H), 4.32-4.20 (m, 1H), 3.91-3.81 (m, 1H), 3.75 (s, 3H), 3.58
(16) (a) Gradillas, A.; Pe´rez-Castells, J. Angew. Chem., Int. Ed. 2006,
45, 6086-6101. (b) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-
2238. (c) Love, J. A. In Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-
VCH: Weinheim, Germany, 2003; pp 296-322. (d) Grubbs, R. H.
Tetrahedron 2004, 60, 7117-7140. (e) Trnka, T. M.; Grubbs, R. H. Acc.
Chem. Res. 2001, 34, 18-19. (f) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000,
39, 3012-3043.
(17) Nicolaou, K. C.; Zipkin, R. E.; Petasis. N. A. J. Am. Chem. Soc.
1982, 104, 5558-5560.
1584 J. Org. Chem., Vol. 73, No. 4, 2008

was added NaHMDS (1.0 M solution in THF, 0.1 mL, 0.1 mmol)
at 0 °C. After stirring for 20 min at 0 °C, the reaction mixture
turned into a dark red color, then aldehyde 8 (6 mg, 0.011 mmol)
in THF (1 mL) was added at the same temperature. The reaction
was continued for 0.5 h at the same temperature, then warmed to
room temperature and stirred for 1 h. The reaction was quenched
with a saturated aqueous NH4Cl solution (3 mL). The layers were
separated, and the aqueous phase was extracted with EtOAc (2 ×
5 mL). The combined organic extracts were washed with brine (2
mL), dried (Na2SO4), and concentrated in vacuo. Purification of
the residue by column chromatography (SiO2, 7% EtOAc in
petroleum ether) provided compound 35 (4 mg, 52%) as a colorless
oil: [R]27D) -32.9 (c 0.33, CHCl3); IR (neat) νmax 2920, 2848,
1710, 1465, 972, 771 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.43-
7.36 (m, 2H), 7.33-7.28 (m, 2H,), 7.21 (m, 1H), 7.04 (dd, J )
6.7, 9.6 Hz, 1H), 6.75 (dd, J ) 10.4, 15.5 Hz, 1H), 6.53 (d, J )
15.5 Hz, 1H), 6.29 (dd, J ) 10.4, 15.5 Hz, 1H), 6.03 (d, J ) 9.6
Hz, 1H), 5.79 (dd, J ) 8.1, 15.5 Hz, 1H), 4.33 (m, 1H), 3.98 (dd,
J ) 3.0, 10.4 Hz, 1H), 3.86 (m, 1H), 2.31 (m, 1H), 2.01-1.90 (m,
3H), 1.86-1.73 (m, 3H), 1.70-1.42 (m, 3H), 1.08-1.04 (m, 42H),
0.93 (t, J ) 7.4 Hz, 3H), 0.89 (d, J ) 7.4 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 164.6, 150.7, 137.5, 137.3, 132.1, 130.2,
128.5, 128.5, 127.5, 127.4, 126.4, 126.3, 121.0, 84.3, 71.3, 69.8,
46.7, 36.7, 34.0, 33.8, 29.7, 29.3, 27.6, 22.7, 20.1, 18.3, 18.2, 18.1,
14.9, 12.8, 12.8, 12.6, 12.5, 11.0; HRMS (ESIMS) calcd for
C42H72O4NaSi2 [M + Na]+ 719.4866, found 719.4875.
in vacuo. Purification by column chromatography (SiO2, 45-50%
EtOAc in petroleum ether) afforded compound 6 (1.5 mg, 71%) as
a hygroscopic yellow solid: [R]25D ) -42.8 (c 0.035, CHCl3); IR
(neat) νmax 3506, 2920, 1706, 1460, 965, 771, 637 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 7.40 (d, J ) 7.6 Hz, 2H), 7.31 (t, J ) 7.6
Hz, 2H), 7.22 (t, J ) 7.6 Hz, 1H), 7.07 (dd, J ) 6.1, 9.8 Hz), 6.78
(dd, J ) 10.4, 15.3 Hz), 6.56 (d, J ) 15.3 Hz, 1H), 6.46 (dd, J )
10.4, 15.3 Hz, 1H), 6.04 (d, J ) 9.8 Hz, 1H), 5.90 (dd, J ) 6.1,
15.3 Hz, 1H), 4.59 (m, 1H), 4.00 (dd, J ) 3.1, 10.5 Hz, 1H), 3.98
(m, 1H), 2.33 (m, 1H), 1.96-1.84 (m, 2H), 1.81-1.74 (m, 2H),
1.69-1.61 (m, 2H), 1.50-1.42 (m, 2H), 1.30 (m, 1H), 0.95 (t, J )
7.6 Hz, 3H), 0.91 (d, J ) 6.7 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 164.8, 151.1, 137.2, 136.0, 132.7, 130.4, 128.2(2), 127.5,
126.4(2), 120.9, 84.4, 70.3, 69.4, 42.6, 36.6, 34.5, 33.6, 28.6, 20.1,
14.9, 11.0; HRMS (ESIMS) calcd for C24H32O4Na [M + Na]+
407.2198, found 407.2194.
Acknowledgment. We are thankful to CSIR (S.U.K.) and
UGC (J.S.), New Delhi, for research fellowships. We are also
thankful to Dr. T. K. Chakraborty, Dr. A. C. Kunwar, the
Director, IICT, for their support and encouragement, and
Professor Tanaka for providing the copies of NMR (1H and 13C)
of natural bitungolide F.
Supporting Information Available: Experimental procedures,
spectral data for compounds 17-20, 12, 26, 11, 28, 29, 10, 30-
Bitungolide-F (6). To a solution of compound 35 (4 mg, 0.005
mmol) in dry THF (1 mL) was added HF‚py complex (40%, 0.1
mL) at 0 °C, and the mixture was stirred at room temperature for
18 h. The reaction mixture was cautiously poured into an aqueous
NaHCO3 solution and extracted with EtOAc. The combined extracts
were washed with water and brine, dried (Na2SO4), and concentrated
1
32, 9, and 34, and the copies of H and 13C NMR spectra for
compounds 17-20, 12, 25, 26, 11, 27-29, 10, 30-32, 9, 33-35,
and 6 and natural bitungolide F. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO7023152
J. Org. Chem, Vol. 73, No. 4, 2008 1585