Stereoselective synthesis of (+)-goniothalesdiol

Article abstract of DOI:10.1021/jo060159f

Stereoselective synthesis of antitumor tetrahydrofuran (+)-goniothalesdiol was achieved in high overall yield from (-)-D-tartaric acid. Key features include an FeCl₃ mediated THF formation with very high selectivity. Synthesis of natural gonith

Full text of DOI:10.1021/jo060159f

SCHEME 1. Retrosynthesis for Goniothalesdiol
Stereoselective Synthesis of (+)-Goniothalesdiol
Kavirayani R. Prasad* and Shivajirao L. Gholap
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560012, India
prasad@orgchem.iisc.ernet.in
ReceiVed January 24, 2006
Four syntheses of this bioactive tetrahydrofuran have been
reported, and a formal approach has also been disclosed. A
chiron approach starting from D-glucuronolactone5 and D-man-
nitol6 were disclosed by Yoda et al. and Babjak et. al. However,
both these methods employ either a lengthy reaction sequence
(16 steps from glucuronolactone for the unnatural goniothales-
diol) or a nonstereoselective process from mannitol, which
involves the separation of diastereomers. The elaboration of anti-
aldol adducts from erythrulose was the key step in the approach
for the formal synthesis of goniothalesdiol by Murga et al.7
Sharpless catalytic asymmetric epoxidation and Sharpless asym-
metric dihydroxylation reactions were utilized in the recent
synthesis reported by Yadav et. al., starting from cinnamyl
alcohol.8 More recently, Carreno et. al. have reported the syn-
thesis starting from tartaric acid ester, involving a sulfoxide
strategy pioneered by Solladie.9
Stereoselective synthesis of antitumor tetrahydrofuran
(+)-goniothalesdiol was achieved in high overall yield from
(-)-D-tartaric acid. Key features include an FeCl3 mediated
THF formation with very high selectivity. Synthesis of
natural gonithalesdiol and its analogue 2,5-bis-epi-goniotha-
lesdiol was achieved from a common intermediate.
Our approach to the synthesis of goniothalesdiol 1 was based
on an intramolecular stereospecific cyclization of the hydroxy
tosylate 5a of 1,4-diol 5 (Scheme 1). It was envisaged to syn-
thesize the required hydroxy tosylate 5a from the silyloxyketone
4, which can easily be obtained from tartaric acid. It was also
visualized that altering the sequence of intramolecular ether
formation, that is, the regioselective cyclization of the hydroxy
tosylate 5b would lead to the synthesis of goniothalesdiol
analogue 2.
The synthetic sequence was started with the silyloxyketone
4, which was readily obtained from the bisdimethylamide of
tartaric acid 3, employing a combination of selective Grignard
additions and a stereoselective reduction.10 Reduction of ketone
4 with L-selectride produced the alcohol 6 with very high
selectivity.11 Alcohol 6 was protected as its methoxy methyl
The tetrahydrofuran backbone is a ubiquitous heterocyclic
unit found in a number of biologically active natural products
such as Annonaceae acetogenins1 and polyether antibiotics.2
Goniothalesdiol (1), isolated from the bark of the Malaysian
tree Goniothalamus borneensis, is another type of tetrahydro-
furan having a 3,4-dihydroxy 2,5-dialkyl substitution.3 The
widespread antitumor activity commonly exhibited by the
styryllactones is also associated with this compound and is found
to show promising activity against P388 mouse leukemia cells.4
(5) (a) Yoda, H.; Nakaseko, Y.; Takabe, K. Synlett 2002, 1532. (b) For
a synthesis of 2-epi-goniothalesdiol, see: Yoda, H.; Simojo, T.; Takabe,
K. Synlett 1999, 1969.
(6) (a) Babjak, M.; Kapitan, P.; Gracza, T. Tetrahedron Lett. 2002, 43,
6983. (b) Babjak, M.; Kapitan, P.; Gracza, T. Tetrahedron 2005, 61, 2471.
(7) Murga, J.; Ruiz, P.; Falomir, E.; Carda, M.; Peris, G.; Marco, J.-A.
J. Org. Chem. 2004, 69, 1987.
(8) Yadav, J. S.; Raju, A. K.; Rao, P. P.; Rajaiah, G. Tetrahedron:
Asymmetry 2005, 16, 3283.
(9) Carreno, M. C.; Hernandez-Torres, G.; Urbano, A.; Colobert, F. Org.
Lett. 2005, 7, 5517.
(10) Prasad, K. R.; Gholap. S. L. Synlett 2005, 2260.
(11) The formation of other diastereomers was not observed within
detectable limits in the 1H NMR spectrum. Reduction with reducing agents
such as NaBH4 and DIBAL-H was not selective and produced diastereomeric
alcohols in varying ratios.
* Corresponding author. Fax: +918023600529.
(1) (a) Bermejo, A.; Figadere, B.; Zafra-Polo, M.-C.; Barrachina, I.;
Estornell, E.; Cortes, D. Nat. Prod. ReV. 2005, 22, 269. (b) Alali, F. Q.;
Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504. (c) Cave, A.;
Figadere, B.; Laurens, A.; Cortes, D. Acetogenins from Annonaceae. In
Progress in the Chemistry of Organic Natural Products; Herz, W., Eds;
Springer-Verlag: New York, 1997; Vol. 70, pp 81-288.
(2) Faul, M. M.; Huff, B. E. Chem. ReV. 2000, 100, 2407.
(3) Cao, S.-G.; Wu, X.-H.; Sim, K.-Y.; Tan, B. K. H.; Pereira, J. T.;
Goh, S.-H. Tetrahedron 1998, 54, 2143.
(4) For a review on the cytotoxic activity and other bioactivity of
styryllactones: (a) Mereyala, H. B.; Joe, M. Curr. Med. Chem: Anti-Cancer
Agents 2001, 1, 293. (b) Bla`zquez, M. A.; Bermejo, A.; Zafra-Polo, M. C.;
Cortes, D. Phytochem. Anal. 1999, 10, 161.
10.1021/jo060159f CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/30/2006
J. Org. Chem. 2006, 71, 3643-3645
3643

SCHEME 2. Stereoselective Synthesis of
(+)-Goniothalesdiol
SCHEME 3. Synthesis of (+)-2,5-bis-epi-Goniothalesdiol
followed by treatment of the resultant methoxyhydroperoxide
with acetic anhydride/Et3N/DMAP in refluxing benzene, pro-
duced the goniothalesdiol bis silyl ether 11 in 66% yield along
with 22% of the corresponding aldehyde. Deprotection of the
silyl ether in 11 produced the natural enantiomer of goniotha-
lesdiol (+)-1 in 75% yield. Synthetic 1, [R]D +7.1 (c 0.3, EtOH),
lit3 [R]D +7.5 (c 0.23, EtOH), showed physical and spectro-
scopic data identical to those described for the natural (+)-
goniothalesdiol (Scheme 2).
Regioselective hydroxy tosylate 5b was synthesized employ-
ing simple synthetic transformations. Attempts to convert the
hydroxy tosylate 5b into the tetrahydrofuran by NaH mediated
ether formation were unsuccessful, which can be attributed to
the strain involved in the formation of the 5,5-trans ring junction.
It was gratifying to find that the reaction of hydroxy tosylate
5b with FeCl3‚6H2O cleanly produced the tetrahydrofuran 12
in very high yield with complete selectivity. Ozonation of the
terminal olefin in 12 in MeOH/DCM, followed by treatment of
the resultant methoxyhydroperoxide with acetic anhydride/Et3N/
DMAP in refluxing benzene, produced methyl ester 13 in 70%
yield. Deprotection of the acyl groups under standard conditions
produced (+)-2,5-bis-epi-goniothalesdiol 2 (Scheme 3).
In summary, an efficient stereoselective synthesis of natural
(+)-goniothalesdiol was accomplished starting from D-tartaric
acid. A convenient and general method for the stereoselective
synthesis of substituted tetrahydrofuran was developed. In the
present sequence, starting from the tartaramide 3, goniothalesdiol
and 2,5-bis-epi-goniothalesdiol were obtained in ∼20 and 28%
overall yields, respectively.
ether (MOM) 7 with chloromethoxy methyl ether in the presence
of diisopropylethylamine and a catalytic amount of DMAP in
97% yield. Treatment of 7 with tetrabutyl ammonium fluoride
(TBAF) yielded the alcohol, which underwent smooth tosylation
to yield the corresponding tosylate 8 in 94% yield. Deprotection
of the MOM ether in 8 was envisioned to yield the hydroxy
tosylate 5a, a precursor for the Williamson ether formation.
However, we were pleased to find that the reaction of 8 with
FeCl3‚6H2O12 resulted in the simultaneous deprotection of MOM
and acetonide as well as cyclization to form the tetrahydrofuran
9 in 66% yield as a single diastereomer. As for the mechanism,
on the basis of the observed high stereoselectivity, we believe
that the reaction is proceeding through a SN2-type substitution.13
Tetrahydrofuran 9 was transformed into its silyl ether 10, which
was then subjected to the ozonolysis under modified Criegee
conditions.14 Ozonolysis in MeOH/dichloromethane (DCM),
(12) For use of FeCl3 in the deprotection of acetals and the formation of
ethers, see: (a) Sen, S. E.; Roach, S. L.; Boggs, J. K.; Ewing, G. J.; Magrath,
J. J. Org. Chem. 1997, 62, 6684. (b) Sharma, G. V. M.; Kumar, K. R.;
Sreenivas, P.; Krishna, P. R.; Chorghade, M. S. Tetrahedron: Asymmetry
2002, 13, 687. It is worth noting that 1,4-diol 5 failed to produce the
tetrahydrofuran under similar conditions.
(13) Hydrolysis of acetals/ketals with FeCl3‚6H2O is already well-
documented in literature.12 We believe that in the present sequence, FeCl3‚
6H2O is transforming the bisketal into the triol (I). The formation of THF
from triol I is proceeding probably through the chelation of Fe3+ with the
tosylate, weakening the C-OTs bond, thereby facilitating the intramolecular
SN2 displacement leading to the product.
Experimental Section
Preparation of (2S,3S,4S,5R)-2-(But-3-enyl)-tetrahydro-5-
phenylfuran-3,4-diol (9): To a solution of 8 (0.65 g, 1.3 mmol)
in dry DCM (16 mL) was added FeCl3‚6H2O (1.43 g, 5.3 mmol)
under an argon atmosphere. After stirring for 2 h at room
temperature, it was filtered through a pad of Celite, and the Celite
pad washed with ether (20 mL). The ethereal layer was washed
with a saturated solution of NaHCO3 (10 mL) and brine (20 mL)
and dried (Na2SO4). Evaporation of the solvent and silica gel
column chromatography of the residue using petroleum ether/ethyl
acetate (6:4) as an eluent yielded the tetrahydrofuran 9 (0.21 g,
66%) as a white solid: mp 124-126 °C; [R]D +21.5 (c 0.9, CHCl3);
IR (neat) 3565, 3405, 2915, 1641, 1562, 1392, 1286, 1110, 1022,
912, 759 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.54-2.05 (m, 4H),
2.10-2.42 (m, 2H), 3.96-4.24 (m, 3H), 4.62 (d, 1H, J ) 3.9 Hz),
(14) (a) Schreiber, S. L.; Liew, W.-F. Tetrahedron Lett. 1983, 24, 2363.
(b) Criegee, R. Ber. Bunsen-Ges. Phys. Chem. 1944, 77, 722. For an
oxidative cleavage of olefins to the corresponding methyl esters, see: (c)
Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58, 3675.
3644 J. Org. Chem., Vol. 71, No. 9, 2006

4.88-5.20 (m, 2H), 5.88 (ddt, 1H, J ) 16.8, 10.2, 6.6 Hz), 7.216-
7.58 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 27.9, 30.2, 79.2, 80.7,
85.5, 86.2, 115.1, 125.9, 127.8, 128.6,138.1, 140.1; HRMS for
C14H18O3 + Na calcd, 257.1156; found, 257.1154.
TBAF (0.2 g, 0.6 mmol). The solution was slowly allowed to warm
to room temperature. After stirring for 2 h at room temperature,
saturated NH4Cl (3 mL) was added, and the solution was extracted
with ether (3 × 10 mL). Combined ethereal extracts were washed
with brine (15 mL) and dried (Na2SO4). To the residue obtained
after evaporation of solvent was added dry MeOH (3 mL) and
Amberlyst-15 (0.12 g) and stirred for 1 h at room temperature. It
was passed through a pad of Celite. Evaporation of the solvent
and silica gel column chromatography of the residue using
petroleum ether/ethyl acetate (1:1) as an eluent afforded goniotha-
lesdiol (31 mg, 75%) as a yellow oil: [R]D +7.1 (c 0.3, EtOH),
lit3 [R]D +7.5 (c 0.23, EtOH); IR (neat) 3448, 2930, 1735, 1588,
1454, 1370, 1234, 1176, 1072, 904, 856, 702 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.98-2.26 (m, 2H), 2.35-2.80 (m, 4H), 3.69 (s,
3H), 4.02-4.21 (m, 3H), 4.61 (d, 1H, J ) 4.8 Hz), 7.22-7.48 (m,
5H); 13C NMR (75 MHz, CDCl3) δ 23.6, 30.5, 51.9, 79.0, 80.7,
85.3, 86.2, 126.1, 127.8, 128.5, 139.9, 174.6; HRMS for C14H18O5
+ Na calcd, 289.1054; found, 289.1052.
Preparation of Goniothalesdiol bis-tert-Butyldimethylsilyl
Ether (11): Ozone was bubbled through a pre-cooled (-70 °C)
solution of 10 (0.12 g, 0.26 mmol) in MeOH/DCM (1:9; 15 mL),
containing a trace of NaHCO3 (80 mg), until the pale blue color
persisted. Excess ozone was flushed off with oxygen. The solvent
was evaporated under reduced pressure, and the residue was
dissolved in dry benzene (12 mL). Triethylamine (0.4 mL, 2.6
mmol), acetic anhydride (0.2 mL, 1.82 mmol), and a catalytic
amount of DMAP (16 mg) were added to the reaction mixture and
refluxed for 4 h. It was then cooled, diluted with water (10 mL),
and extracted with ether (3 × 10 mL). The combined ethereal
extract was washed with brine (15 mL) and dried (Na2SO4).
Evaporation of the solvent and silica gel column chromatography
of the residue using petroleum ether/ethyl acetate (96:4) as an eluent
yielded 11 (0.085 g, 66%) as colorless oil: [R]D +19.8 (c 1, CHCl3);
IR (neat) 2954, 2929, 2857, 1743, 1650, 1562, 1470, 1390, 1257
1
cm-1; H NMR (300 MHz, CDCl3) δ -0.13 (s, 3H), -0.04 (s,
Acknowledgment. We thank Department of Science and
Technology (DST), New Delhi, for funding of this project.
S.L.G. thanks Council of Scientific and Industrial Research
(CSIR), New Delhi, for a junior research fellowship.
3H), -0.02 (s, 3H), 0.00 (s, 3H), 0.76 (s, 9H), 0.85 (s, 9H), 1.80-
2.28 (m, 2H), 2.38-2.66 (m, 2H), 3.61 (s, 3H), 3.84 (dd, 1H, J )
3.0, 1.5 Hz), 3.95 (s, 1H), 4.08 (dt, 1H, J ) 7.8, 4.5 Hz), 4.65 (d,
1H, J ) 1.5 Hz), 7.08-7.30 (m, 3H), 7.34 (d, 2H, J ) 7.2 Hz);
13C NMR (75 MHz, CDCl3) δ -5.1, -4.54, -4.49, -4.4, 17.8,
18.0, 24.7, 25.6, 25.7, 31.1, 51.5, 80.0, 81.1, 85.5, 88.9, 126.7,
127.1, 128.0, 141.0, 174.1; HRMS for C26H46O5 Si2 + Na calcd,
517.2784; found, 517.2782.
Supporting Information Available: Experimental procedures
and spectroscopic data for the compounds and copies of 1H NMR,
13C NMR, and HRMS spectra are provided. This material is
available free of charge via the Internet at http://pubs.acs.org
Preparation of (+)-Goniothalesdiol (1): To a solution of 11
(76 mg, 0.15 mmol) in dry THF (4 mL) cooled to 0 °C was added
JO060159F
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