The first total synthesis of goniothalesdiol

Article abstract of DOI:10.1016/S0040-4039(02)01599-X

The first total synthesis of goniothalesdiol, a dihydroxylated tetrahydrofuran isolated from Goniothalamus borneensis (Annonaceae), and its 7-epimer is described starting with D-mannitol. The key step of these syntheses is palladium(II)-catalyzed oxycarbo

Full text of DOI:10.1016/S0040-4039(02)01599-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6983–6985
The first total synthesis of goniothalesdiol
Matej Babjak, Peter Kapita´n and Tibor Gracza*
Department of Organic Chemistry, Slovak University of Technology, Radlinske´ho 9, SK-812 37 Bratislava, Slovakia
Received 30 May 2002; revised 22 July 2002; accepted 31 July 2002
Abstract—The first total synthesis of goniothalesdiol, a dihydroxylated tetrahydrofuran isolated from Goniothalamus borneensis
(Annonaceae), and its 7-epimer is described starting with
D
-mannitol. The key step of these syntheses is palladium(II)-catalyzed
oxycarbonylation of unsaturated triols with -lyxo and
D
D-xylo configuration, respectively, which allowed efficient construction of
the tetrahydrofuran ring with excellent threo-selectivity at the newly formed stereogenic centre. © 2002 Elsevier Science Ltd. All
rights reserved.
The genus Goniothalamus (Annonaceae) is well known
as an interesting source of various bioactive com-
pounds; acetogenins,1 alkaloids,2 styryl-lactones3 and
flavanoids.4 Recently a new natural compound, gonio-
thalesdiol 1 (Fig. 1), was isolated from the bark of the
Malaysian tree Goniothalamus borneensis (Annonaceae),
and has been revealed to have significant cytotoxicity
against P388 mouse leukemia cells, and insecticidal
activities.5 The structure and relative stereochemistry of
1 was assigned on the basis of 1H, 13C NMR spec-
troscopy and the absolute configuration was confirmed
by semi-synthesis from natural (+)-goniothalenol.
To the best of our knowledge, there is only one paper
in the literature which deals with the synthesis of 7-epi-
goniothalesdiol from
D-tartaric acid based on Lewis
acid-promoted hydrogenation.8 Our synthetic plan
relies on a successful PdCl2-catalyzed oxycarbonylation
of C5- and C6-enitols, leading to corresponding 3,6-
anhydro-2-deoxy-1,4-glyconolactones with high regio-
preference and excellent threo-selectivity concerning the
newly formed stereogenic centre.6
Thus, the targets could be accessible from hexonol-
actones A of
D-gluco and L-ido configuration, respec-
tively, which can be obtained by oxycarbonylating bicy-
clization of the unsaturated triols B of the required
configuration (Scheme 1).
In the course of our program directed towards the
application of palladium(II)-catalyzed oxycarbonyla-
tion of unsaturated polyols6 to natural product synthe-
sis, we have developed the syntheses of goniofu-
furone,7a,b 7-epi-goniofufurone,7a,b and erythrosky-
rine.7c Herein, we report on the first total synthesis of
goniothalesdiol 1 and 7-epi-goniothalesdiol 2.
The intermediates for oxycarbonylation, the 1-phenyl-
4-pentenitols 6 and 7 with
tion were obtained from
standard carbohydrate chemistry (Scheme 2). Follow-
D
-lyxo and
D-xylo configura-
D
-mannitol via the route using
ing the reaction sequence, acetonization of D
-mannitol,9
selective hydrolysis of the terminal acetonide,9 O-mesyl-
ation of both unprotected hydroxyl groups, reductive
elimination with sodium iodide10 and subsequent selec-
tive hydrolysis of the next terminal acetonide with HCl
in ethanol, the tetraol 3 was readily prepared. Treat-
ment of 3 with sodium periodate in water furnished the
HO
OH
HO
OH
COOCH3
COOCH3
O
O
1
2
HO
Ph
OH OH
O
Pd(II)/CO
O
Figure 1. Goniothalesdiol 1 and 7-epi-goniothalesdiol 2.
1 (2)
Ph
O
OH
Keywords: palladium(II) catalysis; stereoselective oxycarbonylation;
natural products; goniothalesdiol.
A
B
* Corresponding author. Tel.: ++421 2 593 25 167; fax: ++421 2 529
68 560; e-mail: gracza@chtf.stuba.sk
Scheme 1. Retrosynthetic analysis of 1 and 2.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01599-X

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M. Babjak et al. / Tetrahedron Letters 43 (2002) 6983–6985
Scheme 2. Reagents and conditions: (a) (1) lit.9 H2SO4, acetone; (2) H2O, HCl, 43%; (b) lit.10 MsCl, pyridine; 90%; (c) lit.10 NaI,
acetone, 80%; (d) HCl, EtOH, 38%; (e) (1) NaIO4, H2O, 90%; (2) PhMgBr, THF, 55% (4:5, d.r. 50:50); (f) flash chromatography;
(g) HCl, EtOH, 90% of 6 (90% of 7); (h) PdCl2, CuCl2, AcONa, AcOH, CO, 70% of 8 (85% of 9); (i) DIBAL-H, CH2Cl2, 90%
t
t
of 10 (90% of 11); (j) Ph3PCH2OCH3Cl, BuOK, BuOH–THF, 55% of 12 (58% of 13); (k) (1) H2SO4, dioxane; (2) Ag2O, NaOH,
H2O; (3) H2SO4, MeOH, 50% of 1 (45% of 2).
at −78°C affording a mixture of anomeric lactols 10
and 11 (exo:endo, 9:1 and 90% yields in both cases),
which were transformed to tetrahydrofuran derivatives
12 and 13 by Wittig reaction with (methoxymethylene)-
triphenylphosphonium chloride and potassium tert-
corresponding aldehyde in 90% yield, which was sub-
jected without further purification to Grignard addition
with phenylmagnesium bromide in THF.
A
diastereomeric mixture of -lyxo (4) and -xylo (5)
D
D
partially protected pentitols in the ratio 50:50 and 55%
yield was obtained. After flash chromatography on
silica (EtOAc–hexane 1:20), the following syntheses
were run in parallel with the pure diastereomers.
t
butoxide in BuOH–THF (55 and 58%).
Finally, the E/Z-isomeric mixtures (E:Z, 2:1) of 12 and
13 were subjected to a three-step sequence in one-pot to
convert the vinyl ether to the methyl carboxylate. Ether
cleavage with sulfuric acid in dioxane, followed by
Ag2O oxidation of the aldehyde and an acidic esterifica-
tion with methanol afforded the target goniothalesdiol
1 and its 7-epimer 2 in 55 and 45% yields, respectively,
over three steps.
Firstly, the protecting group was removed by acidic
hydrolysis in ethanol (90%) and the unprotected penti-
tols 6 and 7 were exposed to oxycarbonylation. The
reaction was carried out under standard conditions
with palladium(II) chloride as catalyst (0.1 equiv.),
copper(II) chloride as oxidant (3 equiv.), sodium ace-
tate (3 equiv.) in acetic acid as buffer under a carbon
monoxide atmosphere (balloon) at room temperature.
Only required lactones 8 and 9, respectively, with high
regio- and threo-selectivity were formed as expected.6,7
After flash chromatography and recrystallization the
key intermediates 8 in 70% ([h]2D5=−75 (c 0.38, CH2Cl2)
and 9 in 85% yield (mp 177–179°C, [h]2D5=+38 (c 0.31,
CH3OH) were isolated. The configuration of both lac-
The physical and spectroscopic data of 1 and 2 were in
good agreement13 with the reported data for the natural
product2 and its 7-epimer.8
In conclusion, (+)-goniothalesdiol and (+)-7-epi-gonio-
thalesdiol have been synthesized in a short sequence
from commercially available and cheap
D-mannitol
using palladium(II)-catalyzed oxycarbonylation
methodology for construction of the tetrahydrofuran
ring.
tones,
D
-gluco for 8 (intermediate with correct stereo-
chemistry for the natural product) and
L
-ido for 9
1
(precursor of 2) was established by comparison of H
NMR data and coupling constants (J5,6=0 Hz for 8,
indicated a trans relationship versus J5,6=3.6 Hz for 9,
corresponding to a cis arrangement)11 with the litera-
ture data of 3,6-anhydro-2-deoxy-1,4-heptonolactones
of the same configurations.6a The final confirmation of
the absolute stereochemistry came from single crystal
X-ray analysis of 9.12
Acknowledgements
The authors are grateful to the Slovak Grant Agency
(VEGA, Slovak Academy of Sciences and Ministry of
Education, Bratislava) for financial support of project
no. 1/7314/20, and fy. TauChem Ltd. (Bratislava) for
supplying of chemicals.
The syntheses continued with partial reduction of the
lactones using diisobutylaluminium hydride in CH2Cl2

M. Babjak et al. / Tetrahedron Letters 43 (2002) 6983–6985
6985
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