Stereoselective synthesis of the naturally occurring 2-pyranone dodoneine

Article abstract of DOI:10.1002/ejoc.200800389

The first total synthesis of the naturally occurring dihydropyranone dodoneine is reported. Asymmetric allylation reactions were used for the stereoselective generation of the two stereogenic centers. The pyranone ring was created by ring-closing metathes

Full text of DOI:10.1002/ejoc.200800389

FULL PAPER
DOI: 10.1002/ejoc.200800389
Stereoselective Synthesis of the Naturally Occurring 2-Pyranone Dodoneine
Paula Álvarez-Bercedo,[a] Eva Falomir,*[a] Juan Murga,[a] Miguel Carda,[a] and
J. Alberto Marco*[b]
Keywords: Dodoneine / Oxygen heterocycles / Dihydropyranones / Allylation / Asymmetric synthesis / Ring-closing
metathesis
The first total synthesis of the naturally occurring dihydropyr-
anone dodoneine is reported. Asymmetric allylation reac-
tions were used for the stereoselective generation of the two
stereogenic centers. The pyranone ring was created by ring-
closing metathesis.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
The retrosynthetic scheme for pyranone 1, based on our
previous experience of the syntheses of several members of
this compound class,[1] is shown in Scheme 1. Thus, 1
should be available via 2 from homoallyl alcohol 3 through
a reaction sequence comprising acylation with acryloyl
chloride, olefin metathesis, and deprotection.[3] Likewise, 3
was to be prepared from homoallyl alcohol 5 via aldehyde
4 by alcohol protection, oxidative cleavage of the olefinic
bond, and asymmetric allylation. The preparation of 5 from
dihydro-p-coumaric acid 6 has already been reported.[4,5]
Introduction
Dodoneine is a compound belonging to the ample group
of naturally occurring 5,6-dihydropyran-2-ones, a com-
pound class whose members exhibit many different bio-
logical activities. They have been shown, for example, to be
cytotoxic, HIV protease inhibitors, apoptosis inductors,
and antileukemic agents. Some of these pharmacological ef-
fects have been related to the Michael acceptor properties
of the conjugated double bond.[1] Dodoneine was very re-
cently isolated from Tapinanthus dodoneifolius, a parasitic
plant that grows on the sheanut tree in Burkina Faso (West
Africa), and was found to exhibit a vasorelaxant effect on
preconstricted rat aortic rings.[2] Its structure was assigned
as 1 (Figure 1) on the basis of spectroscopic analyses com-
bined with an X-ray diffraction analysis of a crystalline de-
rivative. In the present communication, we report the first
synthesis of this natural 2-pyranone.
Figure 1. Structure of dodoneine (1).
Scheme 1. Retrosynthetic analysis of 1.
[a] Departamento de Química Inorgánica y Orgánica, Universitat
Jaume I,
12071 Castellón, Spain
Fax: +34-964-728214
E-mail: efalomir@qio.uji.es
[b] Departamento de Química Orgánica, Universitat de Valencia,
c/D. Moliner, 50, 46100 Burjassot, Spain
Fax: +34-96-3544328
Results and Discussion
Scheme 2 shows the specific details of the synthesis.
Homoallyl alcohol 5 (ca. 95% ee) was prepared from com-
mercial dihydro-p-coumaric acid 6 according to previously
E-mail: alberto.marco@uv.es
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 4015–4018
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4015

P. Álvarez-Bercedo, E. Falomir, J. Murga, M. Carda, J. A. Marco
FULL PAPER
described procedures,[4,5] which included asymmetric Keck
allylation[6] of an intermediate silylated dihydro-p-coumar-
aldehyde. We also prepared homoallyl alcohol 5 by Brown’s
asymmetric allylboration[6b,7] of the same intermediate.
However, we could not improve the reported result[5] as the
ee obtained was only 90%, as determined by chiral
HPLC.[8] Silylation of 5 to 7 (TBS = tert-butyldimethylsilyl)
and ozonolytic cleavage of the olefinic bond in 7 yielded
aldehyde 4, which was then subjected in its crude form to
recorded using the electron impact (EI-MS, 70 eV) or fast atom
bombardment mode (FABMS, m-nitrobenzyl alcohol matrix) with
a VG AutoSpec mass spectrometer. IR data are given only for com-
pounds with significant functions (OH, C=O) and were recorded
as oily films on NaCl plates (oils) or as KBr pellets (solids). Optical
rotations were measured at 25 °C. Reactions that required an inert
atmosphere were carried out under N2 with flame-dried glassware.
Et2O and THF were freshly distilled from sodium/benzophenone
ketyl and transferred through a syringe. Dichloromethane was
freshly distilled from CaH2. Tertiary amines were freshly distilled
asymmetric allylboration with (+)-Ipc2BCl/allylmagnesium from KOH. Toluene was freshly distilled from sodium wire. Com-
bromide (Ipc = diisopinocampheyl).[7] This provided homo-
mercially available reagents were used as received. Unless detailed
otherwise, “work-up” means pouring the reaction mixture into
allyl alcohol 3, which was isolated as a single diastereomer
brine followed by extraction with the solvent indicated in parenthe-
(the minor stereoisomers were lost during chromatographic
ses. If the reaction medium was acidic, additional washing with 5%
separation). Sequential acylation of the latter with acryloyl
aq. NaHCO3 was performed. If the reaction medium was basic,
chloride and ring-closing olefin metathesis of the resulting
additional washing with aq. NH4Cl was performed. Further wash-
ing with brine, drying with anhydrous Na2SO4, and elimination of
the solvent under reduced pressure were followed by chromatog-
acrylate 8 using Grubbs’ first-generation catalyst Ru-I[9]
furnished pyranone 2. Cleavage of the two silyl groups in 2
was achieved with aqueous HF in MeCN to yield a com-
pound with spectroscopic properties coincident with those
reported for dodoneine 1.[2]
raphy on a silica gel column (60–200 µm) and elution with the indi-
cated solvent mixture. When solutions were filtered through a Ce-
lite pad, the pad was additionally washed with the same solvent,
and the washings incorporated into the main organic layer.
1-(tert-Butyldimethylsilyloxy)-4-[(R)-3-(tert-butyldimethylsilyloxy)-
hex-5-enyl]benzene (7): Alcohol 5 (613 mg, 2 mmol) was dissolved
under N2 in dry CH2Cl2 (10 mL) and treated sequentially with 2,6-
lutidine (350 µL, 3 mmol) and TBSOTf (575 µL, 2.5 mmol). The
reaction mixture was then stirred for 2 h at room temp. and worked
up (extraction with CH2Cl2). Column chromatography on silica gel
(hexanes/EtOAc, 19:1) afforded 7 (715 mg, 85%) as an oil. [α]D
=
–2 (c = 1.4, CHCl3). 1H NMR (500 MHz, CDCl3, 25 °C): δ = 7.05
(apparent d, J = 8.3 Hz, 2 H), 6.78 (apparent d, J = 8.3 Hz, 2 H),
5.85 (m, 1 H), 5.10–5.00 (m, 2 H), 3.77 (quint., J ≈ 6 Hz, 1 H),
2.70–2.60 (m, 1 H), 2.60–2.50 (m, 1 H), 2.30 (m, 2 H), 1.80–1.70
(m, 2 H), 1.00 (s, 9 H), 0.93 (s, 9 H), 0.20 (s, 6 H), 0.07 (s, 6 H) ppm.
13C NMR (125 MHz, CDCl3, 25 °C): δ = 153.6, 135.3, 18.3, 18.2
(Cq), 135.2, 129.2 (2ϫ), 119.9 (2ϫ), 71.6 (CH), 116.8, 41.9, 38.8,
31.0 (CH2), 26.0 (3ϫ), 25.8 (3ϫ), –4.4 (4ϫ) (CH3) ppm. HRMS
(EI): m/z (%) = 420.2880 (1) [M]+, 363 (11) [M – tBu]+, 221 (100);
calcd. for C24H44O2Si2: 420.2880.
(4R,6S)-6-(tert-Butyldimethylsilyloxy)-8-[4-(tert-butyldimethylsilyl-
oxy)phenyl]oct-1-en-4-ol (3): Olefin 7 (631 mg, 1.5 mmol) was dis-
solved in CH2Cl2 (25 mL) and cooled to –78 °C. A stream of
ozone-containing air was then bubbled through the solution until
complete consumption of the starting material (TLC monitoring).
Ozone residues were then eliminated by bubbling through the solu-
tion a stream of N2, and the mixture was allowed to reach room
temperature, treated with PPh3 (790 mg, ca. 3 mmol) and stirred
for 2 h. After solvent removal under reduced pressure, the crude
residue was stirred for 10 min in cold pentane (10 mL) and filtered.
The solution was then concentrated under reduced pressure and
the crude residue containing 4 was used directly in the next step.
Scheme 2. Stereoselective synthesis of 1.
Allylmagnesium bromide (commercial 1  solution in Et2O, 2 mL,
2 mmol) was added dropwise under N2 through a syringe to a co-
oled solution of (+)-Ipc2BCl (800 mg, ca. 2.5 mmol) in dry Et2O
(12 mL; dry ice–acetone bath). After finishing the addition, the dry
Experimental Section
General Remarks: 1H and 13C NMR spectra were measured at 500 ice–acetone bath was replaced by an ice bath and the mixture was
and 125 MHz, respectively, in CDCl3 solution at 25 °C. The signals
of the deuteriated solvent CDCl3 were taken as the reference (the
singlet at δ = 7.25 for 1H NMR and the triplet centered at δ =
77.00 ppm for 13C NMR). Carbon atom types (C, CH, CH2, CH3)
were determined with the DEPT pulse sequence. Mass spectra were
stirred for 1 h. The solution was allowed to stand, whereby precipi-
tation of magnesium chloride took place. The supernatant solution
was carefully transferred to another flask through a cannula. After
cooling this flask at –90 °C, a solution of the crude aldehyde 4 from
above in dry Et2O (4 mL) was added dropwise through a syringe.
4016
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4015–4018

Stereoselective Synthesis of the 2-Pyranone Dodoneine
The resulting solution was further stirred at –90 °C for 2 h. The
reaction mixture was quenched by the addition of phosphate pH 7
buffer solution (10 mL), MeOH (10 mL), and 30% H2O2 (5 mL).
After stirring for 30 min, the mixture was poured into saturated
aq. NaHCO3 and worked up (extraction with Et2O). The residue
was subjected to careful column chromatography on silica gel (hex-
anes, then hexanes/EtOAc, 19:1 and 9:1) to afford pure 3 (453 mg,
in water, 30 equiv.). The mixture was stirred for 16 h. After removal
of all volatiles under reduced pressure, column chromatography of
the residue on silica gel (hexanes/EtOAc, 1:1, then EtOAc) afforded
dodoneine (1) (23 mg, 89%) as an amorphous solid. [α]D = +40.2
(c = 0.35, CHCl3) {ref.[2] [α]D = +40.2 (c = 0.4, CHCl3)}. 1H NMR
(500 MHz, CDCl3, 25 °C): δ = 7.07 (apparent d, J = 8.6 Hz, 2 H),
6.88 (dt, J = 9.7, 4.5 Hz, 1 H), 6.76 (apparent d, J = 8.6 Hz, 2 H),
6.02 (dt, J = 9.8, 2 Hz, 1 H), 4.65 (qd, J = 7.8, 5.4 Hz, 1 H), 3.89
(tt, J ≈ 7.8, 4.4 Hz, 1 H), 2.75–2.65 (br. m, 2 H), 2.40–2.35 (m, 2
1
65% overall from 7) as an oil. [α]D = +19.4 (c = 1.4, CHCl3). H
NMR (500 MHz, CDCl3, 25 °C): δ = 7.04 (apparent d, J = 8.2 Hz,
2 H), 6.77 (apparent d, J = 8.2 Hz, 2 H), 5.85 (m, 1 H), 5.15–5.10 H), 2.02 (dt, J = 14.5, 8 Hz, 1 H), 1.85–1.75 (br. m, 3 H) ppm. 13
C
(m, 2 H), 3.96 (m, 1 H), 3.83 (m, 1 H), 3.00 (br. s, 1 H, OH), 2.65–
NMR (125 MHz, CDCl3, 25 °C): δ = 164.2, 154.1, 133.7 (Cq),
2.55 (m, 2 H), 2.25 (t, J ≈ 6.5 Hz, 2 H), 1.90–1.60 (br. m, 4 H), 145.4, 129.6 (2ϫ), 121.4, 115.5 (2ϫ), 77.1, 68.8 (CH), 42.2, 39.5,
1.00 (s, 9 H), 0.93 (s, 9 H), 0.20 (s, 6 H), 0.10 (s, 6 H) ppm. 13C 31.0, 29.7 (CH ) ppm. IR: ν
= 3350 (br., OH), 1698 (C=O),
max
˜
2
NMR (125 MHz, CDCl3, 25 °C): δ = 153.7, 134.7, 18.2, 18.0 (Cq), 1515 cm–1. HRMS (EI): m/z (%) = 262.1206 (11) [M]+, 244 (6) [M –
134.9, 129.1 (2ϫ), 120.0 (2ϫ), 72.2, 70.0 (CH), 117.6, 42.4, 42.2, H2O]+, 159 (40), 107 (100); calcd. for C15H18O4: 262.1205.
39.8, 30.3 (CH2), 25.9 (3ϫ), 25.7 (3ϫ), –4.1, –4.4 (2ϫ), –4.6
Supporting Information (see also the footnote on the first page of
this article): 1H and 13C NMR spectra of compounds 1, 2, 3, 7,
and 8.
(CH ) ppm. IR: νmax = 3450 (br., OH) cm–1. HRMS (FAB): calcd.
˜
3
for C26H49O3Si2, 465.3220; found 465.3236 [M + H]+.
(4R,6S)-6-(tert-Butyldimethylsilyloxy)-8-[4-(tert-butyldimethylsilyl-
oxy)phenyl]oct-1-en-4-yl Acrylate (8): Compound 3 (325 mg,
0.7 mmol) was dissolved under N2 in dry CH2Cl2 (20 mL), cooled
to –78 °C and treated sequentially with N,N-diisopropylethylamine
(1.4 mL, 8 mmol) and acryloyl chloride (570 µL, ca. 7 mmol). The
reaction mixture was stirred at –78 °C until consumption of the
starting material (TLC monitoring). Work-up (extraction with
CH2Cl2) and column chromatography on silica gel (hexane/EtOAc,
19:1) provided 8 (225 mg, 62%) as an oil. [α]D = –44.6 (c = 1.1,
CHCl3). 1H NMR (500 MHz, CDCl3, 25 °C): δ = 7.02 (apparent
d, J = 8.2 Hz, 2 H), 6.74 (apparent d, J = 8.2 Hz, 2 H), 6.38 (d, J
= 17.3 Hz, 1 H), 6.10 (dd, J = 17.3, 10.4 Hz, 1 H), 5.80 (d, J =
10.4 Hz, 1 H), 5.80–5.70 (br. m, 1 H), 5.15–5.00 (br. m, 3 H), 3.75
(m, 1 H), 2.65–2.50 (br. m, 2 H), 2.45–2.30 (br. m, 2 H), 1.90–1.65
(br. m, 4 H), 0.98 (s, 9 H), 0.91 (s, 9 H), 0.18 (s, 6 H), 0.07 (s, 3
H), 0.05 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ =
165.6, 153.6, 134.9, 18.2, 18.1 (Cq), 133.4, 130.4, 129.2 (2ϫ), 119.9
(2ϫ), 71.0, 68.9 (CH), 118.0, 117.3, 41.1, 39.0, 38.7, 30.7 (CH2),
Acknowledgments
Financial support from the BANCAJA, Universitat Jaume I (UJI)
Foundation (projects P1-1A-2005-15 and P1-1B-2005-30) and the
Generalitat Valenciana (projects ACOMP07/023 and ACOMP07/
025) is gratefully acknowledged. P. A.-B. thanks the Universitat
Jaume I for a research contract.
[1] a) For a recent review on the synthesis of naturally occurring
representatives of this compound class, see: J. A. Marco, M.
Carda, J. Murga, E. Falomir, Tetrahedron 2007, 63, 2929–2958;
b) see also: V. Boucard, G. Broustal, J. M. Campagne, Eur. J.
Org. Chem. 2007, 225–236.
[2] M. Ouedraogo, H. Carreyre, C. Vandebrouck, J. Bescond, G.
Raymond, I. P. Guissou, C. Cognard, F. Becq, D. Potreau, A.
Cousson, J. Marrot, J. M. Coustard, J. Nat. Prod. 2007, 70,
2006–2009.
25.9 (3ϫ), 25.8 (3ϫ), –4.4 (4ϫ) (CH ) ppm. IR: ν
= 1726
˜
3
max
(C=O) cm–1. FAB MS m/z 519 [M + H+]. HRMS (EI): m/z (%) =
518.3252 (1) [M]+, 461 (5) [M – tBu]+, 315 (100), 221 (76), 129 (38);
calcd. for C29H50O4Si2: 518.3247.
[3] Ref.[1a] gives numerous examples of the synthesis of naturally
occurring 5,6-dihydropyran-2-ones by this methodology. For a
more recent example, see: J. D. Umarye, T. Leßmann, A. B.
García, V. Mamane, S. Sommer, H. Waldmann, Chem. Eur. J.
2007, 13, 3305–3319.
(6R)-{(S)-2-(tert-Butyldimethylsilyloxy)-4-[4-(tert-butyldimethyl-
silyloxy)phenyl]butyl}-5,6-dihydropyran-2-one (2): Diolefin 8 (130 mg,
0.25 mmol) was dissolved under N2 in dry, degassed CH2Cl2
(25 mL) and treated with Grubbs’ catalyst, [PhCH=RuCl2(PCy3)2]
(20 mg, ca. 0.025 mmol). The mixture was heated at reflux until
consumption of the starting material (ca. 4 h). Solvent removal un-
der reduced pressure and column chromatography on silica gel
(hexane/EtOAc, 19:1) yielded pyranone 2 (103 mg, 84%) as an oil.
[α]D = +38.2 (c = 2.3, CHCl3). 1H NMR (500 MHz, CDCl3, 25 °C):
δ = 7.04 (apparent d, J = 8.3 Hz, 2 H), 6.88 (m, 1 H), 6.75 (appar-
ent d, J = 8.3 Hz, 2 H), 6.03 (br. d, J = 9.8 Hz, 1 H), 4.60 (m, 1
H), 3.96 (apparent quint., J ≈ 6 Hz, 1 H), 2.65–2.55 (m, 2 H), 2.40–
2.30 (m, 2 H), 2.15–2.05 (m, 1 H), 1.90–1.70 (br. m, 3 H), 0.99 (s,
9 H), 0.91 (s, 9 H), 0.18 (s, 6 H), 0.08 (s, 3 H), 0.05 (s, 3 H) ppm.
13C NMR (125 MHz, CDCl3, 25 °C): δ = 164.3, 153.7, 134.7, 18.2,
18.0 (Cq), 144.8, 129.1 (ϫ2), 121.5, 120.0 (ϫ2), 75.2, 68.2 (CH),
41.9, 38.6, 30.7, 29.9 (CH2), 25.9 (ϫ 3), 25.7 (ϫ 3), –4.5 (ϫ 4)
[4] a) The conversion of 6 into silylated dihydro-p-coumaraldehyde
has been reported earlier albeit without experimental details:
G. B. Jones, S. B. Heaton, Tetrahedron: Asymmetry 1993, 4,
261–272; b) A. S. K. Hashmi, L. Schwarz, J. W. Bats, J. Prakt.
Chem. 2000, 342, 40–51; c) S. Iimura, K. Manabe, S. Kobaya-
shi, J. Org. Chem. 2003, 68, 8723–8725; d) D. Boschi, G. C.
Tron, L. Lazzarato, K. Chegaev, C. Cena, A. Di Stilo, M.
Giorgis, M. Bertinaria, R. Fruttero, A. Gasco, J. Med. Chem.
2006, 49, 2886–2897; e) A. B. Smith III, J. B. Sperry, Q. Han,
J. Org. Chem. 2007, 72, 6891–6900.
[5] Alcohol 5 has been obtained earlier in 95% enantiomeric ex-
cess by Keck’s asymmetric allylation of the silylated dihydro-p-
coumaraldehyde: P. A. Evans, J. Cui, S. J. Gharpure, Org. Lett.
2003, 5, 3883–3885.
[6] For some reviews on the asymmetric allylations of carbonyl
compounds, see: a) R. O. Duthaler, A. Hafner, Angew. Chem.
Int. Ed. Engl. 1997, 36, 43–45; b) P. V. Ramachandran, Ald-
richim. Acta 2002, 35, 23–35; c) S. E. Denmark, J. Fu, Chem.
Rev. 2003, 103, 2763–2793; d) D. G. Hall, Synlett 2007, 1644–
1655.
(CH ) ppm. IR: νmax = 1732 (C=O) cm–1. HRMS (FAB): calcd. for
˜
3
C27H47O4Si2 491.3013; found 491.3025 [M + H]+.
[7] P. V. Ramachandran, G.-M. Chen, H. C. Brown, Tetrahedron
Lett. 1997, 38, 2417–2420.
[8] P. Álvarez-Bercedo, Ph. D. Thesis, Universitat Jaume I,
Castellón, Spain, in preparation.
(6R)-[(S)-2-Hydroxy-4-(4-hydroxyphenyl)butyl]-5,6-dihydropyran-2-
one (1): A solution of 2 (49 mg, 0.1 mmol) in acetonitrile (2.5 mL)
was treated at room temperature with aqueous HF (125 µL, 48%
Eur. J. Org. Chem. 2008, 4015–4018
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4017

P. Álvarez-Bercedo, E. Falomir, J. Murga, M. Carda, J. A. Marco
FULL PAPER
[9] a) A. Fürstner, Angew. Chem. Int. Ed. 2000, 39, 3012–3043; b)
L. Jafarpour, S. P. Nolan, Adv. Organomet. Chem. 2000, 46,
181–222; c) T. M. Trnka, R. H. Grubbs, Acc. Chem. Res. 2001,
34, 18–29; d) J. A. Love in Handbook of Metathesis (Ed.: R. H.
Grubbs), Wiley-VCH, Weinheim, 2003, vol. 2, pp. 296–322; e)
R. H. Grubbs, Tetrahedron 2004, 60, 7117–7140; f) for uses of
RCM in the synthesis of 5,6-dihydropyran-2-ones see ref.[1a]
Received: April 18, 2008
Published Online: June 23, 2008
4018
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4015–4018