Stereoselective total synthesis of (+)-dodoneine

Article abstract of DOI:10.1055/s-0029-1218741

A total synthesis of the naturally occurring dihydropyranone dodoneine is reported. The combination of a highly catalytic enantioselective allylboration and a highly diastereoselective allylstannation was used for the stereoselective generation of the two stereogenic centers. The pyranone ring was created in two steps through generation of a Z-configured ,-unsaturated ester and lactonization via intramolecular transesterification. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218741

PAPER
1649
Stereoselective Total Synthesis of (+)-Dodoneine
S
tereoselectiv
l
e
T
otal
o
Synthesis of
r
(+)-Dod
e
oneine nt Allais,* Paul-Henri Ducrot*
INRA UMR1318 Institut Jean-Pierre Bourgin, INRA route de Saint-Cyr, 78026 Versailles Cedex, France
Fax +33(1)30833119; E-mail: florent.allais@versailles.inra.fr; E-mail: ducrot@versailles.inra.fr
Received 14 January 2010
nylpropanoid and lactone moieties in order to have access
to structure–activity relationships (Figure 1).
Abstract: A total synthesis of the naturally occurring dihydropyr-
anone dodoneine is reported. The combination of a highly catalytic
enantioselective allylboration and a highly diastereoselective allyl-
stannation was used for the stereoselective generation of the two
stereogenic centers. The pyranone ring was created in two steps
through generation of a Z-configured a,b-unsaturated ester and lac-
tonization via intramolecular transesterification.
Herein, we would like to present a short and efficient
asymmetric synthesis of dodoneine starting from the
known phenylpropanoidic aldehyde 1 while limiting the
use of expensive catalysts and ligands. In order to limit the
cost of the formation of dodoneine, we envisaged initially
controlling the chirality of the C7 center by using a highly
enantioselective allylboration5 followed by a highly dia-
stereoselective allylstannation9 to set the configuration at
C5. The Z-configured unsaturated ester would be thereaf-
ter elaborated via a Wadsworth–Horner–Emmons olefina-
tion using Still–Gennari phosphonoacetate (Scheme 1).10
Key words: asymmetric allylation, diastereoselectivity, enantio-
selectivity, olefination, phenol, total synthesis, lactone
Dodoneine is a naturally occurring dihydropyranone re-
cently isolated from Tapinanthus dodoneinfolius, a para-
sitic plant that feeds from the sheanut tree in Burkina Faso
(West Africa) (Figure 1).1 Like many 5,6-dihydropyran-
2-ones, dodoneine was expected to exhibit potent biolog-
ical activities (HIV protease inhibition, apoptosis induc-
tion, antileukemic effect). Recent biological studies using
(+)-dodoneine revealed a potent relaxing effect on pre-
constricted rat aortic rings.2 Its structure and absolute con-
figuration were assigned as shown in Figure 1 on the basis
of extensive spectroscopic analyses (NMR, HRMS, X-
ray).1
O
O
O
OH
O
MeO2C
6
TBSO
7
HO
(+)-dodoneine
OH OH
O
H
1
3
TBSO
TBSO
Still–Gennari
olefination
O
O
Scheme 1
OH
O
2
1
4
OH
7
O
5
(Z)
R2
(Z)
3
9
10
6
8
The synthesis starts from known aldehyde 1, which can be
readily obtained from the commercially available ester A
in two steps: protection of the phenol through the forma-
tion of the corresponding tert-butyldimethylsilyl ether
(TBSCl, imidazole, CH2Cl2), followed by controlled re-
duction of the methyl ester into the aldehyde (DIBAL-H,
toluene, –78 °C, 85% overall yield) (Scheme 2). In our
quest for an economic synthesis that would be easy to
scale up, we focused our efforts on a design of dodoneine
synthesis that would minimize the use of expensive cata-
lysts (i.e., metal/ligands). Therefore, any asymmetric ally-
lation process involving stoichiometric amounts of metal–
chiral ligand complex (e.g., Brown and Duthaler method-
ologies) was ruled out. Hall recently developed a potent
catalytic enantioselective allylboration using p-F-Vivol
(B) as ligand and applied it to the synthesis of dodoneine
and, thereby, efficiently controlled both C5 and C7 chiral
centers in a sequence involving two allylboration reac-
tions.5 We similarly used this methodology on aldehyde 1
and synthesized optically active homoallylic alcohol 2 in
97% ee and 95% yield, [allylBpin, (R,R)-p-F-vivol (5
13
R3
11
HO
R1 = H, OMe
HO
12
Hall allylboration
R1
diastereoselective
allylstannation
R
2 = H, OMe, OH
R3 = H, Me, Et
(+)-dodoneine
Figure 1
This interesting biological activity has resulted in the re-
cent publication of six total syntheses of dodoneine by
Marco,2 Srihari,3 Cossy,4 Hall,5 Das,6 and Sabitha7 using
established aldehyde asymmetric allylation methodolo-
gies for introducing the stereogenic centers and either
ring-closing metathesis or intramolecular transesterifica-
tion for pyranone ring closure. Due to our interest in phe-
nylpropanoid related compounds,8 we envisaged a design
for a new general synthetic methodology for dodoneine
and related analogues featuring variously substituted phe-
SYNTHESIS 2010, No. 10, pp 1649–1653
Advanced online publication: 19.04.2010
x
x.
x
x
.
2
0
1
0
DOI: 10.1055/s-0029-1218741; Art ID: P00610SS
© Georg Thieme Verlag Stuttgart · New York

1650
F. Allais, P.-H. Ducrot
PAPER
Bpin
OH OH
OH
(S)
O
(R,R)-p-F-vivol B (5 mol%)
1. OsO4, 2,6-lutidine
NaIO4, dioxane–H2O
SnCl4
(R)
(S)
H
Na2CO3, 4 Å MS
toluene (1.3 M), –78 °C
2. allylSiMe3, SnCl4
CH2Cl2, –78 °C
3
1
2
TBSO
TBSO
TBSO
(80%, >97:3 dr)
(95%, 97% ee)
PPTS
2,2-DMP CH2Cl2, r.t.
2 h
O
O
O
O
O
O
C, KHMDS
18-crown-6, THF
OsO4, 2,6-lutidine
NaIO4, dioxane–H2O
(R)
(S)
(R)
(S)
(S)
(S)
O
–78 °C, 4 h
MeO2C
5
4
6
(51%, Z/E = 90:10)
TBSO
TBSO
TBSO
(96%)
80% aq AcOH
60 °C, 1 d
F
F
O
O
O
O
F3C
O
OH
(S)
O
P
OMe
(R)
(R)
OMe
O
(R)
HO
OH
HO
F3C
HO
7
A
B
C
(+)-dodoneine
(68%, overall yield = 24%)
Scheme 2
mol%), SnCl4 (3.8 mol%), Na2CO3, 4 Å MS, toluene (1.3 allyl moiety is too far off from the electrophilic carbonyl,
M), –78 °C].
we cannot reasonably consider an intramolecular allyl
transfer originating from the chelating allyltrichlorostan-
nane. The formation of the syn-1,3-diol can only be ex-
plained by the attack of a second allyltrichlorostannane on
the less hindered face of the carbonyl. This is, in our opin-
ion, the most plausible explanation to account for the for-
mation of the syn-1,3-diol. Unlike alkyltin species (e.g.,
Bu3SnR), the stannane derivatives issued from the allyl-
trichlorostannane are water soluble and can be easily re-
moved by a simple methanol/aqueous work-up leading to
tin-free syn-1,3-diols. The fact that no fluoride ions
(TBAF, HF, or KF)13 are required in the work-up proce-
dure allows the presence of silyl protecting groups on the
substrates. Besides, unlike allylsilylations that often re-
quire polar solvents like N,N-dimethylformamide, these
At this stage of the synthesis, as we had dedicated our-
selves to limit catalyst use, a highly diastereoselective al-
lylation was needed to take advantage of the stereogenic
center at C7 to control the configuration at C5. Thus, after
the one-step oxidative cleavage of the terminal double
bond of 2 (OsO4, 2,6-lutidine, NaIO4, dioxane–H2O), the
crude corresponding b-hydroxyaldehyde produced was
directly treated with a premixed solution of trimethylallyl-
silane and tin(IV) chloride in dichloromethane at –78 °C
and gave the desired homoallylic alcohol 3 in good overall
yield (80%, 2 steps) and with excellent diastereoselectiv-
ity (dr >97:3) in favor of the syn-isomer. The stereochem-
1
ical assignment was achieved by examination of the H
and 13C NMR spectra of ketal 4, obtained from 3 by treat-
ment with 2,2-dimethoxypropane in the presence of pyri-
dinium 4-toluenesulfonate (0.1 equiv) in dichloromethane
at room temperature (96% yield). In fact, the stereochem-
istry of syn- and anti-1,3-diol acetonides can be assigned
from the 13C chemical shifts of the acetal methyl groups
and from the 13C chemical shifts of the acetal carbon. In
general, the syn-1,3-diol acetonides have diastereotopic
acetal methyls shifts at d = 19 and 30 and the acetal carbon
shift at d = 98.5, while the anti-acetonides have enan-
tiotopic acetal methyl shifts at d = 25 and the acetal carbon
shift at d = 100.5.11
H
Cl
Sn Cl
R
H
H
H
H
O
steric strain
Cl
O
H
+
allyl far-off from carbonyl
H
H
R
H
H
OH
OH
H
H
no allyl transfer allowed
from the chelating
allylstannane
Cl
Cl
Sn Cl
R
H
O
O
H
H
OH
OH
Cl
H
Cl
Sn Cl
R
H
R
H
H
The formation of a syn-1,3-diol from unprotected b-hy-
droxyaldehydes/ketones9 suggested that, during the allyl-
trichlorostannation, tin is chelated to both the free
hydroxy group and the aldehyde leading to a ‘chair-like’
six-membered cyclic transition state (Scheme 3).12 How-
ever, in our case, due to steric strain and the fact that the
O
OH
OH
R
O
H
1,2-syn-diol
SnCl3
Scheme 3
Synthesis 2010, No. 10, 1649–1653 © Thieme Stuttgart · New York

PAPER
Stereoselective Total Synthesis of (+)-Dodoneine
1651
tography (CC) were carried out under positive N2 pressure with 40–
63 mm silica gel (Merck) and the indicated solvents. Mp: uncorrect-
ed. 1H Spectra of samples in the indicated solvent were recorded at
300 MHz on a MercuryPlus 300 Varian instrument [1H NMR resid-
ual solvent signals: CDCl3 d = 7.26; CD3OD d = 3.31; acetone-d6
d = 2.05]. 13C NMR spectra of samples in the indicated solvent were
recorded at 75 MHz on a Varian instrument [13C NMR residual sol-
vent signals: CDCl3 d = 77.26; CD3OD d = 49.00; acetone-d6 d =
29.84]. 13C multiplicities were determined by DEPT135 experiments.
Assignments are given relatively to Figure 1 labeling. IR analyzes
were performed on a Nicolet Avatar 320 FT-IR. Optical rotations
were measured on a Bellingham+ ADP410 from Stanley. Electron
impact (EI), and LR-MS and HRMS analyses were obtained from
the mass spectrometry service of the ICSN-CNRS, Gif-sur-Yvette,
Versailles, France. Chemicals were bought from Sigma-Aldrich and
Acros Organics and used without further purification. All reported
yields are uncorrected and refer to purified products.
allyltrichlorostannations are performed in nonpolar sol-
vents (such as CH2Cl2) thus simplifying the reaction pro-
cedure and the work-up.
With the stereogenic centers at C5 and C7 set, the forma-
tion of the Z-configured unsaturated ester was undertaken.
Thus, the double bond of ketal 4 was submitted to an oxi-
dative cleavage (OsO4, 2,6-lutidine, NaIO4, dioxane–
H2O) to furnish the corresponding aldehyde 5, which un-
derwent Horner–Wadsworth–Emmons olefination using
Still–Gennari fluorinated phosphonoacetate C (KHMDS,
18-crown-6, THF, –78 °C, 3 h).10 The Z-configured a,b-
unsaturated ester 6 was thereby obtained in good yield
(51%, 2 steps) and with a Z/E ratio of 90:10. Finally, acid-
ic treatment of 6 (80% aq AcOH, 60 °C, 1 d) led to an one-
pot phenol deprotection/ketal removal/lactonization giv-
ing pure (+)-dodoneine (7) in 68% yield and the bicyclic
product 8 (21% yield) likely due to the Michael addition
of the C7-hydroxy onto the unsaturated lactone
(Scheme 4). The spectral properties of synthetic target 7
and its bicyclic derivative 8 were found similar to those
reported in the literature.1,3
3-[4-(tert-Butyldimethylsiloxy)phenyl]propionaldehyde (1)
To a soln of commercially available ester A (8.0 g, 44.4 mmol, 1.0
equiv) in CH2Cl2 (150 mL) under argon was added TBSCl (7.4 g,
48.9 mmol, 1.1 equiv) followed by imidazole (4.5 g, 66.7 mmol, 1.5
equiv). The mixture was stirred at r.t. overnight. H2O (100 mL) was
then added and the mixture was extracted with Et2O (2 × 200 mL)
and the combined organic layers were washed with brine and then
dried (anhyd MgSO4), filtered, and concentrated in vacuo to afford
the crude product, which was purified by flash chromatography (cy-
clohexane–EtOAc, 9:1) to provide methyl 3-[4-(tert-butyldimethyl-
siloxy)phenyl]propanoate (12.9 g, 99%); Rf = 0.25 (cyclohexane–
EtOAc, 7:3).
O
O
H
OH
O
Michael addition
O
O
H
7
8
H
HO
HO
IR (neat): 2955, 2931, 2859, 1743, 1611, 1512, 1473, 1258, 1170,
917, 840, 781 cm–1.
Scheme 4
1H NMR (300 MHz, CDCl3): d = 7.04 (d, J = 8.4 Hz, 2 H, H11),
6.75 (d, J = 8.4 Hz, 2 H, H12), 3.65 (s, 3 H, CO2CH3), 2.88 (t,
J = 7.5 Hz, 2 H, H9), 2.57 (d, J = 7.5 Hz, 2 H, H8), 0.97 [s, 9 H,
OSiMe2C(CH3)3], 0.18 [s, 6 H, OSi(CH3)2t-Bu].
13C NMR (75 MHz, CDCl3): d = 173.3 (s, CO2Me), 154.3 (s, C13),
133.5 (s, C10), 129.4 (d, C11), 120.2 (d, C12), 51.5 (q, CO2CH3),
36.5 (t, C8), 30.5 (t, C9), 25.9 [q, OSiMe2C(CH3)3], 18.5 [s,
OSiMe2C(CH3)3], –4.2 [q, OSi(CH3)2t-Bu].
In conclusion, the total asymmetric synthesis of (+)-dodo-
neine has been realized in seven steps from known alde-
hyde 1 with an overall yield of 24%. The stereogenic
centers were generated via the unique combination of a
highly stereoselective allylboration (C7) and a highly dia-
stereoselective allylstannation (C5), while the Z-config-
ured lactone was built using a Still–Gennari olefination/
intramolecular transesterification sequence. This synthe-
sis proves itself valuable for biological studies and/or
scale-up as it limits the use of atom-consuming ligands
and avoids the use of expensive catalysts while allowing
the formation of appreciable quantities of material as a
single isomer and in a timely fashion. Moreover, this syn-
thetic pathway is highly flexible as we can start from
readily available substituted cinnamic acids. That will
lead to the synthesis of numerous analogues of dodoneine
whom potential superior activity will be evaluated
through in-depth biological tests. This thorough study will
give access to structure–activity relationships, thus allow-
ing the design of potent biological active analogues for
therapeutic treatments. This work will be published in due
course.
HRMS (EI): m/z [M + Na]+ calcd for C16H26NaO3Si: 317.1549;
found: 317.1552.
Silyl ether (5.13 g, 18.0 mmol, 1.0 equiv) was charged into a flame
dried 250-mL round-bottom flask. Anhyd toluene (100 mL) was
added and the mixture was cooled to –78 °C. 1 M DIBAL-H in tol-
uene (18.0 mL, 18 mmol, 1.0 equiv) was added dropwise and the
mixture was stirred until completion. The mixture was then
quenched with sat. Rochelle’s salts (100 mL) and brought to r.t..
The mixture was stirred for 1 h and filtered through a pad of Celite.
The filtrate was extracted with CH2Cl2 (2 × 250 mL) and the com-
bined organic extracts were washed with brine and then dried (an-
hyd MgSO4), filtered, and concentrated in vacuo to afford the crude
product which was purified by flash chromatography (cyclohex-
ane–EtOAc, 8:2) to provide aldehyde 15 (4.12 g, 86%); Rf = 0.54
(cyclohexane–EtOAc, 6:4).
IR (neat): 3030, 2956, 2931, 2857, 2716, 1726, 1610, 1512, 1263,
1170, 917, 840, 781 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.81 (t, J = 1.2 Hz, 1 H, CHO),
7.04 (d, J = 8.4 Hz, 2 H, H11), 6.76 (d, J = 8.4 Hz, 2 H, H12), 2.89
(t, J = 7.2 Hz, 2 H, H9), 2.74 (t, J = 7.5 Hz, 2 H, H8), 0.97 [s, 9 H,
OSiMe2C(CH3)3], 0.18 [s, 6 H, OSi(CH3)2t-Bu].
13C NMR (75 MHz, CDCl3): d = 202.0 (s, CHO), 154.3 (s, C13),
133.2 (s, C10), 129.4 (d, C11), 120.4 (d, C12), 45.7 (t, C8), 27.6 (t,
CH2Cl2 (stabilized with amylene) was purified by distillation from
CaH2 under N2 immediately before use. THF and Et2O were puri-
fied by distillation from Na/benzoquinone under N2. Moisture and
O2-sensitive reactions were carried out in flame-dried glassware un-
der N2. Evaporations were conducted under reduced pressure at
temperature below 45 °C unless otherwise noted. Column chroma-
Synthesis 2010, No. 10, 1649–1653 © Thieme Stuttgart · New York

1652
F. Allais, P.-H. Ducrot
PAPER
C9), 25.9 [q, OSiMe2C(CH3)3], 18.4 [s, OSiMe2C(CH3)3], –4.2 [q,
OSi(CH3)2t-Bu].
HRMS (EI): m/z[M + Na]+ calcd for C15H24NaO2Si: 287.1443;
anhyd CH2Cl2 (2 mL) at –78 °C under argon. The mixture was al-
lowed to stir at this temperature overnight to ensure completion.
Workup entailed addition of MeOH (0.16 mL) and sat. aq NH4Cl
soln (0.4 mL) and extraction with CH2Cl2 (3 × 5 mL). The com-
bined organic layers were dried (anhyd MgSO4), filtered, and con-
centrated in vacuo to give the crude diol 3 as a yellow oil; Rf = 0.51
(cyclohexane–EtOAc, 5:5).
1H NMR (300 MHz, CDCl3): d = 7.02 (d, J = 8.2 Hz, 2 H, H11),
6.74 (d, J = 8.2 Hz, 2 H, H12), 5.79 (ddt, J = 6.9, 7.2, 13.9 Hz, 1 H,
H3), 5.06 (m, 2 H, H1), 3.85–3.70 (m, 2 H, H7, H5), 2.62 (m, 2 H,
H9), 2.29 (dtapp, J = 6.9, 13.8 Hz, 1 H, H4), 2.14 (dtapp, J = 6.9, 13.8
Hz, 1 H, H4), 1.86–1.57 (m, 2 H, H8), 1.52–1.10 (m, 2 H, H6), 0.98
[s, 9 H, OSiMe2C(CH3)3], 0.18 [s, 6 H, OSi(CH3)2t-Bu].
found: 264.1438.
(R)-1-[4-(tert-Butyldimethylsiloxy)phenyl]hex-5-en-3-ol (2)5
To a flame-dried 50-mL round-bottom flask equipped with a stirrer
bar was added (R,R)-p-F-vivol (B, 213 mg, 0.454 mmol, 0.05
equiv), anhyd Na2CO3 (74 mg, 0.70 mmol, 0.08 equiv), and 4 Å mo-
lecular sieves (50 mg, previously dried under high vacuum at 100
°C and stored in an oven). The flask was capped with a rubber sep-
tum and placed under argon followed by the addition of freshly dis-
tilled toluene (7.0 mL). The mixture was stirred for 2 min followed
by addition of 1.0 M SnCl4 in CH2Cl2 (349 mL, 0.349 mmol, 0.038
equiv). This mixture was stirred at r.t. for 5 min, cooled to –78 °C,
and maintained at this temperature for 15 min, which was followed
by the addition of allylboronic acid pinacol ester (1.91 mL, 9.98
mmol, 1.10 equiv). This mixture was then stirred for an additional
30 min after which, aldehyde 1 (2.4 g, 9.08 mmol, 1 equiv) was add-
ed to the mixture. The mixture was stirred at –78 °C for 12 h after
which, 1.5 M DIBAL-H in toluene (10.0 mL) was added to quench
any unreacted aldehyde. The mixture stirred at –78 °C for an addi-
tional 15 min, after which time 1 M HCl (25 mL) was added. The
mixture was then allowed to warm to r.t. and stirred for 30 min. The
resulting mixture was extracted with Et2O (3 × 50 mL) and the com-
bined organic extracts were washed with brine (30 mL), dried (an-
hyd Na2SO4), filtered, and concentrated in vacuo to give an oily
residue that was purified by flash chromatography (cyclohexane–
EtOAc, 95:5) to provide the requisite homoallylic alcohol product 2
in quantitative yield. The ee of the product was determined by for-
mation of diastereomeric esters by condensation with (S)-Mosher
acid chloride (97% ee).
13C NMR (75 MHz, acetone-d6): d = 154.4 (s, C13), 136.4 (s, C10)
and (d, C3), 130.2 (d, C11), 120.6 (d, C12), 116.9 (t, C2), 71.9 (d,
C5), 71.5 (d, C7), 43.8 (t, C4), 43.5 (t, C8), 41.0 (t, C6), 31.6 (t, C9),
26.1 [q, OSiMe2C(CH3)3], 18.8 [s, OSiMe2C(CH3)3], –4.2 [q,
OSi(CH3)2t-Bu].
The crude diol 3 (0.5 mmol, 1 equiv) was dissolved in CH2Cl2 (1
mL) at r.t. and 2,2-dimethoxypropane (0.6 mL, 5 mmol, 10 equiv)
and PPTS (6.6 mg, 0.05 mmol, 0.1 equiv) were added to the soln.
When the reaction was complete, sat. aq NaHCO3 soln (1 mL) was
added, the organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (3 × 6 mL). The combined organic layers
were dried (anhyd MgSO4), filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (cyclohexane–
EtOAc, 95:5) to afford pure 4 (195.5 mg, 77% yield from 2, dr
>97:3); Rf = 0.61 (cyclohexane–EtOAc, 9:1).
[a]D22 –17.0 (c 0.1, CHCl3).
IR (neat): 2930, 2857, 1609, 1507, 1379, 1249, 911, 782 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.02 (d, J = 8.2 Hz, 2 H, H11),
6.74 (d, J = 8.2 Hz, 2 H, H12), 5.79 (ddt, J = 6.6, 7.5, 13.6 Hz, 1 H,
H3), 5.06 (m, 2 H, H2), 3.85–3.70 (m, 2 H, H5, H7), 2.62 (m, 2 H,
H9), 2.30 (dtapp, J = 6.6, 13.6 Hz, 1 H, H4), 2.13 (dtapp, J = 6.6, 13.6
Hz, 1 H, H4), 1.86–1.57 (m, 2 H, H8), 1.52–1.10 (m, 2 H, H6), 1.42
[s, 3 H, OC(CH3)2O], 1.40 [s, 3 H, OC(CH3)2O], 0.98 [s, 9 H,
OSiMe2C(CH3)3], 0.18 [s, 6 H, OSi(CH3)2t-Bu].
13C NMR (75 MHz, CDCl3): d = 153.8 (s, C13), 134.9 (s, C10),
134.5 (d, C3), 129.6 (d, C11), 120.0 (d, C12), 117.2 (t, C2), 98.8 [s,
OC(CH3)2O], 68.9 (d, C5), 68.0 (d, C7), 41.1 (t, C6), 38.3 (t, C4),
36.8 (t, C8), 30.6 (t, C9), 30.5 [q, OC(CH3)2O], 26.0 [q,
OSiMe2C(CH3)3], 20.1 [q, OC(CH3)2O], 18.4 [s, OSiMe2C(CH3)3],
–4.2 [q, OSi(CH3)2t-Bu].
[a]D25 –13.2 (c 0.68, CHCl3) [Lit.5 [a]D25 –11.96 (c 1.02, CHCl3)].
IR (neat): 3367, 2956, 2930, 2859, 1610, 1472, 1259, 917, 780 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.05 (d, J = 8.2 Hz, 2 H, H11),
6.76 (d, J = 8.2 Hz, 2 H, H12), 5.88–5.77 (m, 1 H, H5), 5.17–5.12
(m, 2 H, H4), 3.64 (tt, J = 4.4, 7.6 Hz, 1 H, H7), 2.70–2.78 (m, 1 H,
H9), 2.66–2.59 (m, 1 H, H9), 2.35–2.29 (m, 1 H, H6), 2.22–2.15 (m,
1 H, H6), 1.73–1.79 (m, 2 H, H8), 1.65 (s, 1 H, OH), 0.99 [s, 9 H,
OSiMe2C(CH3)3], 0.19 (s, 6 H, OSi(CH3)2t-Bu).
13C NMR (100 MHz, CDCl3): d = 153.7 (s, C13), 134.7 (s, C10),
134.6 (d, C5), 129.4 (d, C11), 119.9 (d, C12), 118.2 (t, C4), 70.0 (d,
C7), 42.0 (t, C6), 38.6 (t, C8), 31.2 (t, C9), 25.7 [q,
OSiMe2C(CH3)3], 18.2 [s, OSiMe2C(CH3)3], –4.4 [q, OSi(CH3)2t-
Bu].
HRMS (EI): m/z [M + Na]+ calcd for C23H38NaO3Si: 413.2488;
found: 413.2458.
HRMS (EI): m/z [M + Na]+ calcd for C18H30NaO2Si: 329.1913;
found: 329.1918.
Methyl (Z)-4-{(4R,6S)-6-[4-(tert-Butyldimethylsiloxy)pheneth-
yl]-2,2-dimethyl-1,3-dioxan-4-yl}but-2-enoate (6)
(4-{2-[(4S,6R)-6-Allyl-2,2-dimethyl-1,3-dioxan-4-yl]eth-
yl}phenoxy)-tert-butyldimethylsilane (4)
To a soln of 4 (100 mg, 0.26 mmol, 1 equiv) in dioxane–H2O (3:1,
2.1 mL:0.7 mL) at r.t. was successively added OsO4 (0.005 mmol,
0.02 equiv), 2,6-lutidine (0.06 mL, 0.51 mmol, 2 equiv), and NaIO4
(219 mg, 1 mmol, 4 equiv). The soln was stirred at r.t. until comple-
tion then quenched by addition of H2O (3 mL) followed by the ad-
dition of CH2Cl2 (5 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 10 mL) and the combined organic layers were dried
(anhyd MgSO4), filtered, and concentrated in vacuo. The crude b-
hydroxyaldehyde was used directly without further purification.
To a soln of 2 (200 mg, 0.65 mmol, 1 equiv) in dioxane–H2O (3:1,
5.4 mL:1.8 mL) at r.t. was successively added OsO4 (0.013 mmol,
0.02 equiv), 2,6-lutidine (0.15 mL, 1.29 mmol, 2 equiv), and NaIO4
(554.6 mg, 2.59 mmol, 4 equiv). The soln was stirred at r.t. until
completion then quenched by addition of H2O (10 mL) followed by
the addition of CH2Cl2 (15 mL). The aqueous layer was extracted
with CH2Cl2 (3 × 20 mL) and the combined organic layers were
dried (anhyd MgSO4), filtered, and concentrated in vacuo. The
crude b-hydroxyaldehyde was used directly without further purifi-
cation.
To a stirred soln of 18-crown-6 (169.2 mg, 0.61 mmol) in anhyd
THF (2.6 mL) at –40 °C under argon was added methyl 2-
[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate (C, 195.4 mg, 1.2
mmol) and 0.5 M KHMDS in toluene (1.22 mL, 0.61 mmol), suc-
cessively. After 15 min, the mixture was cooled to –78 °C and
stirred for an additional 30 min. Crude aldehyde 5 (0.26 mmol) in
anhyd THF (2.6 mL) was added and the resulting mixture was
To a round-bottom flask under argon was added anhyd CH2Cl2 (2
mL), SnCl4 (91 mL, 0.78 mmol, 1 equiv), and allyltrimethylsilane
(0.12 mL, 0.78 mmol, 1 equiv) and the mixture was stirred at r.t. for
12 h. The soln was transferred by cannula to a round-bottom flask
containing a soln of b-hydroxyaldehyde (0.62 mmol, 0.8 equiv) in
Synthesis 2010, No. 10, 1649–1653 © Thieme Stuttgart · New York

PAPER
Stereoselective Total Synthesis of (+)-Dodoneine
1653
stirred at –78 °C for 4 h. The starting material 5 was completely con-
sumed by TLC analysis, and the reaction was quenched by sat.
NaHCO3 (5 mL) at –78 °C. The cooling bath was removed and then
the mixture was extracted with Et2O (3 × 15 mL). The combined
Et2O extracts were washed with brine (5 mL), dried (MgSO4), fil-
tered, and concentrated in vacuo. Flash chromatography (cyclohex-
ane–EtOAc, 7:3) afforded the desired ester 6 (59.5 mg, 51%
isolated yield from 4); Rf = 0.67 (cyclohexane–EtOAc, 5:5).
IR (neat): 3338, 2924, 2856, 1685, 1517, 1451, 1382, 1347, 1230,
1076, 1004, 821, 759 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.02 (d, J = 8.2 Hz, 2 H, H11),
6.75 (d, J = 8.2 Hz, 2 H, H12), 5.38 (br s, 1 H, OH), 4.92–4.85 (m,
1 H, H5), 4.45–4.32 (m, 1 H, H7), 3.76–3.66 (m, 1 H, H3), 2.83–
2.78 (m, 2 H, H9), 2.74–2.63 (m, 1 H, H2), 2.60–2.48 (m, 1 H, H2),
2.05–1.90 (m, 2 H, H4), 1.86–1.53 (m, 4 H, H8, H6).
13C NMR (75 MHz, CDCl3): d = 170.3 (s, C1), 154.1 (s, C13), 133.6
(s, C10), 129.5 (d, C11), 115.6 (d, C12), 73.4 (d, C3), 66.1 (d, C7),
65.1 (d, C5), 38.1 (t, C6), 37.2 (t, C4), 36.7 (t, C8), 30.8 (t, C2), 30.1
(t, C9).
[a]D20 –44.2 (c 0.1, acetone).
1H NMR (300 MHz, CDCl3): d = 7.02 (d, J = 8.2 Hz, 2 H, H11),
6.74 (d, J = 8.2 Hz, 2 H, H12), 6.36 (dd, J = 11.4, 7.5 Hz, 1 H, H2),
5.85 (dt, J = 11.4, 1.6 Hz, 1 H, H3), 3.90–3.59 (m, 2 H, H5, H7),
3.77 (s, 3 H, CO2CH3), 2.95–2.64 (m, 4 H, H9, H4), 1.82–1.10 (m,
4 H, H8, H6), 1.42 [s, 3 H, OC(CH3)2O], 1.40 [s, 3 H, OC(CH3)2O],
0.98 [s, 9 H, OSiMe2C(CH3)3], 0.18 [s, 6 H, OSi(CH3)2t-Bu].
HRMS (ESI): m/z [M + H]+ calcd for C15H19O4: 263.1277; found:
263.1278.
13C NMR (75 MHz, CDCl3): d = 166.5 (s, C1), 153.6 (s, C13), 145.6
(d, C3), 134.9 (s, C10), 122.9 (d, C2), 129.6 (d, C11), 119.7 (d,
C12), 98.8 [s, OC(CH3)2O), 68.7 (d, C5), 68.0 (d, C7), 41.1 (t, C6),
38.3 (t, C4), 36.9 (t, C8), 30.5 (t, C9), 30.5 [q, OC(CH3)2O], 26.0 [q,
OSiMe2C(CH3)3], 20.1 [q, OC(CH3)2O], 18.4 [s, OSiMe2C(CH3)3],
–4.3 (q, OSi(CH3)2t-Bu).
Acknowledgment
The authors would like to thank Prof. Dennis G. Hall (University of
Alberta, Edmonton, Canada) for its generous gift of (R,R)-p-F-vi-
vol, and Prof. Eric J. Enholm (University of Florida, Gainesville,
USA) for fruitful discussions. Finally, F.A. also thanks Julien Pons
for its involvement in this project.
HRMS (EI): m/z [M + Na]+ calcd for C25H40NaO5Si: 471.2543;
found: 471.2539.
References
(+)-Dodoneine (7)
(1) Ouedraogo, M.; Carreyre, H.; Vanderbrouck, C.; Bescond,
J.; Raymond, G.; Guissou, A.; Cognard, C.; Beca, F.;
Potreau, D.; Cousson, A.; Marrot, J.; Coustard, J.-M. J. Nat.
Prod. 2007, 70, 2006.
(2) Àlvarez-Bercedo, P.; Falomir, E.; Carda, M.; Marco, J. A.
Eur. J. Org. Chem. 2008, 4015.
(3) Srihari, P.; Rajendar, G.; Srinivasa Rao, R.; Yadav, J. S.
Tetrahedron Lett. 2008, 49, 5590.
(4) Dittoo, A.; Bellosta, V.; Cossy, J. Synlett 2008, 2459.
(5) Rauniyar, V.; Hall, D. G. J. Org. Chem. 2009, 74, 4236.
(6) Das, B.; Sunnel, K.; Satyalakshmi, G.; Nandan Kumar, D.
Tetrahedron: Asymmetry 2009, 20, 1536.
Compound 6 (51 mg, 0.11 mmol, 1 equiv) was dissolved in 80%
AcOH (0.5 mL) and stirred at 60 °C for 24 h. The reaction was
quenched with sat. aq NaHCO3 and extracted with EtOAc (3 × 5
mL). The organic layer was washed with brine and dried (anhyd
MgSO4). After filtration of the mixture and concentration in vacuo,
the crude product was purified by flash chromatography (cyclohex-
ane–EtOAc, 3:7) and afforded (+)-dodoneine (7, 19.6 mg, 68% iso-
lated yield) and its bicyclic derivative 8 (6.0 mg, 21% yield).
Compound 7
Rf = 0.36 (cyclohexane–EtOAc, 1:9).
[a]D25 +42.2 (c 0.2, CHCl3) [Lit.5 [a]D25 +41.03 (c 1.37, CHCl3)].
(7) Sabitha, G.; Bhaskar, V.; Reddy, S. S.; Yadav, J. S. Synthesis
2009, 3285..
IR (neat): 3360, 3018, 2926, 2858, 1703, 1614, 1515, 1393, 1264,
1061, 1037, 815, 756 cm–1.
(8) (a) Allais, F.; Martinet, S.; Ducrot, P.-H. Synthesis 2009,
3571. (b) Quentin, M.; Allasia, V.; Pegard, A.; Allais, F.;
Ducrot, P.-H.; Favery, B.; Levis, C.; Martinet, S.; Masur, C.;
Ponchet, M.; Roby, D.; Schlaich, N.-L.; Jouanin, L.; Keller,
H. PLoS Pathogens 2009, 5 (1), doi:10.1371/
1H NMR (300 MHz, CDCl3): d = 7.04 (d, J = 8.2 Hz, 2 H, H11),
6.89 (dt, J = 4.2, 9.7 Hz, 1 H, H3), 6.76 (d, J = 8.2 Hz, 2 H, H12),
6.02 (dt, J = 1.5, 9.6 Hz, 1 H, H2), 5.08 (br s, 1 H, OH), 4.65 (qd,
J = 5.1, 7.4 Hz, 1 H, H5), 3.88 (tt, J = 4.7, 7.4 Hz, 1 H, H7), 2.74–
2.61 (m, 2 H, H9), 2.40–2.37 (m, 2 H, H4), 2.34 (br s, 1 H, OH),
2.01–1.68 (m, 4 H, H6, H8).
13C NMR (75 MHz, CDCl3): d = 164.2 (s, C1), 154.1 (s, C13), 145.4
(d, C3), 134.0 (s, C10), 129.7 (d, C11), 121.6 (d, C2), 115.6 (d,
C12), 77.3 (d, C5), 68.9 (d, C7), 42.4 (t, C6), 39.7 (t, C8), 31.1 (t,
C9), 29.8 (t, C4).
journal.ppat.1000264.
(9) (a) Allais, F.; Cossy, J. Org. Lett. 2006, 8, 3655. (b) Allais,
F.; Louvel, M.-C.; Cossy, J. Synlett 2007, 451. (c) Ferrié,
L.; Boulard, L.; Pradaux, F.; Bouzbouz, S.; Reymond, S.;
Capdevielle, P.; Cossy, J. J. Org. Chem. 2008, 73, 1864.
(d) Ferrié, L.; Reymond, S.; Capdevielle, P.; Cossy, J. Org.
Lett. 2007, 9, 2461.
(10) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(11) (a) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc.
Chem. Res. 1998, 31, 9. (b) Rychnovsky, S. D.; Rogers, B.
N.; Guang, Y. O. J. Org. Chem. 1993, 58, 3511.
(12) McNeill, A. H.; Thomas, E. J. Synthesis 1994, 322.
(13) Keck, G. E.; Byers, J. H. J. Org. Chem. 1985, 50, 5442.
HRMS (ESI): m/z: [M + Na]+ calcd for C15H18NaO4: 285.1103;
found: 285.1089.
Compound 8
Rf = 0.44 (cyclohexane–EtOAc, 1:9); mp 173–174 °C.
[a]D25 –33.5 (c 0.45, CHCl3).
Synthesis 2010, No. 10, 1649–1653 © Thieme Stuttgart · New York