Total synthesis of (±)-9-deoxygoniopypyrone. Application of the iodocyclofunctionalization reaction of α-allenic alcohol derivatives

Article abstract of DOI:10.1139/v97-212

The synthesis of (±)-9-deoxygoniopypyrone (1) from the α-allenic alcohol 5 is described. Iodocyclofunctionaliztion of the N-tosyl carbamate derivative of 5 using I₂ and Ag₂CO₃ provided, in a highly diastereoselective and r

Full text of DOI:10.1139/v97-212

94
Total synthesis of (±)-9-deoxygoniopypyrone.
Application of the iodocyclofunctionalization
reaction of α-allenic alcohol derivatives
Richard W. Friesen and Suzanne Bissada
Abstract: The synthesis of (±)-9-deoxygoniopypyrone (1) from the α-allenic alcohol 5 is described. Iodocyclofunctionaliztion of
the N-tosyl carbamate derivative of 5 using I2 and Ag2CO3 provided, in a highly diastereoselective and regioselective fashion,
the vinyl iodo syn-vicinal diol 4. Two routes were explored in order to introduce the third stereogenic centre in the molecule.
Reductive deiodination of the vinyl iodide and diastereoselective epoxidation of the derived acetonide 14 using mCPBA
provided a mixture of epoxides 15 and 16 (2:1) in which the desired threo diastereomer predominated. Alternatively,
dihydroxylation of acetonide 14 (OsO4, NMO) yielded a mixture of diols 21 and 22 (2:3) which were separated after
monosilylation (TBDMSCl) of the primary alcohol. The major silyl ether erythro diastereomer 24 was converted to the
desired epoxide 15 by mesylation (MsCl, Et3N) and epoxide formation (TBAF) with inversion of stereochemistry. The minor
threo diastereomer 23 was also converted to the desired epoxide 15 (TBAF; ArSO2Cl; NaOMe). Epoxide opening was
effected with lithium acetylide and the resulting alkyne 27 was carbonylated (MeLi, ClCO2Me) to afford the α,β-acetylenic
ester 28. Semi hydrogenation over Lindlar’s catalyst followed by protecting- group removal under acidic conditions provided
(±)-8-epigoniodiol 30. Finally, conversion of 30 to (±)-9-deoxygoniopypyrone 1 was effected under basic conditions (DBU).
Key words: (±)-9-deoxygoniopypyrone, α-allenic alcohol, iodocyclofunctionalization, syn-diol.
Résumé : On décrit la synthèse de la (±)-9-désoxygoniopyrone (1) à partir de l’alcool α-allénique 5. L’iodocyclofonctionn-
alisation du dérivé N-tosylcarbamate du produit 5 à l’aide de I2 et de Ag2CO3 a conduit au vinyl iodo diol syn-vicinal 4 avec
une diastéréosélectivité et une régiosélectivité élevées. Dans le but d’introduire le troisième centre stéréogénique de la
molécule, on a exploré deux voies. D’une part, la déiodation réductrice de l’iodure de vinyle et l’époxydation
diastéréosélective du dérivé acétonide 14 à l’aide de l’acide m-chloroperbenzoïque (AmCPB) conduisent à un mélange
d’époxydes 15 et 16 (2 : 1) dans lequel le diastéréomère thréo recherché prédomine. D’autre part, la dihydroxylation de
l’acétonide 14 (OsO4, NMO) fournit un mélange des diols 21 et 22 (2 : 3) qui ont pu être séparés après monosilylation
(«TBDMSCl») de l’alcool primaire. On a transformé l’éther silylé du diastéréomère érythro (24) prépondérant en époxyde 15
recherché en procédant à une mésylation («MsCl», Et3N) suivie de la formation d’un époxyde («TBAF») avec inversion de
stéréochimie. Le diastéréomère thréo (23) minoritaire a aussi été transformé en époxyde 15 recherché («TBAF»; ArSO2Cl;
NaOMe). On a effectué l’ouverture de l’époxyde à l’aide d’acétylure de lithium et on a effectué une décarbonylation de
l’alcyne 27 qui en résulte (MeLi, ClCO2Me) pour conduire à l’ester α,β-acétylénique 28 qui, par semihydrogénation sur du
catalyseur de Lindlar suivie de l’élimination des groupes protecteurs dans des conditions acides, fournit le (±)-8-épigoniodiol
30. Enfin, on a effectué la conversion du composé 30 en (±)-9-désoxygoniopyrone (1) dans des conditions basiques («DBU»).
Mots clés : (±)-9-désoxygoniopyrone, alcool α-allénique, iodocyclofonctionnalisation, syn-diol.
[Traduit par la rédaction]
novel 2,6-dioxabicyclo[3.3.1]nonan-3-one molecular scaffold,
that make it attractive as a synthetic target. Within this frame-
work, the key substructure in terms of synthesis is the triol
Introduction
The cytotoxic (ED50 7.4 µg/mL against HT-29 cells) bicyclic
styryl lactone (+)-9-deoxygoniopypyrone (1) was isolated in
1990 from the stem bark of Goniothalamus giganteus Hook. f.
& Thomas (Annonaceae) (1). (+)-9-Deoxygoniopypyrone (1)
possesses several interesting structural features, including the
Received August 18, 1997.
moiety in which the three contiguous oxygen-bearing stereo-
centres (C7/C8/C1) are in a syn,syn relationship (see 2).
We have been interested in the synthesis of natural products
using our recently described method for the highly diastereose-
lective conversion of the N-tosyl carbamate derivatives of sec-
ondary α-allenic alcohols such as 5 into vinyl iodo
syn-vicinal diols 4 (2–6). We felt that the implementation of
R.W. Friesen1 and S. Bissada. Department of Medicinal
Chemistry, Merck Frosst Centre for Therapeutic Research,
P.O. Box 1005, Pointe Claire – Dorval, QC H9R 4P8, Canada.
1Author to whom correspondence may be addressed.
Telephone: (514) 428–3164. Fax: (514) 695–0693. E-mail:
rick_friesen@merck.com
Can. J. Chem. 76: 94–101 (1998)
© 1998 NRC Canada

95
Friesen and Bissada
Scheme 1.
Scheme 2.
this iodocyclofunctionalization strategy would allow us to ad-
dress the structurally interesting features in 1. According to our
retrosynthetic plan, the relative stereochemistry between the
C7/C8 hydroxy moieties in 1 (natural product numbering used
throughout) would be readily established using this method.
Following reductive deiodination of the vinyl iodide moiety in
4, diastereoselective oxidation (epoxidation or dihydroxyl-
ation) of the resulting olefin would introduce the third stereo-
centre and provide the epoxide 3. Homologation of 3 would
afford the α,β-unsaturated ester 2, the immediate precursor to
1. Herein, we describe the full details of the synthesis of (±)-1
(Schemes 1–3) according to this strategy.2
Two syntheses of (+)-1 have been reported in the literature.
The first synthesis by Honda and co-workers (7), which util-
ized 2,3-O-isopropylidene-D-glyceraldehyde as the chiral
iodocyclofunctionalization procedure (2, 4) (Scheme 1). Thus,
alcohol 5 was treated sequentially with TsNCO and I2 to pro-
vide an E/Z mixture of diiodides 7 (5) that was cyclized by
treatment with Ag2CO3 in ether–MeCN (10:1). Filtration of
the silver salts and concentration of the reaction mixture pro-
vided the crude cyclization products. In accord with our earlier
observations (2, 4), inspection of the 1H NMR spectrum of the
crude reaction mixture revealed that the imino carbonate 8 was
obtained in a highly diastereoselective fashion (diastereoselec-
tivity >50:1) together with minor amounts ( <5%) of the re-
lated carbamate 9 (9). From a practical point of view, it is
important to point out that it is essential to wash the solid silver
salt cake extensively with ethyl acetate and methanol in order
to achieve optimum recovery of the initial cyclization prod-
ucts. Hydrolysis of the crude mixture with methanolic sodium
hydroxide yielded the desired vinyl iodo syn-diol 4 in 66%
overall yield after chromatography. Reductive deiodination of
4 using n-Bu3SnH–AIBN provided the unsaturated diol 10 in
81% yield (Scheme 2).
The strategy for the synthesis of 1 from syn-diol 10 required
that the installation of the C1 oxygen occur with threo dia-
stereoselectivity relative to the hydroxy moieties at C7 and C8.
In keeping with the plan that chain extension to an intermediate
such as 2 would be required, epoxidation of 10 appeared to be
an obvious strategy. The directed diastereoselective epoxida-
tion reactions of allylic and homoallylic alcohols or diols are
well documented (10–15). Typically, transition metal (Ti, V)
mediated epoxidations of such olefins, including monosubsti-
tuted alkenes, afford the erythro diastereomers with good to
excellent stereoselectivity. Conversely, epoxidations of both
starting material, demonstrated that the absolute configuration
of the natural product (+)-1 is as depicted. Subsequent to our
published synthesis of (±)-1,2 Yang and Zhou described the
synthesis of (+)-1 from methyl cinnamate using Sharpless
asymmetric dihydroxylation technology (8). In contrast to our
synthesis, both of these groups introduced one of the three
contiguous hydroxy-bearing stereocentres by the nucleophilic
addition of a metalated aromatic to an α-alkoxy aldehyde.
Results and discussion
The vinyl iodo syn-diol 4 was prepared from the racemic
α-allenic alcohol 5,3 using our previously reported
2
For a preliminary account of this work, see ref. 3.
Although 5 is racemic, only a single enantiomer has been drawn
throughout.
3
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Can. J. Chem. Vol. 76, 1998
allylic and homoallylic alcohols with mCPBA are marginally
diastereoselective in favour of the threo epoxides. For exam-
ple, upon treatment of 3-buten-2-ol or 4-penten-2-ol with
mCPBA, the corresponding threo epoxide isomers are ob-
tained in ratios of 3:2 and 1.2:1, respectively (10–12). Not
surprisingly, exposure of ene diol 10 to mCPBA at room tem-
perature provided a mixture of epoxides 11/12 in a ratio of 2:1
(51%) (Scheme 2).
(17). This reaction was extremely capricious and we were
never able to find conditions that would bring about the epox-
ide opening of 15/16 in a reproducible fashion on a quantity
of material. However, treatment of the epoxide mixture 15/16
with lithium acetylide – EDA complex in THF–HMPA at
The stereochemical assignments of the epoxy diol dia-
1
stereomers 11/12 are based on comparison of their H NMR
spectral data with those of structurally similar epoxy alcohols
(13–15). The characteristic proton resonance in these spectra
is that of H7. Typically, the resonance frequency of this proton
is observed at higher field in the threo isomer than in the
erythro isomer. In the case of epoxy diols 11/12, the chemical
shift of H7 in the major isomer (δ 3.68) is 0.25 ppm upfield
relative to the corresponding resonance in the minor isomer
(δ 3.93). This observation is consistent with the reported lit-
erature data (13–15) and suggests that the major isomer is in
fact the threo epoxy diol 11.
A variety of methods, including metal-catalyzed directed
epoxidation (Ti, V) (10–12), were attempted in an effort to
increase the threo diastereoselectivity in the epoxidation of 10
but without any improvement in selectivity. In addition, sev-
eral monoprotected alcohol derivatives of 10 (MOM,
TBDMS) (6) were also oxidized using mCPBA or the
VO(acac)2–t-BuOOH epoxidation system (10–12). All of
these reactions were unsatisfying since they resulted in low
diastereoselectivity and were also plagued by low conversion
or competing side reactions such as benzylic oxidation. As far
as we are aware, the general threo diastereoselective epoxida-
tion of this class of monosubstituted olefinic alcohols (or diols)
remains an unsolved problem in organic synthesis.4
We then turned our attention to the epoxidation of a pro-
tected diol, the acetonide 14 (Scheme 2). Thus, treatment of
14 with mCPBA at room temperature for 3 days provided the
epoxides 15 and 16 as an inseparable 2:1 mixture in a com-
bined isolated yield of 96%. Although in this reaction the dia-
stereoselectivity was no better than that observed in the
epoxidation of diol 10, the yield was substantially better. Fur-
thermore, it was anticipated that the stereocentre at C1 in iso-
mer 16 could be inverted at a later stage in the synthesis and
thus the epoxide mixture 15/16 was carried forward. The as-
signment of the relative stereochemistry in the major epoxide
diastereomer 15 was only tentative and was made primarily by
correlation with the products derived from the epoxidation of
10 described earlier. The epoxide mixture 11/12 derived from
10 was converted into the corresponding mixture of acetonides
15/16 (2:1) and the major isomer from this mixture was iden-
tical with the major epoxide 15 obtained upon epoxidation of
14. The eventual conversion of 15 to 1 (vide infra) confirmed
this stereochemical assignment.
room temperature afforded the readily separable acetylenic al-
cohols 17 and 18 in isolated yields of 55% and 26%, respec-
tively. Omission of the HMPA from this reaction mixture
resulted in only low ( <10%) conversion. The inversion of the
C1 alcohol stereocentre in 18 was attempted using Mitsunobu
chemistry. The conditions described by Martin and Dodge (18)
using p-nitrobenzoic acid and DEAD in PhMe provided pre-
dominantly the E-enyne 20 (76%) along with only 7% of the
desired benzoate 19, which was subsequently hydrolyzed to
the alcohol 17. Other related methods that were attempted for
the inversion of the C1 stereocentre in 18, including a two-step
oxidation–reduction sequence, were also unsatisfactory.
Due to our inability to invert the C1 (natural product num-
bering) stereocentre in the acetylenic alcohol 18, we then con-
sidered the possibility of carrying out a dihydroxylation of
olefin 14 in order to introduce the desired oxygenation pattern.
It was anticipated, based on Kishi’s rules (19) and additional
literature precedent (20), that the bishydroxylation of mono-
substituted olefin 14 would not be highly diastereoselective
and that the major diastereomer would possess the undesired
erythro relative stereochemistry at C1. However, it was ex-
pected that both diol diastereomers resulting from dihydroxyl-
ation could be efficiently converted into the desired epoxide
15. Although this route would be more lengthy than direct
epoxidation of the olefin, it would ultimately provide a single
epoxide with the correct relative stereochemistry at C1.
In the event, olefin 14 was treated with catalytic OsO4 and
NMO to provide a 2:3 (by inspection of the integrated 1H NMR
spectrum) mixture of diols 21 and 22, respectively (Scheme
3). The major diastereomer 22 was assigned the erythro con-
figuration based upon literature precedent (19, 20). The crude
diol mixture was silylated using TBDMSCl at 0°C and the
readily separable monosilylated diols 23 and 24 were obtained
in overall isolated yields of 37 and 57%, respectively, from
olefin 14. A two-step reaction sequence, involving formation
of the mesylate 26 (MsCl, Et3N, 0°C) followed by intra-
molecular displacement using TBAF at room temperature, ef-
fected the transformation of the major diastereomer 24 into the
desired epoxide 15 in 86% overall yield. Desilylation (TBAF)
of silyl ether 23 followed by conversion of the primary alcohol
to the aryl sulfonate 25 using 2-mesitylenesulfonyl chloride
(0°C to room temperature) was accomplished in 92% yield.
Treatment of 25 with K2CO3 in MeOH provided epoxide 15
in 97% yield. Therefore, the overall conversion from 14 to 15
via the dihydroxylation strategy illustrated in Scheme 3 is an
acceptable 82%.
The epoxide mixture 15/16 was treated with the dianion of
propiolic acid according to the conditions of Carlson and Oyler
4
Roush and Michaelides have reported that a MOM
monoprotected syn-diol related to 10 is epoxidized with
exceptionally high threo diastereoselectivity
usingVO(acac)2–t-BuOOH (16). However, in this literature
example, the unprotected non-benzylic homoallylic alcohol is
flanked by a group that is much more sterically bulky than the
phenyl group of 10.
With pure epoxide 15 now in hand, alkylation with lithium
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97
Friesen and Bissada
Scheme 3.
Scheme 4.
acetylide – EDA complex in THF–HMPA at room temperature
as described previously led to the acetylenic alcohol 17 (88%)
(Scheme 4). Protection of the alcohol 17 (TBDMSOTf, Et3N;
96%) followed by methoxycarbonylation (MeLi; ClCO2Me;
91%) provided the α,β-acetylenic ester 28. The three-step
sequence from 15 to 28 (alkylation, silylation, methoxycar-
bonylation), while somewhat more lengthy than the originally
anticipated reaction with propiolic acid dianion (vide supra),
proceeds in excellent overall yield.
The conversion of the α,β-acetylenic ester 28 to the dihy-
dropyran-2-one 30, the immediate precursor to 1, followed the
strategy described by Carlson et al. for the synthesis of simple
dihydropyran-2-ones (17). Thus, semi hydrogenation of the al-
kyne 28 over Lindlar’s catalyst (5% Pd on Ca2CO3) cleanly
provided the Z olefin 29. The 1H NMR spectrum of the crude
material indicated the clean conversion of 28 to 29 without
competing over-reduction or olefin E/Z isomerization. The
crude reaction mixture was treated with a mixture of HOAc, 1
N HCl, and THF (1:1:1 v/v/v) at 65°C, resulting in the com-
plete deprotection of the triol and subsequent cyclization to the
lactone 30 (8-epigoniodiol) (7). Again, analysis of the crude
reaction mixture (1H NMR) revealed that a small amount of
30 had undergone cyclization to 1 under these reaction condi-
tions. Thus, once again, the crude reaction mixture was used
and the cyclization was completed using conditions that had
been described by Honda and co-workers (1% DBU in THF)
(7). Synthetic (±)-9-deoxygoniopypyrone (1) (mp 185–186°C,
EtOH) was isolated in 60% yield for the three steps from 28
and exhibited spectral data (1H and 13C NMR, IR) identical to
the data reported (1) for the natural product.
Experimental
General information
1H NMR spectra were recorded at 300, 400, or 500 MHz in
acetone-d6 or CDCl3 as specified. Broad-band proton-decou-
pled 13C NMR spectra were recorded at 100 or 125 MHz in
CDCl3. IR spectra were recorded on neat samples unless stated
otherwise. Solvents were anhydrous and were transferred via
syringes under an atmosphere of argon or nitrogen. Work-up
procedures involving the drying of organics were carried out
with MgSO4. Flash column chromatography (referred to as
chromatography) was performed with 230–400 mesh silica
gel, eluting with the solvents indicated (v/v). Elemental analy-
ses were performed by Oneida Research Services, Inc.,
Whitesboro, N.Y., or the Laboratoire d’analyse élémentaire,
Université de Montréal. Compounds for which high-resolution
mass measurements are given were homogeneous by TLC
analysis and gave satisfactory spectroscopic data indicative of
their purity.
3,4-Dihydroxy-2-iodo-phenyl-1-butene 4
To a solution of 1-phenyl-2,3-butadien-1-ol 5 (10.5 g,
71.8 mmol) in ether (350 mL) at room temperature was slowly
added p-TsNCO (12.0 mL, 1.1 equiv.). The mixture was
stirred at room temperature for 30 min and then solid I2 (18.2
g, 1.0 equiv.) was added in several portions over 1 h. Ag2CO3
(29.7 g, 1.5 equiv.) and MeCN (35 mL) were added sequen-
tially and the resulting mixture was stirred at room temperature
for 15 h. The reaction mixture was filtered through Celite, and
the filter pad was washed extensively with ethyl acetate
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Can. J. Chem. Vol. 76, 1998
(approximately 2 L) followed by methanol (approximately
500 mL). The filtrate was concentrated, the crude mixture was
dissolved in methanol – 1 N NaOH (3:1 v/v, 320 mL) and
stirred at room temperature for 15 h. The methanol was evapo-
rated and the solution was neutralized to ~pH 7 by the addition
of 1 N HCl. The mixture was extracted with CH2Cl2 (3 ×
500 mL) and the combined organics were dried and concen-
trated. Chromatography (toluene–acetone, 6:1 to 5:1) of the
residual material provided the diol 4 (13.7 g, 66%) as a white
solid, mp 68.5–69.5°C. IR (CHCl3): 3590, 1630, 1275 cm–1;
1H NMR (300 MHz, CDCl3) δ: 3.09 (br s, 1H), 3.23 (br s, 1H),
3.72 (br d, 1H, J = 6.0 Hz), 4.77 (d, 1H, J = 6.5 Hz), 5.80 (d,
1H, J = 1.8 Hz), 6.10 (dd, 1H, J = 1.0, 1.8 Hz), 7.26–7.39 (m,
5H); 13C NMR δ: 75.8, 81.5, 111.6, 126.7, 128.2, 128.3, 128.6,
139.5. Anal. calcd. for C10H11IO2: C 41.40, H 3.82; found: C
41.24, H 3.69.
extracted with ether (4×). The combined organics were washed
with water and brine, dried, and concentrated. Chromatogra-
phy (hexane–ether, 10:1) of the residue provided the acetonide
13 (1.89 g, 92%) as a colourless oil. IR: 1050 cm–1; 1H NMR
(300 MHz, CDCl3) δ: 1.59 (s, 3H), 1.63 (s, 3H), 3.63 (dd, 1H,
J = 0.8, 8.0 Hz), 4.83 (d, 1H, J = 8.0 Hz), 5.99 (d, 1H, J =
1.5 Hz), 6.28 (dd, 1H, J = 0.8, 1.5 Hz), 7.28–7.38 (m, 5H); 13C
NMR δ: 27.4, 27.5, 82.8, 88.0, 109.0, 110.3, 126.5, 128.36,
128.42, 130.0, 136.7. Anal. calcd. for C13H15IO2: C 47.29, H
4.58; found: C 46.88, H 4.50.
Olefin 14
A mixture of vinyl iodide 13 (1.8 g, 6.2 mmol), triphenyltin
hydride (2.6 g, 1.2 equiv.), and AIBN (20 mg) in benzene
(40 mL) was heated at reflux for 90 min. The solution was
cooled to room temperature and then 10% KF (100 mL) and
EtOAc (100 mL) were added. After 15 min, the white precipi-
tate was filtered off and the filtrate was extracted with EtOAc
(2×). The combined organics were washed with 10% KF and
brine, dried, and concentrated. Chromatography (hex-
ane–ether, 15:1) of the residue provided the olefin 14 (1.09 g,
87%) as a colourless oil. IR: 2980, 1365, 1230, 1050 cm–1; 1H
NMR: (300 MHz, CDCl3) δ: 1.53 (s, 3H), 1.57 (s, 3H), 4.17
(app t, 1H, J = 8.4 Hz), 4.64 (d, 1H, J = 8.4 Hz), 5.20–5.27 (m,
2H), 5.87 (m, 1H), 7.26–7.58 (m, 5H); 13C NMR δ: 27.0, 27.1,
82.9, 84.7, 109.3, 119.3, 126.4, 128.2, 128.4, 133.9, 137.2.
Exact Mass calcd. for C13H17O2 (M+H)+: 205.1229; found:
205.1228.
3,4-Dihydroxy-4-phenyl-1-butene 10
To a solution of vinyl iodide 4 (8.0 g, 27.6 mmol) in refluxing
benzene (333 mL) was added n-Bu3SnH (8.2 mL, 1.1 equiv.)
and AIBN (100 mg) and the solution was refluxed for 15 h.
The solution was cooled to room temperature and then 10% KF
(300 mL) and EtOAc (300 mL) were added. After 45 min, the
white precipitate was filtered off and the filtrate was extracted
with EtOAc (2×). The combined organics were washed with
10% KF and with brine, dried, and concentrated. Chromatog-
raphy (hexane followed by hexane–EtOAc, 3:2) of the residue
provided the diol 10 (3.66 g, 81%) as a colourless oil. IR: 3300,
1
1050 cm–1; H NMR (300 MHz, CDCl3) δ: 2.50 (br s, 2H),
4.21 (ddt, 1H, J = 5.5, 6.9, 1.5 Hz), 4.48 (d, 1H, J = 6.9 Hz),
5.13 (dt, 1H, J = 10.6, 1.5 Hz), 5.23 (dt, 1H, J = 17.3, 1.5 Hz),
5.71 (ddd, 1H, J = 5.5, 10.6, 17.3 Hz), 7.25–7.44 (m, 5H); 13C
NMR δ: 76.9, 77.6, 117.0, 127.0, 128.1, 128.4, 136.3, 140.2.
Anal. calcd. for C10H12O2: C 73.15, H 7.37; found: C 73.27, H
7.66.
Epoxidation of olefin 14 (epoxides 15 and 16)
To a solution of olefin 14 (950 mg, 4.65 mmol) in dichlo-
romethane (50 mL) at 0°C was added mCPBA (3.0 g, 3
equiv.). After 30 min, the cold bath was removed and the mix-
ture was stirred at room temperature for 72 h. Saturated
NaHCO3 (100 mL) was added and the mixture was extracted
with dichloromethane (2×). The combined organics were
washed with saturated NaHCO3 (2×), water, and brine, then
dried and concentrated. Chromatography (hexane–EtOAc,
9:1) of the residue provided an inseparable mixture of the
epoxides 15 and 16 (983 mg, 96%) as a colourless oil. Inspec-
tion of this mixture by 1H NMR spectroscopy indicated a 2:1
Epoxidation of 3,4-dihydroxy-4-phenyl-1-butene 10
(epoxides 11 and 12)
To a solution of diol 10 (116 mg, 0.71 mmol) in CH2Cl2
(3 mL) at room temperature was added mCPBA (458 mg, 3.0
equiv.) and the mixture was stirred for 16 h. Saturated sodium
carbonate was added and the mixture was extracted with
EtOAc (2×). The combined organics were washed with 1 N
NaOH and brine, dried, and concentrated. Inspection of this
1
mixture of isomers. Major isomer 15: H NMR (300 MHz,
CDCl3) δ: 1.50 (s, 3H), 1.55 (s, 3H), 2.48 (dd, 1H, J = 2.6,
5.3 Hz), 2.75 (dd, 1H, J = 4.2, 5.3 Hz), 3.06 (ddd, 1H, J = 2.6,
4.2, 5.0 Hz), 3.62 (dd, 1H, J = 5.0, 8.7 Hz), 4.91 (d, 1H, J =
8.7 Hz), 7.35 (m, 5H). Minor isomer 16: 1H NMR (300 MHz,
CDCl3) δ: 1.52 (s, 3H), 1.54 (s, 3H), 2.67 (dd, 1H, J = 2.6,
5.0 Hz), 2.81 (dd, 1H, J = 4.0, 5.0 Hz), 3.14 (ddd, 1H, J = 2.6,
4.0, 5.1 Hz), 3.73 (dd, 1H, J = 5.1, 8.1 Hz), 4.94 (d, 1H, J =
8.1 Hz), 7.35 (m, 5H).
1
crude reaction mixture by H NMR spectroscopy indicated a
2:1 mixture of isomers. Chromatography (hexane–EtOAc, 1:2)
of the residue provided a mixture of the epoxy diols 11 and 12
(65 mg, 51%) as a colourless oil. Major isomer 11: 1H NMR
(500 MHz, CDCl3) δ: 2.55 (dd, 1H, J = 2.8, 4.9 Hz), 2.65 (dd,
1H, J = 4.2, 4.9 Hz), 2.97 (ddd, 1H, J = 2.8, 3.8, 4.2 Hz), 3.68
(dd, 1H, J = 3.8, 7.4 Hz), 4.73 (d, 1H, J = 7.4 Hz), 7.35 (m,
1
5H). Minor isomer 12: H NMR (500 MHz, CDCl3) δ: 2.77
Alkynes 17 and 18
(dd, 1H, J = 4.0, 5.0 Hz), 2.86 (dd, 1H, J = 2.8, 5.0 Hz), 2.94
(ddd, 1H, J = 2.8, 3.6, 4.0 Hz), 3.93 (dd, 1H, J = 3.6, 5.9 Hz),
4.70 (d, 1H, J = 5.9 Hz), 7.35 (m, 5H).
Lithium acetylide – EDA complex (540 mg, 1.3 equiv.) was
added portionwise over 2 min to a solution of the epoxide mix-
ture 15/16 (887 mg, 4.03 mmol) in THF (10 mL) and HMPA
(4 mL). The resulting mixture was stirred at room temperature
for 15 h and then water was carefully added. The mixture was
extracted with EtOAc (3×), and the combined organics were
washed with 10% HCl (3×), water, and brine, then dried and
concentrated. Chromatography (toluene–EtOAc, 10:1) of the
residue provided the alkynes 17 and 18. The first compound to
Acetonide 13
A solution of diol 4 (1.8 g, 6.2 mmol), 2-methoxypropene
(0.9 mL, 1.5 equiv.), and camphorsulfonic acid (25 mg) in
DMF (10 mL) was stirred at room temperature for 2 h. The
mixture was poured into ammonium acetate buffer and
© 1998 NRC Canada

99
Friesen and Bissada
be eluted was the minor isomer 18 (260 mg, 26%), a colourless
(hexane–EtOAc, 10:1). The major diastereomer, silyl ether 24
(985 mg, 57%), was eluted first and was obtained as a colour-
1
oil. IR: 3450, 3300, 2115, 1240, 1055 cm–1; H NMR (300
1
MHz, CDCl3) δ: 1.47 (s, 3H), 1.53 (s, 3H), 1.97 (t, 1H, J =
2.7 Hz), 2.15 (br s, 1H), 2.41–2.44 (m, 2H), 3.92–3.99 (m, 2H),
4.98 (AB q, 1H, J = 3.8, 11.2 Hz), 7.26–7.37 (m, 3H),
7.41–7.45 (m, 2H); 13C NMR δ: 23.7, 27.0, 27.2, 70.4, 71.1,
79.9, 80.3, 84.0, 109.5, 127.4, 128.3, 128.5, 138.4. Anal. calcd.
for C15H18O3: C 73.15, H 7.37; found: C 73.27, H 7.46. Further
elution provided the major isomer 17 (535 mg, 55%) as a white
solid, mp 101.5–102.5°C. IR (KBr): 3460, 3300, 2120, 1240,
1060 cm–1; 1H NMR (300 MHz, CDCl3) δ: 1.51 (s, 3H), 1.56
(s, 3H), 1.95 (t, 1H, J = 2.7 Hz), 2.36 (ddd, 1H, J = 2.7, 6.5,
16.7 Hz), 2.37 (br s, 1H), 2.47 (ddd, 1H, J = 2.7, 7.3, 16.7 Hz),
3.74 (br m, 1H), 3.91 (dd, 1H, J = 2.0, 8.6 Hz), 4.91 (d, 1H, J =
8.6 Hz), 7.30–7.41 (m, 5H); 13C NMR δ: 25.3, 26.9, 27.2, 67.3,
70.5, 79.1, 80.2, 83.8, 109.5, 126.8, 128.4, 128.7, 137.3. Anal.
calcd. for C15H18O3: C 73.15, H 7.37; found: C 73.19, H 7.38.
less oil. IR: 3480, 840 cm–1; H NMR (500 MHz, CDCl3) δ:
0.02 (s, 3H), 0.03 (s, 3H), 0.86 (s, 9H), 1.48 (s, 3H), 1.53 (s,
3H), 2.48 (d, 1H, J = 4.8 Hz), 3.61 (dd, 1H, J = 6.5, 10.1 Hz),
3.71 (dd, 1H, J = 3.9, 10.1 Hz), 3.83 (m, 1H), 3.92 (dd, 1H,
J = 6.8, 7.7 Hz), 5.03 (d, 1H, J = 7.7 Hz), 7.26–7.47 (m, 5H);
13C NMR (125 MHz) δ: –5.6, –5.5, 18.2, 25.7, 27.0, 27.1, 64.0,
72.9, 81.1, 82.3, 109.3, 127.2, 128.0, 128.3, 138.9. Anal. calcd.
for C19H32O4Si: C 64.73, H 9.15; found: C 64.89, H 9.42.
Further elution provided the minor diastereomer, silyl ether 23
1
(648 mg, 37%), as a colourless oil. IR: 3480, 830 cm–1; H
NMR (500 MHz, CDCl3) δ: –0.04 (s, 3H), –0.01 (s, 3H), 0.81
(s, 9H), 1.51 (s, 3H), 1.55 (s, 3H), 2.45 (d, 1H, J = 7.3 Hz), 3.54
(m, 1H), 3.59–3.64 (m, 2H), 3.87 (dd, 1H, J = 1.8, 8.7 Hz),
4.99 (d, 1H, J = 8.7 Hz), 7.27–7.41 (m, 5H); 13C NMR (125
MHz) δ: –5.6, –5.5, 18.1, 25.7, 26.9, 27.2, 64.7, 68.7, 79.0,
82.2, 109.3, 126.8, 128.3, 128.5, 137.5. Anal. calcd. for
C19H32O4Si: C 64.73, H 9.15; found: C 64.48, H 9.06.
Enyne 20 and benzoate 19
To a solution of alcohol 18 (144 mg, 0.58 mmol) in toluene
(12 mL) at room temperature was added sequentially Ph3P
(307 mg, 2 equiv.), DEAD (0.18 mL, 2 equiv.), and p-ni-
trobenzoic acid (195 mg, 2 equiv.). The resulting mixture was
stirred for 2 h and then hexane (30 mL) was added. The white
preciptate was filtered through Celite and to the filtrate was
added EtOAc. The combined organics were washed with satu-
rated NaHCO3 (3×), dried, and concentrated. Chromatography
(hexane–EtOAc, 9:1 to 4:1) of the residue first provided the
enyne 20 (101 mg, 76%) as a white solid, mp 52–53°C. IR
Epoxide 15 from the major silyl ether diastereomer 24
To a solution of alcohol 24 (885 mg, 2.51 mmol) and Et3N
(1.05 mL, 3 equiv.) in CH2Cl2 (10 mL) at 0°C was added
methanesulfonyl chloride (0.29 mL, 1.5 equiv.). After 15 min,
water was added and the resulting mixture was stirred at room
temperature for 15 min. The mixture was extracted with
EtOAc (2×) and the organics were washed with water, dried,
and concentrated. The colourless residue was dissolved in THF
(10 mL) and TBAF (5.0 mL, 2 equiv.) was added. The reaction
mixture was stirred at room temperature for 15 h and then
water was added. The mixture was extracted with EtOAc (2×)
and the organics were washed with water and brine, dried, and
concentrated. Chromatography (hexane–EtOAc, 6:1) of the re-
sidual oil provided epoxide 15 (477 mg, 86%) as a colourless
1
(CHCl3): 3300, 1490, 1450, 1380, 1050, 690 cm–1; H NMR
(300 MHz, CDCl3) δ: 1.52 (s, 3H), 1.57 (s, 3H), 2.90 (d, 1H,
J = 2.3 Hz), 4.20 (ddd, 1H, J = 1.3, 6.4, 8.4 Hz), 4.65 (d, 1H,
J = 8.4 Hz), 5.68 (ddd, 1H, J = 1.3, 2.3, 15.9 Hz), 6.21 (ddd,
1H, J = 0.5, 6.4, 15.9 Hz), 7.27–7.37 (m, 5H); 13C NMR δ:
26.9, 27.0, 78.7, 81.2, 82.8, 83.3, 109.7, 112.1, 126.4, 128.4,
128.6, 136.7, 140.0. Anal. calcd. for C15H16O2: C 78.92, H
7.06; found: C 79.30, H 7.15. Further elution provided the
benzoate 19 (17 mg, 7%), which was obtained as a white solid.
Benzoate 19 was dissolved in MeOH (2 mL) and water
(0.1 mL) and treated with K2CO3 (2 mg). After 24 h, the mix-
ture was concentrated and subjected to chromatography (9:1
toluene–EtOAc). The alkynol 17 was obtained as a white solid
(4 mg, 95%).
1
oil. IR: 1235 cm–1. H NMR (300 MHz, CDCl3) δ: 1.50 (s,
3H), 1.55 (s, 3H), 2.48 (dd, 1H, J = 2.6, 5.3 Hz), 2.75 (dd, 1H,
J = 4.2, 5.3 Hz), 3.06 (ddd, 1H, J = 2.6, 4.2, 5.0 Hz), 3.62 (dd,
1H, J = 5.0, 8.7 Hz), 4.91 (d, 1H, J = 8.7 Hz), 7.35 (m, 5H); 13C
NMR (125 MHz) δ: 26.6, 26.9, 43.7, 50.2, 80.0, 83.2, 109.8,
126.3, 128.3, 128.6, 137.4. Anal. calcd. for C13H16O3: C 70.89,
H 7.32; found: C 70.54, H 7.34.
Aryl sulfonate 25
To a solution of silyl ether 23 (741 mg, 2.10 mmol) in THF
(10 mL) was added TBAF (2.3 mL, 1.1 equiv.) and, after 1 h,
water was added. The mixture was extracted with EtOAc (3×)
and the organics were washed with water and brine, dried, and
concentrated. The residual white solid was dissolved in pyri-
dine (10 mL) and cooled to 0°C. 2-Mesitylenesulfonyl chlo-
ride (520 mg, 1.1 equiv.) was added as a solid and the resulting
mixture was stirred at 0°C for 1 h and then gradually warmed
to room temperature over 6 h. After stirring at room tempera-
ture for 16 h, 1 N HCl was added and the resulting mixture was
extracted with EtOAc (2×). The organics were washed with 1
N HCl and brine, dried, and concentrated. Chromatography
(hexane–EtOAc, 3:1) of the residual oil provided the aryl sul-
fonate 25 (813 mg, 92%) as a colourless glass. IR: 3500,
1380 cm–1; 1H NMR (500 MHz, CDCl3) δ: 1.47 (s, 3H), 1.51
(s, 3H), 2.28 (s, 3H), 2.43 (d, 1H, J = 8.9 Hz), 2.54 (s, 6H), 3.72
(dd, 1H, J = 1.5, 8.6 Hz), 3.77 (m, 1H), 3.94 (dd, 1H, J = 5.3,
10.4 Hz), 3.98 (dd, 1H, J = 7.1, 10.4 Hz), 4.96 (d, 1H,
Silyl ethers 23 and 24
To a solution of alkene 14 (1.0 g, 4.9 mmol) and NMO H2O
(1.4 g, 2.1 equiv.) in acetone (20 mL) and water (2 mL) at
room temperature was added a solution of OsO4 (1 mL of a 4%
solution in water) and the mixture was stirred for 15 h. A
saturated solution of Na2SO3 (30 mL) was added and the re-
sulting mixture was stirred for 1 h. The mixture was extracted
with EtOAc (2×) and the organics were washed successively
with saturated Na2SO3, water, and brine and then dried and
1
concentrated. The residual oil so obtained (analysis by H
NMR spectroscopy indicated it to be a 3:2 mixture of dia-
stereomers) and imidazole (790 mg, 2.4 equiv.) were dissolved
in CH2Cl2 (18 mL) and cooled to 0°C. TBDMSCl (875 mg, 1.2
equiv.) was added as a solid and the resulting mixture was
stirred at 0°C for 2 h. Water (50 mL) was added and extracted
with EtOAc (2×). The organics were washed with brine and
concentrated. The residual oil was subjected to chromatography
© 1998 NRC Canada

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Can. J. Chem. Vol. 76, 1998
Pyranone 30 ((±)-8-epigoniodiol)
J = 8.6 Hz), 6.92 (s, 2H), 7.30–7.38 (m, 5H); 13C NMR (125
MHz) δ: 21.0, 22.4, 26.8, 27.1, 66.0, 70.3, 78.7, 81.9, 109.8,
126.6, 128.6, 128.7, 130.3, 131.7, 136.8, 139.9, 143.4. Anal.
calcd. for C22H28O6S: C 62.84, H 6.71; found: C 62.45, H 6.77.
A mixture of ester 28 (330 mg, 0.79 mmol) and Lindlar’s cata-
lyst (33 mg) in THF (60 mL) was stirred under an atmosphere
of hydrogen gas (1 atm (101.3 kPa)) for 1 h. The mixture was
filtered through Celite, washing with EtOAc. The filtrate was
1
concentrated and inspection by H NMR spectroscopy indi-
Epoxide 15 from the aryl sulfonate 25
cated the absence of starting material and the presence of one
olefin isomer (29). 1H NMR (300 MHz, CDCl3) δ: 0.01 (s, 3H),
0.05 (s, 3H), 0.82 (s, 9H), 1.48 (s, 3H), 1.51 (s, 3H), 2.89 (m,
2H), 3.66 (s, 3H), 3.85–3.96 (m, 2H), 4.90 (d, 1H, J = 8.2 Hz),
5.74 (td, 1H, J = 1.8, 11.5 Hz), 6.30 (td, 1H, J = 7.3, 11.5 Hz),
7.25–7.40 (m, 5H). The crude mixture was stirred in a mixture
of THF (2 mL), 1 N HCl (1 mL), and glacial HOAc (1 mL) at
65°C for 3 h. The solution was cooled to room temperature and
then co-evaporated with toluene (3×). Ammonium acetate
buffer was poured into the residue and the mixture was ex-
tracted with EtOAc (4×). The combined organics were dried
and concentrated. A small portion of this material was purified
by chromatography (toluene–EtOAc, 4:1) to provide the pyra-
none 30 as a white solid, mp 99–100°C. IR (KBr): 3400, 1710,
A mixture of aryl sulfonate 25 (761 mg, 1.81 mmol) and solid
K2CO3 (500 mg, 2 equiv.) in MeOH (20 mL) was stirred at
room temperature for 90 min and then saturated NH4Cl was
added. The mixture was extracted with EtOAc (2×) and the
combined organics were washed with water and brine, dried,
and concentrated. Chromatography (hexane–EtOAc, 7:1) of
the residual oil provided epoxide 15 (387 mg, 97%) as a col-
ourless oil.
Alkyne 17
Following the procedure described above for the alkynylation
of the epoxide mixture 15/16, the pure epoxide 15 (853 mg,
3.87 mmol) was converted to alkyne 17 (839 mg, 88%).
1
1250 cm–1; H NMR (300 MHz, CDCl3) δ: 2.11 (dddd, 1H,
J = 0.7, 3.8, 6.3, 18.6 Hz), 2.81 (tdd, 1H, J = 2.4, 12.6,
18.6 Hz), 3.31 (br s, 1H), 3.44 (br s, 1H), 3.63 (br m, 1H), 4.18
(ddd, 1H, J = 2.2, 3.8, 12.6 Hz), 4.95 (d, 1H, J = 7.3 Hz), 5.92
(ddd, 1H, J = 0.7, 2.4, 9.8 Hz), 6.84 (ddd, 1H, J = 2.4, 6.3,
9.8 Hz), 7.33 (m, 5H). Exact Mass calcd. for C13H15O4
(M+H)+: 235.0971; found: 235.0970. The remainder of the
material was used directly in the subsequent reaction.
Silyl ether 27
To a solution of alcohol 17 (450 mg, 1.83 mmol) and Et3N
(0.6 mL, 2.4 equiv.) in dichloromethane (15 mL) at 0°C was
added TBDMSOTf (0.5 mL, 1.2 equiv.). The mixture was
stirred at 0°C for 30 min and then at room temperature for 2 h.
Ammonium acetate buffer was added and the mixture was
extracted with dichloromethane (3×). The combined organics
were dried and concentrated. Chromatography (hexane–ether,
20:1) of the residue provided the silyl ether 27 (633 mg, 96%)
as a white solid, mp 60.5–61.5°C. IR (CHCl3): 3310, 1250,
1065, 830 cm–1; 1H NMR (300 MHz, CDCl3) δ: 0.07 (s, 3H),
0.12 (s, 3H), 0.89 (s, 9H), 1.50 (s, 3H), 1.55 (s, 3H), 1.93 (t,
1H, J = 2.7 Hz), 2.39 (ddd, 1H, J = 2.7, 6.0, 16.6 Hz), 2.58
(ddd, 1H, J = 2.7, 7.1, 16.6 Hz), 3.90 (ddd, 1H, J = 3.0, 6.0,
7.1 Hz), 4.07 (dd, 1H, J = 3.0, 8.4 Hz), 4.97 (d, 1H, J =
8.4 Hz), 7.34 (m, 5H); 13C NMR δ: –4.5, –4.2, 18.1, 24.2, 25.8,
27.0, 27.4, 69.6, 70.4, 78.6, 81.1, 84.2, 109.1, 127.2, 128.2,
128.5, 138.3. Anal. calcd. for C21H32O3Si: C 69.96, H 8.94;
found: C 70.23, H 9.12.
(±)-9-Deoxygoniopypyrone (1)
The crude material containing the pyranone 30 was stirred in a
solution of 1% DBU in THF (3 mL) at room temperature for
15 h. The mixture was concentrated and the residual material
was subjected to chromatography (toluene–EtOAc, 17:3). (±)-
9-Deoxygoniopypyrone (1) (111 mg, 60% from 28) was ob-
tained as a white solid, mp 183–184°C. IR (KBr): 3450, 1740,
1
1720, 1270 cm–1; H NMR (500 MHz, CDCl3) δ: 1.55 (br s,
1H), 1.83 (dd, 1H, J = 4.0, 14.1 Hz), 2.58 (d quintet, 1H, J =
14.1, 2.1 Hz), 2.85 (dd, 1H, J = 5.1, 19.3 Hz), 2.96 (dm, 1H,
J = 19.3 Hz), 3.94 (m, 1H), 4.51 (m, 1H), 4.86 (app septet, 1H,
J = 1.8 Hz), 4.95 (d, 1H, J = 1.6 Hz), 7.30–7.42 (m, 5H); 13
C
NMR δ: 24.1, 36.4, 66.2, 68.4, 70.6, 74.7, 126.2, 128.4, 129.0,
136.8, 169.3. Anal. calcd. for C13H14O4: C 66.46, H 6.02;
found: C 66.20, H 6.19.
Ester 28
To a solution of alkyne 27 (543 mg, 1.51 mmol) in THF
(15 mL) at –78°C was added MeLi (1.6 mL of a 1.4 M solution
in ether, 1.5 equiv.) and the resulting mixture was stirred at
–78°C for 5 min, and at 0°C for 30 min. Methyl chloroformate
(0.2 mL, 1.5 equiv.) was then added and the mixture was
stirred for a further 30 min at 0°C. Ammonium acetate buffer
was added and the mixture was extracted with EtOAc (3×).
The combined organics were dried and concentrated. Chroma-
tography (hexane–ether, 9:1) of the residue provided the ester
28 (576 mg, 91%) as a white solid, mp 50.5–51.5°C. IR
References
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(CHCl3): 2220, 1710, 1250, 1065, 835 cm–1; H NMR (300
1
MHz, CDCl3) δ: 0.02 (s, 3H), 0.11 (s, 3H), 0.84 (s, 9H), 1.47
(s, 3H), 1.52 (s, 3H), 2.49 (dd, 1H, J = 6.2, 17.0 Hz), 2.69 (dd,
1H, J = 5.7, 17.0 Hz), 3.71 (s, 3H), 3.96–4.08 (m, 2H), 4.91 (d,
1H, J = 8.0 Hz), 7.25–7.40 (m, 5H); 13C NMR δ: –4.6, 18.0,
24.3, 25.7, 26.9, 27.3, 52.4, 69.3, 74.4, 78.6, 84.3, 86.3, 109.2,
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List of abbreviations
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40, 1610 (1975).
mCPBA: m-chloroperoxybenzoic acid
NMO: N-methylmorpholine N-oxide
TBDMSCI: tert-butyldimethylsilyl chloride
TBDMSOTf: tert-butyldimethylsilyl trifluoromethanesul-
fonate
TBAF: tetrabutylammonium fluoride
DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene
AIBN: 2,2′-azobisisobutyronitrile
MOM: methoxymethyl
TBDMS: tert-butyldimethylsilyl
HMPA: hexamethylphosphoramide
DEAD: diethyl azodicarboxylate
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© 1998 NRC Canada