Asymmetric total synthesis of (+)-: O -methylasparvenone, a rare nitrogen-free serotonin 2C receptor antagonist

Article abstract of DOI:10.1039/c6ob01678b

The first enantioselective synthesis of the fungal metabolite (+)-O-methylasparvenone was achieved in eight steps and 22% overall yield from inexpensive 3,4,5-trimethoxybenzaldehyde dimethyl acetal. Key steps include (i) early-stage asymmetric alkynylation of an aromatic aldehyde with a propiolate, (ii) intramolecular Friedel-Crafts acylation, and (iii) site-selective cleavage of an aryl methyl ether.

Full text of DOI:10.1039/c6ob01678b

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Page 1 of 16
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Asymmetric total synthesis of (+)-O-methylasparvenone, a rare
nitrogen-free serotonin 2C receptor antagonist†
Raphaël Lafleur-Lambert and John Boukouvalas*
†Department of Chemistry, Pavillon Alexandre-Vachon, Université Laval, 1045 Avenue de la
Médecine, Quebec City, Quebec G1V 0A6, Canada
E-mail: john.boukouvalas@chm.ulaval.ca
†Electronic supplementary information (ESI) available.
Abstract:
The first enantioselective synthesis of the fungal metabolite (+)-O-methylasparvenone was achieved
in eight steps and 22% overall yield from inexpensive 3,4,5-trimethoxybenzaldehyde dimethyl
acetal. Key steps include (i) early-stage asymmetric alkynylation of an aromatic aldehyde with a
propiolate, (ii) intramolecular Friedel-Crafts acylation, and (iii) site-selective cleavage of an aryl
methyl ether.

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Introduction
Depression is the second leading cause of disability worldwide, affecting more than 20 million
Americans each year.1 Most of the current antidepressants, including Prozac, are selective serotonin
(5-HT) reuptake inhibitors (SSRIs), acting as indirect agonists on multiple 5-HT receptors.
However, these drugs require 2-4 weeks before patients show any improvement (33% don’t),2 and
symptoms of anxiety or agitation are usually exacerbated when treatment is initiated.3,4
A substantial body of evidence suggests that blockage of the serotonin 2C receptor subtype (5-
HT2CR) boosts the therapeutic effects of SSRIs and could provide relief from depression for those
that respond poorly to the current drug regimes.4,5 Indeed, selective 5-HT3CR antagonists exert
antidepressant actions faster than SSRIs in mice (days vs. weeks).6 Moreover, recent preclinical
studies demonstrate the potential of 5-HT2CR antagonists for treating attention deficit hyperactivity
disorder (ADHD) and posttraumatic stress (PTSD).7,8 Hence, structurally novel natural products
that can block 5-HT2CR selectively are compelling targets for synthesis and highly sought after
leads for pharmacological optimization.
OH
O
OH
O
MeO
HO
OH
OH
1a
2
OH
O
R
1b R = Me
1c R = CH OH
2
MeO
1d R = CHO
*
OH
a
Fig. 1 Fungal tetralones 1a-d and 2.
In 1997, Bös and his colleagues at Hoffmann-La Roche made the discovery that the previously
known fungal metabolites (+)-O-methylasparvenone 1a, ent-1a and (+)-asparvenone 2 (Fig. 1)
represent an extremely rare class of non-nitrogenous serotonin receptor antagonists, binding
preferentially to 5-HT2CR.9-11 The most potent of them (1a, pKi = 6.7) was further shown to interact
with 5-HT2CR in a reversible and competitive manner, fully antagonizing 5-HT-induced
phosphoinositol turnover in vitro.9 As such, these metabolites have the distinction of being the first

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nitrogen-free serotonin receptor ligands to be uncovered, natural or otherwise.9,12,13 In addition, 1a
is the prototypical member of a small but growing family of naturally occurring trisubstituted 4-
hydroxy-1-tetralones,14 that also includes (+)-O-methylnorasparvenone 1b,15 the influenza virus
inhibitor (–)-10-norparvulenone 1c16 and the antifungal antibiotic seimatorone 1d17 (Fig. 1).
To date, racemic 1a has been synthesized by the groups of Brassard,18 Bös9 and Zard,19 using Diels-
Alder cycloaddition, a tandem Michael-Dieckman reaction and radical addition-cyclization,
respectively (Scheme 2). The latter process has also served as a key step in two syntheses of (±)-
1c.19,20 However, none of these strategies have been shown to be applicable to the enantioselective
preparation of these natural products. Further, there is a general lack of methods for the asymmetric
assemblage of 4-hydroxy-1-tetralones bearing multiple substituents on the aromatic ring.21,22
MeO
O
OH
O
18
Brassard
OTMS
MeO
Br
Diels-Alder
MeO
O
OH
(±)-1a
9
Bös
19
Zard
MeO
O
O
MeO
O
AcO
O
S
OEt
OBu
S
Michael-Dieckman
MeO
OPiv
radical addition-cyclization
Scheme 1 Previous syntheses of (±)-1a.
Herein we report the first asymmetric synthesis of (+)-O-methylasparvenone (1a), based on a
distinctly different, enatiodivergent strategy for 4-hydroxy-1-tetralone construction.
Retrosynthetically, the intent was to reveal the barely concealed symmetry in these targets (cf. 1,
Scheme 2) through disconnection of the C1-C8a bond. Thus carboxylic acid A was recognized to
represent a key intermediate, possessing a symmetrically substituted aromatic ring, from which 1
would arise via intramolecular Friedel-Crafts acylation23,24 and site-selective O-demethylation.25

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Friedel-Crafts
acylation
Me
site-selective
O-demethylation
OH
O
O
O
1
8a
R
R
3
MeO
MeO
4
*
*
1
OH
1' OPG
O
MeO
MeO
COOR'
R
R
OH
+
+
*
L
n
asymmetric
alkynylation
MeO
MeO
*
M
B
O
A
OPG
Scheme 2 Retrosynthetic analysis of 1.
Access to A was in turn envisioned through asymmetric propiolate addition to benzaldehyde B,
thereby enabling concomitant formation of the C3-C4 bond and the stereogenic center.26-28 The first
method for accomplishing asymmetric addition of propiolates to aromatic aldehydes was reported
by Pu, Yu and co-workers in 2006.29 However, to the best of our knowledge, no one has yet utilized
this particular process29-31 in natural product synthesis. On the other hand, some variants employing
aliphatic aldehydes have found several applications, notably, in the preparation of chiral
γ−lactones.32
Results and discussion
The synthesis began with the preparation of aldehyde 4 from inexpensive 3,4,5-
trimethoxybenzaldehyde dimethyl acetal 3, utilizing a slightly modified version of Azzena’s one-
pot procedure33a (Scheme 3). Thus, regioselective reductive alkylation of 3 using Na/THF and ethyl
iodide at 0 °C, followed by acetal hydrolysis, reproducibly delivered 4 on a gram scale in 68-70%
yield.
The crucial alkynylation of 4 was initially carried out following Pu’s protocol29 (methyl propiolate,
S-BINOL, ZnEt2, HMPA, CH2Cl2, rt). Under these conditions, γ−hydroxy−α,β−acetylenic ester 5

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was obtained in 55% yield and 91% ee, which mirror the reported values29 for the corresponding
alkynylation of m-methoxybenzaldehyde (y. 52%/ee 90%). Given the superior performance of all
other substituted benzaldehydes tested,29 it appears that the presence of meta-methoxy substituent(s)
negatively impacts efficiency. Attempts to remedy this by modifying the original experimental
procedure were only partially successful. Of the various solvent/additive combinations tried,
Et2O/N-methylimidazole (NMI)30 was found to be the most effective, providing 5 in an acceptable
58% yield and high enantiomeric purity (ee 94%).
Next, protection of the alcohol as its TBDPS ether (5  6), followed by saturation of the
superfluous triple bond (6  7) and hydrolysis of the ester group, smoothly afforded carboxylic acid
8 in an overall yield of 88%. It is imperative to note that the TBDPS protecting group was
judiciously chosen so as to withstand the stronger acid generated during the ensuing Friedel-Crafts
acylation. Indeed, γ−silyloxyacids bearing the more labile TBDMS have been known to undergo
facile desilylation and lactonization during conversion of the acid to the acid chloride.34 Previous
work in our laboratory23 further suggested that the task at hand would likely entail the use of a mild
method for carboxylic acid activation, such as that of Tadder and Tatlow.35 Thus, exposure of 8 to
1.3 equiv. of freshly distilled trifluoroacetic anhydride in dichloromethane at 0 °C for 2 h,
uneventfully accomplished cyclization to deliver tetralone 9 in 83% yield after flash column
chromatography.

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Na
THF
0 °C
MeO
MeO
MeO
EtI, 0 °C;
aq. HCl
MeO
MeO
Na
OMe
OMe
OMe
OMe
69%
MeO
CHO
MeO
3
~$3/gram
4
CO Me
2
Et Zn, (S)-BINOL
2
Ti(O-i-Pr) , NMI
58%
ee 94%
4
Et O
2
MeO
MeO
1) TBDPSCl, imid. (95%)
CO R
2
2) H , Pd/C, AcOEt (98%)
2
CO Me
2
3) LiOH, MeOH
65 °C (95%)
MeO
MeO
5 R = H
OTBDPS
OR
7 R = Me
8 R = H
3)
1)
6 R = TBDPS
TFAA
CH2Cl2
0 °C
83%
O
MeO
OH
O
OH
O
BCl , CH Cl
2
TBAF
3
2
89%
83%
MeO
MeO
MeO
1a
(ee 94%)
9
OTBDPS
10
OTBDPS
OH
Scheme 3 Synthesis of (+)-O-methylasparvenone (1a).
The methyl ether ortho to the keto function in 9 was swiftly cleaved with trichloroborane36 (20 min,
rt), giving 10 as the sole detectable reaction product (89%, Scheme 3). Finally, TBAF desilylation
afforded (+)-O-methylasparvenone (1a) whose physical and spectral properties were consistent with
those reported in the literature.9,10 The so obtained sample of 1a had an ee of 94%, suggesting that
no racemization had occurred along the route from 4 (ee 94%).
Conclusions
The first enantioselective synthesis of the non-nitrogenous 5-HT2CR antagonist (+)-O-
methylasparvenone has been accomplished in eight steps and 22% overall yield from inexpensive
starting materials. Besides establishing a flexible, concise and enantiodivergent route to this family
of fungal metabolites, the foregoing work serves to demonstrate the serviceability of asymmetric
propiolate addition to aromatic aldehydes in the context of natural product synthesis.

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Experimental section
General
Unless otherwise indicated, all moisture-sensitive reactions were carried out under an argon
atmosphere in glassware that had been flame-dried with stirrer under a stream of the same inert gas.
New syringes and stainless steel needles or dry cannulæ were used to transfer moisture-sensitive
liquids. Solvents were distilled or dried before use. CH2Cl2 was distilled from calcium hydride,
THF from sodium/acetophenone and Et2O was dried on molecular sieves. Commercial reagents
were used as received except for trifluoroacetic anhydride that was freshly distilled before use. Thin
layer chromatography (TLC) was carried out using Silicyle 0.2 mm silica gel 60 F254 aluminum-
backed plates. These plates were visualized by UV light and either cerium ammonium molybdate
(CAM) or a potassium permanganate solution was used as developing agent. Flash column
chromatography was performed using Silicycle silica gel P60 (230−400 mesh) and on a Teledyne
Isco CombiFlash Rf 200 UV-Vis system. Optical rotation was measured with the digital polarimeter
Jasco Dip-360, with a sodium lamp (589 nm) as light source. Enantiomer ratios were measured
using an Agilent technologies HPLC instrument equipped with the specified chiral column. NMR
spectra were recorded at room temperature on either an Agilent DDR spectrometer operating at 500
MHz for 1H and 125 MHz for 13C nuclei, or a Varian Inova spectrometer operating at 400 MHz for
13
1
13
1H and 100 MHz for C nuclei; H and C spectra are reported in parts per million (ppm) from
tetramethylsilane with the solvent resonance as the internal standard (1H NMR δH 7.260, 13C NMR
δC 77.16 both in CDCl3). Melting points were recorded on a Barnstead Thermolyne Mel Temp
Electrothermal apparatus, electrospray ionization (ESI) high-resolution mass spectra were recorded
on an Agilent 6210 TOF LC/MS instrument. Infra-red spectra were recorded on a Bomem Arid
Zone MB-series FTIR instrument, with samples prepared on single NaCl plates, as either a pure
film if in liquid form, or a neat layer if solid.
4-Ethyl-3,5-dimethoxybenzaldehyde (4)
Freshly cut sodium metal in small particles (0.58 g, 25.4 mmol, 3.1 equiv.) was put in dry THF (50
mL). The mixture was cooled to 0 ˚C and a solution of commercially available 3,4,5-

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trimethoxybenzaldehyde dimethyl acetal 3 (2.00 g, 8.25 mmol, 1.0 equiv.) in dry THF (20 mL) was
added dropwise. The reaction mixture was stirred at room temperature for 24 h, then cooled again
to 0 ˚C, and a solution of EtI (1.37 mL, 17.0 mmol, 2.1 equiv.) in dry THF (5 mL) was added
dropwise. After stirring for 48 h at room temperature, the reaction mixture was dissolved in
THF/1N HCl (1:1, 50 mL) and stirred at the same temperature for 5 min. The mixture was extracted
with Et2O (3 × 20 mL). The combined organic phases were washed with H2O (2 × 20 mL), aq. 10%
sodium thiosulfate (2 × 20 mL), dried (Na2SO4) and evaporated under reduced pressure. The
residue was purified by flash chromatography to afford aldehyde 4 as a white solid (1.10 g, 69%):
mp 68–72 ˚C, (lit.33a 68 ˚C); Rf 0.35 (hexanes/EtOAc; 9:1); IR (NaCl film) ν 2942, 1688, 1585,
1461, 1142 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.06 (s, 2H), 3.89 (s, 6H), 2.71 (q, J =
13
7.4 Hz, 2H), 1.09 (t, J = 7.4 Hz, 3H); C NMR (100 MHz, CDCl3) δ 192.1, 158.5, 135.3, 128.7,
105.0, 56.0, 17.0, 13.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C11H15O3 196.1016, found
196.1014.
(R)-Methyl 4-(4-Ethyl-3,5-dimethoxyphenyl)-4-hydroxybut-2-ynoate (5)
To a mixture of (S)-BINOL (246.8 mg, 0.86 mmol, 0.7 equiv.), 1-methylimidazole (20 µL, 0.25
mmol, 0.2 equiv.) and methyl propiolate (0.43 mL, 4.8 mmol, 4.0 equiv.) in dry Et2O (12 mL) was
slowly added ZnEt2 (1 M in hexanes, 5 mL, 5.0 mmol, 4.0 equiv.). After the solution was stirred at
room temperature for 16 h, Ti(i-PrO)4 (0.37 mL, 1.25 mmol, 1.0 equiv.) was added and the stirring
was continued for 1 h. Then, aldehyde 4 (233.3 mg, 1.20 mmol, 1.0 equiv.) was added and stirring
continued at room temperature for 24 h. Saturated aq NH4Cl (1 × 10 mL) was added, and the
mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were washed with
H2O (2 × 10 mL), dried (Na2SO4) and evaporated under reduced pressure. The crude product was
purified by flash chromatography to give propargyl alcohol 5 as a yellow solid (193.3 mg, 58%):
20
mp 107–111 ˚C; Rf 0.13 (Hexanes/EtOAc; 9:1); [α]D +4.9 (c 0.98, CHCl3); ee > 94% [HPLC
CHIRALCEL OJ-H; n-hexane–i-PrOH 9:1; 1 mL/min; tR = 13.11 (minor), 20.09 (major) min]; IR
(NaCl film) ν 3410, 2963, 2238, 1717, 1605, 1256, 1137 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.68
(s, 2H), 5.51 (d, J = 5.6 Hz, 1H), 3.83 (s, 6H), 3.79 (s, 3H), 2.64 (q, J = 7.4 Hz, 2H), 1.05 (t, J = 7.5
13
Hz, 3H); C NMR (125 MHz, CDCl3) δ 158.4, 153.9, 137.1, 121.7, 102.2, 86.8, 77.5, 64.8, 55.9,
53.0, 16.4, 13.7; HRMS (ESI-TOF) m/z [(M + H) + (–H2O)]+ calcd for C15H17O4 263.1179, found
263.1191.

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(R)-Methyl 4-((tert-Butyldiphenylsilyl)oxy)-4-(4-ethyl-3,5-dimethoxyphenyl)but-2-ynoate (6)
To propargyl alcohol 5 (496.2 mg, 1.78 mmol, 1.0 equiv.) in CH2Cl2 (10 mL), imidazole (267.3 mg,
3.92 mmol, 2.2 equiv.) was added, followed by tert-butyldiphenylsilyl chloride (538.7 mg, 1.96
mmol, 1.1 equiv.), at room temperature and the mixture was stirred 16 h. The volatiles were
evaporated under reduced pressure and the residue was purified by flash chromatography to give
the alkyne 6 as a colorless oil (873.2 mg, 95%): Rf 0.42 (hexanes/EtOAc; 9:1); [α]D20 +24.9 (c 0.96,
CHCl3); IR (NaCl film) ν 2959, 2237, 1719, 1590, 1139 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.80–
7.32 (m, 10H), 6.53 (s, 2H), 5.41 (s, 1H), 3.75 (s, 9H), 2.64 (q, J = 7.4 Hz, 2H), 1.12 (s, 9H), 1.09
(t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 158.1, 154.0, 138.0, 136.1, 136.0, 135.3, 134.9,
132.7, 130.1, 130.0, 129.8, 127.8, 127.7, 120.9, 102.1, 87.8, 77.0, 65.9, 55.8, 52.8, 26.9, 26.7, 19.5,
19.2, 16.4, 13.9; HRMS (ESI-TOF) m/z [M + H]+ Calcd for C31H37O5Si 516.2436, found 516.2462.
(S)-Methyl 4-((tert-Butyldiphenylsilyl)oxy)-4-(4-ethyl-3,5-dimethoxyphenyl)butanoate (7)
Alkyne 6 (363.3 mg, 0.7 mmol, 1.0 equiv.) was dissolved in EtOAc (3 mL) and 10% Pd/C (99.3
mg) was added and the mixture was put in Berghof high pressure reactor BR-25 hydrogenation
system at 50 psi of H2 and stirred 17 h at room temperature. The mixture was filtered over celite,
washed with EtOAc and the solvent was evaporated. The residue was purified by flash
chromatography to afford the ester 7 as a colorless oil (359.9 mg, 98%): Rf 0.45 (hexanes/EtOAc;
20
1
9:1); [α]D –23.6 (c 0.86, CHCl3); IR (NaCl film) ν 2958, 1738, 1588, 1361, 1231, 1112 cm-1; H
NMR (500 MHz, CDCl3) δ 7.67–7.22 (m, 10H), 6.35 (s, 2H), 4.73 (t, J = 5.7 Hz, 1H), 3.70 (s, 6H),
3.58 (s, 3H), 2.61 (q, J = 7.7 Hz, 2H), 2.27 (m, 2H), 2.05 (m, 2H), 1.08 (s, 9H), 1.07 (t, J = 7.5 Hz,
13
3H); C NMR (100 MHz, CDCl3) δ 174.1, 157.7, 142.4, 136.0, 135.9, 134.0, 133.7, 129.7, 129.6,
127.6, 127.4, 119.4, 102.0, 75.2, 55.7, 51.6, 34.9, 29.7, 27.1, 19.6, 16.4, 14.0; HRMS (ESI-TOF)
m/z [M]+ calcd for C31H40O5Si 520.2640, found 520.2611.
(S)-4-((tert-Butyldiphenylsilyl)oxy)-4-(4-ethyl-3,5-dimethoxyphenyl)butanoic Acid (8)
Ester 7 (120.6 mg, 0.23 mmol, 1.0 equiv.) was dissolved in methanol (5 mL) and lithium hydroxide
(1M aq solution, 2.5 mL, 2.5 mmol, 10.9 equiv.) was added dropwise. The reaction mixture was
heated at 65 ˚C for 1 h. The mixture was cooled to room temperature, the pH was adjusted to 3
using a dilute citric acid solution and the cloudy aqueous mixture was extracted with Et2O (2 × 20

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mL). The ethereal layers were combined, dried (Na2SO4), filtered, evaporated and the residue
subjected to flash column chromatography on silica gel to give acid 8 as a colorless oil (111.8 mg,
20
95%): Rf 0.26 (hexanes/EtOAc; 9:1); [α]D –19.8 (c 0.75, CHCl3); IR (NaCl film) ν 3403, 2960,
1708, 1588, 1453, 1426, 1231, 1139 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.65–7.20 (m, 10H), 6.33
(s, 2H), 4.72 (t, J = 5.6 Hz, 1H), 3.69 (s, 6H), 2.59 (q, J = 7.7 Hz, 2H), 2.27 (m, 2H), 2.02 (m, 2H),
13
1.07 (s, 9H), 1.05 (t, J = 7.5 Hz, 3H); C NMR (100 MHz, CDCl3) δ 179.5, 157.8, 142.2, 136.0,
135.9, 134.0, 133.7, 129.8, 129.6, 127.7, 127.4, 119.5, 102.0, 75.0, 55.7, 34.6, 29.5, 27.1, 19.5,
16.4, 14.0; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C30H38NaO5Si 529.2381, found 529.2411.
(S)-4-((tert-Butyldiphenylsilyl)oxy)-7-ethyl-6,8-dimethoxy-3,4-dihydronaphthalen-1(2H)-one
(9)
Acid 8 (27.9 mg, 0.055 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (1 mL) and cooled to 0 ˚C.
Freshly-distilled trifluoroacetic anhydride (10 µL, 0.071 mmol, 1.3 equiv.) was added dropwise and
the reaction was stirred at 0 ˚C for 2 h. The volatiles were evaporated and the residue was purified
by flash chromatography on silica gel to give tetralone 9 as a colorless oil (22.3 mg, 83%): Rf 0.32
20
(hexanes/EtOAc; 9:1); [α]D –23.2 (c 0.97, CHCl3); IR (NaCl film) ν 2961, 1678, 1589, 1462,
1254, 1141 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.74–7.32 (m, 10H), 6.58 (s, 1H), 4.87 (dd, J = 7.6,
3.4 Hz, 1H), 3.79 (s, 3H), 3.62 (s, 3H), 2.86 (m, 1H), 2.63 (q, J = 7.4 Hz, 2H), 2.38 (m, 1H), 2.12
(m, 1H), 2.04 (m, 1H), 1.11 (s, 9H), 1.08 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 195.5,
162.1, 159.9, 147.2, 136.0, 135.9, 133.8, 133.5, 130.1, 129.9, 127.9, 127.8, 126.9, 118.3, 105.1,
70.6, 62.2, 55.6, 36.4, 31.9, 27.1, 19.6, 16.7, 14.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C30H37O4Si 489.2456, found 489.2441.
(S)-4-((tert-Butyldiphenylsilyl)oxy)-7-ethyl-8-hydroxy-6-methoxy-3,4-dihydronaphthalen-
1(2H)-one (10)
To a solution of tetralone 9 (48.7 mg, 0.10 mmol, 1.0 equiv.) in CH2Cl2 (1 mL) at room temperature
was added BCl3 (1M in CH2Cl2, 160 µL, 0.16 mmol, 1.6 equiv.). After stirring for 20 min, TLC
showed complete consumption of 9. The reaction was quenched with NaHCO3 (1 mL), poured into
water (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to
20
give phenol 10 as a colorless oil (42.3 mg, 89%): Rf 0.51 (hexanes/EtOAc; 9:1); [α]D –11.3 (c

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1
0.48, CHCl3); IR (NaCl film) ν 3456, 2960, 1725, 1625, 1427, 1362, 1280, 1111 cm-1; H NMR
(500 MHz, CDCl3) δ 12.87 (s, 1H) 7.78–7.35 (m, 10H), 6.34 (s, 1H), 4.91 (dd, J = 7.25, 3.2 Hz,
1H), 3.63 (s, 3H), 2.96 (m, 1H), 2.64 (q, J = 7.4 Hz, 2H), 2.47 (m, 1H), 2.17 (m, 1H), 2.09 (m, 1H),
13
1.12 (s, 9H), 1.10 (t, J = 7.6 Hz, 3H); C NMR (100 MHz, CDCl3) δ 202.6, 163.3, 162.0, 145.4,
136.0, 135.9, 133.7, 136.0, 135.9, 133.8, 133.4, 130.1, 130.0, 127.9, 127.7, 118.7, 110.1, 101.6,
69.9, 55.6, 34.6, 32.0, 27.1, 19.6, 15.7, 13.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C29H35O4Si
475.2299, found 475.2310.
(+)-O-Methylasparvenone (1a)
To a solution of phenol 10 (10.2 mg, 0.0215 mmol, 1.0 equiv.) in THF (0.7 mL), TBAF (1M in
THF, 27 µL, 0.0270 mmol, 1.2 equiv.) was added and the mixture was stirred for 40 min at room
temperature. The solvent was evaporated in vacuo and the residue was purified by flash
chromatography to give 1a as a yellow solid (4.2 mg, 83%): mp 127–129 ˚C, (lit.9 125–126 ˚C, lit.10
20
132–133 ˚C,); Rf 0.13 (hexanes/EtOAc; 6:4); [α]D +26.8 (c 0.25, CHCl3), lit.9 +27.2 (c 0.25;
CHCl3); ee > 94% [HPLC CHIRALPAK AD-H; n-hexane–i-PrOH, 9:1; 1 mL/min; tR = 8.87
(minor), 10.35 (major) min]. IR (NaCl film) ν 3257, 2963, 1622, 1574, 1417, 1322, 1288, 1148 cm-
1; 1H NMR (500 MHz, CDCl3) δ 12.80 (s, 1H), 6.63 (s, 1H), 4.82 (dd, J = 7.7, 3.4 Hz, 1H), 3.89 (s,
3H), 2.87 (m, 1H), 2.63 (q, J = 7.4 Hz, 2H), 2.58 (m, 1H), 2.30 (m, 2H), 2.10 (m, 1H), 1.06 (t, J =
13
7.4 Hz, 3H); C NMR (125 MHz, CDCl3) δ 202.5, 163.7, 162.1, 145.6, 119.1, 110.0, 100.6, 68.3,
55.9, 34.8, 31.8, 15.7, 13.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H17O4 237.1121, found
237.1108.
Acknowledgements
We are grateful to the Natural Sciences and Engineering Research Council of Canada (NSERC) and
the FRQNT-Québec Centre in Green Chemistry and Catalysis (CGCC) for financial support. We
also thank FRQNT for a doctoral scholarship to R. L.-L.

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Graphical Abstract
Asymmetric total synthesis of (+)-O-methylasparvenone, a rare nitrogen-
free serotonin 2C receptor antagonist
Raphaël Lafleur-Lambert and John Boukouvalas*
O
OH
MeO
MeO
MeO
8 steps
OMe
OMe
22% yield
MeO
OH
~3$/gram
94% ee
The first enantioselective synthesis of the fungal metabolite (+)-O-methylasparvenone is
reported.