New strategy for the synthesis of proaporphine and homoproaporphine-type alkaloids from a common intermediate

Article abstract of DOI:10.1016/j.tet.2015.04.023

Starting with 3-bromo-4,5-dimethoxybenzaldehyde 14, it was coupled with the boronic anhydride 15 using standard Suzuki reaction conditions to give 16 (91%). The aldehyde 16 was exposed to classical nitro-aldol reaction conditions to give 17 (88%), and conjugatively reduced with DIBAL-H to give 18 (91%). Protection of the amine 18 as its N-carbamate derivative 19, followed by condensation with glycol aldehyde dimer under acidic reaction conditions gave 20 (78%). Subsequent conversion of 20 into its mesylate derivative 21, and exposure to CsF under aprotic reaction conditions gave 22 (81%). Deprotection of 22 gave (±)-stepharine 10 in 29% overall yield though 8 steps. A similar sequence of reaction conditions converted the amine 18 into the -NTs protected homoproaporphine adduct 28.

Full text of DOI:10.1016/j.tet.2015.04.023

Accepted Manuscript
New strategy for the synthesis of proaporphine and homoproaporphine-type alkaloids
from a common intermediate
Philip Magnus, Kyle D. Marks, Alan Meis
PII:
S0040-4020(15)00513-X
10.1016/j.tet.2015.04.023
TET 26626
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 January 2015
Revised Date: 7 April 2015
Accepted Date: 8 April 2015
Please cite this article as: Magnus P, Marks KD, Meis A, New strategy for the synthesis of proaporphine
and homoproaporphine-type alkaloids from a common intermediate, Tetrahedron (2015), doi: 10.1016/
j.tet.2015.04.023.
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New strategy for the synthesis of proaporphine and
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Philip Magnus,* Kyle D. Marks and Alan Meis. Department of Chemistry and Biochemistry, University of Texas at Austin,
1 University Station A5300, Austin, Texas 78712
2

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New strategy for the synthesis of proaporphine and
homoproaporphine-type alkaloids
from a common intermediate
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Philip Magnus,* Kyle D. Marks and Alan Meis
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712
Abstract— Starting with 3-bromo-4,5-dimethoxybenzaldehyde 14, it was coupled with the boronic anhydride 15 using standard
Suzuki reaction conditions to give 16 (91%). The aldehyde 16 was exposed to classical nitro-aldol reaction conditions to give
17 (88%), and conjugatively reduced with DIBAL-H to give 18 (91%). Protection of the amine 18 as its N-carbamate
derivative 19, followed by condensation with glycol aldehyde dimer under acidic reaction conditions gave 20 (78%).
Subsequent conversion of 20 into its mesylate derivative 21, and exposure to CsF under aprotic reaction conditions gave 22
(81%). Deprotection of 22 gave (±)-stepharine 10 in 29% overall yield though 8 steps. A similar sequence of reaction
conditions converted the amine 18 into the -NTs protected homoproaporphine adduct 28.
Key words: alkaloids, Suzuki aryl-coupling, proaporphine, stepharine, homoproaporphine, Baldwins-rules.
© 2015 Elsevier Science. All rights reserved
1. Introduction
Recently, we reported a new strategy for the
synthesis of morphinoid alkaloids,1 and structurally
related alkaloids, that makes use of the Suzuki aryl
coupling reaction to form the crucial aryl-phenol bond as
illustrated in figure 1 in blue. This approach has been
successful when combined with p-phenolic alkylation
(illustrated in red), to provide a concise synthesis of a
number of alkaloids, and the results are summarized in
figure 1. The Suzuki coupled product 1 (99%) was
converted into its derived 1-ethoxy-2-bromoacetal
derivative (ethylvinyl ether/Br2/Et3N) and treated with
CsF in DMF at 130 °C to give the cross conjugated 2,5-
cyclohexadienone 2 (96%) by intramolecular C-alkylation
of the insitu generated phenolate.2 Subsequent steps
converted 2 into codeine 3, thus illustrating the utility of
this new strategy as an alternative to o,p-oxidative
coupling of phenols.
Using the o-methoxy analogue of 1, namely 4 (89%),
provided 5 (85%) which was converted into salutaridine
6.3 The more highly substituted biaryl 7 (70%) gave
access to 8 (76%), which in two steps was converted into
cepharatine A 9.4 The formation of the crucial C-C bonds
in high yields illustrate the advantage this strategy has
over the conventional phenolic oxidation approach.
Figure 1. Strategy for the synthesis of codeine 3,
salutaridine 6, and cepharatine 9.
*Corresponding author. e-mail address p.magnus@utexas.edu

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conditions) converted 16 into 17 (88%) which was
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reduced using DIBAl-H12 to the primary amine 18
(91%).
The amine 18 was converted into its carbamate
derivative 19 (84%, two steps from 17), and
condensation with glycol aldehyde dimer in
trifluoroethanol in the presence of trifluoroacetic acid
gave 20 (78%, over the 2 steps). Activation of the
primary hydroxyl group as its mesylate derivative 21
(84%) followed by exposure to CsF/NMP/150 °C/3.5 h
gave 22 (81%). It should be noted that the more reactive
triflate derivative of 20 gave small amounts of 22 (10%)
but predominately elimination to the alkene.13 Exposure
of 22 to KOH/ethylene glycol at 100 °C gave (±)-
stepharine 10 (82%).
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Scheme 1. Retrosynthesis for 10 and 12.
Given the success of the strategy outlined in Figure 1,
it was of interest to explore if this strategy could be
applicable to other alkaloids that are also phenolic
oxidation products, such as the proaporphine5
stepharine 106 and homoproaporphine type alkaloid 12.7
Plants of the genus Stephania that produce these types
of compounds have been used for the treatment of
medical ailments, and are widespread in the traditional
medicine of Asia and Africa.6 The proaporphine
alkaloids were first described in Barton's 1957 work on
phenolic oxidative couplings, several years before any
members of the family had been isolated.8
The first synthesis of stepharine was reported in 1968
by Bernauer.9 The most recent total synthesis of
stepharine was in 2010 by Honda was accomplished
nine steps with an overall yield of 29%.10
Scheme 1 outlines the retrosynthetic analysis for the
compounds 10 and 12. The blue biaryl bond in 11 will
be made by an intermolecular Suzuki reaction, and a 5-
exo-tet cyclization (favored, Baldwins rules)11 forming
the red bond should allow access to the cross-
conjugated 2,5-cyclohexadienone 10. Likewise, the blue
bond in 13 can be formed using a Suzuki reaction, and a
6-exo-tet intramolecular alkylation (favored by
Baldwins rules, red bond)11 leads to the
homoproaporphine skeleton 12.
2. Results and discussion
The known1 aryl boronate anhydride 15 was treated
with 14 under standard Suzuki aryl coupling conditions
to give 16 in 91% yield. The O-trisopropylsilyl ether
(TIPS) derivative was the only phenolic silyl ether
derivative that was stable to the subsequent reaction
conditions.
Scheme 2. Synthesis of (±)-stepharine 10.
Condensation of 16 with nitromethane under standard
nitroaldol reaction conditions (Henry reaction
2

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In the sequence of reactions depicted in Scheme 3 for
recorded on a Nicolet FT-IR spectrophotometer neat
unless otherwise indicated. 1H NMR spectra were
recorded on a Varian spectrometer at 300 MHz, or 500
MHz, or 600 MHz in the indicated solvent and are
reported in ppm relative to tetramethylsilane and
referenced internally to the residually protonated
solvent. 13C NMR spectra were recorded on a Varian
spectrometer at 75 MHz or 125 MHz or 150 MHz in the
solvent indicated and are reported in ppm relative to
tetramethylsilane and referenced internally to the
residually protonated solvent. Mass spectra were
obtained on a VG ZAB2E or a Finnigan TSQ70.
Routine monitoring of reactions was performed using
Merck 60 F254 silica gel, aluminum-backed TLC plates.
Flash column chromatography was performed using
EMD silica gel (particle size 0.040-
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the synthesis of the homoproaporphine 12 it was found
best to utilize the N-Ts derivative 23.14 When 23 was
treated with the acetal 23a in trifluoroethanol with
trifluoroacetic acid at 60° C the tetrahydroisoquinoline
24 was isolated in 87% yield. Hydrogenolysis
(Pd/C/ammonium formate/MeOH/50° C) gave 25.
The alcohol 25 was converted into the bromide 26
(95%) and chloride 27 (83%) by treatment with
CBr4/PPh3/CH2Cl2 and CCl4/PPh3/CH2Cl2 respectively.
Exposure of the bromide 26 to CsF (3eq) in NMP
(0.005 M) at 100-150 °C resulted in conversion into the
cross-conjugated-2,5-cycloheaxadienone 28 in 79%
yield (structure by X-ray). Under the same reaction
conditions the chloride 27 gave 28 in 89% yield. Under
more concentrated reaction conditions dimer formation
(see experimental) became competitive.
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mm). Solvents and commercial reagents were purified
in accordance with Armarego15 or used without further
purification.
4.2 Synthesis
3-bromo-4,5-dimethoxybenzaldehyde 14. To a stirred
solution of vanillin (10.0 g, 66 mmol) in glacial acetic
acid (100 mL) under argon was added bromine (3.7 mL,
72 mmol) over 5 min, and the mixture was stirred at
room temperature for 3 h. The mixture was poured onto
crushed ice (~200 g), and the solid was filtered, and
dissolved in DMF (328 mL). To this solution was added
K3PO4 (22.7 g, 164 mmol) followed by dropwise
addition of iodomethane (4.5 mL, 72 mmol) over 10
min, and the mixture stirred overnight at room
temperature. The mixture was transferred to
a
separatory funnel, diluted with water (300 mL), and
extracted with t-butylmethyl ether (3 x 300 mL). The
extracts were combined and washed with brine (300
mL), dried (Na2SO4) and concentrated in vacuo.
Crystallization of the residue from boiling hexanes gave
1416 (13.03 g, 81% yield) as white crystals. M.p. 59-60
°C. IR (thin film) 2945, 2836, 1692, 1587, 1566, 1486,
Scheme 3. Synthesis of homoproaporphine 28
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1281 cm-1. H NMR (400 MHz, CDCl3)  ppm 9.85
3. Conclusion
(1H, s), 7.66 (1H, d, J = 2.0 Hz), 7.39 (1H, d, J = 2.0
Hz), 3.95 (3H, s), 3.93 (3H, s). 13C NMR (100 MHz,
CDCl3) ppm 189.86, 154.16, 151.78, 133.02, 128.78,
117.92, 110.04, 60.82, 56.23. HRMS calculated for
C9H9BrO3 (MH+) 244.9813 and 246.9793 found
244.9815 and 246.9793.
The synthesis of the proaporphine alkaloid stepharine
10 proceeds in 8 steps with an overall yield of 29%, and
the synthesis of the homoproaporphine derivative 28
proceeds in 8 steps with an overall yield of 31%.
The p-alkylation strategy provides a concise route to
both proaporphine and homoproaporphine alkaloids that
avoids phenolic oxidation.
Bromophenol (20 g, 116 mmol), triisopropylsilyl
chloride (24.5 g, 127 mmol) and imidazole (19.7 g, 289
mmol) was added to 1,2-dichloroethane (200 mL), and
the solution was heated at reflux for 3 h. The reaction
mixture was poured into saturated aqueous ammonium
chloride and extracted with CH2Cl2 (3 x 100 mL). The
combined extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo. The crude oil was
purified by flash chromatography over silica gel to give
4. Experimental Section
4.1 General
All reactions were carried out under an atmosphere of
argon and only degassed when specified. Melting points
were taken on
a Thomas-Hoover capillary tube
apparatus and are uncorrected. Infrared spectra were
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the title compound (38.03 g, 99%) as a clear oil. H
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5.6 mmol). The mixture was heated at reflux overnight
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NMR (400 MHz, CDCl3) ppm 7.31 (2H, d, J = 8.8
Hz), 6.77 (2H, d, J = 8.8 Hz), 1.27-1.21 (3H, m), 1.08
(18H, s). 13C NMR (100 MHz, CDCl3) δ 125.2, 114.7,
10.9, 5.6.
under an argon atmosphere. The flask was removed
from the oil bath and allowed to cool to room
temperature. The orange solution was concentrated in
vacuo, and the resulting viscous orange oil was purified
by column chromatography (SiO2, 5% EtOAc:hexanes)
to give 17 (3.00 g, 88%) as a viscous yellow oil that
formed canary yellow crystals upon standing. M.p. 65-
Boronic Ester Trimer 15. n-Butyl lithium (46 mL, 2.5
M in hexanes) was added dropwise to a stirred solution
of (4-bromophenoxy)triisopropylsilane (14.5 g, 44
mmol) in THF (40 mL) at -78 °C under argon. The
solution was allowed to stir for 0.5 h, and triisopropyl
borane (53 mL, 229 mmol) was added to the solution
dropwise at -78 °C. The solution was allowed to stir and
warm to room temperature overnight. The reaction
mixture was quenched by pouring it onto 10% aqueous
KHSO4 (60 mL), and extracted with ethyl acetate (3 x
150 mL). The combined organic extracts were washed
with brine, dried (Na2SO4), and concentrated in vacuo.
The crude solid was purified by flash chromatography
giving 15 (11.2 g, 92%) as an oil that crystallized upon
standing. IR (thin film) 2944, 2867, 1597, 1374, 1239
cm-1. 1H NMR (400 MHz, CDCl3) δ 8.11 (6H, d, J = 8.4
Hz), 6.99 (6H, d, J = 8.8 Hz), 1.33-1.10 (63H, m). 13C
NMR (100 MHz, CDCl3) δ 160.1, 137.4, 119.6, 17.9,
12.7. HRMS calculated for C45H75B3O6Si3 (M+)
828.5151, found 828.5166.
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67 °C. IR (thin film) 2944, 2867, 1512, 1335, 1264. H
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NMR (400 MHz, CDCl3)  ppm 7.98 (1H, d, J = 13.6
Hz), 7.56 (1H, d, J = 13.6 Hz), 7.38 (2H, d, J = 8.8 Hz),
7.17 (1H, d, J = 2.0 Hz), 7.01 (1H, d, J = 2.0 Hz), 6.95
(2H, d, J = 8.8 Hz), 3.94 (3H, s), 3.61 (3H, s), 1.28 (3H,
sep, J = 7.2 Hz), 1.13, (18H, d, J = 7.2 Hz). 13C NMR
(100 MHz, CDCl3)  ppm 155.9, 153.6, 150.1, 139.1,
136.5, 136.3, 130.1, 129.4, 125.6, 124.9, 119.8, 110.5,
60.6, 59.1, 17.9, 12.7. HRMS calculated for
C25H35NO5Si (M+Na)+ 480.2177, found 480.2175.
2-(5,6-dimethoxy-4'-((triisopropylsilyl)oxy)-[1,1'-
biphenyl]-3-yl)ethanamine 18. To a flame dried round
bottom flask under argon was added DIBAL-H (1 M in
hexanes, 2.0 mL, 2.0 mmol), 1,4-dioxane (1 mL, dried
over 4Å mol sieves) followed by dropwise addition of
17 (0.10 g, 0.2 mmol) as a solution in 1,4-dioxane (1
mL). The mixture was stirred for 1 h at room
temperature, cooled to 0 °C, and quenched with ethyl
acetate (2 mL), followed by addition of aqueous
Rochelle’s salt (3 mL). The solution was stirred at room
temperature for 2 h, the organic layer separated, and the
aqueous layer was extracted with ethyl acetate (3 x 10
mL). The combined organic fractions were dried
(Na2SO4), concentrated in vacuo, and the crude oil was
purified by flash chromatography (SiO2, 0-10%
MeOH:DCM) to give 18 (0.085 g, 91%) as a clear
viscous oil. IR (thin film) 2944, 2867, 1607, 1512, 1263
cm-1. 1H NMR (400 MHz, CDCl3)  ppm 7.41 (2H, d, J
= 8.8 Hz), 6.91, (2H, d, J = 8.8 Hz), 6.77 (1H, d, J = 2.0
Hz), 6.72 (1H, d, J = 2.0 Hz), 3.88 (3H, s), 3.50 (3H, s),
3.03 (4H, brs), 2.71 (2H, t, J = 7.6 Hz), 1.28 (3H, sep, J
= 8.0 Hz), 1.12 (18H, d, J = 7.2 Hz). 13C NMR (100
MHz, CDCl3)  ppm 155.3, 153.0, 144.9, 135.3, 134.8,
130.7, 130.2, 122.6, 119.6, 111.5, 60.3, 56.0, 43.0, 38.8,
17.9, 12.7. HRMS calculated for C25H39NO3Si (M+Na)+
452.2491 found 452.2584.
5,6-dimethoxy-4'-((triisopropylsilyl)oxy)-[1,1'-
biphenyl]-3-carbaldehyde 16. To a degassed mixture of
1,4-dioxane (100 mL) and water (25 mL) was added
solid K3PO4 (16.1 g, 75.8 mmol), 14 (6.20 g, 25.3
mmol), and 15 (8.38 g, 10.1 mmol), followed by
Pd(dppf)Cl2•CH2Cl2 (0.103 g, 0.13 mmol). The solution
turned black. The mixture was placed in an oil bath at
80 °C and stirred for 3 h. When the reaction was
complete, as judged by TLC, the mixture was cooled to
room temperature, diluted with water (100 mL) and
extracted with ethyl acetate (3 x 100 mL). The extracts
were combined, washed with brine (100 mL), dried
(Na2SO4), and concentrated in vacuo. Purification by
flash chromatography (SiO2, 0-15% EtOAc:hexanes)
gave 16 as
a
white solid (8.60 g, 91%).
Recrystallization from methanol gave white needles.
M.p. 75-76 °C. IR (thin film) 2944, 2867, 2360, 1695,
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1513, 1464, 1382, 1265 cm-1. H NMR (400 MHz,
CDCl3)  ppm 9.92 (1H, s), 7.47 (1H, d, J = 2.0 Hz),
7.44-7.40 (3H, m), 6.65 (2H, dt, J = 8.4, 2.0 Hz), 3.96
(3H, s), 3.64 (3H, s), 1.29 (3H, sep, J = 7.6 Hz), 1.12
(18H, d, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3) 
ppm 191.3, 155.9, 153.8, 151.9, 135.8, 132.3, 130.2,
129.6, 127.3, 119.8, 108.9, 60.5, 56.1, 17.9, 12.7.
HRMS calculated for C24H34O4Si (MH)+ 415.2305,
found 415.2305.
Ethyl (2-(5,6-dimethoxy-4'-((triisopropylsilyl)oxy)-
[1,1'-biphenyl]-3-yl)ethyl)carbamate 19. The crude
amine
18
(theoretical
1.94
mmol)
and
diisopropylethylamine (0.877 g, 6.79 mmol) were
dissolved in CH2Cl2 (100 mL) in a flame dried flask and
cooled to 0 ºC. Ethyl chloroformate (0.629 g, 5.82
mmol) was added dropwise with stirring. The solution
was allowed to warm to room temperature and stirred
for 3 h. The mixture was diluted with ether, and the
ether layer washed with saturated aqueous NaHCO3,
and brine. The organic extracts were dried (Na2SO4)
and concentrated in vacuo to give an oil which was
(E)-((2',3'-dimethoxy-5'-(2-nitrovinyl)-[1,1'-
biphenyl]-4-yl)oxy)triisopropylsilane 17. To a flame
dried round bottom flask equipped with an oven dried
Dean-Stark trap was added 16 (3.08 g, 7.4 mmol),
nitromethane (56 mL), and ammonium acetate (0.43 g,
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purified by silica gel flash chromatography to give 19
38.2, 37.1, 28.2, 17.9, 14.6, 12.6. HRMS calculated for
C31H47NO8SiS (M+) 621.2792, found 621.2783.
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(0.823 g, 84% over two-steps from 17) as a clear oil. IR
(thin film) 3345, 2944, 2867, 1700, 1512 cm-1. 1H NMR
(400 MHz, CDCl3) δ 7.41 (2H, d, J = 8.4 Hz), 6.91 (2H,
d, J = 8.8 Hz), 6.76 (1H, d, J = 2.0 Hz), 6.70 (1H, s),
4.73 (1H, s, brs), 4.11 (2H, dd, J = 14.0, 7.2 Hz), 3.88
(3H, s), 3.45 (2H, dd, J = 13.0, 6.4 Hz), 2.79 (2H, t, J =
14.0 Hz), 1.33-1.10 (24H, m). 13C NMR (100 MHz,
CDCl3) δ 156.6, 155.4, 153.0, 145.0, 135.5, 134.5,
130.7, 130.2, 122.5, 119.6, 111.4, 60.7, 60.3, 55.9, 40.1,
63.0, 17.8, 14.6, 12.6. HRMS calculated for
C28H43NO5Si (MH+) 502.2983, found 502.2975.
Ethyl 5' ,6'-dimethoxy-4-oxo-2',3',8',8a'-tetrahydro-
1'H-spiro[cyclohexane-1,7'-
cyclopenta[ij]isoquinoline]-2,5-diene-1'-carboxylate
22. Mesylate 21 (50 mg, 0.086 mmol) was dissolved in
dry N-methylpyrrolidone (1.5 mL) and warmed to 100
ºC. Excess cesium fluoride (flamed dried under
vacuum) was added to the solution and the mixture was
heated to 150 ºC for 3.5 h until the starting material had
been consumed as shown by LCMS. The solution was
cooled to room temperature, poured into brine,
extracted with ether (3 x 50 mL), and dried (Na2SO4).
The extract was concentrated in vacuo and purified by
flash chromatography on basic alumina to give 22 (28
mg, 88%). IR (thin film) 2948, 2932, 1694, 1664, 1282
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Ethyl
1-(hydroxymethyl)-6,7-dimethoxy-8-(4-
((triisopropylsilyl)oxy)phenyl)-3,4-dihydroisoquinoline-
2(1H)-carboxylate 20. Carbamate 19 (0.10 g, 0.20
mmol) and glycolaldehyde dimer (0.018g, 0.15 mmol)
were dissolved in 2,2,2-trifluoroethanol (0.5 mL), and
trifluoroacetic acid (2 drops) added. The solution was
heated to 55 °C, and allowed to stir for 5 h until the
starting material was consumed as judged by LCMS.
The crude mixture was concentrated in vacuo and
purified by silica gel flash chromatography giving 20
(0.083 g, 78%). IR (thin film) 3447, 2943, 2867, 1684,
1512 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.13 (2H, t, J
= 7.2 Hz), 6.97 (2H, d, J = 7.6 Hz), 6.70 (1H, s), 5.21
(1H, m), 4.15 (2H, m), 3.86 (3H, s), 3.76-3.34 (6H, m),
2.88 (2H, d, J = 7.4 Hz), 1.33-1.11(24H, m). 13C NMR
(100 MHz, CDCl3) δ 155.4, 151.8, 131.7, 131.1, 129.9,
124.7, 120.1, 119.7, 119.8, 118.8, 111.5, 71.1, 65.5,
61.5, 60.4, 55.8, 54.4, 39.7, 28.6, 28.1, 17.9, 14.6, 12.6.
HRMS calculated for C30H45NO6Si (MNa+) 566.2908,
found 566.2911.
1
cm-1. H NMR (400 MHz, CDCl3) δ 7.02 (1H, dd, J =
10.0, 2.8 Hz), 6.85 (1H, dd, J = 9.8, 2.8 Hz), 6.71 (1H,
s), 6.41 (1H, dd, J = 9.8, 1.6 Hz), 6.32 (1H, dd, J = 9.6,
2.8 Hz), 4.98 (1H, m), 4.24-4.16 (3H, m), 3.84 (3H, s),
3.63 (3H, s), 2.93-2.64 (4H, m), 2.33 (1H, dd, J = 12.4,
10.4 Hz), 1.30 (3H, t, J = 13.2 Hz). 13C NMR (100
MHz, CDCl3) δ 186.0, 156.3, 152.8, 149.5, 144.8,
132.9, 132.1, 130.9, 125.3, 127.7, 115.5, 61.5, 60.9,
56.3, 55.0, 50.8, 49.7, 42.5, 28.7, 14.7. HRMS
calculated for C21H23NO5 (MH+) 370.1649, found
370.1647.
5',6'-dimethoxy-2',3',8',8a'-tetrahydro-1'H-
spiro[cyclohexane-1,7'-cyclopenta[ij]
isoquinoline]-
2,5-dien-4-one (stepharine) 10. The cyclized product 22
(5 mg, 0.014 mmol) and potassium hydroxide (100 mg,
1.78 mmol) were dissolved in a mixture of water (1.5
mL) and ethylene glycol (1.5 mL) and heated to 100 ºC.
The solution was allowed to stir for 12 h. The crude
mixture was diluted with chloroform and washed with
water and brine. The organic extract was dried
(Na2SO4) and concentrated in vacuo. The product was
purified using preparative TLC to give (±)-stepharine
10 (3.3 mg, 82%). Spectra matching literature values.
Ethyl 6,7-dimethoxy-1-(((methylsulfonyl)oxy)methyl)-
8-(4-((triisopropylsilyl)oxy)phenyl)-3,4-
dihydroisoquinoline-2(1H)-carboxylate 21. Alcohol 20
(0.205 g, 0.41 mmol) and dry triethylamine (0.041 g,
0.41 mmol) were added to a flame dried flask charged
with CH2Cl2 (50 mL) and the mixture was cooled to 0
°C. Freshly distilled methanesulfonyl chloride (0.065 g,
0.61 mmol) was added to the solution dropwise. The
mixture was allowed to stir at 0 ºC for 3 h until the
staring material was consumed as shown by LCMS.
The crude mixture was poured into a saturated aqueous
NaHCO3 and extracted with ether (3 x 50 mL). The
ether extracts were washed with saturated aqueous
NH4Cl, brine, dried (Na2SO4), and concentrated in
vacuo. The crude product was purified by flash
chromatography over neutral alumina to give 21 (0.214
g, 84%) as a clear oil. IR (thin film) 2934, 2867, 1701,
1
IR (thin film) 3584, 2923, 1662, 1490, 1261 cm-1. H
NMR (400 MHz, CDCl3) δ 7.01 (1H, d, J = 10.0 Hz),
6.89 (1H, d, J = 9.2 Hz), 6.64 (1H, s), 6.41 (1H, d, J =
10.0 Hz), 6.29 (1H, d, J = 10.0 Hz), 4.33 (1H, m), 3.81
(3H, s), 3.60 (3H, s), 3.51 (1H, m), 3.21-3.08 (1H, m),
3.16 (1H, m), 2.85-2.74 (2H, m), 2.45-2.39 (1H, m),
2.27-2.23 (1H, m). HRMS calculated for C18H19NO3
(MH+) 298.1438, found 298.1434.
N-(2-(5,6-dimethoxy-4'-((triisopropylsilyl)oxy)-[1,1'-
biphenyl]-3-yl)ethyl)-4-methylbenzenesulfonamide 23.
To a stirred solution of 18 (0.69 g, 1.6 mmol) in THF (5
mL) under argon was added water (15 mL) followed by
p-toluenesulfonyl chloride (0.37 g, 1.9 mmol) and
tetrabutylammonium iodide (spatula tip). The solution
was stirred at room temperature for 6 h then transferred
to a separatory funnel and extracted with ethyl acetate
1
1511, 1176 cm-1. H NMR (400 MHz, CDCl3) δ 7.20-
6.96 (4H, m), 6.70 (1H, d, J = 0.8 Hz), 5.56-5.40 (1H,
m), 4.17-4.02 (4H, m), 3.90-3.87 (4H, m), 3.41 (4H, m),
2.87 (2H, m), 2.64 (3H, d, J = 12.8 Hz), 1.31-1.11
(24H, m). 13C NMR (100 MHz, CDCl3) δ 155.7, 133.2,
131.9, 131.8, 131.5, 129.9, 127.6, 122.6, 120.3, 120.1,
120.0, 111.8, 105.0, 77.2, 69.0, 61.6, 60.4, 55.8, 50.9,
5

ACCEPTED MANUSCRIPT
Tetrahedron
(3 x 20 mL). The organic fractions were combined,
washed with brine (30 mL), dried (Na2SO4) and
concentrated in vacuo. Purification by flash
chromatography (SiO2, 5-10% EtOAc:hexanes) gave 23
(0.751 g, 80%) as an off white solid. M.p. 99-100 ºC. IR
crystals. M.p. 105-107 ºC. IR (thin film) 3545, 2944,
1
2
3
4
5
6
7
8
9
1
2866, 2361, 2340, 1606, 1511, 1464, 1261 cm-1. H
NMR (400 MHz, CDCl3)  J = 7.6
Hz), 7.18 (2H, d, J = 8.2 Hz), 7.12 (1H, d, J = 7.6 Hz),
6.99 (2H, d, J = 8.2 Hz), 6.86 (1H, d, J = 7.2 Hz), 6.53
(1H, s), 4.83 (1H, dd, J = 8.4, 8.0 Hz), 3.81 (3H, s),
3.60 (3H, m), 3.42 (1H, m), 3.41 (3H, s), 2.78 (2H, m),
2.37 (3H, s), 2.19 (1H, t, J = 7.6 Hz), 1.68 (2H, m), 1.31
(3H, sep, J = 7.6 Hz), 1.14 (18H, d, J = 7.6 Hz). 13C
NMR (100 MHz, CDCl3)  ppm 155.6, 151.5, 145.4,
143.3, 136.3, 134.2, 131.4, 130.4, 129.4, 129.2, 128.3,
127.7, 127.3, 120.1, 119.9, 111.5, 60.5, 59.0, 55.7, 51.1,
40.5, 39.0, 27.3, 21.5, 17.9, 12.6. HRMS calculated for
C35H49NO6SSi (M+H)+ 640.3128 found 640.3107.
1
(thin film) 2944, 2866, 1512, 1262 cm-1. H NMR (400
MHz, CDCl3)  ppm 7.68 (2H, d, J = 8.4 Hz), 7.36 (2H,
d, J = 8.4 Hz), 7.26 (1H, d, J = 8.0 Hz), 6.91 (2H, d, J =
8.8 Hz), 6.59 (2H, d, J = 4.8 Hz), 4.39 (1H, t, J = 6.0
Hz), 3.84 (3H, s), 3.51 (3H, s), 3.24 (2H, q, J = 6.8 Hz),
2.74 (2H, t, J = 6.8 Hz), 2.41 (3H, s), 1.27 (3H, sep, J =
6.8 Hz), 1.13 (18H, d, J = 6.8Hz). 13C NMR (100 MHz,
CDCl3) 
143.4, 136.9, 135.7, 133.2, 130.5, 130.2, 129.7, 127.1,
122.4, 119.6, 111.3, 60.3, 55.9, 44.1, 35.6, 21.5, 17.9,
12.7. HRMS calculated for C32H45NO5SSi (M)+
583.2788 found 583.2795.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
1-(2-bromoethyl)-6,7-dimethoxy-2-tosyl-8-(4-
((triisopropylsilyl)oxy)phenyl)-1,2,3,4-
tetrahydroisoquinoline 26. To a flame dried round
bottom flask under argon was added dry CH2Cl2 (25
mL), 25 (0.613 g, 0.96 mmol) and carbon tetrabromide
(0.636 g, 1.92 mmol). The flask was placed in an ice
bath and triphenylphosphine (0.502 g, 1.92 mmol) was
added. The ice bath was removed and the reaction was
stirred at room temperature for 3 h (monitored by TLC).
The mixture was diluted with ether (100 mL) and
filtered. The filtrate was concentrated in vacuo and the
crude material purified by flash chromatography (SiO2,
10% EtOAc:hexanes) to give 26 (0.641 g, 95%) as a
white solid which was recrystallized from methanol to
give white crystals. M.p. 112-113 ºC. IR (thin film)
2944, 2866, 1512, 1463, 1262 cm-1. 1H NMR (400
MHz, CDCl3) ppm 7.62 (2H, d, J = 8.0 Hz), 7.19 (2H,
d, J = 8.0 Hz), 7.10 (1H, m), 7.01-6.98 (3H, m), 6.49
(1H, s), 4.80 (1H, dd, J = 10.4, 3.2 Hz), 3.81 (4H,
comp), 3.48 (1H, ddd, J = 15.6, 10.0, 5.6 Hz), 3.42 (3H,
s), 3.14 (1H, td, J = 10.0, 4.4 Hz), 2.77 (2H, m), 2.67
(1H, dt, J = 16.4, 5.2 Hz), 2.37 (3H, s), 2.02 (1H, m),
1.87 (1H, m), 1.30 (3H, sep, J = 6.8 Hz), 1.14 (18H, d, J
= 6.8 Hz). 13C NMR (100 MHz, CDCl3) 
1-(2-(benzyloxy)ethyl)-6,7-dimethoxy-2-tosyl-8-(4-
((triisopropylsilyl)oxy)phenyl)-1,2,3,4-
tetrahydroisoquinoline 24. To a flame dried round
bottom flask under argon was added 23 (0.732 g, 1.25
mmol), 2,2,2,-trifluoroethanol (15 mL), 23a (0.395 g,
1.88 mmol), and trifluoroacetic acid (0.14 mL, 1.88
mmol). The mixture was heated in an oil bath at 60 ºC
and stirred for 24 h (reaction monitored by LCMS or 1H
NMR). The mixture was cooled to room temperature,
and concentrated in vacuo. The crude mixture was
purified by flash chromatography (SiO2, 5-10%
EtOAc:hexanes) to give 24 (0.794 g, 87%) as a clear
viscous oil. IR (thin film) 2944, 2866, 1511, 1464, 1262
cm-1. 1H NMR (400 MHz, CDCl3)  ppm 7.60 (2H, d, J
= 8.0 Hz), 7.32-6.95 (11H, comp), 6.51 (1H, s), 4.87
(1H, dd, J = 10.4, 4.0 Hz), 4.22 (2H, s), 3.80 (4H,
comp), 3.53 (1H, m), 3.42 (3H, s), 3.26 (1H, td, J = 9.2,
5.2 Hz), 3.04 (1H, m), 2.81 (1H, m), 2.70 (1H, m), 2.34
(3H, s), 1.73 (2H, m), 1.30 (3H, sep, J = 7.6 Hz), 1.14
(18H, d, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3) 
ppm 155.4, 151.4, 145.3, 143.0, 138.5, 137.3, 134.2,
131.8, 130.2, 129.2, 128.8, 128.2, 127.4, 127.3,120.1,
120.0, 111.7, 72.6, 67.7, 60.4, 55.7, 51.2, 38.8, 35.2,
27.0, 21.5, 17.9, 12.6. HRMS calculated for
C42H55NO6SSi (M+Na)+ 752.3412 found 752.3389.
151.7, 145.4, 143.3, 137.0, 134.3, 131.6, 130.1, 129.4,
128.8, 127.7, 127.3, 127.1, 120.3, 120.0, 111.7, 105.0,
60.5, 55.7, 52.9, 39.0, 28.8, 27.0, 21.5, 17.9, 12.7.
HRMS calculated for C35H48BrNO5SSi (M+Na)+
724.2098 and 726.2084 found 724.2068 and 726.2069.
2-(6,7-dimethoxy-2-tosyl-8-(4-
((triisopropylsilyl)oxy)phenyl)-1,2,3,4-
1-(2-chloroethyl)-6,7-dimethoxy-2-tosyl-8-(4-
((triisopropylsilyl)oxy)phenyl)-1,2,3,4-
tetrahydroisoquinolin-1-yl)ethanol 25. To flame dried
round bottom flask under argon was added methanol
(20 mL), 24 (0.396 g, 0.54 mmol), ammonium formate
(0.171 g, 2.71 mmol) and 10% palladium on carbon
(0.30 g). The mixture was heated in an oil bath at 50 ºC
for 6 h until the reaction was complete, as judged by
TLC. The mixture was filtered through a pad of Celite,
washed with copious amounts of methanol, and
concentrated in vacuo. The crude material was purified
tetrahydroisoquinoline 27. To a flame dried round
bottom flask under argon was added dry CH2Cl2 (5
mL), 25 (0.104 g, 0.16 mmol) and carbon tetrachloride
(0.075 g, 0.49 mmol). The flask was placed in an ice
bath and triphenylphosphine (0.128 g, 0.49 mmol) was
added. The ice bath was removed and the reaction
mixture was stirred at room temperature for 5 h
(monitored by TLC). The mixture was diluted with
ether (30 mL), filtered, and the filtrate concentrated in
vacuo. The crude material was purified by flash
chromatography (SiO2, 10% EtOAc:hexanes) to give 27
by
flash
chromatography
(SiO2,
5-20%
EtOAc:hexanes) to give 25 (0.287 g, 83%) as a white
solid. Recrystallization from methanol afforded white
6

ACCEPTED MANUSCRIPT
Tetrahedron
(0.088 g, 83%) as
a white solid which was
1
2
3
recrystallized from methanol to give white crystals.
M.p. 115-118 ºC. IR (thin film) 2944, 2867, 1606,
1511, 1464, 1339,1263 cm-1. 1H NMR (400 MHz,
4.3 Crystallography
4
5
6
7
8
CDCl3) 
7.55 (2H, d, J = 8.4 Hz), 7.24 (1H, d, J
= 7.2 Hz), 7.19 (2H, d, J = 8.0 Hz), 7.10 (1H, d, J = 9.2
Hz), 7.01 (3H, m), 6.50 (1H, s), 4.77 (1H, dd, J = 10.4,
3.2 Hz), 3.73 (4H, comp), 3.49 (1H, ddd, J = 15.2, 10.0,
5.6 Hz), 3.42 (3H, s), 3.27 (1H, ddd, J = 10.8, 9.6, 4.8
Hz), 2.96 (1H, m), 2.80 (1H, m), 2.68 (1H, dt, J = 15.2,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
4.0 Hz), 2.30 (3H, s), 1.92 (1H, m), 1.78 (1H, m), 1.31
13
(3H, sep, J = 7.6 Hz), 1.14 (18H, d, J = 7.6 Hz).
C
NMR (100 MHz, CDCl3)  ppm 155.5, 151.6, 145.4,
143.3, 137.0, 134.3, 131.6, 130.1, 129.4, 128.8, 127.7,
127.3, 127.2, 120.2, 120.0, 111.7, 60.5, 55.7, 51.8, 41.0,
39.0, 38.5, 27.0, 21.5, 17.9, 12.7. HRMS calculated for
C35H48ClNO5SSi (M+Na)+ 680.2603 found 680.2579.
ORTEP representation of 28 (CCDC 1055666)
5,6-dimethoxy-1-tosyl-1,2,3,8,9,9a-
hexahydrospiro[benzo[de]quinoline-7,1'-
cyclohexa[2,5]dien]-4'-one 28. Flame dried cesium
fluoride (32 mg, 0.21 mmol) in a round bottom flask,
was placed in an oil bath at 100 ºC. A solution of 26 (50
mg, 0.071 mmol) in distilled N-methylpyrrolidone (14
mL) was cannulated under a nitrogen atmosphere into
the flask containing cesium fluoride and the resulting
suspension was stirred at 100 ºC for 2 h (reaction
monitored by LCMS). The flask was removed from the
oil bath, allowed to cool to room temperature, and
transferred to a separatory funnel. Water was added (30
mL) and the mixture was extracted with toluene (4 x 30
mL). The organic fractions were combined, washed
with water (30 mL), brine (30 mL), dried (MgSO4) and
concentrated in vacuo. The crude material was purified
ORTEP representation of dimer 28a. (CCDC
1055667)
Acknowledgments
The Welch Chair (F-0018) are thanked for their support
of this research. Vince Lynch is thanked (University of
Texas, Austin) for X-ray structure determinations.
via
column
chromatography
(SiO2,
20%
EtOAc:hexanes) to give 28 (26.2 mg, 79%) as a white
solid. Crystals suitable for X-ray diffraction were grown
via slow diffusion of hexanes into EtOAc. M.p. 174-
175 ºC. IR (thin film) 2939, 2360, 2340, 1659, 1620,
1597, 1477, 1337, 1316. 1H NMR (400 MHz, CDCl3) 
ppm 7.75 (2H, d, J = 8.0 Hz), 7.31 (2H, d, J = 8.0 Hz),
7.02 (1H, dd, J = 10.0, 3.2 Hz), 6.92 (1H, dd, J = 10.0,
3.2 Hz), 6.52 (1H, s), 6.32 (1H, dd, J = 10.0, 2.0 Hz),
6.22 (1H, dd, J = 10.0, 2.0 Hz), 4.50 (1H, dd, J = 11.6,
4.0 Hz), 3.97 (1H, dt, J = 13.6, 4.0 Hz), 3.76 (3H, s),
3.58 (3H, s), 3.15 (1H, ddd, J = 14.0, 11.6, 2.8 Hz),
2.59 (1H, dq, J = 12.8, 3.2 Hz), 2.48 (1H, dt, J = 15.6,
2.8 Hz), 2.42 (3H, s), 2.33 (1H, ddd, J = 15.2, 11.2, 4.0
Hz), 2.20 (1H, td, J = 14.0, 2.8 Hz), 1.99 (1H, m), 1.79
(1H, ddd, J = 14.0, 4.4, 2.8 Hz). 13C NMR (100 MHz,
CDCl3)  ppm 186.0, 156.5, 153.5, 151.4, 143.6, 137.5,
131.4, 129.9, 129.1, 127.2, 126.4, 126.3, 124.4, 112.1,
105.0, 60.9, 55.6, 54.8, 43.7, 42.7, 35.7, 30.2, 29.3,
21.5. HRMS calculated C26H27NO5S (M+H)+ 466.1688
found 466.1685.
There are no conflicting interests with any commercial
organisations in this research.
References and notes
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Am. Chem. Soc. 2009, 131, 16045-16047.
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Cuny, G. D. Org. Lett. 2015, 17, 1134-1137.
Under more dilute reaction conditions the dimer 28a
(structure by X-ray) was isolated in modest yields.
7

ACCEPTED MANUSCRIPT
Tetrahedron
7. Cava, M.P.; Nomura, K.; Schlessinger, R. H.; Buck,
1
2
3
4
5
6
7
8
K. T.; Douhlas, B.; Raffauf, R. F.; Weisbach, J. A.
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Kh. A.; Alimov, A. F. Khimiya Prirodnykh
Soedinenii 1990, 1,67-74.
9
10
11
12
13
14
15
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17
18
19
20
21
22
23
24
25
26
27
28
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30
31
32
33
34
35
36
37
38
39
40
41
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
13. The alkene product from elimination of the triflate
precursor has the structure .
14.The N-CO2Et derivative of 25 (as its mesylate) gave
the dimer II (structure by X-ray) as one of the products
when treated with CsF/DMF/120 °C.
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2003, 44, 8827-8830.
8