Synthetic approaches to pallimamine and analogues using direct imine acylation

Article abstract of DOI:10.1016/j.tet.2016.05.009

The use of Direct Imine Acylation (DIA) methodology for the total synthesis of pallimamine is described, with three different synthetic routes examined. The construction of three advanced δ-lactam precursors, all utilising DIA, is described, along with attempts to progress these compounds further, using three distinct desymmetrisation strategies, two involving alcohol-aryl coupling, and a third involving an unusual diastereoselective lactonisation.

Full text of DOI:10.1016/j.tet.2016.05.009

Tetrahedron xxx (2016) 1e8
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic approaches to pallimamine and analogues using direct
imine acylation
*
*
Thomas O. Ronson, Christiana Kitsiou, William P. Unsworth , Richard J.K. Taylor
University of York, Heslington, York, YO10 5DD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of Direct Imine Acylation (DIA) methodology for the total synthesis of pallimamine is described,
with three different synthetic routes examined. The construction of three advanced -lactam precursors,
all utilising DIA, is described, along with attempts to progress these compounds further, using three
distinct desymmetrisation strategies, two involving alcohol-aryl coupling, and a third involving an un-
usual diastereoselective lactonisation.
Received 18 March 2016
Received in revised form 22 April 2016
Accepted 4 May 2016
d
Available online xxx
Ó 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
Keywords:
N-acyliminium ions
Nitrogen heterocycles
Imines
Berberine alkaloids
Pallimamine
1. Introduction
large number of diversely functionalised protoberberines2 have
been discovered over a number of years, with the family typified by
Protoberberine alkaloid (ꢀ)-pallimamine 1 was isolated in 1989
from Corrydalis pallida var sparsimamma collected in Nan-Shan
village, Taiwan, along with other known protoberberine alkaloids
the bis-isoquinoline motif highlighted below in red. Many proto-
berberines exhibit biological activity,3 which has helped to propa-
gate significant research efforts towards their synthesis.4
a
-allocryptopine 2, protopine 3 and (ꢁ)-capaurimine 4 (Fig. 1).1 A
To the best of our knowledge, the pentacyclic structure of pal-
limamine 1 with its additional tetrahydropyran ring is a unique
feature amongst protoberberine alkaloids and it has not been
synthesised previously. In view of these factors, as well as a long-
standing interest in the application of telescoped/tandem synthetic
methodology in target synthesis,5 we were encouraged to embark
upon its total synthesis. Our basic retrosynthetic analysis is shown
in Fig. 2. We were confident that our recently established ‘Direct
Imine Acylation’ (DIA) methodology6 would facilitate the coupling
of a comparatively simple imine 5 and benzoic acid derivative 6 to
construct the key d
-lactam7 ring system 7; the viability of DIA to
construct CeC bonds has been demonstrated previously in our
group,6a,6deg including an example in a related natural product
synthesis.6d Following reduction (7/8) it was then planned to
exploit the symmetry of the resulting diol 8 to construct the tet-
rahydropyran ring via a CeO coupling reaction, resulting in the
desymmetrisation of the diastereotopic alcohol groups. It was ex-
pected that CeO bond formation would occur selectively via the
pseudo-equatorial alcohol, rather than the alternative pseudo-axial
alcohol, to form a product with the trans-fused ring junction re-
quired in the natural product. While we had no evidence to support
this prediction when starting this work, intuitively we felt that the
trans-fused product (and the associated transition state for its
Fig. 1. Berberine alkaloids 1e4.
* Corresponding authors. E-mail addresses: william.unsworth@york.ac.uk
(W.P. Unsworth), richard.taylor@york.ac.uk (R.J.K. Taylor).
http://dx.doi.org/10.1016/j.tet.2016.05.009
0040-4020/Ó 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Please cite this article in press as: Ronson, T. O.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.009

2
T.O. Ronson et al. / Tetrahedron xxx (2016) 1e8
tetrahydropyran ring later in the synthesis. First, vanillin 13 was
converted into amine 17 by a sequence of known procedures
(bromination, alkylation, Henry reaction and reduction),10 and
was then reacted with paraformaldehyde and formic acid in
a PicteteSpengler reaction to form tetrahydroisoquinoline 18 in
good overall yield. Finally, the synthesis was completed by oxi-
dation using manganese(IV) oxide to furnish imine 12 (Scheme 2).
Fig. 2. Retrosynthetic strategy.
formation) would be more thermodynamically stable than the cis-
variant and therefore form more easily. Indeed, it is plausible that
similar thermodynamic factors are at play during its biosynthesis,
giving rise to the observed trans-configuration in the natural
product; the fact that pallimamine was isolated in racemic form
offers minor supporting evidence for this hypothesis, as this sug-
gests that its biosynthesis may proceed via an intermediate that has
undergone reversible epimerisation. This paper details our efforts
to date to apply the strategy outlined in Fig. 2 to the total synthesis
of pallimamine.
Scheme 2. Synthesis of imine 12. TBAHS ¼ tetrabutylammonium hydrogen sulfate.
The DIA coupling of imine 12 and acid 6 was performed by
stirring both components in chloroform at rt with NEt(i-Pr)2 and
propylphosphonic acid anhydride (T3P), which led to in situ acti-
vation of the carboxylic acid and nucleophilic attack by the imine to
form intermediate N-acyliminium ion 19 (Scheme 3). In line with
the majority of the previous DIA reactions reported by our group
involving CeC bond formation, it was necessary to add a Lewis acid
into the reaction mixture and increase the temperature, in this case
AlCl3 at 50 ꢂC, in order to promote the ring-closing step. Using this
one-pot telescoped procedure, lactam 20 was isolated in 38%
unoptimised yield from imine 12. It was then planned to reduce the
ester and amide groups to form diol 21, with a view towards
forming the key tetrahydropyran ring via a palladium-catalysed
CeO coupling reaction, as described above (i.e., 21/9, see Fig. 2).
2. Results and discussion
The novel benzoic acid derivative
6 was prepared via
a straightforward two-step protocol; commercially available 2,3-
dimethoxybenzoic acid 10 was first reacted with 1,3-dibromo-
5,5-dimethylhydantoin to form bromide 11 which was then con-
verted into diester 6 via a modified Hurtley reaction (Scheme 1).8
The overall yield for the two-step conversion of compound 10
into product 6 was relatively low (36%) but was easily performed on
a large scale (7 g of 6 formed), providing ample quantities of ma-
terial with which the perform the subsequent syntheses.9
Scheme 1. Synthesis of benzoic acid derivative 6.
Next, attention turned to the synthesis of brominated imine
12; this substrate was chosen as the bromo-substituent was
thought to be a useful synthetic handle with which to install the
Scheme 3. Synthesis of lactam 20.
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T.O. Ronson et al. / Tetrahedron xxx (2016) 1e8
3
However, repeated attempts to reduce lactam 20 were unsuccess-
ful11 leading either to no reaction, or complex product mixtures.
The potential for the aryl bromide moiety in compound 20 to
undergo unwanted reduction was postulated to be a factor in our
failure to form diol 21, and in view of this, an alternative synthetic
strategy was devised in which this bromo-group is not required. It
was planned instead to synthesise triol 22, using a similar strategy
to that described earlier, before constructing the tetrahydropyran
ring using an oxidative coupling process,12 as outlined in Fig. 3.
As mentioned above, it was next planned to convert triol 22 into
tetrahydropyran 25 using the oxidative coupling strategy outlined
in Fig. 3. First, triol 22 was treated with PhI(OAc)2 in acetonitrile at
rt. Encouragingly, these conditions did indeed promote oxidation
and cyclisation, but unfortunately the cyclisation took place at the
para-position of the phenol ring, furnishing the unusual bridged
polycyclic compound 33.14 Alternative oxidative coupling condi-
tions were therefore examined, but the use of bromine in acetic
acid also led to oxidation and cyclisation onto the undesired para-
position, along with concomitant acetate and bromide addition,
furnishing bridged polycyclic 34 as a single diastereoisomer, with
its structure confirmed by X-ray crystallography (see Scheme 5).15
Fig. 3. Planned synthesis of tetrahydropyran 25.
The synthesis of triol 22 was completed in seven steps from
vanillin derivative 26. First, based on literature precedent,13 se-
quential Henry condensation, reduction, PicteteSpengler and oxi-
dation reactions delivered the key imine coupling partner 30. This
imine was then coupled with carboxylic acid 6 via the same DIA
procedure used to synthesise lactam 20, but with BCl3 being used
rather than AlCl3 to promote the ring-closure. This delivered lactam
31 in reasonable overall yield, and it was then converted into the
requisite triol 22 via successive reduction with LiAlH4 and hydro-
genolysis (Scheme 4).
Scheme 5. Synthesis of bridged polycyclic compounds 33 and 34.
This strategy was ultimately unsuccessful as a route to generate
pallimamine, due to the apparent bias for cyclisation into the
phenol para-position. Nonetheless, both oxidative coupling pro-
cesses are certainly interesting, especially as both products were
isolated as single diastereoisomers.
Attention then switched to a third synthetic strategy, in which it
was planned to perform the final ring-closure via a lactonisation
reaction. For this route, an imine with a protected oxygen sub-
stituent was required, prompting us to synthesise imine 40 in five
steps. First, lactam 37 was formed in good yield from carboxylic
acid 35 using Canniago’s published method16 and this was then
converted into compound 39 by the sequential installation of Boc
Scheme 4. Synthesis of triol 22.
Scheme 6. Synthesis of imine 40.
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T.O. Ronson et al. / Tetrahedron xxx (2016) 1e8
and benzyl protecting groups. The synthesis of imine 40 was then
completed following partial reduction of the lactam carbonyl with
Super-HydrideÔ and treatment with TFA, as has been demon-
strated for the synthesis of related imines in our earlier work
(Scheme 6).6a
The DIA reaction of imine 40 with acid 6 proceeded well, fur-
nishing lactam 41 in 51% unoptimised yield, with AlCl3 used as an
additive in this case. Subsequent cleavage of the benzyl protecting
group via hydrogenolysis revealed phenol 42, which was then
heated at reflux in toluene with catalytic p-TSA, furnishing lactone
43 in good yield over the two step sequence. Crucially, lactone 43
was formed as a single diastereoisomer, validating our earlier
proposed desymmetrisation strategy. The product was found to
possess the correct relative stereochemistry required in pallim-
amine, with this structural assignment confirmed by X-ray crys-
tallographic data as shown (see Scheme 7).15
gel 60 F254 pre-coated aluminium foil sheets and were visualised
using UV light (254 nm) and stained with either basic aqueous
potassium permanganate or ethanolic p-anisaldehyde as appro-
priate. 1H NMR and 13C NMR spectra were recorded on a Jeol ECX-
400 NMR or Jeol ECS400 spectrometer operating 400 MHz and
100 MHz, respectively, or on a Bruker DRX500 spectrometer, op-
erating at 500 MHz and 125 MHz, respectively. All spectra were
acquired at 295 K. Chemical shifts (d) are quoted in parts per million
(ppm). The multiplicity abbreviations used are: s, singlet; d, dou-
blet; t, triplet; q, quartet; m, multiplet; br, broad or combinations of
these. The residual solvent peaks, dH 7.26 and dC 77.0 for CDCl3 were
used as references. Infrared spectra (IR) were recorded on a Ther-
moNicolet IR-100 spectrometer with NaCl plates as a thin film
dispersed from either CH2Cl2 or CDCl3. High Resolution Mass
Spectra (HRMS) were obtained by University of York Mass spec-
trometer Service, using ionisation (ESI) on a Bruker Daltonics,
MicrOTOF spectrometer. Melting points were measured on a Gal-
lenkamp melting point apparatus and are uncorrected.
4.1. 6-Bromo-2,3-dimethoxybenzoic acid (11)
In an ice bath, 2,3-dimethoxybenzoic acid 10 (10.0 g, 54.9 mmol)
and 1,3-dibromo-5,5-dimethylhydantoin (8.63 g, 30.2 mmol) were
added to 0.7 M aq NaOH (86 mL). The reaction mixture was stirred
at rt for 1 h, then 1 M aq HCl (150 mL) was added and the aqueous
layer was extracted with ethyl acetate (3ꢃ200 mL). The combined
organic layers were dried with MgSO4 and concentrated in vacuo to
give compound 10 as a solid (14.3 g, quantitative), which was used
without further purification in the next step; dH (400 MHz, CDCl3)
11.46 (1H, br s), 7.21 (1H, d, J¼8.9 Hz), 6.81 (1H, d, J¼8.9 Hz), 3.88
(3H, s), 3.82 (3H, s); HRMS (ESIþ) 282.9575 [MþNa]þ, C9H799BrNaO4
requires 282.9576 (0.6 ppm error). The obtained data were in ac-
cord with those reported in the literature.17
4.2. 6-(1,3-Dimethoxy-1,3-dioxopropan-2-yl)-2,3-
dimethoxybenzoic acid (6)
Sodium hydride (6.16 g, 165 mmol, 60% in mineral oil) was
added portionwise to a rapidly stirred cold suspension (0 ꢂC) of 6-
bromo-2,3-dimethoxybenzoic acid 11 (18.0 g, 68.8 mmol), cop-
per(I) bromide (987 mg, 6.88 mmol) and dimethyl malonate
(240 mL) [note: a solid crust formed on top of the reaction during
the addition of sodium hydride]. After the addition of the sodium
hydride was complete, the mixture was stirred for 10 min at rt and
then for 20 h at 70 ꢂC. The resulting suspension was then quenched
with water (800 mL), washed with ether (3ꢃ1500 mL) and then
acidified with 10% hydrochloric acid. The acidic aqueous residues
were then extracted with ethyl acetate (3ꢃ1000 mL) and the or-
ganic extracts were dried over MgSO4 and concentrated in vacuo.
Purification by column chromatography (SiO2, 2:1/1:1 petro-
l:ethyl acetate/ethyl acetate) afforded compound 6 as a white
solid (7.74 g, 36%); Rf 0.47 (CH2Cl2/MeOH, 50:1); mp 104e108 ꢂC;
nmax (thin film)/cmꢁ1 3223, 2955, 1735, 1581, 1494, 1438, 1264, 1150,
1055; dH (400 MHz, CDCl3) 7.22 (1H, d, J¼8.7 Hz), 7.08 (1H, d,
J¼8.7 Hz), 5.36 (1H, s), 3.99 (3H, s), 3.91 (3H, s), 3.78 (6H, s); dC
(100 MHz, CDCl3) 169.0, 167.3, 152.3, 147.6, 126.5, 125.5, 124.8, 115.2,
62.2, 56.0, 54.2, 52.9; HRMS (ESIþ) 335.0728 [MþNa]þ, C14H16NaO8
requires 335.0737.
Scheme 7. Synthesis of lactone 43.
3. Conclusion
Preliminary studies indicated that the reduction of pentacyclic
pallimamine analogue 43 is not straightforward and the total
synthesis of pallimamine 1 has therefore not yet been completed.
Nonetheless, three contrasting synthetic strategies have been de-
veloped to form advanced intermediates 20, 31 and 41, with each
utilising a direct imine acylation reaction as a key step. Lactam 41
was progressed further to give lactone 43 as
a single di-
astereoisomer, a compound in which the complete pallimamine
skeleton has been installed. In future work, we will examine a range
of reduction/protection strategies to complete the synthesis of
pallimamine 1 from advanced pentacyclic precursors related to 43.
4. Experimental section
Except where stated, all reagents were purchased from com-
mercial sources and used without further purification. Anhydrous
dichloromethane and toluene were obtained from an Innovative
Technology Pure Solv solvent purification system. Anhydrous THF
was obtained by distillation over sodium benzophenone ketyl im-
4.3. 6,7-Dimethoxy-8-bromo-1,2,3,4-tetrahydroisoquinoline
(18)
mediately before use. Flash column chromatography was carried
A solution of 2-(3-bromo-4,5-dimethoxyphenyl)ethanamine
1710 (498 mg, 1.91 mmol) and paraformaldehyde (58 mg,
1.91 mmol) in formic acid (1 mL) was heated to 50 ꢂC for 15 h. After
this time, the solvent was removed in vacuo, and 1 M aq NaOH was
ꢀ
out using slurry packed silica gel (SiO2), 35e70
m
m, 60 A, under
light positive pressure eluting with the specified solvent system.
Thin layer chromatography (TLC) was carried out on Merck silica
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T.O. Ronson et al. / Tetrahedron xxx (2016) 1e8
5
added (10 mL). The aqueous solution was extracted with
dichloromethane (3ꢃ10 mL), and the combined organic layers
dried (Na2SO4), concentrated in vacuo and purified by flash chro-
matography (SiO2, ethyl acetate/5% MeOH/ethyl acetate) to afford
the title compound as an off-white solid (317 mg, 61%). Mp
62e64 ꢂC; Rf 0.12 (CH2Cl2/MeOH, 9:1); nmax (thin film)/cmꢁ1 3336,
2934, 2831, 1598, 1563, 1484, 1429, 1325, 1304, 1261, 1110, 1035,
1003, 806; dH (400 MHz, CDCl3) 6.60 (s, 1H), 3.90 (s, 2H), 3.83 (s,
3H). 3.81 (s, 3H), 3.05 (t, J¼5.9 Hz, 2H), 2.72 (t, J¼5.9 Hz, 2H), 2.10
(br s, 1H); dC (100 MHz, CDCl3) 151.6, 144.6, 132.3, 127.7, 118.1, 112.4,
60.6, 56.2, 48.8, 43.3, 29.4; MS (ESIþ) m/z (rel %) 272 ([MþH]þ, 100),
286 ([MþNa]þ, 20); HRMS (ESIþ) 272.0269 [MþH]þ, C11H15BrNO2
requires 272.0291.
filtered. The filtrate was extracted with ethyl acetate (3ꢃ20 mL),
and the organic extracts combined with the filtrant, dried (MgSO4)
and concentrated in vacuo to afford the title compound 27 which
was used without further purification (1.17 g, 99%). Mp 119e120 ꢂC
(lit.13a 119e121 ꢂC); dH (400 MHz, CDCl3) 7.95 (d, J¼13.6 Hz,1H), 7.51
(d, J¼13.6 Hz, 1H), 7.45e7.30 (m, 5H), 7.10 (dd, J¼8.3, 2.0 Hz, 1H),
7.02 (d, J¼2.0 Hz, 1H), 6.92 (d, J¼8.3 Hz, 1H), 5.22 (s, 2H), 3.93 (s, 3H
dC (100 MHz, CDCl3) 152.0, 150.1, 139.4, 136.2, 135.4, 128.9, 128.3,
127.3, 124.5, 123.2, 113.5, 110.9, 71.0, 56.2.
4.7. 2-[4-(Benzyloxy)-3-methoxyphenyl]ethan-1-amine (28)
A solution of nitrostyrene 27 (5.00 g, 17.5 mmol) in dry THF
(20 mL) was added dropwise to a stirred suspension of LiAlH4
(2.00 g, 52.5 mmol) in dry THF (60 mL) at 0 ꢂC. After complete
addition, the reaction mixture was heated 70 ꢂC for 2 h, before
being cooled to 0 ꢂC and quenched by addition of ethyl acetate
(50 mL) followed by H2O until evolution of gas ceased. Na2SO4 was
added and the mixture stirred for 30 min before being filtered and
concentrated in vacuo. The residue was taken up in 1 M aq HCl
(100 mL), washed with Et2O (2ꢃ100 mL), basified to pH 10 with 1 M
NaOH and extracted with Et2O (3ꢃ100 mL). the combined organic
extracts were dried over Na2SO4 and concentrated in vacuo to af-
ford the title compound 28 as an off-white solid which was used
without further purification (3.43 g, 76%). Mp 59e61 ꢂC (lit.13a
63e65 ꢂC); dH (400 MHz, CDCl3) 7.47e7.40 (m, 2H), 7.39e7.33 (m,
2H), 7.32e7.27 (m, 1H), 6.81 (d, J¼8.1 Hz, 1H), 6.74 (d, J¼1.9 Hz, 1H),
6.67 (dd, J¼8.1, 1.9 Hz,1H), 5.13 (s, 2H), 3.88 (s, 3H), 2.93 (t, J¼6.8 Hz,
2H), 2.68 (t, J¼6.8 Hz, 2H); dC (100 MHz, CDCl3) 149.7, 146.7, 137.5,
133.2, 128.7, 127.9, 127.4, 120.9, 114.3, 112.7, 71.3, 56.1, 43.7, 39.7; MS
(ESIþ) m/z (rel %) 241 ([MꢁNH2]þ, 95), 258 ([MþH]þ, 90), 280
([MþNa]þ, 100); HRMS (ESIþ) 258.1492 [MþH]þ, C16H20NO2 re-
quires 258.1489.
4.4. 6,7-Dimethoxy-8-bromo-3,4-dihydroisoquinoline (12)
Amine 18 (285 mg, 1.05 mmol) was dissolved in dichloro-
methane (10.5 mL) and MnO2 (1.82 g, 20.9 mmol) was added. The
resulting suspension was stirred for 16 h at rt, before being filtered
through a short pad of Celite and concentrated in vacuo, affording
the title compound 12 as a pale brown solid which was used without
further purification (283 mg, 84%). Mp 95e96 ꢂC (lit.12 102 ꢂC); Rf
0.44 (CH2Cl2/MeOH, 9:1); nmax (thin film)/cmꢁ1 2938, 1616, 1593,
1551, 1484, 1404, 1309, 1278, 1222,1118, 1032, 1011, 989, 813, 611; dH
(400 MHz, CDCl3) 8.59 (s, 1H), 6.65 (s, 1H), 3.91 (s, 3H), 3.84 (s, 3H),
3.72e3.66 (m, 2H), 2.68e2.61 (m, 2H); dC (100 MHz, CDCl3) 158.6,
155.5, 145.3, 135.5, 120.5, 119.4, 110.5, 60.8, 56.3, 46.8, 25.6; MS
(ESIþ) m/z (rel %) 270 ([MþH]þ, 100), 299 ([MþNa]þ, 10); HRMS
79
(ESIþ) 270.0134 [MþH]þ, C11
H BrNO2 requires 270.0124.
13
4.5. Dimethyl 12-bromo-3,4,10,11-tetramethoxy-5-oxo-
7,8,12b,13-tetrahydro-5H-6-azatetraphene-13,13-dicarboxylate
(20)
Imine 12 (225 mg, 0.83 mmol) and carboxylic acid 6 (390 mg,
1.25 mmol) were dissolved in CHCl3 (12 mL), and N,N-diisopropy-
lethylamine (198 mg, 1.53 mmol) was added, followed by T3P (50%
in THF, 796 mg, 1.25 mmol). The resulting solution was stirred at
room temperature for 40 min before the addition of AlCl3 (221 mg,
1.66 mmol), and heating to 50 ꢂC for 5 h. After this time, the mixture
was poured onto a rapidly stirring mixture of satd aq Rochelle’s salt
and Et2O (1:1, 80 mL) and stirred for 1 h. The aqueous layer was
extracted with Et2O (3ꢃ40 mL), and the combined organic layers
dried (MgSO4) and concentrated in vacuo. The crude residue was
purified by successive flash chromatography (SiO2, 1/2% MeOH/
CH2Cl2), affording the title compound 20 as a colourless oil
(178.7 mg, 38%). Rf 0.42 (ethyl acetate); nmax (thin film)/cmꢁ1 2943,
1736, 1658, 1595, 1484, 1451, 1425, 1395, 1311, 1272, 1258, 1119, 1031,
941, 812, 772, 733; dH (400 MHz, CDCl3) 7.25 (d, J¼8.6 Hz, 1H), 7.07
(d, J¼8.6 Hz, 1H), 6.76 (s, 1H), 5.90 (s, 1H), 4.89 (ddd, J¼12.7, 5.0,
1.5 Hz,1H), 4.04 (s, 3H), 3.92 (s, 3H), 3.91 (s, 3H), 3.80 (s, 3H), 3.69 (s,
3H), 3.67e3.61 (m, 1H), 3.54 (s, 3H), 2.81 (td, J¼12.7, 3.3 Hz, 1H),
2.64e2.56 (m, 1H); dC (100 MHz, CDCl3) 168.1, 166.9, 162.5, 153.7,
152.9, 149.9, 144.4, 138.8, 129.7, 125.2, 124.0, 123.2, 120.9, 114.9,
111.6, 64.5, 61.8, 60.5, 60.4, 56.2, 56.0, 53.4, 53.0, 39.3, 30.3; MS
4.8. 6-Methoxy-7-(benzyloxy)-1,2,3,4-tetrahydroisoquinoline
(29)
Amine 28 (3.34 g, 13.0 mmol) and paraformaldehyde (390 mg,
13.0 mmol) were dissolved in formic acid (6.5 mL) and heated to
50 ꢂC for 17 h. After this time, 1 M aq NaOH (100 mL) was added and
the aqueous solution extracted with CH2Cl2 (3ꢃ100 mL). The
combined organic extracts were dried (Na2SO4) and concentrated
in vacuo. The crude residue was purified by flash chromatography
(SiO2, 5/10% MeOH/CH2Cl2) to afford the title compound 29 as
a
brown solid (1.38 g, 39%). Mp 71e73 ꢂC (CHCl3) (lit.13b
124e126 ꢂC); Rf 0.07 (ethyl acetate); dH (400 MHz, CDCl3)
7.45e7.41 (m, 2H) 7.38e7.33 (m, 2H), 7.32e7.27 (m,1H), 6.60 (s,1H),
6.53 (s, 1H), 5.10 (s, 2H), 3.88 (s, 2H), 3.85 (s, 3H), 3.11 (t, J¼6.0 Hz,
2H), 2.72 (t, J¼6.0 Hz, 2H), 1.92 (br s,1H); dC (100 MHz, CDCl3) 148.3,
146.6, 137.4, 128.7, 127.9, 127.6, 127.4, 127.3, 112.7, 112.1, 71.3, 56.2,
47.9, 44.0, 28.7; MS (ESIþ) m/z (rel %) 270 ([MþH]þ, 100); HRMS
(ESIþ) 270.1482 [MþH]þ, C17H20NO2 requires 270.1489.
4.9. 6-Methoxy-7-(benzyloxy)-3,4-dihydroisoquinoline (30)
(ESIþ) m/z (rel %) 564 ([MþH]þ, 10), 586 ([MþNa]þ, 100); HRMS
Amine 29 (1.38 g, 5.12 mmol) was dissolved in dichloromethane
(50 mL) and MnO2 (8.90 g, 103 mmol) was added. The resulting
suspension was stirred for 16 h at rt, before being filtered through
a short pad of Celite and concentrated in vacuo, affording the title
compound 30 as a pale brown solid which was used without further
purification (980 mg, 72%). Mp 93e94 ꢂC (CHCl3) (lit.13c
101e101.5 ꢂC); Rf 0.11 (ethyl acetate); dH (400 MHz, CDCl3) 8.15 (t,
J¼2.0 Hz, 1H), 7.44 (d, J¼7.3 Hz, 2H), 7.42e7.35 (m, 2H), 7.34e7.29
(m, 1H), 6.82 (s, 1H), 6.69 (s, 1H), 5.15 (s, 2H), 3.92 (s, 3H), 3.71 (ddd,
J¼8.2, 6.5, 2.2 Hz, 2H), 2.70e2.64 (m, 2H); dC (100 MHz, CDCl3)
159.8, 152.1, 147.0, 137.0, 130.6, 128.8, 128.1, 127.5, 121.6, 113.4, 110.9,
79
(ESIþ) 586.0674 [MþNa]þ, C25
H BrNNaO9 requires 586.0683.
26
4.6. 1-(Benzyloxy)-2-methoxy-4-[(E)-2-nitroethenyl]benzene
(27)
4-Benzyloxy-3-methoxybenzaldehyde 26 (1.00 g, 4.13 mmol)
was dissolved in AcOH (5 mL), and NH4OAc (477 mg, 6.20 mmol)
and MeNO2 (756 mg, 12.4 mmol) were added successively. The
resulting mixture was heated to 90 ꢂC for 19 h. After this time, the
reaction mixture was cooled to rt, quenched with H2O (20 mL) and
Please cite this article in press as: Ronson, T. O.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.009

6
T.O. Ronson et al. / Tetrahedron xxx (2016) 1e8
71.5, 56.2, 47.4, 25.0; MS (ESIþ) m/z (rel %) 268 ([MþH]þ, 100);
HRMS (ESIþ) 268.1332 [MþH]þ, C17H18NO2 requires 268.1332.
filtered through a short plug of CeliteÔ and evaporated to afford the
title compound 22 as a colourless oil (53.5 mg, 83%). nmax (thin film)/
cmꢁ1 3275, 2938,1719,1677,1610,1517,1497,1454,1283,1231,1090,
1004, 815; dH (400 MHz, CD3OD) 8.42 (s, 1H), 7.35 (d, J¼8.7 Hz, 1H),
7.13 (d, J¼8.7 Hz, 1H), 7.04 (s, 1H), 6.83 (s, 1H), 4.84 (s, 1H), 4.51 (d,
J¼15.3 Hz, 1H), 4.18 (d, J¼15.3 Hz, 1H), 4.06 (d, J¼11.9 Hz, 1H), 3.89
(s, 3H), 3.88 (s, 6H), 3.81 (d, J¼11.9 Hz, 1H), 3.58 (d, J¼11.0 Hz, 1H),
3.41 (d, J¼9.1 Hz, 1H), 3.29e3.21 (m, 2H), 3.05 (td, J¼11.6, 2.3 Hz,
1H), 2.80 (d, J¼16.1 Hz,1H); dC (100 MHz, CD3OD) 150.7,147.2,144.9,
144.6, 130.0, 127.3, 127.2, 122.1, 122.0, 114.8, 112.8, 111.6, 65.7, 65.2,
62.4, 59.4, 55.0, 55.0, 53.4, 50.9, 49.0, 27.8; MS (ESIþ) m/z (rel %) 402
([MþH]þ, 100); HRMS (ESIþ) 402.1897 [MþH]þ, C22H28NO6 requires
402.1911.
4.10. Dimethyl 3,4,10-trimethoxy-11-(benzyloxy)-5-oxo-
7,8,12b,13-tetrahydro-5H-6-azatetraphene-13,13-dicarboxylate
(31)
Imine 30 (48.5 mg, 0.180 mmol) and carboxylic acid 6 (85 mg,
0.270 mmol) were dissolved in CHCl3 (2.5 mL) and N,N-diisopro-
pylethylamine (43 mg, 0.33 mmol) and T3P (50% in THF, 172 mg,
0.270 mmol) were added successively. The resulting solution was
stirred at rt for 40 min before the addition of BCl3 (1 M in CH2Cl2,
0.36 mL, 0.36 mmol), and heated to 50 ꢂC for 4 h. After this time, the
reaction was quenched with NaHCO3 (10 mL), and extracted with
ethyl acetate (3ꢃ10 mL). The combined organic layers were dried
(MgSO4) and concentrated in vacuo. Purification of the crude resi-
due by flash chromatography (SiO2, 50%/60%, ethyl acetate/hex-
ane) afforded the title compound 31 as a yellow oil (49 mg, 48%). Rf
0.48 (ethyl acetate); nmax (thin film)/cmꢁ1 2941, 1733, 1656, 1515,
1487, 1453, 1422, 1311, 1250, 1228, 1120, 1019, 912, 732; dH
(400 MHz, CDCl3) 7.45e7.40 (m, 2H), 7.39e7.33 (m, 2H), 7.32e7.26
(m, 1H), 7.04 (d, J¼8.6 Hz, 1H), 6.87 (s, 1H), 6.77 (d, J¼8.6 Hz, 1H),
6.72 (s, 1H), 5.48 (s, 1H), 5.08 (d, J¼12.2 Hz, 1H), 5.02 (d, J¼12.2 Hz,
1H), 4.95e4.89 (m,1H), 4.03 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H), 3.74 (s,
3H), 3.54 (s, 3H), 2.92e2.84 (m, 2H), 2.72e2.64 (m, 1H); dC
(100 MHz, CDCl3) 170.2, 167.4, 162.4, 154.0, 150.1, 149.3, 146.5, 137.2,
132.5, 130.7, 128.7, 128.0, 127.6, 123.4, 123.3, 122.4, 115.2, 114.1, 111.7,
71.6, 66.5, 61.8, 60.9, 56.2, 56.0, 53.1, 53.0, 39.1, 29.2; MS (ESIþ) m/z
(rel %) 562 ([MþH]þ, 10), 584 ([MþNa]þ, 100); HRMS (ESIþ)
584.1874 [MþNa]þ, C31H31NNaO9 requires 584.1891.
4.13. 4-(Hydroxymethyl)-8,9,17-trimethoxy-2-oxa-12-
azapentacyclo[10.6.2.01,14.04,13.05,10]icosa-5,7,9,14,17-pentaen-
16-one (33)
Phenol 22 (43.4 mg, 0.108 mmol) was dissolved in MeCN (5 mL)
and diacetoxyiodobenzene (41.7 mg, 0.129 mmol) was added in one
portion. The resulting solution was stirred for 1 h, before being
quenched with NaHCO3 (20 mL). The aqueous solution was
extracted with ethyl acetate (3ꢃ20 mL), and the combined organic
layers were dried (MgSO4) and concentrated in vacuo. Purification
of the crude residue by flash chromatography (SiO2, MeOH/CH2Cl2,
25:1) afforded the title compound 33 as a yellow oil (13.1 mg, 30%).
Rf 0.43 (CH2Cl2/MeOH, 9:1); nmax (thin film)/cmꢁ1 3356, 2928, 2855,
1681, 1656, 1626, 1493, 1454, 1273, 1209, 1175, 1063, 1020, 732; dH
(400 MHz, CDCl3) 7.06 (d, J¼8.6 Hz, 1H), 6.92 (d, J¼8.6 Hz, 1H), 6.41
(s, 1H), 5.68 (s, 1H), 4.22 (d, J¼16.6 Hz, 1H), 4.17 (s, 1H), 4.03 (d,
J¼12.1 Hz, 1H), 3.92 (d, J¼16.6 Hz, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 3.70
(s, 3H), 3.41 (d, J¼11.0 Hz, 1H), 3.37e3.32 (m, 2H), 3.03 (td, J¼11.7,
3.9 Hz, 1H), 2.61 (dd, J¼11.7, 5.1 Hz, 1H), 2.12 (dd, J¼13.0, 3.4, 1H),
1.65 (td, J¼13.0, 5.4 Hz, 1H); dC (100 MHz, CDCl3) 181.2, 158.3, 151.4,
151.2, 146.6, 129.5, 128.7, 124.4, 122.0, 116.7, 111.5, 71.8, 70.5, 67.9,
61.2, 60.8, 55.8, 55.3, 48.8, 45.2, 43.3, 39.6; MS (ESIþ) m/z (rel %) 400
([MþH]þ, 100); HRMS (ESIþ) 400.1746 [MþH]þ, C22H26NO6 requires
400.1755.
4.11. 13,13-Bis(hydroxymethyl)-3,4,10-trimethoxy-11-(benzy-
loxy)-7,8,12b,13-tetrahydro-5H-6-azatetraphene (32)
Lithium aluminium hydride (31.0 mg, 0.817 mmol) was added to
a solution of diester 31 (91.5 mg, 0.16 mmol) in dry THF (4 mL) at
0
ꢂC. The cooling was removed after 5 min, and the reaction mix-
ture allowed to stir for 6 h at rt before being quenched by successive
addition of ethyl acetate, H2O and Na2SO4. The mixture was stirred
for 30 min, filtered and evaporated to afford the title compound 32
as a brown oil which was used without further purification
(78.6 mg, 100%). Rf 0.38 (ethyl acetate); nmax (thin film)/cmꢁ1 3337,
2935, 2836, 1730, 1608, 1515, 1496, 1454, 1330, 1257, 1282, 1227,
1098, 1022, 995, 911, 805, 733; dH (400 MHz, CDCl3) 7.44 (d,
J¼7.0 Hz, 2H), 7.38e7.32 (m, 2H), 7.32e7.27 (m, 1H), 7.13 (d,
J¼8.7 Hz, 1H), 6.92 (s, 1H), 6.90 (d, J¼8.7 Hz, 1H), 6.68 (s, 1H), 5.24
(d, J¼13.1 Hz, 1H), 5.12 (d, J¼13.1 Hz, 1H), 4.17 (s, 1H), 4.13 (d,
J¼15.8 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.86 (s, 3H), 3.71 (d,
J¼12.2 Hz, 1H), 3.66 (d, J¼15.5 Hz, 1H), 3.32e3.20 (m, 2H), 3.18 (d,
J¼10.1 Hz, 1H), 3.16e3.10 (m, 1H), 3.04 (dd, J¼10.1, 1.7 Hz, 1H)
2.63e2.54 (m, 2H); dC (100 MHz, CDCl3) 150.5, 148.3, 145.7, 145.1,
137.7, 131.8, 131.2, 131.0, 128.6, 127.9, 127.3, 124.7, 120.8, 115.1, 112.0,
111.8, 71.0, 67.3, 64.6, 63.1, 60.2, 56.1, 55.9, 54.8, 51.0, 49.0, 30.5; MS
(ESIþ) m/z (rel %) 492 ([MþH]þ, 100); HRMS (ESIþ) 492.2367
[MþH]þ, C29H34NO6 requires 492.2381.
4.14. 18-Bromo-4-(hydroxymethyl)-8,9,17-trimethoxy-16-oxo-
2-oxa-12-azapentacyclo[10.6.2.01,14.04,13.05,10]icosa-5,7,9,14-
tetraen-17-yl acetate (34)
Phenol 22 (12.6 mg, 0.031 mmol) and AcONa (5.0 mg,
0.062 mmol) were dissolved in AcOH (1 mL) and cooled to 0 ꢂC.
Bromine (7.5 mg, 0.047 mmol) was added dropwise and the solu-
tion stirred for 45 min at the same temperature. After this time, the
reaction was quenched by addition of satd aq Na2S2O3 (5 mL), ba-
sified to pH 8 with NaHCO3, and the aqueous solution was extracted
with ethyl acetate (3ꢃ10 mL). The combined organic layers were
dried (MgSO4) and concentrated in vacuo, and the resulting crude
residue was purified by flash chromatography (SiO2, 1/5% MeOH/
CH2Cl2), affording the title compound 34 as a white solid (7.0 mg,
42%). Mp 90e92 ꢂC (CHCl3); Rf 0.44 (CH2Cl2/MeOH, 9:1); nmax (thin
film)/cmꢁ1 3514, 2940, 1745, 1700, 1492, 1370, 1273, 1240, 1073,
1025, 914, 790, 729; dH (400 MHz, CDCl3) 6.99 (d, J¼8.6 Hz,1H), 6.89
(d, J¼8.6 Hz, 1H), 6.27 (s, 1H), 5.17 (s, 1H), 4.17 (d, J¼16.2 Hz, 1H),
4.14 (s, 1H), 4.13 (d, J¼12.0 Hz, 1H), 3.91e3.85 (m, 1H), 3.87 (s, 3H),
3.81 (s, 3H), 3.60 (d, J¼12.4 Hz, 1H), 3.38 (d, J¼10.5 Hz, 1H), 3.38 (s,
3H), 3.31 (d, J¼10.5 Hz, 1H), 2.96 (td, J¼12.2, 3.6 Hz, 1H), 2.57e2.50
(m, 1H), 2.33 (dd, J¼13.6, 2.0 Hz,1H), 2.21 (s, 3H), 1.73e1.63 (m, 1H);
dC (100 MHz, CDCl3) 186.7, 169.8, 158.8, 151.4, 146.5, 129.2, 128.5,
122.1, 121.9, 111.5, 99.2, 72.0, 70.6, 67.9, 62.2, 60.8, 55.9, 55.8, 52.3,
49.1, 46.2, 43.1, 38.6, 21.3; MS (ESIþ) m/z (rel %) 478 ([MꢁOAc]þ, 90),
4.12. 13,13-Bis(hydroxymethyl)-11-hydroxy-3,4,10-
trimethoxy-7,8,12b,13-tetrahydro-5H-6-azatetraphene (22)
Diol 32 (73.6 mg, 0.150 mmol) was dissolved in ethyl acetate
(5 mL), Pd/C (15 mg, 10 wt. %) was added, and the reaction mixture
placed under an atmosphere of hydrogen. The reaction was stirred
for 20 h, before being filtered through a short plug of CeliteÔ and
evaporated. The crude residue was then re-suspended in EtOH
(5 mL), Pd/C (15 mg) was added, the reaction mixture placed under
an atmosphere of hydrogen and stirred for another 5 h before being
538 ([MþH]þ, 100) 560 ([MþNa]þ, 90); HRMS (ESIþ) 538.1073
79
[MþH]þ, C24
H BrNO8 requires 538.1071.
29
Please cite this article in press as: Ronson, T. O.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.009

T.O. Ronson et al. / Tetrahedron xxx (2016) 1e8
7
4.15. 8-Hydroxy-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinolin-1-one (37)16
7.36e7.26 (3H, m), 6.47 (1H, s), 5.16 (2H, s), 3.98 (3H, s), 3.83 (3H, s),
3.81 (2H, t, J¼6.2 Hz), 2.84 (2H, t, J¼6.2 Hz), 1.57 (9H, s); dC
(100 MHz, CDCl3) 161.2, 156.4, 154.3, 152.6, 142.4, 137.4, 137.0, 129.0,
128.1, 127.8, 117.7, 105.6, 82.6, 75.8, 61.0, 56.0, 44.1, 29.5, 28.0; HRMS
(ESIþ) 436.1728; C23H27NNaO6 (MNaþ) requires: 436.1731.
Diphenylphosphorylazide (8.96 mL, 0.0420 mol) was added
dropwise to a stirred solution of carboxylic acid 35 (10.0 g,
0.0420 mol) and triethylamine (5.80 mL, 0.0420 mol) in toluene
(125 mL) at rt. The reaction was then stirred at 90 ꢂC for 1.5 h. Most
of the solvent was removed in vacuo to afford a mobile oil. The flask
was cooled to 0 ꢂC under nitrogen atmosphere and BF3$OEt2
(20.8 mL, 0.169 mol) was added dropwise. The reaction mixture
was stirred for 20 h at rt before it was quenched with 1 M NaOH to
pH 10. Ethyl acetate (300 mL) was added and the rapidly stirred
mixture was heated for 1 h at 50 ꢂC solvating all the crude material.
The mixture was cooled to rt, the layers separated and the aqueous
fraction further extracted with ethyl acetate (2ꢃ300 mL). The
combined organic layers were washed with brine (300 mL), dried
over MgSO4 and the solvent removed in vacuo to give the crude
product. Column chromatography (SiO2, 1:1 petrol:ethyl aceta-
te/pure ethyl acetate) afforded the title compound 37 (7.34 g, 80%)
as a white solid; Rf 0.40 (ethyl acetate); dH (400 MHz, CDCl3) 12.37
(1H, s), 6.45 (1H, br s), 6.25 (1H, s), 3.88 (3H, s), 3.86 (3H, s), 3.52
(2H, dt, J¼6.7, 2.7 Hz), 2.90 (2H, t, J¼6.7 Hz); HRMS (ESIþ) 246.0736;
4.18. 8-(Benzyloxy)-6,7-dimethoxy-3,4-dihydroisoquinoline
(40)
Lactam 39 (102 mg, 0.247 mmol) was dissolved in THF (2.6 mL)
and cooled to ꢁ78 ꢂC. Super-HydrideÔ (0.371 mL, 0.371 mmol, 1 M
solution in THF) was added dropwise and stirring continued for
30 min at ꢁ78 ꢂC. The excess reducing agent was quenched at
ꢁ78 ꢂC by the sequential addition of methanol (0.213 mL), water
(0.107 mL), aq H2O2 solution 30% w/v (0.107 mL) and 6 M aq NaOH
(0.107 mL).18 Stirring was continued while the mixture warmed to
rt. The resulting mixture was then diluted with water (5 mL) and
extracted with ethyl acetate (3ꢃ15 mL). The combined organic
extracts were washed with satd aq NaHCO3 solution (10 mL), satd
aq Na2CO3 solution (10 mL) and brine (10 mL). The organic solution
was dried over MgSO4 and concentrated in vacuo. The crude ma-
terial was used directly in the next step without further purifica-
tion. A 1:1 mixture of CH2Cl2:TFA (2 mL), that had been pre-cooled
to 0 ꢂC, was added immediately to the crude product and the
resulting solution was left to stir for 1 h at rt. The majority of the
volatile organics were then removed in vacuo, before the crude
residue was dissolved in dichloromethane (20 mL), washed with
satd aq NaHCO3 (10 mL), dried over MgSO4 and concentrated in
vacuo. Purification by column chromatography (SiO2, 1:1 ethyl
acetate:petrol/2:1 ethyl acetate:petrol/pure ethyl acetate)
afforded the title compound 40 as colourless oil (37.1 mg, 50%); Rf
0.15 (9:1 ethyl acetate:MeOH); nmax (thin film)/cmꢁ1 2938, 1619,
1597,1570,1492,1454,1427,1379,1348,1311,1234,1123,1093,1191;
dH (400 MHz, CDCl3) 8.49 (1H, br s), 7.44e7.42 (2H, m), 7.39e7.30
(3H, m), 6.47 (1H, s), 5.13 (2H, s), 3.89 (3H, s), 3.87 (3H, s), 3.63 (2H,
t, J¼7.8 Hz), 2.60 (2H, t, J¼7.8 Hz); dC (100 MHz, CDCl3) 155.8, 155.4,
150.5, 140.4, 136.8, 133.3, 128.4, 128.4, 128.2, 115.8, 106.4, 76.1, 61.0,
56.0, 46.8, 25.3; HRMS (ESIþ) 298.1427; C18H20NO3 (MHþ) requires:
298.1438.
C
11H13NNaO4 (MNaþ) requires: 246.0737 (0.2 ppm error); Ele-
mental Analysis: calculated for C11H13NO4 requires C, 59.19; H, 5.87;
N, 6.27; found C, 59.20; H, 5.95; N, 6.17. The obtained data were in
accord with those reported in the literature.16
4.16. tert-Butyl-8-hydroxy-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline-2-carboxylate (38)
n-BuLi (11.0 mL, 27.6 mmol, 2.5 M in hexanes) was added in
a stirred solution of lactam 37 (2.05 g, 9.18 mL) in dry THF (110 mL)
at ꢁ78 ꢂC. After 10 min a solution of Boc2O (2.21 g, 10.1 mmol) in
THF (28 mL) was transferred via syringe at ꢁ78 ꢂC. The reaction
mixture was then allowed to warm to rt and left to stir for 20 h. The
reaction was quenched with satd aq NH4Cl (100 mL) at rt. The
aqueous layer was extracted with ethyl acetate (3ꢃ100 mL) and the
combined organic extracts dried over MgSO4 and filtered. The fil-
trate was concentrated in vacuo and purified by column chroma-
tography (SiO2, 4:1 petrol:ethyl acetate/pure ethyl acetate) to
afford the title compound 38 as colorless crystals (2.35 g, 80%); Rf
0.60 (1:1 petrol:ethyl acetate); mp 115e117 ꢂC; nmax (thin film)/
cmꢁ1 3007, 2977, 2941, 1711, 1643, 1575, 1450, 1420, 1368, 1291,
1254,1228; dH (400 MHz, CDCl3) 12.24 (1H, s), 6.23 (1H, s), 3.90 (2H,
t, J¼6.3 Hz), 3.88 (3H, s), 3.83 (3H, s), 2.90 (2H, t, J¼6.3 Hz), 1.55 (9H,
s); dC (100 MHz, CDCl3) 169.3, 157.5, 157.2, 152.0, 136.1, 135.2, 106.3,
101.6, 83.6, 60.6, 55.9, 44.6, 28.4, 27.9; HRMS (ESIþ) 346.1248;
4.19. 13,13-Dimethyl 12-(benzyloxy)-3,4,10,11-tetramethoxy-
5-oxo-7,8,12b,13-tetrahydro-5H-6-azatetraphene-13,13-
dicarboxylate (41)
Imine 40 (250 mg, 0.841 mmol) and carboxylic acid 6 (315 mg,
1.01 mmol) were dissolved in CHCl3 (25.2 mL), and N,N-diisopro-
pylethylamine (0.270 mL, 1.56 mmol) was added, followed by T3P
(50% in THF, 802 mg, 1.26 mmol). The resulting solution was stirred
at room temperature for 20 min before the addition of AlCl3
(224 mg, 1.68 mmol), and heating to 50 ꢂC for 2 h. After this time,
the mixture was diluted with ethyl acetate (300 mL), washed se-
quentially with sat aq NaHCO3 (150 mL) and 10% aq Rochelle’s salt
(150 mL), dried over MgSO4 and concentrated in vacuo. The crude
residue was purified by column chromatography (SiO2, 5:1/1:1
hexane:ethyl acetate), affording the title compound 41 as a colour-
less oil (255 mg, 51%); Rf 0.60 (ethyl acetate); mp 70e72 ꢂC; nmax
(thin film)/cmꢁ1 2949, 1740, 1654, 1602, 1580, 1453, 1487, 1424,
1308, 1272, 1236, 1124, 1068; dH (400 MHz, CDCl3) 7.26e7.22 (1H,
m), 7.18e7.11 (4H, m), 7.04 (2H, br s), 6.53 (1H, s), 5.09, (1H, s), 4.90
(1H, d, J¼11.0 Hz), 4.81 (1H, ddd, J¼13.3, 5.3, 2.5 Hz), 4.77 (1H, d,
J¼11.0 Hz), 4.03 (3H, s), 3.93 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.53
(3H, s), 3.48 (3H, s), 3.33 (1H, ddd, J¼13.3, 13.3, 4.1 Hz), 2.56e2.48
(2H, m); dC (100 MHz, CDCl3) 168.8, 166.7, 162.2, 153.2, 152.7, 150.3,
149.2, 139.6, 136.3, 136.1, 129.9, 129.5, 128.5, 128.1, 126.0, 123.3,
117.9, 114.5, 107.3, 75.7, 64.6, 61.5, 60.9, 56.2, 55.9, 55.7, 52.8, 52.6,
C
16H21NNaO6 (MNaþ) requires: 346.1261; Elemental Analysis: cal-
culated for C16H21NO6 requires C, 59.43; H, 6.55; N, 4.33; found C,
59.66; H, 6.46; N, 4.25.
4.17. tert-Butyl-8-(benzyloxy)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline-2-carboxylate (39)
Lactam 38 (115 mg, 0.355 mmol) and benzyl bromide (0.063 mL,
0.532 mmol) were dissolved in toluene (3 mL). K2CO3 (98.1 mg,
0.710 mmol) was added and the reaction mixture was stirred at
120 ꢂC for 20 h. The reaction was cooled to rt before it was
quenched with water (10 mL). The aqueous layer was extracted
with ethyl acetate (3ꢃ10 mL) and the combined organic extracts
dried over MgSO4 and filtered. The filtrate was concentrated in
vacuo and purified by column chromatography (SiO2, 4:1 petro-
l:ethyl acetate) to afford the title compound 39 as colourless oil
(118 mg, 80%); Rf 0.50 (1:1 petrol:ethyl acetate); nmax (thin film)/
cmꢁ1 2977, 2936, 1761, 1708, 1592, 1489, 1454, 1423, 1379, 1309,
1279, 1248, 1146, 1121; dH (400 MHz, CDCl3) 7.59e7.57 (2H, m),
Please cite this article in press as: Ronson, T. O.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.009

8
T.O. Ronson et al. / Tetrahedron xxx (2016) 1e8
39.1, 29.7; HRMS (ESIþ) 592.2183; C32H34NO10 (MHþ) requires:
592.2177.
M.; Jones, C. D. J. Am. Chem. Soc. 1970, 92, 4943; (e) Blouin, M.; Frennette, R. J.
Org. Chem. 2001, 66, 9043; (f) Chang, J.-K.; Chang, N.-C. Tetrahedron 2008, 64,
3483; (g) Chang, B. R.; Chen, C. Y.; Chang, N. C. Tetrahedron Lett. 2002, 43, 3233;
(h) Chung, C. Y.; Chang, B. R.; Tsai, M. R.; Chang, M. Y.; Chang, N. C. Tetrahedron
2003, 59, 9383.
5. For recent examples, see: (a) Unsworth, W. P.; Kitsiou, C.; Taylor, R. J. K. Org. Lett.
2013, 15, 3302; (b) Unsworth, W. P.; Cuthbertson, J. D.; Taylor, R. J. K. Org. Lett.
2013, 15, 3306; (c) Lloyd, M. G.; Taylor, R. J. K.; Unsworth, W. P. Org. Lett. 2014,
16, 2772; (d) Cuthbertson, J. D.; Unsworth, W. P.; Moody, C. L.; Taylor, R. J. K.
Tetrahedron Lett. 2015, 56, 3123; (e) Ronson, T. O.; Burns, M. J.; Voelkel, M. H. H.;
Evans, K.; Lynam, J. M.; Taylor, R. J. K.; Fairlamb, I. J. S. Chem.dEur. J. 2015, 21,
18905; (f) Lloyd, M. G.; D’Acunto, M.; Taylor, R. J. K.; Unsworth, W. P. Tetrahe-
dron 2015, 71, 7107; (g) Osler, J. D.; Unsworth, W. P.; Taylor, R. J. K. Synlett 2016,
70.
6. (a) Unsworth, W. P.; Kitsiou, C.; Taylor, R. J. K. Org. Lett. 2013, 15, 258; (b)
Unsworth, W. P.; Gallagher, K. A.; Jean, M.; Schmidt, J. P.; Diorazio, L. J.; Taylor,
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Coulthard, G.; Kitsiou, C.; Taylor, R. J. K. Tetrahedron 2014, 70, 7172; (e)
Coulthard, G.; Unsworth, W. P.; Taylor, R. J. K. Tetrahedron Lett. 2015, 56, 3113; (f)
Chambers, S. J.; Coulthard, G.; Unsworth, W. P.; O’Brien, P.; Taylor, R. J. K. Chem.
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org/10.1055/s-0035-1562095.
4.20. (6SR,11bRS)-Methyl 1,2,8,9-tetramethoxy-7,12-dioxo-
4,5,6,7,11b,12-hexahydrobenzo[g]chromeno[3,4,5-ija]quinoli-
zine-11b-carboxylate (43)
A 100-mL round bottom flask containing benzyl ether 41
(199 mg, 0.337 mmol) and methanol (3.4 mL) was purged with
argon. Palladium hydroxide (35 mg, 20 wt % on carbon) was then
added, and the reaction vessel was re-purged with argon, evacu-
ated and fitted with a hydrogen balloon. The reaction was stirred at
rt for 20 h, then evacuated, flushed with argon, filtered through
CeliteÔ and concentrated in vacuo. The crude product (phenol 42,
169 mg) was then dissolved in toluene (12 mL). p-Toluenesulfonic
acid monohydrate (16.9 mg, 0.0888 mmol) was added and the
resulting solution stirred at 120 ꢂC for 6 h, and then concentrated in
vacuo. Purification by column chromatography (SiO2, 1:1 ethyl
acetate:hexane/2:1 ethyl acetate:hexane) afforded the title com-
pound 43 as colourless oil (101 mg, 64%); Rf 0.50 (ethyl acetate);
nmax (thin film)/cmꢁ1 2939, 1784, 1745, 1661, 1483, 1462, 1308, 1224,
1164, 1075, 731; dH (400 MHz, CDCl3) 8.11 (1H, d, J¼8.8), 7.13 (1H, d,
J¼8.8), 6.61 (1H, s), 5.16 (1H, s), 4.13e405 (2H, m), 4.05 (3H, s), 3.93
(6H, s), 3.90 (3H, s), 3.50 (3H, s), 2.97e2.80 (2H, m); dC (100 MHz,
CDCl3) 166.0, 162.9, 161.9, 154.5, 153.4, 150.4, 142.2, 135.4, 129.5,
124.9, 124.4, 124.3, 114.8, 110.3, 107.6, 61.6, 61.6, 56.2, 56.0, 54.9,
53.5, 52.2, 38.6, 27.4; HRMS (ESIþ) 492.1279; C24H23NNaO9 (MNaþ)
requires: 492.1265.
7. For an alternative d-lactam synthesis, see Maio, W. A.; Sinishtaj, S.; Posner, G. H.
Org. Lett. 2007, 9, 2675.
8. (a) Hurtley, W. R. H. J. Chem. Soc. 1929, 1870; (b) Mayer, W.; Fikentscher, R.
Chem. Ber. 1958, 91, 1536; (c) McKillop, A.; Bruggink, A. Tetrahedron 1975, 31,
2607; (d) Malamas, M. S. J. Heterocycl. Chem. 1994, 31, 565; (e) Setsune, J.;
Matsukawa, K.; Wakemoto, H.; Kitao, T. Chem. Lett. 1981, 367; (f) Aalten, H. L.;
Koten, G.; Goubitz, K.; Stam, K. H. Organometallics 1989, 8, 2293.
9. The sequence was performed on ca. 70 mmol scale furnishing ca. 7 g of diester
6 on three separate occasions. It is noteworthy that the reaction was consis-
tently poorer when performed on smaller scale, with only trace amounts of
diester 6 formed when the same procedure was attempted on <3 mmol scale
under the same conditions.
10. Kabalka, G. W.; Laila, G. M. H.; Varma, R. S. Tetrahedron 1990, 46, 7443.
11. Reduction was attempted using LiAlH4, LiBH4, DIBAL-H, NaBH4/CeCl3 and
NaBH4/CoCl2, with various solvents and temperature combinations tested. All
led either to no reaction or gave complex product mixtures, based on analysis of
the 1H NMR data.
Acknowledgements
12. (a) Hookins, D. R.; Taylor, R. J. K. Tetrahedron Lett. 2010, 51, 6619; (b) Nicolaou,
K. C.; Valiulin, R. A.; Pokorski, J. K.; Chang, V.; Chen, J. S. Bioorg. Med. Chem. Lett.
2012, 22, 3776; (c) White, J. D.; Caravatti, G.; Kline, T. B.; Edstrom, E.; Rice, K. C.;
Brossi, A. Tetrahedron 1983, 39, 2393; (d) Schwartz, M. A.; Pham Phuong Thi, K.
J. Org. Chem. 1988, 53, 2318; (e) McKillop, A.; McLaren, L.; Taylor, R. J. K. J. Chem.
Soc., Perkin Trans. 1 1994, 2047.
The authors thank the University of York Wild Fund for a PhD
bursary (C.K.), the EPSRC (T. O. R., EP/J016128/1) for postdoctoral
support and Euticals for generous donations of the reagent T3P.
13. (a) Schrittwieser, J. H.; Resch, V.; Wallner, S.; Lienhart, W.-D.; Sattler, J. H.;
Resch, J.; Macheroux, P.; Kroutil, W. J. Org. Chem. 2011, 76, 6703; (b) Gawley, B.;
Gawley, R. E.; Smith, G. A. Arkivoc 2011, v, 167; (c) Kametani, T.; Ohkubo, K.
Chem. Pharm. Bull. 1967, 15, 608.
14. The structural assignment of compound 33 was made based on comparisons of
its spectral data with those of related para-quinol ether compounds, see Yang,
C.-S.; Liao, C.-C. Org. Lett. 2007, 9, 4809.
15. CCDC 1455257(34) and 1455250 (43) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
16. Judd, K. E.; Mahon, M. F.; Caggiano, L. Synthesis 2009, 2809.
17. Airiau, E.; Chemin, C.; Girard, N.; Lonzi, G.; Mann, A.; Petricci, E.; Salvadori, J.;
Taddei, M. Synthesis 2010, 2901.
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Please cite this article in press as: Ronson, T. O.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.009