Strategies for the construction of morphinan alkaloid AB-rings: Regioselective Friedel-Crafts-type cyclisations of γ-aryl-β-benzoylamido acids with asymmetrically substituted γ-aryl rings

Article abstract of DOI:10.1016/j.tetasy.2016.02.010

The regioselectivity of the Friedel-Crafts-type cyclisation of a range of γ-aryl-β-benzoylamido acids, bearing oxy substituents at the C(3)- and C(4)-positions of the γ-aryl ring, has been investigated. In all of the cases examined (with 3,4-dimethoxy, 3,4-methylenedioxy and 3-hydroxy-4-methoxy substituents) the Lewis acid promoted cyclisation proceeds with exclusive regioselectivity for attack at the C(6)-position rather than at the C(2)-position, and furnishes the corresponding N- and O-protected 3-amino-6,7-dihydroxy-1-tetralone derivatives. This inherent regioselectivity can be overturned by the regioselective introduction of chlorine as a blocking group for the C(6)-position; subsequent Lewis acid promoted cyclisation then proceeds with exclusive regioselectivity for attack at the C(2)-position to deliver the corresponding N- and O-protected 3-amino-5-chloro-7,8-dihydroxy-1-tetralone derivative. These complementary cyclisation protocols represent useful methods for the preparation of these benzo-fused carbocyclic ring systems, which are the functionalised AB-rings of a range of morphinan alkaloids.

Full text of DOI:10.1016/j.tetasy.2016.02.010

Tetrahedron: Asymmetry 27 (2016) 274–284
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Strategies for the construction of morphinan alkaloid AB-rings:
regioselective Friedel-Crafts-type cyclisations of c-aryl-
b-benzoylamido acids with asymmetrically substituted c-aryl rings
⇑
Stephen G. Davies , Euan C. Goddard, Paul M. Roberts, Angela J. Russell, Andrew D. Smith,
James E. Thomson, Jonathan M. Withey
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The regioselectivity of the Friedel-Crafts-type cyclisation of a range of c-aryl-b-benzoylamido acids, bear-
ing oxy substituents at the C(3)- and C(4)-positions of the c-aryl ring, has been investigated. In all of the
Received 8 February 2016
Accepted 18 February 2016
Available online 2 March 2016
cases examined (with 3,4-dimethoxy, 3,4-methylenedioxy and 3-hydroxy-4-methoxy substituents) the
Lewis acid promoted cyclisation proceeds with exclusive regioselectivity for attack at the C(6)-position
rather than at the C(2)-position, and furnishes the corresponding N- and O-protected 3-amino-6,7-dihy-
droxy-1-tetralone derivatives. This inherent regioselectivity can be overturned by the regioselective intro-
duction of chlorine as a blocking group for the C(6)-position; subsequent Lewis acid promoted cyclisation
then proceeds with exclusive regioselectivity for attack at the C(2)-position to deliver the corresponding
N- and O-protected 3-amino-5-chloro-7,8-dihydroxy-1-tetralone derivative. These complementary cycli-
sation protocols represent useful methods for the preparation of these benzo-fused carbocyclic ring sys-
tems, which are the functionalised AB-rings of a range of morphinan alkaloids.
Ó 2016 Published by Elsevier Ltd.
1. Introduction
B-ring and C-ring can be either cis- or trans-fused, and there is
significant structural variation within the C-ring (which generally
Morphinan 1 is the archetypal molecular framework of a num-
ber of alkaloids of significant importance, including opiates. It com-
prises a partially reduced phenanthrene core with only one of the
rings (denoted the A-ring) remaining aromatic; the other two rings
(denoted the B- and C-rings) are saturated. An additional six-mem-
bered ring (denoted the D-ring) is fused through carbon atoms 9
and 13, and contains an endocyclic nitrogen atom (at position
17). The structures of the morphinan alkaloids themselves are
somewhat diverse. The A-ring is usually substituted with two
vicinal oxy functionalities (which bear a variety of substituents)
either at the C(2)- and C(3)-position, e.g., 2,3-dimethoxy as in
O-methylpallidinine 2,1 sebiferine 52–5 and tannagine 8,6 2,3-
methylenedioxy as in meconoquintupline 3,7–9 amurine 610–14
and nudaurine 9,11,13 and 2-hydroxy-3-methoxy as in pallidinine
41 and pallidine 7,15 or at the C(3)- and C(4)-positions, e.g., 3-meth-
oxy-4-hydroxy as in sinoacutine 1016–18 (the regioisomer of
pallidine 7). In cases where the C(4)-position is oxy-substituted, a
formal etherification to link carbon atoms 4 and 5 and hence close
an additional ring (denoted the E-ring) gives further alkaloids, e.g.,
the opiates morphine 11,19,20 codeine 12,20 and thebaine 13.20 The
contains partial unsaturation) as shown by the structures of
O-methylpallidinine 2,1 sebiferine 52–5 and tannagine 8,6 or meco-
noquintupline 3,7–9 amurine 610–14 and nudaurine 911,13 (Fig. 1).
We have recently reported the Friedel-Crafts-type cyclisation of
a range of
x-aryl-b-benzoylamido acids (e.g., 14–18) for the
construction of 3-amino-substituted, benzo-fused carbocycles:
1-indanones, e.g., 19 (n = 0), 1-tetralones, e.g., 20 and 22–24
(n = 1), and 1-benzosuberones, e.g., 21 (n = 2).21,22 Mixtures of
regioisomeric products were observed in cases where the
x-aryl
ring was not symmetrically substituted: whilst cyclisation of 17
proceeded to give 1-tetralone 22 as the sole product [cyclisation
onto either C(2) or C(6) being equivalent] which was isolated in
73% yield, analogous reaction of 18 gave a 60:40 mixture of the
regioisomers 23 and 24 [resulting from cyclisation onto either C
(6) or C(2), respectively] which were separated and isolated in
58% and 34% yields, respectively21 (Scheme 1).
Described herein are the results of our studies concerning the
application of this methodology to the cyclisation of a range of
c
-aryl-b-benzoylamido acids 25 bearing two oxy substituents at
the C(3)- and C(4)-positions of the -aryl ring. The range of
-aryl-b-benzoylamido acids 25 was chosen such that the com-
monly occurring substitution patterns encountered within the
c
c
⇑
Corresponding author.
E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
http://dx.doi.org/10.1016/j.tetasy.2016.02.010
0957-4166/Ó 2016 Published by Elsevier Ltd.

S. G. Davies et al. / Tetrahedron: Asymmetry 27 (2016) 274–284
275
2
(i)
3
4
1
A
( )n
( )n
11
10
12
13
B
HO2C
15
14
16
NHBz
O
NHBz
D
9
14 (n = 0)
15 (n = 1)
16 (n = 2)
19 (n = 0), 71%
20 (n = 1), 87%
21 (n = 2), 71%
NH
5
C
H 17
6
8
7
morphinan 1
3
MeO
(i)
MeO
2
1
4
5
OMe
O
OH
O
6
MeO
MeO
MeO
HO2C
O
NHBz
22, 73%
NHBz
17
NMe
NMe
NMe
OMe
3
OMe
H
H
H
2
MeO
MeO
MeO
(i)
4
5
+
O
O
O
60:40
[23:24]
1
MeO
O-methylpallidinine 2
meconoquintupline 3
pallidinine 4
6
HO2C
OMe
OH
O
O
NHBz
O
NHBz
23, 58%
O
NHBz
MeO
18
24, 34%
Scheme 1. Reagents and conditions: (i) (COCl)2, DMF, CH2Cl2, rt, 30 min, then add
AlCl3, 0 °C, 16 h.
NMe
NMe
NMe
OR2
MeO
MeO
MeO
MeO
Regioselective
3
5
R1O
2
R1O
6
1
X
introduction
O
O
O
4
4
sebiferine 5
amurine 6
pallidine 7
of a blocking
group at C(6) R2O
5
1
3
OMe
O
6
2
HO2C
HO2C
O
MeO
HO
NHBz
NHBz
25
27
Friedel-Crafts-type
cyclisation onto C(6)
Friedel-Crafts-type
cyclisationonto C(2)
NMe
NMe
NMe
H
OR2
O
OMe
MeO
MeO
R1O
R1O
X
OMe
tannagine 8
OH
nudaurine 9
O
sinoacutine 10
R2O
HO
O
MeO
O
MeO
O
O
NHBz
O
NHBz
26
28
OR2
R1O
NMe
NMe
NMe
H
H
A
HO
MeO
MeO
R2O
B
morphine 11
codeine 12
thebaine 13
NMe
R
Figure 1. Structure and numbering convention of morphinan 1, and structures of
representative morphinan alkaloids 2–13.
morphinan alkaloids 29
morphinan alkaloids were represented: R1 = R2 = Me; R1 = R2 =
ACH2A; R1 = OMe, R2 = OH. It was anticipated that cyclisation of
these substrates would proceed preferentially onto the least steri-
cally congested C(6)-position, which would also be electronically
promoted by the C(3)-oxy substituent, to give the corresponding
1-tetralones 26. For the same reasons, the introduction of a block-
ing group (e.g., a halogen) was expected to proceed regioselectively
at C(6) to give the corresponding C(6)-substituted derivative 27;
subsequent cyclisation was then predicted to proceed preferen-
tially onto the unsubstituted C(2)-position, thus giving
1-tetralones 28. Both families of 1-tetralones 26 and 28, which
should be accessible via this strategy, represent useful 3-amino-
substituted benzo-fused carbocyclic templates comprising the
Figure 2. Proposed strategy for the synthesis of a range of 1-tetralones 26 and 28,
the AB-ring scaffolds of morphinan alkaloids 29.
2. Results and discussion
Our strategy for the synthesis of the range of c-aryl-b-benzoy-
lamido acid 25 was identical to that used for the preparation of
the mono-methoxy substituted analogues 17 and 18.21 The aldehy-
des with the requisite substitution patterns (R1 = R2 = Me;
R1 = R2 = ACH2A; R1 = OMe, R2 = OH) are all commercially avail-
able, viz. veratraldehyde, piperonal and isovanillin. However, to
ensure success in the case of isovanillin, it was decided to employ
an O-protecting group strategy from the outset: commercially
available O-benzylisovanillin was thus used as the starting
functionalised AB-ring scaffolds of
a number of morphinan
alkaloids 29 (Fig. 2).

276
S. G. Davies et al. / Tetrahedron: Asymmetry 27 (2016) 274–284
OMe
OMe
material. Veratraldehyde, piperonal and O-benzylisovanillin were
homologated23 by Wittig reaction with Ph3P@CHOMe followed
by hydrolysis of the resultant vinyl ethers 30, 40 and 50, to give
aldehydes 31, 41 and 51 in 91%, 80% and 57% overall yields, respec-
tively. Next, olefination of 31, 41 and 51 with Ph3P@CHCO2 Bu gave
mixtures of the corresponding, diastereoisomeric (E)- and (Z)-a,
b-unsaturated esters {32:33, 95:5 dr [(E):(Z) ratio]; 42:43, 88:12
dr [(E):(Z) ratio]; 52:53, >95:5 dr [(E):(Z) ratio]} from which 32,
42 and 52 were isolated in 78%, 49% and 71% yields, respectively.
In the case of 42, the yield was compromised by the isolation of
a mixed fraction in 47% yield {42:43, 78:22 dr [(E):(Z) ratio]}. How-
ever, application of the Masamune–Roush conditions24 to effect
olefination of 41 gave superior diastereoselectivity {42:43, 98:2
dr [(E):(Z) ratio]}, allowing 42 to be isolated in 92% yield after chro-
matography. With 32, 42 and 52 in hand, conjugate addition of
MeO
MeO
(i)
71:29 dr
[(E):(Z)]
t
30
71:29 dr
[(E):(Z)]
O
OMe
veratraldehyde
(ii)
OMe
MeO
OMe
MeO
(iii)
95:5 dr
32:33
CO2tBu
O
[( ):( )]
E
Z
lithium (R)-N-benzyl-N-(a-methylbenzyl)amide (>99% ee) fur-
32, 78%, >99:1 dr
31, 91% (from
veratraldehyde)
nished the corresponding b-amino esters 34, 44 and 54, which
were isolated in 93%, 72% and 47% yields, respectively, and in
>99:1 dr in all three cases. The relative (and absolute) configura-
tions within 34, 44 and 54 were assigned by reference to the tran-
sition state mnemonic that we have developed to reliably predict
the stereochemical outcome of this lithium amide in its conjugate
addition reactions.25 Palladium-mediated hydrogenolysis of 34 and
44 was followed by N-benzoylation of the resultant primary ami-
nes 35 and 45 to give 36 and 46 in 92% and 73% yields from 34
and 44, respectively. Meanwhile, hydrogenolysis of 54 cleaved
(iv)
OMe
OMe
MeO
MeO
(v)
tBuO2C
tBuO2C
35
NH2
N
Ph
34, 93%
>99:1 dr
Ph
2
(vi)
OMe
the O-benzyl, N-benzyl and N-a-methylbenzyl protecting groups
to give 55. It was envisaged that the primary amino functionality
within 55 could be selectively protected upon treatment with
1 equiv of PhCOCl, leaving the less reactive phenol functionality
free. However, reaction of 55 (unpurified) under these conditions
gave a 25:21:54 mixture of starting material 55, di-N,O-protected
56 and the corresponding mono-N-protected species, respectively.
When 2 equiv of PhCOCl was used, 56 was produced as the only
product, which was isolated in 71% yield (from 54). Cleavage of
the tert-butyl esters within 36 and 46 with neat TFA then gave
OMe
3
MeO
MeO
4
5
(vii)
1
6
tBuO2C
36, 92% (from 34)
HO2C
NHBz
NHBz
37
(viii)
OMe
c-aryl-b-benzoylamido acids 37 and 47, whilst treatment of 56
with NaOMe in MeOH cleaved the O-benzoyl protecting group,
and the tert-butyl ester was then cleaved with neat TFA to give
MeO
MeO
c-aryl-b-benzoylamido acid 57. Activation of c-aryl-b-benzoy-
lamido acids 37, 47 and 57 upon treatment with (COCl)2 was fol-
lowed by the addition of SnCl4 to the reaction flask, which
resulted in formation of 1-tetralones 38, 48 and 58 as a single
regioisomer in all three cases. Chromatographic purification gave
38, 48 and 58 in 72%, 77% and 69% isolated yields from 36, 46
and 56, respectively. The regiochemistries of 38, 48 and 58 were
easily established by the presence of two aryl hydrogen singlets
at dH ꢀ6.7 ppm and dH ꢀ7.5 ppm [corresponding to C(5)H and
C(8)H, respectively] in the 1H NMR spectra of the crude reaction
mixtures (and isolated products); no traces of the regioisomeric
1-tetralones 39, 49 and 59 were observed in the 1H NMR spectra
of the crude reaction mixtures. These results are consistent with
a mechanism whereby either (i) cyclisation of 37, 47 and 57 is pro-
moted directly onto the least sterically congested C(6)-position by
the action of the C(3)-oxy group, or (ii) cyclisation of 37, 47 and 57
is promoted onto the C(1)-position by the action of the C(4)-oxy
group to form a 5,6-spirocyclic intermediate,26 with subsequent
regioselective dienone-phenol-type rearrangement of the acyl
group to the least sterically congested C(6)-position giving the
same intermediate; in both cases rearomatisation by the loss of a
proton then results in the formation of 1-tetralones 38, 48 and
58 (Schemes 2–4).
MeO
O
NHBz
O
NHBz
38, 72% (from 36)
39, not observed
Scheme 2. Reagents and conditions: (i) [MeOCH2PPh3]+[Cl]ꢁ, KOtBu, THF, rt, 12 h;
(ii) HCO2H, CH2Cl2, rt, 48 h; (iii) Ph3P@CHCO2tBu, CH2Cl2, 0 °C to rt, 12 h;
(iv) lithium (R)-N-benzyl-N-(
a-methylbenzyl)amide, THF, ꢁ78 °C, 2 h; (v) Pd/C,
H2, MeOH, AcOH, H2O, rt, 12 h; (vi) PhCOCl, Et3N, CH2Cl2, rt, 16 h; (vii) TFA, rt, 1 h;
(viii) (COCl)2, CH2Cl2, DMF, rt, 30 min, then SnCl4, 0 °C to rt, 16 h.
the cyclisation to give the alternative, regioisomeric O-protected
3-benzoylamido-7,8-dihydroxy-1-tetralone derivatives. To this
end, the use of a blocking group was considered. In this approach,
a temporary substituent is introduced regioselectively onto the
more reactive position of an aromatic nucleus, such that an ensuing
reaction is directed to an alternative position. Bromine has been a
useful and suitably robust blocking group in related cyclisation
reactions.27 The production of
c-aryl-b-benzoylamido acid 61 was
therefore targeted. Treatment of 36 with Br2 in CHCl3 gave exclusive
C(6)-bromination, furnishing 60 in 97% isolated yield. Cleavage of
the tert-butyl ester then gave 61, which upon carbonyl activation
and treatment with SnCl4 gave tetralone 38 as the sole product,
i.e., the same product resulting from the reaction of 36 (without
introduction of the bromine blocking group) under the same
Having effected the regioselective cyclisation of the range of
c
-aryl-b-benzoylamido acids 37, 47 and 57 to give the correspond-
ing O-protected 3-benzoylamido-6,7-dihydroxy-1-tetralone
derivatives 38, 48 and 58, respectively, attention turned to effecting

S. G. Davies et al. / Tetrahedron: Asymmetry 27 (2016) 274–284
277
O
O
OBn
MeO
OBn
O
O
MeO
(i)
(i)
56:44 dr
65:35 dr
[(E):(Z)]
[( ):( )]
E
Z
40
50
O
O
56:44 dr
[(E):(Z)]
65:35 dr
OMe
OMe
piperonal
O
[(E):(Z)]
O-benzylisovanillin
(ii)
(ii)
OBn
O
MeO
OBn
O
O
MeO
(iii)
(iii)
>95:5 dr
98:2 dr
42:43
[(E):(Z)]
52:53
CO2tBu
t
[( ):( )]
E
Z
CO2 Bu
O
O
42, 92%, >99:1 dr
41, 80% (from
piperonal)
52, 71%, >99:1 dr
51, 57% (from
O-benzylisovanillin)
(iv)
(iv)
O
O
OBn
OH
O
O
MeO
MeO
(v)
(v)
tBuO2C
tBuO2C
55
tBuO2C
tBuO2C
NH2
NH2
N
Ph
N
Ph
44, 72%
>99:1 dr
45
54, 47%
>99:1 dr
Ph
2
Ph
(vi)
(vi)
OBz
O
O
O
OH
3
3
O
MeO
MeO
2
4
5
(vii)
4
5
(vii), (viii)
1
1
6
6
tBuO2C
56, 71% (from 54)
tBuO2C
HO2C
HO2C
NHBz
NHBz
NHBz
NHBz
47
46, 73% (from 44)
57
(viii)
(ix)
OH
O
O
MeO
MeO
O
O
HO
O
48, 77% (from 46)
NHBz
O
NHBz
O
NHBz
O
NHBz
49, not observed
58, 69% (from 56)
59, not observed
Scheme 4. Reagents and conditions: (i) [MeOCH2PPh3]+[Cl]ꢁ, KOtBu, THF, rt, 12 h;
(ii) HCO2H, CH2Cl2, rt, 48 h; (iii) Ph3P@CHCOt2Bu, CH2Cl2, 0 °C to rt, 12 h; (iv) lithium
Scheme 3. Reagents and conditions: (i) [MeOCH2PPh3]+[Cl]ꢁ, KOtBu, THF, rt, 12 h;
(ii) HCO2H, CH2Cl2, rt, 48 h; (iii) (EtO)2P(O)CH2CO2tBu, iPr2NEt, LiCl, MeCN, rt, 48 h;
(R)-N-benzyl-N-(
a-methylbenzyl)amide, THF, ꢁ78 °C, 2 h; (v) Pd/C, H2, MeOH,
(iv) lithium (R)-N-benzyl-N-(
H2, EtOAc, rt, 12 h; (vi) PhCOCl, Et3N, CH2Cl2, rt, 16 h; (vii) TFA, rt, 1 h; (viii) (COCl)2,
CH2Cl2, DMF, rt, 30 min, then SnCl4, 0 °C to rt, 16 h.
a-methylbenzyl)amide, THF, ꢁ78 °C, 2 h; (v) Pd(OH)2/C,
AcOH, H2O, rt, 16 h; (vi) PhCOCl, Et3N, CH2Cl2, rt, 16 h; (vii) NaOMe, MeOH, 5 °C, 1 h;
(viii) TFA, rt, 1 h; (ix) (COCl)2, CH2Cl2, DMF, rt, 30 min, then SnCl4, 0 °C to rt, 16 h.
reaction conditions; purification gave 38 in 77% isolated yield. The
same result was observed when 61 was heated at 90 °C for 5 h in
polyphosphoric acid: tetralone 38 was the sole product and was
isolated in 68% yield (Scheme 5).
be carefully controlled. In contrast, sulfuryl chloride (SO2Cl2) is a rel-
atively weak electrophile29 and monochlorinates activated arenes
in reactions which are generally high yielding when other function-
alities that are present are compatible with this reagent.30 Following
this precedent, treatment of 36 in CH2Cl2 with 1.0 equiv of SO2Cl2
gave C(6)-chlorinated adduct 63. The use of stoichiometric SO2Cl2
was important, since any slight excess of reagent resulted in poly-
chlorination. Ensuing tert-butyl ester cleavage of 63 in neat TFA fur-
nished 64. Attempts to cyclise 64 by sequential treatment with
(COCl)2 and SnCl4, or by heating in polyphosphoric acid, gave no
reaction, with only starting material being isolated. However, this
was not considered a negative result, since both sets of conditions
had previously led to the cyclisation of 61 to give the unwanted
regioisomer 38. Given these positive implications regarding the
efficacy of the new blocking group, attempting the reaction using
It is apparent that the subtle interplay between steric and elec-
tronic effects coupled with blocking group identity is insufficient,
in this case, to overturn the inherent regioselectivity and effect
direction of the cyclisation reaction onto the C(2)-position; thus,
addition occurs onto the C(6)-position to which the bromine is
attached. Although bromine is often the blocking group of choice,
chlorine has also been applied as a blocking group.28 Its use has,
however, been hampered by the difficulties associated with
handling and dispensing of stoichiometric quantities of the gas:
chlorine is a strong electrophile and reacts rapidly and often unse-
lectively with aromatic compounds, unless the stoichiometry can

278
S. G. Davies et al. / Tetrahedron: Asymmetry 27 (2016) 274–284
MeO
MeO
MeO
MeO
Br
derivative, in which cyclisation has been directed exclusively onto
the C(2)-position of the -aryl ring. These complementary cyclisa-
tion protocols represent useful methods for the preparation of the
c
(i)
corresponding, functionalised 1-tetralones, which represent the
tBuO2C
tBuO2C
NHBz
NHBz
functionalised AB-ring systems of
alkaloids.
a number of morphinan
36
60, 97%
(ii)
OMe
4. Experimental section
MeO
MeO
MeO
Br
(iii)
4.1. General experimental details
All reactions involving organometallic or other moisture-
sensitive reagents were carried out under a nitrogen or argon
atmosphere using standard vacuum line techniques and glassware
that was flame dried and cooled under nitrogen before use. Sol-
vents were dried according to the procedure outlined by Grubbs
and co-workers.31 Water was purified by an ElixÒ UV-10 system.
Organic layers were dried over MgSO4. Thin layer chromatography
was performed on aluminium plates coated with 60 F254 silica.
Plates were visualised using UV light (254 nm), iodine, 1% aq
KMnO4, or 10% ethanolic phosphomolybdic acid. Flash column
chromatography was performed on Kieselgel 60 silica or on an
automated flash column chromatography platform.
HO2C
O
NHBz
NHBz
38, 77% (from 60)
61
MeO
Br
MeO
O
NHBz
62, not observed
Scheme 5. Reagents and conditions: (i) Br2, CHCl3, rt, 30 min; (ii) TFA, rt, 1 h; (iii)
(COCl)2, CH2Cl2, DMF, rt, 30 min, then SnCl4, 0 °C to rt, 16 h.
Melting points are uncorrected. Specific rotations are reported
in 10ꢁ1 deg cm2 gꢁ1 and concentrations in g/100 mL. IR spectra
were recorded as a thin film on NaCl plates (film), or as a KBr disc
AlCl3 as the Lewis acid catalyst furnished 65 as the sole product, in
which the regioselective cyclisation onto the C(2)-position had been
accompanied by a selective O-demethylation; chromatographic
purification enabled the isolation of 65 in 86% yield (from 63).
The exact order of events leading to 65 is likely ring-closure and
re-aromatisation followed by Lewis acid assisted dealkylation of
the vinylogous ester (Scheme 6).
(KBr), as stated. Selected characteristic peaks are reported in cmꢁ1
.
NMR spectra were recorded in the deuterated solvent stated. The
field was locked by external referencing to the relevant deuteron
resonance. 1H–1H COSY and 1H–13C HMQC analyses were used to
establish atom connectivity.
4.2. Experimental procedures and characterisation data
MeO
MeO
MeO
MeO
Cl
4.2.1. 3,4-Dimethoxyphenylacetaldehyde 31
Step 1: KOtBu (11.8 g, 0.10 mol) was added portionwise to a stir-
red suspension of [MeOCH2PPh3]+[Cl]ꢁ (37.7 g, 0.11 mol) in THF
(100 mL) at 0 °C. The resultant mixture was stirred for 30 min at
rt and then a solution of veratraldehyde (16.6 g, 0.10 mol) in THF
(100 mL) was added dropwise. The resultant mixture was stirred
at rt for 12 h and then quenched by the addition of satd aq NH4Cl
(100 mL). The aqueous layer was extracted with Et2O (3 ꢂ 150 mL)
and the combined organics were washed with brine (2 ꢂ 200 mL),
then dried and concentrated in vacuo. Pentane (100 mL) was added
to the residue and the resultant suspension was stirred at rt for
30 min. The resultant solution was filtered and the filtrate was
concentrated in vacuo. This trituration process was repeated three
times to give 30 {71:29 dr, [(E):(Z) ratio]} as a pale yellow oil
(19.3 g).
(i)
tBuO2C
tBuO2C
NHBz
NHBz
36
63, 97%
(ii)
MeO
HO
Cl
MeO
MeO
Cl
(iii)
HO2C
O
NHBz
NHBz
65, 86% from 63
64
Scheme 6. Reagents and conditions: (i) SO2Cl2 (1.0 equiv), CH2Cl2, rt, 1 h; (ii) TFA,
rt, 1 h; (iii) (COCl)2, CH2Cl2, DMF, rt, 30 min, then AlCl3, 0 °C to rt, 16 h.
Step 2: Formic acid (50 mL) was added to a stirred solution of
the residue of 30 (19.3 g) in CH2Cl2 (200 mL) at rt. The resultant
solution was stirred in the dark for 48 h. H2O (100 mL) was added
and the aqueous layer was extracted with CH2Cl2 (3 ꢂ 100 mL). The
combined organics were washed with brine (2 ꢂ 500 mL), then
dried and concentrated in vacuo. Purification by vacuum distilla-
tion gave 31 as a colourless oil (16.4 g, 91% from veratraldehyde);
bp 126–130 °C (0.6 mmHg); dH (400 MHz, CDCl3) 3.61 (2H, d, J 2.5,
CH2CHO), 3.85 (6H, app s, OMe), 6.68–6.77 (2H, m, C(2)H, C(6)H),
6.85 (1H, d, J 8.1, C(3)H), 9.70 (1H, t, J 2.5, CH2CHO).
3. Conclusion
In conclusion, a range of c-aryl-b-benzoylamido acids, bearing
oxy substituents at the C(3)- and C(4)-positions of the aromatic
ring, has been prepared; this range incorporates differential
O-protection. In all cases investigated, the cyclisation proceeds
with exclusive regioselectivity for attack at the C(6)-position rather
than C(2)-position of the c-aryl ring, regardless of the nature of the
4.2.2. tert-Butyl (E)-4-(30,40-dimethoxyphenyl)but-2-enoate 32
A solution of 31 (5.41 g, 30.0 mmol) in CH2Cl2 (50 mL) was
added dropwise to a stirred solution of Ph3P@CHCO2 Bu (13.6 g,
O-protecting groups, and furnishes the corresponding N- and
O-protected 3-amino-6,7-dihydroxy-1-tetralone derivatives. This
inherent regioselectivity may be overturned by the use of chlorine
t
36.0 mmol) in CH2Cl2 (200 mL) at 0 °C. The resultant solution
was stirred at rt for 12 h and then concentrated in vacuo. The resi-
due was suspended in a mixture of Et2O (50 mL) and pentane
as a blocking group for the C(6)-position of the
-aryl-b-benzoylamido acid. Cyclisation of this species delivers an
N- and O-protected 3-amino-5-chloro-7,8-dihydroxy-1-tetralone
c-aryl ring within a
c

S. G. Davies et al. / Tetrahedron: Asymmetry 27 (2016) 274–284
279
(50 mL), and the resultant suspension was stirred at rt for 30 min.
The resultant solution was filtered and the filtrate was concen-
trated in vacuo. This trituration process was repeated three times
to give a 95:5 mixture of 32 and 33, respectively. Purification via
flash column chromatography (eluent 5?10?20% Et2O in pen-
tane) gave 33 as a colourless oil {309 mg, 4%, >99:1 dr [(Z):(E)
ratio]}; mmax (film) 2977, 2935, 2835, 1712, 1638, 1606, 1591,
1515, 1465, 1262, 1236, 1152, 1030, 825; dH (400 MHz, CDCl3)
1.52 (9H, s, CMe3), 3.87 (3H, s, OMe), 3.88 (3H, s, OMe), 3.93 (2H,
dd, J 7.6, 1.6, C(4)H2), 5.76 (1H, dt, J 11.5, 1.6, C(2)H), 6.25 (1H,
dt, J 11.5, 7.6, C(3)H), 6.76–6.82 (3H, m, Ar); dC (100 MHz, CDCl3)
28.2 (CMe3), 34.5 (C(4)), 55.8, 55.9 (OMe), 80.4 (CMe3), 111.3,
111.9 (C(20), C(50)), 120.4 (C(60)), 121.5 (C(2)), 132.3 (C(10)), 146.6
(C(3)), 147.5, 149.0 (C(30), C(40)), 165.9 (C(1)); m/z (CI+) 296
([M+NH4]+, 5%), 240 (100%), 222 (30%); HRMS (CI+) C16H26NO+4
([M+NH4]+) requires 296.1856; found 296.1876. Further elution
gave 32 as a pale yellow solid {6.48 g, 78%, >99:1 dr, [(E):(Z) ratio]};
(eluent MeOH) and the filtrate was concentrated in vacuo to give
35 as a pale yellow oil. Purification of an aliquot via flash column
chromatography (eluent Et2O) gave an analytically pure sample
of 35 as a colourless oil; [a]
25 = +1.1 (c 0.75 in CHCl3); mmax (film)
D
3377, 2976, 2934, 2835, 1723, 1607, 1590, 1516, 1465, 1367,
1262, 1238, 1149, 1030; dH (400 MHz, CDCl3) 1.47 (9H, s, CMe3),
1.59 (2H, br s, NH2), 2.25 (1H, dd, J 15.9, 8.7, C(2)HA), 2.42 (1H,
dd, J 15.9, 4.2, C(2)HB), 2.53 (1H, dd, J 13.5, 8.3, C(4)HA), 2.72 (1H,
dd, J 13.5, 5.5, C(4)HB), 3.42 (1H, m, C(3)H), 3.86 (3H, s, OMe),
3.88 (3H, s, OMe), 6.74–6.77 (2H, m, Ar), 6.82 (1H, d, J 7.9, Ar); dC
(100 MHz, CDCl3) 28.1 (CMe3), 43.1, 43.3 (C(2), C(4)), 49.7 (C(3)),
55.8, 55.9 (OMe), 80.6 (CMe3), 111.3, 112.4, 121.3 (C(20), C(50),
C(60)), 131.2 (C(10)), 147.6, 148.9 (C(30), C(40)), 171.8 (C(1)); m/z
(ESI+) 318 ([M+Na]+, 10%), 296 (80%), 240 (100%); HRMS (ESI+)
C
16H25NNaO+4 ([M+Na]+) requires 318.1676; found 318.1679.
Step 2: Et3N (0.53 mL, 3.83 mmol) and benzoyl chloride
(0.18 mL, 1.56 mmol) were added sequentially to a stirred solution
of the residue of 35 (454 mg, 1.53 mmol) in CH2Cl2 (40 mL) at 0 °C.
The resultant solution was stirred at 0 °C for 10 min, then allowed
to warm to rt and stirred for an additional 16 h. 10% aq HCl (40 mL)
was added and the aqueous layer was extracted with CH2Cl2
(3 ꢂ 40 mL). The combined organics were dried and concentrated
in vacuo. Purification via recrystallisation (25% Et2O in pentane)
gave 36 as a white solid (562 mg, 92% from 34); mp 68–70 °C;
mp 58–60 °C; mmax (KBr) 3063, 3004, 2973, 2935, 2834, 1705, 1651,
1592, 1516, 1467, 1263, 1149, 1028, 911, 733; dH (400 MHz, CDCl3)
1.46 (9H, s, CMe3), 3.42 (2H, dd, J 6.8, 1.5, C(4)H2), 3.86 (3H, s, OMe),
3.88 (3H, s, OMe), 5.71 (1H, dt, J 15.5, 1.5, C(2)H), 6.67 (1H, d, J 1.7, C
(20)H), 6.71 (1H, dd, J 8.1, 1.7, C(60)H), 6.81 (1H, d, J 8.1, C(50)H), 6.97
(1H, dt, J 15.5, 6.8, C(3)H); dC (100 MHz, CDCl3) 28.1 (CMe3), 37.9
(C(4)), 55.8, 55.9 (OMe), 80.2 (CMe3), 111.4, 112.0 (C(20), C(50)),
120.8 (C(60)), 123.8 (C(2)), 130.4 (C(10)), 146.3, 147.8, 149.0 (C(3),
C(30), C(40)), 165.8 (C(1)); m/z (CI+) 296 ([M+NH4]+, 10%), 278
(20%), 240 (100%), 222 (20%); HRMS (CI+) C16H26NO+4 ([M+NH4]+)
requires 296.1856; found 296.1860.
[a]
25 = +30.3 (c 1.6 in CHCl3); mmax (KBr) 3349, 3061, 2977, 2933,
D
2838, 1724, 1639, 1603, 1589, 1580, 1518, 1446, 1366, 1290,
1262, 1237, 1152, 1027; dH (400 MHz, CDCl3) 1.48 (9H, s, CMe3),
2.46 (1H, dd, J 15.8, 5.2, C(2)HA), 2.52 (1H, dd, J 15.8, 5.1, C(2)HB),
2.83 (1H, dd, J 13.6, 8.6, C(4)HA), 3.04 (1H, dd, J 13.6, 5.7, C(4)HB),
3.84 (3H, s, OMe), 3.87 (3H, s, OMe), 4.61 (1H, m, C(3)H), 6.76–
6.82 (3H, m, Ar), 7.12 (1H, d, J 8.6, NH), 7.27–7.52 (3H, m, Ph),
7.75–7.78 (2H, m, Ph); dC (100 MHz, CDCl3) 28.1 (CMe3), 37.7
(C(2)), 39.4 (C(4)), 48.0 (C(3)), 55.8, 55.9 (OMe), 81.4 (CMe3),
111.2, 112.3, 121.4 (C(20), C(50), C(60)), 126.8, 128.6, 130.2
(o,m,p-Ph), 131.5 (C(10)), 134.5 (i-Ph), 147.7, 148.9 (C(30), C(40)),
166.5 (NCOPh), 171.6 (C(1)); m/z (ESI+) 422 ([M+Na]+, 25%), 400
(30%), 344 (100%); HRMS (ESI+) C23H30NO5+ ([M+H]+) requires
400.2118; found 400.2128.
4.2.3. tert-Butyl (R,R)-3-[N-benzyl-N-(
4-(30,40-dimethoxyphenyl)butanoate 34
BuLi (2.5 M in hexanes, 2.16 mL, 5.40 mmol) was added drop-
wise via syringe to a stirred solution of (R)-N-benzyl-N-( -methyl-
a-methylbenzyl)amino]-
a
benzyl)amine (1.14 g, 5.40 mmol, >99% ee) in THF (20 mL) at
ꢁ78 °C. The resultant pink solution was stirred for 30 min at
ꢁ78 °C. A solution of 32 {500 mg, 1.80 mmol, >99:1 dr [(E):(Z)
ratio]} in THF (5 mL) at ꢁ78 °C was then added dropwise via can-
nula. The resultant solution was stirred at ꢁ78 °C for 2 h then
quenched with satd aq NH4Cl (20 mL). The resultant mixture was
diluted with Et2O (20 mL). The aqueous layer was extracted with
Et2O (3 ꢂ 50 mL). The combined organics were dried and concen-
trated in vacuo. Purification via flash column chromatography (elu-
ent 5?10% Et2O in pentane) gave 34 as a colourless oil (855 mg,
4.2.5. (R)-3-Benzamido-6,7-dimethoxy-1-tetralone 38
Step 1: TFA (3 mL) was added dropwise to 36 (300 mg,
0.75 mmol) at rt, and the resultant solution was stirred at rt for
1 h. Volatiles were then removed in vacuo to give 37 as a white
93%, >99:1 dr); [
3062, 3027, 2975, 2934, 2835, 1723, 1454, 1262, 1145, 1030,
a
]
25 = ꢁ14.0 (c 1.0 in CHCl3); mmax (film) 3084,
solid (254 mg, quant); mp 162–164 °C; [a]
25 = +39.6 (c 1.0 in
D
D
DMSO); mmax (KBr) 3687–2481, 3302, 2938, 2837, 1695, 1643,
1519, 1490, 1465, 1443, 1419, 1263, 1157, 1027, 807, 695; dH
(400 MHz, d6-DMSO) 2.46 (1H, dd, J 15.4, 7.6, C(2)HA), 2.53 (1H,
dd, J 15.4, 6.2, C(2)HB), 2.72–2.85 (2H, m, C(4)H2), 3.63 (3H, s,
OMe), 3.66 (3H, s, OMe), 4.46 (1H, m, C(3)H), 6.73 (1H, dd, J 8.1,
1.8, Ar), 6.81 (1H, d, J 1.8, Ar), 6.84 (1H, d, J 8.1, Ar), 7.42–7.55
(3H, m, Ph), 7.77–7.79 (2H, m, Ph), 8.32 (1H, d, J 8.2, NH); dC
(100 MHz, d6-DMSO) 39.7 (C(2)), 40.6 (C(4)), 49.1 (C(3)), 56.0,
56.2 (OMe), 112.5, 113.8, 122.0 (C(20), C(50), C(60)), 128.0, 129.0,
131.9, 132.0 (o,m,p-Ph, C(10)), 135.5 (i-Ph), 148.1, 149.2 (C(30), C
(40)), 166.5 (NCOPh), 173.4 (C(1)); m/z (ESI+) 366 ([M+Na]+, 20%),
344 (100%); HRMS (ESI+) C19H22NO+5 ([M+H]+) requires 344.1492;
found 344.1504.
Step 2: Oxalyl chloride (0.10 mL, 1.10 mmol) was added drop-
wise to a stirred solution of the residue of 37 (170 mg, 0.50 mmol)
in CH2Cl2 (10 mL) at rt, followed by one drop of DMF. Stirring was
continued at rt until all the solids dissolved and the evolution of
gas ceased (ꢃ30 min). The resultant solution was then cooled to
0 °C and SnCl4 (0.20 mL, 1.75 mmol) was added dropwise. The
resultant solution was allowed to warm to rt and stirred at rt for
16 h. H2O (5 mL) was then added and the resultant mixture was
stirred vigorously for 10 min. The aqueous layer was extracted
912, 733; dH (400 MHz, CDCl3) 1.17 (3H, d, J 8.0, C(a)Me), 1.43
(9H, s, CMe3), 2.06 (2H, app d, J 6.5, C(2)H2), 2.61 (1H, dd, J 13.7,
5.7, C(4)HA), 2.72 (1H, dd, J 13.7, 8.2, C(4)HB), 3.63 (1H, d, J 15.2,
NCHAHBPh), 3.95 (1H, d, J 15.2, NCHAHBPh), 3.68 (1H, m, C(3)H),
3.84 (3H, s, OMe), 3.91 (3H, s, OMe), 3.88 (1H, q, J 8.0, C(
6.65 (1H, d, J 1.5, Ar), 6.73 (1H, dd, J 8.2, 1.5, Ar), 6.82 (1H, d, J
8.2, Ar), 7.22–7.46 (10H, m, Ph); dC (100 MHz, CDCl3) 20.0 (C(
Me), 28.1 (CMe3), 37.5 (C(2)), 39.4 (C(4)), 50.0 (NCH2Ph), 55.7,
55.9 (OMe), 56.7 (C(3)), 58.3 (C( )), 80.1 (CMe3), 110.9, 112.7,
a)H),
a
)
a
121.5 (C(20), C(50), C(60)), 126.6, 126.8, 127.8, 128.0, 128.2 (o,m,p-
Ph), 133.0 (C(10)), 141.5, 143.1 (i-Ph), 147.2, 148.4 (C(30), C(40)),
171.9 (C(1)); m/z (ESI+) 512 ([M+Na]+, 10%), 490 (100%); HRMS
(ESI+) C31H39NNaO4+ ([M+Na]+) requires 512.2771; found 512.2778.
4.2.4. tert-Butyl (R)-3-benzamido-4-(30,40-dimethoxyphenyl)-
butanoate 36
Step 1: Pd/C (165 mg, 20% w/w substrate) was added to a stirred,
degassed solution of 34 (825 mg, 1.69 mmol) in MeOH (20 mL),
AcOH (2 mL) and H2O (0.5 mL). The reaction vessel was charged
with H2 (1 atm) and the resultant suspension was stirred rapidly
for 12 h. The suspension was filtered through a pad of CeliteÒ

280
S. G. Davies et al. / Tetrahedron: Asymmetry 27 (2016) 274–284
with CH2Cl2 (3 ꢂ 15 mL) and the combined organics were dried
and concentrated in vacuo. Purification via flash column
chromatography (eluent 10?20?40% EtOAc in pentane) gave 38
as a pale yellow crystalline solid (117 mg, 72% from 36); mp
4.2.8. tert-Butyl (R,R)-3-[N-benzyl-N-(a-methylbenyl)amino]-4-
(30,40-methylenedioxyphenyl)butanoate 44
BuLi (2.5 M in hexanes, 1.65 mL, 2.65 mmol) was added drop-
wise via syringe to a stirred solution of (R)-N-benzyl-N-(a-methyl-
124–126 °C; [
a]
25 = ꢁ20.0 (c 0.45 in CHCl3); mmax (KBr) 3308,
benzyl)amine (577 mg, 2.73 mmol, >99% ee) in THF (20 mL) at
ꢁ78 °C. The resultant pink solution was stirred for 30 min at
ꢁ78 °C. A solution of 42 {448 mg, 1.71 mmol, >99:1 dr [(E):(Z)
ratio]} in THF (5 mL) at ꢁ78 °C was then added dropwise via can-
nula. The resultant solution was stirred at ꢁ78 °C for 2 h then
quenched with satd aq NH4Cl (20 mL). The resultant mixture was
diluted with Et2O (20 mL). The aqueous layer was extracted with
Et2O (3 ꢂ 50 mL). The combined organics were dried and concen-
trated in vacuo. Purification via flash column chromatography
(eluent 5% Et2O in pentane) gave 44 as a colourless oil (582 mg,
D
3062, 2944, 2841, 1667, 1636, 1602, 1580, 1537, 1513, 1368,
1277, 1217, 1050, 693; dH (400 MHz, CDCl3) 2.77 (1H, dd, J 16.8,
8.4, C(2)HA), 2.99 (1H, dd, J 16.8, 4.1, C(2)HB), 3.04 (1H, dd, J 15.0,
7.6, C(4)HA), 3.37 (1H, dd, J 15.0, 4.0, C(4)HB), 3.93 (3H, s, OMe),
3.96 (3H, s, OMe), 4.83 (1H, m, C(3)H), 6.35 (1H, d, J 7.5, NH),
6.71 (1H, s, C(5)H), 7.40–7.52 (3H, m, Ph), overlapping 7.52 (1H,
s, C(8)H), 7.70–7.72 (2H, m, Ph); dC (100 MHz, CDCl3) 35.3 (C(4)),
43.8 (C(3)), 46.2 (C(2)), 55.9, 56.0 (OMe), 108.3 (C(8)), 110.9
(C(5)), 125.2 (C(8a)), 126.8, 128.5, 131.6 (o,m,p-Ph), 134.0 (i-Ph),
135.4 (C(4a)), 148.4, 154.2 (C(6), C(7)), 167.0 (NCOPh), 194.3
(C(1)); m/z (ESI+) 348 ([M+Na]+, 70%), 326 (100%); HRMS (ESI+)
C19H20NO+4 ([M+H]+) requires 326.1387; found 326.1397.
72%, >99:1 dr); [
(400 MHz, CDCl3) 1.17 (3H, d, J 7.0, C(a)Me), 1.42 (9H, s, CMe3),
a
]
20 = ꢁ7.7 (c 0.9 in CHCl3); mmax (film) 1724; dH
D
1.99 (1H, dd, J 14.3, 4.4, C(2)HA), 2.04 (1H, dd, J 14.3, 7.1, C(2)HB),
2.55 (1H, dd, J 13.6, 6.0, C(4)HA), 2.69 (1H, dd, J 13.6, 8.0, C(4)HB),
3.62 (1H, d, J 15.0, NCHAHBPh), 3.85 (1H, q, J 7.0, C(a)H), 3.90
4.2.6. 3,4-Methylenedioxyphenylacetaldehyde 41
Step 1: KOtBu (6.48 g, 66.6 mmol) was added portionwise to a
stirred suspension of [MeOCH2PPh3]+[Cl]ꢁ (12.6 g, 36.6 mmol) in
THF (50 mL) at 0 °C. The resultant mixture was stirred for 30 min
at rt and then a solution of piperonal (5.00 g, 33.3 mmol) in THF
(50 mL) was added dropwise. The resultant mixture was stirred
at rt for 12 h and then quenched by the addition of satd aq
NH4Cl (50 mL). The aqueous layer was extracted with Et2O
(3 ꢂ 75 mL) and the combined organics were washed with brine
(2 ꢂ 100 mL), then dried and concentrated in vacuo. Pentane
(50 mL) was added to the residue and the resultant suspension
was stirred at rt for 30 min. The resultant solution was filtered
and the filtrate was concentrated in vacuo. This trituration process
was repeated three times to give 40 {65:35 dr [(E):(Z) ratio]} as a
pale yellow oil (5.93 g).
(1H, d, J 15.0, NCHAHBPh), 4.32 (1H, app dd, J 10.4, 4.7, C(3)H),
5.96 (2H, s, OCH2O), 6.61 (1H, dd, J 7.8, 1.5, C(60)H), 6.64 (1H, d, J
1.5, C(20)H), 6.75 (1H, d, J 7.8, C(50)H), 7.24–7.44 (10H, m, Ph); dC
(100 MHz, CDCl3) 19.8 (C(a)Me), 28.1 (CMe3), 37.6 (C(2)), 39.4
(C(4)), 50.0 (NCH2Ph), 53.1 (C(
a
)), 59.6 (C(3)), 80.2 (CMe3), 100.9
(OCH2O), 108.8 (C(50)), 109.1 (C(20)), 121.9 (C(60)), 126.4, 126.8,
128.0, 128.3 (o,m,p-Ph), 134.1 (C(10)), 137.1, 145.4, 145.9, 147.4
(C(30), C(40), i-Ph), 171.4 (C(1)); m/z (ESI+) 474 ([M+H]+, 100%);
HRMS (ESI+) C30H36NO+4 ([M+H]+) requires 476.2639; found
476.2639.
4.2.9. tert-Butyl (R)-3-benzamido-4-(30,40-methylenedioxy-
phenyl)butanoate 46
Step 1: Pd(OH)2/C (1.85 g, 50% w/w substrate) was added to a
stirred, degassed solution of 44 (3.70 g, 7.81 mmol) in EtOAc
(100 mL). The reaction vessel was charged with H2 (1 atm) and
the resultant suspension was stirred rapidly for 12 h. The suspen-
sion was filtered through a pad of CeliteÒ (eluent EtOAc) and the
filtrate was concentrated in vacuo to give 45 as a pale yellow oil
(1.77 g). Purification of an aliquot via flash column chromatogra-
phy (eluent Et2O) gave an analytically pure sample of 45 as a pale
Step 2: Formic acid (12.5 mL) was added to a stirred solution of
the residue of 40 (5.93 g) in CH2Cl2 (50 mL) at rt. The resultant
solution was stirred in the dark for 48 h. H2O (25 mL) was added
and the aqueous layer was extracted with CH2Cl2 (3 ꢂ 35 mL).
The combined organics were washed with brine (2 ꢂ 100 mL), then
dried and concentrated in vacuo. Purification by vacuum distilla-
tion gave 41 as a pale yellow oil (4.37 g, 80% from piperonal); dH
(400 MHz, CDCl3) 3.61 (2H, d, J 2.3, CH2CHO), 5.97 (2H, s, OCH2O),
6.66–6.70 (2H, m, C(2)H, C(5)H), 6.81 (1H, d, J 7.8, C(6)H), 9.72 (1H,
app td, J 2.3, 0.6, CHO).
yellow oil; [
a
]
D
25 = ꢁ1.8 (c 0.8 in CHCl3); mmax (film) 1724; dH
(400 MHz, CDCl3) 1.46 (9H, s, CMe3), 2.22 (1H, dd, J 15.8, 8.8, C(2)
HA), 2.40 (1H, dd, J 15.8, 4.2, C(2)HB), 2.51 (1H, dd, J 13.5, 8.2,
C(4)HA), 2.67 (1H, dd, J 13.5, 5.5, C(4)HB), 3.33–3.40 (1H, m, C(3)
H), 5.94 (2H, s, OCH2O), 6.65 (1H, dd, J 7.9, 1.6, C(60)H), 6.70 (1H,
d, J 1.6, C(20)H), 6.75 (1H, d, J 7.9, C(50)H); dC (100 MHz, CDCl3)
28.1 (CMe3), 43.0 (C(2)), 43.5 (C(4)), 49.8 (C(3)), 80.7 (CMe3),
100.9 (OCH2O), 108.4 (C(50)), 109.6 (C(60)), 127.3 (C(20)), 132.4
(C(10)), 146.1 (C(40)), 147.7 (C(30)), 171.8 (C(1)); m/z (ESI+) 280
([M+H]+, 100%); HRMS (ESI+) C15H22NO+4 ([M+H]+) requires
280.3389, found 280.1543.
4.2.7. tert-Butyl (E)-4-(30,40-methylenedioxyphenyl)but-2-
enoate 42
t
(EtO)2P(O)CH2CO2 Bu (9.63 mL, 41.0 mmol), LiCl (9.70 g,
229 mmol) and Pr2NEt (6.55 mL, 37.6 mmol) were added sequen-
i
tially to a stirred solution of 41 (5.61 g, 34.2 mmol) in MeCN
(100 mL) at rt. The resultant suspension was stirred at rt for 48 h
and then quenched by the addition of H2O (100 mL). The resultant
mixture was extracted with EtOAc (3 ꢂ 100 mL) and the combined
organics were washed with brine (100 mL), dried and concentrated
in vacuo to give a 98:2 mixture of 42 and 43, respectively.
Purification via flash column chromatography (eluent 2.5% Et2O
in pentane) gave 42 as a colourless oil {8.25 g, 92%, >99:1 dr
[(E):(Z) ratio]}; mmax (film) 1712; dH (400 MHz, CDCl3) 1.48 (9H, s,
CMe3), 3.41 (2H, dd, J 6.7, 1.4, C(4)H2), 5.71 (1H, dt, J 15.5, 1.4, C
(2)H), 5.95 (2H, s, OCH2O), 6.63 (1H, dd, J 7.9, 1.4, C(60)H), 6.66
(1H, d, J 1.4, C(20)H), 6.66 (1H, d, J 7.9, C(50)H), 6.85 (1H, dd, J
15.5, 6.7, C(3)H); dC (100 MHz, CDCl3) 28.2 (CMe3), 38.0 (C(4)),
80.2 (CMe3), 100.9 (OCH2O), 108.3 (C(50)), 109.3 (C(20)), 121.7
(C(60)), 123.9 (C(2)), 131.6 (C(10)), 146.1 (C(30)), 146.2 (C(40)),
147.8 (C(3)), 165.8 (C(1)); m/z (ESI+) 285 ([M+Na]+, 100%); HRMS
(ESI+) C15H18NaO4+ ([M+Na]+) requires 285.1097; found 285.1097.
Step 2: Et3N (2.21 mL, 15.8 mmol) and benzoyl chloride
(0.77 mL, 6.65 mmol) were added sequentially to a stirred solution
of the residue of 45 (1.77 g, 6.34 mmol) in CH2Cl2 (50 mL) at 0 °C.
The resultant solution was stirred at 0 °C for 10 min, then allowed
to warm to rt and stirred for an additional 16 h. 10% aq HCl (50 mL)
was added and the aqueous layer was extracted with CH2Cl2
(3 ꢂ 50 mL). The combined organics were dried and concentrated
in vacuo. Purification by flash column chromatography (eluent
5% Et2O in pentane) gave 46 as a colourless oil (2.19 g, 73% from
44); [
a
]
25 = ꢁ8.4 (c 1.0 in CHCl3); mmax (film) 1724, 1663; dH
D
(400 MHz, CDCl3) 1.44 (9H, s, CMe3), 2.43 (1H, dd, J 15.8, 5.6, C(2)
HA), 2.49 (1H, dd, J 15.8, 5.2, C(2)HB), 2.77 (1H, dd, J 13.6, 8.2, C
(4)HA), 2.96 (1H, dd, J 13.6, 6.0, C(4)HB), 4.52–4.60 (1H, m, C(3)
H), 5.87 (2H, s, OCH2O), 6.63–6.71 (3H, m, C(20)H, C(50)H, C(60)H),
7.19 (1H, d, J 8.6, Ph), 7.34–7.38 (2H, m, Ph), 7.74 (2H, d, J 7.3,

S. G. Davies et al. / Tetrahedron: Asymmetry 27 (2016) 274–284
281
Ph); dC (100 MHz, CDCl3) 28.1 (CMe3), 38.0 (C(2)), 39.7 (C(4)), 48.2
(C(3)), 81.3 (CMe3), 100.8 (OCH2O), 108.2 (C(50)), 109.4 (C(60)),
122.3 (C(20)), 126.9, 128.5, 131.4 (o,m,p-Ph), 131.5 (C(10)), 134.6
(i-Ph), 146.3 (C(30)), 147.7 (C(40)), 166.6 (NCOPh), 171.4 (C(1));
m/z (ESI+) 442 ([M+NH4+MeCN]+, 100%); HRMS (ESI+) C22H25NNaO+5
([M+Na]+) requires 406.1625; found 406.1622.
The combined organics were washed with brine (2 ꢂ 100 mL), then
dried and concentrated in vacuo. Purification by vacuum distillation
gave 51 as a colourless oil (3.00 g, 57% from O-benzylisovanillin);
mmax (film) 1722; dH (250 MHz, CDCl3) 3.60 (2H, s, CH2CHO), 3.92
(3H, s, OMe), 5.17 (2H, s, OCH2Ph), 6.79 (1H, dd, J 8.2, 2.1, C(6)H),
6.83 (1H, d, J 2.1, C(2)H), 6.93 (1H, d, J 8.2, C(5)H), 7.34–7.49 (5H,
m, Ph), 9.70 (1H, app t, J 2.4, CHO); dC (62.5 MHz, CDCl3) 50.4
(CH2CHO), 56.5 (OMe), 71.5 (OCH2Ph), 112.6 (C(2)), 115.8 (C(5)),
122.9 (C(6)), 124.4 (C(1)), 127.8, 128.4, 129.0 (o,m,p-Ph), 137.3
(i-Ph), 148.9, 149.6 (C(3), C(4)), 200.0 (CHO); m/z (GC ToF CI+) 274
([M+NH4]+, 100%), 257 (61%); HRMS (GC ToF CI+) C16H17O3+
([M+H]+) requires 257.1172; found 257.1178.
4.2.10. (R)-3-Benzamido-6,7-methylenedioxy-1-tetralone 48
Step 1: TFA (20 mL) was added dropwise to 36 (2.19 g,
5.71 mmol) at rt, and the resultant solution was stirred at rt for
1 h. Volatiles were then removed in vacuo to give 47 as a white
solid (1.87 g, quant); mp 74–78 °C (dec); [a]
25 = +31.4 (c 0.8 in
D
CHCl3); mmax (film) 1731, 1633; dH (400 MHz, d4-MeOH) 2.60 (2H,
app d, J 6.8, C(2)H2), 2.87 (2H, app d, J 7.3, C(4)H2), 4.57–4.64
(1H, m, C(3)H), 5.89 (2H, s, OCH2O), 6.71 (2H, app d, J 1.0, Ar),
6.78 (1H, app t, J 1.0, Ar), 7.40–7.45 (2H, m, Ph), 7.48–7.52
(1H, m, Ph), 7.71–7.74 (2H, m, Ph); dC (100 MHz, d4-MeOH) 38.2
(C(2)), 40.0 (C(4)), 49.2 (C(3)), 101.2 (OCH2O), 108.1 (C(60)), 109.6
(C(20)), 122.5 (C(50)), 127.3, 128.5, 131.6 (o,m,p-Ph), 132.2 (C(10)),
134.9 (i-Ph), 146.7 (C(40)), 148.1 (C(30)), 168.9 (NCOPh), 174.1
(C(1)); m/z (ESIꢁ) 326 ([MꢁH]ꢁ, 100%); HRMS (ESI+) C18H17NNaO+5
([M+Na]+) requires 350.0999; found 350.0997.
4.2.12. tert-Butyl (E)-4-(30-benzyloxy-40-methoxyphenyl)but-2-
enoate 52
A solution of 51 (3.02 g, 11.8 mmol) in CH2Cl2 (10 mL) was
t
added dropwise to a stirred solution of Ph3P@CHCO2 Bu (4.44 g,
11.8 mmol) in CH2Cl2 (40 mL) at 0 °C. The resultant solution was
stirred at rt for 12 h and then concentrated in vacuo. The residue
was suspended in
a mixture of Et2O (10 mL) and pentane
(10 mL), and the resultant suspension was stirred at rt for
30 min. The resultant solution was filtered and the filtrate was
concentrated in vacuo. This trituration process was repeated three
Step 2: Oxalyl chloride (0.15 mL, 1.73 mmol) was added drop-
wise to a stirred solution of the residue of 47 (200 mg, 1.58 mmol)
in CH2Cl2 (10 mL) at rt, followed by one drop of DMF. Stirring was
continued at rt until all the solids dissolved and the evolution of
gas ceased (ꢃ30 min). The resultant solution was then cooled to
0 °C and SnCl4 (0.58 mL, 3.15 mmol) was added dropwise. The
resultant solution was allowed to warm to rt and stirred at rt for
16 h. H2O (5 mL) was then added and the resultant mixture was
stirred vigorously for 10 min. The aqueous layer was extracted with
CH2Cl2 (3 ꢂ 15 mL) and the combined organics were dried and con-
centrated in vacuo. Purification via flash column chromatography
(eluent 25% EtOAc in pentane) gave 48 as a white solid (517 mg,
times to give
a >95:5 mixture of 52 and 53, respectively.
Purification via flash column chromatography (eluent 10% Et2O in
pentane) gave 52 as a colourless oil {2.96 g, 71%, >99:1 dr [(E):(Z)
ratio]}; mmax (film) 1709; dH (400 MHz, CDCl3) 1.50 (9H, s, CMe3),
3.39 (2H, dd, J 6.7, 1.5, C(4)H2), 3.87 (3H, s, OMe), 5.14 (2H, s,
OCH2Ph), 5.70 (1H, dt, J 15.5, 1.5, C(2)H), 6.73–6.76 (2H, m, C(20)
H, C(60)H), 6.85 (1H, d, J 8.6, C(50)H), 6.97 (1H, dt, J 15.5, 6.7, C(3)
H), 7.31–7.47 (5H, m, Ph); dC (100 MHz, CDCl3) 28.3 (CMe3), 34.4
(C(4)), 56.1 (OMe), 71.1 (OCH2Ph), 80.1 (CMe3), 112.1 (C(50)),
115.0 (C(20)), 121.5 (C(60)), 123.8 (C(2)), 127.4, 127.9, 128.6 (o,m,
p-Ph), 130.4 (C(10)), 137.1 (i-Ph), 146.3 (C(3)), 148.2 (C(40)), 148.5
(C(30)), 165.9 (C(1)); m/z (ESI+) 377 ([M+Na]+, 100%); HRMS (ESI+)
77% from 46); mp 197–200 °C; [
a
]
D
25 = ꢁ16.5 (c 0.5 in CHCl3);
mmax (film) 1724, 1660; dH (400 MHz, CDCl3) 2.74 (1H, dd, J 16.8,
8.7, C(2)HA), 2.98 (1H, dd, J 16.8, 3.8, C(2)HB), 3.01 (1H, dd, J 16.0,
7.9, C(4)HA), 3.32 (1H, dd, J 16.0, 4.1, C(4)HB), 4.78 (1H, app tq, J
8.3, 4.2, C(3)H), 6.04 (2H, s, OCH2O), 6.38 (1H, d, J 7.5, NH), 6.69
(1H, s, C(5)H), 7.41 (2H, app t, J 7.5, Ph), 7.46 (1H, s, C(8)H), 7.49
(1H, tt, J 7.5, 2.0, Ph), 7.71 (2H, app d, J 7.1, Ph); dC (100 MHz, CDCl3)
35.9 (C(4)), 44.1 (C(2)), 46.1 (C(3)), 101.9 (OCH2O), 106.2 (C(8)),
108.7 (C(5)), 126.9, 128.6, 131.7 (o,m,p-Ph), 127.6 (C(8a)), 134.1
(i-Ph), 137.6 (C(4a)), 147.6, 152.8 (C(6), C(7)), 167.2 (NCOPh),
193.9 (C(1)); m/z (ESI+) 322 ([M+Na]+, 100%); HRMS (ESI+)
C
22H26NaO+4 ([M+Na]+) requires 377.1723; found 377.1726.
4.2.13. tert-Butyl (R,R)-3-[N-benzyl-N-(a-methylbenzyl)amino]-
4-(30-benzyloxy-40-methoxyphenyl)butanoate 54
BuLi (2.5 M in hexanes, 5.28 mL, 8.44 mmol) was added drop-
wise via syringe to a stirred solution of (R)-N-benzyl-N-(a-methyl-
benzyl)amine (1.85 g, 8.71 mmol, >99% ee) in THF (40 mL) at
ꢁ78 °C. The resultant pink solution was stirred for 30 min at
ꢁ78 °C. A solution of 52 {1.94 g, 5.44 mmol, >99:1 dr [(E):(Z) ratio]}
in THF (10 mL) at ꢁ78 °C was then added dropwise via cannula.
The resultant solution was stirred at ꢁ78 °C for 2 h then quenched
with satd aq NH4Cl (20 mL). The resultant mixture was diluted
with Et2O (50 mL). The aqueous layer was extracted with Et2O
(3 ꢂ 100 mL). The combined organics were dried and concentrated
in vacuo. Purification via flash column chromatography (eluent 5%
Et2O in pentane) gave 54 as a colourless oil (2.03 g, 47%, >99:1 dr);
C
18H15NNaO+4 ([M+Na]+) requires 322.0893; found 322.0893.
4.2.11. 3-Benzyloxy-4-methoxyphenylacetaldehyde 51
Step 1: KOtBu (2.32 g, 20.6 mmol) was added portionwise to a
stirred suspension of [MeOCH2PPh3]+[Cl]ꢁ (7.78 g, 22.7 mmol) in
THF (50 mL) at 0 °C. The resultant mixture was stirred for 30 min
at rt and then a solution of O-benzylisovanillin (5.00 g, 20.6 mmol)
in THF (50 mL) was added dropwise. The resultant mixture was
stirred at rt for 12 h and then quenched by the addition of satd
aq NH4Cl (50 mL). The aqueous layer was extracted with Et2O
(3 ꢂ 75 mL) and the combined organics were washed with brine
(2 ꢂ 100 mL), then dried and concentrated in vacuo. Pentane
(100 mL) was added to the residue and the resultant suspension
was stirred at rt for 30 min. The resultant solution was filtered
and the filtrate was concentrated in vacuo. This trituration process
was repeated three times to give 50 {56:44 dr [(E):(Z) ratio]} as a
white powder (3.17 g).
[a
]
D
25 = +24.1 (c 1.0 in CHCl3);
mmax (film) 1725; dH (400 MHz, CDCl3)
1.11 (3H, d, J 7.1, C(a)Me), 1.43 (9H, s, CMe3), 2.00–2.03 (2H, m,
C(2)H2), 2.55 (1H, dd, J 13.6, 5.8, C(4)HA), 2.67 (1H, dd, J 13.6, 8.1,
C(4)HB), 3.60–3.64 (2H, m, C(3)H, NCHAHBPh), 3.83 (1H, q, J 7.1,
C(a)H), 3.89–3.93 (1H, m, NCHAHBPh) overlapping 3.92 (3H, s,
OMe), 5.07 (1H, d, J 12.1, OCHAHBPh), 5.11 (1H, d, J 12.1, OCHAHB-
Ph), 6.72–6.75 (1H, m, C(20)H), 6.84–6.87 (1H, m, C(60)H), 7.22–
7.50 (16H, m, C(50)H, Ph); dC (100 MHz, CDCl3) 19.8 (C(
a
)Me),
28.1 (CMe3), 37.6 (C(2)), 39.2 (C(4)), 50.0 (NCH2Ph), 56.2 (OMe),
56.7 (C(3)), 58.1 (C(
)), 70.9 (OCH2Ph), 80.0 (CMe3), 111.6 (C(50)),
a
115.4 (C(20)), 122.2 (C(60)), 126.6, 126.9, 127.4, 127.8, 127.9,
128.1, 128.2, 128.5, 133.3 (Ar), 137.3, 141.5, 143.1 (i-Ph), 147.8
(C(30)), 147.9 (C(40)), 171.9 (C(1)); m/z (ESI+) 566 ([M+H]+, 100%);
HRMS (ESI+) C37H44NO+4 ([M+H]+) requires 566.3265; found
566.3266.
Step 2: Formic acid (12.5 mL) was added to a stirred solution of
the residue of 40 (3.17 g) in CH2Cl2 (50 mL) at rt. The resultant
solution was stirred in the dark for 48 h. H2O (25 mL) was added
and the aqueous layer was extracted with CH2Cl2 (3 ꢂ 35 mL).

282
S. G. Davies et al. / Tetrahedron: Asymmetry 27 (2016) 274–284
4.2.14. tert-Butyl (R)-3-benzamido-4-(30-benzoyloxy-40-meth-
oxyphenyl)butanoate 56
100%); HRMS (ESI+) C18H19NNaO+5 ([M+Na]+) requires 352.1155;
found 352.1155.
Step 1: Pd/C (406 mg, 20% w/w substrate) was added to a stirred,
degassed solution of 54 (2.03 g, 3.59 mmol) in MeOH (60 mL),
AcOH (6 mL) and H2O (1.5 mL). The reaction vessel was charged
with H2 (1 atm) and the resultant suspension was stirred rapidly
for 12 h. The suspension was filtered through a pad of CeliteÒ (elu-
ent MeOH) and the filtrate was concentrated in vacuo to give 55 as
a pale yellow oil. Purification of an aliquot via flash column chro-
matography (eluent 40% CH2Cl2 in MeOH) gave an analytically
Step 2: Oxalyl chloride (0.02 mL, 0.24 mmol) was added drop-
wise to a stirred solution of the residue of 57 (39 mg, 0.12 mmol)
in CH2Cl2 (10 mL) at rt, followed by one drop of DMF. Stirring
was continued at rt until all the solids dissolved and the evolution
of gas ceased (ꢃ30 min). The resultant solution was then cooled to
0 °C and SnCl4 (0.03 mL, 0.24 mmol) was added dropwise. The
resultant solution was allowed to warm to rt and stirred at rt for
16 h. H2O (5 mL) was then added and the resultant mixture was
stirred vigorously for 10 min. The aqueous layer was extracted
with CH2Cl2 (3 ꢂ 15 mL) and the combined organics were dried
and concentrated in vacuo. Purification via flash column chro-
matography (eluent 25% EtOAc in pentane) gave 58 as a colourless
pure sample of 55 as a colourless oil; [
max (film) 1724; dH (400 MHz, CDCl3) 1.41 (9H, s, CMe3), 2.25 (1H,
a]
25 = +2.9 (c 1.3 in CHCl3);
D
m
dd, J 16.1, 8.6, C(2)HA), 2.39 (1H, dd, J 16.1, 4.2, C(2)HB), 2.48 (1H,
dd, J 13.4, 8.1, C(4)HA), 2.63 (1H, dd, J 13.4, 5.5, C(4)HB), 3.32–
3.38 (1H, m, C(3)H), 3.79 (1H, s, OMe), 6.61 (1H, d, J 8.1, C(50)H),
6.70 (1H, d, J 1.5, C(20)H), 6.74 (1H, dd, J 8.1, 1.5, C(60)H); dC
(100 MHz, CDCl3) 28.0 (CMe3), 42.4 (C(2)), 42.6 (C(4)), 49.6 (C(3)),
55.8 (OMe), 80.6 (CMe3), 111.1 (C(60)), 116.2 (C(20)), 120.3 (C(50)),
131.4 (C(10)), 146.0 (C(30)), 146.2 (C(40)), 171.8 (C(1)); m/z (ESI+)
282 ([M+H]+, 100%); HRMS (ESI+) C15H24NO+4 ([M+H]+) requires
282.1700; found 282.1701.
Step 2: Et3N (1.22 mL, 8.71 mmol) and benzoyl chloride
(0.42 mL, 3.66 mmol) were added sequentially to a stirred solution
of the residue of 55 (490 mg, 1.74 mmol) in CH2Cl2 (10 mL) at 0 °C.
The resultant solution was stirred at 0 °C for 10 min, then allowed
to warm to rt and stirred for an additional 16 h. 10% aq HCl (10 mL)
was added and the aqueous layer was extracted with CH2Cl2
(3 ꢂ 10 mL). The combined organics were dried and concentrated
in vacuo. Purification via flash column chromatography (eluent
oil (25 mg, 69% from 56); [
a]
25 = ꢁ10.4 (c 0.6 in CHCl3);
mmax (film)
D
3402, 1721, 1662, 1591; dH (400 MHz, CDCl3) 2.72 (1H, dd, J 15.7,
8.4, C(2)HA), 2.92 (1H, dd, J 15.7, 4.2, C(2)HB), 3.07 (1H, dd, J 16.0,
7.7, C(4)HA), 3.30 (1H, dd, J 16.0, 5.1, C(4)HB), 3.79 (3H, s, OMe),
4.76–4.79 (1H, m, C(3)H), 6.42 (1H, br d, J 7.6, NH), 6.70 (1H, s, C
(5)H), 7.40–7.43 (2H, m, Ph), 7.47 (1H, s, C(8)H), 7.46–7.48
(1H, m, Ph), 7.73 (2H, app d, J 7.5, Ph); dC (100 MHz, CDCl3) 34.9
(C(4)), 44.5 (C(2)), 47.8 (C(3)), 56.2 (OMe), 105.9 (C(8)), 108.8
(C(5)), 126.7, 128.5, 131.5 (o,m,p-Ph), 127.4 (C(8a)), 134.4 (i-Ph),
137.3 (C(4a)), 152.4 (C(6)), 154.6 (C(7)), 167.3 (NCOPh), 195.7
(C(1)); m/z (ESIꢁ) 310 ([MꢁH]ꢁ, 100%); HRMS (ESI+) C18H17NNaO+4
([M+Na]+) requires 334.1050; found 334.1058.
4.2.16. tert-Butyl (R)-3-benzamido-4-(30,40-dimethoxyphenyl-60-
bromo)butanoate 60
pentane/EtOAc/Et3N, 75:25:1) gave 56 as
a
colourless oil
A solution of bromine (320 mg, 2.00 mmol) in CHCl3 (10 mL)
was added dropwise to a solution of 37 (400 mg, 1.00 mmol) in
CHCl3 (25 mL) at rt. The resultant solution was stirred at rt for
30 min and then H2O (20 mL) was added. The aqueous layer was
separated and extracted with CHCl3 (3 ꢂ 20 mL). The combined
organics were washed with satd aq Na2S2O4 (30 mL), then dried
and concentrated in vacuo. Purification via recrystallisation
(25% Et2O in pentane) gave 60 as a white solid (502 mg, 97%);
(605 mg, 71% from 54); [
a]
D
25 = +2.9 (c 1.6 in CHCl3); mmax (film)
1731, 1644; dH (400 MHz, CDCl3) 1.47 (9H, s, CMe3), 2.50 (1H, dd,
J 15.7, 5.5, C(2)HA), 2.54 (1H, dd, J 15.7, 5.1, C(2)HB), 2.86 (1H, dd,
J 13.7, 8.5, C(4)HA), 3.06 (1H, dd, J 13.7, 5.8, C(4)HB), 3.79 (3H, s,
OMe), 4.59–4.67 (1H, m, C(3)H), 6.96 (1H, d, J 8.5, C(50)H), 7.07
(1H, d, J 2.1, C(20)H), 7.13 (1H, dd, J 8.5, 2.1, C(60)H) 7.40–7.53
(5H, m Ph), 7.61–7.65 (1H, m, Ph), 7.77–7.78 (2H, m, Ph), 8.19–
8.21 (2H, m, Ph); dC (100 MHz, CDCl3) 28.1 (CMe3), 37.9 (C(2)),
38.1 (C(4)), 48.1 (C(3)), 56.0 (OMe), 81.4 (CMe3), 112.6 (C(50)),
114.1 (C(20)), 124.1, 126.9, 127.1, 127.6, 128.5, 129.4, 130.2,
131.4 (o,m,p-Ph, C(10), C(60)), 133.5, 134.5 (i-Ph), 139.8 (C(30)),
150.1 (C(40)), 164.7 (OCOPh), 166.6 (NCOPh), 171.5 (C(1)); m/z
(ESI+) 512 ([M+Na]+, 100%), 490 (85%); HRMS (ESI+) C29H31NNaO+6
([M+Na]+) requires 512.2044, found 512.2042.
C
23H28BrNO5 requires C, 57.75; H, 5.9; N, 2.9; found C, 58.1; H,
6.1; N, 3.0; mp 132–134 °C; [
a]
D
25 = +80.7 (c 0.30 in DMSO); mmax
(KBr) 3291, 3061, 2999, 2978, 2934, 2909, 1715, 1640, 1603,
1579, 1533, 1511, 1260, 1222, 1166, 1036, 800, 698; dH
(400 MHz, CDCl3) 1.48 (9H, s, CMe3), 2.58 (1H, dd, J 15.1, 5.1, C(2)
HA), 2.64 (1H, dd, J 15.1, 4.9, C(2)HB), 3.07 (1H, dd, J 13.9, 7.7, C
(4)HA), 3.14 (1H, dd, J 13.9, 7.0, C(4)HB), 3.80 (3H, s, OMe), 3.85
(3H, s, OMe), 4.68–4.72 (1H, m, C(3)H), 6.82 (1H, s, Ar), 7.00
(1H, s, Ar), 7.18 (1H, d, J 8.7, NH), 7.41–7.52 (3H, m, Ph), 7.76
(2H, d, J 7.2, Ph); dC (100 MHz, CDCl3) 28.1 (CMe3), 38.4 (C(2)),
39.2 (C(4)), 47.6 (C(3)), 56.0, 56.1 (OMe), 81.5 (CMe3), 113.5,
114.6, 115.3 (C(20), C(50), C(60)), 126.9, 128.6, 129.4 (o,m,p-Ph),
131.5 (C(10)), 134.4 (i-Ph), 148.1, 148.4 (C(30), C(40)), 166.6 (NCOPh),
171.5 (C(1)); m/z (ESI+) 478 ([M+H]+, 70%), 422 (100%); HRMS (ESI+)
4.2.15. (R)-3-Benzamido-6-hydroxy-7-methoxy-1-tetralone 58
Step 1: NaOMe was prepared by the slow addition of small
pieces of sodium (20 mg, 0.89 mmol) to MeOH (5 mL), stirring at
rt. Once the sodium had reacted (ca. 10 min), the resultant solution
was cooled to 5 °C and a solution of 56 (87 mg, 0.18 mmol) in
MeOH (4 mL) was added dropwise. The resultant solution was stir-
red at 5 °C for 1 h, then poured into a solution of 10% aq citric acid
(25 mL). The resultant slurry was extracted with EtOAc (3 ꢂ 20 mL)
and the combined organics were washed with brine (30 mL), dried
and concentrated in vacuo. TFA (1 mL) was added dropwise to the
residue and the resultant solution was stirred at rt for 1 h. Volatiles
were then removed in vacuo to give 57 as a colourless oil (59 mg,
C
23H29BrNO+5 ([M+H]+) requires 478.1224; found 478.1229.
4.2.17. Attempted preparation of (R)-3-benzamido-5-bromo-
7,8-dimethoxy-1-tetralone 62
Step 1: TFA (5 mL) was added dropwise to 60 (500 mg,
1.05 mmol) at rt, and the resultant solution was stirred at rt for
1 h. Volatiles were then removed in vacuo to give 61 as a white
solid (440 mg, quant); C19H20BrNO5 requires C, 54.0; H, 4.8; N,
quant); [a]
25 = +2.9 (c 1.0 in CHCl3); mmax (film) 3395, 1667, 1641,
D
1585; dH (400 MHz, d4-MeOH) 2.59 (2H, d, J 6.8, C(2)H2), 2.79–
2.95 (2H, m, C(4)H2), 3.81 (3H, s, OMe), 4.57–4.64 (1H, m, C(3)H),
6.70 (1H, dd, J 8.1, 1.6, C(60)H), 6.76 (1H, d, J 1.6, C(20)H), 6.83
(1H, d, J 8.1, C(50)H), 7.41–7.52 (3H, m, Ph), 7.73 (2H, d, J 7.3, Ph);
dC (100 MHz, d4-MeOH) 39.6 (C(2)), 42.9 (C(4)), 49.2 (C(3)), 55.5
(OMe), 111.8 (C(50)), 116.4 (C(20)), 120.7 (C(60)), 127.8, 128.5,
131.0 (o,m,p-Ph), 131.6 (C(10)), 135.0 (i-Ph), 14ꢁ6.4 (C(40)), 146.8
(C(30)), 168.1 (NCOPh), 176.7 (C(1)); m/z (ESI ) 328 ([MꢁH]ꢁ,
3.3; found C, 53.8; H, 4.9; N, 3.2; mp 188–190 °C; [a]
25 = +78.8
D
(c 0.95 in DMSO); mmax (KBr) 3491–2821, 3280, 3001, 2960, 2934,
2841, 1714, 1646, 1604, 1579, 1539, 1506, 1440, 1382, 1260,
1242, 1223, 1205, 1167, 1036, 873, 797, 702; dH (400 MHz,
d6-DMSO) 2.52 (1H, dd, J 15.2, 7.7, C(2)HA), 2.59 (1H, dd, J 15.2,
6.1, C(2)HB), 2.88 (1H, dd, J 13.8, 9.1, C(4)HA), 2.96 (1H, dd, J 13.8,
5.3, C(4)HB), 3.61 (3H, s, OMe), 3.71 (3H, s, OMe), 4.60 (1H, m, C

S. G. Davies et al. / Tetrahedron: Asymmetry 27 (2016) 274–284
283
(3)H), 6.95 (1H, s, Ar), 7.07 (1H, s, Ar), 7.42–7.52 (3H, m, Ph), 7.75–
7.77 (2H, m, Ph), 8.34 (1H, d, J 8.7, NH); dC (100 MHz, d6-DMSO)
40.2, 40.4 (C(2), C(4)), 47.6 (C(3)), 56.2, 56.6 (OMe), 114.8, 115.3,
116.2 (C(20), C(50), C(60)), 127.9, 129.1, 130.5 (o,m,p-Ph), 132.0
(C(10)), 135.3 (i-Ph), 148.6, 148.8 (C(30), C(40)), 166.6 (NCOPh),
173.2 (C(1)); m/z (ESI+) 422 ([M+H]+, 100%); HRMS (ESI+)
Step 2: Oxalyl chloride (0.08 mL, 0.41 mmol) was added drop-
wise to a stirred solution of the residue of 61 (140 mg, 0.37 mmol)
in CH2Cl2 (10 mL) at rt, followed by one drop of DMF. Stirring was
continued at rt until all the solids dissolved and the evolution of
gas ceased (ꢃ30 min). The resultant solution was then cooled to
0 °C and AlCl3 (172 mg, 1.30 mmol) was added portionwise. The
resultant solution was allowed to warm to rt and stirred at rt for
16 h. H2O (5 mL) was then added and the resultant mixture was
stirred vigorously for 10 min. The aqueous layer was extracted
with CH2Cl2 (3 ꢂ 15 mL) and the combined organics were dried
and concentrated in vacuo. Purification via recrystallisation (20%
EtOAc in pentane) gave 65 as a pale yellow crystalline solid
C
19H21BrNO+5 ([M+H]+) requires 422.0598; found 422.0623.
Step 2: Oxalyl chloride (0.07 mL, 0.79 mmol) was added drop-
wise to a stirred solution of the residue of 61 (150 mg, 0.36 mmol)
in CH2Cl2 (5 mL) at rt, followed by one drop of DMF. Stirring was
continued at rt until all the solids dissolved and the evolution of
gas ceased (ꢃ30 min). The resultant solution was then cooled to
0 °C and SnCl4 (0.09 mL, 0.79 mmol) was added dropwise. The
resultant solution was allowed to warm to rt and stirred at rt for
16 h. H2O (5 mL) was then added and the resultant mixture was
stirred vigorously for 10 min. The aqueous layer was extracted
with CH2Cl2 (3 ꢂ 15 mL) and the combined organics were dried
and concentrated in vacuo. Purification via flash column chro-
matography (eluent 10?20?40% EtOAc in pentane) gave 38 as a
pale yellow crystalline solid (90 mg, 77%).
(110 mg, 86%); mp 218–220 °C (dec); [
a]
25 = ꢁ3.7 (c 0.60 in
D
DMSO); mmax (KBr) 3420, 3290, 3057, 3025, 2962, 2944, 2903,
2836, 1641, 1603, 1579, 1529, 1467, 1437, 1334, 1250, 827, 814,
727, 694; dH (400 MHz, CDCl3) 2.92 (1H, dd, J 17.2, 8.8, C(2)HA),
3.11 (1H, dd, J 17.2, 3.2, C(2)HB), 3.03 (1H, dd, J 16.8, 8.0, C(4)HA),
3.43 (1H, dd, J 16.8, J 4.0, C(4)HB), 3.91 (3H, s, OMe), 4.79–4.83
(1H, m, C(3)H), 6.23 (1H, d, J 7.1, NH), 7.10 (1H, s, C(6)H), 7.42–
7.55 (3H, m, Ph), 7.72–7.74 (2H, m, Ph), 12.73 (1H, s, OH); dH
(400 MHz, d6-DMSO) 2.92–3.00 (3H, m, C(2)H2, C(4)HA), 3.25
(1H, dd, J 16.4, 4.3, C(4)HB), 3.82 (3H, s, OMe), 4.50–4.54 (1H, m,
C(3)H), 7.34 (1H, s, C(6)H), 7.43–7.57 (3H, m, Ph), 7.85–7.87 (2H,
m, Ph), 8.78 (1H, d, J 7.2, NH), 12.67 (1H, br s, OH); dC (100 MHz,
d6-DMSO) 32.8 (C(4)), 44.2 (C(2)), 45.5 (C(3)), 57.1 (OMe), 117.7,
122.3 (C(5), C(8a)), 119.6 (C(6)), 128.3, 129.1, 130.4, 132.2 (C(4a),
o,m,p-Ph), 135.0 (i-Ph), 147.9, 152.3 (C(7), C(8)), 167.1 (NCOPh),
204.8 (C(1)); m/z (ESI+) 368 ([M+Na]+, 100%), 346 ([M+H]+, 65%),
279 (40%), 225 (40%); HRMS (ESI+) C18H17ClNO4+ ([M+H]+) requires
346.0841; found 346.0856.
4.2.18. tert-Butyl (R)-3-benzamido-4-(30,40-dimethoxyphenyl-60-
chloro)butanoate 63
SO2Cl2 (0.10 mL, 1.25 mmol) was added dropwise to a solution
of 37 (500 mg, 1.25 mmol) in CH2Cl2 (30 mL) at rt. H2O (20 mL) was
added after 1 h, and the aqueous layer was separated and extracted
with CH2Cl2 (3 ꢂ 20 mL). The combined organics were washed
with brine (30 mL), then dried and concentrated in vacuo. Purifica-
tion via recrystallisation (25% Et2O in pentane) gave 63 as a white
solid (498 mg, 94%); C23H28ClNO5 requires C, 63.7; H, 6.5; N, 3.2;
found C, 63.6; H, 6.8; N, 3.3; mp 134–136 °C; [a]
25 = +57.4 (c 1.0
D
in CHCl3); mmax (KBr) 3350, 3060, 2969, 2933, 2841, 1715, 1639,
1604, 1580, 1532, 1516, 1458, 1439, 1389, 1366, 1264, 1222,
1208, 1168, 1143, 1045, 975, 812, 697; dH (400 MHz, CDCl3) 1.49
(9H, s, CMe3), 2.57 (1H, dd, J 16.4, 5.3, C(2)HA), 2.62 (1H, dd, J
16.4, 5.1, C(2)HB), 3.06 (1H, dd, J 14.0, 7.6, C(4)HA), 3.12 (1H, dd, J
14.0, J 7.4, C(4)HB), 3.80 (3H, s, OMe), 3.84 (3H, s, OMe), 4.66–
4.70 (1H, m, C(3)H), 6.80 (1H, s, Ar), 6.84 (1H, s, Ar), 7.18 (1H, d, J
8.5, NH), 7.41–7.51 (3H, m, Ph), 7.75–7.77 (2H, m, Ph); dC
(100 MHz, CDCl3) 28.1 (CMe3), 36.7 (C(4)), 38.3 (C(2)), 47.6 (C(3)),
56.1 (OMe), 81.4 (CMe3), 112.3, 113.5, 125.1 (C(20), C(50), C(60)),
126.8, 127.5, 128.6 (o,m,p-Ph), 131.5 (C(10)), 147.9, 148.3 (C(30), C
(40)), 166.6 (NCOPh), 171.5 (C(1)); m/z (ESI+) 434 ([M+H]+, 70%),
378 (100%); HRMS (ESI+) C23H29ClNO5+ ([M+H]+) requires
434.1729; found 434.1731.
References
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4.2.19. (R)-3-Benzamido-5-chloro-7-methoxy-8-hydroxy-1-
tetralone 65
Step 1: TFA (5 mL) was added dropwise to 63 (400 mg,
0.92 mmol) at rt, and the resultant solution was stirred at rt for
1 h. Volatiles were then removed in vacuo to give 64 as a white
solid (343 mg, quant); C19H20ClNO5 requires C, 60.4; H, 5.3; N,
12. Flentje, H.; Döpke, W.; Jeffs, P. W. Naturwiss 1965, 52, 259.
13. Döpke, W.; Flentje, H. Tetrahedron 1968, 24, 4459.
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Roberts, M. F., Zenk, M. H., Eds.; Springer, 1985; p 191.
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22. For other applications of this approach to these carbocylces, see: (a) Horton, W.
J.; Thompson, G. J. Am. Chem. Soc. 1954, 76, 1909; (b) Zymalkowski, P.;
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3.7; found C, 60.2; H, 5.1; N, 3.9; mp 202–204 °C; [a]
25 = +74.6
D
(c 1.0 in DMSO); mmax (KBr) 3281, 2999, 2960, 2935, 2842, 1712,
1642, 1604, 1579, 1536, 1506, 1441, 1387, 1262, 1242, 1224,
1206, 1169, 1039, 873, 701; dH (400 MHz, d6-DMSO) 2.52 (1H,
dd, J 15.2, 7.7, C(2)HA), 2.59 (1H, dd, J 15.2, J 6.3, C(2)HB), 2.87
(1H, dd, J 13.7, 9.0, C(4)HA), 2.97 (1H, dd, J 13.7, 5.2, C(4)HB), 3.62
(3H, s, OMe), 3.75 (3H, s, OMe), 4.57–4.61 (1H, m, C(3)H), 6.93
(1H, s, Ar), 6.95 (1H, s, Ar), 7.49–7.56 (3H, m, Ph), 7.75–7.77 (2H,
m, Ph), 8.35 (1H, d, J 8.7, NH); dC (100 MHz, d6-DMSO) 37.7
(C(4)), 40.3 (C(2)), 47.6 (C(3)), 56.3, 56.6 (OMe), 113.3, 115.3,
125.0 (C(20), C(50), C(60)), 128.0, 128.6, 129.0 (o,m,p-Ph), 132.0
(C(10)), 135.4 (i-Ph), 148.1, 148.7 (C(30), C(40)), 166.4 (NCOPh),
173.2 (C(1)); m/z (ESI+) 378 ([M+H]+, 100%); HRMS (ESI+)
C
19H21ClNO+5 ([M+H]+) requires 378.1103; found 378.1107.

284
S. G. Davies et al. / Tetrahedron: Asymmetry 27 (2016) 274–284
25. Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1994, 5, 1999.
26. For instance, see: (a) Coote, S. J.; Davies, S. G.; Middlemiss, D.; Naylor, A. J.
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28. Cyclisation of 3-(30,40-dimethoxy-60-chlorophenyl)butanoic acid proceeds
exclusively at the C(20)-position, see: (a) Gosh, R.; Robinson, R. J. Chem. Soc.
1944, 506; (b) Trauner, D.; Bats, J. W.; Werner, A.; Mulzer, J. J. Org. Chem. 1998,
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29. Bolton, R.; de la Mare, P. B. D. J. Chem. Soc. B 1967, 1044.
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27. Cyclisation of 3-phenyl-4-(30-methoxyphenyl)butanoic acid proceeds
exclusively at the C(60)-position (i.e., para to the OMe group), see: (a) Malik,
M. S.; Rastogi, S. N. Indian J. Chem. 1984, 23B, 834. However, the related
cyclisation
of
3-methyl-4-(30-methoxy-60-bromophenyl)butanoic
acid
proceeds exclusively at the C(20)-position (i.e., ortho to the OMe group), see:
(b) Nishiyama, T.; Kameoka, H. Chem. Express 1991, 6, 109.
31. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
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