An oxidative coupling for the synthesis of arylated quaternary stereocentres and its application in the total synthesis of powelline and buphanidrine

Article abstract of DOI:10.1016/j.tet.2010.04.132

Catechol derivatives directly bonded to all-carbon quaternary stereocentres are prevalent in nature. An oxidative coupling strategy for the synthesis of this motif is described. Pivoting on the base-catalysed Michael addition of carbon-centred pro-nucleop

Full text of DOI:10.1016/j.tet.2010.04.132

Tetrahedron 66 (2010) 6399e6410
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An oxidative coupling for the synthesis of arylated quaternary stereocentres
and its application in the total synthesis of powelline and buphanidrine
,
Katherine M. Bogle a, David J. Hirst b, Darren J. Dixon c
*
a School of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK
b GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK
c 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:
Catechol derivatives directly bonded to all-carbon quaternary stereocentres are prevalent in nature. An
oxidative coupling strategy for the synthesis of this motif is described. Pivoting on the base-catalysed
Michael addition of carbon-centred pro-nucleophiles to in situ generated ortho-benzoquinones, the
method is broad in scope, high yielding and provides remarkably simple access to this challenging motif.
The application of this methodology in the total synthesis of the crinane-type amaryllidaceae alkaloids
(ꢀ)-powelline and (ꢀ)-buphanidrine is demonstrated and our efforts towards an enantioselective
synthesis described.
Received 26 February 2010
Received in revised form 21 April 2010
Accepted 29 April 2010
Available online 13 May 2010
Keywords:
Arylation
Quinone
Ó 2010 Elsevier Ltd. All rights reserved.
Organocatalytic
Powelline
Buphanidrine
1. Introduction
families of the structurally diverse Amaryllidaceae alkaloids, of
which nearly 500 have been isolated and shown to exhibit cytotoxic,
All-carbon quaternary stereocentres covalently bonded to cate-
chol (1,2-dihydroxylated aromatic rings) derivatives are prevalent in
natural and pharmaceutical products (Fig. 1). Examples include the
calcium channel antagonist Verapamil,1 the paraherquamide family
of antiparasitic alkaloids,2 the mastigophorenes3 and several
antibacterial, antifungal, antiviral, antiparasitic and anti-in-
flammatory properties.4 The Amaryllidaceae alkaloid Galanthamine
inhibits acetylcholinesterase and has been approved for the treat-
ment of Alzheimer’s disease.5
The direct synthesis of all-carbon quaternary arylated stereo-
centres remains a significant synthetic challenge.6 Attractive syn-
thetic solutions include FriedeleCrafts alkylations,7 intramolecular
Heck-couplings,8 SNAr reactions of 1,3-dicarbonyl compounds with
para-fluoro nitrobenzenes9 and transition metal catalysed
couplings of carbon-centred nucleophiles to aryl halides. The latter
approach is arguably the most powerful to date with palladium,10
copper11 and nickel12 catalysts being employed in often highly
enantioselective arylation reactions. More recently, and during the
course of our research documented here, an organocatalytic,
enantioselective arylation reaction with commercially available 1,4-
quinones as electrophiles was reported.13,14
Alert to the number of biologically active natural products
containing catechol derivatives bonded to all-carbon quaternary
stereocentres, we became interested in developing
a novel
organocatalytic methodology for their stereocontrolled synthesis.
To this end we recently published an oxidative coupling
methodology15 for the direct construction of this motif, and the
application of this reaction in the total synthesis of the crinane-type
Amaryllidaceae alkaloids (ꢀ)-powelline and (ꢀ)-buphanidrine.16
Herein we disclose our full efforts in this field.
Figure 1. Pharmaceutical and natural products containing catechol derivatives bonded
to all-carbon quaternary stereocentres.
* Corresponding author. Tel.: þ44 1865275648; e-mail address: Darren.Dixon@
chem.ox.ac.uk (D.J. Dixon).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.132

6400
K.M. Bogle et al. / Tetrahedron 66 (2010) 6399e6410
2. Results and discussion
The scope of the pro-nucleophile was then investigated; five-
membered cyclic lactone-, indanone- and oxindole-derived pro-
We believed an attractive strategy for the direct construction of
catechol derived arylated quaternary stereocentres would be the
Michael addition of a carbon based pro-nucleophile (2) to o-ben-
zoquinone reagents (1) (Scheme 1). o-Quinones are powerful
electrophilic reagents, reactive towards a range of carbon and
heteroatom based nucleophiles,17 however in contrast to p-qui-
nones, reports on the use of o-quinones as Michael acceptors are
rare due to their rapid decomposition under attempted reaction
conditions.18 Allyl stannanes, silyl enol ethers and pre-formed
nucleophiles were well-tolerated as five and six-membered cyclic
a-cyanoketones and acyclic
a
-cyano acetates,21 illustrated in
Scheme 3.
sodium enolates of
b-dicarbonyl reagents have been used with
limited success in reactions with relatively stable o-quinones, and
one organocatalytic example with 1,2-naphthoquinone with poor
yield and enantiocontrol have been reported.19
Scheme 1. Concept for the synthesis of arylated quaternary stereocentres with
o-quinone electrophiles.
Initial proof of principle studies for the base-catalysed Michael
addition to o-quinone reagents were conducted with commercially
available 1,2-naphthoquinone 4 and methyl cyclopentanone-2-
carboxylate 5 as a representative pro-nucleophile using a range of
base catalysts (Scheme 2, Table 1). 2-tert-Butylimino-2-dieth-
ylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP)
was quickly identified as the most efficient catalytic base and tert-
butyl methyl ether (TBME) as the most effective solvent. The opti-
mal reaction conditions are illustrated in Table 1, entry 8; 2 equiv of
pro-nucleophile in the presence of 10 mol % BEMP were required to
minimise side reactions of the quinone. Crude 1H NMR spectra
indicated excellent conversion to the catechol intermediate,20
however the only product isolable following silica gel chromato-
graphy was at the quinone oxidation level and was obtained in low
yield. The catechol adduct was found to be liable to oxidation in air
and so to aid handling, the catechol functionality was capped as the
di-acetate. This procedure allowed the desired product to be iso-
lated following chromatography in a pleasing 83% over two steps.
Scheme 3. Range of naphthoquinone adducts formed.
We then looked to expand the scope of the methodology to
a range of o-benzoquinone electrophiles and attempted to syn-
thesize a range of 3-substituted o-benzoquinones through oxida-
tion of the parent catechol.22 3-tert-Butyl, 3-methoxy and 3-phenyl
catechols were oxidized with sodium periodate or polymer-sup-
ported periodate23 (PS-IO4ꢁ) and in all cases a complex mixture was
obtained. Rapidly it became clear that in situ generation of the
reactive o-benzoquinone would be required. Accordingly we de-
veloped a strategy based on a formal oxidative-coupling of 5-
unsubstituted catechols 7 (Scheme 4). In situ oxidation of a catechol
would generate the electrophilic o-benzoquinone intermediate 1
primed for attack by the conjugate base of the carbon-centred pro-
nucleophile 2. Following Michael addition, aromatization would
generate the catechol product 3, substituted at the 5-position as
desired. As 3-substituted catechols are either commercially
Scheme 2. Proof of principle studies and optimization studies with 1,2-
naphthoquinone.
Table 1
Optimization of the base-catalysed Michael addition to 1,2-naphthoquinone
Entry Base, %
Solvent 5 (mol equiv) Temp, ꢂC
Time Yield
(h)
%
1
2
3
4
5
6
7
8
9
10
NEt3, 10%
DABCO, 10% TBME
TBME
2
2
2
2
2
2
1
2
3
2
ꢁ20 ꢂCeRT
ꢁ20 ꢂCeRT
ꢁ20 ꢂCeRT
RT
RT
RT
ꢁ20 ꢂCeRT
ꢁ20 ꢂCeRT
ꢁ20 ꢂCeRT
ꢁ20 ꢂC
1
1
1
24
3
1
1
1
1
5
66
57
56
46
59
77
42
83
84
73
TMG, 10%
BEMP, 1%
BEMP 5%
BEMP, 10%
BEMP, 10%
BEMP, 10%
BEMP, 10%
BEMP, 10%
TBME
TBME
TBME
TBME
TBME
TBME
TBME
TBME
Scheme 4. Oxidative coupling concept for the construction of arylated quaternary
stereocentres.

K.M. Bogle et al. / Tetrahedron 66 (2010) 6399e6410
6401
available or readily prepared,24 this strategy would provide
a powerful and general route to compounds containing arylated
quaternary stereogenic centres.
Initially 1H NMR studies were conducted to demonstrate the
requirement for in situ generation of the o-benzoquinone. 3-
Methoxy and 3-tert-butyl catechols were oxidized with PS-IOꢁ4 in
CDCl3 and the decomposition of the quinone monitored over time.
Figure 2 demonstrates that whilst 1,2-naphthoquinone is stable
indefinitely, o-benzoquinone reagents rapidly degrade even when
bulky or electron donating groups are present.25
Figure 2. Decomposition of o-benzoquinones in CDCl3 compared with stable 1,2-
naphthoquinone, measured against an internal standard.15
Proof of principle studies for the oxidative coupling strategy was
conducted with 3-tert-butyl catechol 7 and ethyl phenylcyanoacetate
8, as representative quinone precursor and pro-nucleophile in con-
junction with PS-IOꢁ4 (Scheme 5). Feasibility was readily established
and optimization showed that 2 equiv of PS-IOꢁ4 were required for
complete consumption of the starting materials, and thatonly 1 equiv
of pro-nucleophile was required with 10 mol % of polymer-supported
BEMP (PS-BEMP) in CH2Cl2 at ꢁ20 ꢂC. Under these conditions, fol-
lowing reductive work-up with Na2S2O4(aq), the desired arylated
product 3a was isolated in a gratifying 85% overall yield.
Scheme 6. Scope of the organocatalytic oxidative coupling, *2 equiv of 2 was required.
This organocatalytic methodology was readily adapted to
allow an efficient asymmetric organocatalytic variant. The ability
of triethylamine to catalyse the Michael addition to 1,2-naph-
thoquinone (Table 1, entry 1) lead us to investigate the ability of
cinchona alkaloid derived organocatalysts to catalyse the aryla-
tion reaction. Replacing PS-BEMP with known catalyst 14 in the
reaction of 3-methoxycatechol with tert-butyl 1-oxoindane-2-
carboxylate 11 afforded the arylated adduct (ꢁ)-12 in 81% yield
and 74% ee.26 This was improved through the synthesis of orga-
nocatalyst 15,15 affording adduct (ꢁ)-12 in 84% yield and 81% ee
(Scheme 7). Pleasingly this level of enantioselectivity was also
achieved with 3-tert-butyl catechol, affording adduct (ꢁ)-13 in
73% yield and 81% ee.
Scheme 5. Proof-of-principle studies: Oxidative coupling of 3-tert-butylcatachol and
ethyl phenylcyanoacetate.
The scope of the reaction with respect to the 3-substituted cat-
echol and pro-nucleophile was then investigated. tert-Butyl, ethyl,
phenyl and methoxy-substituted catechols were all found to be
effective substrates and the scope of the reaction with respect to the
pro-nucleophile was also found to be broad;
b-ketoesters, b-dike-
tones, -ketoamides, -cyanoketones and -cyanoacetates were all
b
a
a
found to be effective. In most cases equimolar amounts of pro-nu-
cleophile and catechol were employed and in all cases the addition
was rapid, completely regioselective and high yielding (Scheme 6).
The significance of the catechol 3-substituent on the reaction
yield is demonstrated by example 3q. When catechol was reacted
with 2 equiv of methyl cyclopentanone-2-carboxylate under the
standard oxidative coupling conditions the 3-unsubstituted arylated
adduct 3q was obtained in only 18% yield. Despite this low yield no
other arylated products could be isolated from the reaction mixture.
Scheme 7. Asymmetric organocatalytic oxidative coupling.

6402
K.M. Bogle et al. / Tetrahedron 66 (2010) 6399e6410
Having developed a broadly applicable protocol for the syn-
thesis of catechol derivatives bonded to all-carbon quaternary
stereocentres, and demonstrated the methodology to be amenable
to asymmetric induction, we turned our attention to the applica-
tion of our methodology in total synthesis.
The crinane-type Amaryllidaceae alkaloids powelline 16 and
buphanidrine 17, characterized by the 5,10b-ethanophenan-
thridine crinane skeleton, both contain 3 stereogenic centres one
of which is quaternary, and differ in the substituent on the allylic
alcohol. They have been isolated from several Amaryllidaceae
species,27 and both have shown affinity for the serotonin trans-
porter in [H3]-citalopram binding assays.28 Several syntheses of
crinane-type alkaloids have been reported and recently a syn-
thesis of powelline utilizing similar chemistries was disclosed.29
Construction of the sterically congested arylated quaternary
stereocentre is pivotal to the synthesis of this class of alkaloid
and we believed that these two alkaloids would be ideal targets
to showcase our methodology for the synthesis of this motif. Our
retrosynthetic analysis is illustrated in Scheme 8.
Scheme 9. Total synthesis of (ꢀ)-powelline.
with superhydrideÒ and gave aminol 25 in 93% yield. Subsequent
acetylation followed by BF3$OEt2 mediated N-acyliminium ion
homologation using (isopropenyloxy)trimethylsilane as a nucleo-
philic trap afforded keto-ester 26. The diastereoselectivity in the
formation of 26 was dependent upon the reaction solvent and
ranged from 3:1 in dichloromethane to 7:1 in acetone. The Die-
ckmann-type cyclization, mediated by 2.1 equiv of potassium tert-
butoxide, proceeded smoothly to give the diketone as a single
diastereoisomer, the yield and diastereoselectivity of the cycli-
zation step were found to be independent of the diastereomeric
ratio of the keto-ester starting material 26. This is consistent with
a rapid and reversible base-catalysed epimerization process,
presumably via retro Michael/Michael addition, occurring faster
than the Dieckmann-type cyclization step to give the cis-fused
5,6-bicyclic diketone. The diketone product (of type 18) was
transformed without purification into methyl enol ether 27
through treatment with TiCl4 in methanol.31 The DIBAL re-
duction/acid hydrolysis of alkyl enol ether systems to their enone
products is known in the literature,32 however, in THF and tolu-
ene the predominant product was that resulting from a compet-
ing reaction sequence of 1,4-reduction, elimination of methanol
and a further 1,4-reduction to give a saturated ketone.16 The
amount of 1,4-reduction product was reduced by switching the
reaction solvent to dichloromethane and gave the desired cyclo-
hexenone 28 in 58% yield over two steps. The cis-stereochemistry
of 28 was unambiguously proven by single crystal X-ray diffrac-
tion (inset Scheme 9).
Scheme 8. Retrosynthetic analysis.
The synthetic plan was based on the direct catalysed construc-
tion of the quaternary carbon-to-aryl bond via the oxidative cou-
pling of readily prepared pro-nucleophile of type 20 and
commercially available 3-methoxycatechol 21. We envisaged that
transformation of 19 to the key cyclohexandione late-stage in-
termediate 18, common to both targets, would be possible via
formal reductive homologation followed by Dieckmann-type
cyclization. Reductive manipulation of cyclohexandione 18, fol-
lowed by deprotection and Pictet/Spengler cyclization should
provide rapid access to the target alkaloids.
Initially we concentrated on the synthesis of the target alkaloids
in racemic form. N-Boc was chosen as the protecting group for the
pro-nucleophile 23, in order to heighten acidity and allow selective
removal at a late stage in the synthesis. Methyl ester pro-nucleo-
phile 23 was readily synthesized from 1-(tert-butoxycarbonyl)-2-
pyrollidinone and reacted with 3-methoxycatechol 21 according to
the oxidative coupling protocol. The crude catechol intermediate
was not purified but reacted directly with bromochloromethane
under standard conditions to give the desired methylenedioxy
product 24 in 52% yield over the two steps (Scheme 9).30
Continuing with the planned synthesis of the key cyclo-
hexandione intermediate of type 18, a three carbon homologation
of the lactam was required to give the keto-ester 26 substrate
ready for the Dieckmann-type cyclization. Chemoselective
reduction of the ketonic gamma-lactam carbonyl was achieved
A diastereoselective reduction of the cyclohexenone carbonyl
was required to transform 28 to the required allylic alcohol sys-
tem. Standard Luche reduction conditions gave the desired
diastereomer 29 as the minor component of a separable 5.5:1

K.M. Bogle et al. / Tetrahedron 66 (2010) 6399e6410
6403
Table 2
mixture. Inversion of the allylic alcohol through mesylation,
Initial screen of organocatalysts and conditions for the synthesis of 24 and 40
displacement with CsOAc and hydrolysis has been shown to be an
effective but lengthy strategy for synthesis of the desired allylic
alcohol in related alkaloids.33 However when this approach was
adopted on our system loss of the stereochemical integrity of the
allylic alcohol was observed. A screen of reducing agents for 28
showed that N, K and L-Selectride all afforded the desired
diastereomer as the major component, with L-Selectride being the
optimal reagent, efficiently generated the desired diastereomer 29
with 3.5:1 dr. NOE studies on both allylic alcohol diastereomers
allowed assignment of relative stereochemical configurations. The
N-Boc protecting group was readily removed in neat TFA, and the
free base of amine 30 was used directly in the final Pictet/Spengler
cyclizationwithout purification. Treatmentof 30 with formaldehyde
in 6 M HCl at room temperature achieved, after 10 min, formation of
the final ring, completing the 13 step total synthesis of (ꢀ)-powel-
line. Gratifyingly the two possible regioisomers in the Pictet/Spen-
gler reaction were formed with w7:1 ratio in favour of the desired
product and were separable by silica gel chromatography.34 The
spectroscopic data (1H NMR, 13C NMR) and high resolution mass
spectrometric data of synthetic powelline were consistent with the
published data.35
Entry
Catalyst (loading)
Conc. (M)
Product
ee %
Yield %
1
2
3
4
5
6
7
8
9
Cat 14 (10 mol %)
Cat 15 (10 mol %)
Cat 33 (10 mol %)
Cat 34 (10 mol %)
Cat 35 (10 mol %)
Cat 36 (10 mol %)
Cat 37 (10 mol %)
Cat 38 (10 mol %)
Cat 39 (10 mol %)
Cat 35 (30 mol %)
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.01
(þ)-24
(þ)-24
(ꢁ)-24
(þ)-40
(þ)-24
(þ)-24
(ꢀ)-40
(þ)-40
(ꢁ)-24
(þ)-40
49
11
34
6
50
55
0
15
35
60
20
28
15
35
35
25
25
30
18
38
10
The total synthesis of (ꢀ)-buphanidrine was accomplished
through O-methylation of allylic alcohol 29 under standard condi-
tions followed by the same deprotection/Pictet/Spengler sequence
(Scheme 10). Again, the Pictet/Spengler step was found to be
regioselective, forming the desired isomer in a w10:1 ratio.
(ꢀ)-Buphanidrine was synthesized in 14 linear steps and a 6%
overall yield. The spectroscopic data (1H NMR, 13C NMR) and high
OH
N
OH
N
N
N
O
O
HN
N
HN
O
N
O
Cat 33
CF3
Cat 15
Cat 14
F3C
OH
N
OH
N
OH
N
N
N
O
O
O
N
O
Cat 36
Cat 34
Cat 35
CF3
N
HN
HN
CF3
O
NH
OH
N
O
NH
Scheme 10. Total synthesis of (ꢀ)-buphanidrine.
N
O
O
N
F3C
CF3
N
resolution mass spectrometric data of synthetic buphanidrine were
in excellent agreement with the published data.28b,36
Cat 37
Cat 38
Cat 39
Having established a synthesis of the target alkaloids in racemic
form, we turned our attention to an asymmetric synthesis, which
we aimed to accomplish through the use of a cinchona-derived
organocatalyst in the oxidative coupling step. A screen of organo-
catalysts (Table 2)37 was undertaken on 0.1 mmol scale and the
enantioselectivities determined by chiral HPLC. No attempts were
made to optimize the reaction yields. To expedite the measurement
of enantiomeric excess during catalyst screening, in some cases the
catechol product was protected as the di-acetate.
Whilst all the enantiomeric excesses were moderate in the
initial catalyst screen, the quinidine-derived benzyl catalysts 35
and 36 emerged as the most promising scaffolds. The wide varia-
tion of enantiomeric excess observed with, previously optimal,
catalyst 15 demonstrates the need to match the catalyst and pro-
nucleophile. The initial enantiomeric excess achieved with catalyst
35 was increased by 10% by increasing the dilution and the catalyst
loading (entry 10). CH2Cl2 remained the optimal solvent.
A range of alternative pro-nucleophiles of type 20 were syn-
thesized and screened with catalyst 35 to identify any opportunity
to increase the levels of enantioselectivity obtained previously with
pro-nucleophile 23 (Table 3). The steric bulk of the protecting group
and ester was varied, however, no improvements in enantio-
selectivity were obtained.

6404
K.M. Bogle et al. / Tetrahedron 66 (2010) 6399e6410
Table 3
Screen of pro-nucleophiles
in 57% yield and 70% ee on a 10 mmol scale and treated with
superhydrideÒ affording aminol (þ)-25 in 90% yield (Scheme 11).
Pro-nucleophile
R1
R2
R3
Product
ee %
Yield %
41
42
43
44
H
H
Ac
Ac
COOtBu
COOMe
CBz
Ph
Ph
Me
Me
(þ)-45
(þ)-46
(þ)-47
(þ)-48
40
9
30
1
29
34
30
24
Ts
A range of novel quinidine-derived organocatalysts with varying
benzyl substitutents (Table 4) were then synthesized from quini-
dine and screened in the oxidative coupling step.
Scheme 11. Attempted enantioselective total synthesis.
Acylation and BF3$OEt2 mediated N-acyliminium ion homolo-
gation gave keto-ester (ꢁ)-26 in 3:1 dr and with no loss of
stereochemical integrity. Subsequent Dieckmann-type cyclization
and methyl enol ether formation yielded (ꢁ)-27, however HPLC
analysis showed a decrease in enantiomeric excess to 24%. This is
attributed to a fast epimerization process, which is presumably also
responsible for the formation of only one diastereomer of (ꢀ)-27
(see Scheme 9 and accompanying text). Due to the loss of stereo-
chemical integrity the enantioselective synthesis was halted, with
an alternative strategy being required to avoid the epimerization
problems.
Table 4
Screen of novel substituted-benzyl catalysts
In summary we have exemplified the ability of o-quinones to act
as Michael acceptors towards carbon-centred nucleophiles and
developed a broadly applicable oxidative coupling process for in
situ generation of the highly reactive and unstable o-benzoquinone
intermediate. The methodology pivots on the base catalysed addi-
tion of a carbon-centred pro-nucleophile and is general, high
yielding, atom economical and provides remarkably efficient access
to this challenging structural motif. We have subsequently exem-
plified the utility of our methodology in the total synthesis of two
members of the crinane-type Amaryllidaceae alkaloids powelline
and buphanidrine.
3. Experimental
3.1. General
All 1H and 13C NMR spectra were recorded using a Bruker AVII
500 MHz, Bruker DPX 500, Bruker DPX 400 and 500 MHz, and
Entry
Catalyst (loading)
Product
Conc./M
ee %
Yield %
1
2
3
4
5
6
Cat 49 (10 mol %)
Cat 50 (10 mol %)
Cat 51 (10 mol %)
Cat 52 (10 mol %)
Cat 52 (20 mol %)
Cat 53 (20 mol %)
(þ)-40
(þ)-40
(þ)-40
(þ)-40
(þ)-24
(ꢁ)-24
0.1
0.1
0.1
0.1
0.025
0.025
43
50
43
64
70
70
41
25
38
56
57
55
Varian 300 MHz spectrometers. Chemical shifts (
parts per million, and coupling constants (J) are given in hertz (Hz).
The 1H NMR spectra are reported as follows:
/ppm (number of
d) are given in
d
protons, multiplicity, coupling constants J/Hz, assignment).
DEPT135, two-dimensional (COSY, HSQC, HMBC) and NOE/NOESY
NMR spectroscopy were used where appropriate to assist the as-
signment of signals in the 1H and 13C NMR spectra. Low resolution
mass spectrometry (electrospray) was recorded on a Micromass
Platform II spectrometer, Micromass Trio 2000 quadrupole and
a Micromass LCT premier. High resolution mass spectra (accurate
mass) were recorded on a Thermo Finnigan Mat95XP mass spec-
trometer and a Bruker MicroTof spectrometer. Infrared spectra
were recorded on a Perkin Elmer Spectrum RX1 FTIR and a Bruker
Tensor FT-IR spectrometer (thin film deposited onto a sodium
chloride plate), only selected absorbances (lmax) are reported.
Melting points were recorded using a Gallenkamp and a Leica Galen
II melting point apparatus and are uncorrected. Optical rotations
Catalysts 49e51 were not found to offer improvements over the
simple benzyl system 35, however ortho-CF3 derivative 52
increased the enantiomeric excess to 64%. This was further in-
creased to 70% by increasing the catalyst loading to 20 mol % at
a concentration of 0.025 M. The absolute stereochemistry of the
major enantiomer is not known, however the opposite enantiomer
(ꢁ)-24 was obtained in 70% ee with the pseudo-enantiomeric
catalyst 53. Since the racemic enone 28 was known to be highly
crystalline the enantioselective synthesis was begun with the
intention of increasing the enantiopurity through recrystallisation.
Accordingly enantioenriched arylated adduct (þ)-24 was prepared

K.M. Bogle et al. / Tetrahedron 66 (2010) 6399e6410
6405
were recorded using an Optical Activity AA-1000 polarimeter and
a PerkineElmer 241 polarimeter; [ values are reported in
J¼9.0, 6.5 Hz, OCH2CH2), 3.73e3.66 (4H, m, OCH2CH2 and C(O)
OCH3), 2.67 (1H, ddd, J¼13.0, 6.5, 3.0 Hz, OCH2CH2), 2.47 (3H, s, OC
(O)CH3), 2.33 (3H, s, O(CO)CH3); 13C NMR (125 MHz, CDCl3) dC 173.3
(C(O)O), 170.1 (C(O)O), 168.1 (OC(O)CH3), 167.9 (OC(O)CH3), 138.1
(4ꢂ ArC), 137.5 (4ꢂ ArC), 131.1 (4ꢂ ArC), 129.3 (4ꢂ ArC), 129.0 (4ꢂ ArC),
127.1 (ArCH), 126.9 (ArCH), 123.5 (ArCH), 122.8 (ArCH), 122.0
(ArCH), 66.4 (OCH2), 60.1 (4ꢂC), 54.0 (C(O)OCH3), 35.1 (OCH2CH2),
20.7 (OC(O)CH3), 20.5 (OC(O)CH3); IR nmax/cmꢁ1 1768, 1763,
1758, 1737, 1609, 1369, 1204, 1168, 1156, 772; mp 141e143 ꢂC; MS
(CIþ) m/z (relative intensity %) 404 (MþNHþ4 , 100%); HRMS (ESþ)
calcd for C20H22O8N (MþNHþ4 ) 404.1340, found 404.1331.
a
]
D
10ꢁ1 degcm2 gꢁ1; concentration (c) is given in g/100 ml at 589 nm.
(þ) and (ꢁ) compound number prefixes indicate the sign of the
optical rotation. Bulk solutions were evaporated under reduced
pressure using a Büchi rotary evaporator. Reagents and solvents
used were obtained from commercial suppliers and used without
further purification unless stated otherwise. Petroleum ether refers
to distilled light petroleum of fraction (40e60 ꢂC). 1,2-Naph-
thoquinone was purchased from fluka and used as received.
3-Substituted catechols were synthesized from the appropriate
2-substituted phenol through a one-pot ortho-formylation and
Dakin oxidation procedure as described by Hansen and Skattebøl24a
Polymer-supported periodate was prepared from amberliteÒ IRA-
900 chloride form resin (Aldrich) as described by Hodge and Har-
rison.23 For determination of the PS-IOꢁ4 loading, 1H NMR quinone
stability studies, and synthesis and characterization of adducts
3aep see Ref. 15. For the preparation of pro-nucleophiles see Ref.
21. For the synthesis of catalysts 14, 33e39 see Ref. 37 and for 15 see
Ref. 15. For the synthesis of compounds 23e32, (ꢀ)-powelline and
(ꢀ)-buphanidrine and X-ray data for 28 see Ref. 16.
3.2.3. [2-Acetoxy-4-(1-cyano-2-oxo-cyclohexyl)-1-naphthyl] acetate
6c. According to the above procedure for the preparation of 6a, 1,2-
naphthoquinone 4 (90 mg, 0.57 mmol) was reacted with 2-oxocy-
clohexanecarbonitrile (140 mg, 1.14 mmol) to give compound 6c
(167 mg, 80%) as a white solid after chromatography on silica gel,
eluting with petroleum ether containing 30% ethyl acetate; 1H NMR
(500 MHz, CDCl3) dH 7.96e7.93 (1H, m, ArH), 7.85e7.82 (1H, m,
ArH), 7.59e7.54 (2H, m, ArH), 7.49 (1H, s, ArH), 2.97e2.91 (1H, ddd,
J¼13.0, 10.0, 5.0 Hz, CH2), 2.84e2.73 (2H, m, CH2), 2.53e2.48 (4H,
m, CH2 and OC(O)CH3), 2.36 (3H, s, 1 of OC(O)CH3), 2.29e2.18 (3H,
m, CH2), 2.04e1.96 (1H, m, CH2); 13C NMR (125 MHz, CDCl3) dC
202.6 (C(O)), 168.2 (OC(O)CH3), 167.7 (OC(O)CH3), 138.2 (4ꢂ ArC),
137.9 (4ꢂ ArC), 129.7 (4ꢂ ArC), 128.7 (4ꢂ ArC), 128.4 (4ꢂ ArC), 127.1
(ArCH), 127.0 (ArCH), 124.9 (ArCH), 122.4 (ArCH), 121.8 (ArCH), 119.1
(CN), 54.8 (4ꢂC), 39.1 (CH2), 38.5 (CH2), 28.7 (CH2), 21.9 (CH2), 20.8
(OC(O)CH3), 20.5 (OC(O)CH3); IR nmax/cmꢁ1 1769, 1764, 1754, 174þ9,
1608, 1369, 1195, 1164, 1095, 1015, 765; mp 142e144 ꢂC; MS (ES )
m/z (relative intensity %) 383 (MþNHþ4 , 15%), 388 (MþNaþ, 100%);
HRMS (ESþ) calcd for C21H19O5NNa (MþNaþ) 388.1155, found
388.1155.
3.2. Experimental procedures and characterization
3.2.1. Methyl 1-(3,4-diacetoxy-1-naphthyl)-2-oxo-cyclopentanecar-
boxylate 6a. To a stirred solution of 2-oxocyclopentanecarboxylate
5
(501 mg, 3.42 mmol) and 2-tert-butylimino-2-diethylamino-
1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP)
(50 mL,
0.17 mmol) in tert-butyl methyl ether (8 mL) at ꢁ20 ꢂC was added,
portion-wise over 10 min, 1,2-naphthoquinone
4
(300 mg,
1.71 mmol). The resulting brown suspension was stirred at this
temperature for 1 h, then allowed to warm to room temperature and
stirred for a further 1 h. The solvent was removed by rotary evapo-
rator and the residue dissolved in pyridine (5 mL) and acetic anhy-
dride (0.53 mL, 5.64 mmol) was added. The mixture was stirred at
room temperature overnight then diluted with Et2O (15 mL) and
washed with saturated aqueous CuSO4 (3ꢃ10 mL). The aqueous
washings were re-extracted with Et2O (2ꢃ5 mL) and the combined
organic portions dried over sodium sulfate, filtered and concentrated
by rotary evaporator. The crude residue was purified by chroma-
tography on silica gel to give 6a (546 mg, 83%) as an off-white solid;
1H NMR (500 MHz, CDCl3) dH 7.89 (1H, d, J¼8.0 Hz, ArH), 7.70 (1H, d,
J¼8.0 Hz, ArH), 7.55e7.48 (2H, m, ArH), 7.02 (1H, s, ArH), 3.65 (3H, s,
C(O)OCH3), 3.23 (1H, ddd, J¼13.0, 9.5, 7.0 Hz, C(O)CH2CH2CH2),
2.61e2.52 (3H, m, C(O)CH2CH2CH2 and C(O)CH2CH2CH2), 2.46 (3H, s,
OC(O)CH3), 2.31 (3H, s, OC(O)CH3), 2.16e2.09 (1H, m, C(O)
CH2CH2CH2), 1.89e1.79 (1H, m, C(O)CH2CH2CH2); 13C NMR
(125 MHz, CDCl3) dC 213.6 (C(O)), 171.6 (C(O)OCH3), 168.2 (OC(O)
CH3), 167.9 (OC(O)CH3), 137.9 (4ꢂ ArC), 136.7 (4ꢂ ArC), 133.7 (4ꢂ ArC),
129.9 (4ꢂ ArC), 128.9 (4ꢂ ArC), 126.7 (ArCH), 126.5 (ArCH), 124.5
(ArCH), 122.4 (ArCH), 121.3 (ArCH), 65.6, (4ꢂ C) 53.3 (C(O)CH3), 38.9
(C(O)CH2CH2CH2), 36.4 (C(O)CH2CH2CH2), 20.7 (OC(O)CH3), 20.5 (OC
(O)CH3), 19.5 (C(O)CH2CH2CH2); IR nmax/cmꢁ1 1765, 1754, 1716, 1371,
1240, 1212, 1199, 770; mp 151e153 ꢂC decomp.; MS (CIþ) m/z (rela-
tive intensity %) 402 (MþNHþ4 , 100%); HRMS (ESþ): calcd for
C21H24O7N (MþNHþ4 ) 402.1547, found 402.1548.
3.2.4. [2-Acetoxy-4-(1-cyano-2-oxo-cyclopentyl)-1-naphthyl] ace-
tate 6d. According to the above procedure for the preparation of 6a,
1,2-naphthoquinone 4 (158 mg, 1.00 mmol) was reacted with
2-oxocyclopentanecarbonitrile (218 mg, 2.00 mmol) to give com-
pound 6d (283 mg, 81%) as a cream coloured solid after chroma-
tography on silica gel, eluting with petroleum ether containing
50e70% diethyl ether; 1H NMR (500 MHz, CDCl3) dH 8.21 (1H, d,
J¼7.5 Hz, ArH), 7.94 (1H, d, J¼7.5 Hz, ArH), 7.65e6.57 (2H, m, ArH),
7.25 (1H, s, ArH), 2.90e2.80 (2H, m, C(O)CH2CH2CH2), 2.66 (2H, app.
t, J¼8.0 Hz, C(O)CH2CH2CH2), 2.45 (3H, s, OC(O)CH3), 2.32 (3H, s, OC
(O)CH3), 2.26e2.18 (1H, m, C(O)CH2CH2CH2), 2.08e1.99 (1H, m, C
(O)CH2CH2CH2); 13C NMR (125 MHz, CDCl3) dC 207.7 (C(O)), 168.1
(OC(O)CH3), 167.7 (OC(O)CH3), 137.9 (4ꢂ ArC), 137.8 (4ꢂ ArC), 129.0
(4ꢂ ArC), 128.7 (4ꢂ ArC), 127.9 (4ꢂ ArC), 127.2 (ArCH), 127.0 (ArCH),
124.7 (ArCH), 122.5 (ArCH), 122.0 (ArCH), 118.5 (CN), 52.7 (4ꢂC), 37.4
(CH2), 36.7 (CH2), 20.6 (OC(O)CH3), 20.3 (OC(O)CH3), 19.3 (CH2); IR
nmax/cmꢁ1 1769, 1766, 1758, 1608, 1369, 1200, 1164, 1015, 768; mp
70e71 ꢂC (decomp.); MS (ESþ) m/z (relative intensity %) 406
(MþNaþþMeOH, 100%), 374 (MþNaþ, 85%); HRMS (ESþ): calcd for
C20H18O5N (MþHþ) 352.1179, found 352.1178.
3.2.5. Methyl 2-(3,4-diacetoxy-1-naphthyl)-1-oxo-indane-2-carboxy-
late 6e. According to the above procedure for the preparation of 6a,
1,2-naphthoquinone 4 (300 mg,1.71 mmol) was reacted with methyl
1-oxoindane-2-carboxylate (650 mg, 3.42 mmol) to give compound
6e (639 mg, 86%) as a yellow solid after chromatography on silica gel,
eluting with petroleum ether containing 30% ethyl acetate; 1H NMR
(500 MHz, CDCl3) dH 7.92e7.89 (2H, m, ArH), 7.76e7.74 (1H, m, ArH),
7.65 (1H, t, J¼7.5, ArH), 7.58e7.53 (2H, m, ArH), 7.45e7.42 (2H, m,
ArH), 7.27 (1H, s. ArH), 4.69 (1H, d, J¼17.0 Hz, CH2), 3.67 (3H, s, C(O)
OCH3), 3.49 (1H, d, J¼17.0 Hz, CH2), 2.44 (3H, s, OC(O)CH3), 2.28 (3H,
s, OC(O)CH3); 13C NMR (125 MHz, CDCl3) dC 200.4 (C(O)), 171.2 (C(O)
OCH3), 168.1 (OC(O)CH3), 168.0 (OC(O)CH3), 153.1 (4ꢂ ArC), 138.1 (4ꢂ
3.2.2. Methyl 3-(3,4-diacetoxy-1-naphthyl)-2-oxo-tetrahydrofuran-
3-carboxylate 6b. According to the above procedure for the prep-
aration of 6a, 1,2-naphthoquinone 4 (300 mg, 1.71 mmol) was
reacted with methyl 2-oxotetrahydrofuran-3-carboxylate (493 mg,
3.42 mmol) to give compound 6b (488 mg, 74%) as an off-white
solid after chromatography on silica gel, eluting with petroleum
ether containing 30% ethyl acetate; 1H NMR (500 MHz, CDCl3) dH
7.93 (1H, dd, J¼8.0, 1.5 Hz, ArH), 7.61e7.51 (3H, m, 3 of ArH), 7.31
(1H, s, ArH), 4.54 (1H, dt, J¼9.0, 3.0 Hz, OCH2CH2), 4.19 (1H, dt,

6406
K.M. Bogle et al. / Tetrahedron 66 (2010) 6399e6410
ArC),136.8 (4ꢂ ArC),136.3 (ArCH), 135.2 (4ꢂ ArC),134.4 (4ꢂ ArC),130.6
(4ꢂ ArC), 128.8 (4ꢂ ArC), 128.1 (ArCH), 126.8 (ArCH), 126.7 (ArCH),
126.5 (ArCH), 125.3 (ArCH), 124.1 (ArCH), 122.6 (ArCH), 121.4 (ArCH),
65.3 (4ꢂC), 53.7 (C(O)OCH3), 41.6 (CH2), 20.7 (OC(O)CH3), 20.5 (OC(O)
CH3); IR nmax/cmꢁ1 1765, 1760, 1748, 1733, 1610, 1426, 1368, 1199,
1170, 763; mp 187e189 ꢂC; MS (CIþ) m/z (relative intensity %) 450
(MþNHþ4 , 100%); HRMS (ESþ) calcd for C25H24O7N (MþNHþ4 )
450.1547, found 450.1537.
residue was purified by chromatography on silica gel to give the
desired arylated products.15
3.3.1. Methyl 1-(3,4-dihydroxyphenyl)-2-oxo-cyclopentanecarboxy-
late 3q. According to the general oxidative coupling procedure,
except that PS-IOꢁ4 was added portion-wise, catechol (55 mg,
0.50 mmol) was reacted with 2-oxocyclopentanecarboxylate
(142 mg,1.00 mmol) to give, after 2 h reaction time, 3q (23 mg,18%)
as a yellow oil following chromatography on silica gel, eluting with
petroleum ether containing 50e70% diethyl ether; 1H NMR
(500 MHz, CDCl3) dH 6.95 (1H, d, J¼2.0 Hz, ArH), 6.80e6.74 (2H, m,
ArH), 6.30 (1H, br s, OH), 5.94 (1H, br s, OH), 3.71 (3H, s, OCH3), 2.79
(1H, td, J¼13.5, 7.0 Hz, CH2), 2.55e2.43 (2H, m, CH2), 2.40e2.34 (1H,
m, CH2), 2.02e1.86 (2H, m, CH2); 13C NMR (75 MHz, CDCl3) dC 212.9
(C]O), 171.6 (C(O)O), 143.6 (4ꢂ ArC), 143.5 (4ꢂ ArC), 128.0 (4ꢂ ArC),
119.8 (ArCH), 115.3 (ArCH), 114.9 (ArCH), 64.3 (4ꢂ C), 53.1 (OCH3),
37.7 (CH2), 34.8 (CH2), 19.2 (CH2); IR nmax/cmꢁ1 3430, 1745, 1718,
1638, 1523, 1436, 1261; MS (ESþ) m/z (relative intensity %) 273
(MþNaþ, 100%), 523 (dimerþNaþ, 45%); HRMS (ESþ): calcd for
C13H14O5Na (MþNaþ) 273.0733, found 273.0731.
3.2.6. Methyl 3-(3,4-diacetoxy-1-naphthyl)-2-oxo-3a,7a-dihydro-1H-
indole-3-carboxylate 6f. According to the above procedure for the
preparation of 6a, 1,2-naphthoquinone 4 (47 mg, 0.30 mmol) was
reacted with methyl 2-oxoindoline-3-carboxylate (114 mg,
0.60 mmol) to give compound 6f (112 mg, 86%) as an off-white solid
after chromatography on silica gel eluting with diethyl ether; 1H
NMR (500 MHz, DMSO-d6) dH 11.0 (1H, s, NH), 8.17e8.15 (1H, m,
ArH), 8.01e7.98 (1H, m, ArH), 7.68e7.64 (2H, m, ArH), 7.43 (1H, dt,
J¼7.5, 1.0 Hz, ArH), 7.29 (1H, d, J¼7.5 Hz, ArH), 7.17 (1H, t, J¼7.5 Hz,
ArH), 7.04 (1H, d, J¼7.5 Hz, ArH), 6.85 (1H, s, ArH), 3.69 (3H, s, C(O)
OCH3), 2.48 (3H, s, OC(O)CH3), 2.25 (3H, s, OC(O)CH3); 13C NMR
(75 MHz, DMSO-d6) dC 172.4 (C(O)), 169.8 (C(O)), 168.3 (OC(O)CH3),
168.2 (OC(O)CH3), 142.5 (ArC), 137.8 (ArC), 137.1 (ArC), 131.9 (ArC),
130.4 (ArC), 130.0 (ArC), 128.2 (ArC), 127.1 (ArC), 126.9 (ArC), 126.7
(ArC), 126.2 (ArC), 125.6 (ArC), 122.7 (ArC), 121.8 (ArC), 121.7 (ArC),
110.5 (ArC), 63.5 (4ꢂC), 53.5 (C(O)OCH3), 20.3 (OC(O)CH3), 20.2 (OC
(O)CH3); IR nmax/cmꢁ1 3361, 1769, 1755, 1738, 1729, 1474, 1370, 1212,
1193,1165, 767, 750; mp 242e246 ꢂC decomp.; MS (CIþ) m/z (relative
intensity %) 451 (MþNHþ4 , 100%); HRMS (ESþ) calcd for C24H23O7N2
(MþNHþ4 ) 451.1500, found 451.1495.
3.3.2. tert-Butyl 2-(3-tert-butyl-4,5-dihydroxy-phenyl)-1-oxo-indane-
2-carboxylate (ꢁ)-13. According to the general oxidative coupling
procedure, replacing PS-BEMP with catalyst 15, 3-tert-butyl catechol
8 (16 mg, 0.10 mmol) was reacted with 11 (23 mg, 0.10 mmol) to
give, after 2 h reaction time, compound (ꢁ)-13 (29 mg, 73%) as
a yellow solid after chromatography on silica gel, eluting with
petroleum ether containing 50e70% diethyl ether, in 81% ee,
determined by HPLC analysis [Chiralpak AD, hexane/iso-propanol
95:5, 1.0 mL minꢁ1
40.96 min] by comparison to a racemic sample prepared according
,
l¼230 nm, t (minor)¼37.62 min, t (major)¼
3.2.7. Ethyl 2-cyano-2-(3,4-diacetoxy-1-naphthyl)-2-phenyl-acetate
6g. According to the above procedure for the preparation of 6a, 1,2-
naphthoquinone 4 (300 mg, 1.71 mmol) was reacted with ethyl
phenylcyanoacetate (647 mg, 3.42 mmol) to give compound 6g
(565 mg, 77%) as a yellow solid after chromatography on silica gel,
eluting with petroleum ether containing 30% ethyl acetate; 1H NMR
(500 MHz, CDCl3) dH 7.98 (1H, d, J¼8.0 Hz, ArH), 7.94 (1H, d,
J¼8.0 Hz, ArH), 7.64e7.63 (2H, m, ArH), 7.59e7.53 (2H, m, ArH),
7.51e7.47 (3H, m, ArH), 6.91 (1H, s, ArH), 4.43e4.31 (2H, m,
OCH2CH3), 2.46 (3H, s, 1 of OC(O)CH3), 2.26 (3H, s, 1 of OC(O)CH3),
1.29 (3H, t, J¼7.0 Hz, OCH2CH3); 13C NMR (125 MHz, CDCl3) dc 167.8
(C(O)), 167.6 (C(O)), 167.0 (C(O)), 138.2 (4ꢂ ArC), 137.9 (4ꢂ ArC), 133.3
(4ꢂ ArC), 130.8 (4ꢂ ArC), 129.4 (ArCH), 129.4 (ArCH), 129.3 (4ꢂ ArC),
128.6 (4ꢂ ArC), 128.2 (ArCH), 127.1 (ArCH), 127.1 (ArCH), 124.4
(ArCH), 124.1 (ArCH), 122.4 (ArCH), 118.0 (CN), 64.0 (OCH2), 57.6
24
to the general oxidative coupling procedure; [
a
]
ꢁ5.3 (c 3.0,
D
CHCl3); 1H NMR (500 MHz, CDCl3) dH 7.78 (1H, d, J¼7.5 Hz, ArH), 7.63
(1H, t, J¼7.5 Hz, ArH), 7.48 (1H, d, J¼7.5 Hz, ArH), 7.39 (1H, t, J¼7.5 Hz,
ArH), 6.91 (1H, d, J¼2.0 Hz ArH), 6.83 (1H, d, J¼2.0 Hz, ArH), 6.24 (1H,
br s, OH), 5.71 (1H, s, OH), 4.09 (1H, d, J¼17.0 Hz, CH2), 3.54 (1H, d,
J¼17.0 Hz, CH2), 1.37 (18H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3) dC
202.7 (C]O), 170.0 (C(O)O), 152.7 (4ꢂ ArC), 143.2 (4ꢂ ArC), 143.0 (4ꢂ
ArC), 135.7 (4ꢂ ArC), 135.6 (ArCH), 135.1 (4ꢂ ArC), 128.6 (4ꢂ ArC),127.8
(ArCH),126.1 (ArCH), 125.0 (ArCH),117.6 (ArCH),112.1 (ArCH), 82.7 (C
(O)OC(CH3)3), 66.1 (4ꢂ C), 40.8 (CH2), 34.8 (C(CH3)3), 29.4 (C(CH3)3),
27.7 (C(CH3)3); mp: 124e126 ꢂC (142e144 ꢂC for racemate); IR nmax
/
cmꢁ1 3388, 2953, 1708, 1693, 1601, 1426, 1368, 1250, 1150; MS (ESþ)
m/z (relative intensity %) 419 (MþNaþ, 100%); HRMS (EIþ): calcd for
C24H32O5N (MþNHþ4 ) 414.2275, found 414.2276.
(4ꢂC), 20.6 (OC(O)CH3), 20.4 (OC(O)CH3), 13.7 (OCH2CH3); IR nmax
/
cmꢁ1 1787, 1761, 1750, 1608, 1373, 1216, 1192, 1175, 1166, 1156, 895,
744, 734; mp 126e128 ꢂC; MS (CIþ) m/z (relative intensity %) 449
(MþNHþ4 , 100%); HRMS (ESþ) calcd for C25H25O6N2 (MþNHþ4 )
449.1707, found 449.1698.
3.3.3. 1-tert-Butyl 3-phenyl 2-oxopyrrolidine-1,3-dicarboxylate 41. A
solution of tert-butyl-2-oxopyrrolidine-1-carboxylate (500 mg,
2.70 mmol) in THF (2 mL) was added to a solution of LHMDS
(5.7 mL of a 1 M solution in THF, 5.70 mmol) at ꢁ78 ꢂC. The reaction
mixture was stirred at this temperature for 5 min, then phenyl
chloroformate (0.34 mL, 2.70 mmol) was added. The reaction
mixture was stirred for 15 min then quenched with 1 M HCl
(20 mL) and warmed to room temperature. The biphasic mixture
was extracted with EtOAc (3ꢃ10 mL) and the combined organic
extracts dried over Na2SO4, filtered and concentrated. The residue
was purified by chromatography on silica gel, eluting with cyclo-
hexane containing 0e40% EtOAc to give 41 (450 mg, 55%) as a white
solid. 1H NMR (500 MHz, CDCl3) dH 7.31 (2H, t, J¼7.5 Hz, ArH), 7.17
(1H, t, J¼7.5 Hz, ArH), 7.13 (2H, d, J¼7.5 Hz, ArH), 3.87 (1H, ddd,
J¼10.5, 9.0, 4.5 Hz, CH2N), 3.72 (1H, t, J¼9.0 Hz CH), 3.68 (1H, dt,
J¼10.5, 7.5 Hz, CH2N), 2.48e2.40 (1H, m, CH2CH2N), 2.31e2.24 (1H,
m, CH2CH2N), 1.47 (9H, s, C(CH3)3); 13C NMR (125 MHz, CDCl3) dC
168.2 (C(O)), 167.4 (C(O)), 150.3 (OC(O)N), 149.7 (4ꢂ ArC), 129.4
(ArCH), 126.1 (ArCH), 121.3 (ArCH), 83.5 (C(CH3)3), 50.2 (CH), 44.7
(CH2), 27.9 (C(CH3)3), 21.4 (CH2); mp: 72e74 ꢂC; IR nmax/cmꢁ1 2980,
3.3. General oxidative coupling procedure
To a stirred solution of catechol (1 equiv), pro-nucleophile
(1 equiv) and PS-BEMP (10 mol %) in dichloromethane (10 mL/
mmol) at ꢁ20 ꢂC, in a flask wrapped in aluminium foil, was added
PS-IOꢁ4 (2 equiv). The resulting suspension was stirred at this
temperature until TLC analysis showed complete consumption of
starting materials. The reaction mixture was filtered to remove the
polymer supported reagents, and the resin washed on the sinter
with CH2Cl2 (10 mL/mmol). The typically deep red filtrate was
stirred vigorously with saturated aqueous Na2S2O4 (20 mL/mmol)
for 10 min (the colour typically fades to pale yellow). The organic
layer was separated and the aqueous extracted with CH2Cl2
(2ꢃ5 mL/mmol). The combined organic portions were dried over
sodium sulfate, filtered and concentrated by rotary evaporator. The

K.M. Bogle et al. / Tetrahedron 66 (2010) 6399e6410
6407
2934,1788, 1756, 1721, 1492, 1370,1295, 1255,1192, 1143, 1020, 936;
MS (ESþ) m/z (relative intensity %) 328 (MþNaþ, 100%), 360
(MþNaþþMeOH, 10%); HRMS (ESþ): calcd for C16H19O5NNa
(MþNaþ) 328.1155, found 328.1151.
AD, heptane/ethanol 55:45, 1.0 mL minꢁ1
,
l
¼215 nm, t (minor)¼
10.78 min, t (major)¼14.85 min] by comparison to a racemic sam-
ple prepared according to the general oxidative coupling pro-
24
cedure. [
a
]
þ34.2 (c 0.7, CHCl3); 1H NMR (500 MHz, CDCl3) dH
D
7.36e7.32 (2H, m, ArH), 7.21 (1H, t, J¼7.5 Hz, ArH), 7.06e7.04 (2H,
m, ArH), 6.84 (1H, d, J¼2.0 Hz, ArH), 6.74 (1H, d, J¼2.0 Hz, ArH), 5.47
(2H, br s, OH), 3.88e3.82 (1H, m, CH2N), 3.87 (3H, s, OCH3), 3.69 (1H,
dt, J¼10.5, 7.0 Hz, CH2N), 3.04 (1H, td, J¼13.0, 7.0 Hz, CH2CH2N),
2.57 (1H, ddd, J¼13.0, 7.0, 5.5 Hz, CH2CH2N), 1.54 (9H, s, C(CH3)3);
13C NMR (125 MHz, CDCl3) dC 169.4 (C(O)), 168.6 (C(O)), 150.6 (OC
(O)N), 150.0 (4ꢂ ArC), 147.0 (4ꢂ ArC), 143.8 (4ꢂ ArC), 132.5 (4ꢂ ArC),
129.4 (ArCH), 126.8 (4ꢂ ArC), 126.1 (ArCH), 121.2 (ArCH), 107.6
(ArCH), 103.0 (ArCH), 83.7 (C(CH3)3), 61.3 (4ꢂ C), 56.3 (OCH3), 43.3
(CH2), 29.9 (CH2), 28.0 (C(CH3)3); mp 137e139 ꢂC (140e141 ꢂC for
racemate); IR nmax/cmꢁ1 3400, 2980, 2934, 1778, 1745, 1723, 1521,
1370, 1308, 1188, 1150; MS (ESþ) m/z (relative intensity %) 466
(MþNaþ, 100%); HRMS (ESþ) calcd for C23H25O8NNa (MþNaþ)
466.1472, found 466.1473.
3.3.4. 1-Methyl 3-phenyl 2-oxopyrrolidine-1,3-dicarboxylate 42.
According to the above procedure for the preparation of 41, methyl
2-oxopyrrolidine-1-carboxylate38 (429 mg, 3.00 mmol) was reac-
ted with phenyl chloroformate (0.38 mL, 3.00 mmol) to give 42
(320 mg, 41%) as a white solid after chromatography on silica gel,
eluting with cyclohexane containing 20e60% EtOAc. 1H NMR
(400 MHz, CDCl3) dH 7.39e7.34 (2H, m, ArH), 7.25e7.21 (1H, m,
ArH), 7.14e7.10 (2H, m, ArH), 3.97 (1H, ddd, J¼11.0, 8.5, 5.0 Hz,
CH2N), 3.86 (3H, s, OCH3), 3.82e3.75 (2H, m, CH and CH2N), 2.52
(1H, dtd, J¼13.0, 8.5, 7.5 Hz, CHCH2CH2N), 2.37 (1H, m,
CHCH2CH2N); 13C NMR (100 MHz, CDCl3) dC 168.2 (C(O)), 167.2 (C
(O)), 151.7 (OC(O)N), 150.3 (4ꢂ ArC), 129.4 (ArCH), 126.2 (ArCH),
121.2 (ArCH), 53.7 (OCH3), 49.9 (CH), 44.7 (NCH2), 21.5 (NCH2CH2);
mp: 88e90 ꢂC; IR nmax/cmꢁ1 1794, 1755, 1731, 1439, 1375, 1293,
1194, 1162, 1142; MS (ESþ) m/z (relative intensity %) 286 (MþNaþ,
100%); HRMS (ESþ): calcd for C13H13O5NNa (MþNaþ) 286.0686,
found 286.0684.
3.3.8. O1-Methyl O3-phenyl 3-(3,4-dihydroxy-5-methoxy-phenyl)-2-
oxo-pyrrolidine-1,3-dicarboxylate (þ)-46. According to the general
oxidative coupling procedure, replacing PS-BEMP with catalyst 35,
3-methoxycatechol 21 (28 mg, 0.20 mmol) was reacted with pro-
nucleophile 42 (53 mg, 0.20 mmol) to give, (þ)-46 (27 mg, 34%) as
a cream coloured solid in 9% ee, determined by HPLC analysis
3.3.5. 1-Benzyl 3-methyl 2-oxopyrrolidine-1,3-dicarboxylate 43.
According to the above procedure for the preparation of 41, benzyl
2-oxopyrrolidine-1-carboxylate38 (440 mg, 2.00 mmol) was reac-
ted with methyl chloroformate (0.15 mL, 2.00 mmol) to give 43
(400 mg, 72%) as a colourless solid following chromatography on
silica gel, eluting with petroleum ether containing 70% diethyl
ether. 1H NMR (500 MHz, CDCl3) dH 7.42e7.41 (2H, m, ArH),
7.37e7.30 (3H, m, ArH), 5.29 (1H, d, J¼12.5 Hz, OCH2Ph), 5.26 (1H, d,
J¼12.5 Hz, OCH2Ph), 3.93 (1H, ddd, J¼10.5, 8.5, 5.5 Hz, CH2N),
3.78e3.73 (1H, m, CH2N), 3.77 (3H, s, OCH3), 3.56 (1H, dd, J¼9.0,
7.5 Hz, CH), 2.44e2.37 (1H, m, CH2CH2N), 2.29e2.22 (1H, m,
CH2CH2N); 13C NMR (75 MHz, CDCl3) dC 168.8 (C(O)), 168.5 (C(O)),
151.1 (NC(O)O), 134.9 (4ꢂ ArC), 128.5 (ArCH), 128.4 (ArCH), 128.1
(ArCH), 68.3 (OCH2Ph), 52.8 (OCH3), 49.8 (CH), 44.8 (CH2N), 21.5
(CH2CH2N); IR nmax/cmꢁ1 2956, 1792, 1730, 1638, 1375, 1289, 1164;
mp 39e41 ꢂC; MS (ESꢁ) m/z (relative intensity %) 276 (MꢁHþ,
100%); HRMS (ESþ): calcd for C14H15O5NNa (MþNaþ) 300.0842,
found 300.0838.
[Chiralpak AD, heptane/ethanol 70:30, 1.0 mL minꢁ1
,
l¼215 nm, t
(minor)¼6.74 min, t (major)¼12.37 min] by comparison to a race-
mic sample prepared according to the general oxidative coupling
procedure (racemate mp 74e75 ꢂC); [
a
]
24 þ12.3 (c 0.65, CHCl3); 1H
D
NMR (400 MHz, CDCl3) dH 7.36e7.32 (2H, m, ArH), 7.23e7.19 (1H, m,
ArH), 7.05e7.02 (2H, m, ArH), 6.84 (1H, d, J¼2 Hz, ArH), 6.74 (1H, d,
J¼2 Hz, ArH), 3.94e3.90 (1H, m, CH2N), 3.90 (3H, s, OCH3), 3.88 (3H,
s, OCH3), 3.75 (1H, td, J¼10.5, 7.0 Hz, CH2N), 3.08 (1H, ddd, J¼13.0,
7.5, 7.0 Hz, CH2CH2N), 2.61 (1H, ddd, J¼13.0, 7.0, 5.5 Hz, CH2CH2N);
13C NMR (100 MHz, CDCl3) dC 169.3 (C(O)), 168.3 (C(O)), 152.1 (OC
(O)N), 150.6 (4ꢂ ArC), 147.1 (4ꢂ ArC), 143.9 (4ꢂ ArC), 132.6 (4ꢂ ArC),
130.1 (4ꢂ ArC), 129.4 (ArCH), 126.2 (ArCH), 121.1 (ArCH), 107.7
(ArCH), 102.9 (ArCH), 61.2 (4ꢂ C), 56.3 (OCH3), 53.9 (OCH3), 43.3
(CH2), 30.1 (CH2); mp 74e75 ꢂC; IR nmax/cmꢁ1 3417,1783, 1738, 1615,
1439, 1372, 1305, 1223, 1188, 1091; MS (ESþ) m/z (relative intensity
%) 424 (MþNaþ, 100%); HRMS (ESþ): calcd for C20H19O8NNa
(MþNaþ) 424.1003, found 424.1001.
3.3.6. 1-[(4-Methylphenyl)sulfonyl]-2-oxopyrrolidine-3-carboxylate
44. According to the above procedure for the preparation of 41, 1-
[(4-methylphenyl)sulfonyl]pyrrolidin-2-one (239 mg, 1.00 mmol)
3.3.9. O1-Benzyl O3-methyl 3-(3,4-diacetoxy-5-methoxy-phenyl)-2-
oxo-pyrrolidine-1,3-dicarboxylate (þ)-47. According to the general
oxidative coupling procedure, replacing PS-BEMP with catalyst 35,
3-methoxycatechol 21 (28 mg, 0.20 mmol) was reacted with 43
(55 mg, 0.20 mmol) and the crude reaction mixture was treated
with Ac2O (0.75 mL) in pyridine (1.5 mL) (see preparation of 40) to
give (þ)-47 (30 mg, 30%) as a pale yellow oil, in 30% ee, determined
by HPLC analysis [Chiralpak AS, hexane/iso-propanol 70:30,
was reacted with methyl chloroformate (77 mL, 1.00 mmol) to give
44 (173 mg, 59%) as a colourless solid following chromatography on
silica gel, eluting with petroleum ether containing 50e70% diethyl
ether. 1H NMR (500 MHz, CDCl3) dH 7.90 (2H, d, J¼8.0 Hz, ArH), 7.33
(2H, d, J¼8.0 Hz, ArH), 3.99 (1H, ddd, J¼9.5, 8.5, 5.5 Hz, NCH2), 3.84
(1H, ddd, J¼9.5, 8.0, 7.0 Hz, NCH2), 3.67 (3H, s, OCH3), 3.45 (1H, dd,
J¼9.0, 7.5 Hz, CH), 2.46e2.39 (1H, m, CH2CH2N), 2.43 (3H, s, CH3),
2.33e2.26 (1H, m, CH2CH2N); 13C NMR (125 MHz, CDCl3) dC 168.2 (C
(O)), 168.1 (C(O)), 145.5 (4ꢂ ArC), 134.5 (4ꢂ ArC), 129.7 (ArCH), 128.1
(ArCH), 52.8 (OCH3), 49.2 (CH), 45.6 (NCH2), 22.2 (NCH2CH2), 21.6
(CH3); IR nmax/cmꢁ1 2956, 1750, 130, 1596, 1437, 1361, 1170, 1123;
mp 70e71 ꢂC; MS (ESþ) m/z (relative intensity %) 320 (MþNaþ,
100%); HRMS (ESþ): calcd for C13H15O5NSNa (MþNaþ) 320.0563,
found 320.0559.
1.0 mL minꢁ1
18.71 min] by comparison to a racemic sample prepared according
,
l¼220 nm,
t
(minor)¼15.14 min,
t
(major)¼
25
to the general oxidative coupling procedure; [
a
]
þ7.1 (c 2.0,
D
CHCl3); 1H NMR (500 MHz, CDCl3) dH 7.43e7.42 (2H, m, ArH),
7.38e7.32 (3H, m, ArH), 7.17 (1H, d, J¼2.0 Hz, ArH), 6.87 (1H, d,
J¼2.0 Hz, ArH), 5.32e5.27 (2H, m, OCH2Ph), 3.83 (3H, s, OCH3),
3.81e3.77 (2H, m, CH2N), 3.75 (3H, s, OCH3), 3.01e2.96 (1H, m,
CH2CH2N), 2.45 (1H, td, J¼13.0, 7.5 Hz, CH2CH2N), 2.28 (3H, s, OC(O)
CH3), 2.26 (3H, s, OC(O)CH3); 13C NMR (75 MHz, CDCl3) dC 169.1 (C
(O)), 168.8 (C(O)), 168.0 (C(O)), 167.5 (C(O)), 152.3 (4ꢂ ArC), 151.2 (NC
(O)O), 143.1 (4ꢂ ArC), 134.9 (4ꢂ ArC), 133.9 (4ꢂ ArC), 131.9 (4ꢂ ArC),
128.6 (ArCH), 128.5 (ArCH), 128.2 (ArCH), 113.8 (ArCH), 109.3
(ArCH), 68.4 (OCH2Ph), 60.6 (4ꢂ C), 56.4 (OCH3), 53.7 (OCH3), 43.2
3.3.7. O1-tert-Butyl O3-phenyl 3-(3,4-dihydroxy-5-methoxy-phe-
nyl)-2-oxo-pyrrolidine-1,3-dicarboxylate (þ)-45. According to the
general oxidative coupling procedure, replacing PS-BEMP with
catalyst 35, 3-methoxycatechol 21 (28 mg, 0.20 mmol) was reacted
with 41 (73 mg, 0.20 mol) to give (þ)-45 (26 mg, 29%) as a peach
coloured solid in 40% ee determined by HPLC analysis [Chiralpak
(CH2N), 30.2 (CH2CH2N), 20.5 (OC(O)CH3), 20.3 (OC(O)CH3); IR nmax
/
cmꢁ1 1781, 1774, 1731, 1371, 1296, 1207, 1098; MS (ESþ) m/z (relative

6408
K.M. Bogle et al. / Tetrahedron 66 (2010) 6399e6410
intensity %) 522 (MþNa, 100%); HRMS (ESþ): calcd for
C25H25O10NNa (MþNaþ) 522.1371, found 522.1366.
combined organic portions were dried over Na2SO4, filtered and
concentrated. The residue was dissolved in DMF and divided equally
between five sealable vials. To each vial was added CH2ClBr (0.19 mL,
3 mmol) and Cs2CO3 (977 mg, 3 mmol). The vials were sealed and
heatedat85 ꢂCfor1 hthencooledtoroomtemperature. Theresulting
purple-brown solution was concentrated and purified by column
chromatography on silica gel, eluting with petroleum ether contain-
ing 30e60% diethyl ether to give the arylated product (þ)-24 (2.24 g,
57% yield) as a pale yellow oil in 70% ee, determined by HPLC analysis
3.3.10. Methyl 3-(3,4-diacetoxy-5-methoxy-phenyl)-2-oxo-1-(p-tolyl-
sulfonyl)pyrrolidine-3-carboxylate (þ)-48. According to the general
oxidative coupling procedure, replacing PS-BEMP with catalyst 35, 3-
methoxycatechol 21 (28 mg, 0.20 mmol) was reacted with 44
(59 mg, 0.20 mmol) and the crude reaction mixture treated with
Ac2O (0.75 mL) in pyridine (1.5 mL) (see preparation of 40) to give
(þ)-48 (25 mg, 24%) as a pale yellow oil, in 1% ee, determined by
HPLC analysis [Chiralpak AD, hexane/iso-propanol 85:15,
[Chiralpak AD, hexane/iso-propanol 85:15,1.0 mL minꢁ1
,
l¼215 nm, t
(minor)¼11.95 min, t (major)¼18.30 min] bycomparisonto a racemic
1.0 mL minꢁ1
,
l
¼215 nm, t (major)¼22.39 min, t (minor)¼28.95 min]
sample prepared in according to the general oxidative coupling pro-
24
by comparison to a racemic sample prepared according to the gen-
eral oxidative coupling procedure; [
cedure. [
a
]
þ38.1 (c 0.52, CHCl3). Other data identical to racemic
D
a]
D
25 þ5.1 (c 1.0, CHCl3); 1H NMR
compound.16
(500 MHz, CDCl3) dH 7.89 (2H, d, J¼8.0 Hz, ArH), 7.33 (2H, d, J¼8.0 Hz,
ArH), 6.95 (1H, d, J¼2.0 Hz, ArH), 6.72 (1H, d, J¼2.0 Hz, ArH),
3.87e3.84 (2H, m, CH2N), 3.72 (3H, s, OCH3), 3.58 (3H, s, OCH3),
3.01e2.96 (1H, m, CH2CH2N), 2.50e2.43 (1H, m, CH2CH2N), 2.43 (3H,
s, CH3), 2.27 (OC(O)CH3), 2.25(3H, s, OC(O)CH3); 13C NMR (75 MHz,
CDCl3) dC 168.6 (C(O)), 168.6 (C(O)), 167.9 (C(O)), 167.5 (C(O)), 152.2
(4ꢂ ArC), 145.5 (4ꢂ ArC), 143.2 (4ꢂ ArC), 134.3 (4ꢂ ArC), 133.2 (4ꢂ ArC),
131.9 (4ꢂ ArC), 129.7 (ArCH),128.2 (ArCH),113.7 (ArCH),109.0 (ArCH),
60.1 (4ꢂ C), 56.2 (OCH3), 53.6 (OCH3), 44.0 (CH2N), 30.9 (CH2CH2N),
21.6 (CH3), 20.5 (OC(O)CH3), 20.3 (OC(O)CH3); IR nmax/cmꢁ1 1774,
1751, 1734, 1422, 1207, 1173, 1093; MS (ESþ) m/z (relative intensity %)
542 (MþNaþ,100%); HRMS (ESþ): calcd for C24H25O10NSNa (MþNaþ)
542.1091, found 542.1091.
3.3.13. O1-tert-Butyl O3-methyl 2-hydroxy-3-(7-methoxy-1,3-benzo-
dioxol-5-yl)pyrrolidine-1,3-dicarboxylate (þ)-25. According to the
procedure for racemate synthesis,16 (þ)-24 (2.06 g, 5.25 mmol) was
reacted with superhydrideÒ (6.3 mL of a 1 M solution in THF,
6.30 mmol) to give (þ)-25 (1.87 g, 90%) as a colourless solid, the four
stereoisomers could not be completely separated by chiral HPLC
24
analysis, [
a
]
þ22.6 (c 0.95, CHCl3); mp 40e44 ꢂC. Other data
D
identical to racemic compound.16
3.3.14. O1-tert-Butyl O3-methyl 2-acetonyl-3-(7-methoxy-1,3-ben-
zodioxol-5-yl)pyrrolidine-1,3-dicarboxylate (ꢁ)-26. According to the
procedure for racemate synthesis,16 (þ)-25 (1.87 g, 4.73 mmol) was
treated with acetic anhydride (2 mL) in pyridine (10 mL) and the
crude acetylated product reacted with (isopropenyloxy)trime-
thylsilane (7.9 mL, 47.3 mmol) to give (ꢁ)-26 (1.89 g, 92%) as a col-
ourless oil in 3:1 dr and 69% ee determined by HPLC analysis
3.3.11. 1. O1-tert-Butyl O3-methyl 3-(3,4-diacetoxy-5-methoxy-phe-
nyl)-2-oxo-pyrrolidine-1,3-dicarboxylate (þ)-40. According to the
general oxidative coupling procedure, replacing PS-BEMP with cata-
lyst 52, 3-methoxycatechol 21 (14 mg, 0.10 mmol) was reacted with
23 (24 mg, 0.10 mmol) and the crude reaction products was dissolved
in pyridine (0.5 mL) and Ac2O (0.25 mL) and stirred at room tem-
perature overnight. The reaction mixture was diluted with EtOAc
(5 mL) and washed with saturated aqueous CuSO4 (3ꢃ5 mL). The
organic phase was dried over Na2SO4, filtered and concentrated. The
residue was purified by chromatography on silica gel, eluting with
70:30 diethyl ether/petroleum ether, to give the arylated product 40
(26 mg, 56%)asacolourlessoilin64%ee, determinedbyHPLCanalysis
[Chiralpak AD, hexane/iso-propanol 95:5, 1.0 mL minꢁ1
,
l¼215 nm,
minor diastereomer: t (major)¼16.12 min, t (minor)¼19.90 min],
major diastereomer: t (minor)¼24.41 min, t (major)¼32.41 min] by
comparison to a racemic sample. [
a
]
D
24 ꢁ15.4 (c 0.46, CHCl3). Other
data identical to racemic compound.16
3.3.15. tert-Butyl 6-methoxy-3a-(7-methoxy-1,3-benzodioxol-5-yl)-
4-oxo-2,3,7,7a-tetrahydroindole-1-carboxylate (ꢁ)-27. According to
the procedure for racemate synthesis16 (ꢁ)-26b(1.83 g, 4.20 mmol)
was treated with KOtBu (8.83 mL of a 1 M solution in THF,
8.83 mmol) and the crude di-ketone treated with TiCl4 (0.19 mL,
0.19 mmol) in MeOH (20 mL) to give (ꢁ)-27 (950 mg, 54%) as
a colourless solid in 24% ee determined by HPLC analysis [Chiralpak
[Chiralpak AD, hexane/iso-propanol 85:15,1.0 mL minꢁ1
,
l
¼215 nm, t
(major)¼11.382 min, t (minor)¼22.29 min] by comparison to a race-
mic sample prepared in according to the general oxidative coupling
procedure. [
a
]
24 þ34.4 (c 0.90, CHCl3); 1H NMR (500 MHz, CDCl3) dH
D
7.17 (1H, d, J¼2.0 Hz, ArH), 6.87 (1H, d, J¼2.0 Hz, ArH), 3.83 (3H, s,
ArOCH3), 3.75e3.67 (2H, m, CH2N), 3.74 (3H, s, OCH3), 2.95 (1H, ddd,
J¼12.5, 7.0, 5.0 Hz, CH2CH2N), 2.42 (1H, dt, J¼13.0, 7.5 Hz, CH2CH2N),
AD, hexane/iso-propanol 95:5, 1.0 mL minꢁ1
,
l
¼215 nm, t (major)¼
27.73 min, t (minor)¼31.62 min], by comparison to a racemic
24
sample. [
a]
ꢁ18.9 (c 1.82, CHCl3); mp 48e52 ꢂC. Other data
D
2.28(3H,s,OC(O)CH3),2.26(3H, s,OC(O)CH3),1.52(9H, s,C(CH3)3);13
C
identical to racemic compound.16
NMR (125 MHz, CDCl3) dC 169.4 (NC(O)), 168.9 (OC(O)OCH3), 168.0
(OC(O)CH3), 167.6 (OC(O)CH3), 152.2 (4ꢂ ArC), 149.8 (NC(O)O), 143.1
(4ꢂ ArC),134.1 (4ꢂ ArC),131.8 (4ꢂ ArC),113.8 (ArCH),109.4 (ArCH), 83.6
(C(CH3)3), 60.8 (4ꢂ C), 56.3 (ArOCH3), 53.6 (OCH3), 43.2 (NCH2), 30.0
3.3.16. 4-[(1R)-5-[(Ethyl(methyl)amino)methyl]-4-methyl-1-[(4-pyr-
azol-1-ylphenyl)methoxy]hept-6-enyl]quinolin-6-ol 50. Catalyst 50
was prepared according to the procedures reported by Deng and co-
(NCH2CH2), 27.9 (C(CH3)3), 20.5(OC(O)CH3), 20.3(OC(O)CH3); IR nmax
/
workers,26e,f
[a]
25 þ88.7 (c 1.10, CHCl3); 1H NMR (500 MHz, CDCl3) dH
D
cmꢁ1 2981, 1777, 1730, 1611, 1370, 1306, 1206, 1096; MS (ESþ) m/z
(relative intensity %) 524 (MþMeCNþNHþ4 ,100%); HRMS (ESþ): calcd
for C22H27O10NNa (MþNaþ) 488.1527, found 488.1536.
6.64 (1H, d, J¼4.5 Hz, ArH), 8.22 (1H, d, J¼2.5 Hz, ArH), 7.94 (1H, d,
J¼9.0 Hz, ArH), 7.74e7.72(3H, m, ArH), 7.58 (1H, brs, ArH), 7.48(2H, br
d, J¼8.0 Hz, ArH), 7.36 (1H, dd, J¼9.0, 2.5 Hz, ArH), 7.33 (1H, br s, ArH),
6.53 (1H, t, J¼2.0 Hz, ArH), 5.99 (1H, ddd, J¼17.5, 10.0, 7.5 Hz, CH]
CH2), 5.32 (1H, br s, CHOCH2Ar), 5.03e4.97 (2H, m, CH]CH2), 4.53
(1H, d, J¼11.5 Hz, OCH2Ar), 4.44 (1H, d, J¼11.5 Hz, OCH2Ar), 4.31 (1H,
br s, aliphatic CH), 3.09 (1H, br s, aliphatic CH), 2.92e2.85 (2H, br m,
aliphatic CH), 2.79e2.73 (1H, br m, aliphatic CH), 2.29 (1H, dd, J¼17.0,
8.0 Hz, aliphatic CH), 2.18 (1H, br m, aliphatic CH), 1.73 (1H, br s, ali-
phatic CH), 1.60e1.50 (2H, br m, aliphatic CH),1.24 (1H, br s, aliphatic
CH); 13C NMR (75 MHz, CDCl3) dC 158.0 (4ꢂ ArC), 147.5 (ArCH), 145.8
(4ꢂ ArC), 144.4 (4ꢂ ArC),142.3 (ArCH), 141.5 (CH]CH2),141.1 (4ꢂ ArC),
137.6 (4ꢂ ArC),131.7 (ArCH),130.7 (ArCH),129.2 (4ꢂ ArC),129.0 (ArCH),
3.3.12. O1-tert-Butyl O3-methyl 3-(7-methoxy-1,3-benzodioxol-5-
yl)-2-oxo-pyrrolidine-1,3-dicarboxylate (þ)-24. To a stirred solution
of 3-methoxycatechol 21 (1.40 g, 10.0 mmol) and 23 (2.43 g,
10.0 mmol) in CH2Cl2 (400 mL) at ꢁ20 ꢂC was added cat. 52 (936 mg,
2.00 mmol) followed by PS-IO4 (3.22 g 20.0 mmol). The reaction
mixture was stirred at this temperature for 7 h then filtered and the
resin on the filter washed with CH2Cl2 (3ꢃ100 mL). The filtrate was
stirred with saturated aqueous Na2S2O4 (200 mL), the organic phase
separated and the aqueous extracted with CH2Cl2 (2ꢃ50 mL). The

K.M. Bogle et al. / Tetrahedron 66 (2010) 6399e6410
6409
123.5 (ArCH), 120.5 (ArCH), 120.3 (ArCH), 115.3 (CH]CH2), 108.8
(ArCH),105.2 (ArCH), 81.0 (COCH2Ar), 72.0 (OCH2Ar), 60.7 (NCH), 50.9
(NCH2), 50.4 (NCH2), 41.1 (CH), 29.5 (CH), 27.1 (CH2), 22.2 (CH2); IR
nmax/cmꢁ1 3070, 2940, 1614, 1526, 1467, 1394, 1030, 830; mp
139e144 ꢂC; MS (ESþ) m/z (relative intensity %) 467 (MþHþ, 100%);
HRMS(ESþ):calcd forC29H31O2N4 (MþXþ)467.2442, found 467.2439.
(ArCH), 122.5 (m, ArCCF3), 120.1 (ArCH), 115.6 (CH]CH2), 105.1
(ArCH), 81.6 (COCH2Ar), 71.2 (OCH2Ar), 60.7 (NCH), 50.9 (NCH2),
50.5 (NCH2), 40.5 (CH), 29.2 (CH), 26.6 (CH2), 22.1 (CH2); IR nmax
/
cmꢁ1 3077, 2941, 2877, 1620, 1469, 1280, 1177, 1134; mp 97e101 ꢂC;
MS (ESþ) m/z (relative intensity %); 537 (MþHþ, 100%); HRMS
(ESþ): calcd for C28H27F6O2N2 (MþHþ) 537.1971, found 537.1957.
3.3.17. 4-[(1R)-5-[(Ethyl(methyl)amino)methyl]-4-methyl-1-[(4-ni-
trophenyl)methoxy]hept-6-enyl]quinolin-6-ol 51. Catalyst 51 was
3.3.19. 4-[(1R)-5-[(Ethyl(methyl)amino)methyl]-4-methyl-1-[[2-(tri-
fluoromethyl)phenyl]methoxy]hept-6-enyl]quinolin-6-ol 52. Accord-
ing to the above procedure for the preparation of catalyst 49,
quinidine (3.24 g, 10.0 mmol) was benzylated with 1-(bromo-
methyl)-2-(trifluoromethyl)benzene (1.52 mL, 10.0 mmol) and
prepared according to the procedures reported by Deng and
25
co-workers,26e,f
[
a]
þ75.4 (c 0.76, CHCl3); 1H NMR (500 MHz,
D
CDCl3) dH 8.63 (1H, d, J¼4.5 Hz, ArH), 8.30 (1H, s, ArH), 8.17 (1H, dd,
J¼8.0, 1.0 Hz, ArH), 7.93 (1H, d, J¼9.0 Hz, ArH), 7.73 (1H, d, J¼8.0 Hz,
ArH), 7.59 (1H, t, J¼8.0 Hz, ArH), 7.56 (1H, br d, J¼4.5 Hz, ArH), 7.36
(1H, dd, J¼9.0, 2.5 Hz, ArH), 7.33 (1H, br s, ArH), 6.04 (1H, ddd,
J¼17.5, 10.0, 7.5 Hz, CH]CH2), 5.36 (1H, br s, CHOCH2Ar), 5.05e5.00
(2H, m, CH]CH2), 4.61 (1H, d, J¼12.0 Hz, OCH2Ar), 4.58 (1H, d,
J¼12.0 Hz, OCH2Ar), 3.37 (1H, br s, aliphatic CH), 3.14 (1H, br s,
aliphatic CH), 2.95e2.86 (2H, m, aliphatic CH), 2.82e2.76 (1H, m,
aliphatic CH), 2.32 (1H, q, J¼8.5 Hz, aliphatic CH), 2.21 (1H, br t,
J¼10.0 Hz, aliphatic CH), 1.77 (1H, br s, aliphatic CH), 1.63e1.53 (2H,
m, aliphatic CH), 1.29 (1H, br s, aliphatic CH); 13C NMR (75 MHz,
CDCl3) dC 158.0 (4ꢂ ArC), 149.8 (4ꢂ ArC), 147.6 (ArCH), 145.4 (4ꢂ ArC),
144.4 (4ꢂ ArC), 141.6 (4ꢂ ArC), 141.4 (CH]CH2), 135.1 (ArCH), 131.7
(ArCH), 130.8 (ArCH), 129.1 (4ꢂ ArC), 123.7 (ArCH), 123.6 (ArCH),
123.5 (ArCH), 120.4 (ArCH), 115.3 (CH]CH2), 105.2 (ArCH), 81.8
(COCH2Ar), 71.4 (OCH2Ar), 60.7 (NCH), 50.9 (NCH2), 50.5 (NCH2),
40.9 (CH), 29.4 (CH), 27.0 (CH2), 22.4 (CH2); IR nmax/cmꢁ1þ3386,
2941, 1617, 1529, 1350, 1270, 809; mp 118e122 ꢂC; MS (ES ) m/z
(relative intensity %) 446 (MþH, 100%); HRMS (ESþ): calcd for
C26H28O4N3 (MþHþ) 446.2074, found 446.2071.
demethylated with 1-dodecanethiol (12.0 mL, 50.0 mmol) to give
25
cat. 52 (3.81 g, 82%) as a pale yellow solid. [
a
]
D
þ104.4 (c 1.78,
CHCl3); 1H NMR (500 MHz, CD3OD) dH 8.63 (1H, d, J¼4.5 Hz, ArH)
7.95 (1H, d, J¼9.5 Hz, ArH), 7.81 (1H, br d, J¼7.5 Hz, ArH), 7.68e7.63
(2H, m, ArH), 7.56 (1H, br d, J¼4.0 Hz, ArH), 7.48 (1H, t, J¼7.5 Hz,
ArH), 7.38e7.36 (2H, m, ArH), 5.95 (1H, ddd, J¼17.5, 10.0, 7.5 Hz,
CH]CH2), 5.43 (1H, br s, CHOCH2Ar), 4.99e4.96 (2H, m, CH]CH2),
4.64 (1H, d, J¼12.0 Hz, OCH2Ar), 4.60 (1H, d, J¼12.0 Hz, OCH2Ar),
3.39 (1H, br s, aliphatic CH), 3.14 (1H, br s. aliphatic CH), 2.95e2.90
(2H, m, aliphatic CH), 2.82e2.76 (1H, m, aliphatic CH), 2.31 (1H, q,
J¼8.0 Hz, aliphatic CH), 2.19 (1H, br m, aliphatic CH), 1.74 (1H, br s,
aliphatic CH), 1.61e1.50 (2H, m, aliphatic CH), 1.25 (1H, br s, ali-
phatic CH); 13C NMR (125 MHz, CD3OD) dC 158.0 (4ꢂ ArC), 147.5
(ArCH), 145.0 (4ꢂ ArC), 144.4 (4ꢂ ArC), 141.0 (CH]CH2), 137.3 (4ꢂ
ArC), 133.5 (ArCH), 131.8 (ArCH), 131.78 (ArCH), 129.4 (4ꢂ ArC), 129.0
(ArCH), 128.9 (q, J¼30.5 Hz, CF3), 126.9 (q, J¼5.5 Hz, ArCCF3) 126.9
(ArCH), 123.6 (ArCH), 120.1 (ArCH), 115.4 (CH]CH2), 105.1 (ArCH),
81.7 (CHOCH2Ar), 68.8 (CHOCH2Ar), 60.8 (NCH), 50.8 (NCH2), 50.3
(NCH2), 40.7 (CH), 29.3 (CH), 26.8 (CH2), 22.1 (CH2); IR nmax/cmꢁ1
3074, 2941, 2877, 1670, 1619, 1469, 1316, 1167, 1119; mp 98e101 ꢂC;
MS (ESþ) m/z (relative intensity %); 469 (MþHþ, 100%); HRMS
(ESþ): calcd for C27H28F3O2N2 (MþHþ) 469.2097, found 469.2088.
3.3.18. 4-[(1R)-1-[[3,5-Bis(trifluoromethyl)phenyl]methoxy]-5-
[(ethyl(methyl)amino)methyl]-4-methyl-hept-6-enyl]quinolin-6-ol
49. To a stirred solution of quinidine (324 mg, 1.00 mmol) in DMF
(5 mL) was added NaH (80 mg of a 60% dispersion in mineral oil,
2.00 mmol) and the reaction mixture was stirred at room temper-
ature for 30 min before adding 1-(bromomethyl)-3,5-bis(tri-
fluoromethyl)benzene (0.18 mL, 1.00 mmol). The reaction mixture
was stirred for 4 h then quenched with saturated NaHCO3(aq)
(10 mL), diluted with EtOAc (20 mL) and washed with water
(3ꢃ10 mL) and brine (10 mL). The organic phase was dried over
Na2SO4, filtered and concentrated. The residue was dissolved in
DMF (10 mL). To the DMF solution was added 1-dodecanethiol
(1.2 mL, 5 mmol) followed by portion-wise addition of NaH
(200 mg of a 60% dispersion in mineral oil, 5 mmol). CAUTION:
significant foaming of the reaction mixture occurred upon addition
of NaH. The reaction mixture was heated to 110 ꢂC overnight,
cooled to room temperature and quenched with saturated NH4Cl
(30 mL). The mixture was diluted with EtOAc (50 mL) and washed
with water (3ꢃ20 mL) and brine (20 mL). The organic phase was
dried over Na2SO4, filtered and concentrated. The residue was pu-
3.3.20. 4-[(1S)-5-[(Ethyl(methyl)amino)methyl]-4-methyl-1-[[2-(tri-
fluoromethyl)phenyl]methoxy]hept-6-enyl]quinolin-6-ol 53. Accord-
ing to the above procedure for the synthesis of catalyst 49, quinine
(1.62 g, 5.00 mmol) was benzylated with 1-(bromomethyl)-2-(tri-
fluoromethyl)benzene (0.76 mL, 5.00 mmol) and demethylated with
25
1-dodecanethiol (6.0 mL, 25.0 mmol) to give cat. 53 (1.61 g, 69%) [a]
D
ꢁ18.5 (c 1.00, CHCl3); 1H NMR (500 MHz, CD3OD) dH 8.61 (1H, d,
J¼4.5 Hz, ArH), 7.95 (1H, d, J¼9.0 Hz, ArH), 7.78 (1H, br s, ArH),
7.67e7.63(2H, m,ArH), 7.56(1H, d,J¼4.0 Hz, ArH), 7.48e7.36(1H, brs,
ArH),7.47(1H,t,J¼7.5 Hz, ArH),7.37(1H,d,J¼9.0 Hz,ArH), 5.74(1H, br
m, CH]CH2), 5.35 (1H, br s, CHOCH2Ar), 4.97e4.88 (2H, m, CH]CH2),
4.65 (1H, d, J¼12.0 Hz, OCH2Ar), 4.58 (1H, d, J¼12.0 Hz, OCH2Ar), 3.45
(1H, br s, aliphatic CH), 3.17 (1H, br s, aliphatic CH), 3.07 (1H, br t,
J¼10.0 Hz, aliphatic CH), 2.71e2.60 (2H, br m, aliphatic CH), 2.33 (1H,
br s, aliphatic CH), 1.90 (1H, br s, aliphatic CH), 1.79e1.75 (2H, br m,
aliphatic CH), 1.64 (1H, br s, aliphatic CH), 1.59e1.54 (1H, br m, ali-
phatic CH); 13C NMR (75 MHz, CD3OD) dC 158.0 (4ꢂ ArC),147.5 (ArCH),
145.3 (4ꢂ ArC), 144.5 (4ꢂ ArC), 142.5 (CH]CH2), 137.5 (4ꢂ ArC), 133.5
(ArCH),131.8 (ArCH),131.3 (ArCH), 129.3 (4ꢂ ArC),129.0 (ArCH),128.7
(q, J¼30.5 Hz, CF3), 126.9 (q, J¼5.5 Hz, ArCCF3), 126.9 (ArCH), 123.5
(ArCH), 120.0 (ArCH), 115.2 (CH]CH2), 105.0 (ArCH), 81.0 (CHO-
CH2Ar),68.7(OCH2Ar),61.1(NCH), 57.5(NCH2),44.1(NCH2),40.8(CH),
29.1 (CH), 28.2 (CH2), 22.4 (CH2); IR nmax/cmꢁ1 3424, 2943,1637,1620,
1315, 1167, 1118; mp 207e212 ꢂC; MS (ESþ) m/z (relative intensity %)
469 (MþHþ, 100%); HRMS (ESþ): calcd for C27H28F3O2N2 (MþHþ)
469.2097, found 469.2094.
rified by chromatography on silica gel to give 49 (300 mg, 56%) as
25
an off-white solid. [
a
]
þ76.3 (c 0.82, CHCl3); 1H NMR (500 MHz,
D
CD3OD) dH 8.62 (1H, d, J¼4.5 Hz, ArH), 7.98 (2H, br s, ArH), 7.93 (1H,
d, J¼9.0 Hz, ArH), 7.89 (1H, br s, ArH), 7.55 (1H, br d, J¼4.0 Hz, ArH),
7.37e7.35 (2H, br m, ArH), 6.01 (1H, ddd, J¼17.5, 10.5, 7.5 Hz, CH]
CH2), 5.46 (1H, br s. CHOCH2Ar), 5.05e5.01 (2H, m, CH]CH2),
4.69e4.64 (2H, br m, OCH2Ar), 3.41 (1H, br s, aliphatic CH), 3.21 (1H,
br s, aliphatic CH), 3.02e2.96 (2H, m, aliphatic CH), 2.88e2.82 (1H,
m, aliphatic CH), 2.37 (1H, q, J¼8.0 Hz, aliphatic CH), 2.24 (1H, br t,
J¼10.0 Hz, aliphatic CH), 1.80 (1H, br s, aliphatic CH), 1.65e1.55 (2H,
m, aliphatic CH), 1.29 (1H, br s, aliphatic CH); 13C NMR (125 MHz,
CD3OD) dC 158.1 (4ꢂ ArC), 147.6 (ArCH), 144.7 (4ꢂ ArC), 144.4 (4ꢂ
ArC), 142.5 (4ꢂ ArC), 140.8 (CH]CH2), 132.82 (q, J¼33.5 Hz, CF3)
131.8 (ArCH), 129.2 (ArCH), 129.0 (4ꢂ ArC), 123.7 (ArCH), 123.5
Acknowledgements
We gratefully thank The University of Manchester and Glaxo-
SmithKline (for a studentship to KMB), the EPSRC for a Leadership

6410
K.M. Bogle et al. / Tetrahedron 66 (2010) 6399e6410
crude NMR in CDCl3 showed a mixture of catechol and quinone that converted
to quinone with time.
Fellowship to DJD, and the Oxford Chemical Crystallography Service
for the use of the instrumentation.
21. (a) For preparation of starting pro-nucleophiles see Moss, T. A.; Alba, A.; Hep-
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thoxy and 3-tert-butylquinones.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.04.132. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
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36. Viladomat, F.; Codina, C.; Bastida, J.; Mathee, S.; Campbell, W. E. Phytochemistry
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37. For synthesis and application of catalysts 14, 34, 35 and 36 see Refs. 26e,f and
(a) Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732; (b) Liu, Y.; Sun, B.;
Wang, B.; Wakem, M.; Deng, L. J. Am. Chem. Soc. 2009, 131, 418 For catalyst 33
see: (c) Amere, M.; Lasne, M.-C.; Rouden, J. Org. Lett. 2007, 9, 2621 For catalyst
37 see: (d) Marcelli, T.; van der Haas, R. N. S.; van Maarseveen, J. H.; Hiemstra,
H. Angew. Chem., Int. Ed. 2006, 45, 929 For catalyst 38 see: (e) Iwabuchi, Y.;
Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219
For catalyst 39 see: (f) Okino, T.; Hoashi, Y.; Forukawa, T.; Xu, X.; Takemoto, Y. J.
Am. Chem. Soc. 2005, 127, 119.
established. For additions of
b-dicarbonyl compounds see: (e) Grinev, A. N.;
Arsenichev, I. K.; Nikolaeva, I. S.; Golovanova, L. A.; Pushkina, T. V.; Okinskevich,
O. V.; Fomina, A. N.; Pershin, G. N. Khim. -Farm. Zh. 1985, 411; (f) Grinev, A. N.;
Arsenichev, I. K. Zh. Org. Khim.1985, 21,1315; (g) Christoffers, J.; Mann, A. Eur. J. Org.
Chem.1999, 2511;(h)Foranisolated exampleofaquininecatalyzedadditionto1,2-
naphthoquinone leading to a 4-substituted-1,2-naphthoquinone see Ref. 14.
20. For earlier work on the use of polymer supported BEMP as a catalyst in Michael
addition reactions, see: (a) Bensa, D.; Constantieux, T.; Rodriguez, J. Synthesis
2004, 923; (b) Crude NMR spectra in DMSO showed only catechol intermediate,
38. Ito, M.; Koo, L. W.; Himizu, A.; Kobayashi, C.; Sakaguchi, A.; Ikariya, T. Angew.
Chem., Int. Ed. 2009, 48, 1324.