Enantioselective organocatalytic aryloxylation of β-keto esters

Article abstract of DOI:10.1055/s-0030-1260059

An efficient enantioselective aryloxylation of cyclic β-keto esters with a selection of substituted o-quinones catalyzed by a bifunctional cinchona alkaloid derivative, giving entry to tricyclic dioxin adducts with high enantio- and diastereoselectivity, is described. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260059

1880
PAPER
Enantioselective Organocatalytic Aryloxylation of b-Keto Esters
Kevin Greenaway,a Paolo Dambruoso,a Alessandro Ferrali,a Andrew J. Hazelwood,b Filippo Sladojevich,c
Darren J. Dixon*c
a
School of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK
GlaxoSmithKline, Pharmaceuticals R&D Facility, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
b
c
E-mail: Darren.Dixon@chem.ox.ac.uk
Received 12 March 2011
induction were performed using commercially available
3,5-di-tert-butyl-o-quinone (9) as the electrophile and
methyl 2-oxocyclopentanecarboxylate (8) as the pro-nu-
cleophile. A range of bifunctional catalysts including
some based on the 9-amino(9-deoxy)epicinchonine scaf-
fold were screened for performance (Table 1).
Abstract: An efficient enantioselective aryloxylation of cyclic b-
keto esters with a selection of substituted o-quinones catalyzed by a
bifunctional cinchona alkaloid derivative, giving entry to tricyclic
dioxin adducts with high enantio- and diastereoselectivity, is de-
scribed.
Key words: aryloxylation, quinones, b-keto ester, organocatalysis,
dioxins
O
EWG
R2
+
N+
Alkyl aryl ether motifs1 are commonplace amongst a
range of biologically relevant natural products and phar-
maceutical compounds. Often bearing a stereogenic cen-
tre at the aliphatic carbon, these structures are usually
considered the products of stereoinvertive substitution re-
actions using phenol or phenolate nucleophiles. When
enantioenriched products are desired the electrophilic
coupling partner is normally an enantioenriched chiral al-
cohol (via Mitsunobu inversion) or a sulfonate ester deriv-
ative. In either case, this approach pivots on the
preparation of the enantioenriched alcohol. Whether by
enantioselective reduction of preformed prochiral ketones
or epoxide-opening strategies, the installation of this alco-
hol, and its subsequent transformation, can result in
lengthy linear sequences. To introduce a complementary
route our group recently reported an enantioselective or-
ganocatalytic aryloxylation reaction of aldehydes using
commercially available and stable o-quinone reagents.2,3
H
R1
H
O–
X
N
II
bifunctional
organocatalyst?
EWG
H
O
R2
N
+
Ar
R1
H
O
O
O
R3
I
R3
stereocontrolled C–O
bond formation?
O
R1
R1
EWG
R2
O
O
EWG
HO
R3
O
R3
R2
HO
III
IV
Scheme 1 Concept of the organocatalyzed b-keto ester aryloxyla-
tion reaction using o-quinone electrophiles
Using chiral secondary amine catalysts the desired stereo-
genic tertiary alkyl aryl ether could be made in a single
step and in good enantioselectivity at ambient tempera-
tures. To further advance and develop this reaction we
reasoned that o-quinone reagents I could be reacted with
methine pro-nucleophiles II4 using suitable organocata-
lysts based on the bifunctional system our group, and oth-
ers, recently introduced.5
Pleasingly, at room temperature in toluene smooth con-
version to the dioxin product 10, the cycloisomeric prod-
uct (IV in Scheme 1) of the direct adduct, was observed
with all the catalysts represented in Figure 1.
Stereoinduction and reaction rate with 9-amino(9-
deoxy)epicinchonine-derived urea catalyst 4 was found to
be superior to the thiourea 3, as well as the parent cincho-
na alkaloids cinchonine 1 and quinidine 2 (entries 1–4). Its
performance was similar to the quinidine derivative 5 but
surpassed that of urea analogues 6 and 7 where the elec-
tronics and steric demand of the urea functionality were
varied (entries 5–7).
This was particularly attractive owing to the ease of han-
dling of the b-keto ester starting materials, and the prod-
ucts III would possess a quaternary alkyl aryl ether motif
difficult to access using the SN2 strategies detailed above
(Scheme 1). Herein we report our findings. Preliminary
studies to assess reaction feasibility, catalysis, and stereo-
The high catalytic activity of 4 warranted more studies to
identify the optimal temperature, solvent, and concentra-
tion. In toluene as the solvent, systematic cooling of the
reaction mixture lead to an increase in enantioselectivity,
but the magnitude of the change (entries 10 vs 4, 84% ee
SYNTHESIS 2011, No. 12, pp 1880–1886
x
x.
x
x
.
2
0
1
1
Advanced online publication: 20.05.2011
DOI: 10.1055/s-0030-1260059; Art ID: C27511SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Enantioselective Organocatalytic Aryloxylation of b-Keto Esters
1881
Table 1 Proof of Principle, Catalyst Identification, and Optimiza-
tion of Reaction Conditions in the Aryloxylation of Keto Ester 8 with
OMe
N
N
9a
O
O
HO
HO
Y
N
N
N
OMe
N
1
2
8
catalyst (10 mol%)
conditions
HN
+
O
HO
O
HN
R
X
OMe
O
10
O
R =
R =
F3C
O
9
F3C
CF3
CF3
Entry Catalyst Solvent
Temp
(°C)
Time
Yieldb
(%)
eec
OMe
Y = OMe,
X = O, 6
(h)
17
13
72
(%)
(–) 6
50
Y = H, X = S, 3
Y = H,
X = O, 4
Y = OMe,
X = O, 7
Y = OMe, X = O, 5
1
2
1
2
3
4
5
6
7
4
4
4
4
4
4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
EtOH
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
66
63
50
83
62
65
45
84
69
86
74
83
91
Figure 1 Bifunctional organocatalysts for preliminary screen
at –78 °C compared to 72% ee at r.t.) was not sufficient to
justify the extended reaction time of 48 hours. Other sol-
vents were then screened at –20 °C and high enantioselec-
tivities were indeed found with typical laboratory solvents
such as ethanol and acetone but only with tert-butyl meth-
yl ether was a practical reaction rate also observed (entry
13, 87% ee, 7 h).
3
44
4
0.5
72
5
17
17
17
73
6
63
7
67
With optimized reaction conditions established the scope
of the reaction was surveyed by probing changes to both
o-quinone oxidant and b-keto ester pro-nucleophiles. A
range of commercially available or readily prepared o-
quinones and five- or six-membered ring cyclic b-keto es-
ters were investigated for reactivity and the results are
presented in Scheme 2.
8
0.6
73
9
–20
–78
–20
–20
–20
3
48
96
96
7
78
10
11
12
13
84
76
acetone
TBME
88
Of the commercially available o-quinones, o-chloranil
and o-bromanil were found to be the most reactive afford-
ing the dioxin products within one hour for cyclopen-
tanone derived pro-nucleophiles. Enantioselectivies with
five and six-membered ring cyclic b-keto esters (methyl
or ethyl) ranged from 76–86% ee with yields up to 87%.
3,5-Di-tert-butyl-o-quinone was found to be less reactive
affording the desired dioxin products 10 and 15 with
methyl and ethyl 2-oxocyclopentanecarboxylates within
24 hours. In both reactions, only one of the two possible
regioisomers was obtained. NOE and 1,n-ADEQUATE6
studies on 10 support the product resulting from preferen-
tial attack at the least sterically hindered oxygen of the o-
quinone electrophile (see the Supporting Information for
details). In both cases the enantiomeric excess of the reac-
tion product was good (87% and 77% ee, respectively).
Encouraged by these results, 5-tert-butyl-3-chloro-o-
quinone and 3-bromo-5-tert-butyl-o-quinone were syn-
thesized and tested in the reaction with five- and six-ring
keto esters. Although mixtures of regioisomeric products
were obtained (ratios ranged from 73:27 to 52:48), reac-
tion yields were generally good and, pleasingly, levels of
stereoinduction were maintained over the series. Interest-
ingly, when halogenated, unsymmetrical quinones were
87
a Reaction conditions: 9 (1.0 equiv), 8 (1.0 equiv), catalysts 1–7 (0.1
equiv), TBME (0.15 M in 9).
b Isolated yield.
c Determined by chiral HPLC (see Supporting Information for condi-
tions).
used, in most cases a reversal in regioselectivity was ob-
served (1,n-ADEQUATE6 and NOE experiments on com-
pound 23, see the Supporting Information for details).
Surprisingly, compound 21 was obtained with opposite
regioselectivity to compounds derived from unsymmetri-
cal halogenated quinones. This reversal in regioselectivity
between 20 and 21 indicates how subtle steric and elec-
tronic factors affect the product distribution (methyl
against ethyl ester for 20 and 21).
In the case of 12, preparative chiral stationary phase
HPLC allowed the isolation of an enantiopure sample
from which the absolute and relative stereochemical con-
figuration was unambiguously determined by single crys-
tal X-ray diffraction. In all other examples the
configurations were assigned by analogy.
Synthesis 2011, No. 12, 1880–1886 © Thieme Stuttgart · New York

1882
K. Greenaway et al.
PAPER
R2
R2
O
O
4 (10 mol%)
R1
+
O
O
HO
TBME, –20 °C
O
O
n
O
O
R1
n
O
10–23
Cl
Br
Cl
Cl
Br
O
Br
Br
O
O
Cl
HO
HO
HO
O
O
O
O
O
O
O
O
O
10 (7 h, 91%, 86% ee) 11 (1 h, 78%, 76% ee) 12 (1 h, 87%, 86% ee)
Cl
Br
Cl
Cl
Cl
Br
Br
Br
O
O
O
HO
HO
HO
O
O
O
O
O
O
O
O
O
Figure 2 X-ray crystal structure of 12 and postulated transition state
leading to its formation
13 (1 h, 77%, 76% ee) 14 (1 h, 79%, 77% ee) 15 (24 h, 90%, 77% ee)
Br
We postulate that the reaction proceeds via a bifunctional
mode of operation of catalyst 4, where both the basic
bridgehead nitrogen and the hydrogen bonding urea are
operating cooperatively to activate and organize the re-
agents in the transition state. As the absolute configura-
tion of 12 has been determined we postulate a transition
state structure for the reaction of methyl 2-oxocyclopen-
tanecarboxylate and o-bromanil as shown in Figure 2.
Br
Br
Br
O
O
Cl
O
HO
HO
HO
O
O
O
O
O
O
O
O
O
16 (5 h, 82%, 79% ee) 17 (168 h, 48%, 77% ee) 18a (24 h, 92%, 79% ee)
In summary the efficient enantioselective a-aryloxylation
of cyclic b-keto esters with o-quinone reagents to yield tri-
cyclic dioxin adducts has been developed. Products are
obtained in excellent yield and with enantiomeric excess-
es up to 87%. Studies to further develop and exploit the re-
action in synthesis are ongoing and will be reported in due
course.
Cl
O
Cl
O
Cl
O
HO
HO
HO
O
O
O
O
O
O
O
O
O
19a (24 h, 86%, 77% ee) 20a (24 h, 90%, 72% ee) 21a (24 h, 87%, 65% ee)
All reactions were performed under an atmosphere of dry N2 unless
otherwise stated. Reagents were used as obtained from commercial
suppliers or purified according to standard procedures. Petroleum
ether (PE) refers to distilled light petroleum of fraction (40–65 °C).
Flash column chromatography was carried out using Merck Kiesel-
gel 60 silica gel (230–400 mesh). TLC was carried out using Merck
Kieselgel 60 F254 (230–400 mesh) fluorescent treated silica which
were visualised under UV light (250 nm) or by staining with aq
KMnO4 solns. All 1H and 13C NMR spectra were recorded using a
Bruker 700, 500, 400, or 300 MHz and Varian 300 MHz spectrom-
eters and were internally referenced to residual protiosolvent.
DEPT135 and 2D (COSY, HMQC, NOE, 1,n-ADEQUATE) NMR
spectroscopy were used where appropriate to assist the assignment
of signals in the 1H and 13C NMR spectra. 1,n-ADEQUATE exper-
iments were performed on a Bruker AV 700 MHz spectrometer.
LR-MS (EI, CI) was recorded on a Fissions VG Trio 2000 quadro-
pole mass spectrometer. HRMSwere recorded on a Thermo Finni-
gan Mat 95XP mass spectrometer. IR spectra were recorded on an
ATI Mattson: Genesis Series FTIR spectrophotometer from a thin
film deposited onto a NaCl plate; only selected absorbances are re-
O
Br
O
Br
HO
HO
O
O
O
O
O
O
22a (24 h, 80%, 80% ee)
23a (24 h, 95%, 77% ee)
Scheme 2 Scope of cyclic b-keto ester aryloxylation reaction; a re-
gioisomeric ratios (rr) and enantiomeric excesses (ee) of the dioxin
adducts determined by chiral stationary phase HPLC analysis of the
crude product: 18 rr = 70:30, 19 rr = 62:38, 20 rr = 56:44, 21
rr = 73:27, 22 rr = 62:38, 23 rr = 52:48. The major regioisomer is re-
presented in the scheme. For a detailed assignment of the regioisome-
ric products see the Supporting Information.
Synthesis 2011, No. 12, 1880–1886 © Thieme Stuttgart · New York

PAPER
Enantioselective Organocatalytic Aryloxylation of b-Keto Esters
1883
ported. Optical rotations were recorded using an Optical Activity
AA-1000 polarimeter; [a]D values are reported in 10–1 deg cm2 g–1;
concentration (c) is given in g/100 mL at 589 nm. Enantiomeric ex-
cesses of the dioxin products were determined by chiral HPLC
(conditions given with compound).
13C NMR (125 MHz, CDCl3): d = 17.8 (CH2), 33.3 (CH2), 33.4
(CH2), 53.6 (OCH3), 82.2 [C(CO2Me)], 105.8 [C(OH)], 114.0 (CAr),
114.3 (CAr), 120.1 (CAr), 121.2 (CAr), 138.4 (CAr), 139.7 (CAr), 171.1
(CO2Me).
HRMS (ES–): m/z (M – H+) calcd for C13H9Br4O5: 560.7183; found:
560.7182.
Enantioenriched Dioxins; General Procedure
A soln of catalyst 4 16.7mg (0.1 equiv) and b-keto ester (1equiv) in
TBME (1.5 mL) at –20 °C was added to a stirred soln o-quinone (1
equiv) in TBME (0.5 mL) at –20 °C. The reaction was monitored by
TLC until the o-quinone was consumed (time is given in Scheme 2).
The mixture was filtered through silica gel, the solvents evaporated
in vacuo and the crude product purified by flash column chromatog-
raphy (PE–EtOAc).
Ethyl 5,6,7,8-Tetrachloro-9a-hydroxy-1,2,3,9a-tetrahydro-
3aH-cyclopenta[b][1,4]benzodioxin-3a-carboxylate (13)
Yield: 77%; 76% ee; HPLC [Daicel Chiralpak AS, hexane–i-PrOH,
98:2 (premixed eluent), flow rate 0.8 mL/min, l = 230 nm]:
tR = 12.5 (major), 20.6 min (minor).
[a]D25 +119.5 (c 0.3, CHCl3).
IR: 3424, 2982, 1713, 1427, 1143, 1090, 1017, 1000 cm–1.
Methyl 6,8-Di-tert-butyl-9a-hydroxy-1,2,3,9a-tetrahydro-3aH-
cyclopenta[b][1,4]benzodioxin-3a-carboxylate (10)
Yield: 91%; 86% ee; HPLC [Daicel Chiralpak AS, hexane–i-PrOH,
98:2 (premixed eluent), flow rate 0.2 mL/min, l = 230 nm]: tR =
27.1 (major), 33.4 min (minor).
[a]D25 +54.4 (c 1.0, CHCl3).
IR: 3440, 2959, 2907, 2870, 1710, 1316, 1140, 1109, 1028 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.28 (s, 9 H), 1.38 (s, 9 H), 1.90–
2.06 (m, 4 H), 2.15–2.20 (m, 1 H), 2.34–2.40 (m, 1 H), 3.75 (s, 3 H),
5.49 (br s, 1 H), 6.87 (d, J = 2.5 Hz, 1 H), 6.94 (d, J = 2.5 Hz, 1 H).
1H NMR (500 MHz, CDCl3): d = 1.18 (t, J = 7.0 Hz, 3 H), 1.89–2.07
(m, 3 H), 2.17–2.23 (m, 1 H), 2.33–2.39 (m, 1 H), 2.44–2.50 (m, 1
H), 4.17 (dq, J1 = 7.0 Hz, J2 = 11.0 Hz, 1 H), 4.20 (dq, J1 = 7.0 Hz,
J2 = 11.0 Hz, 1 H), 5.68 (br s, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.7 (OCH2CH3), 17.7 (CH2),
33.2 (CH2), 33.4 (CH2), 62.9 (OCH2CH3), 81.6 [C(CO2Et)], 105.8
[C(OH)], 120.3 (CAr), 121.0 (CAr), 124.8 (CAr), 126.0 (CAr), 137.0
(CAr), 138.6 (CAr), 170.6 (CO2Et).
HRMS (ES–): m/z (M – H+) calcd for C14H11Cl4O5: 398.9361;
found: 398.9356.
13C NMR (125 MHz, CDCl3): d = 17.8 (CH2), 29.6 (CH3, t-Bu),
31.4 (CH3, t-Bu), 32.4 (CH2), 33.7 (CH2), 34.4 (C, t-Bu), 35.0 (C, t-
Bu), 53.1 (OCH3), 80.4 [C(CO2Me)], 103.8 [C(OH)], 112.2 (CAr),
116.9 (CHAr), 137.6 (CHAr), 137.7 (CAr), 139.4 (CAr), 143.6 (CAr),
172.9 (CO2Me).
HRMS (ES+): m/z [M + NH4]+ calcd for C21H34NO5: 380.2437;
found: 380.2431.
Ethyl 5,6,7,8-Tetrabromo-9a-hydroxy-1,2,3,9a-tetrahydro-
3aH-cyclopenta[b][1,4]benzodioxin-3a-carboxylate (14)
Yield: 79%; 77% ee; HPLC [Daicel Chiralpak AS, hexane–i-PrOH,
97:3 (premixed eluent), flow rate 0.6 mL/min, l = 230 nm]:
tR = 20.7 (major), 37.0 min (minor).
[a]D25 +99.8 (c 0.4, CHCl3).
IR: 3421, 2981, 1713, 14 10, 1142, 1090, 1017, 992 cm–1.
Methyl 5,6,7,8-Tetrachloro-9a-hydroxy-1,2,3,9a-tetrahydro-
3aH-cyclopenta[b][1,4]benzodioxin-3a-carboxylate (11)
Yield: 78%; 76% ee; HPLC [Daicel Chiralpak AS, hexane–i-PrOH,
98:2 (premixed eluent), flow rate 0.8 mL/min, l = 230 nm]: tR =
16.0 (major), 24.5 min (minor).
[a]D25 +122.1 (c 0.5, CHCl3).
IR: 3428, 2957, 1741, 1720, 1427, 1143, 1091, 1020, 1003 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.88–2.07 (m, 3 H), 2.16–2.21 (m,
1 H), 2.32–2.37 (m, 1 H), 2.45–2.52 (m, 1 H), 3.75 (s, 3 H), 5.56 (br
s, 1 H).
1H NMR (500 MHz, CDCl3): d = 1.20 (t, J = 7.0 Hz, 3 H), 1.88–2.08
(m, 3 H), 2.17–2.23 (m, 1 H), 2.35–2.40 (m, 1 H), 2.44–2.50 (m, 1
H), 4.17 (dq, J1 = 7.0 Hz, J2 = 11.0 Hz, 1 H), 4.20 (dq, J1 = 7.0 Hz,
J2 = 11.0 Hz, 1 H), 5.67 (br s, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.8 (OCH2CH3), 17.8 (CH2),
33.3 (CH2), 33.6 (CH2), 63.0 (OCH2CH3), 81.8 [C(CO2Et)], 106.1
[C(OH)], 113.9 (CAr), 114.5 (CAr), 120.0 (CAr), 121.3 (CAr), 138.5
(CAr), 140.0 (CAr), 170.8 (CO2Et).
HRMS (ES–): m/z (M – H+) calcd for C14H11Br4O5: 574.7340;
found: 574.7345.
13C NMR (125 MHz, CDCl3): d = 17.7 (CH2), 33.2 (CH2), 33.3
(CH2), 53.6 (OCH3), 82.0 [C(CO2Me)], 105.5 [C(OH)], 120.4 (CAr),
120.9 (CAr), 125.0 (CAr), 125.9 (CAr), 137.0 (CAr), 138.3 (CAr), 171.0
(CO2Me).
HRMS (ES+): m/z [M + NH4]+ calcd for C13H14Cl4NO5: 403.9626;
found: 403.9607.
Ethyl 6,8-Di-tert-butyl-9a-hydroxy-1,2,3,9a-tetrahydro-3aH-
cyclopenta[b][1,4]benzodioxin-3a-carboxylate (15)
Yield: 90%; 77% ee; HPLC [Daicel Chiralpak OD-H, hexane–i-
PrOH, 99:1 (premixed eluent), flow rate 0.6 mL/min, l = 230 nm]:
tR = 8.3 (major), 7.1 min (minor).
[a]D25 +48.6 (c 1.5, CHCl3).
Methyl 5,6,7,8-Tetrabromo-9a-hydroxy-1,2,3,9a-tetrahydro-
3aH-cyclopenta[b][1,4]benzodioxin-3a-carboxylate (12)
Yield: 87%; 86% ee; HPLC [Daicel Chiralpak AS, hexane–i-PrOH,
99:1 (premixed eluent), flow rate 0.8 mL/min, l = 230 nm]:
tR = 18.4 (major), 35.1 min (minor).
IR: 3439, 2958, 2906, 2870, 1739, 1710, 1140, 1109, 1029, 997
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.11 (t, J = 7.0 Hz, 3 H), 1.28 (t,
9 H), 1.38 (t, 9 H), 1.89–2.11 (m, 4 H), 2.15–2.22 (m, 1 H), 2.34–
2.42 (m, 1 H), 4.14 (dq, J1 = 7.0 Hz, J2 = 11.0 Hz, 1 H), 4.21 (dq,
J1 = 7.0 Hz, J2 = 11.0 Hz, 1 H), 5.59 (br s, 1 H), 6.88 (d, J = 2.5 Hz,
1 H), 6.93 (d, J = 2.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.8 (OCH2CH3), 17.9 (CH2),
29.6 (CH3, t-Bu), 31.5 (CH3, t-Bu), 32.8 (CH2), 33.4 (CH2), 34.4 (C,
t-Bu), 35.0 (C, t-Bu), 62.0 (OCH2CH3), 80.2 [C(CO2Et)], 104.3
[C(OH)], 112.5 (CHAr), 116.9 (CHAr), 137.5 (CAr), 137.9 (CAr),
139.6 (CAr), 143.4 (CAr), 172.5 (CO2Et).
[a]D25 +47.5 (c 0.2, CHCl3).
IR: 3444, 2950, 2868, 1741, 1716, 1417, 1316, 1109, 1030, 1020,
1003, 990 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.87–2.07 (m, 3 H), 2.16–2.21 (m,
1 H), 2.33–2.39 (m, 1 H), 2.45–2.52 (m, 1 H), 3.76 (s, 3 H), 5.53 (br
s, 1 H).
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K. Greenaway et al.
PAPER
HRMS (ES+): m/z [M + NH4]+ calcd for C22H36NO5: 394.2593;
found: 394.2582.
Minor regioisomer
1H NMR (500 MHz, CDCl3): d = 1.27 (s, 9 H), 1.93–2.10 (m, 4 H),
2.29–2.35 (m, 1 H), 2.38–2.45 (m, 1 H), 3.75 (s, 3 H), 5.56 (br s, 1
H), 6.91 (d, J = 2.0 Hz, 1 H), 7.01 (d, J = 2.0 Hz, 1 H).
Methyl 6,7,8,9-Tetrabromo-10a-hydroxy-1,3,4,10a-tetrahydro-
2H-dibenzo[b,e][1,4]dioxin-4a-carboxylate (16)
Yield: 82%; 79% ee; HPLC [Daicel Chiralpak AS, hexane–i-PrOH,
98:2 (premixed eluent), flow rate 0.5 mL/min, l = 230 nm]: tR =
30.0 (major), 43.0 min (minor).
13C NMR (125 MHz, CDCl3): d = 17.7 (CH2), 31.2 (CH3, t-Bu),
32.8 (CH2), 33.6 (CH2), 34.4 (C, t-Bu), 53.2 (OCH3), 81.3
[C(CO2Me)], 104.9 [C(OH)], 112.9 (CHAr), 120.6 (CHAr), 121.1
(CAr), 135.6 (CAr), 140.3 (CAr), 145.2 (CAr), 172.1 (CO2Me).
[a]D25 +51.3 (c 0.4, CHCl3).
Ethyl 6-tert-Butyl-8-chloro-9a-hydroxy-1,2,3,9a-tetrahydro-
3aH-cyclopenta[b][1,4]benzodioxin-3a-carboxylate and Ethyl
7-tert-Butyl-5-chloro-9a-hydroxy-1,2,3,9a-tetrahydro-3aH-cy-
clopenta[b][1,4]benzodioxin-3a-carboxylate (19)
Yield: 86%; regioisomer ratio: major/minor 62:38; 77% ee (major),
65% ee (minor); HPLC [Daicel Chiralpak AD, hexane–i-PrOH,
99:1 (premixed eluent), flow rate 0.7 mL/min, l = 230 nm]: major
regioisomer: tR = 11.1 (major), 14.5 min (minor); minor regioiso-
mer: tR = 17.5 (major), 13.4 min (minor).
IR: 3423, 2949, 2867, 1715, 1409, 1072, 1059, 1024, 981 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.54–1.64 (m, 2 H), 1.65–1.74 (m,
2 H), 1.76–1.84 (m, 1 H), 1.87–1.93 (m, 1 H), 2.18–2.30 (m, 2 H),
3.74 (s, 3 H), 6.00 (br s, 1 H).
13C NMR (125 MHz, CDCl3): d = 19.1 (CH2), 21.8 (CH2), 31.3
(CH2), 32.4 (CH2), 53.9 (OCH3), 79.2 [C(CO2Me)], 98.2 [C(OH)],
113.8 (CAr), 114.1 (CAr), 120.0 (CAr), 120.8 (CAr), 138.7 (CAr), 140.1
(CAr), 172.8 (CO2Me).
HRMS (ES–): m/z (M – H+) calcd for C14H11Br4O5: 574.7340;
found: 574.7345.
IR: 3425, 2960, 1739, 1708, 1492, 1302, 1138, 1094, 1021, 998
cm–1.
HRMS (ES+): m/z [M + NH4]+ calcd for C18H27ClNO5: 372.1578;
Methyl 7,9-Di-tert-butyl-10a-hydroxy-1,3,4,10a-tetrahydro-2H-
dibenzo[b,e][1,4]dioxin-4a-carboxylate (17)
found: 372.1572.
Yield: 48%; 77% ee; HPLC [Daicel Chiralpak IA, hexane–i-PrOH,
99:1 (premixed eluent), flow rate 0.3 mL/min, l = 230 nm]:
tR = 69.2 (major), 59.7 min (minor).
[a]D25 +17.4 (c 0.8, CHCl3).
Major regioisomer
1H NMR (500 MHz, CDCl3): d = 1.14 (t, J = 7.0 Hz, 3 H), 1.25 (s,
9 H), 1.93–2.16 (m, 4 H), 2.27–2.36 (m, 1 H), 2.37–2.45 (m, 1 H),
4.14 (dq, J1 = 7.0 Hz, J2 = 10.5 Hz, 1 H), 4.20 (dq, J1 = 7.0 Hz,
J2 = 10.5 Hz, 1 H), 5.72 (br s, 1 H), 6.82 (d, J = 2.0 Hz, 1 H), 6.96
(d, J = 2.0 Hz, 1 H).
IR: 3440, 2954, 2879, 1716, 1055, 973 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.28 (s, 9 H), 1.36 (s, 9 H), 1.57–
1.84 (m, 6 H), 2.05–2.20 (m, 2 H), 3.70 (s, 3 H), 5.84 (br s, 1 H),
6.86 (d, J = 2.5 Hz, 1 H), 6.90 (d, J = 2.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 19.3 (CH2), 21.9 (CH2), 29.6
(CH3, t-Bu), 31.0 (CH2), 31.5 (CH3, t-Bu), 32.6 (CH2), 34.4 (C, t-
Bu), 35.0 (C, t-Bu), 53.2 (OCH3), 77.7 [C(CO2Me)], 95.6 [C(OH)],
111.8 (CHAr), 116.6 (CHAr), 137.8 (CAr), 137.9 (CAr), 139.8 (CAr),
143.5 (CAr), 174.5 (CO2Me).
13C NMR (125 MHz, CDCl3): d = 13.6 (OCH2CH3), 17.8 (CH2),
31.1 (CH3, t-Bu), 33.0 (CH2), 33.4 (CH2), 34.4 (C, t-Bu), 62.5
(OCH2CH3), 81.0 [C(CO2Et)], 104.9 [C(OH)], 112.9 (CHAr), 119.6
(CHAr), 121.5 (CAr), 134.2 (CAr), 142.1 (CAr), 146.0 (CAr), 172.0
(CO2Et).
Minor regioisomer
1H NMR (500 MHz, CDCl3): d = 1.13 (t, J = 7.0 Hz, 3 H), 1.26 (s,
9 H), 1.93–2.16 (m, 4 H), 2.27–2.36 (m, 1 H), 2.37–2.45 (m, 1 H),
4.14 (dq, J1 = 7.0 Hz, J2 = 10.5 Hz, 1 H), 4.21 (dq, J1 = 7.0 Hz,
J2 = 10.5 Hz, 1 H), 5.67 (br s, 1 H), 6.92 (d, J = 2.0 Hz, 1 H), 7.00
(d, J = 2.0 Hz, 1 H).
HRMS (ES–): m/z (M – H+) calcd for C22H31O5 375.2172; found:
375.2163.
Methyl 6-tert-Butyl-8-chloro-9a-hydroxy-1,2,3,9a-tetrahydro-
3aH-cyclopenta[b][1,4]benzodioxin-3a-carboxylate and Methyl
7-tert-Butyl-5-chloro-9a-hydroxy-1,2,3,9a-tetrahydro-3aH-cy-
clopenta[b][1,4]benzodioxin-3a-carboxylate (18)
Yield: 92%; regioisomer ratio: major/minor 70:30; 79% ee (major),
62% ee (minor); HPLC [Daicel Chiralpak AD, hexane–i-PrOH,
99:1 (premixed eluent), flow rate 0.7 mL/min, l = 230 nm]: major
regioisomer: tR = 14.4 (major), 19.8 min (minor); minor regioiso-
mer: tR = 24.5 (major), 18.4 min (minor).
13C NMR (125 MHz, CDCl3): d = 13.8 (OCH2CH3), 17.7 (CH2),
31.2 (CH3, t-Bu), 32.9 (CH2), 33.4 (CH2), 34.4 (C, t-Bu), 62.4
(OCH2CH3), 80.8 [C(CO2Et)], 105.2 [C(OH)], 113.1 (CHAr), 120.6
(CHAr), 120.8 (CAr), 135.9 (CAr), 140.3 (CAr), 145.0 (CAr), 171.8
(CO2Et).
Methyl 8-tert-Butyl-6-chloro-10a-hydroxy-1,3,4,10a-tetrahy-
dro-2H-dibenzo[b,e][1,4]dioxin-4a-carboxylate and Methyl 7-
tert-Butyl-9-chloro-10a-hydroxy-1,3,4,10a-tetrahydro-2H-
dibenzo[b,e][1,4]dioxin-4a-carboxylate (20)
Yield: 90%; regioisomer ratio: major/minor 56:44; 72% ee (major),
69% ee (minor); HPLC [Daicel Chiralpak AD, hexane–i-PrOH,
99:1 (premixed eluent), flow rate 0.7 mL/min, l = 230 nm]: major
regioisomer: tR = 9.0 (major), 15.2 min (minor); minor regioisomer:
tR = 20.3 (major), 12.0 min (minor).
IR: 3444, 2962, 2870, 1742, 1574, 1439, 1301, 1092, 1003, 980
cm–1.
HRMS (ES+): m/z [M + NH4]+ calcd for C17H25ClNO5: 358.1421;
found: 358.1416.
Major regioisomer
1H NMR (500 MHz, CDCl3): d = 1.25 (s, 9 H), 1.93–2.10 (m, 4 H),
2.29–2.35 (m, 1 H), 2.38–2.45 (m, 1 H), 3.74 (s, 3 H), 5.62 (br s, 1
H), 6,82 (d, J = 2.0 Hz, 1 H), 6.97 (d, J = 2.0 Hz, 1 H).
IR: 3430, 2950, 2861, 1744, 1711, 1489, 1302, 1057, 1024 cm–1.
HRMS (ES+): m/z [M + NH4]+ calcd for C18H27ClNO5: 372.1578;
found: 372.1572.
13C NMR (125 MHz, CDCl3): d = 17.8 (CH2), 31.1 (CH3, t-Bu),
32.8 (CH2), 33.6 (CH2), 34.4 (C, t-Bu), 53.3 (OCH3), 81.3
[C(CO2Me)], 104.6 [C(OH)], 113.0 (CHAr), 119.9 (CHAr), 121.3
(CAr), 134.2 (CAr), 141.8 (CAr), 145.9 (CAr), 172.4 (CO2Me).
Major regioisomer
1H NMR (500 MHz, CDCl3): d = 1.27 (s, 9 H), 1.61–1.86 (m, 6 H),
2.08–2.27 (m, 2 H), 3.71 (s, 3 H), 5.95 (br s, 1 H), 6.90 (d, J = 2.0
Hz, 1 H), 6.97 (d, J = 2.0 Hz, 1 H).
Synthesis 2011, No. 12, 1880–1886 © Thieme Stuttgart · New York

PAPER
Enantioselective Organocatalytic Aryloxylation of b-Keto Esters
1885
13C NMR (125 MHz, CDCl3): d = 19.1 (CH2), 21.9 (CH2), 31.1
(CH3, t-Bu), 31.1 (CH2), 32.7 (CH2), 34.4 (C, t-Bu), 53.4 (OCH3),
78.3 [C(CO2Me)], 97.0 [C(OH)], 112.4 (CHAr), 120.3 (CHAr), 121.0
(CAr), 136.0 (CAr), 140.6 (CAr), 145.0 (CAr), 173.8 (CO2Me).
Major regioisomer
1H NMR (500 MHz, CDCl3): d = 1.26 (s, 9 H), 1.90–2.36 (m, 5 H),
2.37–2.45 (m, 1 H), 3.74 (s, 3 H), 5.61 (br s, 1 H), 6.86 (d, J = 2.0
Hz, 1 H), 7.12 (d, J = 2.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 17.7 (CH2), 31.1 (CH3, t-Bu),
32.7 (CH2), 33.6 (CH2), 34.3 (C, t-Bu), 53.3 (OCH3), 81.3
[C(CO2Me)], 104.6 [C(OH)], 110.1 (CAr), 113.8 (CHAr), 122.7
(CHAr), 135.1 (CAr), 141.6 (CAr), 146.5 (CAr), 172.5 (CO2Me).
Minor regioisomer
1H NMR (500 MHz, CDCl3): d = 1.24 (s, 9 H), 1.61–1.86 (m, 6 H),
2.08–2.27 (m, 2 H), 3.70 (s, 3 H), 6.00 (br s, 1 H), 6.78 (d, J = 2.0
Hz, 1 H), 6.95 (d, J = 2.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 19.2 (CH2), 21.8 (CH2), 31.2
(CH3, t-Bu), 31.2 (CH2), 32.5 (CH2), 34.3 (C, t-Bu), 53.4 (OCH3),
78.5 [C(CO2Me)], 96.5 [C(OH)], 113.1 (CHAr), 119.7 (CHAr), 120.8
(CAr), 134.5 (CAr), 142.1 (CAr), 145.6 (CAr), 174.1 (CO2Me).
Minor regioisomer
1H NMR (500 MHz, CDCl3): d = 1.27 (s, 9 H), 1.90–2.36 (m, 5 H),
2.37–2.45 (m, 1 H), 3.75 (s, 3 H), 5.54 (br s, 1 H), 6.95 (d, J = 2.0
Hz, 1 H), 7.17 (d, J = 2.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 17.7 (CH2), 31.2 (CH3, t-Bu),
32.7 (CH2), 33.6 (CH2), 34.3 (C, t-Bu), 53.3 (OCH3), 81.2
[C(CO2Me)], 105.0 [C(OH)], 110.0 (CAr), 113.6 (CHAr), 123.5
(CHAr), 136.5 (CAr), 140.1 (CAr), 145.8 (CAr), 172.1 (CO2Me).
Ethyl 7-tert-Butyl-9-chloro-10a-hydroxy-1,3,4,10a-tetrahydro-
2H-dibenzo[b,e][1,4]dioxin-4a-carboxylate and Ethyl 8-tert-Bu-
tyl-6-chloro-10a-hydroxy-1,3,4,10a-tetrahydro-2H-diben-
zo[b,e][1,4]dioxin-4a-carboxylate (21)
Yield: 87%; regioisomer ratio: major/minor 73:27; 65% ee (major),
50% ee (minor); HPLC [Daicel Chiralpak AD, hexane–i-PrOH,
99:1 (premixed eluent), flow rate 1.0 mL/min, l = 230 nm]: major
regioisomer: tR = 5.2 (major), 7.3 min (minor); minor regioisomer:
tR = 7.9 (major), 5.9 min (minor).
IR: 3420, 2955, 2861, 1708, 1492, 1307, 1102, 1057, 1034 cm–1.
HRMS (ES+): m/z [M + NH4]+ calcd for C19H29ClNO5: 386.1734;
Ethyl 8-Bromo-6-tert-butyl-9a-hydroxy-1,2,3,9a-tetrahydro-
3aH-cyclopenta[b][1,4]benzodioxin-3a-carboxylate and Ethyl
5-Bromo-7-tert-butyl-9a-hydroxy-1,2,3,9a-tetrahydro-3aH-cy-
clopenta[b][1,4]benzodioxin-3a-carboxylate (23)
Yield: 95%; regioisomer ratio: major/minor 52:48; 77% ee (major),
72% ee (minor); HPLC [Daicel Chiralpak IB, hexane–i-PrOH,
99.5:0.5 (premixed eluent), flow rate 0.7 mL/min, l = 230 nm]: ma-
jor regioisomer: tR = 13.4 (major), 14.7 min (minor); minor regio-
isomer: tR = 19.6 (major), 16.4 min (minor).
found: 386.1729.
Major regioisomer
IR: 3420, 2950, 2898, 2866, 1742, 1713, 1484, 1300, 1136, 1089,
1018, 992 cm–1.
HRMS (ES+): m/z [M + NH4]+ calcd for C18H27BrNO5: 416.1073,
1H NMR (500 MHz, CDCl3): d = 1.05 (t, J = 7.0 Hz, 3 H), 1.26 (s,
9 H), 1.58–1.90 (m, 6 H), 2.08–2.28 (m, 2 H), 4.08 (dq, J1 = 7.0 Hz,
J2 = 10.5 Hz, 1 H), 4.20 (dq, J1 = 7.0 Hz, J2 = 10.5 Hz, 1 H), 6.04
(br s, 1 H), 6.91 (d, J = 2.0 Hz, 1 H), 6.97 (d, J = 2.0 Hz, 1 H).
416.1067.
13C NMR (125 MHz, CDCl3): d = 13.7 (OCH2CH3), 19.1 (CH2),
21.9 (CH2), 31.2 (CH3, t-Bu), 31.2 (CH2), 32.4 (CH2), 34.3 (C, t-
Bu), 62.4 (OCH2CH3), 78.0 [C(CO2Et)], 97.3 [C(OH)], 112.6
(CHAr), 120.2 (CHAr), 120.8 (CAr), 136.2 (CAr), 140.7 (CAr), 144.8
(CAr), 173.3 (CO2Et).
Major regioisomer
1H NMR (500 MHz, CDCl3): d = 1.15 (t, J = 7.0 Hz, 3 H), 1.25 (s,
9 H), 1.93–2.03 (m, 3 H), 2.06–2.12 (m, 1 H), 2.29–2.36 (m, 1 H),
2.37–2.45 (m, 1 H), 4.14 (dq, J1 = 7.0 Hz, J2 = 11.0 Hz, 1 H), 4.20
(dq, J1 = 7.0 Hz, J2 = 11.0 Hz, 1 H), 5.73 (br d, J = 1.0 Hz, 1 H),
6.86 (d, J = 2.0 Hz, 1 H), 7.11 (d, J = 2.0 Hz, 1 H).
Minor regioisomer
13C NMR (125 MHz, CDCl3): d = 13.6 (OCH2CH3), 17.8 (CH2),
31.1 (CH3, t-Bu), 33.0 (CH2), 33.4 (CH2), 34.3 (C, t-Bu), 62.4
(OCH2CH3), 81.0 [C(CO2Et)], 104.9 [C(OH)], 110.3 (CAr), 113.6
(CHAr), 122.5 (CHAr), 135.2 (CAr), 141.9 (CAr), 146.6 (CAr), 172.0
(CO2Et).
1H NMR (500 MHz, CDCl3): d = 1.04 (t, J = 7.0 Hz, 3 H), 1.24 (s,
9 H), 1.58–1.90 (m, 6 H), 2.08–2.28 (m, 2 H), 4.07 (dq, J1 = 7.0 Hz,
J2 = 10.5 Hz, 1 H), 4.20 (dq, J1 = 7.0 Hz, J2 = 10.5 Hz, 1 H), 6.06
(br d, J = 2.0 Hz, 1 H), 6.78 (d, J = 2.0 Hz, 1 H), 6.94 (d, J = 2.0 Hz,
1 H).
13C NMR (125 MHz, CDCl3): d = 13.5 (OCH2CH3), 19.2 (CH2),
21.8 (CH2), 31.1 (CH3, t-Bu), 31.2 (CH2), 32.2 (CH2), 34.3 (C, t-
Bu), 62.4 (OCH2CH3), 78.2 [C(CO2Et)], 96.7 [C(OH)], 112.8
(CHAr), 119.4 (CHAr), 121.0 (CAr), 134.6 (CAr), 142.3 (CAr), 145.7
(CAr), 173.5 (CO2Et).
Minor regioisomer
1H NMR (500 MHz, CDCl3): d = 1.14 (t, J = 7.0 Hz, 3 H), 1.26 (s,
9 H), 1.93–2.03 (m, 3 H), 2.06–2.12 (m, 1 H), 2.18–2.23 (m, 1 H),
2.37–2.45 (m, 1 H), 4.13 (dq, J1 = 7.0 Hz, J2 = 11.0 Hz, 1 H), 4.21
(dq, J1 = 7.0 Hz, J2 = 11.0 Hz, 1 H), 5.66 (br d, J = 1.0 Hz, 1 H),
6.96 (d, J = 2.0 Hz, 1 H), 7.16 (d, J = 2.0 Hz, 1 H).
Methyl 8-Bromo-6-tert-butyl-9a-hydroxy-1,2,3,9a-tetrahydro-
3aH-cyclopenta[b][1,4]benzodioxin-3a-carboxylate and Methyl
5-Bromo-7-tert-butyl-9a-hydroxy-1,2,3,9a-tetrahydro-3aH-cy-
clopenta[b][1,4]benzodioxin-3a-carboxylate (22)
Yield: 80%; regioisomer ratio: major/minor 62:38; 80% ee (major),
71% ee (minor); HPLC [Daicel Chiralpak AD, hexane–i-PrOH,
99:1 (premixed eluent), flow rate 0.7 mL/min, l = 230 nm]: major
regioisomer: tR = 15.0 (major), 21.5 min (minor); minor regioiso-
mer: tR = 33.5 (major), 20.0 min (minor).
13C NMR (125 MHz, CDCl3): d = 13.8 (OCH2CH3), 17.7 (CH2),
31.3 (CH3, t-Bu), 32.9 (CH2), 33.4 (CH2), 34.3 (C, t-Bu), 62.4
(OCH2CH3), 80.9 [C(CO2Et)], 105.4 [C(OH)], 109.8 (CAr), 113.9
(CHAr), 123.5 (CHAr), 136.9 (CAr), 140.2 (CAr), 146.7 (CAr), 171.7
(CO2Et).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are detailed experimental procedures, preparation of catalysts and
noncommercial quinones, spectra of all new compounds, HPLC
traces of 10–23, assignment of regioisomeric mixtures, NOE, and
X-ray data.
IR: 3441, 2961, 2905, 2868, 1743, 1715, 1483, 1302, 1139, 1091,
1020, 1002 cm–1.
HRMS (ES+): m/z [M + NH4]+ calcd for C17H25BrNO5: 402.0916;
found: 402.0911.
Synthesis 2011, No. 12, 1880–1886 © Thieme Stuttgart · New York

1886
K. Greenaway et al.
PAPER
(4) (a) Alemán, J.; Jacobsen, C. B.; Frisch, K.; Overgaard, J.;
Jørgensen, K. A. Chem. Commun. 2008, 632. (b) Alemán,
J.; Cabrera, S.; Maerten, E.; Overgaard, J.; Jørgensen, K. A.
Angew. Chem. Int. Ed. 2007, 46, 5520. (c) Alemán, J.;
Richter, B.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2007,
46, 5515. (d) Zhang, S.-L.; Huang, Z.-S.; Shen, Y.-D.; Li,
Y.-M.; Yao, J.-H.; Huang, M.; Chan, A. S. C.; Gu, L.-G.
Tetrahedron Lett. 2006, 47, 6757. (e) Owton, W. M. J.
Chem. Soc., Perkin Trans. 1 1999, 2409. (f) Jacobsen, N.
J. Chem. Soc., Perkin Trans. 2 1979, 569.
(5) For recent reviews on the use of cinchona alkaloid derived
bifunctional organocatalysts, see: (a) Connon, S. J. Chem.
Commun. 2008, 2499. (b) Doyle, A. G.; Jacobsen, E. N.
Chem. Rev. 2007, 107, 5713. For selected examples of the
use of other cinchona alkaloid derived bifunctional
Acknowledgment
We gratefully acknowledge the EPSRC (EP/D04961X/1) for fun-
ding (to P.D. and F.S.), the EPSRC (Leadership Fellowship to
D.J.D.), the EPSRC and GSK for a studentship (to K.G.) and the Eu-
ropean Commission [IEF to A.F. (MEIF-CT-2006-039981)] and
[IEF to F.S. (PIEF-GA-2009-254068)]. We gratefully acknowledge
Dr. Tim Claridge and Dr. Barbara Odell, of the Department of Che-
mistry, University of Oxford, for assistance with 1,n-ADEQUATE
and NOE experiments. We acknowledge Dr Madeleine Helliwell,
of the Department of Chemistry, University of Manchester, for X-
ray analysis.
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