Studies on the enantioselective synthesis of carbazolones as intermediates in aspidosperma and kopsia alkaloid synthesis

Article abstract of DOI:10.1071/CH13287

Two strategies for the assembly of homochiral carbazolones have been investigated. The first exploited desymmetrisation of 1,3-cyclohexadione derivatives however this failed to deliver satisfactory outcomes. An orthogonal route exploiting palladium catalysed decarboxylative allylation of racemic carbazolone β-ketoesters has been developed. Herein we report full details on the development of this reaction and clarify apparent discrepancies between our preliminary reports and those of Shao.

Full text of DOI:10.1071/CH13287

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2013, 66, 882–890
Full Paper
http://dx.doi.org/10.1071/CH13287
Studies on the Enantioselective Synthesis of Carbazolones
as Intermediates in Aspidosperma and Kopsia Alkaloid
Synthesis*
A
A B
,
Christopher J. Gartshore and David W. Lupton
A
School of Chemistry, Monash University, Clayton, Vic. 3800, Australia.
Corresponding author. Email: david.lupton@monash.edu
B
Two strategies for the assembly of homochiral carbazolones have been investigated. The first exploited desymmetrisation
of 1,3-cyclohexadione derivatives however this failed to deliver satisfactory outcomes. An orthogonal route exploiting
palladium catalysed decarboxylative allylation of racemic carbazolone b-ketoesters has been developed. Herein we report
full details on the development of this reaction and clarify apparent discrepancies between our preliminary reports and
those of Shao.
Manuscript received: 3 June 2013.
Manuscript accepted: 5 July 2013.
Published online: 12 August 2013.
Introduction
Alkaloids derived from the Aspidosperma and Kopsia plants of
the Apocynaceae family (for example 1–3) display significant
structural complexity and in several cases biological activity.[1]
We recently commenced studies focussed on the discovery of
general methods to access homochiral carbazolones (i.e. 4),
materials that could serve as common intermediates in the total
synthesis of natural products such as 1–3.[2] The potential of
such a strategy to expedite natural product synthesis had pre-
viously been identified by d’Angelo and Desmae¨le, however
they were unable to access enantioenriched carbazolones in a
concise fashion (see below).[3] While ultimately our studies
have been successful with enantioselective palladium catalysed
decarboxylative allylation providing access to carbazolones in
four steps from commercial materials (Scheme 1, Strategy 2),[4]
these discoveries were made within a more diverse program of
investigation. Herein, we report full details on the development
of this reaction, and include failed attempts at the desymme-
trisation of 1,3-dicarbonyls (i.e. 7) to produce related enan-
tioenriched building blocks (Scheme 1, Strategy 1).
1, aspidophytine
2, vindoline
3, kopsihainanine A
Strategy 2
Enantioselective
allylation
4
rac-5
Strategy 1
Desymmetrisation
6
7
Scheme 1. Strategies to access Aspidosperma and Kopsia alkaloids.
Knoevengel conditions developed by Ramachary and Kishor.[5]
Subsequent palladium catalysed allylation afforded substrate 7a.
Initial studies focussed on desymmetrisation of the diketone by
enolisation and reduction using conditions defined by Simpkins
etal.[6] While conversionintothe trimethyl silyl (TMS) enolether
and reduction failed to afford the expected product, direct
reduction of the enolate intermediate gave alcohol 6a in 48%
isolated yield. Unfortunately, due to the absence of a chromo-
phore we were unable to determine the enantiomeric excess (ee)
using common strategies. However, the low yield indicated that
this transformation was unlikely to be valuable in multistep
synthesis. An alternate strategy focussed on lipase mediated ester
cleavage. Bis-enol acetates have been desymmetrised by various
Results and Discussion
Desymmetrisation of 1,3-Cyclohexadione
Studies commenced by examining the desymmetrisation of pro-
chiral 1,3-cyclohexadiones bearing a quaternary carbon (i.e. 7). It
was postulated that these materials should be accessible in two
steps, and following desymmetrisation could be converted into
homochiral carbazolones (i.e. 4) through dehydrogenation and
then indolisation, hence defining a concise entry to the required
chiral building block (Scheme 2). To examine this strategy allyl
ester 7a, a molecule possessing functionality suited to subsequent
elaboration, was targeted. The synthesis commenced with the
conversion of 1,3-cyclohexadione 8 into ester 9 using reductive
*Preliminary aspects of this work have been reported: C. J. Gartshore, D. W. Lupton, Angew. Chem. Int. Ed. 2013, 52, 4113.
Journal compilation Ó CSIRO 2013
www.publish.csiro.au/journals/ajc

Enantioselective Synthesis of Carbazolones
883
lipases with good to excellent enantioselectivity observed.[7]
Thus, ketone 7a was converted in two steps into bis-vinyl acetate
10 via TMS enol ether 11.[8] Following reaction screening with a
range of lipases it was found that lipase from Candida Rugosa
gave the highest enantioselectivity. Unfortunately, while the
yield was acceptable, the enantioinduction was modest with 12
isolated in 49 % ee. Although these preliminary studies indicated
that it might be possible to exploit enol acetate 12 in natural
product synthesis, concerns related to the modest enantioselec-
tivity and potential challenges with regioselective introduction of
the indole lead to a revision of this strategy.
alkaloids. Central to achieving this would be the development of
methods to install the quaternary stereocentre common to many
Aspidosperma and Kopsia natural products. While many strat-
egies could potentially avail such materials, examination of the
literature revealed that only one had previously been investi-
gated. In 1979 d’Angelo prepared imine 13 and found that it did
not undergo Michael addition with either methyl acrylate or
phenylselenoethylacrylate to afford 14 using several reaction
conditions (Scheme 3).
The enantioselective palladium catalysed decarboxylative
allylation is well suited to the installation of quaternary stereo-
centres.[9,10] While the palladium catalysed decarboxylative
allylation of carbazolone derivatives had not been reported
before our studies, related reactions of vinylogous esters and
thioesters are known.[11] We postulated that the vinylogous
amide functionality within carbazolones, with appropriate
N-protection, should provide materials (i.e. 5a) electronically
suited to decarboxylative allylation.[12] During the course of our
studies support for this concept was reported by Stoltz and
coworkers who found that the allylation of lactams benefits from
electron-withdrawing N-protection.[13] In the event, preliminary
results indicated that the enantioselective decarboxylative ally-
lation of carbazolones could be achieved allowing Boc-
protected 4a to be prepared in 81 % ee using the i-Pr PHOX
ligand L1 (Scheme 4). Pivotal to the success of this reaction
appeared to be the use of electron-withdrawing N-protection
(4a: 81 % ee cf. 4b: 37 % ee), although contemporaneous reports
by Shao and coworkers demonstrated that N-benzyl-protected
carbazolones (i.e. 5b) react smoothly to give carbazolone 4b in
92 % ee using t-Bu PHOX ligand L1.[14] This apparent disagree-
ment relates to significant differences in enantioselectivity
achieved with similar ligands and is discussed later. While the
reaction discovery has been reported previously, full details on
the development of this reaction and an examination of the
difference between our studies and those of Shao are yet to be
detailed.
Enantioselective Decarboxylative Allylation
of Carbazolone Derivatives
Carbazolone (15) iscommercially available, and couldpotentially
serve as a valuable starting material for the synthesis of indole
4a
6a
7a
8
9
7a
Ϫ
Њ
7a
6a
Њ
7a
11
10
The synthesis of the b-ketoester carbazolone substrates for
this reaction commenced with N-protection of carbazolone 15.
Specifically Boc (16a), benzyl (16b), methyl (16c), Tosyl (16d),
and p-CH3O-Tosyl (16e) protected carbazolones were targeted.
Surprisingly, although alkyl protection is commonplace[15] the
protection of carbazolones with electron withdrawing groups, as
in 16a and d–e, has received far less attention.[16] After screen-
ing a range of bases we found that reacting carbazolone 15 with
sodium hydride, followed by introduction of a range of electro-
philes, gave the expected N-protected carbazolones in good to
excellent yields. With these materials in hand, conversion of
Boc-protected carbazolone 16a into b-ketoester 18a was inves-
tigated using allyl chloroformate, allyl ester transfer reagent
17,[17] or allyl cyanoformate[18] (Table 1, entries 1–3). While
the two former methods gave modest yield the cyanoformate
gave the product in good yield, although the advantage of
this approach is offset by the cost and toxicity of the reagent.
Њ
12
10
Scheme 2. Desymmetrisation of 1,3-cyclohexadione 7a.
ϭ
Њ
ϭ
13
ϭ
14a
Њ
ϭ
14b
Scheme 3. d’Angelo’s attempted Michael addition with 13.
Њ
L1
R
R
5a
b
ϭ
ϭ
4a
b
ϭ
ϭ
L1
Scheme 4. Preliminary studies on the decarboxylative allylation of carbazolones.

884
C. J. Gartshore and D. W. Lupton
As a result, when the yield was of little consequence, as in short
sequences, methods A or B were used. While carbazolones 18b
and c could be accessed using these approaches (Table 1, entries
4 and 5), tosyl-protected carbazolones 16d and e could not be
converted into the required materials using any of these reagents
(Table 1, entries 6 and 7). In these cases the order of synthetic
operations was modified, with carbazolone 15 initially con-
verted into b-ketoester 16f and then N-protected with the
appropriate sulfonyl chloride (Table 1, entries 8 and 9).
Alkylation of b-ketoesters 18a–e with ethyl bromoacetate
provided quaternary carbon containing substrates 5a–e in good
to excellent yields (Table 2, entries 1–6). The subsequent dec-
arboxylative allylation, using i-Pr PHOX L1 in conditions modi-
fied from reports of Stoltz and coworkers,[19] in all cases gave the
expected products in good yields, but with significantly different
enantioselectivity. In general electron-withdrawing substrates
gave the highest enantioselectivity with the Boc, Tos, and
p-MeOPhSO2-protected substrates providing carbazolones 4a, d
and e in 81, 83, and 84% ee respectively (Table 2, entries 1, 5,
and 6). In contrast methyl and benzyl-protected substrates gave
carbazolones 4b and c in 37 and 66 % ee, respectively (Table 2,
entries 2 and 4). Due to the ubiquity of Boc protection, 5a was
used in subsequent optimisations. With conditions essentially
defined, i-Pr PHOX L1 was replaced by t-Bu PHOX L2,
a modification that increased the enantioselectivity of the forma-
tion of 4a from 81 to 87% (Table 2, entry 1 cf. 8). As previously
stated benzyl-protected carbazolone 5b underwent enantioselec-
tive decarboxylative allylation to provide 4b in a modest 37% ee
(Table 2, entry 2), significantly less than the 92 % ee obtained by
Shao using the same substrate, with t-Bu PHOX L2. To examine
this discrepancy we recently re-examined this reaction using our
optimised conditions and L2, a ligand that for most substrates
gave a modest increase in enantioselectivity over L1. Remark-
ably the ee was increased to 92 % ee with this substrate (Table 2,
entries 2 and 3), the same enantioselectivity observed by Shao.
To examine the generality of the reaction a range of sub-
strates were prepared starting from Boc carbazolone b-ketoester
18a, and exploiting either direct alkylation (Method A) of the
sodium enolate (Table 2, entries 9–11, 15–16) or conjugate
addition (Method B) with electron deficient olefins (Table 2,
entries 12–14). Decarboxylative allylation was then performed
using t-Bu PHOX L2, providing the expected products in good
yield and with high enantioselectivity in most cases (Table 2,
entries 9–15). When alkyne 5m was reacted a range of products
were obtained using all reaction conditions (Table 2, entry 16).
The production of carbazolones 4k and l in greater than 90 % ee
(Table 2, entries 14 and 15) was particularly pleasing as these
materials contain functionality well suited to studies in alkaloid
total synthesis.
To demonstrate the utility of chiral carbazolones, we exam-
ined the total synthesis of kopsihainanine A (3) (Scheme 5). The
synthesis of the racemic variant of 3 was reported by Xie and She
via primary amide 19.[20] To prepare this material as a single
enantiomer, nitrile 4k was subjected to acidic hydrolysis,
providing the deprotected amide which, following chemoselec-
tive benzylation, gave amide 19, thus completing a formal
synthesis. Shao explored a similar strategy, but completed the
total synthesis, demonstrating that the previous studies by Xie
and She provided the aluminium complex of the natural product
(i.e. 20) rather than the natural product itself. In addition Shao
and coworkers completed the enantioselective total synthesis of
aspidospermidine (22) in eight steps from lactam 21.
Table 1. Preparation of b-ketoesters 18
Њ
Ϫ
ϭ
Њ
Њ
Њ
Ϫ
17
17
Њ
Ϫ
18
16
15
ϭ
Ϫ
Entry
Electrophile (E)
Product 16
Yield 16A [%]
Method
Yield 18A [%]
1
2
3
4
5
6
7
Boc2O
Boc2O
Boc2O
BnBr
16a, PG ¼ Boc
16a, PG ¼ Boc
16a, PG ¼ Boc
16b, PG ¼ Bn
16c, PG ¼ Me
16d, PG ¼ Tos
90
90
90
73
93
78
62
A
42
39
71
34
82
–
B
C
A
MeI
B
TsCl
A, B, or C
A, B, or C
p-MeOPhSO2Cl
16e, PG ¼ p-MeOPhSO2
–
Ϫ
18
15
16f
8
9
18d, PG ¼ Tos
18e, PG ¼ p-MeOPhSO2
51
62
AIsolated yield following flash column chromatography.

Enantioselective Synthesis of Carbazolones
885
Table 2. Enantioselective decarboxylation of 5
:
:
5
18
4
L1
L2
ϭ
ϭ
Entry
Starting material 18
Method
Product 5
Yield 5A [%]
Ligand
Yield 4A [%]
ee 4B [%]
1
18a, PG ¼ Boc
18b, PG ¼ Bn
18b, PG ¼ Bn
18c, PG ¼ Me
18d, PG ¼ Ts
A
A
A
A
A
A
A
A
A
A
A
B
B
B
A
A
5a, R ¼ CH2CO2Et
5b, R ¼ CH2CO2Et
5b, R ¼ CH2CO2Et
5c, R ¼ CH2CO2Et
5d, R ¼ CH2CO2Et
5e, R ¼ CH2CO2Et
5a
98
73
73
87
68
79
98
98
80
93
71
76
84
90
98
72
L1C
L1C
L2D
L1C
L1C
L1C
L1D
L2C
L2D
L2D
L2D
L2D
L2D
L2D
L2D
L2C,D
94
78
91
69
98
99
92
82
72
93
85
87
82
90
82
–
81
37
92
66
83
84
78
87
88
80
87
91
89
94
91
–
2
3
4
5
6
18e, PG ¼ p-MeOPhSO2
18a, PG ¼ Boc
18a, PG ¼ Boc
18a, PG ¼ Boc
18a, PG ¼ Boc
18a, PG ¼ Boc
18a, PG ¼ Boc
18a, PG ¼ Boc
18a, PG ¼ Boc
18a, PG ¼ Boc
18a, PG ¼ Boc
7
8
5a
9
5f, R ¼ CH3
10
11
12
13
14
15
16
5g, R ¼ CH2CH3
5h, R ¼ Bn
5i, R ¼ (CH2)2CO2Et
5j, R ¼ (CH2)2COMe
5k, R ¼ (CH2)2CN
5l, R ¼ (CH2)3N3
5m, R ¼ CH2CꢀCH
AIsolated yield following flash column chromatography.
BEnantiomeric excess determined by HLPC over chiral stationary phases.
CReaction performed at 80 8C.
DReaction performed at 50 8C.
4k
19
3
’
21
20
Scheme 5. Applications of homochiral carbazolones in total synthesis.
Conclusions
ourselves and others with expedient formal and total syntheses of
aspidospermaandkopsianaturalproducts. Whilethechemistries
describedhereinwilllikelybesuitable fora range ofothernatural
products, other chiral carbazolones should be available through
the development of analogous stereoselective derivatisations.
The development of the palladium catalysed enantioselective
decarboxylative allylation of carbazolones has provided access
to a diverse array of homochiral building blocks for studies in
multistep synthesis. Their utility has been demonstrated by

886
C. J. Gartshore and D. W. Lupton
Experimental
Mp 41.6–42.9 8C; nmax/cmꢁ1 2963, 1722, 1697, 1444, 1403,
1372, 1342, 1197, 1015, 928; dH (400 MHz, CDCl3) 5.50 (ddt,
J 16.8, 10.0, 7.2, 1H), 5.11–5.01 (m, 2H), 4.00 (q, J 7.2, 2H),
2.97 (s, 2H), 2.73–2.57 (m, 4H), 2.33 (d, J 7.2, 2H), 2.11–2.03
(m, 2H), 1.17 (t, J 7.2, 3H); dC (100 MHz, CDCl3) 209.4, 172.0,
131.0, 120.1, 65.0, 61.0, 41.3, 38.6, 38.1, 17.3, 14.1; m/z
(HRMS, ESI) found [M þ Na]þ 261.1102, C13H18O4 requires
[M þ Na]þ 261.1103.
1H and 13C NMR spectra were recorded at 30 8C using a Bruker
DRX400 spectrometer operating at 400 MHz for proton and
100 MHz for carbon nuclei. Chemical shifts (d) are reported
relative to the residual proton peak in the solvent used as spec-
ified. Infrared spectra (nmax) were recorded using a Perkin–
Elmer RXI FTIR Spectrometer or a Bruker Equinox 55 Infrared
Spectrometer fitted with a Specac Diamond ATR source. RXI
FTIR samples were analysed as thin films on NaCl plates for oils
or as KBr discs for solids and all IR bands are expressed in cmꢁ1
.
Ethyl 2-(1-Allyl-2-hydroxy-6-oxocyclohexyl)acetate (6a)
Following a procedure by Simpkins and coworkers.[6] A mag-
netically stirred solution of (þ)-bis[(R)-1-phenylethyl]amine
(0.46 mL, 2.01 mmol) in THF (5 mL) at ꢁ78 8C was treated with
n-BuLi (1.16 mL of a 1.6 M solution in hexanes, 1.85 mmol) in a
dropwise fashion. After 20 min the mixture was transferred by a
cannula to a cooled (ꢁ78 8C) solution of 7a (400 mg, 1.68 mmol)
in THF (4 mL), and the mixture stirred for 1 h. At this time
diisobutylaluminium hydride (DIBAL-H) (2.69 mL of a 1.0 M
solution in hexanes, 2.69 mmol) was added. After 5 h the
reaction was quenched by the addition of HCl (2 mL of a 1M
solution) with the resultant mixture extracted with EtOAc
(2 ꢂ 10 mL), the combined organic extracts were dried
(MgSO4), filtered, and the solvent removed under reduced
pressure. The crude residue was purified by flash column
chromatography (silica, 1 : 1 v/v, EtOAc/hexanes) to afford the
title compound in 48 % yield as a 9 : 1 mixture of diastereomers.
Rf 0.1 (1 : 1 v/v, EtOAc/hexanes); nmax/cmꢁ1 3407, 2943, 1729,
1701, 1452, 1372, 1345, 1272, 1179, 1027, 919, 735; dH
(400 MHz, CDCl3) minor 5.82 (ddt, J 16.8, 10.0, 7.6, 1H), 5.20–
5.15 (m, 2H), 4.42 (t, J 2.8, 1H), 4.11 (q, J 7.2, 2H), 3.69–3.64
(m, 1H), 2.61 and 2.52 (ABq, JAB 17.2, 2H), 2.58–2.51 (m, 3H),
2.18 (dd, J 14.4, 7.2, 1H), 2.03–1.88 (m, 4H), 1.25 (t, J 7.2, 3H);
major 5.64–5.54 (m, 1H), 5.12–5.07 (m, 2H), 4.25–4.21 (m,
1H), 4.11 (q, J 7.2, 2H), 2.89 (br d, J 4.0, 1H), 2.78 and 2.65
(ABq, JAB 16.4, 2H), 2.54–2.50 (m, 2H), 2.41–2.37 (m, 2H),
2.03–1.88 (m, 4H), 1.25 (t, J 7.2, 3H); dC (100 MHz, CDCl3)
major/minor 210.5, 176.4, 173.4, 133.6, 132.6, 119.6, 119.1,
82.8, 74.8, 72.1, 60.9, 57.4, 46.9, 39.0, 38.1, 36.9, 34.3, 29.9,
29.4, 24.8, 20.3, 18.9, 14.2; m/z (HRMS, ESI) found [M þ Na]þ
263.1259, C13H20O4 requires [M þ Na]þ 263.1254.
High resolution mass spectrometry (HRMS) was performed
using an Agilent series 6500 accurate-mass quadrupole time-of-
flight (Q-TOF) LC/MS system. Analytical chiral HPLC was
performed with a Perkin–Elmer Series 200 HPLC using
Chiralpak OD-H, AD-H, or OJ-H columns (4.6 mm ꢂ 25 cm)
obtained from Daicel Chemical Industries, Ltd with visuali-
sation at 238 nm. Melting points were measured on a Stuart
Scientific Melting Point Apparatus in an open capillary. Ana-
lytical thin layer chromatography (TLC) was performed using
aluminium-backed plates coated with 0.2 mm silica (Merck,
DC-Platten, Kieselgel; 60 F254 plates). Eluted plates were
visualised using a 254 nm UV lamp and/or by treatment with a
suitable stain followed by heating. Flash column chromato-
graphy was performed on silica gel (Davisil LC60A, 40–63 mm
silica media) using compressed air or nitrogen.
Starting materials and reagents were purchased from Sigma–
Aldrich, Alfa-Aesar, D-L Chiral, or Oakwood chemicals and
were used as supplied or, in the case of some liquids, distilled.
Tetrahydrofuran (THF) was distilled over sodium benzo-
phenone ketyl. Concentration under reduced pressure was
performed on a rotary evaporator with the bath temperature
not exceeding 40 8C. All reactions were conducted under an
atmosphere of nitrogen unless otherwise specified.
Ethyl 2-(2-Hydroxy-6-oxocyclohex-1-en-1-yl)acetate (9)[21]
Following a procedure by Ramachary and Kishor,[5] a magnet-
ically stirred suspension of Hantzsch’s ester (2.25 g, 8.90 mmol)
and ethyl glyoxylate (2.66 mL of a 50 % solution in toluene,
13.4 mmol) in CH2Cl2 (10 mL) was treated with a solution of
1,3-cyclohexanedione 8 (1.0 g, 8.90 mmol) and L-proline
(103 mg, 0.89 mmol) in CH2Cl2 (5 mL) in a dropwise fashion.
The mixture was stirred overnight and then the solvent was
removed under reduced pressure. The crude residue was purified
by flash column chromatography (silica, 1 : 1 v/v, EtOAc/hexanes)
to afford the title compound as a yellow oil in 92 % yield. Rf 0.2
(1 : 1 v/v, EtOAc/hexanes); nmax/cmꢁ1 3449, 2926, 2364, 1710,
1595, 1386, 1339, 1281, 1194, 1151, 1021, 858; dH (400 MHz,
CDCl3) enol 8.38 (br s, 1H), 4.14 (q, J 7.2, 2H), 3.42 (s, 2H), 2.45
(t, J 6.4, 4H), 1.98 (q, J 6.4, 2H), 1.26 (t, J 7.2, 3H);
dC (100 MHz, CDCl3) enol 191.8, 187.1, 172.2, 108.6, 61.9,
33.0, 32.4, 28.0, 20.6, 14.2.
2-Allyl-2-(2-ethoxy-2-oxoethyl)cyclohexa-
3,6-diene-1,3-diyl Diacetate (10)
A magnetically stirred solution of 7a (70 mg, 0.3 mmol) in DMF
(8 mL) was treated with Et3N (0.12 mL, 0.88 mmol) and TMSCl
(0.23 mL, 0.176 mmol). The resultant mixture was then heated
to 80 8C for 2 h. After this time the mixture was cooled and
extracted with n-pentane (3 ꢂ 10 mL), and the combined
organic extracts were washed with water (10 mL), brine
(10 mL), dried (MgSO4), filtered, and the solvent removed
under reduced pressure to afford ethyl 2-(1-allyl-2,6-bis
((trimethylsilyl)oxy)cyclohexa-2,5-dien-1-yl)acetate (11) in
96 % yield as a clear oil. The crude material was used without
Ethyl 2-(1-Allyl-2,6-dioxocyclohexyl)acetate (7a)
A
magnetically stirred solution of Pd2(dba)3 (23 mg,
further purification. To a magnetically stirred solution
0.025 mmol) in THF (3 mL) was treated with Ph3P (30 mg,
0.1 mmol) and after 20 min was transferred by a cannula to a
solution of 9 (100 mg, 0.50 mmol) and allyl methyl carbonate
(90 mg, 0.76 mmol) in THF (5 mL). After stirring for 3 h the
solvent was removed under reduced pressure. The crude residue
was purified using flash column chromatography (silica,
1 : 4 v/v, ethyl acetate/hexanes) to afford the title compound as a
yellow solid in 99 % yield. Rf 0.3 (1 : 4, v/v EtOAc/hexanes).
of 11 (200 mg, 0.52 mmol) in CH3CN (6 mL) was added
4-dimethylaminopyridine (DMAP, 3.2 mg, 0.026 mmol) and
acetyl fluoride[22] (129 mg, 2.09 mmol). After 2 h the solvent
was removed under reduced pressure to give a brown oil. The
crude material was purified by flash column chromatography
(silica, 1 : 1 v/v, EtOAc/hexanes) to afford the title compound in
93 % yield as a clear oil. Rf 0.1 (1 : 4 v/v, EtOAc/hexanes); nmax
/
cmꢁ1 2981, 1766, 1731, 1445, 1371, 1199, 1141, 1059, 1022,

Enantioselective Synthesis of Carbazolones
887
961, 913; dH (400 MHz, CDCl3) 5.76 (ddt, J 16.8, 10.0, 7.2, 1H),
5.75 (t, J 4.0, 2H), 5.04–4.97 (m, 2H), 4.06 (q, J 7.2, 2H), 2.92
(t, J 4.0, 2H), 2.55 (s, 2H), 2.90 (dt, J 7.2, 1.2, 2H), 2.15 (s, 6H),
1.19 (t, J 7.2, 3H); dC (100 MHz, CDCl3) 170.2, 168.4, 144.3,
133.5, 117.9, 113.4, 60.4, 45.8, 40.3, 40.1, 24.8, 21.5, 14.2. m/z
(HRMS, ESI) found [M þ Na]þ 345.1312, C17H22O6 requires
[M þ Na]þ 345.1314.
9-Benzyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (16b)
The title compound was prepared following the general
procedure outlined above using benzyl bromide (0.19 mL,
1.62 mmol) as the electrophile. Following flash column chro-
matography (1 : 1 v/v, EtOAc/hexanes) the product was isolated
as a white solid in 73 % yield. Rf 0.28 (1 : 1 v/v, EtOAc/hexane);
mp 156.9–157.7 8C; nmax/cmꢁ1 2941, 1641, 1631, 1531, 1465,
1450, 1441, 1357, 1132, 956, 748; dH (400 MHz, CDCl3) 8.27–
8.25 (m, 1H), 7.27–7.15 (m, 6H), 6.98–6.96 (m, 2H), 5.23
(s, 2H), 2.78 (t, J 6.4, 2H), 2.51 (t, J 6.4, 2H), 2.15 (pent.,
J 6.4, 2H); dC (100 MHz, CDCl3) 193.9, 151.9, 137.2, 136.1,
129.1, 127.9, 126.2, 125.0, 123.3, 122.7, 121.8, 113.2, 109.7,
47.1, 37.9, 23.4, 22.4; m/z (HRMS, ESI) found [M þ H]þ
276.1384, C19H17NO requires [M þ H]þ 276.1383.
Ethyl 2-(2-Acetoxy-1-allyl-6-oxocyclohex-2-en-1-yl)
acetate (12)
A magnetically stirred solution of 10 (40 mg, 0.12 mmol) in
phosphate buffered saline (PBS, pH 7, 5 mL) was treated with
lipase from Candida rugosa (2 mg, 5 % w/w) and the mixture
heated to 30 8C. After 3 days the mixture was cooled and then
extracted with EtOAc (3 ꢂ 15 mL), and the combined organic
extracts were washed with brine (10 mL), dried (MgSO4),
filtered, and the solvent removed under reduced pressure. The
crude residue was purified by flash column chromatography
(silica, 1 : 1 v/v, EtOAc/hexanes) to afford the title compound in
9-Methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (16c)
The title compound was prepared following the general
procedure outlined above using methyl iodide (0.10 mL,
1.62 mmol) as the electrophile. Following flash column chro-
matography (1 : 1 v/v, EtOAc/hexanes) the product was isolated
as a white solid in 93 % yield. Rf 0.17 (1 : 1 v/v, EtOAc/hexane);
mp 194.5–195.3 8C; nmax/cmꢁ1 2954, 1632, 1528, 1467, 1401,
1320, 1135, 1093, 959, 748; dH (400 MHz, CDCl3) 8.28–8.21
(m, 1H), 7.31–7.19 (m, 3H), 3.66 (s, 3H), 2.89 (t, J 6.4, 2H), 2.55
(t, J 6.4, 2H), 2.23 (pent., J 6.4, 2H); dC (100 MHz, CDCl3)
193.8, 151.9, 137.5, 124.9, 123.0, 122.6, 121.7, 112.8, 109.2,
37.9, 29.9, 23.4, 22.2; m/z (HRMS, ESI) found [M þ Na]þ
222.0887, C13H13NO requires [M þ Na]þ 222.0889.
60 % yield as a clear oil. Rf 0.2 (1 : 6 v/v, EtOAc/hexanes); nmax
/
cmꢁ1 2980, 1762, 1734, 1717, 1442, 1371, 1340, 1203, 1108,
1020, 929; dH (400 MHz, CDCl3) 5.86–5.84 (m, 1H), 5.74–5.65
(m, 1H), 5.08–4.99 (m, 2H), 4.06 (q, J 7.2, 2H), 3.06 and 2.51
(ABq, JAB 16.8, 2H), 2.68–2.55 (m, 2H), 2.44–2.35 (m, 2H),
2.35–2.30 (m, 1H), 2.28–2.19 (m, 1H), 2.17 (s, 3H), 1.21 (t,
J 7.2, 3H); dC (100 MHz, CDCl3) 210.3, 170.8, 169.1, 145.6,
132.6, 119.3, 117.5, 60.8, 53.3, 41.7, 40.4, 38.1, 21.3, 20.5, 14.2;
m/z (HRMS, ESI) found [M þ Na]þ 303.1203, C15H20O5
requires [M þ Na]þ 303.1203; HPLC Diacel OD-H, l ¼ 238,
hexane: i-PrOH ¼ 95: 5, 1.0 mL minꢁ1, fraction retention time
(tr) ¼ 7.12 (major enantiomer) and 7.94 (minor enantiomer);
49 % ee.
9-Tosyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (16d)
The title compound was prepared following the general
procedure outlined above using 4-toluenesulfonyl chloride
(309mg, 1.62 mmol) as the electrophile. Following flash column
chromatography (1: 1 v/v, EtOAc/hexanes) the product was iso-
lated as a white solid in 78% yield. Rf 0.50 (1: 1 v/v, EtOAc/
hexanes); mp 152.0–153.4 8C; nmax/cmꢁ1 2951, 1670, 1594,
1561, 1450, 1403, 1375, 1239, 1192, 1173, 1091, 1074, 1031,
932, 821, 767, 747; dH (400MHz, CDCl3) 8.18–8.16 (m, 1H),
8.10–8.07 (m, 1H), 7.78(d, J 8.4, 2H), 7.30–7.21 (m, 2H), 7.17(d,
J 8.4, 2H), 3.25 (t, J 6.4, 2H), 2.47 (t, J 6.4, 2H), 2.26 (s, 3H), 2.13
(pent., J 6.4, 2H); dC (100MHz, CDCl3) 194.9, 150.9, 145.8,
135.9, 135.4, 130.2, 126.6, 125.8, 125.3, 124.9, 121.8, 117.9,
113.8, 37.8, 24.5, 23.2, 21.6; m/z (HRMS, ESI) found [Mþ Na]þ
340.0968, C19H17NO3S requires [Mþ H]þ 340.1002.
General Procedure for the Synthesis of N-Substituted
Carbazolones (16)
NaH (65 mg of 60 % dispersion in mineral oil, 1.62 mmol) was
added in a portionwise fashion to a magnetically stirred solution
of carbazolone 15 (200 mg, 1.08 mmol) in THF (15 mL) at 0 8C.
After 30 min the electrophile (1.62 mmol) was added and the
reaction allowed to warm to room temperature over 2 h. After
this time the mixture was diluted with Et2O (20 mL) and water
(10 mL). The organic phase was separated while the aqueous
phase was extracted with Et2O (20 mL). The combined organic
extracts were dried (MgSO4), filtered, and the solvent removed
under reduced pressure.
9-((4-Methoxyphenyl)sulfonyl)-1,2,3,9-tetrahydro-
4H-carbazol-4-one (16e)
tert-Butyl 4-Oxo-1,2,3,4-tetrahydro-9H-
carbazole-9-carboxylate (16a)
The title compound was prepared following the general
procedure outlined above using 4-methoxybenzenesulfonyl
chloride (335 mg, 1.62 mmol) as the electrophile. Following
flash column chromatography (1 : 1 v/v, EtOAc/hexanes) the
product was isolated as a white solid in 62 % yield. Rf 0.40
(1 : 1 v/v, EtOAc/hexanes); mp 158.1–158.7 8C; nmax/cmꢁ1
3744, 2947, 1662, 1593, 1550, 1496, 1450, 1407, 1380, 1266,
1237, 1194, 1168, 1088, 1074, 1027, 925, 831, 754, 673; dH
(400 MHz, CDCl3) 8.21–8.19 (m, 1H), 8.12–8.10 (m, 1H),
7.79–7.75 (m, 2H), 7.32–7.22 (m, 2H), 6.88–6.85 (m, 2H),
3.75 (s, 3H), 3.28 (t, J 6.4, 2H), 2.51 (t, J 6.4, 2H), 2.17 (pent.,
J 6.4, 2H); dC (100 MHz, CDCl3) 195.1, 164.3, 150.9, 135.9,
129.9, 129.0, 125.9, 125.3, 124.9, 121.9, 117.9, 114.9, 113.9,
55.8, 37.9, 24.6, 23.3; m/z (HRMS, ESI) found [M þ Na]þ
356.0956, C19H17NO4S requires [M þ H]þ 356.0951.
The title compound was prepared following the general
procedure outlined above using di-tert-butyl dicarbonate
(354 mg, 1.62 mmol) as the electrophile. Following flash col-
umn chromatography (1 : 1 v/v, EtOAc/hexanes) the product
was isolated as a white solid in 90 % yield. Rf 0.59 (1 : 1 v/v,
EtOAc/hexanes); mp 152.1–153.4 8C; nmax/cmꢁ1 2932, 1739,
1655, 1561, 1456, 1371, 1154, 875, 755; dH (400 MHz, CDCl3)
8.32–8.30 (m, 1H), 8.11–8.04 (m, 1H), 7.35–7.27 (m, 2H), 3.31
(t, J 6.4, 2H), 2.62–2.52 (m, 2H), 2.30–2.14 (m, 2H), 1.71
(s, 9H); dC (100 MHz, CDCl3) 195.6, 152.1, 149.9, 135.9, 125.8,
124.9, 124.5, 121.6, 117.4, 115.2, 85.5, 37.9, 28.3, 26.0, 23.5;
m/z (HRMS, ESI) found [M þ Na]þ 308.1256, C17H19NO3
requires [M þ Na]þ 308.1257.

888
C. J. Gartshore and D. W. Lupton
Allyl 1H-Imidazole-1-carboxylate (17)[17]
1457, 1304, 1228, 1198, 1157, 1081, 1020, 953, 753; dH
(400 MHz, CDCl3) 8.23 (d, J 7.6, 1H), 7.20–7.12 (m, 6H),
6.93–6.91 (m, 2H), 5.85 (ddt, J 17.2, 10.4, 5.6, 1H), 5.26 (dq,
J 17.2, 1.6, 1H), 5.16–5.12 (m, 3H), 4.65–4.55 (m, 2H), 3.49 (dd,
J 9.2, 4.8, 1H), 2.95 (dt, J 17.2, 5.6, 1H), 2.75–2.67 (m, 1H),
2.52–2.43 (m, 1H), 2.32–2.25 (m, 1H); dC (100 MHz, CDCl3)
187.7, 170.4, 151.4, 137.3, 135.8, 132.0, 129.0, 127.9, 126.1,
125.0, 123.5, 122.9, 121.6, 118.3, 112.1, 109.8, 65.6, 53.4, 47.0,
26.4, 20.7; m/z (HRMS, ESI) found [M þ Na]þ 382.1412,
C23H21NO3 requires [M þ Na]þ 382.1414.
Using the method of Trost and Xu,[17] a magnetically stirred
solution of carbonyl 1,10-carbonyldiimidazole (2.0g, 12.3mmol)
in THF (10 mL) at 0 8C was treated with allyl alcohol (0.56 mL,
8.22 mmol) in CH2Cl2 (3 mL). The reaction was stirred for 3 h at
room temperature before the solvent was removed under
reduced pressure. The crude material was purified by flash
column chromatography (1 : 1 v/v, ethyl acetate/hexane) to
afford the title compound in 91 % yield as a clear oil. Rf 0.31
(1 : 1 v/v, ethyl acetate/hexane); nmax/cmꢁ1 3106, 1761, 1669,
1645, 1393, 1242, 996, 748; dH (400 MHz, CDCl3) 8.15 (s, 1H),
7.43 (t, J 1.2, 1H), 7.07 (d, J 0.8, 1H), 6.06–5.96 (m, 1H), 5.42
(m, 2H), 4.89 (dt, J 6.0, 1.2, 2H); dC (100 MHz, CDCl3) 148.6,
137.3, 130.8, 130.6, 120.6, 117.3, 68.8.
Allyl 9-Methyl-4-oxo-2,3,4,9-tetrahydro-1H-
carbazole-3-carboxylate (18c)
The title compound was prepared following the general
procedure outlined above using 16c (97 mg, 0.50 mmol).
Following flash column chromatography (1 : 4 v/v, EtOAc/
hexanes), the product was isolated as an off white solid in
82 % yield. Rf 0.54 (1 : 4 v/v, EtOAc/hexanes); mp 109.8–
112.0 8C; nmax/cmꢁ1 3621, 1763, 1732, 1635, 1528, 1480,
1460, 1397, 1303, 1224, 1129, 1084, 990, 928, 744; dH
(400 MHz, CDCl3) 8.19–8.15 (m, 1H), 7.24–7.17 (m, 3H),
5.93 (ddt, J 17.2, 10.8, 5.6, 1H), 5.33 (dq, J 17.2, 1.6, 1H),
5.21 (dq, J 10.4, 1.2, 1H), 4.70–4.64 (m, 2H), 3.54 (s, 3H), 3.48
(dd, J 9.2, 4.8, 1H), 2.99 (dt, J 17.2, 5.6, 1H), 2.74 (ddd, J 17.2,
8.4, 5.6, 1H), 2.55–2.46 (m, 1H), 2.37–2.30 (m, 1H); dC
(100 MHz, CDCl3) 187.4, 170.5, 151.5, 137.5, 132.0, 124.8,
123.1, 122.6, 121.4, 118.3, 111.4, 109.3, 65.7, 53.2, 29.8, 26.2,
20.4; m/z (HRMS, ESI) found [M þ Na]þ 306.1099, C17H17NO3
requires [M þ Na]þ 306.1101.
General Procedure for the Acylation of N-Protected
Carbazolones (18)
A magnetically stirred solution of diisopropylamine (0.08 mL,
0.60 mmol) in THF (10 mL) at ꢁ78 8C was treated with n-BuLi
(0.38 mL of a 1.6 M solution in hexanes, 0.60 mmol) in a
dropwise fashion. After 20 min the mixture was transferred by a
cannula to a second flask containing a suspension of the car-
bazolone (0.50 mmol) in THF (10 mL) at ꢁ78 8C. The mixture
was stirred for 1 h before the addition of allyl chloroformate 17
(72 mg, 0.60 mmol) as a solution in THF (5 mL), and the reac-
tion was allowed to slowly come to room temperature and stirred
overnight (Method A). For Method B, allyl imidazole 17 (91 mg,
0.60 mmol) as a solution in THF (5 mL) was added. The reaction
was quenched by the addition of NH4Cl (10 mL of a saturated
aqueous solution) and Et2O (20 mL). The phases were separated
and the aqueous phase extracted with Et2O (20 mL). The com-
bined organic extracts were washed with NaHCO3 (10 mL of a
saturated aqueous solution), water (10 mL), and brine (10 mL)
before being dried (MgSO4), filtered, and the solvent removed
under reduced pressure.
Allyl 4-Oxo-2,3,4,9-tetrahydro-1H-carbazole-3-
carboxylate (16f)
A magnetically stirred solution of diisopropylamine (0.17 mL,
1.19 mmol) in THF (10 mL) was cooled to ꢁ78 8C and treated
with n-BuLi (0.75 mL of a 1.6 M solution in hexanes,
1.13 mmol) in a dropwise fashion. After 20 min at this temper-
ature the mixture was transferred by a cannula to a flask con-
taining a suspension of carbazolone 15 (100 mg, 0.54 mmol) in
THF (10 mL) at ꢁ78 8C. The mixture was stirred for 1 h before
the addition of allyl imidazole 17 (99 mg, 0.65 mmol) as a
solution in THF (5 mL). The reaction was allowed to warm to
room temperature overnight and was then quenched by the
addition of NH4Cl (10 mL of a saturated aqueous solution) and
Et2O (20 mL). The phases were separated and the aqueous phase
extracted with Et2O (20 mL). The combined organic extracts
were washed with NaHCO3 (10 mL of a saturated aqueous
solution), water (10 mL), and brine (10 mL), before being dried
(MgSO4), filtered, and the solvent removed under reduced
pressure. The crude residue was purified by flash column
chromatography (silica, 1 : 1 v/v, EtOAc/hexanes) to afford the
title compound in 67 % yield as a clear oil. Rf 0.24 (1 : 1 v/v,
EtOAc/hexanes); mp 149.5–150.9 8C; nmax/cmꢁ1 3219, 1739,
1617, 1457, 1426, 1310, 1249, 1165, 1148, 1078, 873, 755;
dH (400 MHz, CDCl3) 9.66 (s, 1H), 8.15–8.12 (m, 1H), 7.36–
7.32 (m, 1H), 7.22–7.15 (m, 2H), 5.84 (ddt, J 16.8, 10.4, 5.2,
1H), 5.24 (dq, J 17.2, 1.4, 1H), 5.14 (dq, J 10.8, 1.2, 1H), 4.59
(dt, J 5.6, 1.2, 2H), 3.61 (dd, J 9.2, 4.8, 1H), 3.13 (dt, J 17.2, 5.6,
1H), 2.94 (ddd, J 17.2, 8.8, 5.2, 1H), 2.61–2.52 (m, 1H), 2.42–
2.34 (m, 1H); dC (100 MHz, CDCl3) 188.7, 170.8, 151.8, 136.2,
131.8, 124.9, 123.7, 122.8, 121.3, 118.6, 112.3, 111.6, 66.0,
53.9, 27.0, 21.9; m/z (HRMS, ESI) found [M þ Na]þ 270.1127,
C16H15NO3 requires [M þ H]þ 270.1125.
3-Allyl 9-(tert-Butyl) 4-Oxo-1,2,3,4-tetrahydro-
9H-carbazole-3,9-dicarboxylate (18a)
The title compound was prepared following the general
procedure outlined above using 16a (143 mg, 0.50 mmol).
Following flash column chromatography (1 : 4 v/v, EtOAc/
hexanes), the product was isolated as a white solid in 42 %
yield. Rf 0.45 (1 : 4 v/v, EtOAc/hexanes); mp 102.1–104.0 8C;
n
max/cmꢁ1 2926, 1739, 1666, 1457, 1374, 1260, 1144, 959, 763;
dH (400 MHz, CDCl3) 8.26–8.24 (m, 1H), 8.08–8.06 (m, 1H),
7.34–7.30 (m, 2H), 5.95 (ddt, J 17.2, 10.4, 5.6, 1H), 5.36 (dq,
J 17.2, 1.2, 1H), 5.23 (dq, J 10.4, 1.2, 1H), 4.72–4.68 (m, 2H),
3.62 (dd, J 9.6, 4.8, 1H), 3.52 (dt, J 19.2, 5.6, 1H), 3.28 (ddd,
J 19.2, 8.0, 5.2, 1H), 2.66–2.57 (m, 1H), 2.47–2.39 (m, 1H), 1.71
(s, 9H); dC (100 MHz, CDCl3) 189.5, 169.9, 151.7, 149.8, 136.0,
132.0, 125.7, 125.2, 124.6, 121.6, 118.6, 116.5, 115.3, 85.8,
65.9, 53.4, 28.3, 26.5, 24.4; m/z (HRMS, ESI) found [M þ Na]þ
392.1468, C21H23NO5 requires [M þ Na]þ 392.1468.
Allyl 9-Benzyl-4-oxo-2,3,4,9-tetrahydro-1H-
carbazole-3-carboxylate (18b)
The title compound was prepared following the general
procedure outlined above using 16b (138 mg, 0.50 mmol).
Following flash column chromatography (1 : 4 v/v, EtOAc/
hexanes), the product was isolated as an off white solid in
34 % yield. Rf 0.46 (1 : 4 v/v, EtOAc/hexanes); mp 103.2–
104.5 8C; nmax/cmꢁ1 3449, 2933, 1733, 1647, 1535, 1469,

Enantioselective Synthesis of Carbazolones
889
Allyl 4-Oxo-9-tosyl-2,3,4,9-tetrahydro-1H-carbazole-
3-carboxylate (18d)
warm to room temperature over 2 h. The reaction mixture was
then diluted with Et2O (5 mL) and water (5 mL). The phases
were separated and the aqueous phase was extracted with Et2O
(5 mL). The combined organic extracts were washed with brine
(10 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure. Flash column chromatography then afforded
analytically pure materials. Compounds 5a–h and j were pre-
pared using this method with full characterisation provided
previously,[4] details for 5m are provided below.
A magnetically stirred solution of allyl carbazolone 16f
(100 mg, 0.37 mmol) in CH2Cl2 (10 mL) was treated with NaOH
(5 mL of a 1M solution). The resultant biphasic mixture was
cooled to 0 8C and n-Bu4NHSO4 (12.6 mg, 0.037 mmol) added
followed by 4-toluenesulfonyl chloride (74 mg, 0.39 mmol).
The reaction mixture was stirred at this temperature for 3 h and
then the layers were separated and the organic phase washed
with HCl (10 mL of a 1 M solution), dried (MgSO4), filtered, and
the solvent removed under reduced pressure. The crude residue
was purified by flash column chromatography (silica, 1 : 4 v/v,
EtOAc/hexanes) to afford the title compound in 51 % yield as a
pale yellow oil. Rf 0.26 (1 : 4 v/v, EtOAc/hexanes) nmax/cmꢁ1
3340, 2930, 1739, 1668, 1557, 1452, 1410, 1379, 1308, 1248,
1207, 1173, 1089, 1013, 923, 750; dH (400 MHz, CDCl3) 8.22–
8.20 (m, 1H), 8.15–8.13 (m, 1H), 7.76–7.74 (m, 2H), 7.38–7.31
(m, 2H), 7.27 (d, J 8.0, 2H), 5.91 (ddt, J 17.2, 10.4, 5.6, 1H), 5.32
(dq, J 17.2, 1.6, 1H), 5.22 (dq, J 10.4, 1.2, 1H), 4.68–4.66 (m,
2H), 3.60 (dd, J 9.2, 4.8, 1H), 3.56 (dt, J 18.8, 5.6, 1H), 3.30
(ddd, J 18.8, 8.4, 5.2, 1H), 2.64–2.55 (m, 1H), 2.47–2.40 (m,
1H), 2.37 (s, 3H); dC (100 MHz, CDCl3) 189.3, 169.6, 150.6,
146.1, 136.1, 135.5, 131.8, 130.4, 126.8, 126.7, 125.7, 125.2,
122.0, 118.7, 117.2, 114.0, 66.0, 53.5, 26.4, 23.2, 21.8; m/z
(HRMS, ESI) found [M þ Na]þ 424.1210, C23H21NO5S
requires [M þ H]þ 424.1213.
3-Allyl 9-(tert-Butyl) 4-Oxo-3-(prop-2-yn-1-yl)-1,2,3,4-
tetrahydro-9H-carbazole-3,9-dicarboxylate (5m)
Rf 0.2 (1 : 4, v/v EtOAc/hexanes); mp 130.5–132.1 8C; nmax
/
cmꢁ1 2980, 1789, 1651, 1567, 1480, 1450, 1409, 1365, 1299,
1258, 1156, 1113, 916, 668; dH (400 MHz, CDCl3) 8.30–8.27,
(m, 1H), 8.11–8.08 (m, 1H), 7.34–7.32 (m, 2H), 5.82 (ddt,
J 17.2, 10.8, 5.6, 1H), 5.23 (dd, J 17.2, 1.2, 1H), 5.16 (dd, J 10.4,
1.2, 1H), 4.66–4.56 (m, 2H), 3.57–3.41 (m, 2H), 3.10 (dd, J 17.2,
2.8, 1H), 2.87–2.81 (m, 2H), 2.50–2.43 (m, 1H), 2.05 (t, J 2.8,
1H), 1.71 (s, 9H); dC (100 MHz, CDCl3) 189.6, 170.0, 151.6,
149.8, 136.3, 131.6, 125.9, 125.3, 124.7, 121.7, 118.5, 116.3,
115.4, 85.9, 79.9, 71.6, 66.2, 56.4, 30.8, 28.3, 24.3, 23.8; m/z
(HRMS, ESI) found [M þ Na]þ 439.1621, C24H25NO5 requires
[M þ Na]þ 430.1625.
Method B: A magnetically stirred solution of carbazolone
allyl ester (0.30 mmol) in acetone (10 mL) was treated with
K2CO3 (62.0 mg, 0.45 mmol) and the relevant electrophile
(0.45 mmol) added. The reaction was heated to 55 8C for 6 h
before being cooled, filtered, and the filtrate concentrated under
reduced pressure. Flash column chromatography then afforded
analytically pure materials. Compounds 5i, k, and l were
prepared using this method with full characterisation provided
previously.[4]
Allyl 9-((4-Methoxyphenyl)sulfonyl)-4-oxo-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylate (18e)
A magnetically stirred solution of allyl carbazolone 16f
(100 mg, 0.37 mmol) in CH2Cl2 (10 mL) was treated with NaOH
(5 mL of a 1 M solution). The resultant biphasic mixture was
cooled to 0 8C and n-Bu4NHSO4 (12.6 mg, 0.037 mmol) added
followed by 4-methoxybenzenesulfonyl chloride (81 mg,
0.39 mmol). The reaction mixture was stirred at this temperature
for 3 h and then the layers were separated and the organic portion
washed with HCl (10 mL of a 1 M aqueous solution), dried
(MgSO4), filtered, and the solvent removed under reduced
pressure. The crude residue was purified using flash column
chromatography (silica, 1 : 4 v/v, EtOAc/hexanes) to afford the
title compound in 62 % yield as a yellow oil. Rf 0.28 (1 : 4 v/v,
EtOAc/hexanes); nmax/cmꢁ1 3081, 2946, 1737, 1667, 1594,
1497, 1434, 1371, 1314, 1255, 1166, 1095, 1048, 1023, 937,
833, 194, 753; dH (400 MHz, CDCl3) 8.19–8.17 (m, 1H), 8.10
(m, 1H), 7.79–7.77 (m, 2H), 7.31 (pd, J 7.2, 1.2, 2H), 6.90–6.86
(m, 2H), 5.88 (ddt, J 17.2, 10.4, 5.6, 1H), 5.31 (dq, J 17.2, 1.6,
1H), 5.18 (dq, J 10.4, 1.2, 1H), 4.66–4.63 (m, 2H), 3.76 (s, 3H),
3.59 (dd, J 9.6, 4.8, 1H) 3.54 (dt, J 18.8, 5.2, 1H), 3.27 (ddd,
J 18.8, 8.4, 5.2, 1H), 2.61–2.52 (m, 1H), 2.45–2.38 (m, 1H); dC
(100 MHz, CDCl3) 189.2, 169.6, 164.4, 150.5, 135.9, 131.8,
129.5, 129.0, 125.6, 125.5, 125.0, 121.8, 118.5, 116.9, 114.9,
113.8, 65.8, 55.8, 53.4, 26.3, 23.1; m/z (HRMS, ESI) found
[M þ Na]þ 462.0979, C23H21NO6S requires [M þ Na]þ
462.0982.
General Procedure for the Decarboxylative Allylation
As previously reported,[4] a sample vial was charged with t-Bu
PHOX L2 (2.1 mg, 5.5 mmol) and Pd2(dba)3 (2.3 mg, 2.5 mmol)
and then purged with argon for 5 min before being treated with
toluene (2 mL). After 15 min the resultant solution was trans-
ferred by cannula to a vial containing the alkylated b-keto ester 5
(0.1 mmol) under an argon atmosphere. The reaction mix was
heated to 50 8C at which point the solution changed from a dark
red colour to a bright yellow. After 6 h the reaction was cooled to
room temperature and concentrated under reduced pressure. The
crude residue was purified by flash column chromatography
(1 : 4, v/v EtOAc/hexanes) to provide the enantioenriched allyl
carbazolone 4 (Table 2).
Supplementary Material
1
Experimental procedures and H- and 13C-NMR spectra of all
new compounds are available on the Journal’s website.
Acknowledgements
The authors are grateful for the financial support of the Australian Research
Council through the discovery and Future fellowship programs and Monash
University through the Monash Research Accelerator Program (MRA).
General Procedure for the Synthesis of Substituted
a-quaternary Carbazolones (5)
Method A: NaH (30 mg of 60 % dispersion in mineral oil,
0.75 mmol) was added portionwise to a magnetically stirred
solution of carbazolone allyl ester (0.30 mmol) in THF (25 mL)
at 0 8C. The reaction was stirred for 20 min and then the elec-
trophile (0.75 mmol) was added and the reaction was allowed to
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