Applications of NHC-mediated O- to C-carboxyl transfer: synthesis of (±)-N-benzyl-coerulescine and (±)-horsfiline

Article abstract of DOI:10.1016/j.tet.2010.03.047

NHC-promoted O- to C-carboxyl transfer of 3-allyl indolyl phenyl carbonates generates 3-allyl-3-phenoxycarbonyl-oxindoles with good catalytic efficiency, which are readily converted into (±)-N-benzyl-coerulescine and (±)-horsfiline.

Full text of DOI:10.1016/j.tet.2010.03.047

Tetrahedron 66 (2010) 3801–3813
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Applications of NHC-mediated O- to C-carboxyl transfer: synthesis
of (ꢀ)-N-benzyl-coerulescine and (ꢀ)-horsfiline
Jennifer E. Thomson, Andrew F. Kyle, Kenneth B. Ling, Siobhan R. Smith,
*
Alexandra M.Z. Slawin, Andrew D. Smith
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
NHC-promoted O- to C-carboxyl transfer of 3-allyl indolyl phenyl carbonates generates 3-allyl-3-phen-
oxycarbonyl-oxindoles with good catalytic efficiency, which are readily converted into (ꢀ)-N-benzyl-
coerulescine and (ꢀ)-horsfiline.
Received 22 December 2009
Received in revised form
24 February 2010
Accepted 15 March 2010
Available online 20 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Lewis-base catalysis
N-heterocyclic carbene
Organocatalysis
Carboxyl transfer
Spiro[pyrrolidine-3,30-oxindole]
1. Introduction
nitroolefination reactions,16 intramolecular Mannich reactions,17
iodine-induced rearrangement of 3-[(aziridin-1-yl)(methylthio)-
A diverse array of naturally occurring polycyclic alkaloids bear
a quaternary stereocentre at the 3-position of an oxindole. The spi-
ro[pyrrolidine-3,30-oxindole] motif is among the many structural
classes encompassed within this classification, with a range of natural
products of varying complexity such as alstonisine 11 and spiro-
tryprostatin 22 that contain this ring junction possessing significant
biological activity (Fig. 1).3 Given the biological profile and structural
interest in these targets, the synthesis of the spiro[pyrrolidine-3,30-
oxindole] system has been used as a test-bed for the development of
a range of synthetic methodologies in order to tackle the total syn-
theses of these molecules.4 The simplest examples of alkaloids
containing the spiro[pyrrolidine-3,30-oxindole] motif include coeru-
lescine 3 and the structurally related horsfiline 4. Horsfiline was first
isolated in 1991 by Bodo et al. from the Malaysian medical plant
Horsfildea superba warb,5 while coerulescine was isolated in 1998 by
Colegate et al.6 Several different strategies have been developed for
the synthesis of these natural products in either racemic or enantio-
mericallyenriched form. Approaches based upon MgI2 promoted ring
methylene]-2-oxindoles18 and palladium catalysed asymmetric al-
lylic alkylation19 have all been utilised previously.
O
N
O
Me
H
H
H
O
H
N
NMe
O
O
O
N
N
H
MeO
Me
alstonisine 1
spirotryprostatin A 2
NMe
R
O
expansions,7,8 oxidative rearrangement of tetrahydro-
b-carbolines
N
(using N-bromosuccinimide,9 dimethyldioxirane,10 lead tetra-
acetate,5 sodium tungstate,11 or tert-butylhypochlorite12), dipolar
cycloaddition reactions,13 radical cyclisations,14,15 asymmetric
H
R = H, coerulescine 3
R = OMe, horsfiline 4
Figure 1. Representative natural products that contain the spiro[pyrrolidine-3,30-ox-
* Corresponding author; e-mail address: ads10@st-andrews.ac.uk (A.D. Smith).
indole] system.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.047

3802
J.E. Thomson et al. / Tetrahedron 66 (2010) 3801–3813
As part of a programme of research aimed at developing alter-
HO
native Lewis-base mediated catalysts,20 we have shown that
N-heterocyclic carbenes (NHCs)21,22 can promote the O- to C-car-
boxyl transfer reaction (the Steglich rearrangement) of a range of
oxazolyl, indolyl and benzofuranyl carbonate derivatives with good
catalytic efficiency.23,24 A number of elegant asymmetric versions of
this process have been developed for the asymmetric synthesis of
3-carboxyl oxindoles from indolyl carbonates.25 As a demonstration
of the utility of this methodology, its application to the syntheses of
coerulescine and horsfiline was investigated. Our planned retro-
synthetic route to these products targeted a suitably protected diol 6
as a viable precursor to the spiro[pyrrolidine-3,30-oxindole] motif.
Diol 6 could be generated by selective reduction and functional
group manipulation of a 3-allyl-3-phenoxycarbonyl oxindole 7,
prepared by NHC-promoted O-to C-carboxyl transfer of an indolyl
carbonate 8 (Fig. 2).
O
MeO
MeO
OEt
O
OH
O
N
N
oxidative
cleavage
and selective
reduction
OMe
OMe
MeO
MeO
9
10
4 steps
NMe
NMe
Ph3CLi
then
MeO
MeO
O
O
O
LiAlH4 (2 eq)
48% yield
HO
N
H
N
H
NMe
11
horsfiline 4
R
R
OH
O
O
Figure 3. Trost’s successful asymmetric route to horsfiline employing 3-allyl-3-ethoxy-
carbonyl oxindole 9.
N
H
N
P
5
6
extended reaction times. To overcome this problem, initial con-
version of alcohol 13 to chloride 14, and subsequent reduction with
zinc powder27 gave 15 in greatly improved yields and purity.
Treatment of 3-allyloxindole 15 with KHMDS and O-carboxylation
with phenyl chloroformate furnished phenyl carbonate 16 in good
yield. The ability of the NHC derived from triazolium salt 17 to
promote the desired O-to C-carboxyl transfer was next evaluated,
with deprotonation of triazolium salt 17 with KHMDS used to
prepare the corresponding NHC in situ. Good conversion of 16 to
the desired 3-allyl-3-phenoxycarbonyl oxindole 18 was observed
with variation in the catalyst loading of the NHC derived from 17
(from 9 mol % to 1.5 mol %), although trace quantities of 3-allylox-
indole 15 (typically <5%) and diphenylcarbonate were observed,
with the desired product 18 isolated in 49–73% yield (Scheme 1). In
practice, and on a >2 g scale, an NHC catalyst loading of 9 mol % was
diol
spiro[pyrrolidine-3,3'-oxindole]
O
O
OPh
O
R
R
OPh
O
N
N
P
P
8
7
3,3-disubstituted oxindole
indolyl carbonate
Figure 2. Proposed synthetic route to spiro[pyrrolidine-3,30-oxindole] products.
This strategy is related to that employed by Trost et al. in their
asymmetric synthesis of horsfiline, who prepared 3-allyl-3-ethoxy-
carbonyl oxindole 9 as a key intermediate in 98% ee after crys-
tallisation using an asymmetric allylation strategy.19 In this case,
however, attempts to access diol 10 from 9 proved impossible;
following oxidative cleavage of the allyl functionality, selective re-
duction of the ethyl ester could not be accomplished. The com-
pleted synthesis involved oxidative cleavage of the allyl
functionality within 9 and subsequent reductive amination to give
11 after N-deprotection, followed by selective reduction to give the
desired natural product 4 in 11% overall yield (Fig. 3).
Building upon these precedents, we detail herein the successful
selective realisation of our synthetic strategy to prepare the spi-
ro[pyrrolidine-3,30-oxindole] motif via a diol such as 6, and its
application to the synthesis of (ꢀ)-N-benzyl-coerulescine and
(ꢀ)-horsfiline.
O
X
(i)
O
O
56%
N
N
Bn
Bn
12
13 X = OH
14 X = Cl
15 X = H
(ii)
87%
N
BF4
Ph
N
N
O
(iii) 76%
17
2. Results and discussion
O
(iv)
OPh
O
OPh
2.1. Model studies: synthesis of ( )-N-benzyl-coerulescine
49-73%
O
N
N
Initial studies focused upon the preparation of 3-allyloxindole
15 from N-benzylisatin 12. Addition of allylmagnesium bromide to
N-benzyl isatin gave 3-allyl-3-hydroxyisatin 13.26 Attempted re-
duction of 13 to generate 15 in one step through treatment with
SnCl2 proved sluggish, giving 60% conversion to a ~50:50 mixture of
3-chlorooxindole 14 and the desired product 15 even after
Bn
Bn
16
18
Scheme 1. Reagents and conditions: (i). allylMgBr, THF, ꢁ78 ꢂC (10 min) then warm to
0
ꢂC (20 min); (ii). SOCl2, N(i-Pr)2Et, CH2Cl2, rt, 25 min then Zn (powder), AcOH, THF,
0 ꢂC to rt; (iii). KHMDS, THF, ꢁ78 ꢂC then PhOCOCl; (iv). KHMDS (1.5 to 9 mol %), salt 17
(2 to 10 mol %), THF, 15 min then indolyl carbonate 16, rt, 1 h.

J.E. Thomson et al. / Tetrahedron 66 (2010) 3801–3813
3803
used to promote rearrangement of 16, giving 18 in 73% yield.28
Unambiguous verification of the molecular structure of 18 was
confirmed by X-ray crystallographic analysis (Fig. 4).
selective reduction was achieved through treatment with sodium
borohydride and calcium chloride in methanol,30 giving alcohol 20 in
80% yield (Scheme 2). At the moment we cannot distinguish between
the over-reduction process to give 21 proceeding either via direct
reductive retro-Claisen reaction of the ester, or retro-aldol reaction of
in situ formed alcohol 20. The molecular structure of 20 was con-
firmed by X-ray crystallographic analysis (Fig. 5).
Figure 4. Molecular representation of the X-ray crystal structure of 18. The X-ray crystal
structure shows disorder of the allyl group, but only one representation is shown.
Functional group manipulation of 18 to generate the corre-
sponding diol as a key intermediate towards the preparation of the
spiro[pyrrolidine-3,30-oxindole] skeleton was next investigated. Ox-
idative functionalisation of 18 using OsO4 under standard Upjohn
conditions gave spirocyclic lactone 19 (66:34 dr), with purification
giving the separable diastereoisomers, whose relative configurations
were not identified, in 62% overall yield.29 As an alternative strategy,
selective reduction of the ester functionality within 18 was attemp-
ted. Treatment of 18 with LiAlH4 at rt resulted in over-reduction,
generating N-benzyl-3-allylindole 21 in 44% isolated yield, while
Figure 5. Molecular representation of the X-ray crystal structure of 20. There are two
molecules of 20 in the asymmetric unit cell, but only one representation is shown.
Further functionalisation of alcohol 20 was achieved by dihy-
droxylation with OsO4 to give triol 22 in 92% yield, with oxidative
cleavage with sodium periodate giving the spirocyclic lactol 23
OH
O
O
O
N
Bn
19
62%
(i)
66:34 dr
O
OPh
O
N
Bn
18
(ii)
(iii)
80%
44%
OH
O
N
N
Bn
20
Bn
21
Scheme 2. Reagents and conditions: (i). OsO4 (1% wt solution in H2O), NMO, CH2Cl2, rt;
(ii). LiAlH4, THF, 0 ꢂC to rt; (iii). NaBH4, CaCl2, MeOH, rt.
Figure 6. Molecular representation of the X-ray crystal structure of 24.

3804
J.E. Thomson et al. / Tetrahedron 66 (2010) 3801–3813
(78:22 dr). Reduction with NaBH4 gave the desired diol 24 in 67%
yield, whose molecular structure was confirmed unambiguously by
X-ray crystallographic analysis (Fig. 6). Subsequent bis-mesylation
generated 25 in high yield, with addition of methylamine,31 fol-
lowed by purification on silica to promote cyclisation, giving N-
benzyl-coerulescine 26 with comparable spectroscopic properties to
the literature (Scheme 3).15 As N-debenzylation of 26 has previously
been demonstrated, this represents a formal synthesis of coeru-
lescine 3.15
O
X
MeO
MeO
(i)
O
O
74%
N
N
Bn
Bn
27
28 X = OH
29 X = Cl
30 X = H
(ii)
70%
N
BF4
Ph
N
N
O
(iii) 39%
17
OH
OH
O
O
(i)
OH
O
OH
O
(iv)
MeO
OPh
O
MeO
OPh
92%
99%
N
N
N
N
Bn
Bn
20
Bn
22
Bn
32
31
Scheme 4. Reagents and conditions: (i). allylMgBr, THF, ꢁ78 ꢂC (10 min) then warm to
0
0
ꢂC (20 min); (ii). SOCl2, N(i-Pr)2Et, CH2Cl2, rt, 25 min; then Zn (powder), AcOH, THF,
ꢂC to rt; (iii). KHMDS, THF, ꢁ78 ꢂC then PhOCOCl; (iv). KHMDS (4 mol %), salt 17
(ii)
83%
(5 mol %), THF, 15 min then indolyl carbonate 31, rt, 1 h.
HO
HO
O
confirmed by X-ray diffraction (Figs. 7 and 8). Attempted conversion
of methyl ester 34 to alcohol 33 under a range of conditions gave
preferentially 3-allyl-5-methoxyoxindole 30 rather than the desired
alcohol 33, although further optimisation showed that reduction of
phenyl ester 32 with LiAlH4 in THF at ꢁ78 ꢂC gave predominantly
alcohol 33 in an improved 61% yield (Scheme 5).
OH
O
(iii)
O
67%
N
N
Bn
Bn
24
23
(iv)
85%
O
MeO
OPh
O
MsO
NMe
O
N
(v)
32
Bn
OMs
O
Reducing
agent
71%
N
N
Bn
Bn
25
O
( )-N-benzyl
coerulescine 26
MeO
MeO
OH
O
+
OMe
O
Scheme 3. Reagents and Conditions: (i). OsO4 (1% solution in H2O), rt; (ii). NaIO4,
acetone/H2O (4.5:1), THF, rt; (iii). NaBH4, MeOH, rt; (iv). MsCl, NEt3, CH2Cl2, rt; (v). MeNH2
(2.0 M solution in THF), EtOH, 105 ꢂC, sealed tube then chromatography on silica.
N
N
Bn
Bn
34
33
2.2. Synthesis of ( )-horsfiline 4
Reagent
Isolated Yields
Having optimised reaction conditions and demonstrated the
utility of this approach for the synthesis of (ꢀ)-N-benzyl-coeru-
lescine 26, this methodology was applied to the synthesis of
(ꢀ)-horsfiline 4. Addition of allylmagnesium bromide to N-benzyl-
5-methoxyisatin 27 gave 28, which was transformed to 3-allyl-5-
methoxyoxindole 30 via chloride 29 in 70% overall yield over two
steps. Indolyl carbonate formation, followed by O- to C-carboxyl
transfer using 4 mol % of the NHC derived from triazolium salt 17
gave 32 in excellent yield (Scheme 4).
Subsequent ester reduction of 32 using NaBH4/CaCl2 in methanol
gave a 55:45 mixture of the desired alcohol 33: methyl ester 34
(presumably arising from competitive transesterification), with
chromatographic separation giving 33 in 39% yield and 34 in 35%
yield (Scheme 5). The molecular structures of 33 and 34 were both
NaBH4, CaCl2, MeOH, rt
LiAlH4, THF, -78ºC
33 (39%), 34 (35%)
33 (61%)
Scheme 5. Selective reduction of ester 32.
Having optimised the preparation of key alcohol 33, subsequent
dihydroxylation, oxidative cleavage and reduction with NaBH4 gave
diol 35 in 83% yield over three steps. Bis-mesylation and treatment
with methylamine, followed by purification on silica, gave N-ben-
zylhorsfiline 37 in 65% yield over two steps.7,15 N-debenzylation
following the procedure of Carreira et al.7 gave (ꢀ)-horsfiline 4 with
comparable spectroscopic properties to the literature in 57% yield
(Scheme 6).

J.E. Thomson et al. / Tetrahedron 66 (2010) 3801–3813
3805
HO
MeO
(i) 93%
MeO
OH
O
OH
O
(ii),(iii) 89%
N
Bn
33
N
Bn
35
(iv)
69%
MsO
NMe
O
(v)
MeO
MeO
OMs
O
95%
N
N
Bn
Bn
( )-N-benzyl
36
horsfiline 37
(vi)
57%
Figure 7. Molecular representation of the X-ray crystal structure of 33. There are two
molecules of 33 in the asymmetric unit cell, but only one representation is shown.
NMe
O
MeO
N
H
( )-horsfiline 4
Scheme 6. Reagents and conditions: (i). OsO4 (1% wt solution in H2O), rt; (ii). NaIO4,
acetone/H2O (4.5:1), THF, rt; (iii). NaBH4, MeOH, rt; (iv). MsCl, NEt3, CH2Cl2, rt; (v).
MeNH2 (2.0 M solution in THF), EtOH, 105 ꢂC, sealed tube then chromatography on
silica; (vi) Na, NH3(l), ꢁ33 ꢂC, 15 min.
4. General experimental
4.1. General
All reactions involving moisture sensitive reagents were per-
formed under an atmosphere of argon using standard vacuum line
techniques and with freshly distilled solvents. All glassware was
flame dried and allowed to cool under vacuum.
Solvents were dried and purified either by distillation (under an
atmosphere of nitrogen as described below) or obtained from
a solvent purification system (MBraun, SPS-800). Methanol (MeOH)
was distilled from CaH2. Petrol refers to the fraction of petroleum
ether boiling between 40 ꢂC and 60 ꢂC. Osmium tetroxide was
prepared as a 1% wt solution in H2O. All other reagents were used
directly as supplied without further purification.
Flash column chromatography was carried out according to the
method of Still32 with silica gel 60 (0.043–0.060 mm) (Merck) in
the solvent system stated. Analytical thin layer chromatography
was performed on commercially available pre-coated aluminium-
backed plates (Merck silica Kieselgel 60 F254). TLCs were visualised
either by UV fluorescence (254 nm), or by staining with basic
KMnO4 solution.
Melting points were recorded on an Electrothermal apparatus
and are uncorrected. Microanalyses were carried out on a Carlo
Erba CHNS analyser. Infrared spectra were recorded on a Perkin-
Elmer Spectrum GX FT-IR Spectrometer and analysed either as
thin films between NaCl plates (thin film) or KBr discs (KBr disc) as
stated. Absorption maxima (nmax) are quoted in wavenumbers
(cmꢁ1) and only structurally significant peaks are quoted.
1H and 13C nuclear magnetic resonance (NMR) spectra were ac-
quired on either a Bruker Avance 300 (300 MHz 1H, 75.4 MHz 13C),
Figure 8. Molecular representation of the X-ray crystal structure of 34.
3. Conclusion
Inconclusion, we have shownthatNHC-mediatedO-to C-carboxyl
transfer of indolyl carbonates can be used to generate (ꢀ)-3-allyl-3-
phenoxycarbonyloxindoles containing a quaternary stereocentre in
good yield and with excellent catalytic efficiency. These products are
readily functionalised to generate the spiro[pyrrolidine-3,30-
oxindole] motif, and have been used in the synthesis of (ꢀ)-N-ben-
zyl-coerulescine 26 and (ꢀ)-horsfiline 4. Current research is focused
upon developing applications of NHCs and other Lewis-bases in
asymmetric catalysis, and utilising this methodology in complex
natural product synthesis.

3806
J.E. Thomson et al. / Tetrahedron 66 (2010) 3801–3813
a Bruker Avance 400 (400 MHz 1H, 100 MHz 13C) or a Bruker Avance
500 (500 MHz 1H, 125 MHz 13C) spectrometer in the deuterated sol-
vent stated. 13C NMR spectra were recorded with proton decoupling.
bromide (1.0 M solution in Et2O, 46.4 mL, 46.4 mmol) and the
reaction mixture stirred at ꢁ78 ꢂC for 10 min and then at 0 ꢂC for
20 min. After this time, the reaction was quenched with satd aq
NH4Cl solution (210 mL) and extracted with EtOAc (150 mLꢃ3).
The organic extracts were combined, washed with H2O (150 mL),
brine (150 mL), dried (MgSO4), filtered and concentrated in vacuo.
Trituration with Et2O gave 13 (6.55 g, 56%) as a yellow solid with
spectroscopic data in accordance with the literature.33 Mp
142ꢁ143 ꢂC (Et2O) (lit. Mp 124–126 ꢂC);33 dH (300 MHz, CDCl3)
7.43–7.38 (1H, m, ArH), 7.35–7.25 (5H, m, ArH), 7.25–7.17 (1H, m,
ArH), 7.10–7.03 (1H, m, ArH), 6.72–6.68 (1H, m, ArH), 5.72–5.57
(1H, m, HC]CH2), 5.20–5.08 (2H, m, HC]CH2), 5.03 (1H, ABq,
JAB¼15.6, CHAHBPh), 4.73 (1H, ABq, JAB¼15.6, CHAHBPh), 2.85 (1H,
s, OH), 2.84–2.77 (1H, m, CH2CH]CH2), 2.73–2.65 (1H, m,
CH2CH]CH2).
Chemical shifts (
enced to residual solvent peaks or to SiMe4 as an internal standard
¼0.00). Coupling constants, J, are quoted in Hz. The abbreviations s,
d) are quoted in parts per million (ppm) and refer-
(d
d, dd, dt, td, q and m denote singlet, doublet, doublet of doublets,
doublet of triplets, triplet of doublets, quartet and multiplet,
respectively. The abbreviation Ar is used to denote aromatic.
Mass spectrometric (m/z) data was acquired by electrospray
ionisation (ESI) or chemical ionisation (CI), either at the University
of St Andrews Mass Spectrometry facility ([MþNa] quoted) or at the
EPSRC National Mass Spectrometry Service Centre, Swansea
([MþH]þ, [2MþH]þ, [MþNa]þ or [2MþNa]þ quoted). At the Uni-
versity of St Andrews, low and high resolution ESI MS was carried
out on a Micromass LCT spectrometer. At the EPSRC National Mass
Spectrometry Service Centre, CIMS was carried out on a Micromass
Quattro II spectrometer. High resolution ESI was carried out on
a Finnigan MAT 900 XLT; a Thermofisher LTQ Orbitrap XL spec-
trometer was used to obtain high resolution ESI MS for accurate
mass determination but also provided fragmentation data for the
characterisation of samples. Values are quoted as a ratio of mass to
charge in Daltons.
4.3.2. 3-Allyl-1-benzyl-2-oxo-2,3-dihydroindole 15.
H
O
N
Temperatures of 0 ꢂC were obtained using an ice/water bath and
of ꢁ78 ꢂC were obtained using a dry ice/acetone bath.
Bn
Crystallographic data (excluding structure factors) for com-
pounds 18, 20, 24, 33 and 34 have been deposited with the Cam-
bridge Crystallographic Data Centre and allocated the deposition
numbers CCDC 746509, 746510, 746511, 746512 and 746513, re-
spectively. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax:
þ44(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
15
Method 1: To a stirred suspension of 13 (589 mg, 2.11 mmol) in
a solution of glacial AcOH (20 mL) and concd HCl (1.3 mL) was
added stannous chloride dihydrate (1.43 g, 6.33 mmol) and the
reaction mixture heated to 80 ꢂC overnight. After cooling to rt, the
solution was poured into H2O and the aqueous phase extracted
with Et2O (50 mLꢃ3). The organic extracts were combined, washed
with 2 M NaOH (aq) solution (100 mLꢃ3), dried (MgSO4), filtered
and concentrated in vacuo. Residual AcOH was removed azeo-
tropically with toluene (ꢃ3). 1H NMR analysis of the crude residue
indicated it to be a 41:29:29 mixture of 13:14:15.
4.2. General procedure A: rearrangement of carbonates
KHMDS (9, 4, or 1.5 mol %) was added to a stirred solution of
triazolium salt 17 (10, 5 or 2 mol %, respectively) in THF (~10 mL/g of
substrate) and stirred at rt for 30 min. The required carbonate was
then added to the reaction mixture and stirred for 1 h at rt before
concentration in vacuo.
Method 2: Following the method of Trost et al.,27 to a stirred
solution of 13 (6.07 g, 21.8 mmol) in anhydrous CH2Cl2 (200 mL)
was added Hu¨nig’s base (11.4 mL, 65.3 mmol) and thionyl chloride
(1.91 mL, 26.1 mmol) and the resulting solution stirred for 25 min.
After this time, the reaction mixture was poured into satd aq
NaHCO3 solution (100 mL) and extracted with Et2O (100 mLꢃ3).
The organic extracts were combined, dried (MgSO4), filtered and
concentrated in vacuo. The crude residue (chloride 14) was dis-
solved in THF (220 mL) and glacial acetic acid (22 mL) and cooled to
0 ꢂC. Zinc powder (16.9 g, 259 mmol) was added and the resulting
mixture allowed to warm to rt while stirring for 2 h. The reaction
mixture was then filtered through a pad of CeliteÒ, the filtrate di-
luted with Et2O (100 mL) then washed with H2O (200 mL) and satd
aq NaHCO3 solution (3ꢃ150 mL), dried (MgSO4), filtered and con-
centrated in vacuo. Chromatographic purification (petrol/Et2O
80:20) gave 15 (6.81 g, 87%), as an off-white solid. Mp 59–62 ꢂC
(petrol); Found: C, 81.85; H, 6.25; N, 5.0; C18H17NO requires C, 82.1;
H, 6.5; N, 5.3%; nmax (KBr)/cmꢁ1 3060, 2921, 1712, 1612, 1466, 750;
dH (400 MHz, CDCl3) 7.33–7.22 (6H, m, ArH), 7.18–7.13 (1H, m, ArH),
7.03–6.98 (1H, m, ArH), 6.70 (1H, d, J¼7.7, C(7)H), 5.81–5.70 (1H, m,
HC]CH2), 5.17–5.10 (1H, m, HC]CH2), 5.09–5.04 (1H, m, HC]CH2),
4.99 (1H, ABq, JAB¼15.7, CHAHBPh), 4.83 (1H, ABq, JBA¼15.7,
CHAHBPh), 3.61 (1H, dd, J¼7.2 and 5.0, C(3)H), 2.93–2.84 (1H, m,
CH2CH]CH2), 2.70–2.60 (1H, m, CH2CH]CH2); dC (100 MHz,
CDCl3) 177.3, 143.4, 135.9, 133.9, 128.7, 128.6, 127.9, 127.6, 127.3,
124.2, 122.3, 118.2, 109.0, 45.2, 43.7, 35.0; m/z (CI) 264 ([MþH]þ,
100%); HRMS (ESIþ) 264.1384 ([MþH]þ C18H18NO requires 264.1383
(þ0.3 ppm)).
4.3. General procedure B: dihydroxylation with OsO4
Following the method described by Trost et al.,19 osmium
tetroxide (0.02 equiv) was added to a solution of oxindole (1 equiv)
and N-methylmorpholine-N-oxide (2.55 equiv) in CH2Cl2 (10 mL/
mmol) and stirred at rt until deemed complete by TLC (typically 8–
24 h). The reaction was quenched with satd aq Na2SO3 solution. The
solution was diluted with CH2Cl2, the layers separated and the
aqueous phase further extracted with CH2Cl2. The organic extracts
were combined, dried (MgSO4), filtered and concentrated in vacuo.
4.3.1. 3-Allyl-1-benzyl-3-hydroxy-2-oxo-2,3-dihydroindole 13.
OH
O
N
Bn
13
To a stirred solution of N-benzylisatin (10.0 g, 50.6 mmol) in
THF (210 mL) at ꢁ78 ꢂC was slowly added allylmagnesium

J.E. Thomson et al. / Tetrahedron 66 (2010) 3801–3813
3807
4.3.3. 3-Allyl-1-benzylindol-2-yl phenyl carbonate 16.
6.76–6.71 (1H, m, C(7)H), 5.53–5.41 (1H, m, HC]CH2), 5.18–5.12
(1H, m, HC]CH2), 5.04 (1H, ABq, JAB¼15.8, CHAHBPh), 5.02–4.98
(1H, m, HC]CH2), 4.94 (1H, ABq, JBA¼15.8, CHAHBPh), 3.21–3.10
(2H, m, CH2CH]CH2); dC (100 MHz, CDCl3) 173.5, 167.7, 150.4,
143.5, 135.4, 130.9, 129.4 (2C), 128.8, 127.7, 127.2 (2C), 126.2, 123.6,
123.0, 121.2, 120.3, 109.7, 59.4, 44.0, 38.0; m/z (CI) 401
([MþNH4]þ, 55%), 384 ([MþH]þ, 100%); HRMS (ESIþ) 384.1593
([MþH]þ C25H22NO3 requires 384.1594 (ꢁ0.2 ppm)).
O
OPh
O
N
Bn
4.3.5. 10-Benzyl-5-(hydroxymethyl)-4,5-dihydro-2H-spiro[furan-
3,30-indolin]-2,20-dione 19.
16
A solution of 15 (3.90 g, 14.8 mmol) in THF (28 mL) at ꢁ78 ꢂC
was added slowly to a stirred solution of KHMDS (0.42 M solution
in toluene, 42.3 mL, 17.8 mmol) in THF (28 mL) at ꢁ78 ꢂC and stir-
red for 30 min. This solution was then transferred via cannula to
a stirred solution of phenyl chloroformate (2.24 mL, 17.8 mmol) in
THF (34 mL) at ꢁ78 ꢂC and the resulting solution allowed to warm
slowly to rt while stirring for 3 h. The reaction mixture was then
poured into 0.1 N aq HCl (50 mL) and extracted with Et2O
(75 mLꢃ3). The combined organic extracts were washed with
brine, dried (MgSO4), filtered and concentrated in vacuo. Chro-
matographic purification (petrol/Et2O 80:20) gave 16 (4.28 g, 76%)
as a fluffy colourless solid. Mp 58–61 ꢂC (petrol); nmax (KBr)/cmꢁ1
3055, 1788, 1624, 1465, 1229, 1201, 739; dH (300 MHz, CDCl3) 7.65–
7.60 (1H, m, ArH), 7.46–7.07 (13H, m, ArH), 6.14–5.99 (1H, m,
HC]CH2), 5.31 (2H, s, CH2Ph), 5.28–5.19 (1H, m, HC]CH2), 5.16–
5.09 (1H, m, HC]CH2), 3.54 (2H, dt, J¼6.3 and 1.5, CH2CH]CH2); dC
(75 MHz, CDCl3) 150.8, 150.6, 139.0, 137.0, 136.1, 132.4, 129.6, 128.8,
127.6, 126.7, 126.6, 126.0, 122.1, 120.6, 120.0, 119.4, 115.5, 109.6, 99.5,
46.0, 27.8; m/z (CI) 384 ([MþH]þ, 30%), 264 ([MꢁCO2PhþH]þ,
100%); HRMS (ESIþ) 384.1597 ([MþH]þ C25H22NO3 requires
384.1594 (þ0.7 ppm)).
OH
O
O
O
N
Bn
19
Following general procedure B, osmium tetroxide (130 mL, 1%
solution in H2O), 18 (100 mg, 0.26 mmol) and N-methylmorpho-
line-N-oxide (78 mg, 0.66 mmol) in CH2Cl2 (2 mL) gave, after
chromatographic purification (petrol/Et2O 80:20), both di-
astereomers of 19, major (33 mg, 39%); minor (19 mg, 23%) as
colourless gums. Major diastereomer: nmax (KBr)/cmꢁ1 3430,
2928, 1767, 1714, 1611, 1489, 1468, 1170, 734; dH (400 MHz, CDCl3)
7.28–7.12 (7H, m, ArH), 7.02–6.95 (1H, m, ArH), 6.70–6.65 (1H, m,
C(7)H), 4.98–4.88 (1H, m, CHCH2OH), 4.98 (1H, ABq, JAB¼15.8,
CHAHBPh), 4.77 (1H, ABq, JBA¼15.8, CHAHBPh), 3.96 (1H, dd,
J¼12.6 and 4.0, CHAHBOH), 3.90 (1H, dd, J¼12.6 and 3.9, CHAH-
BOH), 2.85 (1H, dd, J¼13.5 and 7.9, CHAHBCHCH2OH), 2.56 (1H, dd,
J¼13.5 and 7.5, CHAHBCHCH2OH); dC (75 MHz; CDCl3) 173.9, 172.3,
143.0, 135.0, 129.8, 129.0, 128.6, 127.9, 127.1, 123.6, 122.7, 110.2,
79.5, 64.3, 56.8, 44.3, 34.0; m/z (ESIþ) 346 ([MþNa], 100%); HRMS
(ESIþ) 346.1064 ([MþNa] C19H17NNaO4 requires 346.1055
(þ2.6 ppm)); Minor diastereomer: dH (400 MHz, CDCl3) 7.36–7.21
(7H, m, ArH), 7.11–7.05 (1H, m, ArH), 6.77–6.72 (1H, m, C(7)H),
5.24–5.16 (1H, m, CHCH2OH), 4.99 (1H, ABq, JAB¼15.8, CHAHBPh),
4.85 (1H, ABq, JBA¼15.8, CHAHBPh), 4.19–4.11 (1H, m, CH2OH),
3.80–3.70 (1H, m, CH2OH), 2.87–2.74 (2H, m, CH2CHCH2OH) and
2.24 (1H, s, OH).
4.3.4. Phenyl-3-allyl-1-benzyl-2-oxo-2,3-dihydroindole carboxylate 18.
O
OPh
O
N
Bn
18
Catalyst loading (9 mol %): following general procedure A,
KHMDS (0.5 M in toluene, 1.67 mL, 0.835 mmol, 9 mol %), tri-
azolium salt 17 (253 mg, 0.927 mmol, 10 mol %), THF (35 mL) and 3-
allyl-1-benzylindol-2-yl phenyl carbonate 16 (3.55 g, 9.26 mmol)
gave, after chromatographic purification (petrol/Et2O 90:10),
compound 18 (2.60 g, 73%) as a colourless solid.
4.3.6. 3-Allyl-1-benzyl-3-(hydroxymethyl)-2-oxo-2,3-dihydro-
indole 20.
Catalyst loading (4 mol %): following general procedure A,
OH
KHMDS (0.5 M in toluene, 46
m
L, 0.023 mmol, 4 mol %), triazolium
O
N
salt 17 (8 mg, 0.029 mmol, 5 mol %), THF (1.1 mL) and 3-allyl-1-
benzylindol-2-yl phenyl carbonate 16 (221 mg, 0.577 mmol) gave,
after chromatographic purification (petrol/Et2O 90:10), compound
18 (154 mg, 70%) as a colourless solid.
Bn
20
Catalyst loading (1.5 mol %): following general procedure A,
KHMDS (0.5 M in toluene, 27
m
L, 0.014 mmol, 1.5 mol %), tri-
Following the method described by Loreto et al.,30 sodium
borohydride (163 mg, 4.30 mmol) was added to a suspension of 18
(550 mg, 1.43 mmol) and calcium chloride (239 mg, 2.15 mmol) in
MeOH (3.5 mL) at 0 ꢂC and the resulting mixture stirred for 4 h then
warmed to rt and stirred overnight before concentration in vacuo.
3 N citric acid was added dropwise until reaching pH 2–3 before
extracting with CH2Cl2 (25 mLꢃ3). The organic extracts were
combined, dried (Na2SO4) and concentrated in vacuo to give, after
chromatographic purification (petrol/Et2O 90:10), 20 (340 mg, 80%)
azolium salt 17 (5 mg, 0.018 mmol, 2 mol %), THF (0.9 mL) and
3-allyl-1-benzylindol-2-yl phenyl carbonate 16 (346 mg,
0.902 mmol) gave, after chromatographic purification (petrol/
Et2O 90:10), compound 18 (170 mg, 49%) as a colourless solid. Mp
62–64 ꢂC (petrol); Found: C, 78.6; H, 5.25; N, 3.9. C25H21NO3 re-
quires C, 78.3; H, 5.5; N, 3.65%; nmax (KBr)/cmꢁ1 3061, 2902, 1754,
1721, 1609, 1466, 1210, 1186, 753; dH (400 MHz, CDCl3) 7.40–7.18
(10H, m, ArH), 7.13–7.06 (1H, m, ArH), 7.00–6.95 (2H, m, ArH),

3808
J.E. Thomson et al. / Tetrahedron 66 (2010) 3801–3813
as a colourless solid. Mp 136–138 ꢂC (petrol); nmax (KBr)/cmꢁ1 3440,
3053, 2923, 1691, 1614, 1490, 1465, 1182, 743; dH (300 MHz, CDCl3)
7.35–7.24 (6H, m, ArH), 7.19 (1H, td, J¼7.7 and 1.3, ArH), 7.07 (1H, td,
J¼7.5 and 0.9, ArH), 6.73 (1H, d, J¼7.7, C(7)H), 5.55–5.41 (1H, m,
HC]CH2), 5.13–5.05 (1H, m, HC]CH2), 5.03–4.95 (1H, m,
HC]CH2), 4.99 (1H, ABq, JAB¼15.7, CHAHBPh), 4.88 (1H, ABq,
JBA¼15.7, CHAHBPh), 3.98 (1H, dd, J¼11.0 and 9.4, CH2OH), 3.84 (1H,
dd, J¼11.0 and 3.5, CH2OH), 2.82–2.74 (1H, m, CH2CH]CH2), 2.72–
2.64 (1H, m, CH2CH]CH2), 2.32 (1H, dd, J¼9.4 and 3.5, CH2OH); dC
(75 MHz, CDCl3) 179.3, 143.7, 136.0, 132.3, 129.8, 129.2, 128.8, 128.0,
127.6, 123.7, 123.1, 119.7, 109.8, 67.2, 54.7, 44.1, 37.8; m/z (ESIþ) 316
([MþNa], 100%); HRMS (ESIþ) 316.1303 ([MþNa] C19H19NNaO2 re-
quires 316.1313 (ꢁ3.3 ppm)).
ABq, JAB¼10.7, CHAHBOH), 3.86 (1H, ABq, JBA¼10.7, CHAHBOH), 3.62–
3.55 (1H, m, CH(OH)CH2OH), 3.33–3.29 (2H, m, CH(OH)CH2OH),
2.13–1.99 (2H, m, CH2CH(OH)CH2OH); dC (75 MHz, CD3OD) 181.8,
145.3, 137.6, 131.7, 129.6, 128.9, 128.3 (2C), 124.8, 123.5, 110.4, 70.1,
68.8, 67.7, 55.1, 44.7, 37.0; m/z (ESIþ) 350 ([MþNa], 100%); HRMS
(ESIþ) 350.1375 ([MþNa] C19H21NNaO4 requires 350.1368
(þ2.0 ppm)).
4.3.9. 10-Benzyl-5-hydroxy-20,30,4,5-tetrahydro-2H-spiro[furan-3,30-
indolin]-20-one 23.
HO
O
4.3.7. 3-Allyl-1-benzyl-1H-indole 21.
O
N
Bn
23
N
Bn
Sodium periodate (73 mg, 0.341 mmol) was added to a solution
of 22 (60 mg, 0.183 mmol) in acetone (0.9 mL) and H2O (0.2 mL)
and the solution stirred at rt for 4 h. The solution was then diluted
with H2O (20 mL) and Et2O (20 mL), the layers separated and the
aqueous phase further extracted with Et2O (25 mLꢃ3). The organic
extracts were combined, dried (MgSO4) and concentrated in vacuo
to give, after chromatographic purification (EtOAc/petrol 50:50),
a 78:22 mixture of diastereomers of lactol 23 (45 mg, 83%) as
a colourless foam. nmax (KBr)/cmꢁ1 3365, 3062, 2942, 1685, 1613,
1489, 1467, 1174, 1028, 730; dH (300 MHz, CDCl3) 7.39–7.07 (8H, m,
ArH), 6.83–6.79 (1H, m, C(7)H), 6.28 (1H, d, J¼12.1, OH), 5.75 (1H,
dd, J¼12.1 and 4.8, CHOH), 4.96 (2H, s, CH2Ph), 4.48 (1H, ABq,
JAB¼9.0, CHAHBOCHOH), 4.11 (1H, ABq, JBA¼9.0, CHAHBOCHOH),
2.55 (1H, dd, J¼13.5 and 4.8, CHAHBCHOH), 2.41 (1H, d, J¼13.5,
CHAHBCHOH); dC (75 MHz, CDCl3) 181.6, 142.7, 135.2, 130.2, 129.0,
128.8, 128.0, 127.4, 123.8, 122.6, 109.7, 100.6, 76.0, 53.7, 44.4, 44.2;
m/z (ESIþ) 318 ([MþNa], 100%); HRMS (ESIþ) 318.1112 ([MþNa]
C18H17NaNO3 requires 318.1106 (þ2.0 ppm)).
21
Lithium aluminium hydride (1.0 M solution in THF, 0.156 mL,
0.156 mmol) was added to a suspension of 18 (60 mg, 0.156 mmol)
in THF (0.6 mL) at 0 ꢂC and stirred for 2 h. The reaction was then
warmed to rt and stirred overnight before being quenched with
ice/water and extracted with CH2Cl2 (25 mLꢃ3). The organic ex-
tracts were combined, dried (MgSO4) and concentrated in vacuo
to give, after chromatographic purification (petrol/Et2O 80:20), 21
(17 mg, 44%) as a colourless gum with spectroscopic data in ac-
cordance with the literature.34 dH (300 MHz, CDCl3) 7.57–7.50 (1H,
m, C(4)H), 7.25–7.13 (4H, m, ArH), 7.12–7.06 (1H, m, ArH), 7.06–
6.99 (3H, m, ArH), 6.84 (1H, s, C(2)H), 6.06–5.92 (1H, m, HC]CH2),
5.19 (2H, s, NCH2Ph), 5.12–5.04 (1H, m, HC]CH2), 5.01–4.95 (1H,
m, HC]CH2), 3.45 (2H, ddd, J¼6.5, 2.4 and 1.3, CH2CH]CH2).
4.3.8. 1-Benzyl-3-(2,3-dihydroxypropyl)-3-(hydroxymethyl)-2-oxo-
4.3.10. 1-Benzyl-3-(2-hydroxyethyl)-3-(hydroxymethyl)-2-oxo-2,3-
2,3-dihydroindole 22.
dihydroindole 24.
OH
OH
HO
OH
O
N
OH
O
N
Bn
Bn
24
22
Sodium borohydride (0.01 g, 0.264 mmol) was added to a so-
lution of 23 (40 mg, 0.135 mmol) in MeOH (0.2 mL) and the so-
lution stirred at rt for 1.5 h. The solution was then quenched with
1 N HCl (1.5 mL) diluted with H2O (20 mL), extracted with EtOAc
(25 mLꢃ3), dried (MgSO4) and concentrated in vacuo to give,
after chromatographic purification (EtOAc/petrol 80:20), 24
(27 mg, 67%) as a colourless solid. Mp 142–146 ꢂC; nmax (KBr)/
cmꢁ1 3460, 2920, 2875, 1675, 1612, 1491, 1466, 1185, 1028, 743; dH
(300 MHz, CD3OD) 7.39–7.14 (7H, m, ArH), 7.08 (1H, td, J¼7.5 and
1.0, ArH), 6.81–6.75 (1H, m, C(7)H), 4.99 (1H, ABq, JAB¼15.9,
CHAHBPh), 4.91 (1H, ABq, JBA¼15.9, CHAHBPh), 3.88 (1H, ABq,
JAB¼10.6, CHAHBOH), 3.84 (1H, ABq, JAB¼10.6, CHAHBOH), 3.33–
3.22 (2H, m, CH2CH2OH), 2.23–2.01 (2H, m, CH2CH2OH); dC
Following general procedure B, osmium tetroxide (187 mL, 1%
solution in water), 20 (110 mg, 0.38 mmol) and N-methylmorpho-
line-N-oxide (112 mg, 0.96 mmol) in CH2Cl2 (3 mL) gave, after
trituration with EtOAc, a 61:39 mixture of diastereomers of 22
(50 mg, 41%) as a colourless solid. The mother liquor was concen-
trated in vacuo to give, after chromatographic purification (EtOAc/
petrol 80:20/100% EtOAc/EtOAc/MeOH 95:5), a further 21:79
mixture of diastereoisomers of 22 (62 mg, 51%). Mp 146–150 ꢂC
(EtOAc); nmax (KBr)/cmꢁ1 3495, 3444, 2933, 2917, 1658, 1611, 1492,
1467, 1183, 1077, 763; dH (400 MHz, CD3OD) 7.44–7.13 (7H, m, ArH),
7.11–7.05 (1H, m, ArH), 6.82–6.76 (1H, m, C(7)H), 5.05 (1H, ABq,
JAB¼15.9, CHAHBPh), 4.89 (1H, ABq, JAB¼15.9, CHAHBPh), 3.99 (1H,

J.E. Thomson et al. / Tetrahedron 66 (2010) 3801–3813
3809
(75 MHz, CD3OD) 181.9, 145.6, 138.3, 132.4, 130.5, 129.9, 129.3,
129.1, 125.4, 124.6, 111.3, 69.1, 59.7, 55.9, 45.4, 37.4; m/z (ESIþ) 320
([MþNa], 100%); HRMS (ESIþ) 320.1274 ([MþNa] C18H19NNaO3
requires 320.1263 (þ3.6 ppm)).
180.6, 142.1, 136.1, 136.0, 128.9, 127.7, 127.7, 127.4, 123.2, 123.0, 108.9,
66.7, 56.9, 53.5, 43.9, 42.1, 38.2.
4.3.13. 3-Allyl-1-benzyl-3-hydroxy-5-methoxy-2-oxo-2,3-dihy-
droindole 28.
4.3.11. 2-(1-Benzyl-3-((methylsulfonyloxy)methyl)-2-oxo-2,3-dihy-
droindol-3-yl)ethyl methanesulfonate 25.
MsO
OH
MeO
O
N
OMs
O
N
Bn
28
Bn
To a stirred solution of 2735 (5.50 g, 1.87 mmol) in THF (100 mL)
cooled to ꢁ78 ꢂC was slowly added allylmagnesium bromide
(22.6 mL, 22.6 mmol, 1.0 M solution in Et2O) and the reaction
mixture stirred at ꢁ78 ꢂC for 10 min and then at 0 ꢂC for 20 min.
After this time, the reaction was quenched with satd aq NH4Cl
solution (210 mL) and extracted with EtOAc (150 mLꢃ3). The or-
ganic extracts were combined, washed with H2O (150 mL), brine
(150 mL), dried (MgSO4), filtered and concentrated in vacuo.
Trituration with Et2O gave 28 as a yellow solid (3.89 g). Chro-
matographic purification (petrol/EtOAc 80:20) of the mother li-
quor also gave 28 as an orange solid (806 mg). Total yield: 4.70 g,
74%. Mp 151–153 ꢂC; nmax (KBr)/cmꢁ1 3277, 2935, 1694, 1610, 1184,
811; dH (400 MHz, CDCl3) 7.37–7.24 (5H, m, ArH), 7.05 (1H, d, J¼2.5,
C(4)H), 6.74 (1H, dd, J¼8.5 and 2.5, C(6)H), 6.61 (1H, d, J¼8.5,
C(7)H), 5.72–5.59 (1H, m, C(3)CH2CHCH2), 5.23–5.10 (2H, m,
C(3)CH2CHCH2), 5.03 (1H, ABq, JAB¼15.7, CHAHBPh), 4.73 (1H, ABq,
JBA¼15.7, CHAHBPh), 3.79 (3H, s, OCH3), 3.48 (1H, s, OH), 2.88–2.68
(2H, m, C(3)CH2CHCH2); dC (75 MHz, CDCl3) 177.9, 156.3, 135.7,
135.5, 131.0, 130.6, 128.8, 127.7, 127.3, 120.6, 114.2, 111.3, 110.1, 76.4,
55.8, 43.9, 43.1; m/z (ESIþ) 619 ([2MþH]þ, 65%), 310.1 ([MþH]þ,
100%); HRMS (ESIþ) 310.1443 ([MþH]þ C19H20NOþ3 requires
310.1438 (þ1.7 ppm)).
25
To a solution of 24 (295 mg, 0.990 mmol) and triethylamine
(0.290 mL, 2.08 mmol) in CH2Cl2 (6.5 mL) at 0 ꢂC was added
dropwise mesyl chloride (0.160 mL, 2.08 mmol) and the resulting
mixture stirred for 2 h. The reaction mixture was then warmed to
rt and stirred overnight before quenching with satd aq NaHCO3
solution (10 mL). CH2Cl2 (25 mL) and brine (10 mL) were added,
the layers separated and the aqueous phase further extracted with
CH2Cl2 (15 mLꢃ3). The organic extracts were combined, dried
(MgSO4) and concentrated in vacuo to give, after chromatographic
purification (EtOAc/petrol 50:50/100% EtOAc), 25 (383 mg, 85%)
as a colourless foam. nmax (KBr)/cmꢁ1 2921, 1708, 1612, 1174; dH
(300 MHz, CDCl3) 7.39–7.22 (7H, m, ArH), 7.13 (1H, td, J¼7.5 and
0.8, ArH), 6.82 (1H, d, J¼7.8, ArH), 5.15 (1H, ABq, JAB¼15.8,
CHAHBPh), 4.77 (1H, ABq, JBA¼15.8, CHAHBPh), 4.58 (1H, ABq,
JAB¼9.7, CHAHBOMs), 4.43 (1H, ABq, JBA¼9.7, CHAHBOMs), 4.18–
3.98 (2H, m, CH2OMs), 2.75 (3H, s, CH3), 2.68 (3H, s, CH3), 2.58–
2.44 (1H, m, CH2), 2.35–2.25 (1H, m, CH2); dC (75 MHz, CDCl3)
176.0, 143.7, 135.8, 130.0, 129.4, 128.3, 127.6, 127.3, 124.4, 123.7,
110.3, 72.8, 65.3, 50.9, 44.5, 37.6 (2C), 32.3; m/z (ESIþ) 476
([MþNa], 100%); HRMS (ESIþ) 476.0811 ([MþNa] C20H23NaNO7S2
requires 476.0814 (ꢁ0.2 ppm)).
4.3.14. 3-Allyl-1-benzyl-3-chloro-5-methoxy-2-oxo-2,3-dihydro-
indole 29.
4.3.12. N-Benzyl-coerulescine 26.
Cl
NMe
MeO
O
N
O
N
Bn
29
Bn
26
To a solution of 28 (0.326 g, 1.06 mmol) in CH2Cl2 (10 mL) was
added Hu¨nig’s base (0.550 mL, 3.16 mmol) and thionyl chloride
To a solution of 25 (35 mg, 0.077 mmol) in EtOH (0.4 mL) was
added methylamine (2.0 M solution in THF, 0.12 mL, 0.23 mmol)
and the solution heated to 105 ꢂC in a sealed tube overnight. The
solution was concentrated in vacuo, the residue dissolved in CH2Cl2
(10 mL), washed with 0.1 N HCl (aq) (5 mLꢃ2), dried (MgSO4), fil-
tered and concentrated in vacuo. Chromatographic purification
(EtOAc/petrol 50:50/100% EtOAc) gave 26 (55 mg, 71%) as a col-
ourless gum with spectroscopic data in accordance with the
literature.15 dH (300 MHz, CDCl3) 7.45 (1H, dd, J¼7.3 and 0.9, ArH),
7.36–7.24 (5H, m, PhH), 7.15 (1H, td, J¼7.7 and 1.4, ArH), 7.04 (1H, td,
J¼7.5 and 1.0, ArH), 6.70 (1H, d, J¼7.3, ArH), 4.92 (2H, s, CH2Ph),
3.15–3.07 (1H, m, CH2), 2.94 (1H, ABq, J¼9.2, CHAHB), 2.89 (1H, ABq,
J¼9.2, CHAHB), 2.79 (1H, q, J¼8.3, CH2), 2.49 (3H, s, NCH3), 2.48–2.40
(1H, m, CH2), 2.14 (1H, dt, J¼12.7 and 7.7, CH2); dC (75 MHz, CDCl3)
(90 mL, 1.26 mmol). The resultant solution was stirred at rt for
15 min, then poured into satd aq NaHCO3 solution and the mixture
extracted with Et2O (25 mLꢃ3). The organic extracts were com-
bined, dried (MgSO4), filtered and concentrated to afford, after
chromatographic purification (petrol/Et2O 85:15), chloride 29
(260 mg, 75%) as a dark yellow oil. nmax (thin film)/cmꢁ1 2927, 1726,
1603, 1496, 1178, 732, 697; dH (300 MHz, CDCl3) 7.28–7.15 (5H, m,
ArH), 6.94 (1H, d, J¼2.5, C(4)H), 6.66 (1H, dd, J¼8.6 and 2.5, C(6)H),
6.51 (1H, d, J¼8.6, C(7)H), 5.54–5.39 (1H, m, C(3)CH2CHCH2), 5.14–
5.00 (2H, m, C(3)CH2CHCH2), 4.90 (1H, ABq, JAB¼15.7, CHAHBPh),
4.74 (1H, ABq, JBA¼15.7, CHAHBPh), 3.70 (3H, s, OCH3), 3.04–2.89
(2H, m, C(3)CH2CHCH2); dC (100 MHz, CDCl3) 173.5, 156.4, 135.2,
135.1, 130.2 (2C), 128.8, 127.8, 127.2, 121.2, 114.7, 111.5, 110.3, 64.2,
55.9, 44.2, 43.3; m/z (ESIþ) 328 ([M (35Cl)þH]þ, 100%), 330 ([M

3810
J.E. Thomson et al. / Tetrahedron 66 (2010) 3801–3813
(
37Cl)þH]þ, 30%); HRMS (ESIþ) 328.1102 ([MþH]þ C19H1935ClNOþ2
resulting solution allowed to warm slowly to rt while stirring for 3 h.
requires 328.1099 (þ1.0 ppm)).
The reaction mixture was then poured into 0.1 N aq HCl (50 mL) and
extracted with Et2O (50 mLꢃ3). The combined organic extracts were
washed with brine, dried (MgSO4), filtered and concentrated in
vacuo. Recrystallisation (Et2O/petrol) afforded 31 (1.52 g, 39%) as
a beige solid. Mp 90–92 ꢂC; nmax (KBr)/cmꢁ1 2956, 1792, 1591, 1224,
1199, 741; dH (400 MHz, CDCl3) 7.44–7.37 (2H, m, ArH), 7.35–7.25 (4H,
m, ArH), 7.22–7.18 (2H, m, ArH), 7.14–7.06 (4H, m, ArH), 6.88–6.83
(1H, m, ArH), 6.11–5.99 (1H, m, C(3)CH2CHCH2), 5.27 (2H, s, CH2Ph),
5.27–5.20 (1H, m, C(3)CH2CHCH2), 5.15–5.10 (1H, m, C(3)CH2CHCH2),
3.87 (3H, s, OCH3), 3.53–3.48 (2H, m, C(3)CH2CHCH2); dC (75 MHz,
CDCl3) 154.3,150.8,150.6,139.4,136.0,137.0,129.6,128.8,127.6,127.4,
126.7,126.6,126.4,120.6,115.5,111.7,110.6,101.8, 99.3, 55.9, 46.2, 27.9;
m/z (ESIþ) 414 ([MþH]þ, 100%); HRMS (ESIþ) 414.1698 ([MþH]þ
C26H24NOþ4 requires 414.1700 (ꢁ0.4 ppm)).
4.3.15. 3-Allyl-1-benzyl-5-methoxy-2-oxo-2,3-dihydroindole 30.
H
MeO
O
N
Bn
30
Method 1: To a stirred solution of 29 (353 mg, 1.08 mmol) in THF
(11 mL) was added glacial acetic acid (1.1 mL) and the resultant
solution cooled to 0 ꢂC. Zinc powder (1.06 g, 16.2 mmol) was then
added and the resulting mixture allowed to warm to rt while stir-
ring for 2 h. The reaction mixture was filtered through a pad of
CeliteÒ, the filtrate diluted with Et2O (20 mL), washed with H2O
(20 mL), satd aq NaHCO3 solution (3ꢃ40 mL), dried (MgSO4), fil-
tered and concentrated in vacuo. Chromatographic purification
(petrol/Et2O 80:20) gave 30 as a yellow oil (260 mg, 82%).
4.3.17. Phenyl-3-allyl-1-benzyl-5-methoxy-2-oxo-2,3-dihydroindole-
3-carboxylate 32.
O
MeO
OPh
Method 2: Following the method of Trost et al.,27 to a stirred so-
lution of 28 (4.45 g, 14.4 mmol) in anhydrous CH2Cl2 (140 mL) was
added Hu¨nig’s base (7.50 mL, 43.2 mmol) and thionyl chloride
(1.26 mL, 17.3 mmol) and the resulting solution stirred for 15 min.
After this time, the reaction mixture was poured into satd aq NaHCO3
solution (100 mL) and extracted with Et2O (50 mLꢃ3). The organic
extracts were combined, dried (MgSO4), filtered and concentrated in
vacuo. The crude residue (chloride 29) was dissolved in THF (140 mL)
andglacialaceticacid(10 mL)thencooledto0 ꢂC.Zincpowder(14.1 g,
216 mmol)wasaddedandtheresultingmixtureallowedtowarmtort
while stirring for 2 h. The reaction mixture was filtered through a pad
of CeliteÒ, the filtrate diluted with Et2O (100 mL), washed with H2O
(200 mL), satd aq NaHCO3 solution (3ꢃ100 mL), dried (MgSO4), fil-
tered and concentrated in vacuo. Chromatographic purification
(petrol/Et2O 80:20) gave 30 as a yellow-brown oil, which solidified on
standing (2.96 g, 70% over two steps). Mp 46–48 ꢂC; nmax (thin film)/
cmꢁ1 2925,1707,1600,1493,1177, 694; dH (300 MHz, CDCl3) 7.38–7.22
(5H, m, ArH), 6.94 (1H, dd, J¼2.5 and 0.9, C(4)H), 6.73–6.67 (1H, m,
C(6)H), 6.63–6.59 (1H, m, C(7)H), 5.86–5.70 (1H, m, C(3)CH2CHCH2),
5.22–5.07 (2H, m, C(3)CH2CHCH2), 4.99 (1H, ABq, JAB¼15.7, CHAHBPh),
4.83 (1H, ABq, JBA¼15.7, CHAHBPh), 3.77 (3H, s, OCH3), 3.61 (1H, dd,
J¼7.3 and 4.9, C(3)H), 2.96–2.85 (1H, m, C(3)CH2CHCH2), 2.73–2.61
(1H, m, C(3)CH2CHCH2); dC (100 MHz, CDCl3) 176.9,155.7,136.9,136.0,
133.9,130.0,128.7,127.5,127.3,118.3,111.9 (2C),109.2, 55.8, 45.6, 43.8,
35.0; m/z (ESIþ) 609 ([2MþNa]þ, 15%), 587 ([2MþH]þ, 20%), 316
([MþNa]þ, 10%), 294 ([MþH]þ, 100%); HRMS (ESIþ) 294.1491
([MþH]þ C19H20NOþ2 requires 294.1489 (þ0.8 ppm)).
O
N
Bn
32
Following general procedure A, KHMDS (0.50 M solution in
toluene, 0.090 mL, 0.045 mmol, 9 mol %), triazolium salt 17
(13.7 mg, 0.050 mmol, 10 mol %), THF (1.0 mL) and 31 (206 mg,
0.500 mmol) gave, after 1 h and chromatographic purification
(petrol/Et2O 90:10/80:20), 32 (205 mg, 0.496 mmol, 99%) as
a yellow solid. Mp 101–103 ꢂC; nmax (KBr)/cmꢁ1 2922, 1751, 1717,
1599, 1187, 1160, 702; dH (400 MHz, CDCl3) 7.28–7.10 (8H, m, ArH),
6.94–6.89 (3H, m, ArH), 6.69–6.67 (1H, m, ArH), 6.56–6.53 (1H, m,
ArH), 5.47–5.34 (1H, m, C(3)CH2CHCH2), 5.12–5.05 (1H, m,
C(3)CH2CHCH2), 4.96–4.80 (3H, m, CH2Ph, C(3)CH2CHCH2), 3.69
(3H, s, OCH3), 3.06 (2H, d, J¼7.3, C(3)CH2CHCH2); dC (125 MHz,
CDCl3) 172.1, 166.7, 155.1, 149.3, 135.7, 134.4, 129.8, 128.4, 127.7,
127.3, 126.6, 126.2, 125.1, 120.2, 119.3, 112.6, 109.8, 109.1, 58.7, 54.8,
43.0, 37.0; m/z (ESIþ) 414 ([MþH]þ, 100%); HRMS (ESIþ) 414.1699
([MþH]þ C26H24NOþ4 requires 414.1700 (ꢁ0.2 ppm)).
4.3.18. 3-Allyl-1-benzyl-3-hydroxymethyl-5-methoxy-2-oxo-2,3-di-
hydroindole 33 and methyl 3-allyl-1-benzyl-5-methoxy-2-oxo-2,3-
dihydroindole-3-carboxylate 34.
O
MeO
4.3.16. 3-Allyl-1-benzyl-5-methoxyindol-2-yl phenyl carbonate 31.
MeO
OH
O
+
OMe
O
N
N
O
Bn
Bn
34
MeO
OPh
33
O
N
Method 1: Following the method described by Loreto et al.,30 so-
dium borohydride (0.192 g, 5.08 mmol) was added to a suspension of
32 (1.05 g, 2.54 mmol) and calcium chloride (0.282 g, 2.54 mmol) in
MeOH (5 mL) at 0 ꢂC and the resulting mixture stirred for 4 h. The
reaction was then warmed to rt and stirred overnight before con-
centrationinvacuo. 3 N citric acidwasaddeddropwiseuntilreaching
pH 2–3 before extracting with CH2Cl2 (25 mLꢃ3). The organic ex-
tracts were combined, dried (Na2SO4) and concentrated in vacuo to
give, afterchromatographicpurification(petrol/Et2O 80:20/40:60),
Bn
31
A solution of 30 (2.78 g, 9.47 mmol) in THF (20 mL) at ꢁ78 ꢂC was
added slowly to a stirred solution of KHMDS (0.5 M solution in tol-
uene, 22.8 mL, 11.4 mmol) at ꢁ78 ꢂC and stirred for 30 min. This so-
lutionwas then transferred via cannula to a stirred solution of phenyl
chloroformate (1.43 mL,11.4 mmol) inTHF (20 mL) at ꢁ78 ꢂC and the

J.E. Thomson et al. / Tetrahedron 66 (2010) 3801–3813
3811
33 (318 mg, 39%) as a colourless solid and 34 (316 mg, 35%) as a yel-
low solid.
(7 mL) and H2O (1.5 mL) and the solution stirred at rt for 4 h. The
solution was then diluted with H2O (20 mL) and Et2O (20 mL), the
layers separated and the aqueous phase further extracted with Et2O
(25 mLꢃ3). The organic extracts were combined, dried (MgSO4) and
concentrated in vacuo. The crude residue was dissolved in MeOH
(14 mL), sodium borohydride (108 mg, 2.85 mmol) was added and
the solution stirred at rt for 1.5 h. The solution was then quenched
with 1 N HCl (15 mL), concentrated in vacuo to remove the MeOH,
diluted with H2O (40 mL), extracted with EtOAc (40 mLꢃ3), dried
(MgSO4) and concentrated in vacuo to give, after chromatographic
purification (EtOAc/petrol 80:20), 35 (415 mg, 89% over two steps) as
a colourless oil. nmax (thin film)/cmꢁ1 3399, 2925, 1687, 1603, 1180,
1046, 737; dH (300 MHz, CD3OD) 7.39–7.20 (5H, m, ArH), 7.02 (1H, d,
J¼2.4, ArH), 6.78–6.66 (2H, m, ArH), 4.97 (1H, ABq, JAB¼15.8,
CHAHBPh), 4.89 (1H, ABq, JBA¼15.8, CHAHBPh), 3.89 (1H, ABq,
JAB¼10.6, C(3)CHAHBOH), 3.85 (1H, ABq, JBA¼10.6, C(3)CHAHBOH),
3.77 (3H, s, OCH3), 3.37–3.20 (2H, m, C(3)CH2CH2OH), 2.24–2.00 (2H,
m, C(3)CH2CH2OH); dC (75 MHz, CD3OD) 180.7, 157.8, 138.1, 137.5,
133.0,129.7,128.5,128.3,113.5,112.1,110.9, 68.3, 58.9, 56.2, 55.5, 44.7,
36.6; m/z (ESIþ) 350 ([MþNa]þ, 45%), 328 ([MþH]þ, 100%); HRMS
(ESIþ) 328.1547 ([MþH]þ C19H22NOþ4 requires 328.1543 (þ1.1 ppm)).
Method 2: To a stirred solution of 32 (103 mg, 0.250 mmol) in
THF (2.0 mL) at ꢁ78 ꢂC was added LiAlH4 (2.0 M solution in THF,
0.075 mL, 0.150 mmol) dropwise and the resulting solution stirred
at ꢁ78 ꢂC for 45 min before the addition of EtOAc (10 mL) and 0.1 N
HCl (10 mL). The mixture was allowed to warm to rt, the organic
layer separated and the aqueous layer extracted with EtOAc
(10 mLꢃ3). The combined organic layers were washed with brine
(10 mL), dried (MgSO4) and concentrated in vacuo to give, after
chromatographic purification (petrol/Et2O 80:20/40:60), 33 as
a colourless solid (49 mg, 0.152 mmol, 61%).
Data for 33: mp 94–96 ꢂC; nmax (KBr)/cmꢁ1 3449, 2947, 1691,
1601, 1180, 695; dH (400 MHz, CDCl3) 7.32–7.22 (5H, m, ArH), 6.85
(1H, d, J¼2.5, ArH), 6.71–6.66 (1H, m, ArH), 6.61–6.57 (1H, m, ArH),
5.54–5.42 (1H, m, C(3)CH2CHCH2), 5.12–5.05 (1H, m,
C(3)CH2CHCH2), 5.00–4.95 (1H, m, C(3)CH2CHCH2), 4.96 (1H, ABq,
JAB¼15.8, CHAHBPh), 4.84 (1H, ABq, JBA¼15.8, CHAHBPh), 3.99–3.91
(1H, m, CHAHBOH), 3.81 (1H, dd, J¼10.9 and 3.4, CHAHBOH), 3.76
(3H, s, OCH3), 2.80–2.72 (1H, m, C(3)CH2CHCH2), 2.68–2.61 (1H, m,
C(3)CH2CHCH2), 2.34 (1H, dd, J¼9.3 and 3.4, CH2OH); dC (75 MHz,
CDCl3) 178.6, 156.0, 136.7, 135.7, 131.9, 130.9, 128.7, 127.6, 127.2,
119.3, 112.3, 111.1, 109.7, 66.8, 55.8, 54.6, 43.8, 37.4; m/z (ESIþ) 346
([MþNa]þ, 30%), 324 ([MþH]þ, 100%); HRMS (ESIþ) 324.1598
([MþH]þ C20H22NOþ3 requires 324.1599 (ꢁ0.4 ppm)).
4.3.20. 2-(1-Benzyl-5-methoxy-3-((methylsulfonyloxy)methyl)-2-
oxo-2,3-dihydroindol-3-yl)ethyl methanesulfonate 36.
Data for 34: mp 109–111 ꢂC; nmax (KBr)/cmꢁ1 2957, 1743, 1701,
1604, 1228, 1200, 695; dH (300 MHz, CDCl3) 7.31–7.26 (5H, m, ArH),
6.88 (1H, d, J¼2.5, ArH), 6.71 (1H, dd, J¼8.5 and 2.6, ArH), 6.59–6.55
(1H, m, ArH), 5.47–5.30 (1H, m, C(3)CH2CHCH2), 5.14–5.06 (1H, m,
C(3)CH2CHCH2), 4.99–4.95 (1H, m, C(3)CH2CHCH2), 4.91 (2H, s,
CH2Ph), 3.75 (3H, s, OCH3), 3.70 (3H, s, OCH3), 3.07–3.01 (2H, m,
C(3)CH2CHCH2); dC (75 MHz; CDCl3) 173.5, 169.6, 156.1, 136.7, 135.5,
131.0, 128.7 (2C), 127.6, 127.3, 120.1, 113.5, 110.8, 109.9, 59.6, 55.8,
53.1, 44.0, 38.2; m/z (ESIþ) 352 ([MþH]þ, 100%); HRMS (ESIþ)
352.1545 ([MþH]þ C21H22NO4þ requires 352.1543 (þ0.5 ppm)).
MsO
MeO
OMs
O
N
Bn
36
To a solution of 35 (197 mg, 0.602 mmol) and triethylamine
(175
mesyl chloride (98
m
L, 1.26 mmol) in CH2Cl2 (6 mL) at 0 ꢂC was added dropwise
4.3.19. 1-Benzyl-3-(2-hydroxyethyl)-3-(hydroxymethyl)-5-methoxy-
2-oxo-2,3-dihydroindole 35.
mL, 1.26 mmol) and stirred for 2 h. The reaction
mixture was then warmed to rt and stirred overnight before
quenching with satd aq NaHCO3 solution (10 mL). CH2Cl2 (25 mL)
and brine (10 mL) were added, the layers separated and the aqueous
phase furtherextracted with CH2Cl2 (15 mLꢃ3). The organic extracts
were combined, dried (MgSO4) and concentrated in vacuo to give,
after chromatographic purification (EtOAc/petrol 80:20), 36
(201 mg, 69%) as a yellow oil. nmax (thin film)/cmꢁ1 2937,1709,1603,
1356, 1175, 736; dH (300 MHz, CDCl3) 7.37–7.23 (5H, m, ArH), 6.92
(1H, d, J¼2.4, ArH), 6.77 (1H, dd, J¼8.6 and 2.5, ArH), 6.69 (1H, d,
J¼8.6, ArH), 5.10 (1H, ABq, JAB¼15.8, CHAHBPh), 4.73 (1H, ABq,
JBA¼15.8, CHAHBPh), 4.53 (1H, ABq, JAB¼9.7, C(3)CHAHBOMs), 4.40
(1H, ABq, JBA¼9.7, C(3)CHAHBOMs), 4.16–3.99 (2H, m,
C(3)CH2CH2OMs), 3.77 (3H, s, OCH3), 2.79 (3H, s, OSO2CH3), 2.73 (3H,
s, OSO2CH3), 2.56–2.44 (1H, m, C(3)CHAHBCH2OMs), 2.31–2.21 (1H,
m, C(3)CHAHBCH2OMs); dC (75 MHz, CDCl3)175.2,156.4,136.5,135.4,
129.0, 128.2, 127.9, 127.2, 113.8, 111.4, 110.4, 72.2, 64.8, 55.9, 50.9,
44.2, 37.3 (2C), 32.1; m/z (ESIþ) 501 ([MþNH4]þ,100%), 484 ([MþH]þ,
45%); HRMS (ESIþ) 501.1353 ([MþNH4]þ C21H29N2O8Sþ2 requires
501.1360 (ꢁ1.4 ppm)).
HO
MeO
OH
O
N
Bn
35
Following general procedure B, osmium tetroxide (234 mL, 1% wt
solution in H2O), 33 (149 mg, 0.461 mmol) and N-methylmorpholine-
N-oxide (138 mg, 1.18 mmol) in CH2Cl2 (5 mL) gave after chro-
matographic purification (petrol/EtOAc 20:80), a 62:38 mixture of
diastereoisomers of triol 1-benzyl-3-(2,3-dihydroxypropyl)-3-
(hydroxymethyl)-5-methoxy-2-oxo-2,3-dihydroindole (153 mg, 93%)
as a yellow gum. Major diastereoisomer: dH (300 MHz, CDCl3) 7.26–
7.17 (5H, m, ArH), 6.89 (1H, d, J¼2.3, C(4)H), 6.63–6.53 (2H, m, C(6)H
and C(7)H), 4.89 (1H, ABq, JAB¼15.7, NCH2Ph), 4.77 (1H, d, JBA¼15.7,
NCH2Ph), 3.67 (3H, s, OMe), 3.59–3.51 (1H, m, CHOH), 3.47–3.38 (2H,
m, CH2OH), 3.35–3.27 (2H, m, CH2OH), 2.36–2.21 (1H, m, CH2CHOH),
1.80–1.75 (1H, m, CH2CHOH). Characteristic peaks for minor di-
astereoisomer: dH (300 MHz, CDCl3) 6.78 (1H, d, J¼2.4, C(4)H), 4.85
(1H, ABq, JAB¼15.7, NCH2Ph), 4.78 (1H, ABq, JBA¼15.7, NCH2Ph).
Sodium periodate (567 mg, 2.65 mmol) was added to a solutionof
4.3.21. N-Benzylhorsfiline 37.
NMe
MeO
O
N
triol
1-benzyl-3-(2,3-dihydroxypropyl)-3-(hydroxymethyl)-5-
methoxy-2-oxo-2,3-dihydroindole (509 mg, 1.42 mmol) in acetone
Bn
37

3812
J.E. Thomson et al. / Tetrahedron 66 (2010) 3801–3813
3. For a recent review of spiro[pyrrolidine-3,30-oxindole] natural products and
To a solution of 36 (97 mg, 0.200 mmol) in EtOH (1.0 mL) was
their therapeutic potential see; Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int.
Ed. 2007, 46, 8748.
4. For a review of the previous methods used to prepare the spiro[pyrrolidine-
3,30-oxindole] motif see Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209;
Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003.
5. Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Bodo, B. J. Org. Chem. 1991, 56,
6527.
6. Anderton, N.; Cockrum, P. A.; Colegate, S. M.; Edgar, J. A.; Flower, K.; Vit, I.;
Willing, R. I. Phytochemistry 1998, 48, 437.
7. Fisher, C.; Meyers, C.; Carreira, E. M. Helv. Chim. Acta 2000, 83, 1175.
8. For other applications of this methodology see: Lerchner, A.; Carreira, E. M.
J. Am. Chem. Soc. 2002, 124, 14826; Lerchner, A.; Carreira, E. M. Chem.dEur. J.
2006, 12, 8208.
9. Pellegrini, C.; Stra¨ssler, C.; Weber, M.; Borschberg, H. J. Tetrahedron: Asymmetry
1994, 5, 1979; Li, C.; Chan, C.; Heimann, A. C.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2007, 46, 1444.
added methylamine (2.0 M solution in THF, 0.30 mL, 0.60 mmol)
and the solution heated to 105 ꢂC in a sealed tube overnight. The
solution was concentrated in vacuo, the residue dissolved in CH2Cl2
(10 mL), washed with 0.1 N HCl (2 mLꢃ2), dried (MgSO4), filtered
and concentrated in vacuo. Chromatographic purification (EtOAc/
acetone 100:0/75:25) gave 37 (61 mg, 0.190 mmol, 95%) as a col-
ourless oil with spectroscopic data in accordance with the litera-
ture.7 dH (400 MHz, CDCl3) 7.25–7.15 (5H, m, ArH), 7.01 (1H, d, J¼2.5,
C(4)H), 6.58 (1H, dd, J¼8.5 and 2.5, C(6)H), 6.50 (1H, d, J¼8.5,
C(7)H), 4.80 (2H, s, CH2Ph), 3.69 (3H, s, OCH3), 3.02 (1H, td, J¼8.2,
3.9, C(50)HAHB), 2.87 (1H, AB q, JAB¼9.3, C(20)HAHB), 2.80 (1H, AB q,
JBA¼9.3, C(20)HAHB), 2.70 (1H, app q, J¼8.2, C(50)HAHB), 2.40 (3H, s,
NCH3), 2.32–2.38 (1H, m, C(40)HAHB), 2.02–2.09 (1H, m, C(40)HAHB);
dC (100 MHz, CDCl3) 180.2, 156.4, 137.2, 136.1, 135.4, 128.8, 127.6,
127.2, 112.2, 110.4, 109.1, 66.4, 56.7, 55.9, 53.8, 43.9, 41.9, 38.2.
10. Sua´rez-Castillo, O. R.; Mele´ndez-Rodrı´guez, M.; Contreras-Martı´nez, Y. M. A.;
´
´
´
Alvarez-Hernandez, A.; Morales-Rıos, M. S.; Joseph-Nathan, P. Nat. Prod.
Commun. 2009, 4, 797.
11. Somei, M.; Noguchi, K.; Yamagami, R.; Kawada, Y.; Yamada, K.; Yamada, F.
Heterocycles 2000, 53, 7.
12. Kuehne, M. E.; Roland, D. M.; Hafter, R. J. Org. Chem. 1978, 43, 3705.
13. (a) Palmisano, G.; Annunziata, R.; Papeo, G.; Sisti, M. Tetrahedron: Asymmetry
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4.3.22. Horsfiline 4.
NMe
MeO
O
N
H
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4
16. Lakshmaiah, G.; Kawabata, T.; Shang, M. H.; Fuji, K. J. Org. Chem. 1999, 64, 1699.
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22. For select other applications of NHCs as Lewis-base catalysts see: Zhang, Y. R.;
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NH3 (~5 mL) was condensed at ꢁ78 ꢂC and Na (~20 mg) was
added with vigorous stirring at ꢁ33 ꢂC until the deep blue colour
persisted. A solution of 37 (10.0 mg, 0.031 mmol) in THF (0.50 mL)
was added dropwise and the mixture stirred at ꢁ33 ꢂC for 15 min
before the addition of NH4Cl (~50 mg). The ammonia was allowed
to evaporate, H2O (10 mL) was added and the mixture extracted
with EtOAc (3ꢃ10 mL). The combined organic layers were dried
(MgSO4), filtered and concentrated in vacuo. Chromatographic
purification (CH2Cl2/MeOH 100:0/90:10) gave
4
(4.1 mg,
0.018 mmol, 57%) as an off-white solid with spectroscopic data in
accordance with the literature.7 mp 140–142 ꢂC (lit. Mp 156–
157ꢂC); dH (400 MHz, CDCl3) 7.87 (1H, br s, NH), 7.04 (1H, d, J¼2.4,
C(4)H), 6.77 (1H, d, J¼8.4, C(7)H), 6.58 (1H, dd, J¼8.4 and 2.4,
C(6)H), 3.79 (3H, s, OCH3), 3.07–3.01 (1H, m, C(50)HAHB), 2.91–2.85
(2H, m, JAB¼9.3, C(20)H2), 2.76 (1H, app q, J¼8.2, C(50)HAHB), 2.46
(3H, s, NCH3), 2.40 (1H, ddd, J¼12.6, 7.9 and 4.6, C(40)HAHB), 2.14–
2.06 (1H, m, C(40)HAHB); dC (100 MHz, CDCl3) 182.4, 156.4, 133.3,
112.9, 110.5, 109.9, 66.0, 56.7, 56.1, 54.1, 41.8, 38.2 [C(3) not
observed].
23. Thomson, J. E.; Rix, K.; Smith, A. D. Org. Lett. 2006, 8, 3785; Thomson, J. E.;
Campbell, C. D.; Concello´n, C.; Duguet, N.; Rix, K.; Slawin, A. M. Z.; Smith, A. D.
´
J. Org. Chem. 2008, 73, 2784; Thomson, J. E.; Kyle, A. F.; Concellon, C.; Gallagher,
K. A.; Lenden, P.; Morrill, L. C.; Miller, A. J.; Joannesse, C.; Slawin, A. M. Z.; Smith,
A. D. Synthesis 2008, 17, 2805; Campbell, C. D.; Duguet, N.; Gallagher, K. A.;
Thomson, J. E.; Lindsay, A. G.; O’Donoghue, A. C.; Smith, A. D. Chem. Commun.
2008, 3528.
24. For other demonstrations of the O-to C-carboxyl transfer of heterocyclic car-
bonates with a variety of Lewis-bases see: Steglich, W.; Ho¨fle, G. Tetrahedron
Lett. 1970, 11, 4727; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532; Shaw,
S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368; Shaw, S. A.;
Aleman, P.; Christy, J.; Kampf, J. W.; Va, P.; Vedejs, E. J. Am. Chem. Soc. 2006, 128,
925; Nguyen, H. Y.; Butler, D. C. D.; Richards, C. J. Org. Lett. 2006, 8, 769;
Seitzberg, J. G.; Dissing, C.; Søtofte, I.; Norrby, P.-O.; Johannsen, M. J. Org. Chem.
2005, 70, 8332.
25. For the O-to C-carboxyl transfer of indolyl carbonates see: Moody, C. J.; Doyle,
K. J.; Elliott, M. C.; Mowlem, T. J. J. Chem. Soc., Perkin Trans. 1997, 1, 2413; Hills, I.
D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921; Duffy, T. A.; Shaw, S. A.;
Vedejs, E. J. Am. Chem. Soc. 2009, 131, 14; Ismail, M.; Nguyen, H. V.; Ilyashenko,
G.; Motevalli, M.; Richards, C. J. Tetrahedron Lett. 2009, 46, 6332.
Acknowledgements
The authors would like to thank the Royal Society for a Univer-
sity Research Fellowship (ADS), the EPSRC (KBL), AstraZeneca (Re-
search Support Fund) for enabling scholarship funding (SRS and
AFK) and the EPSRC mass spectrometry facility.
Supplementary data
26. The use of allylmagnesium chloride leads to addition at the C-2 carbonyl
1H and 13C NMR data is available for all products. Supplementary
data associated with this article can be found, in the online version,
at doi:10.1016/j.tet.2010.03.047.
´
Malapel-Andrieu, B.; Piroe¨lle, S.; Merour, J.-Y. J. Chem. Res. 1998, 9, 594.
27. Trost, B. M.; Frederiksen, M. U. Angew. Chem., Int. Ed. 2005, 44, 308.
28. Unfortunately, attempts to perform a catalytic enantioselective version of this
O- to C-carboxyl group transfer process of indolyl carbonates using either chiral
NHCs or isothioureas led to only modest asymmetric induction (typically <10%
ee) and so the synthesis was continued in the racemic series.
29. The formation of related spirocyclic lactones after dihydroxylation of similar
oxindole substrates with an ester functionality at the 3-position has been
reported.16
30. Loreto, M. A.; Migliorini, A.; Tardella, P. A.; Gambacorta, A. Eur. J. Org. Chem.
2007, 14, 2365.
31. Barrett et al. have previously reported a similar amine promoted cyclisation to
form pyrrolidines from an acyclic bis-mesylate using benzylamine: Barrett, D.
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