Facile nucleophilic substitution at the C3a tertiary carbon of the 3a-bromohexahydropyrrolo[2,3-b]indole scaffold

Article abstract of DOI:10.1039/c0ob00327a

The synthesis of 3a-substituted hexahydropyrrolo[2,3-b]indole derivatives via nucleophilic substitution at the C3a position is reported. Nitrogen-, oxygen-, sulfur-, fluoro- and carbon-based nucleophiles have been employed, using both conventional organic solvents and ionic liquids. The C3a-substituted derivatives were obtained in good to excellent yields. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0ob00327a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Facile nucleophilic substitution at the C3a tertiary carbon of the
3a-bromohexahydropyrrolo[2,3-b]indole scaffold†
Isabel Villanueva-Margalef, David E. Thurston and Giovanna Zinzalla*
Received 27th June 2010, Accepted 4th August 2010
DOI: 10.1039/c0ob00327a
The synthesis of 3a-substituted hexahydropyrrolo[2,3-b]indole derivatives via nucleophilic substitution
at the C3a position is reported. Nitrogen-, oxygen-, sulfur-, fluoro- and carbon-based nucleophiles have
been employed, using both conventional organic solvents and ionic liquids. The C3a-substituted
derivatives were obtained in good to excellent yields.
in the literature of nucleophilic substitution of the bromo atom on
Introduction
the 3a-bromohexahydropyrrolo[2,3-b]indole scaffold focused on
the introduction of indole substituents.18
The hexahydropyrrolo[2,3-b]indole scaffold is present in a variety
of natural products (e.g. the alkaloids shown in Fig. 1) possessing a
wide range of biological activities.1–4 The striking architecture has
generated considerable interest from the synthetic and medicinal
chemistry perspective.5–7 The ability to functionalise at the C3a
position, however, remains limited, and there is a need for more
general synthetic routes.
We report here the first study of the substitution reactions of
the bromo atom at C3a of the 3a-bromohexahydropyrrolo[2,3-
b]indole scaffold for the formation of carbon-, oxygen-, fluoro- and
sulfur-3a-substituted derivatives. The formation of 3a-nitrogen-
substituted derivatives has been further investigated with a wider
range of N-based nucleophiles.
Results and discussion
The 3a-bromohexahydropyrrolo[2,3-b]indole scaffold (3) is an
amenable starting material to generate compound libraries as it
can be efficiently prepared in gram quantities employing Hino’s
methodology.19,20 The precursor hexahydropyrrolo[2,3-b]indole 2
was obtained in good yield and as a single diastereomer (i.e., 2-
endo-isomer) (Scheme 1) via a two-step acid-mediated cyclisation
of the N,N¢-dimethoxycarbonyl L-tryptophan methyl ester 1, fol-
lowed by sulfonylation. Bromination of 2 at C3a had been reported
by Crich and co-workers under free-radical conditions by reaction
with AIBN and NBS.20,21 Similar yields of the C3a-brominated
derivative 3 were obtained in our hands by treatment of 2 with
benzoyl peroxide and 1,3-dibromo-5,5-dimethylhydantoin in CCl4
at reflux.
Fig. 1 Natural products containing the hexahydropyrrolo[2,3-b]indole
scaffold.
To date, formation of hexahydropyrrolo[2,3-b]indole derivatives
bearing a C3a-heteroatom functional group has been achieved
mainly via electrophilic cyclisation reactions on tryptophanderiva-
tives, involving complex synthetic routes.8–16 Recently, Rainier and
co-workers have developed a more efficient synthesis of C3a-
substituted hexahydropyrrolo-[2,3-b]indole derivatives exploiting
the unique activity of a cyclopropylazetoindoline compound via a
two-step synthetic route from the 3a-bromohexahydropyrrolo[2,3-
b]indole scaffold.17 However, nucleophilic displacement of the
bromo would be the most efficient synthetic approach for the
preparation of compound libraries. To date, this has proved to
be particularly challenging due the structural features of the
diazabicyclo[3.3.0]octane framework, and there are no general
methodologies available. In fact, only one example is described
Cancer Research UK Protein-Protein Interactions Drug Discovery Research
Group, School of Pharmacy, University of London, 29–39 Brunswick Square,
London, U K WC1N 1AX. E-mail: giovanna.zinzalla@pharmacy.ac.uk.;
Fax: +44 (0)2077535964; Tel: +44(0)2077535932
Scheme 1 Synthesis of the scaffold (3).
The nucleophilic substitution reactions were investigated in
both conventional organic solvents (i.e., acetonitrile) and in ionic
† Electronic supplementary information (ESI) available: Synthesis of 21,
1H,13C and NOESY spectra. See DOI: 10.1039/c0ob00327a
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liquids (ILs). The latter are an emerging class of solvents22–26 that
offer a number of advantages compared to organic solvents as they
possess a high thermal stability (i.e., decomposition temperatures
>400 ◦C), they are non-flammable, non-toxic and potentially
recyclable.23 Furthermore, they can enhance a wide range of
synthetic transformations.22,27 We screened three ionic liquids
(i.e., [bmim][BF4], [bmim][PF6] and [bmim][NTf2]) for use in the
nucleophilic substitution reactions, and [bmim][BF4] gave the best
results for both yields and reactivities of 3 with the different
nucleophiles. We report here the optimised reaction conditions
for both the aprotic and the ionic liquid solvent systems.
In the nucleophilic substitutions, all of the 3a-derivatives
were isolated as single diastereoisomers, with formation only
of the thermodynamically favoured 2-endo isomer.18 The endo
conformation was confirmed by H1 NMR analysis with regard
to the typical chemical shift of the methyl group of the 2-endo-
CO2Me5,19 and by NOESY experiments.28 With regard to the
stereoselectivity of the endo products, the configuration at C3a is
controlled by the geometry of the cis-fused C3a–C8a bridge, thus
full retention of configuration at C3a was expected with formation
only of A (Fig. 2). Formation of the enantiomer 2-endo B also
requires inversion at C8a (Fig. 2), which has never been observed
for hexahydropyrrolo[2,3-b]indole scaffolds.5,18 Thus, based on the
unique structural features of the pyrroloindole scaffold and due to
the reaction conditions employed in our studies, we speculate that
the substitution reactions proceed via a typical SN1 mechanism.
In the case of reactions conducted in the presence of KOtBu,
however, the SN1 products may also be formed via formation of a
cyclopropylazetoindoline intermediate described by Rainier and
co-workers.17
were able to prepare the acetoxylated product 9 directly from
the 3a-bromohexahydropyrrolo[2,3-b]indole 3 using KOAc and
[bmim][BF4]. The product was obtained as a single 2-endo-isomer
in 65% yield. No reactivity was observed in refluxing acetonitrile
even after 48 h, with or without H2O (Table 1, entry 2a). The
reaction of 3 in a 0.5 M MeONa solution in methanol and
acetonitrile as co-solvent at 65 ◦C afforded 10 in 42% yield, with
complete 2-endo-diastereoselectivity (Table 1, entry 3a). The yield
was improved to 60% using a 1.5 M MeONa solution (Table 1,
entry 3b). The use of [bmim][BF4] with 0.5 M MeONa afforded 10
in 72% yield in a very fast and clean reaction (Table 1, entry 3c).
The introduction of the cyano functionality using [bmim][BF4]
was also successful, affording the desired product 11 in 60% yield
(Table 1, entry 4b). In this case, due to the low solubility of KCN,
the salt was stirred overnight in the ionic liquid before adding 3.
Using acetonitrile, only traces of the substitution product were
formed (Table 1, entry 4a). It is relevant to highlight that the use
of an IL improved greatly the reactivity of the scaffold towards the
nucleophilic substitution with MeONa, and the substitutions with
the other three metals salts would only proceed in the presence of
a IL.
Chlorination and iodination reactions were also investigated
using different reaction conditions, both in acetonitrile and IL,
but only traces of the chloro-derivative were observed by LC-MS,
probably due to steric hindrance. Introduction of the azide and
thiocyanate groups was also attempted using NaN3 and KSCN
as nucleophiles, both in acetonitrile and in [bmim][BF4], but no
reaction was observed even after 72 h heating at 95 ◦C.
The formation of 3a-oxygen-substituted derivatives was also
investigated via solvolysis using the alcohols illustrated in Table 2.13
Solvolysis of 3 with benzyl or allyl alcohol successfully afforded
the desired 3a-oxygen-based derivatives 14 and 15 in 77% and
85% yield, respectively, when [bmim][BF4] was used as a cosolvent
(Table 2, entries 1c and 2c). In acetonitrile, or in neat reaction
conditions, the yields were considerably lower and formation
of side products was observed (Table 2, entries 1a and 2a). In
both solvent systems the solvolysis was carried out aided by one
equivalent of AgNO3. Also in this substitution reaction, the use
of ILs greatly enhanced the solvolysis affording the desired C3a-
oxygen derivatives in a facile manner, in very good yields and as
single isomer.
The formation of 3a-nitrogen-substituted derivatives was also
investigated (Table 3). Reaction of 3 with morpholine (4 eq.) in
the presence of CsCO3 (4 eq.) and KI (0.5 eq.) in acetonitrile at
reflux allowed isolation of the desired product 22 in 94% yield
as a single diastereoisomer (Table 3, entry 1a). The use of the IL
as solvent medium resulted in a more efficient preparation of 22
(Table 3, entry 1b) as KI was not needed, only two equivalents of
morpholine and base were required, and the reaction proceeded
in shorter reaction times. Similar reactivity was observed using
pyrrolidine as nucleophile (Table 2, entries 2a and 2b) for the
preparation of 23. Nucleophilic substitution with the linear N-
benzylmethylamine 18 afforded the desired product 24 in good
yields (Table 3, entries 3a and 3b) and, as in the case of the
secondary amines 16 and 17, the use of an IL allowed a more
efficient preparation.
Fig. 2 Stereoselectivity features of the 3a-bromohexahydropyrrolo-
[2,3-b]indole scaffold in the nucleophilic substitution reactions.
First we examined the reactivity of metal salts (Table 1) for
the introduction at C3a of oxygen-, fluoro- and carbon-based
substituents. For the nucleophilic substitution reaction conducted
in aprotic solvent, bromide 3 was reacted with CsF (5 eq.)
in refluxing acetonitrile, but no reactivity was observed after
48 h (Table 1, ent◦ry 1a). When the reaction was carried out in
[bmim][BF4] at 95 C in the presence of H2O,29 the desired fluoro-
substituted derivative 8 was isolated in good yield (60%) exclusively
as a single diastereoisomer (Table 1, entry 1b).
For the formation of 3a-oxygen-substituted hexahydro-
pyrrolo[2,3-b]indole derivatives, the most efficient methodology
described in the literature utilizes a two-step synthetic ap-
proach starting from a derivative of scaffold 3.17 Instead, we
For the preparation of alkaloids containing the hexahydro-
pyrrolo[2,3-b]indole skeleton, the introduction of indole moieties
at C3a is particularly relevant and, to date, only Rainier and
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Table 1 Using nucleophilic substitution to form 3a-fluoro-, 3a-oxygen- and 3a-carbon-substituted derivatives with metal salts
Entry
M+Nu- (eq.)a
Solvent
Additive (eq.)
Time/h
Temp./◦C
Productb
Yield (%)b
e
1a
1b
2a
2b
3a
3b
3c
4a
4b
4 (5)
4 (5)
5 (5)
5 (5)
6c (8)
6d (10)
6c (8)
7 (8)
7 (8)
MeCN
[bmim][BF4]
MeCN
[bmim][BF4]
MeCN
MeCN
[bmim][BF4]
MeCN
[bmim][BF4]
—
H2O (5)
—
H2O (5)
—
—
—
—
—
48
1.5
48
7
7
1
1.5
72
30
80
95
80
95
65
65
65
80
95
8
—
8
60
c
9
9
10
10
10
11
11
—
66f
42
60
72
5g
60
a The introduction of other nucleophiles (N3, SCN, I, Cl) was investigated. However, only traces of the desired product were observed (less than 5%
by LC-MS). b Isolated yield; >98% purity, characterisation by 1D and 2D NMR, LC-MS, HRMS, CHN, m.p. and IR. c 0.5 M MeONa solution in
MeOH (commercially available). d 1.5 M MeONa solution in MeOH (freshly prepared). e Starting material recovered. f Traces (5–10%) of the 3a-hydroxo
derivative (i.e., Nu = OH) were observed by LC-MS. g Analysed by LC-MS.
Table 2 Using nucleophilic substitution to form 3a-oxygen-substituted derivatives via solvolysis
Entry
R1OH
Solvent
AgNO3 (eq.)
Time/h
Temp./◦C
Producta
Yield (%)
1a
1b
1c
2a
2b
2c
12
—
1
1
1
1
1
1
1
180 (MW)
110 (MW)
110 (MW)
120 (MW)
110 (MW)
110 (MW)
14
14
14
15
15
15
52
40
77
56
44
85
12b
12b
13
MeCN
[bmim][BF4]
—
MeCN
[bmim][BF4]
1.5
1.5
1
1.5
1.5
13b
13b
a >98% purity; characterisation by 1D and 2D NMR, LC-MS, HRMS, CHN, m.p. and IR. b The alcohol has been used as a co-solvent in a 1 : 1 ratio
with the aprotic solvent or the ionic liquid.
co-workers18 have explored the nucleophilic substitution of the
bromo atom of the 3a-bromohexahydropyrrolo[2,3-b]indole scaf-
fold in any detail. Their methodology, however, required an excess
of the scaffold and gave a mixture of 2-exo and 2-endo products.
In our studies, when using acetonitrile as solvent, the indole
anion was prepared using KOtBu as base (1.26 eq.) and then
transferred into a solution of 3a-bromohexahydropyrrolo[2,3-
b]indole 3 (1 eq.). Using this procedure, indoles 19, 2030 and
2131 were reacted with 3 and the desired products 25, 26 and 27
were obtained as single 2-endo-isomers in 71–88% yields (Table 3,
entries 4a, 5a and 6a).
Furthermore, with nucleophiles 18 and 19 full 2-endo selectivity
was also achieved with the corresponding 2-exo isomer of 3
(Table 3, entries 3a and 4a). Using [bmim][BF4] as solvent,
25, 26 and 27 were also successfully prepared (62–71% yields,
Table 3, entries 4b, 5b and 6b) with complete diastereoselectivity.
Furthermore, the use of an IL allowed for a more efficient synthesis
as pre-formation of the indole anion was not required. The
preparation of 3a-sulfur-substituted derivative 28 in acetonitrile
also required pre-formation of the anion using KOtBu (1.4 eq.)
as base (Table 4, entry 1a). This afforded 28 in 80% yield and as
a single 2-endo-isomer. Use of [bmim][BF4] allowed formation of
28 in similar yield (72%) and exclusively as the endo-isomer, with
no pre-formation of anion required. In this case, CsCO3 (1.5 eq.)
as base was required (Table 4, entries 1b and 1c) and no reactivity
was observed with KOtBu.
The effect of the leaving group on the nucleophilic substitution
reaction was also examined in an attempt to prepare azide-
and SCN-substituted derivatives (Scheme 2). Reaction of 3 with
AgOTf (2 eq.) in [bmim][BF4] in the presence of H2O afforded
3a-hydroxohexahydropyrrolo[2,3-b]indole 29 in a fast and clean
reaction in 95% yield and as a single endo-isomer (Scheme 2).
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Table 3 Using nucleophilic substitution to form 3a-nitrogen-substituted derivatives
Entry
R1R2NH (eq.)
Solvent
Base (eq.)
Time/h
Temp./◦C
Product
Yield (%)a
1a
1b
2a
2b
3a
3b
4a
4b
5a
5b
6a
6b
16 (4)
MeCN
[bmim][BF4]
MeCN
[bmim][BF4]
MeCN
[bmim][BF4]
MeCN
[bmim][BF4]
MeCN
[bmim][BF4]
MeCN
CsCO3 (4), KI (0.5)
CsCO3 (2)
CsCO3 (4), KI (0.5)
CsCO3 (1.2)
18
7
18
7
16
7
0.5
7
0.5
2.5
0.5
7
80
95
80
95
80
95
rt
90
rt
95
rt
22
22
23
23
24
24
25
25
26
26
27
27
94
87
84
78
71
77
88
71
71
66
77
62
16 (2)
17 (4)
17 (1.3)
18 (4)b
18 (2)
CsCO3 (4), KI (0.5)
CsCO3 (2)
19 (1.2)c
19 (2.5)
20 (1.3)
20 (2.5)
21 (1.3)
21 (2.5)
KOtBu (1.26)d
KOtBu (2.55)e,f
KOtBu (1.32)d
KOtBu (2.55)e
KOtBu (1.32)d
KOtBu (2.55)e
[bmim][BF4]
95
a Isolated yield; >98% purity, characterisation by 1D and 2D NMR, LC-MS, HRMS, CHN, m.p. and IR. b Reaction also carried out with the corresponding
2-exo-conformer as SM. The 2-endo product was obtained in 65% (>98% purity, [a]2D5 -19.7 (c 0.44, CHCl3)). c Reaction also carried out with the
corresponding 2-exo-conformer as SM. The 2-endo product was obtained in 67% (>98% purity, [a]2D5 +97.8 (c 0.48, CHCl3)). d 1 M KOtBu solution in
THF. e Solid KOtBu. f The reaction was attempted using CsCO3, which afforded product 25 in only 45% yield.
Table 4 Using nucleophilic substitution to form 3a-sulfur-substituted derivatives
Entry
PhSH (eq.)
Solvent
Base (eq.)
Time/h
Temp./◦C
Yield (%)a
1a
1b
1c
1.35
1.4
1.4
MeCN
[bmim][BF4]
[bmim][BF4]
KOtBu (1.4)b
KOtBu (1.5)c
CsCO3 (1.5)b
4
24
7
80
90
90
80
—
72
a >98% purity; characterisation by 1D and 2D NMR, LC-MS, HRMS, CHN, m.p. and IR. b 1 M KOtBu solution in THF. c Solid KOtBu.
This is a significant improvement compared to other methods
reported in the literature for preparation of the hydroxo-derivative
as they involve either unselective electrophilic cyclisations8,13 or
low yielding oxidative processes on 3a-substituted derivatives.11,12,20
The alcohol was then protected in good yield using conventional
reaction conditions (Scheme 2). With the tosylated product (30)
in hand, we investigated the introduction of azide and thiocyanate
ions. To be able to compare the reactivities of 3 and 30, we also
employed KCN as a nucleophile source.
In the nitrilation and azidation reactions conducted in refluxing
acetonitrile, mostly starting material was recovered even after long
reaction times. Instead, the reaction with KSCN afforded the
desired 2-endo-product 31 in 60% yield, along with traces of the
elimination product 32 (Scheme 2). When the substitution reac-
tions with CsN3, KSCN or KCN were carried out in [bmim][BF4]
at 95 ◦C for 3 h the starting material 30 was fully consumed, but
mainly the elimination product 32 was obtained and only traces
of the desired substituted product were observed in the case of
the CsN3 and KSCN reactions. The reactions were repeated at
lower temperature (i.e., 40 ◦C), but after five days the starting
material was not yet fully consumed and the main product was
32. Therefore, in the IL a more labile leaving group did not aid
the nucleophilic substitution, but favoured elimination. The use,
instead, of acetonitrile allowed the formation of the 3a-sulfur-
substituted product 31.
In the literature numerous studies have focused on the reactivity
of nucleophilic substitution reactions in ILs that proceed via
an SN2 mechanism.24,29,32–38 Recently, nucleophilic substitution
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anhydrous conditions, unless water was used as solvent or co-
solvent. All reactions were monitored by analytical thin-layer
chromatography (TLC) using the indicated solvent on E. Merck
silica gel 60 F254 plates (0.25 mm). TLC plates were visualized
using UV light (254 or 360 nm) and/or staining with cerium
sulfate–ammonium molybdate or basic potassium permanganate
solutions followed by heating. LC-MS was also used to monitor
the progress of reactions. Solvents were removed by rotary
◦
evaporation at or below 40 C and products further dried using
low-pressure vacuum pumps. Purification of the products was
achieved by column chromatography using Merck Flash silica gel
60 (230–400 mesh). IR spectra were recorded using neat conditions
on a Perkin–Elmer Spectrum 1000 FT IR Spectrometer. 1H
and 13C NMR spectra were acquired at 300 K using a Bruker
Advance 400 spectrophotometer NMR spectrometer at 400 MHz
1
or 500 MHz for H NMR and 100 MHz or 125 MHz for 13C
NMR. Chemical shifts (d H) are quoted in ppm (parts per million)
and referenced to CDCl3 (residual chloroform signal 1H d = 7.26,
13C d = 77.2) or d6-DMSO (residual dimethyl sulfoxide signal 1H
d = 2.54, 13C d = 40.45). Multiplicities in the 1H NMR spectra are
quoted as: s = singlet, d = doublet, q = quartet, m = multiplet, dd =
double doublet, ddd = double double doublet, dt = double triplet,
td = triple doublet, ddt = double double triplet. Mass spectroscopy
data were collected using a Waters Micromass ZQ instrument
coupled to a Waters 2695 HPLC with a Waters 2996 PDA. Waters
Micromass ZQ parameters used were: capillary, 3.38 kV; cone,
35 V; extractor, 3.0 V; source temperature, 100 ◦C; desolvation
temperature, 200 ◦C; cone flow rate, 50 L h-1; desolvation flow rate,
250 L h-1. High resolution mass spectra (HRMS) were obtained
on a Waters Micromass QTOF Global in positive W-mode using
metal-coated borosilicate glass tips to introduce samples into the
instrument coupled with LC using electrospray (ES) ionization
and time-of-flight (TOF) mass spectrometry.
Scheme 2 Synthesis and use of tosylate derivative 30.
reactions that proceed via SN1 were also investigated.35,39 We
observed faster reaction rates for most of the nucleophiles than
in an organic solvent, and in some cases reactions would only
proceed in the presence of an IL. Gagnon39 and co-workers
have demonstrated that carbocations can be generated in ILs.
Furthermore, Chiappe and co-workers35 have investigated SN2 and
SN1 mechanisms in reactions with primary, secondary and tertiary
halides. Both groups observed that the ion–ion interactions
induced by the ILs affect the rate of both substitution mechanisms.
Thus, the cooperative activation by ILs of both nucleophile and
electrophile via ion–ion interactions may explain the enhanced
reactivity in [bmim][BF4] of our scaffold.
Conclusions
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-3a-bromo-8-
(phenylsulfonyl)-2,3,8a-trihydropyrrolo[2,3-b]indole (3)
In summary, a facile synthetic method for the formation
of 3a-substituted hexahydropyrrolo[2,3-b]indole derivatives has
been developed via nucleophilic substitution on the 3a-
bromohexahydropyrrolo[2,3-b]indole scaffold. The preparation of
fluoro-, cyano-, oxygen-, sulfur- and nitrogen-based derivatives
can be achieved in good to excellent yields and with complete
stereoselectivity. The reactions can be performed both in organic
solvents and in ionic liquids, and we have demonstrated that the
use of ionic liquids improves greatly the reactivity of the scaffold
towards the nucleophilic substitutions, and in a number of cases
reactions would only proceed in the presence of an IL. This
methodology should provide medicinal and synthetic chemists
with a useful tool to exploit the hexahydropyrrolo[2,3-b]indole
scaffold for drug discovery purposes and for the total synthesis of
alkaloids possessing such molecular frameworks.
Benzoyl peroxide (465 mg, 1.34 mmol) and 1,3-dibromo-5,5-
dimethylhydantoin (1.54 g, 5.37 mmol) were added to a stirred
suspension of 219 (1.87 g, 4.48 mmol) in CCl4 (112 mL) at room
temperature. The reaction mixture was heated to 80 ◦C for 3 h at
which point the solution became dark orange–red and a white
solid precipitated. The reaction mixture was cooled to room
temperature, the volatiles were concentrated in vacuo, and the
residue was purified by column chromatography (40% EtOAc in
hexanes) to give 3 (1.6 g, 72%) as a light yellow solid. Rf (40%
EtOAc in hexanes) 0.3; IR (nmax/cm-1: 2955, 1752, 1711, 1599,
1
1309, 1222, 1089, 849, 753; H NMR (400 MHz, CDCl3) d ppm
7.83 (2 H, d, J = 7.6 Hz, SO2Ph-o-H), 7.55 (1 H, d, J = 8.1 Hz,
H7), 7.51 (1 H, t, J = 7.4 Hz, SO2Ph-p-H), 7.41 (2 H, t, J = 7.7 Hz,
SO2Ph-m-H), 7.34 (1 H, perceived t, J = 7.8 Hz, H6), 7.25 (1
H, d, J = 7.4 Hz, H4), 7.14 (1 H, perceived t, J = 7.6 Hz, H5),
6.31 (1 H, bs, H8a), 4.60 (1 H, d, J = 8.4 Hz, H2), 3.68 (3 H, s,
N1C(O)OCH3), 3.25 (1 H, d, J = 13.0 Hz, H3A), 3.14 (3 H, s,
C(O)OCH3), 3.02 (1 H, dd, J = 13.0, 9.1 Hz, H3B); 13C NMR
(100 MHz, CDCl3) d169.9 (CO(O)CH3), 154.0 (N1CO(O)CH3),
141.7 (C7a), 139.3 (SO2Ph-i-C), 133.2 (SO2Ph-p-C), 133.1 (C3b),
131.1 (C6), 128.9 (2 ¥ SO2Ph-m-C), 127.3 (2 ¥ SO2Ph-o-C), 125.7
(C5), 124.5 (C4), 118.2 (C7), 87.1 (C8a), 59.7 (C3a), 59.5 (C2),
Experimental
General experimental details
All reagents and solvents were obtained from commercial sources
unless otherwise indicated. Reactions requiring anhydrous con-
ditions were conducted in glassware which had been oven-dried
overnight. All reactions were carried out under dry N2 and in
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53.0 (N1CO(O)CH3), 52.2 (CO(O)CH3), 44.4 (C3). Spectroscopic
(C3), 21.1 (C(O)CH3); Elem. Anal. calculated for C22H22N2O8S:
C, 55.69; H, 4.67; N, 5.90%. Found: C, 55.65; H, 4.60; N, 5.88%;
HRMS: Theoretical mass [M+H]+, 497.0995; Measured mass
[M+H]+, 497.0996 (d 1 ppm).
data in good agreement with the literature.20
General procedure for nucleophilic substitution with metal salts
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-3a-methoxy-8-(phenyl-
sulfonyl)-2,3,8a-trihydropyrrolo[2,3-b]indole (10). Y = 42 or 60%
in MeCN (depending on which MeONa solution used), 72% in
[bmim][BF4], as a light yellow solid. Rf (40% EtOAc in hexanes)
The metal salt (eq. as indicated in Table 1) was added to a stirred
solution of 3 (1 eq.) in [bmim][BF4] or MeCN (0.25 M) at room
temperature. The reaction was heated at the indicated temperature
and for the indicated time (Table 1), allowed to cool to room
temperature and then quenched with saturated aqueous NH4Cl
solution (2 mL). For the MeCN procedure, the aqueous layer was
separated and extracted with EtOAc (¥3). For the [bmim][BF4]
procedure, the reaction mixture was extracted from the ionic liquid
with EtOAc (¥4) and Et2O (¥4). The combined organic layers
were then dried (Na2SO4), filtered and concentrated in vacuo.
Purification of the residue by column chromatography afforded
the desired substitution products (98% purity assessed by NMR
and LC-MS analysis).
0.5; m.p. 122–123 ◦C; [a]D +35.0 (c 0.46, CHCl3); IR (nmax/cm-1:
25
1
2951, 1714, 1446, 1345, 1163, 1100, 754; H NMR (400 MHz,
CDCl3) d8.02–7.87 (2 H, m, SO2Ph-o-H), 7.59–7.52 (1 H, m,
SO2Ph-p-H), 7.49 (2 H, t, J = 7.2 Hz, SO2Ph-m-H), 7.42–7.34 (2
H, m, H6 + H7), 7.25 (1 H, d, J = 6.2 Hz, H4), 7.14 (1 H, perceived t,
J = 7.5 Hz, H5), 6.19 (1 H, s, H8a), 4.72 (1 H, d, J = 7.6 Hz, H2), 3.32
(3 H, s, NCO2CH3), 3.21 (3 H, s, CO2CH3), 3.01 (3 H, s, OCH3),
2.83 (1 H, d, J = 12.1 Hz, H3A), 2.65 (1 H, dd, J = 12.0, 9.4 Hz,
H3B); 13C NMR (100 MHz, CDCl3) d 170.6 (C(O)CH3), 154.5
(NC(O)CH3), 144.2 (C7a), 141.5 (SO2Ph-i-C), 132.6 (SO2Ph-p-
C), 131.2 (C6), 128.9 (2 ¥ SO2Ph-m-C), 128.4 (C3b), 126.1 (2 ¥
SO2Ph-o-C), 125.1 (C4), 124.5 (C5), 117.2 (C7), 90.7 (C3a), 81.2
(C8a), 59.0 (C2), 52.5 (OCH3), 52.2 (2 ¥ CO(O)CH3), 39.1 (C3);
Elem. Anal. calculated for C21H22O7N2S: C, 56.49; H, 4.97; N,
6.27%. Found: C, 56.53; H, 4.90; N, 6.20%; HRMS: Theoretical
mass [M+H]+, 447.1226; Measured mass [M+H]+, 447.1237 (d
3 ppm).
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-3a-fluoro-8-(phenyl-
sulfonyl)-2,3,8a-trihydropyrrolo[2,3-b]indole (8). H2O (1 eq.) was
added to the reaction mixture.
Y = 60% as a white solid; Rf (40% EtOAc in hexanes) 0.3; m.p.
149–151 ◦C; [a]D +134.9 (c 0.49, CHCl3); IR (nmax/cm-1: 2952,
25
1
1714, 1445, 1314, 1169, 748; H NMR (400 MHz, CDCl3) dPpm
7.71 (2 H, d, J = 7.6 Hz, SO2Ph-o-H), 7.61 (1 H, d, J = 8.2 Hz,
H7), 7.49 (1 H, t, J = 7.5 Hz, SO2Ph-p-H), 7.42 (1 H, perceived
t, J = 7.8 Hz, H6), 7.38 (2 H, t, J = 7.7 Hz, SO2Ph-m-H), 7.27
(1 H, d, J = 6.2 Hz, H4), 7.15 (1 H, perceived t, J = 7.5 Hz,
H5), 6.14 (1 H, d, J = 12.0 Hz, H8a), 4.73 (1 H, d, J = 9.3 Hz,
H2), 3.70 (3 H, s, N1C(O)OCH3), 3.16 (3 H, s, C(O)OCH3), 2.84
(2 H, m, H3); 13C NMR (100 MHz, CDCl3) d170.1 (C(O)CH3),
154.4 (N1CO(O)CH3), 144.2 (d, J = 4.5 Hz, C7), 138.4 (SO2Ph-
i-C), 133.1 (SO2Ph-p-C), 132.3 (d, J = 3.40 Hz, C6), 128.8 (2 ¥
SO2Ph-m-C), 128.3 (d, J = 23.6 Hz, C3b), 127.1 (2 ¥ SO2Ph-o-C),
125.5 (d, J = 2.7 Hz, C5), 125.0 (C4), 118.6 (C7), 103.1 (d, J =
205.5 Hz, C3a), 82.4 (d, J = 31.6 Hz, C8a), 58.9 (d, J = 5.7 Hz,
C2), 53.0 (N1CO(O)CH3), 52.2 (CO(O)CH3), 37.4 (C3); Elem.
Anal. calculated for C20H19O6N2SF: C, 55.29; H, 4.41; N, 6.45%.
Found: C, 55.30; H, 4.41; N, 6.39%; HRMS: Theoretical mass
[M+H]+, 435.1026; Measured mass [M+H]+, 435.1045 (d 4 ppm).
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-3a-cyano-8-(phenyl-
sulfonyl)-2,3,8a-trihydropyrrolo[2,3-b]indole (11). KCN had been
stirred in [bmim][BF4] for 10 h at 95 ◦C before addition of
bromide 3.
Y = 60% as a white solid; Rf (40% EtOAc in hexanes) 0.35; m.p.
74–76 ◦C; [a]D25 +83.5 (c 0.59, CHCl3); IR (nmax/cm-1: 2952, 1720,
1
1446, 1381, 1171, 756; H NMR (400 MHz, CDCl3) d7.71 (2 H,
d, J = 7.7 Hz, SO2Ph-o-H), 7.65 (1 H, d, J = 8.2 Hz, H7), 7.56 (1
H, t, J = 7.5 Hz, SO2Ph-p-H), 7.46–7.37 (3 H, m, SO2Ph-m-H +
H6), 7.24–7.15 (2 H, m, H4 + H5), 6.43 (1 H, s, H8a), 4.73 (1 H, d,
J = 8.7 Hz, H2), 3.78 (3 H, s, NCO2CH3), 3.17 (3 H, s, CO2CH3),
2.97 (1 H, d, J = 13.0 Hz, H3A), 2.83 (1 H, dd, J = 13.0, 8.8 Hz,
H3B); 13C NMR (100 MHz, CDCl3) d 169.6 (C(O)CH3), 153.9
(NC(O)CH3), 142.3 (C3b), 137.9 (SO2Ph-i-C), 133.8 (SO2Ph-p-C),
131.4 (C6), 129.4 (2 ¥ SO2Ph-m-C), 128.1 (C7a), 127.2 (2 ¥ SO2Ph-
o-C), 126.4 (C4), 124.4 (C5), 119.1 (C7), 116.8 (CN), 82.6 (C8a),
58.5 (C2), 53.4 (NCO(O)CH3), 52.4 (CO(O)CH3), 48.0 (C3a), 39.7
(C3); Elem. Anal. calculated for C21H19O6N3S: C, 57.13; H, 4.34; N,
9.52%. Found: C, 57.08; H, 4.29; N, 9.45%; HRMS: Theoretical
mass [M+H]+, 442.1073; Measured mass [M+H]+, 442.1075 (d
1 ppm).
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-3a-acetoxy-8-(phenyl-
sulfonyl)-2,3,8a-trihydropyrrolo[2,3-b]indole (9). H2O (1 eq.) was
added to the reaction mixture.
Y = 66% as a white solid; Rf (40% EtOAc in hexanes) 0.25;
m.p. 69–71 ◦C; [a]D25 +134.7 (c 0.70, CHCl3); IR (nmax/cm-1: 2951,
1
2362, 1734, 1446, 1228, 757; H NMR (400 MHz, CDCl3) dPpm
7.80 (2 H, d, J = 7.3 Hz, SO2Ph-o-H), 7.55 (1 H, d, J = 8.1 Hz,
H7), 7.53–7.48 (2 H, m, SO2Ph-p-H + H4), 7.41 (2 H, t, J =
7.7 Hz, SO2Ph-m-H), 7.37 (1 H, perceived t, J = 7.8 Hz, H6),
7.10 (1 H, dt, J = 7.6, 0.8 Hz, H5), 6.28 (1 H, s, H8a), 4.70
(1 H, d, J = 9.3 Hz, H2), 3.63 (3 H, s, N1C(O)OCH3), 3.32 (1
H, d, J = 13.0 Hz, H3A), 3.16 (3 H, s, C(O)OCH3), 2.75 (1 H,
dd, J = 13.0, 9.5 Hz, H3B), 1.75 (3 H, s, C(O)CH3); 13C NMR
(100 MHz, CDCl3) d170.3 (CO(O)CH3), 169.1 (C(O)CH3), 154.5
(N1CO(O)CH3), 144.0 (C7a), 139.9 (SO2Ph-i-C), 132.8 (C4), 131.5
(C6), 129.6 (C3b), 128.8 (2 ¥ SO2Ph-m-C), 127.3 (SO2Ph-p-C),
127.0 (2 ¥ SO2Ph-o-C), 125.2 (C5), 118.3 (C7), 89.7 (C3a), 83.0
(C8a), 59.2 (C2), 52.9 (N1CO(O)CH3), 52.2 (CO(O)CH3), 37.8
General procedure for the formation of 3a-oxygen-substituted
derivatives via solvolysis
Bromide 3 (1 eq.) was added to a stirred suspension of silver
nitrate (1 eq.) in [bmim][BF4] (0.3 M)◦and the alcohol (0.3 M). This
reaction mixture was heated at 110 C in the microwave reactor
for 1.5 h (Table 2). The reaction mixture was extracted from the
ionic liquid with ethyl acetate (4 ¥ 2 mL) and diethyl ether (4 ¥
2 mL). The combined organic layers were then dried (Na2SO4),
filtered and concentrated in vacuo. Purification of the residue by
column chromatography (35% EtOAc in hexanes) afforded the
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desired substitution products (98% purity assessed by NMR and
LC-MS analysis).
gave the desired substitution product (98% purity assessed by
NMR and LC-MS analysis).
Procedure 2 (using KOtBu). A solution of the nucleophile
(eq. as indicated in Table 2 or 3) and KOtBu (eq. as indicated
in Table 2, 1 M sol. in THF) in MeCN (0.12 M) at 0 ◦C was
stirred for 5 min and transferred via cannula into a solution
of bromide 3 (1 eq.) in MeCN (0.13 M) at 0 ◦C. The reaction
mixture was then stirred for the indicated time (Table 3 or 4) at
room temperature and quenched with saturated aqueous NH4Cl
solution. The aqueous layer was separated and extracted with
EtOAc (¥3) and the combined organic layers were dried (MgSO4),
filtered and concentrated in vacuo. Purification of the residue by
column chromatography gave the desired substitution product.
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-3a-benzyloxy-8-(phe-
nylsulfonyl)-2,3,8a-trihydropyrrolo[2,3-b]indole (14). Y = 77% as
a white solid; Rf (40% EtOAc in hexanes) 0.5; m.p. 59–61 ◦C; [a]D
25
+35.0 (c 0.46, CHCl3); IR (nmax/cm-1: 2951, 2364, 1714, 1446,
1
1344, 1163, 1027, 752; H NMR (400 MHz, CDCl3) d7.97 (2 H,
d, J = 7.51 Hz, SO2Ph-o-H), 7.54–7.47 (1 H, m, SO2Ph-p-H),
7.47–7.42 (3 H, m, H7 + SO2Ph-m-H), 7.38 (1 H, perceived t, J =
7.7 Hz, H6), 7.35–7.26 (4 H, m, H4 + Ph-p-H + Ph-m-H), 7.18–
7.14 (3 H, m, H5 + Ph-o-H), 6.34 (1 H, s, H8a), 4.75 (1 H, d, J =
9.1 Hz, H2), 4.34–3.89 (2 H, m, CH2Ph), 3.34 (3 H, s, NCO2CH3),
3.23 (3 H, s, CO2CH3), 2.89 (1 H, d, J = 12.7 Hz, H3A), 2.77 (1
H, dd, J = 12.7, 9.2 Hz, H3B); 13C NMR (100 MHz, CDCl3) d
170.6 (C(O)CH3), 154.5 (NC(O)CH3), 144.2 (C7a), 141.1 (SO2Ph-
i-C), 137.1 (Ph-i-C), 132.6 (SO2Ph-p-C), 131.3 (C6), 129.0 (2 ¥
SO2Ph-m-C), 128.7 (C3b), 128.3 (2 ¥ Ph-m-C), 127.8 (Ph-p-C),
127.7 (2 ¥ Ph-o-C), 126.0 (2 ¥ SO2Ph-o-C), 125.1 (C4), 124.6
(C5), 117.0 (C7), 90.4 (C3a), 81.5 (C8a), 67.1 (CH2Ph), 59.0 (C2),
52.6 (NCO(O)CH3), 52.2 (CO(O)CH3), 39.9 (C3); Elem. Anal.
calculated for C27H26O7N2S: C, 62.06; H, 5.01; N, 5.36%. Found:
C, 62.10; H, 4.94; N, 5.26%; HRMS: Theoretical mass [M+H]+,
523.1539; Measured mass [M+H]+, 523.1540 (d 1 ppm).
General procedure for the preparation of 3a-nitrogen- and
3a-sulfur-substituted derivatives in [bmim][BF4]
Bromide 3 (1 eq.) was added to a stirred solution of the
nucleophile (eq. as indicated in Table 3 or 4) and CsCO3 or
KOtBu (eq. as indicated in Table 3 or 4) in [bmim][BF4] (0.25 M)
at room temperature. The reaction was stirred at 95 ◦C for the
indicated times (Table 3 or 4), when the reaction mixture was
extracted from the ionic liquid with EtOAc (¥4) and Et2O (¥4).
The combined organic layers were then dried (MgSO4), filtered
and concentrated in vacuo. Purification of the residue by column
chromatography gave the desired substitution product (98% purity
assessed by NMR and LC-MS analysis).
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-3a-allyloxy-8-(phenyl-
sulfonyl)-2,3,8a- trihydropyrrolo[2,3-b]indole (15). Y = 77% as a
light yellow oil; Rf (40% EtOAc in hexanes) 0.4; [a]D25 +72.9 (c 0.51,
CHCl3); IR (nmax/cm-1: 2950, 1358, 1750, 1714, 1445, 1344, 1163,
752; 1H NMR (400 MHz, CDCl3) d7.97 (2 H, d, J = 7.4 Hz, SO2Ph-
o-H), 7.55 (1 H, t, J = 7.3 Hz, SO2Ph-p-H), 7.49 (2 H, t, J = 7.4 Hz,
SO2Ph-m-H), 7.41 (1 H, d, J = 8.0 Hz, H7), 7.35 (1 H, perceived t,
J = 7.7 Hz, H6), 7.27 (1 H, d, J = 7.3 Hz, H4), 7.13 (1 H, t, J = 7.5 Hz,
H5), 6.23 (1 H, s, H8a), 5.71 (1 H, ddd, J = 22.4, 10.6, 5.4 Hz, HB),
5.16 (1 H, d, J = 17.0 Hz, HA), 5.10 (1 H, dd, J = 10.4, 1.3 Hz, HA),
4.73 (1 H, d, J = 9.2 Hz, H2), 3.76–3.50 (2 H, m, HC), 3.36 (3 H,
bs, NCO2CH3), 3.21 (3 H, s, CO2CH3), 2.86 (1 H, d, J = 12.7 Hz,
H3A), 2.72 (1 H, dd, J = 12.7, 9.2 Hz, H3B); 13C NMR (100 MHz,
CDCl3) d 170.7 (C(O)CH3), 154.5 (N1CO(O)CH3), 144.2 (C7a),
141.3 (SO2Ph-i-C), 133.8 (CB), 132.7 (SO2Ph-p-C), 131.2 (C6),
129.0 (2 ¥ SO2Ph-m-C), 128.7 (C3b), 126.2 (2 ¥ SO2Ph-o-C), 125.1
(C4), 124.5 (C5), 117.2 (CA), 117.0 (C7), 90.4 (C3a), 81.6 (C8a),
66.1 (CC), 59.0 (C2), 52.6 (NCO(O)CH3), 52.2 (CO(O)CH3), 39.7
(C3); Elem. Anal. calculated for C23H24O7N2S: C, 58.46; H, 5.12; N,
5.93%. Found: C, 58.38; H, 5.00; N, 5.86%; HRMS: Theoretical
mass [M+H]+, 473.1382; Measured mass [M+H]+, 473.1372 (d
2 ppm).
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-3a-morpholino-8-(phe-
nylsulfonyl)-2,3,8a-trihydropyrrolo[2,3-b]indole (22). Y = 94%
(MeCN, Procedure 1), 87% ([bmim][BF4]), as a light yellow solid;
Rf (40% EtOAc, 4% MeOH in hexanes) 0.23; m.p. 73–75 ◦C; [a]D
25
+45.2 (c 0.25, CHCl3); IR (nmax/cm-1: 2952, 1714, 1446, 1342, 1165,
751; 1H NMR (400 MHz, CDCl3) d8.01 (2 H, d, J = 7.1 Hz, SO2Ph-
o-H), 7.63–7.39 (3 H, m, SO2Ph-m-H + SO2Ph-p-H), 7.32–7.28 (2
H, m, H6 +H7), 7.20 (1 H, d, J = 7.4 Hz, H4), 7.09 (1 H, t, J = 7.6 Hz,
H5), 6.27 (1 H, s, H8a), 4.75 (1 H, d, J = 7.3 Hz, H2), 3.67 (4 H,
bs, 2 ¥ OCH2), 3.20 (3 H, s, CO2CH3), 3.06 (3 H, s, NCO2CH3),
2.82 (1 H, d, J = 12.2 Hz, H3A), 2.73 (2 H, bs, NCH2), 2.64 (1
H, dd, J = 12.2, 9.1 Hz, H3B), 2.42 (2 H, bs, NCH2); 13C NMR
(100 MHz, CDCl3) d 170.7 (C(O)CH3), 154.3 (N1CO(O)CH3),
143.9 (C7a), 142.9 (SO2Ph-i-C), 132.4 (SO2Ph-p-C), 130.4 (C6),
129.1 (2 ¥ SO2Ph-m-C), 127.5 (C3b), 125.5 (C4), 125.1 (2 ¥ SO2Ph-
o-C), 123.5 (C5), 116.1 (C7), 81.6 (C8a), 77.2 (C3a), 66.9 (2 ¥
OCH2), 59.5 (C2), 52.1 (2 ¥ CO(O)CH3), 47.5 (2 ¥ NCH2), 38.2
(C3); Elem. Anal. calculated for C24H27O7N3S: C, 57.47; H, 5.43; N,
8.38%. Found: C, 57.47; H, 5.38; N, 8.28%; HRMS: Theoretical
mass [M+H]+, 502.1648; Measured mass [M+H]+, 502.1644 (d
1 ppm).
General procedure for the preparation of 3a-nitrogen- and
3a-sulfur-substituted derivatives in MeCN
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-8-(phenylsulfonyl)- 3a-
(pyrrolidin-1-yl)-2,3,8a-trihydropyrrolo[2,3-b]indole (23).
Y
=
Procedure 1 (using CsCO3). Bromide 3 (1 eq.) was added to
a solution of the amine (4 eq.), CsCO3 (4 eq.) and KI (0.5 eq.)
in MeCN (0.25 M). The reaction was then heated to reflux for
16–18 h, when it was allowed to cool to room temperature and
quenched with brine solution. The aqueous layer was separated
and extracted with EtOAc (¥3) and Et2O (¥3), and the combined
organic layers were dried (MgSO4), filtered and concentrated
in vacuo. Purification of the residue by column chromatography
84% (MeCN, Procedure 1), 78% ([bmim][BF4]), as a light yellow
solid; Rf (40% EtOAc, 4% MeOH in hexanes) 0.2; m.p. 82–84 ◦C;
25
[a]D +32.1 (c 0.43, CHCl3); IR (nmax/cm-1: 2952, 2360, 1715,
1445, 1163, 751; 1H NMR (400 MHz, CDCl3) d8.01 (2 H, d, J =
7.0 Hz, SO2Ph-o-H), 7.61–7.46 (3 H, m, SO2Ph-p-H + SO2Ph-m-
H), 7.30–7.22 (3 H, m, H4 + H6 + H7), 7.07 (1 H, t, J = 7.7 Hz,
H5), 6.27 (1 H, s, H8a), 4.71 (1 H, d, J = 6.8 Hz, H2), 3.20 (3
H, s, NCO2CH3), 3.06 (3 H, s, CO2CH3), 2.91–2.67 (4 H, m,
5300 | Org. Biomol. Chem., 2010, 8, 5294–5303
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◦
H3A + H3B + NCH2), 2.53–2.37 (2 H, m, NCH2), 1.74–1.66 (4 H, m,
CH2CH2); 13C NMR (100 MHz, CDCl3) d 170.9 (C(O)CH3), 154.4
(N1CO(O)CH3), 143.7 (C7a), 143.0 (SO2Ph-i-C), 132.3 (SO2Ph-p-
C), 130.1 (C6), 129.1 (C3b + 2 ¥ SO2Ph-m-C), 125.4 (C4), 125.3
(2 ¥ SO2Ph-o-C), 123.5 (C5), 116.0 (C7), 80.7 (C8a), 75.6 (C3a),
59.4 (C2), 52.0 (2 ¥ CO(O)CH3), 47.3 (2 ¥ NCH2), 38.7 (C3), 23.2
(2 ¥ CH2CH2);Elem. Anal. calculated for C24H27O6N3S: C, 59.37;
H, 5.60; N, 8.65%. Found: C, 59.40; H, 5.57; N, 8.60%; HRMS:
Theoretical mass [M+H]+, 486.1699; Measured mass [M+H]+,
486.1695 (d 1 ppm).
yellow solid; Rf (50% EtOAc in hexanes) 0.25; m.p. 133–134 C;
25
[a]D + 12.9 (c 0.62, CHCl3); IR (nmax/cm-1: 2926, 1716, 1655,
1446, 1352, 1169, 1029, 745; 1H NMR (400 MHz, CDCl3) d ppm
7.77–7.64 (1 H, m, ArH), 7.58–7.40 (4 H, m, ArH), 7.35 (1 H, t,
J = 7.5 Hz, ArH), 7.32–7.27 (3 H, m, ArH), 7.20 (3 H, bs, ArH),
7.14–7.06 (6 H, m, ArH), 6.86 (2 H, d, J = 4.9 Hz, ArH), 6.71
(2 H, d, J = 8.1 Hz, ArH), 6.67 (1 H, s, H8a), 6.23 (1 H, bs, H2¢¢),
5.25 (1 H, d, J = 14.7 Hz, N1¢¢CHAHBPh), 4.93 (1 H, bs, H2),
4.61 (1 H, d, J = 14.1 Hz, N4¢¢CHAHBPMP), 4.18 (1 H, t, J =
4.5 Hz, H6¢), 3.74 (4 H, bs, OCH3, N1¢¢CHAHBPh), 3.65 (4 H, d,
J = 14.3 Hz, N4¢¢CHAHBPMP; bs, N1C(O)OCH3), 3.41 (1 H, dd,
J = 21.7, 8.6 Hz, H3A), 3.40 (1 H, d, J = 17.1 Hz, H5¢¢A), 3.28 (3
H, s, C(O)OCH3), 3.15 (1 H, dd, J = 14.7, 4.1 Hz, HbA), 3.02–2.83
(2 H, m, H3B + HbB), 2.63 (1 H, d, J = 16.73 Hz, H5¢¢B); 13C
NMR (100 MHz, CDCl3) d 170.2 (C(O)OCH3), 166.1 (C3¢¢(O)),
164.3 (C6¢¢(O)), 159.2 (PMP-OMe-i-C), 154.4 (N1C(O)OCH3),
142.7 (C7a), 139.2 (SO2Ph-i-C), 135.4 (N1¢¢CH2Ph-i-C), 134.2
(C7a¢), 132.4 (ArH), 131.5 (ArH), 129.6 (2 ¥ ArH), 129.5 (2 ¥
ArH), 128.8 (2 ¥ ArH), 128.7 (2 ¥ ArH), 128.4 (2 ¥ ArH),
128.0 (ArH), 126.9 (C3a¢/C3b), 126.6 (C3b/C3a¢), 126.2 (ArH),
125.6 (N4¢¢CH2Ph-i-C), 125.3 (ArH), 124.8 (H2¢), 123.1 (ArH),
120.7 (ArH), 119.6 (ArH), 118.5 (ArH), 114.1 (2 ¥ ArH), 111.2
(ArH), 109.0 (C5¢¢), 82.2 (C8a), 73.7 (C3a), 60.0 (C2¢¢), 59.1
(C2), 55.2 (OCH3), 53.1 (N1C(O)OCH3), 52.4 (C(O)OCH3),
48.4 (N4¢¢CH2PMP), 48.3 (C5¢¢), 47.5 (N1¢¢CH2Ph), 38.6 (C3),
27.5 (Cb); Elem. Anal. calculated for C48H45N5O9S: C, 66.42; H,
5.23; N, 8.07%. Found: C, 66.45; H, 5.18; N, 7.98%; HRMS:
Theoretical mass [M+H]+, 868.3016; Measured mass [M+H]+,
868.3047 (d 4 ppm).
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-3a-(benzyl(methyl)-
amino)-8-(phenylsulfonyl)-2,3,8a-trihydropyrrolo[2,3-b]indole (24).
Y = 71% (MeCN, Procedure 1), 77% ([bmim][BF4]), as a light
yellow solid; Rf (40% EtOAc in hexanes) 0.4; m.p. 78–80 ◦C; [a]D
25
+35.0 (c 0.46, CHCl3); IR (nmax/cm-1: 2951, 1712, 1444, 1339, 1161;
1H NMR (400 MHz, CDCl3) d 8.05 (2 H, d, J = 6.8 Hz, ArH),
7.66–7.48 (3 H, m, ArH), 7.40–7.20 (8 H, m, ArH), 7.14 (1 H,
perceived t, J = 7.8 Hz, ArH), 6.37 (1 H, s, H8a), 4.77 (1 H, d,
J = 6.3 Hz, H2), 3.69–3.54 (1 H, m, CHAHBPh), 3.53–3.43 (1 H,
m, CHAHBPh), 3.24 (3 H, s, CO2CH3), 3.09 (3 H, s, NCO2CH3),
2.93 (1 H, bd, J = 12.4 Hz, H3A), 2.82 (1 H, m, H3B), 2.15 (3 H,
bs, NCH3); 13C NMR (100 MHz, CDCl3) d 170.8 (C(O)CH3),
154.3 (N1CO(O)CH3), 143.9 (C7a), 143.0 (Ph-i-C), 138.7 (SO2Ph-
i-C), 132.4 (ArH), 130.3 (2 ¥ ArH), 129.1 (2 ¥ ArH), 128.7 (C3b),
128.5 (2 ¥ ArH), 128.3 (ArH), 127.1 (ArH), 125.2 (3 ¥ ArH),
123.7 (ArH), 116.1 (ArH), 81.2 (C8a), 77.8 (C3a), 59.4 (C2), 56.0
(CH2Ph), 52.1 (2 ¥ CO(O)CH3), 39.3 (C3), 36.0 (NCH3); Elem.
Anal. calculated for C28H29O6N3S: C, 62.79; H, 5.46; N, 7.85%.
Found: C, 62.67; H, 5.40; N, 7.78%; HRMS: Theoretical mass
[M+H]+, 536.1855; Measured mass [M+H]+, 536.1853 (d 1 ppm).
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-3a-[3-(((2S,5S)-1,4,
5-trimethyl-3,6-dioxopiperazin-2-yl)methyl)-1H -indol-1-yl]-8-
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-3a-(1H-indol-1-yl)-8-
(phenylsulfonyl)-2,3,8a-trihydropyrrolo[2,3-b]indole (27).
Y
=
(phenylsulfonyl)-2,3,8a-trihydropyrrolo[2,3-b]indole (25).
Y
=
77% (MeCN, Procedure 2), 62% ([bmim][BF4]), as a light yellow
88% (MeCN, Procedure 2), 71% ([bmim][BF4]), as a light yellow
solid; Rf (35% EtOAc, 4% meOH in hexanes) 0.25; m.p. 210–
solid; Rf (30% EtOAc in hexanes) 0.18; m.p. 156–157 ◦C; [a]D
25
◦
212 C; [a]D +13.1 (c 0.46, CHCl3); IR (nmax/cm-1: 2951, 1716,
25
-77.5 (c 0.24, CHCl3); IR (nmax/cm-1: 2950, 2009, 1702, 1446,
1358, 1259, 1168, 1088, 756; 1H NMR (400 MHz, CDCl3) d ppm
7.80 (1 H, d, J = 7.9 Hz, H7), 7.61 (1 H, d, J = 7.8 Hz, H4¢), 7.50
(1 H, perceived t, J = 7.8 Hz, H6), 7.34 (1 H, d, J = 7.3 Hz, H4),
7.30–7.17 (5 H, m, H7¢ + H6¢ + H5¢ + H5 + SO2Ph-p-H), 7.14 (2
H, d, J = 5.7 Hz, SO2Ph-o-H), 6.91 (2 H, t, J = 7.8 Hz, SO2Ph-
m-H), 6.80 (1 H, s, H8a), 6.09 (1 H, bs, H2¢), 6.03 (1 H, d, J =
3.4 Hz, H3¢), 4.93 (1 H, bs, H2), 3.88 (3 H, bs, NC(O)OCH3), 3.50
(1 H, dd, J = 13.4 Hz, 9.5 Hz, H3A), 3.21 (3 H, s, C(O)OCH3),
2.81 (1 H, d, J = 13.4, H3B); 13C NMR (100 MHz, CDCl3) d 170.4
(C(O)OCH3), 154.8 (C(O)OCH3), 143.2 (C7a),137.9 (C, SO2Ph-
i-C), 133.3 (C7a’), 132.8 (ArH), 131.6 (C6), 130.5 (C3a’), 130.3
(C3b), 128.6 (2 ¥ SO2Ph-m-C), 126.7 (C4), 126.3 (2 ¥ SO2Ph-o-C),
125.5 (C2¢, ArH), 122.3 (ArH), 121.7 (C4¢), 120.4 (ArH), 119.7
(C7), 110.8 (ArH), 102.5 (C3¢), 82.0 (C8a), 73.4 (C3a), 59.2 (C2),
53.2 (CO2Me), 52.2 (CO2Me), 37.1 (C3); Elem. Anal. calculated
for C28H25N3O6S: C, 63.26; H, 4.71; N, 7.90%. Found: C, 63.56;
H, 4.68; N, 7.84%; HRMS: Theoretical mass [M+H]+, 532.1542;
Measured mass [M+H]+, 532.1548 (d 1 ppm).
1651, 1446, 1365, 1169, 748; 1H NMR (400 MHz, CDCl3) d ppm
7.76 (1 H, d, J = 7.4 Hz, ArH), 7.53–7.44 (2 H, m, ArH), 7.31–7.14
(8 H, m, ArH), 6.92 (2 H, t, J = 7.9 Hz, ArH), 6.70 (1 H, s, H8a),
5.96 (1 H, s, H2¢), 4.99–4.79 (1 H, m, H2), 4.12 (1 H, perceived t, J =
4.5 Hz, H2¢¢), 3.78 (3 H, s, NCO(OCH3)), 3.67 (1 H, q, J = 7.01 Hz,
H5¢¢), 3.39 (1 H, dd, J = 13.2, 9.4 Hz, H3A), 3.21 (3 H, s, CO(OCH3)),
3.14 (1 H, dd, J = 14.8, 3.7 Hz, HbA), 2.91 (3 H, s, N4¢¢CH3), 2.86
(1 H, dd, J = 14.9, 5.4 Hz, HbB), 2.81 (3 H, s, N1¢¢CH3), 2.75
(1 H, d, J = 13.0 Hz, H3B), 0.52 (3 H, d, J = 7.0 Hz, H1¢¢¢¢); 13C
NMR (100 MHz, CDCl3) d170.4 (C(O)OCH3), 166.2 (C6¢¢(O)),
165.2 (C3¢¢(O)), 154.5 (NC(O)OCH3), 143.1 (C7a), 138.3 (SO2Ph-
i-C), 133.5 (C7a¢), 132.2 (ArH), 131.8 (ArH), 130.1 (C3a¢), 129.8
(C3b), 128.6 (2 ¥ ArH), 126.3 (2 ¥ ArH), 126.1 (2 ¥ ArH), 125.7
(ArH), 124.8 (C2¢), 123.0 (ArH), 120.8 (ArH), 119.5 (ArH), 119.4
(ArH), 109.2 (C3¢¢), 81.9 (C8a), 73.3 (C3a), 63.3 (C2¢¢), 59.1 (C2),
57.4 (C5¢¢), 53.2 (N1C(O)OCH3), 52.3 (C(O)OCH3), 37.6 (C3),
33.0 (N1¢¢CH3), 31.7 (N4¢¢CH3), 28.3 (Cb), 17.8 (C1¢¢¢¢); Elem. Anal.
calculated for C36H37N5O8S: C, 61.79; H, 5.33; N, 10.01%. Found:
C, 61.75; H, 5.28; N, 9.98%; HRMS: Theoretical mass [M+H]+,
700.2441; Measured mass [M+H]+, 700.2449 (d 1 ppm).
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-3a-[3-(((S)-1-benzyl-
4-(4-methoxybenzyl)-3,6-dioxopiperazin-2-yl)methyl)-1H-indol-1-
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-3a-phenylthio-8-(phe-
nylsulfonyl)-2,3,8a-trihydropyrrolo[2,3-b]indole (28). Y = 80%
(MeCN, Procedure 2), 72% ([bmim][BF4]), as a light yellow solid;
yl]-8-(phenylsulfonyl)-2,3,8a-trihydropyrrolo[2,3-b]indole
(26).
Y = 71% (MeCN, Procedure 2), 66% ([bmim][BF4]), as a light
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Rf (40% EtOAc in hexanes) 0.4; m.p. 68–70 ◦C; [a]D +24.5 (c
in hexanes) 0.45; m.p. 76–78 ◦C; [a]D +120.6 (c 0.40, CHCl3);
25
25
0.35, CHCl3); IR (nmax/cm-1: 2359, 1747, 1714, 1445, 1347, 1167,
751; H NMR (400 MHz, CDCl3) d7.94 (2 H, d, J = 7.5 Hz,
IR (nmax/cm-1: 2952, 1714, 1445, 1348, 1167, 989, 837; H NMR
1
1
(400 MHz, CDCl3) d7.84 (2 H, d, J = 7.34 Hz, SO2Ph-o-H), 7.51–
7.27 (8 H, m, ArH), 7.19 (2 H, d, J = 8.1 Hz, ArH), 6.96 (1
H, perceived t, J = 7.6 Hz, H5), 6.50 (1 H, s, H8a), 4.74 (1 H,
d, J = 8.3 Hz, H2), 3.50 (3 H, bs, N1CO2 CH3), 3.23 (1 H, d,
J = 12.8 Hz, H3A), 3.15 (3 H, s, CO2CH3), 3.11 (1 H, dd, J =
12.8, 9.3 Hz, H3B), 2.40 (3 H, s, ArCH3); 13C NMR (100 MHz,
CDCl3) d169.9 (C(O)CH3), 154.2 (N1CO(O)CH3), 144.8 (MePh-
i-C), 144.1 (C7a), 140.2 (SO2Ph-i-C), 134.6 (SO3Ph-i-C), 132.8
(SO2Ph-p-C), 132.1 (C4), 129.6 (2 ¥ ArH), 128.8 (2 ¥ SO2Ph-
m-C), 127.4 (2 ¥ ArH), 126.8 (C3b), 126.4 (2 ¥ SO2Ph-o-C,
C6), 124.5 (C5), 117.5 (C7), 94.4 (C3a), 83.0 (C8a), 59.0 (C2),
52.9 (N1CO(O)CH3), 52.2 (CO(O)CH3), 38.3 (C3), 21.6 (ArCH3);
Elem. Anal. calculated for C27H26O9N2S2: C, 55.28; H, 4.47; N,
4.78%. Found: C, 55.30; H, 4.40; N, 4.67%; HRMS: Theoretical
mass [M+H]+, 587.1158; Measured mass [M+H]+, 587.1168 (d
2 ppm).
SO2Ph-o-H), 7.52 (1 H, t, J = 7.3 Hz, SO2Ph-p-H), 7.46 (2 H, t,
J = 7.4 Hz, SO2Ph-m-H), 7.40–7.25 (6 H, m, ArH), 7.24–7.17
(1 H, m, ArH), 7.09–6.97 (2 H, m, ArH), 6.27 (1 H, s, H8a),
4.60 (1 H, d, J = 7.01 Hz, H2), 3.32 (3 H, s, NCO2CH3), 3.17
(3 H, s, CO2CH3), 2.86 (1 H, d, J = 12.7 Hz, H3A), 2.64 (1 H,
dd, J = 12.9, 9.1 Hz, H3B); 13C NMR (100 MHz, CDCl3) d 170.7
(C(O)CH3), 154.2 (NC(O)CH3), 142.7 (C7a), 141.6 (SO2Ph-i-C),
136.8 (2 ¥ ArH), 132.6 (ArH), 131.3 (C3b), 130.0 (ArH), 129.9 (2 ¥
ArH), 129.3 (SPh-i-C), 129.2 (ArH), 128.9 (2 ¥ ArH), 126.1 (2 ¥
ArH), 124.6 (ArH), 124.2 (ArH), 116.4 (ArH), 84.4 (C8a), 63.0
(C3a), 59.2 (C2), 52.6 (N1CO(O)CH3), 52.1 (CO(O)CH3), 39.6
(C3); Elem. Anal. calculated for C26H24O6N2S: C, 59.53; H, 4.61;
N, 5.34%. Found: C, 59.47; H, 4.53; N, 5.29%; HRMS: Theoretical
mass [M+Na]+, 547.0974; Measured mass [M+Na]+, 547.0992 (d
3 ppm).
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-3a-hydroxy-8-(phe-
nylsulfonyl)-2,3,8a-trihydropyrrolo[2,3-b]indole (29). Silver tri-
flate (155 mg, 0.60 eq.) and H2O (0.016 mL, 0.90 eq.) were added to
a stirred solution of bromide 3 (150 mg, 0.3 mmol) in [bmim][BF4]
(1.5 mL) at room temperature and the suspension was stirred
for 20 min. The reaction mixture was extracted from the ionic
liquid with EtOAc (4 ¥ 5 mL) and Et2O (4 ¥ 5 mL). The combined
organic layers were then dried (Na2SO4), filtered and concentrated
in vacuo. Purification of the residue by column chromatography
(40% EtOAc, 4% MeOH in hexanes) afforded 9 (104 mg, 79%) as
a white solid. Rf (40% EtOAc, 4% MeOH in hexanes) 0.25; m.p.
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-3a-thiocyanato-8-(phe-
nylsulfonyl)-2,3,8a-trihydropyrrolo[2,3-b]indole (31) and (S)-1,2-
bis(methoxycarbonyl)-8-(phenylsulfonyl)-2,3-dihydropyrrolo[2,3-
b]indole (32). KSCN (58.2 mg, 0.72 mmol) was added to a
solution of tosyl 30 (70.5 mg, 0.12 mmol) in MeCN (1.2 mL)
at room temperature. The reaction was then heated to reflux
for 3 h, when it was allowed to cool to room temperature and
quenched with brine solution (4 mL). The aqueous layer was
separated and extracted with EtOAc (3 ¥ 10 mL) and the combined
organic layers were dried (MgSO4), filtered and concentrated
in vacuo. Purification of the residue by column chromatography
(35% EtOAc in hexanes) gave the desired substitution product 31
(34.2 mg, 60%) as a light yellow oil and the elimination product
32 (3.5 mg, 7%) as a light yellow oil.
184–186 ◦C; [a]D +123.3 (c 0.26, CHCl3); IR (nmax/cm-1: 3354,
25
1
1737, 1686, 1448, 1151, 757; H NMR (400 MHz, CDCl3) dPpm
7.79 (2H, d, J = 7.6 Hz, SO2Ph-o-H), 7.57–7.52 (2 H, m, SO2Ph-
p-H + H7), 7.44 (2 H, t, J = 7.7 Hz, SO2Ph-m-H), 7.42–7.36 (1 H,
m, H6), 7.25 (1 H, d, J = 7.6 Hz, H4), 7.16 (1 H, perceived t, J =
7.5 Hz, H5), 5.88 (1 H, s, H8a), 4.64 (1 H, d, J = 8.2 Hz, H2), 3.60
(3 H, bs, N1C(O)OCH3), 3.14 (3 H, s, C(O)OCH3), 2.76 (1 H, d,
J = 12.8 Hz, H3A), 2.66 (1 H, dd, J = 12.8, 9.2 Hz, H3B); 13C NMR
(100 MHz, CDCl3) d170.6 (CO(O)CH3), 154.5 (N1CO(O)CH3),
143.0 (C7a), 139.2 (SO2Ph-i-C), 133.2 (SO2Ph-p-C), 133.0 (C3b),
131.3 (C5), 129.0 (2 ¥ SO2Ph-m-C), 127.0 (2 ¥ SO2Ph-o-C), 125.7
(C6), 124.2 (C4), 119.0 (C7), 85.6 (C3a), 84.3 (C8a), 58.9 (C2),
52.8 (N1CO(O)CH3), 52.1 (CO(O)CH3), 38.9 (C3); Elem. Anal.
calculated for C20H20N2O7S: C, 55.55; H, 4.66; N, 6.48%. Found:
C, 55.56; H, 4.71; N, 6.39%;HRMS: Theoretical mass [M+H]+,
433.1069; Measured mass [M+H]+, 433.1060 (d 2 ppm).
31. Rf (40% EtOAc in hexanes) 0.3; m.p. 122–123 ◦C; [a]D
25
+61.7 (c 0.34, CHCl3); IR (nmax/cm-1: 2371, 1717, 1544, 1453,
1
1222, 773; H NMR (400 MHz, CDCl3) d ppm 7.82 (2 H, d, J =
7.6 Hz, 2 ¥ SO2Ph-o-C), 7.63 (1 H, d, J = 8.1 Hz, H7), 7.56 (1
H, t, J = 7.4 Hz, SO2Ph-p-C), 7.47–7.42 (3 H, m, 2 ¥ SO2Ph-m-
C, H6), 7.24–7.13 (2 H, m, H5 + H4), 6.23 (1 H, s, H8a), 4.73 (1
H, d, J = 4.1 Hz, H2), 3.67 (3 H, s, N1C(O)OCH3), 3.17 (3 H, s,
C(O)OCH3), 3.13 (1 H, dd, J = 21.2, 10.3 Hz, H3A), 2.96 (1 H,
dd, J = 13.1, 9.0 Hz, H3B); 13C NMR (100 MHz, CDCl3) dPpm
169.8 (CO(O)CH3), 154.0 (N1CO(O)CH3), 143.0 (C7a), 139.6
(SO2Ph-i-C), 133.6 (SO2Ph-p-C), 132.3 (C6), 129.3 (2 ¥ SO2Ph-
m-C), 127.8 (C3b), 126.9 (2 ¥ SO2Ph-o-C), 125.9 (ArH), 124.4
(ArH), 118.9 (H7), 109.0 (SCN), 84.0 (C8a), 62.9 (C3a), 59.1
(C2), 53.2 (N1CO(O)CH3), 52.4 (CO(O)CH3), 39.9 (C3); Elem.
Anal. calculated for C21H19N3O6S2: C, 53.27; H, 4.04; N, 8.87%.
Found: C, 53.19; H, 3.98; N, 8.78%; HRMS: Theoretical mass
[M+H]+, 474.0793; Measured mass [M+H]+, 474.0781 (d 3 ppm).
(2S,3aS,8aS)-1,2-Bis(methoxycarbonyl)-3a-tosyloxy-8-(phe-
nylsulfonyl)-2,3,8a-trihydropyrrolo[2,3-b]indole (30). To a stirred
solution of hydroxo derivative 29 (59.2 mg, 0.13 mmol) and DMAP
(10 mg, 0.08 mmol) in CH2Cl2 (1 mL) at room temperature
was added tosyl chloride (182 mg, 0.96 mmol), followed by
the addition of Et3N (0.13 mL, 0.95 mmol). The reaction was
stirred for 24 h at room temperature and then quenched with
saturated aqueous NH4Cl solution (2 mL). The aqueous layer was
separated and extracted with CH2Cl2 (3 ¥ 8 mL) and the combined
organic layers were dried (MgSO4), filtered and concentrated
in vacuo. Purification of the residue by column chromatography
(35% EtOAc, 2% MeOH in hexanes) gave tosylated derivative
30 (47.5 mg, 60%) as a white solid. Rf (38% EtOAc, 2% MeOH
25
32. Rf (40% EtOAc in hexanes) 0.55; [a]D -142.3 (c 0.29,
CHCl3); IR (nmax/cm-1: 2951, 2358, 1718, 1623, 1448, 1313, 1180,
753; 1H NMR (400 MHz, CDCl3) d 7.95 (1 H, dd, J = 7.0, 1.6 Hz,
H7), 7.81 (2 H, d, J = 7.5 Hz, SO2Ph-o-H), 7.41 (1 H, t, J = 7.5 Hz,
SO2Ph-p-H), 7.29 (2 H, t, J = 7.9 Hz, SO2Ph-m-H), 7.20–7.05 (3
H, m, H4 + H5 + H6), 5.41 (1 H, dd, J = 9.8, 2.1 Hz, H2), 3.91 (3
H, s, N1CO2CH3), 3.87 (3 H, s, CO2CH3), 3.44 (1 H, dd, J = 15.5,
9.8 Hz, H3A), 3.05 (1 H, dd, J = 15.5, 2.1 Hz, H3B); 13C NMR
(100 MHz, CDCl3) d171.6 (C(O)CH3), 155.3 (N1CO(O)CH3),
5302 | Org. Biomol. Chem., 2010, 8, 5294–5303
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142.2 (C8a), 139.7 (C7a), 135.9 (SO2Ph-i-C), 133.6 (SO2Ph-p-C),
128.5 (2 ¥ SO2Ph-m-C), 127.5 (2 ¥ SO2Ph-o-C), 126.8 (C3b), 124.9
(ArH), 123.3 (ArH), 118.2 (ArH), 116.9 (H7), 111.8 (C3a), 67.9
(C2), 53.9 (N1CO(O)CH3), 52.9 (CO(O)CH3), 28.7 (C3); HRMS:
Theoretical mass [M+H]+, 415.0964; Measured mass [M+H]+,
415.0965 (d 1 ppm).
15 T. Newhouse, C. A. Lewis, K. J. Eastman and P. S. Baran, J. Am. Chem.
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Acknowledgements
We thank Cancer Research UK for financial support to these
studies (C180/A9327 to DET).
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30 Prepared as reported by Reiner and co-workers.
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