Exploratory studies toward a total synthesis of the marine ascidian metabolite perophoramidine

Article abstract of DOI:10.1016/j.tet.2008.10.060

A strategy for a total synthesis of the marine alkaloid perophoramidine has been investigated. Key steps which have been tested include a tandem intramolecular Heck/carbonylation reaction and a stereoselective allylation of a pentacyclic δ-lactam to produ

Full text of DOI:10.1016/j.tet.2008.10.060

Tetrahedron 65 (2009) 6712–6719
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Exploratory studies toward a total synthesis of the marine ascidian metabolite
perophoramidine
*
Michael A. Evans, Joshua R. Sacher, Steven M. Weinreb
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 July 2008
Received in revised form 17 October 2008
Accepted 21 October 2008
Available online 25 October 2008
A strategy for a total synthesis of the marine alkaloid perophoramidine has been investigated. Key steps
which have been tested include a tandem intramolecular Heck/carbonylation reaction and a stereo-
selective allylation of a pentacyclic
d-lactam to produce the C-4/20 vicinal quaternary centers having the
requisite relative configuration of the metabolite.
Ó 2008 Published by Elsevier Ltd.
Keywords:
Natural product
Alkaloid
Heck reaction
Carbonylation
Amidines
1. Introduction and background
Funk and Fuchs have successfully implemented these ideas
and completed the first total synthesis of racemic perophor-
amidine (1) via a biomimetically-patterned route.7a In addi-
tion, Rainier and co-workers have recently reported an
approach to dehaloperophoramidine.8,9 In this paper we de-
scribe our ongoing efforts toward a new total synthesis of
perophoramidine.
In 2002, Ireland and co-workers reported the isolation of an
unusual heterocyclic compound, perophoramidine, from the
marine ascidian Perophora namei collected in the Philippines.1
Based upon spectral analysis, this metabolite was assigned
structure 1, which contains among other notable features six
rings including two amidine units, two chlorines, and a bromine.
In addition, perophoramidine has two adjacent quaternary car-
bons at C-4/20. Perophoramidine has cytotoxicity against the
HCT116 colon carcinoma cell line and also induces apoptosis via
PARP cleavage.
This alkaloid is related in structure to the communesin family of
metabolites, exemplified by communesins A (2) and B (3), which
were isolated by Numata et al. in 1993 from a Penicillium mold
found growing on the marine alga Enteromorpha intestinalis.2–4 An
interesting feature of the communesins is that the contiguous
quaternary centers at C-7/8 are opposite in relative configuration to
the corresponding ones in perophoramidine (1). Communesins A
and B were found to have in vitro cytotoxic activity against P-388
lymphoid leukemia cells (Fig. 1).2
2. Synthetic plan
We have recently published the development of a general
strategy involving a tandem halogen-selective intramolecular Heck
reaction/carbonylation sequence10 to construct the C/E/F portion
and one of the quaternary centers of the communesins and per-
ophoramidine.11 It is our plan to apply such methodology to spe-
cifically access perophoramidine (1). Thus, we originally proposed
to effect a Heck cyclization/carbonylation beginning with dichloro
iodo substrate 7 to produce
compound would then be transformed into pentacyclic
g
-lactam ester 6 (Scheme 1).11c This
-lactam
d
amidine 5, and the lactam enolate would be allylated to produce
key intermediate 4. Based upon a close analogy in the work of the
Rainier group,8 we anticipated that this alkylation would occur
stereoselectively from the least hindered face of the molecule to
provide the desired perophoramidine relative stereochemistry at
the two adjacent C-4/20 quaternary centers. It should then be
The closely related perophoramidine and the communesin
structures are presumed to arise via a common biogenetic
pathway, independently proposed by Stoltz5,6 and by Funk.7
possible to transform the allyl d-lactam 4 to the natural product 1.
In this paper we report some of our exploratory studies on imple-
menting the strategy outlined in Scheme 1.
* Corresponding author. Tel.: þ1 814 863 0189; fax: þ1 814 863 8403.
E-mail address: smw@chem.psu.edu (S.M. Weinreb).
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.10.060

M.A. Evans et al. / Tetrahedron 65 (2009) 6712–6719
6713
O
H
Me
O
H
Me
Me
N
N
7
N
H
N
B
H
F
A
N
N
A
4
C
O
Br
8
O
C
B
Cl
D
G
20
D
10
F
E
N
NH
H
NH
E
N
N
N
Me
H
H
Cl
Me
3 communesin B
1 perophoramidine
2 communesin A
Figure 1. Structures of perophoramidine and the communesins.
P'
N
P'
N
carbonylation was investigated with each of these systems using
the standard set of experimental conditions shown. These explor-
atory reactions were generally conducted on approximately 50 mg
scales. Since products 14, 15 and the starting material 13 were not
easily separable, the reaction mixtures were first partially purified
by column chromatography, and the resulting products were ana-
lyzed by proton NMR. In the case of the 4,6-dichlorinated F-ring
substrates in entries 1 and 2, a large variation was found with the
two amide protecting groups. While the MOM-protected system 13
did give some of the desired diastereomeric ester products 14,
a significant amount of reductive Heck product 15 was usually
formed (entry 1).13 To our surprise, however, the analogous SEM-
protected unsaturated amide was unreactive in the Heck process
(entry 2). In the case of the non-chlorinated substrates in entries 3
and 4, the cyclizations tended to be very slow and significant
amounts of starting material were recovered. This result may be
due to a sluggish oxidative insertion of Pd0 into the iodo com-
pounds lacking the electron withdrawing chlorine substituents.
The C-4 monochloro substrates in entries 5 and 6 both provided
significant amounts of the desired Heck/carbonylation products 14
with lesser amounts of reductive Heck products 15 and starting
materials. It is possible that the dichloro substrates have an un-
favorable amide conformation for the cyclization relative to the
monochloro systems due to steric interactions between the C-6
halogen and the amide nitrogen protecting group. The slightly
larger SEM group (entry 2) may experience an enhanced steric ef-
fect relative to the MOM compound (entry 1). From a preparative
point of view, the SEM-protected system in entry 6 proved to be the
most useful (vide infra). It should be noted that Fuchs and Funk7a
have reported the feasibility of effecting a late-stage F-ring chlori-
nation in their total synthesis of perophoramidine (1).
O
O
H
Cl
Cl
1
N
P
N
Br
N
P
N
Br
Cl
Cl
4
5
O
OMe
NO2
TBSO
Cl
I
O
NO2
Cl
N
P
Cl
N
P
O
Br
Br
Cl
OTBS
7
6
Scheme 1. Retrosynthetic strategy.
3. Results and discussion
In our recent paper we reported that the tandem intramolecular
Heck cyclization/carbonylation of unsaturated amide 7 (P¼MOM)
afforded the desired tricyclic ester 6 in moderate yield along with
some reductive (non-carbonylated) Heck product.11c It was sub-
sequently found, however, that this transformation is quite capri-
cious, particularly upon scaleup. Therefore, we decided to first
explore some Heck/carbonylation reactions of related systems with
varied substitution in the F-ring as well as different protecting
groups on the nitrogen of the
a,b-unsaturated amide. The sub-
strates for this study were prepared as is exemplified for the iodo
chloro unsaturated amide 12 in Scheme 2. Thus, condensation of
the aluminum amide reagent12 derived from commercially avail-
able aniline 8 with unsaturated lactone 911c afforded amide 10 in
high yield. The alcohol functionality of 10 was protected as silyl
ether 11 and the amide nitrogen was N-alkylated with SEM-Cl to
produce 12.
Since some of the dichloro lactone 16 was available from our
earlier work,11c we initially explored a few further transformations
of this compound (Scheme 3). Thus, the lactone 16 was opened
with benzylamine in refluxing toluene to afford hydroxyamide 17
as a mixture of diastereomers. The alcohol functionality of 17 was
initially converted to the tosylate 18, and then to the bromide 19. In
an attempt to intramolecularly N-alkylate the secondary amide
functionality of 19 to produce the corresponding N-benzyllactam
(cf. 5), the compound was heated at 60 ꢀC with cesium carbonate in
DMF. To our surprise, the products of this reaction proved to be
a 1:5 mixture of the epimeric pentacyclic lactams 20 and 21. Re-
moval of the MOM protecting group from the major isomer 21
AlMe3
CH2Cl2
rt, 83%
NO2
Cl
I
O
O
O
NO2
Cl
I
+
N
H
NH2
Br
Br
9
8
10
OH
Cl
I
1) TBSCl, imid.
DMF, rt, DMAP
97%
O
NO2
provided g-lactam 22, whose structure was firmly established by
X-ray crystallography.14
N
R
In order to further explore the elaboration of a Heck/carbonyl-
ation product toward perophoramidine, we opted to continue the
route with the monochloro-N-SEM compound in entry 6 (Table 1)
since we could prepare this intermediate in reasonable quantity.
Therefore, iodo chloro substrate 12 (w6.6 g) was subjected to the
standard intramolecular Heck/carbonylation conditions (Scheme
4). However, since the desired product was not separable from the
starting material or the reductive Heck product, the TBS protecting
group was first removed from the crude material to afford ester
2) LiHMDS
SEMCl, THF
0 °C, 93%
Br
OTBS
11 R = H
12 R = SEM
Scheme 2.
Using this same approach, the substrates 13 shown in Table 1
were prepared. The tandem intramolecular Heck cyclization/

6714
M.A. Evans et al. / Tetrahedron 65 (2009) 6712–6719
Table 1
Tandem Heck reaction/carbonylation
O
OMe
NO2
X1
4
I
TBSO
Pd2(dba)3 (10%)
P(o-tol)3 (40%)
TEA (3 eq)
TBSO
X2
O
NO2
NO2
F
6
X2
X1
X
N
P
+
F
Bu4NBr, CO (1 atm)
DMA:MeOH (5:1)
85 °C, 20 h
Br
N
P
O
Br
N
P
O
Br
OTBS
X2
13
15
14
Entry
X1
X2
P
14 (%)
15 (%)
13 (%)
1
2
3
4
5
6
Cl
Cl
H
H
Cl
Cl
Cl
Cl
H
H
H
H
MOM
SEM
MOM
SEM
MOM
SEM
30
Trace
25
28
57
25
d
d
11
31
23
45
90
75
61
12
24
53
O
O
BnNH2
1) TsCl, TEA
O
NHBn
NO2
O
NHBn
NO2
HO
X
NO2
PhMe
DMAP, CH2Cl2
89%
Cl
110 °C
Cl
Cl
76%
2) LiBr, DMF
N
O
Br
70%
N
O
Br
N
MOM
O
Br
Cl
MOM
Cl
MOM
Cl
17 (1.5:1 dr)
16
18 X = OTs (1.4:1 dr)
19 X = Br (3:1 dr)
Br
Br
Br
O
TFA
CH2Cl2
99%
Cs2CO3
DMF, 60 °C
67%
NO2
O
NO2
O
NO2
O
+
Cl
Cl
Cl
N
N
N
O
N
O
Bn
Bn
Bn
N
N
MOM
20
MOM
21
H
Cl
Cl
Cl
(1:5)
22(X-ray)
Scheme 3.
1) Pd2(dba)3,P(o-Tol)3
TEA, Bu4NBr, CO
5:1 DMA: MeOH
85 °C, 48 h
O
OMe
NO2
O
OMe
NO2
HO
O
Dess-
Martin
CH2Cl2
1) PMBNH2
CH2Cl2
Cl
Cl
2) NaBH4
12
3) PhMe
2) TBAF, THF, rt
45% (two steps)
N
SEM
23
O
Br
N
SEM
O
Br
110 °C
85% (three steps)
24
PMB
N
PMB
N
PMB
N
Pt/C
PhMe
40 atm
98%
O
H
O
H
O
NO2
NO2
NH2
H
Cl
Cl
+
Cl
N
SEM
O
Br
N
O
Br
N
SEM
O
Br
K2CO3
DMF, rt
SEM
26
25
27
Scheme 4.
alcohol 23, which could then be isolated by column chromatogra-
phy as a 1:1 mixture of diastereomers in 45% total yield based on
iodide 12.
To continue the synthesis, alcohol 23 was oxidized with the
Dess–Martin periodinane to aldehyde 24 (1:1 diastereomer mix-
ture), which was subjected to a reductive amination sequence with
p-methoxybenzylamine. The resulting aminoester was then ther-
mally cyclized to afford a chromatographically separable mixture of
diastereomers. Although the trans isomer 25 was not useful for
formation of the lower amidine (vide infra), it was found that the
cis and trans isomers can be easily equilibrated with potassium
carbonate in DMF at rt. For example, a 2:1 mixture of 25:26 can be
equilibrated to a 2:1 mixture favoring the desired cis isomer 26 (see
Section 5). It should be noted that a similar epimerization was re-
quired in the Rainier work prior to formation of the lower amidine.8
Catalytic hydrogenation of the nitro group of 26 over 5% platinum
on carbon then afforded the aniline 27 in high yield.
PMB-protected
d-lactams 25 and 26 as a 1:1.66 mixture of

M.A. Evans et al. / Tetrahedron 65 (2009) 6712–6719
6715
PMB
N
PMB
N
TsOH
PhMe
85 °C
1) BF3·Et2O
CH2Cl2
0 °C
O
H
O
H
NH2
Cl
Cl
27
2) ethylene
diamine
DMF,45 °C
86%
N
H
N
Br
N
H
O
Br
28
29
Scheme 5.
PMB
N
PMB
N
O
O
H
I
Cl
Cl
LiHMDS
THF, -78 °C
83%
NaH
N
N
SEM
Br
N
N
Br
SEMCl
THF,rt
SEM
30
32
+
29
(5:1)
PMB
N
65%
PMB
N
O
O
H
I
Cl
Cl
LiHMDS
THF, -78 °C
N
N
SEM
Br
N
SEM
N
Br
33
31
Scheme 6.
Attempts were initially made to directly cyclize the SEM-pro-
tected cis- -lactam aniline 27 to the lower amidine, but we were
5. Experimental
5.1. General methods
g
unable to effect this transformation cleanly. Therefore, using
a modification of literature procedures,15 the SEM groupof protected
lactam 27 was removed via a two-step sequence to afford NH lactam
28 (Scheme 5). We were pleased to find that this compound cyclized
smoothly to the desired pentacyclic lactam amidine 29 simply by
heating with p-toluenesulfonic acid in toluene (86% overall yield
from lactam 27). However, it was observed that the corresponding
trans lactam aniline prepared from intermediate 25 could not be
cyclized to generate the lower amidine under similar conditions,
perhaps for reasons of strain. In addition, we have been unable to
effect an in situ epimerization/cyclization of the trans lactam aniline.
Our next goal was to introduce the C4 quaternary center with the
requisite perophoramidine configuration into this pentacyclic sys-
tem. To do so, however, it was first necessary to protect the amidine
functionality. Thus, treatment of 29 with SEMCl in the presence of
sodium hydride led to a separable 5:1 mixture of N-SEM amidines 30
and 31 (Scheme 6). The major lactam isomer 30 can be deprotonated
with lithium hexamethyldisilazide followed by addition of allyl io-
dide, which led to a single alkylation product 32 in good yield.
Allylation of the minor SEM-protected isomer 31 under the same
reaction conditions afforded the desired product 33 in similar yield.
The stereochemistry of the alkylation products was assigned as
shown byanalogywith theworkof Rainieret al.,8 and bycomparison
with spectra of a similar compound obtained in their work.
All non-aqueous reactions were carried out under a positive
atmosphere of argon in flame-dried glassware unless otherwise
noted. Anhydrous THF, CH2Cl2, and toluene were obtained from
a solvent dispensing system. All other solvents and reagents were
used as obtained from commercial sources without further purifi-
cation unless noted. 1H and 13C NMR spectra were recorded on
Bruker DPX-300, CDPX-300, AMX-360 or DRX-400 MHz spec-
trometers. Infrared spectral data were recorded using a Perkin–
Elmer 1600 FTIR. Flash column chromatography was performed
using Sorbent Technologies silica gel 60 (230–400 mesh).
5.1.1. (E)-2-(4-Bromo-2-nitrobenzylidene)-N-(4-chloro-2-
iodophenyl)-4-hydroxybutanamide (10)
A mixture of lactone 911c (15.20 g, 51.00 mmol), 4-chloro-2-
iodoaniline (8, 13.08 g, 51.00 mmol), and dichloromethane
(360 mL) was cooled to 0 ꢀC, and 2.0 M trimethylaluminum in
hexanes (40.8 mL, 81.6 mmol) was slowly added. The reaction
mixture was stirred for 24 h and gradually warmed to rt. The
mixture was then slowly poured into ice in small aliquots. The thick
slurry was diluted with a 3:3:1 solution of brine, water, and 1 N HCl.
The aqueous layers were thoroughly extracted with THF. The or-
ganic layers were washed with brine, dried over MgSO4, and the
solvent was removed in vacuo. The resulting solid was triturated
using 50 mL of dichloromethane. The title compound 10 was
obtained as an insoluble, bright yellow solid (23.26 g, 83%). Rf¼0.13
4. Conclusion
We have tested the feasibility of executing the strategy outlined
in Scheme 1 for synthesis of perophoramidine (1). The optimum
substrate for the key tandem Heck cyclization/carbonylation step
proved to be the F-ring C-4 monochlorinated system 12. Therefore
it will be necessary to introduce the remaining C-6 chlorine at a late
stage in the synthesis, as was done by Fuchs and Funk.7 It is also
possible to prepare and stereoselectively alkylate a pentacyclic
(2:1 hexanes/EtOAc); 1H NMR (THF-d8, 360 MHz)
d 8.33 (d,
J¼2.0 Hz, 1H), 8.10 (d, J¼8.8 Hz, 1H), 7.87–7.94 (m, 2H), 7.71
(d, J¼8.4 Hz, 1H), 7.69 (s, 1H), 7.38 (dd, J¼8.8, 2.4 Hz, 1H), 3.64 (t,
J¼6.1 Hz, 2H), 2.60 (t, J¼6.0 Hz, 2H).
5.1.2. (E)-2-(4-Bromo-2-nitrobenzylidene)-4-(tert-butyldimethyl
silyloxy)-N-(4-chloro-2-iodophenyl)butanamide (11)
amidine
d
-lactam like 30 to form the contiguous quaternary C-4/20
A mixture of alcohol 10 (5.00 g, 9.1 mmol), imidazole (926 mg,
13.6 mmol), tert-butyldimethylsilyl chloride (1.57 g, 10.4 mmol),
and DMAP (110 mg, 0.91 mmol) in DMF (90 mL) was stirred at rt for
2 h. The mixture was then poured into aqueous NH4Cl and was
centers of the alkaloid. Our intention is to utilize what we have
learned from the work outlined here to complete a total synthesis
of perophoramidine.

6716
M.A. Evans et al. / Tetrahedron 65 (2009) 6712–6719
extracted with EtOAc. The organic extract was washed with brine,
dried over MgSO4, and the solvent was removed in vacuo. The crude
residual oil was purified via column chromatography, eluting with
9:1 hexanes/EtOAc. The silyl ether 11 was isolated as a viscous
yellow oil (5.83 g, 97%). Rf¼0.65 (2:1 hexanes/EtOAc); 1H NMR
MgSO4, and the solvent was removed in vacuo. The crude residual
oil was purified by column chromatography, eluting with 3:1
hexanes/EtOAc. The tosylate 18 was isolated as a white solid as an
inseparable 1.4:1 mixture of diastereomers (206.1 mg, 89%).
Rf¼0.64 (1:1 hexanes/EtOAc); 1H NMR (CDCl3, 300 MHz)
d 8.00 (d,
(CDCl3, 300 MHz)
d
8.31 (d, J¼2.0 Hz, 1H), 8.28 (br s, 1H), 8.25 (d,
J¼1.9 Hz, 0.41H), 7.87 (d, J¼1.9 Hz, 0.59H), 7.66–7.84 (m, 1.59H),
7.39–7.58 (m, 3H), 6.98–7.38 (m, 8H), 6.84 (d, J¼2.0 Hz, 0.41H), 6.46
(t, J¼5.7 Hz, 0.59H), 6.18 (t, J¼5.7 Hz, 0.41H), 5.22 (d, J¼11.0 Hz,
0.41H), 5.15 (d, J¼11.0 Hz, 0.41H), 5.12 (d, J¼10.9 Hz, 0.59H), 5.00 (d,
J¼10.9 Hz, 0.59H), 4.71 (s, 0.59H), 4.51 (s, 0.41H), 4.38–4.49 (m, 1H),
4.09–4.30 (m, 1H), 3.43–3.77 (m, 2H), 3.32 (s, 1.23H), 2.99 (s, 1.77H),
2.79 (dt, J¼14.2, 4.9 Hz, 0.41H), 2.41 (s, 3H), 2.18–2.38 (m, 1.59H).
J¼8.9 Hz, 1H), 7.74–7.83 (m, 2H), 7.62 (s, 1H), 7.57 (d, J¼8.3 Hz, 1H),
7.34 (dd, J¼8.8, 2.4 Hz, 1H), 3.72 (t, J¼5.9 Hz, 2H), 2.66 (t, J¼5.8 Hz,
2H); 13C NMR (CDCl3, 75 MHz)
d 166.7, 148.0, 138.2, 138.0, 137.1,
136.5, 133.1, 131.2, 130.2, 129.3, 128.0, 122.5, 90.4, 61.5, 31.3, 25.9,
18.3, ꢁ5.5; HRMS-ES [MþH]þ calcd for C23H27BrClIN2O4Si:
664.9736, found: 664.9735.
5.1.3. (E)-2-(4-Bromo-2-nitrobenzylidene)-4-(tert-
5.1.6. N-Benzyl-2-(4-bromo-2-nitrophenyl)-2-(3-(2-bromoethyl)-
butyldimethylsilyloxy)-N-(4-chloro-2-iodophenyl)-N-((2-
5,7-dichloro-1-(methoxymethyl)-2-oxoindolin-3-yl)acetamide (19)
(trimethylsilyl)ethoxy)methyl)butanamide (12)
A mixture of tosylates 18 (31.1 mg, 39.3 mmol), lithium bromide
A solution of amide 11 (6.04 g, 9.07 mmol) in THF (91 mL) was
cooled to ꢁ78 ꢀC and 1.0 M lithium bis-(trimethylsilyl)amide in THF
(9.5 mL, 9.5 mmol) was slowly added over 10 min. After stirring the
mixture for an additional 20 min, 2-(trimethylsilyl)ethoxymethyl
chloride (2.01 mL, 11.33 mmol) was added. The reaction mixture
was then warmed to 0 ꢀC. After stirring for 2 h, the mixture was
poured into aqueous NH4Cl and was extracted with EtOAc. The
organic layers were washed with brine, dried over MgSO4, and the
solvent was removed in vacuo. The crude residual oil was purified
via column chromatography, eluting with 9:1 hexanes/EtOAc. The
title compound 12 was isolated as a viscous yellow oil (6.67 g, 93%).
Rf¼0.44 (5:1 hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz, broad due
(27.3 mg, 0.314 mmol), and DMF (0.69 mL) was heated at 70 ꢀC for
3 h. The mixture was then cooled to rt, poured into water, and
extracted with EtOAc. The combined organic layers were washed
with brine, dried over MgSO4, and the solvent was removed in
vacuo. The crude oil was purified by column chromatography,
eluting with 5:1 hexanes/EtOAc. The bromide 19 was isolated as
a white solid as an inseparable 3:1 mixture of diastereomers
(19.3 mg, 70%). Rf¼0.52 (2:1 hexanes/EtOAc); 1H NMR (CDCl3,
300 MHz)
d
8.02 (s, 0.25H), 7.95 (d, J¼2.0 Hz, 0.75H), 7.82 (d,
J¼2.1 Hz, 0.75H), 7.74 (dd, J¼8.5, 2.1 Hz, 0.75H), 7.20–7.35 (m, 5H),
7.00–7.13 (m, 2H), 6.92 (d, J¼2.0 Hz, 0.25H), 6.39 (t, J¼5.8 Hz,
0.75H), 6.13 (t, J¼5.8 Hz, 0.25H), 5.31 (d, J¼10.7 Hz, 0.25H), 5.21 (d,
J¼10.7 Hz, 0.25H), 5.20 (d, J¼10.7 Hz, 0.75H), 5.12 (d, J¼10.7 Hz,
0.75H), 4.76 (s, 0.75H), 4.62 (s, 0.25H), 4.39–4.54 (m, 1H), 4.14–
4.29 (m, 1H), 3.33 (s, 0.75H), 3.08 (s, 2.25H), 2.30–2.95 (m, 4H);
LRMS (ESþ) calcd for C27H23Br2Cl2N3O5 [MþNa]þ: 719.9, found:
719.9.
to amide rotamers)
d 8.02–8.34 (m, 1H), 7.88 (br s, 1H), 6.65–7.80
(m, 5H), 5.13–5.89 (m, 1H), 4.65 (br s, 1H), 3.28–4.01 (m, 4H), 2.10–
2.76 (m, 2H), 0.75–0.94 (m, 2H), 0.86 (s, 9H), 0.03 (s, 6H), ꢁ0.07 (br
s, 9H); HRMS-ES [MþH]þ calcd for C29H42BrClIN2O5Si2: 794.0527,
found: 794.0528.
5.1.4. N-Benzyl-2-(4-bromo-2-nitrophenyl)-2-(5,7-dichloro-
3-(2-hydroxyethyl)-1-(methoxymethyl)-2-oxoindolin-3-yl)-
acetamide (17)
5.1.7. Conversion of bromides 19 to lactams 20 and 21
A mixture of bromides 19 (19.3 mg, 27.5 mmol), cesium car-
bonate (44.8 mg, 0.138 mmol), and DMF (0.55 mL) was heated at
60 ꢀC for 1 h. The mixture was then cooled to rt, poured into water,
and extracted with EtOAc. The organic extract was washed with
brine, dried over MgSO4, and the solvent was removed in vacuo.
The crude residual oil was purified via column chromatography,
eluting with 5:1 hexanes/EtOAc to afford 20 and 21 as a 1:5
mixture of diastereomers (11.4 mg, 67%). 1H NMR (CDCl3,
To lactone 1611c (86.9 mg, 0.16 mmol) were added toluene
(2.8 mL) and benzylamine (61 mL, 0.56 mmol), and the mixture was
stirred at 110 ꢀC for 6 h. The mixture was cooled, poured into water,
and was extracted with EtOAc. The organic extract was washed
with brine, dried over MgSO4, and the solvent was removed in
vacuo. The crude residual oil was purified via column chromato-
graphy, eluting with 2.5:1 hexanes/EtOAc. The title compound 17
was isolated as an off-white foam as an inseparable 1.5:1 mixture of
diastereomers (86.5 mg, 76%). Rf¼0.33 (1:1 hexanes/EtOAc); 1H
300 MHz) (major diastereomer)
d
8.05 (d, J¼2.0 Hz, 1H), 8.42 (dd,
J¼8.4, 2.0 Hz, 1H), 7.20–7.42 (m, 5H), 6.97 (d, J¼2.1 Hz, 1H), 6.47
(d, J¼8.4 Hz, 1H), 6.25 (d, J¼2.0 Hz, 1H), 4.90 (d, J¼9.8 Hz, 1H), 4.8
(d, J¼15.6 Hz,1H), 4.72 (d, J¼15.6 Hz,1H), 4.71 (d, J¼9.8 Hz,1H), 4.50
(s, 1H), 3.93–4.15 (m, 2H), 3.28 (s, 3H), 2.53–2.74 (m, 2H); LRMS
(ESþ) calcd for C27H22BrCl2N3O5 [MþNa]þ: 640.0, found: 640.0.
NMR (CDCl3, 300 MHz)
d
7.94 (d, J¼1.9 Hz, 0.41H), 7.65–7.85 (m,
1.59H), 7.41 (dd, J¼8.6, 2.0 Hz, 0.59H), 7.17–7.45 (m, 5H), 7.03–7.15
(m, 2H), 6.96 (t, J¼5.8 Hz, 0.59H), 6.80 (d, J¼2.0 Hz, 0.41H), 6.60 (t,
J¼5.8 Hz, 0.41H), 5.23 (d, J¼10.7 Hz, 0.41H), 5.16 (d, J¼10.7 Hz,
0.41H), 5.11 (d, J¼10.7 Hz, 0.59H), 5.01 (d, J¼10.7 Hz, 0.59H), 4.85 (s,
0.59H), 4.68 (s, 0.41H), 4.49 (dd, J¼15.0, 6.1 Hz, 0.59H), 4.39 (dd,
J¼14.9, 6.2 Hz, 0.41H), 4.30 (dd, J¼15.0, 5.6 Hz, 0.59H), 4.18 (dd,
J¼14.9, 5.3 Hz, 0.41H), 3.28–3.42 (m, 1H), 3.29 (s, 1.23H), 3.15–3.28
(m, 0.59H), 3.00 (s, 1.77H), 2.10–2.42 (m, 2H); LRMS (ESþ) calcd for
C27H24BrCl2N3O6 [MþNa]þ: 636.0, found: 635.9.
5.1.8. Synthesis of lactam 22
A mixture of MOM-protected cyclization products 20 and 21
(10.1 mg, 16.3
mmol), dichloromethane (0.33 mL), and TFA (4 mL,
50 mol) was stirred for 2 h at rt. The mixture was then poured into
m
aqueous NaHCO3 and was extracted with EtOAc. The organic extract
was washed with brine, dried over MgSO4, and the solvent was
removed in vacuo. The crude residual oil was purified via chro-
matography, eluting with 4:1 hexanes/EtOAc to afford a white solid,
which was a 5:1 mixture of diastereomers (9.3 mg, 99%). The iso-
mers were separated by preparative TLC eluting with 2.5:1 hex-
anes/EtOAc, and the major isomer 22 was crystallized from CH2Cl2/
hexanes for X-ray analysis. Major diastereomer 22: Rf¼0.43 (2:1
5.1.5. 2-(3-(2-(Benzylamino)-1-(4-bromo-2-nitrophenyl)-2-
oxoethyl)-5,7-dichloro-1-(methoxymethyl)-2-oxoindolin-3-yl)ethyl
4-methylbenzenesulfonate (18)
To alcohol 17 (187.2 mg, 0.294 mmol), p-toluenesulfonyl chlo-
ride (61.6 mg, 0.323 mmol), and DMAP (7.2 mg, 0.059 mmol) was
added a solution of TEA (123
mL, 0.882 mmol) in dichloromethane
hexanes/EtOAc); 1H NMR (CDCl3, 300 MHz)
d
8.04 (d, J¼2.0 Hz, 1H),
(2.9 mL) and the reaction mixture was stirred for 2 h. The mixture
was then poured into saturated NaHCO3 and was extracted with
EtOAc. The organic extract was washed with brine, dried over
7.30–7.55 (m, 6H), 6.89 (d, J¼1.9 Hz, 1H), 6.56 (d, J¼8.4 Hz, 1H), 6.44
(d, J¼1.9 Hz, 1H), 4.97 (d, J¼14.6 Hz, 1H), 4.59 (s, 1H), 4.49 (s, 1H),
4.47 (d, J¼14.2 Hz, 1H), 3.87–4.02 (m, 2H), 2.61 (t, J¼6.4, 1.8 Hz, 2H);

M.A. Evans et al. / Tetrahedron 65 (2009) 6712–6719
6717
HRMS-ES [MþH]þ calcd for C25H19BrCl2N3O4: 573.9936, found:
400 MHz)
d
9.37 (s, 0.5H), 9.34 (s, 0.5H), 8.11 (d, J¼2.1 Hz, 0.5H),
573.9940.
8.02 (dd, J¼7.9, 1.0 Hz, 0.5H), 7.97 (dd, J¼7.8, 1.7 Hz, 0.5H), 7.91 (d,
J¼2.1 Hz, 0.5H), 7.71 (dd, J¼8.5, 2.1 Hz, 0.5H), 7.54 (d, J¼8.5 Hz,
0.5H), 7.49 (d, J¼2.1 Hz, 0.5H), 7.38–7.47 (m, 1H), 7.22–7.30 (m, 1H),
7.17 (dt, J¼7.8, 1.7 Hz, 0.5H), 7.03–7.10 (m, 1.5H), 6.89 (d, J¼8.4 Hz,
0.5H), 5.15, 5.05 (ABq, J¼11.2 Hz, 1H), 5.07 (s, 0.5H), 5.00 (s, 0.5H),
4.95, 4.81 (ABq, J¼11.1 Hz, 1H), 3.88 (d, J¼17.9 Hz, 0.5H), 3.46–3.69
(m, 2H), 3.64 (s, 3H), 3.32–3.40 (m, 0.5H), 3.15 (d, J¼7.3 Hz, 0.5H),
3.10 (d, J¼7.0 Hz, 0.5H), 0.78–0.98 (m, 2H), ꢁ0.05 (s, 4.5H), ꢁ0.06 (s,
4.5H); 13C NMR (CDCl3, 75 MHz) 196.4, 196.2, 176.7, 176.3, 170.0,
169.7, 150.3, 141.9, 141.4, 135.6, 134.9, 132.6, 132.2, 130.2, 129.5,
129.2,128.5,128.4,128.3,127.6,126.1,125.0,124.0,122.9,111.5,111.0,
70.3, 70.0, 66.4, 66.2, 52.9, 52.8, 51.1, 50.1, 49.8, 48.9, 48.6, 45.9, 17.9,
5.1.9. Methyl 2-(4-bromo-2-nitrophenyl)-2-(5-chloro-3-(2-
hydroxyethyl)-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-
3-yl)acetate (23)
A 500 mL Schlenk flask was charged with the Heck-carbonyla-
tion precursor 12 (6.67 g, 8.38 mmol), (dba)3 dipalladium(0)
(767.6 mg, 0.84 mmol), tri-o-tolylphosphine (1.02 g, 3.35 mmol),
and n-tetrabutylammonium bromide (5.40 g, 16.78 mmol). N,N-
Dimethylacetamide (204 mL) was added and the resulting mixture
was stirred for 10 min. MeOH (41 mL) and then TEA (5.84 mL,
41.9 mmol) were added. After stirring the mixture for an additional
10 min, carbon monoxide was introduced. The sealed reaction flask
was then heated at 85 ꢀC for 48 h. After cooling to rt, the mixture
was diluted with 1 L of EtOAc and was washed three times with
water. The aqueous layers were back-extracted with EtOAc. The
combined organic layers were washed with brine, dried over
MgSO4, and the solvent was removed in vacuo. The crude oil was
partially purified via column chromatography, eluting with 9:1
hexanes/EtOAc. Because the desired ester could not be separated
from the reductive Heck by-product or the starting material, the
crude mixture was used directly in the next step.
17.8, ꢁ1.4, ꢁ1.5; IR (thin film)
n
(cmꢁ1) 1728, 1536; HRMS-ES
[MþH]þ calcd for C25H29BrClN2O7Si: 611.0616, found: 611.0628.
5.1.11. 30-(4-Bromo-2-nitrophenyl)-5-chloro-10-(4-methoxy
benzyl)-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-
3,40-piperidine]-2,20-dione (25 and 26)
Amixtureofaldehyde24 (493 mg,0.806 mmol),dichloromethane
(16 mL), and p-methoxybenzylamine (0.110 mL, 0.847 mmol) was
stirred for 30 min at rt, and the solvent was removed in vacuo. The
crude imine was dissolved in methanol (10 mL). The reaction mix-
ture was cooled to 0 ꢀC and sodium borohydride (91.5 mg,
2.42 mmol) was added. After 1 h, the reaction mixture was poured
into aqueous NH4Cl and the aqueous layer was extracted with EtOAc.
The organic extract was washed with brine, dried over MgSO4, and
the solvent was removed in vacuo.
To the above mixture were added THF (320 mL) and glacial acetic
acid (4.80 mL, 83.4 mmol), followed by 1.0 M tetrabutylammonium
fluoride in THF (25.2 mL, 25.2 mmol). The reaction mixture was
stirred for 24 h at rt, poured intowater, and the biphasic mixturewas
then carefully neutralized with aqueous NaHCO3. The phases were
separated and the aqueous layers were extracted with EtOAc. The
combined organic extract was washed with brine, dried over MgSO4,
and the solvent was removed in vacuo. The crude residual oil was
purified via column chromatography, eluting with 3.5:1 hexanes/
EtOAc. The hydroxyester 23 was isolated as a yellow solid (2.32 g,
45% over two steps, mp 50–56 ꢀC), which was an inseparable 1:1
mixture of diastereomers. Rf¼0.55 (1:1 hexanes/EtOAc); 1H NMR
A mixture of the above crude aminoester and toluene (25 mL)
was heated at 110 ꢀC for 5 h. The solvent was removed in vacuo and
the crude residual oil was purified via column chromatography,
eluting with 4:1 hexanes/EtOAc. The lactam was isolated as a light
yellow solid (702 mg, 85% over three steps), consisting of a mixture
of diastereomers in a 1.66:1 cis/trans ratio. The isomers were sep-
arated by careful chromatography of the mixture. cis-Diastereomer
(CDCl3, 400 MHz)
d
8.07 (d, J¼2.1 Hz, 0.5H), 7.92 (d, J¼2.1 Hz, 0.5H),
26: Rf¼0.29 (2:1 hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz)
d 7.86
7.68 (dd, J¼8.5, 2.1 Hz, 0.5H), 7.56 (d, J¼2.1 Hz, 0.5H), 7.46 (dd, J¼8.5,
2.1 Hz, 0.5H), 7.42 (d, J¼8.5 Hz, 0.5H), 7.25–7.33 (m, 1.5H), 7.02 (d,
J¼8.4 Hz, 0.5H), 6.89 (d, J¼8.4 Hz, 0.5H), 6.85 (d, J¼2.1 Hz, 0.5H), 5.18
(s, 0.5H), 5.11 (s, 0.5H), 5.09, 5.04 (ABq, J¼11.1 Hz, 1H), 4.92, 4.86
(ABq, J¼11.0 Hz, 1H), 3.62 (s, 1.5H), 3.61 (s, 1.5H), 3.50–3.60 (m, 1H),
3.28–3.46 (m, 2H), 3.06–3.28 (m, 1H), 2.15–2.34 (m, 2H), 1.14
(dd, J¼7.0, 4.7 Hz, 0.5H), 0.96 (dd, J¼6.8, 4.8 Hz, 0.5H), 0.75–0.93 (m,
2H), ꢁ0.05 (s, 9H); 13C NMR (CDCl3, 75 MHz) 177.9, 177.8, 170.04,
169.98, 150.84, 150.76, 141.7, 141.5, 135.2, 134.9, 133.0, 132.9, 130.0,
129.6,129.2,129.0,128.6,128.1,128.0,127.5,126.8,126.6,125.3,124.8,
122.7,122.3,111.2,110.8, 70.4, 70.0, 66.4, 66.2, 58.5, 53.3, 52.8, 52.61,
(d, J¼2.0 Hz, 1H), 7.59 (dd, J¼8.5, 2.0 Hz, 1H), 7.36 (d, J¼8.6 Hz, 2H),
7.31 (d, J¼8.5 Hz, 1H), 7.22 (dd, J¼8.4, 2.0 Hz, 1H), 6.91–7.00 (m,
3H), 6.85 (d, J¼8.4 Hz, 1H), 5.01 (s, 1H), 4.96, 4.52 (ABq, J¼14.2 Hz,
2H), 4.93, 4.85 (ABq, J¼11.0 Hz, 2H), 3.82 (s, 3H), 3.51–3.69 (m, 1H),
3.39–3.48 (m, 1H), 3.24–3.38 (m, 2H), 2.03–2.17 (m, 2H), 0.70–1.00
(m, 2H), ꢁ0.08 (s, 9H); 13C NMR (CDCl3, 75 MHz)
d 175.9, 166.9,
159.3, 150.4, 139.4, 135.7, 133.5, 130.7, 130.04, 129.98, 129.3, 129.1,
128.3, 127.5, 123.6, 121.6, 114.2, 111.1, 69.6, 66.3, 55.3, 52.0, 50.5,
48.3, 42.5, 29.6, 17.6, ꢁ1.4; IR (thin film)
n
(cmꢁ1) 1717, 1532, 1248;
HRMS-ES [MþH]þ calcd for C32H36BrClN3O6Si: 700.1245, found:
700.1219.
52.56, 49.8, 49.6, 38.6, 35.5, 17.9, 17.8, ꢁ1.4, ꢁ1.45; IR (thin film)
n
trans-Diastereomer 25: Rf¼0.27 (2:1 hexanes/EtOAc); 1H NMR
(cmꢁ1) 3467, 1724, 1535; HRMS-ES [MþH]þ calcd for C25H31
(CDCl3, 400 MHz)
d
7.85 (d, J¼2.1 Hz, 1H), 7.39 (d, J¼8.6 Hz, 2H),
BrClN2O7Si: 613.0772, found: 613.0758.
7.32 (dd, J¼8.5, 2.1 Hz, 1H), 7.21 (dd, J¼8.4, 2.1 Hz, 1H), 6.95 (d,
J¼8.7 Hz, 2H), 6.84 (d, J¼8.4 Hz, 1H), 6.64 (d, J¼2.0 Hz, 1H), 6.61 (d,
J¼8.5 Hz, 1H), 5.23 (s, 1H), 5.10, 4.30 (ABq, J¼14.0 Hz, 2H), 4.93,
4.85 (ABq, J¼11.1 Hz, 2H), 3.83 (s, 3H), 3.53–3.69 (m, 2H), 3.18–3.27
(m, 1H), 2.95–3.04 (m, 1H), 2.43–2.53 (m, 1H), 1.78–1.87 (m, 1H),
5.1.10. Methyl 2-(4-bromo-2-nitrophenyl)-2-(5-chloro-2-oxo-
3-(2-oxoethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-3-yl)-
acetate (24)
To a mixture of alcohol 23 (500 mg, 0.814 mmol) and Dess–
Martin periodinane (520 mg, 1.22 mmol) was added dichloro-
methane (8 mL), and the reaction mixture was stirred for 1 h at rt.
Saturated aqueous Na2S2O3 (10 mL) was added and the biphasic
mixture was vigorously stirred for 5 min. The mixture was sepa-
rated and the aqueous layer was extracted with EtOAc. The com-
bined organic layers were washed with brine, dried over MgSO4,
and the solvent was removed in vacuo. The crude residual oil was
purified via column chromatography, eluting with 4:1 hexanes/
EtOAc. The aldehyde 24 was isolated as a yellow solid (493 mg, 99%,
mp 57–62 ꢀC) consisting of an inseparable 1:1 mixture of di-
astereomers. Rf¼0.44 (2:1 hexanes/EtOAc); 1H NMR (CDCl3,
0.63–0.89 (m, 2H), ꢁ0.08 (s, 9H); 13C NMR (CDCl3, 75 MHz)
d 176.0,
166.8, 159.5, 151.3, 140.2, 134.6, 132.6, 130.3, 130.0, 129.3, 129.2,
128.7, 128.4, 128.1, 127.4, 124.6, 121.6, 114.4, 111.4, 69.6, 65.9, 55.3,
52.4, 50.5, 47.1, 43.0, 30.8, 17.6, ꢁ1.4; IR (thin film)
n
(cmꢁ1) 1724, 1536,
1248; HRMS-ES [MþH]þ calcd for C32H36BrClN3O6Si: 700.1245,
found: 700.1226.
5.1.12. Equilibration of 30-(4-bromo-2-nitrophenyl)-5-chloro-10-
(4-methoxybenzyl)-1-((2-(trimethylsilyl)ethoxy)methyl)spiro
[indoline-3,40-piperidine]-2,20-dione (25 and 26)
A mixture of a 1:2 cis/trans mixture of lactam diastereomers
(193 mg, 0.276 mmol), finely powdered potassium carbonate

6718
M.A. Evans et al. / Tetrahedron 65 (2009) 6712–6719
(110 mg, 0.796 mmol), and DMF (10 mL) was stirred for 18 h at rt.
The mixture was then diluted with EtOAc and was poured into
aqueous NH4Cl. The aqueous layers were extracted with EtOAc. The
organic extract was washed with brine, dried over MgSO4, and the
solvent was removed in vacuo. The crude oil was purified via col-
umn chromatography, eluting with 4:1 hexanes/EtOAc. The title
compound was isolated as a light yellow solid (174 mg, 90%), con-
sisting of a separable mixture of lactam diastereomers in a 2:1 cis/
trans ratio.
4.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz) 165.9, 159.6, 140.9, 130.2,
129.33, 129.27, 128.1, 127.6, 127.1, 123.7, 122.9, 122.3, 118.8, 114.9,
114.4, 55.3, 50.2, 45.0, 43.0, 24.5; HRMS-ES [MþH]þ calcd for
C26H22BrClN3O2: 522.0584, found: 522.0562.
5.1.15. Preparation of SEM-amidines 30 and 31
To a mixture of amidine 29 (19.0 mg, 36.3 mmol) in THF (0.40 mL)
was added a 60% dispersion of sodium hydride in mineral oil (19 mg,
0.475 mmol) and the reaction mixture was stirred for 10 min. 2-
(Trimethylsilyl)ethoxymethyl chloride (9.6 mL, 55 mmol) was added
5.1.13. 30-(2-Amino-4-bromophenyl)-5-chloro-10-(4-methoxy
benzyl)-1-((2-(trimethylsilyl)ethoxy)methyl)spiro
[indoline-3,40-piperidine]-2,20-dione (27)
and the reaction mixture was stirred for 30 min, poured into aque-
ous NH4Cl, and was extracted with EtOAc. The organic extract was
washed with brine, dried over MgSO4, and the solvent was removed
in vacuo. The crude solid consisted of a 5:1 mixture of N-SEM
regioisomers 30 and 31, which were separated via preparative TLC,
eluting with 2:1 hexanes/EtOAc (total yield: 15.5 mg, 65%). The de-
sired N-SEM protected amidines were isolated as light yellow solids.
Major isomer 30: Rf¼0.45 (2:1 hexanes/EtOAc); 1H NMR (CDCl3,
A mixture of cis-lactam 26 (30.2 mg, 43.0
mmol), 5% platinum on
carbon (20.1 mg, 5.16 mol), and toluene (3.3 mL) was placed in
m
a high-pressure reaction vessel, and was flushed with H2. The hy-
drogen pressure was increased to 40 atm and the reaction mixture
was stirred for 5 h at rt. The pressure was released, the suspension
was diluted with EtOAc, and was filtered through Celite. The solvent
was removed in vacuo to give the title compound 27 as a single
diastereomer, which was used in the next step without further
purification (light yellow solid, 28.3 mg, 98%). Rf¼0.27 (2:1 hex-
300 MHz)
d
7.56 (d, J¼1.9 Hz, 1H), 7.50 (dd, J¼8.2, 1.0 Hz, 1H), 7.35
(d, J¼8.7 Hz, 2H), 7.18–7.27 (m, 3H), 6.92 (d, J¼8.7 Hz, 2H), 6.61 (s,
1H), 6.01 (d, J¼10.9 Hz, 1H), 5.10 (d, J¼11.0 Hz, 1H), 5.04 (d,
J¼14.0 Hz, 1H), 4.34 (d, J¼14.0 Hz, 1H), 3.80 (s, 3H), 3.60–3.78 (m,
3H), 3.42 (ddd, J¼24.9, 12.5, 5.9 Hz, 1H), 3.23 (dd, J¼12.9, 6.5 Hz,
1H), 2.35 (ddd, J¼25.4, 13.0, 6.9 Hz,1H), 1.17–1.30 (m, 1H), 0.80–1.07
(m, 2H), ꢁ0.06 (s, 9H); 13C NMR (CDCl3, 75 MHz) 171.3, 166.0, 159.6,
153.0, 139.6, 137.8, 130.2, 129.3, 129.2, 128.2, 128.0, 126.7, 122.74,
122.67, 119.2, 119.1, 118.8, 114.4, 75.2, 66.0, 55.3, 50.2, 49.5, 44.7,
43.3, 24.6,17.8, ꢁ1.4; HRMS-ES [MþH]þ calcd for C32H36BrClN3O3Si:
652.1398, found: 652.1384.
anes/EtOAc); 1H NMR (CDCl3, 300 MHz)
d
7.33 (d, J¼8.6 Hz, 2H),
7.11–7.29 (br m, 2H), 6.89 (br m, 3H), 6.82 (d, J¼8.3 Hz, 1H), 6.10–
6.77 (br m, 2H), 4.93 (br s, 2H), 4.88 (d, J¼14.4 Hz, 1H), 4.50 (d,
J¼14.4 Hz, 1H), 3.86–4.23 (br m, 2H), 3.79 (s, 3H), 2.80–3.83 (br m,
4H), 2.13–2.40 (br m, 1H), 1.80–2.02 (br m, 1H), 0.55–0.97 (br m,
2H), ꢁ0.09 (s, 9H); 13C NMR (CDCl3, 75 MHz) 168.3, 159.1, 139.7,
129.8, 128.8, 123.2, 121.9, 120.7, 119.9, 114.0, 111.0, 69.6, 66.1, 55.2,
52.0, 50.4, 47.4, 17.5, ꢁ1.4 (both the proton and carbon spectra show
Minor isomer 31: Rf¼0.48 (2:1 hexanes/EtOAc); 1H NMR (CDCl3,
broadened peaks); IR (thin film)
n
(cmꢁ1) 3425, 3353, 1712, 1247;
300 MHz)
d
7.42 (dd, J¼8.3, 1.2 Hz, 1H), 7.30–7.39 (m, 3H), 7.19–7.23
HRMS-ES [MþH]þ calcd for C32H38BrClN3O4Si: 670.1503, found:
(m, 2H), 6.95 (d, J¼8.5 Hz, 1H), 6.92 (d, J¼8.6 Hz, 2H), 6.64 (d,
J¼1.9 Hz,1H), 5.40 (d, J¼10.9 Hz,1H), 5.16 (d, J¼10.9 Hz,1H), 5.03 (d,
J¼14.0 Hz, 1H), 4.35 (d, J¼14.0 Hz, 1H), 3.61 (s, 1H), 3.60 (ddd,
J¼16.2, 8.4, 2.3 Hz, 2H), 3.28 (ddd, J¼25.1, 12.3, 5.4 Hz, 1H), 3.16
(dd, J¼12.7, 6.5 Hz, 1H), 2.31 (ddd, J¼25.7, 12.4, 6.8 Hz, 1H), 1.27 (dd,
J¼13.6, 4.1 Hz, 1H), 0.72–1.03 (m, 2H), ꢁ0.08 (s, 9H); 13C NMR
(CDCl3, 75 MHz) 166.7, 166.2, 159.5, 145.1, 142.6, 131.3, 130.1, 129.2,
128.25, 128.17, 127.7, 127.4, 124.0, 122.1, 120.1, 114.4, 110.6, 70.5, 66.3,
55.3, 50.2, 45.5, 43.7, 42.6, 24.1, 17.7, ꢁ1.4; HRMS-ES [MþH]þ calcd
for C32H36BrClN3O3Si: 652.1398, found: 652.1381.
670.1516.
5.1.14. Synthesis of amidine 29
A solution of SEM-protected oxindole 27 (28.3 mg, 42.1
in dichloromethane (28 mL) was cooled to 0 ꢀC, and boron tri-
fluoride etherate (47.6 L, 376 mol) was added in three equal
mmol)
m
m
portions over the course of 4 h. The reaction was monitored by TLC
until all starting material had been consumed. At this time, the
reaction mixture was poured into aqueous NaHCO3. The phases
were separated and the aqueous layer was extracted with EtOAc.
The combined organic extract was washed with brine, dried over
MgSO4, and the solvent was removed in vacuo.
5.1.16. Allylation of SEM-amidine 30
A solution of N-SEM protected amidine 30 (15.3 mg, 23.4 mmol)
A mixture of the above crude N,O-hemiaminal, DMF (1.7 mL),
in THF (1.50 mL) was cooled to ꢁ78 ꢀC and 1.0 M lithium bis(-
and ethylenediamine (14.1
mL, 211
m
mol) was heated at 45 ꢀC for
trimethylsilyl)amide in THF (117 mL, 0.117 mmol) was slowly
1 h. The mixture was diluted with EtOAc and was poured into
water. The aqueous layer was extracted with EtOAc. The organic
extract was washed with brine, dried over MgSO4, and the solvent
was removed in vacuo. This crude mixture was predominantly the
deprotected oxindole 28, along with a small amount of amidine 29.
The mixture was used without further purification.
added. The reaction mixture was stirred for 15 min and allyl iodide
(21.4 L, 0.234 mmol) was added. After stirring for 2 h, the re-
m
action mixture was quenched with aqueous NH4Cl and then
warmed to rt. The mixture was poured into water and was
extracted with EtOAc. The organic extract was washed with brine,
dried over MgSO4, and the solvent was removed in vacuo. The
crude solid was purified via preparative TLC, eluting with 2:1
hexanes/EtOAc. The desired allylated amidine 32 was isolated as
a colorless oil (13.5 mg, 83%) as a single diastereomer. Rf¼0.52 (2:1
A mixture of the above crude oxindole, p-toluenesulfonic acid
monohydrate (24.0 mg, 126 mmol), and toluene (10.5 mL) was
heated at 85 ꢀC for 5 min. After cooling, the solution was poured
into aqueous NaHCO3 and was extracted with EtOAc. The combined
organic layers were washed with brine, dried over MgSO4, and the
solvent was removed in vacuo. The desired amidine 29 was isolated
as a light yellow solid (18.9 mg, 86% over three steps). For charac-
terization purposes, this material was triturated with dichloro-
methane and hexanes. Rf¼0.45 (1:4 hexanes/EtOAc); 1H NMR
hexanes/EtOAc); 1H NMR (CDCl3, 360 MHz)
d
7.52 (d, J¼1.9 Hz, 1H),
7.50 (d, J¼8.4 Hz, 1H), 7.31 (d, J¼8.7 Hz, 2H), 7.15–7.24 (m, 3H),
6.90 (d, J¼8.7 Hz, 2H), 6.63 (d, J¼1.2 Hz, 1H), 5.93 (d, J¼10.9 Hz,
1H), 5.18–5.32 (m, 1H), 5.04 (d, J¼10.9 Hz, 1H), 4.95 (d, J¼13.9 Hz,
1H), 4.57 (d, J¼10.0 Hz, 1H), 4.39 (d, J¼14.0 Hz, 1H), 4.34 (dd,
J¼17.1, 1.4 Hz, 1H), 3.80 (s, 3H), 3.64–3.76 (m, 2H), 3.45
(ddd, J¼25.2, 12.5, 5.7 Hz, 1H), 3.21 (dd, J¼12.9, 5.9 Hz, 1H), 2.76
(dd, J¼14.2, 6.9 Hz, 1H), 2.48 (ddd, J¼26.1, 13.2, 6.7 Hz, 1H),
2.14 (dd, J¼14.2, 8.1 Hz, 1H), 1.19 (dd, J¼13.6, 4.9 Hz, 1H), 0.89–1.07
(m, 2H), ꢁ0.04 (s, 9H); 13C NMR (CDCl3, 75 MHz) 172.6, 168.7,
159.5, 153.6, 139.5, 136.4, 132.7, 130.0, 129.3, 129.2, 128.4, 127.9,
(CDCl3, 300 MHz)
d
7.51 (d, J¼8.2 Hz, 1H), 7.35 (d, J¼8.5 Hz, 2H),
7.17–7.29 (m, 4H), 7.03 (d, J¼8.2 Hz, 1H), 6.92 (d, J¼8.5 Hz, 2H), 6.64
(s, 1H), 5.05 (d, J¼14.0 Hz, 1H), 4.35 (d, J¼14.0 Hz, 1H), 3.83 (s, 1H),
3.80 (s, 3H), 3.37 (ddd, J¼25.0, 12.4, 5.4 Hz, 1H), 3.23 (dd, J¼12.9,
6.6 Hz, 1H), 2.36 (ddd, J¼25.7, 12.6, 6.7 Hz, 1H), 1.34 (dd, J¼13.6,

M.A. Evans et al. / Tetrahedron 65 (2009) 6712–6719
6719
3. For some additional communesins see: (a) Jadulco, R.; Edrada, R. A.; Ebel, R.;
Berg, A.; Schaumann, K.; Wray, V.; Steube, K.; Proksch, P. J. Nat. Prod. 2004, 67,
78; (b) Hayashi, H.; Matsumoto, H.; Akiyama, K. Biosci. Biotechnol. Biochem.
2004, 68, 753; (c) Dalsgaard, P. W.; Blunt, J. W.; Munro, M. H. G.; Frisvad, J. C.;
Christophersen, C. J. Nat. Prod. 2005, 68, 258.
4. See also: (a) Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. K.
J. Org. Chem. 2001, 66, 8717; (b) Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.;
Hemscheidt, T. K. J. Org. Chem. 2003, 68, 1640.
5. For labelling studies on the biosynthesis of the communesins see: Wigley, L. J.;
Mantle, P. G.; Perry, D. A. Phytochemistry 2006, 67, 561.
6. (a) May, J. A.; Zeidan, R. K.; Stoltz, B. M. Tetrahedron Lett. 2003, 44, 1203; (b)
May, J. A.; Stoltz, B. M. Tetrahedron 2006, 62, 5262.
7. (a) Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068; (b) Crawley, S. L.;
Funk, R. L. Org. Lett. 2003, 5, 3169.
8. Sabhi, A.; Novikov, A.; Rainier, J. D. Angew. Chem., Int. Ed. 2006, 45, 4317.
9. A total synthesis of racemic communesin F has recently appeared: (a) Yang, J.;
Song, H.; Xiao, X.; Wang, J.; Qin, Y. Org. Lett. 2006, 8, 2187; (b) Yang, J.; Wu, H.;
Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794.
10. cf.: (a) Grigg, R.; Millington, E. L.; Thornton-Pett, M. Tetrahedron Lett. 2002, 43,
2605; (b) Brown, S.; Clarkson, S.; Grigg, R.; Thomas, W. A.; Sridharan, V.; Wil-
son, D. M. Tetrahedron 2001, 57, 1347; (c) Anwar, U.; Casaschi, A.; Grigg, R.;
Sansano, J. M. Tetrahedron 2001, 57, 1361; (d) de Meijere, A.; Bra¨se, S. J. Orga-
nomet. Chem. 1999, 576, 88; (e) Poli, G.; Giambastiani, G.; Heumann, A. Tetra-
126.8, 123.3, 123.1, 122.6, 119.4, 118.8, 118.7, 114.4, 75.1, 66.1, 55.3,
54.1, 50.8, 49.6, 43.3, 40.6, 27.3, 17.8, ꢁ1.4; HRMS-ES [MþH]þ calcd
for C35H40BrClN3O3Si: 692.1711, found: 692.1715.
The alkylation product 33 from the minor SEM-protected ami-
dine 31 was prepared via a similar procedure. Rf¼0.54 (2:1 hex-
anes/EtOAc); 1H NMR (CDCl3, 360 MHz)
d
7.49 (d, J¼6.3 Hz, 1H),
7.28–7.34 (m, 3H), 7.16–7.23 (m, 2H), 6.91 (d, J¼8.4 Hz, 1H), 6.90 (d,
J¼8.6 Hz, 2H), 6.66 (d, J¼2.0 Hz, 1H), 5.39 (d, J¼11.0 Hz, 1H), 5.30–
5.41 (m, 1H), 4.99 (d, J¼11.2 Hz, 1H), 4.95 (d, J¼10.1 Hz, 1H), 4.37 (d,
J¼14.0 Hz,1H), 4.20 (d, J¼16.8 Hz, 1H), 3.80 (s, 3H), 3.64 (t, J¼8.1 Hz,
2H), 3.34 (ddd, J¼25.2, 12.6, 5.2 Hz, 1H), 3.15 (dd, J¼12.9, 5.6 Hz,
1H), 2.86 (dd, J¼14.2, 5.2 Hz,1H), 2.43 (ddd, J¼26.1,13.2, 6.5 Hz,1H),
2.24 (dd, J¼14.2, 9.7 Hz, 1H), 1.29 (dd, J¼13.7, 4.5 Hz, 1H), 0.86–1.04
(m, 2H), ꢁ0.05 (s, 9H); 13C NMR (CDCl3, 75 MHz) 168.9, 167.9, 159.4,
143.3, 134.0, 129.9, 129.6, 129.0, 128.5, 128.3, 128.2, 127.8, 124.7,
124.3, 122.2, 117.6, 114.4,110.5, 70.9, 66.4, 55.3, 50.8, 50.2, 48.2, 42.6,
41.0, 26.9, 17.8, ꢁ1.4; HRMS-ES [MþH]þ calcd for C35H40BrClN3O3Si:
692.1711, found: 692.1695.
´
hedron 2000, 56, 5959; (f) Negishi, E.; Ma, S.; Amanfu, J.; Coperet, C.; Miller,
J. A.; Tour, J. M. J. Am. Chem. Soc. 1996, 118, 5919.
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8891; (d) Seo, J. Ph.D. Thesis, The Pennsylvania State University, University
Park, PA, 2008.
12. Lipton, M. F.; Basha, A.; Weinreb, S. M. Org. Synth. 1979, 59, 49.
13. For some examples of reductive Heck reactions see: (a) Denmark, S. E.;
Schnute, M. E. J. Org. Chem. 1995, 60, 1013; (b) Diaz, P.; Gendre, F.; Stella, L.;
Charpentier, B. Tetrahedron 1998, 54, 4579; (c) de Meijere, A.; Meyer, F. E.
Angew. Chem., Int. Ed. Engl. 1994, 33, 2379 and references cited therein; (d)
Chen, C.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J. Org.
Chem. 1997, 62, 2876; (e) For a recent example of MeOH acting as a hydride
transfer agent, see: Sajiki, H.; Ikawa, T.; Yamada, H.; Tsubouchi, K.; Hirota.
Tetrahedron Lett. 2003, 44, 171.
Acknowledgements
We gratefully acknowledge financial support from the National
Institutes of Health (CA-034303). We also wish to thank Dr. H.
Yennawar (Penn State Small Molecule X-ray Cystallographic Facil-
ity) for the X-ray determination of compound 22, Jae Hong Seo for
helpful discussions, and Ilia Korboukh for assistance in preparation
of the manuscript.
References and notes
14. CCDC 676455 contains the supplementary crystallographic data for compound
22, which can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
15. cf.: (a) Meghani, P.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1 1988, 1; (b) Garg,
N. K.; Caspi, D. D.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 9552.
1. Verbitski, S. M.; Mayne, C. L.; Davis, R. A.; Concepcion, G. P.; Ireland, C. M. J. Org.
Chem. 2002, 67, 7124; For a related alkaloid see: Verotta, L.; Pilati, T.; Tato, M.;
Elisabetsky, E.; Amador, T. A.; Nunes, D. S. J. Nat. Prod. 1998, 61, 392.
2. Numata, A.; Takahashi, C.; Ito, Y.; Takada, T.; Kawai, K.; Usami, Y.; Matsumura,
E.; Imachi, M.; Ito, T.; Hasegawa, T. Tetrahedron Lett. 1993, 34, 2355.