A dipolar cycloaddition approach toward the kopsifoline alkaloid framework

Article abstract of DOI:10.1016/j.tet.2007.01.064

Using a metal-catalyzed domino reaction as the key step, the heterocyclic skeleton of the kopsifoline alkaloid family was constructed by a 1,3-dipolar cycloaddition of a carbonyl ylide dipole derived from a Rh(II)-catalyzed reaction of a diazo ketoester across the indole π-bond. Ring opening of the resulting 1,3-dipolar cycloadduct followed by a reductive dehydroxylation step resulted in the formation of a critical silyl enol ether necessary for the final F-ring closure of the kopsifoline skeleton.

Full text of DOI:10.1016/j.tet.2007.01.064

Tetrahedron 63 (2007) 5962–5976
A dipolar cycloaddition approach toward the kopsifoline
alkaloid framework
*
Xuechuan Hong, Stefan France and Albert Padwa
Department of Chemistry, Emory University, Atlanta, GA 30322, USA
Received 11 December 2006; revised 29 January 2007; accepted 30 January 2007
Available online 2 February 2007
Abstract—Using a metal-catalyzed domino reaction as the key step, the heterocyclic skeleton of the kopsifoline alkaloid family was con-
structed by a 1,3-dipolar cycloaddition of a carbonyl ylide dipole derived from a Rh(II)-catalyzed reaction of a diazo ketoester across the
indole p-bond. Ring opening of the resulting 1,3-dipolar cycloadduct followed by a reductive dehydroxylation step resulted in the formation
of a critical silyl enol ether necessary for the final F-ring closure of the kopsifoline skeleton.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
by a transition-metal promoted cyclization reaction has
emerged in recent years as an important and efficient method
for the assembly of ring systems that are difficult to prepare
by other means.7 In earlier studies we described the forma-
tion of cyclic carbonyl ylide dipoles by a process involving
cyclization of an electrophilic metallo carbenoid onto an ad-
jacent carbonyl group.8 The general reaction investigated is
illustrated in Scheme 1; variations in chain length (n¼0, 1, 2)
and nature of the activating group (G) were explored.9 With
limited exceptions,10 alkyl and aryl ketones were employed
and dipole 5 was generated by the rhodium(II)-catalyzed de-
composition of the diazoalkanedione in benzene at 80 ꢀC.11
In recent years, a widespread upsurge of activity in the
stereoselective preparation of highly substituted nitrogen
heterocycles, especially structurally complex alkaloids has
occurred.1 In particular, the Aspidosperma alkaloid family
has occupied a central place in natural product chemistry be-
cause of their diverse biological activity.2 This family of in-
dole alkaloids contains over 250 members that share in their
molecular structure a common pentacyclic ABCDE frame-
work, with the C-ring being of critical importance because
all six stereocenters and most of the functionalities are
located in this ring.3 Individual members differ mainly in
functionality and stereochemistry. Over the years, efficient
and elegant routes to this molecular framework have been
developed.4,5
+
A
O
B
O
N2
R
O
G
O
-
A=B
R
G
O
( )n
R
( )n
G
Rh(II)
( )n
O
4
5
6
N
N
E
D
Scheme 1.
H
H
Et
A
B
Et
C
MeO
N
H
OAc
N
R2
More recently, we became interested in the formation of
push–pull dipoles from the Rh(II)-catalyzed reaction of
a-diazoimides12 and noted that a smooth intramolecular
1,3-dipolar cycloaddition occurred across both alkenyl and
heteroaromatic p-bonds to provide novel pentacyclic com-
pounds in good yield and in a stereocontrolled fashion.13,14
Our recent total synthesis of (ꢁ)-aspidophytine nicely dem-
onstrates the utility of this cascade methodology for the con-
struction of complex aspidosperma alkaloids.15 Thus, the
Rh(II)-catalyzed reaction of diazoimido indole 7 produced
cycloadduct 9 in 97% yield via the intermediacy of the
carbonyl ylide dipole 8. The acid lability of cycloadduct 9
was exploited to provide the complete skeleton of aspido-
phytine in several additional steps (Scheme 2).
H
H
R1
HO CO2Me
1; R1 = R2 = H (Aspidospermidine)
3; Vindoline
2; R1 = OMe; R2 = Ac (Aspidospermine)
Our approach to the Aspidosperma skeleton was guided by a
long-standing interest in developing new applications of the
Rh(II) cyclization/cycloaddition cascade for the synthesis of
complex natural products.6 The generation of onium ylides
Keywords: Diazoimide; Synthesis; Indole; Cycloaddition; Rhodium(II);
Kopsifoline; Alkaloid.
* Corresponding author. Tel.: +1 404 727 0283; fax: +1 404 727 6629;
e-mail: chemap@emory.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.064

X. Hong et al. / Tetrahedron 63 (2007) 5962–5976
5963
O
O
derived from diazo ketoester 14 across the indole p-
bond.14,21 Ring opening of the resulting cycloadduct 15 fol-
lowed by a reductive dehydroxylation step15 would lead to
the critical silyl enol ether 16 necessary for the final F-ring
closure. Although the very last step (i.e., 16 /17) appears
to be reasonable, no example of such a reaction had been
previously reported in the literature. Accordingly, we de-
cided to study the facility and stereoselectivity of this pro-
cess with some model substrates prior to commencing the
total synthesis of the kopsifolines. In this paper we detail
the successful implementation of this strategy.22
N
N
CO2t-Bu
MeO
O
N2
CO2t-Bu
Rh(II)
O
+
-
MeO
MeO
N
Me
N
Me
O
MeO
O
CO2Me
97%
CO2Me
7
8
O
N
N
O
O
CO2t-Bu
O
N
N
H
H
MeO
N
O
MeO
N
Me
H
Kopsifolines (13)
H
CH2CHO
OSiR3
CO2Me
OMe Me CO2Me
OMe
N
R
N
R
10; Aspidophytine
9
OH
CO2Me
Scheme 2.
17
16
As an extension of our earlier work on (ꢁ)-aspidophytine
(10) we became interested in using the Rh(II)-catalyzed
cyclization/cycloaddition cascade for the synthesis of the
hexacyclic framework of the kopsifoline alkaloids. The
Malaysian members of the genus Kopsia have yielded a pro-
digious harvest of new natural products possessing novel
carbon skeletons as well as useful bioactivities.16 In 2003,
Kam and Choo reported the structures of several new hexa-
cyclic monoterpenoid indoline alkaloids isolated from a
Malayan Kopsia species known as K. fruticosa.17 The major
components of the alkaloidal extracts were identified as the
kopsifolines.18 The structures were secured by spectral anal-
ysis and are characterized by an unprecedented carbon skel-
eton, in which the C(18) carbon is linked to C(16). The
kopsifolines are structurally intriguing compounds, related
to and possibly derived from an aspidosperma-type alkaloid
precursor 11. A possible biogenetic pathway to the kopsifo-
lines from 11 could involve an intramolecular epoxide-ring
opening followed by loss of H2O as shown in Scheme 3.
O
O
N
N
CH2CO2Me
O
O
CH2CO2Me
O
O
N2
N
R
N
R
H
CO2Me
CO2Me
15
14
Scheme 4.
2. Results and discussion
The 3-substituted diazoimides needed to test this approach
were prepared according to the reaction sequence outlined
in Scheme 5. Deprotonation of piperidone 18 with 1.1 equiv
of n-butyllithium followed by reaction with 2-iodoethyl ben-
zyl ether afforded lactam 19 in 70% yield. The ethyl ester
portion of 19 was converted to the 3-oxopropanoate group
using a modified Masamune procedure,23 which furnished
either b-keto ester 20a or 20b in 82% or 84% yield, res-
pectively. A related sequence of reactions was also used to
prepare lactams 22 and 23. Thus, the anion derived from
piperidone 18 was allowed to react with tert-butyl bromo-
acetate together with a catalytic amount of tetrabutyl ammo-
nium iodide, which lead to the formation of lactam 21 in
80% yield. Treatment of the resulting tert-butyl ester 22 (de-
rived from 21) with (MeO)3CH/MeOH in the presence of
p-TsOH gave the corresponding methyl ester 23 in almost
quantitative yield (Scheme 5). When these lactams were
allowed to react with the acid chloride derived from 2-
(N-phenylsulfonyl) or 2-(N-tosyl-1H-indol-3-yl)acetic acid,
the expected imides were readily formed in high yield and
were easily converted to the corresponding diazo substrates
24–26 using the Regitz diazotization procedure.24
D
N
N
N
H
H+
O
H
H
E
A
OH
C
B
N
F
+
R
R
N
18
N
H
R
16
CO2Me
CO2Me
H
CO2Me
11; R = H or OMe
12
13; R = H or OMe
Kopsifolines
Scheme 3.
The interesting biological activity of these compounds com-
bined with their fascinating and synthetically challenging
structure, make them attractive targets for synthesis.
Our own work on the synthesis of the kopsifolines represents
one component of a broad program focused on the synthesis
of various aspidosperma alkaloids using [3+2]-cycloaddi-
tion chemistry.6 Our retrosynthetic analysis of 13 is shown
in Scheme 4 and envisions the core skeleton to arise from
a metal carbene–cyclization–cycloaddition cascade that
our group has been studying for some time.19,20 Using this
metal-catalyzed domino reaction as a key step, the hetero-
cyclic skeleton of the kopsifolines could eventually be built
by a 1,3-dipolar cycloaddition of a carbonyl ylide dipole
We first carried out a model study using cycloadduct 27 de-
rived from the Rh(II)-catalyzed reaction of diazoimide 24 in
order to test the viability of our design as well as the specific
reactions to be used in a total synthesis effort. Heating a sam-
ple of diazoimide 24 with catalytic Rh2(OAc)4 in benzene at
80 ꢀC afforded cycloadduct 27 in 94% yield as a single
diastereomer (Scheme 6). The isolation of 27 is the

5964
X. Hong et al. / Tetrahedron 63 (2007) 5962–5976
H
N
H
O
HN
O
OBn
N
1. LiOH, 91%
1.1 eq n-BuLi
O
2. CDI, MgCl2 (82%)
ICH2CH2OCH2Ph
70%
O
OBn
OK
R1O2C
EtO
O
EtO
O
CO2R1
19
18
O
20a; R1 = Me
20b; R1 = Et
1. 4 Ao sieves
2. MsN3, NEt3
O
1.1 eq n-BuLi
BrCH2CO2t-Bu
80%
3.
Cl
N
SO2Ar
O
N
H
O
N
HN
O
CO2R3
R2
O
O
N2
1. LiOH, 91%
(indol-3-yl)-
CO2t-Bu
O
acetyl chloride
MsN , NEt
2. CDI, MgCl2 (61%)
N
CO2R1
3
3
OK
EtO
O
SO2Ar
24; R1 = Et; Ar = Ph
MeO2C
CO2Me
O
21
22; R3 = t-Bu
23; R3 = Me
(MeO) CH
3
MeOH, H+
R
2 = CH2CH2OBn
25; R1 = Me, Ar = p-tol
R2 = CH2CH2OBn
26; R1 = Me, Ar = p-tol
R
2 = CH2CO2Me
Scheme 5.
consequence of endo cycloaddition with regard to the di-
pole,14 and this is in full accord with the lowest energy tran-
sition state. The cycloaddition can also be considered doubly
diastereoselective in that the indole moiety approaches the
dipole exclusively from the side of the 2-(benzyloxy)ethyl
group and away from the more sterically encumbered piper-
idone ring.
employed Cossy’s photoreductive approach. We found,
however, that the irradiation of 27 in the presence of NEt3
(5 equiv) using CH3CN as the solvent only furnished the
desulfonylated indoline 28 in 90% yield.
The ready photodesulfonylation of indoline 27 prompted us
to carry out a broader study of this deprotection reaction
since substituted N-sulfonyl-indoles are commonly em-
ployed in organic synthesis. The powerful electron-with-
drawing property of the sulfonyl group coupled with its
ortho-directing effect has been extensively utilized for selec-
tive metallation at the C2-position of the indole ring without
having to use a large excess of metallating agent.27 In addi-
tion, the product N-sulfonamides are often crystalline and
stable to a variety of reaction conditions (e.g., alkaline hy-
drolysis and catalytic reduction). A corollary of the stability
of the N-sulfonyl bond is the difficulty encountered in the re-
moval of this type of protecting group. Harsh deprotection
conditions are often required, which limit the synthetic use-
fulness of these compounds. Thus, arylsulfonamides are
cleaved by sodium in liquid ammonia,28 sodium naphthal-
enide or anthracenide,29 heating to reflux in strong acid30 and
reaction with highly nucleophilic31 or reducing32 reagents.
These harsh conditions have led to the development of new
methods for the deprotection of N-sulfonamides. This has
included deprotection by using SmI2,33 TiCl4/Zn,34 Mg in
methanol,35 TBAF,36 iodotrimethylsilane37 or electrolysis.38
O
O
N
N
O
N2
OBn
OBn
O
Rh(II)
94%
O
O
CO2Et
N
R
N
R
H
CO2Et
24; R = SO2Ph
hv
27; R = SO2Ph
28; R = H
NEt3
O
O
O
Me
Me
O
O
Me
hv
NEt3
Cossy ref #25
O
Me
O
OH
30
29
Scheme 6.
Having established a viable route to cycloadduct 27, efforts
were next centered on the reductive opening of the oxido
bridge. In 1991, Cossy and co-workers reported that a photo-
induced electron transfer reaction from Et3N to 7-oxabicy-
clo[2.2.1]heptan-2-ones easily generated the corresponding
3-hydroxycyclohexanone derivatives (e.g., 29 to 30).25 The
reduction relies on the intermediacy of a ketyl radical an-
ion26 derived from the oxabicycloheptane under the photo-
chemical conditions. With this result in mind, our initial
attempts to carry out the reductive ring opening of 27
While the desulfonylation of several alkyl N-sulfonyl amides
has been achieved photochemically,39 the related reaction
using indoles has not been reported in the literature. Since
the serendipitous deprotection reaction that we encountered
with indoline 27 proceeded in such high yield and under very
mild conditions, we set out to further explore the generality
and scope of the photodesulfonylation of a series of related

X. Hong et al. / Tetrahedron 63 (2007) 5962–5976
5965
indoles. The photolysis of indoles 31 was carried out in the
*
-
presence of 5.0 equiv of Et3N and CH3CN in a quartz vessel
using 254 nm lamps for 1 h under a nitrogen atmosphere
(Scheme 7). Column chromatography of the crude residue
followed by removal of the solvent gave the desired desulfo-
nylated indoles 32 in 48–77% yield based on recovered start-
ing material (entries 1–5). Interestingly, we also observed
the formation of both the ortho- and para-photo Fries like
rearrangement products 33 and 34 in varying quantities
(8–19%) depending on the particular system. In most cases
the para-rearrangement product was the major isomer
formed, suggesting leakage from a radical cage.
SET
:
.
.
+
+
NEt3
+
NEt3
N
N
36
SO2Ph
SO2Ph
35 (a-e)
31 (a-e)
.
-PhSO2
PhO2S
H
.
+
PhSO2
.
N
-
N
-
38 (a-e)
37 (a-e)
n-Bu3SnH
Encouraged by these positive results, we studied the effect of
adding different additives in order to capture the initially
produced sulfonyl radical and thereby enhance the yield of
the desulfonylated indole. The use of tert-butyl mercaptan
as a radical scavenger showed no improvement in the overall
yield of the desulfonylated indole 32. However, in the pres-
ence of 1.0 equiv of n-Bu3SnH, the photoreaction of 31d af-
forded indole 32d in 96% yield (based on recovered starting
material) with no signs of the rearranged aryl sulfones 33d
and 34d. The more highly activated tin hydride (weaker
Sn–H bond) allows for capture of the sulfonyl radical
thereby suppressing attack at the ortho- and para-positions.
36
36
PhSO2H
PhO2S
N
H
N
H
33 (a-e)
32 (a-e)
Scheme 8.
to 36 would afford the rearranged indole 33 (and/or 34). In
the presence of n-Bu3SnH, the phenylsulfonyl radical un-
dergoes bimolecular hydrogen atom transfer and is no longer
available to add to the aromatic ring.42
More than likely, the photodesulfonylation reaction can be
attributed to a photoinduced electron transfer as outlined
in Scheme 8. Amines are well known to undergo such a trans-
fer with electronically excited carbonyl groups.40 The reac-
tion is initiated by single electron transfer from NEt3 to the
electronically excited indole with formation of the radical
cation of triethylamine (36) and the radical anion of the
indole (35). Formation of 35 weakens the N-SO2Ph bond
and facilitates bond cleavage.41 Proton transfer from the rad-
ical cation of NEt3 (36) would lead to the observed desulfo-
nylated indole 32. In competition with this process, the
phenylsulfonyl radical can undergo addition to the aromatic
framework of the indole anion 37 producing radical anion 38
as a transient species. A subsequent electron transfer from 38
At this point of our studies we decided to examine the reduc-
tion of cycloadduct 39, derived from the Rh(II)-catalyzed re-
action of diazoimide 25, using Et3SiH and BF3$OEt2. On the
basis of our previous studies using related aza-oxabicyclic
systems,43 we expected that this reaction would result in a
reductive ring opening reaction. We found, however, that
the rearranged nine-membered lactone 42 was obtained as
the only identifiable product in 60% yield. This unusual re-
organization can be rationalized by the pathway proposed in
Scheme 9. We assume that the first step involves a Lewis
acid promoted debenzylation with Et3SiH and the transient
alcohol 40 so produced undergoes ready cyclization onto
the adjacent carbonyl group to generate a hemiketal interme-
diate. A subsequent ring opening of the oxabicyclic ring af-
fords N-acyliminium ion 41, which then undergoes cleavage
of the C–C bond to dissipate the positive charge on the nitro-
gen atom thereby giving rise to the observed lactone 42.
R1
R1
R1
R1
PhO2S
+
hv
R2
R2
SO2Ph
31 (a-e)
R2
R2
+
N
H
N
N
H
N
H
SO2Ph
32 (a-e)
33 (a-e)
34 (a-e)
We next investigated the key F-ring closure step, that is, the
foundation of our kopsifoline strategy by making use of
hemiketal 43. For these feasibility studies (Scheme 10),
we converted 43 into keto ester 45, which possesses a side
chain mesylate group that could undergo intramolecular dis-
placement with the carbanion derived from ketoester 45.
Hemiketal 43 is easily available from cycloadduct 39 via lac-
tam reduction followed by catalytic hydrogenation, which
causes reductive ring opening of the oxabicyclic ring, deben-
zylation, and cyclization to give 43 in 43% yield for the
three-step sequence. Treatment of 43 with triethylamine/
mesyl chloride furnished 44 (85%), which was then re-
duced with SmI2 to give 45 in 60% yield. Unfortunately,
all of our efforts to induce ring F-closure of 45 with various
bases and under different experimental conditions were
unsuccessful.
Entry
R1
R2
Product + Yield
(%)
31
a
32
48
55
57
77
60
33 34
H
H
11
8
b
c
Me
Me
H
11 11
CH2CH2OTBS
CO2Me
19
4
5
4
-
d
e
H
COMe
CH2OH
-
Scheme 7. Photodesulfonylation of indoles.

5966
X. Hong et al. / Tetrahedron 63 (2007) 5962–5976
O
ester functionality to give 48 in 59% yield for the five-step
N
sequence (Scheme 11). Gratifyingly, when 48 was treated
with CsF in CH3CN at reflux, it was cleanly converted to
the hexacyclic skeleton of the kopsifoline alkaloids (i.e.,
49) in 78% yield.
OBn
O
O
N2
N
CO2Me
TolSO2
25
O
Rh2OAc4
N
O
N
1. P2S5
H
°
C
80
2. Ra-Ni
CH2CO2Me
O
CH2CO2Me
O
O
O
3. PtO2, H2,
HCl
N
O
N
O
N
N
TolSO
H
H
BF3.OEt2
Et3SiH
CO2Me
TolSO2
CO2Me
2 HO
OH
OBn
46
O
BF3
47 (68%)
O
N
N
H
H
CO2Me
CO2Me
TolSO2
TolSO2
1. Cs2CO3
2. SmI2
40
39
3. TBDMSOTf
4. LAH
5. TPAP, NMO
O
O
N
+
N
N
N
O
N
H
H
-BF3
CsF
CH3CN
CH2CHO
OTBS
O
O
OH
N
N
TolSO
N
H
O
OBF3
H
H
H
H
H
CO2Me
TolSO2
TolSO
CO2Me
TolSO2
2 HO
2 HO
49 (78%)
42 (60%)
41
48 (59%)
Scheme 9.
Scheme 11.
Since all members of the kopsifoline family of alkaloids
contain a carbomethoxy group at the C(16)-position of the
core skeleton, we decided to selectively remove the hydroxyl
group from hydroxy ester 47. To this end, the reduction of 47
was carried out with SmI2 in HMPA and the expected ke-
toester 50 was isolated in 93% yield (Scheme 12). This com-
pound was easily converted into the corresponding TBS silyl
enol ether in 96% yield. Reaction of the enol ether with LAH
at 0 ꢀC resulted in the selective reduction of the non-conju-
gated carbomethoxy group affording 51 in 91% yield. The
primary alcohol so formed was then subjected to oxidation
using TPAP (NMO) at 0 ꢀC and the crude reaction mixture
was subsequently treated with CsF in refluxing CH3CN to
give the desired ring F-cyclized ester 52 in 34% yield for
the two-step sequence. Despite the additional manipulations
associated with the processing of intermediate 47 and the
O
N
O
N
H
1. P2S5
2. Ra-Ni
OBn
3. PtO2, H2,
HCl
O
OH
O
N
N
TolSO
H
H
CO2Me
TolSO2
CO2Me
2 HO
39
43 (43%)
Et3N
MsCl
N
N
SmI2
OMs
OMs
CO2Me
H
HMPA
H
O
O
N
TolSO
N
H
H
H
CO2Me
2 HO
TolSO2
44 (85%)
45 (60%)
Scheme 10.
N
N
SmI2
This outcome suggested that the mesylate group was not suf-
ficiently reactive enough to undergo reaction with the anion
resulting from deprotonation of the b-keto ester. Conse-
quently, we turned our attention to replacing the mesylate
group with a more reactive aldehyde functionality on the
side chain. To access a suitable and useful substrate for the
key aldol reaction, we prepared cycloadduct 46, which bears
a 2-methyl acetate group at the ring juncture from the Rh(II)-
catalyzed reaction of diazoimide 26. We then converted 46
into the ring-opened hydroxy ester 47 (68%) using the
same three-step protocol that was used in Scheme 10. At
this point, the carbomethoxy and hydroxyl groups were
sequentially removed using Cs2CO3 followed15,44,45 by a
samarium iodide reduction.46 The remaining keto group
was converted into the corresponding TBS enol ether and
this was followed by a two-step reduction/oxidation of the
CH2CO2Me
O
CO2Me
CH2CO2Me
O
H
H
HMPA
N
N
TolSO
H
H
H
TolSO2
CO2Me
2 HO
50 (93%)
47
1. TBDMSOTf
2. LAH
N
N
H
1. TPAP, NMO
2. CsF, CH3CN
CH2CH2OH
OTBS
CO2Me
51 (87%)
O
H
OH
N
N
H
H
TolSO2
TolSO2
CO2Me
52 (34%)
Scheme 12.

X. Hong et al. / Tetrahedron 63 (2007) 5962–5976
5967
somewhat lower yield, only five steps are required to prepare
a complex racemic hexacyclic structure that contains the
complete skeleton of the kopsifoline alkaloids.
1202, and 1100 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d 1.79–1.92 (m, 2H), 2.03–2.10 (m, 1H), 2.23–2.34 (m,
3H), 3.27–3.36 (m, 2H), 3.59–367 (m, 2H), 4.48 (s, 2H),
6.28 (br s, 1H), and 7.20–7.38 (m, 5H) (the carboxylic acid
proton was too broad to be detected); 13C NMR (100 MHz,
CDCl3) d 19.2, 27.8, 37.9, 42.9, 50.7, 66.4, 73.4, 127.9,
128.6, 138.2, and 175.5. Anal. Calcd for C15H19NO4: C,
64.97; H, 6.91; N, 5.05. Found: C, 64.87; H, 6.74; N, 4.96.
3. Conclusions
In summary, the new cyclization chemistry described herein
gives rapid access to the hexacyclic core skeleton of the kop-
sifoline alkaloids, and the products synthesized appear to be
suitable for further manipulation toward the natural products
and their close analogues. Further application of the metal
carbene cyclization–cycloaddition cascade toward several
other monoterpenoid indoline alkaloids is currently being
investigated.
To a solution of 9.0 g (33 mmol) of the above carboxylic
acid in 150 mL of CH2Cl2 was added 6.3 g (39 mmol) of
1,10-carbonyldiimidazole. The solution was allowed to stir
at rt under N2 overnight, concentrated under reduced pres-
sure, and taken up in 150 mL of THF. A 10.1 g (65 mmol)
sample of potassium methyl malonate, 6.2 g (65 mmol) of
powdered magnesium chloride, and a small amount (0.4 g,
3.2 mmol) of 4-(dimethylamino)pyridine was dissolved in
400 mL of THF and 200 mL of acetonitrile. After stirring
for 2 h, the above lactam in THF was added dropwise to
the malonate solution together with 9.0 mL (65 mmol) of
triethylamine. The solution was allowed to stir at rt over-
night and then 200 mL of a 1 N HCI solution was added.
The organic layer was separated and the aqueous layer was
extracted with ether. The combined organic extracts were
washed with brine, dried over MgSO4, and concentrated un-
der reduced pressure. The residue was subjected to flash
silica gel chromatography to give 8.9 g (82%) of the titled
compound 20a as a colorless solid; mp 57–58 ꢀC; IR
4. Experimental
4.1. General
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise
noted, all reactions were performed in flame dried glassware
under an atmosphere of dry nitrogen. Solutions were evapo-
rated under reduced pressure with a rotary evaporator and the
residue was chromatographed on a silica gel column using
an ethyl acetate–hexane mixture as the eluent unless speci-
fied otherwise.
(neat) 1749, 1706, 1437, 1319, and 1103 cmꢂ1; H NMR
1
(400 MHz, CDCl3) d 1.53 (pent, 1H, J¼7.2 Hz), 1.66–1.75
(m, 2H), 2.08 (dt, 1H, J¼14.4 and 6.0 Hz), 2.28–2.42 (m,
2H), 3.14–3.21 (m, 2H), 3.37–3.43 (m, 1H), 3.49–3.54 (m,
1H), 3.58 (s, 3H), 3.64 (d, 1H, J¼16.6 Hz), 3.89 (d, 1H,
J¼16.6 Hz), 3.35 (s, 2H), and 7.21–7.25 (m, 6H); 13C
NMR (100 MHz, CDCl3) d 19.3, 27.4, 35.9, 41.9, 45.1,
51.7, 58.0, 65.7, 72.7, 127.2, 127.3, 128.0, 137.7, 167.9,
171.1, and 200.9. Anal. Calcd for C18H23NO5: C, 64.85;
H, 6.95; N, 4.20. Found: C, 64.91; H, 7.06; N, 4.31.
4.1.1. 3-[3-{2-Benzyloxyethyl}-2-oxo-piperidin-3-yl]-3-
oxo-propionic acid methyl ester (20a). To a stirred solution
of 8.2 g (48 mmol) of 2-oxopiperidine-3-carboxylic acid
ethyl ester in 125 mL of THF at ꢂ78 ꢀC was added 20 mL
(48 mmol) of a 2.4 M n-butyllithium solution in hexane.
The resulting solution was allowed to warm to 0 ꢀC for
10 min, re-cooled to ꢂ78 ꢀC and 12.6 g (48 mmol) of 2-
iodoethyl benzyl ether was added. The cooling bath was
removed and the solution was heated at reflux for 3 days.
The solution was allowed to cool to rt, the solvent was re-
moved under reduced pressure, and the residue was subjected
to flash silica gel chromatography to give 10.2 g (70%) of 3-
(2-benzyloxyethyl)-2-oxo-piperidine-3-carboxylic acid eth-
yl ester (19) as a colorless oil; IR (neat) 1729, 1669, 1194,
4.1.2. 3-[3-{2-Benzyloxyethyl}-2-oxo-piperidin-3-yl]-3-
oxo-propionic acid ethyl ester (20b). Keto ester 20b was
prepared in the same manner as described for 20a from the
reaction of 9.0 g (33 mmol) of 3-{2-benzyloxyethyl}-2-
oxo-piperidine-3-carboxylic acid and 11.1 g (65.0 mmol)
of potassium ethyl malonate. Purification by flash silica
gel chromatography gave 9.4 g (84%) of the titled com-
pound 20b as a pale yellow oil; IR (neat) 2937, 2869,
1741, 1707, 1654, 1488, 1453, 1366, 1318, 1260, 1101,
1
1119 and 1098 cmꢂ1; H NMR (400 MHz, CDCl3) d 1.23
(t, 3H, J¼7.0 Hz), 1.78–1.90 (m, 2H), 1.95 (td, 1H, J¼13.2
and 4.0 Hz), 2.15–2.35 (m, 3H), 3.20–3.35 (m, 2H), 3.64
(td, 2H, J¼6.8 and 2.0 Hz), 4.10–4.23 (m, 2H), 4.46 (s,
2H), 6.03 (br s, 1H), and 7.20–7.73 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 14.3, 19.8, 30.4, 35.2, 42.5, 53.0,
61.7, 67.3, 73.1, 127.7, 127.8, 128.5, 138.6, 171.0, and 172.8.
1
and 1028 cmꢂ1; H NMR (400 MHz, CDCl3) d 1.26 (t,
3H, J¼7.6 Hz), 1.62–1.65 (m, 1H), 1.77–1.81 (m, 2H),
2.19 (dt, 1H, J¼14.4 and 6.0 Hz), 2.36–2.51 (m, 2H),
3.24–3.28 (m, 2H), 3.48–3.52 (m, 1H), 3.53–3.60 (m, 1H),
3.70 (d, 1H, J¼16.4 Hz), 3.96 (d, 1H, J¼16.4 Hz), 4.16 (q,
2H, J¼16.4 Hz), 4.45 (s, 1H), 6.97 (s, 1H), and 7.20–7.30
(m, 5H); 13C NMR (100 MHz, CDCl3) d 14.1, 19.7, 27.8,
36.3, 42.4, 45.5, 58.5, 61.1, 66.1, 73.1, 127.6, 127.7,
128.4, 138.1, 167.1, 167.8, 171.6, and 201.3; HRMS calcd
for [(C19H25NO5)+H]+: 348.1811. Found: 348.1821.
To a solution of 23.4 g (77 mmol) of the above ethyl ester in
a 1:1 THF/H2O mixture (300 mL) was added 8.6 g of potas-
sium hydroxide (150 mmol) and the mixture was stirred
overnight. The solvent was removed under reduced pressure
and the residue was taken up in water. The solution was
washed with EtOAc and acidified to pH 2. The aqueous layer
was extracted with chloroform and the combined organic
phase was dried over MgSO4, filtered, and concentrated un-
der reduced pressure to give 19.2 g (91%) of 3-{2-benzyl-
oxyethyl}-2-oxo-piperidine-3-carboxylic acid as a white
solid; mp 102–103 ꢀC; IR (neat) 1700, 1653, 1492, 1454,
4.1.3. Methyl 3-(3-(2-methoxy-2-oxoethyl)-2-oxo-piperi-
din-3-yl)-3-oxopropanoate (23). A 8.8 g (28 mmol) sample
of methyl 3-(3-(2-tert-butoxy-2-oxoethyl)-2-oxo-piperidin-
3-yl)-3-oxopropanoate (22) in MeOH (40 mL) and

5968
X. Hong et al. / Tetrahedron 63 (2007) 5962–5976
(MeO)3CH (40 mL) was vigorously stirred for 10 min at
100 ꢀC. To this mixture was added 5.3 g (28 mmol) of
p-TsOH$H2O in one portion and the mixture was allowed
to stir for 4 h. The solution was cooled to rt and concentrated
under reduced pressure. The colorless residue was subjected
to flash chromatography on silica gel to afford 7.5 g (99%) of
the titled compound 23 as a colorless oil; IR (neat) 3349,
2953, 1732, 1710, 1655, 1489, 1436, 1354, 1319, 1271,
190.3; HRMS calcd for [(C35H34N4O8S)+H]+: 671.2176.
Found: 671.2182.
4.1.6. Methyl 3-(3-(2-(benzyloxy)ethyl)-2-oxo-1-(2-(1-
tosyl-1H-indol-3-yl)acetyl)piperidin-3-yl)-3-oxopropa-
noate. To 100 mL of CH2Cl2 in a 200 mL round bottomed
flask was added 6.0 g (18 mmol) of 2-(1-tosyl-1H-indol-
3-yl) acetic acid. After stirring for 5 min, 5.3 mL (60 mmol)
of (COCl)2 was added dropwise. The solution was stirred
for 5 h and then concentrated under reduced pressure. The
resulting solid was taken up in 50 mL of CH2Cl2 and this so-
lution was added dropwise to a solution of 5.0 g (15 mmol)
1
1223, 1194, 1174, and 1002 cmꢂ1; H NMR (400 MHz,
CDCl3) d 1.73–1.89 (m, 3H), 2.33–2.38 (m, 1H), 2.66
(d, 1H, J¼16.4 Hz), 3.01 (d, 1H, J¼16.4 Hz), 3.27–3.39
(m, 2H), 3.63 (s, 3H), 3.68 (s, 3H), 3.79 (dd, 1H, J¼19.6
and 16.8 Hz), and 7.02 (s, 1H); 13C NMR (100 MHz,
CDCl3) d 20.1, 28.9, 40.3, 42.7, 45.9, 52.1, 52.5, 57.8,
167.9, 170.9, 171.1, and 201.0; HRMS calcd for
[(C12H17NO6)+H]+: 272.1134. Found: 272.1129.
˚
of lactam 20a and 50 g of 4 A mesh molecular sieves in
250 mL of CH2Cl2. The reaction mixture was allowed to
stir at rt for 12 h, filtered through a pad of Celite, and concen-
trated under reduced pressure. The residue was subjected to
flash silica gel chromatography to give 8.1 g (84%) of the
titled imide as a clear oil; IR (neat) 2954, 2872, 1752,
1683, 1593, 1446, 1360, 1290, 1160, 1115, 1086, and
4.1.4. 3-[3-(2-Benzyloxyethyl)-2-oxo-piperidin-3-yl]-2-di-
azo-3-oxo-propionic acid ethyl ester. To 0.7 g (2.22 mmol)
of ketoester 20b in 20 mL of CH3CN was added 0.37 mL
(2.7 mmol) of Et3N. The solution was allowed to stir for
30 min at rt and then 0.54 g (4.4 mmol) of mesyl azide
was added and the reaction was allowed to stir for 10 h at
rt. The solution was concentrated under reduced pressure
and the residue was subjected to flash chromatography on
silica gel to give 0.82 g (99%) of the titled compound as
a colorless oil; IR (neat) 3298, 3226, 2975, 2939, 2873,
2146, 1716, 1644, 1501, 1367, 1316, 1209, and
1
976 cmꢂ1; H NMR (400 MHz, CDCl3) d 1.61–1.72 (m,
1H), 1.83 (pent, 2H, J¼7.2 Hz), 2.21–2.32 (m, 2H), 2.30 (s,
3H), 2.46 (dt, 1H, J¼10.4 and 7.2 Hz), 3.42–3.50 (m, 1H),
3.53–3.74 (m, 4H), 3.64 (s, 3H), 3.84 (d, 1H, J¼21.2 Hz),
4.20 (s, 2H), 4.38 (s, 2H), 7.16–7.32 (m, 9H), 7.46 (d, 1H,
J¼8.4 Hz), 7.55 (s, 1H), 7.75 (d, 2H, J¼8.4 Hz), and 7.96
(d, 1H, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3) d 20.0,
21.8, 27.6, 35.6, 36.7, 44.6, 44.9, 52.6, 61.9, 65.9, 73.5,
113.8, 116.0, 120.0, 123.4, 124.9, 125.4, 127.0, 127.8,
127.9, 128.7, 130.1, 131.1, 135.1, 135.5, 137.8, 145.1,
168.0, 173.7, 174.0, and 200.1; HRMS calcd for
[(C35H36N2O8S)+H]+: 645.2271. Found: 645.2275.
1
1106 cmꢂ1; H NMR (400 MHz, CDCl3) d 1.22 (t, 3H,
J¼7.6 Hz), 1.62–1.74 (m, 2H), 1.92–2.04 (m, 1H), 2.18–
2.35 (m, 3H), 3.20–3.23 (m, 1H), 3.39–3.68 (m, 3H), 4.16
(q, 2H, J¼16.4 Hz), 4.42 (s, 1H), 5.81 (s, 1H), and 7.16–
7.27 (m, 5H); 13C NMR (100 MHz, CDCl3) d 141.1, 18.5,
29.0, 34.7, 42.2, 56.2, 61.1, 67.5, 72.8, 127.2, 127.5,
128.1, 138.5, 160.8, 172.2, and 191.0; HRMS calcd for
[(C19H23NO5)+H]+: 374.1716. Found: 374.1723.
4.1.7. Methyl 3-(3-(2-(benzyloxy)ethyl)-2-oxo-1-(2-(1-
tosyl-1H-indol-3-yl)acetyl)piperidin-3-yl)-2-diazo-3-oxo-
propanoate (25). To a 2.4 g (3.7 mmol) sample of the above
ketoester in 100 mL of CH3CN was added 0.6 mL
(4.5 mmol) of Et3N. The solution was allowed to stir for
30 min at which time 0.47 g (3.9 mmol) of mesyl azide
was added and the reaction mixture was allowed to stir at
rt for 5 h. The solution was concentrated under reduced pres-
sure and the residue was subjected to flash chromatography
on silica gel to give 2.2 g (88%) of diazoimide 25 as a pale
yellow oil; IR (neat) 2982, 2864, 2167, 1707, 1687, 1446,
4.1.5. 3-[1-[2-(1-Benzenesulfonyl-1H-indol-3-yl)-acetyl]-
3-(2-benzyloxyethyl)-2-oxo-piperidin-3-yl]-2-diazo-3-
oxo-propionic acid ethyl ester (24). In a 100 mL round
bottomed flask was added 0.19 g (0.6 mmol) of (1-benzene-
sulfonyl-1H-indol-3-yl)acetyl chloride in 10 mL of CH2Cl2.
After stirring for 5 min, 0.14 mL (1.6 mmol) of (COCl)2 in
5 mL of DMF was added. The solution was stirred for 3 h
at rt and then concentrated under reduced pressure. The re-
sulting solid was taken up in 2 mL of THF and was added
dropwise to a solution of 0.2 g of the above diazo lactam
1
1368, 1303, and 1168 cmꢂ1; H NMR (400 MHz, CDCl3)
d 1.68–1.72 (m, 1H), 1.91–2.02 (m, 2H), 2.21–2.26 (m,
2H), 2.28 (s, 3H), 2.34 (dt, 1H, J¼14.4 and 6.0 Hz), 3.51
(dt, 1H, J¼10.0 and 6.0 Hz), 3.64–3.77 (m, 2H), 3.75 (s,
3H), 3.92 (d, 1H, J¼17.2 Hz), 4.21 (d, 1H, J¼17.2 Hz),
4.16–4.23 (m, 1H), 4.39 (s, 2H), 7.14–7.28 (m, 9H), 7.36
(d, 1H, J¼7.6 Hz), 7.43 (s, 1H), 7.72 (d, 2H, J¼8.0 Hz),
7.92 (d, 1H, J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
d 19.5, 21.7, 30.5, 35.1, 35.2, 43.0, 52.7, 59.4, 67.3, 73.2,
113.7, 116.6, 119.9, 123.3, 124.8, 125.1, 127.0, 127.7,
127.8, 128.5, 130.0, 131.2, 135.1, 135.5, 138.3, 145.0,
161.8, 173.7, 174.4, and 190.6; HRMS calcd for
[(C35H34N4O8S)+H]+: 671.2176. Found: 671.2181.
˚
(0.54 mmol) and 3 g of 4 A mesh molecular sieves in
10 mL of THF. The reaction mixture was allowed to stir at
rt overnight, filtered through a pad of Celite, and concen-
trated under reduced pressure. The residue was subjected
to flash silica gel chromatography to give 0.29 g (80%) of
24 as a pale yellow oil; IR (neat) 2975, 2929, 2847, 2130,
1
1726, 1675, 1470, 1388, 1326, 1152, and 1101 cmꢂ1; H
NMR (300 MHz, CDCl3) d 1.60 (t, 3H, J¼7.2 Hz), 1.48–
1.53 (m, 1H), 1.71–1.83 (m, 2H), 2.00–2.23 (m, 3H), 3.29–
3.36 (m, 1H), 3.45–3.58 (m, 2H), 3.72 (d, 1H, J¼17.4 Hz),
3.99–4.05 (m, 4H), 4.20 (s, 1H), 6.94–7.07 (m, 7H), 7.16–
7.29 (m, 5H), 7.63–7.66 (m, 2H), and 7.74 (d, 1H,
J¼8.4 Hz); 13C NMR (75 MHz, CDCl3) d 14.3, 19.3, 30.3,
34.9, 35.0, 44.2, 59.1, 61.7, 67.0, 72.9, 113.4, 116.5, 119.0,
123.0, 124.5, 124.7, 126.6, 127.4, 127.5, 128.1, 129.1,
130.8, 133.5, 134.8, 137.9, 138.2, 161.0, 173.3, 174.0, and
4.1.8. Methyl 3-(3-(2-methoxy-2-oxoethyl)-2-oxo-1-(2-(1-
tosyl-1H-indol-3-yl)acetyl)piperidin-3-yl)-3-oxopropa-
noate. To 100 mL of CH2Cl2 in a 200 mL round bottomed
flask was added 6.9 g (21 mmol) of 2-(1-tosyl-1H-indol-
3-yl) acetic acid. After stirring for 5 min, 7.0 mL (80 mmol)
of (COCl)2 was added dropwise together with two drops

X. Hong et al. / Tetrahedron 63 (2007) 5962–5976
5969
of DMF. The solution was stirred at rt for 4 h and was con-
centrated under reduced pressure. The resulting solid was
taken up in 50 mL of CH2Cl2 and added dropwise to a solu-
tion of 5.4 g (20.0 mmol) of the above lactam 23 and 90 g of
J¼7.2 Hz), 1.43 (t, 3H, J¼7.2 Hz), 1.72–1.82 (m, 3H),
1.97–2.07 (m, 1H), 2.31 (d, 1H, J¼17.1 Hz), 2.78 (d, 1H,
J¼17.1 Hz), 3.04–3.16 (m, 1H), 3.31–3.39 (m, 1H), 3.47–
3.55 (m, 1H), 3.82–3.86 (m, 1H), 4.24 (s, 2H), 4.43 (q, 2H,
J¼7.2 Hz), 4.90 (s, 1H), 6.94 (d, 1H, J¼7.5 Hz), 7.07 (t,
1H, J¼7.5 Hz), 7.15 (d, 2H, J¼6.3 Hz), 7.21–7.35 (m, 4H),
7.42 (t, 2H, J¼7.5 Hz), 7.55 (d, 1H, J¼7.5 Hz), 7.61 (d,
1H, J¼8.4 Hz), and 7.67 (d, 1H, J¼7.5 Hz); 13C NMR
(75 MHz, CDCl3) d 13.9, 17.7, 25.3, 27.1, 39.0, 44.1, 52.2,
57.8, 62.8, 65.8, 72.3, 75.4, 87.9, 103.9, 116.8, 124.5,
125.3, 127.2, 127.3, 127.4, 128.2, 129.1, 130.1, 130.4,
133.9, 135.7, 137.9, 142.4, 164.1, 175.6, and 203.3; HRMS
calcd for [(C35H34N2O8S)+H]+: 643.2114. Found: 643.2129.
˚
4 A mesh molecular sieves in 300 mL of CH2Cl2. The reac-
tion mixture was allowed to stir at rt for 12 h, filtered through
a pad of Celite, and concentrated under reduced pressure.
The residue was subjected to flash silica gel chromatography
to give 10.6 g (91%) of the titled compound as a pale yellow
oil: IR (neat) 2953, 1738, 1703, 1689, 1596, 1446, 1396,
1363, and 1171 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d 1.72–1.91 (m, 2H), 1.95–2.02 (m, 1H), 2.29 (s, 3H), 2.38
(dt, 1H, J¼14.0 and 4.0 Hz), 2.72 (d, 1H, J¼16.8 Hz),
3.19 (d, 1H, J¼16.8 Hz), 3.95 (dt, 1H, J¼12.4 and
4.4 Hz), 4.30 (dd, 1H, J¼25.6 and 17.2 Hz), 7.18 (d, 2H,
J¼8.0 Hz), 7.22 (dt, 1H, J¼8.0 and 0.8 Hz), 7.30 (td, 1H,
J¼8.0 and 1.2 Hz), 7.52 (d, 1H, J¼7.6 Hz), 7.61 (s, 1H),
7.76 (d, 2H, J¼8.4 Hz), and 7.97 (d, 1H, J¼8.0 Hz); 13C
NMR (100 MHz, CDCl3) d 19.7, 21.3, 28.8, 35.2, 40.1,
44.6, 52.1, 52.4, 60.8, 113.3, 115.7, 119.6, 123.0, 124.4,
125.0, 126.6, 129.7, 130.7, 134.7, 135.0, 144.7, 166.9,
170.5, 172.8, 173.6, and 199.4; HRMS calcd for
[(C29H30N2O9S)+H]+: 583.1750. Found: 583.1748.
4.1.11. 3a-{2-Benzyloxyethyl}-5,12b-epoxy-6-H-4,12-di-
oxo-2,3,3a,4,5,5a,6,11,12,12b-decahydro-1H-6,12a-di-
aza-indeno[7,1-cd]fluorene-5-carboxylic acid ethyl ester
(28). A mixture of 0.02 g (0.017 mmol) of cycloadduct 27,
Et3N (12.5 mL, 0.085 mmol), and anhydrous CH3CN
(4 mL) was degassed with N2 for 30 min. The mixture was
irradiated (RPR-2537A lamp in a RPR-100 reactor) in
a quartz tube for 1 h under a nitrogen atmosphere. The solu-
tion was concentrated under reduced pressure and the resi-
due was subjected to flash silica gel chromatography to
give 0.008 g (90%) of the desulfonylated product 28 as a col-
orless oil; IR (neat) 3446, 2955, 2919, 2858, 1721, 1475,
4.1.9. Methyl 2-diazo-3-(3-(2-methoxy-2-oxoethyl)-2-
oxo-1-(2-(1-tosyl-1H-indol-3-yl)acetyl)piperidin-3-yl)-3-
oxopropanoate (26). To a 8.7 g (15 mmol) sample of the
above keto ester in 140 mL of CH3CN at 0 ꢀC was added
2.3 mL (16 mmol) of Et3N. The solution was allowed to
stir for 20 min and then 1.95 g (30 mmol) of mesyl azide
was added and the reaction mixture was allowed to stir for
1.5 h. The solution was concentrated under reduced pressure
and the residue was subjected to flash chromatography on
silica gel to give 8.1 g (89%) of the titled diazoimide 26 as
a pale yellow solid; mp 79–80 ꢀC; IR (neat) 2954, 2143,
1688, 1649, 1437, 1356, 1329, 1294, 1195, 1170, 1127, and
1
1352, 1173, and 1065 cmꢂ1; H NMR (400 MHz, CDCl3)
d 0.70–0.78 (m, 1H), 1.18–1.26 (m, 1H), 1.36 (t, 3H,
J¼7.2 Hz), 1.70–1.92 (m, 3H), 1.88–2.24 (m, 1H), 3.15
(td, 1H, J¼12.8 and 4.8 Hz), 3.34–3.39 (m, 1H), 3.50–3.56
(m, 1H), 3.86 (dd, 1H, J¼12.8 and 4.0 Hz), 4.23 (dd, 2H,
J¼7.2 and 3.2 Hz), 4.31–4.43 (m, 3H), 4.73 (s, 1H), 6.58
(d, 1H, J¼8.0 Hz), 6.73 (t, 1H, J¼8.0 Hz), 6.97 (d, 1H,
J¼6.8 Hz), 7.10–7.17 (m, 3H), and 7.23–7.32 (m, 3H); 13C
NMR (100 MHz, CDCl3) d 14.3, 18.2, 26.2, 26.8, 35.2,
45.7, 51.0, 59.7, 62.8, 66.2, 72.6, 80.9, 92.6, 104.3, 108.1,
118.7, 123.8, 127.5, 127.6, 127.7, 128.5, 130.5, 138.4,
153.1, 166.0, 177.0, and 205.6.
1
1095 cmꢂ1; H NMR (400 MHz, CDCl3) d 1.80–1.95 (m,
2H), 2.25 (s, 3H), 2.29 (dd, 1H, J¼12.0 and 4.4 Hz), 2.48
(dt, 1H, J¼13.2 and 3.6 Hz), 2.85 (d, 2H, J¼4.0 Hz), 3.65 (s,
3H), 3.68–3.76 (m, 1H), 3.74 (s, 3H), 4.07 (dt, 1H, J¼13.2
and 4.0 Hz), 4.20 (dd, 1H, J¼19.6 and 17.6 Hz), 7.13 (d,
2H, J¼8.0 Hz), 7.17 (t, 1H, J¼8.0 Hz), 7.25 (td, 1H, J¼8.0
and 1.2 Hz), 7.45 (d, 1H, J¼7.6 Hz), 7.52 (s, 1H), 7.71 (d,
2H, J¼8.4 Hz), and 7.92 (d, 1H, J¼8.4 Hz); 13C NMR
(100 MHz, CDCl3) d 19.1, 21.3, 27.3, 35.0, 37.2, 44.2,
51.7, 52.3, 60.0, 113.3, 115.9, 119.5, 122.9, 124.4, 124.8,
126.6, 129.6, 130.7, 134.7, 135.1, 144.6, 161.3, 170.7,
172.6, 173.9, and 189.2. Anal. Calcd for C29H28N4O9S: C,
57.23; H, 4.64; N, 9.21. Found: C, 57.35; H, 4.75; N, 9.17.
4.1.12. Irradiation of N-benzenesulfonyl-1H-indole (31a).
The same irradiation procedure as described above was used
starting from commercially available N-benzenesulfonyl-
1H-indole (31a) (0.26 g, 1.0 mmol). Purification by flash sil-
ica gel chromatography afforded 0.04 g (48%) of 1H-indole
32a.
4.1.13. Irradiation of N-benzenesulfonyl-2,3-dimethyl-
1H-indole (31b). The same irradiation procedure as de-
scribed above was used starting from 0.32 g (1.0 mmol) of
N-benzenesulfonyl-2,3-dimethyl-1H-indole (31b).47 Purifi-
cation by flash silica gel chromatography afforded 0.06 g
(55%) of 2,3-dimethyl-1H-indole 32b.
4.1.10. 3a-{2-Benzyloxyethyl}-5,12b-epoxy-6-benzene-
sulfonyl-4,12-dioxo-2,3,3a,4,5,5a,6,11,12,12b-decahydro-
1H-6,12a-diaza-indeno[7,1-cd]fluorene-5-carboxylic
acid ethyl ester (27). To a solution of 0.2 g (0.3 mmol) of
diazoimide 24 in 10 mL benzene under N2 was added
5 mg of rhodium(II) acetate and the mixture was heated at
reflux for 1 h. The mixture was allowed to cool to rt and
was filtered through a pad of Celite. The solvent was removed
under reduced pressure and the residue was subjected to flash
silica gel chromatography to give 0.18 g (94%) of cyclo-
adduct 27 as a clear oil; IR (neat) 2991, 2919, 2873, 1787,
4.1.14. N-Benzenesulfonyl-3-[2-(tert-butyl-dimethylsila-
nyloxy)ethyl]-1H-indole (31c). The same irradiation proce-
dure as described above was used starting from 0.07 g
(0.17 mmol)ofN-benzenesulfonyl-3-[2-(tert-butyl-dimethyl-
silanyloxy)ethyl]-1H-indole (31c).48 Purification by flash
silica gel chromatography yielded 0.03 g (57%) of the known
3-[2-(tert-butyl-dimethylsilanyloxy)ethyl]-1H-indole 32c.49
1726, 1434, 1372, 1296, and 1163 cmꢂ1
;
(300 MHz, CDCl3) d 0.11–0.20 (m, 1H), 1.12 (pent, 1H,
1H NMR
4.1.15. Irradiation of N-benzenesulfonyl-1H-indole-3-
carboxylic acid methyl ester (31d). The same irradiation

5970
X. Hong et al. / Tetrahedron 63 (2007) 5962–5976
procedure as described above was used starting from 0.32 g
(1.0 mmol) of N-benzenesulfonyl-1H-indole-3-carboxylic
acid methyl ester (31d).47 Purification by flash silica gel
chromatography yielded 0.13 g (77%) of 1H-indole-3-car-
boxylic acid methyl ester (32d).
7.07 (t, 1H, J¼7.5 Hz), 7.17–7.33 (m, 7H), 7.55 (d, 2H,
J¼8.1 Hz), and 7.63 (d, 1H, J¼8.1 Hz); 13C NMR
(75 MHz, CDCl3) d 17.7, 21.4, 25.3, 27.1, 39.0, 44.1, 52.2,
53.2, 57.7, 65.7, 72.3, 75.6, 87.9, 104.0, 116.7, 124.4,
125.2, 127.2, 127.3, 128.1, 129.7, 130.1, 130.4, 132.6,
137.9, 142.4, 145.0, 164.6, 175.6, and 203.1. Anal. Calcd
for C35H34N2O8S: C, 65.41; H, 5.33; N, 4.36. Found: C,
65.24; H, 5.50; N, 4.37.
Two additional fractions were obtained from the chromato-
graphy column and each was separately purified. One of the
fractions contained a colorless oil whose structure was
assigned as 5-benzenesulfonyl-1H-indole-3-carboxylic acid
methyl ester (33d); IR (neat) 3350, 2927, 1718, 1536,
4.1.18. Unusual reductive rearrangement of cycloadduct
39 using triethylsilylhydride and boron trifluoride ether-
ate. A solution containing 0.06 g (0.1 mmol) of cycloadduct
39 in CH2Cl2 (4 mL) was cooled to ꢂ78 ꢀC and 160 mL
(1 mmol) of Et3SiH and 65 mL (0.5 mmol) of BF3$Et2O
were added. The solution was allowed to warm to rt for
1 h and was then heated at reflux for 24 h. The reaction mix-
ture was cooled to rt and washed with a satd NaHCO3 solu-
tion, brine, and H2O. The solution was extracted with
CH2Cl2 and dried over MgSO4. Removal of the solvent
left a colorless residue, which was subjected to flash chroma-
tography on silica gel to afford 0.03 g (60%) of 42 as a
colorless solid; mp 250 ꢀC; IR (neat) 3467, 2956, 2159,
1755, 1692, 1641, 1596, 1460, 1359, 1265, 1169, and
1465, 1447, 1334, 1333, and 1152 cmꢂ1
;
1H NMR
(400 MHz, DMSO) d 3.78 (s, 3H), 7.54–7.65 (m, 4H),
7.68 (d, 1H, J¼8.4 Hz), 7.92 (d, 2H, J¼8.4 Hz), 8.08 (s,
1H), 8.13 (d, 1H, J¼8.4 Hz), 8.35 (s, 1H); 13C NMR
(100 MHz, DMSO) d 51.0, 106.9, 112.7, 119.8, 121.5,
127.1, 129.1, 129.7, 133.4, 134.5, 135.3, 136.6, 141.9, and
164.1.
The second fraction was a clear oil and was identified as
7-benzenesulfonyl-1H-indole-3-carboxylic acid methyl
ester (34d); IR (neat) 3319, 2948, 1713, 1531, 1445, 1419,
1
1338, 1302, and 1155 cmꢂ1; H NMR (600 MHz, CDCl3)
1
d 3.65 (s, 3H), 7.27 (t, 1H, J¼8.4 Hz), 7.48 (t, 2H,
J¼7.8 Hz), 7.55–7.57 (m, 1H), 7.65 (d, 1H, J¼8.4 Hz),
7.72 (d, 1H, J¼2.4 Hz), 7.76 (d, 1H, J¼7.8 Hz), 7.89 (s,
1H), 7.90 (d, H, J¼8.4 Hz); 13C NMR (150 MHz, CDCl3)
d 51.7, 110.5, 117.5, 120.6, 122.1, 125.3, 126.7, 128.7,
131.0, 131.8, 132.6, 137.4, 142.6, and 166.4.
1135 cmꢂ1; H NMR (400 MHz, CDCl3) d 1.36–1.42 (m,
2H), 1.63 (d, 1H, J¼15.2 Hz), 1.66–1.78 (m, 2H), 1.90 (dt,
1H, J¼11.2 and 3.2 Hz), 2.10–2.15 (m, 1H), 2.32 (s, 3H),
2.35 (d, 1H, J¼11.2 Hz), 3.25–3.30 (m, 1H), 3.56–3.58
(m, 1H), 7.00 (dd, 1H, J¼5.2 and 0.4 Hz), 7.12–7.14 (m,
3H), 7.30 (d, 2H, J¼5.2 Hz), 7.35 (td, 1H, J¼5.2 and
0.8 Hz), and 7.83 (d, 1H, J¼5.6 Hz); 13C NMR (100 MHz,
CDCl3) d 19.8, 21.5, 29.0, 32.6, 38.7, 51.1, 54.6, 55.6,
64.1, 79.2, 79.9, 115.1, 119.1, 124.3, 125.7, 128.0, 129.0,
129.6, 131.7, 134.8, 137.3, 143.4, 145.1, 169.1, 169.8, and
170.6; HRMS calcd for [(C28H28N2O8S)+H]+: 553.1645.
Found: 553.1636.
4.1.16. Irradiation of N-benzenesulfonyl-(2-hydroxy-
methyl-1H-indol-3-yl)ethanone (31e). The same irradia-
tion procedure as described above was used starting from
0.33 g (1.0 mmol) of N-benzenesulfonyl-(2-hydroxy-
methyl-1H-indol-3-yl)ethanone (31e).50 Purification by
flash silica gel chromatography afforded 0.11 g (60%) of
1-(2-hydroxymethyl-1H-indol-3-yl)ethanone (32e) as a col-
orless oil; IR (neat) 3292, 3060, 2976, 2875, 1748, 1613,
4.1.19. 3a-{2-Benzyloxyethyl}-5,12b-epoxy-6-tosyl-4-
oxo-12-thioxo-2,3,3a,4,5,5a,6,11,12,12b-decahydro-1H-
6,12a-diaza-indeno[7,1-cd]fluorene-5-carboxylic acid
methyl ester. To a solution containing 0.72 g (1.1 mmol)
of the above cycloadduct 39 in 30 mL benzene under N2
were added 0.2 g (0.45 mmol) of P2S5 and 255 mL
(0.76 mmol) of (TMS)2O at rt. The mixture was heated at
reflux for 3 h, cooled to rt, and filtered through a pad of
Celite. The solvent was removed under reduced pressure
and the residue was subjected to flash silica gel chromato-
graphy to give 0.67 g (90%) of the corresponding thioamide
as a clear oil; IR (neat) 2953, 1776, 1746, 1597, 1477, 1390,
1
1574, 1446, 1379, 1358, 1283, 1176, and 1078 cmꢂ1; H
NMR (400 MHz, DMSO) d 2.51 (s, 3H), 3.40 (s, 1H), 4.96
(s, 2H), 5.77 (s, 1H), 7.12–7.14 (m, 2H), 7.47–7.50 (m,
1H), and 7.92–7.94 (m, 1H); 13C NMR (100 MHz,
DMSO) d 30.7, 58.1, 111.6, 112.3, 120.3, 121.5, 121.7,
126.7, 135.0, 149.0, and 193.0.
4.1.17. 3a-{2-Benzyloxyethyl}-5,12b-epoxy-6-tosyl-4,12-
dioxo-2,3,3a,4,5,5a,6,11,12,12b-decahydro-1H-6,12a-
diaza-indeno[7,1-cd]fluorene-5-carboxylic acid methyl
ester (39). To a solution of 2.0 g (3 mmol) of diazoimide
25 in 100 mL of benzene under N2 was added 20 mg rho-
dium(II) acetate, and the mixture was heated at reflux for
1 h. The mixture was allowed to cool to rt and was filtered
through a pad of Celite. The solvent was removed under
reduced pressure and the residue was subjected to flash silica
gel chromatography to give 1.5 g (90%) of the dipolar cyclo-
addition product 39 as a white solid; mp 169–170 ꢀC; IR
(neat) 3076, 3027, 2953, 2859, 1773, 1727, 1478, 1460,
1
1367, 1320, 1170, and 1088 cmꢂ1; H NMR (400 MHz,
CDCl3) d 0.21 (dt, 1H, J¼14.8 and 5.6 Hz), 1.12 (pent,
1H, J¼8.0 Hz), 1.80–1.92 (m, 3H), 1.98–2.07 (m, 1H),
2.36 (s, 3H), 2.95 (d, 1H, J¼17.6 Hz), 3.14–3.22 (m, 1H),
3.23 (d, 1H, J¼17.6 Hz), 3.30–3.36 (m, 1H), 3.47–3.54
(m, 1H), 3.97 (s, 3H), 4.23 (s, 2H), 4.32 (dd, 1H, J¼13.6
and 4.4 Hz), 4.85 (s, 1H), 6.92 (dd, 1H, J¼7.6 and
0.8 Hz), 7.04 (td, 1H, J¼7.6 and 0.8 Hz), 7.15–7.34 (m,
8H), 7.53 (d, 2H, J¼8.4 Hz), and 7.60 (d, 1H, J¼8.4 Hz);
13C NMR (100 MHz, CDCl3) d 18.0, 21.5, 24.7, 27.2,
43.5, 52.8, 53.4, 56.1, 60.4, 65.7, 72.4, 74.7, 88.8, 107.4,
116.6, 124.7, 125.3, 127.3, 127.4, 127.5, 128.2, 129.7,
129.8, 130.7, 132.6, 137.9, 142.4, 145.1, 164.4, 202.5, and
207.0; HRMS calcd for [(C35H34N2O7S2)+H]+: 659.1886.
Found: 659.1875.
1
1399, 1361, 1309, and 1171 cmꢂ1; H NMR (300 MHz,
CDCl3) d 0.18–0.24 (m, 1H), 1.13 (pent, 1H, J¼7.2 Hz),
1.70–2.06 (m, 5H), 2.35 (d, 1H, J¼17.2 Hz), 2.37 (s, 3H),
2.78 (d, 1H, J¼17.2 Hz), 3.04–3.17 (m, 1H), 3.35–3.42
(m, 1H), 3.43–3.59 (m, 2H), 3.82–3.90 (m, 1H), 3.99 (s,
3H), 4.24 (s, 2H), 4.87 (s, 1H), 6.95 (d, 1H, J¼7.5 Hz),

X. Hong et al. / Tetrahedron 63 (2007) 5962–5976
5971
4.1.20. 3a-{2-Benzyloxyethyl}-5,12b-epoxy-6-tosyl-4-
oxo-2,3,3a,4,5,5a,6,11,12,12b-decahydro-1H-6,12a-di-
aza-indeno[7,1-cd]fluorene-5-carboxylic acid methyl
ester. An excess amount of Raney nickel in 100 mL round
bottomed flask under N2 was washed three times with
H2O, twice with dry MeOH, and finally three times with
dry THF. A 0.43 g (0.64 mmol) sample of the above thiolac-
tam in 15 mL of THF was added dropwise to the Raney
nickel suspension. The mixture was vigorously stirred for
14 h under 1 atm of hydrogen gas and then filtered through
a pad of Celite. The solvent was removed under reduced pres-
sure and the residue was subjected to flash chromatography
on silica gel to give 0.38 g (95%) of the titled compound as
a clear oil; IR (neat) 2954, 1769, 1741, 1596, 1477, 1392,
through a pad of Celite, diluted with EtOAc, washed with
a satd NaHCO3 solution, brine, and dried over MgSO4.
Removal of the solvent left a colorless residue, which was
subjected to flash chromatography on silica gel to give
0.17 g (51%) of the titled compound 43 as a colorless oil;
IR (neat) 3047, 2962, 2928, 2850, 1739, 1597, 1358, 1264,
1170, and 1101 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d 0.77–0.82 (m, 1H), 1.29–1.35 (m, 1H), 1.41–1.44 (m,
1H), 1.49 (dt, 1H, J¼9.2 and 2.8 Hz), 1.60–1.67 (m, 2H),
1.85–1.88 (m, 1H), 2.10–2.18 (m, 2H), 2.28–2.33 (m, 1H),
2.30 (s, 3H), 2.42–2.46 (m, 1H), 2.50 (s, 1H), 2.99–3.03
(m, 1H), 3.06–3.10 (m, 1H), 3.52 (q, 1H, J¼5.6 Hz), 3.92
(s, 3H), 4.24 (s, 1H), 6.97 (d, 1H, J¼7.6 Hz), 7.06 (t, 1H,
J¼7.6 Hz), 7.08 (d, 2H, J¼8.4 Hz), 7.22–7.26 (m, 1H),
7.34 (d, 2H, J¼8.4 Hz), and 7.71 (d, 1H, J¼8.4 Hz);
13C NMR (100 MHz, CDCl3) d 21.7, 22.0, 32.2, 41.0,
42.6, 49.6, 50.3, 51.5, 53.2, 54.4, 63.5, 73.4, 76.3, 81.1,
105.1, 119.4, 122.6, 125.1, 128.1, 128.6, 129.5, 133.9,
136.8, 144.4, 144.5, and 170.2; HRMS calcd for
[(C28H32N2O7S)+H]+: 541.2008. Found: 541.1999.
1
1368, 1321, and 1173 cmꢂ1; H NMR (300 MHz, CDCl3)
d 0.21 (dt, 1H, J¼14.7 and 5.7 Hz), 1.14 (pent, 1H,
J¼7.5 Hz), 1.56–1.99 (m, 5H), 2.08–2.16 (m, 1H), 2.34 (s,
3H), 2.81 (td, 1H, J¼11.1 and 3.6 Hz), 2.96 (dd, 1H, J¼9.6
and 3.6 Hz), 3.11–3.19 (m, 1H), 3.35–3.51 (m, 3H), 3.94
(s, 3H), 4.22 (s, 2H), 4.76 (s, 1H), 7.02–7.08 (m, 2H),
7.16–7.29 (m, 8H), and 7.55–7.61 (m, 3H); 13C NMR
(75 MHz, CDCl3) d 20.2, 21.9, 25.9, 27.8, 37.6, 46.7, 51.7,
52.0, 53.3, 62.6, 66.7, 72.4, 77.9, 87.6, 116.3, 125.0, 125.6,
127.6, 127.8, 128.4, 129.8, 129.9, 133.3, 133.5, 138.6,
142.5, 144.8, 166.2, and 206.3; HRMS calcd for
[(C35H36N2O7S)+H]+: 629.2321. Found: 629.2332.
4.1.23. Preparation of mesylate 44 from hemiketal 43. To
a 0.07 g sample of the above compound 15 (0.13 mmol) in
10 mL of CH2Cl2 at 0 ꢀC was added 2.5 mL of Et3N fol-
lowed by 50 mL of MsCl (0.65 mmol). The reaction mixture
was stirred at 0 ꢀC for 1.5 h and then quenched with a satd
NH4Cl solution and washed with brine, H2O, and dried
over MgSO4. Removal of the solvent left a colorless residue,
which was subjected to flash chromatography on silica gel to
afford 0.07 g (85%) of mesylate 44 as a colorless oil; IR
(neat) 3047, 2962, 2921, 2855, 1760, 1711, 1593, 1466,
4.1.21. Methyl 3a-(2-(benzyloxy)ethyl)-5-hydroxy-4-oxo-
6-tosyl-2,3,3a,3a1,4,5,5a,6,11,12-decahydro-1H-indol-
izino[8,1-cd]carbazole-5-carboxylate. To a 0.38 g sample
(0.6 mmol) of the above compound in 10 mL MeOH and
2 mLTHF were added 8 mg of PtO2 and one drop of concen-
trated HCl. The reaction mixture was subjected to hydroge-
nation at 1 atm of hydrogen gas for 1.5 h. The mixture was
filtered through a pad of Celite, diluted with EtOAc, washed
with a satd NaHCO3 solution, brine, and dried over MgSO4.
Removal of the solvent left a colorless residue, which was
subjected to flash chromatography on silica gel to afford
0.26 g (68%) of the titled compound as a clear oil; IR
(neat) 3047, 2926, 2859, 1755, 1712, 1596, 1485, 1361,
1
1352, 1254, and 1176 cmꢂ1; H NMR (600 MHz, CDCl3)
d 1.03–1.07 (m, 1H), 1.24–1.27 (m, 2H), 1.56–1.67 (m,
4H), 2.04–2.08 (m, 1H), 2.16–2.36 (m, 1H), 2.34 (s, 3H),
2.40–2.42 (m, 1H), 2.55 (s, 1H), 2.86 (s, 3H), 3.07–3.09
(m, 1H), 3.14–3.16 (m, 1H), 3.83 (s, 3H), 3.84–3.87 (m,
1H), 3.96–3.99 (m, 1H), 4.47 (s, 1H), 7.04 (d, 1H,
J¼7.2 Hz), 7.11–7.15 (m, 3H), 7.30 (td, 1H, J¼9.0 and
1.2 Hz), 7.50 (d, 2H, J¼8.4 Hz), and 7.68 (d, 1H,
J¼8.4 Hz); 13C NMR (125 MHz, CDCl3) d 21.7, 21.7,
31.1, 33.6, 37.2, 42.0, 48.7, 51.3, 52.4, 52.5, 52.9, 65.6,
73.9, 77.8, 80.5, 117.7, 123.1, 125.8, 127.8, 129.2, 129.5,
133.0, 136.2, 141.8, 144.7, 168.3, and 203.8; HRMS calcd
for [(C29H34N2O9S2)+H]+: 619.1784. Found: 619.1774.
1
1264, 1170, and 1090 cmꢂ1; H NMR (400 MHz, CDCl3)
d 1.06 (hex, 1H, J¼7.2 Hz), 1.23–1.51 (m, 4H), 1.67 (ddd,
1H, J¼14.4, 10.4, and 4.0 Hz), 1.99–2.05 (m, 1H), 2.31 (s,
3H), 2.28–2.40 (m, 2H), 2.50 (s, 1H), 3.03–3.21 (m, 4H),
3.77 (s, 3H), 4.21 (d, 1H, J¼12.0 Hz), 4.46 (s 1H), 6.99
(d, 1H, J¼7.6 Hz), 7.07 (t, 1H, J¼7.6 Hz), 7.11 (d, 2H,
J¼8.4 Hz), 7.16 (d, 2H, J¼7.6 Hz), 7.23–7.31 (m, 4H),
7.48 (d, 2H, J¼8.4 Hz), 7.57 (s, 1H), and 7.67 (d, 1H,
J¼8.4 Hz); 13C NMR (100 MHz, CDCl3) d 21.5, 21.8,
31.0, 33.9, 42.3, 49.1, 51.6, 52.2, 52.5, 52.6, 65.1, 72.5,
74.5, 77.9, 80.1, 117.8, 123.3, 125.5, 127.4, 127.5, 127.9,
128.2, 128.9, 129.3, 132.9, 136.8, 138.1, 141.9, 144.5,
168.3, and 203.7; HRMS calcd for [(C35H38N2O7S)+H]+:
631.2478. Found: 631.2467.
4.1.24. 3a-(2-Methoxy-2-oxoethyl)-5,12b-epoxy-6-tosyl-
4,12-dioxo-2,3,3a,4,5,5a,6,11,12,12b-decahydro-1H-
6,12a-diaza-indeno[7,1-cd]fluorene-5-carboxylic acid
methyl ester (46). To a solution containing 8.4 g
(13.8 mmol) of diazoimide 26 in 200 mL benzene under N2
was added 50 mg rhodium(II) acetate and the mixture was
heated at reflux for 1 h. The mixture was allowed to cool to
rt and was filtered through a pad of Celite. The solvent was
removed under reduced pressure and the residue was sub-
jected to flash chromatography on silica gel to give 7.8 g
(98%) of cycloadduct 46 as a colorless solid; mp 220–
221 ꢀC; IR (neat) 2952, 1781, 1728, 1731, 1597, 1401,
4.1.22. Reductive ring opening of oxabicyclic 39 to give
hemiketal 43. To a 0.38 g (0.6 mmol) sample of 3a-{2-ben-
zyloxyethyl}-5,12b-epoxy-6-tosyl-4-oxo-2,3,3a,4,5,5a,6,11,
12,12b-decahydro-1H-6,12a-diaza-indeno[7,1-cd]fluorene-
5-carboxylic acid methyl ester in 10 mL of MeOH and 2 mL
THF were added 8 mg of PtO2 and one drop of concentrated
HCl. The reaction mixture was hydrogenated at 1 atm of
hydrogen gas but now for 12 h. The mixture was filtered
1
1364, 1188, and 1171 cmꢂ1; H NMR (400 MHz, CDCl3)
d 1.04 (d, 1H, J¼15.2 Hz), 1.60 (d, 1H, J¼15.2 Hz), 1.64–
1.79 (m, 2H), 2.02–2.10 (m, 2H), 2.32 (s, 3H), 2.80 (d, 1H,
J¼17.6 Hz), 2.76 (d, 1H, J¼17.6 Hz), 3.11 (td, 1H, J¼12.4
and 4.0 Hz), 3.49 (s, 3H), 3.78–3.82 (m, 1H), 3.92 (s, 3H),
4.85 (s, 1H), 6.93 (dd, 1H, J¼7.6 and 0.4 Hz), 7.03 (td, 1H,

5972
X. Hong et al. / Tetrahedron 63 (2007) 5962–5976
J¼8.0 and 0.8 Hz), 7.18 (d, 2H, J¼8.0 Hz), 7.33 (td, 1H,
J¼7.8 and 1.2 Hz), 7.50 (d, 2H, J¼8.0 Hz), and 7.58 (d,
1H, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3) d 17.9, 21.5,
26.3, 32.5, 38.9, 44.1, 51.7, 51.8, 53.3, 57.8, 75.6, 87.8,
103.6, 116.9, 124.4, 125.2, 127.3, 129.5, 129.8, 130.8,
132.6, 142.4, 145.1, 164.3, 169.6, 175.2, and 200.3. Anal.
Calcd for C29H28N2O9S: C, 59.99; H, 4.86; N, 4.82. Found:
C, 60.20; H, 5.01; N, 4.73.
4.1.27. Methyl 5-hydroxy-3a-(2-methoxy-2-oxoethyl)-
4-oxo-6-tosyl-2,3,3a,3a1,4,5,5a,6,11,12-decahydro-1H-
indolizino[8,1-cd]carbazole-5-carboxylate (47). To a 0.6 g
(1.0 mmol) sample of above compound in 10 mL MeOH
and 2 mL THF were added 10 mg of PtO2 and one drop of
concentrated HCl. The reaction mixture was hydrogenated
at 1 atm of hydrogen gas for 12 h. The mixture was filtered
through a pad of Celite, diluted with EtOAc, washed with a
satd NaHCO3 solution, brine, and dried over MgSO4.
Removal of the solvent left a colorless residue, which was
subjected to flash chromatography on silica gel to give
0.54 g (95%) of 47 as a white solid; mp 187–188 ꢀC; IR
(neat) 3517, 2950, 2823, 1760, 1739, 1596, 1480, 1435,
4.1.25. 3a-(2-Methoxy-2-oxoethyl)-5,12b-epoxy-6-tosyl-
4-oxo-12-thioxo-2,3,3a,4,5,5a,6,11,12,12b-decahydro-
1H-6,12a-diaza-indeno[7,1-cd]fluorene-5-carboxylic
acid methyl ester. To a solution containing 6.3 g (11 mmol)
of the above cycloadduct 46 in 200 mL benzene under N2
were added 1.9 g (4.3 mmol) of P2S5 and 2.5 mL
(18 mmol) of (TMS)2O at rt. The mixture was heated at re-
flux for 6 h, cooled to rt, and filtered through a pad of Celite.
The solvent was removed under reduced pressure and the
residue was subjected to flash chromatography on silica
gel to give 6.4 g (90%) of the titled thiolactam as a white
solid; mp 221–222 ꢀC; IR (neat) 3052, 2953, 2970, 2929,
1
1358, 1254, 1169, 1114, 1097, and 1039 cmꢂ1; H NMR
(400 MHz, CDCl3) d 1.27–1.35 (m, 1H), 1.51–1.71 (m,
2H), 1.87 (d, 1H, J¼17.4 Hz), 2.07 (d, 1H, J¼17.4 Hz),
2.09–2.14 (m, 2H), 2.29 (s, 3H), 2.37 (td, 1H, J¼10.0 and
6.4 Hz), 3.03 (d, 1H, J¼11.2 Hz), 3.14 (td, 1H, J¼9.2 and
4.0 Hz), 3.24 (s, 1H), 3.36 (s, 3H), 3.82 (s, 3H), 4.45 (s,
1H), 6.96–7.04 (m, 2H), 7.10 (d, 2H, J¼8.4 Hz), 7.22–
7.26 (m, 1H), 7.44 (d, 2H, J¼8.4 Hz), 7.65 (d, 1H,
J¼8.0 Hz), and 8.21 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 21.4, 21.7, 30.2, 37.4, 42.1, 47.5, 51.2, 51.9, 52.1, 52.7,
69.5, 77.6, 79.9, 117.8, 123.7, 125.0, 127.8, 128.9, 129.3,
132.8, 135.6, 141.7, 144.5, 168.0, 169.8, and 202.9;
HRMS calcd for [(C29H32N2O8S)+H]+: 569.1958. Found:
569.1951.
1785, 1744, 1372, 1270, and 1172 cmꢂ1
;
1H NMR
(400 MHz, CDCl3) d 1.30 (d, 1H, J¼16.0 Hz), 1.63 (d, 1H,
J¼16.0 Hz), 1.81–1.97 (m, 2H), 2.06–2.19 (m, 2H), 2.39
(s, 3H), 2.99 (d, 1H, J¼18.0 Hz), 3.26 (d, 1H, J¼18.0 Hz),
3.34 (td, 1H, J¼13.2 and 5.2 Hz), 3.54 (s, 3H), 4.00 (s,
3H), 4.29 (dq, 1H, J¼14.0 and 2.8 Hz), 4.89 (s, 1H), 6.95
(dd, 1H, J¼7.2 and 0.8 Hz), 7.05 (t, 1H, J¼7.2 Hz), 7.22
(d, 2H, J¼8.0 Hz), 7.37 (td, 1H, J¼8.0 and 1.6 Hz), 7.55
(d, 2H, J¼8.0 Hz), and 7.64 (d, 1H, J¼8.0 Hz); 13C NMR
(100 MHz, CDCl3) d 18.3, 21.5, 26.1, 33.1, 43.3, 51.8,
52.2, 53.4, 55.9, 60.5, 74.7, 88.4, 107.0, 116.6, 124.7,
125.1, 127.3, 129.0, 129.8, 130.9, 132.5, 142.4, 145.2,
164.1, 169.5, 199.8, and 206.2; HRMS calcd for
[(C29H28N2O8S2)+H]+: 597.1365. Found: 597.1356.
4.1.28. Methyl 2-(5-(methoxycarbonyloxy)-4-oxo-6-tosyl-
2,3,3a,3a1,4,5,5a,6,11,12-decahydro-1H-indolizino[8,1-
cd]carbazol-3a-yl)acetate. To a 0.55 g (0.97 mmol) sample
of compound 47 in 40 mL CH3CN was added 1.95 g
(6 mmol) of Cs2CO3 and the reaction mixture was heated
at reflux for 1 h. The mixture was cooled to rt and filtered
through a pad of Celite. Removal of the solvent left a color-
less residue, which was subjected to flash chromatography
on silica gel to afford 0.41 g (75%) of the titled carbonate
as a colorless solid; mp 97–98 ꢀC; IR (neat) 2952, 1736,
1597, 1474, 1459, 1439, 1359, 1331, 1267, 1167, and
4.1.26. 3a-(2-Methoxy-2-oxoethyl)-5,12b-epoxy-6-tosyl-
4-oxo-2,3,3a,4,5,5a,6,11,12,12b-decahydro-1H-6,12a-di-
aza-indeno[7,1-cd]fluorene-5-carboxylic acid methyl
ester. An excess amount of Raney nickel in a 250 mL round
bottomed flask under N2 was washed three times with H2O,
twice with dry MeOH, and finally three times with dry THF.
A 6.3 g (10.6 mmol) sample of the above thiolactam in
100 mL THF was added dropwise. The solution was vigor-
ously stirred for 14 h under 1 atm of H2 gas. The reaction
mixture was filtered through a pad of Celite, the solvent
was removed under reduced pressure and the residue was
subjected to flash chromatography on silica gel to give
5.2 g (87%) of the titled compound as a white solid; mp
200–202 ꢀC; IR (neat) 2951, 2859, 1774, 1738, 1598,
1
1097 cmꢂ1; H NMR (400 MHz, CDCl3) d 1.07 (td, 1H,
J¼13.2 and 4.8 Hz), 1.15–1.29 (m, 2H), 1.40–1.44 (m,
1H), 1.73–1.83 (m, 1H), 1.98–2.10 (m, 1H), 2.14–2.20 (m,
2H), 2.18 (d, 1H, J¼14.8 Hz), 2.34 (s, 3H), 2.48 (d, 1H,
J¼14.8 Hz), 2.88–2.91 (m, 2H), 2.93 (s, 1H), 3.49 (s, 3H),
3.74 (s, 3H), 4.47 (d, 1H, J¼8.4 Hz), 5.24 (d, 1H,
J¼8.4 Hz), 7.10 (t, 1H, J¼7.6 Hz), 7.19 (d, 3H, J¼8.4 Hz),
7.28 (t, 1H, J¼7.6 Hz), 7.63 (d, 1H, J¼8.0 Hz), and 7.66
(d, 2H, J¼8.0 Hz); 13C NMR (100 MHz, CDCl3) d 21.2,
21.4, 29.6, 38.0, 42.1, 48.8, 50.5, 51.7, 52.9, 54.3, 55.0,
70.7, 72.8, 78.3, 118.2, 122.7, 125.3, 126.8, 128.9, 129.5,
136.1, 136.6, 140.2, 144.0, 154.5, 169.3, and 200.1. Anal.
Calcd for C29H32N2O8S: C, 61.25; H, 5.67; N, 4.93. Found:
C, 61.36; H, 5.77; N, 4.79.
1
1477, 1436, 1293, 1267, 1170, and 1036 cmꢂ1; H NMR
(400 MHz, CDCl3) d 0.81 (d, 1H, J¼14.4 Hz), 1.60–1.69
(m, 2H), 1.73 (d, 1H, J¼14.4 Hz), 1.87–2.00 (m, 3H),
2.06–2.13 (m, 1H), 2.32 (s, 3H), 2.80 (td, 1H, J¼12.4 and
4.0 Hz), 2.92 (dd, 1H, J¼10.4 and 3.2 Hz), 3.08–3.15 (m,
1H), 3.40 (hex, 1H, J¼4.0 Hz), 3.49 (s, 3H), 3.90 (s, 3H),
4.73 (s, 1H), 7.01 (d, 2H, J¼4.4 Hz), 7.17 (d, 2H,
J¼7.6 Hz), 7.23–7.28 (m, 1H), and 7.54–7.57 (m, 3H); 13C
NMR (100 MHz, CDCl3) d 19.6, 21.4, 25.8, 32.1, 37.0,
46.2, 51.1, 51.5, 51.6, 53.0, 62.3, 87.4, 110.8, 116.3,
124.7, 125.0, 127.4, 129.6, 129.8, 132.3, 133.2, 142.3,
144.5, 165.6, 170.7, and 203.1; HRMS calcd for
[(C29H30N2O8S)+H]+: 567.1801. Found: 567.1794.
4.1.29. Methyl 2-(4-oxo-6-tosyl-2,3,3a,3a1,4,5,5a,6,11,12-
decahydro-1H-indolizino[8,1-cd]carbazol-3a-yl)acetate.
A solution containing 0.6 g (1.0 mmol) of the above carbon-
ate in THF (5 mL) together with 0.5 mL of HMPA was
degassed with argon at rt for 15 min. The mixture was
allowed to react with a solution of samarium iodide in THF
(0.1 M) at 0 ꢀC until a blue color persisted for 10 s. The re-
action mixture was then quenched with a satd NaHCO3 solu-
tion, extracted with EtOAc, and dried over MgSO4. Removal

X. Hong et al. / Tetrahedron 63 (2007) 5962–5976
5973
of the solvent left a colorless residue, which was subjected to
flash chromatography on silica gel to afford 0.37 g (72%) of
the titled compound as a clear oil; IR (neat) 2939, 2795,
(78%) of the aldol product 49 as a colorless solid; mp 249–
250 ꢀC; IR (neat) 3500, 2927, 2787, 1749, 1596, 1553, 1456,
1355, 1168, 1093, and 1043 cmꢂ1 1H NMR (CDCl3,
;
1
1738, 1718, 1475, 1459, 1355, 1168, and 1101 cmꢂ1; H
400 MHz) d 0.89 (dd, 1H, J¼13.2 and 7.6 Hz), 0.94–1.04
(m, 1H), 1.15 (td, 1H, J¼13.6 and 4.8 Hz), 1.34 (d, 1H,
J¼14.4 Hz), 1.48–1.54 (m, 1H), 1.67 (d, 2H, J¼26 Hz),
1.88–2.04 (m, 4H), 2.21–2.31 (m, 1H), 2.34 (s, 3H), 2.51
(s, 1H), 2.73 (d, 1H, J¼5.6 Hz), 2.82 (t, 1H, J¼8.8 Hz),
3.07 (dd, 1H, J¼11.2 and 2.8 Hz), 4.00 (d, 1H, J¼8.0 Hz),
4.38 (d, 1H, J¼5.6 Hz), 7.13–7.16 (m, 2H), 7.18 (d, 2H,
J¼8.4 Hz), 7.30–7.34 (m, 1H), 7.58 (d, 2H, J¼8.0 Hz),
and 7.77 (d, 1H, J¼8.0 Hz); 13C NMR (CDCl3, 100 MHz)
d 21.5, 21.6, 28.4, 40.7, 44.2, 47.7, 51.4, 53.2, 54.2, 61.9,
64.3, 75.8, 81.1, 115.9, 122.6, 125.3, 126.9, 128.8, 129.7,
134.9, 138.5, 141.0, 144.4, and 213.1; HRMS calcd for
[(C26H28N2O4S)+H]+: 465.1848. Found: 465.1843.
NMR (600 MHz, CD3CN) d 1.26–1.34 (m, 2H), 1.40–1.56
(m, 2H), 1.62 (td, 1H, J¼13.8 and 3.6 Hz), 1.94–2.28 (m,
7H), 2.35 (s, 3H), 2.78 (s, 1H), 2.90–3.02 (m, 2H), 3.05
(dd, 1H, J¼16.8 and 6.0 Hz), 3.11–3.14 (m, 1H), 3.35 (s,
3H), 4.26 (s, 1H), 7.10 (t, 1H, J¼7.2 Hz), 7.21 (d, 1H,
J¼7.2 Hz), 7.27 (d, 1H, J¼7.8 Hz), 7.30 (d, 2H, J¼
8.4 Hz), 7.62 (d, 1H, J¼7.8 Hz), and 7.79 (dd, 2H, J¼6.6
and 1.8 Hz); 13C NMR (150 MHz, CD3CN) d 21.9, 23.3,
31.6, 40.8, 41.8, 43.4, 49.7, 52.2, 53.0, 53.8, 71.2, 74.1,
117.1, 125.7, 126.3, 128.7, 130.1, 131.2, 135.2, 137.8,
141.8, 146.5, 171.2, and 209.5. Anal. Calcd for
C27H30N2O5S: C, 65.57; H, 6.11; N, 5.66. Found: C, 65.11;
H, 6.19; N, 5.46.
4.1.32. Samarium iodide reduction of hydroxy ester 47. A
solution containing 0.11 g (0.18 mmol) of the above com-
pound 47 in THF (1 mL) together with 0.2 mL of HMPA
was degassed with argon at rt for 15 min. A solution of
samarium iodide in THF (0.1 M) at 0 ꢀC was added to this
mixture until a blue color persisted for 10 s. The reaction
mixture was quenched with a satd NaHCO3 solution, ex-
tracted with EtOAc, and dried over MgSO4. Removal of
the solvent under reduced pressure left a colorless residue,
which was subjected to flash chromatography on silica gel
to afford 0.08 g (93%) of compound 50 as a clear oil, which
consisted of a 4.3:1 mixture of the keto and enol forms; IR
(neat) 3068, 2954, 2921, 2855, 1728, 1450, 1258, 1237,
4.1.30. 2-(4-(tert-Butyldimethylsilyloxy)-6-tosyl-
2,3,3a,3a1,5a,6,11,12-octahydro-1H-indolizino[8,1-
cd]carbazol-3a-yl)acetaldehyde (48). To a solution con-
taining 0.12 g (0.2 mmol) of the above keto ester and
120 mL (0.5 mmol) of TBDMSOTf in 10 mL of CH2Cl2
was added dropwise 208 mL of (1.5 mmol) Et3N. After 1 h
of stirring at rt, the mixture was hydrolyzed with a satd
NaHCO3 solution. After extraction with CH2Cl2, the organic
layer was dried over MgSO4, filtered, and concentrated un-
der reduced pressure. The residue was dissolved in 10 mL
of THF and a 1.2 mL of a 1.0 M LiAlH4 solution was added
at 0 ꢀC. After stirring for 4 h, the mixture was quenched with
H2O, 15% NaOH, and extracted with EtOAc. The combined
organic layer was dried over MgSO4 and concentrated under
reduced pressure. To the resulting residue was added 5 mL
1176, and 1029 cmꢂ1
;
1H NMR (400 MHz, CD3CN)
d 1.19–1.37 (m, 1H), 1.39–1.67 (m, 3H), 1.67–1.80 (m,
1H), 1.98–2.09 (m, 3H), 2.14 (d, 1H, J¼16.8 Hz), 2.20–
2.29 (m, 1H), 2.36 (s, 3H), 2.83–2.86 (m, 1H), 2.87 (s,
1H), 2.94 (hex, 1H, J¼4.4 Hz), 3.34 (s, 3H), 3.76 (s, 3H),
4.33 (d 1H, J¼4.0 Hz), 4.84 (d 1H, J¼4.0 Hz), 7.04–7.06
(m, 2H), 7.22 (d, 2H, J¼8.0 Hz), 7.25 (t, 1H, J¼8.4 Hz),
7.64 (d, 2H, J¼8.4 Hz), and 7.72 (d, 1H, J¼8.4 Hz); 13C
NMR (100 MHz, CD3CN) d 22.3, 21.6, 29.7, 30.9, 38.5,
41.0, 48.4, 51.2, 51.4, 51.8, 52.4, 116.9, 124.1, 124.7,
127.9, 128.9, 129.6, 132.5, 135.4, 141.3, 144.6, 167.2,
170.0, and 205.0; HRMS calcd for [(C29H32N2O7S)+H]+:
553.2008. Found: 553.2000.
˚
of CH3CN, 0.15 g of 4 A molecular sieves, 0.04 g
(0.35 mmol) of NMO and 0.025 g (0.07 mmol) of TPAP at
0 ꢀC. The mixture was allowed to warm to rt for 4 h and
was filtered through a pad of Celite. After removing the sol-
vent under reduced pressure, the residue was subjected to
flash silica gel chromatography to give 0.092 g (68%) of al-
dehyde 48 as a colorless oil; IR (neat) 2930, 2856, 1718,
1
1664, 1598, 1475, 1461, 1356, 1261, and 1168 cmꢂ1; H
NMR (CDCl3, 400 MHz) d 0.20 (s, 3H), 0.26 (s, 3H), 0.87
(s, 9H), 0.91–1.00 (m, 1H), 1.11–1.18 (m, 1H), 1.34–1.41
(m, 1H), 1.45–1.50 (m, 2H), 1.81 (dd, 1H, J¼15.2 and
3.6 Hz), 1.96–2.00 (m, 1H), 2.06 (dd, 1H, J¼15.2 and
2.0 Hz), 2.14–2.22 (m, 2H), 2.34 (s, 3H), 2.54 (s, 1H),
2.96–3.00 (m, 2H), 4.50 (d, 1H, J¼4.4 Hz), 5.03 (d, 1H,
J¼4.0 Hz), 6.97–7.00 (m, 2H), 7.16–7.25 (m, 3H), 7.57 (d,
2H, J¼8.0 Hz), 7.67 (d, 1H, J¼8.0 Hz), and 9.43–9.45 (m,
1H); 13C NMR (CDCl3, 100 MHz) d ꢂ4.8, ꢂ4.4, 18.0,
21.5, 22.6, 25.6, 30.9, 41.2, 41.9, 51.4, 51.5, 52.4, 54.2,
70.4, 72.0, 101.8, 116.7, 123.5, 124.6, 127.0, 128.6, 129.5,
134.9, 136.7, 140.8, 143.9, 153.6, and 201.4; HRMS calcd
for [(C32H42N2O4SSi)+H]+: 579.2713. Found: 579.2707.
4.1.33. Methyl 4-(tert-butyldimethylsilyloxy)-3a-(2-me-
thoxy-2-oxoethyl)-6-tosyl-2,3,3a,3a1,5a,6,11,12-octa-
hydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate. To
a solution of 0.06 g (0.11 mmol) keto ester 50 and 100 mL
(0.4 mmol) of TBDMSOTf in 5 mL of CH2Cl2 was added
dropwise 121 mL (0.9 mmol) of Et3N. After stirring over-
night at rt, the mixture was hydrolyzed with a satd NaHCO3
solution. After extraction with CH2Cl2, the organic layer was
dried over MgSO4 and filtered. Concentration of the solution
under reduced pressure followed by flash chromatography
on silica gel afforded 0.07 g (96%) of the titled enol ether
as a colorless oil; IR (neat) 3402, 2948, 2931, 2857, 2787,
1727, 1596, 1477, 1436, 1358, 1260, 1169, and
4.1.31. Cesium fluoride induced intramolecular aldol
reaction of silyl enol ether 48. To a solution of 0.05 g
(0.086 mmol) of the above aldehyde in 10 mL of CH3CN
was added 0.13 g (0.86 mmol) of Cs2CO3 and the reaction
mixture was heated at 100 ꢀC for 1 h. The mixture was
then cooled to rt and filtered through a pad of Celite. Re-
moval of the solvent left a colorless residue, which was sub-
jected to flash chromatography on silica gel to afford 0.03 g
1
1030 cmꢂ1; H NMR (CDCl3, 400 MHz) d 0.26 (s, 3H),
0.31 (s, 3H), 0.94 (s, 9H), 1.30–1.38 (m, 1H), 1.43–1.59
(m, 3H), 1.70 (ddd, 1H, J¼10.8, 8.8, and 2.0 Hz), 1.96–
2.10 (m, 2H), 2.23 (t, 1H, J¼4.8 Hz), 2.32 (s, 3H), 2.45 (d,
1H, J¼16.4 Hz), 2.84 (s, 1H), 2.92–2.98 (m, 2H), 3.31 (s,
3H), 3.81 (s, 3H), 4.94 (s, 1H), 7.00 (td, 1H, J¼7.6 and

5974
X. Hong et al. / Tetrahedron 63 (2007) 5962–5976
1.2 Hz), 7.09 (dd, 1H, J¼7.6 and 1.2 Hz), 7.15–7.20 (m,
3H), and 7.63–7.67 (m, 3H); 13C NMR (CDCl3, 100 MHz)
d ꢂ3.0, ꢂ2.4, 19.2, 21.5, 22.8, 26.2, 30.2, 38.7, 42.0, 43.2,
51.0, 51.6, 51.8, 51.9, 52.6, 70.5, 72.6, 109.2, 116.4,
124.2, 124.4, 127.7, 128.1, 129.4, 134.0, 137.4, 140.8,
143.9, 161.2, 167.1, and 170.7; HRMS calcd for
[(C35H46N2O7SSi)+H]+: 667.2873. Found: 667.2866.
139.8, 141.0, 144.7, 169.4, and 206.2; HRMS calcd for
[(C28H30N2O6S)+H]+: 523.1903. Found: 523.1899.
Acknowledgements
We greatly appreciate the financial support provided by the
National Institutes of Health (GM 059384) and the National
Science Foundation (Grant CHE-0132651). The authors
wish to acknowledge some preliminary experiments carried
4.1.34. Methyl 4-(tert-butyldimethylsilyloxy)-3a-(2-
hydroxyethyl)-6-tosyl-2,3,3a,3a1,5a,6,11,12-octahydro-
1H-indolizino[8,1-cd]carbazole-5-carboxylate (51). To a
solution of 0.069 g (0.1 mmol) of the above compound in
10 mL of THF was added 0.5 mL of a 1.0 M LiAlH4 solution
at ꢂ78 ꢀC. The solution was allowed to warm to 0 ꢀC and
was stirred for 5 h. The mixture was quenched with H2O,
15% NaOH, and extracted with EtOAc. The combined or-
ganic layer was dried over MgSO4 and concentrated under
reduced pressure. The solvent was removed under reduced
pressure and the residue was subjected to flash silica gel
chromatography to give 0.06 g (91%) of the reduced alcohol
51 as a colorless solid; mp 190–192 ꢀC; IR (neat) 3402,
2948, 2931, 2857, 2787, 1727, 1596, 1477, 1436, 1358,
ꢀ
ꢀ
out by Dr. Jose M. Mejıa-Oneto.
References and notes
1. Braekman, J. C.; Daloze, D. Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1990;
Vol. 6, pp 421–466; Elbein, A.; Molyneux, R. I. The
Alkaloids, Chemical and Biological Perspectives; Pelletier,
S. W., Ed.; Wiley: New York, NY, 1990; Vol. 5, pp 1–54.
2. Saxton, J. E. The Alkaloids, Chemistry and Biology; Cordell,
G. A., Ed.; Academic: San Diego, CA, 1998; Vol. 5, pp 1–197.
3. Saxton, J. E. Indoles, Part 4: The Monoterpenoid Indole
Alkaloids; Wiley: Chichester, UK, 1983; Herbert, R. B. The
Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.; The
Chemistry of Heterocyclic Compounds; Wiley: Chichester,
UK, 1994; Supplement to Vol. 25, Part 4, Chapter 1; Toyota,
M.; Ihara, M. Nat. Prod. Rep. 1998, 327 and references therein.
4. For the first synthesis of aspidospermine and vindoline, see:
Stork, G.; Dolfini, J. E. J. Am. Chem. Soc. 1963, 85, 2872;
Ando, M.; Buchi, G.; Ohnuma, T. J. Am. Chem. Soc. 1975,
97, 6880.
1
1260, 1169, and 1030 cmꢂ1; H NMR (CDCl3, 400 MHz)
d 0.30 (s, 3H), 0.33 (s, 3H), 0.95 (s, 9H), 1.07 (td, 1H,
J¼13.6 and 8.0 Hz), 1.42–1.69 (m, 5H), 1.70–1.90 (m,
3H), 2.17 (s, 1H), 2.12–2.23 (m, 2H), 2.34 (s, 3H), 2.96–
3.00 (m, 3H), 3.24 (br s, 1H), 3.81 (s, 3H), 5.01 (s, 1H),
7.03–7.10 (m, 2H), 7.18–7.25 (m, 3H), and 7.65–7.68 (m,
3H); 13C NMR (CDCl3, 100 MHz) d ꢂ2.7, ꢂ2.2, 19.3,
21.5, 22.9, 26.4, 31.0, 39.2, 42.3, 44.3, 51.5, 52.0, 52.4,
53.3, 58.4, 71.0, 76.4, 107.9, 116.1, 123.7, 124.5, 127.7,
128.4, 129.4, 134.0, 138.2, 141.3, 143.9, 164.6, and 167.2;
HRMS calcd for [(C34H46N2O6SSi)+H]+: 639.2924. Found:
639.2919.
5. For some select methods to synthesize the pentacyclic
framework of aspidospermidine (1), see: Camerman, A.;
Camerman, N.; Kutney, J. P.; Piers, E.; Trotter, J. Tetrahedron
Lett. 1965, 637; Harley-Mason, J.; Kaplan, M. J. Chem. Soc.,
Chem. Commun. 1967, 915; Laronze, J.-Y.; Laronze-
4.1.35. Oxidation and cesium fluoride induced aldol reac-
tion of primary alcohol 51. A solution containing 0.06 g
(0.094 mmol) of the above primary alcohol 51 in 5 mL of
ꢀ
Fontaine, J.; Levy, J.; Le Men, J. Tetrahedron Lett. 1974,
491; Ban, Y.; Yoshida, K.; Goto, J.; Oishi, T. J. Am. Chem.
Soc. 1981, 103, 6990; Gallagher, T.; Magnus, P.; Huffman, J.
J. Am. Chem. Soc. 1982, 104, 1140; Wenkert, E.; Hudlicky,
T. J. Org. Chem. 1988, 53, 1953; Mandal, S. B.; Giri, V. S.;
Sabeena, M. S.; Pakrashi, S. C. J. Org. Chem. 1988, 53,
4236; Meyers, A. I.; Berney, D. J. Org. Chem. 1989, 54,
4673; Node, M.; Nagasawa, H.; Fugi, K. J. Org. Chem. 1990,
55, 517; Le Menez, P.; Kunesch, N.; Lui, S.; Wenkert, E.
˚
CH3CN, containing 200 mg of 4 A molecular sieves,
17 mg (0.14 mmol) of NMO and 10 mg (0.028 mmol) of
TPAP at 0 ꢀC was allowed to stir at rt for 12 h. The solution
was filtered through a pad of Celite, the solvent was removed
under reduced pressure and the residue was taken up in 5 mL
of CH3CN. To the resulting mixture was added 0.14 g
(0.94 mmol) of Cs2CO3 and the reaction mixture was heated
at reflux at 80 ꢀC for 1 h. The mixture was cooled to rt and
filtered through a pad of Celite. Removal of the solvent
left a colorless residue, which was subjected to flash chroma-
tography on silica gel to afford 0.017 g (34%) of the aldol
product 52 as a colorless oil; IR (neat) 3497, 2931, 2850,
2785, 1758, 1714, 1596, 1445, 1362, 1271, 1171, and
€
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1
1092 cmꢂ1; H NMR (CDCl3, 400 MHz) d 0.76 (dd, 1H,
1999, 995; Iyengar, R.; Schildknegt, K.; Aube, J. Org. Lett.
ꢀ
J¼13.6 and 7.6 Hz), 0.96–1.04 (m, 1H), 1.15 (td, 1H,
J¼13.6 and 5.2 Hz), 1.33 (d, 1H, J¼14.8 Hz), 1.49–1.53
(m, 1H), 1.79 (dd, 1H, J¼14.8 and 8.0 Hz), 1.84–2.04 (m,
3H), 2.33 (s, 3H), 2.25–2.42 (m, 1H), 2.48 (s, 1H), 2.83 (t,
1H, J¼8.4 Hz), 3.08 (dd, 1H, J¼10.8 and 3.6 Hz), 4.03 (s,
3H), 4.30–4.32 (m, 2H), 4.83 (m, 1H), 7.13 (d, 3H,
J¼8.0 Hz), 7.20 (d, 1H, J¼7.6 Hz), 7.34 (d, 1H, J¼
8.0 Hz), 7.41 (d, 2H, J¼8.0 Hz), and 7.79 (d, 1H, J¼
8.0 Hz); 13C NMR (CDCl3, 100 MHz) d 21.5, 21.6, 29.2,
38.5, 43.7, 46.3, 51.7, 53.0, 53.4, 54.5, 65.9, 68.5, 78.5,
81.4, 118.1, 122.6, 126.3, 127.4, 128.9, 129.6, 134.2,
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