Studies toward welwitindolinones: Formal syntheses of N- methylwelwitindolinone C isothiocyanate and related natural products

Article abstract of DOI:10.1016/j.tet.2013.03.010

The formal syntheses of N-methylwelwitindolinone C isothiocyanate (4) and several other welwitindolinones 5-8 were achieved by the independent synthesis of 79. The synthesis featured a Lewis acid-mediated coupling between a heteroaryl carbinol and bis-TMS enol ether, an intramolecular enolate arylation, and an unprecedented intramolecular allylic alkylation of a γ-acyloxyenone.

Full text of DOI:10.1016/j.tet.2013.03.010

Tetrahedron 69 (2013) 5588e5603
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies toward welwitindolinones: formal syntheses of
N-methylwelwitindolinone C isothiocyanate and related
natural products
Tsung-hao Fu, William T. McElroy, Mariam Shamszad, Richard W. Heidebrecht, Jr.,
*
Brian Gulledge, Stephen F. Martin
Department of Chemistry and Biochemistry, The University of Texas at Austin, 1 University Station A5300, Austin, TX 78712-0165, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The formal syntheses of N-methylwelwitindolinone C isothiocyanate (4) and several other welwi-
tindolinones 5e8 were achieved by the independent synthesis of 79. The synthesis featured a Lewis acid-
mediated coupling between a heteroaryl carbinol and bis-TMS enol ether, an intramolecular enolate
Received 24 December 2012
Received in revised form 21 February 2013
Accepted 4 March 2013
arylation, and an unprecedented intramolecular allylic alkylation of a g-acyloxyenone.
Available online 13 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloids
Allylic alkylation
Lewis acid-mediated coupling
Welwitindolinones
Enolate arylation
Cl
Cl
1. Introduction
O
H
H
H
O
In 1994 Moore and co-workers isolated alkaloids 1e5 (Fig. 1),
which were collectively named welwitindolinones, from the Mi-
cronesian blue-green algae Hapalosiphon welwitschii.1 These novel
alkaloids possess a unique bicyclo[4.3.1]decane skeleton that is
densely functionalized with a bridgehead isothiocyanate or iso-
nitrile, a vinyl or alkyl chloride, a vinyl group, and an oxindole. The
core structure of these alkaloids also contained two contiguous
fully substituted carbon atoms, which poses a significant challenge
for organic synthesis. In 1999 Moore isolated the three additional
structurally-related welwitindolinones 6e8 from cyanophytes
Fischerella muscicola and Fischerella major.2
R2
SCN
CN
O
O
O
R3
H
O
O
O
N
N
N
R1
R
Me
3: R1 = H, R2 = NCS, R3 = H
1: R = H
2: R = Me
8
4: R1 = Me, R2 = NCS, R3 = H
5: R1 = Me, R2 = NC, R3 = H
6: R1 = Me, R2 = NCS, R3 = OH
7: R1 = Me, R2 = NC, R3 = OH
Fig. 1. Selected welwitindolinone natural products.
The welwitindolinones exhibit various useful biological activi-
ties, which include reversal of P-glycoprotein-mediated multiple
drug resistance in human cancer cell lines, induction of microtu-
bule depolymerization, and insecticidal activity.3,4 Of the members
of the welwitindolinone family, N-methylwelwitindolinone C iso-
thiocyanate (4) was found to be the most effective in reversing P-
glycoprotein-mediated multiple drug resistance. Because of the
combination of its novel structural and biological properties, 4 has
attracted the attention of numerous laboratories in the synthetic
community, and these efforts have collectively resulted in a myriad
of publications.5 However, the challenges associated with pre-
paring these compounds are reflected by the fact that the total
syntheses of 4e8 were only recently reported.6
We began our investigations toward the syntheses of the wel-
witindolinone alkaloids with goals of developing an efficient entry
to these compounds that could be adapted for analog synthesis and
of discovering new and generally useful CeC bond constructions. In
particular, we were interested in extending the scope of transition
metal-catalyzed allylic alkylations to include complex ketoesters
and ketones. During the course of this endeavor, we also discovered
* Corresponding author. E-mail address: sfmartin@mail.utexas.edu (S.F. Martin).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.010

T.-hao Fu et al. / Tetrahedron 69 (2013) 5588e5603
Br
a useful means of preparing b-heteroaryl carbonyl compounds. We
5589
Br
now wish to report the details of these studies that ultimately led to
NaH, xylenes, Δ;
formal syntheses of several natural welwitindolinones.7
O
O
Me2SO4
66%
N
H
N
Me
2. Results and discussion
14
13
O
Me
O
2.1. First generation approach
Br
OMe
Me
OMe
Our first approach to welwitindolinones 3e8 is outlined in
retrosynthetic format in Scheme 1. The objective was to design
a strategy that would enable access to a variety of welwitindoli-
nones through a common intermediate, such as 9, which might be
derived from alkene 10 via oxidative cleavage of the exocyclic
methylene group followed by regioselective enolate alkylations. We
envisioned that 10 could be prepared from 11 by two sequential
allylic alkylations. The tricycle 11 would then be formed by the
intramolecular enolate arylation of the ketoester 12, which would
be assembled by a Michael addition involving the enolate of N-
methyl-4-bromooxindole (13).
15
t-BuOAc, LDA
O
NaOMe, MeOH, 55 °C
62%
72%
N
Me
16
O
O
Br
CO2tBu
Br
CO2Me
CF3CO2H
O
O
then CH2N2
95%
N
Me
12
N
Me
17
Scheme 2.
Refunctionalize
O
In order to advance the synthesis, the intramolecular enolate
arylation of ketoester 12 was then examined (Scheme 3). In initial
experiments, we found that the use of Pd(OAc)2 and bis-tert-butyl-
2-biphenylphosphine10 provided tricycle 11 in 58% yield, but sig-
nificant quantities (25e30%) of 12 were also recovered, and we
were unable to effect complete conversion of 12 into 11. After
screening various catalysts and reaction conditions, we discovered
that a modified procedure, in which a combination of tri-tert-
butylphosphine palladium dimer11 and bis-dibenzylideneacetone
were employed in accord with a report by Fu,12 gave the tricycle
11 in 88% yield; the structure of 11 was confirmed with X-ray
analysis. In each of these reactions it was necessary to exclude
oxygen using a freezeepumpethaw protocol in order to obtain
optimal yields. In an attempt to form the final ring of the welwi-
tindolinone skeleton, tricycle 11 was treated with the bis-allylic
carbonate 18 in the presence of Pd(Ph3P)4 and DBU. However,
neither epimer of the requisite tetracycle 21 was detected in the
H
3 – 8
MeO2C
O
H
O
N
Refunctionalize
Me
9
Allylic Alkylations
HO
H
MeO2C
MeO2C
O
H
H
O
O
N
N
Enolate
Arylation
Me
Me
11
10
O
HO
O
Br
Br
CO2Me
Br
CO2Me
MeO2C
[Pd(tBu3P)2]2, Pd(dba)2
O
O
H
NaOtBu, DMF, 75 °C
88%
O
N
Me
N
Me
Michael
O
N
Me
12
Addition
N
Me
13
12
11
Scheme 1.
OCO2Me
MeO2CO
OCO2Me
Having thus formulated our plan, the first task required the
preparation of the ketoester 12. Toward this objective, readily
available 4-bromooxindole (14)8 was N-methylated using the
Bordwell protocol9 to give 13 in 66% yield (Scheme 2). Reaction of
13 with methyl 3-methylcrotonate (15) in methanolic sodium
methoxide gave ester 16 in 74% yield. We found that it was essential
to rigorously deoxygenate the sodium methoxide solution prior to
the reaction in order to avoid forming the isatin derivative of 13. The
Claisen condensation of 16 with the anion generated from tert-butyl
acetate provided ketoester 17 in good yield. We discovered that the
tert-butyl ester moiety was not sufficiently stable for our needs as it
underwent relatively facile decarboxylation under the somewhat
forcing conditions of the subsequent enolate arylation. Accordingly,
it was converted into the methyl ester 12 in 95% yield in a two-step
procedure that furnished 12 in higher overall yield than the base-
promoted Claisen condensation of 16 with methyl acetate.
18
MeO2C
Pd(Ph3P)4, DBU, THF, rt
O
H
3
O
N
Me
19
O
H
MeO2C
MeO2C
O
H
3
O
O
59%
N
Me
N
Me
21 (not detected)
20
Scheme 3.

5590
T.-hao Fu et al. / Tetrahedron 69 (2013) 5588e5603
TBDPSO
reaction mixture, and 20 was obtained in 59% yield. The undesired
product 20 presumably formed because the proton to the amide
moiety in intermediate 19, which could be isolated as a mixture
a
O
O
O
O
LDA, THF, –78 °C
then
OtBu
OtBu
(4:1) of two diastereomers, was more acidic than those
group. A revised plan was thus pursued.
a to the keto
27
29
TBDPSO
Br
28
2.2. Second generation approach
70%
We reasoned that the aforementioned deleterious cyclization
could be avoided simply by removing the offending acidic proton
on the indole moiety. Accordingly, we decided to target the alter-
native tetracycle 22 (Scheme 4). Moreover, because we anticipated
TBDPSO
acetone
TFA, Ac2O
NaHMDS, TMSCl
THF, –78 °C
O
O
26
O
67%
that an allylic alkylation of a b-ketoester would be easier to achieve
30
Scheme 5.
than an allylic alkylation of a ketone, we decided to explore a dif-
ferent sequence of carbonecarbon bond forming steps in which the
C11eC12 bond of 22 would be formed after the C14eC15 bond. In
order to test this idea, we needed to prepare the enol 23, and one
viable precursor would be the ketoester 24. Because preliminary
furnished the alcohol 25, which was somewhat unstable and hence
used directly without purification. After screening several Lewis
acids, we found that TMSOTf facilitated the coupling of 25 and 26 to
give 33 in 35% yield over two steps. To our knowledge, this reaction
represents the first Lewis acid-mediated coupling between a het-
erocyclic carbinol and a vinyl silyl ketene acetal. The ability to
generate a stabilized carbocation from a hydroxyl group is benefi-
cial from a synthetic perspective because alcohols are often more
readily available than their corresponding halides or acetates. It is
also noteworthy that this experiment served as the basis for de-
efforts to prepare 24 via alkylation of precursor b-ketoester dia-
nions using an appropriate alkyl halide failed (Scheme 4, Path A),
alternative pathways were explored. One of these involved a Lewis
acid-mediated coupling between the tertiary alcohol 25 and the
silyl ketene acetal 26 (Scheme 4, Path B), a bond construction that
benefited from little literature precedent at the time we initiated
the study,13 although a related reaction was reported by Rawal
subsequent to our early experiments in the area.5j
veloping a general method for preparing
b-heteroaryl carbonyl
OR
14
compounds by trapping carbocations with different
p-
H
12
nucleophiles.14,15
HO
15
11
MeO2C
MeO2C
O
O
Br
Br
1) (MeO)2CO, K2CO3
DMF, 135 °C
N
Me
N
Me
Enolate
N
Me
N
H
2) AcCl, Me2AlCl
CH2Cl2, –20 °C
76%
Arylation
23
22
32
31
Path B
O
Br
CO2Me
Br
OH
MeMgBr, THF
–20 °C to rt
N
Me
N
Me
25
OR
Path A
24
Br
TBDPSO
OH
O
O
Path B
O
O
Br
26, TMSOTf
CH2Cl2, –78 °C
+
O
N
Me
25
OTMS
35%
N
26
OTBDPS
Me
Scheme 4.
33
Scheme 6.
At this juncture, it was necessary to set the stage to examine the
key Lewis acid-mediated coupling of 25 and 26, the silyl ketene
acetal 26 was first prepared by alkylation of the dianion generated
from tert-butylacetoacetate (27) with the allylic halide 28 to give
ketoester 29 in 70% yield (Scheme 5). Transformation of 29 into 26
was then achieved by acid-catalyzed acetonide formation to give
the dioxinone 30, subsequent treatment of which with NaHMDS
and TMSCl gave silyl ketene acetal 26, which was used without
purification in the next step of the sequence.
The synthesis of the requisite tertiary alcohol 25 commenced
with the N-methylation of 4-bromoindole (31) followed by
subsequent FriedeleCrafts acetylation to provide ketone 32
(Scheme 6). Treatment of 32 with methylmagnesium bromide
Dioxinone 33 was then converted into the b-ketoester 34 by
heating in the presence of MeOH to trap the acylketene in-
termediate (Scheme 7). Cyclization of 34 by a palladium-catalyzed
enolate arylation followed by cleavage of the TBDPS protecting
group gave 35 in 51% yield. In initial attempts to acetylate the
primary alcohol in 35, we observed that competitive acetylation of
the enol moiety also occurred. However, after some experimenta-
tion, we found that the combination of collidine and AcCl at ꢀ78 ꢁC
selectively provided an intermediate allylic acetate that underwent
cyclization in the presence of NaH and Pd2dba3 to deliver 22 in 43%
overall yield from 35. Oxidative cleavage of the exocyclic olefin in
22 then gave tetracycle 36 in 66% yield.

T.-hao Fu et al. / Tetrahedron 69 (2013) 5588e5603
5591
O
O
be formulated that provided a solution to the problem of generat-
ing the quaternary center at C(12) in an intermediate such as 39
(Scheme 9). For example, the vinyl moiety in 40 would favor
dienolate formation at C(12), thereby allowing selective methyla-
tion. We envisioned that the tetracycle 40 might be formed via
Br
MeOH, PhMe
100 °C
OMe
33
94%
N
Me
OTBDPS
a novel intramolecular allylic alkylation of the
Although intramolecular allylic alkylations have been extensively
utilized in syntheses,16 alkylations of
-acyloxyenone moieties,
g-acyloxyenone 41.
34
HO
HO
g
such as that present in 41 have not been reported. The preparation
of tricycle 41 via a palladium-catalyzed enolate arylation of 42
follows directly from the precedent established for the syntheses of
11 and 35. Because we had exploited furans as latent 1,4-
enedicarbonyl compounds several times in the past,17 it occurred
to us that the furan ring in 42 might serve as a precursor to the
1) [Pd(tBu3P)2]2, NaOtBu
PhMe, 150 °C (MW)
1) AcCl, Collidine
CH2Cl2, –78 °C
MeO2C
2) Et3N•3HF, Et3N
MeCN
2) Pd2(dba)3, NaH
THF, 50 °C
43%
N
Me
51%
requisite
g-acyloxyenone moiety needed for the key allylic alkyl-
35
ation. The assembly of 42 would then be accomplished by the Lewis
O
acid-mediated coupling of 25 with
p-nucleophile 43.
H
H
OsO4, NaIO4
MeO2C
O
MeO2C
Refunctionalize
THF, H2O
66%
O
O
N
Me
N
Me
H
12
3 – 8
MeO2C
22
36
O
Refunctionalize
Scheme 7.
N
Refunctionalize
Me
39
At this point the tetracyclic core of the welwitindolinones was in
place, and the next objective was to create the quaternary carbon
center at C(12) via enolate alkylation. However, prior to embarking
on this effort, studies were conducted to determine if selective
deprotonation at C(12) was possible (Scheme 8). When the lithium
enolate of 36 was generated under kinetic conditions and then
quenched with CD3OD, a mixture (ca. 3:4) of 37 and 38 was ob-
tained. Interestingly, deuterium incorporation occurred with
complete facial selectivity, as one diastereomer of 37 and one di-
astereomer of 38 were obtained. The tentative assignments shown
are based upon steric considerations. When the deprotonation of
36 and enolate quenching was repeated under equilibrating con-
ditions, 37 was favored by a factor of about 3.5:1 over 38, but equal
amounts of two diastereomers of 37 were formed. These studies
suggested that selective alkylation of C(12) of 36 might be prob-
lematic. Confirming this hypothesis, we found that methylation of
the lithium enolate of ketone 36 under equilibrating and non-
equilibrating conditions was not selective.
Allylic
Alkylation
RO
O
12
H
HO
O
MeO2C
O
MeO2C
N
N
Me
Me
Enolate
Arylation
40
41
Oxidative
Refunctionalization
CO2Me
O
Br
O
N
Me
Lewis Acid
Mediated
Coupling
42
O
O
O
D
H
Br
14
OH
R3Si O
OSiR3
OR
H
12
D
H
conditions
MeO2C
MeO2C
MeO2C
N
Me
O
O
O
O
25
43
N
Me
N
Me
N
Me
Scheme 9.
36
37
38
LDA (1.1 eq), THF
33%
41%
11%
–78 °C, then CD3OD
2.3.1. Lewis acid-mediated coupling. Following the precedent set
forth in Scheme 6, we initially choose 49 as the -nucleophile for
LDA (0.8 eq), THF
36%
p
–78 °C to rt, then CD3OD
Scheme 8.
the key Lewis acid-mediated coupling step (Scheme 10). Deproto-
nation of commercially available 2,2,6-trimethyl-4H-1,3-dioxin-4-
one (44) with LDA, followed by a directed aldol reaction of the
intermediate enolate with furfural (45) gave alcohol 46 in 84% yield.
Because several attempts to reduce 46 directly to 48 in one step
(e.g., with TFA and Et3SiH) were unsuccessful, a two step sequence
was developed. In the event, treatment of alcohol 46 with MsCl and
NEt3 afforded diene 47, which was selectively reduced with nickel
2.3. Third generation approach
Given our inability to selectively alkylate ketone 36, it was ap-
parent that a new plan to access welwitindolinones 3e8 needed to

5592
T.-hao Fu et al. / Tetrahedron 69 (2013) 5588e5603
O
O
boride to give 48 in 34% yield. The corresponding palladium-
catalyzed hydrogenation of 47 was problematic because variable
amounts of reduction of the furan ring were observed. Deproto-
nation of 48 with NaHMDS and O-silylation gave the vinyl silyl
ketene acetal 49, which was used directly in the coupling with 25 to
give 51 in 36% overall yield. During the course of optimizing this key
conversion, we discovered that the vinyl silyl ketene acetal 50,
which was prepared analogously as 49, underwent reaction with 25
in the presence of TMSOTf to give 51 in an improved 48% yield.
When 51 was heated to 110 ꢁC in toluene, the dioxinone moiety
underwent retro [4þ2] cycloaddition to give an intermediate
acylketene, which was trapped by MeOH to give ketoester 42 in 73%
yield.
NaH; n-BuLi
THF, 0 °C
O
O
OMe
OMe
then
O
54
52
Cl
O
53
68%
TMSO
OTMS
OMe
25, TMSOTf
THF, –78 °C
NaHMDS, TMS–Cl
CPME, 0 °C
42
60%
O
55
Scheme 11.
LDA, THF
–78 °C
OH
O
O
O
O
then
O
O
previous work, we first examined the use of Pd(Pt-Bu3)2, but we
discovered that it was necessary to use microwave heating to get
significant conversion, and even then 56 was obtained in only 30%
yield. After examining several other catalysts, we found that PEP-
PSI-IPr19 catalyzed the transformation, providing 56 in 89% yield
under the simple thermal conditions of refluxing toluene. This
protocol allowed the facile preparation of 56 in multigram quan-
tities (Scheme 12).
O
46
44
CHO
O
45
84%
O
O
NaBH4, NiCl2
EtOH
MsCl, TEA
CH2Cl2
O
34%
75%
O
CO2Me
47
RO
O
O
MeO2C
PEPPSI-IPr (4 mol %)
t-BuONa, PhMe
Br
O
O
NaHMDS, R3SiCl
THF, –78 °C
O
O
O
reflux
89%
O
OR
N
Me
N
Me
O
O
48
49: R = TES
50: R = TBS
42
NaH, TBSCl
56: R = H
57: R = TBS
THF
99%
NBS, py
aq DMF, 0 °C
34%
O
O
PCC, CH2Cl2
45%
O
O
Br
CHO
25, TMSOTf
THF, –78 °C
MeOH, PhMe
110 °C
O
O
42
TBSO
MeO2C
O
48%
73%
N
O
MeO2C
Me
51
Scheme 10.
N
N
Me
Me
59
Although the sequence depicted in Scheme 10 provided a rea-
58
sonable route to 42, we queried whether we might be able to de-
Scheme 12.
velop a more concise route. Toward this goal, we targeted the
p-
nucleophile 55 as a potential reaction partner for use in the pivotal
Lewis acid-mediated coupling step (Scheme 11). Accordingly, when
the dianion of methyl acetoacetate (52) was allowed to react with
The next step of the synthesis required the oxidative cleavage of
the furan ring of 56 to reveal an enedione or derived functional
array. This conversion proved to be surprisingly difficult. For ex-
ample, treating 56 with standard oxidants,20 such as Br2, N-bro-
mosuccinimide (NBS), or m-chloroperbenzoic acid (m-CPBA) gave
complex mixtures of products. When 56 was treated with pyr-
idinium chlorochromate (PCC),21 lactone 58 was obtained as the
sole product. We reasoned that this product was formed by cycli-
zation of the intermediate Z-enonal array generated from the furan
furfuryl chloride (53), highly selective
g-alkylation occurred to
furnish the ketoester 54 in 68% yield. Treatment of 54 with 2 equiv
of NaHMDS and TMSCl in cyclopentyl methyl ether (CPME) gave 55
as a single isomer.18 Owing to its lability, 55 was coupled directly
without purification with 25 in the presence of TMSOTf to deliver
the requisite ketoester 42 in 60% over two steps. This outcome was
significant for two reasons. Not only was the yield of the Lewis acid-
mediated coupling step higher, but the overall synthetic sequence
was shortened by three steps. This new and more efficient route to
42 significantly facilitated our synthetic efforts.
ring onto the enol moiety of the b-ketoester, followed by oxidation
with PCC. Several preliminary attempts to refunctionalize 58 by
selective reduction were unavailing, so we decided to protect the
enol moiety of 56 as its tert-butylsilyl enol ether 57. However, se-
lective oxidative cleavage of furan 57 once again proved highly
problematic owing to competing halogenation of the indole ring.
Reaction of 57 with Br2 and dibromohydantoin in aqueous solvents
2.3.2. Synthesis and elaboration of tricyclic core. Having developed
an effective route to 42, the next objective was to construct the
seven-membered ring via an enolate arylation. Drawing from our

T.-hao Fu et al. / Tetrahedron 69 (2013) 5588e5603
5593
OH
gave low yields of 59 along with significant quantities of over
brominated products in which one or more bromine atoms had
been introduced onto the indole ring. Utilization of N-chlor-
osuccinimide (NCS) in aqueous solvents led to chlorination of the
furan and indole rings, and no aldehydic products were detected in
the reaction mixtures. Similarly, exposure of 57 to MeReO3/urea
hydrogen peroxide,22 dimethyldioxirane (DMDO),23 and magne-
sium monoperoxyphthalate (MMPP)24 did not provide significant
quantities of 59, whereas reaction of singlet oxygen25 with 57
furnished 20% of the Z-isomer of 59. Eventually, we discovered that
treating 57 with NBS in aqueous DMF gave 59 in 34% yield, along
with 7% of brominated 59 and 6% of brominated 57. Despite ex-
tensive experimentation, we were unable to improve the yield of
this step.
At this juncture, it was necessary to elaborate the enonal moiety
of 59 into the allylic acetate 62 via the selective reduction of the
aldehyde moiety in 59. Although preliminary experiments using
NaBH4 gave mixtures of 1,2- and 1,4-addition products, we found
that reduction of 59 under Luche’s conditions26 gave diol 60 in 36%
yield (Scheme 13). Selective mono-acetylation of the primary al-
cohol in 60, followed by oxidation of the secondary alcohol with 2-
iodoxybenzoic acid (IBX) gave acetate 62.
TBSO
MeO2C
O
t-BuNH2BH3
59
THF, –78 °C
82%
N
Me
63
O2CR
TBSO
MeO2C
O
Collidine, RCOCl
MeCN, 0 °C
or –20 °C
N
Me
62: R = Me (89%)
64: R = Ph (98%)
Scheme 14.
OR
OR
CHO
TBSO
HO
O
TBSO
O
MeO2C
MeO2C
NaBH4, CeCl3 •7H2O
O
TBAF, THF
0 °C
MeOH, –78 °C to rt
36%
MeO2C
N
N
Me
Me
N
62: R = Ac
64: R = Bz
65: R = Ac
66: R = Bz
Me
59
O
OR
OAc
H
Pd2dba3
TBSO
MeO2C
TBSO
P(2-furyl)3
OH
O
MeO2C
MeO2C
O
Bu3SnOMe
PhCH3, 100 °C
IBX, DMSO
88%
N
84% from 64
N
N
Me
67: (Z)-Δα,β
68: (E)-Δα,β
40: Δβ,γ
Me
60: R = H
61: R = Ac
Me
Ac2O, DMAP
CH2Cl2
62
67%
O
Scheme 13.
H
1) NaHMDS, DMF
–40 °C to rt
12
MeO2C
O
2) MeI, –40 °C to rt
80%
Although this approach to 62 could be used to provide sufficient
quantities of material for further study, a more concise route in-
volving the selective reduction of the aldehyde moiety of 59 was
desired. When 59 was treated with L-Selectride at low tempera-
tures, the desired product 63 was obtained, but significant amounts
of diol 60 were also formed. We eventually discovered that
t-BuNH2BH327 reduced 59 cleanly to give the alcohol 63 in 82% yield
(Scheme 14). Acetylation of the alcohol proceeded smoothly to give
62 in 89% yield, shortening the overall synthetic sequence by one
step compared to the route presented in Scheme 13. We would later
find that the benzoate 64, which was prepared from 63 in 98% yield,
would be a better substrate for the eventual intramolecular allylic
alkylation (vide infra).
N
Me
39
Scheme 15.
trifurylphosphine, and Bu3SnOMe furnished a mixture (5.8:1:3.5)
of the isomeric olefins 67, 68, and 40 in 60% yield from 62. The
presence of Bu3SnOMe, which presumably generated the tin eno-
late of 65 in situ and has been reported to enhance allylic alkyl-
ations,30 was critical to the success of this transformation. When
the benzoate 64 was used in identical sequence, the mixture of 67,
68, and 40 was obtained in 84% yield.
In order to set the stage for forming the tetracyclic core of the
welwitindolinones via an intramolecular allylic alkylation, the silyl
protecting group was removed from 62 using TBAF to give 65
(Scheme 15). Enol 65 was treated with a variety of transition metal
catalysts known to induce allylic alkylations, such as Pd2dba3,
Mo(CO)6,28 and W(CO)3(MeCN)3,29 but none of these delivered any
detectable quantity of cyclized product. After some experimenta-
tion, we discovered that reaction of 65 with Pd2dba3,
The creation of the quaternary carbon at C(12) by methylation of
the derived dienolate proceeded according to plan, but it was
necessary to treat the mixture of 67, 68, and 40 with freshly pre-
pared NaHMDS as the base to obtain optimal results. The desired
product 39, with the structure confirmed by X-ray crystallography,
was thus obtained as a single diastereomer in 80% yield. At this
point all of the carbon atoms in the welwitindolinone skeleton had
been installed, and only a few functional group manipulations

5594
T.-hao Fu et al. / Tetrahedron 69 (2013) 5588e5603
remained to complete the synthesis. We were not prepared, how-
ever, for the travails that lurked.
Having exhausted possible one-step procedures for converting
ketones to vinyl chlorides, we turned to examining several two-
step protocols. Mori and Tsuneda had previously shown that
ketone-derived hydrazones can be converted into vinyl chlorides
with NCS.37 When we treated ketone 39 with hydrazine hydrate,
reduction of the vinyl group gave 74 as the sole product, albeit in
only 26% yield (Scheme 17). Presumably 74 was formed by re-
duction of 39 with diimide that was generated during the course of
the reaction by the presence of oxygen or trace metals. Un-
fortunately, even when oxygen and trace metals were rigorously
excluded, none of the desired hydrazone was formed, even under
forcing conditions. This result is also somewhat confounding be-
cause Rawal employed such a procedure to prepare a vinyl chloride
that was structurally similar to 73 in his recent synthesis of 4.6c
The seemingly straightforward task of converting a ketone into
a vinyl chloride was next on the agenda, and we explored a number
of methods that were known to effect this transformation. Un-
fortunately, we would soon realize that this would not be an easy
task. We initiated our efforts by examining known methods for
directly converting ketones into vinyl chlorides. For example, when
39 was treated with 1 equiv of PCl5,31 chloroindole 69 was obtained
in 60% yield (Scheme 16). Use of excess PCl5 produced only poly-
chlorinated products having the general structure 70 while leaving
the ketone moiety untouched. Treatment of 39 with other elec-
trophilic chlorine reagents known to effect conversion of ketones
32
into vinyl chlorides, such as PPh3/CCl4 and P(OPh)3/Cl2,33 also
failed to deliver the desired vinyl chloride, and dichlorination of the
indole ring was again observed. When the more oxophilic reagent
WCl6 was employed,34 a complex mixture was obtained.
O
O
H
H
N2H4•H2O, NEt3
EtOH, 70 °C
MeO2C
MeO2C
O
O
O
O
26%
H
H
N
N
PCl5, CH2Cl2
MeO2C
MeO2C
Me
Me
O
O
39
74
R1
N
N
LiHMDS
R2
Comins Reagent
THF, –40 °C
80%
Me
Me
39
69: R1 = Cl, R2 = H (60%)
70: R1 = Cl, R2 = Cl (56%)
Cl
TfO
O
H
O
NOE
H
14
H
HCl, dioxane
100 °C
H
H
Conditions
MeO2C
MeO2C
MeO2C
MeO2C
O
O
O
O
36%
H
H
3
O
O
N
N
N
N
Me
Me
Me
Me
76
75
71
72
Scheme 17.
Cl
H
Conditions
We also explored several known methods for transforming ke-
tones into vinyl chlorides via intermediate vinyl triflates. For ex-
ample, vinyl triflates may be converted into vinyl stannanes and
then to vinyl chlorides.38,39 Hayashi and co-workers reported a ru-
thenium catalyzed procedure of converting vinyl triflates to vinyl
chlorides,40 and Buchwald recently described a similar process that
was catalyzed by palladium.41 Although the vinyl triflate 75 was
readily prepared in 80% yield by sequential reaction of 39 with
LiHMDS and then Comins’ reagent,42 we were unable to identify
any conditions that enabled conversion of 75 into 76. Inasmuch as
Garg recently converted a closely related ketone into a vinyl halide
using such a two-step method in his synthesis of 3,6b this failure
again highlights the diabolical vagaries inherent in the chemistry of
the compact welwitindolinone skeleton.
Contemporaneous with our efforts to convert 39 into a natu-
rally-occurring welwitindolinone, both Rawal and Garg reported
elegant syntheses of several welwitindolinones from compounds
closely related to 39.6 We thus opted to examine the feasibility of
completing a formal synthesis of these alkaloids using 39 as an
intermediate. Although we were aware that conversion of the
bridgehead ester in 39 into its carboxylic acid might be problem-
atic,5j we still examined several saponification and nucleophilic
dealkylation tactics to prepare 77; however, even forcing condi-
tions failed to yield detectable amounts of 77 (Scheme 18). We
eventually discovered that 39 could be reduced with LiAlH4 to
deliver an inseparable mixture of the diastereomeric triols 78 that
were in turn globally oxidized with DesseMartin periodinane to
give 79 in 89% yield over two steps. The spectroscopic data (1H and
MeO2C
O
H
O
N
Me
73
Scheme 16.
Because the indole ring of 39 thus appeared to be more reactive
toward electrophilic chlorinating reagents than the ketone moiety,
we reasoned that deactivating the indole ring by conversion to its
oxindole counterpart, the oxidation state present in the natural
product, might lead to preferential reaction of the ketone. Recog-
nizing that 2-haloindoles can be hydrolyzed to oxindoles,5r,35
chloroindole 69 was treated with concentrated HCl in dioxane to
give a mixture (1:1.2) of epimeric oxindoles 71 and 72 in 36% yield.
The isolation of epimers was somewhat surprising because Garg
has reported that the hydrolysis of a related 2-bromoindole gave
a single diastereomer.5r We also found that 39 could be converted
directly into a mixture of 71 and 72 in 34% yield with MeReO3/urea
hydrogen peroxide.36 The stereochemical configuration of 71 and
72 was assigned based upon a 2-D NOESY experiment. In particular,
the proton at C(3) (
with the proton at C(14) (
d
¼3.57 ppm) of 71 exhibited an NOE interaction
d
¼2.93 ppm), whereas the C(3) proton of
72 did not. Unfortunately, exposure of the mixture of 71 and 72 to
the action of various electrophilic chlorine reagents did not provide
detectable amounts of the desired vinyl chloride 73.

T.-hao Fu et al. / Tetrahedron 69 (2013) 5588e5603
5595
13C NMR spectroscopy) for the synthetic 79 thus obtained were
consistent with those reported by Rawal,6a who used this com-
pound as a pivotal intermediate in his syntheses of 4e8.6c Our
preparation of 79 thus constitutes a formal synthesis of 4e8.
use. Thionyl chloride was distilled before use. Furfuryl alcohol was
distilled from sodium carbonate before use. Methyl acetoacetate
was distilled from calcium chloride before use. N-Bromosuccini-
mide (NBS) was recrystallized from water. Methyl iodide (MeI) was
distilled from phosphorus pentoxide. Sodium tert-butoxide (NaOt-
Bu) was sublimed before use. Trifurylphosphine44 and
DesseMartin periodinane45 were synthesized according to litera-
ture procedures. All reagents were reagent grade and used without
purification unless otherwise noted, and air or moisture sensitive
reagents were weighed in a glovebox. All reactions involving air or
moisture sensitive reagents or intermediates were performed un-
der an inert atmosphere of nitrogen or argon in glassware that was
flame or oven dried. Reaction temperatures refer to the tempera-
ture of the cooling/heating bath. Volatile solvents were removed
€
under reduced pressure using a Buchi rotary evaporator at
O
O
H
H
Conditions
MeO2C
HO2C
O
O
N
N
Me
Me
39
77
LiAlH4
Et2O, rt
25e30 ꢁC (bath temperature). Thin layer chromatography was run
on pre-coated plates of silica gel with a 0.25 mm thickness con-
taining 60F-254 indicator (EMD Millipore). Chromatography was
performed using forced flow (flash chromatography) and the in-
dicated solvent system on 230e400 mesh silica gel (Silicycle flash
F60) according to the method of Still,46 unless otherwise noted.
Infrared (IR) spectra were obtained either neat on sodium chloride
or as solutions in the solvent indicated and reported as wave-
numbers (cmꢀ1). Proton nuclear magnetic resonance (1H NMR) and
carbon nuclear magnetic resonance (13C NMR) spectra were ob-
tained at the indicated field as solutions in CDCl3 unless otherwise
indicated. Chemical shifts are referenced to the deuterated solvent
HO
O
H
H
Dess-Martin
NaHCO3
OHC
O
OH
HO
CH2Cl2, rt
89% (2 steps)
N
N
Me
Me
78
79
ref 6c
4–8
(e.g., for CDCl3,
d
¼7.24 ppm and 77.0 ppm for 1H and 13C NMR,
Scheme 18.
respectively) and are reported in parts per million (ppm, d) relative
to tetramethylsilane (TMS,
d
¼0.00 ppm). Coupling constants (J) are
reported in hertz and the splitting abbreviations used are: s, sin-
glet; d, doublet; t, triplet; q, quartet; m, multiplet; comp, over-
lapping multiplets of magnetically non-equivalent protons; br,
broad; app, apparent.
3. Conclusions
In summary, formal syntheses of a number of natural welwi-
tindolinones were completed by the synthesis of aldehyde 79, the
pivotal intermediate in Rawal’s elegant syntheses of the welwi-
tindolinone alkaloids, via a sequence of reactions that requires 14
steps in the longest linear sequence. The synthesis showcases
several interesting steps and discoveries. One of these is the Lewis
acid-mediated coupling of alcohol 25 with a number of vinyl silyl
4.2. Experimental procedures
4.2.1. 4-Bromo-1-methyl-1,3-dihydro-2-oxindole (13). A suspension
of sodium hydride (331 mg, 8.63 mmol, 60% in oil) and xylenes
(17.3 mL) was heated to reflux, and 4-bromo-1,3-dihydro-2-
oxindole (14) (1.83 g, 8.63 mmol) was added in w10 equal por-
tions over 5 min. The resulting light orange suspension was heated
ketene acetals to generate
process involves a variant of a vinylogous Mannich reaction in
which a benzylic-type carbocation is trapped by a -nucleophile,
and this discovery was subsequently extended to a more general
entry to the synthesis of
-heteroaryl carbonyl compounds.14 We
also extended the scope of cyclizations via allylic alkylations to
include -acyloxyenones, and we developed an improved method
g-heteroaryl ketoesters. This novel
under reflux for 1 h, whereupon dimethylsulfate (1.09 g, 818 mL,
p
8.63 mmol) was added slowly dropwise at reflux. After heating at
reflux for an additional 1 h, the reaction was cooled and diluted
with EtOAc (30 mL). The organic layer was washed with water
(3ꢂ15 mL), brine (15 mL), dried (MgSO4) and concentrated to
provide a yellow solid that was purified by flash column chroma-
tography eluting with a solvent gradient (CH2Cl2 to 10% Et2O in
CH2Cl2) to give 1.29 g (66%) of 13 as a fluffy light yellow solid: mp
b
g
for enolate arylations of carbonyl compounds.
138e139 ꢁC; 1H NMR (500 MHz)
(m, 1H), 3.43 (s, 2H), 3.17 (s, 3H); 13C NMR (126 MHz)
129.4, 125.4, 125.3, 119.0, 106.8, 37.0, 26.5; IR 3054, 2939, 1717, 1611,
1458, 1340, 1þ296, 1106, 925, 770, 708 cmꢀ1; HRMS (CI) m/z calcd for
C9H979BrNO (Mþ1), 225.9868; found, 225.9875.
d
7.15e7.10 (comp, 2H), 6.73e6.69
173.7, 146.0,
4. Experimental
4.1. General
d
Tetrahydrofuran (THF) and diethyl ether (Et2O) were dried by
filtration through two columns of activated, neutral alumina
according to the procedure described by Grubbs.43 Acetonitrile
(MeCN), and dimethylformamide (DMF) were dried by filtration
through two columns of activated molecular sieves, and toluene
was dried by filtration through one column of activated, neutral
alumina followed by one column of Q5 reactant. These solvents
were determined to have less than 50 ppm H2O by Karl
Fischer coulometric moisture analysis. Methylene chloride
(CH2Cl2), pyridine, chlorotrimethylsilane (TMSCl), trimethylsilyl
trifluoromethanesulfonate (TMSOTf), benzoyl chloride (BzCl), and
collidine were distilled from calcium hydride immediately prior to
4.2.2. Methyl-3-(4-bromo-1-methyl-2,3-dihydro-2-oxindol-3-yl)-3-
methylbutyrate (16). A suspension of 13 (264 mg, 1.17 mmol),
MeOH (780 mL), and methyl 3-methylcrotonate (667 mg, 765 mL,
5.85 mmol) was treated with sodium methoxide (63.2 mg,
1.17 mmol), and the mixture was heated for 40 h. The reaction was
cooled, and 1 M aqueous HCl (w2 mL) and water (15 mL) were
added. The mixture was stirred for 5 min and extracted with EtOAc
(3ꢂ20 mL). The combined organic layers were dried (MgSO4) and
concentrated to provide an orange oil that was purified by flash
column chromatography eluting with 10% EtOAc in benzene (mixed

5596
T.-hao Fu et al. / Tetrahedron 69 (2013) 5588e5603
fractions rechromatographed twice) to give 236 mg (62%) of 16 as
a light yellow solid: mp 75e77 ꢁC; 1H NMR (400 MHz)
7.13 (dd,
temperature). After 3 h, the reaction was cooled, 1 M aqueous HCl
(5 mL) was added, and the mixture was extracted with EtOAc
(3ꢂ5 mL). The combined organic layers were dried (MgSO4) and
concentrated. The residue was purified by flash column chroma-
tography eluting with a solvent gradient (10% EtOAc in hexanes to
30% EtOAc in hexanes) to give 20 mg (88%) of 11 as a white solid, mp
d
J¼7.9, 1.0 Hz, 1H), 7.08 (td, J¼7.9, 1.0 Hz, 1H), 6.68 (dd, J¼7.9, 1.0 Hz,
1H), 3.82 (s, 1H), 3.66 (s, 3H), 3.09 (s, 3H), 2.92 (A of AB, JAB¼15.1 Hz,
1H), 2.49 (B of AB, JAB¼15.1 Hz, 1H), 1.31 (s, 3H), 0.87 (s, 3H); 13C
NMR (101 MHz) d 176.4, 172.4, 147.2, 129.4, 127.9, 126.6, 120.9, 106.4,
54.0, 51.2, 43.3, 39.6, 27.6, 25.9, 24.2; IR (neat) 2950, 2882, 1713 (br),
114e117 ꢁC; 1H NMR (500 MHz)
d
13.1 (d, J¼1.0 Hz, 1H), 7.25 (td,
1603, 1454, 1330,1172,1100, 932, 767 cmꢀ1; HRMS (CI) m/z calcd for
J¼7.8, 0.7 Hz, 1H), 7.11 (dd, J¼7.8, 0.7 Hz, 1H), 6.66 (d, J¼7.8 Hz, 1H),
þ
C15H1979BrNO3 (Mþ1), 340.0548; found, 340.0554.
3.79 (s, 3H), 3.16 (s, 3H), 2.98 (s, 1H), 2.20 (d, J¼12.6 Hz, 1H), 2.06 (d,
J¼12.6 Hz, 1H), 1.51 (s, 3H), 0.88 (s, 3H); 13C NMR (126 MHz)
d 177.5,
4.2.3. tert-Butyl 5-(4-bromo-1-methyl-2,3-dihydro-2-oxindol-3-yl)-
5-methyl-3-oxohexanoate (17). n-BuLi (0.28 mL, 2.5 M in hexanes,
176.1, 171.7, 143.6, 131.3, 127.5, 126.8, 123.4, 105.5, 101.3, 52.5, 51.8,
48.3, 48.2, 28.6, 26.0, 24.8; IR (neat) 3016, 2928, 2855, 1703, 1644,
1604, 1444, 1370, 1334, 1296, 1236, 770 cmꢀ1; HRMS (CI) m/z calcd
0.69 mmol) was added to a solution of i-Pr2NH (70 mg, 97
mL,
þ
0.69 mmol) in THF (4.4 mL) at ꢀ78 ꢁC, and the resulting solution
for C17H20NO4 (Mþ1), 302.1392; found, 302.1382.
was stirred at 0 ꢁC for 30 min. The solution was cooled to ꢀ50 ꢁC,
and a solution of t-BuOAc (81 mg, 94
mL, 0.69 mmol) in THF
4.2.6. Oxindole-bridged[2.2.3]bicycle (20). To
(14 mg, 47 mol) and THF (0.24 mL) was added DBU (8.0 mg, 8.0
mol). To this orange solution was added carbonate 18 (10 mg,
L, 51 mol) and this mixture was added to a solution of tet-
mol) and THF
a
solution of 11
(0.44 mL) was added dropwise. The reaction was stirred for 1 h
between ꢀ45 ꢁC and ꢀ30 ꢁC, whereupon a solution of 16 (39 mg,
0.12 mmol) in THF (0.20 mL) was added dropwise. The reaction was
stirred for 1 h between ꢀ45 ꢁC and ꢀ30 ꢁC and then slowly warmed
to room temperature over the next 1 h. Saturated aqueous NH4Cl
(5 mL) and water (20 mL) were added, and the mixture was
extracted with Et2O (3ꢂ20 mL). The combined organic layers were
dried (MgSO4) and concentrated to provide a yellow oil. The residue
was purified by flash column chromatography eluting with a sol-
vent gradient (10% Et2O in hexanes to 40% Et2O in hexanes) to give
35 mg (72%) of 17 as a light yellow oil; 1H NMR (300 MHz)
m
mL,
51
m
9.0
m
m
rakistriphenylphosphine palladium (5.4 mg, 47
m
(0.24 mL) over 10 min. After 2 h, the reaction was concentrated
under reduced vacuum, and the residue was purified by flash
chromatography eluting with a solvent gradient (10% EtOAc in
hexanes to 20% EtOAc in hexanes) to afford 9.8 mg (59%) of 21 as an
amorphous white solid; 1H NMR (500 MHz)
d
7.29 (t, J¼7.8 Hz, 1H),
6.82 (dd, J¼7.8, 0.8 Hz, 1H), 6.56 (dd, J¼7.8, 0.8 Hz, 1H), 4.91 (br s,
1H), 4.86 (br s, 1H), 3.83 (s, 3H), 3.31 (d, J¼13.8 Hz, 1H), 3.22 (s, 3H),
2.92 (d, J¼14.9 Hz, 1H), 2.65 (d, J¼12.1 Hz, 1H), 2.53 (d, J¼13.8 Hz,
1H), 2.15 (d, J¼12.1 Hz, 1H), 2.13 (d, J¼14.9 Hz, 1H), 1.44 (s, 3H), 0.78
d
7.20e7.08 (comp, 2H), 6.71 (d, J¼7.3 Hz,1H), 3.94 (s,1H), 3.44 (A of
AB, JAB¼15.3 Hz, 1H), 3.39 (B of AB, JAB¼15.3 Hz, 1H), 3.17 (A of AB,
JAB¼17.8 Hz, 1H), 3.11 (s, 3H), 2.70 (B of AB, JAB¼17.8 Hz, 1H), 1.47 (s,
(s, 3H); 13C (126 MHz)
d 208.0, 178.6, 171.1, 143.2, 141.7, 137.3, 129.2,
9H), 1.40 (s, 3H), 0.79 (s, 3H); 13C NMR (75 MHz)
d
202.2, 176.6,
129.0, 119.9, 118.8, 107.3, 67.2, 56.9, 54.4, 52.6, 45.1, 41.6, 38.7, 28.3,
166.5, 147.1, 129.4, 128.1, 126.7, 120.7, 106.4, 81.7, 53.1, 52.0, 51.3,
39.5, 28.4, 28.0, 25.9, 23.9; IR (neat) 2973, 1713 (br), 1603, 1455,
1368, 1327, 12þ51, 1158, 1101, 932, 768 cmꢀ1; HRMS (CI) m/z
C20H2779BrNO4 (Mþ1), 424.1124; found, 424.1109.
26.1, 22.9; IR (neat) 3018, 2955, 1746, 1707, 1607, 1470, 1246 cmꢀ1
;
þ
HRMS (CI) m/z calcd for C21H24NO4 (Mþ1), 354.1705; found,
354.1701.
4.2.7. 2-(tert-Butyl-diphenylsilanyloxymethyl)prop-2-en1-yl bromide
(28). Triphenylphosphine (526 mg, 2.01 mmol) and carbon tetra-
bromide (664 mg, 2.00 mmol) were added to a stirred solution of 2-
((tert-butyldiphenylsilyloxy)methyl)prop-2-en-1-ol47 (662 mg,
2.03 mmol) in CH2Cl2 (8.0 mL) at 0 ꢁC. The reaction mixture was
stirred for 40 min and then concentrated in vacuo. The crude
product was purified via flash chromatography eluting with 10%
EtOAc in hexanes to afford 864 mg (99%) of 28 as a colorless oil; 1H
4.2.4. Methyl 5-(4-bromo-1-methyl-2,3-dihydro-2-oxindol-3-yl)-5-
methyl-3-oxohexanoate (12). A solution of 17 (142 mg, 0.335 mmol)
in trifluoroacetic acid (669 m
L) was stirred at 0 ꢁC for 1 h, whereupon
the reaction was concentrated under reduced pressure, and the resi-
due was dissolved in Et2O (0.669 mL). The solution was cooled to 0 ꢁC,
and an ethereal solution of diazomethane (w0.3 M) was added until
the yellow color persisted. The reaction was quenched with 1 M
aqueous HCl (5 mL), stirred 5 min, and extracted with Et2O (3ꢂ5 mL).
The combined organic layers were dried (MgSO4) and concentrated to
provide a clear light yellow oil. The residue was purified by flash
column chromatographyelutingwith a solvent gradient(20%EtOAc in
hexanes to 40% EtOAc in hexanes) to give 121 mg (95%) of 12 as a clear
NMR (500 MHz)
5.29 (dd, J¼3.0, 1.6 Hz, 1H), 5.27e5.26 (m, 1H), 4.29 (t, J¼1.3 Hz, 2H),
4.01 (s, 2H), 1.06 (s, 9H); 13C NMR (125 MHz)
144.4, 135.5, 133.3,
d
7.67 (dd, J¼8.0, 1.4 Hz, 4H), 7.44e7.36 (comp, 6H),
d
129.7, 127.7, 114.9, 64.2, 32.7, 26.8, 19.3; IR 3070, 2958, 2930, 2857,
1112 cmꢀ1; HRMS (CI) m/z calcd for C20H2679BrOSiþ (Mþ1),
389.0936; found, 389.0921.
light yellow oil; 1H NMR (300 MHz)
d 7.20e7.08 (comp, 2H), 6.71 (dd,
J¼7.3, 1.0 Hz, 1H), 3.95 (s, 3H), 3.75 (s, 3H), 3.55 (s, 2H), 3.23 (A of AB,
JAB¼17.9 Hz, 1H), 3.10 (s, 3H), 2.63 (B of AB, JAB¼17.9 Hz, 1H), 1.43 (s,
4.2.8. tert-Butyl 7-tert-butyldiphenylsilanyloxy-6-methylidene-hept-
3-one-ate (29). n-BuLi (1.0 mL, 2.1 M in hexanes, 2.2 mmol) was
added to a stirred solution of i-Pr2NH (0.23 g, 0.32 mL, 2.3 mmol) in
THF (7.0 mL) at ꢀ78 ꢁC. The solution was warmed to 0 ꢁC (replaced
the dry ice/isopropanol bath with ice), stirred for 40 min, and then
tert-butylacetoacetate (27) (0.17 g, 0.18 mL, 1.1 mmol) was added
dropwise over 5 min and stirring continued for 45 min. The solu-
tion was cooled to ꢀ78 ꢁC, and the allylic bromide 28 (0.24 mg,
0.92 mmol) in THF (3.0 mL) was added over 10 min. The reaction
mixture was stirred for 1.25 h, warmed to room temperature (by
removing the dry ice/isopropanol bath) and stirred for 2.5 h. The
solution was poured into saturated aqueous NH4Cl (40 mL), and the
resultant mixture was extracted with EtOAc (3ꢂ30 mL). The com-
bined organic extracts were washed with brine (40 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified by
flash chromatography eluting with 10% EtOAc in hexanes, afforded
3H), 0.74 (s, 3H); 13C NMR (75 MHz)
d 201.8, 176.6, 167.7, 147.1, 129.4,
128.1, 126.7, 120.7,106.5, 52.8, 52.3, 51.4, 50.5, 39.5, 28.8, 26.9, 23.9; IR
(neat) 2963, 2881, 1747, 1714 (br), 1603, 1454, 1329, 1102, 932,
þ
768 cmꢀ1; HRMS (CI) m/z calcd for C17H2179BrNO4 (Mþ1),
382.0654; found, 382.0654.
4.2.5. Methyl 7-hydroxy-2,9,9-trimethyl-1-oxo-2,8,9,9a-tetrahydro-
2-azabenzo[cd]azulene-6-carboxylate (11). Aryl bromide 12 (28 mg,
74
14
m
m
mol), bis-(tri-tert-butylphosphine)palladium (0) (8.0 mg,
mol), bis-dibenzylidenepalladium (0) (4.0 mg, 7.5 mol), and
mol) were added to a dry
m
sodium tert-butoxide (7.9 mg, 82
m
Kjeldahl-shaped Schlenk flask. The flask was evacuated and back-
filled with argon three times, and DMF (0.52 mL) was added. The
brown suspension was deoxygenated via a freezeepumpethaw
protocol (3 cycles, 20 min each) and then heated at 75 ꢁC (oil bath

T.-hao Fu et al. / Tetrahedron 69 (2013) 5588e5603
5597
0.30 g (70%) of the product 29 as a colorless oil; 1H NMR (400 MHz)
7.69e7.66 (comp, 4H), 7.46e7.36 (comp, 6H), 5.18e5.17 (m, 1H),
The reaction was stirred at room temperature for 4 h, whereupon
50% saturated aqueous NaHCO3 (ca. 32 mL) was added dropwise at
0 ꢁC. The insoluble salts were removed by filtration, and the filtrate
was extracted with EtOAc (3ꢂ30 mL). The combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure to
give crude 25 (1.08 g, 4.03 mmol), which was dissolved in PhMe
(40 mL). The solution was cooled to ꢀ78 ꢁC, and TMSOTf (0.428 g,
d
4.85 (dd, J¼2.7,1.3 Hz,1H), 4.10 (s, 2H), 3.32 (s, 2H), 2.65 (t, J¼7.6 Hz,
2H), 2.30 (t, J¼7.5 Hz, 2H), 1.46 (s, 9H), 1.07 (s, 9H); 13C NMR
(100 MHz) d 202.5, 166.4, 146.5, 135.5, 133.5, 129.7, 127.7, 109.3, 81.9,
66.4, 50.6, 41.1, 27.9, 26.8, 26.2, 19.2; IR (thin film) 3071, 2931, 1739,
1716 cmꢀ1; HRMS (CI) m/z calcd for C28H39O4Siþ (Mþ1), 467.2618;
found, 467.2615.
350 mL, 1.93 mmol) was added with stirring. After 2 min, the above
solution of 26 was added, and the mixture was stirred for 2.5 h. The
reaction mixture was warmed to room temperature and stirred for
17 h, whereupon the mixture was poured into saturated aqueous
NaHCO3 (70 mL) The phases were separated, and the aqueous
portion was extracted with EtOAc (3ꢂ50 mL). The combined or-
ganic extracts were washed with brine (50 mL), dried (Na2SO4), and
concentrated in vacuo. The product was purified via flash chro-
matography eluting with 20/35% EtOAc in hexanes to afford
960 mg (35% from 32) of 33 as a colorless oil; 1H NMR (500 MHz)
4.2.9. 6-(4-tert-Butyldiphenylsilyloxy-2-methylidenebuyl)-2,2-
dimethyl-4H-1,3-dioxin-4-one (30). The
0.378 mmol) was dissolved in acetone (110 mg, 140
trifluoroacetic acid (421 mg, 290 L, 3.70 mmol), and acetic anhy-
b
-ketoester 29 (177 mg,
mL, 1.90 mmol),
m
dride (1.90 g, 1.80 mL, 19.0 mmol). After standing for 22 h, saturated
aqueous NaHCO3 (60 mL) was added. The solution was then
extracted with CH2Cl2 (4ꢂ15 mL), and the combined organic ex-
tracts were washed with brine (20 mL), dried (Na2SO4), and con-
centrated in vacuo. The residue was purified by flash
chromatography eluting with 30% EtOAc in hexanes to give 114 mg
d
7.59e7.51 (comp, 4H), 7.40e7.31 (comp, 7H), 7.20 (dd, J¼8.2,
1.0 Hz, 1H), 6.98 (t, J¼7.9 Hz, 1H), 6.89 (s, 1H), 5.24 (br s, 1H), 5.09 (s,
1H), 4.82 (s, 1H), 4.17 (d, J¼12.1 Hz, 1H), 3.97 (br s, 1H), 3.67 (s, 3H),
2.25 (t, J¼13.3 Hz, 1H), 1.68e1.36 (comp, 14H), 0.94 (s, 9H); 13C NMR
(67%) of 30 as a pale yellow oil; 1H NMR (500 MHz)
d 7.66e7.64
(comp, 4H), 7.44e7.36 (comp, 6H), 5.17 (s,1H), 5.15 (d, J¼1.4 Hz,1H),
4.86 (d, J¼1.2 Hz, 1H), 4.09 (s, 2H), 2.35e2.32 (comp, 2H), 2.31e2.24
(125 MHz)
d 172.6, 161.2, 145.4, 139.9, 135.5, 135.4, 133.54, 133.48,
(comp, 2H), 1.63 (s, 6H), 1.05 (s, 9H); 13C NMR (125 MHz)
d
171.2,
129.62, 129.58, 127.6, 125.9, 122.4, 122.3, 113.7, 110.3, 109.0, 105.9,
66.0, 48.9, 38.0, 34.1, 33.0, 30.3, 26.7, 25.5, 24.9, 22.3, 19.2, 14.0; IR
2958, 2856, 17þ24, 1620, 1112 cmꢀ1; HRMS (CI) m/z calcd for
C39H4779BrO4Si (Mþ1), 700.2458; found, 700.2462.
161.2, 145.9, 135.5, 133.3, 129.8, 127.7, 110.3, 106.3, 93.4, 66.3, 31.8,
28.7, 26.8, 25.0, 19.2; HRMS (CI) m/z calcd for C27H35O4Siþ (Mþ1),
451.2305; found, 451.2320.
4.2.10. 4-Bromo-3-acetyl-1-methyl-1H-indole (32). A suspension of
31 (8.8 g, 45 mmol), potassium carbonate (4.5 g, 32 mmol), and
dimethyl carbonate (12 g, 0.13 mol) in DMF (56 mL) was gradually
heated to 140 ꢁC over 30 min and stirred for 3.5 h. After cooling to
room temperature, the insoluble solids were removed by filtration,
and the filtrate was concentrated under reduced pressure. The
residue was distilled under reduced pressure (0.2 mmHg,
155e180 ꢁC) to give 8.5 g (91%) of 4-bromo-1-methylindole as
a yellow liquid. Its 1H NMR spectroscopic data were consistent with
those reported in the literature.48
4.2.12. (Z)-Methyl
8,9-dihydro-7-hydroxy-8-(2-(tert-butyldiphe-
nylsi-lyloxymethyl)allyl)-2,9,9-trimethyl-2H-cyclohepta[cd]indole-6-
carboxylate (34). The dioxinone 33 (960 mg, 1.37 mmol) was
heated under reflux in a mixture of MeOH (5.5 mL) and PhMe
(110 mL) for 21 h. The reaction mixture was cooled to room tem-
perature and concentrated in vacuo, and the residue was purified
by flash chromatography eluting with 25% EtOAc in hexanes to
afford 871 mg (94%) of 34 as an oil; 1H NMR (400 MHz)
d 7.64e7.52
(comp, 4H), 7.42e7.32 (comp, 7H), 7.26 (d, J¼7.9 Hz, 1H), 7.04 (t,
J¼7.9 Hz, 1H), 6.92 (s, 1H), 5.15 (s, 1H), 4.84 (s, 1H), 4.51 (dd, J¼11.8,
1.9 Hz, 1H), 4.04 (br s, 2H), 3.71 (s, 3H), 3.58 (s, 3H), 3.05 (br s, 2H),
2.52e2.38 (comp, 2H), 1.70e1.46 (comp, 7H), 1.00 (s, 9H); 13C NMR
Me2AlCl (1.0 M in hexanes, 81 mL, 81 mmol) was added drop-
wise over 30 min to a solution of 4-bromo-1-methylindole (8.5 g,
40 mmol) in CH2Cl2 (100 mL) at ꢀ20 ꢁC. The reaction mixture was
stirred for 45 min, and a solution of acetyl chloride (4.7 g, 60 mmol)
in CH2Cl2 (40 mL) was added over 15 min. The resulting suspension
was stirred at room temperature for 5.5 h, whereupon pH 7
phosphate buffer (100 mL) was slowly added at 0 ꢁC. The organic
solvents were removed under reduced pressure, and the resulting
mixture was extracted with CH2Cl2 (3ꢂ80 mL). The combined or-
ganic layers were dried (Na2SO4) and concentrated under reduced
pressure. The residue was recrystallized (CH2Cl2/hexanes) to give
8.5 g (84%) of 32 as a light tan solid: mp¼124e125 ꢁC; 1H NMR
(100 MHz)
d 207.0, 167.5, 146.3, 140.2, 135.7, 133.8, 129.8, 129.3,
127.9, 126.1, 123.0, 122.5, 122.0, 113.7, 110.6, 109.4, 66.1, 57.5, 52.0,
39.0, 38.1, 33.4, 27.0, 19.5; IR 2955, 2856, 1749, 170þ8, 1112,
1075 cmꢀ1; HRMS (CI) m/z calcd for C37H4479BrO4Si (Mþ),
673.2223; found, 673.2220.
4.2.13. Methyl-8,9-dihydro-7-hydroxy-8-(2-(hydroxymethyl)allyl)-
2,9,9-trimethyl-2H-cyclohepta[cd]indole-6-carboxylate (35). NaOt-
Bu (252 mg, 2.62 mmol) was added to a solution of the ketoester 34
(890 mg, 1.32 mmol) in PhMe (20 mL). The solution was then
degassed (freezeepumpethawꢂ2 cycles), and Pd(OAc)2 (30.0 mg,
0.134 mmol) and tri-tert-butylphosphine (0.400 mL, 1 M in PhMe,
0.400 mmol) were added. The solution was partitioned into four
microwave vials (previously purged with argon twice). Each vial
was heated to 150 ꢁC in the microwave for 5 min (80 W, 20 psi) and
cooled to room temperature. The reaction mixtures were combined
and added to 0.5 M aqueous HCl (30 mL). The mixture was
extracted with EtOAc (3ꢂ30 mL), and the combined organic ex-
tracts were washed with brine (20 mL), dried (Na2SO4), and con-
centrated in vacuo. The crude product was purified by column
chromatography, eluting with 25% EtOAc in hexanes to afford
602 mg (77%) of the intermediate tricycle as a colorless oil. Trie-
thylamine trihydrofluoride (1.60 mL, 9.80 mmol) was added to
a stirred solution of the tricycle (0.600 g, 1.00 mmol) and Et3N
(2.10 mL, 15.0 mmol) in MeCN (10 mL). The reaction was stirred for
20 h, and saturated NaHCO3 (15 mL) and H2O (15 mL) were added.
The aqueous portion was extracted with CH2Cl2 (3ꢂ25 mL), and the
(500 MHz)
d
7.59 (s, 1H), 7.44 (dd, J¼8.0, 1.0 Hz, 1H), 7.22 (dd, J¼8.0,
1.0 Hz, 1H), 7.08 (t, J¼8.0 Hz, 1H), 3.76 (s, 3H), 2.52 (s, 3H); 13C NMR
(125 MHz) d 192.1, 139.0,136.1,127.5,125.2, 124.0,118.2,114.9,108.9,
33.6, 29.9; IRþ3106, 1660, 1106 cmꢀ1; HRMS (CI) m/z calcd for
C11H1179BrNO (Mþ1), 252.0024; found, 252.0032.
4.2.11. O-(tert-Butyldiphenylsilyl)-2-methylene-4-(2,2-dimethyl-4H-
1,3-dioxin-4-one)-5-(4-bromo-1-methylindol-3-yl)-5-methyl-hexan-
1-ol (33). A solution of NaHMDS (9.21 mL, 1.27 M in THF,
11.7 mmol) was added to a stirred solution of the dioxinone 30
(1.78 g, 3.95 mmol) in THF (40 mL) at ꢀ78 ꢁC. After stirring for
45 min, TMSCl (2.14 g, 2.50 mL, 19.7 mmol) was added, and the
solution was stirred for 50 min. The mixture was warmed to room
temperature and concentrated in vacuo to give crude silyl ketene
acetal 26 that was then dissolved in PhMe (10 mL). In a separate
flask, MeMgBr (2.37 M, 5.10 mL, 12.1 mmol) was added dropwise to
a solution of ketone 32 (1.01 g, 4.03 mmol) in THF (20 mL) at 0 ꢁC.

5598
T.-hao Fu et al. / Tetrahedron 69 (2013) 5588e5603
combined organic extracts were washed with brine (20 mL), dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
flash chromatography eluting with 40% EtOAc in hexanes to give
(7.89 g, 82.7 mmol) was added dropwise. The mixture was stirred
for 10 min at ꢀ78 ꢁC, whereupon saturated aqueous NH4Cl (ca.
50 mL) was added slowly, and the mixture was warmed to room
temperature. The mixture was extracted with EtOAc (3ꢂ80 mL),
and the combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure. The residue was purified by
flash chromatography eluting with hexanes/EtOAc (1:3/1:1) to
0.24 g (67%) of 35 as an oil; 1H NMR (400 MHz)
d 13.64 (s, 1H), 7.25
(dd, J¼7.4, 1.1 Hz, 1H), 7.20 (t, J¼7.7 Hz, 1H), 7.15 (dd, J¼7.4, 1.1 Hz,
1H), 6.84 (s,1H), 4.94 (s,1H), 4.66 (s,1H), 4.02 (br s, 2H), 3.84 (s, 3H),
3.75 (s, 3H), 2.73 (dd, J¼7.8, 2.4 Hz, 1H), 1.98 (dd, J¼9.8, 2.4 Hz, 1H),
1.65 (dd, J¼9.8, 7.8 Hz, 1H), 1.48 (s, 3H), 1.49 (br s, 1H), 1.38 (s, 3H);
give 15.1 g (84%) of 46 as a yellow oil; 1H NMR (500 MHz)
d 7.38 (dd,
13C NMR (100 MHz)
d
178.6, 174.6, 147.2, 137.1, 125.0, 124.9, 123.9,
J¼2.0, 1.0 Hz, 1H), 6.33 (dd, J¼3.0, 2.0 Hz, 1H), 6.27 (dt, J¼3.0, 1.0 Hz,
1H), 5.30 (s, 1H), 5.01e4.97 (m, 1H), 2.83e2.72 (comp, 2H),
2.12e2.04 (m, 1H), 1.66 (s, 3H), 1.62 (s, 3H); 13C NMR (126 MHz)
121.70, 121.66, 121.1, 112.4, 107.3, 102.3, 66.2, 58.5, 52.2, 36.7, 33.0,
32.1, 31.4, 28.5; IR 3416, 2952, 1741, 163þ3, 1588, 1298, 1224 cmꢀ1
;
HRMS (CI) m/z calcd for C21H25NO4 (M), 355.1784; found,
d
167.7, 161.1, 154.7, 142.7, 110.6, 107.0, 106.9, 95.8, 64.9, 40.0, 25.4,
25.0; IR 3417, 1722, 1634 cmꢀ1. HRMS (CI) m/z calcd for C12H15O5
(Mþ1), 239.0919; found, 239.0921.
þ
355.1786.
4.2.14. 3,3-Dimethyl-4,8-methano-6-methylene-12-oxo-cyclonon[cd]-
N-methyl-indole-8-carboxylate methyl ester (22). To a solution of al-
4.2.17. (E)-6-(2-(Furan-2-yl)vinyl)-2,2-dimethyl-4H-1,3-dioxin-4-
one (47). MsCl (93.0 g, 0.820 mol) was added dropwise to a solu-
tion of alcohol 46 (122 g, 0.510 mol) and NEt3 (165 g, 1.64 mol) in
CH2Cl2 (511 mL) at 0 ꢁC. The solution was stirred for 30 min,
whereupon aqueous HCl (1 M, 450 mL) was added in portions. The
mixture was extracted with CH2Cl2 (3ꢂ450 mL), and the combined
organic layers were dried (Na2SO4) and concentrated under re-
duced pressure. The residue was purified by column chromatog-
raphy eluting with hexanes/EtOAc (1:5/1:1) to give 85.0 g (75%) of
47 as a pale yellow oil that crystallized upon standing in the freezer,
cohol 35 (0.13 g, 0.35 mmol) and collidine (46 mg, 50
mL, 0.38 mmol)
in CH2Cl2 was added AcCl (28 mg, 25 L, 0.36 mmol) dropwise at
m
ꢀ78 ꢁC. The solution was stirred for 3.5 h, whereupon 1 N aqueous
HCl (30 mL) was added. The aqueous layer was extracted with CH2Cl2
(3ꢂ25 mL), and the organic layers were combined, dried (Na2SO4),
and concentrated under reduced pressure. The residue was purified
with column chromatography, eluting with 35% EtOAc in hexanes to
give 0.11 g (78%) of the intermediate acetate. Sodium hydride
(9.0 mg, 0.23 mmol, 60% dispersion in oil) was added to a solution of
a portion of the intermediate acetate (82 mg, 0.21 mmol) in THF
(6.0 mL). The solution was degassed (freezeepumpethawꢂ2 cycles)
mp 84e85 ꢁC; 1H NMR (500 MHz)
d
7.46 (d, J¼2.0 Hz, 1H), 7.03 (d,
J¼15.5 Hz,1H), 6.54 (d, J¼2.0 Hz,1H), 6.46 (app t, J¼2.0 Hz,1H), 6.42
and purged with argon. Pd2(dba)3 (8.7 mg, 9.5 mmol) was added, and
(d, J¼15.5 Hz, 1H), 5.38 (s, 1H), 1.73 (s, 6H); 13C NMR (125 MHz)
the solution was heated with stirring at 50 ꢁC for 17 h. After cooling
to room temperature, 1 N aqueous HCl (20 mL) was added, and the
aqueous layer was extracted with CH2Cl2 (3ꢂ20 mL). The combined
organic extracts were washed with brine (20 mL), dried (Na2SO4),
and concentrated in vacuo. The residue was purified by flash chro-
matography eluting with 25% EtOAc in hexanes to furnish 50 mg
d
163.1, 161.8, 151.4, 144.6, 124.3, 117.6, 114.0, 112.4, 106.4, 94.9, 25.1;
þ
IR 1720, 1629, 1607 cmꢀ1; HRMS (CI) m/z calcd for C12H13O4
(Mþ1), 221.0814; found, 221.0818.
4.2.18. 6-(2-(Furan-2-yl)ethyl)-2,2-dimethyl-4H-1,3-dioxin-4-one
(48). NaBH4 (24.7 g, 654 mmol) was added in one portion to
a mechanically stirred suspension of CoCl2$6H2O (23.3 g,
(55%) of 22 as an oil; 1H NMR (500 MHz)
d
7.21e7.15 (comp, 2H), 6.92
(s, 1H), 6.66 (dd, J¼6.8, 1.6 Hz, 1H), 4.42 (s, 1H), 4.29 (s, 1H), 3.76 (s,
3H), 3.73 (s, 3H), 3.44 (d, J¼14.0 Hz, 1H), 2.88 (d, J¼14.0 Hz, 1H), 2.75
(dd, J¼9.0, 4.5 Hz, 1H), 2.69 (dd, J¼15.0, 4.5 Hz, 1H), 2.62 (dd, J¼15.0,
98.0 mmol) in DMF (540 mL) at ꢀ5 ꢁC. Additional DMF (50 mL)
was added to the resulting paste to facilitate stirring. A solution of
diene 47 (72.1 g, 327 mmol) in DMF (110 mL) was added dropwise
via an addition funnel, and the mixture was stirred for 3 h. Et2O
(ca. 300 mL) and water (ca. 300 mL) were added at 0 ꢁC, and the
suspension was filtered. The filtrate was divided into two por-
tions, and each portion was extracted with Et2O (4ꢂ400 mL). The
combined organic layers were dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified by column
chromatography eluting with EtOAc/hexanes (1:5/1:1) to give
9.0 Hz, 1H), 1.48 (s, 3H), 1.23 (s, 3H); 13C NMR (125 MHz)
d 209.5,
173.1, 140.0, 136.9, 130.9, 126.5, 124.8, 122.1, 120.8, 117.7, 112.9, 108.0,
69.3, 61.3, 52.3,þ48.8, 35.6, 34.3, 32.9, 28.8, 14.0; HRMS (CI) m/z calcd
for C21H24NO3 (Mþ1), 338.1756; found, 338.1745.
4.2.15. 3,3-Dimethyl-4,8-methano-6,12-oxo-cyclonon[cd]-N-methyl-
indole-8-carboxylate methyl ester (36). OsO4 (2.0 mg, 7.9
NaIO4 (97 mg, 0.45 mmol) were added to a solution of the olefin 22
(16 mg, 47 mol) in THF (2.0 mL) and H2O (0.5 mL). After stirring for
mmol) and
24.5 g (34%) of 48 as a yellow liquid; 1H NMR (500 MHz)
d 7.29
m
(dd, J¼2.0, 1.0 Hz, 1H), 6.26 (dd, J¼3.0, 2.0 Hz, 1H), 6.01 (dd, J¼3.0,
22 h, the solution was diluted with H2O (15 mL) and extracted with
CH2Cl2 (3ꢂ15 mL). The combined organic extracts were washed
with brine (20 mL), dried (Na2SO4), and concentrated in vacuo. The
crude product was purified by flash chromatography eluting with
40% EtOAc in hexanes to give 11 mg (66%) of 36 as an oil; 1H NMR
1.0 Hz, 1H) 5.21 (s, 1H), 2.87 (t, J¼7.5 Hz, 2H), 2.56 (t, J¼7.5 Hz, 2H),
1.64 (s, 6H); 13C NMR (125 MHz)
d 170.2, 161.1, 153.1, 141.4, 110.2,
106.5, 105.8, 93.9, 32.1, 25.0, 24.3; þIR 2923, 1729, 1635 cmꢀ1
;
HRMS (CI) m/z calcd for C12H15O4 (Mþ1), 223.0970; found,
223.0972.
(500 MHz)
d
7.23e7.21 (comp, 2H), 7.00 (s, 1H), 6.73 (dd, J¼5.8,
2.6 Hz, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 3.51 (dd, J¼17.9, 0.7 Hz, 1H),
3.24 (d, J¼17.9 Hz, 1H), 2.97 (dd, J¼9.5, 6.6 Hz, 1H), 2.82e2.78
4.2.19. 6-(3-(4-Bromo-1-methyl-1H-indol-3-yl)-1-(furan-2-yl)-3-
methylbutan-2-yl)-2,2-dimethyl-4H-1,3-dioxin-4-one (51). n-BuLi
(2.00 M in hexanes, 0.600 mL, 1.20 mmol) was added dropwise to
a solution of i-Pr2NH2 (131 mg, 1.30 mmol) in THF (1 mL) at 0 ꢁC.
The solution was stirred for 20 min and cooled to ꢀ78 ꢁC. A so-
lution of furan 48 (244 mg, 1.11 mmol) in THF (0.3 mL) was added
dropwise and stirring continued for 1 h. A solution of TBSCl
(203 mg, 1.30 mmol) in THF (0.5 mL) was added dropwise, and the
mixture was gradually warmed up to room temperature over 16 h
and stirred for an additional 5 h. The solvent was concentrated
under reduced pressure, and the residue was partitioned between
pentane (5 mL) and water (5 mL). The aqueous layer was extracted
with pentane (2ꢂ5 mL), and the combined organic layers were
(comp, 2H), 1.43 (s, 3H), 1.33 (s, 3H); 13C NMR (125 MHz)
d 206.9,
205.6, 171.6, 137.4, 127.9, 127.8, 123.7, 122.6, 119.4, 118.9, 109.1, 66.7,
57.4, 53.9, 52.9, 43.2, 37.0, 32.7, 29.3, 13.9; IR 2923, 1737, 1732, 1713,
1454, 1246 cmꢀ1
.
4.2.16. 6-(2-(Furan-2-yl)-2-hydroxyethyl)-2,2-dimethyl-4H-1,3-
dioxin-4-one (46). n-BuLi (2.00 M in hexanes, 41.0 mL, 82.7 mmol)
was added dropwise to a solution of i-Pr2NH (9.09 g, 90.2 mmol) in
THF (62 mL) at 0 ꢁC. The mixture was stirred for 20 min and cooled
to ꢀ78 ꢁC, and dioxinone 44 (10.7 g, 75.2 mmol) was added drop-
wise. The solution was stirred at ꢀ78 ꢁC for 1 h, and furfural (45)

T.-hao Fu et al. / Tetrahedron 69 (2013) 5588e5603
5599
dried (Na2SO4) and concentrated under reduced pressure to give
crude 50 (373 mg, 1.11 mmol). The crude 50 thus obtained and
crude 25 (268 mg, 1.00 mmol), which had been freshly prepared
from 32 (252 mg, 1.00 mmol) according to the same procedure
used for the synthesis of 33, were dissolved in THF (9 mL) at
layer was dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by column chromatography eluting with
hexanes/EtOAc (1:9/1:1) to give 1.12 g (60%) of 42 that had a mp
and spectroscopic properties identical to those obtained by
Method A.
ꢀ78 ꢁC, and TMSOTf (222 mg, 180
mL, 1.00 mmol) was added
dropwise. The resulting solution was stirred for 40 min, where-
upon NEt3 (6 mL) was added dropwise. After warming to room
temperature, water (10 mL) was added. The mixture was extracted
with Et2O (3ꢂ50 mL), and the combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure. The residue
was purified by column chromatography, eluting with EtOAc/
hexanes (1:5/1:2) to give 230 mg (48% over two steps) of 51 as
4.2.21. Furfuryl chloride (53). A solution of benzotriazole (30 g,
0.25 mol) and thionyl chloride (30 g, 19 mL, 0.25 mol) in CH2Cl2
(33 mL) was added dropwise to a solution of freshly distilled fur-
furyl alcohol (20 g, 18 mL, 0.20 mol) in CH2Cl2 (136 mL) at 0 ꢁC. The
reaction was stirred for 30 min, and the solids were removed by
filtration. The filtrate was washed with water (400 mL), 2% aqueous
NaOH (400 mL), and brine (200 mL). The organic layer was dried
(Na2SO4) and concentrated under reduced pressure. The residue
was distilled under reduced pressure (1 mmHg, 25e40 ꢁC) to give
12 g (52%) of 53 as a pale yellow liquid; 1H NMR (400 MHz, C6D6)
a white solid: mp¼145e146 (decomp.); 1H NMR (500 MHz)
d 7.42
(dd, J¼8.0, 1.0 Hz, 1H), 7.24 (dd, J¼8.0, 1.0 Hz, 1H), 7.16 (s, 1H), 7.02
(app t, J¼8.0 Hz, 1H), 6.95 (s, 1H), 6.15 (s, 1H), 5.91 (s, 1H), 5.28 (br
s, 1H), 4.48 (dd, J¼13.0, 3.0 Hz, 1H), 3.71 (s, 3H), 2.90 (t, J¼13.0 Hz,
2H), 1.66 (s, 3H), 1.55 (s, 6H), 1.36 (s, 3H); 13C NMR (125 MHz)
d
7.33 (dd, J¼2.0, 1.0 Hz, 1H), 6.28e6.24 (comp, 2H), 4.50 (s, 2H). The
1H NMR spectroscopic data of 53 were consistent with those re-
d
172.1, 161.3, 153.7, 140.8, 140.0, 128.9, 125.9, 125.2, 122.3, 122.1,
ported in the literature.49
113.7, 110.2, 109.1, 106.2, 105.8, 96.4, 50.0, 37.8, 33.1, 26.9, 25.9,
23.9; IR 292þ0, 1723 cmꢀ1
;
HRMS (CI) m/z calcd for
4.2.22. Methyl 5-(furan-2-yl)-3-oxopentanoate (54). Methyl ace-
toacetate (52) (5.98 g, 51.5 mmol) was added dropwise to a sus-
pension of NaH (60% dispersion in mineral oil, 2.27 g, 56.8 mmol) in
THF (70 mL) at 0 ꢁC. The reaction was stirred for 10 min, and n-BuLi
(2.5 M in hexanes, 22.0 mL, 54.1 mmol) was added dropwise. The
resulting clear orange mixture was stirred for an additional 10 min,
and a solution of furfuryl chloride (53) (7.20 g, 61.8 mmol) in THF
(16 mL) was added dropwise. The reaction was stirred for 45 min at
room temperature, whereupon saturated NH4Cl (ca. 50 mL) was
added, and the layers were separated. The aqueous layer was
extracted with Et2O (3ꢂ50 mL), and the combined organic layers
were washed with saturated NaHCO3 (ca. 50 mL). The aqueous layer
was back-extracted with Et2O (2ꢂ10 mL), and the combined or-
ganic layers were dried (Na2SO4) and concentrated under reduced
pressure. The crude orange oil was purified by distillation (150 ꢁC,
1e2 Torr) to give 6.90 g (68%) of 54 as a yellow oil; 1H NMR
C24H2779BrNO4 (Mþ1), 472.1123; found, 472.1128.
4.2.20. Methyl 5-(4-bromo-1-methyl-1H-indol-3-yl)-4-(furan-2-
ylmethyl)-5-methyl-3-oxohexanoate (42)
4.2.20.1. Method A. A solution of 51 (900 mg, 1.91 mmol) in
MeOH (3 mL) and toluene (30 mL) was heated under reflux for 14 h.
The solution was concentrated under reduced pressure, and the
residue was purified by column chromatography eluting with
EtOAc/hexanes (3:7) to give 620 mg (73%) of 42 as a white solid: mp
111e113 ꢁC. The product existed as a mixture (4:1) of keto and enol
tautomers in CDCl3. Keto isomer: 1H NMR (500 MHz),
d 7.44 (dd,
J¼8.0, 1.0 Hz, 1H), 7.26 (dd, J¼8.0, 1.0 Hz, 1H), 7.20 (s, 1H), 7.04 (t,
J¼8.0 Hz, 1H), 6.94 (s, 1H), 6.18 (br s, 1H), 5.89 (s, 1H), 4.77 (dd,
J¼12.0, 3.0 Hz, 1H), 3.71 (s, 3H), 3.66 (s, 2H), 3.52 (s, 3H), 3.12e3.07
(comp, 2H), 1.67e1.56 (comp, 6H); 13C NMR (125 MHz)
d 206.6,
(400 MHz),
d
7.27 (dd, J¼2.0, 1.0 Hz, 1H), 6.25 (dd, J¼3.0, 2.0 Hz, 1H),
167.2, 153.9, 141.1,140.0, 129.0, 125.9, 125.3, 122.4, 121.6, 113.6,110.2,
109.2, 105.8, 57.7, 51.9, 51.2, 51.0, 37.7, 33.1, 26.8, 26.3. Enol isomer:
5.98 (dd, J¼3.0, 1.0 Hz, 1H), 3.71 (s, 3H), 3.44 (s, 2H), 2.95e2.86
(comp, 4H); 13C NMR (100 MHz)
d 201.2, 167.4, 153.9, 141.1, 110.2,
1H NMR (500 MHz),
d
12.10 (br s, 1H), 7.40 (dd, J¼8.0, 1.0 Hz, 1H),
105.3, 52.3, 48.8, 41.0, 21.8; IR 3119, 2þ955, 1743, 1720, 1656 cmꢀ1
;
7.23 (dd, J¼8.0 Hz,1H), 7.13 (app s,1H), 7.01 (t, J¼8.0 Hz, 1H), 6.98 (s,
1H), 6.12 (dd, J¼3.0, 2.0 Hz, 1H), 5.89 (s, 1H), 5.10 (br s, 1H), 4.26 (dd,
J¼12.0, 3.0 Hz, 1H), 3.71 (s, 3H), 3.52 (s, 3H), 3.06e3.00 (comp, 2H),
HRMS (ESI) m/z calcd for C10H13O4 (Mþ1), 197.0808; found,
197.0807.
1.67e1.56 (comp, 6H); 13C NMR (125 MHz)
d 179.1, 172.9, 154.5,
4.2.23. Methyl-5-(tert-butyldimethylsilyloxy)-4-(furan-2-ylmethyl)-
1,3,3-trimethyl-3,4-dihydro-1H-cyclohepta[cd]indole-6-carboxylate
(57). NaOt-Bu (2.50 g, 26.3 mmol) was added to a mixture of bro-
moindole 42 (5.86 g, 13.1 mmol) and PEPPSI-IPr (356 mg,
0.520 mmol) in a glovebox, and toluene (109 mL) was added. The
suspension was gradually heated to reflux and stirred for 25 min.
The solution was cooled to room temperature, whereupon satu-
rated aqueous NH4Cl (ca. 120 mL) was added. The mixture was
extracted with Et2O (3ꢂ100 mL), and the combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure to
give crude 56 (4.27 g) that was used without further purification.
NaH (60% dispersion in mineral oil, 1.05 g, 26.3 mmol) was added to
a solution of crude 56 (4.27 g) and TBSCl (4.11 g, 26.3 mmol) in THF
(130 mL). The suspension was stirred at room temperature for 41 h,
whereupon the mixture was cooled to 0 ꢁC, and saturated aqueous
NH4Cl (ca.120 mL) was added. The mixture was extracted with Et2O
(3ꢂ100 mL), and the combined organic layers were dried (Na2SO4)
and concentrated under reduced pressure. The residue was purified
by column chromatography eluting with hexanes/EtOAc (1:9/1:5)
to give 5.61 g (89% over two steps) of 57 as an orange oil; 1H NMR
140.6, 140.0, 129.0, 125.7, 125.3, 122.6, 122.1, 113.9, 110.0, 108.9,
105.3, 57.7, 51.9, 51.2, 37.7, 37.2, 33.1, 26.8, 26.3; IR 2952, 1747,
þ
1709 cmꢀ1; HRMS (ESI) m/z calcd for C22H2579BrNO4 (Mþ1),
446.0959; found, 446.0961.
4.2.20.2. Method B. A solution of ketoester 54 (1.60 g,
8.16 mmol) in CPME (1 mL) was added dropwise to a solution of
NaHMDS (1.80 M, 10.0 mL, 17.9 mmol) in CPME (12 mL) at 0 ꢁC. The
solution was stirred for 35 min, and TMSCl (2.12 g, 2.48 mL,
19.6 mmol) was added dropwise. The mixture was stirred for
30 min at 0 ꢁC and then for 2.5 h at room temperature. Hexanes (ca.
200 mL) were added, and the mixture was filtered through Celite.
The filtrate was concentrated under reduced pressure to give crude
55 (2.40 g, 7.04 mmol). The crude 55 thus obtained and crude 25
(1.02 g, 3.80 mmol), which had been freshly prepared from 32
(1.03 g, 4.08 mmol) according to the same procedure used for the
synthesis of 33, were dissolved in THF (14 mL) at ꢀ78 ꢁC, and
TMSOTf (906 mg, 730 mL, 4.08 mmol) was added dropwise. The
resulting solution was stirred for 35 min, whereupon n-Bu3N
(1.4 mL) was added dropwise. The solvent was removed in vacuo,
and the residue was dissolved in Et2O (ca. 50 mL). The solution was
washed with aqueous citric acid (1 M, 3ꢂ8 mL), and the organic
(500 MHz)
d
7.23 (dd, J¼2.0, 1.0 Hz, 1H), 7.16 (app t, J¼7.5 Hz, 1H),
7.11 (dd, J¼7.5, 1.0 Hz, 1H), 6.84 (s, 1H), 6.78 (dd, J¼7.5, 1.0 Hz, 1H),
6.18 (dd, J¼3.0, 2.0 Hz, 1H), 5.90 (dd, J¼3.0, 1.0 Hz, 1H), 3.79 (s, 3H),

5600
T.-hao Fu et al. / Tetrahedron 69 (2013) 5588e5603
3.74 (s, 3H), 2.71 (dd, J¼9.5, 4.5 Hz,1H), 2.52 (dd, J¼15.0, 4.5 Hz,1H),
2.37 (dd, J¼15.0, 9.5 Hz, 1H), 1.46 (s, 3H), 1.34 (s, 3H), 0.84 (s, 9H),
0.24 (s, 3H), 0.21 (s, 3H); 13C NMR (150 Hz)
d 200.2,171.1,154.1,146.3,
137.3, 128.8, 124.9, 124.5, 122.4, 122.0, 121.7, 117.6, 117.0, 107.6, 62.2,
54.5, 52.1, 41.0, 36.4, 32.8, 32.2, 27.9, 25.5 (three overlapping peaks),
18.0, ꢀ2.9, ꢀ3.6; IR 3466, 2927, 2855,1725,1618 cmꢀ1; HRMS (CI) m/
z calcd for C28H39NO5Siþ (Mþ), 497.2598; found, 497.2590.
0.12 (s, 3H), 0.08 (s, 3H); 13C NMR (125 MHz)
d 170.0, 155.6, 154.3,
140.6, 137.2, 125.8, 124.4, 122.7, 121.8, 117.2, 116.8, 110.5, 107.2, 106.7
(two overlapping peaks), 56.7, 51.7, 36.3, 32.8, 32.5, 28.6, 27.9, 25.5
(three overlapping peaks), 18.1, ꢀ3.6, ꢀ3.7; IR 2929, 1729 cmꢀ1
;
HRMS (CI) m/z calcd for C28H38NO4Siþ (Mþ1), 480.2570; found,
4.2.27. (E)-Methyl
butyldimethylsilyl)oxy)-1,3,3-trimethyl-3,4-dihydro-1H-cyclo-
hepta[cd]indole-6-carboxylate (62). AcCl (52 mg, 45 L, 0.66
4-(5-acetoxy-2-oxopent-3-en-1-yl)-5-((tert-
480.2571.
m
4.2.24. (Z)-Methyl 2,13,13-trimethyl-8,11-dioxo-2,8,11,12,12a,13-
hexahydrooxocino[20,30:5,6]cyclohepta[1,2,3-cd]indole-6-carboxylate
(58). PCC (54 mg, 0.25 mmol) was added to a solution of furan 56
(39 mg, 0.11 mmol) in CH2Cl2 (3 mL) at 0 ꢁC. The suspension was
stirred for 2 h, whereupon water (ca. 10 mL) was added. The mix-
ture was extracted with CH2Cl2 (3ꢂ10 mL), and the combined or-
ganic layers were dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by column chromatography
eluting with EtOAc/hexanes (1:5/2:1) to give 18 mg (45%) of 58 as
mmol) was added dropwise to a solution of allylic alcohol 63
(0.29 g, 0.58 mmol) and collidine (70 mg, 0.19 mL, 0.58 mmol) in
MeCN (2.9 mL) at ꢀ20 ꢁC. The solution was stirred for 1.2 h,
whereupon aqueous citric acid (0.2 M, ca. 12 mL) was added. The
solution was saturated with solid NaCl and extracted with CH2Cl2
(4ꢂ10 mL). The combined organic layers were washed with sat-
urated aqueous NaHCO3 (10 mL) and brine (10 mL), dried
(Na2SO4), and concentrated under reduced pressure. The residue
was purified by column chromatography, eluting with EtOAc/
hexanes (1:5/1:2) to give 0.68 g (89%) of 62 as a yellow oil; 1H
a yellow oil; 1H NMR (500 MHz)
d
7.51 (d, J¼5.5 Hz, 1H), 7.29 (d,
J¼8.0 Hz, 1H), 7.21 (t, J¼8.0 Hz, 1H), 7.01 (s, 1H), 6.81 (d, J¼8.0 Hz,
1H), 6.13 (d, J¼5.5 Hz, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 2.70 (app t,
J¼8.5 Hz, 1H), 2.58 (dd, J¼13.5, 8.5 Hz, 1H), 2.15 (dd, J¼13.5, 8.5 Hz,
NMR (500 MHz) d 7.18e7.12 (comp, 2H), 6.84 (s, 1H), 6.75 (dd,
J¼7.0, 1.0 Hz, 1H), 6.49 (dt, J¼16.0 4.5 Hz, 1H), 6.09 (dt, J¼16.0,
2.0 Hz, 1H), 4.64 (dd, J¼4.5, 2.0 Hz, 2H), 3.79 (s, 3H), 3.74 (s, 3H),
3.03 (dd, J¼7.0, 5.0 Hz, 1H), 2.51 (dd, J¼16.5 7.0 Hz, 1H), 2.32 (dd,
J¼16.5, 5.0 Hz, 1H), 2.05 (s, 3H), 1.36 (s, 6H), 0.90 (s, 9H), 0.27 (s,
1H), 1.50 (s, 3H), 1.36 (s, 3H); 13C NMR (125 MHz)
d 205.2, 171.8,
168.5, 157.3, 136.7, 127.8, 124.2, 122.6, 121.8, 121.5, 119.5, 118.8, 109.8,
90.8, 73.6, 57.1, 52.6, 37.1, 34.6, 33.1, 31.8, 31.4; IR 2924, 1756,
3H), 0.25 (s, 3H); 13C NMR (125 MHz)
d 198.7, 170.3, 169.8, 155.8,
1731 cmꢀ1; HRMS (ESI) m/z calcd for C22H21NNaO5 (Mþ23),
139.7, 137.3, 129.9, 125.6, 124.8, 122.5, 121.9, 121.8, 117.2, 117.1,
107.4, 62.6, 52.1, 51.8, 42.1, 36.7, 32.8, 32.0, 28.1, 25.6, 20.7, 18.1,
ꢀ3.4, ꢀ3.5; IR 2929, 1728, 1620 cmꢀ1; HRMS (CI) m/z calcd for
C30H42NO6Siþ (Mþ1), 540.2781; found, 540.2779.
þ
402.1311; found, 402.1313.
4.2.25. (E)-Methyl-5-(tert-butyldimethylsilyloxy)-4-(2,5-dioxopent-
3-enyl)-1,3,3-trimethyl-3,4-dihydro-1H-cyclohepta[cd]indole-6-
carboxylate (59). A solution of NBS (845 mg, 4.75 mmol) in DMF
(5 mL) was added dropwise using an addition funnel to a solution of
furan 57 (2.28 g, 4.75 mmol) and pyridine (1.50 g, 1.46 mL,
19.0 mmol) in DMF/H2O (85:15, 50 mL) at 0 ꢁC. The resulting
orange-brown solution was stirred for 2 h, whereupon furan
(966 mg, 1.00 mL, 14.2 mmol) was added to quench any unreacted
NBS. Brine (40 mL) was added, and the reaction mixture was
extracted with Et2O (3ꢂ60 mL). The combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure, and the
residue was purified on florisil eluting with EtOAc/hexanes
(1:9/1:3) to give 814 mg (34%) of 59 as a yellow solid:
4.2.28. (E)-Methyl-4-[5-(benzoyloxy)-2-oxopent-3-en-1-yl]-5-
[(tert-butyldimethylsilyl)oxy]-1,3,3-trimethyl-3,4-dihydro-1H-cyclo-
hepta[cd]indole-6-carboxylate (64). BzCl (236 mg, 285
1.68 mmol) was added dropwise to a solution of alcohol 63 (380 mg,
0.760 mmol) and collidine (277 mg, 254 L, 2.29 mmol) in MeCN
mL,
m
(3 mL) at 0 ꢁC. The cloudy yellow solution was stirred for 2 h at 0 ꢁC.
The mixture was diluted with CH2Cl2 (10 mL) and washed with
aqueous citric acid (0.2 M, 5 mL). The aqueous layer was saturated
with solid NaCl and extracted with CH2Cl2 (4ꢂ5 mL). The combined
organic layers were washed with saturated aqueous NaHCO3 (5 mL),
dried (Na2SO4), and concentrated under reduced pressure. The
residue was purified by column chromatography eluting with
EtOAc/hexanes (1:9/1:3) to give 452 mg (98%) of 64 as a pale
mp¼127e128 ꢁC; 1H NMR (500 MHz)
d
9.64 (d, J¼7.5 Hz, 1H),
7.20e7.14 (comp, 2H), 6.84 (s, 1H), 6.75 (dd, J¼7.0, 1.0 Hz, 1H), 6.74
(d, J¼16.0 Hz, 1H), 6.44 (dd, J¼16.0, 7.5 Hz, 1H), 3.79 (s, 3H), 3.75 (s,
3H), 2.97 (dd, J¼8.0, 4.5 Hz, 1H), 2.58 (dd, J¼15.5, 8.0 Hz, 1H), 2.46
(dd, J¼15.5, 4.5 Hz, 1H), 1.39 (s, 3H), 1.37 (s, 3H), 0.89 (s, 9H), 0.26 (s,
yellow oil; 1H NMR (400 MHz),
d 8.05e8.02 (comp, 2H), 7.58e7.53
(m, 1H), 7.47e7.41 (comp, 2H), 7.19e7.13 (comp, 2H), 6.86 (s, 1H),
6.76 (dd, J¼1.5, 6.5 Hz, 1H), 6.63 (dt, J¼4.0, 16.0 Hz, 1H), 6.22 (dt,
J¼2.0, 16.0 Hz, 1H), 4.92e4.90 (comp, 2H) 3.80 (s, 3H), 3.75 (s, 3H),
3.06 (dd, J¼4.5, 7.0 Hz, 1H), 2.56 (dd, J¼7.0, 16.0 Hz, 1H), 2.36 (dd,
J¼4.5, 16.0 Hz, 1H), 1.39 (s, 3H), 1.38 (s, 3H), 0.92 (s, 9H), 0.29 (s, 3H),
3H), 0.25 (s, 3H); 13C NMR (125 Hz)
d 199.6, 193.5, 169.5, 154.4,
145.2, 137.4, 137.3, 125.1, 124.7, 122.4, 122.1, 121.5, 117.9, 117.5, 107.8,
53.0, 51.8, 42.7, 36.7, 32.9, 32.0, 28.1, 25.6 (three overlapping peaks),
18.1, ꢀ3.2, ꢀ3.5; IR 2929, 2857, 1729, 1693,1619 cmꢀ1; HRMS (CI) m/
z calcd for C28H37NO5Siþ (Mþ), 495.2441; found, 495.2442.
0.28 (s, 3H); 13C NMR (100 MHz),
d 198.8, 169.7, 165.8, 155.6, 140.0,
137.2, 133.2, 129.8, 129.7, 129.5 (two overlapping peaks), 128.4 (two
overlapping peaks), 125.5, 124.8, 122.4, 121.9, 121.7, 117.2, 117.1, 107.4,
63.0, 52.2, 51.8, 41.9, 36.7, 32.8, 32.0, 28.0, 25.6 (three overlapping
peaks), 18.1, ꢀ3.39, ꢀ3.47; IR 2952, 2859, 1728, 1621 cmꢀ1; HRMS
(CI) m/z calcd for C35H43NO6Siþ (Mþ), 601.2860; found, 601.2855.
4.2.26. (E)-Methyl-5-(tert-butyldimethylsilyloxy)-4-(5-hydroxy-2-
oxopent-3-enyl)-1,3,3-trimethyl-3,4-dihydro-1H-cyclohepta[cd]in-
dole-6-carboxylate (63). A solution of t-BuNH2BH3 (37 mg,
0.42 mmol) in THF (0.5 mL) was added dropwise to a solution of
aldehyde 59 (0.59 g, 1.2 mmol) in THF (6.0 mL) at ꢀ78 ꢁC. The so-
lution was stirred for 3.5 h, whereupon acetone (2 mL) was added.
The solvent was removed under reduced pressure, and the residue
was purified on florisil eluting with EtOAc/hexanes (1:3/1:1) to
give 0.48 g (82%) of 63 as a white foam; 1H NMR (600 MHz)
4.2.29. Methyl-(3Z)-3-ethylidene-7,7,10-trimethyl-4,16-dioxo-10-
azatetracyclo[6.6.1.12,6.011,15]hexadeca-1(15),8,11,13-tetraene-2-
carboxylate (67), methyl (3E)-3-ethylidene-7,7,10-trimethyl-4,16-
dioxo-10-azatetracyclo[6.6.1.12,6.011,15]hexadeca-1(15),8,11,13-
tetraene-2-carboxylate (68), methyl 3-ethenyl-7,7,10-trimethyl-4,16-
dioxo-10-azatetracyclo[6.6.1.12,6.011,15]hexadeca-1(15), 8,11,13-
tetraene-2-carboxylate (40). A solution of TBAF$3H2O (882 mg,
2.80 mmol) in THF (5 mL) was added dropwise to a solution of
benzoate 64 (1.40 g, 2.33 mmol) in THF (120 mL) at 0 ꢁC. The
resulting yellow solution was stirred for 10 min, whereupon
d
7.19e7.14 (comp, 2H), 6.83 (s, 1H), 6.74 (dd, J¼7.0, 1.0 Hz, 1H), 6.60
(ddd, J¼16.0, 4.5, 3.5 Hz,1H), 6.21 (dt, J¼16.0, 2.0 Hz, 1H), 4.28e4.24
(m, 1H), 4.22e4.17 (m, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 2.99 (dd, J¼8.5,
4.5 Hz, 1H), 2.78 (dd, J¼10.0, 4.5 Hz, 1H), 2.48 (dd, J¼13.0, 10.0 Hz,
1H), 2.21 (dd, J¼13.0, 4.5 Hz,1H),1.44 (s, 3H),1.35 (s, 3H), 0.87 (s, 9H),

T.-hao Fu et al. / Tetrahedron 69 (2013) 5588e5603
5601
saturated NH4Cl (ca. 100 mL) was added. The mixture was extracted
with Et2O (3ꢂ200 mL), and the combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. The residue
was dissolved in toluene (25 mL), and a suspension of Pd2dba3
(430 mg, 0.470 mmol) and trifurylphosphine (860 mg, 3.73 mmol)
in toluene (95 mL) was added at room temperature. Bu3SnOMe
(899 mg, 1.00 mL, 2.80 mmol) was added, and the mixture was
heated at 100 ꢁC for 4 h. After cooling to room temperature, satu-
rated aqueous NaHCO3 (ca. 75 mL) was added, and the mixture was
extracted with EtOAc (75 mL) and CH2Cl2 (3ꢂ75 mL). The combined
organic layers were passed through a short plug of florisil, and the
eluent was concentrated under reduced pressure. The residue was
purified by column chromatography eluting with EtOAc/hexanes
(1:3/1:1) to give 710 mg (84% over two steps) of a mixture
(5.8:1:3.5) of 67, 68, and 40 as a yellow oil; 1H NMR (600 MHz)
solid: mp¼240e241 ꢁC; 1H NMR (600 MHz)
d
7.21 (dd, J¼8.0, 1.0 Hz,
1H), 7.14 (t, J¼8.0 Hz, 1H), 6.77 (dd, J¼8.0, 1.0 Hz, 1H), 6.19e6.15 (m,
1H), 5.51e5.46 (comp, 2H), 3.71 (s, 3H), 3.58 (s, 3H), 3.01e2.95 (m,
2H), 2.81e2.75 (m, 1H), 1.72 (s, 3H), 1.65 (s, 3H), 1.36 (s, 3H); 13C
NMR (125 Hz)
d 207.8, 205.1, 170.1, 136.1, 136.0, 125.5, 124.4, 123.8,
123.3, 120.8, 118.8, 113.9, 109.3, 72.8, 58.7, 58.6, 52.1, 39.7, 38.9, 30.0,
28.9, 28.5, 19.5; IR 2948, 1747, 1707 cmꢀ1; HRMS (ESI) m/z calcd for
þ
C23H25NNaO4 (Mþ23), 436.1286; found, 436.1284.
4.2.32. N-Methyl-3-ethenyl-3,7,7,10-tetramethyl-4,9,16-trioxo-10-
azatetracyclo[6.6.1.12,6.011,15]hexadeca-1(15),11,13-triene-2-
carboxylate (71, 72)
4.2.32.1. Method A. Ureaehydrogen peroxide adduct (20 mg,
0.21 mmol) was added to a stirred suspension of MeReO3 (1.0 mg,
4.0
yellow suspension was stirred for 10 min, and a solution of indole
39 (6.0 mg, 10 mol) in CH2Cl2 (0.2 mL) was added dropwise. The
mmol) in CH2Cl2 (0.2 mL) at room temperature. The resulting
d
7.22e7.21 (comp, 2H), 7.20e7.19 (comp, 2H), 7.16 (q, J¼7.5 Hz, 1H),
7.04 (q, J¼8.0 Hz, 1H), 7.00 (s, 1H), 6.97 (s, 1H), 6.87e6.83 (m, 1H),
6.81e6.78 (m, 1H), 5.99 (ddd, J¼17.5, 10.5, 5.5 Hz, 1H), 5.27 (ddd,
J¼10.5, 2.0, 0.5 Hz, 1H), 5.16 (ddd, J¼17.5, 2.0, 0.5 Hz, 1H), 4.06 (dd,
J¼5.5, 2.0 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 3.74 (s, 3H), 3.70 (s, 3H),
3.67 (s, 3H), 2.98e2.94 (m, 1H), 2.91e2.87 (comp, 2H), 2.86e2.80
(m, 1H), 2.73e2.68 (m, 1H), 2.51 (ddd, J¼19.0, 3.5, 1.5 Hz, 1H), 2.13
(d, J¼7.5 Hz, 3H), 2.05 (d, J¼8.0 Hz, 3H), 1.43 (s, 3H), 1.42 (s, 3H), 1.37
m
mixture was stirred for 6 h and then filtered. The filtrate was
concentrated under reduced pressure, and the resulting residue
was purified by column chromatography eluting with EtOAc/hex-
anes (1:3/1:1) to give 2.0 mg (34%) of a mixture (1:1.5) of 71 and
72 as a yellow oil. For 71: 1H NMR (600 MHz)
d 7.19e7.16 (m, 1H),
6.73 (d, J¼8.0 Hz, 1H), 6.39 (d, J¼8.0, 1.0 Hz, 1H), 5.75 (dd, J¼17.5,
11.0 Hz, 1H), 5.40 (dd, J¼17.5, 1.0 Hz, 1H), 5.34 (dd, J¼11.0, 1.0 Hz,
1H), 3.67 (s, 3H), 3.57 (s, 1H), 3.30 (dd, J¼16.5, 10.0 Hz, 1H), 3.16 (s,
3H), 3.08 (d, J¼10.0 Hz, 1H), 2.93 (d, J¼16.5 Hz, 1H), 1.72 (s, 3H), 1.60
(s, 3H), 1.31 (s, 3H), 1.24 (s, 3H); 13C NMR (151 MHz)
d 205.6, 204.6,
204.4, 198.0, 170.9, 170.8, 142.2, 137.2, 131.5, 129.0, 127.9, 127.4,
123.6, 122.8, 122.0, 120.2, 119.71, 119.4, 119.3, 118.4, 109.4, 108.6,
73.4, 69.4, 66.6, 57.4, 56.8, 52.6, 42.4, 39.7, 37.4, 37.0, 33.0, 32.9, 32.6,
(s, 3H), 0.85 (s, 3H); 13C NMR (151 MHz)
d 208.3, 203.8, 173.8, 169.6,
32.4, 29.8, 29.6, 29.0,16.9; IR 2292, 2852,1741,1711,1607,1451,1418,
144.0, 134.3, 129.5, 127.0, 126.5, 124.1, 117.9, 107.3, 75.3, 63.1, 58.9,
þ
1232 cmꢀ1
366.1699; found, 366.1698.
;
HRMS (ESI) m/z calcd for C22H24NO4 (Mþ1),
51.9, 51.0, 39.2, 38.2, 26.3, 25.6, 22.7, 19.3. For 72: 1H NMR
(600 MHz)
d
7.27 (dd, J¼8.0, 1.0 Hz, 1H), 7.22 (dt, J¼8.0, 1.0 Hz, 1H),
6.79 (dd, J¼8.0, 1.0 Hz, 1H), 6.54 (dd, J¼18.0, 11.0 Hz, 1H), 5.55 (dd,
J¼18.0, 1.0 Hz, 1H), 5.51 (dd, J¼11.0, 1.0 Hz, 1H), 3.60 (s, 3H), 3.40 (s,
1H), 3.17 (s, 3H), 2.74 (t, J¼9.0 Hz,1H), 2.62e2.58 (comp, 2H),1.70 (s,
4.2.30. Methyl-3-ethenyl-3,7,7,10-tetramethyl-4,16-dioxo-10-
azatetracyclo[6.6.1.12,6.011,15]hexadeca-1(15),8,11,13-tetraene-2-
carboxylate (39). Freshly prepared NaHMDS (0.72 M in toluene,
0.46 mL, 0.33 mmol) was added dropwise to a solution of 67, 68,
and 40 (0.15 g, 0.41 mmol) in DMF (8 mL) at ꢀ40 ꢁC. The solution
was stirred for 20 min and then for 30 min at room temperature.
3H), 1.55 (s, 3H), 0.89 (s, 3H); 13C NMR (151 MHz)
d 207.3, 205.7,
174.1, 168.2, 144.7, 137.4, 133.6, 128.8, 125.4, 122.5, 119.6, 108.3, 70.9,
58.3, 54.4, 52.6, 51.8, 41.2, 40.3, 28.4, 26.2, 22.8, 20.5; IR 2926, 1746,
þ
1711, 1609, 1590, 1462 cmꢀ1; HRMS (ESI) m/z calcd for C23H26NO5
(Mþ1), 396.1805; found, 396.1804.
The solution was recooled to ꢀ40 ꢁC, and MeI (26
mL, 0.41 mmol)
was added dropwise. The solution was gradually warmed up to
room temperature over 5 h and then stirred for an additional 15 h,
whereupon saturated aqueous NH4Cl (ca. 8 mL) was added. The
mixture was extracted with CH2Cl2 (3ꢂ20 mL), and the combined
organic layers were dried (Na2SO4) and concentrated under re-
duced pressure. The residue was purified by column chromatog-
raphy eluting with EtOAc/hexanes (1:3/1:1) to give 0.10 g (80%) of
39 as a yellow solid: mp 210e211 ꢁC (decomp.); 1H NMR (500 MHz)
4.2.32.2. Method B. Concentrated HCl (0.5 mL) was added to
a solution of chloroindole 69 (12 mg, 0.028 mmol) in dioxane
(0.5 mL) at room temperature. The resulting suspension was stirred
vigorously at 100 ꢁC for 8 h. After cooling to room temperature,
saturated aqueous NaHCO3 was added until gas evolution ceased.
The mixture was extracted with CH2Cl2 (3ꢂ10 mL), and the com-
bined organic layers were dried (Na2SO4) and concentrated under
reduced pressure. The residue was purified by column chroma-
tography eluting with EtOAc/hexanes (1:3/1:1) to give 4.0 mg
(36%) of a mixture (1:1.2) of 71 and 72 as a yellow oil.
d
7.23 (dd, J¼7.5, 1.0 Hz, 1H), 7.15 (t, J¼7.5 Hz, 1H), 6.95 (s, 1H), 6.66
(dd, J¼7.5, 1.0 Hz, 1H), 5.98 (dd, J¼18.0, 11.0 Hz, 1H), 5.45e5.41
(comp, 2H), 3.73 (s, 3H), 3.66 (s, 3H), 3.09 (dd, J¼10.5, 3.0 Hz, 1H),
2.95 (dd, J¼19.0, 10.5 Hz, 1H), 2.64 (dd, J¼19.0, 3.0 Hz, 1H), 1.69 (s,
3H), 1.47 (s, 3H), 1.23 (s, 3H); 13C NMR (125 MHz)
d 207.7, 206.0,
4.2.33. (6S,7S,10R)-Methyl-7-ethyl-2,7,11,11-tetramethyl-8,12-dioxo-
6,7,8,9,10,11-hexahydro-2H-6,10-methanocyclonona[cd]indole-6-
170.3,137.7,135.9,127.2,124.0,123.4, 122.8, 120.7,119.6,118.2,109.4,
73.6, 58.9, 57.7, 52.0, 39.3, 37.2, 33.0, 32.9, 28.4, 19.3; IR 2921, 2847,
þ
1744, 1705 cmꢀ1; HRMS (CI) m/z calcd for C23H26NO4 (Mþ1),
carboxylate (74). NEt3 (9.0 mg, 90
11 mg, 0.23 mmol) were added to a suspension of ketone 39
(4.0 mg, 10 mol) in EtOH (0.2 mL) at room temperature. The
mmol) and N2H4$H2O (64%,
380.1862; found, 380.1860.
m
mixture was heated at 70 ꢁC for 6 h. The solution was diluted with
CH2Cl2 (ca. 2 mL) and washed with water (ca. 1 mL). The aqueous
layer was extracted with CH2Cl2 (2ꢂ3 mL), and the combined or-
ganic layers were dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by column chromatography
eluting with hexanes/EtOAc (1:5/1:2) to give 1.0 mg (26%) of 74 as
4.2.31. Methyl-9-chloro-3-ethenyl-3,7,7,10-tetramet hyl-4,16-dioxo-
10-azatetracyclo[6.6.1.12,6.011,15]hexadeca-1(15),8,11,13-tetraene-2-
carboxylate (69). PCl5 (35 mg, 0.17 mmol) was added to a solution
of ketone 39 (66 mg, 0.17 mmol) in CH2Cl2 (2.8 mL) at room tem-
perature. The suspension was stirred for 1 h, whereupon saturated
aqueous NaHCO3 (ca. 4 mL) was added slowly. The mixture was
extracted with CH2Cl2 (3ꢂ10 mL), and the combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure. The
residue was purified by column chromatography eluting with
hexanes/EtOAc (1:9/1:1) to provide 42 mg (60%) of 69 as a yellow
a yellow oil; 1H NMR (600 MHz)
d
7.20 (dd, J¼8.0, 1.0 Hz, 1H), 7.14 (t,
J¼8.0 Hz, 1H), 6.91 (s, 1H), 6.62 (dd, J¼8.0, 1.0 Hz, 1H), 3.71 (s, 3H),
3.70 (s, 3H), 3.08 (dd, J¼11.0, 2.0 Hz, 1H), 2.92 (dd, J¼17.5, 11.0 Hz,
1H), 2.48 (dd, J¼17.5, 2.0 Hz, 1H), 1.82e1.72 (comp, 2H), 1.51 (s, 3H),

5602
T.-hao Fu et al. / Tetrahedron 69 (2013) 5588e5603
1.47 (s, 3H), 1.17 (s, 3H), 0.83 (t, J¼7.5 Hz, 3H); 13C NMR (150 MHz)
this research. We are also grateful to Vince Lynch (The University of
Texas) for X-ray crystallography and Steve Sorey (The University of
Texas) for NMR spectroscopy.
d
208.2, 207.1, 171.0, 137.6, 126.9, 124.5, 123.5, 122.4, 120.5, 119.6,
109.2, 75.7, 58.8, 57.1, 52.1, 39.1, 36.7, 33.4, 33.0, 28.1, 24.4, 18.5, 10.1;
IR 2918, 2849, 1737, 1702, 1611 cmꢀ1; HRMS (ESI) m/z calcd for
þ
C23H27NNaO4 (Mþ23), 404.1832; found, 404.1835.
References and notes
4.2.34. Methyl-2,7,11,11-tetramethyl-12-oxo-8-(((trifluoromethyl)
s u l fo nyl ) o x y ) - 7 - v i nyl - 6 , 7 ,10 ,11 - t e t ra hy d ro - 2 H - 6 ,10 -
methanocyclonona[cd]indole-6-carboxylate (75). LiHMDS (0.850 M,
3.00 mL, 2.58 mmol) was added dropwise to a solution of ketone 39
(109 mg, 0.290 mmol) in THF (3 mL) at ꢀ40 ꢁC. The reaction mixture
was stirred for 45 min, and a solution of Comins’ reagent (1.01 g,
2.58 mmol) in THF (1 mL) was added dropwise. After stirring for
1 h, the mixture was quenched with saturated aqueous NaHCO3 (ca.
5 mL) and extracted with EtOAc (3ꢂ5 mL). The combined organic
layers were washed with brine (ca. 5 mL), dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified by
flash column chromatography eluting with EtOAc/hexanes
(1:9/1:3) to give 118 mg (80%) of 75 as a yellow oil; 1H NMR
1. Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.; Patterson, G. M. L.;
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5. For reviews, see: (a) Avendano, C.; Menendez, J. C. Curr. Org. Synth. 2004, 1,
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6835e6838; (i) Lopez-Alvarado, P.; García-Granda, S.; Alvarez-Rua, C.;
(400 MHz),
d
7.29 (dd, J¼8.0, 1.0 Hz, 1H), 7.18 (t, J¼8.0 Hz, 1H), 6.96
~
Avendano, C. Eur. J. Org. Chem. 2002, 2002, 1702e1707; (j) MacKay, J. A.; Bishop,
(s, 1H), 6.69 (dd, J¼8.0, 1.0 Hz, 1H), 5.80 (d, J¼3.0 Hz, 1H), 5.69 (dd,
J¼11.0, 17.5 Hz, 1H), 5.50e5.43 (comp, 2H), 3.78 (s, 3H), 3.64 (s, 3H),
3.28 (d, J¼3.0 Hz, 1H), 1.75 (s, 3H), 1.62 (s, 3H), 1.29 (s, 3H); 13C NMR
R. L.; Rawal, V. H. Org. Lett. 2005, 7, 3421e3424; (k) Baudoux, J.; Blake, A. J.;
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Martin, S. F. Org. Lett. 2012, 14, 3834e3837.
8. Kosuge, T.; Ishida, H.; Inaba, A.; Nukaya, H. Chem. Pharm. Bull. 1985, 33,
1414e1418.
9. Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1991, 56, 4218e4223.
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11. Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473e1478.
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atake, H.; Natsume, M. Tetrahedron 1990, 46, 6331e6342; (c) Grieco, P. A.;
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(100 MHz),
d 204.0, 170.4, 152.0, 137.5, 134.8, 126.1, 125.0, 124.2,
123.0, 120.4, 120.3, 118.9, 116.3, 109.2, 74.1, 60.3, 52.1, 52.0, 36.2,
33.2, 33.0, 28.5, 21.1; IR 2952, 1746, 1714, 1418 cmꢀ1; HRMS (CI) m/z
calcd for C24H24F3NO6Sþ (Mþ), 511.1276; found, 511.1275.
4.2.35. 3-Ethenyl-3,7,7,10-tetramethyl-4,16-dioxo-10-azatetra-
tnqh_0009;cyclo[6.6.1.12,6.011,15]-hexadeca-1(14),8,11(15),12-
tetraene-2-carbaldehyde (79). A suspension of LiAlH4 (64 mg,
1.7 mmol) in Et2O (2 mL) was sonicated for 1 min and filtered
through a nylon syringe filter (pore size: 0.45 mm) into a dry 2
DRAM glass vial. An aliquot (0.3 mL) of this solution was added
dropwise to a suspension of 39 (11 mg, 0.029 mmol) in Et2O
(0.8 mL) at 0 ꢁC. The mixture was stirred for 30 min and then for
3.5 h at room temperature. The mixture was cooled to 0 ꢁC, and
water was added dropwise until gas evolution ceased. Aqueous
HCl (1 N, 1 mL) was added, and the mixture was extracted with
CH2Cl2 (4ꢂ4 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure to give
a mixture of diastereomeric triols 78. DesseMartin periodinane
(61 mg, 0.14 mmol) was added to a mixture of crude triols and
NaHCO3 (33 mg, 0.39 mmol) in a glovebox, and CH2Cl2 (1 mL)
was added. The mixture was stirred at room temperature for
2.5 h, whereupon saturated aqueous NaHCO3 (ca. 1 mL) was
added. The mixture was extracted with CH2Cl2 (4ꢂ4 mL), and
the combined organic layers were dried (Na2SO4) and concen-
trated under reduced pressure. The residue was purified by
preparative thin layer chromatography (EtOAc/hexanes¼1:1) to
give 9.0 mg (89% over two steps) of 79 as a light yellow solid; 1H
14. Fu, T.-H.; Bonaparte, A.; Martin, S. F. Tetrahedron Lett. 2009, 50, 3253e3256.
15. For other recent related processes, see: (a) Mendoza, O.; Rossey, G.; Ghosez, L.
Tetrahedron Lett. 2011, 52, 2235e2239; (b) Zhong, X.; Li, Y.; Han, F.-S. Chem.
dEur. J. 2012, 18, 9784e9788.
NMR (600 MHz)
d
9.61 (s, 1H), 7.29 (dd, J¼8.1, 0.5 Hz, 1H), 7.21
(app t, J¼7.5 Hz, 1H), 7.00 (s, 1H), 6.60 (dd, J¼7.5, 0.5 Hz, 1H),
5.81 (dd, J¼17.6, 11.0 Hz, 1H), 5.40 (dd, J¼11.0, 0.8 Hz, 2H), 5.36
(dd, J¼17.6, 0.8 Hz, 1H), 3.76 (s, 3H), 3.01e2.95 (comp, 2H),
2.79e2.74 (m, 1H), 1.65 (s, 3H), 1.49 (s, 3H), 1.26 (s, 3H); 13C NMR
16. (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395e422; (b) Lu, Z.; Ma,
S. Angew. Chem., Int. Ed. 2008, 47, 258e297.
17. For some examples, see: (a) Martin, S. F.; Gluchowski, C.; Campbell, C. L.;
Chapman, R. C. J. Org. Chem. 1984, 49, 2512e2513; (b) Martin, S. F.; Guinn, D.
E. J. Org. Chem. 1987, 52, 5588e5593; (c) Martin, S. F.; Gluchowski, C.;
Campbell, C. L.; Chapman, R. C. Tetrahedron 1988, 44, 3171e3180; (d) Martin,
S. F.; Zinke, P. A. J. Org. Chem. 1991, 56, 6600e6606; (e) Martin, S. F.; Hida, T.;
Kym, P. R.; Loft, M.; Hodgson, A. J. Am. Chem. Soc. 1997, 119, 3193e3194; (f)
Martin, S. F.; Limberakis, C.; Burgess, L. E.; Hartmann, M. Tetrahedron 1999,
55, 3561e3572; (g) Hergenrother, P. J.; Hodgson, A.; Judd, A. S.; Lee, W. C.;
Martin, S. F. Angew. Chem., Int. Ed. 2003, 42, 3278e3281; (h) Breton, P.;
Hergenrother, P. J.; Hida, T.; Hodgson, A.; Judd, A. S.; Kraynack, E.; Kym, P. R.;
Lee, W.-C.; Loft, M. S.; Yamashita, M.; Martin, S. F. Tetrahedron 2007, 63,
5709e5729.
(150 MHz)
d 209.2, 207.7, 194.7, 138.0, 135.9, 127.6, 124.5, 122.8,
121.3, 120.3, 119.7, 117.9, 110.3, 72.4, 58.0, 57.5, 39.6, 37.6, 33.1,
33.0, 28.6, 19.1; IR 2968, 2924, 2853, 1736, 1713, 1692, 1454, 1417,
þ
1333, 1214, 1147 cmꢀ1; HRMS (ESI) m/z calcd for C22H24NO3
(Mþ1), 350.1750; found, 350.1751.
Acknowledgements
18. Okabayashi, T.; Iida, A.; Takai, K.; Nawate, Y.; Misaki, T.; Tanabe, Y. J. Org. Chem.
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Hopkinson, A. C.; Organ, M. G. Chem.dEur. J. 2006, 12, 4743e4748.
We thank the National Institutes of Health (GM 25439) the
Robert A. Welch Foundation (F-0652) for their generous support of

T.-hao Fu et al. / Tetrahedron 69 (2013) 5588e5603
5603
20. (a) Jurczak, J.; Pikul, S. Tetrahedron Lett. 1985, 26, 3039e3040; (b) Kobayashi, Y.;
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