Biomimetic total syntheses of borreverine and flinderole alkaloids

Article abstract of DOI:10.1021/jo4013833

Dimeric indole alkaloids represent a structurally unique class of natural products having interesting biological activities. Recently, we reported the first total synthesis of flinderoles B and C, structurally unique and potent antimalarial natural products. Central to the design of the approach and by virtue of a one-pot, acid-catalyzed dimerization reaction, the route also provided total synthesis of the borreverine class of natural products. This full account details the progress of efforts that culminated in the protecting-group-free, six-step total synthesis of all of the flindersia alkaloids: dimethylisoborreverine, isoborreverine, flinderoles A-C, and their analogues. A biomimetic approach featuring a scalable and catalytic formal [3 + 2] cycloaddition and Diels-Alder reaction is outlined in detail. On the basis of the experimental observations, a detailed mechanism has been proposed for the dimerization of tertiary alcohol 28.

Full text of DOI:10.1021/jo4013833

Article
pubs.acs.org/joc
Biomimetic Total Syntheses of Borreverine and Flinderole Alkaloids
Dattatraya H. Dethe,* Rohan D. Erande, and Alok Ranjan
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur-208016, India
*
S Supporting Information
ABSTRACT: Dimeric indole alkaloids represent a structurally
unique class of natural products having interesting biological
activities. Recently, we reported the first total synthesis of
flinderoles B and C, structurally unique and potent antimalarial
natural products. Central to the design of the approach and by
virtue of a one-pot, acid-catalyzed dimerization reaction, the
route also provided total synthesis of the borreverine class of
natural products. This full account details the progress of efforts
that culminated in the protecting-group-free, six-step total
synthesis of all of the flindersia alkaloids: dimethylisoborreverine,
isoborreverine, flinderoles A−C, and their analogues. A
biomimetic approach featuring a scalable and catalytic formal
[
3 + 2] cycloaddition and Diels−Alder reaction is outlined in
detail. On the basis of the experimental observations, a detailed
mechanism has been proposed for the dimerization of tertiary alcohol 28.
7
INTRODUCTION
Detailed biological activity studies by the Avery group have
shown that these alkaloids inhibit parasitic hemoglobin
metabolism through a mode of action different from that o8f
chloroquine. The biomimetic pathway proposed by Koch et al.
■
Synthetic chemists are always fascinated by biomimetic
1
synthesis of natural products, as it allows them to achieve
the synthesis of complex natural products in the most efficient
way comprising the minimum number of synthetic steps and
economically viable large-scale synthesis for further biological
and pharmaceutical studies. Multidrug-resistant parasites have
driven the quest for the development of new classes of
antimalarial agents with novel modes of action. Natural
products (quinine and artimisinin) have proven to be
9
for the synthesis of borreverine and by our group for the
synthesis of flinderoles is depicted in Scheme 1. The co-
occurrence of borrerine (4) and borreverine (7) in Borreria
verticillata suggested that biosynthetically borreverine (7) and
isoborreverine (5) might have been prepared by dimerization
of borrerine (4). The interesting and novel chemical structures
and vitally important biological activity of flinderoles and
borreverines made them attractive targets for total synthesis,
and a number of groups have reported their synthetic studies
toward this end. Following our initial report on the first total
2
important leads in this regard, due to the development of
modern synthetic tools to assemble such natural products in
the laboratory to readily access a series of analogues for
structure−activity relationships (SARs). Recently, Avery and
3
9
10
11
co-workers have reported the isolation of new class of
synthesis of flinderoles B and C, Toste et al. and May et al.
antimalarial agents, flinderole A (1), from the bark of F.
Acuminata, while flinderoles B (2) and C (3) were obtained
from F. Ambiosis along with the previously known compounds
borrerine (4), borreverine (7), isoborreverine (5), and
dimethylisoborreverine (6) (Figure 1). Borrerine (4) was first
have reported alternative elegant approaches. The route devised
by the Toste group employed a gold(I)-catalyzed hydro-
arylation of an allene with indole; further reactions were then
carried out to produce the final products flinderoles B and C.
May et al. devised a third route that required just three steps for
the total synthesis of flinderoles A−C by acid-catalyzed
4
isolated in 1973 by Goutarel et al. Borreverine (7),
isoborreverine (5), and dimethylisoborreverine (6) were
8
dimerization of borrerine (4). In 1979, Koch et al. reported
5
isolated in 1977 by Riche et al. The structures of borreverine
the biomimetic synthesis of borreverine (7) and isoborreverine
(7) and isoborreverine (5) were established by single-crystal X-
(
5) by the trifluoroacetic acid mediated dimerization of
ray analysis. Another natural product possessing the borreverine
borrerine (4). We present here a concise total synthesis of
isoborreverine (5) and dimethylisoborreverine (6) along with
an improved protecting-group-free synthesis of flinderoles A−
C.
skeleton, spermacoceine (8), was isolated by the research group
6
of Balde et al. in 1991 from Borreria verticillata. Flinderoles A−
C, isoborreverine, and dimethylisoborreverine have shown
selective antimalarial activity, with IC values between 0.08 and
5
0
1.42 μm against the chloroquine-resistant P. falciparum strain.
Dimethylisoborreverine was the most active (IC50 = 80 nm)
Received: July 1, 2013
and selective among all the flindersia alkaloids screened.
©
XXXX American Chemical Society
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Figure 1. Structures of borreverine and flinderole natural products.
a
Scheme 1. Protecting Group Switch Strategy for Synthesis of Borreverines
a
Legend: (a) Cu(OTf) (0.2 equiv), CH Cl , room temperature, 30 min, 95%; (b) BF ·OEt (0.2 equiv), CH Cl , room temperature, 20 min, 92%.
2
2
2
3
2
2
2
a
Scheme 2. Model Studies for the Synthesis of Isoborreverine
a
Legend: (a) 3-chloro-2-methylprop-1-ene (1.5 equiv), Mg turnings (1.5 equiv), I (cat.), THF, room temperature, 2 h, 84%; (b) IBX (6.0 equiv),
2
EtOAc, reflux, 3 h, 80%; (c) DBU (1.0 equiv), CH Cl , room temperature, 1 h, 90%.
2
2
B
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a
Scheme 3. Intermolecular Formal [3 + 2] Cycloaddition Reaction of Alcohol 20 and Ester 21
a
Legend: (a) Na/Hg (4.0 equiv), Na HPO (4.0 equiv), MeOH, room temperature, 1 h, 83%; (b) BF ·OEt (0.2 equiv), CH Cl , room temperature,
2
4
3
2
2
2
5
min, 77%; (c) separation of diastereomers by silica gel column chromatography; (d) MeI (7.0 equiv), Mg turnings (6.0 equiv), I (cat.), Et O, 0 °C
2
2
to room temperature, 2 h, 85%.
Table 1. Screening of Catalyst for Ene Cyclization
entry
cat.
amt of cat. (mol %)
solvent
temp
time (h)
product
yield (%)
1
2
3
4
5
6
7
8
BF ·OEt
TFA
20
20
CH Cl2
room temp
room temp
room temp
reflux
16
48
48
2
23
71
93
87
62
57
70
62
70
3
2
2
CH Cl2
22
2
Cu(OTf)2
20
CH Cl2
22
2
MsCl/Et N
50
THF
24a
24b
23
3
TiCl4
80
CH Cl2
room temp
room temp
reflux
4
2
PTSA
100
50
CH Cl2
24
2
2
PTSA
C H
23
6
6
1
CF SO H
20
CH Cl2
room temp
/2
23
3
2
2
RESULTS AND DISCUSSION
of the dienophile 15 was initiated by addition of Grignard
reagent to aldehyde 17; oxidation of the alcohol 18 thus
generated followed by isomerization of the double bond using
DBU afforded the enone 15. Again, to our disappointment
under various reaction conditions diene 12 and enone 15 failed
to undergo a Diels−Alder reaction (Scheme 2).
■
Armed with the knowledge gained in our earlier synthesis of
9
flinderoles, we were ready to attempt the synthesis of the more
complex natural products isoborreverine (5) and dimethyliso-
borreverine (6). According to our retrosynthetic plan, it was
thought that if we do the phenylsulfonyl protecting group
switch from diene 9 to tertiary alcohol 10 (Scheme 1, eq 1), it
might lead to the formation of [4 + 2] cycloaddition product 14
instead of compound 11, as shown in Scheme 1. However, to
our disappointment, treatment of diene 12 with tertiary alcohol
3 only afforded the diene 9 by dehydration of tertiary alcohol
3. In another direction it was contemplated that diene 12
would react with dienophile 15 to generate the Diels−Alder
product 16, which on further functional group transformation
would lead to borreverine and isoborreverrine cores. Synthesis
We then turned our attention toward another approach; it
was envisioned that the isoborreverine skeleton could be
generated from the suitably substituted pyrrolo[1,2a]indole
derivative 22 by ene type cyclization or olefin cation cyclization.
Compound 22 could be prepared from indolyl alcohol 20 and
ester 21 by a formal [3 + 2] cycloaddition reaction followed by
1
1
9
Grignard reaction. On the basis of our earlier experience, it
was assumed that the use of BF ·OEt for formal [3 + 2]
3
2
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reaction would generate a mixture of diastereomers at the C-1
and C-2 centers.
ester of indole acetic acid 31 with NBS in CCl at room
4
temperature afforded the bromination product 32 in 88% yield.
Stille coupling of 32 with 33 afforded 34 in 77% yield.
Reduction of the ester group in 34 using LAH generated the
key intermediate 28 in 75% yield (Scheme 5). To our surprise,
Accordingly, deprotection of the amine group by reduction
of the sulfonamide of compound 18 under Na/Hg conditions
afforded alcohol 20 in 83% yield. Reaction of ester 21 with
alcohol 20 gave a 2:1 diastereomeric mixture of pyrrolo[1,2-
a]indoles 19a,b in 77% yield. Unfortunately in this reaction the
diastereomers were formed with respect to the C-2 and C-3
centers and not at C-1 and C-2. The stereochemistry of
diastereomers was unambiguously established by single-crystal
X-ray analysis of the minor diastereomer 19b and NOESY of
the major diastereomer. The formation of diastereomers at C-2
and C-3 suggests that the reaction is not concerted but goes
through a stepwise mechanism (Scheme 3). Interestingly
treatment of the major diastereomer 19a with an excess of
MeMgI afforded the tertiary alcohol 22, which on reaction with
BF ·OEt generated the tetramethylpyran derivative 23 by
a
Scheme 5. Synthesis of Tertiary Alcohol 28
3
2
attack of a hydroxyl oxygen at the C−C double bond. Screening
of different Lewis acids did not generate either the ene reaction
product or olefin cation cyclization product; instead, it gave a
mixture of the three different compounds 23 and 24a,b (Table
9
1
). In our earlier synthesis of flinderoles, we were surprised by
the fact that the reaction of diene 25 with tertiary alcohol 26
under Lewis acid conditions generated only the [3 + 2]
cycloaddition product 27 (Scheme 4), and we could not isolate
Scheme 4. Synthesis of Compound 27
a
Legend: (a) NBS (1.1 equiv), CCl , reflux, 1 h, 67%; (b) 33 (1.5
4
equiv), Pd(OAc) (0.1 equiv), Bu NCl (2.0 equiv), DMF, reflux, 3 h,
2
4
7
7%; (c) LiAlH (1.2 equiv), Et O, 0 °C to room temperature, 3 h,
4
2
7
5%.
dimerization of diol 28 using 10 mol % of BF ·OEt in CH Cl
2
3
2
2
generated both [4 + 2] and [3 + 2] cycloaddition products
5a,b and 36a,b with a combined yield of 82% in 5:1 and 4:1
3
diastereomeric ratios, respectively (Scheme 6). This was quite
Scheme 6. Lewis Acid Catalyzed Dimerization of Tertiary
a
Alcohol 28
even a trace of [4 + 2] cycloaddition product which could have
led to the synthesis of borreverine (7) and isoborreverine (5).
We began to wonder about the factor that made this reaction so
selective. The diene 25 and tertiary alcohol 26 are structurally
closely related to borrerine (4) and are analogous to a diene,
which was shown as the intermediate in the borrerine
8
dimerization to borreverine (7) and isoborreverine (5). This
made us reexamine the mechanism of the dimerization reaction.
It was thought that an ethanol side chain at the 3-position of
indole in diene 25 and tertiary alcohol 26 might play an
important role to exclusively generate the [3 + 2] adduct. We
became interested in dimerization of the tertiary alcohol 28.
Alcohol 28 could be synthesized from tryptophol 29 in two
steps by bromination at the 2-position of tryptophol followed
by coupling with an appropriate side chain. However, reaction
of tryptophol 29 with NBS in refluxing CCl4 generated
bromoethylindole (30). To our delight, reaction of the methyl
a
Legend: (a) BF ·OEt (10 mol %), CH Cl , room temperature, 15
3
2
2
2
min, 82%.
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interesting in the sense that, in our earlier synthesis of
flinderoles, tertiary alcohol 26 on reaction with diene 25 using
acetic acid (a comparatively weak acid), they isolated flinderoles
exclusively in excellent yield (path B). This mechanism could
be further supported by the fact that reaction of tertiary alcohol
26 with diene 25 exclusively formed the [3 + 2] cycloaddition
product 27 and no [4 + 2] cycloaddition was observed
(Scheme 4). Oxidation of the diol 35a using IBX followed by
reductive amination of the resultant bis-aldehyde 41 using a 2
N THF solution of dimethylamine afforded dimethylisoborre-
verine (6) in 82% yield. However, reductive amination of the
bis-aldehyde 41 using a 2 N THF solution of methylamine
failed to generate isoborreverine (5) under various conditions.
In our earlier synthesis of flinderoles as well, we faced same
problems, because of which we failed to synthesize flinderole A
9
BF ·OEt or Cu(OTf) afforded only [3 + 2] product. All four
3
2
2
compounds were separated by careful silica gel column
chromatography, and their structures and stereochemistries
were confirmed from their spectral data and comparison of
spectral data of isoborreverine and flinderoles A−C. More
interestingly, when a mixture of tertiary alcohol 28 and diene
25 was treated with Lewis acid, it generated only [3 + 2]
cycloaddition product; no [4 + 2] product was observed in this
reaction (Scheme 7). These results prompted us to propose a
Scheme 7. Intermolecular Formal [3 + 2] Cycloaddition
a
12
Reaction
(1). Fortunately, we came across a literature report by
Bandichhor et al. in which they reported that reductive
amination of aldehyde using methylamine works very well in
the presence of a catalytic amount of Fe(OTf) . To our delight,
3
reductive amination of the bis-aldehyde 41 using a 2 N THF
solution of methylamine in the presence of 30 mol % of
Fe(OTf) afforded isoborreverine (5) in 89% yield (Scheme 9).
3
Similarly, independent oxidation of the diols 36a,b by IBX
followed by reductive amination of the resultant bis-aldehydes
4
2a,b using a 2 N THF solution of dimethylamine afforded
flinderoles B (2) and C (3), respectively, and reductive
amination of the bis-aldehyde 42a using a 2 N THF solution of
methylamine in the presence of 30 mol % of Fe(OTf) afforded
3
flinderole A (1) in 75% yield (Scheme 10).
Thus, we completed the synthesis of flinderoles A (1), B (2),
and C (3), isoborreverine (5) and dimethylisoborreverine (6)
in just six steps starting from tryptophol 29 using a protecting-
group-free approach. We also made diene 43, to check whether
it is an actual intermediate in the dimerization of borrerine (4)
to isoborreverine (5) as proposed by Koch et al. in their
a
8
Legend: (a) BF ·OEt (0.1 equiv), CH Cl , room temperature, 10
mechanism. Tryptamine 44 on treatment with ClCO Et
3
2
2
2
2
min, 75%; (b) Na/Hg (4.0 equiv), Na HPO (4.0 equiv), MeOH,
room temperature, 1 h, 86%.
followed by protection of the indole nitrogen using PhSO Cl
2
4
2
afforded compound 45 in 91% yield. Formylation of 45
followed by a Wittig reaction of the resultant aldehyde 46 and
treatment of ester 47 thus generated with MeMgI afforded the
tertiary alcohol 48 in 75% yield.
Mesylation followed by elimination afforded the diene 49.
Deprotection of the amine group by reduction of the
sulfonamide of compound 49 using Na/Hg followed by
mechanism for [3 + 2] and [4 + 2] cycloaddition different from
that reported earlier by Koch et al. and later by our group. The
tertiary alcohol 28 could first form the cyclic borrerine type
intermediate 37, which could then open in three different ways;
depending on reaction conditions, compound 37 could be
attacked by the indole nitrogen of another molecule of 37 (path
A) to generate the intermediate 38 followed by an intra-
molecular Diels−Alder reaction leading to isoborreverine
analogue 35. On the other hand, compound 37 could first
convert to diene 39 via intermediate 40 (path B or C), which
then dimerizes itself or with compound 40 to afford the
flinderole analogue 36 (Scheme 8). Intermediate 40 could also
be generated directly from tertiary alcohol 28 by the push of
the lone pair of indole nitrogen. If one uses a comparatively
strong acid such as trifluoroacetic acid or BF ·OEt , then path A
becomes dominant as the carbon-bearing isobutenyl group
becomes more electron deficient, which is also in line with our
observation. Another important observation from Schemes 4
and 7 is that the moment diene 39 is present/formed in the
reaction mixture, it undergoes a dimerization reaction with
tertiary alcohol 28/compound 37/intermediate 40 to afford
only [3 + 2] cycloaddition product, as the terminal double
bond in diene 39 is more nucleophilic than indole nitrogen.
This could also be justified from the fact that in May’s synthesis
of flinderole by dimerization of borrerine 4 using TFA, they
only isolated isoborreverine (path A), but when they used
LiAlH reduction of the resultant indole derivative 50 afforded
4
diene 43 in 66% yield (Scheme 11). Diene 43 on treatment
with trifluoroacetic acid afforded isoborreverine (5) but only in
8
2
0% yield; in contrast to previous reports we did not observe
the formation of borreverine (7). May et al. also obtained
similar results in the dimerization of borrerine (4) using
11
trifluoroacetic acid with 90% yield of isoborreverine (5).
Interestingly, however, alcohol 51 generated from 48 by a
deprotection−reduction sequence on treatment with
CF CO H in CH Cl furnished isoborreverine (5) in 86%
3
2
2
2
3
2
yield (Scheme 12).
CONCLUSIONS
■
The chemistry described herein demonstrates the power of
cycloaddition reactions in complex molecule construction and
provides access to flinderoles A (1), B (2), and C (3),
isoborreverine (5) and dimethylisoborreverine (6), two
different classes of structurally intriguing and highly potent
antimalarial natural products. A detailed study of the
dimerization reaction caused us to propose a mechanism for
dimerization of tertiary alcohol 32 slightly different from the
E
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Scheme 8. Proposed Mechanism for the Dimerization of Tertiary Alcohol 28
earlier reported dimerization of borrerine. The preparation and
dimerization of diene 10 also supported the proposed
biosynthetic pathway.
doublet of doublets of doublets, dt = doublet of triplets, td = triplet of
doublets, m = multiplet, br = broad.
Experimental Procedures. 3-Methyl-1-(3-methyl-1-(phenylsul-
fonyl)-1H-indol-2-yl)but-3-en-1-ol (18). To a magnetically stirred
solution of magnesium turnings (243 mg, 10.03 mmol) and a few
crystals of iodine in anhydrous THF (10 mL) was added a mixture of
aldehyde 17 (2.0 g, 6.68 mmol) and 3-chloro-2-methylprop-1-ene
(0.97 mL, 10.03 mmol) in THF (20 mL) dropwise with gentle
heating, and this mixture was stirred for 2 h at room temperature. The
EXPERIMENTAL SECTION
■
General Aspects. All reactions were carried out under a nitrogen
atmosphere with dry solvents under anhydrous conditions, unless
otherwise mentioned. All of the chemicals were purchased
commercially and used without further purification. Anhydrous THF
and diethyl ether were distilled from sodium benzophenone, and
dichloromethane was distilled from calcium hydride. Yields refer to
chromatographically pure compounds, unless otherwise stated.
Reactions were monitored by thin-layer chromatography (TLC)
carried out on 0.25 mm Merck silica gel plates (60F-254) using UV
light as a visualizing agent and an p-anisaldehyde or ninhydrine stain
and heat as developing agents. Merck silica gel (particle size 100−200
and 230−400 mesh) was used for flash column chromatography. Neat
coumpounds were used for recording IR spectra. NMR spectra were
reaction mixture was then quenched with aqueous NH Cl solution (20
4
mL) and worked up. Evaporation of the solvent and purification of the
residue on silica gel column using EtOAc/hexane (1.5/8.5) as eluent
furnished the alcohol 18 (2.0 g, 84%) as a yellowish semisolid: R = 0.5
f
−
1
(EtOAc/hexane 1/4); IR (neat) νmax/cm 3547, 2919, 1448, 1364,
1170, 1151, 740, 594, 576; H NMR (CDCl , 500 MHz) δ 8.08 (br d,
1
3
J = 8.2 Hz, 1H), 7.78 (br d, J = 7.3 Hz, 2H), 7.44 (td, J = 7.6, 7.3 Hz,
1H), 7.39 (dd, J = 7.69, 7.0 Hz, 1H), 7.33 (br t, J = 8.2, Hz, 2H), 7.27
(td, J = 7.3, 1.2 Hz, 1H), 7.22 (td, J = 7.6, 7.3 Hz, 1H), 5.46 (br s, 1H),
4.84 (s, 2H), 3.52 (br s, 1H), 2.87 (dd, J = 8.5, 4.5 Hz, 1H), 2.71 (dd, J
1
13
13
recorded on a Bruker Avance 200 ( H, 200 MHz; C, 50 MHz),
= 7.9, 5.8 Hz, 1H), 2.31 (s, 3H), 1.79 (s, 3H); C NMR (CDCl , 125
3
1
13
Bruker Avance 400 ( H, 400 MHz; C, 100 MHz), Bruker Avance
MHz) δ 141.9 (C), 137.9 (C), 137.5 (C), 136.6 (C), 133.6 (CH),
131.3 (C), 128.9 (2 CH), 126.3 (2 CH), 125.2 (CH), 123.7 (CH),
1
13
5
00 ( H, 500 MHz; C, 125 MHz), or JEOL DELTA (ECX) 500
1
13
instrument ( H, 500 MHz; C, 125 MHz). Mass spectrometric data
were obtained using WATERS-Q-Tof-Premier-HAB213 and
WATERS-Q-Tof-Premier-ESI-MS instruments. Melting point meas-
urements were made using a hot stage apparatus. The following
abbreviations were used to explain the multiplicities: s = singlet, d =
doublet, t = triplet, q = quartet, dd = doublet of doublets, ddd =
120.3 (C), 119.1 (CH), 115.1 (CH), 113.7 (CH ), 65.7 (CH), 45.5
2
(CH ), 22.1 (CH ), 9.7 (CH ); HRMS m/z calcd for C H NO S [M
2
3
3
20 21
3
+
+ Na ] 378.1140, found 378.1142.
3-Methyl-1-(3-methyl-1-(phenylsulfonyl)-1H-indol-2-yl)but-3-en-
1-one (18a). To a solution of the alcohol 18 (1.5 g, 4.24 mmol) in
ethyl acetate (25 mL) was added IBX (7.1 g, 25.5 mmol), and the
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mixture was refluxed for 3 h. Aqueous NaHCO was added to the
Scheme 9. Completion of Total Synthesis of Isoborreverine
3
a
reaction mixture, which was then extracted with ethyl acetate (3 × 20
mL). The organic extract was washed with brine and dried over
Na SO . Evaporation of the solvent and purification of the residue on a
5
and Dimethylisoborreverine 6
2
4
silica gel column using EtOAc/hexane (1/9) as eluent furnished
compound 18a (1.2 g, 80%) as a waxy solid: R = 0.6 (EtOAc/hexane
f
−
1
1
1
8
1
.5/8.5); IR (neat) νmax/cm 3316, 2917, 1679 (CO), 1446, 1365,
1
175, 946, 743, 594, 572; H NMR (CDCl , 400 MHz) δ 8.06 (d, J =
3
.3 Hz, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.42−7.23 (m, 6H), 4.90 (s,
1
3
H), 4.82 (s, 1H), 3.79 (s, 2H), 2.19 (s, 3H), 1.80 (s, 3H); C NMR
(
1
CDCl , 50 MHz) δ 195.5 (CO), 138.9 (C), 137.1 (C), 135.7 (C),
3
34.9 (C), 133.8 (CH), 131.7 (C), 128.6 (2 CH), 127.3 (CH), 127.2
(
(
2 CH), 127.1 (C), 124.8 (CH), 120.7 (CH), 116.0 (CH), 115.2
CH ), 53.2 (CH ), 22.6 (CH ), 9.3 (CH ); HRMS m/z calcd for
2
2
3
3
+
C H NO S [M + H ] 354.1186, found 354.1160.
20
19
3
3
-Methyl-1-(3-methyl-1-(phenylsulfonyl)-1H-indol-2-yl)but-2-en-
1
-one (15). To a magnetically stirred solution of the alcohol 18a (500
mg, 1.41 mmol) in anhydrous CH Cl (10 mL) was added DBU (0.2
2
2
mL, 1.41 mmol) in a dropwise fashion, and the mixture was stirred for
h at room temperature. The progress of the reaction was monitored
1
by TLC until the starting alcohol had been completely consumed.
Water (5 mL) was then added to the reaction mixture, which was then
extracted with CH Cl (3 × 5 mL), washed with brine (5 mL), and
2
2
dried over Na SO . Evaporation of the solvent and purification of the
2
4
residue on a silica gel column using EtOAc/hexane (1/9) as eluent
furnished compound 15 (450 mg, 90%) as a yellowish solid: R = 0.4
f
a
−1
Legend: (a) IBX (4.0 equiv), EtOAc, reflux, 1 h, 80%; (b) NHMe2
(EtOAc/hexane 1/4); mp 79−81 °C; IR (neat) ν /cm 2940, 1666
max
1
(4.0 equiv), NaCNBH3 (4.0 equiv), AcOH (cat.), MeOH, room
(CO), 1612, 1445, 1366, 1182, 945, 862, 772, 577; H NMR (400
temperature, 12 h, 82%; (c) NH Me (5.0 equiv), NaBH (5.0 equiv),
Fe(OTf) (0.3 equiv), CH Cl , room temperature, 30 min, 89%.
MHz, CDCl ): δ 8.05 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 7.5 Hz, 2H),
3
2
4
7.43−7.22 (m, 6H), 6.56 (s, 1H), 2.27 (s, 3H), 2.23 (s, 3H), 1.98 (s,
3
2
2
a
Scheme 10. Completion of Total Synthesis of Flinderoles A−C
a
Legend: (a) IBX (4.0 equiv), EtOAc, reflux, 1 h, 74%; (b) NH Me (5.0 equiv), NaBH (5.0 equiv), Fe (OTf) (0.3 equiv), CH Cl , room
2
4
3
2
2
temperature, 30 min, 75%; (c), NHMe (4.0 equiv), NaCNBH (4.0 equiv), AcOH (cat.), MeOH, room temperature, 12 h, 85%; (d) IBX (4.0
2
3
equiv), EtOAc, reflux, 1 h, 81%; (e) NHMe (4.0 equiv), NaCNBH (4.0 equiv), AcOH (cat.), MeOH, room temperature, 12 h, 81%;
2
3
G
dx.doi.org/10.1021/jo4013833 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Scheme 11. Synthesis of Tertiary Alcohol 51 and Diene 43
Scheme 12. Dimerization of Diene 43 and Tertiary Alcohol
a
51
a
Legend: (a) CF CO H (0.5 equiv), CH Cl , room temperature, 30
3
2
2
2
min.
mL), and dried over anhydrous Na SO . Evaporation of the solvent
2
4
and purification of the residue on a silica gel column using EtOAc/
hexane (2/8) as eluent gave the alcohol 20 (1.0 g, 83%) as a yellow
−
1
waxy solid: R = 0.4 (EtOAc/hexane 1.5/8.5); IR (neat) vmax/cm
3
f
1
406, 2918, 1647, 1526, 1451, 1335, 1306, 894, 742; H NMR
(
CD CN, 400 MHz) δ 6.63 (dt, J = 6.6, 1.2 Hz, 1H), 6.50 (dt, J = 6.3,
.7 Hz, 1H), 6.26 (ddd, J = 7.1, 5.8, 1.2 Hz, 1H), 6.18 (ddd, J = 7.1,
.0, 1.2 Hz, 1H), 4.28 (t, J = 7.5 Hz, 1H), 3.92−3.88 (br d, 2H), 1.70,
3
1
6
(
m, 2H), 1.41 (s, 3H), 0.88 (s, 3H); 13C NMR (CD CN, 125 MHz) δ
3
43.5 (C), 138.0 (C), 136.6 (C), 129.9 (C), 122.2 (CH), 119.6 (CH),
19.2 (CH), 113.6 (CH ), 111.8 (CH), 107.1 (C), 65.4 (CH), 46.4
2
2 3 3 14 17
+
2
(3-Methyl-1-(phenylsulfonyl)-1H-indol-2-yl)methanol (21a). To a
solution of the aldehyde 17 (4.0 g, 13.37 mmol) in anhydrous THF
(
40 mL) was added LiAlH (2.47 g, 66.88 mmol) at 0 °C. The mixture
4
was stirred for 1 h and quenched with a saturated solution of NH Cl
4
and extracted with EtOAc; the organic layer was then washed with
brine and dried over Na SO . Evaporation of the solvent and
2
4
purification of the residue on a silica gel column using EtOAc/hexane
(
7.5/2.5) as eluent gave the alcohol 21a (3.3 g, 82%) as a white waxy
−1
oil: R = 0.5 (EtOAc/hexane 7/3); IR (neat) νmax/cm 3593, 3423
f
1
(OH), 1450, 1361, 1172, 997, 751, 685, 560; H NMR (CDCl , 400
3
MHz) δ 8.12 (d, J = 8.2 Hz, 1H), 7.83 (br d, J = 9.5 Hz, 2H), 7.54−
1
3
7
.27 (m, 6H), 4.92 (s, 2H), 3.29 (br s, 1H), 2.29 (s, 3H); C NMR
a
Legend: (a) NaHCO (1.5 equiv), NaCl (4.4 equiv), ClCO Et (1.5
3
2
(
1
1
CDCl , 50 MHz) δ 138.4 (C), 136.0 (C), 134.9 (C), 133.7 (CH),
3
equiv), CH Cl , H O, room temperature, 3 h, 91%; (b) KOH (5.0
equiv), PhSO Cl (3.0 equiv), THF, room temperature, 6 h, 91%; (c)
Cl CHOCH (5.0 equiv), SnCl (5.0 equiv), CH Cl , −78 to −10 °C,
1
temperature, 6 h, 81%; (e) MeI (6.0 equiv), Mg turnings (5.0
equiv), I (cat.), Et O, 0 °C to room temperature, 2 h, 75%; (f) MsCl
2
2
2
30.6 (C), 129.2 (2 CH), 126.2 (2 CH), 125.4 (CH), 123.6 (CH),
19.5 (CH), 119.4 (C), 114.4 (CH), 54.9 (CH ), 8.9 (CH ); HRMS
2
2
3
2
3
4
2
2
+
m/z calcd for C H NO S [M + NH ] 319.1100, found 319.1118,
and [M + Na ] 324.0700, found 324.0671.
16
15
3
4
h, 74%; (d) Ph PCHCO Et (2.0 equiv), CH Cl , room
+
3
2
2
2
(3-Methyl-1H-indol-2-yl)methanol (21b). To a solution of the
2
2
alcohol 21a (3.0 g, 9.96 mmol) in anhydrous methanol (30 mL) was
added Na HPO (5.6 g, 39.86 mmol) and Na−Hg (8.9 g, 39.86
(
3.0 equiv), Et N (6.0 equiv), THF, 0 °C to room temperature and
3
2
4
reflux, 2 h, 83%; (g) Na/Hg (5.0 equiv), Na HPO4 (4.0 equiv),
MeOH, room temperature, 1 h, 90%; (h) LiAlH (1.0 M solution)
2
mmol). The reaction mixture was stirred for 1 h at room temperature.
Water (15 mL) and ether (20 mL) were added, and the supernatant
was decanted. The residue was washed with ether (3 × 15 mL). The
organic extracts were combined, washed with brine (15 mL), and dried
over anhydrous Na SO . Evaporation of the solvent and purification of
4
(
5.0 equiv), THF, room temperature, 3 h, 66%.
3
H); 13C NMR (50 MHz, CDCl ) δ 186.8 (CO), 155.6 (C), 137.2
3
2
4
(
C), 136.8 (C), 135.9 (C), 133.6 (CH), 131.7 (C), 128.6 (2 CH),
the residue on silica gel column using EtOAc/hexane (1/4) as eluent
1
1
27.1 (2 CH), 126.8 (CH), 125.9 (CH), 125.6 (C), 124.4 (CH),
20.4 (CH), 115.8 (C), 27.9 (CH ), 21.0 (CH ), 9.3 (CH ); HRMS
gave the alcohol 21b (1.3 g, 81%) as a yellow semisolid; R = 0.4
f
−1
(EtOAc/hexane 3/7); IR (neat) νmax/cm 3401, 2921, 1622, 1459,
3
3
3
+
1
m/z calcd for C H NO S [M + H ] 354.1186, found 354.1167.
1333, 1242, 743; H NMR (CDCl , 400 MHz) δ 8.17 (br s, 1H), 7.53
20
19
3
3
3
-Methyl-1-(3-methyl-1H-indol-2-yl)but-3-en-1-ol (20). To a
(br d, J = 7.4 Hz, 1H), 7.30−7.06 (m, 3H), 4.76 (s, 2H), 2.27 (s, 3H),
solution of the alcohol 18 (2 g, 5.63 mmol) in anhydrous methanol
1.92 (br s, 1H); 13C NMR (CDCl , 50 MHz) δ 135.6 (C), 132.8 (C),
3
(
2
30 mL) was added Na HPO (3.2 g, 22.53 mmol) and Na−Hg (5.0 g,
128.7 (C), 122.2 (CH), 119.2 (CH), 118.8 (CH), 110.7 (CH), 108.4
2
4
2.53 mmol). The reaction mixture was stirred for 1 h at room
(C), 56.5 (CH ), 8.3 (CH ); HRMS m/z calcd for C H NO [M +
2
3
10 11
+
temperature. Water (10 mL) and ether (20 mL) were added, and the
supernatant was decanted. The residue was washed with ether (3 × 10
mL). The organic extracts were combined, washed with brine (10
H ] 162.0900, found 162.0914.
3-Methyl-1H-indole-2-carbaldehyde (21c). To a solution of the
alcohol 21b (1.2 g, 7.40 mmol) in ethyl acetate (10 mL) was added
H
dx.doi.org/10.1021/jo4013833 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
IBX (8.2 g, 29.62 mmol), and the mixture was refluxed for 1 h.
119.1 (CH), 118.5 (CH), 118.4 (CH), 113.6 (CH ), 110.9 (CH),
2
Aqueous NaHCO was added to the reaction mixture, which was then
110.3 (C), 109.7 (CH), 102.3 (C), 61.0 (CH ), 58.1 (CH), 53.8
3
2
extracted with ethyl acetate (3 × 10 mL). The organic extract was
(CH), 42.0 (CH ), 37.1 (CH), 22.2 (CH ), 13.5 (CH ), 8.8 (CH ),
2
3
3
3
+
washed with brine and dried over Na SO . Evaporation of the solvent
8.5 (CH ); HRMS m/z calcd for C H N O [M + H ] 427.2407,
2
4
3
28 30
2
2
and purification of the residue on a silica gel column using EtOAc/
hexane (1/9) as eluent furnished the aldehyde 21c (1.0 g, 84%) as a
found 427.2386.
2-((1S,2R,3S)-9-Methyl-3-(3-methyl-1H-indol-2-yl)-1-(2-methylall-
yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-2-yl)propan-2-ol (22). To a
cold (0 °C), magnetically stirred solution of the major isomer ester
19a (500 mg, 1.16 mmol) in anhydrous ether (10 mL) was added
methylmagnesium iodide (prepared from magnesium turnings (170
mg, 7.00 mmol), methyl iodide (0.5 mL, 8.17 mmol), and a few
crystals of iodine in anhydrous ether (10 mL)), and the mixture was
stirred for 2 h at room temperature. The reaction mixture was then
white semisolid: R = 0.6 (EtOAc/hexane 1.5/8.5); IR (neat) νmax/
f
−1
cm 3308, 2849, 1637 (CO), 1574, 1460, 1232, 1114, 873, 741,
1
6
7
2
1
13; H NMR (CDCl , 400 MHz) δ 10.04 (s, 1H), 9.15 (br s, 1H),
3
.70 (br d, J = 8.2 Hz, 1H), 7.41−7.36 (m, 2H), 7.17−7.13 (m, 1H),
.64 (s, 3H); 13C NMR (CDCl , 50 MHz) δ 180.6 (CHO), 137.6 (C),
3
32.1 (C), 128.1 (C), 127.6 (CH), 125.1 (C), 121.3 (CH), 120.3
(
CH), 112.3 (CH), 8.3 (CH ); HRMS m/z calcd for C H NO [M +
3 10 9
+
H ] 160.0800, found 160.0766.
E)-Ethyl 3-(3-Methyl-1H-indol-2-yl)acrylate (21). To a solution of
the aldehyde 21c (1.0 g, 6.25 mmol) in anhydrous CH Cl (20 mL)
quenched with aqueous NH Cl solution (50 mL) and worked up.
4
(
Evaporation of the solvent and purification of the residue on a silica gel
column using EtOAc/hexane (2.5/7.5) as eluent furnished the tertiary
2
2
was added dry Ph PCHCO Et (4.3 g, 12.5 mmol), and the mixture
alcohol 22 (410 mg, 85%) as a white semisolid: R
f
= 0.4 (EtOAc/
3
2
−1
was stirred magnetically for 6 h at room temperature. Evaporation of
the solvent and purification of the residue on silica gel column using
EtOAc/hexane (1/9) as eluent gave the ester 21 (1.3 g, 90%) as a
hexane 3/7); IR (neat) νmax/cm 3397, 2971, 2924, 1459, 1373, 1240,
1
740; H NMR (CDCl , 400 MHz) δ 7.70 (br s, 1H), 7.55−7.49 (m,
3
2H), 7.16−7.02 (m, 4H), 6.98−6.89 (m, 2H), 5.67 (d, J = 3.3 Hz,
1H), 4.86 (s, 1H), 4.61 (s, 1H), 3.39−3.35 (m, 1H), 2.83 (t, J = 3.1
Hz, 1H), 2.57 (dd, J = 7.7, 5.5 Hz, 1H), 2.45 (dd, J = 8.1, 5.1 Hz, 1H),
white crystalline solid: R = 0.45 (EtOAc/hexane 1.5/8.5); mp 163−
f
−1
1
1
7
3
3
65 °C; IR (neat) ν /cm 3326 (NH), 1684 (OCO), 1612,
max
1
13
295, 961, 730, 586; H NMR (CDCl , 200 MHz) δ 8.49 (br s, 1H),
2.33 (s, 3H), 2.31 (s, 3H), 1.81 (s, 3H), 1.25 (s, 3H), 1.12 (s, 3H);
NMR (CDCl
(C), 133.6 (C), 132.1 (C), 129.4 (C), 121.9 (CH), 120.6 (CH), 119.1
(2 CH), 118.5 (CH), 118.3 (CH), 114.7 (CH ), 110.7 (CH), 109.7
(CH), 107.8 (C), 101.3 (C), 72.5 (C), 66.4 (CH), 54.0 (CH), 44.5
(CH ), 37.3 (CH), 28.1 (CH ), 25.9 (CH ), 22.6 (CH ), 8.9 (CH ),
8.5 (CH ); HRMS m/z calcd for C28 O [M + H ] 413.2615,
found 413.2594.
C
3
.81 (d, J = 16.0 Hz, 1H), 7.56 (br d, J = 7.9 Hz, 1H), 7.33−7.06 (m,
3
, 50 MHz) δ 143.4 (C), 143.3 (C), 135.6 (C), 134.1
H), 6.18 (d, J = 16.0 Hz, 1H), 4.30 (q, J = 7.2, 7.0 Hz, 2H), 2.40 (s,
H), 1.35 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl , 50 MHz) δ 167.4
3
2
(
1
OCO), 137.4 (C), 132.3 (CH), 129.9 (C), 128.9 (C), 124.9 (CH),
19.8 (2 CH), 118.6 (C), 113.7 (CH), 110.9 (CH), 60.5 (CH ), 14.3
2
3
3
3
3
2
+
+
(
CH ), 8.8 (CH ); HRMS m/z calcd for C H NO [M + H ]
3
H N
32 2
3
3
14 15
2
230.1203, found 230.1185.
(
1S,2S,3S)-Ethyl 9-Methyl-3-(3-methyl-1H-indol-2-yl)-1-(2-meth-
(6S,6aS,10aS)-7,7,9,9,11-Pentamethyl-6-(3-methyl-1H-indol-2-
yl)-6a,7,8,9,10,10a-hexahydro-8-oxa-isoindolo[2,1-a]indole (23).
To a solution of the tertiary alcohol 22 (70 mg, 0.17 mmol) in
anhydrous CH Cl (5 mL) was added BF ·OEt (24 mg, 0.17 mmol).
ylallyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-carboxylate (19a)
and (1S,2S,3R)-Ethyl 9-Methyl-3-(3-methyl-1H-indol-2-yl)-1-(2-
methylallyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-carboxylate
2
2
3
2
(
19b). 19a: to a solution of the alcohol 20 (300 mg, 1.39 mmol) and
ester 21 (385 mg, 1.67 mmol) in anhydrous CH Cl (10 mL) was
added a catalytic amount of BF ·OEt (39 mg, 0.27 mmol). The
resulting purplish red solution was stirred for 5 min at room
temperature. Aqueous NaHCO (10 mL) was added to the reaction
mixture, which was then extracted with CH Cl , washed with brine,
and dried over Na SO . Evaporation of the solvent and purification of
the residue on a silica gel column using EtOAc/hexane (0.6/9.4) as
The resulting purplish red solution was stirred for 16 h at room
2
2
temperature. Aqueous NaHCO (5 mL) was added to the reaction
3
3
2
mixture, which was then extracted with CH Cl , washed with brine,
2
2
and dried over Na SO . Evaporation of the solvent and purification of
2 4
3
the residue on silica gel column using EtOAc/hexane (0.5/9.5) as
eluent furnished compound 23 (50 mg, 71%) as a white semisolid: Rf
= 0.5 (EtOAc/hexane 1/9) (in a similar fashion PTSA (1.69 mmol),
CH Cl (5 mL), room temperature, and 24 h gave 70% yield, PTSA
2
2
2
4
2
2
eluent furnished the major isomer 19a (340 mg, 52%) as a white
(0.84 mmol), benzene (5 mL), 80 °C, and 2 h gave 62% yield, and
−1
semisolid: R = 0.45 (EtOAc/hexane 1/9); IR (neat) ν /cm1 3387,
triflic acid (0.16 mmol), CH Cl (5 mL), room temperature, and 30
f
max
2
2
−1
2
(
(
1
(
2
922, 1730 (OCO), 1457, 1373, 1301, 1029, 742; H NMR
min gave 70% yield): IR (neat) νmax/cm 3392, 2973, 2929, 1458,
1380, 1331, 1296, 1164, 976, 740; H NMR (CDCl , 400 MHz) δ 7.80
1
CDCl , 400 MHz) δ 7.74 (br s, 1H), 7.59 (br d, J = 7.0 Hz, 1H), 7.50
3
3
br d, J = 8.0 Hz, 1H), 7.14−7.10 (m, 3H), 7.04 (br t, J = 8.0, 7.0 Hz,
H), 6.87 (br t, J = 8.0, 7.2 Hz, 1H), 6.63 (br d, J = 8.0 Hz, 1H), 5.81
d, J = 7.2 Hz, 1H), 4.84 (br s, 1H), 4.73 (br s, 1H), 4.24−4.09 (m,
H), 3.96 (br m, 1H), 3.52 (t, J = 7.0 Hz, 1H), 2.87 (dd, J = 9.2, 4.5
(br s, 1H), 7.63−7.61 (m, 1H), 7.47 (dd, J = 7.7 Hz, 1H), 7.17−7.13
(m, 3H), 6.97 (br t, J = 7.3 Hz, 1H), 6.78 (br t, J = 7.3 Hz, 1H), 6.31
(d, J = 8.2 Hz, 1H), 5.29 (d, J = 10.5 Hz, 1H), 3.51 (br t, J = 12.0 Hz,
1H), 2.52 (dd, J = 9.2, 3.2 Hz, 2H), 2.47 (s, 3H), 2.34 (s, 3H), 1.80 (br
Hz, 1H), 2.51 (dd, J = 9.0, 4.7 Hz, 1H), 2.35 (s, 6H), 1.80 (s, 3H),
t, J = 12.5 Hz, 1H), 1.48 (s, 3H), 1.42 (s, 3H), 1.32 (s, 3H), 0.87 (s,
13
1
.24 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl , 50 MHz) δ 172.4 (OC
3H); C NMR (CDCl , 50 MHz) δ 140.4 (C), 136.1 (C), 132.6 (C),
3
3
O), 142.5 (C), 141.8 (C), 135.9 (C), 134.1 (C), 132.5 (C), 131.3 (C),
132.5 (C), 130.4 (C), 128.6 (C), 122.5 (CH), 121.0 (CH), 119.3
(CH), 118.8 (CH), 118.7 (CH), 118.2 (CH), 111.0 (CH), 110.9 (C),
109.1 (CH), 102.1 (C), 73.9 (C), 72.7 (C), 64.9 (CH), 54.6 (CH),
40.8 (CH ), 33.9 (CH), 33.4 (CH ), 31.0 (CH ), 28.3 (CH ), 24.0
1
1
(
29.3 (C), 122.4 (CH), 121.1 (CH), 119.5 (2 CH), 118.9 (CH),
18.5 (CH), 114.4 (CH ), 111.1 (CH), 110.0 (C), 109.9 (CH), 102.5
C), 61.5 (CH ), 60.2 (CH), 55.9 (CH), 42.2 (CH ), 39.2 (CH), 22.6
CH ), 14.2 (CH ), 8.8 (CH ), 8.5 (CH ); HRMS m/z calcd for
C H N O [M + H ] 427.2407, found 427.2383.
8
1
gave the minor isomer 19b (165 mg, 25%) as a yellow crystalline solid:
R = 0.4 (EtOAc/hexane 1/9); mp 105−107 °C; IR (neat) νmax/cm
386, 2918, 1731, 1458, 1370, 1302, 1188, 1031, 739; H NMR
2
2
2
2
3
3
3
(
(CH ), 8.7 (CH ), 8.4 (CH ); HRMS m/z calcd for C H N O [M +
3
3
3
3
3 3 3 28 32 2
H ] 413.2615, found 413.2590.
+
+
2
30
2
2
9b: further elution of the column with EtOAc/hexane (1.5/8.5)
(1S,2R,3S)-9-Methyl-3-(3-methyl-1H-indol-2-yl)-1-(2-methylallyl)-
2-(prop-1-en-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole (24a). To a
solution of the tertiary alcohol 22 (200 mg, 0.48 mmol) in anhydrous
THF (8 mL) and Et N (0.4 mL, 2.91 mmol) under an N atmosphere
−1
f
1
3
3
2
(
CDCl , 400 MHz) δ 7.52 (br t, J = 7.7, 6.2 Hz, 2H), 7.44 (br s, 1H),
was added MsCl (0.1 mL, 1.45 mmol) slowly over a period of 5 min at
0 °C. The solution was warmed to room temperature for about 1.5 h
and then refluxed for 30 min. The precipitate that formed was filtered
off using ethyl acetate, affording a brown viscous liquid. Evaporation of
the solvent and purification of the residue on a silica gel column using
EtOAc/hexane (1/9) as eluent furnished compound 24a (118 mg,
3
7
.09−7.02 (m, 4H), 6.92 (br t, J = 7.7, 7.2 Hz, 1H), 6.72 (br d, J = 8.2
Hz, 1H), 6.06 (d, J = 8.7 Hz, 1H), 4.83 (br d, 2H), 4.20−4.15 (m,
H), 3.84 (dd, J = 6.0, 2.7 Hz, 1H), 3.79−3.73 (m, 1H), 3.64−3.58
1
(
m, 1H), 2.85 (dd, J = 4.2, 4.2 Hz, 1H), 2.39 (s, 6H), 2.35 (br d, 1H),
1
1
(
.79 (s, 3H), 0.78 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl , 100 MHz) δ
3
71.1 (OCO), 142.8 (C), 141.7 (C), 135.6 (C), 133.9 (C), 131.8
62%) as a colorless waxy solid: R = 0.5 (EtOAc/hexane 1/9); IR
f
−1
1
C), 128.9 (C), 128.6 (C), 122.2 (CH), 121.0 (CH), 119.3 (CH),
(neat) νmax/cm 3394, 2918, 1459, 1373, 1301, 894, 741; H NMR
I
dx.doi.org/10.1021/jo4013833 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
(
6
1
3
7
CDCl , 200 MHz) δ 7.69 (br s, 1H), 7.60−7.49 (m, 2H), 7.17−7.09
of the residue on a silica gel column using EtOAc/hexane (1.5/8.5) as
3
m, 3H), 7.03 (dd, J = 6.8, 1.1 Hz, 1H), 6.89 (td, J = 7.0, 1.1 Hz, 1H),
eluent gave the 2-bromo ester 32 (12.4 g, 88%) as a yellow waxy oil: R
f
−1
.64 (dt, J = 8.0, 1.1 Hz, 1H), 5.39 (d, J = 6.9, 1H), 4.87 (t, J = 7.5 Hz,
H), 4.82−4.78 (m, 2H), 4.71 (br s, 1H), 3.53 (q, J = 6.9, 5.5 Hz, 1H),
.31 (t, J = 6.9 Hz, 1H), 2.72 (dd, J = 8.9, 5.3 Hz, 1H), 2.45 (dd, J =
.8, 6.4 Hz, 1H), 2.35 (s, 3H), 2.33 (s, 3H), 1.76 (s, 6H); 13C NMR
= 0.4 (EtOAc/hexane 1/4); IR (neat) νmax/cm 3335 (NH), 2951,
1
2850, 1728 (OCO), 1435, 1336, 1202, 1167, 1013, 742, 628; H
NMR (CDCl , 500 MHz) δ 8.46 (br s, 1H), 7.55−7.52 (m, 1H),
3
13
7.17−7.10 (m, 3H), 3.78 (s, 2H), 3.73 (s, 3H); C NMR (CDCl ,
3
(
CDCl , 50 MHz) δ 143.3 (C), 143.0 (C), 142.8 (C), 135.6 (C),
125 MHz) δ 171.8 (OCO), 135.9 (C), 127.2 (C), 122.2 (CH),
3
1
33.8 (C), 132.4 (2 C), 129.3 (C), 121.9 (CH), 120.8 (CH), 119.2 (2
120.1 (CH), 118.0 (CH), 110.6 (CH), 109.7 (C), 108.0 (C), 50.1
+
CH), 118.6 (CH), 118.3 (CH), 114.5 (CH ), 113.6 (CH ), 110.9
(CH ), 30.7 (CH ); HRMS m/z calcd for C H BrNO [M + H ]
2
2
3
2
11 10
2
(
(
CH), 109.8 (CH), 109.4 (C), 102.2 (C), 64.0 (CH), 57.2 (CH), 42.0
CH ), 39.0 (CH), 22.6 (CH ), 19.5 (CH ), 8.9 (CH ), 8.6 (CH );
268.0000, found 267.9975.
(E)-Methyl 2-(2-(3-Hydroxy-3-methylbut-1-enyl)-1H-indol-3-yl)-
acetate (34). To a solution of the 2-bromoindole ester 36 (400 mg,
1.42 mmol) in anhydrous DMF (6 mL) was added freshly prepared
(E)-2-methyl-4-(tributylstannyl)but-3-en-2-ol (37; 802 mg, 2.13
mmol) subsequently followed by Pd(OAc)2 (48 mg, 0.21 mmol)
2
3
3
3
3
+
HRMS m/z calcd for C H N [M + H ] 395.2509, found 395.2484.
28
30
2
2
-((1S,2S,3S)-9-Methyl-3-(3-methyl-1H-indol-2-yl)-1-(2-methyl-
prop-1-enyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-2-yl)propan-2-ol
24b). To a solution of the tertiary alcohol 22 (70 mg, 0.17 mmol) in
anhydrous CH Cl (5 mL) was added TiCl (93 mg, 0.84 mmol). The
(
2
2
4
and Bu NCl (789 mg, 2.84 mmol). The mixture was refluxed for 3 h
4
resulting purplish red solution was stirred for 4 h at room temperature.
Aqueous NaHCO (5 mL) was added to the reaction mixture, which
and extracted with a MeOH/EtOAc (5/95) solution. The organic
layer was then washed with brine and dried over Na SO . Evaporation
3
2
4
was then extracted with CH Cl , washed with brine, and dried over
of the solvent and purification of the residue on a silica gel column
2
2
Na SO . Evaporation of the solvent and purification of the residue on
using EtOAc/hexane (2/3) as eluent gave the tertiary alcohol 34 (750
2
4
silica gel column using EtOAc/hexane (1/3) as eluent furnished
mg, 77%) as a chocolaty waxy oil: R = 0.5 (EtOAc/hexane 1/1); IR
f
−1
compound 24b (40 mg, 57%) as a yellow waxy oil: R = 0.5 (EtOAc/
(neat) νmax/cm 3379, 3253, 2950, 1734 (OCO), 1458, 1318,
f
−1
1
hexane 3/7); IR (neat) νmax/cm 3383, 2971, 2925, 1710, 1456, 1374,
248, 742; H NMR (CDCl , 400 MHz) δ 7.70 (br s, 1H), 7.57 (br d,
1162, 1024, 822, 744; H NMR (DMSO-d , 500 MHz) δ 11.0 (s, 1H),
6
1
1
7.38 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.03 (t, J = 7.0, 8.2
Hz, 1H), 6.91 (t, J = 7.0, 7.9 Hz, 1H), 6.59 (d, J = 16.2 Hz, 1H), 6.40
(d, J = 16.2 Hz, 1H), 4.77 (s, 1H), 3.74, (s, 2H), 3.32, (s, 3H), 1.26 (s,
3
J = 4.5, 1.7 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.19−7.09 (m, 3H), 6.98
br t, J = 7.0 Hz, 1H), 6.83 (br t, J = 7.0 Hz, 1H), 6.62 (br d, J = 8.0
Hz, 1H), 5.65 (d, J = 6.5 Hz, 1H), 5.33 (br d, J = 10.0 Hz, 1H), 4.16
(
6H); 13C NMR (DMSO-d , 125 MHz) δ 171.8 (OCO), 138.8
6
(
(
(
dd, J = 6.7, 3.2 Hz, 1H), 2.87 (t, J = 6.5 Hz, 1H), 2.35 (s, 3H), 2.18
(CH), 136.1 (C), 133.7 (C), 128.2 (C), 121.8 (CH), 118.7 (CH),
118.3 (CH), 114.0 (CH), 110.6 (CH), 105.9 (C), 69.3 (C), 51.6
(CH ), 30.2 (2 CH ), 29.4 (CH ); HRMS m/z calcd for C H NO
3
13
s, 3H), 1.90 (s, 3H), 1.80 (s, 3H), 1.26−1.25 (d, 6H); C NMR
CDCl , 50 MHz) δ 141.4, 135.9, 133.5, 133.4, 132.0, 131.9, 129.1,
3
3
3
2
16 19
1
1
26.0, 122.2, 120.6, 119.2, 118.9, 118.7, 118.1, 110.9, 109.5, 109.4,
[M + H − H O] 256.1400, found 256.1332.
2
01.8, 72.4 (CH), 68.3 (CH), 53.9 (C), 38.4 (CH), 29.0 (CH ), 27.1
(E)-4-(3-(2-Hydroxyethyl)-1H-indol-2-yl)-2-methylbut-3-en-2-ol
3
(
CH ), 25.7 (CH ), 18.3 (CH ), 8.7 (CH ), 7.7 (CH ); HRMS m/z
(28). To a solution of the tertiary alcohol 34 (1 g, 3.66 mmol) in
3
3
3
3
3
+
calcd for C H N O [M + H ] 413.2615, found 413.2592.
anhydrous ether (20 mL) was added LiAlH
°C. The mixture was stirred for 3 h at room temperature, quenched
with a solution of NH Cl, and extracted with EtOAc; the organic layer
was then washed with brine and dried over Na SO . Evaporation of
4
(167 mg, 4.39 mmol) at 0
28
32
2
3
-(2-Bromoethyl)-1H-indole (30). To a stirred solution of the
tryptophol 29 (250 mg, 1.55 mmol) in anhydrous CCl (10 mL) was
4
4
added freshly recrystallized NBS (N-bromosuccinimide; 304 mg, 1.70
mmol) in 100 mg portions. The mixture was refluxed for 1 h and
filtered, and the filtrate was concentrated under reduced pressure.
Purification of the residue on a silica gel column using EtOAc/hexane
2
4
the solvent and purification of the residue on silica gel column using
EtOAc/hexane (7/3) as eluent gave the alcohol 28 (750 mg, 75%) as a
−1
white semisolid: R
3329, 3053, 2973, 1613, 1457, 1378, 1150, 906, 741, 702; H NMR
(CD CN, 500 MHz) δ 9.11 (br s, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.1
= 0.35 (EtOAc/hexane 3/2); IR (neat) νmax/cm
f
1
(
1.5/8.5) as eluent gave the bromoethylindole 30 (230 mg, 67%) as a
1
yellow semisolid: R = 0.5 (EtOAc/hexane 1/4); H NMR (CDCl ,
3
f
3
5
7
2
00 MHz) δ 7.52 (br d, J = 7.8 Hz, 1H), 7.29 (br d, J = 8.0 Hz, 1H),
(d, J = 8.2 Hz, 1H), 6.91 (dt, J = 7.0, 7.9 Hz, 1H), 6.8 (dt, J = 7.9, 7.9
Hz, 1H), 6.53 (d, J = 16.2 Hz, 1H), 6.06 (d, J = 16.5 Hz, 1H), 3.48 (q,
J = 7.0, 6.1 Hz, 2H), 2.92, (s, 1H), 2.77 (t, J = 7.0 Hz, 2H), 2.66 (t, J =
.14 (br t, J = 8.0 Hz, 1H), 7.07 (br t, J = 7.7 Hz, 1H), 7.00 (br d, J =
13
.0 Hz, 1H), 3.56 (t, J = 7.7 Hz, 2H), 3.26 (t, J = 7.7 Hz, 2H);
C
5.8 Hz, 1H), 1.17 (s, 6H); 13C NMR (CD
CN, 125 MHz) δ 137.9
NMR (CDCl , 125 MHz) δ 136.1 (C), 126.9 (C), 122.2 (2 CH),
1
3
3
19.6 (CH), 118.4 (CH), 113.5 (C), 111.3 (CH), 32.9 (CH ), 29.3
(CH), 137.6 (C), 134.2 (C), 129.9 (C), 123.2 (CH), 119.9 (CH),
119.6 (CH), 115.7 (CH), 112.3 (C), 111.5 (CH), 71.5 (C), 63.3
2
(
CH2).
Methyl 2-(1H-Indol-3-yl)acetate (31). To a magnetically stirred
solution of the indole 3-acetic acid 31a (10 g, 57.14 mmol) in MeOH
250 mL) was added concentrated H SO (1.5 mL, 28.57 mmol)
(CH
), 30.4 (2 CH ), 28.5 (CH ); HRMS m/z calcd for C15H19NO
2
3
2
2
+
[M − H ] 244.1316, found 244.1333.
(
2-((6R,6aS,10aS)-6-(3-(2-Hydroxyethyl)-1H-indol-2-yl)-7,7,9-tri-
methyl-6a,7,8,10a-tetrahydro-6H-isoindolo[2,1-a]indol-11-yl)-
ethanol (35a), 2-((6S,6aS,10aS)-6-(3-(2-Hydroxyethyl)-1H-indol-2-
yl)-7,7,9-trimethyl-6a,7,8,10a-tetrahydro-6H-isoindolo[2,1-a]indol-
2
4
dropwise at room temperature; the mixture was stirred for 1 h. The
MeOH was evaporated, a saturated solution of NaHCO was added,
and this mixture was extracted with CH Cl . The organic layer was
then washed with brine and dried over Na SO . Evaporation of the
solvent and purification of the residue on a silica gel column using
EtOAc/hexane (2/8) as eluent gave the ester 31 (10 g, 92%) as a
white semisolid; R = 0.45 (EtOAc/hexane 3/7); IR (neat) νmax/cm
3
2
2
1
1-yl)ethanol (35b), 2-((1R,3R)-3-((E)-2-(3-(2-Hydroxyethyl)-1H-
2
4
indol-2-yl)vinyl)-3-methyl-1-(2-methylprop-1-enyl)-2,3-dihydro-1H-
pyrrolo[1,2-a]indol-9-yl)ethanol (36a), and 2-((1R,3S)-3-((E)-2-(3-(2-
Hydroxyethyl)-1H-indol-2-yl)vinyl)-3-methyl-1-(2-methylprop-1-
enyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)ethanol (36b). 35a: to
a solution of the alcohol 28 (500 mg, 2.04 mmol) in anhydrous
CH Cl (10 mL) was added a catalytic amount of BF ·OEt (28 mg,
−1
f
3
7
7
3
1
410 (NH), 3057, 2952, 1731 (OCO), 1457, 1338, 1166, 1010,
1
43, 584; H NMR (CDCl , 500 MHz) δ 8.25 (br s, 1H), 7.69 (d, J =
3
2
2
3
2
.6 Hz, 1H), 7.29−7.20 (m, 3H), 6.98 (s, 1H), 3.85 (s, 2H), 3.76 (s,
0.20 mmol), and the mixture was stirred magnetically for 15 min at
room temperature. The progress of the reaction was monitored by
TLC until the starting alcohol had been completely consumed. A
saturated solution of NaHCO3 (10 mL) was then added to the
reaction mixture, which was then extracted with CH Cl (3 × 10 mL),
H); 13C NMR (CDCl , 125 MHz) δ 172.8 (OCO), 135.9 (C),
3
26.9 (C), 123.2 (CH), 121.8 (CH), 119.3 (CH), 118.5 (CH), 111.2
(
CH), 107.6 (C), 51.8 (CH ), 30.9 (CH ); HRMS m/z calcd for
3 2
+
C H NO [M + H ] 190.0900, found 190.0867.
11
11
2
2
2
Methyl 2-(2-Bromo-1H-indol-3-yl)acetate (32). To a solution of
washed with brine (10 mL), and dried over Na SO . Evaporation of
2 4
the ester 31 (10 g, 52.91 mmol) in anhydrous CCl (200 mL) was
the solvent and purification of the residue on a silica gel column using
EtOAc/hexane (3/7) as eluent furnished the isomer 35a (165 mg,
4
added freshly recrystallized NBS (N-bromosuccinimide; 10.3 g, 58.21
mmol) in 1 g portions. The mixture was stirred at room temperature
for 1 h and was concentrated under reduced pressure. The purification
36%) as a white semisolid: R = 0.5 (EtOAc/hexane 3/7); IR (neat)
f
−1
1
νmax/cm 3377, 2922, 2851, 1457, 1298, 1149, 739; H NMR
J
dx.doi.org/10.1021/jo4013833 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
(
(
CD CN, 500 MHz) δ 9.16 (br s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.45
d, J = 7.9 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.10−7.03 (m, 2H), 6.86
t, J = 7.9, 7.0 Hz, 1H), 6.69 (t, J = 7.9, 7.3 Hz, 1H), 6.46 (d, J = 8.2
mmol) in ethyl acetate (10 mL) was added IBX (222 mg, 0.792
3
mmol), and the mixture was refluxed for 1 h. Aqueous NaHCO was
3
added to the reaction mixture, which was then extracted with ethyl
acetate (3 × 10 mL). The organic extract was washed with brine and
dried over Na SO . Evaporation of the solvent and purification of the
Hz, 1H), 5.53 (s, 1H), 5.52 (s, 1H), 4.11 (br s, 1H), 3.87−3.73 (m,
4
2
1
1
1
1
1
(
2
4
H), 3.12−3.05 (m, 3H), 2.99 (t, J = 7.0 Hz, 2H), 2.81 (br s, 1H),
2
4
.29−2.25 (br d, 1H), 1.78−1.72 (br d, 1H), 1.70 (s, 3H), 1.27 (s,
residue on a silica gel column using EtOAc/hexane (1/4) as eluent
H), 1.09 (s, 3H), 0.76 (s, 3H); 13C NMR (CD CN, 125 MHz) δ
furnished the dial 41 (72 mg, 80%) as a yellow waxy oil: R = 0.6
3
f
−
1
44.1 (C), 137.2 (C), 135.1 (C), 133.7 (C), 133.6 (C), 133.5 (C),
29.4 (C), 122.9 (CH), 120.9 (CH), 120.3 (CH), 120.1 (C and CH),
19.5 (CH), 119.4 (CH), 112.0 (CH), 111.9 (CH), 110.3 (CH),
02.9 (C), 63.3 (CH ), 62.9 (CH ), 59.2 (CH), 54.9 (CH), 41.2
(EtOAc/hexane 1/3); IR (neat) νmax/cm 3389, 2961, 2925, 1718
1
(CO), 1456, 1333, 1240, 1167, 1048, 740; H NMR (CD CN, 500
3
MHz) δ 9.75−9.73 (m, 2H), 9.39 (br s, 1H), 7.48 (d, J = 7.9 Hz, 1H),
7.39 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.15 (td, J = 8.2, 7.0
Hz, 1H), 7.08 (t, J = 7.9, Hz, 1H), 6.92 (t, J = 7.9 Hz, 1H), 6.77 (td, J
= 9.2, 7.9 Hz, 1H), 6.51 (d, J = 8.2 Hz, 1H), 5.54 (d, J = 8.5 Hz, 1H),
5.45−5.44 (m, 1H), 4.12−4.10 (m, 1H), 3.97 (s, 2H), 3.86 (t, J = 2.4
Hz, 2H), 3.14 (t, J = 7.9 Hz, 1H), 2.26 (br d, 1H), 1.78 (br d, 1H),
2
2
CH ), 37.9 (CH ), 32.7 (C), 29.3 (CH ), 29.1 (CH ), 29.0 (CH ),
2 3 2 2 3
+
7.7 (CH ), 24.0 (CH); HRMS m/z calcd for C H N O [M + H ]
3
30 34
2
2
55.2720, found 455.2697.
3
6a: further elution of the column with EtOAc/hexane (4/6) gave
1.70 (s, 3H), 1.09 (s, 3H), 0.76 (s, 3H); 13C NMR (CD CN, 125
the isomer 36a (140 mg, 31%) as a white semisolid: R = 0.4 (EtOAc/
f
3
−1
hexane 3/7); IR (neat) νmax/cm 3405, 2928, 1454, 1344, 1041, 741;
MHz) δ 200.4 (HCO), 200.3 (HCO), 145.4 (C), 137.2 (C),
136.1 (C), 134.2 (C), 133.5 (C), 133.4 (C), 129.2 (C), 123.5 (CH),
121.6 (CH), 120.6 (CH), 120.2 (CH), 119.9 (CH), 119.7 (CH),
119.2 (CH), 112.3 (CH), 110.5 (CH), 106.3 (C), 96.6 (C), 59.2, 55.0,
1
H NMR (CD CN, 500 MHz) δ 9.22 (br s, 1H), 7.51 (dd, J = 6.7, 2.4
3
Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.35 (dd, J = 5.5, 2.4 Hz, 1H), 7.23
(
d, J = 7.9 Hz, 1H), 7.06 (t, J = 8.2 Hz, 1H), 7.00−6.98 (m, 2H), 6.95
(
d, J = 7.3 Hz, 1H), 6.26 (d, J = 15.8 Hz, 1H), 6.00 (d, J = 16.2 Hz,
41.1, 40.2, 40.2, 37.9, 32.6, 28.8, 27.8, 24.0; HRMS m/z calcd for
+
1
2
2
6
(
(
(
H), 5.28 (d, J = 9.4 Hz, 1H), 4.22 (q, J = 8.8 Hz, 1H), 3.65 (br s,
H), 3.44 (br s, 2H), 2.83 (t, J = 7.3 Hz, 2H), 2.80−2.58 (m, 3H),
.26 (dd, J = 8.5, 3.9 Hz, 1H), 2.19 (br s, 1H), 1.92 (s, 3H), 1.77 (d,
C
30
H
30
N
2
O
2
[M + H ] 451.2400, found 451.2388.
Dimethylisoborreverine (6). To a mixture of NHMe
(0.26 mL, 2.0
2
M solution, 0.53 mmol) and NaCNBH (32 mg, 0.53 mmol) in
3
H); 13C NMR (CD CN, 125 MHz) δ 145.1 (C), 137.6 (C), 134.4
MeOH (2 mL) and acetic acid (0.01 mL) was added a solution of the
dialdehyde 41 (60 mg, 0.13 mmol) in MeOH (2 mL), and this mixture
was stirred for 12 h at room temperature. The reaction mixture was
3
C), 134.3 (C), 133.5 (C), 132.7 (C), 132.1 (CH), 129.6 (C), 126.0
CH), 123.5 (CH), 121.1 (CH), 120.0 (CH), 119.7 (CH), 119.6
CH), 119.5 (CH), 117.8 (CH), 113.2 (C), 111.6 (CH), 111.2 (CH),
quenched with a saturated solution of NaHCO
ethyl acetate (2 × 5 mL), washed with brine, and dried over Na
Evaporation of the solvent and purification of the residue on a silica gel
column using MeOH/CH Cl (1/9) as eluent furnished the
compound dimethylisoborreverine (6; 55 mg, 82%) as a white
and extracted with
3
1
2
04.1 (C), 64.8 (C), 63.6 (CH ), 63.2 (CH ), 51.9 (CH), 35.7 (CH ),
2
SO .
4
2
2
2
8.4 (CH ), 28.2 (CH ), 25.9 (2 CH ), 18.3 (CH3); HRMS m/z calcd
2
2
3
+
for C H N O [M + H ] 455.2720, found 455.2691.
2
2
30
34
2
2
3
6b: further elution of the column with EtOAc/hexane (2/3) gave
−1
the isomer 36b (30 mg, 7%) as a white semisolid: R = 0.35 (EtOAc/
hexane 2/3); IR (neat) νmax/cm 3319, 2925, 1454, 1317, 1041, 1011,
7
semisolid: R
2255, 1651, 1049, 1025, 1003, 826, 764, 631; H NMR (DMSO-d ,
6
f
= 0.3 (MeOH/CH Cl 1/9); IR (neat) νmax/cm 3427,
2 2
f
−1
1
1
41; H NMR (CDCl , 500 MHz) δ 8.26 (br s, 1H), 7.56 (d, J = 7.7
500 MHz) δ 11.01 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 7.9
Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.02 (t, J = 7.3 Hz, 1H), 6.96 (t, J =
7.3 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.63 (t, J = 7.6 Hz, 1H), 6.31 (d,
J = 8.2 Hz, 1H), 5.43 (br s, 1H), 5.35 (d, J = 9.2 Hz, 1H), 4.02 (br s,
3
Hz, 2H), 7.29 (d, J = 8.3 Hz, 1H), 7.25 (dd, J = 8.0, 3.4 Hz, 1H), 7.18
(
(
t, J = 7.7 Hz, 1H), 7.11−7.01 (m, 3H), 6.70 (d, J = 16.6 Hz, 1H), 6.29
d, J = 16.3 Hz, 1H), 5.27 (d, J = 9.4 Hz, 1H), 4.28 (q, J = 9.1 Hz,
1
2
0
H), 3.15 (t, J = 8.8 Hz, 1H), 2.87−2.83 (m, 4H), 2.59−2.45 (m, 5H),
1
H), 3.85−3.78 (m, 4H), 3.02−2.87 (m, 4H), 2.71 (dd, J = 8.0, 4.8
.24 (s, 6H), 2.13 (s, 6H), 1.69 (br d, 1H), 1.65 (s, 3H), 1.02 (s, 3H),
Hz, 1H), 2.38 (dd, J = 8.0, 4.5 Hz, 1H), 1.84 (s, 3H), 1.78 (s, 3H),
.69 (s, 3H); 13C NMR (DMSO-d , 125 MHz) δ 141.8 (C), 135.9
1
1
1
1
.76 (s, 3H); 13C NMR (CDCl , 125 MHz) δ 143.6 (C), 136.4 (C),
6
3
(
C), 132.9 (C), 131.9 (2 CH), 127.7 (C), 121.3, 119.7, 119.3, 118.6,
18.4 (2 CH), 118.2, 118.1, 111.2 (C), 111.1 (CH), 109.1 (CH),
02.8 (C), 60.3, 59.6, 57.0, 53.6, 45.2 (2 N−CH ), 45.1 (2 N−CH ),
33.5 (C), 133.2 (C), 132.4 (CH), 132.3 (C), 131.3 (C), 128.6 (C),
25.0 (CH), 123.2 (CH), 120.5 (CH), 119.7 (CH), 118.9 (CH),
18.8 (CH), 118.7 (CH), 118.1 (CH), 112.2 (C), 110.6 (CH), 109.9
1
1
3
2
5
3
3
9.3 (CH , merged in DMSO-d ), 36.4, 31.4, 28.4, 27.3, 23.7, 22.5,
(
(
CH), 102.4 (C), 63.2 (CH ), 63.0 (CH ), 62.9 (C), 51.7 (CH ), 35.2
2
6
2
2
2
+
2.3; HRMS m/z calcd for C H N [M + H ] 509.3666, found
CH ), 27.6 (CH ), 27.3 (CH ), 25.7 (CH ), 23.2 (CH ), 18.1 (CH);
34 44
4
3
2
2
3
3
+
09.3644.
HRMS m/z calcd for C H N O [M + H ] 455.2720, found
30
34
2
2
1
Dimethylisoborreverine (6): H NMR (CDCl , 500 MHz) δ 8.46
4
55.2693.
5b: again, further elution of the column with EtOAc/hexane (7/3)
gave the isomer 35b (35 mg, 8%) as a yellow semisolid: R = 0.3
3
(
7
6
br s, 1H), 7.66 (dd, J = 8.8, 4.5 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H),
.21−7.14 (m, 3H), 6.96 (t, J = 7.6 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H),
.49 (d, J = 8.2 Hz, 1H), 5.47 (br s, 1H), 5.45 (d, J = 8.9 Hz, 1H), 4.05
3
f
−
1
(
EtOAc/hexane 1/1); IR (neat) νmax/cm 3374, 2926, 1457, 1376,
299, 1010, 739; H NMR (CD CN, 500 MHz) δ 9.06 (br s, 1H),
1
(
(
0
1
1
1
br s, 1H), 3.13−3.00 (m, 5H), 2.82−2.66 (m, 4H), 2.40 (s, 6H), 2.37
1
7
1
7
5
3
3
s, 6H), 2.19 (br d, 1H), 1.79 (br d, 1H), 1.71 (s, 3H), 1.11 (s, 3H),
.60 (d, J = 7.0 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 7.3 Hz,
H), 7.08−7.01 (m, 2H), 6.84 (td, J = 7.9, 7.0, Hz, 1H), 6.67 (td, J =
.8, 7.0 Hz, 1H), 6.40 (d, J = 8.2 Hz, 1H), 5.99 (d, J = 9.4 Hz, 1H),
.39 (dt, J = 11.3, 2.4 Hz, 1H), 4.45 (dd, J = 11.0, 3.9 Hz, 1H), 3.91−
.80 (m, 2H), 3.64−3.57 (m, 2H), 3.31 (dd, J = 9.4, 7.3 Hz, 1H), 3.14
.81 (s, 3H); 13C NMR (CDCl , 125 MHz) δ 142.2 (C), 136.3 (C),
3
33.3 (C), 132.7 (C), 132.6 (C), 132.2 (C), 128.1 (C), 122.2 (CH),
20.7 (CH), 119.3 (CH), 119.0 (2 CH), 118.9 (CH), 118.3 (CH),
12.2 (C), 111.4 (CH), 109.8 (CH), 103.1 (C), 60.4 (CH ), 60.0
2
(
4
CH ), 59.0 (CH), 53.8 (CH), 45.5 (2 N−CH ), 45.5 (2 N−CH ),
(
t, J = 6.7 Hz, 2H), 3.08 (br s, 1H), 2.96 (s, 1H), 2.81 (td, J = 7.3, 3.0
2
3
3
1.0 (CH ), 37.2 (CH), 32.0 (C), 28.9 (CH ), 27.4 (CH ), 24.0
Hz, 2H), 2.62 (br s, 1H), 1.88 (s, 3H), 1.26 (s, 3H), 1.24 (m, 1H),
2
3
3
.00 (s, 3H); 13C NMR (CD CN, 125 MHz) δ 144.4 (C), 137.4 (C),
3 2 2
(
CH ), 23.5 (CH ), 23.0 (CH ).
Dimethylisoborreverine (6), TFA Salt. Dimethylisoborreverine (6;
1
1
1
1
3
35.2 (C), 133.5 (C), 133.4 (C), 131.6 (C), 129.1 (C), 123.7 (CH),
22.9 (CH), 120.9 (CH), 120.0 (CH), 119.9 (CH), 119.4 (CH),
19.3 (CH), 112.5 (C), 112.0 (CH), 110.2 (CH), 102.9 (C), 72.0
1
0 mg) was treated with a 0.5 M solution of TFA in acetonitrile to
1
obtain the TFA salt of dimethylisoborreverine: H NMR (DMSO-d ,
6
5
00 MHz) δ 11.21 (br s, 1H), 10.20 (br s, 1H, TFA proton), 10.10 (br
(
CH), 64.9 (CH), 63.1 (CH ), 62.8 (CH ), 54.0 (CH), 39.4 (CH ),
2
2
2
s, 1H, TFA proton), 7.67 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H),
3
0.1 (C), 29.0 (CH ), 28.5 (CH ), 28.1 (CH ), 26.0 (CH ), 18.1
2 2 3 3
+
7
7
.28 (d, J = 7.9 Hz, 1H), 7.09 (dd, J = 7.6, 7.3 Hz, 1H), 7.02 (dd, J =
.6, 7.0 Hz, 1H), 6.88 (dd, J = 7.3, 7.3 Hz, 1H), 6.71 (dd, J = 7.6, 7.3
(
CH ); HRMS m/z calcd for C H N O [M + H ] 455.2720, found
3
30 34
2
2
4
55.2692.
Hz, 1H), 6.22 (d, J = 7.9 Hz, 1H), 5.49 (d, J = 9.5 Hz, 1H), 5.46 (m,
1H), 4.11 (br s, 1H), 3.40−3.26 (m, 2H), 3.25−2.90 (m, 8H), 2.92 (s,
6H), 2.82 (s, 6H), 2.28 (d, J = 14.0 Hz, 1H), 1.69 (br s, 3H), 1.04 (s,
2
-(2-((6R,6aS,10aS)-7,7,9-Trimethyl-11-(2-oxoethyl)-6a,7,8,10a-
tetrahydro-6H-isoindolo[2,1-a]indol-6-yl)-1H-indol-3-yl)-
acetaldehyde (41). To a solution of the alcohol 35a (90 mg, 0.198
K
dx.doi.org/10.1021/jo4013833 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3
1
1
H), 0.69 (s, 3H); 13C NMR (CDCl , 125 MHz) δ 142.9, 135.8,
33.9, 132.1, 131.8, 131.3, 126.9, 121.7, 120.2, 118.9, 118.7, 118.5,
18.5, 118.1, 111.3, 108.9, 107.2, 99.0, 57.1, 56.6, 56.1, 53.5, 42.1 (2
7.05−6.96 (m, 3H), 6.36 (d, J = 16.0 Hz, 1H), 6.07 (d, J = 16.3 Hz,
1H), 5.23 (dt, J = 9.7, 2.8 Hz, 1H), 4.23 (q, J = 8.6 Hz, 1H), 3.66−3.60
(m, 4H), 2.84 (dd, J = 8.0, 4.6 Hz, 1H), 2.31 (dd, J = 8.6, 4.0 Hz, 1H),
3
N−CH ), 41.9 (N−CH ), 41.8 (N−CH ), 39.0 (CH ), 38.9 (CH),
3
1.94 (s, 3H), 1.75 (s, 3H), 1.74 (s, 3H); 13C NMR (CD CN, 125
3
3
3
2
3
6.2 (C), 31.4 (CH ), 28.2 (CH ), 27.4 (CH ), 23.5 (CH ), 19.3
MHz) δ 200.7 (HCO), 199.8 (HCO), 146.3 (C), 137.6 (C),
135.1 (C), 134.4 (C), 134.2 (C), 133.5 (CH), 132.7 (C), 129.6 (C),
125.4 (CH), 123.9 (CH), 121.6 (CH), 120.6 (CH), 120.1 (CH),
119.5 (CH), 119.4 (CH), 117.4 (CH), 111.8 (CH), 111.4 (CH),
106.5 (C), 97.7 (C), 65.2 (C), 51.7 (CH), 39.7 (CH ), 39.5 (CH ),
3
3
3
2
(
CH2).
Isoborreverine (5). To a stirred solution of dialdehyde 41 (60 mg,
0
.13 mmol) and methylamine (0.33 mL, 2.0 M solution, 0.66 mmol)
in CH Cl (6 mL) was added NaBH (25 mg, 0.66 mmol) followed by
2
2
4
2
2
Fe(OTf) (20 mg, 0.04 mmol) sequentially, and the mixture was
35.8 (CH ), 25.8 (CH ), 25.8 (CH ), 18.4 (CH ); HRMS m/z calcd
for C H N O [M + H ] 451.2400, found 451.2386.
30 30 2 2
3
2 3 3 3
+
stirred for 5−10 min at room temperature. Thereafter, MeOH (1 mL)
was added to drive the reaction to completion. After completion of the
reaction (TLC), the reaction was quenched with a saturated solution
of NaHCO and extracted with CH Cl (2 × 10 mL), washed with
Flinderole A (1). To a stirred solution of dialdehyde 42a (30 mg,
0.066 mmol) and methylamine (0.16 mL, 2.0 M solution, 0.33 mmol)
in CH Cl (3 mL) was added NaBH (12 mg, 0.33 mmol) followed by
3
2
2
2
2
4
brine, and dried over Na SO . Evaporation of the solvent and
Fe(OTf) (10 mg, 0.02 mmol) sequentially, and the mixture was
2
4
3
purification of the residue on a silica gel column using MeOH/CH Cl
stirred for 5−10 min at room temperature. Thereafter, MeOH (1 mL)
was added to drive the reaction to completion. After completion of the
reaction (TLC), the reaction mixture was quenched with a saturated
solution of NaHCO and extracted with CH Cl (2 × 5 mL), washed
2
2
(
8
1.5/8.5) as eluent furnished the compound isoborreverine (5; 57 mg,
9%) as a yellow solid: R = 0.3 (MeOH/CH Cl 1/4); mp 107−109
f
2
2
−
1
1
°
C; IR (neat) ν /cm 3428, 1651, 1026, 1004, 826, 764; H NMR
max
3
2
2
(
DMSO-d , 500 MHz) δ 11.05 (br s, 1H), 7.56 (d, J = 7.6 Hz, 1H),
with brine, and dried over Na SO . Evaporation of the solvent and
6
2 4
7.41 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.03 (t, J = 7.6, Hz,
purification of the residue on a silica gel column using MeOH/CH Cl
2 2
1
H), 6.97 (t, J = 7.6, Hz, 1H), 6.81 (t, J = 7.6 Hz, 1H), 6.64 (t, J = 7.9
(1.5/8.5) as eluent furnished the compound flinderole A (1; 24 mg,
75%) as a white semisolid: R = 0.3 (MeOH−CH Cl 1:4); IR (neat)
Hz, 1H), 6.28 (d, J = 8.2 Hz, 1H), 5.44 (s, 1H), 5.39 (d, J = 9.2 Hz,
f
2
2
−1
1
2
H), 4.04 (s, 1H), 3.14 (br t, 1H), 2.93−2.74 (m, 8H), 2.46 (s, 6H),
ν
/cm 3419, 2256, 2129, 1651, 1048, 1025, 1001, 826, 765, 631;
max
.42 (s, 2H), 1.66 (s, 3H), 1.01 (s, 3H), 0.68 (s, 3H); 13C NMR
1
H NMR (DMSO-d , 500 MHz) δ 10.94 (s, 1H), 7.46 (dd, J = 7.0, 1.8
6
(
(
DMSO-d , 125 MHz) δ 143.0 (C), 136.7 (C), 134.0 (C), 132.8
CH), 132.7 (C), 128.5, 122.1, 120.5, 120.0, 119.5, 119.2, 119.0 (2
Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.34 (dd, J = 6.4, 1.5 Hz, 1H), 7.18
(d, J = 8.2 Hz, 1H), 7.00 (t, J = 7.9 Hz, 1H), 6.97−6.91 (m, 2H), 6.87
(t, J = 7.0 Hz, 1H), 6.40 (d, J = 16.2 Hz, 1H), 6.07 (d, J = 16.2 Hz,
1H), 5.25 (d, J = 9.7 Hz, 1H), 4.15 (q, J = 8.9, Hz, 1H), 3.35 (br t, J =
6
CH), 118.9, 111.9 (C and CH), 109.8 (CH), 103.0 (C), 57.8 (CH),
2.7 (CH), 52.6 (2 CH ), 37.2 (CH ), 36.3 (CH), 36.3 (2 CH ), 32.2
5
2
2
3
(
C), 29.2 (CH ), 28.1 (CH ), 25.0 (CH ), 24.8 (CH ), 24.4 (CH );
5.2 Hz, 1H), 2.78−2.60 (m, 8H), 2.29 (s, 3H), 2.25 (dd, J = 8.8, 3.9
3
3
2
2
3
+
13
HRMS m/z calcd for C H N [M + H ] 481.3400, found 481.3335.
Hz, 1H), 2.15 (s, 3H), 1.90 (s, 3H), 1.76 (s, 3H), 1.73 (s, 3H);
C
32
40
4
Isoborreverine (5), TFA Salt. Isoborreverine (5; 10 mg) was treated
NMR (DMSO-d , 125 MHz) δ 142.9 (C), 136.4 (C), 132.7 (C), 132.4
6
with a 0.5 M solution of TFA in acetonitrile to obtain the TFA salt of
isoborreverine: H NMR (DMSO-d , 500 MHz) δ 11.13 (br s, 1H),
7
(C), 131.9 (C), 131.1 (CH), 131.0 (C), 128.1 (C), 125.1 (CH), 122.0
(CH), 119.9 (CH), 118.5 (CH), 118.4 (CH), 118.4 (CH), 118.3
(CH), 116.5 (CH), 112.5 (C), 110.1 (CH), 110.0 (CH), 103.6 (C),
63.4 (C), 60.7 (CH ), 52.4 (CH ), 50.8 (CH ), 35.6 (N−CH ), 35.5
1
6
.63 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.24 (d, J = 7.9 Hz,
H), 7.06 (t, J = 7.6, Hz, 1H), 7.00 (t, J = 7.6, Hz, 1H), 6.85 (t, J = 7.9
1
2
2
2
3
Hz, 1H), 6.68 (t, J = 7.9 Hz, 1H), 6.18 (d, J = 8.2 Hz, 1H), 5.44 (s,
H), 5.41 (d, J = 9.2 Hz, 1H), 4.06 (s, 1H), 3.16−3.03 (m, 8H), 2.66
(N−CH ), 34.4 (CH), 29.2 (CH ), 25.5 (CH ), 25.1 (CH ), 23.4
3
2
3
3
+
1
(CH ), 18.0 (CH ); HRMS m/z calcd for C H N [M + H ]
2 3 32 40 4
(
br t, 3H), 2.58 (s, 3H), 2.45 (s, 2H), 2.24 (br d, 1H), 1.67 (s, 3H),
481.3353, found 481.3333.
Flinderole A (1), TFA Salt. Flinderole A (1; 10 mg) was treated with
1
1
1
.01 (s, 3H), 0.65 (s, 3H); 13C NMR (DMSO-d , 125 MHz) δ 143.4,
6
34.3, 132.8, 132.5, 132.1, 122.3, 120.8, 119.5, 119.3, 119.2, 119.1,
18.6, 118.2, 115.9, 111.9, 109.5, 100.1 (2 C), 57.6 (CH), 49.3 (2
a 0.5 M solution of TFA in acetonitrile to obtain the TFA salt of
1
flinderole A: H NMR (DMSO-d , 500 MHz) δ 11.24 (br s, 1H), 8.78
6
CH ), 48.8 (CH), 36.9 (CH ), 32.9 (CH and CH ), 32.8 (2 CH ),
(m, 2H), 7.58 (d, J = 7.7 Hz, 1H), 7.54 (br d, J = 8.0 Hz, 1H), 7.43 (d,
J = 7.4 Hz, 1H), 7.25 (br d, J = 7.7 Hz, 1H), 7.08 (dd, J = 7.7, 7.7 Hz,
1H), 7.04 (dd, J = 6.3, 6.3 Hz, 1H), 7.02 (dd, J = 6.3, 6.3 Hz, 1H), 6.98
(dd, J = 7.4, 7.4 Hz, 1H), 6.58 (d, J = 16.3 Hz, 1H), 6.52 (d, J = 16.3
Hz, 1H), 5.32 (d sept, J = 8.9, 1.2 Hz, 2H), 4.30 (ddd, J = 8.9, 8.3, 8.0
Hz, 1H), 2.99 (m, 2H), 2.90 (dd, J = 12.9, 8.0 Hz, 2H), 2.90 (br t, J =
2
2
3
3
3
7
2.0, 28.8, 27.9, 24.1, 21.5.
1
Isoborreverine (5): H NMR (CDCl , 400 MHz) δ 8.85 (br s, 1H),
3
.69 (m, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.14 (m, 3H), 6.96 (t, J = 7.6
Hz, 1H), 6.77 (t, J = 7.9, Hz, 1H), 6.45 (d, J = 8.2, Hz, 1H), 5.47 (br s,
1
H), 5.45 (s, 1H), 4.06 (br s, 1H), 3.30−2.80 (m, 10H), 2.47 (s, 3H),
.39 (s, 3H), 2.19 (br d, 1H), 1.70 (s, 3H), 1.10 (s, 3H), 0.81 (s, 3H);
2
8.0 Hz, 1H), 2.62 (br t, 3H), 2.57 (m, 1H), 2.56 (br t, 3H), 2.31 (dd, J
1
3
13
C NMR (CDCl , 100 MHz) δ 143.4 (C), 136.8 (C), 134.0 (C),
= 12.6, 7.7 Hz, 1H), 1.96 (s, 3H), 1.85 (s, 3H), 1.80 (s, 3H);
C
3
1
1
1
33.3 (C), 133.2 (C), 132.8 (C), 128.9 (C), 122.8 (CH), 121.3 (CH),
19.9 (CH), 119.6 (CH), 119.6 (CH), 119.6 (CH), 119.0 (CH),
12.7, 111.8, 110.2 (CH), 103.1 (C), 59.6 (CH), 54.5 (CH), 53.1
NMR (DMSO-d , 125 MHz) δ 143.6, 136.4, 133.1, 132.4, 132.2,
6
132.1, 130.9, 127.6, 124.9, 122.4, 120.3, 118.8, 118.6, 118.3, 118.2,
116.4, 110.8, 110.1, 109.2, 100.3, 63.3 (C), 50.6 (CH ), 48.8 (CH ),
2
2
(
(
(
CH ), 52.6 (CH ), 41.5 (CH ), 37.7 (CH), 37.0 (N−CH ), 36.6
34.5, 32.4 (CH), 32.3 (2 N−CH ), 25.4 (CH ), 24.6 (CH ), 20.3
2
2
2
3
3
2
3
N−CH ), 32.5 (C), 29.5 (CH ), 28.0 (CH ), 26.0 (CH ), 25.1
(CH ), 20.2 (CH ), 18.0 (CH ).
3
3
3
2
3 2 3
CH ), 24.5 (CH ).
Flinderole B (2). To a mixture of NHMe (0.26 mL, 2.0 M solution,
2
3
2
2
-((1R,3R)-3-Methyl-1-(2-methylprop-1-enyl)-3-((E)-2-(3-(2-ox-
0.53 mmol) and NaCNBH (32 mg, 0.53 mmol) in MeOH (2 mL)
and acetic acid (0.01 mL) was added a solution of the dialdehyde 42a
3
oethyl)-1H-indol-2-yl)vinyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-
yl)acetaldehyde (42a). To a solution of the alcohol 36a (30 mg, 0.066
mmol) in ethyl acetate (5 mL) was added IBX (74 mg, 0.264 mmol),
(
60 mg, 0.13 mmol) in MeOH (2 mL), and this mixture was stirred
for 12 h at room temperature. The reaction mixture was quenched
and the mixture was refluxed for 1 h. Aqueous NaHCO was added to
the reaction mixture, which was then extracted with ethyl acetate (3 ×
mL). The organic extract was washed with brine and dried over
3
with a saturated solution of NaHCO and extracted with ethyl acetate
3
(
2 × 5 mL), washed with brine, and dried over Na SO . Evaporation
2 4
5
of the solvent and purification of the residue on a silica gel column
Na SO . Evaporation of the solvent and purification of the residue on a
2
4
using MeOH/CH Cl2 (1/9) as eluent furnished the compound
2
silica gel column using EtOAc/hexane (1/4) as eluent furnished the
compound 42a (22 mg, 74%) as a yellow semisolid: R = 0.6 (EtOAc/
flinderole B (2; 58 mg, 85%) as a white waxy solid: R = 0.4 (MeOH/
f
f
CH Cl 1/4).
2
2
−1
hexane 1/3); IR (neat) νmax/cm 3390, 2923, 1720 (CO), 1454,
2-((1R,3S)-3-Methyl-1-(2-methylprop-1-enyl)-3-((E)-2-(3-(2-ox-
oethyl)-1H-indol-2-yl)vinyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-
yl)acetaldehyde (42b). To a solution of the alcohol 36b (100 mg,
0.22 mmol) in ethyl acetate (10 mL) was added IBX (246 mg, 0.88
1
1
9
7
344, 741; H NMR (CD CN, 500 MHz) δ 9.60 (t, J = 2.3 Hz, 1H),
3
.45 (t, J = 2.0 Hz, 1H), 9.4 (br s, 1H), 7.42−7.35 (ddd, J = 13.2, 9.4,
.7 Hz, 3H), 7.27 (d, J = 8.3 Hz, 1H), 7.11 (td, J = 8.0, 7.2 Hz, 1H),
L
dx.doi.org/10.1021/jo4013833 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
mmol), and the mixture was refluxed for 1 h. Aqueous NaHCO was
746, 601, 571; H NMR (CDCl , 500 MHz) δ 7.98 (d, J = 8.2 Hz,
3
3
added to the reaction mixture, which was then extracted with ethyl
acetate (3 × 10 mL). The organic extract was washed with brine and
dried over Na SO . Evaporation of the solvent and purification of the
1H), 7.84 (d, J = 7.3 Hz, 2H), 7.47 (t, J = 7.9 Hz, 2H), 7.38−7.36 (m,
3H), 7.30 (t, J = 7.9 Hz, 1H), 7.21 (br t, J = 7.0 Hz, 1H), 4.96 (br s,
1H), 4.09 (br d, J = 6.1 Hz, 2H), 3.43 (br d, J = 5.2 Hz, 2H), 2.85 (br
2
4
s, 2H), 1.20 (br s, 3H); 13C NMR (CDCl , 125 MHz) δ 156.5 (OC
residue on a silica gel column using EtOAc/hexane (3/7) as eluent
3
furnished the dial 42b (80 mg, 81%) as a white semisolid: R = 0.6
O), 137.8 (C), 135.1 (C), 133.6 (CH), 130.6 (C), 129.1 (2 CH),
126.5 (2 CH), 124.7 (CH), 123.2 (CH), 123.1 (CH), 119.9 (C),
119.3 (CH), 113.5 (CH), 60.6 (CH ), 40.0 (CH ), 25.4 (CH ), 14.5
f
−1
(
(
(
EtOAc/hexane 3/7); IR (neat) νmax/cm 3385, 2926, 2722, 1721
1
CO), 1454, 1343, 1079, 742; H NMR (CDCl , 500 MHz) δ 9.69
3
2
2
2
+
t, J = 2.7 Hz, 1H), 9.65 (t, J = 2.4 Hz, 1H), 8.25 (br s, 1H), 7.49 (dd, J
(CH ); HRMS m/z calcd for C H N O S [M + H ] 373.1200,
3
19 20
2
4
=
=
7.6, 7.0 Hz, 2H), 7.30−7.21 (m, 3H), 7.15−7.05 (m, 3H), 6.71 (d, J
found 373.1221.
16.5 Hz, 1H), 6.36 (d, J = 16.2 Hz, 1H), 5.21 (d, J = 9.4 Hz, 1H),
Ethyl 2-(2-Formyl-1-(phenylsulfonyl)-1H-indol-3-yl)-
ethylcarbamate (46). To a magnetically stirred solution of the
4
(
1
.30 (q, J = 8.5 Hz, 1H), 3.83 (d, J = 2.4 Hz, 2H), 3.66 (s, 2H), 2.72
dd, J = 7.9, 4.8 Hz, 1H), 2.40 (dd, J = 8.8, 3.9 Hz, 1H), 1.82 (s, 3H),
.78 (s, 3H), 1.77 (s, 3H); 13C NMR (CDCl , 125 MHz) δ 199.9
protected tryptamine 45 (10 g, 26.9 mmol) in CH
added dichloromethyl methyl ether (12 mL, 134.4 mmol) followed by
dropwise addition of SnCl
mixture was then warmed slowly to −10 °C over a period of 1 h. HCl
(1.0 N, 100 mL) was added to the reaction mixture, which was then
extracted with CH Cl . The organic layer was then washed with brine
Cl (100 mL) was
2 2
3
(
CHO), 198.6 (CHO), 144.3 (C), 136.3 (C), 134.4 (C), 133.6 (CH),
4
(15.7 mL, 134.4 mmol) at −78 °C; the
1
1
1
5
33.0 (C), 132.8 (C), 131.3 (C), 128.7 (C), 124.1 (CH), 123.8 (CH),
20.9 (CH), 120.4 (CH), 119.5 (CH), 118.6 (CH), 118.4 (CH),
17.8 (CH), 110.8 (CH), 110.0 (CH), 105.9 (C), 96.5 (C), 63.3 (C),
1.7 (CH ), 39.4 (CH ), 38.9 (CH ), 35.3 (CH ), 25.7 (CH ), 22.9
2
2
and dried over Na SO . Evaporation of the solvent and recrystalliza-
tion of the crude product from 1,2-dichloroethane furnished the
2
2
2
3
3
2
4
+
(
CH ), 18.3 (CH); HRMS m/z calcd for C H N O [M + H ]
3
30 30
2
2
4
51.2407, found 451.2389.
aldehyde 46 (8 g, 74%) as a white semisolid: R = 0.3 (EtOAc/hexane
f
−1
Desmethyl Flinderole C. To a stirred solution of dialdehyde 42b
30 mg, 0.066 mmol) and methylamine (0.16 mL, 2.0 M solution, 0.33
mmol) in CH Cl (3 mL) was added NaBH (12 mg, 0.33 mmol)
3/7); IR (neat) νmax/cm 3425, 2982, 1705 (HCO), 1418, 1349,
1
(
1171, 1016, 721, 593; H NMR (CDCl , 500 MHz) δ 8.91 (s, 1H),
3
7.60 (m, 3H), 7.43 (t, J = 7.7, 8.0 Hz, 1H), 7.29 (t, J = 8.3, 7.1 Hz,
3H), 7.13−7.08 (m, 2H), 6.30 (br s, 1H), 4.12 (q, J = 6.8 Hz, 2H),
3.87 (t, J = 8.0 Hz, 1H), 2.83 (br s, 1H), 2.20 (q, J = 8.3 Hz, 1H), 1.98
2
2
4
followed by Fe(OTf)3 (10 mg, 0.02 mmol) sequentially, and the
mixture was stirred for 5−10 min at room temperature. Thereafter,
methanol (1 mL) was added to drive the reaction to completion. After
completion of the reaction (TLC), the reaction mixture was quenched
with a saturated solution of NaHCO and extracted with CH Cl (2 ×
(dd, J = 7.1, 5.1 Hz, 1H), 1.25 (br s, 3H); 13C NMR (CDCl , 125
3
MHz) δ 194.3 (CHO), 153.7 (NHCO), 142.2 (2 C), 137.1 (2 C),
133.2 (CH), 129.8 (2 CH), 128.8 (2 CH), 126.8 (2 CH), 125.7 (C),
124.4 (CH), 79.3 (CH), 61.8 (CH ), 44.8 (CH ), 33.3 (CH ), 14.2
3
2
2
5
mL), washed with brine, and dried over Na SO . Evaporation of the
2 4
2
2
2
+
solvent and purification of the residue on a silica gel column using
(CH ); HRMS m/z calcd for C H N O S [M + H ] 401.1200,
3
20 20
2
5
MeOH/CH Cl2 (1.5/8.5) as eluent furnished the compound
found 401.1170.
2
desmethyl flinderole C (22 mg, 69%) as a white semisolid: R = 0.3
(E)-Ethyl 3-(3-(2-(Ethoxycarbonylamino)ethyl)-1-(phenylsulfon-
f
−1
(
1
MeOH/CH Cl 1/4); IR (neat) νmax/cm 2921, 2851, 1575, 1456,
yl)-1H-indol-2-yl)acrylate (47). To a solution of the aldehyde 46
2
2
1
377, 1259, 1097, 802, 742; H NMR (DMSO-d , 500 MHz) δ 11.03
(10 g, 25 mmol) in anhydrous CH
Cl (100 mL) was added dry
2 2
6
(
s, 1H), 7.49 (br d, J = 7.9 Hz, 1H), 7.47−7.45 (m, 1H), 7.26−7.24
Ph Et (17 g, 50 mmol), and the mixture was stirred
3
PCHCO
2
(
m, 1H), 7.23 (br d, J = 8.2 Hz, 1H), 7.06 (td, J = 8.2, 7.0 Hz, 1H),
magnetically for 6 h at room temperature. Evaporation of the solvent
and purification of the residue on silica gel column using EtOAc/
hexane (3/7) as eluent gave the ester 47 (9.5 g, 81%) as a white
6
1
8
.96−6.92 (m, 3H), 6.73 (d, J = 16.2 Hz, 1H), 6.58 (d, J = 16.2 Hz,
H), 5.26 (d, J = 9.4 Hz, 1H), 4.33 (q, J = 9.4 Hz, 1H), 2.86 (br t, J =
.5, 5.5 Hz, 2H), 2.75−2.60 (m, 8H), 2.32 (s, 3H), 2.28 (s, 3H), 1.83
crystalline solid: R = 0.45 (EtOAc -hexane 2:3); mp 75−77 °C; IR
f
s, 3H), 1.75 (s, 3H), 1.71 (s, 3H); 13C NMR (DMSO-d , 125 MHz)
−1
(
(neat) νmax/cm 2980, 1712 (OCO), 1653 (NHCO), 1416,
6
1
δ 142.6 (C), 136.5 (C), 132.8 (C), 132.4 (CH), 132.2 (C), 132.0 (C),
30.8 (C), 128.2 (C), 125.4 (CH), 122.2 (CH), 119.8 (CH), 118.6
CH), 118.5 (CH), 118.4 (CH), 118.2 (CH), 117.9 (CH), 113.0 (C),
10.7 (CH), 109.8 (CH), 103.7 (C), 62.7 (C), 52.7 (CH ), 52.6
1367, 1110, 756, 689, 594; H NMR (CDCl , 500 MHz) δ 7.62 (d, J =
3
1
(
8.0 Hz, 1H), 7.54 (br s, 2H), 7.32−7.25 (m, 2H), 7.22 (t, J = 7.7 Hz,
2H), 7.10 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 7.4 Hz, 1H), 6.52 (d, J =
15.7 Hz, 1H), 5.88 (br s, 1H), 4.88 (d, J = 15.7 Hz, 1H), 4.14 (q, J =
7.1, 6.8 Hz, 2H), 4.03 (br q, 2H), 3.80 (dd, J = 7.4, 3.4 Hz, 1H), 2.79
1
2
(
CH ), 51.0 (CH ), 35.8 (2 N−CH ), 34.7 (CH), 25.5 (CH ), 23.8
2
2
3
3
(
CH ), 23.6 (CH ), 22.8 (CH ), 18.0 (CH ); HRMS m/z calcd for
(td, J = 5.7, 5.4 Hz, 1H), 2.09−2.00 (m, 2H), 1.26 (br t, 3H), 1.19 (t, J
2
2
3
3
+
13
C H N [M + H ] 481.3353, found 481.3337.
= 7.2 Hz, 3H); C NMR (CDCl , 125 MHz) δ 165.2 (OCO),
32
40
4
3
Flinderole C (3). To a mixture of NHMe (0.26 mL, 2.0 M solution,
154.0 (NHCO), 146.6 (CH), 142.0 (2 C), 137.9 (2 C), 133.1
(CH), 132.4 (C), 129.4 (CH), 128.7 (2 CH), 127.1 (CH), 125.7
(CH), 124.6 (CH), 121.9 (CH), 118.5 (CH), 83.2 (CH), 61.8 (CH2),
60.3 (CH ), 45.5 (2 CH ), 14.3 (CH ), 14.0 (CH ); HRMS m/z calcd
2
0
.53 mmol) and NaCNBH (32 mg, 0.53 mmol) in MeOH (2 mL)
3
and acetic acid (0.01 mL) was added a solution of the dialdehyde 42b
60 mg, 0.13 mmol) in MeOH (2 mL), and this mixture was stirred
(
2
2
3
3
+
for 12 h at room temperature. The reaction mixture was quenched
for C H N O S [M + H ] 471.1600, found 471.1592.
24 26 2 6
with a saturated solution of NaHCO and extracted with ethyl acetate
(E)-Ethyl 2-(2-(3-Hydroxy-3-methylbut-1-enyl)-1-(phenylsulfon-
yl)-1H-indol-3-yl)ethylcarbamate (48). To a cold (0 °C), magneti-
cally stirred solution of the ester 47 (11 g, 23.4 mmol) in anhydrous
ether (100 mL) was added methylmagnesium iodide (prepared from
magnesium turnings (2.8 g, 117.0 mmol), methyl iodide (8.7 mL,
140.4 mmol), and a few crystals of iodine in anhydrous ether (100
mL)), and the mixture was stirred for 2 h at room temperature. The
3
(
2 × 5 mL), washed with brine, and dried over Na SO . Evaporation
2 4
of the solvent and purification of the residue on a silica gel column
using MeOH/CH Cl (1/9) as eluent furnished flinderole C (3; 55
2
2
mg, 81%) as a colorless waxy solid: R = 0.4 (MeOH/CH Cl 1/4).
f
2
2
Ethyl 2-(1-(Phenylsulfonyl)-1H-indol-3-yl)ethylcarbamate (45).
To a magnetically stirred solution of the tryptamine acetate 44a (12
g, 51.7 mmol) in THF (120 mL) was added KOH powder (14.5 g,
reaction mixture was then quenched with aqueous NH Cl solution
4
2
58.6 mmol) followed by dropwise addition of PhSO Cl (19.8 mL,
(100 mL) and worked up. Evaporation of the solvent and purification
of the residue on a silica gel column using EtOAc/hexane (9/1) as
eluent furnished the tertiary alcohol 48 (8 g, 75%) as a thick yellowish
2
155.2 mmol) at 0 °C, and the mixture was stirred magnetically for 6 h
at room temperature. Water (100 mL) was then added to the reaction
mixture, which was then extracted with EtOAc (3 × 100 mL), washed
with brine (100 mL), and dried over Na SO . Evaporation of the
−1
semisolid: R = 0.3 (EtOAc only); IR (neat) ν /cm 3416, 2974,
f
max
1
1702 (NHCO), 1417, 1349, 1197, 690, 591, 542; H NMR (CDCl ,
2
4
3
solvent and purification of the residue on silica gel column using
EtOAc/hexane (1/4) as eluent furnished compound 45 (17.5 g, 91%)
500 MHz) δ 7.79 (br s, 1H), 7.65−7.61 (m, 1H), 7.52−7.47 (m, 2H),
7.43 (dd, J = 2.8, 2.8 Hz, 1H), 7.41−7.38 (m, 2H), 7.21 (td, J = 7.5,
1.5 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 6.6 Hz, 1H), 5.96 (br
s, 1H), 5.38 (s, 2H), 4.18−4.06 (m, 2H), 3.84 (dd, J = 7.1, 2.8 Hz,
as a yellow solid: R = 0.4 (EtOAc/hexane 3/7); mp 94−96 °C; IR
f
−1
(
neat) ν /cm 3336, 2923, 1698 (NHCO), 1525, 1447, 1174,
max
M
dx.doi.org/10.1021/jo4013833 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
3
1
H), 2.85 (td, J = 5.4, 5.1 Hz, 1H), 2.15−2.05 (m, 2H), 1.24 (t, J = 6.5
C NMR (CDCl , 125 MHz) δ 150.1 (2 C), 141.6 (2 C), 134.9
3
13
Hz, 3H), 1.13 (s, 3H), 1.11 (s, 3H); C NMR (CDCl , 125 MHz) δ
(CH), 133.7 (C), 131.3 (CH), 127.9 (CH), 124.7 (CH), 119.0 (CH),
116.0 (CH ), 109.4 (CH), 52.4 (CH ), 39.8 (CH ), 36.9 (CH ), 18.7
(CH ); HRMS m/z calcd for C H N [M + H ] 241.1700, found
3
1
1
1
54.2 (NHCO), 141.6 (C), 138.9 (CH), 134.4 (C), 132.8 (CH),
31.9 (CH), 131.8, 128.8, 128.6 (2 CH), 128.4, 128.3, 127.4, 127.0,
24.3, 116.6, 83.9 (CH), 70.1 (C), 61.6 (CH ), 45.5 (2 CH ), 29.5
2
2
2
3
+
3
16 20
2
2
2
241.1707.
(
CH ), 29.5 (CH ), 14.3 (CH ); HRMS m/z calcd for C H N O S
(E)-Ethyl 2-(2-(3-Hydroxy-3-methylbut-1-enyl)-1H-indol-3-yl)-
3
3
3
24 28
2
5
+
[
M + H ] 457.1800, found 457.1799.
E)-Ethyl 2-(2-(3-Methylbuta-1,3-dienyl)-1-(phenylsulfonyl)-1H-
indol-3-yl)ethylcarbamate (49). To a solution of the tertiary alcohol
ethylcarbamate (51a). To a solution of the tertiary alcohol 48 (2
g, 4.38 mmol) in anhydrous methanol (30 mL) were added Na HPO
(
2 4
(2.5 g, 17.5 mmol) and Na−Hg (4.9 g, 21.9 mmol). The reaction
mixture was stirred for 1 h at room temperature. Water (10 mL) and
ether (20 mL) were added, and the supernatant was decanted. The
residue was washed with ether (3 × 10 mL). The organic extracts were
combined, washed with brine (10 mL), and dried over anhydrous
Na SO . Evaporation of the solvent and purification of the residue on a
4
8 (2 g, 4.38 mmol) in anhydrous THF (20 mL) and Et N (3.65 mL,
3
26.3 mmol) under an N atmosphere was added MsCl (1.0 mL, 13.15
2
mmol) slowly over a period of 5 min at 0 °C. The solution was
warmed to room temperature for about 1.5 h and then refluxed for 30
min. The precipitate that formed was filtered off using ethyl acetate,
affording a brown viscous liquid. Evaporation of the solvent and
purification of the residue on a silica gel column using EtOAc/hexane
2
4
silica gel column using EtOAc/hexane (1/1) as eluent gave the alcohol
51a (1.2 g, 87%) as a white waxy solid: R = 0.4 (EtOAc/hexane 3:2);
f
−1
(
1/4) as eluent furnished the diene 49 (1.6 g, 83%) as a white
IR (neat) νmax/cm 3396, 2972, 1689 (NHCO), 1424, 1114, 745;
−
1
1
semisolid: R = 0.5 (EtOAc/hexane 3/7); IR (neat) νmax/cm 2977,
H NMR (CDCl , 500 MHz) δ 7.08 (t, J = 7.6 Hz, 1H), 7.03 (d, J =
f
3
1
1
5
3
5
704 (NHCO), 1476, 1349, 1196, 754, 688, 594; H NMR (CDCl ,
7.3 Hz, 1H), 6.78 (q, J = 7.6 Hz, 1H), 6.62 (dd, J = 7.6, 2.7 Hz, 1H),
5.86 (d, J = 15.6 Hz, 1H), 5.57 (d, J = 15.6 Hz, 1H), 5.14 (s, 1H),
4.22−4.07 (m, 2H), 3.77−3.64 (m, 1H), 3.07 (q, J = 8.8 Hz, 1H),
3
00 MHz) δ 7.67 (br d, 3H), 7.37 (td, J = 7.7 Hz, 1H), 7.30−7.25 (m,
H), 7.13 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 5.92 (br s, 1H),
.48 (d, J = 15.7 Hz, 1H), 5.32 (d, J = 16.0 Hz, 1H), 4.87 (s, 1H), 4.65
1
3
2.28−2.23 (m, 2H), 1.95 (br s, 1H), 1.33−1.22 (m, 9H); C NMR
(
(
(
s, 1H), 4.21−4.17 (m, 2H), 3.85 (dd, J = 6.3, 3.7 Hz, 1H), 2.88−2.81
(CDCl , 125 MHz; rotamers) δ 155.1, 154.1 (NHCO), 149.2, 148.9
3
13
m, 1H), 2.15−2.07 (m, 2H), 1.61 (s, 3H), 1.33 (br t, 3H); C NMR
(2 C), 137.7, 137.6 (CH), 130.4, 130.3 (2 C), 128.5, 128.3 (2 CH),
123.9, 123.8 (CH), 119.3, 119.0 (CH), 109.7, 109.6 (CH), 70.4, 70.4
(C), 61.3, 61.1 (CH ), 46.0, 45.7 (CH ), 35.5, 35.3 (CH ), 29.6, 29.7
CDCl , 125 MHz) δ 154.1 (NHCO), 141.7 (C), 140.4 (2 C),
3
1
38.1 (C), 134.1 (C), 133.3 (CH), 133.2 (CH), 130.2 (CH), 128.7
2
2
2
(
(
(
4
CH), 128.6 (C), 128.4 (3 CH), 127.0 (CH), 125.2 (CH), 124.6
CH), 117.6 (CH ), 84.0 (CH), 61.6 (CH ), 45.5 (2 CH ), 18.2
CH ), 14.3 (CH ); HRMS m/z calcd for C H N O S [M + H ]
(2 CH ), 14.8, 14.6 (CH ); HRMS m/z calcd for C H N O [M +
H ] 317.1900, found 317.1866.
3 3 18 24 2 3
+
2
2
2
+
3
3
24 26
2
4
(E)-2-Methyl-4-(3-(2-(methylamino)ethyl)-1H-indol-2-yl)but-3-
39.1700, found 439.1698.
en-2-ol (51). To a solution of the N-acetate tertiary alcohol 51a (1 g,
(
E)-Ethyl 2-(2-(3-Methylbuta-1,3-dienyl)-1H-indol-3-yl)-
3.16 mmol) in anhydrous THF (10 mL) was added LiAlH (15.8 mL,
4
ethylcarbamate (50). To a solution of the diene 49 (3 g, 6.84
1.0 M solution, 15.8 mmol), and the mixture was stirred magnetically
for 3 h at room temperature. The progress of the reaction was
monitored by TLC until the starting 51a had been completely
consumed. Water (10 mL) was then added to the reaction mixture,
which was then extracted with ethyl acetate (3 × 10 mL), washed with
brine (10 mL), and dried over Na SO . Evaporation of the solvent and
mmol) in anhydrous methanol (30 mL) were added Na HPO (3.9 g,
7.39 mmol) and Na−Hg (7.7 g, 34.24 mmol). The reaction mixture
was stirred for 1 h at room temperature. Water (20 mL) and ether (30
mL) were added, and the supernatant was decanted. The residue was
washed with ether (3 × 20 mL). The organic extracts were combined,
washed with brine (20 mL), and dried over anhydrous Na SO .
2
4
2
2
4
2
4
purification of the residue on a silica gel column using MeOH/CH Cl
2
2
Evaporation of the solvent and purification of the residue on a silica gel
column using EtOAc/hexane (3/7) as eluent gave the diene 50 (1.8 g,
(1/9) as eluent furnished compound 51 (700 mg, 85%) as a yellow
solid: R = 0.4 (MeOH/CH Cl 1.5/8.5); mp 101−103 °C; IR (neat)
f
2
2
−1
1
9
0%) as a white semisolid: R = 0.4 (EtOAc/hexane 2/3); IR (neat)
ν
/cm 3283, 2967, 2925, 1607, 1488, 1146, 1031, 750; H NMR
f
max
−1
νmax/cm 3360, 2974, 1692 (NHCO), 1609, 1421, 1201, 1112,
(CDCl , 500 MHz) δ 7.03 (td, J = 7.6 Hz, 1H), 7.00 (d, J = 7.3 Hz,
3
1
8
2
92, 7457; H NMR (CD CN, 500 MHz; rotamers) δ 7.08−7.02 (m,
1H), 6.74 (td, J = 7.3 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 5.93 (d, J =
15.6 Hz, 1H), 5.59 (d, J = 15.6 Hz, 1H), 4.51 (s, 1H), 4.24 (br s, 1H),
2.75−2.71 (ddd, J = 9.4, 5.8, 2.4 Hz, 1H), 2.64−2.59 (ddd, J = 8.8, 6.1,
2.7 Hz, 1H), 2.42 (s, 3H), 2.30−2.25 (ddd, J = 8.8, 7.0, 3.3 Hz, 1H),
3
H), 6.73 (td, J = 7.3, 6.7 Hz, 1H), 6.62 (t, J = 8.8 Hz, 1H), 6.06 (d, J
=
15.9 Hz, 1H), 5.91 (d, J = 15.9 Hz, 1H), 5.37 (br d, 1H), 5.17 (s,
1
H), 4.87 (br d, 2H), 4.16−4.03 (m, 2H), 3.70−3.62 (m, 1H), 2.96−
1
3
2
.89 (m, 1H), 2.29−2.24 (m, 2H), 1.78 (s, 3H), 1.25 (dt, J = 14.3, 7.0
2.04−2.00 (ddd, J = 9.7, 6.1, 3.6 Hz, 1H), 1.28 (d, 6H); C NMR
13
Hz, 3H); C NMR (CD CN, 125 MHz; rotamers) δ 155.7 (NHC
(CDCl , 125 MHz) δ 150.1 (2 C), 136.5 (CH), 133.7 (2 C), 131.6
3
3
O), 155.0, 150.8, 150.7, 142.6, 133.4, 133.3, 132.6, 132.6, 131.5, 131.4,
(CH), 127.7 (CH), 124.5 (CH), 118.8 (CH), 109.2 (CH), 70.4 (C),
1
6
29.5, 125.0, 119.7, 119.7, 117.1, 110.5, 110.4, 82.4, 81.9, 62.0, 61.8,
0.5, 59.4, 46.9, 46.7, 36.4, 36.1 (CH ), 18.9 (CH ), 15.1 (CH );
52.2 (CH ), 39.5 (CH ), 36.7 (CH ), 29.7 (2 CH ); HRMS m/z calcd
2
2
3
3
+
for C H N O [M + H ] 259.1800, found 259.1811.
2
3
3
16 22
2
+
HRMS m/z calcd for C H N O [M + H ] 299.1800, found
Isoborreverine (5). To a solution of the alcohol 51 (100 mg, 0.38
18
22
2
2
2
99.1760.
E)-N-Methyl-2-(2-(3-methylbuta-1,3-dienyl)-1H-indol-3-yl)-
ethanamine (43). To a solution of the N-acetate diene 50 (600 mg,
mmol) in anhydrous CH Cl (5 mL) was added a catalytic amount of
2
2
(
TFA (22 mg, 0.19 mmol), and the mixture was stirred magnetically for
30 min at room temperature. The progress of the reaction was
monitored by TLC until the starting alcohol had been completely
2
1
.01 mmol) in anhydrous THF (10 mL) was added LiAlH (10 mL,
4
.0 M solution, 10.06 mmol), and the mixture was stirred magnetically
consumed. A saturated solution of NaHCO (5 mL) was then added
3
for 3 h at room temperature. The progress of the reaction was
monitored by TLC until the starting 53 had been completely
consumed. Water (10 mL) was then added to the reaction mixture,
which was then extracted with ethyl acetate (3 × 10 mL), washed with
brine (10 mL), and dried over Na SO . Evaporation of the solvent and
to the reaction mixture, which was then extracted with CH Cl (3 × 10
2
2
mL), washed with brine (10 mL), and dried over Na SO . Evaporation
2
4
of the solvent and purification of the residue on a silica gel column
using MeOH/CH Cl (1.5/8.5) as eluent furnished isoborreverine (5;
2
2
2
4
80 mg, 86%) as a yellow solid: R = 0.3 (MeOH/CH Cl 1/9); mp
f
2
2
purification of the residue on a silica gel column using MeOH/CH Cl2
107−109 °C.
2
(
1/9) as eluent furnished the diene 43 (320 mg, 66%) as a white
Isoborreverine (5). To a solution of the diene 43 (100 mg, 0.41
−1
semisolid: R = 0.3 (MeOH/CH Cl 1/9); IR (neat) νmax/cm 2927,
1
mmol) in anhydrous CH Cl (5 mL) was added a catalytic amount of
f
2
2
2
2
1
607, 1486, 1466, 1244, 968, 743; H NMR (CDCl , 500 MHz) δ 7.05
TFA (24 mg, 0.20 mmol), and the mixture was stirred magnetically for
30 min at room temperature. The progress of the reaction was
monitored by TLC until the starting diene 43 had been completely
consumed. A saturated solution of NaHCO (5 mL) was then added
to the reaction mixture, which was then extracted with CH Cl (3 × 10
3
(
dd, J = 8.0, 6.0 Hz, 2H), 6.77 (td, J = 7.4 Hz, 1H), 6.63 (d, J = 7.7 Hz,
1H), 6.12 (d, J = 15.7 Hz, 1H), 5.95 (d, J = 15.7 Hz, 1H), 4.91 (br d,
2H), 4.57 (s, 1H), 2.80−2.77 (m, 1H), 2.68 (dt, J = 6.0, 2.6 Hz, 1H),
2.47 (s, 3H), 2.38−2.31 (m, 1H), 2.12−2.07 (m, 1H), 1.84 (s, 3H);
3
2
2
N
dx.doi.org/10.1021/jo4013833 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mL), washed with brine (10 mL), and dried over Na SO . Evaporation
(11) (a) Vallakati, R.; May, J. A. J. Am. Chem. Soc. 2012, 134, 6936.
(b) Vallakati, R.; May, J. A. Synlett. 2012, 23, 2577. (c) Vallakati, R.;
Lundy, B. J.; Popova, S. J.; May, J. A. Chirality 2013, DOI: 10.1002/
chir.22134.
2
4
of the solvent and purification of the residue on a silica gel column
using MeOH/CH Cl (1.5/8.5) as eluent furnished isoborreverine (5;
2
2
2
0 mg, 20%) as a yellow solid: R = 0.3 (MeOH/CH Cl 1/9). The
f 2 2
data exactly matched those of isoborreverine (5) made earlier from
compound 41.
(12) Kumar, N. U.; Reddy, B. S.; Reddy, V. P.; Bandichhor, R.
Tetrahdron Lett. 2012, 53, 4354.
ASSOCIATED CONTENT
■
*
S
Supporting Information
1
13
Figures giving H and C NMR spectra for all compounds and
a CIF file giving crystallographic data for compound 19b. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
*
Corresponding Author
D.H.D.: fax, (+91)-512-2596537; tel, (+91)-512-2597436; e-
mail, ddethe@iitk.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank Mr. Dipankar Sahoo for solving the crystal structure.
R.D.E. and A.R. thank the CSIR, New Delhi, India, for the
award of research fellowships. Financial support from IIT
Kanpur is gratefully acknowledged.
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