InCl3-mediated addition of indole to isatogens: An expeditious synthesis of 13-deoxy-isatisine A

Article abstract of DOI:10.1002/chem.201103604

A strategy directed towards the total synthesis of isatisine A that involves several late-stage metal-catalyzed transformations that address the key carbon-carbon and carbon-heteroatom bond formations has been developed. As a part of this strategy, methods for the addition of indoles to isatogens that lead selectively to either 2,2-disubstituted N-hydroxyindolin-3-one or 2,2-disubstituted indolin-3-one compounds have been developed by employing InCl₃ as a catalyst or as the reagent. The present methods provide the first examples of the additions of indoles to the isatogen nucleus. To demonstrate its viability, the synthesis of 13-deoxy-isatisine A has been completed in ten steps from a known and easily available lactone. [Metal]-mediated: Methods for the addition of indoles to isatogens have been developed to prepare 2,2-disubstituted indolin-3-ones. The total synthesis of 13-deoxy-isatisine has been executed (see scheme) by featuring several [metal]-mediated reactions at the final stages, such as Sonogashira coupling, [Pd]-mediated nitro-alkyne cycloisomerization, and [In]-mediated addition of indole to an isatogen. Copyright

Full text of DOI:10.1002/chem.201103604

FULL PAPER
DOI: 10.1002/chem.201103604
InCl3-Mediated Addition of Indole to Isatogens: An Expeditious Synthesis of
13-deoxy-Isatisine A
Chepuri V. Suneel Kumar,[a] Vedavati G Puranik,[b] and Chepuri V. Ramana*[a]
Abstract: A strategy directed towards
the total synthesis of isatisine A that
involves several late-stage metal-cata-
lyzed transformations that address the
disubstituted N-hydroxyindolin-3-one
or 2,2-disubstituted indolin-3-one com-
pounds have been developed by em-
ploying InCl3 as a catalyst or as the re-
agent. The present methods provide
the first examples of the additions of
indoles to the isatogen nucleus. To
demonstrate its viability, the synthesis
of 13-deoxy-isatisine A has been com-
pleted in ten steps from a known and
easily available lactone.
key carbon–carbon and carbon–het
ACHTUNGTNEReNUNG ro-
ACHTUNGTRENNUNGatom bond formations has been devel-
Keywords: indium · indoles · isato-
gens · natural products · total syn-
thesis
oped. As a part of this strategy, meth-
ods for the addition of indoles to isato-
gens that lead selectively to either 2,2-
Introduction
In recent years, there has been a great demand for inventing
catalytic methods that address the skeletal complexity of the
targeted natural products by means of new carbon–carbon
and carbon–heteroatom bond-formation reactions.[1] When
such reactions, especially those of an intermolecular nature,
are employed at the final stages of a total synthesis, they
provide the flexibility to access a collection of related small
molecules, which is important in the realm of chemical ge-
netics and lead optimizations.[2] 2,2-Disubstituted indolin-3-
one, informally known as 2,2-disubstituted indoxyl, is one of
the privileged structural units of natural products, medicinal-
ly important molecules, pesticides, and organic dyes,[3] and
has served as the advanced structural unit in the synthesis of
various natural products.[3–5] Austamide A, brevianamide, ar-
istotelone, duocarmycin A, cephalinones B–D, peronatins A
and B, recently isolated isatisine A, and notoamides O
(Figure 1)[4] are some of the natural products that present
the parent 2,2-disubstituted indoxyl unit. Among the various
methods available, the oxidation of the indole derivatives
and subsequent nucleophilic additions to the resulting indo-
Figure 1. Representative natural products with a 2,2-disubstituted indo-
lin-3-one structural unit.
linones,[6] and the Smalley cyclization, which features the in-
tramolecular attack of an enolate on an aryl azide,[7] are the
generally employed methods for the synthesis of 2,2-disub-
stituted indoxyl derivatives.[8]
[a] C. V. S. Kumar, Dr. C. V. Ramana
Division of Organic Chemistry
CSIR-National Chemical Laboratory
Dr. Homi Bhabha Road
On dealing with our ongoing program on the synthesis of
isatisine A,[9,10] we recently documented simple catalytic
methods for the synthesis of indol-3-one-N-oxides, more
commonly known as isatogens as well as (2,2)-spiro-indolin-
3-ones.[10] The central skeleton of the isatisine A is charac-
terized by the presence of 2,2-disubstituted indolin-3-one
derivative with 2-[3-indolyl] and 2-[1-furanosyl] substituents.
We planned to synthesize the central tetracyclic core of
isatisine A (Figure 2) from a suitable C1-ethynyl furanoside
Pune 411 008 (India)
Fax : (+91)20-25902629
E-mail: vr.chepuri@ncl.res.in
[b] Dr. V. G. Puranik
Center for Material Characterization
CSIR-National Chemical Laboratory
Dr. Homi Bhabha Road
Pune 411 008 (India)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103604.
Chem. Eur. J. 2012, 18, 9601 – 9611
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9601

tification of InCl3 as the catalyst of choice in this regard and
acetonitrile as the suitable solvent.[15] The optimized condi-
tions involve the treatment of 2-phenyl isatogen (1a,
1 equiv) with indole (2a, 1 equiv) in acetonitrile in the pres-
ence of InCl3 (20 mol%) under an argon atmosphere at
258C for 3 h (Scheme 1). The N-hydroxyindolin-3-one deriv-
Figure 2. Intended retrosynthetic disconnections for the central core of
isatisine A.
derivative by first preparing the corresponding isatogen by
involving Pd-catalyzed Sonogashira coupling and nitroal-
kyne cycloisomerization in separate steps. Subsequently, we
intended to develop a catalytic method for the indole addi-
tion to the nitrone unit of isatogen to introduce the quater-
nary center of the key 2,2-disubstituted indolin-3-one core
of the natural product. In this manuscript, we document
methods for the addition of indoles to isatogens that lead se-
lectively either to 2,2-disubstituted-N-hydroxyindolin-3-one
or the corresponding indolin-3-one derivatives by employing
InCl3 either as a catalyst or reagent, respectively. Further-
more, the synthesis of 13-deoxy-isatisine has been executed
to demonstrate the compatibility of these new methodolo-
gies directed towards the total synthesis of isatisine A.
Scheme 1. Addition of indole to isatogen.
ative 3aa was isolated in good yields. Among various other
Lewis/Brønsted acids screened, InACTHNUTRGNENUG(OTf)3 gave the required
product 3aa in moderate yields. In other solvents examined,
either the reactions were sluggish or the starting compounds
were found to be completely intact due to the poor solubili-
ty of InCl3 in solvents such as toluene. Interestingly, in antic-
ipation of better solubility for InCl3, when the reaction was
carried out in toluene at 808C the 2,2-disubstituted indolin-
3-one derivative 4aa was formed in appreciable amounts, in-
Results and Discussion
ꢀ
dicating the possible reduction of N O bond under these
With regards to the reactivity of isatogens towards various
nucleophiles, the heteroatom-centered nucleophiles are
known to add at the C2 of the nitrone unit,[11] and the addi-
tion of carbon-centered nucleophiles such as alkyl/aryl
Grignard reagents are in general nonregioselective (C2/
C3),[12] with the addition to the carbonyl carbon being the
dominant reaction. Although the addition of indoles to isat-
conditions (Scheme 2).[16] The reduction of nitro compounds
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ꢀ
Scheme 2. Indole addition to isatogen and N O reduction.
tion of indole derivatives reveal that it should be a viable
process.[13] Also, the Friedel–Crafts-type C3-alkylation of in-
doles with simple nitrones catalyzed by either Lewis acids or
Brønsted acids has already been established.[14]
Our investigations in this regard began with the finding of
a suitable catalyst for the addition of the parent indole to 2-
phenyl isatogen 1a. Table 1 presents the most salient find-
ings of our exploratory experiments, which led to the iden-
and hydroxyl amine derivatives by using indium metal has
been well established. However InCl3 has been rarely em-
ployed for this purpose.[17] We have optimized this reaction
by varying the amount of InCl3. To this end, the use of
1.5 equiv of InCl3 was found to be optimum for a complete
conversion of isatogen, and the indolin-3-one 4aa was ob-
tained in moderate yield. As a control, the isatogen 1a was
heated in toluene with 1.5 equiv InCl3 at 808C for 8 h, and it
was observed that 1a was completely intact. This suggests
Table 1. Optimization with different Lewis acid catalysts.
Catalyst
Sc(OTf)3
Ag(OTf)
Zn(OTf)2
InCl3
CSA
FeCl3
t [h]
Yield [%]
ꢀ
that the indole addition occurs prior to the N O reduc-
tion.[18]
G
24
19
20
3
42
15
4
34
33
39
68
41
31
49
–
ACHTUNGTRENNUNG
Table 2 exemplifies the generality of both the conditions.
Various isatogens with different substituents at the C2 posi-
tion such as aryl, alkyl, and sugar units were employed. In
general, when InCl3 was employed in CH3CN and in catalyt-
ic amounts, the exclusive formation of N-hydroxyindolin-3-
ones was noticed. With regards to the indoles, whereas the
ACHTUNGTRENNUNG
InACHTUNGTRENNUNG(OTf)3
InCl3·4H2O
48
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Chem. Eur. J. 2012, 18, 9601 – 9611

Synthesis of 13-deoxy-Isatisine A
FULL PAPER
Table 2. Scope of the InCl3-mediated addition of indoles to isatogens.
Entry
Product (Yield [%])
Entry
10
Product (Yield [%])
1
2
3ba (69, R=H)
3bb (73, R=Me)
4bb (54)
3
4
3ca (61, R=H)
3cb (67, R=Me)
11
12
4da+5da (47, R=H)
4db+5db (41, R=Me)
5
6
3da (49, R=H)
3db (62, R=Me)
7
8
3ea (72, R=H)
3eb (71, R=Me)
13
14
4 fa (52, R=H) (2:1)
4 fb (56, R=Me)
9
3 fb (74)
addition reactions with simple indole 2a and with N-methyl-
indole 2b to isatogens were facile under either of the condi-
tions discussed above, the N-Boc-protected (N-Boc=t-butyl-
oxycarbonyl) indole was found to be completely inactive.
ACHTUNGTRENNUNG
The addition reactions to the sugar isatogen 1 f deserve spe-
cial mention. The addition of 2b to isatogen 1 f under both
the conditions was diastereoselective and gave the corre-
sponding addition products 3 fb and 4 fb as single diastereo-
mers (Figure 3). With simple indole 2a, a mixture of dia-
ACHTUNGTRENNUNGstereoACHTUNGTRENNUNGmers were obtained in a 2:1 ratio.
Synthesis of 13-deoxy-isatisine A (6): Having developed
a three-step strategy for the construction of the central 2,2-
disubstituted indolin-3-one core from a simple alkyne, to ad-
dress its applicability to the total synthesis of isatisine, we
targeted the synthesis of 13-deoxy-isatisine A (6) as an inter-
im target from the known lactone 9.[20] Figure 4 presents the
key retrosynthetic disconnections that identify the nitroal-
kyne 7 as an advanced intermediate. The synthesis of key in-
termediate 7 began with the protection of primary alcohol
of lactone 9 (prepared in two steps from a-d-lactose mono-
hydrate)[20] as its t-butyldimethylsilyl (TBS) ether by using
Figure 3. ORTEP diagram of the compound 3 fb (ellipsoids are drawn at
50% probability).
TBSCl/imidazole in CH2Cl2 at 08C (Scheme 3). The result-
ing compound 10 was subjected to alkyne addition with tri-
methylsilylacetylene and nBuLi in THF at ꢀ788C and the
deoxygenation of the intermediate hemiacetal was carried
Chem. Eur. J. 2012, 18, 9601 – 9611
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9603

C. V. Ramana et al.
ꢀ
C tetramethylsilyl (TMS) group was also found to be de-
protected under the same conditions to give the compound
8 in 89% yield. The Sonogashira coupling[22] of alkyne 8
with o-iodonitrobenzene was facile and gave the requisite
nitroalkyne 13 in 76% yield. Subsequently, the acid-mediat-
ed acetonide hydrolysis of 13 gave diol 14. The key inter-
mediate 7 was prepared in an overall yield of 56% from
diol 14 by employing three consecutive reactions: 1) oxida-
tion with 2-iodoxybenzoic acid (IBX) in EtOAc at reflux
followed by 2) further oxidation of the intermediate alde-
hyde to carboxylic acid, with NaClO2/NaH2PO4·H2O and 2-
methyl-2-butene as a chloride ion scavenger in tBuOH and
H2O,[23] and subsequent 3) esterification of the resulting car-
[24]
boxylic acid with TMSCHN2 in 20% methanol in toluene
at 08C.
The key Pd-mediated cycloisomerization of 7 was carried
out with [PdACHTNUTRGNEG(UN CH3CN)2Cl2] in acetonitrile at room tempera-
Figure 4. Key retrosynthetic disconnections for the total synthesis of 13-
deoxy-isatisine A (6).
ture to procure isatogen 15 in respectable yields. Isatogen 15
thus obtained was treated with indole and InCl3 (0.2 equiv)
in CH3CN at RT for 3 h. Then the reaction was concentrat-
out with triethylsilane and BF3·OEt2 in acetonitrile/CH2Cl2
(1:1). The TBS ether was also deprotected under these con-
ditions and gave alkynol 12 as a single diastereomer. The
anomeric configuration in 12 was fixed as b[21] with the help
of the 2D NMR spectroscopic analysis of the corresponding
acetate 12-Ac. For example, in the NOESY of 12-Ac, the
ꢀ
ed and the N O reduction was carried out in toluene at
808C by adding an additional 1.3 equiv of InCl3 to get the
indolin-3-one 16 as a single diastereomer in 53%. The
stereoACHTNUTRGNEcNUG hemistry at the newly created quaternary center was
fixed after the cyclization. The conditions developed by Kar-
adeolian and Kerr in the total synthesis of isatisine A were
followed for constructing the central lactam ring.[9b] Thus,
the hydrolysis of ester 16 by using LiOH in MeOH/THF at
08C followed by the cyclization of the resulting crude acid
by using EDCI under high dilution conditions in THF at
reflux for 16 h gave 17. The stereochemistry of the quaterna-
ꢀ
ꢀ
observed cross peaks between the C1 H and C4 H, and be-
ꢀ
tween the C1 H and one of the acetonide methyl groups in-
dicate that they are all on the same side of the ring and that
the anomeric configuration is b. Next, the benzylation of the
primary alcohol in compound 12 was carried out by using
BnBr and NaH in dimethylformamide (DMF) at 08C. The
Scheme 3. Total synthesis of 13-deoxy-isatisine A (6).
9604
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Chem. Eur. J. 2012, 18, 9601 – 9611

Synthesis of 13-deoxy-Isatisine A
FULL PAPER
the contents were concentrated and purified by silica gel (100–200 mesh)
ry carbon in lactam 17 has been established with the help of
column chromatography (30!50% ethyl acetate in petroleum ether).
ꢀ
COSY/NOESY analysis. For example, the C10 H (the
ꢀ
General procedure for InCl3-mediated indole addition/N O reduction re-
anomeric hydrogen resonating at d=4.93 ppm) appeared
actions: A thoroughly degassed solution of isatogen (1 equiv) and indole
(1.5 equiv) and anhydrous InCl3 (1.5 equiv) in toluene (6 mL) was stirred
for 4–8 h at 808C. After completion of the reaction as indicated by TLC,
the contents were concentrated under reduced pressured and the crude
was purified by silica gel (100–200 mesh) column chromatography (20!
40% ethyl acetate in petroleum ether).
ꢀ
through space interaction with the C2’ H (d=7.27 ppm,
ꢀ
next to the nitrogen) and C4’ H (d=8.14 ppm) of indole
ꢀ
ꢀ
and also with the C12 H (d=4.43 ppm, C4 H of the fura-
nose ring). In addition, the C12 H was found to show
a cross peak with the C2’ H of indole, which indicates the
presence of C12 H, C10 H, and C2’ H on the a face of the
furanose ring, thus indicating that the stereochemistry at the
quaternary center is the same as that in the isatisine A. The
obtained lactam 17 was subjected for the debenzylation with
TiCl4 in CH2Cl2 to afford the 13-deoxy-isatisine A (6) in ex-
cellent yields.[25]
ꢀ
ꢀ
1-Hydroxy-2-phenyl-2,3’-biindolin-3-one (3aa): General procedure A;
yield: 68%; yellow solid; Rf (30% ethyl acetate/petroleum ether) 0.35;
m.p. 265–2678C; 1H NMR (500 MHz, 3:2 [D4]methanol+CDCl3, 258C,
TMS): d=6.86 (t, J=7.6 Hz, 1H), 7.00 (t, J=6.6 Hz, 1H), 7.03–7.11 (m,
3H), 7.24 (d, J=7.1 Hz, 1H), 7.27–7.35 (m, 4H), 7.50 (s, 2H), 7.60 (t, J=
7.7 Hz, 1H), 7.68 ppm (d, J=6.2 Hz, 1H); 13C NMR (125 MHz, 3:2
[D4]methanol+CDCl3, 258C, TMS): d=80.0 (s), 111.2 (d), 112.2 (s),
112.6 (d), 118.9 (d), 119.6 (s), 121.1 (d), 121.4 (d), 124.0 (d), 125.3 (d),
126.4 (s), 127.4 (d), 127.8 (d, 2C), 128.1 (d, 2C), 136.2 (s), 137.3 (s), 137.3
(d), 161.6 (s), 197.6 ppm (s); IR (CHCl3): n˜ =3390, 3016, 2923, 1700,
1544, 1216, 1030, 669 cmꢀ1; ESI-MS: m/z (%): 363.30 (50) [M+Na]+,
379.47 (25) [M+K]+; HRMS: m/z calcd for C22H16N2O2H+: 341.1290;
found: 341.1290.
ꢀ
ꢀ
ꢀ
Conclusion
ꢀ
In conclusion, methods for the InCl3-mediated C C bond
1-Hydroxy-1’-methyl-2-phenyl-2,3’-biindolin-3-one (3ab): General proce-
dure A; yield: 70%; yellow solid; Rf (30% ethyl acetate/petroleum
ether) 0.55; m.p. 207–2098C; 1H NMR (500 MHz, 3:2 [D4]methanol+
CDCl3, 258C, TMS): d=3.69 (s, 3H), 6.84 (ddd, J=0.7, 6.9, 7.8 Hz, 1H),
6.93 (s, 1H), 6.97 (t, J=7.5 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 7.10 (ddd,
J=0.9, 7.0, 8.1 Hz, 1H), 7.23 (dd, J=8.6, 11.1 Hz, 2H), 7.26 (dd, J=1.6,
4.9 Hz, 2H), 7.39 (t, J=1.7 Hz, 1H), 7.48 (m, 2H), 7.58 (ddd, J=1.1, 7.0,
8.2 Hz, 1H), 7.64 ppm (d, J=7.7 Hz, 1H); 13C NMR (125 MHz, 3:2
[D4]methanol+CDCl3, 258C, TMS): d=32.3 (q), 80.0 (s), 108.9 (d), 111.4
(s), 112.6 (d), 118.7 (d), 119.5 (s), 120.9 (d), 121.2 (d), 121.8 (d), 123.9 (d),
127.1 (s), 127.4 (d), 127.7 (d, 2C), 128.1 (d, 2C), 129.3 (d), 137.0 (s),
137.3 (d), 137.6 (s), 161.9 (s), 197.9 ppm (s); IR (CHCl3): n˜ =3384, 3021,
formation between isatogens and indoles to synthesize selec-
tively either N-hydroxyindolin-3-one or indolin-3-one com-
pounds have been developed. Our previously developed ni-
troalkyne cycloisomerization along with the present [In]-
mediated indole additions have been amply applied to exe-
cute the synthesis of 13-deoxy-isatisine A. Further studies di-
rected toward the total synthesis of isatisine A by employing
these new methods are in progress and will be reported in
due course.[26]
2923, 1686, 1384, 1215, 665 cmꢀ1
; ESI-MS: m/z (%): 377.20 (100)
[M+Na]+; HRMS: m/z calcd for C23H18N2O2H+: 355.1446; found:
355.1424.
Experimental Section
1-Hydroxy-2-(1H-indol-3-yl)-6-methyl-2-phenylindolin-3-one (3ba): Gen-
eral procedure A; yield: 69%; brown gum; Rf (30% ethyl acetate/petro-
leum ether) 0.30; 1H NMR (500 MHz, 3:2 [D4]methanol+CDCl3, 258C,
TMS): d=2.42 (s, 3H), 6.79 (t, J=7.6 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H),
7.01 (dd, J=4.6, 8.2 Hz, 2H), 7.04 (d, J=7.8 Hz, 2H), 7.24–7.29 (m, 3H),
7.32 (d, J=8.2 Hz, 1H), 7.48 (t, J=4.0 Hz, 2H), 7.52 ppm (d, J=7.9 Hz,
1H); 13C NMR (125 MHz, 3:2 [D4]methanol+CDCl3, 258C, TMS): d=
21.2 (q), 79.9 (s), 110.5 (d), 112.0 (s), 112.0 (d), 116.8 (s), 117.9 (d), 120.5
(d), 121.0 (d), 122.0 (d), 123.1 (d), 124.6 (d), 126.2 (s), 126.7 (d), 127.1 (d,
2C), 127.7 (d, 2C), 136.1 (s), 137.5 (s), 148.9 (s), 162.1 (s), 197.4 ppm (s);
IR (CHCl3): n˜ =3398, 2926, 1703, 1495, 1119, 1031, 696 cmꢀ1; ESI-MS: m/
z (%): 377.12 (100) [M+Na]+, 393.15 (5) [M+K]+; HRMS: m/z calcd for
C23H18N2O2H+: 355.1446; found: 355.1424.
General methods: Air- and/or moisture-sensitive reactions were carried
out in anhydrous solvents under an atmosphere of argon in oven-dried
glassware. All anhydrous solvents were distilled prior to use: acetonitrile,
dichloromethane, and DMF from CaH2; methanol from Mg cake; THF
and toluene on Na/benzophenone; triethylamine and pyridine over
KOH; Ac2O over NaOAc; EtOAc over K2CO3; commercial reagents
were used without purification. Column chromatography was carried out
by using spectrochem silica gel (60–120, 100–200, 230–400 mesh). Optical
rotations were determined using a Jasco DIP-370 digital polarimeter.
1
Specific optical rotations [a]D are given in 10ꢀ1 8cm2 gꢀ1. H and 13C NMR
spectroscopic measurements were carried out using Bruker AC
200 MHz, Bruker DRX 400 MHz, or Bruker DRX 500 MHz spectrome-
ters, and TMS was used as an internal standard. 1H and 13C NMR spec-
troscopic chemical shifts are reported in ppm downfield from [D]chloro-
form (d=7.25 ppm) or TMS. The multiplicity of 13C NMR spectroscopic
signals was assigned with the help of distortionless enhancement by po-
larization transfer (DEPT) spectra and the abbreviations used: s=singlet,
d=doublet, t=triplet, and q=quartet represent C (quaternary), CH,
CH2, and CH3, respectively. Mass spectroscopy was carried out using a PI
QStar Pulsar (Hybrid Quadrupole-TOF LC/MS/MS) and a 4800 plus
MALDI TOF/TOF Applied Biosystem spectrometer. High-resolution
mass spectral (HRMS) analysis was performed using SYNAPT G2 high-
definition mass spectrometry (HDMS) and Micromass ESI-TOF MS in-
struments.
1-Hydroxy-6-methyl-2-(1-methyl-1H-indol-3-yl)-2-phenylindolin-3-one
(3bb): General procedure A; yield: 73%; brown oil; Rf (30% ethyl ace-
tate/petroleum ether) 0.55; 1H NMR (500 MHz, 3:2 [D4]methanol+
CDCl3, 258C, TMS): d=2.41 (s, 3H), 3.69 (s, 3H), 6.82 (t, J=8.4 Hz,
2H), 6.93 (s, 1H), 7.01 (d, J=8.1 Hz, 1H), 7.03 (s, 1H), 7.08 (t, J=
7.4 Hz, 1H), 7.23–7.28 (m, 4H), 7.48 (dd, J=3.6, 7.4 Hz, 2H), 7.53 ppm
(d, J=8.1 Hz, 1H); 13C NMR (125 MHz, 3:2 [D4]methanol+CDCl3,
258C, TMS): d=22.8 (q), 33.0 (q), 81.2 (s), 109.8 (d), 112.6 (s), 113.6 (d),
118.2 (s), 119.5 (d), 122.1 (d), 122.8 (d), 123.5 (d), 124.5 (d), 128.2 (d),
128.5 (d, 2C), 128.7 (s), 129.0 (d, 2C), 130.2 (d), 138.0 (s), 138.8 (s), 150.3
(s), 163.5 (s), 198.6 ppm (s); IR (CHCl3): n˜ =3369, 3018, 2852, 1693, 1449,
1215, 1043, 699 cmꢀ1; ESI-MS: m/z (%): 391.16 (100) [M+Na]+; HRMS:
m/z calcd for C24H20N2O2H+: 369.1603; found: 369.1594.
General procedure for catalytic InCl3-mediated indole additions: Indole
(1 equiv) was added to a solution of isatogen (1 equiv) in acetonitrile
(4 mL) and the reaction mixture was degassed under an argon atmos-
phere. Anhydrous InCl3 (0.2 equiv) was added to this solution and then
degassed under an argon atmosphere. The reaction mixture was stirred
for 2–4 h at RT. After completion of the reaction as indicated by TLC,
5-Chloro-1-hydroxy-2-phenyl-2,3’-biindolin-3-one (3ca): General proce-
dure A; yield: 61%; pale yellow gum; Rf (30% ethyl acetate/petroleum
1
ether) 0.30; H NMR (500 MHz, 3:2 [D4]methanol+CDCl3, 258C, TMS):
d=6.8 (t, J=7.5 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 7.0 (d, J=8.1 Hz,
1H), 7.03 (t, J=7.5 Hz, 1H), 7.06 (s, 1H), 7.19 (s, 1H), 7.28 (m, 3H),
Chem. Eur. J. 2012, 18, 9601 – 9611
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9605

C. V. Ramana et al.
7.32 (d, J=8.1 Hz, 1H), 7.46 (m, 2H), 7.57 ppm (d, J=8.1 Hz, 1H);
13C NMR (125 MHz, 3:2 [D4]methanol+CDCl3, 258C, TMS): d=80.1
(s), 95.3 (s), 110.5 (d), 111.3 (d), 117.2 (s), 118.0 (d), 120.4 (d), 120.6 (d),
120.8 (d), 124.5 (d), 124.7 (d), 126.0 (s), 126.9 (d), 127.1 (d, 2C), 127.6 (d,
2C), 136.2 (s), 136.9 (s), 143.4 (s), 161.7 (s), 196.3 ppm (s); IR (CHCl3):
n˜ =3399, 3019, 1701, 1602, 1316, 1215, 1108, 699 cmꢀ1; ESI-MS: m/z (%):
375.50 (15) [M+H]+; HRMS: m/z calcd for C22H15ClN2O2Na+: 397.0720;
found: 397.0721.
7.4 Hz, 2H); 13C NMR (100 MHz, 3:2 [D4]methanol+CDCl3, 258C,
TMS): d=13.1 (q), 21.9 (t), 23.5 (t), 29.0 (t), 31.0 (t), 32.0 (q), 33.8 (t),
76.5 (s), 108.7 (d), 111.7 (d), 111.9 (s), 118.5 (d), 119.9 (d), 120.0 (s), 120.1
(d), 121.0 (d), 122.9 (d), 125.6 (s), 127.9 (d), 136.8 (s), 137.2 (d), 162.4 (s),
201.3 ppm (s); IR (CHCl3): n˜ =3393, 3018, 2856, 1698, 1541, 1376, 1216,
1017, 668 cmꢀ1; ESI-MS: m/z (%): 385.70 (10) [M+Na]+; HRMS: m/z
calcd for C23H26N2O2H+: 363.2072; found: 363.2072.
2-(6-Methoxy-2,2-dimethyltetrahydrofuroACTHNUTRGENN[GU 2,3-d]ACHUTNGTREN[NUNG 1,3]dioxol-5-yl)-3-oxo-
3H-indole 1-oxide (1 f): 1H NMR (200 MHz, CDCl3, 258C, TMS): d=
1.37 (s, 3H), 1.53 (s, 3H), 3.30 (s, 3H), 4.21 (d, J=5.1 Hz, 1H), 3.91 (d,
J=3.9 Hz, 1H), 5.65 (d, J=5.1 Hz, 1H), 6.17 (d, J=3.9 Hz, 1H), 7.53–
7.65 ppm (m, 4H); 13C NMR (50 MHz, CDCl3, 258C, TMS): d=26.7 (q),
27.3 (q), 58.2 (q), 74.3 (d), 82.8 (d), 85.4 (d), 105.7 (d), 112.7 (s, 2C),
113.9 (d), 121.8 (d), 123.4 (s), 131.6 (d), 134.2 (d), 146.7 (s), 184.2 ppm
(s); ESI-MS: m/z (%): 342.04 (100) [M+Na]+; HRMS: m/z calcd for
C16H17NO6Na+: 342.0954; found: 342.0916.
5-Chloro-1-hydroxy-1’-methyl-2-phenyl-2,3’-biindolin-3-one (3cb): Gener-
al procedure A; yield: 67%; pale yellow liquid; Rf (30% ethyl acetate/
petroleum ether) 0.40; 1H NMR (500 MHz, 3:2 [D4]methanol+CDCl3,
258C, TMS): d=3.69 (s, 3H), 6.86 (t, J=7.4 Hz, 1H), 6.90 (d, J=8.2 Hz,
1H), 6.94 (s, 1H), 7.02 (d, J=8.1 Hz, 1H), 7.11 (t, J=7.4 Hz, 1H), 7.19
(s, 1H), 7.23–7.27 (m,4H), 7.43–7.47 (m, 2H), 7.55 ppm (d, J=8.2 Hz,
1H); 13C NMR (125 MHz, 3:2 [D4]methanol+CDCl3, 258C, TMS): d=
32.4 (q), 80.3 (s), 109.0 (d), 110.8 (s), 112.1 (d),117.7 (s), 118.8 (d), 121.3
(d), 121.3 (d), 121.7 (d), 125.1 (d), 126.9 (s), 127.5 (d), 127.8 (d, 2C),
128.0 (d, 2C), 129.4 (d), 136.9 (s), 137.1 (s), 143.9 (s), 161.9 (s), 196.3 ppm
(s); IR (CHCl3): n˜ =3439, 3019, 1680, 1599, 1215, 1045, 669 cmꢀ1; ESI-
MS: m/z (%): 411.20 (1) [M+Na]+; HRMS: m/z calcd for
C23H17ClN2O2H+: 389.1057; found: 389.1057.
1-Hydroxy-2-(6-methoxy-2,2-dimethyltetrahydrofuroACTHNUGRTNENUG[2,3-d]ACHUTNGTREN[NUNG 1,3]dioxol-5-
yl)-1’-methyl-2,3’-biindolin-3-one (3 fb): General procedure A; yield:
74%; yellow crystalline solid; m.p. 235–2378C; Rf (50% ethyl acetate/pe-
troleum ether) 0.60; 1H NMR (500 MHz, 3:2 [D4]methanol+CDCl3,
258C, TMS): d=1.34 (s, 3H), 1.50 (s, 3H), 2.96 (s, 3H), 3.73 (s, 3H), 3.86
(d, J=3.8 Hz, 1H), 4.59 (d, J=3.8 Hz, 1H), 5.19 (d, J=3.9 Hz, 1H), 6.10
(d, J=3.8 Hz, 1H), 6.87 (t, J=7.6 Hz, 1H), 7.01 (t, J=7.6 Hz, 1H), 7.10
(t, J=7.4 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.26 (d, J=9.3 Hz, 2H), 7.30
(d, J=8.2 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.66 ppm (d, J=3.2 Hz, 1H);
13C NMR (125 MHz, 3:2 [D4]methanol+CDCl3, 258C, TMS): d=25.1
(q), 25.8 (q), 31.6 (q), 56.2 (q), 75.7 (s), 80.9 (d), 82.7 (d), 84.5 (d), 104.5
(d), 108.6 (d), 109.7 (s), 111.2 (s), 112.5 (d), 118.5 (d), 120.1 (d), 120.2 (d),
120.5 (s), 120.8 (d), 122.0 (d), 125.6 (s), 129.5 (d), 136.5 (s), 136.6 (d),
161.7 (s), 198.5 ppm (s); IR (CHCl3): n˜ =3408, 3017, 2930, 2855, 1712,
1610, 1475, 1376, 1162, 1019, 887 cmꢀ1; ESI-MS: m/z (%): 451.70 (10)
[M+H]+, 473.66 (5) [M+Na]+; HRMS: m/z calcd for C25H26N2O6Na+:
473.1689; found: 473.1668.
Methyl 1-hydroxy-3-oxo-2-phenyl-2,3’-biindoline-6-carboxylate (3da):
General procedure A; yield: 49%; yellow liquid; Rf (30% ethyl acetate/
petroleum ether) 0.30; 1H NMR (500 MHz, 3:2 [D4]methanol+CDCl3,
258C, TMS): d=3.92 (s, 3H), 6.82 (t, J=7.7 Hz, 1H), 7.02 (d, J=4.6 Hz,
1H), 7.04 (t, J=7.9 Hz, 1H), 7.07 (s, 1H), 7.28 (m, 3H), 7.32 (d, J=
8.1 Hz, 1H), 7.45–7.49 (m, 2H), 7.51 (s, 1H), 7.58 (dd, J=1.2, 8.1 Hz,
1H), 7.68 (d, J=8.0 Hz, 1H), 7.85 ppm (s, 1H); 13C NMR (125 MHz, 3:2
[D4]methanol+CDCl3, 258C, TMS): d=52.0 (q), 80.7 (s), 110.9 (d), 111.5
(t), 113.2 (d), 118.5 (d), 121.0 (s), 121.1 (d), 121.2 (d), 122.3 (t), 123.7 (d),
125.1 (d), 126.2 (s), 127.3 (d), 127.6 (d, 2C), 128.0 (d, 2C), 136.3 (s),
137.0 (s), 137.4 (s), 161.2 (s), 166.4 (s), 197.6 ppm (s); IR (CHCl3): n˜ =
3410, 3020, 2934, 1769, 1618, 1330, 1217, 1093, 1045, 667 cmꢀ1; ESI-MS:
m/z (%): 421.10 (100) [M+Na]+, 437.34 (10) [M+K]+; HRMS: m/z calcd
for C24H18N2O4H+: 399.1345; found: 399.1345.
Crystal data: Data for the compound was collected at T=296 K using
a SMART APEX CCD single-crystal X-ray diffractometer with MoKa ra-
diation (l=0.7107 ꢁ) to a maximum q range of 25.008. Crystal to detec-
tor distance 6.05 cm, 512ꢂ512 pixels per frame, oscillation per frame
ꢀ0.38, maximum detector swing angle ꢀ30.08, beam center (260.2, 252.5),
in-plane spot width 1.24, SAINT integration. The structure was solved by
direct methods using SHELXTL. All the data were corrected for Lor-
Methyl 1-hydroxy-1’-methyl-3-oxo-2-phenyl-2,3’-biindoline-6-carboxylate
(3db): General procedure A; yield: 62%; yellow gum; Rf (30% ethyl
acetate/petroleum ether) 0.50; 1H NMR (500 MHz, 3:2 [D4]methanol+
CDCl3, 258C, TMS): d=3.71 (s, 3H), 3.93 (s, 3H), 6.85 (t, J=7.5 Hz,
1H), 6.96 (s, 1H), 7.01 (d, J=7.9 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 7.26–
7.32 (m, 4H), 7.45–7.49 (m, 2H), 7.60 (d, J=7.9 Hz, 1H), 7.69 (d, J=
7.9 Hz, 1H), 7.85 ppm (s, 1H); 13C NMR (125 MHz, 3:2 [D4]methanol+
CDCl3, 258C, TMS): d=32.1 (q), 52.0 (q), 80.4 (s), 108.8 (d), 110.6 (s),
113.3 (d), 118.5 (d), 121.1 (d), 121.5 (d), 122.2 (s), 123.7 (d), 126.8 (s),
127.3 (d), 127.5 (d, 2C), 127.9 (d, 2C), 129.2 (d), 136.8 (s), 137.0 (s),
137.4 (s), 161.2 (s), 166.3 (s), 171.5 (s), 197.3 ppm (s); IR (CHCl3): n˜ =
3443, 2989, 1735, 1650, 1615, 1375, 1243, 1097, 635 cmꢀ1; ESI-MS: m/z
(%): 435.20 (100) [M+Na]+, 451.25 (50) [M+K]+; HRMS: m/z calcd for
C25H20N2O4H+: 413.1501; found: 413.1507.
ACHUTNGRENUNeG ntzACHTUGNTRENiNUGN an, polarization, and absorption effects. SADABS correction was ap-
plied. SHELX-97 (SHELXTL)[27] was used for structure solution and
full-matrix least-squares refinement on F2. Hydrogen atoms were includ-
ed in the refinement as per the riding model. The refinements were car-
ried out using SHELXL-97.
Compound (3 fb): C25H27N2O6. Single crystals of the complex were grown
by slow evaporation of the solution in a mixture of methanol and petrole-
um ether. A pale yellow needle crystal of approximately 0.19ꢂ0.15ꢂ
0.11 mm3 in size was used for data collection. Hemisphere data acquisi-
tion. Total scans=3, total frames=1271, exposure per frame=10.0 s per
frame, q range=1.57 to 25.08, completeness to q of 25.08 is 99.6%.
C25H27N2O6; Mr =451.49; monoclinic; space group P21; a=12.180 (1) ,
2-Hexyl-1-hydroxy-2,3’-biindolin-3-one (3ea): General procedure A;
yield: 72%; brown gum; Rf (25% ethyl acetate/petroleum ether) 0.40;
1H NMR (500 MHz, 3:2 [D4]methanol+CDCl3, 258C, TMS): d=0.80 (t,
J=6.4 Hz, 3H), 1.13–1.30 (m, 8H), 2.35–2.45 (m, 2H), 6.85 (t, J=7.3 Hz,
1H), 6.96 (t, J=7.1 Hz, 1H), 7.03 (t, J=7.2 Hz, 1H), 7.18 (d, J=8.0 Hz,
1H), 7.23 (d, J=8.3 Hz, 1H), 7.30 (t, J=3.4 Hz, 2H), 7.61 ppm (t, J=
7.0 Hz, 2H); 13C NMR (125 MHz, 3:2 [D4]methanol+CDCl3, 258C,
TMS): d=13.0 (q), 21.8 (t), 23.4 (t), 28.9 (t), 30.8 (t), 33.6 (t), 76.4 (s),
110.7 (d), 111.6 (d), 112.6 (s), 118.3 (d), 119.4 (d), 119.9 (d), 120.0 (s),
120.8 (d), 122.7 (d), 123.6 (d), 124.9 (s), 136.2 (s), 137.0 (d), 162.3 (s),
201.4 ppm (s); IR (CHCl3): n˜ =3340, 2928, 1677, 1458, 1205, 1020,
655 cmꢀ1; ESI-MS: m/z (%): 349.60 (20) [M+H]+, 371.20 (100) [M+Na]+
; HRMS: m/z calcd for C22H24N2O2H+: 349.1916; found: 349.1916.
b=7.0359 (6)
1.347 gcm3;
,
c=13.294 (1) ꢁ; V=1112.80 (17) ꢁ3; Z=2; 1calcd
(MoKa)=0.097 mmꢀ1
5646 reflections measured, 3418
=
m
;
unique [I>2s(I)]; R value 0.0454, wR2=0.1096; largest diff. peak and
hole, 0.212 and ꢀ0.406 eꢁꢀ3
.
2-(1H-Indol-3-yl)-2-phenylindolin-3-one (4aa): General procedure B;
yield: 53%; brown liquid; Rf (25% ethyl acetate/petroleum ether) 0.45;
1H NMR (500 MHz, CDCl3, 258C, TMS): d=5.37 (brs, 1H), 6.88 (t, J=
7.6 Hz, 1H), 6.92 (d, J=8.3 Hz, 1H), 6.98 (t, J=7.5 Hz, 1H), 7.12–7.18
(m, 3H), 7.26–7.31 (m, 3H), 7.36 (d, J=8.2 Hz, 1H), 7.49 (t, J=7.7 Hz,
1H), 7.55 (dd, J=1.8, 8.1 Hz, 2H), 7.68 (d, J=8.0 Hz, 1H), 8.18 ppm
(brs, 1H); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=71.3 (s), 102.6
(s), 111.6 (d), 112.9 (d), 115.6 (s), 119.5 (s), 119.6 (d), 119.7 (d), 120.1 (d),
122.5 (d), 123.7 (d), 125.6 (d), 126.8 (d, 2C), 127.7 (d), 128.4 (d, 2C),
136.9 (s), 137.5 (d), 139.5 (s), 160.5 (s), 200.5 ppm (s); IR (CHCl3): n˜ =
3411, 3019, 2927, 1707, 1450, 1215, 758 cmꢀ1; ESI-MS: m/z (%): 325.25
2-Hexyl-1-hydroxy-1’-methyl-2,3’-biindolin-3-one (3eb): General proce-
dure A; yield: 71%; pale yellow solid; m.p. 131–1338C; Rf (25% ethyl
acetate/petroleum ether) 0.60; 1H NMR (400 MHz, 3:2 [D4]methanol+
CDCl3, 258C, TMS): d=0.80 (t, J=6.4 Hz, 3H), 1.13–1.30 (m, 8H), 2.39
(t, J=7.6 Hz, 2H), 3.74 (s, 3H), 6.88 (t, J=7.4 Hz, 1H), 6.96 (t, J=
7.5 Hz, 1H), 7.10 (t, J=7.3 Hz, 1H), 7.15–7.26 (m, 4H), 7.62 ppm (d, J=
9606
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 9601 – 9611

Synthesis of 13-deoxy-Isatisine A
FULL PAPER
(20) [M+H]+, 347.22 (50) [M+Na]+; HRMS: m/z calcd for
2-(6-Methoxy-2,2-dimethyltetrahydrofuroACHTUNGRTENNU[G 2,3-d]ACHTUNGTRENUN[NG 1,3]dioxol-5-yl)-2,3’-biin-
C22H16N2OH+: 325.1341; found: 325.1316.
dolin-3-one (4 fa): General procedure B; yield: 52%; brown gum;
1H NMR (500 MHz, CDCl3, 258C, TMS): d=1.27 (s, 2H), 1.30 (s, 3H),
1.45 (s, 3H), 1.53 (s, 1.62H), 2.81 (s, 3H), 3.12 (s, 1.65H), 3.59 (d, J=
3.2 Hz, 0.55H), 3.83 (d, J=3.2 Hz, 1H), 4.42 (d, J=3.8 Hz, 0.56H), 4.46
(d, J=3.8 Hz, 1H), 5.07 (d, J=3.3 Hz, 1H), 5.13 (d, J=3.3 Hz, 0.56H),
5.48 (brs, 1H), 5.85 (d, J=3.7 Hz, 0.54H), 6.01 (d, J=3.8 Hz, 1H), 6.11
(brs, 0.51H), 6.76 (t, J=7.5 Hz, 0.59H), 6.82 (t, J=7.5 Hz, 1H), 6.90 (d,
J=8.2 Hz, 1H), 6.94 (d, J=8.3 Hz, 0.56H), 7.02 (ddd, J=1.2, 7.2, 7.9 Hz,
1H), 7.12 (d, J=8.0 Hz, 1H), 7.13–7.16 (m, 1H), 7.29 (d, J=8.6 Hz, 1H),
7.39 (d, J=2.6 Hz, 1H), 7.41–7.44 (m, 1H), 7.45 (d, J=2.9 Hz, 1H), 7.56
(d, J=7.7 Hz, 0.63H), 7.66 (t, J=7.3 Hz, 2H), 8.11 (d, J=7.9 Hz, 0.63),
8.13 (brs, 1H), 8.20 ppm (brs, 0.57H); 13C NMR (125 MHz, CDCl3,
258C, TMS): d=26.3 (q), 26.5 (q), 26.9 (q), 27.1 (q), 57.6 (q), 57.8 (q),
68.6 (s), 69.8 (s), 80.6 (d), 81.6 (d), 82.2 (d), 82.7 (d), 84.8 (d), 85.5 (d),
105.0 (d), 105.3 (d), 111.2 (d), 111.3 (d), 112.0 (s), 112.0 (s), 112.3 (d),
112.9 (s), 113.0 (s), 115.0 (s), 118.5 (d), 118.8 (d), 119.9 (d), 119.9 (d),
120.0 (s), 120.6 (d), 121.5 (s), 121.7 (d), 122.0 (d), 122.2 (d), 122.3 (d),
123.4 (d), 124.5 (d), 125.0 (s), 125.1 (s), 125.3 (d), 136.8 (s), 137.0 (s),
137.1 (d), 137.1 (d), 162.0 (s), 162.1 (s), 201.4 (s), 201.5 ppm (s); IR
1’-Methyl-2-phenyl-2,3’-biindolin-3-one (4ab): General procedure B;
yield: 56%; brown gum; Rf (25% ethyl acetate/petroleum ether) 0.55;
1H NMR (500 MHz, CDCl3, 258C, TMS): d=3.73 (s, 3H), 5.35 (brs,
1H), 6.88 (d, J=7.4 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.97 (t, J=7.4 Hz,
1H), 7.02 (s, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.20 (t, J=7.5 Hz, 1H), 7.26–
7.31 (m, 4H), 7.43 (t, J=7.5 Hz, 1H), 7.56 (dd, J=1.5, 8.0 Hz, 2H),
7.69 ppm (d, J=7.7 Hz, 1H); 13C NMR (125 MHz, CDCl3, 258C, TMS):
d=32.8 (q), 71.3 (s), 109.7 (d), 112.9 (d), 113.9 (s), 119.6 (d, 2C), 119.8
(d), 122.1 (d), 125.6 (d), 126.1 (s), 126.8 (d, 2C), 127.7 (d), 128.3 (d),
128.4 (d, 2C), 137.5 (d), 137.8 (s), 139.6 (s), 160.5 (s), 200.6 ppm (s); IR
(CHCl3): n˜ =3377, 3058, 2926, 1698, 1615, 1467, 1326, 1217, 1031,
698 cmꢀ1; ESI-MS: m/z (%): 339.28 (20), [M+H]+, 361.36 (10) [M+Na]+;
HRMS: m/z calcd for C23H18N2OH+: 339.1497; found: 339.1471.
6-Methyl-2-(1-methyl-1H-indol-3-yl)-2-phenylindolin-3-one (4bb): Gener-
al procedure B; yield: 54%; yellow liquid; Rf (25% ethyl acetate/petrole-
um ether) 0.65; 1H NMR (500 MHz, CDCl3, 258C, TMS): d=2.36 (s,
3H), 3.72 (s, 3H), 5.27 (brs, 1H), 6.71 (d, J=6.0 Hz, 2H), 6.96 (t, J=
7.5 Hz, 1H), 7.02 (s, 1H), 7.12 (d, J=8.0 Hz, 1H), 7.19 (t, J=7.5 Hz,
1H), 7.27 (dd, J=1.8, 4.1 Hz, 2H), 7.28 (d, J=4.8 Hz, 1H), 7.31 (d, J=
4.4 Hz, 1H), 7.55 (dd, J=1.8, 8.3 Hz, 2H), 7.58 ppm (d, J=8.3 Hz, 1H);
13C NMR (125 MHz, CDCl3, 258C, TMS): d=22.5 (q), 32.8 (q), 71.5 (s),
109.7 (d), 112.9 (d), 114.1 (s), 117.4 (s), 119.5 (d), 119.8 (d), 121.4 (d),
122.0 (d), 125.3 (d), 126.1 (s), 126.8 (d, 2C), 127.6 (d), 128.3 (d, 3C),
137.7 (s), 139.8 (s), 149.2 (s), 161.0 (s), 199.8 ppm (s); IR (CHCl3): n˜ =
3464, 2985, 1742, 1466, 1374, 1242, 1047, 938 cmꢀ1; ESI-MS: m/z (%):
351.10 (5) [M+H]+, 375.09 (100) [M+Na]+, 391.07 (20) [M+K]+;
HRMS: m/z calcd for C24H20N2OH+: 353.1654; found: 353.1678.
(CHCl3): n˜ =3409, 3019, 2853, 1701, 1618, 1457, 1216, 1081, 757 cmꢀ1
;
ESI-MS: m/z (%): 421.12 (3) [M+H]+, 443.15 (100) [M+Na]+, 459.13
(10) [M+K]+; HRMS: m/z calcd for C24H24N2O5H+: 421.1763; found:
421.1755.
2-(Tetrahydro-6-methoxy-2,2-dimethylfuroACTHNUTRGENN[UG 2,3-d]ACHUTNGTREN[NNGU 1,3]dioxol-5-yl)-2-(1-
methyl-1H-indol-3-yl)indolin-3-one (4 fb): General procedure B; yield:
56%; brown liquid; Rf (40% ethyl acetate/petroleum ether) 0.45;
1H NMR (500 MHz, CDCl3, 258C, TMS): d=1.27 (s, 3H), 1.53 (s, 3H),
3.14 (s, 3H), 3.61 (d, J=3.1 Hz, 1H), 3.74 (s, 3H), 4.43 (d, J=3.9 Hz,
1H), 5.07 (d, J=3.1 Hz, 1H), 5.84 (d, J=3.8 Hz, 1H), 6.12 (brs, 1H),
6.74 (t, J=7.4 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 7.10 (t, J=7.7 Hz, 1H),
7.19 (t, J=7.3 Hz, 1H), 7.26 (s, 1H), 7.37 (s, 1H), 7.42 (t, J=7.7 Hz, 1H),
7.55 (d, J=7.5 Hz, 1H), 8.07 ppm (d, J=8.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3, 258C, TMS): d=26.5 (q), 27.1 (q), 32.9 (q), 57.8 (q),
69.7 (s), 80.5 (d), 82.9 (d), 85.4 (d), 105.3 (d), 109.3 (d), 110.9 (s), 112.0
(s), 112.3 (d), 118.5 (d), 119.4 (d), 120.0 (s), 121.6 (d), 121.8 (d), 125.3 (d),
125.7 (s), 127.0 (d), 137.0 (d), 137.5 (s), 161.9 (s), 201.5 ppm (s); IR
Methyl 3-oxo-2-phenyl-2,3’-biindoline-6-carboxylate (4da+5da): General
1
procedure B; yield: 47%; brown gum; H NMR (500 MHz, CDCl3, 258C,
TMS): d=3.92 (s, 1.4H), 3.94 (s, 3H), 5.49 (brs, 0.34H), 6.98 (d, J=
3.6 Hz, 0.51H), 7.02 (d, J=7.6 Hz, 1H), 7.11 (m, 1H), 7.19 (d, J=8.3 Hz,
1H), 7.21 (s, 1H), 7.27–7.29 (m, 3H), 7.37 (d, J=8.3 Hz, 0.69H), 7.45 (d,
J=8.2 Hz, 1H), 7.51 (dd, J=2.4, 7.8 Hz, 2H), 7.53 (t, J=2.2 Hz, 0.66H),
7.54 (s, 1H), 7.60 (d, J=13.1 Hz, 1H), 7.73 (d, J=8.1 Hz, 0.48H), 7.79
(dd, J=1.3, 8.3 Hz, 1H), 8.19 (brs, 0.37H), 8.21 (brs, 1H), 8.30 ppm (brs,
1H); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=52.0 (q), 52.6 (q),
71.9 (s), 77.2 (d), 96.1 (s), 108.0 (s), 109.5 (s), 111.1 (d), 111.7 (d), 113.2
(d), 114.1 (d), 115.3 (s), 119.7 (d), 119.9 (d), 120.2 (d), 120.3 (d), 120.7
(d), 121.1 (d), 122.1 (d), 122.6 (s), 122.7 (d), 123.5 (d), 123.7 (d), 123.9 (s),
125.4 (s), 125.5 (d), 126.7 (d), 127.2 (s), 127.7 (d, 2C), 128.0 (d), 128.5 (d),
128.7 (d, 2C), 132.5 (s), 133.6 (s), 135.3 (s), 136.3 (s), 137.8 (s), 138.0 (s),
139.0 (s), 166.4 (s), 168.2 (s), 200.3 ppm (s); IR (CHCl3): n˜ =3469, 3017,
2851, 1701, 1495, 1450, 1216, 1091, 861, 669 cmꢀ1; ESI-MS: m/z (%):
405.07 (100) [M+Na]+, 421.07 (99) [M+K]+; HRMS: m/z calcd for
C24H18N2O3H+: 383.1395; found: 383.1401.
(CHCl3): n˜ =3439, 3019, 2928, 2852, 1605, 1450, 1215, 1090, 669 cmꢀ1
;
ESI-MS: m/z (%): 457.20 (100) [M+Na]+, 473.22 (20) [M+K]+; HRMS:
m/z calcd for C25H26N2O5H+: 435.1920; found: 435.1920.
8-[(tert-Butyldimethylsilyloxy)methyl]-2,2-dimethyl-1,3,7-trioxaspiro-
AHCTUNGERTG[NNUN 4.4]nonan-6-one (10): At 08C, a solution of alcohol 9 (5.65 g, 27.9 mmol)
in CH2Cl2 (60 mL) was treated with imidazole (2.86 g, 41.8 mmol) fol-
lowed by tert-butyldimethylsilyl chloride (TBDMSCl; 5.06 g, 33.5 mmol)
and stirred for 4 h at the same temperature. After completion of the reac-
tion, ice was added to the reaction mixture and stirred for 10 min. The re-
action mixture was diluted with CH2Cl2 (60 mL) and the resulting layers
were separated. The aqueous layer was extracted with CH2Cl2 (2ꢂ
50 mL). The combined organic layer was washed with brine, dried over
Na2SO4, and concentrated. The crude was purified by flash column chro-
matography (2!5% ethyl acetate/petroleum ether) to yield compound
10 (7.12 g, 81%) as a colorless oil. Rf (10% ethyl acetate/petroleum
ether) 0.60; [a]2D5 = +25.5 (c=0.51 in CHCl3); 1H NMR (200 MHz,
CDCl3, 258C, TMS): d=0.05 (s, 3H), 0.06 (s, 3H), 0.87 (s, 9H), 1.43 (s,
3H), 1.49 (s, 3H), 2.37 (dd, J=5.6, 13.8 Hz, 1H), 2.50 (dd, J=8.0,
13.9 Hz, 1H), 3.66 (dd, J=2.7, 11.5 Hz, 1H), 3.93 (dd, J=2.9, 11.5 Hz,
1H), 4.12 (d, J=8.9 Hz, 1H), 4.30 (d, J=8.9 Hz, 1H), 4.59–4.68 ppm (m,
1H); 13C NMR (50 MHz, CDCl3, 258C, TMS): d=ꢀ5.5 (q), ꢀ5.4 (q),
18.5 (s), 25.6 (q), 25.9 (q, 3C), 26.5 (q), 36.3 (t), 64.1 (t), 72.5 (t), 77.0 (d),
80.8 (s), 112.1 (s), 175.7 ppm (s); IR (CHCl3): n˜ =2989, 2886, 1784, 1463,
1253, 1095, 1061, 837, 758 cmꢀ1; ESI-MS: m/z (%): 339.14 (75) [M+Na]+;
HRMS: m/z calcd for C15H28O5SiH+: 317.1784; found: 317.1789.
Methyl 1’-methyl-3-oxo-2-phenyl-2,3’-biindoline-6-carboxylate (4db+5db):
General procedure B; yield: 41%; brown gum; 1H NMR (500 MHz,
CDCl3, 258C, TMS): d=3.73 (s, 1H), 3.85 (s, 3H), 3.92 (s, 1H), 3.94 (s,
1H), 5.47 (brs, 1H), 6.97 (dd, J=0.9, 2.6 Hz, 0.46H), 6.99 (s, 1H), 7.08
(s, 1H), 7.12 (d, J=7.8 Hz, 0.59H), 7.20 (d, J=8.4 Hz, 0.47H), 7.22 (s,
0.45H), 7.24 (s, 1H), 7.26 (d, J=1.6 Hz, 2H), 7.29 (d, J=3.3 Hz, 2H),
7.32 (d, J=7.3 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.52 (dd, J=1.9, 7.7 Hz,
2H), 7.54–7.56 (m, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.0 Hz,
0.42H), 7.79 (dd, J=1.3, 8.4 Hz, 1H), 8.20 (brs, 1H), 8.61 ppm (brs,
1H); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=32.8 (q), 32.9 (q),
52.0 (q), 52.6 (q), 72.0 (s), 77.2 (d), 107.8 (s), 108.1 (s), 109.2 (d), 109.8
(d), 113.1 (d), 113.5 (s), 114.1 (d), 119.1 (d), 119.7 (d), 119.9 (d), 120.3
(d), 120.8 (d), 121.0 (d), 121.6 (d), 122.2 ( d), 122.5 (s), 123.9 (s), 125.5
(d), 125.9 (s), 126.8 (d), 127.6 (s), 127.6 (d, 2C), 127.9 (d), 128.0 (d), 128.1
(d), 128.3 (d), 128.5 (d), 128.7 (d, 2C), 132.5 (s), 133.6 (s), 135.2 (s), 137.2
(s), 137.5 (s), 137.8 (s), 138.0 (s), 139.1 (s), 159.8 (s), 166.4 (s), 168.2 (s),
200.4 ppm (s); IR (CHCl3): n˜ =3351, 3017, 2928, 2852, 1702, 1618, 1451,
1217, 1091, 697 cmꢀ1; ESI-MS: m/z (%): 397.33 (20) [M+H]+, 419.33 (40)
[M+Na]+, 435.26 (100) [M+K]+; HRMS: m/z calcd for C25H20N2O3Na+:
419.1372; found: 419.1380.
8-[(tert-Butyldimethylsilyloxy)methyl]-2,2-dimethyl-6-[(trimethylsilyl)-
ACHUTNGRENUNeG thynyl]-1,3,7-trioxaspiroACHTUNGTRNE[NUGN 4.4]nonan-6-ol (11): A solution of trimethylsilyl
acetylene (2.2 mL, 15.7 mmol) in THF (7 mL) was cooled to ꢀ788C
under an argon atmosphere and was treated with nBuLi (6.8 mL, 1.6m in
hexane) and stirred at ꢀ788C for 45 min. A solution of lactone 10 (1.0 g,
3.15 mmol) in THF (5 mL) was added dropwise at the same temperature
Chem. Eur. J. 2012, 18, 9601 – 9611
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9607

C. V. Ramana et al.
and stirring was continued for another 1 h at ꢀ788C. The reaction mix-
ture was quenched with saturated aqueous NH4Cl solution and warmed
to RT. The contents were partitioned between ethyl acetate and water.
The organic layer was separated, and the aqueous layer was extracted
with ethyl acetate (2ꢂ20 mL). The combined organic layer was washed
with brine, dried (Na2SO4), and concentrated. Purification of the crude
by silica gel (100–200 mesh) column chromatography (2!5% ethyl ace-
tate/petroleum ether) gave 11 (1.0 g, 88%) as a colorless liquid. Rf (10%
ethyl acetate/petroleum ether) 0.50; [a]2D5 =ꢀ34.5 (c=0.93 in CHCl3);
1H NMR (200 MHz, CDCl3, 258C, TMS): d=0.07 (s, 6H), 0.16 (s, 9H),
0.87 (s, 9H), 1.43 (s, 3H), 1.49 (s, 3H), 2.18 (dd, J=7.4, 13.1 Hz, 1H),
2.33 (dd, J=8.4, 13.1 Hz, 1H), 3.50 (dd, J=1.8, 10.9 Hz, 1H), 3.86 (dd,
J=2.7, 10.9 Hz, 1H), 4.02 (d, J=9.4 Hz, 1H), 4.31 (d, J=9.4 Hz, 1H),
4.46 (s, 1H), 4.51–4.61 ppm (m, 1H); 13C NMR (50 MHz, CDCl3, 258C,
TMS): d=ꢀ5.8 (q), ꢀ5.5 (q), ꢀ0.5 (q), ꢀ0.4 (q, 3C), 18.3 (s), 25.8 (q,
3C), 25.9 (q), 26.2 (q), 27.0 (q), 35.3 (t), 63.4 (t), 68.2 (t), 78.4 (d), 92.0
(s), 99.4 (s), 111.6 ppm (s); IR (CHCl3): n˜ =3381, 2956, 2931, 1463, 1252,
1115, 1064, 843 cmꢀ1; ESI-MS: m/z (%): 437.20 (100) [M+Na]+, 453.17
(5) [M+K]+; HRMS: m/z calcd for C20H38O5Si2Na+: 437.2155; found:
437.2156.
poured into water (10 mL) and extracted with EtOAc (4ꢂ30 mL). The
combined organic layer was washed with water, then brine, then dried
(Na2SO4) and concentrated under reduced pressure. The crude was puri-
fied by flash column chromatography (4!7% ethyl acetate/petroleum
ether) to procure compound 8 (0.47 g, 89%) as a colorless liquid. Rf
(10% ethyl acetate/petroleum ether) 0.45; [a]2D5 =ꢀ38.3 (c=0.77 in
CHCl3); 1H NMR (200 MHz, CDCl3, 258C, TMS): d=1.40 (s, 3H), 1.41
(s, 3H), 2.04 (dd, J=9.5, 12.9 Hz, 1H), 2.24 (dd, J=6.3, 12.9 Hz, 1H),
2.56 (d, J=2.2 Hz, 1H), 3.57 (dd, J=2.9, 8.7 Hz, 1H), 3.65 (dd, J=5.3,
10.4 Hz, 1H), 3.97 (d, J=9.3 Hz, 1H), 4.29–4.37 (m, 1H), 4.43 (d, J=
9.3 Hz, 1H), 4.52 (d, J=2.2 Hz, 1H), 4.59 (s, 2H), 7.30–7.35 ppm (m,
5H); 13C NMR (50 MHz, CDCl3, 258C, TMS): d=26.2 (q), 26.4 (q), 39.3
(t), 69.8 (t), 72.0 (t), 73.3 (t), 76.0 (d, 2C), 77.8 (d), 80.3 (s), 89.1 (s),
110.4 (s), 127.5 (d), 127.6 (d, 2C), 128.2 (d, 2C), 138.1 ppm (s); IR
(CHCl3): n˜ =3063, 2986, 1724, 1454. 1372, 1215, 1028, 698 cmꢀ1; ESI-MS:
m/z (%): 325.16 (100) [M+Na]+; HRMS: m/z calcd for C18H22O4Na+:
325.1416; found: 325.1394.
8-(Benzyloxymethyl)-2,2-dimethyl-6-[(2-nitrophenyl)ethynyl]-1,3,7-
trioxaspiroACTHNUTRGENUGN[4.4]nonane (13): o-Iodonitrobenzene (1.049 g, 4.21 mmol) in
Et3N/DMF (2:1, 12 mL) and PPh3 (73 mg, 0.28 mmol) was added to a so-
{2,2-Dimethyl-6-[(trimethylsilyl)ethynyl]-1,3,7-trioxaspiro
G
lution of alkyne 8 (0.85 g, 2.81 mmol), and the solution was degassed
yl}methanol (12): At ꢀ788C, a solution of lactols 11 (500 mg, 1.2 mmol)
in CH2Cl2/CH3CN (1:1 ratio, 6 mL) was treated with Et3SiH (0.57 mL,
3.61 mmol) followed by BF3·OEt2 (0.46 mL, 3.61 mmol) and was stirred
for 1 h at the same temperature. The reaction mixture was quenched
with saturated aqueous NaHCO3 solution and was partitioned between
CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 (2ꢂ
15 mL), and the combined organic layer was washed with brine solution,
dried over Na2SO4, and concentrated under reduced pressure. The crude
reaction mixture was subjected to (100–200 mesh) column chromatogra-
phy (20!25% ethyl acetate/petroleum ether) to afford 12 (0.21 g, 61%)
under an argon atmosphere for 10 min. [PdACHTNUGTERNU(NG PPh3)2Cl2] (98 mg,
0.14 mmol) was introduced, and the reaction mixture was degassed with
argon for 10 min. Then CuI (107 mg, 0.562 mmol) was added and the
contents were stirred at room temperature for 2 h. The reaction mixture
was partitioned between ethyl acetate and water, and the aqueous layer
was extracted with ethyl acetate (2ꢂ15 mL). The combined ethyl acetate
layer was washed with brine, dried (Na2SO4), concentrated, and then the
residue obtained was purified by silica gel (100–200 mesh) column chro-
matography (12!16% ethyl acetate/petroleum ether) to afford com-
pound 13 (0.92 g, 76%) as a yellow oil. Rf (20% ethyl acetate/petroleum
ether) 0.45; [a]2D5 = +57.7 (c=0.69 in CHCl3); 1H NMR (200 MHz,
CDCl3, 258C, TMS): d=1.42 (s, 3H), 1.44 (s, 3H), 2.14 (dd, J=3.4,
12.6 Hz, 1H), 2.25 (dd, J=6.4, 12.8 Hz, 1H), 3.60 (dd, J=4.8, 10.6 Hz,
1H), 3.67 (dd, J=5.5, 10.4 Hz, 1H), 4.08 (d, J=9.5 Hz, 1H), 4.39–4.47
(m, 1H), 4.53 (d, J=9.5 Hz, 1H), 4.59 (s, 2H), 4.80 (s, 1H), 7.27–7.34 (m,
5H), 7.46–7.50 (m, 1H), 7.54–7.56 (m, 2H), 8.04 ppm (d, J=7.9 Hz, 1H);
13C NMR (50 MHz, CDCl3, 258C, TMS): d=26.3 (q), 26.4 (q), 39.2 (t),
69.3 (t), 72.3 (t), 73.3 (t), 76.6 (d), 78.3 (d), 82.5 (s), 89.8 (s), 93.8 (s),
110.7 (s), 117.7 (s), 124.6 (d), 127.5 (d), 127.6 (d, 2C), 128.2 (d, 2C),
129.1 (d), 132.9 (d), 135.1 (d), 138.2 (s), 149.4 ppm (s); IR (CHCl3): n˜ =
2985, 2924, 2853, 1734, 1707, 1607, 1527, 1062 cmꢀ1; ESI-MS: m/z (%):
446.17 (100) [M+Na]+, 462.18 (3) [M+K]+; HRMS: m/z calcd for
C24H25NO6Na+: 446.1580; found: 446.1587.
as a colorless liquid. Rf (30% ethyl acetate/petroleum ether) 0.40; [a]D25
=
ꢀ38.5 (c=0.38 in CHCl3); 1H NMR (200 MHz, CDCl3, 258C, TMS): d=
0.16 (s, 9H), 1.40 (s, 6H), 2.08 (dd, J=6.4, 12.9 Hz, 1H), 2.25 (dd, J=9.7,
12.9 Hz, 1H), 3.57 (dd, J=3.1, 12.1 Hz, 1H), 3.84 (dd, J=2.8, 12.1 Hz,
1H), 4.00 (d, J=9.3 Hz, 1H), 4.25–4.33 (m, 1H), 4.37 (d, J=9.3 Hz, 1H),
4.52 ppm (s, 1H); 13C NMR (50 MHz, CDCl3, 258C, TMS): d=0.4 (q,
3C), 26.4 (q), 26.4 (q), 37.1 (t), 63.4 (t), 69.3 (t), 76.8 (d), 79.5 (d), 90.0
(s), 93.7 (s), 102.1 (s), 110.7 ppm (s); IR (CHCl3): n˜ =3420, 2960, 2928,
1714, 1382, 1252, 1048, 847 cmꢀ1; ESI-MS: m/z (%): 285.24 (2) [M+H]+,
307.14 (100) [M+Na]+, 323.51 (10) [M+K]+; HRMS: m/z calcd for
C14H24O4SiNa+: 307.1342; found: 307.1335.
{2,2-Dimethyl-6-[(trimethylsilyl)ethynyl]-1,3,7-trioxaspiroACTHNUGRTNEUNG[4.4]nonan-8-
yl}methyl acetate (12-Ac): At 08C, a solution of compound 12 (565 mg,
1.98 mmol) in acetic anhydride (1.87 mL, 19.8 mmol) was cooled, and
pyridine (1.6 mL, 19.8 mmol) was added dropwise and stirred for 2 h at
the same temperature. The reaction mixture was poured into
CuSO4·7H2O solution (20 mL) and extracted with EtOAc (2ꢂ15 mL).
The combined organic layer was washed again with CuSO4·7H2O solu-
tion (2ꢂ15 mL), then brine, then dried (Na2SO4) and concentrated under
reduced pressure. The crude was subjected for purification by flash
column chromatography (2!6% ethyl acetate/petroleum ether) to pro-
cure compound 12-Ac (0.51 g, 79%) as a colorless liquid. Rf (10% ethyl
8-(Benzyloxymethyl)-2,2-dimethyl-6-[(2-nitrophenyl)ethynyl]-1,3,7-
trioxaspiroACTHNUTRGENUG[N 4.4]nonane (14): At 08C, a solution of compound 13 (920 mg,
2.17 mmol) in MeOH (15 mL) was treated with p-toluenesulfonic acid
(p-TSA; 0.1 mmol) and stirred at RT for 8 h. The reaction was neutral-
ized with triethylamine (the pH was adjusted to 7) and concentrated. The
residue was purified by column chromatography to (60!70% ethyl ace-
tate/petroleum ether) to obtain diol 14 (565 mg, 67%) as a yellow oil. Rf
(70% ethyl acetate/petroleum ether) 0.30; [a]2D5 = +3.4 (c=1.5 in
CHCl3); 1H NMR (200 MHz, CDCl3, 258C, TMS): d=1.95 (dd, J=9.7,
13.1 Hz, 1H), 2.14 (dd, J=6.4, 13.1 Hz, 1H), 2.98 (brs, 1H), 3.66 (dd, J=
4.3, 10.4 Hz, 1H), 3.74 (dd, J=5.8, 10.5 Hz, 2H), 3.84 (d, J=11.6 Hz,
1H), 4.19 (d, J=11.5 Hz, 1H), 4.52–4.60 (m, 1H), 4.64 (s, 2H), 4.85 (s,
1H), 7.27–7.40 (m, 5H), 7.46–7.55 (m, 1H), 7.58 (dd, J=3.6, 4.9 Hz, 1H),
7.63 (dd, J=4.5, 5.4 Hz, 1H), 8.06–8.10 ppm (m, 1H); 13C NMR
(50 MHz, CDCl3, 258C, TMS): d=38.2 (t), 66.0 (t), 72.3 (t), 73.3 (t), 77.3
(d), 78.4 (d), 82.9 (s), 84.0 (s), 93.8 (s), 117.7 (s), 124.6 (d), 127.5 (d),
127.7 (d, 2C), 128.2 (d, 2C), 129.1 (d), 133.1 (d), 135.2 (d), 138.0 (s),
149.1 ppm (s); IR (CHCl3): n˜ =3419, 2924, 1716, 1608, 1225, 1344, 1262,
1099 cmꢀ1; ESI-MS: m/z (%): 406.09 (100) [M+Na]+, 422.04 (3) [M+K]+
; HRMS: m/z calcd for C21H21NO6Na+: 406.1267; found: 406.1283.
1
acetate/petroleum ether) 0.45; [a]2D5 =ꢀ29.6 (c=0.24 in CHCl3); H NMR
(400 MHz, CDCl3, 258C, TMS): d=0.15 (s, 9H), 1.39 (s, 6H), 1.98 (dd,
J=9.8, 12.9 Hz, 1H), 2.08 (s, 3H), 2.21 (dd, J=6.4, 12.9 Hz, 1H), 3.97 (d,
J=9.3 Hz, 1H), 4.09 (dd, J=6.3, 11.7 Hz, 1H), 4.27 (dd, J=3.4, 11.7 Hz,
1H), 4.37 (m, 1H), 4.41 (d, J=9.2 Hz, 1H), 4.51 ppm (s, 1H); 13C NMR
(100 MHz, CDCl3, 258C, TMS): d=0.3 (q, 3C), 20.9 (q), 26.4 (q, 2C),
39.0 (t), 66.0 (t), 69.6 (t), 76.3 (d), 76.6 (d), 89.1 (s), 93.3 (s), 101.6 (s),
110.7 (s), 170.9 ppm (s); IR (CHCl3): n˜ =2960, 2174, 1783, 1715, 1370,
1252, 1047, 848 cmꢀ1; ESI-MS: m/z (%): 365.11 (25) [M+K]+; HRMS: m/
z calcd for C16H26O5SiNa+: 349.1448; found: 349.1446.
8-(Benzyloxymethyl)-6-ethynyl-2,2-dimethyl-1,3,7-trioxaspiroACTHUNTGRNEUNG[4.4]nonane
(8): A solution of compound 12 (500 mg, 1.76 mmol) in DMF (10 mL)
was cooled to 08C, treated with NaH (60% in oil, 106 mg, 2.64 mmol),
and stirred for 45 min. Benzyl bromide (0.3 mL, 2.64 mmol) was added
and stirring was continued for 3 h at 08C. The reaction mixture was
Methyl 5-(benzyloxymethyl)-3-hydroxy-2-[(2-nitrophenyl)ethynyl]tetra-
hydrofuran-3-carboxylate (7): IBX (56 mg, 0.2 mmol) was added to a solu-
tion of alcohol 14 (70 mg, 0.182 mmol) in ethyl acetate (5 mL) and
heated to reflux. After 6 h, the reaction mixture was cooled, filtered
9608
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 9601 – 9611

Synthesis of 13-deoxy-Isatisine A
FULL PAPER
(Celite), and concentrated. NaH2PO4·2H2O (80 mg, 0.55 mmol dissolved
in 15 mL water, pH 7) was added to a cooled solution of the above crude
aldehyde in tBuOH and H2O (2:1, 8 mL). Sodium chlorite (54 mg,
0.55 mmol) was added slowly, followed by 2-methyl-2-butene (0.6 mL,
5.5 mmol), and the stirring was continued at RT for an additional 10 h.
After the reaction was complete, solid NaHCO3 was added, and the reac-
tion mixture was partitioned between ethyl acetate and water. The aque-
ous layer was extracted with the ethyl acetate (2ꢂ10 mL), and the com-
bined organic layer was dried (Na2SO4) and concentrated. The resulting
crude acid was dissolved in toluene/MeOH (4:1, 5 mL), cooled to 08C,
and treated with a solution of trimethylsilyldiazomethane (TMSCHN2;
1.1–1.5 mmol) in hexane dropwise until the yellow color persisted. Stir-
ring was continued for 20 min at 08C. The reaction was quenched with
ice at 08C and was partitioned between ethyl acetate and water. The or-
ganic layer was separated and the aqueous layer was extracted with ethyl
acetate (2ꢂ10 mL). The combined organic layer was washed with brine,
dried (Na2SO4), and concentrated. The crude was subjected to silica gel
(100–200 mesh) column chromatography (15!25% ethyl acetate/petrole-
um ether) to afford compound 7 (42 mg, 56% over three steps) as a color-
less gum. Rf (30% ethyl acetate/petroleum ether) 0.45; [a]2D5 = +95.5 (c=
0.25 in CHCl3); 1H NMR (500 MHz, CDCl3, 258C, TMS): d=2.22 (dd,
J=6.5, 13.3 Hz, 1H), 2.50 (dd, J=9.7, 13.3 Hz, 1H), 3.66 (dd, J=4.1,
10.5 Hz, 1H), 3.74 (dd, J=6.4, 10.5 Hz, 1H), 3.79 (brs, 1H), 3.83 (s, 3H),
4.47–4.52 (m, 1H), 4.59 (d, J=12.1 Hz, 1H), 4.64 (d, J=12.1 Hz, 1H),
4.79 (s, 1H), 7.30–7.36 (m, 5H), 7.48 (ddd, J=2.3, 6.8, 8.4 Hz, 1H), 7.53–
7.57 (m, 2H), 8.02 ppm (d, J=8.3 Hz, 1H); 13C NMR (125 MHz, CDCl3,
258C, TMS): d=39.7 (t), 53.4 (d), 71.7 (t), 73.5 (t), 78.7 (d), 78.9 (d), 83.1
(s), 84.4 (s), 91.4 (s), 117.4 (s), 124.6 (d), 127.6 (d), 127.8 (d, 2C), 128.3
(d, 2C), 129.2 (d), 132.8 (d), 135.1 (d), 138.1 (s), 149.6 (s), 173.2 ppm (s);
IR (CHCl3): n˜ =3447, 2922, 1736, 1527, 1345, 1235, 1091, 745 cmꢀ1; ESI-
MS: m/z (%): 434.05 (100) [M+Na]+; HRMS: m/z calcd for
C22H21NO7Na+: 434.1216; found: 434.1230.
(m, 1H), 5.12 (s, 1H), 6.01 (brs, 1H), 6.76 (t, J=7.4 Hz, 1H), 6.90 (d, J=
8.3 Hz, 1H), 7.02 (t, J=7.7 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.11–7.13
(m, 2H), 7.21–7.27 (m, 5H), 7.46 (ddd, J=1.2, 7.0, 8.3 Hz, 1H), 7.58 (d,
J=7.6 Hz, 1H), 7.76 (d, J=8.2 Hz, 1H), 8.28 ppm (brs, 1H); 13C NMR
(125 MHz, CDCl3, 258C, TMS): d=42.9 (t), 52.7 (q), 70.5 (s), 70.8 (t),
73.3 (t), 78.6 (d), 83.2 (s), 93.8 (d), 110.9 (s), 111.3 (d), 111.5 (d), 118.4
(d), 119.7 (s), 120.1 (d), 120.9 (d), 122.3 (d), 122.9 (d), 124.8 (s), 125.4 (d),
127.4 (d), 127.5 (d, 2C), 128.3 (d, 2C), 136.3 (s), 137.4 (d), 138.3 (s),
161.7 (s), 173.9 (s), 200.7 ppm (s); IR (CHCl3): n˜ =3414, 2926, 1734, 1618,
1488, 1374, 1100, 1044, 753 cmꢀ1
; ESI-MS: m/z (%): 535.19 (100)
[M+Na]+, 551.17 (84) [M+K]+; HRMS: m/z calcd for C30H28N2O6Na+:
535.1845; found: 535.1838.
15-O-Benzyl-13-deoxy-isatisine A (17): At 08C, a solution of ester 16
(30 mg, 0.059 mmol) in THF/MeOH (3 mL, 3:2) was treated with
LiOH·H2O (9 mg, 0.23 mmol) and stirred at RT for 8 h. The reaction
mixture was concentrated under reduced pressure and the crude was fil-
tered through a short silica gel column by using 10% MeOH/CH2Cl2 as
eluent. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI; 16 mg,
0.104 mmol) was added to a solution of the aforementioned acid in THF
(20 mL), and the reaction mixture was heated to reflux for 18 h. The re-
action mixture was concentrated under reduced pressure and crude was
diluted with ethyl acetate (20 mL). The ethyl acetate solution was
washed with brine, dried (Na2SO4), and concentrated under reduced pres-
sure. The resulting crude was subjected for purification by silica gel
column chromatography (35!45% ethyl acetate/petroleum ether) to
yield lactam 17 (16 mg, 57%, 2 steps) as a yellow gum. Rf (60% ethyl
1
acetate/petroleum ether) 0.6; [a]2D5 =ꢀ123.5 (c=0.35 in CHCl3); H NMR
(500 MHz, CDCl3, 258C, TMS): d=2.27 (dd, J=9.1, 13.4 Hz, 1H), 2.67
(dd, J=5.4, 13.4 Hz, 1H), 3.20 (dd, J=4.4, 10.7 Hz, 1H), 3.28 (dd, J=4.0,
10.6 Hz, 1H), 4.06 (d, J=12.4 Hz, 1H), 4.13 (d, J=12.5 Hz, 1H), 4.38–
4.43 (m, 1H), 4.93 (s, 1H), 7.01 (d, J=1.6 Hz, 1H), 7.03 (d, J=2.2 Hz,
1H), 7.19–7.22 (m, 5H), 7.25 (s, 1H), 7.30–7.34 (m, 2H), 7.64 (ddd, J=
1.2, 7.4, 8.5 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 8.00 (d, J=8.1 Hz, 1H),
8.14 (dd, J=2.5, 6.8 Hz, 1H), 8.27 ppm (s, 1H); 13C NMR (125 MHz,
CDCl3,): d=38.6 (t), 71.0 (t), 73.1 (t), 74.4 (s), 78.6 (d), 85.1 (d), 89.9 (d),
111.3 (s), 111.7 (d), 116.4 (d), 120.8 (d), 120.9 (d), 122.2 (d), 123.2 (d),
124.4 (s), 125.5 (d), 125.6 (d), 125.7 (s), 127.4 (d), 127.5 (d, 2C), 128.2 (d,
2C), 136.5 (d), 137.2 (s), 137.9 (s), 150.3 (s), 173.2 (s), 194.3 ppm (s); IR
(CHCl3): n˜ =3393, 2926, 1715, 1698, 1602, 1467, 1094, 750 cmꢀ1; ESI-MS:
m/z (%): 503.24 (100) [M+Na]+, 519.18 (5) [M+K]+; HRMS: m/z calcd
for C29H24N2O5Na+: 503.1583; found: 503.1586.
2-[5-(Benzyloxymethyl)-3-hydroxy-3-(methoxycarbonyl)tetrahydrofuran-
2-yl]-3-oxo-3H-indole 1-oxide (15): Compound 7 (300 mg, 0.73 mmol)
was dissolved in acetonitrile (15 mL) and degassed under an argon at-
mosphere for 10 min. [PdACTHNUTRGNEUNG(CH3CN)2Cl2] (9.4 mg, 5 mol%) was introduced
and stirred for 8 h at room temperature. The reaction mixture was fil-
tered (Celite) and concentrated under reduced pressure. The crude was
subjected to (100–200 mesh) column chromatography (15!25% ethyl
acetate/petroleum ether) purification to procure isatogen 15 (177 mg,
59%) as a yellow oil. Rf (30% ethyl acetate/petroleum ether) 0.35;
[a]2D5 = +166.1 (c=0.38 in CHCl3); 1H NMR (500 MHz, [D4]methanol,
258C, TMS): d=2.19 (dd, J=4.9, 12.6 Hz, 1H), 2.58 (t, J=12.2 Hz, 1H),
3.54 (s, 3H), 3.79 (dd, J=3.8, 10.6 Hz, 1H), 3.96 (dd, J=7.1, 10.4 Hz,
1H), 4.59 (d, J=7.2 Hz, 2H), 4.61–4.62 (m, 1H), 5.34 (s, 1H), 7.29–7.35
(m, 5H), 7.60–7.66 (m, 3H), 7.76 ppm (dd, J=7.0, 8.1 Hz, 1H); 13C NMR
(125 MHz, [D4]methanol, 258C, TMS): d=41.9 (t), 53.2 (q), 73.0 (t), 74.3
(t), 81.2 (d), 81.8 (d), 85.8 (s), 115.0 (d), 122.7 (d), 124.3 (s), 128.7 (d),
128.9 (d, 2C), 129.3 (d, 2C), 133.2 (d), 136.0 (d), 136.4 (s), 139.6 (s),
148.0 (s), 172.9 (s), 185.9 ppm (s); IR (CHCl3): n˜ =3337, 3020, 2927, 1735,
1618, 1215, 1100, 698 cmꢀ1; ESI-MS: m/z (%): 434.08 (100) [M+Na]+;
HRMS: m/z calcd for C22H21NO7Na: 434.1216; found: 434.1226.
13-deoxy-Isatisine A (6): At 08C,
a solution of lactam 17 (21 mg,
0.043 mmol) in CH2Cl2 (3 mL) was treated with a solution of TiCl4 in
CH2Cl2 (0.04 mL, 0.437 mmol) and stirred at the same for 1 h. The reac-
tion mixture was quenched with ice and warmed to RT. The contents
were partitioned between ethyl acetate and water, and the aqueous layer
was extracted with EtOAc (2ꢂ5 mL). The combined organic layer was
washed with brine, dried (Na2SO4), and concentrated. The crude was sub-
jected to silica gel (100–200 mesh) column chromatography (50!60%
ethyl acetate/petroleum ether) to obtain 6 (15 mg, 88%) as a colorless
gum. Rf (70% ethyl acetate/petroleum ether) 0.6; [a]2D5 =ꢀ157.7 (c=0.95
in CH3OH); 1H NMR (500 MHz, [D4]methanol, 258C, TMS): d=2.17
(dd, J=8.5, 13.4 Hz, 1H), 2.47 (dd, J=6.3, 13.5 Hz, 1H), 3.27 (dd, J=3.9,
4.9 Hz, 2H), 4.21–4.27 (m, 1H), 4.91 (brs, 3H), 7.07 (ddd, J=0.9, 6.9,
8.0 Hz, 1H), 7.14 (ddd, J=1.1, 6.9, 8.0 Hz, 1H), 7.27 (s, 1H), 7.31–7.36
(m, 2H), 7.64 (d, J=7.5 Hz, 1H), 7.80 (ddd, J=1.2, 7.4, 8.4 Hz, 1H), 7.93
(d, J=8.0 Hz, 1H), 8.0 ppm (d, J=8.1 Hz, 1H); 13C NMR (125 MHz,
[D4]methanol, 258C, TMS): d=39.8 (t), 65.0 (t), 76.1 (s), 80.9 (d), 86.2
(d), 90.6 (s), 110.8 (s), 112.8 (d), 117.7 (d), 120.5 (d), 121.4 (d), 123.0 (d),
124.4 (d), 125.9 (s), 126.2 (d), 126.8 (d), 127.2 (s), 137.8 (d), 139.0 (s),
151.9 (s), 175.4 (s), 196.7 ppm (s); IR (CH3OH): n˜ =3400, 2935, 1709,
Methyl 5-(benzyloxymethyl)-3-hydroxy-2-(3-oxo-2,3’-biindolin-2-yl)tetra-
hydrofuran-3-carboxylate (16): Anhydrous InCl3 (6 mg, 0.02 mmol) was
added to a solution of compound 15 (50 mg, 0.12 mmol) and indole
(22 mg, 0.18 mmol) in acetonitrile (4 mL). It was degassed under an
argon atmosphere for 10 min and stirred at RT for 5 h. After the reaction
was complete as indicated by TLC, acetonitrile was evaporated under re-
duced pressure and crude was dissolved in acetonitrile/toluene (1:5,
5 mL). Additional anhydrous InCl3 (35 mg, 0.16 mmol) was added, and
the reaction mixture was allowed to stir at 808C under an argon atmos-
phere for 4 h. Solvent was removed under reduced pressure, and the
crude was purified by silica gel (60–12 mesh) column chromatography
(40!50% ethyl acetate/petroleum ether) to afford compound 16 (33 mg,
1658, 1467, 1299, 1020, 750 cmꢀ1
; ESI-MS: m/z (%): 413.10 (100)
[M+Na]+; HRMS: m/z calcd for C22H18N2O5Na+: 413.1113; found:
413.1099.
53%) as a red gum. Rf (60% ethyl acetate/petroleum ether) 0.4; [a]D25
=
+12.5 (c=0.23 in CHCl3); 1H NMR (500 MHz, CDCl3, 258C, TMS): d=
2.10 (dd, J=5.0, 12.7 Hz, 1H), 2.50 (dd, J=11.2, 12.7 Hz, 1H), 2.95 (s,
3H), 3.44 (dd, J=5.2, 11.2 Hz, 1H), 3.55 (dd, J=3.7, 11.2 Hz, 1H), 3.59
(brs, 1H), 4.23 (d, J=12.3 Hz, 1H), 4.35 (d, J=12.3 Hz, 1H), 4.37–4.42
Chem. Eur. J. 2012, 18, 9601 – 9611
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9609

C. V. Ramana et al.
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 9601 – 9611

Synthesis of 13-deoxy-Isatisine A
FULL PAPER
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[26] The possibility of dehydration of compound 7 and the subsequent
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toward isatisine A synthesis has been attempted. However, the prod-
uct that resulted from the dehydration was found to be an unwanted
ꢀ
regioisomer with the newly formed olefin between the C1 C2 bond
of the furanose ring.
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Received: November 16, 2011
Revised: April 24, 2012
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Published online: July 4, 2012
Chem. Eur. J. 2012, 18, 9601 – 9611
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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