Total synthesis of (-)-isatisine A

Article abstract of DOI:10.1021/jo302198v

A modular total synthesis of (-)-isatisine A is described in which four consecutive metal-mediated transformations have been employed at the final stage. These include [Pd]-catalyzed Sonogashira coupling, [Pd]-catalyzed nitroalkyne cycloisomerization leading to isatogens, and addition of indoles to isatogens using InCl₃-and [Rh]-catalyzed oxidative N-heterocyclization of amino alcohol to form the key amide bond. In addition to these, the removal of the protecting groups has also been carried out in a selective fashion employing either catalytic or stoichiometric metal/metal-based reagents.

Full text of DOI:10.1021/jo302198v

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pubs.acs.org/joc
Total Synthesis of (−)-Isatisine A
Pitambar Patel and C. V. Ramana*
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhaba Road, Pune-411008, India
S
* Supporting Information
ABSTRACT: A modular total synthesis of (−)-isatisine A is
described in which four consecutive metal-mediated trans-
formations have been employed at the final stage. These include
[Pd]-catalyzed Sonogashira coupling, [Pd]-catalyzed nitroalkyne
cycloisomerization leading to isatogens, and addition of
indoles to isatogens using InCl3- and [Rh]-catalyzed oxidative
N-heterocyclization of amino alcohol to form the key amide
bond. In addition to these, the removal of the protecting groups
has also been carried out in a selective fashion employing either
catalytic or stoichiometric metal/metal-based reagents.
INTRODUCTION
■
The structural complexity and skeletal diversity of natural prod-
ucts have served as inspirations to organic chemists for the dis-
covery and design of new synthetic methods en route to their
chemical synthesis.1 In recent years, methods for new carbon−
carbon and carbon−heteroatom bond formation mediated by
transition metal complexes have found enormous applications
in natural product synthesis.2 The development of modular
strategies involving metal-mediated reactions that enable the
synthesis of structural variants of the targeted natural product is
an active ongoing program in our group.3 In this context, herein
we document a highly modular total synthesis of (−)-isatisine
A,4−9 featuring four consecutive metal-mediated transformations at
the final stagea couple of reactions having been developed
indigenously.
In 2007, Chen and co-workers reported the isolation of
(−)-isatisine A (1), a complex alkaloid having a bisindole skele-
ton, from the leaves of Isatis indigotica Fort, an herbaceous plant
species used in Chinese folk medicine.4 The acetonide derivative
2, which is an artifact during the isolation, was found to exhibit
cytotoxicity against C8166 with CC50 = 302 μM and anti-HIV
activity of EC50 = 37.8 μM. The challenging structural features of
isatisine A (1) is characterized by the presence of a fused tetra-
cyclic system comprising mainly furanose and indolin-3-one units.
These two units are connected through a C-anomeric linkage at
the C(2) position of the indolin-3-one and an amide bridge
between the C(2) of furanose and nitrogen of the indolinone.
There is an indole unit as a substituent at the C(2) position of
indolinone connected with its C(3). Keeping the promising
biological activity in mind, taken together with its unique struc-
ture, several programs aimed at its total synthesis were initiated
immediately after its isolation. In 2010, Kerr’s group reported
the first total synthesis of isatisine A and revised its absolute
configuration, as shown in Figure 1.5 Following this, Panek6
and Liang7 reported the total synthesis of isatisine A. Very re-
cently, Xie et al. have reported its biomimetic synthesis, which
is characterized by its short sequence.8
Figure 1. Revised structure of (−)-isatisine A (1) and its acetonide (2).
Scheme 1 outlines the salient features of our retrosynthetic
disconnections. The construction of the central lactam ring
has been planned as the final key event in our total synthesis
featuring a metal-mediated oxidative N-heterocyclization of the
amino alcohol 3.10,11 The synthesis of amino alcohol 3 features
the addition of indole to the isatogen 4. The nitroalkyne 5 has
been identified as an advanced intermediate for the synthesis of
4 which, in turn, has been planned from the alkyne 6. Alkyne
6 can be prepared from the known ribose derivative 7 by simple
functional group manipulation. In the context of this total syn-
thesis, we have developed methods for the synthesis of isatogens9a
and spiroindolin-3-one derivatives9b based upon the [Pd]-mediated
nitroalkyne cycloisomerization. We have also developed methods
for the addition of indole to isatogens. A model study exploiting
the indole addition to isatogens has resulted in the synthesis of
10-deoxyisatisine A.9c
RESULTS AND DISCUSSION
■
The synthesis commenced with the preparation of key alkyne 6
from the known compound 7 (Scheme 2). Compound 7 was
prepared from D-ribose following the established procedures.12
The C(2) hydroxymethylation of 7 was carried out with an
excess of 40% formaldehyde solution and potassium carbonate
Received: October 6, 2012
© XXXX American Chemical Society
A
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involving addition of trimethylsilylethynyllithium to the lactone
11 followed by reduction of the crude hemiketal using Et3SiH
in the presence of BF3·Et2O in dichloromethane at −78 °C and
subsequent C-TMS deprotection using K2CO3 in a 1:1 mixture
of methanol and dichloromethane furnished the β-alkyne 6
(39%) along with the α-anomer (14%) in a ∼3:1 ratio (overall
yields for three steps).
Scheme 1. Key Retrosynthetic Disconnections for
(−)-Isatisine A
Next, the Sonogashira coupling of 6 with 2-iodonitrobenzene
under standard conditions furnished the nitroalkyne 5 in 85%
yield. The key nitroalkyne cycloisomerization of 5 proceeded
smoothly with 5 mol % of Pd(CH3CN)2Cl2, and the isatogen 4
was obtained in 75% yield (Scheme 3).9a The next concern was
Scheme 3. Attempted Synthesis of (−)-Isatisine A
Scheme 2. Synthesis of Key Alkyne Intermediate 6
executing the alkylation of isatogen with indole and the sub-
sequent N−O reduction by employing InCl3 as a reagent.9c
Accordingly, compound 5 was treated with indole in the pres-
ence of 20 mol % of InCl3 in acetonitrile solvent, which led to
an intractable complex reaction mixture. Varying the temper-
ature, solvent, and the amounts of InCl3 had no effect on the
reaction outcome, and also, the use of other Lewis acids did not
lead to the desired product. In the majority of the cases, the
reaction ended with either deprotection of the TBS group or
formation of a complex reaction mixture. We reasoned that the
presence of a bulky and acid-labile TBS group might be the
possible reason for this.16
We resorted next to switching the protecting group from
TBS to acetate. For this, the alkynol 12 was prepared from lactone
11 following a three-step procedure (Scheme 4), which involves
addition of trimethylsilylethynyllithium to the lactone 11 followed
by reduction of the crude hemiketal using Et3SiH in the presence
of BF3·Et2O in dichloromethane at −78 °C, and subsequent
deprotection of both silyl groups using TBAF in THF furnished
the β-alkynol 12 (37%) along with the α-anomer (13%) in
a ∼3:1 ratio (overall yields for three steps). Sonogashira cou-
pling of 12 with 2-iodonitrobenzene under standard conditions
furnished the nitroalkyne 13 in 90% yield. Protection of the
free −OH group of 13 as its acetate 14 followed by the [Pd]-
mediated nitroalkyne cycloisomerization gave the correspond-
ing isatogen 15 in 72% yield. The key indole addition reaction
with the isatogen 15 needed a substantial optimization. It was
realized that the reaction in acetonitrile at room temperature in
the presence of catalytic amounts of InCl3 was sluggish. The
optimized conditions involve the treatment of 15 with 2 equiv
of indole in the presence of 1 equiv of InCl3 in acetonitrile at
70 °C for 12 h.17 As the deacetylation was a side reaction under
in methanol at 90 °C for 30 h to procure the diol 8 in 90%
yield.13 The primary hydroxyl group was selectively protected
as its TBS ether 9. Our initial attempts to synthesize the
β-alkyne 6 following a two-step sequence involving the addition
of acetylene Grignard to the lactol 9 and subsequent treatment
of the intermediate alkynol with p-TsCl and pyridine at 80 °C
gave the cyclic alkyne 6 in 77% yield as a single diastereomer.14
The 2D NMR spectral analysis revealed that compound 6
was the undesired α-anomer. Nevertheless, Kishi’s15 strategy
B
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Scheme 4. Total Synthesis of (−)-Isatisine A (1) and Its Acetonide 2
these conditions, the intermediate addition product was treated
immediately with K2CO3 in methanol to obtain the key amino
alcohol intermediate 3 in 65% yield over two steps as a single
diastereomer.
EXPERIMENTAL SECTION
■
5-O-Benzyl-2-C-(hydroxymethyl)-2,3-O-isopropylidene-D-ri-
bofuranose (8). A suspension of lactal 7 (20 g, 71.4 mmol) and
K2CO3 (14.8 g, 107 mmol) in MeOH (150 mL) was treated with 37%
aqueous formaldehyde (150 mL) and stirred for 30 h at 90 °C. After
completion of the reaction as indicated by TLC, the reaction mixture
was cooled in an ice bath and neutralized with 10% aqueous HCl. The
reaction mixture was concentrated and extracted with ethyl acetate.
The combined organic layer was dried (Na2SO4), concentrated, and
purified by column chromatography (35% EtOAc/petroleoum ether)
to afford the diol 8 (19.9 g, 90%) as a colorless liquid: Rf (50% ethyl
The oxidative lactamization of 3 has been examined by screening
various transition metal catalysts that have been prescribed for
this purpose.10 The [Cp*RhCl2]2 complex was the most fruitful
catalyst in this regard.18 The optimized conditions involve the
use of [RhCp*Cl2]2 (10 mol %) and catalytic potassium car-
bonate in acetone at 100 °C for 26 h to furnish the lactam com-
pound 16 in moderate yields. Having the complete skeleton in
hand, the stage was now set for the completion of the total
synthesis of (−)-isatisine A by deprotection of the benzyl and
acetonide groups. To this end, the global deprotection of 16
using TiCl4 resulted in the isolation of (−)-isatisine A (1) in
71% yield.19 The spectral and analytical data for (−)-isatisine A
were in accordance with the data reported by the other groups.
The specific rotation of the synthetic (−)-isatisine A (1) was
25
acetate/petroleum ether) 0.3; [α]D = 10.6 (c 2.77, CHCl3); IR
(CHCl3) ν 3428, 2989, 2936, 2870, 1715, 1496, 1455, 1372, 1216,
1
1075, 860, 755 cm−1; H NMR (200 MHz, CDCl3) δ 1.43 (s, 3H,
major), 1.47 (s, 2.3H, minor), 1.5 (s, 3H, major), 1.58 (s, 2.3H,
minor), 2.18−2.24 (m, 0.7H, minor), 2.33−2.39 (m, 1H, major),
3.58−3.68 (m, 3.3H), 3.7−3.83 (m, 4H), 4.23−4.27 (m, 0.8H, minor),
4.34−4.37 (m, 1H, major), 4.51−4.61 (m, 4.7H), 4.64−4.68 (m,
1.4H), 4.73 (s, 0.7H), 5.24 (d, J = 10.3 Hz, 1H, minor), 5.31 (d, J =
10.9 Hz, 1H, major), 7.28−7.4 (m, 8.8H) ppm; 13C NMR (50 MHz,
CDCl3) δ 27.1 (q, minor), 27.3 (q, minor), 27.5 (q, major), 28.1 (q,
major), 62.6 (t, major), 62.9 (t, minor), 70.9 (t, major), 71.5
(t, minor), 73.7 (t, minor), 74.1 (t, major), 80.9 (d, minor), 83.9 (d,
minor), 84.6 (d, major), 85.8 (d, major), 91.4 (s, minor), 94.8 (s,
major), 98.8 (d, minor), 104.6 (d, major), 113.3 (s, major), 114.1 (s,
minor), 127.8 (d, minor), 127.9 (d, minor), 128.2 (d, major), 128.5 (d,
minor), 128.6 (d, major), 128.8 (d, major), 135.9 (s, major), 137.2 (s,
minor) ppm; MS (ESI) m/z 333.2 ([M + Na]+); HRMS (ESI) calcd
for C16H22O6 [M + Na]+ 333.1313, found 333.1308.
25
[α]D = −276 (c = 0.21, MeOH), which is essentially equal
14
and opposite in sign to that reported by Kerr ([α]D = +274)
for its enantiomer.5 Alternatively, to have the access for the
acetonide 2, which showed promising anti-HIV activity,
we explored the possibility of selective debenzylation. This
can be smoothly effected by hydrogenolysis of 16 with
Pd(OH)2 in ethanol at balloon pressure to furnish acetonide
2 in 96% yield. The spectral and analytical data of acetonide
2 are in accordance with the data reported in the isolation
paper.4
5-O-Benzyl-2-C-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-O-
isopropylidene-D-ribofuranose (9). At 0 °C, a solution of alcohol 8
(15 g, 48.3 mmol) in CH2Cl2 (30 mL) was treated with triethylamine
(13.5 mL, 96.7 mmol) followed by TBDMSCl (7.28 g, 48.3 mmol).
The reaction mixture was slowly allowed to reach room temperature
and was stirred for 8 h. After the completion of the reaction, ice was
added to the reaction mixture and stirred for 5 min. The contents were
diluted with CH2Cl2 (60 mL), and the resulting layers were separated.
The aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The com-
bined organic layer was washed with brine, dried over MgSO4, and
concentrated. The crude product was purified by flash column
chromatography (9% EtOAc/petroleoum ether) to afford lactols 9
(18.88 g, 92%) as colorless oil: Rf (15% ethyl acetate/petroleum ether)
CONCLUSION
■
To conclude, a modular total synthesis of (−)-isatisine A start-
ing from D-ribose has been completed featuring four consecutive
metal-catalyzed/mediated transformations at the final stage. The
reactions address two of each of the C−C and C−heteroatom
bond formations. Also, the present synthesis documents
the first application of a [Rh]-catalyzed oxidative N-hetero-
cyclization of amino alcohol leading to the γ-lactam in the
synthesis of a complex natural product. Efforts to optimize
the final synthetic events in a continuous flow manner20
and the synthesis of (−)-isatisine A related small molecules
are currently underway.
25
0.3; [α]D = 14.1 (c 3.24, CHCl3); IR (CHCl3) ν 3432, 2931, 2858,
1725, 1496, 1457, 1381, 1251, 1212, 1090, 838, 777 cm−1; H NMR
1
(200 MHz, CDCl3) δ 0.0 (s, 6H, major), 0.03 (s, 3H, minor), 0.86
C
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(s, 9H, major), 0.89 (s, 4.5H, minor), 1.42 (s, 1.5H, minor), 1.45 (s,
3H, major), 1.47 (s, 1.5H, minor), 1.55 (s, 3H, major), 3.55 (d, J = 4.3
Hz, 2H, major), 3.62 (d, J = 3.0 Hz, 1H, minor), 3.5 (dd, J = 5.4, 10.2
Hz, 1H), 3.55 (dd, J = 5.4, 10.2 Hz, 1H), 3.7 (br s, 2H), 4.2−4.25 (m,
1H), 4.23 (dt, J = 1.3, 4.3 Hz, 1H, major), 4.32 (dt, J = 1.1, 4.3 Hz,
0.5H, minor), 4.55 (d, J = 12.0 Hz, 1H), 4.62 (d, J = 1.4 Hz, 1H), 5.14
(d, J = 10.7 Hz, 1H, major), 5.22 (d, J = 11.4 Hz, 0.5H, minor), 7.27−
2.37 (m, 7.5H) ppm; 13C NMR (50 MHz, CDCl3) δ −5.7 (q), −5.5
(q), 18.3 (s, major), 18.4 (s, minor), 25.8 (q, major), 25.9 (q, minor),
27.3 (q, major), 27.6 (q, major), 27.9 (q, minor), 27.9 (q, minor), 62.3
(t, minor), 62.8 (t, major), 70.8 (t, major), 71.2 (t, minor), 73.6
(t, major), 74.1 (t, minor), 81.0 (d, major), 83.7 (d, major), 84.4 (d,
minor), 85.8 (d, minor), 91.4 (s, major), 95.0 (s, minor), 98.4 (d,
major), 105.1 (d, minor), 113.4 (s, minor), 114.1 (s, major), 127.7 (d,
major), 127.8 (d, minor), 128.2 (d, minor), 128.4 (d, major), 128.7 (d,
minor), 136.2 (s, minor), 137.6 (s, major) ppm; MS (ESI) m/z 447.2
([M + Na]+); HRMS (ESI) calcd for C22H36O6Si ([M + Na]+)
447.2179, found 447.2163.
16.1 mmol) and Ag2CO3 impregnated on Celite (36.7 g, 64.4 mmol,
contains 1 mmol of Ag2CO3 per 0.57 g of prepared reagent) in dry
toluene (50 mL) was refluxed for 6 h. After completion of reaction as
indicated by TLC, the contents were cooled to room temperature and
filtered through a pad of Celite. The Celite pad was washed with
toluene, and the combined filtrate was concentrated under reduced
pressure. The crude product was purified by silica gel column
chromatography (3% EtOAc/petroleoum ether) to procure lactone 11
(4.43 g, 89% yield) as crystalline solid: Rf (5% ethyl acetate/petroleum
25
ether) 0.2; mp 83 °C; [α]D = −12 (c 1.27, CHCl3); IR (CHCl3) ν
2931, 2858, 1789, 1727, 1496, 1463, 1383, 1253, 1214, 1108, 1080,
1
838, 780 cm−1; H NMR (200 MHz, CDCl3) δ 0.0 (s, 3H), 0.02 (s,
3H), 0.86 (s, 9H), 1.40 (s, 3H), 1.44 (s, 3H), 3.67 (d, J = 4.5 Hz, 2H),
3.80 (d, J = 10.6 Hz, 1H), 3.97 (d, J = 10.6 Hz, 1H), 4.50 (d, J = 12.2
Hz, 1H), 4.56 (d, J = 12.2 Hz, 1H), 4.60 (t, J = 4.5 Hz, 1H), 4.72 (s,
1H), 7.26−7.38 (m, 5H) ppm; 13C NMR (50 MHz, CDCl3) δ −5.7
(q), −5.5 (q), 18.3 (s), 25.8 (q, 3C), 26.7 (q), 27.1 (q), 61.8 (t), 69.0
(t), 73.7 (t), 79.7 (d), 82.5 (d), 86.0 (s), 113.4 (s), 127.8 (d, 2C),
128.0 (d), 128.5 (d, 2C), 137.1 (s), 174.7 (s) ppm; MS (ESI) m/z
445.1 ([M + Na]+); HRMS (ESI) calcd for C22H34O6Si ([M + Na]+)
445.2022, found 445.2027.
Synthesis of Compounds 6 and 12 from Lactone 11. A
solution of trimethylsilyl acetylene (3.23 mL, 22.7 mmol) in THF
(15 mL) was cooled to −78 °C under argon and treated with n-BuLi
(13.6 mL, 1.6 M in hexane) and stirred at −78 °C for 45 min. To this
was introduced a solution of lactone 11 (4.0 g, 9.47 mmol) in THF
(15 mol) added dropwise, and stirring was continued for another
5 min at −78 °C and then at −10 °C for 30 min. The reaction mixture
was quenched with saturated aqueous NH4Cl solution and partitioned
between ethyl acetate and water. The organic layer was washed with
brine, dried over Na2SO4, and concentrated. The resulting crude prod-
uct was used for the next step without any further purification.
To a cooled (−78 °C) solution of the 500 mg of crude hemiacetal
and triethylsilane (1.6 mL, 9.6 mmol) in anhydrous CH2Cl2 (20 mL)
was added dropwise BF3·OEt2 (0.57 mL, 4.8 mmol), and stirring was
continued at the same temperature for 30 min. When all of the starting
material was completely consumed as indicated by TLC, the reaction
mixture was neutralized with triethylamine and extracted with di-
chloromethane. The combined organic layer was dried (Na2SO4), filtered,
and concentrated to obtain 600 mg of crude product. The crude was
subjected for next step without further purification.
1-((4S,5R)-5-((R)-2-(Benzyloxy)-1-hydroxyethyl)-4-(((tert-
butyldimethylsilyl)oxy)meth-yl)-2,2-dimethyl-1,3-dioxolan-4-
yl)prop-2-yn-1-ol (10). Flame-dried Mg (86 mg, 3.53 mmol) was
treated with dry THF (4 mL) and a few crystals of iodine. To it was
added n-BuCl (327 mg, 3.53 mmol), and the contents were refluxed
until the generation of Grignard reagent. Heating was removed, and
stirring was continued at room temperature until all of the magnesium
was consumed. Then the reaction mixture was cooled to 0 °C, and
acetylene gas was bubbled into it for 15 min. At the same temperature,
a solution of lactals 9 (300 mg, 0.706 mmol) in THF (3 mL) was
added and stirred for 30 min at 0 °C. The reaction was quenched with
saturated NH4Cl solution, diluted with water, and extracted with ethyl
acetate. The combined organic layer was dried over Na2SO4, con-
centrated, and purified on silica gel chromatography (8% EtOAc/
petroleoum ether) to give the diol 10 (340 mg, 78%) as colorless oil:
25
Rf (15% ethyl acetate/petroleum ether) 0.4; [α]D = −2.3 (c 1.2,
CHCl3); IR (CHCl3) ν 3447, 2988, 2931, 2861, 1725, 1603, 1496,
1
1454, 1381, 1217, 1071, 757 cm−1; H NMR (200 MHz, CDCl3) δ
0.09 (s, 3H), 0.09 (s, 3H), 0.90 (s, 9H), 1.37 (s, 3H), 1.46 (s, 3H),
2.46 (d, J = 2.3 Hz, 1H), 3.54−3.68 (m, 3H), 3.77 (dd, J = 2.4, 10.1
Hz, 1H), 3.87 (d, J = 10.6 Hz, 1H), 4.07 (d, J = 10.6 Hz, 1H), 4.58−
4.65 (m, 3H), 7.29−7.36 (m, 5H) ppm; 13C NMR (50 MHz, CDCl3)
δ −5.7 (q), −5.5 (q), 18.3 (s), 25.9 (q, 3C), 26.1 (q), 27.7 (q), 63.8
(d), 64.0 (t), 68.5 (d), 71.9 (t), 73.4 (t), 74.3 (s), 77.8 (d), 82.5 (s),
84.6 (d), 108.8 (s), 127.6 (d), 127.7 (d, 2C), 128.3 (d, 2C), 138.1 (s)
ppm; MS (ESI) m/z 473.1 ([M + Na]+); HRMS (ESI) calcd for
C24H38O6Si ([M + Na]+) 473.2335, found 473.2334.
(((3aS,4S,6R,6aR)-6-((Benzyloxy)methyl)-4-ethynyl-2,2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-3a-yl)methoxy)(tert-
butyl)dimethylsilane (6-β). Potassium carbonate (0.6 g, 3.44 mmol)
was added to a stirred solution of crude compound (0.5 g) in a 1:1
mixture of methanol−CH2Cl2 (30 mL) at room temperature, and the
reaction mixture was stirred for 4 h. The reaction mixture was con-
centrated and then extracted with dichloromethane. The combined
organic layer was dried (Na2SO4) and concentrated under reduced
pressure. The crude product was subjected to column chromatography
purification (3% EtOAc/petroleoum ether) to afford 6-β (190 mg,
39%) and 6-α (72 mg, 14%); 6-β as colorless liquid; Rf (10% ethyl acetate/
petroleum ether) 0.6; [α]D25 = −34.5 (c 1.55, CHCl3); IR (CHCl3) ν 3932,
2858, 2139, 1722, 1612, 1586, 1513, 1463, 1370, 1250, 1104, 1006,
(((3aS,4R,6R,6aR)-6-((Benzyloxy)methyl)-4-ethynyl-2,2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-3a-yl)methoxy)(tert-
butyl)dimethylsilane (6-α). To a solution of diol 10 (200 mg, 0.44
mmol) in dry pyridine (2 mL) was added tosyl chloride (169 mg, 0.88
mmol), and the resulting solution was heated at 50−60 °C for 3 h. To
this was added water, and the contents were extracted with CH2Cl2.
The combined organic phase was dried with MgSO4 and concentrated
to dryness under reduced pressure. The crude was purified by silica gel
column chromatography (4% EtOAc/petroleoum ether) to procure
alkyne 6-α (148 mg, 77% yield) as colorless oil: Rf (10% ethyl acetate/
1
838, 758 cm−1; H NMR (200 MHz, CDCl3) δ 0.05 (s, 3H), 0.06 (s,
25
3H), 0.90 (s, 9H), 1.41 (s, 3H), 1.52 (s, 3H), 2.53 (d, J = 2.1 Hz, 1H),
3.55 (dd, J = 5.2, 10.1 Hz, 1H), 3.60 (dd, J = 5.2, 10.1 Hz, 1H), 3.76
(d, J = 11.3 Hz, 1H), 4.02 (d, J = 11.3 Hz, 1H), 4.21 (dt, J = 2.6, 5.2
Hz, 1H), 4.53 (d, J = 2.1 Hz, 1H), 4.55 (d, J = 12.2 Hz, 1H), 4.59 (d,
J = 12.2 Hz, 1H), 4.64 (d, J = 2.6 Hz, 1H), 7.26−2.33 (m, 5H) ppm;
13C NMR (50 MHz, CDCl3) δ −5.6 (q), −5.4 (q), 18.4 (s), 25.9 (q,
3C), 26.8 (q), 28.3 (q), 61.7 (t), 69.7 (t), 73.5 (t), 75.5 (d), 76.6 (d),
77.6 (s), 82.0 (d), 83.3 (d), 92.0 (s), 114.8 (s), 127.7 (d), 127.8 (d,
2C), 128.4 (d, 2C), 137.9 (s) ppm; MS (ESI) m/z 433.1 ([M + H]+);
HRMS (ESI) calcd for C24H36O5Si [M + K]+ 471.1969, found 471.1965.
((3aS,4S,6R,6aR)-6-((Benzyloxy)methyl)-4-ethynyl-2,2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-3a-yl)methanol (12-
β). At 0 °C, the reduced crude product (0.6 g) in THF (10 mL) 1 M
TBAF solution in THF (2.54 mL, 2.54 mmol) was added and stirred for
4 h at the same temperature. After completion, the reaction mixture was
petroleum ether) 0.5; [α]D = −12.1 (c 4.03, CHCl3); IR (CHCl3)
ν 3306, 2931, 2858, 2118, 1727, 1496, 1455, 1381, 1253, 1218, 1060, 839,
1
756 cm−1; H NMR (200 MHz, CDCl3) δ 0.03 (s, 6H), 0.87 (s, 9H),
1.43 (s, 3H), 1.58 (s, 3H), 2.58 (d, J = 2.3 Hz, 1H), 3.5 (dd, J = 5.4, 10.2
Hz, 1H), 3.55 (dd, J = 5.4, 10.2 Hz, 1H), 3.7 (br s, 2H), 4.26−4.31 (m,
1H), 4.58 (d, J = 12.0 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H), 4.62 (d, J = 1.4
Hz, 1H), 4.69 (br d, J = 2.3 Hz, 1H), 7.26−2.34 (m, 5H) ppm; 13C NMR
(50 MHz, CDCl3) δ −5.7 (q), −5.5 (q), 18.3 (s), 25.8 (q, 3C), 27.3 (q),
27.9 (q), 63.2 (t), 69.4 (t), 72.9 (d), 73.4 (t), 76.2 (d), 78.5 (s), 83.6 (d),
85.2 (d), 93.5 (s), 114.2 (s), 127.7 (d, 2C), 127.8 (d), 128.4 (d, 2C),
137.7 (s) ppm; MS (ESI) m/z 455.2 ([M + Na]+); HRMS (ESI) calcd
for C24H36O5Si ([M + Na]+) 455.2229, found 455.2225.
(3aR,6R,6aR)-6-((Benzyloxy)methyl)-3a-(((tert-butyl-
dimethylsilyl)oxy)methyl)-2,2-dimethyldihydrofuro[3,4-d]-
[1,3]dioxol-4(3aH)-one (11). A suspension of TBS lactals 9 (5 g,
D
dx.doi.org/10.1021/jo302198v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
quenched with saturated NH4Cl (20 mL) and the contents were
partitioned between ethyl acetate and water. The organic layer was
separated, and the aqueous layer was extracted with ethyl acetate
(20 mL × 3). The combined organic layer was dried (Na2SO4) and
concentrated under reduced pressure. The residue obtained was
purified by column chromatography (18% EtOAc/petroleoum ether)
to afford alkynol 12-β (133 mg, 37% yield) and 12-α (44 mg, 13%) as
colorless oil: Rf (40% ethyl acetate/petroleum ether) 0.5; [α]D25 = −26
(c 1.37, CHCl3); IR (CHCl3) ν 3479, 3291, 2990, 2936, 2862, 2121,
(d), 134.6 (s), 138.0 (s), 146.9 (s), 184.5 (s) ppm; MS (ESI) m/z
576.2 ([M + Na]+); HRMS (ESI) calcd for C30H39NO7Si [M + Na]+
576.2393, found 576.2388.
((3aS,4S,6R,6aR)-6-((Benzyloxy)methyl)-2,2-dimethyl-4-((2-
nitrophenyl)ethynyl)tetrahydrofuro[3,4-d][1,3]dioxol-3a-yl)-
methanol (13). The Sonogashira coupling of alkynol 12-α (200 mg,
0.32 mmol) and 2-nitroiodobenzene (187 mg, 0.753 mmol) was
carried out according to the procedure used for the preparation of 5.
Purification of the crude by column chromatography (20% EtOAc/
petroleoum ether) gave the nitroalkynol 13 (249 mg, 90%) as yellow
1
1723, 1496, 1455, 1382, 1217, 1152, 1072, 755 cm−1; H NMR (200
25
syrup: Rf 0.6 (petroleum ether/EtOAc 7:3); [α]D = −154 (c = 0.5,
MHz, CDCl3) δ 1.42 (s, 3H), 1.55 (s, 3H), 2.12 (br s, 1H), 2.61 (d,
J = 2.2 Hz, 1H), 3.65 (br d, J = 4.5 Hz, 2H), 3.86 (d, J = 12.3 Hz, 1H),
4.01 (d, J = 12.3 Hz, 1H), 4.26 (dt, J = 2.0, 4.5 Hz, 1H), 4.55 (d, J =
12.1 Hz, 1H), 4.6 (d, J = 12.1 Hz, 1H), 4.62 (d, J = 2.2 Hz, 1H), 4.64
(d, J = 2.0 Hz, 1H), 7.28−2.35 (m, 5H) ppm; 13C NMR (100 MHz,
CDCl3) δ 26.9 (q), 28.1 (q), 61.9 (t), 69.7 (t), 73.6 (t), 75.3 (d), 77.1
(d), 78.0 (s), 83.1 (d), 83.2 (d), 91.9 (s), 114.5 (s), 127.8 (d, 3C),
128.4 (d, 2C), 137.6 (s) ppm; MS (ESI) m/z 341.3 ([M + Na]+);
HRMS (ESI) calcd for C18H22O5 [M + Na]+ 341.1365, found
341.1368.
CHCl3); IR (CHCl3) ν 3453, 2990, 2935, 2862, 2839, 1667, 1611,
1
1516, 1463, 1345, 1248, 1162, 1075, 853, 754 cm−1; H NMR (200
MHz, CDCl3) δ 1.45 (s, 3H), 1.58 (s, 3H), 2.26 (br s, 1H), 3.69 (d,
J = 5.2 Hz, 2H), 3.98 (br d, J = 12.2 Hz, 1H), 4.12 (br d, J = 12.2 Hz,
1H), 4.34 (dt, J = 2.2, 5.1 Hz, 1H), 4.56 (d, J = 12.2 Hz, 1H), 4.62 (d,
J = 12.2 Hz, 1H), 4.7 (d, J = 2.0 Hz, 1H), 4.94 (s, 1H), 7.25−7.35 (m,
5H), 7.44−7.66 (m, 3H), 8.06 (dd, J = 1.3, 7.7 Hz, 1H) ppm; 13C
NMR (50 MHz, CDCl3) δ 27.0 (q), 28.0 (q), 62.3 (t), 69.6 (t), 73.5
(t), 76.4 (d), 83.5 (s), 83.7 (d, 2C), 91.5 (s), 92.9 (s), 114.5 (s), 117.5
(s), 124.7 (d), 127.7 (d), 127.7 (d, 2C), 128.3 (d, 2C), 129.3 (d),
132.9 (d), 135.2 (d), 137.6 (s), 149.4 (s) ppm; MS (ESI) m/z 462.1
([M + Na]+); HRMS (ESI) calcd for C24H25NO7 [M + Na]+
462.1529, found 462.1514.
(((3aS,4S,6R,6aR)-6-((Benzyloxy)methyl)-2,2-dimethyl-4-((2-
nitrophenyl)ethynyl)-tetrahydrofuro[3,4-d][1,3]dioxol-3a-yl)-
methoxy)(tert-butyl)dimethylsilane (5). To a solution of alkyne
6-β (500 mg, 1.16 mmol) and aryl iodide (345 mg, 1.39 mmol) in
Et3N/THF (2:1, 9 mL) were added TPP (30 mg, 0.115 mmol) and
Pd(PPh3)2Cl2 (80 mg, 0.115 mmol), and the suspension was degassed
with argon for 10 min. To this CuI (22 mg, 0.115 mmol) was
introduced and degassed with argon for 10 min and stirred at rt for
4 h. The reaction mixture was filtered through a Celite pad, and the
filtrate was concentrated under reduced pressure. The residue obtained
was purified by column chromatography (7% EtOAc/petroleoum
ether) to afford the nitroalkyne 5 (547 mg, 85% yield) as yellow oil:
((3aS,4S,6R,6aR)-6-((Benzyloxy)methyl)-2,2-dimethyl-4-((2-
nitrophenyl)ethynyl)tetrahydrofuro[3,4-d][1,3]dioxol-3a-yl)-
methyl acetate (14). To a stirred solution of nitroalkynol 13
(300 mg, 0.68 mmol) in pyridine (1 mL) and Ac2O (1.5 mL) was
added cat. DMAP at room temperature and stirred for 2 h at rt. The
reaction was diluted with ethyl acetate (30 mL). The organic layer was
separated, washed with saturated CuSO4 solution and brine, dried
(Na2SO4), and concentrated under reduced pressure. The crude was
purified by silica gel column chromatography (15% EtOAc/
petroleoum ether) to afford the compound 14 (313 mg, 95%) as a
25
Rf (15% ethyl acetate/petroleum ether) 0.4; [α]D = −90.5 (c 0.34,
CHCl3); IR (CHCl3) ν 2996, 2912, 2857, 1645, 1496, 1412, 1380,
1256, 1120, 1070, 838, 757 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.09
(s, 6H), 0.90 (s, 9H), 1.44 (s, 3H), 1.56 (s, 3H), 3.59 (dd, J = 5.2, 10.4
Hz, 1H), 3.64 (dd, J = 5.2, 10.4 Hz, 1H), 3.88 (d, J = 11.6 Hz, 1H),
4.18 (d, J = 11.6 Hz, 1H), 4.28 (dt, J = 2.4, 5.2 Hz, 1H), 4.57 (d, J =
12.2 Hz, 1H), 4.60 (d, J = 12.2 Hz, 1H), 4.7 (d, J = 2.4 Hz, 1H), 4.82
(s, 1H), 7.24−7.34 (m, 5H), 7.47 (ddd, J = 1.5, 7.4, 7.5 Hz, 1H), 7.56
(dt, J = 1.5, 7.5 Hz, 1H), 7.61 (dd, J = 1.5, 7.6 Hz, 1H), 8.03 (dd, J =
1.3, 7.6 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ −5.7 (q), −5.4
(q), 18.4 (s), 25.9 (q, 3C), 26.9 (q), 28.4 (q), 61.9 (t), 69.7 (t), 73.5
(t), 76.4 (d), 82.2 (d), 83.0 (s), 83.6 (d), 91.0 (s), 93.1 (s), 114.8 (s),
117.6 (s), 124.6 (d), 127.7 (d), 127.8 (d, 2C), 128.4 (d, 2C), 129.2
(d), 132.7 (d), 135.2 (d), 137.9 (s), 149.7 (s) ppm; MS (ESI) m/z
576.2 ([M + Na]+); HRMS (ESI) calcd for C30H39NO7Si [M + Na]+
576.2394, found 576.2389.
25
yellow liquid: Rf 0.5 (petroleum ether/EtOAc 7:3); [α]D = −144
(c = 0.35, CHCl3); IR (CHCl3) ν 3358. 2925, 2854, 1916, 1720, 1622,
1
1458, 1282, 1089, 750 cm−1; H NMR (400 MHz, CDCl3) δ 1.43 (s,
3H), 1.58 (s, 3H), 2.07 (s, 3H), 3.68 (dd, J = 5.2, 10.5 Hz, 1H), 3.71
(dd, J = 5.2, 10.5 Hz, 1H), 4.33 (dt, J = 2.0, 5.2 Hz, 1H), 3.41 (d, J =
12.3 Hz, 1H), 4.55 (d, J = 12.1 Hz, 1H), 4.60 (d, J = 12.1 Hz, 1H),
4.67 (d, J = 2.0 Hz, 1H), 4.75 (d, J = 12.3 Hz, 1H), 4.93 (s, 1H), 7.25−
7.32 (m, 5H), 7.47−7.51 (m, 1H), 7.58 (dt, J = 1.3, 7.8 Hz, 1H), 7.61
(dd, J = 1.7, 7.8 Hz, 1H), 8.06 (dd, J = 1.2, 8.2 Hz, 1H) ppm; 13C
NMR (100 MHz, CDCl3) δ 20.8 (q), 26.7 (q), 28.1 (q), 62.9 (t), 69.5
(t), 73.5 (d), 76.5 (t), 83.4 (d), 83.7 (d), 90.7 (s), 91.4 (s), 114.9 (s),
117.3 (s), 124.7 (d), 127.7 (d, 3C), 128.3 (d, 2C), 128.5 (s), 129.3
(d), 132.9 (d), 135.1 (d), 137.7 (s), 149.5 (s), 170.4 (s) ppm; MS
(ESI) m/z 482.1 ([M + H]+); HRMS (ESI) calcd for C26H27NO8
[M + Na]+ 504.1635, found 504.1637.
2-((3aS,4S,6R,6aR)-6-((Benzyloxy)methyl)-3a-(((tert-
butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro-
[3,4-d][1,3]dioxol-4-yl)-3-oxo-3H-indole 1-oxide (4). The com-
pound 5 (500 mg, 0.9 mmol) was dissolved in acetonitrile (50 mL)
and degassed under argon atmosphere for 10 min, and Pd-
(CH3CN)2Cl2 (12 mg, 5 mol %) was introduced and stirred for 8 h
at room temperature. The reaction mixture was concentrated under
reduced pressure. The crude was subjected to column chromatography
purification (9% EtOAc/petroleoum ether) to procure isatogen 4
(375 mg, 75%) as yellow oil: Rf (20% ethyl acetate/petroleum ether)
0.5; [α]D25 = −120 (c 0.42, CHCl3); IR (CHCl3) ν 3283, 3104, 2929,
2-((3aS,4S,6R,6aR)-3a-(Acetoxymethyl)-6-((benzyloxy)-
methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-3-
oxo-3H-indole 1-oxide (15). The cycloisomerization of nitroalkyne
14 (300 mg, 0.42 mmol) using Pd(CH3CN)2Cl2 (5 mol %) was
carried out according to the procedure used for the preparation of 4.
Purification of the crude by column chromatography (35% EtOAc/
petroleoum ether) 17 gave 15 (216 mg, 72%) as yellow syrup: Rf 0.5
25
(petroleum ether/EtOAc 7:3); [α]D = −162 (c = 0.87, CHCl3); IR
(CHCl3) ν 3394, 2927, 2850, 1746, 1690, 1606, 1527, 1457, 1382,
1
1233, 1086, 755 cm−1; H NMR (200 MHz, CDCl3) δ 1.40 (s, 3H),
1
2857, 1689, 1600, 1451, 1307, 1264, 1235, 917, 757 cm−1; H NMR
1.68 (s, 3H), 1.79 (s, 3H), 3.68 (dd, J = 4.6, 10.7 Hz, 1H), 3.71 (dd,
J = 4.9, 10.7 Hz, 1H), 4.32−4.38 (m, 3H), 4.62 (d, J = 12.2 Hz, 1H),
4.67 (d, J = 3.0 Hz, 1H), 4.71 (d, J = 12.2 Hz, 1H), 5.41 (s, 1H), 7.30−
7.38 (m, 5H), 7.57−7.68 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3)
δ 14.2 (q), 27.0 (q), 28.4 (q), 63.6 (t), 69.7 (t), 73.7 (t), 77.7 (d), 83.5
(d), 84.0 (d), 92.3 (s), 114.3 (d), 115.6 (s), 121.7 (d), 123.1 (s), 127.7
(d), 127.8 (d, 2C), 128.4 (d, 2C), 131.9 (d), 133.3 (s), 134.5 (d),
137.9 (s), 146.8 (s), 170.1 (s), 184.6 (s) ppm; MS (ESI) m/z 482.1
([M + H]+); HRMS (ESI) calcd for C26H27NO8 [M + Na]+ 504.1635,
found 504.1641.
(500 MHz, CDCl3) δ −0.20 (s, 3H), −0.15 (s, 3H), 0.65 (s, 9H), 1.40
(s, 3H), 1.67 (s, 3H), 3.70 (dd, J = 5.2, 10.4 Hz, 1H), 3.76 (dd, J = 5.2,
10.4 Hz, 1H), 3.78 (d, J = 11.3 Hz, 1H), 3.92 (d, J = 11.3 Hz, 1H),
4.31−4.33 (m, 1H), 4.45 (d, J = 3.4 Hz, 1H), 4.64 (d, J = 12.2 Hz,
1H), 4.70 (d, J = 12.2 Hz, 1H), 5.41 (s, 1H), 7.27 (br d, J = 7.1 Hz,
1H), 7.34 (t, J = 7.3 Hz, 2H), 7.40 (br d, J = 7.6 Hz, 2H), 7.51−7.64
(m, 4H) ppm; 13C NMR (125 MHz, CDCl3) δ −5.9 (q), −5.6 (q),
18.2 (s), 25.6 (q, 3H), 27.5 (q), 28.5 (q), 64.2 (t), 69.9 (t), 73.6 (t),
78.0 (d), 83.7 (d), 83.9 (d), 94.9 (s), 114.1 (d), 115.2 (s), 121.5 (d),
123.4 (s), 127.6 (d), 127.8 (d, 2C), 128.3 (d, 2C), 131.4 (d), 134.2
E
dx.doi.org/10.1021/jo302198v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(S)-2-((3aS,4S,6R,6aR)-6-((Benzyloxy)methyl)-3a-(hydroxy-
methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-2-
(1H-indol-3-yl)indolin-3-one (3). To a solution of compound 15
(100 mg, 0.122 mmol) and indole (22 mg, 0.182 mmol) in acetonitrile
(2 mL) was added anhydrous InCl3 (27 mg, 0.122 mmol) degassed
under argon atmosphere for 5 min. Reaction mixture was allowed to
stir at 60 °C for 12 h. After completion of the reaction, acetonitrile was
evaporated under reduced pressure and the crude was used for the
next step without any further purification.
112.9 (d), 117.8 (d), 120.7 (d), 121.6 (d), 123.2 (d), 124.6 (d), 126.1
(s), 126.3 (d), 127.0 (d), 127.4 (s), 138.0 (d), 139.1 (s), 151.9 (s),
174.7 (s), 196.8 (s) ppm; MS (ESI) m/z 429.01 ([M + Na]+); HRMS
(ESI) calcd for C22H18N2O6 [M + Na]+ 429.1063, found 429.1020.
(−)-Isatisine A Acetonide (2). A suspension of compound 16
(10 mg, 0.019 mmol) and 10% Pd(OH)2/C in ethanol (1.5 mL) was
flushed with hydrogen gas and stirred under hydrogen (20 psi)
atmosphere at rt for 4 h. The reaction mixture was filtered through a
plug of filter aid, washed with ethyl acetate thoroughly (3 × 10 mL),
and concentrated. Purification of crude product by column chromato-
graphy (30% ethyl acetate in petroleum ether) yielded product 2
(8 mg, 96%) as yellow solid: Rf 0.2 (petroleum ether/EtOAc 5:2);
To a solution of the above crude product (130 mg) in methanol
(3 mL) was added K2CO3 (0.5 equiv of the crude mass), and the
mixture was stirred for 30 min at room temperature. After completion
of reaction, methanol was removed and the residue was purified by
column chromatography (33% EtOAc/petroleoum ether) to afford
alcohol 3 (73 mg, 65% over two steps) as yellow oil: Rf 0.2 (40% ethyl
25
[α]D = −278 (c 0.21, CH3OH); IR (CHCl3) ν 3425, 2989, 2915,
2859, 2830, 1720, 1615, 1470, 1376, 1265, 1246, 1215, 1148, 1087,
1055, 875 cm−1; 1H NMR (500 MHz, MeOD) δ 1.36 (s, 3H), 1.49 (s,
3H), 3.43 (dd, J = 11.9, 4.4 Hz, 1H), 3.49 (dd, J = 11.9, 4.2 Hz, 1H),
4.16 (dd, J = 7.7, 4.2 Hz, 1H), 4.79 (d, J = 3.4 Hz, 1H), 4.90 (s, 1H),
7.08 (t, J = 7.2 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H), 7.24 (s, 1H), 7.31 (t,
J = 7.5 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H),
7.80−7.74 (m, 1H), 7.93 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 8.1 HZ, 1H)
ppm; 13C NMR (125 MHz, MeOD) δ = 26.4 (q), 27.4 (q), 62.6 (t),
76.4 (s), 86.1 (d), 87.2 (d), 87.9 (d), 99.6 (s), 111.1 (s), 113.1 (d),
117.6 (d), 119.6 (s), 120.9 (d), 121.4 (d), 123.4 (d), 124.4 (d), 125.8
(s), 126.3 (d), 127.1 (d), 127.4 (s), 138.0 (d), 139.2 (s), 151.3 (s),
171.6 (s), 195.8 (s) ppm; MS (ESI) m/z 469.1 ([M + H]+); HRMS
(ESI) calcd for C25H22N2O6 [M + H]+ 447.1557, found 447.1553.
25
acetate/petroleum ether); [α]D = −132 (c 0.16, CHCl3); IR
(CHCl3) ν 3363, 3215, 2932, 2852, 1627, 1487, 1461, 1382, 1321,
1
1216, 1095, 750 cm−1; H NMR (500 MHz, MeOD) δ 1.36 (s, 3H),
1.64 (s, 3H), 3.44 (d, J = 12.5 Hz, 1H), 3.63 (dd, J = 4.9, 10.4 Hz, 1H),
3.65 (dd, J = 4.9, 10.4 Hz, 1H), 3.87 (d, J = 12.5 Hz, 1H), 4.14 (dt, J =
2.2, 4.9 Hz, 1H), 4.55 (d, J = 11.9 Hz, 1H), 4.59 (d, J = 11.9 Hz, 1H),
4.65 (d, J = 2.2 Hz, 1H), 4.96 (s, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.90−
6.93 (m, 2H), 7.05 (br t, J = 8.1 Hz, 1H), 7.31−7.37 (m, 7H), 7.49−
7.52 (m, 2H), 7.75 (d, J = 8.2 Hz, 1H), ppm; 13C NMR (100 MHz,
CD3OD) δ 27.0 (q), 29.2 (q), 59.3 (t), 71.0 (s), 71.4 (t), 74.6 (t), 82.5
(d), 84.3 (d), 88.5 (d), 93.8 (s), 112.6 (d), 113.3 (d), 114.2 (s), 115.6
(s), 119.2 (d), 119.9 (d), 120.6 (s), 121.9 (d), 122.5 (d), 124.6 (d),
125.8 (d), 126.2 (s), 128.8 (d), 128.9 (s), 129.0 (d, 2C), 129.3 (s),
129.4 (d, 2C), 139.1 (d), 162.5 (s), 201.1 (s) ppm; MS (ESI) m/z
563.2 ([M + Na]+); HRMS (ESI) calcd for C32H32N2O6 [M + H]+
541.2339, found 541.2341.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C NMR, and HRMS spectra of all the new compounds;
COSY and NOESY spectra of compounds 6α and 6β. This
material is available free of charge via the Internet at http://
pubs.acs.org.
15-O-Benzyl Isatisine A Acetonide (16). Under an atmosphere
of argon in a Teflon-sealed tube, compound 3 (40 mg, 0.074 mmol),
[Cp*RhCl2]2 (4.5 mg, 10 mol %), K2CO3 (∼2 mg, 5 mol %), and
acetone (3 mL) were placed. The tube was sealed and was heated at
110 °C (oil bath temp) for 26 h. The reaction mixture was con-
centrated, and the resulting crude was purified by column chro-
matography (9% EtOAc/petroleoum ether) to obtain the lactam 16
(22 mg, 56% yield) as yellow foam: Rf (20% ethyl acetate/petroleum
AUTHOR INFORMATION
Corresponding Author
*Email: vr.chepuri@ncl.res.in.
■
25
ether) 0.5; [α]D = −232.0 (c 0.16, CHCl3); IR (CHCl3) ν 3363,
Notes
2929, 2868, 1794, 1620, 1487, 1456, 1372, 1321, 12156, 1080, 750
cm−1; 1H NMR (500 MHz, CDCl3) δ 1.39 (s, 3H), 1.52 (s, 3H), 3.33
(dd, J = 2.7, 10.7 Hz, 1H), 3.36 (dd, J = 3.3, 10.7 Hz, 1H), 3.81 (d, J =
12.8 Hz, 1H), 3.92 (d, J = 12.8 Hz, 1H), 4.32−4.33 (m, 1H), 4.86 (d,
J = 2.4 Hz, 1 H), 4.91 (s, 1H), 6.96 (br dd, J = 1.8, 7.9 Hz, 2H), 7.17−
7.26 (m, 7H), 7.33−7.35 (m, 1H), 7.58 (br t, J = 7.4 Hz, 1H), 7.65 (d,
J = 7.4, 1H), 7.99 (d, J = 8.2 Hz, 1H), 8.16−8.17 (m, 2H) ppm; 13C
NMR (125 MHz, CDCl3) δ 25.6 (q), 27.0 (q), 68.9 (t), 73.0 (t), 75.0
(s), 84.6 (d), 85.6 (d), 87.2 (d), 98.2 (s), 111.5 (d), 111.8 (s), 116.4
(d), 117.7 (s), 120.6 (d), 121.0 (d), 122.5 (d), 122.9 (d), 124.5 (s),
125.4 (d), 125.5 (d), 126.1 (s), 127.5 (d), 127.6 (d, 2C), 128.2 (d,
2C), 136.2 (d), 137.2 (s), 137.5 (s), 149.9 (s), 169.9 (s), 194.0 (s)
ppm; MS (ESI) m/z 559.2 ([M + H]+); HRMS (ESI) calcd for
C32H28N2O6 [M + Na]+ 559.1845, found 559.1849.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors would like to acknowledge the CSIR (India) for
the providing the financial support for this project under ORIGIN
program of 12FYP. P.P. thanks UGC (New Delhi, for the financial
assistance in the form of a research fellowship.
DEDICATION
■
This paper is dedicated to Professor Goverdhan Mehta on the
occasion of his 70th birthday.
(−)-Isatisine A (1). To an ice-cooled solution of 16 (10 mg, 0.019
mmol) in CH2Cl2 (1 mL) was added a solution of TiCl4 (8 μL) in
CH2Cl2 (1 mL) and stirred for 2 h at the same temperature. The re-
action was quenched with ice and extracted with CH2Cl2 (20 mL × 3);
the combined organic layer was dried (Na2SO4), concentrated, and
the crude was subjected for column chromatography (5% MeOH/
dichloromethane) to procure isatisine A (4.6 mg, 71%) as yellow solid:
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