Total synthesis of dictyodendrins B and E, and formal synthesis of dictyodendrin C

FULL PAPER

DOI: 10.1002/ejoc.201402672

Total Synthesis of Dictyodendrins B and E, and Formal Synthesis of

Dictyodendrin C

Pengyu Tao,^[a]Jingjing Liang,^[a]and Yanxing Jia*^[a,b]

Keywords: Total synthesis / Natural products / Alkaloids / Nitrogen heterocycles / Cyclization / Palladium

A full account of the concise total syntheses of dictyodendrins

B and E, and the formal synthesis of dictyodendrin C are

described. A palladium-catalysed Larock indole synthesis

was used to form the highly substituted indole core, and a

palladium-mediated one-pot consecutive Buchwald–Hartwig

amination/C–H activation reaction was used to construct the

key pyrrolo[2,3-c]carbazole core. Unsuccessful synthetic stra-

tegies are also discussed.

Introduction

Dictyodendrins A–E (1–5) were isolated by Fusetani and

Matsunaga in 2003 from the marine sponge Dictyodendrilla

verongiformis collected off the southern Japanese coast

(Figure 1).^[1]These compounds have a unique pyrrolo[2,3-c]-

carbazole core, and carry at least one sulfate group in their

periphery structure. Furthermore, these alkaloids are the

first marine natural products to show telomerase inhibitory

activity (100% inhibition at 50 μg/mL concentration). As

telomerase is overexpressed in most tumor cell lines,^[2]

telomerase inhibition represents a new promising strategy

for the development of cancer chemotherapy.^[3]

The dictyodendrins have attracted the attention of syn-

thetic chemists as a result of their unique structures and

characteristic biological activities.^[4–8]Fürstner et al. com-

pleted the first total synthesis of dictyodendrins B (2), C

(3), and E (5), which featured a titanium-induced reductive

coupling reaction.^[4]Tokuyama and coworkers ac-

complished the total synthesis of dictyodendrins A–E (1–5)

using a benzyne-mediated one-pot indoline formation/

cross-coupling sequence.^[5]Iwao, Ishibashi, and coworkers

reported their formal synthesis of dictyodendrin B (2) using

a Suzuki–Miyaura coupling reaction as the key step.^[6]We

have recently reported the total synthesis of dictyodendrins

B (2) and E (5). Our synthetic route featured a Pd-catalysed

Larock indole synthesis and a Pd-catalysed Buchwald–

Hartwig amination/C–H activation cascade reaction.^[8]In

this paper, we give a full account of our research into the

synthesis of this class of natural products.

Figure 1. Structures of dictyodendrins A–E (1–5).

Results and Discussion

Initial Synthetic Plan for Dictyodendrins A–E

[a] State Key Laboratory of Natural and Biomimetic Drugs,

School of Pharmaceutical Sciences, Peking University,

Xue Yuan Rd. 38, Beijing 100191, China

As a result of our ongoing study towards the total syn-

thesis of indole and pyrrole alkaloids,^[9,10]we became inter-

ested in the total synthesis of dictyodendrins. We viewed the

central core structure of dictyodendrins as a fully substi-

tuted indole fused with a carbazole moiety. Inspired by a

number of successful total syntheses using C–H activation

as the key strategy,^[11]and by recent advances in the synthe-

E-mail: yxjia@bjmu.edu.cn

http://sklnbd.bjmu.edu.cn/plus/list.php?tid=580

[b] State Key Laboratory of Applied Organic Chemistry, Lanzhou

University,

Tianshui South Rd 222, Lanzhou 730000, China

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201402672.

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Scheme 1. The initial retrosynthetic analysis of dictyodendrins 1–5.

sis of carbazoles using C–H activation,^[12–15]we drew up an

The preparation of o-iodoaniline 12 began with iodin-

initial retrosynthetic analysis of dictyodendrins A–E (1–5) ation of known 4Ј,6-dimethoxybiphenyl-2-amine (17),

as shown in Scheme 1. We assumed that dictyodendrins A– which was prepared by Ullmann coupling of commercially

E (1–5) could be accessed from fully protected precursor 6. available 1,3-dinitrobenzene (13) and p-iodoanisole (14),

The carbazole structure of 6 could be prepared by a palla- followed by aromatic substitution with NaOMe, and re-

dium-catalysed one-pot consecutive Buchwald–Hartwig duction with zinc (Scheme 2).^[17]However, the Ullmann

amination/C–H activation reaction from bromide 7 and 2- coupling reaction was not suitable for the large-scale prepa-

chloroaniline 8.^[13]5-Bromoindole intermediate 7 could be ration of compound 15, due to its poor reproducibility, the

rapidly prepared by Friedel–Crafts alkylation at the C-2 po- excessive amount of copper required, and the difficult sepa-

sition of indole 9 with the corresponding electrophile, fol- ration of the product (i.e., 15) from starting material 13.

lowed by site-selective bromination at the C-5 position. Fi- Therefore, we began to pursue another synthetic approach

nally, common indole intermediate 9 should be easily ob- to compound 16 starting from known aryl iodide 19,^[9b]

tained by the palladium-catalysed annulation reaction of o- which could be prepared from 2-amino-3-nitrophenol (18)

iodoaniline 12 and the corresponding aldehyde, followed by by a sequence of iodination followed by O-methylation.

N-alkylation with bromide 10.^[16,9a–9e]

Treatment of aryl iodide 19 with 4-methoxyphenylboronic

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Synthesis of Dictyodendrins B, C, and E

acid (20) under the standard conditions of the Suzuki–Mi-

Our initial attempts to carry out the direct annulation of

yaura coupling reaction gave intermediate 16 in 97% yield. o-iodoaniline 12 and aldehyde 21 under a variety of reac-

Scheme 2. Synthesis of o-iodoaniline 12. DME = dimethoxyethane; HMPA = hexamethylphosphoramide; dppf = 1,1Ј-bis(diphenylphos-

phino)ferrocene.

Scheme 3. Synthesis of indole 9. TES = triethylsilyl.

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tion conditions did not provide the desired indole (i.e., 11) stable under the basic reaction conditions. This result

(Scheme 3).^[16]We speculated that aldehyde 21 was not prompted us to study the Larock indole synthesis. Thank-

Scheme 4. Friedel–Crafts reaction of indole 9 and bromination of 23; NBS = N-bromosuccinimide.

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Synthesis of Dictyodendrins B, C, and E

fully, the reaction of o-iodoaniline 12 and alkyne 22 under acylation of indole 9 with p-methoxybenzoyl chloride (25)

standard Larock reaction conditions gave the desired indole and ZnCl₂gave 2-acylindole derivative 26,^[5b]which was

(i.e., 23) in 87% yield.^[18]Attempts to carry out the N-alkyl- confirmed by the X-ray crystallographic analysis. Friedel–

ation of indole 23 with bromide 10 did not give the desired Crafts alkylation of 9 with bromide 27 provided indole

N-alkylation product (i.e., 24). Instead, compound 9 was 28.^[19]Meanwhile, as described by Tokuyama,^[5b]alkylation

obtained in 40% yield, along with indole 11 in 35% yield. of 9 with 29 gave 2-benzylated product 30 and 5-benzylated

Most probably, compound 23 could not be directly N-alkyl- product 31 without regioselectivity. It was difficult to sepa-

ated due to steric hindrance, and compound 9 was formed rate these two products from starting material 9 by flash

from indole 11. In an alternative approach, removal of the column chromatography.

silyl group from the C-2 position using TBAF (tetrabut-

Our initial idea for the preparation of 5-bromoindole in-

ylammonium fluoride) provided indole 11 in 89% yield. termediate 7c was to introduce the bromide at the C-5 posi-

Subsequent N-alkylation of indole 11 with bromide 10 pro- tion of indole 23. Surprisingly, reaction of indole 23 with

vided key intermediate 9 in 82% yield.

NBS in CH₂Cl₂(1.0 h) led to the isolation of semi-stable

With key intermediate 9 in hand, we set out to constuct bromine-containing imine 32 in 90% yield, and the forma-

the substructures at the indole 2-position for the synthesis tion of 2-bromoindole product 33 was not detected. More

of dictyodendrins A–E (1–5) (Scheme 4). Friedel–Crafts interestingly, imine 32 could be converted into the corre-

Scheme 5. Total synthesis of dictyodendrin B (2); TBAI = tetrabutylammonium iodide.

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sponding 2-bromoindole (i.e., 33) in 80% yield simply by Table 1. Optimization of the reaction conditions.^[a]

extending the reaction time (to 12 h). Although 2-silyl ind-

Entry

Pd(OAc)₂Solvent

[equiv.]

Temp. Yield of 6b Yield of 26

[°C]

[%]^[b]

oles have been successfully converted into 2-bromoindoles,

the observation of such an intermediate as imine 32 has

never been reported.^[18,20]The isolation of intermediate 32

provides experimental evidences that the bromide was intro-

duced first at the C-3 position, and that it then migrated to

the C-2 position (Scheme 4).

1

2

3

4

0.1

0.2

0.5

1.0

toluene

1,4-dioxane

DMF

DMSO

mesitylene

110

160

0

5

6

30

0

50

91

86

61

95

83

86

58

19

88

5^[c]

6

Bearing in mind that compound 26 was more electron-

deficient and stable, we decided to carry out the synthesis

of dictyodendrin B (2) from 26 first. Site-selective bromina-

tion of compound 26 at the C-5 position with NBS gave 7b

in 98% yield. Unexpectedly, treatment of 7b under

Bedford’s reaction conditions^[13a]did not provide the de-

sired product (i.e., 6b) (Table 1, entry 1). A variety of condi-

tions (ligand, solvent, base, concentration, and tempera-

ture) were screened. Increasing of the amounts of Pd(OAc)₂

and (tBu₃P)HBF₄gave higher yields of product 6b (Table 1,

entries 2–4). Of the bases examined, tBuONa was the most

efficient (Table 1, entries 4 and 5). We were pleased to find

that when DMSO was used as the solvent, the reaction pro-

vided the desired product in 23% yield (Table 1, entries 4

and 6–8). When the reaction was carried out at 160 °C in

DMSO, the desired product was formed in 71% yield

(Table 1, entry 9). Unfortunately, a low yield of compound

6b was obtained when mesitylene was used as the solvent

(Table 1, entry 10). The main side product observed was the

debrominated product (i.e., 26) in all cases. The structure

of compound 6b was confirmed by X-ray crystallographic

analysis. Removal of the benzyl group gave known phenol

7

8

9

10

0

23

71

5

[a] Reaction conditions: 7b (0.1 mmol), 8 (0.3 mmol), Pd(OAc)₂,

(tBu₃P)HBF₄[2 equiv. relative to Pd(OAc)₂], tBuONa (0.5 mmol),

solvent (4.0 mL). [b] Isolated yields. [c] Cs₂CO₃was used as the

base.

We went on to investigate the total synthesis of dictyod-

endrin A (1) from indole 28 (Scheme 6). Bromination of

indole 28 with NBS gave 5-bromoindole 7a in 74% yield.

However, only a trace amount of the desired carbazole (i.e.,

6a) was obtained under the aforementioned optimized reac-

tion conditions, and there was no improvement even after

screening a variety of reaction conditions. In most cases, 5-

bromoindole (7a) decomposed.

Modified Synthetic Plan for Dictyodendrin E

Because of the difficulties in obtaining pure compound

34. Following the procedure reported by Fürstner^[4]and 30 by Friedel–Crafts alkylation with 29, a new synthetic

Tokuyama,^[5]the total synthesis of dictyodendrin B (2) was route for the synthesis of indole 30 was designed, as shown

completed (Scheme 5).

in Scheme 7. We envisioned that indole 30 could be pre-

Scheme 6. Attempted synthesis of 6a.

Scheme 7. Retrosynthesis of indole 30.

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Synthesis of Dictyodendrins B, C, and E

pared by N-alkylation of compound 35, which could be PTSA (para-toluenesulfonic acid) in EtOH gave indole 35

produced by Fischer indole synthesis starting from known in 84% yield.^[24]However, N-alkylation of indole 35 with

ketone 36^[21]and Boc-protected phenylhydrazine 37 (Boc = bromide 10 did not result in the complete conversion of

tert-butoxycarbonyl). In turn, phenylhydrazine 37 could be starting material 35 in one reaction, and it was difficult to

prepared from aniline 17.

separate indole 30 from the remaining 35. Thankfully, re-

Diazotization of aniline 17 followed by iodination under peating the transformation until 35 had been completely

classical acidic conditions gave iodide 38 in 63% yield consumed gave pure product 30 in 70% yield. Bromination

(Scheme 8).^[22]The Ullmann coupling of iodide 38 with of indole 30 followed by carbazole formation provided the

BocNHNH₂produced the desired product (i.e., 37) in 57% desired product (i.e., 6e) in 45% yield. Finally, removal of

yield.^[23]Treatment of compound 37 and ketone 36 with the benzyl group gave known compound 39, which was

Scheme 8. Total synthesis of dictyodendrin E (5).

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then converted into dictyodendrin E (5) following the same

procedure reported by Fürstner and Tokuyama.^[4,5b]

Modified Synthetic Plan for Dictyodendrins A, B, and E

Although we had achieved the total synthesis of dictyo-

dendrins B (2) and E (5), the synthesis of dictyodendrin E

did not go via our originally designed common intermedi-

ate 9, and the synthesis of 2 and 5 could not be modified

to allow the synthesis of dictyodendrin A. Thus, the overall

synthetic efficiency of our syntheses was not high enough.

To improve the synthetic efficiency, we envisioned that ad-

vanced intermediate 6b might be used as a key intermediate,

since it might be converted into compounds 6a and 6e at

what would be a late stage of the synthesis. If this strategy

could be realized, the synthesis of the dictyodendrins from

common intermediate 6b would represent a higher level of

step-economy (Scheme 9). In addition, the preparation of

2-acylindole 26 might also be improved. The original syn-

thesis of indole 26 from o-iodoaniline 12 needed four steps,

involving Larock indole synthesis, removal of the TES

group, N-alkylation, and Friedel–Crafts alkylation. We en-

visioned that 2-acylindole 26 could be prepared directly

from o-iodoaniline 12 in two steps by Larock indole synthe-

sis with a known intermediate alkyne ketone 41^[25]followed

by N-alkylation. Surprisingly, no previous report on the use

of the alkyne ketone for the Larock indole synthesis was

found in the literature.

The preparation of 2-acylindole 26 is shown in

Scheme 10. To our delight, reaction of o-iodoaniline 12 and

alkynylketone 41 under standard Larock conditions

Scheme 9. Retrosynthetic analysis of 6b from 12 and 41.

[Pd(OAc)₂, PPh₃, Na₂CO₃, LiCl, DMF, 100 °C] proceeded 2-acylindole (i.e., 40) in 44% yield.^[18]Reaction conditions

smoothly and with high regioselectivity to give the desired were screened to try to increase the yield. Eventually, we

Scheme 10. Modified synthesis of 26.

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Synthesis of Dictyodendrins B, C, and E

found that under optimized reaction conditions of

Pd(PPh₃)₄(10 mol-%), K₂CO₃(2 equiv.), THF (c = 0.5 m),

65 °C 24 h, 2-acylindole 40 was formed in 95% yield. In

contrast to indole 35, the N-alkylation of 2-acylindole 40

with bromide 10 proceeded smoothly to give the desired

intermediate (i.e., 26) in 95% yield. This short synthetic

route enabled the efficient preparation of intermediate 26

on a multigram scale. With this improvement, our total syn-

thesis of dictyodendrin B was accomplished in only nine

steps and 27% yield from known aniline 17.

With a sufficient amount of intermediate 6b in hand, the

stage was set for the synthesis of compounds 6a and 6e. To

our delight, compound 6e was easily prepared by reduction

of the carbonyl group in intermediate 6b with LiAlH₄in

the presence of AlCl₃. Thus, using the transformations

shown in Scheme 8, the total synthesis of dictyodendrin E

(5) could be accomplished in 11 steps and 29% overall yield

from known aniline 17 (Scheme 11).

Scheme 11. Synthesis of 6e from 6b.

Formal Synthesis of Dictyodendrin C (3)

Having completed the total synthesis of dictyodendrins

B (2) and E (5), we turned our attention to the synthesis of

Having successfully completed the total synthesis of dictyodendrin C (3). As stated above, our initial synthetic

dictyodendrin E (5) from intermediate 6b, we then con- scheme had failed. We envisioned that the bromide could

ducted the transformation of compound 6b into 6a be introduced before the formation of the indole ring.

(Scheme 12). Reduction of intermediate 6b with LiAlH₄fol- Treatment of o-iodoaniline 12 with NBS gave compound 44

lowed by treatment of the resulting alcohol with TMSCN in 97% yield. Reaction of o-iodoaniline 44 with alkyne 22

(TMS = trimethylsilyl) in the presence of InCl₃provided under standard Larock indole reaction conditions did in-

the desired cyanide (i.e., 42).^[26]However, the conversion of deed provide the desired indole (i.e., 45), albeit in low

cyanide 42 into ester 6a failed. Attempts to achieve the di- yield.^[18,28]Indole 45 was obtained in only 27% yield, even

rect introduction of a carboxyl group onto the benzyl posi- after the reaction conditions had been optimized, which

tion of compound 6e with nBuLi and CO₂led to decompo- might be due to the interaction between the bromide at the

sition of the starting material, and none of the desired prod- C-5 position and the catalyst. Deprotection of the TES

uct was obtained.^[27]

group with TBAF gave indole 46 in 98% yield. N-Alkyl-

Scheme 12. Unsuccessful attempts at the synthesis of 6a.

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Scheme 13. Formal synthesis of dictyodendrin C (3).

ation of indole 46 with bromide 10 proceeded smoothly to action to construct the key pyrrolo[2,3-c]carbazole core.

give the desired product (i.e., 7c) in 94% yield. Carbazole The C–H activation strategy represents a powerful tool for

formation under the optimized reaction conditions de- the rapid construction of natural products. The highly ef-

scribed above worked well to give carbazole 6c in 80% ficient synthesis of dictyodendrins B and E from the same

yield. Finally, deprotection of the benzyl group of 6c gave intermediate 6b should be highlighted.

known compound 47, whose spectroscopic data were con-

sistent with those previously reported.^[4,5b]Thus, our formal

synthesis was achieved in seven steps and 14% overall yield

from aniline 17 (Scheme 13).

Experimental Section

General Methods: Reagents were obtained from commercial suppli-

ers unless otherwise stated. Tetrahydrofuran (THF) and diethyl

ether (Et₂O) were distilled from potassium sodium alloys. Dichloro-

methane was distilled from calcium hydride. N,N-Dimethylform-

Conclusions

amide (DMF) was distilled from magnesium sulfate under vacuum.

In summary, we have achieved the highly efficient total

Dimethyl sulfoxide (DMSO) was distilled from calcium hydride un-

synthesis of dictyodendrin B (9 steps and 27% yield) and

der vacuum. Flasks were flame-dried under vacuum and cooled

dictyodendrin E (11 steps and 29% yield), and the formal

under a stream of nitrogen or argon. TLC plates were visualized

synthesis of dictyodendrin C (7 steps and 14% yield) from

under a UV lamp (254 nm and 365 nm), and by developing with

known compound 17. The synthesis featured a palladium-

phosphomolybdic acid or p-methoxybenzaldehyde in ethanol.

catalysed Larock indole synthesis to form the highly substi-

tuted indole core, and a palladium-mediated one-pot con-

Flash column chromatography was carried out using silica gel

(200–300 mesh) with solvents that were distilled before use. ¹H and

secutive Buchwald–Hartwig amination/C–H activation re- ¹³C NMR spectra were recorded at 400 and 100 MHz, respectively,

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Synthesis of Dictyodendrins B, C, and E

unless otherwise stated. The following abbreviations are used for

the multiplicities: s: singlet, d: doublet, t: triplet, q: quartet, m:

multiplet, br. s: broad singlet. Coupling constants (J) are reported

in Hertz (Hz). Infrared spectra were recorded with a thin layer of

the product on a KBr disk. High-resolution mass spectra (HRMS)

were acquired with an FT-MS (7.0 T) instrument equipped with an

ESI source.

(d, J = 8.8 Hz, 2 H), 6.64 (d, J = 8.8 Hz, 2 H), 3.90 (s, 3 H), 3.87

(s, 3 H), 3.77 (s, 3 H), 3.76–3.72 (m, 5 H), 2.58 (t, J = 8.0 Hz, 2 H)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 159.1, 158.2, 158.0, 153.7,

135.2, 132.1, 130.4, 129.6, 128.6, 128.1, 128.0, 126.8, 122.9, 119.2,

116.4, 114.8, 114.2, 113.70, 113.69, 106.8, 57.5, 55.4, 55.3, 55.2,

49.7, 36.8 ppm. IR (KBr): ν = 1609, 1557, 1513, 1457, 1365, 1286,

˜

1245, 1179, 1024, 831, 794 cm^–1. HRMS (ESI): calcd. for

C₃₂H₃₁NO₄[M + H]⁺494.2326; found 494.2316.

6-Methoxy-3,7-bis(4-methoxyphenyl)-2-(triethylsilyl)-1H-indole

(23): Compound 22 (222 mg, 0.9 mmol), PPh₃(16 mg, 0.06 mmol),

Na₂CO₃(159 mg, 1.5 mmol), and LiCl (13 mg, 0.3 mmol) were

added to a stirred solution of compound 12 (107 mg, 0.3 mmol) in

dry DMF (1.0 mL) under an argon atmosphere. The flask was

flushed with argon for 0.5 h to remove oxygen, and then Pd(OAc)₂

Methyl 2-[6-Methoxy-1-(4-methoxyphenethyl)-3,7-bis(4-meth-

oxyphenyl)-1H-indol-2-yl]-2-(4-methoxyphenyl)acetate (28): Com-

pound 27 (171 mg, 0.66 mmol) and Al₂O₃(H⁺; 404 mg, 3.96 mmol)

were added to a stirred solution of 9 (109 mg, 0.22 mmol) in dry

CH₂Cl₂(16 mL). The mixture was heated at reflux for 6 h. The

(6.7 mg, 0.03 mmol) was added under argon. The solution was reaction mixture was diluted with water. The resulting mixture was

heated at 100 °C for 16 h. The mixture was cooled down to room

temperature, diluted with EtOAc, washed with brine, dried with

anhydrous Na₂SO₄, and filtered. The filtrate was concentrated un-

der reduced pressure. The residue was purified by silica gel column

chromatography (petroleum ether/EtOAc, 20:1) to give 23 (124 mg,

87 %) as a yellow solid, m.p. 101–102 °C. ¹H NMR (400 MHz,

CDCl₃): δ = 7.99 (br. s, 1 H), 7.62 (d, J = 8.4 Hz, 2 H), 7.48–7.43

(m, 3 H), 7.14 (d, J = 8.8 Hz, 2 H), 7.03 (d, J = 8.4 Hz, 2 H), 6.97

(d, J = 8.8 Hz, 1 H), 3.95 (s, 3 H), 3.93 (s, 3 H), 3.86 (s, 3 H), 0.93

(t, J = 8.0 Hz, 9 H), 0.70 (q, J = 8.0 Hz, 6 H) ppm. ¹³C NMR

extracted with EtOAc (3ϫ 15 mL). The combined organic extracts

were washed with brine, dried with anhydrous Na₂SO₄, and fil-

tered. The filtrate was concentrated under reduced pressure. The

residue was purified by silica gel column chromatography (petro-

leum ether/EtOAc, 3:1) to give 28 (115 mg, 78 %) as a yellow

amorphous solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.50 (d, J =

8.4 Hz, 1 H), 7.46–7.41 (m, 4 H), 7.11 (d, J = 8.4 Hz, 2 H), 7.03–

6.94 (m, 5 H), 6.82 (d, J = 8.8 Hz, 2 H), 6.61 (d, J = 8.4 Hz, 2 H),

6.28 (d, J = 8.4 Hz, 2 H), 5.38 (s, 1 H), 3.87 (s, 3 H), 3.86 (s, 3 H),

3.78 (s, 3 H), 3.75 (s, 3 H), 3.72 (s, 5 H), 3.51 (s, 3 H), 2.22 (t, J =

(100 MHz, CDCl₃): δ = 158.7, 158.5, 152.6, 137.8, 131.2, 131.0, 8.0 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 171.8, 159.0,

130.9, 128.9, 128.0, 127.0, 124.2, 118.6, 114.3, 113.4, 112.5, 107.1,

158.7, 158.5, 157.9, 154.3, 134.5, 132.6, 132.5, 132.0, 131.5, 130.0,

129.9, 129.6, 129.5, 128.8, 127.8, 126.8, 124.6, 119.2, 117.7, 114.6,

114.0, 113.84, 113.77, 113.5, 113.4, 113.3, 106.9, 57.6, 55.3, 55.2,

57.2, 55.2, 55.18, 7.3, 3.8 ppm. IR (KBr): ν = 3446, 1611, 1516,

˜

1496, 1288, 1241, 1172, 1035, 837, 730 cm^–1. HRMS (ESI): calcd.

for C₂₉H₃₅NO₃Si [M + H]⁺474.2459; found 474.2447.

55.1, 52.2, 47.3, 46.5, 35.5 ppm. IR (KBr): ν = 1732, 1611, 1568,

˜

1514, 1461, 1303, 1285, 1247, 1178, 1083, 1033, 743 cm^–1. HRMS

(ESI): calcd. for C₄₂H₄₁NO₇[M + H]⁺672.2961; found 672.2954.

6-Methoxy-3,7-bis(4-methoxyphenyl)-1H-indole (11): TBAF·3H₂O

(104 mg, 0.40 mmol) was added to a solution of compound 23

(95 mg, 0.20 mmol) in dry THF (1.0 mL). The mixture was stirred

at room temperature for 2 h, then the solvent was removed in

Methyl 2-[5-Bromo-6-methoxy-1-(4-methoxyphenethyl)-3,7-bis(4-

methoxyphenyl)-1H-indol-2-yl]-2-(4-methoxyphenyl)acetate (7a):

vacuo. The residue was extracted with EtOAc (3ϫ 10 mL). The NBS (32 mg, 0.18 mmol) was added to a stirred solution of 28

combined organic extracts were washed with brine, dried with an-

hydrous Na₂SO₄, and filtered. The filtrate was concentrated under

reduced pressure. The residue was purified by silica gel column

chromatography (petroleum ether/EtOAc, 3:1) to give 11 (64 mg,

89 %) as a white solid, m.p. 181–182 °C. ¹H NMR (400 MHz,

(112 mg, 0.17 mmol) in dry CH₂Cl₂(17 mL) in the dark at 0 °C.

The resulting mixture was warmed to room temperature and stirred

for 12 h. Then the mixture was concentrated under reduced pres-

sure. The residue was purified by silica gel column chromatography

(petroleum ether/EtOAc, 4:1) to give 7a (94.5 mg, 74%) as a white

1

CDCl₃): δ = 8.10 (br. s, 1 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.64 (d, J amorphous solid. H NMR (400 MHz, CDCl₃): δ = 7.70 (s, 1 H),

= 8.4 Hz, 2 H), 7.54 (d, J = 8.4 Hz, 2 H), 7.15 (d, J = 1.6 Hz, 1 7.48 (t, J = 8.0 Hz, 2 H), 7.37 (d, J = 7.6 Hz, 2 H), 7.08 (d, J =

H), 7.09–7.03 (m, 5 H), 3.90 (s, 6 H), 3.86 (s, 3 H) ppm. ¹³C NMR

8.0 Hz, 2 H), 7.04–6.97 (m, 4 H), 6.82 (d, J = 7.6 Hz, 2 H), 6.60

(100 MHz, CDCl₃): δ = 158.7, 158.0, 152.4, 136.6, 131.0, 128.4, (d, J = 7.6 Hz, 2 H), 6.24 (d, J = 7.6 Hz, 2 H), 5.36 (s, 1 H), 3.89

128.2, 126.8, 120.9, 120.7, 118.9, 117.8, 114.21, 114.18, 113.3, (s, 3 H), 3.86 (s, 3 H), 3.78–3.72 (m, 8 H), 3.52 (s, 3 H), 3.42 (s, 3

107.1, 57.0, 55.24, 55.20 ppm. IR (KBr): ν = 3436, 1572, 1503,

H), 2.20–2.18 (m, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

˜

1461, 1287, 1247, 1179 cm^–1. HRMS (ESI): calcd. for C₂₃H₂₁NO₃171.4, 159.4, 158.7, 157.9, 150.5, 133.7, 133.1, 132.4, 132.3, 131.5,

[M + H]⁺360.1594; found 360.1594.

129.6, 129.5, 129.4, 128.3, 127.3, 126.8, 125.9, 122.6, 120.9, 117.3,

114.0, 113.9, 113.5, 113.4, 113.3, 109.8, 60.9, 55.3, 55.2, 55.1, 52.3,

6-Methoxy-1-(4-methoxyphenethyl)-3,7-bis(4-methoxyphenyl)-1H-

indole (9): KOH (157 mg, 2.8 mmol) was added to a stirred solution

of 11 (51 mg, 0.14 mmol) in dry DMF (1.5 mL). The resulting sus-

pension was stirred at room temperature for 30 min. Then 10

(149 mg, 0.70 mmol) was added to the solution. The reaction mix-

ture was stirred at room temperature for 24 h. The reaction was

quenched with saturated aqueous NH₄Cl, and the mixture was di-

luted with water and extracted with EtOAc (3ϫ 10 mL). The com-

bined organic extracts were washed with brine, dried with anhy-

drous Na₂SO₄, and filtered. The filtrate was concentrated under

reduced pressure. The residue was purified by silica gel column

chromatography (petroleum ether/EtOAc, 5:1) to give 9 (57 mg,

82 %) as a white solid, m.p. 137–138 °C. ¹H NMR (400 MHz,

CDCl₃): δ = 7.81 (d, J = 8.8 Hz, 1 H), 7.52 (d, J = 8.8 Hz, 2 H),

47.3, 46.6, 35.5 ppm. IR (KBr): ν = 1739, 1611, 1557, 1512, 1461,

˜

1301, 1286, 1247, 1175, 1091, 1033, 766 cm^–1. HRMS (ESI): calcd.

for C₄₂H₄₀BrNO₇[M + Na]⁺772.1886; found 772.1878.

6-Methoxy-2-(4-methoxybenzyl)-3,7-bis(4-methoxyphenyl)-1H-

indole (35): Ketone 36 (157 mg, 0.58 mmol) and PTSA (160 mg,

0.93 mmol) were added to a solution of compound 37 (200 mg,

0.58 mmol) in dry EtOH (4.6 mL). The solution was heated at re-

flux for 3 h. The reaction mixture was cooled to room temperature,

and then the EtOH was removed under vacuum. EtOAc was added,

and then the mixture was neutralized with satd. NaHCO₃solution.

The aqueous phase was extracted with EtOAc (3ϫ), and the com-

bined organic layers were washed with brine, dried with Na₂SO₄,

and concentrated under vacuum. Purification of the crude product

7.39 (d, J = 8.8 Hz, 2 H), 7.05–6.96 (m, 5 H), 6.90 (s, 1 H), 6.72 by flash column chromatography (petroleum ether/EtOAc, 7:1)

Eur. J. Org. Chem. 2014, 5735–5748

www.eurjoc.org

5745

P. Tao, J. Liang, Y. Jia

FULL PAPER

gave compound 35 (234 mg, 84%) as a yellow amorphous solid. ¹H

gen, and then Pd(OAc)₂(2.2 mg, 0.01 mmol) was added under ar-

NMR (400 MHz, CDCl₃): δ = 7.66 (br. s, 1 H), 7.54 (d, J = 8.8 Hz, gon. The solution was heated at 80 °C for 16 h. The mixture was

1 H), 7.44 (d, J = 8.4 Hz, 4 H), 7.05–6.99 (m, 6 H), 6.93 (d, J = cooled down to room temperature, diluted with EtOAc, washed

8.4 Hz, 1 H), 6.80 (d, J = 8.0 Hz, 2 H), 4.08 (s, 2 H), 3.86 (s, 3 H),

3.85 (s, 3 H), 3.80 (s, 3 H), 3.77 (s, 3 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 158.7, 158.2, 158.1, 152.3, 135.4, 132.9, 131.1, 131.0,

130.4, 129.2, 127.5, 126.9, 123.0, 118.2, 115.2, 114.2, 114.1, 113.0,

106.9, 57.2, 55.23, 55.21, 55.19, 31.5 (one signal is missing due to

with brine, dried with anhydrous Na₂SO₄, and filtered. The filtrate

was concentrated under reduced pressure. The residue was purified

by silica gel column chromatography (petroleum ether/EtOAc,

30:1) to give 45 (15 mg, 27%) as a yellow amorphous solid. ¹H

NMR (400 MHz, CDCl₃): δ = 8.01 (br. s, 1 H), 7.65 (s, 1 H), 7.62

overlap) ppm. IR (KBr): ν = 1611, 1576, 1510, 1451, 1285, 1245, (d, J = 8.4 Hz, 2 H), 7.36 (d, J = 8.4 Hz, 2 H), 7.12 (d, J = 8.4 Hz,

˜

1175, 1108, 1033, 835, 761 cm^–1. HRMS (ESI): calcd. for

C₃₁H₂₉NO₄[M + H]⁺480.2169; found 480.2159.

2 H), 7.00 (d, J = 8.4 Hz, 2 H), 3.93 (s, 3 H), 3.90 (s, 3 H), 3.52 (s,

3 H), 0.88 (t, J = 8.0 Hz, 9 H), 0.66 (q, J = 8.0 Hz, 6 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 159.2, 158.7, 149.2, 136.6, 133.0,

131.2, 130.6, 128.0, 127.5, 126.7, 126.3, 121.9, 118.5, 114.4, 113.6,

6-Methoxy-2-(4-methoxybenzyl)-1-(4-methoxyphenethyl)-3,7-bis(4-

methoxyphenyl)-1H-indole (30): KOH (829 mg, 14.8 mmol) was

added to a stirred solution of 35 (355 mg, 0.74 mmol) in dry DMF

(3.1 mL). The resulting suspension was stirred at room temperature

for 30 min, and then 10 (788 mg, 3.70 mmol) was added to the

solution. The reaction mixture was stirred at 40 °C for 24 h. The

reaction was quenched with saturated aqueous NH₄Cl, and the

mixture was diluted with water and extracted with EtOAc (3 ϫ

20 mL). The combined organic extracts were washed with brine,

dried with anhydrous Na₂SO₄, and filtered. The filtrate was con-

centrated under reduced pressure. The residue was purified by silica

gel column chromatography (petroleum ether/EtOAc, 8:1) to give

30 (318 mg, 70 %) as a white amorphous solid. ¹H NMR

(400 MHz, CDCl₃): δ = 7.59 (d, J = 8.8 Hz, 1 H), 7.41 (d, J =

7.6 Hz, 4 H), 7.00–6.93 (m, 7 H), 6.78 (d, J = 8.0 Hz, 2 H), 6.64

(d, J = 8.0 Hz, 2 H), 6.35 (d, J = 8.4 Hz, 2 H), 3.96 (s, 2 H), 3.87

110.3, 61.0, 55.3, 55.2, 7.3, 3.7 ppm. IR (KBr): ν = 3468, 1609,

˜

1513, 1484, 1296, 1248, 1174, 1044, 838, 727 cm^–1. HRMS (ESI):

calcd. for C₂₉H₃₄BrNO₃Si [M + H]⁺552.1564; found 552.1591.

5-Bromo-6-methoxy-3,7-bis(4-methoxyphenyl)-1H-indole (46):

TBAF·3H₂O (1.41 g, 5.40 mmol) was added to a solution of com-

pound 45 (1.49 g, 2.70 mmol) in dry THF (27 mL). The mixture

was stirred at room temperature for 2 h, then the solvent was re-

moved in vacuo. The residue was extracted with EtOAc (3 ϫ

30 mL). The combined organic extracts were washed with brine,

dried with anhydrous Na₂SO₄, and filtered. The filtrate was con-

centrated under reduced pressure. The residue was purified by silica

gel column chromatography (petroleum ether/EtOAc, 3:1) to give

46 (1.16 g, 98 %) as a white solid, m.p. 184–185 °C. ¹H NMR

(400 MHz, CDCl₃): δ = 8.14 (br. s, 1 H), 8.02 (s, 1 H), 7.53 (d, J

(s, 3 H), 3.85 (s, 3 H), 3.76 (s, 6 H), 3.73 (s, 3 H), 3.62 (t, J = = 8.4 Hz, 4 H), 7.21 (d, J = 2.4 Hz, 1 H), 7.06 (d, J = 8.8 Hz, 2

8.0 Hz, 2 H), 2.30 (t, J = 8.0 Hz, 2 H) ppm. ¹³C NMR (100 MHz, H), 7.01 (d, J = 8.4 Hz, 2 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.52 (s,

CDCl₃): δ = 158.9, 158.1, 158.0, 153.8, 135.0, 134.6, 132.3, 131.4,

130.7, 130.4, 129.5, 128.9, 128.1, 127.8, 124.1, 118.6, 116.1, 114.6,

114.0, 113.48, 113.46, 106.5, 57.6, 55.3, 55.22, 55.16, 46.0, 36.2,

3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 159.3, 158.3, 149.2,

135.3, 130.7, 128.6, 127.3, 126.0, 123.6, 122.3, 121.9, 119.5, 117.8,

114.4, 114.3, 110.6, 61.1, 55.34, 55.31 ppm. IR (KBr): ν = 3444,

˜

30.1 (three signals are missing due to overlap) ppm. IR (KBr): ν =

1564, 1512, 1501, 1290, 1247, 1182 cm^–1. HRMS (ESI): calcd. for

˜

1611, 1570, 1511, 1459, 1285, 1250, 1173, 1084, 1034, 832, C₂₃H₂₀BrNO₃[M + H]⁺438.0699; found 438.0693.

769 cm^–1. HRMS (ESI): calcd. for C₄₀H₃₉NO₅[M + H]⁺614.2901;

5-Bromo-6-methoxy-1-(4-methoxyphenethyl)-3,7-bis(4-methoxy-

phenyl)-1H-indole (7c): KOH (370 mg, 6.6 mmol) was added to a

found 614.2891.

5-Bromo-6-methoxy-2-(4-methoxybenzyl)-1-(4-methoxyphenethyl)-

3,7-bis(4-methoxyphenyl)-1H-indole (7e): NBS (46.3 mg,

0.26 mmol) was added to a stirred solution of 30 (149 mg,

0.24 mmol) in dry CH₂Cl₂(24 mL) in the dark at 0 °C. The re-

sulting mixture was warmed to room temperature and stirred for

12 h. Then the mixture was concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (pe-

troleum ether/EtOAc, 10:1) to give 7e (96.5 mg, 58%) as a white

stirred solution of 46 (145 mg, 0.33 mmol) in dry DMF (1.6 mL).

The resulting suspension was stirred at room temperature for

30 min, then 10 (351 mg, 1.65 mmol) was added to the solution.

The reaction mixture was stirred at room temperature for 24 h.

The reaction was quenched with saturated aqueous NH₄Cl, and

the mixture was diluted with water and extracted with EtOAc (3ϫ

15 mL). The combined organic extracts were washed with brine,

dried with anhydrous Na₂SO₄, and filtered. The filtrate was con-

centrated under reduced pressure. The residue was purified by silica

1

amorphous solid. H NMR (400 MHz, CDCl₃): δ = 7.79 (s, 1 H),

7.45 (d, J = 7.2 Hz, 2 H), 7.36 (d, J = 8.0 Hz, 2 H), 6.99–6.95 (m, gel column chromatography (petroleum ether/EtOAc, 8:1) to give

6 H), 6.79 (d, J = 8.4 Hz, 2 H), 6.63 (d, J = 7.6 Hz, 2 H), 6.32 (d,

7c (177 mg, 94%) as a white amorphous solid. ¹H NMR (400 MHz,

J = 6.8 Hz, 2 H), 3.92 (s, 2 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 3.76 (s, CDCl₃): δ = 8.03 (s, 1 H), 7.46 (d, J = 7.6 Hz, 2 H), 7.42 (d, J =

3 H), 3.73 (s, 3 H), 3.63 (m, 2 H), 3.47 (s, 3 H), 2.29–2.27 (m, 2 H)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 159.3, 158.4, 158.2, 158.1,

150.0, 136.8, 133.3, 132.2, 130.9, 130.8, 130.1, 129.5, 128.8, 127.2,

8.0 Hz, 2 H), 7.05 (d, J = 8.0 Hz, 2 H), 7.01 (d, J = 8.0 Hz, 2 H),

6.93 (s, 1 H), 6.72 (d, J = 7.2 Hz, 2 H), 6.62 (d, J = 8.0 Hz, 2 H),

3.92 (s, 3 H), 3.87 (s, 3 H), 3.76–3.74 (m, 5 H), 3.52 (s, 3 H), 2.56

126.88, 126.85, 122.1, 120.8, 115.8, 114.2, 114.1, 113.5, 113.4, (t, J = 7.6 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 159.4,

109.5, 61.1, 55.33, 55.26, 55.24, 55.18, 46.1, 36.2, 30.1 ppm. IR

158.2, 150.0, 133.9, 131.9, 130.0, 129.6, 128.7, 128.2, 127.2, 127.0,

(KBr): ν = 1610, 1558, 1511, 1461, 1285, 1247, 1175, 1108, 1032, 125.6, 122.7, 121.1, 116.1, 114.3, 113.7, 113.6, 109.7, 61.3, 55.3,

˜

834, 763 cm^–1. HRMS (ESI): calcd. for C₄₀H₃₈BrNO₅[M + H]⁺55.2, 49.7, 36.8 (two signals are missing due to overlap) ppm. IR

692.2006; found 692.1996.

(KBr): ν = 1611, 1555, 1513, 1458, 1357, 1289, 1246, 1178, 1031,

˜

836, 761 cm^–1. HRMS (ESI): calcd. for C₃₂H₃₀BrNO₄[M]⁺

571.1358; found 571.1361.

5-Bromo-6-methoxy-3,7-bis(4-methoxyphenyl)-2-(triethylsilyl)-1H-

indole (45): Compound 22 (74 mg, 0.3 mmol), PPh₃(5.2 mg,

0.02 mmol), Na₂CO₃(53 mg, 0.5 mmol), and LiCl (4.7 mg,

0.11 mmol) were added to a stirred solution of compound 44

(43 mg, 0.1 mmol) in dry DMF (1.0 mL) under an argon atmo-

sphere. The flask was flushed with argon for 0.5 h to remove oxy-

7-(Benzyloxy)-5-methoxy-3-(4-methoxyphenethyl)-1,4-bis(4-meth-

oxyphenyl)-3,6-dihydropyrrolo[2,3-c]carbazole (6c): Compound 8

(210.6 mg, 0.9 mmol) and NaOtBu (144.0 mg, 1.5 mmol) were suc-

cessively added to a stirred solution of compound 7c (172.6 mg,

5746

www.eurjoc.org

Eur. J. Org. Chem. 2014, 5735–5748

Synthesis of Dictyodendrins B, C, and E

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0.3 mmol) in dry DMSO (12 mL) under an argon atmosphere. The

flask was flushed with argon for 0.5 h to remove oxygen, and then

Pd(OAc)₂(67.2 mg, 0.3 mmol) and (tBu₃P)·HBF₄(174.1 mg,

0.6 mmol) were added under argon. The solution was heated at

160 °C for 6 h. The mixture was then filtered through a pad of

Celite, and extracted with EtOAc. The organic extracts were

washed with brine, dried with anhydrous Na₂SO₄, and filtered. The

filtrate was evaporated under reduced pressure, and the resulting

residue was purified by flash column chromatography (petroleum

ether/acetone, 4:1) to give 6c (164.2 mg, 80%) as a yellow amorph-

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1

ous solid. H NMR (400 MHz, CDCl₃): δ = 8.61 (br. s, 1 H), 7.56

(t, J = 8.0 Hz, 4 H), 7.52–7.40 (m, 5 H), 7.10 (d, J = 8.0 Hz, 2 H),

7.06 (d, J = 8.0 Hz, 2 H), 6.94 (s, 1 H), 6.88 (d, J = 7.6 Hz, 1 H),

6.81 (t, J = 8.0 Hz, 1 H), 6.75 (d, J = 8.0 Hz, 2 H), 6.66 (d, J =

8.4 Hz, 2 H), 6.38 (d, J = 7.6 Hz, 1 H), 5.29 (s, 2 H), 3.96 (s, 3 H),

3.95 (s, 3 H), 3.88 (t, J = 7.2 Hz, 2 H), 3.79 (s, 3 H), 3.65 (s, 3 H),

2.66 (t, J = 7.2 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

159.2, 158.7, 158.1, 144.6, 140.4, 137.1, 132.2, 131.9, 130.4, 130.1,

129.6, 129.0, 128.8, 128.7, 128.6, 128.1, 127.9, 127.6, 124.9, 119.3,

118.5, 117.8, 117.6, 116.9, 115.2, 113.61, 113.58, 113.3, 105.6, 70.4,

61.3, 55.4, 55.3, 55.2, 50.1, 37.0 (one signal is missing due to over-

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lap) ppm. IR (KBr): ν = 3033, 2927, 1610, 1573, 1547, 1514, 1465,

˜

1360, 1302, 1284, 1243, 1173, 1132, 1026, 836, 794, 733 cm^–1

.

HRMS (ESI): calcd. for C₄₅H₄₀N₂O₅[M + H]⁺689.3015; found

689.2999.

5-Methoxy-3-(4-methoxyphenethyl)-1,4-bis(4-methoxyphenyl)-3,6-

dihydropyrrolo[2,3-c]carbazol-7-ol (47): Compound 6c (72.1 mg,

0.105 mmol) was hydrogenated over Pd/C (10%; 111.5 mg,

0.105 mmol) in EtOAc (10 mL) at 50 °C for 1 h. The mixture was

then filtered through a pad of Celite, and the insoluble material

was washed well with hot EtOAc. The filtrate was evaporated under

reduced pressure, and the resulting residue was purified by flash

column chromatography (petroleum ether/EtOAc, 3:1) to give 47

(56.4 mg, 90%) as a grey amorphous solid. ¹H NMR (400 MHz,

[D₆]acetone): δ = 9.87 (s, 1 H), 8.34 (br. s, 1 H), 7.47 (d, J = 8.8 Hz,

2 H), 7.34 (d, J = 8.4 Hz, 2 H), 7.06 (d, J = 8.4 Hz, 2 H), 7.02 (s,

1 H), 6.98 (d, J = 8.4 Hz, 2 H), 6.69–6.68 (m, 5 H), 6.54 (t, J =

8.0 Hz, 1 H), 6.23 (d, J = 8.0 Hz, 1 H), 3.864 (s, 3 H), 3.857 (s, 3

H), 3.80 (t, J = 8.0 Hz, 2 H), 3.69 (s, 3 H), 3.61 (s, 3 H), 2.59 (t, J

= 8.0 Hz, 2 H) ppm. ¹³C NMR (100 MHz, [D₆]acetone): δ = 160.5,

159.9, 159.3, 143.6, 141.7, 133.3, 132.8, 131.5, 131.4, 130.7, 130.4,

130.2, 129.9, 129.8, 128.9, 126.4, 120.3, 119.3, 119.0, 117.9, 117.3,

116.2, 114.49, 114.45, 114.2, 109.5, 61.6, 55.81, 55.79, 55.5, 50.7,

[10]

[11]

[12]

[13]

37.7 ppm. IR (KBr): ν = 3437, 2927, 2837, 1610, 1579, 1513, 1244,

˜

1174, 1034 cm^–1. HRMS (ESI): calcd. for C₃₈H₃₄N₂O₅[M + H]⁺

599.2546; found 599.2546.

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1

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Acknowledgments

This research was supported by the National Natural Science

Foundation of China (NSFC) (grant numbers 21372017 and

21290183), the National Basic Research Program of China (973

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Received: June 1, 2014

Published Online: July 28, 2014

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5748

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Article Doi

Total synthesis of dictyodendrins B and E, and formal synthesis of dictyodendrin C

DOI: 10.1002/ejoc.201402672

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Article abstract of DOI:10.1002/ejoc.201402672

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