macrolactones built from the bis-3,4(indol-1-yl)maleimide scaffold

Accepted Manuscript

Macrolactones built from the bis-3,4(indol-1-yl)maleimide scaffold

Alexander Y. Simonov, Evgeny E. Bykov, Sergey A. Lakatosh, Yury N. Luzikov,Alexander M. Korolev, Marina I. Reznikova, Maria N. Preobrazhenskaya

PII: S0040-4020(13)01844-9

DOI: 10.1016/j.tet.2013.12.004

Reference: TET 25088

To appear in: Tetrahedron

Received Date: 29 April 2013

Revised Date: 22 November 2013

Accepted Date: 2 December 2013

Please cite this article as: Simonov AY, Bykov EE, Lakatosh SA, Luzikov YN, Korolev AM, ReznikovaMI, Preobrazhenskaya MN, Macrolactones built from the bis-3,4(indol-1-yl)maleimide scaffold,Tetrahedron (2014), doi: 10.1016/j.tet.2013.12.004.

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http://dx.doi.org/10.1016/j.tet.2013.12.004

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Macrolactones built from the bis-3,4(indol-1-yl)maleimide scaffold

Alexander Y. Simonov, Evgeny E. Bykov, Sergey A. Lakatosh , Yury N. Luzikov , Alexander

M. Korolev, Marina I. Reznikova, and Maria N. Preobrazhenskaya*

Gause Institute of New Antibiotics, Russian Academy of Medical Sciences,

11 B. Pirogovskaya Street, Moscow 119021, Russian Federation.

*Corresponding author. Fax 74992450295; Tel 74992453753; e-mail: [email protected]

keywords: Bis-3,4(indol-1-yl)maleimides, 15, 16 and 17-membered macrolactones, quantum

chemical calculations

Graphical abstract

HNO O

N N

OO

n m

DDQ

toluene,t

HNO O

N N

OO

n m

HNO

O

N

OTBDMS

N

O

HO

benzene,t

TsOH

n m

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Abstract

15, 16 and 17-Membered lactones based on the bis-3,4(indol-1-yl)maleimide framework were

obtained using intramolecular esterification reaction starting from 3-(1-ω-carboxyalkyl-2,3-

dihydroindol-1-yl)-4-(1-ω-hydroxyalkyl-2,3-dihydroindol-1-yl)-maleimides. 3,4-Dibromo-

maleimide, ω-(2,3-dihydroindol-3-yl)alkanoic acids and ω-(2,3-dihydroindol-3-yl)alkanoles

were used as starting compounds. Substitution of Br for the substituted indolines followed by the

intramolecular cyclization of O-silylated hydroxyl acids derivatives led to macrolactones that

incorporated 4-(dihydroindol-1-yl)-3-(indol-1-yl)maleimide moieties. Indoline nuclei in these

compounds were dehydrogenated by DDQ in refluxing toluene to give 15, 16 or 17-membered

lactones 3-[(ω-3-carboxyalkylindol-1-yl)-4-(ω-hydroxyalkylindol-1-yl)maleimides. Quantum

chemical calculations showed that the formation of macrolactones of smaller size (13-

membered) corresponds to the higher Gibbs energy ∆G# and correlates with the absence of the

target reaction product.

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1. Introduction

Protein kinases are the key regulators of cellular signaling, representing attractive targets for

therapeutic intervention in a variety of diseases. Among the derivatives of bis-3,4(indolyl)-

maleimides and their congeners potent inhibitors of protein kinases with valuable biological

properties have been found1,2. Whereas a plethora of derivatives of 3,4-bis(indolyl)maleimides

substituted at C3 and C4 of the maleimide ring by various heterocyclic or aromatic moieties and

polyannelated structures constructed on their skeletons are known, there are scarce examples of

bis(indolyl)maleimides incorporated into macrocycles by means of N,N’-chains. Ruboxistaurin3,

a potent and isoform-selective protein kinase Cβ inhibitor belongs to this type of

bis(indolyl)maleimides (Fig.1). The derivatives constructed on 3,4-bis(indol-1-yl)maleimides are

less studied than the 3,4-bis(indol-3-yl)maleimide compounds though it has been shown that

some of maleimides of this type have valuable biological properties4. The study of 3,4-bis(indol-

1-yl)maleimides incorporated into a macrolactone ring is of special interest as in spite of large

number of indolylmaleimide derivatives published5,6, macrolactones of this type are not known.

In this report, we describe the development of a method of synthesis of the first representatives

of macrolactones built of 3,4-bis(indol-1-yl)maleimide framework as highly versatile and

medicinally useful scaffolds.

FIGURE 1

2. Results and Discussion.

In our work we used a strategy previously elaborated for the syntheses of various 3,4-

bis(indol-1-yl)maleimides containing substituents in positions 3 of indole rings7 using 3,4-

dibromomaleimide 1a8, ω-(indolin-3-yl)alkanols 2a-c and ω-(indolin-3-yl)alkanoic acids 3a-c as

starting compound. ω-(2,3-Dihydroindol-3-yl)alkanols 2a-c9 and ω-(2,3-dihydroindol-3-

yl)alkanoic acids 3a-c10 were prepared as previously described.

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The interaction of 1a with (2,3-dihydroindol-3-yl)alkanols in DMF in the presence of

iPr2EtN or Et3N yielded the corresponding ω-hydroxyalkyl derivatives 4а-с in 77-83% yields.

Hydroxy groups in these compounds were protected by the interaction with TBDMSCl (tert-

butylchlorodimethylsilane) in DMF in the presence of imidazole to give TBDMS-protected

derivatives 5а-с in 72-80% yields. To enhance the reactivity of 4-bromo derivatives 5a-c they

were dehydrogenated by DDQ in toluene to give 3-bromo-4-[3-(ω-hydroxyalkyl)indol-1-

yl)maleimides 6a-c in 72-75% yields. The following substitution of Br atom in 6a-c for (3,4-

dihydroindol-3-yl)alkanoic acids 3a-c led to 3-(indol-1-yl)-4-(3,4-dihydroindol-1-yl)maleimide

derivatives 7a-c in 51-63% yields (Scheme 1).

SCHEME 1

Compounds 7b,c,d gave macrolactones 8b,c,d in benzene at reflux in the presence of

catalytic amounts of p-toluenesulfonic acid in 15-35% yields. Additionally to macrolactones

8b,c,d the desilylation products 9b,c,d were isolated. Dihydroindole moieties of compounds

9b,c,d were dehydrogenated by DDQ in refluxing toluene to give compounds 10b,c,d

respectively in 68-75 % yields (Scheme 2). We failed to obtain the macrolactone by the

cyclization of 7а.The structures of the compounds obtained were supported by NMR and mass-

spectrometry data. Additional support was obtained by the comparison of IR-spectra obtained in

the region of 1750 - 1680 cm-1 of hydroxyacid 7b and macrolactone of 8b. The spectrum of 7b

coincides with the frequency spacing of maleic acid imide, and the peak positions with

maximum absorption is shifted to 1717 cm-1, the change of peak position of amide 7b can be

associated with a frequency band of a carbonyl group of a carbonic acid residue connected to a

indole. The IR spectrum of 8b demonstrates overlapping peak with maximum absorption at 1715

cm-1 corresponding to the frequencies of 7b and the appearance of a new peak with maximum

absorption at 1724 cm-1 indicating a formation of a lactone. Our attempts to prepare

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macrolactones from hydroxy acids 9 with an unprotected hydroxyl group using various methods

failed.

SCHEME 2

Presumably the mechanism of intramolecular cyclization AAC211 includes a nucleophilic

attack of the carbon atom of the protonated carboxyl group on a silyl-ether group or a hydroxyl

group after preliminary hydrolysis: after protonation of the carbonyl oxygen of 7 the formed

intermediates 7’ are converted through the transition state 7’’ into 7''’ , which after the separation

of water and a proton are transformed into the target products 8b,c,d (Scheme 3).

SCHEME 3

Quantum chemical calculations of the reaction by using a software package Gaussian-0911 and

the density functional methode B3LYP/6-31G (d)12, which was made with the assumption of

pre-hydrolysis (R = H) (Scheme 2) showed that at the n = 4 and m = 3 (product 8d) ∆G#

esterification reaction abruptly decreased compared to those of 8b and 8c, which correlates well

with the sharp increase yield of 8d to a relatively to relatively low yields of 8b and 8c (Table 1).

The highest value of Gibbs energy ∆G# for 8a corresponds to the absence of the cyclization

product. The correlation of the calculated activation barriers with practical product yields

suggests that the target reaction is controlled kinetically.

TABLE 1

3. Conclusion

Starting from 4-(dihydroindol-1-yl)-3-(indol-1-yl)maleimides containing ω-hydroxyalkyl

and ω-carboxyalkyl moieties in positions 3 of indole rings 15, 16 and 17-membered

macrolactones were synthesized. For the lactonization reactions the O-silylated ω-hydroxyalkyl

indole derivatives were used as the attempts to cyclize the O-nonprotected hydroxyacids failed.

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By means of quantum chemical methods AM1 and density functional B3LYP/6-31G (d) it was

demonstrated that the activation barrier ∆G # of esterification reaction leading to macrolactones

decreases with the increase of the macrolactone size wheraus the highest value of ∆G# calculated

for 13-membered lactone 8a (64.2 kcal/mol) corresponds to the absence of the target reaction

product. It suggests that the cause of decrease of the activation barrier in the line of

macrolactones 13>15>16>17 is the increase of the number of degrees of freedom of the side

chains connected with the indole nuclei.

4. Experimental section

4.1. General

Melting points were determined on a Buchi SMP-20 apparatus. NMR spectra were

recorded with a Varian VXR-400 instrument at 400 MHz (1H-NMR) or at 100 MHz (13C-NMR)

with internal reference. Chemical shifts are given in ppm and coupling constants in Hz. High-

resolution electrospray mass spectra were recorded on a Bruker «micrOTOF-Q II»- MS

instrument (Bruker Daltonics GmbH, Bremen, Germany). Analytical TLC was performed on

Silica Gel F254 plates (Merck) and column chromatography on Silica Gel Merck 60. Extracts

were dried over anhydrous Na2SO4 and evaporated under reduced pressure. Solvents and

reagents were obtained from commercial suppliers unless otherwise specified. Compounds 1,

2a,b,c and 3a,b,c were obtained as previously described. The IR spectra were obtained on a

Nicolet-iS10 Fourier transform IR spectrometer (Thermo scientific, USA ) with DTGS detector,

splitter KBr and a Smart Performer module equipped with a ZnSe-crystal(ATR). The spectra

were run on the range of 3000—650 cm–1 with a resolution of 4 cm–1. The spectra were

proceeded using the OMNIC-7.0 program package.

4.2. 3-Bromo-4-(3-(ω-hydroxyalkyl)indolin-1-yl)maleimides 4

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4.2.1. 3-Bromo-4-(3-(2-hydroxyethyl)indolin-1-yl)maleimide (4а). (Indolin-3-yl)ethanole 2a

(1.700 g, 10.4 mmol) and Et(iPr)2N (3.5 mL, 20 mmol) were added to solution of 3,4-

dibrommalemide 1 (2.540 g, 10 mmol) in dry DMF (5 mL). The reaction mixture was left to stir

overnight at 50ºС. The cooled to rt reaction mixture was diluted with EtOAc (100 mL), washed

with water (200 mL), brine (50 mL), dried and evaporated. The residue was chromatographed

(33.3% EtOAc/petroleum ether) to give 4a as a red amorphous solid (2.642 g, 7.8 mmol, 80%);

m.p. 137-139ºC; Rf (50% EtOAc/petroleum ether) 0.35; νmax 1767, 1715, 1624, 1591 cm-1; δН

(400 MHz, DMSO-d6): 1.60-1.69 (2 Н, m), 1.89-1.97 (2 Н, m), 3.52-3.55 (2 Н, m), 4.00-4.05 (1

Н, m), 4.37-4.42 (1 Н, m), 6.95 (1 Н, d, J 8.0 Hz), 6.99 (1 Н, t, J 7.5 Hz), 7.16 (1 Н, t, J 7.6 Hz),

7.25 (1 Н, d, J 7.5 Hz), 11.02 (1 Н, s); δc (100 MHz, DMSO-d6): 36.5, 38.3, 58.7, 59.5, 91.0(q),

115.8, 122.8, 123.9, 126.3, 136.4(q), 141,7(q), 142.0(q), 166.8(C=O), 167.1(C=O); HRMS

[M+Na]+, found: 358.9987, [C14H13BrN2O3+Na] requires 359.0007.

4.2.2. 3-Bromo-4-(3-(3-hydroxypropyl)indolin-1-yl)maleimide (4b). Compound 4b was obtained

from 1 (2.540 g, 10 mmol) and 2b (1.860 g, 10.5 mmol) as described for 4a as a red amorphous

solid (2.914 g, 8.3 mmol, 83%), m.p. 145-147ºC; Rf (50% EtOAc/petroleum ether) 0.4; νmax

1777, 1724, 1634, 1455 cm-1; δН (400 MHz, DMSO-d6): 1.46-1.54 (2 Н, m), 1.74-1.78 (1 Н, m),

3.35-3.38 (2 Н, m), 3.41-3.45 (2 Н, m), 3.58-3.62 (1 Н, m), 3.93-3.97 (1 Н, m), 4.38-4,43 (1 Н,

m), 6.96 (1 Н, d, J 7.7 Hz), 7.01 (1 Н, t, J 7.5 Hz), 7.16 (1 Н, t, J 7.7 Hz), 7.25 (1 Н, d, J 7.5 Hz),

11.08 (1 Н, s); δc (100 MHz, DMSO-d6): 29.7, 30.0, 40.5, 59.2, 60.6, 91.1(q), 115.7. 122.7,

123.9, 126.3, 136.3(q), 141.8(q). 141.9(q), 166.8(C=O), 167.1(C=O); HRMS [M+H]+, found

351.0318, [C15H15BrN2O3 +H]+ requires 351.0339.

4.2.3. 3-Bromo-4-(3-(4-hydroxybutyl)indolin-1-yl)maleimide (4с). Compound 4c was obtained

from 1 (2.540 g, 10 mmol) and 2c (2.000 g, 10.5 mmol) as described for 4a as a red amorphous

solid (2.812 g, 7.7 mmol, 77%); m.p. 140-142ºC; Rf (50% EtOAc/petroleum ether) 0.45; νmax

1767, 1721, 1624, 1591 cm-1; δН (400 MHz, DMSO-d6): 1.37-1.40 (2 Н, m), 1.43-1.53 (2 Н, m),

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1.72-1.80 (2 Н, m), 3.30-3.36 (1 Н, m), 3.40-3.45 (2 Н, m), 3.92-3.96 (1 Н, m), 4.36-4,40 (2 Н,

m), 6.93 (1 Н, d, J 8.0 Hz), 6.97 (1 Н, t, J 7.5 Hz), 7.14 (1 Н, t, J 7.7 Hz), 7.23 (1 Н, d, J 7.3 Hz),

11.09 (1 Н, s); δc (100 MHz, DMSO-d6): 23.0, 32.5, 33.4, 40.8, 59.3, 60.6, 91.1(q), 115.7, 122.7,

123.9, 126.3, 136.3(q), 141.8(q), 141.9(q), 166.8(C=O), 167.1(C=O); HRMS [M+Na]+, found

387.0345, [C16H17BrN2O3 +Na]+ requires 387.0320.

4.3. 3-Bromo-4-(3-(ω-(tert-butyldimethylsilyloxy)alkyl)indolin-1-yl)maleimides 5

4.3.1. 3-Bromo-4-(3-(2-(tert-butyldimethylsilyloxy)ethyl)indolin-1-yl)maleimide (5а). To the

solution of 4а (2.642 g, 7.8 mmol,) and imidazole (0.571 g, 8.4 mmol) in dry DMF (25 ml) was

added TBDMSCl (1.266 g, 8.4 mmol). The reaction mixture was left to stir overnight at rt,

diluted with EtOAc (100 mL), washed with water (300 mL), brine (50 mL), dried and

evaporated. The residue was chromatographed (5% EtOAc/petroleum ether) to give 5a as a red

amorphous solid (2.600 g, 5.7 mmol, 73%); m.p. 171-173ºC; Rf (10% EtOAc/petroleum ether)

0.35; νmax 1770, 1715, 1622, 1591. 834-775 cm-1; δН (400 MHz, DMSO-d6): 0.04 (6 Н, s), 0.87

(9 Н, s), 1.63-1.82 (1 Н, m), 1.93-2.0 (1 Н, m), 3.40-3.46 (1 Н, m), 3.65-3.74 (2 Н, m), 4.04-4.09

(1 Н, m), 4.35-4.39 (1 Н, m), 6.94 (1 Н, d, J 7.7 Hz), 6.97 (1 Н, t, J 7.5 Hz), 7.14 (1 Н, t, J 7.7

Hz), 7.22 (1 Н, d, J 7.3 Hz), 11.01 (1 Н, s); δc (100 MHz, DMSO-d6): -5.5(2С), 17.8(q),

25.7(3С), 36.2, 38.5, 59.4, 60.7, 91.0(q). 115.7, 122.6, 123.7, 126.3, 136.0(q), 141.7(q),

141.8(q), 166.7(C=O), 167.0(C=O); HRMS [M-Н]- , found 449.0912, [C20H27BrN2O3Si -Н]-

requires 449.0896.

4.3.2. 3-Bromo-4-(3-(3-(tert-butyldimethylsilyloxy)propyl)indolin-1-yl)maleimide (5b).

Compound 5b was obtained from 4b (2.914 g, 8.3 mmol), TBDMSCl (1.326 g, 8.8 mmol) and

imidazole (0.600 g, 8.8 mmol) as described for 5a as a red amorphous solid (2.978 g, 6.4 mmol,

77%); m.p. 165-167ºC; Rf (10% EtOAc/petroleum ether) 0.45; νmax 1770, 1723, 1623, 1591.

834-775 cm-1; δН (400 MHz, DMSO-d6): 0.02 (6 Н, s), 0.85 (9 Н, s), 1.46-1.57 (2 Н, m), 1.76-

1.82 (1 Н, m), 1.93-2.0 (1 Н, m), 3.32-3.40 (1 Н, m), 3.57-3.63 (2 Н, m), 3.92-3.96 (1 Н, m),

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4.38-4.42 (1 Н, m), 6.95 (1 Н, d, J 8.4 Hz), 6.98 (1 Н, t, J 7.5 Hz), 7.16 (1 Н, t, J 7.5 Hz), 7.22 (1

Н, d, J 7.1 Hz), 11.10 (1 Н, s); δc (100 MHz, DMSO-d6): -5.3(2С), 17.8(q), 25.7(3С), 29.5, 29.8,

40.4, 59.1, 62.2, 91.1(q), 115.7, 122.7, 123.8, 126.3, 136.2(q), 141.7(q), 141.8(q), 166.8(C=O),

167.0(C=O); HRMS [M+Н]+, found 465.1191, [C21H29BrN2O3Si +Н]+ requires 465.1204.

4.3.3. 3-Bromo-4-(3-(3-(tert-butyldimethylsilyloxy)butyl)indolin-1-yl)maleimide (5с). Compound

5c was obtained from 4c (2.812 g, 7.7 mmol), TBDMSCl (1.220 g, 8.1 mmol) and imidazole

(0.551 g, 8.1 mmol) as described for 5a as a red amorphous solid (3.065 g, 6.4 mmol, 83%); m.p.

170-172ºC; Rf (10% EtOAc/petroleum ether) 0.5; νmax 1770, 1715, 1622, 1591. 834-775 cm-1; δН

(400 MHz, DMSO-d6): 0.00 (6 Н, s), 0.84 (9 Н, s), 1.32-1.41 (2 Н, m), 1.43-1.50 (2 Н, m), 3.17-

3.22 (2 Н, m), 3.27-3.33 (1 Н, m), 3.55-3.58 (2 Н, m), 3.89-3.94 (1 Н, m), 4.35-4.39 (1 Н, m),

6.92 (1 Н, d, J 8.0 Hz), 6.94 (1 Н, t, J 7.40 Hz), 7.12 (1 Н, t, J 7.5 Hz), 7.18 (1 Н, d, J 7.3 Hz),

11.08 (1 Н, s); δc (100 MHz, DMSO-d6): -5.4(2С), 17.9(q), 22.7, 25.7(3С), 32.2, 40.9, 48.6,

59.3, 62.2, 91.1(q), 115.8, 122.7, 123.9, 126.3, 136.2(q), 141.84(q), 141.86(q), 166.8(C=O),

167.1(C=O). HRMS [M+Na]+, found 501.1203, [C22H31BrN2O3Si+Na]+ requires 501.1185.

4.4. 3-Bromo-4-(3-(ω-(tert-butyldimethylsilyloxy)alkyl)-1H-indol-1-yl)maleimide 6

4.4.1. 3-Bromo-4-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-indol-1-yl)maleimide (6а). To the

solution of 5а (2.600 g, 5.7 mmol) in toluene (50 mL) was added DDQ (1.930 g, 8.5 mmol). The

reaction mixture was refluxed for 6 h. After cooling to rt it was filtrated, diluted with EtOAc (50

mL), washed with saturated aq NaHSO3 (30 ml), aq NaHCO3 (2х50 mL), dried and evaporated.

The residue was chromatographed (5% EtOAc/petroleum ether) to give 6a as a red amorphous

solid (1.844 g, 4.1 mmol, 72%); m.p. 160-162ºC; Rf (10% EtOAc/petroleum ether) 0.3; νmax

1780, 1729, 1639, 1455. 834-738 cm-1; δН (400 MHz, DMSO-d6): 0.01 (6 Н, s), 0.85 (9 Н, s),

2.93 (2 Н, t, J 6.8 Hz), 3.88 (2 Н, t, J 6.8 Hz), 7.21 (1 Н, t, J 7.3 Hz), 7.27 (1 Н, t, J 7.1 Hz), 7.41

(1 Н, s), 7.43 (1 Н, d, J 7.8 Hz), 7.64 (1 Н, d, J 7.7 Hz), 11.67 (1 Н, s); δc (100 MHz, DMSO-

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d6): -5.3(2С), 17.9(q), 25.8(3С), 28.1, 62.5, 111.2, 114.0(q), 117.1, 119.2(q), 121.4(q). 122.6(q),

125.4(q), 129.2, 134.3, 138.5, 165.9(C=O), 166.6(C=O); HRMS [M-H]-, found 447.0736,

[C20H25BrN2O3Si -H]- requires 447.0740.

4.4.2. 3-Bromo-4-(3-(3-(tert-butyldimethylsilyloxy)propyl)-1H-indol-1-yl)maleimide (6b).

Compound 6b was obtained from 5b (2.978 g, 6.4 mmol) and DDQ (2.179 g, 9.6 mmol) as

described for 6a as a red amorphous solid (2.178 g, 4.7 mmol, 73%); m.p. 158-160ºC; Rf (10%

EtOAc/petroleum ether) 0.4; νmax 1780, 1733, 1639, 1456. 836-740 cm-1; δН (400 MHz, DMSO-

d6): 0.05 (6 Н, s), 0.89 (9 Н, s), 1.83-1.90 (2 Н, m), 2.75-2.79 (2 Н, m), 3.67-3.70 (2 Н, m), 7.22

(1 Н, t, J 7.3 Hz), 7.27 (1 Н, t, J 8.2 Hz), 7.34 (1 Н, s), 7.43 (1 Н, d, J 8.0 Hz), 7.61 (1 Н, d, J 7.5

Hz), 11.65 (1 Н, s); δc (100 MHz, DMSO-d6): -5.2(2С), 17.9(q). 20.5, 25.8(3С), 32.1, 61.9,

111.0. 114.0(q), 119.0(q), 119.8, 121.5(q). 122.7(q). 124.5(q), 129.1, 134.5, 138.6, 165.9(C=O),

166.7(C=O); HRMS [M+H]+, found 463.1068 [C21H27BrN2O3Si +H]+ requires 463.1047.

4.4.3. 3-Bromo-4-(3-(4-(tert-butyldimethylsilyloxy)butyl)-1H-indol-1-yl)maleimide (6с).

Compound 6c was obtained from 5c (3.065 g, 6.4 mmol) and DDQ (2.179 g, 9.6 mmol) as

described for 6a as a red amorphous solid (2.291 g, 4.8 mmol, 75%), m.p. 177-179ºC; Rf (10%

EtOAc/petroleum ether) 0.45; νmax 1780, 1730, 1636, 1456. 836-739 cm-1; δН (400 MHz,

DMSO-d6): 0.03 (6 Н, s), 0.86 (9 Н, s), 1.55-1.61 (2 Н, m), 1.70-1.77 (2 Н, m), 2.74 (2 Н, t, J

7.5 Hz), 3.64 (2 Н, t, J 6.2 Hz), 7.21 (1 Н, t, J 7.4 Hz), 7.27 (1 Н, t, J 6.9 Hz), 7.34 (1 Н, s), 7.44

(1 Н, d, J 8.1 Hz), 7.61 (1 Н, d, J 7.5 Hz), 11.66 (1 Н, s); δc (100 MHz, DMSO-d6): -5,3(2С),

17.8(q), 23.9. 24.7, 25.3(3С), 32.0, 62.2, 110.8, 114.0(q), 119.0(q), 120.2, 121.4(q), 122.6(q),

124.4(q), 129.1, 134.5, 138.6, 165.9 (C=O), 166.7 (C=O); HRMS [M-H]-, found 475.1056,

[C22H29BrN2O3Si -H]- requires 475.1053.

4.5. ω-(1-(4-(3-(ω-(tert-butyldimethylsilyloxy)alkyl)-1H-indol-1-yl)-2,5-dioxo-2,5-dihydro-

1H-pyrrol-3-yl)indolin-3-yl)alkancarbonic acid 7

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4.5.1. 2-(1-(4-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-indol-1-yl)-2,5-dioxo-2,5-dihydro-1H-

pyrrol-3-yl)indolin-3-yl)acetic acid (7а). To the solution of 6а (1.844 g, 4.1 mmol) and 2-

(indolin-3-yl)acetic acid hydrochloride 3а (1.030 g, 4.8 mmol) in dry DMF (20 mL) was added

Et(iPr)2N (4.4 mL, 25 mmol). The reaction mixture was left to stir overnight at rt, diluted with

EtOAc (100 mL), washed with water (300 mL), brine (50 mL), dried and evaporated. The

residue was chromatographed (EtOAc/iPrOH/AcOH 10:1:0.1), washed with aq NaHCO3 (2х50

mL), water (300 mL), brine (50 mL), dried and evaporated to give 7a as a red amorphous solid

(1.145 g, 2.1 mmol, 51%), m.p. 145-147ºC; Rf (10% iPrOH/EtOAc) 0.5; νmax 1757, 1714, 1650,

1573, 1483, 1458, 1433, 1098; δН (400 MHz, DMSO-d6): -0.05 (6H, s), 0.89 (9H, s), 2.22-2.29

(1 Н, m), 2.45-2.48 (1 Н, m), 2.84 (2 Н, t, J 7.2 Hz), 3.29-3.36 (1 Н, m), 3.71 (2 Н, t, J 7.3 Hz),

3.95-4.04 (1 Н, m), 4.51 (1 Н, t, J 9.0 Hz), 5.79 (1 Н, d, J 7.9 Hz), 6.35 (1 Н, t, J 7.9 Hz), 6.57 (1

Н, t, J 6.4 Hz); 6.90-6.98 (2 Н, m), 7.05 (1 Н, d, J 7.9 Hz), 7.08 (1 Н, t, J 8.2 Hz), 7.17 (1 Н, s),

7.42 (1 Н, d, J 7.6 Hz); HRMS [M+Н]+, found 546.2442, [C30H35N3O5Si +Н]+ requires

546.2424.

4.5.2. 3-(1-(4-(3-(3-(tert-butyldimethylsilyloxy)propyl)-1H-indol-1-yl)-2,5-dioxo-2,5-dihydro-

1H-pyrrol-3-yl)indolin-3-yl)propanoic acid (7b). Compound 7b was obtained from 3b (1.138 g,

5 mmol) and 6b (2.178 g, 4.7 mmol) as described for 7a as a red amorphous solid (1.617 g, 2.8

mmol, 60%); m.p. 161-163ºC; Rf (10% iPrOH/EtOAc) 0.5; νmax 1759, 1714, 1649, 1599, 1482,

1458, 1433, 1101; δН (400 MHz, DMSO-d6): -0.05 (6H, s), 0.89 (9H, s), 1.74-1.80 (3 Н, m),

1.92-2.00 (1 Н, m), 2.21-2.25 (2 Н, m), 2.72 (2 Н, t, J 7.2 Hz), 3.29-3.36 (1 Н, m), 3.63 (2 Н, t, J

6.2 Hz), 3.97 (1 Н, dd, J 11.0 Hz, 5.3 Hz), 4.41 (1 Н, t, J 9.0 Hz), 5.87 (1 Н, d, J 8.1 Hz), 6.41 (1

Н, t, J 8.3 Hz), 6.60 (1 Н, t, J 7.5 Hz); 6.91-6.96 (2 Н, m), 7.02 (1 Н, d, J 7.3 Hz), 7.12 (1 Н, d, J

7.2 Hz), 7.15 (1 Н, s), 7.43 (1 Н, d, J 7.3 Hz); HRMS [M+Н]+, found 574.2743, [C32H39N3O5Si

+Н]+ requires 574.2732.

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4.5.3. 4-(1-(4-(3-(3-(tert-butyldimethylsilyloxy)propyl)-1H-indol-1-yl)-2,5-dioxo-2,5-dihydro-

1H-pyrrol-3-yl)indolin-3-yl)butanoic acid (7с). Compound 7c was obtained from 3c (0.966 g, 4

mmol) and 6b (1.530 g, 3.3 mmol) as described for 7a as a red amorphous solid (1.200 g, 2.0



1.76 (2 Н, d, J 7.0 Hz m), 2.28 (2 Н, t, J 6.9 Hz), 2.70 (2 Н, t, J 7.3 Hz), 3.32-3.48 (2 Н, m), 3.63

(2 Н, t, J 6.3 Hz), 3.98 (1 Н, dd, J 11.4 Hz, 6.2 Hz), 4.38-4.46 (2 Н, m), 5.89 (1 Н, d, J 8.0 Hz),

6.42 (1 Н, t, J 7.8 Hz), 6.62 (1 Н, t, J 7.3 Hz), 6.94 (1 Н, t, J 6.8 Hz), 6.99 (1 Н, t, J 7.5 Hz), 7.01

(1 Н, d, J 8.6 Hz), 7.13 (1 Н, d, J 9.1 Hz), 7.14 (1 Н, s), 7.42 (1 Н, d, J 7.7 Hz) 10.97 (1 Н, s);

HRMS [M+Н]+, found 588.2878, [C33H41N3O5Si +Н]+ requires 588.2894.

4.5.4. 4-(1-(4-(3-(4-(tert-butyldimethylsilyloxy)butyl)-1H-indol-1-yl)-2,5-dioxo-2,5-dihydro-1H-

pyrrol-3-yl)indolin-3-yl)butanoic acid (7d). Compound 7d was obtained from 3c (0.725 g, 3

mmol) and 6c (1.241 g, 2.6 mmol) as described for 7a as a red amorphous solid (1.063 g, 1.7



1.56-1.60 (2 Н, m), 1.60-1.63 (2 Н, m), 2.24-2.28 (2 Н, m), 2.68 (2 Н, t, J 6.4 Hz), 3.61 (2 Н, d,

J 6.6 Hz), 4.00 (1 Н, dd, J 12.3 Hz, 6.1 Hz), 4.46 (2 Н, t, J 8.2 Hz), 5.88 (1 Н, d, J 7.8 Hz), 6.42

(1 Н, t, J 7.6 Hz), 6.60 (1 Н, t, J 7.7 Hz), 6.93 (1 Н, t, J 7.7 Hz), 6.99 (1 Н, t, J 11.2 Hz), 7.00 (1

Н, d, J 11.2 Hz), 7.12 (1 Н, d, J 8.4 Hz), 7.15 (1 Н, s), 7.41 (1 Н, d, J 7.7 Hz), 11.01 (1 Н, s);

HRMS [M+Н]+, found 602.3013, [C34H43N3O5Si +Н]+ requires 602.3040.

4.6. Macrolactones

4.6.1. Lactone of 3-(1-(4-(3-(3-hydroxypropyl)-1H-indol-1-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-

3-yl)indolin-3-yl)propanoic acid (8b) and 3-(1-(4-(3-(3-hydroxypropyl)-1H-indol-1-yl)-2,5-

dioxo-2,5-dihydro-1H-pyrrol-3-yl)indolin-3-yl)propanoic acid (9b). To the solution of 7b (0.956

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g, 1.6 mmol) in benzene (50 mL) was added TsOH (0.010 g, 1.05 mmol).The reaction mixture

was refluxed with a Dean-Stark distillation trap for 30 min. After cooling to RT it was diluted

with EtOAc (50 mL), washed with saturated aq NaHCO3 (50 mL), dried and evaporated. The

residue was chromatographed (20→100% EtOAc/petroleum ether→10% EtOAc/ iPrOH) to give

8b as a red amorphous solid (0.112 g, 0.25 mmol, 15%); m.p. 160-162ºC; Rf (33%

EtOAc/petroleum ether) 0.3; νmax 1727, 1645, 1456 cm-1; δН (400 MHz, DMSO-d6): 1.64-1.70

(1 Н, m), 1.81-1.86 (1 Н, m), 2.05-2.09 (2 Н, m), 2.70 (2 Н, t, J 6.0 Hz), 3.07-3.13 (1 Н, m),

3.39-3.43 (3 Н, m), 3.74-3.78 (1 Н, m), 3.94-3.98 (1 Н, m), 4.24-4.29 (1 Н, m), 5.91 (1 Н, d, J

7.9 Hz), 6.4 (1 Н, t, J 7.5 Hz), 6.69 (1 Н, t, J 6.9 Hz), 6.98 (1 Н, s), 7.05 (1 Н, d, J 7.5 Hz), 7.14

(1 Н, t, J 7.9 Hz), 7.23 (1 Н, t, J 7.2 Hz), 7.48 (1 Н, d, J 8.10 Hz), 7.53 (1 Н, d, J 7.7 Hz), δc (100

MHz, DMSO-d6): 22.0, 26.0, 27.7, 30.1, 39.7(q), 57.3, 63.6, 109.8(q), 111.7, 111.9, 115.3(q),

118.5, 119.9, 121.8, 122.3, 125.3, 126.6, 128.3(q), 133.3(q), 134.3(q), 136.3(q), 142.8(q),

167.4(C=O), 168.0(C=O), 172.5(COO); HRMS [M-H]-, found: 440.1608, [C26H23N3O4 - H]-

requires 440.1610, and 9b as a red amorphous solid (0.074 g, 0.16 mmol, 10%) Rf (33%

iPrOH/EtOAc) 0.5; m.p. 155-157ºC; νmax 1712, 1645, 1599, 1481-1434 cm-1; δН (400 MHz,

DMSO-d6): 1.72-1.78 (3 Н, m), 1.94-1.98 (1 Н, m), 2.29-2.34 (2 Н, m), 1.68-1.72 (2 Н, m), 3.45

(2 Н, t, J 5.3 Hz), 4.02 (1 Н, dd, J 10.3 Hz, 3.0 Hz), 4.40-4.50 (2 Н, m), 5.89 (1 Н, d, J 8.0 Hz),

6.44 (1 Н, t, J 7.5 Hz), 6.63 (1 Н, t, J 7.1 Hz); 6.93 (2 Н, t, J 3.6 Hz)), 7.03 (1 Н, d, J 7.5 Hz),

7.12-7.15 (1 Н, m), 7.17 (1 Н, s), 7.42-7.44 (1 Н, m), 10.97 (1 Н, s), 12.13 (1 Н, s); HRMS [M-

H]-, found: 458.1733, [C26H25N3O5 - H]- requires 458.1716.


3-yl)indolin-3-yl)butanoic acid (8с) and 4-(1-(4-(3-(3-hydroxypropyl)-1H-indol-1-yl)-2,5-dioxo-

2,5-dihydro-1H-pyrrol-3-yl)indolin-3-yl)butanoic acid (9c). Compounds 8c and 9c were

obtained from 7c (0.646 g, 1.1 mmol) as described for 8b and 9b. Compound 8c was obtained as

a red amorphous solid (0.135 g, 0.29 mmol, 27%); m.p. 181-183ºC; Rf (33% EtOAc/petroleum

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ether) 0.3; νmax 1729, 1646, 1457 cm-1; δН (400 MHz, DMSO-d6): 1.41-1.50 (1 Н, m), 1.56-1.67

(3 Н, m), 1.71-1.82 (2 Н, m), 2.40-2.47 (1 Н, m), 2.68 (1 Н, t, J 5.6 Hz), 3.28 (2 Н, t, J 5.6 Hz),

3.72 (1 Н, dd, J 10.7 Hz, 3.3 Hz), 3.93 (2 Н, t, J 5.3 Hz), 4.04-4.13 (2 Н, m), 6.13 (1 Н, d, J 8.0

Hz), 6.54 (1 Н, t, J 7.7 Hz), 6.65 (1 Н, s), 6.79 (1 Н, t, J 7.4 Hz), 7.13 (1 Н, d, J 7.7 Hz), 7.17 (1

Н, t, J 7.3 Hz), 7.21 (1 Н, d, J 7.15 Hz), 7.48 (1 Н, d, J 8.10 Hz), 7.54 (1 Н, d, J 7.89 Hz), 11.01

(1 Н, s); δc (100 MHz, DMSO-d6): 19.5. 21.7, 27.2, 32.8, 34.2, 40.1, 54.4, 62.7. 109.9(q), 111.8.

112.5, 114. 8(q), 118.5, 120.0, 122.2(2С), 124.7, 126.6. 127.1, 128.2(q), 134.6(q), 134.9(q),

136.1(q), 142.3(q), 167.2 (C=O), 168.1 (C=O), 172.4 (COO). HRMS [M-Н]-, found 454.1816,

[C27H25N3O4-Н]- requires 454.1767; HRMS [M+Na]+ ,found 478.1736, [C27H25N3O4+Na]+

requires 478.1737; and 9c as a red amorphous solid (0.060 g, 0.13 mmol, 12%); m.p. 173-174ºC;

Rf (33% iPrOH/EtOAc1) 0.3; νmax 1716, 1649, 1599, 1482-1435 cm-1; δН (400 MHz, DMSO-d6):

1.53-1.59 (2 Н, m), 1.71-1.78 (2 Н, m), 2.29 (2 Н, t, J 4.4 Hz), 2.70 (2 Н, t, J 7.30 Hz), 3.32 (2

Н, t, J 6.1 Hz), 3.46 (2 Н, t, J 6.9 Hz), 3.98 (1 Н, dd, J 11.2 Hz, 5.5 Hz), 4.42-4.49 (2 Н, m), 5.89

(1 Н, d, J 8.1 Hz), 6.43 (1 Н, t, J 7.6 Hz), 6.62 (1 Н, t, J 7.5 Hz), 6.92 (1 Н, t, J 7.0 Hz), 6.95 (1

Н, t, J 6.3 Hz), 7.00 (1 Н, d, J 7.1 Hz), 7.11 (1 Н, d, J 7.3 Hz), 7.17 (1 Н, s), 7.42 (1 Н, d, J 7.01

Hz), 10.98 (1 Н, s), 12.09 (1 Н, s); δc (100 MHz, DMSO-d6): 20.7, 22.1, 33.0, 33.6, 40.4, 57.6,

60.2, 108.9(q), 111.2, 111.5, 117.8(q), 118.60, 119.7, 121.9, 122.1, 123.6, 125.2, 126.2,

127.3(q), 130.0, 131.9(q), 135.1(q), 136.7(q), 142.4(q), 167.7 (C=O), 168.6 (C=O), 174.4

(СOOH); HRMS [M+Na]+, found 496.1841, [C27H27N3O5+Na]+ requires 496.1848; HRMS [M-

Н]- found: 472.1889, [C27H27N3O5-Н]- requires 472.1872.

4.6.3. Lactone of 4-(1-(4-(3-(4-hydroxybutyl)-1H-indol-1-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-

yl)indolin-3-yl)butanoic acid (8d) and 4-(1-(4-(3-(4-hydroxybutyl)-1H-indol-1-yl)-2,5-dioxo-2,5-

dihydro-1H-pyrrol-3-yl)indolin-3-yl)butanoic acid (9d). Compounds 8d and 9d were obtained

from 7d (0.300 g, 0.5 mmol) as described for 8b and 9b. Compound 8d was obtained as a red

amorphous solid (0.082 g, 0.17 mmol, 35%); m.p. 146-148ºC; Rf (33% EtOAc/petroleum ether)

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0.3; νmax 1725, 1646, 1457 cm-1; δН (400 MHz, DMSO-d6): 1.28-1.33 (2 Н, m), 1.36-1.43 (2 Н,

m), 1.48-1.55 (1 Н, m), 1.60-1.66 (2 Н, m), 1.70-1.78 (1 Н, m), 2.20-2.28 (1 Н, m), 2.31-2.38 (1

Н, m), 2.46-2.50 (1 Н, m), 3.28-3.32 (2 Н, m) 3.76-3.81 (1 Н, m), 3.87 (1 Н, dd, J 11.1 Hz, 1.9

Hz), 4.23-4.28 (1 Н, m), 4.31 (1 Н, t, J 8.9 Hz), 5.87 (1 Н, d, J 8.2 Hz), 6.41 (1 Н, t, J 7.4 Hz),

6.59 (1 Н, s), 6.75 (1 Н, t, J 7.4 Hz), 7.12 (1 Н, d, J 7.8 Hz), 7.15 (1 Н, t, J 7.7 Hz), 7.24 (1 Н, d,

J 7.0 Hz), 7.48 (1 Н, d, J 8.2 Hz), 7.49 (1 Н, d, J 7.31 Hz), 10.92 (1 Н, s); δc (100 MHz, DMSO-

d6): 21.8, 22.6, 24.7, 27.2, 34.2, 34.8, 40.0, 58.0, 62.9, 109.2(q), 111.8, 112.2, 116.2(q), 118.4,

119.9, 122.1, 122.4, 124.4, 125.7, 126.4, 128.1(q), 134.1(q), 135.0(q), 136.3(q), 142.2(q), 167.4

(C=O), 168.0 (C=O), 172.1 (COO); HRMS [M+Na]-, found 492.1890, [C28H27N3O4+Na]-

requires 492.1899; and 9d as a red amorphous solid (0.017 g, 0.035 mmol, 7%); m.p. 163-165ºC;

Rf (33% iPrOH/EtOAc) 0.3; νmax 1714, 1646, 1598, 1481-1434 cm-1; δН (400 MHz, DMSO-d6):

1.45-1.50 (2 Н, m), 1.55-1.64 (4 Н, m), 2.26-2.31 (2 Н, m), 2.67 (2 Н, t, J 7.2 Hz), 3.43 (4 Н, d,

J 6.3 Hz), 3.98 (1 Н, dd, J 11.0 Hz, 5.5 Hz), 4.40-4.47 (2 Н, m), 5.90 (1 Н, d, J 7.2 Hz), 6.44 (1

Н, t, J 7.9 Hz), 6.62 (1 Н, t, J 7.5 Hz), 6.93 (1 Н, t, J 7.0 Hz), 6.95 (1 Н, t, J 6.9 Hz), 7.00 (1 Н,

d, J 7.1 Hz), 7.11 (1 Н, dd, J 6.4 Hz, 1.4 Hz), 7.16 (1 Н, s), 7.42 (1 Н, dd, J 6.8 Hz, 2.3 Hz),

10.97 (1 Н, s); HRMS [M-Н]-, found 486.2034, [C28H29N3O5-Н]- requires 486.2029.


3-yl)-1H-indol-3-yl)propanoic acid (10b). To the solution of 8b (0.112 g, 0.25 mmol) in toluene

(20 ml) was added DDQ (0.070 g, 0.3 mmol). The reaction mixture was heated to 70ºC for 1 h.

After cooling to RT it was filtrated, diluted with EtOAc (30 mL), washed with saturated aq

NaHSO3 (1 mL), aq NaHCO3 (2х10 mL), dried and evaporated. The residue was

chromatographed (20% EtOAc/petroleum ether) to give 10b as a red amorphous solid (0.075 g,

0.17 mmol, 68%), m.p. 187-188ºC; Rf (33% EtOAc/petroleum ether) 0.35; νmax 1730, 1658,

1458 cm-1; δН (400 MHz, DMSO-d6): 2.04-2.09 (2 Н, m), 2.30-2.32 (2 Н, m), 2.65-2.68 (2 Н,

m), 2.85-2.87 (2 Н, m), 3.78 (2 Н, t, J 5.4 Hz), 6.20 (1 Н, s), 6.39 (1 Н, s), 7.13-7.16 (2 Н, m),

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7.18-7.27 (2 Н, m), 7.51-7.53 (1 Н, m), 7.59-7.62 (3 Н, m), 11.45 (1 Н, s); δc (100 MHz, DMSO-

d6): 18.9, 21.5, 24.7, 34.2, 62.6, 112.9, 113.6, 118.3(q), 118.4, 119.1(q), 119.4, 121.1, 121.3,

122.7, 123.0, 123.7, 124.5, 124.6(q), 128.0(q), 128.2(q), 128.6(q), 135.3(q), 135.7(q), 166.7

(C=O), 166.9 (C=O), 173.0 (COO); HRMS [M-H]-, found 438.1438, [C26H21N3O4-H]- requires

438.1459.


3-yl)-1H-indol-3-yl)butanoic acid (10c). Compound 10c was obtained from 8c (0.060 g, 0.13

mmol) and DDQ (0.034 g, 0.15 mmol) as described for 10b as a red amorphous solid (0.044 g,

0.097 mmol, 75%); m.p. 169-171ºC; Rf (33% EtOAc/petroleum ether) 0.5; νmax 1730, 1662,

1456 cm-1; δН (400 MHz, DMSO-d6): 1.13-1.20 (4 Н, m), 1.60-1.66 (2 Н, m), 2.06-2.11 (2 Н,

m), 2.88 (2 Н, t, J 5.55 Hz), 4.02 (2 Н, t, J 7.1 Hz), 6.21 (1 Н, s), 6.67 (1Н, d, J 8.1 Hz), 6.73 (1

Н, t, J 7.2 Hz), 6.99 (1 Н, t, J 6.8 Hz), 7.18 (1 Н, t, J 7.1 Hz), 7.22 (1 Н, s), 7.28 (1 Н, t, J 7.2

Hz), 7.45 (1 Н, d, J 7.5 Hz), 7.55 (1 Н, d, J 8.0 Hz), 7.77 (1 Н, d, J 8.4 Hz), 11.49 (1 Н, s); δc

(100 MHz, DMSO-d6): 21.5, 21.9. 22.9, 27.7, 30.7, 64.2, 110.9, 113.3, 117.9(q), 118.6, 119.6,

119.8(q), 120.9. 121.2, 122.3, 123.1, 123.5, 124.90, 124.97(q), 126.1(q), 128.8(q), 129.3(q),

134.9(q), 135.4(q), 166.9 (C=O), 167.5 (C=O), 172.5 (COO); HRMS [M+Na]+, found 476.1573 ,

[C27H23N3O4+Na]+ requires 476.1586.

4.6.6. Lactone of 4-(1-(4-(3-(4-hydroxybutyl)-1H-indol-1-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-

yl)-1H-indol-3-yl)butanoic acid (10d). Compound 10d was obtained from 8d (0.070 g, 0.15

mmol) and DDQ (0.038 g, 0.17 mmol) as described for 10d as a red amorphous solid (0.049 g,

0.10 mmol, 71%); m.p. 159-161ºC; Rf (33% EtOAc/petroleum ether) 0.35; νmax 1730, 1658,

1456 cm-1; δН (400 MHz, DMSO-d6): 1.51-1.57 (4 Н, m), 1.70-1.75 (2 Н, m), 2.21 (2 Н, t, J 5.1

Hz), 2.73 (2 Н, t, J 7.8 Hz), 3.36 (2 Н, t, J 6.3 Hz), 3.48 (2 Н, t, J 6.8 Hz), 5.89 (1 Н, d, J 8.1

Hz), 6.41 (1 Н, t, J 7.7 Hz), 6.65 (1 Н, t, J 7.7 Hz), 6.88 (1 Н, t, J 7.1 Hz), 6.92 (1 Н, s), 6.94 (1

Н, t, J 6.8 Hz), 7.03 (1 Н, d, J 7.1 Hz), 7.14 (1 Н, d, J 7.4 Hz), 7.20 (1 Н, s), 7.39 (1 Н, d, J 7.0

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Hz), 11.02 (1 Н, s); HRMS [M-H]-, found 466.1743, [C28H25N3O4-H]- requires 466.1767;

HRMS [M+Na]-, found 490.1735, [C28H25N3O4+Na]+ requires 490.1743.

References

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http://www.gaussian.com/g_prod/g09.htm

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12. Jensen F. Introduction to Computational Chemistry, second edition, John Wiley & sons LTD.

2007, 54-263.

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Table 1. ∆G# of the cyclization of the protonated intermediates 7’’b,c,d

n m ∆G#

(kcal/mol)

B3LYP/6-

31G(d)

Macrolactone

formed

The yields of

macrolactones

%

2 1 64.2 8a -

3 2 40.6 8b 10

3 3 43.8 8c 25

4 3 16.5 8d 45-55

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Fig. 1. Ruboxistaurin.

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Scheme 1. Synthesis of ω-(1-(4-((3-ω-(tert-butyldimethylsilyloxy)alkyl)-1H-indol-1-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)indolin-3-yl)alkanecarbonic acids 7а-d.

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benzene,t, 30 min

HNO O

N N

O

O

TsOH

n mHNO O

N N

OO

n m

t0, 3 h, 71-75%

7b,c,d

DDQ

9b, n = 3, m = 29c, n = 3, m = 3 9d, n = 4, m = 3

10b, n = 3, m = 210c, n = 3, m = 3 10d, n = 4, m = 3

HNO O

N

HO

N

OHO

8b, n = 3, m = 28c, n = 3, m = 3 8d, n = 4, m = 3

n m

15-35%

7-12%

68-75%

toluene

Scheme 2. Synthesis of macrolactones 9b,c,d and 10b,c.d.

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Scheme 3. The mechanism of acid-catalyzed esterification reaction to form macrolactones 8

from the derivatives of 4-(2,3-dihydroindol-1-yl)-3-(indol-1-yl)maleimides, R =H or TBDMS.

macrolactones built from the bis-3,4(indol-1-yl)maleimide scaffold

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