EP2673276A1 - Flinderole analogues and process for synthesis thereof - Google Patents

Flinderole analogues and process for synthesis thereof

Info

Publication number
EP2673276A1
EP2673276A1 EP11817423.4A EP11817423A EP2673276A1 EP 2673276 A1 EP2673276 A1 EP 2673276A1 EP 11817423 A EP11817423 A EP 11817423A EP 2673276 A1 EP2673276 A1 EP 2673276A1
Authority
EP
European Patent Office
Prior art keywords
och
chc0
conh
ococh
nhme
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP11817423.4A
Other languages
German (de)
French (fr)
Inventor
Dattatraya Hanumant DETHE
Rohan Diliprao ERANDE
Alok RANJAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Council of Scientific and Industrial Research CSIR
Original Assignee
Council of Scientific and Industrial Research CSIR
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Council of Scientific and Industrial Research CSIR filed Critical Council of Scientific and Industrial Research CSIR
Publication of EP2673276A1 publication Critical patent/EP2673276A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention provides a compound of general formula I and analogues thereof. Particularly, the present invention further discloses a highly stereo- and regioselective [3 +2] cycloaddition process for the preparation of Flinderole compound/analogues of general formula 1.
  • the present invention further provides compounds of general formula 1 which are useful as antimalarial compounds.
  • Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium.
  • Four strains of the parasite are responsible for malaria in humans, Plasmodium falciparum, P. vivax, P. ovale, and P. malariae.
  • Plasmodium falciparum the most severe form of malaria, is responsible for the vast majority of deaths associated with the disease.
  • Malaria is commonly associated with poverty, and can indeed be a cause of poverty and a major hindrance to economic development.
  • Nitrogen-containing heterocycles have been used as medicinal compounds for centuries, and form the basis for many common drugs such as Morphine (analgesic), Captopril (treatment of hypertension) and Vincristine (cancer chemotherapy).
  • Morphine analgesic
  • Captopril treatment of hypertension
  • Vincristine cancer chemotherapy
  • the chemical structure of the flinderoles is based on the nitrogen-containing indole ring system; however, these compounds have a novel structure not reported in the literature, due to the attachment of the two indole rings.
  • the flinderoles are related to the borreverine compounds, such as isoborreverine,
  • FIG. 1 Proposed routes for coupling Fragments A and B.
  • flinderoles disclosed in the prior art are either isolated from the natural sources which have the limitations in view of environmental, biodiversity issues etc. or are synthesized by lengthy, non-economical processes.
  • the inventors proposed to further research into these novel compounds for use as an agent against potent and resistant P.falciparum.
  • the inventors have also perceived the need to evolve a synthetic process for such effective compounds, such that the process fulfills the market needs for such effective compounds and also leads to compounds with enhanced bioactivity.
  • the main object of the present invention is to provide flinderole compounds /analogues of general formula I, excluding the proviso which comprises known Flinderoles A, B and C, as effective antimalarials.
  • the another object of the invention is to provide a feasible, cost effective process for the preparation of Flinderoles and its analogues of general formula I as antimalarials especially for effective treatment against Plasmodium falciparum.
  • Another object of the invention is to provide a highly stereo- and regioselective [3 +2] cycloaddition process for the preparation of Flinderole compound/analogues of general formula 1.
  • Yet another object of the present invention is to provide a process for the synthesis of compounds of formula I such that the process is useful for production of commercial quantities of such compounds with improved level of bioactivity.
  • the present invention provides flinderole compounds /analogues of formula I, , excluding the provisos which comprises known Flinderoles A, B and C, as effective antimalarials.
  • R 6 is -CH 2 CH 2 NHMe and R 7 is -H;
  • R 6 is -CH 2 CH 2 NMe 2 and R 7 is -H are known compounds in the art and represent Flinderoles A, B and C.
  • R 9 represents -H, -CH 3
  • R 7 -H, -CH 3 , -COCH 3 , -S02Ph, -(BOC), -(Ph-F), -(Bn), -(C 5 Hi 0 F), -(C0 2 Et), -(MOM).
  • R 8 represents -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -Br, -CI, -F, -I, -CH 2 OH, -CH 2 OCH 3 , -CH 2 OBn -CH 2 OCH 2 CH 3 , -CH 2 CH 2 OH, -CH 2 CH 2 Br.
  • R 3 is -H
  • R 5 is CH 3 ,
  • R 6 is -CH 2 CH 2 NHMe and R 7 is -H;
  • R 6 is -CH 2 CH 2 NMe 2 and R 7 is -H are excluded.
  • said compounds are useful as anti-malarial compound.
  • step (d) e. reacting alcohol (la') as obtained in step (d) optionally with sulphonated diene (lb') as obtained in step (b) or desulphonated diene (le') as obtained in step (c) in presence of Lewis acid and a non- polar solvent at temperature in the range of 25 to 32°C to obtain sulphonated or desuphonated compound of general formula 1;
  • step (e) desulfonylating sulphonated compound of general formula 1 as obtained in step (e) using methanoiic NaOH to obtain desulphonated Flinderole A-C and compounds of general formula I .
  • Lewis acid used in step (e) is selected from Cu(OTf)2 or BF 3 OEt 2 .
  • reaction mixture 50 to 70 minutes at temperature in the range of 25 to 32°C followed by adding water to obtain reaction mixture;
  • step (b) extracting the reaction mixture as obtained in step (a) with non-polar solvent, washing with brine, drying followed by evaporating the solvent;
  • Lewis acid used in step (a) is selected from Cu(OTf)2 or BF 3 OEt 2 .
  • compositions for the treatment of malaria comprising compounds of general formula I optionally along with pharmaceutically acceptable excipients.
  • Scheme 1 represents the cycloaddition reaction between a tertiary alcohol (la') and an olefin (lb') to obtain compound of general formula 1.
  • Scheme 2 represents the structures of flinderoles A-C and the proposed biosynthetic pathway.
  • Scheme 3 represents flow chart for the preparation of compound of general formula 1.
  • Scheme 4 represents process steps for the preparation of intermediate compounds.
  • Scheme 5 represents compound 11 to 17 and process steps for the preparation of compound 9a, 9b, 10a and 10b.
  • Scheme 6 represents process steps for the preparation of compound 17-28 and flinderole B and C.
  • Figure 1' represents proposed stereo chemical model for the [3+2] cycloaddition.
  • the present invention provides Flinderole compounds/ analogues of general formula I,
  • the present invention also relates to a highly stereo- and regioselective [3 +2] cycloaddition reaction between a tertiary alcohol (la') and a diene (lb') (olefin) in presence of Lewis acid and a non-polar solvent at room temperature (25 to 32°C). (Scheme 1).
  • the process for the preparation of flinderoles of compounds/ analogues of formula I by the instsnt invention includes Flinderoles A, B and C.
  • Flinderoles A, B and C contain an unprecedented rearranged skeleton compared to their related isomers of the borreverine class of compounds. (Scheme 2)
  • diene (lb') Mesylation of alcohol (la') and subsequent elimination yielded diene (lb'), which give the required diene (le') upon desulfonylation using methanolic NaOH.
  • the diene (le') is found to polymerize with different Lewis acids under various reaction conditions employed, resulting in intractable mixtures. It is reasonably concluded that the actual site of protonation in 4 is at C3 of the indole nucleus to produce a conjugated enamine, which could undergo cationic polymerization.
  • the pesent invention discloses the preparation of flinderoles 9a and 9b by dimerization of alcohol (8) in presence of various Lewis acids as shown in Scheme 4 nd Table 1 below. Various Lewis acids were screened for the proposed dimerization of the alcohol 8 and results are summarized in Table 1.
  • the present invention provides a highly stereo- and regioselective [3 +2] cycloaddition reaction between a tertiary alcohol (la') and a sulphonated diene (lb') in presence of Lewis acid selected from Cu(OTf)2 or BF 3 Et 2 for the synthesis of flinderole compounds and its analogues of formula I comprising;
  • Dehydration of the hydroxyl group of alcohol 24 is achieved via its mesylate followed by elimination to furnish the requisite olefin 19.
  • Deprotection of the phenylsulfonyl group in alcohol 24 with sodium amalgam gives the other coupling partner, alcohol 18 (Scheme 6).
  • An equimolar mixture of the tert alcohol 18 and the diene 19 are treated with catalytic amount of copper(ll) triflate, which lead to the adduct 25a in 62% yield with diastereoselectivity.
  • TFA salt of synthetic flinderoles B and C possess physical properties (IR, mass, H, 13 C) identical to those reported in the literature.
  • compound of formula 9a and 9b are obtained by desulphonation of compounds of formula 10a and 10b using sodium amalgam as shown in Scheme 6.
  • the flinderole compounds/analogues of formula I finds use in pharmaceutical industry, in agriculture; preferably in pharmaceutical industry for the treatment of malaria especially against Plasmodium falciparum.
  • the present invention provides a method of treatment or prevention of malaria to a subject by administering an effective amount of the compound of Formula I along with one or more suitable pharmaceutical carriers/excipients.
  • the dosage forms include solid dosage forms such as tablets, powders, capsules, liquid dosage forms as well as parenteral dosage forms.
  • the dosage forms can also be prepared as sustained, controlled, modified and immediate release dosage forms. Active ingredient(s) and excipients can be formulated into compositions and dosage forms according to methods known in the art.
  • Reaction were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm Merck silica gel plates (60F-254) using UV light as a visualizing agent and an p- anisaldehyde or ninhydrine stain, and heat as developing agents.
  • TLC thin-layer chromatography
  • Merck silica gel particle size 100-200 and 230-400 mesh
  • Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated.
  • methylmagnesium iodide [prepared from magnesium turnings (3.4 g, 138.1 mmol), methyl iodide (11.5 ml, 184.4 mmol) and few crystals of iodine in anhydrous ether (50 ml)] was added slowly a mixture of the ester lOf (13 g, 46.1 mmol ) in anhydrous ether (50 ml) .
  • the reaction mixture was stirred for 2 h at RT. It was then quenched with aq .
  • methylmagnesium iodide [prepared from magnesium turnings (6.4 g, 29.2 mmol), methyl iodide (18.2 ml, 292.4 mmol) and few crystals of iodine in anhydrous ether (50 ml)] was added slowly a mixture of the ester 23' (15 g, 269.1 mmol) in anhydrous ether (50 ml).
  • the reaction mixture was stirred for 2 h at RT. It was then quenched with aq. NH 4 CI solution (50 ml), extracted with ethyl acetate (3 x 15 ml), washed with brine and dried over Na 2 S0 4 . Evaporation of the solvent and purification of the residue on a silica gel column using EtOAc-hexane (3:7) as eluent furnished the alcohol 24 (13 g, 89%) as a white solid;
  • Flinderole C (10 mg) was treated with 0.5 solution of TFA in acetonitrile to obtain the TFA salt of flinderole C;
  • Flinderole B (30 mg) was treated with 0.5M solution of TFA in acetonitrile to obtain the TFA salt of flinderole B;

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention discloses flinderole compounds/analogues of formula I and to a process for the preparation of same, comprising stereo- and regioselective [3+2] cycloaddition reaction of a tertiary alcohol (1a') and a sulphonated diene (1b') in presence of Lewis acid selected from Cu(OTf)2 or BF3OEt2 and a non-polar solvent at room temperature. The flinderole compounds /analogues of the instant invention and prepared by the process described therein is represented by the general formula I,(The formula I should be inserted here) wherein R1-R4 are described herein in the specification.

Description

FLINDEROLE ANALOGUES AND PROCESS FOR SYNTHESIS THEREOF
FIELD OF THE INVENTION
The present invention provides a compound of general formula I and analogues thereof. Particularly, the present invention further discloses a highly stereo- and regioselective [3 +2] cycloaddition process for the preparation of Flinderole compound/analogues of general formula 1.
The present invention further provides compounds of general formula 1 which are useful as antimalarial compounds.
BACKGROUND AND PRIOR ART OF THE INVENTION
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. Four strains of the parasite are responsible for malaria in humans, Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. There were an estimated 225 million cases of malaria worldwide in 2009. Ninety percent of malaria-related deaths occur in sub-Saharan Africa, with the majority of deaths being young children. Plasmodium falciparum, the most severe form of malaria, is responsible for the vast majority of deaths associated with the disease. Malaria is commonly associated with poverty, and can indeed be a cause of poverty and a major hindrance to economic development.
With the continuous threat of evolution and rise of multi drug resistant strains of Plasmodium, particularly P. falciparum, there is a growing need to evolve alternatives to drugs such as Chloroquine, Artemisinin and such like. Research along these lines is being carried out to identify new compounds from various resources including plant, microbiological and synthetic.
To respond to the threat of resistance, structurally and functionally novel antimalarial compounds with new mechanisms of action are needed. There are articles and research papers which address flinderole compounds as antimalarial agents and the process for their synthesis. Nitrogen-containing heterocycles have been used as medicinal compounds for centuries, and form the basis for many common drugs such as Morphine (analgesic), Captopril (treatment of hypertension) and Vincristine (cancer chemotherapy). The chemical structure of the flinderoles is based on the nitrogen-containing indole ring system; however, these compounds have a novel structure not reported in the literature, due to the attachment of the two indole rings. The flinderoles are related to the borreverine compounds, such as isoborreverine,
References may be made to an article titled "Flinderoles A-C: Antimalarial Bis-indole Alkaloids from Flindersia Species" by Liza S. Fernandez et.al in Org. Lett., 2009, 11 (2), pp 329-332, discloses natural product antimalarials, the novel indole alkaloids flinderole A-C which have selective antimalarial activities with IC5o values between 0.15-1.42 μΜ. Flinderole A was isolated from the Australian plant Flindersia acuminata and flinderoles B and C from the Papua New Guinean plant F. amboinensis. The article further states that Flinderoles A-C contain an unprecedented rearranged skeleton compared to their related isomers of the borreverine class of compounds.
References may be made to PhD research paper titled "The Total Synthesis of the Antimalarial Natural Products, Flinderoles" discusses a methodology for the total synthesis of the novel bis-indole alkaloid ring-system found in the recently isolated natural products, the flinderoles. The thesis proposes two options for coupling the fragments together (Figure 1); a metathesis reaction between two terminal olefins, or a
Wittig reaction between a phosphine and a carbonyl group on the respective fragments.
Fragment A Fragment EC
Figure 1. Proposed routes for coupling Fragments A and B.
The flinderoles disclosed in the prior art are either isolated from the natural sources which have the limitations in view of environmental, biodiversity issues etc. or are synthesized by lengthy, non-economical processes. To bridge the gap in the therapy for malaria, and with the information that flinderole, isolated from natural product extract, present new molecular scaffold for antimalarial drug discovery, the inventors proposed to further research into these novel compounds for use as an agent against potent and resistant P.falciparum. Also, with the increasing prevalence of the infection, the inventors have also perceived the need to evolve a synthetic process for such effective compounds, such that the process fulfills the market needs for such effective compounds and also leads to compounds with enhanced bioactivity. OBJECTS OF THE INVENTION
The main object of the present invention is to provide flinderole compounds /analogues of general formula I, excluding the proviso which comprises known Flinderoles A, B and C, as effective antimalarials.
The another object of the invention is to provide a feasible, cost effective process for the preparation of Flinderoles and its analogues of general formula I as antimalarials especially for effective treatment against Plasmodium falciparum.
Another object of the invention is to provide a highly stereo- and regioselective [3 +2] cycloaddition process for the preparation of Flinderole compound/analogues of general formula 1.
Yet another object of the present invention is to provide a process for the synthesis of compounds of formula I such that the process is useful for production of commercial quantities of such compounds with improved level of bioactivity.
SUMMARY OF THE INVENTION
In an aspect, the present invention provides flinderole compounds /analogues of formula I, , excluding the provisos which comprises known Flinderoles A, B and C, as effective antimalarials.
Formula I Wherein, Rl to R5 are described herein below.
Flinderole compounds of formula I wherein (i) Ri is -CH2CH2NHMe, R2 is -CH=CMe2,, R3 is - H,
R6 is -CH2CH2NHMe and R7 is -H;
and when i is --CH2CH2NMe2, R2 is -CH=CMe2, R3 is -H, R5 -CH3,
R6 is -CH2CH2NMe2 and R7 is -H are known compounds in the art and represent Flinderoles A, B and C.
Accordingly, present invention provides compounds of general formula
General Formula I
wherein,
Ri is selected independently from -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2N e2, -CH2NH2/ -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCON e2, -CH2CH2C02H, -CONHNHz, -CH2CONHNH2, -COCON e2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3. OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
R2 is selected independently from-CH=CH2, -CH=CHMe, -CH=CMe2, -CH=CHEt, -CH=CEt2, -CH=CH(Pr), -CH=C(Pr)2, -CH=CH(i-Pr), -CH=C(i-Pr)2, -CH=CHPh, -CH=C(Ph)2. -Ph, -PhCI, -PhCH3, -PhOMe, -CH2Ph, -CH2PhCH3, -CH2PhOMe, -CH(Me)2, -CH2CH3, -C(Me)3, -C6H6| -CH2CH=CH2, -CH eEt, -CH2C(Me)3, -CH2CH=CH2, -CCPh.
R3 is selected independently from -H, CH3, -Ph, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, - CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, 0CH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COC0NH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
R4 is selected independently from -H, CH3, -Ph, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NH e, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, - CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONH e, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -C0CH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
R5 is selected independently from -CH3, -CH=CH2, -CH=CHMe, -CH=CMe2, -CH=CHEt, -CH=CEt2, -CH=CH(Pr), -CH=C(Pr)2, -CH=CH(i-Pr), -CH=C(i-Pr)2, -CH=CHPh, -CH=C(Ph)2. -CH=CH(lndole).
With the provisio, when R4 is as indicated herein below,
e selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CHzCHjCONMej, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COCO2H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me;
7 repesents -H, -CH3, -COCH3, -S02Ph, -(BOC), -(Ph-F), -(Bn), -(C5Hi0F), -(C02Et), -(MOM); with the provisio, when
Re represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH3, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2. -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
R9 represents -H, -CH3| -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2B1-, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2l -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02 e, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COCO2H, -COCON 2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2CO2H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
io represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI. -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2CO2H, -OCOCH3l -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
Flu represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3( -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -CO2H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
Ri2 represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3. OCH2CH3. -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COCO2H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2CO2CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
With the provisio, when R4 is as indicated herein below.
R6 represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3l -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2f CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COCO2H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
R7 = -H, -CH3, -COCH3, -S02Ph, -(BOC), -(Ph-F), -(Bn), -(C5Hi0F), -(C02Et), -(MOM).
With the provisio, when
R8 represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br. -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2 -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2 -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2 -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
9 represents -H, -CH3, -CH2CH3( -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, 0CH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et( - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC0 Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2C0NHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
Rio represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
R11 represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COCO2H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
i2 represents -H, -CH3, -CH2CH3, -CH2CH2CH3( -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2N e2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2) -OCH3 OCH2CH3, -COCH3, -OH, -CHO, -CONH2 -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2( -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2( -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me;
with the pro NHMe, R2 is -CH=CMe2l, R3 is -H, R5 is CH3,
R6 is -CH2CH2NHMe and R7 is -H;
with the provisio, when R s --CH2CH2NMe2, R2 is -CH=CMe2, R3 is -H, R5 -CH3,
R6 is -CH2CH2NMe2 and R7 is -H are excluded.
In an embodiment of the present invention, said compounds are useful as anti-malarial compound.
In yet another embodiment of the present invention, process for the preparation of Flinderole A-C and compounds of general formula I as claimed in claim 1 comprising the steps of: a. reacting indole aldehyde (lc') with Ph3P=CHC02Et followed by reaction of the resultant ester with MeMgBr to obtain tertiary alcohol (Id');
lc' Id*
b. mesylating tertiary alcohol (Id') as obtained in step (a) followed by elimination to obtain sulphonated diene (lb');
c. desulfonylating (lb') as obtained in step (b) using methanolic NaOH to obtain desulphonated diene (le');
le' R = H
d. desulfonylating alcohol (Id') as obtained in step (a) with sodium amalgam to obtain alcohol (la'); and
e. reacting alcohol (la') as obtained in step (d) optionally with sulphonated diene (lb') as obtained in step (b) or desulphonated diene (le') as obtained in step (c) in presence of Lewis acid and a non- polar solvent at temperature in the range of 25 to 32°C to obtain sulphonated or desuphonated compound of general formula 1;
f. desulfonylating sulphonated compound of general formula 1 as obtained in step (e) using methanoiic NaOH to obtain desulphonated Flinderole A-C and compounds of general formula I .
Flinderole A ( =H) Flinderole C General Formula I
Flinderole B ( =H)
In yet another embodiment of the present invention, Lewis acid used in step (e) is selected from Cu(OTf)2 or BF3 OEt2.
In yet another embodiment of the present invention, the process for the preparation of compounds of general formula I, optionally comprising dimerization of alcohol (la') and the said process comprising the steps of:
a. adding alcohol (la') with lewis acid with stirring foer period in the range of
50 to 70 minutes at temperature in the range of 25 to 32°C followed by adding water to obtain reaction mixture;
b. extracting the reaction mixture as obtained in step (a) with non-polar solvent, washing with brine, drying followed by evaporating the solvent;
c. purifying the residue on silica gel column using EtOAc-hexane (1:39) to obtain compound of general formula 1.
In yet another embodiment of the present invention, Lewis acid used in step (a) is selected from Cu(OTf)2 or BF3 OEt2.
In yet another embodiment of the present invention, a pharmaceutical composition for the treatment of malaria comprising compounds of general formula I optionally along with pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE FIGURES
Scheme 1 represents the cycloaddition reaction between a tertiary alcohol (la') and an olefin (lb') to obtain compound of general formula 1.
Scheme 2 represents the structures of flinderoles A-C and the proposed biosynthetic pathway.
Scheme 3 represents flow chart for the preparation of compound of general formula 1. Scheme 4 represents process steps for the preparation of intermediate compounds. Scheme 5 represents compound 11 to 17 and process steps for the preparation of compound 9a, 9b, 10a and 10b.
Scheme 6 represents process steps for the preparation of compound 17-28 and flinderole B and C.
Figure 1' represents proposed stereo chemical model for the [3+2] cycloaddition.
DETAILED DESCRIPTION OF INVENTION
The present invention provides Flinderole compounds/ analogues of general formula I,
General formula 1
The present invention also relates to a highly stereo- and regioselective [3 +2] cycloaddition reaction between a tertiary alcohol (la') and a diene (lb') (olefin) in presence of Lewis acid and a non-polar solvent at room temperature (25 to 32°C). (Scheme 1).
In an aspect, the process for the preparation of flinderoles of compounds/ analogues of formula I by the instsnt invention includes Flinderoles A, B and C.
Flinderoles A, B and C contain an unprecedented rearranged skeleton compared to their related isomers of the borreverine class of compounds. (Scheme 2)
Symmetrical retrosynthetic analysis of the dimeric structure of flinderoles revealed monomeric tryptamine diene as a possible precursor for the synthesis of flinderoles. Exploration of the biosynthetic pathway as shown in Scheme 1 above lead to the conclusion that diene might undergo dimerization leading to the flinderole framework. The diene (le') is prepared from the known indole aldehyde (lc') (Scheme 3). Treatment of indole aldehyde (lc') with Ph3P=CHC02Et followed by reaction of the resultant ester with MeMgBr generated the tertiary alcohol (la'). Mesylation of alcohol (la') and subsequent elimination yielded diene (lb'), which give the required diene (le') upon desulfonylation using methanolic NaOH. The diene (le') is found to polymerize with different Lewis acids under various reaction conditions employed, resulting in intractable mixtures. It is reasonably concluded that the actual site of protonation in 4 is at C3 of the indole nucleus to produce a conjugated enamine, which could undergo cationic polymerization.
At this juncture, it was reasoned that if diene (le') is generated in situ in sufficiently low concentration, it might undergo dimerization by a formal intermolecular [3+2] cycloaddition, leading to the flinderole framework. Accordingly, the available alcohol (Id') is desulfonylated to obtain alcohol (la') as shown in Scheme 3.
The pesent invention discloses the preparation of flinderoles 9a and 9b by dimerization of alcohol (8) in presence of various Lewis acids as shown in Scheme 4 nd Table 1 below. Various Lewis acids were screened for the proposed dimerization of the alcohol 8 and results are summarized in Table 1.
Table 1: Invention and optimization of dimerization reaction of the alcohol (8)
entr Lewis Yield dr
y acid (%) (9a:9b)
1 TMSOTf 10 1:1
2 Yb(OTf) 25 1:1
3 Sc(OTf) 25 1:1
4 BF3-OEt 38 3:2
5 Cu(OTf) 46 2:1
6 CF3C02 35 3:2
H
7 Tf20 0 N.A. Reaction of the alcohol (8) with TMSOTf furnished a complex mixture of products and the dimers (9a, b) were obtained in poor yield as 1:1 mixture of diastereomers (Table 1, entry 1). Similarly, Yb(OTf)3 and Sc(OTf)3 gave the desired adducts (9a, b) in low yield (Table 1, entries 2 and 3). BF3 OEt2 was found to be useful catalyst for effecting this transformation in much cleaner manner generating the products (9a, b) albeit in moderate yield and diastereoselectivity (Table 1, entry 4). Even though Tf20 did not give any desired product, trifluoroacetic acid did furnish the required product (9a, b) in comparable yield (Table 1, entries 6 and 7). More interestingly Cu(OTf)2 generated the framework 9a and 9b in much improved yield and diastereoselectivity (Table 1, entry 5). The dimers 9a and 9b could be separated by careful column chromatography and their structures were established by spectroscopic analysis (1H, 13C, IR, HRMS) and with the comparison of spectral data. Their relative stereochemistry was determined by ROESY.
The scope of the dimerization reaction discussed above was further extended to reaction between the intermediate generated in situ of alcohol(la') and the diene (lb') bearing a sulfonyl group in presence of Cu(OTf)2 to obtain flinderoles in good yield and diastereoselectivity. (Figure 1)
The present invention provides a highly stereo- and regioselective [3 +2] cycloaddition reaction between a tertiary alcohol (la') and a sulphonated diene (lb') in presence of Lewis acid selected from Cu(OTf)2 or BF3 Et2 for the synthesis of flinderole compounds and its analogues of formula I comprising;
2. reacting indole aldehyde (la') with Ph3P=CHC02Et followed by reaction of the resultant ester with MeMgBr to obtain tertiary alcohol (Id');
3. mesylating alcohol (Id') followed by elimination to yield sulphonated diene (lb');
4. desulfonylating (lb') using methanolic NaOH to obtain diene (le');
5. desulfonylating alcohol (Id*) to obtain alcohol(la'); and
6. reacting alcohol (la') with sulphonated diene (lb') in presence of Lewis acid Cu(OTf)2 and a nono polar solvent at room temperature to obtain desired compounds of formula I.
The processes for the preparation of various Flinderoles are described in Scheme 5 and Scheme 6.
Scheme 5 describes the dimerization reaction. Tert-alcohol 8 and the diene 7 are mixed together and treated with Cu(OTf)2, the dimers 10a, b are obtained in requisite yield and diastereosectivity .(>19: 1). When BF3 OEt2 is used as catalyst, diastereomeric ratio drops to 2:1. Reaction is found to work with equal efficiency when tert-alcohol had ethyl rather than methyl substitution (cf. the adduct 11) . Similarly, having an ethoxymethyl substituent on the C3 of indole did not affect the yield or selectivity (cf. the adducts 12 and 13)
According to Scheme 6, primary hydroxyl group of the compound 20 is acylated using acetic anhydride to furnish the acetate 21. Formylation of the acetate 21 using dichloromethyl methyl ether and stannic chloride gave the acetate 22. The acetyl protection in the indole derivative 22 is changed to TBS-protection following hydrolysis of acetate and reaction of the resultant alcohol with TBSCI to obtain TBS-ether 23. Wittig olefination of the aldehyde 23 with Ph3P=CHC02Et generated the unsaturated ester in 91% yield, which on treatment with methyl magnesium iodide give tertiary alcohol 24. Dehydration of the hydroxyl group of alcohol 24 is achieved via its mesylate followed by elimination to furnish the requisite olefin 19. Deprotection of the phenylsulfonyl group in alcohol 24 with sodium amalgam gives the other coupling partner, alcohol 18 (Scheme 6). An equimolar mixture of the tert alcohol 18 and the diene 19 are treated with catalytic amount of copper(ll) triflate, which lead to the adduct 25a in 62% yield with diastereoselectivity. Surprisingly, when a mixture of the tert-alcohol 18 and the diene 19 is treated with excess of BF3-OEt2, not only it gives the expected dimerization product but also deprotected both TBDMS groups to directly generate the diols 26a, b. The major compound is found to be the isomer 26a in which the methyl and isobutylene groups are cis to each other. Oxidation of the mixture of the diols 26a, b using IBX followed by reductive amination of the resultant bisaldehydes 27a,b give a mixture of the amines 28a, b in 91% yield . Deprotection of indole nitrogen of 28a, b followed by purification by preparative TLC deliveres flinderole B (2) and flinderole C (3), which is treated individually with 0.005M TFA in acetonitriie to get the TFA salt of Flinderoles B and C. The TFA salt of synthetic flinderoles B and C thus obtained possess physical properties (IR, mass, H, 13C) identical to those reported in the literature.
Compounds of formula 9a and 9b are obtained by dimerization of alcohol (8). According to the process, to a solution of the alcohol 8 in anhydrous CH2CI2 is added a catalytic amount of Cu(OTf)2 and stirred magnetically for 1 h at RT. The progress of reaction is monitored by TLC till the starting alcohol had been completely consumed. Water is added to the reaction mixture, extracted with CH2CI2, washed with brine and dried over Na2504. The solvent is evaporated followed by purification of the residue on silica gel column using EtOAc-hexane (1:39) as eluent to furnish isomer 9a. Further, elution of the column with EtOAc-hexane (1:39) yield isomer 9b as white crystalline solid.
In yet another embodiment, compound of formula 9a and 9b are obtained by desulphonation of compounds of formula 10a and 10b using sodium amalgam as shown in Scheme 6.
The flinderole compounds/analogues of formula I finds use in pharmaceutical industry, in agriculture; preferably in pharmaceutical industry for the treatment of malaria especially against Plasmodium falciparum.
The present invention provides a method of treatment or prevention of malaria to a subject by administering an effective amount of the compound of Formula I along with one or more suitable pharmaceutical carriers/excipients. The dosage forms include solid dosage forms such as tablets, powders, capsules, liquid dosage forms as well as parenteral dosage forms. The dosage forms can also be prepared as sustained, controlled, modified and immediate release dosage forms. Active ingredient(s) and excipients can be formulated into compositions and dosage forms according to methods known in the art.
In summary, a highly stereo- and regioselective formal [3+2] cycloaddition reaction between a tertiary alcohol (la') and sulphonated olefin(lb') has been developed for use in the synthesis of pyrrolo[l,2-a] indoles, i.e Flinderole compounds/ analogues of formula I. The potential of this methodology has been amply demonstrated in the first total synthesis of the isomeric flinderoles B and C, which involves 11 steps in the longest linear sequence and gave an overall yield of 17.2%. The strategy is fairly general and is amenable to the synthesis of other natural products of this class as well as their analogues.
Examples
Following examples are given by way of illustration therefore should not be construed to limit the scope of the invention.
All reactions were carried out under nitrogen atmosphere with dry solvents under anhydrou conditions, unless otherwise mentioned. All the chemicals were purchased commercially, and used without further purification. Anhydrous THF and diethyl ether were distilled from sodium-benzophenone, and dichloromethane was distilled from calcium hydride. Yields refer to chromatographically pure material, unless otherwise stated.
Reaction were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm Merck silica gel plates (60F-254) using UV light as a visualizing agent and an p- anisaldehyde or ninhydrine stain, and heat as developing agents. Merck silica gel (particle size 100-200 and 230-400 mesh) was used for flash column chromatography. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. NMR spectra were recorded on either a Bruker Avance 200 ^H: 200 MHz, 13C: 50MHz), Bruker Avance 400 (Ή: 400 MHz, 13C: 100MHz), Bruker Avance 500 ^H: 500 MHz, 13C: 125 MHz). Mass spectrometric data were obtained using QTOF-Micromass-UK.
The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, ddd = doublet of a doublet of a doublet, dt = doublet of a triplet, m = multiplet, br = broad.
Example 1
Synthesis of compound 9a and 9b
9 a, 31% 9b, 15%
solution of the alcohol 8 (50 mg, 0.23 mmol) in anhydrous CH2CI2 (6 ml) was added a catalytic amount of Cu(OTf)2 (15 mg, 0.04 mmol) and stirred magnetically for 1 h at RT. The progress of reaction was monitored by TLC till the starting alcohol has been completely consumed. Water (5 ml) was added to the reaction mixture, extracted with CH2CI2 (3 x 5 ml), washed with brine (5 ml) and dried over Na2S0 . Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1:39) as eluent furnished the isomer 9a (28 mg, 31 %) as white crystalline solid; Rf = 0.5 (EtOAc- hexane 1:19);
IR (neat): ^ cm 1 3362, 3053, 2926, 1697, 1454, 1377, 789, 457; XH NMR (CDCI3, 400 MHz): 5 7.91 (br s, 1H), 7.60-6.95 (m, 8H), 6.80 (d, J = 16.6 Hz, 1H), 6.23 (d, J = 16.3 Hz, 1H), 5.27 (d, J = 9.3 Hz, 1H), 4.24 (q, J = 17.3 Hz, 1H), 2.69-2.60 (m, 1H), 2.41-2.30 (m, 4H), 2.20 (s, 3H), 1.82 (d, J = 16 Hz, 6H), 1.72 (s, 3H); 13C NMR (CDCI3, 100 MHz): δ 142.0, 136.2, 133.7, 133.1, 132.0, 131.2, 131.1, 129.9, 124.9, 123.1, 120.2, 119.5, 118.9, 118.5, 118.4, 118.3, 111.9, 110.4, 109.7, 101.8, 62.7, 52.0, 35.2, 25.7, 22.9, 18.2, 8.7, 7.9; HRMS: m/z calcd for C28H3iN2 [M+H+]: 395.2487; found: 395.2496.
Further elution of the column with EtOAc-hexane (1:39) gave the isomer 9b (14 mg, 15%) as white crystalline solid; Rf = 0.45 (EtOAc-hexane 1:19).
IR (neat): 3479, 3410 (-NH), 3049, 2925, 1615, 1455, 1376, 1172, 973, 599; l NMR (CDCI3, 400 MHz): 5 7.81 (br s, 1H), 7.60-7.00 (m, 8H), 6.22 (d, J = 16.3 Hz), 6.08 (d, J = 16.1 Hz, 1H), 5.28 (d, J = 9.3 Hz, 1H), 4.17 (q, J = 17.3 Hz, 1H), 2.80-2.75 (m, 1H), 2.35-2.25 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.94 (s, 3H), 1.8 (s, 6H); 13C NMR (CDCI3, 100 MHz): δ 142.6, 136.1, 133.7, 133.1, 131.4, 131.0, 129.4, 124.9, 122.9, 120.2, 119.4, 118.8, 118.5, 118.4, 117.1, 111.5, 110.3, 109.9, 101.7, 63.5, 51.9, 34.7, 25.9, 25.7, 18.2, 8.6, 7.8; HRMS: m/z calcd for C28H3oN2Na [M+Na+]: 395.2487; found: 395.2493. Example 2
Synthesis of compound 10a and 10b:
To a solution of the alcohol 8 (100 mg, 0.46 mmol) and diene 7 (156 mg, 0.46 mmol) in anhydrous CH2CI2 (6 ml)was is added a catalytic amount of Cu(OTf)2 (32.5 mg, 0.09 mmol) and stirred magnetically for 0.5 h at RT. The progress of reaction was monitored by TLC till the starting alcohol had been completely consumed. Water (5 ml) was added to the reaction mixture, extracted with CH2CI2 (3 x 5 ml), washed with brine (5 ml) and dried over Na2S04. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1:99) as eluent furnished the isomer 10a (176 mg, 71 %) as white crystalline solid; f = 0.5 (EtOAc-hexane 1 :49); IR (neat): Vmax/cm 1 2925, 1615, 1454, 1366, 1170, 967, 787, 603; Ή NMR (CDCI3, 200 MHz): 5 8.18 (d, J = 8.1 Hz, 1H), 7.60-6.90 (m, 12H), 6.38 (d, J = 15.8 Hz, 1H), 5.98 (d, J = 16Hz, 1H), 5.32 (d, J = 9.3 Hz, 1H), 4.38 (q, J = 17.3 Hz, 1H), 2.90-2.80 (m, 1H), 2.28-2.39 (m, 1H), 2.23 (s, 3H), 2.15 (s, 3H), 2.02 (s, 3H), 1.83 (d, J = 4.9 Hz, 6H); 13C NMR (CDCI3, 50 MHz) : δ 142.7, 139.3, 138.3, 136.0, 133.8, 133.6, 133.3, 133.2, 131.5, 131.4, 128.8, 126.4, 124.9, 124.6, 123.5 , 120.3, 119.0, 118.6, 118.5, 117.9, 114.8, 110.0, 101.8, 63.6, 51.2 , 34.8, 25.7, 25.5, 18.2, 10.1, 7.8; HRMS: m/z calcd for C34H34N202S Na [M+Na+]: 557.2239; found : 557.2235.
Further elution of the column with EtOAc-hexane (1:99) gave the isomer 10b (60 mg, 24%) as white crystalline solid; Rf = 0.45 (EtOAc-hexane 1:49) .
IR (neat): 2923, 1614, 1452, 1372, 1171, 972, 761, 471. lH NMR (CDCI3, 200 MHz) : δ 8.18 (d, J = 7.3 Hz, 1H), 7.75-6.90 (m, 13H), 6.18 (d, J = 16.4 Hz, 1H), 5.32 (dt, J = 9.3, 1.4, 2.6 Hz, 1H), 4.27 (q, J = 16.9 Hz, 1H), 2.84-2.67 (m, 1H), 2.50-2.30 (m, 1H), 2.21 (s, 6H), 1.90-1.70 (m, 9H); 13C NMR (CDCI3, 50 MHz): δ 142.1, 140.6, 138.2, 136.3, 133.6, 133.5, 133.4, 133.2, 131.8, 131.1, 128.9, 126.5, 125.1, 125.0, 123.7, 120.2, 120.0, 119.2, 119.0, 118.5, 115.0, 109.7, 101.8, 62.7, 52.0, 35.1 , 25.7, 22.6, 18.2, 10.4, 7.81; HRMS: m/z calcd for C34H34N202S Na [M+ Na+]: 557.2239; found: 557.2237.
Example 3: Synthesis of compound 5:
To a magnetically stirred solution of the indole 5a (30 g, 110.7 mmol) in CH2CI2 (130 ml) was added dichloromethyl methyl ether (34.4 ml, 387.5 mmol) followed by dropwise addition of SnCI4 (45.4 ml, 387.5 mmol ) at -78 °C, the mixture was allowed to come to -10 °C slowly over a period of lh. 1.0 N HCI (20 ml) was added to the reaction mixture and extracted with CH2CI2. The organic layer is washed with brine and dried over Na2S04. Evaporation of the solvent and recrystallization of the crude product from 1,2- dichloroethane furnished the aldehyde 5 (27 g, 82%) as a white crystalline solid;
Rf = 0.4 (EtOAc -hexane 1:9); IR (neat): 2924, 2855, 2725, 1676 (C=0), 1462, 1365, 1173, 955, 722, 601; lH NMR (CDCI3, 200 MHz): 5 10.60 (s, 1H), 8.22 (dt, J = 8.3 Hz, 1H), 7.75-7.60 (m, 2H), 7.60-7.20 (m, 6H), 2.51 (s, 3H); 13C NMR (CDCI3, 50 MHz): 6 185.2, 137.5, 137.0, 134.1, 133.0, 132.5, 130.6, 129.2, 129.2, 126.7, 124.8, 121.7, 115.8, 10.5; HRMS: m/z calcd for Ci6H13N03S [M+H+]: 300.0694; found: 300.0686.
Example 4: Synthesis of compound 5':
5 To a solution of the aldehyde 5 (12 g, 40.13 mmol) in anhydrous CH2CI2 (200 ml) was added dry Ph3P=CHC02Et (20.9 g, 60.2 mmol) and stirred magnetically for 6 h at RT. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc -hexane (1.5:8.5) as eluent gave the ester 5' (14 g, 95 %) as white crystalline solid;
Rf = 0.45 (EtOAc -hexane 3:7); I (neat): ^cm 1 2984, 1712 (0-C=0), 1623, 1445, 1371, 1170, 982, 760, 598; XH NMR (CDCI3, 200 MHz): δ 8.25 (m, 2 H), 8.21 (m, 1H), 7.75-7.60 (m, 2H), 7.55-7.20 (m, 6H), 6.12 (d, J = 16.2 Hz, 1 H), 4.33 (q, ; = 7.14, 2H), 2.31 (s, 3H), 1.39 (t, = 7.1 Hz, 3H); 13C NMR (CDCI3, 50 MHz): 5 166.40, 137.8, 137.1, 134.5, 133.8, 131.8, 131.5, 129.0, 126.7, 126.5, 124.2, 123.5, 122.6, 119.9, 115.4, 60.8, 14.4, 10.9; HRMS: m/z calcd for C2oH19N04SNa [M+Na+]: 392.0935; found: 392.0933. Example 5: Synthesis of compound 6:
To a cold (0 °C), magnetically stirred solution of the ester 5' (10.0 g, 27.1 mmol) was added methyl magnesium iodide [prepared from magnesium turnings (2.6 g, 108.4 mmol), methyl iodide (10.1 ml, 162.6 mmol) and few crystals of iodine in anhydrous ether (50 ml)] and stirred for 2 h at RT. The reaction mixture was quenched with aq.NH4CI solution (50 ml) and worked up. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1:4) as eluent furnished the tertiary alcohol 6 (7.8 g, 81%) as a white solid;
Rf = 0.4 (EtOAc -hexane 2:3); IR (neat): 1583, 1455, 1170, 963, 725, 595; XH NMR (CDCI3, 200 MHz): δ 8.20 (dtj = 7.20, 1H), 7.75-7.60 (m, 2H), 7.50-7.15 (m, 6H), 7.00-6.85 (m, 1H), 5.94 (d, y = 16.2 Hz, 1H), 2.18 (br s. 1H), 2.18 (s, 3 H), 1.50 (s, 6H); 13C NMR (CDCI3, 50 MHz): δ 144.4, 138.4, 136.3, 133.9, 133.5, 131.9, 128.9, 126.7, 125.0, 123.7, 119.1, 118.2, 117.1, 115.1, 71.2, 29.7, 10.2; HRMS: m/z calcd for C2oH21N03S Na [M+Na+]: 378.1142; found: 378.1139.
Example 6: Synthesis of compound 7:
6 7
To a solution of the alcohol 6 (3.6 g, 10.14 mmol) in anhydrous THF (50 ml) and Et3N (8.45 ml, 60.84 mmol) under N2 atmosphere was added MsCI (2.35 ml, 30.42 mmol) slowly over a period of 5 min at 0 °C. The solution was allowed to warm to RT for about 1.5 h and then refluxed for 30 min. The precipitate formed is filtered off using ethyl acetate affording a brown viscous liquid. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1 :9) as eluent furnished the diene 7 (2.8 g, 82%) as a white solid;
Rf = 0.5. (EtOAc-hexane 1:9); IR (neat): 2919, 1447, 1363, 1171, 968, 755, 603; l NMR (CDCI3, 200 MHz): δ 8.30-7.20 (m, 9H), 7.04 (dj = 16.3Hz, 1H), 6.43 (dj = 16.3 Hz, 1H), 5.14 (d, y = 4.9 Hz, 2H), 2.25 (s, 3H), 2.08 (s, 3H); 13C NMR (CDCI3, 50 MHz): δ 142.3, 137.4, 133.5, 128.9, 126.7, 125.0, 123.8, 119.4, 119.1, 118.1, 115.2, 18.5, 10.6; HRMS: m/z calcd for C2oH20N02S [M+H+]: 338.1214; found: 338.1208.
Example 7: Synthesis of compound 4:
To a solution of the protected diene 7 (2.5 g, 7.4 mmol) in MeOH (30 ml) is added NaOH (3 g, 74.2 mmol) in H20 (10 ml) and the reaction mixture was heated to 70 °C for 3 h . Excess MeOH was removed under reduced pressure. The residue was washed with ether (3 x 20 ml). The organic extracts were combined, washed with brine (20 ml) and dried over anhydrous Na2S04. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1:3) as eluent gave the diene 4 (1.1 g, 75%) as a yellow solid;
3414, 1644, 1449, 1215, 1022, 756.5, ), 7.48 (dj = 7.9 Hz, 1H), 7.30 (dj = 1H), 7.01 (ddd, J = 0.9 Hz, 7.0 Hz, 7.9 Hz, 1H), 5.11 (d. J = 19.8 Hz, 2 H), 2.33 δ 143.5, 137.8, 133.6, 130.3, 130.2, 123.7, 120.0, 119.5, 117.2, 112.4, 111.4, 18.6, 8.7; HRMS: m/z calcd for G4H15 [M+H+] :
198.1204; found: 198.0914.
Example 8: Synthesis of compound 8:
6 8
To a solution of the alcohol 6 (6 g, 16.9 mmol) in anhydrous methanol (50 ml) was added
Na2HP04 (9.6 g, 67.6 mmol) and Na-Hg (15.5 g, 67.6 mmol) . The reaction mixture was stirred for 1 h at RT until all of the amalgam had become converted to liquid mercury. Water (20 ml) and ether (40 ml) were added and the supernatant was decanted. The residue was washed with ether (3 x 20 ml). The organic extracts were combined, washed with brine (20 ml) and dried over anhydrous Na2S04. Evaporation of the solvent and purification of the residue on si lica gel column using EtOAc-hexane ( 1:3) as eluent gave the alcohol 8 (3.3 g, 91%) as a yellow solid;
Rf = 0.35 (EtOAc-hexane 1: 1); IR (neat): vjcnr1 3362 (OH), 3056 (NH), 2864. 1583, 1377, 1086, 786; *H NMR (CDCI3. 200 MHz) : δ 7.98 (br s, 1H), 7.60-7.00 (m, 4H), 6.74 (d, J = 16.3 Hz, 1H), 6.08 (dj = 16.2 Hz, 1H), 2.33 (s, 3 H), 1.64 (br s, 1H), 1.46 (s, 6H); "C NMR (CDCU, 50 M Hz): δ 136.27, 134.78, 131.38, 129.61, 122.83, 119.37, 118.88, 115.73, 111.49, 110.38, 71.23, 30.04, 8.65; HRMS: m/z calcd for C14Hi6N [M-OH ]: 198.1283; found: 198.1281.
Example 9: Synthesis of compound 9a:
To a solution of the 10a (50 mg, 0.09 mmol) in anhydrous methanol (6 ml) was added Na2HP04 (56 mg, 0.36 mmol) and Na-Hg (82 mg, 0.36 mmol). The reaction mixture was stirred for 1 h at RT until all of the amalgam had become liquid mercury. Water (5 ml) and ether (10 ml) were added and the supernatant solution was decanted, extracted with ether (3 x 5 ml), washed with brine (5 ml) and dried over Na2S04. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1:39) furnished the compound 9a (35 mg, 94%) as a white solid; Rf = 0.5 (EtOAc-hexane 1:19); whose data (IR, 2H NMR, I3C NMR and HRMS) was identical with earlier compound 9a obtained from dimerization of terr-alcohol 8.
Example 10: Synthesis of compound 9b:
To a solution of the 10b (50 mg, 0.09 mmol) in anhydrous methanol (6 ml) was added Na2HP04 (56 mg, 0.36 mmol) and Na-Hg (82 mg, 0.36 mmol). The reaction mixture was stirred for 1 h at RT until all of the amalgam had become converted into liquid mercury. Water (5 ml) was added to the reaction mixture, extracted with ether (3 x 5 ml), washed with brine (5 ml) and dried over Na2S04. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1:39) as eluent gave the compound 9b (35 mg, 94%) as a white solid Rf = 0.45 (EtOAc-hexane 1:19); whose data (IR, XH NMR, 13C NMR and HRMS) was identical with earlier compound 9b obtained from dimerization of tert-alcohol 8.
Example 11: Synthesis of compound 8':
8'
To a cold (0 °C), magnetically stirred solution of the ester 5' (1 g, 2.71 mmol) was added methyl magnesium iodide [prepared from magnesium turnings (395 mg, 16.3 mmol), ethyl bromide (1.4 ml, 19.0 mmol) and few crystals of iodine in anhydrous ether (15 ml)] and stirred for 2 h at RT. The reaction mixture was then quenched with aq.NH4CI solution (10 ml) and worked up. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1:4) as eluent furnished the tertiary alcohol 8' (800 mg, 80%) as a white solid; Rf = 0.4 (EtOAc -hexane 1:4). IR (neat): 1879, 1724, 1584, 1449, 1372, 1271, 1174, 1091, 1023, 980.4, 758.9, 592.0; XH NMR (CDCI3, 200 MHz): δ 8.19 (dd = 1.5, 7.1 Hz, 1H), 7.74-7.68 (m. 2H), 7.49-7.19 (m, 6H), 6.99 (d, J = 16.9 Hz, 1H), 5.85 (dj = 16.3 Hz, 1H), 2.21 (s, 3H), 1.72 (q, J = 7.6, 15.3 Hz, 4H), 0.99 (t, J = 7.5Hz, 6H); 13C NMR (CDCI3, 50 MHz): δ 142.1, 138.4, 136.1, 134.3, 133.4, 131.8, 128.8, 126.5, 124.8, 123.6, 119.0, 118.8, 117.9, 115.0, 75.9, 33.0, 10.3, 7.9; HRMS-ESI: m/z calcd for C22H25NO3S Na [M+Na+]: 422.1555; found: 422.1107.
Example 12: Synthesis of compound 8":
8"
To a solution of the alcohol 8' (230 mg, 0.59 mmol) in anhydrous methanol (5ml) was added Na2HP04 (339 mg, 2.38 mmol) and Na-Hg (548 mg, 2.36 mmol). The reaction mixture was stirred for 1 h at RT until all of the amalgam had become converted to liquid mercury. Water (5 ml) and ether (10 ml) were added and the supernatant was decanted. The residue was washed with ether (3 x 5ml). The organic extracts were combined, washed with brine (5 ml) and dried over anhydrous Na2S04. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1:4) as eluent gave the alcohol 8" (148 mg, 91%) as a yellow solid;
Rf = 0.5 (EtOAc-hexane 1:4); IR (neat): 2929, 1654, 1523, 1457, 1246, 872.6, 788.2; *H NMR (CDCI3, 200 MHz): 6 9.18 (br s, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.14-6.96 (m, 2H), 6.69 (d, J = 16.2 Hz, 1H), 6.07 (d, J = 16.3 Hz, 1H), 2.3 (s, 3H), 1.61 (qj = 7.2, 15.2 Hz, 4H), 0.89 (t, J = 7.6 Hz, 6H); 13C NMR (CDCI3, 50 MHz): δ 137.8, 135.5, 133.8, 130.7, 123.5, 120.1, 119.7, 117.9, 111.7, 110.6, 76.54, 34.6, 9.0, 8.7; HRMS-ESI: m/z calcd for C16H2iNO [M+ H+]: 244.1701; found: 244.1709.
Example 13: Synthesis of compound lOd
To a magnetically stirred solution of methylmagnesium iodide, [prepared from magnesium turnings (2.8 g, 112.8 mmol), methyl iodide (9.37 ml, 150.4 mmol) and few crystals of iodine in anhydrous ether (50 ml)] was added slowly a mixture of the ester
10c (11 g, 37.6 mmol) in anhydrous ether (40 ml). The reaction mixture was stirred for 2 h at RT. It was then quenched with aq. NH4CI solution (40 ml), extracted with ethyl acetate (3 x 15 ml), washed with brine and dried over Na2S04. Evaporation of the solvent and purification of the residue on a silica gel column using EtOAc-hexane (2:8) as eluent furnished the alcohol lOd (9.2 g, 88%) as a white solid.
Rf = 0.3 (EtOAc-hexane 1:3); IR (neat): Vmax/cm 1 3436 (OH), 2975, 1584, 1215, 1129, 668; XH NMR (200 MHz, CDCI3): δ 6.60 (s, 2H), 6.51 (dj = 16.1 Hz, 1H), 6.27 (dj = 16.1 Hz, 1H), 3.85(d J = 5.3 Hz, 9H), 2.11 (br s, 1H), 1.43 (s, 6H); 13C NMR (50 MHz, CDCI3): 5 153.3, 137.5, 137.1, 132.7, 126.3, 103.3, 70.9, 60.9, 56.0, 29.9; HRMS-ESI: m/z calcd for CigHiv OsSNa [M+Na+]: 275.1259; found: 275.1266.
Example 14: Synthesis of compound lOe:
To a e
, , ,
alcohol 7 mmol) in F
(60 ml) and Et3N (26.3 ml, 190.6 mmol) under IM2 atmosphere was added MsCI (7.35 ml,
95.1 mmol) slowly over a period of 5 min at 0 °C. The solution was allowed to warm at RT for 1.5 h and then refluxed for 30 min. The precipitate formed was filtered off using ethyl acetate affording a colourless viscous liquid. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1:9) as eluent furnished the diene lOe (6.3 g, 85%) as a colourless viscous liquid
Rf = 0.5 (EtOAc-hexane 1:4); IR (neat): vm3Jcm l 2938, 2838, 1584, 1507, 1463, 1419, 1239, 1130, 1007, 667; XH NMR (200 MHz, CDCI3): 6 6.80 (dj = 16.1, 1H), 6.66 (s, 2H), 6.46 (dj = 16.1 Hz, 1H), 5.1(dJ = 9.8 Hz, 2H), 3.87 (d, J = 6.9 Hz, 9H), 1.97 (s, 3H); 13C NMR (50 MHz, CDCI3): 6 153.3, 141.9, 137.7, 133.1, 131.2, 128.6, 117.2, 103.5, 77.7, 77.1, 76.4, 60.9, 56.0, 18.6; HRMS-ESI: m/z calcd for Ci4Hi803K [M+K+]: 273.0893; found: 273.0887.
Example 15: Synthesis of compound lOg:
lOf lOg
To a magnetically stirred solution of methylmagnesium iodide, [prepared from magnesium turnings (3.4 g, 138.1 mmol), methyl iodide (11.5 ml, 184.4 mmol) and few crystals of iodine in anhydrous ether (50 ml)] was added slowly a mixture of the ester lOf (13 g, 46.1 mmol ) in anhydrous ether (50 ml) . The reaction mixture was stirred for 2 h at RT. It was then quenched with aq . NH4CI sol ution (50 ml), extracted with ethyl acetate (3 x 15 ml), washed with brine and dried over Na2S04. Evaporation of the solvent and purification of the residue on a silica gel column using EtOAc-hexane (1:4) as eluent furnished the alcohol lOg (10.5 g, 90%) as a viscous liquid
Rf = 0.3 (EtOAc-hexane 1:3); IR (neat) : 3402 (OH), 2927, 2856, 1607 , 1509, 1216, 1174, 1024, 756, 697, 668; lH NMR (200 MHz, CDCI3): δ 7.50-7.25 (m, 7H), 7.92 (d, J = 8.8 Hz, 2H), 6.53 (d, ; = 16.1 Hz, 1H), 6.2 (d, J = 16.1 Hz, 1 H), 5.06 (s, 2H), 1.63(s, 1H), 1.41 (s, 6H); I3C NMR (50 MHz, CDCI3): δ 158.2, 136.9, 135.5, 129.8, 128.6, 127.9, 127.6, 127.5, 127.4, 125.7, 114.9, 71.03, 69.95, 29.87, 18.60; HRMS-ESI: m/z calcd for Ci8H2o02 K [ M + K+]: 307.1463; found: 307.0933.
Example 16: Synthesis of compound lOh:
lOg lOh
To a sol ution of the alcohol lOg (4.0 g, 14.9 mmol) in anhydrous THF (40 ml) and Et3N (2.4 ml, 89.6 mmol) under N2 atm was added MsCI (3.5 ml, 44.7 mmol) slowly over a period of 5 min at -78 °C. The solution was allowed to warm to RT for 1.5 h and then refluxed for 30 min. The precipitate formed was filtered off using ethyl acetate affording a viscous liquid. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1 : 19) as eluent furnished the diene lOh (3.1 g, 83%) as a viscous liquid
Rf = 0.3 (EtOAc-hexane 1:19); IR (neat): 2975, 2400, 1601, 1509, 1239, 1216, 1025, 963, 668, 541; lH NMR (200 MHz, CDCI3) : δ 7.50-7.15 (m,7H), 7.92 (t of d J = 8.8 and 2.9 Hz, 2H), 6.76 (dj = 16.1Hz, 1H), 6.46 (d, J = 16.1 Hz, 1H), 6.46 (d, J = 16.1 Hz, 1H), 5.10-4.98 (m, 4H), 1.95 (s, 3H); 13C NMR (50 MHz, CDCI3): 5 158.4, 142.2, 137.0, 130.5, 129.9, 128.6, 128.2, 128.0, 127.7, 127.5, 116.4, 115.0, 70.0, 18.7; HRMS-ESI: m/z calcd for C18Hi80 K [M+ K+]: 289.1358; found: 289.0661.
Example 17: Synthesis of compound lOi:
2-Formyl-3-methyl-l-phenylsulphonylindole 5 (5.0 g, 16.7 mmol) was added to powdered potassium hydroxide (4.7 g, 83.6 mmol) in ethanol (150 ml) and the mixture was stirred under reflux for 45 min and then concentrated under reduced pressure. Water (50 ml) was added and the reaction mixture was extracted with CH2CI2 (3 x 50 ml), dried over Na2S04. Evaporation of the solvent and purification of the residue on a silica gel column using EtOAc-hexane (1: 19) as eluent furnished the aldehyde lOi (3.1 g, 90%) as a yellow solid
Rf = 0.35 (EtOAc-hexane 1:9). IR (neat) : 2926, 2850, 2735, 1680 (C=0), 1462, 1365, 1174, 960, 724, 601; XH NMR (200 MHz, CDCI3) : δ 10.18 (s, 1H), 9.22 (s, lH), 7.80 (d, y = 8.2 Hz, 1H), 7.47-7.33 (m, 2H), 7.24-7.12 (m, 1H), 5.02 (s, 2H), 3.66 (q, J = 7.0 Hz, 2H), 1.28 (t, J = 7.0 Hz, 3H); 13C NMR (50MHz, CDCI3): δ 181.9, 137.2, 132.9, 127.5. 127.1, 124.2, 121.7, 121.1, 112.4, 66.2, 62.9, 15.3; HRMS-ESI : m/z calcd for Ci2H13N02 [ M+H+]: 204.0946; found: 204.0733.
Exam le 18: Synthesis of compound lOj:
magnetically stirred indole lOi (1.4 g, 6.86 mmol) in THF (15 ml) was added KOH powder (1.9 g, 34.3 mmol) followed by dropwise addition of PhS02CI (2.6 ml, 20.6 mmol) at 0 °C, and stirred magnetically for 6 h at RT. Water (20 ml) was then added to the reaction mixture, extracted with EtOAc (3 x 20 ml), washed with bri ne (20 ml) and dried over Na2S04. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1 :9) as eluent furnished the compound lOj (2.1 g, 91%) as white crystalline solid;
Rf = 0.3 (EtOAc -hexane 1:9); IR (neat): v^cm 1 2974, 2926, 1677, 1543, 1372, 1175, 1088, 751, 724, 685; *Η NMR (200 MHz, CDCI3): 6 10.61 (s, 1H), 8.21 (t of d. J = 8.5 and 0.8 Hz, 1H), 7.97 (t of d, J = 8.0 and 1.0 Hz, 1H ), 7.75-7.67 (m, 2 H), 7.58-7.47 (m, 2H), 7.45-7.25 (m, 3H), 4.94 (s, 2H), 1.50 (qj = 7.0 Hz, 2H), 1.20 (tj = 7.0 Hz, 3H); 13C NMR (50 MHz, CDCI3): δ 153.3, 137.5, 137.1, 132.7, 126.3, 103.3, 70.9, 60.9, 56.0, 29.9; HRMS-ESI: m/z calcd for C18H17NO4S [M+H+]: 344.0957; found: 344.0955.
Example 19: Synthesis of compound 10k:
To a solution of the aldehyde lOj (11 g, 32.1 mmol ) in anhydrous CH2CI2 (200 ml) was added dry Ph3P=CHC02Et (16.8 g, 48.2 mmol) and stirred magnetically for 6 h at RT. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (2 :8) as eluent gave the ester 10k (12.5 g, 94 %) as white crystalline solid Rf = 0.35 (EtOAc-hexa ne 3:7); IR (neat): vmax/cm 1 3019, 1708 (OC=0), 1630, 1448, 1374, 1215, 758, 669; XH NMR (200 MHz, CDCI3): 6 8.30-8.15 (m, 2H), 7.80-7.60 (m, 3H), 7.55- 7.20 (m, 5H), 6.30 (d. J = 15.9 Hz, 1H), 4.55 (s, 2H) 4.33 (q, J = 7.1 Hz, 2H), 3.51 (q, J = 7.1 Hz, 2H), 1.39 (t. J = 7.1 Hz, 3H), 1.20 (t. J = 7.1 Hz, 3H); 13C NMR (50 MHz, CD3CN): 6 175.4, 175.1, 162.6, 147.8, 130.2, 129.7, 116.5, 95.7, 81.8, 81.1, 69.9, 69.4, 67.3, 67.2, 67.1, 66.7, 66.6, 60.3, 52.8, 52.7, 40.7, 40.1, 28.5, 27.7, 26.8, 24.5, 23.4; HRMS- ESI: calcd for C22H23N05SNa [M+Na+] 436.1195; found : 436.1194.
Example 20: S nthesis of compound 101:
10k 101
To a cold (0 °C), magnetically stirred solution of the ester 10k (10.0 g, 24.2 mmol ) was added methyl magnesium iodide [prepared from magnesium turnings (2.6 g, 72.6 mmol), methyl iodide (10.1 ml, 96.8 mmol) and few crystals of iodine in anhydrous ether (75 ml)] and stirred for 2 h at RT. The reaction mixture was then quenched with aq .NH4CI sol ution (50 ml) and worked up. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (2 :8) as eluent furnished the tertiary alcohol 101 (8.0 g, 83%) as a waxy solid;
Rf = 0.3 (EtOAc-hexane 2 :3); I (neat) : 2853, 1583, 1455, 1170, 963, 725, 595; XH NMR (200 MHz, CDCI3): δ 8.20 (ddj = 7.3, 1.5 Hz, 1H), 7.74 (dj = 7.3Hz, 2H), 7.65- 7.15 (m, 6H), 7.02 (d, J = 16.0, 1H), 4.48 (s, 2H), 3.48 (q, J = 7.0 Hz, 2 H), 1.48 (s, 6H), 1.18 (t, y = 7.0 Hz, 3H); 13C NMR (CDCI3, 50 MHz): 6 146.2, 138.4, 137.3, 136.1, 133.8, 130.4, 129.0, 126.7, 125.0, 123.9, 119.7, 1189.4, 116.0, 114.6, 71.1, 65.6, 29.7, 15.2; HRMS-ESI: calcd for C22H25N04SNa [M+Na+] 422.1402; found: 422.1393.
Example 21: Synthesis of compound 10m:
To a solution of alcohol 101 (6.0 g, 15.0 mmol) in anhydrous THF (40 ml) and Et3N (12.5 ml, 90.0 mmol) under N2 atmosphere was added MsCI (3.5 ml, 45.0 mmol) slowly over a period of 4 min at 0°C The solution was allowed to warm at RT for 1.5 h and then refluxed for 30 min . The precipitate formed was filtered off using ethyl acetate affording a brown viscous liquid. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1 :19) as eluent furnished the diene 10m (5.0 g, 87%) as a white solid
Rf = 0.40 (EtOAc-hexane 1 :9); IR (neat): vmax/cm 1 3019, 1646, 1449, 1363, 1216, 1088, 586; XH NMR (200 MHz, CDCI3): δ 8.21 (dj = 8.2 Hz, 1H), 7.80-7.53 (m, 3H), 7.50-7.16 (m, 5H), 7.05 (dj = 16.1 Hz, 1H), 6.61 {d, J = 16.1 Hz, 1H), 5.17 (d,7 = 5.6 Hz, 2H), 4.51 (s, 2H), 3.50 (q, J = 7.0, 2 H), 2.07 (s, 3H), 1.13 (t, ; = 7.1 Hz, 3H); 13C NMR (CDCI3, 50 MHz): δ 142.1, 139.0, 138.3, 138.1, 136.3, 133.8, 130.7, 129.0, 126.8, 125.1, 124.0, 119.7, 119.1, 118.7, 118.2, 114.8, 65.7, 63.5, 18.5, 15.3; HRMS-ESI: Calcd for C22H23N03SNa [M+ Na+] 404.1296; Found: 404.1296.
Example 22: Synthesis of compound 11:
To a solution of the alcohol 8" (40 mg, 0.16 mmol ) and diene 7 (55 mg, 0.16 mmol) in anhydrous CH2CI2 (5 ml) was added a catalytic amount of Cu(OTf)2 ( 11 mg, 0.03 mmol) and stirred magnetically for 0.5 h at RT. The progress of reaction was monitored by TLC till the starting alcohol had been completely consumed. Water (10 ml) was then added to the reaction mixture, extracted with CH2CI2 (3 x 5 ml), washed with brine (5 ml) and dried over Na2S04. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1 :49) as eluent furnished the isomer 11 (76 mg, 82 %) as white crystalline solid
Rf = 0.4 (EtOAc-hexane 1:49); IR (neat): v^cm 1 2970, 1641, 1454, 1371, 1215, 1022, 668; 1H NMR (500 MHz, CDCI3): 6 8.21 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 4.4 Hz, 1H), 7.46 (t, J = 4.1 Hz, 1H), 7.39-7.18 (m, 5H), 7.11-7.06 (m, 2H), 7.02 (t, J = 7.9 Hz, 2H), 6.35 (d, J = 16.1 Hz, 1H), 5.99 (dj = 16.1 Hz, 1H), 5.26 (d, J = 9.5 Hz, 1H), 4.40 (q, y = 8.8 Hz, 1H ), 2.83 (dd, J = 12.6 and 7.7 Hz, 1H), 2.40-2.26 (m, 2H), 2.24 (s, 3H), 2.21-2.09 (m, 6H), 2.02 (s, 3H), 1.07 (tj = 7.5 Hz, .3H), 1.06 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCI3): δ 144.9, 142.9, 139.4, 138.3, 136.1, 133.8, 133.3, 131.6, 131.4, 128.9, 126.5, 124.9, 123.6, 122.7, 120.3, 119.0, 118.6, 118.5, 117.9, 114.9, 109.9, 101.9, 63.7, 51.7, 34.4, 29.2, 25.5, 23.7, 13.7, 12.9, 10.2, 7.9; HRMS-ESI: m/z calcd for Ci9H17N05S [M+H+]: 563.2732; found: 563.2736.
Example 23: Synthesis of compound 12:
To a solution of the alcohol 8 (40 mg, 0.186 mmol) and diene 10m (68 mg, 0.204 mmol) in anhydrous CH2CI2 (5 ml) was added a catalytic amount of Cu(OTf)2 (11 mg, 0.03 mmol) and stirred magnetically for 0.5 h at RT. The progress of reaction was monitored by TLC till the starting alcohol had been completely consumed. Water (5 ml) was then added to the reaction mixture, extracted with CH2CI2 (3 x 5 ml), washed with brine (5 ml) and dried over Na2S04. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1:19) as eluent furnished the isomer 12 (86 mg, 81 %) as white crystalline solid
Rf = 0.4 (EtOAc-hexane 1:19); IR (neat): v^cm 1 2977, 1450, 1377, 1174, 1089, 929, 669; Ή NMR (200 MHz, CDCI3): δ 8.17 (dd = 7.5, 1.3 Hz, 1H), 7.60-7.48 (m, 2H), 7.45- 7.16 (m, 6H), 7.14-7.00 (m, 4H), 6.37 (d, y = 15.8 Hz 1H), 6.17 (d, ; = 15.9 Hz, 1H), 5.30 (septet of a doublet, ; = 9.5 and 1.3 Hz, 1H), 4.38 (d, J = 2.1 Hz, 2 H), 4.45-4.25 (m, 1 H), 3.45-3.20 (m, 2 H), 2.80 (dd, J = 12.5 and 7.5 Hz, 1H), 3.45-3.20 (m, 2 H), 2.80 (dd, J = 12.5 and 7.5 Hz, 1H), 2.33 (dd, y = 12.6 and 9.6 Hz,), 2.03 (s, 3H), 1.82 (s, 6H), 1.12 (t, J = 7.0 Hz, 3H); 13C NMR (50 MHz, CDCI3): δ 142.0, 140.7, 138.4, 136.7, 135.9, 129.7, 116.5, 133.9, 133.7, 133.6, 131.55, 130.2, 129.0, 126.5, 125.0, 124.6, 123.7, 120.3 119.5, 118.6, 118.2, 117.5, 114.5, 110.0, 102.0, 65.6, 63.6, 63.3, 51.2, 34.8, 25.7, 25.4, 18.2, 15.2, 7.8; HRMS-ESI: calcd for C36H38N203S [M+H+] 579.2681; found: 579.2695. Example 24: Synthesis of com ound 13:
To a solution of the alcohol 8" (50 mg, 0.205 mmol) and diene 10m (69 mg, 0.205 mmol) in anhydrous CH2CI2 (5 ml) was added a catalytic amount of Cu(OTf)2 (15 mg, 0.04 mmol) and stirred magnetically for 0.5 h at RT. The progress of reaction was monitored by TLC till the starting alcohol had been completely consumed. Water (5 ml) was then added to the reaction mixture, extracted with CH2CI2 (3 x 5 ml), washed with brine (5 ml) and dried over Na2S0 . Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1: 19) as eluent furnished the isomer 13 (106 mg, 85 %) as white crystalline solid
Rf = 0.4 (EtOAc-hexane 1 : 19); IR (neat): 2975, 1449, 1046, 929, 669; XH NMR (200 MHz, CDCI3): 6 8.17 (dd. y = 7.5, 1.3 Hz, 1H), 7.60-7.49 (m, 2H), 7.45-7.16 (m, 6H), 7.14-7.00 (m, 4 H), 6.37 (dj = 15.8 Hz, 1H), 6.18 (d, J = 15.7 Hz, 1H), 5.26 (d, J = 9.6 Hz, 1H), 4.38 (d, y = 2.9 ,2H), 4.45-4.25 (m, 1 H), 3.60-3.17 (m, 2 H), 2.79 (dd, J = 12.5 and 7.5 Hz, 1H), 2.45-2.09 (m, 9H), 2.04 (s,3H ), 1.12 (t, J = 7.0 Hz), 2.80 (dd, y = 12.5, 7.5 Hz, 1H), 2.33 (ddj = 12.6, 9.6 Hz), 2.03(s, 3H), 1.82 (s, 6H), 1.12 {t, J = 7.0 Hz, 3H); 13C NMR (50 MHz, CDCI3): δ 144.9, 142.7, 140.7, 138.4, 136.8, 135.9, 133.8, 133.5, 131.5, 130.2, 129.0, 126.5, 125.0, 123.7, 122.6, 120.4, 119.5, 118.6, 118.2, 117.6, 114.5, 110.0, 102.12, 65.6, 63.3, 51.7, 34.4, 29.125.3, 23.7, 15.2, 13.7, 12.9, 7.9; HRMS (ESI) m/z calcd for C38H42N203S [M+ H+] : 607.2994; found: 607.2994.
Example 25: Synthesis of compound 14
To a sol ution of the alcohol 8 (40 mg, 0.19 mmol) and diene lOe (43 mg, 0.19 mmol) in anhydrous CH2CI2 (5 ml) was added a catalytic amount of Cu(OTf)2 (11 mg, 0.03 mmol) and stirred magnetically for 0.5 h at T. The progress of reaction was monitored by TLC ti ll the starting alcohol had been completely consumed. Water (5 ml) was then added to the reaction mixture, extracted with CH2CI2 (3 x 5 ml), washed with brine (5 ml) and dried over Na2S04. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1:4) as eluent furnished the mixture of isomer 14 (64 mg, 75 %) as colourless oil;
Rf = 0.4 (EtOAc-hexane 1:4); IR (neat): vjcm 2924, 1585, 1420, 1129, 1044, 929, 669; XH NMR (200 MHz, CDCI3): δ 7.60-7.42 (m, 1H), 7.35-7.20 (m, 1H), 7.17-6.92 (m, 2H), 6.63 (s, 0.72H), 6.54 (s, 0.28H), 6.50 (5,1.16Η), 6.45 ( (dj = 16.1 Hz, 0.46H), 6.31 (dj = 16.1 Hz, 0.63H), 5.90 (d ; = 16.1Hz, 0.63H), 5.27 (dj = 9.4Hz, 1H), 4.00-4.35 (m, 1H), 3.85 (s, 3H), 3.82 (d, J = 3.2 Hz,6H), 2.85-2.50 (m, 1H), 2.45-2.23 (m, 1H), 2.20 (dd, J = 1.0 Hz, 3H), 1.90 (s, 2H), 1.80 (s, 6H), 1.58 (s, 1H); 13C NMR (50 MHz, CDCI3): 5 153.4, 153.3, 142.7, 142.1, 137.9, 137.7, 134.2, 133.6, 133.5, 133.2, 133.0, 132.8, 132.3, 132.2, 131.4, 131.2, 129.1, 127.6, 124.9, 124.8, 120.2, 118.4, 118.3, 110.0, 109.9, 103.5, 103.5, 101.7, 101.5, 63.5, 62.6, 60.9, 56.1, 52.1, 51.9, 35.2, 34.7, 26.2, 25.7, 23.0, 18.2, 7.8; H MS-ESI: calcd for C28H33N03 [M+H+] 432.2539; found: 432.2529.
Example 26: Synthesis of compound 15
To a solution of the
alcohol 8" (57 mg,
0.23 mmol) and diene lOe (55 mg, 0.23 mmol) in anhydrous CH2CI2 (5 ml) was added a catalytic amount of Cu(OTf)2 (15 mg, 0.04 mmol) and stirred magnetically for 0.5 h at RT. The progress of reaction was monitored by TLC till the starting alcohol had been completely consumed. Water (5 ml) was then added to the reaction mixture, extracted with CH2CI2 (3 x 5 ml), washed with brine (5 ml) and dried over Na2S04. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1:9) as eluent furnished the mixture of isomers 15 (81 mg, 75 %) as colourless oil
Rf = 0.35 (EtOAc-hexane 1:9); IR (neat): v^cnr1 2965, 2934, 2875, 1582, 1454, 1340, 1242, 1127, 1009, 813, 665; XH NMR (200 MHz, CDCI3): δ 7.60-7.42 (m, 1H), 7.35-7.20 (m, 1H), 7.17-6.92 (m, 2H), 6.63 (s, 0. 2H), 6.54 (s, 0.28H), 6.50 (s, 1.06H), 6.45 (d, J = 16.1 Hz, 0.46H), 6.33 (d, = 16.1 Hz, 0.63 H), 5.90 (d, J = 16.1 Hz, 0.63H), 5.23 (d, J = 9.7Hz, 1H), 4.35-4.00 (m, 1H), 3.85 (s, 3H), 3.82 (d, J = 3.5 Hz, 6H), 2.75 (d, J = 12.5, 7.8 Hz, 0.6H), 2.60 (dj = 12.5, 7.8 Hz, 0.40H), 2.50-2.00 (m, 8H). 1.90 (s, 1.8H), 1.65 (ddj = 18.8 Hz, 1.8H), 1.15-0.98 (m, 6H); 13C NMR (50 MHz, CDCI3): δ 153.4, 153.3, 144.4, 144.2, 142.8, 142.1, 137.8, 137.7, 134.2, 133.6, 133.5, 132.8, 132.3, 132.2, 131.4, 131.1, 129.1, 127.5, 123.0, 122.9, 120.2, 118.4, 118.3, 110.1, 109.9, 103.5, 103.4, 101.8, 101.6, 63.5, 62.6, 60.9, 56.1, 56.1, 52.6, 52.3, 34.8, 34.2, 29.1, 26.3, 23.6, 22.9, 13.6, 12.9, 7.9; HRMS-ESI: calcd for C30H37NO3 [M+H+] 460.2852; found: 460.2842. Example 27: Synthesis of compound 16
To a solution
alcohol 8 (50 mg, 0.23 mmol) and diene lOh (58 mg 0.23 mmol) in anhydrous CH2CI2 (5 ml) was added a catalytic amount of Cu(OTf)2 (15 mg, 0.04 mmol) and stirred magnetically for 0.5 h at T. The progress of reaction was monitored by TLC till the starting alcohol had been completely consumed. Water (5 ml) was then added to the reaction mixture, extracted with CH2CI2 (3 x 5 ml), washed with brine (5 ml) and dried over Na2S0 . Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1:49) as eluent furnished the mixture of isomers 16 (60 mg, 74 %) as white crystalline solid;
Rf = 0.3 (EtOAc-hexane 1:49). IR (neat): 2972, 2928, 1880, 1606, 1509, 1454, 1174, 1013, 697, 667; H NMR (200 MHz, CDCI3): 6 7.55-7.45 (m, 1H), 7.44-7.15 ( m, 8H), 7.10-6.80 (m, 4H), 6.59 (d, J = 16.1 Hz, 0.36H), 6.39 (dj = 16.1 Hz, 0.36H), 6.24 (d, J = 16.1 Hz, 0.64H), 5.91 (dj = 16.1 Hz, 0.64H), 5.26 (d, J = 9.5 Hz, 1H), 5.04(d, 7 = 7.2 Hz, 2 H), 4.15 (septet, y = 7.6 Hz, 1H), 2.73 (ddj = 12.6 and 7.8 Hz, 0.64H), 2.60 (dd = 12.6, 7.8 Hz, 0.36H), 2.40-2.1 (m, 4H), 1.87 (s, 2 H), 1.79 (s, 6H), 1.65 (s, 1H); 13C NMR (50 MHz, CDCh): 5 158.5, 158.3, 142.7, 142.1, 136.9, 133.6, 133.6, 133.1, 132.8, 132.7, 131.5, 131.3, 131.2, 129.7, 129.5, 128.6, 128.0, 127.7, 127.4, 127.1, 125.1, 125.0, 120.1, 118.4, 118.3, 118.2, 115.0, 114.9, 110.0, 101.5, 70.0, 63.5, 62.7, 52.0, 51.9, 35.2, 34.7, 26.1, 25.7, 23.1, 18.2, 7.8; HRMS-ESI: m/z calcd for C32H33NONa [M+ Na+]: 470.2460; found: 470.2463.
Exam le 28: Synthesis of compound 17
17 0.164 mmol) and diene lOh (41 mg, 0.164 mmol) in anhydrous CH2CI2 (5 ml) was added a catalytic amount of Cu(OTf)2 (11 mg, 0.03 mmol) and stirred magnetically for 0.5 h at T. The progress of reaction was monitored by TLC till the starting alcohol had been completely consumed. Water (5 ml) was then added to the reaction mixture, extracted with CH2CI2 (3 x 5 ml), washed with brine (5 ml) and dried over Na2S04. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1 :49) as eluent furnished the mixture of isomer 17 (66 mg, 86 %) as white crystalline solid
Rf = 0.4 (EtOAc-hexane 1:49); IR (neat): 3020, 1648, 1444, 1049, 668, 967, 787, 603; XH NMR (200 MHz, CDCI3): δ 7.55-7.45 (m, 1H), 7.44-7.15 (m, 8H), 7.10-6.80 (m, 4H), 6.61 (d, J = 16.1 Hz, 0.36H), 6.40 (d, J = 16.1 Hz, 0.36 H), 6.25 (d, J = 16.1 Hz, 0.64H), 5.91 (dj = 16.1Hz, 0.64H), 5.22 (d, J = 9.5 Ηζ, ΙΗ), 5.04 (d, J = 7.2 Hz, 2H), 4.20 (septet, J = 7.6 Hz, 1H), 2.72 (dd, J = 12.6, 7.8 Hz, 0.64H), 2.58 (dd, J = 12.6, 7.8 Hz, 0.36H), 2.40-2.00 (m, 8 H), 1.88 (s, 2H), 1.66 (s, 1H), 1.15-0.95 (m, 6H); 13C NMR (50 MHz, CDCI3): 5 158.5, 158.3, 144.3, 144.1, 142.8, 136.9, 133.6, 133.5, 132.7, 131.5, 131.3, 131.2, 129.7, 129.5, 128.6, 128.0, 127.7, 127.4, 127.0, 123.1, 120.1, 118.4, 118.3, 118.2, 115.0, 114.9, 110.0, 109.9, 101.6, 101.5, 70.0, 63.5, 62.7, 52.4, 52.3, 34.8, 34.2, 29.1, 26.2, 23.5, 23.0, 13.6, 12.9, 7.9; HRMS-ESI: m/z calcd for C34H37NO [M-H ]: 474.2875; found : 474.2701.
Example 29: Synthesis of compound 21
20 21
To a magnetically stirred solution of the N-protected tryptophol 20 (25 g, 83.05 mmol) in CH2CI2 (200 ml) was added pyridine (36.45 ml, 415.3 mmol), Ac20 (39.2 ml, 415.3 mmol) and DMAP (2 g, 16.6 mmol). The reaction mixture was stirred for 6 h at RT and extracted with CH2CI2, washed with brine, dil . HCI and dried over Na2S04. Evaporation of the solvent under reduced pressure and purification of the residue on a silica gel column using EtOAc- hexane (1:4) as eluent furnished the compound 21 (16 g, 91%) as white crystalline solid
Rf = 0.4 (EtOAc-hexane 1:4); IR (neat): vfflax/cm 2958, 1736, 1448, 1176 (0-C=0), 787,571; l NMR (200 MHz, CDCI3): δ 8.02-7.84 (m, 3H), 7.57-7.06 (m, 7H), 4.32 (t, J = 6.95, 2H), 3.0 (t, J = 6.95, 2 H), 2.03 (s, 3H); 13C NMR (50 MHz, CDCI3): δ 170.9, 138.1, 135.1, 133.7, 130.7, 129.2, 126.6, 124.8, 123.4, 123.2, 119.3, 118.9, 113.6, 63.1, 24.4, 20.9; HRMS-ESI: calcd for Ci8Hi7 N04S [M+IMa+] 366.0776; found: 366.0759. Example 30: Synthesis of compound 22
(200 ml) was added MeOCHCI. (38.8 ml, 437.3 mmol) and SnC (51.2 ml, 437.3 mmol). The reaction mixture was allowed to come to -10 °C slowly over a period of 1 h and was poured into HCI {1M 500 ml). It was then extracted with CH2CI2, washed with brine and dried over Na2S04. Evaporation of the solvent and recrystallisation of the crude product from 1,2-dichloroethane furnished the aldehyde 22 (26 g, 80%) as a white solid.
Rf = 0.4 (EtOAc-hexane 2:8); I (neat): 2853, 1738 (0-C=0), 1675 (C=0), 1543, 1448, 1175, 904, 724; 1 H NMR (CDCI3, 200 MHz): 6 10.6 (s, 1H), 8.2 (dj = 8.5 Hz, 1H), 7.75-7.25 (m, 8H), 4.26 (t, J = 6.7 Hz, 2H), 3.30 (tj = 6.7 Hz, 2H), 1.83 (s, 3H); 13C NMR (CDCI3, 50MHz): δ 184.5, 170.5, 137.2, 136.5, 134.0, 133.2, 132.0, 130.0, 129.1, 128.9, 126.3, 124.7, 121.5, 115.6, 60.3, 24.2, 20.5; HRMS: m/z calcd for C19Hi7N05SNa [M+Na+]: 394.0725; found: 394.0725.
Example 31: Synthesis of compound 23
mmol) in THF (600 ml) was added a solution of LiOH (4.6 g, 202.2 mmol) in water (150 ml) and stirred magnetically for 3 h at RT. The reaction mixture was extracted with ethyl acetate, washed with brine and dried over Na2S04. Evaporation of the solvent gave the crude alcohol 22' which was used in next step without further purification. To a cold (0 °C) solution of the crude alcohol 22' (12 g, 36.5 mmol) in CH2CI2 (200 ml) was added imidazole (3.7 g, 54.7 mmol), TBSCI (7.1 g, 47.4 mmol) at 0°C and stirred magnetically for 6 h at RT. It was then extracted with CH2CI2, washed with brine and dried over Na2S04.
Evaporation of the solvent and purification of the residue on a silica gel column using EtOAc-hexane (1:19) as eluent furnished the compound 23 (16 g, 81%, over 2 steps) as a white crystalline solid;
Rf = 0.4 (EtOAc-hexane 1:19); IR (neat): v^ m 1 2928, 1674 (C=0), 1448, 1368, 1174, 1089, 753, 595; X H NMR (CD3CN, 200 MHz): δ 10.46 (s, 1H), 8.1 (dt, y = 8.5 and 0.8 Hz, 1H), 7.75-7.20 (m. 8H), 3.75 (t, J = 6.2 Hz, 2H), 3.08 (tj = 6.2 Hz, 2H), 0.86 (s, 9H), -0.24 (s, 6H); 13C NMR (CD3CN): δ 183.8, 136.7, 136.1, 134.1, 133.6, 128.9, 128.7, 126.2, 124.2, 122.3, 116.8, 114.9, 62.3, 27.6, 24.7, -4.6, -6.7.
Example 32: Synthesis of compound 23'
To a stirred solution of
the aldehyde 23 23" 23 (15 g,
33.9 mmol) in CH2CI2 (150 ml) was added stabilised two carbon Wittig salt (17.7 g, 50.8 mmol) [prepared from Ph3P (50 g, 190.0 mmol), ethyl bromoacetate (21.1 ml, 190.0 mmol) and toluene (300 ml)]. The reaction mixture was stirred for 6 h at RT. Evaporation of the solvent under reduced pressure and purification of the residue on a silica gel column using EtOAc-hexane (1:19) as eluent furnished the ester 23' (16 g, 91%) as white crystalline solid;
Rf = 0.5 (EtOAc-hexane 1:9); IR (neat): vmax/cm 12929, 2856, 1711 (0-C=0), 1630, 1174, 751, 577; lH NMR (CDCI3, 200 MHz): δ 8.37-7.29 (m, 10H), 6.52 (d, J = 16Hz, 1H), 4.39 (qj = 14.3, 7.2 Hz, 2H), 3.91 (t, ; = 6.2 Hz, 2H), 3.04 (t, J = 6.4 Hz, 2H), 1.45 (t, ; = 7.2 Hz, 3H), 0.85 (s, 9H), -0.1 (s, 6H); 13C NMR (CDCI3, 50MHz): δ 166.3, 137.8, 137.0, 133.8, 133.7, 132.9, 130.8, 128.9, 126.6, 126.2, 124.5, 123.9, 122.5, 120.1, 115.2, 62.6, 60.6, 28.5, 25.8, 18.1, 14.2, -5.6; HRMS: m/z calcd for C27H35N05SSi Na [M+Na+]: 536.1903; found: 536.1909.
Example 33: Synthesis of compound 24
23" 24
To a magnetically stirred solution of methylmagnesium iodide, [prepared from magnesium turnings (6.4 g, 29.2 mmol), methyl iodide (18.2 ml, 292.4 mmol) and few crystals of iodine in anhydrous ether (50 ml)] was added slowly a mixture of the ester 23' (15 g, 269.1 mmol) in anhydrous ether (50 ml). The reaction mixture was stirred for 2 h at RT. It was then quenched with aq. NH4CI solution (50 ml), extracted with ethyl acetate (3 x 15 ml), washed with brine and dried over Na2S04. Evaporation of the solvent and purification of the residue on a silica gel column using EtOAc-hexane (3:7) as eluent furnished the alcohol 24 (13 g, 89%) as a white solid;
Rf = 0.35 (EtOAc-hexane 1:3); IR (neat): vmax/cm 1 3547 (OH), 2927, 1449, 1356, 1109, 751, 577; *H NMR (CDCI3, 200 MHz): δ 8.35 (dt, J = 8.3 Hz, 1.1Hz, 1H), 7.84 (dtj = 7.1, 1.5 Hz, 2H), 7.64-7.28 (m, 6H), 7.06 (dj = 16.2 Hz, 1H), 6.28 (dj = 16.2 Hz, 1H), 3.91 (t, J = 6.7 Hz, 2H), 3.01 (t, J = 6.8 Hz, 2H), 1.63 (s, 6H), 0.9 (s, 9H), -0.05 (s, 6H); 13C NMR (CDCI3, 100 MHz): 6 144.1, 138.3, 136.1, 135.0, 133.4, 131.1, 128.7, 126.5, 124.7, 123.5, 119.4, 116.5, 114.8, 71.0, 62.7, 29.6, 28.4, 25.8, 18.1, 5.5; HRMS: m/z calcd for C27H37N04SSiNa [M+Na+]: 522.2110; found: 522.2100.
Example 34: Synthesis of compound 18
anhydrous methanol (50 ml) was added Na2HP04 (5.7 g, 40.2 mmol) and Na-Hg (9.2 g, 40.2 mmol). The reaction mixture was stirred for 1 h at RT until all the amalgam had converted into liquid mercury. Water (20 ml) was added to the reaction mixture, extracted with ether (3 x 15 ml), washed with brine (20 ml) and dried over Na2S04. Evaporation of the solvent and purification of the residue on a silica gel column using EtOAc-hexane (3:7) as eluent furnished the alcohol 18 (3.5 g, 97%) as a yellow solid;
Rf = 0.3 (EtOAc-hexane 3:7); IR (neat): v^/crrr1 3455 (OH), 3361 (NH), 3058, 2929, 1462, 1255, 1092,793; *H NMR (CD3CN, 400 MHz): δ 9.11 (br s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.16 (d. J = 8 Hz, 1H), 6.97 (tj = 7 Hz, 1H), 6.86 (t, J = 7.3 Hz, 1H), 6.56 (dj = 16.3 Hz, 1H), 6.12 (d = 16.3 Hz, 1H), 3.66 (t, J = 7 Hz, 2H), 2.84 (t, J = 7 Hz, 2H), 2.80 (br s, 1H), 1.23 (s, 6H), 0.71 (s, 9H), -0.18 (s, 6H); 13C NMR (CD3CN, 50 MHz): δ 136.4, 136.1, 132.8, 128.5, 121.8, 118.5, 118.2, 116.9, 114.5, 111.0, 110.1, 69.7, 63.1, 29.0, 27.2, 25.0, 17.6, 6.4; HRMS: m/z calcd for C21H33N02SiK [M+K+]: 398.1918; found: 398.1931. Example 35: Synthesis of compound 19
To a cold (-78 °C), magnetically stirred solution of the alcohol 24 (5 g, 10 mmol) and dry Et3N (8.3 ml, 60.24 mmol) in anhydrous THF (50 ml) was added MsCI (2 ml, 26 mmol). The reaction mixture was slowly allowed to warm to RT for 1.5 h and refluxed for 30 min. The precipitate formed was filtered using ethyl acetate. Evaporation of the solvent and purification of the residue on a silica gel column using EtOAc-hexane (1:19) as eluent furnished the diene 19 (4.7 g, 81%) as a white crystalline solid;
Rf = 0.5 (EtOAc-hexane 1:19); IR (neat): vmax/cm 1 3068, 2954, 2857, 1603, 1449, 1376, 1173, 1091, 748, 579; *H NMR (CDCI3, 200 MHz): δ 8.23 (dtj = 8.2, 1.01 Hz, 1H), 7.71- 7.16 (m, 8H), 6.98 (dj = 16.2 Hz, 1H), 6.62 (dj = 16.3 Hz, 1H), 5.14 (dj = 5.9 Hz, 2H), 3.8 (t, J = 6.8 Hz, 2H), 2.93 (t, J = 6.9 Hz, 2H), 2.07 (s, 3H), 0.78 (s, 9H), -0.17 (s, 6H); "C NMR (CDCI3, 50 MHz): δ 142.1, 138.3, 137.0, 136.4, 135.7, 133.4, 131.3, 128.8, 126.6, 124.8, 123.6, 119.6, 119.4, 118.9, 118.3, 115.1, 62.7, 28.6, 25.8, 18.5, 18.2, -5.5; HRMS: m/z calcd for C^Has OaSSi [M+H+]: 482.2185; found: 482.2178.
Example 36: Synthesis of compound 25a and 25b
25a,b To a solution of the alcohol 18 (200 mg, 0.55 mmol) and diene 19 (268 mg, 0.55 mmol) in anhydrous CH2CI2 (12 ml) was added Cu(OTf)2 (40 mg, 0.11 mmol) . The resulting purplish red solution was stirred for 0.5 h at RT. Aq. NaHC03 (10 ml) was added to the reaction mixture, extracted with CH2CI2, washed with brine and dried over Na2S04. Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (1:49) as eluent furnished the dimer 25a, b (290 mg, 62%) as white crystalline solid;
Rf = 0.35 (EtOAc-hexane 1:49); I (neat): v^ cnrr1 2928, 1471, 1453, 1377, 1253, 1173, 1090, 835, 741, 578; XH NMR (CDCI3, 200 M Hz): 6 8.15 (d, J = 7.7 Hz, 1H), 7.63-7.58 (m, 1H), 7.44-7.18 (m, 7H), 7.11-6.93 (m, 4H), 5.32 (dj = 9.3 Hz, 2 H), 4.38 (dd, 9.1, 17.2 Hz, 1H), 3.81-3.64 (m, 4H), 2.97-2.78 (m, 5H), 2.30 (dt, J = 3.15, 9.5 and 12.5 Hz, 1H), 2.00 (s, 3H), 1.82-1.80 (m, 6H), 1.59 (s, 2H), 0.86 (s, 9H), 0.74 (s, 9H), 0.00 (s, 6H), -0.25 (s, 6H); 13C NMR (CDCI3, 50 MHz): δ 143.7, 138.6, 138.3, 136.0, 134.4, 133.8, 133.3, 131.5, 130.9, 128.9, 126.4, 124.8, 124.7, 123.4, 120.3, 119.4, 119.2, 118.8, 118.7, 118.3, 114.7, 110.2, 103.0, 64.1, 63.7, 62.7, 51.2, 34.9, 28.5, 27.7, 26.0, 25.8, 25.5, 18.4, 18.1, -5.2, -5.6; HRMS: m/z calcd for C48H66N204Ssi2l\la [M+ Na+]: 823.4360; found: 823.4359.
Example 37: Synthesis of compound 26a and 26b
To a solution of the alcohol 18 (100 mg, 0.27 mmol) and diene 19 ( 134 mg, 0.27 mmol) in anhydrous CH2CI2 (10 ml ) was added BF3.OEt2 (150 mg, 1.05 mmol) . The resulting purplish red solution was stirred for 0.5 h at RT. Aq. NaHC03 (10 ml) was added to the reaction mixture, extracted with CH2CI2, washed with brine and dried over Na2S0 . Evaporation of the solvent and purification of the residue on silica gel column using EtOAc-hexane (2:3) as eluent furnished the diol 26a, b (130 mg, 78%) as yellow crystalline solid; small portion of diols 26a, b (20mg) was purified by preparative TLC for data collection .
Rf = 0.35 (EtOAc-hexane 1: 1); IR (neat) : 3401 (OH), 2929, 1613, 1454, 1367, 1172, 1043, 751, 586; *Η NMR (CDCI3, 500 MHz) for 26b (major isomer): δ 8.15 (dj = 8.2 Hz, 1H), 7.65-7.03 (m, 12H), 6.21 (d, J = 16.2 Hz, 1H), 6.13 (dj = 15.9 Hz, 1H), 5.29 (d, ; = 9.8 Hz, 1H), 4.39 (q, J = 17.1 Hz, 1H), 3.81 (t, = 6.1 Hz, 2H), 3.71-3.63 (m, 2H), 3.00- 2.91 (m, 2H), 2.85-2.83 (m, 1H), 2.80 (tj = 6.7 Hz, 2H), 2.39-2.29 (m, 1H), 2.05 (s, 3H), 1.82 (d, J = 4 Hz, 6H); 13C NMR (CDCI3, 125 MHz): δ 144.3, 138.8, 137.9, 136.2, 134.8, 134.1, 133.5, 133.3, 131.8, 130.7, 128.9, 126.3, 125.1, 124.4, 123.8, 120.5, 119.1, 119.0, 118.8, 118.1, 115.1, 110.2, 103.0, 64.0, 63.1, 62.0, 50.8, 34.9, 28.2, 27.2, 25.7, 25.4, 18 631; found: 595.2621.
Exampl
To a solution of the alcohol 26a,b (90 mg, 0.15 mmol) in ethyl acetate (10 ml) was added IBX (254 mg, 0.90 mmol) and refluxed for 1 h. Aq. NaHC03 was added to the reaction mixture and extracted with ethyl acetate (3 x 10 ml). The organic extract was washed with brine and dried over Na2S04. Evaporation of the solvent and purification of the residue on a silica gel column using EtOAc-hexane (1:4) as eluent furnished the dial 27a,b (75 mg, 84%) as a waxy solid;
Rf = 0.6 (EtOAc-hexane 1:4); IR (neat): 2928, 2851. 1726 (C=0), 1452, 1382, 1175, 785, 685,591; lH NMR (CD3CN, 500 MHz): δ 9.6 (s, 2H), 8.1 (d, J = 8.5 Hz, 1H), 7.56-6.98 (m, 12H), 6.07 (dj = 16.2 Hz, 1H), 5.99 (d, J = 16.2 Hz, 1H), 5.26 (d, J = 9.5 Hz, 1H), 4.40 (q, J = 17.4 Hz, 1H), 3.78 (d. J = 4.2 Hz, 2H), 3.68 (d, J = 2.1 Hz, 2H), 2.87 (dd = 12.5, 7.6 Hz, 1H), 2.36 (dd, J = 12.8, 10.1 Hz, IH), 2.01 (s, 3H), 1.77 (d, J = 6.1 Hz, 6H); 13C NMR (CD3CN, 100MHz): δ 200.9, 200.1, 146.7, 141.0, 138.8, 137.1, 137.0, 135.9, 135.5, 134.5, 133.1, 132.0, 130.7, 127.7, 127.6, 126.8, 125.4, 125.1, 122.1, 120.8, 120.5. 119.7, 116.0, 115.5, 111.9, 98.1. 65.8, 51.7, 41.0, 39.6, 36.14, 26.13, 25.9, 18.7; HRMS: m/z calcd for [M+Na+]: 591.2318; found: 591.2304.
Example 39: Synthesis of compound 28a and 28b
mixture of NH e2 (0.30 ml, 2.0 soln, 0.60 mmol) and NaCNBH3 (18.5 mg, 0.30 mmol) in MeOH (2 ml) and acetic acid (0.01 ml) was added a solution of the dialdehyde 27a,b (45 mg, 0.075 mmol) in MeOH (2 ml) and stirred for 12 h at T. The reaction was quenched with a saturated solution of NaHC03 and extracted with ethyl acetate (2 x 5 ml), washed with brine and dried over Na2S04. Evaporation of the solvent and purification of the residue on a silica gel column using Me0H-CH2CI2 (1 :9) as eluent furnished the compound 28a,b (45 mg, 91%) as white crystalline solid;
Rf = 0.4 (Me0H-CH2CI2 1 :9). I (neat): 2935, 1642, 1455, 1383, 1088, 751, 589; XH NMR (CD3OD, 400 MHz): 5 8.11 (dj = 8 Hz, 1H), 7.64-6.87 (m, 12H), 6.15 (0, J = 16.1 Hz, 1H), 6.05 (d, J = 16.1 Hz, 1H), 5.35 (d, J = 9.8 Hz, 1H), 4.54 (m, 1H), 3.36-3.32 (m, 2H), 2.96-2.45 (m, 8H), 2.34 (s, 6H), 2.25 (s, 6H), 2.05 (s, 3H), 1.86 (d, J = 9.5 Hz, 6H); 13C NMR (CD3OD, 100 MHz): δ 144.8, 139.7, 139.1, 137.7, 135.3, 135.1, 134.9, 134.4, 133.2, 132.1, 130.2, 127.5, 126.3, 126.1, 125.2, 121.7, 121.4, 120.3, 120.0, 119.6, 119.5, 116.2, 111.5, 104.8, 65.4, 61.6, 60.0, 51.6, 45.3, 45.2, 36.3, 26.1, 26.0, 23.5, 22.2, 18.6; HRMS: m/z calcd for C4oH48N402S [M+H+]: 649.3576; found: 649.3591.
Example 40: Synthesis of flinderole B (2, Major) and flinderole C (3, Minor)
The mixture of the compound
Flinderole B, 2 28a,b (180 mg, 62% (major)
0.36 mmol) in anhydrous MeOH (20 ml), Na2HP04 (200 mg, 1.6 mmol) and Na-Hg (368 mg, 1.6 mmol) was stirred for 1 h at RT. Water (20 ml) was added to the reaction mixture, extracted with ether (3 x 15 ml), washed with brine and dried over Na2S04. Evaporation of the solvent and purification of the residue on a silica gel column using MeOH-CH2CI2 (1 : 19) as eluent furnished the flinderole C (3, Minor isomer) (20 mg, 15 %) as a colourless waxy solid. ΧΗ NMR (DMSO-de, 500 MHz): δ 11.01 (s, 1H), 7.45 (dd J = 9.8 and 6.4 Hz, 2H), 7.24 (dd, J = 8.8 and 9.4 Hz, 2H), 7.06 (ddj = 7.6 and 7.3 Hz, 1H), 6.94 (m, 3H), 6.61 (dj = 16.2 Hz, 1H), 6.56 (dj = 16.2 Hz, 1H), 5.26 (br.d J = 9.8, 1H), 4.33 (dddj = 9.5, 7.9 and 7.9 Hz, 1H), 2.84-2.68 (m. 5H), 2.37-2.28 (m, 4H), 2.21 (s. 6H), 2.15 (s, 6H), 1.83 (s, 3H), 1.74 (s, 3H), 1.73 (S, 3H); 13C NMR (DMSO-d6 125MHz): 5 142.7, 136.6, 132.8, 132.5, 132.1, 131.9, 131.0, 128.2, 125.7, 122.3, 119.9, 118.7, 118.6, 118.4, 118.4, 117.9, 113.2, 110.9,
110.0, 103.7, 63.0, 60.7, 51.2, 45.2, 45.1, 40.3, 34.9, 25.7, 23.3, 21.8, 21.7, 18.2; HRMS: m/z calcd for C34H44N4 [M+H+]: 509.3644; found: 509.3656.
Flinderole C (10 mg) was treated with 0.5 solution of TFA in acetonitrile to obtain the TFA salt of flinderole C;
IR (neat): Vmax/cnr1 3434, 2990, 2254, 2128, 1660, 1026, 825,762; XH NMR (DMSO-d5, 500 MHz): δ 11.23 (s, 1H), 10.22 (brs, 2H, TFA protons), 7.60 (d J = 7.8 Hz, 1H), 7.58-7.56 (m, 1H), 7.36-7.29 (m, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.11 (dd, J = 7.8 and 7.8 Hz, 1H), 7.02-6.99 (m, 3H), 6.86 (dj = 16.2 Hz, 1H), 6.66 (dj = 16.2 Hz, 1H), 5.28 (br.dj = 9.6 Hz, 1H), 4.40 (ddd, J = 9.6, 9.0 and 7.8 Hz, 1H), 3.29-2.19 (m, 5H), 3.11-3.05 (m, 1H), 2.96 (m, 2H), 2.87 (s, 6H), 2.86 (s, 6H), 2.73 (ddj = 12.6, 7.8 Hz, 1H), 2.33 (ddj = 12.6, 9.0 Hz, 1H), 1.86 (s, 3H), 1.80 (s, 3H), 1.74 (s, 3H); 13C NMR (DMSO-d6 125MHz): δ 142.9, 136.3, 133.3, 133.1, 132.2, 131.8, 130.6, 127.3, 124.3, 122.4, 120.1, 118.7, 118.4, 118.3,
118.1, 117.5, 110.7, 109.7, 108.9, 99.6, 62.7, 56.8, 56.6, 50.6, 42.1, 41.9, 41.8, 41.6, 34.5, 25.2, 22.2, 18.8, 18.4, 17.8.
Further elution of the column with MeOH-CH2CI2 (1:9) gave the flinderole B (2, Major isomer) (89 mg, 62 %) as a white waxy solid.
*H NMR (DMSO-d6, 500 MHz): δ 10.9 (s, 1H), 7.48 (ddj = 8.5 and 7.0 Hz, 1H), 7.39 (ddj = 7.8 and 5.2 Hz, 2H), 7.25 (dj = 8.1 Hz, 1H), 7.07-6.97 (m, 3H), 6.93-6.90 (m, 1H), 6.47 (dj = 16.0 Hz, 1H), 5.87 (dj = 16.0 Hz, 1H), 5.30 (br.d, / = 9.6 Hz, 1H), 4.16 (ddj = 8.8 and 8.4 Hz, 1H), 2.79-2.73 (m, 3H), 2.61-2.45 (m, 4H), 2.42-2.36 (m, 1H), 2.32-2.37 (m, 1H), 2.23 (s, 6H), 2.20-2.09 (m, 2H), 2.03 (s, 6H), 1.95 (s, 3H), 1.79 (s, 6H); 13C NMR (DMSO-de 125MHz): δ 142.9, 136.6, 132.7, 132.6, 131.8, 131.4, 131.1, 128.1, 125.2,
122.2, 120.2, 118.7, 118.5, 118.5, 118.4, 116.4, 112.7, 110.9, 110.3, 103.8, 63.8, 60.7, 60.4, 51.0, 45.1, 44.9, 34.5, 25.7, 25.5, 21.6, 21.5, 18.2; HRMS: m/z calcd for C34H44N4
[M+H+]: 509.3644; found: 509.3656.
Flinderole B (30 mg) was treated with 0.5M solution of TFA in acetonitrile to obtain the TFA salt of flinderole B;
IR (neat): 3229 (NH), 2931, 1613, 1455, 1345, 1040, 745, 661, 592; lH NMR (DMSO-d6, 500 MHz): 6 11.19 (s, 1H), 10.37 (s, 1H, TFA proton), 10.26 (s, 1H, TFA proton), 7.60 (dj = 7.8 Hz, 1H), 7.54 (d = 7.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.09 (dd, / = 7.8 and 7.8 Hz, 1H), 7.05 (dd = 7.8 and 7.8 Hz, 1H), 7.03 (dd, J = 7.8 and 7.8 Hz, 1H), 6.97 (dd, 7.8 and 7.8 Hz, 1H), 6.54 (dj = 16.2 Hz, 1H), 6.34 (dj = 16.2 Hz, 1H), 5.32 (br.d J = 9.0 Hz, 1H), 4.28 (dddj = 9.0, 8.4 and 8.0 Hz, 1H), 3.29-3.22 (m, 1H), 3.13-3.04 (m, 3H), 3.01-2.88 (m, 6H), 2.86 (s, 6H), 2.75 (s, 6H), 2.32 (dd, J = 12.6 and 8.4 Hz, 1H), 1.96 (s. 3H), 1.83 (s, 3H), 1.80 (s, 3H); 13C NMR (DMSO-d6 125MHz): δ 143.5, 136.3, 133.2, 132.2, 132.0, 131.9, 130.9, 127.4, 124.5, 122.3, 120.3, 118.7, 118.5, 118.2, 118.2, 116.0, 110.7, 110.1, 108.5, 99.8, 63.4, 56.9, 56.6, 50.5, 42.1, 42.0, .7, 41.5, 34.3, 25.2, 24.7, 18.
Flinderole B (2)
Comparative table of the spectral characteristics of Synthetic Flinderole (B) and Natural Flinderole (B)
Flinderole C (3)
Comparative table of the spectral characteristics of Synthetic Flinderole (C) and Natural Flinderole (C)

Claims

We claim
1. Compounds of general formula I
General Formula I
wherein,
Ri is selected independently from -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2( -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
R2 is selected independently from-CH=CH2, -CH=CHMe, -CH=CMe2, -CH=CHEt, -CH=CEt2, -CH=CH(Pr), -CH=C(Pr)2, -CH=CH(i-Pr), -CH=C(i-Pr)2, -CH=CHPh, -CH=C(Ph)2, -Ph, -PhCI, -PhCH3, -PhOMe, -CH2Ph, -CH2PhCH3, -CH2PhOMe, -CH(Me)2, -CH2CH3, -C(Me)3, -C6H6, -CH2CH=CH2, -CHMeEt, -CH2C(Me)3, -CH2CH=CH2, -CCPh.
R3 is selected independently from -H, CH3, -Ph, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, - CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2/ CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2( -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
R4 is selected independently from -H, CH3, -Ph, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2l -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, - CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2 -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe. -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me. R5 is selected independently from -CH3, -CH=CH2, -CH=CHMe, -CH=CMe2, -CH=CHEt, -CH=CEt2, -CH=CH(Pr), -CH=C(Pr)2, -CH=CH(i-Pr), -CH=C(i-Pr)2, -CH=CHPh, -CH=C(Ph)2, -CH=CH(lndole).
With the provisio, when R4 is as indicated herein below,
R6 selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me; R7 repesents -H, -CH3, -COCH3, -S02Ph, -(BOC), -(Ph-F), -(Bn), -(C5H10F), -(C02Et), -(MOM); With the provisio, when
e represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -C0C0NMe2, -CH2CH2C02H, -C0NHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
R9 represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3l -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2IMHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2( -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
Rio represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H. -COCONH2( -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2. -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -0C0(CH2)6Me.
n represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn. -CH20CH2CH3, -CH2CH20H, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, 0CH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2C0NH2, -CH2CONHMe, -CH2C0NMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
R12 represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -0CH3, 0CH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2C0NMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5( -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
With the provisio, when R4 is as indicated herein below,
R6 represents -H, -CH3( -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -C0C02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me.
R7 = -H, -CH3, -COCH3, -S02Ph, -(BOC), -(Ph-F), -(Bn), -(C5Hi0F), -(C02Et), -(MOM).
With the provisio, when
R8 represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2l -CH=CMe2, -CH=CEt2, -0CH3, 0CH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2C0NMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COCO2H, -C0C0NH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me;
R9 represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2( -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2l CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2CO2CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me;
Rio represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH3C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02E -CH2=CHCN, -COCO2H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2C02H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3( -OCOCH2CH3, OCOCH2CH2CH3, -CH2CO2CH3, -CH2CO2CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me;
Ri! represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2. -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2. -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2CO2H, -CONHNH2, -CH2C0NHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me;
i2 represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -Br, -CI, -F, -I, -CH2OH, -CH2OCH3, -CH2OBn, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2Br, -CH2CH2NH2, -CH2CH2NHMe, -CH2CH2NMe2, -CH2NH2, -CH2NHMe, CH2NMe2, - (4-Fluorophenyl), -C02H, -Ph, -CH2CH=CH2, -CH=CMe2, -CH=CEt2, -OCH3, OCH2CH3, -COCH3, -OH, -CHO, -CONH2, -CH2CONH2, -CH2CONHMe, -CH2CONMe2, -CH2CH2CONH2, CH2CH2CONHMe, -CH2CH2CONMe2, -CN, -CH2CN, -CH2C02H, -CH2C02Me, -CH2C02Et, - (2-Nitrovinyl), -CH2=CHC02H, -CH=CHC02Me, -CH=CHC02Et, -CH2=CHCN, -COC02H, -COCONH2, -COCONHMe, -COCONMe2, -CH2CH2CO2H, -CONHNH2, -CH2CONHNH2, -COCONMe2, -SH, -SC2H5, -SCH=CH2, -CH2CH2CH2C02H, -OCOCH3, -OCOCH2CH3, OCOCH2CH2CH3, -CH2C02CH3, -CH2C02CH2CH3, -COCH2Ph, -COCH2Ph, -COCOCI, -OCO(CH2)6Me; with the provisio, when Ri is -CH2CH2NHMe, R2 is -CH=CMe2,, R3 is -H, R5 is CH 3i
R6 is -CH2CH2NHMe and R7 is -H;
with the provisio, when s --CH2CH2NMe2, R2 is -CH=C e2, R3 is -H, Rs -CH3,
R6 is -CH2CH2NMe2 and R7 is -H are excluded.
2. The compound as claimed in claim 1, wherein said compounds are useful as antimalarial compound.
3. A process for the preparation of Flinderole A-C and compounds of general formula I as claimed in claim 1 comprising the steps of:
a. reacting indole aldehyde (lc') with Ph3P=CHC02Et followed by reaction of the resultant ester with MeMgBr to obtain tertiary alcohol (Id');
b. mesylating tertiary alcohol (Id') as obtained in step (a) followed by elimination to obtain sulphonated diene (lb');
c. desulfonylating (lb') as obtained in step (b) using methanolic NaOH to obtain desulphonated diene (le');
le» = H
d. desulfonylating alcohol (Id') as obtained in step (a) with sodium amalgam to obtain alcohol (la'); and
e. reacting alcohol (la') as obtained in step (d) optionally with sulphonated diene (lb') as obtained in step (b) or desulphonated diene (le') as obtained in step (c) in presence of Lewis acid and a non- polar solvent at temperature in the range of 25 to 32°C to obtain sulphonated or desuphonated compound of general formula 1;
f. desulfonylating sulphonated compound of general formula 1 as obtained in step (e) using methanolic NaOH to obtain desulphonated Flinderole A-C and compounds of general formula I .
Flinderole A (R=H) Flinderole C General Formula I
Flinderole B (R=H)
4. The process as claimed in claim 1, wherein Lewis acid used in step (e) is selected from Cu(OTf)2 or BF3-OEt2.
5. The process for the preparation of compounds of general formula I as claimed in claim 1, optionally comprising dimerization of alcohol (la') and the said process comprising the steps of:
a. adding alcohol (la') with lewis acid with stirring foer period in the range of 50 to 70 minutes at temperature in the range of 25 to 32°C followed by adding water to obtain reaction mixture;
b. extracting the reaction mixture as obtained in step (a) with non-polar solvent, washing with brine, drying followed by evaporating the solvent;
c. purifying the residue on silica gel column using EtOAc-hexane (1:39) to obtain compound of general formula 1.
6. The process as claimed in claim 6, wherein Lewis acid used in step (a) is selected from Cu(OTf)2 or BF3 OEt2.
7. A pharmaceutical composition for the treatment of malaria comprising compounds of general formula I optionally along with pharmaceutically acceptable excipients.
8. The compounds of general formula 1 useful as anti-malarial compound and process for the preparation thereof substantially as herein described with references of examples and drawing accompanying the specification.
EP11817423.4A 2011-02-10 2011-12-28 Flinderole analogues and process for synthesis thereof Withdrawn EP2673276A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN336DE2011 2011-02-10
PCT/IN2011/000899 WO2012107934A1 (en) 2011-02-10 2011-12-28 Flinderole analogues and process for synthesis thereof

Publications (1)

Publication Number Publication Date
EP2673276A1 true EP2673276A1 (en) 2013-12-18

Family

ID=45581952

Family Applications (1)

Application Number Title Priority Date Filing Date
EP11817423.4A Withdrawn EP2673276A1 (en) 2011-02-10 2011-12-28 Flinderole analogues and process for synthesis thereof

Country Status (3)

Country Link
EP (1) EP2673276A1 (en)
CN (1) CN103476775A (en)
WO (1) WO2012107934A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102964352B (en) * 2012-11-23 2015-04-08 华中师范大学 Chiral 2,3-dihydropyrrole[1,2-a] indole derivatives with biological activity and asymmetric synthesizing method thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006046949A1 (en) * 2004-10-22 2006-05-04 Walter Reed Army Institute Of Research (Wrair) SYNTHESIS AND ANTIMALARIAL ACTIVITY OF PYRROLO[3,2-f]QUINAZOLINE-1,3- DIAMINE DERIVATIVES
JP2011510073A (en) * 2008-01-25 2011-03-31 アリーナ ファーマシューティカルズ， インコーポレイテッド Dihydro-1H-pyrrolo [1,2-a] indol-1-ylcarboxylic acid derivatives acting as S1P1 agonists
FR2932484B1 (en) * 2008-06-16 2010-06-18 Sanofi Aventis NOVEL PYRROLOINDOLE DERIVATIVES INHIBITORS OF HSP90, COMPOSITIONS CONTAINING SAME AND USE THEREOF

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2012107934A1 *

Also Published As

Publication number Publication date
CN103476775A (en) 2013-12-25
WO2012107934A1 (en) 2012-08-16

Similar Documents

Publication Publication Date Title
KR101519682B1 (en) Quaternary opioid carboxamides
KR101586112B1 (en) Carbazole compounds and therapeutic uses of the compounds
CS273314B2 (en) Method of polycyclic aromatic alkanol derivatives preparation
JP7212142B2 (en) HPK1 inhibitor and its preparation method and application
CN101094836A (en) Methods for preparing indazole compounds
KR102337149B1 (en) Novel derivatives of indole and pyrrole, method for the production thereof and pharmaceutical compositions containing same
EP2693876A1 (en) Substituted methylformyl reagents and method of using same to modify physicochemical and/or pharmacokinetic properties of compounds
CN111479817A (en) Novel spirobicyclic analogs
Moshkin et al. Synthesis of benzopyranopyrrolidines via 1, 3-dipolar cycloaddition of nonstabilized azomethine ylides with 3-substituted coumarins
TW200922937A (en) Process for the synthesis of E1 activating enzyme inhibitors
AU606621B2 (en) Azaindole and indolizine derivatives, processes for their production and their use as pharmaceuticals
JP5149193B2 (en) Novel pyrrolo [2,1-c] [1,4] benzodiazepine hybrids and methods for their preparation
SK7592000A3 (en) Tricyclic compound substituted by the heterocyclic group, pharmaceutical composition containing such compound and use thereof
JP7245918B2 (en) Sarsasapogenin structure-based derivative, pharmaceutical composition and use thereof
TWI412363B (en) 5-(3,4-dichloro-phenyl)-n-(2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide and salts thereof
AU2012229859C1 (en) Nitrogen-containing saturated heterocyclic compound
Yadav et al. Synthesis of β-carboline-fused 1, 4-oxazepines and their assessment as antiplasmodial agents
RU2162470C2 (en) 2,7-substituted derivatives of octahydropyrrolo[1,2-a]pyrazine, method of treatment, pharmaceutical composition, and intermediates
Barker et al. Synthesis of tricyclic analogues of methyllycaconitine using ring closing metathesis to append a B ring to an AE azabicyclic fragment
Callis et al. The role of polycyclic frameworks in modulating P2X7 receptor function
EP2673276A1 (en) Flinderole analogues and process for synthesis thereof
KR20050009293A (en) Compounds Useful in Preparing Camptothecin Derivatives
Naito et al. Synthesis and antitumor activity of novel pyrimidinyl pyrazole derivatives
JP5960130B2 (en) Preparation of tesetaxel and related compounds and corresponding synthetic intermediates
JPS62502684A (en) Synthesis of vinblastine and vincristine type compounds

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20130812

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20140912

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20150324