Stereocontrolled Total Synthesis of Bastimolide B Using Iterative Homologation of Boronic Esters

[Image: see text] Bastimolide B is a polyhydroxy macrolide isolated from marine cyanobacteria displaying antimalarial activity. It features a dense array of hydroxylated stereogenic centers with 1,5-relationships along a hydrocarbon chain. These 1,5-polyols represent a particularly challenging motif for synthesis, as the remote position of the stereocenters hampers stereocontrol. Herein, we present a strategy for 1,5-polyol stereocontrolled synthesis based on iterative boronic ester homologation with enantiopure magnesium carbenoids. By merging boronic ester homologation and transition-metal-catalyzed alkene hydroboration and diboration, the acyclic backbone of bastimolide B was rapidly assembled from readily available building blocks with full control over the remote stereocenters, enabling the total synthesis to be completed in 16 steps (LLS)

İndol , kinazolin ve benzodiazepin sistemleri için yeni sentetik yöntemlerin geliştirilmesi

TÜBİTAK MAG30.11.2010İndol, altılı bir halka ile pirol halkasından oluşan bisiklik yapıya sahip heterosiklik ve aromatik bileşiktir. İndol türevleri çok geniş bir yelpezade çeşitli biyolojik aktivite gösterirler. Kinazolin halkası, benzen halkası ve pirimidin halkasının kenetlenmesi sonucu oluşmuş bir bileşiktir. Tıbbi açıdan, çeşitli alanlarda, örneğin; sıtma ve kanser hastalıklarının tedavisinde yaygın bir şekilde kullanılmaktadır. Benzodiazepinler, benzen ve iki azot atomu içeren yedili bir halkanın kenetlenmesi sonucunda oluşmuş bir bileşiktir. Piyasada 15’in üzerinde benzodiazepin türevi çeşitli psikolojik ve organik rahatsızlıkların tedavisinde ilaç olarak kullanılmaktadır. Bu bileşikler için literatürde sayısız ve çok çeşitli sentez yöntemleri mevcuttur. Bu proje kapsamında, bu bileşiklerin sentezi için, benzen ve furan halkasına bağlı diasitlerden hareket ederek ilgili diizosiyanatlar sentezlendi. Asit grupları aromatik halkaya bir veya iki metilen grubu aracılığı ile de bağlanmış olabilirler. İzosiyanat gruplarından ikisi veya biri kontrollü bir şekilde üretan veya üreye çevrildi.Üre ve/veya üretan fonksiyonel grubun diğer izosiyanat grubuna intramoleküler katılması sağlanarak yapıları aşağıda verilen aromatik halkaya kenetlenmiş yeni heterosiklik bileşiklerin sentezi gerçekleştirildi. Diasitlerin yanı sıra, heterosiklik halkanın oluşturulması için yarıesterler devreye sokuldu. Serbest asit fonksiyonel grubu, önce üretan ve/veya üreye çevrildi. Bazik şartlarda halka kapanma reaksiyonu heterosiklik halkayı oluşturdu. Diaçil azid sentezini gerçekleştiremediğimiz homoftalik asitte ise benzokromenon tipi kondenzasyon ürünlerinin oluştuğu belirlendi. Böylece bu sistemlerin sentezi için de yeni bir yöntem geliştirilmiş oldu.Indole is an aromatic heterocyclic compound, which has a bicyclic structure consisting of six-membered ring and pyrole ring. The derivatives of indoles show a variety of biological activity. Quinazoline is a compound made up of two fused six-membered simple aromatic rings, a benzene ring and a pyrimidine ring. Medicinally, it has been used in various areas especially as an anti-malarial agent and in cancer treatment. Benzodiazepines have a bicyclic structure consisting of benzene ring and a seven-membered ring having two nitrogen atoms. More than 15 different types of benzodiazepine medications exist to treat a wide array of both psychological and physical maladies based on dosage and implications. For the synthesis of these class of compounds, varies synthetic procedures have been published in the literature. In this project, for the synthesis of these compounds benzene and furan having two carboxylic acid groups have been used as the starting material and diacids were transformed into the corresponding diisocyanates. The acid functionalities may be directly attached to the aromatic or heterocyclic ring or they may be separated by one or two methylene groups. Both or one of these isocyanate groups have been converted into the corresponding urethane and/or urea derivatives. Intramolecular cyclization, by the addition of the urethane or urea derivative to the second isocyanate function opened up a new entry for the synthesis of various heterocyclic compounds their structures are given below. Furthermore, halfester were used for the construction of a heteroring. Acid functionality was transferred into urethane or urea derivatives. Ring-closure under the basic conditions gave also the heterocyclic unit. It was not possible to convert the homophthalic acid into diacylazide, however, it underwent condensation reaction and formed benzochromenone derivatives. This opened up a new entry to the synthesis of this class of compounds

Benzen halkasına kondense olmuş heterohalkalı bileşiklerin sentezleri için yeni yöntemlerin geliştirilmesi: aminoftalazinonlar, kromenopiridinonlar ve benzopirazolokzazepinler.

The interest in the synthesis of heterocyclic compounds has increased day by day due to their biological activities. This study focuses on the synthesis of different benzene-fused heterocycles. In the first part, we synthesized novel class of compounds, 4-aminophthalazin-1(2H)-ones starting from methyl 2-(2-methoxy-2-oxoethyl)-benzoate. Methylene group in this starting material was oxidized to the corresponding ketoester. Reaction of ketoesters with hydrazine derivatives provided the hydrazone derivatives. An intramolecular cyclization in the presence of thionyl chloride formed fused pyridazinone skeleton. Hydrolysis of the remaining ester groups and transformation of the acid functionalities to the acyl azides followed by Curtius rearrangement gave the isocyanates. Reaction of the isocyanates with methanol and water produced urethane and aminopyridazinone derivatives, respectively. In the second part of this thesis, a concise and regioselective approach to the synthesis of chromenopyridine and chromenopyridinone derivatives was developed. The synthetic strategy relies on the O-propargylation of aromatic hydroxyaldehydes followed by the reaction with propargylamine. The intramolecular cycloaddition reaction between the alkyne and azadiene, which was formed as an intermediate, furnished the desired skeleton. Benzopyrazoloxazepine and benzopyrazoloxazocine skeletons were also formed via alkyne cyclization in the presence of gold catalyst.Ph.D. - Doctoral Progra

Intramolecular Heterocyclization of O-Propargylated Aromatic Hydroxyaldehydes as an Expedient Route to Substituted Chromenopyridines under Metal-Free Conditions

A concise and regioselective approach to the synthesis of chromenopyridine and chromenopyridinone derivatives was developed. The synthetic strategy relies on the O-propargylation of aromatic hydroxyaldehydes followed by reaction with propargylamine. The intramolecular cycloaddition reaction between the alkyne and azadiene, which is formed as an intermediate, furnished the desired skeletons

Concise design and synthesis of pyridine-fused heterocycles via 6 pi- Azaelectrocyclization process of iminoalkyne derivatives

WOS: 000497251300003A concise and regioselective approach to the synthesis of pyridine-fused heterocycles and benzoxazepine derivatives was developed. Propargyl imines derived from aromatic aldehydes and propargyl amine underwent 6 pi-electrocyclization reactions at high temperatures in high yields to form pyridine-fused heterocycles. Application of the same methodology to aromatic imines having a hydroxyl group in the ortho position resulted in the formation of (benz)oxazepine derivatives. The formation mechanism of the products was discussed. (C) 2019 Elsevier Ltd. All rights reserved.Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [TBAG-112 T360]; Turkish Academy of Sciences (TUBA)Turkish Academy of Sciences; Middle East Technical University (METU)Financial support from the Scientific and Technological Research Council of Turkey (TUBITAK, grant no. TBAG-112 T360), the Turkish Academy of Sciences (TUBA), and the Middle East Technical University (METU) is gratefully acknowledged

Regioselective Synthesis of Benzo[h][1,6]- naphthyridines and Chromenopyrazinones through Alkyne Cyclization

WOS: 000397849300015A regioselective approach to the synthesis of benzo[h][1,6]-naphthyridine and chromenopyrazinone derivatives was developed. The synthetic route to benzo[h][1,6]naphthyridines involves the N-propargylation of aromatic aminobenzaldehydes, followed by reaction with propargylamine in the presence of DBU (1,8-diazabicyclo[5.4.0] undec-7ene). For the synthesis of chromenopyrazine and chromeno-pyrazinone derivatives, the acetonitrile group was introduced to salicylaldehyde derivatives, and a DBU-promoted cyclization reaction between aldehydes and propargylamine gave the chromenopyrazines. The intramolecular heterocycloaddition reaction between the triple bond and the azadiene, which is formed as an intermediate, gave the desired structures.Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [TBAG-112 T360]; Turkish Academy of Sciences (TUBA)Turkish Academy of Sciences; Middle East Technical University (METU)Financial support from the Scientific and Technological Research Council of Turkey (TUBITAK) (grant no. TBAG-112 T360), the Turkish Academy of Sciences (TUBA), and the Middle East Technical University (METU) is gratefully acknowledged

Intramolecular Heterocyclization of <i>O</i>‑Propargylated Aromatic Hydroxyaldehydes as an Expedient Route to Substituted Chromenopyridines under Metal-Free Conditions

A concise and regioselective approach to the synthesis of chromenopyridine and chromenopyridinone derivatives was developed. The synthetic strategy relies on the <i>O</i>-propargylation of aromatic hydroxyaldehydes followed by reaction with propargylamine. The intramolecular cycloaddition reaction between the alkyne and azadiene, which is formed as an intermediate, furnished the desired skeletons

Synthesis of pyrrole-fused C,N-Cyclic Azomethine Imines and Pyrazolopyrrolopyrazines: Analysis of their aromaticity using nucleus-independent chemical shifts values

Menges, Nurettin/0000-0002-5990-6275WOS: 000369771800017PubMed: 26752224The AgOTf-catalyzed reaction of C-2 substituted pyrrole hydrazones having an N-propargyl group was studied. The selective 6-endo-dig mode of cyclization was observed, giving rise to the formation of pyrrole-fused C,N-cyclic azomethine imine derivatives. The reaction of one azomethine imine derivative with various dipolarophiles resulted in the formation of cycloadducts having a pyrazolopyrrolopyrazine skeleton. The aromaticity of C,N-cyclic azomethine imines as well as that of pyrazolopyrrolopyrazines was determined by calculating of nucleus-independent chemical shifts values.Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [TBAG-112 T360]; Yuzuncu Yil UniversityYuzuncu Yil University [2014-ECZ-B170]; Turkish Academy of Sciences (TUBA)Turkish Academy of Sciences; Middle East Technical University (METU)Financial support from the Scientific and Technological Research Council of Turkey (TUBITAK, Grant No. TBAG-112 T360), Yuzuncu Yil University (Grant No. 2014-ECZ-B170), the Turkish Academy of Sciences (TUBA), and the Middle East Technical University (METU) is gratefully acknowledged

Stereocontrolled Total Synthesis of Bastimolide B using Iterative Homologation of Boronic Esters

Bastimolide B is a polyhydroxy macrolide isolated from marine cyanobacteria displaying antimalarial activity. It features a dense array of hydroxylated stereogenic centers with 1,5-relationships along a hydrocarbon chain. These 1,5-polyols represent a particularly challenging motif for synthesis, as the remote position of the stereocenters hampers stereocontrol. Herein, we present a strategy for 1,5-polyol stereocontrolled synthesis based on iterative boronic ester homologation with enantiopure magnesium carbenoids. By merging boronic ester homologation and transition metal-catalyzed alkene hydroboration and diboration, the acyclic backbone of bastimolide B was rapidly assembled from readily available building blocks with full control over the remote stereocenters

Facile synthesis of novel 7-aminofuro- and 7-aminothieno[2,3-d]pyridazin-4(5H)-one and 4-aminophthalazin-1(2H)-ones

WOS: 000313386100050We hereby report the synthesis of a novel class of compounds, 7-aminofuro- and 7-aminothieno[2,3-d]pyridazin-4(5H)-one and 4-aminophthalazin-1(2H)-ones starting from methyl 2-(2-methoxy-2-oxoethyl)furan- and thiophene-3-carboxylate and methyl 2-(2-methoxy-2-oxoethyl)benzoate. The ester functionalities connected directly to the aromatic ring were regiospecifically converted to the acid, whereas methylene groups were oxidized to the corresponding ketoesters. Reaction of the ketoesters with hydrazine provided the hydrazone derivatives. An intramolecular cyclization in the presence of thionyl chloride formed a fused pyridazinone skeleton. Hydrolysis of the remaining ester groups and transformation of the acid functionalities to the acyl azides followed by Curtius rearrangement gave the isocyanates. Reaction of the isocyanates with methanol and water produced urethane and amino-pyridazinone derivatives, respectively. (C) 2012 Elsevier Ltd. All rights reserved.Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [110-R001]; Department of Chemistry at Middle East Technical University; Turkish Academy of Sciences (TUBA)Turkish Academy of SciencesThe authors are indebted to the Scientific and Technological Research Council of Turkey (TUBITAK, Grant No: 110-R001), the Department of Chemistry at Middle East Technical University and the Turkish Academy of Sciences (TUBA) for their financial support of this work