Efficient Total Synthesis of the Pharmacophore of the Anticancer Antibiotic CC‐1065 by Zirconocene‐ and Palladium‐Initiated Cyclizations

Tietze, Lutz F.; Buhr, Wilm

doi:10.1002/anie.199513661

Cited by 52 publications

(20 citation statements)

References 22 publications

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“…Therefore the iodomethyl group in 11 was first transformed into an acetoxymethyl group. In earlier work on the synthesis of CC-1065 analogues [8] we had shown that, by means of 1,8-diazabicyclo [5.4.0]undec-7-ene, the iodomethyl group can easily be transformed into an exocyclic double bond, which on hydroboration becomes a hydroxymethyl group. Since the yields for this twostep transformation are not very high and a hydroboration is not possible due to the second double bond in 11, we tried to replace the iodo atom by a simple substitution with sodium acetate, cesium acetate, tetrabutylammonium acetate and several other nucleophiles.…”

Section: Resultsmentioning

confidence: 99%

“…Benzenesulfonyl chloride (14.0 g, 79.4 mmol) was added to a solution of 18 (8.61 g, 39.7 mmol) in dry degassed pyridine (300 mL) and the mixture stirred for 3 h at 80 8C. After concentration to a volume of about 100 mL, ice-cold aqueous hydrochloric acid (500 mL, 5 % HCl) was added, the resulting black oil separated and C-6), 127.6 (C-2'', C-6''), 127.7 (C-2', C-6'), 128.1 (C-1), 128.5 (C-3'', C-5''), 128.9 (C-3', C-5'), 132.2, 132.4 (2 Â CHCH 2 ), 132.7 (C-4''), 133.1 (C-4'), 137.5 (C-1''), 140.7 (C-1', C-4), 158.1 (C-2); MS (70 eV): m/z (%) 437 (12) 5.83 ± 5.97 (mc,1 H,7.14 (s,1 H,7.48 ± 7.69 (m,6 H,7.72 ± 7.79 (m,2 H,Ph ± H),7.82 (d,J 8.0 Hz,2 H,Ph ± H); 13 C NMR (50 MHz, CDCl 3 ): d 7.643 (CH 2 ± I), 47.54 (C-3), 53.08 (N ± CH 2 ), 55.34 (O-CH 3 ), 55.37 (C-2), 98.63 (C-7), 105.6 (C-4), 119.1 (CHCH 2 ), 125.6 (C-5), 127.2 (C-2'', C-6''), 132.8 (CHCH 2 ),, 140.9 (C-1'), 142.1 (C-1''), 157.9 (C-6); MS (70 eV (C-7), 105.4 (C-4), 118.9 (CHCH 2 ), 125.0 (C-5), 127.3 (C-2'', C-6''), 127.8 (C-2', C-6'), 127.9 (C-3a), 128.5 (C-3'', C-5''), 129.3 (C-3', C-5'), 132.3 (C-4''), 133.0 (CHCH 2 ), 133.8 (C-4'), 136.8 (C-7a), 141.0 (C-1'), 142.8 (C-1''), 157.6 (C-6); MS (70 eV): m/z (%) 640 (8) -5), 127.0 (C-3a), 127.2 (C-2'', C-6''), 127.9 (C-2', C-6'), 128.5 (C-3'', C-5''), 129.4 (C-3', C-5'), 132.3 (C-4''), 132.7 (CHCH 2 ), 134.0 (C-4'), 136.7 (C-7a), 141.0 (C-1'), 142.8 (C-1''), 157.9 (C-6), 170.5 (CO); MS (70 eV): m/z (%) 682 (7) (1-RS)-6-Benzenesulfonyl-3-benzenesulfonyl-1-acetoxymethyl-8-methylidene-1,2,7,8-tetrahydro-6H-pyrrolo [3,2-e] 6 (C-1a), 127.3, 127.4 (C-2'', C-6'', C-2', C-6'), 128.5, 129.3 (C-3'', C-5'', C-3', C-5'), 130.6 (C-5a), 131.3 (C-8), 132.7, 133.7 (C-4'', C-4'), 136.5 (C-3a), 139.0 (C-1'), 140.8 (C-8a), 141.4 (C-1''), 151.7 (C-5) …”

Section: Methodsmentioning

confidence: 99%

“…[7] Here we describe an efficient and short synthesis of the seco-CPI derivative 4, which is used for the preparation of prodrugs of CC-1065, [4] and the N-(benzenesulfonyl)-CPI (3) from commercially available 2-methoxy-4-nitroaniline (8) based on two successive organotransition metal complexcontrolled cyclizations. [8] This allows the consecutive formation of the pyrroline and the pyrrole ring of the CPI and the seco-CPI systems in 4 steps with 51 % yield based on 6.…”

Section: Introductionmentioning

confidence: 99%

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Efficient Synthesis of the Pharmacophore of the Highly Potent Antitumor Antibiotic CC-1065

et al. 1998

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The pharmacophore CPI (3) of the potent antitumor antibiotic CC-1065 (1) was synthesized in a very short reaction sequence of 11 steps with an overall yield of 23 %. The key steps are two consecutive cyclizations mediated by organotransition metal complexes, which form first the pyrroline and then the pyrrole ring in 3. Thus, halogen metal exchange of the N,N'-bisallylbromobenzene with tBuLi and subsequent reaction with Cp 2 ZrMeCl gave 11 as a single product in 60 % yield after quenching with two equivalents of iodine. Transformation of the iodomethyl group in 11 into an acetoxymethyl group, followed by Heck reaction, isomerization, and reductive cleavage, provided the pyrroloindoline system 4, which was converted into 3.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficient Synthesis of the Pharmacophore of the Highly Potent Antitumor Antibiotic CC-1065

et al. 1998

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“…Soluble palladiums, generally palladium complexes such as [Pd(OAc) 2 ] and [Pd(PPh 3 ) 2 Cl 2 ], are the most efficient catalysts for the Heck reaction because of the stabilisation effect between the ligands and metal nanoparticles [4,5]. However, the main drawback of the homogenous catalysts is the difficulty of recycling and reusing the expensive metals and ligands.…”

Section: Introductionmentioning

confidence: 99%

“…Heck reaction of aryl halide with olefins has recently been one of the most intensively studied transition-metal catalysed carbon-carbon bond-forming reactions and has been applied to many areas, including natural products [1,2] and fine chemicals [3]. Soluble palladiums, generally palladium complexes such as [Pd(OAc) 2 ] and [Pd(PPh 3 ) 2 Cl 2 ], are the most efficient catalysts for the Heck reaction because of the stabilisation effect between the ligands and metal nanoparticles [4,5].…”

Section: Introductionmentioning

confidence: 99%

Self-assembled spherical palladium/HMS nanocomposites and their catalytic application

Wang

Jin

Zhu

et al. 2012

Journal of Experimental Nanoscience

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A novel palladium catalyst immobilised the mesoporous molecular sieve Hexagonal Mesoporous Silica (HMS) was prepared via a self-assembly process. The catalytic activity and recycle ability of the spherical palladium/HMS nanocomposites were examined for the Heck reaction. Palladium nanoparticles incorporated into HMS are characterised by X-ray powder diffraction (XRD) and transmission electron microscopy (TEM). The morphology of HMS is predominated with spheres, and Pd nanoparticles are randomly distributed throughout the entire silica framework without severe agglomeration. The heterogeneous catalyst is proved to be an active and reusable catalyst in the coupling of ethyl acrylate with aryl halides because of combination, the advantages of stabilising agent and mesoporous silica support. Keywords: Pd nanoparticles; HMS; composites; Heck reactionSubject Classification Codes: TQ032.41; TQ138.2þ3; TQ426.81 IntroductionHeck reaction of aryl halide with olefins has recently been one of the most intensively studied transition-metal catalysed carbon-carbon bond-forming reactions and has been applied to many areas, including natural products [1,2] and fine chemicals [3]. Soluble palladiums, generally palladium complexes such as [Pd(OAc) 2 ] and [Pd(PPh 3 ) 2 Cl 2 ], are the most efficient catalysts for the Heck reaction because of the stabilisation effect between the ligands and metal nanoparticles [4,5]. However, the main drawback of the homogenous catalysts is the difficulty of recycling and reusing the expensive metals and ligands. Thus, it is not surprising that very few homogeneous catalytic systems have been commercialised. Immobilisation of transition metals will not only facilitate separation and reuse of the expensive and toxic catalysts but can also reduce contamination of the heavy metal to the environment.In the past few decades, a variety of heterogeneous palladium catalysts have been developed through the immobilisation of transition metals on various solid supports such as g-alumina, carbon, zirconia, zeolite, polymer, mesoporous silica and so on by using impregnation or ionexchange methods [6][7][8][9][10][11][12][13]. However, these approaches have not provided a simple way to form robust and reusable catalysts for heterogeneous catalysis. Thus, if approach can combine the advantage of stabilising agents with insoluble supports especially mesoporous silica, it would improve the lifetime and the reusability of catalysts.

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The IntramolecularHeck Reaction

Link

2002

Organic Reactions

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Since the discovery of the Heck reaction, the process has gained widespread acceptance within the synthetic community both as a practical tool and a research area. The intramolecular Heck reaction has enjoyed a similar renaissance, particularly within the last decade. The reaction has emerged as a reliable method for efficiently constructing small, medium, and large rings. Since the reaction occurs under mild and nearly neutral conditions, the functional group tolerance is high. Tandem reactions, which are initiated by intramolecular Heck reactions, have been developed allowing for multiple ring formations, cyclization and intermolecular coupling, and a multitude of other ever‐expanding possibilities. Furthermore, congested tertiary and quaternary centers can be efficiently constructed diastereoselectively or enantioselectively during the ring‐forming reaction. The numerous advances in reaction technology and capability have led to frequent application of the reaction in complex molecule synthesis and combinatorial library preparation. For the purposes of this chapter, the intramolecular Heck reaction is defined as the palladium[0]‐catalyzed intramolecular coupling of an aryl or alkenyl halide or perfluorosulfonate with an alkene, alkyne, allene, or arene. The mechanism of the Heck reaction is an active area of research. Precise mechanistic details vary substantially depending upon catalyst, substrate, additives, and reaction conditions. The introduction given here is designed to give the chemist a basic understanding of the currently accepted mechanisms to aid in the rational selection and optimization of reaction conditions. Application to total synthesis of natural products and intramolecular Heck reactions on polymer supports are discussed.

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Efficient Total Synthesis of the Pharmacophore of the Anticancer Antibiotic CC‐1065 by Zirconocene‐ and Palladium‐Initiated Cyclizations

Abstract: Three steps suffice for constructing the pyrroloindolino framework of the pharmacophoric moiety 2 of the highly potent anticancer agent CC‐1065. The easily accessible bis(allylamino)bromobenzene 1 was transformed by successive cyclizations mediated by [Cp2Zr(Me)Cl] and by a Pd° complex.

Cited by 52 publications

References 22 publications

Efficient Synthesis of the Pharmacophore of the Highly Potent Antitumor Antibiotic CC-1065

Efficient Synthesis of the Pharmacophore of the Highly Potent Antitumor Antibiotic CC-1065

Self-assembled spherical palladium/HMS nanocomposites and their catalytic application

The IntramolecularHeck Reaction

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