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WO2003106438A1 - Synthese de noyau de diazonamide "a" - Google Patents

Synthese de noyau de diazonamide "a" Download PDF

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Publication number
WO2003106438A1
WO2003106438A1 PCT/US2002/019662 US0219662W WO03106438A1 WO 2003106438 A1 WO2003106438 A1 WO 2003106438A1 US 0219662 W US0219662 W US 0219662W WO 03106438 A1 WO03106438 A1 WO 03106438A1
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WO
WIPO (PCT)
Prior art keywords
diazonamide
chem
represented
equiv
analog
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Ceased
Application number
PCT/US2002/019662
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English (en)
Inventor
K. C. Nicolaou
Scott. A Snyder
Xianhai Huang
Paraselli Bheema Rao
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Scripps Research Institute
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Scripps Research Institute
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Filing date
Publication date
Application filed by Scripps Research Institute filed Critical Scripps Research Institute
Priority to PCT/US2002/019662 priority Critical patent/WO2003106438A1/fr
Priority to AU2002316317A priority patent/AU2002316317A1/en
Publication of WO2003106438A1 publication Critical patent/WO2003106438A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the invention relates to diazonamide "A” and to macrocyclization cascade reactions employable for synthesizing same. More particularly, the invention relates to analogs of the aromatic core of diazonamide "A” and to samarium (II) based hetero pinacol macrocyclization cascade reactions.
  • Figure 1 a secondary metabolite isolated from the colonial ascidian Diazona chinensis, whose unprecedented molecular architecture includes a cyclic polypeptide backbone, a strained halogenated heteroaromatic core trapped as a single atropisomer, and a lone quaternary center at the epicenter of the two major macrocyclic subunits (N. Lindquist, et al. J. Am. Chem. Soc. 1991 , 113, 2303-2304).
  • One aspect of the invention is directed to an analog of diazonamide "A" represented by the following structure:
  • R 1 and R 2 are each radicals independently selected from the group consisting of hydrogen and halide;
  • R 3 is a radical selected from the group consisting of hydrogen, methyl, and MOM;
  • R 4 is a radical selected from the group consisting of hydrogen and -OR 8 , wherein R 8 is an alkyl group having from 1 to 6 carbons;
  • R 5 is a radical selected from the group consisting of hydrogen and hydroxyl;
  • R 6 and R 7 are each radicals independently selected from the group consisting of hydrogen and alkyls having from 1 to 6 carbons or together form a bridge represented by the following structure:
  • Another aspect of the invention is directed to a process for performing a hetero pinacol macrocylization reaction.
  • a bifunctional reactant having an oxime ether and an alkyl, vinyl, or ketyl radical is provided.
  • the oxime ether is coupled with the alkyl, vinyl, or ketyl radical by a samarium (II) based cascade reaction for cyclizing the bifunctional reactant and forming a ring having a size greater than seven.
  • II samarium
  • Figure 1 illustrates the structure of diazonamide "A” and a retrosynthetic analysis of model system 2.
  • Figure 2 illustrates a scheme for the synthesis of an analog of the aromatic core of diazonamide "A,” i.e., compound 8.
  • Figure 3 illustrates a scheme for the synthesis of advanced intermediates employable for constructing the aromatic core of diazonamide "A" and analogs thereof.
  • Figure 4 illustrates a macrocyclization scheme employing a pinacol coupling cascade sequence for synthesizing the aromatic core of diazonamide "A" and analogs thereof.
  • Figure 5 illustrates a scheme for the completing of the synthesis of the aromatic core of diazonamide "A” and analogs thereof, after the macrocylization procedure of Figure 4.
  • the A-ring oxazole could also be fashioned from 23 with pTsOH in refluxing benzene, albeit in lower yield with prolonged reaction times, whereas the use of the Burgess reagent in refluxing THF (Brain, C. T.; Paul, J. M. Synlett 1999, 1642-1644) afforded 24 exclusively in comparable yield to that obtained with POCI 3 .
  • Figure 1 shows the structure of diazonamide A (1) and retrosynthetic analysis of model system used in this study.
  • Figure 2 illustrates the initial model studies which led to the complete heteroaromatic skeleton (8) of diazonamide A: a) KMn0 4 (6.0 equiv), Ac 2 0, 0 °C, 2 h, 35 %; b) MeONH 2 -HCI (20 equiv), EtOH, 25 °C, 12 h, 95 %; c) Pd/C (10 %, 2.0 equiv), H 2 (3.0 atm), TFA/MeOH (1 :20), 25 °C, 12 h; then AcCI (3.0 equiv), Et 3 N (3.0 equiv), CH 2 CI 2 , 25 °C, 30 min, 80 %; d) p-TsOH, benzene, 80 °C, 20 h, 50 %.
  • TFA trifluoroacetic acid
  • p-TsOH p-toluenesu!fonic acid.
  • Figure 3 shows the synthesis of key intermediate 18: a) LiBH 4 (8.0 equiv), THF, 25 °C, 4 h, 95 %; b) CDI (2.0 equiv), THF, reflux, 2 h, 95 %; c) BPD (1.2 equiv), [Pd(dppf)CI 2 ]»CH 2 CI 2 (0.2 equiv), KOAc (3.0 equiv), DMSO, 90 °C, 6 h, 70 %; d) 12 (1.0 equiv), 13 (1.0 equiv), H 2 S0 4 (70 % aq.), 45 min, 42% (95% based on recovered 13); e) Et 3 N (3.0 equiv), TMSOTf (1.2 equiv), CH 2 CI 2 , 0 °C, 1 h; then HCHO (37 % in H 2 0, 5.0 equiv), [Yb(OTf) 3 ] (0.1 equiv), T
  • CDI 1 ,1'-carbonyldiimidazole
  • BPD bis(pinacolato)diboron
  • dppf (diphenylphosphanyl)ferrocene
  • LiHMDS lithium salt of 1 ,1 , 1 ,3,3, 3-hexa- methyldisilazane
  • TBS tert-butyldimethylsilyl
  • TBDPS tert-butyldiphenylsilyl
  • MOM methoxymethyl
  • TBAF tetrabutylammonium fluoride.
  • Figure 4 shows the novel pinacol coupling cascade sequence to efficiently prepare ketoamide 23. a) Sml 2 (0.1 M in THF, 9.0 equiv), HMPA (36 equiv), THF, 25 °C, 1 h; then saturated aq.
  • HMPA hexamethyIphosphoramide
  • EDC 3-(3-dimethylaminopropyl)-1- ethylcarbodiimide
  • HOBt 1-hydroxy-1H- benzotriazole.
  • Figure 5 shows the completion of the synthesis of the fully elaborated heterocyclic skeleton 2 of diazonamide A (1).
  • BBr 3 1.0 M in CH 2 CI 2 , 2.0 equiv), CH 2 CI 2 , -78 °C, 20 min; then aq. NaOH (15 %, excess), THF, 25 °C, 10 min, 61 %.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Selon l'invention, l'utilisation d'une nouvelle réaction en cascade de macrocyclisation à base de samarium (II) permet de construire l'ensemble du noyau aromatique ABCDEF hautement sollicité de diazonamide "A" et plusieurs nouveaux analogues de ce noyau.
PCT/US2002/019662 2002-06-18 2002-06-18 Synthese de noyau de diazonamide "a" Ceased WO2003106438A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/US2002/019662 WO2003106438A1 (fr) 2002-06-18 2002-06-18 Synthese de noyau de diazonamide "a"
AU2002316317A AU2002316317A1 (en) 2002-06-18 2002-06-18 Synthesis of diazonamide "a" core

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2002/019662 WO2003106438A1 (fr) 2002-06-18 2002-06-18 Synthese de noyau de diazonamide "a"

Publications (1)

Publication Number Publication Date
WO2003106438A1 true WO2003106438A1 (fr) 2003-12-24

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PCT/US2002/019662 Ceased WO2003106438A1 (fr) 2002-06-18 2002-06-18 Synthese de noyau de diazonamide "a"

Country Status (2)

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AU (1) AU2002316317A1 (fr)
WO (1) WO2003106438A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7851620B2 (en) 2007-06-07 2010-12-14 Board Of Regents, The University Of Texas System Methods for preparing diazonamides
US7960420B2 (en) 2007-12-21 2011-06-14 Joyant Pharmaceuticals, Inc Diazonamide analogs with improved solubility
US8090462B2 (en) 2007-12-19 2012-01-03 Mobideo Technologies Ltd Maintenance assistance and control system method and apparatus
JP2013519678A (ja) * 2010-02-11 2013-05-30 ブリストル−マイヤーズ スクイブ カンパニー 第ｘｉａ因子阻害剤としてのマクロ環
CN103664742A (zh) * 2012-09-12 2014-03-26 上海药明康德新药开发有限公司 反式-N-Boc-3-氨基-4-羟基哌啶的制备方法
US9453018B2 (en) 2014-10-01 2016-09-27 Bristol-Myers Squibb Company Pyrimidinones as factor XIa inhibitors
US9777001B2 (en) 2014-01-31 2017-10-03 Bristol-Myers Squibb Company Macrocycles with aromatic P2′ groups as factor xia inhibitors
US10081623B2 (en) 2014-09-04 2018-09-25 Bristol-Myers Squibb Company Diamide macrocycles that are FXIa inhibitors
CN109503533A (zh) * 2019-01-04 2019-03-22 湖南大学 一种苯并呋喃酮类化合物及其高效催化合成方法
US10273236B2 (en) 2014-01-31 2019-04-30 Bristol-Myers Squibb Macrocyclic factor XIa inhibitors bearing heterocyclic groups

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHAN et al: "Synthesis of the 4-arylindole portion of the antitumor agent diazonamide and related studies" Tetrahedron letters, 2000, Vol 41, 835-838 *
KREISBERG et al: "Vilsmeier methodology for the synthesis of 3-(2-N-phthaloylacyl)indole derivatives, and its application to the synthesis of the GCDEF rings of diazonamide" Tetrahedron letters, 2001, Vol 42, 627-629 *
MAGNUS et al: "Photo-Fries rearrangement for the synthesis of the diazonamide macrocycle" Tetrahedron letters, 2001, Vol 42, 7193-7196 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7851620B2 (en) 2007-06-07 2010-12-14 Board Of Regents, The University Of Texas System Methods for preparing diazonamides
US8090462B2 (en) 2007-12-19 2012-01-03 Mobideo Technologies Ltd Maintenance assistance and control system method and apparatus
US7960420B2 (en) 2007-12-21 2011-06-14 Joyant Pharmaceuticals, Inc Diazonamide analogs with improved solubility
US10487086B2 (en) 2010-02-11 2019-11-26 Bristol-Myers Squibb Company Macrocycles as factor XIa inhibitors
JP2013519678A (ja) * 2010-02-11 2013-05-30 ブリストル−マイヤーズ スクイブ カンパニー 第ｘｉａ因子阻害剤としてのマクロ環
US12404274B2 (en) 2010-02-11 2025-09-02 Bristol-Myers Squibb Company Macrocycles as factor xia inhibitors
US11136327B2 (en) 2010-02-11 2021-10-05 Bristol-Myers Squibb Company Macrocycles as factor XIA inhibitors
US9802939B2 (en) 2010-02-11 2017-10-31 Bristol-Myers Squibb Company Macrocycles as factor XIa inhibitors
CN103664742A (zh) * 2012-09-12 2014-03-26 上海药明康德新药开发有限公司 反式-N-Boc-3-氨基-4-羟基哌啶的制备方法
US10273236B2 (en) 2014-01-31 2019-04-30 Bristol-Myers Squibb Macrocyclic factor XIa inhibitors bearing heterocyclic groups
US9777001B2 (en) 2014-01-31 2017-10-03 Bristol-Myers Squibb Company Macrocycles with aromatic P2′ groups as factor xia inhibitors
US10081623B2 (en) 2014-09-04 2018-09-25 Bristol-Myers Squibb Company Diamide macrocycles that are FXIa inhibitors
US10336754B2 (en) 2014-10-01 2019-07-02 Bristol-Myers Squibb Company Pyrimidinones as factor XIa inhibitors
US11053247B2 (en) 2014-10-01 2021-07-06 Bristol-Myers Squibb Company Pyrimidinones as factor XIA inhibitors
US9453018B2 (en) 2014-10-01 2016-09-27 Bristol-Myers Squibb Company Pyrimidinones as factor XIa inhibitors
US12428421B2 (en) 2014-10-01 2025-09-30 Bristol-Myers Squibb Company Pyrimidinones as factor XIA inhibitors
CN109503533A (zh) * 2019-01-04 2019-03-22 湖南大学 一种苯并呋喃酮类化合物及其高效催化合成方法

Also Published As

Publication number Publication date
AU2002316317A1 (en) 2003-12-31

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