Miller Group at the University of Notre Dame

Synthesis and Elaboration of Acylnitroso-Derived Hetero-Diels-Alder Cycloadducts

Acylnitroso-derived hetero-Diels-Alder adducts 1 (Scheme 1), generated from the reaction of transient acylnitroso species 3 with cyclopentadiene, are synthetically important precursors to a variety of bioactive molecules. As a versatile synthon, cycloadduct 1 may be elaborated in stereo- and regioselective fashion via metal-mediated ring openings in the presence of nucleophiles and/or electrophiles to provide small molecule carbocyclic scaffolds 4a and 4b. Further manipulation of these highly functionalized carbocyclic derivatives provides access to targeted biomolecules and analogs, including carbocyclic nucleosides, 5-lipoxygenase inhibitors, and novel benzodiazepines.

In order to access diversified cyclopentene scaffolds, several metal-mediated ring opening strategies have been established with key cycloadduct intermediate 1 to introduce different functionalities as well as defined stereo- and regiochemistries (Scheme 2). Reduction of the N-O bond in cycloadduct 1 with Mo(CO)₆ and NaBH₄ affords syn-1,4 aminocyclopentenols 5a. Exposing bicycle 1 to Grignard reagents, as well as Lewis acids, results in the formation of anti-1,2 products 5b and anti-1,4 products 5c, respectively. Attaining syn-1,4 hydroxamates 5d and 5e may be achieved through Pd(0)-promoted ring openings or Pd(0)-InI mediated ring openings, respectively.

Although cycloadducts such as 1 have been shown to be appropriate substrates for metal mediated reactions, the resulting formation of hydroxamic acids may not always be desirable. To synthesize cyclopentene derivatives without the hydroxamic acid functionality, reduction of the N-O bond in cycloadduct 1 with Mo(CO)₆ followed by kinetic enzymatic resolution affords enantiopure allyl acetate 6. This allyl acetate has been used as a key intermediate in a number of syntheses in the Miller group. One example is the synthesis of PDE inhibitor 8 through an intramolcular palladium(0) mediated cyclization under basic conditions. Another involves the palladium(0) mediated substitution of nitroacetate to form key intermediate 9, which was elaborated to the carbocyclic uracil polyoxin C 10 (Scheme 3).

Jiang, M. X.-W.; Warshakoon, N. C.; Miller, M. J. Chemoenzymatic Asymmetric Total Synthesis of Phosphodiesterase Inhibitors: Preparation of a Polycyclic Pyrazolo[3,4-d]pyrimidine from an Acylnitroso Diels-Alder Cycloadduct-Derived Aminocyclopentenol. J. Org. Chem. 2005, 70, 2824-2827.

Li, F.; Brogan, J. B.; Gage, J. L.; Zhang, D.; Miller, M. J. Chemoenzymatic Synthesis and Synthetic Application of Enantiopure Aminocyclopentenols: Total Synthesis of Carbocyclic (+)-Uracil Polyoxin C and Its –Epimer. J. Org. Chem. 2004, 69, 4538-4540

Mulvihill, M. J.; Gage, J. L.; Miller, M. J. Enzymatic Resolution of Aminocyclopentenols as Precursors to D- and L-Carbocyclic Nucleosides. Journal of Organic Chemistry 1998, 63, 3357-3363.

Mulvihill, M. J.; Surman, M. D.; Miller, M. J. Regio- and Stereoselective Fe(III)- and Pd(0)-Mediated Ring Openings of 3-Aza-2-oxabicyclo[2.2.1]hept-5-ene Systems. Journal of Organic Chemistry 1998, 63, 4874-4875.

Surman, M. D.; Miller, M. J. Regio- and Stereochemically Controlled Formation of Hydroxamic Acid Containing anti- or syn-1,4-Cycloalkenols from Acylnitroso-Derived Diels-Alder Adducts. Journal of Organic Chemistry 2001, 66, 2466-2469.

Lee, W.; Kim, K.H.; Surman, M. D.; Miller, M. J.; “Stereo- and Regioselectivities of Pd(0)/InI-Mediated Allylic Additions to Aldehydes and Ketones. In Situ Generation of Allylindium (III) Intermediates from N-Acylnitroso Diels-Alder Cycloadducts and 1-Amino-4-acetoxycyclopentenes. Journal of Organic Chemistry 2003, 68, 139-149.

Mulvihill, M. J.; Miller, M. J. Syntheses of Novel Hydroxylamine Carbonucleosides. Tetrahedron 1998, 54, 6605-6626.

Zhang, D. Y.; Miller, M. J. Total Synthesis of (+/-) Carbocyclic Polyoxin C and its a-Epimer. Journal of Organic Chemistry 1998, 63, 755-759.

Surman, M. D.; Mulvihill, M. J.; Miller, M. J. Regio- and Stereoselective Ring Openings of 3-Aza-2-oxabicyclo[2.2.1]hept-5-ene Systems with Copper Catalyst-Modified Grignard Reagents: Application to the Synthesis of an Inhibitor of 5-Lipoxygenase. Journal of Organic Chemistry 2002, 67, 4115-4121.

Surman, M. D.; Mulvihill, M. J.; Miller, M. J. Novel 1,4-Benzodiazepines from Acylnitroso-Derived Hetero-Diels-Alder Cycloadducts. Organic Letters 2002, 4, 139-141.

	Exploitation of Bacterial Iron Acquisition for Antibiotic Delivery The increasing occurrence of antibiotic resistance in community spread infections is now recognized as one of modern medicine’s most pressing health problems. Bacterial iron acquisition processes have proven to be promising targets for the development of antibiotic therapies that limit the development of resistance. Our group is actively involved in the synthesis and biological evaluation of siderophores and siderophore-drug conjugates for use in “Trojan Horse” drug delivery. Our group is particularly interested in understanding the role drug release plays in this delivery system. This project offers a unique opportunity for cross-disciplinary research that combines synthetic organic chemistry, microbiology, and molecular imaging.



	Synthesis and Elaboration of Acylnitroso-Derived Hetero-Diels-Alder Cycloadducts Acylnitroso-derived hetero-Diels-Alder adducts 1 (Scheme 1), generated from the reaction of transient acylnitroso species 3 with cyclopentadiene, are synthetically important precursors to a variety of bioactive molecules. As a versatile synthon, cycloadduct 1 may be elaborated in stereo- and regioselective fashion via metal-mediated ring openings in the presence of nucleophiles and/or electrophiles to provide small molecule carbocyclic scaffolds 4a and 4b. Further manipulation of these highly functionalized carbocyclic derivatives provides access to targeted biomolecules and analogs, including carbocyclic nucleosides, 5-lipoxygenase inhibitors, and novel benzodiazepines. Scheme 1. In order to access diversified cyclopentene scaffolds, several metal-mediated ring opening strategies have been established with key cycloadduct intermediate 1 to introduce different functionalities as well as defined stereo- and regiochemistries (Scheme 2). Reduction of the N-O bond in cycloadduct 1 with Mo(CO)₆ and NaBH₄ affords syn-1,4 aminocyclopentenols 5a. Exposing bicycle 1 to Grignard reagents, as well as Lewis acids, results in the formation of anti-1,2 products 5b and anti-1,4 products 5c, respectively. Attaining syn-1,4 hydroxamates 5d and 5e may be achieved through Pd(0)-promoted ring openings or Pd(0)-InI mediated ring openings, respectively. Scheme 2. Although cycloadducts such as 1 have been shown to be appropriate substrates for metal mediated reactions, the resulting formation of hydroxamic acids may not always be desirable. To synthesize cyclopentene derivatives without the hydroxamic acid functionality, reduction of the N-O bond in cycloadduct 1 with Mo(CO)₆ followed by kinetic enzymatic resolution affords enantiopure allyl acetate 6. This allyl acetate has been used as a key intermediate in a number of syntheses in the Miller group. One example is the synthesis of PDE inhibitor 8 through an intramolcular palladium(0) mediated cyclization under basic conditions. Another involves the palladium(0) mediated substitution of nitroacetate to form key intermediate 9, which was elaborated to the carbocyclic uracil polyoxin C 10 (Scheme 3). Scheme 3. Summary of Syntheses Utilizing Nitroso Cycloadducts by the Miller Group: Jiang, M. X.-W.; Warshakoon, N. C.; Miller, M. J. Chemoenzymatic Asymmetric Total Synthesis of Phosphodiesterase Inhibitors: Preparation of a Polycyclic Pyrazolo[3,4-d]pyrimidine from an Acylnitroso Diels-Alder Cycloadduct-Derived Aminocyclopentenol. J. Org. Chem. 2005, 70, 2824-2827. Li, F.; Brogan, J. B.; Gage, J. L.; Zhang, D.; Miller, M. J. Chemoenzymatic Synthesis and Synthetic Application of Enantiopure Aminocyclopentenols: Total Synthesis of Carbocyclic (+)-Uracil Polyoxin C and Its –Epimer. J. Org. Chem. 2004, 69, 4538-4540 Mulvihill, M. J.; Gage, J. L.; Miller, M. J. Enzymatic Resolution of Aminocyclopentenols as Precursors to D- and L-Carbocyclic Nucleosides. Journal of Organic Chemistry 1998, 63, 3357-3363. Mulvihill, M. J.; Surman, M. D.; Miller, M. J. Regio- and Stereoselective Fe(III)- and Pd(0)-Mediated Ring Openings of 3-Aza-2-oxabicyclo[2.2.1]hept-5-ene Systems. Journal of Organic Chemistry 1998, 63, 4874-4875. Surman, M. D.; Miller, M. J. Regio- and Stereochemically Controlled Formation of Hydroxamic Acid Containing anti- or syn-1,4-Cycloalkenols from Acylnitroso-Derived Diels-Alder Adducts. Journal of Organic Chemistry 2001, 66, 2466-2469. Lee, W.; Kim, K.H.; Surman, M. D.; Miller, M. J.; “Stereo- and Regioselectivities of Pd(0)/InI-Mediated Allylic Additions to Aldehydes and Ketones. In Situ Generation of Allylindium (III) Intermediates from N-Acylnitroso Diels-Alder Cycloadducts and 1-Amino-4-acetoxycyclopentenes. Journal of Organic Chemistry 2003, 68, 139-149. Mulvihill, M. J.; Miller, M. J. Syntheses of Novel Hydroxylamine Carbonucleosides. Tetrahedron 1998, 54, 6605-6626. Zhang, D. Y.; Miller, M. J. Total Synthesis of (+/-) Carbocyclic Polyoxin C and its a-Epimer. Journal of Organic Chemistry 1998, 63, 755-759. Surman, M. D.; Mulvihill, M. J.; Miller, M. J. Regio- and Stereoselective Ring Openings of 3-Aza-2-oxabicyclo[2.2.1]hept-5-ene Systems with Copper Catalyst-Modified Grignard Reagents: Application to the Synthesis of an Inhibitor of 5-Lipoxygenase. Journal of Organic Chemistry 2002, 67, 4115-4121. Surman, M. D.; Mulvihill, M. J.; Miller, M. J. Novel 1,4-Benzodiazepines from Acylnitroso-Derived Hetero-Diels-Alder Cycloadducts. Organic Letters 2002, 4, 139-141.

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