Ireneusz Nowak - Academia.edu (original) (raw)
Papers by Ireneusz Nowak
J Med Chem, 2007
Sonogashira coupling strategies were employed to synthesize new furo [2, 3-d] pyrimidin-2 (3 H)-o... more Sonogashira coupling strategies were employed to synthesize new furo [2, 3-d] pyrimidin-2 (3 H)-one (FuPyrm) 2'-deoxynucleoside analogues. Partial or complete reduction of ethyne-linked compounds afforded ethenyl-and ethyl-linked derivatives. Levels of inhibition of ...
![Research paper thumbnail of Deoxygenative [1,2]-Hydride Shift Rearrangements in Nucleoside and Sugar Chemistry: Analogy with the [1,2]-Electron Shift in the Deoxygenation of Ribonucleotides by Ribonucleotide Reductases 1](https://attachments.academia-assets.com/43349976/thumbnails/1.jpg)
](J Org Chem, 2007
A variant of the semipinacol rearrangement that was observed in our laboratory has been applied t... more A variant of the semipinacol rearrangement that was observed in our laboratory has been applied to the synthesis of several furanose and pyranose derivatives. The process consists of an "orchestrated" [1,2]hydride shift with departure of a leaving group from the opposite face. Transient formation of a CdO group is followed by rapid transfer of a hydride-equivalent from the same face from which the leaving group departed, which results in double inversion of stereochemistry at the two vicinal carbon atoms. Treatment of 2′-O-and 3′-O-tosyladenosine with lithium triethylborohydride in DMSO/THF gave the respective 2′-and 3′-deoxynucleoside analogues with -D-threo configurations. Identical treatment of 5′-O-TPS-2′-O-tosyladenosine gave 9-(5-O-TPS-2-deoxy--D-threo-pentofuranosyl)adenine. The same [1,2]-hydride shift and stereochemistry with the 5′-OH and 5′-O-TPS compounds demonstrated the absence of remote hydroxyl-group participation. Application of this process to other nucleoside 2′-O-tosyl derivatives gave the 2′-deoxy-threo compounds in good yields. The reaction-rate order was OTs ≈ Br . Cl for 2′-O-tosyladenosine, 2′-bromo-2′-deoxyadenosine, and 2′-chloro-2′-deoxyadenosine (all with -Dribo configurations). Analogous results were obtained with mannopyranoside derivatives with either 4,6-O-benzylidene protection or a free OH group at C4. Deuterium labeling clearly defined the stereochemical course as a cis-vicinal [1,2]-hydride shift on the face opposite to the original cis OH and OTs groups followed by hydride transfer from the face opposite to the [1,2]-hydride shift. Synthetic and mechanistic considerations are discussed. (1) Nucleic Acid Related Compounds. 146. Paper 145: Robins, M. J.; Nowak, I.; Rajwanshi, V. K.; Miranda, K.; Cannon, J. F.; Peterson, M. A.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. J. Med. Chem. 2007, 50, 3897-3905. (2) Spiegel, D. A.; Wiberg, K. B.; Schacherer, L. N.; Madeiros, M. R.; Wood, J. L. company unrestricted gift funds (M.J.R.), and Brigham Young University for support of this work, and thank Professor Steven R. Herron (BYU) for determining the X-ray crystal structure of 3a.
Collection of Czechoslovak Chemical Communications, 2011
ChemInform, 2012
ABSTRACT Nucleosides with an aromatic five-membered ring heterocycle (N, O, or S) fused at C4-C5 ... more ABSTRACT Nucleosides with an aromatic five-membered ring heterocycle (N, O, or S) fused at C4-C5 of pyrimidin-2-one were prepared by ring closures with 5-(alkyn-1-yl)pyrimidin-2-one intermediates, heterocyclic atom replacements, and ring closure with a 5-aminocytidine derivative. Ultraviolet absorption and emission properties of the autofluorescent products enabled studies on permeation and inhibition of the trans-cellular trafficking effected by human equilibrative nucleoside transporters (hENTs). Some of the autofluorescent nucleosides were shown to be potent and selective inhibitors of human concentrative nucleoside transporters (hCNTs) in a companion study reported elsewhere.
Journal f�r Praktische Chemie/Chemiker-Zeitung, 1995
Arylmethylenemalononitrile and conjugate nitroalkenes, being markedly electron deficient, are ver... more Arylmethylenemalononitrile and conjugate nitroalkenes, being markedly electron deficient, are versatile Michael acceptors for conjugated addition with various compounds containing acidic hydrogen atoms. In majority of reactions the Michael adducts are reactive intermediates that undergo spontaneous cyclization to carbo- [l] or heterocyclic [Z, 31 compounds.
Molecular pharmacology, 2005
Human concentrative nucleoside transporters 1, 2, and 3 (hCNT1, hCNT2, and hCNT3) exhibit differe... more Human concentrative nucleoside transporters 1, 2, and 3 (hCNT1, hCNT2, and hCNT3) exhibit different functional characteristics, and a better understanding of their permeant selectivities is critical for development of nucleoside analog drugs with optimal pharmacokinetic properties. In this study, the sensitivity of a high-throughput yeast expression system used previously for hCNT1 and hCNT3 was improved and used to characterize determinants for interaction of uridine (Urd) with hCNT2. The observed changes of binding energy between hCNT2 and different Urd analogs suggested that it interacts with C3'-OH, C5'-OH, and N3-H of Urd. The C2' and C5 regions of Urd played minor but significant roles for Urd-hCNT2 binding, possibly through Van der Waals interactions. Because the yeast assay only provided information about potential transportability, the permeant selectivities of recombinant hCNT1, hCNT2, and hCNT3 produced in Xenopus laevis oocytes were investigated using a two-e...
Organic letters, Jan 28, 2006
Treatment of acylated adenosine N-oxides with carboxylic anhydrides and thiophenol resulted in py... more Treatment of acylated adenosine N-oxides with carboxylic anhydrides and thiophenol resulted in pyrimidine ring opening followed by exocyclic ring closure. Ammonolysis gave 5-amino-4-(5-substituted-1,2,4-oxadiazol-3-yl)-1-(beta-d-ribofuranosyl)imidazole derivatives, whereas iodine in methanol selectively unmasked the 5-amino group. Related flexible nucleoside analogues can be prepared from adenine-type precursors.
Encyclopedia of Reagents for Organic Synthesis, 2001
Organic Letters, 2003
[reaction: see text] Protection of the amino group of adenine and guanine nucleosides was effecte... more [reaction: see text] Protection of the amino group of adenine and guanine nucleosides was effected by heating the substrates in 2,5-hexanedione. The resulting 2,5-dimethylpyrrole adducts were stable toward bases but were hydrolyzed with TFA/H(2)O to regenerate the amino function.
![Research paper thumbnail of Synthesis and Properties of g em -(Difluorocyclopropyl)amine Derivatives of Bicyclo[ n .1.0]alkanes](https://attachments.academia-assets.com/43349974/thumbnails/1.jpg)
](Organic Letters, 2004
Synthesis and Properties of gem-(Difluorocyclopropyl)amine Derivatives of Bicyclo[n.1.0]alkanes. ... more Synthesis and Properties of gem-(Difluorocyclopropyl)amine Derivatives of Bicyclo[n.1.0]alkanes. -The addition of difluorocarbene to enamines derived from cyclic ketones provides convenient access to bicyclic difluorocyclopropylamines with significantly different stabilities. The seven-membered fused-ring analogues are shown to be the most stable ones. The thermal decomposition of (III) with following hydrolysis leads to ring extension with formation of ketones IV). -(NOWAK, I.; CANNON, J. F.; ROBINS*, M. J.; Org. Lett. 6 (2004) 25, 4767-4770; Dep. Chem. Biochem., Brigham Young Univ., Provo, UT 84602, USA; Eng.) -Steudel 12-046
Organic Letters, 2005
[reaction: see text] N,O-Peracylated cytidine and 2'-deoxycytidine deriva... more [reaction: see text] N,O-Peracylated cytidine and 2'-deoxycytidine derivatives in superheated water/DME solutions (oil bath at 125 degrees C) undergo hydrolytic deamidation (and/or N-deacylation). Acylated starting materials derived from arylcarboxylic acids give the corresponding uridine esters cleanly, and such derivatives crystallize selectively from the cooled reaction mixtures in high yields.
Organic Letters, 2005
[reaction: see text] Regioselective control of glycosylation of purines at N9 (versus N7) has bee... more [reaction: see text] Regioselective control of glycosylation of purines at N9 (versus N7) has been a continuing challenge. We now report Lewis acid catalyzed regiospecific glycosylations of 6-(2-alkylimidazol-1-yl)purines at N9. The 6-(2-alkyl)imidazole moiety also functions as a versatile leaving group that can be replaced by nucleophiles (S(N)Ar) and aryl groups (Suzuki cross-coupling).
Organic Letters, 2005
Generation of difluoromethylene phosphorus ylides in the presence of aldehydes and ketones result... more Generation of difluoromethylene phosphorus ylides in the presence of aldehydes and ketones results in Wittig-type reactions to give gem-difluoroalkenes. Subsequent in situ addition of difluorocarbene (carbenoid) can occur (increased with triphenylphosphine and decreased with tributylphosphine) to give tetrafluorocyclopropanes. [Reaction: see text]
J Med Chem, 2007
Sonogashira coupling strategies were employed to synthesize new furo [2, 3-d] pyrimidin-2 (3 H)-o... more Sonogashira coupling strategies were employed to synthesize new furo [2, 3-d] pyrimidin-2 (3 H)-one (FuPyrm) 2'-deoxynucleoside analogues. Partial or complete reduction of ethyne-linked compounds afforded ethenyl-and ethyl-linked derivatives. Levels of inhibition of ...
J Org Chem, 2007
A variant of the semipinacol rearrangement that was observed in our laboratory has been applied t... more A variant of the semipinacol rearrangement that was observed in our laboratory has been applied to the synthesis of several furanose and pyranose derivatives. The process consists of an "orchestrated" [1,2]hydride shift with departure of a leaving group from the opposite face. Transient formation of a CdO group is followed by rapid transfer of a hydride-equivalent from the same face from which the leaving group departed, which results in double inversion of stereochemistry at the two vicinal carbon atoms. Treatment of 2′-O-and 3′-O-tosyladenosine with lithium triethylborohydride in DMSO/THF gave the respective 2′-and 3′-deoxynucleoside analogues with -D-threo configurations. Identical treatment of 5′-O-TPS-2′-O-tosyladenosine gave 9-(5-O-TPS-2-deoxy--D-threo-pentofuranosyl)adenine. The same [1,2]-hydride shift and stereochemistry with the 5′-OH and 5′-O-TPS compounds demonstrated the absence of remote hydroxyl-group participation. Application of this process to other nucleoside 2′-O-tosyl derivatives gave the 2′-deoxy-threo compounds in good yields. The reaction-rate order was OTs ≈ Br . Cl for 2′-O-tosyladenosine, 2′-bromo-2′-deoxyadenosine, and 2′-chloro-2′-deoxyadenosine (all with -Dribo configurations). Analogous results were obtained with mannopyranoside derivatives with either 4,6-O-benzylidene protection or a free OH group at C4. Deuterium labeling clearly defined the stereochemical course as a cis-vicinal [1,2]-hydride shift on the face opposite to the original cis OH and OTs groups followed by hydride transfer from the face opposite to the [1,2]-hydride shift. Synthetic and mechanistic considerations are discussed. (1) Nucleic Acid Related Compounds. 146. Paper 145: Robins, M. J.; Nowak, I.; Rajwanshi, V. K.; Miranda, K.; Cannon, J. F.; Peterson, M. A.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. J. Med. Chem. 2007, 50, 3897-3905. (2) Spiegel, D. A.; Wiberg, K. B.; Schacherer, L. N.; Madeiros, M. R.; Wood, J. L. company unrestricted gift funds (M.J.R.), and Brigham Young University for support of this work, and thank Professor Steven R. Herron (BYU) for determining the X-ray crystal structure of 3a.
Collection of Czechoslovak Chemical Communications, 2011
ChemInform, 2012
ABSTRACT Nucleosides with an aromatic five-membered ring heterocycle (N, O, or S) fused at C4-C5 ... more ABSTRACT Nucleosides with an aromatic five-membered ring heterocycle (N, O, or S) fused at C4-C5 of pyrimidin-2-one were prepared by ring closures with 5-(alkyn-1-yl)pyrimidin-2-one intermediates, heterocyclic atom replacements, and ring closure with a 5-aminocytidine derivative. Ultraviolet absorption and emission properties of the autofluorescent products enabled studies on permeation and inhibition of the trans-cellular trafficking effected by human equilibrative nucleoside transporters (hENTs). Some of the autofluorescent nucleosides were shown to be potent and selective inhibitors of human concentrative nucleoside transporters (hCNTs) in a companion study reported elsewhere.
Journal f�r Praktische Chemie/Chemiker-Zeitung, 1995
Arylmethylenemalononitrile and conjugate nitroalkenes, being markedly electron deficient, are ver... more Arylmethylenemalononitrile and conjugate nitroalkenes, being markedly electron deficient, are versatile Michael acceptors for conjugated addition with various compounds containing acidic hydrogen atoms. In majority of reactions the Michael adducts are reactive intermediates that undergo spontaneous cyclization to carbo- [l] or heterocyclic [Z, 31 compounds.
Molecular pharmacology, 2005
Human concentrative nucleoside transporters 1, 2, and 3 (hCNT1, hCNT2, and hCNT3) exhibit differe... more Human concentrative nucleoside transporters 1, 2, and 3 (hCNT1, hCNT2, and hCNT3) exhibit different functional characteristics, and a better understanding of their permeant selectivities is critical for development of nucleoside analog drugs with optimal pharmacokinetic properties. In this study, the sensitivity of a high-throughput yeast expression system used previously for hCNT1 and hCNT3 was improved and used to characterize determinants for interaction of uridine (Urd) with hCNT2. The observed changes of binding energy between hCNT2 and different Urd analogs suggested that it interacts with C3'-OH, C5'-OH, and N3-H of Urd. The C2' and C5 regions of Urd played minor but significant roles for Urd-hCNT2 binding, possibly through Van der Waals interactions. Because the yeast assay only provided information about potential transportability, the permeant selectivities of recombinant hCNT1, hCNT2, and hCNT3 produced in Xenopus laevis oocytes were investigated using a two-e...
Organic letters, Jan 28, 2006
Treatment of acylated adenosine N-oxides with carboxylic anhydrides and thiophenol resulted in py... more Treatment of acylated adenosine N-oxides with carboxylic anhydrides and thiophenol resulted in pyrimidine ring opening followed by exocyclic ring closure. Ammonolysis gave 5-amino-4-(5-substituted-1,2,4-oxadiazol-3-yl)-1-(beta-d-ribofuranosyl)imidazole derivatives, whereas iodine in methanol selectively unmasked the 5-amino group. Related flexible nucleoside analogues can be prepared from adenine-type precursors.
Encyclopedia of Reagents for Organic Synthesis, 2001
Organic Letters, 2003
[reaction: see text] Protection of the amino group of adenine and guanine nucleosides was effecte... more [reaction: see text] Protection of the amino group of adenine and guanine nucleosides was effected by heating the substrates in 2,5-hexanedione. The resulting 2,5-dimethylpyrrole adducts were stable toward bases but were hydrolyzed with TFA/H(2)O to regenerate the amino function.
Organic Letters, 2004
Synthesis and Properties of gem-(Difluorocyclopropyl)amine Derivatives of Bicyclo[n.1.0]alkanes. ... more Synthesis and Properties of gem-(Difluorocyclopropyl)amine Derivatives of Bicyclo[n.1.0]alkanes. -The addition of difluorocarbene to enamines derived from cyclic ketones provides convenient access to bicyclic difluorocyclopropylamines with significantly different stabilities. The seven-membered fused-ring analogues are shown to be the most stable ones. The thermal decomposition of (III) with following hydrolysis leads to ring extension with formation of ketones IV). -(NOWAK, I.; CANNON, J. F.; ROBINS*, M. J.; Org. Lett. 6 (2004) 25, 4767-4770; Dep. Chem. Biochem., Brigham Young Univ., Provo, UT 84602, USA; Eng.) -Steudel 12-046
Organic Letters, 2005
[reaction: see text] N,O-Peracylated cytidine and 2'-deoxycytidine deriva... more [reaction: see text] N,O-Peracylated cytidine and 2'-deoxycytidine derivatives in superheated water/DME solutions (oil bath at 125 degrees C) undergo hydrolytic deamidation (and/or N-deacylation). Acylated starting materials derived from arylcarboxylic acids give the corresponding uridine esters cleanly, and such derivatives crystallize selectively from the cooled reaction mixtures in high yields.
Organic Letters, 2005
[reaction: see text] Regioselective control of glycosylation of purines at N9 (versus N7) has bee... more [reaction: see text] Regioselective control of glycosylation of purines at N9 (versus N7) has been a continuing challenge. We now report Lewis acid catalyzed regiospecific glycosylations of 6-(2-alkylimidazol-1-yl)purines at N9. The 6-(2-alkyl)imidazole moiety also functions as a versatile leaving group that can be replaced by nucleophiles (S(N)Ar) and aryl groups (Suzuki cross-coupling).
Organic Letters, 2005
Generation of difluoromethylene phosphorus ylides in the presence of aldehydes and ketones result... more Generation of difluoromethylene phosphorus ylides in the presence of aldehydes and ketones results in Wittig-type reactions to give gem-difluoroalkenes. Subsequent in situ addition of difluorocarbene (carbenoid) can occur (increased with triphenylphosphine and decreased with tributylphosphine) to give tetrafluorocyclopropanes. [Reaction: see text]