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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Org Chem. Author manuscript; available in PMC 2010 August 7.
Published in final edited form as:
PMCID: PMC2745051

Syntheses of Carbocyclic Uracil Polyoxin C Analogs: Application of Pd(0)/InI-Allylation of 4-Acetoxy-2-azetidinone


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Carbocyclic uracil polyoxin C analogs are synthesized in less than nine steps from an acylnitroso-derived hetero Diels–Alder adduct. Pd(0)/InI-mediated allylation of 4-acetoxy-2-azetidinone is used to install the β-amino acid side chain at the C-5' position of the carbocycle.

Polyoxins and nikkomycins are peptidyl nucleoside natural products that selectively target fungi while remaining nontoxic to plants, animals and bacteria.1 Specifically, these molecules are inhibitors of chitin synthase,2 an enzyme responsible for the synthesis of the fungal cell wall component chitin. Disrupting chitin biosynthesis compromises the structural integrity of fungal cell walls and results in death of the pathogen.3 Because plant and mammalian cells do not produce chitin, inhibition of chitin synthase only affects fungal cells and is considered a potentially safe and nontoxic approach toward combating fungal infections.

Although polyoxins and nikkomycins demonstrate competitive inhibition of chitin synthase in enzyme assays,4 the ionized amino acid side chain significantly impedes their cellular transport and has precluded their development as fungicidal agents. Additionally, polyoxins and nikkomycins are less effective in vivo due to their instability toward intracellular proteases.5 In efforts to prepare polyoxin and nikkomycin derivatives with increased potency, several analogs have been synthesized with diverse amino acid side chains,6 inverted configurations7 and different nucleoside bases.8

Additionally, prodrug variants of polyoxins and nikkomycins have been designed to permeate fungal cell membranes and release the active component upon intracellular hydrolysis.9 Despite extensive modification of the peptidyl subunits, less effort has focused on structural changes at the central ribose core. By replacing the furanose oxygen with a methylene unit, several classes of carbocyclic nucleosides have displayed increased metabolic stability and improved biological activity.10 To date, syntheses of carbocyclic derivatives of polyoxins and nikkomycins have been limited.11 Herein, we disclose the synthesis of carbocyclic uracil polyoxin C analogs 1a and 2a as potential antifungal agents (Chart 1).

Chart 1
Representative Polyoxins and Related Carbocyclic Analogs.

Recently, we reported the diastereoselective allylation of 4-acetoxy-2-azetidinone from a unique allylindium precursor, acylnitroso-derived hetero-Diels-Alder adduct 3, to incorporate highly functionalized cyclopentenes at the azetidinone C-4 position.12 Further elaboration of synthon 4 would reveal an unprecedented polyoxin C analog bearing an azetidinone at the C-5' position. Interestingly, several naturally occurring polyoxins (i.e. Polyoxin I)13 contain 2-carboxyazetidine side chains and illustrate the structural diversity in this class of molecules. The protected β-amino acid side chain renders polyoxin C analog 1a as having the potential for improved antifungal activity due to its neutral character. Furthermore, intracellular hydrolysis of target molecule 1a would provide compound 2a and reveal the free amino and carboxy groups, two functionalities that are required for inhibition.14

In a first attempt to synthesize key intermediate 8, N-hydroxycarbamate 4 was reduced to carbamate 5 in the presence of titanocene (III) monochloride15 generated in situ (Scheme 1). Treatment of compound 5 with TFA and anisole in refluxing CH2Cl2 formed the amine salt in quantitative yield after 3 h. The crude material was treated with acyl isocyanate 616 freshly dissolved in benzene. The reaction was complete within 18 h to afford acyl urea 7 in 47% yield. Cyclization of compound 7 to uracil 8 proved problematic. Starting material 7 was unreactive towards ZnCl2 and p-toluene sulfonic acid at 60 °C. Strong acidic conditions (i.e. 1M H2SO4 or TFA) or strong basic conditions (i.e. NH4OH) opened the azetidinone ring. The desired product 8 was never observed.

Scheme 1
Initial Synthetic Route to Uracil 8.

We recognized that the N-protio β-lactam required protection to survive cyclization to uracil 8. As the azetidinone ring of compound 7 is susceptible to opening in the presence of strong acid or base, we required a protecting group that could be installed and removed under neutral conditions. Our group has previously reported N-sulfenylation of 2-azetidinones with N-methylthiophthalimide.17 Additionally, the N-methylthio group is easily removed under neutral conditions with 2-mercaptopyridine.18 Accordingly, compound 5 was refluxed in CH2Cl2 with N-methylthiophthalimide 919 to afford protected azetidinone 10 in 88% isolated yield20 (Scheme 2). N-Methylthio-β-lactam 10 was refluxed in the presence of TFA and anisole to remove the Boc group. The resultant crude material was treated with a freshly prepared benzene solution of acyl isocyanate 6 to provide acyl urea 11 in an improved 77% yield. With the N-methylthio group installed in compound 11, cyclization to the uracil base readily occurred in 1M H2SO4 and CH3CN at 80 °C to afford desired product 12. Removal of the N-methylthio group was achieved with 2-mercaptopyridine to afford key carbocycle 8.

Scheme 2
Revised Synthetic Route to Uracil 8.

Although we developed an optimized route to intermediate 8, we anticipated low diastereoselectivity for 1a in the subsequent dihydroxylation reaction.21 As predicted, a 1:3 mixture of cis-diols 1a and 1b, respectively, was obtained after OsO4-catalyzed dihydroxylation of cyclopentene 8 (Scheme 3). In an effort to increase the ratio of 1a, we investigated Woodward-Prévost conditions22 as an alternative method to install the cis-diol from the same face as the allylic methine protons in cyclopentene 8.23 Although the Woodward-Prévost method has previously been used in the synthesis of carbocyclic nucleosides,24 the strong oxidizing conditions (i.e. I2 and AgOAc) were not compatible with 8, yielding a complex product mixture.

Scheme 3
Syntheses of Uracil Polyoxin C Analogs

Finally, a mixture of cis-diols 1a and 1b was treated with an aqueous solution of NaOH to afford carbocyclic homo-uracil polyoxin C analogs 2a and 2b, respectively.

In summary, Pd(0)/InI-mediated allylation chemistry has been applied in the syntheses of azetidinone-derived and carboxylic acid-related carbocyclic nucleosides 1a and 1b and β-amino acid related-carbocyclic nucleosides 2a and 2b. We are currently screening final compounds 1a-b and 2a-b as well as relevant intermediates 4, 5, 8, 10 and 12 for anti-cancer, antimicrobial, antiviral and antifungal activity. Detailed biological studies will be described subsequently.

Experimental Section

(±)-tert-Butyl-(1R*,4S*)-4-((S*)-4-oxoazetidin-2-yl)cyclopent-2-enylcarbamate 5

A clean flame-dried 250 mL round bottom flask was evacuated and purged with Ar. A THF solution (50 mL) of Cp2TiCl2 (2.55 g, 10.2 mmol) and activated zinc (1.34 g, 20.5 mmol) was stirred at rt under Ar for 45 min. The reaction mixture changed color from dark red to olive green. The reaction mixture was cooled to −30 °C and treated dropwise over 3 min with a MeOH solution (40 mL) of compound 4 (1.1 g, 4.1 mmol). The reaction mixture was stirred for 45 min and while maintaining the bath temperature between −10 °C and −30 °C. The reaction mixture was warmed to rt and partitioned between sat. K2CO3 (10 mL) and EtOAc (40 mL). The organic layer was removed via pipet and filtered through Whatman Glass Microfiber Filter (Type GF/F) (to remove insoluble titanium salts). The aqueous layer was extracted with EtOAc (4 × 40 mL) and the organic layer was filtered through Whatman Glass Microfiber Filter (Type GF/F) after each extraction. The combined organic layers were dried over MgSO4, again filtered through Whatman Glass Microfiber Filter (Type GF/F), and the filtrate was adsorbed on silica gel. The adsorbed material was purified by silica gel chromatography (2% MeOH/CH2Cl2) to afford 5 as an off white foam (747 mg, 72%). An analytical sample was recrystallized from EtOAc to provide a white powder from which all analytical data was obtained. mp 132–133 °C; 1H NMR (600 MHz, CD3OD) δ 1.27 (1H, ddd, J = 13.4 Hz, 6.5 Hz, 6.5 Hz), 1.44 (s, 9H), 2.49 (ddd, 1H, J = 13.4 Hz, 8.2 Hz, 8.2 Hz), 2.61 (dd, 1H, J = 15.0 Hz, 2.3 Hz), 2.85–2.89 (m, 1H), 2.94 (dd, 1H, J = 15.0 Hz, 5.0 Hz), 3.61 (ddd, 1H, J = 6.2 Hz, 5.0 Hz, 2.4 Hz), 4.60–4.65 (m, 1H), 5.76–5.80 (m, 2H); 13C NMR (150 MHz, CD3OD) δ 28.9, 34.8, 48.7, 49.8, 51.8, 57.8, 80.2, 133.7, 136.6, 158.0, 171.1; IR (thin film, cm−1) 3296, 2978, 2931, 1748, 1694, 1520, 1367; HRMS (FAB) m/z [M+H]+: calcd for C13H21N2O3+, 253.1552; found, 253.1570.

3-Methoxy-2-propenoyl isocyanate 616

A clean flame-dried 100 mL round bottom flask equipped with a stir bar and condenser was evacuated and purged with Ar. Silver cyanate (3.02 g, 20.2 mmol) was added to the flask and was heated to 50 °C (bath temperature) under vacuum for 18 h and then heated to 100 °C (bath temperature) for 2 h while the acid chloride was prepared. A clean flame-dried 50 mL round bottom flask equipped with a stir bar, 4Å molecular sieves and a condenser was evacuated and purged with Ar. A CH2Cl2 (16 mL) suspension of sodium-3-methoxy-2-propenoate (1.0 g, 8.06 mmol) was cooled to 0 °C and treated with oxalyl chloride (0.82 mL, 9.67 mmol) followed by DMF (0.06 mL, 0.81 mmol) and the reaction mixture was refluxed for 2 h. The reaction mixture was then cooled to rt and filtered through a glass fritted funnel. The filtrate was transferred to a 50 mL round bottom flask (previously flamed dried and purged with Ar), concentrated in vacuo to yellow solids and the flask was back-filled with Ar. Meanwhile, dry benzene (20 mL) was added to the heated flask containing silver cyanate and the solution was refluxed for 30 min. A benzene solution (20 mL) of the acid chloride was added dropwise to the refluxing solution of silver cyanate. The reaction mixture was refluxed for 1.5 h and then cooled to rt. The solids were filtered through Whatman Glass Microfiber Filter (Type GF/F) and the filtrate was used directly in the preparation of 7 or 11.

(±)-(E)-3-Methoxy-N-((1R*,4S*)-4-((S*)-4-oxoazetidin-2-yl)cyclopent-2-enylcarbamoyl)acrylamide 7

A clean flame-dried 10 mL round bottom flask equipped with a stir bar and condenser was evacuated and purged with Ar. A CH2Cl2 (2 mL) solution of compound 5 (100 mg, 0.40 mmol) was treated with anisole (0.047 mL, 0.44 mmol) and then TFA (0.15 mL, 1.99 mmol). The reaction mixture was refluxed for 3 h at 60 °C (bath temperature). The reaction mixture was concentrated to a brown oil, toluene (1 mL) was added, and the solution was concentrated to an oil. CH2Cl2 (2 mL) was added to the resultant residue. The solution was cooled to 0 °C and then treated with DIPEA (0.69 mL, 3.96 mmol). The reaction mixture was stirred for 5 min under Ar at 0 °C and was then treated with a benzene solution of 3-methoxy-2-propenoyl isocyanate 6 (100 mg, 0.80 mmol, assuming quantitative yield from the previous step). The reaction was stirred for 15 h under Ar as the temperature warmed to rt overnight. The reaction mixture was concentrated to a tan oil and partitioned between CH2Cl2 (3 mL) and 10% citric acid (2 mL). The aqueous layer was extracted with CH2Cl2 (4 × 3 mL). The combined organic layers were washed with brine (8 mL), dried over Na2SO4, filtered and concentrated to a tan oil. The residue was purified by silica gel chromatography (100% EtOAc) to afford 7 as a yellow gum (52 mg, 47%). 1H NMR (600 MHz, CDCl3) δ 1.41 (ddd, 1H, J = 13.5 Hz, 5.9 Hz, 5.9 Hz), 2.56 (ddd, 1H, J = 13.5 Hz, 8.2 Hz, 8.2 Hz), 2.65 (ddd, 1H, J = 14.7 Hz, 2.6 Hz, 1.2 Hz), 2.91–2.95 (m, 1H), 3.02 (ddd, 1H, J = 15.0 Hz, 2.6 Hz, 1.2 Hz), 3.67 (ddd, 1H, J = 5.3 Hz, 5.3 Hz, 2.3 Hz), 3.74 (s, 3H), 4.92–4.97 (m, 1H), 5.20 (d, 1H, J = 12.3 Hz), 5.81 (ddd, H, J = 5.6 Hz, 3.8 Hz, 2.1 Hz), 5.88 (ddd, 1H, J = 5.6 Hz, 4.4 Hz, 2.1 Hz), 5.90 (bs, 1H), 7.66 (d, 1H, J =12.3 Hz), 8.00 (bs, 1H), 8.61 (bd, 1H, J = 8.2 Hz); 13C NMR (150 MHz, CDCl3) δ 33.9, 41.8, 48.9, 50.9, 55.9, 58.5, 97.6, 133.6, 134.6, 153.7, 164.5, 167.8, 167.9; IR (thin film, cm−1) 3258, 2921, 1737, 1678, 1614, 1538; HRMS (FAB) m/z [M+H]+: calcd for C13H18N3O4+, 280.1297; found, 280.1303.

(±)-1-((1R*,4S*)-4-((S*)-4-Oxoazetidin-2-yl)cyclopent-2-enyl)pyrimidine-2,4(1H,3H)-dione 8

A CH2Cl2 solution (10 mL) of 12 (0.56 g, 1.91 mmol) and 2-mercaptopyridine (0.26 g, 2.29 mmol) in a pressure tube was treated with Et3N (0.32 mL, 2.29 mmol). The tube was sealed with a teflon screw cap and the heterogeneous reaction mixture was stirred for 18 h at 60 °C (bath temperature). The reaction mixture was cooled to 0 °C and the precipitate was filtered and washed with hexanes to afford 8 as an off-white solid (0.40 g, 84%). mp 246–247 °C (dec); 1H NMR (600 MHz, DMSO-d6) δ 1.21 (ddd, 1H, J = 13.8 Hz, 6.8 Hz, 6.8 Hz), 2.50–2.56 (m, 2H), 2.85 (dd, 1H, J = 5.0 Hz, 2.1 Hz), 2.86–2.90 (m, 1H), 3.57 (ddd, 1H, J = 8.5 Hz, 2.6 Hz, 2.6 Hz), 5.46–5.50 (m, 1H), 5.57 (d, 1H, J = 8.2 Hz), 5.78 (ddd, 1H, J = 5.6 Hz, 2.1 Hz, 2.1 Hz), 6.01 (ddd, 1H, J = 5.6 Hz, 2.1 Hz, 2.1 Hz), 7.42 (d, 1H, J = 7.9 Hz), 7.97 (s, 1H), 11.27 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ 32.2, 40.9, 48.4, 48.8, 60.8, 101.6, 131.0, 137.1, 141.7, 150.9, 163.3, 167.0; IR (thin film, cm−1) 1749, 1689, 1614, 1461; HRMS (FAB) m/z [M+H]+: calcd for C12H14N3O3+, 248.1035; found, 248.1026.

(±)-1-((1R*,2S*,3R*,4R*)-2,3-Dihydroxy-4-((S*)-4-oxoazetidin-2-yl)cyclopentyl)pyrimidine-2,4(1H,3H)-dione 1a and 1-((1R*,2R*,3S*,4R*)-2,3-dihydroxy-4-((S*)-4-oxoazetidin-2-yl)cyclopentyl)pyrimidine-2,4(1H,3H)-dione 1b

A t-BuOH:H2O solution (9:1, 1.8 mL: 0.2 mL) of 8 (50 mg, 0.20 mmol) and N-methylmorpholine N-oxide (47 mg, 0.40 mol) was treated with a 2.5% (w/w) solution of osmium tetraoxide in t-BuOH (0.40 mL, 0.04 mmol) and the heterogeneous reaction mixture was stirred at rt for 18 h. After 18 h, the clear yellow reaction mixture was treated with solid Na2S2O5 (576 mg, 3.03 mmol) and the mixture was stirred at rt for 30 min. The clear solution was filtered through a Whatman Glass Microfiber Filter (Type GF/F) to remove the brown precipitate. The clear filtrate was concentrated to solids under reduced pressure, toluene (3 mL) was added, and the solution was concentrated to solids. The solids were triturated with MeOH (3 × 5 mL) and the wet solids were dried under vacuum to afford a 1:8 ratio of 1a:1b as white solids (45 mg, 80%). 1H NMR of the crude reaction mixture indicated a 1:3 ratio of 1a:1b. Compound 1a: 1H NMR (600 MHz, D2O) δ 1.61 (ddd, 1H, J = 12.3 Hz, 12.3 Hz, 9.1 Hz), 2.19–2.28 (m, 2H), 2.73 (dd, 1H, J = 15.2 Hz, 2.4 Hz), 3.11 (dd, 1H, J = 15.3 Hz, 4.7 Hz), 3.87 (ddd, 1H, J = 6.8 Hz, 4.7 Hz, 2.1 Hz), 3.94 (dd, 1H, J = 6.2 Hz, 4.7 Hz), 4.24–4.27 (m, 1H), 4.63–4.68 (m, 1H), 5.86 (d, 1H, J = 7.9 Hz), 7.66 (d, 1H, J = 7.9 Hz); 13C NMR (150 MHz, D2O) δ 26.0, 40.1, 45.9, 49.6, 55.4, 71.2, 73.4, 101.9, 144.4, 152.3, 166.3, 171.9; HRMS (FAB) m/z [M+H]+: calcd for C12H16N3O5+, 282.1090; found, 282.1081. Compound 1b: 1H NMR (600 MHz, D2O) δ 1.95–2.01 (m, 1H), 2.19–2.26 (m, 2H), 2.76 (dd, 1H, J = 15.2 Hz, 2.3 Hz), 3.13 (dd, 1H, J = 15.3 Hz, 4.7 Hz), 3.98 (ddd, 1H, J = 6.5 Hz, 5.0 Hz, 2.4 Hz), 4.24–4.27 (m, 1H), 4.29 (dd, 1H, J = 7.3 Hz, 4.4 Hz), 4.99–5.04 (m, 1H), 5.82 (d, 1H, J = 8.2 Hz), 7.90 (d, 1H, J = 7.9 Hz); 13C NMR (150 MHz, D2O) δ 28.5, 40.8, 42.4, 48.1, 55.4, 71.2, 72.1, 100.6, 146.1, 152.7, 166.3, 171.9; HRMS (FAB) m/z [M+H]+: calcd for C12H16N3O5+, 282.1090; found, 282.1081.

(±)-(S*)-3-amino-3-((1R*,2R*,3S*,4R*)-4-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,3-dihydroxycyclopentyl) propanoic acid 2a and (±)-(S*)-3-amino-3-((1R*,2S*,3R*,4R*)-4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,3-dihydroxycyclopentyl)propanoic acid 2b

A water solution (0.36 mL) of a 1:8 ratio of 1a:1b (10 mg, 0.036 mmol) was treated with 2M NaOH (0.089 mL, 0.18 mmol) and was stirred for 18 h at rt. The reaction mixture was adjusted to pH 7 with 1M HCl. The neutralized reaction mixture was concentrated to solids under reduced pressure. The crude material was adsorbed on Sephadex LH20 and eluted with MeOH to afford a 1:6 ratio of 2a:2b as white solids (10.6 mg, 94%). Compound 2a: 1H NMR (600 MHz, D2O) δ 1.67–1.72 (m, 1H), 2.22–2.29 (m, 2H), 2.50 (dd, 1H, J = 17.5 Hz, 9.5 Hz), 2.75 (dd, 1H, J = 17.5 Hz, 4.0 Hz), 3.58 (ddd, 1H, J = 9.2 Hz, 8.6 Hz, 3.4 Hz), 3.91–3.94 (m, 1H), 4.06–4.08 (m, 1H), 4.56–4.62 (m, 1H), 5.86 (d, 1H, J = 8.0 Hz), 7.67 (d, 1H, J = 8.0 Hz); 13C NMR (125 MHz, D2O) δ 27.0, 37.0, 40.3, 45.3, 51.5, 70.5, 72.8, 102.0, 144.5, 152.5, 166.5, 177.9; HRMS (ESI) m/z [M+H]+: calcd for C12H18N3O6+, 300.1196; found, 300.1190. HRMS (ESI) m/z [M+Na]+: calcd for C12H17N3NaO6, 322.1015; found, 322.1010. Compound 2b: 1H NMR (600 MHz, D2O) δ 1.97 (ddd, 1H, J = 12.6 Hz, 12.6, Hz, 10.0 Hz), 2.21–2.26 (m, 1H), 2.33 (ddd, 1H, J = 12.6 Hz, 8.2 Hz, 7.0 Hz), 2.50 (dd, 1H, J = 16.7 Hz, 8.5 Hz), 2.66 (dd, 1H, J = 16.4 Hz, 4.7 Hz), 3.72 (ddd, 1H, J = 10.8 Hz, 7.3 Hz, 4.7 Hz), 4.29–4.32 (m, 2H), 5.08 (ddd, 1H, J = 10.0 Hz, 8.2 Hz, 8.2 Hz), 5.84 (d, 1H, J = 7.9 Hz), 7.92 (d, 1H, J = 7.9 Hz); 13C NMR (150 MHz, D2O) δ 29.0, 38.6, 40.7, 49.2, 54.8, 70.9, 71.6, 100.9, 146.0, 156.9, 166.3, 178.1; HRMS (ESI) m/z [M+H]+: calcd for C12H18N3O6+, 300.1196; found, 300.1190. HRMS (ESI) m/z [M+Na]+: calcd for C12H17N3NaO6, 322.1015; found, 322.1010.

Supplementary Material


Supporting Information Available:

General methods and experimental details for the preparation of 9–12. 1H and 13C NMR spectra for compounds 1a–b, 2a–b, 5, 7, 8, 10, 11 and 12. This material is available free of charge via the Internet at


We would like to thank Dr. Jed Fisher for helpful discussions, Dr. Bill Boggess and Nonka Sevova for mass spectroscopic analyses and Dr. Jaroslav Zajicek for NMR assistance. We acknowledge The University of Notre Dame and NIH (GM068012) for support of this work.


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