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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Tetrahedron Lett. Author manuscript; available in PMC 2011 July 1.
Published in final edited form as:
Tetrahedron Lett. 2010 July 1; 51(29): 3789–3791.
doi:  10.1016/j.tetlet.2010.05.062
PMCID: PMC2894734

Cyclopropanation of nitroso Diels–Alder cycloadducts and application to the synthesis of a 2’,3’-methano carbocyclic nucleoside


Treatment of nitroso Diels–Alder cycloadducts 1 with diazomethane in the presence of palladium acetate gives synthetically useful exo-6-oxa-7-azatricyclo[,4]octane derivatives 7 in good to excellent yield. Using this methodology, a conformationally restricted 2’,3’-methano carbocyclic nucleoside was efficiently synthesized from nitroso cycloadduct 1a in 7 steps.

Nitroso Diels–Alder (NDA) cycloadducts 1, derived from nitroso agents and cyclopentadiene, are synthetically valuable precursors for many biologically interesting molecules.1 Site selective modification of 1, including the separate cleavage of the N–O2 or C–O36 bonds, has been employed in the preparation of various carbocyclic nucleosides7 and natural products.8

The unsaturated C=C bond in 1 also allows introduction of multiple functionalities in one step (Scheme 1). Previous modifications of the olefin mainly focused on oxidative cleavage,9 reduction10 and dihydroxylation.11 Recently, our group demonstrated that additions of azides to the olefin in nitroso cycloadducts afforded the exo-triazoline 5 in excellent yield.12 Quadrelli et. al. also reported formation of isoxazoline 6 by cycloaddition between a nitrile oxide and cycloadduct 1.13 To further explore the synthetic utility of the olefin and expand the versatility of nitroso cycloadducts, here we report a study of Pd-catalyzed cyclopropanation of 1 with diazomethane to form exo-6-oxa-7-azatricyclo[,4] octane derivatives 7 and demonstrate the utility of the process by the synthesis of a methano carbocyclic nucleoside.

Scheme 1
Previously reported modifications of the olefin in nitroso Diels-Alder (NDA) cycloadduct 1.

Palladium catalyzed cyclopropanations of strained bicyclic alkenes with diazomethane are known in the literature. Because of its excellent catalytic activity, palladium(II) acetate is a particularly useful and efficient reagent for this transformation. Examples include additions to norbornene,14 2-azabicyclo[2.2.1]hept-5-en-3-one (ABH),15 and 2,3-dioxabicyclo[2.2.1]heptane.16 However, no report has yet appeared on the catalytic cyclopropanation of bicyclic oxazines, such as nitroso cycloadducts 1, with diazomethane.

We were pleased to find that by treating N-carbamate based nitroso cycloadduct 1a with 8 equiv of diazomethane in the presence of 5 mol% of Pd(OAc)2 at 0 °C, exo cyclopropane product 7a was exclusively obtained in 96% yield within 30 min (Table 1, entry 1).17 To further explore the functional group compatibility in this cyclopropanation reaction, a series of N-substituted cycloadducts were examined using the same reaction conditions. The results are summarized in Table 1. All of the cycloadducts selected, including acyl (1c–e), carbamate (1a–b), urea (1f), and pyridine (1g) derived substrates, reacted quickly and efficiently with diazomethane to afford the corresponding cyclopropanated products 7a–g in good to excellent yields (Table 1, entries 1–7). This indicates that pendent functional groups on nitroso cycloadducts are well-tolerated in this Pd-catalyzed cyclopropanation.

Table 1
Cyclopropanation of nitroso cycloadducts 1a–g

The exo-stereochemistry of the cyclopropanated products was comfirmed by 2D NMR experiments and was consistent with previously reported cycloaddition reactions of 1 with azides or nitrile oxides. Interestingly, the 4J-coupling (“W-coupling”)12,13b of H2 and H4 with H8’ which has been often seen in systems like triazoline 5 and isoxazoline 6 was not observed in this case. Nevertheless, ROSEY correlation studies revealed the NOE interaction between H3’ and H8 (Figure 1), which supported the exo configuration of the fused cyclopropane ring.

Figure 1
Observed NOE in ROSEY spectrum of 7.

Carbocyclic nucleosides have attracted much attention in the development of novel antiviral and antitumor agents. The isosteric replacement of an oxygen atom in the parent furanose with a methylene unit confers metabolic stability toward cleavage by nucleoside phosphorylases or hydrolases.18 However, their bioactivities are often diminished because of the lowered conformational rigidity induced by the methylene function.19 To overcome this problem, a number of conformationally rigid carbocyclic nucleoside analogs have been designed and synthesized, including nucleosides based on bicyclo[3.1.0]hexane systems which are known as methano carbocyclic nucleosides.15,20 The cyclopropanation methodology presented here provides a new synthetic scaffold for quick access 2’,3’-methano carbocyclic nucleosides, starting from the cyclopropanated compound 7a (Scheme 2). Hydrogenation of 7a catalyzed by 10% Pd/C provided the N-Boc protected 1,4-amino alcohol 8 in quantitative yield. Compound 9 was obtained from 8 by acetylation under basic conditions. Subsequent TFA-mediated N-Boc removal gave free amine 10, which was ready to serve as an evolvable scaffold to build various nucleobases. In this case, an adenine ring, as a representative base, was constructed in 3 steps to afford the 2’,3’-methano carbocyclic noradenosine 13. 21

Scheme 2
Synthesis of 2’,3’-methano carbocyclic noradenosine from 7a. Reagents and conditions: (a) H2, Pd/C, MeOH, rt, 99%; (b) Ac2O, DMAP, pyridine, rt, 99%; (c) TFA, 0 °C, 1 h; (d) 5-amino-4,6-dichloropyrimidine, Et3N, n-BuOH, 110 °C, ...

In summary, an efficient and stereoselective cyclopropanation reaction between nitroso cycloadducts and diazomethane catalyzed by palladium acetate was developed. The resulting cyclopropane product was demonstrated to be a synthetically useful scaffold by the synthesis of a methano carbocyclic nucleoside. Further application of this chemistry for the syntheses of various carbocyclic nucleosides and the biological evaluation of these analogs are in progress.


We thank the Lizzadro Magnetic Resonance Research Center at Notre Dame for NMR facilities and Nonka Sevova for mass spectroscopic analyses. We acknowledge The University of Notre Dame and NIH (GM068012) for support of this research.


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References and notes

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17. (a) Attempts to decrease the catalyst loading to 1 or 2 mol% led to incomplete reaction. (b) General experimental procedure for Pd(OAc)2 catalyzed cyclopropanation: To the reaction vessel of a mini Diazald apparatus was added a 3 M KOH solution (9 mL, EtOH/H2O 5/4) and the condenser was cooled to −78 °C with dry ice/acetone. To a 50 mL round-bottom flask as the receiver were added NDA cycloadduct (0.5 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol) and Et2O (5 mL). This suspension was cooled to 0 °C and stirred vigorously. The reaction vessel was heated with an oil bath to 65–70 °C, before Diazald (1.07 g, 5.0 mmol) in Et2O (12 mL) was added slowly over a period of 15 min. Diazomethane and Et2O started to collect immediately. After the addition was complete, another portion of Et2O (5 mL) was added and allowed to distill over. This step was repeated until the distillate was colorless. Upon completion of the distillation, the solution in receiver flask was stirred for additional 15 min. The reaction mixture was filtered through Celite and concentrated. Purification of the residue by silica gel chromatography (Hexanes/EtOAc) afforded the cyclopropanated product. Spectral data of 7a (white solid): mp: 83–85 °C; 1H NMR (600 MHz, CDCl3) δ 4.76 (m, 1H), 4.54 (m, 1H), 1.53 (d, J=11.4 Hz, 1H), 1.49 (s, 9H), 1.37–1.44 (m, 3H), 0.36–0.38 (m, 1H), 0.31–0.35 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 157.9, 82.0, 80.8, 61.0, 28.4, 27.8, 14.0, 13.0, 4.3; HRMS (FAB) calcd. for C11H17NNaO3 (M+Na)+: 234.1101, found 234.1126.
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21. Spectral data of 13 (white solid): mp: 211 °C (dec.); 1H NMR (600 MHz, CD3OD) δ 8.54 (s, 1H), 8.21 (s, 1H), 5.03 (d, J=7.3 Hz, 1H), 4.35 (d, J=5.3 Hz, 1H), 2.18–2.23 (m, 1H), 1.79–1.89 (m, 3H), 0.76–0.80 (m, 1H), 0.25–0.27 (m, 1H); 13C NMR (150 MHz, CD3OD) δ 157.4, 153.4, 150.2, 142.7, 120.2, 74.0, 57.4, 40.5, 27.5, 23.8, 7.5; HRMS (FAB) calcd. for C11H14N5O (M+H)+: 232.1193, found 232.1202.