Direct Access to Highly Functionalized Heterocycles through the

Department of Chemistry, College of Sciences, North Carolina State University, Raleigh, North Carolina 27695, United States. J. Org. Chem. , 2017, 82 ...
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Direct Access to Highly Functionalized Heterocycles through the Condensation of Cyclic Imines and α‑Oxoesters Alexander Q. Cusumano, Matthew W. Boudreau, and Joshua G. Pierce* Department of Chemistry, College of Sciences, North Carolina State University, Raleigh, North Carolina 27695, United States S Supporting Information *

ABSTRACT: A facile, gram-scale preparation of 2-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-3-ones and 2-hydroxy-6,7,8,8atetrahydroindolizin-3(5H)-ones from a condensation cyclization of α-oxoesters with five- and six-membered cyclic imines, respectively, is reported. This transformation enables a concise, three-step synthesis of the natural products phenopyrrozin and phydroxyphenopyrrozin. Further, biologically relevant scaffolds, such as α-quaternary β-homo prolines and β-lactams, are also prepared in two- to three-steps from the versatile 2-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-3-one core.

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wing to a broad prevalence in natural products and pharmaceutical agents, nitrogen-containing heterocycles are highly sought-after motifs. Advances in synthetic methodology to access such scaffolds are directly related to our ability to investigate biological processes and treat human disease. Isolated in 1995 and 2005 from the marine fungus Chromocleista sp., phenopyrrozin1 and p-hydroxyphenopyrrozin2 are marine alkaloids containing the 2-hydroxy-5,6,7,7atetrahydro-3H-pyrrolizin-3-one core. Both compounds have been reported to possess moderate antimalarial and antituberculosis activity.3 To date, the only reported synthesis of phenopyrrozin and p-hydroxyphenopyrrozin is that of Kothapalli and co-workers, accessing the natural products from proline in 8 and 11 steps, with 4.7% and 5.8% overall yields, respectively (Figure 1a).4 Previously, we reported a facile multicomponent reaction, in which in situ generated imines undergo cyclization with αoxoesters to yield the 3-hydroxy-1,5-dihydro-2H-pyrrol-2-one core.5 These reactions are carried out at room temperature in aprotic solvents (Figure 1b). Building upon this work, and expanding our program directed toward the synthesis of nitrogen heterocycles,5 we envisioned a concise and general approach to the 2-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-3one and 2-hydroxy-6,7,8,8a-tetrahydroindolizin-3(5H)-one scaffolds from the condensation-cyclization of 1-pyrroline and 2,3,4,5-tetrahydropyridine, respectively, with α-oxoesters (Figure 1c). Surprisingly, under our previously reported conditions, 1pyrroline does not condense with methyl phenylpyruvate to form phenopyrrozin (3a) as expected, but rather undergoes a rapid di-addition to compound 9 (Scheme 1a). Interestingly, 9 is formed as a single diastereomer, and the relative configuration was confirmed by a 1H−1H NOSEY experiment. When performed in both polar and nonpolar aprotic solvents, 9 © 2017 American Chemical Society

Figure 1. (a) Previous synthesis of phenopyrrozin and phydroxyphenopyrrozin. (b) Our previous investigations into the reactivity of in situ generated imines toward α-oxoacid chlorides and α-oxoesters. (c) This work.

is readily furnished, while only traces of 3a are observed. In contrast, when the reaction is carried out in polar protic solvents (EtOH, MeOH, MeOH/H2O), the desired product 3 can be isolated in good yield. It is worth mentioning that polar protic and/or aqueous conditions do not inhibit the rapid formation of 9, but rather facilitate its conversion to 3. This surprising reactivity was observed across all substrates, for both five- and six-membered imines. Received: October 10, 2017 Published: December 5, 2017 13714

DOI: 10.1021/acs.joc.7b02572 J. Org. Chem. 2017, 82, 13714−13721

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The Journal of Organic Chemistry

unsuccessful with the di-addition to 9 prevailing regardless of concentration, order of addition, and stoichiometry. Similar to our previous work is the rapid rate at which reaction occurs, favoring electron-poor α-oxoesters and electron-rich imines.5 We propose such reactivity arises from an initial acid−base reaction between the basic imine and enol moiety of the α-oxoesters, generating an iminium and enolate ion pair, followed by addition of the enolate to the iminium ion, ring closure, and loss of methanol to yield 3. In the case of cyclic imines, the addition of a second imine occurs before ring closure and condenses with the α-keto moiety of the αoxoesters to yield 9. To explore the substrate scope of this reaction, a variety of heterocycles with the general structure 3 have been prepared from the respective α-oxoester and cyclic imine (Scheme 2). 1Pyrroline,6 2,3,4,5-tetrahydropyridine,7a,b and α-oxoesters9 were prepared in accordance with literature procedures. Previous reports note the instability of the 3-hydroxy-1,5dihydro-2H-pyrrol-2-one moiety to silica gel.6,10 As such, we were pleased to find the 5:1 methanol/water solvent system allowed for isolation of products by filtration. To this end, phenopyrrozin (3a) and p-hydroxyphenopyrrozin (3b) were isolated in 69% and 55% yields, respectively (Scheme 2). Both 1-pyrroline and phenylpyruvate ester starting materials are prepared in one step each in quantitative yield or are commercially available; hence, the natural products were synthesized in 3 steps with 69% and 55% overall yields. 1-Pyrroline was then reacted with a variety of electron-rich and electron-poor aromatic pyruvate esters, providing 3c−3g in high purity and good yields. Our method is also successful for aliphatic-substituted pyruvate esters, providing 3h and 3i; however, to prevent depreciation of yields, these derivatives were isolated as their TBS ethers 4h and 4i, respectively, before purification by silica gel column chromatography (Scheme 2). The reaction also performs well for six-membered imines, providing 3j−3n (Scheme 2) in good yields. Unfortunately, unsubstituted product 3o, arising from methyl pyruvate, was not isolated under our optimized conditions. We next envisioned leveraging the innate functionality of 3 as a viable platform from which unique, biologically relevant scaffolds may be accessed. One such example is an operationally simple, two- to three-step conversion of 3 to α-quaternary center-containing β-homo prolines (7) and bicyclic β-lactams (8). When subjected to standard Tsuji−Trost allylation conditions (Pd-allyl chloride dimer catalyst, rac-BINAP ligand, and base), 2-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-3-ones readily yield the tetrahydro-1H-pyrrolizine-2,3-dione scaffold (5) (Figure 2).11 For substrates 5a, 5g, and 5e, the reaction proceeded in good yields and 3:1 to 4:1 diastereomeric ratios, and the diastereomers were separable by column chromatography. Alkyl-substituted 3i did not function as well in this reaction, with 5i isolated in 20% yield. Oxidative ring opening of the pyrrolizine-2,3-dione scaffolds was achieved by subjecting 5 to 1 M NaOH in 30% hydrogen

Scheme 1. (a) Unexpected Reactivity of 1-Pyrroline with Methyl Phenylpyruvate to 9 under Aprotic Conditions and to Phenopyrrozin (3a) in 5:1 MeOH/H2O and (b) Equilibrium between Monomeric Imine and Trimer

Although initially unforeseen, this reactivity is supported by the fact that both 1-pyrroline and 2,3,4,5-tetrahydropyridine are known to exist in equilibrium between the monomeric imine and a 1,3,5-triazinane trimer,6,7 thus, demonstrating a similar intermolecular head-to-tail interaction between cyclic imines as is observed here (Scheme 1b). Recently, Cui and co-workers reported a similar [2+2+2] addition of 3,4-dihydrocarboline imine to ynones.8 In addition to aiding in hydrolysis of 9, we further attribute the high yields of the 5:1 MeOH/H2O solvent system (Scheme 2) to the poor solubility of 3 in aqueous methanol, which Scheme 2. Substrate Scope of α-Oxoester and Cyclic Imine Condensation to Scaffold 3

precipitates as the reaction progresses, thus, driving forward the proposed equilibrium between 9 and 3. This is supported by the observation that as the reaction progresses in 5:1 MeOH/ H2O, the ratio of 9 to 3 in solution remains relatively constant. As expected, the use of aqueous/organic solvent systems, such as DMF/H2O and THF/H2O, in which 3 is soluble, also results in poor conversion. All attempts to disfavor formation of 9 were

Figure 2. Tsuji−Trost allylation of 3. 13715

DOI: 10.1021/acs.joc.7b02572 J. Org. Chem. 2017, 82, 13714−13721

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The Journal of Organic Chemistry peroxide,12 followed by in situ protection of the resultant amino acid with Boc-anhydride to yield β-homo proline 7. Boc protection of the nitrogen enabled the amino acids to be purified readily by normal phase column chromatography, where as the nonprotected amino acids proved to be difficult to purify. The N-Boc amino acids (7a, 7e, 7g) were then able to be converted directly into their corresponding β-lactams in a onepot, two-step deprotection cyclization (Scheme 3). Treatment

in toluene for 24−48 h. With substrate 5i in hand, we then planned a ring-closing metathesis (RCM) to 6i, introducing an α-quaternary spiro-cyclic center. Employing the secondgeneration Grubbs’ catalyst in refluxing DCM, 6i was prepared in 79% yield. As previously described, pyrrolizine-2,3-dione 6i was converted to β-homo proline 7i by oxidative ring opening and subsequently 8i via deprotection and ring closure (Scheme 4). Given the prevalence of β-lactams in infectious disease related therapeutics, as either β-lactam antibiotics (BLAs) or antibiotic adjuvants, scaffolds such as 8 provide an exciting platform from which unique, α-quaternary center-containing βlactams may be accessed. In summary, we have developed a facile method to access 2hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-3-ones and 2-hydroxy-6,7,8,8a-tetrahydroindo-lizin-3(5H)-ones from the condensation of α-oxoesters with five- and six-membered cyclic imines. This method provides direct access to the natural products phenopyrrozin and p-hydroxyphenopyrrozin in a three-step synthesis. Additionally, the unique reactivity of cyclic imines was explored in the case of compound 9. Furthermore, we provide a two- to three-step, operationally simple route to biologically relevant β-homo prolines and β-lactams from the 3hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-3-one scaffold.

Scheme 3. Conversion of 5 to β-Homo Prolines (7) and Bicyclic β-Lactams (8)

of 7 with TFA/DCM (1:1) removed the Boc group, revealing the deprotected amino acid. The β-amino acids were then cyclized with EDC to provide β-lactams 8a, 8e, and 8g.13 Additionally, it was found that the in situ generation of the acid chloride of 7a resulted in intramolecular cyclization to the β-amino acid N-carboxyanhydride (NCA) (10, Scheme 3). This observation is in agreement with previous literature accounts of the synthesis of NCAs.14 Over the past decade, NCAs have gained popularity for their applications in ROP peptide coupling, which has seen utility in the synthesis of biomaterials,15 functionalized peptides,16 and pharmaceuticals.17 This further exemplifies the value of synthetic approaches to functionalized β-amino acids. In an effort to further expand the scope of the β-lactam synthesis to include spiro-cyclic systems, a similar approach to access β-lactam 8i was envisioned (Scheme 4); however, poor

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EXPERIMENTAL SECTION

DCM and THF were purified using an alumina filtration system. Reagents were purchased and used as received unless otherwise noted. Reactions were monitored by TLC analysis (precoated silica gel 60 F254 plates, 500 μm layer thickness), and visualization was accomplished with a 254 nm UV light and by staining with a KMnO4 solution (1.5 g of KMnO4, 10 g of K2CO3, and 1.25 mL of a 10% NaOH solution in 200 mL of water) and/or staining with I2 (1 g of I2, 10 g SiO2, dry). Reactions were also monitored by HPLC-MS (2.6 μm C18 50 × 2.10 mm column). Flash chromatography on SiO2 was used to purify the crude reaction mixtures and performed on a flash system utilizing prepacked cartridges and linear gradients. Melting points were determined using a capillary melting point apparatus. Chemical shifts were reported in parts per million with the residual solvent peak spectra run at 300, 400, or 700 MHz and are tabulated as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet, bs = broad singlet, dt = doublet of triplet, tt = triplet of triplet), number of protons, and pulse sequence with a d1 of 0 s unless otherwise noted, and are tabulated by observed peak. High-resolution mass spectra were obtained on an ion trap mass spectrometer using heated electrospray ionization (HESI). All cyclic imines,6,7a,b 2-oxoacids,9b and their methyl esters9a,c−e were prepared according to general procedures previously described in literature. General Procedure for the Synthesis of 2-Hydroxy-5,6,7,7atetrahydro-3H-pyrrolizin-3-ones 3a−3g and 2-Hydroxy6,7,8,8a-tetrahydroindolizin-3(5H)-ones 3j−3n (I). To a stirred suspension of methyl 2-oxoester (1 equiv) in 5:1 MeOH/H2O (0.5 M) under inert atmosphere is added dropwise imine (1 equiv) in 5:1 MeOH/H2O (1.0 M). Stirring is continued at room temperature for 72 h. Upon completion, the product is collected by vacuum filtration and residual solvent is removed in vacuo to yield the title compound.

Scheme 4. Revised Approach to Compounds 7i and 8i

isolated yields of 3i after purification by column chromatography, in conjunction with consistently low yields in the Tsuji− Trost allylation of 3i to 5i, prompted us to investigate an alternative approach to access dione 5i. This revised route consisted of protecting the enol moiety of crude 3i as a vinyl allyl ether, by treatment of 3i with allyl bromide and K2CO3 in acetone. Full conversion was observed in 24 h at room temperature. Interestingly, only O-allylation was observed under these conditions. The vinyl allyl ether then underwent thermal [3 + 3] sigmatropic rearrangement to 5i upon refluxing

(RS)-2-Hydroxy-1-phenyl-5,6,7,7a-tetrahydro-3H-pyrrolizin-3-one (3a). According to general procedure I, methyl-2-hydroxy-3-phenyl acrylate (50 mg, 0.28 mmol) and 1-pyrroline (19 mg, 0.28 mmol) were reacted to yield 3a (42 mg, 69% yield) as a colorless solid. [65% isolated yield (1.56 g) when run on 11.2 mmol scale]: Mp 177−180 13716

DOI: 10.1021/acs.joc.7b02572 J. Org. Chem. 2017, 82, 13714−13721

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The Journal of Organic Chemistry °C. Rf = 0.40 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ = 7.74 (dd, J= 7.6, 0.9 Hz, 2H), 7.40 (m, 2H), 7.28 (dd, J = 7.8, 7.1, 1H), 4.53 (dd, J = 10.6, 5.6 Hz, 1H), 3.56 (m, 1H), 3.40 (m, 1H), 2.43 (m, 1H), 2.35 (m, 2H), 1.28 (m, 1H). 13C NMR (100 MHz, CDCl3): δ = 171.2, 142.4, 132.4, 128.6, 127.6, 126.8, 124.1, 62.6, 41.8, 30.7, 28.5. HRMS (ESI) m/z calcd for C13H14NO2 [M + H]+ 216.1019, found 216.1018.

(RS)-1-(4-Bromophenyl)-2-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-3-one (3e). According to general procedure I, methyl (Z)-3-(4bromophenyl)-2-hydroxyacrylate (50 mg, 0.19 mmol) and 1-pyrroline (13 mg, 0.19 mmol) were reacted to yield 3e (49 mg, 86% yield) as a colorless solid [86% isolated yield (1.97 g) when run on 7.78 mmol scale]: Mp 216−218 °C. 1H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 4.53 (dd, J = 10.8, 5.4 Hz, 1H), 3.57−3.52 (m, 1H), 3.40 (dd, J = 11.3, 8.4 Hz, 1H), 2.44−2.28 (m, 3H), 1.32−1.22 (m, 1H). 13C NMR (100 MHz, CDCl3): δ = 171.1, 143.1, 131.9, 131.4, 128.3, 123.1, 121.6, 62.6, 41.9, 30.8, 28.7. HRMS (ESI) m/z calcd for C13H13NO2Br [M + H]+ 294.0124, found 294.0120.

(RS)-2-Hydroxy-1-(4-hydroxyphenyl)-5,6,7,7a-tetrahydro-3H-pyrrolizin-3-one (3b). According to general procedure I, methyl-2hydroxy-3-phenyl acrylate (50 mg, 0.26 mmol) and 1-pyrroline (18 mg, 0.26 mmol) were reacted to yield 3b (33 mg, 55% yield) as a colorless solid: Mp 214−216 °C. Rf = 0.40 (50% EtOAc/hexanes). 1H NMR (400 MHz, CD3OD): δ = 7.63 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 4.48 (dd, J = 10.5, 5.6 Hz, 1H), 3.42−3.36 (m, 1H), 3.33−3.29 (m, 1H), 2.45−2.38 (m, 1H), 2.34−2.27 (m, 2H), 1.18− 1.08 (m, 1H). 13C NMR (100 MHz, CD3OD): δ = 173.7, 158.3, 142.0, 129.4, 127.4, 125.7, 116.4, 63.8, 42.9, 32.0, 29.3. HRMS (ESI) m/z calcd for C13H14NO3 [M + H]+ 232.0968, found 232.0964.

(RS)-2-Hydroxy-1-(2-nitrophenyl)-5,6,7,7a-tetrahydro-3H-pyrrolizin-3-one (3f). According to general procedure I, methyl (Z)-2hydroxy-3-(2-nitrophenyl)acrylate (mixture of enol and keto tautomer, 50 mg, 0.22 mmol) and 1-pyrroline (18 mg, 0.26 mmol, 1.2 equiv) were reacted to yield 3f (32 mg, 55% yield) as a pale yellow solid: Mp 207−211 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.90 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 4.60 (dd, J = 10.3, 5.5 Hz, 1H), 3.36−3.30 (m, 1H), 3.26−3.22 (m, 1H), 2.28−2.22 (m, 1H), 2.19−2.12 (m, 1H), 2.09− 2.03 (m, 1H), 1.21−1.11 (m, 1H). 13C NMR (100 MHz, DMSO-d6): δ = 169.0, 148.8, 144.7, 132.6, 129.2, 128.3, 126.4, 124.3, 120.0, 61.9, 41.8, 29.3 27.8. HRMS (ESI) m/z calcd for C13H13N2O4 [M + H]+ 261.0870, found 261.0865.

(RS)-2-Hydroxy-1-(4-methoxyphenyl)-5,6,7,7a-tetrahydro-3Hpyrrolizin-3-one (3c). According to general procedure I, methyl (Z)-2hydroxy-3-(4-methoxyphenyl)acrylate (53 mg, 0.25 mmol) and 1pyrroline (18 mg, 0.25 mmol) were reacted to yield 3c (43 mg, 69% yield) as a colorless solid: Mp 187−189 °C. 1H NMR (400 MHz, CDCl3): δ = 8.67 (b, 1H), 7.72 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 4.46 (dd, J = 10.6, 5.5 Hz, 1H), 3.82 (s, 3H), 3.59−3.49 (m, 1H), 3.36 (ddd, J = 11.3, 8.2, 3.1 Hz, 1H), 2.43−2.22 (m, 3H), 1.33− 1.19 (m, 1H). 13C NMR (100 MHz, CDCl3): δ = 171.8, 159.0, 141.0, 128.2, 125.3, 124.7, 114.0, 62.6, 55.3, 41.8, 30.7, 28.5. HRMS (ESI) m/ z calcd for C14H16NO3 [M + H]+ 246.1125, found 246.1124. Trace acetone (