Synthesis and Functionalization of 4-Aminocyclopentenones

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Exploring Pharmaceutical Applications of 4-aminocyclopentenones SYNTHESIS AND FUNCTIONALIZATION OF 4-AMINOCYCLOPENTENONES

Alex Huszagh1, Donald Wenz2, and Javier Read del Alaniz3

Due to the degradation of proteins by enzyme the heterocyclic oxygen followed by a cascade reaction catalysis, synthetic amino acids provide a ending in a conrotatory 4π electron cyclization which method to improve the longevity of protein does not typically cause product isomerization. drugs. We propose a mechanistic pathway to Although the aza-Piancatelli reaction was previously produce a variable alkynamide scaffold as an limited by basic interactions to the Lewis acid catalyst, intermediate in amino acid synthesis that eliminating electron rich amines as potential proceeds via the fragmentation of 4- nucleophiles, lanthanide salts catalyze these aminocyclopentenones. These cyclopentenones rearrangements in the presence of mildly basic amines are frequently found in biologically active (particularly anilines) (2). molecules with burgeoning varying Since 5-aryl 2-furylcarbinol synthesis occurs in high methodologies for their synthesis. Synthetic yield by a 1,2 nucleophilic addition to furfural (a low methodologies now include the use of low cost, cost renewable agricultural byproduct), we have focused renewable starting materials in the aza- on potential applications of these 5-substituted Piancatelli rearrangement, which ends in a 4π furylcarbinols. Our methodology has been extended to Nazarov cyclization. These rearrangements account for disubstitution at the 5 position, increasing afford 5-substituted 4-aminocyclopentenones in the potential variability in cyclopentone structure. This high yields under Lewis acidic catalytic 4-aminocyclopentenone scaffold mirrors those found in conditions with a 2-furylcarbinol; these 2- certain carbocyclic nucleosides with anti-retroviral furylcarbinols can be synthesized in high yield properties (3), showing the potential of the Aza- by nucleophilic addition to furfural, an Piancatelli rearrangement in the synthesis of agricultural byproduct. By epoxidizing the pharmaceuticals. double bond and proceeding with an We hypothesize that cleaving the olefin in 5,5-diaryl Eschenmoser-Tanabe fragmentation, we propose 4-aminocyclopentenones will produce a useful scaffold that these 4,5-substituted cyclopentenones could by creating a 5 carbon main chain with defined relative form short 5 carbon chain molecules with stereochemistry at adjacent carbons. This variability is substituted carbons 4,5 in the center, useful as further increased by the transposition of the enone possible intermediates in pharmaceutical functional group through the creation of an α,β synthesis. We predict the fragmentation epoxyenone. This epoxyenone undergoes Wharton’s products to be racemic in this instance owing to transposition to afford a 2° allylic alcohol which is then the undefined stereochemistry following the 4π oxidized to re-afford an enone (4). Crucially, through electro cyclization. Via an enone transposition, this methodology we can synthesize both structural we should be able to access all racemic isomers isomers with what we hope will have strong anti- of our 4,5 aryl- amino- compounds. In other diasteroselectivity, allowing for the low cost synthesis substrates, the trans- selectivity of the of a wide variety of synthetic amino acids. rearrangement could be partitioned into an anti- EXPERIMENTAL METHODS substituted product. Therefore, we hope to Reactions were monitored for completion through synthesize low cost functionalizable molecules as the use of thin layer chromatography (TLC) and then intermediates in the production of biologically analyzed for purity and identity by 1H NMR active molecules. spectroscopy. INTRODUCTION Aryl addition to the carbonyl in furfural 1 was The prevalence of the cyclopentenone scaffold performed using a Grignard reagent with PhBr 2 and in biologically active molecules makes it an Mg0 3 in THF under a nitrogenated atmosphere (Scheme appealing product of synthetic methodologies. 1). Small quantities of I2 were added to reduce the Previously, we have synthesized substituted exterior Mg2+ into Mg0 3. Upon completion, the reaction cyclopentenones from 2-furylcarbinols through an was quenched with NH4Cl. Product was then extracted aza-Piancatelli rearrangement (1). The with ethyl acetate (EtAc) 3x, dried with MgSO4 rearrangement proceeds by an aromatic ring anhydrous and purified using silica column opening dependant on a nucleophilic addition α to

1 Undergraduate student at Macalester College, 1600 Grand Ave., Saint Paul, MN 55105, USA

2 Graduate student at University of California at Santa Barbara. To contact, address to [email protected]

Professor at University of California at Santa Barbara. To contact, address to Javier Read [email protected]

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Exploring Pharmaceutical Applications of 4-aminocyclopentenones chromatography. The product was then NH4Cl, extracted with 3x EtAc, dried with MgSO4 and concentrated under reduced pressure. concentrated under reduced pressure. The resulting 2° alcohol 4 was then oxidized 5 to a ketone in THF by MnO2 6 under a nitrogenated Scheme 3. Formation of an epoxide with H2O2 and a atmosphere (Scheme 1). After completion, the persulfate O solution was filtered to separate MnO2 6 from the O Ph D, H2O2, NaOH Ph product before further workup. This flow through MeOH O Ph Ph R2 2 was then concentrated under reduced pressure. N N R 1 Formation of a 3° 2-furylcarbinol 7 was R R1 8, 1 equiv performed with a 1,2 nucleophilic addition to the 11 O O resulting ketone 5 by another Grignard reaction Bu4N O S O O S O NBu4 with PhBr 2 and Mg0 3 under a nitrogenated 12 O atmosphere with I2 present (Scheme 1). Quenching, O Ph extraction, drying, purification, and concentration Ph Ph all proceeded as previously mentioned. Ph N HN

Scheme 1. Creation of 3° 2-furylcarbinols from 8c 8d furfural O O RESULTS

Mg0 O OH Br Mg Br H 3 (1.5 equiv) 1 (1 equiv) The 3 steps to afford the afford the 4- THF, r.t., 1 hr 2 hrs Ph 4 84% aminocyclopentenone went mostly as previously noted, 2 (1.2 equiv) with high yields noted for each step (Scheme 1, Scheme

DCM MnO2 2). However, dehydration of the 2-furylcarbinols in the r.t., 10 hrs 6 (6 equiv) presence of acid proved detrimental to their synthesis

O O (Scheme 4), and the resulting impurity was visible by

Ph TLC and 1H NMR spectra, particularly due to the Mg0 5 73% OH Br Mg Br O 3 (1.5 equiv) (1 equiv) Phirreversible polymerization of these carbocations. THF, r.t., 1 hr 2 hrs Ph 2 (1.2 equiv) 7 67%

To produce a 4-aminocyclopentenone 8, 1 Scheme 4. Dehydration of 2-furylcarbinols R equivalent of an aniline 9 was added to a flask R Ph Ph R Ph H+ (LA) O O O containing furan-2-yldiphenylmethanol 7 in the H2O HO H2O solvent. This solution was placed in a pre-heated oil 4 or 7 R = H, Ph bath followed by the addition of Dy(OTf)3 10 (Scheme 2). The rearrangement occurred with 4 Selection of ideal reaction conditions for the aza- differing anilines. Upon completion, the reaction Piancatelli rearrangement was done varying the was quenched with NH4Cl, extracted 3x with EtAc, temperature and mol% of Dy(OTf)3 10. Synthesis of dried with MgSO4, and concentrated under reduced 5,5-diphenyl 4-aminocyclopentenones proved difficult pressure. with N-methylaniline (produces 8a), with a balance between reaction rate and purity. At 40°C, the reaction Scheme 2. Formation of 4- was not complete after 3 days, however, the purity was aminocyclopentenones by the aza-Piancatelli noted by both TLC and 1H NMR spectra. At 80°C, the rearrangement reaction was complete within 5 hours, however, TLC O H O OH N Ph and NMR spectra showed the production of numerous 1 10 Dy(OTf)3 (5 mol%) Ph R 2 Ph + R MeCN, 80°C Ph impurities inseparable based on Rf values. Similar 2 7 (1 equiv) 9 (1 equiv) N R results were noted at 60°C, the reaction completed R1 8 quickly but TLC and NMR spectra noted numerous O O O O impurities with similar Rf values. Ph Ph Ph Ph Ph Ph Ph Ph Therefore, p-iodoaniline (produces 8b) was selected HN N HN N owing to the electron withdrawing group para to the 1° I aniline which should increase the reaction rate. The 8a 5 hrs 8b < 1 hr 8c 40% 8d 89% 2 days 2 hrs reaction reached completion within 1 hour, however, To epoxidize and form an epoxyenone 11, some impurities were noted and so the reaction was cyclopentenone 8 underwent an epoxidation in the abandoned. presence of hydrogen peroxide, NaOH and an 1,2,3,4-tetrahydroquinoline (produces 8c) was organic catalyst 12 (5). This epoxidation was selected with the goal of forming a 3° amine in high attempted with both 8c and 8d. Workup was with yield. However, the reaction took 2 days to finish and

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Exploring Pharmaceutical Applications of 4-aminocyclopentenones had only a 40.4% yield. Due to the slow nature of alcohol to an olefin. Through an oxidation of the 2° the reaction and the unexpected low yields, 1,2,3,4- alcohol 12, we should produce a structural isomer 13 of tetrahydroquinoline was abandoned as an aniline. our initial cyclopentenone 8 (Scheme 6). However, reaction conditions for the epoxidation have proven We then chose another 1° aniline, aniline difficult. Oxidation of the amine to form an amine oxide (produces 8d), to note the reaction time and purity. is suspected to occur, which could be prevented Although aniline finished in 2 hours, somewhat primarily with a protecting group forming a tertiary slower than -iodoaniline, the purified yield amine. reached 89%. Upon scaling up, the reaction rate and yield stayed identical, signifying anilines potential Scheme 6. Wharton’s Transposition in the production of 4-aminocyclopentenones. O O Ph H2O2 Ph Additionally, base washed glassware during the Ph NaOH O Ph MeOH aza-Piancatelli rearrangement finished faster, in N N H H comparison with acid washed glassware, the latter 8 11 which finished in approximately 3 hours. H2NNH2 MeOH AcOH Significantly, the epoxidation conditions to Ph Ph form 11 resulted in the suspected formation of Ph Ph O MnO2 HO amine oxides. NMR data showed that the –enone N DCM N functional group remained, however, chemical H H 13 12 shifts occurred for many hydrogens. Further With our two cyclopentenones 8 and 13, we hope to evidence of amine oxide formation occurred while synthesize these structural isomers 14a and 14b with using a 3° 4-aminocyclopentenone 8c created a using the Eschenmoser Tanabe Fragmentation (6) more polar molecule, resulting in a lower R value f (Scheme 7). Although currently racemic, we hope to as well as a similar NMR spectra. further functionalize these alkynamides to separate the DISCUSSION enantiomers so that they may be used as intermediates in Our research suggests that 1° amines have a pharmaceutical synthesis. faster reaction rate than 2° amines in the aza- Piancatelli rearrangement, suggesting that the Scheme 7. Eschenmoser Tanabe Fragmentation O sterics play a substantial role in the nuceleophilic Ph Ph addition of the aniline 9 to the conjugated  system Ph Ph O (Scheme 5). N N H H 8 13 Scheme 5. Current Mechanism of the aza- H2O2 MeOH H2O2 MeOH Piancatelli Reaction NaOH NaOH R Ar N O H O Ph Ph Ph Ph Ph 9 Ph Ph Ar Ph H+ (LA) O Ph Ph O O NH O N O O HO H2O Ph Ph H 7 R Ar R N N H H 11 HO HO HO O

R TsNHNH2 EtOH TsNHNH2 EtOH Ph Ph Ph N Ph R Ph R Ph N R Ph N Ph N Ar Ar Ar Ar Ph Ph O 8 H H N O I hope to functionalize these 4- N H H aminocyclopentenones through further reactions to Ph Ph create small alkynamides. We hypothesize that a 14a 14b Wharton’s transposition (4) (Scheme 6) could transpose the –enone functional group through an epoxidation 11 and elimination 12 to afford a 

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REFERENCES

(1) Veits, GK; Wenz, DR; Read de Alaniz, J. Angewandte Chemie (International ed. in English). 2010, 49, 9484.

(2) Gibson, SE and Mainolfi, N. Angewandte Chemie. 2005, 117, 3082.

(3) Huang, W. 2007. Synthetic studies on carbocylic nucleosides. Ph.D. Thesis, University of Notre Dame, Notre Dame, 217 pp

(4) Barrero, AF; Cortés, M; Manzaneda, EA; Cabrera, E; Chahboun, R; Lara, Rivas, AR. J. Nat. Prod. 1999, 62, 1488.

(5) Hwang, JP and Yang, SG. Tetrahedron Letters. 1997, 38, 3009.

(6) Trost, BM; Chang, VK. Synthesis. 1993, 1993, 824

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This research was partially supported by the RISE internship program through the UCSB Materials Research

Laboratory Award No. DMR -1121053