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DOI: 10.1055/s-0036-1591755
Aldol Condensations on a 3-Alkylidene-2,5-diketopiperazine: Synthesis of Two Marine Natural Products
This research was financially supported by UiT – The Artic University of Norway, the University of Bergen and the Norwegian Research Council (grant no. 224790/O30)Publication History
Received: 30 October 2017
Accepted after revision: 30 December 2017
Publication Date:
30 January 2018 (online)
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Published as part of the Special Section 9th EuCheMS Organic Division Young Investigator Workshop
This work is dedicated to Prof. Leiv K. Sydnes on the occasion of his 70th birthday.
Abstract
The synthesis of two marine natural products containing a 3-alkylidene-6-arylidene-2,5-diketopiperazine scaffold by employing two consecutive aldol condensations starting with 1,4-diacetyl-2,5-diketopiperazine is reported. The target compounds contain a phenol or an imidazole group as aryl substituents, respectively, and suitable conditions for the aldol condensation of 1-acyl-3-alkylidene-2,5-diketopiperazine with the required functionalised aromatic aldehydes were developed. Provided the optimal base was used, introduction of the phenol group did not require use of a protecting group. Boc-protection was beneficial for introduction of the imidazole group, and conditions for carrying out the aldol condensation and Boc-deprotection in one step were identified. The stereochemistry of the target compounds was confirmed by NMR analysis.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0036-1591755.
- Supporting Information
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References and Notes
- 1 New address: Department of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, NO-5007 Bergen, Norway.
- 2a Martins MB. Carvalho I. Tetrahedron 2007; 63: 9923
- 2b Huang R. Zhou X. Xu T. Yang X. Liu Y. Chem. Biodivers. 2010; 7: 2809
- 2c Borthwick AD. Chem. Rev. 2012; 112: 3641
- 2d Huang R.-M. Yi X.-X. Zhou Y. Su X. Peng Y. Gao C.-H. Mar. Drugs 2014; 12: 6213
- 3 Kanoh K. Kohno S. Asari T. Harada T. Katada J. Muramatsu M. Kawashima H. Sekiya H. Uno I. Bioorg. Med. Chem. Lett. 1997; 7: 2847
- 4 Nicholson B. Lloyd GK. Miller BR. Palladino MA. Kiso Y. Hayashi Y. Neuteboom ST. C. Anticancer Drugs 2006; 17: 25
- 5 Brooks TD. Wang SW. Brünner N. Charlton PA. Anticancer Drugs 2004; 15: 37
- 6a Yamazaki Y. Tanaka K. Nicholson B. Deyanat-Yazdi G. Potts B. Yoshida T. Oda A. Kitagawa T. Orikasa S. Kiso Y. Yasui H. Akamatsu M. Chinen T. Usui T. Shinozaki Y. Yakushiji F. Miller BR. Neuteboom S. Palladino M. Kanoh K. Lloyd GK. Hayashi Y. J. Med. Chem. 2012; 55: 1056
- 6b Hayashi Y. Takeno H. Chinen T. Muguruma K. Okuyama K. Taguchi A. Takayama K. Yakushiji F. Miura M. Usui T. Hayashi Y. ACS Med. Chem. Lett. 2014; 5: 1094
- 6c Liao S. Qin X. Li D. Tu Z. Li J. Zhou X. Wang J. Yang B. Lin X. Liu J. Yang X. Liu Y. Eur. J. Med. Chem. 2014; 83: 236
- 6d Liao S.-R. Du L.-J. Qin X.-C. Xu L. Wang J.-F. Zhou X.-F. Tu Z.-C. Li J. Liu Y.-H. Tetrahedron 2016; 72: 1051
- 7a Shin CG. Nakajima Y. Haga T. Sato Y. Bull. Chem. Soc. Jpn. 1986; 59: 3917
- 7b Shin CC. i. Chigira Y. Masaki M. Ohta M. Tetrahedron Lett. 1967; 4601
- 7c Shin C.-G. Sato K. Ohtsuka A. Mikami K. Yoshimura J. Bull. Chem. Soc. Jpn. 1973; 46: 3876
- 7d Gallina C. Liberatori A. Tetrahedron 1974; 30: 667
- 7e Villemin D. Alloum AB. Synth. Commun. 1990; 20: 3325
- 7f Du Z. Zhou X. Shi Y. Hu H. Chin. J. Chem. 1992; 10: 82
- 7g Nohara S. Sawaki K. Yanase E. Nakatsuka S.-I. ITE Lett. Batteries, New Technol. Med. 2004; 5: 373
- 7h Liao S.-R. Qin X.-C. Wang Z. Li D. Xu L. Li J.-S. Tu Z.-C. Liu Y. Eur. J. Med. Chem. 2016; 121: 500
- 8a Aoyagi H. Horike F. Nakagawa A. Yokote S. Park N. Hashimoto Y. Kato T. Izumiya N. Bull. Chem. Soc. Jpn. 1986; 59: 323
- 8b Park NG. Lee S. Maeda H. Aoyagi H. Kato T. Bull. Chem. Soc. Jpn. 1989; 62: 2315
- 8c Jin S. Wessig P. Liebscher J. Eur. J. Org. Chem. 2000; 1993
- 8d Loughlin WA. Marshall RL. Carreiro A. Elson KE. Bioorg. Med. Chem. Lett. 2000; 10: 91
- 8e Leeming P. Fronczek FR. Ager DJ. Laneman SA. Top. Catal. 2000; 13: 175
- 8f Oba M. Ishihara T. Satake H. Nishiyama K. J. Labelled Compd. Radiopharm. 2002; 45: 619
- 8g Davies SG. Rodríguez-Solla H. Tamayo JA. Cowley AR. Concellón C. Garner AC. Parkes AL. Smith AD. Org. Biomol. Chem. 2005; 3: 1435
- 8h Balducci D. Conway PA. Sapuppo G. Müller-Bunz H. Paradisi F. Tetrahedron 2012; 68: 7374
- 8i Kelley EW. Norman SG. Scheerer JR. Org. Biomol. Chem. 2017; 15: 8634
- 9 Lieberknecht A. Griesser H. Tetrahedron Lett. 1987; 28: 4275
- 10 Wang P. Xi L. Liu P. Wang Y. Wang W. Huang Y. Zhu W. Mar. Drugs 2013; 11: 1035
- 11 Khokhlov AS. Lokshin GB. Tetrahedron Lett. 1963; 1881
- 12 Folkes A. Roe MB. Sohal S. Golec J. Faint R. Brooks T. Charlton P. Bioorg. Med. Chem. Lett. 2001; 11: 2589
- 13 Experimental procedure and characterization data for 6 are in accordance with reference 6d.
- 14 Experimental procedure for the condensation of 6 with 4-hydroxybenzaldehyde: Compound 6 (100 mg, 0.5 mmol), 4-hydroxybenzaldehyde (58 mg, 0.5 mmol) and Cs2CO3 (163 mg, 0.5 mmol) were mixed in anhydrous degassed DMF (3 mL) and the reaction mixture was stirred at 80 °C for 6 h. After cooling to room temperature, crushed ice was added and the resulting white precipitate was isolated by filtration and washed with water. The solid material was dried in vacuo to give the title compound (57 mg, 42%) as a white solid. Characterisation data for 3 are in accordance with reference 9. See the Supporting Information for comparison. 1H NMR (400 MHz, DMSO-d 6): δ = 10.24 (s, 1 H), 9.80 (s, 1 H), 9.78 (s, 1 H), 7.36 (d, J = 8.6 Hz, 2 H), 6.79 (d, J = 8.6 Hz, 2 H), 6.67 (s, 1 H), 5.67 (d, J = 10.4 Hz, 1 H), 2.94 (dhept, J = 10.4, 6.5 Hz, 1 H), 0.97 (d, J = 6.5 Hz, 7 H); 13C NMR (101 MHz, DMSO-d 6): δ = 158.1, 157.6, 157.6, 131.0, 125.4, 125.1, 124.01, 123.96, 115.6, 115.1, 23.9, 22.3. HRMS (ESI): m/z [M+Na]+ calcd for C15H16N2O3Na+: 295.1053; found: 295.1057.
- 15 Experimental procedure for the condensation of 6 with N-Boc-protected imidazole-5-carbaldehyde: Compound 6 (168 mg, 0.8 mmol), N-Boc imidazole-5-carbaldehyde (392 mg, 2.0 mmol), t-BuOK (185 mg, 1.65 mmol) and t-BuOH (1.7 mL) were added to a dried round-bottomed flask. The flask was evacuated, back-filled with argon and sealed with a septum before anhydrous DMF (6 mL) was added. The mixture was stirred at 80 °C for 8 h and then cooled to room temperature before the reaction mixture was partitioned between ethyl acetate (15 mL) and saturated aqueous NH4Cl (15 mL). The aqueous layer was extracted further with ethyl acetate (2 × 15 mL) before the combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo until ca. 1 mL of an oily residue remained (containing residual DMF). The oily residue was purified by flash column chromatography, eluting with EtOAc, to give the title compound as a pale-yellow amorphous solid (116 mg, 59%). Rf = 0.58 (EtOAc). Characterisation data for 4 are in accordance with reference 9. See the Supporting Information for comparison. 1H NMR (500 MHz, DMSO-d6): δ = 12.60 (s, 1 H), 11.73 (s, 1 H), 10.18 (s, 1 H), 7.95 (s, 1 H), 7.52 (s, 1 H), 6.60 (s, 1 H), 5.69 (d, J = 10.4 Hz, 1 H), 2.96 (dhept, J = 10.4, 6.5 Hz, 1 H), 0.97 (d, J = 6.5 Hz, 6 H); 13C NMR (126 MHz, DMSO-d 6): δ = 157.3, 156.2, 136.5, 136.5, 125.4, 124.9, 124.7, 119.2, 104.4, 23.8, 22.2. HRMS (ESI): m/z [M – H]– calcd for C12H13N4O2 –: 245.1044; found: 245.1041.
- 16 Use of 1.8 equiv of t-BuOK gave an estimated 1:0.6 ratio of 4 and deacetylated 6 in the crude product.
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