Aldol Condensations on a 3-Alkylidene-2,5-diketopiperazine: Synthesis of Two Marine Natural Products

Magnus E. Fairhurst; Muhammad Zeeshan; Bengt Erik Haug; Annette Bayer

doi:10.1055/s-0036-1591755

Synlett, Inhaltsverzeichnis

Synlett 2018; 29(10): 1303-1306
DOI: 10.1055/s-0036-1591755

letter

Aldol Condensations on a 3-Alkylidene-2,5-diketopiperazine: Synthesis of Two Marine Natural Products

Magnus E. Fairhurst

^aDepartment of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, 5007 Bergen, Norway eMail: bengt-erik.haug@uib.no

,

Muhammad Zeeshan

^bDepartment of Chemistry, UiT – The Arctic University of Norway, Breivika, 9037 Tromsø, Norway eMail: annette.bayer@uit.no

,

Bengt Erik Haug

^aDepartment of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, 5007 Bergen, Norway eMail: bengt-erik.haug@uib.no

,

Annette Bayer

^bDepartment of Chemistry, UiT – The Arctic University of Norway, Breivika, 9037 Tromsø, Norway eMail: annette.bayer@uit.no

› Institutsangaben

Abstract

Alle Artikel dieser Rubrik

Published as part of the Special Section 9^th 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.

Key words

2,5-diketopiperazine - natural product - total synthesis - aldol condensation

Volltext

Referenzen

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

For some examples, see:

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%). R_f = 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.

Zusatzmaterial

Supporting Information