Synthesis of Enantiopure ω-(4-Fluorophenyl)-6,11-Methylene Lipoxin B₄ Methyl Ester

Abstract

The synthesis of Lipoxin B₄ analogues (LXB₄) to gain access to stabilized inflammation-resolving compounds is an active field of research. Focusing on variation and stabilization of the conjugated E,Z,E,E C6–C13 tetraene moiety of natural LXB₄, a methylene bridge introduced between C6 and C11 suppresses any Z/E isomerization of the C8–C9 olefin. Furthermore, rapid ω-oxidation (C20) should be avoided by replacing the C18–C20 segment by an aromatic moiety. Optically active C1–C12 building blocks were accessed from methyl cycloheptatriene-1-carboxylate (C6–C11, C21) and glutaryl chloride (C1–C5) as described earlier. The ω-segment was generated via a five-step sequence starting from 4-arylbutanoic acid. Horner key olefination enabled assembly of the carbon backbone. A final five-step sequence including a chelate Cram reduction of the unsaturated ketone moiety afforded the target ω-aryl 6,11-methylene-LXB₄ methyl ester.

Key words

lipoxin B₄ analogue - convergent total synthesis - Horner olefination - optically active β-ketophosphonate - diastereoselective reduction

Publication History

Received: 21 April 2021

Accepted: 19 May 2021

Accepted Manuscript online:
19 May 2021

Article published online:
15 June 2021

• References

• 1a Serhan CN, Chiang N, Van Dyke TE. Nat. Rev. Immunol. 2008; 8: 349
• 1b Serhan CN. Histochem. Cell Biol. 2004; 122: 305
• 2a Serhan CN. Nature 2014; 510: 92
• 2b Serhan CN, Chiang N, Dalli J. Sem. Immunol. 2015; 27: 200
• 2c Serhan CN, Petasis NA. Chem. Rev. 2011; 111: 5922
• 3a Chiang N, Fredman G, Backhed F, Oh SF, Vickery T, Schmidt BA, Serhan CN. Nature 2012; 484: 524
• 3b Cianci E, Recchiuti A, Trubiani O, Diomede F, Marchisio M, Miscia S, Colas RA, Dalli J, Serhan CN, Romano M. Stem Cells Transl. Med. 2016; 5: 20
• 3c Hu S, Mao-Ying Q.-L, Wang J, Wang Z.-F, Mi W.-L, Wang X.-W, Jiang J.-W, Huang Y.-L, Wu G.-C, Wang Y.-Q. J. Neuroinflamm. 2012; 9: Art. No. 278
• 3d Svensson CI, Zattoni M, Serhan CN. J. Experim. Med. 2007; 294: 245
• 4 Green AR, Freedman C, Tena J, Tourdot BE, Liu B, Holinstat M, Holman TR. Biochemistry 2018; 57: 6726
• 5a Szczuko M, Palma J, Kikut J, Komorniak N, Zietk M. Inflamm. Res. 2020; 69: 869
• 5b Bäck M, Powell WS, Dahlén S.-E, Drazen JM, Evans JF, Serhan CN, Shimizu T, Yokomizu T, Rovati GE. Br. J. Pharmacol. 2014; 171: 3551
• 6a Fierro IM, Serhan CN. Braz. J. Med. Biol. Res. 2001; 34: 555
• 6b Dakin SG, Colas RA, Wheway K, Watkins B, Appleton L, Rees J, Gwilym S, Little C, Dalli J, Carr AJ. Am. J. Pathol. 2019; 189: 2258
• 6c Okada K, Hosooka T, Shinohara M, Ogawa W. Biochem. Biophys. Res. Commun. 2018; 505: 29
• 6d Börgeson E. Cardiovasc. Endocrinol. 2016; 5: 4
• 7a Leblanc Y, Fitzsimmons B, Adams J, Rokach J. Tetrahedron Lett. 1985; 26: 1399
• 7b Corey EJ, Mehrota MM, Su W.-G. Tetrahedron Lett. 1985; 26: 1919
• 7c Nicolaou KC, Webber SE. J. Chem. Soc., Chem. Commun. 1985; 297
• 7d Nicolaou KC, Webber SE. Synthesis 1986; 453
• 7e Morris J, Wishka DG. Tetrahedron Lett. 1986; 27: 803
• 7f Alami M, Crousse B, Linstrumelle G, Mambu L, Larchevêque M. Tetrahedron: Asymmetry 1997; 8: 2949
• 7g Gravier-Pelletier C, Dumas J, Le Merrer Y, Depezay J.-C. Tetrahedron 1992; 48: 2441
• 7h Nicolaou KC, Marron BE, Veale CA, Webber SE, Serhan CN. J. Org. Chem. 1989; 54: 5527
• 7i Alami M, Crousse B, Linstrumelle G, Mambu L, Larcheveque M. Synlett 1993; 217
• 8a Maderna P, Godson C. Br. J. Pharmacol. 2009; 158: 947
• 8b O’Sullivan PT, Vallin KS. A, Shah ST. A, Fakhry J, Maderna P, Scannell M, Sampaio AL. F, Peretti M, Godson C, Guiry PJ. J. Med. Chem. 2007; 50: 5894
• 8c Maddox JF, Colgan SC, Clish CB, Petasis NA, Fokin VV, Serhan CN. FASEB J. 1998; 12: 487
• 9a Mizukami Y, Sumimoto H, Isobe R, Minakami S, Takeshige K. Eur. J. Biochem. 1994; 224: 959
• 9b Mizukami Y, Sumitomo H, Isobe R, Minakami S. Biochim. Biophys. Acta 1993; 1168: 87
• 9c Boucher JL, Delaforge M, Mansuy D. Biochem. Biophys. Res. Commun. 1991; 177: 134
• 10a Bannenberg GL. Expert Opin. Ther. Patents 2007; 17: 591
• 10b Van Dyke TE, Petasis NA, Serhan CN. PCT US 7812054 B2, 2010
• 10c Van Dyke TE, Petasis NA, Serhan CN. PCT US 2009311201 A1, 2009
• 10d Van Dyke TE, Petasis NA, Serhan CN. PCT Int. Appl. WO 0170664 A2, 2001
• 10e Van Dyke TE, Petasis NA, Serhan CN. PCT US 2004019110 A1, 2004
• 11a Trippe L, Nava A, Frank A, Nubbemeyer U. Eur. J. Org. Chem. 2021; 1156
• 11b For a stabilization of the tetraene moiety, benzo LXA₄ and LXB₄ analogues had been introduced.
• 11c For a review, see: Duffy CD, Guiry PJ. Med. Chem. Commun. 2010; 1: 249
• 12 Nava A, Trippe L, Frank A, Andernach L, Opatz T, Nubbemeyer U. Synlett 2021; 32: 45
• 13 Corey EJ, Kwiatkowski T. J. Am. Chem. Soc. 1966; 88: 5654
• 14a Davis FA, Chattopadhyay S, Towson JC, Lal S, Reddy T. J. Org. Chem. 1988; 53: 2087
• 14b Evans DA, Morissey MM, Dorow RL. J. Am. Chem. Soc. 1985; 107: 4346

4-(4-Fluorophenyl)butyric acid:
• 15a Duhamel T, Muniz K. Chem. Commun. 2019; 55: 933
• 15b Jung H.-Y, Chang S, Hong S. Org. Lett. 2019; 21: 7099

4-(4-Fluorophenyl)-3-butenoic acid:
• 16a Drikermann D, Mößel RS, Al-Jammal WK, Vilotijevic I. Org. Lett. 2020; 22: 1091
• 16b Drikermann D, Görls H, Kerndl V, Vilotijevic I. Synlett 2020; 31: 1158
• 16c Yu K, Miao B, Wang W, Zakarian A. Org. Lett. 2019; 21: 1930
• 16d Specklin S, Fenneteau J, Subramanian P, Cossy J. Chem. Eur. J. 2018; 24: 332
• 16e Shim SY, Cho SM, Venkatesvarlu A, Ryu DH. Angew. Chem. Int. Ed. 2017; 56: 8663
• 16f Zhang M, Yu S, Hu F, Liao Y, Liao L, Xu X, Yuan W, Zhang X. Chem. Commun. 2016; 52: 8757
• 16g Hajra S, Akhtar SM. S, Aziz SM. Chem. Commun. 2014; 50: 6913
• 16h Thibonnet J, Abrabri M, Parrein J.-L, Duchêne A. Tetrahedron 2003; 59: 4433
• 17a Hoffmann RW, Haeberlin E, Rhode T. Synthesis 2002; 207
• 17b Abele S, Guichard G, Seebach D. Helv. Chim. Acta 1998; 81: 2141
• 17c Mamane V, Garcia AB, Umarje JD, Lessmann T, Sommer S, Waldmann H. Tetrahedron 2007; 63: 5754
• 17d Schaab C, Kling RC, Einsiedel J, Hübner H, Clark T, Seebach D, Gmeiner P. Chem. Open 2014; 3: 206
• 17e Umehara A, Ueda H, Tokuyama H. J. Org. Chem. 2016; 81: 11444
• 17f Choi J, Laird JM, Salomon RG. Bioorg. Med. Chem. 2011; 19: 580
• 17g Guimont-Tremblay J, Gagnon MC, Pineault-Maltrais J.-A, Turotte V, Auger M, Paquin J.-F. Org. Biomol, Chem. 2012; 10: 1145
• 18 CCDC 2077847 (5) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
• 19a Smith WW, Bartlett PA. J. Am. Chem. Soc. 1998; 120: 4622
• 19b Greenlee ML, Laub JB, Balcovec JM, Hammond ML, Hammond GG, Pompliano DL, Epstein-Toney JH. Bioorg. Med. Chem. Lett. 1999; 9: 2549
• 19c Zhang W, Liu J, Macho JM, Jiang X, Xie D, Jiang F, Liu W, Fu L. Eur. J. Med. Chem. 2017; 126: 7
• 20 Stevens JM, Ana-Rivera AC, Dixon DD, Beutner GL, Delmonte AJ, Frantz DE, Janey JM, Paulson J, Talley MR. J. Org. Chem. 2018; 83: 14245
• 21a Sánchez D, Carneros H, Castro-Alvarez A, Llàcer E, Planas F, Villarasa J. Tetrahedron Lett. 2016; 57: 5254
• 21b Szczesniak P, Padzierniok-Holewa A, Klimczak U, Stecko S. J. Org. Chem. 2014; 79: 11700
• 21c Liu Y, Liu S, Li D, Zhang N, Peng L, Ao J, Song CE, Lan Y, Yan H. J. Am. Chem. Soc. 2019; 141: 1150
• 22a Schaaf TK, Johnson MR, Constantine JW, Bindra JS, Hess H.-J, Eigner W. J. Med. Chem. 1983; 26: 328
• 22b Eichenauer NC, Tscherisch R, Pietruszka J. J. Nat. Prod. 2015; 78: 2782
• 23 Despite of the long reaction time and the use of a 2.5-fold excess of Cs₂CO₃/phosphonate the Horner olefination suffered from incomplete conversion of the reactants 7 and 8. Generally, remaining reactants were recycled pointing out a somewhat higher yield based on recovered starting material (>70%). Presumably, the base (slight excess of Cs₂CO₃) might have deprotonated some lactone 8 generating intermediate enolate. Obviously, such anion was protected against the nucleophilic attack of the deprotonated phosphonate 7 suppressing any Horner olefination. Finally, aqueous workup caused protonation of the anions regenerating the reactants. For a competing reaction, see (5R)-8 series (Scheme 5 and referring text, and Supporting Information).
• 24a Stepniewski TM, Torrens-Fontanals M, Rodriguez-Espigares I, Giorgino T, Primdal KG, Vik A, Stenstrøm Y, Selent J, Hansen TV. Bioorg. Med. Chem. 2018; 26: 3580
• 24b Moustakis CA, Viala J, Capdevilla J, Falk JR. J. Am. Chem. Soc. 1985; 107: 5283
• 25a Salunkhe VT, Bhosale S, Punde P, Bhuniya D, Koul S. Tetrahedron Lett. 2013; 54: 2489
• 25b Nicolaou KC, Chung YS, Hernandez PE, Taffer IM, Zipkin RE. Tetrahedron Lett. 1986; 27: 1881
• 26a Ahmed A, Hoegenauer EK, Enev VS, Hanbauer M, Kaelig H, Ohler E, Mulzer J. J. Org. Chem. 2003; 68: 3026
• 26b Prasad KR, Gutala P. Tetrahedron 2012; 68: 7489
• 27 Soeda H, Towada R, Ogura Y, Mohri T, Pohnert G, Kuwahara S. Tetrahedron 2019; 75: 1555
• 28 The TBS group removal was accompanied by some C15 dehydrogenation affording C14, C15 diketone as a side product. However, the reaction was conducted under inert gas atmosphere. The nature of the oxidant inducing the dehydrogenation remains unclear. For data, see Supporting Information.
• 29a Ishigami K, Kobayashi M, Takagi M, Shin-Ya K, Watanabe H. Tetrahedron 2015; 71: 8436
• 29b Sunnam SK, Prasad KR. Synthesis 2013; 45: 1991
• 30a Palimkar SS, Uenishi J. J. Org. Chem. 2012; 77: 388
• 30b Kang S.-K, Park D.-C, Jeon J.-H, Rho H.-S, Yu C.-M. Tetrahedron Lett. 1994; 35: 2357
• 30c Kang S.-K, Lee D.-H, Sim H.-S, Lim J.-S. Tetrahedron Lett. 1993; 34: 91
• 30d Kang S.-K, Cho D.-G, Park C.-H, Namkong E.-Y, Shin J.-S. Synth. Commun. 1995; 25: 1659
• 31 Generally, such a Zn(BH₄)₂ is known to induce higher OH group directed 1,2-inductions upon reduction of a defined configured α-hydroxy vinyl ketone moiety favoring the (14R,15S) product. Presumably, the S-configured C5 acetoxy group provoked a mismatched combination of stereodirecting factors leading to the weak diastereoselectivity as found here. Analyzing the ¹H NMR spectrum of the diol 11, a 4:1 mixture of diastereomers was identified. After carbonate formation, a 2:1 mixture of diastereomers 12 and 13 remained. Obviously, compared to the cis-carbonate 12 cyclization, the formation of the trans-carbonate 13 was much faster inducing some resolution of the diastereomers. However, the isolation of carbonate 13 with nearly 30% yield (estimated maximum: 20% yield from the 1:4 mixture of carbinols 11) indicated some C14 epimerization within carbonate formation. Treatment of carbonate 12 with imidazole caused any 12/13 epimerization. Alternatively, an intramolecular C–O substitution of a CDI activated C14 OH group by a C15 carboxyl C=O moiety (carbamate from CDI) potentially delivered trans-carbamate 13, too. In contrast, the R-configured C5 acetoxy group induced a high selectivity (see 5-epi series, Scheme 5 and referring text, and Supporting Information). For related reactions, see ref. 11.
• 32 Conrow RE. Org. Lett. 2006; 8: 2441
• 33a Hunter TJ, Wang Y, Zheng J, O’Dotherty GA. Synthesis 2016; 48: 1700
• 33b Walleser P, Brückner R. Eur. J. Org. Chem. 2010; 4802
• 33c Chany A.-C, Casarotto V, Schmitt M, Tarnus C, Guenin-Mace L, Demangel C, Mirguet O, Eustache J, Blanchard N. Chem. Eur. J. 2011; 17: 14413
• 34 The lowered yield originates from some decomposition while running the cyclization using the highly reactive phosgene reagent. Any predominant diastereoselective decomposition of some epi-(14S) compound cannot be excluded.
• 35 At first glance, the long distance between the stereocenters C5 and C14/C15 were regarded as independent of each other. However, the 1,3-disubstitution situation within the cycloheptatriene moiety enforced a proximity of both chain segments provoking pronounced matched and mismatched combinations upon running diastereoselective processes such as the reduction of the C14 keto group.
• 36 For a synthesis of β-oxidation-resistant 3-oxa-LXA₄ analogues, see: Guilford WJ, Bauman JG, Skuballa W, Bauer S, Wei GP, Davey D, Schaefer C, Mallari J, Terkelsen J, Tseng J.-L, Shen J, Subramanyam B, Schottelius AJ, Parkinson JF. J. Med. Chem. 2004; 47: 2157