Macrocycles via Doebner Reaction Followed by Macrolactonization

Abstract

The synthesis of 14 different macrocycles is reported. Upon reacting different formylphenoxyacetic acid derivatives with 5-aminopentanol and a diketo compound, eight different Doebner product intermediates were obtained. These intermediates were then subjected to cyclization by using polymer-bound carbodiimide to give macrolactones. Both the monomers and the dimers could be isolated and characterized. In some cases trimers could be seen from the HPLC-MS. The ratios and distribution of the different-sized rings are discussed.

macrocycles - multicomponent reactions - lactones - ­heterocycles - tandem reactions

References and Notes

<A NAME="RG08006ST-1">1</A> McGuire JM. Bunch RL. Anderson RC. Boaz HE. Flynn EH. Powell HM. Smith JW. Antibiot. Chemother.  1952,  2:  281 

<A NAME="RG08006ST-2">2</A> Katz L. Ashley GW. Chem. Rev.  2005,  105:  499 

<A NAME="RG08006ST-3">3</A> Kino T. Hatanaka H. Hashimoto M. Nishiyama M. Goto T. Okuhara M. Kohsaka M. Aoki H. Imanaka H. J. Antibiot. (Tokyo)  1987,  40:  1249 

<A NAME="RG08006ST-4">4</A> Sehgal SN. Baker H. Vezina C. J. Antibiot. (Tokyo)  1975,  28:  727 

<A NAME="RG08006ST-5">5</A> Gold W. Stout HA. Pagano JF. Donovick R. Antibiot. Ann.  1955-1956,  579 

<A NAME="RG08006ST-6">6</A> Hazen EL. Brown R. Science  1950,  112:  423 

<A NAME="RG08006ST-7">7</A> Höfle G. Bedorf N. Steinmetz H. Schomburg D. Gerth K. Reichenbach H. Angew. Chem., Int. Ed. Engl.  1996,  35:  1567 

<A NAME="RG08006ST-8">8</A> Li JY. Strobel G. Harper J. Lobkovsky E. Clardy J. Org. Lett.  2000,  2:  767 

<A NAME="RG08006ST-9">9</A> Stickings CE. Biochem. J.  1959,  72:  332 

<A NAME="RG08006ST-10A">10a</A> Ito S. Hirata Y. Tetrahedron Lett.  1972,  13:  1181 

<A NAME="RG08006ST-10B">10b</A> Ito S. Hirata Y. Tetrahedron Lett.  1972,  13:  1185 

<A NAME="RG08006ST-10C">10c</A> Ito S. Hirata Y. Tetrahedron Lett.  1972,  13:  2557 

<A NAME="RG08006ST-11">11</A> Jomon K. Ajisaka M. Sakai H. J. Antibiot.  1972,  25:  271 

<A NAME="RG08006ST-12A">12a</A> Bughin C. Zhao G. Bienaymè H. Zhu J. Chem. Eur. J.  2006,  12:  1174 

<A NAME="RG08006ST-12B">12b</A> Cristau P. Vors J.-P. Zhu J. Org. Lett.  2001,  3:  4079 

<A NAME="RG08006ST-12C">12c</A> Beck B. Larbig G. Mejat B. Magnin-Lachaux M. Picard A. Herdtweck E. Dömling A. Org. Lett.  2003,  5:  1047 

<A NAME="RG08006ST-13A">13a</A> Döbner O. Ber. Dtsch. Chem. Ges.  1887,  20:  277 

<A NAME="RG08006ST-13B">13b</A> Gein VL. Popov AV. Andeichikov YS. Zh. Org. Khim.  1992,  28:  2774 

<A NAME="RG08006ST-13C">13c</A> Andeichikov YS. Gein VL. Anikina IN. Zh. Org. Khim.  1988,  24:  875 

<A NAME="RG08006ST-13D">13d</A> Andeichikov YS. Gein VL. Ivanenko OI. Maslivets AN. Zh. Org. Khim.  1986,  22:  2208 

<A NAME="RG08006ST-13E">13e</A> Schiff R. Bertini C. Ber. Dtsch. Chem. Ges.  1897,  30:  601 

<A NAME="RG08006ST-13F">13f</A> Dohrn M. Thiele A. Ber. Dtsch. Chem. Ges. B  1931,  64:  2863 

<A NAME="RG08006ST-14">14</A>

Amine (2 mmol) and aldehyde (2 mmol) were dissolved in 3 mL of a 1:1 mixture of CH₂Cl₂ and EtOH. After 30 min stirring at r.t. pyruvic acid derivative (2 mmol) was added. The mixture was stirred for 16 h. The solvent was removed and the remainder taken up in Et₂O for solidifying. Compounds 4, 5 and 6 could be used for the next step without purification. All other compounds were purified via preparative HPLC (column Grom-Sil 120 ODS-5, 10 × 4 cm, 10 µm, flow 50 mL/min, gradient 20-100% A in 15 min, solvent A = MeOH + 0.5% AcOH, solvent B = H₂O + 0.5% AcOH). Yields of 1-8 are given in Table [1] .

<A NAME="RG08006ST-15A">15a</A> Buckman BO. Morrissey MM. Mohan R. Tetrahedron Lett.  1998,  39:  1487 

<A NAME="RG08006ST-15B">15b</A> Keck GE. Sanchez C. Wagner CA. Tetrahedron Lett.  2000,  41:  8673 

<A NAME="RG08006ST-15C">15c</A> Neisses B. Steglich W. Angew. Chem., Int. Ed. Engl.  1978,  17:  522 

<A NAME="RG08006ST-16">16</A>

Compound 1 (250.8 mg, 0.6 mmol) was dissolved in 5 mL of anhydrous CH₂Cl₂ together with N,N-dimethylamino-pyridine (15.9 mg, 0.13 mmol). Then, N-cyclohexyl-N′-methyl polystyrene (Novabiochem, 750 mg, 1.2 mmol) was added and the mixture agitated overnight at r.t. Resin was filtered off and thoroughly washed with CH₂Cl₂. The combined solvents were evaporated and the remainder was subjected to preparative HPLC (column Waters SunFire Prep C18 OBD, 19 × 50 mm, 5 µm, flow 30 mL/min, gradient 20-90% A in 15 min, solvent A = MeOH + 0.03% formic acid, solvent B = H₂O + 0.03% formic acid). Yield of 9: 60 mg (25%), 17: 28 mg (5.8%), 25: 6 mg (0.8%).
Compound 9: ¹H NMR (400 MHz, CDCl₃): δ = 1.05 (9 H, s, CH₃), 1.10-1.80 (6 H, m, CH₂CH₂CH₂), 2.79-2.88 (1 H, t, CH of CH₂, J = 13.3 Hz), 3.51-3.61 (1 H, t, CH′ of CH₂, J = 13.3 Hz), 4.02-4.14 (2 H, m, CH₂), 4.76-4.82 (1 H, d, CH of CH₂, J = 17.2 Hz), 4.92-4.98 (1 H, d, CH′ of CH₂, J = 17.2 Hz), 6.06 (1 H, s, CH), 6.76-6.88 (3 H, m, H_arom), 7.16-7.22 (1 H, d, J = 8.6 Hz, H_arom). ¹³C NMR (100 MHz, CDCl₃): δ = 24.3, 25.4, 25.8, 26.1, 40.5, 43.0, 54.2, 64.4, 67.7, 110.2, 118.1, 122.0, 124.8, 127.0, 129.8, 154.5, 155.5, 164.5, 168.9, 202.5.
Compound 17: ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.10 (18 H, s, CH₃), 1.14-1.68 (12 H, m, 2 × CH₂CH₂CH₂), 3.30-3.54 (4 H, m, 2 × CH₂), 4.06-4.18 (4 H, m, 2 × CH₂), 4.83-4.93 (4 H, m, 2 × CH₂), 5.83 (2 H, s, 2 × CH), 6.70-6.78 (2 H, m, H_arom), 6.85-6.92 (2 H, m, H_arom), 6.95-7.03 (2 H, m, H_arom), 7.17-7.26 (2 H, m, H_arom). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 22.4, 24.6, 25.3, 27.0, 40.1, 42.5, 54.1, 64.3, 67.3, 110.0, 118.5, 122.1, 125.2, 127.4, 129.9, 156.0, 156.3, 165.0, 168.5, 202.7.
Compound 25: No NMR spectra could be recorded due to lack of substance.

<A NAME="RG08006ST-17">17</A> Granik VG. Russ. Chem. Rev.  1982,  51:  119