Microwave-Enhanced α-Functionalisation of Tetramates

Abstract

Bicyclic tetramic acids may be efficiently allylated or arylated either directly or via the corresponding triflate, using a microwave-enhanced protocol; under these conditions, the yield and diastereoselectivity are very high.

Key words

allylations - arylations - antibiotics

References and Notes

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18

General Method without Microwave To a solution of tetramic acid 3 (50 mg, 0.20 mmol) in dry THF [5 mL; or dry CH₂Cl₂ (5 mL)] was added the allyl bromide (0.22 mmol) and Et₃N (0.22 mmol) at 0 ˚C and the mixture stirred for 3 d at r.t. The reaction was monitored by TLC, and when complete it was quenched with sat. aq NH₄Cl solution, extracted with EtOAc (3 × 20 mL), washed with brine (10 mL), dried over MgSO₄, and the solvent was evaporated in vacuo. Column chromatography with PE-EtOAc gave the product.
General Method with Microwave
To a solution of tetramic acid 3 (100 mg, 0.37 mmol) in dry THF (2 mL) in a microwave reaction tube was added allyl bromide (0.1 mL, 0.40 mmol) and Et₃N (0.1 mL, 0.40 mmol) and stirred at 60 ˚C for 10 min at 13.8 bar under microwave power of 75 W. The solvent was evaporated the product obtained by column chromatography.
(3 R ,6 R ,7a R )-Methyl 6-Allyl-3- tert -butyl-6-methyl-5,7-dioxohexahydropyrrolo[1,2- c ]oxazole-7a-carboxylate ( 4a) and (3 R ,7a R )-Methyl 7-(Allyloxy)-3- tert -butyl-6-methyl-5-oxo-1,3,5,7a-tetrahydropyrrolo[1,2- c ]oxazole-7a-carboxylate (5a) Product 4a: R _f = 0.65 (PE-EtOAc, 4:1); [α]_D ^²4 +93 (c 1, CHCl₃). IR (neat): ν_max = 2960 (m), 1780 (m), 1750 (s), 1720 (s), 1484 (w), 1280 (s), 1015 (m) cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.92 [9 H, s, C(CH₃)₃], 1.22 (3 H, s, CH₃), 2.63 (2 H, m, CH₂CH=CH₂), 3.42 (1 H, d, J = 8.9 Hz, CH₂O), 3.83 (3 H, s, CO₂CH₃), 4.85 (1 H, d, J = 8.9 Hz, CH₂O), 5.06 (1 H, s, CHt-Bu), 5.16 (2 H, m, CH₂CH=CH₂), 5.75 (1 H, m, CH₂CH=CH₂). ^¹³C NMR (100 MHz, CDCl₃): δ = 17.1 (CH₃), 24.7 [C(CH₃)₃], 35.3 (C), 40.9 (CH₂), 53.5 (CO₂CH₃), 54.7 (C), 69.3 (CH₂O), 78.6 (C), 99.0 (CH), 120.1 (CH₂), 130.5 (CH), 167.1 (CO), 179.8 (CO), 204.1 (CO). HRMS (microTOF): m/z calcd for C₁₆H₂₃NO₅Na: 332.1474; found: 332.1468 [M + Na]⁺.
Product 5a: R _f  = 0.3 (PE-EtOAc, 4:1); [α]_D ^²4 +96 (c 0.83, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 0.91 (9 H, s, t-Bu), 1.90 (3 H, s, CH₃), 3.39 (1 H, d, J = 8.4 Hz, CH₂O), 3.78 (3 H, s, CO₂CH₃), 4.68 (1 H, s, CHt-Bu), 4.72 (1 H, m, OCH₂CH=CH₂), 4.82 (1 H, d, J = 8.4 Hz, CH₂O), 5.30 (2 H, m, OCH₂CH=CH₂), 5.90 (1 H, m, OCH₂CH=CH₂). ^¹³C NMR (100 MHz, CDCl₃): δ = 8.37 (CH₃), 24.6 [C(CH₃)₃], 35.1 (C), 53.0 (CO₂CH₃), 70.1 (CH₂O), 71.8 (OCH₂CH=CH₂), 74.0 (C), 96.7 (CHt-Bu), 105.4 (C), 118.4 (OCH₂CH=CH₂), 131.9 (OCH₂CH=CH₂), 166.7 (C), 169.2 (C), 179.7 (C). HRMS (microTOF): m/z calcd for C₁₆H₂₃NO₅Na: 332.1474; found: 332.1468 [M + Na]⁺.
(3 R ,6 R ,7a R )-Methyl 3- tert -Butyl-6-cinnamyl-6-methyl-5,7-dioxohexahydropyrrolo[1,2- c ]oxazole-7a-carboxylate (4b) R _f = 0.56 (PE-EtOAc, 4:1); [α]_D ^²4 +81.0 (c 0.4, CHCl₃). IR (neat): ν_max = 3485 (w), 3030 (s), 2960 (s), 1715 (s), 1600 (w), 1485 (s), 1450 (s), 1280 (s), 1100 (s), 750 (s) cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.92 [9 H, s, (C(CH₃)₃], 1.27 (3 H, s, CH₃), 2.79 (2 H, d, J = 7.6 Hz, CH₂CHCHPh), 3.45 (1 H, d, J = 8.9 Hz, CH₂O), 3.73 (3 H, s, CO₂CH₃), 4.86 (1 H, d, J = 8.9 Hz, CH₂O), 5.03 (1 H, s, CHt-Bu), 6.13 (1 H, s, m, CH₂CHCHPh), 6.46 (1 H, d, J = 15.7 Hz, CH₂CHCHPh), 7.22-7.38 (5 H, m, Ph). ^¹³C NMR (100 MHz, CDCl₃): δ = 17.9 (CH₃), 24.8 [C(CH₃)₃], 35.3 [C(CH₃)₃], 40.2 (CH₂CHCHPh), 53.6 (CO₂CH₃), 55.0 (C), 69.3 (CH₂O), 78.7 (C), 99.2 (CHt-Bu), 122.0 (CH), 126.4 (CH), 127.7 (CH), 128.5 (CH), 134.9 (CH), 136.8 (C), 167.1 (CO), 180.0 (CO), 204.3 (CO). MS (ES⁺): m/z (%) = 444.28 (60) [M + 59]⁺, 277.3 (100). HRMS (microTOF): m/z calcd for C₂₂H₂₇NO₅Na: 408.1787; found: 408.1781 [M + Na]⁺.
(3 R ,6 R ,7a R )-Methyl 3- tert -Butyl-6-(2,4-dinitrophenyl)-6-methyl-5,7-dioxohexahydro-pyrrolo-[1,2- c ]oxazole-7a-carboxylate (6) R _f = 0.33 [PE (40-60)-EtOAc, 4:1]; [α]_D ^²¹ +121.0 (c, 0.33, CHCl₃). IR (neat): ν_max = 3425 (w), 3110 (s), 2960 (s), 1715 (s), 1615 (s), 1540 (s), 1480 (s), 1350 (s), 1065 (s), 740 (s) cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.93 (9 H, s, t-Bu), 1.49 (3 H, s, CH₃), 3.57 (1 H, d, J = 8.6 Hz, CH₂O), 3.90 (3 H, s, CO₂CH₃), 4.75 (1 H, s, CHt-Bu), 4.83 (1 H, d, J = 8.6 Hz, CH₂O), 7.44 (1 H, d, J = 9.1 Hz, CHAr), 8.51 (1 H, dd, J = 2.7, 9.1 Hz, CHAr), 8.87 (1 H, d, J = 2.7 Hz, CHAr). ^¹³C NMR (100 MHz, CDCl₃): δ = 8.3 (CH₃), 24.6 [C(CH₃)₃], 35.1 [C(CH₃)₃], 53.5 (CO₂CH₃), 70.1 (CH₂O), 73.8 (C), 80.5 (C), 96.9 (CHt-Bu), 121.4 (CH, Ar), 122.1 (CH, Ar), 127.8 (CH, Ar), 140.3 (C, Ar), 143.9 (C, Ar), 151.6 (C, Ar), 168.1 (CO), 176.5 (CO), 198.0 (CO). MS (ES^-): m/z (%) = 434.26 (20) [M - H]⁺, 568.13 (100). HRMS (microTOF): m/z calcd for C₁₉H₂₂N₃O₉: 436.1351; found: 436.1351 [M + H]⁺.

27

(3 R ,7a R )-Methyl 3- tert -Butyl-6-methyl-5-oxo-7-(trifluoromethylsulfonyloxy)-1,3,5,7a-tetrahydro-pyrrolo[1,2- c ]oxazole-7a-carboxylate (7) To a solution of tetramic acid 3 (100 mg, 0.37 mmol), dry Et₃N (0.16 mL, 1.16 mmol, 3 equiv) in dry CH₂Cl₂ (2 mL) at 0 ˚C was added Tf₂O (0.19 mL, 1.13 mmol, 3 equiv) via syringe and stirred for 1 h. The solvent was evaporated in vacuo and the residue purified by flash column chromatography in PE (40-60)-EtOAc (4:1) to give the product 7 (110 mg, 73%) as a colourless oil.
R _f  = 0.6 [PE (40-60)-EtOAc, 4:1]; [α]_D ^²³ +91 (c 0.7 in CHCl₃). IR (neat): ν_max = 2960 (m), 1730 (m), 1295 (m) cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.94 [9 H, s, C(CH₃)₃], 1.94 (3 H, s, CH₃), 3.51 (1 H, d, J = 8.9 Hz, H-4_endo), 3.83 (3 H, s, CO₂CH₃), 4.74 (1 H, s, H-2), 4.83 (1 H, d, J = 8.9 Hz, H-4_exo). ^¹³C NMR (100 MHz, CDCl₃): δ = 8.2 (CH₃), 24.7 [C(CH₃)₃], 35.1 [C(CH₃)₃], 53.6 (CO₂CH₃), 70.6 (C-4), 74.2 (C-5), 96.7 (C-2), 127.2 (C-7), 154.9 (C-6), 166.7 (CO₂CH₃), 173.8 (C-8). HRMS (CI⁺): m/z calcd for C₁₄H₁₉NO₇F₃S: 402.0834; found: 402.0831 [M + H]⁺.

28

Allylations of Triflate 7 (with MW) in the Presence of Pd(OAc) ₂ - General Method To a solution of the enol triflate 7 (20 mg, 0.05 mmol) in dry THF (2 mL) was added allyl bromide (0.2 mL, 2.3 mmol), Pd(OAc)₂ (35 mg, 0.16 mmol), and Et₃N (0.2 mL, 1.44 mmol) under N₂. The reaction tube was inserted in microwave reactor, and the reaction was carried out for 10 min at 50 ˚C under 100 W microwave power. The reaction course was monitored by TLC. When the reaction was complete, it was diluted with EtOAc (20 mL), quenched with sat. aq NH₄Cl (10 mL), washed with brine (5 mL), dried over MgSO₄, and the solvent was evaporated in vacuum. Column chromatography with PE-EtOAc (4:1) afforded the product.

29

Bioassay of Products
Microbiological assays were performed by the hole-plate method with the test organism Staphylococcus aureus N.C.T.C. 6571 or E. coli X580. Solutions (100 mL) of the compounds to be tested (4 mg/mL) were loaded into wells in bioassay plates, and incubated overnight at 37 ˚C. The diameters of the resultant inhibition zones were measured, and relative potency estimated by reference to standards prepared with Cephalosporin C.