Total Synthesis and Structure Revision of (−)-Avicennone C

Abstract

All four possible stereoisomers of the natural product (−)-avicennone C were synthesized using two different methods for ring closure. The absolute stereochemistry was elucidated unambiguously by comparison of the analytical data with those of the reported natural product and by single X-ray crystal diffraction of synthetic intermediates. The proposed structure needed to be revised with regard to the absolute configuration of the stereogenic center bearing the secondary hydroxyl group. The reported synthesis offers a flexible, selective, and efficient access to all possible stereoisomers and may be of value for the stereoselective synthesis of other epoxyquinone natural products.

The Discovery and Structure‐Activity Evaluation of (+)‐Floyocidin B and Synthetic Analogs

“…Consecutive TIPS protection and saponification of the acetate resulted in primary alcohols 17 and 21, which were oxidized to nitriles 8 and 22 (Scheme 2). The reaction sequence was performed in close analogy to the total synthesis of (À )-avicennone C [6] (2) with two significant differences: (1) a direct conversion of 12 and 13 to 17 and 21 via TIPS protection and selective TBDPS deprotection (not shown) was hampered by very low yields (< 20 % over two steps) due to double deprotection of both silyl protecting groups and (2) the acetate migration in the conversion of 14 and 18 to 15 and 19 occurred without addition of a base. The absolute stereochemistry of alcohol intermediate 17 was unambiguously assigned by single X-ray crystal diffraction and the stereochemistry of the other stereoisomers was deduced thereof (Figure 2).…”

“…To compensate the loss of yield in the conversion of 8 to 7, the previously developed recycling strategy via Mitsunobu inversion and saponification of the acetate was successfully applied to the conversion of 27 to 4 (Scheme 3). [6] Comparison of NMR spectra, specific rotations (Table 1), and chiral HPLC (see Supporting Information) elucidated the 1aR,2R,7aR-isomer (4) as the correct structure of NP (+)-floyocidin B.…”

“…[14] Ideally, SAR with these parameters that can be established on a small series of structurally related analogs, should allow for an efficient multi-objective molecular optimization toward a valuable lead structure and clinical development candidate. [15] To this end, the antibacterial activities of NP (+)-floyocidin A (3) from isolation and in total 12 synthesized compounds (all four stereoisomers of (+)-floyocidin B and (À )-avicennone C [6] (2) as well as hybrids 35, ent-35, 36, and ent-36) were tested in vitro against a panel of seven indicator strains (E. coli, P. aeruginosa, M. catarrhalis, S. aureus, C. albicans, M. smegmatis, M. tuberculosis) (Table 2 and see Supporting Information). While none of the tested substrates inhibited the growth of E. coli, P. aeruginosa or C. albicans, only (+)-floyocidin A (3) showed a weak activity against S. aureus (64 μg/mL).…”

“…(dt, 1H, J = 15.7, 7.0 Hz, CH 2 -CH = CH), 6.46 (dt, 1H, J = 15.7, 1.6 Hz, CH 2 -CH=CH), 5.27 (d, 1H, J = 2.3 Hz, CH-OH), 5.09 (m, 1H, Me 2 C=CH), 3.85 (d, 1H, J = 2.3 Hz, epoxy-CH), 3.18 (s, br, 1H, OH), 2.84 (dd, 1H, J = 15.5, 7.9 Hz, Me 2 C=CH-CH 2 ), 2.64 (dd, 1H, J = 15.4, 6.7 Hz, Me 2 C=CH-CH 2 ), 2.24 (m, 2H, CH 2 -CH=CH), 1.73 (s, 3H, E-CH 3 ), 1.68 (s, 3H, Z-CH 3 ), 1.53 (m, 2H, CH 3 -CH 2 ), 0.96 (t, 3H, J = 7.4 Hz, CH 3 -CH 2 ); 13 C-NMR (CDCl 3 , 100 MHz): δ = 194.5 (C = O), 157.9 (N-C q ), 151.1 (N-CH), 138.8 (CH 2 -CH=CH), 136.8 (Ar-C q -CO), 136.6 (C q Me 2 ), 131.1 (N-CH-C q ), 128.9 (CH 2 -CH = CH), 116.9 (pentenyl-C q -CH), 116.1 (CH=CMe 2 ), 64.6 (CH-OH), 61.1 (epoxy-C q ), 60.…”

“…+)-Floyocidin B[21] / (1aR,2R,7aR)-2-Hydroxy-7 a-(3-methylbut-2en-1-yl)-5-((E)-pent-1-en-1-yl)-1 a,7 a-dihydrooxire-no[2,3-g] isoquinolin-7(2H)-one (4): 1 H-NMR (MeOD, 500 MHz): δ = 8.74 (s, 1H, N-CH), 7.67 (s, 1H, pentenyl-C q -CH),6.78 (dt, 1H, J = 15.8, 7.1 Hz, CH 2 -CH = CH),6.55 (dt, 1H, J = 15.8, 1.5 Hz, CH 2 -CH=CH), 5.17 (s, br, 1H, CH-OH), 5.14 (m, 1H, Me 2 C=CH), 3.82 (d, 1H, J = 1.9 Hz, epoxy-CH), 2.81 (dd, 1H, J = 15.2, 8.0 Hz, Me 2 C=CH-CH 2 ), 2.64 (dd, 1H, J = 15.2, 6.9 Hz, Me 2 C=CH-CH 2 ), 2.27 (m, 2H, CH 2 -CH=CH), 1.73 (s, 3H, E-CH 3 ), 1.69 (s, 3H, Z-CH 3 ), 1.55 (m, 2H, CH 3 -CH 2 ), 0.98 (t, 3H, J = 7.4 Hz, CH 3 -CH 2 ); 13 C-NMR (MeOD, 125 MHz): δ = 195.4 (C = O), 157.5 (N-C q ), 150.0 (N-CH), 138.5 (CH 2 -CH=CH), 137.7 (Ar-C q -CO), 137.0 (C q Me 2 ), 133.8 (N-CH-C q ), 130.1 (CH 2 -CH = CH), 117.8 (CH=CMe 2 ), 117.1 (pentenyl-C q -CH), 65.3 (CH-OH), 63.1 (epoxy-C q ), 61.1 (epoxy-CH), 36.0 (CH 2 -CH=CH), 27.2 (Me 2 C=CH-CH 2 ), 26.0 (E-CH 3 ), 23.2 (CH 3 -CH 2 ), 18.1 (Z-CH 3 ), 14.1 (CH 3 -CH 2 ); HRMS (ESI) m/z calcd. for C 19 H 24 NO 3 : 314.1751 (M + H) + ; found: 314.1751 (M + H) + ; R f (n-heptane/ethyl acetate 1 : 1): 0.37; Specific rotation a ½ � 24:4 D = + 160.0 (c = 0.03; CHCl 3 ).Floyocidin C [22] / (1R,5R,6R)-3-((1E,3Z)-Hepta-1,3-dien-1-yl)-5hydroxy-4-(hydroxymethyl)-1-(3-methylbut-2-en-1-yl)-7-oxabicyclo[4.1.0]hept-3-en-2-one (5): 1 H-NMR (MeOD, 500 MHz): δ = 6.86 (dd, 1H, J = 15.7, 11.2 Hz, C q -CH=CH), 6.32 (d, 1H, J = 15.5 Hz, C q -CH = CH), 6.09 (dd, 1H, J = 11.2, 10.8 Hz, C q -CH=CH-CH), 5.55 (m, 1H, CH 2 -CH 2 -CH), 5.07 (m, 1H, Me 2 C=CH), 4.77 (s, br, 1H, CH-OH), 4.48 (d, 1H, J = 12.8 Hz, CH 2 -OH), 4.42 (d, 1H, J = 12.8 Hz, CH 2 -OH), 3.68 (d, 1H, J = 2.7 Hz, epoxy-CH), 2.73 (dd, 1H, J = 15.0, 7.6 Hz, Me 2 C=CH-CH 2 ), 2.49 (dd, 1H, J = 15.0, 6.9 Hz, Me 2 C=CH-CH 2 ), 2.20 (m, 2H, CH 3 -CH 2 -CH 2 ), 1.70 (s, 3H, E-CH 3 ), 1.66 (s, 3H, Z-CH 3 ), 1.43 (m, 2H, CH 3 -CH 2 ), 0.93 (t, 3H, J = 7.4 Hz, CH 3 -CH 2 ); 13 C-NMR (MeOD, 125 MHz): δ = 196.7 (C = O), 150.6 (OH-CH 2 -C q ), 136.5 (br, C q Me 2 ), 135.1 (CH 2 -CH 2 -CH), 133.0 (C q -CH = CH), 132.0 (C q -CH=CH), 130.5 (C q -CH=CH-CH), 124.7 (C q -CH=CH), 118.2 (CH=CMe 2 ), 86.3 (CH-OH), 62.0 (epoxy-C q ), 60.5 (epoxy-CH), 60.0 (CH 2 -OH), 31.0 (CH 3 -CH 2 -CH 2 ), 27.6 (Me 2 C=CH-CH 2 ), 26.0 (E-CH 3 ), 23.9 (CH 3 -CH 2 ), 18.1 (Z-CH 3 ), 14.0 (CH 3 -CH 2 ); HRMS (ESI) m/z calcd.…”