Asymmetric Synthesis and Antibacterial Activity of Chiral 2-Methoxycarbonyl-4-fluorophenyl-1,5-benzothiazepines†

doi:10.7503/cjcu20160546

Abstract

Abstract:

The synthetic route was confirmed via the study of introduction or removing chiral auxiliary (R)-4-phenyl-2-oxazolidinone and optimizing reaction conditions. Eighteen optically active 1,5-benzothiazepines were synthesized under the chiral induction of (S)/(R)-4-benzyl-2-oxazolidinone and characterized by ¹H NMR, ¹³C NMR, IR and HRMS. The relative configuration of compound 9h was validated by X-ray diffraction analysis. The e.e. values of the products were analyzed by HPLC. The antifungal activities of compounds were screened using the disk diffusion method against C. neoformans. The compounds which were synthesized with S-4-benzyl-2-oxazolidinone had high antibacterial effects against C. Neoformans. By contrast, the compounds which were synthesized with R-4-benzyl-2-oxazolidinone and racemic compounds had lower antibacterial effects. Moreover, The MIC and MFC values of the highly biological compounds 14a—14f were lower than those of fluconazole.

Key words: 1,5-Benzothiazepine, Antifungal activity, Asymmetric synthesis, Chiral auxiliariy

CLC Number:

O626

TrendMD:

MU Boshuai, CHANG Suna, BIAN Yanqing, LI Yuan. Asymmetric Synthesis and Antibacterial Activity of Chiral 2-Methoxycarbonyl-4-fluorophenyl-1,5-benzothiazepines^†[J]. Chem. J. Chinese Universities, 2017, 38(3): 413.

Figures/Tables 12

Scheme 1 Synthesis route of 1,5-benzothiazepines(9a—9i and 14a—14i) 3a—14a: Ar=4-FC6H4; 1b—14b: Ar=3-FC6H4; 1c—14c: Ar=2-FC6H4; 1d—14d: Ar=3,4-F2C6H3; 1e—14e: Ar=2,5-F2C6H3; 1f—14f: Ar=2,3-F2C6H3; 1g—14g: Ar=3,5-F2C6H3; 1h—14h: Ar=2,6-F2C6H3; 1i—14i: Ar=2,4-F2C6H3

Table 1 Yields, melting points, HRMS and IR data for compounds 9a—9i and 14a—14i

Compd.	Isolated yield(%)	m. p./℃	HRMS(calcd., [M+Na]⁺), m/z	IR(KBr), $ν ˙$ /cm^-1	e.e.(%)
9a	32.0	93—96	338.0625(338.0621)	1611, 1717	84
9b	28.2	102—103	338.0623(338.0621)	1610, 1733	65
9c	23.5	83—85	338.0625(338.0621)	1603, 1739	35
9d	35.0	98—100	356.0531(356.0527)	1598, 1733	93
9e	24.8	111—113	356.0531(356.0527)	1616, 1737	76
9f	29.0	105—107	356.0528(356.0527)	1607, 1728	67
9g	36.3	86—88	356.0533(356.0527)	1610, 1721	65
9h	34.3	95—97	356.0532(356.0527)	1615, 1728	71
9i	25.7	76—78	356.0527(356.0527)	1600, 1728	40
14a	37.0	94—96	338.0629(338.0621)	1595, 1708	60
14b	25.8	102—103	338.0625(338.0621)	1615, 1728	70
14c	29.5	83—86	338.0625(338.0621)	1621, 1746	34
14d	33.4	98—99	356.0534(356.0527)	1597, 1731	95
14e	36.2	111—113	356.0534(356.0527)	1605, 1731	70
14f	38.2	106—108	356.0528(356.0527)	1597, 1731	54
14g	36.2	86—89	356.0525(356.0527)	1601, 1729	73
14h	42.1	95—97	356.0532(356.0527)	1627, 1727	71
14i	25.9	77—79	356.0534(356.0527)	1611, 1731	40

Table 1 Yields, melting points, HRMS and IR data for compounds 9a—9i and 14a—14i

Compd.	Isolated yield(%)	m. p./℃	HRMS(calcd., [M+Na]⁺), m/z	IR(KBr), $ν ˙$ /cm^-1	e.e.(%)
9a	32.0	93—96	338.0625(338.0621)	1611, 1717	84
9b	28.2	102—103	338.0623(338.0621)	1610, 1733	65
9c	23.5	83—85	338.0625(338.0621)	1603, 1739	35
9d	35.0	98—100	356.0531(356.0527)	1598, 1733	93
9e	24.8	111—113	356.0531(356.0527)	1616, 1737	76
9f	29.0	105—107	356.0528(356.0527)	1607, 1728	67
9g	36.3	86—88	356.0533(356.0527)	1610, 1721	65
9h	34.3	95—97	356.0532(356.0527)	1615, 1728	71
9i	25.7	76—78	356.0527(356.0527)	1600, 1728	40
14a	37.0	94—96	338.0629(338.0621)	1595, 1708	60
14b	25.8	102—103	338.0625(338.0621)	1615, 1728	70
14c	29.5	83—86	338.0625(338.0621)	1621, 1746	34
14d	33.4	98—99	356.0534(356.0527)	1597, 1731	95
14e	36.2	111—113	356.0534(356.0527)	1605, 1731	70
14f	38.2	106—108	356.0528(356.0527)	1597, 1731	54
14g	36.2	86—89	356.0525(356.0527)	1601, 1729	73
14h	42.1	95—97	356.0532(356.0527)	1627, 1727	71
14i	25.9	77—79	356.0534(356.0527)	1611, 1731	40

Table 2 1H NMR and 13C NMR data for compounds 9a—9i and 14a—14i

Compd.	¹H NMR(500 MHz, CDCl₃), δ	¹³C NMR(125 MHz, CDCl₃), δ
9a	7.09—8.06(m, 8H, PhH), 4.34(dd, 1H, SCH, J=12.00, 5.00 Hz), 3.75(s, 3H, OCH₃), 3.09—3.20(m, 2H, CH₂)	170.7, 168.1, 165.9, 163.9, 152.1, 135.4, 130.6, 129.6(d, J_C—F=8.7 Hz), 125.5, 125.0, 121.0, 118.3, 115.8(d, J_C—F=21.6 Hz), 125.2, 55.4, 52.6, 34.9
9b	7.10—7.80(m, 8H, PhH), 4.34(dd, 1H, SCH, J=12.00, 6.00 Hz), 3.76(s, 3H, OCH₃), 3.10—3.19(m, 2H, CH₂)	170.6, 168.0, 164.1, 162.1, 152.1 135.4, 130.5, 130.3(d, J_C—F=8.0 Hz), 125.7, 125.0, 123.0, 121.0, 118.3, 114.2(d, J_C—F=22.6 Hz), 55.8, 52.7, 31.6
9c	7.10—8.08(m, 8H, PhH), 4.52(dd, 1H, SCH, J=11.50, 6.50 Hz), 3.73(s, 3H, OCH₃), 3.09—3.18(m, 2H, CH₂)	170.9, 168.0, 162.3, 160.4, 151.5 135.5, 132.6(d, J_C—F=8.7 Hz), 130.8, 130.5, 125.7, 124.9, 124.6, 121.5, 116.4(d, J_C—F=23.1 Hz) 55.4, 52.6, 34.9
9d	7.12—7.81(m, 7H, PhH), 4.51(dd, 1H, SCH, J=12.00, 5.50 Hz), 3.74(s, 3H, OCH₃), 3.17(t, 1H, CH₂, J=12.50 Hz), 3.08(dd, 1H, CH₂, J=13.00, 5.50 Hz)	170.7, 166.8, 151.3(dd, J_C—F=145.5, 13.5 Hz), 151.2, 149.3(dd, J_C—F=149.3, 13.5 Hz), 135.5, 130.5, 128.9(d, J_C—F=8.1 Hz), 126.0, 125.2(d, J_C—F=1.6 Hz), 125.0, 124.4(d, J_C—F=6.8 Hz), 121.5, 119.4(d, J_C—F=17.1 Hz), 55.5, 52.6, 34.9
9e	7.12—7.82(m, 7H, PhH), 4.51(dd, 1H, SCH, J=11.50, 6.50 Hz), 3.75(s, 3H, OCH₃), 3.08—3.16(m, 2H, CH₂)	170.7, 166.7, 159.7(dd, J_C—F=164.37, 1.50 Hz), 157.1(dd, J_C—F=167.00, 1.62 Hz), 151.1, 135.5, 130.5, 127.9(dd, J_C—F=13.50, 7.38 Hz), 126.0, 125.0, 121.6, 119.2(dd, J_C—F=24.38, 9.25 Hz), 117.7(dd, J_C—F=26.50, 8.37 Hz), 116.7(dd, J_C—F=25.37, 3.62 Hz), 55.5, 52.6, 34.7
9f	7.13—7.82(m, 7H, PhH), 4.51(dd, 1H, SCH, J=12.00, 5.50 Hz), 3.74(s, 3H, OCH₃), 3.17(t, 1H, CH₂, J=12.75 Hz), 3.08(dd, 1H, CH₂, J=13.00, 5.50 Hz)	170.7, 167.0, 151.9, 151.3(dd, J_C—F=145.5, 13.5 Hz), 149.8(dd, J_C—F=149.3, 13.5 Hz), 135.5, 130.6, 128.8(d, J_C—F=8.2 Hz), 126.0, 125.3(d, J_C—F=1.6 Hz), 125.0, 124.4(d, J_C—F=6.8 Hz), 121.5, 119.4(d, J_C—F=17.1 Hz), 55.5, 52.6, 34.9
9g	6.94—7.58(m, 7H, PhH), 4.35(dd, 1H, SCH, J=12.00, 6.00 Hz), 3.77(s, 3H, OCH₃), 3.06—3.16(m, 2H, CH₂)	170.5, 166.7, 163.2(dd, J_C—F=247.6, 12.5 Hz), 151.9, 140.8(t, J_C—F=8.6 Hz), 135.5, 130.6, 125.9, 125.0, 120.9, 110.3(dd, J_C—F=20.6, 6.1 Hz), 106.4(t, J_C—F=25.7 Hz), 55.8, 52.7, 31.5
9h	7.01—7.60(m, 7H, PhH), 4.49(dd, 1H, SCH, J=12.0, 5.5 Hz), 3.73(s, 3H, OCH₃), 3.23(t, 1H, CH₂, J=12.5 Hz), 2.87(dd, 1H, CH₂, J=13.0, 5.0 Hz)	170.6, 163.8, 160.3(dd, J_C—F=250.2, 6.7 Hz), 151.4, 135.4, 131.1(t, J_C—F=10.1 Hz), 130.4, 126.1, 125.3, 121.5, 118.1(t, J_C—F=18.1 Hz), 112.1(dd, J_C—F=20.2, 4.8 Hz), 55.6, 52.6, 35.8
9i	6.84—8.15(m, 7H, PhH), 4.48(dd, 1H, SCH, J=12.00, 5.50 Hz), 3.74(s, 3H, OCH₃), 3.06—3.17(m, 2H, CH₂)	170.7, 167.0, 164.7(dd, J_C—F=253.2, 12.5 Hz), 161.7(dd, J_C—F=251.6, 12.2 Hz), 151.0, 135.5, 132.3(dd, J_C—F=9.8, 4.5 Hz), 130.6, 127.9, 127.3, 126.0, 125.0, 112.3(dd, J_C—F=21.0, 3.0 Hz), 104.6(t, J_C—F=26.1 Hz), 55.4, 52.6, 34.8
14a	7.09—8.06(m, 8H, PhH), 4.34(dd, 1H, SCH, J=12.00, 5.50 Hz), 3.75(s, 3H, OCH₃), 3.09—3.20(m, 2H, CH₂)	170.7, 168.1, 165.9, 163.9, 152.1, 135.4, 130.6, 129.6(d, J_C—F=8.7 Hz), 125.5, 125.0, 121.0, 118.3, 115.8(d, J_C—F=21.2 Hz) , 125.2, 55.6, 52.7, 31.5
14b	7.11—7.81(m, 8H, PhH), 4.36(dd, 1H, SCH, J=12.00, 5.50 Hz), 3.76(s, 3H, OCH₃), 3.10—3.20(m, 2H, CH₂)	170.6, 168.1, 164.1, 162.1, 152.0, 135.0, 130.6, 130.3(d, J_C—F=7.2 Hz), 125.7, 125.0, 123.0, 121.0, 118.3, 114.2(d, J_C—F=22.7 Hz) 55.8, 52.7, 31.6
14c	7.12—8.08(m, 8H, PhH), 4.51(dd, 1H, SCH, J=12.00, 6.00 Hz), 3.73(s, 3H, OCH₃), 3.09—3.18(m, 2H, CH₂)	170.8, 168.1, 162.3, 160.4, 151.4, 135.5, 132.70(d, J_C—F=8.8 Hz), 130.8, 130.5, 125.8, 125.0, 124.6, 121.5, 116.4(d, J_C—F=23.1 Hz) 55.4, 52.6, 34.9
14d	7.13—8.01(m, 7H, PhH), 4.50(dd, 1H, SCH, J=12.00, 5.50 Hz), 3.74(s, 3H, OCH₃), 3.16(t, 1H, CH₂, J=12.50 Hz), 3.07(dd, 1H, CH₂, J=13.00, 5.50 Hz)	170.6, 166.7, 152.5(dd, J_C—F=145.7, 12.8 Hz), 152.1, 150.5(dd, J_C—F=149.1, 13.5 Hz), 135.5, 134.6(d, J_C—F=8.1 Hz), 130.6, 125.7, 125.0, 123.8(d, J_C—F=6.5 Hz), 120.8, 117.4(d, J_C—F=17.5 Hz), 116.5(d, J_C—F=18.5 Hz), 55.7, 52.7, 31.3
14e	7.12—7.84(m, 7H, PhH), 4.52(dd, 1H, SCH, J=11.00, 7.00 Hz), 3.75(s, 3H, OCH₃), 3.12—3.18(m, 2H, CH₂)	170.8, 166.7, 159.7(dd, J_C—F=164.4, 1.5 Hz), 157.1(dd, J_C—F=166.7, 1.6 Hz), 151.1, 135.5, 130.5, 127.9(dd, J_C—F=13.5, 7.3 Hz), 126.0, 125.0, 121.6, 119.2(dd, J_C—F=24.3, 9.2 Hz), 117.7(dd, J_C—F=26.5, 8.2 Hz), 116.7(dd, J_C—F=25.3, 3.6 Hz), 55.4, 52.6, 34.7
14f	7.12—7.81(m, 7H, PhH), 4.50(dd, 1H, SCH, J=12.00, 5.50 Hz), 3.74(s, 3H, OCH₃), 3.17(t, 1H, CH₂, J=12.75 Hz), 3.08(dd, 1H, CH₂, J=13.00, 5.50 Hz)	170.7, 166.9, 151.4, 151.3(dd, J_C—F=144.6, 13.5 Hz), 149.3(dd, J_C—F=153.0, 13.5 Hz), 135.5, 130.6, 128.8(d, J_C—F=8.1 Hz), 126.0, 125.3(d, J_C—F=1.6 Hz), 125.0, 124.4(d, J_C—F=6.8 Hz), 121.5, 119.4(d, J_C—F=17.0 Hz), 55.5, 52.6, 34.9
14g	6.94—7.58(m, 7H, PhH), 4.35(dd, 1H, SCH, J=12.00, 6.00 Hz), 3.77(s, 3H, OCH₃), 3.07—3.16(m, 2H, CH₂)	170.5, 166.7, 163.2(dd, J_C—F=247.2, 12.6 Hz), 151.9, 140.8(t, J_C—F=8.8 Hz), 135.5, 130.6, 125.9, 125.0, 120.9, 110.3(dd, J_C—F=20.6, 6.1 Hz), 106.4(t, J_C—F=25.7 Hz), 55.8, 52.7, 31.5
14h	7.00—7.60(m, 7H, PhH), 4.49(dd, 1H, SCH, J=12.0, 5.5 Hz), 3.73(s, 3H, OCH₃), 3.23(t, 1H, CH₂, J=12.5 Hz), 2.87(dd, 1H, CH₂, J=13.0, 5.0 Hz)	170.7, 163.9, 160.3(dd, J_C—F=250.1, 6.7 Hz), 151.3, 135.4, 131.1(t, J_C—F=10.1 Hz), 130.4, 126.1, 125.3, 121.5, 118.1(t, J_C—F=18.1 Hz), 112.1(dd, J_C—F=20.2, 4.8 Hz), 55.6, 52.6, 35.8
14i	6.86—8.19(m, 7H, PhH), 4.49(dd, 1H, SCH, J=12.00, 6.50 Hz), 3.74(s, 3H, OCH₃), 3.10—3.20(m, 2H, CH₂)	170.7, 167.1, 164.7(dd, J_C—F=246.7, 12.5 Hz), 161.7(dd, J_C—F=251.6, 12.2 Hz), 151.3, 135.6, 132.2(dd, J_C—F=9.8, 4.5 Hz), 130.5, 127.9, 127.3, 126.7, 125.0, 112.3(dd, J_C—F=21.0, 3.0 Hz), 104.3(t, J_C—F=26.1 Hz), 55.4, 52.6, 34.8

Table 2 1H NMR and 13C NMR data for compounds 9a—9i and 14a—14i

Compd.	¹H NMR(500 MHz, CDCl₃), δ	¹³C NMR(125 MHz, CDCl₃), δ
9a	7.09—8.06(m, 8H, PhH), 4.34(dd, 1H, SCH, J=12.00, 5.00 Hz), 3.75(s, 3H, OCH₃), 3.09—3.20(m, 2H, CH₂)	170.7, 168.1, 165.9, 163.9, 152.1, 135.4, 130.6, 129.6(d, J_C—F=8.7 Hz), 125.5, 125.0, 121.0, 118.3, 115.8(d, J_C—F=21.6 Hz), 125.2, 55.4, 52.6, 34.9
9b	7.10—7.80(m, 8H, PhH), 4.34(dd, 1H, SCH, J=12.00, 6.00 Hz), 3.76(s, 3H, OCH₃), 3.10—3.19(m, 2H, CH₂)	170.6, 168.0, 164.1, 162.1, 152.1 135.4, 130.5, 130.3(d, J_C—F=8.0 Hz), 125.7, 125.0, 123.0, 121.0, 118.3, 114.2(d, J_C—F=22.6 Hz), 55.8, 52.7, 31.6
9c	7.10—8.08(m, 8H, PhH), 4.52(dd, 1H, SCH, J=11.50, 6.50 Hz), 3.73(s, 3H, OCH₃), 3.09—3.18(m, 2H, CH₂)	170.9, 168.0, 162.3, 160.4, 151.5 135.5, 132.6(d, J_C—F=8.7 Hz), 130.8, 130.5, 125.7, 124.9, 124.6, 121.5, 116.4(d, J_C—F=23.1 Hz) 55.4, 52.6, 34.9
9d	7.12—7.81(m, 7H, PhH), 4.51(dd, 1H, SCH, J=12.00, 5.50 Hz), 3.74(s, 3H, OCH₃), 3.17(t, 1H, CH₂, J=12.50 Hz), 3.08(dd, 1H, CH₂, J=13.00, 5.50 Hz)	170.7, 166.8, 151.3(dd, J_C—F=145.5, 13.5 Hz), 151.2, 149.3(dd, J_C—F=149.3, 13.5 Hz), 135.5, 130.5, 128.9(d, J_C—F=8.1 Hz), 126.0, 125.2(d, J_C—F=1.6 Hz), 125.0, 124.4(d, J_C—F=6.8 Hz), 121.5, 119.4(d, J_C—F=17.1 Hz), 55.5, 52.6, 34.9
9e	7.12—7.82(m, 7H, PhH), 4.51(dd, 1H, SCH, J=11.50, 6.50 Hz), 3.75(s, 3H, OCH₃), 3.08—3.16(m, 2H, CH₂)	170.7, 166.7, 159.7(dd, J_C—F=164.37, 1.50 Hz), 157.1(dd, J_C—F=167.00, 1.62 Hz), 151.1, 135.5, 130.5, 127.9(dd, J_C—F=13.50, 7.38 Hz), 126.0, 125.0, 121.6, 119.2(dd, J_C—F=24.38, 9.25 Hz), 117.7(dd, J_C—F=26.50, 8.37 Hz), 116.7(dd, J_C—F=25.37, 3.62 Hz), 55.5, 52.6, 34.7
9f	7.13—7.82(m, 7H, PhH), 4.51(dd, 1H, SCH, J=12.00, 5.50 Hz), 3.74(s, 3H, OCH₃), 3.17(t, 1H, CH₂, J=12.75 Hz), 3.08(dd, 1H, CH₂, J=13.00, 5.50 Hz)	170.7, 167.0, 151.9, 151.3(dd, J_C—F=145.5, 13.5 Hz), 149.8(dd, J_C—F=149.3, 13.5 Hz), 135.5, 130.6, 128.8(d, J_C—F=8.2 Hz), 126.0, 125.3(d, J_C—F=1.6 Hz), 125.0, 124.4(d, J_C—F=6.8 Hz), 121.5, 119.4(d, J_C—F=17.1 Hz), 55.5, 52.6, 34.9
9g	6.94—7.58(m, 7H, PhH), 4.35(dd, 1H, SCH, J=12.00, 6.00 Hz), 3.77(s, 3H, OCH₃), 3.06—3.16(m, 2H, CH₂)	170.5, 166.7, 163.2(dd, J_C—F=247.6, 12.5 Hz), 151.9, 140.8(t, J_C—F=8.6 Hz), 135.5, 130.6, 125.9, 125.0, 120.9, 110.3(dd, J_C—F=20.6, 6.1 Hz), 106.4(t, J_C—F=25.7 Hz), 55.8, 52.7, 31.5
9h	7.01—7.60(m, 7H, PhH), 4.49(dd, 1H, SCH, J=12.0, 5.5 Hz), 3.73(s, 3H, OCH₃), 3.23(t, 1H, CH₂, J=12.5 Hz), 2.87(dd, 1H, CH₂, J=13.0, 5.0 Hz)	170.6, 163.8, 160.3(dd, J_C—F=250.2, 6.7 Hz), 151.4, 135.4, 131.1(t, J_C—F=10.1 Hz), 130.4, 126.1, 125.3, 121.5, 118.1(t, J_C—F=18.1 Hz), 112.1(dd, J_C—F=20.2, 4.8 Hz), 55.6, 52.6, 35.8
9i	6.84—8.15(m, 7H, PhH), 4.48(dd, 1H, SCH, J=12.00, 5.50 Hz), 3.74(s, 3H, OCH₃), 3.06—3.17(m, 2H, CH₂)	170.7, 167.0, 164.7(dd, J_C—F=253.2, 12.5 Hz), 161.7(dd, J_C—F=251.6, 12.2 Hz), 151.0, 135.5, 132.3(dd, J_C—F=9.8, 4.5 Hz), 130.6, 127.9, 127.3, 126.0, 125.0, 112.3(dd, J_C—F=21.0, 3.0 Hz), 104.6(t, J_C—F=26.1 Hz), 55.4, 52.6, 34.8
14a	7.09—8.06(m, 8H, PhH), 4.34(dd, 1H, SCH, J=12.00, 5.50 Hz), 3.75(s, 3H, OCH₃), 3.09—3.20(m, 2H, CH₂)	170.7, 168.1, 165.9, 163.9, 152.1, 135.4, 130.6, 129.6(d, J_C—F=8.7 Hz), 125.5, 125.0, 121.0, 118.3, 115.8(d, J_C—F=21.2 Hz) , 125.2, 55.6, 52.7, 31.5
14b	7.11—7.81(m, 8H, PhH), 4.36(dd, 1H, SCH, J=12.00, 5.50 Hz), 3.76(s, 3H, OCH₃), 3.10—3.20(m, 2H, CH₂)	170.6, 168.1, 164.1, 162.1, 152.0, 135.0, 130.6, 130.3(d, J_C—F=7.2 Hz), 125.7, 125.0, 123.0, 121.0, 118.3, 114.2(d, J_C—F=22.7 Hz) 55.8, 52.7, 31.6
14c	7.12—8.08(m, 8H, PhH), 4.51(dd, 1H, SCH, J=12.00, 6.00 Hz), 3.73(s, 3H, OCH₃), 3.09—3.18(m, 2H, CH₂)	170.8, 168.1, 162.3, 160.4, 151.4, 135.5, 132.70(d, J_C—F=8.8 Hz), 130.8, 130.5, 125.8, 125.0, 124.6, 121.5, 116.4(d, J_C—F=23.1 Hz) 55.4, 52.6, 34.9
14d	7.13—8.01(m, 7H, PhH), 4.50(dd, 1H, SCH, J=12.00, 5.50 Hz), 3.74(s, 3H, OCH₃), 3.16(t, 1H, CH₂, J=12.50 Hz), 3.07(dd, 1H, CH₂, J=13.00, 5.50 Hz)	170.6, 166.7, 152.5(dd, J_C—F=145.7, 12.8 Hz), 152.1, 150.5(dd, J_C—F=149.1, 13.5 Hz), 135.5, 134.6(d, J_C—F=8.1 Hz), 130.6, 125.7, 125.0, 123.8(d, J_C—F=6.5 Hz), 120.8, 117.4(d, J_C—F=17.5 Hz), 116.5(d, J_C—F=18.5 Hz), 55.7, 52.7, 31.3
14e	7.12—7.84(m, 7H, PhH), 4.52(dd, 1H, SCH, J=11.00, 7.00 Hz), 3.75(s, 3H, OCH₃), 3.12—3.18(m, 2H, CH₂)	170.8, 166.7, 159.7(dd, J_C—F=164.4, 1.5 Hz), 157.1(dd, J_C—F=166.7, 1.6 Hz), 151.1, 135.5, 130.5, 127.9(dd, J_C—F=13.5, 7.3 Hz), 126.0, 125.0, 121.6, 119.2(dd, J_C—F=24.3, 9.2 Hz), 117.7(dd, J_C—F=26.5, 8.2 Hz), 116.7(dd, J_C—F=25.3, 3.6 Hz), 55.4, 52.6, 34.7
14f	7.12—7.81(m, 7H, PhH), 4.50(dd, 1H, SCH, J=12.00, 5.50 Hz), 3.74(s, 3H, OCH₃), 3.17(t, 1H, CH₂, J=12.75 Hz), 3.08(dd, 1H, CH₂, J=13.00, 5.50 Hz)	170.7, 166.9, 151.4, 151.3(dd, J_C—F=144.6, 13.5 Hz), 149.3(dd, J_C—F=153.0, 13.5 Hz), 135.5, 130.6, 128.8(d, J_C—F=8.1 Hz), 126.0, 125.3(d, J_C—F=1.6 Hz), 125.0, 124.4(d, J_C—F=6.8 Hz), 121.5, 119.4(d, J_C—F=17.0 Hz), 55.5, 52.6, 34.9
14g	6.94—7.58(m, 7H, PhH), 4.35(dd, 1H, SCH, J=12.00, 6.00 Hz), 3.77(s, 3H, OCH₃), 3.07—3.16(m, 2H, CH₂)	170.5, 166.7, 163.2(dd, J_C—F=247.2, 12.6 Hz), 151.9, 140.8(t, J_C—F=8.8 Hz), 135.5, 130.6, 125.9, 125.0, 120.9, 110.3(dd, J_C—F=20.6, 6.1 Hz), 106.4(t, J_C—F=25.7 Hz), 55.8, 52.7, 31.5
14h	7.00—7.60(m, 7H, PhH), 4.49(dd, 1H, SCH, J=12.0, 5.5 Hz), 3.73(s, 3H, OCH₃), 3.23(t, 1H, CH₂, J=12.5 Hz), 2.87(dd, 1H, CH₂, J=13.0, 5.0 Hz)	170.7, 163.9, 160.3(dd, J_C—F=250.1, 6.7 Hz), 151.3, 135.4, 131.1(t, J_C—F=10.1 Hz), 130.4, 126.1, 125.3, 121.5, 118.1(t, J_C—F=18.1 Hz), 112.1(dd, J_C—F=20.2, 4.8 Hz), 55.6, 52.6, 35.8
14i	6.86—8.19(m, 7H, PhH), 4.49(dd, 1H, SCH, J=12.00, 6.50 Hz), 3.74(s, 3H, OCH₃), 3.10—3.20(m, 2H, CH₂)	170.7, 167.1, 164.7(dd, J_C—F=246.7, 12.5 Hz), 161.7(dd, J_C—F=251.6, 12.2 Hz), 151.3, 135.6, 132.2(dd, J_C—F=9.8, 4.5 Hz), 130.5, 127.9, 127.3, 126.7, 125.0, 112.3(dd, J_C—F=21.0, 3.0 Hz), 104.3(t, J_C—F=26.1 Hz), 55.4, 52.6, 34.8

Scheme 2 Introduction of (R)-4-phenyl-2-oxazolidinone

Scheme 3 Introduction of (R)-4-phenyl-2-oxazolidinone

Scheme 4 Removal of (R)-4-phenyl-2-oxazolidinone

Scheme 5 Asymmetric synthesis of compound 9a

Fig.1 Structure of compound C

Fig.2 Crystal structure of compound 9h

Table 3 X-ray crystallographic data of compound 9h

Empirical formula	C₁₇H₁₃F₂NO₂S	T/K	298(2)
Formula mass	333.34	F(000)	688
Crystal system	Monoclinic	θ range for data collection/(°)	2.83—25.02
Space group	P2₁/n	Limiting indices	-8≤h≤9, -16≤k≤25, -11≤l≤10
a/nm	7.6497(7)	Reflections collected/unique	7578/2704(R_int=0.0294)
b/nm	21.5632(19)	Completeness to θ=25.02°(%)	99.80
c/nm	9.3170(8)	Absorption correction	Semi-empirical from equivalents
α/(°)	90	Max. and min. transmission	0.9249 and 0.9037
β/(°)	90.9530(10)	Refinement method	Full-matrix least-squares on F²
γ/(°)	90	Data/restraints/parameters	2704/0/209
Volume/nm³	1536.6(2)	Goodness-of-fit on F²	1.07
Z	4	FinalR indices [I>2σ(I)]	R₁=0.0447, wR₂=0.1060
Calculated density/(g·cm^-3)	1.441	R indices(all data)	R₁=0.0686, wR₂=0.1164
Absorption coefficient/mm^-1	0.240	Largest diff. peak and hole/(e·nm^-3)	0.218 and -0.225

Table 4 Zone(mm) of growth inhibition of compounds 9a—9i and 14a—14i*

Compd.	e.e.(%)	C. Neofonmans		Compd.	e.e.(%)	C. Neofonmans
Compd.	e.e.(%)	ATCC 34874		Compd.	Clinical isolate	ATCC 34874	Clinical isolate
9a, 14a(Raceme)	0	18.30	19.30	14e	70	21.47	21.90
9a	84	12.03	12.97	9f, 14f(Raceme)	0	18.23	18.87
14a	60	21.60	22.70	9f	67	15.30	15.23
9b, 14b(Raceme)	0	18.57	19.23	14f	54	20.07	19.70
9b	65	13.20	12.60	9g, 14g(Raceme)	0	14.67	17.53
14b	70	21.37	21.63	9g	65	13.23	16.20
9c, 14c(Raceme)	0	20.07	22.50	14g	73	15.23	17.50
9c	35	18.73	20.13	9h, 14h(Raceme)	0	6.00	6.00
14c	34	21.83	24.10	9h	71	6.00	6.00
9d, 14d(Raceme)	0	19.47	18.67	14h	40	6.00	6.00
9d	93	12.90	13.03	9i, 14i(Raceme)	0	11.70	10.57
14d	95	23.33	20.47	9i	71	6.00	6.00
9e, 14e(Raceme)	0	17.60	18.33	14i	40	13.83	14.20
9e	76	16.73	17.03	DMSO		6.00	6.00

Table 5 MIC and MFC values(μg/mL) for compounds 14a—14f and fluconazole

Compd.	MIC(C. Neofonmans)		MFC(C. Neofonmans)
Compd.	ATCC 34874	Clinical isolate	ATCC 34874	Clinical isolate
14a	10.0	4.0	22.0	20.0
14b	8.0	8.0	22.0	22.0
14c	10.0	8.0	22.0	22.0
14d	8.0	6.0	20.0	22.0
14e	10.0	8.0	20.0	24.0
14f	10.0	4.0	22.0	20.0
A	20.0	22.0	>128.0	>128.0

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