Pollex et al.
Viridiofungin A ester (+)-38a and (-)-39a. To a solution
of the â-hydroxy acid 37a (27 mg, 0.06 mmol, 1.0 equiv) in
CH2Cl2 (20 mL/mmol 37a) were added benzotriazol-1-yloxy-
tripyrolidinophosphonium hexaflurophosphate (PyBOP) (44
mg, 0 08 mmol, 1.5 equiv), N-methylmorpholine (NMM) (27
µL, 0.24 mmol, 4.4 equiv), and L-tyrosine methyl ester (16 mg,
0.08 mmol, 1.5 equiv) at ambient temperature. The resulting
mixture was stirred overnight and then added to saturated
aq NaHCO3. The aqueous layer was extracted with CH2Cl2 (3
× 5 mL). The combined organic phases were dried over MgSO4
and concentrated. Flash chromatography (heptane/ethyl ac-
etate 1/1 to pure ethyl acetate) afforded 38a and 39a as a 1:1
mixture (26 mg, 0.04 mmol, 71%): Rf 0.53 ethyl acetate. The
diastereomers were separated by reversed-phase HPLC. For
details, see the Supporting Information.
to pure ethyl acetate) afforded 38b and 39b as a 1:1 mixture
(28 mg, 0.04 mmol, 90%): Rf 0.38 ethyl acetate. The diaster-
eomers were separated by reversed-phase HPLC; see the
Supporting Information for details.
1
(+)-38b: H NMR (500 MHz, CDCl3) δ 7.06 (d, J ) 7.7 Hz,
1H, NH), 6.93 (d, J ) 8.4 Hz, 2H, 5′-CH-Ar), 6.77 (d, J ) 8.4
Hz, 2H, 6′-CH-Ar), 5.54 (ddd, J ) 15.2, 6.4, 6.4 Hz, 1H, 6-CHd
), 5.23 (dd, J ) 15.3, 9.6 Hz, 1H, 5-CHd), 5.03 (sept, J ) 6.3
Hz, 1H, OiPr-CH), 4.73 (ddd, J ) 7.8, 7.8, 4.7 Hz, 1H, 2′-H),
4.23 (s, 1H, 3-OH), 3.75 (s, 3H, 1′-CO2CH3), 3.64 (s, 3H, 1-CO2-
CH3), 3.16 (ddAB, J ) 14.3, 4.7 Hz, 1H, 3′-CH2), 3.13 (d, J )
9.6 Hz, 1H, 4-H), 3.05 (dAB, J ) 16.4 Hz, 1H, 2-CH2), 2.89 (dAB
,
J ) 16.4 Hz, 1 H, 2-CH2), 2.88 (ddAB, J ) 14.4, 8.0 Hz, 1H,
3′-CH2) 2.45 (t, J ) 7.0 Hz, 2H, 12- or 14-CH2), 2.42 (t, J ) 7.6
Hz, 2H, 12- or 14-CH2), 1.91-1.86 (m, 2H, 7-CH2), 1.59-1.52
(m, 4H, 11- and 15-CH2), 1.29-1.20 (m, 24H, OiPr-CH3, 8-,9-
,10-CH2 and 16-,17-,18-,19-,20-,21-CH2), 0.86 (t, J ) 7.0 Hz,
3H, 22-CH3), no signal detected for 7′-OH; 13C NMR (CDCl3,
125.8 MHz) δ 214.2 (13-CdO), 172.3 (CO2iPr), 171.9 (1′-CO2-
CH3), 170.6 (1-CO2CH3), 170.4 (CONH), 155.6 (7′-COH), 137.1
(6-CH), 130.2 (2 × 5′-CH), 127.1 (4′-C), 121.6 (5-CH), 115.4 (2
× 6′-CH), 75.8 (3-C), 70.5 (OiPr-CH), 58.0 (4-CH), 53.2 (2′-
CH), 52.4 (CO2CH3), 51.8 (CO2CH3), 43.0 (12- or 14-CH2), 42.7
(12- or 14-CH2), 41.0 (2-CH2), 36.5 (3′-CH2), 32.3 (7-CH2), 31.8
(20-CH2), 29.4 (CH2), 29.3 (CH2), 29.24 (CH2), 29.20 (CH2), 28.8
(CH2), 28.7 (CH2), 28.0 (CH2), 23.9 (11- or 15-CH2), 23.4 (11-
or 15-CH2), 22.6 (21-CH2), 21.7 (OiPr-CH3), 21.5 (OiPr-CH3),
14.1 (22-CH3); IR (in substance) ν 3354, 2926, 2490, 2854,
1
(+)-38a: H NMR (500 MHz, CDCl3) δ 7.05 (d, J ) 7.7 Hz,
1H, NH), 7.01 (br s, 1H, Ph-OH), 6.94 (d, J ) 8.5 Hz, 2H, 5′-
CH-Ar), 6.77 (d, J ) 8.5 Hz, 2H, 6′-CH-Ar), 5.55 (ddd, J )
15.2, 6.4, 6.4 Hz, 1H, 6-CHd), 5.23 (dd, J ) 15.3, 9.6 Hz, 1H,
5-CHd), 5.03 (sept, J ) 6.2 Hz, 1H, OiPr-CH), 4.73 (ddd, J )
7.9, 7.9, 4.7 Hz, 1H, 2′-CH), 4.23 (s, 1H, 3-OH), 3.75 (s, 3H,
1′-CO2CH3), 3.64 (s, 3H, 1-CO2CH3), 3.15-3.08 (m, 1H, 3′-CH2),
3.13 (d, J ) 9.5 Hz, 1H, 4-CH), 3.05 (d, J ) 16.3 Hz, 1H,
2-CH2), 2.89 (d, J ) 16.1 Hz, 1H, 2-CH2), 2.91-2.86 (m, 1H,
3′-CH2) 2.45 (t, J ) 7.0 Hz, 2H, 12- or 14-CH2), 2.43 (t, J ) 7.5
Hz, 2H, 12- or 14-CH2), 1.92-1.83 (m, 2H, 7-CH2), 1.62-1.48
(m, 4H, 11- and 15-CH2), 1.30-1.15 (m, 20H, OiPr-CH3, 8-,9-
,10-CH2 and 16-,17-,18-,19-CH2), 0.86 (t, J ) 6.9 Hz, 3H, 20-
CH3) 13C NMR (CDCl3, 125.8 MHz) δ 214.3 (13-CdO), 172.3
(CO2iPr), 171.9 (1′-CO2CH3), 170.6 (1-CO2CH3), 170.4 (CONH),
155.6 (7′-COH-Ar), 137.1 (6-CHd), 130.2 (2 × 5′-CH-Ar), 127.1
(4′-C-Ar), 121.6 (5-CHd), 115.4 (2 × 6′-CH-Ar), 75.9 (3-C), 70.5
(OiPr-CH), 58.0 (4-CH), 53.2 (2′-CH), 52.4 (CO2CH3), 51.8
(CO2CH3), 43.0 (12- or 14-CH2), 42.7 (12- or 14-CH2), 41.0 (2-
CH2), 36.5 (3′-CH2), 32.3 (7-CH2), 31.6 (18-CH2), 29.2 (CH2),
29.0 (CH2), 28.8 (CH2), 28.7 (CH2), 28.0 (CH2), 23.9 (11- or 15-
CH2), 23.4 (11- or 15-CH2), 22.6 (19-CH2), 21.8 (OiPr-CH3), 21.5
(OiPr-CH3), 14.0 (20-CH3); IR (in substance) ν 3372, 2931,
2491, 1742 cm-1; [R]25D +52.9 (c 0.51, CHCl3). Anal. Calcd for
C36H55NO10: C, 65.33; H, 8.38. Found: C, 65.06; H, 8.48.
1741-1; [R]25 +22.9 (c 1.0, CHCl3). Anal. Calcd for C38H59-
D
NO10: C, 66.16; H, 8.62; N, 2.03. Found: C, 66.55; H, 8.62; N,
2.01.
(-)-39b: 1H NMR (500 MHz, CDCl3) δ 6.95 (d, J ) 8.4 Hz,
2H, 5′-CH-Ar), 6.75 (d, J ) 9.0 Hz, 1H, NH), 6.74 (d, J ) 8.5
Hz, 2H, 6′-CH-Ar), 5.62 (ddd, J ) 15.2, 6.6, 6.6 Hz, 1H, 6-CHd
), 5.48 (dd, J ) 15.3, 9.5 Hz, 1H, 5-CHd), 5.04 (sept, J ) 6.3
Hz, 1H, CO2iPr-CH), 4.76 (ddd, J ) 7.5, 7.4, 5.0 Hz, 1H, 2′-
CH), 4.47 (s, 1H, 3-OH), 3.72 (s, 3 H, 1′-CO2CH3), 3.65 (s, 3H,
1-CO2CH3), 3.15 (d, J ) 9.5 Hz, 1H, 4-H), 3.09 (ddAB, J ) 14.2,
4.9 Hz, 1H, 3′-CH2), 2.98 (ddAB, J ) 14.1, 6.8 Hz, 1H, 3′-CH2),
2.83 (dAB, J ) 16.0 Hz, 1H, 2-CH2), 2.62 (dAB, J ) 16.0 Hz, 1H,
2-CH2), 2.45 (t, J ) 7.2 Hz, 2H, 12- or 14-CH2), 2.43 (t, J ) 7.5
Hz, 2H, 12- or 14-CH2), 1.98-1.92 (m, 2H, 7-CH2), 1.58-1.50
(m, 4H, 11- and 15-CH2), 1.29-1.20 (m, 24H, OiPr-CH3, 8-,9-
,10-CH2 and 16-,17-,18-,19-,20-,21-CH2), 0.86 (t, J ) 6.9 Hz,
3H, 22-CH3) no signal detected for 7′-OH; 13C NMR (CDCl3,
125.8 MHz) δ 213.3 (13-CdO), 172.1 (CO2iPr), 171.6 (1′-CO2-
CH3), 170.7 (CONH), 170.5 (1-CO2CH3), 155.5 (7′-COH-Ar),
137.8 (6-CHd), 130.4 (2 × 5′-CH-Ar), 127.1 (4′-C-Ar), 122.3
(5-CHd), 115.5 (2 × 6′-CH-Ar), 76.1 (3-C), 70.2 (OiPr-CH), 57.6
(4-CH), 53.3 (2′-CH), 52.3 (CO2CH3), 51.8 (CO2CH3), 43.0 (12-
or 14-CH2), 42.7 (12- or 14-CH2), 41.5 (2-CH2), 36.7 (3′-CH2),
32.4 (7-CH2), 31.8 (20-CH2), 29.40 (CH2), 29.36 (CH2), 29.24
(CH2), 29.20 (CH2), 28.9 (2 × CH2), 28.6 (CH2), 23.9 (11- or
15-CH2), 23.5 (11- or 15-CH2), 22.6 (21-CH2), 21.7 (OiPr-CH3),
21.5 (OiPr-CH3), 14.1 (22-CH3); IR (in substance) ν 3346, 2926,
(-)-39a: 1H NMR (500 MHz, CDCl3) δ 6.95 (d, J ) 8.4 Hz,
2H, 5′-CH-Ar), 6.76 (d, J ) 8.5 Hz, 2H, 6′-CH-Ar), 6.67 (d, J )
7.9 Hz, 1H, NH), 6.34 (s, 1H, Ph-OH), 5.63 (ddd, J ) 15.2, 6.6,
6.6 Hz, H, 6-CHd), 5.49 (dd, J ) 15.3, 9.6 Hz, 1H, 5-CHd),
5.05 (sept, J ) 6.3 Hz, 1H, CO2iPr-CH), 4.74 (ddd, J ) 7.1,
7.0, 5.1 Hz, 1H, 2′-CH), 4.49 (s, 1H, 3-OH), 3.72 (s, 3H, 1′-
CO2CH3), 3.65 (s, 3H, 1-CO2CH3), 3.16 (d, J ) 9.5 Hz, 1H,
4-CH), 3.09 (ddAB, J ) 14.1, 4.9 Hz, 1H, 3′-CH2), 3.00 (ddAB, J
) 14.1, 6.8 Hz, 1H, 3′-CH2), 2.85 (dAB, J ) 16.0 Hz, 1H, 2-CH2),
2.68 (dAB, J ) 16.0 Hz, 1H, 2-CH2), 2.42 (t, J ) 7.2 Hz, 2H,
12- or 14-CH2), 2.41 (t, J ) 7.4 Hz, 2H, 12- or 14-CH2), 2.01-
1.92 (m, 2H, 7-CH2), 1.59-1.48 (m, 4H, 11- and 15-CH2), 1.34-
1.18 (m, 20 H, OiPr-CH3, 8-,9-,10-CH2 and 16-,17-,18-,19-CH2),
0.86 (t, J ) 6.9 Hz, 3H, 20-CH3); 13C NMR (CDCl3, 125.8 MHz)
δ 213.4 (13-CdO), 172.2 (CO2iPr), 171.6 (1′-CO2CH3), 170.6
(CONH), 170.5 (1-CO2CH3), 155.4 (7′-COH-Ar), 137.8 (6-CHd
), 130.4 (2 × 5′-CH-Ar), 127.3 (4′-C-Ar), 122.4 (5-CHd), 115.5
(2 × 6′-CH-Ar), 76.1 (3-C), 70.2 (OiPr-CH), 57.6 (4-CH), 53.3
(2′-CH), 52.3 (CO2CH3), 51.8 (CO2CH3), 43.0 (12- or 14-CH2),
42.7 (12- or 14-CH2), 41.6 (2-CH2), 36.6 (3′-CH2), 32.5 (7-CH2),
31.7 (18-CH2), 29.7 (CH2), 29.2 (CH2), 29.0 (CH2), 28.9 (CH2),
28.5 (CH2), 23.9 (11- or 15-CH2), 23.5 (11- or 15-CH2), 22.6 (19-
CH2), 21.7 (OiPr-CH3), 21.6 (OiPr-CH3), 14.1 (20-CH3); IR (in
substance) ν 3334, 2926, 2464, 1743 cm-1; [R]25D -6.6 (c 0.15,
CHCl3) (lit. trimethyl ester [R]25D -23.0 (c 0.47, MeOH)). Anal.
Calcd for C36H55NO10: C, 65.33; H, 8.38. Found: C, 65.47; H,
8.48.
2854, 1741 cm-1; [R]25 -5.1 (c 1.4, CHCl3). Anal. Calcd for
D
C38H59NO10: C, 66.16; H, 8.62; N, 2.03. Found: C, 66.50; H,
8.78; N, 2.09.
Viridiofungin A2 Ester (+)-38c and (-)-39c. As described
for the preparation of 38a and 39a, â-hydroxy acid 37c (30
mg, 0.06 mmol) was treated with PyBOP (50 mg, 0.10 mmol),
NMM (31 µL, 0.28 mmol), and L-tyrosine methyl ester (19 mg,
0.10 mmol). Flash chromatography (heptane/ethyl acetate 1/1
to ethyl acetate) afforded 38c and 39c as a 1:1 mixture (33
mg, 0.05 mmol, 80%): Rf 0.38 ethyl acetate. The diastereomers
were separated by reversed-phase HPLC; see the Supporting
Information for details.
Viridiofungin A4 Ester (+)-38b and (-)-39b. As described
for the preparation of 38a and 39a, â-hydroxy acid 37b (22
mg, 0.045 mmol) was treated with PyBOP (36 mg, 0.07 mmol),
NMM (23 µL, 0.2 mmol), and L-tyrosine methyl ester (13 mg,
0.07 mmol). Flash chromatography (heptane/ethyl acetate 1/1
(+)-38c: 1H NMR (500 MHz, CDCl3) δ 7.06 (d, J ) 7.9 Hz,
1H, NH), 6.96 (d, J ) 8.5 Hz, 2H, 5′-CH-Ar), 6.71 (d, J ) 8.5
Hz, 2H, 6′-CH-Ar), 5.56 (ddd, J ) 14.8, 6.6, 6.6 Hz, 1H, 6-CHd
), 5.31 (dd, J ) 15.2, 9.6 Hz, 1H, 5-CHd), 5.04 (sept, J ) 6.2
Hz, 1H, OiPr-CH), 5.02 (br s, 1H, 7′-OH), 4.77 (ddd, J ) 7.1,
5590 J. Org. Chem., Vol. 70, No. 14, 2005