3950 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18
Chen and Seto
1
95%). H NMR (300 MHz, CDCl3): δ 1.45 (s, 9 H), 3.71 (s, 3
Com p ou n d 20. Yield, 86%. 1H NMR (300 MHz, DMSO-
d6): δ 1.12 (t, J ) 7.1 Hz, 6 H), 2.21 (s, 4 H), 4.04 (m, 4 H),
4.42 (s, 2 H), 5.09 (s, 4 H), 6.95 (d, J ) 8.7 Hz, 4 H), 7.28 (d,
J ) 8.7 Hz, 4 H), 7.44 (s, 4 H). 13C NMR (75 MHz, DMSO-d6):
δ 14.9, 58.4, 61.1, 69.8, 115.4, 128.6, 128.8, 134.2, 137.6, 158.4,
175.0. ESI (M + H+) calcd for C28H33N2O6, 493.2339; found,
493.2327.
H), 5.23 (d, J ) 7.1 Hz, 1 H), 5.61 (d, J ) 6.5 Hz, 1 H), 6.56 (s,
1 H), 6.75 (d, J ) 8.6 Hz, 2 H), 7.17 (d, J ) 8.1 Hz, 2 H). 13C
NMR (75 MHz, CDCl3): δ 28.7, 53.1, 57.5, 80.9, 116.2, 128.6,
128.8, 147.2, 155.5, 172.4. HRMS-FAB (M + Na+) calcd for
C
14H19NNaO5, 304.1161; found, 304.1166.
Rep r esen ta tive P r oced u r e for th e Syn th esis of Com -
Com p ou n d 21. Yield, 89%. 1H NMR (300 MHz, DMSO-
d6): δ 1.12 (t, J ) 7.1 Hz, 9 H), 2.17 (s, 6 H), 4.05 (m, 6 H),
4.43 (s, 3 H), 5.12 (s, 6 H), 6.97 (d, J ) 7.6 Hz, 6 H), 7.29 (d,
J ) 7.8 Hz, 6 H), 7.48 (s, 3 H). 13C NMR (75 MHz, DMSO-d6):
δ 14.9, 58.4, 61.1, 69.8, 115.4, 127.2, 128.8, 134.3, 138.5, 158.4,
175.1. ESI (M + H+) calcd for C39H46N3O9, 700.3234; found,
700.3252.
p ou n d s 14-17. Com p ou n d 15. To a solution of sodium (0.302
g, 13.1 mmol) dissolved in ethanol (50 mL) was added 9 (3.09
g, 11.0 mmol) and then R,R′-dibromo-m-xylene (11, 1.61 g, 4.40
mmol). The mixture was stirred continuously at room tem-
perature for 23 h under a N2 atmosphere, the solvent was
removed, and the residue was treated with H2O (30 mL) and
ethyl acetate (30 mL). The layers were separated, and the
aqueous layer was extracted with two portions of ethyl acetate
(30 mL). The organic layers were combined and washed with
H2O (30 mL), twice with a saturated solution of aqueous Na2-
CO3 (30 mL), and brine (30 mL), dried over Na2SO4, and
concentrated to dryness. Purification by flash column chro-
matography (1:1 hexane:ethyl ether) yielded compound 15
Rep r esen ta tive P r oced u r e for th e Syn th esis of Com -
p ou n d s 22-25. Com p ou n d 23. To a solution of 19 (0.344 g,
0.70 mmol) in dioxane (6 mL) was added a freshly prepared
aqueous solution (10 mL) of glyoxylic acid (0.736 g, 8.0 mmol)
and copper(II) sulfate pentahydrate (200 mg, 0.80 mmol) in a
buffer containing 2.5 M pyridine and 0.5 M acetic acid. The
mixture was stirred overnight at room temperature and then
extracted with three portions of methylene chloride (25 mL).
The organic layers were combined, washed twice with 1 N HCl
(20 mL), dried over Na2SO4, and then concentrated to dryness.
The residue was purified by flash column chromatography
1
(1.49 g, 2.15 mmol, 49%) as white foam. H NMR (300 MHz,
CDCl3): δ 1.23 (t, J ) 7.1 Hz, 6 H), 1.45 (s, 18 H), 4.19 (m, 4
H), 5.08 (s, 4 H), 5.25 (d, J ) 7.3 Hz, 2 H), 5.53 (d, J ) 6.6 Hz,
2 H), 6.96 (d, J ) 8.7 Hz, 4 H), 7.30 (d, J ) 8.7 Hz, 4 H), 7.41
(s, 3 H), 7.50 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ 14.4, 28.7,
57.5, 62.1, 70.2, 80.5, 115.5, 126.9, 127.5, 128.8, 129.3, 129.9,
1
(CHCl3) to yield 23 (66.4 mg, 0.14 mmol, 19%) as clear oil. H
137.6, 155.3, 159.1, 171.8. ESI (M + H+) calcd for C38H49N2O10
,
NMR (300 MHz, CDCl3): δ 1.44 (t, J ) 7.1 Hz, 6 H), 4.45 (q,
J ) 7.1 Hz, 4 H), 5.20 (s, 4 H), 7.07 (d, J ) 8.9 Hz, 4 H), 7.44
(m, 3 H), 7.52 (s, 1 H), 8.04 (d, J ) 8.9 Hz, 4 H). 13C NMR (75
MHz, CDCl3): δ 14.5, 62.6, 70.4, 115.4, 126.3, 126.8, 127.8,
129.6, 133.0, 136.9, 164.3, 164.5, 185.2. ESI (M + H+) calcd
for C28H27O8, 491.1706; found, 491.1721.
693.3387; found, 693.3369.
1
Com p ou n d 14. Yield, 43%. H NMR (300 MHz, CDCl3): δ
1.23 (t, J ) 7.1 Hz, 6 H), 1.45 (s, 18 H), 4.19 (m, 4 H), 5.16 (s,
4 H), 5.25 (d, J ) 7.9 Hz, 2 H), 5.52 (m, 2 H), 6.95 (d, J ) 8.4
Hz, 4 H), 7.29 (d, J ) 8.4 Hz, 4 H), 7.39 (dd, J ) 5.6, 3.3 Hz,
2 H), 7.52 (dd, J ) 5.5, 3.5 Hz, 2 H). 13C NMR (75 MHz,
CDCl3): δ 14.4, 28.7, 57.4, 62.1, 68.4, 80.4, 115.5, 128.8, 129.0,
129.4, 130.1, 135.3, 155.2, 159.0, 171.7. ESI (M + H+) calcd
for C38H49N2O10, 693.3387; found, 693.3407.
Com p ou n d 22. Yield, 16%. 1H NMR (300 MHz, DMSO-
d6): δ 1.31 (t, J ) 7.1 Hz, 6 H), 4.39 (q, J ) 7.1 Hz, 4 H), 5.39
(s, 4 H), 7.21 (d, J ) 8.9 Hz, 4 H), 7.42 (dd, J ) 5.5, 3.5 Hz, 2
H), 7.56 (dd, J ) 5.5, 3.5 Hz, 2 H), 7.91 (d, J ) 8.9 Hz, 4 H).
13C NMR (75 MHz, DMSO-d6): δ 14.7, 63.0, 68.6, 116.4, 125.6,
129.4, 129.8, 133.1, 135.3, 164.7, 165.0, 186.1. ESI (M + Na+)
calcd for C28H26NaO8, 513.1526; found, 513.1502.
1
Com p ou n d 16. Yield, 47%. H NMR (300 MHz, CDCl3): δ
1.23 (t, J ) 7.1 Hz, 6 H), 1.45 (s, 18 H), 4.19 (m, 4 H), 5.07 (s,
4 H), 5.25 (d, J ) 6.9 Hz, 2 H), 5.51 (d, J ) 6.6 Hz), 6.96 (d, J
) 8.7 Hz, 4 H), 7.30 (d, J ) 8.7 Hz, 4 H), 7.45 (s, 4 H). 13C
NMR (75 MHz, CDCl3): δ 14.4, 28.7, 57.5, 62.1, 70.1, 80.4,
115.5, 128.1, 128.8, 130.0, 137.1, 155.2, 159.1, 171.7. ESI (M
+ H+) calcd for C38H49N2O10, 693.3387; found, 693.3395.
1
Com p ou n d 24. Yield, 21%. H NMR (300 MHz, CDCl3): δ
1.44 (t, J ) 7.1 Hz, 6 H), 4.45 (q, J ) 7.1 Hz, 4 H), 5.19 (s, 4
H), 7.06 (d, J ) 8.8 Hz, 4 H), 7.48 (s, 4 H), 8.03 (d, J ) 8.8 Hz,
4 H). 13C NMR (75 MHz, CDCl3): δ 14.5, 62.6, 70.3, 115.4,
126.2, 128.3, 133.0, 136.4, 164.4, 164.5, 185.2. ESI (M + Na+)
calcd for C28H26NaO8, 513.1526; found, 513.1514.
1
Com p ou n d 17. Yield, 21%. H NMR (300 MHz, CDCl3): δ
1.23 (t, J ) 7.1 Hz, 9 H), 1.45 (s, 27 H), 4.20 (m, 6 H), 5.09 (s,
6 H), 5.26 (d, J ) 7.1 Hz, 3 H), 5.54 (d, J ) 6.0 Hz, 3 H), 6.96
1
Com p ou n d 25. Yield, 15%. H NMR (300 MHz, CDCl3): δ
(d, J ) 8.7 Hz, 6 H), 7.31 (d, J ) 8.7 Hz, 6 H) 7.46 (s, 3 H). 13
C
1.44 (t, J ) 7.1 Hz, 9 H), 4.45 (q, J ) 7.1 Hz, 6 H), 5.21 (s, 6
H), 7.07 (d, J ) 8.9 Hz, 6 H), 7.50 (s, 3 H), 8.04 (d, J ) 8.9 Hz,
6 H). 13C NMR (75 MHz, CDCl3): δ 14.5, 62.6, 70.1, 115.4,
126.4, 126.6, 133.1, 137.6, 164.2, 164.4, 185.1. ESI (M + H+)
calcd for C39H37O12, 697.2285; found, 697.2306.
NMR (75 MHz, CDCl3): δ 14.4, 28.7, 57.5, 62.1, 70.1, 80.5,
115.5, 126.4, 128.8, 130.1, 138.2, 155.2, 159.1, 171.7. ESI (M
+ H+) calcd for C54H70N3O15, 1000.4807; found, 1000.4817.
Rep r esen ta tive P r oced u r e for th e Syn th esis of Com -
p ou n d s 18-21. Com p ou n d 19. Compound 15 (1.85 g, 2.67
mmol) was dissolved in a solution of 20% trifluoroacetic acid
(TFA) in methylene chloride (10 mL), and the solution was
stirred in an ice bath for 2 h. The solvent was removed, and
the residue was taken up in methylene chloride (30 mL) and
washed twice with a saturated solution of aqueous NaHCO3
(20 mL). The organic layer was dried over Na2SO4, and the
solvent was removed by rotary evaporation to yield compound
19 (1.19 g, 2.42 mmol, 91%) as a clear oil. 1H NMR (300 MHz,
DMSO-d6): δ 1.11 (t, J ) 7.1 Hz, 6 H), 2.19 (s, 4 H), 4.04 (m,
4 H), 4.42 (s, 2 H), 5.09 (s, 4 H), 6.96 (d, J ) 8.5 Hz, 4 H), 7.28
(d, J ) 8.5 Hz, 4 H), 7.39 (s, 3 H), 7.51 (s, 1 H). 13C NMR (75
MHz, DMSO-d6): δ 14.9, 55.8, 58.4, 61.1, 69.9, 115.4, 127.7,
128.0, 129.4, 134.3, 138.2, 158.5, 175.1. ESI (M + H+) calcd
for C28H33N2O6, 493.2339; found, 493.2344.
Com p ou n d 18. Yield, 85%. 1H NMR (300 MHz, DMSO-
d6): δ 1.12 (t, J ) 7.1 Hz, 6 H), 2.21 (s, 4 H), 4.04 (s, 4 H), 4.42
(s, 2 H), 5.21 (s, 4 H), 6.97 (d, J ) 8.7 Hz, 4 H), 7.28 (d, J )
8.7 Hz, 4 H), 7.36 (dd, J ) 5.6, 3.4 Hz, 2 H), 7.51 (dd, J ) 5.4,
3.4 Hz, 2 H). 13C NMR (75 MHz, DMSO-d6): δ 14.9, 58.5, 61.1,
112.7, 115.4, 128.8, 129.3, 134.4, 136.0, 158.4, 175.0. ESI (M
+ H+) calcd for C28H33N2O6, 493.2339; found, 493.2340.
Rep r esen ta tive P r oced u r e for th e Syn th esis of Com -
p ou n d s 3-6. Com p ou n d 4. To a solution of compound 23
(66.4 mg, 0.135 mmol) in methanol (2 mL) was added 2.5 M
NaOH (2 mL). The mixture was stirred at 50 °C for 1 h, cooled,
and acidified with concentrated HCl to approximately pH 2.
The precipitate was collected by centrifugation and then
resuspended in water (5 mL). Addition of ethyl acetate (5 mL)
dissolved the precipitate, and after the layers were separated,
the aqueous layer was extracted twice with ethyl acetate (5
mL). The ethyl acetate layers were combined, dried over Na2-
SO4, and concentrated to dryness to yield 4 as a yellow solid
(40.5 mg, 0.093 mmol, 69%). The compounds were purified
1
further by HPLC (see the Supporting Information). H NMR
(300 MHz, DMSO-d6): δ 5.27 (s, 4 H), 7.22 (d, J ) 8.8 Hz, 4
H), 7.46 (s, 3 H), 7.59 (s, 1 H), 7.89 (d, J ) 8.8 Hz, 4 H). 13C
NMR (75 MHz, DMSO-d6): δ 70.4, 116.3, 125.8, 128.2, 128.5,
129.7, 132.8, 137.4, 164.5, 167.4, 188.1. ESI (M - H+, negative
ion mode) calcd for C24H17O8, 433.0923; found, 433.0932.
1
Com p ou n d 3. Yield, 93%. H NMR (300 MHz, DMSO-d6):
δ 5.38 (s, 4 H), 7.22 (d, J ) 8.9 Hz, 4 H), 7.41 (dd, J ) 5.5, 3.5
Hz, 2 H), 7.56 (dd, J ) 5.5, 3.5 Hz, 2 H), 7.89 (d, J ) 8.9 Hz,
4 H). 13C NMR (75 MHz, DMSO-d6): δ 68.5, 116.3, 125.8,