134 J . Org. Chem., Vol. 67, No. 1, 2002
Cano et al.
calcd for C20H22O4S2 413.0857, found 413.0847. Anal. Calcd
for C20H22O4S2: C, 61.51; H, 5.68; S, 16.42. Found: C, 61.61;
H, 5.22; S, 16.22.
2-(9H-F lu or en -9-ylm eth oxyca r bon yla m in o)-3-m eth yl-
bu tyr ic Acid [3-(3-ter t-bu toxyca r bon ylp r op oxy)-5-m eth -
oxyp h en yl](2-p h en yl[1,3]d ith ia n -2-yl)m eth yl Ester (20a ).
Into a dry round-bottom flask were placed PS-carbodiimide
resin (2.13 g, 2 × 10-3 mol, 4 equiv, 0.94 mmol/g) and N-R-
Fmoc-L-valine (0.52 g, 1.53 × 10-4 mol, 3 equiv). The system
was purged with argon/vacuum and dissolved in DCM. The
mixture was stirred for 10 min prior to addition of a solution
of the alcohol linker 10 (0.250 g, 1.53 × 10-4 mol, 1 equiv) and
DMAP (6.2 mg, 5.1 × 10-5 mol, 0.1 equiv) in DCM. The
reaction was shaken at room temperature for 5 h, when
monitoring by LCMS showed no alcohol 10 left. The DMAP
was scavenged using Dowex (H+) resin. The two resins were
removed by filtration, and the evaporation of the filtrate
yielded the desired ester. The product was finally purified by
column chromatography eluting with hexane/ethyl acetate (7:
(()-4-{3-[Acetoxy-(2-p h en yl[1,3]d ith ia n -2-yl)m eth yl]-5-
m eth oxyp h en oxy}bu tyr ic Acid ter t-Bu tyl Ester (15). A
solution of phenol 14 (0.45 g, 1.15 × 10-3 mol), tert-butyl
4-bromobutanoate (0.3 g, 1.38 × 10-3 mol, 1.2 equiv), potas-
sium carbonate (0.38 g, 2.76 × 10-3 mol, 2.4 equiv), and
catalytic tetrabutylammonium iodide (85 mg, 2.3 × 10-4 mol,
0.2 equiv) in 65 mL of MeCN was heated at 90 °C for 20 h
under argon. Then the mixture was allowed to cool and washed
with brine. The combined organic layers were dried with Na2-
SO4 and concentrated in vacuo to leave 0.97 g. Purification by
flash chromatography afforded compound 15 (0.408 g, 75%
1
isolated yield) and recovered 14 (40 mg). H NMR (400 MHz,
δ, ppm): 7.74-7.77 (m, 2H), 7.25-7.33 (m, 3H), 6.29 (s, 1H),
6.00 (s, 1H), 6.07 (s, 1H), 5.99 (s, 1H), 3.73 (t, J ) 6, 2H), 3.56
(s, 3H), 2.61-2.69 (m, 4H), 2.34 (t, J ) 7, 2H), 2.09 (s, 3H),
1.95 (q, J ) 7, 4H), 1.44 (s, 9H). 13C NMR (100 MHz, δ, ppm):
172.47, 169.33, 159.41, 158.78, 138.13, 136.88, 130.94, 127.94,
127.51, 107.12, 106.64, 101.44, 80.22, 66.75, 63.26, 55.08,
31.99, 28.66, 27.29, 27.16, 24.64, 24.61, 20.88. FTIR (film, ν,
cm-1): 2975, 1751, 1729, 1599, 1467, 1367, 1226, 1151, 1034,
908, 732. HPLC: Rt ) 5.84 min. MS (ESI + ve, m/z, rel intes):
550.72 (30, M + 18), 474.6 (100, M - tBu). HRMS (ESI + ve):
[MNa+] calcd for C28H36O6S2 555.1851, found 555.1847. Anal.
Calcd for C28H36O6S2: C, 63.13; H, 6.81; S, 12.04. Found: C,
62.81; H, 6.91; S, 11.76.
1
3) to give product 20a as a white solid (0.41 g, 90%). H NMR
(400 MHz, δ, ppm): 7.79-7.72 (m, 6H), 7.56-7.60 (m, 2H),
7.39-7.23 (m, 5H), 6.29 (s, 1H), 6.09, 6.06 (s, 1H), 6.02 (s, 1H),
5.95 (s, 1H), 5.31 (t, J ) 11, 1H), 4.42-4.33 (m, 3H), 4.25, 4.21
(t, J ) 7, 1H), 3.76 (t, 7 Hz, 2H), 3.55 (s, 3H), 2.67-2.61 (m,
4H), 2.36-2.32 (m, 2H), 2.15-2.16 (m, 1H), 1.95-1.94 (m, 2H),
1.88-1.87 (m, 2H), 1.44 (s, 9H), 0.99, 0.89, 0.74 (d, J ) 7 Hz,
6H). 13C NMR (100 MHz, δ, ppm) (most of the signals are
doublets because of the mixture of diastereomers): 170.36,
170.46, 172.46, 158.83, 159.48, 156.14, 141.24, 143.94, 143.77,
136.20, 136.28, 136.58, 136.66, 119.89, 125.08, 127.05, 127.63,
127.68, 128.00, 128.06, 131.07, 106.39, 106.45, 107.18, 101.83,
81.79, 81.63, 67.01, 67.09, 66.74, 63.08, 62.94, 59.18, 58.88,
55.02, 55.08, 47.19, 31.99, 31.27, 31.35, 28.10, 27.20, 27.14,
24.62, 19.37, 19.02, 17.20, 17.33. HPLC: Rt ) 6.37 min. MS
(ESI + ve, m/z, rel intens): 829 (30, M + 18), 473 (100, M -
valine). HRMS (ESI + ve): [MNa+] calcd for C46H53NO8S2
834.3110, found 834.30940.
(()-4-{3-[Hyd r oxy(2-p h en yl[1,3]d ith ia n -2-yl)m eth yl]-5-
m eth oxyp h en oxy}bu tyr ic Acid ter t-Bu tyl Ester (10). A
solution of 15 (0.95 gm 1,78 × 10-3 mol), potassium carbonate
(1.52 g, 3.75 × 10-3 mol, 2.1 equiv), and triethylamine (7.4
mL, 5.34 × 10-2 mol, 30 equiv) in 80 mL of MeOH/water (1:1)
was heated at 70 °C for 3 h, when TLC showed complete
conversion. The mixture was concentrated in vacuo and the
aqueous residue extracted with EtOAc. The aqueous layer was
neutralized with HCl (1 M) and re-extracted with EtOAc. The
combined organic layers were dried (Na2SO4) and concentrated
2-(9H-F lu or en -9-ylm eth oxyca r bon yla m in o)-3-m eth yl-
bu tyr ic Acid [3-(3-Ca r boxyp r op oxy)-5-m eth oxyp h en yl]-
(2-p h en yl[1,3]d ith ia n -2-yl)m eth yl Ester (20b). 20b was
prepared by the same procedure as that for the synthesis of
16. tert-Butyl derivative 20a (0.2 g, 2.5 × 10-4 mol) was stirred
in 10 mL of HCOOH for 6 h, when the crude mixture was
worked up following the former procedure to leave 0.206 g.
This was purified by column chromatography to give 20b as
1
in vacuo to afford product 10 (0.83 g, 95%) in 99% purity. H
NMR (400 MHz, δ, ppm): 7.69-7.72 (m, 2H), 7.23-7.31 (m,
3H), 6.27 (s, 1H), 5.98 (s, 1H), 4.90 (s, 1H), 5.95 (s, 1H), 3.71
(t, J ) 6, 2H), 3.54 (s, 3H), 2.64-2.73 (m, 4H), 2.33 (t, J ) 6,
2H), 1.88-1.95 (m, 4H), 1.43 (s, 9H). 13C NMR (100 MHz, δ,
ppm): 172.5, 159.41, 158.77, 139.37, 137.57, 130.69, 128.14,
127.51, 107.12, 106.66, 106.09, 101.38, 80.29, 66.78, 66.30,
55.12, 32.05, 28.13, 27.34, 27.07, 24.79, 24.68. FTIR (film, ν,
cm-1): 3500, 2933, 1728, 1597, 1467, 1367, 1226, 1153, 1059.
HPLC: Rt ) 5.68 min. MS (ESI + ve, m/z, rel intens): 508.76
(50, M + 18), 473 (100, M - 17). HRMS (ESI + ve): [MNa+]
calcd for C26H34O5S2 513.1745, found 513.1750.
(()-4-{3-[Hyd r oxy(2-p h en yl[1,3]d ith ia n -2-yl)m eth yl]-5-
m eth oxyp h en oxy}bu tyr ic Acid (16). A solution of 10 (0.83
g, 1.69 × 10-3 mol) in formic acid (35 mL) was stirred at room
temperature for 5 h,29 when complete disappearance of 10 was
detected by TLC. The solvent was removed under reduced
pressure, and the crude product was redissolved in EtOAc and
washed with saturated NaHCO3 solution and brine. The
combined organic layers were dried (Na2SO4) and evaporated
in vacuo to afford 0.76 g. Purification by column chromatog-
raphy gave deprotected linker 16 (0.70 g, 90%) in high purity.
1H NMR (400 MHz, δ, ppm): 7.69-7.71 (m, 2H), 7.31-7.24
(m, 3H), 6.27 (s, 1H), 5.98 (s, 1H), 4.91 (s, 1H), 5.95 (s, 1H),
3.73 (t, J ) 6, 2H), 3.55 (s, 3H), 2.71-2.63 (m, 4H), 2.51 (t, J
) 5 Hz, 2H), 1.99 (q, J ) 6, 2H), 1.98-1.88 (m, 2H). 13C NMR
(100 MHz, δ, ppm): 178.8, 159.1, 158.14, 138.98, 137.09,
130.30, 127.73, 127.09, 106.05, 105.81, 100.91, 80.57, 65.94,
52.06, 54.72, 30.10, 26.91, 26.55, 24.36, 23.83. FTIR (film, ν,
cm-1): 3415, 2917, 1732, 1608. HPLC: Rt ) 5.68 min. MS (ESI
+ ve, m/z, rel intens): 417.4 (100, M - OH), 452 (30, M + 18).
HRMS (ESI + ve): [MNa+] calcd for C22H26O5S2 457.1119,
found 457.1110.
1
an oil (0.13 g, 70%). H NMR (500 MHz, δ, ppm): 7.79-7.72
(m, 5H), 7.63-7.60 (m, 2H), 7.57-7.55 (m,1H), 7.4-7.29 (m,
5H), 6.30 (s, 1H), 6.06, 6.04 (s, 1H), 6.02, (s, 1H), 5.97 (s, 1H),
5.34, 5.28 (1H, d, J ) 9, 2H), 4.58-4.36 (m, 2H), 4.32, 4.26 (t,
J ) 7, 1H), 3.79-3.75 (m, 2H), 3.57, 3.55 (s, 3H), 2.66-2.65
(m, 4H), 2.50-2.47 (m, 2H), 2.21-2.16 (m, 1H), 2.00-1.96 (m,
2H), 1.88-1.87 (m, 2H), 1.02, 0.92, 0.75 (d, J ) 7 Hz, 6H). 13
C
NMR (100 MHz, δ, ppm) (most of the signals are doublets
because of the mixture of diastereomers): 182.34, 175.44,
170.49, 157.83, 159.03, 156.26, 141.26, 143.94, 143.82, 136.70,
136.37, 127.04, 127.29, 127.66, 128.02, 131.03, 119.91, 125.04,
106.59, 106.86, 107.09, 101.77, 101.96, 81.79, 81.65, 66.43,
67.15, 63.06, 59.07, 58.92, 55.09, 55.02, 47.20, 47.12, 31.13,
29.64, 29.84, 27.23, 27.13, 24.28, 23.56, 19.38, 19.02, 17.05,
17.27. FTIR (film, ν, cm-1): 2963, 1714, 1598, 1514, 1468, 1265,
1159, 1066, 738. HPLC: Rt ) 5.91 min. MS (ESI + ve, m/z,
rel intens): 773.7 (10, M + 18), 417.4 (100, M - valine). HRMS
(ESI + ve): [MNa+] calcd for C42H45NO8S2 778.2484, found
778.2474.
Gen er a l P r oced u r e for th e Loa d in g of Lin k er 16
(Lea d in g to Resin 2) or 20b (Lea d in g to Resin 17b) on to
TG Am in o Resin . TG amino resin (0.100 g, 0.2 mmol/g) was
treated with 2 mL of 20% piperidine in DMF for 10 min. The
resin was drained, washed with DMF and DCM, and dried
under vacuum for 1 h. A solution under argon of HOBt (9.5
mg, 2.2 equiv) and TBTU (19.7 mg, 2.5 equiv) in 0.5 mL of
DMF was added to the resin. Triethylamine (19.7 µL, 4 equiv)
and then linker (2 equiv) in DCM (0.5 mL) were syringed into
the previous solution, and the mixture was gently stirred for
24 h, by which time a negative Kaiser test was obtained. The
resin was filtered, washed, and dried under vacuum to yield
yellow beads.
(29) A longer reaction time (up to overnight) produced the formate
ester of the alcohol 16 in addition to free alcohol 16.