Total Synthesis of Arylomycins A2 and B2
FULL PAPER
4.87 (m, 1H), 4.77–4.67 (m, 1H), 3.83 (s, 3H), 3.82 and 3.81 (s, 6H),
3.58–3.47 (m, 1H), 3.05 and 3.04 (dd, J=15.9, 6.9 Hz, 1H), 2.71 and 2.70
(s, 3H), 1.51 and 1.49 (brs, 9H), 1.42–1.37 ppm (m, 3H); 1H NMR
(500 MHz, [D6]DMSO, 1:1 mixture of rotamers): d=9.06–9.01 (m, 1H),
8.37 and 8.31 (d, J=8.3 Hz, 1H), 7.24–7.11 (m, 2H), 7.10–7.05 (m, 1H),
7.00 (d, J=8.5 Hz, 1H), 6.70–6.60 (m, 2H), 5.92 and 5.74 (s, 1H), 4.91–
4.79 (m, 1H), 4.78–4.65 (m, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.70 (s, 3H),
3.33–3.27 (m, 1H, overlaps with solvent), 3.07–2.96 (m, 1H), 2.53 (s, 3H,
overlaps with solvent), 1.44 and 1.41 (s, 9H), 1.18 ppm (d, J=6.8 Hz,
3H); 13C NMR (75 MHz, CDCl3, mixture of rotamers): d=172.2, 171.8,
171.0, 158.6, 156.8 and 156.7 (1C), 155.9, 134.8, 134.3, 129.7, 128.7, 128.6,
128.4, 127.1, 126.5, 111.8, 111.6, 80.0, 62.6 and 61.2 (1C), 55.9 (2C), 52.8,
52.6, 49.6 and 49.5 (1C), 34.3, 31.8, 28.5 and 28.3 (3C), 19.6 ppm; IR
(neat) n˜ =3280, 2361, 1745, 1694, 1649, 1509, 1440, 1367, 1272, 1254,
3.11 and 2.89 (s, 3H), 2.80 and 2.76 (s, 3H), 2.57–2.42 (m, 2H), 1.67–1.58
(m, 2H), 1.52 (septet, J=6.6 Hz, 1H), 1.41 (d, J=7.0 Hz, 3H), 1.35 (d,
J=6.6 Hz, 3H), 1.42–1.26 (m, 10H), 1.21–1.15 (m, 2H), 0.88 ppm (d, J=
6.6 Hz, 6H); 1H NMR (500 MHz, [D6]DMSO, 1:3.1 mixture of isomers):
d=12.81 (brs, 1H), 9.69 (brs, 2H), 9.07–8.95 and 8.35–8.27 (m, 1H),
8.62–8.54 (m, 1H), 8.03–7.87 (m, 2H), 7.14 and 7.10 (d, J=7.8 Hz, 1H),
6.98 (d, J=8.5 Hz, 1H), 6.95 and 6.93 (brs, 1H), 6.91–6.80 (m, 3H), 6.29
and 5.85 (s, 1H), 5.03–4.98 and 4.91–4.84 (m, 1H), 4.97 and 3.44 (dd, J=
8.2, 5.8 Hz, 1H), 4.83–4.73 (m, 1H), 4.69–4.61 (m, 1H), 4.41–4.30 (m,
1H), 4.20 and 4.02 (d, J=17.3 Hz, 1H), 3.96 (dd, J=17.3, 4.4 Hz, 1H),
4.85–4.74 (m, 1H), 3.71–3.62 (m, 1H), 3.28–3.20 (m, 1H), 3.16–3.07 (dd,
J=16.7, 12.1 Hz, 1H), 2.93 and 2.76 (s, 3H), 2.69 and 2.63 (s, 3H), 2.39–
2.27 (m, 2H), 1.56–1.45 (m, 3H), 1.25 (d, J=7.3 Hz, 3H), 1.32–1.20 (m,
10H), 1.18 (d, J=6.7 Hz, 3H), 1.18–1.11 (m, 2H), 0.85 ppm (d, J=
6.6 Hz, 6H); 13C NMR (125 MHz, [D6]DMSO, mixture of isomers): d=
173.1, 173.0, 171.9, 171.4, 169.7, 168.9, 168.6, 152.9, 151.8, 133.7, 130.2,
129.1 and 129.0 (1C), 128.7, 127.8, 127.1, 126.0, 125.6, 116.9 and 116.8
(1C), 116.4 and 116.2 (1C), 59.1, 59.0, 58.1, 50.8, 48.0 and 48.1 (1C), 47.4,
40.8, 38.5, 32.9 and 32.8 (1C), 32.4, 31.7 and 31.5 (1C), 31.2, 29.3, 29.0
and 28.9 (1C), 28.8, 28.7 and 28.6 (1C), 27.3, 26.8, 24.8, 22.5, 19.1 and
19.0 (1C), 18.2 and 18.1 ppm (1C); IR (neat): n˜ =3278, 2926, 1644, 1658,
1506, 1454, 1413 1200, 1140, 799, 723 cmÀ1; HRMS (ESÀ): m/z: calcd for
C42H59N6O11: 823.4242 [MÀH]À; found: 823.4269; HPLC (SunFire C18,
5 mm, 3ꢄ150 mm, H2O+0.1% TFA/CH3CN+0.1% TFA 60:40,
0.7 mLminÀ1): tR =17.7 min.
1148 cmÀ1
;
HRMS (ES+): m/z: calcd for C29H37N3O8Na: 578.2478
[M+Na]+; found: 578.2490.
Compound 52: At 08C, TFA (0.1 mL) was slowly added to a solution of
24 (25.0 mg, 45.0 mmol) in CH2Cl2 (0.4 mL). The solution was allowed to
warm to RT and stirred for 2 h. The solvent was evaporated and the resi-
due was diluted with EtOAc, washed with saturated aqueous NaHCO3
solution, and concentrated under reduced pressure to yield the free
amine, which was used in the next step without purification. At 08C, acid
50 (35.1 mg, 67.5 mmol, 1.5 equiv), DEPBT (21.6 mg, 72.2 mmol,
1.6 equiv), and NaHCO3 (3.8 mg, 45.0 mmol, 1.0 equiv) were successively
added to a solution of the amine in THF (0.3 mL). The resulting mixture
was allowed to warm to RT and stirred for 18 h. The reaction was con-
centrated under reduced pressure and the residue was dissolved in
EtOAc. The organic layer was washed with saturated aqueous NaHCO3
solution and brine, dried over Na2SO4 and concentrated under reduced
pressure. Purification by flash-column chromatography (SiO2, 28:1
CH2Cl2/MeOH) afforded 52 as a white solid (36.0 mg, 83%). Rf =0.39
(28:1 CH2Cl2/MeOH); m.p. 181–1848C; [a]2D4 =+106 (c=1.0, CHCl3);
1H NMR (500 MHz, CDCl3): d=7.36–7.26 (m, 5H), 7.17 (brs, 1H), 7.12
(d, J=8.7 Hz, 1H), 7.09 (d, J=7.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.93
(d, J=8.7 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.81 (brs, 1H), 6.73 (brs,
1H), 6.61 (d, J=8.1 Hz, 1H), 6.43 (d, J=6.8 Hz, 1H), 6.31 (s, 1H), 5.29
(t, J=6.6 Hz, 1H), 4.99–4.91 (m, 1H), 4.76–4.67 (m, 1H), 4.60 (d, J=
11.8 Hz, 1H), 4.57–4.51 (m, 1H), 4.48 (d, J=11.8 Hz, 1H), 4.17 (dd, J=
17.8, 3.7 Hz, 1H), 4.09 (dd, J=17.8, 3.7 Hz, 1H), 3.73 (dd, J=10.3,
6.6 Hz, 1H), 3.84–3.78 (m, 1H), 3.84 (s, 3H), 3.81 (brs, 6H), 3.55 (dd, J=
15.9, 3.8 Hz, 1H), 3.05 (dd, J=15.9, 7.6 Hz, 1H), 2.97 (s, 3H), 2.81–2.79
(brs, 3H), 2.39–2.31 (m, 2H), 1.67–1.58 (m, 2H), 1.51 (septet, J=6.6 Hz,
1H), 1.37 (d, J=6.8 Hz, 3H), 1.32 (d, J=7.0 Hz, 3H), 1.34–1.20 (m,
10H), 1.18–1.11 (m, 2H), 0.86 ppm (d, J=6.6 Hz, 6H); 13C NMR
(125 MHz, CDCl3): d=174.6, 172.1, 171.9, 171.8, 170.0, 169.2, 169.1,
157.1, 156.0, 137.6, 135.1, 134.1, 129.6, 128.9, 128.8, 128.4, 128.2, 127.8,
127.8, 127.1, 125.7, 112.0, 111.6, 73.1, 67.2, 60.1, 56.3, 55.9 (2C), 52.8, 52.5,
49.7, 48.7, 41.8, 39.0, 34.3, 33.7, 32.5, 31.7, 29.9, 29.7, 29.6, 29.4, 28.0, 27.4,
25.0, 22.7, 19.5, 18.4 ppm; IR (neat): n˜ =3296, 2926, 1747, 1634, 1509,
Compound 42: Under argon, KOAc (34.9 mg, 355.6 mmol, 7.0 equiv),
bis(neopentylglycolato)diboron (23.0 mg, 101.6 mmol, 2.0 equiv), and Pd-
AHCTUNGRTEG(NNUN OAc)2 (0.6 mg, 2.5 mmol, 5 mol%) were added to a solution of 32
(24.0 mg, 50.8 mmol) in degassed DMSO (1.0 mL). The resulting mixture
was heated at 908C for 2 h, then allowed to cool to RT and poured into
water (5 mL). The aqueous layer was carefully acidified to pH 2–3 by ad-
dition of aqueous HCl (0.1m) then extracted with EtOAc. The combined
organic layers were washed with a saturated aqueous NH4Cl solution,
brine, and water, then dried over Na2SO4 and concentrated under re-
duced pressure. Filtration through Celite afforded the boronic ester 46 as
a brown residue (23 mg), which was used in the next step without further
purification.
At 08C, TFA (0.1 mL) was added slowly to a solution of the crude boron-
ic ester 46 in CH2Cl2 (0.4 mL). The solution was allowed to warm to RT
and stirred for 2 h. The solvent was evaporated under reduced pressure.
At 08C, EDC·HCl (14.6 mg, 76.2 mmol, 1.5 equiv), HOAt (10.4 mg,
76.2 mmol, 1.5 equiv), acid 39 (25 mg, 50.8 mmol, 1.0 equiv), and NaHCO3
(5.1 mg, 61.0 mmol, 1.2 equiv) were added successively to a solution of
the residue in DMF (0.5 mL). The resulting mixture was allowed to
warm to RT and stirred for 18 h. The aqueous layer was carefully acidi-
fied to pH 3–4 by addition of aqueous HCl (0.1m) and extracted with
EtOAc. The combined organic layers were washed with aqueous HCl
(0.1m), saturated aqueous NH4Cl solution, and brine, then dried and con-
centrated under reduced pressure to afford a crude brown oil (43.0 mg),
which was used without purification in the next step.
1410, 1271, 1134, 1031, 803 cmÀ1
;
HRMS (ES+): m/z: calcd for
C52H72N6O11Na: 979.5157 [M+Na]+; found: 979.5164.
Under argon, KOAc (34.9 mg, 355.6 mmol, 7.0 equiv) and [{PdACHTUNGTRENNUNG(allyl)Cl}2]
Arylomycin A2 (1): Under argon, at 08C, AlBr3 (1m in CH2Br2, 271.6 mL,
271.6 mmol, 20 equiv) was added slowly to a solution of 52 (13.0 mg,
13.6 mmol) in EtSH (0.7 mL). The solution was allowed to warm to RT
and stirred for 6 h. The volatile components were evaporated under re-
duced pressure and the residue was taken up in a minimum of CH2Cl2
and quenched by a few drops of MeOH at 08C. Purification by prepara-
tive TLC (SiO2, 9:2.5:1 EtOAc/MeOH/H2O) and preparative reverse-
phase HPLC (SunFire C18, 19ꢄ150 mm, H2O+0.1% TFA/CH3CN+0.1%
TFA 60:40, 28 mLminÀ1; retention time (tR)=14 min) afforded 1 as a
white solid (7.3 mg, 65%). Rf =0.40 (9:2.5:1 EtOAc/MeOH/H2O); m.p.>
(0.9 mg, 2.5 mmol, 5 mol%) were added successively to a solution of the
previous crude product in degassed DMSO (2.8 mL). The flask was
purged with argon, heated to 908C, and stirred at this temperature for
2 h. The reaction mixture was cooled and partitioned between EtOAc
and water. The aqueous layer was carefully acidified to pH 2–3 by addi-
tion of aqueous HCl (0.1m) and extracted with EtOAc. The combined or-
ganic layers were washed with a saturated aqueous NH4Cl solution,
water, and brine, then dried and concentrated under reduced pressure.
Purification by preparative TLC (SiO2, 2:1 EtOAc/heptane) afforded 42
as a yellow solid (5.6 mg, 19% over 4 steps). Rf =0.42 (2:1 EtOAc/hep-
tane); m.p. 236–2378C; [a]D25 =+94 (c=0.5, CHCl3); 1H NMR (500 MHz,
CDCl3, 1:2.3 mixture of rotamers): d=10.77 and 10.75 (s, 1H), 7.81 (s,
1H), 7.31 (dd, J=8.5, 1.9 Hz, 1H), 7.12 and 7.06 (s, 1H), 6.99 and 7.00
(d, J=8.5 Hz, 1H), 6.76 and 6.73 (d, J=1.9 Hz, 1H), 6.48 and 6.43 (d, J=
6.2 Hz, 1H), 6.27 and 6.23 (d, J=8.5 Hz, 1H), 5.94 and 5.61 (s, 1H),
4.89–4.81 (m, 1H), 4.83–4.75 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.61 and
3.57 (dd, J=15.2, 4.3 Hz, 1H), 3.09 (dd, J=15.2, 6.6 Hz, 1H), 2.71 (s,
1
2008C, decomposition; [a]2D4 =+29 (c=0.3, MeOH); H NMR (500 MHz,
MeOD, 1:6.4 mixture of isomers, hydrogen atoms of the amides were par-
tially exchanged): d=8.91 (d, J=8.0 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H),
8.17–8.05 (m, 2H), 7.23 and 8.13 (d, J=8.3 Hz, 1H), 7.11 (d, J=8.3 Hz,
1H), 7.03 (brs, 1H), 7.00 (brs, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.87 (d, J=
8.4 Hz, 1H), 6.35 and 5.87 (s, 1H), 4.99–4.94 (m, 1H), 4.57–4.51 (m, 2H,
overlaps with solvent), 4.56–4.46 (m, 1H), 4.25 (d, J=17.1 Hz, 1H), 4.08–
4.00 (m, 2H), 3.95–3.85 (m, 1H), 3.46–3.36 (m, 1H), 3.16–3.07 (m, 1H),
Chem. Eur. J. 2010, 16, 10523 – 10534
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10531