An aldol-based approach to the synthesis of the antibiotic anisomycin

Article abstract of DOI:10.1021/ol017016u

Chemical equation presented A new approach to the synthesis of the antibiotic anisomycin is reported that relies upon a key aldol disconnection. The glycolate aldol coupling proceeds in 75% yield and with >95% diastereoselectivity, which allows the 13-step synthesis to proceed in 35% overall yield.

Full text of DOI:10.1021/ol017016u

Supplementary Material
General
All reactions involving air- or water-sensitive reagents were carried out under an atmosphere of argon using flame- or
oven-dried glassware. Unless otherwise noted, starting materials and reagents were obtained from commercial suppliers and
were used without further purification. THF was distilled from Na-benzophenone ketyl immediately prior to use. Toluene,
CH2Cl2, and Et3N were distilled from calcium hydride. Anhydrous methanol, DMF, and acetonitrile were used as supplied by
Acros. Unless otherwise indicated, organic extracts were dried over anhydrous sodium sulfate and concentrated under
reduced pressure using a rotary evaporator. Purification by flash column chromatography was carried out using Merck
Kieselgel 60 silica gel as the stationary phase. Chiral HPLC was performed using a Waters instrument equipped with a UV
detector and a Chiracel OD-H column (internal diameter 4.6 mm, column length 250 mm). All solvents for use in HPLC
analysis were vacuum filtered and degassed prior to use, and a standard flow rate of 0.5 cm3min-1 was used. IR spectra were
measured on a Biorad FTS-7 or Perkin-Elmer Paragon 1000 FT-IR spectrometer as thin films unless otherwise stated. 1H and
13C NMR spectra were measured on a Varian Gemini 200, Bruker AC250, Bruker AM360 or Varian Inova 600 spectrometer;
J-values are in Hz. Melting points were determined on a Gallenkamp Electrothermal Melting Point apparatus and are
uncorrected. Optical rotations were measured on an AA-1000 polarimeter with a path length of 1.0 dm, at the sodium D-line
at room temperature. Elemental analysis was carried out on a Perkin-Elmer 2400 CHN Elemental Analyser. Fast atom
bombardment (FAB) mass spectra were obtained using a Kratos MS50TC mass spectrometer at The University of
Edinburgh.
(2’R,3’S,4R,4’R)-3-(2’-Benzyloxy-4’-N,N-dibenzylamino-3’-hydroxy-5’-(4’’-methoxy-phenyl)-1’-oxopentyl)-4-
phenylmethyloxazolidin-2-one 7
To a solution of glycolate equivalent 3[ref.12] (0.661 g, 2.00 mmol) in CH2Cl2 (5 cm3) at -78 °C was added triethylamine
(0.27 g, 0.37 cm3, 2.7 mmol) followed by dropwise addition of dibutylboron triflate (2.50 cm3, 1.0 M in CH2Cl2, 2.50 mmol).
The solution was stirred at -78 °C for 45 min, then allowed to warm to 0 °C over 30 min and stirred at 0 °C for 1.25 h. The
solution was then recooled to -78 °C and a -78 °C solution of aldehyde 2 (0.200 g, 0.554 mmol) in CH2Cl2 (3 cm3) was added
dropwise via cannula. The reaction mixture was stirred at -78 °C for 1 h, and allowed to warm to 0 °C over a period of 4 h.
The reaction was quenched by the addition of methanol (8 cm3) followed by pH 7 phosphate buffer (5 cm3). Hydrogen
peroxide (5 cm3, 30% aq. solution) in methanol (5 cm3) was added dropwise to the solution and the mixture was stirred and
warmed to room temperature over ca. 1 h. The organic phase was separated and the aqueous phase was extracted with
CH2Cl2 (3 × 20 cm3); the combined organic phase was washed sequentially with saturated aq. sodium bicarbonate (25 cm3)
and brine (25 cm3) then dried, and concentrated under reduced pressure. The residue was chromatographed on silica gel
[hexane-EtOAc (7 : 3)] to give 7 (0.286 g, 75%) as a foam. [α]D -47.0 (c 2.8, CHCl3); λmax (neat)/cm-1 3334, 1771, 1709,
1611, 1582, 1512 ; δH (200 MHz; CDCl3) 7.38-7.09 (18H, m), 7.08 (2H, d, J 8.6), 6.90-6.88 (2H, m), 6.66 (2H, d, J 8.6),
4.89 (1H, d, J 1.6), 4.67 (1H, dddd, J 9.9, 6.8, 3.1, 2.2), 4.52 (1H, br s), 4.25 (1H, dd, J 8.9, 6.8), 4.24 (1H, d, J 11.4), 4.17
(1H, dd, J 8.9, 2.2), 4.06 (1H, dd, J 9.5, 1.6), 3.91 (2H, d, J 13.2), 3.69 (3H, s), 3.58 (1H, ddd, J 9.5, 7.7, 4.6), 3.46 (2H, d, J
13.2), 3.30 (1H, d, J 11.4), 3.31 (1H, dd, J 13.4, 3.1), 3.14 (1H, dd, J 14.6, 4.6), 2.74 (1H, dd, J 13.4, 9.9), 2.72 (1H, dd, J
14.6, 7.7); δC (62.9 MHz; CDCl3) 170.0, 157.7, 153.4, 138.3, 137.5, 135.1, 131.7, 130.1, 129.2, 128.8, 128.7, 128.4, 127.7,
127.1, 126.7, 113.5, 76.9, 71.1, 70.9, 66.9, 59.9, 55.7, 55.0, 37.5, 30.1; m/z (FAB) 685 ([M + H])+, 5%), 307 (28), 289 (16),
154 (100); HRMS (FAB) (Found: [M + H]+, 685.3260. C43H44N2O6 requires m/z, 685.3278).
(2S,3S,4R)-Benzyloxy-4-N,N,-dibenzylamino-3-hydroxy-5-(4’methoxy-phenyl)pentan-1-ol 8
To a solution of aldol adduct 7 (0.148 g, 0.216 mmol) in THF (10 cm3) at 0 °C was added methanol (0.040 cm3, 1.1 mmol)
and LiBH4 (0.024 g, 1.1 mmol). The solution was warmed to room temperature and stirred for 18 h then re-cooled to 0 °C
and quenched by the addition of 1M sodium hydroxide (1 cm3). The organic phase was separated and the aqueous phase was
extracted with CH2Cl2 (3 × 20 cm3); the combined organic phase was washed with brine (30 cm3), dried, and concentrated
under reduced pressure. The residue was chromatographed on silica gel [hexane-EtOAc (7 : 3)] to give the diol 8 (0.0886 g,
80%) as a foam. [α]D -29.6 (c 1.1, CHCl3); λmax (neat)/cm-1 3402, 2927, 1609, 1510; δH (360 MHz; CDCl3) 7.37-6.96 (15H,
m), 7.04 (2H, d, J 8.7), 6.73 (2H, d, J 8.7), 4.46 (1H, d, J 11.8), 3.96 (2H, d, J 14.5), 3.90 (1H, d, J 11.8), 3.74 (3H, s), 3.72
(1H, dd, J 8.1, 3.5), 3.69 (1H, dd, J 11.7, 4.8), 3.52 (1H, dd, J 11.7, 3.8), 3.42 (2H, d, J 14.5), 3.40-3.31 (2H, m), 3.08 (1H,
dd, J 14.1, 5.8), 2.70 (1H, dd, J 14.1, 7.2), 2.52 (1H, br s), 1.78 (1H, br s); δC (62.9 MHz; CDCl3) 157.9, 138.7, 138.2, 131.6,
130.0, 129.0, 128.4, 128.1, 127.2, 127.1, 127.0, 113.8, 77.6, 72.1, 70.9, 61.6, 59.0, 55.1, 54.0, 31.0; m/z (FAB) 512 ([M +
H]+, 25%), 330 (21), 154 (24), 91 (100); HRMS (FAB) (Found: [M + H]+, 512.2801. C33H37NO4 requires m/z, 512.2801).

(2R,3S,4S)- 4-(Benzyloxy)-1,1-dibenzyl-3-hydroxy-2-(4-methoxybenzyl)pyrrolidinium chloride 9
To a solution of alcohol 8 (0.110 g, 0.215 mmol) in CH2Cl2 (5 cm3) at 0 °C was added DMAP (0.118 g, 0.967 mmol) and
toluene-4-sulphonyl-chloride (0.123 g, 0.646 mmol). The solution was stirred for 18 h then diluted with CH2Cl2 (20 cm3) and
water (25 cm3). The organic phase was separated and washed with 1% HCl (2 × 25 cm3) then dried and concentrated under
reduced pressure. The residue was chromatographed on silica gel [CH2Cl2-MeOH (19:1)] to give a white foam. The salt
obtained was subjected to ion exchange chromatography [Dowex Cl-; prepared by treatment of Dowex 1-X2 with 1% HCl,
followed by flushing with methanol until the eluent returned to pH 7] eluting with methanol to give the chloride salt 9
(0.0963 g, 85%) as an amorphous solid. [α]D +4.1 (c 0.8, CHCl3); λmax (neat)/cm-1 3147, 1612, 1513, 1250; δH (360 MHz;
CDCl3) 7.73-6.71 (17H, m), 6.69 (2H, d, 8.7), 5.66 (1H, d, 13.5), 5.04 (2H, s), 4.71 (1H, br s), 4.42 (2H, s), 4.26 (1H, s),
4.26-4.18 (1H, m), 4.20 (1H, d, 13.5), 3.82 (1H, dt, 12.2, 2.9), 3.69 (3H, s), 3.66 (1H, br d, 13.3), 3.50 (1H, t, 12.2), 3.09
(1H, dd, 13.3, 3.1), 2.18 (1H, br s); δC (62.9 MHz; CDCl3) 158.5, 137.1, 133.5, 133.0, 130.7, 130.5, 129.3, 128.1, 128.0,
127.5, 127.4, 126.9, 114.1, 80.2, 75.1, 72.3, 71.8, 63.8, 63.5, 62.2, 55.0, 27.7; m/z (FAB) 494 ([M]+, 75%), 402 (6), 282 (11),
154 (43), 91 (100); HRMS (FAB) (Found: [M]+, 494.2695. [C33H36NO3]+Cl- requires m/z, 494.2695).
(2R,3S,4S)-1-Benzyl-4-(benzyloxy)-3-hydroxy-2-(4-methoxybenzyl)pyrrolidine 10
To a solution of pyrrolidinium salt 9 (0.0493 g, 0.0931 mmol) in methanol (5 cm3) was added 5% Pd/C (0.0057 g) and
potassium carbonate (0.0446 g, 0.323 mmol). The mixture was exposed to an atmosphere of hydrogen (1 atm.) and stirred
vigorously for 10 min. The suspension was filtered through a pad of Celite and concentrated under reduced pressure. To the
residue was added CH2Cl2 (25 cm3) and water (25 cm3). The organic phase was separated and the aqueous phase was
extracted with CH2Cl2 (3 × 10 cm3); the combined organic extracts were washed with saturated aq. sodium bicarbonate (25
cm3) then dried and concentrated under reduced pressure. The residue was chromatographed on silica gel [hexane-EtOAc (7 :
3)] to give pyrrolidine 10 (0.0353 g, 94%) as a solid; [α]D -96.1 (c 0.4, CHCl3); λmax (neat)/cm-1 3419, 2917, 1610, 1511; δH
(250 MHz; CDCl3) 7.33-7.19 (12H, m), 6.84 (2H, d, J 8.7), 4.46 (1H, d, J 11.9), 4.39 (1H, d, J 11.9), 4.14 (1H, d, J 12.9),
3.80 (2H, dd, J 6.5, 4.1), 3.79 (3H, s), 3.33 (1H, d, J 12.9), 3.32 (1H, dd, J 10.6, 6.7), 2.97-2.81 (3H, m), 2.20 (1H, dd, J
10.4, 4.4); δc (62.9 MHz; CDCl3) 157.9, 138.4, 137.8, 130.8, 130.1, 128.7, 128.3, 128.2, 127.5, 127.0, 113.8, 82.6, 75.4,
71.2, 68.2, 58.4, 57.7, 55.1, 32.5; m/z (FAB) 404 ([M + H])+, 16%), 307 (19), 154 (100) 136 (72), 91 (30); HRMS (FAB)
(Found: [M + H]+, 404.2226. C26H30NO3 requires m/z 404.2226).
(2R,3S,4S)-3-Acetoxy-1-benzyl-4-(benzyloxy)-2-(4-methoxybenzyl)pyrrolidine 11
[α]D -105.7 (c 1.1, CHCl3); λmax (neat)/cm-1 2932, 1738, 1612, 1583, 1512, 1247; δH (250 MHz; CDCl3) 7.33-7.20 (10H, m),
7.07 (2H, d, J 8.8), 6.81 (2H, d, J 8.8), 4.91 (1H, dd, J 4.9, 1.5), 4.62 (1H, d, J 12.1), 4.05 (1H, d, J 13.1), 3.82-3.71 (1H, m),
3.77 (3H, s), 3.38 (1H, d, J 13.1), 3.33 (1H, dd, J 10.7, 6.7), 3.10 (1H, dt, J 9.6, 5.0), 2.96 (1H, dd, J 13.6, 5.1), 2.76 (1H, dd,
J 13.6, 9.6), 2.32 (1H, dd, J 10.7, 4.9), 2.11 (3H, s); δc (62.9 MHz; CDCl3) 170.2, 157.9, 138.2, 137.9, 130.6, 129.6, 128.9,
128.2, 127.5, 127.4, 127.0, 113.8, 81.0, 77.8, 71.3, 66.5, 58.3, 55.1, 33.1, 21.1; m/z (FAB) 446 ([M + H]+, 35%), 356 (10)
324 (10), 217 (19), 91 (100); HRMS (FAB) (Found: [M + H]+, 446.2332. C28H32NO4 requires m/z 446.2331).
(2R,3S,4S)-3-Acetoxy-4-(hydroxy)-2-(4-methoxybenzyl)pyrrolidine hydrochloride 1
mp 187-188 °C; [α]D +4.0 (c 0.28, CH3OH) {lit.,[ref.7w] [α]D (c +4.2, CH3OH)}; λmax (KBr)/cm-1 3395, 3291, 3252, 1749,
1612, 1514; δH (250 MHz; CD3OD) 7.26 (2H, d, J 8.6), 6.95 (2H, d, J 8.6), 5.08 (1H, d, J 3.0), 4.38 (1H, d, J 4.2), 4.23-4.15
(1H, m), 3.81 (3H, s), 3.63 (1H, dd, J 12.8, 4.3), 3.22 (1H, d, J 12.8), 3.11 (1H, dd, J 14.3, 6.7), 2.99 (1H, dd, J 14.3, 8.8),
2.21 (3H, s); δc (62.9 MHz; CD3OD) 169.8, 159.6, 130.0, 127.9, 114.5, 77.3, 72.4, 62.7, 54.7, 51.6, 31.2, 19.7.