Synthesis of New Analogs of the C-13 Docetaxel Side Chain
afforded 2d (30.3 mg, 38%) as a yellow foam and 2Јd (12.7 mg, 116.3, 129.1, 129.8, 141.9 (Ph), 144.8 (CHϭ), 167.4 (COOMe),
SHORT COMMUNICATION
15.7%).
171.7 (-NHCO-), 174.8 (-COOH) ppm. IR (KBr): ν˜ ϭ 3313 cmϪ1
2d:1H NMR (300 MHz, CDCl3, 25 °C): δ ϭ 1.39 (s, 9 H, Boc), (NϪH), 1699 (CϭO ester). MS (EIϩ): m/z ϭ 291 [Mϩ].
3.64 (s, 1 H, OH), 3.90 (s, 3 H, OCH3), 4.67 (br. s, 1 H, CHOH),
c) Benzyloxyglutaryl-p-aminocinnamate Methyl Ester (6e): Gluta-
3
3
5.59 (br. d, JH,H ϭ 9.0 Hz, 1 H, CHNH), 5.89 (d, JH,H ϭ 9.0 Hz,
1 H, NH), 7.46 (t, 3JH,H ϭ 8.4 Hz, 1 H, Ph), 7.62 (m, 2 H, Ph), 8.02
(d, 3JH,H ϭ 7.8 Hz, 1 H, Ph) ppm. 13C NMR (75 MHz, CDCl3, 25
°C): δ ϭ 28.3 (CH3 Boc), 52.1 (OCH3), 53.6 (CHNH), 72.3
(CHOH), 80.4 [C(CH3)3], 125.0, 128.6, 129.4, 133.3, 135.3, 148.3
(Ph), 154.8 (CO-Boc), 173.5 (COOMe) ppm. IR (CHCl3, NaCl):
ν˜ ϭ 3390 (OH and NH), 1740 (CϭO ester), 1709 (CϭO carba-
mate), 1524 (NϭO nitro) cmϪ1. MS (ESI ϩ): m/z ϭ 363 [M ϩ
Naϩ]. C15H20N2O7 (340.3): calcd. C 52.94, H 5.92, N 8.23, O 32.91;
found C 52.01, H 5.95, N 8.21, O 32.9. HPLC: chiralcel OD, iP-
ryl-p-aminocinnamate methyl ester (500 mg, 2.04 mmol) was dis-
solved in methanol (6.02 mL). Then K2CO3 solution (20% aq) was
added dropwise until pH 8, and the solvents evaporated to dryness.
N,N-Dimethylformamide (6 mL) and benzyl chloride (0.3 mL,
2.24 mmol) were then added and the resulting mixture was stirred
at room temperature under argon overnight. The reaction was
monitored by TLC analysis (CH2Cl2/MeOH, 18:1); after this time,
water (20 mL) and ethyl acetate (20 mL) was added and the phases
were separated. The organic phase was dried over Na2SO4 and con-
centrated to dryness to give 622 mg of pure benzyloxyglutaryl-p-
aminocinnamate methyl ester (95% yield) as a white solid; m.p.
90Ϫ92 °C. 1H NMR (400 MHz, CDCl3, 25 °C): δ ϭ 2.04 (m, 2
rOH/hexane (7:93), 1 mL·minϪ1
, 14.1 min (2S,3R), 21.3 min
(2R,3S), 82% ee. [α]2D0 ϭ Ϫ235 (c ϭ 0.2, CHCl3) for the pure enanti-
omer (2R,3S).
3
H, -CH2-), 2.39 (t, JH,H ϭ 7.3 Hz, 2 H, -CH2-CONH), 2.46 (t,
1
2Јd: H NMR (300 MHz, CDCl3, 25 °C): δ ϭ 1.27 (s, 9 H, Boc),
3JH,H ϭ 6.9 Hz, 2 H, -CH2-COOBn), 3.77 (s, 3 H, OCH3), 5.10 (s,
3
3.85 (s, 3 H, OCH3), 4.94 (d, JH,H ϭ 9.2 Hz, 1 H, NH), 5.42 (br. 2 H, -OCH2-Ph) 6.32 (d, 3JH,H ϭ 16.1 Hz, CHϭ), 7.59 (d, 3JH,H ϭ
3
d, JH,H ϭ 9.2 Hz, 1 H, CHNH), 5.94 (br. s, 1 H, CHOH), 7.46 (t,
16.1 Hz, 1 H, CHϭ),7.34Ϫ7.50 (m, 9 H, Ph), 7.80 (s, 1 H, -NH)
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ ϭ 20.8 (-CH2-), 33.2
(-CH2-CONH), 36.4 (-CH2-COOMe), 51.7 (OCH3), 66.5 (PhCH2-
3
3JH,H ϭ 7.7 Hz, 1 H, Ph), 7.64 (t, JH,H ϭ 7.5 Hz, 1 H, Ph), 7.85
3
3
(d, JH,H ϭ 7.5 Hz, 1 H, Ph), 8.06 (d, JH,H ϭ 8.0 Hz, 1 H, Ph).
MS (ESIϩ): m/z ϭ 363 [M ϩ Naϩ]. HPLC: chiralcel OD, iPrOH/ O), 116.7 (CHϭ), 119.8, 129.1, 128.3, 128.4, 129.1, 135.9, 139.9
hexane (7:93), 1 mL·minϪ1, 16.2 min, 21.3 min.
(Ph), 144.3 (CHϭ), 167.7 (COOMe), 170.8 (-NHCO-), 173.2 (-CO-
OBz) ppm. IR (KBr): ν˜ ϭ 3350 cmϪ1 (NϪH), 1733 (CϭO ester).
MS (ESIϩ): m/z ϭ 404 [M ϩ Naϩ]. C22H23NO5 (381.4): calcd. C
69.27, H 6.08, N 3.67, O 20.97; found C 69.39, H 6.17, N 3.53,
O 21.17.
Benzyloxyglutaryl-p-aminocinnamate Methyl Ester (6e)
a) Methyl p-Aminocinnamate Hydrochloride: Methanol (20 mL)
and acetyl chloride (100 µL) were placed in a round-bottomed flask
and stirred for 15 min at 0 °C. Then, the p-aminocinnamic acid
(500 mg, 2.5 mmol) was added and the mixture was heated to reflux
temperature for 3 h. The TLC analysis (CH2Cl2/MeOH, 13:1) con-
firmed the absence of starting material after this time. The reaction
mixture was concentrated and the product precipitated out of solu-
tion. The mixture was filtered and washed with cold MeOH to
afford 465 mg of pure methyl p-aminocinnamate hydrochloride
(87% yield) as slightly yellow crystals; m.p. 194Ϫ196 °C. 1H NMR
(2R,3S)-(؉)-N-(tert-butoxycarbonyl)-3-(benzyloxyglutaryl-p-amino-
phenyl)isoserine Methyl Ester (2e)
Preparation of N-Bromo-tert-butoxycarboxamide: Oxone (9.22 g,
15 mmol) was added to a suspension of KBr (1.78 g, 15 mmol) and
wet alumina (0.2 mL H2O/g alumina, 15 g) in a 3:1 mixture of CCl4
and CHCl3 (60 mL). The mixture was heated at 45 °C for 15 min.
A solution of the tert-butoxycarboxamide (351 mg, 3 mmol) in a
(400 MHz, CD3SOCD3, 25 °C): δ ϭ 3.71 (s, 3 H, OCH3), 6.58 (d, 1:1 mixture of CCl4 and CHCl3 (15 mL) was then added and the
3
3JH,H ϭ 15.7 Hz, CHϭ), 7.31 (d, JH,H ϭ 8.4 Hz, 2 H, Ph), 7.61 resulting mixture stirred for 60 h at room temperature. The mixture
(d, 3JH,H ϭ 15.7 Hz, 1 H, CHϭ), 7.75 (d, 3JH,H ϭ 8.4 Hz, 2 H, Ph)
was then filtered and the solution evaporated to dryness. The crude
ppm. 13C NMR (100 MHz, CD3SOCD3, 25 °C): δ ϭ 50.0 (OCH3), material was purified by flash chromatography on silica gel (petro-
122.6 (CHϭ), 118.0, 130.2, 132.1, 137.3 (Ph), 144.2 (CHϭ), 167.2
(COOMe) ppm. IR (KBr): ν˜ ϭ 1716 cmϪ1 (CϭO ester). MS (EIϩ):
leum ether/EtOAc, 11:1) to afford pure N-bromo-tert-butoxycar-
boxamide (372 mg, 63.5%) as a yellow oil. 1H NMR (400 MHz,
m/z ϭ 177 [Mϩ]. C10H12NO2 (178.2): calcd. C 56.21, H 5.66, N CDCl3, 25 °C): δ ϭ 1.39 [s, 9 H, -C(CH3)3], 6.5 (s, 1 H, -CONHBr)
6.55, O 14.97; found C 56.37, H 5.63, N 6.55, O 15.06.
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ ϭ 28.0 [C(CH3)3],
83.3 [C(CH3)3], 156.1(CONHBr) ppm. IR (KBr): ν˜ ϭ 3240 cmϪ1
(NϪH), 1701 (CϭO), 1248 (CϪO).
b) Glutaryl-p-aminocinnamate Methyl Ester: Methyl p-aminocinna-
mate hydrochloride (500 mg, 2.34 mmol) was dissolved in a mixture
H2O/THF (2:1; 6 mL). Then, solid K2CO3 (330 mg) was added un-
til pH 8. The reaction mixture was then stirred for 10 min at room
temperature. Glutaric anhydride (1.0 g, 8.76 mmol) was added and
Lithium hydroxide (43 mg, 1.02 mmol) and K2OsO2(OH)4
(14.7 mg, 0.04 mmol, 4 mol %) were dissolved in water (9 mL) with
stirring. To this solution were added tBuOH (6 mL) and
the reaction mixture was stirred for 30 min. TLC analysis (CH2Cl2/ (DHQ)2PHAL (39 mg, 0.05 mmol, 5 mol %). The mixture was
MeOH, 10:1) confirmed the absence of starting material after this
time. The reaction mixture was then concentrated and the product
precipitated out of solution. The product was isolated by filtration,
stirred for 10 min and the flask was cooled to between 0 and 5
°C. Benzyloxyglutaryl-p-aminocinnamate methyl ester 6e (381 mg,
1 mmol) was then added followed by tBuOCONHBr (216.7 mg,
washed with water and dried under high vacuum to give 578 mg of 1.1 mmol). The color of the reaction changed immediately from
pure glutaryl-p-aminocinnamate methyl ester (85% yield) as a white
yellow to green and then back to yellow at the end of the reaction.
The reaction mixture was stirred at 0Ϫ5 °C until the reaction was
solid; m.p. 139Ϫ141 °C. 1H NMR (400 MHz, CD3SOCD3, 25 °C):
3
δ ϭ 1.80 (m, 2 H, -CH2-), 2.27 (t, JH,H ϭ 7.3 Hz, 2 H, -CH2- complete. The reaction was quenched with sodium sulfite (0.5 g)
3
CONH), 2.35 (t, JH,H ϭ 7.3 Hz, 2 H, -CH2-COOMe), 3.70 (s, 3 and stirred for 30 min at room temperature. The aqueous phase
3
3
H, OCH3), 6.49 (d, JH,H ϭ 16.1 Hz, CHϭ), 7.57 (d, JH,H
ϭ
was separated and extracted with ethyl acetate. The combined or-
16.1 Hz, 1 H, CHϭ), 7.65 (s, 4 H, Ph), 10.16 (s, 1 H, -NH) ppm. ganic phases were dried over sodium sulfate and concentrated. The
13C NMR (100 MHz, CD3SOCD3, 25 °C): δ ϭ 20.9 (-CH2-), 33.5 crude product was purified by flash chromatography (EtOAc/di-
(-CH2-CONH), 36.0 (-CH2-COOMe), 51.9 (OCH3), 119.5 (CHϭ), ethyl ether, 1:1) to afford 2e (122.8 mg, 24%) as a white solid. Three
Eur. J. Org. Chem. 2002, 2260Ϫ2264
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