Side-Chain-Functionalized Dipeptides
Ethyl (3R,6S,7R,8S,8aS)-8-Benzyloxy-6,7-dihydroxy-5-oxohexahy- 3.8 Hz, 1 H, 7-OH), 5.27 (d, J8a,8 ϭ 2.1 Hz, 1 H, 8a-H), 5.24 (d,
FULL PAPER
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dro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate (10): Alcohol 9
(1.2 g, 3.8 mmol) was dissolved in DMF (50 mL), followed by the H, 3-H), 4.77 (d, Jgem ϭ 12.0 Hz, 1 H, PhCH2), 4.70 (d, Jgem
3J6,7 ϭ 3.2 Hz, 1 H, 6-H), 5.00 (dd, J3,2h ϭ 5.3, J3,2t ϭ 7.6 Hz, 1
2
2
ϭ
addition of benzyl bromide (1.5 mL, 12.6 mmol). The reaction
vessel was cooled in an ice bath, NaH (70 mg, 2.9 mmol) was ad-
11.7 Hz, 1 H, PhCH2), 4.42 (m, 1 H, 7-H), 4.1 (m, 2 H, CH2CH3),
3.40 (dd, 2Jgem ϭ 11.4, 3J2l,3 ϭ 7.6 Hz, 1 H, 2-Hl), 3.14 (dd, 2Jgem ϭ
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3
ded, the mixture was stirred for 30 min, and then the ice bath was 11.4, J2h,3 ϭ 5.3 Hz, 1 H, 2-Hh), 1.19 (t, JEt ϭ 7.0 Hz, 3 H,
removed. Twice more, NaH (40 mg, 1.7 mmol) was added in inter-
vals of 30 min. The solvent was evaporated, then toluene was added
and evaporated. The dried residue was dissolved in ethyl acetate/
H2O (4:1, 250 mL). The aqueous phase was extracted twice with
ethyl acetate and the combined organic phases were dried (MgSO4).
At this stage, separation of 10 from the side product was not pos-
sible by flash chromatography (ethyl acetate/toluene, 4:5) (Rf ϭ
0.5). The acetonide was cleaved using TFA (15 mL) in EtOH
(10 mL) and H2O (0.7 mL). The solvent was evaporated after 15 h
at room temp. and flash chromatography (ethyl acetate/toluene,
5:1) of the residue yielded 10 (470 mg, 1.28 mmol, 34%) (Rf ϭ 0.36)
CH2CH3) ppm. 13C NMR: δ ϭ 169.05, 160.62 (C-5, CO2), 137.58,
128.41, 127.99, 127.82 (Ph), 82.23 (C-6), 74.37 (C-8), 73.36
(CH2Ph), 67.77 (C-7), 63.12 (C-8a), 61.35 (CH2CH3), 60.34 (C-3),
31.44 (C-2), 13.92 (CH2CH3) ppm. FAB-MS: m/z ϭ 500 [M ϩ H]ϩ,
522 [M ϩ Na]ϩ. C18H20F3NO8S2 (499.48): calcd. C 43.28, H 4.04,
N 2.80; found C 43.53, H 4.30, N 2.75.
Analytical Data of the Side Product Ethyl (3R,8S,8aS)-8-Benzyloxy-
5-oxo-6-(trifluoromethanesulfonyloxy)-2,3,8,8a-tetrahydro-5H-
[1,3]thiazolo[3,2-a]pyridine-3-carboxylate (15): 1H NMR (600 MHz,
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[D6]DMSO): δ ϭ 7.30 (m, 6 H, Ph), 5.29 (d, J8a,8 ϭ 2.9 Hz, 1 H,
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3
8a-H), 5.26 (dd, J3,2l ϭ 6.5, J3,2h ϭ 1.8 Hz, 1 H, 3-H), 4.72 (d,
1
and the side product 14 (115 mg, 0.25 mmol, 7%) (Rf ϭ 0.43). H
2Jgem ϭ 11.4 Hz, 1 H, CH2Ph), 4.69 (d, Jgem ϭ 11.4 Hz, 1 H,
2
NMR (600 MHz, [D6]DMSO): δ ϭ 7.35 (m, 5 H, Ph), 5.57 (d,
CH2Bn), 4.39 (dd, J8,8a ϭ 3.2, 3J8,7 ϭ 6.5 Hz, 1 H, 8-H), 4.15 (m,
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3
3J7-OH,7 ϭ 3.8 Hz, 1 H, 7-OH), 5.45 (d, J6-OH,6 ϭ 5.9 Hz, 1 H, 6-
2 H, CH2Et), 3.34 (dd, Jgem ϭ 11.4, J2l,3 ϭ 6.8 Hz, 1 H, 2-Hl),
2
3
3
3
OH) 5.24 (d, J8a,8 ϭ 2.6 Hz, 1 H, 8a-H), 4.91 (dd, J3,2h ϭ 5.0,
3.22 (dd, Jgem ϭ 11.4, J2h,3 ϭ 2.1 Hz, 1 H, 2-Hh), 1.19 (t, JEt
ϭ
2
3
3
3J3,2l 7.6 Hz, 1 H, 3-H), 4.69 (m, 2 H, PhCH2), 4.17 (m, 1 H, 7-H),
4.11 (m, 2 H, CH2CH3), 4.05 (dd, J6,6-OH ϭ 5.9, J6,7 ϭ 3.5 Hz, 1
7.0 Hz, 3 H, CH2CH3) ppm. 13C NMR: δ ϭ 168.69, 154.78 (5-CO,
CO2), 141.31 (C-6), 137.76 (C-Ph), 128.47 (C-7), 128.32, 127.80,
127.65 (Ph), 72.15 (CH2Ph), 69.06 (C-8), 63.79 (C-8a), 61.60
(CH2CH3), 61.24 (C-3), 32. 87 (C-2), 13.83 (CH2CH3) ppm.
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H, 6-H), 3.99 (dd, J8,8a ϭ 2.6, J8,7 ϭ 4.7 Hz, 1 H, 8-H), 3.31 (m,
1 H, Hl), 3.05 (dd, Jgem ϭ 11.4, J2h,3 ϭ 5.0 Hz, 1 H, 2-Hh),1.19
2
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(t, JEt ϭ 7.3 Hz, 3 H, CH2CH3) ppm. 13C NMR: δ ϭ 169.85,
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168.92 (C-5, CO2), 138.09, 128.27, 127.66, 127.63 (Ph), 74.61 (C-
8), 72.71 (PhCH2), 68.75 (C-7), 67.37 (C-6), 63.32 (C-8a), 60.99
Ethyl
(3R,6R,7R,8S,8aS)-6-Azido-8-benzyloxy-7-hydroxy-5-oxo-
hexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate (12): Com-
pound 11 (200 mg, 0.4 mmol) was dissolved in CH2Cl2 (30 mL) and
then NaN3 (50 mg, 0.77 mmol) and 15-crown-5 (100 µL,
0.51 mmol) were added and the mixture was stirred at room temp.
for 16 h. H2O (10 mL) was added and the aqueous phase was ex-
tracted twice with CH2Cl2. The combined organic phases were
dried (MgSO4) and flash chromatography (toluene/ethyl acetate,
(CH2CH3), 60.06 (C-3), 31.39 (C-2), 13.97 (CH2CH3) ppm. [α]2D4
ϭ
Ϫ197.4 (c ϭ 1, CHCl3). FAB-MS: m/z ϭ 368 [M ϩ Hϩ], 390 [M
ϩ Na]ϩ. C17H21NO6S (367.42): calcd. C 55.57, H 5.76, N 3.81;
found C 56.30, H 5.57, N 3.90.
Analytical Data of the Minor Product
1
Ethyl 2-[(2S,3S,4R,5S)-3-Benzyloxy-2-benzylsulfanyl-4,5-dihydroxy-
2:1) yielded 12 (130 mg, 0.33 mmol, 83%) (Rf ϭ 0.37) as an oil. H
6-oxopiperidin-1-yl]acrylate (14): 1H NMR (600 MHz, [D6]DMSO): NMR (600 MHz, [D6]DMSO): δ ϭ 7.35 (m, 5 H, Ph), 6.06 (d, 3J7-
δ ϭ 7.30 (m, 10 H, Ph), 6.24 (s, 1 H, 3-Hl), 5.74 (s, 1 H, 3-Hh),
ϭ 5.0 Hz, 1 H, 7-OH), 5.22 (dd, J3,2l ϭ 7.0, J3,2h ϭ 2.6 Hz,
3
3
OH,7
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5.48 (d, J4-OH,4 ϭ 3.8 Hz, 1 H, 4-OH), 5.25 (d, J5-OH,5 ϭ 5.3 Hz, 1 H, 3 H), 5.17 (d, J8a,8 ϭ 2.1 Hz, 1 H, 8a-H), 4.71 (d, Jgem
ϭ
3
2
1 H, 5-OH), 5.09 (d, J2,3 ϭ 4.4 Hz, 1 H, 2-H), 4.65 (m, 2 H, 11.7 Hz, 1 H, CH2Ph), 4.62 (d, Jgem ϭ 12.0 Hz, 1 H, CH2-Ph),
3
3
PhCH2), 4.37 (pt, J5,5-OH/7 ϭ 4.4 Hz, 1 H, 5-H), 4.1 (m, 3 H, 7-
4.31 (d, J6,7 ϭ 5.9 Hz, 1 H, 6-H), 4.13 (m, 2 H, CH2CH3), 3.80
H, CH2CH3), 3.89 (pt, 3J3,2/4 ϭ 4.4 Hz, 1 H, 3-H), 3.85 (d, 2Jgem ϭ (m, 1 H, 7-H), 3.75 (pt, J8,8a/7 ϭ 2.6 Hz, 1 H, 8-H), 3.23 (dd,
3
12.9 Hz, 1 H, PhCH2S), 3.76 (d, Jgem ϭ 12.6 Hz, 1 H, PhCH2S), 2Jgem ϭ 11.4, J2l, 3 ϭ 7.0 Hz, 1 H, 2-Hl), 3.13 (dd, Jgem ϭ 11.4,
2
3
2
1.17 (t, 3JEt ϭ 7.3 Hz, 3 H, CH2CH3) ppm. 13C NMR: δ ϭ 171.27, 3J2h,3 ϭ 2.6 Hz, 1 H, 2-Hh), 1.19 (t, JEt ϭ 7.0 Hz, 3 H, CH2CH3)
3
163.14 (C-6, CO2), 138.16, 137.94 137.76 (Ph, C-2), 128.85, 128.44, ppm. 13C NMR: δ ϭ 169.11, 164.70 (C-5, CO2), 137.85, 128.26,
128.25, 127.72, 127.66, 127.06 (Ph), 123.36 (C-3 acrylic ester), 79.63 127.62, 127.53 (Ph), 79.39 (C-8), 71.69 (CH2Ph), 71.06 (C-7), 64.06
(C-3), 72.22 (OCH2Ph), 69.62 (C-4), 67.62 (C-5), 65.80 (C-2), 60.83
(C-6), 61.82 (C-8a), 61.37 (CH2CH3) 61.20 (C-3), 31.55 (C-2), 13.97
(CH2CH3), 36.03 (SCH2Ph), 13.90 (CH2CH3) ppm. [α]2D4 ϭ Ϫ53.2 (CH2CH3) ppm. [α]2D4 ϭ Ϫ49.6 (c ϭ 1, CHCl3). FAB-MS: m/z ϭ
(c ϭ 1, CHCl3). FAB-MS: m/z ϭ 480 [M ϩ Na]ϩ, 502 [M ϩ 2 Naϩ 393 [M ϩ H]ϩ, 415 [M ϩ Na]ϩ, 565 [M ϩ 2 Na ϩ I]ϩ.
Ϫ Hϩ]ϩ, 630 [M ϩ 2 Na ϩ I]ϩ.
Ethyl (3R,6R,7R,8S,8aS)-8-Benzyloxy-6-tert-butoxycarbonylamino-
Ethyl (3R,6S,7R,8S,8aS)-8-benzyloxy-7-hydroxy-5-oxo-6-(trifluoro- 7-hydroxy-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carb-
methanesulfonyloxy)hexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-
carboxylate (11): Compound 10 (450 mg, 1.2 mmol) and DMAP
(9 mg) were dissolved in CH2Cl2 (50 mL). The solution was cooled
to Ϫ30 °C and Tf2O (300 µL, 1.8 mmol, 1.5 equiv.) was added. The
solution was cooled to Ϫ50 °C and pyridine (3 mL) was added.
The mixture was warmed to room temperature, stirred for 2 h, and
then the solvent was evaporated. The residue was dissolved in ethyl
acetate (100 mL) and H2O (20 mL), and the aqueous phase was
extracted twice with ethyl acetate and the combined organic phases
oxylate (13): Azide 12 (90 mg, 0.23 mmol) was dissolved in pyrid-
ine/H2O (2:1, 23 mL). H2S was bubbled through the solution for
10 min and then the reaction mixture was stirred at room temp. for
16 h. The solvent was evaporated and the residue dissolved in
CH2Cl2 (30 mL). Boc2O (100 mg, 0.46 mmol) and DIPEA (40 µL)
were added and the solution was stirred for 16 h at room temp.,
before being concentrated in vacuo. The product was isolated by
flash chromatography (toluene/ethyl acetate, 2:1) to yield 13
(93 mg, 0.2 mmol, 87%) (Rf
ϭ
0.4). 1H NMR (600 MHz,
3
were dried (MgSO4). Flash chromatography (toluene/ethyl acetate, [D6]DMSO): δ ϭ 7.30 (m, 5 H, Ph), 7.03 (d, JNHBoc,6 ϭ 9.1 Hz, 1
5:1) yielded 11 (228 mg, 0.46 mmol, 38%) (Rf ϭ 0.26) and the side
H, BocNH), 5.61 (d, 3J7-OH,7 ϭ 5.9 Hz, 7-OH), 5.10 (m, 2 H, 3, 8a),
4.69 (d, 2J gem ϭ 11.7 Hz, 1 H, CH2Ph), 4.56 (d, 2Jgem ϭ 12.0 Hz, 1
H, CH2Ph), 4.10 (m, 2 H, CH2CH3), 4.05 (pt, 3J6,7/NHBoc ϭ 8.2 Hz,
product 15 (217 mg, 0.45 mmol, 37%) (Rf ϭ 0.54). 1H NMR
(600 MHz, [D6]DMSO): δ ϭ 7.35 (m, 5 H, Ph), 6.61 (d, 3J7-OH,7
Eur. J. Org. Chem. 2003, 878Ϫ884
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883