63%) as a colourless oil; dH (400 MHz; CDCl3) 1.95 (2 H, d,
J 4.5, CHCH2), 2.40 (1 H, br s, CD2OH), 3.83–4.05 (4 H, m,
OCH2CH2O) and 5.02 (1 H, t, J 4.5, CHCH2); dC (101 MHz;
CDCl3) 35.3, 57.7 (quin, J 22.0), 64.8 and 103.8; m/z (HR-ESI+)
143.0648 (M + Na+. C5H8D2NaO3 requires 143.0648).
28.2, 28.6, 34.3, 65.4, 80.0, 82.8, 104.4, 120.2 (t, J 18.0), 153.4
and 163.9; m/z (HR-ESI+) 353.1793 (M + Na+. C16H26DNNaO6
requires 353.1793).
tert-Butyl (2S,3S)-2-(tert-butyloxycarbonyl-amino)-2,3-[2H2]-4-
(1,3-dioxolan-2-yl)-butanoate 21. A solution of didehydro-amino
acid (Z)-19 (100 mg, 0.304 mmol) and (S,S)-Me-DUPHOS-Rh
(4.0 mg, 6.6 mmol) in MeOH (10 mL) was stirred under an
atmosphere of 2H2 (1 bar) at rt for 6 days. The solvent was
evaporated under reduced pressure. The residue was purified by
column chromatography (petroleum ether–EtOAc, 4 : 1) to give
21 (99 mg, 98%) as a colourless oil; [a]2D5 +6.4 (c 1.00 in CHCl3); dH
(500 MHz; C6D6) 1.27 (9 H, s, t-Bu), 1.41 (9 H, s, t-Bu), 1.69–1.84
(3 H, m, CHDCH2), 3.24–3.31 (2 H, m, OCH2CH2O), 3.40–3.47
(2 H, m, OCH2CH2O), 4.68–4.74 (1 H, m, CHCH2) and 5.11
(1 H, br s, NH); dD (77 MHz; C6H6) 1.99 (1 D, s, CHDCH2) and
4.43 (1 D, s, NHCD); dC (126 MHz; C6D6) 27.2 (t, J 19.5), 28.2,
28.8, 30.2, 54.2 (t, J 22.5), 65.2, 79.5, 81.5, 104.3, 155.9 and 172.3;
m/z (HR-ESI+) 356.2017 (M + Na+. C16H27D2NNaO6 requires
356.2013).
tert-Butyl 2-(tert-butyloxycarbonyl-amino)-4-(1,3-dioxolan-2-
yl)-but-2-enoate 19. To
a solution of KOt-Bu (100 mg,
0.891 mmol) in anhydrous THF (8 mL), a solution of phosphonate
14 (312 mg, 0.849 mmol) in anhydrous THF (8 mL) was added at
◦
-70 C. After 5 min, a solution of crude aldehyde 1559 (197 mg)
in anhydrous THF (8 mL) was added dropwise at -70 ◦C over
10 min. The reaction mixture was stirred for 20 h and slowly
warmed to rt during this period. The reaction was quenched by
addition of MeOH (5 mL) and the solvent evaporated under
reduced pressure. The residue was dissolved in EtOAc (50 mL)
and water (50 mL). The organic phase was washed with water
(1 ¥ 50 mL), dried over Na2SO4 and evaporated under reduced
pressure. The resultant yellowish oil (310 mg) was purified by
column chromatography (hexane–EtOAc, 4 : 1) to give (Z)-19
(229 mg, 82%) and (E)-19 (20 mg, 7%) as colourless oils; (Z)-19:
dH (500 MHz; C6D6) 1.38 (9 H, s, t-Bu), 1.40 (9 H, s, t-Bu),
2.51–2.64 (2 H, m, CHCH2), 3.11–3.19 (2 H, m, OCH2CH2O),
3.30–3.37 (2 H, m, OCH2CH2O), 4.68–4.76 (1 H, m, CHCH2)
tert-Butyl (2S,3R)-2-(tert-butyloxycarbonyl-amino)-3-[2H]-4-
(1,3-dioxolan-2-yl)-butanoate 22. A solution of didehydro-amino
acid (Z)-20 (92 mg, 0.28 mmol) and (S,S)-Me-DUPHOS-Rh
(4.0 mg, 6.6 mmol) in MeOH (10 mL) was stirred under an
atmosphere of H2 (1 bar) at rt for 6 days. The solvent was
evaporated under reduced pressure. The residue was purified
by column chromatography (hexane–EtOAc, 4 : 1) to give 22
(84 mg, 90%) as a colourless oil; [a]2D5 +7.2 (c 1.00 in CHCl3); dH
(500 MHz; C6D6) 1.28 (9 H, s, t-Bu), 1.41 (9 H, s, t-Bu), 1.71–1.83
(2 H, m, CHDCH2), 2.01–2.08 (1 H, m, CHDCH2), 3.24–3.31
(2 H, m, OCH2CH2O), 3.40–3.47 (2 H, m, OCH2CH2O), 4.50
(1 H, dd, J 5.5 and 8.0, NHCH), 4.71 (1 H, t, J 4.5, CHCH2)
and 5.11 (1 H, d, J 8.0, NHCH); dD (77 MHz; C6H6) 1.73 (s); dC
(126 MHz; C6D6) 27.3 (t, J 19.5), 28.2, 28.8, 30.3, 54.5, 65.2, 79.5,
81.5, 104.3, 156.0 and 172.3; m/z (HR-ESI+) 355.1954 (M + Na+.
C16H28DNNaO6 requires 355.1950).
=
and 6.56–6.72 (2 H, m, C CH, NH); dC (126 MHz; C6D6)
28.3, 28.6, 33.5, 65.2, 80.2, 81.4, 103.9, 126.0, 153.6 and 164.3;
m/z (HR-ESI+) 352.1727 (M + Na+. C16H27NNaO6 requires
352.1731); (E)-19: dH (500 MHz; C6D6) 1.26 (9 H, s, t-Bu), 1.36
(9 H, s, t-Bu), 3.12 (2 H, dd, J 4.5 and 7.5, CHCH2), 3.30–3.37
(2 H, m, OCH2CH2O), 3.53–3.59 (2 H, m, OCH2CH2O), 4.97
(1 H, t, J 4.5, CHCH2), 6.96 (1 H, br s, NH) and 7.27–7.36 (1 H,
=
m, C CH); dC (126 MHz; C6D6) 28.2, 28.6, 34.4, 65.4, 80.0, 82.8,
104.5, 120.6, 153.4 and 163.9; m/z (HR-ESI+) 352.1732 (M +
Na+. C16H27NNaO6 requires 352.1731).
tert-Butyl 2-(tert-butyloxycarbonyl-amino)-3-[2H]-4-(1,3-dioxo-
lan-2-yl)-but-2-enoate 20. To a solution of KOt-Bu (89 mg,
0.79 mmol) in anhydrous THF (7 mL), a solution of phosphonate
14 (279 mg, 0.759 mmol) in anhydrous THF (7 mL) was added
at -70 ◦C. After 5 min, a solution of crude deutero-aldehyde
16 (133 mg) in anhydrous THF (7 mL) was added dropwise at
-70 ◦C over 10 min. The reaction mixture was stirred for 20 h and
slowly warmed to rt during this period. The reaction was quenched
by addition of MeOH (5 mL) and the solvent evaporated under
reduced pressure. The residue was dissolved in EtOAc (50 mL)
and water (50 mL). The organic phase was washed with water
(1 ¥ 50 mL), dried over Na2SO4 and evaporated under reduced
pressure. The resultant yellow-brown oil (300 mg) was purified
by column chromatography (hexane–EtOAc, 4 : 1) to give (Z)-20
(189 mg, 75%) and (E)-20 (27 mg, 11%) as colourless oils; (Z)-20:
dH (500 MHz; C6D6) 1.38 (9 H, s, t-Bu), 1.40 (9 H, s, t-Bu), 2.47–
2.66 (2 H, m, CHCH2), 3.10–3.17 (2 H, m, OCH2CH2O), 3.29–3.35
(2 H, m, OCH2CH2O), 4.67–4.77 (1 H, m, CHCH2) and 6.68 (1 H,
br s, NH); dC (126 MHz; C6D6) 28.3, 28.6, 33.3, 65.2, 80.2, 81.4,
103.9, 125.6 (t, J 24.0), 153.6 and 164.3; dD (77 MHz; C6H6) 6.59
(s); m/z (HR-ESI+) 353.1791 (M + Na+. C16H26DNNaO6 requires
353.1793); (E)-20: dH (500 MHz; C6D6) 1.25 (9 H, s, t-Bu), 1.36
(9 H, s, t-Bu), 3.13 (2 H, d, J 4.5, CHCH2), 3.29–3.36 (2 H, m,
OCH2CH2O), 3.52–3.59 (2 H, m, OCH2CH2O), 4.98 (1 H, t, J
4.5, CHCH2) and 7.00 (1 H, br s, NH); dC (126 MHz; C6D6)
tert-Butyl N2-Boc-N5-methoxy-N5-methyl-L-glutaminate 25.
To a solution of N-Boc-L-Glu-Ot-Bu 24 (267 mg, 0.882 mmol)
in anhydrous CH2Cl2 (10 mL), PyBOP (459 mg, 0.882 mmol)
and NEt3 (122 mL, 0.882 mmol) were added at rt. After stirring
for 20 min at rt, more NEt3 (245 mL, 1.76 mmol) and N,O-
dimethylhydroxylamine hydrochloride (124 mg, 1.32 mmol) were
added and the reaction mixture was stirred at rt for 20 h. More
CH2Cl2 (20 mL) was added, and the organic solution was washed
with 5% NaHSO4 solution (1 ¥ 10 mL), water (1 ¥ 10 mL),
saturated NaHCO3 solution (1 ¥ 10 mL), water (2 ¥ 10 mL), brine
(1 ¥ 10 mL) and again water (1 ¥ 10 mL). The organic phase was
dried over MgSO4 and evaporated under reduced pressure. The
resultant crude product was purified by column chromatography
(hexane–EtOAc, 4 : 1) to give 25 (246 mg, 81%) as a colourless oil;
d
H (400 MHz; CDCl3) 1.43 (9 H, s, t-Bu), 1.44 (9 H, s, t-Bu), 1.85–
=
=
1.94 (1 H, m, CH2CH2C O), 2.08–2.15 (1 H, m, CH2CH2C O),
2.43–2.56 (2 H, m, CH2CH2C O), 3.14 (3 H, s, NCH3), 3.65 (3 H,
s, NOCH3), 4.08–4.19 (1 H, m, NHCH) and 5.19 (1 H, br d, J 8.0,
NHCH); dC (101 MHz; CDCl3) 24.7, 27.6, 28.0, 28.3, 32.2, 53.7,
61.2, 79.6, 81.9, 155.5, 171.6 and 173.5.
=
N-Boc-5-[2H]-L-GSA tert-butyl ester 26. To a suspension of
Cp2Zr2HCl (160 mg, 0.618 mmol) in anhydrous THF (2 mL), a
2776 | Org. Biomol. Chem., 2009, 7, 2770–2779
This journal is
The Royal Society of Chemistry 2009
©