PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Aminocyclopropanecarboxylic Acid Derivatives
3413
HRMS (CI-CH4): m/z [M + H]+ calcd for C9H16NO4: 202.1079;
CH2), 3.74 (br s, 1 H, OH), 5.02–5.10 (m, 2 H, NH, CH2), 5.15 (d,
found: 202.1082.
J = 17.2 Hz, 1 H, CH2), 5.55 (ddd, J = 17.2, 10, 8.5 Hz, 1 H, CH).
13C NMR (100 MHz, CDCl3): d = 19.0, 27.0, 28.4, 40.7, 69.9, 80.3,
tert-Butyl cis-5-Oxo-1-vinyl-6-oxa-4-azaspiro[2.4]heptane-4-
carboxylate (5)
116.4, 135.0, 157.7.
HRMS (CI-NH3): m/z [M + H]+ calcd for C11H20NO3: 214.1443;
found: 214.1445.
To a soln of the nitrile 1 (2.10 g, 13.36 mmol) and Ti(Oi-Pr)4 (800
mL, 2.68 mmol) in THF (100 mL) under argon at 50 °C was added
dropwise 1.2 M EtMgBr in THF (24.4 mL, 29.4 mmol). The soln
turned gradually from clear yellow to brown. At the end of the ad-
dition (ca. 30 min), TLC analysis (cyclohexane–EtOAc, 7:3, vanil-
lin development) showed the disappearance of the starting material.
H2O (ca. 40 mL) was slowly added, followed by EtOAc (40 mL)
and 1 M HCl until the two layers became clear (acidic pH). The
aqueous phase was extracted with EtOAc (3 × 25 mL) and the com-
bined organic phases were washed with brine (30 mL), dried
(MgSO4), and concentrated under reduced pressure to give a crude
mixture of amino alcohol 2c and oxazolidinone 4c.15
1H NMR (200 MHz, CDCl3): d = 0.85 (m, 1 H, 2c-CH2), 1.05 (m, 2
H, 4c-CH2), 1.17 (m, 1H, 2c-CH2), 1.40 (s, 9 H, 2c-CH3), 1.64 (m,
1 H, 4c-CH), 1.74 (m, 1 H, 2c-CH), 3.50–3.78 (m, 3 H, 2c-OH, 2c-
CH2), 4.34 (d, J = 8.3 Hz, 1 H, 4c-CH2), 4.37 (d, J = 8.3 Hz, 1 H,
4c-CH2), 4.90–5.30 (m, 3 H, 2c-NH, 2c-CH2), 5.15 (ddd, J = 10.1,
1.6, 0.6 Hz, 1 H, 4c-CH2), 5.17 (ddd, J = 17.2, 1.6, 0.7 Hz, 1 H, 4c-
CH2), 5.40–5.60 (m, 1 H, 2c-CH), 5.56 (ddd, J = 17.2, 10.1, 7.9 Hz,
1 H, 4c-CH), 6.90 (s, 1 H, 4c-NH).
cis-1-(tert-Butoxycarbonylamino)-2-vinylcyclopropanecarbox-
ylic Acid (3c)
To a soln of alcohol 2c (633 mg, 2.97 mmol) in CH2Cl2 (6 mL) un-
der argon were successively added NMO (522 mg, 4.46 mmol),
powdered 4Å molecular sieves (1.50 g), and TPAP (52 mg, 5
mol%). The mixture was stirred at r.t. until TLC showed complete
consumption of the starting material (1 h). Filtration through a pad
of silica gel (100% EtOAc) afforded the pure corresponding alde-
hyde (625 mg, quantitative yield) as a colorless oil which was used
directly in the next step; Rf = 0.75 (cyclohexane–EtOAc, 1:1).
IR (neat): 3357, 3088, 2979, 2933, 1702, 1639, 1500, 1456, 1366,
1162 cm–1.
1H NMR (400 MHz, CDCl3, 16:1 mixture of rotamers): d = 1.38–
1.48 (m, 10 H, CH2, CH3), 1.83 (br m, 1 H, CH2), 2.33 (q, J = 8.3
Hz, 1 H, CH), 5.11 (m, 1 H, NH), 5.20 (m, 1 H, CH2), 5.26 (d,
J = 17.2 Hz, 1 H, CH2), 5.55 (ddd, J = 17.2, 9.8, 8.0 Hz, 0.94 H,
CH), 5.77 (m, 0.06 H, CH), 9.30–9.50 (br s, 1 H, CHO).
13C NMR (100 MHz, CDCl3, 16:1 mixture of rotamers): d = 22.7
(0.94 C), 23.6 (0.06 C), 28.3 (3 × 0.94 C), 28.4 (3 × 0.06 C), 32.0
(0.94 C), 33.2 (0.06 C), 47.2, 80.6, 119.0, 132.8, 156.2, 200.0.
HRMS (CIN-NH3): m/z [M–] calcd for C11H17NO3: 211.1208;
found: 211.1205.
To a soln of the crude mixture of 2c and 4c in THF (30 mL) was
added successively Boc2O (3.50 g, 16.0 mmol), Et3N (2.42 mL,
17.4 mmol), and DMAP (328 mg, 2.68 mmol). The soln was stirred
at r.t. for 1 h then sat. aq NH4Cl soln (30 mL) was added. The aque-
ous phase was extracted with Et2O (3 × 25 mL) and the combined
organic fractions were washed with brine, dried (MgSO4), and fil-
tered. After concentration under reduced pressure, the crude prod-
uct was purified by flash chromatography (silica gel, cyclohexane–
EtOAc, 7:3, vanillin development) to afford the pure cis-Boc-
oxazolidinone 5 (2.20 g, 69% yield over two steps) as a colorless
oil; Rf = 0.30 (cyclohexane–EtOAc, 7:3).
To a soln of the aldehyde in MeCN (10 mL) cooled to 0 °C was add-
ed successively a soln of NaH2PO4 (232 mg, 1.49 mmol) in H2O (4
mL), 37% aq H2O2 soln (0.34 mL, 2.97 mmol), and a soln of
NaClO2 (403 mg, 4.46 mmol) in H2O (6 mL). The mixture was al-
lowed to warm up to r.t. and vigorously stirred at this temperature
until TLC showed complete consumption of the starting material (1
h). Na2SO3 (300 mg, 2.38 mmol) was added to destroy the excess of
NaClO2 and the soln was stirred for an additional 1 h. After the ad-
dition of 1 M aq KHSO4 (2 mL), the aqueous phase was extracted
with EtOAc (3 × 10 mL) and the combined organic layers were
washed with sat. NaHCO3 soln (2 × 10 mL). The combined basic
aqueous extracts were acidified by addition of aq 1 M HCl and the
resulting aqueous phase was extracted with EtOAc (3 × 10 mL). The
combined organic extracts were dried (MgSO4), the organic fraction
was concentrated under reduced pressure, and the crude oil was fil-
tered through a pad of silica gel (cyclohexane–EtOAc, 1:1, vanillin
development) to afford pure acid (440 mg, 70% yield) as a colorless
oil; Rf = 0.20 (cyclohexane–EtOAc, 1:1).
IR (neat): 2981, 1790, 1724, 1636, 1477, 1457, 1332, 1154, 1069
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.07 (dd, J = 10.0, 7.0 Hz, 1 H,
CH2), 1.52 (s, 9 H, CH3), 1.68 (m, 1 H, CH), 2.51 (t, J = 7.0 Hz, 1
H, CH2), 3.90 (d, J = 8.3 Hz, 1 H, CH2), 4.36 (d, J = 8.3 Hz, 1 H,
CH2), 5.08 (ddd, J = 10.4, 1.6, 0.6 Hz, 1 H, CH2), 5.21 (ddd,
J = 17.2, 1.6, 0.7 Hz, 1 H, CH2), 5.66 (ddd, J = 17.2, 10.4, 8.6 Hz,
1 H, CH).
13C NMR (100 MHz, CDCl3): d = 12.5, 28.1, 29.9, 46.4, 71.2, 84.2,
118.0, 133.7, 149.9, 152.9.
HRMS (CI-NH3): m/z [M + NH4]+ calcd for C12H21N2O4: 257.1501;
found: 257.1499.
IR (neat): 3321, 3087, 2977, 2929, 2852, 2568, 1698, 1498, 1478,
1450, 1367, 1258, 1159 cm–1.
tert-Butylcis-1-(Hydroxymethyl)-2-vinylcyclopropylcarbamate
(2c)
1H NMR (400 MHz, CDCl3, 5:1 mixture of rotamers): d = 1.24–
1.30 (m, 1 H, CH2), 1.43 (s, 9 × 0.83 H, CH3), 1.44 (s, 9 × 0.17 H,
CH3), 1.80 (br s, 0.17 H, CH2), 1.94 (br s, 0.83 H, CH2), 2.42 (br q,
J = 7.9 Hz, 1 H, CH), 4.99 (br s, 0.83 H, NH), 5.07–5.33 (m, 2 H,
CH2), 5.77 (m, 0.17 H, CH), 5.87 (br s, 0.17 H, NH), 8.95–9.61 (br
s, 1 H, COOH).
13C NMR (100 MHz, CDCl3, 5:1 mixture of rotamers): d = 23.4
(0.83 C), 23.6 (0.17 C), 28.3 (3 × 0.83 C), 28.4 (3 × 0.17 C), 32.0
(0.83 C), 32.3 (0.17 C), 39.4 (0.83 C), 39.8 (0.17 C), 80.5 (0.83 C),
81.2 (0.17 C), 118.6, 133.8, 156.3, 177.8.
To a soln of Boc-oxazolidinone 5 (710 mg, 2.97 mmol) in THF (15
mL) was added aq 2 M LiOH (15 mL, 29.7 mmol). The mixture was
stirred at r.t. for 1 h and H2O (15 mL) was added. The aqueous phase
was extracted with EtOAc (3 × 10 mL) and the combined organic
extracts were washed with brine, dried (MgSO4), filtered, and con-
centrated under reduced pressure. The residue was filtered through
a pad of silica gel (cyclohexane–EtOAc, 1:1, vanillin development)
to provide amino alcohol 2c (633 mg, quantitative yield) as a white
solid; mp 44–45 °C; Rf = 0.25 (cyclohexane–EtOAc, 1:1).
IR (neat): 3332, 2977, 2934, 1689, 1638, 1496, 1455, 1366, 1250,
1163 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.85 (m, 1 H, CH2), 1.17 (m, 1 H,
CH2), 1.40 (s, 9 H, CH3), 1.74 (m, 1 H, CH), 3.47–3.66 (m, 2 H,
HRMS (CI-NH3): m/z [M + H]+ calcd for C11H18NO4: 228.1236;
found: 228.1238.
Synthesis 2010, No. 20, 3410–3414 © Thieme Stuttgart · New York