1.80 (m, 2H), 1.59 (m, 2H); 13C NMR (DMSO-d6) δ 174.0,
52.2, 45.7, 29.8, 26.9, 21.2; MS (ESI) m/z 129.6 [(M + H)+];
Anal. Calcd for C6H12ClNO2: C, 43.51; H, 7.30; N, 8.46.
Found: C, 43.49; H, 7.19; N, 8.39.
Table 1. Reaction temperatures and approximate reaction
times for the reaction of CSI with alkenes 7a-c
alkene
time (h)
temperature (°C)
7a
7b
7c
7
24
96
25
40
25
(()-cis-2-Aminocyclohexane-1-carboxylic Acid (10c).
The cyclohexane â-lactam 9c (300.4 g; 2.4 mol) was
dissolved in water (100 mL), and then the mixture was
treated with 100 mL of concentrated HCl. The reaction
mixture was stirred for 2 h, and then the solution was allowed
to stand at room temperature for 12 h. The solution was
concentrated to give an oil which was triturated with a large
amount of acetone (∼30:1 volume ratio) to afford 404 g
when an aliquot of the reaction mixture no longer gave a
reaction with water (also monitored by HPLC). The reaction
mixture was cooled in an ice bath and was quenched by
careful addition of cold water. This mixture was used
immediately in the next step.
1
(92%) of crystalline â-amino acid hydrochloride 10c. H
A suspension15 of Na2SO3 (133.6 g, 1.06 mol) in water
(400 mL) was stirred in an ice-water bath. The aqueous
suspension was then treated with the dichloromethane
solution of the crude N-chlorosulfonyl â-lactam 8a-c, which
was added in small portions, keeping the internal temperature
below 25 °C. The pH of the aqueous solution was maintained
between 5 and 7 by the concurrent addition of 20% aqueous
NaOH. After the addition was complete, the reaction mixture
was stirred for an additional hour at 0 °C. The organic layer
was separated, and the aqueous layer was extracted with
dichloromethane, with the exception of cyclohexyl-â-lactam
9c, which was extracted with ethyl acetate. The combined
organic phases were dried (MgSO4), filtered, and concen-
trated in vacuo to afford the parent â-lactams 9a-c as stable,
crystalline white solids or viscous oils.
NMR (DMSO-d6) δ 3.24 (m, 1 H), 2.90 (m, 1H), 1.92 (m,
2H), 1.71 (m, 2H), 1.56 (m, 2H), 1.26 (m, 2H);13C NMR
(DMSO-d6) δ 174.1, 49.5, 42.2, 27.4, 22.7, 26.2, 22.7; MS
(ESI) m/z 143.8 [(M + H)+]; Anal. Calcd for C7H14ClNO2:
C, 46.80; H, 7.86; N, 7.80. Found: C 46.90; H, 7.69; N,
7.74.
Other runs to prepare 10c proceeded in variable yields
(48-94%).
General Procedure for FMOC-Protection of cis-â-
Amino Acids 10a-c. To a 5-L, three-necked flask equipped
with a mechanical stirrer was added KHCO3 (301.6 g, 3.01
mol) followed by water (1.5 L). Stirring was initiated, and
once all the solids had dissolved, solid amino acid 10a-c
(1.56 mol) was added in small portions over a period of
1-1.5 h. The resulting mixture was stirred at room temper-
ature until complete dissolution was achieved. The reaction
mixture was diluted with acetonitrile (1.5 L), followed by
the addition of solid FMOC-OSu (4; 576 g, 1.5 mol). The
white suspension was stirred vigorously at room temperature
until TLC analysis indicated that the reaction was complete.
The mixture was acidified with concentrated HCl to pH 2
and then stirred at room temperature for 1 h. The white
suspension was then filtered through a coarse sintered glass
funnel. The cake was suspended in water (5.5 L), filtered,
and the process repeated. The FMOC-amino acid was dried
to constant weight in a vacuum oven at room temperature.
(()-cis-3-FMOC-aminobicyclo[2.2.1]heptane-2-car-
boxylic acid (13a): isolated as a white powder, 435.7 g
(74%); 1H NMR (DMSO-d6) δ 7.78-7.21 (m, 8H), 4.18 (s,
2H), 3.89 (m, 1H), 2.56 (m, 1H), 2.37 (m, 1H), 2.09 (m,
1H), 1.96 (m, 1H), 1.47 (m, 2H), 1.17 (m, 4H);13C NMR
(DMSO-d6) δ 173.5, 155.5, 144.6, 144.3, 141.3, 128.2, 127.6,
126.1, 120.6, 66.3, 56.9, 53.4, 47.3, 42.4, 35.7, 28.5, 26.9.
MS (ESI) m/z 378.2 [(M + H)+]; Anal. Calcd for C23H23-
NO4: C, 73.19; H, 6.14; N, 3.71. Found C, 73.06; H, 6.17;
N 3.65.
(()-cis-6-Azabicyclo[3.2.0]heptan-7-one (9b): isolated
1
as a white powder; H NMR (DMSO-d6) δ 3.88 (m, 1H),
3.34 (m, 1H), 1.79-1.21 (m, 6H); 13C NMR (DMSO-d6) δ
169.4, 55.1, 52.3, 29.7, 24.8, 22.3. MS (ESI) m/z 112.0 [(M
+ H)+].
(()-cis-3-Aminobicyclo[2.2.1]heptane-2-carboxylic Acid
Hydrochloride (10a). The norbornane â-lactam 9a (290.8
g; 2.12 mol) was cooled in an ice-water bath, and to it was
added just enough concentrated HCl to cover the solid. After
several minutes an exothermic reaction was observed,
affording a white solid. The mixture was allowed to stand
for an additional 3-4 h and diluted with diethyl ether, and
the solid was filtered. The white solid was washed with
diethyl ether to afford 333.2 g (82%) of amino acid
1
hydrochloride 10a. H NMR (DMSO-d6) δ 3.21 (m, 1H),
2.66 (d, J ) 8.16 Hz, 1H), 1.86 (d, J ) 10.39 Hz, 1H), 1.47
(m, 1H), 1.45 (m, 2H), 1.14 (m, 4H); 13C NMR (DMSO-d6)
δ 171.1, 52.6, 47.3, 39.5, 38.6, 31.8, 26.1, 24.1; MS (ESI)
m/z 155.8 [(M + H)+]; Anal. Calcd for C8H14ClNO2: C,
50.13; H, 7.36; N, 7.31. Found: C, 50.05; H, 7.24; N, 7.21.
(()-cis-2-Aminocyclopentane-1-carboxylic Acid Hy-
drochloride (10b). The cyclopentane â-lactam 9b (115.6 g;
1.04 mol) was dissolved in water (100 mL), and then the
mixture was treated with 100 mL of concentrated HCl. The
reaction mixture was stirred for 2 h after which it was
allowed to stand at room temperature for 12 h. The resulting
crystalline solid was isolated by filtration to give 142.9 g
(()-cis-2-(FMOC-amino)cyclopentane-1-carboxylic acid
(13b): isolated as a white powder; 535.8 g (94%); 1H NMR
(DMSO-d6) δ 7.94-7.29 (m, 8H), 4.26 (s, 2 H), 4.21 (d, J
) 6.68 Hz, 1H), 3.34 (m, 1H), 2.85 (m, 1H), 1.78 (m,
6H);13C NMR (DMSO-d6) δ 174.4, 155.6, 144.1, 140.7,
127.6, 127.1, 125.3, 120.1, 65.6, 54.3, 47.5, 46.8, 31.4, 26.4,
21.7; MS (ESI) m/z 352.2 [(M + H)+]; Anal. Calcd for
C21H21NO4: C, 71.78; H, 6.02; N, 3.99. Found: C, 71.70;
H, 5.97; N, 4.05.
1
(83%) of the â-amino acid hydrochloride 10b. H NMR
(DMSO-d6) δ 3.61 (m, 1H), 3.01 (m, 1H), 1.96 (m, 2H),
(15) In some cases complete dissolution of sodium sulfite was observed.
448
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Vol. 5, No. 4, 2001 / Organic Process Research & Development