SYNTHESIS OF ENANTIOPURE BICYCLIC AMINO ACIDS
247
TABLE 1. Diels-Alder reaction of the 1,3-cyclohexadiene with the nitroacrylate (R)-2a
Entry
T (8C)
Solvent
Additive (equiv)
Time (h)
Conversion (%)b
Cycloadducts ratioc
1
2
3
4
5
6
7
278
RT
220
MW 60
RT
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
–
–
–
–
–
24
5/24
48
0
10/90
>99
–
52/28/13/7
60/26/10/4
53/27/13/7
68/17/12/3
52/31/11/6
–
0.5
>99
–
5/24
5/24
20
55d
RT
220
CH2Cl2
CH2Cl2
ZnCl2 (1)
ZnCl2 (1)
70/>99
10
aIn CH2Cl2 using 10 equivalents of 1,3-cyclohexadiene, 0.5M acrylate concentration or in solvent free condition using 20 equivalents of cyclohexadiene.
bDetermined by HPLC analysis and based on acrylate disappearance.
cDetermined by 1H NMR, HPLC (achiral and chiral), and LC/MS analysis.13,14
dIncomplete solubility of the nitroacrylate in solvent-free conditions.
the expected compound (2S,3S,30R)-4 (310 mg, 0.62 mmol, 65 % yield)
as a white solid; m.p. 1238C; [a]D 5 210 (c 5 0.9 in CH2Cl2); tR
(CDCl3) d 1.35–1.60 (m, 11H, CH2, 1-H, 4-H, 2-H), 1.38 (s, 9H, C(CH3)3),
3.27 (br s, 1H, 3-H), 3.46 (dd, J 5 5.1 and 10.8, 1H, HCH-OH), 3.60 (t, J
5 10.8, 1H, HCH-OH), 4.05 (br s, 1H, OH), 4.87 (br s, 1H, NH); 13C
NMR (CDCl3) 18.0 (CH2), 18.7 (CH2), 23.4 (CH2), 25.0 (CH2), 25.4 (C-1
or C-4), 26.9 (C(CH3)3), 28.2 (C-1 or C-4), 48.5 (C-2), 51.8 (C-3), 64.8
(CH2OH), 78.4 (C(CH3)3), 154.9 (CO); HRMS (FAB) Calcd for
20
(HPLC, column A) 9.8 min; MS (ESI) m/z: 501.3 [(M1H)1], 445.3,
401.3; 1H NMR (CDCl3) d 1.00–1.80 (m 1 s, 2(CH3), C(CH3)3, 4(CH2),
CH), 2.04 (br s, 1H, CH), 2.37, and 2.55 (br s, 1H, CH), 3.49 (d, J 5 9.5,
1H, 50-H), 3.57 (d, J 5 9.5, 1H, 50-H), 3.98 (br s, 1H, CH), 4.64 (br s, 1H,
NH), 5.40 (s, 1H, 30-H), 7.60 (d, J 5 8.5, 2H, H-arom), 7.90 (d, J 5 8.5,
2H, H-arom); 13C NMR (CDCl3) 19.6 (CH2), 20.2 (CH3), 23.2 (CH2), 23.6
(CH3), 24.84 (CH2), 27.4 (CH), 27.5 (C(CH3)3), 28.2 (CH), 28.4 (CH2),
36.4 (C-40), 49.9 (C-2 and C-3), 56.5 (C-50), 77.1 (C-30), 81.18 (C(CH3)3),
117.3 (CH-arom), 124.4 (C-arom), 130.2 (CH-arom), 142.5 (C-arom),
155.8, 168.7, 169.5, and 172.6 (CO); HRMS (FAB) Calcd for C27H37N2O7
(MH1) 501.2601, found 501.2602.
C
14H26NO3 (MH1) 256.1913 , found 256.1906.
Trans-(2 S,3 S)-3-(Hydroxymethyl)-2-
aminobicyclic[2,2,2]octanic acid-Trifluoroacetic acid salt
[(2 S,3 S)-7]
Trifluoroacetic acid (450 ll) was added at 08C and under argon to a
stirred solution of the N-Boc bicyclic 1,3-amino alcohol (2S,3S)-6 (56
mg, 0.22 mmol) in CH2Cl2 (1.5 ml). After stirring 30 min at room temper-
ature, the reaction mixture was diluted with cyclohexane (5 ml) and con-
centrated in vacuo to give the deprotected compound 7 (59 mg, quantita-
tive yield) as a colorless oil; [a]D20 5 241 (c 5 0.7 in CH2Cl2); MS (ESI)
(2 S,3 S)-3-tert-Butoxycarbonylaminobicyclo[2.2.2]octane-
2-carboxylic acid [(2 S,3 S)-5]
A solution of LiOH, H2O (55 mg, 1.32 mmol, 2.2 equiv) in water was
added dropwise to a solution of compound (2S,3S,30R)-4 (300 mg, 0.6
mmol) in THF/H2O (2/1) (18 ml) and the mixture was stirred at room
temperature till completion of the hydrolysis (~ 6 h) (monitored by
HPLC, column A). The organic solvent was removed in vacuo, the resi-
due was taken up in ethyl acetate/H2O (10/5 ml), the aqueous phase
was acidified (pH 3) and extracted with ethyl acetate. The residue
obtained after evaporation of the ethyl acetate phase was submitted to a
column chromatography on silica gel, using CH2Cl2/ethyl acetate/
AcOH (9/1/0.01) as eluent to yield the expected pure b-amino acid
(2S,3S)-5 (94 mg, 0.35 mmol, 58% yield) as a white solid; m.p. 1428C;
1
m/z: 156.1 [(M1H)1]; H NMR (CDCl3) d 1.12–1.90 (m, 10H, CH2, 1-H,
4-H), 2.31 (m, 1H, 2-H), 3.12 (br s, 1H, OH), 3.38 (t, J 5 9.6, 1H, 3-H),
3.50 (dd, J 5 6.5 and 4.5, 1H, HCH-OH), 3.86 (t, J 5 6.5, 1H, HCH-OH),
13C NMR (CDCl3) 23.7 (C-1 or C-4), 25.2 (CH2), 25.4 (C-1 or C-4), 27.8
(CH2), 28.2 (CH2), 30.1 (CH2), 61.1 (CH2OH), 62.8 (C-2), 63.2 (C-3);
HRMS (FAB) Calcd for C9H18NO (MH1) 156.1388, found 156.1391. The
same synthetic route could be achieved using the chiral auxiliary
(R)-1
[a]D 5 1 9 (c 5 1.2 in CH2Cl2); MS (ESI) m/z: 270.3 [(M1H)1],
20
RESULTS AND DISCUSSION
214.2 and 170.2; 1H NMR (CDCl3) d 1.38 (s, 9H, C(CH3)3), 1.40–1.58 (m,
8H, CH2), 1.62(br s, 1H, 4-H), 1.76 (br m, 1H, HCH), 2.02 (br s, 1H, 1-
H), 2.29 (br s, 1H, 2-H), 3.78 (br m, 1H, 3-H), 4.97 (br s, 1H, NH); 13C
NMR (CDCl3) 18.1 (CH2), 19.3 (CH2), 23.3 (CH2), 24.6 (CH2), 26.1 (C-1),
27.3 (C(CH3)3), 28.1 (C-4), 50.1 (C-3), 51.0 (C-2), 79.9(C(CH3)3), 155.9,
and 175.3 (CO); HRMS (FAB) Calcd for C14H24NO4 (MH1) 270.1705,
found 270.1709.
The asymmetric Diels-Alder cycloaddition (Scheme 1) was
first carried out using the optimized conditions previously
defined, when using cyclopentadiene as diene7 i.e., without
catalyst in dry CH2Cl2 at 2788C for 20 h (Table 1, Entry 1).
In these conditions no Diels-Alder adduct formation was
detected and the starting nitroacrylate was recovered. How-
ever, the reaction was successfully carried out at room tem-
perature for 24 h to yield a mixture of the four expected
cycloadducts with one predominant diastereoisomer (Table
1, Entry 2).
Trans-(2 S,3 S)-N-Boc 3-(hydroxymethyl)-2-
aminobicyclic[2,2,2]octane [(2 S,3 S)-6]
To a stirred solution of the amino acid (2S,3S)-5 (90 mg, 0.33
mmol) in THF (3 ml) was added at room temperature benzotriazol-1-
yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP rea-
gent) (148 mg, 0.33 mmol, 1 equiv) and N,N-Diisopropylethylamine
(DIEA) (86 mg, 0.49 mmol, 1.5 equiv). The resulting solution was stirred
for 10 min, then NaBH4 (38 mg, 1 mmol, 3 equiv) was added by portion-
wise at 08C. After stirring 40 min at room temperature, the solvent was
evaporated and the residue was dissolved in ethyl acetate (20 ml). This
organic phase was washed with 0.1N HCl (2 3 5 ml), dried over Na2SO4
and concentrated in vacuo. The residue obtained was submitted to a col-
umn chromatography on silica gel, using ethyl acetate/cyclohexane (1/
1) as eluent to yield the expected compound (2S,3S)-6 as a white solid
We also observed total consumption of the nitroacrylate
(R)-2 with formation of the cycloadducts within 0.5 h using
microwave irradiation at 608C without modification of the dia-
stereoisomeric ratios (Table 1, Entry 4).
A moderate
enhancement of the stereoselectivity could be achieved by
carrying out the reaction in dry CH2Cl2 at 2208C (Table 1,
Entry 3) or in solvent-free conditions using 20 equivalents of
cyclohexadiene at room temperature (Table 1, Entry 5).
However, the latter conditions were not really usable
because of the incomplete solubility of the nitroacrylate in
cyclohexadiene that limits yield whatever is the reaction
time. The addition of ZnCl2 as a Lewis acid catalyst enhanced
20
(56 mg, 0.22 mmol, 67% yield); m.p. 1178C; [a]D 5 247 (c 5 1.3 in
CH2Cl2); MS (ESI) m/z: 256.3 [(M1H)1], 200.2 and 156.2; 1H NMR
Chirality DOI 10.1002/chir