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ARTICLE
RSC Advances
(
s, 3H), 2.43–2.58 (m, 3H), 2.11 (m, 1H), 1.87–s1.92 (m, 2H). added. A steam of hydrogen was passed through the resulting
DOI: 10.1039/C6RA01548D
1
3
C NMR (125 MHz, CDCl ) δ 173.1, 172.4, 138.6, 128.4, mixture with stirring for 6 h. The catalyst was filtered off, and
3
1
27.63, 127.57, 79.7, 70.7, 59.1, 52.9, 52.8, 40.1, 32.0, 31.9.
the solvent was removed in vacuo to give the product (R)-
20
1
6
HCl (8.74 g, 95%). White powder. Mp 138–139
C. [α]D
Dimethyl (3S)-3-hydroxycyclopentane-1,1-dicarboxylate ((S)-19).
+
+12.1 (c 1.0, MeOH). MS (m/z, CI): 202 (MH ). Anal. calc. for
The crude 30 obtained in the previous experiment (ca. 75 g) C H ClNO C 45.48, H 6.79, Cl 14.92, N 5.89. Found C 45.62, H
9
16
4
1
was dissolved in MeOH (800 mL), and 5% Pd-C (40 g) was 7.06, Cl 15.13, N 6.02. H NMR (500 MHz, DMSO-d ) δ 8.47
6
added. The mixture was hydrogenated in an autoclave at 70 °C (br.s, 3H), 3.66 (s, 3H), 3.65 (s, 3H), 3.40–3.50 (m, 1H), 2.58–
and 100 atm of H for 3 d. The catalyst was filtered off, the 2.62 (m, 1H), 2.31–2.36 (m, 1H), 1.97–2.14 (m, 3H), 3.67–1.75
2
13
solvent was removed in vacuo, and the residue was purified by (m, 1H). C NMR (125 MHz, DMSO-d ) δ 171.4, 171.0, 58.4,
6
chromatography (hexanes – EtOAc (2 : 1 to 1 : 1) as an eluent) 53.0, 52.9, 50.0, 37.6, 31.3, 29.6.
to give the product (S)-19 (18.8 g, 76% over 2 steps).
2
0
Methyl (1R,4R)-3-oxo-2-azabicyclo[2.2.1]heptane-4-carboxylate
((R,R)-43).
Colourless oil. [α]D –4.7 (c 0.8, CHCl ). MS (m/z, CI): 203
3
+
(
MH ). Anal. calc. for C H O C 53.46, H 6.98. Found C 53.21, H
.37. H NMR (500 MHz, CDCl ) δ 4.36–4.40 (m, 1H), 3.74 (s, Compound (R)-16
H), 3.71 (s, 3H), 2.41–2.47 (m, 1H), 2.31–2.39 (m, 2H), 2.22– MeCN (170 mL), and Cs CO (16.9 g, 51.8 mmol) was added.
.28 (m, 1H), 2.02 (br.s, 1H), 1.87–1.95 (m, 1H), 1.72–1.79 (m, The mixture was refluxed with stirring for 6 h and then cooled.
H). C NMR (125 MHz, CDCl ) δ 173.8, 172.9, 73.3, 59.2, 53.2, Saturated HCl in dioxane (100 mL) was added, and the mixture
3.0, 43.6, 35.3, 32.3.
9 14 5
1
7
3
2
1
5
HCl (3.01 g, 17.3 mmol) was dissolved in
3
2
3
13
3
was stirred for 30 min, then filtered through silica gel. The
filtrates were evaporated in vacuo to give the product (1R,4R)-
Dimethyl (3S)-3-[(methylsulfonyl)oxy]cyclopentane-1,1-
dicarboxylate ((S)-33).
4
3
(2.10 g, 72%) pure enough for the next step. An analytical
sample was obtained by gradient chromatography (hexanes –
20
D
Alcohol (S)-19 (8.02 g, 39.5 mmol) and Et N (5.95 g, 55.3 t-BuOMe to MeCN). Colourless oil. [α] +84.4 (c 1.0, CHCl3).
3
+
mmol) were dissolved in CH Cl (120 mL). The solution was MS (m/z, CI): 170 (MH ). Anal. calc. for C H NO C 56.80, H
2
2
8
11
3
1
cooled to –10 °C, and mesyl chloride (5.44 g, 47.5 mmol) was 6.55, N 8.28. Found C 56.48, H 6.31, N 8.02. H NMR (500 MHz,
added dropwise. The resulting mixture was stirred at –10 – CDCl ) δ 6.78 (br.s., 1H), 3.89 (s, 1H), 3.80 (s, 3H), 2.23–2.27
3
0
°C for 3h, and H O (100 mL) was added. The phases were (m, 1H), 2.13 (m, 1H), 1.81–1.96 (m, 2H), 1.71–1.76 (m, 2H).
2
13
separated, and the aqueous phase was extracted with CH Cl2
C NMR (100 MHz, CDCl ) δ 176.8, 170.5, 59.2, 54.4, 52.5,
3
2
(2
100 mL). The combined organic phases were dried over 44.6, 31.4, 26.6.
Na SO , filtered, and evaporated in vacuo to give the product
2
4
20
2-tert-Butyl 4-methyl (1R,4R)-3-oxo-2-azabicyclo[2.2.1]heptane-
2,4-dicarboxylate ((R,R)-51).
(
S)-33 (11.1 g, 99%). Colourless oil. [α] +12.1 (c 1.0, CHCl3).
D
+
+
MS (m/z, CI): 303 (MNa ), 185 (M –OMs). Anal. calc. for
C H O S C 42.85, H 5.75, S 11.44. Found C 42.83, H 6.10, S Bicyclic lactam (1R,4S)-43 (2.02 g, 11.8 mmol) was dissolved in
1
0 16 7
1
1
3
2
1.15. H NMR (500 MHz, CDCl ) δ 5.19 (m, 1H), 3.75 (s, 3H), MeCN (50 mL), and dimethylaminopyridine (DMAP, 0.14 g, 1.2
3
.72 (s, 3H), 2.99 (s, 3H), 2.59–2.69 (m, 2H), 2.49–2.55 (m, 1H), mmol) was added, followed by Boc O (3.87 g, 17.7 mmol). The
2
13
.20–2.25 (m, 1H), 2.01–2.13 (m, 2H). C NMR (125 MHz, mixture was stirred at rt for 4 h. The solvent was removed in
CDCl ) δ 172.2, 171.6, 82.6, 58.8, 53.2, 53.2, 41.1, 38.8, 33.1, vacuo, and the residue was purified by column
3
3
1.9.
chromatography (hexanes – EtOAc (2 : 1)) to give the product
(
[
1R,4S)-51 (2.86 g, 90%). Yellowish powder. Mp 93–94 C.
α]D –5.2 (c 1.0, CHCl ). MS (m/z, CI): 292 (MNa ), 214 (MH –
3
Dimethyl (3R)-3-azidocyclopentane-1,1-dicarboxylate ((R)-35).
20
+
+
Mesylate (S)-33 (11.1 g, 39.5 mmol) was dissolved in MeCN C H ). Anal. calc. for C H NO C 57.98, H 7.11, N 5.20. Found
4
8
13 19
1
5
(
110 mL), NaN3 (15.4 g, 0.237 mol) was added, and the C 58.25, H 7.36, N 4.83. H NMR (400 MHz, CDCl ) δ 4.53–4.57
3
resulting mixture was refluxed for 8 d, then cooled, filtered (m, 1H), 3.80 (s, 3H), 2.17–2.31 (m, 2H), 1.96–2.06 (m, 2H),
1
3
through silica gel, and evaporated in vacuo to give the product 1.85–1.92 (m, 1H), 1.76 (d, J = 10.2 Hz, 2H), 1.52 (s, 9H).
C
20
(
R)-35 (8.81 g, 98%). Colourless oil. [α] –8.4 (c 1.58, CHCl3). NMR (100 MHz, CDCl ) δ 170.7, 169.2, 149.5, 83.5, 61.0, 57.7,
D
3
+
MS (m/z, EI): 199 (M –N ), 171, 127, 113. Anal. calc. for 52.6, 41.2, 29.5, 28.2, 26.9.
2
C H N O C 47.57, H 5.77, N 18.49. Found C 47.38, H 5.54, N
9
13
3
1
4
tert-Butyl (1R,4R)-4-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-
-carboxylate ((R,R)-52).
1
3
2
8.27. H NMR (500 MHz, CDCl ) δ 4.03–4.07 (m, 1H), 3.74 (s,
H), 3.72 (s, 3H), 2.53–2.57 (m, 1H), 2.44–2.47 (m, 1H), 2.30–
3
2
.33 (m, 1H), 2.15–2.21 (m, 1H), 1.92–2.00 (m, 1H), 1.76–1.83 Prepared from (1R,4R)-43 using the method described above
1
3
(
m, 1H). C NMR (125 MHz, CDCl ) δ 172.5, 171.9, 62.0, 58.9, for the synthesis of 44, except the purification was done by
3
5
3.1, 53.1, 39.9, 32.3, 31.8.
column chromatography (hexanes – EtOAc (1:1) as an eluent).
20
Yield 1.62 g (62%). Colourless oil. [α] –51.9 (c 1.0, MeOH).
D
Dimethyl (3R)-3-aminocyclopentane-1,1-dicarboxylate,
hydrochloride ((R)-16HCl).
+
+
+
MS (m/z, EI): 227 (M ), 171 (M –C H ), 140, 96, 57 (C H ).
4
8
4 9
Anal. calc. for C H NO C 63.41, H 9.31, N 6.16. Found C
12
21
3
1
To a solution of (R)-35 (8.81 g, 38.7 mmol) in MeOH (150 mL), 63.34, H 8.95, N 6.37. H NMR (500 MHz, CDCl ) δ 4.22 (s,
3
5
% Pd-C (6 g) and saturated HCl in dioxane (30 mL) were 0.5H), 4.11 (s, 0.5H), 3.73 (s, 2H), 3.21 (m, 1H), 2.98 (m, 1H),
1
0 | RCS Adv., 2016, 00, 1-12
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