2402
L. Planas et al. / Tetrahedron: Asymmetry 15 (2004) 2399–2403
(br s, 2H), 1.02 (m, 1H), 1.55–1.75 (m, 2H), 1.80–1.95
(m, 2H), 1.96 (d, J ¼ 7:2 Hz, 3H), 1.95–2.10 (m, 2H),
2.33 (m, 1H), 2.47 (ddd, J ¼ 6:2, 9.2, 14.8 Hz, 1H), 2.66
(m, 1H), 2.91 (t, J ¼ 7:3 Hz, 1H), 5.39 (q, J ¼ 7:1 Hz,
1H), 7.48 (t, J ¼ 7:6 Hz, 2H), 7.54 (t, J ¼ 7:0 Hz, 1H),
7.75 (d, J ¼ 8:1 Hz, 1H), 7.87 (d, J ¼ 8:0 Hz, 1H), 7.91
(d, J ¼ 8:4 Hz, 1H), 7.99 (d, J ¼ 7:2 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d 20.1, 20.8, 31.6, 33.8, 33.9, 34.4,
51.9, 62.4, 75.1, 122.4, 125.5, 125.6, 126.2, 126.7, 128.0,
129.6, 130.2, 134.2, 139.2, 178.2. Anal. Calcd for
C20H24N2O: C, 77.89; H, 7.84; N, 9.08. Found: C, 77.81;
H, 7.81; N, 9.28.
CDCl3): d 20.6, 21.7, 22.2, 22.3, 23.8, 25.8, 34.4, 38.0,
57.9, 58.7, 64.4, 60.7, 77.7, 89.4, 122.7, 125.5, 125.9,
126.2, 127.5, 129.7, 130.0, 131.5, 134.2, 135.3; HRMS
(ESIþ, [MH]þ): m=z calcd 349.2644, found 349.2648.
4.2.5. (5R,6R)-6-Pyrrolidin-1-yl-1-aza-spiro[4.4]nonane,
13. To a solution of crude 12 (102 mg, ꢀ0.26 mmol) in
MeOH (3 mL, 0.1 M) was added Pd/C 10% (50 mg,
ꢀ50% w/w) under an N2 atmosphere. N2 was replaced
by H2 (1 atm) and the mixture stirred for 16 h, filtered
through a Celite pad, concentrated under vacuum, and
retaken with a 1 M aqueous solution of HCl. This
aqueous phase was washed with CH2Cl2, basified by
15% aqueous solution of NaOH, and extracted with
Et2O. Organic phase was dried over Na2SO4 and con-
centrated under vacuum, providing 13 (38 mg, 76%, two
4.2.3.
(50R,60R,100S)-1-[1-(1-Naphthalen-1-yl-ethyl)-2-
oxo-1-aza-spiro[4.4]non-6-yl]-pyrrolidine-2,5-dione, 11.
To a solution of 10 (840 mg, 2.75 mmol) in toluene
(14 mL, 0.2 M) was added succinic anhydride (289 mg,
2.89 mmol). The reaction mixture was refluxed for 1.5 h,
cooled to rt, concentrated under vacuum, and dissolved
in acetyl chloride (14 mL, 0.2 M). The reaction mixture
was refluxed for 2 h and concentrated again. Water was
added and the mixture extracted with CH2Cl2. The or-
ganic phase was washed with a saturated aqueous
solution of NaHCO3, dried over Na2SO4, and concen-
trated under vacuum. The crude product was purified by
flash chromatography (CH2Cl2–MeOH 95:5) providing
1
steps) as a colorless oil. H NMR (400 MHz, CDCl3): d
1.45–1.63 (m, 4H), 1.65–1.95 (m, 10H), 2.45–2.60 (m,
6H), 2.71 (m, 1H), 3.05 (m, 1H); 13C NMR (75 MHz,
CDCl3): d 20.7, 23.7, 27.5, 30.8, 36.6, 41.1, 46.8, 53.4,
71.5, 77.4. IR (KBr): m 3278, 2956, 2870, 2785, 1458,
1415, 1343 cmÀ1; HRMS (ESIþ, [MH]þ): m=z calcd
195.1861, found 195.1867.
25
13-Picric acid (3/2): mp 185 °C (EtOH); ½aꢁ ¼ À48 (c
D
0.4, CHCl3).
11 (867 mg, 81%) as a white solid. Mp 219 °C (i-Pr2O);
25
½aꢁ ¼ þ71 (c 1.00, CHCl3); IR (KBr): m 2966, 1699,
D
1686, 1363, 1169 cmÀ1
;
MS(CI, NH3): m=z ¼ 391
4.2.6. (1R,60R,100R)-{[1-(1-Naphthalen-2-yl-ethyl)-2-oxo-
1-aza-spiro[4.4]non-6-ylcarbamoyl]-phenyl-methyl}-car-
bamamic acid tert-butyl ester, 14a. Spirodiamine 13
(50 mg, 0.16 mmol) and (R)-N-Boc-phenylglycine
(40.7 mg, 0.16 mmol) were dissolved in dry CH2Cl2
(1 mL, c ¼ 0:16 M) under an argon atmosphere. The
solution was cooled to 0 °C and N,N0-dicyclohexylcar-
bodiimide (37 mg, 0.18 mmol) added in one drop. The
mixture was allowed to warm to rt and stirred at this
temperature for 90 min. The white precipitate, which
formed, was filtered and washed with CH2Cl2. The
solvent was evaporated to dryness and the crude reac-
tion mixture purified by flash chromatography on silica
gel (AcOEt–cyclohexane 60:40) to provide 14a (80 mg,
1
(MHþ); H NMR (400 MHz, CDCl3): d 1.10 (m, 4H),
1.65–1.80 (m, 2H), 1.82 (d, J ¼ 7:2 Hz, 3H), 1.96 (m,
1H), 2.00–2.20 (m, 3H), 2.22 (m, 1H), 2.41 (ddd,
J ¼ 1:8, 9.0, 16.3 Hz, 1H), 2.82 (ddd, J ¼ 8:9, 11.5,
16.3 Hz, 1H), 3.01 (m, 1H), 4.40 (m, 1H), 5.29 (q,
J ¼ 7:1 Hz, 1H), 7.47 (m, 2H), 7.57 (td, J ¼ 7:0, 1.1 Hz,
1H), 7.62 (d, J ¼ 8:2 Hz, 1H), 7.73 (d, J ¼ 8:1 Hz, 1H),
7.85 (m, 2H); 13C NMR (75 MHz, CDCl3): d 20.5, 21.1,
26.0, 27.4, 30.3, 36.9, 37.1, 50.8, 56.0, 76.0, 123.5, 125.8,
126.3, 126.6, 127.7, 129.2, 130.1, 133.7, 138.1, 178.3,
178.3; HRMS (ESIþ, [MH]þ): m=z calcd 391.2022,
found 391.2019.
91%) as a white solid. Mp 153–155 °C (EtOH);
20
4.2.4. (5R,6R,10S)-1-(1-Naphtalen-1-yl-ethyl)-6-pyrrol-
½aꢁ ¼ þ203 (c 1.03, CHCl3); IR (film): m 3387, 3058,
D
idin-1-yl-1-aza-spiro[4.4]nonan-2-one, 12. To
a
1 M
2973, 2934, 2884, 1714, 1682, 1510, 1367; 1H NMR
(400 MHz, CDCl3): d 0.96 (m, 1H), 1.46 (s, 9H), 1.73 (m,
2H), 1.93 (m with d, J ¼ 7:1 Hz, 2H), 1.95 (m, 1H), 2.00
(m, 1H), 2.04 (m, 1H), 2.16 (m, 1H), 2.28 (m, 1H), 4.06
(m, 1H), 4.68 (br s, 1H), 5.14 (q, J ¼ 7:1 Hz, 1H), 5.29
(d, J ¼ 5:4 Hz, 1H), 5.66 (d, J ¼ 8:0 Hz, 1H), 6.97 (m,
2H), 7.25 (m, 3H), 7.45–7.65 (m, 3H), 7.81 (t,
J ¼ 7:2 Hz, 2H), 7.89 (dd, J ¼ 1:5, 7.0 Hz, 1H), 7.98 (d,
J ¼ 6:7 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 20.7,
21.1, 28.6, 31.0, 33.1, 36.4, 51.7, 58.8, 59.7, 74.2, 80.7,
121.7, 124.9, 126.3, 127.2, 127.4, 128.9, 129.4,129.9,
130.2, 134.3, 138.0, 140.2, 154.9, 170.6, 178.0; HRMS
(ESIþ, [MH]þ): m=z calcd 564.2838, found 564.2818.
solution of BH3ÆTHF in THF was added 11 (220 mg,
0.56 mmol). The reaction mixture was refluxed for 16 h
and cooled to rt after which MeOH (1 mL) was slowly
added. The reaction mixture was stirred for 15 min,
poured into a large quantity of brine, and extracted with
CH2Cl2. Organic phase was dried over Na2SO4 and
concentrated under vacuum providing 12 (867 mg,
25
D
quant.) as a white amorphous solid. ½aꢁ ¼ þ107 (c 1.1,
CHCl3); IR (KBr): m 3048, 2968, 2885, 2442, 2391, 2121,
1
1458 cmÀ1; MS(CI, NH3): m=z ¼ 349 (MHþ); H NMR
(400 MHz, CDCl3): d 1.45–1.80 (m, 3H), 1.75 (d,
J ¼ 7:2 Hz, 3H), 1.80–2.00 (m, 2H), 2.00–2.15 (m, 2H),
2.15–2.50 (m, 6H), 2.62 (m, 1H), 2.96 (m, 1H), 3.05–3.25
(m, 3H), 3.59 (m, 1H), 3.78 (m, 1H), 4.45 (m, 1H), 5.52
(q, J ¼ 7:2 Hz, 1H), 7.35–7.55 (m, 2H), 7.63 (t,
J ¼ 8:2 Hz, 1H), 7.76 (d, J ¼ 7:3 Hz, 1H), 7.80–7.90 (m,
2H), 8.10 (d, J ¼ 8:6 Hz, 1H); 13C NMR (75 MHz,
4.2.7. (1S,60R,100R)-{[1-(1-Naphthalen-2-yl-ethyl)-2-oxo-
1-aza-spiro[4.4]non-6-ylcarbamoyl]-phenyl-methyl}-car-
bamamic acid tert-butyl ester, 14b. The same procedure