A. Puglisi et al. / Tetrahedron: Asymmetry 19 (2008) 2258–2264
2263
2.46 (m, 1H, CH2CHNH), 2.34 (s, 6H, N(CH3)2), 1.91 (m, 1H,
CH2CHN(CH3)2), 1.87 (m, 1H, CH), 1.73 (m, 1H, CH), 1.3–1.2 (m,
4H, CH), 1.09 (s, 9H, C(CH3)3). 13C NMR (75 MHz, CDCl3, compound
exists as a 4:1 mixture of rotamers: the major is indicated): d
182.8, 172.4, 136.9, 128.5, 128.1, 127.3, 66.9, 60.5, 55.3, 51.3,
40.0, 36.1, 35.9, 33.0, 26.8, 24.9, 24.6, 22.0. MS-ESI+: m/z 419
[M+H]+, Elem. Anal. Calcd for C23H38N4OS: C, 65.99; H, 9.15; N,
13.38, S, 7.66. Found: C, 66.05; H, 9.17; N, 13.37, S, 7.69.
182.5, 171.0, 138.0, 128.7, 128.4, 127.4, 66.8, 66.2, 55.7, 43.5,
40.2, 34.7, 33.1, 27.0, 24.9, 24.6, 22.0. MS-ESI+: m/z 405 [M+H]+,
Elem. Anal. Calcd for C22H36N4OS: C, 65.31; H, 8.97; N, 13.85, S,
7.92. Found: C, 65.29; H, 8.93; N, 13.89, S, 7.93.
Catalyst 5d: (flash chromatography, 3 ꢁ 16 cm silica, CH2Cl2/
CH3OH 95:5, then CH2Cl2/CH3OH 9:1, then CH2Cl2/CH3OH
9:1 + 1% TEA, Rf = 0.50, ninhydrin TLC visualization). ½a D23
¼ þ1:5
ꢂ
(c 1.01, CHCl3). 1H NMR (300 MHz, CDCl3): d 7.0 (br, 1H, CHNHCS),
6.02 (br, 1H, HNCH3), 4.75 (br, 1H, CH), 3.65 (m, 1H, CHNHCS), 2.84
(d, J = 4.9 Hz, 3H, NHCH3), 2.50 (m, 1H, CHN(CH3)2), 2.30 (s, 3H,
N(CH3)2), 2.26 (s, 3H, N(CH3)2), 2.33 (m, 1H, NHCHCH2), 1.90 (m,
1H, CH2CHN(CH3)2), 1.87 (m, 1H, CH2CH2CHNH), 1.77 (m, 1H,
CH2CH2CHN(CH3)2), 1.30 (m, 2H, CH2CH2CHNH and CH2CH2-
CHN(CH3)2),1.23 (m, 1H, CH2CHN(CH3)2),1.20 (m, 1H, NHCHCH2),
1.10 (s, 9H, CHC(CH3)3). 13C NMR (75 MHz, CDCl3): d 182.8,
171.4, 66.9, 66.2, 55.8, 40.2, 34.7, 33.1, 26.8, 26.0, 25.0, 24.5,
22.0. MS-ESI+: m/z 329 [M+H]+, Elem. Anal. Calcd for C16H32N4OS:
C, 58.50; H, 9.82; N, 17.05, S, 9.76. Found: C, 58.55; H, 9.83; N,
16.99, S, 9. 71.
4.1.5. Isolation of catalyst 5aH+-AcOꢀ
Thiourea 4a (312 mg, 0.80 mmol, 1 equiv) was dissolved in THF
(16 mL); formaldehyde (37% aqueous solution, 0.72 mL,
9.60 mmol, 12 equiv) was then added, and the reaction mixture
was allowed to stir at 50 °C for 15 h. The mixture was then cooled
to 23 °C, and NaCNBH3 (350 mg, 5.6 mmol, 7 equiv) was added; the
reaction mixture was stirred at 23 °C for 2 h. Acetic acid (1.3 mL)
was then added, and the reaction mixture heated at 50 °C for addi-
tional 4 h. After this time, the reaction mixture was cooled to 23 °C
and 1 M NaOH was added until pH 8 was reached; the layers were
then partitioned, and the aqueous layer was extracted with dichlo-
romethane (3 ꢁ 20 mL). The combined organic layers were dried
over Na2SO4, filtered and concentrated in vacuo to afford crude
product that was purified by flash chromatography on silica gel
(3 ꢁ 16 cm silica, CH2Cl2/CH3OH 95:5, CH2Cl2/CH3OH 9:1, then
CH2Cl2/CH3OH 9:1 + 3% TEA, Rf = 0.31, ninhydrin TLC visualization)
to give pure thiourea (201 mg, 0.45 mmol, 57% yield). 1H NMR
(300 MHz, CDCl3; compound exists as a 3:1 mixture of rotamers:
the major is indicated): d 9.00 (d, J = 9.1 Hz, 1 H, NHCS), 7.35–
7.25 (m, 5H, ArH), 7.43 (br s, 1H, CSNH cy), 4.90 (d, J = 9.1 Hz, 1H,
CH), 4.75 (B part of a AB system, d, J = 13.6 Hz, 1H, CH2Ph), 4.71
(m, 1H, CHNH), 4.50 (A part of a AB system, d, J = 13.6 Hz, 1H,
CH2Ph), 3.55 (m, 1H, CHN(CH3)2), 3.31 (s, 3H, NCH3), 2.51 (m, 1H,
CH2CHNH), 2.75 (s, 6H, N(CH3)2), 2.11 (m, 1H, CH2CHN(CH3)2),
1.97 (m, 1H, CH), 1.77 (m, 1H, CH), 1.3–1.2 (m, 4H, CH), 1.12 (s,
9H, C(CH3)3). 13C NMR (75 MHz, CDCl3, compound exists as a 3:1
mixture of rotamers: the major is indicated): d 183.3, 172.8,
136.5, 128.4, 128.0, 127.3, 68.7, 61.5, 53.3, 51.8, 40.0, 36.3, 32.3,
26.9, 24.3, 23.8, 23.1. MS-ESI+: m/z 420 [M+H]+.
4.2. General procedure for Michael addition reaction of 2,4-
pentanedione to trans-b-nitrostyrene
Thiourea catalyst 5a (8.4 mg, 0.02 mmol, 0.1 equiv) and trans-b-
nitrostyrene (30 mg, 0.20 mmol, 1 equiv) were charged in a 10 mL
round bottom flask under nitrogen. Next Et2O (0.5 mL) was added,
and after 5 min of stirring at 23 °C, 2,4-pentanedione (0.023 mL,
0.22 mmol, 1.1 equiv) was added via syringe. The reaction mixture
was stirred at 23 °C for 18 h, then the solvent was evaporated in
vacuo and the crude product was purified by flash chromatography
on silica gel (1 ꢁ 16 cm silica, petroleum ether/AcOEt 7:3, Rf = 0.25)
to afford pure 3-((R)-2-nitro-1-phenylethyl)pentane-2,4-dione (45
mg, 0.18 mmol, 90% yield). 1H NMR (300 MHz, CDCl3): d 7.35–7.1
(m, 5H), 4.65–4.55 (m, 2H), 4.3 (d, J = 10.9 Hz, 1H), 4.2 (m, 1H),
2.3 (s, 3H), 1.9 (s, 3H). HPLC (Daicel Chiralpak AD, hexane/i-propa-
nol 85:15, flow rate = 1 mL/min, P = 22 bar, k = 210 nm): tminor
=
9.6 min, tmajor = 12.8 min, ee = 85%. ½a D20
¼ ꢀ14:0 (c 0.1, CHCl3).
ꢂ
Data are in agreement with those reported by Wang et al.20
Catalysts 5b, 5c and 5d were prepared according to the general
procedure reported for catalyst 5a.
4.3. General procedure for Mannich reaction of diethyl
malonate to imines
Catalyst 5b: (flash chromatography, 3 ꢁ 16 cm alumina, CH2Cl2/
CH3OH 9:1, then CH2Cl2/CH3OH 9:1 + 1% TEA, Rf = 0.15, ninhydrin
TLC visualization). ½a D23
ꢂ
¼ þ9:5 (c 1.31, CHCl3); 1H NMR (300 MHz,
Thiourea catalyst 5a (8 mg, 0.019 mmol, 0.1 equiv) and imine
(0.19 mmol, 1 equiv) were charged in a 10 mL round bottom flask
under nitrogen. Toluene (0.5 mL) was added, and after 5 min of
stirring at indicated temperature, diethyl malonate (0.058 mL,
0.38 mmol, 2 equiv) was added via syringe. The reaction mixture
was stirred at the indicated temperature for the appropriate time,
then the solvent was evaporated in vacuo and the crude was puri-
fied by flash chromatography on silica gel.
CDCl3): d 7.09 (d, J = 9.5 Hz, 1H, CHNHCS), 6.65 (br s, 1H, CSNH),
5.59 (d, J = 9.5 Hz, 1H, CH), 3.55 (m, 1H, CHNHCS), 3.22 (s, 3H,
N(CH3)2CO), 2.93 (s, 3H, N(CH3)2CO), 2.58 (m, 1H, CHN(CH3)2),
2.40 (m, 1H, NHCHCH2), 2.32 (m, 1H, CHN(CH3)2), 2.20 (s, 6H,
N(CH3)2), 1.90 (m, 1H, CH2CHN(CH3)2), 1.80 (m, 1H, CH2CHN(CH3)2),
1.77 (m, 1H, CH2CH2CHNH), 1.67 (m, 1H, CH2CH2CHN(CH3)2), 1.20
(m, 3H, CH2CHN(CH3)2, CH2CH2 CHN(CH3)2 and CH2CH2CHNH),
1.13 (m, 1H, NHCHCH2), 1.02 (s, 9H, CHC(CH3)3). 13C NMR
(75 MHz, CDCl3): d 182.5, 172.1, 66.7, 60.0, 55.5, 40.2, 38.5, 36.0,
35.5, 33.0, 26.7, 25.0, 24.6, 22.0. MS-ESI+: m/z 343 [M+H]+, Elem.
Anal. Calcd for C17H34N4OS: C, 59,61; H, 10.00; N, 16.36, S, 9.36.
Found: C, 59.65; H, 10.03; N, 16.29, S, 9.31.
4.3.1. N-Cbz product 10b
(1 ꢁ 16 cm silica, petroleum ether/AcOEt 85:15, Rf = 0.17, cer-
ium sulfate-ammonium molybdate TLC visualization). 1H NMR
(300 MHz, CDCl3): d 7.4–7.2 (m, 10H), 6.45 (d, 1H), 5.55 (m, 1H),
5.05 (dd, 2H), 4.2–4.0 (m, 4H), 3.85 (d, 1H), 1.2 (t, 3H), 1.1 (t,
3H). HPLC (Daicel Chiralpak IB, hexane/i-propanol 98:2, flow
rate = 0,8 mL/min, P = 27 bar, k = 210 nm): tminor = 41.7 min,
Catalyst 5c: (flash chromatography, 3 ꢁ 16 cm alumina, CH2Cl2/
CH3OH 95:5 then CH2Cl2/CH3OH 9:1, Rf = 0.34, ninhydrin TLC visu-
alization). ½a 2D3
ꢂ
¼ ꢀ6:5 (c 1.06, CHCl3); 1H NMR (300 MHz, CDCl3) d
7.40–7.25 (m, 5H, ArH), 6.65 (br s, 1H, NHCS), 6.52 (br s, 1H, CSNH
cy), 4.80 (br, 1H, CH), 4.45 (B part of a AB system, d, J = 13.0 Hz, 1H,
CH2Ph), 4.30 (A part of a AB system, d, J = 13.0 Hz, 1H, CH2Ph), 3.75
(m, 1H, CHNHCS), 2.42 (m, 2H, CHN(CH3)2 and CH2CHNH), 2.20 (s,
6H, N(CH3)2), 1.90 (m, 1H, CH2CHN(CH3)2), 1.80 (m, 1H,
CH2CH2CHNH), 1.73 (m, 1H, CH2CH2CHN(CH3)2), 1.20 (m, 1H,
CH2CHN(CH3)2), 1.15 (m, 3H, CH2CH2CHN(CH3)2, CH2CH2CHNH
and CH2CHNH), 1.05 (s, 9H, C(CH3)3). 13C NMR (75 MHz, CDCl3): d
tmajor = 44.3 min. ½a D20
¼ þ6:1 (c 0.1, CHCl3). (S)-enantiomer.
ꢂ
Data are in agreement with those reported by Yamaoka et al.21
4.3.2. N-Boc product 10a
(1 ꢁ 16 cm silica, petroleum ether/AcOEt 7:3, Rf = 0.25) 1H NMR
(300 MHz, CDCl3): d 7.3 (m, 5H), 6.25 (br s, 1H), 5.4 (br s, 1H), 4.35–
4.25 (m, 4H), 4.1 (d, 1H), 3.7 (s, 3H), 1.5 (t, 3H), 1.25 (t, 9H), 1.15 (t,