A Novel Proline-Valinol Thioamide Small Organic Molecule
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9H), 1.71–1.80 (m, 3H), 1.85–1.99 (m, 2H), 2.10–2.25 (m,
1H), 2.37–3.47 (m, 2H), 3.72 (s, 3H), 4.36–4.44 (m, 2H).
A mixture of compound 3a (657 mg, 2 mmol) and Lawes-
sonꢀs reagent (410 mg, 1 mmol) in dry THF was stirred for
2 h at room temperature and then refluxed for 0.5 h under
an argon atmosphere. After removal of the solvent under re-
duced pressure the resulting residue was purified by flash
chromatography (hexane/EtOAc) to afford compound 3b as
a white solid; yield: 448 mg (65%); 1H NMR (400 MHz,
CDCl3): d=0.92–0.99 (m, 6H), 1.44 (s, 9H), 1.72–1.75 (m,
2H), 1.86–1.87 (m, 2H), 2.01 (brs, 1H), 2.29–2.34 (m, 1H),
3.45- 3.50 (m, 2H), 3.75 (s, 3H), 4.68–4.70 (m, 1H), 5.06–
5.08 (m, 1H).
3.51 (m, 3H), 3.70–3.72 (m, 2H), 4.22–4.29 (m, 1H), 6.21
(brs, 1H).
A mixture of compound 4b (830 mg, 2 mmol) and Lawes-
sonꢀs reagent (410 mg, 1 mmol) in THF was refluxed for 4 h
under an argon atmosphere. After removal of the solvent
under reduced pressure the resulting residue was purified by
flash chromatography (hexane/EtOAc) to afford compound
1
4c as a yellow oil; yield: 670 mg (78%); H NMR (400 MHz,
CDCl3): d=0.04 (s, 6H), 0.89–0.94 (m, 15H), 1.43 (s, 9H),
1.65–1.66 (m, 2H), 1.86–1.87 (m, 2H), 2.13–2.15 (m, 2H),
3.42–3.61 (m, 3H), 3.83–3.85 (m, 1H), 4.40–4.41 (m, 1H),
4.46–4.48 (m, 1H).
Compound 4c (624 mg, 1.4 mmol) was dissolved in dry
CH2Cl2 (2.8 mL) and then TFA (1.4 mL) was added. After
4 h the solvent had been removed, and residue was diluted
with CH2Cl2. The mixture was treated with 1M NaOH until
pH 7–8 and then extracted with EtOAc. The organic layer
was dried over anhydrous MgSO4, filtered and the solvent
was removed under reduced pressure. The resulting residue
was purified by flash chromatography (hexane/EtOAc) to
afford compound 4 as a white solid; yield: 202 mg (67%);
mp 66–688C; [a]D20: À207.6 (c 1.0, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=0.94–0.99 (dd, J=6.7, 14.9 Hz, 6H),
1.66–1.81 (m, 2H), 2.00–2.11 (m, 2H), 2.40–2.48 (m, 2H),
2.78 (brs, 1H), 3.13–3.18 (m, 2H), 3.74–3.85 (m, 2H), 4.35–
4.46 (m, 2H), 10.22 (brs, 1H); 13C NMR (100 MHz, CDCl3):
d=205.3, 67.9, 68.2, 62.0, 60.8, 47.3, 28.7, 25.9, 19.5, 18.6;
HR-MS (ESI): m/z=217.1363, calcd. for C10H20N2OS (M+
1): 217.1369.
Compound 3b (482 mg, 1.4 mmol) was dissolved in dry
CH2Cl2 (2.8 mL) and then TFA (1.4 mL) and Et3SiH
(0.55 mL) were added. After 2 h the solvent was removed,
the residue diluted with CH2Cl2 and washed with saturated
NaHCO3, dried over Na2SO4, filtered, and then concentrat-
ed under reduced pressure to give catalyst 3 as a yellow oil;
1
yield: 266 mg (78%); [a]2D0: À53.6 (c 1.0, CH2Cl2); H NMR
(400 MHz, CDCl3): d=0.94–1.00 (dd, 6H, J=6.9, 10.9 Hz),
1.65–1.78 (m, 2H), 2.00–2.04 (m, 2H), 2.35–2.38 (m, 2H),
3.01–3.09 (m, 2H), 3.75 (s, 3H), 4.21–4.26 (dd, 1H, J=3.8,
9.0 Hz), 5.12–5.14 (m, 1H), 10.36 (brs, 1H); 13C NMR
(100 MHz, CDCl3): d 205.9, 171.2, 67.9, 61.8, 52.3, 47.5, 34.7,
31.2, 26.1, 18.9, 18.5; HR-MS (ESI): m/z=245.1322, calcd.
for C11H20N2O2S (M+1): 245.1318.
Preparation of Prolinethioamide 4
Typical Procedure for the Intermolecular Aldol
Reaction
To a stirred solution of N-Boc-l-proline (1.25 g, 5.81 mmol)
in CH2Cl2, Et3N (1.2 mL, 8.71 mmol) was slowly added at
08C. After the solution had been stirred for 10 min, isobutyl
chloroformate (875 mL, 6.67 mmol) was added dropwise to
the reaction mixture at 08C. After the solution had been
stirred for an additional 20 min at 08C, Et3N (900 mL,
6.67 mmol) and l-valinol (687 mg, 6.67 mmol) were added
to the reaction mixture. The reaction mixture was then
warmed up to room temperature. After 3 h, TLC analysis in-
dicated complete consumption of starting material. The re-
action was quenched by addition of 1M HCl and diluted
with CH2Cl2, the organic phase was washed with H2O, brine
and dried over Na2SO4, filtered, and then concentrated
under reduced pressure. Purification was accomplished by
recrystallization (EtOAc/hexane) to give compound 4a as a
white solid; yield: 1.62 g (93%); 1H NMR (400 MHz,
CDCl3): d=0.90–0.94 (m, 6H), 1.46 (s, 9H), 1.72–1.75 (m,
2H), 1.87–1.92 (m, 2H), 2.15–2.20 (m, 1H), 2.87–3.10 (m,
To a mixture of catalyst 4 (2.2 mg, 0.01 mmol) and benzoic
acid (6 mg, 0.05 mmol) in DMSO (0.2 mL), the anhydrous
acetone (0.5 mL) was added. After the corresponding mix-
ture had been stirred for 5 min, the aldehyde (0.5 mmol)
was added at 08C. After 12 h, TLC analysis indicated com-
plete consumption of starting material, and then the reac-
tion mixture was quenched with saturated NH4Cl solution,
extracted with EtOAc and dried over Na2SO4. The crude
product was purified by flash silica gel chromatography
(Hexane/EtOAc) to afford aldol product 5.
Acknowledgements
We are grateful for financial support from the National Natu-
ral Science Foundation of China (grants 20421202 and
20372033).
2H), 2.90 (br, 1H), 3.58–3.79 (m, 4H), 7.92ACTHNUTRGENUG(N br, 1H).
To a stirred solution of compound 4a (300 mg, 1 mmol) in
CH2Cl2, Et3N (0.17 mL, 1.15 mmol), TBDMSCl (175 mg,
1.2 mmol) and DMAP (14 mg, 0.09 mmol) were added in
this order at 08C. The reaction mixture was stirred at room References
temperature for 24 h. And then the reaction mixture was di-
luted with CH2Cl2 and washed with saturated NaHCO3, sa-
turated NH4Cl and water. The organic layer was dried over
anhydrous Na2SO4, filtered, and the solvent was removed
under reduced pressure. The resulting residue was purified
by flash chromatography (hexane/EtOAc) to give compound
[1] a) A. Berkessel, H. Grçger, Asymmetric Organocataly-
sis: From Biomimetic Concepts to Applications in
Asymmetric Synthesis, Wiley-VCH, Weinheim, 2005;
b) H. Pellissier, Tetrahedron 2007, 63, 9267; c) P. I.
Dalko, Enantioselective Organocatalysis, Reactions and
Experimental Procedures, Wiley-VCH, Weinheim,
2007; d) Special issue on organocatalysis: Chem. Rev.
2007, 107, 5413; e) R. M. Figueiredo, M. Christmann,
4b as
a
yellow oil; yield: 410 mg (99%); 1H NMR
(400 MHz, CDCl3): d=0.03 (s, 6H), 0.87–0.88 (m, 15H),
1.45 (s, 9H), 1.80–1.94 (m, 3H), 2.15–2.30 (m, 2H), 3.35–
Adv. Synth. Catal. 2009, 351, 2441 – 2448
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2447