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<A NAME="RG11003ST-14">14</A>
Preparation of1: Isobutyraldehyde (0.13 mL, 1.3 mmol) was added to a solutionof ammonium benzoate
(139 mg, 1.0 mmol) in trifluoroethanol (2 mL)at 0 °C. After stirring for 30 min, methyl
isocyanoacetate(100 mg, 1.0 mmol) was added via syringe over a period of 5 min.Trifluoroethanol
was added (1.5 mL) to get a homogeneous solution.The mixture was allowed to warm to
15 °C overnight.After stirring at r.t. for further 24 h, the solution was dilutedwith
CH2Cl2 (30 mL) and washed with 1 N KHSO4 andsat. NaHCO3 solution. The organic layer was dried (Na2SO4)and the solvent was evaporated in vacuo. The crude product was purifiedby crystallization
from EtOAc and hexanes giving rise to 1 (132 mg, 0.45 mmol) as colorless crystals,mp 146-148 °C. 1H NMR (300MHz, CDCl3): δ = 0.96 (d, J = 6.7Hz, 3 H), 0.99 (d, J = 6.4 Hz, 3 H), 2.12(m, 1 H), 3.68 (s, 3 H), 3.79 (bs, 2 H, H2O), 3.85 (dd, J = 17.9,3.7 Hz, 1 H), 4.05 (dd, J = 17.8, 3.8 Hz, 1 H),4.41 (m, 1 H), 7.31-7.73 (m, 5 H), 7.57-7.78 (m,2 H).
<A NAME="RG11003ST-15">15</A>
Preparation of2: Isobutyraldehyde (0.11 mL, 1.0 mmol) was added to a solutionof ammonium benzoate
(139 mg, 1.0 mmol) in MeOH (2 mL) at 0 °C.After stirring for 40 min, the solution
was warmed to 40 °Cfor 10 min, before it was cooled to 0 °C again.Methyl isocyanoacetate
(100 mg, 1.0 mmol) was added via syringeover a period of 5 min. The mixture was allowed
to warm to 15 °Covernight. After stirring at r.t. for further 24 h, the solutionwas
diluted with CH2Cl2 and washed with 1N KHSO4 and sat. NaHCO3 solution. The organiclayer was dried (Na2SO4) and the solvent wasevaporated in vacuo. The crude product was purified by flash
chromatographyon silica gel (hexanes/EtOAc: 7/3, 6/4,3/7, 0/1) giving rise to 2 (121mg, 0.32 mmol) as a diastereomeric mixture. 1HNMR (300 MHz, CDCl3): δ = 0.72 (d, J = 6.7Hz, 3 H), 0.75 (d, J = 6.7 Hz, 3 H), 1.01(d, J = 6.6Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 H), 2.08 (m,1 H), 2.98 (m, 1 H), 3.31 (s, 3 H), 3.59 (d, J = 11.2 Hz, 1 H), 3.70(s, 3 H), 3.94 (dd, J = 15.2, 2.5 Hz, 1 H),4.01-4.16 (m, 2 H), 7.32-7.40 (m, 5 H), 8.95 (bs,1 H).
<A NAME="RG11003ST-16">16</A>
Preparation of3: Isobutyraldehyde (0.23 mL, 2.0 mmol) was added to a solutionof ammonium benzoate
(139 mg, 1.0 mmol) in MeOH (2 mL) at 0 °C.After stirring for 30 min methyl isocyanoacetate
(100 mg, 1.0 mmol)was added via syringe over a period of 5 min. The mixture was allowedto
warm to 15 °C over night. After stirring atr.t. for further 24 h, the solution was
evaporated in vacuo. Thecrude product was crystallized from hexanes and EtOAc giving
riseto 3 (226 mg, 0.68 mmol) as a colorlesssolid, mp. 171-173 °C. 1HNMR (300 MHz, CDCl3): δ = 0.90 (sbr,3 H), 0.99 (d, J = 6.6 Hz, 3 H), 1.00(d, J = 6.5Hz, 3 H), 1.32 (sbr, 3 H), 1.70-1.74 (m, 2 H),4.00 (d, J = 9.5Hz, 1 H), 4.73 (d, J = 7.9 Hz,1 H), 6.09 (sbr, 1 H), 6.63 (d, 1 H, J = 7.5Hz), 7.39-7.53 (m, 5 H), 7.79-7.82 (m, 2 H).
<A NAME="RG11003ST-17">17</A>
Floyd CD.
Harnett LA.
Miller A.
Patel S.
Saroglou L.
Whittaker M.
Synlett
1998,
637
<A NAME="RG11003ST-18">18</A>
General Procedurefor the Ugi 4 Component Peptide Syntheses: 5 Mmol of the aldehydewere added to a 1.5 N solution of ammonia (4 mL, 6 mmol) in
MeOHat 0 °C. After 10 min 5 mmol of the isonitrilewere added, followed by 5.05 mmol
of the protected amino acid. Thereaction mixture was allowed to warm to r.t. overnight.
To thismixture CH2Cl2 (50 mL) was added and the organiclayer was washed with 1 N KHSO4 and sat. NaHCO3 solution.Drying over Na2SO4 and evaporation of thesolvent gave the crude peptide, which was purified flash chromatography.The
diastereomers were separated by preparative medium pressurechromatography on silica
(LiChroprep Si60) using EtOAc/hexanesas eluents.
<A NAME="RG11003ST-19">19</A>
1H NMR data ofall peptides 4 obtained, all of which gave satisfactoryelemental analyses. The configuration of
the diastereomeric peptideswas determined by HPLC analysis (comparison with reference
samplesobtained by standard peptide coupling from the (S)-aminoacids). (S,R)-4a: 1H NMR (200 MHz,CDCl3): δ = 0.90(d, J = 7.0Hz, 6 H), 1.02 (s, 9 H), 2.12 (m, 1 H), 3.63 (s, 3 H), 3.84 (d, J = 5.5 Hz,1 H), 4.12 (d, J = 5.5Hz, 1 H), 4.33 (m, 1 H), 4.74 (d, J = 9.0 Hz,1 H), 5.08 (s, 2 H), 6.30 (dbržJ = 9.0Hz, 1 H), 7.33 (sbr, 6 H), 7.97 (t, J = 5.5Hz, 1 H). (S,S)-4a: 1H NMR (200 MHz, CDCl3): δ = 0.89(d, J = 7.0Hz, 6 H), 1.01 (s, 9 H), 2.01 (m, 1 H), 3.69 (s, 3 H), 3.85 (d, J = 5.0 Hz,1 H), 4.11 (d, J = 5.0 Hz,1 H), 4.29 (dd, J = 9Hz, J = 7.0Hz, 1 H), 4.61 (d, J = 9.0Hz, 1 H), 5.12 (s, 2 H), 6.13 (dbr, J = 9.0Hz, 1 H), 7.33 (sbr, 6 H), 7.65 (t, J = 5.5Hz, 1 H). (S,R)-4b: 1H NMR (200 MHz,CDCl3): δ = 0.90(d, J = 7.0Hz, 6 H), 0.99 (s, 9 H), 1.44 (s, 9 H), 2.08 (m, 1 H), 3.77 (t, J = 3.5 Hz,1 H), 4.02 (m, 1 H), 4.23 (m, 1 H), 4.63 (d, J = 9.0Hz, 1 H), 5.10 (s, 2 H), 6.31 (dbr, J = 8.5Hz, 1 H), 7.35 (sbr, 6 H), 7.42 (m, 1 H). (S,S)-4b: 1H NMR (200 MHz,CDCl3): δ = 0.94(d, J = 6.5 Hz,6 H), 1.01 (s, 9 H), 1.45 (s, 9 H), 2.03 (m, 1 H), 3.75 (m, 1 H),4.00 (m,
1 H), 4.23 (m, 1 H); 4.68 (d, J = 9.0Hz, 1 H), 5.12 (s, 2 H), 6.09 (dbr, J = 9.0Hz, 1 H), 7.04 (dbr, J = 8.5Hz, 1 H), 7.36 (sbr, 6 H). (S,R)-4c: 1HNMR (200 MHz, CDCl3): δ = 0.90(d, J = 7.0Hz, 3 H), 0.97 (d, J = 7.0Hz, 3 H), 1.04 (s, 9 H), 1.45 (s, 9 H), 1.47 (s, 9 H), 2.06-2.44(m, 1 H), 3.82-4.20
(m, 3 H), 4.52 (d, J = 8.5Hz, 1 H), 5.41 (dbr, J = 9Hz, 1 H), 6.95 (dbr, J = 9Hz, 1 H), 7.18 (tbr, J = 5.5Hz, 1 H). (S,S)-4c: 1H NMR (200 MHz,CDCl3): δ = 0.92(d, J = 7.0 Hz,6 H), 1.02 (s, 9 H), 1.43 (s, 9 H), 1.46 (s, 9H), 1.94-2.33 (m,1 H), 3.77-4.20
(m, 3 H), 4.53 (d, J = 9.0Hz, 1 H), 5.54 (dbr, J = 9.0Hz, 1 H), 7.07 (dbr, J = 9.0Hz, 1 H), 7.31 (tbr, J = 5.5Hz, 1 H). (S,R)-4d: 1H NMR (200 MHz,CDCl3): δ = 0.84(d, J = 7.5Hz, 3 H), 0.90 (d, J = 7.0Hz, 3 H), 1.05 (s, 9 H), 1.76-2.32 (m, 5 H), 3.52 (t, J = 7.0 Hz,2 H), 3.70 (s, 3 H), 3.94 (d, J = 5.0Hz, 1 H), 4.01 (d, J = 5.0Hz, 1 H), 4.25-4.56 (m, 2 H), 7.46 (m, 2 H), 7.34 (s, 5 H). (S,S)-4d: 1H NMR (200 MHz,CDCl3): δ = 0.84(d, J = 6.5Hz, 6 H), 1.00 (s, 9 H), 1.75-2.27 (m, 5 H), 3.57 (t, J = 6.0 Hz,2 H), 3.68 (s, 3 H), 3.93 (d, J = 5.5Hz, 1 H), 4.07 (d, J = 5.5Hz, 1 H), 4.23-4.60 (m, 2 H), 4.59 (d, J = 9.0Hz, 1 H), 5.20 (s, 2 H), 7.33 (sbr, 6 H), 7.49 (dbr, J = 9.0 Hz,1 H), 7.73 (t, J = 5.0Hz, 1 H). (S,R)-4e: 1H NMR (200 MHz,CD3OD): δ = 0.90-1.14 (m,12 H), 2.02 (m, 1 H), 2.31 (m, 1 H), 3.69 (s, 3 H), 4.00 (d,
J = 3.5 Hz,2 H), 4.27 (d, J = 8.0Hz, 1 H), 4.53 (d, J = 8.0 Hz,1 H), 4.77 (sbr, acidic H’s), 7.48-7.63(m, 3 H), 7.84-8.00 (m, 2 H). (S,S)-4e: 1HNMR (200 MHz, CD3OD): δ = 0.98(d, J = 7.0Hz, 6 H), 1.02 (J = 7.0Hz, 6 H), 2.13 (m, 2 H), 3.73 (s, 3 H), 3.98 (d, J = 3.5Hz, 2 H), 4.32 (d, J = 7.5 Hz,1 H), 4.49 (d, J = 8.5Hz, 1 H), 4.79 (sbr, acidic H’s), 7.48-7.65(m, 3 H), 7.82-7.99 (m, 2 H).