Våbenø et al.
reaction was extracted with diethyl ether, the organic phase
was dried (MgSO4), and the solvent was removed under
reduced pressure. Flash chromatography [diethyl ether:pen-
tane (1:2)] afforded 1 (654 mg, 73%) as a light yellow solid:
mp 68-70 °C; [R]D +7.7° (c 1, CHCl3); analytical HPLC: tR
Felkin-Anh-controlled reductions. This reasoning is
expected to be highly useful in stereoselective reductions
of keto ester derivatives other than 1.
1
Exp er im en ta l Section
5.41 min (1% EtOH in n-hexane); H NMR (CDCl3) δ 7.33-
7.07 (m, 5H), 7.02 (d, 1H, J ) 15.7 Hz), 6.67 (d, 1H, J ) 15.7
Hz), 5.13 (br d, 1H), 4.82-4.75 (m, 1H), 3.16-2.95 (m, 2H),
1.49 (s, 9H), 1.40 (s, 9H). 13C NMR (CDCl3) δ 197.7, 164.3,
155.1, 135.6, 135.5, 134.4, 129.5 (2 C:s), 128.7 (2 C:s), 127.2,
82.2, 80.2, 59.6, 37.6, 28.3 (3 C:s), 28.0 (3 C:s). Anal. Calcd for
Gen er a l. 1H and 13C NMR spectra were recorded at 400
and 100 MHz, respectively. CDCl3 was used as NMR solvent,
and chemical shifts are given relative to the solvent signal (δ
7.26 and 77.0, respectively). Thin-layer chromatography (TLC)
was performed using silica gel (Silicagel 60 F254), with visu-
alization by either UV detection or 5% phosphomolybdic acid
hydrate (PMA) in EtOH, followed by heating. Flash chroma-
tography was performed on silica gel (Silicagel 60 (0.040-0.063
mm)) under nitrogen pressure. THF was distilled from Na/
benzophenone ketyl. Other solvents were of analytical or
synthetic grade and were used without further purification.
Elemental analyses were done by Mikro Kemi AB, Uppsala,
Sweden. Melting points are uncorrected. In HPLC, a UV
detector operating at 254 nm was used. Analytical chroma-
tography was performed on a LiChrosorb Si 60 (5 µm) 4 × 250
mm analytical column (flow rate 1.0 mL/min). Preparative
chromatography was performed on a Prep Nova-Pak HR Silica
6 µm 60 Å 25 × 100 mm column (flow rate 6.0 mL/min).
Dim et h yl [(3S)-3-[N-(ter t-Bu t oxyca r b on yl)a m in o]-2-
oxo-4-p h en ylbu tyl]p h osp h on a te (4).44 n-Butyllithium (15%
in n-hexane) (6.64 mL, 10.5 mmol) was added to a solution of
dimethyl methyl phosphonate (1.15 mL, 10.7 mmol) in THF
(10 mL) at -78 °C. The solution was stirred for 30 min at -78
°C. A solution of Boc-L-phenylalanine methyl ester (1.0 g, 3.6
mmol) in THF (7.5 mL) was added, and the reaction was
stirred for 1 h at -78 °C. The reaction was quenched with 10%
citric acid and partitioned between diethyl ether and brine.
The organic phase was dried (MgSO4) and the solvent removed
under reduced pressure. Flash chromatography [n-hexane/
CHCl3/MeOH (14:5:1)] afforded 723 mg (54%) of 4 as a white
solid. For spectroscopical data on 4, see ref 27.
Di-ter t-bu tyl Ta r tr a te. The method used was modified
from ref 45. A mixture of DCC (10 g, 48.5 mmol), tert-butyl
alcohol (5.6 mL, 58 mmol), and CuCl (200 mg, 2 mmol) was
stirred at room temperature for 5 days. CH2Cl2 (70 mL) and
L-tartaric acid (2.41 g, 16 mmol) were added. The reaction was
stirred at room temperature for 28 h and then filtered through
Celite. The filtrate was partitioned between CH2Cl2 and H2O.
The organic phase was dried (MgSO4) and the solvent removed
under reduced pressure. Flash chromatography [diethyl ether:
pentane (1:1)] afforded 801 mg (19%) of di-tert-butyl tartrate
as a white solid. For spectroscopical data on di-tert-butyl
tartrate, see ref 46.
ter t-Bu tyl Glyoxyla te (5).47 Di-tert-butyl tartrate (1.5 g,
5.7 mmol) was dissolved in MeOH (30 mL), and a solution of
NaIO4 (1.47 g, 6.9 mmol) in H2O (15 mL) was added. The
reaction was stirred for 80 min at 0 °C. The reaction was
partitioned between H2O and diethyl ether. The organic phase
was dried (MgSO4) and the solvent removed under reduced
pressure to give 1.46 g (98%) of 5 as a colorless oil. The product
was used as such in the synthesis of 1.
C
21H29NO5: C, 67.18; H, 7.79; N, 3.73. Found: C, 67.2; H, 7.8;
N, 3.8. (The reaction also gave 103 mg (11%) of the cis-isomer
(trans:cis 6.3:1)).
(R)-(+)-2-Am in o-3-m eth yl-1,1-d ip h en ylbu ta n -1-ol (6). A
solution of Boc-D-valine methyl ester (390 mg, 1.69 mmol) in
diethyl ether (15 mL) was added to an ethereal solution of
phenylmagnesium bromide [prepared from bromobenzene
(1.42 mL, 13.49 mmol) and magnesium (328 mg, 13.49 mmol)
in diethyl ether (15 mL)] at 0 °C. The reaction was stirred at
room temperature for 4 h and thereafter quenched with
saturated aqueous NH4Cl and extracted with diethyl ether.
The organic phase was dried (MgSO4) and the solvent removed
under reduced pressure. Flash chromatography (CHCl3:MeOH
9:1) afforded 160 mg (27%) Boc-6 as a white solid.
Dep r otection . Boc-6 (160 mg) was dissolved in MeOH
saturated with HCl(g) (15 mL) and stirred at room tempera-
ture overnight. Diethyl ether was added and the solvent was
removed under reduced pressure. Because of incomplete
deprotection, the crude product was extracted with aqueous
NH3 and diethyl ether. The organic phase was dried (Na2SO4)
and the solvent removed under reduced pressure. Flash
chromatography [CHCl3:MeOH (9:1)] afforded 30 mg (26%) of
6 after evaporation. For spectroscopical data on 6, see ref 39.
Ch em ica l Red u ction s. The two diastereomeric alcohols 2
and 3 were synthesized by reduction of 1 with different
reducing agents (Table 1). The anti/syn ratio was determined
by NMR spectroscopy on the crude product mixture in order
to avoid errors caused by fractionation of the alcohols during
work up. When this was not possible due to interfering signals,
the crude mixture was filtered through a short pad of silica
gel before the ratio was determined by NMR spectroscopy.
Care was taken so that this filtration did not cause any
changes in the isomeric ratio. Where needed, the final puri-
fication of the alcohols was performed by flash chromatography
[diethyl ether:pentane (1:2)]. The anti/syn ratio was increased
by recrystallization of the mixture from EtOH/n-hexane before
the final purification by preparative HPLC (1% EtOH in
isohexane). Below the experimental procedures for the differ-
ent reduction reactions are described. Only one procedure is
given for reductions where enantiomeric forms of the reducing
agent are used. Procedures for reductions resulting in low or
no stereoselectivity (NaBH4/CeCl3,10 Superhydride, L-Selec-
tride40) are omitted.
ter t-Bu tyl (4R,5S)-5-[N-(ter t-bu toxyca r bon yl)a m in o]-
4-h yd r oxy-6-p h en yl-(E)-2-h exen oa te (2): white solid; mp
117-119 °C; [R]D -8.9° (c 1, CHCl3); analytical HPLC tR 13.61
min (2% EtOH in n-hexane); 1H NMR (CDCl3) δ 7.35-7.15
(m, 5H), 6.87 (dd, 1H, J ) 4.6, 15.6 Hz), 6.08 (dd, 1H, J ) 1.7,
15.6 Hz), 4.66 (br d, 1H), 4.41 (br s, 1H), 4.02 (br d, 1H), 3.83
(br s, 1H), 2.85-2.70 (m, 2H), 1.48 (s, 9H), 1.35 (s, 9H). 13C
NMR (CDCl3) δ 165.7, 156.8, 144.8, 137.4, 129.2 (2 C:s), 128.7
(2 C:s), 126.8, 124.5, 80.7, 80.3, 73.5, 56.9, 36.2, 28.3 (3 C:s),
28.2 (3 C:s). Anal. Calcd for C21H31NO5: C, 66.82; H, 8.28; N,
3.71. Found: C, 67.2; H, 8.4; N, 3.7.
ter t-Bu tyl (5S)-5-[N-(ter t-Bu t oxyca r b on yl)a m in o]-4-
oxo-6-p h en yl-(E)-2-h exen oa te (1).44 Oven-dried LiCl (101
mg, 2.4 mmol) and Et3N (330 µL, 2.4 mmol) were added to a
solution of phosphonate 4 (887 mg, 2.4 mmol) in acetonitrile
(20 mL) at 0 °C. A solution of tert-butyl glyoxylate 5 (710 mg,
5.5 mmol) in acetonitrile (20 mL) was added. The reaction was
stirred at 0 °C for 70 min and allowed to reach room
temperature before quenching with 10% citric acid. The
ter t-Bu tyl (4S,5S)-5-[N-(ter t-bu toxyca r bon yl)a m in o]-4-
h yd r oxy-6-p h en yl-(E)-2-h exen oa te (3): white solid; mp 89-
91 °C; [R]D +1.9° (c 1, CHCl3); analytical HPLC tR 12.06 min
(2% EtOH in n-hexane); 1H NMR (CDCl3) δ 7.33-7.16 (m, 5H),
6.80 (dd, 1H, J ) 4.2, 15.6 Hz), 5.98 (dd, 1H, J ) 1.8, 15.4
Hz), 5.00 (br d, 1H), 4.26 (br s, 1H), 3.80 (br d, 1H), 3.72 (br s,
1H), 3.06-2.82 (m, 2H), 1.44 (s, 9H), 1.37 (s, 9H). 13C NMR
(44) Berts, W.; Luthman, K. Unpublished results.
(45) Henry, R. A. J . Heterocycl. Chem. 1976, 13, 391-392.
(46) Uray, G.; Lindner, W. Tetrahedron 1988, 44, 4357-4362.
(47) Grinde, S. Master thesis: Design og syntese av dipeptidomime-
tika som ligand for transportmolekylet PepT1; University of Tromsø:
Tromsø, 1999.
9190 J . Org. Chem., Vol. 67, No. 26, 2002