LITHIUM AMIDES AS HOMOCHIRAL AMMONIA EQUIVALENTS FOR CONJUGATE ADDITIONS TO α,β-UNSATURATED ESTERS: ASYMMETRIC SYNTHESIS OF (S)-β-LEUCINE
1. Procedure
2. Notes
1.
t-Butyl diethylphosphonoacetate (95%) was obtained from Alfa Aesar. The submitters prepared it by heating
t-butyl bromoacetate (Sigma-Aldrich, 98%) and
triethylphosphite (Sigma-Aldrich, 98%) for 2 h without solvent, followed by distillation under vacuum.
3
2.
The following materials used in step A were obtained from Sigma-Aldrich: tetrahydrofuran (anhydrous, >99.9%, inhibitor-free), methylmagnesium bromide (3.0 M in diethyl ether), isobutyraldehyde (=99%), pentane (Chromasolv, >99%), diethyl ether (ACS reagent, anhydrous, BHT-inhibited), and silica gel (230-400 mesh, 60 Å). De-ionized tap water was used throughout.
3.
Methylmagnesium bromide was titrated before use as follows:
n-Butanol (350 mg, 4.72 mmol) and
1,10-phenanthroline (2 mg) are dissolved in
tetrahydrofuran (7 mL) in a 25-mL round-bottomed flask equipped with a 0.5-cm oval Teflon-coated magnetic stir bar and a septum pierced with an 18-gauge nitrogen-inlet needle connected to a nitrogen line and gas bubbler. The stirred solution is cooled in an ice-bath, then 3 M methylmagnesium bromide in diethyl ether is added dropwise via a weighed syringe to a persistent pink endpoint. The syringe is weighed before and after addition (difference 1.67 g, 1.61 mL, corresponding to a solution molarity of 2.93). The submitters titrated against salicylaldehyde phenylhydrazone following the procedure described by Love and Jones.
4
4.
The reaction is >98% complete as determined by
1H NMR analysis as follows: A 0.1 mL aliquot of the reaction mixture is added to 1 mL of CDCl
3 and 0.5 mL of saturated aqueous ammonium chloride, shaken, then the bottom organic phase is filtered through a cotton plug into an NMR tube for analysis. The doublet of the CH
2 group at 2.9 ppm and the quartet of the CH
2 group of the ethyl group at 4.2 ppm of the starting material compared to the olefinic resonances of the product at 5.7 and 6.8 ppm are diagnostic for reaction completion.
5.
When ammonium chloride solution is first added to the reaction mixture a white precipitate is formed; this subsequently dissolves when addition of all the ammonium chloride solution is complete, giving a clear solution. The mixture warms to 30 °C during the quench with no external cooling.
6.
The product
1 is volatile and the temperature of the water bath should not be increased above 20 °C while the solution is being concentrated on the rotary evaporator.
7.
A 3-cm glass column is wet-packed (pentane) with 80 g of silica gel topped with 0.5 cm of sand. The crude reaction product
1 is loaded neat on the column and eluted with 500 mL of a 5:1 mixture of pentane:diethyl ether, taking 50 mL fractions. The chromatography is monitored by TLC (
Rf = 0.3 in pentane:diethyl ether, 50:1). The product elutes in fractions 3-5. The eluent is concentrated by rotary evaporation (20 °C water bath, 150 mm Hg, decreased to 20 mm Hg)
(Note 6) to constant weight. The pure product
1 contains 0.7 wt% residual tetrahydrofuran by
1H NMR analysis.
8.
The geometric isomer purity of
1 is assessed by peak integration of the
13C-
1H satellite peaks corresponding to C(2)
H of the (
E)-isomer (δ
H 5.68 ppm) against the
12C-
1H peaks corresponding to C(2)
H and C(3)
H of the (
Z)-isomer [δ
H 5.56 ppm (dd,
J 11.5, 1.0 Hz) and 5.90 ppm (dd,
J 11.5, 9.9 Hz), respectively] in the quantitative
1H NMR spectra of the crude reaction mixture and the pure product.
5
9.
t-Butyl (
E)-4-methylpent-2-enoate
1 has the following physical and spectroscopic data: ν
max (thin film) 2968, 2873, 1715, 1652, 1460, 1367, 1301, 1155 cm
-1;
1H NMR
pdf (400 MHz, CDCl
3) δ: 1.04 (6 H, d,
J = 6.8 Hz, C(4)
Me2), 1.48 (9 H, s, C
Me3), 2.40-2.45 (1 H, m, C(4)
H), 5.68 (1 H, dd,
J = 15.7, 1.5 Hz, C(2)
H), 6.83 (1 H, dd,
J = 15.7, 6.6 Hz, C(3)
H);
13C NMR
pdf (100 MHz, CDCl
3) δ: 21.5 (C(4)
Me2), 28.4 (C
Me3), 31.0 (
C(4)), 80.1 (
CMe
3), 120.5 (
C(2)), 154.3 (C(3)), 166.6 (
C(1)); MS (ESI
+)
m/z 193 ([M+Na]
+, 100%); HRMS (ESI
+)
m/z calcd. for C
10H
18NaO
2+ ([M+Na]
+) 193.1199; found 193.1205.
10.
(
R)-
N-Benzyl-
N-(α-methylbenzyl)amine was obtained from Sigma-Aldrich and used without purification. The enantiomeric excess quoted by the vendor was 97.1%. The submitters prepared it from reductive alkylation of (
R)-α-methylbenzylamine (Acros Organics, >99%, 99% ee).
11.
The following materials used in step B were obtained from Sigma-Aldrich: tetrahydrofuran (anhydrous, >99.9%, inhibitor-free), 2.5 M butyllithium in hexanes, citric acid (ACS reagent grade, >99.5%), dichloromethane (ACS reagent grade, >99.5%), ethyl acetate (ACS reagent grade, >99.5%), and hexanes (ACS reagent grade, >98.5%). Ammonium chloride, sodium bicarbonate, and sodium sulfate were sourced from Fisher.
12.
n-Butyllithium was titrated against diphenylacetic acid before use as follows:
Diphenylacetic acid (0.766 g, 3.61 mmol) is dissolved in
tetrahydrofuran (10 mL) in a 25-mL round-bottomed flask equipped with a 0.5 cm oval Teflon-coated magnetic stir bar and a septum pierced with an 18-gauge nitrogen-inlet needle connected to a nitrogen line and gas bubbler. The stirred solution is cooled in an ice-bath.
n-Butyllithium is added dropwise via a weighed syringe until a yellow color persists. The syringe is weighed before and after addition (difference 1.05 g, 1.52 mL, corresponding to a solution molarity of 2.37).
13.
The syringe is weighed before and after addition to determine the amount of
n-butyllithium and
t-butyl (
E)-4-methylpent-2-enoate
1 added.
14.
With the addition of the first few drops of
n-butyllithium the reaction mixture turns from clear and colorless to clear and light pink, and darkens as further
n-butyllithium solution is added.
15.
With the addition of the first few drops of
t-butyl (
E)-4-methylpent-2-enoate
1 solution, the reaction mixture turns from dark pink to bright orange, which persists as further
t-butyl (
E)-4-methylpent-2-enoate
1 solution is added. The solution remains orange for the rest of the reaction.
16.
The reaction is followed by
1H NMR as follows. A 0.1 mL reaction aliquot is quenched into a mixture of 1 mL of CDCl
3 and 1 mL of saturated aqueous ammonium chloride. The organic layer is separated and filtered through a plug of sodium sulfate and cotton into an NMR tube. The olefin peaks at 5.7 and 6.8 ppm of the starting material are compared to the product peak at 3.2 ppm to assess reaction completion. After a 1.5 h reaction time, 13% starting material remained.
17.
The submitters quenched the reaction at −78 °C after 2 h. In cases where the intermediate lithium β-amino enolate is unstable with respect to retro-conjugate addition at elevated temperatures, the quench should be performed at −78 °C.
18.
1H NMR analysis of the crude product indicated about 1% unreacted starting material.
19.
The citric acid wash removes >95% of the unreacted (
R)-
N-benzyl-
N-(α-methylbenzyl)amine.
20.
A 3-cm glass column is wet-packed (hexanes) with silica gel (100 g) topped with 0.5 cm sand. The crude reaction product
2 is dissolved in dichloromethane (10 mL), loaded on the column, and eluted with 1 L of a 97:3 mixture of hexanes:ethyl acetate, taking 75 mL fractions. The chromatography is monitored by TLC (
Rf = 0.5 in ethyl acetate:hexanes, 5:95). The product elutes in fractions 3-10. The eluent is concentrated by rotary evaporation (40 °C water bath, 20 mmHg) to constant weight.
21.
t-Butyl (3
S,α
R)-3-[
N-benzyl-
N-(α-methylbenzyl)amino]-4-methyl-pentanoate
2 has the following physical and spectroscopic data: [α]
22D -1.7 (
c 2.0, chloroform); IR (thin film) ν
max 3102, 3080, 2973, 1947, 1875, 1807, 1731, 1601, 1454, 1369, 950 cm
-1;
1H NMR
pdf (400 MHz, CDCl
3) δ: 0.89 (3 H, d,
J = 6.8 Hz, C(4)
MeA), 1.12 (3 H, d,
J = 6.8 Hz, C(4)
MeB), 1.41 (3 H, d,
J = 7.1 Hz, C(α)
Me), 1.42 (9 H, s, C
Me3), 1.67-1.73 (1 H, m, C(4)
H), 1.81 (1 H, dd,
J = 16.1, 2.0 Hz, C(2)
HA), 1.97 (1 H, dd
J = 16.1, 9.5 Hz, C(2)
HB), 3.24-3.28 (1 H, m, C(3)
H), 3.49 (1 H, d,
J = 15.0 Hz, NC
HA), 3.77 (1 H, d,
J = 15.0 Hz, NC
HB), 3.74-3.81 (1 H, m, C(α)
H), 7.22-7.48 (10 H, m,
Ph);
13C NMR
pdf (100 MHz, CDCl
3) δ: 19.8 (C(4)
MeA), 20.4 (C(α)
Me), 21.3 (C(4)
MeB), 28.2 (C
Me3), 33.0 (
C(4)), 36.5 (
C(2)), 51.4 (N
CH
2), 58.0 (
C(3)), 58.2 (
C(α)), 80.1 (
CMe
3), 126.8, 127.1 (
p-
Ph), 128.2, 128.4, 128.5 (2 degenerate peaks) (
o-,
m-
Ph), 141.8, 142.1 (
i-
Ph), 172.6 (
C(1)); MS (ESI
+)
m/z 382 ([M+H]
+, 100%); HRMS (ESI
+) calcd. for C
25H
36NO
2+ ([M+H]
+) 382.2741; found 382.2742. An analytically pure sample was prepared by dissolving 200 mg of the product oil in 5 mL of 50:50 pentane:diethyl ether, filtering through a 0.45 micron PTFE syringe filter, concentrating under vacuum, and vacuum drying at 50 °C for 20 h: Anal. calcd. for C
25H
35NO
2: C, 78.70; H, 9.25; N, 3.67; found: C, 78.34; H, 9.15; N, 3.70.
22.
The following materials used in step C were obtained from Sigma-Aldrich: methanol (ACS reagent grade, 99.8%), triethylamine (>99.5%, SureSeal bottle), ethyl acetate (ACS reagent grade, >99.5%), and hexanes (ACS reagent grade, >98.5%). 20% Palladium hydroxide (wet) on carbon was sourced from BASF.
23.
The reaction was monitored by hydrogen pressure drop. Hydrogen uptake was complete in 1 h, but the hydrogenation was continued for 6 h to ensure complete conversion.
24.
Once the cake is thoroughly rinsed with methanol to wash off all product, it is wetted with water and transferred as a water slurry to a PTFE bottle to hold the palladium waste for recycling.
25.
A 3-cm glass column is wet-packed (1.5% triethylamine in hexanes) with silica gel (150 g) topped with 0.5 cm sea sand. The crude product is loaded neat to the column and the flask rinsed with dichloromethane (2 × 5 mL) to ensure complete transfer. The column is eluted as follows: (1) 400 mL of 1:3 ethyl acetate:hexanes containing 1.5% triethylamine, (2) 400 mL of 1:1 ethyl acetate:hexanes containing 1.5% triethylamine, (3) 400 mL ethyl acetate containing 2 % triethylamine, taking 50 mL fractions. The product
3 (
Rf = 0.25 in 1:2 ethyl acetate:hexanes containing 1.5% triethylamine, visualized using both potassium permanganate (yellow spot on purple background) and iodine) is obtained in fractions 9-20, which are concentrated by rotary evaporation (40 °C water bath, 20 mmHg) in a 500 mL round-bottomed flask to constant weight (7.82 g, 83% yield).
1H NMR analysis indicated <1 % ethyl acetate in the product. Fractions 8 and 21-25 were combined and concentrated to constant weight (0.55 g). The purity of these fractions was assessed by
1H NMR as approx. 80% (0.44 g corrected for purity, 5% yield).
26.
t-Butyl (
S)-3-amino-4-methylpentanoate
3 has the following physical and spectroscopic data: [α]
22D -24 (
c 2.0, chloroform); IR (thin film) ν
max 3387, 3321, 2964, 2933, 2874, 1727, 1597, 1466, 1392, 1367, 1152 cm
-1;
1H NMR
pdf (400 MHz, CDCl
3) δ: 0.90 (3 H, d,
J = 6.7 Hz, C(4)
MeA), 0.91 (3 H, d,
J = 6.7 Hz, C(4)
MeB), 1.30 (2 H, br s, N
H2), 1.45 (9 H, s, C
Me3), 1.58-1.63 (1 H, m, C(4)
H), 2.14 (1 H, dd,
J = 15.3, 10.0 Hz, C(2)
HA), 2.37 (1 H, dd
J = 15.3, 3.5 Hz, C(2)
HB), 2.98 (1 H, ddd,
J = 10.0, 15.3, 3.5 Hz, C(3)
H);
13C NMR
pdf (100 MHz, CDCl
3) δ: 17.9, 19.0 (C(4)
Me2), 28.3 (C
Me3), 33.5 (
C(4)), 41.2 (
C(2)), 53.8 (
C(3)), 80.6 (
CMe
3), 172.6 (
C(1)); MS (ESI
+)
m/z 210 ([M+Na]
+, 100%); HRMS (ESI
+)
m/z calcd. for C
10H
21NNaO
2+ ([M+Na]
+) 210.1465; found 210.1469. An analytical sample is prepared by re-chromatographing a portion of the rich cut of the original chromatography, as follows: silica gel (15 g) is wet-packed (3:1 hexanes:ethyl acetate containing 1.5% triethylamine) in a 1-cm column topped with 0.5 cm sand. Compound
3 (0.53 g) is added neat to the column and is eluted sequentially with 30 mL 3:1 hexanes: ethyl acetate containing 1.5% triethylamine, 60 mL 1:1 hexanes: ethyl acetate containing 1.5% triethylamine, and 90 mL 1:2 hexanes: ethyl acetate, taking 10 mL fractions. Fractions 6 and 7 are combined, filtered through a 0.45 micron syringe filter and concentrated by rotary evaporation to constant weight (290 mg). Anal. calcd. for C
10H
21NO
2: C, 64.13; H, 11.30; N, 7.48; found: C, 63.87; H, 11.20; N, 7.48.
27.
The following materials used in step D were sourced from Sigma-Aldrich and used as received: trifluoroacetic acid (ReagentPlus, >99%), dichloromethane (ACS reagent grade, >99.5%), 2 M hydrogen chloride in diethyl ether, Dowex resin 50WX4-200, and racemic β-leucine. Ammonium hydroxide was sourced from Fisher.
28.
1H NMR analysis (CD
3OD) indicated approx 8% unreacted starting material.
29.
1H NMR analysis (CD
3OD) indicated approx 4% unreacted starting material and an equimolar quantity of diethyl ether.
30.
A glass column (3 cm internal diameter) is wet-packed (water) with Dowex
® 50WX4-200 ion-exchange resin (100 g). The column is equilibrated by sequential elution with
water (200 mL),
methanol (200 mL),
water (200 mL), 1 M aqueous hydrogen chloride solution (200 mL) and
water (500 mL). The crude reaction product
4 is diluted with distilled
water (20 mL) and the resultant solution is loaded on to the column. The column is eluted with 100 mL of distilled water followed by 800 mL of 1 M aqueous ammonium hydroxide solution, taking 150 mL fractions. The fractions containing product are identified by spotting on a silica TLC plate and staining with potassium permanganate solution (yellow spot on purple background upon heating). Fractions 3-5 are concentrated by rotary evaporation (60 °C water bath, 20 mmHg) to constant weight in a 500-mL round-bottomed flask to afford 4.19-4.30 g (88-93% yield) of product
4. This material contained 0.5 wt% water by Karl Fisher titration. Fractions 2, 6, and 7 are combined and concentrated to afford 4.75 g of a white solid that contained no product by
1H NMR (peak at -75.5 ppm by
19F analysis indicates the presence of a trifluoromethyl group).
31.
Due to lack of a chromophore and lack of volatility, the purity of
4 could not be assessed by HPLC or GC. Therefore, the weight percent purity of
4 recovered from the ion-exchange chromatography was determined by
1H NMR using both ethylene glycol and 1,2-dimethoxyethane as internal standards, as follows. β-Leucine (41.1 mg, 31.3 μmol) and 1,2-dimethoxyethane (67.1 mg, 74.5 μmol) are accurately weighed in a 5-mm NMR tube, then D
2O (0.7 mL) is added. The
1H NMR analysis is carried out with a 5 second delay to ensure complete relaxation (10 second delay gave the same results, while a 0.1 second delay gave a 6% lower response for 1,2-dimethoxyethane). The dimethyl resonances (apparent triplet) of the product at 0.9 ppm are integrated vs. the 4 CH
2 protons at 3.6 ppm for 1,2-dimethoxyethane. The average of several integrations gave a molar ratio of product:standard of 0.414 vs. the 0.420 ratio of the weighed samples, indicating a wt % of 98.6%. An additional weighing was carried out with 1,2-dimethoxyethane and 2 weighings and NMR analyses were carried out using ethylene glycol as standard, providing an average wt% assay of 98.4 ± 0.7% for material isolated directly from the ion-exchange chromatography.
32.
A chiral HPLC assay was developed on the β-leucine
N-
p-toluenesulfonamide derivative
5. The derivatization procedure is as follows:
β-Leucine (108 mg, 0.82 mmol),
p-toluenesulfonyl chloride (1.48 g, 7.8 mmol, 10 equiv), 2 N
sodium hydroxide (7 mL, 14 mmol),
toluene (7 mL), and a 1-cm oval Teflon-coated magnetic stir bar are added to a 50-mL round-bottomed flask sealed with a septum through which is inserted a thermocouple thermometer probe and an 18-gauge syringe needle connected to a nitrogen line and gas bubbler. The mixture is warmed to 55-60 °C using a heating mantle and vigorously stirred for 22 h at this temperature. The mixture is cooled, and transferred to a 50-mL separatory funnel along with
water (5 mL) and
toluene (5 mL). The layers are separated. 6 M aqueous
hydrogen chloride (3 mL) is added to the aqueous layer. The mixture is transferred to a 50-mL separatory funnel and extracted with
diethyl ether (2 × 15 mL). The organic layer is washed with
water (10 mL), then filtered through a bed of magnesium sulfate and concentrated by rotary evaporation (40 °C water bath, 20 mmHg) to constant weight to afford
(S)-3-[N-(p-toluenesulfonyl)amino]-4-methylpentanoic acid 5 (132 mg, 56% yield). This non-purified material is used to determine the optical purity of β-leucine using the chiral SFC method described below. A portion of
5 is recrystallized (90 mg dissolved in 3 mL toluene at 80 °C, cooled to ambient temperature, held for 15 h, filtered to afford 70 mg) to provide
5 with the following physical and spectroscopic data: mp 131-133 °C;
1H NMR
pdf (400 MHz, CDCl
3) δ: 0.87 (6 H, app t,
J = 6.7 Hz, C(4)
Me2), 1.88 (1 H, app octet,
J = 6.8 Hz, C(4)
H), 2.45 (1 H, dd,
J = 16.2, 5.7 Hz, C(2)
HA), 2.46 (3 H, s, C
H3), 2.54 (1 H, dd,
J = 16.2, 5.0 Hz, C(2)
HB), 3.32-3.41 (1 H, m, C(3)
H), 5.17 (1 H, d,
J = 9.2 Hz, N
H), 7.30-7.34 (2 H, m,
Ar), 7.78-7.81 (2 H, m,
Ar);
13C NMR
pdf (100 MHz, CDCl
3) δ: 18.6, 19.0 (C(4)
Me2), 21.6 (Ar
Me), 31.6 (
C(4)), 36.1 (
C(2)), 56.0 (
C(3)), 127.2, 129.7, 137.8, 143.5 (
Ar), 175.8 (
C(1)). The racemic derivative was similarly prepared and recrystallized from toluene, providing racemic
5 with mp 117-119 °C. A chiral supercritical fluid chromatography (SFC) method was developed for chiral analysis of the 4-toluenesulfonamide derivative (
5): AD-H (250 × 4.6 mm, 5 μm) column, gradient method using methanol with 25mM
i-butylamine, 4% methanol /CO
2 for 4 min then ramp at 6%/min to 40% methanol /CO
2, hold at 40% for 5 minutes, 3.0 mL/min, 200 bar, 35 °C, 230 nm, 15 minutes run time; minor enantiomer elutes at 7.3 min, major at 8.0 min. The enantiomeric excess of the derivatized, non-recrystallized
5 derived from β-leucine isolated directly from the resin column was 96% ee. Since the enantiomeric excess of (
R)-
N-benzyl-
N-(α-methylbenzyl)amine used in the conjugate addition was 97%, the reaction diastereoselectivity of this step was 99%.
33.
An analytically pure sample is prepared by recrystallization. β-Leucine
4 (1.04 g) is added to
methanol (20 mL) in a 100-mL round bottomed flask with a 1-cm oval Teflon-coated stir bar and warmed in a 50 °C oil bath with stirring to dissolve the solids. The solution is quickly poured into a 50-mL syringe and hot filtered through a 0.45 micron PTFE syringe filter into a 100-mL round-bottomed flask. The solution is concentrated by rotary evaporation (40 °C water bath, 20 mmHg) to 5 mL. Partial crystallization occurs during this concentration step. After concentration, a 1-cm oval Teflon-coated stir bar is added to the flask, then
t-butyl methyl ether (15 mL) is added at 22 °C over 20 min to the stirred mixture, resulting in further crystallization. After the addition is complete, the mixture is stirred for 1 h at 21-22 °C, then vacuum filtered through a 30-mL medium porosity sintered glass funnel, washed with
t-butyl methyl ether (5 mL) and dried in a vacuum oven for 3 h at 60 °C to afford
(S)-3-amino-4-methylpentanoic acid 4 (0.82 g, 79% yield) as a white crystalline powder. The ee of the recrystallized β-leucine is only marginally improved over the crude material (97 vs 96%).
34.
(
S)-3-Amino-4-methylpentanoic acid
4 purified by recrystallization has the following physical and spectroscopic data: ee 97%; mp 197-198 °C, lit.
6a 182 °C, lit.
6b 201-202.5 °C, lit.
6c 202-210 °C, lit.
6d 206 °C, lit.
6e 212 °C; [α]
D20 -53 (
c 2.0, water), -52 (c 0.5, water), -40 (c 0.5, 1.N hydrochloric acid), lit.
6a +40.3 [(
R)-isomer,
c 1, water], lit.
6b +55.2 [(
R)-isomer,
c 1, water], lit.
6c -39.2 [(
S)-isomer, c 0.5, water], lit.
6d +47 [(
R)-isomer,
c 1, water], lit.
6e +52.3 [reported as (
S)-isomer, but drawn as (
R)-isomer, c 0.6 water], lit.
6f +51.5 [reported as (
S)-isomer, c 0.6, water]; IR (KBr) ν
max 3397, 2965, 2936, 1649, 1621, 1467, 1326, 1262 cm
-1;
1H NMR
pdf (400 MHz, D
2O) δ: 0.92 (6 H, app t,
J = 7.0 Hz, C(4)
Me2), 1.88 (1 H, app octet,
J = 6.8 Hz, C(4)
H), 2.33 (1 H, dd,
J = 16.7, 9.3 Hz, C(2)
HA), 2.50 (1 H, dd
J = 16.7, 4.2 Hz, C(2)
HB), 3.24-3.28 (1 H, m, C(3)
H);
13C NMR
pdf (100 MHz, D
2O) δ: 17.3, 17.4 (C(4)
Me2), 30.0 (
C(4)), 36.0 (
C(2)), 54.9 (
C(3)), 178.5 (
C(1));
m/z (ESI
+) 154 ([M+Na]
+, 100%); HRMS (ESI
+)
m/z calcd. for C
6H
13NNaO
2+ ([M+Na]
+) 154.0838; found 154.0841; Anal. calcd. for C
6H
13NO
2: C, 54.94; H, 9.99; N, 10.68; found: C, 54.84; H, 9.95; N, 10.64.
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
The conjugate addition reaction was first reported by Komnenos in 1883, who demonstrated the 1,4-addition of diethyl sodiomalonate to diethyl ethylidenemalonate.
7 A range of carbon and heteroatom based nucleophiles have since been shown to participate in this reaction manifold. In 1991, Davies and Ichihara described the highly diastereoselective conjugate addition of lithium (
R)-
N-benzyl-
N-(α-methylbenzyl)amide
6 to benzyl crotonate
12, which gave β-amino ester (3
R,α
R)-
18 in 95% de. Global hydrogenolytic
N-deprotection of β-amino ester mediated by Pearlman's catalyst [Pd(OH)
2/C] proceeded under 5 atm of hydrogen to give the corresponding free β-amino acid, (
R)-3-aminobutanoic acid, in quantitative yield and >95% ee.
8 This methodology has since been developed into a generally applicable synthesis of either enantiomer of homochiral β-amino acids, via conjugate addition of homochiral lithium
N-benzyl-
N-(α-methylbenzyl)amide to an α,β-unsaturated
t-butyl ester,
9 followed by hydrogenolytic
N-debenzylation and ester hydrolysis.
10 A range of homochiral lithium amides that are readily derived from commercially available, homochiral α-methylbenzylamine derivatives has been developed, which allow for either differential
N-deprotection or further elaboration in synthesis. All members of this family of lithium amides undergo highly diastereoselective conjugate addition to a wide range of α,β-unsaturated esters and amides to give the corresponding diastereo- and enantiomerically pure, homochiral β-amino ester or amide product (Table 1). This lithium amide conjugate addition methodology has been expanded to allow the stereoselective, in situ elaboration of the intermediate lithium (
Z)-β-amino enolate to give access to homochiral α-substituted-β-amino esters; it has been employed for the synthesis of hundreds of β-amino esters, amides and acids in enantiomerically pure form, and has found utility in a plethora of synthetic applications, including total syntheses, initiation of tandem asymmetric processes, and molecular recognition phenomena. Its scope and utility was comprehensively reviewed in 2005.
11
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