Notes
J . Org. Chem., Vol. 64, No. 18, 1999 6909
m/z 199, 184, 156, 113, 111, 96, 70, 43; HRMS calcd for C10H18
NO3 200.1287, found 200.1286.
-
BICP catalyst (entry 3). From a practical point of view,
hydrogenation of E/Z mixtures of â-(acylamino)acrylates
with the Rh-BICP catalyst offers the most convenient
access to corresponding â-amino acid derivatives because
high enantiomeric excesses can be obtained from both
isomers. Our results with Rh-BICP represent the high-
est enantioselectivity achieved for the hydrogenation of
â-(acylamino)acrylates with alkyl substituents. A limita-
tion of the reaction is that only moderate ee’s were
obtained with an aryl substituent in the â-(acylamino)-
acrylates using both Rh-BICP and Rh-Me-DuPhos
catalysts (entries 25 and 26).
In summary, highly enantioselective hydrogenation of
the E isomer of â-(acylamino)acrylates with a Rh-Me-
DuPhos catalyst and E/Z isomers of â-(acylamino)-
acrylates with a Rh-BICP catalyst has been achieved
in this study. This method provides an efficient approach
to important â-amino acid building blocks. Future re-
search will explore the scope of this reaction with other
enamides, especially â-(acylamino)acrylates with an R-sub-
stituent or containing a ring.
(Z)-Eth yl 3-Aceta m id o-2-h exen oa te: 1H NMR (360 MHz,
CDCl3) δ 0.94 (t, J ) 7.39 Hz, 3H), 1.27 (t, J ) 7.11 Hz, 3H),
1.60 (m, 2H), 2.12 (s, 3H), 2.72 (t, 2H), 4.13 (t, J ) 7.12 Hz, 2H),
4.92 (s, 1H), 11.10 (br, 1H); 13C NMR (90.5 MHz, CDCl3) δ 13.4,
14.0, 21.3, 25.1, 35.8, 59.6, 95.7, 158.7, 168.1, 169.1; MS m/z 199,
184, 170, 156, 129, 113, 96, 83, 43; HRMS calcd for C10H18NO3
200.1287, found 200.1290.
(E)-Eth yl 3-Aceta m id o-2-h exen oa te: 1H NMR (360 MHz,
acetone-d6) δ 1.15 (t, J ) 7.39 Hz, 3H), 1.44 (t, J ) 7.13 Hz,
3H), 1.53 (m, 2H), 2.28 (s, 3H), 2.95 (m, 2H), 4.30 (q, J ) 7.14
Hz, 2H), 7.14 (s, 1H), 8.91 (br, 1H); 13C NMR (90.6 MHz, acetone-
d6) δ 14.4, 15.1, 23.2, 25.1, 34.1, 59.9, 101.8, 155.4, 168.9, 170.8;
MS m/z 199, 184, 170, 156, 156, 129, 112, 96, 83, 43; HRMS
calcd for C10H18NO3 200.1287, found 200.1289.
(Z)-Isop r op yl 3-Aceta m id o-2-bu ten oa te: 1H NMR (360
MHz, CDCl3) δ 1.42-1.45 (m, 6H), 2.32 (s, 3H), 2.55 (m, 3H),
5.05 (s, 1H), 5.20 (m, 1H), 11.3 (br, 1H); 13C NMR (90.6 MHz,
CDCl3) δ 21.7, 21.8, 25.1, 67.0, 96.8, 154.5, 168.5, 168.7; MS m/z
185, 142, 126, 101, 83, 57, 43; HRMS calcd for C9H16NO3
186.1130, found 186.1130.
(E)-Isop r op yl 3-Aceta m id o-2-bu ten oa te: 1H NMR (360
MHz, acetone-d6) δ 1.10 (d, J ) 6.33 Hz, 6H), 1.94 (s, 3H), 2.20
(s, 3H), 4.85 (m, 1H), 6.74 (s, 1H), 8.55 (br, 1H); 13C NMR (90.6
MHz, acetone-d6) δ 18.5, 22.6, 25.1, 66.9, 102.5, 151.1, 168.7,
170.5; MS m/z 185, 142, 126, 110, 83, 57, 43; HRMS calcd for
C9H16NO3 186.1130, found 186.1130.
Exp er im en ta l Section
(Z)-Eth yl 3-Aceta m id o-2-bu ten oa te: 1H NMR (360 MHz,
CDCl3) δ 1.05-1.09 (m, 3H), 1.93 (s, 3H), 2.17 (s, 3H), 3.93-
3.95 (m, 2H), 4.68 (s, 1H), 10.9 (br, 1H); 13C NMR (90.6 MHz,
CDCl3) δ 14.1, 21.7, 25.1, 59.7, 96.3, 154.9, 168.8, 169.0; MS m/z
171, 129, 98, 84, 69, 57, 43; HRMS calcd for C8H14NO3 172.0974,
found 172.0976.
Gen er a l Meth od s. All reactions and manipulations were
performed in
a nitrogen-filled glovebox or using standard
Schlenk techniques. Toluene, benzene, and THF were distilled
from sodium benzophenone ketyl under nitrogen. Methylene
chloride was distilled from CaH2. Methanol, ethanol, and 2-pro-
panol were distilled from Mg under nitrogen. Chiral BICP ligand
was prepared using previously described procedures.5a (R)-
BINAP and (+)-DIOP were purchased from Aldrich. (R,R)-Me-
DuPHOS was purchased from Strem. Column chromatography
was performed using EM Merck Silica Gel 60 (230-400 mesh).
Syn th esis of Su bstr a tes (Sch em e 1): Step a . A solution
of â-keto ester 3 (12 mmol) and NH4OAc (4.6 g, 60 mmol) in
MeOH (15 mL) was stirred at rt for 3 d. After the solvent was
evaporated under reduced pressure, the residue was diluted with
CHCl3 (30 mL). The resulting solid was filtered off and washed
with CHCl3 (2 × 30 mL). The combined filtrate was washed with
water and brine, and dried over sodium sulfate. Evaporation of
the solvent gave the 3-amino-2-alkenoate 4, which was used for
the next step without purification.
Step b. To a solution of 3-amino-2-alkenoate 4 in THF (12
mL) were added pyridine (2 mL) and acetic anhydride (6 mL).
The reaction mixture was then heated under reflux for 24 h.
After the mixture was cooled to rt, the volatile was evaporated.
The residue was dissolved in EtOAc (20 mL), and the solution
was washed with water (10 mL), 1 N HCl (10 mL), 1 M KH2PO4
(10 mL), NaHCO3 (saturated, 10 mL), and brine (15 mL). After
the solution was dried over sodium sulfate, the solvent was
evaporated under reduced pressure. Chromatography of the
residue on silica gel with a gradient solvent of EtOAc in hexanes
(15-70%) as eluant gave the Z isomer, followed by a byproduct
and then the E isomer.
(Z)-Meth yl 3-Aceta m id o-2-bu ten oa te:4a 1H NMR (360
MHz, CDCl3) δ 1.89 (s, 3 H), 2.24 (s, 3H), 3.57 (s, 3H), 4.76 (s,
1H), 10.9 (br, 1H).
(E)-Meth yl 3-Aceta m id o-2-bu ten oa te:4a 1H NMR (360
MHz, acetone-d6) δ 2.02 (s, 3 H), 2.29 (s, 3H), 3.58 (s, 3H), 6.85
(s, 1H), 8.72 (br, 1H).
(Z)-Eth yl 4-Meth yl-3-a ceta m id o-2-p en ten oa te:: 1H NMR
(360 MHz, CDCl3) δ 1.10-1.24 (m, 6 H), 1.25-1.30 (m, 3H), 2.13
(s, 3H), 3.87 (m, 1H), 4.13-4.19 (m, 2H), 5.04 (s, 1 H), 11.10 (br,
1 H); 13C NMR (90.5 MHz, CDCl3) δ 13.9, 14.0, 21.0, 25.2, 29.0,
59.6, 92.4, 165.2, 168.0, 169.4; MS m/z 199, 184, 156, 111, 96,
70, 43; HRMS calcd for C10H18NO3 200.1287, found 200.1295.
(E)-Eth yl 4-Meth yl-3-a ceta m id o-2-p en ten oa te: 1H NMR
(200 MHz, acetone-d6) δ 1.12 (d, J ) 7.08 Hz, 6 H), 1.20 (t, J )
7.08 Hz, 3H), 2.08 (s, 3H), 4.05 (q, J ) 7.09 Hz, 2H), 4.30 (m,
1H), 6.97 (s, 1 H), 8.14 (br, 1 H); 13C NMR (50.3 MHz, acetone-
d6) δ 14.5, 19.6, 24.6, 27.7, 59.4, 100.8, 158.7, 168.3, 170.6; MS
(E)-Eth yl 3-Aceta m id o-2-bu ten oa te: 1H NMR (360 MHz,
acetone-d6) δ 1.39 (t, J ) 7.04 Hz, 3H), 2.23 (s, 3H), 2.49 (s, 3H),
4.25 (q, J ) 7.27 Hz, 2H), 7.04 (s, 1H), 8.91 (br, 1H); 13C NMR
(90.6 MHz, acetone-d6) δ 15.1, 18.5, 25.1, 59.9, 102.0, 151.4,
169.1, 170.6; MS m/z 171, 156, 129, 98, 84, 57, 43; HRMS calcd
for C8H13NO3 171.0895, found 171.0900.
(Z)-Meth yl 3-Aceta m id o-2-p en ten oa te: 1H NMR (360
MHz, CDCl3) δ 1.03 (t, J ) 7.35 Hz, 3H), 2.07 (s, 3H), 2.72 (m,
2H), 3.62 (s, 2H), 4.89 (s, 1H), 11.0 (br, 1H); 13C NMR (90.6 MHz,
CDCl3) δ 12.1, 24.8, 26.9, 50.5, 93.9, 160.3, 167.9, 169.4; MS m/z
171, 140, 129, 98, 84, 69, 43; HRMS calcd for C8H13NO3 171.0895,
found 171.0898.
(E)-Meth yl 3-Aceta m id o-2-p en ten oa te: 1H NMR (360
MHz, acetone-d6) δ 1.21 (t, J ) 7.52 Hz, 3H), 2.15 (s, 3H), 2.84
(q, J ) 7.47 Hz, 2H), 3.69 (s, 2H), 6.96 (s, 1H), 8.80 (br, 1H); 13
C
NMR (90.6 MHz, acetone-d6) δ 13.2, 24.4, 25.0, 50.4, 99.9, 156.6,
168.5, 170.3; MS m/z 171, 140, 129, 112, 98, 84, 69, 43; HRMS
calcd for C8H13NO3 171.0895, found 171.0890.
(E)-Meth yl 5-Meth yl-3-acetam ido-2-h exen oate:4a 1H NMR
(360 MHz, acetone-d6) δ 1.01 (d, J ) 6.72 Hz, 6H), 2.13-2.15
(m, 3H), 2.79 (d, J ) 7.44 Hz, 2H), 3.68 (s, 3H), 7.07 (s, 1H),
8.75 (br, 1H).
Meth yl 3-Aceta m id o-3-p h en yl-2-p r op en oa te:4a 1H NMR
(200 MHz, CDCl3) δ (Z isomer) 2.17 (s, 3H), 3.77 (s, 3H), 5.29 (s,
1H), 7.37-7.45 (m, 5H); (E isomer) 2.38 (s, 3H), 3.77 (s, 3H),
6.65 (s, 1H), 7.37-7.45 (m, 5H).
Gen er a l P r oced u r e for Asym m etr ic Hyd r ogen a tion . To
a solution of [Rh(COD)2]OTf (2.0 mg, 4.27 × 10-3 mmol) in
toluene (3.4 mL) in a glovebox was added the chiral ligand (0.047
mL of a 0.1 M solution in toluene, 4.7 × 10-3 mmol). After the
mixture was stirred for 30 min, substrate 1 (0.427 mmol) was
added. The hydrogenation was performed at rt under 10 atm of
hydrogen for 24 h. The hydrogen pressure was released carefully
in a hood, and the reaction mixture was passed through a short
silica gel column to remove the catalyst. The enantiomeric
excesses were measured by GC without further purification.
(R)-Meth yl 3-Aceta m id obu ta n oa te:4a,b [R]25 25 ) +21.4 (c
D
1.4, MeOH); 1H NMR (360 MHz, CDCl3) δ 1.16 (d, J ) 6.81 Hz,
3 H), 1.90 (s, 3H), 2.47 (m, 3H), 3.63 (s, 3H), 4.28 (m, 1H), 6.14
(br, 1H).
(S)-Eth yl 4-Meth yl-3-acetam idopen tan oate: [R]25D ) +52.8
(c 1.2, CHCl3); 1H NMR (360 MHz, CDCl3) δ 0.83-0.86 (m, 6
H), 1.15-1.20 (m, 3H), 1.75 (m, 1H), 1.90 (s, 3H), 2.40-2.43 (m,