Expedient asymmetric synthesis of all four isomers of N,N′-protected 2,3-diaminobutanoic acid

Article abstract of DOI:10.1021/jo001152f

2,3-Diaminobutanoic acid (DAB) is found in several peptide antibiotics, toxins, and biologically active molecules. This paper describes the practical and highly enantioselective synthesis of all four N,N′-protected DAB stereoisomers using an asymmetric Rh(I)-phosphine-catalyzed hydrogenation of isomeric enamides as the key step. Thermal and photochemical isomerization of the enamide hydrogenation substrates coupled with catalyst-geometric isomer pairing allows targeted synthesis of single DAB isomers in maximum yield.

Full text of DOI:10.1021/jo001152f

4148
J . Org. Chem. 2001, 66, 4148-4152
Exp ed ien t Asym m etr ic Syn th esis of All F ou r Isom er s of
N,N′-P r otected 2,3-Dia m in obu ta n oic Acid
Andrea J . Robinson,* Pauline Stanislawski, and Dean Mulholland
School of Chemistry, Monash University, Clayton, Victoria 3800, Australia
Linnan He and Hui-Yin Li*,†
DuPont Pharmaceuticals Company, Chemical Process R&D, Experimental Station,
Wilmington, Delaware 19880-0336
A.Robinson@sci.monash.edu.au
2,3-Diaminobutanoic acid (DAB) is found in several peptide antibiotics, toxins, and biologically
active molecules. This paper describes the practical and highly enantioselective synthesis of all
four N,N′-protected DAB stereoisomers using an asymmetric Rh(I)-phosphine-catalyzed hydroge-
nation of isomeric enamides as the key step. Thermal and photochemical isomerization of the
enamide hydrogenation substrates coupled with catalyst-geometric isomer pairing allows targeted
synthesis of single DAB isomers in maximum yield.
Sch em e 1
Optically active R,â-diamino acids are important struc-
tural components of many natural products and medici-
nal agents.1 In particular, the â-branched nonproteino-
genic amino acid 2,3-diaminobutanoic acid (DAB) (1) has
attracted considerable attention because of its inclusion
in several molecules possessing biological activity.2 The
(2S,3S)-epimer (1a ) is a constituent of several tubercu-
lostatic heptapeptide antibiotics, including the antrimy-
cin and cirratiomycin classes,3 and is also found in the
highly potent antibiotic peptide lavendomycin, isolated
from culture filtrates of Streptomyces lavendulae.4 Inter-
estingly, amphomycin, a peptide antibiotic isolated from
Streptomyces canus, contains both (2S,3S)- and (2S,3R)-
DAB.5 The DAB unit is also found in plant extracts,6
antifungal dipeptides,7 toxins,8,9 and other biologically
active molecules.10-12 Several syntheses of optically pure
diaminobutanoic acid have been reported but only a few
of these preparations offer easy access to both syn and
anti isomers. Approaches to the anti-isomers (1a and 1b)
mainly capitalize on the ready availability of L- and
D-threonine and introduce the â-N-substituent via a
Mitsunobu reaction.13 Routes starting from the more
expensive allo-threonines, or a double inversion at the
â-position of L- and D-threonine,14 need to be employed
to access the syn-diastereomers (1c and 1d ). More recent
approaches to DAB (1) have included an asymmetric
conjugate addition of a chiral lithium amide to tert-butyl
crotonate,9 asymmetric aminohydroxylation of tert-butyl
crotonate15 and Grignard addition to chiral nitrones
derived from L-serine.2 We were interested in investigat-
ing a stereodivergent synthesis of all four stereoisomers
of DAB (1) from a common disubstituted crotonate
precursor (2a , X ) Me) using catalytic asymmetric
hydrogenation as the key transformation (Scheme 1). We
were encouraged by our previous studies on the reduction
of the related 2,3-diamidopropenoate system (2b, X ) H)
where the use of rhodium(I) hydrogenation catalysts,
* To whom correspondence should be addressed.
† Email: Hui-Yin.Li@dupontpharma.com.
(1) Pfammatter, E.; Seebach, D. Liebigs Ann. Chem. 1991, 1323-
1326.
(2) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. Tetrahedron
Lett. 1997, 38, 1813-1816.
(3) Schmidt, U.; Riedl, B. J . Chem. Soc., Chem. Commun. 1992,
1186-1187.
(4) Schmidt, U.; Mundinger, K.; Mangold, R.; Lieberknecht, A. J .
Chem. Soc., Chem. Commun. 1990, 1216-1219.
(5) Bodanszky, M.; Sigler, G. F.; Bodanszky, A. J . Am. Chem. Soc.
1973, 95, 2352-2357.
(6) Evans, C. S.; Qureshi, M. Y.; Bell, E. A. Phytochemistry 1977,
16, 565.
(7) Rane, D. F.; Girijavallabhan, V. M.; Ganguly, A. K.; Pike, R. E.;
Saksena, A. K.; McPhail, A. T. Tetrahedron Lett. 1993, 34, 3201-3204.
(8) Nakamura, Y.; Shin, C. Chem. Lett. 1992, 49-52.
(9) Burke, A. J .; Davies, S. G.; Hedgecock, C. J . R. Synlett 1996, 7,
621.
(10) Dunn, P. J .; Haner, R.; Rapoport, H. J . Org. Chem. 1990, 55,
5017-5025.
(11) Palomo, C.; Aizpurua, J . M.; Galarza, R.; Mielgo, A. Chem.
Commun. 1996, 633-634.
(12) Shigematsu, N.; Setoi, H.; Uchida, I.; Shibata, T.; Terano, H.;
Hashimoto, M. Tetrahedron Lett. 1988, 29, 5147-5150.
(13) Schmidt, U.; Mundinger, K.; Riedl, B.; Haas, G.; Lau, R.
Synthesis 1992, 1201-1202.
incorporating
chiral
1,2-bis(phospholano)benzene
(DuPHOS)16 and 1,2-bis(phospholano)ethane (BPE)
ligands,17 provided a highly efficient and enantioselective
route (>98% ee) to both enantiomers.18 Importantly,
these same catalysts have also been employed in the
asymmetric hydrogenation of â,â-disubstituted R-enam-
(14) Nakamura, Y.; Hirai, M.; Tamotsu, K.; Yonezawa, Y.; Shin, C.
Bull. Chem. Soc. J pn. 1995, 68, 1369-1377.
(15) Han, H.; Yoon, J .; J anda, K. D. J . Org. Chem. 1998, 63, 2045-
2048.
(16) Burk, M. J .; Feaster, J . E.; Nugent, W. A.; Harlow, R. L. J .
Am. Chem. Soc. 1993, 115, 5, 10125-10138.
(17) Burk, M. J .; Feaster, J . E.; Harlow, R. L. Organometallics 1990,
9, 2653-2655.
(18) Robinson, A. J .; Lim, C.-Y.; Li, H.-Y. J . Org. Chem. 2001, 66,
4141-4147.
10.1021/jo001152f CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/16/2001

Synthesis of N,N′-Protected 2,3-Diaminobutanoic Acids
J . Org. Chem., Vol. 66, No. 12, 2001 4149
Ta ble 1.
reaction time,
hydrogen pressure,
absolute
entry
substrate
ligand
min
solvent
psi
% yield
% eec
configurationd
1
2
E-5
E-5
E-5
E-5
E-5
E-5
E-5
E-5
Z-5
Z-5
Z-5
Z-5
Z-5
Z-5
R,R-MeDuPHOS
S,S-MeDuPHOS
R,R-MeDuPHOS
R,R-MeDuPHOS
R,R-MeDuPHOS
R,R-MeDuPHOS
S,S-MeDuPHOS
R,R-MeBPE
R,R-MeDuPHOS
S,S-MeDuPHOS
R,R-MeDuPHOS
R,R-MeBPE
48
48
15
15
12
64
64
72
15
15
16
96
96
96
MeOH
MeOH
MeOH
Ph-H
60
60
90
60
90
90
90
90
60
90
90
90
90
90
100
100
100
50a
70a
95
71
69
2R,3S
2S,3R
2R,3S
2R,3S
2R,3S
2R,3S
2S,3R
2R,3S
-
3
72
4
>99
>98
>98
>98
96
5
Ph-H
6
Ph-H
7
Ph-H
97
8
Ph-H
92
9
MeOH
MeOH
Ph-H
45b
58b
100
100
100
1
-
-
10
11
12
13
14
-
96
2R,3R
2R,3R
2S,3S
-
Ph-H
Ph-H
Hexane
80
S,S-MeBPE
R,R-MeBPE
80
-
a
Isolated yield of 6c; starting enamide (5) also recovered from the reaction mixture. b Expected butanoate (6) accompanied by unidentified
isomeric compound. c Enantiomeric excess determined by chiral HPLC. Absolute configuration determined by comparison to authentic
d
samples of (6a and 6d ) derived from L-threonine.
Sch em e 2
Sch em e 3
a
Conditions: (a) NaNO2, aq AcOH, 0 °C, 81%; (b) Al/Hg, THF;
(c) BzCl, 63% over two steps; (d) NH4OAc, MeOH, rt, 81%; (e) AcCl,
pyridine, CH2Cl2/Et2O, 58%.
ides to yield chiral â-branched amino acids19 and can
therefore accommodate increasing steric bulk at the
â-position.
Hydrogenation substrates were easily assembled from
ethyl acetoacetate. Thus, R-nitrosation gave the R-ox-
imino-â-keto ester (3)20 which was then reduced with
aluminum amalgam and benzoylated in situ to give
ketoester (4) in excellent yield. Careful control of the
reaction temperature during the reduction step was
needed to minimize concomitant reduction of the ketone.
Subsequent treatment of 4 with ammonium acetate
followed by acetylation installed the requisite â-amide
group and afforded the E- and Z-enamides (5) as a 4:1
mixture (Scheme 2). The geometric isomers were readily
separated by conventional column chromatography. On
a larger scale, however, it was more convenient to
isomerize the mixture into a single isomer: Thermal
isomerization of Z-enamide gave pure E-enamide (E-5)
and photochemical isomerization of the E-enamide at
room temperature afforded pure samples of the Z-isomer
(Z-5) (Scheme 3). This process eliminates the need for
isomer separation prior to hydrogenation and signifi-
cantly enhances the convenience and efficiency of this
synthetic approach to DAB derivatives.
strates (MeOH, RT, 60-90 psi)18 gave excellent chemical
yields of R,â-diamidobutanoate (6). The Me-DuPHOS-
Rh(I) triflate catalyzed hydrogenation of E-enamide (5)
in methanol, however, gave disappointingly low enanti-
oselectivities (69-71% ee, entries 1-3). The more steri-
cally congested ligand, Et-DuPHOS, provided even poorer
selectivity (65% ee). However, Me-DuPHOS-Rh(I)-cata-
lyzed hydrogenation of E-enamide (5) in benzene gave
butanoate (6) in >98% ee and excellent yield. A higher
hydrogen pressure (90 psi) was employed to compensate
for a reduced reaction rate in this solvent (entries 4-7).
Enantiomeric excess was determined by chiral HPLC and
assignment of absolute configuration was made by com-
parison with an authentic sample of (2S,3R)-6d obtained
from L-threonine. Hence, hydrogenation of (E)-enamide
(5) with [R,R]-Me-DuPHOS-Rh afforded (2R,3S)-diami-
dobutanoate (6c) whereas use of the ligand antipode,
[S,S]-Me-DuPHOS, gave the enantiomeric syn-isomer,
(2S,3R)-6d (Scheme 3). This sense of induction is analo-
gous to that observed in the Rh(I)-DuPHOS-catalyzed
hydrogenation of R-enamides16,19 and R,â-diamidoprop-
enoates.18 Reduction with the more flexible Rh(I)-Me-BPE
catalyst afforded butanoate (6c) in comparable yield and
The results of the hydrogenation studies are sum-
marized in Table 1. The conditions previously employed
for the hydrogenation of R,â-diamidopropenoate sub-
(19) Burk, M. J .; Gross, M. F.; Martinez, J . P. J . Am. Chem. Soc.
1995, 117, 9375-9376.
(20) Bouveault, L.; Locquin, R. Bull. Soc. Chim. Fr. 1904, 31, 1159-
1164.

4150 J . Org. Chem., Vol. 66, No. 12, 2001
Robinson et al.
Rh(I)-BPE refers to [(1,5-cyclooctadiene)Rh(I)(bis(2,5-dialkyl-
phospholano)benzene)] triflate and [(1,5-cyclooctadiene)Rh(I)-
(bis(2,5-dialkylphospholano)ethane)] triflate, respectively. In
all Rh(I)-phosphine hydrogenations, high purity (<10 ppm)
hydrogen and nitrogen were used and purified by passage
through water, oxygen, and hydrocarbon traps. The enantio-
meric excess of the hydrogenation products was determined
via chiral HPLC analysis using Diacel Chiracel OJ and AS
columns.
enantiomeric excess (entry 8). Interestingly, hydrogena-
tion of analogous â-substituted R,â-diamidoacrylates with
Me-DuPHOS-Rh(I) hexafluorophosphonate was report-
edly unsuccessful;21 (2S,3R)-2,3-bis(acylamino)carboxy-
lates were successfully prepared, however, with TRAP-
Rh(I) complexes in 79-82% ee.
Hydrogenation of the Z-enamide (5) in methanol gave
the required butanoate (6) under mild conditions (60psi
H2, 15 h) but was accompanied by an as yet unidentified
and unstable byproduct which was isomeric with (6)
(entries 9 and 10). In benzene, however, formation of this
byproduct was completely eliminated and excellent yields
of the desired anti-butanoates (6a and 6b) were obtained
with both the Rh(I)-DuPHOS and Rh(I)-BPE catalysts
(entries 11-13). Hence, the anti-diamidobutanoate de-
rivatives, (2S,3S)-6a and (2R,3R)-6b, were produced in
80% ee, respectively, via (S,S)- and (R,R)-Me-BPE-
Rh(I)-catalyzed hydrogenation of the Z-enamide (Z-5)
(Scheme 3). Furthermore, hydrogenation of Z-5 using
MeDuPHOS-Rh(I) catalysts gave anti-butanoates in
96% ee. Hydrogenation in hexane was unsuccessful
(entry 14).
The high yields, excellent enantioselectivity, and mild
hydrogenation conditions, coupled with the ability to
access any one of the four DAB isomers from a common
starting material, makes this synthetic approach to DAB
derivatives particularly attractive. Notably, a variety of
amine protecting groups are known to be compatible with
the rhodium-DuPHOS/BPE catalysts and could be readily
employed without major detriment to enantioselectivity.
To access units suitable for natural product synthesis and
antibiotic monobactams, such as aztreonam, we needed
to demonstrate that the Z-enamide (Z-5) could be hydro-
genated to give the anti-isomers, (2R,3R)-6b and par-
ticularly the (2S,3S)-6a stereoisomer. The slightly lower
enantioselectivity (96% ee) observed in the hydrogenation
of the Z-enamide compared with the E-enamide (>98%
ee) is perhaps not surprising. Our previous 13C-labeling
experiments on the related R,â-diamidopropenoate sys-
tem clearly showed the coordinative involvement of the
R-amido group carbonyl during hydrogenation.18 It is
therefore reasonable to postulate that a cis-orientation
of a bulky â-substituent may compromise the binding of
the substrate to the rhodium metal center and result in
lower enantioselectivity. In conclusion, we have success-
fully demonstrated the use of catalytic asymmetric
hydrogenation and geometric isomer-ligand antipode
matching to access all four stereoisomers of diamidobu-
tanoate (6).
P r ep a r a tion of Hyd r ogen a tion Su bstr a tes
Eth yl 2-Hyd r oxyim in o-3-oxobu ta n oa te (3). A solution
of sodium nitrite (10.6 g, 0.153 mol) in water (20 mL) was
added dropwise to a stirred solution of ethyl acetoacetate (20.0
g, 0.154 mol) in glacial acetic acid (40 mL) at 0 °C. After the
addition was complete, the light yellow reaction mixture was
allowed to warm to ambient temperature. After 0.5 h, TLC
(light petroleum:ethyl acetate; 1:1) showed the disappearance
of the starting material, and the reaction mixture was quenched
with water (100 mL) and extracted with ethyl acetate (2 × 35
mL). The organic extracts were combined and washed with
water (2 × 30 mL) and saturated sodium bicarbonate solution
(2 × 30 mL). The organic phase was dried (Na2SO4) and
evaporated under reduced pressure to give the oxime (3) (19.9
g, 81%) as a pale yellow oil. Spectroscopic analysis showed that
the oxime (3) did not require purification. υmax (neat): 3331bs,
1748s, 1701s, 1628m cm-1. 1H NMR (300 MHz, CDCl3): δ 1.35
(t, J 7.1 Hz, 3H), 2.42 (s, 3H), 4.38 (q, J 7.1 Hz, 2H), 10.72 (s,
1H). 13C NMR (100 MHz, CDCl3): δ 14.0, 25.3, 62.5, 151.1,
162.0, 194.2. Mass spectrum (EI): m/z 159 (M+, 7%), 131 (100).
Accurate mass spectrum: m/z 159.0537, C6H9NO4 requires
159.0532.
Eth yl 2-Ben zoyla m in o-3-oxobu ta n oa te (4). Aluminum
turnings were activated according to the following procedure:
Sodium hydroxide solution (1 M, 100 mL) was added to fine
aluminum turnings (8.00 g, 0.297 mol) resulting in the
evolution of hydrogen gas. The sodium hydroxide solution was
decanted after 10-15 s, and the aluminum turnings were
washed with water (100 mL). Aqueous mercury(II) chloride
solution (0.5%, 50 mL) was then added to the aluminum and
allowed to stand for 1-2 min before decanting. This procedure
was repeated, and the amalgamated aluminum was washed
in turn with water (100 mL), absolute ethanol (100 mL), and
dry diethyl ether (100 mL). A solution of oxime (3) (10.0 g,
62.9 mmol) in tetrahydrofuran (50 mL) was added dropwise
to a stirred suspension of the above aluminum amalgam in
tetrahydrofuran (50 mL). A few drops of water were cautiously
added to the reaction mixture. The temperature of the reaction
was maintained below ca. 50 °C by periodic immersion of the
flask in a cool water bath. After ca. 2 h, TLC (light petroleum:
ethyl acetate; 2:1) showed the absence of the oxime (3). The
reaction mixture was filtered, benzoyl chloride (8.1 mL, 70
mmol) was added dropwise to the filtrate, and the resulting
solution was left to stir overnight. The reaction mixture was
quenched with water (100 mL) and extracted with ethyl
acetate (2 × 40 mL). The organic extracts were combined,
washed with water (2 × 40 mL) and saturated sodium chloride
solution (2 × 40 mL), and dried (MgSO4). Evaporation under
reduced pressure gave an orange oil (13.8 g). Purification by
column chromatography (light petroleum:ethyl acetate; 1:1)
first gave the title ketone (4) (9.80 g, 63%) as a yellow oil. υmax
(neat): 3359m, 1750s, 1727s, 1655s cm-1. 1H NMR (400 MHz,
CDCl3) δ 1.33 (t, J 7.1 Hz, 3H), 2.46 (s, 3H), 4.31 (qd, J 5.3,
1.8 Hz, 2H), 5.45 (d, J 6.4 Hz, 1H), 7.35 (bd, J 5.5 Hz, 1H),
7.45 (t, J 6.7 Hz, 2H), 7.51-7.55 (m, 1H), 7.85 (d, J 8.3 Hz,
2H). 13C NMR (100 MHz, CDCl3) δ 14.0, 28.1, 62.7, 63.5, 127.3,
128.6, 132.1, 133.3, 166.1, 166.9, 198.6. Mass spectrum (EI):
m/z 249 (M+, 0.2%), 105 (100), 77 (73). Accurate mass
spectrum: m/z 250.1080 ([M + H]+), C13H15NO4 requires
250.1079. Further elution gave ethyl 2-benzoylamino-3-hy-
droxybutanoate (1.67 g, 11%) as a viscous yellow oil which
crystallized on standing. υmax (neat): 3325bs, 1742s, 1644s,
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were determined
using a hot-stage melting point apparatus and are uncorrected.
Infrared spectra were recorded on a FT-IR spectrophotometer
as potassium bromide disks of solids (KBr) or as thin films of
liquids (neat) between sodium chloride plates. Nuclear mag-
netic resonance spectra (1H, 31P, and 13C NMR) were recorded
on either 200, 300, or 400 MHz spectrometers. Electron impact
ionization (EI) spectra (m/z) were recorded on a spectrometer
operating at 200 °C/70 eV. Analytical thin-layer chromatog-
raphy (TLC) was performed on plastic or glass slides coated
with silica gel (Polygram SIL G/UV254). Column chromatog-
raphy was performed using Merck silica gel 60, 0.063-0.200
mm (70-230 mesh). Degassed methanol and benzene (HPLC
grade) were used in all hydrogenation reactions. Catalysts
were used as received from the suppliers; Rh(I)-DuPHOS and
1
1602m cm-1. H NMR (400 MHz, CDCl3) δ 1.23 (d, J 6.5 Hz,
3H), 1.34 (t, J 7.1 Hz, 3H), 4.29-4.34 (m, 3H), 4.89 (dd, J 6.7,
3.2 Hz, 1H), 7.16 (d, J 5.8 Hz, 1H), 7.45-7.50 (m, 2H), 7.55-
7.57 (m, 1H), 7.83-7.86 (m, 2H). 13C NMR (100 MHz, CDCl3)
(21) Kuwano, R.; Okuda, S.; Ito, Y. Tetrahedron Asymmetry 1998,
2773-2775.

Synthesis of N,N′-Protected 2,3-Diaminobutanoic Acids
J . Org. Chem., Vol. 66, No. 12, 2001 4151
δ 14.2, 18.7, 58.9, 62.2, 69.4, 127.3, 128.7, 132.1, 133.2, 168.4,
170.3. Mass spectrum (EI): m/z 251 (M+, 0.5%), 105 (100), 77
(49). Accurate mass spectrum: m/z 314.1400, C13H17NO4
requires 314.1398.
monitored by TLC and was typically complete after 3 h of
continuous irradiation. After removal of solvent under reduced
pressure, 1H NMR spectroscopy revealed the product to be pure
Z-enamide isomer (Z-5). To avoid isomerization into the
E-isomer, the Z-isomer was stored at 0 °C.
Eth yl 2-Ben zoyla m in o-3-a m in o-2-bu ten oa te. A solution
of ammonium acetate (25.8 g, 334 mmol) in methanol (60 mL)
was added to the ketone (4) (8.29 g, 33.3 mmol), and the
resulting light yellow solution was stirred overnight at ambient
temperature. The reaction mixture was quenched with satu-
rated sodium bicarbonate solution (100 mL), and the methanol
was evaporated under reduced pressure. The mixture was
extracted with dichloromethane (2 × 50 mL), and the combined
organic extract was washed with saturated sodium chloride
solution (2 × 40 mL) and dried (Na2SO4). Evaporation under
reduced pressure gave the title enamine (6.68 g, 81%) as a
pale yellow solid. Spectroscopic analysis showed that the
enamine did not require purification. υmax (KBr): 3428s,
Hyd r ogen a tion Stu d y
Gen er a l Hyd r ogen a tion P r oced u r e. In
a drybox, a
Fisher-Porter tube was charged with catalyst (1 mg), deoxy-
genated solvent (∼5 mL), and substrate (50-200 mg). Three
vacuum/N2 cycles to purge the gas line of any oxygen followed
by three vacuum/N2 cycles of the vessel were carried out before
the tube was pressurized with hydrogen to the required
pressure (psi). The reaction was then stirred at room temper-
ature for the specified period of time. The pressure in the vessel
was then released, and the contents were evaporated to
dryness under reduced pressure. The crude product (6) was
passed through a short plug of silica prior to spectroscopic and
chromatographic analysis. Hydrogenation experiments are
described using the following format: substrate, solvent,
catalyst, hydrogen pressure, reaction time, isolated yield,
enantiomeric excess (assigned configuration), retention time
(HPLC conditions) (See also Table 1).
1736m, 1642s cm-1 1H NMR (400 MHz, CDCl3) δ 1.22 (t, J
.
7.1 Hz, 3H), 2.01 (s, 3H), 4.13 (q, J 7.1 Hz, 2H), 7.02 (s, 1H),
7.47 (t, 7.3 Hz, 2H), 7.50-7.53 (m, 1H), 7.84 (d, J 7.0 Hz, 2H):
NH2 protons were not observed. 13C NMR (100 MHz, CDCl3)
δ 14.5, 19.6, 59.5, 93.8, 127.2, 128.6, 131.4, 135.1, 159.3, 167.6,
167.7. Mass spectrum (EI): m/z 248 (M+, 35%), 105 (100).
(2S,3R)-Eth yl 2-Ben zoylam in o-3-acetylam in obu tan oate
(6d ). [(2E)-Ethyl 2-benzoylamino-3-acetylamino-2-butenoate
(E-5), benzene, [(COD)Rh(I)((S,S)-Me-DuPHOS)]OTf, 90 psi
H2, 64 h; 97% yield, >98% ee (2S,3R-6d ), tR ) 6.8 min
(Chiralcel OJ , ambient temperature, flow rate ) 1.0 mL/min,
detection at 250 nm, eluent ) 20% IPA:80% hexane)].
Eth yl 2-Ben zoyla m in o-3-a cetyla m in o-2-bu ten oa te (5).
Acetyl chloride (0.32 mL, 4.4 mmol) was added dropwise to a
stirred and ice-cooled solution of the enamine (1.00 g, 4.03
mmol) and pyridine (0.36 mL, 4.43 mmol) in dichloromethane
(14 mL) and diethyl ether (7 mL). Once addition of acetyl
chloride was complete, the reaction mixture was left to stir
overnight at ambient temperature and then quenched with
water (50 mL) and extracted with dichloromethane (2 × 20
mL). The organic extracts were combined, washed with 2 M
sulfuric acid (2 × 20 mL) and saturated sodium chloride
solution (2 × 30 mL), dried (Na2SO4), and evaporated under
reduced pressure to give a viscous orange oil (1.25 g). Purifica-
tion by column chromatography (light petroleum:ethyl acetate;
2:1) first gave the E-butenoate (E-5) (0.504 g, 43%) as a
colorless solid, mp 148-151 °C. υmax (KBr): 3300s, 3200s,
6d : Colorless solid, mp 102-103 °C: [R]25 +41.4° (c 1.6,
D
CHCl3). υmax (KBr): 3422s, 3297s, 1736m, 1686w, 1654s, 1696s
cm-1 1H NMR (400 MHz, CDCl3): δ 1.28 (d, J 6.7 Hz, 3H),
.
1.29 (t, J 7.2 Hz, 3H), 1.91 (s, 3H), 4.22 (q, J 7.2 Hz, 2H), 4.49
(p, J 7.0 Hz, 1H, H3), 4.65 (t, J 7.5 Hz, 1H), 6.44 (bd, J 7.0
Hz, 1H), 7.36-7.51 (m, J 7.1 Hz, 3H), 7.72 (d, J 7.5 Hz, 1H),
7.83 (d, J 6.6 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 14.1,
18.0, 23.2, 47.8, 58.4, 61.9, 127.0, 128.5, 132.0, 133.5, 167.7,
170.5, 171.0. Mass spectrum (ESI+, MeOH): m/z 315.1 ([M +
Na]+), 293.1 ([M + H] +). Microanalysis: Found, C 61.57%, H
6.88%, N 9.63%. C15H20N2O4 requires C 61.61%, H 6.90%, N
9.59%.
1
1720s, 1672s, 1648s, 1615s cm-1. H NMR (400 MHz, CDCl3)
δ 1.25 (t, J 7.1 Hz, 3H), 2.17 (s, 3H), 2.46 (s, 3H), 4.20 (q, J
7.1 Hz, 2H), 7.19 (s, 1H), 7.46-7.49 (m, 2H), 7.53-7.57 (m,
1H), 7.84-7.87 (m, 2H), 11.54 (s, 1H). 13C NMR (100 MHz,
CDCl3) δ 14.2, 16.8, 25.6, 61.1, 104.5, 127.2, 128.7, 131.9, 134.1,
153.9, 167.2, 167.23, 169.2. Mass spectrum (EI): m/z 290 (M+,
3%), 105 (100). Microanalysis: Found; C 61.92%, H 6.44%, N
9.39%. C15H18N2O4 requires C 62.06%, H 6.26%, N 9.66%.
Further elution gave the Z-butenoate (Z-5) (0.174 g, 15%) as
a colorless solid, mp 76-78 °C. υmax (KBr): 3297s, 1734s,
(2R,3S)-Eth yl 2-Ben zoylam in o-3-acetylam in obu tan oate
(6c). [(2E)-Ethyl 2-benzoylamino-3-acetylamino-2-butenoate
(E-5), benzene, [(COD)Rh(I)((R,R)-Me-DuPHOS)]OTf, 90 psi
H2, 64 h; 95% yield, >98% ee (2R,3S-6c), tR ) 4.8 min
(Chiralcel OJ , ambient temperature, flow rate ) 1.0 mL/min,
detection at 250 nm, eluent ) 20% IPA:80% hexane)].
6c: Colorless solid, mp 102-103 °C: [R]25 -41.4° (c 1.7,
D
CHCl3). Accurate mass spectrum (ESI+, MeOH): m/z 315.1311
1
1703s, 1635s, 1578s cm-1. H NMR (400 MHz, CDCl3) δ 1.25
([M + Na]+), C15H20N2O4Na requires 315.1314.
(t, J 7.1 Hz, 3H), 2.13 (s, 3H), 2.30 (s, 3H), 4.23 (q, J 7.1 Hz,
2H), 7.46-7.50 (m, 2H), 7.54-7.58 (m, 1H), 7.88 (dd, J 7.1,
1.4 Hz, 2H), 8.67 (s, 1H), 8.89 (s, 1H). 13C NMR (100 MHz,
CDCl3) δ 14.2, 18.5, 24.1, 61.4, 116.4, 127.4, 128.8, 132.1, 132.4,
135.6, 165.0, 166.5, 169.3. Mass spectrum (EI): m/z 290 (M+,
2%), 105 (100), 77 (62), 51. Microanalysis: Found; C 62.18%,
H 6.07%, N 9.56%. C15H18N2O4 requires C 62.06%, H 6.26%,
N 9.66%.
(2S,3S)-Eth yl 2-Ben zoylam in o-3-acetylam in obu tan oate
(6a ). [(2Z)-Ethyl 2-benzoylamino-3-acetylamino-2-butenoate
(Z-5), benzene, [(COD)Rh(I)((S,S)-Me-BPE)]OTf, 90 psi H2, 96
h; 100% yield, 80% ee (2S,3S-6a ), tR ) 16.1 min (Chiralcel AS,
ambient temperature, flow rate ) 1.0 mL/min, detection at
250 nm, eluent ) 10% IPA:90% hexane)].
6a : Colorless solid, mp 134-135 °C: [R]25 +10.8° (c 3.6,
D
CHCl3). υmax (KBr): 3422s, 3297s, 1736m, 1654s, 1696s cm-1
.
1H NMR (400 MHz, CDCl3): δ 1.25 (d, J 6.9 Hz, 3H), 1.31 (t,
J 7.1 Hz, 3H), 2.01 (s, 3H), 4.26 (qd, J 7.1, 2.5 Hz, 2H), 4.51
(pd, J 7.1, 2.5 Hz, 1H), 4.75 (dd, J 6.4, 2.5 Hz, 1H), 6.82 (d, J
7.0 Hz, 1H), 7.46 (t, J 7.1 Hz, 2H), 7.53 (t, J 7.3 Hz, 1H), 7.82
(d, J 6.1 Hz, 1H), 7.86 (d, J 7.0 Hz, 2H). 13C NMR (100 MHz,
CDCl3): δ 14.1,16.5, 23.2, 48.4, 58.3, 62.0, 127.2, 128.7, 132.0,
133.2, 168.0, 170.0, 171.0. Mass spectrum (ESI+, MeOH): m/z
315.2 ([M + Na]+), 293.1 ([M + H] +). Microanalysis: Found,
C 61.58%, H 7.09%, N 9.43%. C15H20N2O4 requires C 61.61%,
H 6.90%, N 9.59%.
(2R,3R)-Eth yl 2-Ben zoylam in o-3-acetylam in obu tan oate
(6b). [(2Z)-Ethyl 2-benzoylamino-3-acetylamino-2-butenoate
(Z-5), benzene, [(COD)Rh((R,R)-Me-BPE)]OTf, 90 psi H2, 96
h; 100% yield, 80% ee (2R,3R-6b), tR ) 23.1 min (Chiralcel
AS, ambient temperature, flow rate ) 1.0 mL/min, detection
at 250 nm, eluent ) 10% IPA:90% hexane)].
Isom er ization of Eth yl 2-Ben zoylam in o-3-acetylam in o-
2-bu ten oa te (5). For the isomerization of Z-enamide into
E-enamide, an E/ Z-mixture of ethyl 2-benzoylamino-3-acetyl-
amino-2-butenoate (5) (1-2 g) was dissolved in dichlo-
romethane or toluene (100-150 mL) and heated at reflux until
TLC showed the disappearance of the Z-isomer. After removal
of the solvent under reduced pressure, H NMR spectroscopy
revealed the product to be 100% E-isomer (E-5). The E-isomer
is stable at room temperature.
1
For the isomerization of E-enamide into Z-enamide, an E/ Z-
mixture of ethyl 2-benzoylamino-3-acetylamino-2-butenoate (5)
(0.5-1 g) was dissolved in toluene (150 mL) and irradiated
with ultraviolet light in a Hanovia photochemical reactor
operating at 125 W using a medium-pressure mercury arc
lamp. An internal condenser was used to maintain the reaction
temperature between 10 and 20 °C. The isomerization was

4152 J . Org. Chem., Vol. 66, No. 12, 2001
Robinson et al.
6b: Colorless solid, mp 134-135 °C: [R]25 -10.8° (c 2.5,
Note Ad d ed a fter ASAP P ostin g. The version of this
paper posted on J anuary 16, 2001, had incorrect author
attributions and was withdrawn from the Web on J anu-
ary 31, 2001. The version with full authorship and
affiliations was posted on May 22, 2001.
D
CHCl3). Accurate mass spectrum (ESI+, MeOH): m/z 315.1311
([M + Na]+), C15H20N2O4Na requires 315.1321.
Ack n ow led gm en t. We would like to thank the
Australian Research Council for their financial support
of this research.
J O001152F