Highly enantioselective synthesis of α,β-diaminopropanoic acid derivatives using a catalytic asymmetric hydrogenation approach

Article abstract of DOI:10.1021/jo001151n

Rh-DuPhos-catalyzed asymmetric hydrogenation of α,β-diamidoacrylates provides a highly efficient and enantioselective route to chiral α,β-diaminopropanoic acid derivatives. The mechanistic course of the hydrogenation was studied using isotopically enriched enamide complexes and phosphorus and carbon NMR. Addition of methyl α-N-benzoyl-β-N-acetyl-diaminopropenoate to the solvated catalyst gave a single 1:1 enamide complex and demonstrated the binding of the olefin and α-amide carbonyl group; the carboxylate and β-N-acyl groups did not bind to the metal. Changes to the electronic and steric properties of the β-N-acyl group were well tolerated; however, small changes to the binding α-N-acyl group were found to significantly affect hydrogenation yields.

Full text of DOI:10.1021/jo001151n

J . Org. Chem. 2001, 66, 4141-4147
4141
High ly En a n tioselective Syn th esis of r,â-Dia m in op r op a n oic Acid
Der iva tives Usin g a Ca ta lytic Asym m etr ic Hyd r ogen a tion
Ap p r oa ch
Andrea J . Robinson* and Chin Yu Lim
School of Chemistry, Monash University, Clayton, Victoria 3800, Australia
Linnan He, Philip Ma, and Hui-Yin Li*,†
DuPont Pharmaceuticals Company, Chemical Process R&D, Experimental Station,
Wilmington, Delaware 19880-0336
A.Robinson@sci.monash.edu.au
Received J uly 28, 2000
Rh-DuPhos-catalyzed asymmetric hydrogenation of R,â-diamidoacrylates provides a highly efficient
and enantioselective route to chiral R,â-diaminopropanoic acid derivatives. The mechanistic course
of the hydrogenation was studied using isotopically enriched enamide complexes and phosphorus
and carbon NMR. Addition of methyl R-N-benzoyl-â-N-acetyl-diaminopropenoate to the solvated
catalyst gave a single 1:1 enamide complex and demonstrated the binding of the olefin and R-amide
carbonyl group; the carboxylate and â-N-acyl groups did not bind to the metal. Changes to the
electronic and steric properties of the â-N-acyl group were well tolerated; however, small changes
to the binding R-N-acyl group were found to significantly affect hydrogenation yields.
Sch em e 1
In tr od u ction
The recent development of several Rh-bisphosphine
catalysts has significantly expanded the synthetic utility
of asymmetric hydrogenation.1 For example, highly ef-
ficient and selective routes to chiral alcohols,2 amines,3
and R-amino acids4 have been accomplished through
hydrogenation of enol acetates, N-acylhydrazones, and
N-acylamino acrylates. We were interested in applying
this methodology to the synthesis of R,â-diaminoprop-
anoates (1) (DAP). This diamine is a structural compo-
nent of several natural products, such as bleomycin,5
sulfazecin,6 and capreomycin7 and can be used in the
construction of azetidinones,8 protease inhibitors,9 and
peptides.10 Existing routes to this molecule utilize R-ami-
no acid starting materials. For example, Mitsunobu
reactions on serine,11 Hofmann and Curtius rearrange-
ments of asparagine derivatives,12 and Schmidt reactions
of aspartic acid13 have all been used to access chiral R,â-
diaminopropanoic acid. Many of these routes, however,
are marred by poor yields and/or protecting group
sensitivity. We believed that a catalytic asymmetric
hydrogenation approach to DAP would provide an ef-
ficient route to R,â-diaminopropanoates and also allow
equal access to the orthogonally N-protected (S)- and (R)-
isomers (Scheme 1).
Resu lts a n d Discu ssion
Syn th esis of th e Hyd r ogen a tion Su bstr a tes. The
required R,â-diamidopropenoate substrates were readily
synthesized in three steps from N-acyl-protected glycine
(2) (Scheme 2). Hence, condensation of hippuric acid (2,
R′ ) Ph) with dimethylformamide dimethylacetal first
gave â-N,N-(dimethylamino)-R,â-dehydroamino acid meth-
yl ester (3) in 75% yield.14 N-Benzoylglycine methyl ester
was an isolated byproduct of this reaction and was easily
separated from the required enamine (3) via trituration.
The use of diethylformamide diethylacetal similarly
afforded the ethyl ester derivative in 68% yield. Under
mild amination conditions, the primary enamines (4)
were prepared in excellent yield by treatment of the
* To whom correspondence should be addressed.
† Email: Hui-Yin.Li@dupontpharma.com.
(1) (a) BPE/DuPHOS: Burk, M. J .; Feaster, J . E.; Harlow, R. L.
Tetrahedron: Asymmetry 1991, 2, 569-592. (b) PennPhos: Qiong-
zhong, J .; J iang, Y.; Xiao, D.; Cao, P.; Zhang, X. Angew. Chem., Int.
Ed. 1998, 37, 1100-1103. (c) BICP: Zhu, G.; Cao, P.; J iang, Q.; Zhang,
X. J . Am. Chem. Soc. 1997, 119, 1799-1800.
(2) Burk, M. J . J . Am. Chem. Soc. 1991, 113, 8518-8519.
(3) Burk, M. J .; Feaster, J . E. J . Am. Chem. Soc. 1992, 114, 6266-
6267.
(4) Burk, M. J .; Feaster, J . E.; Nugent, W. A.; Harlow, R. L. J . Am.
Chem. Soc. 1993, 115, 10125-10138.
(5) Umezawa, H. Bleomycin: Current Status and New Developments;
Academic Press: New York, 1978.
(6) Imada, A.; Kitanc, K.; Kintaka, K.; Murol, M.; Asai, M. Nature
1981, 289, 590-591.
(12) (a) Otsuka, M.; Kittaka, A.; Iimori, T.; Yamashita, H.; Koba-
yashi, S.; Ohno, M. Chem. Pharm. Bull. 1985, 33, 509-514. (b) Rich,
D. H.; J asensky, R. D.; J ueller, G. C.; Anderson, K. E. J . Med. Chem.
1981, 24, 567-572. (c) Rudinger, J .; Poduska, K.; Zaoral, M. Collect.
Czech. Chem. Commun. 1960, 25, 2022.
(13) Kitagawa, T.; Ozasa, T.; Taniyama, H. Yakugaku Zasshi 1969,
89, 285.
(7) Wang, M.; Gould, S. J . J . Org. Chem. 1993, 58, 5176-5180.
(8) (a) van der Steen, F. H.; Koten, G. V. Tetrahedron 1991, 47, 7503.
(b) Murayama, T.; Kobayashi, T.; Miura, T. Tetrahedron Lett. 1995,
36, 3703-3706.
(9) Schirlin, D.; Altenburger, J .-M. Synthesis 1995, 1351-1352.
(10) Choi, D.; Kohn, H. Tetrahedron Lett 1995, 36 (41), 7371-7374.
(11) Golding, B. T.; Howes, C. J . Chem. Res., Synop. 1984, 1.
(14) Svete, J .; Stanovnik, B.; Tisler, M.; Golic, L.; Leban, I. J .
Heterocycl. Chem. 1989, 26, 145-153.
10.1021/jo001151n CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/13/2001

4142 J . Org. Chem., Vol. 66, No. 12, 2001
Ta ble 1. Rh -Ca ta lyzed Asym m etr ic Hyd r ogen a tion of r,â-Dia m id op r op en oa tes
Robinson et al.
absolute
configuration
entry
substratea
R′
R′′
catalyst
solvent
% yieldb (6)
% ee
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
3
4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
-
-
-
R,R-Et-DuPhos
R,R-Et-DuPhos
R,R-Et-DuPhos
R-(+)-BiNAP
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
THF
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
0
-
-
-
-
-
99
99
-
-
-
-
-
-
R
S
0
4‚HCl
0c
5a
5a
5a
5a
5
5
5
5
5
5
5
5
5
5
5
5
5
Me
Me
Me
Me
Ph
Ph
5
5
(+)-DIOP
R,R-Et-DuPhos
S,S-Et-DuPhos
S,S-Et-DuPhos
S,S-Et-DuPhos
R,R-Et-DuPhos
S,S-Et-DuPhos
S,S-Et-DuPhos
R,R-Me-DuPhos
R,R-Me-BPE
S,S-Et-DuPhos
R,R-Me-DuPhos
S,S-Me-DuPhos
R,R-Et-DuPhos
S,S-Et-DuPhos
R,R-Et-DuPhos
S,S-Et-DuPhos
100
100
0
100
100
100
50
-
-
-
OC(CH3)3
OC(CH3)3
OCH2Ph
OCH2Ph
OCH2Ph
OCH2CHdCH2
OCH2Fm
OCH2Fm
OCH2Fm
OCH2Fm
OCH2Ph
Me
95
95
-
79
78
-
88
88
92
91
-
Rf
Sf
-
100
100
0d
Rg
Rg
-
90e
98
Rg
Sg
Rg
Sg
-
100
98
20
OC(CH3)3
pNO2Ph
5
50-75
95
-
a
All hydrogenation substrates are methyl esters. Reactions were conducted at room temperature under an atmosphere of hydrogen
(60-90 psi) for 15-60 h. Isolated yields. c N-Benzoylalanine isolated (55% yield) with starting enamide. Allyl carbamate protecting
b
d
group was unstable under the hydrogenation conditions. e Dibenzofulvene identified as a reaction byproduct. f Assigned by HPLC analysis
g
and comparison to an authentic sample of the product obtained from Hofmann rearrangement of L-asparagine. Assigned by HPLC
analysis after conversion of product to 6a .
Sch em e 2a
and would also allow UV-chromatographic monitoring of
reaction progress.
Hyd r ogen a tion Stu d y. To effect the hydrogenation
of our prepared R,â-diamidopropenoates (5) we required
a catalyst that operated under mild experimental condi-
tions. The Rh-DuPhos catalysts, developed by Burk and
co-workers,1a were chosen to achieve this end, since these
catalysts facilitate highly selective hydrogenation of
related R-enamides,4 operate at low temperatures and
hydrogen pressures and are commercially available.
Attempted hydrogenation of N,N-dimethylenamine (3)
and enamine (4) (entries 1 and 2, respectively) was
unsuccessful, and only starting material was recovered
(Table 1). This emphasizes the need to redirect electron
density away from the CdC being reduced; acylation of
the â-amino group therefore potentially serves two
ends: it renders the olefin electron-poor and serves as a
chelation site during hydrogenation. Interestingly, at-
tempted hydrogenation of the hydrochloride salt of 4
(entry 3) resulted in deamination to give N-benzoylala-
nine. The enantiomeric excess of this reaction was not
assessed.
a
Conditions: (a) DMFDMA or DMFDEA, PhCH3, reflux; (b)
NH4OAc, MeOH, rt; (c) R′′COCl or (R′′CO)2O, base, CH2Cl2/Et2O.
acrylates (3) with excess ammonium acetate in methanol.
Subsequent acylation of enamines (4) then gave the
required hydrogenation substrates (5). In each case, only
the E-isomer was isolated from the reaction mixture.
Intramolecular hydrogen-bonding between the â-amide
hydrogen and ester carbonyl group was evident in the
1H NMR spectra of the enamides (5) where a significant
downfield shift of the â-amide proton (δ 10-11) was
observed. The R-N-benzoyl-â-N-acetyl-protected propen-
oate (5a ) was chosen as our initial hydrogenation sub-
strate, since both amine protecting groups were expected
to be stable under the planned experimental conditions
Introduction of a second N-acyl group into the hydro-
genation substrate provides two potential rhodium-
chelation sites during reduction. Concern about whether
these would behave in a matched or mismatched manner,
however, was unwarranted. Et-DuPhos-Rh(I)-catalyzed
hydrogenation of enamide (5a ) (entries 6 and 7) in
methanol under mild reaction conditions (60 psi H2
pressure, room temperature) gave quantitative yields of

Synthesis of R,â-Diaminopropanoic Acid Derivatives
J . Org. Chem., Vol. 66, No. 12, 2001 4143
enamide esters could also be reduced with a similarly
high enantiomeric excess of 95% (entries 10 and 11). To
achieve complete reduction of â-N-Cbz-protected enam-
ides, longer reaction times and less sterically demanding
Me-DuPhos and Me-BPE phosphine ligands were em-
ployed (entries 12 and 14). Fmoc-protected enamide
esters also underwent quantitative hydrogenation at 60
psi H2 pressure over 48 h. The Et-DuPhos ligands
resulted in slightly higher enantioselectivity (91-92% ee)
compared with the Me-Duphos ligands (88% ee) (entries
16-19). Surprisingly, partial cleavage of the fluorenyl-
methyl carbamate group was observed in one reaction
(entry 16) and this accounts for the lower than expected
yield of diamidopropanoate (6). The allyl carbamate
protecting group was found to be reactive under the
hydrogenation conditions employed. Hydrogenation of the
allyl group competed with enamide reduction to give a
mixture of â-N-ethyloxycarbonylaminopropenoate (5) and
â-N-ethyloxycarbonylaminopropanoate (6) (entry 15).
R,â-Benzoylamino acrylate (5) (entry 8) failed to undergo
hydrogenation with Rh-Et-DuPhos in methanol due to
poor solubility. The expected diaminopropanoate (6) was
obtained in excellent yield, however, using THF as the
reaction solvent (entry 9).
The above study shows that the Rh-DuPhos catalyst
can accommodate an increase in heteroatom substitution
on the acrylate system provided that each amino group
is first derivatized as its amide or carbamate. Impor-
tantly, the catalyst also tolerates changes to the electronic
and steric properties of the â-N-acylamino protecting
group and would therefore allow initial protection of this
site with a group that would remain in the final target
molecule. Despite this flexibility at the â-position, in our
study so far we had examined only R-N-benzoyl-protected
substrates. Although we found that this group could be
removed without epimerization, strongly acidic conditions
are required to achieve this end. To lend flexibility to the
synthesis we turned our focus to the preparation and
hydrogenation of R-N-carbamate-protected substrates to
enable mild deprotection conditions to be employed.
Synthesis of the required R-N-carbamate-protected ena-
mide hydrogenation substrates, however, was hampered
by very low yielding condensation reactions (<10%)
between DMFDMA and R-N-Boc- and R-N-Cbz-protected
glycines. Furthermore, all intermediates leading to the
hydrogenation substrates bearing R-carbamate groups
were unstable and difficult to handle. An alternative
route to R-N-Boc-protected enamide esters (5) was even-
tually accomplished via a transprotection reaction de-
veloped by Burk and co-workers.16 For example, selective
transamidation of the R-benzoyl group of propenoate (5a )
was achieved via reaction with di-tert-butyl dicarbonate
followed by treatment with hydrazine hydrate. This
strategy was not successful, however, in preparing the
corresponding R-N-Cbz derivatives.
F igu r e 1. Chromatograms showing the separation of R- and
S-R,â-diamidopropanoate (6a ) using a chiral Daicel OJ HPLC
column: (A) racemic 6a generated by Pd/C-catalyzed hydro-
genation of 5a ; (B) (S)-6a generated from L-asparagine; (C)
crude product from [S,S]-Et-DuPhos-Rh(I)-catalyzed hydrogen-
ation, 99% ee; and (D) crude product from [R,R]-Et-DuPhos-
Rh(I)-catalyzed hydrogenation, 99% ee.
chiral diaminopropanoate (6a ) in 99% ee.15 Enantiomeric
excess was determined by chiral HPLC and assignment
of absolute configuration was facilitated through com-
parison of the reaction product with an authentic sample
of (S)-6a obtained via Hofmann rearrangement of
L-asparagine. Hydrogenation with the [R,R]-Et-DuPhos
ligand afforded R-configured diaminopropanoate (6a ); use
of the antipode, [S,S]-Et-DuPhos, gave the enantiomeric
S-isomer (Figure 1). Hydrogenation of (5a ) with Rh-
DIOP and Rh-BINAP catalysts under analogous reac-
tion conditions resulted in only poor conversion (<5%)
(entries 4 and 5). â-N-Carbamate-protected enamides also
underwent quantitative and highly enantioselective re-
duction. Our studies showed that â-N-Boc-protected
Hydrogenation of R-N-Boc-protected enamides proved
to be very difficult. For example, hydrogenation of
propenoate (5, R ) Me, R′ ) OtBu, R′′ ) OCH2Ph) (entry
20) with Rh(I)-Et-DuPhos gave only a 20% conversion
to the corresponding propanoate (6) after 15 h at elevated
hydrogen pressure (90 psi). This result was surprising
since related N-Cbz-protected enamide esters are re-
ported to undergo smooth and highly enantioselective
reduction with the Rh(I)-DuPhos catalyst.4 In conclu-
(15) Li, H.-Y.; Robinson, A. J . Book of Abstracts; 216th ACS National
Meeting, Boston; American Chemical Society: Washington, D. C, 1998.
(16) Burk, M. J .; Allen J . G. J . Org. Chem. 1997, 62, 7054-7057.

4144 J . Org. Chem., Vol. 66, No. 12, 2001
Robinson et al.
sion, the catalyst is considerably more sensitive to steric
encumberment at the R-position of the enamide than at
the â-position. This finding not only accounts for the
prevalent use of N-acetyl-protected enamides in this field
but also suggests that hydrogenation of the R,â-diami-
dopropenoate system is controlled via coordination through
the R-N-acylamino group.
Mech a n istic Stu d y. The origin of the high enanti-
oselection in the above hydrogenations merited further
investigation. On the basis of literature precedent, we
expected the formation of diastereromeric complexes
upon chelation of the enamide substrate to the catalyst
through normal symmetrical (µ2) coordination of the
CdC bond in addition to the oxygen atom of the amide
carbonyl group.17 Hence, four diastereomeric enamide-
RhDuPhos complexes could be involved in the above
transformations: The olefin can interact with either the
re or si faces and coordinate through the R- or â-amide
group. Due to the excellent selectivity demonstrated in
the above hydrogenations, we believed that one diaster-
eomer was playing a major role in the reduction. To
investigate this postulate we synthesized 13C-enriched
analogues of the hydrogenation substrate (5a ),
R-N-[13CO]-benzoylamino enamide (7a ), and â-N-[13CO]-
acetylamino enamide (7b), via the synthetic pathway
shown in Scheme 2.
The 31P NMR spectrum of the commercially available
[(COD)Rh(DuPhos)]OTf catalyst in d4 methanol at room
temperature displayed a doublet at δ70.9 (J 148 (Rh-P))
(Figure 2). Hydrogenative removal of the COD ligand
over 30-60 min at 90 psi H2 generated the mononuclear
[Rh(DuPhos)(CD3OD)2]OTf species and resulted in a
downfield shift of the phosphine doublet to δ 95.4 (J 205
(Rh-P)). Significantly, after addition of an equimolar
amount of R-N-[13CO]-benzoylamino enamide (7a ) to the
solvated catalyst at room temperature the NMR spec-
trum showed only one diastereomeric complex. Upon
formation of the complex, the two phosphorus nuclei
become inequivalent and two signals were observed at δ
88.8 (dd, J 166 (Rh-PA), 34 (PA-PB)) and δ 82.5 (ddd, J
154 (Rh-PB), 34 (PA-PB), 4 (PB-13C)). The additional
splitting in the highfield signal suggested that the
observed complex was arising through chelation of the
R-amide carbonyl group.
F igu r e 2. Hydrogenation sequence for Rh-DuPhos-catalyzed
hydrogenation of R,â-diamidopropenoate (7a ): 31P NMR spec-
tra of (A) [(COD)Rh(1,2-bis((2R,5R)-2,5-diethylphospholano)-
benzene)]OTf in methanol-d4; (B) methanol complex after
exposure to hydrogen atmosphere; and (C) stable intermediate
after the addition of 13C-labeled enamide substrate (7a ).
This mode of chelation was further supported by the
13C NMR spectrum of the diastereomeric complex. Un-
equivocal 13C-assignment of the three carbonyl groups in
the hydrogenation substrate was performed prior to the
binding studies, and upon chelation to the rhodium
cation, only the R-amido carbonyl signal was affected with
a downfield shift from δ 169 to δ 182. This signal was
also split into a doublet (J ) 4 (13C-PB). The ester and
â-acetyl groups on the other hand remained relatively
uneffected by chelation (δ 167 f 168, 171.2 f 171.4,
respectively) (Figure 3). 13C and 31P NMR binding studies
with the â-N-[13CO]-acetylamino enamide (7b) and sol-
vated catalyst gave analogous spectra, now without the
long range 13C-31P coupling between the highfield phos-
phorus nucleus and R-amide carbonyl. The importance
of this chelation in the above hydrogenations was evident
from studies performed on an R-p-nitrobenzoylamino
F igu r e 3. Carbonyl region of 13C NMR spectra of carbon-13
enriched enamide in methanol-d4: (A) unlabeled enamide (5a );
(B) complex of 7a with Rh-DuPhos catalyst; and (C) complex
of 7b with Rh-DuPhos catalyst.
derivative of 5a . Under identical and more forceful
experimental conditions, this substrate failed to reduce
to completion and gave only a 50-75% yield of the R,â-
diamidopropanoate (entry 21, Table 1). The electron-
(17) (a) Brown, J . M.; Chaloner, P. A. J . Am. Chem. Soc. 1980, 102,
3040-3048. (b) Brown, J . M.; Maddox, P. J . Chirality 1991, 3, 345. (c)
Halpern, J .; Riley, D. P.; Chan, A. S. C.; Pluth, J . J . J . Am. Chem.
Soc. 1977, 99, 8056 and references therein.

Synthesis of R,â-Diaminopropanoic Acid Derivatives
J . Org. Chem., Vol. 66, No. 12, 2001 4145
0.200 mm (70-230 mesh). Degassed methanol (HPLC grade)
was used in all hydrogenation reactions.
withdrawing effect of the nitro group not only affected
chemical yield but also reduced enantioselectivity which
dropped to 95% ee. From these studies, strong support
for the coordinative involvement of the R-amido group
has been obtained, and since hydrogenation with the
[R,R]-DuPhos-Rh catalyst leads to (R)-configured prod-
ucts, coordination of the R-si-face of the enamide sub-
strate must also occur during reduction. On the basis of
molecular models and previous mechanistic studies,18 it
appears that the observed diastereomeric Rh-enamide
complex does not correspond to the chirality of the
product. Hence, hydrogenation must therefore be pro-
ceeding in an analogous fashion to that of bis(diarylphos-
phino)alkane-catalyzed hydrogenations of R-(acetamido)-
cinnamates where the major enantiomeric product is
produced from the less stable, minor diastereomeric
complex.17
DMFDMA refers to N,N-dimethylformamide dimethyl acetal
and was used as supplied. Carbon-13-labeled Ba13CO3 (90%)
was used to prepare benzoyl-carbonyl-13C-chloride21 for the
synthesis of N-benzoyl-carbonyl-13C-glycine.22 Acetyl-1-13C chlo-
ride was distilled prior to use. Deuterated methanol was used
as supplied and degassed via three freeze-thaw cycles on a
high vacuum line prior to NMR studies. All hydrogenation
catalysts were used as received from the suppliers. In all Rh-
phosphine hydrogenations, high purity (<10 ppm) hydrogen
and nitrogen were used and purified by passage through water,
oxygen, and hydrocarbon traps. The enantiomeric excess of the
hydrogenation products was determined via chiral HPLC
analysis using a Diacel Chiracel OJ column. For the NMR-
hydrogenation studies, all procedures were performed under
a dry and inert atmosphere of nitrogen using modified Schlenk
techniques.
P r ep a r a tion of Hyd r ogen a tion Su bstr a tes
Meth yl 2-N-Ben zoyla m in o-3-a m in o-2-p r op en oa te (4, R
) Me, R′ ) P h ). Ammonium acetate (6.92 g, 89.8 mmol) was
added to a solution of the tertiary amine (3, R ) Me, R′ ) Ph)
(2.22 g, 8.93 mmol) in ethanol (100 mL), and the resulting
mixture was stirred overnight at room temperature. The
reaction mixture was then evaporated to dryness under
reduced pressure. The resulting white precipitate was treated
with a 10% sodium bicarbonate solution (100 mL) and diluted
with dichloromethane (80 mL). The phases were separated,
and the aqueous phase was diluted with saturated sodium
chloride solution (50 mL) and further extracted with dichlo-
romethane (2 × 40 mL). The organic extracts were combined,
washed with saturated sodium chloride solution (2 × 50 mL),
dried (MgSO4), and evaporated under reduced pressure to give
the primary enamine (4, R ) Me, R′ ) Ph) as a colorless
precipitate (1.66 g, 84%), mp 148-150 °C. (HRMS: Found:
M + H+, 221.0910. C11H13N2O3 requires 221.0926). νmax
(KBr): 3406s, 1676m, 1655s, 1637s cm-1. 1H NMR (200 MHz,
CDCl3): δ 3.76 (s, 3H), 5.10-5.40 (m, 2H), 7.42-7.54 (m, 4H),
7.80-7.91 (m, 3H). 13C NMR (75 MHz, CDCl3): δ 51.8, 101.1,
127.3, 128.4, 131.8, 134.0, 137.0, 164.7, 166.5. Mass spectrum
(ESI+, MeOH): m/z 243.1 ([M + Na]+); 221.2 ([M + H]+). The
isolated enamine (4) was used without further purification and
stored at 0 °C to avoid decomposition.
Con clu sion s
In summary, Rh(I)-DuPhos-catalyzed hydrogenation
of R,â-diamidopropenoates provides a convenient and
highly enantioselective route to chiral R,â-diaminopro-
panoic acid derivatives. Our studies strongly support the
coordinative involvement of the R-amido group, as in
simpler R-(N-acylamino)acrylate systems, during reduc-
tion. Changes to the electronic and steric properties of
the R-N-acyl group were found to have a profound effect
on hydrogenation yields but were well tolerated at the
â-N-acyl position. We postulate that internal hydrogen
bonding favors coordination through the R-amide group
and renders the â-amide group unsuitably oriented for
interaction with the rhodium cation. In our parallel
studies on the simpler â-amino acid system, E-â-
substituted-â-N-acylaminoacrylates were found to reduce
in quantitative yields and high enantioselectivity with
the Rh-DuPhos system. In the corresponding ·-series,
however, where internal hydrogen bonding is evident, no
reduction is observed under mild operating conditions,
and forcing conditions are required for reduction to the
detriment of enantioselectivity.19 This does not wholly
account for the excellent selectivity described herein since
Rh-DuPhos-catalyzed hydrogenation of R-substituted-
â-N-acylaminoacrylates does not display the same geo-
metric-isomer bias.20 Future work will explore the scope
of Rh-phosphine catalysis to reduce enamides of increas-
ing complexity with a view to â-lactam synthesis.
Meth yl 2-N-[13CO]-Ben zoylam in o-3-am in o-2-pr open oate
(4*, R ) Me, R′ ) P h ). Ammonium acetate (1.44 g, 18.7 mmol)
was added to a solution of methyl 2-N-[13CO]-benzoylamino-
3-N,N-(dimethylamino)-2-propenoate (3) (0.46 g, 1.87 mmol)
in methanol (35 mL), and the mixture was stirred at room
temperature. After 15 h, the solvent was removed under
reduced pressure. The resulting precipitate was treated with
a 10% sodium bicarbonate solution (45 mL), and the mixture
was then extracted into dichloromethane (3 × 10 mL). The
aqueous phase was further diluted with saturated sodium
chloride solution (25 mL) and extracted with dichloromethane
(2 × 25 mL). The combined organic extract was then washed
with saturated sodium chloride solution (35 mL), dried
(MgSO4), and evaporated under reduced pressure to give the
13C-labeled primary enamine (4*, R ) Me, R′ ) Ph) (0.37 g,
89%) as a colorless solid, mp 152-154 °C. νmax (KBr): 3410s,
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
with 200, 300, or 400 MHz spectrometers. Electron impact
ionization (EI) spectra (m/z) were recorded on a mass spec-
trometer operating at 200 °C/70 eV. Analytical thin-layer
chromatography (TLC) was performed on plastic or glass slides
coated with silica gel (Polygram SIL G/UV254). Column chro-
matography was performed using Merck silica gel 60, 0.063-
1676m, 1654m, 1633m cm-1 1H NMR (300 MHz, CDCl3): δ
.
3.78 (s, 3H), 5.10-5.30 (m, 2H), 7.40-7.58 (m, 4H), 7.84-7.91
(m, 3H). 13C NMR (100 MHz, CDCl3): δ 52.3, 127.4 (d, J 16.9
Hz), 128.6 (d, J 21.1 Hz), 131.8, 134.1 (d, J 65.0 Hz), 165.4,
166.5; C2 and C3 were not observed. Mass spectrum (ESI+,
12
MeOH): m/z 244.0763 ([M + Na]+).
C
13C1H12N2O3Na
10
requires 244.0779. The isolated enamine (4*) was used without
further purification and stored at 0 °C to avoid decomposition.
Met h yl 2-N-Ben zoyla m in o-3-N-a cet yla m in o-2-p r op -
en oa te (5a , R ) Me, R′ ) P h ). Distilled acetyl chloride (0.20
mL, 2.81 mmol) in dichloromethane (5 mL) was added drop-
(18) Armstrong, S. K.; Brown, J . M.; Burk, M. J . Tetrahedron Lett.
1993, 34, 879-882.
(19) See also: Zhu, G.; Chen, Z.; Zhang, X. J . Org. Chem. 1999, 64,
6907-6910.
(21) Blatt, A. H. Organic Syntheses; Wiley: New York, 1943; Collect.
Vol. II, pp 328-330.
(22) Murray, A.; Williams, D. L. Organic Syntheses with Isotopes:
Part 1; Interscience Publishers: New York, 1958; pp 379-380.
(20) Prosser, A.; Suraweera, R.; Robinson, A. J . Manuscript in
preparation.

4146 J . Org. Chem., Vol. 66, No. 12, 2001
Robinson et al.
wise to a stirred and ice-cooled solution of methyl 2-N-
benzoylamino-3-amino-2-propenoate (4) (0.52 g, 2.34 mmol)
and pyridine (0.23 mL, 2.81 mmol) in dichloromethane (14 mL)
and diethyl ether (7 mL). After complete addition, the reaction
mixture was warmed to room temperature, and reaction
progress was monitored at 30 min intervals by TLC (SiO2,
petroleum ether:ethyl acetate; 1:1). After 1.5 h, TLC showed
the absence of starting primary amine, and the reaction
mixture was quenched with water (10 mL) and extracted with
dichloromethane (2 × 8 mL). The combined organic extract
was washed with saturated sodium chloride solution (5 mL),
dried (MgSO4), and evaporated under reduced pressure to a
yellow solid. Purification by column chromatography (SiO2,
light petroleum:ethyl acetate; 1:1) gave the title enamide as
an off-white solid (0.64 g, 90%), mp 118-120 °C. Microanaly-
sis: Found, C 59.51%, H 5.37%, N 10.68%; C13H14N2O4 requires
reaction mixture was allowed to warm to room temperature,
and reaction progress was monitored at 30 min intervals by
TLC (SiO2, petroleum ether:ethyl acetate; 1:1). After 2.5 h, TLC
showed the absence of starting primary amine (4*), and the
reaction mixture was quenched with water (10 mL) and
extracted with dichloromethane (2 × 8 mL). The combined
organic extract was washed with dilute (2 M) hydrochloric acid
solution (15 mL) and saturated sodium chloride solution (15
mL), dried (MgSO4), and evaporated under reduced pressure
to give the title 13C-labeled enamide (7a ) as a colorless solid
(0.28 g, 73%), mp 117-120 °C. νmax (KBr): 3416s, 1722w,
1696m, 1655s cm-1 1H NMR (300 MHz, CDCl3): δ 2.20 (s,
.
3H, COCH3), 3.84 (s, 3H, COOCH3), 7.51 (t, J 7.5 Hz, 2H, H3′,
5′), 7.60 (t, J 7.2 Hz, 1H, H4′), 7.85-7.90 (m, 3H, H2′, 6′, Cd
CH), 8.44 (s, 1H, Ph13CONH), 10.42 (d, J 9.9 Hz, 1H, NH-
COCH3). 13C NMR (100 MHz, CDCl3): δ 23.8 (COCH3), 52.9
(COOCH3), 108.4 (C2), 122.1 (C3), 127.3 (d, J 2.3 Hz, C3′,5′),
129.0 (d, J 4.24 Hz, C2′,6′), 132.6 (C4′), 133.3 (d, J 66.0 Hz,
C1′), 165.9 (Ph13CO), 166.3 (COOCH3), 167.9 (COCH3). 1H
NMR (300 MHz, CD3OD): δ 2.10 (s, 3H, COCH3), 3.77 (s, 3H,
OCH3), 7.50 (t, J 7.8 Hz, 2H, H3′, 5′), 7.58 (t, J 7.2 Hz, 1H,
H4′), 7.95-8.00 (m, 2H, H2′, 6′), 8.06 (s, 1H, CdCH). 13C NMR
(75 MHz, CD3OD): δ 22.8 (COCH3), 52.6 (OCH3), 109.7 (C2),
128.8 (d, J 2.6 Hz, C3′, 5′), 129.3 (d, J 4.3 Hz, C2′, 6′), 131.4
(C3), 133.0 (C4′), 134.9 (d, J 64.9 Hz, C1′); 167.0 (C1), 169.1
(Ph13CO), 171.2 (COCH3). Mass spectrum (ESI+, MeOH): m/z
286.0884 [(M + Na)+]. 12C1213C1H14N2O4Na requires 286.0885.
Hyd r ogen a tion Stu d y
C 59.54%, H 5.38%, N 10.68%. νmax (KBr): 3449s, 1702m cm-1
.
1H NMR (400 MHz, CDCl3): δ 2.20 (s, 3H, COCH3), 3.85 (s,
3H, COOCH3), 7.50 (t, J 7.8 Hz, 2H, H3′, 5′), 7.59 (t, J 7.5 Hz,
1H, H4′), 7.81-7.89 (m, 3H, H2′, 6′, CdCH), 8.45 (bs, 1H,
NHCOPh), 10.41 (d, J 10.1 Hz, 1H, NHCOCH3). 13C NMR (100
MHz, CDCl3): δ 23.8 (COCH3), 52.9 (OCH3), 108.3 (C2), 122.0
(C3), 127.3 (C3′, 5′), 128.9 (C2′, 6′), 132.5 (C4′), 133.2 (C1′),
165.9 (COPh), 166.2 (C1), 168.0 (COCH3). 1H NMR (300 MHz,
CD3OD): δ 2.10 (s, 3H, COCH3), 3.77 (s, 3H, OCH3), 7.49 (t, J
7.5 Hz, 2H, H3′, 5′), 7.58 (t, J 7.2 Hz, 1H, H4′), 7.96 (d, J 6.8
Hz, 2H, H2′, 6′), 8.06 (s, 1H, CdCH). 13C NMR (75 MHz, CD3-
OD): δ 22.8 (COCH3), 52.6 (OCH3), 109.7 (C2), 128.8 (C3′, 5′),
129.4 (C2′, 6′), 131.4 (C3), 133.0 (C4′), 134.8 (C1′), 167.0 (C1),
169.1 (PhCO), 171.2 (COCH3). Mass spectrum (ESI+,
MeOH): m/z 285.1 ([M + Na]+), 263.1 ([M + H]+).
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 (30-200 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 under
reduced pressure to dryness. 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).
Met h yl 2-N-Ben zoyla m in o-3-N-[13CO]-a cet yla m in o-2-
p r op en oa te (7b, R ) Me, R′ ) P h , R′′ ) Me). Pyridine (0.31
mL, 3.78 mmol) was added to a solution of methyl 2-N-
benzoylamino-3-amino-2-propenoate (4) (0.69 g, 3.15 mmol) in
dichloromethane (14 mL) and diethyl ether (7 mL). The
mixture was cooled to 0 °C, and a solution of acetyl-13C-chloride
(0.25 g, 3.15 mmol) in dichloromethane (2 mL) was then added.
The reaction mixture was allowed to rise to room temperature
over 10 min, and the reaction progress was monitored at 30
min interval by TLC (SiO2, petroleum ether:ethyl acetate; 1:1).
After 3.5 h, TLC showed the absence of starting primary
amine, and the reaction mixture was quenched with water (10
mL) and extracted with dichloromethane (2 × 10 mL). The
combined organic extract was washed with dilute (2 M)
hydrochloric acid (20 mL) and saturated sodium chloride
solution (5 mL), dried (MgSO4), and evaporated under reduced
pressure to give a yellow solid (0.75 g). Purification by column
chromatography (SiO2, light petroleum:ethyl acetate; 1:1) gave
the title 13C-labeled enamide (7b) (0.42 g, 51%) as a fine white
(2S)-Meth yl 2-N-Ben zoyla m in o-3-N-a cetyla m in op r op -
a n oa te. (a) [Methyl 2-N-benzoylamino-3-N-acetylamino-2-
propenoate (110 mg), methanol, [(COD)Rh((S,S)-Et-DuPHOS)]-
OTf, 60 psi H2, 15 h; 100% yield, 99.0% ee (S), t1 ) 7.5 min
(Chiralcel OJ , ambient temperature, flow rate ) 1.0 mL/min,
detection at 250 nm, eluent ) 20% IPA:80% hexane)]. (b)
[Methyl 2-N-benzoylamino-3-N-acetylamino-2-propenoate (50
mg), methanol, [(COD)Rh((S,S)-Me-DuPHOS)]OTf, 60 psi H2,
60 h; 100% yield, 79.9% ee (S), t1 ) 7.5 min].
solid, mp 116-118 °C. νmax (KBr): 3413s, 1686m cm-1 1H
.
NMR (300 MHz, CDCl3): δ 2.24 (d, J 6.3 Hz, 3H, 13COCH3),
3.89 (s, 3H, COOCH3), 7.54 (t, J 7.6 Hz, 2H, H3′, 5′), 7.62 (t,
J 7.3 Hz, 1H, H4′), 7.90-8.00 (m, 3H, H2′, 6′, CdCH), 8.48
(bs, 1H, PhCONH), 10.44-10.52 (m, 1H, NHCOCH3). 13C NMR
(100 MHz, CDCl3): δ 23.8 (d, J 52.8 Hz, 13COCH3), 52.9
(COOCH3), 108.4 (d, J 5.0 Hz, C2), 122.0 (C3), 127.3 (C3′, 5′),
129.0 (C2′, 6′), 132.6 (C4′), 133.3 (C1′), 166.0 (COPh), 166.3
6a (R, R′′ ) Me, R′ ) P h ): Colorless solid: [R]25 -1.30°
D
(c 1.00, MeOH). Microanalysis: Found, C 59.06%, H 5.99%, N
10.60%; C13H16N2O4 requires C 59.08%, H 6.10%, N 10.60%.
νmax (KBr): 3556m, 3478s, 3414s, 1736m, 1650m cm-1 1H
.
NMR (300 MHz, CDCl3): δ 2.00 (s, 3H), 3.75 (t, J 5.7 Hz, 2H),
3.77 (s, 3H), 4.77 (q, J 5.7 Hz, 1H), 6.58 (bs, 1H), 7.43 (t, J 6.9
Hz, 2H), 7.51 (t, J 6.0 Hz, 1H), 7.84 (d, J 7.2 Hz, 2H), 7.90 (d,
J 6.3 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 23.1, 41.6, 52.8,
54.7, 127.1, 128.5, 131.8, 133.0, 167.4, 170.5, 172.2. Mass
spectrum (ESI+, MeOH): m/z 265.1, ([M + H]+), 287.1 ([M +
Na]+). Accurate mass spectrum (ESI+, MeOH): m/z 265.1184
([M + H]+), C13H17N2O4 requires 265.1188.
1
(COOCH3), 167.9 (13COCH3). H NMR (300 MHz, CD3OD): δ
2.10 (d, J 6.6 Hz, 3H, COCH3), 3.76 (s, 3H, OCH3), 7.49 (t, J
7.5 Hz, 2H, H3′, 5′), 7.58 (t, J 7.2 Hz, 1H, H4′), 7.97 (d, J 6.9
Hz, 2H, H2′, 6′), 8.06 (d, J 3.0 Hz, 1H, CdCH). 13C NMR (75
MHz, CD3OD): δ 23.5 (d, J 50.9 Hz, COCH3), 52.6 (OCH3),
109.7 (d, J 4.3 Hz, C2), 128.8 (C3′, 5′), 129.4 (C2′, 6′), 131.4
(C3), 133.0 (C4′), 134.8 (C1′), 167.0 (COOCH3), 169.1 (PhCO),
171.2 (13COCH3). Mass spectrum (ESI+, MeOH): m/z 286.0870
(2R)-Meth yl 2-N-Ben zoyla m in o-3-N-a cetyla m in op r op -
a n oa te. [Methyl 2-N-benzoylamino-3-N-acetylamino-2-prop-
enoate (62 mg), methanol, [(COD)Rh((R,R)-Et-DuPHOS)]OTf,
60 psi H2, 15 h; 100% yield, 99.1% ee (R), t2 ) 6 min (Chiralcel
OJ , ambient temperature, flow rate ) 1.0 mL/min, detection
at 250 nm, eluent ) 20% IPA:80% hexane)].
([M + Na]+).
C
13C1H14N2O4Na requires 286.0885.
12
12
Met h yl 2-N-[13CO]-Ben zoyla m in o-3-N-a cet yla m in o-2-
p r op en oa te (7a , R ) Me, R′ ) P h , R′′ ) Me). Pyridine (0.14
mL, 1.71 mmol) was added to a solution of methyl 2-N-[13CO]-
benzoylamino-3-amino-2-propenoate (4*) (0.31 g, 1.42 mmol)
in dichloromethane (14 mL) and diethyl ether (7 mL). The
mixture was then cooled to 0 °C. Distilled acetyl chloride (0.12
mL, 1.71 mmol) in dichloromethane (5 mL) was added drop-
wise to the reaction mixture. After complete addition, the
6a : Colorless solid: [R]25 +1.32° (c 2.12, MeOH).
D
Mech a n istic Stu d y: 31P a n d 13C NMR Bin d in g Stu d ies
betw een [R,R]-Eth yl-Du P HOS-Rh (I) a n d 13C-La beled
Su bstr a tes (7a a n d 7b)

Synthesis of R,â-Diaminopropanoic Acid Derivatives
J . Org. Chem., Vol. 66, No. 12, 2001 4147
31P NMR of [(1,5-Cycloocta d ien e)Rh (I)(1,2-bis((2R,5R)-
2,5-d ieth ylp h osp h a la n o)ben zen e)] Tr ifla te in CD3OD. In
a drybox, the catalyst [(COD)Rh((R,R)-Et-DuPHOS)]OTf (ca.
3 mg) was dissolved in degassed deuterated methanol to form
a yellow solution. The resulting solution was transferred under
an atmosphere of argon into a 5 mm NMR tube. The tube was
then reversibly sealed with a screw-cap Teflon seal, and 31P
NMR spectra (162 MHz, CD3OD) were recorded at different
temperatures.
substrate: δ 76.6 (d, J 20.1 Hz (Rh-C), C2), 90.6 (d, J 12.1
Hz (Rh-C), C3), 129.7 (d, J 2.3 Hz, C3′, 5′), 130.0 (d, J 4.4
Hz, C2′,6′), 134.8 (C4′), 168.3 (COOCH3), 171.4 (COCH3), 181.8
(d, J 3.5 Hz, Ph13CO).
31P a n d 13C NMR of th e Solva ted Ca ta lyst w ith th e
La beled Su bstr a te (7b). Under an atmosphere of argon,
[(COD)Rh((R,R)-Et-DuPHOS)]OTf (47.8 mg, 66.2 µmol) was
dissolved in deuterated methanol (1.5 mL) to form a bright
yellow solution. Hydrogen gas was added to the stirred solution
at a pressure of 90 psi. After 1 h, a dark brown solution had
formed. The solution was transferred to a 5 mm NMR tube
under an atmosphere of argon, and the labeled substrate,
methyl 2-N-benzoylamino-3-N-[13CO]-acetylamino-2-prop-
enoate (7b) (17.4 mg, 66.2 µmol), was added. 31P and 13C NMR
spectra were then recorded:
31P NMR (162 MHz, CD3OD, 25 °C): δ 95.4 (d, J 205.3 Hz
(Rh-P), unbound catalyst), 88.7 (dd, J 165.9 Hz (Rh-P)), 34.0
Hz (P1-P2)), 82.4 (dd, J 153.6 Hz (Rh-P)), 33.9 Hz (P1-P2)).
13C NMR (100 MHz, CD3OD, 25 °C): shows bound and
unbound enamide (7b). Unbound substrate: δ 109.8 (C2),
129.0 (C3′, 5′), 129.5 (C2′, 6′), 131.6 (C3), 133.1 (C4′), 134.9
(C1′), 167.2 (COOCH3), 169.3 (PhCO), 171.3 (13COCH3). Bound
substrate: δ 76.7 (d, J 21.3 Hz, C2), 90.6 (d, J 12.4 Hz, C3),
129.7 (C3′,5′), 130.0 (C2′, 6′), 130.6 (C1′), 134.8 (C4′), 168.3
(COOCH3), 171.4 (13COCH3), 181.8 (PhCO).
31P NMR (25 °C): δ 70.9 (d, J 148.3 Hz); 31P NMR (-30 °C):
δ 70.9 (d, J 148.3 Hz); 31P NMR (-60 °C): δ 70.9 (d, J 148.3
Hz), 71.8; 31P NMR (-80 °C): δ 70.9 (d, J 148.3 Hz), 71.8; 31
NMR (-80 °C f 25 °C): δ 70.9 (d, J 148.3 Hz.
P
31P NMR of [Rh (1,2-bis((2R,5R)-2,5-d ieth ylp h osp h a l-
a n o)ben zen e)] Tr ifla te (“solva ted ca ta lyst”) in CD3OD.
[(COD)Rh((R,R)-Et-DuPHOS)]OTf (ca. 5 mg) was dissolved in
degassed methanol-d4 (CD3OD). The bright yellow solution was
exposed to a hydrogen atmosphere (90 psi) at room tempera-
ture. After 1 h, a dark brown solution had formed. The 31P
spectrum was then recorded: 31P NMR (162 MHz, CD3OD, 25
°C): δ 84.0 (minor); δ 95.4 (d, J 205.3 Hz). In a separate
experiment, hydrogenation of the catalyst over a 20 min period
at 60 psi pressure of hydrogen was found to be incomplete.
31P a n d 13C NMR of t h e Solva t ed Ca t a lyst w it h
La beled Su bstr a te (7a ). Under an atmosphere of argon,
[(COD)Rh((R,R)-Et-DuPHOS)]OTf (50.0 mg, 69.1 µmol) was
dissolved in deuterated methanol (1.5 mL) to form a bright
yellow solution. Hydrogen gas was added to the stirred solution
at a pressure of 90 psi. After 1 h, a dark brown solution had
formed. The solution was transferred to a 5 mm NMR tube
under an atmosphere of argon and the R-labeled substrate,
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the Australian Research Council.
Note Ad d ed a fter ASAP P ostin g. The version of this
paper posted on J anuary 13, 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.
methyl
2-N-[13CO]-benzoylamino-3-N-acetylamino-2-prop-
enoate (7a ) (18.2 mg, 69.1 µmol), was added. 31P and 13C NMR
spectra were then recorded: 31P NMR (162 MHz, CD3OD): δ
95.4 (d, J 205.3 Hz (Rh-P), unbound catalyst), 88.8 (dd, J
165.9 Hz (Rh-P), 33.7 Hz (P1-P2)), 82.5 (ddd, J 153.7 Hz (Rh-
P), 33.7 Hz (P1-P2), 3.5 Hz (P1-13C)). 13C NMR (100 MHz, CD3-
OD, 25 °C): shows bound and unbound enamide (7a ). Unbound
substrate: δ 109.8 (C2), 129.0 (d, J 2.2 Hz, C3′, 5′), 129.5 (d,
J 4.4 Hz, C2′, 6′), 131.6 (C3), 133.1 (C4′), 167.2 (COOCH3),
169.3 (Ph13CO), 171.3 (COCH3), C1′ not observed. Bound
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for compounds 3-6. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O001151N