Pd(II)-catalyzed regio-, enantio-, and diastereoselective 1,4-addition of azlactones formed in situ from racemic unprotected amino acids and acetic anhydride

Article abstract of DOI:10.1021/jo302177t

A multicomponent reaction is reported generating highly enantioenriched and diastereomerically pure quaternary amino acid derivatives via 1,4-addition of azlactones to enones. The azlactone intermediates are generated in situ from unprotected α-amino acids and acetic anhydride. Previous attempts using bis-palladacycle catalysts required the use of a large excess of benzoic anhydride (which is very difficult to remove from the products), since acetic anhydride provided regioisomeric product mixtures. Key for the high regioselectivity is a pentaphenylferrocene monopalladacycle catalyst.

Full text of DOI:10.1021/jo302177t

Article
pubs.acs.org/joc
Pd(II)-Catalyzed Regio‑, Enantio‑, and Diastereoselective 1,4-Addition
of Azlactones Formed in Situ From Racemic Unprotected Amino
Acids and Acetic Anhydride
Manuel Weber and Rene Peters*
́
Institut fur Organische Chemie, Universitat Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A multicomponent reaction is reported gen-
erating highly enantioenriched and diastereomerically pure
quaternary amino acid derivatives via 1,4-addition of azlactones
to enones. The azlactone intermediates are generated in situ
from unprotected α-amino acids and acetic anhydride.
Previous attempts using bis-palladacycle catalysts required
the use of a large excess of benzoic anhydride (which is very
difficult to remove from the products), since acetic anhydride provided regioisomeric product mixtures. Key for the high
regioselectivity is a pentaphenylferrocene monopalladacycle catalyst.
azlactone regioselectivity issue has been reported in several
other cases for catalytic asymmetric 1,4-additions.7c,f,g
INTRODUCTION
■
Azlactones (oxazol-5-(4H)-ones) have been reported as very
versatile masked and activated amino acid equivalents for a
diversity oriented access to natural and unnatural α-amino acid
derivatives.1 Their broad utility is mainly explained by two
reasons: (1) the relatively high tendency to enolize forming an
aromatic heterocycle with a nucleophilic site at the C-4 position
and (2) the masked cyclic anhydride type structure, which
allows for ring-opening reactions with various nucleophiles
under mild conditions. The sequential combination of these
two orthogonal reactivities has been shown to be particularly
valuable for the asymmetric synthesis of enantioenriched
biologically interesting2 α,α-disubstituted (quaternary) α-
amino acids.1,3,4 In this context, we have recently reported
the first catalytic asymmetric 1,4-additions5 of azlactones to
enones, and we have demonstrated the value of the addition
products for a divergent access to a number of different classes
of biologically interesting quaternary amino acid derivatives
including bicyclic dipeptides.6,7 In these previous studies, we
have found that the azlactone substrates can be generated in
situ from either racemic N-benzoylated6a,c or unprotected
amino acids6b,c using a planar chiral bis-palladacycle catalyst. In
that way the sometimes tedious preparation (2−4 steps) and
isolation of the azlactone substrates could be avoided.
For practical reasons, the use of acetic anhydride/acid is
considered to be much more convenient for the 1,4-addition to
enones than that of benzoic acid/anhydride, because acetic
acid/anhydride can be readily evaporated, whereas removal of a
large excess of the solid benzoic anhydride proved to be tedious
and required two sequential column chromatographies.6b,c
Moreover, regeneration of the amino group by hydrolysis of the
amide protecting group might be more effective for acetamides
(e.g., enzymatically) compared to benzamides.
Herein we report that the monopalladacycle catalyst 7a8−10 is
capable to regioselectively form the azlactone-C-4 Michael
addition products with high enantio- and diastereoselectivity in
a single step starting from racemic unprotected amino acids,
enones and acetic anhydride (Scheme 1, bottom). This
efficiency was surprising, because in the above-mentioned
studies using the azlactones 2-Ph (with a 2-phenyl substituent),
this and other related monopalladacycles generally provided the
product in poor yields and with only low to moderate
enantioselectivity, and a bimetallic catalyst system was essential
for synthetically attractive results. However, the situation
completely changes upon using azlactones 2-Me with a 2-
methyl substituent.
The in situ generation of the azlactones starting from N-
benzoylated amino acids 1 could be accomplished by the use of
an excess of acetic anhydride (Scheme 1, first row).6a,c
Unprotected amino acids required the use of a large excess of
benzoic anhydride (in combination with benzoic acid) for the
regioselective formation of the C-4 addition product, whereas
azlactones bearing a 2-methyl substituent, introduced by N-
acetylation of the unprotected amino acid with Ac2O, provided
mixtures of the C-4 and the undesired C-2 addition products
(Scheme 1, third and second row, respectively). The C-4/C-2
RESULTS AND DISCUSSION
■
Application of reaction conditions initially investigated for the
bimetallic precatalyst to the model reaction of racemic alanine
(3a) and enone 4a formed the C-4 addition product 5a in 57%
yield with 99% ee (Table 1, entry 1),11 while the C-2 addition
product could not be detected.12
Received: October 4, 2012
Published: November 29, 2012
© 2012 American Chemical Society
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Scheme 1. Cooperative Influence of the Azlactone C-2
Substituent and the Catalyst Type on the Regioselectivity
Table 1. Investigation of the Reaction Conditions Using
Racemic Alanine (3a), Enone 4a and Acetic Anhydride
yield 5a
b
ee 5a
c
a
a
#
7/8
X
solvent
5a/6a
(%)
dr 5a
(%)
1
7a
7b
7c
8
3
3
3
3
3
5
3
3
3
3
3
3
3
3
>50:1
4:1
57
59
51
68
38
58
56
55
54
59
69
48
54
71
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
99
55
96
98
99
99
99
99
99
99
99
99
99
98
2
3
4
5
6
7
8
9
6:1
>50:1
>50:1
>50:1
33:1
21:1
d
e
7a
7a
7a
7a
7a
7a
7a
7a
7a
8
acetone
diglyme
THF
f
n.d.
10
11
12
13
14
15:1
>50:1
>50:1
45:1
6:1
CH2Cl2
toluene
hexane
CH2Cl2
a
b
1
1
Determined by H NMR of the crude product. Determined by H
NMR analysis of the crude product using mesitylene as an internal
c
d
e
standard. Determined by HPLC. No NaOAc was used. The
precatalyst was activated by 12 mol % AgOTf. Not determined, since
f
diglyme signals overlay the relevant product signals.
The steric demand of the pentaphenyl-Cp moiety of
precatalyst 7a is a key factor for high enantio- and
regioselectivity as demonstrated by entry 2, in which catalyst
7b was used lacking the five phenyl rings on the spectator Cp
ligand. With this catalyst the product was formed with only
moderate enantioselectivity (ee = 55%) and regioselectivity
(4:1). Accordingly, the sterically more demanding pentamethyl-
ferrocene derivative 7c provided both better C-4 selectivity and
an excellent enantioselectivity (entry 3). The pentaphenylfer-
rocene oxazoline palladacycle 8 performed similar to the related
imidazoline 7a (entry 4). Entry 5 shows that the product yield
is significantly reduced by the absence of NaOAc. We therefore
assume that the azlactone coordinated to (and acidified by) the
Pd-center is deprotonated by acetate to form an enolate as
reactive intermediate under the acidic reaction conditions. An
increased precatalyst loading of 5 mol % (entry 6) or oxidation
of the catalyst to the corresponding Pd(III) species13 (entry 7)
had almost no impact on the reaction outcome.
catalyst 8, but with a significant amount of the regioisomer as
side product (ratio 5a/6a = 6:1, entry 14).
The investigation of a number of amino acids 3 and enones 4
(Table 2) was performed under the best conditions found
(Table 1, entry 11).14 Product 5a of the model reaction could
be isolated in a yield of 50% after silica gel column
chromatography. This yield is somewhat lower than determined
via 1H NMR (using an internal standard) and can be attributed
to partial hydrolysis of the azlactone moiety during workup and
on silica gel. As a general trend, the isolated yield increased with
a growing length of an unbranched alkyl amino acid residue R1
(compare entries 1−4). This might reflect the higher product
stability toward hydrolysis based on steric effects. On the other
hand, the enantioselectivity gradually slightly decreased from
alanine via ethylglycine and norvaline to norleucine from 99 to
92% ee. Branched α-residues like in leucine (entry 5) and
phenylalanine (entry 6) resulted in a lower substrate reactivity
and enantioselectivity.15 Gratifyingly, functionalized amino
acids like glutamic acid 5-methyl ester (entry 7) and tryptophan
(entry 8) are also well tolerated.
Catalyst 7a provided product 5a with excellent enantiose-
lectivity (ee = 99%) in solvents of widely variable polarities such
as acetone, diglyme, THF, CH2Cl2, toluene and n-hexane in
comparable yields (entries 8−13). By using CH2Cl2 or toluene
as solvent, the undesired C-2 regioisomer 6a was not detectable
The enone scope was investigated with racemic norvaline.
Unfortunately, increasing the size of the enone substituent R3
from methyl to isopropyl resulted in a low product yield as a
result of a reduced reactivity, but stereoselectivity was still very
high (entry 9). π-Donors (entries 10−11) as well σ- (entries 12
and 14) and π-acceptors (entry 15) in 4-position of an aryl
1
by H NMR (entries 11−12). Product 5a was obtained in a
yield of 69% (determined by 1H NMR via an internal standard)
by this multicomponent reaction in CH2Cl2 as solvent (entry
11). A similar yield (71%) was also obtained in this solvent with
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Table 2. Investigation of the Substrate Scope
a
b
c
1
Yield of isolated product 5. Determined by H NMR. Determined by HPLC.
residue R2 were all tolerated and permitted useful product
yields and high stereoselectivity. Similar results were attained
with enones carrying heteroaromatic (entry 16) or aliphatic
residues R2 (entries 17−18), albeit branched alkyl substituents
R2 like i-Pr did not result in useful yield and enantioselectivity
(entry 19).16
The absolute configuration was determined by chemical
correlation (Scheme 2, top). Hydrolysis of 5a (ee = 98%) and
the known compound 10 (ee = 75%)6a,c with 1 M HCl at 80 °C
provided the known quaternary amino acid 9 (as hydrochloride
salt) without partial epimerization.6a,c Since the sign of the
specific optical rotation is negative in both cases, the absolute
configuration of 5a and 10 is identical. The hydrolysis of 5a
proceeded quantitatively, whereas hydrolysis of 10 was less
efficient. Under less forcing conditions, acetyl protected amino
acids like, e.g., 11, can also be readily prepared (Scheme 2,
bottom). Because of the considerable electrophilicity of the
azlactone moiety, hydrolysis proceeded already under neutral
aqueous conditions. Also in that case partial epimerization has
not been observed.
was found to be essential for high efficiency in terms of high
enantioselectivity and reactivity using azlactones carrying a 2-Ph
substituent, the pentaphenyl ferrocene based mono-Pd-catalysts
performed significantly better for azlactones carrying a 2-Me
substituent, because the undesired C-4 addition regioisomer is
not formed, which is the major side product for the bimetallic
catalyst. A possible reason for the superiority of the bimetallic
catalyst using 2-Ph-substituted azlactones might be a lower
inherent nucleophilicity of the corresponding enolates as
compared to the 2-Me-substituted analogues owing to a more
widespread π-system of the former resulting in a lower energy
of the HOMO. This might lead to a situation in which a
simultaneous activation of the enone is essential to efficiently
trigger the C−C-bond formation. In contrast, the higher
nucleophilicity of the 2-methyl substituted derivative might
already be sufficient for a nucleophilic attack at the enone
without additional activation of the Michael acceptor by the
catalyst explaining the good reactivity with the monopallada-
cycle in this specific case. For the bis-Pd-catalyst this would
mean that a monometallic pathway might compete with the
bimetallic pathway for 2-methylazlactones, but not for 2-
phenylazlactones.
The reasons for the complementarity of the bis-Pd-catalysts
reported earlier and mono-Pd-catalysts reported in this study
are not yet fully understood. Whereas the use of bis-Pd-catalysts
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with an electrophile,17 enolate 12 can be considered more
nucleophilic by electronic effects.
Scheme 2. (Top) Determination of the Absolute
Configuration by Hydrolysis of 5a via Chemical Correlation;
(Bottom) Partial Hydrolysis toward the N-Acetyl Protected
Amino Acid 11
The fact that the regioselectivity is poor for 2-methyl-
azlactones using the bimetallic catalyst18 might, e.g., reflect two
competing reactive conformations IIa and IIb for a bimetallic
pathway in which either the 2-methyl substituent or the C-4-
substituent R1 adopt an exo orientation with regard to the
catalyst core (Figure 2). In comparison, using the 2-Ph-
azlactone the reactive conformer I with an exo orientation of
the Ph moiety might be strongly preferred for steric reasons to
minimize repulsive interactions of the Ph group with the
catalyst core. Only the nucleophilic azlactone atom (either C-2
or C-4) in endo position would be in close spatial proximity to
the enone for such a bimetallic reaction pathway.
For the monometallic catalyst, we think that the preferred
reacting intermediate might be species III, in which the 2-
methyl group points toward the sterically demanding
pentaphenylcyclopentadienide spectator ligand, because the
fragment CH3−C(2)−O is less bulky compared to R1−C(4)−
C(5)−ONa(solv) (Figure 3, left). If III is the reactive confomer,
C-2 (in endo-position relative to the ferrocene core and
shielded by C5Ph5) is less accessible than C-4 in exo-position.
Since the Si-face of the enolate is shielded by the pentaphenyl
ferrocene moiety (Figure 3, middle and right), the Re-face
should selectively attack the enone, thus explaining the good
enantioselectivity.
Like for the 2-Ph substrates6a,c the high diastereoselectivity
might be the consequence of a transition state with a staggered
conformation around the generating C−C-bond. The frontier
molecular orbitals were calculated for enone 4a (LUMO) and
Na-enolate 12a (HOMO) by DFT computations (B3LYP/6-
31G*) in vacuum (Figure 4). Our model suggests a maximum
molecular orbital overlap in a transition state leading to the
observed diastereomer. Next to the orbital overlap at the
azlactone C-4 atom and the 4-position of the enone resulting in
the C−C bond formation, we suggest a secondary molecular
orbital interaction of the azlactone C-2 atom and the 2-position
Quantum mechanical computations were used to survey our
hypothesis. By the DFT/B3LYP/6-31G* method the equili-
brium conformers of the azlactone sodium enolates 12 and 13
were identified and used for more detailed considerations.
Figure 1 shows the calculated HOMOs of both enolates as well
as the HOMO densities. The phenyl-π-system of 13 displays
some participation to the HOMO, and as a consequence of the
delocalization, the HOMO of 13 is ca. 4.2 kcal/mol (17.6 kJ/
mol) lower in energy than that of 12. Since the higher HOMO
energy corresponds to a more reactive molecule in reactions
Figure 1. Comparison of sodium enolates 12 (top) and 13 (bottom) by quantum mechanical computations (DFT/B3LYP/6-31G*). (Left)
representation of the equilibrium conformers; (middle) representation of the HOMOs of the enolates; (right) HOMO densities (blue color indicates
high electron density; red color means low electron density).
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Figure 2. Representation of the assumed reactive intermediates to form a C−C bond to explain the exclusive regioselectivity with 2-Ph azlactones
and the poor regioselectivity with 2-Me azlactones using a bis-Pd catalyst.
Figure 3. Representations of the assumed reactive intermediate using the mono-Pd catalyst to explain (a) the exclusive regioselectivity with 2-Me
azlactones by the preference of the exo-attack (left formula) and (b) the high enantioselectivity (middle and right). The latter 3D-models (two
different views) show that the Si-face at C-4 is shielded by the pentaphenylferrocene core, whereas th Re-face is considerably more accessible.
Figure 4. Rationale for the observed high diastereoselectivity by a secondary molecular orbital interaction of the azlactone C-2 atom and the 2-
position of the enone.
of the enone to explain the inherent diastereoselectivity of the
title reaction.
by the use of a pentaphenylferrocene monopalladacycle catalyst.
The observed complementarity of mono- and bis-palladacycle
catalysts might at least be partly explained by a higher
nucleophilicity of the enolates derived from 2-methyl
azlactones, which could allow for a monometallic reaction
pathway in which the enone does not need to be activated by
the catalyst, whereas the less nucleophilic 2-phenyl azlactones
might prefer a bimetallic pathway in which both the azlactone
and enone should be activated to achieve a sufficient reactivity.
CONCLUSION
■
In conclusion, we have presented an enantio- and diastereo-
selective 1,4-addition of azlactones generated in situ from
racemic unprotected amino acids and acetic anhydride that
proceeds regioselectively forming exclusively the azlactone C-4
regioisomer. In contrast, previous attempts with unprotected
amino acids required the use of a large excess of benzoic
anhydride (via the azlactone intermediate 2-Ph), whereas the
use of acetic anhydride had provided regioisomeric mixtures of
the azlactone C-2/C-4 addition products. The use of acetic
anhydride offers a significant practical advantage: it can be
conveniently removed due to its volatility, whereas removal of a
large excess of the solid benzoic anhydride as previously
described6b,c proved to be tedious and required two sequential
column chromatographies. The new development was allowed
EXPERIMENTAL SECTION
■
General Procedure for the Activation of the Precatalyst
[PPFIP-Cl]2 (GP1). [PPFIP-Cl]2 (1 equiv) and the silver salt (2
equiv) were dissolved/suspended in acetonitrile (1 mL per 5 mg of
[PPFIP-Cl]2) and stirred overnight at room temperature. The
reaction flask was covered with aluminum foil to shield from light
during that period. After the activation was complete, the mixture was
filtered through Celite, and then free acetonitrile was removed under
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reduced pressure (ca. 5 min at 15 mbar and room temperature). A
stock solution was subsequently prepared.
670, 659, 647, 601, 568, 543, 531; MS (ESI) m/z 1045.17 (100%, [M
−
MeCN −
OAc]+); HRMS (ESI) m/z calculated for
General Procedure for the Catalytic Asymmetric Synthesis
of α,α-Disubstituted α-Amino Acid Derivatives Using Un-
protected Amino Acids (GP2). The corresponding racemic amino
acid (3, 1.00 equiv, 0.30 mmol), the corresponding enone (4, 6.00
equiv, 1.80 mmol) and NaOAc (0.25 equiv, 75.0 μmol, 6.2 mg) were
successively charged into a vial. To this mixture was added the
activated catalyst (prepared from 0.03 equiv of [PPFIP-Cl]2, 9.00
μmol, 19.5 mg; see GP1) as a stock solution in AcOH/Ac2O (4/1, 900
μL) and CH2Cl2 (900 μL). The resulting slurry was heated to 50 °C
for 18 h. After this time, the mixture was cooled to room temperature
and was then directly used for silica gel column chromatography to
isolate the targeted products. To completely remove residual traces of
catalyst, the material was dried under reduced pressure (0.1 mbar) and
was then extracted several times with n-pentane.
C62H47FeN2O2PdS (M − MeCN − OAc) 1045.1759, found
1045.1743.
Asymmetric Synthesis of the α,α-Disubstituted Amino Acid
Derivatives (5). (R)-2,4-Dimethyl-4-((R)-3-oxo-1-phenylbutyl)-
oxazol-5(4H)-one (5a). D,L-Alanine (26.7 mg) was treated with
trans-4-phenyl-but-3-en-2-one (263 mg) according to GP2. Flash
column chromatography (petrol ether/ethyl acetate = 0/1) yielded 5a
as a colorless oil (150 μmol, 38.8 mg, 50%; dr > 99:1, ee = 99%).
23
1
C15H17NO3: MW 259.30; [α]D +3.8 (c = 1.60, PhH); H NMR
(300 MHz, C6D6) δ = 7.21−7.13 (m, 2 H), 7.06−6.93 (2 × m, 3 H),
3.83 (t, J = 7.0, 1 H), 2.73 (d, J = 6.8, 2 H), 1.51 (s, 3 H), 1.44 (s, 3 H),
1.18 (s, 3 H); 13C NMR (75 MHz, C6D6) δ = 204.1, 179.6, 161.2,
139.0, 129.6, 128.2, 127.7, 72.3, 46.6, 43.7, 29.7, 21.8, 14.3; IR (in
C6D6) ν = 3032, 2978, 2937, 1821, 1801, 1715, 1685, 1493, 1454,
1431, 1382, 1244, 1166, 1062, 1046, 1020, 903, 703, 667, 620; MS
(ESI) m/z 282.1 (25%, [M + Na]+), 254.1 (10%), 241.1 (100%),
213.1 (12%), 197.1 (10%), 170.1 (8%); HRMS (ESI) m/z calculated
for C15H17NO3 + Na 282.1101, found 282.1129.
General Procedure for the Synthesis of the Racemic α,α-
Disubstituted α-Amino Acid Derivatives (GP3). The syntheses
were carried out like described in GP2 but using a ca. 1:1 mixture of
both catalyst enantiomers and applying a smaller scale: the
corresponding racemic amino acid (3, 1.00 equiv, 0.05 mmol), the
corresponding enone (4, 6.00 equiv, 0.30 mmol) and NaOAc (0.25
equiv, 12.0 μmol, 1 mg) were successively charged into a vial. To this
mixture was added the activated, nearly racemic catalyst mixture
(prepared from a mixture of 0.015 equiv of Sp-[PPFIP-Cl]2 and 0.015
equiv of Rp-[PPFIP-Cl]2, each 0.75 μmol, 1.63 mg, see GP1) as a
stock solution in AcOH/Ac2O (4/1, 150 μL) and CH2Cl2 (150 μL).
The resulting slurry was heated to 50 °C for 18 h. After this time, the
mixture was cooled to room temperature and was then directly used
for silica gel column chromatography to isolate the racemic products
rac-5.
(R)-4-Ethyl-2-methyl-4-((R)-3-oxo-1-phenylbutyl)oxazol-5(4H)-
one (5b). D,L-Ethyl glycine (30.9 mg) was treated with trans-4-phenyl-
but-3-en-2-one (263 mg) according to GP2. Flash column
chromatography (petrol ether/ethyl acetate = 1/10) yielded 5b as a
colorless oil (166 μmol, 45.3 mg, 55%; dr > 99:1, ee = 98%).
23
1
C16H19NO3: MW 273.33; [α]D −6.2 (c = 0.95, PhH); H NMR
(300 MHz, C6D6) δ = 7.24−7.17 (m, 2 H), 7.02−6.94 (2 × m, 3 H),
3.88 (t, J = 6.8, 1 H), 2.82−2.66 (m, 2 H), 1.83−1.67 (m, 1 H), 1.66−
1.52 (m, 1 H), 1.51 (s, 3 H), 1.48 (s, 3 H), 0.66 (t, J = 7.2, 3 H); 13C
NMR (75 MHz, C6D6) δ = 204.1, 178.9, 161.7, 139.1, 129.7, 128.2,
127.7, 77.1, 46.4, 44.0, 29.7, 28.3, 14.1, 8.2; IR (in C6D6) ν = 3031,
2973, 2935, 2882, 1814, 1716, 1683, 1455, 1433, 1357, 1243, 1165,
1067, 967, 900, 755, 735, 703, 670, 620, 528; MS (ESI) m/z 274.1
(5%, [M + H]+), 246.1 (5%), 204.1 (5%), 187.1 (100%); HRMS (ESI)
m/z calculated for C16H19NO3 + H 274.1438, found 274.1428.
(R)-2-Methyl-4-((R)-3-oxo-1-phenylbutyl)-4-propyloxazol-5(4H)-
one (5c). D,L-Norvaline (35.1 mg) was treated with trans-4-phenyl-but-
3-en-2-one (263 mg) according to GP2. Flash column chromato-
graphy (petrol ether/ethyl acetate = 1/7) yielded 5c as a colorless oil
(192 μmol, 54.8 mg, 64%; dr > 99:1, ee = 93%).
Activated Catalysts. {[η5-(4′R,5′R)-(Sp)-2-(2′-4′,5′-Dihydro-4′,5′-
diphenyl-1′-tosyl-1′H-imid-azolyl)cyclopentadienyl,1-C, 3′-N)(η5-
pentaphenylcyclopentadienyl)-iron(II)]palladium(II)}-triflate aceto-
nitrile complex (PPFIP-OTf). The catalyst precursor [PPFIP-Cl]2 (1.0
equiv, 6.93 μmol, 15 mg) was activated according to GP1 using
AgOTf (2 equiv, 13.9 μmol, 3.56 mg). PPFIP-OTf was isolated as a
crystalline purple-red solid (13.6 μmol, 16.8 mg, 98%).
C65H50F3FeN3O5PdS2: MW 1236.50; mp >250 °C (decomp.);
[α]D23 −853.3 (c = 0.00656, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ
= 7.55 (d, J = 8.2, 2 H), 7.33 (d, J = 7.9, 2 H), 7.25−6.95 (m, 31 H),
6.46 (d, J = 7.8, 2 H), 6.33 (d, J = 7.4, 2 H), 5.81 (d, J = 1.5, 1 H), 4.77
(t, J = 2.0, 1 H), 4.65 (d, J = 1.0, 1 H), 4.55−4.42 (m, 2 H), 2.52 (s, 3
H), 2.42 (s, 3 H), 1.94 (s); 13C NMR (75 MHz, CDCl3) δ = 172.5,
146.4, 140.0, 138.4, 134.6, 134.2, 132.7, 132.4, 131.7, 130.5, 129.3,
129.0, 128.7, 128.2, 127.8, 127.2, 127.0, 126.9, 126.7, 126.3, 125.7,
122.6, 118.5, 89.7, 79.8, 79.4, 75.5, 75.4, 73.2, 21.7, 3.7, 1.9; 19F NMR
(235 MHz, CDCl3) δ = −78.33; IR (in CDCl3) ν = 3059, 2932, 2322,
2250, 1599, 1543, 1503, 1453, 1383, 1280, 1255, 1224, 1172, 1078,
1030, 972, 911, 739, 699, 670, 659, 638, 603, 570, 543; MS (ESI) m/z
1045.17 (100%, [M − MeCN − OTf]+); HRMS (ESI) m/z calculated
for C62H47FeN2O2PdS (M − MeCN − OTf) 1045.1759, found
1045.1743.
23
1
C17H21NO3: MW 287.35; [α]D +4.8 (c = 1.60, PhH); H NMR
(300 MHz, C6D6) δ = 7.25−7.18 (m, 2 H), 7.08−6.94 (2 × m, 3 H),
3.87 (dd, J = 8.5, 5.3, 1 H), 2.82 (dd, J = 17.1, 8.4, 1 H), 2.73 (dd, J =
17.2, 5.3, 1 H), 1.82−1.69 (m, 1 H), 1.69−1.55 (m, 1 H), 1.52 (s, 3
H), 1.49 (s, 3 H), 1.20−1.01 (m, 2 H), 0.69 (t, J = 7.3, 3 H); 13C NMR
(75 MHz, C6D6) δ = 204.1, 179.0, 161.6, 138.9, 129.7, 128.2, 127.7,
76.6, 46.7, 44.0, 37.3, 29.8, 17.7, 14.2, 13.9; IR (in C6D6) ν = 3032,
2962, 2933, 2875, 2279, 1818, 1716, 1683, 1494, 1455, 1432, 1381,
1358, 1244, 1201, 1164, 1068, 901, 811, 750, 733, 703, 671, 619, 535;
MS (ESI) m/z 310.1 (15%, [M + H]+), 282.1 (5%), 269.1 (100%),
241.1 (5%), 225.1 (10%), 170.1 (5%); HRMS (ESI) m/z calculated
for C17H21NO3 + Na 310.1414, found 310.1429.
{[η5-(4′R,5′R)-(Sp)-2-(2′-4′,5′-Dihydro-4′,5′-diphenyl-1′-tosyl-1′H-
imid-azolyl)cyclopentadienyl,1-C, 3′-N)(η5 pentaphenylcyclopenta-
dienyl)-iron(II)]palladium(II)}-acetate acetonitrile complex (PPFIP-
OAc). The catalyst precursor [PPFIP-Cl]2 (1.0 equiv, 6.93 μmol, 15
mg) was activated according to GP1 using AgOAc (2 equiv, 13.9
μmol, 2.31 mg). PPFIP-OAc was isolated as a crystalline purple-red
solid (13.2 μmol, 15.1 mg, 95%).
(R)-4-Butyl-2-methyl-4-((R)-3-oxo-1-phenylbutyl)oxazol-5(4H)-
one (5d). D,L-Norleucine (39.4 mg) was treated with trans-4-phenyl-
but-3-en-2-one (263 mg) according to GP2. Flash column
chromatography (petrol ether/ethyl acetate = 1/3) yielded 5d as a
colorless oil (216 μmol, 65.0 mg, 72%; dr > 99:1, ee = 92%).
23
1
C18H23NO3: MW 301.38; [α]D −8.7 (c = 1.01, PhH); H NMR
(300 MHz, C6D6) δ = 7.26−7.18 (m, 2 H), 7.08−6.95 (2 × m, 3 H),
3.89 (dd, J = 8.4, 5.7, 1 H), 2.83 (dd, J = 17.2, 8.4, 1 H), 2.76 (dd, J =
17.2, 5.5, 1 H), 1.92−1.75 (m, 1 H), 1.75−1.61 (m, 1 H), 1.52 (s, 3
H), 1.49 (s), 1.20−1.03 (m, 4 H), 0.73 (t, J = 6.9); 13C NMR (75
MHz, C6D6) δ = 204.2, 179.1, 161.6, 138.9, 129.7, 128.2, 127.7, 76.6,
46.8, 44.0, 35.0, 29.8, 26.4, 22.8, 14.2, 13.9; IR (in C6D6) ν = 3032,
2958, 2930, 2872, 1818, 1716, 1683, 1494, 1455, 1382, 1357, 1243,
1198, 1164, 1063, 1020, 970, 900, 742, 702, 670, 536; MS (ESI) m/z
302.2 (5%, [M + H]+, 274.2 (5%), 232.2 (5%), 215.1 (100%); HRMS
(ESI) m/z calculated for C18H23NO3 + H 302.1751, found 302.1743.
(R)-4-Isobutyl-2-methyl-4-((R)-3-oxo-1-phenylbutyl)oxazol-5(4H)-
one (5e). D,L-Leucine (39.4 mg) was treated with trans-4-phenyl-but-3-
23
C66H53FeN3O4PdS: MW 1146.47; mp >250 °C (decomp.); [α]D
−845.7 (c = 0.01313, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ = 7.56
(d, J = 8.3, 2 H), 7.42−7.17 (m, 12 H), 7.17−6.93 (m, 21 H), 6.48 (d, J
= 7.7, 2 H), 6.43 (d, J = 7.5, 2 H), 5.72 (d, J = 1.9, 1 H), 4.88 (d, J =
1.2, 1 H), 4.65 (t, J = 2.3, 1 H), 4.49 (d, J = 7.7, 1 H), 4.46 (d, J = 7.8, 1
H), 2.50 (s, 3 H), 2.00 (s, 3 H), 1.97 (s, 3 H); 13C NMR (62.5 MHz,
CDCl3) δ = 171.1, 145.8, 139.9, 139.0, 134.9, 133.1, 132.7, 132.2,
130.4, 129.1, 128.9, 128.6, 128.0, 127.9, 127.1, 126.5, 126.2, 99.2, 89.3,
88.9, 79.4, 77.9, 75.7, 75.5, 74.7, 72.6, 24.4, 21.7, 14.1, 1.9; IR (in
CDCl3) ν = 3056, 2243, 1597, 1541, 1502, 1444, 1407, 1380, 1328,
1286, 1171, 1155, 1076, 1045, 1027, 969, 907, 814, 801, 784, 729, 696,
10851
dx.doi.org/10.1021/jo302177t | J. Org. Chem. 2012, 77, 10846−10855

The Journal of Organic Chemistry
Article
en-2-one (263 mg) according to GP2. Flash column chromatography
(petrol ether/ethyl acetate = 1/3) yielded 5e as a colorless oil (126
μmol, 37.7 mg, 42%; dr > 99:1, ee = 79%).
methyl-1-phenylpent-1-en-3-one (314 mg) according to GP2. Flash
column chromatography (petrol ether/ethyl acetate = 1/1 to 1/4)
yielded 5i as a colorless gummy solid (48.0 μmol, 15.6 mg, 16%; dr >
99:1, ee = 96%).
23
1
C18H23NO3: MW 301.38; [α]D +12.2 (c = 1.31, PhH); H NMR
(300 MHz, C6D6) δ = 7.22−7.17 (m, 2 H), 7.07−6.94 (2 × m, 3 H),
3.83 (dd, J = 8.4, 5.3, 1 H), 2.82 (dd, J = 17.3, 8.5, 1 H), 2.74 (dd, J =
17.2, 5.2, 1 H), 1.80 (dd, J = 13.9, 5.8, 1 H), 1.72 (dd, J = 14.2, 6.3, 1
H), 1.51 (s, 3 H), 1.50 (s, 3 H), 1.33−1.20 (m, 1 H), 0.79 (d, J = 6.6, 6
H); 13C NMR (75 MHz, C6D6) δ = 204.1, 179.5, 161.4, 138.7, 129.8,
128.2, 127.8, 76.4, 47.7, 44.2, 43.8, 29.8, 25.5, 24.0, 23.6, 14.3; IR (in
C6D6) ν = 3032, 2958, 2873, 1817, 1717, 1683, 1494, 1469, 1455,
1431, 1382, 1358, 1283, 1244, 1165, 1070, 900, 764, 740, 703, 672,
619, 604; MS (ESI) m/z 302.2 (10%, [M + H]+), 274.2 (10%), 232.2
(5%), 215.1 (100%); HRMS (ESI) m/z calculated for C18H23NO3 + H
302.1751, found 302.1735.
C19H25NO3: MW 315.41; [α]D23 −27.7 (c = 0.30, PhH); 1H NMR
(300 MHz, C6D6) δ = 7.30−7.24 (m, 2 H), 7.08−6.93 (m, 3 H), 4.02
(dd, J = 8.7, 5.0, 1 H), 2.99 (dd, J = 17.3, 8.7, 1 H), 2.88 (dd, J = 17.3,
5.0, 1 H), 2.10 (sep, J = 6.9, 1 H), 1.88−1.74 (m, 1 H), 1.74−1.61 (m,
1 H), 1.51 (s, 3 H), 1.22−1.06 (m, 2 H), 0.82 and 0.69 (2 × d, 2 × J =
6.8, 2 × 3 H), 0.68 (t, J = 7.2, 3 H); 13C NMR (75 MHz, C6D6) δ =
210.1, 179.0, 161.6, 139.2, 129.8, 128.2, 128.1, 76.7, 46.7, 41.3, 41.2,
37.4, 18.0, 17.99, 17.89, 17.7, 14.2, 13.9; IR (in C6D6) ν = 2965, 2932,
2874, 1818, 1712, 1683, 1494, 1455, 1433, 1382, 1244, 1201, 1150,
1067, 1035, 1009, 899, 752, 730, 702, 674, 619; MS (ESI) m/z 338.2
(1%, [M + Na]+), 274.2 (5%), 229.2 (100%), 175.1 (5%); HRMS
(ESI) m/z calculated for C19H25NO3 + Na 338.1727, found 338.1709.
(R)-4-((R)-1-(4-Methoxyphenyl)-3-oxobutyl)-2-methyl-4-propy-
loxazol-5(4H)-one (5j). D,L-Norvaline (35.1 mg) was treated with
trans-4-(4-methoxyphenyl)but-3-en-2-one (317 mg) according to
GP2. Flash column chromatography (petrol ether/ethyl acetate = 1/
3) yielded 5j as a colorless oil (123 μmol, 38.7 mg, 41%; dr > 99:1, ee
= 99%).
(R)-4-Benzyl-2-methyl-4-((R)-3-oxo-1-phenylbutyl)oxazol-5(4H)-
one (5f). D,L-Phenyl alanine (49.6 mg) was treated with trans-4-
phenyl-but-3-en-2-one (263 mg) according to GP2. Flash column
chromatography (petrol ether/ethyl acetate = 1/2) yielded 5f as a
colorless solid (147 μmol, 48.9 mg, 49%; dr > 99:1, ee = 82%).
C21H21NO3: MW 335.40; mp 117.2 − 117.7 °C; [α]D23 −61.8 (c =
1
0.73, PhH); H NMR (300 MHz, C6D6) δ = 7.29−7.23 (m, 2 H),
23
1
7.19−7.16 (m, 2 H), 7.08−6.93 (m, 6 H), 4.03 (t, J = 6.9, 1 H), 3.04−
2.89 (m, 2 H), 2.86 (s, 1 H), 2.84 (s, 1 H), 1.55 (s, 3 H), 1.26 (s, 3 H);
13C NMR (75 MHz, C6D6) δ = 204.0, 178.1, 161.7, 139.0, 134.9,
C18H23NO4: MW 317.38; [α]D −8.0 (c = 0.66, PhH); H NMR
(300 MHz, C6D6) δ = 7.20−7.12 (m, 2 H), 6.70−6.62 (m, 2 H), 3.85
(dd, J = 9.2, 4.9, 1 H), 3.21 (s, 3 H), 2.84 (dd, J = 17.0, 9.4, 1 H), 2.72
(dd, J = 17.0, 4.8, 1 H), 1.84−1.71 (m, 1 H), 1.70−1.58 (m, 1 H), 1.56
(s, 3 H), 1.52 (s, 3 H), 1.24−1.05 (m, 2 H), 0.71 (t, J = 7.2, 3 H); 13C
NMR (75 MHz, C6D6) δ = 204.4, 179.2, 161.5, 159.4, 130.7, 130.6,
113.7, 76.9, 54.6, 46.2, 44.1, 37.3, 29.9, 17.7, 14.2, 14.0; IR (in C6D6) ν
= 2962, 2934, 2875, 2838, 1817, 1715, 1684, 1611, 1513, 1463, 1432,
1381, 1360, 1247, 1180, 1165, 1068, 1034, 900, 833, 783, 670, 619,
548; MS (ESI) m/z 340.2 (20%, [M + Na]+), 299.1 (100%), 255.1
(40%), 200.1 (10%), 157.1 (5%); HRMS (ESI) m/z calculated for
C18H23NO4 + Na 340.1519, found 340.1511.
130.8, 129.8, 128.31, 128.27, 127.7, 127.4, 77.8, 46.6, 44.2, 41.6, 29.8,
13.9; IR (in C6D6) ν = 3062, 2929, 1817, 1716, 1684, 1603, 1494,
1455, 1431, 1382, 1358, 1244, 1162, 1100, 1061, 1030, 984, 902, 749,
701, 670, 642, 620, 602, 583; MS (ESI) m/z 336.2 (15%, [M + H]+),
308.2 (20%), 290.1 (4%), 266.2 (25%), 249.1 (100%), 190.1 (2%);
HRMS (ESI) m/z calculated for C21H21NO3 + Na 358.1414, found
358.1405.
Methyl 3-((R)-2-methyl-5-oxo-4-((R)-3-oxo-1-phenylbutyl)-4,5-di-
hydrooxazol-4-yl)propanoate (5g). D,L-Glutamic acid γ-methyl ester
(48.4 mg) was treated with trans-4-phenyl-but-3-en-2-one (263 mg)
according to GP2. Flash column chromatography (petrol ether/ethyl
acetate = 1/6) yielded 5g as a colorless oil (168 μmol, 55.5 mg, 56%;
dr > 99:1, ee = 95%).
(R)-4-((R)-1-(3,4-Dimethoxyphenyl)-3-oxobutyl)-2-methyl-4-pro-
pyloxazol-5(4H)-one (5k). D,L-Norvaline (35.1 mg) was treated with
trans-4-(3,4-dimethoxyphenyl)but-3-en-2-one (371 mg) according to
GP2. Flash column chromatography (petrol ether/ethyl acetate = 1/3
to 0/1) yielded 5k as a gummy solid (168 μmol, 58.7 mg, 56%; dr >
99:1, ee = 86%).
C18H21NO5: MW 331.36; [α]D23 −2.55 (c = 0.98, PhH); 1H NMR
(300 MHz, C6D6) δ = 7.20−7.13 (m, 2 H), 7.06−6.94 (m, 3 H), 3.84
(t, J = 7.0, 1 H), 3.29 (s, 3 H), 2.76 (d, J = 6.9, 2 H), 2.28−2.04 (m, 4
H), 1.51 (s, 3 H), 1.47 (s, 3 H); 13C NMR (75 MHz, C6D6) δ =
204.03, 204.02, 178.7, 172.0, 162.4, 138.6, 129.7, 128.2, 127.8, 75.69,
75.68, 51.3, 46.3, 43.8, 30.3, 29.7, 29.1, 14.2; IR (in C6D6) ν = 2953,
1817, 1736, 1717, 1683, 1494, 1454, 1436, 1381, 1296, 1243, 1202,
1164, 1109, 1062, 1022, 901, 761, 739, 704, 669, 643, 620; MS (ESI)
m/z 332.1 (20%, [M + H]+), 304.2 (22%), 286.1 (23%), 262.1 (24%),
245.1 (100%), 230.1 (15%), 212.1 (15%), 171.1 (35%); HRMS (ESI)
m/z calculated for C18H21NO5 + Na 354.1312, found 354.1310.
(R)-4-((1H-Indol-3-yl)methyl)-2-methyl-4-((R)-3-oxo-1-
phenylbutyl)oxazol-5(4H)-one (5h). D,L-Tryptophan (61.3 mg) was
treated with trans-4-phenyl-but-3-en-2-one (263 mg) according to
GP2. Flash column chromatography (petrol ether/ethyl acetate = 1/5)
yielded 5h as a colorless solid (198 μmol, 73.8 mg, 66%; dr > 99:1, ee =
87%).
23
1
C19H25NO5: MW 347.41; [α]D +6.1 (c = 0.31, PhH); H NMR
(300 MHz, C6D6) δ = 6.84 (s, 1 H), 2.82 (dd, J = 9.9, 2.1, 1 H), 6.47
(d, J = 8.1, 1 H), 3.87 (dd, J = 9.2, 4.8, 1 H), 3.45 and 3.31(2 × s, 2 × 3
H), 2.90 (dd, J = 16.8, 9.5, 1 H), 2.75 (dd, J = 16.8, 4.7, 1 H), 1.87−
1.74 (m, 1 H), 1.74−1.62 (m, 1 H), 1.60 (s, 3 H), 1.53 (s, 3 H), 1.27−
1.06 (m, 2 H), 0.72 (t, J = 7.4, 3 H); 13C NMR (75 MHz, C6D6) δ =
204.5, 179.2, 161.6, 149.59, 149.56, 131.1, 122.1, 113.8, 111.7, 77.0,
55.7, 46.5, 44.3, 37.4, 29.9, 17.7, 14.3, 14.0; IR (in C6D6) ν = 2961,
2935, 2875, 2836, 1817, 1715, 1684, 1606, 1590, 1516, 1464, 1423,
1381, 1359, 1260, 1242, 1157, 1144, 1069, 1027, 901, 812, 765, 677,
617; MS (ESI) m/z 370.2 (50%, [M + Na]+), 342.2 (10%), 329.1
(100%), 285.1 (40%), 230.1 (15%), 187.1 (15%); HRMS (ESI) m/z
calculated for C19H25NO5 + Na 370.1625, found 370.1631.
(R)-4-((R)-1-(4-Chlorophenyl)-3-oxobutyl)-2-methyl-4-propyloxa-
zol-5(4H)-one (5l). D,L-Norvaline (35.1 mg) was treated with trans-4-
(4-chlorophenyl)but-3-en-2-one (325 mg) according to GP2. Flash
column chromatography (petrol ether/ethyl acetate = 1/1 to 1/8)
yielded 5l as a colorless gummy solid (177 μmol, 56.5 mg, 59%; dr >
99:1, ee = 93%).
C23H22N2O3: MW 374.43; mp 63.5 − 63.9 °C; [α]D23 −265.3 (c =
1
0.81, PhH); H NMR (300 MHz, C6D6) δ = 7.96−7.87 (m, 1 H),
7.35−7.27 (m, 2 H), 7.23−7.13 (m, 2 H), 7.09−6.93 (m, 5 H), 6.68 (d,
J = 2.5, 1 H), 4.12 (dd, J = 7.7, 5.9, 1 H), 3.29 (d, J = 13.9, 1 H), 3.20
(d, J = 13.9, 1 H), 3.05−2.87 (m, 2 H), 1.58 (s, 3 H), 1.12 (s, 3 H); 13C
NMR (75 MHz, C6D6) δ = 204.6, 179.0, 161.9, 139.3, 136.3, 129.7,
128.3, 128.1, 124.5, 122.0, 120.4, 119.6, 111.4, 109.0, 79.1, 46.5, 44.3,
32.0, 29.9, 13.9; IR (in C6D6) ν = 3412, 3059, 2921, 2279, 1816, 1713,
1685, 1547, 1493, 1456, 1426, 1381, 1357, 1340, 1242, 1163, 1100,
1062, 1011, 984, 904, 743, 703, 670, 621; MS (ESI) m/z 375.2 (35%,
[M + H]+), 347.2 (65%), 315.1 (75%), 246.1 (100%), 229.1 (70%),
218.1 (40%), 201.1 (35%), 171.1 (45%), 130.1 (85%); HRMS (ESI)
m/z calculated for C23H22N2O3 + H 375.1703, found 375.1706.
(R)-2-Methyl-4-((R)-4-methyl-3-oxo-1-phenylpentyl)-4-propylox-
azol-5(4H)-one (5i). D,L-Norvaline (35.1 mg) was treated with trans-4-
C17H20ClNO3: MW 321.80; [α]D23 −2.9 (c = 0.59, PhH); 1H NMR
(300 MHz, C6D6) δ = 7.04−6.94 (m, 4 H), 3.76 (t, J = 7.1, 1 H), 2.66
(d, J = 7.0, 2 H), 1.75−1.62 (m, 1 H), 1.62−1.50 (m, 1 H), 1.52 (s, 3
H), 1.45 (s, 3 H), 1.16−0.99 (m, 2 H), 0.69 (t, J = 7.3, 3 H); 13C NMR
(75 MHz, C6D6) δ = 203.8, 178.9, 161.8, 137.4, 131.1, 128.4, 76.3,
45.9, 43.7, 37.2, 29.8, 17.6, 14.1, 13.9; IR (in C6D6) ν = 2962, 2933,
2875, 1817, 1717, 1684, 1493, 1431, 1381, 1360, 1244, 1201, 1165,
1093, 1069, 1014, 901, 831, 782, 741, 717, 674, 619; MS (ESI) m/z
344.1 (25%, [M + Na]+), 303.1 (100%), 280.1 (20%), 235.1 (100%),
204.0 (5%), 179.1 (10%); HRMS (ESI) m/z calculated for
C17H20ClNO3 + Na 344.1024, found 344.1034.
10852
dx.doi.org/10.1021/jo302177t | J. Org. Chem. 2012, 77, 10846−10855

The Journal of Organic Chemistry
Article
(R)-4-((R)-1-(2-Chlorophenyl)-3-oxobutyl)-2-methyl-4-propyloxa-
zol-5(4H)-one (5m). D,L-Norvaline (35.1 mg) was treated with trans-4-
(2-chlorophenyl)but-3-en-2-one (325 mg) according to GP2. Flash
column chromatography (petrol ether/ethyl acetate = 1/1 to 1/7)
yielded 5m as a colorless oil (111 μmol, 35.6 mg, 37%; dr > 99:1, ee =
92%).
(R)-2-Methyl-4-((S)-2-oxoheptan-4-yl)-4-propyloxazol-5(4H)-one
(5q). D,L-Norvaline (35.1 mg) was treated with trans-hept-3-en-2-one
(177 mg) according to GP2. Flash column chromatography (petrol
ether/ethyl acetate = 3/1 to 1/1) yielded 5q as a colorless oil (210
μmol, 50.1 mg, 70%; dr > 99:1, ee = 86%).
C13H21NO3: MW 239.31; [α]D23 −20.4 (c = 1.23, PhH); 1H NMR
(300 MHz, C6D6) δ = 2.75−2.61 (m, 1 H), 2.43 (dd, J = 16.8, 3.5, 1
H), 2.04 (dd, J = 16.9, 9.5, 1 H), 1.96−1.78 (m, 2 H), 1.63 (s, 3 H),
1.61−1.53 (m, 2 H), 1.21−1.00 (m, 2 H), 0.88 (d, J = 6.7, 3 H), 0.87
(t, J = 7.3, 3 H), 0.69 (t, J = 7.2, 3 H); 13C NMR (75 MHz, C6D6) δ =
207.8, 180.0, 161.2, 75.5, 43.8, 36.6, 36.2, 35.1, 17.4, 14.9, 14.2, 14.0,
7.8; IR (in C6D6) ν = 2965, 2937, 2877, 1816, 1713, 1684, 1459, 1434,
1415, 1380, 1241, 1168, 1108, 1077, 1059, 1032, 982, 896, 866, 650,
620; MS (ESI) m/z 240.3 (1%, [M + H]+), 170.2 (10%), 153.1
(100%); HRMS (ESI) m/z calculated for C13H21NO3 + Na 262.1414,
found 262.1415.
23
C17H20ClNO3: MW 321.80; [α]D −13.2 (c = 0.44, PhH); 1H
NMR (300 MHz, C6D6) δ = 7.21−7.16 (m, 2 H), 6.82 (td, J = 7.7, 1.4,
1 H), 6.72−6.64 (m, 1 H), 4.70 (dd, J = 8.9, 5.4, 1 H), 2.75 (dd, J =
16.8, 5.3, 1 H), 2.63 (dd, J = 16.9, 9.2, 1 H), 1.81−1.69 (m, 2 H), 1.57
and 1.55 (2 × s, 2 × 3 H), 1.19−0.97 (m, 2 H), 0.65 (t, J = 7.1, 3 H);
13C NMR (75 MHz, C6D6) δ = 203.5, 178.3, 161.9, 137.1, 136.1,
130.4, 128.7, 128.1, 126.3, 76.0, 44.9, 41.2, 37.1, 29.3, 17.5, 14.3, 13.8;
IR (in C6D6) ν = 2963, 2933, 2875, 2279, 1821, 1717, 1683, 1475,
1432, 1382, 1360, 1330, 1245, 1199, 1166, 1059, 1037, 1010, 901, 814,
783, 755, 688, 669, 619; MS (ESI) m/z 344.1 (15%, [M + Na]+),
316.1 (5%), 303.1 (100%), 275.1 (5%), 259.1 (5%), 204.0 (5%);
HRMS (ESI) m/z calculated for C17H20ClNO3 + Na 344.1024, found
344.1018.
(R)-4-((R)-1-(4-Bromophenyl)-3-oxobutyl)-2-methyl-4-propyloxa-
zol-5(4H)-one (5n). D,L-Norvaline (35.1 mg) was treated with trans-4-
(4-bromophenyl)but-3-en-2-one (405 mg) according to GP2. Flash
column chromatography (petrol ether/ethyl acetate = 2/1 to 1/6)
yielded 5n as a colorless oil (189 μmol, 69.4 mg, 63%; dr > 99:1, ee =
94%).
(R)-2-Methyl-4-((S)-4-oxohexan-2-yl)-4-propyloxazol-5(4H)-one
(5r). D,L-Norvaline (35.1 mg) was treated with trans-hex-4-en-3-one
(202 mg) according to GP2. Flash column chromatography (petrol
ether/ethyl acetate = 3/1 to 1/1) yielded 5r as a colorless oil (156
μmol, 39.6 mg, 52%; dr > 99:1, ee = 78%).
C14H23NO3: MW 253.34; [α]D23 −19.1 (c = 1.18, PhH); 1H NMR
(300 MHz, C6D6) δ = 2.77−2.66 (m, 1 H), 2.60 (dd, J = 18.0, 5.5, 1
H), 1.99 (dd, J = 18.0, 5.0, 1 H), 1.78−1.38 (3 × m, 4 H), 1.72 (s, 3
H), 1.62 (s, 3 H), 1.22−1.00 (m, 4 H), 0.78 (t, J = 6.8, 3 H), 0.69 (t, J
= 7.1, 3 H); 13C NMR (75 MHz, C6D6) δ = 205.1, 180.3, 161.2, 76.0,
43.8, 39.3, 36.6, 33.3, 21.0, 17.3, 14.3, 14.2, 13.9; IR (in C6D6) ν =
2961, 2933, 2874, 1815, 1716, 1684, 1459, 1433, 1381, 1362, 1241,
1167, 1055, 1036, 1005, 896, 743, 701, 665, 618; MS (ESI) m/z 276.2
(10%, [M + Na]+), 248.2 (8%), 235.1 (100%), 207.1 (5%), 191.1
(5%), 167.1 (10%); HRMS (ESI) m/z calculated for C14H23NO3 + Na
276.1570, found 276.1558.
C17H20BrNO3: MW 366.25; [α]D23 −4.2 (c = 0.93, PhH); 1H NMR
(300 MHz, C6D6) δ = 7.20−7.13 (m, 2 H), 6.94−6.85 (m, 2 H), 3.74
(t, J = 7.1, 1 H), 2.64 (d, J = 7.0, 2 H), 1.74−1.61 (m, 1 H), 1.61−1.48
(m, 1 H), 1.51 (s, 3 H), 1.44 (s, 3 H), 1.16−0.99 (m, 2 H), 0.68 (t, J =
7.3, 3 H); 13C NMR (75 MHz, C6D6) δ = 203.8, 178.9, 161.8, 137.9,
131.4, 121.9, 76.2, 46.0, 43.7, 37.2, 29.8, 17.6, 14.1, 13.9; IR (in C6D6)
ν = 2962, 2932, 2875, 2359, 1818, 1717, 1684, 1489, 1431, 1381, 1360,
1244, 1201, 1165, 1072, 1010, 900, 828, 781, 740, 715, 672, 619, 537;
MS (ESI) m/z 390.1 (45%, [M + Na]+), 347.0 (100%), 281.0 (90%),
201.0 (20%), 144.1 (50%), 129.1 (10%); HRMS (ESI) m/z calculated
for C17H20BrNO3 + Na 390.0500, found 390.0495.
(R)-2-Methyl-4-((R)-1-(4-nitrophenyl)-3-oxobutyl)-4-propyloxa-
zol-5(4H)-one (5o). D,L-Norvaline (35.1 mg) was treated with trans-4-
(4-nitrophenyl)but-3-en-2-one (344 mg) according to GP2. Flash
column chromatography (petrol ether/ethyl acetate = 1/3) yielded 5o
as a colorless gummy solid (123 μmol, 41.3 mg, 41%; dr > 99:1, ee =
97%).
(R)-2-Methyl-4-((S)-4-oxohexan-2-yl)-4-propyloxazol-5(4H)-one
(5s). D,L-Norvaline (35.1 mg) was treated with trans-5-methylhex-3-en-
2-one (202 mg) according to GP2. Flash column chromatography
(petrol ether/ethyl acetate = 2/1) yielded 5s as a colorless oil (78
μmol, 19.5 mg, 26%; dr > 99:1, ee = 62%).
C14H23NO3: MW 253.34; [α]D23 −18.1 (c = 0.16, PhH); 1H NMR
(300 MHz, C6D6) δ = 2.90−2.81 (m, 1 H), 2.62 (dd, J = 18.5, 6.6, 1
H), 2.07 (dd, J = 18.3, 4.0, 1 H), 1.96−1.72 (m, 2 H), 1.71 (s, 3 H),
1.60 (s, 3 H), 1.59−1.45 (m, 2 H), 1.15−0.98 (m, 1 H), 0.77 (d, J =
6.9, 3 H), 0.69 (d, J = 7.0, 3 H), 0.66 (t, J = 7.7, 3 H); 13C NMR (75
MHz, C6D6) δ = 205.3, 180.2, 160.9, 77.1, 44.1, 39.3, 38.0, 29.3, 29.3,
23.4, 17.8, 17.1, 14.3, 13.8, 13.7; IR (in C6D6) ν = 2962, 2931, 2876,
2358, 2342, 1817, 1758, 1716, 1686, 1466, 1433, 1383, 1355, 1243,
1170, 1097, 1034, 1013, 970, 945, 899; MS (ESI) m/z 254.2 (5%, [M
+ H]+), 212.2 (100%), 166.2 (60%); HRMS (ESI) m/z calculated for
C14H23NO3 + Na 276.1570, found 276.1575.
C17H20N2O5: MW 332.35; [α]D23 −10.0 (c = 0.90, PhH); 1H NMR
(300 MHz, C6D6) δ = 7.79−7.71 (m, 2 H), 7.01−6.94 (m, 2 H), 3.75
(dd, J = 8.0, 5.8, 1 H), 2.70−2.53 (m, 2 H), 1.71−1.47 (m, 2 H), 1.53
(s, 3 H), 1.45 (s, 3 H), 1.13−0.95 (m, 2 H), 0.68 (t, J = 7.2, 3 H); 13C
NMR (75 MHz, C6D6) δ = 203.4, 178.6, 162.0, 147.6, 145.9, 130.2,
123.2, 75.9, 46.1, 43.4, 37.2, 29.7, 17.5, 14.1, 13.9; IR (in C6D6) ν =
2963, 2933, 2875, 1817, 1716, 1682, 1604, 1519, 1431, 1382, 1345,
1317, 1277, 1242, 1166, 1110, 1068, 1014, 899, 854, 735, 702, 671,
618; MS (ESI) m/z 333.1 (1%, [M + H]+), 263.1 (35%), 246.1
(100%); HRMS (ESI) m/z calculated for C17H20N2O5 + Na 355.1264,
found 355.1271.
Synthesis of the α,α-Disubstituted α-Amino Acids. (2R,3R)-2-
Amino-2-methyl-5-oxo-3-phenylhexanoic acid hydrochloride (9).
Synthesis starting from azlactone 10 with known configuration:
According to literature,6a the azlactone 10 (1.00 equiv, 38.0 μmol, 12.2
mg, 75% ee) was stirred in aqueous HCl (1 M, 2 mL) in a preheated
oil bath to 80 °C for 3 h. The mixture was cooled to room temperature
and subsequently filtered through cotton. After dilution with
demineralized water the filtrate was washed twice with CH2Cl2. All
volatiles were removed under reduced pressure to yield 9 as a colorless
(R)-4-((S)-1-(Furan-2-yl)-3-oxobutyl)-2-methyl-4-propyloxazol-
5(4H)-one (5p). D,L-Norvaline (35.1 mg) was treated with trans-4-
(furan-2-yl)but-3-en-2-one (245 mg) according to GP2. Flash column
chromatography (petrol ether/ethyl acetate = 2/1 to 1/2) yielded 5p
as a colorless oil (174 μmol, 48.2 mg, 58%; dr > 99:1, ee = 84%).
23
solid (27.7 μmol, 7.5 mg, 73%); [α]D −109.8 (c = 0.45, H2O). All
other data are in accordance with the literature.
23
1
C15H19NO4: MW 277.32; [α]D +22.5 (c = 0.67, PhH); H NMR
(300 MHz, C6D6) δ = 6.97 (dd, J = 1.9, 0.7, 1 H), 6.08 (d, J = 3.5, 1
H), 5.97 (dd, J = 3.4, 1.9, 1 H), 4.05 (dd, J = 9.5, 4.3, 1 H), 2.89 (dd, J
= 17.4, 9.6, 1 H), 2.64 (dd, J = 17.4, 4.4, 1 H), 1.79−1.52 (m, 2 H),
1.574 and 1.571 (2 × s, 2 × 3 H), 1.21−0.97 (m, 2 H), 0.67 (t, J = 7.3,
3 H); 13C NMR (75 MHz, C6D6) δ = 203.8, 178.9, 161.8, 153.1, 141.9,
110.7, 108.4, 75.7, 41.9, 40.7, 36.8, 29.5, 17.5, 14.3, 13.9; IR (in C6D6)
ν = 2963, 2934, 2876, 1818, 1717, 1683, 1503, 1432, 1382, 1361, 1277,
1243, 1163, 1148, 1071, 1012, 899, 813, 740, 653, 619, 600; MS (ESI)
m/z 300.1 (100%, [M + Na]+), 259.1 (12%), 191.1 (10%); HRMS
(ESI) m/z calculated for C15H19NO4 + Na 300.1206, found 300.1200.
Synthesis starting from azlactone 5a: A mixture of the azlactone 5a
(1.00 equiv, 122 μmol, 32.4 mg, 98% ee) in aqueous HCl (1 M, 5 mL)
was stirred in a preheated oil bath at 80 °C for 3 h. The mixture was
cooled to room temperature, and after dilution with demineralized
water, the mixture was washed twice with CH2Cl2. All volatiles were
removed under reduced pressure to yield 9 as a colorless solid (120
23
μmol, 32.4 mg, 98%); [α]D −159.1 (c = 1.00, H2O).
C13H17NO3: MW 271.74; mp 89.8 − 92.4 °C; 1H NMR (300 MHz,
D2O) δ = 7.46−7.34 (m, 3 H), 7.34−7.22 (m, 2 H), 3.91 (t, J = 8.3, 1
H), 3.70 (dd, J = 20.5, 8.4, 1 H), 3.58 (dd, J = 20.5, 8.3, 1 H), 2.66 (s, 3
H), 1.76 (s, 3 H); 13C NMR (75 MHz, D2O) δ = 196.3, 171.6, 135.4,
10853
dx.doi.org/10.1021/jo302177t | J. Org. Chem. 2012, 77, 10846−10855

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Article
128.9, 128.6, 127.8, 79.3, 51.8, 43.6, 21.6, 18.3; IR (ATR) ν = 3354,
2869, 2738, 1727, 1675, 1455, 1405, 1377, 1328, 1151, 1029, 921, 845,
777; MS (ESI) m/z 218.1 (6%, [M − H2O − HCl]+), 172.1 (100%),
131.1 (27%); HRMS (ESI) m/z calculated for [C13H16NO2]+ (M −
H2O − HCl) 218.1176, found 218.1170.
A. D.; Amarante, G. W.; Wang, Z. J.; Luparia, M.; Toste, F. D. J. Am.
Chem. Soc. 2011, 133, 3517. (l) Terada, M.; Moriya, K.; Kanomata, K.;
Sorimachi, K. Angew. Chem., Int. Ed. 2011, 50, 12586.
(5) Recent reviews about conjugate additions: (a) Kanai, M.;
Shibasaki, M. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
Wiley: New York, 2000; pp 569−592. (b) Krause, N.; Hoffmann-
(2R,3R)-2-Acetamido-3-(4-methoxyphenyl)-5-oxo-2-propylhexa-
noic acid (11). The azlactone 5j (1.00 equiv, 29.9 μmol, 9.5 mg, 99%
ee) was stirred in acetonitrile/water (3 mL, 1/1) at room temperature
for 64 h. After this time, all volatiles were removed under reduced
pressure. The crude product was then washed with cold demineralized
water (ca. 1 mL) once and dried in a vacuum to yield pure N-acetyl
amino acid 11 as an off-white solid (25.1 mmol, 8.4 mg, 84%).
Roder, A. Synthesis 2001, 171. (c) Christoffers, J.; Baro, A. Angew.
̈
Chem., Int. Ed. 2003, 42, 1688. (d) Christoffers, J.; Koripelly, G.;
Rosiak, A.; Rossle, M. Synthesis 2007, 1279.
̈
(6) (a) Weber, M.; Jautze, S.; Frey, W.; Peters, R. J. Am. Chem. Soc.
2010, 132, 12222. (b) Weber, M.; Frey, W.; Peters, R. Adv. Synth.
Catal. 2012, 354, 1443. (c) full paper: Weber, M.; Jautze, S.; Frey, W.;
Peters, R. Chem.Eur. J. 2012, 18, 14792.
23
C18H25NO5: MW 335.39; mp 72.5−73.1 °C; [α]D −42.4 (c =
0.21, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ = 7.15−7.07 (m, 2 H),
6.84−6.77 (m, 2 H), 6.42 (s, 1 H), 3.96 (dd, J = 8.7, 5.0, 1 H), 3.77 (s,
3 H), 3.37 (dd, J = 17.5, 4.7, 1 H), 2.99 (dd, J = 17.5, 4.7, 1 H), 2.44−
2.29 (m, 1 H), 2.05 and 2.04 (2 × s, 2 × 3 H), 1.91−1.77 (m, 1 H),
1.36−1.20 (m, 1 H), 1.20−1.07 (m, 1 H), 0.89 (t, J = 7.2, 3 H); 13C
NMR (75 MHz, CDCl3) δ = 208.3, 174.8, 170.8, 158.8, 130.9, 113.6,
68.1, 55.1, 45.5, 45.2, 34.0, 30.5, 24.2, 17.7, 14.0; IR (in CDCl3) ν =
3371, 2958, 2924, 2853, 2360, 1715, 1612, 1513, 1463, 1440, 1372,
1302, 1250, 1180, 1033, 910, 834, 734, 648, 581; MS (ESI) m/z 358.2
(85%, [M + Na]+), 340.2 (15%), 298.1 (75%), 270.1 (100%), 181.1
(15%); HRMS (ESI) m/z calculated for C18H25NO5 + Na 358.1625,
found 358.1636.
(7) Selected 1,4 additions of azlactones to alternative acceptors
́
classes: (a) Aleman, J.; Milelli, A.; Cabrera, S.; Reyes, E.; Jørgensen, K.
A. Chem.Eur. J. 2008, 14, 10958. (b) Cabrera, S.; Reyes, E.; Aleman
́
,
J.; Milelli, A.; Kobbelgaard, S.; Jørgensen, K. A. J. Am. Chem. Soc. 2008,
130, 12031. (c) Uraguchi, D.; Ueki, Y.; Ooi, T. Science 2009, 326, 120.
(d) Hayashi, Y.; Obi, K.; Ohta, Y.; Okamura, D.; Ishikawa, H. Chem.
́
Asian J. 2009, 4, 246. (e) Alba, A.-N. R.; Companyo, X.; Valero, G.;
Moyano, A.; Rios, R. Chem.Eur. J. 2010, 16, 5354. (f) Jiang, H.;
Paixao, M. W.; Monge, D.; Jørgensen, K. A. J. Am. Chem. Soc. 2010,
̃
132, 2775. (g) Alba, A.-N. R.; Valero, G.; Calbet, T.; Font-Bardia, M.;
Moyano, A.; Rios, R. Chem.Eur. J. 2010, 16, 9884.
(8) (a) Peters, R.; Xin, Z.-q.; Fischer, D. F.; Schweizer, W. B.
Organometallics 2006, 25, 2917. (b) Weiss, M. E.; Fischer, D. F.; Xin,
Z.-q.; Jautze, S.; Schweizer, W. B.; Peters, R. Angew. Chem., Int. Ed.
2006, 45, 5694. (c) Fischer, D. F.; Xin, Z.-q.; Peters, R. Angew. Chem.,
Int. Ed. 2007, 46, 7704. (d) Xin, Z.-q.; Fischer, D. F.; Peters, R. Synlett
2008, 1495. (e) Fischer, D. F.; Barakat, A.; Xin, Z.-q.; Weiss, M. E.;
Peters, R. Chem.Eur. J. 2009, 15, 8722. (f) Peters, R.; Xin, Z.-q.;
Maier, F. Chem.Asian J. 2010, 5, 1770.
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedures, NMR spectra, HPLC data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Reviews about ferrocene palladacycles in asymmetric catalysis:
(a) Richards, C. J. In Chiral Ferrocenes in Asymmetric Catalysis; Dai, L.-
X., Hou, X.-L., Eds.; Wiley-VCH: Weinheim, 2010; pp 337−368.
(b) Peters, R.; Fischer, D. F.; Jautze, S. Top. Organomet. Chem. 2011,
33, 139.
AUTHOR INFORMATION
Corresponding Author
*E-mail: rene.peters@oc.uni-stuttgart.de.
■
Notes
(10) First preparation of an enantiopure 2-ferrocenylimidazoline:
Peters, R.; Fischer, D. F. Org. Lett. 2005, 7, 4137.
The authors declare no competing financial interest.
(11) An excess of enone (6 equiv in Table 1, entry 1) was found to
be necessary for useful yields. On the other hand, regio-, enantio- and
diastereoselectivity remain unaffected by lower amounts of enone
under otherwise identical conditions. 1 equiv of 4a: 25% yield, dr >
99:1, 99% ee. 2 equiv of 4a: 34% yield, dr > 99:1, 97% ee. 3 equiv of 4a:
44% yield, dr > 99:1, 98% ee. 4 equiv of 4a: 50% yield, dr > 99:1, 99%
ee.
(12) Under similar conditions, the bis-Pd-catalyst provided a 1.7:1
mixture of C-4 and C-2 addition product after 18 h using norvaline.
Kinetic investigtions showed that both regioisomers were initially
formed with nearly identical rates, but the C-2 addition product
partially decomposes at longer reaction times (see ref 6b, c).
(13) Eitel, S. H.; Bauer, M.; Schweinfurth, D.; Deibel, N.; Sarkar, B.;
ACKNOWLEDGMENTS
This work was financially supported by the Deutsche
Forschungsgemeinschaft (DFG, PE 818/4-1).
■
REFERENCES
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(15) Unfortunately, phenyglycine provided no desired product (not
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(16) No product was obtained with chalcone or cinnamic acid
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