Biotransformations of racemic 2,3-allenenitriles in biphasic systems: Synthesis and transformations of enantioenriched axially chiral 2,3-allenoic acids and their derivatives

Article abstract of DOI:10.1021/jo500228z

Catalyzed by Rhodococcus erythropolis AJ270 whole cells in an aqueous phosphate buffer-n-hexane biphasic system, racemic axially chiral 2,3-allenenitriles underwent hydrolysis to afford enantioenriched (aR)-2,3-allenamides and (aS)-2,3-allenoic acids with

Full text of DOI:10.1021/jo500228z

Article
pubs.acs.org/joc
Biotransformations of Racemic 2,3-Allenenitriles in Biphasic Systems:
Synthesis and Transformations of Enantioenriched Axially Chiral 2,3-
Allenoic Acids and Their Derivatives
Yu-Fei Ao,† De-Xian Wang,† Liang Zhao,‡ and Mei-Xiang Wang*,‡
†Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190, China
‡Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Ministry of Education, Tsinghua University, Beijing
100084, China
S
* Supporting Information
ABSTRACT: Catalyzed by Rhodococcus erythropolis AJ270 whole
cells in an aqueous phosphate buffer−n-hexane biphasic system,
racemic axially chiral 2,3-allenenitriles underwent hydrolysis to afford
enantioenriched (aR)-2,3-allenamides and (aS)-2,3-allenoic acids with
ee’s up to >99.5%. Overall biotransformations proceeded through the
nitrile hydratase-catalyzed efficient but nonselective hydration of
nitriles followed by the amide hydrolysis catalyzed by the substrate-
dependent enantioselective amidase. The application of the method
has been demonstrated by the transformations of the resulting allene
products into highly functionalized heterocyclic compounds with axial
chirality of reactants being entirely transferred into or expressed as
point chirality of products.
Biotransformations of nitriles proceed through either the
nitrilase-catalyzed direct conversion of nitriles into carboxylic
acids or the nitrile hydratase-catalyzed hydration of nitriles
followed by the amidase-effected amide hydrolysis.13 Nitrile
biotransformations have become attractive methods in organic
synthesis because of high biocatalytic efficiency, excellent
selectivity, and environmentally benign conditions.14 Studies
have also demonstrated convincingly that biotransformations of
nitriles complement the existing asymmetric chemical and
enzymatic methods for the synthesis of chiral carboxylic acids
and their derivatives.15 It is especially worth noting that, in
comparison with enzymatic ester hydrolysis, one distinct
feature of biocatalysis of nitrile is the straightforward generation
of enantiopure amides, which are invaluable compounds in
synthetic chemistry, in addition to the formation of enantiopure
carboxylic acids. Among a few widely used nitrile-hydrolyzing
biocatalysts,14,15 Rhodococcus erythropolis AJ270 is a nitrile
hydratase and amidase-containing microbial whole cell
catalyst.16 The versatility of this whole-cell biocatalyst has
been exemplified by enantioselective biotransformations of a
large number of structurally diverse racemic nitriles including
functionalized nitriles and (hetero)cyclic nitriles to produce
highly enantiopure carboxylic acid and amide products.13,17 It
has been also revealed that while the nitrile hydratase exhibits
low or virtually no enantioselectivity, the amidase is highly
INTRODUCTION
■
As cumulative diene species, allenes and their derivatives have
now become powerful and versatile entities in organic
synthesis.1 One of the unique features of allenes is their axial
chirality. The molecular symmetry is broken when substituents
are introduced properly into a parent allene skeleton. In
contrast to a vast majority of literatures that report the
synthetic applications of allene derivatives, it is quite noticeable
that the use of optically active axially chiral allenes in synthesis
has been rare.1,2 This scarcity is attributable mainly to the lack
of general methods for the preparation of enantiopure allene
compounds, a formidable challenge faced by synthetic
chemists.1f,3,4 As functionalized allenes, 2,3-allenoic acids and
their derivatives5 are highly useful intermediates in the synthesis
of diverse organic compounds. Unfortunately, the accessibility
to these important building blocks in enantiomerically pure
form is still limited.6 For instance, enantiopure precursors are
required in the synthesis of 2,3-allenoic acids and derivatives
through so-called central-to-axial chirality transfer reactions.7−9
While organocatalytic kinetic resolution is confined to 1,3-
dipolar cycloaddition of 2,3-allenoates,10 kinetic resolutions
through biocatalytic hydrolysis of 2,3-allenoates give moderate
to good enantioselectivity.11 Until very recently, catalytic
asymmetric syntheses of axially chiral 2,3-allenoates have
been scatteringly reported.12 It is therefore highly desirable to
develop new synthetic methods and to provide enantioenriched
novel 2,3-allenoic acids and their derivatives.
Received: January 31, 2014
Published: March 14, 2014
© 2014 American Chemical Society
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Article
enantioselective.13,17 The amidase has been therefore utilized
recently to achieve enantioselective desymmetrization of
prochiral18 and meso dicarboxamides.19
Table 1. Optimization of Biotransformations of Racemic
Nitrile 3a
a
Our continuous interest in developing synthetic biocatalysis
of nitriles and amides led us to investigate the enantioselective
biotransformations of axially chiral nitriles and amides. We
report herein the Rhodococcus erythropolis AJ270 whole-cell
catalyzed transformations of racemic 2,3-allenenitriles in
biphasic systems. The reaction afforded enantioenriched 2,3-
allenamides and 2,3-allenoic acids in good yields with
enantiomeric excess values up to >99.5%. To the best of our
knowledge, the study represents the first successful example in
enantioselective biotransformations of axially chiral nitriles, as
the very first attempt of biocatalytic hydrolysis of racemic 4-
ethyl-4-methyl-2,3-allenenitrile gave appallingly low conversion
and no enantioselectivity.20 Synthetic potential of the resulting
chiral allene derivatives is demonstrated by the synthesis of
densely functionalized heterocyclic compounds from highly
diastereoselective intramolecular bromolactamization and
cycloaddition reactions with furan and azomethine ylide. In
all cases, axial chirality of allenes is fully expressed as point
chirality (stereogenic center) in products.
solvent +
additive
volume
(mL)
4a
ee
5a
ee
dimer
b
b
c
b
d
entry
(%)
(%)
(%)
(%)
(%)
e
1
−
−
−
−
20
18
92.0
−
−
−
84.0
17
−
−
−
29
90.0
−
−
−
90.6
55
91
87
85
22
f
2
−
trace
3
4
5
toluene
MTBE
20
−
40
n-octane +
ether
18 + 2
6
c-hexane +
ether
18 + 2
18 + 2
9 + 1
−
−
−
−
88
19
22
19
18
25
7
n-hexane +
ether
35
35
37
37
−
94.8
90.1
93.2
88.2
−
37
34
36
32
−
90.2
88.5
90.4
89.4
−
8
n-hexane +
ether
9
n-hexane +
ether
27 + 3
45 + 5
18 + 2
10
n-hexane +
ether
f
11
n-hexane +
ether
RESULTS AND DISCUSSION
■
Racemic 2,3-allenenitriles 3 were prepared from the reaction
between α-haloalkanenitrile-derived ylides 1 and acyl chlorides
2 in the presence of triethylamine following a literature
method21 (Scheme 1). Moderate chemical yields were obtained
because reaction always gave alkyne as a byproduct.
a
A mixture of substrate 3a (1 mmol), ether, and organic solvent was
injected into the suspension of Rhodococcus erythropolis AJ270 (2 g wet
weight) in neutral phosphate buffer (0.1 M, 50 mL), and then the
b
c
mixture was incubated at 30 °C. Isolated yield. Determined by chiral
d
HPLC analysis. Determined by chiral HPLC analysis of methyl ester
5a′, which was obtained efficiently from the reaction with CH2N2.
e
f
The reaction was performed for 4 h. In the absence of whole cell
Scheme 1. Preparation of Racemic 2,3-Allenenitriles 1a−l
biocatalyst.
to microbial cells. A small amount of diethyl ether (10%) was
also added to increase the solubility of nitrile in alkanes. As
summarized in Table 1, in biphasic systems that use toluene or
methyl t-butyl ether (MTBE) as organic phase, almost no
hydrolysis of nitrile was observed after 24 h (entries 3 and 4,
Table 1). When cyclohexane was used as organic phase,
biotransformations did not take place either (entry 6, Table 1).
In all these cases, a mixture of dimers derived from 3a was
formed in high yields in 24 h. Although the dimerization
reactions proceeded slower than in pure aqueous buffer, the
presence of organic solvents employed had pronouncedly a
detrimental effect on catalytic activity of the nitrile hydratase.
To our delight, allenenitrile 3a underwent biocatalytic
hydrolysis in a mixture of aqueous phosphate buffer and n-
hexane or n-octane with diethyl ether as an additive (entries 5
and 7, Table 1). Except for the formation of dimers in about
20% yield, all starting material was transformed into (aR-(−)-4-
phenyl-2,3-allenamide 4a and (aS)-(+)-4-phenyl-2,3-allenoic
acid 5a24 in good yields and with high enantiomeric excess
values (ee) of 94.8 and 90.2%, respectively (entry 7, Table 1).
Gratifyingly, both 2,3-allenamide and 2,3-allenoic acid products
were stable, and they did not form dimeric compounds under
the reaction conditions. In terms of chemical yields of products,
the amidase involved in Rhodococcus erythropolis AJ270 showed
slightly higher enzyme activity in a biphasic buffer-n-hexane
system than in a buffer-n-octane mixture (entries 5 and 7, Table
1). Variation of the volume of organic phase from 10 to 50 mL
did not remarkably influence performance of both the nitrile
hydratase and the amidase within microbial cells, as only
marginal differences in chemical yields and ee values of the
We first examined the biotransformations of nitrile 3a under
standard biocatalytic conditions. Thus, racemic 4-phenyl-2,3-
allenenitrile 3a was incubated with Rhodococcus erythropolis
AJ270 whole cells16 at 30 °C in neutral aqueous phosphate
buffer. Unfortunately, the desired amide and acid products were
obtained only in very low yields. Instead of enzymatic
hydrolysis, allenenitrile 3a underwent rapid and predominant
dimerization reactions to give a mixture of diastereoisomers as
reported previously in literature.22 Dimerizations were not
enzymatic processes, as in the absence of whole-cell catalyst
dimerizations occurred spontaneously in aqueous phosphate
buffer (entries 1 and 2, Table 1). Since allenenitrile 3a was
stable in organic media as it was prepared, dimerizations of 3a
were most probably promoted by water. Assuming the nitrile
hydratase within Rhodococcus erythropolis AJ270 is active against
substrate 3a and it is able to tolerate organic solvents, effective
biotransformations in aqueous and organic biphasic systems23
would be anticipated. To test this working hypothesis, we then
attempted biotransformations in biphasic systems. To create a
biphasic system, several water-immiscible solvents were
optimized except ethyl acetate and chloroform that are harmful
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a
Table 2. Biotransformations of Racemic Nitriles 3
b
c
b
d
entry
3
t (h)
4 (%) (ee %)
5 (%) (ee %)
e
1
3a (R1 = R2 = H, R3 = Ph)
5
4a (32) (61.2)
4a (35) (94.8)
4b (49) (80.6)
4c (45) (49.8)
5a (11) (90.2)
5a (37) (90.2)
5b (49) (84.2)
5c (51) (49.0)
5d (44) (26.0)
5e (−)
f
2
3a (R1 = R2 = H, R3 = Ph)
24
6.5
6.5
44
120
72
7
3
4
5
3b (R1 = R2 = H, R3 = Bn)
3c (R1 = R2 = H, R3 = Ph(CH2)2)
3d (R1 = R2 = H, R3 = c-HexCH2)
3e (R1 = Me, R2 = H, R3 = Bn)
3f (R1 = H, R2 = Me, R3 = Ph)
3g (R1 = H, R2 = Me, R3 = Bn)
3h (R1 = R2 = H, R3 = Allyl)
3i (R1 = R2 = H, R3 =n-Pr)
4d (54) (15.8)
4e (−)
4f (39) (>99.5)
4g (42) (43.4)
4h (91) (2.2)
4i (90) (3.2)
g
6
h
7
5f (38) (>99.5)
i
8
5g′ (50) (48.4)
j
9
96
96
5h (−)
5i (−)
k
10
a
A mixture of substrate 3 (1 mmol), ether, and n-hexane was injected into the suspension of Rhodococcus erythropolis AJ270 (2 g wet weight) in
b
c
neutral phosphate buffer (0.1 M, 50 mL), and then the mixture was incubated at 30 °C. Isolated yield. Determined by chiral HPLC analysis.
d
e
Determined by chiral HPLC analysis of methyl esters 5′, which were obtained efficiently from the reaction with CH2N2. Optically inactive nitrile
f
g
h
3a (38%, 2.6% ee) was recovered. Dimer of 3a (19%) was formed. Starting nitrile 3e (93%) was recovered. Dimer of 3f (18%) was formed.
i
j
Without isolation and purification, acid product 5g was converted directly into methyl ester 5g′ after biocatalytic reaction. The nitrile 3h was
k
hydrated completely in 2 h. The nitrile 3i was hydrated completely in 2.5 h.
products were yielded (entries 8−10, Table 1). It should be
addressed that effective biotransformations of allenenitrile 3a in
a biphasic system indicate clearly the inhibition of spontaneous
dimerization of allenenitrile. This has been exemplified by a
control experiment from which dimeric products were obtained
in 25% yield (entry 11, Table 1). More importantly,
Rhodococcus erythropolis AJ270 whole-cell catalyst or the nitrile
hydratase and amidase involved are stable in a biphasic system
of buffer and n-hexane or n-octane, showing high enzymatic
activity and good enantioselectivity.
allenenitrile 3c was also observed, and enantioselectivity was
however only moderate (entry 4, Table 2). In sharp contrast to
4-benzyl-2,3-allenenitrile 3b (entry 3, Table 2), 4-cyclo-
hexylmethyl-2,3-allenenitrile 3d took 44 h to furnish the
corresponding amide and acid products in very low ee’s (entry
5, Table 2). These results suggest a beneficial effect of a phenyl
ring of 4-substituted 2,3-allenenitrile substrates on kinetic
resolution catalyzed by Rhodococcus erythropolis AJ270. An
optimally positioned phenyl substituent can result in both high
reaction velocity and enantioselectivity. In addition to
electronic effect, steric effect of the substrates was also vital
to the amidase-catalyzed reaction. A stark contrast was
evidenced by the biotransformations between 4-benzyl-2-
methyl-2,3-allenenitrile 3e and 4-methyl-4-phenyl-2,3-alleneni-
trile 3f. While the former substrate remained almost intact after
5 days’ interaction with biocatalyst, the later underwent
effective biotransformations within 72 h to afford highly
enantiopure allenamide (aR)-4f and allenoic acid (aS)-5f in
good yields (entries 6 and 7, Table 2). The presence of methyl
substituent at 2-position of 2,3-allenenitrile 3e most probably
increases the steric hindrance of cyano group, prohibiting
therefore the accessibility of cyano group by the active site of
the nitrile hydratase. In the case of 3f and 4f, methyl group at 4-
position imposes probably little steric influence on the
interaction between cyano or amido functional group and the
nitrile hydratase or the amidase, respectively. Most strikingly,
while 4-allyl-2,3-allenenitrile 3h and 4-n-propyl-2,3-allenenitrile
3i were hydrated very efficiently by the nitrile hydratase in a
biphasic system, the amidase-catalyzed hydrolysis of resulting
amides 4h and 4i was not observed at all. It was unexpected
that the amidase did not function on substrate 4h, as it was
contrary to our previous observation that the amidase-catalyzed
kinetic resolution is accelerated by the presence of a carbon−
carbon unsaturated bond of amide substrates.27
Encouraged by the highly enantioselective biotransforma-
tions of 3a in aqueous buffer−n-hexane biphasic media, a
number of racemic 2,3-allenenitriles 3b−i (Scheme 1) were
subjected to biocatalytic transformations (Table 2). To
facilitate the determination of enantiomeric excess values of
products, 2,3-allenoic acids were converted almost quantita-
tively into their methyl esters using CH2N2. As monitored by
TLC analysis, we found that all nitrile substrates tested were
completely hydrated within 2 to 10 h to give virtually optically
inactive 2,3-allenamides. It is worth mentioning that 2,3-
allenamides are difficult to prepare by other synthetic methods.
Chemical hydration of 2,3-allenenitriles, for example, did not
lead to amides because of the lability of starting nitriles under
chemical hydrolytic reaction conditions.25 To understand the
enantioselectivity of the nitrile hydratase toward racemic axially
chiral 2,3-allenenitriles, the biocatalytic hydration of 3a was
quenched when about a half amount of starting nitrile was
consumed. The ee value of recovered 3a was only 2.6% (entry
1, Table 2), indicating very low enantioselectivity of the nitrile
hydratase. This is in agreement with previous conclusion that
there is a spacious pocket near the active site.17,26 Noticeably, as
indicated by the results compiled in Table 2, both biocatalytic
efficiency and enantioselectivity of amide hydrolysis or overall
reactions were strongly determined by the structures of the
substrates. The replacement of phenyl group of 3a (entry 2,
Table 2) by benzyl led racemic 4-benzyl-2,3-allenenitrile 3b
(entry 3, Table 1) to undergo a much more rapid reaction than
3a to produce almost quantitatively (aR)-(−)-amide 4b and
(aS)-(+)-acid 5b in 80.6 and 84.2% ee values, respectively.
Equally efficient reaction of racemic 4-(2-phenylethyl)-2,3-
The previous studies have concluded that the catalytic
efficiency and enantioselectivity of the amidase within
Rhodococcus erythropolis AJ270 cell are determined by the
structures of different types of amides.13,17−19 To a specific
catalog of racemic amides of central chirality, dependence of
biocatalysis on the nature of substituents has been observed.
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For example, the amidase-catalyzed kinetic resolution of 2-allyl-
3-phenylpropanamide proceed more efficiently and enantiose-
lectively than that of 3-phenyl-2-n-propylpropanamide, attribut-
ing to the presence of an unsaturated carbon−carbon bond
binding domain of the amidase.27 The unprecedented high
sensitivity of the amidase toward the variation of a substituent
and the substitution pattern of 2,3-allenamides 4 suggested a
unique influence of axial chirality on biocatalysis. In other
words, the interaction between perpendicular substituent(s) at
γ-position to amido functional group of 2,3-allenamides and the
active site of the amidase played a subtle but critical role in
dictating catalytic efficiency and enantiocontrol. Although
elucidation of detailed mechanism of enantioselective amidase
awaits further study, the unusual profile of biotransformation of
aforementioned axially chiral amides implies that the amidase
may comprise most likely a relatively deep-buried and space-
limited active site.
(aR)-4f underwent bromolactamization reaction to furnish the
formation of lactam 12, which contains a tetrasubstituted
carbon center. It is interesting to note that, as Ma and Xie30
showed previously, intramolecular cyclization of racemic N-
benzyl-4-methyl-4-phenyl-2,3-allenamide and N-benzyl-4,4-di-
methyl-2,3-allenamide gave an iminolactone (resulting from the
reaction of the oxygen of amide moiety as a nucleophile) and a
lactam (resulting from the reaction of the nitrogen of amide as
a nucleophile), respectively. Regioselective cyclization reactions
was rationalized as the result of the steric hindrance of the 4,4-
disubstituents at allenamides. In our case, however, no
iminolactone product was observed at all. It appeared clearly
that not only the substituents directly attaching to allene moiety
but also the steric effect of N-substituent of amide would
influence substantially the course of cyclization reactions.
Remarkably, in all cases, axial chirality of allene reactants was
fully transferred into or expressed as point chirality (stereogenic
center) in the densely functionalized heterocyclic products, as
the enantiomeric excess values of products were almost
identical to that of the starting materials.
The resulting axially chiral allenes are conceivably important
intermediates.1−3 To demonstrate their utility in organic
synthesis, cycloaddition reactions of enantioenriched (aR)-4a
with furan and azomethine ylide were implemented. As
illustrated in Scheme 2, Diels−Alder reaction between (aR)-
CONCLUSION
■
In summary, we have shown Rhodococcus erythropolis AJ270, a
nitrile hydratase-amidase containing microbial whole cell
catalyst, is able to catalyze hydrolysis of racemic 2,3-
allenenitriles in an aqueous phosphate buffer−n-hexane
biphasic system. The method provides a unique approach to
enantioenriched axially chiral 2,3-allenamides and 2,3-allenoic
acids. The overall catalytic efficiency and enantioselectivity of
biotransformations originated from a combination of an active
but virtually nonenantioselective nitrile hydratase and a highly
substrate-dependent enantioselective amidase. The resulting
axially chiral allenes, which are not readily available by other
means, are useful synthetic intermediates, and their applications
are demonstrated by the constructions of densely function-
alized heterocyclic compounds from cyclization and cyclo-
addition reactions in which the axial chirality of reactants was
fully transferred into or expressed as point chirality of products.
Scheme 2. Diels−Alder Reaction of (aR)-4a with Furan
4a with furan 6 proceeded effectively at 80 °C in a sealed tube
to afford a mixture of endo-adduct 7 and exo-adduct 8 in the
yield of 77 and 15%, respectively.28 1,3-Dipolar cycloaddition
reaction of methyl 2,3-allenoate (aS)-5a′ with azomethine
ylide29 that was formed in situ from the condensation between
benzaldehyde 9 and amine 10 led to the formation of
pyrrolidine product 11 in 87% yield as a single stereoisomer
(Scheme 3). Illustrated in Scheme 4 is a further example of
EXPERIMENTAL SECTION
■
General Procedure for the Preparation of Racemic 2,3-
Allenenitriles 3. To a solution of ylides 1 (10 mmol) in dry DCM
(30 mL) at 0 °C was added dropwise a solution of triethylamine (11
mmol) in DCM (10 mL) while stirring. After the resulting mixture was
stirred for 20 min, a solution of acyl chloride 2 (10 mmol) in DCM
(10 mL) was added slowly through a dropping funnel during 20 min.
The reaction mixture was kept stirring overnight at room temperature.
DCM was removed using a rotary evaporator, and diethyl ether was
then added to precipitate triphenylphosphine oxide. After filtration,
the filtrate was concentrated and the residue was chromatographed on
a silica gel column using a mixture of n-hexane and diethyl ether as
mobile phase to afford pure products 3.
Scheme 3. Synthesis of 11
4-Phenyl-2,3-allenenitrile 3a. Colorless oil31 (465 mg, 33%): H
1
NMR (300 MHz, CDCl3) δ 7.38−7.28 (m, 5H), 6.72 (d, J = 6.7 Hz,
1H), 5.67 (d, J = 6.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 217.8,
129.4, 129.1, 127.9, 112.5, 100.0, 71.3.
Scheme 4. Bromolactamization of (R)-4f
4-Benzyl-2,3-allenenitrile 3b. Colorless oil (853 mg, 55%): 1H
NMR (300 MHz, CDCl3) δ 7.36−7.19 (m, 5H), 5.89 (dd, J = 13.9, 7.3
Hz, 1H), 5.22 (dd, J = 13.9, 2.9 Hz, 1H), 3.47 (dd, J = 7.3, 2.9 Hz,
2H); 13C NMR (75 MHz, CDCl3) δ 214.1, 136.1, 127.3, 127.0, 125.6,
112.0, 95.2, 66.6, 32.3; IR (KBr) ν 3023, 2919, 2223, 1961, 1598, 1494
cm−1; MS (EI) m/z (%) 156 [M + 1]+ (10), 155 [M]+ (100), 128
(80), 91 (83); HRMS (TOF-MS-EI) Anal. Calcd. for C11H9N
155.0735 [M]+, found 155.0737 [M]+.
intramolecular cyclization reaction of 2,3-allenamide. In the
presence of excess CuBr2 under mild conditions, 2,3-allenamide
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4-(2-Phenylethyl)-2,3-allenenitrile 3c. Colorless oil (676 mg,
40%): H NMR (300 MHz, CDCl3) δ 7.33−7.17 (m, 5H), 5.74 (dt,
excess values of 2,3-allenamides 4 were measured directly using chiral
HPLC analysis, all racemic 2,3-allenoic acids 5 were not resolved by
chiral HPLC columns tested. To circumvent the problem, acids 5 were
transformed into methyl esters 5′ by CH2N2, and their enantiomeric
excess values were readily determined by means of chiral HPLC
analysis. In practice, the enantiomeric excess values of amide products
can be further increased easily by recrystallization. For example,
recrystallization of (aR)-(−)-4a (94.8% ee) once from its acetone
solution led to highly enantiopure 4a with 97.6% ee.
1
J = 15.1, 6.3 Hz, 1H), 5.18 (dt, J = 6.3, 3.1 Hz, 1H), 2.78 (t, J = 7.6 Hz,
2H), 2.50−2.42 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 215.2, 140.2,
128.6, 128.4, 126.4, 113.6, 96.1, 67.7, 34.6, 28.9; IR (KBr) ν 3022,
2927, 2223, 1959, 1494 cm−1; MS (EI) m/z (%) 169 [M]+ (18), 168
(55), 154 (30), 142 (60), 91 (100). Anal. Calcd for C12H11N: C,
85.17; H, 6.55; N, 8.28. Found: C, 85.11; H, 6.60; N, 8.37.
4-(Cyclohexyl)methyl-2,3-allenenitrile 3d. Colorless oil (740 mg,
46%): 1H NMR (300 MHz, CDCl3) δ 5.71−5.63 (m, 1H), 5.20−5.16
(m, 1H), 2.07−2.01 (m, 2H), 1.75−1.71 (m, 5H), 1.41−1.35 (m, 1H),
1.26−1.16 (m, 3H), 0.99−0.89 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 215.4, 113.9, 95.3, 66.6, 37.5, 35.1, 32.9, 32.8, 26.3, 26.1; IR (KBr) ν
2925, 2852, 2225, 1959, 1445 cm−1; MS (EI) m/z (%) 161 [M]+ (6),
160 (4), 83 (100), 79 (73), 55 (60). Anal. Calcd for C11H15N: C,
81.94; H, 9.38; N, 8.69; Found: C, 82.11; H, 9.58; N, 8.66.
(aR)-4-Phenyl-2,3-allenamide 4a. White solid (56 mg, 35%): mp
141−142 °C; [α]25 = −355.6° (c 0.45, CHCl3; ee 94.8% (chiral
D
1
HPLC analysis); H NMR (300 MHz, CDCl3) δ 7.39−7.29 (m, 5H),
6.64 (d, J = 6.4 Hz, 1H), 6.00 (d, J = 6.4 Hz, 1H), 5.82 (brs, 1H), 5.47
(brs, 1H); 13C NMR (75 MHz, CDCl3) δ 210.4, 166.2, 130.9, 129.1,
128.5, 127.4, 99.6, 94.4; IR (KBr) ν 3384, 3202, 1948, 1654, 1604,
1365 cm−1. MS (EI) m/z (%) 159 [M]+ (58), 141 (15), 116 (40), 115
(100). Anal. Calcd. for C10H9NO: C, 75.45; H, 5.70; N, 8.80. Found:
C, 75.41; H, 5.76; N, 8.82.
4-Benzyl-2-methyl-2,3-allenenitrile 3e. Colorless oil (507 mg,
1
30%): H NMR (300 MHz, CDCl3) δ 7.35 − 7.18 (m, 5H), 5.73−
5.72 (m, J = 7.2, 3.0 Hz, 1H), 3.43 (d, J = 7.2 Hz, 2H), 1.87 (d, J = 3.0
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 212.3, 138.0, 128.7, 128.4,
126.9, 116.2, 95.9, 34.3, 17.4; IR (KBr) ν 3029, 2924, 2219, 1958,
1598, 1495, 1445 cm−1; MS (EI) m/z (%) 170 [M + H]+ (10), 169
[M]+ (78), 154 (75), 142 (38), 91 (100). Anal. Calcd for C12H11N: C,
85.17; H, 6.55; N, 8.28. Found: C, 85.37; H, 6.65; N, 8.24.
(aR)-4-Benzyl-2,3-allenamide 4b. White solid (85 mg, 49%): mp
125−126 °C; [α]25 = −156.0° (c 0.3, CHCl3); ee 80.6% (chiral
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1
HPLC analysis); H NMR (300 MHz, CDCl3) δ 7.35−7.22 (m, 5H),
5.84 (dd, J = 13.8, 7.3 Hz, 1H), 5.63 (brs, 1H), 5.60 (dd, J = 13.8, 2.6
Hz, 1H), 5.43 (brs, 1H), 3.48 (dd, J = 7.3, 2.6 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 208.9, 167.3, 138.6, 128.8, 128.4, 126.8, 96.3, 91.2,
34.4; IR (KBr) ν 3324, 3164, 1959, 1658, 1626, 1439, 1360 cm−1. MS
(EI) m/z (%) 173 [M]+ (3), 172 (11), 156 (10), 129 (100), 91 (54).
Anal. Calcd. for C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C,
76.22; H, 6.40; N, 8.02.
4-Methyl-4-phenyl-2,3-allenenitrile 3f. Colorless oil (481 mg,
31%): 1H NMR (300 MHz, CDCl3) δ 7.39−7.32 (m, 5H), 5.54 (q, J =
3.0 Hz, 1H), 2.21 (d, J = 3.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
217.0, 132.7, 128.9, 128.7, 126.5, 113.3, 107.4, 69.0, 16.2; IR (KBr) ν
3000, 2222, 1946, 1492, 1448 cm−1; MS (EI) m/z (%) 156 [M + H]+
(10), 155 [M]+ (100), 140 (65), 128 (28); HRMS (TOF-MS-EI)
Anal. Calcd. for C11H9N 155.0735 [M]+, found 155.0737 [M]+.
4-Benzyl-4-methyl-2,3-allenenitrile 3g. Colorless oil (253 mg,
15%): 1H NMR (300 MHz, CDCl3) δ 7.28−7.19 (m, 3H), 7.13−7.10
(m, 2H), 5.04−5.01 (m, 1H), 3.31 (s, 2H), 1.70 (d, J = 2.9 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 213.9, 136.9, 128.9, 128.6, 127.0, 114.1,
106.3, 66.4, 39.8, 17.3; IR (KBr) ν 2225, 1959 cm−1; MS (EI) m/z (%)
169 [M]+ (10), 168 (33), 142 (40), 91 (100); HRMS (TOF-MS-EI)
Anal. Calcd. for C12H11N 169.0891 [M]+, found 169.0894 [M]+.
4-Allyl-2,3-allenenitrile 3h. Colorless oil32 (557 mg, 53%): 1H
NMR (300 MHz, CDCl3) δ 5.88−5.72 (m, 2H), 5.28−5.23 (m, 1H),
5.18−5.12 (m, 2H), 2.92−2.87 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 215.4, 133.6, 117.4, 113.5, 95.3, 68.0, 31.4.
(aR)-4-(2-Phenyl)ethyl-2,3-allenamide 4c. White solid (84 mg,
45%): mp 104−105 °C; [α]25 = −57.5° (c 0.8, CHCl3); ee 49.8%
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1
(chiral HPLC analysis); H NMR (300 MHz, CDCl3) δ 7.34−7.18
(m, 5H), 5.62−5.55 (m, 1H), 5.48−7.47 (m, 1H), 5.07−4.93 (m, 2H),
2.93−2.69 (m, 2H), 2.63−2.43 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 208.4, 167.4, 140.6, 128.7, 128.6, 126.3, 95.5, 90.7, 34.8, 29.6; IR
(KBr) ν 3330, 3168, 2927, 1958, 1653, 1619, 1444 cm−1. MS (EI) m/z
(%) 187 [M]+ (8), 186 (45), 144 (6), 129 (18), 91 (100). Anal. Calcd.
for C12H13NO: C, 76.98; H, 7.00; N, 7.48. Found: C, 77.03; H, 6.93;
N, 7.70.
(aR)-4-Cyclohexylmethyl-2,3-allenamide 4d. White solid (97 mg,
54%): mp 131−132 °C; [α]25 = −19.2° (c 0.85, CHCl3); ee 5.8%
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1
(chiral HPLC analysis); H NMR (300 MHz, CDCl3) δ 5.75 (brs,
1H), 5.63−5.56 (m, 1H), 5.54−5.53 (m, 1H), 5.45 (brs, 1H), 2.08−
2.04 (m, 2H), 1.74−1.70 (m, 5H), 1.44−1.37 (m, 1H), 1.26−1.16 (m,
3H), 1.01−0. 93 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 208.6,
167.7, 95.0, 90.1, 37.8, 35.8, 33.0, 26.3, 26.1; IR (KBr) ν 3334, 3173,
2921, 2847, 1959, 1656, 1616, 1446 cm−1. MS (EI) m/z (%) 179 [M]+
(3), 178 (5), 98 (40), 97 (67), 96 (100). Anal. Calcd. for C11H17NO:
C, 73.70; H, 9.56; N, 7.81. Found: C, 73.49; H, 9.50; N, 7.72.
(aR)-4-Methyl-4-phenyl-2,3-allenamide 4f. White solid (68 mg,
39%): mp 144−145 °C; [α]25D = −298.7° (c 0.50, CHCl3); ee >99.5%
(chiral HPLC analysis); 1H NMR (300 MHz, CDCl3) δ 7.44−7.29(m,
5H), 5.88 (q, J = 2.9 Hz, 1H), 5.76 (brs, 1H), 5.45 (brs, 1H), 2.24 (d, J
= 2.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 209.5, 167.1, 133.9,
128.8, 128.1, 126.0, 106.3, 92.6, 16.3; IR (KBr) ν 3382, 3195, 1945,
1656, 1608, 1433 cm−1; MS (EI) m/z (%) 173 [M]+ (28), 128 (86),
115 (55), 44 (100). Anal. Calcd. for C11H11NO: C, 76.28; H, 6.40; N,
8.09. Found: C, 76.14; H, 6.45; N, 8.20.
4-n-Propyl-2,3-allenenitrile 3i. Colorless oil33 (482 mg, 45%): H
1
NMR (300 MHz, CDCl3) δ 5.75−5.68 (m, 1H), 5.23−5.19 (m, 1H),
2.17−2.08 (m, 2H), 1.54−1.44 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 215.3, 113.8, 96.7, 67.3, 29.3, 21.7, 13.5.
General Procedure for Biotransformations of Nitriles in a
Biphasic System. In an Erlenmeyer flask (150 mL) with a screw cap
a suspension of Rhodococcus erythropolis AJ270 cells16 (2 g wet weight)
in aqueous phosphate buffer (pH 7.0, 0.1 M, 50 mL) was activated at
30 °C for 0.5 h. A solution of nitriles 3 (1 mmol) in n-hexane (18 mL)
and diethyl ether (2 mL) was then added in one portion, and the
resulting biphasic mixture was incubated at 30 °C with orbital shaking
(200 rpm). The reaction process was monitored using TLC method.
After a period of time (see Table 2), the reaction was quenched by
removing microbial cells through a Celite pad filtration. The filtration
cake was washed consecutively by water (3 × 15 mL) and ethyl acetate
(3 × 15 mL), and the organic phase of filtrate was separated and dried
with anhydrous MgSO4. The organic solvent was removed under a
vacuum, and the residue was chromatographed on a silica gel column
with a mixture of petroleum ether and ethyl acetate (2:1) and then
pure ethyl acetate as the mobile phase to give pure 2,3-allenoic acids 5
and then 2,3-allenamides 4. 2,3-Allenoic acids 5 were converted into
their methyl esters 5′ upon the treatment with a solution of CH2N2 in
diethyl ether at −10 °C for a couple of minutes.
(aR)-4-Benzyl-4-methyl-2,3-allenamide 4g. White solid (79 mg,
42%): mp 131−132 °C; [α]25 = −68.4° (c 0.50, CHCl3); ee 43.4%
D
1
(chiral HPLC analysis); H NMR (300 MHz, CDCl3) δ 7.34−7.19
(m, 5H), 5.92 (brs, 1H), 5.66 (brs, 1H), 5.46 (s, 1H), 3.45−3.33 (m,
2H), 1.80 (t, J = 2.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 206.7,
168.4, 138.0, 128.8, 128.6, 126.9, 105.5, 89.9, 40.4, 17.8; IR (KBr) ν
3329, 3183, 1962, 1658, 1606, 1431 cm−1; MS (ESI) m/z (%) 210 [M
+ Na]+ (95), 188 [M + H]+ (100); HRMS (FTMS-ESI) Anal. Calcd.
for C12H13NO 188.1070 [M + H]+, found 188.1069 [M + H]+.
(aR)-4-Allyl-2,3-allenamide 4h. White solid (112 mg, 91%): mp
Structures of all biotransformation products were established on the
basis of their spectroscopic and microanalytic data. The absolute
configurations of kinetically resolved products were assigned by
comparison of the optical rotation of (aS)-5a and (aS)-5f with that of
authentic samples reported in literature.24 While the enantiomeric
91−92 °C; [α]25 = −1.5° (c 1.35, CHCl3); ee 2.2% (chiral HPLC
D
1
analysis); H NMR (300 MHz, CDCl3) δ 5.90−5.58 (m, 5H), 5.18−
5.09 (m, 2H), 5.13−5.11 (m, 1H), 2.94−2.88 (m, 2H); 13C NMR (75
3107
dx.doi.org/10.1021/jo500228z | J. Org. Chem. 2014, 79, 3103−3110

The Journal of Organic Chemistry
Article
MHz, CDCl3) δ 208.7, 167.5, 134.7, 116.7, 94.8, 91.2, 32.0; IR (KBr) ν
3333, 3174, 1961, 1657, 1440 cm−1; MS (EI) m/z (%) 123 [M]+ (3),
122 (15), 106 (24), 79 (100). Anal. Calcd. for C7H9NO: C, 68.27; H,
7.37; N, 11.37. Found: C, 68.15; H, 7.35; N, 11.41.
CDCl3) δ 212.4, 166.6, 140.9, 128.5, 128.4, 126.2, 94.8, 88.4, 52.1,
34.9, 29.1; IR (KBr) ν 3027, 2945, 1959, 1721, 1443, 1261 cm−1; MS
(EI) m/z (%) 202 [M]+ (5), 201 (20), 170 (78), 143 (63), 91 (100).
Anal. Calcd. for C13H14O2: C, 77.20; H, 6.98. Found: C, 77.19; H,
7.06.
(aR)-4-n-Propyl-2,3-allenamide 4i. White solid34 (113 mg, 90%):
1
[α]25 = −1.4° (c 1.40, CHCl3); ee 3.2% (chiral HPLC analysis); H
Methyl (aS)-4-cyclohexylmethyl-2,3-allenoate 5d′. Light yellow
D
oil (81 mg, 95%): [α]25 = +19.9° (c 0.60, CHCl3); ee 26.0% (chiral
NMR (300 MHz, CDCl3) δ 5.75 (brs, 1H), 5.68−5.62 (m, 1H), 5.57−
5.55 (m, 1H), 5.28 (brs, 1H), 2.18−2.10 (m, 2H), 1.55−1.45 (m, 2H),
0.97 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 208.5, 167.9,
96.4, 90.7, 29.9, 22.1, 13.6; IR (KBr) ν 3339, 3177, 2959, 1962, 1658,
1624, 1442 cm−1; MS (EI) m/z (%) 125 [M]+ (11), 124 (25), 108
(14), 96 (100), 67 (55). Anal. Calcd. for C7H11NO: C, 67.17; H, 8.86;
N, 11.19. Found: C, 66.96; H, 8.93; N, 11.04.
D
1
HPLC analysis); H NMR (300 MHz, CDCl3) δ 5.61−5.55 (m, 2H),
3.73 (s, 3H), 2.06−2.01(m, 2H), 1.81−1.64 (m, 5H), 1.41−1.35 (m,
1H), 1.27−1.15 (m, 3H), 1.00−0.87 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 212.6, 166.8, 93.8, 87.2, 51.9, 37.7, 35.4, 32.9, 32.8, 26.4,
26.2; IR (KBr) ν 2925, 2851, 1958, 1723, 1442 cm−1. MS (EI) m/z
(%) 194 [M]+ (3), 163 (7), 135 (12), 113 (100), 81 (41). Anal. Calcd.
for C12H18O2: C, 74.19; H, 9.34. Found: C, 74.22; H, 9.41.
(aS)-4-Phenyl-2,3-allenoic acid 5a. White solid24,35 (59 mg, 37%):
[α]25D = +368.5° (c 0.50, CHCl3); ee 90.2% (chiral HPLC analysis of
Methyl (aS)-4-methyl-4-phenyl-2,3-allenoate 5f′. Light yellow
1
oil37 (67 mg, 94%): [α]25 = +261.0° (c 0.50, CHCl3); ee >99.5%
its methyl ester); H NMR (300 MHz, CDCl3) δ 11.20 (br, 1H),
D
1
7.35−7.25 (m, 5H), 6.69 (d, J = 6.3 Hz, 1H), 6.02 (d, J = 6.3 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 216.3, 171.0, 130.5, 129.0, 128.4, 127.6,
99.1, 91.5.
(chiral HPLC analysis); H NMR (300 MHz, CDCl3) δ 7.41−7.24
(m, 5H), 5.90 (q, J = 2.9 Hz, 1H), 3.75 (s, 3H), 2.20 (d, J = 2.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 214.0, 166.2, 134.2, 128.6, 127.9,
126.2, 105.5, 89.5, 52.1, 16.2.
(aS)-4-Benzyl-2,3-allenoic acid 5b. Light yellow oil (85 mg, 49%):
[α]25D = +61.5° (c 0.65, CHCl3); ee 84.2% (chiral HPLC analysis of its
Methyl (aS)-4-benzyl-4-methyl-2,3-allenoate 5g′. Light yellow oil
methyl ester); H NMR (300 MHz, CDCl3) δ 7.35−7.24 (m, 5H),
(101 mg, 50%): [α]25 = +33.5° (c 0.40, CHCl3); ee 48.4% (chiral
1
D
1
5.84 (dd, J = 13.6, 7.4 Hz, 1H), 5.63 (dd, J = 13.6, 2.2 Hz, 1H), 3.50
(dd, J = 7.4, 2.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 214.1, 172.1,
138.3, 128.6, 128.6, 126.8, 95.3, 88.3, 34.0; IR (KBr) ν 3032, 2921,
2656, 2550, 1958, 1688, 1443 cm−1; MS (EI) m/z (%) 174 [M]+ (7),
157 (3), 129 (100), 91 (54); HRMS (TOF-MS-EI) Anal. Calcd. for
C11H10O2 174.0681 [M]+, found 174.0683 [M]+.
HPLC analysis); H NMR (300 MHz, CDCl3) δ 7.33−7.23 (m, 5H),
5.51 (m, 1H), 3.74 (s, 3H), 3.40 (s, 2H), 1.74 (d, J = 2.6 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 211.1, 166.9, 137.9, 129.0, 128.4, 126.7,
103.8, 86.7, 51.9, 40.1, 17.2; IR (KBr) ν 2948, 1964, 1720, 1443 cm−1;
MS (EI) m/z (%) 202 [M]+ (4),, 170 (31), 143 (100), 91 (90);
HRMS (TOF-MS-EI) Anal. Calcd. for C13H14O2 202.0994 [M]+,
found 202.0996 [M]+.
(aS)-4-(2-Phenyl)ethyl-2,3-allenoic acid 5c. Light yellow oil (96
mg, 51%): [α]25 = +72.7° (c 0.55, CHCl3); ee 49.0% (chiral HPLC
Diels−Alder Reaction of (R)-4-Phenyl-2,3-allenamide 4a
with Furan 6. A mixture of (aR)-4a (1 mmol, 159 mg) and furan
6 (10 mL) was sealed in a tube and was then stirred at 80 °C for 60 h.
After removal of unreacted furan, the residue was chromatographed on
a silica gel column eluted with a mixture of petrolum ether and ethyl
acetate (1:1) to afford pure products 7 (175 mg, 77%) and 8 (34 mg,
D
analysis of its methyl ester); 1H NMR (300 MHz, CDCl3) δ 7.32−7.18
(m, 5H), 5.75−5.69 (m, 1H), 5.61−5.57 (m, 1H), 2.82−2.77 (m, 2H),
2.52−2.44 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 213.6, 171.5,
140.8, 128.5, 126.2, 95.1, 88.2, 34.9, 28.9; IR (KBr) ν 3027, 2925,
2657, 1957, 1687, 1443 cm−1; MS (EI) m/z (%) 188 [M]+ (8), 187
[M − 1]+ (15), 170 (36), 143 (55), 91 (100); HRMS (TOF-MS-EI)
Anal. Calcd. for C12H12O2 188.0837 [M]+, found 188.0835 [M]+.
(aS)-4-Cyclohexylmethyl-2,3-allenoic acid 5d. Light yellow oil (79
15%). 7: White solid; mp 160−162 °C; [α]25 = +206.7° (c 0.90,
D
CHCl3); ee 93.0% (chiral HPLC analysis); 1H NMR (300 MHz,
CDCl3) δ 7.34−7.25 (m, 5H), 6.70−6.69 (m, 1H), 6.59 (d, J = 5.6 Hz,
1H), 6.45 (d, J = 5.6 Hz, 1H), 5.44 (d, J = 4.7 Hz, 1H), 5.26 (s, 1H),
5.20 (brs, 1H), 5.11 (brs, 1H), 4.02−4.00 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 171.2, 136.2, 135.7, 134.8, 134.4, 128.7, 128.0, 124.5,
85.2, 81.4, 50.4; IR (KBr) ν 3409, 3175, 1666 cm−1; MS (EI) m/z (%)
227 [M]+ (5), 159 (52), 140 (50), 115 (100), 68 (68). Anal. Calcd. for
C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 73.76; H, 5.98; N,
6.12.
mg, 44%): [α]25 = +21.1° (c 0.56, CHCl3); ee 26.0% (chiral HPLC
D
analysis of its methyl ester); 1H NMR (300 MHz, CDCl3) δ 5.67−5.59
(m, 1H),5.58−5.51 (m, 1H), 2.08−2.03 (m, 2H), 1.73−1.69 (m, 5H),
1.41−1.36 (m, 1H), 1.26−1.09 (m, 3H), 1.00−0.88 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 213.8, 172.1, 94.1, 87.1, 37.7, 35.2, 32.9,
32.8, 26.4, 26.1; IR (KBr) ν 3431, 2925, 2852, 1956, 1695,1443 cm−1;
MS (EI) m/z (%) 180 [M]+ (3), 162 (5), 120 (22), 99 (95), 55 (100);
HRMS (TOF-MS-EI) Anal. Calcd. for C11H16O2 180.1150 [M]+,
found 180.1152 [M]+.
8: White solid; mp 192−193 °C; [α]25D = −215.2° (c 0.45, CHCl3);
1
ee 92.0% (chiral HPLC analysis); H NMR (300 MHz, CDCl3) δ
(aS)-4-Methyl-4-phenyl-2,3-allenoic acid 5f. White solid24 (66 mg,
7.39−7.31 (m, 4H), 7.26 − 7.24 (m, 1H), 6.67 (s, 1H), 6.53−6.46 (m,
2H), 6.02 (brs, 1H), 5.30−5.27 (m, 2H), 5.23 (brs, 1H), 3.29 (s, 1H);
13C NMR (75 MHz, CDCl3) δ 173.3, 135.9, 135.7, 135.4, 135.3, 128.7,
128.2, 128.0, 125.1, 84.0, 83.8, 50.8; IR (KBr) ν 3435, 3203, 1631
cm−1; MS (EI) m/z (%) 227 [M]+ (9), 155 (40), 140 (83), 115 (80),
68 (100). Anal. Calcd. for C14H13NO2: C, 73.99; H, 5.77; N, 6.16.
Found: C, 73.72; H, 5.90; N, 5.88.
Reaction of Methyl (S)-4-Phenyl-2,3-allenoate 5a′ with
Benzaldehyde 9 and Amine 10. To a well stirred mixture of
benzaldehyde (1.1 mmol, 117 mg), p-toluenesulfonic acid (0.15 mmol,
26 mg), molecular sieve (3 Å, 1 g) and methyl (aS)-4-phenyl-2,3-
allenoate 5a′ (1 mmol, 174 mg) in toluene (5 mL) was added a
solution of amine 10 (1 mmol, 175 mg) in toluene (5 mL) at room
temperature. The resulting reaction mixture was stirred at ambient
temperature for another 3 days. Molecular sieves were removed by
filtration, and the filtration cake was washed with ethyl acetate. The
combined filtrate was mixed with a saturated aqueous solution of
NaHCO3 (50 mL). After separation, aqueous phase was extracted with
ethyl acetate (2 × 30 mL), and combined organic solution was dried
with anhydrous MgSO4. Organic solvent was removed using a rotary
evaporator, and the residue was chromatographed on a silica gel
column eluted with a mixture of petrolum ether and ethyl acetate
(15:1) to afford pure product 11 (380 mg, 87%): White solid; mp 86−
38%): [α]25 = +307.0° (c 0.48, CHCl3); ee >99.5% (chiral HPLC
D
analysis of its methyl ester); 1H NMR (300 MHz, CDCl3) δ 7.40−7.25
(m, 5H), 5.89 (q, J = 2.9 Hz, 1H), 2.22 (d, J = 2.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 215.5, 171.2, 133.8, 128.7, 128.1, 126.3, 106.0,
89.3, 16.1.
Methyl (aS)-4-phenyl-2,3-allenoate 5a′. Light yellow oil21 (61 mg,
95%): [α]25 = +308.5° (c 0.65, CHCl3); ee 90.2% (chiral HPLC
D
analysis); 1H NMR (300 MHz, CDCl3) δ 7.37−7.24 (m, 5H), 6.63 (d,
J = 6.4 Hz, 1H), 6.03 (d, J = 6.4 Hz, 1H), 3.76 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 214.8, 165.6, 131.0, 128.9, 128.2, 127.5, 98.7, 91.6,
52.3.
Methyl (aS)-4-benzyl-2,3-allenoate 5b′. Light yellow oil36 (89 mg,
97%): [α]25 = +57.5° (c 0.83, CHCl3); ee 84.2% (chiral HPLC
D
1
analysis); H NMR (300 MHz, CDCl3) δ 7.34−7.21 (m, 5H), 5.81−
5.74 (m, 1H), 5.66−5.61 (m, 1H), 3.75 (s, 3H), 3.50−3.47 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 212.9, 166.4, 138.6, 128.6, 128.5, 126.7,
94.9, 88.3, 52.1, 34.1.
Methyl (aS)-4-(2-phenyl)ethyl-2,3-allenoate 5c′. Light yellow oil
(99 mg, 96%): [α]25 = +89.7° (c 0.85, CHCl3); ee 49.0% (chiral
D
1
HPLC analysis); H NMR (300 MHz, CDCl3) δ 7.32−7.26 (m, 2H),
7.25−7.19 (m, 3H), 5.70−5.63 (m, 1H), 5.62−5.58 (m, 1H), 3.72 (s,
3H), 2.81−2.76 (m, 2H), 2.50−2.42 (m, 2H); 13C NMR (75 MHz,
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87 °C; [α]25 = +26.6° (c 0.58, CHCl3); ee 90.0% (chiral HPLC
analysis); H NMR (300 MHz, CDCl3) δ 7.40−7.26 (m, 10H), 7.06
Fan, W.; Kuang, J.; Liu, J.; Liu, Y.; Miao, B.; Wan, B.; Wang, Y.; Xie,
X.; Yu, Q.; Yuan, W.; Ma, S.-M. Org. Lett. 2012, 14, 1346. (f) Li, H.;
D
1
(s, 1H), 4.79 (d, J = 6.5 Hz, 1H), 4.39−4.28 (m, 4H), 4.03 (d, J = 6.5,
1H), 3.28 (s, 3H), 1.37−1.31 (m, 6H); 13C NMR (75 MHz, CDCl3) δ
170.8, 170.8, 168.5, 137.4, 136.1, 136.1, 131.4, 128.7, 128.6, 128.3,
127.9, 126.6, 76.0, 64.9, 62.3, 62.2, 54.8, 51.6, 14.1; IR (KBr) ν 3348,
2927, 1738, 1444 cm−1; MS (ESI) m/z (%) 460 [M + Na]+ (90), 438
[M + H]+ (100); HRMS (FT-ICRMS) Anal. Calcd. for C25H27NO6
438.1911 [M + H]+, found 438.1912 [M + H]+.
́ ́
Muller, D.; Guenee, L.; Alexakis, A. Org. Lett. 2012, 14, 5880.
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Conversion of (R)-4-Methyl-4-phenyl-2,3-allenamide 4f into
Lactam 12. Under argon protection, a mixture of (aR)-4f (1 mmol,
173 mg) and CuBr2 (4 mmol) in dry THF (10 mL) was stirred at
room temperature for 24 h. After removal of THF, an aqueous
solution of NaOH (1 M, 20 mL) was added. Copper salts were
removed by filtration through a Celite pad, and the filtration cake was
washed with ethyl acetate. The filtrate was extracted with diethyl ether,
and combined organic phase was dried over anhydrous MgSO4.
Organic solvents were evaporated, and the residue was chromato-
graphed on a silca gel column. Elution with a mixture of petrolum
ether and ethyl acetate (1:1) gave pure 12 (224 mg, 89%): Light
yellow oil; [α]25D = −137.5° (c 0.75, CHCl3); ee 98.0% (chiral HPLC
analysis); 1H NMR (300 MHz, CDCl3) δ 7.39 (m, 5H), 6.37 (s, 1H),
1.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 169.90, 156.91, 136.4,
129.2, 128.8, 125.6, 120.6, 90.5, 23.7; IR (KBr) ν 1673 cm−1; MS
(ESI) m/z (%) 252 [M + H]+ (100), 254 [M + H]+ (96); HRMS (FT-
MS-ESI) Anal. Calcd. for C11H10BrNO 252.0019 [M + H]+, found
252.0016 [M + H]+.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of products, HPLC chromatograms
of products. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wangmx@mail.tsinghua.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank National Natural Science Foundation of
China (21320102002), Tsinghua University and Chinese
Academy of Sciences for financial Support.
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dez, V.; Gotor, V. Chem. Rev. 2011,
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