α-allyl-α-aryl α-amino esters in the asymmetric synthesis of acyclic and cyclic amino acid derivatives by alkene metathesis

Article abstract of DOI:10.1021/jo500707t

Allylating agents were explored for the asymmetric synthesis of α-allyl-α-aryl α-amino acids by tandem N-alkylation/π- allylation. Cross-metathesis of the tandem product was developed to provide allylic diversity not afforded in the parent reaction; the synthesis of homotyrosine and homoglutamate analogues was completed. Cyclic α-amino acid derivatives could be accessed by ring-closing metathesis presenting a viable strategy to higher ring homologue of enantioenriched α-substituted proline. The eight-membered proline analogue was successfully converted to the pyrrolizidine natural product backbone.

Full text of DOI:10.1021/jo500707t

Note
pubs.acs.org/joc
α‑Allyl-α-aryl α‑Amino Esters in the Asymmetric Synthesis of Acyclic
and Cyclic Amino Acid Derivatives by Alkene Metathesis
John M. Curto and Marisa C. Kozlowski*
Penn Merck High Throughput Experimentation Laboratory, Department of Chemistry, University of Pennsylvania, Philadelphia,
Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: Allylating agents were explored for the
asymmetric synthesis of α-allyl-α-aryl α-amino acids by tandem
N-alkylation/π-allylation. Cross-metathesis of the tandem
product was developed to provide allylic diversity not afforded
in the parent reaction; the synthesis of homotyrosine and
homoglutamate analogues was completed. Cyclic α-amino acid
derivatives could be accessed by ring-closing metathesis
presenting a viable strategy to higher ring homologue of
enantioenriched α-substituted proline. The eight-membered proline analogue was successfully converted to the pyrrolizidine
natural product backbone.
he α,α-disubstituted α-amino acid structure, found in
noesters.9 The phenyl substituent on 1 could be substituted
with electron-donating or -withdrawing groups, representing
the first asymmetric synthesis of α-allyl-α-aryl α-amino acids
where the aryl is other than phenyl.7 Further variation of the
phenyl group on 2 to the 2-naphthalene or 2-thiophene also
proceeded well.9 The p-methoxyphenyl (PMP) was the best
activating group for preferential N-alkylation; the methyl ester
could be modified (ethyl, tert-butyl, benzyl), but enantiose-
lectivity was reduced.9
Table 1 describes the further exploration of the substrate
scope by looking at allylating agents beyond cinnamyl acetate.
Replacing the phenyl ring of cinnamyl acetate with hydrogen
reduced selectivity (Table 1, 2d). This result is in line with the
phenyl differentiating the termini of the allylpalladium complex
(Scheme 1), which is expected to increase selectivity.12
However, modification of the phenyl group in cinnamyl acetate
with either electron-donating or -withdrawing groups did not
increase selectivity (Table 1, 2f and 2g). Driven by a desire to
generate aspartic/glutamic acid analogues, the corresponding
furyl allyl acetate was surveyed, but no product was observed
(Table 1, 2h). Lastly, 1,3-disubstituted allylating agents
generated no tandem product (Table 1, 2i and 2j).
α-Aryl homologues of tyrosine and glutamate have been
shown to be biologically active.13 Yet, the challenges described
above (Table 1) with various allylating agents prevented access
to such compounds by this technology. In an alternate
approach, cross-metathesis was studied to enable generation
of a broad range of different allyl adducts from a single
intermediate 2a (Table 2). Notably, cross-metathesis between
type 1 and type 2 olefins has proven difficult.14 Cross-
metathesis of α,α-disubstituted α-amino acids has been limited
T
many natural products,1 has been employed in antibiotics2
and is important in peptidomimetics.3 Synthesis of α,α-
disubstituted α-amino acids is difficult, with congeners beyond
the α-Me, α-Et, and α-Bn becoming even more difficult.4
Furthermore, the construction of enantioenriched α-allyl-α-aryl
α-amino acids is extremely challenging. Kinetic resolutions were
first reported by Tourwe in 1997.5 Diastereoselective processes
were reported by Tayama6a and Barrett.6b Maruoka and Ooi in
2000 established the use of phase-transfer catalyst to generate
α,α-disubstituted α-amino acids.7a,b Yet, in the asymmetric
synthesis of α-allyl-α-aryl α-amino acids, only the parent α-allyl-
α-phenylglycine α-amino acid has been made efficiently.7a−d
Asymmetric allylic alkylation (AAA) to generate α,α-
disubstituted α-amino acids was pioneered in 1997 by Trost
utilizing azlactones.8 α-Aryl α-amino acids pose a challenge to
AAA because of the large steric bulk of the aryl ring near the
nucleophilic carbon of the α-amino acids. Recently, we
developed an asymmetric method for synthesizing α-allyl-α-
aryl α-amino acids,9 which relies on the formation of a chelated
magnesium enolate10 that is generated in situ. This work was
the first example of an asymmetric tandem N-alkylation/π-
allylation of α-iminoesters (Scheme 1). The α-iminoester
undergoes an umpolung N-alkylation with the Grignard
reagent, generating an enolate in situ that can be used in
AAA.11 This example was the first utilization of phenylglycine
amino acid in AAA and enables the synthesis of previously
inaccessible enantioenriched α-allyl-α-aryl α-amino acids. In
this paper, the use of cross-metathesis is described to overcome
challenges incurred when other allylating agents were
employed. Capitalizing on the N-alkyl group introduced in
the α-iminoester addition, the construction of cyclic α-amino
acids by ring-closing metathesis is also reported.
Scheme 2 displays representative examples of the three-
component coupling by N-alkylation/π-allylation of α-imi-
Received: March 26, 2014
Published: May 14, 2014
© 2014 American Chemical Society
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Scheme 1. Tandem N-Alkylation/π-Allylation of α-
Table 2. Cross-Metathesis of the Tandem Product 2a
Iminoesters
Scheme 2. Our Previous Work on the Tandem N-Alkylation/
π-Allylation of α-Iminoesters
Table 1. Exploration of Allylating Agent in the Tandem N-
Alkylation/π-Allylation of α-Iminoesters
a
b
Isolated yield. 1,2-Dichloroethane substituted for toluene at 70 °C.
c
Yield based on recovered starting material.
Table 2 showcases that 2a does indeed undergo cross-
metathesis with various type 1 olefins, accessing previously
unknown α-amino acid analogues in good yields with retention
of enantiopurity. Importantly, p-tert-butoxystyrene and methyl
acrylate could be employed. Microwave conditions did not
accelerate the cross-metathesis, and other catalysts were inferior
to the second-generation Hoveyda−Grubbs catalyst.16 Ethylene
proved recalcitrant but did afford product 2d with high
enantioselectivity, in contrast to direct allylation (see Table 1,
entry 1) and low conversion (with high yield based on
recovered starting material).
To further our objective of generating α-amino acid
homologues, hydrogenation and PMP removal was performed
on 2k to provide the α-aryl tyrosine homologue 5 (Scheme 3).
Notably, N-ethylamino acids can be difficult to generate due to
the difficulty of reductive amination with acetaldehyde. We
have shown previously that the primary amines can be
generated by using but-3-enyl Grignard in the N-alkylation/π-
allylation,9 where the N-butenyl is ultimately removed by an
isomerization/hydrolysis using the Grotjahn catalyst.17
There is much great synthetic and pharmaceutical interest in
cyclic α-amino acid derivatives.18 Further, α-substituted pro-
lines have been shown to be important as organocatalysts and
privileged ligands. Seebach pioneered the asymmetric synthesis
of α-substituted prolines in 1983,19 yet the development of
asymmetric methodology for the synthesis of higher ring
homologues of proline has received little attention.20 The N-
a
b
Isolated yield. Determined by chiral stationary phase (CSP) HPLC.
c
(R)-BINAP was substituted for (R)-DIFLUORPHOS.
to α-allyl-α-methyl- and α-allylproline with the nitrogen
protected as a carbamate to prevent coordination to the
ruthenium catalyst.15 Indeed, amines are notoriously poor in
metathesis due to deactivation of the ruthenium. However, we
envisioned that the enantioenriched tandem product 2a could
be an acceptable type 2 olefin for cross-metathesis because the
tertiary amine does not behave as expected. For example, the
hydrochloride salts of 2 could not be formed. Apparently, the
N-substitution and the sterics at the α-carbon contribute to this
unique profile.
Scheme 3. Generation of α-Aryl Tyrosine Homologue
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Note
substituents and the α-alkene functionality present in the α-
iminoester addition products 2b and 2c described above
provide an effective entry to cyclic analogues via ring-closing
metathesis (Scheme 4). Microwave irradiation allowed for the
formation of 6 to occur in 1 h vs 20−24 h under thermal
conditions.
Scheme 5. Establishing the Absolute Configuration of
Products 2a−n
Hydrogenation of RCM product 6 provided crystalline 7
(Scheme 5), which was triturated with dichloromethane to
provide >95% ee material. The absolute configurations of
products 2a−n were inferred by the X-ray crystal structure of 7.
The corresponding 8-membered ring analogue 8 could be
formed by ring-closing metathesis of 2c (Scheme 6). Micro-
wave irradiation not only expedited the reaction but also
increased its efficiency compared to thermal conditions.
Furthermore, azocine 8 presents an expeditious entry to
substituted pyrrolizidines via transannular cyclization.
Scheme 6. Ring-Closing Metathesis To Generate Cyclic
Pyrrolizidine Analogue
The naturally occurring pyrrolizidine structural motif exists
in over 370 natural products and has been shown to have
toxicity against livestock, wildlife, and humans.21 The PMP
group was removed from azocine 8 to provide 9. Secondary
amine 9 is poised to undergo an iodine-induced transannular
cyclization.22 Treatment of 9 with NIS led exclusively to cis-
iodide 10, consistent with a formal syn-addition across the
olefin.23 Since most naturally occurring pyrrolizidines are
substituted at C1, this route offers a labile functional group
for further manipulation.21 The relative configuration of 10 was
assigned by comparing the MM2* calculated bond distances
and coupling constants of the four potential diastereomers with
the NOESY and coupling constant data of 10.16
In summary, this paper outlines an entry to enantioenriched
acylic and cyclic α,α-disubstituted amino acid derivatives by
means of cross-metathesis or ring-closing metathesis of the
previously disclosed products from asymmetric tandem N-
alkylation/π-allylation of α-iminoesters. This approach pro-
vided rapid entry to homologues of tyrosine and glutamate as
well as to higher ring homologues of proline. The eight-
membered cyclic α-amino acid was further transformed to the
pyrrolizidine natural product backbone in three steps.
solution was stirred for 5 min at ambient temperature under argon,
cooled to −78 °C, and added to the cooled first solution via syringe.
The combined mixture warmed to room temperature and stirred for
45 min. The resultant reaction mixture was quenched with satd NH4Cl
(5 mL) and extracted with EtOAc (3 × 10 mL). The combined
organic layers were washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. Purification via column chromatography
(prewash SiO2 with 5% NEt3/hexanes, eluent 3% EtOAc/hexanes)
1
provided product 2d (26 mg) in 82% yield as a yellow oil: H NMR
(500 MHz, CDCl3) δ 7.43 (d, J = 8.1 Hz, 2H), 7.34 (t, J = 7.5 Hz,
2H), 7.28−7.25 (m, 1H), 7.10 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 8.8 Hz,
2H), 5.43−5.35 (m, 1H), 4.72 (d, J = 10.3 Hz, 1H), 4.59 (d, J = 17.2
Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.02−2.88 (m, 2H), 2.48 (dd, J =
13.9, 6.8 Hz, 1H), 2.28 (dd, J = 13.9, 7.3 Hz, 1H), 0.79 (t, J = 7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 173.3, 157.9, 141.5, 139.2,
134.2, 131.2, 128.0, 127.8, 127.3, 117.7, 113.8, 74.8, 55.5, 51.4, 46.6,
45.3, 14.7; IR (film) 2962, 2929, 1726, 1605, 1507, 1243 cm−1; HRMS
(ESI) calcd for C21H26NO3 [M + H]+ m/z = 340.1913, found
340.1900; [α]25D = +58.6 (c 0.08, 54% ee, CH2Cl2); chiral HPLC (IA,
97.5:2.5 hexanes/i-PrOH, 1 mL/min, 254 nm): tR of 2d: 4.8 min
(major) and 5.2 min (minor).
EXPERIMENTAL SECTION
■
Starting material compounds 1 and 2a−c were made following our
previous report.9
(S,E)-Methyl 2-(N-Ethyl-N-(4-methoxyphenyl)amino)-2-phe-
nylpent-4-enoate (2d). General Procedure A. Compound 1 (25
mg, 0.093 mmol) was added to a flamed dried Schlenk flask that had
been charged with a stir bar and was then vacuum-purged three times
under argon. THF (0.5 mL) was added, the reaction was cooled to
−78 °C, and EtMgBr (3.0 M in Et2O, 50 μL, 0.15 mmol) was added.
The mixture was slowly warmed to room temperature, allowed to stir
for an additional 30 min and then cooled to −78 °C. A flame-dried
round-bottom flask equipped with a stir bar was charged with [η3-
C3H5PdCl]2 (0.85 mg, 0.0023 mmol) and (R)-DIFLUORPHOS (3.1
mg, 0.0045 mmol) and vacuum-purged three times under argon. THF
(0.5 mL) and allyl acetate (11 μL, 0.10 mmol) were added. The
(S,E)-Methyl 2-(N-Ethyl-N-(4-methoxyphenyl)amino)-2-phe-
nyloct-4-enoate (2e). General procedure A was followed using 1
(50 mg, 0.19 mmol) in THF (1.0 mL), 3.0 M EtMgBr (100 μL, 0.30
mmol), [η3-C3H5PdCl]2 (1.7 mg, 0.0047 mmol), R-BINAP (5.7 mg,
0.0091 mmol), and hex-2-enyl acetate (31 μL, 0.20 mmol) in THF
(1.0 mL). Purification by column chromatography (8% EtOAc/
hexanes) provided product 2e (49 mg) in 70% yield as a yellow oil: 1H
NMR (500 MHz, CDCl3) δ 7.43 (d, J = 7.5 Hz, 2H), 7.32 (t, J = 7.6
Hz, 2H), 7.27−7.22 (m, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 9
Hz, 2H), 5.03−4.88 (m, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.03−2.86
(m, 2H), 2.42 (dd, J = 14, 6.3 Hz, 1H), 2.19 (dd, J = 14, 7.0 Hz, 1H),
1.71 (dt, J = 7.6, 6.9 Hz, 2H), 1.16−1.09 (m, 2H), 0.79 (t, J = 7.0 Hz,
3H), 0.71 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 173.2,
157.8, 141.7, 139.2, 134.1, 131.2, 128.1, 127.6, 127.0, 125.2, 113.7; IR
(film) 2959, 1726, 1508, 1244 cm−1; HRMS (ESI) calcd for
Scheme 4. Synthesis of Higher Ring Homologue of α-
Substituted Proline
C24H32NO3 [M + H]+ m/z = 382.2382, found 382.2388; [α]25
=
D
+128.75 (c 0.32, 58% ee, CH2Cl2); chiral HPLC (IA, 97.5:2.5
hexanes/i-PrOH, 1 mL/min, 254 nm): tR of 2e: 4.8 min (major) and
6.8 min (minor).
(S,E)-Methyl 2-(N-Ethyl-N-(4-methoxyphenyl)amino)-5-(4-
methoxyphenyl)-2-phenylpent-4-enoate (2f). General procedure
A was followed using 1 (40 mg, 0.15 mmol) in THF (1.0 mL), 3.0 M
EtMgBr (80 μL, 0.24 mmol), [η3-C3H5PdCl]2 (1.36 mg, 0.0037
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mmol), R-BINAP (4.6 mg, 0.0073 mmol) and (4-methoxy)cinnamyl
acetate (32 mg, 0.16 mmol) in THF (1.0 mL). Purification by column
chromatography (prewash SiO2 with 5% NEt3/hexanes, eluent 8%
EtOAc/hexanes) provided 2f (48 mg) in 72% yield as a yellow oil: 1H
NMR (500 MHz, CDCl3) δ 7.46 (d, J = 8.4 Hz, 2H), 7.34 (t, J = 7.3
Hz, 2H), 7.28−7.27 (m, 1H), 7.14 (d, J = 8.8 Hz, 2H), 7.01 (m, J = 8.6
Hz, 2H), 6.86 (d, J = 8.9 Hz, 2H), 6.74 (d, J = 8.7 Hz, 2H), 5.82 (d, J
= 15.8 Hz, 1H), 5.26 (dt, J = 15.8, 7.4 Hz, 1H), 3.86 (s, 3H), 3.82 (s,
3H), 3.76 (s, 3H), 3.06−2.99 (m, 1H), 2.97−2.90 (m, 1H), 2.59 (ddd,
J = 13.7, 7.0, 1.3 Hz, 1H), 2.39 (ddd, J = 13.8, 7.5, 1.1 Hz, 1H), 0.81 (t,
J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 173.3, 158.7, 157.8,
141.7, 139.2, 132.4, 131.3, 130.9, 127.9, 127.8, 127.3, 127.1, 123.8,
113.9, 113.8, 75.2, 55.5, 55.4, 51.4, 46.6, 44.3, 14.7; IR (film) 2960,
2931, 1724, 1607, 1509, 1246 cm−1; HRMS (ESI) calcd for
calcd for C31H38NO4 [M + H]+ m/z = 488.2801, found 488.2811;
[α]25 = +170.1 (c 0.13, 88% ee, CH2Cl2).
D
(S,E)-Methyl 2-(N-Ethyl-N-(4-methoxyphenyl)amino)-5-
(naphthalene-2-yl)-2-phenylpent-4-enoate (2l). General proce-
dure B was followed using 2a (20 mg, 0.048 mmol, 81% ee), 3b (22
mg, 0.15 mmol), and 4 (6.0 mg, 0.0096 mmol) in dichloroethane (482
μL) at 70 °C for 20 h. Purification by column chromatography
(prewash SiO2 with 5% NEt3 in hexanes, eluent 7% EtOAc in hexanes)
provided 2l (15 mg) in 68% yield as a yellow oil: 1H NMR (500 MHz,
CDCl3) δ 7.72 (dd, J = 12.0, 4.0 Hz, 2H), 7.66 (d, J = 8.6 Hz, 1H),
7.48 (d, J = 7.7 Hz, 2H), 7.42−7.33 (m, 5H), 7.29 (t, J = 8.0 Hz, 2H),
7.16 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 6.02 (d, J = 16.0 Hz,
1H), 5.84 (dt, J = 16.0, 7.1 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.08−
3.01 (m, 1H), 2.98−2.92 (m, 1H), 2.66 (dd, J = 14.0, 7.2 Hz, 1H),
2.47 (dd, J = 13.6, 7.5 Hz, 1H), 0.82 (t, J = 7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 173.4, 157.9, 141.6, 139.2, 135.4, 133.7, 133.1,
132.7, 131.3, 128.0, 127.9 (3), 127.7, 127.4, 126.6, 126.2, 125.6, 125.5,
123.7, 113.9, 75.2, 55.5, 51.5, 46.7, 44.6, 14.7; IR (film) 2924, 2853,
1725, 1507 cm−1; HRMS (ESI) calcd for C31H32NO3 [M + H]+ m/z =
466.2382, found 466.2399; [α]25D = +125.5 (c 0.21, 81% ee, CH2Cl2).
(S,E)-Dimethyl 5-(N-Ethyl-N-(4-methoxyphenyl)amino)-5-
phenylhex-2-enedioate (2m). General procedure B was followed
using 2a (20 mg, 0.048 mmol), 3c (42 mg, 0.48 mmol), and 4 (6.0 mg,
0.0096 mmol) in toluene (482 μL). Purification by column
chromatography (prewash SiO2 with 5% NEt3 in hexanes, eluent 3%
acetone in hexanes) provided 2m (14 mg) in 72% yield as a yellow oil:
1H NMR (500 MHz, CDCl3) δ 7.39 (d, J = 7.5 Hz, 2H), 7.34 (t, J =
C28H32NO4 [M + H]+ m/z = 446.2331, found 446.2322; [α]25
=
D
+95.3 (c 0.21, 60% ee, CH2Cl2); chiral HPLC (IA, 97.5:2.5 hexanes/i-
PrOH, 1 mL/min, 254 nm): tR of 2f: 9.9 min (major) and 11.8 min
(minor).
(S,E)-Methyl 2-(N-Ethyl-N-(4-methoxyphenyl)amino)-5-(3-(3-
trifluoromethyl)phenyl)-2-phenylpent-4-enoate (2g). General
procedure A was followed using 1 (40 mg, 0.149 mmol) in THF
(1.0 mL), 3.0 M EtMgBr (80 μL, 0.240 mmol), [η3-C3H5PdCl]2 (1.36
mg, 0.0037 mmol), R-DIFLUORPHOS (4.98 mg, 0.0073 mmol), and
(3-trifluoromethyl)cinnamyl acetate (38 mg, 0.156 mmol) in THF
(1.0 mL). Purification by column chromatography (prewash SiO2 with
5% NEt3/hexanes, eluent 8% EtOAc/hexanes) provided 2g (55 mg) in
76% yield as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.45 (d, J =
7.9 Hz, 2H), 7.38−7.34 (m, 3H), 7.30 (t, J = 7.9 Hz, 2 H), 7.22 (d, J =
7.9, 1H), 7.14 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.87 (d, J
= 15.8 Hz, 1H), 5.80−5.74 (dt, J = 15.6, 7.0 Hz, 1H), 3.89 (s, 3H),
3.82 (s, 3H), 3.08−3.01 (m, 1H), 2.98−2.92 (m, 1H), 2.63 (dd, J =
13.7, 6.8 Hz, 1H), 2.43 (dd, J = 13.7, 7.3 Hz, 1 H), 0.82 (t, J = 7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 173.3, 158.0, 141.5, 139.1,
138.7, 131.6, 131.3, 130.8 (q, J = 32 Hz), 129.0, 128.8, 128.4, 128.0,
127.7, 127.5, 124.4 (q, J = 254 Hz), 123.5−123.4 (m), 122.8−122.7
(m), 113.9, 75.1, 55.5, 51.6, 46.8, 44.5, 14.7; IR (film) 3036, 2837,
1725, 1606, 1508, 1328, 1245, 1124 cm−1; HRMS (ESI) calcd for
7.4 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 6.86 (d,
J = 8.9 Hz, 2H), 6.61−6.55 (m, 1H), 5.32 (d, J = 16.5 Hz, 1H), 3.88
(s, 3H), 3.81 (s, 3H), 3.60 (s, 3H), 3.05−2.98 (m, 1H), 2.95−2.88 (m,
1H), 2.57 (ddd, J = 14.5, 7.3, 0.6 Hz, 1H), 2.43 (ddd, J = 14.4, 7.6, 0.6
Hz, 1H), 0.79 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
173.2, 166.8, 158.1, 145.1, 140.9, 138.9, 131.2, 128.2, 127.7, 127.4,
123.2, 114.0, 74.5, 55.5, 51.7, 51.4, 46.8, 43.7, 14.7; IR (film) 2951,
2855, 1724, 1655, 1508, 1245, 1035 cm−1; HRMS (ESI) calcd for
C23H28NO5 [M + H]+ m/z = 398.1967, found 398.1963; [α]20
+107.2 (c 0.13, 88% ee, CH2Cl2).
=
D
2d. General procedure B was followed using 2a (20 mg, 0.0482
mmol) and 4 (8.2 mg, 0.0096 mmol) in dichloroethane (482 μL) and
the following modification: ethylene gas 3d was sparged through the
flask for 10 min and then subjected to microwave (100 W, 100 psi, 90
°C) conditions for 30 min. The mixture was cooled, ethyl vinyl ether
(50 μL, 0.523 mmol) was added, and the mixture ws stirred for 30
min. The mixture was passed through SiO2 with 30% EtOAc in
hexanes and concentrated in vacuo. Purification by column
chromatography (prewash SiO2 with 5% NEt3 in hexanes, eluent 5%
EtOAc in hexanes) provided 2d (3.9 mg) in 24% yield (character-
ization the same as 2d above) with unreacted 2a (15 mg, 0.036 mmol)
recovered.
C28H29F3NO3 [M + H]+ m/z = 484.2100, found 484.2099; [α]25
=
D
+99.5 (c 0.26, 64% ee, CH2Cl2); chiral HPLC (IA, 97.5:2.5 hexanes/i-
PrOH, 1 mL/min, 254 nm): tR of 2g: 6.0 min (major) and 5.6 min
(minor).
(3-Trifluoromethyl)cinnamyl Acetate. Following the modified
procedure previously reported.24 Reaction conditions: 3-iodobenzotri-
fluoride (577 μL, 4.0 mmol), allyl acetate (1.6 g, 16.0 mmol),
Pd(OAc)2 (45 mg, 0.20 mmol), Ag2CO3 (662 mg, 2.4 mmol), toluene
(24 mL). (3-Trifluoromethyl)cinnamyl acetate (315 mg) was
obtained in 32% yield as a colorless liquid. Spectral data agreed with
those reported previously.25
(S,E)-Methyl 2-(N-ethyl-N-(4-methoxyphenyl)amino)-5-(4-
(tert-butoxy)phenyl)-2-phenylpent-4-enoate (2k). General Pro-
cedure B. Compound 4 (6.0 mg, 0.0096 mmol) was added to a flame-
dried 8 mL microwave vial equipped with stir bar in the glovebox.
Compound 3a (85 mg, 0.48 mmol) was added followed by 2a (20 mg,
0.048 mmol) in toluene (482 μL). The vial was sealed with a Teflon
cap, taken out of the glovebox, placed in a 90 °C oil bath, and stirred
for 20 h. The mixture was cooled, passed through SiO2 with 30%
EtOAc in hexanes, and concentrated in vacuo. Purification by column
chromatography (prewash SiO2 with 5% NEt3 in hexanes, eluent 3%
acetone in hexanes) provided 2k (17 mg) in 74% yield as a yellow oil:
1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.4 Hz, 2H), 7.35 (t, J =
7.1 Hz, 2H), 7.29 (d, J = 7.0 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 6.97
(d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H),
5.86 (d, J = 15.7 Hz, 1H), 5.58 (dt, J = 15.9, 7.3 Hz, 1H), 3.86 (s, 3H),
3.82 (s, 3H), 3.06−2.99 (m, 1H), 2.96−2.91 (m, 1H), 2.60 (dd, J =
13.9, 7.4 Hz, 1H), 2.41 (dd, J = 13.9, 7.4 Hz, 1H), 1.31 (s, 9H), 0.81
(t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 173.2, 157.8,
154.5, 141.6, 139.1, 133.2, 132.4, 131.3, 127.9, 127.8, 127.3, 126.5,
124.7, 124.1, 113.8, 78.6, 75.1, 55.5, 51.5, 46.6, 44.3, 29.0, 14.7; IR
(film) 2975, 2855, 1725, 1604, 1507, 1241, 1162 cm−1; HRMS (ESI)
(S)-Methyl 2-(N-Ethyl-N-(4-methoxyphenyl)amino)-5-(4-tert-
butoxyphenyl)-2-phenylpentanoate (2ksat). General Procedure
C. Compound 2k (17 mg, 0.035 mmol), 10% Pd/C (3.7 mg, 0.0035
mmol), and EtOAc (1.1 mL) were added to a flame-dried 10 mL
round-bottom flask equipped with a stir bar. At ambient temperature,
the flask was purged with one hydrogen balloon and then subjected to
a hydrogen atmosphere with a new hydrogen balloon for 45 min. The
flask was opened to air, passed through SiO2 with 30% EtOAc/
hexanes, and concentrated in vacuo. Purification by column
chromatography (10% EtOAc in hexanes) provided 2ksat (14.4 mg)
in 85% yield as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.43 (d,
J = 7.7 Hz, 2H), 7.34 (t, J = 7.2 Hz, 2H), 7.28 (d, J = 7.3 Hz, 1H), 7.07
(d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 6.77 (b, 4H), 3.83 (s,
3H), 3.01−2.83 (m, 2H), 2.25−2.19 (m, 1H), 2.15−2.09 (m, 1H),
1.72−1.66 (m, 1H), 1.56−1.50 (m, 1H), 1.29 (s, 9H), 1.28−1.25 (b,
2H); 13C NMR (125 MHz, CDCl3) δ 173.5, 157.8, 153.1, 141.9,
139.3, 137.3, 131.1, 128.6, 127.9, 127.8, 127.1, 124.0, 113.8, 78.1, 74.5,
55.5, 51.3, 46.6, 40.1, 35.5, 29.0, 26.6, 14.7; IR (film) 3337, 2974, 2930,
1724, 1507, 1241, 1162 cm−1; HRMS (ESI) calcd for C31H40NO4 [M
+ H]+ m/z = 490.2957, found 490.2947; [α]25 = +67.9 (c 0.11, 88%
D
ee, CH2Cl2).
5362
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The Journal of Organic Chemistry
Note
(S)-Methyl 2-(Ethylamino)-5-(4-tert-butoxyphenyl)-2-phe-
nylpentanoate (5). General Procedure D. A solution of 2ksat (15
mg, 0.031 mmol) in MeCN (618 μL) was cooled to 0 °C and put
under N2 in an 8 mL microwave vial equipped with stir bar. A solution
of ceric ammonium nitrate (51 mg, 0.092 mmol) in H2O (309 μL) was
added dropwise. The mixture was allowed to warm to ambient
temperature, stirred for 45 min, cooled to 0 °C, and quenched with 5%
NaHCO3 until a pH of 9 was obtained (∼1 mL). The mixture was
diluted with 20% Na2SO3 (20 mL) and extracted with EtOAc (3 × 20
mL). The combined organic phases were washed with brine (2×),
dried over Na2SO4, and concentrated in vacuo. Purification by column
chromatography (5% to 30% EtOAc/hexanes) provided 5 (7.5 mg) in
64% yield as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.41 (d, J
= 8.4 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.27−7.25 (m, 1H), 6.99 (d, J
= 8.5 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 3.66 (s, 3H), 2.52 (t, J = 7.5
Hz, 2H), 2.32−2.24 (m, 2H), 2.18−2.12 (m, 1H), 2.06−1.97 (m, 1H),
1.54−1.39 (m, 2H), 1.31 (s, 9H), 1.09 (t, J = 7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 175.8, 153.2, 142.0 (b), 137.3, 128.8, 128.4,
127.4, 126.2, 124.2, 78.2, 68.4, 52.4, 37.6, 35.3, 34.4, 29.0, 25.0, 15.8;
IR (film) 2965, 2928, 1733, 1607, 1505, 1234 cm−1; HRMS (ESI)
calcd for C24H34NO3 [M + H]+ m/z = 384.2539, found 384.2547;
142.5, 140.7, 132.9, 128.8, 128.0, 127.5, 127.4, 121.1 (b), 113.7, 75.4,
55.5, 52.4, 48.3, 33.6, 29.1, 24.1; IR (film) 3021, 2860, 1728, 1511,
1244, 1038 cm−1; HRMS (ESI) calcd for C22H26NO3 [M + H]+ m/z =
352.1913, found 352.1923; [α]24 = −1.03 (c 0.33, 83% ee, CH2Cl2).
(S,Z)-Methyl 2-Phenyl-1,2,D3,6,7,8-hexahydroazocine-2-car-
boxylate (9). General procedure D was followed using 8 (10 mg,
0.029 mmol), CAN (50 mg, 0.086 mmol), MeCN (3.2 mL), and H2O
(1.6 mL). The mixture was allowed to stir at ambient temperature for
15 min instead of 45 min then cooled to 0 °C and quenched with 10%
NaHCO3 until a pH of 7 was obtained (∼0.5 mL). Purification by
column chromatography (prewash SiO2 with 3% NEt3 in hexanes,
eluent 5% to 30% EtOAc in hexanes) provided 9 (4 mg) in 59% yield
as a yellow oil. The reaction did not scale up well so it was more
effective to run multiple reactions with the scale indicated above side-
by-side and then combine the material for purification: 1H NMR (500
MHz, CDCl3) δ 7.55 (d, J = 7.8 Hz, 2H), 7.34 (t, J = 7.7 Hz, 2H),
7.28−7.27 (m, 1H), 5.98−5.93 (m, 1H), 5.55−5.50 (m, 1H), 3.67 (s,
3H), 3.06−3.01 (m, 1H), 2.87−2.78 (b, 1H), 2.76−2.72 (m, 1H),
2.69−2.57 (b, 1H), 2.22−2.15 (m, 2H), 1.69−1.63 (m, 1H), 1.60−
1.51 (m, 1H), 1.3 (b, 1H); 13C NMR (125 MHz, CDCl3) δ 175.0,
142.3, 134.3, 128.5, 127.6, 126.8, 126.3, 70.0, 52.6, 44.5, 35.0, 32.2,
26.0; IR (film) 3419, 2924, 1731, 1645, 1220, 1032 cm−1; HRMS
(ESI) calcd for C15H20NO2 [M + H]+ m/z = 246.1494, found
246.1497; [α]25 = −4.8 (c 0.09, 90% ee, CH2Cl2).
[α]24 = −1.5 (c 0.36, 88% ee, CH2Cl2).
D
(S)-Methyl 1-(4-Methoxyphenyl)-2-phenyl-2,3,6,7-tetrahy-
dro-1H-azepine-2-carboxylate (6). General procedure B was
followed using 2b (29 mg, 0.066 mmol, 81% ee) and 4 (2.8 mg,
0.003 mmol) in toluene (6 mL). The reaction was subjected to
microwave (100 W, 100 psi, 115 °C) conditions for 1 h. The mixture
cooled to ambient temperature, ethyl vinyl ether (75 μL, 0.78 mmol)
was added, and the mixture was allowed to stir for 30 min. The
mixture was passed through SiO2 with 30% EtOAc in hexanes and
concentrated in vacuo. Purification by column chromatography
(prewash SiO2 with 5% NEt3 in hexanes, eluent 5% EtOAc in
hexanes) provided 6 (23 mg) in >98% yield as a light yellow oil.
Spectral data agreed with our previous report.9
(S,S,S)-MethDyl 1-Iodo-3-phenyloctahydro-1H-pyrrolizine-3-
carboxylate (10). A solution of 9 (23 mg, 0.094 mmol) in CH2Cl2
(1 mL) open to air was cooled to 0 °C in a flame-dried 5 mL round-
bottom flask equipped with stirbar. NIS (freshly recrystallized from
dichloromethane, 42 mg, 0.19 mmol) was added. The mixture was
warmed to ambient temperature and stirred for 1.5 h. At 0 °C, the
mixture was quenched with 500 μL of 10% aq Na2S2O3. The mixture
was diluted with H2O (5 mL) and extracted with EtOAc (3 × 10 mL).
The combined organic phases were dried over Na2SO4, filtered, and
concentrated in vacuo. Purification by column chromatography
(prewash SiO2 with 5% NEt3 in hexanes, gradient eluent 5% to 30%
EtOAc in hexanes) provided 10 (23 mg) in 67% yield as a light yellow
(S)-Methyl 1-(4-Methoxyphenyl)-2-phenylazepane-2-car-
boxylate (7). General procedure C was followed using 6 (0.033 M
ethyl acetate solution, 0.20 mmol) and 10% Pd/C (22 mg, 0.020
mmol). Purification by column chromatography (prewash SiO2 with
3% NEt3 in hexanes, eluent 6% EtOAc/hexanes) provided 7 (55 mg)
in 81% yield as a white solid. Trituration of 7 in CH2Cl2 provided
undissolved white solid that was close to racemic and liquid that had
enhanced ee to 98%. The liquid was concentrated and recrystallized
from Et2O via slow evaporation over 24 h: mp (98% ee material) =
113−110 °C; 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.6 Hz, 2H),
7.29−7.26 (m, 2H), 7.22 (t, J = 7.1 Hz, 1H), 6.65−6.63 (m, 2H),
6.54−6.52 (m, 2H), 3.75−3.70 (m, 4H), 3.59 (s, 3H), 3.53 (dd, J =
15.6, 8.8 Hz, 1H), 2.61 (dd, J = 15.4, 8.9 Hz, 1H), 2.08 (dd, J = 15.1,
10 Hz, 1H), 1.96−1.93 (b, 1H), 1.88−1.84 (b, 2H), 1.72−1.69 (b,
1H), 1.63−1.60 (b, 1H), 1.50−1.41 (b, 1H); 13C NMR (125 MHz,
CDCl3) δ 175.4, 151.8, 145.1, 141.1, 128.8, 127.9, 126.9, 117.0, 113.8,
72.2, 55.7, 52.4, 51.6, 44.8, 31.0, 29.7, 23.6; IR (film) 2929, 2855, 1731,
1511, 1246, 1222, 1036, 823 cm−1; HRMS (ESI) calcd for C21H26NO3
1
oil: H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 7.0 Hz, 2H), 7.36−
7.30 (m, 3H), 4.27 (ddd, J = 14, 7.5, 6.5 Hz, 1H, C1−H), 3.65 (s, 3H),
3.60−3.52 (b, 1H, C8−H), 3.16 (dd, J = 12.3, 6.1 Hz, 1H, C2−Ha),
2.88−2.80 (b, 1H, C5−Ha), 2.58 (t, J = 12.0 Hz, 1H, C2−Hb), 2.14−
2.09 (m, 2H, C7−Ha, C5−Hb), 1.87−1.71 (m, 3H, C7−Hb, C6−Ha,
C6−Hb); 13C NMR (125 MHz, CDCl3) δ 173.8, 137.4, 128.6, 128.2,
127.6, 77.2, 66.2, 58.1, 53.2, 52.2, 42.1, 36.7, 25.5; IR (film) 2949,
2868, 1741, 1725, 1448, 1251 cm−1; HRMS (ESI) calcd for
C15H19NO2I [M + H]+ m/z = 372.0461, found 372.0450; [α]25
+8.2 (c 0.58, 90% ee, CH2Cl2).
=
D
ASSOCIATED CONTENT
* Supporting Information
■
S
Figures giving spectroscopic data for the products as well as
computational studies on 10 and the CIF for 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
[M + H]+ m/z = 340.1913, found 340.1926; [α]25 = −7.1 (c 0.34,
D
98% ee, CH2Cl2).
AUTHOR INFORMATION
Corresponding Author
*E-mail: marisa@sas.upenn.edu.
(S,Z)-Methyl 1-(4-Methoxyphenyl)-2-phenyl-1,2,3,6,7,8-hex-
ahydroazocine-2-carboxylate (8). General procedure B was
followed using 2c (30 mg, 0.066 mmol) and 4 (2.82 mg, 0.003
mmol) in toluene (6 mL). The reaction was subjected to microwave
(100 W, 100 psi, 115 °C) conditions for 1 h. The mixture was cooled
to ambient temperature, and ethyl vinyl ether (75 μL, 0.784 mmol)
was added and stirred for 30 min. The mixture was passed through
SiO2 with 30% EtOAc in hexanes, concentrated in vacuo, and
chromatographed (prewash SiO2 with 5% NEt3 in hexanes, eluent 5%
EtOAc in hexanes) to provide 8 (22 mg) in 95% yield as a light yellow
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NIH (GM-087605) and the NSF
(CHE0911713) for financial support of this research. Partial
instrumentation support was provided by the NIH for MS
(1S10RR023444) and NMR (1S10RR022442) and by the NSF
for an X-ray diffractometer (CHE 0840438). Our collaboration
with Dr. P. Carroll (UPenn) in obtaining the crystal structure is
gratefully acknowledged, as is the help from Dr. G. Furst
1
oil: H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 8.34 Hz, 2H), 7.29−
7.26 (m, 2H), 7.20 (t, J = 7.0 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 6.70
(d, J = 8.3 Hz, 2H), 5.92−5.87 (m, 1H), 5.72−5.67 (m, 1H), 3.72 (s,
3H), 3.60−3.50 (m, 1H), 3.43 (s, 3H), 3.35−3.30 (m, 2H), 3.27−3.15
(b, 1H), 2.11−2.03 (m, 1H), 2.03−1.93 (b, 1H), 1.92−1.77 (b, 1H),
1.58−1.44 (b, 1H); 13C NMR (125 MHz, CDCl3) δ 174.2, 152.7,
5363
dx.doi.org/10.1021/jo500707t | J. Org. Chem. 2014, 79, 5359−5364

The Journal of Organic Chemistry
Note
(13) Wehbe, J.; Rolland, V.; Fruchier, A.; Roumestant, M.; Martinez,
J. Tetrahedron: Asymmetry 2004, 15, 851−858.
(UPenn) in conducting 2D NMR experiments. We also
acknowledge the contributions of P. Huynh (UPenn).
(14) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360−11370.
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