Reactivity of a propiolate dimer with nucleophiles and an efficient synthesis of dimethyl α-aminoadipate

Article abstract of DOI:10.1016/j.tetlet.2009.11.048

An enyne dimer (1) of methyl propiolate was reacted with amines to form dimethyl (E,E)-2-amino-2,4-hexadiene dioates with remarkable chemospecificity, regiospecificity, and stereospecificity. This enyne was also reduced by Ph₃P stereospecifically to form dimethyl (E,E)-muconic ester. Hydrogenation of the conjugated amino-diene led to an efficient production of dimethyl α-aminoadipate. A lactam of dimethyl α-aminoadipate was obtained in high yield by simply varying the hydrogenation conditions.

Full text of DOI:10.1016/j.tetlet.2009.11.048

Tetrahedron Letters 51 (2010) 425–427
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reactivity of a propiolate dimer with nucleophiles and an efficient synthesis
of dimethyl
a-aminoadipate
a,
Li-Hong Zhou a,b, Xiao-Qi Yu b, , Lin Pu
*
*
a Department of Chemistry, University of Virginia, Charlottesville, VA 22904 4319, USA
b Department of Chemistry, Key Laboratory of Green Chemistry and Technology (Ministry of Education), Sichuan University, Chengdu 610064, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An enyne dimer (1) of methyl propiolate was reacted with amines to form dimethyl (E,E)-2-amino-2,4-
hexadiene dioates with remarkable chemospecificity, regiospecificity, and stereospecificity. This enyne
was also reduced by Ph3P stereospecifically to form dimethyl (E,E)-muconic ester. Hydrogenation of
Received 28 October 2009
Revised 11 November 2009
Accepted 12 November 2009
Available online 18 November 2009
the conjugated amino-diene led to an efficient production of dimethyl
a-aminoadipate. A lactam of
dimethyl -aminoadipate was obtained in high yield by simply varying the hydrogenation conditions.
a
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Methyl propiolate
Dimethyl a-aminoadipate
Muconic ester
Lactam
Propiolates are very useful functional precursors in organic syn-
thesis.1–10 For example, the nucleophilic addition of alkyl propio-
In our laboratory, we are interested in studying the reactivity of
methyl propiolate and its derivatives.1h,i The DABCO-catalyzed effi-
cient synthesis of (E)-hex-2-en-4-yne dioates from propiolates
prompted us to explore the synthetic application of these com-
pounds.12 Herein, our work on the reactions of a propiolate dimer
with amine and phosphine nucleophiles and an efficient synthesis
lates to aldehydes can generate
c-hydroxy-a,b-acetylenic esters
of broad synthetic applications.1 Propiolates can also undergo
many other reactions such as Diels–Alder reaction,2 additional
cycloadditons,3 the Baylis–Hillman-type reaction,4 ene reaction,5
ring annulation,6 coupling with alkyl halides,7 hydrosilylation,8
reaction with ketene silyl acetals,9a and conjugate addition.9b
Dimerization of propiolates in the presence of bases can produce
hex-2-en-4-yne dioates. For example, Ramachandran found that
a catalytic amount of DABCO (<1%) catalyzed this dimerization at
0 °C in minutes in 99% yield (Scheme 1).11 In the presence of Lind-
lar’s catalyst, the (E)-hex-2-en-4-yne dioates were hydrogenated to
(E,Z)-muconic acid diesters for natural product synthesis.
of dimethyl a-aminoadipate is reported.
Dimethyl (E)-hex-2-en-4-yne dioate (1) was obtained by treat-
ment of methyl propiolate with DABCO (1%) in THF at 0 °C in
almost quantitative yield.11 When 1 was reacted with 1 equiv of
dibenzylamine in CH2Cl2 at room temperature for 16 h, compound
2 was obtained in 99% yield (Scheme 2).13 This nucleophilic addi-
tion proceeded with remarkable chemospecificity, regiospecificity,
and stereospecificity. That is, the reaction occurred on the alkyne
unit rather than the alkene unit; at position 2 rather than 3; and
O
O
DABCO (<1%)
0 oC, THF
OR
Lindlar
H2
RO
OR
OR
O
RO
O
O
propiolate
(E)-hex-2-en-4-yn dioate
(E,Z)-muconic acid diester
R = alkyl, aryl
Scheme 1. Catalytic dimerization of propiolates.
* Corresponding authors.
E-mail address: lp6n@virginia.edu (L. Pu).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.048

426
L.-H. Zhou et al. / Tetrahedron Letters 51 (2010) 425–427
MeO
N
O
O
(PhCH2)2NH
DCM
99%
99%
OMe
Ph
O
Ph
2
MeO
OMe
2
3
4
O
O
PPh3 (1.0 equiv)
OMe
1
MeO
H2O (1.0 equiv)
THF
O
3
Scheme 2. Reactions of enyne 1 with nucleophiles.
Pd/C,
H2 (100 psi)
O
OMe
O
O
NH2
O
1. DABCO (1%), 0oC, THF, 10 min
2. PhCH2NH2 (1.1 equiv), r.t.
O
OMe
OMe
MeO
MeO
94%
NHCH2Ph
H2O (1.85 equiv)
EtOH, 18 h
4
99%
5
Scheme 3. Synthesis of dimethyl a-aminoadipate 5.
giving only the (2E,4E)-stereoisomer. In C6D6, the 1H NMR signals
of the three vinyl protons of 2 were observed at d 7.86 (dd,
J = 14.7, 12.0 Hz, 1H, 4-H), 5.73 (d, J = 14.7 Hz, 1H, 5-H), and 5.27
(d, J = 12.0 Hz, 1H, 3-H). The large coupling constancy between
5-H and 4-H indicates a 4E configuration. The Noesy NMR experi-
ment of 2 showed correlation between 3-H and those of the
benzylic protons, indicating a 2E configuration. The regioselectivity
of the amine addition is apparently controlled by the remote ester
group rather than the adjacent one. This unusual regioselectivity is
consistent with Houk’s observation in a Diels–Alder reaction of this
enyne.12
the same chemospecificity, regiospecificity, and stereospecificity
as the formation of 2 from the dibenzylamine addition (Scheme
3).25a Catalytic hydrogenation of 4 in the presence of Pd/C and
H2O gave the desired dimethyl a-aminoadipate 5 in almost quan-
titative yield.25b In this step, the hydrogenation of the diene and
debenzylation occurred simultaneously. This two-pot preparation
of 5 involves less number of steps than the previously reported
synthesis of the racemic a
-aminoadipates.24a,b
In the above catalytic hydrogenation of 4, addition of H2O was
necessary. We found that in the absence of H2O, an intramolecular
cyclization of dimethyl
a-aminoadipate was observed to give the
We also investigated the reaction of enyne 1 with Ph3P.14 Under
nitrogen in dry THF solution, no reaction between 1 and Ph3P was
observed. However, when H2O (1 equiv) was added, 1 was reduced
stereospecifically by Ph3P to give dimethyl (E,E)-muconic ester 3,15
a synthetically useful diene (Scheme 2).12,16,17
lactam 6. The addition of H2O probably deactivated the carbon sup-
port that might be responsible for the intramolecular condensa-
tion. The formation of
6 was optimized by conducting the
hydrogenation of 4 in the presence of Pd/C under 200 psi H2 in
methanol which gave the lactam 6 in 99% yield in 1 h.26,27 This
reaction provides a very convenient way to synthesize a useful
lactam.
The high yield formation of 2 from 1 under the mild reaction
conditions encouraged us to use this method to develop a new syn-
thesis of dimethyl
a-aminoadipate. a-Aminoadipate, a product of
lysine degradation in mammals,18 has attracted considerable re-
search activity in neuroscience, biosynthesis, organic synthesis,
O
and peptide chemistry.19 For example,
a
-aminoadipate is probably
best known as an experimental gliotoxin, which can influence var-
ious elements of glutamatergic neurotransmission.20
-Aminoadi-
NH
6
COOMe
a
pate is also an essential intermediate in lysine biosynthesis in
fungi21a and a well-known precursor in the synthesis of penicillin
or cephalosporin.21b Its derivatives have been used as effective
agents for the treatment of antileukemic, rheumatoid arthritis,
In summary, we have studied the reactions of the methyl propi-
olate dimerization product 1 with the amine and phosphine nucle-
ophiles. The reaction of 1 with dibenzylamine or benzylamine has
exhibited unusual chemospecificity, regiospecificity, and stereo-
specificity to generate the corresponding conjugated amino-diene
products. The base-catalyzed dimerization of methyl propiolate
and the benzylamine addition can be conducted in one-pot to form
psoriasis, and other autoimmune diseases.22 Usually,
a-aminoadi-
pate was obtained from the biosynthesis and catabolism of lysine
in Penicillium chrysogenum.23 A number of synthetic methods for
the preparation of a
-aminoadipates were also reported.24
4 which can then be hydrogenated to give dimethyl
pate, a molecule of significant biological interests. This is a new
and efficient synthesis of an -aminoadpate. Modification of the
a-aminoad-
O
NH2
a
O-
-O
hydrogenation condition allows an easy preparation of lactam 6.
O
Acknowledgments
α-aminoadipate
Partial supports of this work from the US National Science
Foundation (CHE-0717995), the donors of the Petroleum Research
Fund-administered by the American Chemical Society, the National
We combined the catalytic dimerization of methyl propiolate
and the nucleophilic addition of benzylamine into a one-pot reac-
tion to generate the conjugated amino-diene 4 in 94% yield with

L.-H. Zhou et al. / Tetrahedron Letters 51 (2010) 425–427
15. Preparation of 3. Under nitrogen, to
427
a
stirred solution of
1
(0.1 mmol,
Science Foundation of China (Nos. 20725206 and 20732004), and
the Specialized Research Fund for the Doctoral Program of Higher
Education in China are gratefully acknowledged. LHZ also thanks
the fellowship from the China Scholarship Council [No.
(2007)3020].
16.8 mg) in THF (3 mL) was added PPh3 (0.1 mmol, 26 mg) and H2O
(1.0 equiv) at rt. After 4 h, the reaction was shown to be complete by TLC.
The solvent was evaporated and 3 was obtained as a colorless crystalline
solid in 99% yield after column chromatography on silica gel eluted with
25% ethyl acetate in hexanes.
16. Boisvert, L.; Beaumier, F.; Spino, C. Org. Lett. 2007, 9, 5361–5363.
17. (a) Spino, C.; Rezaei, H.; Dupont-Gaudet, K.; Bélanger, F. J. Am. Chem. Soc. 2004,
126, 9926–9927; (b) Buchert, M.; Reissig, H. U. Tetrahedron Lett. 1988, 29,
2319–2320.
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25. (a) Preparation and characterization of 4: Under nitrogen, to a stirred solution of
methyl propiolate (0.2 mmol, 18
0 °C. After 10 min, benzylamine (0.11 mmol, 24
l
L) in THF (2 mL) was added DABCO (1 mg) at
L) was added and the
l
resulting solution was stirred at rt for 16 h. After TLC showed the completion
of the reaction, the solvent was evaporated and the residue was purified by
column chromatography on silica gel eluted with 25% ethyl acetate in hexanes
which gave 4 as a colorless liquid in 94% yield. 1H NMR (300 MHz, CDCl3) d 8.27
(dd, J = 15.0, 12.0 Hz, 1H), 7.37–7.29 (m, 5H), 5.70 (d, J = 15.0 Hz, 1H), 5.53 (d,
J = 12.0 Hz, 1H), 5.26 (br, 1H), 4.24 (2, 2H), 3.92 (s, 3H), 3.72 (s, 3H). 13C NMR
(75 MHz, CDCl3) d 168.0, 164.1, 142.2, 139.0, 136.8, 128.5, 127.4, 127.3, 115.9,
102.9, 52.5, 50.9, 47.4. HRMS (ESI) calcd for C15H17NO4+H+: 276.1230; found:
276.1234.(b) Preparation and characterization of 5: Under nitrogen in a par
7. Davies, K. A.; Abel, R. C.; Wulff, J. E. J. Org. Chem. 2009, 74, 3997–4000.
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reactor, a mixture of 5 wt % Pd/C (3 mg) and H2O (3 lL, 1.85 equiv) in ethanol
(3 mL) was stirred at rt for 10 min. A degassed solution of 4 (24 mg, 0.09 mmol)
in ethanol (2.5 mL) was added, and the mixture was degassed by bubbling with
nitrogen. Hydrogen (100 psi) was introduced and the mixture was stirred at rt
for 18 h. After filtration and evaporation of ethanol, 5 was obtained as a
colorless liquid in 99% yield. 1H NMR (300 MHz, CDCl3) d 8.83 (br, 1H), 4.19 (s,
1H), 3.81 (s, 3H), 3.65 (s, 3H), 2.40 (t, J = 7.2 Hz, 1H), 2.15–2.08 (m, 2H), 1.91–
1.80 (m, 3H). 13C NMR (75 MHz, CDCl3) d 173.43, 169.82, 53.20, 52.96, 51.68,
33.01, 29.71, 20.45.
12. A Diels–Alder reaction was reported: Dai, M.; Sarlah, D.; Yu, M.; Danishefsky, S.
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13. Preparation and characterization of 2. Under nitrogen, to a stirred solution of 1
(0.1 mmol, 16.8 mg) in CH2Cl2 (3 mL) was added dibenzylamine (0.1 mmol,
20 mg) at rt. After 16 h, the reaction was shown to be complete by TLC. The
solvent was evaporated and 2 was obtained as a colorless liquid in 99% yield
after column chromatography on silica gel eluted with 25% ethyl acetate in
hexanes. 1H NMR (300 MHz, C6D6) d 7.86 (dd, J = 14.7, 12.0 Hz, 1H), 7.12–6.98
(m, 10H), 5.73 (d, J = 14.7 Hz, 1H), 5.27 (d, J = 12.0 Hz, 1H), 3.86 (s, 4H), 3.41 (s,
3H), 3.20 (s, 3H). 13C NMR (75 MHz, CDCl3) d 168.0, 165.7, 148.7, 142.0, 135.9,
128.6, 128.5, 128.3, 128.1, 127.6, 127.3, 113.5, 101.2, 53.5, 52.6, 51.0. HRMS
(ESI) calcd for C22H23NO4+H+: 366.1700; found: 366.1710.
26. Preparation of 6: In a par reactor, a solution of 4 (50 mg, 0.18 mmol) in
methanol (3 mL) was treated with 5 wt % Pd/C (3 mg) and the mixture was
degassed by bubbling with nitrogen. Hydrogen (200 psi) was introduced and
the mixture was stirred at rt for 2 h. After filtration and evaporation of
methanol, 6 was obtained as a colorless liquid in 99% yield.
14. A Ph3P promoted addition of the enyne to C60 was reported: Chuang, S.-C.;
Santhosh, K. C.; Lin, C.-H.; Wang, S.-L.; Cheng, C.-H. J. Org. Chem. 1999, 64,
6664–6669.
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