Efficient synthesis of γ,δ-alkynyl-β-amino acid derivatives by a new copper-catalyzed amine-alkyne-alkyne addition reaction

Article abstract of DOI:10.1002/adsc.200800447

A simple and efficient method for the synthesis of γ,δ-alkynyl- β-amino acid derivatives by a new copper-catalyzed amines-alkynes-alkynes addition was developed. Various γ,δ-alkynyl-β-amino acid derivatives were obtained in moderate to good yields in one step.

Full text of DOI:10.1002/adsc.200800447

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DOI: 10.1002/adsc.200800447
Efficient Synthesis of g,d-Alkynyl-b-amino Acid Derivatives by a
New Copper-Catalyzed Amine-Alkyne-Alkyne Addition Reaction
Lei Zhou,a,b Huan-feng Jiang,a,* and Chao-Jun Lib,*
a
College of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, Peopleꢀs
Republic of China
b
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, Quebec, Canada, H3A 2K6
Fax : (+1)-514-398-3797; phone: (+1)-514-398-8457; e-mail: cj.li@mcgill.ca
Received: June 29, 2008; Revised: July 21, 2008; Published online: October 7, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800447.
Abstract: A simple and efficient method for the
synthesis of g,d-alkynyl-b-amino acid derivatives by
a new copper-catalyzed amines-alkynes-alkynes ad-
dition was developed. Various g,d-alkynyl-b-amino
acid derivatives were obtained in moderate to good
yields in one step.
amino acids but also is the key intermediate of certain
designed drugs, such as Xemilofiban, which is a plate-
let aggregation inhibitor that can prevent ischemia,
heart attacks and other major adverse cardiac
events.[8] However, the g,d-alkynyl-b-amino acid de-
rivatives are challenging structures to synthesize.
Compared with numerous reports about the prepara-
tion of alkynyl-b-amino acid,[9] until now only a few
reports for the synthesis of alkynyl-b-amino acid de-
rivatives are known.[10] For example, Awasthi and co-
worker reported the synthesis of such b-amino esters
via the coupling of a terminal alkyne with a Refor-
matsky reagent.[10a] Boys reported the synthesis of
Keywords: addition reactions; alkynes; b-amino
esters; copper catalysis; three-component addition
In recent years, the stereoselective synthesis of b- such compounds from aspartic acid through a four-
amino acids has gained increasing attention due to step precedure.[10b] However, the multi-step synthesis
their biological importance, occurrence in various nat- with the use of expensive reagents made these meth-
ural products,[1] and as potential precursors for b-lac- ods both difficult to operate and not atom-economi-
tams[2] and various heterocyclic compounds.[3] Free b- cal.[11] Thus, the development of methods to synthe-
amino acids show interesting biological and pharma- size such compounds in one step would be highly val-
cological properties such as antiketogenic,[4] antihel- uable and desirable. Herein, we report a simple and
minthic[5] and antitumor properties.[6] Another inter- efficient method for the synthesis of g,d-alkynyl-b-
esting discovery is that only six b-amino acids were amino acid derivatives by a Cu-catalyzed three-com-
required for the formation of a stable helix,[7] whereas ponent addition of amine, alkyne and alkyne
for a-amino acids, 15–20 residues were necessary. (Scheme 1).
Considering their importance, it is of great signifi-
cance to develop new methods for synthesizing b- mixture of diallylamine (1a), phenylacetylene (2a)
amino acids and their derivatives efficiently. and ethyl propiolate (3a) with 5 mol% CuBr as the
To begin our study, we discovered that heating the
Among the various b-amino acids, g,d-alkynyl-b- catalyst at 608C for 24 h generated a 26% yield of 4a
amino acid derivatives are a special class of non-pro- (Table 1, entry 1). Increasing the reaction temperature
teinogenic amino acids. It is now recognized that b- increased the yield, giving 47% and 81% yields when
ethynyl-substituted amino acid not only can greatly carried out at 808C and 1008C, respectively (Table 1,
change the biological properties of some natural entries 2 and 3). Adding a ligand such as bipyridine
Scheme 1.
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Efficient Synthesis of g,d-Alkynyl-b-amino Acid Derivatives
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Table 1. The coupling of diallylamine, phenylacetylene and
groups including bromide, acetylene and protected al-
cohols present in alkyne 2. In the reaction of diallyl-
ethyl propiolate catalyzed by copper.[a]
A
only a mono-addition adduct was obtained as the sole
product (Table 2, entry 9) in 60% yield. By increasing
the steric hindrance of the protecting groups, the
yields of the addition decreased [(All)2 >(All)Bn>
Bn2]. Treatment of ethyl propiolate and phenylacety-
lene with allylbenzylamine (1b) or dibenzylamine (1c)
gave the corresponding g,d-alkynyl-b-amino ester de-
rivatives 4k or 4m in yields of 72% or 70%, respec-
tively (Table 2, entries 11 and 13). It is noteworthy
that the yield of this addition reaction is substantially
affected by the substituted group in alkyne 3. 2-Buty-
noate gave a lower yield relative to ethyl propiolate
(Table 2, entries 9 and 16). When ethyl propiolate was
switched to diethyl acetylenedicarboxylate as the sub-
strate, none of desired product was detected (Table 2,
entry 10).
Free b-amino esters can be obtained selectively by
the removal of the diallyl or dibenzyl residues accord-
ing to the known methods.[12,13] Treatment of g,d-al-
kynyl-b-amino acid derivatives 4a with thiosalicylic
acid (5) in the presence of a palladium(0) catalyst
{[Pd(dba)2] (5 mol%) and DPPB (10 mol%)} at room
G
temperature for 1 hour leads to the monoallylate b-
amino ester 6 in 85% yield (Scheme 2). Free b-amino
ester 7 can be obtained in 68% yield by increasing the
temperature and the loading of thiosalicylic acid. Pri-
mary amines can also be obtained by hydrogenation
of the g,d-alkynyl-b-amino acid derivatives 4. For ex-
ample, hydrogenation of 4m in the presence of Pd on
charcoal in methanol under a hydrogen atmosphere
(1 bar) afforded b-amino ester 8 in 55% yield. To
demonstrate further synthetic applications, the allyl-
[a]
All reactions were carried out by using 0.5 mmol of
diallylamine, 0.5 mmol of ethyl propiolate, 0.75 mmol
A
phenylacetylene and 5% mol of copper catalysts in 2 mL
solvent for 24 h.
[b]
Measured by 1H NMR.
and phenanthroline did not favor the reaction protected amino ester 4a was employed for cycliza-
(Table 1, entries 4 and 5). Among the various copper tion to produce the a-chloromethylene-pyrrolidine
catalysts examined (Table 1, entries 6–11), the rela- derivatives. In the presence of Pd(PhCN)2Cl2, CuCl2
N
tively common and inexpensive CuBr2 gave the best and LiCl, cyclic product 9 was obtained as a single
result (entry 9). The use of solvents also affected the product in 92% yield.
reaction. Toluene is the best choice for the reaction
A plausible mechanism for the three-component
and its use resulted in high conversions to the desired addition of amine, alkyne and alkyne catalyzed by
product. Use of polar solvents such as DMF, N-meth- copper is shown in Scheme 3. A copper-catalyzed hy-
ylpyrrolidinone (NMP) and ethanol gave lower yields droamination[15] of electron-deficient propiolate 3 by
of the product as compared with the less polar 1,4-di- amine 1 generates intermediate A. Subsequent reac-
oxane and xylene (Table 1, entries 12–16). The reac- tion of A with alkyne 2 results in intermediate B,
tion carried out in pure water also resulted in 21% which is protonated to give an iminium intermediate
yield while no product was obtained when TBAB was C.[16] Subsequently, an intramolecular transfer of the
added as phase-transfer reagent (Table 1, entries 17 alkyne moiety to the iminium ion produces the g,d-al-
and 18).
kynyl-b-amino ester 4 and regenerates the copper cat-
Having optimized the reaction conditions, we ex- alyst. As Cu(I) and Cu(II) generated similar results,
plored the scope of the reaction and the results are the active catalyst is most likely Cu(I) as Cu(II) can
summarized in Table 2. Treatment of diallylamine and be converted into Cu(I) readily by reacting with the
ethyl propiolate with different terminal alkynes 2a–h enolate, terminal alkyne, or amine.
furnished the corresponding g,d-alkynyl-b-amino ester
In conclusion, we have developed a simple and effi-
4a–h in moderate to good yields (Table 2, entries 1– cient method for g,d-alkynyl-b-amino acid derivatives
9). The reaction can tolerate various functional by a new copper-catalyzed amines-alkynes-alkynes
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Table 2. Copper-catalyzed addition of amine, alkyne and alkyne in toluene.[a]
[a]
[b]
All the reactions were carried out by using 0.5 mmol amine, 0.5 mmol alkyne and 0.75 mmol
terminal alkyne with 5 mol% CuBr2 as the catalyst in toluene at 1008C for 24 h.
Isolated yield.
addition. Various g,d-alkynyl-b-amino acid derivatives added. The resulting solution was stirred at 1008C for 24 h.
After cooling to room temperature, the resulting mixture
was filtered through a short path of silica gel in a pipette
eluting with ethyl acetate. The volatiles were removed
under vacuum and the residue was purified by column chro-
matography (SiO2, hexane/ethyl acetate 10:1) to give 4a as a
pale yellow oil; yield: 114 mg (77%). 1H NMR (CDCl3,
400 MHz): d=7.44–7.40 (m, 2H), 7.31–7.29 (m, 3H), 5.86–
5.77 (m, 2H), 5.23 (d, J=17.2 Hz, 2H), 5.14 (d, J=10.0 Hz,
2H), 4.31 (t, J=8.4 Hz, 1H), 4.17 (q, J=7.6 Hz, 2H),
3.33(dt, J=14.0, 2.4 Hz, 2H), 2.98 (dd, J=14.0, 8.0 Hz, 2H);
2.74–2.68 (m, 2H), 1.26 (t, J=6.8 Hz, 3H); 13C NMR
(CDCl3, 75 MHz): d=170.8, 136.5, 132.0, 128.5, 128.3, 123.2,
117.5, 86.2, 85.8, 60.7, 54.2, 50.0, 39.9, 14.4; MS (70 eV):
m/z=296 (M+), 256, 210 (100); HR-MS (EI): m/z=
296.16432, calcd. for C19H23NO2 [M+]: 296.16505.
were obtained in moderate to good yields in one step.
The asymmetric addition, mechanism and synthetic
applications of this efficient addition reaction are
under investigation.
Experimental Section
Representative Experimental Procedure (4a)
CuBr2 (6 mg, 0.025 mmol, 5 mol%) was suspended in tolu-
ene (2 mL) in a 10-mL Schlenk tube under nitrogen. Then
diallylamine (49 mg, 0.5 mmol), ethyl propiolate (49 mg,
0.5 mmol), and phenylacetylene (76.5 mg, 0.75 mmol) were
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Efficient Synthesis of g,d-Alkynyl-b-amino Acid Derivatives
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Scheme 2. Selective transformations of g,d-alkynyl-b-amino acid derivatives.
Scheme 3. Tentative mechanism for the copper-catalyzed amine-alkyne-alkyne addition.
The experiments in Table 2 were carried out analogously.
All products were purified by column chromatography and
characterized by NMR spectroscopy and standard/high-reso-
lution mass spectrometry.
AcOEt to eliminate the by-product and the catalyst in the
organic layer. The aqueous layer containing the protonated
amine was basified with l M NaOH and extracted by
AcOEt. The organic layer was dried over MgSO4 and con-
centrated under vacuum, affording clean crude products.
Further purification was performed by flash chromatogra-
phy with hexane:AcOEt (3:1) as the elute.
Generation of Free g,d-Alkynyl-b-amino Esters
A mixture of Pd(dba)2 (5 mol%) and DPPB (10 mol%) in
G
THF (0.5 mL) was stirred at room temperature, under a ni-
trogen atmosphere, for 15 min. The preformed catalyst and
2-mercaptobenzoic acid (1.2 or 4 equiv.) were added to a so-
lution of 4a in THF and the reaction mixture was stirred
under argon atmosphere at 20 or 608C. After completion
(the reaction was monitored by TLC and GC-MS), the mix-
ture was treated by a solution of 10% HCl and extracted by
Acknowledgements
We are grateful to the Canada Research Chair (Tier I) foun-
dation (to CJL), the CFI, NSERC and McGill University for
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Lei Zhou et al.
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support of our research. LZ thanks the China Scholarship
Council for a Visiting Scholarship.
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