Indium(III)-catalyzed addition of diethyl acetamidomalonate to terminal alkynes: An efficient approach to β-branched α-amino acids

Article abstract of DOI:10.1021/jo070878+

(Chemical Equation Presented) The indium(III)-catalyzed Markovnikov addition of active methylene compounds to terminal alkynes has been expanded further to include diethyl acetamidomalonate. This reaction has been studied, and a practical approach to β-branched α-amino acids was developed.

Full text of DOI:10.1021/jo070878+

Indium(III)-Catalyzed Addition of Diethyl
Acetamidomalonate to Terminal Alkynes: An
Efficient Approach to â-Branched r-Amino Acids
Paul Angell, Peter G. Blazecka, Mark Lovdahl,
and Ji Zhang*
FIGURE 1. Some useful and inexpensive starting materials (1a, 1b)
for the addition to 1-alkynes catalyzed by indium(III) and previously
prepared adduct 3 from phenylacetylene and 1b.
Research API, Pfizer Global Research & DeVelopment,
Ann Arbor Laboratories, Pfizer, Inc., 2800 Plymouth Road,
Ann Arbor, Michigan 48105
are numerous methods to prepare optically pure R-amino acids,7
the number of highly enantioselective routes to â-branched
R-amino acids is still limited.8 The current highly efficient and
practical catalytic asymmetric hydrogenation technology9
prompted us to examine ways of making novel alkenes from
which optically pure â-branched R-amino acids can be accessed
expediently.10
ji.zhang@bms.com
ReceiVed April 26, 2007
Diethyl acetamidomalonate (1a, DEAM) has been used for
the synthesis of R-amino acids by C-alkylation via Michael
addition under basic conditions.11 It was also reported that the
combination of C-alkylation and N-alkylation makes the forma-
tion of cyclic R-amino acid feasible.12 However, to the best of
our knowledge, there are no reports that employ 1a or its
(4) (a) Kempf, D. J.; Molla, A.; Hsu, A. AntiretroViral Ther. 2001, 147.
(b) Kempf, D. J.; Sham, H. L.; Marsh, K. C.; Flentge, C. A.; Betebenner,
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Plattner, J. J.; Norbeck, D. W. J. Med. Chem. 1998, 41, 602. (c) Wang, G.
T.; Li, S.; Wideburg, N.; Krafft, G. A.; Kempf, D. J. J. Med. Chem. 1995,
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(e) Kempf, D. J.; Codacovi, L.; Wang, X. C.; Kohlbrenner, W. E.; Wideburg,
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J.; Codacovi, L.; Wang, X. C.; Kohlbrenner, W. E.; Wideburg, N. E.; Paul,
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Chem. 1990, 33, 2687.
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Hruby, V. J. Tetrahedron Lett. 1989, 30, 6845.
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M. J. Acc. Chem. Res. 2004, 37, 506. (c) Co´rdova, A. Acc. Chem. Res.
2004, 37, 102. (d) Tararov, V. I.; Bo¨rner, A. Synlett 2005, 203. (e) Ma,
J.-A. Angew. Chem., Int. Ed. 2003, 42, 4290.
The indium(III)-catalyzed Markovnikov addition of active
methylene compounds to terminal alkynes has been expanded
further to include diethyl acetamidomalonate. This reaction
has been studied, and a practical approach to â-branched
R-amino acids was developed.
â-Branched R-amino acids are important and valuable build-
ing blocks for drug discovery since incorporation of confor-
mationally constrained R-amino acids into peptides improves
the pharmacokinetics and binding potency of drug candidates.1
For example, L-valine was utilized successfully in the synthesis
of pharmaceuticals such as Reprintrivir (AG-7088)2 and Ritonavir
(ABT-538, or Norvir),3 as well as HIV protease inhibitors.4
Meanwhile, the cyclic depsipeptide hormaomycin5 is a naturally
occurring product with interesting biological activities that
contains two units of 3-methylphenylalanine.6 Although there
(8) (a) Kawabata, T.; Chen, J.; Suzuki, H.; Fuji, K. Synthesis 2005, 1368.
(b) Chowdari, N. S.; Suri, J. T.; Barbas, C. F., III. Org. Lett. 2004, 6, 2507.
(c) Roff, G. J.; Lloyd, R. C.; Turner, N. J. J. Am. Chem. Soc. 2004, 126,
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D.; Zurbano, M. M. Tetrahedron: Asymmetry 2003, 14, 399. (e) Shapiro,
G.; Buechler, D.; Marzi, M.; Schmidt, K.; Gomez-Lor, B. J. Org. Chem.
1995, 60, 4978. (f) D’Aniello, F.; Mann, A.; Taddei, M.; Wermuth, C.-G.
Tetrahedron Lett. 1994, 35, 7775.
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1995, 117, 9375. (b) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R.
L. J. Am. Chem. Soc. 1993, 115, 10125. (c) Knowles, W. S.; Sabacky, M.
J.; Vineyard, B. D.; Weinkauff, D. J. J. Am. Chem. Soc. 1975, 97, 2567.
(10) (a) Burk, M. J.; Bedingfield, K. M.; Kiesman, W. F.; Allen, J. G.
Tetrahedron Lett. 1999, 40, 3093. (b) Davis, F. A.; Liu, H.; Zhou, P.; Fang,
T.; Reddy, G. V.; Zhang, Y. J. Org. Chem. 1999, 64, 7559.
* To whom correspondence should be addressed. Fax: +1-609-252-7825.
Tel: +1-609-252-5469.
(1) (a) Al´ıas, M.; Pilar Lo´pez, M.; Cativiela, C. Tetrahedron 2004, 60,
885. (b) Reginato, G.; Mordini, A.; Valacchi, M.; Piccardi, R. Tetrahe-
dron: Asymmetry 2002, 13, 595. (c) Hruby, V. J. Acc. Chem. Res. 2001,
34, 389. (d) Hruby, V. J.; Al-Obeidi, F. A.; Kazmierski, W. Biochem. J.
1990, 268, 249.
(2) (a) Chng, S.-S.; Hoang, T.-G.; Lee, W.-W. W.; Tham, M.-P.; Ling,
H. Y.; Loh, T.-P. Tetrahedron Lett. 2004, 45, 9501. (b) Ma, D.; Xie, W.;
Zou, B.; Lei, Q.; Pei, D. Tetrahedron Lett. 2004, 45, 8103. (c) Dragovich,
P. S.; Prins, T. J.; Zhou, R.; Webber, S. E.; Marakovits, J. T.; Fuhrman, S.
A.; Patick, A. K.; Matthews, D. A.; Lee, C. A.; Ford, C. E.; Burke, B. J.;
Rejto, P. A.; Hendrickson, T. F.; Tuntland, T.; Brown, E. L.; Meador, J.
W., III; Ferre, R. A.; Harr, J. E. V.; Kosa, M. B.; Worland, S. T. J. Med.
Chem. 1999, 42, 1213.
(3) (a) Kempf, D. J.; Marsh, K. C.; Denissen, J. F.; McDonald, E.;
Vasavanonda, S.; Flentge, C. A.; Green, B. E.; Fino, L.; Park, C. H.; Kong,
X.-P.; Wideburg, N. E.; Salvidar, A.; Ruiz, L.; Kati, W. M.; Sham, H. L.;
Robins, T.; Stewart, K. D.; Hsu, A.; Plattner, J. J.; Leonard, J. M.; Norbeck,
D. W. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2484. (b) Markowitz, M.;
Mo, H.; Kempf, D. J.; Norbeck, D. W.; Bhat, T. N.; Erickson, J. W.; Ho,
D. D. J. Virol. 1995, 69, 701.
(11) (a) Kotha, S.; Singh, K. Tetrahedron Lett. 2004, 45, 9607. (b)
Watanabe, L. A.; Jose, B.; Kato, T.; Nishino, N.; Yoshida, M. Tetrahedron
Lett. 2004, 45, 491. (c) Leanna, M. R.; Morton, H. E. Tetrahedron Lett.
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Chem. 1979, 44, 3063.
(12) Rogers, L. M.-A.; Rouden, J.; Lecomte, L.; Lasne, M.-C. Tetrahe-
dron Lett. 2003, 44, 3047.
10.1021/jo070878+ CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/21/2007
6606
J. Org. Chem. 2007, 72, 6606-6609

TABLE 1. Reaction Condition Screena
TABLE 3. DEAM Addition to 1-Alkyne Catalyzed by In(OTf)3
a
addition
product
area %
catalyst
(mol %)
entry
base
temp (°C)/time (h)
1
2
3
4
5
6
7
8
9
10
11
12
13
10% In(OTf)3
140/3
120/3
120/20
140/1
140/3
140/1
140/3
140/4
120/4.5
120/20
120/20
120/20
120/4.5
63
57
83
78
75
44
71
56
62
85
62
72
75
10% In(OTf)3 20% NMM
10% In(OTf)3 20% NMM
10% In(OTf)3 20% NMM
10% In(OTf)3 20% NMM
10% InCl3
10% InCl3
10% In(OTf)3 20% DBU
10% In(OTf)3 20% t-BuOLi
10% In(OTf)3 20% t-BuOLi
10% In(OTf)3 20% t-BuONa
10% In(OTf)3 20% t-BuOK
10% In(OTf)3 20% LiOTf
20% NMM
20% NMM
a Reaction conditions: DEAM (2.0 mmol), phenylacetylene (1 mL), and
InX3 (0.2 mmol) were combined with or without base and heated as
indicated.
TABLE 2. NMM Loading Study on Addition of DEAM to
Phenylacetylenea
a Reaction conditions: 1 equiv (2-20 mmol) of DEAM, 2-5 equiv of
desired alkyne, 0.10 equiv of In(OTf)3, 20 mol % of NMM, 16-24 h at
120-130 °C, neat conditions. The reaction time was not optimized.
b Isolated yield after purification by silica gel chromatography. Products
estimated to be >95% pure by 1H NMR and elemental analysis. c Reaction
repeated on 20 mmol (vs 2 mmol) scale with similar results. d Product 3l
provided the conjugate addition product (anti-Markovnikov).
NMM
(mol %)
ratio of
base/In(OTf)3
addition
product %
entry
1
2
3
4
5
6
5
0.5/1
1/1
2/1
3/1
4/1
5/1
91.1 (7 h)
90.9 (7 h)
86.1 (7 h)
5.6 (7 h)
7.8 (7 h)
7.8 (7 h)
10
20
30
40
50
of R-hydrogen. Indeed, when 1a was combined with pheny-
lacetylene under our previously reported conditions,15 the desired
product was not observed. When 5% DBU was added as catalyst
and the mixture heated to reflux for another 20 h, only a trace
amount of the desired product (<5%) was detected. Thus we
decided to increase the reaction temperature to 140 °C by using
xylene as solvent and 10 mol % of InCl3 as Lewis acid. After
20 h, the desired product was isolated, although the yield was
still poor.
After the desired conversion was achieved, further screening
experiments were performed employing several In(III) salts,
including InCl3, In(OTf)3, In(OAc)3, and InF3, and amine bases,
including DIEA, N-methylmorpholine (NMM), DBU, DABCO,
sparteine and imidazole in o-xylene, and mesitylene, or under
neat conditions (using excess acetylene). The reaction contents
were heated from 100 to 160 °C for as long as 20 h. Little or
no desired product was observed using either In(OAc)3 or InF3.
In contrast, a good yield (as high as 71 area % by HPLC) of
the desired product was seen with InCl3 in the presence of NMM
(Table 1). However, even better conversion was observed using
In(OTf)3 in the presence of NMM (20 mol %) at 140 °C under
a Reaction conditions: DEAM (2.0 mmol), phenylacetylene (1 mL), and
In(OTf)3 (0.2 mmol) were combined with NMM (5-50 mol %) and heated
at 120 °C for 7 h.
derivative as nucleophiles under acidic conditions to form the
C-C bond. Recently, Nakamura and co-workers reported the
indium triflate promoted addition of â-ketoesters and 1,3-
diketones to 1-alkynes.13 We later found that most indium(III)
salts, green Lewis acids,14 can assist this reaction and that
malonates can be used as starting materials.15 Surprisingly, when
diethyl methoxymalonate (1b) was used under our previously
published conditions (InCl3, 130 °C), adduct 3 was formed in
81% isolated yield (Figure 1). This exceptional result encouraged
us to further study its application. Herein we report an efficient
method for the synthesis of â-branched R-amino acids with
indium(III)-mediated addition of diethyl acetamidomalonate to
terminal alkynes as the key step.
Unlike malonate 1b, we expected formation of the enol-
indium complex with 1a to be difficult due to the lower acidity
(14) (a) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209. (b)
Loh, T.-P.; Chua, G.-L. AdV. Org. Synth. 2005, 1, 173. (c) Zhang, Z.-H.
Synlett 2005, 4, 711.
(15) Zhang, J.; Blazecka, P. G.; Angell, P.; Curran, T. T. Tetrahedron
2005, 61, 7807.
(13) (a) Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem. Soc. 2003,
125, 13002. See also: (b) Nakamura, M.; Fujimoto, T.; Endo, K.; Nakamura,
E. Org. Lett. 2004, 6, 4837. (c) Endo, K.; Hatakeyama, T.; Nakamura, M.;
Nakamura, E. J. Am. Chem. Soc. 2007, 129, 5264.
J. Org. Chem, Vol. 72, No. 17, 2007 6607

TABLE 4. Synthesis of â-Branched r-Amino Acidsa
a Reaction conditions for 1-7 mmol of substituted malonates 3a,d,f,j-l: (i) Pd(C) or Pt(C)/H2 50 psi, EtOH or THF, 3-16 h at 20-25 °C; (ii) 6 N
aqueous HCl (w/ or w/o p-dioxane), 16-24 h at 90-100 °C. The reaction time was not optimized. b Isolated yield after purification by precipitation from
acetonitrile. Products estimated to be >95% pure by 1H NMR and elemental analysis. c Syn/anti ratio was determined by 1H NMR integration; assignments
of syn/anti diastereomers were based on previously published assignments for 5a1a and 5f,8c while the remaining â-methyl-R-amino acids were assigned by
correlation.
neat conditions. The rate, purity profile, and conversion (as high
as 90 area % by HPLC in 3 h) to the desired addition products
were superior to all other conditions examined.
unproductive. Disubstituted alkynes did not provide the desired
addition product either.
With this novel application for In(III)-catalyzed addition of
DEAM to alkynes available, we then developed a practical and
efficient approach to prepare â-branched R-amino acids (Table
4). To that end, the addition products of DEAM and alkyne
were subjected to hydrogenation using Pd(C); however, deha-
logenation was avoided for 3d f 4d when Pt(C) was used. The
hydrogenated product was treated with 6 N HCl in refluxing
conditions, resulting in concomitant N-deacylation/ester hy-
drolysis and decarboxylation of 4 to provide the target â-methyl
R-amino acid in excellent overall yield.
In conclusion, we have demonstrated the general application
for the In(III)-catalyzed addition of DEAM to terminal alkynes.
The addition appears to be fairly broad in scope and generally
works well with phenyl acetylenes or aliphatic acetylenes. The
choice and amount of base have a significant effect on the
outcome of the addition reaction.
The addition products were further elaborated after hydro-
genation followed by a practical one-pot concomitant N-
deacylation/ester hydrolysis and decarboxylation under HCl
reflux conditions to provide the target â-branched R-amino acids
in excellent overall yield and purity. Further utilization of this
reaction, including the synthesis of optically enriched â-branched
R-amino acids via catalytic asymmetric hydrogenation, will be
reported in due course.
It was found that the reaction temperature must be at least
120 °C for a satisfactory reaction rate (reaction completion less
than 24 h). Higher temperatures (e.g., 140 °C) increased the
rate but appeared to lead to product decomposition. Interestingly,
good conversion was also observed using t-BuOM (M ) Li,
Na, K) or LiOTf as bases, with yields ranging from 62 to 85%
after 4.5-20 h. In the further study (Table 2) with NMM as an
additive for the assistance of the deprotonation of DEAM to
generate the indium enolate intermediate,16 up to 20 mol % of
base was tolerated. 5-10 mol % NMM loading gave nearly
identical and optimal results, and 30-50 mol % provided very
poor results. This finding clearly shows the deleterious effect
for the desired addition reaction when the base/catalyst ratio
approaches or exceeds 3/1.
With the success of this screening experiment, we further
investigated the scope and limitation of the In(III)-catalyzed
addition reaction of DEAM with various alkynes. These results
are shown in Table 3.
We also found that functionalized terminal alkynes, such as
5-hexynenitrile, 6-chloro-1-hexyne, and 5-chloro-1-pentyne,
provided low to moderate yields (15-35%). Unsubstituted
aliphatic alkynes gave moderate yields (mid-50% range, entries
3j and 3k) and generally good yields (up to 85%, entries 3a
and 3h) for aromatic alkynes. Electron-withdrawing substitution
on the aromatic ring led to sub-par yield, and the electron-
deficient ethyl propiolate provided a good (73%, entry 3l) yield
of the expected E/Z mixture of the Michael addition product.
Alcoholic alkynes or the labile acetal functional groups were
Experimental Section
All reactions were carried out under nitrogen atmosphere unless
otherwise noted.
General Method for the Preparation of Vinylmalonates 3a-
l. N-Methylmorpholine (NMM) is added to a mixture of diethyl
acetamidomalonate (1, DEAM) and In(OTf)3 in alkyne (2a-l). The
mixture is heated at 120-140 °C for 3-72 h. After cooling to rt,
(16) (a) Yang, D.; Li, J.-H.; Gao, Q.; Yan, Y.-L. Org. Lett. 2003, 5,
2869. (b) Yang, D.; Gao, Q.; Lee, C.-S.; Cheung, K.-K. Org. Lett. 2002, 4,
3271.
6608 J. Org. Chem., Vol. 72, No. 17, 2007

the reaction solution is applied directly to a column of SiO2 and
purified by flash chromatography to provide the addition product
(3a-l).
General Method for the Preparation of Ethylmalonates 4a-
l. A mixture of vinylmalonates 3a-l and 10% Pd on carbon in
EtOH is hydrogenated (H2/50 psi) at rt for 1-5 h. The catalyst is
removed, and the filtrate is concentrated in vacuo to provide
ethylmalonates 4a-l.
General Method for the Preparation of â-Methyl-R-amino
acid•HCl 5a-l. A mixture of ethylmalonates 4a-l in 6 M HCl is
heated at reflux for 16-48 h. The resultant solution is concentrated
in vacuo. The residue is diluted with CH3CN and reconcentrated
to effect azeotropic water removal. The concentrate is slurried in
CH3CN, collected by filtration, and dried in vacuo to provide
â-methyl-R-amino acid•HCl 5a,d,f,j-l as a mixture of diastereo-
mers.
Supporting Information Available: Experimental procedures,
spectral and analytical data for all products, and additional
structures. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO070878+
J. Org. Chem, Vol. 72, No. 17, 2007 6609