Catalytic α-allylation of unprotected amino acid esters

Article abstract of DOI:10.1021/ol300665n

Catalytic α-allylation of unprotected amino acid esters to produce α-quaternary α-allyl amino acid esters is reported. Catalytic loadings of picolinaldehyde and Ni(II) salts induce preferential reactivity at the enolizable α-carbon of amino acid esters ov

Full text of DOI:10.1021/ol300665n

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2130–2133
Catalytic r-Allylation of Unprotected
Amino Acid Esters
Ping Fang, Mani Raj Chaulagain, and Zachary D. Aron*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington,
Indiana 47405-7102, United States
zaron@indiana.edu
Received March 15, 2012
ABSTRACT
Catalytic R-allylation of unprotected amino acid esters to produce R-quaternary R-allyl amino acid esters is reported. Catalytic loadings of
picolinaldehyde and Ni(II) salts induce preferential reactivity at the enolizable R-carbon of amino acid esters over the free nitrogen with
electrophilic palladium π-allyl complexes. Fourteen examples are given. Additionally, the use of chiral ligands to access enantioenriched R-
quaternary amino acid esters from racemic precursors is demonstrated by the enantioselective synthesis of R-allyl phenylalanine methyl ester
from racemic phenylalanine methyl ester.
Developing protecting-group-free reactions and synth-
eses streamlines our access to complex chemical entities.1
Of particular use are carbonÀcarbon bond forming reac-
tions that occur in the presence of reactive functionalities
including alcohols, carboxylates, carbonyls, and basic
amines. To date, however, few polar bond-forming reac-
tions selectively occur in the presence of unprotected
primary amines, and none produce fully substituted car-
bon centers.2,3 This drawback limits access to R-quatern-
ary amino acids that form the core of numerous natural
Figure 1. R-Quaternary amino acids.
(1) (a) Hoffmann, R. W. Synthesis 2006, 21, 3531. (b) Young, I. S.;
Baran, P. S. Nat. Chem. 2009, 1, 193.
(2) For examples of enolate alkylation in the presence of primary
amines, see: (a) Myers, A. G.; Gleason, J. L.; Yoon, T. J. Am. Chem.
Soc. 1995, 117, 8488. (b) Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung,
D. W. J. Am. Chem. Soc. 1997, 119, 656. (c) Nagula, G.; Huber, V. J.;
acids such as aib (2) into peptides stabilizes them toward
Lum, C.; Goodman, B. A. Org. Lett. 2000, 2, 3527. (d) McNeil, A. J.;
Toombes, G. E. S.; Gruner, S. M.; Lobkovsky, E.; Collum, D. B.;
Chandramouli, S. V.; Vanasse, B. J.; Ayers, T. A. J. Am. Chem. Soc.
2004, 126, 16559.
(3) For an example of alcohol acylation in the presence of a primary
amine, see: Ohshima, T.; Iwasaki, T.; Maegawa, Y.; Yoshiyama, A.;
Mashima, K. J. Am. Chem. Soc. 2008, 130, 2944.
(4) (a) Horn, W. S.; Smith, J. L.; Bills, G. F.; Raghoobar, S. L.;
Helms, G. L.; Kurtz, M. B.; Marrinan, J. A.; Frommer, B. R.; Thornton,
R. A.; Mandala, S. M. J. Antibiot. 1992, 45, 1692. (b) Omura, S.;
Fujimoto, T.; Otoguro, K.; Matsuzaki, K.; Moriguchi, R.; Tanaka,
H.; Sasaki, Y. J. Antibiot. 1991, 44, 113. (c) Omura, S.; Matsuzaki,
K.; Fujimoto, T.; Kosuge, K.; Furuya, T.; Fujita, S.; Nakagawa, A.
J. Antibiot. 1991, 44, 117. (d) Feling, R. H.; Buchanan, G. O.; Mincer,
T. J.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Angew. Chem., Int. Ed.
2003, 42, 355.
products and pharmaceuticals including inhibitors of
sphingolipid biosynthesis (1)4a and the 20s proteasome
(3) (Figure 1).4bÀd Incorporation of R-quaternary amino
proteolysis5 and provides a bias for R-helical conforma-
tions, controlling peptabiotic- and peptabiol-mediated ion
channel formation.4a,6a Numerous methods for generating
R-quaternary amino acids have been described; however,
none of these produce the desired materials in a single
transformation.7 In this communication, we report the
first catalytic, enantioselective R-allylation of unprotected
(5) Adessi, C.; Soto, C. Curr. Med. Chem. 2002, 9, 963.
(6) Peggion, C.; Formaggio, F.; Crisma, M.; Epand, R. F.; Epand,
R. M.; Toniolo, C. J. Peptide Sci. 2003, 9, 679.
r
10.1021/ol300665n
Published on Web 04/09/2012
2012 American Chemical Society

amino acid esters to produce enantioenriched R-quatern-
ary amino acid esters in a single transformation.
complex enzymatic systems are required to control the
competing reactivity of the quinonoid and the nucleophilic
nitrogen of the starting material 5.
Recently, we reported the intermediate presence of
azomethine ylides in picolinaldehyde/metal-mediated ami-
no acid racemizations and condensations.8 This work
demonstrated that azomethine ylide formation is facili-
tated by metal chelation, allowing racemization to occur
under mild conditions. We report here an important
extension of this chemistry showing that nickel chelates
of picolinaldehyde, in concert with palladium complexes,
catalyze the TsujiÀTrost allylation of unprotected amino
acid esters in excellent yields and demonstrate the potential
for excellent enantioselectivities (Scheme 1).9
Table 1. Initial Screens
entry
-Y
X
method
yield (%)a
1
2
3
4
-Br
1.0
0.1
1.0
0.1
A
A
B
B
11%
trace
47%
43%
Scheme 1. Picolinaldehyde-Catalyzed Amino Acid Allylation
-Br
-OAc
-OAc
a Yields were determined by 1H NMR using an internal standard.
Table 2. Reaction Optimization
Quinonoid intermediates are effective nucleophiles in
biological systems,10 suggesting that intermediates such as
6 should react well with appropriate electrophiles. Similar
intermediates are wellestablished inthe workofO’Donnell
and co-workers who use deprotonated amino acid imines
as nucleophiles in a variety of carbonÀcarbon bond form-
ing reactions.11 These intermediates are further established
to react with metal π-allyl complexes.12 However, in the
preceding examples, stoichiometric imine formation or
entry
additive (equiv)
yielda
1
2
3
4
5
6
N/A
24À73%
75%
H2O (3.0)
(7) (a) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2708. (b) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 1998, 9, 3517. (c) Cativiela, C.; Diaz-de-Villegas, M. D. Tetra-
hedron: Asymmetry 2000, 11, 645. (d) Najera, C.; Sansano, J. M. Chem. Rev.
2007, 4584. (e) Maruoka, K. Org. Process Res. Dev. 2008, 12, 679. (f)
Cativiela, C.; Mario, O. Tetrahedron: Asymmetry 2009, 20, 1.
(8) (a) Felten, A.; Zhu, G.; Aron, Z. D. Org. Lett. 2010, 12, 1916. (b)
Chaulagain, M. R.; Aron, Z. D. J. Org. Chem. 2010, 75, 8271.
(9) (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett.
1965, 6, 4387. (b) Trost, B. M.; VanVranken, D. L. Chem. Rev. 1996, 96,
395. (c) Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140.
H2O (3.0), NH4Cl (0.5)
H2O (3.0), NH4OAc (0.5)
H2O (3.0), Me4NOAc (0.5)
H2O (3.0), HOAc (0.5)
70%
82%b
58%
52%
a Yields were determined by 1H NMR using an internal standard.
b Isolated yield.
(10) (a) Eliot, A. C.; Kirsch, J. F. Annu. Rev. Biochem. 2004, 73, 383.
(b) Richard, J. P.; Amyes, T. L.; Crugeiras, J.; Rios, A. Biochim. Biophys.
Acta 2011, 1814, 1419.
(11) (a) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506. (b) O’Donnell,
M. J.; Boniece, J. M.; Earp, S. E. Tetrahedron Lett. 1978, 2641. (c)
O’Donnell, M. J.; Eckrich, T. M. Tetrahedron Lett. 1978, 4625.
(12) (a) Kanayama, T.; Yoshida, K.; Miyabe, H.; Kimachi, T.;
Takemoto, Y. J. Org. Chem. 2003, 68, 6197. (b) Kanayama, T.; Yoshida,
K.; Miyabe, H.; Takemoto, Y. Angew. Chem., Int. Ed. 2003, 42, 2054. (c)
Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto, Y. J. Org. Chem.
2002, 67, 7418. (d) Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto, Y.
Org. Lett. 2001, 3, 3329. (e) Chen, G.; Deng, Y.; Gong, L.; Mi, A.; Cui,
X.; Jiang, Y.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron: Asymmetry
2001, 12, 1567. (f) Kazmaier, U.; Maier, S.; Zumpe, F. L. Synlett 2000,
1523. (g) You, S.-L.; Hou, X.-L.; Dai, L.-X.; Cao, B.-X.; Sun, J. Chem.
Commun. 2000, 1933. (h) Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999,
121, 10727. (i) Kazmaier, U.; Zumpe, F. L. Angew. Chem., Int. Ed. 1999,
38, 1468. (j) Hiroi, K.; Hidaka, A.; Sezaki, R.; Imamura, Y. Chem.
Pharm. Bull. 1997, 45, 769. (k) Baldwin, I. C.; Williams, J. M. J.; Beckett,
R. P. Tetrahedron: Asymmetry 1995, 6, 1515. (l) Genet, J.-P.; Juge, S.;
Achi, S.; Mallart, S.; Montes, J. R.; Levif, G. Tetrahedron 1988, 44, 5263.
We hypothesized that the delocalization seen in quino-
noid 6 would cause it to react as a “soft” nucleophile in
contrast to the competing “hard” nitrogen nucleophile,
suggesting a mechanism for chemoselectivity. Early at-
tempts at the condensation using allyl bromide did not
bear this hypothesis out (Table 1, entries 1 and 2). Stoi-
chiometric loadings of picolinaldehyde were necessary to
minimize reaction at nitrogen, yet even these conditions
gave poor conversions. Accordingly, we turned our atten-
tion to softer metal π-allyl complexes. To our gratifica-
tion, reactions involving palladium π-allyl species gave im-
proved yields and exhibited multiple turnovers with respect
to the aldehyde-based catalyst (Table 1, entries 3 and 4).
It should be noted that the pH of these systems was critical
to selectivity, as superstoichiometric quantities of base led
Org. Lett., Vol. 14, No. 8, 2012
2131

to predominant N-allylation. These results established that
catalytically generated picolinaldehyde quinonoid intermedi-
ates can act as nucleophiles in carbonÀcarbon bond forming
reactions and indicated a viable route for the direct synthesis
of R-quaternary amino acid esters.
Variation of the Lewis acid, solvent, ligand, and additives
were used to optimize the reaction (Tables 2 and S1). Lewis
acid screens revealed that Ni(II) salts provided optimal
reactivity (Table S1, entries 1À5). Interestingly, anhydrous
Zn(OTf)2 proved a poor cocatalyst for the reaction,
whereasZn(OAc)2 2H2O wasmoreefficacious, suggesting
3
that water and/or acetate might prove to be important
additives in the reaction (Table S1, entries 4 and 5). The
reaction proceeds well in noncoordinating solvents, with
moderately polar, aprotic solvents such as chlorobenzene
and dichloroethane providing optimal results (Table S1,
entries 6À10). Both mono- and bidentate ligands effec-
tively promote the reaction, with good reactivity observed
using trifurylphosphine in the monodentate series, and an
overall preference for dppf (Table S1, entries 11À15).
Unfortunately, reactions with dppf alone proved incon-
sistent, requiring the addition of small quantities of water
to achieve reproducibility (Table 2, entries 1 and 2). As the
reaction involves several cationic species, we examined
various ammonium salt additives, identifying ammonium
acetate as key to improving overall yields (Table 2, entries
2À6). It is noteworthy that both the ammonium and
acetate components of the salt proved important for over-
all reactivity as seen by examining entries 3À6 in Table 2.
Following reaction optimization, we sought to explore
the substrate scope (Figure 2). The reaction works well
with a variety of simple amino acid esters, providing the
desired products in excellent yields. Additionally, the
reaction shows broad functional group tolerance, with
substrates bearing indole, phenol, ester, thioether, car-
bamate, and amides providing the corresponding pro-
ducts in high yields (Figure 2, entries 7d and 7gÀ7m).
Reactions with glutamate esters gave the pyroglutamate
derivative, although use of glutamine methyl ester pre-
vented this cyclization (7n). The reaction exhibits sensi-
tivity to branching at the β-carbon, requiring the use of
an alternative ligand with phenylglycine and exhibiting
poor yields in the case of valine. Histidine and cysteine
bearing a free thiol appear to be outside of the scope of
the reaction, likely due to either disruptive chelation
between the side chain and the Lewis acid or reactivity at
the β-carbon.
Figure 2. Reaction scope. aYields given are isolated yields.
bReaction run using the tosylate salt of phenylglycine methyl
ester.
effect of ammonium acetate. The reaction is sensitive to the
structure of the chelating ligand, with yield and enantio-
selectivity varying widely with minor structural variations
(Table 3, entries 3À7).13 Under optimized conditions, the
reaction produces (S)-R-quaternary phenylalanine deriva-
tive 7o in 95% yield and 91% ee from the corresponding
racemic methyl ester (Table 3, entry 3).14 This one step
dynamic kinetic resolution protocol dramatically simplifies
Having developed an efficient R-allylation protocol, we
turned our attention to enantioselectivity (Table 3). Using
the well-developed ligands reported by Trost and co-workers,
these efforts focused on ligating the palladium π-allyl
complex.13 Variation of base proved to have a notable impact
on both yield and enantioselectivity (Table 3, entries 1À3).
These results suggest that the base plays a direct role in the
transformation, consistent with our observations on the
(13) (a) Trost, B. M.; Van Vranken, D. L. Angew. Chem., Int. Ed.
Engl. 1992, 31, 228. (b) Trost, B. M.; Van Vranken, D. L.; Bingel, C.
J. Am. Chem. Soc. 1992, 114, 9327. (c) Trost, B. M. Acc. Chem. Res.
1996, 29, 355.
(14) The identity of the major enantiomer was determined by com-
parison with the literature optical rotation of the known product.
Dolbeare, K.; Pontoriero, G. F.; Gupta, S. K.; Mishra, R. K.; Johnson,
R. L. J. Med. Chem. 2003, 46, 727.
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Org. Lett., Vol. 14, No. 8, 2012

Table 3. Enantioselective Variant
Scheme 2. Proposed Allylation Mechanism
complete the cycle. It is likely that the added water and/
or ammonium salts catalyze this step by acting as sterically
unencumbered nucleophiles through a mechanism parallel
to that proposed by Jencks in their work with aniline-
catalyzed Schiff base exchange.15 Additionally, the anions
of these salts likely solubilize or otherwise interact benefi-
cially with one or more of the many cationic intermediates
in this pathway, suggesting a potential role for the acetate
in the enantioselective variant.
In conclusion, we have developed a catalytic one step
synthesis of R-allylated R-quaternary amino acid esters
and demonstrated its potential for application as a dy-
namic kinetic resolution. The reaction exhibits broad
substrate scope with moderate functional group sensitiv-
ity. This chemistry simplifies access to an important family
of compounds and provides an attractive alternative to
existing multistep methods.7 Further studies of the dy-
namic kinetic resolution are currently underway.
a Yields were determined by 1H NMR using an internal standard.
b Enantioselectivities were determined by chiral HPLC of isolated
products. c Isolated yield.
access to enantioenriched R-quaternary amino acids. Ad-
ditionally, as the HCl salts of product esters are highly
crystalline, enantioselectivities can potentially be upgraded
through simple recrystallization.
A plausible mechanistic rationale for this reaction is
shown below (Scheme 2). Schiff base formation and nickel
association result in tridentate complex 9, which stabilizes
deprotonation at the amino acid R-carbon.8a The resultant
quinonoid/enolate intermediate 10 reacts with a palladium
π-allyl complex to produce complex 11. Subsequent de-
complexation produces Schiff base 12. An imine exchange
regenerates imine 9 and releases the final product to
Acknowledgment. We acknowledge the financial sup-
port of Indiana University.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds gener-
ated through this work. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) (a) Cordes, E. H.; Jencks, W. P. J. Am. Chem. Soc. 1962, 84, 826.
(b) Dirksen, A.; Hackeng, T. M.; Dawson, P. E. Angew. Chem., Int. Ed.
2006, 45, 7581. (c) Dirksen, A.; Dirksen, S.; Hackeng, T. M.; Dawson,
P. E. J. Am. Chem. Soc. 2006, 128, 15602.
The authors declare no competing financial interest.
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