Enantioselective Synthesis of Quaternary α-Amino Acids Enabled by the Versatility of the Phenylselenonyl Group

Article abstract of DOI:10.1002/chem.201604781

A novel Cinchona alkaloid-catalyzed enantioselective conjugate addition of α-alkyl substituted α-nitroacetates to phenyl vinyl selenone was developed. The resulting enantio-enriched α,α-dialkyl substituted α-nitroacetates were subsequently converted to various cyclic and acyclic quaternary α-amino acids, taking advantage of the rich functionalities of the resulting Michael adducts. Novel protocols allowing chemoselective reduction of phenyl selenone to phenyl selenide and reduction of alkyl phenyl selenones to alkanes are also reported.

Full text of DOI:10.1002/chem.201604781

DOI: 10.1002/chem.201604781
Communication
&
Asymmetric Synthesis
Enantioselective Synthesis of Quaternary a-Amino Acids Enabled
by the Versatility of the Phenylselenonyl Group
Antonin Clemenceau, Qian Wang, and Jieping Zhu*[a]
Abstract: A novel Cinchona alkaloid-catalyzed enantiose-
lective conjugate addition of a-alkyl substituted a-nitroa-
cetates to phenyl vinyl selenone was developed. The re-
sulting enantio-enriched a,a-dialkyl substituted a-nitroa-
cetates were subsequently converted to various cyclic and
acyclic quaternary a-amino acids, taking advantage of the
rich functionalities of the resulting Michael adducts. Novel
protocols allowing chemoselective reduction of phenyl se-
lenone to phenyl selenide and reduction of alkyl phenyl
selenones to alkanes are also reported.
Quaternary a-amino acids (a,a-disubstituted a-amino acids)
have been found in nature either in their free form[1] or as key
subunits of bioactive natural products,[2] pharmaceuticals,[3]
and agrochemicals.[4] When incorporated in a given peptide,
Scheme 1. a-Substituted glycine template and its equivalents in the synthe-
sis of quaternary a-amino acid surrogates.
they reduce the conformational flexibility, induce a well-de-
fined three-dimensional structure and increases the metabolic
stability of the peptide, desirable properties in drug develop-
ment endeavors. It is therefore not surprising that great efforts
have been dedicated to the development of efficient enantio-
selective synthesis of quaternary a-amino acids for the past
quarter century.[5] Among them, 1,4-additions of glycine tem-
plate (A),[6] its synthetic equivalents such as oxazolones (B),[7]
a-substituted a-nitroacetates (C)[8] and to a less extent a-sub-
stituted a-isocyanoacetates (D)[9] have been examined.
lenge, we became interested in the conjugate addition of a-ni-
troacetates 4 to phenyl vinyl selenone (2a). Although good to
excellent enantioselectivity has been achieved between a-ni-
troacetates 4 and a variety of Michael acceptors such as a,b-
unsaturated carbonyl compounds and nitroalkenes,[8] most of
them suffered from the low substrate scope (R=Me or Et) and
limited possibilities for post-functionalization of the adducts.
We report herein the development of an organocatalytic enan-
tioselective Michael addition of a-alkyl substituted a-nitroace-
tates 4[8,12] to aryl vinyl selenones 2 with a broad substrate
scope (Eq. 2). The advantage of this reaction is that the result-
ing a,a-disubstituted nitroacetates 5 are readily functionalized
to a-alkyl-a-(2’-FG-alkyl) glycine 6 and heterocycles thereof
taking advantage of the leaving group capacity of the phenyl-
selenonyl group. In particular, we document novel protocols
for the chemoselective reduction of phenyl selenones to
phenyl selenides and alkyl phenyl selenones to alkanes that
further enlarged the utility of the phenylselenonyl group
(Scheme 1).
The aptitude of phenylselenonyl group to act as leaving
group has been known for many years.[10] It is therefore inter-
esting to note that phenyl vinyl selenone has been seldom
used as a Michael acceptor in catalytic enantioselective trans-
formations.[11] We have recently described a Cinchona alkaloid-
catalyzed Michael addition of methyl a-aryl-a-isocyanoacetates
1 to phenyl vinyl selenone (2a, Ar=Ph) for the synthesis of
enantioenriched quaternary a-isocyanoacetates
3
(Eq. 1,
Scheme 1).[9a] Unfortunately, the protocol cannot be applied to
the a-alkyl substituted counterpart due most probably to the
reduced acidity of its a-CH. To circumvent this synthetic chal-
Using Cinchona alkaloid derivatives as bifunctional cata-
lysts,[13] the reaction of methyl 2-nitrobutanoate (4a) with
phenyl vinyl selenone (2a) was chosen for optimizing the cata-
lytic conditions. Initial screening indicated that performing the
reaction in toluene at À308C was optimum in terms of yield
and enantioselectivity (see the Supporting Information). The in-
fluence of catalyst structure (Figure 1) on the reaction outcome
is summarized in Table 1. As it is seen, quinine itself (QN-1)
was capable of catalyzing the reaction, albeit with low enantio-
[a] A. Clemenceau, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201604781.
Chem. Eur. J. 2016, 22, 1 – 6
1
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
the Michael adduct 5a in a low yield and er (entries 9–11). b-
Isocupreidine (b-ICD, QN-12) can catalyze the reaction, but less
efficiently relative to other quinine derivatives (entry 12).[15] In-
triguingly, the absolute configuration at C9 seems not to be
important for the catalytic activities of the catalysts since the
epi-QN-3, epi-QN-6 and epi-QN-7 were all efficient catalysts af-
fording the adduct in good to excellent yields with er higher
than 94:6 (entries 13–15). Overall, the best conditions consisted
of performing the reaction of 2a and 4a in toluene in the
presence of catalyst QN-7 at À308C for 48 h. Under these con-
ditions, the Michael adduct 5a was isolated in 96% yield with
an er of 96:4. The absolute configuration (S) of 5a was as-
signed based on the X-ray crystal structure of 7 (vide supra).
The effect of the alkyl residue of ester was evaluated under
the optimum conditions (Scheme 2). While comparable enan-
tioselectivities were observed with the methyl and ethyl esters
(5b, 5c), the reaction of the tert-butyl ester 4c with 2a afford-
ed the Michael adduct 5c with significantly reduced er. On the
other hand, reaction of 4a with b-substituted phenyl vinylsele-
nones failed to produce the desired Michael adducts.
The scope of the catalytic enantioselective Michael addition
was next examined (Table 2). Methyl, ethyl, butyl and isobutyl
substituted a-nitroacetates reacted with phenyl vinyl selenone
(2a) to afford the corresponding a,a-dialkyl substituted a-ni-
Figure 1. Structures of Cinchona alkaloid derivatives.
Table 1. Optimization of reaction conditions.
Entry
Cat
Isolated yield [%]
er[b]
1
2
3
4
5
6
7
8
QN-1
QN-2
QN-3
QN-4
QN-5
QN-6
QN-7
QN-8
84
65
96
99
58
87
96
84
10
27
15
96
99
90
74
56:44
87:13
92:8
94:6
82:18
95:5
Scheme 2. Effect of ester size on the enantioselectivity of the reaction.
Table 2. Scope of enantioselective Michael addition.
96:4
94:6
9
QN-9
43:57
74:26
34:66
20:80
95:5
10
11
12
13
14
15
QN-10
QN-11
QN-12
epi-QN-3
epi-QN-6
epi-QN-7
Entry
R
Ar
Product Yield [%][b] er[c]
1
2
3
4
5
6
7
8
Et
Me
nBu
iBu
CH2-CH=CH2
CH2CH2COMe
CH2CH2CN
CH2CH2SO2Ph
CH2CH2CO2Me
CH2CO2Me
Bn
4-MeO-C6H4À CH2 Ph
4-Br-C6H4-CH2
Ph
Et
Et
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5a
5d
5e
5 f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
96
96
quant.
quant.
97
84
86
90
quant.
95
95
88
85
83
99
67
90
96:4
98:2
96:4
92:8
95:5
96:4
91:9
87:13
93:7
87:13
91:9
91:9
91:9
61:39
95:5
91:9
94:6
95:5
94:6
[a] General conditions: 2a (0.05 mmol), 4a (0.06 mmol), Cat (0.1 equiv),
toluene, c 0.1m, À308C, 48 h. [b] determined by SFC analysis on a chiral
stationary phase.
9
10
11
12
13
14
15
16
17
selectivity (entry 1). The enantioselectivity increased significant-
ly when the 6’-OMe was converted to 6’-OH group (QN-2,
entry 2) and the 9-OH was protected as n-butyl (QN-3, entry 3)
and isobutyl ether (QN-4, entry 4).[14] However, the 9-OBn deriv-
ative QN-5 was less efficient (entry 5). Excellent enantioselectiv-
ities were also obtained with 9-OH arylated derivatives QN-6,
QN-7 and QN-8 (entries 6–8). On the other hand, the 6’-amino-
6’-deoxyquinine (QN-9), its thiourea derivative (QN-10) and C-9
thiourea derivative QN-11 were inefficient catalysts providing
Ph
Ph
4-MeO-C6H4
4-F3C-C6H4
3,5-diMeC6H3 5s
[a] General conditions: 2 (0.05 mmol), 4 (0.06 mmol), QN-7 (0.1 equiv), tol-
uene, c 0.1m, À308C, 48 h. [b] Yield of isolated product. [c] determined
by SFC analysis on a chiral stationary phase.
&
&
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
troacetate in excellent yields and er values (entries 1–4). Side
chains bearing functional groups such as double bond, ketone,
cyano, phenylsulfonyl, ester are well tolerated (entries 5–10).
Compounds 5i, 5k, 5l are clear precursors of a-substituted an-
alogues of aspartic acid, asparagine, glutamic acid, glutamine,
arginine, methionine and proline. Benzyl substituent and its
functionalized ones are compatible with the reaction to afford
5m–5o (entries 11–13), surrogates for a-substituted phenylala-
nine and tyrosine. On the other hand, reaction of a-phenyl
substituted a-nitroacetate with 2a afforded the Michael
adduct 5p with low enantioselectivity (entry 14). The present
method is therefore complementary to that based on a-aryl a-
isocyanoacetates.[9a] Finally, the nature of the aryl group of the
selenonyl function had no obvious effect on the reaction effi-
ciency (entries 15–17).
Scheme 5. Chemoselective reduction of the phenylselenonyl group.
catalyst chemoselectively reduced the phenyl selenone to
phenyl selenide 13m in a quantitative yield (Scheme 5). The
nitro group was stable under these conditions. To the best of
our knowledge, there is only one example on the reduction of
phenyl selenone to phenyl selenide (PI3, CHCl3, 08C) accom-
plished in a simple substrate.[10c] Treatment of 13m with
sodium periodate furnished the vinyl substituted derivative
14m in 95% yield. Reduction of the nitro group in 14m (Zn,
AcOH/MeOH, 508C) furnished then the methyl a-vinyl phenyla-
lanate (15m).[19] The conversion of 5m to 14m can be realized
in a one-pot fashion in 91% yield. This one-pot process is com-
patible with a number of functions such as cyano, phenylsul-
fonyl and ester groups as illustrated by the successful synthesis
of compounds 14i, 14j and 14k. We note that this two-step
sequence represented formally an enantioselective vinylation
of an enolate. Inspite of the clear synthetic potentials, only few
methods exist for accomplishing such transformation.[20]
Reduction of 5m (H2, Raney nickel, 40 bar) afforded directly
the methyl 2-ethyl (R)-phenylalanate (12) in which both nitro
and phenylselenonyl groups were reduced (Scheme 6). This
represented, to the best of our knowledge, the first example of
reduction of alkyl phenyl selenone to alkane. Applying this
protocol to 5k allowed a one-pot synthesis of methyl (R)-2-
ethyl pyroglutamate (16k) by a reduction/lactamizaiton se-
quence. To further illustrate the versatility of our approach,
compound 5k was successfully converted to methyl (S)-2-vinyl
pyroglutamate (17k) using the chemistry detailed in Scheme 5.
We stress that examples of quaternary a-amino acids (10, 12,
15m, 16k and 17k) presented herein are all difficultly accessi-
ble otherwise.
Treatment of 5o with NaN3 followed by aza-Wittig reaction
of the resulting azido compound with 4-nitrobenzaldehyde
and reductive cyclization afforded pyrrolidinone 7, the struc-
ture of which was solved by X-ray crystal structural analysis
(Scheme 3).[16] The absolute configuration of 7 was determined
to be (S). Consequently, that of its precursor 5o and those of
other Michael adducts were assigned accordingly.
Scheme 3. Synthesis and X-ray structure of pyrrolidinone 7.
Chemical transformations taking advantage of the phenylse-
lenonyl and nitro groups are illustrated in Scheme 4. Reaction
of 5m with NaN3 afforded the azido derivative 8,[9a,10c,11c,e]
which, upon Staudinger reduction and lactamization cascade,
furnished the pyrrolidinone 9. The latter was further reduced
to the amino derivative 10, a constrained analogue of phenyla-
laninamide, the enantioselective synthesis of which remained
unknown.[17] Substitution of the phenylselenonyl group by
iodide proceeded smoothly to furnish iodide derivative 11,
which was reduced (Raney Ni, H2, MeOH, RT) to methyl 2-ethyl
phenylalanate (12) in 65% yield.[18]
A new reaction was serendipitously discovered in the course
of this study. Hydrogenation of 5m in the presence of Adam’s
Finally, performing the reaction of 4m with 2a in a gram
scale afforded the Michael adduct 5m in similar yield and
enantioselectivity (Eq. 1, Scheme 7). In this case, the catalyst
Scheme 4. Chemical transformations of the enantio-enriched Michael
adduct.
Scheme 6. Reduction of alkyl phenyl selenones to alkanes.
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
3
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
[8] a) E. Keller, N. Veldman, A. L. Spek, B. L. Feringa, Tetrahedron: Asymmetry
1997, 8, 3403; b) H. Li, Y. Wang, L. Tang, F. Wu, X. Liu, C. Guo, B. M.
Foxman, L. Deng, Angew. Chem. Int. Ed. 2005, 44, 105; Angew. Chem.
2005, 117, 107; c) J. R. Duvall, F. Wu, B. B. Snider, J. Org. Chem. 2006, 71,
8579; d) B. R. Linton, M. H. Reutershan, C. M. Aderman, E. A. Richardson,
K. R. Brownell, C. W. Ashley, C. A. Evans, S. J. Miller, Tetrahedron Lett.
2007, 48, 1993; e) X.-Q. Dong, H.-L. Teng, C.-J. Wang, Org. Lett. 2009, 11,
1265; f) Y. Kato, Z. Chen, S. Matsunaga, M. Shibasaki, Synlett 2009, 1635;
g) A. Quintard, A. Alexakis, Org. Biomol. Chem. 2011, 9, 1407; h) S. Shira-
kawa, S. J. Terao, R. He, K. Maruoka, Chem. Commun. 2011, 47, 10557;
i) Y.-Z. Li, F. Li, P. Tian, G.-Q. Lin, Eur. J. Org. Chem. 2013, 1558; j) L. Wen,
L. Yin, Q. Shen, L. Lu., ACS Catal. 2013, 3, 502; k) For a general review,
see: R. Ballini, G. Bosica, D. Fiorini, A. Palmieri, M. Petrini, Chem. Rev.
2005, 105, 933.
[9] a) T. Buyck, Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2013, 52, 12714;
Angew. Chem. 2013, 125, 12946; b) J.-F. Bai, L.-L. Wang, L. Peng, Y.-L.
Guo, L.-N. Jia, F. Tian, G.-Y. He, X.-Y. Xu, L.-X. Wang, J. Org. Chem. 2012,
77, 2947.
[10] a) M. Shimizu, I. Kuwajima, J. Org. Chem. 1980, 45, 4063; b) I. Kuwajima,
R. Ando, T. Sugawara, Tetrahedron Lett. 1983, 24, 4429; c) A. Krief, W.
Dumont, J.-N. Denis, J. Chem. Soc. Chem. Commun. 1985, 571; d) T.
Buyck, Q. Wang, J. Zhu, J. Am. Chem. Soc. 2014, 136, 11524; e) T. Buyck,
D. Pasche, Q. Wang, J. Zhu, Chem. Eur. J. 2016, 22, 2278; f) M. Palomba,
L. Rossi, L. Sancineto, E. Tramontano, A. Corona, L. Bagnoli, C. Santi, C.
Pannecouque, O. Tabbarrini, F. Marini, Org. Biomol. Chem. 2016, 14,
2015.
[11] a) M. Tiecco, L. Testaferri, A. Temperini, R. Terlizzi, L. Bagnoli, F. Marini, C.
Santi, Org. Biomol. Chem. 2007, 5, 3510; b) M. Tiecco, A. Carlone, S. Ster-
nativo, F. Marini, G. Bartoli, P. Melchiorre, Angew. Chem. Int. Ed. 2007, 46,
6882; Angew. Chem. 2007, 119, 7006; c) F. Marini, S. Sterativo, F. Del V-
erme, L. Testaferri, M. Tiecco, Adv. Synth. Catal. 2009, 351, 103; d) F.
Marini, S. Sterativo, F. Del Verme, L. Testaferri, M. Tiecco, Adv. Synth.
Catal. 2009, 351, 1801; e) T. Zhang, L. Cheng, S. Hameed, L. Liu, D.
Wang, Y.-J. Chen, Chem. Commun. 2011, 47, 6644; f) S. Sternativo, A. Cal-
andriello, F. Costantino, L. Testaferri, M. Tiecco, F. Marini, Angew. Chem.
Int. Ed. 2011, 50, 9382; Angew. Chem. 2011, 123, 9554; g) S. Sternativo,
O. Walczak, B. Battistelli, L. Testaferri, F. Marini, Tetrahedron 2012, 68,
10536; h) For a review, see: F. Marini, S. Sternativo, Synlett 2012, 24, 11.
[12] Selected examples of other enantioselective transformations involving
a-substituted a-nitroacetates, see: a) K. R. Knudsen, K. A. Jørgensen,
Org. Biomol. Chem. 2005, 3, 1362; b) J. Ramꢁrez, D. P. Huber, A. Togni,
Synlett 2007, 1143; c) D. Uraguchi, K. Koshimoto, T. Ooi, J. Am. Chem.
Soc. 2008, 130, 10878; d) S. Shirakawa, K. Ota, S. J. Terao, K. Maruoka,
Org. Biomol. Chem. 2012, 10, 5753; e) K. Ohmatsu, M. Ito, T. Kunieda, T.
Ooi, Nat. Chem. 2012, 4, 473. For a recent review on nitro-Mannich re-
actions, see: f) A. Noble, J. C. Anderson, Chem. Rev. 2013, 113, 2887.
[13] For reviews, see: a) S.-K. Tian, Y. Chen, J. Hang, L. Tang, P. McDaid, L.
Deng, Acc. Chem. Res. 2004, 37, 621; b) T. Marcelli, H. Hiemstra, Synthesis
2010, 1229; c) L. Stegbauer, F. Sladojevich, D. J. Dixon, Chem. Sci. 2012,
3, 942.
Scheme 7. Gram-scale synthesis and Michael addition catalyzed by quini-
dine-derived catalyst.
QN-7 was easily recovered (96%) and can be re-used without
diminishing the catalytic efficiency. On the other hand, Michael
addition of 4d to 2a in the presence of quinidine-derived cata-
lyst QD-7 afforded, as expected, the ent-5d in 96% yield with
er of 5:95 (Eq. 2, Scheme 7).
In conclusion, we have developed a Cinchona alkaloid-cata-
lyzed Michael addition of methyl a-alkyl-a-nitroacetates to
phenyl vinyl selenone. The resulting adducts can be subse-
quently elaborated to a diverse set of a,a-disubstituted a-ni-
troacetates and quaternary a-amino acids taking advantage of
the reactivity of the phenylselenonyl and nitro groups. We be-
lieved that chemoselective reduction of phenyl selenones to
phenyl selenides and reduction of alkyl phenyl selenones to al-
kanes uncovered in this study would find applications in or-
ganic synthesis.
Acknowledgements
Financial supports from EPFL (Switzerland) and the Swiss Na-
tional Science Foundation (SNSF) are gratefully acknowledged.
We are grateful to Dr. Rosario Scopelliti for performing X-ray
structural analysis of compound 7.
Keywords: asymmetric
synthesis
·
nitroacetate
·
organocatalysis · quaternary amino acid · selenium
[1] See for example: W. S. Horn, J. L. Smith, G. F. Bills, S. L. Raghoobar, G. L.
Helms, M. B. Kurtz, J. A. Marrinan, B. R. Frommer, R. A. Thornton, S. M.
Mandara, J. Antibiot. 1992, 45, 1692.
[14] Pioneering work on the 6’-OH Cinchona alkaloids derived bifunctional
catalysts, see: a) H. Li, Y. Wang, L. Tang, L. Deng, J. Am. Chem. Soc. 2004,
126, 9906; b) F. Wu, H. Li, R. Hong, L. Deng, Angew. Chem. Int. Ed. 2006,
45, 947; Angew. Chem. 2006, 118, 961; c) H. Li, B. Wang, L. Deng, J. Am.
Chem. Soc. 2006, 128, 732; d) Y. Wu, R. P. Singh, L. Deng, J. Am. Chem.
Soc. 2011, 133, 12458; e) X. Xiao, Y. Xie, C. Su, M. Liu, Y. Shi, J. Am.
Chem. Soc. 2011, 133, 12914; f) Y. Wu, L. Deng, J. Am. Chem. Soc. 2012,
134, 14334.
[15] a) Y. Iwabuchi, M. Nakatani, N. Yokoyama, S. Hatakeyama, J. Am. Chem.
Soc. 1999, 121, 10219; b) N. Abermil, G. Masson, J. Zhu, J. Am. Chem.
Soc. 2008, 130, 12596; c) N. Abermil, G. Masson, J. Zhu, Org. Lett. 2009,
11, 4648; d) N. Abermil, G. Masson, J. Zhu, Adv. Synth. Catal. 2010, 352,
656; e) J.-B. Denis, G. Masson, P. Retailleau, J. Zhu, Angew. Chem. Int. Ed.
2011, 50, 5356; Angew. Chem. 2011, 123, 5468.
[16] CCDC 1496191 (7) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www. ccdc.cam.ac.uk/data re-
quest/cif.
[17] Synthesis of racemic 10, see: M. W. Holladay, A. M. Nadzan, J. Org.
Chem. 1991, 56, 3900.
[2] a) S. Omura, T. Fujimoto, K. Otaguro, K. Matsuzaki, R. Moriguchi, H.
Tanaka, Y. Sasaki, J. Antibiot. 1991, 44, 113; b) S. Omura, K. Matsuzaki, T.
Fujimoto, K. Kosuge, T. Furuya, S. Fujita, A. Nakagawa, J. Antibiot. 1991,
44, 117; c) G. Fenteany, R. F. Standaert, W. S. Lane, S. Choi, E. J. Corey,
S. L. Schreiber, Science 1995, 268, 726.
[3] See for example: J. A. Monn, M. J. Valli, S. M. Massey, R. A. Wright, C. R.
Salhoff, B. G. Johnson, T. Howe, C. A. Alt, G. A. Rhodes, R. L. Robey, K. R.
Griffey, J. P. Tizzano, M. J. Kallman, D. R. Helton, D. D. Schoepp, J. Med.
Chem. 1997, 40, 528.
[4] See for example (S)-fenamidone in “The Pesticide Encyclopedia” (Eds: K.
Paranjape, V. Gowariker, V. N. Krishnamurthy, S. Gowariker), CABI, Ox-
fordshire, UK, 2015, p. 194.
[5] Recent reviews on a,a-disubstituted amino acids: a) C. Cativiela, M. D.
Dꢁaz-de-Villegas, Tetrahedron: Asymmetry 2007, 18, 569; b) H. Vogt, S.
Brꢂse, Org. Biomol. Chem. 2007, 5, 406; c) K. Bera, I. N. N. Namboothiri,
Asian J. Org. Chem. 2014, 3, 1234; d) A. E. Metz, M. C. Kozlowski, J. Org.
Chem. 2015, 80, 1.
[6] T. Ooi, K. Maruoka, Angew. Chem. Int. Ed. 2007, 46, 4222; Angew. Chem.
2007, 119, 4300.
[7] A.-N. R. Alba, R. Rios, Chem. Asian J. 2011, 6, 720.
&
&
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
4
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
[18] Chiral auxiliary-based synthesis of enantio-enriched 12, see: a) M. Kolb,
J. Barth, Liebigs Ann. Chem. 1983, 1668; b) A. Studer, D. Seebach, Liebigs
Ann. 1995, 217; c) T. Satoh, M. Hirano, A. Kuroiwa, Y. Kaneko, Tetrahe-
dron 2006, 62, 9268.
nardi, M. Bell, K. A. Jørgensen, Angew. Chem. Int. Ed. 2006, 45, 6551;
Angew. Chem. 2006, 118, 6701; c) H. Kim, D. W. C. MacMillan, J. Am.
Chem. Soc. 2008, 130, 398.
[19] A multistep synthesis of enantio-enriched 15m using Seebach’s diaster-
eoseletive alkylation approach, see: A. Sacchetti, A. Silvani, G. Lesma, T.
Pilati, J. Org. Chem. 2011, 76, 833.
Received: October 11, 2016
[20] Pd-catalyzed: a) A. Chieffi, K. Kamikawa, J. ꢃhman, J. M. Fox, S. L. Buch-
wald, Org. Lett. 2001, 3, 1897; organocatalyzed: b) T. B. Poulsen, L. Ber-
Published online on && &&, 0000
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Asymmetric Synthesis
A. Clemenceau, Q. Wang, J. Zhu*
&& – &&
Enantioselective Synthesis of
Quaternary a-Amino Acids Enabled by
the Versatility of the Phenylselenonyl
Group
Selective selenium: Cinchona alkaloid-
catalyzed conjugate addition of a-alkyl
substituted a-nitroacetates to phenyl
vinyl selenone afforded the Michael ad-
ducts in excellent yields and enantiose-
lectivities. Chemoselective reduction of
phenyl selenonones to phenyl selenides
and reduction of alkyl phenyl selenones
to alkanes were uncovered and exploit-
ed for the further functionalization of
these quaternary a-nitroacetates (see
scheme).
&
&
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!