Synthesis of α-amino acids by umpolung of weinreb amide enolates

Article abstract of DOI:10.1002/ejoc.200800683

An efficient and diastereoselective synthesis of α-amino acids from readily available starting materials has been developed. The key feature of this reaction is an umpolung of a glycine-derived enolate, providing an alternative approach for the synthesis of α-amino acids. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800683

FULL PAPER
DOI: 10.1002/ejoc.200800683
Synthesis of α-Amino Acids by Umpolung of Weinreb Amide Enolates
Sebastian Hirner,[a] Donata K. Kirchner,[a] and Peter Somfai*[a,b]
Keywords: Amino acids / Umpolung / Arylglycines / Grignard reaction / Weinreb amides
An efficient and diastereoselective synthesis of α-amino acids
from readily available starting materials has been developed.
The key feature of this reaction is an umpolung of a glycine-
derived enolate, providing an alternative approach for the
synthesis of α-amino acids.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
One of the most common strategies towards the synthesis
of arylglycines and other α-amino acids is the reaction of
Introduction
α-Amino acids and their derivatives serve a central role glycine α-cation equivalents with nucleophiles [Scheme 1,
in chemistry and biology, being the fundamental constitu- Equation (1)].[8] Typically, imines, iminium ions and α-sub-
ents of peptides and proteins. Moreover, they are important stituted glycine derivatives are used as electrophilic glycine
templates in asymmetric catalysis, versatile building blocks surrogates. An alternative entry to glycine α-cation equiva-
in total synthesis and common subunits in many bioactive lents would be by umpolung of enolates derived from α-
compounds and natural products.[1] Arylglycines, for exam- amino Weinreb amides. In this respect, it has previously
ple, are prevalent in widely used drugs, such as β-lactam been shown that subjecting compound 1 to base leads to
and glycopeptide antibiotics (e.g. vancomycin)[2] and the the formation of α-lactam 2 [Scheme 1, Equation (2)].[9,10]
cardiovascular agent Plavix.[3] As a consequence, much ef- When this material was treated with weak nucleophiles,
fort has been dedicated to the development of novel syn- such as hindered amines, chloride[9b] or azide,[9c] the lactam
thetic methods, especially for the synthesis of enantiomer- was regioselectively opened to give α-substituted amides 3,
ically pure α-amino acids.[4] During the last decades, a wide the reaction most likely proceeding through an oxa-aza-al-
range of asymmetric, often catalytic syntheses has been de- lyl cation intermediate. We became interested in the pos-
veloped, such as catalytic asymmetric hydrogenations of de- sibility of generating lactam 2 from a suitable precursor and
hydro-α-amino acids,[4a] asymmetric modifications of the investigating its reaction with Grignard reagents as a novel
Strecker reaction,[5] enantioselective alkylations of glycine entry to non-proteogenic α-amino acids. Recently, we com-
derivatives under phase-transfer conditions[4b,4c] and cata- municated the initial results,[11] and herein we give a full
lytic asymmetric addition of nucleophiles to α-imino es- account of this study.
ters.[4d] Despite the great variety of well-tried methods and
new asymmetric methodologies for the synthesis of α-amino
acids, there is still need for efficient and technically feasible
methods. For example, the synthesis of arylglycines remains
a challenging task in organic synthesis[4e] and is still a very
active field of research. Recent developments in that area
include the transition-metal-catalyzed addition of aryl-
boronic acids to imino esters[6] and the asymmetric inser-
tion of α-diazocarbonyl compounds into the N–H bonds of
carbamates.[7]
Scheme 1.
[a] Organic Chemistry, KTH Chemical Science and Engineering,
Royal Institute of Technology,
Results and Discussion
10044 Stockholm, Sweden,
Fax: +46-8-791-2333
Initial focus was directed towards identifying the optimal
base and reaction conditions for generating the desired α-
lactam and to study its reaction with Grignard reagents.
Deprotonation of Weinreb amide 4a[12] at room tempera-
[b] Institute of Technology, University of Tartu,
Nooruse 1, 50411 Tartu, Estonia
E-mail: somfai@kth.se
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 5583–5589
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Hirner, D. K. Kirchner, P. Somfai
FULL PAPER
ture with NaH, followed by addition of PhMgCl yielded gave only traces of the desired product (Entries 5, 6). When
only small amounts of the desired α-arylated product 5a LDA was used as base, formation of the acylation product
(Table 1, Entry 1), the main product being ketone 6a (Fig- 6b could be completely prevented, but the desired product
ure 1).[13] A similar result was obtained when the Grignard 5b was isolated in only 12% yield (Entry 7). Instead, the
reagent itself was used as base and added at 0 °C to the main product from this reaction was amide 8 (Figure 1), the
reaction mixture (Entry 2). It was speculated that the steri- result of an undesired E2 pathway, together with N,O-acetal
cally demanding NBn2 moiety in 4a prevented a facile de- 7a.[14] In order to minimize the formation of the demeth-
protonation at the α-carbon atom, and to test this, com- oxylated product 8, the N-methoxy substituent in 4b was
pounds 4b,c, having smaller N-protecting groups, were pre- replaced by an N-tert-butoxy moiety to give compound
pared and subjected to the reaction conditions (Entries 3 4e,[15] and when this material was subjected to the same
and 4). Indeed, this resulted in an improved yield of the reaction conditions, the desired arylation product 5b could
desired α-arylated products 5b,c and lower amounts of the be isolated in 77% yield (Entry 8). Simply decreasing the
corresponding ketones 6b,c. Although these results were en- amount of base used resulted in an increased yield, allowing
couraging, there is obviously room for improvement. To for 86 % of 5b (Entry 9). Excellent yields were also obtained
suppress the formation of ketone 6, it is necessary that for diallyl derivative 4f (Entry 10), while the use of amide
amide 4 is completely converted into the corresponding 4d (Entry 11) required that the LDA was added at 0 °C to
enolate prior to the addition of the nucleophile. However, the reaction mixture in order to obtain full conversion. For
deprotonation of 4b with stronger bases such as LiHMDS this case, however, considerable amounts of N,O-acetal 7b
and nBuLi at –78 °C, followed by the addition of PhMgCl was formed that could not be separated from the desired
Table 1. Optimization of α-arylation.[a]
Entry
4
Base (equiv.)
T [°C]
Product
Product ratio[b]
Yield of 5 (%)[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
a
a
b
c
b
b
b
e
e
f
NaH (1.2)
–
25
0
0
5a + 6a
5a + 6a
5b + 6b
5c + 6c
n. d.
1:6
1:7
1:1
1:1
n. d.
n. d.
n. d.
Ͼ20:1
Ͼ20:1
Ͼ20:1
7:1
10
12[d]
44[d]
38[d]
n. d.
n. d.
12
–
–
0
LiHMDS (1.5)
BuLi (1.5)
LDA (1.5)
LDA (1.5)
LDA (1.0)
LDA (1.0)
LDA (1.0)
LDA (1.0)
LDA (1.0)
–78
–78
–78
–78
–78
–78
–78
–78
–78
n. d.
5b + 7a + 8
5b + 7b
5b + 7b
5c + 7d
5a + 7b
5d
77
86
87
d
g
h
72[e]
70
n. d.
n. d.
n. d.
n. d.
[a] The reaction was carried out with amide 4 (1.0 equiv.), base and PhMgCl (2.0 equiv.) in THF. [b] Ratio determined by 1H NMR
spectroscopic analysis of the crude reaction mixture. [c] Isolated yields. [d] No base and 3.0 equiv. PhMgCl were used. [e] LDA was added
at 0 °C.
Figure 1. Byproducts formed during the α-arylation.
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α-Amino Acids by Umpolung of Weinreb Amide Enolates
product. Thus, it seems that increased steric bulk at the α- Weinreb amide 4e is deprotonated to afford enolate 9. As
amino moiety in 4 significantly slows down the enolization seen in Table 1, it is important that the base is sufficiently
and, more importantly, allows for competing reaction path- strong to allow for a fast and complete enolization in order
ways. In order to avoid the formation of 7, the N-methyl to avoid undesired ketone formation. Similarly, if the α-car-
substituent in 4b was replaced by a phenyl group to give bon atom in 4 is sterically hindered, the base will preferen-
amide 4g. However, this compound gave the desired aryl- tially deprotonate the amide N-Me moiety. Lithium enol-
ated product only in moderate yields (Entry 12). Finally, ates derived from amides are known to have (Z) geometry,
use of N-Bn,N-Ts derivative 4h gave a complex mixture of due to A1,3 interactions between the α-carbon substituent
products, from which none of the desired product could be and the N-substituent,[17] although recent studies suggests
isolated (Entry 13).
that similar enolates derived from Weinreb amides favour
With optimized conditions in hand, the reaction of 4e (E) geometry.[18] In any respect, the enolate geometry is in-
with various nucleophiles was investigated (Table 2). Both consequential for the present investigation. Subsequent eli-
PhLi and Ph2CuLi gave complex reaction mixtures with mination of tBuO– from 9 constitutes the key step and gen-
only trace amounts of 5b being formed (Entries 2, 3). Use erates iminium ion 10. Addition of PhMgCl to 10 then gives
of PhZnCl gave good yields of 5b, provided that the base amide 5b. For the base-promoted addition of amines and
was added at 0 °C (Entry 4).[16] Both electron-poor and halides to O-sulfonylated hydroxamic acid derivatives it has
electron-rich aryl Grignard reagents proved compatible been shown that both α-CH deprotonation and loss of the
with the substrate and gave good to excellent yields of the N-OR moiety are occurring at the transition state of the
corresponding adduct (Entries 5, 6). Similar yields were rate-determining step.[9d] Application of this scenario to the
also obtained with biphenyl (Entry 7), heteroaromatic (En- present reaction suggests the direct formation of iminium
tries 8, 9) and functionalized heteroaromatic Grignard rea- ion 10 from enolate 9, or conversion of 9 into the corre-
gents (Entry 10). Alkyl and alkenyl Grignard reagents can sponding α-lactam (cf. structure 2, Scheme 1) followed by
also be successfully used in the addition to 4e (Entries 11– ring opening to give 10 (compounds 2 and 10 are valence
13), whereas the use of the Grignard reagent derived from tautomers). Although the exact course of events cannot be
(trimethylsilyl)acetylene gave only trace amounts of the de- deduced from the data available, the formation of com-
sired product after column chromatography (Entry 14). In pound 5b as the sole regioisomer strongly suggests the in-
most of the reactions it was necessary to add the LDA at volvement of iminium ion 10. The overall result of this eli-
0 °C or to use an excess of the base in order to obtain full mination is an unusual dipole reversal (umpolung) of the
conversion. An explanation for this might be an incomplete α-carbon atom in 4e,[19] converting the nucleophilic charac-
enolization of the Weinreb amide, which is caused by side ter of the enolate into an electrophilic one (Scheme 2). De-
reactions of the LDA with the Grignard reagent. Further spite the synthetic potential of such transformation, only
investigations on that topic are ongoing and will be re- relatively few examples of umpolung of enolates have been
ported in due course.
reported. Typical examples involve the use of dithioketene
The proposed mechanism for the formation of com- acetals,[20] SET oxidation of enolates[21] and the anodic oxi-
pound 5b from 4e is depicted in Scheme 2. In the first step, dation of silyl enol ethers.[22]
Table 2. Reaction of Weinreb amide 4e with various nucleophiles.[a]
Entry
RM
Product (R)
Yield (%)[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
PhMgCl
PhLi
Ph2CuLi
5b (Ph)
5b (Ph)
5b (Ph)
86
n. d.
n. d.
75
PhZnCl
5b (Ph)
4-FC6H4MgBr
4-MeOC6H4MgBr
3-PhC6H4MgBr
(2-thiophenyl)MgBr
(3-pyridinyl)MgCl·LiCl
5e (4-FC6H4)
5f (4-MeOC6H4)
5g (3-PhC6H4)
5h (2-thiophenyl)
5i (3-pyridinyl)
77[c]
92
Scheme 2. Suggested mechanism for the α-arylation of Weinreb
amide 5b.
81[d]
91[c]
77[d]
76[d]
82[d]
79[d]
82
5-Br(3-pyridinyl)MgCl·LiCl 5j [5-Br(3-pyridinyl)]
With an operationally simple and high-yielding pro-
cedure at hand, we next set out to develop an auxiliary con-
trolled synthesis of enantiomerically enriched α-amino ac-
ids, and amide 4i, synthesized in 2 steps from (–)-α-methyl-
benzylamine, was selected for initial screening. Under stan-
dard reaction conditions with PhMgCl, the desired product
5o was formed as a 2:1 mixture of diastereomers together
MeMgBr
iPrMgCl
CH2=CHMgBr
TMSCϵCMgBr
5k (Me)
5l (iPr)
5m (CH2=CH)
5n (TMSCϵC)
n. d.
[a] The reaction was carried out with amide 4e (1.0 equiv.), LDA
(1.0 equiv.) and RM (2.0 equiv.) in THF. [b] Yield of isolated prod-
uct. [c] LDA (1.5 equiv.) was used. [d] LDA was added at 0 °C.
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S. Hirner, D. K. Kirchner, P. Somfai
FULL PAPER
with considerable amounts of compound 7e (Table 3, En- sponding acid or ester were unsuccessful, and it was instead
try 1). Apparently, the increased steric bulk imposed by the decided to use a 2-step procedure to accomplish this trans-
α-methylbenzyl moiety retards the desired enolization, formation.[25] N-Nitrosation of 5o under standard condi-
making rearrangement to the N,O-acetal 7e competitive. tions gave complete conversion to nitrosoamide 11, which
Screening of less basic nucleophiles showed that zinc rea- was directly subjected to MeOH and saturated NaHCO3 to
gents gave both higher diastereoselectivities and less re- give ester 12 in 84% yield. Interestingly, attempts to hydro-
arranged product (Entries 3–5). By optimizing the solvent lyse 11 to give the corresponding acid [LiOOH, THF/H2O
and amount of base, high selectivities were achieved when (3:1), 0 °C] proved unsuccessful. Subsequent deallylation[26]
the reaction was performed in Et2O with PhZnCl (En- and catalytic hydrogenolysis with Pd(OH)2 gave enantio-
tries 6–8). These optimized conditions afforded the desired merically pure 14[27] in good overall yield and without epi-
α-arylated product in good yield and selectivity (Scheme 3, merization.[28] For ee determination, 14 was converted into
74%, dr = 7:1).
the free amine by treatment with NaHCO3 in H2O, and the
The diastereomers could be separated by flash ee was shown to be Ͼ96% by chiral HPLC.[29] It is notable
chromatography, and the absolute configuration of the that the hydrogenolysis was not regioselective when the re-
newly formed stereocenter in 5o was determined to be (S) action was performed with catalytic amounts of Pd/C; in
by transformation into phenylglycine methyl ester hydro- this case, 20% of the product derived from cleavage at the
chloride 14 (Scheme 3). It has been noted previously that a α-carbon atom was obtained.
secondary amide functionality, as in compound 5, consti-
α-Amino acids having a quaternary α-stereocenter are an
tutes an advantageous protective group for the carboxyl important class of compounds that has been used to impose
group, especially in racemization-prone arylglycines (phen- restricted conformations onto a peptide chain,[30] and it was
ylglycine is 60 times more prone toward reacemization than decided to briefly investigate if the current methodology
alanine).[23] For example, an N-methyl-amide protection could be used for preparing such compounds. Thus, sub-
strategy has been used for the synthesis of vancomycin anti- jecting the alanine-derived amide 15 to the standard condi-
biotics to circumvent epimerization of the terminal arylgly- tions gave none of the desired product, and only recovered
cine residue.[24] Not surprisingly, however, all attempts to starting material and N,O-acetal 16 were isolated
directly convert the N-methyl-amide moiety into the corre- (Scheme 4). Apparently, the additional steric hindrance at
Table 3. Optimization of α-arylation by using chiral amide 4i.[a]
Entry
Nu
Solvent
LDA [equiv.]
T [°C]
5o/7e[b]
dr of 5o[b]
1
2
3
4
5
6
7
8
PhMgCl
PhMgBr
PhCeCl2
Ph2Zn
PhZnCl
PhZnCl
PhZnCl
PhZnCl
THF
THF
THF
THF
THF
toluene
Et2O
Et2O
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.05
–78
–78
–78
0
0
0
1.9:1
2.5:1
1.3:1
2.2:1
2.5:1
1.8:1
4.0:1
4.4:1
2.0:1
1.4:1
1.9:1
4.7:1
6.3:1
5.7:1
5.5:1
6.9:1[c]
0
0
1
[a] The reaction was carried out with amide 4i (1.0 equiv.) and Nu (2.0 equiv.). [b] Determined by H NMR spectroscopic analysis of the
crude reaction mixture. [c] PhZnCl (1.2 equiv.) was used.
Scheme 3. Diastereoselective nucleophilic addition to amide 4i: (a) LDA, THF, 0 °C; then PhZnCl, 74%; (b) NaNO2, CH2Cl2, Ac2O,
AcOH; (c) MeOH, NaHCO3, reflux, 84% (over 2 steps); (d) [Pd(PPh3)4], N,NЈ-dimethylbarbituric acid, CH2Cl2, reflux, 92%; (e) Pd-
(OH)2, MeOH, HCl, 100%.
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α-Amino Acids by Umpolung of Weinreb Amide Enolates
141.2, 141.1, 138.6, 135.3, 135.2, 134.8, 128.8, 128.8, 128.7, 128.6,
128.6, 127.3, 127.3, 126.8, 118.6, 69.2, 54.8, 53.4, 26.2 ppm. IR
the α-carbon atom in 15 prevents an efficient enolization,
making the formation of N,O-acetal 16 a more favoured
process.
(film): ν
= 3310, 2928, 1660, 1521, 1411 cm–1. HRMS (ESI+):
˜
max
calcd. for C25H27N2O [M + H]+ 371.2118; found 371.2114.
2-(Dibenzylamino)-N-methyl-2-phenylacetamide (5a): General Pro-
cedure A was applied by using amide 4d and PhMgCl (2.0  in
THF, 0.10 mL, 0.20 mmol). Flash chromatography [pentane (+ 1%
iPrNH2)/EtOAc, 95:5 Ǟ 60:40] of the residue gave 5a (20.8 mg,
1
72%) as a colourless oil. H NMR (500 MHz, CDCl3): δ = 7.37–
Scheme 4.
7.13 (m, 15 H), 6.95 (br., 1 H), 4.32 (s, 1 H), 3.77 (d, J = 13.9 Hz,
2 H), 3.28 (d, J = 13.9 Hz, 2 H), 2.81 (d, J = 5.0 Hz, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 172.1, 138.6, 134.4, 130.2, 128.6,
128.6, 128.2, 127.8, 127.3, 67.9, 54.6, 26.1 ppm. IR (film): ν
=
˜
max
3313, 3028, 1660, 1522, 1240 cm–1. HRMS (ESI+): calcd. for
Conclusions
C23H25N2O [M + H]+ 345.1961; found 345.1690.
An efficient and diastereoselective synthesis of α-amino
acids from readily available starting materials has been de-
veloped. The key feature of this reaction is an umpolung of
a glycine-derived enolate, providing an alternative approach
for the synthesis of α-amino acids. Further studies of this
reaction and its application in total synthesis are in progress
and will be reported in due course.
2-(Diallylamino)-N-methyl-2-phenylacetamide (5c): General Pro-
cedure A was applied by using amide 4f and PhMgCl (2.0  in
THF, 0.10 mL, 0.20 mmol). Flash chromatography [pentane (+ 1%
iPrNH2)/EtOAc, 95:5 Ǟ 60:40] of the residue gave 5c (20.8 mg,
1
87%) as a colourless oil. H NMR (500 MHz, CDCl3): δ = 7.31–
7.12 (m, 5 H), 5.73 (m, 2 H), 5.10 (m, 4 H), 4.33 (s, 1 H), 3.17 (m,
2 H), 2.80 (d, J = 4.9 Hz, 3 H), 2.77 (m, 2 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 172.5, 135.0, 134.9, 129.7, 128.2, 127.8,
118.2, 69.6, 53.3, 26.0 ppm. IR (film): ν
= 3304, 3073, 1659,
˜
max
1524, 1157 cm–1. HRMS (ESI+): calcd. for C15H21N2O [M + H]+
Experimental Section
245.1648; found 245.1649.
General Procedure A. 2-[(Allyl)(benzyl)amino]-N-methyl-2-phenyl-
acetamide (5b): LDA (1.40 , 71 µL, 0.10 mmol) was added to a
solution of amide 4e (29.0 mg, 0.10 mmol) in THF (2 mL) at
–78 °C. The solution was stirred for 1 min, and PhMgCl (2.0  in
THF, 100 µL, 0.20 mmol) was added. The mixture was allowed to
reach room temperature and the reaction quenched with satd.
NH4Cl (1 mL) and brine (1 mL). The aqueous phase was extracted
twice with Et2O, and the combined organic extracts were dried
(K2CO3) and concentrated under reduced pressure. Flash
chromatography [pentane (+ 1% iPrNH2)/EtOAc, 95:5 Ǟ 60:40] of
the residue gave 5b (25.2 mg, 86%) as a colourless oil. 1H NMR
(500 MHz, CDCl3): δ = 7.39–7.25 (m, 10 H), 7.20 (br., 1 H), 5.84
(m, 1 H), 5.18 (m, 2 H), 4.2 (s, 1 H), 3.82 (d, J = 14.0 Hz, 1 H),
3.33 (d, J = 14.0 Hz, 1 H), 3.25 (m, 1 H), 2.88 (d, J = 4.9 Hz, 3
H), 2.85 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 172.2,
138.5, 134.7, 129.8, 128.5, 128.4, 128.1, 127.8, 127.2, 118.4, 68.9,
2-[(Allyl)(benzyl)amino]-N,2-diphenylacetamide (5d): General Pro-
cedure A was applied by using amide 4g and PhMgCl (2.0  in
THF, 0.10 mL, 0.20 mmol). Flash chromatography [pentane (+ 1%
iPrNH2)/EtOAc, 100:0 Ǟ 88:12] of the residue gave 5d (24.9 mg,
1
70%) as a pale yellow oil. H NMR (400 MHz, CDCl3): δ = 9.47
(s, 1 H), 7.68–7.06 (m, 15 H), 5.92 (m, 1 H), 5.31–5.23 (m, 2 H),
4.58 (s, 1 H), 3.94 (d, J = 16.0 Hz, 1 H), 3.37 (m, 2 H), 2.90 (dd, J
= 8.0 Hz, 1 H) ppm. 13C NMR (500 MHz, CDCl3): δ = 169.8,
138.2, 137.8, 134.5, 133.7, 130.3, 129.1, 128.8, 128.6, 128.4, 128.1,
127.5, 124.1, 119.3, 118.9, 69.4, 54.8, 53.3 ppm. IR (film): ν˜max
=
3312, 3028, 1682, 1516, 1443 cm–1. HRMS (ESI+): calcd. for
C24H25N2O [M + H]+ 357.1961; found 357.1963.
2-[(Allyl)(benzyl)amino]-2-(4-fluorophenyl)-N-methylacetamide (5e):
General Procedure A was applied by using LDA (1.5 equiv., 1.40 ,
107 µL, 0.15 mmol) and 4-FC6H4MgBr (1.0  in THF, 0.20 mL,
0.20 mmol). Flash chromatography [pentane (+ 1% iPrNH2)/
EtOAc, 95:5 Ǟ 60:40] of the residue gave 5e as a colourless oil
54.5, 53.2, 26.0 ppm. IR (film): νmax = 3308, 1657, 1521, 1453 cm–1.
˜
HRMS (ESI+): calcd. for C19H23N2O3 [M + H]+ 295.1805; found
295.1801.
1
(24.1 mg, 77%). H NMR (500 MHz, CDCl3): δ = 7.29–7.12 (m, 8
H), 6.95 (m, 2 H), 5.74 (m, 1 H), 5.10 (m, 2 H), 4.32 (s, 1 H), 3.72
(d, J = 14.0 Hz, 1 H), 3.20 (d, J = 14.0 Hz, 1 H), 3.15 (m, 1 H),
2.78 (d, J = 4.8 Hz, 3 H), 2.73 (m, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 172.0, 163.3, 161.3, 138.3, 134.7, 131.5, 131.5, 130.3,
130.3, 128.5, 128.4, 127.3, 118.5, 115.1, 114.9, 67.9, 54.5, 53.2,
General Procedure B. 2-[(Allyl)(benzyl)amino]-2-(biphenyl-3-yl)-N-
methylacetamide (5g): The Grignard reagent was prepared from 3-
bromobiphenyl (333 µL, 2.0 mmol) and magnesium powder
(73 mg, 3.0 mmol) in THF (5 mL). To a solution of amide 4e
(29.0 mg, 0.10 mmol) in THF (2 mL) was added LDA (1.40 ,
71 µL, 0.10 mmol) at 0 °C. The solution was stirred for 1 min, co-
oled to –78 °C and the freshly prepared Grignard solution (0.27 
in THF, 0.74 mL, 0.20 mmol) was added. The mixture was allowed
to reach room temperature and the reaction quenched with satd.
NH4Cl (1 mL) and brine (1 mL). The aqueous phase was extracted
twice with Et2O, and the combined organic extracts were dried
(K2CO3) and concentrated under reduced pressure. Flash
chromatography [pentane (+ 1% iPrNH2)/EtOAc, 95:5 Ǟ 65:35] of
the residue gave 5g (29.9 mg, 81%) as a yellow oil. 1H NMR
(500 MHz, CDCl3): δ = 7.52–711 (m, 15 H), 5.79 (m, 1 H), 5.12
(m, 2 H), 4.42 (s, 1 H), 3.79 (d, J = 14.0 Hz, 1 H), 3.31 (d, J =
26.0 ppm. IR (film): ν
= 3309, 1660, 1508, 1224 cm–1. HRMS
˜
max
(ESI+): calcd. for C19H22FN2O [M
+
H]+ 313.1711; found
313.1711.
2-[(Allyl)(benzyl)amino]-2-(4-methoxyphenyl)-N-methylacetamide
(5f): General Procedure A was applied by using 4-MeOC6H4MgBr
(1.0  in THF, 0.20 mL, 0.20 mmol). Flash chromatography [pen-
tane (+ 1% iPrNH2)/EtOAc, 95:5 Ǟ 60:40] of the residue gave 5f
(29.8 mg, 92%) as a colourless oil. 1H NMR (400 MHz, CDCl3): δ
= 7.28–7.10 (m, 8 H), 6.81 (m, 2 H), 5.76 (m, 1 H), 5.10 (m, 2 H),
4.29 (s, 1 H), 3.72 (m, 4 H), 3.23 (d, J = 14.0 Hz, 1 H), 3.15 (m, 1
H), 2.79 (d, J = 4.1 Hz, 3 H), 2.76 (m, 1 H) ppm. 13C NMR
14.0 Hz, 1 H), 3.21 (dd, J = 14.6, 4.9 Hz), 2.85 (m, 1 H), 2.83 (d, (125 MHz, CDCl3): δ = 172.5, 159.1, 138.6, 134.8, 130.9, 128.47,
J = 4.6 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 172.2,
128.42, 127.1, 126.8, 118.3, 113.6, 68.3, 55.1, 54.5, 53.1, 26.0 ppm.
Eur. J. Org. Chem. 2008, 5583–5589
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5587

S. Hirner, D. K. Kirchner, P. Somfai
FULL PAPER
IR (film): νmax = 3309, 2934, 1659, 1511, 1248 cm–1. HRMS (ESI+):
7.13 (m, 5 H), 5.76 (m, 1 H), 5.44 (br., 1 H), 5.09 (m, 2 H), 3.99
(d, J = 14.6 Hz, 1 H), 3.44–3.37 (m, 1 H), 3.30 (d, J = 14.6 Hz, 1
H), 2.86 (m, 1 H), 2.77 (d, J = 4.9 Hz, 3 H), 2.53 (d, J = 9.7 Hz, 1
H), 2.14 (m, 1 H), 0.96 (d, J = 6.6 Hz, 3 H), 0.76 (d, J = 6.6 Hz, 3
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 171.9, 140.0, 137.2,
128.3, 128.2, 126.8, 116.8, 70.0, 54.3, 53.3, 27.0, 25.5, 19.9,
˜
calcd. for C20H25N2O2 [M + H]+ 325.1911; found 325.1911.
2-[(Allyl)(benzyl)amino]-N-methyl-2-(thiophen-2-yl)acetamide (5h):
General Procedure A was applied by using LDA (1.5 equiv., 1.40 ,
107 µL, 0.15 mmol) and (2-thiophenyl)MgBr (1.0  in THF,
0.20 mL, 0.20 mmol). Flash chromatography [pentane (+ 1 %
iPrNH2)/EtOAc, 95:5 Ǟ 65:35] of the residue gave 5h (27.3 mg,
19.8 ppm. IR (film): ν
= 3305, 2933, 1659, 1524, 920 cm–1
.
˜
max
HRMS (ESI+): calcd. for C16H25N2O [M + H]+ 261.1961; found
1
91%) as a colourless oil. H NMR (500 MHz, CDCl3): δ = 7.37–
261.1962.
7.25 (m, 6 H), 7.16 (br., 1 H), 7.02 (m, 1 H), 6.98 (m, 1 H), 5.86
(m, 1 H), 5.23 (m, 2 H), 4.71 (s, 1 H), 3.83 (d, J = 13.8 Hz, 1 H),
3.39 (d, J = 13.8 Hz, 1 H), 3.25 (m, 1 H), 2.93 (m, 1 H), 2.87 (d, J
= 5.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.1,
138.4, 136.4,135.0, 128.6, 128.5, 128.4, 127.3, 126.3, 125.6, 118.4,
2-[(Allyl)(benzyl)amino]-N-methylbut-3-enamide (5m): General Pro-
cedure A was applied by using vinylmagnesium bromide (0.7  in
THF, 0.29 mL, 0.20 mmol). Flash chromatography [pentane (+ 1%
iPrNH2)/EtOAc, 95:5 Ǟ 60:40] of the residue gave 5m (20.3 mg,
1
63.3, 54.6, 53.5, 26.1 ppm. IR (film): ν
= 3307, 1661, 1522,
˜
83%) as a colourless oil: H NMR (500 MHz, CDCl3): δ = 7.40–
max
1409 cm–1. HRMS (ESI+): calcd. for C17H21N2OS [M + H]+
7.25 (m, 5 H), 7.19 (br., 1 H), 5.96–5.80 (m, 2 H), 5.51 (m, 1 H),
5.29–5.19 (m, 3 H), 3.85 (d, J = 13.7 Hz, 1 H), 3.74 (d, J = 9.3 Hz,
1 H), 3.39 (d, J = 13.7 Hz, 1 H), 3.25 (m, 1 H), 2.99 (m, 1 H), 2.86
(d, J = 5.0 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 172.6,
138.6, 135.2, 130.6, 128.6, 128.5, 127.3, 122.1, 118.2, 66.8, 54.7,
301.1369; found 301.1366.
2-[(Allyl)(benzyl)amino]-N-methyl-2-(pyridin-3-yl)acetamide (5i):
General Procedure B was applied by using (3-pyridinyl)MgBr·LiCl,
which was freshly prepared from 3-bromopyridine (19.3 µL,
0.20 mmol) and iPrMgCl·LiCl (1.0  in THF, 200 µL,
0.20 mmol).[31] Flash chromatography [pentane (+ 1% iPrNH2)/
EtOAc, 95:5 Ǟ 50:50] of the residue gave 5i (22.7 mg, 77%) as a
53.4, 26.0 ppm. IR (film): ν
= 3073, 2928, 1663, 1524,
˜
max
1412 cm–1. HRMS (ESI+): calcd. for C15H21N2O [M + H]+
245.1648; found 233.1649.
1
pale yellow oil. H NMR (500 MHz, CDCl3): δ = 8.48 (m, 1 H),
(S)-2-{(Allyl)[(S)-1-phenylethyl]amino}-N-methyl-2-phenylacetamide
(5o): PhMgCl (2.0  in THF, 1.20 mL, 2.40 mmol) was added to a
solution of dry ZnCl2 (327 mg, 2.40 mmol) in THF (5 mL), and
the resultant mixture was stirred at room temperature for 30 min.
LDA (1.39 , 1.52 Ml, 2.10 mmol) was added to a solution of
amide 4i (609 mg, 2.0 mmol) in Et2O (20 mL) at 0 °C, and the re-
sultant yellow solution was stirred for 1 min. The mixture was co-
oled to –78 °C, and the freshly prepared solution of PhZnCl was
added. The reaction was quenched with satd. NH4Cl (5 mL) and
brine (10 mL), and the phases were separated. The aqueous layer
was extracted twice with Et2O, and the combined organic extracts
were dried (MgSO4) and concentrated under reduced pressure (dia-
8.41 (s, 1 H), 7.54 (m, 1 H), 7.33–7.12 (m, 7 H), 5.76 (m, 1 H), 5.15
(m, 2 H), 4.40 (s, 1 H), 3.77 (d, J = 13.9 Hz, 1 H), 3.19 (m, 1 H),
3.15 (d, J = 13.9 Hz, 1 H), 2.82 (d, J = 4.9 Hz, 3 H), 2.69 (m, 1 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 171.2, 151.1, 149.1, 138.0,
137.5, 134.6, 127.5, 123.0, 118.8, 65.9, 54.7, 53.4, 26.1 ppm. IR
(film): ν
= 3293, 2930, 1664, 1524, 1424 cm–1. HRMS (ESI+):
˜
max
calcd. for C18H21N3O [M + H] 296.1757; found 296.1758.
2-[(Allyl)(benzyl)amino]-2-(5-bromopyridin-3-yl)-N-methylacetamide
(5j): General Procedure B was applied by using [5-Br(3-pyridinyl)]-
MgBr·LiCl, which was freshly prepared from 3,5-dibromopyridine
(47.4 mg, 0.20 mmol) and iPrMgCl·LiCl (1.0  in THF, 200 µL,
0.20 mmol).[31] Flash chromatography [pentane (+ 1% iPrNH2)/
EtOAc, 95:5 Ǟ 50:50] of the residue gave 5j (28.4 mg, 76%) as a
1
stereomeric ratio 87:13, H NMR analysis on the crude product).
Flash chromatography (hexane/THF, 98:2 Ǟ 82:18) of the residue
gave 5o as a diasteromeric mixture (458 mg, 74 %). The dia-
stereomers could be separated by flash chromatography (pentane/
1
yellow oil. H NMR (500 MHz, CDCl3): δ = 8.56 (s, 1 H), 8.32 (s,
1 H), 7.68 (s, 1 H), 7.33–7.19 (m, 6 H), 5.76 (m, 1 H), 5.18 (m, 2
H), 4.38 (s, 1 H), 3.78 (d, J = 13.8 Hz, 1 H), 3.20 (m, 1 H), 3.14
(d, J = 13.8 Hz, 1 H), 2.83 (d, J = 5.3 Hz, 3 H), 2.68 (m, 1 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 170.6, 150.2, 149.2, 140.1, 137.7,
134.5, 131.4, 128.8, 128.4, 127.7, 120.4, 119.1, 65.3, 54.8, 53.5,
Et2O, 95:5 Ǟ 80:20) to yield pure 5o as a colourless oil. [α]2D0
=
1
+9.2 (c = 0.85, CH2Cl2). H NMR (500 MHz, CDCl3): δ = 7.41–
7.24 (m, 10 H), 6.94 (br., 1 H), 5.65 (m, 1 H), 5.03 (m, 2 H), 4.47
(s, 1 H), 4.12 (q, J = 6.9 Hz, 1 H), 3.31 (m, 1 H), 3.15 (m, 1 H),
2.75 (d, J = 5.0 Hz, 3 H), 1.17 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 172.9, 143.6, 137.2, 129.6, 128.4, 128.4,
127.8, 127.5, 127.0, 116.8, 69.1, 57.5, 51.1, 25.8, 15.3 ppm. IR
26.2 ppm. IR (film): ν
= 3321, 3065, 2929, 1667, 1523,
˜
max
1420 cm–1. HRMS (ESI+): calcd. for C18H21BrN3O [M + H]+
374.0863; found 374.0861.
(film): ν
= 2970, 2931, 1658, 1523, 1452 cm–1. HRMS (ESI+):
˜
max
2-[(Allyl)(benzyl)amino]-N-methylpropanamide (5k): General Pro-
cedure B was applied by using MeMgBr (3.0  in THF, 67 µL,
0.20 mmol). Flash chromatography [pentane (+ 1 % iPrNH2)/
EtOAc, 95:5 Ǟ 60:40] of the residue gave 5k (22.3 mg, 96%) as a
colourless oil. 1H NMR (500 MHz, CDCl3): δ = 7.30–7.15 (m, 6
H), 5.81–5.71 (m, 1 H), 5.20–5.08 (m, 2 H), 3.71 (d, J = 13.7 Hz,
1 H), 3.37–3.29 (m, 2 H), 3.09 (m, 1 H), 2.90 (m, 1 H), 2.73 (d, J
= 5.0 Hz, 3 H), 1.18 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 174.5, 138.9, 135.6, 128.6, 128.5, 127.3,
calcd. for C20H25N2O [M + H]+ 309.1961; found 309.1958.
(S)-2-{(Allyl)[(S)-1-phenylethyl]amino}-N-methyl-N-nitroso-2-
phenylacetamide (11): Sodium nitrite (263 mg, 3.8 mmol) was
added to a solution of amide 5o in CH2Cl2 (6 mL), Ac2O (2 mL)
and acetic acid (0.2 mL), and the mixture was stirred at room temp.
for 6 h. The mixture was diluted with toluene (20 mL), filtered and
concentrated under reduced pressure to give crude nitroso-amide
11 as a deep yellow oil, which was directly used in the next step.
117.8, 58.1, 54.6, 53.2, 26.0, 8.1 ppm. IR (film): νmax = 2933, 1663,
˜
Methyl (S)-2-{(Allyl)[(S)-1-phenylethyl]amino}-2-phenylacetate (12):
Satd. NaHCO3 (5 mL) was added to a solution of the crude ni-
troso-amide 11 in MeOH (10 mL). The mixture was slowly heated
to reflux, diluted with brine and extracted three times with Et2O.
The combined organic extracts were dried (MgSO4) and concen-
trated under reduced pressure. Flash chromatography (pentane/
Et2O, 98:2 Ǟ 80:20) gave 12 as a colourless oil. [α]2D0 = +(c = 0.85,
1522, 1158 cm–1. HRMS (ESI+): calcd. for C14H21N2O [M + H]+
233.1648; found 233.1646.
2-[(Allyl)(benzyl)amino]-N,3-dimethylbutanamide (5l): General Pro-
cedure A was applied by using iPrMgCl·LiCl (1.0  in THF,
0.20 mL, 0.20 mmol). Flash chromatography [pentane (+ 1 %
iPrNH2)/EtOAc, 95:5 Ǟ 70:30] of the residue gave 5l (20.6 mg,
1
1
79%) as a colourless oil. H NMR (500 MHz, CDCl3): δ = 7.32–
CH2Cl2). H NMR (500 MHz, CDCl3): δ = 7.36–7.14 (m, 10 H),
5588
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5583–5589

α-Amino Acids by Umpolung of Weinreb Amide Enolates
[7] E. C. Lee, G. C. Fu, J. Am. Chem. Soc. 2007, 129, 12066–
12067.
5.63 (m, 1 H), 4.98 (m, 1 H), 4.85 (m, 1 H), 4.57 (s, 1 H), 4.01 (q,
J = 6.9 Hz, 1 H), 3.50 (s, 3 H), 3.31 (m, 2 H), 1.29 (d, J = 6.9 Hz,
3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 173.1, 143.9, 139.1,
137.9, 128.6, 128.3, 128.2, 127.7, 127.6, 126.9, 115.0, 66.3, 59.1,
[8] For a review, see: a) P. D. Bailey, A. N. Boa, J. Clayson,
Contemp. Org. Synth. 1995, 2, 173–187. For recent examples,
see: b) S. D. Bull, S. G. Davies, A. C. Garner, E. D. Savory, E. J.
Snow, A. D. Smith, Tetrahedron: Asymmetry 2004, 15, 3989–
4001; c) P. Calí, M. Begtrup, Synthesis 2002, 1, 63–66; and
references cited therein.
56.2, 50.5, 19.1 ppm. IR (film): ν
= 3029, 2975, 1738, 1453,
˜
max
1157 cm–1. HRMS (ESI+): calcd. for C20H24NO2 [M + H]+
310,1802; found 310,1802.
[9] a) R. V. Hoffman, N. K. Nayyar, B. W. Klinekole, J. Am. Chem.
Soc. 1992, 114, 6262–6263; b) R. V. Hoffman, N. K. Nayyar,
W. Chen, J. Org. Chem. 1992, 57, 5700–5707; c) R. V. Hoffman,
N. K. Nayyar, W. Chen, J. Org. Chem. 1993, 58, 2355–2359; d)
R. V. Hoffman, N. K. Nayyar, W. Chen, J. Am. Chem. Soc.
1993, 115, 5031–5034; e) R. V. Hoffman, N. K. Nayyar, W.
Chen, J. Org. Chem. 1995, 60, 4121–4125.
[10] G. L. Mislin, A. Burger, M. A. Abdallah, Tetrahedron 2004, 60,
12139–12145.
[11] S. Hirner, O. Panknin, M. Edefuhr, P. Somfai, Angew. Chem.
Int. Ed. 2008, 47, 1907–1909.
Methyl (S)-2-[(S)-1-Phenylethylamino]-2-phenylacetate (13): A solu-
tion of ester 12 (60.0 mg, 0.194 mmol), Pd(PPh3)4 (11.2 mg,
0.010 mmol) and N,N-dimethylbarbituric acid (151.4 mg,
0.97 mmol) in CH2Cl2 (1 mL) was refluxed for 3 h. The mixture
was diluted with Et2O, filtered and concentrated under reduced
pressure. Flash chromatography [heptane (+ 1% iPrNH2)/Et2O,
97:3Ǟ80:20)oftheresidue gave13asa colourlessoil(48.7 mg, 93%):
1
[α]2D0 = +26.3 (c = 1.0, CH2Cl2). H NMR (500 MHz, CDCl3): δ =
7.28–7.17 (m, 10 H), 4.15 (s, 1 H), 3.73 (q, J = 6.5 Hz, 1 H), 3.64
(s, 1 H), 2.25 (br., 1 H), 1.31 (d, J = 6.5 Hz) ppm. 13C NMR
(125 MHz, CDCl3): δ = 174.2, 144.7, 138.4,128.7, 128.5, 127.9,
[12] M. A. Tius, J. Busch-Petersen, Synlett 1997, 531–533.
[13] S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815–
3818.
127.2, 127.1, 126.9, 62.9, 56.5, 52.1, 24.6 ppm. IR (film): ν
=
˜
max
2954, 1736, 1688, 1453, 1170 cm–1. HRMS (ESI+): calcd. for
C20H25N2O [M + H]+ 270,1489; found 270,1487.
[14] For similar results, see: a) S. L. Graham, T. H. Scholz, Tetrahe-
dron Lett. 1990, 31, 6269–6272; b) I. Williams, K. Reeves, B. M.
Kariuki, L. R. Cox, Org. Biomol. Chem. 2007, 5, 3325–3329.
[15] Such types of modified Weinreb amides have been shown to
efficiently prevent demethoxylation, see: O. Labeeuw, P. Phan-
savath, J.-P. Genêt, Tetrahedron Lett. 2004, 45, 7107–7110.
[16] Mostly, starting material was recovered, when the LDA was
added at –78 °C.
[17] D. A. Evans in Asymmetric Synthesis, vol. 3 (Ed.: J. D. Mor-
rison), Academic Press, New York, 1984, p. 1.
[18] F. A. Davis, M. Song, Org. Lett. 2007, 9, 2413–2416.
[19] T. Hase, Umpoled Synthons: A Survey of Sources and Uses in
Synthesis, Wiley, New York, 1987.
Methyl (S)-2-Amino-2-phenylacetate Hydrochloride (14): A catalytic
amount of Pd(OH)2 (20% on C) was added to a solution of 13
(5.7 mg, 0.021 mmol) in MeOH (5 mL) and concd. HCl (0.25 mL).
The resultant mixture was stirred under H2 (1 atm) for 15 h, filtered
through a pad of Celite and concentrated under reduced pressure
to give 14 as a white solid (4.3 mg, 100%) with spectroscopic data
characterizations in accordance with those previously reported in
the literature.[27]
Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedure, preparation and analytical
data for compounds 4a,c,d,f–h and 15 and NMR spectra for all
new compounds.
[20] For a review on ketene dithioacetals in organic synthesis, see:
M. Kolb, Synthesis 1990, 171–190.
[21] a) U. Jahn, P. Hartmann, E. Kaasalainen, Org. Lett. 2004, 6,
257–260; b) U. Jahn, J. Org. Chem. 1998, 63, 7130–7131, and
references cited therein.
[22] For a recent review, see: J. B. Sperry, D. L. Wright, Chem. Soc.
Rev. 2006, 35, 605–621.
Acknowledgments
[23] G. G. Smith, T. Sivakua, J. Org. Chem. 1983, 48, 627–634.
[24] a) D. A. Evans, J. C. Barrow, P. S. Watson, A. M. Ratz, C. J.
Dinsmore, D. A. Evrard, K. M. DeVries, J. A. Ellman, S. D.
Rychnovsky, J. Lacour, J. Am. Chem. Soc. 1997, 119, 3419–
3420; b) D. A. Evans, J. L. Katz, G. S. Peterson, T. Hinter-
mann, J. Am. Chem. Soc. 2001, 123, 12411–12413.
[25] D. A. Evans, P. H. Carter, C. J. Dinsmore, J. C. Barrow, J. L.
Katz, D. W. Kung, Tetrahedron Lett. 1997, 38, 4535–4538.
[26] F. Garro-Helion, A. Merzouk, F. Guibé, J. Org. Chem. 1993,
58, 6109–6113.
This work was financially supported by the Swedish Research
Council and the Knut and Alice Wallenberg Foundation.
[1] For a review, see: G. M. Coppola, H. F. Schuster, Asymmetric
Synthesis Construction of Chiral Molecules Using Amino Acids,
Wiley, New York, 1987.
[2] B. K. Hubbard, C. T. Walsh, Angew. Chem. Int. Ed. 2003, 42,
730.
[3] J. M. Herbert, D. Frehel, E. Valee, G. Kieffer, D. Gouy, Y. Ber-
ger, J. Necciari, G. Defreyn, J. P. Maffrand, Cardiovasc. Drug
Rev. 1993, 11, 180–198.
[4] For reviews on the synthesis of α-amino acids, see: a) C.
Nájera, J. M. Sansano, Chem. Rev. 2007, 107, 4584–4671; b)
M. J. O’Donell, Acc. Chem. Res. 2004, 37, 506–517; c) K. Ma-
ruoka, T. Ooi, Chem. Rev. 2003, 103, 3013–3028; d) A. E.
Taggi, A. M. Hafez, T. Lectka, Acc. Chem. Res. 2003, 36, 10–
19; e) R. M. Williams, J. A. Hendrix, Chem. Rev. 1992, 92, 889–
917.
[27] [α]2D0 = +125.6 (c = 0.43, MeOH); for comparison see: G.-I. Li,
G. Zhao, Org. Lett. 2006, 8, 633–636.
[28] No epimerization of the α-stereocenter could be observed dur-
ing the ester formation and deallylation steps (Scheme 3,
steps b–d) as determined by 1H NMR spectroscopic analysis
of the crude products.
[29] Chiralcel OD-RH, 50 m KPF6/MeCN (85:15 Ǟ 70:30),
0.4 mL/min.
[30] For a recent review on the synthesis of α,α-disubstituted α-
amino acids, see: H. Vogt, S. Bräse, Org. Biomol. Chem. 2007,
5, 406–430.
[5] For reviews, see: a) S. J. Connon, Angew. Chem. Int. Ed. 2008,
47, 1176–1178; b) H. Gröger, Chem. Rev. 2003, 103, 2795–2827. [31] A. Krasovskiy, P. Knochel, Angew. Chem. Int. Ed. 2004, 43,
[6] a) H. Dai, M. Yang, X. Lu, Adv. Synth. Catal. 2008, 350, 249–
253; b) M. A. Beenen, D. J. Weix, J. A. Ellman, J. Am. Chem.
Soc. 2006, 128, 6304–6305.
3333–3336.
Received: July 10, 2008
Published Online: October 13, 2008
Eur. J. Org. Chem. 2008, 5583–5589
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5589