Enantioselective organocatalytic addition of oxazolones to 1,1-bis(phenylsulfonyl)ethylene: A convenient asymmetric synthesis of quaternary α-amino acids

Article abstract of DOI:10.1002/chem.200903025

A new, easy, and highly enantioselective method for the synthesis of quaternary α-alkyl-α-amino acids based on organocatalysis is reported. The addition of oxazolones to 1, 1-bis(phenylsulfonyl)ethylene is efficiently catalyzed by simple chiral bases or thioureas. The reaction affords α-disubstituted α-amino acid derivatives with complete C4 regioselectivity and with excellent yields and enantioselectivities. This methodology is complementary to previously reported enantioselec-tive approaches to quaternary ot-amino acids and allows the synthesis of αphenyl-α- alkyl-α-amino acids and αiert-butyl-α-alky1-α-amino acids. It has distinct advantages in terms of operational simplicity, enviromentally friendly conditions, and suitability for largescale reactions.

Full text of DOI:10.1002/chem.200903025

DOI: 10.1002/chem.200903025
Enantioselective Organocatalytic Addition of Oxazolones to 1,1-
Bis(phenylsulfonyl)ethylene: A Convenient Asymmetric Synthesis of
Quaternary a-Amino Acids
Andrea-Nekane R. Alba, Xavier Companyꢀ, Guillem Valero, Albert Moyano,* and
Ramon Rios*[a]
Dedicated to Professor Josep M. Ribꢀ on the occasion of his 70th birthday
Abstract:
A
new, easy, and highly
complete C4 regioselectivity and with
excellent yields and enantioselectivi-
ties. This methodology is complementa-
ry to previously reported enantioselec-
tive approaches to quaternary a-amino
acids and allows the synthesis of a-
phenyl-a-alkyl-a-amino acids and a-
tert-butyl-a-alkyl-a-amino acids. It has
distinct advantages in terms of opera-
tional simplicity, enviromentally friend-
ly conditions, and suitability for large-
scale reactions.
enantioselective method for the synthe-
sis of quaternary a-alkyl-a-amino acids
based on organocatalysis is reported.
The addition of oxazolones to 1,1-bi-
s(phenylsulfonyl)ethylene is efficiently
catalyzed by simple chiral bases or thi-
oureas. The reaction affords a,a-disub-
stituted a-amino acid derivatives with
Keywords:
amino
acids
·
Michael addition · organocatalysis ·
oxazolones · stereoselectivity
Introduction
15% ee for l-isovaline) has led to interesting speculations
on their possible contribution to terrestrial chemical evolu-
tion and the origin of biological homochirality.[6]
The asymmetric synthesis of nonproteinogenic quaternary
a-amino acids is a topic of growing interest. In particular, a-
alkyl-a-amino acids have proven to be extremely useful
building blocks for the design and construction of new pep-
tides or proteins with improved pharmacological properties,
due to the restricted conformational mobility that these
amino acids are able to impart to the peptide backbone[1,2]
and also due to the enhanced resistance to enzymatic degra-
dation exhibited by the products.[3] Quaternary a-amino
acids have also been found in some natural antibiotics[4]
and, more recently, in some carbonaceous meteorites,[5]
where their presence in the optically active form (up to
There are several synthetic methods for the enantioselec-
tive preparation of quaternary amino acids.[7] One of the
most classical approaches is based on the principle of “self-
regeneration of stereocenters”,[8] developed by Seebach
et al., in which the stereogenic center of an a-amino acid
generates a temporary center of chirality on a suitable deriv-
ative (such as the 5-oxazolidinone in the procedure de-
scribed by Seebach et al.); this, in turn, is used to introduce
diastereoselectively a new substituent at the original stereo-
genic center.[9] A related strategy, based on the principle of
“memory of chirality”,[10] has been recently used for the
enantioselective quaternization of a-amino acid deriva-
tives.[11] The asymmetric alkylation of amino acid derived
Schiff bases by using chiral phase-transfer organocatalysts,
pioneered by OꢀDonnell et al.[12] and further improved by
Lygo,[13] Corey,[14] Maruoka,[15] and their respective co-work-
ers, has become one of the most reliable procedures for the
enantioselective preparation of a-amino acids.[16] However,
its application to the asymmetric synthesis of a-alkyl-a-
amino acids is not straightforward and still presents impor-
tant limitations, both in scope and in enantioselectivity.[17]
Very recently, Jørgensen and co-workers have reported on
the use of 5-oxazolones (azalactones) in the synthesis of
[a] A.-N. R. Alba, X. Companyꢁ, G. Valero, Prof. Dr. A. Moyano,
Dr. R. Rios+
Department of Organic Chemistry
Universitat de Barcelona, Faculty of Chemistry
Martꢂ i Franquꢃs 1-11, 08028 Barcelona (Spain)
Fax : (+34)9333-97-878
E-mail: amoyano@ub.edu
rios.ramon@icrea.cat
[+] Dr. Ramon Rios is an ICREA Researcher at Universitat de Barcelo-
na and an ICC-UB Researcher
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903025.
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Chem. Eur. J. 2010, 16, 5354 – 5361

FULL PAPER
quaternary a-amino acids by asymmetric organocatalytic
Michael addition[18] to a,b-unsaturated aldehydes[19] and ni-
troalkenes,[20] whereas Terada and co-workers have de-
scribed an efficient access to b-hydroxy-a-amino acid deriv-
atives with a quaternary stereocenter at the a-carbon
atom.[21] These reactions afforded the desired amino acids
with excellent yields and enantioselectivities. However, one
of the drawbacks of these methodologies is the presence of
several functional groups in the final amino acid, which
makes the synthesis of a,a-dialkylamino acids difficult.
The use of sulfones and vinyl sulfones in enantioselective
synthesis is receiving much attention. Between the pioneer-
ing work of Mossꢅ and Alexakis concerning the asymmetric
addition of aldehydes to vinyl sulfones[22] and the recent ad-
dition of 2-fluoromethylenedisulfones and methylenedisul-
fones to a,b-unsaturated aldehydes developed in our re-
search group,[23] the use of sulfones has grown exponentially
in the last few years, due to their easy modification or re-
moval by reduction.[24] These characteristics make sulfones
synthetically versatile groups that can be introduced in
either nucleophilic or electrophilic synthons.
Scheme 2. Regioselectivity of oxazolone addition.
Table 1. Solvent screening in the addition of oxazolone 1a to vinylsul-
fone 2.[a]
Results and Discussion
With this information in mind, and based on our previous
experience in asymmetric organocatalysis,[23,25] we became
interested in studying the unprecedented addition of 5-oxa-
zolones to vinyl sulfones catalyzed by chiral bases, in order
to synthesize quaternary a-amino acids (Scheme 1). This
Entry
Solvent
Conversion [%][b]
e.r.[c]
1
CH2Cl2
CHCl3
toluene
AcOEt
DMF[e]
EtOH
100
100
100
100
100
100
20
85:15
15.5:84.5
86:14
83:17
racemic
72:28
2[d]
3
4
5
6
7
hexane
77:23
[a] In all cases, 1,1-bis(phenylsulfonyl)ethene (2; 1.0 equiv) was added to
a mixture of 1a (1.5 equiv) and catalyst I (0.1 equiv) in the appropriate
solvent at room temperature. [b] Determined by NMR spectroscopy after
1 h. [c] Determined by chiral HPLC analysis. [d] (R,R)-I was used as the
catalyst. [e] DMF: N,N-dimethylformamide.
Scheme 1. The proposed reaction.
strategy would allow some of the limitations shown by the
methodologies cited above to be avoided. Another concern
was the possible regioselectivity in the reaction of the oxa-
zolones. As previously reported, the regioselectivity of oxa-
zolone additions is strongly dependent on both the nature of
the substituents of the oxazolone and on the Michael ac-
ceptor. Thus, when unsaturated aldehydes were used as the
Michael acceptors, only C4 addition on the oxazolone ring
was observed.[19] However, when nitrostyrenes were used as
the Michael acceptors, the regioselectivity could be totally
reversed depending on the substituent at the C2 position, as
shown in Scheme 2.[20,26]
To our delight, when 2-phenyl-4-isopropyl-5-oxazolone
(1a) was treated with 1,1-bis(phenylsulphonyl)ethene (2) in
several solvents and in the presence of the thiourea-based
catalyst of Takemoto and co-workers,[27] (S,S)-I (Table 1),
the addition product 3a was obtained with complete C4 re-
gioselectivity and in moderate enantioselectivity (up to
86:14 enantiomeric ratio (e.r.)). The reaction took place
with excellent conversion in all solvents except hexane
(Table 1, entry 7). Dichloromethane, chloroform, toluene,
and ethyl acetate (Table 1, entries 1–4, respectively) afford-
ed very similar enantioselectivities. The enantiomeric ratio
of the adduct decreased with the use of ethanol as the sol-
vent (Table 1, entry 6), and the racemic product was ob-
tained in N,N-dimethylformamide (Table 1, entry 5).
Next, we decided to optimize the nature of the catalyst,
by testing several chiral thioureas and bases derived from
Cinchona alkaloids (II–XII) in the benchmark addition of
1a to 2 (Table 2) with toluene as the solvent. The reaction
was efficiently catalyzed (100% conversion after 1 h at
room temperature) by all of the catalysts; remarkably, when
the
Sharpless
ligands
(DHQD)2AQN
(IV)
or
(DHQD)2PHAL (V) were used (Table 2, entries 1 and 2),
we obtained good enantioselectivities, at the same level as
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R. Rios, A. Moyano et al.
Table 2. Catalyst screening in the addition of oxazolone 1a to vinylsul-
fone 2.[a]
In order to improve the overall results of the reaction, we
also investigated the effect of temperature. Rather unex-
pectedly, if the reaction was catalyzed by thioureas, the
enantioselectivity did not improve upon a decrease in the
temperature. On the other hand, the Sharpless ligands pro-
duced better enantioselectivities at lower temperatures, at
the expense of a reduced reaction rate. Gratifyingly, the use
of (DHQD)2AQN (IV) afforded the final quaternary amino
acid derivative 3a with excellent yield (84%) and enantiose-
lectivity (96.5:3.5 e.r.) after 3 days at À408C (Table 3,
entry 1).
With these results on hand, we decided to study the effect
of the aromatic C2 substituent of the oxazolone derived
from valine. As previously noticed by Jørgensen and co-
workers,[20] the presence of halogens (F, Cl) in the ortho
and/or para positions of the phenyl ring increased the enan-
tioselectivity of the reaction with the thiourea-derived cata-
lysts I–III. In Table 3, we summarize the best conditions
(catalyst, reaction temperature) finally achieved for each of
the studied compounds 1a–e (see the Supporting Informa-
tion for additional screening results). As expected, when
there are halogenated substituents in the aromatic ring, the
enantioselectivity increases to 95:5 e.r. at room temperature
upon catalysis with the Takemoto thiourea I (Table 3,
entry 4). This opens a new door to achieve high enantiose-
lectivities by only changing the nature of the aromatic ring
substituents.
Entry
Catalyst[b]
(DHQD)2AQN (IV)
(DHQD)2PHAL (V)
(DHQD)2PYR (VI)
(DHQ)2AQN (VII)
(DHQ)2PHAL (VIII)
(DHQ)2PYR (IX)
(S,S)-I
Conversion [%][c]
e.r.[d]
1
2
3
4
5
6
7
8
N
100
100
100
100
100
100
100
100
100
100
100
87:13
87:13
61:39
24:76
30:70
28:72
86:14
9:91
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
II
III
9
10
11
86:14
52:48
47:53
quinine (XI)
quinidine (XII)
[a] In all cases, 1,1-bis(phenylsulfonyl)ethene (2) (1.0 equiv) was added to
a mixture of 1a (1.5 equiv) and of the catalyst I-XII (0.1 equiv) in tolu-
ene at room temperature. [b] (DHQD)2AQN: hydroquinidine(anthra-
quinone-1,4-diyl) diether; (DHQD)2PHAL: 1,4-bis(dihydroquinidinyl)-
phthalazine; (DHQD)2PYR: hydroquinidine-2,5-diphenyl-4,6-pyrimidine-
diyl diether. The DHQ catalysts are the equivalent dihydroquininyl com-
pounds. [c] Determined by NMR spectroscopy after 1 h. [d] Determined
by chiral HPLC analysis.
To further examine the scope of the reaction, we prepared
a library of oxazolones bearing different substituents in posi-
tions 2 and 4 (Tables 4–7). The reaction is strongly depen-
dent on the oxazolone substitution pattern, so in order to
achieve good enantioselectivities, we optimized the reaction
those provided by the Takemoto thiourea
entry 7). The best results were
I (Table 2,
obtained with the quinidine-de-
Table 3. Effect of the substitution pattern of the C2 aromatic substituent on the addition of valine-derived ox-
rived thiourea catalyst II
(Table 2, entry 8). The pseudoe-
nantiomeric catalyst III, derived
from quinine, gave the opposite
enantiomer as expected, albeit
with somewhat lower enantiose-
azolones 1a–e to vinylsulfone 2.[a]
Entry
1
Ar
Product
Catalyst
(DHQD)2AQN (IV)
T
t
Yield [%][b]
84
e.r.[c]
lectivity
(Table 2,
entry 9).
When we used pseudoenan-
tiomers of the Sharpless cata-
lysts (Table 2, entries 4 and 5)
or alkaloids such as quinine or
quinidine (Table 2, entries 10
and 11), the enantioselectivities
dropped dramatically. It is
worth noting that both the qui-
nidine-derived Sharpless ligands
IV–VI and the quinine-derived
bifunctional thiourea catalyst
III gave the same sense of
asymmetric induction as that
obtained with the Takemoto
catalyst (S,S)-I.
3a
G
À408C
3 days
96.5:3.5
2
3b
(S,S)-I
À208C
1 day
96
96:4
3
4
3c
3d
G
RT
RT
14 h
14 h
78
82
94:6
95:5
5
6
3e
3a
U
RT
RT
14 h
14 h
93
79
92:8
86:14
[a] In all cases, 1,1-bis(phenylsulfonyl)ethene (2; 1.0 equiv) was added to 1a–e (1.5 equiv) and the catalyst
(0.1 equiv) in toluene at the specified temperature. [b] Determined after isolation by column chromatography.
[c] Determined by chiral HPLC analysis.
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Asymmetric Synthesis of Quaternary a-Amino Acids
FULL PAPER
temperature, catalyst, and C2 substituent for each initial
amino acid.
When the oxazolones derived from phenylglycine were
used (Table 4), the best results were obtained with phenyl
(1 f) or tert-butyl (1g) substituents at the C2 position and
about a substantial decrease in the yield. Moreover, the re-
action, probably due to the steric bulk of the tert-butyl C4
substituent, afforded the product in only moderate yields
when other catalysts were used (Table 5, entries 2 and 3)
and did not proceed at all when run at low temperatures
(Table 5, entry 5). It is worth noting, however, that the qua-
ternary amino acid obtained from 3h cannot be obtained by
any of the previously described enantioselective methodolo-
gies.
Table 4. Addition of oxazolones derived from phenylglycine to vinylsul-
fone 2.[a]
When oxazolones derived from alanine, 1i–k, were used
(Table 6), the effect of fluorine substitution on the aromatic
C2 substituent was evident, and we could obtain high yields
(up to 98%) and enantioselectivities (up to 93:7 er; Table 6,
entry 7) for compound 3k.
Entry
1
R
Product
Catalyst
T
[8C]
t
A
Yield
72
e.r.[c]
[days] [%][b]
With oxazolone 1l, derived from leucine (Table 7), high
enantioselectivities and good yields were obtained at room
3 f
A
À80
3
90:10
temperature either with Takemoto catalyst
entry 1) or with the quinidine-derived thiourea catalyst II
I (Table 7,
2
3
4
tBu
tBu
3g
3 f
3 f
II
A
À40
À40
À40
À40
3
2
2
82
78
67
9:91
85:15
68:32
5
3g
A
2
77
88:12
Table 6. Addition of oxazolones derived from alanine to vinylsulfone 2.[a]
[a] In all cases, 1,1-bis(phenylsulfonyl)ethene (2; 1.0 equiv) was added to
1 f or 1g (1.5 equiv) and the catalyst (0.1 equiv) in toluene at the speci-
fied temperature. [b] Determined after isolation by column chromatogra-
phy. [c] Determined by chiral HPLC analysis.
Entry
R
Product Catalyst
T
[8C]
t
Yield
[%][b]
e.r.[c]
the Takemoto catalyst I or quinidine-derived bifunctional
thiourea catalyst II, respectively, to afford the final quater-
nary amino acid derivatives with 90:10 e.r. and 72% yield
(3 f; Table 4, entry 1) and 9:91 e.r. and 82% yield (3g;
Table 4, entry 2). It should be highlighted that, in both cases,
the corresponding amino acids cannot be synthesized with
the methodology of Maruoka and co-workers.[15]
1
2
3
4
3i
3i
3i
3i
G
RT
RT
14 h
14 h
86
85
75:25
24:76
83:17
68:32
À40 2 days 68
RT
14 h
67
5
3j
N
À40 2 days
0
–
The oxazolone 1h, derived from tert-leucine, reacted with
vinylsulfone 2 to afford the corresponding quaternary amino
acid derivative 3h with moderate yield (76%) and enantio-
selectivity (85:15 e.r.) when the Takemoto thiourea I was
used as the catalyst at room temperature (Table 5, entry 1).
A decrease in the temperature to 48C (Table 5, entry 4)
marginally improved the enantioselectivity but brought
6
3k
3k
N
À40 2 days 77
À40 2 days 98
88:12
93:7
7[d]
[a] In all cases, 1,1-bis(phenylsulfonyl)ethene (2; 1.0 equiv) was added to
1i–k (1.5 equiv) and the catalyst (0.1 equiv) in toluene at the specified
temperature. [b] Determined after isolation by column chromatography.
[c] Determined by chiral HPLC analysis. [d] CH2Cl2 was used as the sol-
vent.
Table 5. Addition of the oxazolone derived from tert-leucine, 1h, to vi-
nylsulfone 2.[a]
Table 7. Addition of oxazolone 1l, derived from leucine, to vinylsulfone
2.[a]
Entry
R
Product Catalyst
T
[8C]
t
Yield
[%][b]
e.r.[c]
Entry
R
Product
Catalyst
(S,S)-I
II
II
II
T
[8C]
t
Yield
[%][b]
e.r.[c]
[h]
1
2
3
4
5
3h
3h
3h
3h
3h
(S,S)-I
II
IV
R
RT
RT
RT
4
14 h
14 h
14 h
14 h
76
73
68
66
0
85:15
30:70
65:35
86:14
–
1
2
3l
3l
3l
3l
G
RT
RT
4
14
14
14
14
77
75
35
67
92:8
7:93
25:75
30:70
3
4[d]
4
A
À40 2 days
[a] In all cases, 1,1-bis(phenylsulfonyl)ethene (2; 1.0 equiv) was added to
1l (1.5 equiv) and the catalyst (0.1 equiv) in toluene at the specified tem-
perature. [b] Determined after isolation by column chromatography.
[c] Determined by chiral HPLC analysis. [d] CH2Cl2 was used as the sol-
vent.
[a] In all cases, 1,1-bis(phenylsulfonyl)ethene (2; 1.0 equiv) was added to
1h (1.5 equiv) and the catalyst (0.1 equiv) in toluene at the specified tem-
perature. [b] Determined after isolation by column chromatography.
[c] Determined by chiral HPLC analysis.
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R. Rios, A. Moyano et al.
(Table 7, entry 2). However, at lower temperatures, the reac-
tion became sluggish and afforded the addition product in
low yield and, surprisingly, with poor enantioselectivity
(Table 7, entries 3 and 4).
In summary, with the appropriate choice of C2 substitu-
ent, catalyst, and reaction temperature, the addition of oxa-
zolones 1 to 1,1-bis(phenylsulfonyl)ethene (2) can take
place with good to excellent
(R)-(À)-isovaline upon hydrolysis of the amide,[28] allowed
us to determine the absolute configuration as R. We con-
clude that the stereochemical outcome of the reaction, in ac-
cordance with the results shown in Table 2 and Tables 4–7, is
that depicted in Scheme 4.
Based on this absolute configuration result, we decided to
further investigate the possible mechanism of the reaction.
yields and good enantioselectiv-
ities. The best catalysts are, in
general, the Takemoto thiourea
I (both enantiomers of which
are commercially available) and
Scheme 4. Stereochemical outcome of the reaction
the quinidine thiourea deriva-
tive II, although Sharpless
ligand IV proved to be the cata-
lyst of choice for the addition of oxazolone 1a. The scope of
the reaction is very broad and enantiomeric ratios higher
than 90:10 can be achieved for several amino acid derived
oxazolones. Only in the case of tert-leucine derived oxazo-
lones was the enantiomeric ratio of the addition product not
greater than 86:14; however, this result stands out as the
only successful example of catalytic asymmetric a-alkylation
of a tert-leucine derivative.
The obtained adducts could be easily derivatized into N-
protected a-amino acids or N-protected a-amino esters.
Moreover, the resulting adducts can also be derivatized by
addition of different electrophiles to the disulfone moiety or
even by reductive removal of the sulfone groups with Mg in
MeOH to afford the naked alkyl chain.[23] In all cases, the
final compounds were obtained in excellent yields, as illus-
trated in Scheme 3.
Figure 1. Representation of nonlinear effects on the reaction between 1a
and 2 catalyzed by thiourea I.
Comparison of the optical rotation of 6i with that report-
ed in the literature for the same compound, which gives
Scheme 5. Proposed transition state for the reaction.
In order to see whether only one molecule of the Takemoto
catalyst or two were involved in the reaction, we performed
the addition of oxazolone 1a to vinylsulfone 2 in toluene at
room temperature with the Takemoto thiourea catalyst in
different enantiomeric purities. As illustrated in Figure 1, no
nonlinear effects were observed, which suggests that only
one molecule of the catalyst was involved in the transition
state.[29]
With these data to hand, we tentatively propose a transi-
tion state in which the tertiary amine deprotonates the oxa-
zolone while the thiourea moiety activates the vinylsulfone,
as shown in Scheme 5.[30]
Conclusion
In conclusion, we have reported a new, easy, and highly
Scheme 3. Derivatization of products 3. Bz: benzoyl; THF: tetrahydrofur-
an; TMS: trimethylsilyl.
enantioselective method for the synthesis of quaternary a-
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Asymmetric Synthesis of Quaternary a-Amino Acids
FULL PAPER
CDCl3): d=178.3, 166.9 (d, J=11.9 Hz), 164.4 (d, J=11.5 Hz), 163.6 (d,
J=12.3 Hz), 161.0 (d, J=12.7 Hz), 157.9 (d, J=6.5 Hz), 140.3, 137.5,
136.5, 134.7 (d, J=9.2 Hz), 132.5 (dd, J1 =2.3, J2 =10.4 Hz), 130.2, 129.8,
129.5, 128.9, 128.5, 112.2 (dd, J1 =3.8, J2 =21.9 Hz), 105.6 (t, J=25.1 Hz),
79.0, 72.3, 37.4, 29.2, 16.4, 16.2 ppm; HRMS (ESI): m/z calcd for
[2M+Na]+ (C52H46F4N2NaO12S4): 1117.1762; found: 1117.1756; HPLC
(Chiralpak IA, hexane/IPA=80:20, l=254 nm, 1 mLminÀ1): tR =11.3,
13.6 min (major); [a]D25 =À10.3 (c=1.1, CHCl3, 88% ee).
(4R)-4-(2,2-Bisphenylsulfonyl)ethyl)-2-(2-fluorophenyl)-4-isopropyloxa-
zol-5(4H)-one (3d): This was prepared according to the general proce-
dure from 4-isopropyl-2-(2-fluorophenyl)-oxazol-5(4H)-one (1d; 17 mg,
0.078 mmol, 1.5 equiv), 1,1-bis(phenylsulfonyl)ethylene (2; 16 mg,
0.052 mmol, 1 equiv), and catalyst I at room temperature: Colorless oil;
yield: 23 mg (82%); 1H NMR (300 MHz, CDCl3, TMSint): d=7.99–7.88
(m, 5H), 7.69–7.55 (m, 5H), 7.51–7.46 (m, 2H), 7.31–7.28 (m, 2H), 7.25–
7.22 (m, 2H), 5.08 (dd, J=7.9, J’=2.6 Hz, 1H), 2.90 (dd, J=16.4, J’=
2,6 Hz, 1H), 2.76 (dd, J=16.4, J’=7.9 Hz, 1H), 2.09 (h, J=6.7 Hz, 1H),
0.96 (d, J=6.7 Hz, 3H), 0.95 ppm (d, J=6.7 Hz, 3H); 19F NMR
(376 MHz, CDCl3): d=À108.0 ppm; 13C NMR (75 MHz, CDCl3, TMSint):
d=178.6, 161.4 (d, J=261.5 Hz), 158.6 (d, J=5.7 Hz), 136.1 (d, J=
90.1 Hz), 134.7 (d, J=4.6 Hz), 134.5 (d, J=8.8 Hz), 130.9, 130.2, 129.5,
129.2, 128.9, 124.5 (d, J=3.8 Hz), 117.1 (d, J=20.7 Hz), 78.9, 72.3, 37.4,
29.3, 16.4, 16.2 ppm; HRMS (ESI): m/z calcd for [2M+Na]+
(C52H48F2N2NaO12S4): 1081.1950; found: 1081.1935; HPLC (Chiralpak
IA, n-hexane/iPrOH=90:10, l=254 nm, 1.0 mLminÀ1): tR =11.6,
14.2 min; [a]2D5 =À9.6 (c=0.86, CHCl3, 92% ee).
alkyl-a-amino acids based on organocatalysis. The addition
of oxazolones to bis(phenylsulfonyl)ethylene (2) is efficient-
ly catalyzed by chiral bases or thioureas with complete C4
regioselectivity[26] and with good yields and enantioselectivi-
ties. Moreover, this methodology is complementary to previ-
ously reported enantioselective approaches to quaternary a-
amino acids and allows the synthesis of a-phenyl-a-alkyl-a-
amino acids and of a-tert-butyl-a-alkyl-a-amino acids.
Therefore, the procedure presented here has distinct advan-
tages in terms of operational simplicity, enviromentally
friendly conditions, and suitability for large-scale reactions
for practical industrial preparations.[31]
Experimental Section
General procedure for oxazolone addition to 1,1-bis(phenylsulfonyl)ethy-
lene (2): 1,1-Bis(phenylsulfonyl)ethylene (16 mg, 0.052 mmol, 1 equiv)
was added in one portion to a flask containing a solution of the oxazol-5-
one (0.078 mmol, 1.5 equiv) and the corresponding catalyst (0.0052 mmol,
0.1 equiv) at the desired temperature in toluene (0.5 mL). The reaction
mixture was stirred overnight at this temperature. The crude residue was
purified by column chromatography to afford compound 3.
(4S)-4-(2,2-Bis(phenylsulfonyl)ethyl)-2-(2-chlorophenyl)-4-isopropyloxa-
zol-5(4H)-one (3e): This was prepared according to the general proce-
dure from 4-isopropyl-2-(2-chlorophenyl)-oxazol-5(4H)-one (1e; 19 mg,
0.078 mmol, 1.5 equiv), 1,1-bis(phenylsulfonyl)ethylene (2; 16 mg,
0.052 mmol, 1 equiv), and catalyst I at room temperature: Colorless oil;
yield: 26 mg (93%); 1H NMR (300 MHz, CDCl3, TMSint): d=8.00–7.85
(m, 5H), 7.76–7.45 (m, 8H), 7.44–7.35 (m, 1H), 5.11 (dd, J1 =2.3, J2 =
8.2 Hz, 1H), 2.92 (dd, J1 =2.3, J2 =16.4 Hz, 1H), 2.76 (dd, J1 =8.2, J2 =
16.4 Hz, 1H), 2.15–2.02 (m, 1H), 0.97 (d, J=6.7 Hz, 3H), 0.96 ppm (d,
J=6.7 Hz); 13C NMR (100 MHz, CDCl3): d=178.7, 160.0, 140.3, 137.6,
136.5, 134.9, 134.7, 134.7, 133.9, 133.0, 131.7, 131.4, 130.3, 129.8, 129.4,
129.2, 128.9, 128.4, 127.0, 124.7, 79.1, 73.0, 37.5, 29.1, 16.4, 16.3 ppm;
HRMS (ESI): m/z calcd for [M+H]+ (C26H25ClNO6S2): 546.0806; found:
546.0795; HPLC (Chiralpak IA, hexane/iPrOH=90:10, l=254 nm,
1 mLminÀ1): tR =21.9, 25.4 min (major); [a]D25 =À5.6 (c=0.9, CHCl3, 84%
ee).
(4S)-4-(2,2-Bis(phenylsulfonyl)ethyl)-4-isopropyl-2-phenyloxazol-5(4H)-
one (3a): This was prepared according to the general procedure from 4-
isopropyl-2-phenyl-oxazol-5(4H)-one (1a; 16 mg, 0.078 mmol, 1.5 equiv),
1,1-bis(phenylsulfonyl)ethylene (2; 16 mg, 0.052 mmol, 1 equiv), and cata-
1
lyst IV at À408C: Colorless oil; yield: 22 mg (84%); H NMR (300 MHz,
CDCl3, tetramethylsilane as the internal standard (TMSint)): d=8.08–8.05
(m, 2H), 8.01–7.98 (m, 2H), 7.83–7.81 (m, 2H), 7.64–7.51 (m, 6H), 7.44–
7.39 (m, 2H), 5.05 (dd, J=8.2, J’=2.6 Hz, 1H), 2.89 (dd, J=16.4, J’=
2.3 Hz, 1H), 2.74 (dd, J=16.1, J’=7.9 Hz, 1H), 2.08 (h, J=6.7 Hz, 1H),
0.98 (d, J=6.7 Hz, 1H), 0.95 ppm (d, J=6.7 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=206.9, 162.0, 137.3, 136.9, 134.7, 134.6, 133.1, 130.0,
129.7, 129.1, 128.8, 128.2, 79.3, 72.3, 37.4, 30.9, 29.5, 16.4 ppm; HRMS
(ESI): m/z calcd for [M+H]+ (C26H26NO6S2): 512.1196; found: 512.1198;
HPLC
(Chiralpak
IA,
n-hexane/iPrOH=80:20,
l=254 nm,
1.0 mLminÀ1): tR =9.5, 12.4 min; [a]D25 =À11.2 (c=0.77, CHCl3, 93% ee).
(4S)-4-(2,2-Bis(phenylsulfonyl)ethyl)-2-(2,6-difluorophenyl)-4-isopropy-
loxazol-5(4H)-one (3b): This was prepared according to the general pro-
cedure from 4-isopropyl-2-(2,6-difluorophenyl)-oxazol-5(4H)-one (1b;
19 mg, 0.078 mmol,1.5 equiv), 1,1-bis(phenylsulfonyl)ethylene (2; 16 mg,
0.052 mmol, 1 equiv), and catalyst I at À208C: Colorless oil; yield: 28 mg
(4S)-4-(2,2-Bis(phenylsulfonyl)ethyl)-2,4-diphenyloxazol-5(4H)-one (3 f):
This was prepared according to the general procedure from 2,4-dipheny-
loxazol-5(4H)-one (1 f; 19 mg, 0.078 mmol, 1.5 equiv), 1,1-bis(phenylsul-
fonyl)ethylene (2; 16 mg, 0.052 mmol, 1 equiv), and catalyst I at À408C:
Colorless oil; yield: 20 mg (72%); 1H NMR (300 MHz, CDCl3): d=8.10
(d, J=7.3 Hz, 2H), 7.88–7.82 (m, 5H), 7.32–7.11 (m, 18H), 5.08 (dd, J=
6.4, J’=4.1 Hz, 1H), 3.16–3.14 ppm (m, 2H); 13C NMR (75 MHz,
CDCl3): d=177.3, 162.1, 138.8, 137.4, 137.1, 134.6, 133.3, 133.0, 129.9,
129.6, 129.2, 129.1, 129.1, 128.9, 128.9, 128.9, 128.8, 128.7, 128.3, 127.8,
125.3, 79.4, 70.5, 35.1 ppm; HRMS (ESI): m/z calcd for [M+H]+
(C29H24NO6S2): 546.1040; found: 546.1037; HPLC (Chiralpak IA, n-
hexane/iPrOH=80:20, l=254 nm, 1.0 mLminÀ1): tR =15.5, 18.7 min;
[a]2D5 =À12.3 (c=0.95, CHCl3, 80% ee).
(4S)-4-(2,2-Bis(phenylsulfonyl)ethyl)-2-tert-butyl-4-phenyloxazol-5(4H)-
one (3g): This was prepared according to the general procedure from 2-
tert-butyl-4-phenyloxazol-5(4H)-one (1g; 17 mg, 0.078 mmol, 1.5 equiv),
1,1-bis(phenylsulfonyl)ethylene (2; 16 mg, 0.052 mmol, 1 equiv), and cata-
lyst II at À408C: Colorless oil; yield: 22 mg (82%); 1H NMR (300 MHz,
CDCl3, TMSint): d=8.04–7.99 (m, 2H), 7.82–7.48 (m, 8H), 7.46–7.40 (m,
2H), 7.33–7.28 (m, 1H), 4.99–4.94 (m, 1H), 3.02–2.97 (m, 2H), 1.36 ppm
(s, 9H); 13C NMR (100 MHz, CDCl3): d=178.3, 172.3, 138.4, 137.7, 136.9,
134.5, 130.3, 129.4, 129.4, 129.1, 129.0, 128.9, 128.7, 125.2, 79.2, 69.8, 34.4,
29.7, 26.8 ppm; HRMS (ESI): m/z calcd for [2M+Na]+
(C54H54N2NaO12S4): 1073.2452; found: 1073.245; HPLC (Chiralpak IA,
hexane/IPA=80:20, l=254 nm, 1 mLminÀ1): tR =7.9, 9.7 min (major);
[a]2D5 =+10.3 (c=0.6, CHCl3, 82% ee).
1
(98%); H NMR (300 MHz, CDCl3, TMSint): d=8.01–7.93 (m, 4H), 7.73–
7.66 (m, 2H), 7.61–7.50 (m, 5H), 7.10–7.02 (m, 2H), 5.01 (dd, J1 =2.3,
J2 =7.9 Hz, 1H), 2.95 (dd, J1 =2.5, J2 =16.4 Hz, 1H), 2.76 (dd, J1 =7.8,
J2 =16.3 Hz, 1H), 2.15–2.03 (m, 1H), 0.97 ppm (t, J=7.0 Hz, 6H);
19F NMR (376 MHz, CDCl3): d=À107.6, À107.7 ppm; 13C NMR
(100 MHz, CDCl3): d=178.2, 162.5 (d, J=5.4 Hz), 159.9 (d, J=5.4 Hz),
155.5, 137.8, 136.1, 134.8, 134.6, 134.1, 134.0, 133.9, 130.6, 129.3, 129.2,
129.0, 112.3 (dd, J1 =3.1, J2 =21.9 Hz), 78.7, 72.3, 37.1, 28.9, 16.4,
16.1 ppm; HRMS (ESI): m/z calcd for [2M+K]+ (C52H46F4N2KO12S4):
1133.1501; found: 1133.1503; HPLC (Chiralpak IA, hexane/iPrOH=
90:10, l=254 nm, 1 mLminÀ1): tR =25.7 (major), 27.3 min; [a]2D5 =À12.7
(c=0.9, CHCl3, 92% ee).
(4S)-4-(2,2-Bis(phenylsulfonyl)ethyl)-2-(2,4-difluorophenyl)-4-isopropyl-
oxazol-5(4H)-one (3c): This was prepared according to the general pro-
cedure from 4-isopropyl-2-(2,4-difluorophenyl)-oxazol-5ACTHNUTRGNEUG(N 4H)-one (1c;
19 mg, 0.078 mmol,1.5 equiv), 1,1-bis(phenylsulfonyl)ethylene (2; 16 mg,
0.052 mmol, 1 equiv), and catalyst I at room temperature: Colorless oil;
yield: 22 mg (78%); 1H NMR (300 MHz, CDCl3, TMSint): d=7.99–7.89
(m, 5H), 7.74–7.48 (m, 6H), 7.06–6.96 (m, 2H), 5.05 (dd, J1 =2.6, J2 =
7.9 Hz, 1H), 2.89 (dd, J1 =2.6, J2 =16.4 Hz, 1H), 2.73 (dd, J1 =7.9, J2 =
16.4 Hz, 1H), 2.15–2.00 (m, 1H), 0.95 ppm (d, J=6.7 Hz, 6H); 19F NMR
(376 MHz, CDCl3): d=À100.9, À103.0 ppm; 13C NMR (100 MHz,
Chem. Eur. J. 2010, 16, 5354 – 5361
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5359

R. Rios, A. Moyano et al.
(4S)-4-(2,2-Bis(phenylsulfonyl)ethyl)-4-tert-butyl-2-phenyloxazol-5(4H)-
one (3h): This was prepared according to the general procedure from 4-
tert-butyl-2-phenyloxazol-5(4H)-one (1h; 17 mg, 0.078 mmol, 1.5 equiv),
1,1-bis(phenylsulfonyl)ethylene (2; 16 mg, 0.052 mmol, 1 equiv), and cata-
lyst I at 48C: Colorless oil; yield: 18 mg (66%); 1H NMR (300 MHz,
CDCl3, TMSint): d=8.08–7.98 (m, 4H), 7.79–7.76 (m, 2H), 7.71–7.52 (m,
7H), 7.41–7.36 (m, 2H), 5.03 (d, J=8.8 Hz, 1H), 2.99 (d, J=16.4 Hz,
1H), 2.68–2.59 (m, 1H), 0.98 ppm (s, 9H); 13C NMR (75 MHz, CDCl3,
TMSint): d=178.7, 162.1, 137.3, 137.2, 134.7, 134.5, 133.1, 129.9, 129.7,
129.2, 128.9, 128.8, 128.2, 125.7, 79.6, 73.9, 40.2, 28.0, 23.9 ppm; HRMS
(ESI): m/z calcd for [2M+Na]+ (C54H54N2NaO12S4): 1073.2452; found:
1073.2447; HPLC (Chiralpak IA, n-hexane/iPrOH=90:10, l=254 nm,
1.0 mLminÀ1): tR =7.8, 11.1 min; [a]D25 =À5.2 (c=0.9, CHCl3, 72% ee).
(4R)-4-(2,2-bis(phenylsulfonyl)ethyl)-4-methyl-2-phenyloxazol-5(4H)-one
(3i): This was prepared according to the general procedure from 4-
methyl-2-phenyloxazol-5(4H)-one (1i; 15 mg, 0.078 mmol, 1.5 equiv), 1,1-
bis(phenylsulfonyl)ethylene (2; 16 mg, 0.052 mmol, 1 equiv), and catalyst
IV at À408C: Colorless oil; yield: 18 mg (68%); 1H NMR (300 MHz,
CDCl3, TMSint): d=8.05–7.96 (m, 4H), 7.88–7.85 (m, 2H), 7.74–7.69 (m,
1H), 7.64–7.56 (m, 4H), 7.52–7.42 (m, 4H), 5.04 (dd, J1 =6.0, J2 =4.2 Hz,
1H), 2.81–2.77 (m, 2H), 1.51 ppm (s, 3H); 13C NMR (75 MHz, CDCl3,
TMSint): d=179.4, 161.5, 137.5, 136.8, 134.7, 134.7, 133.2, 130.0, 129.8,
129.1, 129.0, 128.8, 128.1, 125.5, 78.9, 66.2, 32.2, 25.8 ppm; HRMS (ESI):
m/z calcd for [M+H]+ (C24H22NO6S2): 484.0885; found: 484.0885; HPLC
(Chiralpack IA, hexane/iPrOH=80:20, l=254 nm, 1 mLminÀ1): tR =12.1,
15.0 min; [a]2D5 =À2.2 (c=0.9, CHCl3, 66% ee).
7.0 Hz, 3H), 1.03 ppm (d, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=171.8, 166.4, 137.9, 136.7, 134.7, 134.3, 133.4, 131.8, 129.7, 129.4, 129.0,
128.9, 127.0, 79.1, 63.9, 52.9, 32.7, 27.3, 18.4, 18.0 ppm; HRMS (ESI): m/z
calcd for [2M+Na]+ (C54H58N2NaO14S4): 1109.2663; found: 1109.2656;
[a]2D5 =+13.7 (c=1.4, CHCl3, 73% ee).
(4R)-4-(2,2-Bis(phenylsulfonyl)propyl)-4-isopropyl-2-phenyloxazol-
5(4H)-one (7a): A suspension of sodium hydride (60%) in mineral oil
(6 mg, 1.1 equiv) was added to a round-bottomed flask under an argon
atmosphere. Anhydrous THF and compound 3a (75 mg, 1 equiv) were
added at 08C. The temperature was raised to room temperature, and the
reaction mixture was stirred for 1 h. The reaction mixture was cooled to
08C and methyl iodide (0.03 mL, 3 equiv) was added. The reaction mix-
ture was stirred at room temperature overnight. The reaction was
quenched by addition of a saturated solution of NH4Cl. The aqueous
layer was extracted with dichloromethane, and the combined organic
layers were cleaned with an aqueous solution of NaOH (1m) and dried
over MgSO4. The solvent was evaporated. The crude residue was purified
by flash chromatography with mixtures of hexane and ethyl acetate as
1
the eluent, to obtain compound 7a in 48% yield: Colorless oil; H NMR
(400 MHz, CDCl3, TMSint): d=8.10–7.40 (m, 15H), 3.04 (d, J=15.6 Hz,
1H), 2.74 (d, J=15.6 Hz, 1H), 1.99 (h, J=6.7 Hz, 1H), 1.85 (s, 3H), 0.93
(d, J=6.7 Hz, 3H), 0.92 ppm (d, J=6.7 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=169.6, 154.9, 134.8, 134.6, 132.8, 131.5, 131.2, 129.4, 129.2,
128.9, 128.9, 128.8, 128.7, 128.6, 128.1, 127.3, 87.8, 73.5, 39.2, 35.2, 19.3,
16.6, 16.2 ppm; HRMS (ESI): m/z calcd for [2M+Na]+
(C54H54N2NaO12S4): 1073.2452; found: 1073.2442; [a]2D5 =À7.2 (c=0.6,
CHCl3, 73% ee).
(4R)-4-(2,2-Bis(phenylsulfonyl)ethyl)-2-(2,6-difluorophenyl)-4-methyloxa-
zol-5(4H)-one (3k): This was prepared according to the general proce-
dure from 4-methyl-2-(2,6-difluorophenyl)oxazol-5(4H)-one (1j; 17 mg,
0.078 mmol, 1.5 equiv), 1,1-bis(phenylsulfonyl)ethylene (2; 16 mg,
0.052 mmol, 1 equiv), and catalyst I at À408C: Colorless oil; yield: 26 mg
(4S)-2-Benzamido-2-methyl-4,4-bis(phenylsulfonyl)butanoic acid (5i): An
ordinary vial equipped with a magnetic stirring bar was charged with
compound 3i (400 mg, 1 equiv) and acetonitrile (5 mL). Concentrated
HCl (0.34 mL, 5 equiv) was then added in one portion. Stirring was main-
tained at room temperature until consumption of the starting materials
was complete. A solution of 1n NaOH was added until the pH value
reached 12. The aqueous layer was then washed three times with di-
chloromethane. Next, the pH value of the solution was adjusted to 1 with
concentrated HCl. The aqueous layer was extracted three times with di-
chloromethane. The combined organic layers were dried over MgSO4,
and the solvent was removed under reduced pressure. The pure product
was obtained without further purification (78% yield): Colorless oil;
1H NMR (300 MHz, [D6]DMSO): d=7.99 (s, 1H), 7.83 (m, 5H), 7.47 (m,
10H), 5.34 (m, 1H), 2.96 (dd, J1 =16.4, J2 =3.5 Hz, 1H), 2.73 (dd, J1 =
16.4, J2 =4.1 Hz, 1H), 1.17 ppm (s, 3H); 13C NMR (75 MHz, [D6]DMSO):
d=173.7, 166.5, 136.3, 134.1, 134.0, 130.7, 129.7, 129.1, 128.5, 128.3, 127.6,
127.1, 56.9, 28.8, 22.5 ppm; HRMS (ESI): m/z calcd for [M+H]+
(C24H24NO7S2): 502.0989; found: 502.0993.
1
(98%); H NMR (300 MHz, CDCl3, TMSint): d=8.01–7.95 (m, 4H), 7.75–
7.48 (m, 7H), 7.09–7.01 (m, 2H), 5.01 (dd, J1 =3.5, J2 =6.4 Hz, 1H), 2.86–
2.80 (m, 2H), 1.55 ppm (s, 3H); 19F NMR (376 MHz, CDCl3): d=À107.2,
À107.4 ppm; 13C NMR (100 MHz, CDCl3): d=178.6, 162.5 (d, J=
5.0 Hz), 159.9 (d, J=5.4 Hz), 155.2, 137.7, 136.3, 134.8, 134.7, 134.3,
134.2, 134.1, 130.4, 129.7, 129.5, 129.3, 129.2, 129.0, 112.4 (dd, J1 =3.4, J2 =
21.5 Hz), 78.7, 65.9, 31.7, 25.9 ppm; HRMS (ESI): m/z calcd for [2M+
Na]+ (C48H38F4N2NaO12S4): 1061.1136; found: 1061.1130; HPLC (Chiral-
pak IC, hexane/iPrOH=60:40, l=254 nm, 0.8 mLminÀ1): tR =47.8,
52.6 min (major); [a]D25 =À7.2 (c=0.9, CHCl3, 86% ee).
(4S)-4-(2,2-Bis(phenylsulfonyl)ethyl)-4-isobutyl-2-(2-fluorophenyl)oxazol-
5(4H)-one (3l): This was prepared according to the general procedure
from
4-isobutyl-2-(2-fluorophenyl)oxazol-5(4H)-one
1,1-bis(phenylsulfonyl)ethylene
(1k;
(2;
18 mg,
16 mg,
0.078 mmol,1.5 equiv),
(4R)-2-Benzamido-2-phenyl-4,4-bis(phenylsulfonyl)butanoic acid (5 f):
This was prepared by a similar procedure to that described above: Color-
less oil; 1H NMR (300 MHz, [D6]DMSO, TMSint): d=7.96 (s, 1H), 7.75–
7.20 (m, 20H), 5.25 (m, 1H), 2.92 ppm (m, 2H); 13C NMR (75 MHz,
[D6]DMSO, TMSint): d=177.3, 162.1, 138.8, 137.4, 137.1, 134.6, 133.3,
133.0, 129.9, 129.6, 129.2, 129.1, 129.1, 128.9, 128.9, 128.9, 128.8, 128.7,
128.3, 127.8, 125.3, 79.4, 70.5, 35.1 ppm; HRMS (ESI): m/z calcd for [M+
H]+ (C29H25NNaO7S2): 586.0965; found: 586.0972.
0.052 mmol, 1 equiv), and catalyst II at room temperature: Colorless oil;
yield: 21 mg (75%); 1H NMR (300 MHz, CDCl3, TMSint): d=8.05–7.88
(m, 5H), 7.76–7.47 (m, 7H), 7.32–7.20 (m, 3H), 5.10–5.03 (m, 1H), 2.80–
2.74 (m, 2H), 1.81 (dd, J1 =5.6, J2 =14.1 Hz, 1H), 1.70 (dd, J1 =6.4, J2 =
14.1 Hz, 1H), 1.55–1.45 (m, 1H), 0.85 (d, J=6.4 Hz, 3H), 0.83 ppm (d,
J=6.4 Hz, 3H); 19F NMR (376 MHz, CDCl3): d=À107.9, À108.0 ppm;
13C NMR (100 MHz, CDCl3): d=179.3, 161.4 (d, J=261.5 Hz), 158.0 (d,
J=6.1 Hz), 137.7, 136.8, 134.7, 134.7, 134.6, 130.9, 130.1, 129.8, 129.2,
129.0, 124.5 (d, J=3.8 Hz), 117.1 (d, J=21.1 Hz), 114.1 (d, J=10.0 Hz),
78.7, 69.7, 47.2, 32.2, 24.6, 24.1, 23.4 ppm; HRMS (ESI): m/z calcd for
[M+H]+ (C27H27FNO6S2): 544.1258; found: 544.1248; HPLC (Chiralpak
IA, hexane/iPrOH=80:20, l=254 nm, 0.9 mLminÀ1): tR =12.2, 13.1 min
(major); [a]2D5 =+6.5 (c=1.05, CHCl3, 83% ee).
(4R)-2-Benzamido-2-isopropyl-4,4-bis(phenylsulfonyl)butanoic acid (5a):
This was prepared by a similar procedure to that described above:
1H NMR (300 MHz, CDCl3, TMSint): d=7.96 (s, 1H), 7.74 (m, 5H), 7.43
(m, 10H), 5.18 (m, 1H), 2.92 (m, 2H), 2.11 (m, 1H), 0.95 ppm (d, J=
6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3, TMSint): d=173.5, 167.2, 137.4,
134.6, 133.05, 131.9, 129.6, 129.3, 128.9, 128.5, 127.0, 79.6, 64.0, 32.4, 18.0,
17.5 ppm; HRMS (ESI): m/z calcd for [M+H]+ (C26H28NO7S2): 530.1302;
found: 530.1300.
(4S)-Methyl 2-benzamido-2-isopropyl-4,4-bis(phenylsulfonyl)butanoate
(4a): An ordinary vial equipped with a magnetic stirring bar was charged
with MeOH (0.8 mL) and product 3a. TMSCl (0.05 mL) was then added
in one portion. Stirring was maintained at room temperature until con-
sumption of the starting materials was complete. The solvent was then
evaporated, and the product was purified by flash chromatography with
mixtures of hexane and ethyl acetate as the eluent, to obtain compound
4a in 52% yield: Colorless oil; 1H NMR (300 MHz, CDCl3, TMSint): d=
7.91–7.80 (m, 6H), 7.68–7.55 (m, 2H), 7.55–7.40 (m, 7H), 5.25–5.19 (m,
1H), 3.82 (s, 3H), 3.10–2.90 (m, 3H), 1.28–1.24 (m, 1H), 1.07 (d, J=
(4R)-2-Benzamido-2-methylbutanoic acid (6i):
A Schlenk apparatus
equipped with a magnetic stirring bar under a nitrogen atmosphere was
charged with previously activated magnessium (188 mg, 30 equiv). A so-
lution of product 5i in MeOH (2 mL) was added, and stirring was main-
tained at room temperature until consumption of the starting material
was complete. A solution of 1n NaOH was added until the pH reached
12. The aqueous layer was then washed three times with dichlorome-
5360
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Asymmetric Synthesis of Quaternary a-Amino Acids
FULL PAPER
thane. Next, the pH value of the solution was adjusted to 1 with concen-
trated HCl. The aqueous layer was extracted three times with dichloro-
methane. The combined organic layers were dried over MgSO4, and the
solvent was removed under reduced pressure. The pure product was ob-
tained without further purification (61% yield): Colorless oil; NMR:
matched with literature data;[28] HRMS (ESI): m/z calcd for [M+Na]+
(C12H15NO3Na): 244.0944; found: 244.0948; [a]2D5 =À5.1 (c=1.75, MeOH,
55% ee).
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Acknowledgements
We thank the Spanish Ministry of Science and Innovation (MICINN) for
financial support (Project AYA2009-13920-C02-02). A.-N.R.A. is also
grateful to the MICINN for a predoctoral fellowship.
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Received: November 2, 2009
Published online: March 5, 2010
Chem. Eur. J. 2010, 16, 5354 – 5361
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5361