Chiral 3,6-dihydro-2H-1,4-oxazin-2-ones as alanine equivalents for the asymmetric synthesis of α-methyl α-amino acids (AMAAs) under mild reaction conditions

Article abstract of DOI:10.1055/s-1999-3456

3,6-Dihydro-2H-1,4-oxazin-2-ones 1 act as very reactive chiral cyclic alanine equivalents and can be diastereoselectively alkylated or allylated using mild reaction conditions: potassium carbonate under phase-transfer catalysis (PTC) conditions when using activated alkyl halides, organic bases such as tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2- diazaphosphorine (BEMP) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) when using unactivated alkyl halides, and neutral Pd(0)-catalysis when allylic carbonates are used. In most cases, the diastereoselectivity under all these different reaction conditions is excellent although the reactions are always carried out at room temperature. Hydrolysis of the obtained alkylated or allylated oxazinones allows the preparation of enantiomerically enriched (S)- α-methyl α-amino acids (S)-AMAAs. The PTC and organic base methodologies have also been applied to the synthesis of (R)-α-methyl α-amino acids starting from (R)-alanine. When dihalides are used as electrophiles under PTC or BEMP conditions, a spontaneous N-alkylation also takes place giving bicyclic oxazinones, which can be hydrolyzed to enantiomerically pure cyclic (S)-AMAAs.

Full text of DOI:10.1055/s-1999-3456

704
FEATURE ARTICLE
Chiral 3,6-Dihydro-2H-1,4-oxazin-2-ones as Alanine Equivalents for the
Asymmetric Synthesis of a-Methyl a-Amino Acids (AMAAs) under Mild
Reaction Conditions
Rafael Chinchilla, Nuria Galindo, Carmen Nájera*
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
Fax +34(96)5903549; E-mail: cnajera@ua.es; chinchilla@ua.es
Received 10 October 1998
The most direct synthetic approach to scalemic AMAAs
Abstract: 3,6-Dihydro-2H-1,4-oxazin-2-ones 1 act as very reactive
is the diastereoselective a-alkylation of an enolate ob-
chiral cyclic alanine equivalents and can be diastereoselectively
alkylated or allylated using mild reaction conditions: potassium
carbonate under phase-transfer catalysis (PTC) conditions when
tained from an alanine equivalent. This has been achieved
by phase-transfer catalytic (PTC) alkylation of alanine-ar-
using activated alkyl halides, organic bases such as tert-butylimi- omatic aldehydes Schiff bases, using cinchoninium and
cinchonidinium salts as chiral catalysts (up to 50% ee)6a,b
no-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine
(BEMP) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) when using
unactivated alkyl halides, and neutral Pd(0)-catalysis when allylic
and promising method7 because of the experimental sim-
carbonates are used. In most cases, the diastereoselectivity under all
these different reaction conditions is excellent although the reac-
tions are always carried out at room temperature. Hydrolysis of the
obtained alkylated or allylated oxazinones allows the preparation of
enantiomerically enriched (S)-a-methyl a-amino acids (S)-
AMAAs. The PTC and organic base methodologies have also been
or TADDOL (up to 82% ee),6c which is a very attractive
plicity and the potential for scaleup. Also, several chiral
cyclic alanine-derived systems such as bis-lactim ethers,8a
imidazolidinones,8b oxazolidinones,8c oxazinones8d and
nickel complexes,8e together with acyclic chiral systems9
have been developed, some of them with impressive dias-
tereofacial enolate bias. However, when using these tem-
applied to the synthesis of (R)-a-methyl a-amino acids starting from
(R)-alanine. When dihalides are used as electrophiles under PTC or
plates the key alkylation step requires in most cases the
BEMP conditions, a spontaneous N-alkylation also takes place giv-
use of strong bases (BuLi, LDA, LHMDS, t-BuOK, etc.),
ing bicyclic oxazinones, which can be hydrolyzed to enantiomeri-
very anhydrous conditions, and low reaction temperatures
in order to achieve a high degree of asymmetric induction.
Such strict reaction conditions, together with a trouble-
some hydrolysis of a,a-dialkylated a-amino acid deriva-
tives,8b made the development of an economical
industrial process for the preparation of these amino acids
difficult. The development of new chiral alanine equiva-
lents able to asymmetrically induce the quaternary stereo-
genic carbon using simpler and milder reaction conditions
then seems desirable.
cally pure cyclic (S)-AMAAs.
Key words: amino acids, asymmetric synthesis, oxazinones, phase-
transfer catalysis, palladium catalysis
Introduction
The development of versatile and new methodologies for
the synthesis of natural and non-natural a-amino acids in
optically pure form is an important and challenging syn-
thetic endeavour for organic chemists nowadays due to
their central role in chemistry and biology.1 Among them,
a-alkyl- and especially a-methyl a-amino acids (AMAAs)
are valuable tools for restricting the conformational mo-
bility of a peptide backbone and promote particular struc-
tures in the de novo design of peptides and proteins.2
Moreover, they can make peptides resistant to degrada-
tion,3 an example being the a-methylphenylalanine ana-
logue of aspartame which was found to possess the same
sweetness and superior stability.3c Also, they are present
in natural antibiotics,4 and can act as enzyme inhibitors,5
possessing important therapeutic activity such as (S)-a-
methyl-DOPA (Aldomet) which is a very well-known
commercial antihypertensive.5b In spite of this array of in-
teresting features, there is a lack of commercially avail-
able enantiomerically pure a-methyl a-amino acids,
which is in part probably due to the nonexistence of a gen-
eral and economical large-scale synthesis for these com-
pounds.
In this context, we envisaged the usefulness of com-
pounds of the type 3,6-dihydro-2H-1,4-oxazin-2-ones,10
for instance as chiral alanine templates 110a,b by consider-
ing its structural features: a presumably highly acidic Ca-
hydrogen and then easy enolate formation due to the
strong stabilizing effect of the conjugated phenylimine
moiety, and a cyclic structure with a bulky substituent
able to block one of the diastereomeric faces of the formed
enolate. In addition, we have recently prepared the chiral
glycine equivalent 210c which condenses readily with al-
dehydes under mild PTC reaction conditions, proving the
high reactivity of these type of heterocycles.11
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FEATURE ARTICLE
Chiral Alanine Equivalents for the Asymmetric Synthesis of a-Methyl a-Amino Acids
705
diastereomers in a ca. 1/20 ratio. It seemed that C3 had a
certain tendency to epimerization, but as this carbon will
Results and Discussion
The desired oxazinone 1 was obtained according to a become part of the enolate after deprotonation, this con-
modification of the procedure described by Sunjic et al.,12 figurational instability is irrelevant. An analytical sample
which is outlined in Scheme 1. The starting material a- of the major isomer (3S,6R)-1 was obtained after chroma-
bromoisovalerophenone (3) was prepared by AlCl3-cata- tography/recrystallization and its configuration fully con-
lyzed bromination of the corresponding ketone following firmed by NOE experiments and X-ray diffraction
a standard method.13 Subsequent reaction of the potassi- analysis.14 In this way we had a system with an isopropyl
um salt of the N-Boc-protected (S)-alanine (4) with a-bro- group at the C6 stereogenic (R)-carbon which presumably
mo ketone 3, afforded a ca. 1/1 mixture of diastereomeric would create the appropriate diastereofacial bias for the
esters 5 which were separated by flash chromatography attack of an electrophile after the base-induced proton ab-
and crystallization into pure isomers (R,S)-5 and (S,S)-5 in straction on C3. Semiempirical calculations were carried
31% yield each. Isomer (R,S)-5 was then Boc-deprotected out on a model lithium enolate of (6R)-115 with an opti-
in acid conditions and cyclized after treatment with trieth- mized geometry showing the shielding effect of the iso-
ylamine to afford 3,6-dihydro-2H-1,4-oxazin-2-one (6R)- propyl group lying at C6 on the planar enolate (Figure).
1 in 70% yield after column chromatography through Flo-
risil. This purification was later overcome by considering
that the crude oxazinone was suitable for further use after
Obviously, if the cyclization reaction could be carried out
from the ester (S,S)-5, the final oxazinone would have a
stereogenic (S)-carbon at C6 and then we could get the op-
posite sense of induction at C3. In other words, it would
be possible to obtain both new configurations on C3 after
proton abstraction and alkylation with the corresponding
a simple filtration through a plug of Florisil (>90% pure
by GLC). Analysis of the final reaction crude by 1H NMR
(300 MHz) revealed the presence of a mixture of cis/trans
Biographical Sketches
Rafael Chinchilla was born of Professor C. Nájera at the
in Alicante in 1959. He University of Alicante
studied chemistry at the where he was appointed As-
University of Alicante sociate Professor in 1997.
where he also obtained his His current research interest
Ph.D. in 1990. After doing include sulfone chemistry,
postdoctoral research with asymmetric synthesis, ami-
Professor J.-E. Bäckvall at no acids and peptide cou-
the University of Uppsala, pling reagents.
Sweden, he joined the group
Nuria Galindo was born in
Madrid in 1972. She studied
chemistry at the University
of Alicante to earn B.Sc.
and M.Sc. degrees in 1995.
Currently she is carrying out
her Ph.D. studies within the
research group of Professor
C. Nájera in asymmetric
synthesis of amino acids.
Carmen Nájera was born E. Baldwin at the Dyson Her current research inter-
in Nájera (La Rioja), Spain, Perrins Laboratory (Ox- ests are focused on organo-
in 1951 and graduated in ford), Prof. E. J. Corey at metallic
chemistry,
chemistry from the Univer- Harvard University and sulfones, amino acids,
sity of Zaragoza in 1973. Prof. J.-E. Bäckvall at Upp- asymmetric synthesis and
She obtained her Ph.D. from sala University. She became peptide coupling reagents.
the University of Oviedo in Associate Professor in 1985
1979 and spent postdoctoral at the University of Oviedo
stays with Prof. D. Seebach and full Professor in 1993 at
at the ETH (Zürich), Prof. J. the University of Alicante.
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706
R. Chinchilla et al.
FEATURE ARTICLE
structure of the alanine-ketone Schiff base derivative
(6R)-1 allowed this PTC-induced alkylation, which previ-
ously only has been achieved in the case of alanine-alde-
hyde Schiff base derivatives.6 Oxazinones (6R)-6, such as
a precursor of (S)-a-methyl-DOPA (Table 1, entry 6),
were thus obtained generally with excellent diastereose-
lectivities even working at room temperature, proving the
effectiveness of the predicted blocking effect of the iso-
propyl group towards one face of the planar enolate. Un-
der these reaction conditions also an aldol reaction with
paraformaldehyde and a conjugate addition with methyl
acrylate took place, affording the corresponding oxazino-
nes (6R)-6g and (6R)-6h, respectively (Table 1, entries 7
and 8). Yields of isolated oxazinones 6 were in most cases
moderate due to partial decomposition observed during
the chromatographic purification. The proposed configu-
ration was confirmed by NOE experiments and, in the
case of (6R)-6b, also by X-ray diffraction analysis.14 In or-
der to check if the use of strong bases and low reaction
temperatures could improve yields or diastereoselectivi-
ties, oxazinone (6R)-1 was deprotonated with LDA at
-78ºC and alkylated with allyl iodide or benzyl bromide as
electrophiles, but compound (6R)-6a and 6b were ob-
tained with the same yield and de as when PTC conditions
were used.
Scheme 1
Figure. AM1-optimized geometry of a lithium enolate of (6R)-1
electrophile. Thus, it was possible to obtain supposed
(6S)-1 in a 1/2.5 cis/trans ratio following the same proce-
dure as with (6R)-1 but, surprisingly, isolation of a pure
analytical sample of the apparent enantiomer of (3S,6R)-
1
1, which showed identical H and 13C NMR spectra, re-
vealed a totally different and much lower optical rotation
absolute value for this compound. Moreover, this value
proved to be erratic when the cyclization was repeated,
showing the strong tendency towards racemization of this
isomer (3S,6S)-1 which blocked the possibility of its fur-
ther synthetic use.
Scheme 2
The ease of enolate formation on oxazinones 1 was dem-
onstrated when the ca. 1/20 cis/trans diastereomeric mix-
ture of (6R)-1 was diastereoselectively alkylated with
activated halides such as allyl, propargyl and benzyl ha-
lides as well as ethyl iodoacetate, under solid-liquid PTC
reaction conditions using potassium carbonate as base and
tetrabutylammonium bromide (TBAB) as phase-transfer
catalyst (Scheme 2, Table 1, entries 1–6). The cyclic
Although the highly diastereoselective alkylation of ox-
azinone (6R)-1 under such simple and mild reaction con-
ditions seemed promising due to the particularly attractive
use of PTC, when these methodologies were used with un-
activated electrophiles, such as ethyl or butyl iodide, the
reaction failed and only partial decomposition of the start-
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FEATURE ARTICLE
Chiral Alanine Equivalents for the Asymmetric Synthesis of a-Methyl a-Amino Acids
707
ing material was observed. Strong bases (LDA, LHMDS, to strong organic bases, particularly to Schwesinger’s16
t-BuOK and NaH) at low temperatures even in the pres- 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-
ence of co-solvents (HMPA, DMPU) were also attempt- 1,3,2-diazaphosphorine (BEMP), which has been recently
ed, but no alkylation was observed. We then pay attention used in the alkylation of the resin-bound benzophenone
Table 1 Diastereoselective Alkylation of (6R)–1 under PTC Conditions
Entry
Electrophile
R
t (h)a
Product 6,
% dec
% yieldb
1
2
3
4
CH2=CHCH2I
HC≡CCH2Br
PhCH2Br
CH2=CHCH2
HC≡CCH2
PhCH2
24
12
8
(6R)–6a, 62
(6R)–6b, 70
(6R)–6c, 75
92
>96
>96
12
12
(6R)–6d, 75
(6R)–6e, 68
90
84
5
6
7
8
EtO2CCH2I
(CH2O)n
EtO2CCH2
HOCH2
24
12
12
(6R)–6f, 60
(6R)–6g, 63
(6R)–6h, 60
90
60
90
CH2=CHCO2Me
MeO2CCH2CH2
a Monitored by GLC.
b Isolated yield for the pure major diastereomer after flash chromatography.
c Determined by 1H NMR (300 MHz) and/or GLC for the reaction crude.
Table 2 Diastereoselective Alkylation of Oxazinones (6R)-1 under Organic Base Conditions
Entry
RHal
Base, LiI (eq)
Solvent
t (h)a
C/O-Alkylation ratiob
Product (6R)–6,c
% yieldd
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
EtI
i-PrI
BuI
BuI
BuI
BuI
BuI
BuBr
BEMP, LiI (1.2)
BEMP, LiI (1.2)
BEMP
BEMP
BEMP
NMP
NMP
THF
1
1
12
1
1
1
1
1
1
1
1
1
1
25/1
24/1
5/3
(6R)–6i, 55
(6R)–6j, 48
(6R)–6k, 38
(6R)–6k, 56
(6R)–6k, 58
(6R)–6k, 64
(6R)–6k, 65
(6R)–6k, 38
(6R)–6l, 45
(6R)–6m, 52
(6R)–6n, 57e
(6R)–6a, 38
(6R)–6c, 44
(6R)–6i, 53
(6R)–6j, 46
(6R)–6j, 33
(6R)–6k, 53
(6R)–6l, 28
(6R)–6n, 52e
(6R)–6a, 37
(6R)–6c, 43
(6R)–6c, 45
DMF
MeCN
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
9/1
10/1
17/1
50/1
1/0
1/0
1/0
1/0
1/0
5/1
50/1
5/1
100/1
25/1
10/1
1/0
1/0
5/1
BEMP
BEMP, LiI (1.1)
BEMP, LiI (2)
BEMP, LiI (1.5)
BEMP, LiI (1.5)
BEMP
BEMP
BEMP
DBU
DBU
DBU, LiI (1.2)
DBU
DBU
DBU
DBU
i-BuI
Ph(CH2)2I
ClCH2I
CH2=CHCH2Cl
PhCH2Cl
EtI
i-PrI
i-PrI
BuI
i-BuI
ClCH2I
CH2=CHCH2Cl
PhCH2Cl
PhCH2Cl
1
1.75
1.25
1
2.5
1.25
1
DBU
DBU, LiI (1.2)
1
1
1/0
a Monitored by GLC.
b Determined by 1H NMR (300 MHz) and/or GLC.
c Diastereomeric ratio >98:2: 1H NMR (300 MHz) and/or GLC of the reaction crude.
d Isolated yield of the major diastereomer (6R)–6 after flash chromatography.
e Neutral silica gel was used.
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R. Chinchilla et al.
FEATURE ARTICLE
imine of glycine with unactivated alkyl halides,17 and also biochemically interesting free (S)-AMAAs (S)-a-meth-
to 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Thus, the ylphenylalanine (7c),3c (S)-a-methylaspartic acid (7f),2c,d
reaction of (6R)-1 with a series of unactivated alkyl io- (S)-a-methylserine (7g),2e (S)-a-methylglutamic acid
dides in the presence of BEMP or DBU and also at room (7h)2d and (S)-a-methylleucine (7l)2g in general with high
temperature afforded the alkylated oxazinones (6R)-7 ee, also confirming the proposed stereochemistry for the
with diastereoselectivities higher than 96% (1H NMR, 300 alkylated starting oxazinones (6R)-6. Attempts at recover-
MHz) in moderate yields and in shorter reaction times ing the chiral auxiliary, in the form of hydroxy ketone, af-
than when using PTC conditions (Scheme 2 and Table 2). ter the hydrolysis was unfruitful due to decomposition/
In all cases, the presence of a certain amount of the corre- racemization.
sponding O-alkylation product in the reaction crude was
detected. When the reaction was carried out with butyl io-
dide as electrophile and different solvents (Table 2, en-
tries 3–6), 1-methyl-2-pyrrolidinone (NMP) was more
appropriate due to improvement in the C/O-alkylation ra-
tio and isolated yield of the desired oxazinone (Table 2,
entry 6). A significant increment of the C/O-alkylation ra-
tio was observed if a certain amount of LiI was added to
the reaction mixture when using this alkyl iodide (from
Scheme 3
17/1 to 50/1, Table 2, entries 6 and 7). A strong hard-hard
coordination between the lithium cation and the enolate
It was then logical that both of these methodologies (PTC
and organic base conditions) could be applied to the syn-
thesis of the corresponding enantiomeric (R)-AMAAs.
The only change should be then the use of the potassium
salt of the Boc-protected (R)-alanine as starting material
in the procedure illustrated in Scheme 1. Oxazinones (6S)-
1 were thus obtained following this synthetic route again
as a ca. 1/20 cis/trans diastereomeric mixture, and also di-
astereoselectively alkylated under PTC reaction condi-
tions to afford alkylated oxazinones (6S)-6 which were
hydrolyzed as above to the corresponding enantiomeric
free (R)-AMAAs (Scheme 4 and Table 4, entries 1–3). In
oxygen could explain the improving of the C/O-alkylation
ratio.18 Thus, other alkyl iodides were used as alkylating
agents always in the presence of LiI (Table 2, entries 1, 2,
9 and 10). Moreover, the presence of 2 equiv of LiI even
allowed the use of an alkyl bromide as alkylating agent
(Table 2, entry 8). In general, higher yields of (6R)-6 were
obtained when using 1.1 equiv of BEMP as base than
when using DBU. In this last case, an excess of base (5
equiv) was always necessary and the addition of LiI also
showed improvements in the C/O-alkylation ratio (com-
pare entries 15 and 16, and entries 21 and 22). With some
electrophiles, and using both bases, only the C-alkylation
addition, (R)-a-ethylalanine (R)-7i (D-isovaline: D-Iva)19
product was detected even in the absence of LiI (entries
was prepared following the organic base methodology
11, 12, 19 and 20). These reaction conditions with organic
(BEMP) (Scheme 4 and Table 4, entry 4).
bases also allowed employing allyl and benzyl chlorides
as alkylating agents (Table 2, entries 12, 13, 20, 21 and
22), or even chloroiodomethane (Table 2, entries 11 and
19), whereas the reaction with all these electrophiles un-
der PTC conditions failed. Polymer-bound BEMP was
also attempted as base, but the reaction needed much
longer reaction times and was rather sluggish.
Representative oxazinones (6R)-6 were submitted to acid-
ic hydrolysis (Scheme 3 and Table 3). Thus, they were
treated with 6M hydrochloric acid at 150 ºC in a pressure
tube, and the resulting hydrochlorides were refluxed with
propylene oxide in ethanol allowing the isolation of the
Scheme 4
Table 3 Hydrolysis of Oxazinones (6R)–7. Synthesis of (S)-a-Methyl a-Amino Acids 7
Entry
R1
Substrate (6R)–6
R2
Product 7,
% eeb
% yielda
1
2
3
4
5
PhCH2
EtO2CCH2
HOCH2
MeO2C(CH2)2
i-Bu
(6R)–6c
(6R)–6f
(6R)–6g
(6R)–6h
(6R)–6l
PhCH2
(S)–7c, 80
(S)–7f, 78
(S)–7g, 75
(S)–7h, 70
(S)–7l, 72
98
92
58
90
99
HO2CCH2
HOCH2
HO2C(CH2)2
i-Bu
a
Referred to oxazinone (6R)–6.
b Determined by comparison with [a] values in the literature.
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Chiral Alanine Equivalents for the Asymmetric Synthesis of a-Methyl a-Amino Acids
709
When an activated dihalide such as o-dibromomethylben-
zene was used as alkylating agent of (6R)-1 following the
PTC procedure, the expected C-alkylation took place, but
interestingly also further N-alkylation and isomerization
of the iminic double bond, affording the tricylic system 8
in 80% isolated yield after flash chromatography (Scheme
5). Hydrolysis of this compound under the previously de-
scribed acid conditions afforded the cyclic (S)-AMAA 9
with ee>99%, deduced from its optical rotation sign and
value,20a thus confirming the supposed stereochemistry of
8 and the high asymmetric induction achieved in the C-
alkylation step, respectively. This interesting spontaneous
cyclization could allow the preparation of other cyclic
amino acids following a more simple and direct experi-
mental procedure than when using other chiral tem-
plates.20,21
Scheme 6
the bicyclic system 12 in 60% isolated yield, which was
now hydrolyzed under milder reaction conditions, thus
preventing a possible addition reaction of HCl to the dou-
ble bond when using more concentrated acid and higher
temperatures (Scheme 6). Thus, the enamine moiety in 12
was hydrolyzed with diluted acid and the ester function
with LiOH. Final treatment with a Dowex column al-
lowed the isolation of the new AMAA (S)-2-methyl-4-
methyleneproline (13) in 79% yield. Its final ee could not
be determined, but taking into account the ee obtained in
the synthesis of (S)-a-methylproline and the de obtained
in the alkylation reaction of (6R)-1 using an allyl halide
and BEMP (Table 2, entry 12), it seems reasonable to sup-
pose an ee higher than 96% for this new obtained AMAA.
The non-methylated analogue of 13, (S)-4-methylenepro-
line, is a potent proline dehydrogenase inhibitor.23 Sur-
Scheme 5
This cyclization reaction was also observed using an un-
activated dihalide such as 1,3-diiodopropane and using
BEMP as base in the presence of LiI and at room temper-
ature (Scheme 6). Under these reaction conditions bicy-
clic oxazinone 10 was obtained in 55% isolated yield, and
further acid hydrolysis yielded (S)-a-methylproline (11)
in ee>99%. If DBU was used as base, the necessary large
excess (5 equiv) produced competing dehydroiodination
before the N-alkylation step, affording variable amounts
of the allylic derivative (6R)-6a together with the desired
compound 10. The reaction was also carried out using 3-
iodo-2-iodomethylprop-1-ene22 as electrophile, affording
Table 4 Synthesis of (R)-a-Methyl a-Amino Acids from (6S)–1
Entry
Electrophile
R1
Product 6,
R2
Product 7,
% yielda (% de)b
% yieldc (% ee)d
1e
2e
3e
4f
PhCH2Br
ICH2CO2Et
CH2=CHCO2Me
EtI
CH2Ph
(6S)–6c, 75 (>96)
(6S)–6f, 65 (90)
(6S)–6h, 59 (90)
(6S)–6i, 60 (96)
CH2Ph
(R)–7c, 76 (98)
(R)–7f, 80 (93)
(R)–7h, 66 (92)
(R)–7i, 89 (97)
CH2CO2Et
CH2CH2CO2Me
Et
CH2CO2H
CH2CH2CO2H
Et
a Isolated yield of pure major diastereomer after flash chromatography.
b Determined by 1H NMR (300 MHz) and/or GLC on the reaction crude.
c Referred to oxazinone 6.
d Determined by comparison with [a] values in the literature.
e PTC Conditions.
f Organic base conditions (BEMP).
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R. Chinchilla et al.
FEATURE ARTICLE
prisingly, the use of 1,4-diiodobutane as dielectrophile flash chromatography. However, when LiI, which has re-
failed to allow the cyclization reaction. Also, attempts at cently been used to improve the regioselectivity of Pd(0)-
achieving a C-dialkylation reaction using activated or un- catalyzed allylation reactions,27 was added to the reaction
activated dihalides together with 2 equivalents of (6R)-1 mixture only the starting oxazinone was recovered. The
under different reaction conditions, as a possible route to reaction, although slower, could also be performed with in
bis-a-methyl a-amino acids, failed.
situ generation of the Pd(0) catalyst. Thus, reaction of
(6R)-1 with allyl ethyl carbonate in the presence of
Pd(OAc)2 (5 mol%) and PPh3 (10 mol%) for 12h afforded
(6R)-6a in 69% isolated yield (Table 5, entry 2).
We then realized the possibility that substrate (6R)-1
could be diastereoselectively allylated using allylic car-
bonates under mild neutral Pd(0) catalysis, taking into ac-
count that chemically similar O’Donnell’s benzophenone Hydrolysis of one of these allylated oxazinones (6R)-6a
imines of glycine and alanine ester derivatives have been was carried out using similar reaction conditions as with
previously allylated under these reaction conditions.24 bicyclic system 12 (see above), yielding (S)-a-allylala-
The final enantiomerically enriched analogs of allylgly- nine (7a) in 57% isolated yield and 93% ee (Scheme 7).
cine would be useful chirons for the synthesis of pharma-
cologically important molecules,25 as well as of natural
products.26 Following this methodology, oxazinones
(6R)-1 were smoothly allylated with different allylic car-
bonates in the presence of catalytic amounts of Pd(PPh3)4
(5 mol%) and 1,2-bis(diphenylphosphino)ethane (dppe)
(14 mol%) at room temperature with good diastereoselec-
tivities (Scheme 2 and Table 5). In some cases a certain
lack of regioselectivity was observed (Table 5, entries 4–
Scheme 7
7), although the major regioisomer was easily purified by
Table 5 Diastereoselective Allylation of (6R)–1 under Pd(0)-Catalysis
Entry
R'OCO2Et
t (h)
R
Product (6R)–6,
% deb
>96
% yielda
1
2
(6R)–6a, 60
(6R)–6a, 69
(6R)–6o, 65
2c
3
12
2
>96
>96
4
5
2
3
(6R)–6p, 53d
(6R)–6q, 65e
82
84
6
7
3
3
(6R)–6q, 60e
(6R)–6r, 56f
84
70
8
3
(6R)–6s, 53
88
a Isolated yield of the major regio- and diastereoisomer after flash chromatography.
b Determined by 1H NMR (300 MHz) and/or GLC on the reaction crude.
c A mixture of Pd(OAc)2 (5 mol%) and PPh3 (10 mol%) was used as catalyst.
d 28% of the other regioisomer was also detected (1H NMR).
e 13% of the other regioisomer was also detected (1H NMR).
f 21% of the other regioisomer was also detected (1H NMR).
Synthesis 1999, No. 4, 704–717 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Conclusion
Chiral Alanine Equivalents for the Asymmetric Synthesis of a-Methyl a-Amino Acids
711
were separated by flash chromatography (silica gel, hex-
aneÆhexane/EtOAc 8/2) and crystallization (hexane/EtOAc) af-
fording 3.75 g (31%) of each pure diastereomer. The pure (R,S)- or
(S,R)-5 isomers also can be isolated in 27% yield directly by crys-
tallization (hexane/EtOAc) from the reaction crude.
As a summary, we have shown the potential interest of ox-
azinones 1 as chiral alanine equivalents, which can be
used for the asymmetric synthesis of interesting enantio-
merically enriched acyclic and cyclic (S)- and (R)-
AMAAs. The most remarkable characteristic of these sys-
tems is their ability to achieve a high degree of asymmet-
ric induction working under very simple and mild reaction
conditions and always at room temperature. In this way,
PTC or organic bases, and also neutral Pd(0)-catalysis
conditions have been used for alkylation or allylation re-
actions, in most cases with excellent diastereoselectivi-
ties. These experimental procedures are easy to scale up,
a reason that could make these heterocycles promising
starting materials for the industrial preparation of nowa-
days important AMAAs.
(1R)- and (1S)-1-Benzoyl-2-methylpropyl (2S)- and (2R)-2-(tert-
Butoxycarbonylamino) propanoate ((R,S)-5 and (S,R)-5)
White needles; mp 129ºC (hexane/EtOAc); TLC: Rf 0.51 (hexane/
EtOAc = 7/3).
(R,S)-Isomer: [a]D24 -52.9 (c = 1.2; CH2Cl2); (S,R)-isomer: [a]D
+55.1 (c = 1.2; CH2Cl2).
25
IR (KBr): n = 1686, 1737, 3376 cm–1.
1H NMR (CDCl3): d = 0.93 (d, 3 H, J = 6.7 Hz), 1.05 (d, 3 H, J =
7.0 Hz), 1.45 (s, 9 H) 1.46 (d, 3 H, J = 7.3 Hz), 2.33 (m, 1 H), 4.46
(t, 1 H, J = 7.3 Hz), 5.11 (d, 1 H, J = 6.4 Hz), 5.77 (d, 1 H, J = 4.5
Hz), 7.48 (m, 2 H), 7.60 (m, 1 H), 7.93 (m, 2 H).
13C NMR (CDCl3): d = 16.7, 18.6, 19.5, 28.3, 30.2, 49.4, 79.7, 79.9,
128.3, 128.8, 133.5, 135.3, 155.0, 172.8, 196.0.
MS: m/z (%) = 233 (M+–NHBoc, 0.5), 105 (100), 77 (25), 59 (22),
57 (38), 56 (23), 44 (80), 41 (63).
Melting points are uncorrected. IR were recorded on a Nicolet 510
P-FT and only the structurally most important peaks are listed.
NMR spectra were determined on a Bruker AC-300 at 300 MHz for
1H and 75 MHz for 13C using CDCl3 as solvent and TMS as internal
standard unless otherwise stated. Optical rotations were measured
on a Jasco DIP-1000 polarimeter. GLC analyses were performed on
a HP-5890 instrument (HP-1, 12 m x 0.22 mm column) equipped
with a flame ionization detector, using nitrogen as the carrier gas
(1.5 mL/min); Tcolumn=60ºC (3 min) and 15ºC/min. Low resolution
electron impact (EI) mass spectra were obtained at 70 eV on a Shi-
madzu QP-5000. HRMS (EI) were recorded on VG-Micromass
ZAB-ZF, Kratos MS 80 RFA, and Finnigan MAT 95 S. Microanal-
yses were performed by the Microanalyses Service of the Universi-
ty of Alicante. Analytical TLC was performed on Schleicher &
Schuell F1400/LS silica gel plates and the spots visualized with UV
light at 254 nm. Flash chromatography employed Merck silica gel
60 (0.040–0.063 mm).
Anal. Calcd for C19H25NO7: C 65.31, H 7.79, N 4.01. Found: C
65.38, H 7.92, N 4.00.
(1S)- and (1R)-1-Benzoyl-2-methylpropyl (2S)- and (2R)-2-(tert-
Butoxycarbonylamino) propanoate ((S,S)-5 and (R,R)-5)
White crystals; mp 99ºC (hexane/EtOAc); TLC: R 0.55 (hexane/
f
EtOAc: 7/3); [a]D29 -0.3 (c = 2; CH Cl ).
2
2
IR (KBr): n = 1698, 1749, 3377 cm–1.
1H NMR (CDCl3): d = 0.92 (d, 3 H, J = 7.0), 1.07 (d, 3 H, J = 6.7),
1.44 (s, 9 H), 1.46 (d, 3 H, J = 7.3), 2.32 (m, 1 H), 4.47 (q, 1 H, J =
7.6), 5.04 (d, 1 H, J = 7.0), 7.47 (m, 2 H), 7.58 (m, 1 H), 7.92 (m, 2
H).
13C NMR (CDCl3): d = 16.6, 18.6, 19.5, 28.3, 30.8, 48.9, 79.7, 79.9,
128.2, 128.7, 133.5, 135.3, 155.1, 173.2, 196.0.
MS: m/z (%) = 233 (M+–NHBoc, 0.7), 105 (100), 77 (30), 57 (32),
44 (85), 41 (44).
a-Bromoisovalerophenone (3)
To a solution of isovalerophenone (8.4 mL, 50 mmol) and AlCl3
(133 mg, 1 mmol) in Et2O (40 mL) was added Br2 (2.57 mL, 50
mmol) dropwise at r.t. The resulting mixture was refluxed for 4 h
and filtered through a pad of silica gel (hexane/EtOAc: 1/1) yield-
ing, after evaporation (15 Torr), compound 3 (11.8 g, 98%) as a
Oxazinones (6R)- and (6S)-1
The ester (R,S)-5 or (S,R)-5 (3.49 g, 10 mmol) was dissolved in sat.
HCl(g) in EtOAc (30 mL) and the mixture was stirred for 1 h at r.t.
The solvent was removed (15 Torr) and the obtained solid hydro-
chloride was suspended in CH2Cl2 (20 mL). Et3N (2.79 mL, 20
mmol) was added and the resulting mixture was stirred for 1 h at r.t.
and filtered through a pad of Florisil (EtOAc) affording oxazinones
(6R)- or (6S)-1 (2.2 g) as ca. 1/20 cis/trans mixtures which were
>90% pure by GLC (82% based on this purity) and used without
further purification. Analytical samples of (3S,6R)- and (3R,6S)-1
were obtained after further column chromatography on Florisil
(hexane/EtOAc gradients) and recrystallization in hexane/EtOAc.
white solid; mp 53ºC (hexane/EtOAc); TLC: R 0.62 (hexane/
f
EtOAc = 4/1).
IR (KBr): n = 1686 cm–1.
1H NMR (CDCl3):28 d = 1.02 (d, 3 H, J = 6.7 Hz), 1.21 (d, 3 H, J =
6.7 Hz), 2.49 (m, 1 H), 4.96 (d, 1 H, J = 8.5 Hz), 7.47 (m, 2 H), 7.50
(m, 1 H), 7.99 (m, 2 H).
13C NMR (CDCl3): d = 20.3, 20.6, 31.0, 55.8, 128.6, 128.7, 133.5,
134.9, 193.5.
(3S,6R)- and (3R,6S)-6-Isopropyl-3-methyl-5-phenyl-3,6-dihy-
dro-2H-1,4-oxazin-2-one ((3S,6R)-1 and (3R,6S)-1)
White solid; mp 100 ºC (hexane/EtOAc); TLC: Rf 0.56 (hexane/
MS: m/z (%) = 198 (M+–Pri, 2), 161 (22), 106 (24), 105 (100), 77
(54), 51 (38), 41 (26).
25
EtOAc = 7/3); (3S,6R)-isomer: [a]D -201.4 (c = 1; CH2Cl2);
(3R,6S)-isomer: [a]D25 +208.4 (c = 1; CH2Cl2).
IR (KBr): n = 1633, 1744 cm–1.
Esters 5
To a mixture of (S)- or (R)-N-Boc-alanine (6.65 g, 35 mmol) in
MeOH (35 mL) was added 1M KOH in MeOH (35 mL). The sol-
vent was evaporated (15 Torr) and the residue was dissolved in
DMF (70 mL). To this solution was added a-bromoisovalerophe-
none 3 (8.44 g, 35 mmol) and the resulting mixture was stirred for
24 h at r.t. The mixture was diluted with EtOAc (90 mL) and
washed with H2O (4 x 50 mL). Evaporation of the solvent (15 Torr)
yielded a ca. 1/1 diastereomeric mixture of esters (1H NMR) which
1H NMR (CDCl3): d = 0.94 (d, 3 H, J = 6.7 Hz), 1.04 (d, 3 H, J =
7.0 Hz), 1.74 (d, 3 H, J = 7.2 Hz), 2.22 (m, 1 H), 4.28 (m, 1 H), 5.47
(m, 1 H), 7.42 (m, 3 H), 7.71 (m, 2 H).
13C NMR (CDCl3): d = 16.9, 19.3, 19.8, 32.5, 54.3, 84.4, 126.7,
128.8, 130.9, 135.8, 165.1, 170.5.
MS: m/z (%) = 231 (M+, 4), 172 (32), 131 (61), 104 (48), 56 (100).
Synthesis 1999, No. 4, 704–717 ISSN 0039-7881 © Thieme Stuttgart · New York

712
R. Chinchilla et al.
FEATURE ARTICLE
Anal. Calcd for C14H17NO2: C 72.70, H 7.41, N 6.06. Found: C
72.70, H 7.42, N, 6.12.
(3S,6R)-3-(3,4-Dimethoxybenzyl)-6-isopropyl-3-methyl-5-phe-
nyl-3,6-dihydro-2H-1,4-oxazin-2-one [(6R)-6d]
Colorless oil; TLC: Rf 0.29 (hexane/EtOAc = 7/3); [a]D25 +140.5
(c = 1.82; CH2Cl2).
Alkylation of Oxazinone 1 under Solid–Liquid PTC Condi-
tions; General Procedure
IR (film): n = 1660, 1739 cm–1.
A heterogeneous mixture of crude (6R)-1 or (6S)-1 (257 mg of
crude of ca. 90% purity, equivalent to 231 mg of pure compound, 1
mmol), tetrabutylammonium bromide (TBAB, 33 mg, 0.1 mmol),
K2CO3 (400 mg, 3 mmol), and the corresponding electrophile (1.5
mmol) in MeCN (3 mL) was stirred at r.t. until total consumption of
the starting material (GLC). The resulting mixture was filtered
through a pad of silica gel, the solvent was evaporated (15 Torr) and
the crude was analyzed by 1H NMR and/or GLC for the determina-
tion of the de. Purification by flash chromatography (silica gel, hex-
ane/EtOAc gradients) afforded pure major diastereoisomers (6R)-6
or (6S)-6 (see Tables 1 and 4) or compound 8.
1H NMR (CDCl3): d = 0.67 (d, 3 H, J = 6.9 Hz), 0.96 (d, 3 H, J =
6.9 Hz), 1.78 (s, 3H), 1.90 (dsept, 1 H, J = 6.9, 2.1 Hz), 3.01 (d, 1
H, J = 13.1 Hz), 3.31 (d, 1 H, J = 13.1 Hz), 3.43 (s, 3 H), 3.85 (s, 3
H), 4.56 (d, 1 H, J = 2.1 Hz), 6.46 (d, 1 H, J = 1.8 Hz), 6.64 (dd, 1
H, J = 8.2, 1.8 Hz), 6.74 (d, 1 H, J = 8.2 Hz), 7.43 (m, 5 H).
13C NMR (CDCl3): d = 14.5, 18.7, 27.4, 31.2, 47.9, 55.1, 55.6, 62.8,
83.8, 110.6, 113.5, 122.2, 126.2, 128.2, 128.5, 130.1, 136.6, 147.7,
147.8, 162.8, 170.4.
MS: m/z (%) = 381 (M+, 2), 151 (100).
HRMS for C15H18NO4 calcd 381.1940, found 381.1929.
(3S,6R)-3-Allyl-6-isopropyl-3-methyl-5-phenyl-3,6-dihydro-
2H-1,4-oxazin-2-one [(6R)-6a]
Methyl (E)-4-[(3S,6R)-6-Isopropyl-3-methyl-2-oxo-5-phenyl-
3,6-dihydro-2H-1,4-oxazin-3-yl]but-2-enoate [(6R)-6e]
Colorless oil; TLC: Rf 0.54 (hexane/EtOAc = 7/3); [a]D24 +56.4 (c =
1.5; CH2Cl2).
Colorless oil; TLC: Rf 0.68 (hexane/EtOAc = 7/3); [a]D23 +63.5 (c
= 1.3; CH2Cl2).
IR (film): n = 1659, 1741 cm–1.
IR (film): n = 1659, 1727 cm–1.
1H NMR (CDCl3): d = 0.77 (d, 3 H, J = 6.9 Hz), 1.11 (d, 3 H, J =
6.9 Hz), 1.65 (s, 3H), 2.09 (dsept, 1 H, J = 6.9, 2.4 Hz), 2.59 (dd, 1
H, J = 13.3, 6.7 Hz), 2.79 (dd, 1 H, J = 13.3, 7.9 Hz), 5.10 (m, 2 H),
5.48 (d, 1 H, J = 2.4 Hz), 5.62 (m, 1 H), 7.44 (m, 3 H), 7.58 (m, 2 H).
13C NMR (CDCl3): d = 15.1, 19.0, 27.4, 31.8, 46.7, 61.2, 84.5,
119.9, 126.6, 128.7, 130.4, 132.3, 136.4, 162.3, 170.9.
1H NMR (CDCl3): d = 0.79 (d, 3 H, J = 6.9 Hz), 1.10 (d, 3 H, J =
6.9 Hz), 1.66 (s, 3 H), 2.10 (dsept, 1 H, J = 6.9, 2.9 Hz), 2.76 (ddd,
1 H, J = 13.6, 7.3, 1.5 Hz), 2.92 (ddd, 1 H, J = 13.6, 7.9, 1.2 Hz),
3.70 (s, 3H), 5.50 (d, 1 H, J = 2.9 Hz), 5.88 (d, 1 H, J = 15.6 Hz),
6.77 (m, 1 H), 7.44 (m, 3 H), 7.60 (m, 2 H).
13C NMR (CDCl3): d = 15.4, 19.0, 27.6, 32.0, 44.8, 54.4, 60.6, 84.7,
125.1, 126.7, 128.7, 130.6, 136.0, 142.5, 162.9, 166.4, 170.5.
MS: m/z (%) = 271 (M+, 24), 230 (42), 157 (79), 145 (57), 91 (46),
43 (52), 41 (100).
MS: m/z (%) = 329 (M+, 4), 270 (43), 230 (65), 186 (44), 145 (73),
43 (100).
HRMS for C17H21NO2 calcd 271.1572, found 271.1569.
(3S,6R)-6-Isopropyl-3-methyl-5-phenyl-3-propargyl-3,6-dihy-
dro-2H-1,4-oxazin-2-one [(6R)-6b]
HRMS for C19H23NO4 calcd 329.1627, found: 329.1621.
Ethyl 2-[(3S,6R)- and (3R,6S)-6-Isopropyl-3-methyl-2-oxo-5-
phenyl-3,6-dihydro-2H-1,4-oxazin-3-yl]acetate [(6R)-6f and
(6S)-6f]
Colorless oil; TLC: Rf 0.57 (hexane/EtOAc = 7/3); (3S,6R)-isomer:
[a]D30 +73.8 (c = 1.6; CH2Cl2), (3R,6S)-isomer: [a]D25 -69.8 (c = 1.6;
CH2Cl2).
White crystals; mp 132 ºC (hexane/EtOAc); TLC: Rf 0.56 (hexane/
EtOAc = 7/3); [a]D30 +93.4 (c = 1.1; CH2Cl2).
IR (KBr): n = 1662, 1741, 3292 cm–1.
1H NMR (CDCl3): d = 0.78 (d, 3 H, J = 6.9 Hz), 1.14 (d, 3 H, J =
6.9 Hz), 1.66 (s, 3 H), 2.00 (t, 1 H, J = 2.4 Hz), 2.11 (dsept, 1 H, J
= 6.9, 2.6 Hz), 2.70 (dd, 1 H, J = 16.4, 2.7 Hz), 2.97 (dd, 1 H, J =
16.4, 2.7 Hz), 5.6 (d, 1 H, J = 2.6 Hz), 7.43 (m, 3 H), 7.61 (m, 2 H).
13C NMR (CDCl3): d = 15.1, 19.0, 27.0, 31.8, 33.0, 60.5, 71.4, 79.5,
84.8, 126.7, 128.7, 130.5, 136.3, 163.4, 170.1.
IR (film): n = 1663, 1739 cm–1.
1H NMR (CDCl3): d = 0.81 (d, 3 H, J = 6.9 Hz), 1.16 (m, 6 H), 1.62
(s, 3 H), 2.12 (dsept, 1 H, J = 6.9, 2.4 Hz), 2.88 (d, 1 H, J = 17.1 Hz),
3.31 (d, 1 H, J=17.1Hz), 4.00 (m, 2 H), 5.66 (d, 1 H, J = 2.4 Hz),
7.41 (m, 3 H), 7.55 (m, 2 H).
MS: m/z (%) = 269 (M+, 29), 268 (49), 230 (100), 182 (77), 128
(78), 77 (55), 43 (95).
13C NMR (CDCl3): d = 14.0, 15.2, 19.0, 27.8, 31.3, 46.1, 57.8, 60.7,
Anal. Calcd for C17H19NO2: C 75.81, H 7.11, N 5.20. Found: C
75.45, H 7.08, N 5.04.
84.8, 126.6, 128.7, 130.2, 136.8, 163.8, 170.8, 171.1.
MS: m/z (%) = 317 (M+, 15), 258 (46), 202 (88), 144 (52), 104
(3S,6R)- and (3R,6S)-3-Benzyl-6-isopropyl-3-methyl-5-phenyl-
3,6-dihydro-2H-1,4-oxazin-2-one [(6R)-6c and (6S)-6c]
Colorless oil; TLC: Rf 0.58 (hexane/EtOAc = 7/3); (3S,6R)-isomer:
[a]D25 +153.4 (c = 1.8; CH2Cl2), (3R,6S)-isomer: [a]D25 -153.5 (c =
2; CH2Cl2).
(100), 43 (64).
HRMS for C18H23NO4 calcd 317.2627, found: 317.2627.
(3S,6R)-3-Hydroxymethyl-6-isopropyl-3-methyl-5-phenyl-3,6-
dihydro-2H-1,4-oxazin-2-one [(6R)-6g]
Colorless oil; TLC: Rf 0.47 (hexane/EtOAc = 1/1); [a]D26 -13.1 (c =
1.2; CH2Cl2).
IR (film): n = 1660, 1739 cm–1.
1H NMR (CDCl3): d = 0.64 (d, 3 H, J = 6.9 Hz), 0.92 (d, 3 H, J =
6.9 Hz), 1.78 (s, 3 H), 1.83 (dsept, 1 H, J = 6.9, 2.4 Hz), 3.07 (d, 1
H, J = 12.8 Hz), 3.35 (d, 1 H, J = 12.8 Hz), 4.38 (d, 1 H, J = 2.4 Hz),
7.0 (m, 2 H), 7.2 (m, 3 H), 7.4 (m, 5 H).
13C NMR (CDCl3): d = 14.5, 18.8, 27.7, 31.2, 48.4, 62.8, 84.0,
126.3, 127.0, 128.0, 128.6, 130.0, 130.6, 135.8, 136.9, 163.4, 170.7.
IR (film): n = 1662, 1739, 3418 cm–1.
1H NMR (CDCl3): d = 0.81 (d, 3 H, J = 6.9 Hz), 1.11 (d, 3 H, J =
6.9 Hz), 1.55 (s, 3 H), 2.11 (dsept, 1 H, J = 6.9, 3.0 Hz), 2.39 (br s,
1 H), 3.76 (d, 1 H, J = 10.6 Hz), 3.98 (d, 1 H, J = 10.6 Hz), 5.57 (d,
1 H, J = 3.0 Hz), 7.45 (m, 3 H), 7.62 (m, 2 H).
13C NMR (CDCl3): d = 15.6, 19.1, 23.2, 32.1, 62.1, 70.6, 84.5,
126.8, 128.8, 130.8, 136.2, 164.6, 170.9.
MS: m/z (%) = 321 (M+, 11), 145 (71), 105 (40), 91 (100), 43 (47).
HRMS for C21H23NO calcd 321.1729, found: 321.1729.
Synthesis 1999, No. 4, 704–717 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Chiral Alanine Equivalents for the Asymmetric Synthesis of a-Methyl a-Amino Acids
713
MS: m/z (%) = 261 (M+, 8), 231 (54), 230 (70), 202 (69), 186 (96),
160 (72), 105 (66), 104 (67), 91 (53), 86 (62), 77 (65), 43 (100), 42
(58).
MS: m/z (%) = 259 (M+, 2), 200 (84), 104 (100).
HRMS for C16H21NO2 calcd 259.1572, found 259.1577.
(3S,6R)-3,6-Diisopropyl-3-methyl-5-phenyl-3,6-dihydro-2H-
1,4-oxazin-2-one [(6R)-6j]
HRMS for C15H19NO3 calcd 261.1365, found 261.1363.
Methyl 3-[(3S,6R)- and (3R,6S)-6-Isopropyl-3-methyl-2-oxo-5-
phenyl-3,6-dihydro-2H-1,4-oxazin-3-yl]propanoate [(6R)-6h
and (6S)-6h]
Colorless oil; TLC: Rf 0.47 (hexane/EtOAc = 7/3); (3S,6R)-isomer:
[a]D26 +12.5 (c = 1.5; CH2Cl2), (3R,6S)-isomer: [a]D25 -10.9 (c = 1.5;
CH2Cl2)
IR (film): n = 1658, 1739 cm–1.
1H NMR (CDCl3): d = 0.80 (d, 3 H, J = 7.0 Hz), 1.12 (d, 3 H, J =
7.0 Hz), 1.63 (s, 3 H), 2.07–2.48 (m, 5 H), 3.46 (s, 3 H), 5.56 (d, 1
H, J = 3.1 Hz), 7.45 (m, 3 H), 7.62 (m, 2 H).
13C NMR (CDCl3): d = 15.5, 19.1, 27.7, 29.8, 32.0, 37.5, 51.5, 59.8,
84.6, 126.7, 128.7, 130.6, 136.1, 162.7, 171.1, 173.0.
MS: m/z (%) = 317 (M+, 7), 258 (80), 202 (62), 144 (52), 115 (47),
104 (100), 55 (79), 43 (88), 42 (43).
Colorless oil; TLC: Rf 0.61 (hexane/EtOAc = 7/3); [a]D25 +42.8
(c = 2; CH2Cl2).
IR (film): n = 1660, 1736 cm–1
1H NMR (CDCl3): d = 0.77 (d, 3 H, J = 6.9 Hz), 0.88 (d, 3 H, J =
6.7 Hz), 1.00 (d, 3 H, J = 6.7 Hz), 1.13 (d, 3 H, J = 6.9 Hz), 1.58 (s,
3 H), 2.13 (dsept, 1 H, J = 6.9, 2.6 Hz), 2.28 (sept, 1 H, J = 6.7 Hz),
5.50 (d, 1 H, J = 2.6 Hz), 7.44 (m, 3 H), 7.63 (m, 2 H).
13C NMR (CDCl3): d = 15.2, 16.0, 18.0, 19.1, 25.5, 31.9, 38.7, 63.0,
84.2, 126.6, 128.6, 130.3, 136.5, 161.4, 171.7.
MS: m/z (%) = 273 (M+, 1), 214 (47), 104 (48), 71 (46), 55 (61), 43
(94), 41 (100).
HRMS for C17H23NO2 calcd 273.1729, found 273.1726.
(3S,6R)-3-Butyl-6-isopropyl-3-methyl-5-phenyl-3,6-dihydro-
2H-1,4-oxazin-2-one [(6R)-6k]
HRMS for C18H23NO4 calcd 317.1627, found: 317.1638.
Colorless oil; TLC: Rf 0.67 (hexane/EtOAc = 7/3); [a]D25 +28.5
(c = 1.1; CH2Cl2).
(11aS)-3-Isopropyl-11a-methyl-4-phenyl-1,6-dihydro[1,4]ox-
azino[4,3-b]isoquinolin-1-one (8)
IR (film): n = 1659, 1739 cm–1.
White solid; yield: 80%; mp 101ºC (hexane/EtOAc); TLC: Rf 0.73
1H NMR (CDCl3): d = 0.78 (d, 3 H, J = 7.0 Hz), 0.83 (t, 3 H, J = 7.2
Hz), 1.12 (d, 3 H, J = 7.0 Hz), 1.12 (m, 2 H), 1.25 (m, 2 H), 1.62 (s,
3 H), 1.82 (m, 1 H), 2.09 (m, 2 H), 5.52 (d, 3 H, J = 2.5 Hz), 7.43
(m, 3 H), 7.60 (m, 2 H).
13C NMR (CDCl3): d = 13.9, 15.3, 19.1, 22.5, 26.8, 28.0, 31.9, 42.8,
60.8, 84.5, 126.7, 128.8, 130.4, 136.5, 161.9, 171.7.
(hexane/EtOAc = 7/3); [a]D25 -117.0 (c = 1; CH2Cl2).
IR (KBr): n = 1742 cm–1.
1H NMR (CDCl3): d = 0.99 (d, 3 H, J = 6.9 Hz), 1.25 (d, 3 H, J =
6.9 Hz), 1.32 (s, 3 H), 2.69 (sept, 1 H, J = 6.9 Hz), 3.02 (d, 1 H, J =
15.4 Hz), 3.26 (d, 1 H, J = 15.4 Hz), 3.70 (d, 1 H, J = 14.8 Hz), 3.89
(d, 1 H, J = 14.8 Hz), 6.87 (d, 1 H, J = 7.0 Hz), 7.12–7.42 (m, 8 H).
13C NMR (CDCl3): d = 19.5, 21.0, 21.9, 28.0, 36.8, 48.0, 56.0,
122.9, 124.7, 126.4, 127.2, 128.3, 128.4, 128.5, 129.6, 134.1, 134.3,
136.2, 138.1, 168.5.
MS: m/z (%) = 287 (M+, 3), 187 (55), 186 (52), 104 (100), 43 (77).
HRMS for C18H25NO2 calcd 287.1885, found 287.1883.
(3S,6R)-3-Isobutyl-6-isopropyl-3-methyl-5-phenyl-3,6-dihydro-
2H-1,4-oxazin-2-one ((6R)-6l)
MS: m/z (%) = 333 (M+, 32), 290 (100), 104 (34).
Colorless oil; TLC: Rf 0.65 (hexane/EtOAc = 7/3); [a]D25 +72.7
(c = 1.4; CH2Cl2).
Anal. Calcd for C22H23NO2: C 79.25, H 6.95, N 4.20. Found: C
79.56, H 6.93, N, 4.19.
IR (film): n = 1659, 1742 cm–1.
1H NMR (CDCl3): d = 0.80 (d, 3 H, J = 7.0 Hz), 0.81 (d, 3 H, J =
6.7 Hz), 0.84 (d, 3 H, J = 6.7 Hz), 1.13 (d, 3 H, J = 7.0 Hz), 1.57 (m,
1 H), 1.86 (dd, 1 H, J = 13.6, 5.4 Hz), 2.1 (m, 2 H), 5.53 (d, 1 H, J
= 2.4 Hz), 7.44 (m, 3 H), 7.59 (m, 2 H).
13C NMR (CDCl3): d = 15.4, 19.1, 22.6, 23.8, 25.1, 29.5, 31.8, 50.9,
60.0, 84.5, 126.6, 128.7, 130.3, 136.5, 161.5, 172.0.
Alkylation of Oxazinone (6R)-1 under Organic Base Condi-
tions; General Procedure
To a solution of the oxazinone 1 (257 mg of crude of ca. 90% purity,
equivalent to 231 mg of pure compound, 1 mmol) LiI if necessary
(see Table 2) in the appropriate solvent (2 mL) was added the cor-
responding base (BEMP: 1.1 mmol, 318 mL; DBU: 5 mmol, 748
mL) at 0ºC. The alkyl halide (2 mmol) was added in one portion and
the temperature was allowed to rise to r.t. until total consumption of
the starting material (GLC). The mixture was diluted with EtOAc
(25 mL), washed with H2O (3 x 15 mL), dried (Na2SO4) and evap-
MS: m/z (%) = 287 (M+, 2), (43), 43 (87), 41 (100).
HRMS for C18H25NO2 calcd 287.1885, found: 287.1893.
(3S,6R)-6-Isopropyl-3-methyl-5-phenyl-3-phenylethyl-3,6-di-
hydro-2H-1,4-oxazin-2-one [(6R)-6m]
1
orated (15 Torr). The residue was analyzed by H NMR to deter-
mine the de. Further purification by flash chromatography (silica
gel, hexane/EtOAc gradients) afforded pure major diastereomer 6
(see Table 2), and compounds 10 or 12.
Colorless oil; TLC: Rf 0.60 (hexane/EtOAc = 7/3); [a]D25 +20.7
(c = 1.3; CH2Cl2).
IR (film): n = 1658, 1739 cm–1.
(3S,6R)- and (3R,6S)-3-Ethyl-6-isopropyl-3-methyl-5-phenyl-
3,6-dihydro-2H-1,4-oxazin-2-one [(6R)-6i and (6S)-6i]
Colorless oil; TLC: Rf 0.60 (hexane/EtOAc = 7/3); (3S,6R)-isomer:
[a]D25 +26.5 (c = 1.6; CH2Cl2), (3R,6S)-isomer: [a]D25 -25.1 (c = 1.6;
CH2Cl2).
1H NMR (CDCl3): d = 0.81 (d, 3 H, J = 6.7 Hz), 1.13 (d, 3 H, J =
6.7 Hz), 1.65 (s, 3 H), 2.04–2.25 (m, 2 H), 2.36–2.51 (m, 3 H), 5.52
(d, 1 H, J = 2.8 Hz), 7.10–7.24 (m, 5 H), 7.46 (m, 3 H), 7.62 (m, 2
H).
13C NMR (CDCl3): d = 15.4, 19.1, 28.0, 31.1, 32.0, 44.5, 60.7, 84.7,
IR (film): n = 1659, 1743 cm–1.
1H NMR (CDCl3): d = 0.79 (m, 6 H), 1.13 (d, 3 H, J = 7.0 Hz), 1.62
(s, 3 H), 1.86 (m, 1 H), 2.13 (m, 2H), 5.53 (d, 1 H, J = 2.4 Hz), 7.44
(m, 3 H), 7.60 (m, 2 H).
125.9, 126.7, 128.3, 128.4, 128.8, 130.5, 136.4, 141.0, 162.3, 171.4.
MS: m/z (%) = 335 (M+, 4), 202 (42), 188 (48), 104 (58), 91 (100),
69 (56), 41 (76).
13C NMR (CDCl3): d = 8.9, 15.2, 19.0, 27.6, 31.9, 35.9, 61.3, 84.5,
126.6, 128.8, 130.4, 136.4, 162.4, 171.5.
HRMS for C22H25NO2 calcd 335.1885, found 335.1874.
Synthesis 1999, No. 4, 704–717 ISSN 0039-7881 © Thieme Stuttgart · New York

714
R. Chinchilla et al.
FEATURE ARTICLE
(3S,6R)-3-Chloromethyl-6-isopropyl-3-methyl-5-phenyl-3,6-di-
hydro-2H-1,4-oxazin-2-one [(6R)-6n]
1H NMR (D2O): d = 1.48 (s, 3 H), 2.76 (d, 1 H, J = 17.7 Hz), 3.01
(d, 1 H, J = 17.7 Hz).
Colorless oil; TLC: Rf 0.53 (hexane/EtOAc = 7/3); [a]D25 +31.1
(c = 1.5; CH2Cl2).
(S)-a-Methylserine [(S)-7g]
White solid; [a]D25 +3.6 (c = 1; H2O), lit.31 [a]D +6.3 (c = 1; H2O).
IR (film): n = 1661, 1743 cm–1.
1H NMR (D2O): d = 1.37 (s, 3 H), 3.61 (d, 1 H, J = 12.2 Hz), 3.85
(d, 1 H, J = 12.2 Hz).
1H NMR (CDCl3): d = 0.78 (d, 3 H, J = 7.0 Hz), 1.14 (d, 3 H, J =
7.0 Hz), 1.68 (s, 3 H), 2.13 (dsept, 1 H, J = 7.0, 2.7 Hz), 3.73 (d, 1
H, J = 10.2 Hz), 4.11 (d, 1 H, J = 10.2 Hz), 5.62 (d, 1 H, J = 2.7 Hz),
7.44 (m, 3 H), 7.62 (m, 2 H).
13C NMR (CDCl3): d = 15.0, 18.9, 25.6, 31.7, 52.8, 61.8, 84.7,
126.6, 128.7, 130.6, 135.9, 164.5, 168.8.
(S)- and (R)-a-Methylglutamic acid [(S)- and (R)-7h]
(S)-Isomer: white solid; [a]43625 +22.0 (c = 2.7; 6M HCl), lit.31 [a]436
25
+23.7 (c = 4; 6M HCl) for ≥97% ee. (R)-isomer: white solid; [a]436
-22.4 (c = 2.8; 6M HCl).
1H NMR (D2O): d = 1.47 (s, 3 H), 2.06 (m, 2 H), 2.34 (m, 2 H).
MS: m/z (%) = 279 (M+, 1), 144 (42), 104 (100), 77 (45), 69 (68),
41 (79).
(R)-a-Ethylalanine [(R)-7i]
White solid; [a]D25 -10.0 (c = 1; H2O), lit.32 [a]D20 -10.3 (c = 1; H2O).
1H NMR (D2O): d = 0.90 (t, 3 H, J = 7.6 Hz), 1.44 (s, 3 H), 1.73 (dq,
1 H, J = 14.7, 7.6 Hz), 1.89 (dq, 1 H, J = 14.7, 7.6 Hz).
HRMS for C15H18ClNO2 calcd 279.1026, found 278.0956.
(8aS)-3-Isopropyl-8a-methyl-4-phenyl-6,7,8,8a-tetrahydro-1H-
pyrrolo[2,1-c][1,4]oxazin-1-one (10)
(S)-a-Methylleucine [(S)-7l]
White solid; yield: 81%; mp 115 ºC (hexane/EtOAc); TLC: Rf 0.80
25
20
White solid; [a]D +38.2 (c = 2; H2O), lit.33 [a]D +34.2 (c = 3;
(hexane/EtOAc = 7/3); [a]D25 -317.8 (c = 1; CH2Cl2).
H2O).
IR (KBr): n = 1743 cm–1.
1H NMR (CDCl3): d = 1.01 (d, 3 H, J = 6.7 Hz); 1.30 (d, 3 H, J =
7.0 Hz), 1.31 (s, 3 H), 1.66–1.86 (m, 2 H), 1.94 (m, 1 H), 2.67–2.84
(m, 3 H), 3.16 (m, 1 H), 7.34 (m, 5 H).
13C NMR (CDCl3): d = 19.8, 21.1, 21.8, 22.9, 27.8, 35.5, 50.8, 61.2,
122.4, 128.1, 128.3, 129.2, 134.8, 139.3, 169.1.
1H NMR (D2O): d = 0.87 (d, 3 H, J = 6.1 Hz), 0.92 (d, 3 H, J = 6.1
Hz), 1.43 (s, 3 H), 1.62 (m, 2 H), 1.82 (m, 1 H).
(S)-3-Methyl-1,2,3,4-tetrahydro-3-isoquinolinocarboxylic Acid
(9)
White solid; yield: 73%; [a]D25 -31.9 (c = 1; 6N HCl), lit.20a (R)-iso-
mer [a]D20 +31.6 (c = 1; 6N HCl).
MS: m/z (%) = 271 (M+, 2), 104 (46), 41 (100).
1H NMR (D2O): d = 1.52 (s, 3 H), 3.03 (d, 1 H, J = 17.1 Hz), 3.28
(d, 1 H, J = 17.1 Hz), 4.32 (d, 1 H, J = 16.2 Hz), 4.45 (d, 1 H, J =
16.2 Hz), 7.27 (m, 4 H).
HRMS for C17H21NO2 calcd 271.1572, found 271.1572.
(8aS)-3-Isopropyl-8a-methyl-7-methylene-4-phenyl-6,7,8,8a-
tetrahydro-1H-pirrolo[2,1-c][1,4]oxazin-1-one (12)
Colorless oil; TLC: Rf 0.79 (hexane EtOAc = 7/3); [a]D25 -221.4
(c = 1; CH2Cl2).
(S)-a-Methylproline (11)
25
White solid; yield: 81%; [a]D -71.9 (c = 1; MeOH), lit.20a [a]D -
72.1 (c = 1; MeOH).
IR (film): 1755 cm–1.
1H NMR (D2O): d = 1.53 (s, 3 H), 3.59, 2.03 (2m, 3 H), 2.28 (m, 1
H), 3.22–3.39 (m, 2 H).
1H NMR (CDCl3): d = 1.02 (d, 3 H, J = 6.9 Hz), 1.31 (d, 3 H, J =
6.9 Hz), 1.35 (s, 3 H), 2.62 (d, 1 H, J = 16.5 Hz), 2.81 (sept, 1 H, J
= 6.9 Hz), 3.29 (d, 1 H, J = 13.7 Hz), 3.50 (d, 1 H, J = 16.5 Hz), 3.78
(d, 1 H, J = 13.7 Hz), 4.80 (s, 1 H), 4.97 (s, 1 H), 7.36 (m, 5 H).
Palladium(0)-Catalyzed Allylation of Oxazinones (6R)-1; Gen-
eral Procedure
To a solution of the oxazinone (6R)-1 (116 mg, 0.5 mmol) and the
corresponding allylic carbonate (0.5 mmol) in anhyd THF (1 mL)
was added a solution of Pd(PPh3)4 (29 mg, 0.025 mmol) and dppe
(28 mg, 0.07 mmol) [or Pd(OAc)2 (6 mg, 0.025 mmol) and PPh3 (13
mg, 0.05 mmol), see Table 5 entry 2] in anhyd THF (0.5 mL). The
reaction was stirred at r.t. until completion (GLC), the solvent was
13C NMR (CDCl3): d = 19.6, 21.0, 21.7, 27.8, 41.3, 55.7, 61.9,
107.0, 122.3, 128.2, 128.3, 129.2, 134.4, 141.3, 142.6, 168.6.
MS: m/z (%) = 283 (M+, 9), 43 (58), 41 (100).
HRMS for C18H21NO2 calcd 283.1572, found 283.1576.
1
evaporated (15 Torr) and the residue analyzed by H NMR and/or
Hydrolysis of Oxazinones 6; Synthesis of AMAAs 7, 9 and 11;
General Procedure
GLC to determine the de. Further purification by flash chromatog-
raphy (silica gel, hexane/EtOAc gradients) afforded the correspond-
ing major pure regio- and diastereoisomers (6R)-6 (see Table 5).
A mixture of the corresponding oxazinone 6 (0.5 mmol) in 6M HCl
(1 mL) was heated at 150 ºC (bath temperature) in a pressure tube
for 24 h. H2O (10 mL) was added and the mixture was extracted
with EtOAc (10 mL). The aqueous layer was evaporated (15 Torr),
and the resulting solid hydrochloride was dissolved in EtOH (2 mL)
and refluxed with propylene oxide (1 mL) for 30 min. The formed
precipitate was filtered off yielding the corresponding free amino
acids (see Tables 3 and 4).
(3S,6R)-6-Isopropyl-3-methyl-3-(2-methylprop-2-enyl)-5-phe-
nyl-3,6-dihydro-2H-1,4-oxazin-2-one [(6R)-6o]
Colorless oil; TLC: Rf 0.68 (hexane/EtOAc = 7/3); [a]D27 +80.0 (c =
1.4; CH2Cl2).
IR (film): n = 1645, 1660, 1745 cm–1.
1H NMR (CDCl3): d = 0.76 (d, 3 H, J = 6.9 Hz), 1.12 (d, 3 H, J =
6.9 Hz), 1.63 (s, 3 H), 1.65 (s, 3 H), 2.07 (dsept, 1 H, J = 6.9, 2.4
Hz), 2.55 (d, 1 H, J = 13.1 Hz), 2.83 (d, 1 H, J = 13.1 Hz), 4.69 (s,
1 H), 4.83 (t, 1 H, J = 1.7 Hz), 5.46 (d, 1 H, J = 2.4 Hz), 7.43 (m, 3
H), 7.57 (m, 2 H).
13C NMR (CDCl3): d = 15.1, 19.0, 24.2, 28.3, 31.8, 49.6, 61.7, 84.6,
115.4, 126.5, 128.7, 130.3, 136.6, 141.1, 161.9, 171.0.
(S)- and (R)-a-Methylphenylalanine [(S)- and (R)-7c]
(S)-Isomer: white solid; [a]D25 -21.5 (c = 1; H2O), lit.29 [a]D -22.0
(c = 1; H2O). (R)-Isomer: white solid; [a]D +21.6 (c = 1; H2O).
1H NMR (D2O): d = 1.52 (s, 3 H), 2.95 (d, 1 H, J = 14.7 Hz), 3.27
(d, 1 H, J = 14.7 Hz), 7.24 (m, 2 H), 7.36 (m, 3 H).
(S)- and (R)-a-Methylaspartic acid [(S)- and (R)-7f]
25
MS: m/z (%) = 285 (M+, 25), 230 (100), 185 (44), 145 (63), 105
(56), 91 (56), 43 (80).
(S)-Isomer: white solid; [a]D +48.9 (c = 1; H2O). (R)-Isomer:
white solid; [a]D25 -49.5 (c = 1; H2O), lit.30 [a]D -52.9 (c = 1; H2O).
HRMS for C18H23NO2 calcd 285.1729, found 285.1711.
Synthesis 1999, No. 4, 704–717 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Chiral Alanine Equivalents for the Asymmetric Synthesis of a-Methyl a-Amino Acids
715
(3S,6R)-6-Isopropyl-3-methyl-5-phenyl-3-[(E)-3-phenylprop-2-
enyl]-3,6-dihydro-2H-1,4-oxazin-2-one [(6R)-6p]
Colorless oil; TLC: Rf 0.60 (hexane/EtOAc = 7/3); [a]D29 +92.6 (c
= 1.3; CH2Cl2).
MS: m/z (%) = 313 (M+, 3), 231 (53), 230 (100), 145 (80), 105 (53),
55 (68), 43 (93).
HRMS for C20H27NO2 calcd 313.2042, found 313.2042.
IR (film): n =1659, 1740 cm–1.
Hydrolysis of Oxazinones (6R)-6a and 12; Synthesis of AMAAs
(S)-7a and 13; General Procedure
1H NMR (CDCl)3: d = 0.75 (d, 3 H, J = 6.9 Hz), 1.06 (d, 3 H, J =
6.9 Hz), 1.70 (s, 3 H), 2.02 (dsept, 1 H, J = 6.9, 2.4 Hz), 2.71 (dd, 1
H, J = 13.4, 7.6 Hz), 2.94 (dd, 1 H, J = 13.4, 7.6 Hz), 5.35 (d, 1 H,
J = 2.4 Hz), 6.03 (m, 1 H), 6.39 (d, 1 H, J = 15.9 Hz), 7.23 (m, 5 H),
7.41–7.52 (m, 5 H).
13C NMR (CDCl)3: d = 15.1, 18.9, 27.3, 31.7, 45.9, 61.5, 84.5,
123.5, 126.2, 126.5, 127.4, 128.5, 128.7, 130.3, 134.9, 136.5, 137.1,
162.7, 170.9.
The corresponding oxazinone (0.5 mmol) was dissolved in THF (2
mL) and 2M HCl (3 mL) and the mixture was stirred at r.t. for 3 h.
The solvents were evaporated and the residue was dissolved in a
mixture of THF (2 mL) and aq 1M LiOH◊H2O (1.5 mL). The solu-
tion was stirred overnight at r.t., the solvent evaporated (15 Torr),
and the crude was purified using a Dowex-50 column (H2O and
10% NH4OH) yielding the free amino acids.
(S)-a-Allylalanine [(S)-7a]
MS: m/z (%) = 347 (M+, 2), 117 (100).
25
White solid; yield: 57%; (S)-7a◊HCl: [a]D -13.4 (c = 1.3; D2O),
lit.8d [a]D -14.4 (c = 1.3; D2O).
HRMS for C23H25NO2 calcd 347.1885, found 347.1871.
1H NMR (D2O): d = 1.44 (s, 3 H), 2.41 (dd, 1 H, J = 14.7, 8.9 Hz),
(3S,6R)-3-[(E)-But-2-enyl]-6-isopropyl-3-methyl-5-phenyl-3,6-
dihydro-2H-1,4-oxazin-2-one [(6R)-6q]
2.62 (dd, 1 H, J = 14.7, 7.0 Hz), 5.22 (m, 2 H), 5.71 (m, 1 H).
Colorless oil; TLC: Rf 0.68 (hexane/EtOAc = 7/3); [a]D25 +66 (c =
1; CH2Cl2) (for a 96:4 diast. ratio).
(S)-2-Methyl-4-methyleneproline (13)
White solid; yield: 79%; mp 240–250 ºC (dec.); [a]D25 -29.5 (c = 1;
H2O).
IR (film): n = 1659, 1742 cm–1.
1H NMR (CDCl3): d = 0.76 (d, 3 H, J = 7.0), 1.11 (d, 3 H, J = 7.0
Hz), 1.62 (d, 3 H, J = 6.4 Hz), 1.63 (s, 3 H), 2.06 (dsept, 1 H, J =
7.0, 2.4 Hz), 2.49 (dd, 1 H, J = 13.4, 7.0 Hz), 2.71 (dd, 1 H, J = 13.4,
8.2 Hz), 5.27 (m, 1 H), 5.42 (d, 1 H, J = 2.4 Hz), 5.50 (m, 1 H), 7.44
(m, 3 H), 7.57 (m, 2 H).
13C NMR (CDCl3): d = 15.1, 18.2, 19.0, 27.2, 31.8, 45.7, 61.5, 84.5,
124.5, 126.5, 128.8, 130.3, 130.7, 136.6, 162.2, 171.12.
IR (KBr): n = 1609, 3070, 3426 cm–1.
1H NMR (D2O): d = 1.57 (s, 3 H), 2.65 (d, 1 H, J = 16.5 Hz), 2.97
(d, 1 H, J = 16.5 Hz), 3.97 (s, 2 H), 5.14 (s, 1 H), 5.18 (s, 1H).
13C NMR (H2O, acetone): d = 21.1, 41.4, 48.4, 70.7, 110.6, 139.8,
176.7.
Anal. Calcd for C8H11NO2: C 59.54, H 7.86, N 9.93. Found: C
59.09, H 7.57, N, 9.29.
MS: m/z (%) = 285 (M+, 12), 231 (51), 230 (63), 188 (61), 145 (89),
105 (70), 91 (59), 55 (80), 43 (100).
HRMS for C18H23NO2 calcd 285.1729, found 285.1725.
Acknowledgement
(3S,6R)-6-Isopropyl-3-methyl-3-[(2E)-penta-2,4-dienyl]-5-phe-
nyl-3,6-dihydro-2H-1,4-oxazin-2-one [(6R)-6r]
Colorless oil; TLC: Rf 0.66 (hexane/EtOAc = 7/3); [a]D25 +97.7
(c = 1.2; CH2Cl2).
We thank the Dirección General de Investigación Científica y Téc-
nica (DGICYT) of the Spanish Ministerio de Educación y Cultura
(MEC) (PB94-1515) for financial support. N. G. thanks MEC for a
grant.
IR (film): n = 1658, 1741 cm–1.
1H NMR (CDCl3): d = 0.76 (d, 3 H, J = 6.9 Hz), 1.10 (d, 3 H, J =
6.9 Hz), 1.65 (s, 3 H), 2.05 (dsept, 1 H, J = 6.9, 2.4 Hz), 2.59 (dd, 1
H, J = 13.4, 7.6 Hz), 2.81 (dd, 1 H, J = 13.4, 7.9 Hz), 5.01 (d, 1 H,
J = 10.4 Hz), 5.08 (d, 1 H, J = 16.8 Hz), 5.40 (d, 1 H, J = 2.4 Hz),
5.51 (m, 1 H), 6.05 (dd, 1 H, J = 15.2, 10.7 Hz), 6.25 (m, 1 H), 7.43
(m, 3 H), 7.56 (m, 2 H).
13C NMR (CDCl3): d = 15.1, 19.0, 27.3, 31.7, 45.5, 61.3, 84.6,
116.9, 126.6, 127.6, 128.7, 130.3, 135.9, 136.5, 136.6, 162.6, 170.9.
MS: m/z (%) = 297 (M+, 20), 230 (81), 188 (63), 161 (50), 105 (75),
91 (62), 67 (52), 43 (100).
References
(1) For reviews see:
(a) Williams, R. M. Synthesis of Optically Active Amino
Acids; Pergamon: Oxford, 1989.
(b) Heimgartner, H. Angew. Chem., Int. Ed. Engl. 1991, 30,
238.
(c) Duthaler, R. O. Tetrahedron 1994, 50, 1540.
(d) North, M. Contemp. Org. Synth. 1996, 323.
(e) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem.,
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(f) Wirth, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225.
(2) For some examples see:
HRMS for C19H23NO2 calcd 297.1729, found 297.1719.
(3S,6R)-3-[(E)-Hex-2-enyl]-6-isopropyl-3-methyl-5-phenyl-3,6-
dihydro-2H-1,4-oxazin-2-one [(6R)-6s]
(a) Polese, A.; Formaggio, F.; Crisma, M.; Valle, G.; Toniolo,
C.; Bonora, G. M.; Broxterman, Q. B.; Kamphuis, J. Chem.
Eur. J. 1996, 2, 1104.
(b) Higginbotton, M.; Kneen, C.; Ratcliffe, G. S. J. Med.
Chem. 1992, 35, 1572.
Colorless oil; TLC: Rf 0.76 (hexane/EtOAc = 7/3); [a]D30 +66.6 (c
= 2; CH2Cl2).
IR (film): n = 1660, 1742 cm–1.
1H NMR (CDCl)3: d = 0.76 (d, 3 H, J = 6.9 Hz), 0.83 (t, 3 H, J = 7.3
Hz), 1.11 (d, 3 H, J = 6.9 Hz), 1.30 (sext, 2 H, J = 7.3 Hz), 1.64 (s,
3 H), 1.92 (q, 2 H, J=7.0 Hz), 2.06 (dsept, 1 H, J = 6.9, 2.4 Hz), 2.51
(dd, 1 H, J = 13.3, 7.0 Hz), 2.73 (dd, 1 H, J = 13.3, 7.6 Hz), 5.24 (m,
1 H), 5.42 (d, 1 H, J = 2.4 Hz), 5.46 (m, 1 H), 7.43 (m, 3 H), 7.57
(m, 2 H).
(c) Altmann, K.-H.; Altmann, E.; Mutter, M. Helv. Chim. Acta
1992, 75, 1198.
(d) Obrecht, D.; Bohdal, U.; Daly, J.; Lehmann, C.;
Schönholzer, P.; Müller, K. Tetrahedron 1995, 51, 10883.
(e) Obrecht, D.; Altolfer, M.; Lehmann, C.; Schönholzer, P.;
Müller, K. J. Org. Chem. 1996, 61, 4080.
(f) Bisang, C.; Weber, C.; Inglis, J.; Schiffer, C. A.; van
Gunsteren, W. F.; Jelesarov, I.; Bosshard, H. R.; Robinson, J.
A. J. Am. Chem. Soc. 1995, 117, 7904.
13C NMR (CDCl3): d = 13.5, 15.1, 19.0, 22.4, 27.3, 31.8, 34.7, 45.7,
61.5, 84.4, 123.5, 126.6, 128.7, 130.3, 136.0, 136.6, 162.1, 171.1.
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FEATURE ARTICLE
(g) Hernández, J.-F.; Kornreich, W.; Rivier, C.; Miranda, A.;
Yamamoto, G.; Andrews, J.; Taché, Y.; Vale, W.; Rivier, J. J.
Med. Chem. 1993, 36, 2860.
PTC conditions: Abellán, T.; Nájera, C.; Sansano, J. M.
Tetrahedron: Asymmetry 1998, 9, 2211.
(12) Caplar, V.; Lisini, A.; Kajfez, Kolbah, D.; Sunjic, V. J. Org.
Chem. 1978, 43, 1355.
(3) For some examples see:
(a) Horwell, D. C.; Ratcliffe, G. S.; Roberts, E. Bioorg. Med.
Chem. Lett. 1991, 1, 169.
(13) Cowper, R. M.; Davidson, L. H. Organic Syntheses; Wiley:
New York, 1943; Collect Vol. II, p 480.
(b) Khosla, A.; Stachowiak, K.; Sunby, R. R.; Bumpus, F. G.;
Pirion, F.; Lintner, K.; Fermandjian, S. Proc. Nat. Acad. Sci.
U.S.A. 1981, 78, 757.
(14) For X-ray diffraction data see ref. 10a.
(15) The AM1 semiempirical method, as implemented in
Hyperchem 5 from Hypercube Inc., was used for these
calculations.
(16) Schwesinger, R.; Willaredt, J.; Schlemper, H.; Keller, M.;
Schmitt, D.; Fritz, H. Chem. Ber. 1994, 127, 2435, and
references cited therein.
(c) Boesten, W. H. J.; Dassen, B. H. N.; Kleijans, J. C. S.; van
Agen, B.; van der Wal, S.; de Vries, N. K.; Shoemaker, H. E.;
Meijer, E. M. J. Agric. Food Chem. 1991, 39, 154.
(4) For some examples see:
Yano, S.; Nakanishi, Y.; Ikuina, Y.; Ando, K.; Yoshida, M.;
Saitoh, Y.; Matsuda, Y.; Bando, C. J. Antibiot. 1997, 50, 992.
Yamashita, T.; Iijima, M.; Nakamura, H.; Isshiki, K.;
Naganawa, H.; Hattori, S.; Hamada, M.; Ishizuka, M.;
Takeuchi, T. J. Antibiot. 1991, 44, 557.
Horn, W. S.; Smith, J. L.; Bills, G. F.; Raghoobar, S. L.;
Helms, G. L.; Kurtz, M. B.; Marrinan, J. A.; Frommer, B. R.;
Thornton, R. A.; Mandala, S. M. J. Antibiot. 1992, 45, 1692.
Becker, D.; Kiess, M.; Brückner, H. Liebigs Ann/Recueil
1997, 767.
(17) O’Donnell, M. J.; Lugar, C, W.; Pottorf, R. S.; Zhou, C.; Scott,
W. L.; Cwi, C. L. Tetrahedron Lett. 1997, 38, 7163.
O’Donnell, M. J.; Zhou, C.; Scott, W. L. J. Am. Chem. Soc.
1996, 118, 6070.
(18) Seebach, D.; Beck, A. K.; Studer, A. In Modern Synthetic
Methods 1995; VCH Publishers: Basel, 1995; Vol. 7, p 1.
(19) D-isovaline and a-aminoisobutyric acid (Aib) are the a,a-
disubstituted a-amino acids which are found primarily in
nature: see ref. 1b.
(20) For synthesis of cyclic AMAAs by dialkylation of chiral
(5) (a) Kiick, D. M.; Cook, P. F. Biochemistry 1983, 22, 375.
(b) Stinson, J. C. Chem. Eng. News 1992, 70(39), 46.
(6) (a) O’Donnell, M. J.; Wu, S. Tetrahedron: Asymmetry 1992,
3, 591.
cyclic alanine templates see:
(a) Schöllkopf, U.; Hinrichs, R.; Lonsky, R. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 143.
(b) Bajgrowicz, J.; El Achquar, A.; Roumestant, M.-L.;
Pigière, C.; Viallefont, P. Heterocycles 1986, 24, 2165.
(c) Seebach, D.; Dziadulewicz, E.; Behrendt, L.; Cantoreggi,
S.; Fitzi, R. Liebigs. Ann. Chem. 1989, 1215.
(21) For synthesis of cyclic AAs by dialkylation of glycine
templates see:
(b) O’Donnell, M. J.; Wu, S.; Huffman, J. C. Tetrahedron
1994, 50, 4507.
(c) Belokon, Y. N.; Kochetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Chesnokov, A. A.; Larionov, O. V.; Parmár,
V. S.; Kumar, R.; Kagan, H. B. Tetrahedron: Asymmetry
1998, 9, 851.
Mazón, A.; Nájera, C. Tetrahedron: Asymmetry 1997, 8,
1855.
Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W. J. Am.
Chem. Soc. 1997, 119, 656.
(7) Recently O’Donnell’s glycine-benzophenone Schiff base
(Ph2C=NCH2CO2t-Bu) has been monoalkylated under PTC
conditions using cinchonium or cinchonidinium salts as
catalysts at -60 or -78 ºC with up to 99.5% ee (Corey, E. J.; Xu,
F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414) or at r.t.
with up to 94% ee (Lygo, B.; Wainwright, P. G. Tetrahedron
Lett. 1997, 38, 8595).
(22) Prepared from 3-chloro-2-chloromethylprop-1-ene by
reaction with NaI in acetone.
(23) Manfre, F.; Kern, J.-M.; Biellmann, J.-F. J. Org. Chem. 1992,
57, 2060.
(8) (a) Schöllkopf, U.; Westphalen, K.-O.; Schröder, J.; Horn, K.
Liebigs Ann. Chem. 1988, 781.
(24) Non-chiral imino esters of glycine and alanine have been
previously allylated under neutral Pd(0)-catalysis: Genêt, J.
P.; Juge, S.; Achi, S.; Mallart, S.; Ruiz Montes, J.; Levif, G.
Tetrahedron 1988, 44, 5263.
(b) Studer, A.; Seebach, D. Liebigs Ann. 1995, 217.
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Chem. 1990, 55, 5437.
(d) Williams, R. M.; Im, M.-N. J. Am. Chem. Soc. 1991, 113,
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(e) Belokon, Y. N.; Chernoglazova, N. I.; Kochetkov, C. A.;
Garbalinskaya, N. S.; Belikov, V. M. J. Chem. Soc., Chem.
Commun. 1985, 171.
Chiral Oppolzer’s benzophenone glycine equivalent has been
diastereoselectively allylated under neutral Pd(0)-catalysis:
Voigt, K.; Stolle, A.; Salaün, J.; de Meijere, A. Synlett 1995,
226.
(25) For selected references, see:
Denniel, V.; Bauchat, P.; Danion, D.; Danion-Bougot, R.
Tetrahedron Lett. 1996, 37, 5111.
Ojima, I.; Tzamarioudaki, M.; Eguchi, M. J. Org. Chem.
1995, 60, 7078.
(9) Berkowitz, D. B.; Smith, M. K. J. Org. Chem. 1995, 60, 1233.
Cativiela, C.; Díaz-de-Villegas, M. D.; Gálvez, J. A.; Lapeña,
Y. Tetrahedron 1997, 53, 5891.
Ayoub, M.; Chassaing, G.; Loffet, A.; Lavielle, S.
Tetrahedron Lett. 1995, 36, 4069.
Ferey, V.; Toupet, L.; Le Gall, T.; Mioskowski, C. Angew.
Chem., Int. Ed. Engl. 1996, 35, 430.
(26) Kurokawa, N.; Ohfune, Y. J. Am. Chem. Soc. 1986, 108, 6041.
Ohfune, Y.; Hori, K.; Sakaitani, M. Tetrahedron Lett. 1986,
27, 6079.
Ohfune, Y.; Kurokawa, N. Tetrahedron Lett. 1985, 26, 5307.
(27) Kawatsura, M.; Uozumi, Y.; Hayashi, T. Chem. Commun.
1998, 217.
(28) Kihara, M.; Ikeuchi, M.; Jinno, K.; Kashimoto, M.;
Kobayashi, Y.; Nagao, Y. Tetrahedron 1993, 49, 1017.
(29) Cativiela, C.; Diaz-de-Villegas, M. D.; Gálvez, J. A.
Tetrahedron: Asymmetry 1994, 5, 261.
(30) Dictionary of Organic Compounds; Chapman & Hall: New
York, 1982.
(10) For preliminary communications see:
(a) Chinchilla, R.; Falvello, L. R.; Galindo, N.; Nájera, C.
Angew. Chem., Int. Ed. Engl. 1997, 36, 995.
(b) Chinchilla, R.; Galindo, N.; Nájera, C. Tetrahedron:
Asymmetry 1998, 9, 2769.
(c) Chinchilla, R.; Falvello, L. R.; Galindo, N.; Nájera, C.
Tetrahedron: Asymmetry 1998, 9, 2223.
(11) We have shown that chiral 1,2,3,6-tetrahydro-2-pyrazinones
from alanine can also be diastereoselectively alkylated under
(31) Acher, F.; Azerad, R. Tetrahedron: Asymmetry 1994, 5, 731.
Synthesis 1999, No. 4, 704–717 ISSN 0039-7881 © Thieme Stuttgart · New York

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Chiral Alanine Equivalents for the Asymmetric Synthesis of a-Methyl a-Amino Acids
717
(32) Achiwa, K.; Terashima, S.; Mizuno, H.; Takamura, N.;
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(33) Kruizinga, W. H.; Bolster, J.; Kellog, R. M.; Kamphuis, J.;
Boesten, W. H. J.; Meijer, E. M.; Schoemaker, H. E. J. Org.
Chem. 1988, 53, 1826.
Synthesis 1999, No. 4, 704–717 ISSN 0039-7881 © Thieme Stuttgart · New York