An improved synthesis of deuterated Schoellkopf's bis-lactim ether and its use for the asymmetric synthesis of (R)-[α-2H]-phenylalanine methyl esters

Article abstract of DOI:10.1016/j.tetasy.2006.04.005

Treatment of (S)-3-isopropyl-2,5-dimethoxy-3,6-dihydropyrazine with trifluoroacetic acid in MeOD results in regioselective deuteration at its C₆-position affording its corresponding (S)-[6-²H₂]-isotopomer in excellent yield with no loss of stereochemical integrity at its C₃-stereocentre. The lithium aza-enolate of this deuterated chiral template has been alkylated with a range of substituted benzyl bromides to afford (3S,6R)-[6-²H]-3-isopropyl-6-benzyl-bis-lactim ethers that were hydrolysed to afford their corresponding (R)-[α-²H]-phenylalanine methyl esters as hydrochloride salts in good yield.

Full text of DOI:10.1016/j.tetasy.2006.04.005

Tetrahedron: Asymmetry 17 (2006) 1170–1178
¨
An improved synthesis of deuterated Schollkopf’s
bis-lactim ether and its use for the asymmetric synthesis
of (R)-[a-2H]-phenylalanine methyl esters
Piers J. M. Taylor and Steven D. Bull*
Department of Chemistry, University of Bath, BA2 7AY, UK
Received 21 February 2006; accepted 3 April 2006
Abstract—Treatment of (S)-3-isopropyl-2,5-dimethoxy-3,6-dihydropyrazine with trifluoroacetic acid in MeOD results in regioselective
deuteration at its C6-position affording its corresponding (S)-[6-2H2]-isotopomer in excellent yield with no loss of stereochemical integrity
at its C3-stereocentre. The lithium aza-enolate of this deuterated chiral template has been alkylated with a range of substituted benzyl
bromides to afford (3S,6R)-[6-2H]-3-isopropyl-6-benzyl-bis-lactim ethers that were hydrolysed to afford their corresponding (R)-[a-2H]-
phenylalanine methyl esters as hydrochloride salts in good yield.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
MeOD.15 Despite the availability of this diverse range of
methodologies, there still remains a strong demand for
the development of efficient synthetic routes for the prepa-
ration of enantiopure [a-2H]-a-amino-acids that proceed in
a reliable manner, since relatively few enantiopure [a-2H]-
a-amino-acids are available commercially.
Amino acid derivatives that contain stable isotopes1 are
important for studying biosynthetic pathways,2 enzyme
mechanisms3 and for probing the secondary and tertiary
structures of peptides and proteins by NMR spectroscopy.4
Enantiopure a-amino acids that are labelled with deute-
rium at their a-position have often been used for these pur-
poses, and as a consequence, a range of methods have been
developed for their syntheses.5 They may be prepared via
kinetic resolution6 or chiral chromatography7 of readily
available racemic [a-2H]-amino acids or their derivatives.
A range of enzymatic based protocols have also been devel-
oped using different synthetic strategies, including the reso-
lution of racemic [a-2H]-a-amino acid derivatives,8
biocatalytic deuteration of a-amino acids,9 reductive
amination of a-keto acid substrates10 or derivatisation of
deuterated building blocks that have been prepared
chemoenzymatically.11 Alternative synthetic approaches
to a-deuterated-a-amino acids include asymmetric
alkylation of deuterated glycine enolate derivatives,12
asymmetric deuteration of enolates,13 reduction of 2,3-
dehydroamino acid derivatives with D2 or SmI2/D2O,14
and photolysis of chiral chromium carbene complexes in
Scho¨llkopf’s bis-lactim ether 116 is a chiral glycine enolate
equivalent that has been widely used for the asymmetric
synthesis of enantiopure a-amino acids, with over 200
reports having been described on its use to date.17 In this
approach, an enantiopure bis-lactim ether 1 is deprotonated
with n-BuLi in THF at ꢀ78 ꢁC, and the resultant aza-eno-
late 2 alkylated with an electrophile to afford a trans-alkyl-
ated bis-lactim ether 3 in high de. Subsequent purification
of the trans-alkylated-bis-lactim ether 3 to homogeneity,
followed by mild acid catalysed hydrolysis, affords a mix-
ture of enantiopure valine methyl ester 4 and the target
enantiopure a-amino methyl ester 5 as their hydrochloride
salts, whose free amines may be separated by chromatogra-
phy or fractional distillation in vacuo (Scheme 1).
Given its popularity, it is unsurprising that this versatile
methodology has been adapted for the asymmetric synthe-
sis of enantiopure [a-2H]-a-amino acid methyl esters, which
has been achieved using enantiopure [6-2H2]-3-isopropyl-
2,5-dimethoxy-3,6-dihydropyrazine 6 as a chiral tem-
plate for synthesis.18,19 We herein report on an improved
*
Corresponding author. Tel.: +44 1225 383551; fax: +44 1225 386231;
e-mail: s.d.bull@bath.ac.uk
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.04.005

P. J. M. Taylor, S. D. Bull / Tetrahedron: Asymmetry 17 (2006) 1170–1178
1171
N
OMe
(i)
CO2Me
R
N
N
OMe
R
NH3Cl
OMe
Li
3
RX
(ii)
+
N
6
ClH3N
CO2Me
MeO
N
N
MeO
H
OMe
(S)-1
(3S,6R)-3
(S)-4
(R)-5
(S)-2
Scheme 1. Reagents and conditions: (i) n-BuLi, THF, ꢀ78 ꢁC; (ii) 0.1 M HCl(aq)/CH3CN.
synthesis of enantiopure [6-2H2]-bis-lactim ether 6 that may
be used to prepare gram quantities of this isotopomer in
excellent yield and further demonstrate its synthetic utility
for the asymmetric synthesis of a series of enantiopure
[a-2H]-phenylalanine methyl esters.
then bis-O-methylated using Me3OBF4 to afford (R)-
[6-2H2]-bis-lactim ether 6 (Scheme 2). They reported that
both these multi-step approaches were expensive and inef-
ficient, and as a consequence, developed an alternative
synthesis of (R)-[6-2H2]-bis-lactim ether 6 involving treat-
ment of (R)-bis-lactim ether 1 with potassium hydroxide
in refluxing MeOD/D2O. This approach resulted in regio-
selective bis-deuteration of bis-lactim ether (R)-1 at its
C6-position to afford (R)-[6-2H2]-bis-lactim ether 6 in 80%
yield, with no racemisation having occurred at its C3-stereo-
genic centre (Scheme 2).
2. Results and discussion
We were interested in preparing a series of enantiopure (R)-
[a-2H]-phenylalanine methyl esters20 as mechanistic probes
and required access to gram quantities of (S)-[6-2H2]-bis-
lactim ether 6 for synthesis. Four approaches had previ-
ously been reported for its preparation in enantiopure
form. In the first approach, Vederas et al. employed a
deprotonation–deuteration protocol involving treatment
of bis-lactim ether (S)-1 with n-BuLi, followed by quench-
ing of the resultant aza-enolate with CD3OD. This depro-
tonation–deuteration process was repeated two further
times on the same substrate to afford (S)-[6-2H2]-bis-lactim
ether 6 in 77% yield (Scheme 2).18 Gani et al. subsequently
reported that they found this repeated deprotonation–deu-
teration strategy to be low-yielding, and as a consequence,
investigated three alternative routes to [6-2H2]-bis-lactim
ether 6.19 Their first two approaches employed the expen-
sive [a-2H2]-glycine methyl ester 7 as a deuterated building
block to prepare diketopiperazine (R)-[6-2H2]-8, which was
Whilst Gani’s base catalysed deuteration strategy was prac-
tically appealing, our attempts to reproduce this capri-
cious protocol to prepare (S)-[6-2H2]-bis-lactim ether 6
proved unsatisfactory, resulting in either incomplete incor-
poration of deuterium at its C6-position, or low yields due
to the prolonged reaction times required for complete
deuterium incorporation. It has been reported that simple
monolactim ethers tautomerise in protic solvents to afford
their corresponding enamine tautomers, with O-ethyl-val-
erolactim ether undergoing bis-deuteration at its C3-position
in CD3OD under acidic conditions.21 This result was con-
firmed by carrying out a model study involving treatment
of O-methyl-valerolactim ether 9 with trifluoroacetic acid
in MeOD (20:80, v/v) over a period of 18 h, which resulted
in quantitative incorporation of 2 equiv of deuterium to
N
OMe
H
N
N
OMe
D
(i)
MeO
N
MeO
H
D
(S)-[6-2H2]-6
(S)-1
H
N
O
D
N
N
OMe
D
MeO2C
H2N
(ii),(iii)
(iv)
D
D
O
N
H
MeO
D
D
[α-2H2]-7
(R)-[6-2H2]-6
(R)-[6-2H2]-8
(v)
(viii)
(vi),(iii)
N
OMe
H
O
D
D
H
N
BnO
N
CO2Me
MeO
N
H
H
O
(R)-1
Scheme 2. Reagents and conditions: (i) n-BuLi, THF, ꢀ78 ꢁC; CD3OD; repeat deprotonation–deuteration protocol two further times; (ii) (R)-4-
isopropyloxazolidin-2,4-dione, Et3N, CHCl3, ꢀ78 ꢁC; (iii) toluene, D; (iv) Me3OBF4, CH2Cl2; (v) isobutyl chloroformate, N-methylmorpholine, (R)-N-
benzyloxycarbonyl-valine, EtOAc–DMF; (vi) H2, Pd/C, CH2Cl2–MeOH; (viii) MeOD–D2O (10:1, v/v), KOH, D.

1172
P. J. M. Taylor, S. D. Bull / Tetrahedron: Asymmetry 17 (2006) 1170–1178
D
N
N
OMe
H
N
OMe
D
N
OMe
H
(i)
N
N
OMe
D
OMe
H
(i)
91%
H
MeO
N
D
MeO
H
D
[3-2H2]-10
(S)-1
(S)-[6-2H2]-6
9
Scheme 3. Reagents and conditions: (i) trifluoroacetic acid, MeOD (20:80, v/v), 24 h.
afford [3-2H2]-O-methyl-valerolactim ether 10 (Scheme 3).
Encouraged by this result, it was proposed that treatment
of (S)-bis-lactim ether 1 under identical conditions might
result in regioselective incorporation of deuterium at its
C6-position. Therefore, (S)-bis-lactim ether 122 was dis-
solved in a mixture of trifluoroacetic acid and MeOD
(20:80, v/v) over a period of 18 h, which after neutralisa-
tion with aqueous potassium carbonate solution afforded
(S)-[6-2H2]-bis-lactim ether 6 in 91% yield (Scheme 3). This
was evident from examination of its clean 1H NMR spectra
in CDCl3, which clearly revealed that two atoms of deute-
rium had been regioselectively incorporated into its C6-
position, with no deuterium having been incorporated into
the C3-stereogenic position.23 Analysis of a standard 13C
NMR spectra of (S)-[6-2H2]-bis-lactim ether 6 in CDCl3
revealed only eight resonances, with no resonance being
observed for the C6-2H carbon due to quadropolar relaxation
effects caused by the neighbouring deuterium nuclei, whilst
mass spectroscopic analysis revealed a molecular ion
lactim ether 1 proceeds via an enamine-like tautomer
whose formation requires one of the C6–H r-bonds to
align itself syn-periplanar to the p orbitals of the N4–C5
imidic bond. This alignment can be achieved by either of
the C6-protons through conformational ‘wagging’ of the
dihydropyrazine ring, which therefore results in stepwise
incorporation of two atoms of deuterium into its C6-posi-
tion (Fig. 1). In contrast, the sterically demanding C3-iso-
propyl group of bis-lactim ether 1 occupies a pseudo-axial
conformation with its C3-H proton in a pseudo-equatorial
environment that is orthogonal to the p orbitals of the
N1–C2-imidic bond. This prevents enamine formation from
occurring, and as a consequence, no deuterium was incor-
porated into its C3-position (Fig. 2).
In order to provide further evidence for this deuteration
model, a sample of (3S,6R)-3-isopropyl-6-benzyl-bis-lactim
ether 11 was prepared via treatment of (S)-bis-lactim ether
1 with n-BuLi in THF at ꢀ78 ꢁC, followed by addition of
benzyl bromide.16 It was found that treatment of the resul-
tant (3S,6R)-bis-lactim ether 11 with trifluoroacetic acid in
MeOD (20:80, v/v) over a period of 7 days failed to result
for C9H142H2N2O2. Measurement of the specific rotation
23
of (S)-[6-2H2]-bis-lactim ether 6 afforded an ½aꢁ ¼ þ72:0
D
(c 1.0, EtOH), which compared favourably with that pre-
23
viously reported by Gani et al. of ½aꢁD ¼ þ65:6 (c 1.38,
EtOH).19 Therefore, it was concluded that no deuterium
incorporation or racemisation had occurred at the C3-stereo-
genic centre of (S)-1 under these acidic conditions.
OMe
OMe
N
D2O
X
N
2
3
1
N
H
D
OMe
In order to rationalise why deuteration of bis-lactim ether 1
had occurred selectively at its C6-position, we considered
the conformation of its dihydropyrazine ring that is known
to adopt a half-boat ring conformation with its sterically
demanding isopropyl group occupying a pseudo-axial posi-
tion.24 Deuterium incorporation at the C6-position of bis-
OMe
No deuterium incorporation
Figure 2. Tautomerisation of the C3-proton of bis-lactim ether 1 does not
occur because of poor orbital overlap between the equatorial C3–H
r-bond and the N1–C2 p-bond.
HA
MeO
D
D
MeO
OMe
6
4
HB
N
N
5
HB
D2O
HB
N
N
N
D2O
H
H
H
OMe
OMe
OMe
(S)-1
'Wag'
D
MeO
N
OMe
OMe
N
D
D
N
D
D
N
D2O
D2O
H
H
N
OMe
OMe
H
HB
OMe
(S)-[6-2H2]-6
Figure 1. Conformational wagging of the dihydropyrazine ring of (S)-bis-lactim ether 1 enables stepwise incorporation of two deuterium atoms into its C6-
position to selectively afford (S)-[6-2H2]-bis-lactim ether 6.

P. J. M. Taylor, S. D. Bull / Tetrahedron: Asymmetry 17 (2006) 1170–1178
1173
Table 1. Yields of (3S,6R)-[6-2H]-bis-lactim ether 12a–f and (R)-[a-2H]-
phenylalanine methyl ester hydrochlorides 13a–f
Ph
MeO
N
N
OMe
H
R
(3S,6R)-[6-2H]-
Bis-lactim
de
Yield
(%)
(R)-[a-2H]-
Phenylalanine
methyl ester
hydrochlorides
13a–f
Yield
(%)
3
N
H
6
(%)
N
MeO
ether 12a–f
H
OMe
11
H
2-Br
2-I
4-F
4-Br
4-CF3
12a
12b
12c
12d
12e
12f
>90
>90
>90
>90
>90
>90
80
73
68
71
75
83
13a
13b
13c
13d
13e
13f
88
75
77
82
85
86
Figure 3.
in any deuterium being incorporated into either its C3 or C6
positions. This implies that the trans-diaxial conformation
adopted by the isopropyl and benzyl substituents of lactim
ether substrate 11 is sufficiently rigid to ensure that neither
the C3 nor C6 protons can adopt pseudo-axial orientations
required for tautomerisation, and as a consequence, deute-
rium incorporation does not occur (Fig. 3).
followed by chromatographic purification of the resultant
mixture of free amines to afford (R)-[a-2H]–phenylalanine
methyl esters 13a–f that were converted into their hydro-
chloride salts in 75–88% isolated yield (Scheme 4 and Table
1
With a high yielding route to gram quantities of (S)-
[6-2H2]-bis-lactim ether 6, we next employed it for the
asymmetric synthesis of a range of substituted (R)-
[a-2H]–phenylalanine methyl esters. Therefore, (S)-
[6-2H2]-bis-lactim ether 6 was treated with 1.1 equiv of
n-BuLi in THF in ꢀ78 ꢁC for 1 h before the addition of
1.3 equiv of benzyl bromide to afford (3S,6R)-[6-2H]-3-iso-
propyl-6-benzyl-2,5-dimethoxy-3,6-dihydropyrazine 12a in
>90% de, which was isolated in 80% yield and >95% de
after chromatographic purification. Analysis of the 1H
and 13C NMR spectra of (3S,6R)-[6-2H]-12a revealed no
1). Analysis of the H NMR spectra of (R)-[a-2H]–phenyl-
alanine methyl esters 13a–f revealed no a-proton reso-
nances, and as a consequence, the level of a-deuterium
incorporation was assigned as >95%.
The enantiopurity of (R)-[a-2H]-phenylalanine methyl ester
13a was confirmed as >95% ee using a 1H NMR chiral der-
ivatisation protocol that we have recently developed for
determining the enantiopurity of primary amines.25 There-
fore, (R)-[a-2H]-phenylalanine methyl ester 13a was treated
with enantiopure (R)-BINOL and 2-formylphenylboronic
acid in CDCl3 to afford diastereoisomerically pure imino-
boronate ester (R,R)-[a-2H]-14 as a single compound. This
was confirmed by comparison with the 1H NMR spectra of
an authentic 50:50 mixture of diastereoisomeric imino-bor-
onate esters (R,R)-14 and (R,S)-15 that were prepared in an
analogous manner using racemic phenylalanine methyl
ester hydrochloride as a substrate for derivatisation (Scheme
5). Finally, it follows that the value of >95% ee obtained
for (R)-[a-2H]-phenylalanine methyl ester 13a confirms that
the acidic deuteration protocol employed for the prepara-
tion of (S)-[6-2H2]-bis-lactim ether 6 must have proceeded
regioselectively, with no deuterium incorporation or rac-
emisation occurring at its C3 stereocentre (vide supra).
evidence of any deuterium being present at its C3-position,
25
whilst its ½aꢁD ¼ ꢀ41:2 (c 1.3, CH2Cl2) compared well
with the value previously reported by Gani et al. for its
23
(3R,6S)-antipode of ½aꢁD ¼ þ40:4 (c 1.55, CH2Cl2). These
conditions were subsequently employed to react the aza-
enolate of (S)-[6-2H2]-bis-lactim ether 6 with five further
benzyl bromide electrophiles containing different halide
substituents at their ortho- and para-position, to afford a
series of (3S,6R)-[6-2H]-3-isopropyl-6-benzyl-bis-lactim
ethers 12b–f in >90% de that were isolated in 68–83% yield
and in >95% de after chromatographic purification
(Scheme 4 and Table 1).
Subsequent hydrolysis of these (3S,6R)-[6-2H]-bis-lactim
ethers 12a–f was carried out by dissolving each substrate
in a 1:1 mixture of acetonitrile:0.3 M HCl(aq) and stirring
the resulting solutions for 30 min, which afforded clean
mixtures of (S)-valine-methyl ester 4 and their respective
(R)-[a-2H]–phenylalanine methyl esters 13a–f as hydrochlo-
ride salts. Purification of these 50:50 mixtures of a-amino-
acid methyl esters hydrochloride salts was then achieved by
neutralisation with aqueous sodium bicarbonate solution,
3. Conclusion
In conclusion, we have shown that treatment of (S)-3-iso-
propyl-2,5-dimethoxy-3,6-dihydropyrazine with trifluoro-
acetic acid in MeOD results in regioselective deuteration
at its C6-position to afford its corresponding [6-2H2]-isoto-
pomer in excellent yield with no loss in stereochemical
MeO2C
NH3Cl
O
N
N
OMe
D
N
N
OMe
D
D
(ii)
(i)
+
R
ClH3N
R
MeO
MeO
MeO
D
(S)-[6-2H2]-6
(3S,6R)-[6-2H]-12a-f
(S)-4
Separated via chromatography of their free amines
Scheme 4. Reagents and conditions: (i) n-BuLi, THF, ꢀ78 ꢁC; ArCH2Br; (ii) 0.1 M HCl(aq)/CH3CN.
(R)-[α-2H]-13a-f

1174
P. J. M. Taylor, S. D. Bull / Tetrahedron: Asymmetry 17 (2006) 1170–1178
Ph
D
CO2Me
H
HO
OH
MeO2C
B
OH
OH
N
D
CDCl3
CsCO3
10 min
O
O
+
+
CHO
Ph
B
ClH3N
(R)-[α-2H]-13a
(R)-BINOL
2-formylphenyl
boronic acid
> 95% e.e.
[2H]-(R,R)-14
δ =3.45
CO2Me
δ = 3.78
Ph
H
H
N
CO2Me
Ph
H
δ = 8.41
δ = 8.00
(R)-BINOL
MeO2C
+
H
N
H
O
O
O
CDCl3
CsCO3
10 min
+
Ph
+
B
B
ClH3N
O
2-formylphenyl
boronic acid
(rac)-13a
50
(R,R)-14
:
50
(R,S)-15
Scheme 5. Determination of the enantiomeric excess of (R)-[a-2H]-phenylalanine methyl ester 13a as >95% ee via derivatisation with (S)-BINOL and
2-formylphenyl boronic acid.
integrity at its C3-stereocentre. The lithium aza-enolate of
this deuterated chiral template has been alkylated with a
range of substituted benzyl bromides to afford (3S,6R)-
[6-2H]-3-isopropyl-6-benzyl-bis-lactim ethers that were
subsequently hydrolysed to give a series of (R)-[a-2H]-
phenylalanine methyl esters as their hydrochloride salts in
good yield.
MAT 900 XLT instrument. Optical rotations were re-
corded on an Optical Activity Ltd AA-10 automatic polar-
imeter, using a path length of 10 cm, in spectroscopic grade
solvents (Aldrich), with concentrations (c) given in g
per 100 cm3. (S)-3-Isopropyl-2,5-dimethoxy-3,6-dihydro-
pyrazine
1 and (3S,6R)-3-isopropyl,6-benzyl-2,5-dime-
thoxy-3,6-dihydropyrazine 11 were prepared according to
previously published procedures.16,22
4. Experimental
4.1.1. (S)-[6-2H2]-3-Isopropyl-2,5-dimethoxy-3,6-dihydro-
pyrazine 6.19
A solution of (S)-bis-lactim ether 1
4.1. General experimental
(12.54 g, 68.0 mmol) was dissolved in a mixture of MeOD
(24.0 ml) and trifluoroacetic acid (6.0 ml) and the resultant
solution stirred for 24 h. Aqueous 1 M potassium carbon-
ate solution was added to the reaction mixture until pH
>7.0, which was then extracted with Et2O (3 · 50 ml).
The combined organic extracts were dried over MgSO4
All reactions were carried out under nitrogen or argon
using standard vacuum line techniques, and glassware that
was oven dried and cooled under nitrogen. THF was dis-
tilled from sodium/benzophenone ketyl. All other reagents
were used as supplied without further purification. Flash
column chromatography was performed on silica gel (Kie-
selgel 60). TLC was performed on Merck aluminium sheets
coated with 0.2 mm silica gel 60 F254. Plates were visual-
ised either by UV light (254 nm), iodine, ammonium
molybdate (7% solution in ethanol) or potassium perman-
ganate (1% in 2% aqueous acetic acid, containing 7%
potassium carbonate). Infrared spectra were recorded as
thin films or KBr discs using a Perkin–Elmer PARAGON
1000 FT-IR spectrometer, with selected peaks reported in
and concentrated in vacuo to afford the title compound 6
23
(11.53 g, 62.0 mmol) in 91% yield. ½aꢁD ¼ þ72:0 (c 1.0,
23
EtOH) [lit.19 ½aꢁD ¼ þ65:6 (c 1.38, EtOH)]; mmax/cmꢀ1
1694 (C@N); dH (300 MHz, CDCl3) 0.68 (3H, d, J 6.8 Hz,
CH3(CH3)CH), 0.96 (3H, d, J 6.8 Hz, CH3(CH3)CH),
2.16 (1H, m, CH(CH3)2), 3.61 (3H, s, OMe), 3.65
(3H, s, OMe), 3.92 (1H, d, J 3.5 Hz, H3); dC (75 MHz,
CDCl3) 16.8, 18.9, 32.3, 52.3, 52.4, 60.8, 162.2, 164.7; m/z
(CI) 187 (MH+, 62%), 173 (MH+ꢀMe, 100%); HRMS
(FAB+) [MH+] for C9H142H2N2O2 requires 187.1410,
found 187.1409.
cmꢀ1. H, H and 13C NMR spectra were recorded on a
Bruker AM-300 spectrometer. Chemical shifts are reported
in parts per million (ppm) and are referenced to the resid-
ual solvent peak, with coupling constants (J) measured in
Hertz. Low resolution mass spectra (m/z) were recorded
on either a Finnigan MAT 8340 instrument or a Finnigan
MAT 900 XLT instrument. Selected peaks are listed with
intensities quoted as percentages of the base peak. Accu-
rate mass measurements were recorded on a Finnigan
1
2
4.2. General procedure for the synthesis of (3S,6R)-[6-2H]-
bis-lactim ethers 12a–f
n-BuLi in hexanes (1.1 equiv) was added dropwise to a stir-
red solution of (S)-[6-2H2]-bis-lactim ether 6 (1.0 equiv) in
THF under nitrogen at ꢀ78 ꢁC and the reaction mixture

P. J. M. Taylor, S. D. Bull / Tetrahedron: Asymmetry 17 (2006) 1170–1178
1175
allowed to stir for 1 h. A solution of benzyl bromide
(1.3 equiv) in THF was then added dropwise and the reac-
tion mixture allowed to stir for a further 16 h whilst slowly
warming to room temperature. Aqueous potassium car-
bonate solution (pH >8) was then added and the reaction
extracted with Et2O (·3). The combined organic extracts
were dried over MgSO4 and concentrated in vacuo to
afford the corresponding (3S,6R)-[6-2H]-bis-lactim ethers
12a–f in >90% de that were then purified to >95% de via
column chromatography.
3.57 (3H, s, OMe), 3.64 (1H, d, J 3.4 Hz, H3), 3.66 (3H,
s, OMe), 6.80 (1H, ddd, J, 7.9, 6.4 and 2.6 Hz, ArH),
7.10–7.19 (2H, br m, ArH), 7.73 (1H, d, J 7.9 Hz, ArH);
dC (75 MHz, CHCl3) 15.5, 18.1, 30.4, 43.7, 51.5, 51.6,
59.5, 100.8, 126.7, 127.0, 130.0, 138.3, 140.2, 162.0, 162.8;
m/z (CI) 402 (MH+, 17%), 358 (M+ꢀi-Pr, 100%); HRMS
(FAB+) [MH+] for C16H202HIN2O2 requires 402.0783,
found 402.0783.
4.2.4.
(3S,6R)-[6-2H]-3-Isopropyl-6-(4-fluorobenzyl)-2,5-
dimethoxy-3,6-dihydropyrazine 12d. The reaction of (S)-
[6-2H2]-bis-lactim ether 6 (0.200 g, 1.08 mmol) in THF
(10 ml) with 2.36 M n-BuLi in hexanes (0.5 ml, 1.18 mmol)
and 4-fluorobenzyl bromide (0.265 g, 1.40 mmol) in THF
(2 ml) according to the general procedure afforded the title
4.2.1. (3S,6R)-[6-2H]-3-Isopropyl-6-benzyl-2,5-dimethoxy-
3,6-dihydropyrazine 12a.19 The reaction of (S)-[6-2H2]-
bis-lactim ether 6 (0.200 g, 1.08 mmol) in THF (10 ml) with
2.36 M n-BuLi in hexanes (0.5 ml, 1.18 mmol) and benzyl
bromide (0.240 g, 1.40 mmol) in THF (2 ml) according to
the general procedure gave the title compound 12a as a clear
compound 12d as a clear oil (0.225 g, 0.77 mmol) in 71%
25
yield and >95% de; ½aꢁD ¼ ꢀ62:4 (c 1.0, EtOAc); mmax
/
oil (0.238 g, 0.865 mmol) in 80% yield and >95% de;
cmꢀ1 1694 (C@N); dH (300 MHz, CDCl3) 0.53 (3H, d,
6.8 Hz, CH3(CH3)CH), 0.88 (3H, d, 6.8 Hz,
25
½aꢁD ¼ ꢀ41:2 (c 1.3, CH2Cl2) [lit.19 for (3R,6S)-12a, +40.4
J
J
(c 1.55, CH2Cl2)]; mmax/cmꢀ1 1681 (C@N); dH (300 MHz,
CDCl3) 0.53 (3H, d, J 6.8 Hz, CH3(CH3)CH), 0.87 (3H,
d, J 6.8 Hz, CH3(CH3)CH), 2.07 (1H, m, CH(CH3)2), 3.01
(2H, app s, CH2Ph), 3.18 (1H, d, J 3.2 Hz, H3), 3.61 (3H,
s, OMe), 3.65 (3H, s, OMe), 6.99–7.20 (5H, br m, ArH);
dC (75 MHz, MeOD) 16.8, 19.4, 31.5, 40.3, 52.5, 52.8,
60.6, 126.7, 128.2, 130.4, 137.7, 162.8, 164.4; m/z (CI)
276 (MH+, 100%); HRMS (FAB+) [MH+] for
C16H212HN2O2 requires 276.1817, found 276.1814.
CH3(CH3)CH), 2.08 (1H, m, CH(CH3)2), 2.98 (2H, app t,
J 14.0 Hz, CH2Ph), 3.25 (1H, d, J 3.0 Hz, H3), 3.59 (3H,
s, OMe), 3.63 (3H, s, OMe), 6.82 (2H, app t, J 8.1 Hz,
ArH), 6.97 (2H, dd, J 8.1, 5.8 Hz, ArH); dC (75 MHz,
MeOD) 16.8, 19.4, 31.6, 39.4, 52.5, 52.7, 60.7, 115.0 (d, J
10.5 Hz), 131.7 (d, J 3.8 Hz), 133.4, 162.6, 164.4;26 m/z
(CI) 294 (MH+, 32%), 278 (M+ꢀMe, 100%); HRMS
(FAB+) [MH+] for C16H202HFN2O2 requires 294.1723,
found 294.1721.
4.2.2.
(3S,6R)-[6-2H]-3-Isopropyl-6-(2-bromobenzyl)-2,5-
4.2.5.
(3S,6R)-[6-2H]-3-Isopropyl-6-(4-bromobenzyl)-2,5-
dimethoxy-3,6-dihydropyrazine 12b. The reaction of (S)-
[6-2H2]-bis-lactim ether 6 (0.200 g, 1.08 mmol) in THF
(10 ml) with 2.36 M n-BuLi in hexanes (0.5 ml, 1.18 mmol)
and 2-bromobenzyl bromide (0.358 g, 1.43 mmol) in THF
(2 ml) according to the general procedure afforded the title
dimethoxy-3,6-dihydropyrazine 12e.27 The reaction of
(S)-[6-2H2]-bis-lactim ether 6 (0.200 g, 1.08 mmol) in THF
(10 ml) with 2.36 M n-BuLi in hexanes (0.5 ml, 1.18 mmol)
and 4-bromobenzyl bromide (0.354 g, 1.42 mmol) in THF
(2 ml) according to the general procedure afforded the title
compound 12b as a clear oil (0.279 g, 0.79 mmol) in 73%
compound 12e as a amorphous solid (0.287 g, 0.81 mmol)
25
25
yield and >95% de; ½aꢁD ¼ ꢀ7:5 (c 1.0, EtOAc); mmax
/
in 75% yield and >95% de; mp = 58–64 ꢁC; ½aꢁD ¼ ꢀ5:2
cmꢀ1 1694 (C@N); dH (300 MHz, CDCl3) 0.58 (3H, d, J
6.8 Hz, CH3(CH3)CH), 0.94 (3H, d, J 6.8 Hz, CH3(CH3)-
CH), 2.14 (1H, m, CH(CH3)2), 2.86 (1H, d, J 14.0 Hz,
CHAHBPh), 3.39 (1H, d, J 14.0 Hz, CHAHBPh), 3.57
(3H, s, OMe), 3.59 (1H, d, J 3.6 Hz, H3), 3.66 (3H, s,
OMe), 6.99 (1H, ddd, J 9.0, 5.8 and 3.2 Hz, ArH), 7.06–
7.26 (2H, br m, ArH), 7.37–7.50 (1H, m, ArH); dC
(75 MHz, MeOD) 16.9, 19.5, 31.8, 40.6, 52.9, 56.3, 60.8,
125.8, 127.2, 128.3, 132.3, 133.0, 138.2, 163.5, 164.2; m/z
(CI) 356 (MBr81H+, 98%), 354 (100%, MBr79H+); HRMS
(FAB+) [MH+] for C16H202H79BrN2O2 requires 354.0921,
found 354.0922.
(c 1.0, EtOAc); mmax/cmꢀ11694 (C@N); dH (300 MHz,
CDCl3) 0.54 (3H, d, J 6.8 Hz, CH3(CH3)CH), 0.88 (3H,
d, J 6.8 Hz, CH3(CH3)CH), 2.08 (1H, m, CH(CH3)2),
2.96 (2H, app s, CH2Ph), 3.32 (1H, d, J 3.0 Hz, H3), 3.49
(3H, s, OMe), 3.63 (3H, s, OMe), 6.89 (2H, d, J 7.9 Hz,
ArH), 7.25 (2H, d, J 7.9 Hz, ArH); dC (75 MHz, CDCl3)
16.8, 19.4, 31.7, 39.6, 52.6, 56.7, 60.7, 120.7, 131.3, 132.0,
136.8, 162.5, 164.4; m/z (CI) 356 (M81BrH+, 33%), 354
(M79BrH+, 34%), 340 (M81Br+ꢀMe, 100%), 338
(M79Br+ꢀMe, 100%); HRMS (FAB+) [MH+] for
C16H202H79BrN2O2 requires 354.0921, found 354.0922.
4.2.6.
(3S,6R)-[6-2H]-3-Isopropyl-6-(4-trifluoromethyl-
4.2.3. (3S,6R)-[6-2H]-3-Isopropyl-6-(2-iodobenzyl)-2,5-di-
methoxy-3,6-dihydropyrazine 12c. The reaction of (S)-
[6-2H2]-bis-lactim ether 6 (0.200 g, 1.08 mmol) in THF
(10 ml) with 2.36 M n-BuLi in hexanes (0.50 ml,
1.18 mmol) and 2-iodobenzyl bromide (0.414 g, 1.40 mmol)
in THF (2 ml) according to the general procedure afforded
benzyl)-2,5-dimethoxy-3,6-dihydropyrazine 12f. The reaction
of (S)-[6-2H2]-bis-lactim ether 6 (0.200 g, 1.08 mmol) in
THF (10 ml) with 2.36 M n-BuLi in hexanes (0.5 ml,
1.18 mmol) and 4-trifluoromethylbenzyl bromide (0.330 g,
1.39 mmol) in THF (2 ml) according to the general proce-
dure afforded the title compound 12f as a crystalline solid
the title compound 12c as a clear oil (0.295 g, 0.74 mmol) in
(0.308 g, 0.90 mmol) in 83% yield and >95% de;
25
25
68% yield and >95% de; ½aꢁD ¼ ꢀ15:5 (c 1.0, EtOAc); mmax
/
mp = 57–58 ꢁC; ½aꢁD ¼ ꢀ20:7 (c 1.0, EtOAc); mmax/cmꢀ1
cmꢀ1 1692 (C@N); dH (300 MHz, CDCl3) 0.58 (3H, d, J
7.0 Hz, CH3(CH3)CH), 0.94 (3H, d, 7.0 Hz,
1694 (C@N); dH (300 MHz, CDCl3) 0.54 (3H, d, J 7.2 Hz,
CH3(CH3)CH), 0.87 (3H, d, J 7.2 Hz, CH3(CH3)CH),
J
CH3(CH3)CH), 2.15 (1H, m, CH(CH3)2), 2.86 (1H, d, J
13.6 Hz, CHAHBPh), 3.35 (1H, d, J 13.6 Hz, CHAHBPh),
2.08 (1H, m, CH(CH3)2), 2.99 (1H, d,
CHAHBPh), 3.11 (1H, d, J 13.2 Hz, CHAHBPh), 3.33 (1H,
J 13.2 Hz,

1176
P. J. M. Taylor, S. D. Bull / Tetrahedron: Asymmetry 17 (2006) 1170–1178
d, J 3.2 Hz, H3), 3.58 (3H, s, OMe), 3.63 (3H, s, OMe), 7.14
(2H, d, J 8.0 Hz, ArH), 7.39 (2H, d, J 8.0 Hz, ArH); dC
(75 MHz, MeOD); 16.7, 19.3, 31.9, 40.2, 52.5, 52.7, 60.8,
124.8 (q, J 270 Hz), 125.0 (q, J 3.8 Hz), 131.0 (q, J
32.3 Hz), 130.6, 142.2, 162.5, 164.5; m/z (CI) 344 (MH+,
15%) 300 (M+ꢀi-Pr, 100%); HRMS (FAB+) [MH+] for
C17H202HF3N2O2 requires 344.1691, found 344.1692.
0.065 mmol) in CH3CN (0.7 ml) and 0.3 M HCl (0.7 ml)
followed by chromatographic purification according to
the general procedure afforded the title compound 13c
(0.017 g, 0.05 mmol) as its hydrochloride salt in 77% yield;
25
½aꢁD ¼ ꢀ13:3 (c 1.0, EtOH); mmax/cmꢀ1 3420 (NH), 1740
(C@O); dH (300 MHz, CDCl3) 2.84 (1H, d, J 13.6 Hz,
CHAHBPh), 3.16 (1H, d, J 13.6 Hz, CHAHBPh), 3.70
(3H, s, OMe), 6.87 (1H, td, J 7.5 and 1.5 Hz, ArH), 7.14
(1H, dd, J 7.5 and 1.5 Hz, ArH), 7.22 (1H, td, J 7.5 and
1.1 Hz, ArH), 7.78 (1H, dd, J 7.5 and 1.1 Hz, ArH); dD
(60 MHz, EtOH) 4.32 (1 · 2H, s, 6-2H); dC (75 MHz,
CDCl3) 40.8, 54.0, 130.2, 131.2, 131.3, 132.1, 137.0,
140.5, 170.0; m/z (CI) 307 (MH+, 65%), 181 (MH+ꢀI,
100%); HRMS (FAB+) [MH+] for C10H112HINO2 requires
307.0048, found 307.0049.
4.3. General procedure B: synthesis of (R)-[a-2H]-phenyl-
alanine methyl esters 13a–f
(3S,6R)-[6-2H]-Bis-lactim ethers 12a–f (1.0 equiv) were
dissolved in a 1:1 solution of 0.3 M HCl and MeCN
and the resultant solution stirred vigorously for 30 min.
The reaction mixture was then concentrated in vacuo to
afford a 50:50 mixture of (S)-valine methyl ester hydro-
chloride and the respective (R)-[a-2H]-phenylalanine
methyl esters 13a–f as their hydrochloride salts. The resul-
tant mixture of a-amino acid methyl ester hydrochloride
salts was dissolved in CHCl3, neutralised via treatment
with concentrated NaHCO3 solution (1.5 equiv), before
being purified by column chromatography. The (R)-
[a-2H]-phenylalanine methyl ester obtained was then reaci-
dified via treatment with 0.3 M HCl(aq) (2 ml) and the
solvent removed in vacuo to afford the desired (R)-[a-2H]-
phenylalanine methyl esters 13a–f as their hydrochloride
salts.
4.3.4. (R)-[a-2H]-4-Fluorophenylalanine methyl ester hydro-
chloride 13d.30 The reaction of a solution of 12d (0.029 g,
0.099 mmol) in CH3CN (1.0 ml) and 0.3 M HCl (1.0 ml)
followed by chromatographic purification according to the
general procedure afforded the title compound 13d
(0.019 g, 0.081 mmol) as its hydrochloride salt in 82% yield;
25
½aꢁD ¼ ꢀ34:3 (c 1.0, EtOH); mmax/cmꢀ1 3389 (NH), 1740
(C@O); dH (300 MHz, CDCl3) 3.22 (1H, d, J 14.0 Hz,
CHAHBPh), 3.32 (1H, d, J 14.0 Hz, CHAHBPh), 3.86 (3H,
s, OMe), 7.13 (2H, m, ArH), 7.31 (2H, m, ArH); dD
(60 MHz, EtOH) 4.14 (1 · 2H, s, 6-2H); dC (75 MHz, CDCl3)
35.0, 53.9, 116.3 (J 21.8 Hz), 131.5 (J 6.8 Hz), 168.2;26 m/z
(CI) 199 (MH+, 100%); HRMS (FAB+) [MH+] for
C10H112HFNO2 requires 199.0988, found 199.0987.
4.3.1. (R)-[a-2H]-Phenylalanine methyl ester hydrochloride
13a.28 The reaction of a solution of 12a (0.022 g,
0.08 mmol) in CH3CN (1.2 ml) and 0.3 M HCl (1.2 ml)
followed by chromatographic purification according to
the general procedure afforded the title compound 13a
4.3.5. (R)-[a-2H]-4-Bromophenylalanine methyl ester hydro-
chloride 13e.31 The reaction of a solution of 12e (0.021 g,
0.060 mmol) in CH3CN (0.6 ml) and 0.3 M HCl (0.6 ml)
followed by chromatographic purification according to
the general procedure afforded the title compound 13e
(0.015 g, 0.070 mmol) as its hydrochloride salt in 88% yield;
25
½aꢁD ¼ ꢀ28:3 (c 1.0, EtOH);28
m
max/cmꢀ1 3412 (NH), 1740
(C@O); dH (300 MHz, D2O) 3.24 (1H, d, J 14.5 Hz,
CHAHBPh), 3.35 (1H, d, J 14.5 Hz, CHAHBPh), 3.85
(3H, s, OMe), 7.26–7.49 (5H, br m, ArH); dD (60 MHz,
EtOH) 4.22 (1 · 2H, s, 6-2H); dC (75 MHz, CDCl3) 35.7,
53.8, 128.3, 129.5, 129.7, 134.0, 170.3; m/z (CI) 181
(MH+, 100%); HRMS (FAB+) [MH+] for C10H122HNO2
requires 181.1082, found 181.1080.
(0.015 g, 0.051 mmol) as its hydrochloride salt in 85% yield;
25
½aꢁD ¼ ꢀ18:5 (c 1.0, EtOH); mmax/cmꢀ1 3420 (NH), 1740
(C@O); dH (300 MHz, CDCl3) 3.21 (1H, d, J 14.7 Hz,
CHAHBPh), 3.31 (1H, d, J 14.7 Hz, CHAHBPh), 3.84
(3H, s, OMe), 7.20 (2H, d, J 8.5 Hz, ArH), 7.58 (2H, d, J
8.5 Hz, ArH); dD (60 MHz, EtOH) 4.35 (1 · 2H, s, 6-2H);
dC (75 MHz, CDCl3) 35.2, 53.9, 121.8, 131.5, 132.5, 133.2,
170.2; m/z (CI) 261 (MBr81H+, 100%), 259 (MBr79H+,
99%); HRMS (FAB+) [MH+] for C10H112H79BrNO2
requires 259.0187, found 259.0184.
4.3.2. (R)-[a-2H]-2-Bromophenylalanine methyl ester hydro-
chloride 13b. The reaction of a solution of 12b (0.021 g,
0.060 mmol) in CH3CN (1.2 ml) and 0.3 M HCl (1.2 ml)
followed by chromatographic purification according to
the general procedure afforded the title compound 13b
4.3.6. (R)-[a-2H]-4-Trifluoromethylphenylalanine methyl
ester hydrochloride 13f.30 The reaction of a solution of
12f (0.031 g, 0.090 mmol) in CH3CN (1.0 ml) and 0.3 M
HCl (0.9 ml, 0.27 mmol) followed by chromatographic
purification according to the general procedure afforded
(0.013 g, 0.044 mmol) as its hydrochloride salt in 75% yield;
25
½aꢁD ¼ ꢀ20:1 (c 1.0, EtOH); mmax/cmꢀ1 3435 (NH), 1740
(C@O); dH (300 MHz, CDCl3) 3.21 (1H, d, J 14.7 Hz,
CHAHBPh), 3.53 (1H, d, J 14.7 Hz, CHAHBPh), 3.81
(3H, s, OMe), 7.25–7.44 (3H, br m, ArH), 7.70 (1H, dd,
J 7.9 and 1.0 Hz, ArH); dD (60 MHz, H2O) 4.35 (1 · 2H,
s, 6-2H); dC (75 MHz, CDCl3) 34.6, 52.1, 122.7, 126.8,
128.5, 130.3, 131.8, 131.9, 168.3; m/z (CI) 261 (MH+,
100%); MS (FAB+) [MH+] for C10H112H79BrNO2
requires 259.0187, found 259.0184.
the title compound 13f (0.022 g, 0.077 mmol) as its
25
hydrochloride salt in 86% yield; ½aꢁD ¼ ꢀ24:8 (c 1.0,
EtOH); mmax/cmꢀ1 3402 (NH), 1742 (C@O); dH (300
MHz, CDCl3) 3.33 (1H, d, J 14.5 Hz, CHAHBPh), 3.43
(1H, d, J 14.5 Hz, CHAHBPh), 3.83 (3H, s, OMe), 7.46
(2H, d, J 7.9 Hz, ArH), 7.74 (2H, d, J 7.9 Hz, ArH);
dD (60 MHz, EtOH) 4.23 (1 · 2H, s, 6-2H); m/z (CI)
2
4.3.3. (R)-[a-2H]-2-Iodophenylalanine methyl ester hydro-
chloride 13c.29 The reaction of a solution of 12c (0.026 g,
249 (MH+, 100%); HRMS (FAB+) [MH+] for C11H11
HF3NO2 requires 249.0956, found 249.0955.
-

P. J. M. Taylor, S. D. Bull / Tetrahedron: Asymmetry 17 (2006) 1170–1178
1177
4.4. Determination of the enantiomeric excess of (R)-[a-2H]-
2003, 46, 691; Nibeilliu, M. E.; Malthouse, J. P. G. Biochem.
J. 2004, 381, 847.
phenylalanine methyl ester hydrochloride 13a25
10. Raap, J.; Nieuwenhuis, S.; Creemers, A.; Hexspoor, S.;
Kragl, U.; Lugtenburg, J. Eur. J. Org. Chem. 1999, 10, 2609;
Wong, C.-H.; Whitesides, G. M. J. Am. Chem. Soc. 1983,
105, 5012.
11. Axelsson, B. S.; O’Toole, K. J.; Spencer, P. A.; Young, D. W.
J. Chem. Soc., Chem. Commun. 1991, 1085.
12. Lygo, B.; Humphreys, L. D. Tetrahedron Lett. 2002, 43, 6677;
Elemes, Y.; Ragnarsson, U. J. Chem. Soc., Perkin Trans. 1
1996, 537.
13. Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am.
Chem. Soc. 1983, 105, 5390; Seebach, D.; Dziadulewicz, E.;
Behrendt, L.; Cantoreggi, S.; Fitzi, R. Liebigs Ann. Chem.
1989, 1215.
(R)-[a-2H]-Phenylalanine methyl ester hydrochloride 13a
(5 mg), (R)-BINOL (1.05 equiv), 2-formyl-phenylboronic
acid (1.05 equiv) and caesium carbonate (2.00 equiv) were
dissolved in CDCl3 (0.5 ml). The resultant solution was fil-
tered after 10 min and the 1H NMR spectra of the resultant
(R,R)-imino-boronate ester 14 were acquired. A similar
derivatisation experiment was carried out using commer-
cially available (rac)-phenylalanine methyl ester hydrochlo-
ride salt to afford a 50:50 mixture of (R,R)-imino-boronate
ester 14 and (R,S)-imino-boronate ester 15. The enantio-
meric excess of (R)-[a-2H]-13a was assigned via comparison
of the integrals of the methoxy resonances for (R,R)-14 at
dH 3.78 with those for (R,S)-15 at dH 3.45, as well as com-
parison of the imine resonances for (R,R)-14 at dH 8.00
with those for (R,S)-15 at dH 8.41, both of which revealed
that (R)-[a-2H]-13a had been formed in >95% ee.
14. Oba, M.; Terauchi, T.; Owari, Y.; Imai, Y.; Motoyama, I.;
Nishiyama, K. J. Chem. Soc., Perkin Trans. 1 1998, 1275;
´
Davies, S. G.; Rodrıguez-Solla, H.; Tamayo, J. A.; Cowley,
´
A. R.; Concellon, C.; Garner, A. C.; Parkes, A. L.; Smith, A.
D. Org. Biomol. Chem. 2005, 3, 1435.
15. Lastra, E.; Hegedus, L. S. J. Am. Chem. Soc. 1993, 115, 87.
16. Scho¨llkopf, U.; Groth, U.; Deng, C. Angew. Chem., Int. Ed.
Engl. 1981, 20, 798.
17. For recent examples on the use of bis-lactim ether 1 for
asymmetric synthesis see: Zhou, H.; Liao, X.; Cook, J. M.
Org. Lett. 2004, 6, 249; Andrei, M.; Undheim, K. Tetra-
hedron: Asymmetry 2004, 15, 53; Hoven, G. B.; Efskind, J.;
Romming, C.; Undheim, K. J. Org. Chem. 2002, 67, 2459;
Hinterding, K.; Albert, R.; Cottens, S. Tetrahedron Lett.
2002, 43, 8095; Vivet, B.; Cavelier, F.; Martinez, J. Eur. J.
Org. Chem. 2000, 807; Ojea, V.; Ruiz, M.; Shapiro, G.;
Pombo-Villar, E. J. Org. Chem. 2000, 65, 1984; Kotha, S.;
Sreenivasachary, N.; Halder, S. Bioorg. Med. Chem. Lett.
1999, 9, 2565; Bull, S. D.; Chernega, A. N.; Davies, S. G.;
Moss, W. O.; Parkin, R. M. Tetrahedron 1998, 54, 10379.
18. Gelb, M. H.; Lin, Y.; Pickard, M. A.; Song, Y.; Vederas, J. C.
J. Am. Chem. Soc. 1990, 112, 4932.
Acknowledgements
We would like to thank the EPSRC (P.J.M.T.) and the
Royal Society (S.D.B.) for funding, CELLTECH
(P.J.M.T.) for a CASE award, and the Mass Spectrometry
Service at the University of Wales, Swansea, for their
assistance.
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20. For previous syntheses of enantiopure [2H]-phenylalanine
derivatives see: Maegawa, T.; Akashi, A.; Esaki, H.; Aoki, F.;
Sajiki, H.; Hirota, K. Synlett 2005, 845.
21. Granik, V. G.; Pyatin, B. M.; Persianova, I. V.; Peresleni, E.
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Tetrahedron 1970, 26, 4367.
22. (S)-Bis-lactim ether 1 was prepared according to our previously
reported synthesis, see: Bull, S. D.; Davies, S. G.; Moss, W. O.
Tetrahedron: Asymmetry 1998, 9, 321; See also Chen, J.;
Corbin, S. P.; Holman, N. J. Org. Proc. Res. Dev. 2005, 9, 185.
23. The integral of the C3-proton doublet resonance of (S)-
[6-2H2]-bis-lactim ether 6 was equivalent to one proton when
compared with the integrals of the sharp OCH3 and
CH(CH3)2 resonances that were known to correspond to
three protons.
5. Kelly, N. M.; Sutherland, A.; Willis, C. L. Nat. Prod. Rep.
1997, 14, 205.
6. Reider, P. J.; Conn, R. S. E.; Davis, P.; Grenda, V. J.;
Zambito, A. J.; Grabowski, E. J. J. J. Org. Chem. 1987, 52,
3326.
7. Mitulovi, G.; La¨mmerhofer, M.; Maier, N. M.; Lindner, W.
J. Labelled Compd. Radiopharm. 2000, 43, 449.
24. For a report of a monomeric X-ray crystal structure of (R)-
bis-lactim ether
1
complexed with N,N,N0,N0,N00-penta-
8. Fujihara, H.; Schowen, R. L. J. Org. Chem. 1984, 49, 2819;
Chen, S. T.; Tu, C. C.; Wang, K. T. Biotechnol. Lett. 1992,
14, 269.
methyldiethylenetriamine that clearly displays the half-boat
conformation of the dihydropyrazine ring, see: Andrews, P.
C.; Maguire, M.; Pombo-Villar, E. Helv. Chim. Acta 2002, 85,
3516.
9. Faleev, N. G.; Ruvinov, S. B.; Saporovskaya, M. B.; Belikov,
V. M.; Zakomyrdina, L. N.; Sakharova, I. S.; Torchinsky, Y.
M. Tetrahedron Lett. 1990, 31, 7051; Milne, J. J.; Malthouse,
J. P. G. Biochem. Soc. Trans. 1996, 24, 133S; Lim, Y. H.;
Yoshimura, T.; Soda, K.; Esaki, N. J. Ferment. Bioeng. 1998,
86, 400; Mosin, O. V.; Skladnev, D. A.; Shvets, V. I. Biosci.,
Biotechnol., Biochem. 1998, 62, 225; Boroda, E.; Rakowska,
S.; Kanski, R.; Kanska, M. J. Labelled Compd. Radiopharm.
´
25. Perez-Fuertes, Y.; Kelly, A. M.; Johnson, A. L.; Arimori, S.;
Bull, S. D.; James, T. D. Org. Lett. 2006, 8, 609.
26. Resonances were not observed for the weak quaternary aro-
matic resonances in the 13C NMR spectra of these compounds.
27. For a previous report of non-deuterated (3S,6R)-3-isopropyl-
6-(4-bromobenzyl)-2,5-dimethoxy-3,6-dihydropyrazine 12e
25
(½aꢁD ¼ ꢀ50:3 (c 6.7, CH2Cl2)), see: Fauq, A. H.;

1178
P. J. M. Taylor, S. D. Bull / Tetrahedron: Asymmetry 17 (2006) 1170–1178
Ziani-Cherif, C.; Richelson, E. Tetrahedron: Asymmetry
1998, 9, 2333.
1.0, EtOH)) and non-deuterated (S)-4-trifluoromethyl-
24
phenylalanine methyl ester hydrochloride 13f (½aꢁD
¼
28. For a previous report of non-deuterated (R)-phenylalanine
þ24:0 (c 0.5, EtOH)), see: Gerisch, S.; Jakubke, H.-D.;
Kreuzfeld, H.-J. Tetrahedron: Asymmetry 1995, 6,
3039.
25
methyl ester hydrochloride (½aꢁD ¼ ꢀ24:8 (c 2.2, EtOH)), see:
Ref. 16.
29. For a previous report of non-deuterated (S)-2-iodophenyl-
alanine methyl ester hydrochloride 13c, see: Barluenga, J.;
31. For a previous use of non-deuterated (S)-4-bromophenyl-
alanine methyl ester hydrochloride 13e, see: Sircar, I.;
Gudmundsson, K. S.; Martin, R.; Liang, J.; Nomura, S.;
Jayakumar, H.; Teegarden, B. R.; Nowlin, D. M.; Cardarelli,
P. M.; Mah, J. R.; Connell, S.; Griffith, R. C.; Lazarides, E.
Bioorg. Med. Chem. 2002, 10, 2051.
´
´
´
Garcıa-Martin, M. A.; Gonzalez, J. M.; Clapes, P.; Valencia,
G. Chem. Commun. 1996, 1505.
30. For previous reports of non-deuterated (S)-4-fluorophen-
24
ylalanine methyl ester hydrochloride 13d (½aꢁD ¼ þ32:2 (c