Orthogonally Protected Sch?llkopf's Bis-lactim Ethers for the Asymmetric Synthesis of α-Amino Acid Derivatives and Dipeptide Esters

Article abstract of DOI:10.1055/s-0035-1561943

Alkylation of the aza-enolates of orthogonally protected chiral bis-lactim ethers with electrophiles proceeds with good levels of diastereocontrol to afford trans-alkylated adducts that can be efficiently deprotected via hydrolysis/hydrogenation procedures to afford non-proteinogenic α-amino acid or dipeptide ester derivatives.

Full text of DOI:10.1055/s-0035-1561943

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–N
feature
A
M. Hutchby et al.
Feature
Synthesis
Orthogonally Protected Schöllkopf’s Bis-lactim Ethers for the
Asymmetric Synthesis of α-Amino Acid Derivatives and Dipeptide
Esters
Marc Hutchby
H2N
CO2Et
H3N
CO2
hydrolysis
Adam C. Sedgwick
Steven D. Bull*
+
E
hydrogenolysis
i. n-BuLi, THF
–78 °C
organic
phase
aqueous
phase
N
N
OBn
E
N
N
OBn
Department of Chemistry, University of Bath, Bath BA2 7AY, UK
s.d.bull@bath.ac.uk
ii. EX
EtO
E
EtO
H
hydrogenolysis
hydrolysis
EtO2C
N
NH2
O
non-proteinogenic
dipeptide ester
Received: 01.02.2016
Accepted: 19.02.2016
Published online: 26.04.2016
DOI: 10.1055/s-0035-1561943; Art ID: ss-2016-z0082-fa
lective alkylation of glycine enolate equivalents derived
from peptidic substrates.8 For example, enolates of chiral
heterocyclic mono-lactim ether templates derived from va-
line have been alkylated with high levels of diastereocontrol
to afford trans-alkylated adducts that could then be hydro-
lysed to afford dipeptide derivatives.9 Given the potential
importance, we now report herein on methodology that en-
ables orthogonally protected bis-lactim ethers 5 and 17 to
be used as glycine enolate equivalents for the efficient
asymmetric synthesis of non-proteinogenic α-amino acid
and dipeptide ester derivatives.
Abstract Alkylation of the aza-enolates of orthogonally protected chi-
ral bis-lactim ethers with electrophiles proceeds with good levels of di-
astereocontrol to afford trans-alkylated adducts that can be efficiently
deprotected via hydrolysis/hydrogenation procedures to afford non-
proteinogenic α-amino acid or dipeptide ester derivatives.
Key words asymmetric synthesis, orthogonal protection, bis-lactim
ethers, hydrogenolysis, separation, non-proteinogenic, chiral α-amino
acids, dipeptide esters
Schöllkopf’s chiral bis-lactim ether methodology has
proven to be one of the most popular glycine enolate equiv-
alents for the asymmetric synthesis of α-amino acid deriva-
tives,10 with >475 reports of its use by >225 research groups
having been reported to date.11 In this approach, a bis-lac-
tim ether 1 is deprotonated with a strong base to afford an
aza-enolate that reacts with an electrophile at –78 °C to af-
ford a trans-disubstituted bis-lactim ether 2 with good lev-
els of diastereocontrol (Scheme 1). The major trans-diaste-
reomer 2 is then hydrolysed under mild acidic conditions to
afford a mixture of the desired α-amino ester 3 and volatile
valine ester 4, whose free amines may then be separated via
fractional distillation or chromatography.10 This final sepa-
ration step can be problematic however, particularly if the
desired α-amino ester 3 has a similar volatility/polarity to
the valine ester 4 component. As part of our ongoing re-
search program into the development of efficient method-
ology for the asymmetric synthesis of α-amino acid deriva-
tives,12 we envisaged that an orthogonally protected 2nd
generation Schöllkopf auxiliary 5 (or 17) might prove useful
in addressing this separation problem (Scheme 1).13 In this
approach, mild acid-catalysed hydrolysis of trans-alkylated
bis-lactim ether 6 would afford a mixture of a less volatile
α-amino benzyl ester 7 and valine ethyl ester (4) that could
then be easily separated via fractional distillation. Alterna-
Chiral non-proteinogenic α-amino acids are attractive
synthetic targets that occur widely throughout nature,
where they are often present as structural components
within peptides.1 They are also widely used as chiral build-
ing blocks for the synthesis of drug candidates, chiral auxil-
iaries, ligands and catalysts for asymmetric synthesis.2 Mo-
lecular biology techniques have been developed that allow
their incorporation into nonnatural proteins and antibodies
that exhibit catalytic and therapeutic applications.3 As a
consequence, a wide range of methods have been devel-
oped for their stereoselective synthesis, including ap-
proaches that rely on derivatisation of the side chains of
proteinogenic α-amino acids.4 They have also been pre-
pared using a myriad of synthetic protocols that rely on the
use of chiral auxiliaries, transition-metal catalysts, organo-
catalysts and biocatalysts for stereocontrol.5 Peptides con-
taining non-proteinogenic α-amino acids are normally pre-
pared using conventional peptide bond coupling reactions
between appropriately protected α-amino acids.6 However,
a few reports have described how non-proteinogenic pep-
tides can be prepared via diastereoselective functionalisa-
tion of achiral fragments present within chiral peptide sub-
strates.7 These include approaches that rely on diastereose-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

B
M. Hutchby et al.
Feature
Synthesis
tively, if this mixture of α-amino esters (7 and 4) was sub-
jected to hydrogenolysis, then the resultant mixture of α-
amino acid 8 and valine ethyl ester (4) could be easily sepa-
rated via partitioning between aqueous and organic sol-
vents. Finally, hydrogenolysis of trans-alkylated bis-lactim
ethers 6 would result in selective O-debenzylation to afford
a lactam 9 whose mono-lactim ether bond could then be
hydrolysed to afford a non-proteinogenic dipeptide ester 10
as required.14,15
steps (Scheme 2a).18 Its regioisomeric bis-lactim ether 17
was prepared by treatment of N-(p-methoxybenzyl)diketo-
piperazine 1416 with benzyl trichloroacetimidate and a cat-
alytic amount of BF3·OEt2 to afford mono-lactim ether 15,
whose p-methoxybenzyl group was removed oxidatively
using excess cerium(IV) ammonium nitrate.16 The amide
functionality of lactam 16 was then alkylated using excess
Et3OBF4 to afford bis-lactim ether 17 in 49% yield over three
steps (Scheme 2b).
Our synthesis of bis-lactim ether 5 commenced with
treatment of L-valine-derived N-benzyldiketopiperazine
1116 with excess triethyloxonium tetrafluoroborate
(Et3OBF4) in dichloromethane to afford mono-lactim ether
12.17 The N-benzyl group of 12 was then removed using
Birch conditions (Na/NH3) to afford lactam 13 which was O-
benzylated via treatment with excess benzyl trichloroace-
timidate and a catalytic amount of BF3·OEt2 in dichloro-
methane to give bis-lactim ether 5 in 58% yield over three
Orthogonally protected bis-lactim ether 5 was then
treated with n-BuLi in THF at –78 °C to provide an aza-eno-
late that was reacted with benzyl bromide to afford trans-
benzylated bis-lactim ether 6a in 83% and 95% de (Table 1,
entry 1).19 This result is comparable with that observed for
benzylation of the aza-enolate of Schöllkopf’s bis-lactim
ether 1 (R = Me),10b which in our hands gave its correspond-
ing trans-benzylated bis-lactim ether in 89% yield and 95%
de.
Biographical Sketches
Marc Hutchby, who is origi-
nally from Carlisle, graduated
under the supervision of Prof.
Kevin Booker-Milburn and Prof.
Guy Lloyd-Jones (2007–2011).
After spending 2 years as a Pub-
lishing Editor at the RSC work-
ing on Chemical Communications
and Chemical Science, he was ap-
pointed as a Postdoctoral Re-
search Assistant at the
with
a
BSc in Medicinal and
University of Bath working on
the development and catalytic
upgrading of biorenewable
feedstocks.
Pharmaceutical Chemistry in
2007 from Loughborough Uni-
versity. Following this, he head-
ed to Bristol, obtaining his PhD
Adam Sedgwick, who is origi-
nally from Surrey, graduated
trial placement at BioFocus
working as a medicinal chemist
synthesising compound libraries
for various drug discovery appli-
cations. He is currently working
towards the completion of his
PhD studies at the University of
Bath developing methodology
for the synthesis of novel fluo-
rescent sensors for the detec-
tion of reactive oxygen species
in vivo.
with
a 1st class MChem in
Chemistry for Drug Discovery
from the University of Bath in
2014. During his undergraduate
degree he undertook an indus-
Steven Bull was born in Cardiff
in 1964. He received a BSc Jt
Hons degree from the Universi-
ty of Cardiff and a PhD from the
University of Cardiff (with Dr D.
R. Kelly), and was a Postdoctoral
Fellow at the University of
Queensland with Dr R. M.
Carman (1991–1993) and the
University of Oxford with Prof.
S. G. Davies (1994–2000). He
was appointed to a Lectureship
in Organic Chemistry at the Uni-
versity of Bath in 2000 and is
currently Reader and Head of
Organic Chemistry at Bath. He
has published around 150 pa-
pers on the development of
novel methodology for the syn-
thesis of drug molecules, natu-
cals. He has also introduced a
number of NMR protocols for
determining the enantiomeric
excess of chiral analytes and has
also developed novel fluores-
cent and electrochemical sen-
sors for the detection of a range
of analytes, including fluoride,
alkylating agents and reactive
oxygen species.
ral
products,
metabolic
intermediates and fine chemi-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

C
M. Hutchby et al.
Feature
Synthesis
a) Schöllkopf bis-lactim ether methodology10
nBuLi, THF,
–78 °C; EX
i. TFA–MeCN
rt, 16 h
N
OR
N
OR
E
H2N
CO2R
H2N
CO2R
+
ii. Et3N, CHCl3
E
RO
N
RO
N
1
2
3
4
good levels of
diastereoselectivity
R = Me or Et
non-proteinogenic
α-amino ester
volatile
b) This work
nBuLi, THF,
–78 °C; EX
acid-catalysed
hydrolysis
N
OBn
N
OBn
E
H2N
CO2Et
H2N
CO2Bn
+
neutralisation
EtO
N
E
EtO
N
5
6
7
4
more volatile
hydrogenation
hydrogenation
H
N
O
H2N
CO2Et
H3N
CO2
+
EtO
N
E
E
8
9
4
aqueous
soluble
organic
soluble
E
H
acid-catalysed
hydrolysis
EtO2C
N
NH2
neutralisation
O
10
dipeptide ester
Scheme 1 (a) Schöllkopf’s bis-lactim ether 1 as a chiral template for the asymmetric synthesis of chiral α-amino esters 3; (b) Orthogonally protected
bis-lactim ether 5 for the asymmetric synthesis of chiral α-amino esters 7, α-amino acids 8 or dipeptide esters 10.
The aza-enolate of bis-lactim ether 5 was then reacted
with a range of activated alkyl bromides to give the corre-
sponding trans-alkylated products 6b–e in 59–90% yield
and ≥90% de (Table 1, entries 2–5). Reaction with the less
sterically demanding iodomethane gave trans-bis-lactim
ether 6f in 89% yield in a significantly reduced 70% de (Table
1, entry 6). However, reaction of the aza-enolate of bis-lac-
tim ether 5 with iodoethane, an electrophile that is prone
to competing E2 elimination reactions, gave trans-bis-lac-
tim ether 6g in 92% yield and 90% de (Table 1, entry 7).
Subsequent treatment of 6g with n-BuLi in THF at –78 °C,
followed by reaction with iodomethane, gave bis-lactim
ether 6h, containing a new quaternary centre, in 71% yield
and 98% de (Table 1, entry 8). A deuterated version of bis-
lactim ether 5-d2 was prepared via reaction of 5 with AcOD
in CD3OD at room temperature for 18 hours.20 The aza-eno-
late of bis-lactim ether 5-d2 was then alkylated with benzyl
bromide under standard conditions to afford trans-ben-
zylated bis-lactim ether 6a-d in 78% yield and 95% de (Table
1, entry 9), with no scrambling or loss of the deuterium la-
bel. The aza-enolate of bis-lactim ether 5 also reacted effec-
tively with benzophenone to afford aldol product 6i in 79%
yield and 95% de (Table 1, entry 10),21 while the conjugate
addition reaction with methyl cinnamate afforded ester 6j
containing two new stereocentres in 58% yield and 90% de
(Table 1, entry 11).22 Finally, reaction of the aza-enolate of
bis-lactim ether 5 with iodine resulted in dimerisation oc-
curring, to afford bis-lactim ether dimer 6k in 61% yield and
98% de (Table 1, entry 12).23
Our attention then turned to the corresponding enolate
alkylation reactions of the regioisomeric bis-lactim ether
17. The aza-enolate of 17 was generated using n-BuLi in
THF at –78 °C and reacted with benzyl bromide, iodoethane
and iodine to afford the corresponding trans-alkylated bis-
lactim ethers 18a–c in 56–68% yield and 95–98% de
(Scheme 3). Although the yields observed for the aza-eno-
late alkylation reactions of 17 are lower than those for bis-
lactim ether 5, the trans-bis-lactim ether adducts 18a–c
were all produced with excellent levels of diastereocontrol.
We next explored the hydrolytic properties of trans-bis-
lactim ether 6c that contains a hydrogenolytically sensitive
allyl group. After considerable optimisation studies, it was
found that stirring a solution of 6c in a mixture of 0.3 M HCl
and acetonitrile for 18 hours resulted in clean hydrolysis to
afford allylglycine benzyl ester hydrochloride (7a·HCl) and
valine ethyl ester hydrochloride (4·HCl). Neutralisation
with aqueous NaHCO3, followed by extraction into chloro-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

D
M. Hutchby et al.
Feature
Synthesis
trans-bis-lactim ether 6d gave a mixture of the aspartate
bis-ester 7b and valine ethyl ester (4) as their hydrochloride
salts. This mixture of α-amino esters was then hydrogenat-
ed over Pd/C in THF using 1 atmosphere of hydrogen to af-
ford a mixture of β-tert-butyl aspartate (19) and valine eth-
yl ester (4) as their hydrochloride salts. Neutralisation with
aqueous NaHCO3, followed by extraction of valine ethyl es-
ter (4) into chloroform, acidification of the aqueous layer
with HCl and removal of water, afforded β-tert-butyl aspar-
tate hydrochloride (19·HCl) in 88% isolated yield (Scheme
4b). Finally, hydrolysis of bis-lactim ether 18b, followed by
hydrogenation of the resultant mixture of α-amino esters
20 and 21, allowed ethyl 2-aminobutyrate (20) to be ob-
tained cleanly by extraction into chloroform in 75% yield,
with valine (22) being recovered from the aqueous phase as
required (Scheme 4c). Therefore, these three examples
clearly demonstrate that bis-lactim ether templates 5 and
17 can be used to simplify the asymmetric synthesis of α-
(a)
Bn
N
Bn
N
O
O
Et3OBF4
CH2Cl2
EtO
O
N
H
N
11
12
Na/NH3
THF, –78 °C
NH
H
N
N
OBn
O
Cl3C
OBn
BF3·OEt2 (cat)
CH2Cl2
EtO
N
EtO
N
5
13
58% over 3 steps
(b)
NH
PMB
N
PMB
Cl3C
OBn
O
N
O
BF3·OEt2 (cat)
CH2Cl2
BnO
N
O
N
H
14
15
CAN (2 equiv)
MeCN–H2O
(a) Separation by fractional distillation
i. 0.3 M HCl–MeCN
rt, 18 h, quant
H2N
CO2Bn
CO2Et
H2N
6c
+
H
N
ii. 10% NaHCO3 (aq)
N
OEt
O
Et3OBF4
CH2Cl2
7a
4
more volatile
BnO
N
BnO
N
separated by fractional distillation
17
16
(b) Hydrogenolytic separation approach 1
49% over 3 steps
0.3 M HCl–MeCN
rt, 18 h, quant
H3N
CO2Bn
CO2Et
H3N
Scheme 2 Synthesis of orthogonally protected bis-lactim ethers 5 and
17
+
6d
CO2tBu
7b
4
i. 10% Pd/C
1 atm H2
THF, rt, 18 h
ii. 10% NaHCO3 (aq)
iii. HCl (aq)
nBuLi, THF
–78 °C
N
OEt
N
N
OEt
R
BnBr or EtI
H2N
CO2Et
H3N
CO2H
BnO
N
BnO
+
18a R = Bn, 68%, 98% de
18b R = Et, 56%, 95% de
17
CO2tBu
nBuLi, THF
–78 °C; I2
19
4
soluble in H2O
soluble in CHCl3
N
OEt
(c) Hydrogenolytic separation approach 2
H
0.3 M HCl–MeCN
rt, 18 h, quant
N
OBn
H3N
CO2Bn
H3N
CO2Et
BnO
N
+
H
18b
EtO
N
20
21
ii. 10% NaHCO3 (aq)
18c 66%, 98% de
(i) 10% Pd/C
1 atm H2
THF, rt, 18 h
Scheme 3 trans-Alkylation reactions of the aza-enolate of bis-lactim
ether 17
H2N
CO2
H2N
CO2Et
+
form and careful removal of the solvent and volatile valine
ethyl ester (4, bp 202 °C) in vacuo, resulted in isolation of
allylglycine benzyl ester (7a, bp 285 °C) in 85% yield
(Scheme 4a). This clearly demonstrates the potential advan-
tage of using orthogonally protected bis-lactim ether 5 for
synthesis, since employing bis-lactim ether 1 (R = Et) would
have afforded a mixture of allylglycine ethyl ester and va-
line ethyl ester, whose similar physical properties would
have made them very difficult to separate by fractional dis-
tillation or chromatography. Alternatively, hydrolysis of
20
soluble in CHCl3
22
soluble in H2O
Scheme 4 (a) Hydrolysis of bis-lactim ether 6c to afford a mixture of
allylglycine benzyl ester (7a) and valine ethyl ester (4) that were sepa-
rated by fractional distillation; (b) Hydrolysis/hydrogenation of bis-lac-
tim ether 6d to afford a mixture of β-tert-butyl aspartate (19) and
valine ethyl ester (4) that were separated by partitioning between wa-
ter and chloroform; (c) Hydrolysis/hydrogenation of bis-lactim ether
18b to afford a mixture of ethyl 2-aminobutyrate (20) and valine (22)
that were separated by partitioning between chloroform and water.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

E
M. Hutchby et al.
Feature
Synthesis
Table 1 (continued)
Entry R, R1 EX
amino esters (or α-amino acids) using hydrolytic/hydroge-
nation protocols that facilitate their efficient separation
from their valine chiral auxiliary components.
Bis-lactim ether 6a–kb
Yield dec
(%)
(%)
Table 1 Stereoselective Alkylation of the Aza-enolate of Orthogonally
Protected Bis-lactim Ether 5a
N
N
OBn
D
Br
9
D, D
H, H
78
95
Ph
EtO
6a-d
i. nBuLi, THF, –78 °C, 15 min
ii. EX, THF, –78 °C to rt, 18 h
N
OBn
R1
N
OBn
R1
N
N
OBn
EtO
N
EtO
N
E
R
O
6a–k
5
10
Ph
OH
79
58
95
90
EtO
Ph
Ph
Ph
Ph
Entry R, R1 EX
Bis-lactim ether 6a–kb
Yield dec
(%) (%)
6i
N
N
OBn
H
N
N
OBn
Ph
O
Br
11
12
H, H
1
2
3
H, H
H, H
H, H
83
95
EtO
CO2Me
OMe
EtO
H
Ph
6a
6j
N
N
OBn
2-Naph
Br
N
N
OBn
H
90
88
59
89
89
92
98
95
90
98
70
90
EtO
N
OEt
EtO
H, H I2
61
98
6b
H
BnO
N
N
N
OBn
6k
Br
Br
a Reaction conditions: i. bis-lactim ether 5 (1 mmol), n-BuLi (1.6 M in hex-
anes, 1.5 mmol), THF (5 mL), –78 °C, 15 min; ii. EX (2 mmol), THF (5 mL),
–78 °C to r.t., 18 h.
EtO
6c
b The trans configuration was assigned from literature precedent for reaction
of the aza-enolate of bis-lactim ether 1 with electrophiles.10
c Diastereoselectivities determined from 1H NMR analysis of crude reaction
products.
N
N
OBn
CO2tBu
O
4
5
6
7
H, H
H, H
OtBu
EtO
6d
We then explored an alternative deprotection strategy
for bis-lactim ethers 6 and 18, based on reversal of the hy-
drolysis/hydrogenation steps, that would allow for the syn-
thesis of non-proteinogenic dipeptide esters 10 and 23.
Thus, hydrogenolysis of the benzyl lactim ether bond of bis-
lactim ether 6a resulted in formation of the amide moiety
of mono-lactim ether 9 (E = Bn),23 that was then hydrolysed
under our standard conditions (0.3 M HCl, MeCN, 18 h) to
afford dipeptide 10a in 97% yield (Table 2, entry 1). Treat-
ment of bis-lactim ether 18a using these conditions also re-
sulted in clean hydrogenation/hydrolysis to afford the cor-
responding regioisomeric dipeptide ester 23a in 95% yield
(Table 2, entry 2). Deuterated bis-lactim ether 6a-d was ef-
ficiently converted into its corresponding dipeptide 10a-d
with no scrambling or loss of deuterium in 98% yield (Table
2, entry 3), whilst 2-naphthylmethyl-substituted bis-lactim
ether 6b afforded its corresponding dipeptide 10b in 97%
yield (Table 2, entry 4). Standard peptide coupling reactions
of sterically hindered α,α-dialkylated amino acids are often
problematic,6a,24 so it was pleasing that hydrogenation/hy-
drolysis of bis-lactim ether 6h cleanly afforded dipeptide
10c containing a quaternary carbon stereocentre in an ex-
N
N
OBn
OBn
OBn
Br
EtO
6e
N
N
H, H MeI
EtO
6f
N
N
H, H EtI
EtO
6g
N
N
OBn
8
Me, H EtI
71
98
EtO
6h
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

F
M. Hutchby et al.
Feature
Synthesis
cellent 96% yield (Table 2, entry 5). Bis-lactim ether 6j was
hydrogenated/hydrolysed to afford dipeptide 10d contain-
ed chiral bis-lactim ethers derived from other amino acid
precursors for this hydrogenolysis/hydrolysis methodology
should allow for the asymmetric synthesis of a wide range
of structurally diverse non-proteinogenic dipeptide esters.
In conclusion, we have demonstrated that alkylation of
the aza-enolate of orthogonally protected chiral bis-lactim
ether 5 (or 17) proceeds with good levels of diastereocon-
trol. The resultant trans-alkylated adducts 6 (or 18) can
then be efficiently deprotected using hydrolysis/hydroge-
nation protocols to afford the respective non-proteinogenic
α-amino esters or α-amino acids, as required. Alternatively,
employing hydrogenation/hydrolysis deprotection steps for
trans-alkylated adducts 6 (or 18) enables chiral non-pro-
teinogenic dipeptide esters to be prepared in good yield.
ing
a β-aryl-substituted methyl glutamate derivative,
whose analogues have previously shown activity as glyco-
gen phosphorylase and thrombin inhibitors (Table 2, entry
6).25 Deprotection of bis-lactim ether dimers 6k and 18c
gave symmetric dipeptides 10e and 23b derived from a
central (R,R)-3-aminoaspartic acid core, in 90% and 96%
yield respectively. Analogues of 10e and 23b have previous-
ly been shown to demonstrate haemoregulatory and ad-
vanced glycation endpoint inhibitory activities.26 It should
be noted that alkylation reactions of aza-enolates of bis-lac-
tim ethers derived from other types of nonbranched α-ami-
no acids also proceed with good levels of diastereocontrol.27
Consequently, employing alternative orthogonally protect-
Table 2 Hydrogenolytic/Hydrolysis Deprotection Strategy for Bis-lactim Ethers 6 and 18 for the Synthesis of Non-proteinogenic Dipeptide Esters 10
and 23a
i. 10% Pd/C (10 mol%)
1 atm H2, THF, rt, 1 h
R
N
OBn
R
H
N
EtO2C
NH2
ii. 0.3 M HCl–MeCN
rt, 18 h
EtO
N
O
10% NaHCO3 (aq)
6
10
or
i. 10% Pd/C (10 mol%)
1 atm H2, THF, rt, 1 h
O
R
N
OEt
R
H2N
N
H
CO2Et
ii. 0.3 M HCl–MeCN
rt, 18 h
BnO
N
10% NaHCO3 (aq)
23
18
Entry
1
Bis-lactim ether
Dipeptide
Yield (%)
97
Ph
H
N
OBn
Ph
EtO2C
N
NH2
O
EtO
N
6a
10a
Ph
O
N
N
OEt
H
H2N
2
3
4
N
CO2Et
95
98
97
H
Ph
BnO
18a
23a
D
Ph
NH2
H
N
N
OBn
D
EtO2C
N
Ph
O
EtO
10a-d
6a-d
2-Naph
NH2
H
N
N
N
OBn
2-Naph
EtO2C
O
EtO
6b
10b
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

G
M. Hutchby et al.
Feature
Synthesis
Table 2 (continued)
Entry
Bis-lactim ether
Dipeptide
Yield (%)
N
OBn
H
N
EtO2C
5
6
96
89
NH2
EtO
N
O
10c
6h
Ph
O
N
N
OBn
H
CO2Me
NH2
H
N
EtO2C
EtO
CO2Me
H
Ph
10d
6j
N
N
OBn
H
NH2
O
H
N
EtO2C
N
OEt
N
CO2Et
EtO
7
90
H
H
O
NH2
BnO
N
10e
6k
N
N
OEt
CO2Et
O
H
H
N
N
OBn
H2N
N
BnO
N
NH2
8
96
H
H
O
EtO2C
EtO
23b
18c
a Reaction conditions: i. bis-lactim ether 6 or 18 (0.5 mmol), Pd/C (10 mol%), H2 (1 atm), THF (10 mL), r.t., 1 h; ii. 0.3 M HCl–MeCN (1:1, 20 mL), r.t., 18 h; then,
10% aq NaHCO3, CH2Cl2 extraction.
alised under UV light (at 254 nm) or by staining with potassium per-
manganate, ninhydrin or phosphomolybdic acid followed by gentle
heating. Flash chromatography was performed under manually gen-
erated medium pressure using Merck 60 H silica gel (35–75 μm), un-
less otherwise stated. ORD measurements were recorded on a Jasco J-
600 spectrometer scanning from 400 to 204 nm, using a cell with a
length of 0.2 cm.
Reactions that required the use of anhydrous solvents were conduct-
ed in oven-dried glassware under an atmosphere of nitrogen using in-
ert atmosphere techniques. Dried solvents were obtained by passage
through anhydrous alumina columns using an Innovative Technology
Inc. PS-400-7 solvent purification system. THF was further dried by
distillation over sodium/benzophenone. All commercially available
compounds were used as obtained from chemical suppliers. n-BuLi
was titrated (menthol/2,2′-bipyridyl) prior to use. 1H and 13C NMR
spectra were run in CDCl3 using Bruker Avance 300 and 500 MHz
spectrometers. Chemical shifts (δ) are quoted in parts per million and
are referenced to the residual solvent peak. The multiplicities and
general assignments of spectroscopic data are denoted as singlet (s),
doublet (d), triplet (t), quartet (q), quintet (quint), sextet (sex), septet
(sept), doublet of doublets (dd), triplet of doublets (td), triplet of trip-
lets (tt), doublet of quartets (dq), multiplet (m), aromatic (ArH), broad
(br) and apparent (app). Coupling constants (J) are quoted to the
nearest 0.1 Hz. All structural assignments of both 1H and 13C NMR
spectra were achieved with the aid of COSY, HMQC and HMBC experi-
ments wherever possible and with comparisons from analogous pre-
viously reported compounds. Infrared spectra were recorded on a
Perkin Elmer Spectrum 100 FT-IR spectrometer, using a Universal ATR
accessory for sampling, with only selected absorbances quoted as ν in
cm–1. Mass spectra were recorded on a micrOTOF electrospray ionisa-
tion time-of-flight (ESI-TOF) mass spectrometer (Bruker Daltonik
GmbH, Bremen, Germany), using MeCN or water to dissolve the sam-
ple. TLC was carried out using commercially available polyethylene-
backed plates coated with Merck Kieselgel 60 GF254. Plates were visu-
(S)-2-Isopropyl-3-ethoxy-6-benzyloxy-2,5-dihydropyrazine (5)
To a suspension of 1116 (10 g, 40.65 mmol) in anhydrous CH2Cl2 (50
mL) was added Et3OBF4 (9.5 g, 50 mmol). This suspension was stirred
at r.t. under N2 for 36 h, resulting in a clear solution. To this solution
was added phosphate buffer (100 mL) followed by separation and se-
quential washings (phosphate buffer, water, sat. NaCl) of the organic
layer. After drying (MgSO4) and solvent evaporation in vacuo, the re-
sultant yellow oil 12 was used without purification. 12 was dissolved
in anhydrous THF (30 mL) and was added slowly to a deep blue/black
solution of dissolved Na in liquid NH3 (100 mL) at –78 °C. After warm-
ing to 0 °C and careful quenching of the excess sodium, the solvent
was removed in vacuo to leave 13 as an orange oil. This crude materi-
al was dissolved in anhydrous CH2Cl2 (50 mL) to which was added
benzyl trichloroacetimidate (18.9 g, 75 mmol). The solution was
cooled to 0 °C and BF3·OEt2 (1.83 mL, 5 mmol) was added dropwise
followed by gradual warming to r.t. and stirring for 48 h. Upon com-
pletion, sat. NaHCO3 (200 mL) was added, and the organic layer was
separated and further washed with additional portions of water and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

H
M. Hutchby et al.
Feature
Synthesis
sat. NaCl. After solvent evaporation, the resultant yellow oil was puri-
fied by column chromatography (Et2O–pentane, 3:97) to yield 5 as a
colourless oil (6.46 g, 58% over 3 steps); [α]D23 +9 (c 1.0, EtOH).
1H NMR (300 MHz, CDCl3): δ = 7.30–7.40 (m, 5 H, ArH), 5.17 (app q,
J = 12.2 Hz, 2 H, OCH2Ar), 4.06–4.14 (m, 2 H, OCH2CH3), 3.99 (d, J = 3.4
Hz, 1 H, NCHC(OEt)), 2.25 (sept of d, J = 6.8, 3.9 Hz, 1 H, CH3CHCH3),
1.29 (t, J = 7.3 Hz, 3 H, OCH2CH3), 1.02 (d, J = 6.8 Hz, 3 H, CH3CHCH3),
0.72 (d, J = 6.8 Hz, 3 H, CH3CHCH3).
13C NMR (75 MHz, CDCl3): δ = 164.0, 161.3, 137.0, 128.8, 128.2, 127.6,
127.3, 66.5, 61.0, 60.6, 32.2, 19.0, 16.7, 14.2.
IR: 1695 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.40 (m, 5 H, ArH), 5.18 (app q, J = 12.4
Hz, 2 H, OCH2Ar), 4.07 (m, 5 H, NC(OCH2Ar)CH2N, OCH2CH3 and
NCHC(OEt)), 2.26 (sept of d, J = 6.7, 3.5 Hz, 1 H, CH3CHCH3), 1.30 (t,
J = 7.1 Hz, 3 H, OCH2CH3), 1.03 (d, J = 6.9 Hz, 3 H, CH3CHCH3), 0.73 (d,
J = 6.7 Hz, 3 H, CH3CHCH3).
HRMS (ESI+): m/z [M + Na+] calcd for C16H20D2N2O2Na: 299.1705;
found: 229.1693.
13C NMR (75 MHz, CDCl3): δ = 164.0, 161.5, 137.1, 128.4, 127.8,
127.79, 66.7, 61.1, 60.8, 46.7, 32.3, 19.0, 16.8, 14.3.
HRMS (ESI+): m/z [M + H+] calcd for C16H23N2O2: 275.1810; found:
275.1817.
Stereoselective Alkylation of the Aza-enolates of Orthogonally
Protected Bis-lactim Ethers 5 and 17 (Table 1 and Scheme 3); Gen-
eral Procedure
n-BuLi (1.6 M in hexanes; 0.93 mL, 1.5 mmol) was added dropwise to
a solution of bis-lactim ether 5 or 17 (274 mg, 1 mmol) in anhydrous
THF (5 mL) at –78 °C. After the mixture was stirred at –78 °C for 15
min, a solution of the appropriate electrophile (2 mmol) in anhydrous
THF (5 mL) was added dropwise over 5 min. The reaction mixture was
stirred for 3 h at –78 °C and then allowed to warm to r.t. with further
stirring for a total reaction time of 18 h. The reaction was then
quenched via the careful addition of sat. NaHCO3, and the mixture
was extracted with EtOAc (3 × 50 mL). The combined organic extracts
were washed with brine and water, dried over anhydrous MgSO4, fil-
tered and concentrated in vacuo, and then purified by silica gel chro-
matography to afford the desired alkylated bis-lactim ether product 6
or 18.
(S)-2-Isopropyl-3-benzyloxy-6-ethoxy-2,5-dihydropyrazine (17)
A suspension of 1416 (10 g, 36.23 mmol) in anhydrous CH2Cl2 (50 mL)
was cooled to 0 °C, followed by the sequential addition of benzyl tri-
chloroacetimidate (12.6 g, 50 mmol) in a single portion and BF3·OEt2
(1.83 mL, 5 mmol) dropwise over 10 min. After gradual warming to
r.t. and stirring for 48 h, sat. NaHCO3 (200 mL) was added, and the or-
ganic layer was separated and further washed with additional por-
tions of water and sat. NaCl. After solvent evaporation, the resultant
orange oil 15 was used without further purification. CAN (38.36 g, 70
mmol) was added to a solution of 15 in MeCN–H2O (5:1, 120 mL) and
the bright orange solution stirred at r.t. for 18 h before sat. NaHCO3
(500 mL) was added. The mixture was partitioned between sat. NaCl
and Et2O, and the aqueous layer was further extracted with Et2O
(2 × 200 mL). The combined organic extracts were dried over anhy-
drous MgSO4, filtered and concentrated in vacuo. The resultant crude
product 16 was dissolved in anhydrous CH2Cl2 (50 mL), cooled to 0 °C
and Et3OBF4 (9.5 g, 50 mmol) was added as a single portion under N2.
After warming to r.t. and stirring for 18 h, phosphate buffer (150 mL)
was added followed by separation and sequential washings (phos-
phate buffer, water, sat. NaCl) of the organic layer. After drying (Mg-
SO4) and solvent evaporation in vacuo, the resultant crude orange oil
was purified by column chromatography (Et2O–pentane, 3:97) to
yield 17 as a colourless oil (4.86 g, 49% over 3 steps); [α]D23 +28 (c 1.0,
EtOH).
(2S,5R)-2-Isopropyl-3-ethoxy-5-benzyl-6-benzyloxy-2,5-dihydro-
pyrazine (6a)
Following the general procedure, 5 (274 mg, 1 mmol) was alkylated
with BnBr (342 mg, 2 mmol) to produce 6a (302 mg, 83%); colourless
oil; [α]D23 –7 (c 1.0, EtOH).
IR: 1691 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.42 (m, 5 H, OCH2ArH), 7.22 (m, 3 H,
CHCH2ArH), 7.10 (m, 2 H, CHCH2ArH), 5.19 (app q, J = 12.4 Hz, 2 H,
OCH2Ar), 4.44 (m, 1 H, NCHC(OEt)), 4.17 (dq, J = 9.1, 7.2 Hz, 2 H,
OCH2CH3), 3.26 (t, J = 3.3 Hz, 1 H, CHCH2Ar), 3.16 (m, 2 H, CHCH2Ar),
2.22 (sept of d, J = 6.7, 3.2 Hz, 1 H, CH3CHCH3), 1.31 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 0.98 (d, J = 6.9 Hz, 3 H, CH3CHCH3), 0.62 (d, J = 6.9 Hz, 3 H,
CH3CHCH3).
13C NMR (75 MHz, CDCl3): δ = 163.5, 161.4, 137.5, 137.3, 130.1, 128.4,
128.2, 127.8, 127.8, 126.3, 66.5, 60.7, 60.3, 56.7, 40.0, 31.0, 19.2, 16.4,
14.5.
IR: 1692 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.36 (m, 5 H, ArH), 5.11 (app d, J = 2.8
Hz, H, OCH2Ar), 4.11 (m, H, NC(OEt)CH2N, OCH2CH3 and
.
2
5
NCHC(OBn)), 2.30 (sept of d, J = 6.9, 3.1 Hz, 1 H, CH3CHCH3), 1.31 (t,
J = 7.2 Hz, 3 H, OCH2CH3), 1.05 (d, J = 6.9 Hz, 3 H, CH3CHCH3), 0.79 (d,
J = 6.9 Hz, 3 H, CH3CHCH3).
13C NMR (75 MHz, CDCl3): δ = 164.1, 161.7, 137.0, 128.4, 127.8, 66.8,
HRMS (ESI+): m/z [M + Na+] calcd for C23H28N2O2Na: 387.2050; found:
387.2046.
60.9, 60.8, 46.8, 32.5, 19.0, 16.9, 14.3.
HRMS (ESI+): m/z [M + H+] calcd for C16H23N2O2: 275.1810; found:
(2S,5R)-2-Isopropyl-3-ethoxy-5-(naphthalen-2-ylmethyl)-6-ben-
275.1820.
zyloxy-2,5-dihydropyrazine (6b)
Following the general procedure, 5 (274 mg, 1 mmol) was alkylated
with 2-(bromomethyl)naphthalene (442 mg, 2 mmol) to produce 6b
(372 mg, 90%); colourless oil; [α]D23 –43 (c 1.0, EtOH).
(S)-2-Isopropyl-3-ethoxy-6-benzyloxy-2,5-dihydro[5,5-2H2]pyra-
zine (5-d2)
IR: 2959, 1690, 1228 cm–1
.
To a stirred solution of 5 (274 mg, 1 mmol) in CD3OD (3 mL) was add-
ed AcOD (0.1 mL) and the reaction mixture was stirred at r.t. for 18 h.
Then, the solution was neutralised with 1 M K2CO3 and extracted
with Et2O (3 × 10 mL). The organic layer was separated and subse-
quently washed with brine, dried over MgSO4 and evaporated to dry-
ness to yield 5-d2 as a clear oil (270 mg, 99%); [α]D23 +8 (c 1.0, EtOH).
1H NMR (300 MHz, CDCl3): δ = 7.67–7.70 (m, 1 H, ArH), 7.56–7.60 (m,
2 H, ArH), 7.43 (br s, 1 H, ArH), 7.24–7.37 (m, 7 H, ArH), 7.12–7.16 (m,
1 H, ArH), 5.07 (m, 2 H, OCH2Ar), 4.35 (app q, J = 3.7 Hz, 1 H,
CHCH2Ar), 3.99–4.12 (m,
2 H, OCH2CH3), 3.12–3.27 (m, 3 H,
NCHC(OEt) and CHCH2Ar), 2.03 (sept of d, J = 6.7, 3.2 Hz, 1 H,
CH3CHCH3), 1.17 (t, J = 6.9 Hz, 3 H, OCH2CH3), 0.81 (d, J = 6.7 Hz, 3 H,
CH3CHCH3), 0.48 (d, J = 6.7 Hz, 3 H, CH3CHCH3).
IR: 1696 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

I
M. Hutchby et al.
Feature
Synthesis
13C NMR (75 MHz, CDCl3): δ = 163.4, 161.7, 137.4, 135.2, 133.3, 132.2,
128.7, 128.6, 128.5, 128.1, 127.7, 127.6, 127.5, 127.1, 125.6, 125.2,
66.5, 60.6, 60.4, 56.7, 40.1, 31.1, 19.0, 16.3, 14.4.
HRMS (ESI+): m/z [M + Na+] calcd for C27H30N2O2Na: 437.2205; found:
437.2215.
(2S,5R)-2-Isopropyl-3-ethoxy-5-methyl-6-benzyloxy-2,5-dihydro-
pyrazine (6f)
Following the general procedure, 5 (274 mg, 1 mmol) was alkylated
with MeI (282 mg, 2 mmol) to produce 6f (256 mg, 89%); colourless
oil; [α]D23 –10 (c 1.0, EtOH).
IR: 2970, 1689, 1223 cm–1
.
(2S,5R)-2-Isopropyl-3-ethoxy-5-allyl-6-benzyloxy-2,5-dihydropyr-
azine (6c)
1H NMR (300 MHz, CDCl3): δ = 7.27–7.40 (m, 5 H, ArH), 5.16 (app q,
J = 12.7 Hz, 2 H, OCH2Ar), 4.06–4.16 (m, 3 H, OCH2CH3 and CHCH3),
3.96 (m, 1 H, NCHC(OEt)), 2.29 (sept of d, J = 6.9, 3.1 Hz, 1 H,
CH3CHCH3), 1.42 (d, J = 6.8 Hz, 3 H, CHCH3), 1.29 (t, J = 7.3 Hz, 3 H,
OCH2CH3), 1.05 (d, J = 6.8 Hz, 3 H, CH3CHCH3), 0.68 (d, J = 6.8 Hz, 3 H,
CH3CHCH3).
13C NMR (75 MHz, CDCl3): δ = 164.1, 162.8, 137.6, 128.3, 127.6, 127.6,
66.5, 61.0, 60.6, 51.4, 31.7, 21.3, 19.1, 16.5, 14.3.
HRMS (ESI+): m/z [M + Na+] calcd for C17H24N2O2Na: 311.1735; found:
311.1714.
Following the general procedure, 5 (274 mg, 1 mmol) was alkylated
with allyl bromide (242 mg, 2 mmol) to produce 6c (276 mg, 88%);
colourless oil; [α]D23 –5 (c 1.0, EtOH).
IR: 2958, 1690, 1227 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.27–7.42 (m, 5 H, ArH), 5.72 (m, 1 H,
CH2CHCH2), 5.26 (app q, J = 9.3 Hz, 2 H, OCH2Ar), 5.07 (m, 2 H,
CH2CHCH2), 4.06–4.20 (m, 3 H, OCH2CH3 and CHCH2CHCH2), 3.93 (app
t, J = 3.5 Hz, 1 H, NCHC(OEt)), 2.60 (m, 2 H, CHCH2CHCH2), 2.31 (sept
of d, J = 6.9, 3.1 Hz, 1 H, CH3CHCH3), 1.29 (t, J = 7.1 Hz, 3 H, OCH2CH3),
1.05 (d, J = 6.7 Hz, 3 H, CH3CHCH3), 0.66 (d, J = 6.7 Hz, 3 H, CH3CHCH3).
(2S,5R)-2-Isopropyl-3-ethoxy-5-ethyl-6-benzyloxy-2,5-dihydropy-
razine (6g)
13C NMR (75 MHz, CDCl3): δ = 163.2, 162.3, 137.4, 133.9, 128.3, 127.8,
127.6, 117.9, 66.5, 60.8, 60.6, 55.4, 38.5, 31.5, 19.1, 16.4, 14.3.
HRMS (ESI+): m/z [M + Na+] calcd for C19H26N2O2Na: 337.1892; found:
337.1900.
Following the general procedure, 5 (274 mg, 1 mmol) was alkylated
with iodoethane (312 mg, 2 mmol) to produce 6g (278 mg, 92%); co-
lourless oil; [α]D23 –18 (c 1.0, EtOH).
IR: 2962, 1689, 1221 cm–1
.
tert-Butyl ((2R,5S)-3-Benzyloxy-5-isopropyl-6-ethoxy-2,5-dihy-
dropyrazin-2-yl)acetate (6d)
1H NMR (500 MHz, CDCl3): δ = 7.29–7.41 (m, 5 H, ArH), 5.18 (app q,
J = 12.2 Hz, 2 H, OCH2Ar), 4.09–4.21 (m, 3 H, OCH2CH3 and CHCH2CH3),
3.96 (app t, J = 3.6 Hz, 1 H, NCHC(OEt)), 2.32 (sept of d, J = 6.8, 2.9 Hz,
1 H, CH3CHCH3), 1.88 (dq, J = 7.3, 2.5 Hz, 2 H, CHCH2CH3), 1.30 (t,
J = 7.3 Hz, 3 H, OCH2CH3), 1.07 (d, J = 6.8 Hz, 3 H, CH3CHCH3), 0.84 (t,
J = 7.3 Hz, 3 H, CHCH2CH3), 0.67 (d, J = 6.8 Hz, 3 H, CH3CHCH3).
13C NMR (75 MHz, CDCl3): δ = 163.0, 162.9, 137.6, 128.3, 127.5, 66.4,
60.9, 60.5, 56.2, 31.6, 27.1, 19.1, 16.4, 14.3, 8.6.
HRMS (ESI+): m/z [M + Na+] calcd for C18H26N2O2Na: 325.1892; found:
325.1885.
Following the general procedure, 5 (274 mg, 1 mmol) was alkylated
with tert-butyl bromoacetate (390 mg, 2 mmol) to produce 6d (229
mg, 59%); colourless oil; [α]D23 –23 (c 1.0, EtOH).
IR: 2973, 1732, 1693, 1223 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.28–7.37 (m, 5 H, ArH), 5.16 (q, J = 9.8
Hz, 2 H, OCH2Ar), 4.32 (m, 1 H, CHCH2CO), 4.10 (dq, J = 6.9, 2.8 Hz, 2 H,
OCH2CH3), 4.00 (t, J = 3.5 Hz, 1 H, NCHC(OEt)), 2.72 (qdd, J = 29.2, 14.8,
5.4 Hz, 2 H, CH2CO2t-Bu), 2.22 (sept of d, J = 6.7, 3.2 Hz, 1 H,
CH3CHCH3), 1.41 (s, 9 H, OC(CH3)3), 1.26 (t, J = 6.9 Hz, 3 H, OCH2CH3),
1.02 (d, J = 6.9 Hz, 3 H, CH3CHCH3), 0.70 (d, J = 6.7 Hz, 3 H, CH3CHCH3).
(2R,5S)-2-Ethyl-2-methyl-3-benzyloxy-5-isopropyl-6-ethoxy-2,5-
dihydropyrazine (6h)
13C NMR (75 MHz, CDCl3): δ = 170.4, 163.5, 162.0, 137.3, 128.3, 127.7,
127.6, 80.3, 66.7, 61.4, 60.7, 52.8, 40.7, 32.1, 28.0, 19.1, 16.8, 14.3.
HRMS (ESI+): m/z [M + Na+] calcd for C22H32N2O4Na: 411.2254; found:
411.2329.
Following the general procedure, 6f (288 mg, 1 mmol) was alkylated
with EtI (302 mg, 2 mmol) to produce 6h (224 mg, 71%); colourless
oil; [α]D23 –32 (c 1.0, EtOH).
IR: 2968, 1686, 1235, 1196 cm–1
.
(2S,5R)-2-Isopropyl-3-ethoxy-5-(prop-2-yn-1-yl)-6-benzyloxy-2,5-
dihydropyrazine (6e)
1H NMR (300 MHz, CDCl3): δ = 7.35–7.41 (m, 3 H, ArH), 7.30 (tt,
J = 6.8, 1.9 Hz, 2 H, ArH), 5.19 (app q, J = 12.7 Hz, 2 H, OCH2Ar), 4.17
(dq, J = 27.3, 6.8 Hz, 2 H, OCH2CH3), 3.26 (d, J = 3.4 Hz, 1 H, NCH), 2.39
(sept of d, J = 6.8, 3.4 Hz, 1 H, CH3CHCH3), 1.96 (app sex, J = 6.3 Hz, 1
H, CCHHCH3), 1.61 (app sex, J = 6.3 Hz, 1 H, CCHHCH3), 1.33 (s, 3 H,
CCH3), 1.29 (t, J = 7.3 Hz, 3 H, OCH2CH3), 1.11 (d, J = 6.8 Hz, 3 H,
CH3CHCH3), 0.74 (t, J = 7.3 Hz, 3 H, CCH2CH3), 0.65 (d, J = 6.8 Hz, 3 H,
CH3CHCH3).
13C NMR (75 MHz, CDCl3): δ = 164.9, 161.1, 138.0, 128.2, 127.7, 127.4,
66.1, 60.5, 60.3, 58.6, 33.4, 30.5, 28.5, 19.6, 16.8, 14.3, 9.3.
HRMS (ESI+): m/z [M + H+] calcd for C19H29N2O2: 317.2323; found:
317.2326.
Following the general procedure, 5 (274 mg, 1 mmol) was alkylated
with propargyl bromide (80 wt % in toluene; 238 mg, 2 mmol) to pro-
duce 6e (278 mg, 89%); colourless oil; [α]D23 –26 (c 1.0, EtOH).
IR: 3302, 2960, 1694, 1227 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.29–7.41 (m, 5 H, ArH), 5.19 (q,
J = 12.23 Hz, 2 H, OCH2Ar), 4.11–4.24 (m, 3 H, CHCH2CCH and
OCH2CH3), 4.05 (t, J = 3.4 Hz, 1 H, NCHC(OEt)), 2.70–2.84 (m, 2 H,
CHCH2CCH), 2.32 (sept of d, J = 6.7, 3.2 Hz, 1 H, CH3CHCH3), 1.91 (app
t, J = 2.4 Hz, 1 H, CHCH2CCH), 1.30 (t, J = 7.3 Hz, 3 H, OCH2CH3), 1.05
(d, J = 6.8 Hz, 3 H, CH3CHCH3), 0.66 (d, J = 6.8 Hz, 3 H, CH3CHCH3).
13C NMR (75 MHz, CDCl3): δ = 161.1, 137.4, 128.3, 127.8, 127.6, 80.7,
70.1, 66.7, 61.2, 60.9, 31.6, 25.1, 19.1, 16.5, 14.3.
HRMS (ESI+): m/z [M + Na+] calcd for C19H24N2O2Na: 335.1735; found:
(2S,5R)-2-Isopropyl-3-ethoxy-5-benzyl-6-benzyloxy-2,5-dihy-
dro[5-2H]pyrazine (6a-d)
Following the general procedure, 5-d2 (274 mg, 1 mmol) was alkylat-
ed with BnBr (342 mg, 2 mmol) to produce 6a-d (285 mg, 78%); co-
lourless oil; [α]D23 –9 (c 1.0, EtOH).
335.1719.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

J
M. Hutchby et al.
Feature
Synthesis
IR: 2959, 1691, 1233 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.26–7.44 (m, 5 H, ArH), 5.25 (s, 2 H,
OCH2Ar), 4.64–4.67 (m, 1 H, NCHC(OEt)), 4.01 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 3.88 (app t, J = 2.6 Hz, 1 H, NCHC(OBn)), 2.25 (sept of d,
J = 7.1, 3.0 Hz, 1 H, CH3CHCH3), 1.19 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.02
(d, J = 6.8 Hz, 3 H, CH3CHCH3), 0.63 (d, J = 6.8 Hz, 3 H, CH3CHCH3).
13C NMR (75 MHz, CDCl3): δ = 163.8, 160.9, 137.9, 128.2, 127.6, 127.4,
63.3, 60.9, 60.5, 58.0, 31.6, 19.1, 16.9, 14.2.
1H NMR (300 MHz, CDCl3): δ = 7.46–7.47 (m, 2 H, OCH2ArH), 7.40–
7.43 (m, 2 H, OCH2ArH), 7.34–7.37 (m, 1 H, OCH2ArH), 7.19–7.23 (m, 3
H, CDCH2ArH), 7.09–7.11 (m, 2 H, CDCH2ArH), 5.19 (app q, J = 12.7 Hz,
2 H, OCH2Ar), 4.15 (dq, J = 7.3, 3.4 Hz, 2 H, OCH2CH3), 3.26 (d, J = 3.4
Hz, 1 H, NCHC(OEt)), 3.15 (app q, J = 18.1 Hz, 2 H, CDCH2Ar), 2.22
(sept of d, J = 6.8, 3.4 Hz, 1 H, CH3CHCH3), 1.30 (t, J = 6.8 Hz, 3 H,
OCH2CH3), 0.98 (d, J = 6.8 Hz, 3 H, CH3CHCH3), 0.62 (d, J = 6.8 Hz, 3 H,
CH3CHCH3).
HRMS (ESI+): m/z [M + Na+] calcd for C32H42N4O4Na: 569.3104; found:
569.3083.
13C NMR (75 MHz, CDCl3): δ = 163.5, 161.7, 137.4, 137.2, 130.0, 128.3,
128.1, 127.7, 127.7, 126.2, 66.4, 60.5, 60.2, 39.9, 30.9, 19.1, 16.3, 14.4.
HRMS (ESI+): m/z [M + Na+] calcd for C23H27DN2O2Na: 388.2112;
(2S,5R)-2-Isopropyl-3-benzyloxy-5-benzyl-6-ethoxy-2,5-dihydro-
pyrazine (18a)
found: 388.2111.
Following the general procedure, 17 (274 mg, 1 mmol) was alkylated
with BnBr (342 mg, 2 mmol) to produce 18a (247 mg, 68%); colour-
less oil; [α]D23 –82 (c 1.0, EtOH).
((2R,5S)-3-Benzyloxy-5-isopropyl-6-ethoxy-2,5-dihydropyrazin-2-
IR: 2958, 1691, 1220 cm–1
.
yl)(diphenyl)methanol (6i)
Following the general procedure, 5 (274 mg, 1 mmol) was alkylated
with benzophenone (364 mg, 2 mmol) to produce 6i (360 mg, 79%);
colourless oil; [α]D23 –92 (c 1.0, EtOH).
1H NMR (300 MHz, CDCl3): δ = 7.29 (m, 5 H, OCH2ArH), 7.12 (m, 3 H,
CHCH2ArH), 7.01 (m, 2 H, CHCH2ArH), 5.08 (app q, J = 12.6 Hz, 2 H,
OCH2Ar), 4.28 (app q, J = 3.7 Hz, 1 H, NCHC(OBn)), 4.10 (dq, J = 19.9,
7.1 Hz, 2 H, OCH2CH3), 3.28 (t, J = 3.3 Hz, 1 H, CHCH2Ar), 3.03 (d, J = 4.9
Hz, 2 H, CHCH2Ar), 2.16 (sept of d, J = 6.7, 3.2 Hz, 1 H, CH3CHCH3), 1.28
(t, J = 6.9 Hz, 3 H, OCH2CH3), 0.89 (d, J = 6.9 Hz, 3 H, CH3CHCH3), 0.58
(d, J = 6.7 Hz, 3 H, CH3CHCH3).
13C NMR (75 MHz, CDCl3): δ = 163.3, 161.9, 137.4, 137.4, 130.0, 128.3,
127.8, 127.6, 126.2, 66.5, 60.5, 60.2, 56.8, 40.0, 31.2, 19.1, 16.5, 14.4.
HRMS (ESI+): m/z [M + Na+] calcd for C23H28N2O2Na: 387.2050; found:
387.2065.
IR: 2958, 1686, 1234 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.33–7.38 (m, 4 H, ArH), 7.19–7.22 (m,
9 H, ArH), 6.92–6.95 (m, 2 H, ArH), 4.91–5.01 (m, 3 H, OCH2Ar and CH-
CPh2OH), 4.68 (s, 1 H, OH), 3.95 (dq, J = 7.1, 3.5 Hz, 2 H, OCH2CH3),
3.32 (app t, J = 3.5 Hz, 1 H, NCHC(OEt)), 2.16 (sept of d, J = 6.9, 3.3 Hz,
1 H, CH3CHCH3), 1.14 (t, J = 7.1 Hz, 3 H, OCH2CH3), 0.93 (d, J = 6.7 Hz, 3
H, CH3CHCH3), 0.59 (d, J = 6.7 Hz, 3 H, CH3CHCH3).
13C NMR (75 MHz, CDCl3): δ = 164.3, 160.4, 143.9, 143.5, 136.4, 128.2,
127.8, 127.7, 127.7, 127.6, 127.5, 127.3, 127.1, 126.9, 80.7, 66.8, 63.8,
61.1, 60.7, 31.1, 19.1, 16.5, 14.2.
(2S,5R)-2-Isopropyl-3-benzyloxy-5-ethyl-6-ethoxy-2,5-dihydropy-
razine (18b)
HRMS (ESI+): m/z [M + Na+] calcd for C29H32N2O3Na: 479.2310; found:
479.2299.
Following the general procedure, 17 (274 mg, 1 mmol) was alkylated
with iodoethane (312 mg, 2 mmol) to produce 18b (169 mg, 56%); co-
lourless oil; [α]D23 –55 (c 1.0, EtOH).
Methyl (3S)-3-((2R,5S)-3-Benzyloxy-5-isopropyl-6-ethoxy-2,5-di-
IR: 2961, 1687, 1220 cm–1
.
hydropyrazin-2-yl)-3-phenylpropanoate (6j)
Following the general procedure, 5 (274 mg, 1 mmol) was alkylated
with methyl cinnamate (324 mg, 2 mmol) to produce 6j (252 mg,
58%); colourless oil; [α]D23 –11 (c 1.0, EtOH).
1H NMR (300 MHz, CDCl3): δ = 7.23–7.38 (m, 5 H, ArH), 5.14 (app q,
J = 12.6 Hz, 2 H, OCH2Ar), 4.11 (m, 3 H, NCHC(OBn) and OCH2CH3),
3.93 (t, J = 3.3 Hz, 1 H, CHCH2CH3), 2.29 (sept of d, J = 6.7, 3.2 Hz, 1 H,
CH3CHCH3), 1.85 (dq, J = 7.3, 2.5 Hz, 2 H, CHCH2CH3), 1.27 (t, J = 6.9
Hz, 3 H, OCH2CH3), 1.02 (d, J = 6.9 Hz, 3 H, CH3CHCH3), 0.80 (t, J = 7.3
Hz, 3 H, CHCH2CH3), 0.65 (d, J = 6.7 Hz, 3 H, CH3CHCH3).
13C NMR (75 MHz, CDCl3): δ = 163.0, 162.9, 137.7, 128.3, 127.7, 127.6,
66.4, 60.9, 60.5, 56.2, 31.6, 27.1, 19.2, 16.4, 14.4, 8.7.
HRMS (ESI+): m/z [M + Na+] calcd for C18H26N2O2Na: 325.1892; found:
325.1890.
IR: 2955, 1738, 1688, 1217 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.11–7.35 (m, 10 H, ArH), 5.09 (m, 2 H,
OCH2Ar), 4.19 (app t, J = 3.39 Hz, 1 H, CNCHCHPh), 4.06 (dq, J = 7.1, 3.5
Hz, 2 H, OCH2CH3), 3.76 (td, J = 6.0, 3.2 Hz, 1 H, CNCHCHPh), 3.45 (s, 3
H, OCH3), 3.39 (app t, J = 3.3 Hz, 1 H, NCHC(OEt)), 2.63 (dq, J = 16.0, 6.0
Hz, 2 H, CH2CO2Me), 2.22 (sept of d, J = 6.7, 3.2 Hz, 1 H, CH3CHCH3),
1.20 (t, J = 7.1 Hz, 3 H, OCH2CH3), 0.88 (d, J = 6.9 Hz, 3 H, CH3CHCH3),
0.48 (d, J = 6.7 Hz, 3 H, CH3CHCH3).
13C NMR (75 MHz, CDCl3): δ = 172.6, 163.9, 161.1, 140.7, 137.3, 128.9,
128.3, 127.9, 127.6, 126.8, 66.6, 60.8, 60.4, 59.9, 51.5, 45.0, 35.7, 31.2,
19.1, 16.3, 14.4.
HRMS (ESI+): m/z [M + H+] calcd for C26H33N2O4: 437.2490; found:
437.2498.
(2R,2′R,5S,5′S)-3,3′-Diethoxy-5,5′-diisopropyl-6,6′-bis(benzyloxy)-
2,2′,5,5′-tetrahydro-2,2′-bipyrazine (18c)
Following the general procedure, 17 (274 mg, 1 mmol) was alkylated
with iodine (506 mg, 2 mmol) to produce 18c (180 mg, 66%); white
solid; mp 141–142 °C; [α]D23 +21 (c 1.0, EtOH).
IR: 2956, 2923, 1693, 1680, 1229 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.25–7.32 (m, 5 H, ArH), 5.00 (s, 2 H,
OCH2Ar), 4.55–4.56 (m, H, NCHC(OEt)), 4.17–4.32 (m, H,
OCH2CH3), 3.86–3.87 (m, 1 H, NCHC(OBn)), 2.28 (sept of d, J = 6.3, 2.9
Hz, 1 H, CH3CHCH3), 1.34 (t, J = 6.8 Hz, 3 H, OCH2CH3), 1.03 (d, J = 6.8
Hz, 3 H, CH3CHCH3), 0.68 (d, J = 6.8 Hz, 3 H, CH3CHCH3).
.
(2R,2′R,5S,5′S)-3,3′-Bis(benzyloxy)-5,5′-diisopropyl-6,6′-diethoxy-
2,2′,5,5′-tetrahydro-2,2′-bipyrazine (6k)
1
2
Following the general procedure, 5 (274 mg, 1 mmol) was alkylated
with iodine (506 mg, 2 mmol) to produce 6k (167 mg, 61%); white
solid; mp 156–159 °C; [α]D23 –29 (c 1.0, EtOH).
IR: 2957, 2923, 1693, 1228 cm–1
.
13C NMR (75 MHz, CDCl3): δ = 163.9, 161.0, 137.5 128.3, 127.9, 127.5,
66.3, 60.7, 60.7, 58.0, 31.7, 19.1, 16.6, 14.4.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

K
M. Hutchby et al.
Feature
Synthesis
HRMS (ESI+): m/z [M + H+] calcd for C32H43N4O4: 547.3211; found:
IR: 3286, 2933, 1732, 1677, 1050 cm–1
.
547.3220.
1H NMR (300 MHz, CDCl3): δ = 7.80 (br dd, J = 34.1, 8.8 Hz, 1 H, NH),
7.20–7.35 (m, 5 H, ArH), 4.51 (dd, J = 9.2, 4.9 Hz, 1 H, NHCHCO), 4.17
(dq, J = 7.1, 2.8 Hz, 2 H, OCH2CH3), 3.65 (m, 1 H, H2NCHCH2Ar), 3.30
(m, 1 H, CHCHHAr), 2.68 (m, 1 H, CHCHHAr), 2.19 (sept of d, J = 6.9,
3.0 Hz, 1 H, CH3CHCH3), 1.47 (br s, 2 H, NH2), 1.29 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 0.92 (m, 6 H, CH3CHCH3).
13C NMR (75 MHz, CDCl3): δ = 174.3, 171.8, 138.0, 129.3, 129.2, 128.7,
126.7, 61.1, 56.8, 56.6, 41.0, 31.1, 19.0, 17.7, 14.2.
HRMS (ESI+): m/z [M + H+] calcd for C16H25N2O3: 293.1928; found:
293.1936.
Hydrolysis and Separation of Bis-lactim Ether 6c (Scheme 4a)
Bis-lactim ether 6c (276 mg 0.88 mmol) was dissolved in 0.3 M HCl–
MeCN (1:1, 20 mL), and the solution was stirred at r.t. for 18 h. Then,
the solvent was removed in vacuo and the resultant white solid was
suspended in CHCl3 (5 mL); 10% aq NaHCO3 (5 mL) was added and the
organic layer was separated. The solvent and valine ethyl ester (4)
were then removed by distillation under reduced pressure (1.6 mbar,
50 °C) to yield allylglycine benzyl ester (7a) as a clear oil (157 mg,
85%) whose analytical data were identical to those reported in the lit-
erature for 7a.28
Ethyl L-Valyl-D-phenylalaninate (23a)
Following the general procedure, 18a (182 mg, 0.5 mmol) was hydro-
genated/hydrolysed to produce 23a (139 mg, 95%); white solid; mp
211–214 °C; [α]D23 +22 (c 1.0, EtOH).
Hydrogenolytic Separation Approach 1 (Scheme 4b)
A solution of 6d (229 mg, 0.59 mmol) in 0.3 M HCl–MeCN (1:1, 20 mL)
was stirred at r.t. for 18 h. After removal of solvents in vacuo, the re-
sulting white solid was dissolved in THF (10 mL) and Pd/C (10 wt %
Pd; 63 mg, 0.059 mmol) was added. The flask was then evacuated and
backfilled with 1 atm H2 (3 ×) and stirred under a balloon of H2 for 18
h at r.t. Upon completion, the reaction mixture was filtered through
Celite® and the solvent was removed in vacuo, which was followed by
partitioning between CHCl3 (5 mL) and 10% aq NaHCO3 (5 mL). The
organic layer containing valine ethyl ester (4) was removed and the
remaining aqueous layer was acidified with 1 M HCl prior to evapo-
rating to dryness in vacuo to afford amino acid 19·HCl as a white solid
(99 mg, 88%), whose analytical data were identical to those reported
in the literature for 19.29
IR: 3293, 2962, 1736, 1662, 1060 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.70 (br m, 1 H, NH), 7.14–7.33 (m, 5 H,
ArH), 4.86 (m, 1 H, NHCHCH2Ph), 4.17 (q, J = 7.16 Hz, 2 H, OCH2CH3),
3.21 (m, 1 H, H2NCHCO), 3.14 (m, 2 H, CHCH2Ar), 2.28 (sept of d,
J = 6.9, 3.0 Hz, 1 H, CH3CHCH3), 1.30 (br s, 2 H, NH2), 1.24 (t, J = 7.3 Hz,
3 H, OCH2CH3), 0.97 (d, J = 6.9 Hz, 3 H, CH3CHCH3), 0.82 (d, J = 6.9 Hz, 3
H, CH3CHCH3).
13C NMR (75 MHz, CDCl3): δ = 174.2, 171.6, 136.2, 129.2, 128.5, 127.0,
61.3, 60.0, 52.7, 37.7, 30.8, 19.7, 15.8, 14.1.
HRMS (ESI+): m/z [M + Na+] calcd for C16H24N2O3: 315.1684; found:
315.1669.
Hydrogenolytic Separation Approach 2 (Scheme 4c)
Ethyl D-[α-2H]-Phenylalanyl-L-valinate (10a-d)
A solution of 18b (169 mg, 0.56 mmol) in 0.3 M HCl–MeCN (1:1, 20
mL) was stirred at r.t. for 18 h. After removal of solvents in vacuo, the
resulting white solid was dissolved in THF (10 mL) and Pd/C (10 wt %
Pd; 60 mg, 0.056 mmol) was added. The flask was then evacuated and
backfilled with 1 atm H2 (3 ×) and stirred under a balloon of H2 for 18
h at r.t. Upon completion, the reaction mixture was filtered through
Celite® and the solvent was removed in vacuo, which was followed by
partitioning between CHCl3 (5 mL) and 10% aq NaHCO3 (5 mL). The
organic later containing ethyl 2-aminobutyrate (20) was separated
and evaporated to dryness, yielding 20 as a white solid (55 mg, 75%),
whose analytical data were identical to a commercial sample of 2030
(CAS No.: 55410-21-4).
Following the general procedure, 6a-d (183 mg, 0.5 mmol) was hy-
drogenated/hydrolysed to produce 10a-d (144 mg, 98%); white solid;
mp 230–232 °C; [α]D23 +44 (c 1.0, EtOH).
IR: 3289, 2934, 1731, 1677, 1059 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.70 (br d, J = 8.8 Hz, 1 H, NH), 7.21–
7.31 (m, 5 H, ArH), 4.50 (dd, J = 9.3, 4.9 Hz, 1 H, CHNH), 4.15–4.20 (m,
2 H, OCH2CH3), 3.27 (d, J = 13.7 Hz, 1 H, CDCHHAr), 2.66 (d, J = 13.7
Hz, 1 H, CDCHHAr), 2.18 (sept of d, J = 6.8, 1.9 Hz, 1 H, CH3CHCH3),
1.27 (t, J = 6.8 Hz, 3 H, OCH2CH3), 0.92 (d, J = 6.8 Hz, 3 H, CH3CHCH3),
0.80 (d, J = 6.8 Hz, 3 H, CH3CHCH3).
13C NMR (125 MHz, CDCl3): δ = 174.2, 171.1, 137.9, 129.1, 128.6,
126.6, 61.0, 56.8, 40.8, 31.0, 18.9, 17.7, 14.1.
HRMS (ESI+): m/z [M + Na+] calcd for C16H23DN2O3Na: 316.1679;
found: 316.1683.
Hydrogenolytic/Hydrolysis Deprotection Strategy for Bis-lactim
Ethers 6 and 18 (Table 2); General Procedure for the Synthesis of
Dipeptide Esters 10 and 23
Pd/C (10 wt % Pd; 50 mg, 0.05 mmol) was added to a solution of the
bis-lactim ether 6 or 18 (0.5 mmol) in THF (10 mL). The flask was
then evacuated and backfilled with 1 atm H2 (3 ×) and stirred under a
balloon of H2 for 1 h at r.t. Upon completion, the reaction mixture was
filtered through Celite® and the solvent was removed in vacuo. The
resulting amide was dissolved in 0.3 M HCl–MeCN (1:1, 20 mL) and
stirred at r.t. for 18 h, before the solution was evaporated to dryness.
The HCl salt was neutralised by the addition of 10% aq NaHCO3 (10
mL); extraction into CH2Cl2 (10 mL) followed by solvent removal in
vacuo yielded the pure dipeptide 10 or 23.
Ethyl N-((R)-2-Amino-3-(naphthalen-2-yl)propanoyl)-L-valinate
(10b)
Following the general procedure, 6b (207 mg, 0.5 mmol) was hydro-
genated/hydrolysed to produce 10b (166 mg, 97%); white solid; mp
189–191 °C; [α]D23 +61 (c 1.0, EtOH).
IR: 3289, 2961, 1738, 1660, 1059 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.76–7.83 (m, 4 H, 3ArH and 1NH),
7.67 (s, 1 H, ArH), 7.45–7.49 (m, 2 H, ArH), 7.38 (d, J = 9.7 Hz, 1 H,
ArH), 4.53 (dd, J = 9.3, 4.9 Hz, 1 H, NHCHCO), 4.17 (dq, J = 10.3, 3.9 Hz,
2 H, OCH2CH3), 3.75 (dd, J = 9.3, 4.9 Hz, 1 H, H2NCHCH2Ar), 3.47 (dd,
J = 13.7, 3.9 Hz, 1 H, CHHAr), 2.85 (dd, J = 13.7, 3.9 Hz, 1 H, CHHAr),
2.19 (sept of d, J = 6.9, 1.9 Hz, 1 H, CH3CHCH3), 1.50 (br s, 2 H, NH2),
1.27 (t, J = 7.3 Hz, 3 H, OCH2CH3), 0.93 (d, J = 6.8 Hz, 3 H, CH3CHCH3),
0.91 (d, J = 6.8 Hz, 3 H, CH3CHCH3).
Ethyl D-Phenylalanyl-L-valinate (10a)
Following the general procedure, 6a (182 mg, 0.5 mmol) was hydro-
genated/hydrolysed to produce 10a (117 mg, 97%); white solid; mp
234–235 °C; [α]D23 +48 (c 1.0, EtOH).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

L
M. Hutchby et al.
Feature
Synthesis
13C NMR (125 MHz, CDCl3): δ = 174.2, 171.7, 135.4, 133.4, 132.3,
128.4, 127.9, 127.6, 127.4, 127.1, 126.1, 125.6, 61.0, 56.9, 56.4, 41.1,
31.1, 18.9, 17.7, 14.1.
HRMS (ESI+): m/z [M + Na+] calcd for C20H26N2O3Na: 365.1835; found:
365.1830.
Diethyl (2R,3R)-2,3-Bis((S)-2-amino-3-methylbutanamido)succi-
nate (23b)
Following the general procedure, 18c (273 mg, 0.5 mmol) was hydro-
genated/hydrolysed to produce 23b (193 mg, 96%); white solid; mp
277–278 °C; [α]D23 –11 (c 1.0, EtOH).
IR: 3301, 2956, 1695, 1665, 1621, 1232 cm–1
.
Ethyl N-((S)-2-Amino-2-methylbutanoyl)-L-valinate (10c)
1H NMR (500 MHz, D2O): δ = 5.12 (s, 2 H, CHCO2Et), 4.13–4.16 (m, 4 H,
OCH2CH3), 3.20 (d, J = 7.3 Hz, 2 H, CHNH2), 1.84 (sept, J = 6.9 Hz, 2 H,
CH3CHCH3), 1.19 (t, J = 6.9 Hz, 6 H, OCH2CH3), 0.84 (d, J = 7.3 Hz, 6 H,
CH3CHCH3), 0.80 (d, J = 7.3 Hz, 6 H, CH3CHCH3).
Following the general procedure, 6h (158 mg, 0.5 mmol) was hydro-
genated/hydrolysed to produce 10c (117 mg, 96%); white solid; mp
201–202 °C; [α]D23 +36 (c 1.0, EtOH).
IR: 3288, 2935, 1731, 1666, 1049 cm–1
.
13C NMR (125 MHz, D2O): δ = 170.2, 167.9, 60.1, 59.7, 56.0, 32.9, 18.4,
1H NMR (500 MHz, D2O): δ = 4.09–4.13 (m, 3 H, OCH2CH3 and CHNH),
2.09 (sept, J = 6.8 Hz, 1 H, CH3CHCH3), 1.79 (app sex, J = 7.3 Hz, 1 H,
CCHHCH3), 1.60 (app sex, J = 7.3 Hz, 1 H, CCHHCH3), 1.33 (s, 3 H,
CCH3), 1.15 (t, J = 7.3 Hz, 3 H, OCH2CH3), 0.85 (d, J = 2.9 Hz, 3 H,
CH3CHCH3), 0.83 (d, J = 2.9 Hz, 3 H, CH3CHCH3), 0.75 (t, J = 7.3 Hz, 3 H,
CCH2CH3).
17.7, 15.3.
HRMS (ESI+): m/z [M + Na+] calcd for C18H34N4O6Na: 425.2370; found:
425.2369.
Acknowledgment
13C NMR (125 MHz, D2O): δ = 176.9, 173.5, 62.5, 59.3, 59.0, 32.0, 29.7,
We would like to thank the EPSRC and the University of Bath for fund-
ing.
24.0, 18.3, 17.1, 13.3, 7.3.
HRMS (ESI+): m/z [M + Na+] calcd for C12H24N2O3Na: 267.1679; found:
267.1689.
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E. Bioconjugate Chem. 2009, 20, 1281. (b) Lang, K.; Chin, J. W.
Chem. Rev. 2014, 114, 4764. (c) Haney, C. M.; Wissner, R. F.;
Petersson, E. J. Curr. Opin. Chem. Biol. 2015, 28, 123. (d) Hallam,
T. J.; Wold, E.; Wahl, A.; Smider, V. V. Mol. Pharmaceutics 2015,
12, 1848.
(5) (a) Vogt, H.; Bräse, S. Org. Biomol. Chem. 2007, 5, 406.
(b) Sorochinsky, A. E.; Acena, J. L.; Moriwaki, H.; Sato, T.;
Soloshonok, V. A. Amino Acids 2013, 45, 1017. (c) Asymmetric
Synthesis and Application of α-Amino Acids; Soloshonok, V. A.;
Izawa, K., Eds.; ACS Symposium Series 1009: Washington, DC,
2009. (d) Duthaler, R. O. Tetrahedron 1994, 50, 1539.
Following the general procedure, 6j (218 mg, 0.5 mmol) was hydroge-
nated/hydrolysed to produce 10d (162 mg, 89%); white solid; mp
211–212 °C; [α]D23 +35 (c 1.0, EtOH).
IR: 3331, 2958, 1736, 1662, 1658, 1051 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.70 (br d, J = 7.3 Hz, 1 H, NH), 7.21–
7.30 (m, 5 H, ArH), 4.11–4.25 (m, 4 H, OCH2CH3 and CH2CO2Me), 3.66
(m, 1 H, ArCHCH2CO2Me), 3.55 (s, 3 H, CO2CH3), 3.09 (dd, J = 16.1, 5.4
Hz, 1 H, NHCHCO2Et), 2.81 (dd, J = 16.6, 9.2 Hz, 1 H, CHNH2), 2.03
(sept of d, J = 6.8, 1.9 Hz, 1 H, CH3CHCH3), 1.25 (t, J = 7.3 Hz, 3 H,
OCH2CH3), 0.80 (d, J = 6.8 Hz, 3 H, CH3CHCH3), 0.72 (d, J = 6.8 Hz, 3 H,
CH3CHCH3).
13C NMR (125 MHz, CDCl3): δ = 172.5, 171.8, 170.8, 141.1, 129.1,
128.7, 127.2, 61.4, 57.3, 51.8, 45.3, 38.5, 30.9, 18.9, 17.8, 14.1.
HRMS (ESI+): m/z [M + Na+] calcd for C19H28N2O5Na: 387.1890; found:
387.1881.
Diethyl (2S,2′S)-2,2′-(((2R,3R)-2,3-Diaminosuccinyl)bis(azanedi-
yl))bis(3-methylbutanoate) (10e)
Following the general procedure, 6k (273 mg, 0.5 mmol) was hydro-
genated/hydrolysed to produce 10e (181 mg, 90%); white solid; mp
289–291 °C; [α]D23 +53 (c 1.0, EtOH).
IR: 3186, 2960, 1704, 1694, 1661, 1232 cm–1
.
1H NMR (500 MHz, D2O): δ = 4.20–4.26 (m, 6 H, OCH2CH3 and NHCH-
CO2Et), 3.74 (s, 2 H, CHNH2), 2.20 (sept, J = 6.9 Hz, 2 H, CH3CHCH3),
1.28 (t, J = 6.9 Hz, 6 H, OCH2CH3), 0.94–0.97 (m, 12 H, CH3CHCH3).
13C NMR (125 MHz, D2O): δ = 174.3, 173.6, 62.6, 58.7, 57.5, 29.9, 18.3,
17.5, 13.4.
HRMS (ESI+): m/z [M + Na+] calcd for C18H34N4O6Na: 425.2370; found:
425.2375.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

M
M. Hutchby et al.
Feature
Synthesis
(e) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry
1998, 9, 3517. (f) Ma, J. Angew. Chem. Int. Ed. 2003, 42, 4290.
(g) Bordusa, F. Chem. Rev. 2002, 102, 4817.
(14) For examples where hydrolysis of sterically hindered bis-lactim
ethers resulted in the formation of unwanted mixtures of α-
amino esters and dipeptide products, see: (a) Cremonesi, G.;
Dalla Croce, P.; Forni, A.; Gallanti, M.; La Rosa, C. Tetrahedron
2011, 67, 2925. (b) Jones, E. P.; Jones, P.; White, A. J. P.; Barrett,
A. G. M. Beilstein J. Org. Chem. 2011, 7, 1570.
(6) (a) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243. (b) Nájera, C. Synlett 2002, 1388. (c) Hamada, Y.; Shioiri, T.
Chem. Rev. 2005, 105, 4441.
(7) (a) Ojima, I.; Kogure, T.; Yoda, N.; Suzuki, T.; Yatabe, M.; Tanaka,
T. J. Org. Chem. 1982, 47, 1329. (b) Apitz, G.; Jager, M.; Jaroch, S.;
Kratzel, M.; Schaffleer, L.; Steglich, W. Tetrahedron 1993, 49,
8223. (c) Dunn, M. J.; Gomez, S.; Jackson, R. F. W. J. Chem. Soc.,
Perkin Trans. 1 1995, 1639. (d) Easton, C. J.; Scharfbillig, I. M.;
Tan, E. W. Tetrahedron Lett. 1988, 29, 1565. (e) Elad, D.; Sperling,
J. J. Chem. Soc. C 1969, 1579.
(15) For previous examples where intramolecular cyclisation reac-
tions have been employed to convert trans-alkylated bis-lactim
ethers into mono-lactim ethers that could then be hydrolysed
to afford dipeptide esters, see: (a) Schöllkopf, U.; Wick, R.;
Hinrichs, R.; Lange, M. Liebigs Ann. Chem. 1988, 1025.
(b) Andrei, M.; Römming, C.; Undheim, K. Tetrahedron: Asym-
metry 2004, 15, 1359.
(8) (a) Ager, D. J.; Froen, D. E.; Klix, R. C.; Zhi, B. X.; McIntosh, J. M.;
Thangarasa, R. Tetrahedron 1994, 50, 1975. (b) O’Donnell, M. J.;
Zhou, C. Y.; Scott, W. L. J. Am. Chem. Soc. 1996, 118, 6070.
(c) Ricci, M.; Blakskjaer, P.; Skrydstrup, T. J. Am. Chem. Soc.
2000, 122, 12413. (d) Bossler, H. G.; Seebach, D. Helv. Chim. Acta
1994, 77, 1124. (e) Miller, S. A.; Griffiths, S. L.; Seebach, D. Helv.
Chim. Acta 1993, 76, 563. (f) Kazmaier, U.; Maier, S. J. Org. Chem.
1999, 64, 4574. (g) Polt, R.; Seebach, D. Helv. Chim. Acta 1987, 70,
1930.
(9) (a) Balducci, D.; Porzi, G. Helv. Chim. Acta 2011, 94, 127.
(b) Davies, S. G.; Garner, A. C.; Ouzman, J. V. A.; Roberts, P. M.;
Smith, A. D.; Snow, E. J.; Thomson, J. E.; Tamayo, J. A.; Vickers, R.
J. Org. Biomol. Chem. 2007, 5, 2138. (c) Di Felice, P.; Porzi, G.;
Sandri, S. Tetrahedron: Asymmetry 1999, 10, 2191. (d) Porzi, G.;
Sandri, S.; Verrocchio, P. Tetrahedron: Asymmetry 1998, 9, 119.
(e) Favero, V.; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 1997,
8, 599.
(16) (a) Bull, S. D.; Davies, S. G.; Garner, A. C.; Parkes, A. L.; Roberts, P.
M.; Sellers, T. G. R.; Smith, A. D.; Tamayo, J. A.; Thomson, J. E.;
Vickers, R. J. New J. Chem. 2007, 31, 486. (b) Paradisi, F.; Porzi,
G.; Sandri, S. Tetrahedron: Asymmetry 2001, 12, 3319.
(17) Bull, S. D.; Davies, S. G.; Moss, W. O. Tetrahedron: Asymmetry
1998, 9, 321.
(18) A similar O-benzylation approach was used to prepare a bis-
benzyl bis-lactim ether 1 (R = Bn) that was used for the asym-
metric synthesis of α-amino benzyl esters; see: Groth, U.;
Schmeck, C.; Schöllkopf, U. Liebigs Ann. Chem. 1993, 321.
(19) Bis-lactim ether template 24 has been used previously for the
synthesis of cis-bis-lactim ether 26 using
a sequence of
aldol/retro-aldol reactions to selectively invert the C5-stereo-
centre of trans-bis-lactim ether 25 (Scheme 5); see: Groth, U.;
Schmeck, C. Ger. Offen 4231298, 1994.
(20) Taylor, P. J. M.; Bull, S. D. Tetrahedron: Asymmetry 2006, 17,
1170.
(10) (a) Sano, S.; Nakao, M. Heterocycles 2015, 91, 1349.
(b) Schöllkopf, U. Tetrahedron 1983, 39, 2085. (c) Williams, R. M.
Synthesis of Optically Active α-Amino Acids; Pergamon Press:
Oxford, 1989.
(21) For examples of stereoselective aldol reactions of titanium aza-
enolates of bis-lactim ether 1, see: Beulshausen, T.; Groth, U.;
Schöllkopf, U. Liebigs Ann. Chem. 1991, 1207.
(11) Data generated from a CAS SciFinder structure search on bis-
lactim ether 1 (R = Me or Et) carried out on 31.12.2015.
(12) (a) Perez-Fuertes, Y.; Taylor, J. E.; Tickell, D. A.; Mahon, M. F.;
Bull, S. D.; James, T. D. J. Org. Chem. 2011, 76, 6038. (b) Bull, S.
D.; Davies, S. G.; Epstein, S. W.; Garner, A. C.; Mujtaba, N.;
Roberts, P. M.; Savory, E. D.; Smith, A. D.; Tamayo, J. A.; Watkin,
D. J. Tetrahedron 2006, 62, 7911. (c) Bull, S. D.; Davies, S. G.;
Garner, A. C.; Savory, E. D.; Snow, E. J.; Smith, A. D. Tetrahedron:
Asymmetry 2004, 15, 3989. (d) Bull, S. D.; Davies, S. G.; Garner,
A. C.; O’Shea, M. D.; Savory, E. D.; Snow, E. J. J. Chem. Soc., Perkin
Trans. 1 2002, 2442. (e) Bull, S. D.; Davies, S. G.; Garner, A. C.;
Mujtaba, N. Synlett 2001, 781. (f) Mellin-Morliere, C.; Aitken, D.
J.; Bull, S. D.; Davies, S. G.; Husson, H. P. Tetrahedron: Asymmetry
2001, 12, 149. (g) Bull, S. D.; Davies, S. G.; Garner, A. C.; O’Shea,
M. D. J. Chem. Soc., Perkin Trans. 1 2001, 3281. (h) Bull, S. D.;
Davies, S. G.; O’Shea, M. D. J. Chem. Soc., Perkin Trans. 1 1998,
3657. (i) Bull, S. D.; Chernega, A. N.; Davies, S. G.; Moss, W. O.;
Parkin, R. M. Tetrahedron 1998, 54, 10379. (j) Bull, S. D.; Epstein,
S. W.; Ouzman, J. V. A. Tetrahedron: Asymmetry 1998, 9, 2795.
(k) Bull, S. D.; Davies, S. G.; Epstein, S. W.; Leech, M. A.; Ouzman,
J. V. A. J. Chem. Soc., Perkin Trans. 1 1998, 2321. (l) Bull, S. D.;
Davies, S. G.; Epstein, S. W.; Ouzman, J. V. A. Chem. Commun.
1998, 659.
nBuLi, THF
–78 °C; BnBr
OBn
Ph
N
N
OBn
MeO
N
MeO
N
24
25
nBuLi
THF, –78 °C
acetone
KOtBu
OBn
OBn
Ph
N
N
N
N
OH
Ph
O
MeO
MeO
26
good levels of
diastereoselectivity
2 N HCl (aq)
H2N
CO2Bn
4 (R = Me)
+
Ph
neutralise with NH3 then
purify via chromatography
(13) For a previous report where these separation problems were
addressed using a bis-lactim ether derived from the expensive
non-proteinogenic D-penicillamine, see: Richter, L. S.; Gadek, T.
R. Tetrahedron: Asymmetry 1996, 7, 427.
Scheme 5 Groth’s aldol/retro-aldol stereoinversion protocol using bis-
lactim ether 5 for the asymmetric synthesis of L-phenylalanine benzyl
ester
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

N
M. Hutchby et al.
Feature
Synthesis
(22) The configuration of 6j was assigned from literature precedent
for an analogous conjugate addition reaction of bis-lactim ether
1 (R = Me); see: Schöllkopf, U.; Pettig, D.; Busse, U.; Egert, E.;
Dyrbusch, M. Synthesis 1986, 737.
(23) (a) Alvarez-Ibarra, C.; Csaky, A. G.; Colmenero, B.; Quiroga, M. L.
J. Org. Chem. 1997, 62, 2478. (b) Efskind, J.; Hope, H.; Undheim,
K. Eur. J. Org. Chem. 2002, 464. (c) Undheim, K.; Lange, M.;
Sandosham, J. PCT Int. Appl WO 9515336 A1, 1995.
(24) (a) Brown, Z. Z.; Schafmeister, C. E. J. Am. Chem. Soc. 2008, 130,
14382. (b) Li, P.; Xu, J. Tetrahedron 2000, 56, 8119.
(25) (a) Sher, P.; Wu, G.; Stouch, T.; Ellsworth, B. US Pat. Appl. Publ
US20040002495 A1, 2004. (b) Boehn, H.-J.; Koser, S.; Mack, H.;
Pfeiffer, T.; Seitz, W.; Hoeffken, H. W.; Hornberger, W. Ger.
Offen. DE 4421052 A1, 1995.
(27) For examples where alkylation of the aza-enolates of bis-lactim
ether templates derived from norleucine, leucine and norvaline
were reported to proceed with good levels of trans diastereo-
control, see: (a) Groth, U.; Huhn, T.; Porsch, B.; Schmeck, C.;
Schöllkopf, U. Liebigs Ann. Chem. 1993, 715. (b) Jiang, Y.;
Schöllkopf, U.; Groth, U. Sci. Sin., Series B: Chem., Biol., Agric.,
Med. Earth Sci. 1984, 27, 566. (c) Bull, S. D.; Davies, S. G.; Parkin,
R. M.; Sanchez-Sancho, F. J. Chem. Soc., Perkin Trans. 1 1998,
2313.
(28) Kastrinsky, D. B.; Kumar, P.; Marriner, G. A.; Barry, C. E. Synthe-
sis 2012, 44, 3043.
(29) Felpin, F.-X.; Fouquet, E. Chem. Eur. J. 2010, 16, 12440.
(30) Mangawa, S. K.; Singh, A. K.; Awasthi, S. K. RSC Adv. 2015, 5,
61144.
(26) (a) Potier, P.; Sasaki, N.; Andre, A.; Maria, C.; Wang-Zhu, Q.;
Ermolenko, L.; Bakala, J.; Franck, G.; Nhiri, N. PCT Int. Appl WO
2006103274 A1, 2006. (b) Undheim, K.; Kremminger, P. PCT Int.
Appl WO 9324523 A1, 1993.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N