Resolution and absolute configuration of some a-aminoacetals: En route to enantiopure N-protected a-aminoaldehydes

Article abstract of DOI:10.1007/s00726-011-1117-6

The first successful resolution of rac-a-aminoacetals via diastereoisomeric salt formation with optically pure N-protected aminoacids is reported. The absolute configuration assignment of a-aminoacetal enantiomers is performed by an entirely non-racemizing chemical correlation method involving N-protection and a new efficient hydrolysis step followed by a reduction of the resulting N-protected a-aminoaldehyde intermediates. A racemization method of optically enriched a-aminoacetals is exemplified to allow valorisation of both enantiomers. Springer-Verlag 2011.

Full text of DOI:10.1007/s00726-011-1117-6

Amino Acids (2012) 43:687–696
DOI 10.1007/s00726-011-1117-6
ORIGINAL ARTICLE
Resolution and absolute configuration of some a-aminoacetals:
en route to enantiopure N-protected a-aminoaldehydes
•
Muriel Albalat-Serradeil Geraldine Primazot
•
´
Didier Wilhelm Jean-Claude Vallejos
•
•
•
Nicolas Vanthuyne Christian Roussel
Received: 15 July 2011 / Accepted: 1 October 2011 / Published online: 21 October 2011
Ó Springer-Verlag 2011
Abstract The first successful resolution of rac-a-amino-
acetals via diastereoisomeric salt formation with optically
pure N-protected aminoacids is reported. The absolute
configuration assignment of a-aminoacetal enantiomers is
performed by an entirely non-racemizing chemical corre-
lation method involving N-protection and a new efficient
hydrolysis step followed by a reduction of the resulting
N-protected a-aminoaldehyde intermediates. A racemiza-
tion method of optically enriched a-aminoacetals is
exemplified to allow valorisation of both enantiomers.
1993; Serradeil-Albalat et al. 2008; Bringmann and Geisler
1989) (Scheme 1). Enders et al. (1993) and Denmark and
Nicaise (1993) used expensive reactants such as SAMP or
RAMP chiral inductors. In other cases, starting materials
which are not easily available with the exception of pyr-
uvaldehyde dimethylacetal have been employed (Bring-
mann and Geisler 1989). We obtained moderate
enantioselectivities up to 70% when (1S,10S)-1,10-(4-amino-
4H-1,2,4-triazole-3,5-diyl)diethanol was used as chiral
auxiliary in the asymmetric synthesis of a-aminoacetals
(Serradeil-Albalat et al. 2008). These moderate enantiose-
lectivities were in accordance with the lower chiral induc-
tion efficiency already noticed for hydrazones bearing an
acetal group (Enders et al. 1993; Denmark and Nicaise
1993; Serradeil-Albalat et al. 2008). The acetal group is
probably providing detrimental binding sites for the metal
during asymmetric alkylation or asymmetric reduction.
Herein, we report on the first successful resolution of
rac-a-aminoacetals (rac-A) via diastereoisomeric salt for-
mation. The absolute configuration assignment of a-amin-
oacetal enantiomers is performed by a completely non-
racemizing chemical correlation method involving N-pro-
tection and a new efficient hydrolysis step followed by a
reduction of the resulting N-protected a-aminoaldehyde
intermediates. A racemization method of optically enriched
a-aminoacetals is exemplified to allow valorisation of both
enantiomers (Scheme 2).
Keywords Chiral a-aminoalcohols ꢀ Chiral
a-aminoaldehydes ꢀ Chiral HPLC ꢀ Resolving agents ꢀ
Absolute configuration ꢀ Chemical correlation method
Introduction
Optically pure a-aminoacetals (A) are direct precursors of
optically pure a-aminoaldehydes by hydrolysis of the acetal
group. Few methods, which are not requiring aminoacids as
precursors, have been developed to obtain enantio-enriched
a-aminoacetals (Enders et al. 1993; Denmark and Nicaise
Electronic supplementary material The online version of this
article (doi:10.1007/s00726-011-1117-6) contains supplementary
material, which is available to authorized users.
M. Albalat-Serradeil ꢀ G. Primazot ꢀ D. Wilhelm
Clariant France, Usine de Lamotte, LRA,
60350 Trosly Breuil, France
Results and discussion
Synthesis of racemic a-aminoacetals rac-3
J.-C. Vallejos ꢀ N. Vanthuyne ꢀ C. Roussel (&)
ISM2, Chirosciences, UMR 6263,
13397 Marseille Cedex 20, France
The most common synthetic routes for the preparation of
racemic a-aminoacetals start from either a-haloacetals
e-mail: christian.roussel@univ-cezanne.fr
123

688
M. Albalat-Serradeil et al.
MeO
MeO
MeO
MeO
OR'
PhCH2NH2
toluene / rt
OR'
X
N
1
CH2Ph
O
R
R'O
*
DME
R'O
entry
product
2a / 3a
2b / 3b
2c / 3c CH2CH2Ph
2d / 3d Ph
2e / 3e cyclohexyl
R
Bn
iBu
1
2
3
4
5
O
NH2
A
RMgX
R
MeO
MeO
R
5%Pd-C / H2
MeOH
MeO
MeO
OR'
OR'
NH2
N
H
CH2Ph
(i) or (ii)
X
rac -3a-e
R
rac-2a-e
R'O
*
R'O
N
Scheme 3 Route to racemic a-aminoacetals rac-3a–e from glyoxal
monoacetal (DME)
N
R*
R*
R"
Scheme 1 Literature route to optically active a-aminoacetals
A. (i) X = R [1,2]-asymmetric addition [RM], (ii) X = H asymmetric
reduction [H], R*= chiral auxiliary like (D)-(?)- or (L)-(-)-a-
methylbenzylamine, SAMP/RAMP or (1S, 10S)-1,10-(4-amino-4H-
1,2,4-triazole-3,5-diyl)diethanol, R00 = H or protecting group
a-aminoacids (Narjes et al. 2002; Matassa et al. 1999;
Attwood et al. 1998, 1999; Liu et al. 2009).
Racemic a-aminoacetals rac-3 were here obtained by a
straightforward route from glyoxal monoacetal (dimeth-
oxyethanal, DME) according to Scheme 3.
Reaction of DME and benzylamine afforded the imine 1
(Terinek and Vasella 2004a). 1 was treated with various
Grignard reagents to give racemic N-benzyl protected
aminoacetals, rac-2a–e (Enders et al. 1993; Quelet and
Chastrette 1959; Chastrette 1962; Kido and Watanabe
1987). Hydrogenolysis of rac-2a–e with palladium on
carbon in methanol, afforded the expected racemic a-am-
inoacetals, rac-3a–e (Muralidharan et al. 1994; Bringmann
and Geisler 1989; Terinek and Vasella 2004b; Urban and
Noe 2003; Winkler et al. 2004). The combined yields in
isolated rac-3a–e from DME after the three chemical steps
reported in Scheme 3 and a final purification step by dis-
tillation were ranging between 25 and 45% (Albalat et al.
2010). These operating conditions were not further opti-
mized, they provided the starting material for the present
study.
Racemization process
HO
N
OMe
R
OMe
[red]
[ox]
NH2
NH2
*
Resolution
OMe
OMe
R
R
OMe
rac-A
OMe
(S) or (R)
Cbz
R
Cbz
NH
*
NH
OMe
OMe
Hydrolysis
O
Resolution of rac-3
*
R
H
rac-1-Benzyl-2,2-dimethoxyethylamine (rac-3a) and rac-
1-dimethoxymethyl-3-methyl-butylamine (rac-3b), were
chosen as models compounds to carry out preliminary
screening of the resolving agents (Jacques et al. 1981;
Sheldon 1993; Baley and Vaidya 1992; Kozma 2002;
Rouhi 2003; Sakai et al. 2003, 2006; Hirose et al. 2008).
The conventional acidic resolving agents for primary
amines (Kozma 2002) such as (L)-(?)-tartaric acid,
(D)-(?)-dibenzoyltartaric acid, (D)-(?)-camphor-10-sul-
fonic acid, (L)-(-)-di-p-toluyltartaric acid, (S)-(?)-man-
delic acid and (L)-(-)-N-tosylproline, were screened
without success in various solvents.
(
S
) or (R)
(
S
) or (R)
Cbz
R
Cbz
R
NH
NH
*
Reduction
O
*
OH
OMe
(
R
)
or
(
S
)
(S)
Chiral HPLC
Absolute configuration assigment by chemical correlation method
Scheme 2 Route to optically active a-aminoacetals, chemical corre-
lation method for the assignment of the absolute configuration and
racemization process
We turned our attention to N-protected aminoacids like
N-acetyl-(L)-leucine, (L)-4 and N-acetyl-(L)-phenylalanine,
(L)-5 which possess some structural similarity with rac-3b
and rac-3a, respectively, and an acidic N–H prone to
enantioselectively interact with the oxygen of the acetal in
(Burtles et al. 1925; Boon 1957; Brumby et al. 2002;
Albaugh and Hutchison 1995; Johnson et al. 1947; Walsh
et al. 1987; Gall and Kamdar 1981; Upjohn Co 1976) or
123

Resolution and absolute configuration of some a-aminoacetals
689
the diastereomeric complexes. Both enantiomers of the
resolving agent 5 were synthesized by acetylation of
commercially available (L)- and (D)-phenylalanine by
known method (Huffman and Ingersoll 1951; Synge 1939;
Fones 1952; Holland et al. 1953). High yields (85–90%)
and high-optical purities (ee C 99.5%, as determined by
chiral HPLC analyses on Chiralpak AD-H, hexane-iPrOH
90/10) were obtained.
diastereoisomeric salt was further enriched in one diaste-
reoisomer by recrystallization or washing.
Selected examples of favorable operating conditions
leading to (S)- or (R)-3a–d are reported in Table 1 (Albalat
et al. 2009).
High enantioselectivities (ee C 96%) were achieved for
all a-aminoacetals 3a–d with (L)- or (D)-5 as resolving
agent. The diastereoisomeric purity of the crude salts could
be easily further improved by one or several recrystalli-
zations (Table 1).
The optically pure salts (R)-3a.(L)-4, (S)-3a.(L)-4, (R)-
3a.(L)-5 and (S)-3a.(L)-5 were independently prepared
from optically pure (R)- and (S)-3a, provided by pre-
parative chiral HPLC, and their melting points were
recorded. The melting points were in the range 149–160°C
and the difference in melting points was 2°C for the dia-
stereomeric pair (R)-3a.(L)-4, (S)-3a.(L)-4 and 10°C for the
pair (R)-3a.(L)-5 and (S)-3a.(L)-5. (L)-5 which provided a
larger difference in the melting points of the diastereoiso-
meric pair was thus selected for further optimization of the
operating conditions.
The R substituent in a-aminoacetals 3 plays a decisive
role on the chiroselective molecular recognition: using (L)-
5, the (R) enantiomer is collected from the solid diaste-
reoisomer in the case of rac-3a and rac-3b (entries 1 and 3,
Table 1), while the (S) form is obtained in the case of rac-
3c and rac-3d (entries 5 and 7, Table 1).
rac-3e resisted to all resolution attempts using (L)- and
(D)-5. A series of resolution tests was performed using
N-acetyl-(L)-leucine, (L)-4 (Scheme 4; Table 2). It was
known from the literature that not all structurally analogous
racemates can be resolved under similar conditions
(Pallavicini et al. 1997; Loiodice et al. 1995; Albright and
Snyder 1959).
ðRÞꢁ3a:ðLÞꢁ4 m:p: ¼ 151ꢂC
ðSÞꢁ3a:ðLÞꢁ4 m:p: ¼ 149ꢂC
ðRÞꢁ3a:ðLÞꢁ5 m:p: ¼ 160ꢂC
Results in Table 2 show that the optical resolution of
rac-3e with (L)-4, was very instable and was strongly
dependent on the operating conditions. In all cases, the ee of
the first crop was poor and comprised only between 23 and
50%. The ee can be noticeably improved up to 94% at the
expense of the yield by further washing and crystallization.
An illuminating proof of the great instability of the system
was the occurrence of an unexpected reversal of selectivity
in the preferred crystallized diastereoisomer which occurred
under very minor changes in operating conditions or solvent
(entries 2–3 and 4–5). The change of the configuration of
the aminoacetal component in the precipitating salt was
firmly established by chiral chromatography for each entry
to Table 2. The two diastereoisomeric salts (D)-3e/(L)-4
ðSÞꢁ3a:ðLÞꢁ5 m:p: ¼ 150ꢂC
Preliminary screenings on rac-3a and rac-3b showed
that optically enriched 3a and 3b were indeed obtained but
the enantiomeric excess and the yield were depending, as
usually, on the solvent, the concentration, the operating
conditions and the acidic resolving agent.
The main parameters for diastereoisomeric resolution
are the resolving agent, the molar ratio of the resolving
agent to racemic substrate, the substrate concentration, the
solvent and the temperature. The conditions for the reso-
lution of rac-3 with half molar equivalent amount of (L)- or
(D)-5 were screened. The detailed resolution process is
illustrated in Fig. 1 for rac-3a with (L)-5. The resulting
Fig. 1 Flow chart for the
resolution of rac-3a with (L)-5
Ph
+
rac-3a
(
S
>
R
)-3a + (L)-5
+
>S
)-3a.(
solid
L)-5
(
R
AcHN
COOH
liquor
(L)-5
Recryst.
or Washing
filtrate
(
R
)-3a.(
L
)-5
(S>R)-3a.(L)-5
φaq
φorg
)-3a
φorg
φaq
>R)-3a
(L)-5
(
R
(S
123

690
M. Albalat-Serradeil et al.
Table 1 Resolution of rac-3a–d with (L)- or (D)-5 as resolving agent (RA)
5
3
Solvent (w/w)
Conditions
Yield (ee %)
AC
1
2
3
4
5
6
7
8
L
3a
3a
3b
3b
3c
3c
3d
3d
A(6%)
50°C (3 h)/40°C (2 h)/20°C
50°C (3 h)/40°C (2 h)/20°C
50°C (3 h)/19°C
41a (97)
44a (99)
50–55b (96)
50b (96)
19c (96)
23c (96)
56c (98)
70–75d (97)
(R)
(S)
(R)
(S)
(R)
(S)
(S)
(R)
D
L
A(6%)
A/B 13/87 (6%)
A/B 13/87 (9%)
A (6%)
D
L
50°C (3 h)/23°C
28°C (2 h)/50°C/30°C
19°C (2 h)/50°C/30°C
50°C (3 h)/23°C
D
L
A (6%)
A (6%)
D
A (6%)
50°C (3 h)/23°C
Solvent A = iPrOH, B = acetone; Resolving agent/rac-3 = 0.5/1 (molar ratio). Yield with respect to limiting reactant (resolving agent) after
salt decomposition. ee determined by chiral HPLC analyses after salt decomposition on free 3a, c–d and on N-Cbz-carbamate derivative for 3b,
e. For the assignment of the absolute configuration (AC), see text
a
One recrystallization 5.5% w/w in iPrOH
b
Two recrystallizations 7% w/w in iPrOH
c
Two recrystallizations 3% w/w in iPrOH
d
Two recrystallizations 5.5% w/w in iPrOH
Scheme 4 Resolution of rac-3e
with (L)-4
O
O
MeO
MeO
MeO
MeO
+
NH2
+
-
AcHN
COOH
.
NHAc
NH3
(
L)-4
(S>R)-3e.(L)-4
rac-3e
and (L)-3e/(L)-4 should have very similar physical
properties.
mixture of methanol and water, afforded the corresponding
oximes 6a–b in good yields (70–90%) (Kahr and Berther
1960; Kahr 1956; Synthese-Chemie GmbH 1956). The
reduction of the resulting oximes 6a–b to yield rac-3a–b
was successfully accomplished using catalytic hydrogena-
tion (20–50 bar H2) with Raney nickel as catalyst in ethanol
at room temperature (crude yield = 75–90%) (Nielsen and
Lies 1990; Paul 1937; Shivers and Hauser 1974; Ikeda et al.
1977).
Racemization/recycling of the undesired enantiomer
The main drawback to any resolution process is the max-
imal theoretical yield which is limited to 50% in the
desired optically pure product in the absence of dynamic
kinetic resolution. A way to improve the whole process is
to find an efficient racemization method which transforms
the undesired enantiomer or a non-racemic mixture of the
two enantiomers into a racemic mixture which can be
engaged again in the resolution step.
An efficient resolution process of a-aminoacetals 3 has
been developed with N-acetyl-phenylalanine, 5, or with
N-acetyl-leucine, 4. High selectivities (ee C 94%) were
achieved thanks to recrystallization and both enantiomers
of rac-3 can be obtained. The recycling of the unresolved
enantiomer in the starting racemic material was developed
on two examples.
Unfortunately, most of the reported conventional race-
mization methods for the a-aminoacids and derivatives
(catalysis with a base or an acid, formation of a Schiff’s
base-type intermediate) (Ebbers et al. 1997) or for chiral
`
amines (catalysis with a base, reducing conditions) (Pamies
Determination of ee’s and absolute configuration
of enantiomers of 3a–e isolated during the resolution
process
et al. 2002; Fujino and Sato 2001; Vitt 1980), were not
efficient to racemize a-aminoacetals under mild operating
conditions.
A sequence of oxidation and reduction on the optically
enriched a-aminoacetals 3 (Scheme 5) was explored
(Albalat et al. 2008b). Treatment of a-aminoacetals 3a–b
with aqueous hydrogen peroxide and catalytic amount of
sodium tungstate (Na2WO4ꢀ2H2O) at room temperature in a
The ee’s of the enriched 3a and 3c–d resulting from the
resolution process were determined by liquid chromatog-
raphy on chiral support without additional derivatization.
Ee’s of 3b and 3e were determined on the corresponding
N-Cbz-protected forms. It is worth noting that excellent
123

Resolution and absolute configuration of some a-aminoacetals
Table 2 Resolution of rac-3e with (L)-4 (0.5 mol.eq.)
691
AC
Solvent (w/w)
Conditions
Yield
Ee%
1
2
3
4
5
6
Acetone (3.6%)
19°C (2 h)/reflux (1 h)/filtration (30°C)
21°C (2 h)/56°C (1 h)/filtration (21°C)
19°C (2 h)/reflux/filtration (30°C)
19°C (2 h)/reflux/filtration (30°C)
19°C (2 h)/reflux/filtration (30°C)
19°C (2 h)/reflux/filtration (22°C)
96
72
88
64
88
93
32a
70b
21c
6d
30
29
45
27
32
50
91
23
84
94
(S)
(R)
(S)
(R)
(S)
(S)
(S)
(S)
(S)
(S)
THF (3.6%)
THF (3.6%)
THF/CH3CN (50/50) (3.5%)
THF/AcOEt (50/50) (3.5%)
THF/acetone (75/25) (3.5%)
7
THF/acetone (75/25) (3.5%)
19°C (2 h)/D (62°C?40°C/seeding/filtration (22°C)
a
b
c
d
Two recrystallizations 4% w/w in THF/acetone (75/25)
Washing with THF/acetone (75/25)
One recrystallization 4% in THF/acetone (75/25) and washing with THF/acetone (75/25)
Two recrystallizations 4% in THF/acetone (75/25)
MeO
MeO
R
MeO
MeO
R
MeO
MeO
R
N
(i)
(ii)
NH2
NH2
OH
(
S
>
R
)-3a-b
6a-b
rac-3a-b
Scheme 5 Tandem oxidation and reduction to recycle the unresolved a-aminoacetal 3. (i) 30% H2O2/Na2WO4.2H2O/MeOH. (ii) Raney-Ni/H2/
EtOH
Scheme 6 Process for chemical
correlation to assign the
absolute configuration of
a-aminoacetal 3a–e. Step one:
chromatographic data
acquisition for rac-9a–e. (i) Cbz
N-protection, (ii) HCO2H, H2O,
(iii) metal hydride reduction
MeO
MeO
R
R
O
H
R
(i)
(iii)
(ii)
NH2
HO
NHCbz
NHCbz
rac-3a-e
rac-8a-e
rac-9a-e
chiral HPLC analyses
retention time for (
)- and
)-isomers
S
(
R
separations were obtained for all the N-Cbz-protected
a-aminoacetals (see Supporting Information).
hydride reduction gave the N-protected a-aminoalcohols
9a–e.
The assignment of the absolute configuration of the
enantiomers of 3a–e was envisioned by the adaptation of
the chemical correlation method to modern chiral chro-
matography. The classical chemical correlation method
refers to a series of non-racemizing chemical transforma-
tions leading to an enantiomer of known configuration
associated to a sign of the optical rotation. The chemical
correlation method involving chiral chromatography
requires the comparison of the retention time of the enan-
tiomer resulting from a series of non-racemizing chemical
transformations with the retention times of the enantiomers
of known absolute configuration of the corresponding
racemate. The chemical correlation we used is reported in
Scheme 6 for its racemic version. a-Aminoacetals 3a–e
were N-Cbz-protected yielding 7a–e, acetal hydrolysis
afforded N-protected a-aminoaldehydes 8a–e, and metal
In a first step the analytical conditions (column, mobile
phase) which gave a baseline separation of the enantiomers
of rac-N-protected a-aminoalcohols 9a–e were screened
(see Supporting Information). In a second step, the injec-
tion of the pure (S)-enantiomer of 9a–c, e, obtained from
commercially available ester of (S)-a-aminoacids 10a–c,
e according to Scheme 7, allowed the assignment of the
order of elution. Chiroptical detection (polarimeter on-line)
offered additional validation of the assignments.
The metal hydride reduction of the ester of (S)-phenyl
glycine 10d produced in our hands rac-9d precluding the
assignment of the order of elution for 9d. The absolute
configuration of the enantiomers of 3d should be assigned by
another chemical correlation method. We decided to explore
the reduction of 3d into 3e (Scheme 8) to catch up with the
chemical correlation scheme already established for 3e.
123

692
M. Albalat-Serradeil et al.
Scheme 7 Synthesis of (S)-9a–
c and (S)-9e from optically pure
a-aminoesters chlorhydrate salt
(S)-10a–c and (S)-10e. (i) Cbz
N-protection, (ii) metal hydride
reduction
O
R
O
R
R
(i)
(ii)
+
. Cl-
R1O
NH3
R1O
NHCbz
HO
NHCbz
(S
)-9a-c,e
chiral HPLC analyses
retention time for (S)-isomer
(
S
)-10a-c,e
commercially available
Optically enriched N-Cbz-a-aminoacetals 7a and 7b
were used as model compounds to study the configuration
stability during the acetal hydrolysis step. They were pre-
pared from optically pure a-aminoacid derivatives accord-
ing to the literature (Enders et al. 1993; Attwood et al. 1998;
Guillaumie et al. 2000; Iqbal et al. 1996; Edwards et al.
1988; Trainor and Stein 1987; Gacek and Undheim 1974) or
from the optically pure a-aminocetals obtained by the res-
olution process here described. Hydrolysis of optically
enriched 7a and 7b were performed using 95% formic acid
and the isolated N-protected a-aminoacetals 8a, b were
acetalized with methanol to restore 7a and 7b, respectively.
The ee’s of compounds 7a–b after ketalization showed no
appreciable changes when compared with the ee’s of
compounds 7a–b before the acetal hydrolysis with formic
acid. It is worth noting that the very mild procedure to
obtain N-protected-a-aminoaldehydes through the corre-
sponding acetal hydrolysis without detectable racemization
constitutes a valuable route to these useful chiral building
blocks (Jurczak and Golebiowski 1989; Reetz 1999, 1991;
Gryko et al. 2003; Hili et al. 2008; Baktharaman et al. 2008;
Izawa and Onishi 2006; Garner and Park 1987; Chowdari
et al. 2003; Tokuyama et al. 2002; Dias et al. 2003; Kwon
and Myers 2005; Wen and Crews 1998; Hili and Yudin
2006; Myers et al. 2000; Diness et al. 2004).
H2 / catalyst
MeO
MeO
MeO
MeO
NH2
NH2
3d
3e
Scheme 8 Aromatic ring hydrogenation of 3d on Ru or Rh catalyst.
The reduction proceeded without any racemization
Inspection of the literature provided several examples of the
selective and non-racemizing catalytic hydrogenation of a
phenyl group in phenylglycine, phenylalanine or pheneth-
ylamine and analogues using ruthenium on carbon or rho-
dium on Al2O3 (Sato et al. 1998; Herlinger et al. 1967;
¨
Strotmann and Butenschon 2000; Nugent 2002; Minnaard
et al. 1999; Hayashi et al. 1983). These methods when
applied to the hydrogenation of 3d on Rh/Al2O3 or Ru/C
catalyst gave quantitatively 3e. Furthermore, starting from
diversely enantio-enriched samples of 3d, the corresponding
enriched 3e was obtained without any detectable racemiza-
tion accordingto chiralHPLC on the N-Cbz-protected forms.
The acetal hydrolysis step in Scheme 6 which leads to
the corresponding N-protected a-aminoaldehydes was
highly critical in terms of chemical stability and racemi-
zation risk. The literature procedures to obtain optically
active N-protected a-aminoaldehydes from optically active
N-protected a-aminoacetals, were not encouraging. Den-
mark and Nicaise (1993) reported that the deacetalization
step of N-Boc-a-aminoacetals with 3 molar equivalents of
trimethylsilyl iodide, led to a substantial loss of optical
purity for most of the tested products. Severe operating
conditions (reflux in aqueous DMSO), followed by flash
chromatography purification, were used to hydrolyze chiral
N-benzyloxycarbonyl-a-aminoacetals without racemization
(Muralidharan et al. 1994). We found that rac-7a–e were
efficiently hydrolyzed using 95% formic acid to give N-
protected a-aminoaldehydes rac-8a–e under very mild
conditions (Albalat et al. 2008a) (Scheme 9).
The various steps described in Scheme 6 when applied
to optically pure 3a–e allowed a very safe assignment of
the absolute configuration of 3a–e and all the intermediates
7a–e and 8a–e. Furthermore, chiral HPLC analysis
revealed that all the steps described in Scheme 6 proceeded
without any noticeable change in the ee’s.
Conclusion
Resolution of racemic a-aminoacetals via diastereoiso-
meric salt formation was successfully achieved for the
first time. A careful chemical correlation method was
MeO
MeO
R
MeO
MeO
R
O
H
R
(i)
(ii)
NH2
NHCbz
NHCbz
7a-e
8a-e
3a-e
Scheme 9 Protection and hydrolysis of compounds rac-3a–e into N-Cbz-a-aminoaldehydes rac-8a–e. (i) CbzCl/K2CO3/MTBE/H2O, (ii)
HCO2H/H2O
123

Resolution and absolute configuration of some a-aminoacetals
693
washed with cyclohexane (50 mL), oven-dried (40°C) and
then treated with an aqueous solution of sodium hydroxide.
The aqueous phase was extracted with CH2Cl2. After
solvent concentration, (R)-1-benzyl-2,2-dimethoxyethyl-
amine was obtained (1.23 g, 41% relative to (L)-5,
ee(R) = 97% determined by chiral HPLC).
established to assign the absolute configuration of the
isolated enantiomers. Furthermore, a method for the race-
mization of enantio-enriched a-aminoacetals and a non-
racemizing hydrolysis of N-protected a-aminoacetals to
give N-protected a-aminoaldehydes were exemplified. The
method using N-protected amino-acids as resolving agents
has been used with success to resolve some undisclosed
proprietary a-aminoacetals related to non-natural amino-
acids with the usual case by case optimization of the res-
olution step conditions.
Isolation of enriched (S)-1-benzyl-2,2-
dimethoxyethylamine (S)-3a
Filtrate 1 was concentrated and the solid residue was tritu-
rated in cyclohexane (ca 100 mL), filtered under vacuum and
washed with cyclohexane (60 mL). After drying and treat-
ment with an aqueous solution of sodium hydroxide, enri-
ched (S)-1-benzyl-2,2-dimethoxyethylamine was obtained
(1.29 g, 43% relative to (L)-5, ee(S) = 74% determined by
chiral HPLC).
Experimental section
Experimental details: the full experimental details and
product characterizations are reported in the Supporting
Information.
Optical resolution of racemic 1-benzyl-2,2-dimethoxy-
ethylamine rac-3a with N-acetyl-(D)-phenylalanine (D)-5
was performed according to a mirrored experimental pro-
cedure and yielded (S)-1-benzyl-2,2-dimethoxyethylamine
(1.32 g, 44% relative to (D)-5 ee(S) C 99% determined by
chiral HPLC).
Optical resolution of racemic 1-benzyl-2,2-
dimethoxyethylamine rac-3a with N-acetyl (L)-
phenylalanine (L)-5:
In a 250-mL three-necked flask equipped with a mechan-
ical stirrer, a condenser and a thermometer, racemic
(S)-1-benzyl-2,2-dimethoxyethylammonium N-acetyl-
(D)-phenylalaninate: m.p. 159°C; [a]2D5 = -39.6 (c = 1 in
MeOH); 1H NMR (200 MHz, [D6] DMSO, TMS):
d = 1.78 (s, 3 H), 2.63–2.74 (AB syst., 1 H), 2.85 (m, 2 H),
3.05–3.14 (AB syst., 1 H), 3.2–3.4 (m, 1 H), 3.33 (s, 3 H),
3.38 (s, 3 H), 4.2 (d, 1 H, J = 4.8 Hz), 4.32 (m, 1 H),
7.1–7.4 ppm (m, 10 H), 7.86 (d, 1 H, J = 8.1 Hz); 13C
NMR (75 MHz, [D6] DMSO, TMS): d = 22.56, 36.06,
37.31, 53.36, 54.51, 54.85, 55.12, 105.25, 125.95, 126.23,
127.88, 128.27, 129.16, 129.29, 137.96, 138.59, 168.66,
173.71; HRMS (ESI): for C11H17NO2 [M?H]?: calcd.
196.1338; found 196.1337 and for C11H12NO3 [M?H]?:
calcd. 208.0974; found 208.0973.
1-benzyl-2,2-dimethoxyethylamine
rac-3a
(6 g,
30.8 mmol) and N-acetyl-(L)-phenylalanine (L)-5 (3.18 g,
15.4 mmol) were added to iPrOH (94 g, 6% solution). The
medium was stirred and heated at 50°C for 3 h, and then
kept at 40°C for 2 h. Heating was switched off and stirring
was maintained overnight.
Isolation of (R)-1-benzyl-2,2-dimethoxyethylamine (R)-
3a The precipitate was filtered off, washed with cyclo-
hexane (ca 100 mL) (filtrate 1), and then oven-dried at 40°C
under vacuum. (R)-1-benzyl-2,2-dimethoxyethylammoni-
um N-acetyl-(L)-phenylalaninate, (R)-3a.(L)-5, was obtained
as a white solid (3.06 g, 50% relative to the N-acetyl-(L)-
phenylalanine (L)-5); m.p. 159°C; [a]2D5 = ?42.2 (c = 1 in
MeOH); 1H NMR (200 MHz, [D6] DMSO, TMS): d = 1.78
(s, 3 H), 2.63–2.74 (AB syst., 1 H), 2.85 (m, 2 H), 3.05–3.14
(AB syst., 1 H), 3.2–3.4 (m, 1 H), 3.33 (s, 3 H), 3.38 (s, 3 H),
4.2 (d, 1 H, J = 4.8 Hz), 4.32 (m, 1 H), 7.1–7.4 (m, 10 H),
7.86 ppm (d, 1 H, J = 8.1 Hz); 13C NMR (75 MHz, [D6]
DMSO, TMS): d = 22.56, 36.06, 37.31, 53.36, 54.51, 54.85,
55.12, 105.25, 125.95, 126.23, 127.88, 128.27, 129.16,
129.29, 137.96, 138.59, 168.66, 173.71 ppm; HRMS (ESI):
for C11H17NO2 [M?H]?: calcd. 196.1338; found 196.1337
and for C11H12NO3 [M?H]?: calcd. 208.0974; found
208.0973.
1-Benzyl-2,2-dimethoxyethylamine 3a (Guillaumie et al.
2000; Gacek and Undheim 1974; Grobelny and Galardy
1986) rac-3a: colorless oil (58.2 g, 45%); b.p. 115–
1
120°C/5 mmHg; GC tR=13.65 min; H NMR (300 MHz,
CDCl3, TMS): d = 1.3 (s, 2 H), 2.5 (m, 1 H), 3 (m, 1 H), 3.15
(m, 1 H), 3.49 (s, 6 H), 4.14 (d, 1 H, J = 5.6 Hz),
7.19–7.4 ppm (m, 5 H); 13C NMR (75 MHz, CDCl3, TMS):
d = 38.7, 54.2, 55.05, 55.19, 107.9, 126.3, 128.3, 128.56,
129.1, 129.4, 139.1 ppm; EI MS: m/z (%): 164 (M-31, 11),
120 (M-75, 96), 104 (M-91, 39), 91 (62), 75 (100).
(S)-(-)-3a: chiral HPLC (Chiralcel OD-H, hexane/
iPrOH 90/10 v/v, 1 mL/min): tR = 5.6 min; Optical rota-
tion: [a]2D5 = -27.7 (c = 1 in MeOH).
The salt (R)-3a.(L)-5 was triturated in iPrOH (53 g,
solution at 5.5%) and the medium was heated at 50°C for
approximately 1.5 h. Heating was switched off and stirring
was maintained overnight. The resulting solid was filtrated,
(R)-(?)-3a:chiral HPLC (Chiralcel OD-H, hexane/
iPrOH 90/10 v/v, 1 mL/min): tR= 6.5 min; Optical rota-
tion: [a]2D5 = ?27.6 (c = 1 in MeOH).
123

694
M. Albalat-Serradeil et al.
1-Dimethoxymethyl-3-methyl-butylamine 3b rac-3b:
colorless oil (32.2 g, 30%); b.p. 75°C/10 mmHg; GC
tR = 8.65 min; 1H NMR (300 MHz, CDCl3, TMS):
d = 0.85 (dd, 6 H, J = 6.4 Hz, J = 6.6 Hz), 1.2 (m, 4 H),
1.7 (m, 1 H), 2.8 (m, 1 H), 3.33 (s, 3 H), 3.36 (s, 3 H),
3.9 ppm (d, 1 H, J = 5.6 Hz); 13C NMR (75 MHz, CDCl3,
TMS): d = 21.5, 23.97, 24.5, 41.5, 50.6, 54.8, 55.2,
108.9 ppm; EI MS: m/z (%): 130 (M-31, 7), 86 (M-75,
100), 75 (67), 43 (80); HRMS (ESI): for C8H19NO2
[M?H]?: calcd. 162.1494; found 162.1482.
54.6, 54.74, 57, 106.4 ppm; HRMS (ESI): for C10H21NO2
[M?H]?: calcd. 188.1645; found 188.1646.
(S)-(?)-3e: Optical rotation: 0 \ [a]2D5 \ 1 (c = 15 in
MeOH).
(R)-(-)-3e: optical rotation: -1 \ [a]2D5 \ 0 (c = 15 in
MeOH).
Conflict of interest The authors declare that they have no conflict
of interest.
(S)-(-)-3b: Optical rotation: [a]2D5 = -20.4 (c = 1 in
MeOH).
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