Procedure for the oxidation of β-amino alcohols to α-amino aldehydes

Article abstract of DOI:10.1055/s-2005-918918

A novel procedure for the mild oxidation of β-amino alcohols to α-amino aldehydes using commercially available manganese(IV) oxide is reported. There are several important advantages of the new method, such as high enantiopurity of the reaction and the absence of either over-oxidation or any reaction by-products during the process. A number of N-protected L-α-amino aldehydes was obtained. All new compounds were characterized by their NMR spectra and optical rotation data. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918918

2802
LETTER
Procedure for the Oxidation of b-Amino Alcohols to a-Amino Aldehydes
Oxidation of
b
-Amino
a
A
lcohols to
x
a
-Amino
A
i
ldehyd
m
e
s
E. Sergeev,* Victor B. Pronin, Tatiana L. Voyushina
Laboratory of Protein Science, Institute of Microbial Genetics, 1st Dorozhny pr. 1, Moscow 113545, Russia
Fax +7(095)3150501; E-mail: maxsergeev@iskra-net.ru
Received 1 August 2005
system DMSO/acetic anhydride could be used for the
Abstract: A novel procedure for the mild oxidation of b-amino al-
cohols to a-amino aldehydes using commercially available manga-
nese(IV) oxide is reported. There are several important advantages
of the new method, such as high enantiopurity of the reaction and
synthesis of a-amino aldehydes in about 60% yield.10 The
method is very sensitive to reagent purity and reaction
conditions: even slight excess of acetic anhydride leads to
the absence of either over-oxidation or any reaction by-products the formation of hydroxy-acylated by-product and a de-
during the process. A number of N-protected L-a-amino aldehydes
was obtained. All new compounds were characterized by their
NMR spectra and optical rotation data.
creased yield of the target compound. Oxidation could
also be carried out with pyridine–CrO3 complex with
moderate yields, but the further experiments revealed that
this reaction was often irreproducible and the yield de-
pended strongly on the freshness of pyridine–CrO3 com-
plex.11 It also should be noted that some oxidizers require
the heating during the reaction while the a-amino alde-
hydes are unstable upon heating. Another important group
of oxidizers are the hypervalent iodine compounds, which
have been of great interest over the last years.12–14 The
most well known examples of such a compounds are
diacetoxyiodosobenzene (DIB), iodoxybenzoic acid
(IBX) and Dess–Martin periodinane (DMP). The yields of
oxidation reactions with IBX are usually pretty good and
stereopurity of the desired product is high.
Key words: amino alcohols, amino aldehydes, enzymes, manga-
nese, oxidations
Peptidoaldehydes are known to be inhibitors of thiol and
serine proteinases.1 When interacting with protease, the
peptide moiety of the peptidoaldehyde contacts the sub-
strate-binding site of the enzyme and its aldehyde group
forms tetrahedral complex with the serine hydroxyl group
in the active site of the enzyme thus giving rise to the non-
productive analogue of transition state.2 Peptidoaldehydes
are reversible inhibitors which might have medical appli-
cations, for instance for treating Alzheimer’s disease,
HHAV (human hepatitis A virus) and rhinoviruses.3,4 An-
other important route of application of peptidoaldehydes
is the affinity chromatography.5 Sorbents based on poly-
mer-bound amino aldehydes could be used for effective
purification of enzymes and proteins.6 It is known that bi-
ologically active peptidyl-a-amino aldehydes have the
strictly defined stereoconfiguration of C-terminal residue
(D or L) and under no conditions are racemic. Thus, there
exists a problem to prepare peptidyl-a-amino aldehydes
of high stereopurity.
We have developed a new method for the synthesis of the
N-protected a-amino aldehydes in high enantiopurity and
in good yields shown in Scheme 1.
The manganese(IV) oxide MnO2 was found to be the ex-
cellent oxidizing agent, that allowed to carry out the reac-
tion under mild conditions (r.t., CHCl3) and also it is much
more commercially available than DMP or IBX. A num-
ber of N-protected L-a-amino aldehydes 1 starting from
N-protected L-amino acids 4 was prepared according to
Scheme 1, where PG stands for protecting group [formyl
(For), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl
(Z)].
There are several frequently used methods to obtain the
desired aldehydes.7 One of them is the oxidation of pepti-
dyl-b-amino alcohols with a number of known oxidizers.8
Another way, which is more convenient, is the condensa-
tion of the carbonyl-protected a-amino aldehyde deriva-
tives (such as semicarbazones, acetals, etc.) with
acylpeptides followed by the deprotection.9 The a-amino
aldehyde derivatives can be synthesized by means of
oxidation of N-protected b-amino alcohols with well
known oxidizers, but the most of those ones give rise to
the two products, i.e. the desirable aldehyde and the acid
as the product of overoxidation, or lead to the racemiza-
tion (or invertion) of the a-stereocenter in the molecule.
Voyushina with co-workers showed that the oxidizing
We have applied natural amino acids because their
aldehyde-derivatives could be used in the synthesis of
affinity sorbents for enzyme purification. The suggested
O
PG
PG
HN
N
O
HN
HO
O
O
OH
O
R
N
R
O
O
DCC, EtOAc
r.t., 20 h
4
3
PG
PG
MnO2
CHCl3
NaBH4, AcOH
MeOH/dioxane
HN
HN
O
OH
R
R
SYNLETT 2005, No. 18, pp 2802–2804
0
3
.1
1
.2
0
0
5
2
1
Advanced online publication: 10.10.2005
DOI: 10.1055/s-2005-918918; Art ID: G24405ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

LETTER
Oxidation of b-Amino Alcohols to a-Amino Aldehydes
2803
Table 2 Physical Properties of Synthesized N-Protected
L-a-Aminoaldehydes
procedure could be used for different types of amino ac-
ids: hydrophobic, hydrophilic and multifunctional. Amino
alcohols 2 were obtained starting from N-protected L-ami-
no acids 4 following the well-known procedure.7 N-pro-
tected L-b-amino alcohols were obtained as white solids
and their NMR spectra were consistent with the structure.
The oxidation of these alcohols was performed in dry
chloroform using MnO2 of analytical grade. Correspond-
ing N-protected L-a-amino aldehydes 1a–i were obtained
as enantiopure isomers and yields are as high as 67–91%.
NMR and mass spectra, melting points and optical rota-
Mp (°C) MSa
[a]D
23
Entry
Aldehyde
(MeOH)
–52
1a
1b
1c
1d
Z-Phenylalaninal
Z-Leucinal
83–85
148.2
114.2
100.1
128.2
148.2
115.1
–
–
–
–
–
–47
Z-Valinal
–43
Z2-Lysinal
–33
tion degrees for the obtained compounds are consistent 1e
For-phenylalaninal
–52
with those reported in literature.15–17 The results are
shown in Table 1 and Table 2. Boc-valinal (1i) was ob-
tained as white crystals, Z-phenylalaninal (1a) and Boc-
1f
Boc-asparaginal
–38
tert-butyl ester
1g
Boc-phenylalaninal
Boc-leucinal
–
148.2
114.2
–50
–41
–44
leucinal (1h) were obtained as colorless crystals, all the
other aldehydes 1b–g were obtained as pale yellow oils.18
1h
64–66
Table 1 Reaction Conditions for the Synthesis of N-Protected
L-a-Aminoaldehydes
1i
Boc-valinal
122–125 100.1
a SALDI MS: [M – PG]+.
Entry
Aldehyde
Time Yield ee
(h)
24
18
18
24
24
12
(%)a
(%)b
a ready building block for the preparation of peptidic sor-
bent, was prepared. The reagents and conditions for the
reaction of derivatization are depicted in Scheme 2.20,21
1a
1b
1c
Z-Phenylalaninal
Z-Leucinal
85
97
72
>99
98
Z-Valinal
86
H2N
HN
O
N
1d
1e
Z2-Lysinal
74
98
O
semicarbazide
O
O
For-phenylalaninal
67
99
NaOAc, EtOH/H2O
O
NHBoc
O
NHBoc
1f19
Boc-asparaginal tert-butyl
91
>99
1f
5
ester
H2N
HN
O
N
1g
Boc-phenylalaninal
Boc-leucinal
18
18
12
77
81
83
97
>99
>99
TFA, CH2Cl2
HO
1h19
1i
O
NH2
Boc-valinal
6
a Isolated yield.
Scheme 2
b Calculated by chiral HPLC of the corresponding b-amino alcohols
2a–i obtained by NaBH4 reduction of crude aldehydes.
In conclusion, we have presented a very simple novel pro-
cedure for the synthesis of enantiopure a-amino aldehydes
based on oxidation of corresponding b-amino alcohols
with MnO2. The reactions can be carried out under very
mild conditions and in very high yields. Besides, no race-
mization at stereogenic carbon atom takes place under
reported conditions.
One of the most important advantages of our procedure
was the absence of any organic by-products in the reac-
tion. The purification of the product was very simple be-
cause the final reaction mixture contained only two
compounds, namely the desired aldehyde and unreacted
alcohol, which differed in their chromatographic mobility
significantly. The purified N-protected a-amino alde-
hydes should be stored at low temperatures (about –20° C)
in dark due to their chemical and optical instability at
room temperature. Another way to preserve the com-
pounds was to convert the desired aldehyde into its deriv-
ative, for example semicarbazone. We have obtained the
semicarbazone 5 of Boc-Asp(Ot-Bu)al by the standard
reaction of aldehyde with semicarbazide in the presence
of sodium acetate in water–ethanol mixture. This semicar-
bazone was then N-deprotected with trifluoroacetic acid
and as result pure asparaginal-semicarbazone 6, which is
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Synlett 2005, No. 18, 2802–2804 © Thieme Stuttgart · New York

2804
M. E. Sergeev et al.
LETTER
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1.30 (m, J = 10.35 Hz, 2 H, –CH2–i-Pr), 1.60 (s, 9 H, Boc),
2.00–2.10 (m, J = 6.60 Hz, 1 H, –CHMe2), 4.20 (m, J = 6.89
Hz, 1 H, C*H asymm.), 4.89 (br s, 1 H, –NH–), 10.30 (dd,
J = 2.33 Hz, 1 H, –CHO) ppm. [a]D23 –41 (c 2.5, MeOH).
SALDI-MS [M – Boc]+: 114.2.
N-Boc-O-tert-butyl-asparaginal (1f).
(11) Voyushina, T. L.; Potetinova, J. V.; Milgotina, E. I.;
Stepanov, V. M. Bioorg. Med. Chem. 1999, 7, 2953.
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(18) Caution: pure aminoaldehydes may cause acute allergic
reaction on contact with skin or upon inhalation.
(19) Representative Experimental Procedure for the
Synthesis of Aldehydes 1h and 1f.
The reaction was carried out over 12 h, the product was
purified by silica gel flash chromatography eluting with
CHCl3, then CHCl3–MeOH 1:1; the title compound was
obtained as a light yellow oil. 1H NMR (400 MHz, CDCl3):
d = 1.40–1.50 (s, 18 H, Boc + t-Bu), 2.91–3.30 (m, J = 16
Hz, 2 H, –CH2–COOt-Bu), 4.90 (m, J = 10.45 Hz, 1 H, C*H
asymm.), 6.22 (br s, 1 H, –NH–), 8.40 (d, J = 2.33 Hz, 1 H,
–CHO) ppm. [a]D23 –38 (c 1, MeOH). SALDI-MS [M –
Boc – t-Bu]+: 115.2.
(20) Synthesis of N-Boc-O-tert-butyl-asparaginal-
semicarbazone (5).
To a stirred solution of NaOAc (1.3 equiv) and
semicarbazide hydrochloride (1.3 equiv) in 70% EtOH the
solution of Boc(Ot-Bu)-asparaginal (1f) in 3 mL of EtOH
was added. The reaction mixture was heated at 80 °C for 2 h
and then at r.t. overnight. The reaction product was purified
by silica gel flash chromatography, eluting with EtOAc–
hexane 5:1. Yield 67%. 1H NMR (400 MHz, CDCl3): d =
1.40 (dd, J = 5.23 Hz, 18 H, 6 × CH3), 2.40–2.60 (m, J =
3.41, 9.57 Hz, 2 H, –CH2–), 8.00 (br s, 1 H, –NH–amino
acid), 4.20 (m, J = 5.53 Hz, 1 H, C*H asymm.), 6.00 (m,
3 H, –NH2 and –NH–Sem.), 9.83 (dd, 1 H, –CH=N) ppm.
(21) Synthesis of Asparaginal-semicarbazone (6).
TFA (10 equiv) was added to a stirred solution of protected
semicarbazone 5 in CH2Cl2. The reaction mixture was stirred
at r.t. for 12 h and the solvent with an excess of TFA were
vacuum distilled. The resulting product was rinsed with Et2O
and recrystallized from EtOH–H2O 2:1. The title compound
was obtained as white amorphous solid. Yield 96%. 1H
NMR spectra were consistent with the structure.
An aminoalcohol 2h or 2f (0.05 mmol) was dissolved in 2 mL
of CHCl3 and MnO2 (0.2 mmol) was added in one portion.
The mixture was stirred vigorously at r.t. for 12–24 h. The
reaction was monitored by TLC on silica gel plates eluting
with EtOAc–hexane 5:1. The resulting aldehyde was dried in
a dark vacuum desiccator at –20 °C. Aldehydes should be
stored in dark place at about –20 °C.
N-Boc-leucinal (1h).
The reaction was carried out over 18 h, the product was
purified by silica gel flash chromatography eluting with
CHCl3, then CHCl3–MeOH 1:1; the title compound was
obtained as colorless crystals; mp 64–66 °C. 1H NMR (400
MHz, CDCl3): d = 0.80–0.90 (dd, J = 5.21 Hz, 6 H, 2 × CH3),
Synlett 2005, No. 18, 2802–2804 © Thieme Stuttgart · New York