AN EFFICIENT METHOD FOR PREPARATION OF OPTICALLY ACTIVE N-PROTECTED α-AMINO ALDEHYDES FROM N-PROTECTED α-AMINO ALCOHOLS

Article abstract of DOI:10.1135/cccc19950693

N-Protected α-amino aldehydes of high optical purity were prepared in excellent yields from corresponding α-amino alcohols by 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzodioxol-3(H)-one (periodinane) oxidation.

Full text of DOI:10.1135/cccc19950693

Short Communication
693
AN EFFICIENT METHOD FOR PREPARATION OF OPTICALLY ACTIVE
N-PROTECTED α-AMINO ALDEHYDES FROM N-PROTECTED α-AMINO
ALCOHOLS
Milan SOUCEK and Jan URBAN
Institute of Organic Chemistry and Biochemistry,
Academy of Sciences of the Czech Republic, 166 10 Prague 6, The Czech Republic
Received January 4, 1994
Accepted January 22, 1995
N-Protected α-amino aldehydes of high optical purity were prepared in excellent yields from corre-
sponding α-amino alcohols by 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzoidoxol-3(H)-one (periodi-
nane) oxidation.
The preparation of N-protected α-amino aldehydes either by reduction of naturally oc-
curring amino acid derivatives or by oxidation of corresponding amino alcohols has
1
been recently reviewed . Retention of optical activity was demonstrated in all cases but
optical purity of amino aldehydes was not investigated. Only recently has been re-
2
3
ported that the much frequented reduction of N-methoxyamides of α-amino acids
4
leads to partial racemization on α-carbon. We have found that neither of published
methods checked in our laboratory was suitable for fast, by-product free and in-
expensive production of optically pure α-amino aldehyde derivatives.
3
–7
Our preparation of N-protected α-amino aldehydes is based on the method of Dess
8
and Martin , in which primary or secondary alcohols are oxidized by 1,1,1-tris-
(
acetoxy)-1,1-dihydro-1,2-benzoiodoxol-3(H)-one (periodinane) to aldehydes or
ketones. Starting chiral N-protected α-amino alcohols* are readily available from corre-
1
0
sponding amino acid methyl esters by sodium acetoxyborohydride reduction . The oxi-
dations (Scheme 1) were performed in dichloromethane or chloroform solutions, with
1
.2 molar excess of oxidant (for yields and analytical data see Table I). In some experi-
ments the reaction medium was supplemented with tert-butyl alcohol which, repor-
8
tedly , aids the oxidation. Nevertheless, even in the absence of tert-butyl alcohol the
*
Abbreviations used obey the recommendations of IUPAC-IUB Commision on Biochemical Nomenclature9.
The following additional abbreviations are used: MeOH, methanol; CHF, chloroform; 2,6-DCB,
2
,6-dichlorobenzyl; DCM, dichloromethane; Ptg, protecting group.
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

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Soucek, Urban:
TABLE I
Yields and analytical data of N-protected α-amino aldehydes
Calculated/Found
M.p., °C
Yield, %
[α] , °
c, solvent
Formula
M.w.
D
Aldehyde
%
C
% H
% N
a
b
Boc-L-Ala-al
86 – 88
−36.0
–
–
–
–
–
9
7
0.5, MeOH
c
d
Boc-L-Phe-al
88
−42.2
–
–
–
9
1
1.0, MeOH
6
0.28
Boc-L-Pro-al
26 – 32
−70.8
C H NO
3
8.60
8.93
7.03
7.27
10
17
9
9
1.3, MeOH
199.3
59.83
e
Boc-L-Leu-al
oil
−43.8
–
–
–
–
9
8
0.5, MeOH
Boc-D-Leu-al
Boc-L-Nle-al
oil
+44.4
C11H21NO3
215.3
61.37
61.55
9.83
9.61
6.51
6.77
9
6
0.5, MeOH
oil
+39.9
C11H21NO3
215.3
61.37
61.63
9.83
9.56
6.51
6.19
9
7
0.6, DCM
f
Boc-L-Met-al
Boc-L-Tyr(2,6-DCB)-al
Z-L-Phe-al
oil
+12.6
–
–
–
–
9
2
0.6, DCM
112 – 115
−20.0
C21H23Cl2NO4 59.44
5.46
5.31
3.30
3.52
9
8
0.6, MeOH
424.3
59.75
g
h
77 – 80
−47.8
–
–
–
–
9
0
0.9, MeOH
Fmoc-L-Leu-al
Boc-L-Pro-L-Phe-al
77 – 79
+22.8
C21H23NO3
337.4
74.75
74.93
6.87
6.76
4.15
3.87
8
1
0.6, DCM
amorphous
−47.8
65.88
65.60
7.56
7.24
8.09
8.00
C19H26N2O4
9
2
0.5, CHF
346.4
a
3
b
11
c
3
d
3
e
11
Ref. , m.p. 88 – 89 °C. Ref. , [α] −40.9°. Ref. , m.p. 86 °C. Ref. , [α] −44.4°. Ref. ,
D
D
f
11
g
11
h
12
[
α]D −34.0°. Ref. , [α] +27.8°. Ref. , m.p. 78 – 80 °C. Ref. , [α] −52.9°.
D
D
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

Short Communication
695
oxidations were so fast that with most alcohols investigated the reaction course could
not be followed even by short-path TLC. Excess of the oxidant was destroyed by
aqueous solution of sodium thiosulfate and bicarbonate, which simplified product iso-
lation. The yields of amino aldehydes were almost quantitative except for S-benzyl-N-
(
tert-butoxycarbonyl)cysteinol which suffered oxidative deprotection with formation of
benzaldehyde (88%, as 2,4-dinitrophenylhydrazone).
Optical rotations of several N-Boc-amino aldehydes prepared by periodinane method
3
were in good agreement with data published by Fehrenz and Castro . However, we have
observed that optical rotations of amino aldehydes in methanol were time-dependent
(
Table II), e.g. for Boc-Phe-al [α] −35.2° at zero time and −42.2° after 48 h. As a
D
plausible mechanism for the optical rotation drift we suggest transformation of α-amino
aldehyde carbonyl to a hemiacetal group. Corroboration for this hypothesis we have
1
found in H NMR spectra of Boc-L-Phe-al. In CDCl solution doublet for CHO appeared at
3
δ 9.62 ppm, but in CD OD solution was shifted upfield to δ 3.82 ppm.
3
Retention of optical activity was observed in all α-amino aldehyde syntheses re-
3
,11
ported (e.g. refs ), but its extent has never been investigated. To be assured that there
is no racemization in the course of amino alkohol oxidation and/or amino aldehyde
SCHEME 1
TABLE II
Time dependence of optical rotation of N-protected α-amino aldehydes in methanol (c 0.5) at 23 °C
[
α] , °
D
Aldehyde
t = 0 h
t = 48 h
Boc-L-Phe-al
−35.2
−46.0
−69.8
−23.8
−42.2
−30.4
−74.5
−34.4
Boc-L-Leu-al
Boc-L-Pro-al
Boc-L-Val-L-Phe-al
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

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Soucek, Urban:
isolation we measured optical rotation of N-Boc-phenylalaninol ([α] −23.7°, c 1.0,
D
methanol) and oxidized it by periodinane. N-Boc-phenylalaninal formed ([α] −42.4°,
D
c 0.5, methanol) afforded by sodium borohydride reduction N-Boc-phenylalaninol of
the same optical purity ([α] −23.3°, c 1.0, methanol) as the starting material.
D
EXPERIMENTAL
Optical rotations were recorded on a Perkin–Elmer 241 automatic polarimeter at 22 °C; the measure-
ments were performed 2 h after dissolution of the amino aldehydes. The melting points were deter-
mined on a micro melting point apparatus (Boetius) and are uncorrected. Reagent grade chloroform
and dichloromethane (Fluka) were distilled from P O . Periodinane reagent was prepared as reported
2
5
8
in literature and was stored in a dessicator over 3A molecular sieves.
General Procedure for the Oxidation of N-Protected α-Amino Alcohols by Periodinane
N-Protected α-amino alcohol (1.0 mmol) in dry dichloromethane (2 ml) was added to a stirred solu-
tion of periodinane (530 mg, 1.25 mmol) and tert-butyl alcohol (0.10 ml, 1.1 mmol) in dichloromethane
(
5 ml) at room temperature (cooling with ice-water was necessary if the amount of oxidized alcohol
exceeded 5 mmol). When the reaction was finished (usually 10 min) excess of the oxidant was de-
stroyed by addition of a solution of sodium bicarbonate (1 g) and sodium thiosulfate (1 g) in water
(
15 ml). After 5 min of vigorous stirring the mixture was diluted with dichloromethane (10 ml),
organic layer was separated, washed with brine, dried with magnesium sulfate and the solvent was
evaporated. Solid residue was triturated with tert-butyl methyl ether (5 ml) and filtered through a
short pad of silica gel deactivated with water (15%). Pure aldehydes (TLC, HPLC) were obtained by
evaporation of the solvent in 81 – 99% yield. Analytical samples were obtained by crystallization
from tert-butyl methyl ether–hexane.
This work was partly supported by the Grant Agency of the Academy of Sciences of the Czech Repub-
lic (Grants No. 45524 and No. 455101).
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