Preparation of L-threoninol and its bisoxazoline derivative

Article abstract of DOI:10.1081/SCC-120015822

(R,R)-Threoninol was prepared in one step from L-threonine in 86% isolated yield. The product was regioselectively transformed into 2,2-bis[(4R,5R)4-(hydroxymethyl)-5-methyl-1,3-oxazolin-2-yl]propane in 42% isolated yield.

Full text of DOI:10.1081/SCC-120015822

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Preparation of l-Threoninol and Its Bisoxazoline
Derivative
a
a
a
Serghey Lutsenko , Ulla Jacobsson & Christina Moberg
a
Department of Chemistry , Organic Chemistry , Royal Institute of Technology , Stockholm,
Sweden
Published online: 16 Aug 2006.
To cite this article: Serghey Lutsenko , Ulla Jacobsson & Christina Moberg (2003) Preparation of l-Threoninol and Its
Bisoxazoline Derivative, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:4, 661-666, DOI: 10.1081/SCC-120015822
To link to this article: http://dx.doi.org/10.1081/SCC-120015822
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 4, pp. 661–666, 2003
Preparation of L-Threoninol and
Its Bisoxazoline Derivative
Serghey Lutsenko, Ulla Jacobsson, and Christina Moberg*
Department of Chemistry, Organic Chemistry,
Royal Institute of Technology, Stockholm, Sweden
ABSTRACT
(
R,R)-Threoninol was prepared in one step from L-threonine in 86%
isolated yield. The product was regioselectively transformed into
,2-bis[(4R,5R)-4-(hydroxymethyl)-5-methyl-1,3-oxazolin-2-yl]propane
2
in 42% isolated yield.
Key Words: Threoninal; Amino alcohol; Bisoxazoline; Ligand.
*Correspondence: Christina Moberg, Department of Chemistry, Organic
Chemistry, Royal Institute of Technology, Teknikringen 56, SE-100 44
Stockholm, Sweden; Fax: þ468 791 2333; E-mail: kimo@kth.se.
6
61
DOI: 10.1081/SCC-120015822
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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6
62
Lutsenko, Jacobsson, and Moberg
Amino alcohols constitute versatile building blocks for the synthesis
[
1]
of a variety of biologically active compounds and they can also be
employed, directly or subsequent to suitable chemical transformations,
[
2,3]
as chiral ligands for asymmetric metal catalysis.
A useful synthetic
route for their preparation consists of the reduction of naturally occur-
ring or synthetically obtained amino acids, a procedure which employs
reducing agents such as lithium aluminum hydride, diisobutylaluminum
.
hydride, BH THF, and sodiumborohydride–iodine. These reduc-
3
[
4,5]
tions commonly proceed in high yield.
For water-soluble amino alco-
hols low yields have occasionally been reported due to difficulties
encountered during isolation, and there is thus a need for improved
procedures.
We were interested in employing L-threoninol (1a) for the preparation
of bisoxazoline 2a, as this compound serves as a potential starting material
for the preparation of a variety of bisoxazoline derivatives e.g., via ester or
[
6]
ether formation. The analogous compound 2b, obtained from 1b, can be
employed for the same purpose, but we have encountered problems with
low reactivity in attempted formation of esters from sterically hindered
[7]
acid derivatives.
Threoninol has previously been obtained via a general procedure for
the reduction of N-terminal and side chain protected amino acids and their
[4]
esters. This procedure requires several steps and yields are commonly
[
8,9]
not reported.
lithiumalu mi numhydride has been reported to proceed in excellent
yield,
[11]
Reduction of the methyl ester of racemic threonine with
[10]
but the ester was obtained in merely 56% yield from the
acid. Sodiumborohydride reduction of the ethyl ester of D-allothreo-
nine afforded 70% of an oil, fromwhich D-allothreoninol hydrogen
oxalate was isolated in 76% yield.
2-methoxyethoxy)aluminate has been reported to result in high yield of
amino alcohol, but no procedure for the isolation of the product was
provided.
O-benzyl protected threonine in as much as three steps to threoninol in
an overall yield of 71%. Finally, the hydrogenation under pressure of
[
12]
Reduction employing dihydro-bis-
(
[13]
Another method consists of transformation of N-Boc-
[14]

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L-Threoninol and Its Bisoxazoline Derivative
663
the amino acid in the presence of a ruthenium catalyst was reported to
[
result in 61% of threoninol.
15]
Herein is described an efficient, one-step procedure for the reduction
of L-threonine, yielding the desired amino alcohol in 86% isolated yield,
as well as details for the preparation of 2a, obtained from 1a in 42%
isolated yield.
The reduction of L-threonine was achieved using sodiumborohydride
and iodine in THF. To ensure a high yield of product, a fourfold excess
of sodiumborohydride and a 1.5 fold excess of iodine had to be used.
The product was isolated by chromatography followed by absorption on
Dowex and elution with diethylamine in methanol.
Bisoxazoline 2a was prepared in one step from( R,R)-threoninol and
dimethylmalononitrile in the presence of cadmium diacetate in analogy to
[
the procedure described for 2b. The product, obtained as a single
6]
regioisomer, was purified by crystallization. The structure was deter-
1
mined by NMR spectroscopy. H– H cosy and hmqc were run to assign
1
1
13
all H and C resonances (see Experimental). In order to determine the
position of the methyl group, which theoretically could be positioned
either on the oxazoline ring or on the hydroxymethyl substituent, an
hmbc experiment was performed. The correlation peaks observed in the
1
13
spectrumcorrespond to H– C long-range couplings, where the nuclei
are separated by 2–3 bonds. Since there is a clear correlation between C-2
and H-5, i.e., the a-proton to the methyl group, the methyl group must be
positioned on the oxazoline ring as shown in structure 2a. It would not be
possible to see a correlation to the corresponding proton when the methyl
group is positioned in the hydroxymethyl moiety.
EXPERIMENTAL
Dimethylmalononitrile was prepared according to a described
THF was distilled over Na/benzophenone, CH Cl was
2 2
[16]
procedure.
distilled fromCaH 2. Sodiumborohydride, iodine, L-threonine, and
1
Dowex 50WX4-400 were obtained fromLancaster. H and C spectra
13
were recorded in CDCl at 400.13 and 100.62 MHz, respectively. All 2D
3
1
3
experiments were performed at 500.13 MHz (125.77 MHz for C) using
the gradient mode. Coupling constants were measured from resolution
enhanced spectra. Standard Bruker software was used for the cosy, hmqc,
and hmbc experiments. High resolution mass spectra were recorded on a
JEOL SX 102 spectrometer. The optical rotation value was measured
using a Perkin–Elmer 343 polarimeter. The melting point is uncorrected.

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64
Lutsenko, Jacobsson, and Moberg
R,R)-Threoninol
An oven-dried round-bottomed flask was charged with sodium
(
borohydride (3.04 g, 80 mmol) and 100 mL of anhydrous THF. The
solution was stirred while L-threonine (2.38 g, 20 mmol) was added in
one portion. A solution of iodine (7.62 g, 30 mmol) in 50 mL of THF
ꢀ
was added dropwise to the mixture under inert atmosphere at 0 C over
a period of 0.5 h. The solution was allowed to warmto roomtemperature
and the reaction mixture was brought to reflux for 18 h. Methanol was
added dropwise to the cloudy white suspension at roomtemperature until
the white material had dissolved. The clear solution was next acidified with
conc. HCl (to pH 2–3). The precipitated solid was filtered off and the
concentrated filtrate was purified by column chromatography (20%
MeOH in CHCl , R 0.13). The obtained oil was then absorbed on 15 g
3
F
of Dowex, washed with methanol, and liberated with a 10% solution of
diethylamine in methanol. After evaporation of the solvent threoninol
1
1.82 g, 86%) was obtained as a yellowish viscous oil. H NMR (D O)
(
2
ꢀ
1
: 1.22 (d, J ¼ 6.3 Hz, 3H), 2.71 (m, 1H), 3.51 (dd, J ¼ 6.8 and 11.3 Hz,
H), 3.67 (dd, J ¼ 4.8 and 11.3 Hz, 1H), 3.80 (m, 1H).
(
Q)-2,2-Bis[(4R,5R)-4-hydroxymethyl-5-methyl-
,3-oxazolin-2-yl]propane
1
Threoninol (1.82 g, 17.3 mmol), dimethylmalononitrile (0.64 g,
.8 mmol), and cadmium acetate dihydrate (90 mg, 0.34 mmol) were
6
refluxed in 25 mL of chlorobenzene for 16 h. The product was purified
[
15]
by column chromatography (9% MeOH in CH Cl , R 0.55). White
F
2
2
crystals of 2a (771 mg, 42%) were obtained upon cooling from an ethyl
ꢀ
acetate or ether solution after addition of light petroleum: m.p. 107 C.
1
2
D
5
½
ꢁŠ ¼ þ168 (c ¼ 1, CHCl ). H NMR ꢀ: 1.20 (d, J ¼ 6.3 Hz, CH -CH, 6H),
3
3
1
.39 (s, (CH ) -C, 6H), 3.39 (dd, J ¼ 3.15, and 11.2 Hz, CHH-O, 2H), 3.61
3
2
(
ddd, J ¼ 3.15, 3.15 and 5.3 Hz, CH-N, 2H), 3.66 (dd, J ¼ 3.15 and 11.2 Hz,
1
3
CHH-O, 2H), 4.54 (dq, J ¼ 5.3 and 6.3 Hz, CH-O, 2H). C NMR ꢀ: 19.7
(
CH -CH), 23.9 ((CH ) -C), 39.8 ((CH ) -C), 64.1 (CH ), 73.8 (CH-N),
3 3 2 3 2 2
7
2
9.2 (CH-O), 171.6 (C¼). HRMS (FABþH) calcd. for C H N O ,
1
3
22
2
4
þ
70.1580; found, 271.1667 (MH ).
ACKNOWLEDGMENT
This work was supported by the Swedish Research Council.

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L-Threoninol and Its Bisoxazoline Derivative
665
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Received in the UK January 2, 2002