An efficient asymmetric synthesis of (2S,3S)- and (2R,3R)-β-hydroxyornithine

Article abstract of DOI:10.1016/S0040-4039(00)01945-6

Asymmetric syntheses of (2S,3S)- and (2R,3R)-β-hydroxyornithine have been achieved in four steps and 46% overall yield. The key step in this synthesis involved an aldol reaction between a chiral glycine boron enolate and (3-oxo-propyl)-carbamic acid benzy

Full text of DOI:10.1016/S0040-4039(00)01945-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 183–185
An efficient asymmetric synthesis of (2S,3S)- and
(2R,3R)-b-hydroxyornithine
Duane E. DeMong and Robert M. Williams*
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Received 22 September 2000; accepted 2 November 2000
Abstract—Asymmetric syntheses of (2S,3S)- and (2R,3R)-b-hydroxyornithine have been achieved in four steps and 46% overall
yield. The key step in this synthesis involved an aldol reaction between a chiral glycine boron enolate and (3-oxo-propyl)-carbamic
acid benzyl ester. © 2000 Elsevier Science Ltd. All rights reserved.
b-Hydroxyornithine in its various stereoisomeric forms
1a–d (Fig. 1) has been previously investigated as a
potential biosynthetic precursor to both the b-lacta-
mase inhibitor clavulanic acid (2) and the antibiotic and
anticancer agent acivicin (3). Clavulanic acid has been
shown to be derived from (2S,3R)-proclavaminic acid
4, a molecule that is structurally similar to b-hydroxy-
ornithine.1 In addition, both (2S,3R)- and (2S,3S)-b-
hydroxyornithine have been shown by Gould et al. not
to be incorporated into acivicin.2 Recently, it has been
suggested that a new antibiotic xanthobaccin A could
also be derived from this unusual amino acid.3
diastereomers of 2S-b-hydroxyornithine via the dipolar
cycloaddition of vinyl glycine derivatives with a suitable
nitrone. Misiti and co-workers developed a synthesis of
(2S,3R)-b-hydroxyornithine, starting from
D
-serine.6
More recently, Gurjar and co-workers synthesized the
same enantiomer as that reported by Misiti by opening
an enantiomerically pure epoxy alcohol with benzyl
isocyanate.7 Baldwin, Baggaley, and Wakamiya have
used aldol chemistry to synthesize protected forms or
derivatives of b-hydroxyornithine.1,8
Given the important roles that various isotopomers of
b-hydroxyornithine have played in biosynthetic studies,
an efficient asymmetric synthesis of both (2S,3S)- and
(2R,3R)-b-hydroxyornithine that is compatible with
various simple strategies to incorporate both stable-
and radioisotopes was deemed justified. Herein, we
Along with these biosynthetic investigations, efforts
have been made to develop efficient syntheses of the
erythro- and threo-forms of b-hydroxyornithine. Gould
et al.4 and Townsend et al.5 have accessed both
Figure 1.
* Corresponding author. E-mail: rmw@chem.colostate.edu
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01945-6

184
D. E. DeMong, R. M. Williams / Tetrahedron Letters 42 (2001) 183–185
report an efficient and stereoselective synthesis of
(2S,3S)- and (2R,3R)-b-hydroxyornithine. In order to
arrive at the desired hydroxy amino acid, an aldol
reaction between the benzyloxycarbonyl protected 3-
amino-propanal 6 and the commercially available chiral
oxazinone 7a was investigated (Scheme 1).9 Upon treat-
ment of 3-amino-propanol with dibenzyl dicarbonate in
refluxing 10% triethylamine in methanol, a quantitative
2.80 mmol, 1.4 equiv.). The resulting solution was
refluxed under argon for 1 h, at which time the solvent
was removed in vacuo resulting in a clear oil. Silica gel
chromatography of the crude oil (eluted with 75:20:5
CH2Cl2:EtOAc:MeOH) provided 427 mg (99%) of 5 as
a white solid. Mp 51–52°C (recryst. CH2Cl2:EtOAc).
1H NMR (300 MHz) (CDCl3) l 1.71 (2H, m); 2.47 (1H,
bs); 3.36 (2H, bm); 3.69 (2H, t); 5.09 (1H, bs); 5.12 (2H,
s); 7.32–7.38 (5H, m). 13C NMR (75 MHz) (CDCl3) l
32.6, 38.0, 59.7, 66.9, 128.1, 128.2, 128.6, 136.5, 157.4.
IR (NaCl, Neat) 3326, 3030, 2955, 2931, 2873, 1684,
1651, 1586, 1535, 1499, 1489, 1454, 1374, 1327, 1298,
1266, 1216, 1144, 1116, 1086, 1066, 1023, 984, 966
cm−1. HRMS (FAB) calcd for C11H15NO3 (MH+)
210.1130; found 210.1125.
yield of the desired benzyloxycarbamate
5 was
achieved. Treatment of 5 under Dess–Martin periodi-
nane conditions resulted in a 98% yield of the requisite
(3-oxo-propyl)-carbamic acid benzyl ester 6. Lactone 7a
was then treated with di-n-butyl boron triflate to yield
the resulting boron enolate. Addition of aldehyde 6 to
this enolate provided the expected aldol product 8a in
69% yield with a diastereoselectivity of 8:1 (1H NMR).
The undesired diastereomer was easily removed by
recrystallization of 8a from ethyl acetate and hexanes.
Hydrogenolysis of the benzyloxycarbonyl groups as
well as the chiral auxiliary was achieved by treatment
of 8a with palladium chloride and hydrogen. The di-
hydrochloride salt of the amino acid, obtained from
this protocol, was neutralized with ammonium hydrox-
ide (pH 6.5); recrystallization from water/ethanol,
afforded (2S,3S)-b-hydroxyornithine 1a in 68% yield and
>99.5:0.5 er as determined by chiral HPLC analysis.
Compound 6: To a solution of 5 (427 mg, 2.04 mmol,
1 equiv.) in non-distilled methylene chloride (17 mL)
was added the Dess–Martin periodinane (1.47 g, 3.47
mmol, 1.7 equiv.). The resulting heterogeneous mixture
was stirred overnight at room temp. Upon taking up
the reaction mixture in diethyl ether (70 mL) and satd.
aq. NaHCO3 (70 mL), sodium thiosulfate (6.03 g, 24.3
mmol, 11.9 equiv.) was added, and the biphasic solu-
tion was stirred for 30 min. After removing the organic
layer via separatory funnel, the aqueous layer was
extracted twice more with ether. The organic layers
were combined and dried over anhydrous MgSO4. Fil-
tration followed by removal of solvent under reduced
pressure provided a crude white solid that was purified
by silica gel chromatography (eluted with 1:1
EtOAc:hexanes) to provide 416 mg (98%) of 6 as a
white solid. Mp 53–54°C (recryst. EtOAc/hexanes).
Using the commercially available antipode of the oxazi-
none (7b)10 the enantiomeric (2R,3R)-b-hydroxyor-
nithine 1b was prepared in a similar manner. Full
experimental details are provided.
It has been demonstrated that both (2S,3S)- and
(2R,3R)-b-hydroxyornithine can be prepared from
commercially available starting materials in an efficient
and stereocontrolled manner. The synthetic approach
described herein, maintaining a 46% overall yield, com-
pares favorably with other published syntheses that
contain longer sequences, lower overall yields, and
lower stereoselectivity.
1H NMR (300 MHz) (CDCl3) l 2.75 (2H, t); 3.50 (2H,
q); 5.09 (2H, s); 5.18 (1H, bs); 7.32–7.37 (5H, m); 9.81
(1H, s). 13C NMR (75 MHz) (CDCl3) l 34.7, 44.3, 66.9,
128.2, 128.3, 128.6, 136.5, 156.4, 201.2. IR (NaCl,
Neat) 3449, 3054, 2986, 2305, 2254, 1720, 1512, 1422,
1265, 1144, 1094, 1027, 909 cm−1. HRMS (FAB) calcd
for C11H13NO3 (MH+) 208.0974; found 208.0975.
Experimental
Compound 8a: Under argon atmosphere, compound 7a
(624 mg, 1.61 mmol, 1 equiv.) was dissolved in dry
methylene chloride (19 mL). The resulting solution is
then cooled to −5°C (ice/acetone bath). Di-n-butyl-
Compound 5: To a 10% solution of triethylamine in
methanol (2 mL) was added 3-aminopropanol (150 mg,
2.00 mmol, 1 equiv.) and dibenzyl dicarbonate (802 mg,
Scheme 1.

D. E. DeMong, R. M. Williams / Tetrahedron Letters 42 (2001) 183–185
185
boron triflate (1 M in CH2Cl2) (3.22 mL, 3.22 mmol, 2
equiv.) was added via syringe followed by addition of
triethylamine (673 mL, 4.83 mmol, 3 equiv.). The mix-
ture was stirred 15 min at −5°C then cooled to −78°C.
In a separate flask, compound 6 (400 mg, 1.93 mmol,
1.2 equiv.) was dissolved in methylene chloride (3.5
mL) and the resulting aldehyde solution was added via
canula to the boron enolate, and the reaction was
stirred one hour at −78°C. The reaction was quenched
by the addition of 0.025 M pH 7 potassium phosphate
buffer at −78°C, and the mixture was allowed to warm
to room temperature. The organic layer was separated
and the aqueous layer was extracted twice more with
methylene chloride. The organic layers were combined
and dried over anhydrous sodium sulfate. Filtration
and removal of the solvent under reduced pressure
produced an orange oil that was purified by silica gel
chromatography (eluted with 30% EtOAc in hexanes).
This initial separation resulted in co-elution of both the
aldehyde and aldol product. A second silica gel chro-
29.0, 37.7, 59.5, 68.0, 171.6. IR (NaCl, 1% KBr) 3074,
1612, 1576, 1529, 1508, 1431, 1358, 1325, 1180, 1140,
1065, 1032 cm−1. Mp 232°C dec (lit.5 mp 232°C dec).
Compound 1a. [h]2D5= +24.1 (c=0.56, 6N HCl) [lit.5
[h]D= +18.0 (c=2.2, 6N HCl)]. Compound 1b. [h]2D5=
−20.2 (c=0.47, 6N HCl). The enantiomeric purities of
1a and 1b were determined to be >99.5:0.5 er by chiral
HPLC analysis (Daicel Chiral Pak WH, column tem-
perature 50°C, 0.25 mM CuSO4 mobile phase, Waters
600 HPLC, dual wavelength UV detection at 210 and
254 nm).
Acknowledgements
This work was supported by the National Science
Foundation (Grant CHE 9731947).
matographic
separation
(eluted
with
3:1:1
References
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cryst. EtOAc/hexanes).
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.
.