Lipase-catalyzed acetylation of tert-butyl N-(2-hydroxy-3- phenoxypropoxy)carbamates-preparation of optically active aminooxypropanols

Article abstract of DOI:10.1081/SCC-120005944

A simple method was developed for the preparation of optically active-3-aryloxy-1-aminooxy-2-propanols by a lipase-catalyzed kinetic resolution of racemic mixtures of their N-tert-butylcarbamate-protected derivatives.

Full text of DOI:10.1081/SCC-120005944

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
LIPASE-CATALYZED ACETYLATION
OF tert-BUTYL N-(2-HYDROXY-3-
PHENOXYPROPOXY)CARBAMATES—PREPARATION
OF OPTICALLY ACTIVE AMINOOXYPROPANOLS
Ewa Buchalska & Jan Plenkiewicz
To cite this article: Ewa Buchalska & Jan Plenkiewicz (2002) LIPASE-CATALYZED ACETYLATION
OF tert-BUTYL N-(2-HYDROXY-3-PHENOXYPROPOXY)CARBAMATES—PREPARATION OF
OPTICALLY ACTIVE AMINOOXYPROPANOLS, Synthetic Communications, 32:16, 2591-2599, DOI:
10.1081/SCC-120005944
To link to this article: http://dx.doi.org/10.1081/SCC-120005944
Published online: 16 Aug 2006.
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 16, pp. 2591–2599, 2002
LIPASE-CATALYZED ACETYLATION OF
tert-BUTYL N-(2-HYDROXY-3-
PHENOXYPROPOXY)CARBAMATES—
PREPARATION OF OPTICALLY ACTIVE
AMINOOXYPROPANOLS
*
Ewa Buchalska and Jan Plenkiewicz
Faculty of Chemistry, Warsaw University of
Technology, Noakowskiego 3, 00-664Warsaw, Poland
ABSTRACT
A simple method was developed for the preparation of
optically active-3-aryloxy-1-aminooxy-2-propanols by
lipase-catalyzed kinetic resolution of racemic mixtures of their
a
N-tert-butylcarbamate-protected derivatives.
Many types of optically active amino alcohols, but not aminooxy
alcohols, have been obtained to data and used in pharmacy, cosmetics,
etc., as well as chiral auxiliares in organic synthesis. It may be expected
therefore that b-aminooxy alcohols of the general formula 1 in an optically
active form will prove to be valuable synthons or chiral auxiliaries in the
synthesis of new biologically active compounds.
*Corresponding author. E-mail: planki@chemix.ch.pw.edu.pl
2591
DOI: 10.1081/SCC-120005944
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2592
BUCHALSKA AND PLENKIEWICZ
For example, some alkoxyamino groups are known as common
fragments of the semisynthetic cephalosporin antibiotics of the second
and third generation, such as: cefmenoxime, ceftriaxone, cefuroxime, cefta-
zidime, or of a synthetic monobactam antibiotic aztreonam.[1] However,
none of the known antibiotic molecules contains a b-aminooxy alcohol
fragment and to the best of our knowledge optically active b-aminooxy
alcohols have been described only by us.[2,3]
In the research on a lipase-catalyzed kinetic separation of the
enantiomers of b-aminooxy alcohols we were looking for a suitable protec-
tion of the amino function. In the preliminary experiments the protection
by the phthaloyl and iso-propylidene groups was investigated.[2] Simple
protection and deprotection procedures and very low cost of the substrates
were considered as the main advantages of these groups. However, when
some popular commercial lipase preparations were used in the experiments,
the optical purities of the separated enantiomers were not always
satisfactory. For that reason we decided to investigate the lipase-catalyzed
kinetic resolution of some b-aminooxy alcohols with their amino function
protected with the tert-butylcarbamate group. According to the litera-
ture,[4,5] tert-butyl N-hydroxycarbamate (2) can be easily prepared from
hydroxylamine and tert-butoxycarbonyl azide. When the commercially
available di-tert-butyl dicarbonate was used instead of the azide, the yield
of 2 was by almost 20% higher. In the second step the prepared carbamate
was made to react with some epoxides. As it is known,[6] the acylation or
alkoxycarbonylation of hydroxylamine occurs at the nitrogen atom.
However, further reaction with a mono-N-substituted hydroxylamine
takes place either on the hydroxyl group if the N-substituent is electron-
withdrawing or on the nitrogen atom if the substituent has the electron-
donating properties. The reactions of monosubstituted epoxides with
stoichiometric amounts of the potassium salt of tert-butyl N-hydroxycarba-
mate were carried out at room temperature in an ethanol solution to yield
the appropriate 1,2-diols with a carbamoyl-protected primary hydroxy
group and a free secondary hydroxy group (Scheme 1).
The yields and properties of the prepared tert-butyl carbamates of
1
the general formula 3 as well as their H NMR and IR spectral data are
presented in Table 1.

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OPTICALLY ACTIVE AMINOOXYPROPANOLS
2593
Scheme 1.
Scheme 2.
The prepared N-(2-hydroxyalkoxy)-tert-butyl carbamates (3) were
subjected to the lipase-catalyzed esterification with an excess of vinyl acetate
as the acyl donor. The reactions were carried out in a tert-butyl methyl ether
solution. In the preliminary experiments, tert-butyl N-(2-hydroxy-3-
phenoxypropoxy)carbamate (3a) was the substrate and the lipase prepara-
tions used were: Amano PS (Pseudomonas cepacia), Amano 20
(Pseudomonas fluorescens), and Novozym 435 (Candida antarctica). With
all three lipases the reactions were very slow at room temperature; the slow-
est was that with Amano PS, but this enzyme gave the product of a highest
enantiomeric excess. All the reactions were monitored by TLC and the
conversion degree (c%) was determined by HPLC (Scheme 2).
The mixtures of the resulting acetates (4) and unchanged alcohols (5)
were separated by a column chromatography on silica gel; the results are
presented in Table 2, and the spectral data of the resulting acetoxycarba-
mates in Table 3.
As it may be seen, the fastest reaction was that with Novozym 435
but its enantioselectivity E was very poor. On the other hand, the use of
Amano PS looked very promising. For this reason, the acetylations of

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2594
BUCHALSKA AND PLENKIEWICZ

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OPTICALLY ACTIVE AMINOOXYPROPANOLS
2595
the remaining three carbamates (3b, 3c, 3d) were catalyzed by Amano PS;
the results are collected in Tables 2 and 3. The enantioselectivities of the
reactions were good with the exception of that with compound 3d as the
substrate. This can be easily explained since in the case of styrene oxide,
as found by Kliegel,[7] the anion attacks the phenyl-substituted carbon atom
to yield the corresponding primary alcohol.
The tert-butylcarbamate protecting groups of the separated enantio-
mers of N-(2-acetoxy-3-phenoxypropoxy)carbamates (4) and N-(2-hydroxy-
3-phenoxypropoxy)carbamates (5) were easily removed by dissolving the
compounds in an excess of trifluoroacetic acid at room temperature.
Under these conditions the acetyl group was also removed thus yielding
free aminooxy alcohols 6 and 7, respectively (Scheme 3).
The aminooxy alcohols 6 and 7 were isolated as hydrochlorides by
treating the reaction mixtures with a solution of hydrogen chloride in diethyl
ether. The melting points of the aminooxy alcohol hydrochlorides prepared
by this method were identical with those obtained[2] with the phthaloyl
or iso-propylidene protecting groups, but the yields were considerably
higher. In addition, their optical purities (Table 4) were much higher than
those prepared previously.[2]
The signs of optical rotation were consistent with those previously
determined[2] for the hydrochlorides 6a–c and 7a–c. Taking into account
enantioselectivities of the used lipases and comparing the optical rotation
data with those available for other b-aminooxy alcohols prepared by
the enantiomer separation[2] and by the stereoselective reduction[3] of the
appropriate ketone (for which the X-ray structure was determined) we
presume the levorotatory aminooxy alcohol hydrochlorides posses (S)
configuration at the stereogenic center.
Scheme 3.

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2596
BUCHALSKA AND PLENKIEWICZ

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OPTICALLY ACTIVE AMINOOXYPROPANOLS
2597
Table 3. 1H NMR Chemical Shifts and Characteristic Ir Bands of the
Acetoxycarbamates of the General Formula 4
No.
1H NMR (ꢀ ppm, CDCl3)
IR (cmꢁ1, film)
4a
1.47 (s, 9H); 2.13 (s, 3H); 4.08–4.14
(m, 4H); 5.45–5.55 (m, 1H); 6.87–7.38
(m, 5H); 7.44 (bs, 1H).
3300; 1730; 1720; 1580.
4b
4c
1.48 (s, 9H); 2.13 (s, 3H); 2.20 (s, 3H);
4.10–4.14 (m, 4H); 5.48–5.59 (m, 1H);
6.83–7.18 (m, 4H); 7.44 (bs, 1H).
1.48 (s, 9H); 2.15 (s, 3H); 4.22 (d, 2H,
J ¼ 5.2 Hz); 4.32 (d, 2H, J ¼ 4.6 Hz);
5.63–5.73 (n, 1H); 6.78–8.22 (m, 7H);
7.46 (bs, 1H).
3300; 1730; 1720; 1580.
3300; 1740; 1720; 1570.
4d
1.44 (s, 9H); 2.10 (s, 3H); 4.35 (dd,
1H, J1 ¼ 12.3 Hz, J2 ¼ 7.1 Hz); 4.38
(dd, J1 ¼ 12.3 Hz, J2 ¼ 4.0 Hz); 6.17
(dd, 1H, J1 ¼ 8.0 Hz, J2 ¼ 4.0 Hz);
7.34–7.38 (m, 5H); 7.58 (bs, 1H).
3300; 1740; 1720; 1600.
Table 4. The Yields and Properties of the 2-Hydroxy-3-substituted Propoxyamine
Hydrochlorides of the General Formulas 6 and 7
Enantiomer 6 (from Acetate) Enantiomer 7 (from Alcohol)
M.p.
(ꢀC)
20
D
20
D
No.
Yield (%) ee (%)
75 86
½ꢁŠ
Yield (%) ee (%)
½ꢁŠ
6a and 7a 120–122
6b and 7b 132–13482
6c and 7c 192–19453
þ 10.5
þ 12.5
þ 15.0
89
91
85
92
81
59
ꢁ 11.0
ꢁ 11.8
ꢁ 8.9
57
99
Because of its preparative simplicity the above presented method may
turn out to be useful in the preparation of other optically active aminooxy
alcohols.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian Gemini 200 MHz spectro-
meter in CDCl3 solution. IR spectra were taken on a Carl Zeiss Specord
M80 instrument. Optical rotation measurements were recorded on P20
Bellingham and Stanley polarimeter. HPLC analyses were performed on a

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2598
BUCHALSKA AND PLENKIEWICZ
Thermo-Separation products P-100 instrument. The element analyses
were determined on a Perkin-Elmer apparatus. The determination of the
products purity, and reactions monitoring were accomplished by TLC on
Silica Gel 60 F254 plates and the column chromatography on Silica Gel
60 (less than 230 mesh). Lipases Amano AK, Amano PS and Amano 20
were generously provided by Amano Japan, while the Novozym SP-435 by
Novo-Nordisk, Enzyme Business, Poland.
General Method for the Preparation of tert-Butyl
N-(2-Hydroxy-3-phenoxypropoxy)carbamates
The appropriate 2-substituted oxirane (0.055 mol) was added dropwise
to a stirred solution of tert-butyl N-hydroxycarbamate (6.65 g, 0.05 mol)
and K2CO3 (2.08 g, 0.05 mol) in 100 ml of 96% ethanol. The mixture
was stirred overnight at room temperature and the volatile materials
were completely removed under reduced pressure. The inorganic com-
pounds were washed out with water and the organic residue was extracted
with three 50 mL portions of chloroform. The combined extracts were
dried over MgSO4 and the solvent was removed. Crystallization from
an ethyl acetate/hexane (3 : 1) mixture afforded colorless crystals.
The yields and properties of the prepared compounds are collected in
Table 1.
Enzymatic Acetylation of tert-Butyl
N-(2-Hydroxy-3-phenoxypropoxy)carbamates
Vinyl acetate (0.93 g, 1 mL, 0.1 mol) was added to the stirred solution
of the appropriate racemic alcohol (1 g, 0.004mol) and the enzyme
(lipase Amano AK, 1 g) in methyl tert-butyl ether (30 mL). The mixture
was stirred at room temperature for several hours, the enzyme was removed
by filtration, and the solvent was evaporated under reduced pressure.
The remaining mixture of the substrate (alcohol) and the corresponding
acetate was separated by a column chromatography on silica gel with a
hexane/ethyl acetate mixture (1 : 3) as the eluent. The results of the lipase
catalyzed acetylation are collected in Table 2.
Acidolysis of tert-Butyl-(þ)-N-(2-Hydroxy-3-phenoxypropoxy) and
(þ)-N-(2-Acetoxy-3-phenoxypropoxy)carbamates
Trifluoroacetic acid (1.48 g, 1 mL, 0.013 mol) was added to the stirred
solution of the appropriate tert-butyl (þ)-N-(2-hydroxy-3-phenoxyprop-

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OPTICALLY ACTIVE AMINOOXYPROPANOLS
2599
oxy)-or(þ)-N-(2-acetoxy-3-phenoxypropoxy)carbamate (1 g, ca. 0.004mol)
in 10 mL of diethyl ether. The mixture was stirred for 1 h at room
temperature, whereupon 20 mL of 29% HCI in diethyl ether was added to
precipitate the product which was separated by filtration and washed with a
cold diethyl ether/isopropanol (2 : 1) mixture. The yields and properties of
the prepared compounds are collected in Table 4.
REFERENCES
1. Roth, H.J.; Kleemann, A.; Beisswenger, T. Pharmaceutical Chemistry,
Vol. 1. Drug Synthesis; Ellis Horwood Ltd.: Chichester, England, 1988;
p. 159–169.
2. Buchalska, E.; Plenkiewicz, J. J. Mol. Catal. B. Enzymatic 2001, 11, 255.
3. Buchalska, E.; Plenkiewicz, J. Tetrahedron: Asymmetry 2000, 11, 1781.
4. Carpino, L.A.; Giza, C.A.; Carpino, B.A. J. Am. Chem. Soc. 1959,
81, 955.
5. Marmer, W.N.; Maerker, G. J. Org. Chem. 1972, 37, 3520.
6. Boyland, E.; Nery, R. J. Chem. Soc. (C) 1966, 346.
7. Kliegel, W. Pharmazie 1971, 525.
Received in the UK August 6, 2001

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