Resolution of racemic 1-azido-3-aryloxy-2-propanols by lipase-catalyzed enantioselective acetylation

Article abstract of DOI:10.1016/S0957-4166(00)00229-9

Kinetic resolution of racemic 1-azido-3-aryloxy-2-propanols 1a-g was performed using supported lipase of Candida antarctica-B (Novozym() SP 435) in toluene at 4°C with isopropenyl acetate as the acyl donor to afford the optically active (S)-alcohols 2a-g and their corresponding (R)-acetates 3a-g with E values from 56 to 72. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00229-9

Tetrahedron: Asymmetry 11 (2000) 2719±2732
Resolution of racemic 1-azido-3-aryloxy-2-propanols by
lipase-catalyzed enantioselective acetylation
Beata Krystyna Pchelka,a,b,* Andre Loupy,a Jan Plenkiewiczb and Luis Blancoc
a
  Â
Laboratoire des Reactions Selectives sur Supports (CNRS UMR 8615), Institut de Chimie Moleculaire d'Orsay,
Â
BaÃt. 410, Universite de Paris-Sud, 91405 Orsay Cedex, France
bFaculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
c
Â
Laboratoire des Carbocycles (CNRS UMR 8615), Institut de Chimie Moleculaire d'Orsay, Bat. 420,
Ã
Â
Universite de Paris-Sud, 91405 Orsay Cedex, France
Received 8 May 2000; accepted 8 June 2000
Abstract
Kinetic resolution of racemic 1-azido-3-aryloxy-2-propanols 1a±g was performed using supported lipase
of Candida antarctica-B (Novozym1 SP 435) in toluene at 4ꢀC with isopropenyl acetate as the acyl donor to
a€ord the optically active (S)-alcohols 2a±g and their corresponding (R)-acetates 3a±g with E values from
56 to 72. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
During the course of our investigations dealing with bioconversions,1 we have been interested
particularly in the kinetic resolution of 1-azido-3-aryloxy-2-propanols 1 by transesteri®cation to
obtain the pure enantiomers for synthesis. These alcohols are, for instance, direct precursors of
N±H aziridines 6 using triphenylphosphine as the cyclizing reagent2 and of 1-amino-3-aryloxy-2-
propanols 7 by reduction of the azido group2 (Fig. 1).
Figure 1.
This last structure is present in numerous biologically active compounds such as b-adrenolytic
drugs (b-blockers), which are widely used for the treatment of angina pectoris, hypertension and
* Corresponding author. Tel: +33(0)1-69157256; fax: +33(0)1-69154679; e-mail: pbeata@icmo.u-psud.fr
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00229-9

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B. K. Pchelka et al. / Tetrahedron: Asymmetry 11 (2000) 2719±2732
other cardiac diseases.3 Most of these b-blockers are still prepared and commercialized as
racemates.4 However, in numerous cases, the adrenolytic activity was found to be strongly
dependent on the con®guration, as for instance in propranolol (Ar=1-naphthyl) where the (S)-
enantiomer is much more active than the (R)-enantiomer which presents moreover a
contraceptive activity.5 In connection with the importance of this class of compounds, several methods
have been reported for their synthesis.6 Among the alternative routes to pure (R)- and (S)-7, a special
interest has been devoted to direct reduction of azido moiety in 1-azido-3-aryloxy-2-propanols 1.
The growing importance of functionalized aziridines in organic synthesis7 and their presence in
bioactive molecules8 has created a need for synthesizing optically active aziridines. At the present
time they are used as antitumor and radiation sensitizers,9 antidiabetic compounds,10 enzyme
12
inhibitors,11 chiral auxiliaries in combination with LiAlH4 and precursors in the synthesis of
several enantiopure amide-containing surfactants.13
Few chemical methods have been reported for the synthesis of homochiral azido alcohols. They
concern either ring-opening of epoxides14 or the conversion of b-diols via cyclic sulphates15 or
sulphites.16 Presently the only direct method is the one described by Matteson et al.17 involving a
great number of steps starting from homochiral pinanediol boronic esters and resulting in a low
overall yield.
The enzymatic methods employed so far for their syntheses consist of:
(i) the asymmetric ring-opening of oxiranes [e.g. (RS) 2-methyl-2-pentyl oxirane] by azide
anion with a crude immobilized enzyme preparation derived from Rhodococcus sp.
(Novo SP 409)18 which exhibits epoxide±hydrolase activity;
(ii) the microbiological reduction of a-azidoketones with appropriate choice of the micro-
organism2,19 such as yeasts (e.g. Saccharomyces cerevisiae), fungi (e.g. Aspergillus niger)
or bacteria (e.g. Lactobacillus ke®r);
(iii) the kinetic resolution by hydrolysis of racemic cyclic azido alcohol esters,20 butanoates
of racemic acyclic 2-azidoalkanols21 as well as the 2-acetoxy-3-azido propanal diethyl
acetal22 with lipases from Candida cylindracea, Pseudomonas ¯uorescens and Pseudo-
monas cepacia (LP-80), respectively.
Surprisingly, to our knowledge, there exist only three reports on the enzymatic resolution of
racemic 1-azido-3-aryloxy-2-propanols 1 and their corresponding acetates. Ader and Schneider23
resolved racemic 1-azido-3-phenoxy-2-propanol by lipase from Pseudomonas cepacia-catalyzed
acylation or hydrolysis of the acetate with enantiomeric ratios (E) of 21 and 51, respectively. 1-Azido-
3-(4-tert-octyl)phenoxy-2-propanol24 was similarly acylated with moderate enantioselectivity
(E=29). Recently,1a our group reported the preparation of various ring-substituted racemic azido
alcohols 1 as well as their kinetic resolution by acylation using lipase from Pseudomonas ¯uorescens
(Amano AK). However, only poor enantioselectivities (E=5±14) were obtained, except for
Ar=1-naphthyl (E=41).
Although some of the azido alcohols 1 have already been resolved by lipase-catalyzed acetylation,
these cases constitute only isolated examples which demonstrate the potentiality of lipases for the
preparation of such optically active compounds. To establish the general scope and applicability
of this biocatalytic method, we undertook the present detailed study of the kinetic resolution by
transesteri®cation of a larger range of racemic azido alcohols 1a±g (Scheme 1), investigating the
in¯uence of several parameters in order to improve the enantioselectivity described in our previous
paper.1a

B. K. Pchelka et al. / Tetrahedron: Asymmetry 11 (2000) 2719±2732
2721
Scheme 1.
2. Results and discussion
2.1. 1-Azido-3-aryloxy-2-propanol synthesis
The racemic 1-azido-3-aryloxy-2-propanols 1a±g were obtained by ring-opening of appropriate
arylglycidyl ethers 4a±g with sodium azide in the presence of ammonium chloride in a MeOH:H2O
(8:1 v/v) solution.25 The latter were prepared in high yields by the Williamson reaction from the
corresponding phenols 5a±g and epichlorhydrin under solvent-free phase transfer catalysis
coupled with microwave (MW) activation.26 (Scheme 2)
Scheme 2.
2.2. Screening of di€erent lipases
In a ®rst series of experiments, the eciency of di€erent commercially available lipases to catalyze
the transesteri®cation of chiral azido alcohols 1 was investigated. For this purpose, racemic 1a
and 1e taken as model substrates, were treated at room temperature (ca. 22ꢀC) with three
equivalents of isopropenyl acetate in tert-butyl methyl ether in the presence of a microbial lipase.
In control experiments, it was shown that the reaction did not proceed in the absence of enzyme.
Generally, enzyme-catalyzed transesteri®cations were stopped at roughly 50% conversion by
removing the enzyme by ®ltration. Then the acetates 3a and 3e and unreacted alcohols 2a and 2e
were separated by silica gel column chromatography. The enantiomeric excess of 2a, 2e and 3a, 3e
was assessed by chiral gas chromatography. In all cases the unreacted alcohols 2a, 2e and their
acetates 3a, 3e had the (S)-(^) and (R)-(+) con®guration, respectively.
The absolute con®gurations of alcohol 2a and acetate 3a were determined by comparison of
their chiroptical and chromatographic properties with those of samples of known con®guration,
prepared using the method described by Ader and Schneider.23 The main results are given in
Table 1.

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B. K. Pchelka et al. / Tetrahedron: Asymmetry 11 (2000) 2719±2732
Table 1
Lipase-catalyzed kinetic resolutions of rac-1a and rac-1e by transesteri®cationa)
It is obvious from Table 1 that the best results (E=28±36) were obtained with immobilized
lipase from Candida antarctica, fraction B [Novozym1 SP 435 and Chirazyme1 L-2, c.-f., C2,
lyo.]. Similar enantioselectivities for 1a (E=23±28) were obtained with lipase from Pseudomonas
¯uorescens (Amano AK-20) and Pseudomonas cepacia (Amano PS, Amano P), but the reactions
proceeded slowly (41±47% conversion after 51±60 h). The other examined lipases showed no
reaction after 5±15 days [lipase from porcine pancreas (Sigma Type II), Rhizomucor javanicus
(Amano M), Rhizomucor miehei (Lipozyme1)] or poor selectivities [Candida rugosa (Sigma
L1754), E=4±5].
2.3. Solvent e€ect
It is known that solvent variation in many cases of lipase-catalyzed kinetic resolutions can
in¯uence the enantiomeric or enantiotopic selectivity as well as the reaction rate.28 The e€ect of
the solvent on substrate speci®city as well as on eciency of various enzymes is well-documented
in the literature.29 Attempts have been made to get correlations between enantioselectivity and
any physicochemical characteristics of the solvent such as hydrophobicity or dielectric constant.30
Acetylation of rac-1a with isopropenyl acetate at 22ꢀC in the presence of Novozym1 SP 435
was performed in various non-polar organic solvents. The results reported in Table 2 show that
the activity of Novozym1 SP 435 in transesteri®cation of 1a is higher in solvents of low polarity
as judged by their log P29a (the logarithm of the partition coecient of a given solvent between
1-octanol and water).
With n-hexane, n-pentane, toluene, benzene and tert-butyl methyl ether (log P=1.3±3.5), the
reaction rates were similar in all cases and generally higher than for isopropenyl acetate, THF,
acetone or dioxane (log P=^1.1±0.6). In general, enzyme selectivity was good enough for pratical
use in all the tested solvents (E=26±43) excepted acetone (E=9) and isopropenyl acetate (E=16)
which acts both as acylating agent and solvent. Benzene and toluene showed the best results with

B. K. Pchelka et al. / Tetrahedron: Asymmetry 11 (2000) 2719±2732
2723
Table 2
Transesteri®cation of rac-1a and rac-1e with isopropenyl acetate in various solventsa)
E=42, 43 within 17, 21 h for 42 and 50% of conversion, respectively. Enantioselectivity in dioxane
was slightly higher (E=48) but the reaction proceeded with a signi®cantly slower reaction rate
(37% of conversion within 48 h). Changing the enzyme from Novozym1 SP 435 to Chirazyme1
L-2, c.-f., C2, lyo. in the transesteri®cation of 1a and 1e in toluene (Entries 4, 5, 14 and 15) as well
as in benzene (Entries 6 and 7) did not alter the reaction rate considerably but led to a noticeable
decrease in the enantioselectivity. With 1a in tert-butyl methyl ether a lower decrease of selectivity
was also noticed going from Novozym1 SP 435 to Chirazyme1 L-2, c.-f., C2. (This fact is highly
surprising as these two enzyme preparations are identical according to the provider.) Concerning
compound 1e, no noticeable di€erences for enantioselectivity (E=48) and reaction rate (18 h for
37% of conversion) were observed on comparison with 1a when the reaction was performed in
toluene with Novozym1 SP 435 (Table 2, Entries 4 and 14).
The amount of enzyme used in all assays was changed when performed in toluene in the range
50±500 mg/mmol of substrate. A good conversion rate was provided in reasonable times (not
optimized) without any modi®cation in enantioselectivity (Table 3).
Table 3
In¯uence of the amount of Chirazyme1 L-2, c.-f., C2, lyo. on the transesteri®cation of rac-1aa)

2724
B. K. Pchelka et al. / Tetrahedron: Asymmetry 11 (2000) 2719±2732
2.4. Acyl donor in¯uence
The in¯uence of the acyl donor nature on the enantioselectivity of lipase-catalyzed trans-
esteri®cation reaction has been well documented by Ema et al.31 Consequently, the in¯uence of
various acyl donors was screened for the Novozym1 SP 435-catalyzed transesteri®cation of rac-1a
in toluene at 22ꢀC (Scheme 3) and the results are reported in Table 4.
Scheme 3.
Table 4
Novozym1 SP 435-catalyzed transesteri®cation of rac-1a by use of various acylating agentsa)
The use of enol esters (Table 4, Entries 1±4) results in higher enantioselectivity (E=23±43)
when compared to ethyl acetate (E=15) and O-isobutyryl-acetoxime (E=19). It is interesting to
note that lengthening in the alkyl chain of vinyl esters produces a decrease in the reaction rate,
but only a marginal e€ect on the enantioselectivity of this reaction [enantiomeric ratio (E) ranging
from 23 to 28]. The higher enantioselectivity was observed for the transesteri®cation with isopropenyl
acetate (E=43). The decrease in enantioselectivity in the case of vinyl acetate may be attributed
to a deactivation of the enzyme by the acetaldehyde generated in this reaction.32 Therefore, in the
next investigation, isopropenyl acetate was selected as the acylating agent.
2.5. Temperature e€ect
We disclosed from Sakai et al.33 that a lipase from Pseudomonas cepacia (Amano PS) exerts its
function at a very low temperature with markedly enhanced enantioselectivity. The thermo-
stability of the lipase in organic solvent allows the reaction over a large range of temperatures.34
Novozym1 SP 435 (immobilized lipase fromꢀCandida antarctica, fraction B) is thermostable with
a maximum activity in the range of 70±90 C.35 The reaction of rac-1a was carried out with
Novozym1 SP 435 under the same conditions as described in Table 4 at temperatures ranging from
4 to 80ꢀC (Table 5). Moreover, we examined the possible e€ect of microwave irradiation37 44 on

B. K. Pchelka et al. / Tetrahedron: Asymmetry 11 (2000) 2719±2732
2725
Novozym1 SP 435-catalyzed transesteri®cation of rac-1a with isopropenyl acetate at 70 and 80ꢀC
in toluene44 as well as in solvent-free conditions.40 For the sake of comparison, reactions were
also performed in a thermostated oil bath at the same temperature for the same time with heating
pro®les as close as possible (Table 5).
Table 5
Temperature in¯uence in the Novozym1 SP 435-catalyzed transesteri®cation of rac-1aa)
For this reaction, a decrease of the temperature was found to have a bene®cial e€ect on enzyme
enantioselectivity. In fact, at 4ꢀC the E-value was markedly increased and reached 72 for 51% of
conversion within 50 h (Table 5, Entry 1). When the temperature was increased up to 40ꢀC,
the reaction time decreased to 3 h 30 min but the enantiomeric ratio decreased to 33; however,
suciently enough for practical use. Further elevations in the temperature induced considerable
decreases in enantiomeric ratio (E=18 and E=14 at 70 and 80ꢀC, respectively). The results listed
in Table 5 are used to plot ln E as a function of 1/T (K^1) (Fig. 2). The observed straight line of
this correlation was in agreement with the theoretical calculation: ln E=ÁÁS{/R-ÁÁH{/(RT).36
Figure 2. Correlation between ln E versus the inverse of temperature for the Novozym1 SP 435-catalyzed transester-
i®cation of rac-1a

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B. K. Pchelka et al. / Tetrahedron: Asymmetry 11 (2000) 2719±2732
It is obvious from Table 5, that we cannot observe any advantages of microwave irradiation
either in terms of reaction rates or enantioselectivity when compared to classical heating. As it is
one of the most important problems in manufacturing process, it is interesting to note that the re-use
of Novozym1 SP 435 either under microvave irradiation or classical heating up to seven cycles
revealed no modi®cation in its original eciency.
2.6. E€ect of additives
The in¯uence of triethylamine,45 crown ethers46,47 (15-crown-5, 18-crown-6), thiacrown ethers48
(TTCTD, TTCHD) as well as TDA-147b were studied in the lipase from Candida antarctica-
catalyzed transesteri®cation of rac-1a with isopropenyl acetate. Main results using Novozym1 SP
435 or Chirazyme1 L-2, c.-f., C2, lyo are given in Table 6.
Table 6
Additive e€ects on the transesteri®cation of rac-1a using Novozym1 SP 435 (A) or Chirazyme1
L-2, c.-f., C2, lyo. (B)a)
It is obvious from Table 6 that only TTCHD-D (Entries 13 and 14) was found to have a bene®cial
e€ect on enzyme enantioselectivity and reaction time. The addition of triethylamine (14 mol%) at
22ꢀC by using Novozym1 SP 435 induces acceleration of the reaction rate (42% of conversion
within 1 h), but the enantiomeric ratio (E) was markedly decreased (Entry 2). It is interesting to
note that if the conversion of rac-1a in this reaction is increased up to 64%, the enantiomeric

B. K. Pchelka et al. / Tetrahedron: Asymmetry 11 (2000) 2719±2732
2727
ratio (E) of this reaction decreased to 16 (Entry 4). Although the function of triethylamine was
uncertain, the same acceleration e€ect was also observed in kinetic resolutions of certain sub-
strates using the same lipase Novozym1 SP 435.45d Finally, the highest enantioselectivities (E=41
at 22ꢀC, E=50 at 40ꢀC) were recorded when the transesteri®cation of rac-1a by using Chir-
azyme1 L-2, c.-f., C2, lyo. was carried out in the presence of 5 mol% of TTCHD-D (Entry 14).
Only a slight increase in enantioselectivity was observed at 22ꢀC as well as at 40ꢀC using TTCTD
as the additive (Entries 11 and 12). On the other hand, when this transesteri®cation was performed
at 40ꢀC, addition of 15-crown-5, 18-crown-6 and TDA-1 signi®cantly increased the reaction time
but produced only a marginal e€ect on enantioselectivity (E=23, 26, 25, respectively).
2.7. E€ect of the aromatic substituents
In order to investigate the in¯uence of the aromatic substituent (Ar), all transesteri®cations of
rac-1a±g were carried out in toluene with isopropenyl acetate by using Novozym1 SP 435 at 4ꢀC
which is the best compromise in terms of enantioselectivity and reaction rate. To our knowledge,
no data are available for the absolute con®gurations of 2b±g or 3b±g or of any derivatives. For
these compounds the absolute con®gurations were assigned by comparison of the sign of the
speci®c rotation with the reported data for (S)-(^)-2a and (R)-(+)-3a.1a The results are collected in
Table 7.
Table 7
Transesteri®cation of rac-1a±g with isopropenyl acetate using Novozym1 SP 435 in toluene at 4ꢀCa)
It appears clearly from Table 7 that it is possible to run transesteri®cation of 1-azido-3-aryloxy-
2-propanols 1a±g with good enantioselectivities (E=56±72) whatever the substituents on the
phenyl ring are.
3. Conclusion
We have presented a general method to realize enantioselective acetylations of 1-azido-3-aryloxy-
2-propanols 2a±g whatever the aromatic substituents are. High enantioselectivities (E=56±72)
were obtained using Novozym1 SP 435 and isopropenyl acetate in toluene at 4ꢀC.

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B. K. Pchelka et al. / Tetrahedron: Asymmetry 11 (2000) 2719±2732
4. Experimental
4.1. General
Lipases from Pseudomonas cepacia (Amano P, Amano PS), Pseudomonas ¯uorescens (Amano
AK, Amano AK-20) and Rhizomucor javanicus (Amano M) were purchased from Amano Pharma-
ceutical Co. Ltd. (Nagoya, Japan). Novozym1 SP 435 (immobilized Candida antarctica-B lipase)
and Lipozyme1 (immobilized Mucor miehei lipase) were kindly given by Novo Nordisk (Bagsvaerd,
Denmark). Lipases from Candida rugosa (Sigma L1754) and porcine pancreas (Sigma Type II)
were obtained from Sigma (Deisenhofen, Germany). Chirazyme1 L2, c.-f. C2, lyo. was kindly
given by Roche Molecular Biochemicals (Mannheim, Germany). All the commercially available
chemicals were obtained from Aldrich and Fluka. Solvents were of analytical-grade quality and
were obtained from Lab Scan Ltd. and Aldrich. The racemic azido alcohols 1a±g were prepared
using previously described methods.1a,25 The racemic acetates, as well as the other esters, were
synthesized from the corresponding alcohols and chloride or anhydride according to the usual
procedures [e.g. 10 mmol of rac-1a±g, 15 mmol of acetyl chloride, 15 mmol of pyridine in CH2Cl2
(30 mL) at 22ꢀC].
4.2. Analytical methods
Microanalyses were performed by the Laboratoire Central de Microanalyse du CNRS, Gif sur
1
Yvette, France. H (200 or 250 MHz) and 13C (62.9 MHz) NMR spectra were recorded on
Bruker AC-200 or 250 spectrometers in CDCl3 with TMS as the internal standard. Chemical
shifts (ꢀ) are quoted in ppm. Optical rotation measurements were recorded on a DiP-370 JASCO
polarimeter. Gas chromatographic analyses were run on a 6000 Vega Series instrument equipped
with a FID detector and Spectra-Physics SP 4290 integrator. Optical purities of unreacted azido
alcohols 2a±f and their acetates 3a±f were controlled by GC analysis on a capillary chiral column
Lipodex D (25 m) and directly determined using racemic compounds as references. The condi-
tions were: detector and injector temperature 250ꢀC, column temperature was 145ꢀC (0.8 bar) in
the cases of 2±3a±d, f and 170ꢀC (0.9 bar) for 2±3e. The following retention times (tr/min) were:
2a: 79.4 (R), 81.3 (S); 3a: 59.6 (S), 60.7 (R); 2b: 102.3 (R), 103.4 (S); 3b: 82.1 (S), 83.3 (R); 2c:
112.1 (R), 114.0 (S); 3c: 88.0 (S), 80.4 (R); 2d: 104.2 (R), 105.1 (S); 3d: 83.0 (S), 84.3 (R); 2e:
85.4 (R), 87.0 (S); 3e: 54.0 (S), 55.0 (R); 2f: 112.3 (R), 114.2 (S); 3f: 74.8 (S), 77.5 (R). HPLC
analyses for the determination of enantiomeric purities of 2g and 3g were performed on a
Thermo-Separation Products P-100 instrument and Chiracel OD-H column (n-hexane:iso-
propanol=90:10, 1 mL/min, 43 bar, 254 nm, 22ꢀC) using racemic compounds as references. The
following retention times (tr/min) were 57.0 (R), 62.7 (S) for 2g and 48.2 (S), 55.3 (R) for 3g.
Column chromatography was performed on Merck silica gel 60 (230±400 mesh). TLC was carried
out using glass sheets pre-coated with silica gel 60 F254 prepared by Merck. The reaction under
microwave irradiations were performed in a monomode microwave reactor (Synthewave 402
from Prolabo), ®tted with a stirring system and an IR temperature detector which indicates
the surface temperature. Reaction conditions were controlled using the algorithm tout ou peu
which allows temperature control at the given value during the reaction time by modulating the
power between an adequate value and 20 W (to operate under electromagnetic ®eld all along the
reaction).

B. K. Pchelka et al. / Tetrahedron: Asymmetry 11 (2000) 2719±2732
2729
4.3. Typical transesteri®cation procedure for rac-1a±g by using Novozym1 SP 435 in toluene at
4ꢀC
Isopropenyl acetate (3 mmol) and 500 mg of immobilized lipase from Candida antarctica-B
(Novozym1 SP 435) were added to a solution of the racemic azido alcohol 1a±g (1 mmol) in 5 mL
of toluene. The mixture was stirred at 4ꢀC and followed by TLC. After the appropriate time
(Table 6), the reaction was stopped by ®ltering o€ the solid enzyme and the solvent was evapo-
rated under reduced pressure. The crude mixture of acetate (R)-(+)-3a±g and unreacted alcohol
(S)-(^)-2a±g was separated by ¯ash chromatography on silica gel with hexane:ethyl acetate (15:1)
as the eluent. In the case of 2a±f and 3a±f determination of enantiomeric excess was possible by
means of a chiral GC column [Lipodex-D (25 m)], while for 2g and 3g by chiral HPLC analysis
using a Chiracel OD-H column. Optical rotation values in all cases of compounds were in
accordance with the literature data.1a 1H NMR spectras of enantiomeric azido alcohols 2a±g were
identical with those of the racemic compounds as described in the literature1a,23,25 and their 13C
NMR spectras are reported below:
2a: 13C NMR (62.9 MHz, CDCl3, ppm) ꢀ 53.15 (CH2N3), 68.72 (CH2O), 69.01 (CH),
114.29, 121.17, 129.38, 157.96 (C±Ar);
2b: 13C NMR (62.9 MHz, CDCl3, ppm) ꢀ 16.09 (CH3±Ar), 53.43 (CH2N3), 68.79 (CH2O),
69.90 (CH), 110.99, 120.99, 126.54, 126.81, 130.72, 156.10 (C±Ar);
2c: 13C NMR (62.9 MHz, CDCl3, ppm) ꢀ 21.42 (CH3±Ar), 53.35 (CH2N3), 68.89 (CH2O),
69.27 (CH), 111.37, 115.33, 122.21, 129.26, 139.63, 158.17 (C±Ar);
2d: 13C NMR (62.9 MHz, CDCl3, ppm) ꢀ 21.09 (CH3±Ar), 53.28 (CH2N3), 68.80 (CH2O),
69.30 (CH), 114.32, 129.39, 130.22, 157.97 (C±Ar);
2e: 13C NMR (62.9 MHz, CDCl3, ppm) ꢀ 53.24 (CH2N3), 69.12 (CH2O), 69.25 (CH), 115.72,
126.25, 129.38, 156.71 (C±Ar);
2f: 13C NMR (62.9 MHz, CDCl3, ppm) ꢀ 20.19 (CH3±Ar), 53.22 (CH2N3), 69.14 (CH2O,
CH), 112.98, 116.93, 126.41, 129.57, 137.09, 156.59 (C±Ar);
2g: 13C NMR (62.9 MHz, CDCl3, ppm) ꢀ 53.54 (CH2N3), 69.24 (CH2O, CH), 105.05,
120.90, 121.45, 125.29, 125.62, 126.39, 127.47, 134.42, 153,76 (C±Ar).
1H and 13C NMR spectra, IR data, and microanalysis of acetates 3a±f are reported below:
1
3a: H NMR (250 MHz, CDCl3, ppm) ꢀ 2.08 (s, 3H, COCH3), 3.55 (d, J=5.13 Hz, 2H,
CH2N3), 4.06 (d, J=5.23 Hz, 2H, OCH2), 5.19±5.29 (m, 1H, chiral CH), 6.80±7.01 (m, 3H,
aromatic CH), 7.20±7.31 (m, 2H, aromatic CH); 13C NMR (62.9 MHz, CDCl3, ppm) ꢀ 20.73
(COCH3), 50.55 (CH2N3), 65.76 (CH2O), 70.56 (CH), 114.32, 121.58, 129.39, 157.97 (C±Ar),
170.05 (CˆO); IR (neat, cm^1) 2060 (N3), 1710 (CˆO); anal. calcd for C11H13O3N3 (235): C,
56.17; H, 5.53; N, 17.87. Found: C, 56.23; H, 5.49; N, 17.91.
1
3b: H NMR (250 MHz, CDCl3, ppm) ꢀ 2.12 (s, 3H, COCH3), 2.21 (s, 3H, aromatic CH3),
3.62 (d, J=5.13 Hz, 2H, CH2N3), 4.10 (d, J=5.24 Hz, 2H, OCH2), 5.26±5.40 (m, 1H, chiral
CH), 6.78±6.96 (m, 2H, aromatic CH), 7.12±7.21 (m, 2H, aromatic CH); 13C NMR (62.9
MHz, CDCl3, ppm) ꢀ 16.06 (CH3±Ar) 20.85 (COCH3), 50.80 (CH2N3), 65.95 (CH2O), 70.74
(CH), 110.87, 121.05, 126.81, 130.77, 156,07 (C±Ar), 174.50 (CˆO); IR (neat, cm^1) 2060
(N3), 1710 (CˆO); anal. calcd for C12H15O3N3 (249): C, 57.83; H, 6.02; N, 16.87. Found: C,
57.78; H, 5.97; N, 16.92.

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B. K. Pchelka et al. / Tetrahedron: Asymmetry 11 (2000) 2719±2732
1
3c: H NMR (250 MHz, CDCl3, ppm) ꢀ 2.13 (s, 3H, COCH3), 2.33 (s, 3H, aromatic CH3),
3.61 (d, J=5.14 Hz, 2H, CH2N3), 4.09 (d, J=5.21 Hz, 2H, OCH2), 5.24 ±5.36 (m, 1H, chiral
CH), 6.68±6.89 (m, 3H, aromatic CH), 7.12±7.24 (m, 1H, aromatic CH); 13C NMR (62.9
MHz, CDCl3, ppm) ꢀ 20.87 (COCH3), 21.41 (CH3±Ar), 50.73 (CH2N3), 65.85 (CH2O), 70.73
(CH), 111.32, 115.35, 122.21, 129.23, 139.60, 158.07 (C±Ar), 170.16 (CˆO); IR (neat, cm^1)
2060 (N3), 1710 (CˆO); anal. calcd for C12H15O3N3 (249): C, 57.83; H, 6.02; N, 16.87.
Found: C, 57.80; H, 6.10; N, 16.80.
3d: 1H NMR (250 MHz, CDCl3, ppm) ꢀ 2.12 (s, 3H, COCH3), 2.21 (s, 3H, aromatic CH3), 3.61
(d, J=5.12 Hz, 2H, CH2N3), 4.09 (d, J=5.20 Hz, 2H, OCH2), 5.23±5.35 (m, 1H, chiral CH),
6.65±6.89 (m, 2H, aromatic CH), 7.10±7.24 (m, 2H, aromatic CH); 13C NMR (62.9 MHz,
CDCl3, ppm) ꢀ 20.50 (COCH3), 21.10 (CH3±Ar), 50.65 (CH2N3), 65.25 (CH2O), 70.60 (CH),
114.38, 129.21, 130.40, 158.07 (C±Ar), 170.01 (CˆO); IR (neat, cm^1) 2060 (N3), 1710 (CˆO);
anal. calcd for C12H15O3N3 (249): C, 57.83; H, 6.02; N, 16.87. Found: C, 57.86; H, 5.94; N, 16.76.
1
3e: H NMR (200 MHz, CDCl3, ppm) ꢀ 2.13 (s, 3H, COCH3), 3.61 (d, J=5.11 Hz, 2H,
CH2N3), 4.08 (d, J=5.14 Hz, 2H, OCH2), 5.20±5.36 (m, 1H, chiral CH), 6.78±6.90 (m, 2H,
aromatic CH), 7.19±7.30 (m, 2H, aromatic CH); 13C NMR (62.9 MHz, CDCl3, ppm) ꢀ 20.85
(COCH3), 50.63 (CH2N3), 66.28 (CH2O), 70.50 (CH), 115.81, 126.39, 129.39, 156.67 (C±Ar),
170.11 (CˆO); IR (neat, cm^1) 2190 (N3), 1720 (CˆO); anal. calcd for C11H12O3N3Cl
(269.5): C, 48.98; H, 4.45; N, 15.58. Found: C, 48.86; H, 4.38; N, 15.62.
1
3f: H NMR (200 MHz, CDCl3, ppm) ꢀ 2.13 (s, 3H, COCH3), 2.33 (s, 3H, aromatic CH3),
3.60 (d, J=5.02 Hz, 2H, CH2N3), 4.07 (d, J=5.10 Hz, 2H, OCH2), 5.16±5.34 (m, 1H, chiral
CH), 6.60±6.75 (m, 1H, aromatic CH), 6.75±6.87 (m,1H, aromatic CH), 7.13±7.30 (m, 1H,
aromatic CH); 13C NMR (62.9 MHz, CDCl3, ppm) ꢀ 20.22 (CH3±Ar), 20.84 (COCH3),
50.64 (CH2N3), 66.20 (CH2O), 70.55 (CH), 113.07, 117.09, 126.55, 129.63, 137.15, 156.58
(C±Ar), 170.09 (CˆO); IR (neat, cm^1) 2160 (N3), 1760 (CˆO); anal. calcd for C12H14O3N3Cl
(283.5): C, 50.79; H, 4.94; N, 14.81. Found: C, 50.72; H, 4.86; N, 14.76.
1
3g: H NMR (250 MHz, CDCl3, ppm) ꢀ 2.09 (s, 3H, COCH3), 3.64 (d, J=5.10 Hz, 2H,
CH2N3), 4.10 (d, J=5.25 Hz, 2H, OCH2), 5.20±5.36 (m, 1H, chiral CH), 6.78 (d, J=7.3 Hz,
1H, aromatic CH), 7.25±7.69 (m, 4H, aromatic CH), 7.73±7.88 (m, 1H, aromatic CH), 8.20±
8.27 (m, 1H, aromatic CH); 13C NMR (62.9 MHz, CDCl3, ppm) ꢀ 20.97 (COCH3), 50.70
(CH2N3), 65.76 (CH2O), 70.64 (CH), 105.00, 120.65, 121.21, 125.23, 125.40, 126.20, 127.33,
134.60, 153.90 (C±Ar), 169.76 (CˆO); IR (neat, cm^1) 2060 (N3), 1710 (CˆO); anal. calcd
for C15H15O3N3 (285): C, 63.16; H, 5.26; N, 14.74. Found: C, 63.00; H, 5.17; N, 14.66.
Acknowledgements
We are grateful to Roche Molecular Biochemicals (Mannheim) for the kind gift of Chirazyme1
L-2, c.-f., C2, lyo. We also thank Amano Co. for a welcome supply of Pseudomonas cepacia lipase
and Novo Nordisk for Lipozyme1 and Novozym1 SP 435.
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