Resolution of chiral aliphatic and arylalkyl amines using immobilized Candida antarctica lipase and isolation of their R- and S-enantiomers

Article abstract of DOI:10.1081/SCC-100000584

The resolution of chiral aliphatic and arylalkyl amines in high enantiomeric excess (up to 97.5% ee for the R-enantiomers and up to 99.9% ee for the S-enantiomers) and good yield (50-80%) using immobilized Candida antarctica lipase and ethyl acetate as acyl donor has been demonstrated. A second resolution on the Ramine increased the enantiomeric excess to more than 99.5% (up to 99.9%).

Full text of DOI:10.1081/SCC-100000584

This article was downloaded by: [Moskow State Univ Bibliote]
On: 16 November 2013, At: 03:51
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
RESOLUTION OF CHIRAL ALIPHATIC AND ARYLALKYL
AMINES USING IMMOBILIZED CANDIDA ANTARCTICA
LIPASE AND ISOLATION OF THEIR R- AND S-
ENANTIOMERS
Bruce A. Davis a & David A. Durden a
a University of Saskatchewan , Neuropsychiatry Research Unit, A114 Medical Research
Building, 103 Wiggins Road, Saskatoon, Saskatchewan, S7N 5E4, Canada
Published online: 16 Aug 2006.
To cite this article: Bruce A. Davis & David A. Durden (2001) RESOLUTION OF CHIRAL ALIPHATIC AND ARYLALKYL
AMINES USING IMMOBILIZED CANDIDA ANTARCTICA LIPASE AND ISOLATION OF THEIR R- AND S-ENANTIOMERS, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:4, 569-578, DOI:
10.1081/SCC-100000584
To link to this article: http://dx.doi.org/10.1081/SCC-100000584
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONS, 31(4), 569–578 (2001)
RESOLUTION OF CHIRAL ALIPHATIC
AND ARYLALKYL AMINES USING
IMMOBILIZED CANDIDA ANTARCTICA
LIPASE AND ISOLATION OF THEIR
R- AND S-ENANTIOMERS
Bruce A. Davis∗ and David A. Durden
Neuropsychiatry Research Unit, A114 Medical Research
Building, University of Saskatchewan, 103 Wiggins Road,
Saskatoon, Saskatchewan, Canada S7N 5E4
ABSTRACT
The resolution of chiral aliphatic and arylalkyl amines in
high enantiomeric excess (up to 97.5% ee for the R-enantiomers
and up to 99.9% ee for the S-enantiomers) and good yield (50–80%)
using immobilized Candida antarctica lipase and ethyl acetate as
acyl donor has been demonstrated. A second resolution on the R-
amine increased the enantiomeric excess to more than 99.5% (up
to 99.9%).
In conjunction with a drug development program, a cost-effective method
of obtaining the enantiomers of chiral 2-alkylamines in very high enantiomeric
excess (99.0% minimum, preferably >99.5%) was required. Optically pure enan-
tiomers of chiral amines have been prepared by a variety of methods (1), including
∗Corresponding author.
569
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

ORDER
REPRINTS
570
DAVIS AND DURDEN
multi-step transformations starting from optically pure amino acids (2–5), the
resolution of racemic mixtures via multiple fractional recrystallizations of di-
astereomeric complexes with chiral acids (6–9), and kinetic resolution of race-
mates by enzyme-catalyzed acyl transfer reactions (10–20). In addition to the
numerous steps involved and the risk of racemization, transformations from op-
tically pure amino acids suffer from the disadvantages that the starting materi-
als, if commercially available, are usually expensive and may not be available in
the required optical purity. Fractional recrystallizations of diastereomeric com-
plexes are tedious and very inefficient. The major disadvantages of enzymatic
resolutions, namely, the relatively low purity of the commercial natural enzyme
preparations and their expense, have been overcome in recent years for some
enzymes with the introduction of very pure, re-usable, immobilized enzymes,
which function well in many organic solvents. Several enzymes have been stud-
ied for their efficiency in kinetic resolution of chiral amines, including Pseu-
domonas aeruginosa lipase (11), subtilisin (10,12,21) and Candida antarctica
lipase(13–17,19,20).
Candida antarctica lipase (CAL) in an immobilized form (Novozym 435)
has been demonstrated to be a versatile catalyst in acyl transfer reactions with
amines in non-aqueous media using simple procedures (Scheme). It has been
shown to catalyze selectively the acylation of the R-enantiomer of 2-butylamine
(13,15,16), 2-pentylamine (17), 2-heptylamine (13,15,16) and 2-octylamine (14),
as well as 1-phenylethylamine (13–17), utilizing a variety of acyl donors in several
organic solvents, giving products in poor to moderate yields (25–75%) and good
to high enantiomeric excess (up to 98%). The best results in terms of % yield and
enantiomeric excess of the R-enantiomer have been obtained for 2-heptylamine
(79% and >95% ee, respectively) and 1-phenylethylamine (84% and 95% ee)
using methyl 3-phenylpropanoate as acyl donor and di-isopropyl ether as solvent
(13). This acyl donor, however, is expensive and the excess is difficult to remove
(b.p. = 238◦C). Resolution of 2-pentylamine to 98% ee with ethyl acetate, which
is both inexpensive and easy to remove, as acyl donor has been demonstrated, but
at a conversion of only 44% (17).
None of the reported procedures met our criteria of good yield and very high
enantiomeric excess of both enantiomers (in the cited papers, the S-enantiomers
were not isolated), ease of work-up, and use of inexpensive reagents. In this paper
we report procedures that realize these objectives.
O
CAL
EtOAc
NH
C
CH3
R
NH2
R
+ R
NH2
R = ethyl, propyl, pentyl, hexyl, nonyl, phenyl
Scheme.

ORDER
REPRINTS
CHIRAL ALIPHATIC AND ARYLALKYL AMINES
571
Table 1. Kinetic Resolution of Racemic Aliphatic Amines (R-Enantiomers)
Reaction
Time (days)
% Yield
(product)
% ee
R
Amine
Solvent
2-Butyl
Hexane
Ether
Hexane
Ether
Et3N
EtOAc
Ether
EtOAc
Hexane
Ether
THF
Et3N
EtOAc
Hexane
Ether
EtOAc
Ether
2
2
2
2
2
1
2
1
2
2
2
1
8 h
2
2
1
1
26
43
48
58
70
72
71
75
63
80
76
74
66
70
99
93
80
86
70.0
67.2
97.2
97.2
95.4
92.9
94.8
84.8
96.0
95.6
95.2
95.4
95.2
97.6
96.2
92.0
96.5
90.4
2-Pentyl
2-Hexyl
2-Heptyl
2-Octyl
2-Undecyl
EtOAc
16 h
RESOLUTION AND ISOLATION OF THE R-ENANTIOMER
Effect of Solvent and Reaction Time on
Enantioselectivity and % Yield
The effect of solvent and reaction time on % yield and enantiomeric excess
for the acylation of 2-heptylamine by ethyl acetate was examined for five sol-
vents (hexane, diethyl ether, tetrahydrofuran, triethylamine, ethyl acetate) and a
range of reaction times (8 hours to 7 days). Similar but less extensive experiments
were carried out for the other chiral amines. Conditions for the highest % ee are
summarized in Tables 1 and 2.
The possibility that non-enzymatic (and therefore non-stereoselective) acy-
lation may occur was investigated. After 7 days at room temperature, a solution of
(RS)-2-heptylamine in ethyl acetate (without Novozym 435) gave only a trace of
product (<0.3%).
Increase in Enantiomeric Excess After Second Resolution
No combination of reaction conditions gave enantiomeric excesses of the
R-enantiomers that met requirements. In order to enhance the % ee, a second

ORDER
REPRINTS
572
DAVIS AND DURDEN
Table 2. Kinetic Resolution of Racemic Arylalkyl Amines (R-Enantiomers)
Reaction
Time (days)
% Yield
(product)
% ee
R
Amine
Solvent
1-Phenylethyl
Ether
EtOAc
Et3N
Ether
EtOAc
Et3N
2
1
1
2
1
71
59
41
66
62
56
81.4
80.4
86.4
85.8
82.6
88.9
1-Phenyl-2-propyl
31 h
resolution was carried out. The amide product of the first resolution was hydrolyzed
to the hydrochloride salt of the primary amine, which was converted to the free base
and treated again with ethyl acetate and Novozym 435. Three methods of convert-
ing the salt to the free base were investigated: (a) basification with aqueous NaOH,
extraction with ether and distillation of the free amine; (b) basification with aque-
ous NaOH, extraction with ether, and use of the extract for the second resolution;
and (c) treatment of the hydrochloride salt with triethylamine in ether, filtration
of the triethylamine hydrochloride, and then use of the filtrate for the second
resolution. The results for 2-heptylamine are summarized in Table 3. Method C is
preferred for the isolation of the free bases of 2-butylamine, 2-pentylamine, and
2-hexylamine, the volatility and solubility in water of which markedly reduced
the efficiency of methods A and B. For 2-octylamine, 2-undecylamine, and for
the arylalkylamines, the simpler and faster Method B is preferred over Method C.
2-Butylamine requires a third resolution to reach an enantiomeric excess of 99.0%.
Removal of Unreacted Substrate
Unreacted substrate was removed either by oxalate precipitation or by silica
gel chromatography. The precipitation of unreacted substrate as the oxalate salt was
Table 3. Effect of Second Resolution on Enantiomeric Excess for
2-Heptylamine (R-Enantiomers)
Reaction
Solvent
Reaction
Time (h) (initial)
% ee
% ee
(final)
%Yield
(amide)
Method
A
A
A
B
C
Hexane
Ether
Et3N
Ether
Et3N/ether
72
72
40
48
96
90.6
90.6
90.6
87.3
87.3
99.7
>99.9
>99.9
99.6
65
81
81
54
61
99.4

ORDER
REPRINTS
CHIRAL ALIPHATIC AND ARYLALKYL AMINES
573
used routinely for all the amines because these salts, which are essentially insoluble
in ether, THF, hexane, and ethyl acetate, provide superior recovery. Excess oxalic
acid was removed from the acetylated product in the filtrate during the subsequent
isolation and purification of the free (R)-amine by hydrolysis, basification, and
extraction.
Alternatively, if the presence of excess oxalic acid in the N-acetyl product
was undesirable, the filtered reaction solution was added directly to a silica gel
column. Unreacted substrate, which is retained on the column during elution of
the amide product with hexane:ethyl acetate, was recovered in quite good yield
(60–70% for 2-heptylamine) by elution with methanol into methanolic HCl. This
method was unsuitable when reaction solvent was triethylamine; evaporation of
the solvent prior to loading onto the column resulted in substantial or complete
loss of substrate.
RESOLUTION AND ISOLATION OF THE S-ENANTIOMER
The effect of reaction time on % recovery and enantiomeric excess of
unreacted (S-enriched)-substrates (recovered as the oxalate) was examined for
two solvents, diethyl ether and ethyl acetate (Table 4). With ethyl acetate as
solvent, enantiomeric excess improved with increasing reaction time such that,
for example, after 14 days the R-enantiomer of 2-heptylamine was essentially
undetectable.
Table 4. Kinetic Resolution of Racemic Aliphatic and Arylalkyl
Amines (S-Enantiomers)
Reaction
Solvent Time (days)
Recovery
(%)∗
% ee
(S)
Amine
2-Butyl
2-Pentyl
2-Hexyl
2-Heptyl
EtOAc
EtOAc
EtOAc
Ether
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
7
7
7
21
5
14
5
38
82
84
94
91
81
94
86
73
46
72
46
94.2
99.8
99.1
99.6
99.4
>99.9
99.8
99.4
93.8
99.0
86.7
93.6
2-Octyl
2-Undecyl
1-Phenylethyl
7
10
21
10
21
1-Phenyl-2-propyl
∗% recovery of the theoretical amount of S-enantiomer.

ORDER
REPRINTS
574
DAVIS AND DURDEN
EXPERIMENTAL
Materials
Candida antarctica lipase (Novozym 435) was a gift from Novo Nordisk A/S
(Denmark)/Novo Nordisk BioChem North America, Inc. Racemic 2-butylamine,
2-pentylamine, 2-heptylamine, 2-octylamine, and 1-phenylethylamine were pur-
chased (Lancaster Synthesis, Inc.). Racemic 2-hexylamine, 2-undecylamine and
1-phenyl-2-propylamine were synthesized from 2-hexanone, 2-undecanone, and 1-
phenyl-2-propanone, respectively, by lithium aluminum hydride reduction of their
oximes. All solvents were reagent grade (Caledon Laboratories Ltd., Edmonton,
Canada). Silica gel (70–230 mesh, 60A) and lithium aluminum hydride were pur-
chased from the Aldrich Chemical Co.
Enantiomeric Analysis
The enantiomeric purity of the products (after hydrolysis) and of recovered
substrates was determined by derivatization of the amine (R-amine hydrochloride
or S-amine oxalate) with (S)-N-trifluoroacetylprolyl chloride and separation of the
diastereomers by gas chromatography on a chiral column (22).
General Procedure: Resolution of (RS)-2-Alkylamines
and Arylalkylamines
The (RS)-2-alkylamine or arylalkylamine (2 mmol) was dissolved in an
organic solvent (5 mL) and then ethyl acetate (8 mmol, 800 uL) and Novozym
435 (100 mg) were added. The mixture was gently shaken for the specified time
at room temperature (21◦C). The reaction was terminated by suction filtration of
the enzyme, which was washed with diethyl ether (2 × 3 mL) and ethyl acetate
(2 × 3 mL). [Novozym 435 is re-usable: even after 4 uses, each for 48 h, no
reduction in % yield or enantiomeric purity was observed].
The combined filtrates were loaded onto a silica gel column (4 g), and the
R-amide was eluted with hexane:ethyl acetate (1:1). Unreacted substrate was then
eluted with methanol into methanolic HCl. The (R)-amide was hydrolyzed by
refluxing in concentrated hydrochloric acid for 48 h at 135◦–140◦C. After rotary
evaporation, the residue was taken up in water, extracted with ethyl acetate (to
remove unhydrolyzed amide), and the aqueous solution was evaporated to give the
R-amine hydrochloride.
Experimental data for characterization of the isolated (R)-amine hydrochlo-
rides (all of which are known compounds) are: observed m.p. (solvent of recrys-
tallization); literature m.p.; MH + [MS-CI (isobutane)]: (R)-2-butylamine. HCl:

ORDER
REPRINTS
CHIRAL ALIPHATIC AND ARYLALKYL AMINES
575
153.5◦–154◦C (methanol/ether); 151◦–152◦C (24); MH+, 74. (R)-2-Pentylamine.
HCl: 175.5◦–176◦C (methanol/ether); 168◦C (racemate)(23); MH+, 88. (R)-2-
hexylamine. HCl: 106◦–107◦C (methanol/ether); 102◦–103◦C(23); MH+, 102.
(R)-2-heptylamine.HCl: 100◦–101◦C (hexane); 81◦–83◦C (racemate)(23) MH+,
116. (R)-2-octylamine.HCl: 89◦–90◦C (hexane); 90◦–91◦C(23); MH+, 130. (R)-
2-undecylamine.HCl: 85◦C (hexane); 84◦C (racemate)(23); MH+, 172. (R)-1-
phenylethylamine.HCI:171.5◦–172◦C (methanol/ether); 171◦–173◦C(25);
MH+, 122; also m/z 106, 105. (R)-2-phenylisopropylamine.HCl: l54◦–155◦C
(methanol/ether); 156◦C(23); MH+, 136.
Each of the alkyl and arylalkylamines (as the trifluoroacetyl-L-prolyl deriva-
tive) and N-acetyl amides was further characterized by comparison of its gas chro-
matographic retention time to that of an authentic sample.
Alternatively, the filtrates were added to a solution of oxalic acid (180 mg,
2 mmol) in ether (15 mL), and the oxalate salt was filtered and washed with ether.
The filtrates were rotary evaporated at 70◦C, the residue was loaded onto a column
of silica gel (4.0 g), and the N-acetyl amide (enriched in the R-enantiomer) was
eluted with hexane:ethyl acetate (1:1) (some of the excess oxalic acid also elutes
under these conditions).
Experimental data for characterization of the (S)-amine oxalates (recrystal-
lized from methanol-ether), all of which are new compounds, are: (S)-2-
butylamine.oxalate: 152.5◦–153◦C; 1NMR (D2O): δ 0.80 (t, 3H, terminal CH3),
δ 1.15 (d, 3H, α-CH3), δ 1.48 (m, 2H, β-CH2), δ 3.15 (m, 1H, α-CH). Elemental
analysis: calculated (found): %C = 44.17 (44.14); %H = 8.03 (8.15); %N = 8.58
(8.38).
(S)-2-pentylamine.oxalate: 149◦–150◦C; 1NMR (D2O): δ 0.80 (t, 3H, ter-
minal CH3), δ 1.15 (d, 3H, α-CH3), δ 1.27 (m, 2H, γ -CH2), δ 1.41 (m, 2H, β-CH2).
δ 3.22 (m,1H, α-CH). Elemental analysis: calculated (found): %C = 47.45 (47.54);
%H = 8.53 (8.76); %N = 7.90 (7.81).
1
(S)-2-hexylamine.oxalate: 141◦–143◦C; NMR (D2O): δ 0.78 (t, 3H, ter-
minal CH3), δ 1.14 (d, 3H, α-CH3), δ 1.21 (m, 4H, γ ,δ-CH2), δ 1.47 (m, 2H,
β-CH2), δ 3.21 (m, 1H, α-CH). Elemental analysis: calculated (found): % C =
50.25(50.04); %H = 8.96 (8.71); % N = 7.32 (7.18).
(S)-2-heptylamine.oxalate: 103◦–104◦C; 1NMR (D2O): δ 0.75 (t, 3H termi-
nal CH3), δ 1.05–1.30 (m, 9H, α-CH3) plus γ ,δ,ꢀ-CH2), δ 1.45 (m, 2H, β-CH2), δ
3.21 (m, 1H, α-CH). Elemental analysis: calculated (found): %C = 52.67 (52.30);
%H = 9.33 (9.15); %N = 6.82 (6.61).
1
(S)-2-octylamine.oxalate: 109◦–111◦C; NMR (D2O): δ 0.74 (t, 3H, ter-
minal CH3), δ 1.05–130 (m, 11H, α-CH3) plus γ ,δ,ε,φ-CH2,) δ 1.44 (m, 2H,
β-CH2), δ 3.19 (m, 1H, α-CH). Elemental analysis: calculated (found): %C =
54.77 (54.01); %H = 9.65 (9.98); %N = 6.39 (6.19).
1
(S)-2-undecylamine.oxalate: 103◦–107◦C; NMR (D2O): δ 0.72 (t, 3H,
terminal CH3), δ 1.05–1.30 (m, 17H, α-CH3) plus (7 × CH2), δ 1.48 (m, 2H,

ORDER
REPRINTS
576
DAVIS AND DURDEN
β-CH2), δ 3.20 (m, 1H, α-CH). Elemental analysis: calculated (found): %C =
59.74 (59.10); %H = 10.41 (9.20); %N = 5.36 (5.30).
(S)-1-Phenylethylamine.oxalate(amine:oxalate2:1):225◦–226◦C;1NMR
(D2O): δ 1.52 (d, 3H, α-CH3), δ 4.41 (q, 1H, α-CH), δ 7.37 (s, 5H phenyl H).
Elemental analysis: calculated (found): %C = 65.04 (64.66); %H = 7.28 (7.48);
%N = 8.43 (8.15).
1
(S)-1-phenylisopropylamine.oxalate: 170◦–171◦C; NMR (D2O): δ 1.20
(d, 3H, α-CH3), δ 2.81 (d, 2H, β-CH2), δ 3.50 (m, 1H, α-CH), δ 7.27 (m, 5H,
phenyl H). Elemental analysis: calculated (found): %C = 58.66 (58.21); %H =
6.71 (7.28); % N = 6.22(6.06).
Methods for Converting the Amine Salt to the Free Amine
for Second Resolution
(A) Aqueous Basification of the Amine Salt and Isolation by Distillation
The (R)-amide (200 mmol) was hydrolyzed by refluxing in concentrated
hydrochloric acid (150 mL) for 48 h at 135◦–140◦C. After rotary evaporation, the
residue was taken up in water, extracted with ethyl acetate (to remove unhydrolyzed
amide), and the aqueous solution was evaporated. The residue was suspended in
ether/water(300/100mL)andstirredvigorouslywhileadding50%NaOH(60mL).
The mixture was shaken vigorously and the aqueous layer extracted once more
with diethyl ether (70 mL). The extracts were dried over MgSO4, concentrated,
and distilled (for 2-heptylamine, yield 70%). The amine was then enzymatically
resolved and the acyl product isolated as described in the General Procedure.
(B) Aqueous Basification of Amine Salt Without Isolation of Free Amine
The amide (2 mmol) was hydrolyzed by refluxing in concentrated hydrochlo-
ric acid (15 mL) for 48 h at 135◦–140◦C. After rotary evaporation, the residue was
taken up in water, extracted with ethyl acetate, and then the aqueous solution was
evaporated. The residue was dissolved in 50% NaoH (1 mL) and the amine was
extracted by vortex mixing with diethyl ether (3 × 2 mL). The extracts were dried
over MgSO4, and then treated with ethyl acetate and Novozym 435; the product
was purified in the usual way.
(C) In situ Basification with Triethylamine in an Organic Solvent
The R-amine hydrochloride or the S-amine oxalate (2 mmol) was neutralized
in situ by gentle shaking for 3 h with an excess of triethylamine (2.5 mL) in ether

ORDER
REPRINTS
CHIRAL ALIPHATIC AND ARYLALKYL AMINES
577
(5 mL). The precipitated triethylamine hydrochloride (or oxalate) was filtered and
washed with ether (2.5 mL). The combined filtrate was treated with ethyl acetate
and Novozym 435, and the product isolated in the usual way.
CONCLUSION
Candida antarctica lipase (Novozym 435) with ethyl acetate as acyl donor
in an organic solvent constitutes a simple method for the resolution of several
chiral aliphatic and arylalkyl amines on both small and large scales. Conditions
are described permitting both R- and S-enantiomers to be isolated in good yield
with enantiomeric excess up to 99.9%.
ACKNOWLEDGMENTS
We thank Novo-Nordisk North America, Inc., for the generous gift of
Novozym 435. Financial support from Saskatchewan Health and technical as-
sistance from D. Young are gratefully acknowledged.
REFERENCES
1. Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley and Sons:
New York, 1994.
2. Copola, G.M.; Shuster, H.F. Asymmetric Synthesis. Construction of Chiral
Molecules Using Amino Acids; John Wiley and Sons: New York, 1987.
3. Gal, J. J. Labelled Compd. Radiopharm. 1977, 13, 3.
4. Kinbara, K.; Sakai, K.; Hashimoto, Y.; Nohira, H.; Saigo, K. Tetrahedron:
Asymmetry 1996, 7, 1539.
5. Donner, B.G. Tetrahedron Lett. 1995, 36, 1223.
6. Acs, M.; Szili, T.; Fogassy, E. Tetrahedron Lett. 1991, 32, 7325.
7. Dostert, P.; O’Brien, E.M.; Tipton, K.F.; Meroni, M.; Melloni, P.; Strolin
Benedetti, M. Eur. J. Med Chem. 1992, 27, 45.
8. Foreman, R.L.; Siegal, F.P.; Mrtek, R.G. J. Pharm. Sci. 1969, 58, 189.
9. Mazur, R.H.. J. Org. Chem. 1970, 35, 2050.
10. Gutman, A.L; Meyer, E.; Kalerin, E.; Polyak, F.; Sterling, J. Biotechnol.
Bioengin. 1992, 40, 760.
11. Jaeger, K.-E.; Liebeton, K.; Zonta, A.; Schimossek, K.; Reetz, M.T. Appl.
Microbiol. Biotechnol. 1996, 46, 99.
12. Kitaguchi, H.; Fitzpatrick, P.A.; Huber, J. E.; Klibanov, A.M. J. Am. Chem.
Soc. 1989, 111, 3094.

ORDER
REPRINTS
578
DAVIS AND DURDEN
13. Gotor, V.; Menendez, E.; Mouloungui, Z.; Gaset, A. J. Chem. Soc. Perkin
Trans. I 1993, 2453.
14. Ohrner, N.; Orrenius, C.; Mattson, A.; Norin, T.; Hult, K. Enzyme Microb.
Technol. 1996, 19, 328.
15. Puertas, S.; Brieva, R.; Rebolledo, F.; Gotor, V. Tetrahedron. 1993, 49, 4007.
16. Puertas, S.; Rebolledo, F.; Gotor, V. Tetrahedron 1995, 51, 1495.
17. Reetz, M.T.; Dreisbach, C. Chimia 1994, 48, 570.
18. Takayama, S.; Moree, W.J.; Wong, C.H. Tetrahedron Lett. 1996, 37, 6287.
19. Sanchez, V.M.;Rebolledo, F.;Gotor, V. Tetrahedron:Asymmetry 1997, 8, 37.
20. Iglesias, L.E.; Sanchez, V.M.; Rebolledo, F.; Gotor, V. Tetrahedron: Asym-
metry 1997, 8, 2675.
21. Wang, Y.-F.; Yakovlevsky, K.; Margolin, A.L. Tetrahedron Lett. 1996, 37,
5317.
22. Durden, D.A.; Davis, B.A.; Boulton, A.A. J. Chromatogr. B 1997, 689, 165.
23. Heilbron, L.; Bunbury, H.M. Dictionary of Organic Compounds; Eyre and
Spottiswoode: London, 1953.
24. Acheson, R.M.; Harvey, C.W.C. J. Chem. Soc., Perkin Trans. I 1956, 465.
25. Smith, H.E.; Warren, M.E. Tetrahedron 1968, 24, 1327.
Received in the USA May 10, 2000

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request
Permission/Reprints Here" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
(AAP) website for guidelines on Fair Use in the Classroom.
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.
Order now!
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC100000584