Enzymatic desymmetrization of 2,5-dideoxystreptamine precursors

Article abstract of DOI:10.1016/j.tetasy.2006.03.014

The stereoselective enzymatic acylation of meso-6,7-diazabicyclo[3.2.1]oct-6-ene-2,4-diol 4 and meso-4,6-diazidocyclohexane-1,3-diol 5 in organic media gave the corresponding monoesters in high enantiomeric excess. The hydrolysis of the corresponding diac

Full text of DOI:10.1016/j.tetasy.2006.03.014

Tetrahedron: Asymmetry 17 (2006) 1017–1021
Enzymatic desymmetrization of 2,5-dideoxystreptamine precursors
*
´ ´
Robert Cheˆnevert and Frederic Jacques
De´partement de Chimie, CREFSIP, Faculte´ des Sciences et de Ge´nie, Universite´ Laval, Que´bec, Canada G1K 7P4
Received 10 March 2006; accepted 22 March 2006
Abstract—The stereoselective enzymatic acylation of meso-6,7-diazabicyclo[3.2.1]oct-6-ene-2,4-diol 4 and meso-4,6-diazidocyclohexane-
1,3-diol 5 in organic media gave the corresponding monoesters in high enantiomeric excess. The hydrolysis of the corresponding
diacetate derivatives in the presence of a different set of enzymes provided the same monoesters. The products are precursors of
dideoxystreptamine, an aminocyclitol found in synthetic aminoglycoside antibiotics.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
R
streptamine : R = OH R' = OH
H2N
HO
NH2
OH
2-deoxystreptamine : R = H
R' = OH
R' = H
Aminoglycosides form a large class of antibiotics with a
broad antibacterial spectrum particularly against Gram-
negative bacteria. They exert their antibacterial activity
by binding to specific sites in ribosomal RNA of bacteria
and affecting the fidelity of protein biosynthesis.1–3 The
clinical usefulness of aminoglycoside antibiotics is ham-
pered by their adverse side effects and by the emergence
of bacterial resistance.3,4 More recently, aminoglycosides
have been shown to target a variety of other RNA struc-
tures (ribozymes, regulatory domains of HIV mRNA,
group I intron, oncogenic Bcr-Abl mRNA sequence) and
have, therefore, become lead models for the study of
RNA-ligand recognition.5–10 RNA molecules are involved
in essential cellular processes and they are central targets
for drug design.11,12 Accordingly, there has been consider-
able interest in the synthesis of aminoglycosides analogues
with improved biological activities.13–23
2,5-dideoxystreptamine : R = H
R'
Figure 1.
2. Results and discussion
2.1. Substrate preparation
Diepoxide 1 was prepared by epoxidation of 1,4-cyclohex-
adiene with m-chloroperbenzoic acid according to a known
procedure.24 Two pathways were used to obtain diol 5
from diepoxide 1 (Scheme 1). One route involves the reac-
tion of 1 with hydrazine24 to form 2, followed by hydro-
genolysis and azide transfer.25 However, compound 2 is
unstable and is decomposed gradually by air oxidation.
Azo compound 4 was obtained from 2 by oxidation with
hydrogen peroxide.26 In an alternative route, regioselective
ring opening of diepoxide 1 with benzylamine27 (nucleo-
phile and solvent) at 150 ꢁC provided 3 in excellent yield
(94%) after recrystallization; hydrogenolysis and azide
transfer gave 5. Corresponding diacetates 6 and 7 were pre-
pared by the acetylation of 4 and 5 with acetic anhydride in
pyridine.
Their general structure consists of an aminocyclitol central
core linked to one or more aminosugars by glycosidic
bonds. The most common aminocyclitols are either natural
streptamine and 2-deoxystreptamine or synthetic 2,5-di-
deoxystreptamine (Fig. 1). Although these aminocyclitols
are meso compounds, the preparation of desymmetrized
enantiopure derivatives is a prerequisite for the synthesis
of aminoglycoside analogues. Herein, we report the
enzymatic desymmetrization of 2,5-dideoxystreptamine
precursors.
2.2. Enzymatic desymmetrizations
We first completed some screening experiments in order to
find hydrolases with the ability to distinguish the enantio-
topic groups of meso-substrates 4–7. Diol 4 (Scheme 2)
*
Corresponding author. Tel.: +1 418 656 3283; fax: +1 418 656 7916;
e-mail: robert.chenevert@chm.ulaval.ca
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.03.014

ˆ
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R. Chenevert, F. Jacques / Tetrahedron: Asymmetry 17 (2006) 1017–1021
2 HCl
HN
NH
of CAL-B provided monoester (+)-9 in high ee (P99%) but
low yield (32%). In the meantime, Vourloumis et al.28
reported the same reaction under similar conditions
(Novozym 435 is CAL-B immobilized on a macroporous
acrylic resin, yield = 21%). Acylation of diol 5 by treatment
with CRL in vinyl acetate gave (+)-9 in high enantiomeric
excess (ee P99%) and higher yield (85%).
BnHN
HO
NHBn
OH
a
c
O
O
HO
HO
OH
OH
OAc
1
3
2
d
b
d
N
N
N3
N3
2.3. Determination of absolute configuration
HO
OH
5
4
The absolute configuration of compound 8 was determined
by chemical correlation (Scheme 4) with compound (+)-9
of known absolute configuration (1R,2R,4S,5S).28 Hydro-
e
e
genation of (+)-9 in methanol in the presence of 10%
N
N
22
N3
N3
Pd/C gave dideoxystreptamine monoester (ꢀ)-10 {½aꢁD
¼
ꢀ10:8 (c 0.6, MeOH)}, while hydrogenation of (ꢀ)-8 under
AcO
AcO
OAc
the same conditions gave the opposite enantiomer (+)-10
7
6
22
{½aꢁD ¼ þ9:7 (c 1.0, MeOH)}.
Scheme 1. Reagents and conditions: (a) NH2NH2, EtOH; (b) H2O2, H2O;
(c) BnNH2; (d) (i) Pd/C, AcOH/H2O; (ii) TfN3, ZnCl2, Et3N, CH2Cl2/
MeOH/H2O; (e) Ac2O, pyridine.
N
N
a
a
H2N
AcO
NH2
OH
was subjected to the enzyme-catalyzed esterification by
treatment with Candida rugosa lipase (CRL) in vinyl ace-
tate at 21 ꢁC for 3 days to give optically active ester (ꢀ)-8
in moderate yield (63%) and good enantiomeric excess
(ee = 92%). The reaction is very sensitive to experimental
conditions and any change (temperature, solvent, and time)
will have a negative effect. Also, the formation of the cor-
responding diacetate 6 lowers the enantiomeric purity of
product 8. In general, the esterification (transesterification)
of meso-diols and the hydrolysis of the corresponding
meso-diesters are complementary and give opposite enantio-
mers. Unexpectedly, CRL showed very little hydrolytic
activity in the presence of diester 6. However, hydrolysis
of diester 6 (Scheme 2) by pig liver esterase (PLE) in a
phosphate buffer provided the same monoester (ꢀ)-8
(92% yield) in good enantiomeric excess (ee = 90%).
AcO
OH
(-)-8
(+)-10
(-)-10
H2N
HO
NH2
OAc
N3
N3
HO
OAc
(+)-9
Scheme 4. Reagents and conditions: (a) H2, Pd/C, MeOH.
3. Experimental
3.1. General
NMR spectra were recorded on a Varian Inova AS400
spectrometer (400 MHz). Infrared spectra were recorded
on a Bomem MB-100 spectrometer. Optical rotations were
measured using a JASCO DIP-360 digital polarimeter (c as
gram of compound per 100 mL). Flash column chromato-
graphy was carried out using 40–63 lm (230–400 mesh) sil-
ica gel. The enantiomeric excesses (ee) were determined by
N
N
N
N
N
N
a
b
AcO
OH
HO
OH
AcO
OAc
chiral HPLC analysis on
a
CHIRALCEL OD-H
4
(-)-8
6
(4.6 mm · 250 mm) using racemic compounds as refer-
ences. Candida antarctica lipase B (Chirazyme L-2) was ob-
tained from Boehringer Mannheim. PLE (porcine liver
esterase) and CRL (C. rugosa lipase) were from Aldrich.
Scheme 2. Reagents and conditions: (a) Candida rugosa lipase, vinyl
acetate; (b) pig liver esterase, phosphate buffer, pH 7.7.
Following the procedure reported by Wong et al.23 for the
enzymatic desymmetrization of a deoxystreptamine precur-
sor, the hydrolysis of diacetate 7 (Scheme 3) in the presence
3.2. (1R,2R,4S,5S)-6,7-Diazabicyclo[3.2.1]octane-2,4-diol
meso-2
To a solution of cis-epoxide 1 (3.08 g, 27.5 mmol) in anhy-
drous EtOH (20 mL) was added anhydrous hydrazine
(1.16 mL, 1.3 equiv). The solution was then refluxed for
20 h under nitrogen. The reaction mixture was cooled on
ice and after 2 h, the crystalline product was collected,
washed with cold ether, and dried to give 2 (3.24 g, 82%)
as a white solid: mp 190–194 ꢁC; lit.24 mp 185–190 ꢁC
N3
N3
N3
N3
N3
N3
a
b
HO
OH
HO
OAc
AcO
OAc
( )-
+
5
9
7
Scheme 3. Reagents and conditions: (a) Candida rugosa lipase, vinyl
acetate; (b) Candida antarctica lipase B, phosphate buffer, pH 6.2/toluene
(1:1).
1
(dec.); IR (KBr) 3240, 1641, 1438, 1110, 1050 cmꢀ1; H
NMR (400 MHz, CD3OD): d 1.42 (td, J = 11.9, 6.4 Hz,

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R. Chenevert, F. Jacques / Tetrahedron: Asymmetry 17 (2006) 1017–1021
1019
1H), 1.55 (d, J = 15.8 Hz, 1H), 2.01 (dt, J = 15.8, 5.3 Hz,
1H), 2.85 (d, J = 11.9 Hz, 1H), 3.38 (m, 2H), 3.74 (m,
2H), 4.87 (s, 4H); 13C NMR (100 MHz, CD3OD): d 26.5,
32.7, 58.8, 68.6.
dDOS. The mixture was stirred overnight, evaporated
and the crude product was purified by flash chromatogra-
phy (hexanes/EtOAc, 1:1) to give 5 (1.46 g, 53% from 2
and 1.68 g, 61% from 3) as a white solid: mp 80–81 ꢁC;
lit.30 mp 80–81 ꢁC; IR (KBr) 3256, 2923, 2098, 1448,
1
3.3. (1R,3S,4S,6R)-4,6-Bis(benzylamino)cyclohexane-1,3-
diol dihydrochloride meso-3
1257, 1016 cmꢀ1; H NMR (400 MHz, CD3OD): d 1.16
(m, 1H), 1.43 (m, 1H), 2.11 (m, 2H), 3.26 (m, 2H), 3.40
(m, 2H); 13C NMR (100 MHz, CD3OD): d 32.4, 40.1,
64.2, 71.2.
Diepoxide 1 (2.40 g, 21.4 mmol) was dissolved in benzyl-
amine (4 equiv) and the solution was heated at 150 ꢁC for
24 h. The solution was diluted with HCl 1 N (30 mL), fol-
lowed by addition of EtOAc (30 mL), and the mixture was
stirred at 0 ꢁC for 30 min. The organic phase was discarded
and the aqueous phase evaporated. The yellow residue was
recrystallized in MeOH/dioxane/EtOAc to give 327,29
(8.01 g, 94%) as white needles: mp 269–271 ꢁC (dec.);
lit.29 mp 267–270 ꢁC (dec.); IR (KBr) 3439, 2966, 1647,
3.6. Preparation of diacetates 6 and 7: general procedure
To a stirred solution of alcohol 4 or 5 (12.1 mmol) in pyr-
idine (10 mL) was added acetic anhydride (3 equiv) and the
solution stirred overnight at rt under nitrogen. The solu-
tion was diluted with ether, washed with brine, dried over
MgSO4, and evaporated. Crude diacetate 6 was recrystal-
lized from a hot solution of ethanol to give 1.64 g (60%)
as white needles. Crude diacetate 7 was purified by flash
chromatography (hexanes/EtOAc, 6:1) to give 2.77 g
(81%) as a white solid.
1499, 1360, 1234 cmꢀ1 1H NMR (400 MHz, D2O): d
;
1.46 (m, 2H), 2.31 (m, 2H), 3.03 (m, 2H), 3.69 (m, 2H),
4.18 (m, 4H), 7.31 (m, 10H); 13C NMR (100 MHz, D2O):
d 24.7, 39.2, 48.7, 58.3, 66.6, 129.6, 129.8, 130.0, 130.2.
3.4. (1R,2R,4S,5S)-6,7-Diazabicyclo[3.2.1]oct-6-ene-2,4-diol
meso-4
3.6.1. (1R,2R,4S,5S)-4-(Acetyloxy)-6,7-diazabicyclo-[3.2.1]oct-
6-en-2-yl acetate meso-6. White needles: mp 101–103 ꢁC;
lit.26 mp 103–104 ꢁC; IR (KBr) 3445, 2958, 1727, 1361,
To a solution of 2 (2.40 g, 16.7 mmol) in water (15 mL) was
added a fresh 30% H2O2 solution (5.2 mL, 3 equiv) and the
solution was vigorously stirred for 3 days at room temper-
ature. Raney Nickel was added and the stirring maintained
for a few minutes. The mixture was filtered, washed with
water and evaporated. The crude product was purified
by flash chromatography (acetone/CH2Cl2, 1:2) to yield 4
(1.23 g, 52%) as a white solid: mp 142–145 ꢁC; lit.26
mp 140–145 ꢁC; IR (KBr) 2926, 1728, 1518, 910,
1242, 1033 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.36–
;
1.72 (m, 3H), 2.05 (s, 6H), 2.34 (d, J = 12.5 Hz, 1H), 4.98
(sextuplet, J = 1.4 Hz, 1H), 5.24 (t, J = 4.7 Hz, 1H); 13C
NMR (100 MHz, CD3OD): d 19.8, 23.8, 29.5, 62.5, 81.1,
170.5.
3.6.2. (1R,2R,4S,5S)-5-(Acetyloxy)-2,4-diazidocyclohexyl
acetate meso-7. White solid: mp 77–79 ꢁC; lit.30 mp 78
ꢁC; IR (KBr) 2920, 2101, 1735, 1368, 1246, 1025 cmꢀ1
;
1
876 cmꢀ1; H NMR (400 MHz, CD3OD): d 1.33 (m, 1H),
1H NMR (400 MHz, CDCl3): d 1.39 (m, 2H), 2.03 (s,
6H), 2.20 (m, 1H), 2.40 (m, 1H), 3.45 (m, 2H), 4.72 (m,
2H); 13C NMR (100 MHz, CDCl3): d 21.1, 32.5, 33.8,
60.5, 72.1, 169.8.
1.43 (m, 1H), 1.69 (m, 1H), 2.47 (dd, J = 1.4, 12.3 Hz,
1H), 3.74 (m, 2H), 4.82 (m, 2H), 4.94 (dd, J = 5.5,
3.1 Hz, 2H); 13C NMR (100 MHz, CD3OD): d 22.5, 35.9,
59.9, 84.2.
3.7. (1S,2S,4R,5R)-4-(Hydroxy)-6,7-diazabicyclo[3.2.1]oct-
6-en-2-yl acetate 8
3.5. (1R,3S,4S,6R)-4,6-Diazidocyclohexane-1,3-diol meso-5
A solution of meso-diol 2 or 3 (13.9 mmol) in AcOH/H2O
(1:1, 30 mL) was stirred at 60 ꢁC with 10% Pd-on-carbon
(200 mg) under hydrogen (55 psi) for 3 days. The catalyst
was removed by filtration and the solvent evaporated to
give a white residue. The solid was dispersed in EtOH, fil-
tered, and dried to afford 2,5-dideoxystreptamine (2,5-
dDOS) (90% from 2 and 100% from 3) as a white solid.
2,5-dDOS (1.80 g, 12.3 mmol) was dissolved in H2O
(12 mL), then ZnCl2 (2 mol %) and Et3N (6 mol %) were
added followed by the slow addition of MeOH (36 mL).
In another flask, NaN3 (12 equiv) was dissolved in H2O
(15 mL), CH2Cl2 (15 mL) was added and the temperature
was reduced to 0 ꢁC. Tf2O (5.5 equiv) was carefully added
(dropwise) under nitrogen. The solution was stirred for 2 h
at 0 ꢁC. A solution of NaHCO3 (satd) was slowly added
until the production of CO2 stopped. This mixture was
then transferred in a separatory funnel followed by extrac-
tion with CH2Cl2 (2 · 10 mL). The organic phase was
washed with NaHCO3 (satd) (1 · 8 mL) and this solution
was finally added to the first solution containing the 2,5-
3.7.1. Enzymatic acylation of diol 4. To a suspension of
diol 4 (80 mg, 0.56 mmol) in vinyl acetate (6 mL) was
added C. rugosa lipase (80 mg) and the mixture stirred at
room temperature. The reaction was monitored by TLC
and stopped when the formation of the diacetate was de-
tected (ꢂ3 days). The mixture was filtered and the solvent
evaporated. The crude product was purified by flash chro-
matography with CH2Cl2/acetone (3:1) to give (ꢀ)-8
22
(65 mg, 63%, ee = 92%) as a colorless oil. ½aꢁD ¼ ꢀ63:3 (c
1.90, CHCl3); IR (NaCl) 3433, 2964, 2252, 1738, 1247,
1
910 cmꢀ1; H NMR (400 MHz, CD3OD): d 1.25–1.67 (m,
4H), 2.04 (s, 3H), 2.46 (d, J = 12.3 Hz, 1H), 3.88 (dd,
J = 2.9, 6.1 Hz, 1H), 4.83 (s, 1H), 5.09 (m, 2H); 13C
NMR (100 MHz, CD3OD): d 19.9, 23.2, 32.4, 59.5, 63.1,
81.0, 84.5, 170.7; HRMS (CI, NH3) calcd for C8H13N2O3
(M+H)+: 185.0926. Found: 185.0929.
3.7.2. Enzymatic hydrolysis of diacetate 6. Diacetate 6
(270 mg, 1.19 mmol) was suspended in a buffered aqueous
solution (10 mL phosphate, pH 7.7). Porcine liver esterase

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R. Chenevert, F. Jacques / Tetrahedron: Asymmetry 17 (2006) 1017–1021
1020
was added and the pH maintained at its initial value by
addition of 0.25 M aqueous NaOH. After 2 h, the solution
became clear and the aqueous mixture was filtered using
0.22 lm membrane filter, and the retained enzyme was
washed with H2O. The aqueous solution was extracted
with CH2Cl2 (10 · 20 mL), and the organic layer was dried
over MgSO4 and concentrated. Flash chromatography of
189.1239. Found: 189.1237. The same protocol was applied
to the reduction of (+)-9 (16 mg, 0.067 mmol; from CRL
acylation) to yield (ꢀ)-10 (12 mg, 96%) as a colorless
22
oil: ½aꢁD ¼ ꢀ10:8 (c 0.6, CH3OH); spectral data as above.
Acknowledgements
the residue with Et2O gave monoacetate (ꢀ)-8 (202 mg,
22
92%, ee = 90%) as a colorless oil. ½aꢁD ¼ ꢀ61:9 (c 1.44,
The authors would like to thank the Natural Sciences and
Engineering Research Council of Canada (NSERC), for
financial support. We also thank Dr. Vourloumis from
Anadys Pharmaceuticals, for providing the specific rotation
of compound (+)-9.
CHCl3), spectral data as above.
3.8. (1R,2R,4S,5S)-2,4-Diazido-5-hydroxycyclohexyl
acetate 9
3.8.1. Enzymatic acylation of diol 5. To a solution of diol
5 (250 mg, 1.26 mmol) in vinyl acetate (5 mL) was added
C. rugosa lipase (100 mg) and the mixture stirred at rt for
2 days. The enzyme was filtered, washed with CH2Cl2
and the solvent evaporated. Flash chromatography of the
crude product with hexanes/EtOAc (3:1) provided mono-
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497.
acetate (+)-9 (258 mg, 85%, ee P99%) as a colorless oil.
22
½aꢁD ¼ þ22 (c 0.6, CHCl3); IR (NaCl) 3440, 2919, 2101,
1732, 1374, 1235, 1031 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 1.22 (s, 1H), 1.36 (m, 1H), 1.46 (m, 1H), 2.08 (s, 3H), 2.25
(m, 1H), 2.36 (m, 1H), 3.30 (m, 2H), 3.52 (m, 1H), 4.70 (m,
1H); 13C NMR (100 MHz, CDCl3): d 21.2, 32.2, 36.1, 60.7,
63.9, 70.9, 72.7, 170.2; HRMS (CI, NH3) calcd for
C8H13N6O3 (M+H)+: 241.1049. Found: 241.1044.
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3.8.2. Enzymatic hydrolysis of diacetate 7. Diacetate 7
(524 mg, 1.86 mmol) was suspended in a mixture of buf-
fered aqueous solution (10 mL, 0.1 M sodium phosphate,
pH 6.2) and toluene (10 mL) at room temperature. CAL-
B (500 mg) was added and the pH was maintained at its ini-
tial value by addition of 0.25 M aqueous NaOH. The reac-
tion was monitored by TLC and stopped when the
diacetate had disappeared (ꢂ3 days). The mixture was
filtered using 0.22 lm membrane filter and the retained
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separated and aqueous phase extracted with CH2Cl2
(3 · 20 mL). The combined organic layers were dried over
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(+)-9 (144 mg, 32%, ee P99%) as
a colorless oil.
½aꢁD ¼ þ21:6 (c 1.0, CHCl3), spectral data as above.
22
3.9. Determination of absolute configurations by chemical
correlation and preparation of both enantiomers of
dideoxystreptamine monoacetate 10
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22
(20 mg, 93%) as a colorless oil: ½aꢁD ¼ þ9:7 (c 1.0,
´
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1H NMR (400 MHz, CD3OD): d 1.25 (s, 1H), 1.35 (m,
1H), 1.93 (s, 3H), 2.10 (m, 1H), 2.55 (m, 1H), 3.20 (m,
2H), 3.40 (m, 1H), 3.60 (m, 1H); 13C NMR (100 MHz,
CD3OD): d 22.0, 29.9, 41.6, 54.6, 55.9, 71.4, 73.2, 171.3;
HRMS (CI, NH3) calcd for C8H17O3N2 (M+H)+:

ˆ
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