Preparation of chiral 1,3 skipped anti- and syn-tetrols via highly enantioselective biocatalytic resolution

Article abstract of DOI:10.1016/S0957-4166(01)00467-0

Biocatalytic resolution of the 7-benzyloxy-3,5-anti-dioxolan-1,3,5,7-tetrol and the 7-benzyloxy-3,5-syn-dioxolan-1,3,5,7-tetrol was found to be highly enantioselective leading to differently functionalized chiral tetrols with significantly high e.e.

Full text of DOI:10.1016/S0957-4166(01)00467-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2755–2760
Preparation of chiral 1,3 skipped anti- and syn-tetrols via highly
enantioselective biocatalytic resolution
Carlo Bonini,* Lucia Chiummiento and Maria Funicello
Dipartimento di Chimica, Universita` della Basilicata, Via N. Sauro 85, 85100 Potenza, Italy
Received 11 October 2001; accepted 22 October 2001
Abstract—Biocatalytic resolution of the 7-benzyloxy-3,5-anti-dioxolan-1,3,5,7-tetrol and the 7-benzyloxy-3,5-syn-dioxolan-1,3,5,7-
tetrol was found to be highly enantioselective leading to differently functionalized chiral tetrols with significantly high e.e. © 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
Since we need a new approach to the synthesis of
polyol antibiotics, 1,3-tetrols of the type 2, with an
anti- relative configuration, we thought it may be possi-
ble to prepare the desired compound in optically active
form by biocatalytic resolution, and eventually, to
extend this approach to the analogous racemic 1,3-syn-
tetrols.
Optically active 1,3-polyol units with anti- or syn-
configuration are important fragments of the carbon
framework of many natural products possessing potent
biological and pharmacological activities. Examples
include Macrolactine,1 Bryostatins,2 and the well
known macrolide antibiotics Amphotericin B and Nys-
tatin A1,3 which have been used clinically for the treat-
ment of systemic fungal infections. The stereoselective
synthesis of 1,3-skipped polyols has attained a level of
considerable sophistication4 and they are often pre-
pared from stereodefined anti- or syn-1,3-diol subunits.
2. Results and discussion
The racemic compounds to be resolved were easily
prepared as shown in Scheme 1. The known b-hydroxy
ketoester 35 was reduced to 3,5-anti-diol 4 using
Previous reports from this laboratory have described
the preparation of 15 (see Fig. 1) by biocatalytic desym-
metrization of the appropriate meso- precursor com-
pound and the transformation of the resulting
homochiral skipped 1,3-syn-tetrol into mevinic acid
analogues5b as well as into the C(1)–C(10)6 and C(1)–
C(13)7 fragments of the macrolide antibiotic Nystatin
A1.
8
Me4NBH(OAc)3 or to the corresponding 3,5-syn-diol
using Et2BOMe/NaBH4.9 Both reactions proceeded
with excellent diastereoselection as has already been
shown for these well known procedures.
The diols were then protected as acetonides and the
ester groups were reduced to primary alcohols with
LiAlH4 to afford, ( )-6 and ( )-810 and, after subse-
quent acylation, the corresponding acetates ( )-7 and
( )-9 in high overall yield.
Enzymatic resolution (Table 1) of the four racemic
compounds was performed under transesterification
conditions on the alcohols ( )-6 and ( )-8 (see Scheme
2) and under hydrolysis conditions on the respective
( )-7 and ( )-9 acetylated products (see Scheme 3),
utilising the commercially available and inexpensive
enzyme Pseudomonas sp. lipase (PSL, AMANO). The
experiments were performed at different conversions
and reaction times in order to optimise the enan-
Figure 1.
* Corresponding author. Tel.: +39 971 202254; fax: +39 971 202223;
e-mail: bonini@unibas.it
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00467-0

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C. Bonini et al. / Tetrahedron: Asymmetry 12 (2001) 2755–2760
Scheme 1. Synthesis of the 1,3 skipped tetrols. (a) Me4NHB(OAc)3, AcOH/CH3CN, −40°C, 18 h, 72%; (b) Et3B/MeOH, NaBH4,
THF, −65°C, 90 min, 98%; (c) H+, (CH3)2C(OCH3)2, rt, 24 h, 100%; (d) LiAlH4, THF, rt, 30 min, 100%; (e) Ac2O, DMAP, Et3N,
rt, 1.5 h, 90%.
Table 1. Enantioselective lipase catalysed reactions
Entry
Reaction
Products
E.e.
Unreacted compounds
Eb
a
a
Substrate
t (h)
Conversion (%)
Product
[h]D
Substrate
E.e.
[h]D
1
2
3
4
(9)-6
(9)-8
(9)-7
(9)-9
20
20
11
18
53
50
36
57
(+)-7
(−)-9
(−)-6
(−)-8
85
98
98
74
+0.66
−1.31
−9.11
–
(+)-6
(+)-8
(−)-7
(+)-9
98
98
56c
98
+ 8.6
+10.2
65
\100
\100
30
–
+1.3
a CHCl3 as solvent, concentration ꢀ1.0.
b See Ref. 11.
c [h]D=−1.53 from acetylation of (+)-6.
Scheme 2. Lipase-catalysed esterification.
tiomeric excess of the products and the enantiomeric
ratio (E) which represents the ratio between the specific
constant of the enzyme for the two competing
enantiomers11 (Table 1). This table shows the trans-
esterification results of ( )-6 and ( )-8 in entries 1 and
2 and reports the hydrolysis results of ( )-7 and ( )-9 in
entries 3 and 4.
high selectivity in the biocatalytic resolution of sub-
strates like compounds 15 and 6–9, is noteworthy
because the stereogenic centres are two carbons away
from the reaction centres. The high substrate affinity of
this enzyme is probably related to the presence of the
rigid acetonide ring12 which fits well in the active site of
the enzyme.
The data (the e.e. values and the E values which exceed
30 in every case, normally considered as excellent) show
indeed the exceptional ability of the enzyme for the
enantiomeric discrimination of these substrates. This
The enantiomeric excesses of the resolved compounds
were evaluated by HPLC (compounds 6, 7 and 8) and
1
by H NMR analysis with chiral shift reagents (com-
pound 9) as described in Section 4.

C. Bonini et al. / Tetrahedron: Asymmetry 12 (2001) 2755–2760
2757
Scheme 3. Lipase-catalysed hydrolysis.
The absolute configuration of compounds 6 and 7 have
been determined on compound (+)-7, obtained in
homochiral form after esterification of (−)-6, using a
new general method13 suitable for non-chromophoric
alkyl-substituted diols, in which the diols are trans-
formed into dioxolanes of the 2,2%-bridged biphenyl
ketone. Efficient transfer of chirality from the diol to
the twisted biphenyl occurs and then the absolute
configuration of the diols can be determined simply by
recognising the prevailing sense of twist of the biphenyl
moiety. The relationship between the sense and angle of
torsion of a biphenyl moiety and its CD spectrum is
clearly and reliably established. The method in the cited
reference is reported for commercially available (R,R)-
pentane-2,4-diol, as an example of an anti-1,3-diol and
the CD spectrum shows the same curve of adduct 10 as
reported in Fig. 2.
3. Conclusion
By appropriate choice of the biocatalytic reaction con-
ditions (time and conversion rate), the present protocol
allows the preparation of pairs of anti- and syn-tetrol
derivatives,15 which are useful as chiral synthons for the
asymmetric synthesis of complex polyols. Studies
toward this aim are under intensive investigation and
the results will be reported in due course.
4. Experimental
4.1. General
All reactions were carried out in oven-dried or flame-
dried glassware under nitrogen atmosphere, unless oth-
erwise noted. All solvents were reagent grade. n-Hexane
and propan-2-ol were all HPLC-grade and purchased
from Aldrich. Acetonitrile (CH3CN) and chloroform
(CHCl3) were freshly distilled from phosphoric anhy-
dride (P2O5), acetic acid was freshly distilled from acetic
anhydride, diethyl ether and tetrahydrofuran (THF)
The absolute configuration of the analogous syn com-
pounds 8 and 9 have been determined by comparison of
the optical rotation of known compound (−)-8, already
reported in the literature ([h]D=−9.0, c=1.0 in
CHCl3).14
Figure 2.

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C. Bonini et al. / Tetrahedron: Asymmetry 12 (2001) 2755–2760
1
were freshly distilled from sodium/benzophenone under
nitrogen before use. Pseudomonas sp. lipase was pur-
acetate 7:3); H NMR (CDCl3): l 7.48–7.29 (m, 5H),
4.52 (s, 2H), 4.36–4.20 (m, 1H), 4.12–3.92 (m, 1H), 3.72
(s, 3H), 3.64–3.50 (m, 2H), 2.62–2.40 (m, 2H), 1.90–1.54
(m, 4H), 1.38 (s, 3H), 1.33 (s, 3H); 13C NMR (CDCl3):
l 173.0, 138.5, 128.4, 127.7, 100.6, 73.1, 69.2, 66.5, 63.5,
51.6, 40.6, 37.9, 35.9, 24.6.
1
chased from AMANO. H and 13C NMR spectra were
recorded in CDCl3 at 300 and 75.5 MHz, respectively
on a Bruker 300 spectrometer; chemical shifts being
expressed in ppm with reference to CHCl3, coupling
constants (J) in Hz. Mass spectra were obtained on a
Hewlett–Packard GC–MS 6890-5973. The optical rota-
tions were determined with a Jasco Mod Dip-370 in
CHCl3. A high performance liquid chromatograph
4.4. 7-Benzyloxy-anti-3,5-O-isopropylidene-heptane-
1,3,5-triol ( )-6
(HPLC) Hewlett–Packard 1060, equipped with
a
Varian 2550 absorbance detector, at 254 nm, and with
a Chiralcel OJ column, was used. TLC were carried out
on Merck Kieselgel precoated on silica gel 60 F-254.
Column chromatographies were performed by Merck
70–230 mesh silica gel. Absorption and CD spectra
were recorded on a Jasco J600 spectropolarimeter at rt
in THF (cꢀ2×10−3 M) in 0.1 mm cell.
To a stirred solution of ( )-5 (0.380 g, 1.14 mmol) in
dry THF (50 mL), lithium aluminium hydride 95%
(LiAlH4, 0.105 g, 2.62 mmol) was slowly added at 0°C.
After 0.5 h the mixture was quenched with methanol,
diluted with aqueous saturated ammonium chloride,
extracted with ethyl acetate and dried on anhydrous
sodium sulphate to afford, after solvent evaporation,
compound ( )-6 as a pale yellow oil, in quantitative
yield (0.335 g, 1.14 mmol): Rf 0.38 (petroleum ether/
4.2. Methyl 7-benzyloxy-anti-3,5-dihydroxy-heptanoate
( )-4
1
ethyl acetate 75:25); H NMR (CDCl3): l 7.38–7.3 (m,
5H), 4.50 (s, 2H), 4.18–3.88 (m, 2H), 3.84–3.72 (m, 2H),
3.62–3.52 (m, 2H), 2.52 (bs, 1H), 1.88–1.7 (m, 4H),
1.7–1.6 (m, 2H), 1.38 (s, 3H), 1.32 (s, 3H); 13C NMR
(CDCl3): l 138.5, 128.3, 127.6, 127.5, 100.4, 73.1, 66.8,
66.5, 63.7, 61.1, 38.2, 37.7, 35.9, 24.8, 24.7; m/z: M+−
Me, 279; (100) 91.
A solution of tetramethylammonium triacetoxyborohy-
dride (4.5 g, 17.14 mmol) in anhydrous CH3CN (9.5
mL) was treated with anhydrous acetic acid (9.5 mL)
and the mixture was stirred at room temperature for 0.5
h. The mixture was cooled to −40°C, and a solution of
3 (0.6 g, 2.14 mmol) in anhydrous CH3CN (3.15 mL)
was added via cannula. The mixture was stirred at
−40°C for 18 h. The reaction was quenched with
aqueous sodium potassium tartrate (0.5 M, 4 mL) and
the mixture was allowed to warm slowly to room
temperature. The mixture was diluted with
dichloromethane and washed with aqueous saturated
sodium bicarbonate. The aqueous layer was back-
extracted with dichloromethane four times, and the
combined organic layers were washed with saturated
aqueous sodium bicarbonate. The aqueous layer was
back-extracted four times with dichloromethane, and
the combined organic layers were dried with anhydrous
sodium sulphate and concentrated in vacuum.
4.5. 1-Acetoxy-7-benzyloxy-anti-3,5-dihydroxy-3,5-O-
isopropylidene-heptane ( )-7
Compound ( )-6 (0.084 g, 0.29 mmol) was acetylated
by the standard procedure (1.5 mL of triethylamine,
0.073 g (0.7 mmol) of acetic anhydride and a catalytic
amount of 4-N,N-dimethylaminopyridine). After 1 h,
the mixture was quenched with methanol in an ice bath.
The solvent was evaporated in vacuum and n-hexane
was added in order to remove traces of acetic acid. The
crude mixture was chromatographed on silica gel
(petroleum ether/ethyl acetate 7:3) to give ( )-7, as a
pale yellow oil in 90% yield (0.087 g, 0.25 mmol): Rf
0.87 (petroleum ether/ethyl acetate 7:3); 1H NMR
(CDCl3): l 7.40–7.30 (m, 5H), 4.50 (s, 2H), 4.20–4.10
(bt, 2H), 4.08–3.88 (m, 2H), 3.60–3.50 (m, 2H), 2.05 (s,
3H), 1.80–1.77 (m, 2H), 1.65–1.55 (m, 4H), 1.31 (s, 6H);
13C NMR (CDCl3): l 171.0, 138.5, 128.4, 127.9, 127.7,
100.4, 73.1, 66.6, 63.7, 63.5, 61.2, 38.5, 36.0, 34.7, 24.6,
20.9; m/z: M+−Me, 321; (100) 91.
The mixture was passed through silica gel column with
petroleum ether/ethyl acetate 6:4 as eluent to give diol
( )-4 as a colourless oil (0.434 g, 72%): Rf 0.44
1
(petroleum ether/ethyl acetate 6:4); H NMR (CDCl3):
l 7.36–7.20 (m, 5H), 4.5 (s, 2H), 4.40–4.28 (m, 1H),
4.18–4.08 (m, 1H); 3.74–3.52 (m, 2H), 3.68 (s, 3H),
2.60–2.42 (m, 2H), 1.98–1.54 (m, 4H); 13C NMR
(CDCl3): l 171.5, 138.0, 128.0, 127.8, 73.3, 69.1, 65.8,
65.6, 51.6, 41.4, 37.9, 35.8.
4.6. 1-Acetoxy-7-benzyloxy-syn-3,5-dihydroxy-3,5-O-
isopropylidene-heptane ( )-9
4.3. Methyl 7-benzyloxy-anti-3,5-dihydroxy-3,5-O-iso-
propylidene-heptanoate ( )-5
The protocol for the esterification of ( )-8 was the same
to have compound ( )-7 with 90% yield: Rf 0.87
Compound ( )-4 (0.536 g, 1.9 mmol) was transformed
to the acetonide ( )-5 by standard procedure (in 2,2-
dimethoxypropane (12 mL) in the presence of catalytic
10-camphorsulfonic acid) which was quenched with few
drops of triethylamine and concentrated in vacuum.
Silica gel chromatography (petroleum ether/ethyl ace-
tate 7:3) gave the desired compound as a colourless oil
in quantitative yield: Rf 0.85 (petroleum ether/ethyl
1
(petroleum ether/ethyl acetate 7:3); H NMR (CDCl3):
l 7.42–7.28 (m, 5H), 4.50 (s, 2H), 4.22–4.12 (m, 2H),
4.10–4.0 (m, 1H), 3.98–3.88 (m, 1H), 3.64–3.5 (m, 2H),
2.08 (s, 3H), 1.88–1.68 (m, 4H), 1.42 (s, 3H), 1.38 (s,
3H), 1.32–1.18 (m, 2H); 13C NMR (CDCl3): l 173.1,
138.5, 128.2, 127.5, 98.5, 72.9, 66.0, 65.9, 60.8, 36.9,
36.4, 35.3, 30.0, 20.8, 19.6; m/z: M+−Me, 221; (100) 91.

C. Bonini et al. / Tetrahedron: Asymmetry 12 (2001) 2755–2760
2759
4.7. Enzyme-catalysed transesterification: general
procedure
in dry THF (1 mL) was added a solution of HCl (1
M, 1 mL). After stirring the mixture for 20 min the
mixture was quenched with saturated aqueous sodium
bicarbonate and extracted a few times with ethyl ace-
tate. The organic layers were dried on anhydrous
sodium sulphate and the crude diol (18 mg) was
immediately used to prepare the dioxolane 10. To the
A solution of compound 6 or 8 (0.2 mmol) in dry
Et2O (10 mL) was vigorously shaken at room temper-
ature. Vinyl acetate (6 mmol, 0.55 mL) and PSL (6.7
mg, 200 U) were then added in the flask and the
reaction was monitored by TLC and by HPLC (n-hex-
ane/propan-2-ol 95:5 v/v%, flow 0.5 mL/min). After
the suitable reaction time, the suspension was filtered
and washed with ethyl acetate. The organic solvent
was removed in vacuum and the crude mixture was
chromatographed (silica gel, eluent petroleum ether/
ethyl acetate 75:25) to afford the alcohols and the
acetylated compounds as reported in Table 1.
,
above crude diol and actived 4 A molecular sieves in
dry CHCl3 (4 mL) was added the dimethyl-acetal16 of
the corresponding 2,2%-bridged diphenyl ketone (16
mg) and a catalytic amount of p-toluensulphonic acid,
at room temperature. After 2 h the reaction mixture
was filtered to remove molecular sieves and the solvent
was evaporated in vacuum. The crude product was
then chromatographed (silica gel, petroleum ether/
diethyl ether 9:1) to afford 10 as a pale yellow oil (4.5
mg, 15%). Rf: 0.5 (petroleum ether/diethyl ether 9:1);
1H NMR (CDCl3): l 7.5–7.1 (m, 13H), 4.6 (bs, 2H),
4.35–4.1 (m, 4H), 3.78–3.66 (m 1H), 3.6–3.5 (m, 1H),
3.05–2.9 (m, 2H), 2.58–2.4 (m, 2H), 2.12 (s, 3H), 1.98–
1.68 (m, 6H).
4.8. Enzyme-catalysed hydrolysis: general procedure
To compound 7 or 9 (0.15 mmol) suspended in a 0.5
M phosphate buffer solution (pH 7, 15 mL), PSL (5
mg, 150 U), was added. The reaction was monitored
by TLC and by HPLC (n-hexane/propan-2-ol 95:5
v/v%, flow 0.5 mL/min). After the suitable reaction
time the mixture was extracted many times with ethyl
acetate. The organic layers were combined, dried over
Na2SO4 and evaporated to afford a crude mixture
which was purified by chromatography (eluent
petroleum ether/ethyl acetate 75:25) to afford the alco-
hols and the acetylated compounds as reported in
Table 1.
Acknowledgements
Thanks are due to MIUR and University of Basilicata
for generous grants supporting the research project.
References
4.9. Determination of enantiomeric excess of compounds
6, 7 and 8 by HPLC
1. Gustafson, K.; Roman, M.; Fenical, W. J. Am. Chem.
Soc. 1989, 111, 7519–7524.
The column used was Chiralcel OJ column.
2. (a) Pettit, G. R.; Day, J. F.; Wood, H. B. Nature 1970,
227, 962; (b) Pettit, G. R. The Chemist 1989, 11.
3. Omura, S. Macrolide Antibiotics: Chemistry, Biology,
Practice; Academic Press: New York, 1984.
For compound ( )-6 eluent: n-hexane/propan-2-ol 96:4
v/v%, flow: 0.4 mL/min, retention time: t(+)=30.53
min, t(−)=36.35 min.
4. (a) Oishi, T.; Nakata, T. Synthesis 1990, 635–645; (b)
Rychnovsky, S. D. Chem. Rev. 1995, 95, 2021–2040.
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R.; Righi, G.; Rossi, L.; Viggiani, L. Tetrahedron: Asym-
metry 1993, 4, 793–805.
For compound ( )-7 eluent: n-hexane/propan-2-ol 95:5
v/v%, flow: 0.5 mL/min, retention time: t(−)=7.54 min,
t(+)=11.38 min.
For compound ( )-8 eluent: n-hexane/propan-2-ol 95:5
v/v%, flow: 0.5 mL/min, retention time: t(−)=20.87
min, t(+)=23.05 min.
6. Bonini, C.; Giugliano, A.; Racioppi, R.; Righi, G. Tetra-
hedron Lett. 1996, 37, 2487–2491.
7. Solladie`, G.; Wilb, N.; Bauder, C.; Bonini, C.; Viggiani,
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Chem. Soc. 1988, 110, 3560–3578.
9. Chen, K. M.; Hardtmann, G. E.; Prasad, K.; Repic, O.;
Shapiro, M. J. Tetrahedron Lett. 1987, 28, 155–158.
10. This compound has been synthesised and characterised as
reported in Ref. 5.
11. E is calculated according to this equation: E=ln[(1−c)(1−
e.e.S)]/ln[(1−c)(1+e.e.S)], where c=e.e.S/e.e.S+e.e.P: Chen,
C. S.; Sih, C. J. Angew. Chem., Int. Ed. Engl. 1989, 28,
695–707.
12. For another related example see: Bonini, C.; Chium-
miento, L.; Funicello, M.; Marcone, L.; Righi, G. Tetra-
hedron: Asymmetry 1998, 9, 2559–2561.
4.10. Determination of enantiomeric excess of com-
pound 9 by NMR analysis
The e.e.s for the two enantiomers of compound 9 were
1
determined by H NMR analysis. In the presence of
the chiral shift reagent, tri[3-(heptafluoropropylhydroxy-
methylene)-(+)camphorato] europium, Eu(hfc)3, in a
0.3–0.6 molar ratio, the acetyl signal have shown a
significant difference in their chemical shift values. For
(+)-9 l=2.58 ppm; for (−)-9 l=2.38 ppm.
4.11. (3R,5R)-1-Acetoxy-7-benzyloxy-3,5-dihydroxy-3,5-
O-[(2,2%-biphenyl)-1,3-isopropylidene]-heptane 10
To a solution of compound (+)-7 (0.06 mmol, 20 mg)

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C. Bonini et al. / Tetrahedron: Asymmetry 12 (2001) 2755–2760
13. Superchi, S.; Casarini, D.; Laurita, A.; Bavoso, A.;
Rosini, C. Angew. Chem., Int. Ed. 2001, 40, 451–454.
14. Mc Garvey, G. J.; Mathys, J. A.; Wilson, K. J.; Overly,
K. R.; Buonora, P. T.; Spoors, P. G. J. Org. Chem. 1995,
60, 7778–7790.
15. For other recent approaches to skipped 1,3-polyol sub-
units see: (a) Enders, D.; Hundertmark, T. Tetrahedron
Lett. 1999, 40, 4169–4172; (b) Kim, Y.; Singer, R. A.;
Carreira, E. M. Angew. Chem., Int. Ed. 1998, 37, 1261–
1263.
16. The dimethyl acetal of the bridged 2,2%-biphenyl ketone
was generously purchased by Professor C. Rosini of
University of Basilicata. Thanks are also due to Dr.
Superchi of University of Basilicata for carrying out the
CD experiments for determination of the absolute
configuration on compound (+)-7.