Lipase-mediated partial resolution of 1,2-diol and 2-alkanol derivatives: Towards chiral building-blocks for pheromone synthesis

Article abstract of DOI:10.1016/S0957-4166(00)00117-8

1,2-Propanediol 5, 1-chloro-2-propanol 8 and its related 2-O-acetate 9 were partially resolved by chemoenzymatic acetylation and deacetylation, in the presence of Pseudomonas fluorescens lipase (Amano P.; PFL), to (R)-(-)-1- acetoxy-2-propanol 6, (R)-(+)-2-acetoxy-1-chloropropane 9 and (R)-(-)-1- chloro-2-propanol 8, respectively. On the other hand, treatment of (2RS)-2 with vinyl acetate in ether and Chirazyme L-2 gave 2-O-acetyl-1,3,4- trideoxy-5,6:7,8-di-O-isopropylidene-β-D-manno-non-5-ulo-5,9-pyranose 1 and 1,3,4-trideoxy-5,6:7,8-di-O-isopropylidene-β-D-gluco-non-5-ulo-5,9-pyranose 11, respectively. Compound 10 was subsequently deacylated to 12. Both alcohols 11 and 12 were treated with Me₂CO/H⁺ to cause their rearrangement to (2S,5R,8R,9R,10S)-10-hydroxy-8,9-isopropylidenedioxy-2-methyl-1,6- dioxaspiro[4.5]decane 3 and its (2R)-epimer 4, which closely matched the skeleton of the odour bouquet minor components of Paravespula vulgaris (L.). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00117-8

Tetrahedron: Asymmetry 11 (2000) 1749±1756
Lipase-mediated partial resolution of 1,2-diol and
2-alkanol derivatives: towards chiral building-blocks
for pheromone synthesis
Isidoro Izquierdo,* Maria T. Plaza, Miguel Rodrõguez and Juan Tamayo
Department of Organic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
Received 8 February 2000; accepted 27 March 2000
Abstract
1,2-Propanediol 5, 1-chloro-2-propanol 8 and its related 2-O-acetate 9 were partially resolved by chemo-
enzymatic acetylation and deacetylation, in the presence of Pseudomonas ¯uorescens lipase (Amano P.; PFL),
to (R)-(^)-1-acetoxy-2-propanol 6, (R)-(+)-2-acetoxy-1-chloropropane 9 and (R)-(^)-1-chloro-2-propanol 8,
respectively. On the other hand, treatment of (2RS)-2 with vinyl acetate in ether and Chirazyme1 L-2
gave 2-O-acetyl-1,3,4-trideoxy-5,6:7,8-di-O-isopropylidene-b-d-manno-non-5-ulo-5,9-pyranose 1 and 1,3,4-
trideoxy-5,6:7,8-di-O-isopropylidene-b-d-gluco-non-5-ulo-5,9-pyranose 11, respectively. Compound 10
was subsequently deacylated to 12. Both alcohols 11 and 12 were treated with Me2CO/H+ to cause their
rearrangement to (2S,5R,8R,9R,10S)-10-hydroxy-8,9-isopropylidenedioxy-2-methyl-1,6-dioxaspiro[4.5]decane 3
and its (2R)-epimer 4, which closely matched the skeleton of the odour bouquet minor components of
Paravespula vulgaris (L.). # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The E/Z mixture of 2-methyl-1,6-dioxaspiro[4.5]decane was identi®ed by Francke et al.1 as
minor components of the odour bouquet of workers of the common wasp Paravespula vulgaris
(L.), but no information about the absolute con®guration of such compounds was given. In a
previous paper,2 the preparation from the 1,3,4-trideoxy-non-5-ulose derivative 2 of the epimeric
1,6-dioxaspiro compounds 3 and 4, key intermediates for the synthesis of all possible stereo-
isomers of the pheromone minor components (see Scheme 1), has been reported by our group.
Nevertheless, the synthesis was poor in stereoselectivity during the formation of a stereogenic
centre at C-2 in 2, it being necessary to use tedious chromatographical separations and recrystal-
lizations for the resolution of 3 and 4. Thus, the need to explore new synthetic methodologies
leading to both epimers of 2 and allow their preparation in a highly stereoselective manner was
apparent. Scheme 1 clearly shows that there are two means of achieving the above synthesis:
* Corresponding author. E-mail: isidoro@platon.ugr.es
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00117-8

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known Wittig methodology, but using the suitably protected aldulose 1, derived from d-fructose,
and the appropriate chiral phosphonium salts, readily available in one or more steps from 1,2-
propanediol derivatives, or the resolution of both epimers of 2 prior to their transformation into
the dioxaspiro compounds 3 and 4.
Scheme 1.
Both strategies have been applied using a chemoenzymatic approach and the results are
reported herein.
2. Results and discussion
Since 1,2-propanediol 5 is a cheap commercial product, it was used as starting material. Thus,
treatment of 5 with vinyl acetate in CH2Cl2, in the presence of lipase from Pseudomonas
¯uorescens (Amano P.; PFL) at room temperature (see Scheme 2), caused its partial resolution
to a€ord (R)-(^)-1-acetoxy-2-propanol 6, isolated in 50.3% yield with 27% ee, determined after
its transformation into (R)-(+)-1,2-diacetoxypropane 73 by GLC (E) on a b-DEXTM column,
together with (S)-(+)-54 in a 48% yield with a 32.5 ee, determined through its 1,2-diacetate
(S)-(^)-7 (see Fig. 1). The enantiomer of 6 has previously been synthesized by chemoenzymatic
reduction with baker's yeast of 1-acetoxipropanone.5 Transformation of (R)-(^)-6 and (S)-(+)-5
into their corresponding mentioned diacetoxy derivatives was justi®ed as a consequence of the
higher resolution found in the GLC analysis as peracetylated compounds on the b-DEXTM column.
Due to the low ee found in this resolution process, the chemoenzymatic hydrolysis of (þ)-7 with
PFL was investigated, but unfortunately the reaction proceeded without regio- or enantioselectivity
and a new strategy, consisting of the use of (þ)-1-chloro-2-propanol 8 as the substrate, was envisaged.
Since pure 8 is not commercially available, it was straightforwardly prepared in an 85% yield
from chloroacetone by reduction with sodium borohydride. Treatment of 8 as mentioned above
for 5 (see Scheme 2) for 3 days produced the corresponding (R)-(+)-2-acetoxy-1-chloropropane 9
(15% yield) with 74% ee, together with (S)-(+)-86 (19% yield) with 43% ee, both isolated after
chromatography. The ees for (R)-(+)-9 and (S)-(+)-8 were established by GLC (D) as above, after
acetylation of the latter compound (see Fig. 2). A systematic study of the enzymatic trans-
esteri®cation of 8 with vinyl butyrate and Novozym1 made by Norin et al.7 a€orded similar
results, but neither the isolation nor practical yield of the products was given.

I. Izquierdo et al. / Tetrahedron: Asymmetry 11 (2000) 1749±1756
1751
Scheme 2. (a) Pseudomonas ¯uorescens lipase (PFL)/vinyl acetate/Cl2CH2/rt; (b) Ac2O/Py; (c) PFL/bu€er (pH 7)/rt
Figure 1. Kinetics for enzymatically (PFL) catalyzed monoacetylation of 5 and GLC analysis (ee) on b-DEXTM
column data of acetate of (R)-(^)-6
Figure 2. Kinetics for enzymatically (PFL) catalyzed acetylation of 8 and hydrolysis of 9 and GLC analysis (ee)
on b-DEXTM column data

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I. Izquierdo et al. / Tetrahedron: Asymmetry 11 (2000) 1749±1756
Due to the low rate found in the acetylation of 8, the chemoenzymatic hydrolysis (PFL) of
(þ)-9 was explored. Monitoring of the reaction by GLC (A) showed that after 110 min the 50%
conversion of (þ)-9 was reached. Work-up of the reaction mixture allowed the isolation of (S)-(^)-9
(7% yield) with 95% ee as well as (R)-(^)-8 (15% yield) with 36% ee, after its acetylation (see Fig. 2).
The low practical yield obtained in both processes made it necessary to plan a new strategy.
Since not entirely satisfactory results were achieved in the above resolutions, we investigated the
diastereomeric resolution of (2R,S)-2 through its partial esteri®cation using an immobilized enzyme
as catalyst (Fig. 3). Thus, reaction of (2R,S)-2 in ether with vinyl acetate in the presence of
Chirazyme1 L-2 gave the corresponding (2R)-2-O-acetyl derivatives of 2 (10) and (2S)-2 (11), both
in the pure state. The con®gurations for 10 and 11 were established after previous deacetylation of
10 to (2R)-2 (12), followed by treatment of both alcohols 11 and 12 with Me2CO/H+ that caused
an internal glycosidation to a€ord the corresponding (2S,5R,8R,9R,10S)- 3 and (2R,5R,8R,9R,10S)-
10-hydroxy-8,9-isopropylidenedioxy-2-methyl-1,6-dioxaspiro[4.5]decane 4, respectively (Scheme 3).
The physical and spectroscopic data for 10, 11 and 12, not previously reported, as well as the
13C NMR signal assignments (13C±1H heteronuclear shift correlation), are included herein.
Figure 3. Kinetics for enzymatically (Chirazyme1 L-2 c.-f., c2, lyo) catalyzed partial acetylation of (2RS)-2
Scheme 3.
3. Conclusions
The results described above indicate that the use of the chiral pool (carbohydrates) combined
with chiral catalysts (enzymes), both from natural sources, could be an excellent methodology in
order to overcome many problems in the stereoselective synthesis of complex biologically active
natural products.

I. Izquierdo et al. / Tetrahedron: Asymmetry 11 (2000) 1749±1756
1753
4. Experimental
4.1. General
Melting points were determined with a Gallenkamp apparatus and are uncorrected. Solutions
1
were dried over MgSO4 before concentration under reduced pressure. The H and 13C NMR
spectra were recorded with Bruker AMX-300, AM-300 and ARX-400 spectrometers for solutions
in CDCl3 (internal Me4Si). IR spectra were recorded with a Perkin±Elmer 782 instrument and
mass spectra with Hewlett±Packard HP-5988-A and Fisons mod. Platform II and VG Autospec-Q
mass spectrometers. Optical rotations were measured for solutions in CHCl3 (1 dm tube) with a
Jasco DIP-370 polarimeter. GLC was performed on a Hewlett±Packard 6890 gas chromatograph
equipped with split/splitless injector, a ¯ame-ionization detector and a capillary HP-5 column (30
mÂ0.25 mm i.d.Â0.25 mm ®lm thickness) at: (A) 70ꢀC; (B) 80ꢀC; (C) 3 min at 180ꢀC, program to
250ꢀC, 10ꢀC/min; or a b-DEXTM 325 (SupelcoTM) capillary column (30 mÂ0.25 mm i.d.Â0.25
mm ®lm thickness) at: (D) 90ꢀC: (E) 110ꢀC; (F) 2 min at 50ꢀC, program to 100ꢀC, 2ꢀC/min. The
He ¯ow rate was 1.1 mL/min, the injection port and the zone-detector temperatures were 275ꢀC.
TLC was performed on precoated silica gel 60 F254 aluminium sheets and detection by charring
with H2SO4. Column chromatography was performed on silica gel (Merck, 7734). The non-
crystalline compounds were shown to be homogeneous by chromatography and characterized by
NMR and HRMS.
4.2. Partial enzymatic (PFL) acetylation of 1,2-propanediol 5
To a gently stirred solution of 5 (2.76 g, 36.4 mmol) in dry CH2Cl2 (75 mL) and vinyl acetate
(7.5 mL, 81 mmol) was added PFL (Amano P., 1.82 g), and the mixture was kept at room
temperature for 2.5 h. The reaction was monitored by GLC analysis (B). The reaction was
quenched by ®ltering o€ the enzyme that was thoroughly washed with dichloromethane. The
combined ®ltrate and washings were concentrated to a residue that was chromatographed
(ether:hexane=1:1!ether!ether:methanol=10:1) to a€ord ®rst (R)-(^)-1-acetoxy-2-propanol
27
27
(6, 2.16 g, 50.3%), TR 3.99 min (B), ‰ꢀŠ ^6, ‰ꢀŠ ^14 (c 1.4) [lit.5 [ꢀ]D +20 (c 1.65, chloroform)
D
405
27
D
27
405
for (S)-(+)-6]. The second fraction was (S)-(+)-5 (1.34 g, 48%), TR 2.58 min (B), ‰ꢀŠ +6, ‰ꢀŠ
23
D
+14 (c 7.57, water) [lit.4a [ꢀ]D +20.1 (c 7.5, water); lit.4b ‰ꢀŠ +21.9 (c 0.74, water)].
Conventional acetylation of (R)-(^)-6 (137 mg, 1.16 mmol) in dry pyridine (1 mL) and acetic
anhydride (0.5 mL) gave, after work-up and column chromatography (ether:hexane=1:2),
(R)-(+)-1,2-diacetoxypropane (7, 143 mg, 77%), TR 6.83 min (E), ee 27% (E=2.2) (see Fig. 1),
26
405
28
D
‰ꢀŠ +3 (c 1.6) [lit.3 ‰ꢀŠ +2 (c 6.5, chloroform)].
Conventional acetylation of (S)-(+)-5 (130 mg, 1.71 mmol) in dry pyridine (1 mL) and acetic
anhydride (0.5 mL), as above, gave (S)-(^)-7 (164 mg, 60%), TR 6.56 min (E), ee 32.5% (E=2.6)
25
405
(see Fig. 1), ‰ꢀŠ ^3 (c 1.9).
4.3. Partial enzymatic (PFL) acetylation of 1-chloro-2-propanol 8
Compound 8 (1.65 g, 17.5 mmol) in CH2Cl2 (30 mL) was treated with vinyl acetate (6.5 mL, 70
mmol) and PFL (Amano P., 900 mg) for 3 days, as above. The reaction was monitored by GLC
analysis (A). Work-up of the reaction mixture and column chromatograhy (ether:hexane=
1:10!ether) a€orded ®rst (R)-(+)-2-acetoxy-1-chloropropane (9, 360 mg, 15%), TR 4.60 min (A),

1754
27
I. Izquierdo et al. / Tetrahedron: Asymmetry 11 (2000) 1749±1756
26
405
‰ꢀŠ +9.3, ‰ꢀŠ +22 (c 1.9), TR 6.22 min (D), ee 74% (E=14.7) (see Fig. 2). The second fraction
D
26
D
26
405
was (S)-(+)-8 (315 mg, 19%), TR 2.42 min (A), ‰ꢀŠ +7, ‰ꢀŠ +18 (c 1.5) [lit.6a [ꢀ]D +22.1 (c 1.06,
chloroform); lit.6b [ꢀ]D +15.5 (c 3.5, chloroform)].
Conventional acetylation of (S)-(+)-8 (120 mg, 1.27 mmol) in dry CH2Cl2 (3 mL) with triethyl-
amine (0.2 mL) and acetic anhydride (0.2 mL) gave, after work-up and column chromatography,
(S)-(^)-(9) (160 mg, 92%), TR 6.03 min (D), ee 43% (E=3.8) (see Fig. 2).
4.4. Partial enzymatic (PFL) hydrolysis of 9
To a gently stirred suspension of 9 (1.45 g, 10.6 mmol) in 100 mL of a bu€ered (pH 7) aqueous
0.5 M phosphate solution (KH2PO4) was added PFL (500 mg) and the mixture was kept at room
temperature for 2 h. The reaction was monitored by GLC analysis (A). The enzyme was ®ltered
o€ and the ®ltrate saturated with sodium chloride and extracted with ethyl acetate. The combined
extracts were concentrated to give a residue that was constituted [GLC (A)] by 8 (60%) and 9
(40%). Column chromatography (ether:hexane=1:10!ether) of the residue gave ®rst (S)-(^)-9
26
27
(100 mg, 7%); ‰ꢀŠ ^11.3, ‰ꢀŠ ^27.5 (c 1.5), TR 5.98 min (D), ee 95% (E=146) (see Fig. 2).
D
405
25
D
25
405
The second fraction was (R)-(^)-8 (150 mg, 15%); ‰ꢀŠ ^5.5, ‰ꢀŠ ^14.5 (c 1.6). Conventional
acetylation of (R)-(^)-8 as above a€orded (R)-(+)-9, ee 36% (E=3) (see Fig. 2).
4.5. Partial enzymatic (Chirazyme1 L-2) acetylation of 1,3,4-trideoxy-5,6:7,8-di-O-isopropylidene-
b-d-manno- and gluco-non-5-ulo-5,9-pyranose 2
Compound 2 (1.08 g, 3.5 mmol) in ether (25 mL) was treated with vinyl acetate (2.7 mL, 29.3
mmol) and Chirazyme1 L-2 c.-f., c2, lyo (Roche Co., 270 mg) for 80 min as above. The reaction
was monitored by GLC analysis (C). Work-up of the reaction mixture and column chromato-
graphy (ether:hexane=1:2!ether) gave ®rst 2-O-acetyl-1,3,4-trideoxy-5,6:7,8-di-O-isopropylidene-
27
D
film
max
b-d-manno-non-5-ulo-5,9-pyranose (10, 580 mg, 47.4%), TR 7.60 min (C), ‰ꢀŠ ^6.7 (c 1); ꢁ
1740 (CˆO, acetate), 1383 and 1373 cm^1 (CMe2). NMR data: 1H, ꢂ 4.87 (m, 1H, H-2), 4.54 (dd,
1H, J6,7=2.5, J7,8=8 Hz, H-7), 4.20 (dd, 1H, H-8), 4.07 (d, 1H, H-6), 3.82 (dd, 1 H, J8,9ax=1.8,
J9ax,9eq=13 Hz, H-9ax), 3.69 (d, 1H, H-9eq), 1.99 (s, 3H, Ac), 1.89±1.72 (m, 4H, H-3,30,4,40), 1.49,
1.46 and 1.32 (3 s, 12H, 2 CMe2) and 1.20 (d, 3H, J1,2=6.2 Hz, H-1,1,1); 13C, ꢂ 170.86 (MeCO),
108.96 and 107.53 (2 CMe2), 103.83 (C-5), 73.87 (C-6), 71.10 (C-2), 70.83 (C-8), 70.60 (C-7), 60.96
(C-9), 36.88 (C-4), 29.64 (C-3), 26.45, 25.83, 25.13 and 24.13 (2 CMe2), 21.40 (MeCO) and 20.07
(C-1). Mass spectrum (LSIMS): m/z 367.17458 (M++Na). For C17H28O7Na 367.17327 (deviation
±3.6 ppm).
The second fraction was syrupy 1,3,4-trideoxy-5,6:7,8-di-O-isopropylidene-b-d-gluco-non-5-
24
D
film
max
ulo-5,9-pyranose (11, 550 mg, 51%); ‰ꢀŠ ^4.6 (c 1); ꢁ
3465 (OH), 1381, 1378 and 1373 cm^1
(CMe2). NMR data: 1H, ꢂ 4.57 (dd, 1H, J6,7=2.5, J7,8=8 Hz, H-7), 4.22 (bdd, 1H, H-8), 4.11 (d,
1H, H-6), 3.86 (dd, 1H, J8,9ax=1.9, J9ax,9eq=13 Hz, H-9ax), 3.85 (m, 1H, H-2), 3.73 (bd, 1H,
H-9eq), 2.02±1.98 and 1.87±1.65 (2 m, 4H, H-3,30,4,40), 1.96 (bs, 1H, OH-2), 1.52, 1.49, 1.36 and
1.35 (4 s, 12H, 2 CMe2) and 1.20 (d, 3H, J1,2=6.2 Hz, H-1,1,1); 13C, ꢂ 109.02 and 107.65 (2
CMe2), 104.04 (C-5), 74.04 (C-6), 70.82 (C-8), 70.63 (C-7), 67.86 (C-2), 61.05 (C-9), 37.17 (C-4),
32.74 (C-3), 26.45, 25.88, 25.13 and 24.16 (2 CMe2) and 23.50 (C-1). Mass spectrum (LSIMS):
m/z 325.16294 (M++Na). For C15H26O6Na 325.16271 (deviation ±0.7 ppm).

I. Izquierdo et al. / Tetrahedron: Asymmetry 11 (2000) 1749±1756
1755
4.6. (2S,5R,8R,9R,10S)-10-Hydroxy-8,9-isopropylidenedioxy-2-methyl-1,6-dioxaspiro[4.5]decane 3
To a stirred solution of 11 (550 mg, 1.82 mmol) in a 2 M solution of sulfuric acid in dry acetone
(5 mL) was added anhydrous copper sulfate (2 g) and the mixture was kept at room temperature
for 3 h. GLC (C) then revealed the presence of 3. The reaction mixture was neutralized (NH3),
®ltered and concentrated. Column chromatography (ether:hexane=1:1.5) of the residue gave
crystalline 3 (310 mg, 70%) which had the same physical spectroscopic data as those previously
reported.2 13C NMR data: ꢂ 109.16 (CMe2), 107.43 (C-5), 78.09 (C-9), 75.91 (C-2), 73.86 (C-8),
72.15 (C-10), 59.73 (C-7), 33.99 (C-4), 31.62 (C-3), 28.19 and 26.19 (CMe2) and 20.81 (Me-2).
4.7. 1,3,4-Trideoxy-5,6:7,8-di-O-isopropylidene-b-d-manno-non-5-ulo-5,9-pyranose 12
To a solution of 10 (580 mg, 1.69 mmol) in dry methanol (20 mL) 0.5 M sodium methoxide (0.2
mL) was added and the mixture left at room temperature for 2 h. TLC (ether:hexane=3:2) then
revealed a slower-running compound. The mixture was neutralized (acetic acid) and concentrated.
The residue was partitioned in ether±water and the organic phase was separated and the aqueous
extracted with ether. Concentration of the combined extracts gave a residue that was chromato-
24
graphed (ether:hexane=1:1!ether) to give 12 (480 mg, 93%) as a colourless oil; ‰ꢀŠ ^19 (c 1);
D
film
max
1
ꢁ
3465 (OH), 1382 and 1373 cm^1 (CMe2). NMR data: H, ꢂ 4.54 (dd, 1H, J6,7=2.5, J7,8=8
Hz, H-7), 4.20 (dd, 1H, H-8), 4.07 (d, 1H, H-6), 3.82 (dd, 1H, J8,9ax=2, J9ax,9eq=13 Hz, H-9ax),
3.80 (m, 1H, H-2), 3.70 (d, 1H, H-9eq), 2.03 (bs, 1H, OH-2), 1.99±1.91 and 1.84±1.62 (2 m, 4H,
H-3,30,4,40), 1.49, 1.46, 1.33 and 1.32 (4 s, 12H, 2 CMe2) and 1.17 (d, 3H, J1,2=6.2 Hz, H-1,1,1);
13C, ꢂ 108.97 and 107.66 (2 CMe2), 103.95 (C-5), 74.18 (C-6), 70.82 (C-8), 70.61 (C-7), 68.07 (C-2),
60.99 (C-9), 37.42 (C-4), 32.64 (C-3), 26.43, 25.89, 25.11 and 24.12 (2 CMe2) and 23.53 (C-1). Mass
spectrum (LSIMS): m/z 325.16294 (M++Na). For C15H26O6Na 325.16271 (deviation ^0.7 ppm).
4.8. (2R,5R,8R,9R,10S)-10-Hydroxy-8,9-isopropylidenedioxy-2-methyl-1,6-dioxaspiro[4.5]decane 4
Treatment of compound 12 (480 mg, 1.59 mmol) with a 2 M solution of sulfuric acid in dry
acetone (5 mL) and anhydrous copper sulfate (2 g) for 3 h, as above, gave, after work-up and
column chromatography (ether:hexane=1:1.5), crystalline 4 (284 mg, 83%) which had the same
physical spectroscopic data as those previously reported.2 13C NMR data: ꢂ 109.22 (CMe2),
107.38 (C-5), 79.14 (C-2), 78.27 (C-9), 74.00 (C-8), 72.20 (C-10), 59.37 (C-7), 34.40 (C-4), 31.37
(C-3), 28.31 and 26.29 (CMe2) and 22.67 (Me-2).
Acknowledgements
The authors are deeply grateful to the Ministerio de Educacion y Cultura (Spain) (Project
PB98-1357) for a grant (J. Tamayo), and to Amano Pharmaceutical for a gift of PFL and Roche
Co. for a gift of Chirazyme1 L-2.
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