Chemoenzymatic enantioselective synthesis of (1S,5R)-(-)-frontalin

Article abstract of DOI:10.1016/S0957-4166(02)00085-X

The pheromone (1S,5R)-(-)-frontalin was synthesized in 90% e.e. via a chemoenzymatic route. The key step was the stereoselective acylation (desymmetrization) of 2-(4,5-dihydroxy-4-hydroxymethylpentyl)-2-methyl-1,3-dioxolane with vinyl acetate in organic m

Full text of DOI:10.1016/S0957-4166(02)00085-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 339–342
Chemoenzymatic enantioselective synthesis of
(1S,5R)-(−)-frontalin
Robert Cheˆnevert* and Dave Caron
De´partement de chimie, Faculte´ des sciences et de ge´nie, Universite´ Laval, Que´bec (Qc), Canada G1K 7P4
Received 20 June 2001; revised 25 October 2001; accepted 15 February 2002
Abstract—The pheromone (1S,5R)-(−)-frontalin was synthesized in 90% e.e. via a chemoenzymatic route. The key step was the
stereoselective acylation (desymmetrization) of 2-(4,5-dihydroxy-4-hydroxymethylpentyl)-2-methyl-1,3-dioxolane with vinyl acetate
in organic media in the presence of Pseudomonas sp. lipase. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Frontalin (1,5-dimethyl-6,8-dioxabicyclo[3,2,1]octane)
is the aggregation pheromone of pine beetles of the
Dendroctonus family.1,2 Frontalin was also isolated
from the temporal gland secretion in the male Asian
elephant during the condition of musth3 and frontalin
has recently been identified in the bark of several
angiosperm trees.4 The ecological role of frontalin in
trees that are not hosts for the insects using this
pheromone is still unknown. Frontalin from the pine
beetle Dendroctonus frontalis is an 85:15 mixture of
(1S,5R)- and (1R,5S)-enantiomers. Bioassays have
shown that the (1S,5R)-(−) enantiomer of frontalin is
much more active than the (1R,5S)-(+)-enantiomer.2,5
Pheromones have been successfully used in strategies to
control the progression of pine beetle infestations in
forests.6
Retrosynthetic analysis of the frontalin structure sug-
gested that the prochiral triol 4 might serve as a suit-
able substrate for an enzyme-catalyzed desymmetriza-
tion. Synthesis and desymmetrization of triol 4 are
described in Scheme 1. Addition of the Grignard
reagent 1 prepared from the ethylene acetal of 5-
bromo-2-pentanone8 to the dihydroxyacetone derivative
29 in THF provided tertiary alcohol 3 in 86% yield.
Desilylation of 3 with tetrabutylammonium fluoride
(TBAF) afforded triol 4 in 90% yield.
Next, we completed some screening experiments to find
enzymes with the ability to distinguish the enantiotopic
groups of compound 4. Of the enzymes and conditions
studied, the esterification of triol 4 with vinyl acetate in
Frontalin is a valuable simple target to test diverse
enantioselective synthetic methods. Many syntheses of
frontalin have been reported7 but only a few chemoen-
zymatic syntheses have been achieved. The biotransfor-
mations involved in these chemoenzymatic syntheses
were hydrolase-catalyzed kinetic resolutions7h of race-
mates or enantioselective reductions with microorgan-
isms.7i Herein, we describe an enantioselective synthesis
of (−)-frontalin via the enzymatic desymmetrization of
an achiral substrate.
Scheme 1. Reagents and conditions: (a) THF −78°C; (b)
TBAF, THF; (c) Pseudomonas sp. lipase, vinyl acetate, ben-
zene.
* Corresponding author.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00085-X

340
R. Cheˆne6ert, D. Caron / Tetrahedron: Asymmetry 13 (2002) 339–342
ral substrate was accomplished in five steps giving 31%
overall yield (six steps and 26% overall yield for the
alternative reactions sequence).
3. Experimental
3.1. General
Optical rotations were measured using a JASCO DIP-
360 digital polarimeter. NMR spectra were recorded at
300 MHz (1H) and 75 MHz (13C) on a Bruker AC-300
instrument. Infrared spectra were recorded on a
Bomem MB-100 spectrometer. Flash column chro-
matography was carried out using 40–63 mm (230–400
mesh) silica gel. Lipase from Pseudomonas sp. (lipase
AK) was purchased from Amano.
Scheme 2. Reagents and conditions: (a) (i) TsCl, DMAP,
pyridine, (ii) TsOH, CH2Cl2, H2O; (b) LiEt3BH, THF, reflux;
(c) TsCl, Et3N, DMAP, CH2Cl2; (d) LiAlH4, THF; (e) TsOH,
Et2O, H2O.
the presence of Pseudomonas sp. lipase (lipase AK) in
benzene gave enantiomerically enriched monoester (R)-
(−)-5 (45% yield) and the corresponding achiral diester
6 (55% yield). The reaction was monitored by TLC
analysis and terminated when all the starting material 4
was consumed. The enzymatic reaction was fast and
regioselective for the primary alcohol and stereoselec-
tive. However, the monoacetate 5 also acted as a sub-
strate for the enzyme and thus the acylation reaction
also afforded diester 6 leading to only moderate yield of
monoester 5. The enantiomeric composition of 5 (e.e.=
90%) was determined by reaction with (R)-(−)-ace-
toxyphenylacetic acid in the presence of 1-[3-(di-
methylamino)propyl]-3-ethylcarbodiimide hydrochlo-
ride (EDC) and dimethylaminopyridine (DMAP), fol-
lowed by NMR analysis (300 MHz) of the resulting
diastereomeric esters. The absolute configuration of
monoester 5 was established by its transformation into
(1S,5R)-(−)-frontalin.
3.2. 2-(5-tert-Butyldiphenylsiloxy-4-tert-butyldiphenyl-
siloxymethyl-4-hydroxypentyl)-2-methyl-1,3-dioxolane 3
A solution of the ethylene ketal of 5-bromo-2-pen-
tanone (7.76 g, 37.1 mmol) and methyl iodide (200 mL)
in dry THF (30 mL) was added dropwise to a slurry of
magnesium (2.70 g, 111.1 mmol) in THF (10 mL). The
mixture was stirred at room temperature for 30 min.
The mixture was cooled to −78°C and a solution of
ketone 2 (6.56 g, 11.57 mmol) in THF (45 mL) was
added dropwise. The resulting mixture was stirred at
−78°C for 6 h and allowed to warm to 0°C at which
time saturated NH4Cl (500 mL) was added dropwise.
The mixture was extracted with ethyl acetate (3×500
mL), and the combined organic extracts were dried
(MgSO4) and concentrated. The crude product was
purified by flash chromatography (ether–hexane, gradi-
ent 1/19 to 1/4) to give 3 as a white solid (6.95 g, 86%).
Mp 75–76°C (from hexane); IR (KBr) 3580–3260, 1418,
1
1207, 806, 690, 675 cm−1; H NMR (CDCl3) 7.66–7.74
Monoester (R)-5 provided a multifunctional intermedi-
ate that can be transformed into frontalin by two routes
differing in the timing of the reduction of the hydroxy-
methyl group to the 1-methyl group (Scheme 2).
Monoester (R)-5 was treated with tosyl chloride in
pyridine and acid-catalyzed intramolecular transacetal-
ization of the resulting crude tosylate provided bicyclic
compound (1S,5R)-7 in 93% yield. Reduction of 7 with
lithium triethylborohydride following the procedure
reported by Monneret et al.10 gave (1S,5R)-(−)-fron-
talin in 95% yield.
(m, 8H), 7.34–7.46 (m, 12H), 3.90 (m, 4H), 3.72 (d,
J=9.7 Hz, 2H), 3.64 (d, J=9.7 Hz, 2H), 2.43 (br s,
1H), 1.40–1.64 (m, 6H), 1.30 (s, 3H), 1.07 (s, 18H); 13C
NMR (CDCl3) 135.5, 133.1, 129.6, 127.6, 109.9, 74.4,
65.9, 64.5, 39.7, 33.8, 26.8, 23.6, 19.2, 17.3; HRMS (CI,
NH3) calcd for C40H51O3Si2 (M−C2H5O2): 635.3377.
Found: 635.3352.
3.3. 2-(4,5-Dihydroxy-4-hydroxymethylpentyl)-2-methyl-
1,3-dioxolane 4
The alternative route to frontalin is illustrated in
Scheme 2. Formation of the tosylate in the presence of
a stronger base such as triethylamine afforded epoxide
(R)-8 (yield: 90%). Double reduction of epoxy-ester 8
with LiAlH4 gave the diol (S)-9 in 90% yield. Hydroly-
sis of 9 under acidic conditions gave the corresponding
dihydroxyketone, which underwent intramolecular
acetalization to yield (1S,5R)-(−)-frontalin 10 (yield:
92%) ([h]2D5 −52.1 (c 0.5, Et2O); lit.7i [h]2D5 −50.3 (c 1.63,
Et2O)).
Compound 3 (1.17 g, 1.68 mmol) in 6 mL of dry THF
was treated with tetrabutylammonium fluoride (1 M in
THF, 5.2 mL, 5.2 mmol) at room temperature for 5 h.
The solvent was evaporated and the crude product was
purified by flash chromatography (ethyl acetate–hex-
ane, 1/3, to ethyl acetate–methanol, 9/1) to yield 4 as a
colorless oil (329 mg, 90%). IR (neat) 3350, 2920, 1366,
1
1210, 1036 cm−1; H NMR (CDCl3) 4.06 (br s, 3H),
3.91 (m, 4H), 3.63 (d, J=11.2 Hz, 2H), 3.56 (d, J=11.2
Hz, 2H), 1.61 (m, 2H), 1.42 (m, 4H), 1.28 (s, 3H); 13C
NMR (CDCl3) 109.8, 74.3, 66.6, 64.5, 39.4, 34.5, 23.6,
17.4; HRMS (CI, NH3) calcd for C9H17O5 (M−CH3):
205.1076. Found: 205.1081.
In summary, a synthesis of (−)-frontalin based on the
enantioselective enzyme-catalyzed acylation of a prochi-

R. Cheˆne6ert, D. Caron / Tetrahedron: Asymmetry 13 (2002) 339–342
341
3.6. (1S,5R)-(−)-1,5-Dimethyl-6,8-dioxabicyclo[3,2,1]-
octane or (1S)-(−)-frontalin 10
3.4. (R)-2-(4-Acetoxymethyl-4,5-dihydroxypentyl)-2-
methyl-1,3-dioxolane 5
A 1 M solution of lithium triethylborohydride in
THF (4 mL) was added to a cold (0°C) solution of
tosylate 7 (45 mg, 0.144 mmol) in dry THF. The
mixture was heated at reflux for 3 h. The mixture
was allowed to cool to room temperature and then
poured into ice-water (3 mL). The solution was aci-
dified with 1N HCl and extracted with ether. The
extracts were washed with 1N HCl, saturated
NaHCO3, water, dried (MgSO4), and concentrated
without the application of heat. The crude product
was purified by flash chromatography (hexane) to
yield (−)-frontaline 10 (19.5 mg, 95%) as a colorless
oil. [h]2D3 −52.0 (c 0.5, ether); lit.:10 [h]2D0 −52 (c 1,
ether). Spectroscopic data were identical to those
reported in the literature.
Compound 4 (302 mg, 1.37 mmol) was dissolved in
,
35 mL of dry benzene containing 300 mg of 4 A
molecular sieves. Vinyl acetate (675 mL, 7.32 mmol)
and crude Pseudomonas sp. lipase (700 mg) were
added and the mixture was stirred for 1.5 h at room
temperature; it was then filtered and the solids were
washed with ether. The solvents were evaporated and
the crude product was purified by flash chromatogra-
phy (ethyl acetate–hexane, 1/1, to ethyl acetate–
methanol, 4/1) to provide monoester 5 (160 mg, 45%)
and the corresponding diester 6 (232 mg, 55%). Com-
pound 5: [h]2D3 −2.6 (c 2.3, acetone); IR (neat) 3380,
2930, 2875, 1712, 1450, 1368, 1235, 1138, 1030 cm−1;
1H NMR (CDCl3) 4.12 (d, J=11.5 Hz, 1H), 4.01 (d,
J=11.5 Hz, 1H), 3.92 (m, 4H), 3.48 (d, J=11.5 Hz,
1H), 3.42 (d, J=11.5 Hz, 1H), 2.57 and 2.67 (br s,
2H), 2.09 (s, 3H), 1.63 (m, 2H), 1.48 (m, 4H), 1.29 (s,
3H); 13C NMR (CDCl3) 171.5, 109.8, 73.3, 66.4, 65.2,
64.5, 39.3, 34.2, 23.6, 20.7, 17.2; HRMS (CI, NH3)
calcd for C12H26O6N (M+NH4): 280.1760. Found:
280.1764. Compound 6: IR (neat) 3468, 2959, 2884,
1743, 1464, 1436, 1376, 1236, 1044 cm−1; 1H NMR
(CDCl3) 4.04 (m, 4H), 3.91 (m, 4H), 2.08 (s, 6H),
1.64 (m, 2H), 1.53 (m, 4H), 1.29 (s, 3H); 13C NMR
(CDCl3) 170.8, 109.7, 72.2, 66.6, 64.5, 39.3, 34.6,
23.7, 20.7, 17.0; HRMS (CI, NH3) calcd for
C14H28O7N (M+NH4): 322.1866. Found: 322.1869.
3.7. (R)-2-(4-Acetoxymethyl-4,5-epoxypentyl)-2-methyl-
1,3-dioxolane 8
Triethylamine (1.5 mL, 10.8 mmol) and 4-(N,N-
dimethylamino)pyridine (5 mg) were added to a solu-
tion of diol 5 (156 mg, 0.595 mmol) in anhydrous
methylene chloride (10 mL). Tosyl chloride (370 mg,
1.94 mmol) was added and the solution was stirred at
room temperature for 7 days. Ether (100 mL) was
added and the organic phase was washed with 1N
HCl, saturated NaHCO3, brine, dried (MgSO4) and
concentrated. The crude product was purified by flash
chromatography (hexane–ethyl acetate–triethylamine,
74/25/1) to give 8 as a colorless oil (130 mg, 90%).
[h]2D3 −6.0 (c 1.84, acetone); IR (neat) 3053, 1743,
1241, 1227, 1041 cm−1; 1H NMR (CDCl3) 4.24 (d,
J=12 Hz, 1H), 3.93 (d, J=12 Hz, 1H), 3.87 (m, 4H),
2.69 (d, J=5 Hz, 1H), 2.65 (d, J=5 Hz, 1H), 2.02 (s,
3H), 1.43–1.80 (m, 6H), 1.22 (s, 3H); 13C NMR
(CDCl3 170.5, 110.1, 66.3, 65.1, 57.5, 50.4, 39.6, 32.5,
23.9, 20.5, 19.8; HRMS (CI, NH3) calcd for C12H21O5
(M+H): 245.1389. Found: 245.1395.
3.5. (1S,5R)-5-Methyl-1-para-toluenesulfonyloxymethyl-
6,8-dioxabicyclo[3,2,1]octane 7
A solution of compound 5 (112.5 mg, 0.430 mmol),
p-toluenesulfonyl chloride (163.6 mg, 0.859 mmol)
and 4-dimethylaminopyridine (10 mg) in dry pyridine
(2 mL) was stirred for 24 h at room temperature.
Ether (100 mL) was added and the organic layer was
washed with a 1N HCl solution (3×100 mL), with a
saturated NaHCO3 solution (3×100 mL) and with
brine (3×100 mL), dried, and evaporated. A mixture
of the crude tosylate (153 mg, 0.367 mmol), water
(100 mL), p-toluenesulfonic acid monohydrate (105
mg, 0.552 mmol) and CH2Cl2 (2 mL) was stirred at
room temperature for 72 h. Ether (50 mL) was added
and the organic layer was washed with saturated
NaHCO3 (3×50 mL), water (3×50 mL), dried
(MgSO4) and concentrated. The crude product was
purified by flash chromatography (ethyl acetate–hex-
ane, 1/4 to 4/1) to give tosylate 7 (106.6 mg, 93%) as
a white solid. Mp 103–104°C (from hexane); [h]D23
−18.2 (c 1.32, CHCl3); lit.10: mp 110°C, [h]D20 −20 (sol-
vent and concentration not specified); IR (KBr) 1360,
1193, 1174, 975, 843, 819, 556, 524 cm−1; 1H NMR
(CDCl3) 7.72 (d, J=8 Hz, 2H), 7.28 (d, J=8 Hz,
2H), 3.98 (d, J=10 Hz, 1H), 3.96 (d, J=10 Hz, 1H),
3.82 (d, J=7 Hz, 1H), 3.44 (d, J=7 Hz, 1H), 2.38 (s,
3H), 1.46–1.87 (m, 6H), 1.30 (s, 3H); 13C NMR
(CDCl3) 144.9, 132.5, 129.7, 127.9, 109.0, 80.1, 71.6,
70.5, 34.4, 29.0, 24.1, 21.5, 17.0.
3.8. (S)-2-(4,5-Dihydroxy-4-methylpentyl)-2-methyl-1,3-
dioxolane 9
Epoxide 8 (44.8 mg, 0.183 mmol) was dissolved in
anhydrous THF (1 mL) under N2, LiAlH4 (28 mg,
0.74 mmol) was added and the mixture was stirred at
room temperature for 1 h. Ether (20 mL) was added
and the reaction was quenched with sodium sulfate
monohydrate. The mixture was filtered through Celite
and the solvent was evaporated. The crude product
was purified by flash chromatography (ethyl acetate–
hexane, 1/4, to pure ethyl acetate) to give 9 as a
colorless oil (33.4 mg, 90%). [h]2D3 −2.1 (c 1.2, ether);
lit.:11 [h]2D5 −1.8 (c 1.2, ether); IR (neat) 3583, 3410,
1378, 1152, 1055 cm−1; 1H NMR (CDCl3) 3.55 (m,
4H), 3.34 (d, J=11 Hz, 1H), 3.28 (d, J=11 Hz, 1H),
2.47–2.65 (br s, 2H), 1.32–1.76 (m, 6H), 1.32 (s, 3H),
1.08 (s, 3H); 13C NMR (CDCl3) 110.2, 72.7, 70.0,
64.6, 40.2, 39.1, 24.0, 23.4, 18.6.

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R. Cheˆne6ert, D. Caron / Tetrahedron: Asymmetry 13 (2002) 339–342
3.9. Synthesis of (−)-frontalin 10 from diol 9
4. Huber, D. P. W.; Gries, R.; Borben, J. H.; Pierce, H. D.
J. Chem. Ecol. 1999, 25, 805.
A mixture of diol 9 (24 mg, 0.12 mmol), ether (5 mL),
water (100 mL) and p-toluenesulfonic acid (3.0 mg,
0.016 mmol) was stirred at room temperature for 24 h.
Ether (25 mL) was added and the organic layer was
washed with saturated NaHCO3 (2×25 mL), water (2×
25 mL), dried (MgSO4) and evaporated. The crude
product was purified by flash chromatography (hexane)
to yield (−)-frontaline (15.6 mg, 0.11 mmol, 92%) as a
colorless oil. [h]D23 −52.1 (c 0.5, Et2O); lit.11 [h]2D5 −51.5 (c
1.2, ether). Spectroscopic data were identical to those
reported in the literature.
5. Payne, T. L.; Richerson, J. V.; Dickens, J. C.; West, J.
R.; Mori, K.; Brisford, C. W.; Hedden, R. L.; Vite´, J. P.;
Blum, M. S. J. Chem. Ecol. 1982, 8, 873.
6. Salom, S. M.; Grossman, D. M.; McClellan, Q. C.;
Payne, T. L. J. Econ. Entomol. 1995, 88, 1703.
7. For recent syntheses of frontalin, see: (a) Kanada, R. M.;
Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2000, 41,
3631; (b) Scholl, M.; Grubbs, R. H. Tetrahedron Lett.
1999, 40, 1425; (c) List, B.; Shabat, D.; Zhong, G. F.;
Turner, J. M.; Li, A.; Bui, T.; Anderson, J.; Lerner, R.
A.; Barbas, C. F. J. Am. Chem. Soc. 1999, 121, 7283; (d)
Mori, K. Eur. J. Org. Chem. 1998, 1479; (e) Majewshi,
M.; Nowak, P. Tetrahedron: Asymmetry 1998, 9, 2611; (f)
Kouklovsky, C.; Dirat, O.; Berranger, T.; Langlois, Y.;
Tran-Huu-Dau, M. E.; Riche, C. J. Org. Chem. 1998, 63,
5123; (g) Maezaki, N.; Shogaki, T.; Uchida, M.; Tokuno,
K.; Imamura, T.; Tanaka, T.; Iwata, C. Chem. Pharm.
Bull. 1998, 46, 217; (h) Kroutil, W.; Osprian, I.; Mischitz,
M.; Faber, K. Synthesis 1997, 156; (i) Nishimura, Y.;
Mori, K. Eur. J. Org. Chem. 1998, 233 and references
cited therein.
Acknowledgements
The authors would like to thank the Natural Sciences
and Engineering Research Council of Canada
(NSERC) for financial support. D.C. was holder of an
undergraduate student research award (NSERC).
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