Enantiodivergent synthesis of the key intermediate for a marine natural furanoterpene by chemoenzymatic process

Article abstract of DOI:10.1016/S0957-4166(98)00268-7

A short chemoenzymatic route to both enantiomers of the key intermediate in the preparation of a marine natural furanoterpene was developed by employing a prochiral malonate derivative as a starting material.

Full text of DOI:10.1016/S0957-4166(98)00268-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2663–2669
Enantiodivergent synthesis of the key intermediate for a marine
natural furanoterpene by chemoenzymatic process
Toshio Honda ∗ and Tomoko Ogino
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan
Received 1 June 1998; accepted 4 July 1998
Abstract
A short chemoenzymatic route to both enantiomers of the key intermediate in the preparation of a marine natural
furanoterpene was developed by employing a prochiral malonate derivative as a starting material. © 1998 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Many biologically active compounds containing a furan subunit with a benzylic quaternary carbon
center have been discovered as natural products. For example, hippospongin A 1,1 and furanoterpenes
22 and 33 contain 7-methyl-7-substituted 4,5,6,7-tetrahydrobenzofuran units as part of their structures
(Fig. 1). In searching the general synthetic route for these furanoterpenes, we concentrated our attention
on the construction of a potential key intermediate 4 in an optically active form, since this unit seems to
function as a common starting material. Recently we reported4 an asymmetric synthetic procedure for
the alcohol 5, the key intermediate for the synthesis of a marine natural product, (−)-aphanorphine 6,
by a chemoenzymatic process using PLE as shown in Scheme 1. We thought that this procedure would
be applicable to the synthesis of the target molecule 4, because of the structural similarity between 4
and 5. Our synthesis began with the preparation of dimethyl 4,5,6,7-tetrahydrofuran-7,7-dicarboxylate
11 having a prochiral center at the benzylic position as follows.
2. Results and discussion
Treatment of methyl 2-oxocyclohexanecarboxylate 75 with methyl chloroformate in the presence of
magnesium perchlorate6 and sodium hydride in refluxing tetrahydrofuran afforded the dicarboxylate 8 in
∗
Corresponding author. E-mail: honda@hoshi.ac.jp
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00268-7

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T. Honda, T. Ogino / Tetrahedron: Asymmetry 9 (1998) 2663–2669
Fig. 1.
Scheme 1.
72% yield. Alkylation of the ketone 8 with allyl bromide in the presence of lithium hexamethyldisilazide
in N,N-dimethylformamide at −30°C gave the allylated compound 9, which on oxidative cleavage
with osmium tetroxide and sodium periodate in tert-butyl alcohol–water afforded the aldehyde 10 in
92% yield from 8. Treatment of the aldehyde 10 with p-toluenesulfonic acid in refluxing toluene in
a Dean–Stark apparatus brought about furan formation to provide the desired starting material 11 in
83% yield. Incubation with PLE of the malonate derivative 11 in a 0.2 M phosphate buffer solution
with 5% acetone between 15 and 20°C resulted in the desired acid–ester 12 in quantitative yield
(Scheme 2). Although the absolute configuration at the newly created stereogenic center of 12 could
not be determined at this stage, it was assumed to be R based on the proposed models for PLE hydrolysis
of malonate derivatives7 and also on our earlier work.4 Because of the relative instability of 12 at room
temperature, the enantiomeric excess from the enzymatic hydrolysis was determined after the reduction
to the corresponding alcohol–ester 13. The selective reduction of both acid and ester groups enabled the
synthesis divergence for the preparation of both enantiomers of the product alcohol. Thus, reduction of
the acid was carried out using sodium borohydride via the mixed anhydride, prepared from the acid with
methyl chloroformate, to give the (S)-alcohol–ester 13, mp: 56.5–56.8°C, [α]D +17.9 (c=1.0, CHCl3), in
71% yield.
The enantiomeric excess of 13 was determined to be 94% using Chiralcel OD. Whereas the reduction
of the ester group of 12 was achieved by employing lithium borohydride to afford the (R)-alcohol–acid
16, in 82% yield, which on esterification with methyl iodide and potassium carbonate furnished the (R)-
alcohol–ester 17, mp: 55–56°C; [α]D −17.2 (c=0.8, CHCl3), in 84% yield with 89% e.e. Both alcohols
13 and 17 were successfully converted into the corresponding primary alcohols 15 and 19, by two steps
involving tosylation with p-toluenesulfonyl chloride, followed by lithium aluminum hydride reduction of
the tosylates 14 and 18 in 85% and 84% yields, respectively (Scheme 3). By comparison of the sign of
rotations for the synthetic products 15, [α]D −13.5 (c=0.5, CHCl3), and 19, [α]D +12.7 (c=0.1, CHCl3),

T. Honda, T. Ogino / Tetrahedron: Asymmetry 9 (1998) 2663–2669
2665
Scheme 2.
with that of the known compound [lit.,8 [α]D +15.6 (c=0.87, CHCl3)], their absolute stereochemistries
can now be unambiguously assigned. The compound 19 has already been transformed to the antipode of
3,9 this synthesis thus constitutes its formal synthesis.
Scheme 3.
In summary, we have disclosed a short procedure for the preparation of both enantiomers of the key
intermediate, in very high enantiomeric excess and chemical yield, for the synthesis of the furanoterpene
3 via asymmetric enzymatic hydrolysis and selective reduction. The synthesis of other furanoterpenes
using the alcohol 15 or 19 is under investigation.
3. Experimental
3.1. General procedures
Melting points were measured with a Yanagimoto MP apparatus and are uncorrected. IR spectra were
1
recorded for thin films on a JASCO FT/IR-200 Fourier transform infrared spectrophotometer. H and
13C NMR spectra were obtained for solutions in CDCl3 on a JEOL PMX 270 instrument (270 MHz), and
chemical shifts are reported in ppm on the δ-scale from internal Me4Si. Mass spectra were measured with
a JEOL JMS D-300 spectrometer. Optical rotations were taken with a JASCO DIP-360 polarimeter. All
new compounds described in the Experimental section were homogeneous on TLC. E.e. determinations

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T. Honda, T. Ogino / Tetrahedron: Asymmetry 9 (1998) 2663–2669
were carried out using a 5% iso-propanol in n-hexane mobile phase with a Chiralcel OD (Daicel Chemical
Industries Limited) on a Senshu HPLC.
3.2. Dimethyl 2-oxocyclohexane-1,1-dicarboxylate 8
Compound 86 was prepared from methyl 2-oxocyclohexanecarboxylate5 and methyl chloroformate
according to a previous report using NaH and magnesium perchlorate as the base in THF.
3.3. Dimethyl 2-oxo-3-(20-propenyl)cyclohexane-1,1-dicarboxylate 9
To a stirred solution of the ketone 8 (3 g, 14 mmol) in dry DMF (30 ml) was added 1 M solution
of lithium hexamethyldisilazide in THF (15.5 ml, 15.5 mmol) at −30°C and the mixture was stirred at
the same temperature for a further 1 h. To this solution was added allyl bromide (1.3 ml, 15.4 mmol)
and the resulting mixture was stirred for 30 min at −30°C. The solution was poured into a saturated
KHSO4 solution and extracted with ethyl acetate. The organic layer was washed with brine and dried
over Na2SO4. Evaporation of the solvent gave a residue, which was subjected to column chromatography
on silica gel. Elution with hexane:ethyl acetate (5:1, by volume) afforded the allylated compound 9 (3.4
g, 94%) as a colorless oil; IR νmax: 2955, 1736, 1435, 1257 cm−1; 1H-NMR (CDCl3): δ 1.35–1.44 (1H,
m, 4-H), 1.51–1.61 (1H, m, 5-H), 1.86–1.90 (1H, m, 5-H), 1.98–2.01 (1H, m, 10-H), 2.09–2.15 (1H, m,
4-H), 2.28 (1H, ddd, J=4.0, 13.7, and 14.0 Hz, 6-H), 2.55–2.61 (1H, m, 10-H), 2.62–2.67 (1H, m, 6-H),
2.67–2.73 (1H, m, 3-H), 3.79 (3H, s, OMe), 3.83 (3H, s, OMe), 5.01–5.09 (2H, m, 30-H), 5.70–5.85
(1H, m, 20-H); MS m/z (M+) 254.1154. C13H18O5 (M+) requires 254.1155. Anal. calcd for C13H18O5: C,
61.40; H, 7.14. Found: C, 61.24; H, 7.13.
3.4. Dimethyl 2-oxo-3-(20-formylmethyl)cyclohexane-1,1-dicarboxylate 10
To a stirred solution of 9 (2.0 g, 7.9 mmol) in tert-butyl alcohol (10 ml) were successively added
pyridine (2 ml, 23.7 mmol), osmium tetroxide [200 mg in tert-butyl alcohol (40 ml)], and 0.5 M NaIO4
solution in water (47 ml, 23.7 mmol) at ambient temperature and the resulting mixture was stirred for 10
h at the same temperature. The mixture was treated with saturated KHSO4 solution and extracted with
chloroform. The organic layer was washed with brine and dried over Na2SO4. Evaporation of the solvent
gave a residue, which was subjected to column chromatography on silica gel. Elution with hexane:Et2O
(1:1, by volume) afforded the aldehyde 10 (2.0 g, 98%) as a colorless oil; IR νmax: 2955, 2928, 2866,
1
2340, 1732, 1435, 1262 cm−1; H-NMR (CDCl3): δ 1.46–1.54 (1H, m, 4-H), 1.60–1.69 (1H, m, 5-
H), 1.86–1.91 (1H, m, 5-H), 2.10–2.15 (1H, m, 4-H), 2.26–2.36 (2H, m, 6-H2), 2.66–2.70 (1H, m, 10-
H), 2.98–3.01 (1H, m, 10-H), 3.26–3.33 (1H, m, 3-H), 3.75 (3H, s, OMe), 3.77 (3H, s, OMe), 9.79
(1H, s, CHO); MS m/z (M+−H2O) 238.0845. C12H14O5 (M+−H2O) requires 238.0842. Anal. calcd for
C12H16O6: C, 56.24; H, 6.29. Found: C, 56.04; H, 6.29.
3.5. Dimethyl 4,5,6,7-tetrahydrobenzofuran-7,7-dicarboxylate 11
A solution of the aldehyde 10 (184 mg, 0.7 mmol) in benzene (46 ml) in the presence of p-
toluenesulfonic acid (137 mg, 0.7 mmol) was heated at reflux for 1 h. The mixture was treated with
saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with brine
and dried over Na2SO4. Evaporation of the solvent gave a residue, which was subjected to column
chromatography on silica gel. Elution with hexane:Et2O (4:1, by volume) afforded 11 (142 mg, 83%)

T. Honda, T. Ogino / Tetrahedron: Asymmetry 9 (1998) 2663–2669
2667
as a colorless oil; IR νmax: 2958, 1733, 1502, 1435, 1259 cm−1; 1H-NMR (CDCl3): δ 1.75–1.85 (2H, m,
5-H2), 2.47–2.51 (2H, m, 6-H2), 2.49 (2H, t, J=6.2 Hz, 4-H2), 3.78 (6H, s, 2×OMe), 6.25 (1H, d, J=2.0
Hz, 3-H), 7.38 (1H, d, J=2.0 Hz, 2-H); MS m/z (M+) 238.0840. C12H14O5 (M+) requires 238.0840. Anal.
calcd for C12H14O5: C, 60.50; H, 5.92. Found: C, 60.66; H, 6.06.
3.6. (7R)-7-Methoxycarbonyl-4,5,6,7-tetrahydrobenzofuran-7-carboxylic acid 12
The diester 11 (100 mg, 0.42 mmol) was incubated with PLE (Amano, 29 mg) in a solution of 5%
acetone in 0.2 M phosphate buffer (pH 7.2, 10 ml) at 15–20°C. After the stirring had been continued for
3 days, the reaction mixture was acidified by addition of 1 M KHSO4 with ethyl acetate. The precipitated
enzyme was removed by filtration and the filtrate was extracted with ethyl acetate. The organic layer was
washed with 1 M NaHCO3 solution to remove the acidic components and the aqueous layer was again
acidified as before and re-extracted with ethyl acetate. The organic layer was washed with brine and
dried over Na2SO4. Evaporation of the solvent gave a residue, which was used in the next step without
1
further purification; (R)-12 (94 mg, 100%); IR νmax: 3700–2220, 1732, 1503, 1437, 1260 cm−1; H-
NMR (CDCl3): δ 1.80–1.88 (2H, m, 5-H2), 2.35–2.43 (2H, m, 6-H2), 2.50 (2H, t, J=6.3 Hz, 4-H2), 3.80
(3H, s, OMe), 6.26 (1H, d, J=1.5 Hz, 3-H), 7.39 (1H, d, J=1.5 Hz, 2-H); MS m/z (M+−44) 180.0782.
C10H12O3 (M+−44) requires 180.0786.
3.7. (7S)-Methyl 7-hydroxymethyl-4,5,6,7-tetrahydrobenzofuran-7-carboxylate 13
To a stirred solution of the acid 12 (660 mg, 2.9 mmol) in dry THF (10 ml) were added triethylamine
(0.45 ml, 3.2 mmol) and methyl chloroformate (0.25 ml, 3.2 mmol) dropwise at 0°C and the mixture
was stirred for a further 1 h. After removal of the precipitated triethylamine hydrochloride by filtration,
the filtrate was concentrated to give a residue, which was dissolved in MeOH (10 ml). NaBH4 (120
mg, 3.2 mmol) was added portionwise to this solution at 0°C and the mixture was stirred for a further
1 h at the same temperature. After quenching the reaction by addition of saturated KHSO4 solution,
the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over
Na2SO4. Evaporation of the solvent gave a residue, which was purified by column chromatography on
silica gel using hexane:ethyl acetate (10:1, by volume) as eluent to give the alcohol–ester 13 (618 mg,
71%) as needles; mp: 56.5–56.8°C; [α]D +17.9 (c=1.0, CHCl3); IR νmax: 3475, 2950, 1734, 1505, 1435,
1
1233, 1055, 893 cm−1; H-NMR (CDCl3): δ 1.74–1.97 (3H, m, 5-H2 and 6-H), 2.17–2.25 (1H, m, 6-
H), 2.46–2.56 (3H, m, 4-H2 and OH), 3.73 (3H, s, OMe), 3.82 (1H, dd, J=9.5 and 10.2 Hz, CHHOH),
4.03 (1H, dd, J=4.7 and 10.2 Hz, CHHOH), 6.26 (1H, d, J=1.6 Hz, 3-H), 7.32 (1H, d, J=1.6 Hz, 2-H);
13C-NMR (CDCl3); 20.0, 21.7, 29.6, 49.7, 52.1, 66.4, 110.0, 119.6, 141.6, 147.7, 174.2; MS m/z (M+)
210.0893. C11H14O4 (M+) requires 210.0885. Anal. calcd for C11H14O4: C, 62.84; H, 6.71. Found: C,
62.72; H, 6.68. The enantiomeric excess of 13 was determined to be 94% by using a 5% iso-propanol in
n-hexane mobile phase with a Chiralcel OD (Daicel Chemical Industries Limited) on a Senshu HPLC.
3.8. (7S)-Methyl 7-p-tosyloxymethyl-4,5,6,7-tetrahydrobenzofuran-7-carboxylate 14
A solution of the alcohol 13 (100 mg, 0.48 mmol), triethylamine (0.2 ml, 1.44 mmol), p-
toluenesulfonyl chloride (272 mg, 1.44 mmol), and a catalytic amount of DMAP in CH2Cl2 (3 ml)
was stirred for 2 h at room temperature. The mixture was diluted with CH2Cl2 and washed with brine,
and dried over Na2SO4. Evaporation of the solvent gave a residue, which was purified by column
chromatography on silica gel using hexane:ethyl acetate (10:1, by volume) as eluent to give the tosylate

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T. Honda, T. Ogino / Tetrahedron: Asymmetry 9 (1998) 2663–2669
14 (618 mg, 71%) as an oil; IR νmax: 2950, 1740, 1598, 1503, 1475, 1364, 1236, 1178, 1097, 992 cm−1
;
1H-NMR (CDCl3): δ 1.75–1.90 (2H, m, 5-H2), 2.25–2.43 (4H, m, 6-H2 and 4-H2), 2.46 (3H, s, Me),
3.64 (3H, s, OMe), 4.17 (1H, d, J=10.2 Hz, CHHOTs), 4.52 (1H, d, J=10.2 Hz, CHHOTs), 6.19 (1H,
d, J=1.6 Hz, 3-H), 7.22 (1H, d, J=1.6 Hz, 2-H), 7.34 (2H, d, J=8.1 Hz, PhH), 7.74 (2H, d, J=8.1 Hz,
PhH); 13C-NMR (CDCl3); 19.8, 21.4, 21.5, 29.5, 47.4, 52.4, 71.6, 110.3, 121.0, 127.8, 129.6, 132.4,
142.1, 144.7, 144.8, 171.1; MS m/z (M+) 364.0978. C18H20O6S (M+) requires 364.0980. Anal. calcd for
C18H20O6S: C, 59.33; H, 5.53. Found: C, 59.27; H, 5.74.
3.9. (7S)-4,5,6,7-Tetrahydro-7-methylbenzofuran-7-methanol 15
To a stirred suspension of lithium aluminum hydride (100 mg, 2.76 mmol) in refluxing THF (5 ml)
was slowly added a solution of the tosylate 14 (156 mg, 0.43 mmol) in THF (2 ml) and the mixture
was stirred for a further 6 h. The mixture was treated with ethyl acetate and then with water, and the
precipitate formed was removed by filtration through a pad of Celite. The filtrate was concentrated to
leave a residue, which was subjected to column chromatography on silica gel. Elution with hexane:ethyl
acetate (10:1, by volume) gave the alcohol 15 (61 mg, 85%) as an oil; [α]D −13.5 (c=0.5, CHCl3); lit.,8
[α]D +15.6 (c=0.87, CHCl3) for its antipode; IR νmax: 3380, 2933, 1504, 1456, 1152, 1101, 1036, 891,
733 cm−1; 1H-NMR (CDCl3): δ 1.24 (3H, s, Me), 1.48–1.60 (2H, m, 5-H2), 1.68–1.89 (3H, m, 6-H2 and
OH), 2.41 (2H, t, J=7.6 Hz, 4-H2), 3.57 (1H, d, J=10.7 Hz, CHHOH), 3.68 (1H, d, J=10.7 Hz, CHHOH),
6.18 (1H, d, J=1.6 Hz, 3-H), 7.25 (1H, d, J=1.6 Hz, 2-H); 13C-NMR (CDCl3); 20.0, 22.4, 22.5, 33.6,
37.9, 70.1, 110.3, 117.9, 140.9, 154.4; MS m/z (M+) 166.0995. C18H20O6 (M+) requires 166.0994.
3.10. (7R)-Hydroxymethyl-4,5,6,7-tetrahydrobenzofuran-7-carboxylic acid 16
To a stirred solution of the ester 12 (416 mg, 1.8 mmol) in dry Et2O (5 ml) was added lithium
borohydride (400 mg, 18 mmol) portionwise at 0°C and the resulting mixture was stirred for a further
5 h at the same temperature. After addition of 1 M KHSO4, the mixture was extracted with Et2O and
the extract was washed with brine, and dried over Na2SO4. Evaporation of the solvent gave a residue,
which was purified by column chromatography on silica gel using chloroform:MeOH (10:1, by volume)
as eluent to give the acid 16 (299 mg, 82%) as an oil. This compound was used in the next step without
further purification because of its instability.
3.11. (7R)-Methyl 7-hydroxymethyl-4,5,6,7-tetrahydrobenzofuran-7-carboxylate 17
To a stirred solution of potassium carbonate (11 mg, 0.088 mmol) in HMPA (1 ml) was added a solution
of iodomethane (0.02 ml, 0.32 mmol) and the acid 16 (15.6 mg, 0.08 mmol) in HMPA (1 ml) at room
temperature and the resulting mixture was stirred for a further 2 h at ambient temperature. After treatment
with water, the mixture was extracted with Et2O and the extract was washed with brine, and dried over
Na2SO4. Evaporation of the solvent gave a residue, which was purified by column chromatography on
silica gel using hexane:ethyl acetate (3:1, by volume) as eluent to give the ester 17 (14.1 mg, 84%) as
needles; mp: 55–56°C; [α]D −17.2 (c=0.8, CHCl3). The spectroscopic data except for the specific optical
rotation were identical to those of 13. The enantiomeric excess of 17 was determined to be 89% by using
a 5% iso-propanol in n-hexane mobile phase with a Chiralcel OD (Daicel Chemical Industries Limited)
on a Senshu HPLC.

T. Honda, T. Ogino / Tetrahedron: Asymmetry 9 (1998) 2663–2669
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3.12. (7R)-Methyl 7-p-tosyloxymethyl-4,5,6,7-tetrahydrobenzofuran-7-carboxylate 18
Tosylation of 17 was carried out by using the same procedure as for the preparation of 14 to give 18 in
70% yield, whose spectroscopic data except for the specific optical rotation were identical with those of
14.
3.13. (7R)-4,5,6,7-Tetrahydro-7-methylbenzofuran-7-methanol 19
Reduction of 18 was carried out by using the same procedure as for the preparation of 15 to give
19, [α]D +12.7 (c=0.1, CHCl3), lit.,8 [α]D +15.6 (c=0.87, CHCl3), as an oil, in 84% yield, whose
spectroscopic data except for the specific optical rotation were identical with those of 15.
Acknowledgements
We are grateful to Professor Kozo Shishido, Institute for Medicinal Resources, University of Tokushi-
ma, for informing us of the specific optical rotation of compound 19 prior to publication. We also thank
the Amano Pharmaceutical Co. Ltd, of Japan for the donation of enzymes. This work was supported by
the Ministry of Education, Science, Sports, and Culture of Japan.
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