Synthesis of (+)-goniothalamin and its enantiomer by combination of lipase catalyzed resolution and alkene metathesis

Article abstract of DOI:10.1016/j.tet.2003.10.102

(+)-Goniothalamin has been synthesized by lipase catalyzed resolution of (1E)-1-phenylhexa-1,5-dien-3-ol using vinyl acrylate as acyl donor followed by ring closing metathesis of the formed (1R)-1-[(E)-2-phenylvinyl]but-3-enyl acrylate. The unreacted alcohol from the resolution, (1E,3S)-1-phenylhexa-1,5- dien-3-ol, was esterified non-enzymatically, and used for synthesis of (-)-goniothalamin.

Full text of DOI:10.1016/j.tet.2003.10.102

Tetrahedron 60 (2004) 521–524
Synthesis of (1)-goniothalamin and its enantiomer by
combination of lipase catalyzed resolution and alkene metathesis
a
Eirik Sundby, Lars Perk, Thorleif Anthonsen, Arne Jørgen Aasen
a
a,*
b
b,*
and Trond Vidar Hansen
a
Department of Chemistry, Norwegian University of Science and Technology, N-7491 Trondheim, Norway
Department of Medicinal Chemistry, School of Pharmacy, University of Oslo, P.O. Box 1068, N-0316 Blindern, Oslo, Norway
b
Received 20 June 2003; revised 24 July 2003; accepted 17 October 2003
Abstract—(þ)-Goniothalamin has been synthesized by lipase catalyzed resolution of (1E)-1-phenylhexa-1,5-dien-3-ol using vinyl acrylate
as acyl donor followed by ring closing metathesis of the formed (1R)-1-[(E)-2-phenylvinyl]but-3-enyl acrylate. The unreacted alcohol from
the resolution, (1E,3S)-1-phenylhexa-1,5-dien-3-ol, was esterified non-enzymatically, and used for synthesis of (2)-goniothalamin.
q 2003 Elsevier Ltd. All rights reserved.
1
. Introduction
Other natural products which contain the a,b-unsaturated
6
–8
d-lactone moiety, such as (2)-argentilactone,
9
parasorbic
acid and ratjadone, have also been targets for several
Chiral unsaturated lactones are structural elements com-
monly found in natural products of medicinal interest.
Furthermore, they are often used as intermediates in the
syntheses of natural products. (þ)-Goniothalamin (1) was
first isolated in 1967 from dried bark of Cryptocarya
caloneura and given (S)-configuration. The configuration
of its stereocenter has been revised and established as being
(R). Later 1 has been obtained from several other sources as
well. The chemistry of naturally occurring 6-substituted 5,6-
2
,9–16
syntheses. Syntheses of (þ)-goniothalamin
and its
non-natural (2)-enantiomer have previously been
2
,11,17–19
reported.
1
Acrylates as acyl donors in lipase-catalyzed transesterifica-
tions have been reported; e.g. for making starting materials
2
20,21
22
for sugar-based polymers,
2
glycolipids, pantolactone
24
3
acrylate, and (R)-(þ)-1-phenylethyl acrylate. The
25
dihydro-a-pyrones including goniothalamin, has been
3
efficiency of vinyl acrylate as acyl donor has been
investigated. Combination of enzymatic transesterifica-
reviewed. This class of compounds shows several biologi-
cal effects. (þ)-Goniothalamin, for instance, exhibits
2
6
tion and alkene metathesis have been reported, but not
directly combined in two steps as in the present work.
4
antifungal effect, immunosuppressive and anti-inflam-
5
matory activity.
2. Results and discussion
The alcohol 2 was prepared by Grignard reaction between
allylmagnesium bromide and cinnamaldehyde. The racemic
alcohol was kinetically resolved by a transesterification
reaction in hexane using vinyl acrylate as acyl donor and
Candida antarctica lipase B (CALB) as catalyst (Scheme 1).
Optical rotation values confirmed that the (R)-enantiomer
2
7
was the faster reacting enantiomer, in accordance with the
2
8
stereopreference of CALB. The resolution proceeded with
an E-value of 65.
Keywords: (þ)-Goniothalamin; (2)-Goniothalamin; Candida antarctica
lipase B; Resolution; Alkene metathesis; Grubbs’ catalyst.
*
The transesterification reaction was stopped after 45%
conversion, and the ester and remaining unreacted alcohol
were separated by column chromatography affording (1R)-
1-[(E)-2-phenylvinyl]but-3-enyl acrylate [(R)-3], with 93%
Corresponding authors. Tel.: þ47-73596206; fax: þ47-73550877 (T.A.)
Fax: þ47-22-85-59-47 (T.V.H.)
e-mail addresses: thorleif.anthonsen@chem.ntnu.no;
t.v.hansen@farmasi.uio.no
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.102

522
E. Sundby et al. / Tetrahedron 60 (2004) 521–524
2 2 3
Scheme 1. (i) CALB, vinyl acrylate, hexane. (ii) Separation by chromatography, (iii) Grubbs’cat., CH Cl , d, (iv) Acryloyl chloride, Et N, THF.
ee and (1E,3S)-1-phenylhexa-1,5-dien-3-ol [(S)-2], with
4% ee. The configuration was established by comparing
laborious; attempts with three different chiral stationary
phases on GLC columns failed. Derivatization of (^)-2
using (R)-4-methoxyphenylacetyl chloride, (S)-(1)-
naphthylethylisocyanate or (R)-1-phenylethyl isocyanate
also failed. Careful selection of chiral stationary phase for
HPLC (Table 2) allowed accurate chiral analyses of 1, 2 and
3.
7
2
0
the measured optical rotation which was [a] ¼þ10.70 (c
D
2
of an (S)-enriched sample of 2 with 24% ee and
.0, Et O), with the rotation of a previously reported value
2
2
0
29
[
a] ¼þ3.60 (c 10.08, Et O). The alcohol (S)-2 was
D
2
esterified with acryloyl chloride to give (1S)-1-[(E)-2-
phenylvinyl]but-3-enyl acrylate, [(S)-3], with no change of
enantiomeric excess.
The absolute configuration was determined as (R) by
2
0
D
comparing the measured specific rotation, [a] ¼þ172.2
3
0
Treatment of (R)-3 with 8 mol% of Grubbs’ catalyst gave
the unsaturated lactone, (R)-(þ)-goniothalamin [(R)-1] via a
ring closing metathesis reaction in 92% yield. It was
observed that during this reaction the ee-value increased to
(c 0.8, CHCl ), with that of a previously reported value for
3
2
0
(þ)-(R)-goniothalamin (1) with 92% ee, [a] ¼þ160.2 (c
D
1
6
0.8, CHCl ). The spectral data were in accordance with
3
those reported earlier. When (S)-3 with an ee of 74% was
treated in the same manner, (S)-1 was obtained, also with
increased ee (85%). The increase of enantiomeric excess
values triggered further investigations, and the results are
summarized in Table 1. Two samples of (R)-3 and one of
.99% in comparison to 93% ee of (R)-3. The ee was
determined by HPLC analysis using a chiral stationary
phase. Chiral analysis of the enantiomers of 1–3 was
(S)-3 with different ee-values led to products with increased
ee-values. Racemic 3 furnished racemic goniothalamin (1).
Table 1. Enantiomeric excesses before and after the ring-closing reaction
Acrylate
% ee
Product
% ee
One might expect that these results were due to inaccuracy
of the chiral analysis. However, both racemic 1 and 3 were
baseline separated by HPLC, giving optimum R -values of
S
2.78 and 3.54, respectively (see Table 2, entries 1 and 5). As
a further check, the samples were also analysed using
(
(
(
(
R)-3
R)-3
S)-3
^)-3
88
93
74
0
(R)-1
(R)-1
(S)-1
(^)-1
96
.99
85
0
Table 2. Chiral HPLC chromatography of 1–3
Entry
Compound
Column
2-Propanol:hexane:EtOH
t
S
(min)
t
R
(min)
R
S
1
2
3
4
5
6
7
1
1
1
2
3
3
3
Chirasil AD
Chirasil AD
Chirasil OD-H
Chirasil AD
Chirasil AD
Chirasil AD
Chirasil OD-H
5:91:4
3:95:2
5:95:0
5:95:0
2:98:0
3:95:2
5:95:0
50.90
34.27
27.21
28.10
11.88
24.13
67.20
59.90
36.72
29.10
26.49
13.94
27.01
20.13
2.78
1.39
1.46
1.61
3.54
2.16
1.37

E. Sundby et al. / Tetrahedron 60 (2004) 521–524
523
different conditions. No change of the ee-values were
observed (Table 2, entries 2, 3, 6 and 7).
The reaction was monitored by GLC. Saturated NH Cl
4
(30 mL) and Et O (50 mL) was added. The water phase was
2
extracted with Et O (3£50 mL), and the combined organic
2
The reaction is homogeneous, and no crystallization is
expected to occur during reaction since 1 and 3 are oils. In
previously reported syntheses of analogs of goniothalamin,
a similar increase of the ee-values during the ring-closing
reaction were not observed, since the ee-values of the final
products were assumed to be the same as the ee-values of
fractions washed with brine (50 mL) and dried (Na SO ).
2
4
Removal of solvent afforded the racemic alcohol (^)-2
1
(3.22 g, 93%). H NMR: d 1.9 (br s, OH), 2.37–2.43 (m,
2H), 4.35 (q, J¼6.4 Hz, 1H), 5.14–5.20 (m, 2H), 5.84 (m,
1H), 6.23 (dd, J¼16.0, 6.4 Hz, 1H), 6.60 (d, J¼16.0 Hz,
1
3
1H), 7.23–7.39 (m, 5H). C NMR: d 42.43, 72.15, 118.86,
126.91, 128.08, 129.00, 130.76, 132.02, 134.50, and 137.10.
1
6
the intermediates.
4
.1.2. Lipase catalyzed kinetic resolution of (6)-2. The
alcohol (^)-2 (400 mg, 2.3 mmol) and vinyl acrylate
1.13 g, 11.5 mmol) were dissolved in hexane (60 mL).
3. Conclusion
(
In conclusion, we have carried out the synthesis of (þ)-
goniothalamin with high enantiomeric excess and its (2)-
enantiomer with moderate enantiomeric excess by lipase
catalyzed kinetic resolution of (1E)-1-phenylhexa-1,5-dien-
Immobilized CALB (300 mg) was added and the reaction
mixture was shaken at 30 8C for 54 h when 45% conversion
was reached. The enzyme was filtered off and the solvent
removed in vacuo. The remaining alcohol (S)-2, and the
ester (R)-3 were separated by column chromatography
(hexane/acetone, 4:1).
3
-ol, followed by separation and non-enzymatic esterifica-
tion of the remaining (S)-alcohol. Subsequent ring-closing
metathesis produced both lactones. This efficient procedure
can easily be extended to the synthesis of other chiral
natural products with an a,b-unsaturated d-lactone moiety.
4.1.3. (1R)-1-[(E)-2-Phenylvinyl]but-3-enyl acrylate [(R)-
2
0
3]. Yield: 200 mg (38%), 93% ee, [a]
1
¼þ66.1 (c 2.0,
D
CHCl ). H NMR: d 2.53 (m, 2H), 5.09–5.16 (m, 2H), 5.56
3
(
q, J¼6.6 Hz, 1H), 5.75–5.85 (m, 2H), 6.11–6.21 (m, 2H),
4
. Experimental
6.43 (dd, J¼17.4, 1.4 Hz, 1H), 6.64 (d, J¼16.0 Hz, 1H),
7
.24–7.39 (m, 5H).
4
.1. General
4
.1.4.
(3S)-(1E)-1-Phenylhexa-1,5-dien-3-ol
2
[(S)-2].
0
D
Immobilized lipase B from Candida antarctica, CALB
Novozyme 435) with an activity of approx. 10,000 PLU/g
Yield: 170 mg (42%), 74% ee, [a]
Spectroscopic data as for (^)-2.
¼þ10.7 (c 2.0, Et O).
2
(
and a water content of 1–2% was used. Solvents were
distilled and dried over molecular sieves. Column chroma-
tography was performed on silica gel 60 from Fluka. First
generation Grubbs’ catalyst, benzylidenebis-(tricyclo-
hexylphosphine)-dichlororuthenium, was purchased from
Aldrich. Enzyme reactions were performed in a shaker
incubator (New Brunswick, Edison, NJ, USA). Optical
rotations were determined using a Perkin–Elmer 243B
polarimeter, concentrations are given in g/100 mL. NMR
spectra were recorded on a Bruker DPX 400 instrument,
4.1.5. (1S)-1-[(E)-2-Phenylvinyl]but-3-enyl acrylate [(S)-
3]. The alcohol (S)-2, (170 mg, 0.98 mmol) was dissolved in
dry THF (10 mL), to this solution was added Et N (two
3
drops) and the solution was cooled to 0 8C. Acryloyl
chloride (111 mg, 1.3 mmol) in THF (5 mL) was added
dropwise to the solution. Stirring at 0 8C was continued for
3 h. Water (5 mL) and HCl (0.05%, 10 mL) was added and
THF was removed in vacuo. The product was extracted with
CH
the solvent evaporated affording 216 mg of (S)-3, yield
Cl
(2£20 mL), the extract was dried over Na
SO and
2 4
2
2
1
13
using CDCl as solvent. H and C spectra were recorded at
3
2
0
4
rel. to TMS and coupling constants in Hertz. Analytical
00 and 100 MHz, respectively. Chemical shifts are in ppm
97%, ee 74% by HPLC analysis, [a] ¼250.6 (c 2.1,
D
CHCl ).
3
TM
GLC analyses were performed on a Supelco SPB -5
column (30 m£0.25 mm, film thickness of 0.25 mm) at
4.1.6. 1-[(E)-2-Phenylvinyl]but-3-enyl acrylate [(6)-3].
The alcohol (^)-2 (300 mg) was treated in the same manner
as described for (S)-2 to give the racemic ester (^)-3, yield
370 mg (94%), spectroscopic data in accord with (S)-3.
1
2
0 psi, split ratio 60 mL/min. The inlet temperature was
50 8C and the FID temperature was 270 8C for all samples.
The temperature program was as follows: 100 8C (0)–
50 8C (2 min hold), 15 8C/min. Chiral HPLC analyses were
performed on a Varian 9010 HPLC with a Varian 2550
2
4.1.7. (1)-Goniothalamin. 6-(6R)-[(E)-2-phenylvinyl]-
5,6-dihydro-2H-pyran-2-one [(1)-1]. Grubbs’ catalyst
variable l detector, equipped with a Chiralcel AD column
(
25£0.46 cm) or Chiralcel OD-H column (25£0.46 cm)
from Daicel Chemical Industries, LTD). The flow rate was
.5 mL/min. Enantiomeric ratios, E, were calculated using
the computer program E and K calculator version 2.1b
http://bendik.chembio.ntnu.no).
(30 mg, 8 mol%,) was dissolved in dry CH Cl (5 mL)
2 2
and this solution was added dropwise to a refluxing solution
of the ester (R)-3 (100 mg, 0.47 mmol, ee 93%) in dry
0
CH Cl (15 mL). The mixture was heated under reflux in an
2 2
(
argon atmosphere for 3 h. The solvent was removed in
vacuo and the mixture purified by column chromatography
(acetone/hexane, 1:4) to afford 86 mg (92%) of (þ)-
goniothalamin, (R)-1, ee.99% as determined by HPLC
4
.1.1. (1E)-1-Phenylhexa-1,5-dien-3-ol [(6)-2]. Allyl-
magnesium bromide (Aldrich, 1 M, 24 mL, 24 mmol) was
added dropwise to a cooled (0 8C) solution of cinnamalde-
hyde (2.64 g, 20 mmol) in dry THF (30 mL). The cooling
bath was removed and the reaction mixture stirred for 4 h.
2
0
1
analysis, [a]
¼þ172.2 (c 0.8, CHCl
), H NMR: d 2.55 (m,
3
D
2H), 5.11 (m, 1H), 6.1 (dt, J¼9.8, 1.6 Hz, 1H), 6.29 (dd,
J¼16.0, 6.3 Hz, 1H), 6.73 (d, J¼16.0 Hz, 1H), 6.93 (dt,

524
E. Sundby et al. / Tetrahedron 60 (2004) 521–524
1
3
J¼9.7, 4.5 Hz, 1H), 7.3 (m, 5H); C NMR: d 30.07, 78.13,
7. Saeed, M.; Abbas, M.; Khan, K. M.; Voelter, W.
Z. Naturforsch. 2001, 325.
8. Hansen, T. V. Tetrahedron: Asymmetry 2002, 13, 547.
1
1
21.86, 125.83, 126.88, 128.54, 128.88, 133.31, 135.94,
44.82, and 164.07.
9
. Quitschalle, M.; Christmann, M.; Bhatt, U.; Kalesse, M.
Tetrahedron Lett. 2001, 42, 1263.
4
5
.1.8. (2)-Goniothalamin, 6-(6S)-[(E)-2-phenylvinyl]-
,6-dihydro-2H-pyran-2-one [(2)-1]. Using the same
10. O’Connor, B.; Just, G. Tetrahedron Lett. 1986, 27, 5201.
11. Bennett, F.; Knight, D. W. Tetrahedron Lett. 1988, 29, 4625.
12. Rahman, S. S.; Wakefield, B. J.; Roberts, S. M.; Dowle, M. D.
J. Chem. Soc. Chem. Commun. 1989, 303.
procedure as under Section 4.1.7 afforded 141 mg (81%)
2
0
D
of (2)-1, ee 85% by HPLC analysis, [a] ¼2146.0 (c 0.8,
CHCl ) with spectroscopic properties in accord with (þ)-1.
3
1
3. Honda, T.; Kametani, T.; Kanai, K.; Tatsuzaki, Y.; Tsubuki,
M. J. Chem. Soc. Perkin Trans. 1 1990, 1733.
4.1.9. (6)-Goniothalamin, 6-[(E)-2-phenylvinyl]-5,6-
dihydro-2H-pyran-2-one [(6)-1]. Using the same pro-
14. Tsubuki, M.; Kanai, K.; Honda, T. Heterocycles 1993, 35, 281.
15. Fuganti, C.; Pedrocche-Fantoni, G.; Sarra, A.; Servi, S.
Tetrahedron: Asymmetry 1994, 5, 1135.
cedure as described under Section 4.1.7 afforded 261 mg
86%) of (^)-1 with spectroscopic properties in agreement
(
with (þ)-1.
16. Ramachandran, P. V.; Reddy, M. V. R.; Brown, H. C.
Tetrahedron Lett. 2000, 41, 583.
1
1
1
2
2
2
7. Takano, S.; Kamikubo, T.; Sugihara, T.; Ogasawara, K.
Tetrahedron: Asymmetry 1992, 3, 853.
8. Henkel, B.; Kunath, A.; Schick, H. Liebigs Ann. Chem. 1992,
Acknowledgements
8
09.
9. Job, A.; Wolberg, M.; Muller, M.; Enders, D. Synlett 2001,
796.
Financial support from The Research Council of Norway is
gratefully acknowledged. We are also grateful to
Novozymes A/S, Denmark for a gift of Novozyme 435.
1
0. Martin, B. D.; Ampofo, S. A.; Linhardt, R. J.; Dordick, J. S.
Macromolecules 1992, 25, 7081.
1. Rethwisch, D. G.; Chen, X.; Martin, B. D.; Dordick, J. S.
Mater. Res. Soc. Symp. Proc. 1994, 330, 225.
2. Bisht, K.; Watterson, A. C.; Gross, R. A. Polym. Mater. Sci.
Engng 1998, 79, 246.
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