Short and efficient chemoenzymatic synthesis of goniothalamin

Article abstract of DOI:10.1016/j.tetlet.2003.10.115

A high-yielding three-step synthesis of goniothalamin involving an enzymatic kinetic resolution in the presence of vinyl acrylate followed by ring-closing metathesis is discussed.

Full text of DOI:10.1016/j.tetlet.2003.10.115

Tetrahedron
Letters
Tetrahedron Letters45 (2004) 83–85
Short and efficient chemoenzymatic synthesis of goniothalamin
Michelangelo Gruttadauria,* Paolo Lo Meo and Renato Noto
Dipartimento di Chimica Organica ‘E. Paternꢀo’, Universitꢀa di Palermo, Viale delle Scienze, Parco d’Orleans II, 90128 Palermo, Italy
Received 26 September 2003; revised 15 October 2003; accepted 21 October 2003
Abstract—A high-yielding three-step synthesis of goniothalamin involving an enzymatic kinetic resolution in the presence of vinyl
acrylate followed by ring-closing metathesis is discussed.
Ó 2003 Elsevier Ltd. All rights reserved.
Enzyme-catalyzed enantioselective acetylation of race-
mates in organic solvents is well recognized as a useful
procedure for preparing chiral building blocksfor
organic synthesis.1 Lipases (EC 3.1.1.3) are the most
widely employed enzymesbecaues they are cheap and
readily available from many different sources, and in
addition they possess high enantioselectivity for a broad
range of substrates and high stability in organic sol-
vents. One of the most popular lipases used in organic
synthesis is lipase PS (Pseudomonas cepacia) from
Amano Pharmaceutical Co. Ltd., and in particular the
lipase immobilized on ceramic particles (PS-C Amano
II).2–6 The enzymatic kinetic resolution of alcoholsisa
well-studied reaction. However, such methods limit the
yield of the pure enantiomer to 50%. The disadvantages
of kinetic resolution can largely be avoided by employ-
ing a so-called dynamic kinetic resolution.1;4–8
O
O
R
Figure 1.
matic synthesis of 6-substituted 5,6-dihydro-a-pyrone
derivatives. In order to develop our approach we have
chosen goniothalamin as the target compound. Gonio-
thalamin shows antiprogestagenic and antiestrogenic
effects16 in vivo without toxic effects.17 Moreover, the
antitumor activity of goniothalamin hasbeen evaluated
in vitro showing antiproliferative effects, like tamoxifen,
on both MCF-7 and T47-D cell lines.16
A number of compounds possessing a 6-substituted 5,6-
dihydro-a-pyrone ring system (Fig. 1) such as gonio-
thalamin,9 argentilactone,10 goniodiol,11 goniotriol,12
callystatin,13 fostriecin14 have been isolated from plants
and marine organisms. These natural products have
been the targets of several syntheses due to their inter-
esting biological activities.
Astsarting material we employed the racemic allylic
alcohol 1 readily obtained from cinnamaldehyde and
allylmagnesium bromide. As resolving agent for the
transesterification reaction we chose vinyl acrylate. To
the best of our knowledge vinyl acrylate has never been
used as a resolving agent. In this way, following the
empirical ÔKazlauskas ruleÕ,1 we can directly obtain the
ester 3 with the correct configuration. The resolution
wascarried out with PS-C Amano II (1 equiv w/w) (see
Table 1).
Our group is interested in the stereoselective synthesis of
oxygenated heterocyclic rings such as tetrahydrofurans,
tetrahydropyrans, and lactones.15 In thiscommunica-
tion we report preliminary results on the chemoenzy-
In the first instance we performed the reaction with an
excess of vinyl acrylate (5 equiv). The reactions gave
nearly quantitative yieldsand good to high ee, particu-
larly the reaction carried out in CH2Cl2. Moreover,
good results were obtained with 3 or 1.5 equiv of vinyl
acrylate. The control experiment without the enzyme
proved that the nonenzymatic reaction wasextremely
Keywords: lipase; d-lactones; goniothalamin.
* Corresponding author. Tel.: +39-091-596919; fax: +39-091-596825;
e-mail: mgrutt@unipa.it
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.115

84
M. Gruttadauria et al. / Tetrahedron Letters 45 (2004) 83–85
Table 1. Lipase-catalyzed transesterification of 1a
Entry
Solvent
Vinyl acrylate (equiv) Yield 2 (%)b
Ee 2 (%)
Yield 3 (%)b
Ee 3 (%)
Ec
1
2
3
4
5
6
THF
5
50
48
49
48
50
48
92
>99
>99
>99
92
49
47
50
48
49
41
96
98
92
96
94
94
162
525
126
259
106
149
CH2Cl2
Toluene
Toluene
Toluene
CH2Cl2
5
5
3
1.5
1.5
98
a Reactionswere carried out at 25 °C in 1 M solution for 24 h.
b Isolated yield.
c Calculated from E ¼ lnf½eeP ð1 À eeSފ=ðeeP þ eeSÞg= lnf½eeP ð1 þ eeSފ=ðeeP þ eeSÞg.
O
O
b
OH
O
d
OH
a
O
+
Ph
Ph
Ph
Ph
c
( )1
2
3
4
Scheme 1. Reagents and conditions: (a) PS-C Amano II, solvent, vinyl acrylate, 25 °C, 24 h; (b) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ),
diethyl ether, then CH3OH, NaBH4, rt; (c) PPh3, DEAD, acrylic acid, toluene, 0 °C–rt 21%, 20% ee; (d) (Pcy3)2Cl2Ru@CHPh, Ti(OiPr)4, CH2Cl2,
18 h, reflux.
O
slow. The ee was determined by formation of the cor-
responding acetyl-(R)-mandelatesand 1H NMR analy-
sis. Olefin metathesis of 3 with commercially available
GrubbsÕ catalyst (10 mol%) in the presence of Ti(OiPr)4
(0.3 equiv) in refluxing CH2Cl2 overnight gave gonio-
thalamin 4 in 85% yield (Scheme 1).
O
a
b
O
O
2
Ph
d
Ph
Ph
5
6
c
O
OH OH
O
7
In order to improve the yield of the resolution step, a
dynamic kinetic resolution was carried out. Recently,
(p-cymene)ruthenium(II) complexes have been success-
fully employed for dynamic kinetic resolution reactions
O
MeOOC
MeOOC
Ph
8
e
f
O
O
O
10
O
of allylic alcoholsin the preesnce of
p-chlorophenyl
acetate.4 With our substrate the reaction was unsuc-
cessful. Quantitative racemization of 2 wasachieved in
one pot by treatment with DDQ in diethyl ether, then
adding methanol and NaBH4.
MeOOC
OH
Ph
9
Scheme 2. Reagentsand condition:s (a) CH
2@CHCOCl, Et3N,
DMAP (cat.), 0 °C, 90%; (b) (Pcy3)2Cl2Ru@CHPh, Ti(OiPr)4, CH2Cl2,
18 h, reflux, 80%; (c) NaOH(aq), H2O2, MeOH, rt, 75%; (d) (PhSe)2,
NaBH4, MeOH, rt, 88%; (e) CH3COCH3, PTSA, CuSO4, rt, 85%;
(f) O3, MeOH, )78 °C, NaBH4, rt, 75%.
Alcohol 2 was also treated under Mitsunobu reaction
conditionsusing acrylic acid. However, both yield (21%)
and ee (20%) of ester 3 were low.
Alcohol 2 wasconverted into ent-goniothalamin 6, both
in order to test its activity and because it is a convenient
material for the synthesis of the interesting building
block 10. Moreover, the latter compound isthe open
form of the d-lactone unit of mevinolin, a potent and
selective HMG-CoA reductase inhibitor18 and a key
intermediate for the synthesis of several mevinolic acid
Acknowledgements
Financial support from the University of Palermo
(funds for selected research topics) is gratefully
acknowledged.
19
analogs(Scheme 2).
References and Notes
In conclusion a short synthesis of goniothalamin was
realized starting from inexpensive cinnamaldehyde. The
key steps were the kinetic resolution in the presence of
vinyl acrylate followed by RCM. Enzymatic kinetic
resolution of allylic alcohols with vinyl acrylate could
be a useful shortcut for the synthesis of a,b-unsaturated
d-lactones.
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