Asymmetric synthesis of S-(+)-argentilactone and S-(-)-goniothalamin

Article abstract of DOI:10.1055/s-2001-18088

The asymmetric synthesis of an α,β-unsaturated δ-lactone equivalent 8 as a key intermediate towards the total synthesis of a variety of natural products bearing such structural motifs is reported. An enzymatic approach was applied to provide both enantiomers of compound 8 using recLBADH (ee > 99%) and baker's yeast (ee = 94%), respectively. The utility of the intermediate was demonstrated by the total synthesis of the non-natural enantiomers of argentilactone [(S)-1] and goniothalamin [(S)-2].

Full text of DOI:10.1055/s-2001-18088

1796
LETTER
Asymmetric Synthesis of S-(+)-Argentilactone and S-(–)-Goniothalamin
A
symmetric Synth
n
esis of
S
-(+)
d
-
Argentilacto
r
ne and
S
e
-(–)-Gonio
a
thalamin s Job,a Michael Wolberg,b Michael Müller,b Dieter Enders*a
a
Institut für Organische Chemie, RWTH Aachen, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
b
Institut für Biotechnologie 2, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany
Fax +49(241)8888127; E-mail: enders@rwth-aachen.de
Received 6 July 2001
both non-natural enantiomers of 1 and 2 employing a Wit-
tig reaction.
Abstract: The asymmetric synthesis of an , -unsaturated -lac-
tone equivalent 8 as a key intermediate towards the total synthesis
of a variety of natural products bearing such structural motifs is re-
ported. An enzymatic approach was applied to provide both enanti-
omers of compound 8 using recLBADH (ee > 99%) and baker's
yeast (ee = 94%), respectively. The utility of the intermediate was
demonstrated by the total synthesis of the non-natural enantiomers
of argentilactone [(S)-1] and goniothalamin [(S)-2].
We recently demonstrated that NADP-dependent alcohol
dehydrogenase of Lactobacillus brevis (recLBADH) can
be used for the enantioselective reduction of tert-butyl 6-
chloro-3,5-dioxohexanoate (3). The enantiopure hydroxy
keto ester (S)-4 was thus obtained in good yield and high
selectivity on an attractive scale (up to 75 g per batch,
Scheme 1).15 Further investigations revealed that the use
of baker’s yeast as biocatalyst provided the opposite enan-
tiomer (R)-4 in 50% yield and 94% enantiomeric excess in
a biphasic system water/XAD-7 adsorber resin.16 Both
enantiomers of 4 were then reduced by sodium borohy-
dride to obtain the dihydroxy esters which on heating un-
derwent lactonization with elimination of water to give
the corresponding , -unsaturated chloro lactones 5, re-
spectively.
Key words: natural products, enzymes, asymmetric synthesis, Wit-
tig reactions, lactones
Argentilactone (1) (Figure) was first isolated in 1977 from
the rhizomes of Aristolochia argentia.1 It shows both
antileishmanial2 and cytotoxic activity (P-388, mouse leu-
kaemia cells).3 Goniothalamin (2) (Figure) was isolated in
1967 from the dried bark of Cryptocarya caloneura.4 In
several tests goniothalamin revealed teratogenic5 and cy-
totoxic activity (P-388 and leukaemia T-cell line Jurkat:
E6-1).6 Several asymmetric syntheses of argentilactone7
and goniothalamin8 have been published, including the
non-natural enantiomers.9 Both substances contain an
, -unsaturated -lactone moiety and bear the (R)-config-
uration in the natural form.
O
O
O
Cl
OtBu
3
a
72%
50%
b
OH
O
O
OH
O
O
Cl
Cl
O
OtBu
(S)-4 (ee > 99%)
OtBu
O
O
O
(R)-4 (ee = 94%)
c
c
78%
78%
CH3
O
O
argentilactone [(R)-1]
goniothalamin [(R)-2]
O
O
Cl
Cl
Figure
(S)-5
(R)-5
Scheme 1 Reagents and Conditions: (a) recLBADH, cat. NADP+
(cat), i-PrOH, pH 5.5 buffer (b) Bakers yeast, XAD-7/H2O (c) i)
NaBH4, EtOH, 0 °C; ii) p-TsOH (cat), toluene, r.t.(14h), 120 °C (4h)
This important structural motif also occurs in other highly
active substances, e.g. callystatin A (cytotoxic),10
leptomycin B (antifungal),11 kazusamycin (cytotoxic),12
ratjadone (cytotoxic)13 and fostriecin (cytotoxic)14 and is
mostly introduced by a Wittig type reaction. To provide a
useful building block for natural product synthesis we
have developed an asymmetric synthesis of both enanti-
omers of -lactone equivalent 8 based on an enzymatic ap-
proach. Starting from 8 as key intermediate we obtained
Our first attempts to convert the chlorine from (S)-5 into
an acetoxy group with tetrabutyl ammonium acetate
(TBAA) and 1-methyl-2-pyrrolidinone (NMP)17 resulted
in decomposition. The observation of a carbon dioxide
elimination of a similar iodo lactone in a related reaction
published by Lichtenthaler et al.18 required us to protect
the lactone functionality with an acetal group. Therefore,
(S)-5 was reduced with DIBAL under standard conditions
and subsequent pyridinium p-toluenesulfonate (PPTS)-
catalyzed acetalization with iso-propanol provided the
protected lactol (S,S)-6 in good yield (Scheme 2). As by-
Synlett 2001, No. 11, 26 10 2001. Article Identifier:
1437-2096,E;2001,0,11,1796,1798,ftx,en;G13901ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Asymmetric Synthesis of S-(+)-Argentilactone and S-(–)-Goniothalamin
1797
product of the thermodynamically preferred -anomeric
product of 6 we obtained 5-8% of the corresponding -
anomeric compound.19 Due to the oxidation of the lactol
in a later step of the total synthesis, 6 can be used as mix-
ture of isomers although a separation via column chroma-
tography is possible. Treatment of lactone 6 with TBAA
led to (S,S)-7, which was easily saponified with potassium
carbonate in methanol giving rise to known (S,S)-820 as a
crystalline enantiopure substance in very good overall
yield.21 According to this protocol we obtained the enan-
tiomer (R,R)-8 in 54% overall yield starting from the chlo-
ro-substituted -lactone (R)-5 with ee = 94%.
OiPr
O
OiPr
a, b
c, d
O
CH3
O
CH3
CO2Et
O
88%
61%
CO2Et
OH
rac-8
rac-9
rac-10
e
O
CH3
+
rac-10 (55%)
O
CO2Et
rac-11 (11%)
Scheme 3 Reagents and Conditions: (a) (COCl)2, DMSO, 8,
EtNi-Pr2, CH2Cl2, –78 °C to r.t. (b) EtO2CC(CH3)=PPh3, CH2Cl2, 40
°C (c) PPTS, acetone–H2O, 3:1, r.t. (d) Ag2CO3/celite, benzene,
80°C (e) PCC, CH2Cl2, r.t.
O
OiPr
a
O
O
79%
Cl
Cl
(S,S)-6 (de = 85%, ee > 99%)
95%
(S)-5
For the synthesis of goniothalamin, (S,S)-8 was also oxi-
dized under Swern conditions and directly used in the
Wittig reaction to obtain (S,S)-14 in good yield
(Scheme 4). As we found in the synthesis of argentilac-
tone the lithium salt conditions led to Z-selectivity with
our substrate. Even the use of benzyl triphenylphosphoni-
um bromide in the presence of tert-butoxide provided 14
with the poor E/Z-ratio of 1:4. Therefore, we chose the
more E-selective conditions with benzyl tributylphospho-
nium bromide and tert-butoxide first introduced by Crim-
mins et al.20 in his total synthesis of callystatin A. These
conditions at 0 °C gave an E/Z-ratio of 3:1. Even lowering
the temperature to –30 °C had no effect on the E/Z-ratio.24
73%
b
OiPr
OiPr
O
O
c
OH
OAc
97%
(S,S)-8
(S,S)-7
Scheme 2 Reagents and Conditions: (a) i) DIBAL, CH2Cl2, –78 °C;
ii) i-PrOH, PPTS, C6H6, 80 °C (b) TBAA, NMP, 85 °C (c) K2CO3,
MeOH, r.t.
To find the appropriate conditions for the later oxidation
step we first investigated a model system. Swern oxida-
tion of rac-8, which was also obtained according to the
above described procedure provided the corresponding al-
dehyde (Scheme 3). The reaction of the latter with a stabi-
lized ylide in refluxing dichloromethane gave rise to the
racemic model compound 9. The acetal cleavage of 9 with
PPTS in acetone/water gave the free lactol, which was ox-
idized by silver carbonate on celite® in refluxing benzene
to provide the desired product 10 in 61% yield. In compar-
ison, we ran a single step oxidation with pyridinium chlo-
rochromate (PCC) in dichloromethane at room
temperature to give desired 10 in 55% yield and addition-
ally 11% of the interesting by-product 11. These kind of
compounds are usually generated in a hetero Diels-Alder
reaction employing Danishefsky’s diene on an aldehyde.22
OiPr
O
OiPr
d
a, b
O
O
O
77%
OH
4 CH3
4 CH3
(S,S)-8
a, c
(S,S)-12
(S)-1
81%
+
OiPr
O
O
O
4 CH3
Ph
(S)-13
(S,S)-14
d
According to these results we decided to run the single
step procedure with our compounds.
O
O
O
+
O
O
O
Swern oxidation of (S,S)-8 and subsequent Wittig reaction
with hexyl triphenylphosphonium bromide in the pres-
ence of n-butyllithium gave rise to (S,S)-12 (Scheme 4).
Only the Z-olefin was observed as expected for this reac-
tion type.7c,9a PCC-oxidation of 12 led to the title argenti-
lactone (1) in 52% yield, while by-product (S)-13 was
isolated in 12% yield. The absolute configuration of (S)-1
is based on the comparison of the rotation value which
was in good correspondence to the literature.23
+
+
O
O
Ph
Ph
Ph
Ph
(S)-2
(S)-15
(S)-16
(S)-17
Scheme 4 Reagents and Conditions: (a) (COCl)2, DMSO, 8,
EtNi-Pr2, CH2Cl2, –78 °C to r.t. (b) C6H13PPh3Br, nBuLi, THF, 0 °C,
then aldehyde (c) PhCH2Br, Bu3P, MeCN, r.t., then aldehyde in tolue-
ne, t-BuOK, 0 °C, E/Z = 3:1. (d) PCC, CH2Cl2, r.t. 52% (1), 12% (13),
41% (2), 29% (15 +16), 3% (17).
Synlett 2001, No. 11, 1796–1798 ISSN 0936-5214 © Thieme Stuttgart · New York

1798
A. Job et al.
LETTER
(12) Isolation: Umezawa, I.; Komiyama, K.; Oka, H.; Okada, K.;
Tomisaka, S.; Miyano, T.; Takano, S. J. Antibiotics 1984,
37, 706.
Therefore PCC-oxidation in the next step provided 4
products. We isolated enantiopure goniothalamin (2) in
41% yield and the absolute configuration was established
by polarimetry.25 Additionally, we isolated (S)-17 in 3%
yield and a mixture of (S)-15 and (S)-16 (15/16 = 1.4:1) in
29% yield.
(13) (a) Isolation: Schummer, D.; Gerth, K.; Reichenbach, H.;
Höfle, G. Liebigs Ann. 1995, 685. (b) First synthesis:
Christmann, M.; Bhatt, U.; Quitschalle, M.; Claus, E.;
Kalesse, M. Angew. Chem. Int. Ed. 2000, 39, 4364.
(14) (a) Isolation: Tunac, J. B.; Graham, B. D.; Dobson, W. E. J.
Antibiotics 1983, 36, 1595. (b) Also see: Stampwala, S. S.;
Bunge, R. H.; Hurley, T. R.; Willmer, N. E.; Brankiewicz, A.
J.; Steinman, C. E.; Smitka, T. A.; French, J. C. J. Antibiotics
1983, 36, 1601. (c) First synthesis: Boger, D. L.; Ichikawa,
S.; Zhong, W. J. Am. Chem. Soc. 2001, 123, 4161.
(15) Wolberg, M.; Hummel, W.; Wandrey, C.; Müller, M.
Angew. Chem. Int. Ed. 2000, 39, 4306.
(16) Wolberg, M.; Hummel, W.; Müller, M. Chem. Eur. J. 2001,
7, 4562.
(17) Thottathil, J. K.; Pendri, Y.; Li, W.-S.; Kronenthal, D. R. US
Patent, 5278313A, 1994. Chem. Abstr. 1994, 120, 217700j.
(18) Lichtenthaler, F. W.; Lorenz, K.; Ma, W.-Y. Tetrahedron
Lett. 1987, 28, 47.
In conclusion, we have developed an efficient asymmetric
synthesis of the important -lactone equivalent 8 for natu-
ral product synthesis. The utility of 8 was demonstrated by
the total synthesis of virtually enantiopure (S)-argentilac-
tone and (S)-goniothalamin.
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 380, GK 440). We are grateful to Degussa AG, BASF AG,
Bayer AG and Aventis for the donation of chemicals.
(19) Both structures were assigned by NOE-experiments.
(20) Crimmins, M. T.; King, B. W. J. Am. Chem. Soc. 1998, 120,
9084.
(21) We obtained for the pure -anomeric compound: [ ]D –40.5
(c 0.75, CHCl3), mp 45–46 °C [Ref. 21: [ ]D +40.4 (c 0.47,
CH2Cl2) for the enantiomer]. All other data were in good
agreement with the literature.
References and Notes
(1) Priestap, H. A.; Bonafede, J. D.; Rúveda, E. A.
Phytochemistry 1977, 16, 1579.
(2) Waechter, A. I.; Ferreira, M. E.; Fournet, A.; Rojas de Arias,
A.; Nakayama, H.; Torres, S.; Hocquemiller, R.; Cave, A.
Planta Medica 1997, 63 , 433.
(3) Matsuda, M.; Endo, Y.; Fushiya, S.; Endo, T.; Nozoe, S.
Heterocycles 1994, 38, 1229.
(4) Hlubucek, J. R.; Robertson, A. V. Aust. J. Chem. 1967, 20,
2199.
(22) (a) Danishefsky, S. J.; Larson, E.; Askin, D.; Kato, N. J. Am.
Chem. Soc. 1985, 107, 1246. (b) Aikawa, K.; Irie, R.;
Katsuki, T. Tetrahedron 2001, 57, 845.
(23) Spectroscopic data for (S)-1: [ ]D +19.4 (c 0.5, EtOH), [Ref.
1: [ ]D –21.1 (c 2.3, EtOH) for isolated (R)-1; Ref. 7b:
[ ]D –19.1 (c 1.0, EtOH) for synthetic (R)-1]. 1H NMR
(300 MHz, CDCl3): (ppm) = 0.90 (t, J = 7.0 Hz, 3 H, CH3),
1.24–1.44 (m, 6 H, 3 CH2), 2.10 (m, 2 H, CH2), 2.40 (m,
2 H, pyran-CH2), 5.24 (ddd, J = 10.2, 8.5, 4.9 Hz, 1 H,
CHOR), 5.57 (dddd, J = 11.0, 8.5, 1.4, 1.1 Hz, 1 H, CH),
5.68 (dtd, J = 11.0, 7.4, 0.6 Hz, 1 H, CH), 6.06 (ddd, J = 9.9,
2.5, 1.4 Hz, 1 H, pyran-CH), 6.91 (ddd, J = 9.9, 5.3, 3.1 Hz,
1 H, pyran-CH). 13C NMR (75 MHz, CDCl3):
(5) Sam, T. W.; Sew-Yeu, C.; Matsjeh, S.; Gan, E. K.; Razak,
D.; Mohamed, A. L. Tetrahedron Lett. 1987, 28, 2541.
(6) (a) Goh, S. H. Pure Appl. Chem. 1998, 70, 2133. (b) Inayat-
Hussain, S. H.; Osman, A. B.; Din, L. B.; Ali, A. M.;
Snowden, R. T.; MacFarlane, M.; Cain, K. FEBS Letters
1999, 456, 379.
(7) For example see: (a) O' Connor, B.; Just, G. Tetrahedron
Lett. 1986, 27, 5201. (b) Carretero, J. C.; Ghosez, L.
Tetrahedron Lett. 1988, 29, 2059. (c) Tsubuki, M.; Kanai,
K.; Honda, T. Heterocycles 1993, 35, 281.
(ppm)= 14.01 (CH3), 22.48 (CH2), 27.78 (CH2), 29.05
(CH2), 29.91 (CH2), 31.39 (CH2), 73.91 (CHOR), 121.56
(pyran-CH), 126.36 (CH), 135.69 (CH), 144.92 (pyran-CH),
164.26 (C=O). IR (neat): max=1723 (C=O), 1244 cm–1. MS
(EI): m/z (%) = 194.1 (M+, 6). HRMS (C12H18O2): calcd.:
194.1307; found: 194.1303.
(d) Ramachandran, P. V.; Reddy, M. V. R.; Brown, H. C. J.
Ind. Chem. Soc. 1999, 76, 739.
(8) For example see: (a) Meyer, H. H. Liebigs Ann. Chem. 1979,
484. (b) Ramachandran, P. V.; Reddy, M. V. R.; Brown, H.
C. Tetrahedron Lett. 2000, 41, 583. (c) Quitschalle, M.;
Christmann, M.; Bhatt, U.; Kalesse, M. Tetrahedron Lett.
2001, 42, 1263.
(24) The same reaction was published by Kalesse et al. (see Ref.
8c), the E/Z-ratio was not given.
(9) (a) ent-Argentilactone: Saeed, M.; Abbas, M.; Khan, K. M.;
Voelter, W. Z. Naturforsch. 2001, 56b, 325. (b) ent-
Goniothalamin: Takano, S.; Kamikubo, T.; Sugihara, T.;
Ogasawara, K. Tetrahedron: Asymmetry 1992, 3, 853.
(c) Also see: Henkel, B.; Kunath, A.; Schick, H. Liebigs Ann.
Chem. 1992, 809.
(10) (a) Isolation: Kobayashi, M.; Higuchi, K.; Murakami, N.;
Tajima, H.; Aoki, S. Tetrahedron Lett. 1997, 38, 2859.
(b) First synthesis: Murakami, N.; Wang, W.; Aoki, M.;
Tsutsui, Y.; Sugimoto, M.; Kobayashi, M. Tetrahedron Lett.
1998, 39, 2349.
(25) Spectroscopic data for (S)-2: [ ]D –178.5 (c 0.2, CHCl3),
[Ref. 5: [ ]D +178.5 (c 2.0, CHCl3) for isolated (R)-2].
mp 79–80 °C. 1H NMR (400 MHz, CDCl3): (ppm)= 2.55
(m, 2 H, CH2), 5.11 (m, 1 H, CHOR), 6.10 (ddd, J = 9.9, 1.9,
1.7 Hz, 1 H, pyran-CH), 6.28 (dd, J = 15.9, 6.3 Hz, 1 H, CH),
6.73 (d, J = 15.9 Hz, 1 H, CH), 6.93 (ddd, J = 9.9, 4.4, 3.8
Hz, 1 H, pyran-CH), 7.26–7.42 (m, 5 H, Ph-H). 13C NMR
(100 MHz, CDCl3): (ppm)= 29.86 (CH2), 77.83 (CHOR),
121.54 (pyran-CH), 125.45, 126.52 (C-Ph), 128.18 (CH),
128.51 (C-Ph), 132.94 (CH), 135.56 (C-ipso), 144.37
(pyran-CH), 163.62 (C=O). IR (KBr): max=1717 (C=O),
1384, 1240, 1054, 1023, 833, 781, 701 cm–1. MS (EI): m/z
(%) = 200.1 (M+, 54). HRMS (C13H12O2): calcd.: 200.0837;
found: 200.0837.
(11) (a) Isolation: Hamamoto, T.; Gunji, S.; Tsuji, H.; Beppu, T.
J. Antibiotics 1983, 36, 639. (b) First synthesis: Kobayashi,
M.; Wang, W.; Tsutsui, Y.; Sugimoto, M.; Murakami, N.
Tetrahedron Lett. 1998, 39, 8291.
Synlett 2001, No. 11, 1796–1798 ISSN 0936-5214 © Thieme Stuttgart · New York