Total syntheses of (R)-argentilactone and (R)-goniothalamin via catalytic enantioselective allylation of aldehydes

Article abstract of DOI:10.1016/j.tetlet.2003.09.122

The total syntheses of (R)-argentilactone (five steps, 25% overall yield) and (R)-goniothalamin (three steps, 61% overall yield) have been described through the enantioselective catalytic allylation of aldehydes (including a propargylic aldehyde) which provided a rapid access to these natural products that display very interesting biological activities.

Full text of DOI:10.1016/j.tetlet.2003.09.122

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8721–8724
Total syntheses of (R)-argentilactone and (R)-goniothalamin via
catalytic enantioselective allylation of aldehydes
.
Angelo de Fa´tima and Ronaldo Aloise Pilli*
Instituto de Qu´ımica, UNICAMP, CP 6154, 13083-970, Campinas, SP, Brazil
Received 28 July 2003; revised 12 September 2003; accepted 15 September 2003
Abstract—The total syntheses of (R)-argentilactone (five steps, 25% overall yield) and (R)-goniothalamin (three steps, 61% overall
yield) have been described through the enantioselective catalytic allylation of aldehydes (including a propargylic aldehyde) which
provided a rapid access to these natural products that display very interesting biological activities.
© 2003 Published by Elsevier Ltd.
In 1977, Ru´veda and co-workers reported the isolation
of argentilactone (1) from Aristolochia argentina (Aris-
tolochiaceae) (Fig. 1).1 This compound was also isolated
from Chorisia crispflora (Bombaceae)2 and Annona
haematantha (Annonaceae).3 Later, this natural pyra-
none was shown to have antileishmanial activity equiv-
alent to the reference drug N-methylglucamine
antimonate against Leishmania amazonensis,3 as well as
cytotoxic activity against mouse leukaemia cells (P-
388).2
pases-3 and 7.10 Deregulation of apoptosis has now been
implicated in the onset or progression of cancer.11
Consequently, apoptosis represents an innate cellular
defense against carcinogen-induced cellular damage by
removing and inhibiting survival and growth of altered
cells at different stages of carcinogenesis.
Both argentilactone (1) and goniothalamin (2) contain
the 5,6-dihydro-2H-pyran-2-one moiety and bear the
(R)-configuration in their natural form. This important
structural motif also occurs in other highly active sub-
stances, e.g. kurzilactone (cytotoxic),12 leptomycin B
(antifungal),13 ratjadone (cytotoxic),14 and strictifolione
(antifungal).15 Due to the interesting biological activity
displayed by argentilactone (1) and goniothalamin (2),
several successful approaches to these natural products
have been reported.16,17 The absolute configuration in
the pyran-2-one moiety has generally been secured from
chiral starting material or through asymmetric reduc-
tion using enzymes or microorganisms.16,17 A notewor-
thy exception is the asymmetric allylboration of
aldehydes with B-allyldiisopinocampheylborane devel-
oped by Brown and co-workers.18 While high levels of
enantiomeric excess and yield are generally achieved,
the use of a stoichiometric amount of the chiral allylbo-
rane is not the more efficient solution for the transfer of
chirality and catalytic asymmetric protocols are cer-
tainly a more attractive alternative to chiral non-racemic
6-substituted 5,6-dihydro-2H-pyran-2-ones.19
Goniothalamin (2) was isolated in 1967 from the dried
bark of Cryptocarya caloneura (Fig. 1).4 Later it was
isolated from Cryptocarya moschata,5 Bryonopsis
laciniosa6 and various species of Goniothalamus.7 It is a
potential cytotoxic compound that has been demon-
strated to have antiproliferative activities in a number of
transformed cell lines including MCF-7 (breast car-
cinoma) and HeLa cells (human cervical carcinoma).8,9
Recent studies have indicated that goniothalamin
induces apoptosis in JurKat T-cells through activation
of two members of the cysteine proteases family, cas-
Figure 1. Structures of (R)-argentilactone (1) and (R)-gonio-
thalamin (2).
As one of the fundamental and powerful CꢀC bond-
forming reactions, catalytic enantioselective allylation of
aldehydes attracted considerable attention in asymmet-
ric synthesis.20 Particularly, Maruoka and co-workers
have developed a new class of highly reactive and
Keywords: (R)-argentilactone; (R)-goniothalamin; catalytic asymmet-
ric allylation.
* Corresponding author. E-mail: pilli@iqm.unicamp.br
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.09.122

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A. de Fa´tima, R. A. Pilli / Tetrahedron Letters 44 (2003) 8721–8724
8722
reported.20 In the event, the enantioselective addition of
allyltributyltin propargylic aldehyde 4 under the influ-
ence of in situ generated chiral (R,R)-A complex
(CH2Cl2, −20°C for 24 h), afforded 5 in 89% yield and
86% ee. Enantiomeric excess was determined by chiral
GC (column Chirasil-DEX CB) after conversion of
propargylic alcohol 5 to (Z)-allylic alcohol 6 [Lindlar
catalyst, quinoline, EtOAc:1-octene (1:1, v/v), H2 (1
atm), 30 min, rt] in 74% yield.23 Ring-closing
metathesis24 of 7, prepared in 86% yield from homoal-
lylic alcohol 6 and acryloyl chloride, with 10 mol% of
Grubbs’ catalyst in refluxing CH2Cl2 for 6 h (70% yield)
provided argentilactone (1)25 in 25% overall yield from
3 (Scheme 1).
Figure 2. The m-oxo bis(binaphthoxy)(isopropoxy)titanium
complexes (S,S)-A developed by Maruoka and co-workers.
selective titanium complexes for the allylation of alde-
hydes.21,22 The m-oxo bis(binaphthoxy)(isopropoxy)-
titanium complex (S,S)-A (Fig. 2), which display excel-
lent enantioselectivity for the addition of allyltributyltin
to aldehydes, including cinnamaldehyde.22 The
efficiency of this catalyst is proposed to be due to
simultaneous coordination and double activation ability
of the bidentate Ti(IV) catalyst (S,S)-A.
The above methodology proved also to be of value in
the total syntheses of goniothalamin (2). Catalytic
asymmetric allylation of trans-cinnamaldehyde (8) with
allyltributyltin, under the influence of chiral (R,R)-A
complex (CH2Cl2, −20°C, 24 h) afforded 9 in 78% yield
and 96% ee. Enantiomeric excess was determined by
chiral GC (column Chirasil-DEX CB) after conversion
of allylic alcohol 9 to acrylate 10 (acryloyl chloride,
Et3N, cat. DMAP in CH2Cl2 at −23°C) in 80% yield.
When compared to other catalytic asymmetric allyla-
tion protocols, the one developed by Maruoka and
co-workers provided higher level of enantioselection in
the addition of allyltributyltin to trans-cinnamaldehyde.
In this work, we describe the total synthesis of argenti-
lactone (1) and goniothamin (2) from 1-heptyne and
trans-cinnamaldehyde respectively, featuring enantiose-
lective Maruoka allylation22 and ring-closing metathesis
as the key steps.
Our approach to argentilactone (1) centered around the
catalytic asymmetric allylation of propargylic aldehyde
4, prepared in 65% yield from 1-heptyne (treatment
with n-BuLi, followed by reaction with DMF). Despite
the recent developments in the catalytic asymmetric
allylation catalyzed by chiral Lewis acids, no successful
example with propargylic aldehydes has yet been
Ring-closing metathesis24 of 10 with 10 mol% Grubbs’
catalyst in refluxing CH2Cl2 for 12 h (98% yield) fur-
nished goniothalamin (2)26 in 61% overall yield from
cinnamaldehyde (Scheme 2).
Scheme 1. Total synthesis of (R)-argentilactone (1). Reagents and conditions: (a) n-BuLi (1.5 M in hexane, 1.2 equiv.), Me2NCHO
(2.0 equiv.), THF −78 to 0°C (65%); (b) (R)-BINOL (10 mol%), Ti(OiPr)4 (15 mol%), TiCl4 (5 mol%), Ag2O (10 mol%),
allyltributyltin (1.1. equiv.), CH2Cl2, −20°C, 24 h (89%; 86% ee); (c) Lindlar catalyst (10 mol%), quinoline (2.0 equiv.),
EtOAc:1-octene (1:1) (74%); (d) acryloyl chloride (1.8 equiv.), Et3N (3.6 equiv.), CH2Cl2, 0°C (86%); (e) Grubbs’ catalyst
[(Pcy3)2Cl2RuꢁCHPh] (10 mol%), CH2Cl2 (70%).
Scheme 2. Total synthesis of (R)-goniothalamin (2). Reagents and conditions: (a) (R)-BINOL (10 mol%), Ti(OiPr)4 (15 mol%),
TiCl4 (5 mol%), Ag2O (10 mol%), allyltributyltin (1.1. equiv.), CH2Cl2, −20°C, 24 h (78%; 96% ee); (b) acryloyl chloride (1.8
equiv.), Et3N (3.6 equiv.), CH2Cl2, 0°C (80%); (c) Grubbs’ catalyst [(Pcy3)2Cl2RuꢁCHPh] (10 mol%), CH2Cl2 (98%).

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A. de Fa´tima, R. A. Pilli / Tetrahedron Letters 44 (2003) 8721–8724
8723
In this work, we carried out the total syntheses of
(R)-argentilactone (1) in five steps and 25% yield from
1-heptyne and (R)-goniothalamin (2) in three steps and
61% overall yield from trans-cinnamaldehyde. This
concise and efficient approach compares favorably with
the more efficient approaches so far reported in the
literature for these natural products16a,17a and illustrates
the utility of the asymmetric catalytic allylation proto-
col developed by Maruoka and co-workers to provide
rapid access to chiral 6-substituted pyran-2-ones. The
extension of the methodology described herein to syn-
thesis of other natural pyranones is underway in our
laboratory.
12. Fu, X.; Sevenet, T.; Hamid, A.; Hadi, A.; Remy, F.; Pais,
M. Phytochemistry 1993, 33, 1272–1274.
13. Hamamoto, T.; Gunji, S.; Tsuji, H.; Beppu, T. J.
Antibiot. 1983, 36, 639–645.
14. Schummer, D.; Gerth, K.; Reichenbach, H.; Ho¨fle, G.
Liebigs Ann. 1995, 4, 685–688.
15. Juliawaty, L. D.; Kitajima, M.; Takayama, H.; Achmad,
S. A.; Aimi, N. Phytochemistry 2000, 54, 989–993.
16. For more recently synthesis of (R)-argentilactone, see: (a)
Ramachandran, P. V.; Reddy, M. V. R.; Brown, H. C. J.
Ind. Chem. Soc. 1999, 76, 739–742; (b) Saeed, M.; Ilg, T.;
Schick, M.; Abbas, M.; Voelter, W. Tetrahedron Lett.
2001, 42, 7401–7403; (c) Hansen, T. V. Tetrahedron:
Asymmetry 2002, 13, 547–550. For other synthesis of
(R)-argentilactone from chiral starting material or
through asymmetric reduction using enzymes or microor-
ganisms, see: (d) O’Connor, B.; Just, G. Tetrahedron Lett.
1986, 27, 5201–5202; (e) Rahman, S. S.; Wakefield, B. J.;
Roberts, S. M.; Dowle, M. D. J. Chem. Soc., Chem.
Commun. 1989, 303–304; (f) Carretero, J. C.; Ghosez, L.
Tetrahedron Lett. 1988, 29, 2059–2062.
17. For more recently synthesis of (R)-goniothalamin, see:
(a) Ramachandran, P. V.; Reddy, M. V. R.; Brown, H.
C. Tetrahedron Lett. 2000, 41, 583–586; (b) Peng, X. S.;
Li, A. P.; Shen, H.; Wu, T. X.; Pan, X. F. J. Chem. Res.
2002, 7, 330–332; (c) Tsubuki, M.; Honda, T. Heterocy-
cles 1993, 35, 281–288; (d) Fa´tima, A.; Pilli, R. A.
Arkivoc. 2003, 10, 118–126. For other synthesis of (R)-
goniothalamin from chiral starting material or through
asymmetric reduction using enzymes or microorganisms,
see: (e) Bennett, F.; Knight, D. W. Tetrahedron Lett.
1988, 29, 4625–4628; (f) Fuganti, C.; Pedrocchi-Fantoni,
G.; Sarra, A.; Servi, S. Tetrahedron: Asymmetry 1994, 5,
1135–1138; (g) Henkel, B.; Kunath, A. Schick, H. Liebigs
Ann. Chem. 1992, 809–811; (h) Bennett, F.; Knight, D.
W.; Fenton, G. J. Chem. Soc., Perkin. Trans. 1 1991,
519–523.
Acknowledgements
The authors would like to thank FAPESP (Fundac¸a˜o
de Amparo a Pesquisa no Estado de Sa˜o Paulo) for
financial support and fellowships (A.F.) and CNPq
(Conselho Nacional de Desenvolvimento Cient´ıfico e
Tecnolo´gico) for fellowship (R.A.P.).
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25. Representative analytical data for (R)-argentilactone: IR
(film): 3020, 2956, 2927, 2858, 1722, 1466, 1381, 1244,
1149, 1055, 1022, 816 cm−1; 1H NMR (300 MHz, CDCl3):
l 6.90 (ddd, 1H, J=9.7, 5.5, 3.1 Hz), 6.05 (ddd, 1H,
J=9.7, 2.2 and 1.4 Hz), 5.71–5.52 (m, 2H), 5.22 (ddd,
1H, J=10.2, 8.4 and 4.9 Hz), 2.49–2.30 (m, 2H), 2.17–
2.03 (m, 2H), 1.46–1.26 (m, 6H), 0.90 (t, 3H, J=7.0 Hz);
13C NMR (125 MHz, CDCl3): l 163.9, 144.6, 135.5,
126.3, 121.5, 73.9, 31.5, 29.9, 29.1, 27.8, 22.5, 14.1. [h]D=
−22 (c 2.2, EtOH), {lit.,4 [h]D=−21.1 (c 2.3, EtOH)}.
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CIIT Act. 1995, 15, 1–10.

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A. de Fa´tima, R. A. Pilli / Tetrahedron Letters 44 (2003) 8721–8724
8724
Hz), 6.08 (d, 1H, J=9.5 Hz), 5.10 (q, 1H, J=6.9 Hz),
2.56–2.52 (m, 2H); 13C NMR (75 MHz, CDCl3): l 163.6,
144.5, 135.5, 132.8, 128.5, 128.1, 126.5, 125.5, 121.4, 77.8,
29.8. [h]D=+164 (c 1.7, CHCl3), {lit.,7c [h]D=+170.3 (c
1.38, CHCl3)}.
26. Representative analytical data for (R)-goniothalamin: mp
81–82°C, {lit.,7c mp 85°C}; IR (film): 3055, 3024, 2924,
1
1720, 1246, 814, 698 cm−1; H NMR (300 MHz, CDCl3):
l 7.41–7.25 (m, 5H), 6.92 (dt, 1H, J=9.5 and 4.0 Hz),
6.72 (d, 1H, J=15.9 Hz), 6.27 (dd, 1H, J=15.9 and 6.2