Total synthesis of (+)-strictifolione.

Article abstract of DOI:10.1021/ol034619s

[reaction: see text] The synthesis of (+)-strictifolione was achieved from 3-phenylproprionaldehyde by using enantioselective allyltitanations to control the stereogenic centers at C6, C4', and C6' and a cross-methathesis to control the configuration of t

Full text of DOI:10.1021/ol034619s

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1995-1997
Total Synthesis of (+)-Strictifolione
Samir BouzBouz and Janine Cossy*
Laboratoire de Chimie Organique Associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 Paris, Cedex 05, France
janine.cossy@espci.fr
Received April 10, 2003
ABSTRACT
The synthesis of (+)-strictifolione was achieved from 3-phenylproprionaldehyde by using enantioselective allyltitanations to control the stereogenic
centers at C6, C4′, and C6′ and a cross-methathesis to control the configuration of the double bond at C1′−C2′.
Recently, a number of 5,6-dihydro-R-pyrone derivatives
having an alkyl side chain at the C6 position, with 1,3- or
1,5-diol units, have been isolated from plants. The biological
activities of these compounds have not been completely
studied, but it seems that the activity depends on the
substituents on the alkyl side chain. Some of these com-
pounds have been found to exhibit antifungal activity such
as passifloricin A,1 to inhibit the cell cycle progression in
the M-phase and to be an immunosuppressive agent such as
(-)-pironetin,2 to exhibit cytotoxic activity such as callystatin
A3 and leptomycin B,4 or to be an anticancer agent such as
fostriecin5 (Figure 1). In the course of our program to
synthesize 6-substituted 5,6-dihydro-R-pyrones, we became
interested in the synthesis of (+)-strictifolione.
(1) Echeverri, F.; Arango, V.; Quin˜ones, W.; Torres, F.; Escobar, G.;
Rosero, Y.; Archbold, R. Phytochemistry 2001, 56, 88.
(2) (a) Kobayashi, S.; Tsuchiya, K.; Harada, T.; Nishide, M.; Kurokawa,
T.; Nakagawa, T.; Shimada, N.; Kobayashi, K. J. Antibiot. 1994, 47, 697.
(b) Kobayashi, S.; Tsuchiya, K.; Kurokawa, T.; Nakagawa, T.; Shimada,
N.; Iitaka, Y. J. Antibiot. 1994, 47, 703. (c) Tsuchiya, K.; Kobayashi, S.;
Harada, T.; Nishikiori, T.; Nakagawa, T.; Tatsuta, K. J. Antibiot. 1997, 50,
259.
(3) (a) Kobayashi, M.; Higuchi, K.; Murakami, N.; Tajima, H.; Aoki,
S.; Tetrahedron Lett. 1997, 38, 2859. (b) Murakami, N.; Wang, W.; Aoki,
S.; Kobayashi, M. Tetrahedron Lett. 1997, 38, 5533.
Figure 1.
(4) (a) Hamamoto, T.; Seto, H.; Beppu, T. J. Antibiot. 1983, 36, 646.
(b) Yoshida, M.; Nishikawa, M.; Nishi, K.; Abe, K.; Horinouchi, S.; Beppu,
T.; Shimada, N.; Kobayashi, K. Exp. Cell. Res. 1990, 187, 150.
(+)-Strictifolione was isolated from Cryptocaria strictifolia
and has shown to display antifungal activity.6 Its structure
(5) (a) Hokanson, G. C.; French, J. C. J. Org. Chem. 1985, 50, 462. (b)
Scheithauer, W.; Von Hoff, D. D.; Clark, G. M.; Shillis, J. L.; Elslager, E.
F. Eur. J. Cancer Clin. Oncol. 1986, 22, 921. (c) Fry, D. W.; Boritzki, T.
J.; Jackson, R. C. Cancer Chemother. Pharmacol. 1984, 13, 171. (d)
Leopold, W. R.; Shillis, J. L.; Mertus, A. E.; Nelson, J. M.; Roberts, B. J.;
Jackson, R. C. Cancer Res. 1984, 44, 1928.
1
was elucidated from the H NMR spectra of an acetonide
(6) Juliawaty, L. D.; Kitajima, M.; Takayama, H.; Achmad, S. A.; Aimi,
N. Phytochemistry 2000, 54, 989-993.
10.1021/ol034619s CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/06/2003

Scheme 1. Retrosynthetic Analysis of (+)-Strictifolione and Structure of the Titanium Complexes and Ruthenium Catalysts
Scheme 2. Total Synthesis of (+)-Strictifolionea
a Conditions: (a) (S,S)-I, ether, -78 °C, 4 h, 83%. (b) (1) OsO4, NMO, acetone/H2O, NaIO4, 25 °C; (2) (R,R)-I, ether, -78 °C, 4 h, 76%
for the two steps. (c) DMP/acetone, CSA, 25 °C, 95%. (d) acrolein, catalyst H (5 mol%), CH2Cl2, 25 °C, 70%. (e) (S,S)-I, ether, -78 °C,
4 h, 84%. (f) acryloyl chloride, iPr2NEt, CH2Cl2, -78 °C, 92%. (g) Catalyst G (5 mol%), refluxing CH2Cl2, 82%. (h) 1 N HCl, MeOH, 40
°C, 87%.
derivative. The (S)-absolute configuration of the stereo-
genic centers at C4′ and C6′ was established by the Mosher
method. The (R)-absolute configuration at C6 was assumed
on the basis of the Cotton effect in the CD spectrum and
confirmed by the synthesis of the two isomers at C6 with
the (R)- and (S)-configurations. The first total synthesis of
(+)-strictifolione was achieved from (S)-malic acid in 18
steps.7
Due to a recent report on a catalytic asymmetric approach
to (+)-strictifolione,8 we would like to disclose our short
total synthesis of (+)-strictifolione from the commercially
available 3-phenylpropionaldehyde by using three enantio-
selective allyltitanations to control the stereogenic centers,
a cross-metathesis reaction to introduce the (E)- double bond
at C1′-C2′,9 and a ring-closing metathesis reaction to build
up the lactone ring. The retrosynthetic scheme is summarized
in Scheme 1.
When 3-phenylpropionaldehyde 1 was treated with the
allyltitanium complex (S,S)-I according to the reported
procedure,10 homoallylic alcohol 2 was obtained in 83% yield
with an enantiomeric excess greater than 95%.11 After the
oxidative cleavage of the olefin (OsO4/NMO, NaIO4), the
obtained aldehyde was treated directly with the allyltitanium
(9) Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. Organomet. Chem. 2001,
624, 327.
(10) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, J.; Rothe-Streit, P.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321.
(11) BouzBouz, S.; Cossy, J. Tetrahedron Lett. 2000, 41, 3363.
(7) Juliawaty, L. D.; Watanabe, Y.; Kitajima, M.; Achmad, S. A.;
Takayama, H.; Aimi, N. Tetrahedron Lett. 2002, 43, 8657.
(8) Tosaki, S.; Nemoto, T.; Ohshima, T.; Shibasaki, M. Org. Lett. 2003,
5, 495.
1996
Org. Lett., Vol. 5, No. 11, 2003

complex (R,R)- I at -78 °C (Scheme 1) and transformed to
1,3-diol 3 with an overall yield of 76% for the two steps12
(Scheme 2). The anti relative stereochemistry of the 1,3-
diol 3 was established by its conversion to the corresponding
acetonide 4 (CSA, acetone, dimethoxypropane, 25 °C, 20
min, 95% yield, dr > 95/5). The anti relative configuration
of the hydroxy groups was confirmed by the analysis of the
13C NMR spectra (δ ) 24.79 and 24.77 ppm for the methyl
groups and 100.18 ppm for the quaternary center).13
As we have shown recently that (E)-hexa-1,5-dien-3-ols
can be obtained very easily from homoallylic alcohols by
using a cross-metathesis reaction followed by an enantiose-
lective allyltitanation, we used this methodology to control
the (E)-double bond at C1′-C2′ and the C6 stereogenic
center of (+)-strictifolione. The treatment of a mixture of 4
and acrolein (3 equiv) with Hoveyda’s catalyst H (5 mol%)
(Scheme 1), in refluxing methylene chloride, afforded the
unsaturated aldehyde 5 in 70% yield with an E/Z ratio
superior to 30/1. Aldehyde 5 was transformed to the desired
homoallylic alcohol 6 in 84% yield by using the allyltitanium
complex (S,S)-I (Scheme 1). The (R)-absolute configuration
of the newly formed stereogenic center was assigned by using
Trost’s madelic ester method.14
The construction of the lactone was achieved in two steps
from the allylic alcohol 6, which was converted into the
unsaturated ester 7 in 92% yield by treatment with acryloyl
chloride (iPr2NEt, CH2Cl2, -78 °C) followed by a ring-
closing metathesis reaction induced by Grubbs’ catalyst G15
(Scheme 1) that led to lactone 8 in 82% yield. This lactone
was subjected to deprotection (MeOH, 1 N HCl, 40 °C) pro-
ducing (+)-strictifolione in 87% yield, the spectroscopic data
1
of which were identical (IR, MS, and H and 13C NMR) to
those of the natural one. The synthesis of (+)-strictifolione
was accomplished in nine steps with an overall yield of 23%
(Scheme 2).
Supporting Information Available: Spectroscopic data
for compounds 5 and 7 and the spectrum of (+)-strictifolione.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL034619S
(13) Rychnovsky, S. D.; Rogers, B. N.; Richardson, R. I. Acc. Chem.
Res. 1998, 31, 9.
(14) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S.
L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370.
(12) BouzBouz, S.; Cossy, J. Org. Lett. 2000, 2, 501.
(15) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
Org. Lett., Vol. 5, No. 11, 2003
1997