A novel entry to naturally occurring 5-alkenyl α,β-unsaturated δ-lactones from D-glucose: Syntheses of (+)-acetylphomalactone and (+)-asperlin

Article abstract of DOI:10.1039/a703561f

A bicyclic pyranosidic glycoside 6, readily obtained from D-glucose, has been used as the key intermediate in enantioselective syntheses of (+)-acetylphomalactone and (+)-asperlin, in which the configuration at C-5 corresponds to that of the hexopyranosides in the L-sugar series.

Full text of DOI:10.1039/a703561f

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A novel entry to naturally occurring 5-alkenyl a,b-unsaturated d-lactones from
d-glucose: syntheses of (+)-acetylphomalactone and (+)-asperlin
Ana M. Go´mez,* Beatriz Lo´pez de Uralde, Seraf´ın Valverde and J. Cristo´bal Lo´pez*†
Instituto de Qu´ımica Orga´nica General (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
HO
A bicyclic pyranosidic glycoside 6, readily obtained from
microwave
irradiation
EtO2C
O
O
D-glucose, has been used as the key intermediate in
enantioselective syntheses of (+)-acetylphomalactone and
(+)-asperlin, in which the configuration at C-5 corresponds
to that of the hexopyranosides in the L-sugar series.
'one pot'
ref. 9
OEt
HO
6
HO
OEt
silica gel
73%
8
7
Scheme 2
Naturally occurring 5-substituted a,b-unsaturated d-lactones,
e.g. 1–4, represent an important class of products with a diverse
range of biological activity.1 They have been reported to be
plant growth inhibitors, insect antifeedants and antifungal and
antitumour agents.1 They are widely distributed and have been
isolated from both plants and fungi. Acetylphomalactone 12 and
asperlin 23 are prominent members of this family. (+)-Acetyl-
phomalactone 1 is an antimicrobial metabolite isolated from
Aspergillus caespitous,2 and (+)-Asperlin 2 was isolated from
Aspergillus nidulans and possesses antitumour and antibacterial
activity.3 Among the more relevant structural characteristics of
this family are: (i) the absolute configuration at C-5, and (ii) the
Additionally, the feasibility of this approach greatly benefits
from the facile preparation of 6 from readily available Ferrier’s
diol 78 (Scheme 2). Thus, compound 7 is efficiently trans-
formed, via a one pot operation, into hydroxy ester 8,9 and
microwave-induced lactonization of the latter on silica gel gives
rise to glycoside lactone 6 in fairly good yield (73%).§ The
glycosidic moiety on 6 can be unravelled under acid catalysis in
the presence of ethanedithiol to furnish a ca. 2:1 mixture of
5-alquenil lactones (E)-9 and (Z)-9, which upon further
treatment leads to (E)-9 as a single isomer (83% overall)
(Scheme 3). At this stage, direct desulfurization of (E)-9 to yield
11 was attempted under a variety of conditions,¶ although in our
hands this transformation still remains elusive. A less direct
route to 11 was then designed which involves deprotection of
6,7
presence of a chain at C-5, which normally presents a D
unsaturation or an epoxide derived therefrom.1 The design of a
general, enantioselective approach to this family of lactones
from currently available carbohydrates (d- series) is not obvious
because the absolute configuration at C-5 correlates with that of
a hexopyranoside of the l-series. Accordingly, d-sugars have
S
been used in syntheses of unnatural isomers of asperlin 24,5
‡
H
S
and anamarine 36 as well as synthetic precursors for ent-olguine
4.7 Herein we report the first general approach to this family of
lactones, starting from d-glucose, and its application to the
syntheses of acetylphomalactone 1 and asperlin 2.
i
iii
O
(E)-5
6
HO
O
(E)-9
(Z)-9 + (E)-9
iv
O
8
ii
H
H
7
6
4
7
6
O
O
5
5
HO
AcO
O
AcO
O
1
H
O
O
H
v
3
2
O
O
1
2
HO
HO
O
OAc OAc
O
11
10
OAc
H
H
6
6
O
O
O
OAc OAc
5
5
H
vi
AcO
O
O
OAc
AcO
O
3
4
H
O
O
2
+
vii (ref. 10)
Our strategy (Scheme 1) is based on the recognition that
d-glucose-derived bicyclic glycoside 6 can be viewed as a
5-alkenyl a,b-unsaturated d-lactone. Chemoselective cleavage
of ring A on 6 leads to lactone 5, which already fulfils the above-
mentioned structural requirements.
2.5:1
AcO
O
H
1
O
AcO
O
12
CHO
6
H
.
H
A
Scheme 3 Reagents and conditions: i, HSCH2CH2SH, BF3 OEt2, CH2Cl2,
220 °C; ii, BF3·OEt2, CH2Cl2, 0 °C, 83% from 6; iii, CaCO3, MeI, MeCN–
H2O (8:2), 60 °C; iv, BH3·Me2S, THF, 0 °C, 66% from (E)-9; v,
N-(phenylseleno)phthalimide, PBu3, CH2Cl2, 220 °C, then Bu3SnH,
AIBN, PhMe, 80 °C, 41% from 10; vi, PPh3, AcOH, diisopropyl
azodicarboxylate, THF, room temp., 61%; vii, MCPBA, CH2Cl2, 4 days,
room temp.
H
7
EtO
O
O
O
A
H
B
H
O
O
B
O
O
OEt
HO
O
5
6
6
Scheme 1
Chem. Commun., 1997
1647

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¶ Treatment of (E)-9 with several kinds of Ni-Raney in different solvents
and under different conditions, in our hands, did not result in the formation
of 11.
the dithiane group followed by reduction of the resulting
aldehyde function in 5∑ to furnish diol 10 (66% overall).
Sequential phenylselenation–tin mediated deselenation of the
∑ Hydroxy aldehyde 5 is not a very stable compound. It dehydrates slowly
latter yielded 11 (41% overall). One additional isomer with a
at room temperature or upon purification on silica gel.
7,8
D
unsaturation, resulting from the reduction of the allylic
1
** Spectral data (300 MHz H NMR) for 1,2b and 2,10a are identical with
radical at C-6, was also observed (ca. 3.5:1 ratio). Mitsunobu
inversion of 11 with acetic acid at C-4 led to 1** (61%), which
upon epoxidation gave raise to asperlin 2,** along with its
6R,7S-diastereoisomer.10
those already reported for the natural compounds.
1 M. T. Davies-Coleman and D. E. A. Rivett, in Progress in the Chemistry
of Organic Natural Products, ed. W. Herz, H. Grisebach, G. W. Kirby
and Ch. Tamm, Springer-Verlag, Wien and New York, 1989, vol. 55,
pp. 1–35.
2 (a) S. Mizuba, K. Lee and J. Jiu, Can. J. Microbiol., 1975, 21, 1781; (b)
T. Honda, T. Kametani, K. Kanai, Y. Tatsuzaki and M. Tsubuki,
J. Chem. Soc., Perkin Trans. 1, 1990, 1733.
3 A. D. Argoudelis and J. F. Zieserl, Tetrahedron Lett., 1966, 7, 1969.
4 (a) T. K. M. Shing and M. Aloui, Can. J. Chem., 1990, 68, 1035;
(b) T. K. M. Shing and M. Aloui, J. Chem. Soc., Chem. Commun., 1988,
1525; (c) S. Valverde, B. Herrado´n, R. M. Rabanal and M. Martin-
Lomas, Can. J. Chem., 1987, 65, 339.
5 S. Ramesh and R. W. Franck, Tetrahedron: Asymmetry, 1990, 1, 137.
6 S. Valverde, A. Herna´ndez, B. Herrado´n, R. M. Rabanal and M. Martin-
Lomas, Tetrahedron, 1987, 43, 3499; F. W. Lichtenthaler, K. Lorenz
and W-y. Ma, Tetrahedron Lett., 1987, 28, 47.
In summary, we have developed an efficient synthetic
approach to naturally occurring 5-alkyl and 5-alkenyl a,b-
unsaturated d-lactones1 using d-glucose as the starting material.
The approach illustrates the usefulness of bicyclic d-glycoside
6 as a key intermediate for biologically active lactones in which
C-5 correlates with that of a hexopyranoside of the l-series.
Further studies along this line for the preparation of other
lactones are under way.
This research was supported by funds from the Direccio´n
General de Investigacio´n Cient´ıfica y Te´cnica (grants PB96-
0822 and PB94-0104). A. M. G. thanks the Consejo Superior de
Investigaciones Cient´ıficas for financial support.
7 S. Valverde, B. Herrado´n, R. M. Rabanal and M. Martin-Lomas, Can. J.
Chem., 1987, 65, 332; S. Valverde, M. Martin-Lomas and B. Herrado´n,
J. Carbohydr. Chem., 1987, 6, 685; R. M. Rabanal, J. Escudero, M.
Martin-Lomas and S. Valverde, Carbohydr. Res., 1985, 141, 49.
8 R. J. Ferrier and N. Prasad, J. Chem. Soc. C, 1969, 570.
9 A. M. Go´mez, J. C. Lo´pez and B. Fraser-Reid, Synlett, 1993, 557.
10 (a) T. Murayama, T. Sugiyama and K. Yamashita, Agric. Biol. Chem.,
1987, 51, 2055; (b) H. Hiraoka, K. Furuta, N. Ikeda and H. Yamamoto,
Bull. Chem. Soc. Jpn., 1984, 57, 2777.
Footnotes and References
† E-mail: clopez@cc.csic.es
‡Shing and Aloui prepared the 6R,7S diastereomer of 2 from d- glucose
[refs. 4(a) and (b)]. Ramesh and Franck reported the synthesis of (+)-2 from
l-rhamnose (ref. 5).
§ Hydroxyester 8 (300 mg) was adsorbed on silica gel (4.5 g) and placed in
a Pyrex vessel with an external bath of about 200 g of silica gel. Irradiation
of the mixture in a commercial microwave oven (466 W, 6 min) afforded
lactone 6. A large number of different sets of conditions were investigated
for this transformation but were not found to be synthetically useful because
of low yields and/or long reaction times.
Received in Cambridge, UK, 22nd May 1997; 7/03561F
1648
Chem. Commun., 1997