Synthetic access to biologically active butenolides from Streptomyces antibioticus

Article abstract of DOI:10.1055/s-2001-10760

A synthetic route to a class of substituted butenolides isolated from Streptomyces antibioticus has been elaborated. The process involves coupling of the readily available menthylated furanone 5 with aldehydes.

Full text of DOI:10.1055/s-2001-10760

278
LETTER
Synthetic Access to Biologically Active Butenolides from Streptomyces
antibioticus
Gilles Grossmann, Urs Séquin*
Institut für Organische Chemie der Universität Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Tel. +41 61 267 11 10; Fax +41 61 267 11 03; E-mail: urs.sequin@unibas.ch
Received 6 November 2000
is easily accessible in optically pure form4,5 from the
condensation product of propanal with glyoxylic acid and
(-)-menthol. In compound 5 the hemiacetalic HO-group is
blocked.
Abstract: A synthetic route to a class of substituted butenolides iso-
lated from Streptomyces antibioticus has been elaborated. The pro-
cess involves coupling of the readily available menthylated
furanone 5 with aldehydes.
Key words: furanones, Streptomyces antibioticus, natural products, The key step of our synthesis is the nucleophilic addition
equilibrating hemiacetals, nucleophilic additions
of the furanone ring to an aldehyde to introduce the side
chain (Scheme 2).6 LDA was used as the base, which,
together with the large protecting menthyl group, led to
abstraction of H-C(3) rather than of the more activated
H-C(5). The diastereomeric mixture 6 thus obtained from
5 and 2-methylpropanal was then separated into the two
epimers 7 and 8 by flash chromatography (Scheme 3). The
configurations at C(1') of these two compounds were as-
signed by esterification of HO-C(1') with Mosher's
reagent7 and 1H NMR spectroscopy.
The four lactones 1-4 (Scheme 1) were isolated a few
years ago from Streptomyces antibioticus Tü99,1 using a
photoconductivity screening.2 Since the compounds
showed an antibiotic activity against Pseudomonas as
well as a weak inhibition of the chitinase from Serratia
marcescens, a synthetic access route to this class of com-
pounds was sought.
OH
OH
OH
1'
O
O
O
O
2'
2
3
4
O
O
O
O
1
a, b
5
O
O
OH
1
2
OH
OH
O
O
6 (70%)
5
O
O
Reagents and conditions: (a) THF, LDA (1.1 eq), -78 °C, 30 min; (b)
2-methylpropanal, -78 °C, 30 min.
OH
3
4
Scheme 2
Scheme 1
After removal of the menthyl group with BBr3,8,9 9 and 10
were obtained, respectively, the latter being identical to
the natural product. The hemiacetalic furanones 9 and 10
were each reduced with NaBH4 to give eventually 11 and
12, respectively.10 Again, the latter proved to be identical
to the compound isolated from the Streptomyces fermen-
tation broth.
A synthetic pathway was thus developed, which allows
the introduction of different side chains. Deliberately, a
non-stereoselective approach was used: Stereoisomers of
biologically active natural products often allow interest-
ing conclusions with respect to structure-activity relation-
ships.3
The hemiacetalic compounds 1 and 3 equilibrate in
solution to a mixture of epimers, which makes their
isolation and characterization tedious. To alleviate this
problem, we started with the menthyl ether 5 which
When 2-methylbutanal was used instead of 2-methylpro-
panal in the reaction sequence described above, the natu-
ral products 3 and 4 could be obtained together with the
respective 1’-epimers.
Synlett 2001, No. 2, 278–280 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthetic Access to Biologically Active Butenolides from Streptomyces antibioticus
279
solution was cooled to 78 °C and 10.0 g (40.0 mmol) of 5
were added dropwise. After 30 min of stirring at this
temperature 4.00 ml (3.14 g, 43.7 mmol) of 2-methylpropanal
were added dropwise and the solution was stirred for
additional 30 min at 78 °C. Then, a saturated solution of
NH4Cl (100 ml) was added. The reaction mixture was
extracted with CH2Cl2 (3 300 ml) and the combined organic
layers were dried over MgSO4. After evaporation of the
solvent under reduced pressure, the residue was
6
a
OH
OH
O
O
O
O
chromatographed on silica gel (AcOEt/hexane 1:5) to afford
3.60 g (11.1 mmol, 28%) of 7 and 5.40 g (16.7 mmol, 42%) of
+
8.
O-(-)menthyl
O-(-)menthyl
7 (28%)
8 (42%)
20
7: Colorless plates, mp 82.0-83.5 °C. [ ]D
= 130 (c = 1.00
in CHCl3, stab. 1% EtOH). 1H NMR (500 MHz, CDCl3):
= 5.75 (s, 1H, H-C(5)); 4.13 (t, 1H, H-C(1'), J = 8.4 Hz);
2.89 (d, 1H, HO-C(1'), J = 9.1 Hz); 2.05-1.97 (m, 1H, H-
C(2')); 1.99 (s, 3H, CH3-C(4)); 1.04 (d, 3H, CH3-C(2'), J = 6.6
Hz); 0.84 (d, 3H, CH3-C(2'), J = 6.9 Hz); menthyl resonances:
3.63 (td); 2.14 (m); 2.10 (m); 1.70 (m); 1.65 (m); 1.41 (m); 1.25
(m); 1.03 (m); 0.96 (d); 0.87 (m); 0.87 (d); 0.80 (d). 13C NMR
(125 MHz, CDCl3): = 171.6 (C(2)); 156.4 (C(4)); 129.9
(C(3)); 100.6 (C(5)); 72.4 (C(1')); 33.9 (C(2')); 18.8 and 18.3
((CH3)2C(2')); 11.7 (CH3C(4)); menthyl resonances: 79.4;
47.7; 40.4; 34.2; 31.4; 25.2; 23.1; 22.2; 20.8; 15.7. Anal.
calcd. for C19H32O4: C 70.33, H 9.94, O 19.72; found: C 70.54,
b
b
OH
OH
O
O
O
O
OH
OH
9 (83%)
10 (79%)
H 10.04, O 19.48.
8: Colorless plates, mp 51.5-53.0 °C. [ ]D
20
= 111 (c = 1.00
c
c
in CHCl3, stab. 1% EtOH). 1H NMR (500 MHz, CDCl3):
= 5.70 (s, 1H, H-C(5)); 4.09 (dd, 1H, H-C(1') J = 8.1 Hz and
J = 9.7 Hz); 2.97 (d, 1H, HO-C(1'), J = 9.7 Hz); 2.05-1.98 (m,
1H, H-C(2')); 1.96 (s, 3H, CH3-C(4)); 1.04 (d, 3H, CH3-C(2'),
J = 6.6 Hz); 0.84 (d, 3H, CH3-C(2'), J = 6.9 Hz); menthyl
resonances: 3.62 (td); 2.10 (m); 2.06 (m); 1.68 (m); 1.64 (m);
1.41 (m); 1.25 (m); 1.00 (m); 0.95 (d); 0.87 (m); 0.87 (d); 0.80
(d). 13C NMR (125 MHz, CDCl3): = 171.7 (C(2)); 156.3
(C(4)); 129.7 (C(3)); 100.8 (C(5)); 72.6 (C(1')); 34.2 (C2'));
18.8 and 18.5 ((CH3)2C(2')); 11.8 (CH3C(4)); menthyl
resonances: 79.4; 47.7; 40.4; 34.2; 31.4; 25.5; 23.3; 22.2;
20.8; 16.0. Anal. calcd. for C19H32O4: C 70.33, H 9.94, O
19.72; found: C 70.56, H 9.84, O 19.68.
OH
OH
O
O
O
O
11 (58%)
12 (58%)
Reagents and conditions: (a) flash chromatography, SiO2, AcOEt/
hexane 1:5; (b) CH2Cl2, BBr3, -78 °C, 4 h; (c) MeOH, NaBH4, 0 °C,
(7) Miyake, S.; Horinouchi, S.; Yoshida, M.; Chiba, N.; Mori, K.;
Nogawa N.; Morikawa, N.; Beppu, T. J. Bacteriol. 1989, 171,
6986.
2 h.
Scheme 3
(8) Demuynck, M.; De Clercq, P.; Vandewalle, M. J. Org. Chem.
1979, 26, 4863.
(9) Typical procedure: To a stirred solution of 400 mg (1.23
mmol) of 8 in 20 ml of dry dichloromethane was added at
78 °C a solution of 600 l (1.54 g, 6.17 mmol) of BBr3 in 1
ml of dichloromethane. After 4 h the mixture was warmed to
25 °C. The mixture was quenched with saturated sodium
hydrogen carbonate solution and extracted with AcOEt
(3 20 ml). The combined organic layers were dried over
MgSO4. After evaporation of the solvents under reduced
pressure, the residue was chromatographed on silica gel
(AcOEt/hexane 1:1) to afford 190 mg (1.02 mmol, 83%) of
10.
Acknowledgement
This work was supported by the Swiss National Science Foun-
dation (grant No. 20-55342.98).
References and Notes
(1) Braun, D.; Pauli, N.; Séquin, U.; Zähner, H. FEMS Microbiol.
Lett. 1995, 126, 37.
(2) Fiedler, H. P. J. Chromatogr. 1984, 316, 487.
(3) cf. Busch, J.; Grether, Y.; Ochs, D.; Séquin, U. J. Nat. Prod.
1998, 61, 591.
(4) Bourguignon, J. J.; Wermuth, C. G. J. Org. Chem. 1981, 46,
4889.
(5) Feringa, B. L.; de Lange, B.; de Jong, J. C. J. Org. Chem.
1989, 54, 2471.
(6) Typical procedure: In a dry apparatus 31.7 ml n-BuLi (1.5 M
in hexane, 47.6 mmol) were added dropwise to a solution of
500 ml of dry THF and 6.77 ml (4.81 g, 47.6 mmol) of
diisopropylamine at 0 °C. After 30 min of stirring at 0 °C, this
10 (mixture of epimers): Colorless prisms, mp 103.5-
20
105.0 °C. [ ]D
= 16 (c = 1.00 in CHCl3, stab. 1% EtOH).
1H NMR (500 MHz, CDCl3): = 5.88/5.87 (2s, 2 1H, H-
C(5)); 5.25/5.05 (2d, 2 1H, HO-C(5), J = 9.3 Hz); 4.15-4.05
(m, 2 1H, H-C(1')); 3.33/3.09 (2br s, 2 1H, HO-C(1'));
2.08/2.06 (2s, 2 3H, CH3-C(4)); 2.05-1.95 (m; 2 1H; H-
C(2')); 1.04/1.03 (2d, 2 3H, (CH3)-C(2'), J = 6.6 Hz); 0.85/
0.83 (2d, 2 3H, (CH3)-C(2'), J = 6.6 Hz). 13C NMR (125
MHz, CDCl3): = 172.1/172.0 (C(2)); 158.54/158.52 (C(4));
129.7/129.2 (C(3)); 98.9/98.8 (C(5)); 72.33/72.26 (C(1'));
33.9/33.5 (C(2')); 18.7/18.7/18.5/18.4 ((CH3)2-C(2')); 11.9/
Synlett 2001, No. 2, 278–280 ISSN 0936-5214 © Thieme Stuttgart · New York

280
G. Grossmann, U. Séquin
LETTER
20
11.6 (CH3-C(4)). Anal. calcd. for C9H14O4: C 58.05, H 7.58,
12: Colorless, amorphous solid. [ ]D
=
16.5 (c = 1.00 in
O 34.37; found: C 58.06, H 7.58, O 34.40.
CHCl3, stab. 1% EtOH). 1H NMR (500 MHz, CDCl3):
= 4.71 (d, 1H, Ha-C(5), J = 17.3 Hz); 4.66 (s, 1H, Hb-C(5),
J = 17.3 Hz); 4.14 (d, 1H, H-C(1'), J = 7.9 Hz); 3.13 (br. s, 1H,
HO-C(1')); 2.09 (s, 3H, CH3-C(4)); 2.08-1.98 (m, 1H, H-
C(2')); 1.04 (d, 3H, CH3-C(2'), J = 6.7 Hz); 0.84 (d, 3H, CH3-
C(2'), J = 6.7 Hz). 13C NMR (125 MHz, CDCl3): = 174.2
(C(2)); 158.5 (C(4)); 127.3 (C(3)); 72.7 (C(5)); 72.3 (C(1'));
33.8 (C(2')); 18.7 and 18.3 ((CH3)2C(2')); 12.4 (CH3C(4)).
Anal. calcd. for C9H14O3: C 63.51, H 8.29, O 28.20; found: C
63.22, H 8.33, O 28.27.
(10) Typical procedure: A solution of 750 mg (4.03 mmol) of 10
in MeOH (20 ml) was cooled to 0 °C. NaBH4 (620 mg, 16.1
mmol) was added in portions within 10 min and the solution
was stirred for 2 h at 0 °C. Then the reaction mixture was
quenched with water (5 ml) and extracted with CH2Cl2 (3 20
ml) and with AcOEt (3 20 ml). The combined organic layers
were dried over MgSO4. After evaporation of the solvents
under reduced pressure, the residue was chromatographed on
silica gel (tert-butyl methyl ether) to afford 397 mg (2.34
mmol, 58%) of 12.
Article Identifier:
1437-2096,E;2001,0,02,0278,0280,ftx,en;G23100ST.pdf
Synlett 2001, No. 2, 278–280 ISSN 0936-5214 © Thieme Stuttgart · New York