A synthetic approach to sporotricale methylether

Article abstract of DOI:10.1055/s-2005-917096

A synthetic approach to sporotricale methylether, a metabolite of the fungus Sporotrichum laxum with inhibitory activity against Helicobacter pylori, is described. The synthesis relies on the condensation of 13-hydroxy-10- oxotetradecanal, prepared via reaction of a sulfone-activated moiety with valerolactone, with diethyl 3,5-dimethoxyphthalide-7-phosphonate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-917096

2676
LETTER
A Synthetic Approach to Sporotricale Methylether
A
Synthetic
A
a
pproach to
b
S
porotricale
r
Methyle
i
the
r
na Dallavalle,*a Raffaella Nannei,a Lucio Merlini,a Adriana Bava,b Gianluca Nasinib
a
Dipartimento di Scienze Molecolari Agroalimentari, Sezione di Chimica, Università di Milano, Via Celoria 2, 20133 Milano, Italy
E-mail: sabrina.dallavalle@unimi.it
b
CNR, ICRM, Dipartimento di Chimica, Materiali ed Ingegneria Chimica, Politecnico di Milano, Via Mancinelli 7, 20131 Milano, Italy
Received 11 July 2005
OCH3
O
Abstract: A synthetic approach to sporotricale methylether, a me-
tabolite of the fungus Sporotrichum laxum with inhibitory activity
against Helicobacter pylori, is described. The synthesis relies on the
condensation of 13-hydroxy-10-oxotetradecanal, prepared via reac-
tion of a sulfone-activated moiety with valerolactone, with diethyl
3,5-dimethoxyphthalide-7-phosphonate.
O
O
H3CO
O
3
Figure 1
Key words: natural products, total synthesis, sulfones, condensa-
tion, hydrogenation
Apart from the activity against Helicobacter pylori,
sporotricale and sporotricale methylether exhibit hypo-
lipemic activity, compound 1 was showing 158% promo-
tion of LDL uptake by HEP G2 cells.5
(+)-Sporotricale [1, 5-hydroxy-3-(13¢-hydroxy-10¢-oxo-
tetradecyl)-7-methoxy-3H-isobenzofuran-1-one] and (+)-
sporotricale methylether (2) are polyketide-derived natu-
ral substances that were isolated some years ago from a
culture of the fungus Sporotrichum laxum (basidiomyce-
tae).1 They exist as an equilibrium mixture of the two
epimeric hemiketals and of the open hydroxy ketone de-
pending on the solvent (Scheme 1).1
Herein we report a synthesis of (+)-sporotricale methyl-
ether (2), hinged on the Horner–Wadsworth–Emmons
condensation of diethyl 5,7-dimethoxyphthalide-3-phos-
phonate (4) with 13-hydroxy-10-oxotetradecanal (5) fol-
lowed by hydrogenation of the obtained alkene.
We found that a convenient route to the synthesis of alde-
hyde 5, containing a g-hydroxyketone moiety, is provided
by the condensation of a sulfone-activated methylene
group6 onto commercially available g-valerolactone as a
masked 1,4-bifunctional compound (Scheme 2).
OCH3
O
O
HO
R
CH3
O
Reaction of 9-bromononan-1-ol (6) with sodium benzene-
sulfinate gave the sulfone 7, that, after silylation of the OH
group, was added with 2 equivalents of n-butyllithium in
THF to give the soluble dilithio-derivative. Addition of a
small amount of hexamethylphosphoramide followed by
the stoichiometric amount of g-valerolactone at –78 °C af-
forded 9 in a 60% yield. Sulfone cleavage was accom-
plished with Na/Hg amalgam in methanol to give the
silylated hydroxyketone 10. Desilylation of this latter re-
quired the use of aqueous HF7 in order to obtain the pri-
mary alcohol that was oxidized to the aldehyde 5 with
polymer-supported TEMPO.
OCH3
O
7
O
O
5
1 R = OH
2 R = OMe
13'
R
3
10'
OH
H
Scheme 1 Ring–chain equilibrium in sporotricale
Sporotricale and sporotricale methylether belong to a
small group of fungal metabolites that have received at-
tention for their inhibitory activity against Helicobacter
pylori2 and therefore may become leading compounds for
the development of drugs for the treatment of gas-
troduodenal disorders and prevention of gastric cancer.
The members of this group contain the same 5-hydroxy-
7-methoxy- or 5,7-dimethoxyphthalide nucleus, but have
chains of different length and of different oxidation state,
also containing a spiroketal group, with respect to sporo-
tricale.3 The synthesis of one of these compounds, CJ-
13015 (3, stereochemistry unknown, Figure 1), where the
g-diketone system derived from a furan nucleus, was re-
ported recently.4
Compound 4 was prepared following a procedure de-
scribed by Watanabe8 for the synthesis of various diethyl
phthalide-3-phosphonates, that requires the reaction of
appropriate diethyl-2-formylbenzamides (in our case 12)
with tert-butyldimethylsilyldimethylphosphite. However,
in our hands the synthesis of tert-butyldimethylsilyldi-
methylphosphite gave variable yields due to unsatisfac-
tory purification of the product by vacuum distillation.
Therefore we modified this step of the synthesis, so that
the phosphonate 4 could be prepared more easily and with
higher yields by direct treatment of 12 with chlorotri-
methylsilane and triethylphosphite,9 followed by desilylation
and cyclization using methanesulfonic acid (Scheme 3).
SYNLETT 2005, No. 17, pp 2676–2678
Advanced online publication: 05.10.2005
DOI: 10.1055/s-2005-917096; Art ID: G22305ST
© Georg Thieme Verlag Stuttgart · New York
1
7
.1
0
.2
0
0
5

LETTER
A Synthetic Approach to Sporotricale Methylether
2677
a
SO2Ph
HO
Br
HO
7
6
c
b
TBDMSO
SO2Ph
8
SO2Ph
O
OH
d
TBDMSO
9
OH
e, f
TBDMSO
OHC
O
10
OH
O
5
Scheme 2 Reagents and conditions: (a) PhSO2Na, NaI, DMF, r.t., 5 h, 82%; (b) TBDMSCl, Et3N, DMAP, DMF, r.t., 48 h, 87%; (c) THF,
0 °C, n-BuLi, 30 min then HMPTA, ( )-g-valerolactone, –78 °C, 3 h, 60%; (d) Na/Hg 10%, MeOH, r.t., 24 h, 66%; (e) 40% aq HF, MeCN,
r.t., 3 h, 52%; (f) NaOCl, KBr, polymer-supported TEMPO, CH2Cl2, r.t., 5 h, 50%
The Horner–Wadsworth–Emmons reaction in the pres- When this work was already in an advanced stage, the ab-
ence of NaH10gave the expected alkene 13 as a mixture of solute configuration of (+)-sporotricale was established as
E/Z isomers. Hydrogenation of the exocyclic double bond 3R,13¢R.12 The present synthetic approach, although the
was first attempted in ethyl acetate using Pd/C 10% as a yields have not been optimized, should be amenable to the
catalyst, but in these conditions also the keto group of the stereocontrolled synthesis of (+)-sporotricale itself. In fact
chain was reduced to the corresponding alcohol.
R-stereochemistry at C13 could derive from the use of
(R)-valerolactone, that has now become commercially
available, instead of racemic g-valerolactone, and asym-
metric hydrogenation of the alkene 13 could provide the
3R-stereochemistry of the natural metabolite. Indeed,
there are examples in the literature of asymmetric hydro-
genation of 2-alkylidene-g-butyrolactones catalyzed by
BINAP–Ru (II) complexes with high enantioselectivi-
ties.13
To avoid overreduction, we took advantage of the ob-
served shift of the ring–chain equilibrium of 2 toward the
hemiketal in methanol.1 Thus, the selective catalytic re-
duction of the double bond was performed successfully in
this solvent to give 2, identical to the natural product in the
NMR spectrum1 (Scheme 3). By HPLC comparison, the
isomeric mixture appeared to contain the natural isomer.11
In conclusion a simple first total synthesis of the helico-
bactericidal agent sporotricale methylether has been
achieved by condensation of the phthalide phosphonate 4
with aldehyde 5, on its turn obtained by the use of g-vale-
rolactone exploiting the mobile activating sulfonyl group.
Moreover, this synthetic approach can be easily extended
to the synthesis of analogues with different chain length.
Acknowledgment
We are indebted to Sigma-tau, Pomezia, for financial support.
OCH3
O
OCH3
OCH3
CON(Et)2
COOH
a, b
c
O
H3CO
H3CO
H3CO
CHO
P(O)(OC2H5)2
4
12
OCH3
O
5
O
e
O
2
d
H3CO
OH
13
Scheme 3 Reagents and conditions: (a) SOCl2, Et2NH, toluene, reflux, 2 h, 92% (b) s-BuLi, TMEDA, DMF, –78 °C to r.t., 2 h, 85%; (c)
(CH3)3SiCl, P(OEt)3, then MeSO3H, MeOH, 53%; (d) NaH 60%, anhyd THF, r.t., 5 d, 42%; (e) H2/Pd/C, MeOH, 50%
Synlett 2005, No. 17, 2676–2678 © Thieme Stuttgart · New York

2678
S. Dallavalle et al.
LETTER
H, d, J = 6.2 Hz, H-14¢), 2.00–1.20 (14 H, m, 7 × CH2), 2.48
and 2.33 (4 H, m, H-9¢ and H-11¢), 2.49 (2 H, dt, J = 7.8, 7.5
Hz, H-2¢), 3.87 (1 H, m, H-13¢), 3.93 (3 H, s, OMe), 3.98 (3
H, s, OMe), 5.79 (1 H, t, J = 7.8 Hz, H-1¢), 6.80 and 6.47 (2
H, br d, J = 1.8 Hz, H-4 and H-6). MS (EI): m/z (%) = 400
(41), 345 (15), 219 (80), 111 (90), 55 (100).
References
(1) Arnone, A.; Assante, G.; Nasini, G.; Vajna de Pava, O.
Phytochemistry 1990, 29, 613.
(2) Pfizer Inc. USA, WO Pat. 9605204, 1996; Chem. Abstr.
1996, 125, 58200f.
(3) Dekker, K. A.; Inagaki, T.; Gootz, T. D.; Kaneda, K.;
Nomura, E.; Sakakibara, T.; Sakemi, S.; Sugie, Y.;
Yamauchi, Y.; Yoshikawa, N.; Kojima, N. J. Antibiotics
1997, 50, 833.
(4) Mondal, M.; Argade, N. P. Tetrahedron Lett. 2004, 45,
5693.
(5) Taisho Pharma Co. Ltd, WO Pat. 9610020, 1996; Chem.
Abstr. 1996, 125, 86482t.
(6) Mussatto, M. C.; Savoia, D.; Trombini, C.; Umani-Ronchi,
A. J. Org. Chem. 1980, 45, 4002.
(7) Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly, D.
R.; Roberts, S. M. Tetrahedron Lett. 1979, 3981.
(8) Watanabe, M.; Ijichi, S.; Furukawa, S. Synthesis 1993, 94.
(9) Olah, G. A.; Wu, A. J. Org. Chem. 1991, 56, 902.
(10) Napolitano, E.; Spinelli, G.; Fiaschi, R.; Marsili, A.
Synthesis 1985, 38.
(11) Preparation of E/Z 3-(13-Hydroxy-10-oxo-tridecyl-
idene)-5,7-dimethoxy-3H-isobenzofuran-1-one (13).
To a stirred solution of phosphonate 4 (0.024 g, 0.12 mmol)
and aldehyde 5 (0.024 g, 0.12 mmol) in dry THF (0.8 mL),
NaH (7.4 mg of a 60% dispersion in mineral oil; 0.154
mmol) was added and the mixture stirred under nitrogen at
r.t. for 5 d. After addition of H2O, the organic layer was
separated and evaporated in vacuo to give a residue which
was purified by preparative layer chromatography (PLC)
using 1:1 hexane–EtOAc as eluent to afford the Z-isomer 13
as a solid (11 mg, 24%), mp 79–81 °C and the E-isomer as
an oil, (8 mg, 18%). 1 H NMR (CDCl3): d (Z-isomer) = 1.22
(3 H, d, J = 6.2 Hz, H-14¢), 2.00–1.20 (14 H, m, 7 × CH2),
2.45 and 2.35 (4 H, m, H-9¢ and H-11¢), 2.51 (2 H, dt, J = 7.8,
7.5 Hz, H-2¢), 3.85 (1 H, m, H-13¢), 3.92 (3 H, s, OMe), 3.97
(3 H, s, OMe), 5.55 (1 H, t, J = 7.8 Hz, H-1¢), 6.70 and 6.45
(2 H, br d, J = 1.8 Hz, H-4 and H-6); d (E-isomer) = 1.22 (3
Preparation of ( ) Sporotricale Methylether(2).
Compound 13 (12 mg) dissolved in MeOH (5 mL) was
hydrogenated at r.t. with 10% Pd/C (3 mg) for 20 min. PLC
of the residue in 50:50 hexane–EtOAc gave 6 mg (50%) of
2, mp 94–96 °C. 1H NMR (CDCl3): d (hemiketal) = 1.22 (3
H, d, J = 6.2 Hz, H-14¢), 2.50–1.20 (22 H, m, 11 × CH2), 3.83
(1 H, m, H-13¢). 3.90 (3 H, s, OMe), 3.95 (3 H, s, OMe), 5.29
(1 H, br dd, J = 7.2, 4.0 Hz, H-7), 6.42 and 6.40 (2 H, br d,
J = 1.7 Hz, H-4 and H-6); 1H NMR (acetone-d6):
d (hydroxyketone) = 1.10 (3 H, d, J = 7.2 Hz, H-14¢), 2.00–
1.20 (18 H, m, 9 × CH2), 2.53 and 2.44 (4 H, t, J = 7.5 Hz,
H-9¢ and H-11¢), 3.66 (1 H, m, H-13¢), 3.92 (3 H, s, OMe),
3.93 (3 H, s, OMe), 5.35 (1 H, br dd, J = 7.6, 3.6 Hz, H-7),
6.71 and 6.59 (2 H, br d, J = 1.7 Hz, H-4 and H-6). 13C NMR
(acetone-d6): d = 210.01 (C-10¢), 166.92 (C-1), 166.73,
159.49, 155.30, 106.45, 98.53, 98.02, 79.22 (C-3), 66.06 (C-
13¢), 55.57 (OMe), 55.30 (OMe), 42.10–23.60 (11 × CH2),
21.87. MS (EI): m/z (%) = 403 (75) [MH+], 402 (44) [M+],
207 (34), 193 (55), 111 (55), 55 (100).
The 1H NMR spectrum of this product was identical with
that of natural sporotricale methylether. HPLC comparison:
natural 2, column LiChroCART 250-4 SiO2 (Merck), eluent
hexane–EtOAc (1:3), retention time (tR) = 14.72 min;
column Chiral Daicel OB, eluent hexane–i-PrOH (9:1)
tR = 3.19; synthetic 2, column LiChroCART 250-4 SiO2
(Merck), tR = 14.78, column Chiral Daicel OB, tR = 3.19
(48.6%); 10.91 (51.4%). Analyses were performed using a
Merck-Hitachi L-4000 instrument equipped with a L-6000A
pump and a UV detector (250 nm); flow rate 0.5 mL/min.
(12) Nasini, G. et al. manuscript in preparation.
(13) Ohta, T.; Miyake, T.; Seido, N.; Kumobayashi, H.;
Akutagawa, S.; Takaya, H. Tetrahedron Lett. 1992, 33, 635.
Synlett 2005, No. 17, 2676–2678 © Thieme Stuttgart · New York