A unified strategy for the regiospecific assembly of homoallyl-substituted butenolides and γ-hydroxybutenolides: First synthesis of luffariellolide

Article abstract of DOI:10.1055/s-2006-949641

The first synthesis of the antiinflammatory marine natural product luffariellolide has been achieved by a convergent pathway involving sp ³-sp³ cross-coupling and silyloxyfuran oxyfunctionalisation as key steps. An illustration of the inherent flexibility of this strategy is provided by a simple synthesis of α,β-acariolide and its γ-hydroxylated derivative from a common silyloxyfuran precursor. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-949641

2480
LETTER
A Unified Strategy for the Regiospecific Assembly of Homoallyl-Substituted
Butenolides and g-Hydroxybutenolides: First Synthesis of Luffariellolide
F
irst Synth
o
esisof
L
uffa
h
riellolide n Boukouvalas,* Joël Robichaud, François Maltais
Département de Chimie, Université Laval, Quebec City, Quebec G1K 7P4, Canada
Fax +1(418)6567916; E-mail: john.boukouvalas@chm.ulaval.ca
Received 31 May 2006
Herein we report the first synthesis of luffariellolide (1)
Abstract: The first synthesis of the antiinflammatory marine
natural product luffariellolide has been achieved by a convergent
pathway involving sp3–sp3 cross-coupling and silyloxyfuran oxy-
functionalisation as key steps. An illustration of the inherent
flexibility of this strategy is provided by a simple synthesis of a,b-
acariolide and its g-hydroxylated derivative from a common silyl-
oxyfuran precursor.
by a convergent, versatile strategy that should be useful
for preparing related butenolides with or without a g-hy-
droxyl substituent (cf. 2 and 3).
As indicated in Scheme 1, we envisioned assembly of 1
by the union of fragments 4–6 and subsequent application
of our silyloxyfuran oxyfunctionalisation protocol for un-
masking the g-hydroxybutenolide.10,11 The versatility of
this approach stems from the latent functionality hidden
within the silyloxyfuran ring, making 6 the reagent of
choice for either synthon A or B (Figure 2).
Key words: cross-coupling, Grignard reagents, lactones, oxyfunc-
tionalisation, 2-silyloxyfurans
First isolated in 1987 from the Palauan sponge Luffariella
sp.,1 luffariellolide (1, Figure 1) is a non-steroidal sester-
terpene g-hydroxybutenolide that has attracted consider-
able synthetic2,3 and biomedical4 interest on account of its
potent in vivo antiinflammatory activity through partially
reversible inhibition of phospholipase A2 (PLA2).1 The
inhibition of PLA2 by 1 and related natural products, such
as manoalide,5 does not appear to involve binding at the
active site, but reaction of the aldehyde tautomer of the
g-hydroxybutenolide moiety with lysine residues at the
surface of PLA2, thereby preventing the enzyme from
moving across membranes.4a,6 Recently, luffariellolide
and some of its relatives, e.g. acantholide B (2),7 were
found to exhibit broad antimicrobial activity in vitro,7a
while the non-hydroxylated butenolide cyclolinteinone
(3)8 has been shown to reduce COX-2 and iNOS protein
expression,9 and may thus represent a new lead for the
pharmacological control of inflammation.
O
O
1
OH
SO2Ph
OTIPS
X
Y
O
4
5
6
ClMg
Scheme 1
O
OTIPS
O
O
O
O
ClMg
CH2
CH2
A
6
B
OH
O
O
Figure 2
To probe the feasibility of this strategy, especially the
crucial sp3-sp3 cross-coupling of the hitherto unknown
Grignard reagent 6 with an allylic partner,12 we initially
chose as targets the structurally simple natural products
a,b-acariolide (11)13 and its g-hydroxyl derivative14 12
(Scheme 2). The precursor of 6, 4-(chloromethyl)-2-(tri-
isopropylsilyloxy)furan (8),15 was prepared from the
readily available butenolide 716 as previously described.10
After several futile attempts to generate 6 from 8 by con-
ventional means,12 an effective procedure was ultimately
found involving treatment of 8 with properly activated
magnesium turnings in tetrahydrofuran at 0 °C.17 Subse-
quent reaction of 6 with prenyl chloride (9) in the presence
of Kochi’s catalyst18 (Li2CuCl4) at 0 °C for 20 minutes
delivered silyloxyfuran 10 which was hydrolyzed to give
a,b-acariolide (11) in 84% yield after chromatography.17
OH
1 X = H, H; luffariellolide
2 X = O; acantholide B
X
O
O
3; cyclolinteinone
O
Figure 1
SYNLETT 2006, No. 15, pp 2480–2482
Advanced online publication: 08.09.2006
1
8
.0
9
.2
0
0
6
DOI: 10.1055/s-2006-949641; Art ID: S12006ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
First Synthesis of Luffariellolide
2481
Alternatively, exposure of crude 10 to dimethyldioxirane
(DMDO) in acetone at –78 °C and subsequent quenching
with aqueous acetone/Amberlyst-15,10 afforded hydroxy-
butenolide 12 in a yield of 75% over two steps.17
SO2Ph
Br
+
OAc
5a
4
n-BuLi, HMPA, THF, –78 °C
then MeONa, MeOH, r.t.
81% (based on 5a)
O
OTIPS
O
TIPSOTf
Et3N
SO2Ph
O
CH2Cl2, 0 °C
(87%)
Cl
Cl
Mg*
OH
13
7
8
THF, 0 °C
Li, EtNH2, Et2O, –78 °C
76%
OTIPS
O
OTIPS
Cl
9
X
O
Li2CuCl4
THF, 0 °C
ClMg
14 X = OH
15 X = Cl
NCS
DMS
10
6
86%
OTIPS
H3O+
DMDO, –78 °C
then H3O+
Li2CuCl4
O
THF, 0 °C
O
O
ClMg
OTIPS
O
6
O
O
11
(84% from 9)
12
(75% from 9)
16
OH
DMDO, –78 °C
then H3O+
74%
(from 15)
Scheme 2
O
O
Having established the viability of this strategy, the syn-
thesis of luffariellolide began with the coupling of sulfone
419 with bromide 5a20 (Scheme 3). Thus, reaction of the
anion of 4 (1.5 equiv) with 5a followed by treatment of the
resulting mixture of alcohol 13 and its acetate with sodi-
um methoxide in methanol, provided 13 in 81% yield. Re-
moval of the phenylsulfonyl group was best accomplished
by using the procedure of Sato21 to furnish alcohol 14
which was subsequently converted to chloride 15 on treat-
ment with N-chlorosuccinimide and dimethyl sulfide.22 In
a manner analogous to that described for the synthesis of
hydroxybutenolide 12 (vide supra), coupling of 15 with 6
and ensuing oxyfunctionalisation of silyloxyfuran 1623
delivered luffariellolide (1, 74%) whose spectral proper-
1
OH
Scheme 3
References and Notes
(1) Albizati, K. F.; Holman, T.; Faulkner, D. J.; Glaser, K. B.;
Jacobs, R. S. Experientia 1987, 43, 949.
(2) (a) Kernan, M. R.; Faulkner, D. J. J. Org. Chem. 1988, 53,
2733. (b) Lee, G. C. M.; Syage, E. T.; Harcourt, D. A.;
Holmes, J. M.; Garst, M. E. J. Org. Chem. 1991, 56, 7007.
(3) For the synthesis of a simpler luffariellolide relative
(dictyodendrillin-B), see: Gerlach, K.; Hoffmann, H. M. R.
Synlett 1998, 682.
(4) (a) Potts, B. C. M.; Faulkner, D. J.; de Carvalho, M. S.;
Jacobs, R. S. J. Am. Chem. Soc. 1992, 114, 5093. (b)Mann,
I. Nature (London) 1992, 358, 540. (c) Hope, W. C.; Chen,
T.; Morgan, D. W. Agents Actions 1993, 39, C39.
(d) Blanchard, J. L.; Epstein, D. M.; Boisclair, M. D.;
Rudolph, J.; Pal, K. Bioorg. Med. Chem. Lett. 1999, 9, 2537.
(e) Capasso, A.; Casapullo, A.; Randazzo, A.; Gomez-
Paloma, L. Life Sci. 2003, 73, 611. (f) Izzo, I.; Avallone, E.;
Della Monica, C.; Casapullo, A.; Amigo, M.; De Riccardis,
F. Tetrahedron 2004, 60, 5587.
1
ties (IR, H and 13C NMR) were in full agreement with
those reported for authentic samples of the natural
product.1,7a
In summary, the first synthesis of luffariellolide has been
achieved in highly convergent fashion by the combined
use of sp3-sp3 cross-coupling and silyloxyfuran oxyfunc-
tionalisation. The strategy offers considerable flexibility,
allowing regiospecific access to both butenolides and g-
hydroxylbutenolides. It should prove useful for preparing
several related natural products7,8 and new analogues for
biological studies.
(5) For the synthesis of manoalide see: Pommier, A.;
Stepanenko, V.; Jarowicki, K.; Kocienski, P. J. J. Org.
Chem. 2003, 68, 4008; and references therein.
(6) Faulkner, D. J.; Newman, D. J.; Cragg, G. M. Nat. Prod.
Rep. 2004, 21, 50.
Acknowledgment
(7) (a) Elkhayat, E.; Edrada, R.; Ebel, R.; Wray, V.; van Soest,
R.; Wiryowidagdo, S.; Mohamed, M. H.; Müller, W. E. G.;
Proksch, P. J. Nat. Prod. 2004, 67, 1809. (b) See also: Cao,
S.; Foster, C.; Lazo, J. S.; Kingston, D. G. I. Bioorg. Med.
Chem. 2005, 13, 5094.
We thank the Natural Sciences and Engineering Research Council
of Canada (NSERC), Merck Frosst Canada and Eisai Research
Institute (MA, USA) for financial support.
Synlett 2006, No. 15, 2480–2482 © Thieme Stuttgart · New York

2482
J. Boukouvalas et al.
LETTER
(8) Carotenuto, A.; Fattorusso, E.; Lanzotti, V.; Magno, S.;
Carnuccio, R.; D’Acquisto, F. Tetrahedron 1997, 53, 7305;
and cited references.
(9) D’Acquisto, F.; Lanzotti, V.; Carnuccio, R. Biochem. J.
2000, 346, 793.
(10) Boukouvalas, J.; Lachance, N. Synlett 1998, 31.
(11) For previous applications in natural product synthesis, see:
(a) Boukouvalas, J.; Cheng, Y.-X.; Robichaud, J. J. Org.
Chem. 1998, 63, 228. (b) Marcos, I. S.; Pedrero, A. B.;
Sexmero, M. J.; Diez, D.; Basabe, P.; Hernández, F. A.;
Urones, J. G. Tetrahedron Lett. 2003, 44, 369. (c) Bagal, S.
K.; Adlington, R. M.; Baldwin, J. E.; Marquez, R. J. Org.
Chem. 2004, 69, 9100. (d) Marcos, I. S.; Pedrero, A. B.;
Sexmero, M. J.; Diez, D.; García, N.; Escola, M. A.; Basabe,
P.; Conde, A.; Moro, R. F.; Urones, J. G. Synthesis 2005,
3301. (e) Boukouvalas, J.; Wang, J.-X.; Marion, O.; Ndzi, B.
J. Org. Chem. 2006, 71, 6670.
carried forward without further purification. TLC, Rf = 0.81
(EtOAc–hexanes, 1:9). 1H NMR (300 MHz, CDCl3): d =
6.57 (s, 1 H), 5.12 (t, J = 7.0 Hz, 1 H), 5.02 (s, 1 H), 2.31 (m,
2 H), 2.18 (t, J = 7.3 Hz, 2 H), 1.66 (s, 3 H), 1.57 (s, 3 H),
1.24 (m, 3 H), 1.07 (d, J = 7.0 Hz, 18 H). 13C NMR (75 MHz,
CDCl3): d = 156.5, 131.6, 127.5, 126.5, 123.9, 85.1, 28.1,
25.8, 25.5, 17.4, 15.1, 12.0.
Preparation of a,b-Acariolide (11): To a solution of 10
(112 mg) in acetone (10 mL) and H2O (5 drops) was added
Amberlyst-15 (25 mg) and the mixture was stirred at r.t. for
45 min. The resin was filtered, washed with acetone (15
mL), and the solvent was evaporated in vacuo. The resulting
oil was purified by flash chromatography (EtOAc–hexanes,
15:85, then 2:8) to afford 11 as a colourless oil (98 mg,
84%); TLC: Rf = 0.24 (EtOAc–hexanes, 2:8), whose NMR
data matched those reported in ref. 13.
Preparation of g-Hydroxybutenolide 12: To a solution of
10 (112 mg) in anhyd CH2Cl2 (10 mL) at –78 °C was added
an acetone solution of DMDO (ca. 0.1 M, 0.4 mL). The
mixture was stirred at –78 °C for 1 h and concentrated in
vacuo at –78 °C. The crude oil was dissolved in acetone (10
mL) and H2O (5 drops) was added followed by Amberlyst-
15 (25 mg). The mixture was stirred at r.t. for 1.5 h, the resin
was filtered off, washed with acetone (15 mL), and the
solvent was evaporated in vacuo. The resulting oil was
purified by flash chromatography (EtOAc–hexanes, 2:8,
then 25:75) to afford 12 as a colourless oil (88 mg, 75%);
TLC: Rf = 0.32 (EtOAc–hexanes, 3:7), whose NMR data
matched those reported in ref. 14.
(12) Tanis, S. P. Tetrahedron Lett. 1982, 23, 3115.
(13) Tarui, H.; Mori, N.; Nishida, R.; Okabe, K.; Kuwahara, Y.
Biosci. Biotechnol. Biochem. 2002, 66, 135.
(14) Díaz, J. G.; Barba, B.; Herz, W. Phytochemistry 1994, 36,
703.
(15) Data for 8: TLC, Rf = 0.42 (100% hexanes). 1H NMR (300
MHz, CDCl3): d = 6.85 (s, 1 H), 5.22 (s, 1 H), 4.38 (s, 2 H),
1.23 (m, 3 H) 1.09 (d, J = 7.1 Hz, 18 H). 13C NMR (75 MHz,
CDCl3): d = 167.5, 129.6, 123.5, 84.2, 38.1, 17.4, 12.0.
(16) LaLonde, R. T.; Parakyla, H.; Hayes, M. P. J. Org. Chem.
1990, 55, 2847.
(17) Experimental Procedure: Magnesium turnings (212 mg,
8.70 mmol) were activated by washing successively with aq
10% HCl, H2O, acetone and Et2O, and dried in a vacuum
desiccator. The turnings were then flame-heated under an
atmosphere of dry nitrogen, allowed to cool, and 1,2-
dibromoethane (75 mL, 0.87 mmol) and anhyd THF (4 mL)
were added. The mixture was heated to reflux, stirred for 15
min, and the THF was cannulated out and replaced with
anhyd THF (3 mL). The resulting suspension was cooled to
0 °C and silyloxyfuran 8 (835 mg, 2.89 mmol), which was
purified on a short column (SiO2) before use, was added.
Stirring was continued at 0 °C for 1 h, at which time no more
starting material was detected by TLC. Anhyd THF (2 mL)
was added, and the mixture was divided into two equal parts
and placed into two separate dry vials at 0 °C. In each vial
was then added prenyl chloride (9; 80 mL, 0.70 mmol) at 0
°C, followed immediately by a solution of Li2CuCl4 (0.1 M,
350 mL, 0.035 mmol) in THF. Each reaction mixture was
stirred for 20 min at 0 °C and then poured (in parallel
fashion) into H2O (50 mL) and Et2O (50 mL), and a solution
of aq sat. NH4Cl was added until the two layers separated.
The product was extracted with Et2O (3 × 50 mL), washed
with brine (25 mL), dried (MgSO4), and concentrated in
vacuo to afford silyloxyfuran 10 as a yellowish oil that was
(18) Tamura, M.; Kochi, J. Synthesis 1971, 303.
(19) (a) Prepared in two steps from geranyl bromide: Torii, S.;
Uneyama, K.; Ishihara, M. Chem. Lett. 1975, 479. (b) For
the coupling of sulfone 4 with allylic halides see: Jeong, Y.
C.; Ji, M.; Lee, J. S.; Yang, J.-D.; Jin, J.; Baik, W.; Koo, S.
Tetrahedron 2004, 60, 10181; and references therein.
(20) Prepared in two steps from geranyl acetate: Dauben, W. G.;
Saugier, R. K.; Fleishhauer, I. J. Org. Chem. 1985, 50, 3767.
(21) Sato, K.; Inoue, S.; Onishi, A.; Uchida, N.; Minowa, N. J.
Chem. Soc., Perkin Trans. 1 1981, 761.
(22) For an alternative synthesis of alcohol 14 and its conversion
to chloride 15, see: Demotie, A.; Fairlamb, I. J. S.; Lu, F.-J.;
Shaw, N. J.; Spencer, P. A.; Southgate, J. Bioorg. Med.
Chem. Lett. 2004, 14, 2883.
(23) Data for 16: TLC, Rf = 0.77 (100% hexanes). 1H NMR (300
MHz, CDCl3): d = 6.58 (s, 1 H), 4.94-5.21 (m, 3 H), 1.89-
2.37 (m, 14 H), 1.53-1.65 (m, 11 H), 1.42 (m, 2 H), 1.17-
1.31 (m, 3 H), 1.09 (d, J = 7.1 Hz, 18 H), 1.06 (s, 6 H). 13
NMR (75 MHz, CDCl3): d = 156.5, 137.1, 135.9, 135.3,
127.6, 126.8, 126.5, 123.8, 123.5, 85.1, 40.2, 39.7, 39.6,
C
34.9, 32.6, 29.6, 28.5, 28.0, 27.8, 26.5, 25.9, 19.7, 19.4, 17.4,
15.9, 12.1, 10.5.
Synlett 2006, No. 15, 2480–2482 © Thieme Stuttgart · New York