Stereoselective synthesis of (-)-spicigerolide

Article abstract of DOI:10.1021/jo8025753

(-)-Spicigerolide was stereoselectively synthesized from a protected (S)-lactaldehyde. The synthesis of the polyacetylated framework relied on two Zn-mediated stereoselective additions of alkynes to aldehydes as well as a regiocontrolled [3,3]-sigmatropic

Full text of DOI:10.1021/jo8025753

Stereoselective Synthesis of (-)-Spicigerolide†
Yohan Georges, Xavier Ariza,* and Jordi Garcia*
Departament de Qu´ımica Orga`nica, UniVersitat de Barcelona, Mart´ı i Franque`s 1,
08028 Barcelona, Spain
xariza@ub.edu
ReceiVed NoVember 20, 2008
(-)-Spicigerolide was stereoselectively synthesized from a protected (S)-lactaldehyde. The synthesis of
the polyacetylated framework relied on two Zn-mediated stereoselective additions of alkynes to aldehydes
as well as a regiocontrolled [3,3]-sigmatropic rearrangement of an allylic acetate. The pyranone moiety
was constructed via ring-closing metathesis.
Introduction
(-)-Spicigerolide (1) belongs to a family of polyacetate
pyranone-containing natural products that exhibit a broad
spectrum of pharmacological properties (Figure 1).1 These
polyoxygenated 6-heptenyl-5,6-dihydro-R-pyrones have been
found in several species of the genus Hyptis and other related
genera.2,3 In particular, spicigerolide has been isolated from
Hyptis spicigera, a plant that is used in traditional Mexican
medicine to treat gastrointestinal disturbances, skin infections,
wounds and insects bites. The Michael acceptor moiety present
in all of these molecules potentially endows them with cytotoxic
properties. Indeed, spicigerolide and some of its stereoisomers
have shown cytotoxic activity in some cell tumoral lines.1,4 As
a result of their biological activity, several stereoselective
approaches have already been applied to this group of poly-
† Dedicated to Professor Josep Font on the occasion of his 70th birthday.
(1) (a) Pereda-Miranda, R.; Fragoso-Serrano, M.; Cerda-Garc´ıa-Rojas, C. M.
Tetrahedron 2001, 57, 47–53. (b) Falomir, E.; Murga, J.; Carda, M.; Marco,
J. A. Tetrahedron Lett. 2003, 44, 539–541. (c) Falomir, E.; Murga, J.; Ruiz, P.;
Carda, M.; Marco, J. A.; Pereda-Miranda, R.; Fragoso-Serrano, M.; Cerda-Garc´ıa-
Rojas, C. M. J. Org. Chem. 2003, 68, 5672–5676.
(2) (a) Birch, A. J.; Butler, D. N. J. Chem. Soc. 1964, 4167–4168. (b)
Alemany, A.; Ma´rquez, C.; Pascual, C.; Valverde, S.; Perales, A.; Fayos, J.;
Mart´ınez-Ripoll, M. Tetrahedron Lett. 1979, 37, 3583–3586. (c) Achmad, S.;
Høyer, T.; Kjær, A.; Makmur, L.; Norrestam, R. Acta Chem. Scand. 1987, 41B,
599–609. (d) Davis-Coleman, M. T.; English, R. B.; Rivett, D. E. A. Phytochem-
istry 1987, 26, 1497–1499. (e) Davies-Coleman, M. T.; Rivett, D. E. A.
Phytochemistry 1996, 41, 1085–1092. (f) Collet, L. A.; Davies-Coleman, M. T.;
Rivett, D. E. A. Phytochemistry 1998, 48, 651–656. (g) Boalino, D. M.; Connolly,
J. D.; McLean, S.; Reynolds, W. F.; Tinto, W. F. Phytochemistry 2003, 64, 1303–
1307.
FIGURE 1. Some naturally occurring 5,6-dihydropyran-2-ones.
oxygenated compounds. Thus, syntheses of (+)-anamarine (2),5
(-)-anamarine,6 and spicigerolide (1)1 have been described from
carbohydrates. In contrast, the synthesis of (+)-hyptolide (3)7
is based on carbonyl additions, and there are alternate ap-
(4) For related compounds with cytotoxic properties, see: Pereda-Miranda,
R.; Herna´ndez, L.; Villavivencio, M. J.; Novelo, M.; Ibarra, P.; Chai, H.; Pezzuto,
J. M. J. Nat. Prod. 1993, 56, 583–593.
(5) Lichtenthaler, F. W.; Lorenz, K. Tetrahedron Lett. 1987, 28, 6437–6440.
(6) (a) Lichtenthaler, F. W.; Lorenz, K.; Ma, W.-Y. Tetrahedron Lett. 1987,
28, 47–50. (b) Valverde, S.; Hernandez, A.; Herradon, B.; Rabanal, R. M.; Martin-
Lomas, M. Tetrahedron 1987, 43, 3499–3504.
(3) The structure of synargentolide A has been questioned recently: Garc´ıa-Fortanet,
J.; Murga, J.; Carda, M.; Marco, J. A. ArkiVoc 2005, ix, 175–188.
2008 J. Org. Chem. 2009, 74, 2008–2012
10.1021/jo8025753 CCC: $40.75 2009 American Chemical Society
Published on Web 02/05/2009

Synthesis of (-)-Spicigerolide
SCHEME 1
SCHEME 3
SCHEME 2
groups as acetates and using only silicon-derived protecting
groups for transient protections. Thus, the R,ꢀ-unsaturated
aldehyde 7 could arise from the related alkynol 8 obtained by
stereoselective alkynylation of aldehyde 9 with a protected
2-propyn-1-ol.
We considered that the key aldehyde 9 could be prepared
from the protected (S)-lactaldehyde 10 and propargylic acetate
11 via our stereoselective approach to polyhydroxylated
arrays.10a Therefore, we had to combine two stereoselective
reactions: (i) Carreira’s asymmetric alkynylation of aldehydes12
with propargylic esters13 and (ii) stereoselective [3,3]-sigmat-
ropic rearrangement of an allylic acetate (Scheme 3). Ozonolysis
of the olefin moiety would afford aldehyde 9.
proaches to (+)-anamarine (2) that exploit asymmetric dihy-
droxylation8 or aldol reactions.9
As a part of our work on the stereocontrolled construction
of sugar-type polyhydroxylated frameworks,10 we have explored
a novel synthetic approach to these polyacetylated lactones.
Specifically, we focused on the synthesis of the (-)-spicigerolide
(1) as a representative example of this class of compounds. We
envisaged that our recently reported methodology10a could be
applied easily to the synthesis of 1. In contrast to the previous
synthesis,1b,c our strategy creates the stereocenters independently
rather than relying on carbohydrates as chiral starting materials
(Scheme 1).
Analysis of the structure of (-)-spicigerolide prompted us
to consider that the pyranone could be obtained by selective
olefin ring-closing metathesis (RCM) of the homoallyl acrylate
6, which in turn could be prepared via asymmetric allylation of
aldehyde 7 followed by acylation (Scheme 2).11 Regarding the
remaining polyoxygenated chain, we tried to minimize the use
of protecting groups by maintaining the oxygenated functional
Results and Discussion
As expected, (R)-1-phenylprop-2-ynyl acetate (R)-11 reacted
with aldehyde 10 under Carreira’s conditions12 mediated by (-)-
N-methylephedrine ((-)-NME) to afford anti,syn-12 in 95% yield
as a single stereoisomer. The configuration of the alkyne 11 did
not affect the diastereomeric ratio.14 Analogously, the same
Felkin-Anh-type addition was observed when (S)-11 was used,
leading to the single stereoisomer anti,anti-12 (Scheme 4).15
Treatment of anti,syn-12 with LiAlH4 reduced the triple
bond to an E-alkene with concomitant alcohol deprotection
leading to a triol (13), which was acetylated in situ with acetic
anhydride to form the triacetate 14 in 87% yield for the two
steps (Scheme 5). Having achieved the right stereochemistry
at C-2 and C-3 in 14, we next attempted to transfer the
chirality from C-6 to C-4 by a Pd-catalyzed [3,3]-sigmatropic
(12) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806–1807. (b) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001,
123, 9687–9688.
(7) (a) Murga, J.; Garc´ıa-Fortanet, J.; Carda, M.; Marco, J. A. Tetrahedron
Lett. 2003, 44, 1737–1739. (b) Garc´ıa-Fortanet, J.; Murga, J.; Carda, M.; Marco,
J. A. Tetrahedron 2004, 60, 12261–12267.
(8) (a) Gao, D.; O’Doherty, G. A. Org. Lett. 2005, 7, 1069–1072. (b) Gao,
D.; O’Doherty, G. A. J. Org. Chem. 2005, 70, 9932–9939.
(9) D´ıaz-Oltra, S.; Murga, J.; Falomir, E.; Carda, M.; Marco, J. A.
Tetrahedron 2004, 60, 2979–2985.
(10) (a) Ariza, X.; Garcia, J.; Georges, Y.; Vicente, M. Org. Lett. 2006, 8,
4501–4504. (b) Boyer, J.; Allenbach, Y.; Ariza, X.; Garcia, J.; Georges, Y.;
Vicente, M. Synlett 2006, 1895–1898.
(13) For the use of allylic esters in Carreira’s alkynylations, see: (a) El-Sayed,
E.; Anand, N. K.; Carreira, E. M. Org. Lett. 2001, 3, 3017–3020. (b) Amador,
M.; Ariza, X.; Garcia, J.; Ortiz, J. Tetrahedron Lett. 2002, 43, 2691–2694. (c)
Diez, R. S.; Adger, B.; Carreira, E. M. Tetrahedron 2002, 58, 8341–8344.
(14) However, addition in the presence of (+)-NME led to the opposite
configuration of the new stereocenter (90:10 dr), showing that stereoselectivity
is ruled by either the (+) or (-)-NME used. As reported in ref 13a, the influence
of the configuration of the silicon-protected lactaldehyde on the stereochemistry
of the addition is low when an achiral ligand was used.
(11) For reviews on stereoselective approaches to these R,ꢀ-unsaturated
δ-lactones, see: (a) Boucard, V.; Broustal, G.; Campagne, J.-M. Eur. J. Org.
Chem. 2007, 225–236. (b) Marco, J. A.; Carda, M.; Murga, J.; Falomir, E.
Tetrahedron 2007, 63, 2929–2958.
(15) The relative stereochemistry of syn and anti adducts was confirmed by
comparison of the spectral data following the analysis in Kojima, N.; Maezaki,
N.; Tominaga, H.; Asai, M.; Yanai, M.; Tanaka, T. Chem. Eur. J. 2003, 9, 4980–
4990.
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Georges et al.
SCHEME 4
SCHEME 5
SCHEME 6
rearrangement.10a,16 Assuming a six-membered transition state
having a chair conformation, we expected this reaction to
be stereospecific and, therefore, that the configuration of C-6
in 14 would be conserved at C-4 in 15. Moreover, this
rearrangement is an equilibrium that can be shifted sterically
or electronically. In our case, we anticipated that formation
of a double bond conjugated with a phenyl group would favor
formation of the isomeric allylic triacetate 15. Indeed, when
triacetate 14 was treated with 5% PdCl2(NCPh)2 in CH2Cl2
for 24 h, the rearranged product 15 was obtained as a major
product in 70% yield (Scheme 5).
The key aldehyde 9 was obtained by ozonolysis followed by
treatment with Me2S. This unstable aldehyde was immediately
submitted to Carreira’s asymmetric alkynylation with 2-tert-
butyldiphenylsilyloxy-1-propyne (16) mediated by (+)-N-
methylephedrine. Unfortunately, aldehyde 9 did not react
efficiently under the standard Carreira conditions; instead, 3
equiv of alkyne 16, zinc triflate, (+)-NME, and triethylamine
were required to achieve good yields.17 Under these conditions,
partial acetyl deprotection was observed. Therefore, the crude
mixture was acetylated again to afford tetraacetate 8 in 71%
yield (for three steps) and as a single diastereoisomer. Partial
hydrogenation of the triple bond to the Z-olefin with Lindlar’s
catalyst afforded allylic acetate 17 in 87% yield. Cleavage of
the silicon protecting group with TBAF caused the acetyl groups
to migrate to the primary alcohol. Fortunately, deprotection with
HF/pyridine furnished allylic alcohol 18 in 91% yield without
any migration (Scheme 6).
We then focused on assembling the pyranone ring. Swern
oxidation of alcohol 18 afforded aldehyde 7 (Scheme 7).
Stereoselective allylation of 7 was initially attempted with
(Ipc)2B-allyl without success.18 However, Duthaler’s Ti-TAD-
DOL-mediated allylation19 with 19 provided the expected
homoallylic alcohol 20 in good yield (84%) as a separable
diastereomeric mixture (87:13). Acylation of alcohol 20 with
acryloyl chloride followed by RCM20 in the presence of the
second-generation Grubbs’ ruthenium catalyst (21, 2% mol)
afforded the (-)-spicigerolide (1), whose spectroscopic data was
identical to that of the natural product.1
(18) Ramachandran, P. V.; Chen, G.-M.; Brown, H. C. Tetrahedron Lett.
1997, 38, 2417–2420.
(16) For recent stereoselective applications, see: (a) Saito, S.; Kuroda, A.;
Matsunaga, H.; Ikeda, S. Tetrahedron 1996, 52, 13919–13932. (b) Trost, B. M.;
Lee, C. B. J. Am. Chem. Soc. 2001, 123, 3687–3696.
(17) The fact that the stoichiometry of NME, Zn(OTf)2, and amine base
should be increased to improve the yields and enantioselectivities in some
reluctant substrates was first reported by Boyal, D.; Lo´pez, F.; Sasaki, H.; Frantz,
D.; Carreira, E. M. Org. Lett. 2000, 2, 4233–4236.
(19) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321–2336.
(20) For a recent review on ring-closing metathesis reactions, see: (a) Fu¨rstner,
A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043. (b) Trnka, T.; Grubbs, R. H.
Acc. Chem. Res. 2001, 34, 18–29. (c) Connon, S. J.; Blechert, S. Angew. Chem.,
Int. Ed. 2003, 42, 1900–1923. (d) Hoveyda, A. H.; Zhugralin, A. R. Nature
2007, 450, 243–251.
2010 J. Org. Chem. Vol. 74, No. 5, 2009

Synthesis of (-)-Spicigerolide
SCHEME 7
did not show significant changes). The reaction was quenched
with saturated potassium and sodium tartrate. The aqueous layer
was extracted with CH2Cl2. The combined organic layer was
dried over MgSO4 and evaporated under reduced pressure. Triol
13 was obtained as a colorless oil and used as a crude mixture
for the next transformation: Rf 0.31 (AcOEt); [R]25 +5.9 (c
D
1
0.58, CHCl3); IR (film) 3347, 2922, 1452, 1366 cm-1; H NMR
(300 MHz, CDCl3) δ 7.36-7.28 (m, 5H), 5.97 (dd, J ) 6.0,
15.3 Hz, 1H), 5.86 (dd, J ) 6.0, 15.3 Hz, 1H), 5.23 (d, J ) 6.0
Hz, 1H), 4.08 (dd, J ) 3.3, 6.0 Hz, 1H), 3.87 (qd, J ) 3.3, 6.3
Hz, 1H), 2.90-2.40 (bs, 3H), 1.11 (d, J ) 6.3 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 142.5, 135.6, 128.8, 128.6, 127.8,
126.2, 75.5, 74.4, 70.2, 17.8; HMRS (ESI+) calcd for
C12H16O3Na (M + Na)+ 231.0992, found 231.0899.
(1R,4R,5S,E)-1-Phenylhex-2-ene-1,4,5-triyl Triacetate (14).
Anhydrous Et3N (5.02 mL, 36.0 mmol), Ac2O (2.84 mL, 30.0
mmol), and DMAP (36 mg, 0.30 mmol) were added to a solution
of triol 13 (6 mmol from anti,syn-12) in anhydrous CH2Cl2 (100
mL) under nitrogen atmosphere at room temperature. The mixture
was stirred at room temperature until TLC showed no significant
changes. The solvent was removed under reduced pressure, and
the mixture was purified by flash chromatography with silica gel
(hexane/AcOEt 80/20) to give 14 (1.662 g, 87% from anti,syn-12)
as a colorless oil: Rf 0.69 (CH2Cl2); [R]25D -21.8 (c 1.05, CHCl3);
IR (film) 2924, 1737, 1455, 1369, 1226 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.36-7.28 (m, 5H), 6.28 (d, J ) 6.0 Hz, 1H), 5.94 (ddd,
J ) 1.1, 6.0, 15.6 Hz, 1H), 5.68 (ddd, J ) 1.3, 6.7, 15.6 Hz, 1H),
5.38 (ddt, J ) 1.0, 3.9, 6.7 Hz, 1H), 5.04 (qd, J ) 3.9, 6.6 Hz,
1H), 2.10 (s, 3H), 2.08 (s, 3H), 1.97 (s, 3H), 1.17 (d, J ) 6.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 170.3, 169.9, 169.8, 138.6,
133.1, 128.6, 128.3, 127.1, 126.6, 75.0, 74.4, 70.3, 21.2, 21.0, 21.0,
15.1; HMRS (ESI+) calcd for C18H22O6Na (M + Na)+ 357.1309,
found 357.1299.
Conclusion
We have reported an enantioselective synthesis of (-)-
spicigerolide (1) that features independent stereocontrolled
access to the different chiral centers. It constitutes the first
application to natural product synthesis of our recently
developed strategy for building polyhydroxylated chains,
which is based on Pd(II) [3,3]-sigmatropic rearrangements
and Carreira’s alkynylations. Furthermore, we were able to
shorten the sequence by minimizing the use of protecting
groups.
(2S,3S,4S,E)-6-Phenylhex-5-ene-2,3,4-triyl Triacetate (15).
PdCl2(NCPh)2 (95 mg, 0.25 mmol) was added to a solution of 14
(1.66 g, 4.97 mmol) in CH2Cl2 (30 mL) and stirred at room
temperature for 24 h. The solvent was removed under reduced
pressure, and the crude mixture was purified by flash chromatog-
raphy with silica gel (hexane/Et2O 70/30) to afford 15 (1.165 mg,
70%) as a colorless solid: Rf 0.41 (hexane/Et2O 50/50); mp 68-70
°C; [R]25D +21.2 (c 0.40, CHCl3); IR (film) 2925, 1740, 1457, 1370,
Experimental Section
(1S,4R,5S)-5-tert-Butyldiphenylsilyloxy-4-hydroxy-1-phen-
ylhex-2-ynyl Acetate (anti,syn-12). Zn(OTf)2 (2.4 g, 6.6 mmol)
was heated under vacuum in a flask. (-)-NME (1.3 g, 7.2 mmol)
was added, and the flask was purged with nitrogen. Anhydrous
toluene (10 mL) and Et3N (1.0 mL, 7.2 mmol) were added, and
the mixture was stirred at room temperature for 2 h 30 min. A
solution of alkyne (R)-11 (1.04 g, 6.00 mmol) in toluene (5 mL)
was added, and the mixture was stirred at room temperature for 30
min. Then, a solution of (S)-2-tert-butyldiphenylsilyloxypropanal
(10, 2.25 mg, 7.20 mmol) in toluene (5 mL) was added, and the
final mixture was stirred for 4 h (until TLC did not show significant
changes). The reaction was quenched with saturated aqueous NH4Cl
and CH2Cl2. The organic layer was washed with brine, dried over
MgSO4, and evaporated under reduced pressure. The crude mixture
was purified by flash chromatography with silica gel (hexane/AcOEt
70/30) to afford anti,syn-12 (2781 mg, 95%, >98% dr) as a
1
1218 cm-1; H NMR (300 MHz, CDCl3) δ 7.38-7.25 (m, 5H),
6.69 (d, J ) 15.8 Hz, 1H), 6.06 (dd, J ) 7.3, 15.9 Hz, 1H), 5.64
(ddd, J ) 0.9, 5.7, 7.3 Hz, 1H), 5.30 (t, J ) 5.8 Hz, 1H), 5.07 (m,
1H), 2.10 (s, 3H), 2.09 (s, 3H), 2.02 (s, 3H), 1.24 (d, J ) 6.5 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 170.3, 170.1, 169.9, 135.8,
134.9, 128.6, 128.4, 126.7, 122.7, 74.1, 72.2, 67.9, 21.0, 21.0, 20.8,
15.4; HMRS (ESI+) calcd for C18H22O6Na (M + Na)+ 357.1309,
found 357.1301.
(2S,3S,4S,5S)-8-(tert-Butyldiphenylsilyloxy)oct-6-yne-
2,3,4,5-tetrayl Tetraacetate (8). A solution of 15 (167 mg, 0.500
mmol) in a mixture CH2Cl2/MeOH (4 mL/1 mL) was treated with O3
at -78 °C until a blue color appeared. The flask was purged with N2,
and Me2S (183 µL, 2.50 mmol) was added at -78 °C. The reaction
was stirred overnight at room temperature. The solvent was removed
under reduced pressure, and the residue was coevaporated with toluene
(4 × 30 mL) at 40 °C. The aldehyde 9 was obtained as a colorless oil
and used as a crude mixture for the next transformation. Zn(OTf)2
(600 mg, 1.65 mmol) was activated by heating under vacuum. (+)-
NME (323 mg, 1.80 mmol) was added, and the flask was purged with
N2. Anhydrous toluene (2 mL) and Et3N (251 µL, 1.80 mmol) were
added, and the mixture was vigorously stirred for 2 h. A solution of
alkyne 16 (441 mg, 1.50 mmol) in toluene (0.7 mL) was added and
stirred for 30 min, aldehyde 9 (0.5 mmol from 15) was added in
solution in toluene (0.7 mL), and the mixture was stirred for 2 h 30
min. The reaction was quenched with saturated aqueous NH4Cl. The
organic layer was washed with brine, dried over MgSO4, and
evaporated under reduced pressure. The crude mixture was treated with
4-DMAP (3.0 mg, 0.025 mmol), anhydrous Et3N (280 µL, 2.00 mmol),
colorless oil: Rf 0.30 (hexane/AcOEt 80/20); [R]25 -5.9 (c 0.95,
D
CHCl3); IR (film) 3460, 2932, 1742, 1457, 1369, 1227 cm-1; H
1
NMR (400 MHz, CDCl3) δ 7.70-7.65 (m, 4H), 7.55-7.49 (m,
2H), 7.46-7.41 (m, 2H), 7.40-7.33 (m, 7H), 6.52 (d, J ) 1.5 Hz,
1H), 4.32 (ddd, J ) 1.6, 3.2, 6.9 Hz, 1H), 4.00 (qd, J ) 3.2, 6.3
Hz, 1H), 2.42 (d, J ) 6.9 Hz, 1H), 2.08 (s, 3H), 1.12 (d, J ) 6.3
Hz, 3H), 1.06 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 169.6, 136.8,
135.9, 135.7, 133.5, 133.4, 129.9, 129.8, 128.9, 128.6, 127.8, 127.7,
127.6, 85.1, 82.6, 72.1, 67.3, 65.5, 26.9, 21.0, 19.3, 18.4; HMRS
(ESI+) calcd for C30H34O4SiNa (M + Na)+ 509.2119, found
509.2120.
(1R,4R,5S,E)-1-Phenylhex-2-ene-1,4,5-triol (13). A solution of
alkyne anti,syn-12 (2.92 g, 6.00 mmol) in anhydrous THF (20
mL) was added dropwise at 0 °C to a suspension of LiAlH4
(1.14 g, 30.0 mmol), in anhydrous THF (50 mL) under N2. The
mixture was stirred at room temperature for 15 h (until TLC
J. Org. Chem. Vol. 74, No. 5, 2009 2011

Georges et al.
and Ac2O (142 µL, 1.50 mmol) in anhydrous CH2Cl2 (10 mL) under
N2. The reaction was stirred until TLC showed no significant change.
The solvent was removed under reduced pressure. Purification by flash
chromatography with silica gel (hexane/AcOEt 80/20) gave 8 (198
mg, 71% for 3 steps) as a colorless oil: Rf 0.23 (hexane/AcOEt 80/
20); [R]25D +11.2 (c 0.80, CHCl3); IR (film) 2933, 1752, 1429, 1371
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.70-7.65 (m, 4H), 7.46-7.36
(m, 6H), 5.49 (dt, J ) 1.6, 7.5 Hz, 1H), 5.45 (dd, J ) 2.7, 7.5 Hz,
1H), 5.29 (dd, J ) 2.7, 8.0 Hz, 1H), 4.97 (dq, J ) 6.4, 8.0 Hz, 1H),
4.30 (d, J ) 1.6 Hz, 2H), 2.10 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 2.04
(s, 3H), 1.20 (d, J ) 6.4 Hz, 3H), 1.04 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 170.0, 170.0, 169.6, 169.3, 135.6, 132.8, 129.8, 127.7, 85.2,
78.6, 71.0, 69.6, 67.1, 61.5, 52.5, 26.6, 21.0, 20.7, 20.7, 20.6, 19.1,
16.4; HMRS (ESI+) calcd for C32H40O928SiNa (M + Na)+ 619.2334,
found 619.2308; HMRS (ESI+) calcd for C32H40O929SiNa (M + Na)+
620.2329, found 620.2342.
(2S,3S,4S,5S,Z)-8-(tert-Butyldiphenylsilyloxy)oct-6-ene-
2,3,4,5-tetrayl Tetraacetate (17). Quinoline (3 µL) and Pd/CaCO3
poisoned with lead (Lindlar’s catalyst, 5 wt %, 40 mg) were added to
a solution of 8 (147 mg, 0.246 mmol) in AcOEt (8 mL). The mixture
was shaken under hydrogen (1-2 atm) until TLC showed complete
conversion. The suspension was filtered through a short pad of Celite.
The organic layer was washed with 2 N HCl (2 × 1 mL) and brine,
dried over MgSO4, and evaporated under reduced pressure. Purification
by flash chromatography with silica gel (hexane/AcOEt 90/10) gave
17 (129 mg, 87%) as a colorless oil: Rf 0.65 (hexane/AcOEt 70/30);
[R]25D -37.8 (c 1.19, CHCl3); IR (film) 2935, 1750, 1429, 1370 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.71-7.66 (m, 4H), 7.45-7.36 (m,
6H), 5.87 (dt, J ) 6.0, 11.2 Hz, 1H), 5.41-5.28 (m, 3H), 5.23 (dd, J
) 2.3, 8.4 Hz, 1H), 4.90 (dq, J ) 6.4, 8.4 Hz, 1H), 4.40 (ddd, J )
1.6, 6.0, 13.7 Hz, 1H), 4.33 (ddd, J ) 1.6, 6.0, 13.7, 1H), 2.00 (s,
3H), 1.98 (s, 3H), 1.98 (s, 3H), 1.91 (s, 3H), 1.16 (d, J ) 6.4 Hz, 3H),
1.04 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.0, 170.0, 169.8,
169.4, 136.6, 135.6, 135.5, 133.5, 133.4, 129.7, 127.7, 124.1, 71.0,
69.7, 67.0, 66.3, 60.2, 26.7, 21.0, 20.9, 20.6, 20.6, 19.1, 16.6; HMRS
(ESI+) calcd for C32H42O928SiNa (M + Na)+ 621.2490, found
621.2485; HMRS (ESI+) calcd for C32H40O929SiNa (M + Na)+
622.2486, found 622.2516.
(S,S)-TADDOL19 (19, 77 mg, 0.13 mmol) in anhydrous Et2O (2 mL)
were stirred for 1 h 30 at 0 °C. A solution of aldehyde 7 (0.090 mmol
from 18) in Et2O (1 mL) was added dropwise at -78 °C and stirred
for 1 h. The reaction was quenched with pH 7 buffer (1 mL) and stirred
for 30 min. The aqueous layer was extracted with CH2Cl2. The organic
layer was dried over MgSO4 and evaporated under reduced pressure.
Purification by flash chromatography with silica gel (hexane/AcOEt
70/30) gave 20 (30.2 mg, 84%) and its minor diastereomer (4.5 mg,
12%) as colorless oils: Rf 0.25 (hexane/AcOEt 70/30); [R]25 -13.6
D
1
(c 1.06, CHCl3); IR (film) 3529, 2934, 1748, 1436, 1372 cm-1; H
NMR (300 MHz, CDCl3) δ 5.87-5.66 (m, 3H), 5.48 (m, 1H), 5.37
(dd, J ) 3.9, 6.4 Hz, 1H), 5.25 (dd, J ) 3.9, 7.1 Hz, 1H), 5.17-5.07
(m, 2H), 4.96 (dq, J ) 6.4, 7.0 Hz, 1H), 4.54 (m, 1H), 2.66 (bs, 1H),
2.30 (m, 2H), 2.10 (s, 3H), 2.08 (s, 3H), 2.02 (s, 3H), 2.02 (s, 3H),
1.22 (d, J ) 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.4, 170.3,
169.9, 169.9, 139.1, 133.8, 123.8, 118.1, 71.2, 69.9, 67.3, 67.2, 67.1,
41.4, 21.0, 20.9, 20.8, 20.7, 15.8; HMRS (ESI+) calcd for C19H28O9Na
(M + Na)+ 423.1626, found 423.1623.
(2S,3S,4S,5S,8R,Z)-8-(Acryloyloxy)undeca-6,10-diene-
2,3,4,5-tetrayl Tetraacetate (6). Anhydrous Et3N (30 µL, 0.21
mmol), acryloyl chloride (9 µL, 0.106 mmol), and 4-DMAP (0.3 mg,
0.003 mmol) were added to a solution of 20 (21.3 mg, 0.053 mmol)
in anhydrous CH2Cl2 (1 mL) under N2. The reaction was stirred until
TLC showed no significant change. The solvent was removed under
reduced pressure. Purification by flash chromatography with silica gel
(hexane/AcOEt 80/20) gave 6 (11.8 mg, 50%) as a colorless oil: Rf
0.50 (hexane/AcOEt 70/30); [R]25D -37.0 (c 0.84, CHCl3); IR (film)
2925, 1748, 1372 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.38 (dd, J
) 1.6, 17.3 Hz, 1H), 6.09 (dd, J ) 10.4, 17.3 Hz, 1H), 5.89 (m, 1H),
5.81 (dd, J ) 1.6, 10.4 Hz, 1H), 5.78-5.58 (m, 3H), 5.45 (m, 1H),
5.36 (dd, J ) 2.3, 8.7 Hz, 1H), 5.28 (dd, J ) 2.3, 8.6 Hz, 1H),
5.14-5.04 (m, 2H), 4.95 (dq, J ) 6.3, 8.6 Hz, 1H), 2.43 (m, 2H),
2.16 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H), 1.97 (s, 3H), 1.19 (d, J ) 6.3
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.3, 170.1, 170.0, 169.5,
164.8, 134.5, 132.8, 130.6, 128.7, 127.4, 118.2, 71.0, 69.6, 69.2, 66.9,
66.6, 39.0, 21.1, 20.9, 20.7, 20.6, 16.6; HMRS (ESI+) calcd for
C22H30O10Na (M + Na)+ 477.1731, found 477.1719.
(-)-Spicigerolide (1). A 0.01 M solution of 6 (10.8 mg, 0.025
mmol) in CH2Cl2 (2.5 mL) was refluxed in presence of ben-
zylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidin-ylidene]dichlo-
ro(tricyclo-hexylphosphine)ruthenium (21, Grubbs’ second generation
catalyst) (0.4 mg, 0.0005 mmol) for 2 h. The solvent was removed
under reduced pressure. Purification by flash chromatography with
silica gel (hexane/AcOEt 80/20) gave 1 (9.8 mg, 94%) as a colorless
oil: Rf 0.11 (hexane/AcOEt 70/30); [R]25D -23.0 (c 1.34, CHCl3); IR
(film) 2925, 1735, 1457, 1372 cm-1; 1H NMR (400 MHz, CDCl3) δ
6.90 (ddd, J ) 2.6, 5.8, 9.8 Hz, 1H), 6.05 (ddd, J ) 0.9, 2.5, 9.8 Hz,
1H), 5.79 (dd, J ) 9.3, 10.7 Hz, 1H), 5.51-5.29 (m, 5H), 4.96 (dq, J
) 6.3, 8.4 Hz, 1H), 2.51 (dddd, J ) 0.9, 4.3, 5.8, 18.5 Hz, 1H), 2.35
(ddt, J ) 2.5, 11.1, 18.5 Hz, 1H), 2.12 (s, 3H), 2.12 (s, 3H), 2.04 (s,
3H), 2.03 (s, 3H), 1.19 (d, J ) 6.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.2, 170.1, 169.9, 169.9, 163.5, 144.8, 132.7, 128.6, 121.4,
73.7, 70.9, 69.2, 66.9, 66.2, 29.2, 21.0, 20.9, 20.8, 20.7, 16.6; HMRS
(ESI+) calcd for C20H26O10Na (M + Na)+ 449.1418, found 449.1415.
(2S,3S,4S,5S,Z)-8-Hydroxyoct-6-ene-2,3,4,5-tetrayl Tetra-
acetate (18). Hydrogen fluoride pyridine (500 µL) was added to a
solution of 17 (176 mg, 0.294 mmol) in anhydrous CH3CN (5 mL)
and stirred until TLC showed complete conversion. The mixture was
poured onto a solution of KF (10 mL), NaHCO3 (20 mL), and Et2O
(30 mL). The aqueous layer was extracted with Et2O. The organic
layer was dried over MgSO4 and evaporated under reduced pressure.
Purification by flash chromatography with silica gel (hexane/AcOEt
50/50) gave 18 (96 mg, 91%) as a colorless oil: Rf 0.08 (hexane/AcOEt
70/30); [R]25 -19.3 (c 0.650, CHCl3); IR (film) 3531, 2939, 1746,
D
1432, 1372 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.94 (dt, J ) 6.8,
11.1 Hz, 1H), 5.60 (dd, J ) 7.8, 9.9 Hz, 1H), 5.45 (dd, J ) 9.9, 11.1
Hz, 1H), 5.38 (dd, J ) 3.1, 7.7 Hz, 1H), 5.28 (dd, J ) 3.1, 7.9 Hz,
1H), 4.95 (dq, J ) 6.4, 7.8 Hz, 1H), 4.34 (m, 1H), 4.15 (m, 1H), 2.36
(dd, J ) 5.8, 6.9 Hz, 1H), 2.12 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H),
2.03 (s, 3H), 1.21 (d, J ) 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 170.4, 170.1, 170.1, 169.8, 135.8, 125.2, 71.2, 69.7, 67.0, 66.8, 58.5,
21.0, 21.0, 20.7, 20.6, 16.2; HMRS (ESI+) calcd for C16H24O9Na (M
+ Na)+ 383.1313, found 383.1305.
Acknowledgment. This work has been supported by the
Ministerio de Ciencia y Tecnologia (BQU2003-01269 and
CTQ2006-13249). We thank the Generalitat de Catalunya and
Universitat de Barcelona for doctorate studentships to Y.G. The
authors also acknowledge a generous gift of Novozym 435 from
Novozymes Spain SA.
(2S,3S,4S,5S,8R,Z)-8-Hydroxyundeca-6,10-diene-2,3,4,5-
tetrayl Tetraacetate (20). Oxalyl chloride (21 µL, 0.25 mmol) and
DMSO (30 µL, 0.42 mmol) were stirred in anhydrous CH2Cl2 (2 mL)
for 45 min at -78 °C. A solution of 18 (32.5 mg, 0.090 mmol) in
CH2Cl2 (1 mL) was added and stirred for 30 min at -78 °C. Et3N
(116 µL, 0.822 mmol) was added and stirred 15 min at -78 °C then
20 min at room temperature. The mixture was poured onto Et2O (50
mL), and ammonium salts were filtered. The solvent was removed
under reduced pressure, and the residue was coevaporated with toluene
(4 × 20 mL) at 40 °C. The aldehyde 7 was obtained as a colorless oil
and used as a crude mixture for the next transformation. Allylmag-
nesium bromide (1 M in Et2O, 117 µL, 0.117 mmol) and CpTiCl-
1
Supporting Information Available: Copies of H and 13C
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO8025753
2012 J. Org. Chem. Vol. 74, No. 5, 2009