Synthesis of tuckolide, a new cholesterol biosynthesis inhibitor

Article abstract of DOI:10.1021/jo961686+

Tuckolide (decarestrictine D), a 10-membered lactone isolated from P. corylophilum and polyporus tuberaster fungi that potently inhibits cholesterol biosynthesis, was synthesized. The key steps include a Sharpless catalytic asymmetric dihydroxylation reaction (AD) of the methoxymethyl (MOM) ether protected diene 2 and a direct Corey-Nicolaou lactonization reaction of seco-acid 1 with added silver perchlorate. The selectivity of the dihydroxylation step was found to be highly dependent on the nature of the protecting group adjacent to the diene in 2. The selectivity of the asymmetric dihydroxylation reaction of 2 indicates that both steric and electronic effects can lead to significant amounts of the undesired isomers. This synthesis establishes the absolute stereochemistry of tuckolide showing the C3 hydroxyl bearing carbon with an S-configuration comparable in an absolute sense to that in the lactone portion of the HMG-CoA reductase inhibitor compactin.

Full text of DOI:10.1021/jo961686+

8780
J . Org. Chem. 1996, 61, 8780-8785
Syn th esis of Tu ck olid e, a New Ch olester ol Biosyn th esis In h ibitor
Merritt B. Andrus* and Tzenge-Lien Shih
Purdue University, Department of Chemistry, West Lafayette, Indiana 47907
Received September 3, 1996X
Tuckolide (decarestrictine D), a 10-membered lactone isolated from P. corylophilum and polyporus
tuberaster fungi that potently inhibits cholesterol biosynthesis, was synthesized. The key steps
include a Sharpless catalytic asymmetric dihydroxylation reaction (AD) of the methoxymethyl
(MOM) ether protected diene 2 and a direct Corey-Nicolaou lactonization reaction of seco-acid 1
with added silver perchlorate. The selectivity of the dihydroxylation step was found to be highly
dependent on the nature of the protecting group adjacent to the diene in 2. The selectivity of the
asymmetric dihydroxylation reaction of 2 indicates that both steric and electronic effects can lead
to significant amounts of the undesired isomers. This synthesis establishes the absolute stereo-
chemistry of tuckolide showing the C3 hydroxyl bearing carbon with an S-configuration comparable
in an absolute sense to that in the lactone portion of the HMG-CoA reductase inhibitor compactin.
Tuckolide (decarestrictine D), recently isolated from
Penicillium corylophilum, simplicissimum1 and indepen-
dently from the Canadian Tuckahoe fungi polyporus
tuberaster,2 is an important new member of a growing
class of 10-membered lactone natural products (Figure
1).3 A general panel of whole cell screens demonstrated
that tuckolide potently inhibits liver cell cholesterol
biosynthesis (HEP cells, IC50 of 100 nm).1 This level of
activity is somewhat surprising since the structure of
tuckolide is far more simple than the well-known HMG-
CoA inhibitors mevinolin and compactin and other
synthetic cholesterol-lowering agents.4a In addition, it
appears that tuckolide is highly selective in that it
exhibits no significant antibacterial, antifungal, antipro-
tozoal, or antiviral activity.1 Toxicity studies further
revealed that tuckolide exhibits good tolerability, showing
a lack of change in a standard set of defined safety
parameters. A synthesis of tuckolide may then provide
for a new, more direct starting point for the design of
new HMG-CoA inhibitors.
While the relative stereochemistry was provided by
X-ray analysis,2 the absolute stereochemistry at the C3
hydroxyl-bearing carbon was assumed for the purposes
of the synthesis to be in an (S)-configuration by analogy
to the lactone portion of lovastatin (IC50 24 nm, HEP
assay).4 Other members of the 10-ring lactone class of
compounds include the decarestrictines A-C,1 phero-
mone phoracantholide I,5 diplodialides A-D,6 pyrenolide
A,7 and achaetolide.8 Synthetic attention has focused
primarily on the simplest compound of the class, phora-
cantholide,9 where both fragmentation/ring expansion
and direct lactonization routes have been developed. An
approach to pyrenolide has also recently appeared.10
F igu r e 1. Ten-membered lactone class of natural products
and the cholesterol biosynthesis inhibitor mevinolin.
The synthesis of medium-sized lactones is a difficult
challenge where destabilizing nonbonded, transannular
interactions and unfavorable entropic factors must be
overcome.3 Recent success with the eight-membered
lactone octalactin prompted the decision to employ a
(9) Synthesis of racemic material: Wakamatsu, T.; Akasaka, K.;
Ban, Y. Tetrahedron Lett. 1977, 18, 2755. Gerlach, H.; Kunzler, P.;
Oertle, K. Helv. Chim. Acta 1978, 61, 1226. Malherbe, R.; Bellus, D.
Helv. Chim. Acta 1978, 61, 3096. Takahashi, T.; Hasiguchi, S.; Kasuga,
K.; Tsuji, J . J . Am. Chem. Soc. 1978, 100, 7424. Trost, B. M.;
Verhoeven, T. R. J . Am. Chem. Soc. 1979, 101, 1595. Wakamatsu, T.;
Akasaka, K.; Ban, Y. J . Org. Chem. 1979, 44, 2008. Mahajan, J . R.; de
Araujo, H. C. Synthesis 1981, 49. Vedejs, E.; Powell, D. W. J . Am.
Chem. Soc. 1982, 104, 2046. Ono, N.; Miyaki, H.; Kaji, A. J . Org. Chem.
1984, 49, 4997. Suginome, H.; Yamada, S. Tetrahedron Lett. 1985,
3715. Wada, M.; Shige,hisa, T.; Akiba, K. Tetrahedron Lett. 1985, 5191.
Ohnuma, T.; Hata, N.; Miyachi, N.; Wakamatsu, T.; Ban, Y. Tetrahe-
dron Lett. 1986, 27, 219. enantioselective routes: Kitahara, T.; Koseki,
K.; Mori, K. Agric. Biol. Chem. 1983, 47, 389. Nagumo, S.; Suemune,
H.; Sakai, K. Tetrahedron 1992, 48, 8667. J ones, G. B.; Chapman, B.
J .; Huber, R. S.; Beaty, R. Tetrahedron: Asymmetry 1994, 5, 1199.
Enders, D.; Plant, A.; Drechel, K.; Prokopenko, O. F. Liebigs Ann. 1995,
1127.
* E-mail: mandrus@chem.purdue.edu.
X Abstract published in Advance ACS Abstracts, December 1, 1996.
(1) (a) Grabley, S.; Granzer, E.; Hutter, K.; Ludwig, D.; Mayer, M.;
Thiericke, R.; Till, G.; Wink, J . Phillips, S.; Zeeck, A. J . Antibiot. 1992,
45, 56. (b) Gohrt, A.; Zeeck, A.; Hutter, K.; Kirsch, R.; Kluge, H.;
Thiericke, R. J . Antibiot. 1992, 45, 66. (HEP-G2 cell assay, cholesterol
sodium [14C]acetate uptake.)
(2) Ayer, W. A.; Sun, M.; Browne, L. M.; Brinen, L. S. Clardy, J . J .
Nat. Prod. 1992, 55, 649.
(3) Rousseau, G. Tetrahedron 1995, 51, 2777.
(4) (a) Endo, A.; Hasumi, K. Nat. Prod. Rep. 1993, 541. (b) Abe, I.;
Tomesch, J . C.; Wattanasin, S.; Prestwich, G. D. J . Nat. Prod. 1994,
56, 279.
(5) Moore, B. P.; Brown, W. V. Aust. J . Chem. 1976, 29, 1365.
(6) Wada, K.; Ishida, T. J . Chem. Soc., Perkin Trans. 1 1979, 1154.
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(8) Bodo, B.; Molho, L.; Davoust, D.; Molho, D. Phytochemistry 1983,
22, 447.
(10) Synthesis of racemic material: Moricz, A.; Gassmann, E.; Bienz,
S. Hesse, M. Helv. Chim. Acta 1995, 78, 663.
S0022-3263(96)01686-6 CCC: $12.00 © 1996 American Chemical Society

Synthesis of Tuckolide
J . Org. Chem., Vol. 61, No. 25, 1996 8781
Sch em e 2
F igu r e 2. Retrosynthesis of tuckolide involving lactonization
of 1 and asymmetric dihydroxylation of diene 2.
Sch em e 1
flash chromatography from the desired anti-isomer 5
after addition of lithio(trimethylsilyl)acetylene.16 Isomer
4 was subjected to Mitsunobu conditions using p-ni-
trobenzoic acid (PNBA), triphenylphosphine, and diethyl
azodicarboxylate (DEAD) to give 5.17 The benzoate ester
and trimethylsilyl groups in 5 were removed in the same
step using potassium carbonate in methanol in 93% yield.
The resultant propargyl alcohol 6 was then combined
with identical material obtained from the trimethylsilyl
removal of the separated anti-isomer 5.
Coupling of 6 with vinyl iodide 718 using a catalytic
amount of palladium(0) and cuprous iodide produced the
(E)-enyne alcohol 8 in 84% yield (Scheme 2).19 Reduction
using LAH gave the corresponding (E,E)-diene20 which
was protected as its MOM ether 2a . Asymmetric cata-
lytic osmium tetroxide dihydroxylation of 2a using com-
mercial AD-mix-R reagent in the presence of methane-
sulfonamide according to the Sharpless conditions
generated the desired diol 9a in 78% yield.21 After
workup, the crude diol products were treated with 2,2-
dimethoxypropane under acid catalysis (PPTS, 5 mol %)
direct lactonization of the protected seco-acid 1.11 The
precursor seco-acid 1 was planned to be prepared using
a regioselective Sharpless asymmetric dihydroxylation of
the diene intermediate 2 (Figure 2). It was anticipated
that the nature of the protecting group adjacent to the
internal position of diene 2 may prove to be a critical
factor for achieving high regio- and diastereoselectivity.
Methoxymethyl (MOM) ether, acetate, p-nitrobenzoate,
and tert-butyldiphenylsilyl (TBDPS) ether were screened
to optimize the dihydroxylation step.
Our synthesis begins with protection of (R)-(-)-methyl
3-hydroxybutanoate12 as the p-methoxybenzyl (PMB)
ether,13 followed by reduction with 1 equiv of diisobutyl-
aluminum hydride (DIBAL) at -78 °C to give aldehyde
3 in 90% yield (Scheme 1).14 Acetylenic and vinyl
reagents were then investigated in an effort to find a
substrate-directed route to the desired anti-hydroxy
diastereomeric product 5. Lithium, magnesium, and
trimethylsilylalkynyl reagents both without and with
added Lewis acid failed to give more than essentially a
1:1 ratio of products.15 This lack of selectivity was
circumvented by separating the syn-isomer 4 by simple
(16) Compounds 4 and 5 were treated separately with dicyano-
dichloroquinone giving the isomeric p-methoxybenzylidine acetals. The
1H NMR J -couplings for the oxygen-bearing methine protons (12 Hz
axial, 5 Hz equatorial) were then used to make the syn/anti assign-
ments.
(17) Martin, S. F.; Dodge, J . A. Tetrahedron Lett. 1991, 32, 3017.
(18) Obtained from the reaction of DIBAL with 1-hydroxy-3-butyne
followed by trapping with iodine and protection as the TBS ether (30%
overall yield, unoptimized). Zweifel, G.; Whitney, C. C. J . Am. Chem.
Soc. 1967, 89, 2753. On, H. P.; Lewis, W.; Zweifel, G. Synthesis 1981,
999. Reich, H. J .; Eisenhart, E. K.; Olson, R. E.; Kelly, M. J . J . Am.
Chem. Soc. 1986, 108, 7791.
(11) (a) Buszek, K. R.; Sato, N.; J eong,Y. J . Am. Chem. Soc. 1994,
116, 5510. (b) Andrus, M. B.; Argade, A. B. Tetrahedron Lett. 1996,
37, 5049.
(19) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467.
(12) Seebach, D.; Zuger, M. F. Tetrahedron Lett. 1985, 25, 2747.
Seebach, D.; Beck, A. K.; Breitschuh, R. Org. Synth. 1991, 71, 39.
(13) (a) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahe-
dron Lett. 1988, 29, 4139. (b) Iversen, T.; Bundle, D. R. J . Chem. Soc.,
Chem. Commun. 1981, 1240.
(14) Keck, G. E.; Palani, A.; McHardy, S. F. J . Org. Chem. 1994,
59, 3121.
(20) Rossi, R.; Carpita, A. Synthesis 1977, 561. Holmes, A. B.; Tabor,
A. B.; Baker, R. J . Chem. Soc., Perkin Trans. 1 1991, 3307.
(21) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483. (b) Crispino, G. A.; J eong, K.; Kolb, H. C.; Wang
Z. M.; Xu, D.; Sharpless, K. B. J . Org. Chem. 1993, 58, 3785. (c) Xu,
D.; Crispino, G. A.; Sharpless, K. B. J . Am. Chem. Soc. 1992, 114, 7570.
(d) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J .; J eong, K.; Kwong, H.; Morikawa, K.; Wang Z. Xu, D.;
Zhang, X. J . Org. Chem. 1992, 57, 2768.
(15) Mead, K. T. Tetrahedron Lett. 1987, 28, 1019. Mauvais, A.;
Hetru, C.; Luu, B. Tetrahedron Lett. 1993, 34, 4337.

8782 J . Org. Chem., Vol. 61, No. 25, 1996
Andrus and Shih
Sch em e 3
F igu r e 3. A transition state depiction of the bis-dihydroqui-
nine phthalazine (DHQ2-PHAL)‚OsO4‚diene (2) complex that
leads to dihydroxylation of the less hindered olefin.
in methylene chloride to form the acetonides 9-11. It
was reasoned that the less hindered and more electron
rich olefin of the diene would be preferentially dihydroxy-
lated to give the desired (S,S)-diol according to the
mnemonic of Sharpless.21b,c While the reaction proceeded
as predicted, a small amount of the minor regioisomer
11a , which was easily separated by chromatography, was
also obtained in 5% yield. Other protecting groups, in
place of the MOM ether, were also investigated. Acetate
2b gave the expected product 9b in 90% de along with a
small amount of the isomeric diol 10b and a significant
amount (13%) of the regioisomeric product 11b. Dihy-
droxylation of the TBDPS ether 2c and the p-nitroben-
zoate ester 2d gave diols in lower yield and selectivity.
A model for the selectivity of the asymmetric dihy-
droxylation reaction with diene 9 is shown in Figure 3.
The selectivity is consistent with the transition state
arrangement model proposed by Corey where the phthal-
azine linker acts as a floor for the substrate, the remote
quinoline group functions as a perpendicular fence, the
proximal quinoline points up forming a U-shaped binding
pocket, and the osmium tetroxide is coordinated to the
opposite quinuclidine.22 The diene 9 is situated with the
ethylene-TBS ether portion extending out away from the
interior and the less hindered less reactive olefin end of
the diene is positioned inside the binding cavity where a
π-stacking interaction with the fence quinoline can occur.
The selectivity of the reaction is a function of both
electronic and steric nature of the protecting group (OP).
As the size of the protecting group on 2 (OP) increases
from MOM (2a ) to the TBS ether (2c), the selectivity
drops. More of the diol isomers (10 and 11) are formed
due to destabilizing steric interactions with the methoxy-
quinoline. The change to the more electron-withdrawing
ester protecting groups, acetate (2b) and p-nitrobenzoate
(2d ), also leads to formation of more diol isomers,
especially the regioisomer 11. This may be due to an
increased tendency to form a favorable π-stacking inter-
action with the protecting group and the methoxyquino-
line. This interaction pulls the diene down into the
binding cavity, leading to increased dihydroxylation of
the more hindered olefin. Studies by Corey and Sharp-
less have demonstrated that the nature of protecting
groups can have a pronounced effect on AD selectivity
with monosubstituted alkenes, in particular benzoate
esters and silyl ethers of allyl alcohols.23 Now with the
more extended diene system, simple changes in the allylic
protecting group have been shown to greatly affect the
selectivity of the AD reaction. The size of this portion of
the diene appears to be critical in that the simpler diene
substrate where R is replaced with hydrogen gave very
poor selectivity when reacted with AD-mix-R.24
To complete the synthesis of tuckolide, the TBS ether
of 9b was removed in high yield using TBAF followed by
oxidation using o-iodoxybenzoic acid (IBX)25 to generate
aldehyde 12 in 92% overall yield (Scheme 3). Sodium
chlorite oxidation of 12 to the corresponding carboxylic
acid26 followed by DDQ (dicyanodichloroquinone) removal
of the PMB ether were carried out in high yield to
produce hydroxy acid 1.13a Reagents that have proven
successful for large-ring lactonizations, carbodiimide and
mixed anhydride reagents,27 were screened without suc-
cess. In addition a promising new reagent p-nitrobenzoic
anhydride with catalytic Sc(OTf)3 also failed.28 Finally
it was found that the optimal conditions for cyclization
were those of Corey and Nicolaou, using 2,2′-dipyridyl
disulfide and triphenylphosphine with added silver per-
chlorate.29 The desired 10-membered protected lactone
was obtained in 33% isolated yield after chromatography.
The low yield is partially the result of MOM ether and
acetonide removal (∼15%) that occurred during the reflux
(23) Corey, E. J .; Guzman-Perez, A.; Noe, M. C. J . Am. Chem. Soc.
1995, 117, 10805. Corey, E. J .; Guzman-Perez, A.; Noe, M. C. J . Am.
Chem. Soc. 1994, 116, 12109. Wang, Z. -M.; Zhang, X.-L.; Sharpless,
K. B. Tetrahedron Lett. 1993, 34, 2267.
(24) P ) MOM, R ) H. Four isomers where formed with the
approximate ratio: (2:1:1:trace). The stereochemistry was not assigned.
(25) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J .
Org. Chem. 1995, 60, 7272.
(26) Bal, B. S.; Childers, W. E., J r.; Pinnick, H. W. Tetrahedron 1981,
37, 2091.
(27) For DCC, DMAP‚HCl, and DMAP, see: Boden, P. B.; Keck, G.
E. J . Org. Chem. 1985, 50, 2394; no lactone was obtained. Mixed
anhydride method: Inanaga, J .; Katsuki, T.; Takimoto, S.; Ouchida,
S.; Inone, K.; Nakano, A.; Okunkuda, N.; Yamaguchi, M. Chem. Lett.
1979, 1021.
(28) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J . Org.
Chem. 1996, 61, 4560.
(29) Corey, E. J .; Nicolaou, K. C. J . Am. Chem. Soc. 1974, 96, 5614.
Corey, E. J .; Nicolaou, K. C.; Melvin, L. S., J r. J . Am. Chem. Soc. 1975,
97, 653. Gerlach, von H.; Kunzler, P.; Oertle, K. Helv. Chim. Acta 1978,
61, 1226.
(22) Corey, E. J .; Noe, M. C. J . Am. Chem. Soc. 1996, 118, 319.

Synthesis of Tuckolide
J . Org. Chem., Vol. 61, No. 25, 1996 8783
organic layer was dried (MgSO4) and concentrated. Column
chromatography (CH2Cl2) furnished 3 (2.49 g, 90%) as a pale
yellow oil: 1H NMR δ 9.76 (1 H, t, J ) 2.2 Hz), 7.24 (2 H, d,
J ) 8.7 Hz), 6.86 (2 H, d, J ) 8.7 Hz), 4.53 (1 H, d, J ) 11.2
Hz), 4.40 (1 H, d, J ) 11.2 Hz), 4.06 (1 H, m), 3.79 (3 H, s),
2.67 (1 H, ddd, J ) 16.4, 7.5, 2.2 Hz), 2.49 (1 H, ddd, J ) 16.4,
5.0, 2.2 Hz), 1.28 (3 H, d, J ) 6.2 Hz); 13C NMR δ 201.5, 159.1,
130.2, 129.2, 113.7, 70.2, 69.8, 55.2, 50.4, 19.7. Anal. Calcd
for C12H16O3: C, 69.23; H, 7.69. Found: C, 68.85; H, 7.91.
4: (3R,5R)-3-Hyd r oxy-5-((4-m eth oxyben zyl)oxy)-1-(tr i-
m eth ylsilyl)-1-h exyn e. 5: (3S,5R)-3-Hyd r oxy-5-((4-m eth -
oxyben zyl)oxy)-1-(tr im eth ylsilyl)-1-h exyn e. A solution of
lithio(trimethylsilyl)acetylene was first generated in THF by
slowly adding n-butyllithium (2.43 M in hexanes, 10.3 mL, 25.1
mmol, 1.05 equiv) to (trimethylsilyl)acetylene (23.9 mmol, 1
equiv) at 0 °C. After the addition was complete, this mixture
was allowed to stir at that temperature for 30 min before being
cannulated into aldehyde 3. To a stirring solution of 3 (4.97
g, 23.9 mmol) in THF (45 mL) at -78 °C was added the lithium
trimethylacetylide solution in THF solution via cannula. After
the mixture was stirred for 40 min, the cooling bath was
removed, and this mixture was stirred at ambient temperature
for 30 min before being diluted with aqueous 30% NH4Cl (20
mL). The mixture was extracted with CH2Cl2, dried (MgSO4),
step. This lactonization, while low in yield, is remarkable
in that the parent unsubstituted hydroxy acid, 9-hydroxy-
nonanoic acid, does not lactonize under these conditions.
Substrates with suitably placed substituents within the
hydroxy acid tether can form medium-sized lactones in
high yields with the proper reagents, while the simple
parent unsubstituted hydroxy acids fail.11 Substrates
bearing substituents that can occupy pseudoequatorial
positions appear to enforce the proper transition state
leading to lactone formation. With the eight-membered
lactone octalactin, the effect was found to be additive and
reinforcing depending on the nature of the substituents.11b
Finally, one-step removal of the MOM ether and the
acetonide was then performed using Dowex resin in
methanol at rt to give (-)-tuckolide in 58% yield after
chromatography. The synthetic material was found to
be identical in all respects to the natural material (1H,
13C NMR, mp 118 °C, TLC, [R]D -67, nat. [R]D -62).1a
The absolute configuration, confirmed as shown by the
optical rotation of -62 with an (S)-C3 hydroxyl-bearing
carbon, suggests a compactin-like mode of action for
tuckolide.
and concentrated. Column chromatography (hex/CH2Cl2
)
1/1) afforded 4 (4.39 g, 60%) and 5 (1.933 g, 26.4%) as yellow
oils. Thin layer chromatography (hex/EtOAc ) 2/1) indicated
that the less polar spot corresponded to 5. The more polar
one was 4. Spectroscopic data for 4: 1H NMR δ 7.25 (2 H, d,
J ) 8.7 Hz), 6.87 (2 H, d, J ) 8.7 Hz), 4.49-4.71 (2 H, d + m
(merge)), 3.79 (4 H, br s), 3.24 (1 H, s), 2.02 (1 H, dt, J ) 14.1,
9.3, 8.3 Hz), 1.80 (1 H, ddd, J ) 14.1, 5.3, 3.8 Hz), 1.24 (3 H,
d, J ) 6.1 Hz), 0.16 (9 H, s); 13C NMR δ 159.1, 130.1, 129.3,
113.8, 106.3, 88.8, 73.8, 70.1, 61.8, 55.2, 44.5, 19.5, -0.19.
Spectroscopic data for 5: 1H NMR δ 7.30 (2 H, d, J ) 8.5 Hz),
6.88 (2 H, d, J ) 8.5 Hz), 4.49-4.65 (2 H, m), 4.40 (2 H, d, J
) 10.7 Hz), 3.80 (3 H, s), 3.58 (1 H, d, J ) 7.8 Hz), 1.94 (1 H,
ddd, J ) 14.4, 6.4, 3.3 Hz), 1.83 (1 H, ddd, J ) 14.4, 6.4, 3.3
Hz), 1.26 (3 H, d, J ) 6.2 Hz), 0.19 (9 H, s); 13C NMR δ 159.2,
130.2, 129.5, 113.9, 106.7, 89.1, 73.3, 70.6, 61.1, 55.2, 43.0, 19.3,
-0.07. Anal. Calcd for C17H26O3Si: C, 66.67; H, 8.50.
Found: C, 66.49; H, 8.72.
(3S,5R)-3-H yd r oxy-5-((4-m et h oxyb en zyl)oxy)-1-h ex-
yn e. To a stirring solution of 5 (0.696 g, 2.27 mmol) in THF
(10 mL) was added dropwise TBAF (1.0 M solution in THF, 3
mmol) at 0 °C. After addition was complete, the ice bath was
removed and the mixture was stirred at ambient temperature
for 15 min. The solution was poured into NH4Cl (saturated),
extracted with CH2Cl2, dried (MgSO4), and concentrated.
Column chromatography (CH2Cl2) afforded 6 (0.525 g, 99%)
as a pale yellow oil: 1H NMR δ 7.28 (2 H, d, J ) 8.5 Hz), 6.88
(2 H, d, J ) 8.5 Hz), 4.57 (2 H, br d), 4.41 (1 H, d, J ) 10.8
Hz), 4.08-4.15 (1 H, m), 3.79 (3 H, s), 3.71-3.86 (4 H, s + m),
2.46 (1 H, d, J ) 2.1 Hz), 1.97 (1 H, septet, J ) 14.6, 9.6, 3.3
Hz), 1.82 (1 H, ddd, J ) 14.6, 6.4, 3.2 Hz), 1.26 (3 H, d, J )
6.1 Hz); 13C NMR δ 159.2, 130.2, 129.5, 113.8, 84.7, 72.8, 72.6,
70.3, 60.4, 55.2, 42.8, 19.2. Anal. Calcd for C14H138O3: C,
71.79; H, 7.67. Found: C, 71.51; H, 7.68.
(3E,7S,9R)-1-O-(ter t-Bu tyld im eth ylsilyl)-7-h yd r oxy-9-
((4-m eth oxyben zyl)oxy)-3-d eca n en -5-yn -1-ol. To a de-
gassed benzene solution of 6 (0.873 g, 3.73 mmol) and vinyl
iodide 7 (1.3 g, 4.16 mmol) were added n-propylamine (0.46
mL, 5.59 mmol) and Pd(PPh3)4 (0.108 g, 2.5 mmol %). The
solution was stirred at ambient temperature for 45 min. The
reaction flask was protected from light by aluminum foil.
Copper(I) iodide (0.106 g, 0.556 mmol, 15 mol %) was added
to the mixture and stirring continued for 4 h. The mixture
was diluted with Et2O, washed with aqueous 10% NH4Cl, dried
(MgSO4), and concentrated. Column chromatography (hex/
EtOAc ) 9/1) furnished 8 (2.14 g, 84%) as a yellow oil: 1H
NMR δ 7.28 (2 H, d, J ) 8.4 Hz), 6.87 (2 H, d, J ) 8.4 Hz),
6.13 (1 H, ddd, J ) 16.0, 8.0, 7.0 Hz), 5.55 (1 H, d, J ) 16 Hz),
4.66 (1 H, br s), 4.52 (1 H, d, J ) 10.8 Hz), 4.40 (1 H, d, J )
10.8 Hz), 4.04-4.10 (1 H, m), 3.78 (3 H, s), 3.65 (2 H, t, J )
6.4 Hz), 2.31 (2 H, dd, J ) 13.3, 6.4 Hz), 1.97 (1 H, ddd, J )
14.4, 9.8, 3.2 Hz), 1.82 (1 H, ddd, J ) 14.4, 6.0, 3.2 Hz), 1.25
Exp er im en ta l Section
Gen er a l. Unless otherwise stated, all reactions were run
under
a nitrogen atmosphere. Anhydrous solvents were
freshly distilled before use: diethyl ether and tetrahydrofuran
(THF) were distilled from sodium benzophenone ketyl. Meth-
ylene chloride was distilled from CaH2. Triethylamine was
distilled from CaH2 and stored over NaOH. Dimethyl sulfox-
ide, n-propylamine, diisopropylethylamine, and methoxy-
methyl chloride were purchased and used without purification.
1H (300 MHz) and 13C NMR (75 MHz) spectra were recorded
on a QE-300 instrument. 1H NMR spectra were referenced
to residual CHCl3 at 7.26 ppm. 13C NMR spectra were
referenced to CDCl3 at 77.0 ppm. Multiplicities were reported
as the following: s (singlet), d (doublet), t (triplet), dd (doublet
of doublets), dt (doublet of triplets), ddd (doublet, doublet of
doublets), m (multiplet), br (broad), br s (broad singlet).
Combustion analyses and mass spectroscopy were conducted
at the Microanalysis Laboratory and Mass Spectrometry
Service Laboratory in the Chemistry Department at Purdue
University. Optical rotations were measured at 589.3 nm.
Column chromatography was gravity-driven using silica gel
60 (70-230 mesh) except where otherwise stated.
(3R)-(-)-Meth yl 3-((4-Meth oxyben zyl)oxy)bu ta n oa te.
To a stirring solution of (3R)-(-)-methyl-3-hydroxybutanoate
(2.38 g, 20.2 mmol) in CH2Cl2 (5 mL) and cyclohexane (20 mL)
was added a solution of p-methoxybenzyl trichloroacetimidate
in CH2Cl2 (10 mL + 5 mL rinse) via cannula. To this mixture
was added a catalytic amount of PPTS (0.51 g, 5-10 mol %),
and stirring continued at rt for 24 h. The reaction was
quenched by the addition of pyridine (1 mL), and the mixture
was diluted with H2O, extracted (CH2Cl2)), dried (MgSO4), and
concentrated. Column chromatography (hex/EtOAc ) 12/1)
afforded the PMB-protected ester (3.45 g, 74%) as a clear oil:
1
[R]D ) -22.0 (c 10.7, CHCl3); H NMR δ 7.24 (2 H, d, J ) 8.4
Hz), 6.86 (2 H, d, J ) 8.4 Hz), 4.50 (1 H, d, J ) 11.2 Hz), 4.42
(1 H, d, J ) 11.2 Hz), 3.98 (2 H, m), 3.78 (3 H, d, J ) 1.5 Hz),
3.67 (3 H, s), 2.64 (1 H, dd, J ) 15.1, 7.3 Hz), 2.42 (1 H, dd, J
) 15.1, 5.8 Hz), 1.24 (3 H, d, J ) 6.1 Hz); 13C NMR δ 171.8,
159.0, 130.5, 129.1, 113.6, 71.4, 70.4, 55.1, 51.4, 41.7, 19.7;
LRMS (EI) m/z (relative intensity) M+ 238, 137 (100), 121
(62.4). Anal. Calcd for C13H18O4: C, 65.55; H, 7.56. Found:
C, 65.22; H, 7.50.
(3R)-3-((4-Meth oxyben zyl)oxy)bu ta n a l. To a stirring
solution of ester (3.17 g, 13.3 mmol) in CH2Cl2 (50 mL) at -78
°C was added DIBAL (1.0 M solution in hexane, 16 mmol) via
syringe pump over 50 min. After addition was complete, this
mixture was stirred for 20 min. The reaction was quenched
by the addition of MeOH (3 mL), and the mixture was
extracted with CH2Cl2 and was filtered through Celite. The

8784 J . Org. Chem., Vol. 61, No. 25, 1996
Andrus and Shih
(3 H, d, J ) 6.0 Hz), 0.89 (10 H (3 × CH3 + OH), s), 0.05 (6 H,
s); 13C NMR δ 159.1, 141.0, 130.1, 129.4, 113.7, 110.9, 88.8,
83.2, 72.9, 70.3, 62.1, 60.9, 55.1, 43.2, 36.5, 25.8, 19.2, 18.2,
-5.4. Anal. Calcd for C24H38O4Si: C, 68.90; H, 9.09. Found:
C, 68.84; H, 9.38.
(4 H, m), 1.40 (3 H, s), 1.38 (3 H, s), 1.22 (3 H, d, J ) 6.1 Hz),
0.89 (9 H, s), 0.05 (6 H, s); 13C NMR δ 159.0, 134.8, 131.0,
129.4, 129.2, 113.7, 108.5, 94.3, 81.5, 77.5, 73.1, 71.2, 70.1, 59.7,
55.6, 43.7, 34.8, 27.2, 26.8, 25.9, 19.9, 18.2, -5.4. Anal. Calcd
for C29H50O7Si: C, 64.68; H, 9.29. Found: C, 64.41; H, 9.48.
(5E,3S,4S,7S,9R)-3,4-(Isop r op ylid en ed ioxy)-7-(m et h -
oxym eth oxy)-9-((4-m eth oxyben zyl)oxy)-5-d ecen a l. To a
stirring solution of 9a (0.441 g, 0.82 mmol) was added TBAF
(0.9 mmol, 1 M solution in THF) at rt. After being stirred for
3 h, the mixture was poured into H2O, extracted (CH2Cl2), and
dried (MgSO4). Without further purification, this colorless oil
was dissolved in DMSO (4 mL) and IBX (0.395 g, 1.49 mmol)
was added. After being stirred at ambient temperature for
14-20 h, this turbid solution was poured into H2O, extracted
(Et2O), and dried (MgSO4). Column chromatography (hex/
EtOAc ) 10/1 to 5/1) afforded the aldehyde 12 (0.319 g, 92%,
two steps) as a pale yellow to near-clear oil: 1H NMR δ 9.78
(1 H, t, J ) 2.0 Hz), 7.28 (2 H, d, J ) 8.6 Hz), 6.87 (2 H, d, J
) 8.6 Hz), 5.73 (1 H, dd, J ) 6.5 Hz), 5.63 (1 H, dd, J ) 15.5,
6.5 Hz), 4.62 (1 H, d, J ) 6.7 Hz), 4.53 (1 H, d, J ) 10.9 Hz),
4.50 (1 H, d, J ) 6.7 Hz), 4.28-4.35 (2 H, d + m, J ) 10.9 Hz),
3.99-4.20 (2 H, m), 3.67-3.89 (4 H, s + m), 3.41 (3 H, s), 2.50-
2.70 (2 H, m), 1.55-1.82 (2 H, m), 1.41 (3 H, s), 1.40 (3 H, s),
1.21 (3 H, d, J ) 6.1 Hz); 13C NMR δ 199.5, 159.0, 136.5, 130.9,
129.2, 127.5, 113.7, 109.4, 94.6, 81.3, 75.4, 73.4, 71.1, 70.1, 55.6,
55.2, 45.1, 43.6, 27.0, 26.9, 19.9. Anal. Calcd for C23H34O7:
C, 65.40; H, 8.06. Found: C, 65.13; H, 8.34.
(3E,5E,7S,9R)-1-O-(ter t-Bu tyld im eth ylsilyl)-7-h yd r oxy-
9-((4-m eth oxyben zyl)oxy)-3,5-d eca d ien -1-ol. To a stirring
solution of 8 (1.685 g, 4.03 mmol) in THF (2 mL) was added
lithium aluminum hydride (1.0 M solution in Et2O, 7.5 mmol)
at 0 °C. After addition was complete, the ice bath was removed
and the reaction mixture was stirred at ambient temperature
for 2 h. The reaction mixture was cooled to 0 °C. To this
mixture was slowly added Na2SO4‚10H2O until the release of
hydrogen gas ceased. The solid was filtered washing with
methylene chloride, and the organic layer was concentrated.
Column chromatography (hex/EtOAc ) 9/1) afforded (E,E)-
diene (1.56 g, 92%) as a pale yellow oil: 1H NMR δ 7.26 (2 H,
d, J ) 8.7 Hz), 6.87 (2 H, d, J ) 8.7 Hz), 6.12 (1 H, ddd, J )
15.0, 10.5, 0.9 Hz), 6.07 (1 H, dd, J ) 15.0, 5.8 Hz), 4.54 (1 H,
d, J ) 11.1 Hz), 4.42 (1 H, br s), 4.35 (1 H, d, J ) 11.1 Hz),
3.74-3.94 (4 H, s + m (merge)), 3.65 (2 H, t, J ) 6.8 Hz), 2.98
(1 H, s), 2.30 (2 H, td, J ) 13.1, 6.6 Hz), 1.54-1.87 (2 H, m),
1.24 (3 H, d, J ) 6.2 Hz), 0.89 (9 H, s), 0.48 (6 H, s); 13C NMR
δ 159.2, 134.1, 131.3, 130.7, 130.3, 129.8, 129.4, 113.8, 72.3,
70.2, 69.4, 62.8, 55.2, 43.0, 36.3, 25.9, 19.3, 18.3, -5.3; LRMS
(EI) m/z (relative intensity) M+ 420, 363 (31), 121 (100). Anal.
Calcd for C24H40O5Si: C, 68.57; H, 9.52. Found: C, 68.35; H,
9.74.
(5E,3S,4S,7S,9R)-9-Hyd r oxy-3,4-(isop r op ylid en ed ioxy)-
7-(m eth oxym eth oxy)-5-d ecen oic Acid . To a stirring solu-
tion of aldehyde 12 (0.277 g, 0.656 mmol) in tert-butyl alcohol
(3.3 mL) and 2-methyl-2-butene (1.7 mL, 16.0 mmol) was
added a solution of NaClO2 (0.6 g, 6.63 mmol) and NaH2-
PO4‚H2O (0.725 g, 5.25 mmol) in H2O (5 mL) dropwise at rt.
This mixture was stirred at that temperature for 5 h. At the
end of which time, the turbid solution was diluted with CH2-
Cl2. The organic layer was washed with H2O and NaCl
(saturated) and dried (MgSO4) to give a clear oil. Without
further purification, this oil was dissolved in CH2Cl2 (6 mL).
To this mixture were added NaHCO3 (0.138 g, 1.64 mmol) and
DDQ (0.378 g, 1.67 mmol), sequentially, and the mixture was
stirred at rt for 5 h. At the end of which time, this brown
solution was directly applied on the top of the column for
chromatography (hex/EtOAc ) 1/1, 15% wet silica gel) furnish-
ing a red oil. This oil was repurified by column chromatog-
raphy using the same solvent system to supply hydroxy acid
1 (0.186 g, 89%, two steps) as a pale yellow to yellow oil: 1H
NMR δ 5.81 (1 H, dd, J ) 15.5, 6.7 Hz), 5.68 (1 H, dd, J )
15.5, 6.7 Hz), 4.67 (1 H, d, J ) 6.8 Hz), 4.60 (1 H, d, J ) 6.8
Hz), 4.36 (1 H, dd, J ) 11.9, 6.1 Hz), 3.96-4.2 (3 H, m), 2.69
(1 H, dd, J ) 15.2, 6.7 Hz), 2.55 (1 H, dd, J ) 15.2, 4.7 Hz),
1.69 (2 H, t, J ) 5.8 Hz), 1.43 (3 H, s), 1.42 (3 H, s), 1.20 (3 H,
d, J ) 6.2 Hz); 13C NMR δ 174.1, 135.1, 128.3, 109.3, 94.5,
81.0, 76.6, 74.2, 64.4, 55.6, 43.7, 36.7, 26.9, 26.8, 23.2; HRMS
m/z for C15H26O7 (M + H)+ calcd 319.1757, found 319.1766.
(5E,3S,4S,7S,9R)-3,4-(Isop r op ylid en ed ioxy)-7-(m et h -
oxym eth oxy)-9-m eth yl-5-n on en e La cton e. To hydroxy
acid 1 (50 mg, 0.157 mmol) was added 2,2′-dipyridyl disulfide
(Aldrithol-2, 47 mg, 0.213 mmol) and Ph3P (58 mg, 0.221
mmol). The mixture was dissolved in 10 mL of degassed
benzene. The solution was stirred at rt for 3 h. At the end of
time, the mixture was added to refluxing benzene (105 mL)
containing AgClO4 (0.168 g, 0.81 mmol) over 12 h via a syringe
pump. After the first addition was complete, the residual was
washed with another 8 mL of benzene that was then added to
the refluxing reaction mixture over 4 h. The solution was
refluxed for an additional 2 h after the second addition was
completed. This mixture was cooled to room temperature and
filtered through Celite. The solvent was concentrated, and the
mixture was purified by flash column chromatography (hex/
EtOAc ) 10/1, 230-400 mesh silica gel) to afford an insepa-
rable mixture of conformational isomers with ca. 7.25:5:1 ratio
(15.4 mg, 33%) as a pale yellow semi-oil: 1H NMR δ 5.69-
5.94 (m), 5.53 (dd, J ) 15.6, 9.3 Hz), 4.90-5.10 (septet + m),
4.69 (1 H, d, J ) 6.7 Hz), 4.50 (1 H, d, J ) 6.7 Hz), 3.40-4.30
(3 H, m), 3.33 and 3.35 (s, 3 H), 3.07 (dd, J ) 14.8, 5.4 Hz),
2.99 (dd, J ) 13.2, 5.4 Hz), 2.79 (dd, J ) 11.5, 2.5 Hz), 2.42
(3E,5E,7S,9R)-1-O-(ter t-Bu t yld im et h ylsilyl)-7-(m et h -
oxym eth oxy)-9-((4-m eth oxyben zyl)oxy)-3,5-d eca d ien -1-
ol. To a stirring solution of (E,E)-diene (0.632 g, 1.5 mmol) in
CH2Cl2 (8 mL) were added diisopropylethylamine (1.37 mL,
7.86 mmol) and methoxymethyl chloride (0.57 mL, 7.5 mmol)
at 0 °C. After 1 h, the mixture was warmed to ambient
temperature, and stirring continued for 8 h. The mixture was
poured into NH4Cl (saturated) and was extracted with CH2-
Cl2. The organic layer was dried (MgSO4) and purified by
column chromatography (hex/EtOAc ) 20/1 to 18/1) to afford
2a (0.681 g, 98%) as a pale yellow oil: 1H NMR δ 7.29 (2 H, d,
J ) 8.7 Hz), 6.88 (2 H, d, J ) 8.7 Hz), 6.18 (1 H, dd, J ) 14.8,
10.5 Hz), 6.06 (1 H, dd, J ) 14.8, 10.5 Hz), 5.67 (1 H, dd, J )
14.8, 7.1 Hz), 5.42 (1 H, dd, J ) 14.8, 8.0 Hz), 4.70 (1 H, d, J
) 6.7 Hz), 4.53 (1 H, d, J ) 10.9 Hz), 4.49 (1 H, d, J ) 6.7 Hz),
4.36 (1 H, d, J ) 10.9 Hz), 4.26-4.33 (1 H, m), 3.73-3.87 (4
H, s + br), 3.65 (2 H, t, J ) 6.7 Hz), 3.54 (3 H, s), 2.30 (2 H,
dd, J ) 13.4, 6.7 Hz), 1.67-1.76 (2 H, m), 1.22 (3 H, d, J ) 6.1
Hz), 0.89 (9 H, s), 0.05 (6 H, s); 13C NMR δ 159.0, 132.5, 131.4,
131.3, 131.2, 130.9, 129.1, 113.6, 93.8, 73.5, 71.4, 70.1, 62.6,
55.5, 55.1, 43.7, 36.2, 25.8, 19.9, 18.2, -5.3. Anal. Calcd for
C26H44O5Si: C, 67.24; H, 9.48. Found: C, 66.83; H, 9.74.
(5E,3S,4S,7S,9R)-1-O-(ter t-Bu tyld im eth ylsilyl)-3,4-(iso-
p r op ylid en ed ioxy)-7-(m eth oxym eth oxy)-9-((4-m eth oxy-
ben zyl)oxy)-5-d ecen -1-ol. To a stirring solution of 2a (3.01
g, 6.49 mmol) in t-BuOH/H2O (1:1 (v/v), 64 mL) was added
AD-mix-R (Aldrich, 1.4 g/mmol 2a , 9.08 g) and methane-
sulfonamide (1.23 g, 12.9 mmol) at 0 °C. This mixture was
gradually warmed to ambient temperature and was stirred
vigorously for 12 h. An additional amount of AD-mix-R (2.0
g) was added, and stirring continued for an additional 9 h until
the starting material was consumed. To the yellow mixture
was added Na2SO3 (3.27 g, 25.9 mmol), and vigorous stirring
continued for 30 min. The mixture was poured into H2O (20
mL) and was extracted with CH2Cl2. The aqueous layer was
extracted with EtOAc. The combined organic extracts were
dried (MgSO4) and concentrated. The resulting oil was dis-
solved in CH2Cl2 (35 mL). To this solution were added 2,2-
dimethoxypropane (24 mL, 0.195 mol) and PPTS (0.166 g, 10
mol %), and the mixture was stirred at rt overnight. After
completion, the mixture was poured into NaHCO3 (saturated),
extracted (CH2Cl2), dried (MgSO4), and concentrated. Column
chromatography (hex/EtOAc ) 20/1 to 12.5/1) provided 9a
(2.701 g, 77.4%) as a pale yellow oil: 1H NMR δ 7.29 (2 H, d,
J ) 8.6 Hz), 6.88 (2 H, d, J ) 8.6 Hz), 5.67 (2 H, m), 4.65 (1 H,
d, J ) 6.7 Hz), 4.53 (1 H, d, J ) 10.7 Hz), 4.51 (1 H, d, J ) 6.7
Hz), 4.23-4.45 (2 H, d + m, J ) 10.7 Hz), 4.05 (1 H, dd, J )
8.6, 6.0 Hz), 3.69-3.91 (7 H, s + m), 3.35 (3 H, s), 1.54-1.87

Synthesis of Tuckolide
J . Org. Chem., Vol. 61, No. 25, 1996 8785
(dd, J ) 14.8, 10.7 Hz), 2.29 (dd, J ) 13.2, 11.5 Hz), 2.09 (dd,
J ) 14.3, 5.7 Hz), 1.61-1.91 (2 H, m), 1.44 (3 H, s), 1.41 (3 H,
s), 1.25 (3 H, d, J ) 6.6 Hz).
(c 0.26, CHCl3) [lit. [R]D ) -62 (c 0.4, CHCl3)]; mp ) 118-120
°C (lit. mp ) 114-115 °C).
Tu ck olid e. To a stirring solution of acetonide MOM-
protected lactone (10 mg, 0.033 mmol) in MeOH (2 mL) was
added Dowex-50 at rt. The mixture was stirred at that
temperature for 4 days. At the end of this time, the resin was
removed by filtration and washed with MeOH. The solvent
was evaporated, and the residual material was chromato-
graphed (hex/EtOAc ) 1/1, 15% wet silica gel) to give tuckolide
(4.2 mg, 58%) as a pale yellow to transparent solid: 1H NMR
δ 5.91 (1 H, dd, J ) 15.8, 8.3 Hz), 5.85 (1 H, dd, J ) 15.8, 2.4
Hz), 5.25 (1 H, ddq, J ) 14.0, 6.4, 1.9 Hz), 4.54-4.78 (1 H, br
s), 4.43 (1 H, dd, J ) 3.7, 1.6 Hz), 4.20 (1 H, ddd, J ) 11.0,
8.3, 4.0 Hz), 3.94-4.13 (1 H, brs), 2.61 (1 H, d, J ) 14.4, 1.9
Hz), 2.40 (1 H, d, J ) 14.4, 6.2 Hz), 1.92 (1 H, ddd, J ) 14.0,
4.0, 1.9 Hz), 1.81 (1 H, d, J ) 14.0, 11.0 Hz), 1.52-1.72 (2 ×
OH, br s), 1.25 (3 H, d, J ) 6.4 Hz); 13C NMR δ 174.9, 133.7,
129.9, 73.9, 72.5, 72.2, 68.2, 43.0, 33.2, 21.3 (lit. (CD3OD) 174.7,
135.9, 129.4, 75.4, 73.6, 73.1, 69.4, 44.2, 35.6, 21.6); [R]D ) -67
Ack n ow led gm en t. We gratefully thank the Na-
tional Science Foundation, Purdue Research Founda-
tion, and American Cancer Society, Indiana Section, for
funding. We thank Prof. William A. Ayer (University
of Alberta) for providing a sample of natural tuckolide.
We also thank Arlene Rothwell for mass spectroscopy
and H. D. Lee for elemental analysis.
Su p p or tin g In for m a tion Ava ila ble: Proton and 13C
NMR spectra for hydroxy acid 1, MOM acetonide tuckolide,
and (-)-tuckolide (5 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from ACS;
see any current masthead page for ordering information.
J O961686+