Total synthesis of trilobin

Article abstract of DOI:10.1021/jo982110i

The first total synthesis of (+)-trilobin (1a) was achieved in 22 steps and 2.74% yield by means of the 'naked' carbon skeleton strategy, with all of the asymmetric centers in the bis-THF fragment of the molecules being produced by the Sharpless asymmetric dihydroxylation and the asymmetric epoxidation reactions. The synthetic Scheme represents a general methodology for the preparation of trans,cis-bis-THF ring systems.

Full text of DOI:10.1021/jo982110i

J . Org. Chem. 1999, 64, 2381-2386
2381
Tota l Syn th esis of Tr ilobin
Anjana Sinha,† Santosh C. Sinha,† Subhash C. Sinha,*,† and Ehud Keinan*,†,‡,§
Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research
Institute, 10550 North Torrey Pines Road, La J olla, California 92037, and Department of Chemistry,
Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel
Received October 19, 1998
The first total synthesis of (+)-trilobin (1a ) was achieved in 22 steps and 2.74% yield by means of
the “naked” carbon skeleton strategy, with all of the asymmetric centers in the bis-THF fragment
of the molecules being produced by the Sharpless asymmetric dihydroxylation and the asymmetric
epoxidation reactions. The synthetic scheme represents a general methodology for the preparation
of trans,cis-bis-THF ring systems.
In tr od u ction
lectively placed onto a nonfunctionalized, unsaturated
carbon skeleton.6
Approximately 300 acetogenins have been isolated
from various Annonaceae plants, many of which have
shown remarkable cytotoxic, antitumor, antimalarial,
immunosuppressive, pesticidal, and antifeedant activi-
ties.1 The past few years have witnessed an explosion of
activity in the isolation, structural elucidation, and
synthesis of these long-chain fatty acid derivatives.2,3 Our
synthetic approaches to the various classes of the An-
nonaceous acetogenins are based on either a convergent
strategy or a linear scheme. The convergent synthesis,
which employs asymmetric oxygenation reactions with
chirality transfer methods, can provide access to libraries
of bis-THF stereoisomers.4 Alternatively, in the “naked”
carbon skeleton strategy,5 all oxygen functions are se-
A dominant structural feature that appears in more
than 40% of the Annonaceous acetogenins, particularly
in those showing the highest antitumor activity, is a 10-
carbon fragment containing two adjacent tetrahydrofuran
rings flanked by two hydroxyl groups. Studies on the
primary mode of action have established the role of such
acetogenins as powerful, potent inhibitors of the NADH-
ubiquinone oxidoreductase (complex I) of mammalian and
insect mitochondrial electron-transport systems.7 More
recent studies have also demonstrated that these aceto-
genins are efficient inhibitors of the ubiquinone-linked
NADH oxidase that is specifically active in the plasma
membranes of tumor cells and is inactive in normal cells.8
These combined actions may lead to programmed cell
death (apoptosis) and could account for the observed high
potencies of these compounds.9 Two recently discovered
members of this subgroup, trilobin (1a ) and trilobacin
(1b) (Figure 1) have attracted much interest as a result
of their high biological activity.10 Studies with human
solid-tumor cell lines show that these acetogenins are
cytotoxic agents over a billion times more potent than
adriamycin. Interestingly, the corrected structures of
both 1a and 1b exhibit two very unusual features: an
* Phone: (619) 784-8511. Fax: (619) 784-8732. E-mail: keinan@
scripps.edu or subhash@scripps.edu.
† The Scripps Research Institute.
‡ Technion-Israel Institute of Technology.
§ Incumbent of the Benno Gitter and Ilana Ben-Ami chair of
Biotechnology, Technion.
(1) (a) Gu, Z.-M.; Zhao, G.-X.; Oberlies, N. H.; Zeng, L.; McLaughlin,
J . L. In Recent Advances in Phytochemistry; Arnason, J . T., Mata, R.,
Romeo, J . T., Eds.; Plenum Press: New York, 1995, pp 249-310. (b)
Rupprecht, J . K.; Hui, Y.-H.; McLaughlin, J . L. J . Nat. Prod. 1990,
53, 237. (c) Fang, X.-P.; Rieser, M. J .; Gu, Z.-M.; Zhao, G.-X.;
McLaughlin, J . L. Phytochem. Anal. 1993, 4, 27.
(2) For review articles, see: (a) Figade´re, B. Acc. Chem. Res. 1995,
28, 359. (b) Koert, U. Synthesis 1995, 115. (c) Hoppe, R.; Scharf, H.-D.
Synthesis 1995, 1447. (d) Marshall, J . A.; Hinkle, K. W.; Hagedorn, C.
E. Isr. J . Chem. 1997, 37, 97.
(3) For total synthesis of Annonaceous aceogenins and analogues
by other groups, see: (a) Hoye, T. R.; Hanson, P. R.; Kovelesky, A. C.;
Ocain, T. D.; Zhuang, Z. J . Am. Chem. Soc. 1991, 113, 9369. (b) Hoye,
T. R.; Hanson, P. R. Tetrahedron Lett. 1993, 34, 5043. (c) Tam, V. T.;
Chaboche, C.; Figadere, B.; Chappe, B.; Hieu, B. C.; Cave´, A.
Tetrahedron Lett. 1994, 35, 883. (d) Trost, B. M.; Shi, Z. P. J . Am.
Chem. Soc. 1994, 116, 7459. (e) Koert, U. Tetrahedron Lett. 1994, 35,
2517. (f) Yao Z. J .; Wu, Y. L. Tetrahedron Lett. 1994, 35, 157. (g)
Makabe, H.; Tanaka, A.; Oritani, T. J . Chem. Soc., Perkin Trans. 1
1994, 1975. (h) Konno, H.; Makabe, H.; Tanaka, A.; Oritani, T. Biosci.
Biotechnol. Biochem. 1995, 59, 2355. (i) Hoye, T. R.; Tan, L. Tetrahe-
dron Lett. 1995, 36, 1981. (j) Yao Z. J .; Wu, Y. L. J . Org. Chem. 1995,
60, 1170. (k) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki,
S. J . Org. Chem. 1995, 60, 4419. (l) Hoye, T. R.; Ye, Z. J . Am. Chem.
Soc. 1996, 118, 1801. (m) Konno, H.; Makabe, H.; Tanaka, A.; Oritani,
T. Tetrahedron Lett. 1996, 37, 5393. (n) Konno, H.; Makabe, H.;
Tanaka, A.; Oritani, T. Tetrahedron 1996, 52, 9399. (o) Franck, X.;
Figadere, B.; Cave´, A. Tetrahedron Lett. 1996, 37, 1593. (p) Marshall,
J . A.; Chen, M. J . Org. Chem. 1997, 62, 5996. (q) Marshall, J . A.;
Hinkle, K. W. J . Org. Chem. 1997, 62, 5989. (r) Trost, B. M.; Calkins,
T. L.; Bochet, C. G. Angew. Chem., Int. Ed. Engl. 1997, 36, 2632. (s)
Marshall, J . A.; Hinkle, K. W. Tetrahedron Lett. 1998, 39, 1303. (t)
Marshall, J . A.; J iang, H. J . Tetrahedron Lett. 1998, 39, 1493.
(4) (a) Sinha, S. C.; Keinan, E. J . Am. Chem. Soc. 1993, 115, 4891.
(b) Sinha, S. C.; Sinha-Bagchi, A.; Yazbak, A.; Keinan, E. Tetrahedron
Lett. 1995, 36, 9257. (c) Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E. J .
Am. Chem. Soc. 1995, 117, 1447. (d) Sinha, S. C.; Sinha, A.; Yazbak,
A.; Keinan, E. J . Org. Chem. 1996, 61, 7640. (e) Sinha, S. C.; Sinha,
A.; Sinha, S. C.; Keinan, E. J . Am. Chem. Soc. 1997, 119, 12014. (f)
Sinha, S. C.; Sinha, S. C.; Keinan, E. J . Am. Chem. Soc. 1998, 120,
4017. (g) Yazbak, A.; Sinha, S. C.; Keinan, E. J . Org. Chem. 1998, 63,
5863. (h) Neogi, P.; Doundoulakis, T.; Yazbak, A.; Sinha, S. C.; Sinha,
S. C.; Keinan, E. J . Am. Chem. Soc. 1998, 120, 11279.
(5) (a) Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E. J . Org. Chem. 1993,
58, 7789. (b) Sinha, S. C.; Keinan, E. J . Org. Chem. 1994, 59, 949. (c)
Sinha, S. C.; Keinan, E. J . Org. Chem. 1997, 62, 377.
(6) Keinan, E.; Sinha, A.; Yazbak, A.; Sinha, S. C.; Sinha, S. C. Pure
Appl. Chem. 1997, 69, 423.
(7) (a) Ahammadsahib, K. I.; Hollingworth, R. M.; McGovern, P. J .;
Hui, Y.-H.; McLaughlin, J . L. Life Sci. 1993, 53, 1113. (b) Degli Esposti,
M.; Ghelli, A.; Ratta, M.; Cortes, D. Biochem. J . 1994, 301, 161. (c)
Hollingworth, R. M.; Ahammadsahib, K. I.; Gadelhak, G.; McLaughlin,
J . L. Biochem. Soc. Trans. 1994, 22, 230.
(8) Morre, D. J .; de Cabo, R.; Farley, C.; Oberlies, N. H.; McLaughlin,
J . L. Life Sci. 1995, 56, 343.
(9) Wolvetang, E. J .; J ohnson, K. L.; Krauer, K.; Ralph, S. J .;
Linnane, A. W. FEBS Lett. 1994, 339, 40.
(10) (a) Zhao, G.-X.; Hui, Y.-H.; Rupprecht, J . K.; McLaughlin J . L.;
Wood, K. V. J . Nat. Prod. 1992, 55, 347. (b) Zhao, G.-X.; Gu, Z.-M.;
Zeng, L.; Chao, J .-F.; Kozlowski, J . F.; Wood, K. V.; McLaughlin J . L.
Tetrahedron 1995, 51, 7149 and references therein.
10.1021/jo982110i CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/13/1999

2382 J . Org. Chem., Vol. 64, No. 7, 1999
Sinha et al.
achieved, followed by in situ ring closure to give 9, when
half of the stoichiometric amount of ligand and catalyst
were used as reported.3i However, the epoxidation of 8
in the presence of a stoichiometric amount of the catalyst
improved the yield to 75% of the bis-THF diol 9. By
means of a four-step sequence, the diol was converted
into an epoxide with inversion of the configuration at the
secondary carbinol function. Thus, the primary alcohol
was first protected in the form of a TBDMS ether, the
secondary alcohol was converted to the corresponding
mesylate, and the TBDMS ether was cleaved by treat-
ment with TsOH in methanol. Finally, reaction with K2-
CO3 in methanol affected the desired ring-closure reac-
tion to produce epoxide 10, another key intermediate in
this synthesis.
F igu r e 1. Structures of trilobin (1a ) and trilobacin (1b).
erythro junction between the two adjacent THF rings and
a cis stereochemistry in the B ring.10b
Epoxide 10 was used for a new C-C bond forming
reaction using trimethylsilylethynyllithium in the pres-
ence of BF3‚Et2O to produce alkyne 11.14 Cleavage of both
silyl protecting groups in 11 afforded the terminal alkyne-
diol 12, which was then converted to the bis-MOM ether
derivative 13. This set the stage for completion of the
carbon skeleton of the target molecule via coupling of
alkyne 13 with the butenolide precursor 14. Thus, the
lithiated derivative of alkyne 13 was reacted with the
known epoxide 1415 to produce intermediate 15 with the
desired (10R) absolute configuration. Catalytic hydroge-
nation of the alkyne was achieved using Wilkinson’s
catalyst, affording 16. Oxidation of sulfide to sulfoxide,
followed by pyrolysis, produced the desired butenolide
function in 17. Finally, deprotection of the MOM ethers
using BF3‚Et2O in dimethyl sulfide afforded 1a . Synthetic
We have recently reported on the first total synthesis
of (+)-trilobacin (1b) using the convergent synthetic
approach.4d Here, we report on the first total synthesis
of 1a using the “naked” carbon skeleton strategy, with
all of the asymmetric centers in the bis-THF fragment
being produced by the Sharpless asymmetric dihydroxy-
lation (AD)11 and the asymmetric epoxidation (AE)12
reactions.
Resu lts a n d Discu ssion
Our synthesis of 1a (Scheme 1) starts with alcohol 2,
which was prepared by LAH reduction of the readily
available ethyl pentadec-4-enoate.4g,13 Alcohol 2 was
oxidized with PCC to the corresponding aldehyde, the
aldehyde was reacted with vinylmagnesium bromide, and
the resultant allylic alcohol underwent the J ohnson-
Claisen rearrangement using triethyl orthoacetate in
xylene to produce the desired “naked” carbon skeleton
3. By means of our previously described strategy,4a diene
3 underwent double asymmetric dihydroxylation using
AD-mix-â followed by base-acid treatment to produce
the crystalline lactone 4.3i Recrystallization of 4 from
ethyl acetate afforded enantiomerically pure material.
The vicinal diol was protected in the form of an acetonide
5a using dimethoxypropane, and the remaining alcohol
was converted to the corresponding mesylate 5b. Acidic
hydrolysis of the acetonide back to a vicinal diol was
achieved with toluenesulfonic acid in aqueous methanol.
Ring closure was achieved by heating in pyridine to give
the THF derivative 6a , which represents one of the key
intermediates in the synthetic scheme. Compounds 6a
and its precursor 4 are >98% enantiomerically pure as
1
trilobin 1a and its R- and S-Mosher’s esters showed H
NMR data identical to those of the naturally occurring
trilobin and its R- and S-Mosher’s ester derivatives.10b
In conclusion, the first total synthesis16 of (+)-trilobin
1a was achieved in 22 steps and 2.74% yield starting with
the “naked” carbon skeleton 3. The synthetic scheme
represents a general methodology for the preparation of
trans,cis-bis-THF ring systems. Because all steps are
conveniently carried out on a millimole scale, this meth-
odology is currently being used in our laboratories as a
general approach for the preparation of chemical libraries
of bis-THF acetogenin stereoisomers.
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were measured
in CDCl3 at 400 and 100 MHz, respectively, unless otherwise
mentioned. Positive ion mass spectra, using the fast ion
bombardment (FIB) technique, were obtained on a high-
resolution mass spectrometer equipped with either a cesium
or sodium ion gun. Optical rotations were measured in a 1-dm
(1 mL) cell. TLC was performed on glass sheets precoated with
silica gel (Merck, Kieselgel 60, F254). Column chromatographic
separations (flash chromatography) were performed on silica
gel (Merck, Kieselgel 60, 230-400 mesh). THF was dried by
distillation over sodium-benzophenone ketyl. AD-mix-â was
purchased from Aldrich (39276-6).
1
judged by H NMR spectra of the Mosher’s esters of 6a .
The alcohol function in 6a was protected in the form
of a tert-butyldiphenylsilyl ether (BPS) (6b), and the
lactone was partially reduced to the corresponding lactol.
Wittig-Horner olefination of the lactol using carbe-
thoxymethyl triphenylphosphorane afforded the unsatur-
ated ester 7. Reduction of the ester with DIBAL-H at low
temperature provided the allylic alcohol 8. Asymmetric
epoxidation of 8 was carried out in analogy to previous
work with a similar skeleton.3i Only 50% epoxidation was
P en ta d ec-4-en -1-ol, 2. LiAlH4 (2.6 g, 68 mmol) was slowly
added to a solution of ethyl pentadec-4-enoate13 (8.84 g, 33
(14) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(15) Makabe, H.; Tanimoyo, H.; Tanaka, A.; Oritani, T. Heterocycles
1996, 43, 2229. Compound 14 thus prepared was enantiomerically
impure, containing 10-15% of the C2 epimer. This fact, however, did
not interfere with the synthesis, because the stereochemistry at C2
was irrelevant to the final product.
(16) Note added in proof: a total synthesis of 1 has also been
reported simultaneously to this work. See: Marshall, J . A.; J iang, H.
J . Org. Chem. 1999, 64, 971.
(11) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
(12) (a) J ohnson, R. A.; Sharpless, K. B. Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH Publishers Inc.: New York, 1993; p 103.
(b) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.
(13) Keinan, E.; Sinha, S. C.; Sinha-Bagchi, A.; Wang, Z.-M.; Zhang,
X.-L.; Sharpless, K. B.; Tetrahedron Lett. 1992, 33, 6411.

Total Synthesis of Trilobin
J . Org. Chem., Vol. 64, No. 7, 1999 2383
Sch em e 1. Tota l Syn th esis of Tr ilobin a
a
(a) i. PCC, celite, CH2Cl2, 2 h; ii. vinylmagnesium bromide, THF, -20 °C, 0.5 h; iii. triethyl orthoacetate, xylene, propionic acid (cat.),
2 h. (b) i. AD-mix-â, MeSO2NH2, t-butanol/water (1:1), 0 °C, 16 h; ii. 3 N aq KOH then HCl (3 N); iii. TsOH (cat.), CH2Cl2, rt, 0.5 h. (c)
DMP, acetone, TsOH (cat.), 0 °C, 1 h. (d) MsCl, Et3N, CH2Cl2, 0 °C, 2 h. (e) i. MeOH/H2O (9:1), TsOH, 16 h; ii. pyridine, 140 °C, 2 h. (f)
TBDPSCl, imidazole, DMF, 16 h. (g) i. DIBAL-H, THF, -78 °C, 1.5 h; ii. carbethoxymethylene triphenylphosphorane, toluene, 80 °C, 16
h. (h) DIBAL-H, THF, -78 °C, 1 h. (i) i. TBHP, (+)-DET, Ti(Oi-Pr)4, CH2Cl2, -20 °C, 16 h. (j) TBDMSCl, diisopropylethylamine, DMAP,
CH2Cl2, 16 h. (k) MsCl, Et3N, CH2Cl2, 0 °C, 2 h. (l) TsOH, MeOH, rt, 2 h. (m) MeOH, K2CO3, rt, 1 h. (n) trimethylethynylsilane, n-BuLi,
BF3‚Et2O, THF, -78 °C, 2 h. (o) TBAF, THF, 40 °C, 48 h. (p) MOMCl, diisopropylethylamine, CH2Cl2, 0 °C to rt, 16 h. (q) n-BuLi, BF3‚Et2O,
THF, then 14, 2 h. (r) RhCl(PPh3)3, benzene, H2, rt, 16 h. (s) i. m-CPBA, CH2Cl2, 0 °C, 20 min; ii. toluene, 90 °C, 1 h. (t) BF3‚Et2O, Me2S,
CH2Cl2, 0 °C, 10 min.
mmol) in dry ether (100 mL) at 0 °C. The mixture was allowed
to warm to room temperature over 1 h, and then worked up
by slow addition of wet ether and water. The resultant crude
2 was found to be pure by TLC and was taken to the next
step without further purification. 1H NMR: δ 5.42 (m, 2H),
3.64 (t, J ) 6.5 Hz, 2H), 2.06 (q, J ) 7.2 Hz, 2H), 1.96 (q, J )
5.5 Hz, 2H) 1.64 (m, 2H), 1.38-1.22 (m and br s, 16H), 0.87
(t, J ) 7.1 Hz, 3H). 13C NMR: δ 131.3, 129.3, 62.6, 32.5, 32.4,
31.9, 29.6, 29.6, 29.5, 29.4, 29.3, 29.2, 28.9, 22.7, 14.1. MS:
249 (MNa+).
(6.57 g, 89%). A solution of vinylmagnesium bromide (1 M in
THF, 35 mL, 35 mmol) was added to the solution of the crude
aldehyde in dry THF at 0 °C, and the mixture was stirred for
0.5 h. Workup with saturated aqueous NH4Cl and ether
produced heptadeca-1,6-dien-3-ol (7.28 g), which was taken to
next step without further purification.1H NMR: δ 5.86 (ddd,
J ) 16.9, 10.5, 6.2 Hz, 1H), 5.42 (m, 2H), 5.22 (dt, J ) 16.9,
1.5 Hz, 1H), 5.10 (dt, J ) 10.5, 1.5 Hz, 1H), 4.12 (q, J ) 6.3
Hz, 1H), 2.06 (q, J ) 7.2 Hz, 2H), 1.96 (q, J ) 5.5 Hz, 2H),
1.64 (m, 3H), 1.38-1.22 (m and br s, 16H), 0.87 (t, J ) 7.1 Hz,
3H).
Eth yl Non a d eca -4,8-d ien oa te, 3. Celite (14 g) and PCC
(14 g, 65 mmol) were added to a solution of 2 (7.5 g, 33 mmol)
in CH2Cl2 (150 mL), and the mixture was stirred for 2 h.
Filtration over silica gel afforded the corresponding aldehyde
A solution of the crude alcohol (7.28 g), triethylorthoacetate
(11 mL, 60 mmol), and propionic acid (37 mg, 0.5 mmol) in
xylene (11 mL) was heated at reflux for 2 h. Removal of the

2384 J . Org. Chem., Vol. 64, No. 7, 1999
Sinha et al.
solvent under high vaccum followed by column chromatogra-
phy (silica gel, hexanes/ethyl acetate 49:1-19:1) afforded 3 (7.5
g, 70% from 2). 1H NMR: δ 5.50-5.30 (m, 4H), 4.11 (q, J )
7.2 Hz, 2H), 2.37-2.23 (m, 4H), 2.05-1.90 (m, 6H), 1.35-1.22
(m and br s, 16H), 1.23 (t, J ) 7.2 Hz, 3H), 0.86 (t, J ) 7.1 Hz,
3H). 13C NMR: δ 173.2, 131.1, 130.8, 129.4, 128.2, 60.2, 34.4,
32.6, 31.9, 29.6, 29.5, 29.3, 29.1, 27.9, 22.7, 14.2, 14.1.
(4R,5R,8R,9R)-5,8,9-Tr ih yd r oxyn on a d eca n -1,4-olid e, 4.
Methanesulfonamide (3.6 g, 40 mmol) and 3 (6.44 g, 20 mmol)
were added to a two-phase homogeneous mixture of AD-mix-â
(56 g, Os content 0.4%) in tert-butyl alcohol/water (1:1, 600
mL). The mixture was stirred at 0 °C for 16 h and then worked
up by slow addition of sodium metabisulfite (60 g). The crude
lactone thus obtained was mixed with methanol (40 mL) and
aqueous NaOH (3N, 20 mL), and the mixture was stirred at
60 °C for 2 h, cooled, acidified with aqueous HCl (3 N, 25 mL),
and extracted with ethyl acetate. The solvent was removed
under reduced pressure, and the residue was dissolved in CH2-
Cl2 (100 mL). The mixture was stirred with TsOH (0.5 g) for
1 h and washed with saturated aqueous NaHCO3. Solvent was
removed again, and the residue was crystallized from ethyl
acetate to give lactone 4 (4.48 g, 65%). Mp: 94-97 °C. [R]D:
+ 7.32° (c 1.64, CHCl3). 1H NMR (CDCl3 + CD3OD): δ 4.39
(td, J ) 6.9, 4.0 Hz, 1H), 3.52 (dt, J ) 4.5, 4.0 Hz, 1H), 3.31
(m, 2H), 2.80 (br s, 3H), 2.58 (ddd, J ) 17.9, 10.0, 5.5 Hz, 1H),
2.46 (ddd, J ) 17.9, 9.9 Hz, 1H), 2.21 (m, 1H), 2.10 (m, 1H),
1.70-1.18 (m and br s, 22H), 0.82 (t, J ) 7.0 Hz, 3H). 13C
NMR: δ 178.4, 83.5, 77.4, 73.9, 73.0, 33.3, 31.8, 29.6, 29.5 (two
signals), 29.2, 29.1, 28.6, 25.6, 23.9, 22.6, 14.0. MS: 345 (MH+),
377 (MNa+).
(4R,5R,8R,9R)-5-Hyd r oxy-8,9-isop r op ylid en ed ioxyn on -
a d eca n -1,4-olid e, 5a . Compound 4 (4.40 g, 12.8 mmol) and
TsOH (0.5 g) were dissolved in a 1:1 mixture of dimethoxypro-
pane and acetone (50 mL), and the mixture was stirred at room
temperature for 0.5 h. Saturated aqueous NaHCO3 was added,
and the mixture was extracted with CH2Cl2. Filtration through
a short bed of silica gel afforded acetonide 5a (4.53 g, 92%) in
the form of a colorless oil. 1H NMR: δ 4.43 (td, J ) 7.5, 4.0
Hz, 1H), 3.59 (m, 3H), 2.63 (ddd, J ) 17.8, 9.9, 5.6 Hz, 1H),
2.50 (ddd, J ) 17.8, 9.9, 8.1 Hz, 1H), 2.30-2.10 (m, 2H), 1.80-
1.22 (m and br s, 23H), 1.36 (s, 6H), 0.86 (t, J ) 7.1 Hz, 3H).
13C NMR: δ 177.5, 108.0, 82.9, 80.9, 80.6, 73.2, 32.6, 31.8, 29.8,
29.7, 29.5, 29.4, 29.2, 29.1, 28.5, 27.2, 27.1, 26.0, 23.9, 22.6,
14.0. MS: 407 (MNa+).
(4R ,5S ,8R ,9R )-9-t er t -Bu t yld ip h e n ylsilyloxy-5,8-oxi-
d on on a d eca n -1,4-olid e, 6b. Compound 6a (1.37 g, 4.2 mmol)
and imidazole (571 mg, 8.4 mmol) were dissolved in dry DMF
(3 mL), TBDPSCl (1.76 g, 6.4 mmol) was added, and the
mixture was stirred at room temperature for 16 h. Workup
with water and ether followed by column chromatography
(silica gel, hexane/ethyl acetate 9:1-4:1) afforded 6b (2.30 g,
1
95%) in the form of a colorless oil. H NMR: δ 7.68 (m, 4H),
7.38 (m, 6H), 4.24 (dt, J ) 7.3, 6.1 Hz, 1H), 3.90 (td, J ) 7.3,
5.5 Hz, 1H), 3.80 (q, J ) 6.3 Hz, 1H), 3.67 (q, J ) 5.5 Hz, 1H),
2.47 (ddd, J ) 17.7, 9.8, 6.6 Hz, 1H), 2.39 (ddd, J ) 17.7, 9.5,
7.4 Hz, 1H), 2.11 (m, 1H), 1.96 (m, 2H), 1.82 (m, 1H), 1.74 (m,
2H), 1.48 (m, 1H), 1.40-1.08 (m and br s, 17H), 1.03 (s, 3H),
0.87 (t, J ) 7.1 Hz, 3H). 13C NMR: δ 177.3, 135.9, 135.8, 134.5,
134.2, 129.4, 127.3, 82.0, 81.6, 79.5, 75.2, 33.5, 31.9, 29.6, 29.5,
29.4, 29.3, 28.2, 28.1, 27.0, 26.6, 25.0, 23.8, 21.7, 19.6, 14.1.
MS: 697 (MCs+).
(E,6R,7S,10R,11R)-Eth yl 11-ter t-Bu tyldiph en ylsilyloxy-
6-h yd r oxy-7,10-oxid oh en eicosa -2-en oa te, 7. Compound 6b
(2.50 g, 4.4 mmol) was dissolved in dry THF (10 mL), DIBAL-H
(1 M in toluene, 6.0 mL, 6.0 mmol) was added at -78 °C, and
the mixture was stirred at the same temperature for 1.5 h.
Water (2 mL), Celite (2 g), and ether (10 mL) were added, and
the mixture was stirred at 0 °C for 0.5 h. Filtration over Celite
and removal of the solvent under reduced pressure afforded
the corresponding lactol (2.21 g), which was taken to next step
1
without purification. H NMR: δ 7.70 (m, 4H), 7.36 (m, 6H),
5.49 and 5.41 (t, J ) 3.2 Hz, and ddd, J ) 8.6, 5.5, 1.6 Hz,
together 1H), 4.20-3.95 (m, 2H), 3.89 (m, 1H), 3.74-3.66 (m,
2H), 2.20-1.12 (m, 26H), 1.04 (s, 9H), 0.88 (t, J ) 7.2 Hz, 3H).
The crude lactol (2.21 g) and ethoxycarbonylmethyltriph-
enylphosphorane (2.09 g, 5.7 mmol) were dissolved in dry
toluene (20 mL), and the mixture was stirred at 80 °C for 16
h. The solvent was removed under reduced pressure, and the
residue was purified by column chromatography (silica gel,
1
hexanes/ethyl acetate 9:1) to give 7 (2.31 g, 82% from 6b). H
NMR: δ 7.70 (m, 4H), 7.38 (m, 6H), 6.94 (dt, J ) 14.7, 6.4 Hz,
1H), 5.82 (dt, J ) 14.7, 1.5 Hz, 1H), 4.18 (q, J ) 7.2 Hz, 2H),
3.82 (m, 1H), 3.68-3.56 (m, 3H), 2.35 (m, 1H), 2.20 (m, 1H),
1.94 (d, J ) 3.4 Hz, 1H), 1.82-1.12 (m, 24H), 1.28 (t, J ) 7.2
Hz, 3H), 1.04 (s, 9H), 0.87 (t, J ) 7.2 Hz, 3H). 13C NMR: δ
166.6, 148.7, 135.8, 134.6, 134.2, 129.4, 127.5, 127.4, 121.5,
81.7, 81.2, 75.8, 71.0, 60.1, 33.7, 31.9, 30.6, 29.6, 29.5, 29.4,
29.3, 28.6, 27.6, 27.0, 25.1, 24.2, 22.7, 19.5, 14.3, 14.1. MS:
659 (MNa+).
(4R,5R,8R,9R)-5-Mesyloxy-8,9-isopr opyliden edioxyn on -
a d eca n -1,4-olid e, 5b. Methanesulfonyl chloride (1.8 mL, 23.2
mmol) was added dropwise to a solution of 5a (4.50 g, 11.7
mmol) and triethylamine (5 mL) in CH2Cl2 (20 mL) at -30
°C, and the mixture was stirred at between -30 and 0 °C for
2 h. Workup with water and methylene chloride and filtration
through a short bed of silica gel afforded mesylate 5b (5.08 g,
94%), which was taken to the next step without further
(E,6R,7S,10R,11R)-11-ter t-Bu tyld ip h en ylsilyloxy-7,10-
oxid oh en eicos-2-en -1,6-d iol, 8. Compound 7 (2.31 g, 3.63
mmol) was dissolved in dry THF (15 mL), DIBAL-H (1 M in
toluene, 14.5 mL, 14.5 mmol) was added at -78 °C, and the
mixture was stirred at the same temperature for 1h. Water (5
mL), Celite (5 g), and ether (25 mL) were added, and the
mixture was stirred at 0 °C for 0.5 h. Filtration over Celite,
removal of the solvent, and column chromatography (silica gel,
hexanes/ethyl acetate 4:1) produced allylic alcohol 8 (2.10 g,
1
purification. H NMR: δ 4.75 (m, 1H), 4.61 (m, 1H), 3.59 (m,
2H), 3.12 (s, 3H), 2.60 (m, 2H), 2.35 (m, 1H), 2.10 (m, 1H),
1.88 (m, 2H), 1.76-1.18 (m and br s, 20H), 1.34 (s, 3H), 1.33
(s, 3H), 0.85 (t, J ) 7.1 Hz, 3H). 13C NMR: δ 175.9, 108.1,
82.9, 80.9, 79.8, 79.5, 39.0, 32.6, 31.8, 31.5, 29.7, 29.5, 29.4,
29.3, 28.0, 27.8, 27.6, 27.3, 27.2, 26.0, 24.2, 22.6, 14.1. MS:
485 (MNa+).
1
97%) in the form of a colorless oil. H NMR: δ 7.66 (m, 4H),
7.44 (m, 6H), 5.65 (m, 2H), 4.01 (d, J ) 6.7 Hz, 2H), 3.83 (q, J
) 5.2 Hz, 1H), 3.66 (m, 1H), 3.60 (m, 2H), 2.21 (m, 1H), 2.05
(m, 1H), 1.80-1.12 (m and br s, 26H), 1.03 (s, 9H), 0.87 (t, J
) 7.2 Hz, 3H). 13C NMR: δ 135.9, 132.7, 129.4, 127.4, 127.3,
81.8, 81.1, 75.7, 71.1, 63.7, 33.6, 31.9, 31.8, 29.6, 29.5, 29.4,
29.3, 28.6, 27.6, 27.0, 25.1, 24.1, 22.7, 14.1. MS: 595 (MH+).
(2S,3R,6R,7S,10R,11R)-11-ter t-Bu tyld ip h en ylsilyloxy-
3,6:7,10-d ioxid oh en eicosa n e-1,2-d iol, 9a . A mixture of 8
(1.74 g, 2.92 mmol), activated molecular sieves (4A, 0.3 g), (+)-
diethyl tartrate (0.71 g, 3.44 mmol), and Ti(i-OPr)4 (823 mg,
2.9 mmol) in dry CH2Cl2 was stirred at -20 °C for 0.5 h. tert-
Butyl hydroperoxide (TBHP, 5-6 M in isooctane, 2.9 mL) was
added dropwise, and the mixture was stirred at the same
temperature for 16 h. Workup with water, aqueous NaOH, and
ether followed by column chromatography (silica gel, hexanes/
ethyl acetate 1:4) afforded 9a (1.34 g, 75%, 88% on the basis
of recovered starting material) in the form of a colorless oil.
[R]D: -3.5° (c 5.56, CHCl3). 1H NMR: δ 7.69 (m, 4H), 7.38 (m,
6H), 3.95-3.84 (m, 2H), 3.83 (q, J ) 6.0 Hz, 1H), 3.78-3.57
(m, 5H), 2.46 (d, J ) 3.6 Hz, 1H), 2.37 (m, 1H), 1.98-1.02 (m
(4R ,5S ,8R ,9R )-9-H yd r oxy-5,8-oxid on on a d e ca n -1,4-
olid e, 6a . Compound 5b (5.08 g, 11 mmol) and TsOH (200
mg) were dissolved in methanol/water (4:1, 20 mL), and the
mixture was stirred at room temperature for 16 h. Saturated
aqueous NaHCO3 was added, and the mixture was extracted
with CH2Cl2. Solvent was removed under reduced pressure,
and the residue was dissolved in pyridine (20 mL) and refluxed
for 2 h. Workup with CH2Cl2 water followed by column
chromatography (silica gel, hexanes/ethyl acetate 1:1) afforded
6a (2.80 g, 78%). [R]D: - 7.38° (c 1.3, CHCl3). 1H NMR: δ 4.42
(td, J ) 7.2, 5.6 Hz, 1H), 3.97 (q, J ) 6.3 Hz, 1H), 3.75 (q, J )
6.9 Hz, 1H), 3.38 (m, 1H), 2.58-2.42 (m, 2H), 2.30 (m, 1H),
2.18-1.60 (m, 5H), 1.50-1.18 (m and br s, 19H), 0.87 (t, J )
7.0 Hz, 3H). 13C NMR: δ 176.9, 83.3, 81.1, 80.0, 74.2, 33.6,
31.8, 29.6, 29.5, 29.2, 28.1, 27.5, 27.3, 25.5, 23.9, 22.6, 14.0.
HRMS: calcd for C29H34O4Na 349.2355, found 349.2366 (MNa+).

Total Synthesis of Trilobin
J . Org. Chem., Vol. 64, No. 7, 1999 2385
and br s, 26H), 1.03 (s, 9H), 0.89 (t, J ) 7.2 Hz, 3H). 13C
NMR: δ 136.0, 135.9, 134.4, 134.3, 129.3, 127.3, 81.7, 81.4,
80.9, 80.4, 75.3, 73.0, 64.0, 32.9, 31.9, 29.6, 29.5, 29.4, 29.3,
28.4, 28.0, 27.2, 27.0, 20.5, 25.1, 22.7, 19.5, 14.1. MS: 633
(MNa+).
ature for 1 h. BF3‚Et2O (0.37 mL, 3 mmol) was added dropwise,
the mixture was stirred for 10 min, epoxide 10 (575 mg, 0.97
mmol) in dry THF (2 mL) was added dropwise, and the mixture
was stirred at the same temperature for 1 h. Workup with
saturated aqueous NH4Cl and ether followed by column
chromatography (silica gel, hexanes/ethyl acetate 6:4) afforded
11 (575 mg, 86%) in the form of a colorless oil. [R]D: -12.6° (c
(2S,3R,6R,7S,10R,11R)-1-ter t-Bu t yld im et h ylsilyloxy-
11-ter t-bu tyldiph en ylsilyloxy-3,6:7,10-dioxidoh en eicosan -
2-ol, 9b. Compound 9a (1.34 g, 2.2 mmol), diisopropylethyl-
amine (2 mL), and DMAP (15 mg) were dissolved in dry CH2-
Cl2 (10 mL). TBDMSCl (365 mg, 2.4 mmol) was added, and
the mixture was stirred at room temperature for 16 h. Workup
with water and CH2Cl2 and purification by column chroma-
tography (silica gel, hexanes/ethyl acetate 1:1) afforded 9b
(1.41 g, 89%) in the form of a colorless oil. 1H NMR: δ 7.70
(m, 4H), 7.35 (m, 6H), 3.89 (m, 1H), 3.85 (q, J ) 6.6 Hz, 1H),
3.78 (q, J ) 6.5 Hz, 1H), 3.74-3.66 (m, 3H), 3.65-3.52 (m,
2H), 2.43 (d, J ) 4.2 Hz, 1H), 2.05-1.02 (m and br s, 26H),
1.04 (s, 9H), 0.89 (s, 9H), 0.88 (t, J ) 7.0 Hz, 3H), 0.06 (s, 6H).
13C NMR: δ 136.0, 134.6, 134.3, 129.3, 127.5, 127.3, 127.1,
81.7, 81.4, 81.2, 81.0, 79.1, 75.2, 73.2, 64.4, 32.8, 31.9, 29.6,
29.5, 29.4, 29.3, 28.5, 27.5, 27.0, 26.4, 25.8, 25.6, 25.1, 22.6,
19.5, 14.1. MS: 723 (MH-).
1
3.58, CHCl3). H NMR: δ 7.68 (m, 4H), 7.36 (m, 6H), 3.89 (m,
2H), 3.77 (m, 1H), 3.69 (m, 2H), 3.52 (m, 1H), 2.41 (m, 3H),
2.02-1.12 (m, 26H), 1.02 (s, 9H), 0.87 (t, J ) 7.0 Hz, 3H), 0.13
(s, 6H). 13C NMR: δ 135.9, 134.6, 134.3, 129.2, 127.2, 103.0,
86.7, 81.7, 81.3, 81.1, 80.9, 75.2, 71.9, 71.1, 32.8, 31.8, 29.6,
29.5, 29.4, 29.3, 29.2, 28.7, 28.4, 28.0, 27.0, 26.4, 25.2, 25.1,
22.6, 19.5, 14.0, -0.1. MS: 713 (MNa+).
(4R,5R,8R,9S,12R,13R)-5,8:9,12-Dioxid otr icos-1-yn e-4,-
13-d iol, 12. Compound 11 (279 mg, 0.40 mmol) was dissolved
in dry THF (5 mL). TBAF (1 M in THF, 1.5 mL, 1.5 mmol)
was added at 0 °C, and the mixture was stirred at 40 °C for
48 h. Workup with water and ether and filtration through a
short bed of silica gel afforded 12 (140 mg, 92%) in the form
of a colorless oil. [R]D: -11.4° (c 4.2, CHCl3). 1H NMR: δ 4.08-
3.97 (m, 2H), 3.94 (q, J ) 4.8 Hz, 1H), 3.7 (q, J ) 6.4 Hz, 1H),
3.58 (br, 1H), 3.34 (br, 1H), 2.75 (br, 1H), 2.62 (br, 1H), 2.64
(dd, J ) 6.2, 2.6 Hz, 2H), 2.03-1.68 (m, 11H), 1.41-1.22 (m,
bs, 16H), 0.84 (t, J ) 6.4 Hz, 3H). 13C NMR δ 82.6, 81.5, 81.4,
81.2, 80.5, 74.4, 71.8, 70.2, 34.1, 31.8, 29.7, 29.6, 29.2, 28.8,
28.1, 28.0, 26.9, 25.7, 23.9, 22.6, 14.1. MS: 403 (MNa+).
(2S,3R,6R,7S,10R,11R)-1-ter t-Bu t yld im et h ylsilyloxy-
11-ter t-bu tyld ip h en ylsilyloxy-2-m esyloxy-3,6:7,10-d ioxi-
d oh en eicosa n e, 9c. Methanesulfonyl chloride (0.5 mL, 6.5
mmol) was added dropwise to a solution of 9b (1.41 g, 1.96
mmol) and triethylamine (2 mL) in CH2Cl2 (10 mL) at -30
°C, and the mixture was stirred at between -30 and 0 °C for
2 h. Workup with water and CH2Cl2 followed by filtration
through a short bed of silica gel afforded 9c (1.50 g, 96%),
which was taken to next step without further purification.
[R]D: -3.71° (c 5.81, CHCl3). 1H NMR: δ 7.68 (m, 4H), 7.36
(m, 6H), 4.59 (dt, J ) 6.3, 4.9 Hz, 1H), 4.06 (q, J ) 6.3 Hz,
1H), 3.90-3.70 (m, 6H), 3.03 (s, 3H), 2.05-1.02 (m, 26H), 1.03
(4R,5R,8R,9S,12R,13R)-4,13-Di(m eth oxym eth oxy)-5,8:
9,12-d ioxid otr icos-1-yn e, 13. Diol 12 (140 mg, 0.37 mmol)
and di-iso-propylethylamine (0.26 mL, 1.5 mmol) were dis-
solved in CH2Cl2 (2 mL). MOMCl (0.11 mL, 1.4 mmol) was
added at 0 °C, and the mixture was stirred at between 0 °C
and room temperature for 16 h. Workup with water and CH2-
Cl2 and filtration through a short bed of silica gel followed by
removal of solvent under reduced pressure afforded 13 (155
(s, 9H), 0.88 (s, 9H), 0.87 (t, J ) 7.1 Hz, 3H), 0.06 (s, 6H).13
C
1
NMR: δ 136.0, 135.9, 134.7, 134.4, 129.3, 127.3, 127.2, 84.1,
81.8, 80.7, 77.4, 75.3, 63.1, 38.3, 33.1, 31.8, 29.6, 29.5, 29.4,
29.2, 28.5, 27.9, 27.0, 26.4, 25.8, 25.1, 22.6, 19.5, 14.0, -5.5.
MS: 801 (MH-).
mg, 89%) in the form of a colorless oil. H NMR: δ 4.83 (d, J
) 6.8 Hz, 1H), 4.77 (s, 2H), 4.65 (d, J ) 6.8 Hz, 1H), 4.13 (m,
1H), 3.90-3.78 (m, 3H), 3.63 (m, 1H), 3.44 (m, 1H), 3.41 (s,
3H), 3.38 (s, 3H), 2.57-2.36 (m, 2H), 2.08-1.22 (m and br s,
27H), 0.87 (t, J ) 6.9 Hz, 3H). 13C NMR: δ 96.5, 96.4, 82.4,
81.4, 81.3, 80.4, 79.9, 77.3, 55.7, 55.6, 31.8, 31.3, 29.7, 29.5,
29.3, 28.9, 28.4, 28.0, 27.5, 25.3, 22.6, 21.6, 14.1. HRMS: calcd
for C27H48O6Cs 601.2505, found, 601.2528 (MCs+).
(2S,3R,6R,7S,10R,11R)-11-ter t-Bu tyld ip h en ylsilyloxy-
2-m esyloxy-3,6:7,10-d ioxid oh en eicosa n -1-ol, 9d . Com-
pound 9c (1.50 g, 1.87 mmol) and TsOH (200 mg) were
dissolved in methanol/water (4:1, 20 mL), and the mixture was
stirred at room temperature for 16 h. Saturated aqueous
NaHCO3 was added, the mixture was extracted with CH2Cl2,
and the organic extract was filtered through a short bed of
silica gel. Removal of solvents under reduced pressure afforded
9d (1.17 g, 91%) in the form of a colorless oil. 1H NMR: δ 7.67
(m, 4H), 7.33 (m, 6H), 4.62 (dt, J ) 6.5, 3.5 Hz, 1H), 4.03 (q,
J ) 7 Hz, 1H), 3.89-3.64 (m, 5H), 3.05 (s, 3H), 2.00-1.05 (m
and bs, 26H), 0.87 (t, J ) 7 Hz, 3H).13C NMR: δ 136.0, 135.9,
134.6, 134.4, 129.4, 127.3, 127.2, 83.8, 81.8, 80.6, 77.8, 75.3,
62.6, 38.3, 33.1, 31.8, 29.6, 29.4, 29.2, 28.4, 27.6, 27.0, 26.9,
25.0, 22.6, 20.9, 19.5, 14.0. MS: 711 (MNa+).
(2RS)-2-Th iop h en oxy-2,35:12,13:12,13-h exa d eh yd r otr i-
lobin -bis(m eth oxym eth oxy) Eth er , 15. n-BuLi (1.6 M, 0.2
mL, 0.32 mmol) was added at -78 °C to a solution of 13 (153
mg, 0.32 mmol) in dry THF (2 mL), and the mixture was
stirred at the same temperature for 1 h. BF3‚Et2O (45 µL, 0.36
mmol) was added, and the mixture was stirred for 20 min. A
solution of epoxide 14 (130 mg, 0.37 mmol) in dry THF (1 mL)
was added dropwise at -78 °C, and the mixture was stirred
at the same temperature for 1 h. Workup with saturated
aqueous NH4Cl and ether and filtration through a short bed
of silica gel afforded 15 (143 mg, 55%) in the form of a colorless
oil. 1H NMR: δ 7.52 (m, 2H), 7.34 (m, 3H), 4.80 (d, J ) 6.8
Hz, 1H), 4.76 (d, J ) 6.8 Hz, 1H), 4.71 (d, J ) 6.8 Hz, 1H),
4.62 (d, J ) 6.8 Hz, 1H), 4.45 (m, 1H), 4.08 (m, 1H), 3.86-
3.72 (m, 3H), 3.63 (m, 1H), 3.56 (q, J ) 5.6 Hz, 1H), 3.41 (m,
1H), 3.37 (s, 3H), 3.35 (s, 3H), 2.47 (dd, J ) 14.0, 7.6 Hz, 2H),
2.40-2.16 (m, 4H), 2.08-1.62 (m, 10H), 1.58-1.16 (m and br
s, 30H), 1.15 (d, J ) 6.3 Hz, 3H), 0.84 (t, J ) 7.0 Hz, 3H). 13C
NMR: δ 177.0, 136.7, 130.4, 129.6, 128.9, 96.5, 96.3, 82.4, 81.4,
81.3, 80.6, 79.9, 79.4, 77.9, 73.1, 70.0, 55.6, 40.0, 36.4, 36.2,
31.8, 31.3, 29.7, 29.5, 29.4, 29.3, 29.2, 28.9, 28.4, 27.9, 27.8,
27.4, 25.5, 25.3, 24.5, 22.6, 21.8, 21.4, 14.0.
(2R,3R,6R,7S,10R,11R)-11-ter t-Bu tyld ip h en ylsilyloxy-
1,2:3,6:7,10-tr ioxid oh en eicosa n e, 10. Compound 9d (1.17 g,
1.70 mmol) was dissolved in methanol (10 mL), K2CO3 (828
mg, 6 mmol) was added, and the mixture was stirred at room
temperature for 1 h. Workup with water and CH2Cl2 followed
by column chromatography (silica gel, hexane/ethyl acetate
8:2) afforded epoxide 10 (930 mg, 92%) in the form of a colorless
1
oil. [R]D: -5.6° (c 3.0, CHCl3). H NMR: δ 7.69 (m, 4H), 7.36
(m, 6H), 3.94-3.78 (m, 3H), 3.68 (m, 2H), 2.92 (m, 1H), 2.72
(dd, J ) 5.2, 4.2 Hz, 1H), 2.66 (dd, J ) 5.2, 2.7 Hz, 1H), 2.05-
1.02 (m, 26H), 1.03 (s, 9H), 0.87 (t, J ) 7.2 Hz, 3H). 13C NMR:
δ 136.0, 135.9, 129.3, 127.2, 82.1, 81.9, 81.0, 78.9, 75.3, 32.9,
31.8, 29.6, 29.5, 29.4, 29.3, 29.2, 28.7, 28.6, 28.0, 27.0, 26.4,
25.1, 22.7, 14.1. MS: 615 (M+Na+).
(2R S )-2-T h io p h e n o x y -2,35-d id e h y d r o t r ilo b in -b is -
(m eth oxym eth oxy) Eth er , 16. Compound 15 (143 mg, 0.18
mmol) and chlorotriphenylphosphine rhodium(I) (40 mg) were
dissolved in benzene (2 mL), and the mixture was stirred under
a H2 atmosphere for 16 h and then filtered over Celite. Solvent
was removed under reduced pressure, and the residue was
filtered through a short bed of silica gel to give 16 (116 mg,
78%) in the form of a colorless oil. 1H NMR: δ 7.52 (d, J ) 8.0
(4R,5R,8R,9S,12R,13R)-1-Tr im eth ylsilyl-13-ter t-bu tyl-
d ip h en ylsilyloxy-5,8:9,12-d ioxid otr icos-1-yn -4-ol, 11. n-
BuLi (1.6 M, 1.9 mL, 3.04 mmol) was added to a solution of
trimethylsilylacetylene (295 mg, 3 mmol) in dry THF (5 mL)
at -30 °C, and the mixture was stirred at the same temper-

2386 J . Org. Chem., Vol. 64, No. 7, 1999
Sinha et al.
Hz, 2H), 7.34 (m, 3H), 4.82 (d, J ) 6.5 Hz, 1H), 4.79 (d, J )
7.0 Hz, 1H), 4.64 (d, J ) 6.5 Hz, 1H), 4.63 (d, J ) 7.0 Hz, 1H),
4.46 (m, 1H), 3.95 (dt, J ) 8.5, 6.5 Hz, 1H), 3.85 (dt, J ) 8.5,
7.0 Hz, 1H), 3.78 (m, 2H), 3.54 (m, 1H), 3.42 (m, 2H), 3.37 (s,
6H), 2.48 (dd, J ) 14.0, 8.0 Hz, 1H), 2.05-1.18 (m and br s,
48H), 1.15 (d, J ) 6.5 Hz, 3H), 0.85 (t, J ) 7.0 Hz, 3H). 13C
NMR: δ 177.1, 136.8, 130.4, 129.7, 129.0, 96.7, 82.5, 81.7, 81.5,
81.1, 80.0, 79.6, 73.2, 71.8, 56.3, 55.7, 40.1, 37.4, 36.5, 31.9,
31.3, 31.1, 29.8, 29.6, 29.5, 29.3, 29.1, 28.5, 28.3, 27.5, 25.8,
25.6, 25.5, 24.6, 22.7, 21.5, 14.1. HRMS: calcd for C47H80O9-
SCs 953.4577, found 953.4544 (MCs+).
Tr ilobin , 1a . BF3‚Et2O (0.4 mL, 0.25 mmol) was added at
0 °C to a solution of 17 (63 mg, 0.089 mmol) and Me2S (1 mL)
in CH2Cl2 (1 mL), and the mixture was stirred for 10 min.
Workup with saturated aqueous NaHCO3 and CH2Cl2 followed
by filtration through a short bed of silica gel afforded 1a (45
mg, 81%) in the form of a white powder (recrystallized from
diethyl ether). Mp: 65-67 °C. [R]D: +20.0° (c 0.20, MeOH),
[lit.10b +33.3° (c 0.00015 g/mL, MeOH)]. 1H NMR: δ 6.96 (q, J
) 1.4 Hz, 1H), 4.96 (qq, J ) 7.0, 1.4 Hz, 1H), 4.01 (m, 1H),
3.93 (q, J ) 6.2 Hz, 1H), 3.80 (m, 2H), 3.55 (m, 1H), 3.43 (m,
2H), 3.36 (m, 2H), 2.80 (br s, 1H), 2.35 (br s, 1H), 2.23 (t, J )
7.2 Hz, 2H), 2.20-1.18 (m and br s, 47H), 1.38 (d, J ) 6.8 Hz,
3H), 0.85 (t, J ) 7.0 Hz, 3H). 13C NMR: δ 148.9, 134.2, 83.2,
82.6, 81.6, 80.9, 77.4, 74.5, 73.7, 71.8, 37.4, 37.3, 34.2, 33.5,
31.9, 29.7, 29.6, 29.5, 29.3, 29.2, 29.0, 28.8, 28.2, 28.1, 27.3,
26.9, 25.8, 25.7, 25.6, 25.1, 22.7, 19.2, 14.1. MS: 623 (MH+).
Tr ilobin -bis(m eth oxym eth oxy) Eth er , 17. Compound 16
(116 mg, 0.14 mmol) was dissolved in CH2Cl2, m-CPBA (50-
60%, 60 mg, 0.17 mmol) was added at 0 °C, and the mixture
was stirred at the same temperature for 20 min and then
worked up with saturated aqueous NaHCO3 and CH2Cl2. The
crude product was dissolved in toluene (8 mL) and heated at
90 °C for 1 h, the solvent was removed under reduced pressure,
and the residue was purified by column chromatography (silica
gel, hexanes/ethyl acetate 1:3) to give 17 (63 mg, 63%) in the
form of a colorless oil. 1H NMR: δ 7.52 (d, J ) 8.0 Hz, 2H),
6.96 (q, J ) 1.4 Hz, 1H), 4.97 (qq, J ) 7.1, 1.4 Hz, 1H), 4.81
(d, J ) 6.8 Hz, 1H), 4.79 (d, J ) 6.8 Hz, 1H), 4.64 (d, J ) 6.8
Hz, 1H), 4.63 (d, J ) 6.8 Hz, 1H), 3.95 (dt, J ) 8.2, 6.3 Hz,
1H), 3.85 (dt, J ) 8.2, 6.3 Hz, 1H), 3.79 (m, 2H), 3.55 (m, 1H),
3.43 (m, 2H), 3.36 (s, 6H), 2.23 (tt, J ) 8.0, 1.4 Hz, 1H), 2.05-
1.18 (m and br s, 46H), 1.37 (d, J ) 6.8 Hz, 3H), 0.85 (t, J )
7.1 Hz, 3H). 13C NMR: δ 148.9, 134.2, 96.6, 82.5, 81.7, 81.5,
81.1, 80.0, 79.6, 77.4, 71.8, 55.7, 40.1, 37.4, 31.9, 31.3, 31.1,
29.8, 29.6, 29.5, 29.3, 29.2, 29.1, 29.0, 28.5, 28.3, 27.5, 27.3,
25.8, 25.6, 25.5, 25.3, 25.1, 22.6, 19.2, 14.1. HRMS: calcd for
Ack n ow led gm en t. We are grateful to Professor J .
L. McLaughlin of Purdue University for providing us
1
with the H NMR spectra of 1a and its Mosher’s esters.
We thank the Skaggs Institute for Chemical Biology,
US-Israel Binational Science Foundation, the Israel
Cancer Research Fund, and PharMore Biotechnologies
Ltd. for financial support.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 1a , 4, 5a , 5b, 6a , 6b, 7, 8, 9a , 10, 11,
13, 16, and 17. This material is available free of charge via
the Internet at http://pubs.acs.org.
C
41H74O9Cs 843.4387, found 843.4416 (MCs+).
J O982110I