Total synthesis of eleutherobin and eleuthosides A and B

Article abstract of DOI:10.1021/ja9810639

The total synthesis of the cytotoxic marine natural products eleutherobin (1) and eleuthosides A (2) and B (3) is described. The strategy involves glycosidation of the (+)-carvone-derived intermediate 7 with the arabinose-derived trichloroacetimidate 9 fo

Full text of DOI:10.1021/ja9810639

8674
J. Am. Chem. Soc. 1998, 120, 8674-8680
Total Synthesis of Eleutherobin and Eleuthosides A and B
K. C. Nicolaou,* T. Ohshima, S. Hosokawa, F. L. van Delft, D. Vourloumis, J. Y. Xu,
J. Pfefferkorn, and S. Kim
Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and
Department of Chemistry and Biochemistry, UniVersity of California, San Diego 9500 Gilman DriVe,
La Jolla, California 92093
ReceiVed March 30, 1998
Abstract: The total synthesis of the cytotoxic marine natural products eleutherobin (1) and eleuthosides A (2)
and B (3) is described. The strategy involves glycosidation of the (+)-carvone-derived intermediate 7 with
the arabinose-derived trichloroacetimidate 9 followed by base-induced ring closure and elaboration to afford
the dihydroxy eneynone 19. Selective hydrogenation of 19 led to the generation and intramolecular collapse
of dienone 20 furnishing 21 and thence 22 with the required structural framework of the target molecules.
Finally, esterification with mixed anhydride 24 followed by deprotection gave eleutherobin (1) which served
as a precursor to eleuthosides A (2) and B (3). The R-glycoside anomer of eleutherobin, compound 27, was
also synthesized by application of the developed chemistry, demonstrating the flexibility of the sequence in
generating designed analogues for biological screening.
1. Introduction
In 1995, Fenical et al. disclosed in a patent1 the isolation
and structure of a marine natural product with potent cytotox-
icity, which they called eleutherobin (1, Figure 1). In more
detailed accounts in 1997, the Fenical group revealed further
information about the cytotoxic properties of 1 and disclosed
its Taxol-like mechanism of action.2,3 This mechanism involves
tubulin polymerization and microtubule stabilization.4 Isolated
from an Eleutherobia species of soft coral (possibly E. albiflora
Alcynacea, Alcyoniidea collected from the Indian Ocean near
Bennett’s Shoal in Western Australia), eleutherobin (1) was
structurally elucidated by spectroscopic means, even though its
absolute stereochemistry remained unknown. In the meantime,
Kashman and his group5 reported in 1996 the isolation and
structural elucidation of eleuthosides A (2) and B (3). Isolated
from an Eleutherobia aurea species of soft coral (collected near
the Kwazula-Natal coast of South Africa), these substances are
closely related to eleutherobin (1) and differ only by the position
of their acetate groups. Also related to eleutherobin (1) and
the eleuthosides A (2) and B (3) are sarcodictyins A (4) and B
(5), reported in 1987 by Pietra et al.,6 and valdivone (6), first
reported by Kennart and Watson in 19687 and, subsequently,
by Faulkner and his group in 1993.8 In the preceding paper,
Figure 1. Molecular structures of eleutherobin (1), eleuthosides A (2)
and B (3), and sarcodictyins A (4) and B (5) (Ac ) acetyl).
we described the total synthesis of sarcodictyins A and B.9 In
this paper, we present the details of our total synthesis of
eleutherobin (1)10-12 and eleuthosides A (2) and B (3), the
(1) Fenical, W.-H.; Hensen, P. R.; Lindel, T. US Pat. 5,473,057, Dec. 5,
1995.
(2) Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.; Casazza, A. M.;
Carboni, J.; Fairchild, C. R. J. Am. Chem. Soc. 1997, 119, 8744-8745.
(3) Long, B. H.; Carboni, J. M.; Wasserman, A. J.; Cornell, L. A.;
Casazza, A. M.; Jensen, P. R.; Lindel, T.; Fenical, W.-H.; Fairchild, C. R.
Cancer Res. 1998, 58, 1111-1115.
(4) Schiff, P. B.; Fant, J.; Horwitz, S. B. Nature 1979, 277, 665-667.
(5) Ketzinel, S.; Rudi, A.; Schleyer, M.; Benayahu, Y.; Kashman, Y. J.
Nat. Prod. 1996, 59, 873-875.
(6) (a) D’Ambrosio, M.; Guerriero, A.; Pietra, F. HelV. Chim. Acta 1987,
70, 2019-2027. (b) D’Ambrosio, M.; Guerriero, A.; Pietra, F. HelV. Chim.
Acta 1988, 71, 964-976. (c) Ciomei, M.; Albanese, C.; Pastori, W.; Grandi,
M.; Pietra, F.; D’Ambrosio, M.; Guerriero, A.; Battistini, C. Proc. Am. Ass.
Canc. Res. 1997, 38, 5 (Abstract 30).
(8) Lin, Y.; Bowley, C. A.; Faulkner, D. J. Tetrahedron 1993, 49, 7977-
7984.
(9) Nicolaou, K. C.; Xu, J. Y.; Kim, S.; Pfefferkorn, J.; Ohshima, T.;
Vourloumis, D.; Hosokawa, S. J Am. Chem. Soc. 1998, 120, 8661-8673.
(10) For a preliminary communication, see: Nicolaou, K. C.; van Delft,
F.; Ohshima, T.; Vourloumis, D.; Xu, J.; Hosokawa, S.; Pfefferkorn, J.;
Kim, S.; Li, T. Angew. Chem. Int. Ed. Engl. 1997, 36, 2520-2524.
(11) For another total synthesis of eleutherobin, see: Chen, X.-T.; Zhou,
B.; Bhattacharya, S. K.; Gutteridge, C. E.; Pettus, T. R. R.; Danishefsky,
S. J. Angew. Chem. Int. Ed. 1998, 110, 835-838; Chen, X.-T.; Gutteridge,
C. E.; Bhattacharya, S. K.; Zhou, B.; Pettus, T. R. R.; Hascall, T.;
Danishefsky, S. J. Angew. Chem. Int. Ed. 1998, 37, 185-187.
(7) Kennard, O.; Watson, D. G. Tetrahedron Lett. 1968, 2879-2884.
S0002-7863(98)01063-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/13/1998

Synthesis of Eleutherobin and Eleuthosides A and B
J. Am. Chem. Soc., Vol. 120, No. 34, 1998 8675
Scheme 1. Construction of Glycodise Donor 9a
a Reagents and conditions: (a) 1.1 equiv of NaH, DMF, 0 °C, 30
min; then 1.2 equiv of PMB-Cl, 2 h, 93%; (b) 0.1 equiv of TsOH‚H2O,
ethylene glycol-MeOH (1:10), 25 °C, 6 h, 84%; (c) 4.0 equiv of
TBSOTf, 10 equiv of Et3N, CH2Cl2, 0 °C, 2 h, 97%; (d) 3.4 equiv of
NBS, 11 equiv of pyridine, acetone-H2O (93:7), 80% (ca. 2:1 ratio of
anomers); (e) 0.2 equiv of NaH, 5.0 equiv of Cl3CCN, CH2Cl2, 25 °C,
3.5 h, 93%. Ts ) p-toluenesulfonyl. TBSOTf ) tert-butyldimethylsilyl
trifluoromethanesulfonate. NBS ) N-bromosuccinimide. PMB )
p-methoxybenzyl.
Figure 2. Retrosynthetic analysis of eleutherobin (1) and eleuthosides
A (2) and B (3).
absolute stereochemistry of eleutherobin (1), and the construc-
tion of a number of analogues of these compounds.12
was removed by treatment with TsOH in ethylene glycol:
methanol (1:10), furnishing diol 13 in 84% yield. Both hydroxyl
groups in 13 were then silylated (TBSOTf-Et3N, 97% yield
of 14), and the anomeric position was freed by the action of
NBS-pyridine in aqueous acetone, affording lactol 15 (80%
yield, ca. 2:1 mixture of anomers). Finally, treatment of 15
with NaH, followed by addition of Cl3CCN gave the desired
trichloroacetimidate 9 in 93% yield as the major isomer (greater
than 95% purity).13 Purification of this sensitive intermediate
could be achieved by flash chromatography with a short column
(silica, 10% ether in hexane containing 1% Et3N). The next
task was to define suitable conditions for the stereospecific
glycosidation of hydroxyaldehyde 7 with the arabinose-derived
carbohydrate donor 9. To this end, the study in Table 1 was
carried out. Indeed, it was possible to reverse the stereoselec-
tivity of the formed glycoside bond by varying the experimental
conditions. Thus, while reaction of 7 with 9 in hexane in the
presence of TMSOTf as a catalyst at -78 °C gave a ca. 8:1
ratio of glycosides in favor of the R-anomer 26 (75% combined
yield), the use of dioxane:toluene (2:1) as solvent at 0 °C led
to a ca. 8:1 ratio of products in favor of the desired â-anomer
25 (75% yield after flash chromatography purification). Flash
chromatography produced pure 25 ready for the next step.
2. Retrosynthetic Analysis and Strategy
With the exception of the D-arabinopyranose moiety, the
structural features of eleutherobin (1) and the eleuthosides A
(2) and B (3) are similar to those of the sarcodictyins (4 and 5).
Thus, the strategy for their total synthesis was devised from a
similar retrosynthetic analysis with appropriate provisions for
the introduction of the carbohydrate unit. Figure 2 outlines the
retrosynthetic analysis for eleutherobin (1) and the eleuthosides
(2, 3). Thus, removal of the (E)-N(6′)-methylurocanic acid
residue from the target structure (I) and dismantling of the
oxygen bridge of the central bicyclic core leads to the 10-
membered ring dihydroxy dienone II, whose origin can be traced
to the open-chain acetylenic aldehyde III. Further carbon-
carbon bond disconnections and retroglycosidation led to
hydroxy acetylene 7, whose relationship to (+)-carvone 8 was
amply evident. It was comforting to know that, although the
(+)-enantiomer of carvone was chosen as the initial starting
material, the (-)-enantiomer was also available in case the
absolute stereochemistry of the natural substances required it.
The trichloroacetimidate 9 required for the projected total
synthesis was traced to D-arabinose tetraacetate 10. The
execution of the total synthesis of eleutherobin (1) and eleutho-
sides A (2) and B (3) was carried out as described below.
Reaction of the pure â-anomer 25 with LiHMDS in THF at
-30 °C caused smooth cyclization via acetylide formation and
intramolecular attack on the aldehyde group affording an
intermediate secondary alcohol (mixture of diastereomers) which
was immediately oxidized with Dess-Martin reagent to dienone
16 (Scheme 2).14
3. Total Synthesis of Eleutherobin (1)
The construction of the (+)-carvone-derived hydroxy alde-
hyde fragment 7 (Scheme 2) has been described in the preceding
paper.9 We, therefore, begin here with the synthesis of the
requisite fragment, trichloroacetimidate 9 (Scheme 1). Thus,
arabinosetetraacetate (10) was efficiently converted to thiogly-
coside 11 by a sequence recently reported from these labora-
tories.12 The hydroxyl group of 11 was then protected as a PMB
ether by the action of PMB-Cl in the presence of NaH (93%
yield), and the acetonide group of the resulting compound 12
It was now time to install the acetate group at the C-2 position
of the pyranose ring. Selective removal of the PMB group from
16 with DDQ led to the formation of the corresponding hydroxy
compound 17 (Scheme 2) in 91% yield. Standard acetylation
then led to acetate 18 (95% yield). Both TES groups were then
(12) Nicolaou, K. C.; Trujillo, J. I.; Chibale, K. Tetrahedron 1997, 53,
8751-8778. For a highlight review, see: Lindel, T. Angew. Chem. Int. Ed.
1998, 37, 774-776.
(13) Schmidt, R. R.; Jung, K.-H. in PreparatiVe Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker Inc.: New York, 1997; pp 283-312.
(14) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.

8676 J. Am. Chem. Soc., Vol. 120, No. 34, 1998
Scheme 2. Total Synthesis of Eleutherobin (1)a
Nicolaou et al.
Table 1. Toward the Total Synthesis of Eleutherobin (1): Studies
for the Attachment of the Sugar Moiety
products
conditions
(25:26)c
yield (%)
CH2Cl2, -78 °Ca
1:3
1:8
1:4
2:1
2.5:1
3:1
7:1
8:1
7:1
52 (mixture of 25 and 26)
34 (mixture of 25 and 26)
62 (mixture of 25 and 26)
65 (mixture of 25 and 26)
54 (of 25)
60 (mixture of 25 and 26)
67 (of 25)
hexane, -78 °Ca
MeCN, -35 °Ca
Et2O, -80 °Ca
Et2O, 0 °Ca
Et2O, 25 °Ca
dioxane-toluene (1:1), 0 °Cb
dioxane-toluene (2:1), 0 °Cb
dioxane-toluene (3:1), 0 °Cb
75 (of 25)
70 (of 25)
a Concentration of starting material is 0.1 M, TMSOTf (2-5%), 1.5
equiv of imidate. b Concentration of starting material is 0.07 M,
TMSOTf (2-5%) 2.5 equiv of imidate. c The ratio of the two anomers
was determined by NRM. TES ) triethylsilyl, PMB ) p-methoxy-
benzyl, TBS ) t-butyldimethylsilyl, NIS ) N-iodosuccinimide.
Scheme 3. Synthesis of the R-Anomer of Eleutherobin (27)
catalyst, H2, toluene, 25 °C), compound 19 gave rise to the
expected lactol 21, whose conversion to the methoxy ketal 22
proved straightforward (MeOH, PPTS, 76% yield from 19).
The attachment of the (E)-N(6′)-methylurocanic acid residue
onto the main framework of the target molecule was ac-
complished by reaction of alcohol 22 with mixed anhydride 249
in the presence of Et3N and DMAP in CH2Cl2 at 25 °C, leading
to esterified product 23 (97% yield). Finally, exposure of 23
to TBAF-AcOH in THF resulted in the cleavage of the TBS
group and the liberation of eleutherobin (1) in 96% yield.
Synthetic eleutherobin (1) exhibited identical physical data to
those reported for the natural substance. Furthermore, the sign
of its rotation [R]D -67 (c ) 0.2, MeOH) was the same as that
reported for the natural eleutherobin, establishing the absolute
stereochemistry of the latter as that corresponding to (+)-carvone
(6) and structure 1.
a Reagents and conditions: (a) 9, TMSOTf, see Table 1; (b) 2.0 equiv
of LiHMDS, THF, -30 °C, 20 min; (c) 2.0 equiv of Dess-Martin
periodinane, 10 equiv of NaHCO3, 10 equiv of pyridine, CH2Cl2, 0
°C, 15 min, 93% for two steps; (d) 2.2 equiv of DDQ, CH2Cl2-H2O
(20:1), 25 °C, 91%; (e) 12 equiv of Ac2O, 16 equiv of Et3N, 0.5 equiv
of DMAP, CH2Cl2, 25 °C, 1 h, 95%; (f) Et3N‚3HF-THF (1:7), 25 °C,
3 h, 81%; (g) H2, 50 mol % Lindlar’s catalyst, PhCH3, 25 °C, 20 min;
(h) 0.2 equiv of PPTS, MeOH, 25 °C, 20 min, 76% for two steps; (i)
10 equiv of 24, 15 equiv of Et3N, 2.0 equiv of DMAP, CH2Cl2, 25 °C,
18 h, 97%; (j) 17 equiv of TBAF, 4.0 equiv of AcOH, THF, 25 °C,
2.5 h, 96%. TMSOTf ) trimethylsilyl trifluoromethanesulfonate.
LiHMDS ) lithium hexamethyldisilazane. DDQ ) 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone, DMAP ) 4-(dimethylamino)pyridine. Lind-
lar’s catalyst ) Pd/CaCO3/Pb. PPTS ) pyridinium p-toluenesulfonate.
TBAF ) tetra-n-butylammonium fluoride.
The R-glycoside analogue 27 of eleutherobin (Scheme 3) was
synthesized from the R-anomer 26 (Table 1) by following the
same route as for 1 (shown in Scheme 2). The yields for the
steps involved in this construction were similar to those for the
eleutherobin sequence.
removed from 18 without damage of the TBS group by the
discriminating action of Et3N‚3HF in THF at 25 °C furnishing
diol 19.
The next objective in the synthesis was the generation of the
key dienone 20, the fleeting intermediate expected to readily
collapse in favor of its bridged isomer 21 (Scheme 2). Indeed,
upon selective hydrogenation of the acetylene moiety (Lindlar
4. Total Synthesis of Eleuthosides
The eleuthosides A (2) and B (3) were synthesized from
eleutherobin (1) as indicated in Scheme 4. Thus, exposure of

Synthesis of Eleutherobin and Eleuthosides A and B
J. Am. Chem. Soc., Vol. 120, No. 34, 1998 8677
Scheme 4. Synthesis of Eleuthosides A (2) and B (3)a
methods and was characterized as such, matching, in all respects,
the data reported for the natural eleuthosides A (2) and B (3).5
Exposure of bis-TBS ether 23 (or 1) to TBAF in THF at 25 °C
caused slow migration of the acetate group from the 2′-position
to the 4′-hydroxyl group, leading to the isomeric eluetherobin
31 (60% yield) as well as deacylation leading to deacetoxy-
eleutherobin 32 (8% yield). The structure of 31 was established
by NMR spectroscopic methods (1H 1D and 2D COSY) and
comparisons with 1 and 23.
5. Conclusion
Following a strategy similar to that described for the
sarcodictyins A and B in the preceding paper9 and by incor-
porating the arabinose pyranoside moiety into the molecule prior
to ring closure, the total synthesis of the marine natural products
eleutherobin (1) and eleuthosides A (2) and B (3) has been
accomplished. In addition, the chemical synthesis of the
isomeric eleutherobin (27) in which the glycosidic bond is
oriented in the R-position as well as the eleuthoside analogues
28-32 is described. The reported chemistry allows access not
only to the rare naturally occurring substances but also to
designed analogues and combinatorial libraries for biological
screening purposes. Combined with their appealing mechanism
of tubulin polymerization and microtubule stabilization, the
described technology makes the eleutherobins and eleuthosides
an attractive proposition as a new class of potential anticancer
agents for further investigation.
6. Experimental Section
General Techniques. For general techniques, see the preceding
paper.9 Procedures and data for compounds 9 and 12-15 can be found
in the Supporting Information accompanying this paper.
Enynone 16. A solution of LiHDMS (1.0 M in THF, 0.150 mL,
0.150 mmol, 2.0 equiv) was added dropwise to a solution of 25 (77.5
mg, 0.0742 mmol, 1.0 equiv) in THF (4.0 mL) at -30 °C and the
reaction was stirred for 10 min at -30 °C. After the reaction was
complete as indicated by TLC analysis, saturated NH4Cl solution (5
mL) was added and the resulting biphasic mixture was extracted with
ether (3 × 30 mL). The combined extracts were washed with brine,
dried over over Na2SO4, and concentrated to give a crude residue which
was was purified by short column chromatography (silica gel, 10%
EtOAc in hexanes). The purified mixture of isomers was then used
immediately for the next step. To a solution of this mixture in CH2Cl2
(4.0 mL) at 0 °C was added NaHCO3 (62.3 mg, 0.742 mmol, 10.0
equiv) and pyridine (60 mL, 0.742 mmol, 10.0 equiv), and the resulting
solution was chilled to 0 °C and stirred for 10 min. Dess-Martin
reagent (63.0 mg, 0.149 mmol, 2.0 equiv) was added, and the reaction
was stirred for an additional 15 min at 0 °C. After the reaction was
complete as indicated by TLC analysis, it was quenched by addition
of saturated Na2S2O3 (2 mL). The mixture was extracted with CH2Cl2
(3 × 30 mL), and the combined extracts were dried over Na2SO4 and
concentrated to provide a crude residue which was purified by flash
chromatography (silica gel, 5% EtOAc in hexanes) to afford 16 (72.0
mg, 93% for two steps): Rf ) 0.80 (silica, Et2O-hexane,1:3); [R] -11.5
(c 0.46, CHCl3); FT-IR (neat) νmax 2954, 2878, 1663, 1512, 1462, 1250,
1115, 1037, 1004, 834, 777, 741 cm-1; 1H NMR (500 MHz, CDCl3) δ
7.21 (d, J ) 8.5 Hz, 2 H), 6.82 (d, J ) 8.5 Hz, 2 H), 6.28 (d, J ) 11.8
Hz, 1 H, C-2), 5.38 (bs, 1 H, C-12), 4.64 (d, J ) 2.3 Hz, 1 H, C-1′′),
4.63-4.59 (m, 1 H, C-15), 4.48 (d, J ) 12.5 Hz, 2 H), 3.96-3.87 (m,
2 H, C-14, C-4′′ or C-5′′), 3.80-3.73 (m, 1 H, C-4′′ or C-5′′), 3.78 (s,
3 H), 3.70-3.68 (m, 1 H, C-1), 3.58 (dd, J ) 11.4, 2.3 hz, 1 H, C-2′′)
3.55-3.48 (m, 2 H, C-8, C-3′′), 3.45 (dd, J ) 10.3, 5.3 Hz, 1 H, C-5′′),
2.35 (bd, J ) 9.1 Hz, 1 H, C-10), 2.20 (bd, J ) 18.5 Hz, 1 H, C-13),
1.98 (bd, J ) 18.5 Hz, 1 H, C-13), 1.87-1.76 (m, 2 H, C-9), 1.69 (s,
3 H, C-17), 1.56-1.45 (m, 2 H), 1.34 (s, 3 H, C-16), 0.96-0.89 (m,
24 H, C-19, C-20), 0.83-0.51 (m, 12 H), 0.86 (s, 9 H), 0.83 (s, 9 H),
0.04 (s, 3 H), 0.02 (s, 6 H), -0.02 (s, 3 H); 13C NMR (125.7 MHz,
a Reagents and conditions: (1) 1.1 equiv of Ac2O, 3.0 equiv of Et3N,
0.2 equiv of DMAP, 0 °C, 1 h, 16% of 28 along with 73% of the
mixture of 29 and 30 (2.2:1 by NMR); (b) 2.0 equiv of CSA, CH2Cl2-
H2O (10:1), 25 °C, 48 h, 80% of the mixture of 2 and 3 (based on
87% conversion of the starting material); (c) 4.0 equiv of TBAF, THF,
25 °C, 6 h, 1 (22%), 31 (60%) and 32 (8%). DMAP ) 4-(dimethyl-
amino)pyridine. CSA ) 10-camphorsulfonic acid.
1 to 1.1 equiv of Ac2O in the presence of excess Et3N and 0.2
equiv of DMAP in CH2Cl2 at 0 °C resulted in the formation of
triacetate 28 (12% yield) and diacetates 29 and 30 (75% yield
1
as a ca. 1:2 mixture in favor of 29 by H NMR), plus some
unreacted starting material (13%). The inseparable mixture of
diacetates (29 and 30) was exposed to CSA in moist CH2Cl2,
furnishing a mixture of eleuthosides A and B (2 + 3). This
mixture could not be separated by conventional chromatographic

8678 J. Am. Chem. Soc., Vol. 120, No. 34, 1998
Nicolaou et al.
CDCl3) δ 180.7, 159.1, 141.9, 139.7, 134.0, 130.9, 129.5, 121.6, 113.6,
103.8, 98.1, 87.7, 83.4, 73.0, 72.5, 68.6, 64.2, 39.0, 38.5, 36.1, 29.9,
25.9, 25.9, 25.8, 22.0, 21.5, 21.2, 20.2, 18.2, 7.0, 6.9, 5.8, 5.7, -4.5,
-4.7, -4.8; HRMS (FAB) calcd for C57H100O9Si4 (M + Cs+)
1173.5569, found 1173.5499.
diol 19 (100 mg, 81%): Rf ) 0.40 (silica gel, Et2O-hexane, 3:1); [R]
-53.5 (c 0.85, CHCl3); FT-IR (neat) νmax 3410, 2929, 2856, 1744, 1652,
1
1370, 1254, 1123, 1063, 1037, 837, 777 cm-1; H NMR (500 MHz,
CDCl3) δ 6.21 (d, J ) 5.9 Hz, 1 H, C-2), 5.43 (bs, 1 H, C-12), 5.01-
4.99 (m, 2 H, C-1′′, C-2′′), 4.89 (s, 1 H), 4.53 (dd, J ) 12.5, 1.5 Hz,
1 H, C-15), 3.96-3.94 (m, 1 H, C-3′′), 3.92 (dd, J ) 5.9, 1.5 Hz, 1
H), 3.89-3.87 (m, 1 H, C-4′′), 3.76-3.72 (m, 1 H, C-1), 3.67 (dd, J
) 12.0, 1.4 Hz, 1 H, C-5′′), 3.52 (dd, J ) 12.0, 3.6 Hz, 1 H, C-5′′),
3.46 (dt, J ) 11.5, 2.9 Hz, 1 H, C-8), 2.55 (bs, 1 H, OH), 2.43 (bd, J
) 10.3 Hz, 1 H, C-10), 2.28 (bs, 1 H, OH), 2.17 (bd, J ) 18.4 Hz, 1
H, C-13), 2.06 (s, 3 H, C-2′′′), 2.01 (bd, J ) 18.4 Hz, 1 H, C-13), 1.95
(dd, J ) 14.5, 4.5 Hz, 1 H, C-5), 1.75 (s, 3 H, C-17), 1.67-1.62 (m,
1 H, C-9), 1.57-1.51 (m, 1 H, C-18), 1.50 (s, 3 H, C-16), 1.12-1.07
(m, 1 H, C-14), 0.93-0.89 (m, 6 H, C-19, C-20), 0.90 (s, 9 H), 0.88
(s, 9 H), 0.09 (s, 3 H), 0.07 (s, 6 H), 0.07 (s, 3 H); 13C NMR (125.7
MHz, CDCl3) δ 180.4, 170.4, 143.0, 139.9, 121.8, 102.8, 95.0, 87.7,
80.7, 71.3, 71.3, 68.1, 45.0, 38.9, 38.5, 33.2, 29.7, 29.5, 25.8, 25.5,
21.9, 21.5, 21.3, 20.4, 20.0, 18.1, 18.1, -4.1, -4.6, -4.6, -4.8; HRMS
(FAB) calcd for C39H66O9Si2 (M + Cs+) 867.3336, found 867.3300.
Tricyclic Core Compound 22. A heterogeneous mixture of
eneynone 19 (103 mg, 0.140 mmol, 1.0 equiv) and Lindlar catalyst
(148 mg, 0.069 mmol, 0.5 equiv) was treated with hydrogen (1 atm),
and the reaction was stirred at 25 °C for 20 min. The reaction mixture
was then filtered through a Celite pad eluting with ether and
concentrated to give a crude residue which was used without further
purification. This residue was dissolved in MeOH (4.0 mL), PPTS
(7.0 mg, 0.028 mmol, 0.2 equiv) was added, and the reaction was stirred
at 25 °C for 20 min. Once complete (TLC monitoring), the reaction
was quenched by addition of saturated NaHCO3 solution (2.0 mL). The
reaction mixture was then extracted with ether (3 × 20 mL), and the
combined extracts were washed with brine, dried over Na2SO4, and
concentrated to provide a crude residue which was purified by flash
chromatography (silica gel, 50% EtOAc in hexanes) to afford methyl
ketal 22 (80.1 mg, 76%): Rf ) 0.74 (silica gel, Et2O-hexane, 3:1);
[R] -38.61 (c 0.65, CHCl3); FT-IR (neat) νmax 3448, 2929, 2856, 1748,
1254, 1144, 1038, 837, 775 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.08
(d, J ) 5.9 Hz, 1 H, C-5), 6.02 (d, J ) 5.9 Hz, 1 H, C-6), 5.52 (d, J
) 9.5 Hz, 1 H, C-2), 5.27 (br, 1 H, C-12), 4.98 (dd, J ) 8.4, 2.8 Hz,
1 H, C-2′′), 4.89 (d, J ) 2.8 Hz, 1 H, C-1′′), 4.25 (d, J ) 12.5 Hz, 1
H, C-15), 3.97 (dd, J ) 8.4, 2.8 Hz, 1 H, C-3′′), 3.90-3.87 (m, 1 H,
C-4′′), 3.86-3.84 (m, 1 H, C-1), 3.84 (d, J ) 12.5 Hz, 1 H, C-15),
3.67 (d, J ) 7.2 Hz, 1 H, C-8), 3.65 (d, J ) 11.7 Hz, 1 H, C-5′′), 3.48
(dd, J ) 11.7, 4.5 Hz, 1 H, C-5′′), 3.18 (s, 3 H, C-21), 2.38-2.32 (m,
2 H, C-10, C-13), 2.04 (s, 3 H, C-2′′′), 1.95 (bd, J ) 19.4 Hz, 1 H,
C-13), 1.58 (s, 3 H, C-17), 1.52 (s, 3 H, C-16), 1.50-1.43 (m, 3 H,
C-9, C-18), 1.20-1.17 (m, 1 H, C-14), 0.93-0.78 (m, 6 H, C-19, C-20),
0.88 (s, 9 H), 0.87 (s, 9 H), 0.08 (s, 3 H), 0.05 (s, 3 H), 0.04 (s, 6 H);
13C NMR (125.7 MHz, CDCl3) δ 170.2, 134.6, 133.8, 133.5, 130.5,
121.6, 115.7, 95.0, 91.32, 80.7, 76.8, 76.8, 71.5, 69.4, 64.0, 49.6, 42.4,
39.2, 34.5, 33.8, 29.7, 29.2, 25.9, 24.9, 24.6, 24.5, 22.3, 22.1, 21.2,
20.4, 18.1, -4.2, -4.5, -4.7, -4.8; HRMS (FAB) calcd for C40H70O9-
Si2 (M + Cs+) 883.3580, found 883.3613.
Enynone Alcohol 17. To a solution of PMB-ether 16 (202 mg,
0.194 mmol, 1.0 equiv) in CH2Cl2 (7.0 mL) and water (0.35 mL) at 0
°C was added DDQ (98.0 mg, 0.432 mmol, 2.3 equiv), and the resulting
solution was allowed to warm to 25 °C and stirred for 20 min. Once
complete by TLC analysis, the reaction was quenched by addition of
saturated Na2S2O3 solution (2.0 mL) and saturated NaHCO3 solution
(2.0 mL). The reaction mixture was then extracted with CH2Cl2 (3 ×
40 mL), and the combined extracts were dried over Na2SO4 and
concentrated to afford a crude residue which was purified by flash
chromatography (silica gel, 10% EtOAc in hexanes) to provide alcohol
17 (163 mg, 91%): Rf ) 0.6 (silica gel, EtOAc-hexane, 1:5); [R]
-0.176 (c 1.6, CHCl3); FT-IR (neat) νmax 2955, 2929, 2203, 1663, 1462,
1
1366, 1252, 1214, 1118, 1076, 1004, 835, 740 cm-1; H NMR (500
MHz, CDCl3) δ 6.19 (d, J ) 11.8 Hz, 1 H, C-2), 5.40 (bs, 1 H, C-12),
4.79 (d, J ) 2.8 Hz, 1 H, C-1′′), 4.57 (d, J ) 11.8 Hz, 1 H, C-15),
3.89-3.83 (m, 2 H), 3.78 (m, 1 H, C-2′′), 3.74 (dd, J ) 8.3, 1.7 Hz,
1 H, C-3′′), 3.69 (bs, 1 H), 3.62 (dd, J ) 10.3, 1.4 Hz, 1 H, C-8),
3.51-3.45 (m, 2 H), 2.37-2.30 (m, 1 H, C-10), 2.14 (bd, J ) 17.5
Hz, 1 H, C-13), 1.98 (bd, J ) 17.5 Hz, 1 H, C-13), 1.85 (dd, J ) 14.5,
3.3 Hz, 1 H, C-12), 1.76 (dd, J ) 14.5, 2.1 Hz, 1 H, C-12), 1.70 (s, 3
H, C-17), 1.53-1.42 (m, 1 H, C-18), 1.37 (s, 3 H, C-16), 1.09-1.05
(m, 1 H, C-14), 0.97-0.86 (m, 2 H), 0.96-0.89 (m, 24 H, C-19, C-20),
0.89 (s, 9 H), 0.86 (s, 9 H), 0.80-0.54 (m, 12 H), 0.06 (s, 3 H), 0.05
(s, 6 H), 0.04 (s, 3 H); 13C NMR (125.7 MHz, CDCl3) δ 180.7, 143.2,
139.5, 133.8, 125.5, 121.7, 104.6, 98.0, 87.7, 83.3, 72.5, 71.8, 70.4,
69.9, 69.0, 64.6, 44.8, 38.8, 38.6, 36.1, 30.3, 29.9, 29.7, 26.0, 25.8,
25.7, 22.0, 21.4, 21.2, 20.1, 18.3, 18.1, 7.0, 6.9, 5.8, 5.2, -4.2, -4.5,
-4.6, -4.7; HRMS (FAB) calcd for C49H92O8Si4 (M + Cs+):
1053.4924, found 1053.4974.
Enynone Acetate 18. To a solution of alcohol 17 (163 mg, 0.177
mmol, 1.0 equiv) in CH2Cl2 (5.0 mL) at 0 °C were added Et3N (400
µL, 2.86 mmol, 16.1 equiv), DMAP (10.0 mg, 0.0818 mmol, 0.46
equiv), and Ac2O (0.2 mL, 2.12 mmol, 12.0 equiv), and the reaction
was warmed to 25 °C and stirred for 1 h. After completion was
established by TLC analysis, the reaction was quenched by addition
of saturated NaHCO3 solution (2.0 mL). The reaction mixture was
then extracted with CH2Cl2 (3 × 40 mL), and the combined extracts
were dried over Na2SO4 and concentrated to give a crude residue which
was purified by flash chromatography (silica gel, 10% EtOAc in
hexanes) to afford acetate 18 (162 mg, 95%): Rf ) 0.57 (silica, Et2O-
hexane, 1:5); [R] -0.34 (c 1.4, CHCl3); FT-IR (neat) νmax 2956, 1746,
1661, 1461, 1371, 1237, 1119, 1004 cm-1; 1H NMR (500 MHz, CDCl3)
δ 6.18 (d, J ) 11.8, Hz, 1 H, C-2), 5.40 (bs, 1 H, C-12), 4.98-4.94
(m, 2 H, C-1′′, C-2′′), 4.51 (dd J ) 12.2, 1.2 hz, 1 H, C-15), 3.93 (dd,
J ) 8.4, 2.5 Hz, 1 H, C-3), 3.85 (bs, 2 H), 3.69 (bs, 1 H, C-1), 3.65 (d,
J ) 11.8 Hz, 1 H), 3.51-3.45 (m, 1 H), 3.48 (d, J ) 11.7 Hz, 1 H),
2.36 (bd, J ) 10.6 Hz, 1 H, C-10), 2.17-2.12 (m, 1 H, C-13), 2.03 (s,
3 H, C-2′′′), 1.99 (bd, J ) 16.4 Hz, 1 H, C-13), 1.84 (dd, J ) 14.5, 3.4
Hz, 1 H, C-9), 1.76 (dd, J ) 14.5, 2.0 hz, 1 H, C-9), 1.69 (s, 3 H,
C-17), 1.63-1.44 (m, 1 H, C-18), 1.39 (s, 3 H, C-16),1.08-1.03 (m,
1 H, C-14), 0.96-0.88 (m, 24 H, C-19, C-20), 0.88 (s, 9 H), 0.86 (s,
9 H), 0.80-0.50 (m, 12 H), 0.06 (s, 3 H), 0.05 (s, 6 H), 0.04 (s, 3 H);
13C NMR (125.7 MHz, CDCl3) δ 180.3, 170.2, 143.1, 139.3, 133.8,
121.7, 103.9, 95.3, 87.7, 83.4, 72.5, 71.3, 68.8, 68.2, 64.1, 44.8, 38.9,
38.6, 36.0, 29.9, 29.7, 25.8, 25.7, 21.9, 21.4, 21.1, 20.2, 18.1, 14.1,
7.0, 6.9, 5.8, 5.2, -4.1, -4.6, -4.7, -4.8; HRMS (FAB) calcd for
C51H94O9Si4 (M + Cs+) 1095.5030, found 1095.5088.
Eleutherobin bis-TBS Ether 23. To a solution of alcohol 22 (64
mg, 0.0871 mmol, 1.0 equiv) in CH2Cl2 (0.4 mL) were added Et3N
(0.177 mL, 1.27 mmol, 15.0 equiv) and DMAP (21 mg, 0.0017 mmol,
0.02 equiv). The solution was then chilled to 0 °C, and a 0.2 M CH2-
Cl2 solution of mixed anhydride 249 was added (4.2 mL, 0.84 mmol,
9.6 equiv). The reaction mixture was then warmed to 25 °C and stirred
for 18 h. After completion was established (TLC analysis), the reaction
was quenched by addition of saturated NaHCO3 solution and extracted
with CH2Cl2 (3 × 20 mL). The combined organic extracts were dried
over Na2SO4 and concentrated to afford a crude residue which was
purified by flash chromatography (silica gel, 67% EtOAc in hexanes)
to produce urocanic ester 23 (73.0 mg, 97%): Rf ) 0.35 (silica gel,
EtOAc-hexane, 1:3); [R] -61.3 (c 0.6, CHCl3); FT-IR (neat) νmax 2929,
2856, 2362, 2338, 1746, 1707, 1639, 1468, 1367, 1296, 1253, 1150,
1062, 1038, 1001, 886, 837, 775 cm-1; 1H NMR (600 MHz, CDCl3) δ
7.52 (d, J ) 15.6 Hz, 1 H, C-3′), 7.44 (s, 1 H, C-7′), 7.07 (s, 1 H,
C-5′), 6.55 (d, J ) 15.6 Hz, 1 H, C-2′), 6.08-6.05 (m, 2 H, C-5, C-6),
5.55 (d, J ) 9.5 Hz, 1 H, C-2), 5.24 (bs, 1 H, C-12), 4.99-4.96 (m, 1
H, C-2′′), 4.88 (s, 1 H, C-1′′), 4.79 (d, J ) 7.4 Hz, 1 H, C-8), 4.25 (d,
Enynone Diol 19. To a solution of silyl ether 18 (161 mg, 0.167
mmol, 1.0 equiv) in THF (4.2 mL) at 0 °C was added Et3N‚3HF (0.60
mL, 3.68 mmol, 22.0 equiv), and the reaction mixture was warmed to
25 °C and stirred for 4 h. After completion (TLC analysis), the reaction
was quenched by addition of saturated NaHCO3 solution (2.0 mL) at
0 °C. The biphasic mixture was then extracted with ether (3 × 40
mL), and the combined extracts were washed with brine, dried over
Na2SO4, and concentrated to produce a crude residue which was purified
by flash chromatography (silica gel, 50% EtOAc in hexanes) to afford

Synthesis of Eleutherobin and Eleuthosides A and B
J. Am. Chem. Soc., Vol. 120, No. 34, 1998 8679
J ) 12.4 Hz, 1 H, C-15), 3.97 (dd, J ) 8.3, 2.3 Hz, 1 H, C-3′′), 3.95-
3.92 (m, 1 H, C-1), 3.88-3.84 (m, 2 H, C-4′′, C-15), 3.66 (d, J ) 11.6
hz, 1 H, C-5′′), 3.69 (s, 3 H, C-9), 3.47 (dd, J ) 11.6, 4.4 Hz, 1 H,
C-5′′), 3.19 (s, 3 H, C-21), 2.58 (bd, J ) 11.2 Hz, 1 H, C-10), 2.26
(bd, J ) 17.0 Hz, 1 H, C-13), 2.05-1.94 (m, 2 H), 2.02 (s, 3 H, C-2′′),
1.97 (bd, J ) 17.8 Hz, 1 H, C-13), 1.61-1.51 (m, 2 H, C-9), 1.51 (s,
3 H, C-17), 1.43-1.40 (m, 1 H, C-18), 1.42 (s, 3 H, C-16), 1.25-1.22
(m, 1 H, C-14), 0.95 (d, J ) 6.6 Hz, 3 H, C-19 or C-20), 0.90 (d, J )
6.6 Hz, 3 H, C-19 or C-20), 0.87 (s, 9 H), 0.86 (s, 9 H), 0.08 (s, 3 H),
0.05 (s, 3 H), 0.04 (s, 3 H), 0.04 (s, 3 H); 13C NMR (150 MHz,
CDCl3): δ 170.2, 166.7, 139.2, 138.4, 136.3, 134.2, 133.9, 133.3, 130.8,
122.7, 121.2, 115.9, 95.0, 89.8, 81.5, 71.5, 69.5, 69.3, 64.0, 60.4, 49.6,
42.5, 38.6, 34.0, 33.6, 29.6, 29.0, 25.8, 24.4, 24.3, 22.2, 22.0, 21.1,
21.0, 20.6, 18.2, 18.1, 14.2, -4.2, -4.5, -4.7, -4.9; HRMS (FAB)
calcd for C47H76N2O10Si2 (M + Cs+) 1017.4093, found 1017.4139.
Eleutherobin (1). To a solution of disilyl ether 23 (15.5 mg, 0.017
mmol, 1.0 equiv) in THF (4.0 mL) at 0 °C were added AcOH (1.0 M
in THF, 0.070 mL, 0.070 mmol, 4.1 equiv) and TBAF (1.0 M in THF,
0.30 mL, 0.30 mmol, 17.6 equiv). The reaction mixture was warmed
to 25 °C and stirred for 2.5 h, after which water (1.0 mL) and saturated
NaHCO3 solution (1.0 mL) were added, and the mixture was extracted
with CH2Cl2 (3 × 20 mL). The combined extracts were dried over
Na2SO4 and concentrated to provide a crude residue which was purified
by flash chromatography (silica gel, 2% MeOH in CH2Cl2 with 1%
Et3N) to afford eleutherobin 1 (11.0 mg, 96%): Rf ) 0.22 (silica gel,
MeOH-CH2Cl2, 1:20); [R] -67 (c 0.15, MeOH); FT-IR (neat) νmax
1:20); 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J ) 15.6 Hz, 1 H, C-3′),
7.47 (s, 1 H, C-7), 7.11 (s, 1 H, C-5′), 6.57 (d, J ) 15.6 Hz, 1 H,
C-2′), 6.21 (d, J ) 5.9 Hz, 1 H, C-5), 6.00 (d, J ) 5.9 Hz, 1 H, C-6),
5.62 (d, J ) 9.5 Hz, 1 H, C-2), 5.30-5.26 (m, 1 H), 4.97 (dd, J ) 3.8,
2.0 Hz, 1 H, C-2′′), 4.82 (d, J ) 7.5 Hz, 1 H, C-8), 4.70 (d, J ) 2.0
Hz, 1 H, C-1′′), 4.17 (d, J ) 10.8 Hz, 1 H, C-15), 3.99-3.96 (m, 1 H),
3.96 (d, J ) 10.8 Hz, 1 H, C-15), 3.92-3.88 (m, 1 H), 3.88-3.84 (m,
1 H), 3.72 (s, 3 H, C-9), 3.65-3.62 (m, 2 H), 3.55-3.43 (m, 2 H),
3.23 (s, 3 H, C-21), 3.02-2.94 (m, 1 H), 2.71-2.63 (m, 1 H), 2.40-
2.25 (m, 2 H), 2.11 (s, 3 H, C-2′′′), 2.01-1.96 (m, 2 H), 1.56-1.21
(m, 1 H), 1.53 (s, 3 H, C-17), 1.46 (s, 3 H, C-16), 1.28-1.20 (m, 1 H),
1.00 (d, J ) 6.6 Hz, 3 H, C-18 or C-19), 0.94 (d, J ) 6.6 Hz, 3 H,
C-18 or C-19); 13C NMR (62.5 MHz, CDCl3) δ 171.2, 166.3, 139.7,
138.1, 137.4, 136.3, 135.8, 134.9, 133.8, 130.2, 123.2, 121.7, 116.7,
91.2, 86.7, 81.7, 72.7, 72.0, 71.9, 70.2, 62.1, 49.9, 38.9, 34.4, 33.9,
33.8, 29.9, 29.6, 29.3, 24.7, 24.3, 22.5, 22.3, 21.3, 20.7.
Bis-acetoxy Eleutherobin (28) and Methyl Ketal Precursors of
Eleuthosides A and B (29 and 30). To a solution of natural
eleutherobin (1) (10.0 mg, 0.015 mmol, 1.0 equiv), Et3N (6.0 µL, 0.043
mmol, 3.0 equiv), and DMAP (0.40 mg, 0.0033 mmol, 0.2 equiv) in
CH2Cl2 (0.60 mL) at 0 °C was added Ac2O (1.0 M in CH2Cl2, 0.017
mL, 0.017 mmol, 1.1 equiv), and the reaction was stirred at the same
temperature for 1 h. The reaction was then quenched by addition of
saturated NaHCO3 solution (0.50 mL) and extracted with CH2Cl2 (5 ×
20 mL). The combined organic extracts were dried over Na2SO4 and
concentrated to provide a crude residue which was was purified by
flash chromatography (silica gel, 2% MeOH in CH2Cl2) to afford
triacetate 28 (1.8 mg, 16%) along with an inseparable mixture of
eleuthosides 29 and 30 (7.8 mg, 73%) and recovered 1 (0.5 mg, 5%).
For 28: Rf ) 0.44 (silica gel, MeOH- CH2Cl2, 1:20); [R] -67.3 (c
1.2, CHCl3); FT-IR (neat) νmax 2962, 1746, 1740, 1644, 1634, 1372,
1226, 1156, 1068, 759, 668, 617 cm-1; 1H NMR (500 MHz, CDCl3) δ
7.53 (d, J ) 15.5 Hz, 1 H, C-3′), 7.45 (s, 1 H, C-7′), 7.09 (s, 1 H,
C-5′), 6.55 (d, J ) 15.5 Hz, 1 H, C-2′), 6.11 (d, J ) 5.5 Hz, 1 H, C-5),
6.07 (d, J ) 5.5 Hz, 1 H, C-6), 5.52 (d, J ) 9.5 Hz, 1 H, C-2), 5.36
(dd, J ) 11.0, 3.5 Hz, 1 H, C-3′′), 5.34-5.30 (m, 1 H, C-4′′), 5.30-
5.27 (m, 1 H, C-12), 5.18 (dd, J ) 11.0, 3.5 Hz, 1 H, C-2), 4.96 (d, J
) 3.5 Hz, 1 H, C-1′′), 4.81 (d, J ) 7.5 Hz, 1 H, C-8), 4.33 (d, J )
11.5 Hz, 1 H, C-15), 3.97-3.93 (m, 1 H, C-1), 3.90 (dd, J ) 13.0, 1.0
Hz, 1 H, C-5′′), 3.88 (d, J ) 11.5 Hz, 1 H, C-15), 3.70 (s, 3 H, C-9′),
3.63 (dd, J ) 13.0, 2.0 Hz, 1 H, C-5′′), 3.66-3.62 (m, 1 H), 3.21 (s,
3 H, C-21), 2.60 (bd, J ) 10.6 Hz, 1 H, C-10), 2.30 (bd, J ) 16.0 Hz,
1 H, C-13), 2.12 (s, 3 H), 2.03 (s, 3 H), 1.99 (s, 3 H), 1.99-1.92 (m,
1 H, C-13), 1.68-1.55 (m, 2 H, C-9, C-18), 1.53 (s, 3 H, C-17), 1.44
(s, 3 H, C-16), 1.36 (ddd, J ) 15.0, 12.0, 7.5 Hz, 1 H, C-9), 1.25-
1.20 (m, 1 H, C-14), 0.96 (d, J ) 6.5 Hz, 3 H), 0.91 (d, J ) 6.6 Hz,
3 H); 13C NMR (125.7 MHz, CDCl3) δ 170.4, 170.1, 170.0, 166.7,
139.2, 138.4, 137.6, 136.4, 134.1, 133.6, 132.8, 131.0, 122.8, 121.3,
115.8, 115.7, 93.15, 89.8, 81.5, 69.2, 69.0, 68.0, 67.3, 60.5, 49.7, 42.2,
38.0, 34.2, 33.0, 31.4, 29.0, 24.4, 24.1, 22.2, 21.9, 21.0, 20.9, 20.7,
20.5; HRMS (FAB) calcd for C39H52N2O12 (M + Cs+) 873.2575, found
873.2546.
3388, 2933, 2851, 1735, 1708, 1637, 1367, 1247, 1162, 1039, 998 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.52 (d, J ) 15.6 Hz, 1 H), 7.44 (s, 1
H), 7.08 (s, 1 H), 6.54 (d, J ) 15.6 Hz, 1 H), 6.10 (d, J ) 5.9 Hz, 1
H), 6.06 (d, J ) 5.9 Hz, 1 H), 5.54 (d, J ) 9.4 Hz, 1 H), 5.26 (bs, 1
H), 4.96 (dd, J ) 9.9, 3.6 Hz, 1 H), 4.89 (d, J ) 3.5 Hz, 1 H), 4.80 (d,
J ) 7.4 Hz, 1 H), 4.29 (d, J ) 12.3 Hz, 1 H), 4.05-3.92 (m, 3 H),
3.86 (d, J ) 12.3 Hz, 1 H), 3.82 (d, J ) 12.3 Hz, 1 H), 3.70 (s, 3 H),
3.70-3.68 (m, 1 H), 3.20 (s, 3 H), 2.66-2.57 (m, 2 H, OH), 2.42-
2.39 (m, 1 H), 2.33-2.24 (m, 1 H), 2.10 (s, 3 H), 2.00-1.94 (m, 1 H),
1.62-1.56 (m, 2 H), 1.50 (s, 3 H), 1.43 (s, 3 H), 1.38 (ddd, J ) 15.0,
12.5, 7.5 Hz, 1 H), 1.26-1.17 (m, 1 H), 0.96 (d, J ) 6.6 Hz, 3 H),
0.91 (d, J ) 6.4 Hz, 3 H); 13C NMR (125.7 MHz, CDCl3) δ 171.4,
166.7, 139.2, 138.4, 137.4, 136.4, 134.1, 133.6, 132.8, 131.0, 122.8,
121.3, 115.9, 115.8, 93.4, 89.9, 81.5, 77.2, 71.8, 69.4, 69.1, 68.1, 62.1,
49.7, 42.3, 38.7, 34.2, 33.6, 31.4, 29.0, 24.5, 24.2, 22.2, 22.0, 21.1,
20.5, 19.8, 14.1, 13.7; HRMS (FAB) calcd for C35H48N2O10 (M + Cs+)
789.2334, found 789.2363.
â-Glycoside 25. A solution of alcohol 7 (20.0 mg, 0.0355 mmol,
1.0 equiv) and imidate 9 (62.1 mg, 0.0966 mmol, 2.7 equiv) in 2:1
dioxane-toluene (6.0 mL) was chilled to 0 °C, TMSOTf (0.05 M in
ether, 40 µL, 0.002 mmol, 0.05 equiv) was added, and the reaction
was stirred at 0 °C for 10 min after which Et3N (20 µL) was added
followed by NaHCO3 (3 mL). The reaction mixture was then extracted
with ether (3 × 20 mL), and the combined extracts were washed with
brine, dried over Na2SO4, and concentrated to give a crude residue
which was purified by flash chromatography (silica gel, 3% EtOAc in
hexanes) to afford 25 (27.9 mg, 75%): Rf ) 0.56 (silica gel, EtOAc-
hexane,1:5); [R] -27.7 (c 1.0, CHCl3); FT-IR (neat) νmax 2954, 1676,
Eleuthosides A and B (2 and 3). To a solution of 27 and 28 mixture
(7.8 mg, 0.011 mmol, 1.0 equiv) in CH2Cl2 (2.0 mL) and H2O (0.20
mL) at 25 °C was added CSA (5.2 mg, 0.022 mmol, 2.0 equiv), and
the reaction was stirred at the same temperature for 48 h. Once
complete (TLC monitoring), the reaction was quenched by addition of
saturated NaHCO3 solution (0.50 mL) and extracted with CH2Cl2 (5 ×
20 mL). The combined organic extracts were dried over Na2SO4 and
concentrated to provide a crude residue which was purified by flash
chromatography (silica gel, 3% MeOH in CH2Cl2) to afford an
inseparable mixture of eleuthoside A (2) and B (3) (5.3 mg, 80%).
Data for mixture of 2 and 3: Rf ) 0.32 (silica, MeOH-CH2Cl2, 1:20);
FT-IR (neat) νmax 3734, 3628, 2962, 2928, 2866, 1734, 1700, 1684,
1652, 1646, 1636, 1558, 1456, 1374, 1252, 1160, 1065, 1037, 986,
1
1612, 1512, 1461, 1364, 1250, 1114, 1038, 835, 740 cm-1; H NMR
(500 MHz, CDCl3) δ 10.16 (s, 1 H, C-4), 7.21 (d, J ) 8.5 Hz, 2 H),
6.94 (d, J ) 11.5 Hz, 1 H, C-2), 6.82 (d, J ) 8.5 Hz, 2 H), 5.38 (bs,
1 H, C-12), 4.74 (d, J ) 2.0 Hz, 1 H), 4.62 (d, J ) 11.9 Hz, 1 H), 4.42
(d, J ) 11.9 Hz, 1 H), 4.21 (m, 2 H), 3.92 (bs, 1 H), 3.78 (s, 3 H),
3.72 (m, 1 H), 3.50 (m, 4 H), 2.25 (m, 1 H), 2.01 (m, 3 H), 1.89 (m,
2 H), 1.75 (m, 1 H), 1.66 (s, 3 H), 1.57 (m, 2 H), 1.42 (m, 2 H), 1.31
(s, 3 H), 1.23 (m, 2 H), 0.89 (m, 35 H), 0.66 (m, 16 H), -0.03 (m, 12
H); 13C NMR (125.7 MHz, CDCl3) δ 189.6, 159.1, 155.5, 136.3, 136.2,
130.8, 129.5, 121.0, 113.6, 99.3, 86.8, 78.8, 76.4, 75.5, 73.0, 72.7, 71.4,
67.1, 64.0, 55.2, 39.0, 37.2, 34.2, 29.7, 28.4, 26.0, 25.9, 24.4, 23.6,
21.9, 21.2, 18.2, 18.1, 17.0, 7.1, 7.0, 6.0, 5.6, -4.5, -4.6, -4.7, -4.9;
HRMS (FAB) calcd for C57H102O9Si4 (M + Na+) 1065.6499, found
1065.6543.
1
884, 874 cm-1; H NMR (500 MHz, CDCl3) δ 7.52 (d, J ) 15.5 Hz,
1 H), 7.45 (s, 1 H), 7.09 (s, 1 H), 6.55 (d, J ) 15.5 Hz, 1 H), 6.13 (d,
J ) 5.5 Hz, 1 H), 6.12 (d, J ) 5.0 Hz, 1 H), 6.08 (d, J ) 5.5 Hz, 1 H),
6.07 (d, J ) 5.0, 1 H), 5.51 (d, J ) 9.5 Hz, 1 H), 5.50 (d, J ) 9.5 Hz,
1 H), 5.31-5.23 (m) 5.15-5.13 (m, 1 H), 5.04 (dd, J ) 10.0, 3.5 Hz,
1 H), 4.99 (d, J ) 3.5 Hz, 1 H), 4.81 (d, J ) 7.0 Hz, 1 H), 4.23 (d, J
r-Anomer of Eleutherobin (27). The R-anomer of eleutherobin
was constructed by following the same reaction sequence depicted in
Scheme 2 from compound 26: Rf ) 0.1 (silica gel, MeOH-CH2Cl2,

8680 J. Am. Chem. Soc., Vol. 120, No. 34, 1998
Nicolaou et al.
) 11.0 Hz, 1 H), 4.16 (dd, J ) 10.5, 4.0 Hz, 1 H), 4.12 (m, 1 H), 4.02
(m, 1 H), 3.93 (d, J ) 11.0 Hz, 1 H), 3.89-3.72 (m, 3 H), 3.74 (s, 3
H), 3.70 (s, 3 H), 3.33 (m, 1 H), 2.68-2.62 (m, 1 H), 2.36-2.26 (m,
1 H), 2.16 (s, 3 H), 2.12 (s, 3 H), 2.09 (s, 1 H), 2.08-2.00 (m, 1 H),
2.05 (s, 3 H), 2.00 (s, 3 H), 1.69-1.53 (m, 3 H), 1.48 (s, 3 H), 1.47 (s,
3 H), 1.37-1.28 (m, 1 H), 0.99 (d, J ) 6.5 Hz, 3 H), 0.97 (d, J ) 6.0
Hz, 3 H), 0.94 (d, J ) 6.0 Hz, 3 H), 0.93 (d, J ) 6.5 Hz, 3 H); 13C
NMR (125.7 MHz, CDCl3) δ 171.2, 170.8, 170.3, 169.9, 166.7, 139.2,
138.4, 138.2, 138.0, 137.8, 136.4, 136.4, 134.2, 134.1, 133.2, 133.1,
132.1, 133.0, 126.3, 122.7, 121.3, 121.2, 115.8, 115.8, 112.2, 95.4,
95.3, 90.3, 81.1, 71.9, 71.2, 69.9, 67.9, 66.4, 62.2, 60.5, 58.9, 53.4,
42.2, 41.9, 38.6, 38.6, 34.3, 33.6, 31.6, 29.0, 25.6, 24.4, 24.1, 22.2,
22.0, 21.1, 21.0, 20.5, 19.7, 13.7; HRMS (FAB) calcd for C36H48N2O11
(M + Cs+) 817.2312, found 817.2283.
CHCl3). For 32: Rf ) 0.16 (silica, ×2, MeOH-CH2Cl2,1:20); FT-IR
(neat) νmax 3355, 2964, 2925, 2872, 1704, 1634, 1260, 1070, 800 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.53 (d, J ) 15.5 Hz, 1 H, C-3′), 7.45
(s, 1 H, C-7′), 7.09 (s, 1 H, C-5′), 6.56 (d, J ) 15.5 Hz, 1 H, C-2′),
6.18 (d, J ) 6.0 Hz, 1 H, C-5′), 5.99 (d, J ) 6.0 Hz, 1 H, C-6′), 5.59
(d, J ) 10.0 Hz, 1 H, C-2′), 5.27 (bs, 1 H, C-12), 4.92-4.85 (m, 1 H,
C-1′′), 4.81 (d, J ) 7.0 Hz, 1 H, C-8), 4.28 (d, J ) 12.0 Hz, 1 H,
C-15), 3.98-3.95 (m, 1 H), 3.91 (d, J ) 12.0 Hz, 1 H, C-15), 3.82-
3.73 (m, 4 H), 3.71 (s, 3 H), 3.38 (-3.32 (m, 4 H), 3.22 (s, 3 H, C-21),
2.69-2.59 (m, 1 H, C-10), 2.37-2.25 (m, 1 H, C-13), 2.08-1.96 (m,
1 H, C-13), 1.61-1.40 (m, 3 H), 1.51 (s, 3 H, C-17), 1.45 (s, 3 H,
C-16), 1.28-1.22 (m, 1 H, C-14), 0.98 (d, J ) 6.6 Hz, 3 H), 0.93 (d,
J ) 6.5 Hz, 3 H); 13C NMR (125.7 MHz, CDCl3) δ 181.2, 165.6, 139.2,
136.4, 135.0, 134.1, 133.4, 130.9, 129.8, 122.7, 121.3, 115.9, 97.7,
90.2, 81.2, 70.9, 68.1, 59.0, 49.7, 42.2, 38.6, 34.1, 33.6, 31.5, 29.0,
28.9, 24.2, 24.1, 22.2, 22.0, 20.5, 19.8, 13.7; HRMS (FAB) calcd for
C33H46N2O9 (M + Cs+) 747.2258, found 747.2282.
Regioisomeric Eleutherobin (31) and Deacetoeleutherobin (32).
To a solution of disilyl ether 23 (5.4 mg, 6.1 µmol) in THF (350 µL)
was added TBAF (1.0 M in THF, 20 µL, 20 µmol, 3.3 equiv), and the
reaction mixture was stirred for 6 h at ambient temperature. After
completion (TLC analysis), the crude residue was immediately purified
by column chromatography (gradually increasing the eluting solvent
from 2 to 10% MeOH in CH2Cl2) to afford eleutherobin 1 (22%),
migration product 31 (60%), and triol 32 (8%). For 31: Rf ) 0.28
(silica, ×2, MeOH-CH2Cl2,1:20); FT-IR (neat) νmax 3355, 2964, 2925,
Acknowledgment. We thank Dr. W.-H. Fenical for the
spectral data of natural eleutherobin. We also thank Dr. D. H.
Huang and Dr. G. Siuzdak for NMR and mass spectroscopic
assistance, respectively. This work was supported by The Skaggs
Institute for Chemical Biology, the National Institutes of Health
USA, CaP CURE, Novartis, and by fellowships from The
Netherlands Organization for Scientific Research (NWO) (to
F.v.D.), Novartis (to D.V.), the Japanese Society for the
Promotion of Science for Young Scientists (to S.H.), and the
Department of Defense, USA (to J.P.).
1
1704, 1638, 1260, 1070, 800 cm-1; H NMR (500 MHz, CDCl3) δ
7.52 (d, J ) 15.5 Hz, 1 H, C-3′), 7.44 (s, 1 H, C-7′), 7.08 (s, 1 H,
C-5′), 6.55 (d, J ) 15.5 Hz, 1 H, C-2′), 6.18 (d, J ) 5.8 Hz, 1 H, C-5),
5.96 (d J ) 5.8 Hz, 1 H, C-6), 5.92 (d, J ) 9.2 Hz, 1 H, C-2), 5.27 (m,
1 H, C-12), 4.89 (s, 1 H), 4.81 (d, J ) 7.0 Hz, 1 H), 4.27 (d, J ) 12.1
Hz, 1 H, C-15), 3.98-3.94 (m, 1 H), 3.91 (d, J ) 12.1 Hz, 1 H, C-15),
3.89 (dt, J ) 9.9, 3.7 Hz, 1 H), 3.83 (d, J ) 12.8 Hz, 1 H), 3.76 (d, J
) 9.9 Hz, 1 H), 3.74-3.68 (m, 2 H), 3.69 (s, 3 H, C-9′), 3.21 (s, 3 H,
C-21), 2.65-2.59 (m, 1 H), 2.32-2.24 (m, 1 H), 2.27 (d, J ) 4.0 Hz,
1 H), 2.24 (d, J ) 10.3 Hz, 1 H), 2.12 (s, 3 H), 2.03-1.97 (m, 1 H),
1.65-1.60 (m, 1 H), 1.56 (s, 3 H), 1.51 (bs, 2 H), 1.44 (s, 3 H), 1.39
(ddd, J ) 15.0, 12.0, 7.0 Hz, 1 H), 1.29-1.22 (m, 2 H), 0.97 (d, J )
6.6 Hz, 3 H), 0.92 (d, J ) 6.2 Hz, 3 H); HRMS (FAB) calcd for
C35H48N2O10 (M + Cs+) 789.2363, found 789.2384; [R] -22.5 (c 0.2,
Supporting Information Available: Selected physical data
for intermediates leading to the R-anomer of eleutherobin (27)
from R-glycoside 26 (11 pages, print/PDF). See any current
masthead page for ordering information and Web access
instructions.
JA9810639