Oxidative polycyclization with rhenium(VII) oxides: Application of the stereoselectivity rules in the total synthesis of rollidecins C and D

Article abstract of DOI:10.1016/S0040-4020(01)00381-7

Rollidecin C, 1, and rollidecin D, 2, two adjacent bis-THF Annonaceous acetogenins, were synthesized from the partially functionalized 'naked' carbon skeletons 14 and 15, respectively. The retrosynthetic route to the target compounds was guided by the rec

Full text of DOI:10.1016/S0040-4020(01)00381-7

TETRAHEDRON
Pergamon
Tetrahedron 57 72001) 5255±5262
Oxidative polycyclization with rheniumꢀVII) oxides: application
of the stereoselectivity rules in the total synthesis of rollidecins
C and D
Lawrence J. D'Souza,a Santosh C. Sinha,a,b Shou-Fu Lu,a Ehud Keinana,b,p,²
and Subhash C. Sinhaa,p
aDepartment of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, CA 92037, USA
bDepartment of Chemistry and Institute of Catalysis Science and Technology, Technion±Israel Institute of Technology, Technion City,
Haifa 32000, Israel
Dedicated to Professor BarryM. Trost on the occasion of his 60th birthday
Received 1 March 2001; accepted 30 March 2001
AbstractÐRollidecin C, 1, and rollidecin D, 2, two adjacent bis-THF Annonaceous acetogenins, were synthesized from the partially
functionalized `naked' carbon skeletons 14 and 15, respectively. The retrosynthetic route to the target compounds was guided by the recently
proposed rules of stereoselectivity for the tandem oxidative cyclization reaction with tri¯uoroacetylperrhenate. Thus, the rapid
transformation of compounds 14 and 15 to 1 and 2, respectively, was achieved with a predictable stereochemistry by the oxidative
bis-cyclization with Re7VII) followed by one or two simple transformations. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Conversely, when they have an erythro relationship, the
next cyclization will produce a trans THF ring.2
The tandem oxidative polycyclization reaction with
rhenium7VII) reagents, ®rst reported in 1995,1 represents a
powerful methodology by which polyenic bis-homoallylic
alcohols can be converted in a single step into poly-THF
products with veryhigh diastereoselectivity. This method is
particularly useful for asymmetric synthesis of polyether
natural products. We have recentlyused tri¯uoroacetly-
perrhenate for the oxidative bis-cyclization of four isomeric
disubstituted dienol substrates 7I, Scheme 1) and obtained
bis-THF products with veryhigh stereoselectivity. On the
basis of these and previous results, we deduced a set of rules
to predict the product's con®guration in these reactions. We
proposed for the single-step tandem polycyclization
reactions with tri¯uoroacetylperrhenate that the stereo-
chemistryof the ®rst THF ring is always trans. However,
the stereochemistryof the subsequent rings depends on the
relative con®guration of the two vicinal oxygen functions
that were formed in the ®rst cyclization step 7Scheme 1).
When these vicinal oxygen functions have a threo relation-
ship, the next cyclization will produce a cis THF ring.
Since the two oxygen atoms add to the double bond in a syn
fashion, the relative con®guration of the resultant pair of
vicinal carbinol centers depends on the double bond
geometry: a cis double bond leads to an erythro diol and a
trans double bond leads to a threo diol. Therefore, any
desired absolute stereochemistrycan be achieved bythe
appropriate choice of a double bond geometryand absolute
con®guration of the bis-homoallylic alcohol in the substrate.
Here we report on the application of these rules in the total
synthesis of two homologous acetogenins, rollidecin C, 1,
and rollidecin D, 2, which were discovered in the bioactive
leaf extracts of Rollinia mucosa.3 Compounds 1 and 2 are
members of a rapidlygrowing familyof natural products,
the Annonaceous acetogenins,4 which are known not only
for their antitumor activity, but also for being potent anti-
malarial, immunosuppressive, pesticidal and antifeedant
agents.5 More than 350 acetogenins have alreadybeen
isolated from 37 species in the Annonaceae, a familyof
tropical trees and shrubs that accommodates over 2300
species.6 While most of these fattyacid derivatives exhibit
remarkable structural diversity, they share very similar
carbon skeletons, with the main variations being the relative
and absolute con®guration of the various stereogenic
oxygen functions. For example, a dominant structural
Keywords: Annonaceous acetogenins; rollidecin C; rollidecin D; oxidative
cyclization; rhenium7VII) oxides; tri¯uoroacetylperrhenate.
p
Corresponding authors. Tel.: 11-858-784-8512; fax: 11-858-784-8732.
Incumbent of the Benno Gitter & Ilana Ben-Ami chair of Biotechnology,
Technion; e-mail: keinan@scripps.edu; subhash@scripps.edu
²
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020701)00381-7

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L. J. D'Souza et al. / Tetrahedron 57 22001) 5255±5262
Scheme 1. Rules for predicting the stereochemistry in oxidative polycyclization with tri¯uoroacetylperrhenate.
feature that appears in more than 40% of the Annonaceous
acetogenins, including 1 and 2, is a ten-carbon fragment
containing two adjacent tetrahydrofuran rings ¯anked by
either one or two hydroxyl groups. The Annonaceous
acetogenins have attracted intense synthetic activity in
recent years.7,8 Our contribution to this effort includes the
total synthesis of solamin, reticulatacin, asimicin,
bullatacin, trilobacin, trilobin, uvaricin, squamotacin,
goniocin, 17,18-bis-epigoniocin, cyclogoniodenin T, and
mucosin.9
are typical adjacent bis-THF acetogenins with an exception
that they have only one hydroxyl group ¯anking the
bis-THF moiety.
Both compounds 1 and 2 have exhibited cytotoxicity against
six human tumor cell lines. Compound 1 was found to be
uniformlymore potent than 2 and showed selectivitytoward
the colon cell line HT-29, exhibiting potencythat
approaches that of adriamycin.3 Although the mode of
action of 1 and 2 has not yet been established, studies on
the primarymode of action with other, structurallysimilar
acetogenins have established that theyare powerful
inhibitors of complex I 7NADH-ubiquinone oxidoreductase)
in mammalian and in insect mitochondrial electron transport
systems.11 In addition, theyare potent inhibitors of NADH
oxidase that is speci®callyactive in the plasma membranes
of tumors and is inactive in normal cells.12
The structure of 1 and 2 was assigned mainlyon the basis of
1H 71D and 2D) and 13C NMR spectroscopyand MS
analysis.3 Although, no speci®c data have been provided
to support the proposed absolute con®guration of both
compounds 1 and 2, theyhave probablybeen determined
using the Mosher esters methodology.10 Compounds 1 and 2
Scheme 2. Retrosynthetic analysis of rollidecins C and D.

L. J. D'Souza et al. / Tetrahedron 57 22001) 5255±5262
5257
Scheme 3. Total synthesis of rollidecins C and D. Key: 7a) DIBAL-H, toluene, 2788C, 2 h then 7EtO)2P7O)CHNaCO2Et, THF, 2788C to rt, 16 h;
7b) DIBAL-H, THF, 2788C, 2 h; 7c) Ti7O-i-Pr)4, 71)-DET, TBHP, powdered molecular sieves 4A, 2208C, 4 h; 7d) Red-Al, THF, 08C, 4 h; 7e) TBDPSCl,
diisopropylethylamine, CH2Cl2, rt, 16 h then in situ MOMCl, diisopropylethylamine, CH2Cl2, 08C to rt, 16 h; 7f) TBAF, THF, 08C to rt, 2 h; 7g) I2, PPh3,
imidazole, 08C to rt, 2 h; 7h) PPh3, NaHCO3, CH3CN, 608C, 24 h; 7i) n-BuLi, THF, 08C, then either aldehyde 10 or 11, 0.5 h; 7j) TMSBr, CH2Cl2, 2308C, 0.5 h;
7k) Re2O7, TFAA, THF, rt, 1 h concentration under vacuum and washing with cold pentane, then alcohol 14, CH2Cl2, TFAA, 08C to rt, 3 h. The same
procedure was used for compound 15 with the exception that the mixture was left at rt overnight; 7l) H2, Wilkinson's catalyst 720%, w/w), benzene-ethanol
74:1), rt, 4 h; 7m) 4% AcCl in MeOH, CH2Cl2 71:1), rt, 16 h.
2. Results and discussion
tion14 followed byreductive cleavage of the resultant
epoxide.13
Our retrosynthetic analysis of 1 and 2 7Scheme 2) dissects
the target molecules into two major fragments, the
butenolide portion, which contains two asymmetric carbinol
centers, and the bis-THF fragment, which contains
additional ®ve asymmetric centers. The synthesis of this
fragment with correct stereochemistryrepresents the main
challenge in the entire synthesis. In fact, the potential
diastereomeric diversityof this fragment represents the
origin of diversityin the bis-THF subgroup of the
Annonaceous acetogenins. To meet the challenge of
structural variabilitywe designed a general snythetic
approach that is suitable for the title compounds, 1 and 2,
as well as for manyof their stereoisomers. We anticipated
that the introduction of both THF rings could be achieved in
a single step at the ®nal stages of the synthesis by a Re7VII)-
mediated oxidative cyclization of a bis homoallylic dienol,
II. The expected product could be onlytwo simple steps
7hydrogenation and deprotection) away from the target
molecule. This strategywas based on our previous
observation that the oxidative cyclization reaction is
compatible with manyfunctional groups, including a homo-
allylic alcohol.13 Therefore, the bis-cyclization could be
carried out at a verylate stage, after the completion of the
molecular carbon skeleton. We have alreadydemonstrated
the tandem oxidative cyclization reaction with a substrate in
which the secondaryalcohol was both homoallylic as well
as bis-homoallylic and the cyclization with tri¯uoroacetyl
perrhenate and tri¯uoroacetic anhydride took place
exclusivelyat the bis-homoallylic site. The keyintermediate
II could be obtained byWittig ole®nation using the
phosphonium salt III and aldehyde IV. Compound III
could be prepared bythe Sharpless asymmetric epoxida-
The total synthesis of 1 and 2 is described in Scheme 3. Our
starting material, 3, was easilyprepared from ethyl hepta-
dec-4-enoate9h in four steps, i.e. LAH reduction of the ester
to the corresponding primaryalcohol, PCC oxidation of the
alcohol to produce aldehyde, Grignard reaction of the latter
with vinylmagnesium bromide to give an allylic alcohol,
and ®nally, Claisen±Johnson rearrangement15 using
triethylorthoacetate. One pot two-step conversion of 3 to
the unsaturated ester 4 was achieved bythe low
temperature, DIBAL-H reduction of the ester in 3 to the
corresponding aldehyde followed by a Wittig±Horner
ole®nation using sodium triethylphosphonoacetate.
Reduction of 4 with DIBAL-H in THF produced the allylic
alcohol 5 and the latter was subjected to the Sharpless
asymmetric epoxidation using 71)-DET as the chiral
auxiliaryto iyeld the epoxaylcohol
6. Regioselective
reductive opening of the epoxide to diol 7 was achieved at
08C using Red-Al. The primaryalcohol in 7 was ®rst
protected in the form of a TBDPS ether and the secondary
alcohol was then converted to the MOM ether in the same
pot to produce the fullyprotected intermediate 8a. The
primaryalcohol was regenerated bydesillyation using
TBAF in THF and the resultant alcohol, 8b, was ®rst
converted to the corresponding iodide, 9a, and then to the
phosphonium salt, 9b. Compound 9b 7III in Scheme 1)
represents a keyintermediate in our snythetic strategy
because it is designed to couple with aladehyde IV to
produce the complete carbon skeletons of the target
molecules.
The Wittig reactions between the ylide derived from 9b

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L. J. D'Souza et al. / Tetrahedron 57 22001) 5255±5262
Scheme 4. Comparison of two routes to the bis-THF system of rollidecins C and D. The proposed biosynthetic pathway follows steps 7a) and 7b) while 7c)
represents a direct oxidative cyclization approach with Re7VII).
7using n-BuLi) and either of the two homologous butenolide
aldehydes, 10 or 11, were achieved in THF at 08C to
produce 12 or 13, respectively, both in the form of a mixture
of both E and Z isomers. The MOM ether in 12 and 13 was
selectivelycleaved using TMSBr at low temperature,
affording 14 and 15, respectively, setting the stage for the
keystep in the entire synthetic scheme, the oxidative bis-
cyclization reaction.16,17 This reaction was carried out with
either 14 or 15 using CF3CO2ReO3 with tri¯uoroacetic
anhydride 7TFAA) at 08C to room temperature, affording
the desired bis-THF products, 16 or 17, respectively. We
found that the required subsequent cleavage of the TBDPS
ether could be achieved during the cyclization step. Thus,
keeping the mixture longer 7overnight rather than 3 h) under
the reaction conditions resulted in partial, probablyacid-
catalyzed, desilylation of 15 to produce alcohol 17. The
latter was converted to 2 byhydrogenation over Wilkinson's
catalyst with 1 atm of hydrogen. Using a slightly different
protocol, compound 16 was ®rst hydrogenated and the
product, 18, was desilylated with 4% AcCl in MeOH at
room temperature, affording 1. Both synthetic compounds
1 and 2 were found to be identical by 1H- and 13C NMR with
the naturallyoccurring rollidecins C and D, respectively.
In conclusion, the rules of stereoselectivityin the tandem
oxidative polycyclization with CF3CO2ReO3 have been
applied here in the total synthesis of 1 and 2. The synthesis
of 1 was achieved in 13 steps and 5.2% overall yield and that
of 2 was achieved in 12 steps and 2.9% yield. Further
studies are currentlyunderwayto gain better understanding
of the origin of stereoselectivityin the oxidative pol-y
cyclization reaction and of the dependence of product
stereochemistryon the oxidant and on the reaction
conditions.
3. Experimental section
3.1. General methods
1H and 13C NMR spectra were measured in CDCl3. Positive
ion mass spectra, using the fast ion bombardment 7FIB)
technique, were obtained on a VG ZAB-VSE double focus-
ing, high-resolution mass spectrometer equipped with either
a cesium or sodium ion gun. Negative mass spectra were
obtained with Sciex API 100. Optical rotations were
measured in a one-decimeter 71.3 mL) cell using an Autopol
III automatic polarimeter. TLC was performed on glass
sheets precoated with silica gel 7Merck, Kieselgel 60,
F254, Art. 5715). Column chromatographic separations
were performed on silica gel 7Merck, Kieselgel 60, 230±
400 mesh, Art. 9385) under pressure. THF was dried and
distilled over sodium ketyl.
According to the Cane±Celmer±Westleyhpyothesis
concerning the biosynthesis of microbial polyether anti-
biotics, initial polyepoxidation of a polyene is followed by
a cascade of intramolecular nucleophilic epoxide ring
openings.18 This hypothesis has been used to propose the
biosynthetic pathway leading to the bis-THF fragment of 1
and 2 7Scheme 4).3 Here we have used an alternative, abio-
3.1.1. ꢀ4E,8E)-Ethyl eicosa-4,8-dienoate, 3. To a suspen-
sion of LiAlH4 74.7 g, 124 mmol) in dryEt O 7150 mL), a
19
genic strategyof ligand-assisted
oxygenation, featuring
2
solution of ethyl heptadec-4-enoate9h 716.81 g, 57 mmol) in
dryEt O 7100 mL) was added dropwise at 08C 7ice-water
two major advantages: 7a) high effective molarityof the
oxidant; and 7b) high regio- and stereochemical control
over the reaction. Townsend and Basak have suggested
that nature could also be using this approach for the
biosynthesis of polyethers.20 The keypoint in their hypo-
thesis is that the oxidative cyclization route requires a
polyene substrate with opposite double bond con®guration.
For example, in Scheme 4 the direct route requires a polyene
substrate that has E-double bonds, whereas the stepwise,
polyepoxide model requires Z-double bonds. Since the
actual polyene intermediates in polyether antibiotics have
never been observed there is no direct evidence bearing on
this issue.21 We believe that the a hydroxyl-directed, metal-
controlled oxidative polycyclization option is a less likely
biosynthetic option than the polyepoxide pathway because
high effective molarityand stereochemical control are
already available to enzymes. Thus, in enzyme-catalyzed
reactions there is no need for substrate-assisted catalysis
of speci®citysince this control arises normallyfrom binding
speci®city.
2
bath). The mixture was warmed to room temperature and
stirred for 2.5 h. Upon completion, as judged byTLC, the
reaction mixture was diluted with ether and quenched by
careful addition of water. The mixture was stirred for
another 0.5 h, dried over anhydrous Na2SO4 and ®ltered
over Celite to remove inorganic materials. Solvents were
removed under reduced pressure to afford heptadec-4-en-
1
1-ol 714.15 g, 98%) in the form of a white solid. H NMR
7CDCl3, 300 MHz): d 5.41 7m, 2H), 3.62 7t, Jˆ6.5 Hz, 2H),
2.05 7m, 2H), 1.95 7m, 2H), 1.60 7m, 3H), 1.35±1.20 7m and
br s, 20H), 0.86 7t, Jˆ7.0 Hz, 3H); 13C NMR 7CDCl3,
75 MHz): 131.3, 129.3, 62.5, 32.5, 32.4, 31.9, 29.7, 29.6,
29.5, 29.3, 29.2, 28.9, 22.7, 14.1.
Celite 726 g) and PCC 726 g, 121 mmol) were added to a
solution of heptadec-4-en-1-ol 714.12 g, 55 mmol) in
anhydrous CH2Cl2 7250 mL) and the mixture was stirred
at room temperature for 2.5 h, then ®ltered over a short

L. J. D'Souza et al. / Tetrahedron 57 22001) 5255±5262
5259
silica gel column using CH2Cl2 to give the corresponding
aldehyde 712.18 g, 87%), which was taken to next step
d 6.97 7dt, Jˆ15.8, 6.6 Hz, 1H), 5.83 7dt, Jˆ15.4, 1.5 Hz,
1H), 5.49±5.37 7m, 4H), 4.20 7q, Jˆ7.4 Hz, 2H), 2.30±2.25
7m, 2H), 2.18±2.14 7m, 2H), 2.09±2.02 7m, 4H), 2.00±1.96
7m, 2H), 1.36±1.25 7m, 20H), 1.30 7t, Jˆ7.3 Hz, 3H), 0.90
7t, Jˆ7.0 Hz, 3H); 13C NMR 7CDCl3, 125 MHz): d 166.9,
148.8, 131.1, 129.7, 128.9, 121.7, 60.3, 32.9, 32.8, 32.5,
32.1, 31.2, 29.9, 29.9, 29.8, 29.6, 29.4, 22.9, 14.5, 14.3;
MS 7ESI): 399 7M1Na1).
1
without further puri®cation. H NMR 7CDCl3, 300 MHz):
d 9.75 7t, Jˆ1.6 Hz, 1H), 5.41 7m, 2H), 2.47 7t, Jˆ7.4 Hz,
2H), 2.32 7q, Jˆ6.5 Hz, 2H), 1.95 7q, Jˆ6.8 Hz, 2H), 1.40±
1.20 7m and br s, 20H), 0.86 7t, Jˆ7.2 Hz, 3H); 13C NMR
CDCl3, 75 MHz): d 202.5, 132.1, 127.5, 43.5, 32.5, 31.9,
29.7, 29.5, 29.3, 25.2, 22.7, 14.1.
Vinylmagnesium bromide 71.0 M in THF, 64.4 mL,
64.4 mmol) was added dropwise to a solution of the above
mentioned aldehyde 712.10 g, 48 mmol) in dry THF
7100 mL) at 08C 7ice-water bath). The mixture was stirred
at the same temperature for 1 h and then quenched byslow
addition of a saturated aqueous NH4Cl. The organic layer
was separated and the aqueous layer was extracted with
ether. The combined organic layer was washed with brine,
dried over Na2SO4, concentrated and ®ltered through a short
column of silica gel using hexane-ethyl acetate, 4:1, to
produce the corresponding allylic alcohol 713.36 g, 99%)
in the form of a light yellow oil, which was taken to next
step without further puri®cation. 1H NMR 7CDCl3,
300 MHz): d 5.85 7ddd, Jˆ16.8, 10.2, 6.2 Hz, 1H), 5.41
7m, 2H), 5.21 7dt, Jˆ16.8, 1.4 Hz, 1H), 5.09 7dt, Jˆ10.2,
1.6 Hz, 1H), 4.11 7q, Jˆ6.3 Hz, 1H), 2.08 7m, 2H), 1.96 7q,
Jˆ7.2 Hz, 2H), 1.58 7m, 3H), 1.40±1.20 7m and br s, 20H),
0.87 7t, Jˆ6.8 Hz, 3H); 13C NMR 7CDCl3, 75 MHz): d
141.1, 131.3, 129.3, 72.7, 36.7, 32.6, 31.9, 29.7, 29.5,
29.3, 29.2, 28.5, 22.7, 14.1.
3.1.3. ꢀ2E,6E,10E)-Tricosa-2,6,10-trien-1-ol, 5. DIBAL-H
71.5 M in toluene, 22 mL, 33 mmol) was added dropwise to
a solution of 4 75.25 g, 14 mmol) in dryTHF 754 mL) at
2788C. The mixture was stirred at 2788C for 1.5 h and then
quenched with dropwise addition of H2O 712 mL). Celite
712 g) and ether 7100 mL) were added to the mixture and
stirred at 08C for 1 h. After clear separation of layers the
mixture was ®ltered through Celite, concentrated and
puri®ed by¯ash chromatography7gradient from 10 to
20% ethyl acetate in hexanes) to afford 5 74.23 g, 91%) in
1
the form of a white solid. H NMR 7CDCl3, 300 MHz): d
5.70±5.67 7m, 2H), 5.43±5.41 7m, 4H), 4.12±4.10 7m, 2H),
2.10±1.99 7m, 10H), 1.27 7br s, 20H), 0.90 7t, Jˆ6.6 Hz,
3H); MS 7ESI): 357 7M1Na1).
3.1.4. ꢀ2S,3S,6E,10E)-2,3-Epoxytricosa-6,10-dien-1-ol, 6.
To a mixture of 5 73.26 g, 9.8 mmol), molecular sieves 74A,
1.0 g) in dryCH 2Cl2 7100 mL) and 71)-DET 72.4 g,
11.5 mmol), Ti7O-i-Pr)4 72.6 mL, 9.63 mmol) were added
at 220 oC and the mixture was stirred at the same
temperature for 0.5 h. TBHP 79.7 mL) was added dropwise
at ±20 oC and the mixture was stirred for 4 h. Upon
completion, as judged byTLC, 10% aqueous NaOH
721 mL) was added, the mixture was stirred at room
temperature for 1 h, and then ®ltered over Celite using
ethyl acetate. The organic solution was washed with
water, dried over anhydrous Na2SO4, solvents were removed
under reduced pressure and the residue was puri®ed by¯ash
chromatography7gradient 10±20% ethl y acetate in
hexanes), affording 6 72.745 g, 99% based on recovered
A solution of the above-mentioned allylic alcohol 713.36 g,
48 mmol), triethylorthoacetate 720 mL, 110 mmol) and
propionic acid 70.068 mL, 0.9 mmol) in xylene 720 mL)
was re¯uxed for 2 h using an azeotropic distillation
condenser. The volatile components were removed under
reduced pressure and the residue was puri®ed by¯ash
chromatography7hexane-ethly acetate, 24:1) to give
78.52 g, 51% yield from aldehyde) in the form of a light
3
1
yellow oil. H NMR 7CDCl3, 500 MHz): d 5.50±5.36 7m,
4H), 4.13 7q, Jˆ7.0 Hz, 2H), 2.38±2.30 7m, 4H), 2.08±1.95
7m, 6H), 1.36±1.24 7m, 23H), 0.89 7t, Jˆ6.6 Hz, 3H); 13C
NMR 7CDCl3, 125 MHz): d 173.4, 131.4, 131.1, 129.6,
128.5, 60.4, 34.6, 32.9, 32.8, 32.7, 32.1, 30.0, 29.9, 29.8,
29.7, 29.6, 29.4, 28.1, 22.9, 14.4, 14.3; MS 7ESI): 373
7M1Na1).
starting material) in the form of a white solid.
[a]Dˆ215.1 7CHCl3, cˆ0.6); 1H NMR 7CDCl3,
500 MHz): d 5.44±5.32 7m, 4H), 3.87 7ddd, Jˆ12.5, 5.1,
2.6 Hz, 1H), 3.59 7ddd, Jˆ12.1, 7.0, 4.0 Hz, 1H), 2.95±2.92
and 2.90±2.88 7m each, 2H), 2.17±2.07 7m, 2H), 2.01 7br s,
4H), 1.95±1.91 7m, 2H), 1.66±1.55 7m, 2H), 1.31±1.23 7m,
20H), 0.85 7t, Jˆ7.0 Hz, 3H); 13C NMR 7CDCl3, 125 MHz):
d?131.2, 131.1, 129.7, 129.2, 61.9, 58.7, 55.7, 32.9, 32.8,
32.2, 31.8, 29.9, 29.9, 29.8, 29.8, 29.6, 29.4, 29.2, 22.9,
14.3; MS 7ESI): 373 7M1Na1).
3.1.2. ꢀ2E,6E,10E)-Ethyl tricosa-2,6,10-trienoate, 4.
DIBAL-H 71.5 M in toluene, 17.6 mL, 26 mmol) was
added dropwise to a solution of 5 78.38 g, 24 mmol) in
drytoluene 7100 mL) at 2788C, and the mixture was stirred
at the same temperature for 2.5 h. In a separate ¯ask, triethyl
phosphonoacetate 75.8 mL, 29 mmol) was added dropwise
to a mixture of NaH 760% in mineral oil, 1.16 g, 29 mmol)
in dryTHF 750 mL) at 0 8C, the mixture was stirred at 08C
for 0.5 h and then was added dropwise to the ®rst mixture at
2788C. The combined mixture was stirred overnight with
gradual warming to the room temperature, then it was then
quenched bydropwise addition of water 79 mL). Celite 79 g)
and ether 745 mL) were added and the mixture was stirred at
08C for 0.5 h, ®ltered over Celite, concentrated and the resi-
due was puri®ed by¯ash chromatography7gradient from 2
to 30% ethyl acetate in hexanes) to afford 4 75.33 g, 59%) in
the form of a light yellow oil. 1H NMR 7CDCl3, 500 MHz):
3.1.5. ꢀ3S,6E,10E)-Tricosa-6,10-dien-1,3-diol, 7. Red-Al
765% in toluene, 10 mL, 33.3 mmol) was added dropwise
to a solution of 6 73.289 g, 9.3 mmol) in dryTHF 750 mL) at
08C. The mixture was stirred at 08C for 4 h, then quenched
with H2O 77 mL), stirred for additional 20 min at room
temperature and ®ltered over Celite using ethyl acetate.
The organic solution was washed with brine, dried over
anhydrous Na2SO4, concentrated and puri®ed by¯ash
chromatography7silica gel, gradient from 20 to 40% ethyl
acetate in hexanes), affording 7 73.21 g, 97%) in the form of
a white solid. [a]Dˆ22.5 7CHCl3, cˆ0.6); 1H NMR
7CDCl3, 500 MHz): d 5.47±5.36 7m, 4H), 3.91±3.81 7m,
3H), 2.57±2.51 7m, 2H), 2.17±2.09 7m, 2H), 2.08±2.05

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L. J. D'Souza et al. / Tetrahedron 57 22001) 5255±5262
7m, 4H), 2.00±1.96 7m, 2H), 1.75±1.52 7m, 4H), 1.35±1.27
7m, 18H), 0.90 7t, Jˆ7.0 Hz, 3H); 13C NMR 7CDCl3,
125 MHz): d 131.1, 130.9, 130.0, 129.7, 72.2, 62.0, 38.5,
37.6, 32.9, 32.8, 32.8, 32.1, 29.9, 29.9, 29.8, 28.8, 29.6,
29.4, 29.0, 22.9, 14.3; MS 7ESI): 375 7M1Na1).
131.0, 129.9, 129.9, 96.3, 77.8, 56.1, 39.2, 34.3, 33.1, 33.0,
32.3, 30.1, 30.0, 29.8, 29.6, 28.6, 23.1, 14.5, 2.5; MS 7ESI):
529 7M1Na1).
3.1.9. ꢀ3S,6E,10E)-3-ꢀMethoxy)methoxy-tricosa-6,10-dien-
1-yl triphenylphosphoniumiodide, 9b. A mixture of 9a
71.52 g, 3.0 mmol), NaHCO3 71.0 g, 12 mmol) and Ph3P
3.1.6. ꢀ3S,6E,10E)-1-tert-Butyldiphenylsilyloxy-3-ꢀmeth-
oxy)methoxy-tricosa-6,10-dien, 8a. TBDPSCl 73.5 mL,
13.4 mmol) was added dropwise to a solution of 7 73.13 g,
8.9 mmol), i-Pr2NEt 74.3 mL, 26 mmol) and DMAP
76.0 g, 23 mmol) in dryCH CN 710 mL) was stirred at
3
658C for 24 h. Solvents were removed under reduced pres-
sure, the residue was diluted with CH2Cl2, ®ltered 7to
remove NaHCO3), the organic layer was concentrated and
the residue was puri®ed by¯ash chromatography7silica gel,
from hexanes-ethyl acetate, 3:1 to CH2Cl2±MeOH, 1:1) to
7100 mg) in dryCH Cl2 750 mL), at 08C and the mixture
2
was stirred at room temperature for 18 h. Upon completion,
as judged byTLC, the mixture was cooled to 0 C, and more
o
1
i-Pr2NEt 719 mL, 108 mmol) was added dropwise followed
byMOMCl 79 mL, 119 mmol). The mixture was stirred at
room temperature for 22 h, then worked-up with CH2Cl2
and H2O, the combined organic layer was washed with
water, dried over anhydrous Na2SO4 and concentrated to
dryness. The residue was puri®ed by ¯ash chromatography
7silica gel, hexanes-ethyl acetate, 49:1), affording 8a 75.80
g) in the form of a colorless oil. [a]Dˆ13.0 7CHCl3,
cˆ2.0); 1H NMR 7CDCl3, 500 MHz): d 7.73±7.68 7m,
4H), 7.46±7.39 7m, 6H), 5.47±5.39 7m, 4H), 4.63 7dd,
Jˆ11.8, 7.0 Hz, 2H), 3.82±3.74 7m, 3H), 3.34 7s, 3H),
2.09±2.03 7m, 6H), 2.01±1.98 7m, 2H), 1.79±1.76 7m, 2H),
1.64±1.56 7m, 2H), 1.37±1.29 7m, 20H), 1.08 7s, 9H), 0.91
7t, Jˆ7.0 Hz, 3H); 13C NMR 7CDCl3, 125 MHz): d 136.0,
134.3, 131.2, 130.6, 130.4, 130.0, 128.0, 96.2, 74.9, 61.0,
55.9, 37.8, 35.2, 33.2, 33.1, 33.0, 32.3, 30.1, 30.0, 29.8,
29.6, 28.8, 27.3, 23.1, 19.6, 14.5; MS 7ESI): 657 7M1Na1).
afford 9b 71.84 g, 80%); H NMR 7CDCl3, 300 MHz): d
7.70±7.82 7m, 15H), 5.42±5.46 7m, 4H), 4.60v4.72 7m,
2H), 3.85±3.95 7m, 2H), 3.52±3.62 7m, 1H), 3.35 7s, 3H),
1.85±1.95 7m, 8H), 1.55±1.72 7m, 4H), 1,32±1.40 7m,
20H), 0.95 7t, Jˆ7.0, 3H).
3.1.10. Compound 12. n-BuLi 71.5 M in hexane, 0.38 mL,
0.57 mmol) was added to a solution of the Wittig salt 9b
7450 mg, 0.59 mmol) in dryTHF 75 mL) at 0 8C. After
stirring for 15 min, a solution of aldehyde 1013 7320 mg,
0.70 mmol) in dryTHF 71 mL) was added and the mixture
was stirred at same temperature for additional 15 min.
Workup with aqueous NH4Cl and ether followed bycolumn
chromatography7silica gel, 50% ethyl acetate in hexanes)
1
afforded 12 7360 mg, 84%) in the form of an oil. H NMR
7CDCl3, 300 MHz): d 7.66±7.60 7m, 4H), 7.39±7.30 7m,
6H), 6.90 7s, 1H), 5.35±5.40 7m, 6H), 4.80 7m, 1H), 4.60
7m, 2H), 4.00 7quintet, Jˆ8 Hz, 1H), 3.57 7quintet, Jˆ8 Hz,
1H), 3.35 7s, 3H), 2.42 7m, 2H), 2.26 7m, 2H), 2.10±1.85 7m,
9H), 1.52±1.30 7m, 5H), 1.29 7d, Jˆ6.4 Hz, 3H), 1.25±1.10
7m, 22H), 1.15 7m, 2H), 1.05 7s, 9H), 0.85 7t, Jˆ6.4 Hz, 3H);
MS 7ESI): 849 7M1Na1).
3.1.7. ꢀ3S,6E,10E)-3-ꢀMethoxy)methoxy-tricosa-6,10-dien-
1-ol, 8b. To a solution of 8a 75.698 g, 8.97 mmol) in dry
THF 7100 mL), a solution of TBAF 71 M in THF, 34 mL,
34 mmol) was added at 08C and the mixture was warmed at
408C for 2.5 h. Solvents were removed under reduced pres-
sure and the residue was puri®ed by¯ash chromatography
7silica gel, gradient from 10 to 20% ethyl acetate in
hexanes), affording 8b 73.34 g, 94%) in the form of a color-
less oil. 1H NMR 7CDCl3, 500 MHz): d 5.54±5.44 7m, 4H),
4.74 7dd, Jˆ8.8, 6.6 Hz, 2H), 3.72±3.67 7m, 1H), 3.47 7s,
3H), 2.41 7m, 1H), 2.14±2.10 7m, 8H), 2.06±2.02 7m, 2H),
1.74±1.58 7m, 4H), 1.42±1.34 7m, 18H), 0.96 7t, Jˆ7.0 Hz,
3H); MS 7ESI): 419 7M1Na1).
3.1.11. Compound 13. Using the above described proce-
dure with the Wittig salt 9b 7215 mg, 0.28 mmol), n-BuLi
71.5 M in hexanes, 0.19 mL, 0.30 mmol) and aldehyde 119c
7100 mg, 0.22 mmol) in dryTHF 76 mL) at 0 8C and puri®-
cation over silica gel afforded 13 785 mg, 46%) in the form
1
of an oil. H NMR 7CDCl3, 300 MHz): d 7.66±7.61 7m,
4H), 7.42±7.33 7m, 6H), 6.9 7s, 1H), 5.43±5.35 7m, 6H),
4.87 7m, 1H), 4.67 7m, 1H), 4.61 7m, 1H), 4.00 7quintet,
Jˆ8 Hz, 1H), 3.57 7quintet, Jˆ8 Hz, 1H), 3.36 7s, 3H),
2.4 7m, 2H), 2.25 7m, 2H), 2.13±1.94 7m, 8H), 1.53 7m,
3H), 1.42±1.24 7m and br s, 32H), 1.30 7t, Jˆ8.0 Hz, 3H),
1.02 7s, 9H), 0.86 7t, Jˆ6.4 Hz, 3H); MS 7ESI): 877
7M1Na1).
3.1.8. ꢀ3S,6E,10E)-1-Iodo-3-ꢀmethoxy)methoxy-tricosa-
6,10-dien, 9a. Iodine 71.66 g, 6.6 mmol) was added in
portions to
a
cold 70 oC) solution of 8b 71.5 g,
3.78 mmol), Ph3P 72.5 g, 9.5 mmol) and imidazole 70.53 g,
7.9 mmol) in CH2Cl2 715 mL). The mixture was stirred at
the same temperature for 3 h, aqueous NaHCO3 was added
followed byiodine until the color of iodine persisted. The
mixture was extracted with CH2Cl2, the combined organic
layer was washed several times with aqueous Na2S2O3 and
water, dried over anhydrous Na2SO4 and concentrated to
dryness. The residue was puri®ed by ¯ash chromatography
7silica gel, hexanes-ethyl acetate, 99:1) to afford 9a 71.60 g,
83%) in the form of a colorless oil. [a]Dˆ118.7 7CHCl3,
cˆ0.9); 1H NMR 7CDCl3, 500 MHz): d 5.54±5.44 7m, 4H),
4.74 7dd, Jˆ8.8, 6.6 Hz, 2H), 3.72±3.67 7m, 1H), 3.47
7s, 3H), 3.36±3.29 7m, 2H), 2.14±2.10 7m, 8H), 2.06±2.02
7m, 2H), 1.74±1.58 7m, 2H), 1.42±1.34 7m, 20H), 0.96
7t, Jˆ7.0 Hz, 3H); 13C NMR 7CDCl3, 125 MHz): d 131.3,
3.1.12. Compound 14. TMSBr 70.096 mL, 0.726 mmol)
was added dropwise to a solution of 12 7300 mg,
0.363 mmol) in CH2Cl2 75 mL) at 2308C, the mixture was
stirred at the same temperature for 0.5 h an then quenched
with water and extracted with CH2Cl2. The combined
organic layer was washed with water, dried over Na2SO4
and concentrated to dryness. The residue was puri®ed by
column chromatography7silica gel, ethyl acetate-hexanes,
1
1:1) to afford 14 7230 mg, 83%) in the form of an oil. H
NMR 7CDCl3, 500 MHz): d 7.60 7m, 4H), 7.36 7m, 6H),
6.90 7s, 1H), 5.56±5.42 7m, 6H), 4.88 7m, 1H), 4.00 7quintet,
Jˆ5.6 Hz, 1H), 3.62 7quintet, Jˆ5.55 Hz, 1H), 2.42 7br s,
2H), 2.15±2.12 7m, 2H), 2.01±1.88 7m, 8H), 1.59±1.50 7m,

L. J. D'Souza et al. / Tetrahedron 57 22001) 5255±5262
5261
2H), 1.49±1.40 7m, 2H), 1.39±1.36 7m, 2H), 1.30 7d,
Jˆ6.9 Hz, 3H), 1.29±1.20 7m, 23H), 1.19±1.10 7m, 2H),
1.016 7s, 9H), 0.85 7t, Jˆ6.5 Hz, 3H); MS 7ESI): 805
7M1Na1).
silica gel to give 18 756 mg, 70%). 1H NMR 7CDCl3,
500 MHz): d 7.61±7.54 7m, 4H), 7.35±7.40 7m, 6H), 6.90
7s, 1H), 4.85 7m, 1H), 3.95±3.80 7m, 5H), 3.30 7m, 1H), 2.42
7m, 2H), 2.20±1.85 7m, 15H), 1.52±1.39 7m, 10H), 1.29
7d, Jˆ6.9 Hz, 3H), 1.25±1.20 7m, 20H), 1.03 7s, 9H), 0.90
7t, Jˆ6.4 Hz, 3H); 13C NMR 7CDCl3, 125 MHz): d 174.4,
151.6, 136.3, 136.2, 134.5, 131.1, 130.0, 128.1, 127.9, 82.9,
82.0, 81.6, 77.7, 72.2, 36.3, 34.9, 33.2, 32.6, 32.3, 30.2,
30.1, 30.0, 29.8, 29.5, 28.9, 28.8, 27.4, 26.5, 26.4, 26.3,
23.1, 19.8, 19.3, 14.5; MS 7ESI): 817 7M1H1).
3.1.13. Alcohol 15. Using the above-described procedure
compound 13 785 mg, 0.1 mmol) and TMSBr 70.017 mL,
0.129 mmol) were reacted in CH2Cl2 72 mL) at 2308C
followed bycolumn chromatographyto produce
15
749 mg, 61%). 1H NMR 7CDCl3, 400 MHz): 7.64 7dd,
Jˆ13.0, 6.5 Hz, 4H), 7.36 7m, 6H), 6.90 7s, 1H), 5.48±
5.37 7m, 6H), 4.88 7m, 1H), 4.00 7quintet, Jˆ5.5 Hz, 1H),
3.62 7quintet, Jˆ5.5 Hz, 1H), 2.42 7br s, 2H), 2.19±1.96 7m
and br s, 8H), 1.58±1.25 7m and br s, 36H), 1.30
7t, Jˆ6.5 Hz, 3H), 1.03 7s, 9H), 0.87 7t, Jˆ6.5 Hz, 3H);
MS 7ESI): 833 7M1Na1).
3.1.17. Rollidecin C, 1. A solution of 4% AcCl in MeOH
72 mL) was added to a solution of the 18 745 mg,
0.056 mmol) in dryCH Cl2 72 mL) and the mixture was
2
stirred at room temperature for 16 h. The mixture was
quenched with saturated aqueous NaHCO3, the organic
layer was washed with brine, dried over anhydrous
Na2SO4, and ®ltered. Removal of solvents under reduced
pressure followed bycolumn chromatography7silica gel,
20±30% ethyl acetate in hexanes) afforded 1 738 mg,
94%) in the form of a white solid. Mp. 39±418C;
[a]Dˆ15.9 7CHCl3, cˆ0.15); 1H NMR 7CDCl3,
600 MHz): d 7.10 7s, 1H), 5.05 7m, 1H), 3.95±3.82 7m,
4H), 3.34 7m, 1H), 2.53 7m, 1H), 2.40 7m, 1H), 2.03±1.80
7m, 7H), 1.56±1.34 7m and br s, 15H), 1.43 7d, Jˆ6.9 Hz,
3H), 1.25±1.20 7m, 28H), 0.86 7t, Jˆ6.4 Hz, 3H); 13C NMR
7CDCl3, 150 MHz); d 174.6, 151.7, 131.1, 82.4, 81.5, 80.6,
80.0, 78.0, 77.9, 69.8, 37.3, 35.7, 34.4, 33.3, 32.1, 31.9,
29.7, 29.6, 29.5, 29.4, 29.3, 20.0, 28.4, 26.1, 25.8, 25.4,
22.6, 19.1, 14.0; MS 7ESI): 579 7M1H1).
3.1.14. ꢀ9E,10Z)-9,10-Dehydro-rollidecin D-4-tert-butyl-
diphenylsilyl ether, 16. Re2O7 7300 mg, 0.69 mmol) was
placed in a dry¯ask under argon, dryTHF 75 mL) was
added followed byTFAA 70.123 mL, 0.87 mmol) and the
mixture was stirred at room temperature for 1 h. Solvents
were removed under reduced pressure at 08C and the residue
was washed twice with cold, drypentane. DryCH 2Cl2
75 mL), TFAA 70.123 mL, 0.87 mmol) and 14 7200 mg,
0.256 mmol) in CH2Cl2 72 mL) were added sequentiallyat
08C, the mixture was stirred at the same temperature for 3 h
and then worked up byslow addition of saturated aqueous
NaHCO3 75 mL) followed byH 2O2 70.5 mL) and extraction
with ether. The combined organic layer was washed with
brine and dried over anhydrous Na2SO4. The solvents were
removed under reduced pressure and the residue was puri-
®ed bycolumn chromatography7silica gel, 30% ethly
3.1.18. Rollidecin D, 2. Compound 17 710 mg, 0.016 mmol)
was dissolved in ethanol±benzene 71:1, 2 mL) and purged
with argon for 10 min. Wilkinson's catalyst 76 mg) was
added and the mixture was stirred at rt under hydrogen
71 atm) for 4 h. Solvents were removed under reduced
pressure and the residue was ®ltered through silica gel to
give 2 79.6 mg, 96%) in the form of a low melting solid. Mp.
41±428C; [a]Dˆ11.5 7CHCl3, cˆ0.003); 1H NMR 7CDCl3,
500 MHz): d 7.10 7s, 1H), 5.05 7m, 1H), 3.95±3.82 7m, 4H),
3.34 7m, 1H), 2.53 7m, 1H), 2.40 7m, 1H), 2.03±1.73 7m,
1H), 1.56±1.24 7m and br s, 39H), 1.42 7t, Jˆ6.5 Hz, 3H),
0.86 7t, Jˆ7 Hz, 3H); 13C NMR 7125 MHz): 179.0, 151.7,
131.2, 82.5, 81.6, 80.7, 80.2, 78.0, 74.6, 70.0, 37.4, 35.8,
34.5, 33.4, 32.2, 31.9, 29.7, 29.1, 28.8, 26.2, 25.8, 25.5,
22.7, 19.1, 14.1; MS 7ESI): 607 7M1H1).
1
acetate in hexanes) to afford 16 7110 mg, 49 %). H NMR
7CDCl3, 300 MHz): d 7.60±7.54 7m, 4H), 7.35±7.40 7m,
6H), 6.90 7s, 1H), 5.35±5.40 7m, 2H), 4.80±4.85 7m, 1H),
4.00±3.85 7m, 5H), 3.40±3.31 7m, 1H), 2.45±2.40 7m, 2H),
2.00±1.75 7m, 15H), 1.52±1.39 7m, 6H), 1.29±1.25 7d,
Jˆ7.0 Hz, 3H), 1.20±1.15 7m, 20H), 1.08 7s, 9H), 0.95 7t,
Jˆ6.4 Hz, 3H). MS 7ESI): 815 7M1H1).
3.1.15. ꢀ11E,12Z) 11,12-Dehydro-rollidecin C 4-tert-
butyldiphenylsilyl ether, 17. Following the above-
described procedure compound 15 749 mg, 61%) was
reacted with CF3CO2ReO3 7prepared from Re2O7 7100 mg,
0.20 mmol) and TFAA 70.038 mL, 0.26 mmol) in dryTHF
75 mL) at room temperature) and TFAA 70.037 mL,
0.26 mmol) in CH2Cl2 at 08C for 16 h. Workup followed
byextraction with ether and puri®cation bycolumn chro-
matography7silica gel, hexane-ethyl acetate, 3:7) afforded
Acknowledgements
1
17 710 mg, 29 %) in the form of an oil. H NMR 7CDCl3,
We thank the Skaggs Institute for Chemical Biology, US-
Israel Binational Science Foundation, the Israel Cancer
Research Fund and the CaP CURE Foundation for ®nancial
support.
300 MHz): d 7.18 7d, Jˆ4.0 Hz, 1H), 5.46±5.28 7m, 2H),
5.04 7m, 1H), 4.00±3.83 7m, 4H), 3.35 7m, 1H), 2.49 7m,
1H), 2.37 7m, 2H), 2.17 7m, 1H), 2.01±1.24 7m and br s,
40H), 1.43 7t, Jˆ6.8 Hz, 3H), 0.86 7t, Jˆ6.4 Hz, 3H); MS:
605 7M1H1).
3.1.16. Compound 18. Compound 16 780 mg, 0.1 mmol)
was dissolved in ethanol-benzene 71:1, 2 mL) and purged
with argon for 10 min. Wilkinson's catalyst 720 mg) was
added and the mixture was stirred at room temperature
under hydrogen 7balloon) for 4 h. Solvents were removed
under reduced pressure and the residue was ®ltered through
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