Synthesis and biological evaluation of analogs of altohyrtin C (spongistatin 2)

Article abstract of DOI:10.1016/j.tet.2007.10.065

Several structural analogs that contain only part of the altohyrtin structure have been prepared and compared with synthetic altohyrtin C (2) for in vitro cytotoxicity against human colon (HCT116) and ovarian (A2780) cell lines. Whereas altohyrtin C was f

Full text of DOI:10.1016/j.tet.2007.10.065

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 124e136
www.elsevier.com/locate/tet
Synthesis and biological evaluation of analogs
of altohyrtin C (spongistatin 2)
b
d
c
Carl E. Wagner a, , Qiang Wang , Alexander Melamed , Craig R. Fairchild ,
*
Robert Wild c, Clayton H. Heathcock d
a Arizona State University at the West Campus, Department of Integrated Natural Sciences, Glendale, AZ 85306, United States
b Chemocentryx, Inc, Mountain View, CA 94043, United States
c BristoleMyers Squibb Co., Oncology Drug Discovery, Princeton, NJ 08534, United States
d Center for New Directions in Organic Synthesis, Department of Chemistry, University of California, Berkeley, CA 94720, United States
Received 16 September 2007; received in revised form 18 October 2007; accepted 19 October 2007
Available online 22 October 2007
Abstract
Several structural analogs that contain only part of the altohyrtin structure have been prepared and compared with synthetic altohyrtin C (2)
for in vitro cytotoxicity against human colon (HCT116) and ovarian (A2780) cell lines. Whereas altohyrtin C was found to be exceedingly potent
against these lines (IC50¼0.0003 mM), analogs 3e5 were >27,000-fold less potent (IC50>8 mM). Analogs 6 and 7 also demonstrated weak
cytotoxicity with IC50 values for the HCT116 and A2780 cells of 4.8 mM and 2.4 mM, respectively, for 6.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
The spongistatins are rather complex molecules, and it is
not known which part of the structure is involved in binding
to the microtubules and which portions might play mainly
an organzational role, holding the actual binding region in
an optimum conformation for efficient binding (Fig. 1). There
is some suggestion that the portion of the molecule comprising
rings E and F and the diene side chain might be involved in
binding, since there is a 10-fold difference in potency associ-
ated with substitution at C50 (i.e., altohyrtin A, with Cl at
C50, is 10 times more potent than altohyrtin C, which has H
at this position).1,2
Smith and Lin have reported two simplified analogs having
only the F ring and the C44eC51 side chain and report that
these analogs are active against several cultured cancer cell
lines at the micromolar level.9 It has also been found that de-
hydration of the ring E secondary alcohol in either the altohyr-
tin A or altohyrtin C series results in a 10-fold increase in
potency against some cell lines.10,11 It was further noted by
Paterson and co-workers that a full altohyrtin analog, but lack-
ing carbons 47e51, is dramatically less potent than altohyrtin
The spongipyran natural products are a family of potent cy-
totoxins that were isolated and characterized in the early 1990s
by the research groups of Pettit (spongistatins),1,2 Kitagawa
(altohyrtins),3e5 and Fusetanai (cinachyrolides).6 Two mem-
bers of this unusual family of compounds are 1 and 2, altohyr-
tin A (spongistatin 1) and altohyrtin C (spongistatin 2). The
antitumor activity of these compounds has been described as
‘probably the best to date in the NCI’s evaluation programs.’7
Altohyrtin A (spongistatin 1), the most active member, has an
average IC50 of 0.13 nM against the NCI’s panel of 60 cancer
cell lines and is even more active against certain cell lines in
the panel.8 Although the mechanism of this cytotoxicity has
not been determined, it has been established that the altohyr-
tins inhibit tubulin polymerization and bind at a unique site
on the tubulin dimer.8
* Corresponding author. Tel.: þ1 602 543 6937; fax: þ1 602 543 6073.
E-mail address: carl.wagner@asu.edu (C.E. Wagner).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.065

C.E. Wagner et al. / Tetrahedron 64 (2008) 124e136
125
Figure 1.
A or altohyrtin C.11b Against this background, we set out to
prepare several simplified altohyrtin analogs that include two
to four of the original six altohyrtin ring systems and a linear
polymethylene hydrocarbon chain to substitute for the missing
ring systems. Through this procedure, we hoped to generate al-
tohyrtin analogs retaining the potency of the parent compound,
but lacking the synthetic complexity. The identification of po-
tent analogs would not only present synthetically accessible
pharmaceutical targets, but it would also elucidate the most
important structural motifs of altohyrtin for microtubule
binding.
For example, compounds 3 and 4, which lack C1eC28
completely, lactone 5, in which the two spiroketals and their
associated functionality are replaced by a simple polymethyl-
ene linker, were synthesized. Lactone 6, which contains all of
the altohyrtin structure except the ring C/D spiroketal and the
functionality in the C13eC17 region, and lactone 7, which
contains all of the altohyrtin structure except the E and F rings,
were also synthesized (Fig. 2). In this article, we report the
preparation and biological evaluation of these five synthetic
analogs. As will be seen, we were quite surprised to find
that none of the compounds show any significant activity in
a number of cell lines.
Figure 2.
Compound 3, comprising the C29eC51 portion of spongis-
tatin 2 was prepared by deprotection (HF in acetonitrile) of the
previously reported10 synthetic intermediate 8. For preparation
of tetrahydro analog 4, the tris-p-methoxybenzyl ether 9 was
selectively hydrogenated to provide tetrahydro derivative 10,
which was oxidatively deprotected to obtain 11. Desilylation
of 11 provided analog 4 (Scheme 1).
As shown in Scheme 2, phosphonium salt 1210 was treated
with methyllithium to obtain the corresponding Wittig reagent,
which was coupled with ester-aldehyde 13, prepared from cy-
clododecanone as shown in the inset. Alkene 14 was obtained
as a 3:1 mixture of cis and trans isomers. Reaction with tetra-
n-butylammonium flouride in tetrahydrofuran removed the
triisopropylsilyl group and the two triethylsilyl groups from
the F ring to provide the corresponding dihydroxy acid. This
material was cyclized under Yamaguchi’s conditions12 to ob-
tain lactones 15 in 43% yield for the three steps. The geomet-
ric isomers were separated by preparative HPLC to obtain pure
samples of isomers 15a and 15b. The separated isomers were
each deprotected by treatment with HF in acetonitrile to ac-
quire geometrically homogeneous samples of lactones 5a
and 5b.
The synthesis of analog 6 began (Scheme 3) by benzylation
of with 1,12-dodecanediol to obtain mono-ether 16, which was
converted into iodide 17 by treatment with triphenylphosphine
and iodine.13 Displacement of the primary iodide with triphe-
nylphosphine resulted in almost quantitative conversion into
the phosphonium salt 18.

126
C.E. Wagner et al. / Tetrahedron 64 (2008) 124e136
lactone 25, still as a mixture of cis and trans isomers. Global
deprotection was accomplished by treatment of 25 with HF in
acetonitrile, yielding analog 6.
Attempted separation of the double bond isomers of 24, 25,
and 6 by preparative HPLC was not successful.
The synthesis of lactone 7 started from the TIPS protection
of 1,10-dodecane diol to give the mono-protected TIPS ether
26 in 48% yield. The TIPS ether 26 was subsequently con-
verted to iodide 27 in 82% yield, and reaction of 27 with tri-
phenylphosphine provided the triphenylphosphonium iodide
salt 28 in 80% yield. The TIPS ether phosphonium iodide
salt 28 was deprotonated by LiHMDS in THF, and the previ-
ously described aldehyde 2910 was added to the ylide solution
to obtain the Wittig product 30 in 41% yield as the cis-alkene
isomer. The TIPS protecting groups were removed by treat-
ment with TBAF to give lactone precursor 31 in 69% yield,
and 31 was lactonized by the Yamaguchi procedure12 to give
lactone 32 in 18% yield. Lactone 32 was deprotected by treat-
ment with HF in acetonitrile at ꢁ15 ꢀC to give lactone 7
(Scheme 6).
2. Biological evaluation
In vitro cytotoxicity of synthetic altohyrtin C (2) and ana-
logs 3e7 in human tumor cell lines was assessed as previously
described using a tetrazolium-based colorimetric assay in
which MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxyme-
thoxyphenyl)-2-(4-sulphenyl)-2H-tetrazolium, inner salt) is
metabolically converted in live cells to a reduced form, which
absorbs light at 492 nm.16 IC50 values, defined as the concen-
tration required to inhibit cell growth by 50%, were deter-
mined after 72-h drug exposures. Although altohyrtin C
demonstrated very potent cytotoxicity against human colon
(HCT116) and ovarian (A2780) cells (IC50 values of
0.0003 mM), analogs 3e5 were >27,000-fold less potent
(IC50 values of >8 mM) than the parent compound. Analog 6
demonstrated weak cytotoxicity potency with IC50 values for
the HCT116 and A2780 cells of 4.8 mM and 2.4 mM, respec-
tively. Analog 7 also demonstrated weak cytotoxicity potency
with IC50 values for the HCT116 and A2780 cells of 4.5 mM
and 6.3 mM, respectively.
Scheme 1.
Salt 18 was deprotonated and the resulting ylide coupled
with the previously described aldehyde 1914 to obtain exclu-
sively the cis-alkene 20 in 44% yield. The tert-butyl ester 20
was converted into the corresponding triisopropylsilyl ester
21 by treatment with TMS-triflate followed by triisopropylsi-
lylchloride in 87% overall yield for the two steps. Treatment
of 21 with hydrogen over palladium on charcoal saturated
the double bond and removed the benzyl group, giving pri-
mary alcohol 22, which was oxidized by the MoffateSwern
procedure15 to obtain aldehyde 23 (Scheme 4).
3. Conclusion
We have prepared several altohyrtin analogs (3e7) that in-
clude two to four of the original ring systems and a simple
polymethylene hydrocarbon chain as a substitute for the ring
systems that are absent. The biological tests indicate that
none of the analogs 3e7 demonstrate significant cytotoxicity
compared to the parent altohyrtin compounds. The results of
this work suggest that all ring systems are necessary to confer
potent cytotoxicity to the altohyrtin compound, and a simple
polymethylene hydrocarbon substitute for two to four of the
ring systems is not adequate to retain potent cytotoxycity in
altohyrtin analogs.
As shown in Scheme 5, the previously described phospho-
nium salt 12 was deprotonated with methyllithium in tetrahy-
drofuran and the resulting ylide was treated with aldehyde 23
to obtain alkene 24 as a 3:1 mixture of cis and trans double
bond isomers. Treatment with tetra-n-butylammonium fluoride
in tetrahydrofuran at 0 ꢀC cleaved the TIPS ester and removed
the two TES groups on ring E. The resulting dihydroxy acid
was lactonized by the Yamaguchi procedure12 to obtain

C.E. Wagner et al. / Tetrahedron 64 (2008) 124e136
127
Scheme 2.
4. Experimental section
per million against an internal reference. Coupling constants
(J ) are reported in Hertz, and the abbreviations for splitting in-
clude: s, single; d, doublet; t, triplet; q, quartet; p, pentet; m,
multiplet; br, broad. 13C NMR spectra were acquired on
Bruker instruments at 125.8 MHz. Chemical shifts (d) are
listed in parts per million against solvent carbon peaks as an
internal reference.
4.1. General
1H NMR spectra were acquired at 400 MHz or 500 MHz on
Bruker spectrometers. Chemical shifts (d) are listed in parts
4.2. Intermediate 3
Compound 817 (40.1 mg, 34.3 mmol) was placed in a poly-
propylene vessel, and THF (0.5 mL) was added, followed by
acetonitrile (0.5 mL). The mixture was cooled to ꢁ18 ꢀC,
and a solution of HF (3.0 mL, 5.0 M in acetonitrile) was added
dropwise over 1 h. The reaction mixture was then stirred over-
night while the temperature was maintained between ꢁ15 ꢀC
and ꢁ19 ꢀC. The reaction was quenched at low temperature
by the addition of triethylamine (2.0 mL) and the mixture
was allowed to warm to rt, and was transferred to a separatory
funnel with satd NaHCO3 (20 mL) and extracted with ethyl
acetate. The organic phase was washed with brine and dried
over Na2SO4, filtered, and concentrated to leave an oil. This
material was purified by column chromatography (10%
MeOH/CH2Cl2) and compound 3 was obtained as a foaming
Scheme 3.

128
C.E. Wagner et al. / Tetrahedron 64 (2008) 124e136
Scheme 5.
Scheme 4.
d 178.1, 143.4, 137.1, 136.8, 130.0, 116.5, 114.4, 99.0, 80.2,
77.7, 77.0, 75.3, 72.1, 70.5, 70.2, 66.2, 64.0, 43.4, 39.1,
38.4, 37.6, 32.6, 31.8, 28.6, 26.6, 22.5, 11.7, 9.9; HRMS (elec-
trospray) calcd for C31H52O10Li (MþLiþ) 591.3720, found
591.3717. Anal. Calcd for C31H52O10: C 63.67, H 8.96. Found:
C 63.52, H 9.21.
solid (10.2 mg, 51%). [a]D þ17.3 (c 0.78, CH2Cl2); IR: 3411,
1
2968, 2874, 1724, 1711 cmꢁ1; H NMR (400 MHz, CD3CN):
d 6.42e6.21 (m, 2H), 5.75 (dd, J¼15.2, 6.4 Hz, 1H), 5.22 (dd,
J¼16.4, 1.6 Hz, 1H), 5.07 (dd, J¼10.0, 1.2 Hz, 1H), 5.00 (d,
J¼2.0 Hz, 1H), 4.93 (s, 1H), 4.89 (s, 1H), 4.28e4.20 (m,
2H), 4.10e4.02 (m, 2H), 3.95 (d, J¼9.2 Hz, 1H), 3.72e3.64
(m, 1H), 3.68 (d, J¼9.6 Hz, 1H), 3.42e3.27 (m, 4H), 3.10
(t, J¼9.4 Hz, 1H), 3.04e3.02 (m, 1H), 2.98 (t, J¼8.8 Hz,
1H), 2.90 (d, J¼10.0 Hz, 1H), 2.72 (d, J¼14.4 Hz, 1H),
2.32e2.15 (m, 4H), 2.08 (dd, J¼14.8, 10.4 Hz, 1H), 1.99e
1.95 (m, 2H), 1.93 (dd, J¼14.4, 2.0 Hz, 1H), 1.83e1.76 (m,
1H), 1.69e1.61 (m, 4H), 1.20 (s, 9H), 0.92 (d, J¼6.8 Hz,
3H), 0.82 (d, J¼7.2 Hz, 3H); 13C NMR (125 MHz, CD3CN):
4.3. Intermediate 10
Compound 9 (60 mg, 50.6 mmol) was dissolved in 20 mL
of methanol. The flask was purged with nitrogen and the cat-
alyst (10% Pd/C, 18 mg) was added. After purging with hydro-
gen, a balloon filled with hydrogen was placed on top of the

C.E. Wagner et al. / Tetrahedron 64 (2008) 124e136
129
Scheme 6.
flask and the reaction mixture was stirred for 2 h at rt. Crude
1H NMR showed that the starting material disappeared and
the reaction mixture was filtered through a short silica gel
pad. The silica gel pad was washed several times with metha-
nol and the combined solution was concentrated under vac-
uum. The residue (54.2 mg, 90%) was used directly for the
next step without further purification. [a]D þ10.6 (c 1.08,
(s, 1H), 3.61 (t, J¼8.8 Hz, 1H), 3.37 (t, J¼10.8 Hz, 1H),
3.31 (s, 3H), 3.30 (s, 3H), 3.27 (s, 3H), 3.22 (s, 3H), 3.22e
3.18 (m, 1H), 2.73 (d, J¼14.4 Hz, 1H), 2.61 (dd, J¼13.4,
5.4 Hz, 1H), 2.57 (dd, J¼15.6, 4.0 Hz, 1H), 2.46 (dd,
J¼13.6, 8.0 Hz, 1H), 2.29 (dd, J¼14.8, 9.6 Hz, 1H), 2.24e
2.18 (m, 1H), 2.02 (d, J¼15.6 Hz, 1H), 1.70e1.50 (m, 8H),
1.42e1.25 (m, 6H), 1.20 (s, 9H), 1.11 (s, 9H), 1.04 (s, 9H),
0.97e0.88 (m, 6H), 0.83 (d, J¼6.4 Hz, 3H), 0.27 (s, 3H),
0.22 (s, 3H), 0.15 (s, 3H), 0.13 (s, 3H); 13C NMR
(125 MHz, C6D6): d 177.3, 159.5, 159.4, 144.0, 131.3,
131.2, 131.1, 130.1, 129.1, 129.0, 114.5, 113.7, 102.6, 86.8,
83.1, 79.6, 77.9, 76.2, 74.5, 74.5, 74.3, 70.7, 70.6, 66.8,
63.9, 54.4, 46.9, 45.1, 38.8, 38.5, 38.2, 36.4, 32.5, 31.2,
28.8, 27.5, 27.0, 25.9, 25.8, 23.0, 22.6, 18.0, 17.9, 14.1,
1
CH2Cl2); IR: 2953, 2932, 2857, 1729, 1613, 1514 cmꢁ1; H
NMR (400 MHz, C6D6): d 7.40 (d, J¼8.8 Hz, 2H), 7.34 (d,
J¼8.4 Hz, 2H), 7.26 (d, J¼8.4 Hz, 2H), 6.84e6.77 (m, 6H),
5.11 (s, 2H), 5.03 (d, J¼11.2 Hz, 1H), 4.97 (d, J¼10.8 Hz,
1H), 4.90 (d, J¼10.8 Hz, 1H), 4.71 (d, J¼11.2 Hz, 1H), 4.61
(d, J¼10.8 Hz, 1H), 4.51 (d, J¼10.8 Hz, 1H), 4.34e4.31 (m,
1H), 4.07 (dt, J¼6.0, 1.6 Hz, 2H), 4.11e3.94 (m, 2H), 3.71

130
C.E. Wagner et al. / Tetrahedron 64 (2008) 124e136
13.1, 10.1, ꢁ4.2, ꢁ4.5, ꢁ4.6, ꢁ4.8; HRMS (electrospray)
calcd for C68H110O13Si2Li (MþLiþ) 1197.7645, found
1197.7637. Anal. Calcd for C68H110O13Si2: C 68.53, H 9.30.
Found: C 68.35, H 9.61.
1H), 3.10 (td, J¼9.4, 4.8 Hz, 1H), 2.97 (td, J¼8.8, 3.6 Hz,
1H), 2.89 (d, J¼10.4 Hz, 1H), 2.71 (d, J¼14.8 Hz, 1H), 2.65
(d, J¼5.2 Hz, 1H), 2.21 (s, 2H), 2.16 (t, J¼6.4 Hz, 1H), 2.06
(dd, J¼15.0, 10.2 Hz, 1H), 2.00e1.90 (m, 3H), 1.82e1.70 (m,
1H), 1.70e1.62 (m, 4H), 1.56e1.42 (m, 7H), 1.20 (s, 9H),
0.95e0.89 (m, 6H), 0.82 (d, J¼7.2 Hz, 3H); 13C NMR
(125 MHz, CD3CN): d 178.1, 144.5, 113.7, 99.0, 80.1, 77.7,
77.1, 75.3, 72.1, 70.5, 69.7, 66.2, 64.0, 43.9, 39.0, 38.4, 37.6,
37.5, 36.7, 32.6, 31.8, 28.6, 27.6, 26.6, 26.5, 22.5, 13.5, 11.7,
9.9; HRMS (electrospray) calcd for C31H56O10Li (MþLiþ)
595.4033, found 595.4039. Anal. Calcd for C31H56O10: C
63.24, H 9.59. Found: C 62.98, H 9.79.
4.4. Intermediate 11
To a solution of compound 10 (99 mg, 83.1 mmol) in CH2Cl2
(10 mL) and pH 7 aqueous phosphate buffer solution (1 mL) was
added DDQ (75 mg, 0.33 mmol). The reaction mixture was
stirred vigorously for 1 h at rt, and the color of the mixture
changed from green to yellow. A solution of satd NaHCO3 was
then added and the mixture was extracted with EtOAc. The com-
bined organic layers werewashed with brine, dried over MgSO4,
filtered, and concentrated. The crude material was purified by
flash chromatography on silica gel (50% EtOAc/hexanes) to af-
ford the product as a colorless oil (45 mg, 66%). [a]D þ7.7 (c
4.6. Intermediate 13
To a cooled (0 ꢀC) solution of cyclododecanone (5.0 g,
27.5 mmol) in acetonitrile (40 mL) was added triethylamine
(4.8 mL, 34.3 mmol) followed by TIPSCl (7.3 mL, 34.3 mmol).
Then NaI (5.1 g, 34.3 mmol) was added and the reaction mix-
ture turned pink-white and a copious precipitate appeared.
The reaction mixture was warmed to rt and stirred overnight.
The reaction was quenched with satd NaHCO3 solution and
the resulting mixture was extracted with hexanes. The organic
layers were combined and washed with brine, dried over anhy-
drous K2CO3, filtered, and concentrated. The residue was used
directly for ozonolysis without further purification.
The crude silyl enol ether was dissolved in methanol (50 mL)
and dichloromethane (40 mL), and the mixture was cooled to
ꢁ78 ꢀC. To the mixture was added dimethyl sulfide (4 mL) and
ozone was bubbled into the mixture for 1 h. The ozone flow
was stopped after the color of the mixture turned to blue, the re-
sulting mixture was warmed to rt, and the solvent was removed
undervacuum. Theresiduewas purifiedbycolumn chromatogra-
phy (20% EtOAc/hexanes) togive the desired aldehyde 13(7.1 g,
70% for two steps) as a colorless oil. 1H NMR (400 MHz, C6D6):
d 9.40 (s, 1H), 2.30 (t, J¼7.4 Hz, 2H), 1.92 (td, J¼7.2, 1.2 Hz,
2H), 1.72e1.65 (m, 2H), 1.40e1.20 (m, 17H), 1.18 (d, 18H);
13C NMR (125 MHz, C6D6): d 200.4, 172.9, 43.5, 35.6, 29.5,
29.4, 29.3, 29.2, 29.1, 25.3, 21.9, 17.7, 12.0.
1
0.31, CH2Cl2); IR: 3458, 2954, 2932, 2858, 1730 cmꢁ1; H
NMR (400 MHz, C6D6): d 5.28 (s, 1H), 5.07 (d, J¼12.0 Hz,
2H), 4.50 (t, J¼5.4 Hz, 1H), 4.04 (t, J¼6.4 Hz, 1H), 4.06e
3.95 (m, 2H), 3.90 (d, J¼2.8 Hz, 1H), 3.79 (d, J¼10.4 Hz,
1H), 3.67 (d, J¼7.6 Hz, 1H), 3.57 (t, J¼8.8 Hz, 1H), 3.20e
3.10 (m, 2H), 2.93 (s, 1H), 2.88 (d, J¼14.8 Hz, 1H), 2.74 (d,
J¼8.0 Hz, 1H), 2.58 (s, 1H), 2.51 (dd, J¼13.4, 5.4 Hz, 1H),
2.39 (dd, J¼13.6, 7.6 Hz, 1H), 2.26 (dd, J¼14.8, 10.0 Hz, 1H),
2.16e1.99 (m, 3H), 1.70e1.50 (m, 8H), 1.42e1.25 (m, 6H),
1.20 (s, 9H), 1.06 (s, 9H), 1.05e1.00 (m, 5H), 0.99 (s, 9H),
0.81 (d, J¼7.2 Hz, 3H), 0.24 (s, 3H), 0.19 (s, 3H), 0.12 (s, 3H),
0.03 (s, 3H); 13C NMR (125 MHz, C6D6): d 177.5, 144.1,
114.4, 98.5, 79.3, 79.0, 77.7, 75.5, 74.0, 72.5, 70.9, 65.9, 63.9,
44.7, 38.7, 38.5, 38.3, 37.8, 36.5, 32.8, 31.7, 28.6, 27.4, 27.0,
25.9, 25.6, 22.9, 22.3, 18.0, 17.8, 14.1, 12.6, 10.2, ꢁ4.2, ꢁ4.6,
ꢁ5.0, ꢁ5.1; HRMS (electrospray) calcd for C43H84O10Si2Li
(MþLiþ) 823.5763, found 823.5789. Anal. Calcd for
C43H84O10Si2: C 63.19, H 10.36. Found: C 62.95, H 10.41.
4.5. Intermediate 4
Compound 11 (23 mg, 28.1 mmol) was placed in a polypro-
pylene vessel, and THF (0.5 mL) was added followed by aceto-
nitrile (0.5 mL). The mixture was cooled to ꢁ18 ꢀC, and then
a solution of HF (2.0 mL, 5.0 M in acetonitrile) was added drop-
wise over 1 h. The reaction mixture was then stirred overnight
while the temperature was maintained between ꢁ15 ꢀC and
ꢁ19 ꢀC. The reaction was quenched at low temperature by the
addition of triethylamine (2.0 mL) and then allowed to warm
to rt. The mixture was transferred to a separation funnel with
satd NaHCO3 (20 mL) and extracted with ethyl acetate. The or-
ganic phase was washed with brine, dried over Na2SO4, filtered,
and concentrated to leave an oil. The residuewas purified by col-
umn chromatography (10% MeOH/CH2Cl2) and the product
was obtained as a foaming solid (8.3 mg, 50%). [a]D þ21.4 (c
4.7. Intermediate 14
To a cooled (ꢁ78 ꢀC) solution of Wittig salt 1218 (252 mg,
0.17 mmol) in THF (2 mL) was added dropwise a 1.4 M solu-
tion of MeLi$LiBr in ether (115 mL). The color of the solution
turned orange-red immediately. After stirring for 30 min, a solu-
tion of aldehyde 13 (77 mg, 0.21 mmol) in THF (1 mL) was
added dropwise. The flask containing the aldehyde was rinsed
with an additional 1 mL of THF, which was added to the reaction
mixture. The color of the reaction faded immediately to pale yel-
low upon the addition of the aldehyde. The reaction mixture was
stirred for 1 h at ꢁ78 ꢀC, warmed slowly to rt, and quenched
with satd NH4Cl solution. The mixture was extracted with
EtOAc and thecombined organiclayers werewashed with brine,
dried over MgSO4, filtered, and concentrated. The residue was
purified by column chromatography (10% EtOAc/hexanes)
to give the desired product (100 mg, 41%) as a colorless oil.
1
0.14, CH2Cl2); IR: 3409, 2957, 2871, 1727 cmꢁ1; H NMR
(400 MHz, CD3CN): d 5.00 (d, J¼2.4 Hz, 1H), 4.91 (m, 1H),
4.87 (m, 1H), 4.24 (td, J¼7.8, 2.4 Hz, 1H), 4.07 (td, J¼6.4,
0.8 Hz, 2H), 3.95 (d, J¼9.2 Hz, 1H), 3.73e3.62 (m, 2H), 3.68
(d, J¼11.6 Hz, 1H), 3.42e3.31 (m, 3H), 3.25 (d, J¼4.8 Hz,

C.E. Wagner et al. / Tetrahedron 64 (2008) 124e136
131
1H NMR (400 MHz, C6D6): d 6.50e6.34 (m, 2H), 5.93 (dd,
J¼14.0, 6.0 Hz, 1H), 5.66e5.52 (m, 2H), 5.30e5.01 (m, 4H),
4.49 (q, J¼6.8 Hz, 1H), 4.35 (m, 1H), 3.99e3.97 (m, 1H).
3.93 (s, 1H), 3.68e3.48 (m, 4H), 3.21 (s, 3H), 2.75 (d,
J¼12.8 Hz, 1H), 2.72e2.56 (m, 2H), 2.48e2.08 (m, 8H),
2.02e2.00 (m, 1H), 1.82e1.78 (m, 3H), 1.69e1.60 (m, 3H),
1.45e1.28 (m, 12H), 1.28e1.10 (m, 72H), 0.90e0.82 (m,
21H), 0.29 (s, 3H), 0.24 (s, 3H), 0.20 (s, 6H); 13C NMR
(125 MHz, C6D6): d 172.9, 144.1, 137.4, 136.7, 130.8 (trans),
130.1 (cis), 130.0, 129.6 (cis), 116.3, 114.9, 101.2, 81.0, 80.4,
77.5, 77.1, 72.1, 71.3, 70.9, 68.3, 67.0, 66.8 (trans), 46.8, 46.6,
40.1, 40.0 (trans), 38.7, 38.6 (trans), 35.6, 32.9 (trans), 32.8,
32.6, 32.3, 30.0, 29.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 27.5,
27.4, 26.5, 26.4 (trans), 25.9, 25.8, 25.3, 18.2, 18.0, 17.8, 15.8,
12.0, 10.4, 7.2, 7.1, 7.0, 5.8, 5.7, ꢁ4.3, ꢁ4.4. ꢁ4.8, ꢁ4.9;
LRMS (FAB, low resolution) calcd for C78H156O10Si6
(MþHþ) 1422.1, found 1422.2.
(295 mg, 2.41 mmol) in toluene (50 mL), heated in an oil
bath set at 90 ꢀC. A white precipitate was observed. Upon
completion of the addition, the flask in which the mixed
anhydride formed was rinsed with toluene (3 mL) and this
rinse was added to the DMAP solution over 12 h. After cool-
ing to rt, the mixture was washed with satd NaHCO3 (50 mL)
and then with brine (50 mL). The aqueous phases were back-
extracted with EtOAc and the combined organic phases were
dried over MgSO4, filtered, and concentrated. The residue
was purified by column chromatography (20% EtOAc/
hexanes) to give the desired product (30 mg, 61%) as a color-
less oil.
The mixture of isomers was further purified by preparative
HPLC (98.5% hexanes/isopropanol) to give the cis isomer
(16 mg) and the trans isomer (5 mg) separately.
4.8.1. Cis isomer 15a
[a]D þ25.7 (c 0.4, CH2Cl2); IR: 2928, 2855, 1717 cmꢁ1; 1H
NMR (400 MHz, C6D6): d 6.40e6.28 (m, 2H), 5.81 (dd,
J¼14.4, 6.0 Hz, 1H), 5.49e5.40 (m, 2H), 5.22e5.08 (m,
3H), 4.98e4.94 (m, 1H), 4.66 (t, J¼9.6 Hz, 1H), 4.43 (q,
J¼6.4 Hz, 1H), 4.28 (d, J¼10.4 Hz, 1H), 3.91 (br s, 2H),
3.45 (t, J¼9.0 Hz, 1H), 3.39 (d, J¼10.8 Hz, 1H), 3.27 (td,
J¼8.6, 2.4 Hz, 1H), 3.22 (s, 3H), 2.91 (d, J¼13.6 Hz, 1H),
2.78e2.63 (m, 2H), 2.59 (dd, J¼13.4, 7.4 Hz, 1H), 2.51 (dd,
J¼13.2, 6.0 Hz, 1H), 2.36 (dd, J¼14.4, 8.0 Hz, 1H), 2.27
(dd, J¼15.2, 3.6 Hz, 1H), 2.23e1.92 (m, 6H), 1.80 (d,
J¼15.2 Hz, 1H), 1.62e1.42 (m, 6H), 1.40e1.18 (m, 18H),
1.14e1.04 (m, 26H), 0.93 (d, J¼7.2 Hz, 3H), 0.84e0.72 (m,
6H), 0.50 (br s, 1H), 0.25 (s, 3H), 0.17 (s, 3H), 0.14 (s, 3H),
0.12 (s, 3H); 13C NMR (125 MHz, C6D6): d 175.2, 143.4,
137.6, 136.8, 130.3, 130.0, 129.4, 116.4, 115.1, 101.2, 81.5,
79.4, 77.6, 73.6, 72.6, 72.4, 71.0, 69.5, 47.5, 46.6, 39.9,
38.6, 37.5, 34.7, 32.8, 31.1, 30.9, 30.2, 30.0, 29.7, 29.2,
29.1, 28.9, 28.7, 28.5, 25.9, 25.9, 25.8, 25.4, 18.2, 18.1,
14.7, 14.1, 10.7, 7.2, 6.0, ꢁ4.3, ꢁ4.4, ꢁ4.8, ꢁ4.9; LRMS
(electrospray) calcd for C57H106O9Si3Na (MþNaþ) 1041.7,
found 1041.7.
4.8. Lactones 15
To a cooled (0 ꢀC) solution of the Wittig product 14
(23 mg, 16.2 mmol) in THF (2 mL) was added a 1.0 M solu-
tion of TBAF in THF (50 mL, 50.2 mmol) dropwise. The mix-
ture was stirred for 2 h at 0 ꢀC, quenched with satd NH4Cl
solution, and extracted with EtOAc. The combined organic
layers were washed with brine, dried over MgSO4, filtered,
and concentrated. The residue was purified by column chro-
matography (75% EtOAc/hexanes) to give the desired carbox-
ylic acid intermediate (12 mg, 70%) as a colorless oil. IR:
1
3384, 2928, 2855, 1710 cmꢁ1; H NMR (400 MHz, C6D6):
d 6.42e6.30 (m, 2H), 5.83 (dd, J¼14.2, 6.6 Hz, 1H), 5.60e
5.47 (m, 2H), 5.24e4.96 (m, 4H), 4.42 (q, J¼6.4 Hz, 1H),
4.28e4.20 (m, 1H), 3.95e3.93 (m, 1H), 3.89 (s, 1H), 3.39e
3.33 (m, 1H), 3.32 (d, J¼10.4 Hz, 1H), 3.27 (t, J¼8.8 Hz,
1H), 3.13 (s, 3H), 3.11e3.07 (m, 1H), 2.77 (d, J¼12.0 Hz,
1H), 2.59 (dd, J¼13.6, 7.6 Hz, 1H), 2.51 (dd, J¼13.6,
6.0 Hz, 1H), 2.37 (dd, J¼14.2, 7.8 Hz, 1H), 2.32 (dd,
J¼15.2, 3.6 Hz, 1H), 2.22e2.04 (m, 6H), 1.90e1.61 (m,
4H), 1.58e1.01 (m, 55H), 0.98 (d, J¼7.2 Hz, 3H), 0.86e
0.75 (m, 6H), 0.25 (s, 3H), 0.19 (s, 3H), 0.15 (s, 3H), 0.14
(s, 3H); 13C NMR (125 MHz, C6D6): d 178.8, 143.7, 137.5,
136.7, 130.7 (trans), 130.2 (trans), 130.1, 130.0 (cis), 129.6
(cis), 116.4, 115.1, 101.2, 79.0, 78.5, 78.4, 75.4, 72.6, 70.9,
67.0, 66.8 (trans), 46.6, 46.2, 39.2, 38.8, 38.7, 33.8, 32.9
(trans), 32.8, 32.7, 32.3, 30.1 (trans), 30.0, 29.7, 29.6, 29.5,
29.3, 29.2, 29.0, 27.5, 27.4, 26.6, 26.4 (trans), 25.9, 25.8,
24.7, 18.2, 18.0, 13.5, 10.4, 7.2, 5.8, ꢁ4.3, ꢁ4.4. ꢁ4.8,
ꢁ4.9; LRMS (electrospray) calcd for C57H108O10Si3 (M)
1035.72, found 1036.73. Anal. Calcd for C57H108O10Si3: C
65.97, H 10.49. Found: C 65.76, H 10.52.
4.8.2. Trans isomer 15b
[a]D þ20.5 (c 0.2, CH2Cl2); IR: 2928, 2855, 1717 cmꢁ1; 1H
NMR (400 MHz, C6D6): d 6.40e6.28 (m, 2H), 5.81 (dd,
J¼14.4, 6.4 Hz, 1H), 5.59e5.53 (m, 2H), 5.20e5.06 (m, 3H),
4.97e4.94 (m, 1H), 4.75 (t, J¼9.8 Hz, 1H), 4.43 (q,
J¼6.4 Hz, 1H), 4.38e4.30 (m, 1H), 3.93 (m, 1H), 3.91 (s,
1H), 3.49e3.42 (m, 1H), 3.45 (d, J¼10.8 Hz, 1H), 3.34 (td,
J¼8.8, 2.4 Hz, 1H), 3.24 (s, 3H), 2.90 (d, J¼14.8 Hz, 1H),
2.59 (dd, J¼13.4, 7.4 Hz, 1H), 2.51 (dd, J¼13.4, 5.8 Hz, 1H),
2.35 (dd, J¼14.4, 8.0 Hz, 1H), 2.42e2.28 (m, 3H), 2.22 (dd,
J¼15.2, 3.6 Hz, 1H), 2.23e1.98 (m, 6H), 1.85 (d, J¼15.2 Hz,
1H), 1.67e1.50 (m, 6H), 1.41e1.18 (m, 18H), 1.12e1.02 (m,
26H), 0.94 (d, J¼7.2 Hz, 3H), 0.83e0.72 (m, 6H), 0.24 (s,
3H), 0.17 (s, 3H), 0.14 (s, 3H), 0.12 (s, 3H); 13C NMR
(125 MHz, C6D6): d 175.0, 143.4, 137.6, 136.8, 131.2, 130.0,
129.8, 116.4, 115.1, 101.0, 81.2, 79.3, 77.5, 73.6, 73.1, 72.5,
71.3, 67.8, 48.0, 46.5, 39.4, 38.6, 37.8, 34.3, 33.0, 32.8, 31.5,
31.0, 30.7, 30.1, 29.9, 29.8, 29.4, 29.3, 28.7, 27.1, 25.9, 25.8,
To a flask containing the aforementioned acid (50 mg,
48.2 mmol) was added a 0.4 M solution of N,N-diisopropyl-
ethylamine in toluene (3.6 mL, 1.45 mmol) followed by
0.4 M 2,4,6-trichlorobenzoyl chloride in toluene (2.4 mL,
0.96 mmol). The reaction mixture was stirred for 3 h at rt
and then diluted with toluene (20 mL), and added over
a 24 h period (via syringe pump) to a solution of DMAP

132
C.E. Wagner et al. / Tetrahedron 64 (2008) 124e136
25.4, 18.2, 18.1, 14.6, 10.8, 7.2, 5.9, ꢁ4.3, ꢁ4.4. ꢁ4.8, ꢁ4.9;
LRMS (electrospray, low resolution) calcd for C57H106O9Si3Na
(MþNaþ) 1041.7, found 1041.7.
70.9, 70.8, 67.3, 43.7, 39.4, 38.9, 36.1, 33.9, 33.6, 33.0,
32.3, 31.6, 30.2, 30.0, 29.9, 29.3, 28.2, 28.0, 27.5, 27.4,
27.2, 23.5, 12.4, 10.9; HRMS (FAB) calcd for C38H62O9Li
(MþLiþ) 669.4558, found 669.4554.
4.9. Lactone 5a
4.11. 1,12-Dodecanediol, monobenzyl ether (16)
The cis isomer of macrolactone 15 (8.0 mg, 7.85 mmol) was
placedinapolypropylenevessel,andthenTHF(0.2 mL)wasad-
ded followed by acetonitrile (0.2 mL). The mixture was cooled
to ꢁ18 ꢀC, and a solution of HF (0.55 mL, 5.0 M in acetonitrile)
was added dropwise over 1 h. The reaction mixture was stirred
overnight while the temperature was maintained between
ꢁ15 ꢀC and ꢁ19 ꢀC. The reaction was then quenched at low
temperature by the addition of triethylamine (1.0 mL). The re-
sulting mixture was allowed to warm to rt, transferred to a sepa-
ration funnel with satd NaHCO3 (20 mL), and extracted with
ethyl acetate. The organic phase was washed with brine, dried
over Na2SO4, filtered, and concentrated to leave an oil. The res-
idue was purified by column chromatography (75% EtOAc/hex-
anes) and the product was obtained as a foaming solid (4.9 mg,
77%). [a]D þ25.3 (c 0.19, CH2Cl2); IR: 3412, 2926, 2854, 1736,
1715 cmꢁ1; 1H NMR (500 MHz, C6D6): d 6.32e6.18 (m, 2H),
5.61 (dd, J¼15.0, 6.0 Hz, 1H), 5.57e5.47 (m, 2H), 5.12 (dd,
J¼16.0, 1.5 Hz, 1H), 4.97 (dd, J¼9.5, 1.5 Hz, 1H), 4.90 (d,
J¼7.0 Hz, 1H), 4.89 (s, 2H), 4.57 (dd, J¼10.5, 9.0 Hz, 1H),
4.37 (d, J¼10.0 Hz, 1H), 4.25 (br s, 2H), 4.16 (q, J¼6.5 Hz,
1H), 3.87 (d, J¼10.5 Hz, 1H), 3.82 (br s, 1H), 3.48 (td,
J¼10.0, 2.0 Hz, 1H), 3.45e3.40 (m, 1H), 3.39 (br s, 1H), 3.26
(t, J¼9.0 Hz, 1H), 2.87 (d, J¼15.0 Hz, 1H), 2.41e2.33 (m,
1H), 2.30e2.20 (m, 3H), 2.18e1.92 (m, 9H), 1.76e1.67 (m,
1H), 1.57e1.41 (m, 4H), 1.40e1.08 (m, 16H), 0.84 (d,
J¼6.5 Hz, 3H), 0.64 (d, J¼7.5 Hz, 3H); 13C NMR (125 MHz,
C6D6): d 176.6, 142.9, 136.6, 136.5, 130.6, 130.3, 129.5,
128.8, 117.1, 115.3, 98.9, 81.8, 79.8, 78.4, 73.9, 72.8, 70.9,
70.8, 67.5, 43.8, 39.3, 38.6, 36.0, 34.0, 32.9, 32.4, 30.5, 30.0,
29.2, 28.5, 28.2, 28.1, 28.0, 27.8, 27.5, 26.9, 23.4, 12.6, 10.9;
HRMS (FAB) calcd for C38H62O9Li (MþLiþ) 669.4558, found
669.4554.
To a heterogeneous solution of 1,12-dodecanediol (5.0 g,
25 mmol) in DMF was added a dispersion of NaH (60% by
weight) in mineral oil (1.09 g, 27 mmol) with stirring at rt.
Virtually no gas evolution was observed. To this heterogeneous
reaction mixture, benzyl bromide (3.0 mL, 25 mmol) was added
and the reaction was stirred 12 h by which time the reaction so-
lution had become homogeneous. The reaction solution was
slowly added into 100 mL of water and extracted with 100 mL
of diethyl ether. The organic layer was washed with 100 mL
of brine, dried over Na2SO4, and concentrated in vacuo. The re-
sulting products were purified by column chromatography
(SiO2, 15% EtOAc/hexanes) to afford the monobenzyl ether
(16) as a white solid (3.34 g, 46%). 1H NMR (400 MHz,
CD3Cl): d 7.45e7.21 (m, 5H), 4.50 (s, 2H), 3.63 (t, J¼6.8,
2H), 3.47 (t, J¼6.8, 2H), 2.10 (br s, 1H), 1.62 (p, J¼6.8, 2H),
1.56 (p, J¼7.2, 2H), 1.44e1.22 (m, 16H); 13C NMR
(100.6 MHz, CD3Cl): d 138.6, 128.3, 127.6, 127.4, 126.9,
72.8, 70.5, 63.0, 32.7, 29.7, 29.5, 29.4 (br), 29.3 26.1, 25.7;
HRMS (FAB) m/z calcd for C19H33O2 (MþH)þ 293.2481,
found 293.2482.
4.12. 12-Iodododecanol, benzyl ether (17)13
To 20 mL of CH2Cl2 was added triphenylphosphine (3.61 g,
13.8 mmol), imidazole (0.94 g, 13.8 mmol) and iodine (3.49 g,
13.8 mmol). To this prepared reaction mixturewas added a solu-
tionof 3(3.35 g, 11.5 mmol) in 36 mL of CH2Cl2, and the result-
ing solution was stirred for 1 h. The solvent was removed in
vacuo, and the crude product was purified by column chroma-
tography (SiO2, 5% EtOAc/hexanes) to afford 17 as a colorless
oil (3.8 g, 86%). 1H NMR (400 MHz, CD3Cl): d 7.36e7.28 (m,
5H), 4.52 (s, 2H), 3.48 (t, J¼6.8, 2H), 3.19 (t, J¼6.8, 2H), 1.82
4.10. Lactone 5b
(p, J¼7.2, 2H), 1.63 (p, J¼6.8, 2H), 1.39e1.28 (m, 16H); 13
C
NMR (100.6 MHz, CD3Cl): d 138.6, 128.3, 127.5, 127.4,
72.8, 70.4, 33.5, 30.4, 29.7, 29.6, 29.5, 29.4 (br), 29.3, 28.5,
26.1, 7.23; HRMS (EI) m/z calcd for C19H32OI (MþH)þ
403.1498, found 403.1482.
The trans isomer of lactone 15 (4.0 mg, 3.93 mmol) was de-
protected following the foregoing procedure and the final
product was obtained as a foaming solid (1.5 mg, 58%).
[a]D þ26.7 (c 0.075, CH2Cl2); IR: 3405, 2926, 2854, 1736,
1716 cmꢁ1
;
1H NMR (400 MHz, C6D6): d 6.43e6.25 (m,
4.13. Wittig salt 18
2H), 5.72e5.61 (m, 3H), 5.23 (d, J¼16.4 Hz, 1H), 5.09 (d,
J¼9.6 Hz, 1H), 4.99 (d, J¼10.4 Hz, 1H), 4.98 (s, 2H), 4.81
(dd, J¼10.4, 9.2 Hz, 1H), 4.55e4.35 (m, 2H), 4.23 (q,
J¼6.4 Hz, 1H), 4.04 (d, J¼10.4 Hz, 1H), 3.94 (br s, 1H),
3.60 (td, J¼9.6, 2.0 Hz, 1H), 3.49 (br s, 1H), 3.31 (t,
J¼9.2 Hz, 1H), 2.92 (d, J¼14.8 Hz, 1H), 2.85 (br s, 1H),
2.45e2.23 (m, 6H), 2.18e2.08 (m, 6H), 2.07e1.96 (m, 2H),
1.87e1.79 (m, 1H), 1.57e1.50 (m, 4H), 1.49e1.10 (m,
16H), 0.93 (d, J¼6.8 Hz, 3H), 0.77 (d, J¼7.2 Hz, 3H); 13C
NMR (125 MHz, C6D6): d 175.5, 142.9, 136.5, 136.4, 130.9,
130.7, 129.8, 117.2, 115.4, 98.9, 80.6, 80.0, 78.3, 73.9, 72.7,
Triphenylphosphine (0.507 g, 1.9 mmol) was dissolved in
iPr2NEt (0.35 mL, 2 mmol) and 3 mL of acetonitrile, and iodide
17 (0.26 g, 0.67 mmol) was added to this solution in a screw-cap
vial. The vial was sealed and heated to 80e90 ꢀC overnight. The
solvent was removed in vacuo, and the crude product was puri-
fied by column chromatography (SiO2, 5% MeOH/EtOAc) to
1
afford 18 as a yellow oil (0.34 g, 81%). H NMR (400 MHz,
CD3Cl): d 7.8e7.67 (m, 15H), 7.32e7.23 (m, 5H), 4.47 (s,
2H), 3.62 (br s, 2H), 3.44 (t, J¼6.8, 2H), 1.62e1.56 (m, 6H),
1.36e1.17 (m, 14H).

C.E. Wagner et al. / Tetrahedron 64 (2008) 124e136
133
4.14. Intermediate 20
4.16. Intermediate 22
To a solution of Wittig salt 18 (1.85 g, 2.85 mmol) in 16 mL
of THF cooled to ꢁ78 ꢀC was added a 1.6 M solution of MeLi
(1.8 mL, 2.88 mmol), whereupon the solution changed from col-
orless to bright orange. After stirring at ꢁ78 ꢀC for 30 min, a so-
lution of aldehyde 1919 (1.2 g, 2.4 mmol) in 18 mL of THF was
added whereupon the solution became colorless. The solution
was allowed to warm to rt, and was diluted with 100 mL of di-
ethyl ether and treated with 60 mL of satd NH4Cl. The organic
layer was separated and washed with 100 mL of satd NaCl, dried
over Na2SO4 and concentrated in vacuo to give a crude product
that was purified by column chromatography (SiO2, 10% EtOAc
to 30% EtOAc/hexanes) to afford 20 as a colorless oil (0.81 g,
To 10 mL of THF in a 100-mL round-bottomed flask was
added compound 21 (0.32 g, 0.47 mmol) and 5 mol % Pt on car-
bon (0.30 g). The flask was purged under high vacuum and back-
filled with hydrogen gas from a balloon four times. The
suspension was allowed to stir under hydrogen at atmospheric
pressure and monitored by TLC. After 4 h, the reaction mixture
was filtered, through a medium glass filter. The solvent was re-
moved in vacuo, and the crude product was purified by column
chromatography (SiO2, 15% EtOAc to 30% EtOAc/hexanes) to
afford 22 as a colorless oil (0.18 g, 63%). 1H NMR (400 MHz,
CD3Cl): d 5.05e5.01 (m, 1H), 4.38e4.33 (m, 1H), 3.98e3.96
(m, 1H), 3.63 (t, J¼6.8, 2H), 2.76 (dd, J¼15.2, 3.6, 1H), 2.38
(dd, J¼15.2, 10.4, 1H), 2.0 (s, 3H), 2.98e2.93 (m, 1H), 2.89e
83 (m, 1H), 1.75e1.70 (m, 2H), 1.68e1.50 (m, 6H), 1.40e
1.21 (m, 26H), 1.18 (s, 3H), 1.09e1.05 (m, 18H), 0.95 (t,
J¼8.0, 9H), 0.55 (q, J¼8.0, 6H); 13C NMR (100.6 MHz,
CD3Cl): d 170.9, 170.8, 96.7, 70.4, 67.2, 65.5, 63.0, 61.3,
47.5, 45.0, 42.6, 38.2, 35.8, 34.2, 32.8, 32.1, 31.6, 30.2, 29.9,
29.8, 29.7 (br), 29.6, 29.4, 25.9, 25.8, 25.7, 22.6, 21.4, 17.7,
14.1, 11.9, 7.2, 6.8; HRMS (FAB) m/z calcd for C42H82Si2O8Li
(MþLi)þ 777.5708, found 777.5688.
1
44%). H NMR (400 MHz, CD3Cl): d 7.34e7.26 (m, 5H),
5.45 (ddd, J¼10.8, 3.6, 1H), 5.36 (t, J¼10.8, 1H), 4.99e4.96
(m, 1H), 4.88 (t, J¼10, 1H), 4.50 (s, 2H), 4.39e4.30 (m, 1H),
3.46 (t, J¼6.8, 2H), 2.40 (dd, J¼15.6, 4.8, 1H), 2.28 (dd,
J¼15.6, 9.2, 1H), 2.21e2.10 (m, 2H), 2.01 (s, 3H), 1.95e1.70
(m, 3H), 1.68e1.50 (m, 6H), 1.44 (s, 9H), 1.39e1.20 (m,
17H), 1.19 (s, 3H), 0.98 (t, J¼8.0, 9H), 0.55(q, J¼8.0, 6H);
13C NMR (100.6 MHz, CD3Cl): d 171.1, 170.1, 138.6, 131.8,
130.5, 128.3, 127.5, 127.4, 96.9, 80.3, 72.8, 70.5, 70.2, 67.3,
62.1, 61.4, 47.1, 45.1, 41.8, 38.3, 33.9, 31.9, 31.6, 29.9, 29.8,
29.7, 29.6, 29.5, 28.1, 27.9, 26.2, 22.6, 21.4, 14.1, 7.3, 6.9;
HRMS (EI) m/z calcd for C44H74SiO8Li (MþLi)þ 765.5310,
found 765.5313.
4.17. Intermediate 23
ToasolutionofDMSO (0.90 mL, 12 mmol)in10.0 mLofdry
CH2Cl2 cooled to ꢁ78 ꢀC was added oxalyl chloride (0.50 mL,
5.7 mmol). After stirring the mixture for 15 min at ꢁ78 ꢀC, a so-
lution of compound 22 (0.28 g, 0.36 mmol) in 10.0 mL of dry
CH2Cl2 was slowly added. The mixture was stirred for an addi-
tional 45 minat ꢁ78 ꢀC and Et3N (2.1 mL, 15 mmol) was added.
The resulting mixture was allowed to warm to rt and poured into
150 mL of diethyl ether, and then washed with 100 mL of satd
NaHCO3. The organic layer was then washed with 100 mL of
1 M KHSO4 followed by 100 mL of satd NaHCO3. The organic
layer was dried over Na2SO4, concentrated invacuo, and purified
by column chromatography (SiO2, 15% EtOAc/hexanes) to af-
4.15. Intermediate 21
To the tert-butyl ester 20 (0.52 g, 0.68 mmol) in 7.0 mL of
CH2Cl2 was added 2,6-lutidine (0.82 mL, 7.1 mmol) and
TMS-triflate (0.40 mL, 2.2 mmol). The solution was allowed
to stir overnight after which time the solution was added to
50 mLof diethylether, washed with 20 mL of1 M KHSO4, dried
over Na2SO4 and concentrated in vacuo. To the crude carboxylic
acid dissolved in 2.0 mL of CH2Cl2 was added triethylamine
(0.2 mL, 1.43 mmol) followed by triisopropylsilylchloride
(0.2 mL, 0.93 mmol). The solution was stirred for 1 h after
which time it was poured into 40 mL of diethyl ether and washed
with 20 mL of 1 M KHSO4, followed by 20 mL of a satd
NaHCO3 solution. The organic layer was dried over Na2SO4
and concentrated in vacuo to give a crude product that was puri-
fied by column chromatography (SiO2, 10% EtOAc/hexanes) to
afford 21 as a colorless oil (0.51 g, 87%). 1H NMR (400 MHz,
CD3Cl): d 7.33e7.24 (m, 5H), 5.45 (ddd, J¼10.8, 3.6, 1H),
5.36 (t, J¼10.8, 1H), 4.99e4.95 (m, 1H), 4.88 (t, J¼9.2, 1H),
4.50 (s, 2H), 4.42e4.38 (m, 1H), 3.46 (t, J¼6.8, 2H), 2.79 (dd,
J¼15.6, 4.0, 1H), 2.42 (dd, J¼15.6, 10.4, 1H), 2.10e1.91 (m,
7H), 1.74 (d, J¼14.4, 1H), 1.62 (p, J¼6.4, 2H), 1.52e1.49 (m,
3H), 1.40e1.26 (m, 21H), 1.20 (s, 3H), 1.08e1.05 (m, 18H),
0.95(t, J¼8.0, 9H), 0.55(q, J¼8.0, 6H); 13C NMR (100.6 MHz,
CD3Cl): d 171.0, 170.6, 138.7, 131.3, 130.6, 128.3, 127.5,
127.4, 96.9, 72.8, 70.5, 70.2, 67.1, 62.2, 61.4, 47.0, 45.1, 42.4,
38.1, 34.2, 31.9, 29.9, 29.8, 29.7, 29.6 (br), 29.5, 27.9, 26.1,
21.3, 17.7, 11.9 7.2, 6.9; HRMS (FAB) m/z calcd for
C49H86Si2O8Li (MþLi)þ 865.6021, found 865.6010.
1
ford 23 as a colorless oil (0.19 g, 68%). H NMR (400 MHz,
CD3Cl): d 9.74e9.72 (m, 1H), 5.04e5.02 (m, 1H), 4.34e4.29
(m, 1H), 3.93e3.89 (m, 1H), 2.75 (dd, J¼15.2, 3.6, 1H), 2.38
(m, 3H), 2.02 (m, 4H), 1.85 (d, J¼14.8, 1H), 1.73 (d, J¼14.0,
1H), 1.60 (m, 6H), 1.23 (m, 24H), 1.19 (s, 3H), 1.03 (m, 18H),
0.92 (t, J¼8.0, 9H), 0.52 (q, J¼8.0, 6H); 13C NMR
(100.6 MHz, CD3Cl): d 202.8, 170.8, 170.7, 96.7, 70.4, 67.1,
65.5, 61.3, 60.32, 47.4, 45.0, 43.9, 42.6, 38.1, 35.7, 34.2, 32.0,
31.5, 29.9, 29.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.1, 25.7, 22.6,
22.0, 21.4, 17.7, 17.3, 11.9, 7.2, 6.8; HRMS (FAB) m/z calcd
for C42H80Si2O8Li (MþLi)þ 775.5551, found 775.5552.
4.18. Intermediate 24
To a cooled (ꢁ78 ꢀC) solution of Wittig salt 12 (250 mg,
0.17 mmol) in THF (2 mL) was addeddropwise a 1.4 M solution
ofMeLi$LiBrin ether(126 mL). The colorofthesolutionturned
orange-red immediately. After stirring for 30 min, a solution of
aldehyde 23 (185 mg, 0.24 mmol) in THF (1 mL) was added

134
C.E. Wagner et al. / Tetrahedron 64 (2008) 124e136
dropwise. The flask containing the aldehyde was rinsed with an
additional 1 mL of THF, which was added to the reaction mix-
ture. The color of the reaction faded immediately to pale yellow
upon the addition of the aldehyde. The reaction mixture was
stirred for 1 h at ꢁ78 ꢀC and then warmed slowly to rt. The re-
action was quenched with satd NH4Cl solution and the resulting
mixture extracted with EtOAc. The combined organic extracts
werewashed with brine, dried overMgSO4, filtered, and concen-
trated. The residue was purified by column chromatography
(20% EtOAc/hexanes) to give the desired product (210 mg,
85%) as a colorless oil. IR: 3424, 2928, 2855, 1737,
1713 cmꢁ1; 1H NMR (400 MHz, C6D6): d 6.47e6.34 (m, 2H),
5.94e5.83 (m, 1H), 5.64e5.50 (m, 2H), 5.30e5.00 (m, 5H),
4.72e4.62 (m, 1H), 4.49 (q, J¼6.4 Hz, 1H), 4.38e4.28 (m,
1H), 4.27e4.15 (m, 1H), 3.98 (br s, 1H), 3.92 (s, 1H), 3.64e
3.48 (m, 4H), 3.21 (s, 3H), 3.02 (dd, J¼15.6, 4.0 Hz, 1H), 2.75
(d, J¼12.8 Hz, 1H), 2.68 (dd, J¼13.2, 6.0 Hz, 1H), 2.62e2.52
(m, 2H), 2.43e2.33 (m, 1H), 2.37 (dd, J¼15.2, 3.6 Hz, 1H),
1.98 (s, 3H), 1.89e1.65 (m, 5H), 1.65e1.53 (m, 4H), 1.51e
1.22 (m, 28H), 1.20e1.01 (m, 88H), 0.89e0.77 (m, 18H),
0.75e0.65 (m, 6H), 0.29 (s, 3H), 0.23 (s, 3H), 0.19 (s, 6H);
13C NMR (125 MHz, C6D6): d 170.3, 169.5, 144.1, 137.4,
136.7, 130.8 (trans), 130.2 (trans), 130.1 (cis), 130.0, 129.6
(cis), 116.3, 114.8, 101.2, 96.8, 81.0, 80.4, 77.4, 77.1, 72.1,
71.3, 70.9, 70.4, 67.1, 66.9, 66.8 (trans), 65.2, 61.5, 47.3, 46.7,
46.6, 45.3, 42.5, 40.1, 39.9, 38.7, 38.6 (trans), 38.1, 36.1, 34.3,
32.9, 32.8, 32.6, 32.3 (trans), 31.9, 30.1, 30.0, 29.9, 29.8, 29.7,
29.6, 29.4, 27.5, 27.4, 26.5, 25.9, 25.8, 20.9, 18.2, 18.0, 17.8,
15.8, 12.0, 10.4, 7.3, 7.2, 7.1, 7.0, 6.9, 5.2, 5.0, ꢁ4.3, ꢁ4.4.
ꢁ4.8, ꢁ4.9; LRMS (FAB, low resolution) calcd for C99H194O15-
Si7Li (MþLiþ) 1828, found 1827. Anal. Calcd for
C99H194O15Si7: C 65.29, H 10.74. Found: C 65.44, H 10.79.
70.5, 67.2, 67.1, 65.2, 61.0, 47.4, 46.6, 46.2, 45.2, 40.1, 39.4,
38.8, 38.7, 38.1, 36.2, 33.9, 32.8, 32.0, 30.2, 30.1, 30.0,
29.9, 29.8, 29.7, 29.6, 29.2, 27.6, 27.5, 26.5, 25.9, 25.8, 20.9,
18.2, 18.1, 13.5, 10.4, 7.3, 7.2, 6.9, 5.9, ꢁ4.3, ꢁ4.4. ꢁ4.7,
ꢁ4.9; LRMS (FAB, low resolution) calcd for C78H146O15Si4
(MꢁHþ) 1435.3, found 1435.0. Anal. Calcd for C78H146O15-
Si4: C 65.22, H 10.25. Found: C 65.41, H 10.44.
To a flask containing the aforementioned carboxylic acid
(55 mg, 38.3 mmol) was added a 0.4 M solution of N,N-diiso-
propylethylamine in toluene (2.9 mL, 1.15 mmol) followed
by 0.4 M 2,4,6-trichlorobenzoyl chloride in toluene (1.9 mL,
0.77 mmol). The reaction mixture was stirred for 3 h at rt, then
diluted with toluene (16 mL), added over a 24 h period (via
syringe pump) to a solution of DMAP (244 mg, 1.91 mmol) in
toluene (50 mL), and heated in an oil bath set at 90 ꢀC. A white
precipitate was observed. Upon completion of the addition, the
flask in which the mixed anhydride formed was rinsed with
toluene (3 mL) and this rinse was added to the DMAP solution
over 12 h. After cooling to rt, the mixture was washed with
satd NaHCO3 (50 mL)and then with brine (50 mL). The aqueous
phases were back-extracted with EtOAc and the combined ex-
tracts were dried over MgSO4, filtered, and concentrated. The
residue was purified by column chromatography (20% EtOAc/
hexanes) to give the desired product (30 mg, 72%) as a colorless
1
oil. IR: 2928, 2854, 1736 cmꢁ1; H NMR (400 MHz, C6D6):
d 6.40e6.25 (m, 2H), 5.81 (dd, J¼14.4, 6.4 Hz, 1H), 5.57e
5.40 (m, 2H), 5.20e4.93 (m, 5H), 4.79 (t, J¼9.6 Hz, 1H),
4.63e4.53 (m, 1H), 4.39 (q, J¼6.4 Hz, 1H), 4.34e4.22 (m,
2H), 4.00e3.87 (m, 2H), 3.43e3.37 (m, 1H), 3.32 (d,
J¼10.4 Hz, 1H), 3.27e3.25 (m, 1H), 3.14 (s, 3H), 3.00e2.91
(m, 1H), 2.82 (d, J¼13.6 Hz, 1H), 2.59e2.45 (m, 3H), 2.37e
2.21 (m, 3H), 2.12e1.96 (m, 10H), 1.82e1.51 (m, 9H), 1.50e
1.15 (m, 24H), 1.12e0.93 (m, 46H), 0.80e0.72 (m, 6H),
0.65e0.57 (m, 6H), 0.26 (s, 3H), 0.15 (s, 3H), 0.14 (s, 3H),
0.11 (s, 3H); 13C NMR (125 MHz, C6D6): d 171.5, 169.6,
143.3, 137.5, 136.7, 130.6 (trans), 130.5 (trans), 130.0, 129.6
(cis), 116.3, 115.3, 101.2, 96.9, 80.8, 79.0, 77.9, 73.4, 72.7,
70.8, 70.7, 70.4, 67.5, 67.1, 66.6 (trans), 65.0, 61.2, 47.3, 46.7,
46.5 (trans), 46.3, 45.4, 41.5, 39.0, 38.9, 38.0, 37.3, 35.8, 34.5,
33.1, 32.4, 32.3, 31.9, 30.2, 30.1, 30.0, 29.9, 29.8, 29.7, 29.6,
29.4, 29.2, 29.1, 28.6, 27.7, 27.3, 27.0, 26.1, 25.9, 25.8, 20.9,
18.1, 18.0, 13.7, 10.3, 7.2, 7.1, 6.9, 5.8, ꢁ4.4, ꢁ4.5, ꢁ4.8,
ꢁ4.9; LRMS (FAB, low resolution) calcd for C78H144O14Si4Li
(MþLiþ) 1425, found 1425. Anal. Calcd for C78H144O14Si4: C
66.05, H 10.23. Found: C 65.71, H 10.43.
4.19. Lactone 25
To a cooled (0 ꢀC) solution of the Wittig product 24 (49 mg,
26.9 mmol) in THF (2 mL) was added a 1.0 M solution of TBAF
in THF (83 mL, 83.4 mmol) dropwise. The mixture was stirred
for 2 h at 0 ꢀC, quenched with satd NH4Cl solution, and ex-
tracted with EtOAc. The combined extracts were washed with
brine, dried over MgSO4, filtered, and concentrated. The residue
was purified by column chromatography (50% EtOAc/hexanes)
to givethe ring F desilylated material (23 mg, 60%) as a foaming
1
solid. IR: 2952, 2876, 1737, 1722 cmꢁ1; H NMR (400 MHz,
C6D6): d 6.48e6.38 (m, 2H), 5.90 (dd, J¼14.0, 6.0 Hz, 1H),
5.66e5.57 (m, 2H), 5.30e5.01 (m, 5H), 4.69 (m, 1H), 4.50 (q,
J¼6.8 Hz, 1H), 4.40e4.27 (m, 2H), 4.03 (m, 1H), 3.98 (s,
1H). 3.48e3.39 (m, 1H), 3.42 (d, J¼10.8 Hz, 1H), 3.31
(t, J¼8.8 Hz, 1H), 3.23 (s, 3H), 3.13 (t, J¼10.0 Hz, 1H), 2.83
(d, J¼12.0 Hz, 1H), 2.74e2.56 (m, 3H), 2.46e2.36 (m, 3H),
2.25e2.05 (m, 5H), 2.04 (s, 3H), 1.98e1.61 (m, 11H), 1.59e
1.35 (m, 22H), 1.32 (dd, J¼14.8, 3.6 Hz, 1H), 1.25e1.05
(m, 50H), 0.94e0.84 (m, 6H), 0.76 (q, J¼8.0 Hz, 6H), 0.33 (s,
3H), 0.25 (s, 3H), 0.23 (s, 3H), 0.22 (s, 3H); 13C NMR
(125 MHz, C6D6): d 174.1, 170.0, 143.8, 137.5, 136.8, 130.8
(trans), 130.4 (trans), 130.2 (cis), 130.1, 129.7 (cis), 116.5,
115.1, 101.4, 96.9, 78.9, 78.5, 78.4, 75.6, 72.6, 71.0, 70.9,
4.20. Lactones 6
Lactone 25 (26 mg, 18.3 mmol) was placed in a polypropyl-
ene vessel, THF (0.5 mL) was added followed by acetonitrile
(0.5 mL). The mixture was cooled to ꢁ18 ꢀC, and a solution
of HF (1.3 mL, 5.0 M in acetonitrile) was added dropwise
over 1 h. The reaction mixture was then stirred overnight while
the temperature was maintained between ꢁ15 ꢀC and ꢁ19 ꢀC.
The reaction was quenched at low temperature by the addition
of triethylamine (1.0 mL), the resulting mixture allowed to
warm to rt, transferred to a separation funnel with satd NaHCO3

C.E. Wagner et al. / Tetrahedron 64 (2008) 124e136
135
(20 mL), and extracted with ethyl acetate. The organic phase
4.23. Wittig salt 28
was washed with brine, dried over Na2SO4, filtered, and concen-
trated to leave an oil. The residue was purified by column chro-
matography (75% EtOAc/hexanes) and the product was
obtained as a white solid (14 mg, 82%). IR: 3421, 2925,
In a 20 mL screw-cap vial, iodide 27 (0.28 g, 0.64 mmol) was
added to a solution of triphenylphosphine (0.51 g, 1.9 mmol) and
iPr2NEt (0.32 mL, 1.8 mmol) in 3 mL of acetonitrile. The vial
was flushed with nitrogen, sealed, and heated to 90 ꢀC overnight.
Thesolventwas removed invacuo, andthe crudeproduct waspu-
rified by column chromatography (SiO2, 5% MeOH/EtOAc) to
1
2854, 1737 cmꢁ1; H NMR (400 MHz, C6D6): d 6.49e6.29
(m, 2H), 5.73e5.68 (m, 1H), 5.66e5.49 (m, 2H), 5.41 (br s,
1H), 5.26 (d, J¼16.4 Hz, 1H), 5.20e5.08 (m, 3H), 4.74 (t, J¼
10.8 Hz, 1H), 4.61e4.57 (m, 1H), 4.48 (br s, 1H), 4.25
(q, J¼6.4 Hz, 1H), 4.18e4.11 (m, 1H), 3.96 (br s, 1H), 3.89
(d, J¼10.0 Hz, 1H), 3.64 (t, J¼9.2 Hz, 1H), 3.50e3.35 (m,
2H), 3.04 (d, J¼15.2 Hz, 1H), 2.44e2.05 (m, 6H), 1.98 (s,
3H), 1.95e1.75 (m, 7H), 1.72e1.25 (m, 35H), 1.12 (dd,
J¼14.8, 3.6 Hz, 1H), 1.10e0.95 (m, 7H), 0.82 (d, J¼7.2 Hz,
3H), 0.73 (d, J¼6.4 Hz, 3H); 13C NMR (125 MHz, C6D6):
d 171.4, 169.6, 143.3, 136.8, 136.7, 131.3 (trans), 130.7 (cis),
130.5, 129.8 (trans), 129.6 (cis), 116.9, 115.0, 99.3, 98.2, 80.8,
79.9, 77.7, 72.6, 72.4, 70.6, 70.5, 69.4, 67.1, 66.2, 66.0, 63.7,
45.3, 43.7, 43.3, 40.5, 39.6, 37.1, 36.7, 36.6, 36.2 (trans), 35.9,
33.7, 33.3, 33.0 (trans), 32.3 (trans), 32.1, 29.9, 29.7, 29.6,
29.5, 29.4, 29.3, 29.2, 29.1, 28.6 (trans), 27.6, 27.4, 25.6, 25.5,
20.8, 11.8, 11.7 (trans), 10.4 (trans), 10.3; HRMS (FAB) calcd
for C53H86O14Li (MþLiþ) 953.6175, found 953.6178. Anal.
Calcd for C53H86O14: C 67.20, H 9.15. Found: C 67.40, H 9.52.
1
afford 28 as a yellow oil (0.36 g, 80%). H NMR (400 MHz,
CD3Cl): d 7.84e7.78 (m, 9H), 7.74e7.69 (m, 6H), 3.65e3.62
(m, 4H), 1.63e1.60 (m, 4H), 1.51e1.46 (m, 2H), 1.35e1.20
(m, 10H), 1.11e1.03 (m, 21H); 13C NMR (100.6 MHz,
CD3Cl): d 135.1, 133.7, 133.6, 130.6, 130.5, 118.7, 117.8,
63.5, 33.0, 30.5, 30.4, 29.5, 29.3, 29.1, 25.7, 22.6, 18.0, 11.9.
4.24. Intermediate 30
Wittig salt (28) (0.1258 g, 0.177 mmol) was dissolved in
a 10% HMPA solution in THF (1.7 mL), cooled to ꢁ78 ꢀC,
and LiHMDS (1.0 M, 177 mL, 0.177 mmol) was added, and
the reaction was stirred for 30 min. To this stirred reaction was
added aldehyde 29 (99 mg, 0.088 mmol) in THF (1.45 mL),
and the reaction was allowed to warm to rt and stir overnight.
The crude reaction mixture was poured into diethyl ether
(10 mL) and washed with saturated ammonium chloride
(10 mL), followed by water (10 mL) and brine (10 mL). The or-
ganic layer was dried over sodium sulfate, concentrated in va-
cuo, and purified by flash chromatography (25 mL SiO2, 30%
EtOAc in hexanes) to give the product as the cis-alkene isomer
4.21. 1,10-Decane diol, mono-TIPS ether (26)
To a solution of 1,10-decane diol (2.6 g, 15 mmol) in 25 mL
of DMF was added imidazole (0.68 g, 10 mmol) followed by
TIPSCl (2.14 mL, 10 mmol), and the solution was stirred for
2 h at rt. The solution was then added to 200 mL of diethyl ether,
washed with 60 mL of aqueous 1 M KHSO4 followed by 60 mL
of satd K2CO3 and washed again with 60 mL of aqueous 1 M
KHSO4. The organics were dried over sodium sulfate, concen-
trated and purified by flash chromatography (20% EtOAc/
hexanes) to give the product as a colorless oil (1.58 g, 48%).
1H NMR (400 MHz, CD3Cl): d 3.67e3.61 (m, 4H), 1.57e
1.51 (m, 5H), 1.27e1.19 (m, 12H), 1.10 (d, J¼6.8 Hz, 21H);
13C NMR (100.6 MHz, CD3Cl): d 63.4, 63.0, 32.9, 32.7, 29.6,
29.5, 29.4, 29.3, 25.8, 25.7 17.9, 11.9.
1
(52 mg, 41%). H NMR (400 MHz, CD3Cl): d 5.42e5.40 (m,
2H), 5.21e5.13 (m, 2H), 5.03e5.00 (m, 1H), 4.97 (s, 1H),
4.82 (s, 1H), 4.44e4.08 (m, 3H), 3.94e3.89 (m, 1H), 3.66 (t,
J¼6.8 Hz, 1H), 3.45e3.39 (m, 1H), 3.29 (s, 3H), 2.91e2.81
(m, 2H), 2.75e2.62 (m, 2H), 2.41e2.31 (m, 2H), 2.26 (d,
J¼6.8 Hz, 2H), 2.14e2.08 (m, 2H), 2.04e2.02 (m, 4H), 2.01
(s, 3H), 1.96e1.94 (m, 1H), 1.90 (s, 3H), 1.84e1.82 (m, 1H),
1.73e1.70 (m, 1H), 1.59e1.40 (m, 9H), 1.29e1.15 (m, 25H),
1.19 (s, 3H), 1.09e1.00 (m, 33H), 0.94 (t, J¼8 Hz, 9H),
0.85e0.80 (m, 12H), 0.55e0.45 (m, 6H), 0.01e0.00 (m, 6H);
13C NMR (100.6 MHz, CD3Cl): d 209.8, 171.0, 170.5, 169.2,
146.9, 131.6, 130.3, 113.6, 98.1, 96.8, 77.19, 74.1, 73.7, 70.4,
66.6, 66.1, 64.4, 64.3, 63.4, 62.4, 61.0, 55.5, 49.9, 47.6, 47.6,
45.1, 43.6, 42.2, 41.9, 38.9, 38.4, 37.8, 36.9, 34.8, 33.9, 33.0,
31.9, 29.7, 29.6, 29.5, 29.4, 28.1, 25.8, 21.5, 20.7, 18.0, 17.8,
13.4, 12.0, 11.9, 11.8, 7.3, 6.9, ꢁ4.9, ꢁ5.0.
4.22. 10-Iododecanol, TIPS ether (27)
To a solution of triphenylphosphine (2.4 g, 9.2 mmol) in
50 mL of DCM was added imidazole (0.63 g, 9.2 mmol), iodine
(2.34 g, 9.2 mmol), and the ether 26 (2.6 g, 7.7 mmol). The re-
action was stirred for 3 h and then poured into 200 mL of ether
and washed with 30 mL of aqueous 1 M KHSO4, 30 mL of satd
NaHCO3, and 30 mL of brine. The organics were dried over so-
dium sulfate, concentrated, and the crude residue was purified
by flash chromatography (5% EtOAc/hexanes) to give 27
(2.84 g, 82%). 1H NMR (300 MHz, CD3Cl): d 3.66 (t,
J¼6.6 Hz, 2H), 3.18 (t, J¼7.2 Hz, 2H), 1.82 (p, J¼7.2 Hz,
2H), 1.58e1.51 (m, 2H), 1.37e1.28 (m, 12H) 1.11e1.05 (m,
21H); 13C NMR (75.5 MHz, CD3Cl): d 63.7, 33.8, 33.2, 30.7,
29.8, 29.7, 29.6, 28.8, 26.0, 18.3, 12.2, 7.6.
4.25. Intermediate 31
To a solution of TIPS ester (30) (19.5 mg, 0.014 mmol) in
THF (2 mL) cooled to 0 ꢀC was added a solution of TBAF in
THF (1 M, 28 mL, 0.028 mmol), and the reaction was stirred
for 2.5 h. The reaction solution was diluted in diethyl ether
(10 mL) and washed with an aqueous solution of 10% KHSO4
followed by brine. The organic layer was dried over sodium sul-
fate, concentrated and purified by flash column chromatography
(SiO2, 1:1 EtOAc/hexanes) to give alcohol 31 (10.5 mg, 69%).
1H NMR (400 MHz, CD3Cl): d 9.1 (br s, 1H), 5.45e5.35 (m,

136
C.E. Wagner et al. / Tetrahedron 64 (2008) 124e136
2H), 5.22e5.20 (m, 2H), 5.03e5.00 (m, 1H), 4.97e4.95 (m,
1H), 4.82e4.79 (m, 1H), 4.27e4.20 (m, 1H), 4.14e4.10
(m, 1H), 4.08e4.04 (m, 1H), 3.94e3.91 (m, 1H), 3.67e3.60
(m, 2H), 3.46e3.40 (m, 2H), 3.29 (s, 3H), 2.92e2.80 (m, 2H),
2.71e2.63 (m, 1H), 2.50e2.32 (m, 2H), 2.30e2.15 (m, 1H),
2.14e2.09 (m, 2H), 2.08e2.05 (m, 2H), 2.04 (s, 3H), 2.91 (s,
3H), 1.81e1.79 (m, 2H), 1.60e1.50 (m, 6H), 1.49e1.35 (m,
6H), 1.30e1.18 (m, 20H), 1.07e1.02 (m, 8H), 0.91 (t,
J¼8.0 Hz, 9H), 0.85 (s, 9H), 0.57 (q, J¼7.6 Hz, 6H), 0.02e
0.00 (m, 6H); 13C NMR (100.6 MHz, CD3Cl): d 209.87,
170.9, 169.4, 146.8, 131.9, 130.3, 128.3, 98.1, 97.4, 77.2,
74.0, 73.7, 70.6, 66.2, 66.0, 64.4, 62.9, 62.2, 61.1, 55.4, 53.4,
47.5, 44.9, 43.5, 40.2, 38.8, 38.4, 37.2, 36.9, 34.8, 34.0, 32.5,
31.9, 29.5, 29.4, 29.3, 29.2, 27.8, 25.8, 25.6, 21.4, 20.7, 19.3,
17.9, 13.3, 11.8, 7.2, 6.6.
4.00 (m, 4H), 3.91e3.85 (m, 1H), 3.49e3.40 (m, 2H), 3.32 (s,
3H), 2.95e2.90 (m, 2H), 2.71e2.65 (m, 1H), 2.60e2.55 (m,
1H), 2.45e2.40 (m, 1H), 2.36e2.30 (m, 1H), 2.22e2.17 (m,
2H) 2.11e2.06 (m, 1H), 2.05 (s, 3H), 1.95e1.91 (m, 1H),
1.90 (s, 3H), 1.65e1.50 (m, 16H), 1.16 (s, 3H), 1.25e1.10 (m,
26H), 1.08 (d, J¼6.8 Hz, 3H), 0.87e0.80 (m, 3H); LRMS (elec-
trospray) m/e calcd for C47H74NaO14 (MþNa)þ 885.5 (100%),
886.5 (50.8%), 887.5 (12.6%), found 885.5 (100%), 886.5
(54%), 887.5 (17%).
Acknowledgements
This research was supported by a grant from the University
of California Cancer Research Coordinating Committee.
4.26. Lactone 32
Supplementary data
To a flask containing alcohol 31 (25 mg, 0.023 mmol) was
added triisopropylethylamine (1.7 mL, 0.4 M in toluene) fol-
lowed by 2,4,6-trichlorobenzoyl chloride (1.13 mL, 0.4 M in tol-
uene). The mixture was stirred for 3 h at rt. The mixture was
diluted with toluene (13.5 mL) and slowly added (over 24 h) to
a solution of DMAP (137 mg, 1.13 mmol) in toluene (24 mL).
After cooling to rt, the mixture was washed with satd NaHCO3
(50 mL) and then with brine (50 mL). The aqueous phases
were back-extracted with EtOAc and the combined organic
phases were dried over Na2SO4, filtered, and concentrated.
The residue was purified by column chromatography (20%
EtOAc/hexanes) to give the desired lactone (4.5 mg, 18%) as
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2007.10.065.
References and notes
1. Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R.; Schmidt,
J. M.; Hooper, J. N. A. J. Org. Chem. 1993, 58, 1302.
2. (a) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R.
J. Chem. Soc., Chem. Commun. 1993, 1166; (b) Pettit, G. R.; Herald,
C. L.; Cichacz, Z. A.; Gao, F.; Boyd, M. R.; Christie, N. D.; Schmidt,
J. M. Nat. Prod. Lett. 1993, 3, 239; (c) Pettit, G. R.; Herald, C. L.;
Cichacz, Z. A.; Gao, F.; Schmidt, J. M.; Boyd, M. R.; Christie, N. D.;
Boettner, F. E. J. Chem. Soc., Chem. Commun. 1993, 1805; (d) Pettit,
G. R.; Cichacz, Z. A.; Herald, C. L.; Gao, F.; Boyd, M. R.; Schmidt,
J. M.; Hamel, E.; Bai, R. J. Chem. Soc., Chem. Commun. 1994, 1605.
3. Kobayashi, M.; Aoki, S.; Sakai, H.; Kawazon, K.; Kihara, N.; Sasaki, T.;
Kitagawa, I. Tetrahedron Lett. 1993, 34, 1993.
1
a colorless oil. H NMR (400 MHz, CD3Cl): d 5.51e5.50 (m,
1H), 5.39e5.32 (m, 1H), 5.25e5.20 (m, 1H), 5.02e5.00 (m,
1H), 4.91e4.89 (m, 1H), 4.78e4.75 (m, 1H), 4.25e4.20
(m, 1H), 4.19e4.00 (m, 4H), 3.95e3.91 (m, 1H), 3.49e3.45
(m, 1H), 3.28 (s, 3H), 3.07e2.90 (m, 2H), 2.72e2.62 (m, 3H),
2.53e2.50 (m, 1H), 2.35e2.30 (m, 1H), 2.10e2.03 (m, 2H),
2.02 (s, 3H), 1.95e1.90 (m, 1H), 1.88 (s, 3H), 1.81e1.75 (m,
1H), 1.70e1.65 (m, 1H), 1.62e1.50 (m, 10H), 1.35e1.20 (m,
20H), 1.19 (s, 3H), 1.11e1.07 (m, 7H), 0.93 (t, J¼8.0 Hz, 9H),
0.86 (s, 9H), 0.55 (q, J¼7.6 Hz, 6H), 0.02e0.00 (m, 6H).
4. Kobayashi, M.; Aoki, S.; Kitagawa, I. Tetrahedron Lett. 1994, 35, 1243.
5. Kobayashi, M.; Aoki, S.; Sakai, H.; Kawazon, K.; Kihara, N.; Sasaki, T.;
Kitagawa, I. Chem. Pharm. Bull. 1993, 41, 989.
6. Fusetanai, N.; Shinoda, K.; Matsunaga, S. J. Am. Chem. Soc. 1993, 115,
3977.
7. Pettit, G. R. J. Nat. Prod. 1996, 59, 812.
8. Bai, R.; Taylor, G. F.; Cichacz, Z. A.; Herald, C. L.; Kepler, J. A.; Pettit,
G. R.; Hamel, E. Biochemistry 1995, 34, 9714.
9. Smith, A. B.; Lin, Q. Biorg. Med. Chem. Lett. 1998, 8, 567.
10. Heathcock, C. H.; McLaughlin, M.; Medina, J.; Hubbs, J. L.; Wallace,
G. A.; Scott, R.; Claffey, M. M.; Hayes, C. J.; Ott, G. R. J. Am. Chem.
Soc. 2003, 125, 12844.
4.27. Lactone 7
The reaction took place in a polypropylene reaction vessel.
To a solution of lactone 32 (4.5 mg, 0.0041 mmol) in acetoni-
trile (100 mL) and THF (100 mL) cooled to ꢁ18 ꢀC (methanol/
ice bath) was added a solution of HF (290 mL of a 5 M solution
prepared from 10 mL of 48% aqueous HF and 40 mL of aceto-
nitrile) over a period of 1 h. The solution was stirred for 5 h be-
tween ꢁ15 ꢀC and ꢁ18 ꢀC. The reaction mixture was diluted
with a mixture of EtOAc/DCM (2:1, 50 mL) and the organic
phase was dried over Na2SO4, filtered, and concentrated. The re-
sulting crude oil was purified by running two subsequent col-
umns on silica using DCM/3% MeOH/DCM to afford
lactone 7 (2 mg, 56%) as an oil. 1H NMR (400 MHz, CD3Cl):
d 5.45e5.40 (m, 1H), 5.35e5.31 (m, 1H), 5.23e5.19 (m, 1H),
5.04e4.98 (m, 2H), 4.80 (s, 1H), 4.23e4.20 (m, 2H), 4.10e
~
11. (a) Paterson, I.; Chen, D. Y.-K.; Coster, M. J.; Acena, J. L.; Bach, J.;
Wallace, D. J. Org. Biomol. Chem. 2005, 3, 2431; (b) Paterson, I.; Acena,
J. L.; Bach, J.; Chen, D. Y.-K.; Coster, M. J. Chem. Commun. 2003, 462.
12. Inanaga, J.; Hirata, K.; Sa, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989.
13. Lange, G. L.; Gottardo, C. Synth. Commun. 1990, 20, 1473.
14. Hubbs, J. L.; Heathcock, C. H. J. Am. Chem. Soc. 2003, 125, 12836.
15. (a) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651; (b) Tidwell, T. T.
Org. React. 1990, 39, 297.
16. Lee, F. Y. F.; Borzilleri, R.; Fairchild, C. R.; Kim, S. H.; Long, B. H.;
Reventos-Suarez, C.; Vite, G. D.; Rose, W. C.; Kramer, R. A. Clin. Cancer
Res. 2001, 7, 1429.
17. Compound 21 in Ref. 10.
18. Prepared as described in Ref. 10, by the reaction of iodide 23 with triphe-
nylphosphine in acetonitrile.
19. Compound 29 in Ref. 14.