Synthesis of the non-classical acetogenin mucocin: A modular approach based on olefinic coupling reactions

Article abstract of DOI:10.1039/b504937g

A three component modular synthesis of the potent antitumor agent mucocin, based on olefinic coupling reactions, is described. A cross-metathesis on tetrahydropyran and tetrahydrofuran alkene components was used to assemble a stereochemically complex, non

Full text of DOI:10.1039/b504937g

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A R T I C L E
Synthesis of the non-classical acetogenin mucocin: a modular
approach based on olefinic coupling reactions†
Lei Zhu and David R. Mootoo*
Department of Chemistry, Hunter College, 695 Park Avenue, New York, NY 10021.
E-mail: dmootoo@hunter.cuny.edu; Fax: 212-772-5332; Tel: 212-772-4356
Received (Pittsburgh, PA, USA) 7th April 2005, Accepted 5th May 2005
First published as an Advance Article on the web 30th June 2005
A three component modular synthesis of the potent antitumor agent mucocin, based on olefinic coupling reactions, is
described. A cross-metathesis on tetrahydropyran and tetrahydrofuran alkene components was used to assemble a
stereochemically complex, non-adjacently-linked bicyclic ether. The latter was elaborated to a sulfone and partnered
with a butenolide aldehyde component in a Julia–Kocienski olefination to provide the mucocin framework, which
was converted to the natural product after hydrogenation and alcohol deprotection.
Introduction
The tetrahydrofuran (THF) containing acetogenins are known
for their potent antitumor properties.1 The mechanism of action
has been linked to inhibition of the NADH–ubiquinone oxi-
doreductase (complex I) of the mitochondrial electron transport
system, as well as the ubiquinone-linked NADH oxidase in
the plasma membrane of specific cancer cell lines.2 Growth
inhibition has also been observed for certain multi-drug resistant
tumors.3 Mucocin 1 4 belongs to the acetogenin subgroup that
contains two non-adjacent cyclic ether residues connected by a
1,4-dihydroxybutyl linker (Fig. 1). Mucocin is unique in that it
comprises a THF and a tetrahydropyran (THP) residue, unlike
other congeners which contain two THF rings. In spite of this
structural variation, mucocin displays activity that is similar
to other members of this subgroup. For example, 1 showed
selective inhibitory effects against A-549 (lung cancer) and
PACA-2 (pancreatic cancer), with potencies up to 10 000 times
that of adriamycin.4 That different non-adjacently-linked THF–
THP and THF–THF analogues like 1 and bullatanocin 5,
and adjacently-linked bis-THF acetogenins, show comparable
Fig. 1 Retrosynthesis for mucocin.
activity suggests that there is a relatively wide structure–activity
tolerance with respect to the constitution of the bis-ether
segment in these molecules.5
bullatanocin, and their syntheses are described in our earlier
report on the latter.6 The pseudosymmetry in the C15–C20
segment of mucocin suggested that 2 and 3 could emmanate
from a central precursor. Accordingly, aldehyde 6 (five steps
from 3-hydroxy-1,4-pentadiene), which was previously used for
3, was chosen as the starting material for 2 (Scheme 1). Addition
of the anion derived from dithiane 7, to 6, gave an approximately
From a synthetic standpoint, non-adjacently-linked struc-
tures like 1 and 5 are attractive structure–activity probes because
of the possibility of generating, in a convergent fashion, ana-
logues with different combinations of THF and THP rings. Since
activity also depends on the length and degree of hydroxylation
of the linker that connects the cyclic ether segment to the
butenolide, a triply convergent synthesis from individual cyclic
ether and butenolide precursors is appealing. In this vein,
we have previously reported a three component synthesis of
bullatanocin 5.6 This synthesis entailed the Wittig coupling of
a butenolide segment with a stereochemically complex bis-THF
component, which was asembled via an olefin cross-metathesis
of two relatively simple THF precursors. Herein, we describe
the potential generality of this methodology in the synthesis of
mucocin.7
Results and discussion
Our retrosynthetic analysis relates mucocin to three precursors:
THP and THF alkenes 2 and 3, and butenolide aldehyde 4
(Fig. 1). Components 3 and 4 are common to mucocin and
† Electronic supplementary information (ESI) available: 1H and 13C
NMR charts for selected compounds and comparison of spectra of the
final product and mucocin. See http://dx.doi.org/10.1039/b504937g
Scheme 1 Reagents and conditions: (a) 7, BuLi, THF then 6; (b)
Hg(ClO4)2, THF, two steps, 63%; (c) 8R, Et3SiH, BF3·OEt2, CH2Cl2,
−30 ◦C, 80%.
2 7 5 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 5 0 – 2 7 5 4
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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1 : 1 mixture of alcohol epimers, which was chromatographically
inseparable. Treatment of this mixture with mercuric perchlorate
resulted in hydrolysis of both the dithiane and acetal residues and
concomitant formation of a mixture of bicyclic acetals 8R and
8S in 63% yield over two steps. Chromatography of this mixture
provided the required acetal 8R and the undesired isomer 8S
in similar amounts. Exposure of 8R to triethylsilane and boron
trifluoride etherate at low temperature afforded the THP alkene
precursor 2 for the cross-metathesis step. The stereochemistry
of 2 was assigned from Jvic values and NOE data for the
diacetate derivative. The stereochemistry of reductive cleavage
of acetal 8R is consistent with axial attack on an oxocarbenium
intermediate like 9. This trajectory of attack is well-precedented
in the reaction of related oxocarbenium systems.7d,e,8 Compound
2 was obtained in an overall yield of 25% over three steps from
6. In comparison, the THF alkene precursor 3 was obtained in
38% yield over four steps from 6.6 While this route to 2 is not
stereoselective, it benefits from the use of a relay intermediate
(i.e. 6) and straightforward synthetic procedures. In principle,
it should be possible to develop more stereoselective conditions
for the dithiane coupling.9
The cross-metathesis of 2 and 3 was next performed
(Scheme 2). Following our earlier studies a more reactive
precursor (i.e. allylic alcohol 2) was paired with an excess of a less
reactive partner (i.e. allylic acetate 3).10,11 Alcohol 2 was chosen
as the limiting reactant because it is not as easily accessible
as the reaction partner 3. This plan was expected to favor the
cross-metathesis product (together with unreacted 3) over the
homodimeric products, on the basis of statistical and reactivity
considerations.12 Indeed, reaction of 2 with three equivalents
of 3 led to heterodimer 10 as the major metathesis product in
51% yield based on allylic alcohol 2 (86% based on consumed
3), with less than 5% of homodimeric products. Alkene 10 was
obtained as essentially a single compound, which was presumed
to be the E-isomer. In view of the small amount of homodimer
formation, the somewhat low conversion of 2 to 10 is likely a
result of unproductive side reactions of 2. This may be in part due
to the diol nature of 2, since higher conversions were obtained
in our bullatanocin synthesis in which a mono-hydroxy, allylic
alcohol substrate was used.
Scheme 3 Reagents and conditions: (a) H2, Pd/C, EtOAc, 99%; (b)
K2CO3, MeOH, 79%; (c) MOMCl, i-Pr2NEt, CH2Cl2, 90%; (d) NaOMe,
MeOH, 93%; (e) Ph3P, DIAD, 1-phenyl-1H-tetrazole-5-thiol, THF,
97%; (f) m-CPBA, NaHCO3, CH2Cl2, 79%. DIAD = diisopropyl
azodicarboxylate; m-CPBA = m-chloroperoxybenzoic acid.
Scheme 4 Reagents and conditions: (a) 16, LiHMDS, THF, −78 ◦C
then 4; (b) H2, Rh(Ph3P)3Cl, benzene–EtOH, 36%, two steps from 16;
(c) 5% AcCl, MeOH–CH2Cl2, 51%.
(Scheme 4). However the product was difficult to separate from
unreacted 4 and by-products from the tetrazole residue, and
purification was therefore deferred until after the subsequent
step. Thus hydrogenation of the crude product in the presence
of Wilkinson’s catalyst gave a mixture from which the dihydro
derivative 17 was easily obtained. Unfortunately the overall
yield of 17 from sulfone 16 (36%) was similar to the yield for
the analogous Wittig-reduction sequence that was used in the
bullatanocin synthesis (40%).
Finally, removal of the alcohol protecting groups in 17,
provided a material that was essentially identical to samples
of mucocin obtained from natural and synthetic sources ([a]2D5,
1H and 13C NMR).
Scheme 2
Conclusions
For the connection of the bis-THF and butenolide segments,
we explored a Julia–Kocienski strategy, in light of the success of
this approach in a recent acetogenin synthesis (Scheme 3).13 In
our bullatanocin synthesis, we had adopted a Wittig methodol-
ogy, which met with modest yield in the coupling step. Thus,
10 was hydrogenated to 11, which was transformed to 14
via straightforward alcohol protecting group transformations.
Primary alcohol 14 was converted to sulfone 16 in two additional
steps through known procedures for thioether formation and
oxidation.
In summary, our earlier synthesis of bullatanocin and the route
to mucocin described herein suggests a potentially general
approach for non-adjacently-linked bis-THF/THP acetogenins.
A tactical feature is the use of the operationally simple cross-
metathesis protocol for the assembly of stereochemically com-
plex bis-cyclic ether intermediates. The coupling of these core
structures with butenolide or butenolide substitutes represents a
second point of convergence, making the overall plan attractive
for assembly of acetogenin libraries. The present execution
of this methodology would benefit from improvements in the
syntheses of the butenolide component and the coupling of
the butenolide and bis-cyclic ether segments. Solutions to these
Treatment of the anion generated from sulfone 16 with
an excess of butenolide aldehyde 4 gave the desired alkene
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 5 0 – 2 7 5 4
2 7 5 1

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limitations are suggested in a number of other syntheses of the
THF containing acetogenins and are currently being explored.
137.8, 116.5, 110.0, 80.0, 79.5, 68.4, 33.5, 31.9, 29.8, 29.6, 29.6,
29.6, 29.3, 25.0, 24.2, 22.7, 22.5, 14.1; m/z (ESI) 319.2242 (M +
Na, C18H32O3Na requires 319.2249). For 8S: Rf = 0.21 (15%
EtOAc in petroleum ether); mmax(thin film) 3461 (m), 1644 (vw);
Experimental
1
=
H NMR (CDCl3, 500 MHz) d 5.90–5.70 (1 H, m, CH CH2),
=
=
5.32 (1H, d, J 17.1, CH CHH), 5.11 (1H, d, J 10.2, CH CHH),
4.39 (1 H, d, J 7.5, H-7), 4.21 (1 H, br s, H-5), 3.55 (1 H, ddd, J
6.0, 10.0 and 10.1, H-2), 2.14 (1 H, m, CHH), 1.90–1.80 (3 H, m,
3 × CHH), 1.71 (1 H, m, CHH), 1.58 (1 H, m, CHH), 1.48 (3 H,
m, OH, 2 × CHH), 1.45–1.25 (14 H, m, 7 × CH2), 0.90 (3 H,
t, J 6.8, CH3); 13C (CDCl3, 125 MHz) d 138.0, 116.4, 110.9, 81.0,
78.8, 70.4, 33.1, 31.9, 29.9, 29.6, 29.3, 28.4, 27.6, 22.9, 22.7, 14.1.
Solvents were purified by standard procedures or used from
commercial sources as appropriate. Petroleum ether refers to the
fraction of petroleum ether boiling between 40 and 60 ◦C. Ether
refers to diethyl ether. Unless otherwise stated thin layer
chromatography (TLC) was done on 0.25 mm thick precoated
silica gel 60 (HF-254, Whatman) aluminium sheets, and flash
column chromatography (FCC) was performed using Kieselgel
60 (32–63 mesh, Scientific Adsorbents). Elution for FCC usually
employed a stepwise solvent polarity gradient, correlated with
TLC mobility. Chromatograms were observed under UV (short
and long wavelength) light, and/or were visualized by heating
plates that were dipped in a solution of ammonium(VI) molyb-
date tetrahydrate (12.5 g) and cerium(IV) sulfate tetrahydrate
(5.0 g) in 10% aqueous sulfuric acid (500 mL). Optical rotations
([a]2D5 were recorded using a Rudolph Autopol III polarimeter
which has a thermally jacketed 10 cm cell (path length of
1 dm) and are given in units of 10−1 deg cm2 g−1 at 589 nm
(sodium D-line). Infra-red spectra were obtained using a Perkin-
Elmer 1600 FTIR spectrometer as thin film liquid samples
between sodium chloride plates. Only selected absorbances
(mmax) are reported. NMR spectra were recorded using either
Varian Unity Plus 500 or Bruker Ultra Shield instruments
(1H and 13C; 500 and 125 MHz respectively). Spectra were
recorded in CDCl3 solutions with residual CHCl3 as internal
standard (dH 7.27 and dC 77.0 ppm). Chemical shifts are quoted
in ppm relative to tetramethysilane (dsH 0.00) and coupling
constants (J) are given in Hertz. First order approximations
are employed throughout. High resolution mass spectrometry
was performed on an Ultima Micromass Q-Tof instrument at
the Mass Spectrometry Laboratory of the University of Illinois,
Urbana-Champaign.
(2S,3R,6S)-2-Decyl-6-[(1S)-1-(1-hydroxy)prop-2-en-1-
yl]tetrahydro-2H-pyran-3-ol (2)
A mixture of BF3·Et2O (76 lL) and Et3SiH (405 lL) was added
dropwise to a solution of 8R (0.15 g 0.50 mmol) in CH2Cl2 (7 mL)
at −40 ◦C, and the reaction maintained at this temperature for
3.5 h. Saturated aqueous NaHCO3 was then added and the
mixture extracted with CH2Cl2. The organic phase was washed
with brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure. FCC of the residue afforded 2 (118 mg, 80%):
Rf = 0.34 (30% EtOAc in petroleum ether); mmax(thin film) 3400
1
(s), 1646 (vw); H NMR (CDCl3, 500 MHz) d 5.90–5.70 (1 H,
m, CH = CH2), 5.31 (1H, d, J 17.5, CH = CHH), 5.10 (1H, d, J
=
10.0, CH = CHH), 3.87 [1 H, t, J 7.0, CH(OH)CH CH2], 3.26
(1 H, m, H-3), 3.13 (1 H, t, J 7.0, H-6), 3.04 (1 H, dt, t, J 2.0
and 8.0 H-2), 2.76 (1 H, br s, OH), 2.15 (1 H, s, OH), 2.05 (1 H,
m, CHH), 1.80 (1 H, m, CHH), 1.62 (1 H, m, CHH), 1.60–1.20
(19 H, m, 19 × CHH), 0.85 (3 H, t, J 6.5, CH3); 13C (CDCl3,
125 MHz) d 136.4, 117.6, 82.1, 79.9, 75.9, 70.5, 32.6, 32.0, 31.9,
29.7, 29.6, 29.3, 26.9, 25.4, 22.7, 14.1; m/z (ESI) 321.2399 (M +
Na, C18H34O3Na requires 321.2406).
Compound 2 was characterized as the diacetate derivative. To
a solution of 2 (8 mg, 27 lmol) in ethyl acetate (1.0 mL) was
added DMAP (1 mg, 10.8 lmol) and acetic anhydride (15 lL,
0.16 mmol) at rt. The reaction mixture was stirred for 1 h,
quenched with MeOH, and the solvent was removed in vacuo.
The crude product was purified by FCC to afford 2-di-O-acetate
(10.2 mg, 99%): Rf = 0.30 (10% EtOAc in petroleum ether); 1H
NMR (CDCl3, 500 MHz) d 5.75 (1 H, m, CH = CH2), 5.27 [3 H,
m, CH(OH), CH = CH2], 4.43 (1 H, ddd, J 4.0, 9.5 and 10, H-3),
3.37 (1 H, br dd, J 7.0 and 8.5, H-6), 3.17 (1 H, dt, J 2.0 and
9.5, H-2), 2.16 (1 H, m, CHH), 2.05, 2.00 (3 H ea, both s, 2 ×
CH3CO), 1.63 (1 H, m, CHH), 1.56–1.20 (20 H, m, 20 × CHH),
0.85 (3 H, t, J 6.0, CH3).
(1R,2R,5S,7S)-Decyl-7-ethenyl-6,8-dioxabicyclo[3.2.1]octan-2-
ol (8R) and (1R,2S,5S,7S)-decyl-7-ethenyl-6,8-
dioxabicyclo[3.2.1]octan-2-ol (8S)
n-Butyllithium (2.5 M, 0.76 mL) was added to a solution of
2-decyl-1,3-dithiane 7 (0.62 g, 2.4 mmol) in anhydrous THF
(4 mL) at 0 ◦C, under an atmosphere of argon. After 1 h at
this temperature aldehyde 6 (0.29 g, 1.6 mmol) was added, and
stirring continued at rt for 1.5 h. The reaction mixture was then
diluted with ether, washed with saturated aqueous NH4Cl and
brine, dried (Na2SO4), filtered, and concentrated under reduced
pressure. FCC of the residue afforded an inseparable mixture
of alcohol epimers (533.0 mg, 76%): Rf = 0.59 (10% EtOAc in
petroleum ether); 1H NMR (CDCl3, 300 MHz) d 5.9–5.7 (1 H,
m), 5.6 (1H, d, J 17), 5.2 (1 H, d, J 9.5), 4.1–3.9 (2 H, m), 3.8–3.7
(1 H, m), 2.8–3.1 (4H, m), 2.7–2.5 (2 H, m), 2.2–1.5 (6H, m), 1.4
(3H, s), 1.4 (3H, s), 1.3 (16 H, br s), 0.90 (3 H, t, J 6.2).
Cross-metathesis of 2 and 3: (5R,8S,9S,12S,13S,16R,17S)-
5,8:13,17-dioxido-9-acetoxy-1-pivaloxy-10-heptacosan-
12,16-diol (10)
Grubb’s catalyst second generation (17 mg, 20 lmol) in CH2Cl2
(2 mL) was injected at rt into a degassed solution of diol 2 (60 mg,
0.2 mmol) and acetate 3 (197 mg, 0.6 mmol) in CH2Cl2 (12 mL).
After 18 h at this temperature, additional catalyst (17 mg,
20 lmol) in CH2Cl2 (1 mL) was introduced. The mixture was
stirred for an additional 18 h at rt, then quenched by addition of
DMSO (150 lL), stirred for an additional 18 h and concentrated
in vacuo. The residue was purified by FCC to afford 10 (61 mg,
86% based on recovered 3, 51% relative to 2) and recovered 3
(159 mg). For 10: Rf = 0.26 (30% EtOAc in petroleum ether); 1H
Hg(ClO4)2 (1.00 g, 2.5 mmol) was added at 0 ◦C to a solution
of the product mixture from the previous step (0.58 g, 1.3 mmol)
in anhydrous THF (25 mL). The mixture was maintained at this
temperature for 1 h, then warmed and stirred for an additional
1 h at rt. The solution was diluted with saturated aqueous
NaHCO3 and extracted with ether. The organic phase was dried
(Na2SO4), filtered, and concentrated under reduced pressure.
FCC of the residue gave 8R (158.3 mg, 41%) and 8S (161.8 mg,
42%). For 8R: Rf = 0.32 (15% EtOAc in petroleum ether, neutral
=
NMR (CDCl3, 500 MHz) d 5.76 (2 H, m, CH CH), 5.26 (1 H,
1
Al2O3); mmax(thin film) 3462 (m), 1644 (vw); H NMR (CDCl3,
m, H-9), 4.06, 3.93 (3 H, 2 H respectively, both m, CH2-1, H-5,
8, 12), 3.29 (1 H, m, H-16), 3.17 (1 H, m, H-13), 3.08 (1 H,
dt, J 2.3 and 8.8, H-17), 2.80 (1 H, br s, OH), 2.05 (3 H,
s, CH3CO), 2.00 (2 H, m, 2 × CHH), 1.85 (1 H, m, CHH),
1.75–1.30 (30 H, m, OH, 29 × CHH), 1.20 [9 H, s, (CH3)3C],
0.90 (3 H, t, J 6.8, CH3-24); 13C (CDCl3, 125 MHz) d 178.6,
170.2, 132.5, 127.9, 82.2, 79.9, 79.3, 79.1, 75.5, 74.7, 70.4, 64.2,
=
500 MHz) d 5.90–5.70 (1 H, m, CH CH2), 5.33 (1H, d, J 17.1,
=
=
CH CHH), 5.12 (1H, d, J 10.2, CH CHH), 4.39 (1 H, d, J 7.5,
H-7), 4.21 (1 H, br s, H-5), 3.54 (1H, d, J2,OH 10.3, H-2), 2.00–
2.18 (3 H, m, 3 × CHH), 1.88–1.76 (2 H, m, 2 × CHH), 1.70
(1 H, m), 1.55–1.40 (3 H, m, OH, 2 × CHH), 1.40–1.25 (14 H,
m, 7 × CH2), 0.90 (3 H, t, J 6.7, CH3); 13C (CDCl3, 125 MHz) d
2 7 5 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 5 0 – 2 7 5 4

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38.7, 35.1, 32.5, 32.0, 31.9, 31.8, 29.8, 29.7, 29.6, 29.3, 28.6, 28.1,
27.2, 26.9, 25.4, 22.7, 22.6, 14.1; m/z (ESI) 619.4167 (M + Na,
C34H60O8Na requires 619.4186).
to rt and neutralized with 5% HCl. Most of the methanol was
evaporated under reduced pressure and the residue extracted
with EtOAc. The organic layer was washed with water and
brine, dried (Na2SO4), filtered, and concentrated under reduced
pressure. FCC of the residue provided 14 (75 mg, 93%): Rf = 0.28
(40% EtOAc in petroleum ether); 1H NMR (CDCl3, 500 MHz)
d 4.90–4.50 (6 H, m), 4.01 (1 H, m), 3.92 (1 H, m), 3.66 (2 H, t,
J 6.5), 3.50 (2 H, m), 3.41 (3 H, s), 3.40 (3 H, s), 3.39 (3 H, s),
3.35 (1 H, m), 3.22 (1 H, m), 3.12 (1 H, dt, J 2.3 and 8.9), 2.22
(1 H, m), 2.00–1,90 (2 H, m), 1.8 (1 H, m), 1.80–1.30 (17 H, m),
1.32 (16 H, br s), 0.90 (3 H, t, J 6.8); 13C (CDCl3, 125 MHz) d
97.0, 96.8, 95.4, 81.0, 79.9, 79.5, 79.2, 79.2, 75.9, 62.8, 55.7, 55.7,
55.5, 35.4, 32.7, 32.2, 32.1, 31.9, 30.1, 29.8, 29.7, 29.7, 29.6, 29.3,
28.5, 26.9, 26.7, 26.4, 25.5, 22.7, 22.5, 14.1; m/z (ESI) 627.4429
(M + Na, C33H64O9Na requires 627.4448).
(5R,8S,9S,12S,13S,16R,17S)-5,8:13,17-Dioxido-9-acetoxy-1-
pivaloxy-heptacosan-12,16-diol (11)
A mixture of alkene 10 (86 mg, 0.14 mmol) and 10% Pd/C
(86 mg) in ethyl acetate (10 mL) was stirred under an atmosphere
of hydrogen (balloon) at rt, for 18 h. The suspension was
then filtered through Celite and the filtrate concentrated under
reduced pressure. FCC of the residue provided 11 (86.7 mg,
1
99%): Rf = 0.26 (30% EtOAc in petroleum ether); H NMR
(CDCl3, 500 MHz) d 4.90 (1 H, m, H-9), 4.07 (t, 2H, J 6.6, CH2-
1), 4.0 (1 H, apparent q, J 6.8, H-8), 3.9 (1 H, m, H-5), 3.5 (1 H,
m, H-12), 3.3 (1 H, m, H-16), 3.1 (1 H, m, H-13), 3.06 (1 H, dt,
J 2.1 and 8.8, H-17), 2.59 (1 H, d, J 3.3, OH), 2.12 (1 H, m,
CHH), 2.10 (3 H, s, CH3CO), 1.99 (2 H, m, 2 × CHH), 1.86 (1 H,
m, CHH), 1.81–1.23 (33 H, m, OH, 32 × CHH), 1.20 [9 H, s,
(CH3)3C], 0.90 (3 H, t, J 6.8, CH3-24); 13C (CDCl3, 125 MHz)
d 178.6, 171.0, 82.0, 80.0, 79.3, 79.0, 75.0, 73.1, 70.5, 64.3, 38.7,
35.1, 32.6, 32.1, 32.0, 31.9, 29.7, 29.6, 29.3, 28.6, 28.5, 28.3, 27.2,
27.0, 26.6, 25.5, 22.7, 22.6, 21.1, 14.1; m/z (ESI) 621.4355 (M +
Na, C34H62O8Na requires 621.4342).
Tetrazole thioether (15)
To a stirred solution of alcohol 14 (52 mg, 87 lmol) in THF
(1.2 mL) was added PPh3 (35 mg, 0.13 mmol) and 1-phenyl-1H-
tetrazole-5-thiol (24 mg, 0.13 mmol). The mixture was cooled to
0 ◦C and DIAD (26 mL, 0.13 mmol) was then slowly introduced.
The resulting yellow solution was maintained at this temperature
for 5 min, then warmed to rt and stirred for an additional 0.5 h.
The reaction mixture was concentrated in vacuo. FCC of the
residue afforded 15 (64.2 mg, 97%): Rf = 0.60 (40% EtOAc in
petroleum ether); 1H NMR (CDCl3, 500 MHz) d 7.53 (5 H, m),
4.90–4.50 (6 H, m), 3.98 (1 H, apparent q, J 6.5), 3.92 (1 H, m),
3.49 (2 H, m), 3.42 (2 H, t, J 7.4), 3.41 (3 H, s), 3.40 (3 H, s), 3.39
(3 H, s), 3.35 (1 H, m), 3.22 (1 H, m), 3.12 (1 H, dt, J 2.2 and
8.9), 2.22 (1 H, m), 2.05–1.90 (2 H, m), 1.90–1.30 (17 H, m), 1.31
(16 H, br s), 0.9 (3 H, t, J 6.7); 13C (CDCl3, 125 MHz) d 154.4,
130.0, 129.8, 123.9, 97.0, 96.8, 95.4, 81.1, 81.0, 79.9, 79.5, 79.3,
78.9, 75.9, 55.7, 55.5, 35.1, 33.3, 32.2, 32.1, 31.9, 30.1, 29.8, 29.7,
29.6, 29.3, 29.2, 28.6, 27.0, 26.6, 26.4, 25.5, 25.4, 22.7, 14.1; m/z
(ESI) 787.4652 (M + Na, C40H68N4O8NaS requires 787.4656).
(5R,8S,9S,12S,13S,16R,17S)-5,8:13,17-Dioxido-1-pivaloxy-
heptacosan-9,12,16-triol (12)
A solution of acetate 11 (125 mg, 0.2 mmol) in dry methanol
(13 mL) was treated with K2CO3 (57.7 mg, 0.4 mmol). The
reaction mixture was stirred for 18 h at rt, then neutralized with
5% HCl, and concentrated under reduced pressure. The residue
was extracted with EtOAc, and the organic phase was dried
(Na2SO4), filtered, and evaporated in vacuo. FCC of the residue
gave 12 (83.5 mg, 79%) and recovered 11 (11.4 mg). For 12:
Rf = 0.24 (60% EtOAc in petroleum ether); 1H NMR (CDCl3,
500 MHz) d 4.02 (2 H, t, J 6.5), 3.84 (1 H, m), 3.75 (1 H, apparent
q, J 6.5), 3.42 (1 H, m), 3.38 (1 H, m), 3.21 (1 H, m), 3.10 (1 H,
m), 3.00 (1 H, t, J 8.0), 2.79 (1 H, br s, OH), 1.75–2.10 (5 H,
m), 1.70–1.17 (32 H, m), 1.15 (9 H, s), 0.83 (3 H, t, J 6.5); 13C
(CDCl3, 75 MHz) d 178.6, 82.3, 82.2, 80.4, 79.3, 74.0, 73.7, 70.7,
64.4, 39.0, 35.5, 33.0, 32.7, 32.3, 32.2, 30.0, 29.9, 29.6, 29.1, 29.0,
28.6, 27.5, 27.2, 25.8, 22.9, 14.4; m/z (ESI) 557.4404 (M + Na,
C32H61O7 requires 557.4417).
Sulfone (16)
To a stirred solution of thioether 15 (64 mg, 84 lmol) in
CH2Cl2 (4 mL) was added m-CPBA (58 mg, 0.34 mmol) and
NaHCO3 (56 mg, 0.67 mmol) in one portion. The suspension
was stirred for 12 h at rt, then diluted with 10% aqueous
Na2S2O3 (4 mL). The mixture was extracted with CH2Cl2, the
organic phase washed with saturated aqueous NaHCO3 and
brine, dried (Na2SO4), filtered, and concentrated under reduced
pressure. FCC of the residue provided 16 (39.9 mg, 79% based
on recovered 14): Rf = 0.76 (5% acetone in CH2Cl2); 1H NMR
(CDCl3, 500 MHz) d 7.80 (2 H, m), 7.60 (3 H, m), 4.83, 4.78 and
4.75 (1 H ea, all apparent d, J 6.8), 4.70 (2 H, apparent br d, J
6.8), 4.62 (1 H, apparent d, J 6.8), 4.00 (1 H, apparent q, J 6.5),
3.92 (1 H, m), 3.76 (2 H, m), 3.50 (2 H, m), 3.41 (3 H, s), 3.40
(3 H, s), 3.39 (3 H, s), 3.35 (1 H, m), 3.22 (1 H, m), 3.12 (1 H,
dt, J 2.0 and 8.8), 2.21 (1 H, m), 2.04–1.92 (4 H, m), 1.80 (1 H,
m), 1.80–1.30 (14 H, m), 1.30 (16 H, br s), 0.90 (3 H, t, J 6.6);
13C (CDCl3, 125 MHz) d 153.5, 131.4, 129.7, 125.1, 97.0, 96.8,
95.4, 81.2, 81.0, 79.8, 79.6, 79.3, 78.6, 75.9, 56.0, 55.8, 55.7, 55.5,
35.0, 32.3, 32.1, 31.9, 30.1, 29.8, 29.7, 29.6, 29.3, 28.5, 27.0, 26.6,
26.4, 25.5, 25.1, 22.7, 22.1, 14.1; m/z (ESI) 819.4536 (M + Na,
C40H68N4O10NaS requires 819.4554).
(5R,8S,9S,12S,13S,16R,17S)-5,8:13,17-Dioxido-9,12,16-
tris(methoxymethoxy)-1-pivaloxy-heptacosane 13
MOMCl (91 lL, 1.2 mmol) was added to a solution of triol
12 (83 mg, 0.2 mmol) and i-Pr2NEt (392 mL, 2.3 mmol) in
anhydrous CH2Cl2 (10 mL) at 0 ◦C. The mixture was stirred
for 24 h at rt, then diluted with saturated aqueous NH4Cl and
extracted with ether. The organic layer was washed with water
and brine, dried (Na2SO4), filtered, and concentrated in vacuo.
FCC of the residue afforded 13 (92 mg, 90%): Rf = 0.90 (40%
EtOAc in petroleum ether); 1H NMR (CDCl3, 500 MHz) d 4.85,
4.78, 4.41, 4.70, 4.68 and 4.62 (1 H ea, all apparent d, J 6.8),
4.07 (2 H, t, J 6.6), 4.00 (1 H, m), 3.92 (1 H, m), 3.5 (2 H, m),
3.41 (3 H, s), 3.40 (3 H, s), 3.39 (3 H, s), 3.35 (1 H, m), 3.22 (1 H,
m), 3.12 (1 H, dt, J 2.3 and 8.9), 2.2 (1 H, m), 2.00–1.90 (2 H,
m), 1.81 (1 H, m), 1.80–1.30 (32 H, m), 1.22 (9 H, s), 0.90 (3 H,
t, J 6.8); 13C (CDCl3, 125 MHz) d 178.6, 97.0, 96.8, 95.4, 81.1,
81.0, 79.9, 79.5, 79.3, 79.0, 75.9, 64.3, 55.7, 55.5, 38.7, 35.4,
32.2, 32.1, 31.9, 30.1, 29.8, 29.7, 29.6, 29.3, 28.9, 28.6, 27.2,
27.0, 26.7, 26.4, 25.5, 22.8, 22.7, 14.1; m/z (ESI) 711.5035 (M +
Na, C38H72O10Na requires 711.5023).
Julia–Kocienski coupling: protected mucocin (17)
To a solution of sulfone 16 (30 mg, 37.7 lmol) in toluene (1.5 mL)
◦
was added LiHMDS (1.0 M in THF, 98 lL) at −78 C. After
(5R,8S,9S,12S,13S,16R,17S)-5,8:13,17-Dioxido-9,12,16-
tris(methoxymethoxy)-heptacosan-1-ol (14)
stirring the yellow mixture for 1 h, aldehyde 4 (27 mg, 62.0
lmol) in toluene (1.0 mL) was slowly added. The mixture was
stirred for another 1 h at −78 ◦C, warmed to rt, and maintained
at this temperature for an additional 1 h. The reaction was
then quenched with saturated aqueous NH4Cl and extracted
Sodium methoxide (37 mg, 0.7 mmol) was added to a solution
of pivalate 13 (92 mg, 0.14 mmol) in anhydrous MeOH (8 mL)
at rt. The mixture was heated at reflux for 12 h, then cooled
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 5 0 – 2 7 5 4
2 7 5 3

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with ether. The organic layer was dried (Na2SO4), filtered, and
concentrated under reduced pressure. FCC (25% EtOAc in
petroleum ether) of the residue provided an unseparated mixture
(24 mg, Rf = 0.47) which contained the desired alkene together
with 4 and another unidentified reaction product. For alkene:
1H NMR (CDCl3, 500 MHz) d 6.9 (1H, d, J 1.2), 5.12 (1 H, m),
5.27 (1 H, m), 4.87 (1 H, m), 4.85–4.60 (6 H, m), 4.04 (1 H, m),
4.0 (1 H, m), 3.92 (1 H, m), 3.48 (2 H, m), 3.41 (3 H, s), 3.40
(3 H, s), 3.39 (3 H, s), 3.35 (1 H, m), 3.23 (1 H, m), 3.12 (1 H,
dt, J 2.2 and 8.8), 2.45 (2 H, m), 2.22 (1 H, m), 1.30 (3 H, d,
J 6.8), 0.90 (3 H, t, J 6.8).
28.74, 28.35, 26.94, 26.16, 25.52, 25.48, 22.67, 19.11, 14.09; m/z
(ESI) 639.4811 (M + Na, C37H67O8 requires 639.4836).
Acknowledgements
This investigation was supported by NIH grant R01 GM57865
and the NIH SCORE Program (S06 GM60654). “Research
Centers in Minority Institutions” award RR-03037 from the
National Center for Research Resources of the NIH, which sup-
ports the infrastructure and instrumentation of the Chemistry
Department at Hunter College, is also acknowledged.
Chlorotris(triphenylphosphine)rhodium(I) (3.9 mg) was
added to a degassed solution of the material obtained from
the previous step in a mixture of benzene (1.1 mL) and EtOH
(0.6 mL). The reaction mixture was stirred under an atmosphere
(balloon) of hydrogen for 24 h. The solvent was removed under
reduced pressure, and the residue purified by FCC to give 17
(13.6 mg, 36% from 16): Rf = 0.47 (25% EtOAc in petroleum
ether); 1H NMR (CDCl3, 500 MHz) d 7.70–7.60 (4 H, m), 7.50–
7.30 (6 H, m), 6.93 (1 H, d, J 1.2 Hz), 4.91 (1 H, br q, J 6.8),
4.86, 4.78, 4.75, 4.71, 4.70, 4.65 (1 H ea, all apparent d, J 6.7),
4.04 (1 H, m), 4.00 (1 H, apparent q, J 6.7), 3.89 (1 H, m), 3.5
(2 H m), 3.42 (3 H, s), 3.40 (3 H, s), 3.39 (3 H, s), 3.35 (1 H, m),
3.22 (1 H, m), 3.12 (1 H, dt, J 2.2 and 8.8), 2.46 (2 H, m), 2.23
(1 H, m), 1.95 (2 H, m), 1.80 (1 H, m), 1.75–1.20 (42 H, m), 1.34
(3 H, d, J 6.8), 1.06 (9 H, br s), 0.9 (3 H, t, J 6.8); 13C (CDCl3,
125 MHz) d 173.9, 151.1, 135.8, 135.8, 135.7, 134.2, 134.1, 130.7,
129.7, 129.6, 127.6, 127.6, 97.0, 96.9, 95.4, 81.0, 79.9, 79.6, 79.3
(2C), 77.4, 77.3, 75.9, 71.8, 55.7, 55.5, 36.4, 35.9, 32.2, 32.1, 31.9,
31.8, 30.2, 29.8, 29.7, 29.6, 29.4, 29.3, 28.6, 27.0, 26.9, 26.7, 26.4,
26.2, 25.5, 24.9, 22.7, 18.9, 14.1; m/z (ESI) 1031.6605 (M + Na,
C59H96O11NaSi requires 1031.6620).
References and notes
1 J. K. Rupprecht, Y.-H. Hui and J. L. McLaughlin, J. Nat. Prod.,
1990, 53, 237–278; X.-P. Fang, M. J. Rieser, Z.-M. Gu, G.-X. Zhao
and J. L. McLaughlin, Phytochem. Anal., 1993, 4, 27–48; L. Zeng, Q.
Ye, N. H. Oberlis, G. Shi, Z.-M. Gu, K. He and J. L. McLaughlin,
Nat. Prod. Rep., 1996, 13, 275–306; F. Q. Alali, X.-X. Liu and J. L.
McLaughlin, J. Nat. Prod., 1999, 62, 504–540.
2 M. C. Gonzalez, J. R. Tormo, A. Bermejo, M. C. Zafra-Polo, E.
Estornell and D. Cortes, Bioorg. Med. Chem. Lett., 1997, 7, 1113–
1118 and refs. cited therein.
3 N. H. Oberlies, V. L. Croy, M. L. Harrison and J. L. McLaughlin,
Cancer Lett., 1997, 115, 73–79.
4 G. Shi, D. Alfonso, M. O. Fatope, L.-M. Zheng, Z.-X. Gu, G.-X.
Zhao, K. He, J. M. MacDougal and J. L. McLaughlin, J. Am. Chem.
Soc., 1995, 117, 10 409–10 410.
5 H. Miyoshi, M. Ohshima, H. Shimada, T. Akagi, H. Iwamura and
J. L. McLaughlin, Biochim. Biophys. Acta, 1998, 1365, 443–452.
6 L. Zhu and D. R. Mootoo, J. Org. Chem., 2004, 69, 3154–3157.
7 For other total syntheses of mucocin, see: (a) P. Neogi, T.
Doundoulakis, A. Yazbak, S. C. Sinha, S. C. Sinha and E. Keinan,
J. Am. Chem. Soc., 1998, 120, 11 279–11 284; (b) S. Hoppen, S. Ba¨urle
and U. Koert, Chem. Eur. J., 2000, 6, 2382–2396; (c) S. Takahashi, A.
Kubota and T. Nakata, Angew. Chem., Int. Ed., 2002, 41, 4751–4754;
(d) S. Takahashi and T. Nakata, J. Org. Chem., 2002, 67, 5739–
5752; (e) P. A. Evans, J. Cui, S. J. Gharpure, A. Polosukhin and H.-
R. Zhang, J. Am. Chem. Soc., 2003, 125, 14 702–14 703. For a ring
closing metathesis strategy related to the cross-metathesis approach
described herein, see ref. 7e.
8 J. A. C. Romero, S. A. Tabacco and K. A. Woerpel, J. Am. Chem.
Soc., 2000, 122, 168–169.
9 For examples of asymmetric addition of acyl anion equivalents
to aldehydes, see: V. K. Aggarwal, A. Thomas and S. Steffen,
Tetrahedron, 1997, 53, 16 213–16 228; H. Choi, K. Nakajima, D.
Demeke, F.-A. Kang, H.-S. Jun, Z.-K. Wan and Y. Kishi, Org. Lett.,
2004, 4, 4435–4438.
Mucocin (1)
5% Acetyl chloride in MeOH (0.59 mL) was added at rt to a
solution of 17 (13.6 mg, 13.5 lmol) in CH2Cl2 (1.0 mL). The
mixture was stirred at this temperature for 4 h, then diluted
with CH2Cl2, and washed with saturated aqueous NaHCO3.
The organic layer was dried (Na2SO4), filtered and concentrated
under reduced pressure. FCC of the residue (EtOAc) afforded 1
(4.2 mg, 51%) and a mixture of less polar products (7.1 mg) that
appeared to be partially deprotected products. For 1: wax; Rf =
0.63 (EtOAc); [a]2D5 −12.4 (c 0.42, CH2Cl2); lit14: −13.9 (c 0.11,
CH2Cl2); mmax(thin film) 3426 (s), 2834 (s), 2852 (s), 1745 (s); 1H
NMR (CDCl3, 500 MHz) d 7.16 (1H, br s), 5.07 (1 H, dq, J 1.2
and 6.8), 3.94–3.82 (2 H, m), 3.83 (1 H, q, J 7.1), 3.50 (1 H, m),
3.45 (1 H, br t, J 7.3), 3.30 (1 H, m), 3.18 (1 H, m), 3.09 (1 H, dt,
J 2.2 and 8.9), 2.85 (1 H, d, J 2.4, OH), 2.73 (1 H, br s, OH), 2.55
(1 H, dt, A of ABX2, JAX 1.6 and JAB 15.2), 2.42 (1 H, dd, B of
ABX2, JBX 8.2 and JAB 15.2), 2.27 (1 H, br s, OH), 2.16–2.10 (1 H,
m), 2.08–1.97 (2 H, m), 1.90–1.82 (1 H, m), 1.75–1.20 (41 H, m),
1.46 (3 H, d J 6.8), 0.9 (3 H, t J 6.9); 13C (CDCl3, 125 MHz) d
174.55, 151.74, 131.23, 82.06, 81.92, 80.18, 79.34, 77.94, 73.79,
73.52, 70.60, 69.99, 37.40, 35.60, 33.38, 32.68, 32.40, 32.00,
31.91, 29.73, 29.69, 29.63, 29.54, 29.45, 29.41, 29.32, 28.85,
10 For the application of a similar concept to the synthesis of dipeptide
alkene isoteres, see: M. M. Vasbinder and S. J. Miller, J. Org. Chem.,
2002, 67, 6240–6242.
11 For other examples of cross-metathesis with complex reactants, see:
G. Chen, J. Schmieg, M. Tsuji and R. W. Franck, Org. Lett., 2004, 6,
4077–4080 and refs. cited therein.
12 R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54, 4413–4450; H. E.
Blackwell, D. J. O’Leary, A. K. Chatterjee, R. A. Washenfelder, D. A.
Bussmann and R. H. Grubbs, J. Am. Chem. Soc., 2000, 122, 58–71;
A. K. Chatterjee, T.-L. Choi, D. P. Sanders and R. H. Grubbs, J. Am.
Chem. Soc., 2003, 125, 11 360–11 370.
13 Q. Zhang, H. Lu, C. Richard and D. P. Curran, J. Am. Chem. Soc.,
2004, 126, 36–37.
14 Ref. 7a: a value of −10.8◦ (ref. 4) was reported for the natural product
but the concentration and solvent were not listed.
2 7 5 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 5 0 – 2 7 5 4