Total synthesis of mucocin

Article abstract of DOI:10.1021/ja981302s

The synthesis of the potent antitumor agent, mucocin, 1, was efficiently achieved in 20 steps from cyclodecatriene, thus confirming the proposed structure of this unusual member of the Annonaceous acetogenins. Demonstrating the power of the 'naked' carbon skeleton strategy, all seven asymmetric centers in the key fragment of the molecule were introduced by double AE reaction followed by double AD reaction. Simultaneous two ring closure reactions provided both the THP and THF rings in a single step.

Full text of DOI:10.1021/ja981302s

J. Am. Chem. Soc. 1998, 120, 11279-11284
11279
Total Synthesis of Mucocin
Partha Neogi,† Thomas Doundoulakis,† Ahmad Yazbak,†,‡ Santosh C. Sinha,†,‡
Subhash C. Sinha,*,† and Ehud Keinan*,†,‡,§
Contribution from the Department of Molecular Biology and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and
Department of Chemistry, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel
ReceiVed April 17, 1998
Abstract: The synthesis of the potent antitumor agent, mucocin, 1, was efficiently achieved in 20 steps from
cyclododecatriene, thus confirming the proposed structure of this unusual member of the Annonaceous
acetogenins. Demonstrating the power of the “naked” carbon skeleton strategy, all seven asymmetric centers
in the key fragment of the molecule were introduced by double AE reaction followed by double AD reaction.
Simultaneous two ring closure reactions provided both the THP and THF rings in a single step.
The diverse bioactivities of the Annonaceous acetogenins as
antitumor, immunosuppressive, pesticidal, antiprotozoal, anti-
feedant, anthelmintic, and antimicrobial agents have attracted
increasing interest.1,2 On the basis of the number and relative
positioning of the tetrahydrofuran moieties within the molecule,
these acetogenins have been classified into three subgroups: the
mono-THF, the adjacent bis-THF, and the nonadjacent bis-THF
acetogenins.1 The structure and absolute configuration of many
of these acetogenins have been unequivocally confirmed by total
synthesis.
Mucocin, 1,3 which was recently isolated from leaves of
Rollinia mucosa (Jacq.) Baill. (Annonaceae), was the first
Annonaceous acetogenin reported that bears a hydroxylated
tetrahydropyran (THP) ring along with a THF ring, thus
representing a new skeletal type in this rapidly growing family
of bioactive natural products. Mucocin was found to be quite
active in the BST assay4 (IC50 1.3 µg/mL) and showed selective
inhibitory effect against A-549 (lung cancer) and PACA-2
(pancreatic cancer) in a panel of six human solid tumor cell
lines.3 Its selective potency was up to 10000 times that of
adriamycin. Interestingly, mucocin was found to be as active
as bullatacin in inhibition of oxygen uptake by rat liver
mitochondria (LC50 18 and 9 nM/mg protein, respectively).3
These findings suggest that 1, like other potent antitumor bis-
THF acetogenins, may also block the mitochondrial complex I
(NADH-ubiquinone oxidoreductase)5 and inhibit the plasma
membrane NADH oxidase,6 thus depleting ATP and likely to
induce apoptosis.7
* Corresponding author. Phone: (619) 784-8511, Fax: (619) 784-8732,
E-Mail: Keinan@scripps.edu or subhash@scripps.edu.
† The Scripps Research Institute.
‡ Technion-Israel Institute of Technology.
§ Incumbent of the Benno Gitter & Ilana Ben-Ami chair of Biotechnol-
ogy, Technion.
(1) (a) Gu, Z.-M.; Zhao, G.-X.; Oberlies, N. H.; Zeng, L.; McLaughlin,
J. L. In Recent AdVances in Phytochemistry; Arnason, J. T., Mata, R.,
Romeo, J. T., Eds.; Plenum Press: New York, 1995; Vol. 29, pp 249-
310. (b) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.;
McLaughlin, J. L. Nat. Prod. Rep. 1996, 275. (c) Oberlies, N. H.; Chang,
C.; McLaughlin, J. L. J. Med. Chem. 1997, 40, 2102. (d) Zafra-Polo, M.
C.; Figadere, B.; Gallardo, T.; Tormo, J.; Cortes, D. Phytochemistry 1998,
48, 1087.
Structure 1 was proposed for mucocin on the basis of its MS,
1
1H, 13C and 2D H -1H NMR spectral data (relative stereo-
chemistry)3 and data derived from advanced Mosher ester
technology (absolute configuration).8 Biogenetically, 1 seems
to originate from a different pathway than the proposed
pathways for known nonadjacent bis-THF Annonaceous aceto-
genins.1,3 Therefore, an efficient total synthesis of 1 was
required not only for making the compound available for further
biological studies, but also for verification of the proposed
(2) For total synthesis of annonaceous acetogenins and their diasteromers,
see: (a) Hoye, T. R.; Hanson, P. R.; Kovelesky, A. C.; Ocain, T. D.; Zhuang,
Z. J. Am. Chem. Soc. 1991, 113, 9369. (b) Sinha, S. C.; Keinan, E. J. Am.
Chem. Soc. 1993, 115, 4891. (c) Hoye, T. R.; Hanson, P. R. Tetrahedron
Lett. 1993, 34, 5043. (d) Tam, V. T.; Chaboche, C.; Figadere, B.; Chappe,
B.; Hieu, B. C.; Cave´, A. Tetrahedron Lett. 1994, 35, 883. (e) Trost, B.
M.; Shi, Z. P. J. Am. Chem. Soc. 1994, 116, 7459. (f) Koert, U. Tetrahedron
Lett. 1994, 35, 2517. (g) Yao, Z. J.; Wu, Y. L. Tetrahedron Lett. 1994, 35,
157. (h) Makabe, H.; Tanaka, A.; Oritani, T. J. Chem. Soc., Perkin Trans.
1 1994, 1975. (i) Sinha, S. C.; Sinha-Bagchi, A.; Yazbak, A.; Keinan, E.
Tetrahedron Lett. 1995, 36, 9257. (j) Sinha, S. C.; Sinha-Bagchi, A.; Keinan,
E. J. Am. Chem. Soc. 1995, 117, 1447. (k) Konno, H.; Makabe, H.; Tanaka,
A.; Oritani, T. Biosci. Biotech. Biochem. 1995, 59, 2355. (l) Hoye, T. R.;
Tan, L. Tetrahedron Lett. 1995, 36, 1981. (m) Yao, Z. J.; Wu, Y. L. J. Org.
Chem. 1995, 60, 1170. (n) Naito, H.; Kawahara, E.; Maruta, K.; Maeda,
M.; Sasaki, S. J. Org. Chem. 1995, 60, 4419. (o) Sinha, S. C.; Sinha, A.;
Yazbak, A.; Keinan, E. J. Org. Chem. 1996, 61, 7640. (p) Hoye, T. R.; Ye,
Z. J. Am. Chem. Soc. 1996, 118, 1801. (q) Konno, H.; Makabe, H.; Tanaka,
A.; Oritani, T. Tetrahedron Lett. 1996, 37, 5393. (r) Konno, H.; Makabe,
H.; Tanaka, A.; Oritani, T. Tetrahedron 1996, 52, 9399. (s) Franck, X.;
Figadere, B.; Cave´, A. Tetrahedron Lett. 1996, 37, 1593. (t) Marshall, J.
A.; Chen, M. J. Org. Chem. 1997, 62, 5996. (u) Marshall, J. A.; Hinkle, K.
W.; Hagedorn, C. E. Isr. J. Chem. 1997, 37, 97. (v) Marshall, J. A.; Hinkle,
K. W. J. Org. Chem. 1997, 62, 2, 5989. (w) Sinha, S. C.; Sinha, A.; Sinha,
S. C.; Keinan, E. J. Am. Chem. Soc. 1997, 119, 12014. (x) Sinha, S. C.;
Sinha, A.; Sinha, S. C.; Keinan, E. J. Am. Chem. Soc. 1998, 120, 4017.
(3) Shi, G.; Alfonso, D.; Fatope, M. O.; Zeng, L.; Gu, Z.-M.; Gu, Z.-
M.; He, K.; McDougal, J. M.; McLaughlin, J. L. J. Am. Chem. Soc. 1995,
117, 10409.
(4) McLaughlin, J. L. In Methods in Plant Biochemistry; Hostettmann,
K., Ed.; Academic Press: London, 1991; Vol. 6, pp 1-35.
(5) (a) Ahammadsahib, K. I.; Hollingworth, R. M.; McGovren, J. P.;
Hui, Y.-H.; McLaughlin, J. L. Life Sci. 1993, 53, 1113. (b) Oberlies, N.
H.; Croy, V. L., Harrison, M. L., McLaughlin, J. L. Cancer Lett. 1997,
115, 73.
(6) Morre´, D. J.; Cabo, R. D.; Farley, C.; Oberlies, N. H.; McLaughlin,
J. L. Life Sci. 1995, 56, 343.
(7) Wolvetang, E. J.; Johnson, K. L.; Krauer, K.; Ralph, S. J.; Linnane,
A. W. FEBS Lett. 1994, 339, 40.
(8) (a) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973,
38, 2143. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092. (c) Rieser, M. J.; Hui, Y.-H.; Rupprecht, J.
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Zhuang, Z.; Hoye, T. R. J. Am. Chem. Soc. 1992, 114, 10203.
10.1021/ja981302s CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/27/1998

11280 J. Am. Chem. Soc., Vol. 120, No. 44, 1998
Scheme 1. Retrosynthetic Analysis of Mucocin
Neogi et al.
major steps starting with the “naked” carbon skeleton, V. First,
the AE reaction is used to epoxidize the two allylic double
bonds, affording IV, and then the AD reaction is used to
dihydroxylate the remaining two double bonds, producing the
fully oxidized intermediate III.
Our synthesis of 1 (Scheme 3) starts with trans,trans,trans-
1,5,9-cyclododecatriene as a convenient source of a 12-carbon
skeleton.16 Selective dihydroxylation of one of the three double
bonds was achieved using NMO and catalytic amounts of
osmium tetraoxide. The resultant diol was oxidatively cleaved
with sodium metaperiodate to produce dialdehyde 2. Wittig
olefination of the latter afforded the bis-enoate 3 which was
reduced with DIBAL-H to provide the desired “naked” carbon
skeleton intermediate, 4. Double AE reaction with the bis-allylic
alcohol, 4, in the presence of (-)-diethyl tartrate followed by
chromatographic purification and recrystallization afforded the
C2 symmetric diepoxide 5 in 98% ee. Desymmetrization of 5
was achieved by monosilation with TBDMSCl to give silyl ether
6. Oxidation of the unprotected alcohol in 6 with SO3-pyridine
produced aldehyde 7. The Wittig reaction of aldehyde 7 with
triphenylnonylphosphorane produced the (Z) alkene 8 which
contained the required unsaturation next to the epoxide function
(vide supra). We took advantage of the known higher reactivity
of (E) disubstituted alkenes relative to (Z) alkenes in the AD
reaction,16 which, added to the steric hindrance of the latter
double bond, could enable selective dihydroxylation of the
former in the presence of the latter. Indeed, asymmetric
dihydroxylation of 8 using AD-mix-R selectively oxidized the
two trans double bonds in the molecule, affording the tetrahy-
droxylated intermediate 9, and keeping the (Z) double bond
intact. This reaction set the stage for the key step in the entire
synthetic strategy, i.e., double ring closure of the diepoxytetrol
intermediate 9 to produce the nonadjacent THP-THF ring
system, 10a, with the required stereochemistry. Thus, treatment
of 9 with a catalytic amount of TsOH for 1 h produced 10a in
high yield. Treatment of 10a with TsOH for an additional
period of 16 h at room-temperature hydrolyzed the silyl ether
to give pentol 10b. The latter was reacted with 2,2-dimethoxy-
propane and TsOH, affording the bis-acetonide 11. The less
stable, seven-membered ring acetonide was selectively hydro-
lyzed in aqueous TsOH at 0 °C to produce triol 12a. The latter
was fully protected by reaction with MEM-Cl to give 12b.
Cleavage of the acetonide function with aqueous acetic acid
followed by oxidative cleavage of the resultant 1,2-diol with
sodium metaperiodate yielded aldehyde 14. The latter was
transformed to the dibromide 15,17 which, upon treatment with
2 equiv of n-BuLi at -78 °C, produced the terminal alkyne 16
in 50% yield, along with the trans-alkene monobromide (20%),
thus completing the crucial fragment of the target molecule.
Generation of an alkyne from a dibromoalkene is usually a high-
yielding process;17,18 however, the low yield in this case can
be attributed due to the instability of the produced alkyne. In
fact, when the same reaction was left till all the produced
monobromide was consumed, the alkyne 16 was obtained in
only 25% yield.
structure. Here we report on the first total synthesis of 1, thus
unequivocally confirming its absolute configuration.
As illustrated in our retrosynthetic analysis (Scheme 1), 1
may be constructed from two key building blocks, I and II.
While the fragment II is relatively easy to synthesize considering
a number of well documented precedents, construction of the
main fragment, I, which contains both THP and THF rings with
seven asymmetric carbon atoms, represents a nontrivial synthetic
challenge. In fact, previous attempts to synthesize mucocin have
focused on the preparation of the hydroxylated THP ring.9 Our
synthetic design was based on a key step in which two ring
closure reactions lead from the linear intermediate III to the
bicyclic intermediate I. According to the Baldwin rules, the
formation of a six-membered ring via a 6-endo hydroxy epoxide
opening (route b, Scheme 2) is disfavored in comparison with
the alternative formation of a five-membered ring via a 5-exo
ring closure (route a).10 Therefore, in our synthetic design we
have incorporated an unsaturated substituent (R ) alkenyl) to
revert the regioselectivity and promote formation of a THP ring
rather than the THF product.11
Scheme 2
Our synthetic approach to III was based on the “naked”
carbon skeleton strategy, i.e., selective placement of the oxygen
functions onto a naked, unsaturated carbon skeleton.12,13 For
that purpose we planned to use the Sharpless asymmetric
dihydroxylation (AD)14 and asymmetric epoxidation (AE)15
reactions. Thus, one may envision the synthesis of III in two
(14) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(9) (a) Evans, P. A.; Roseman, J. D. Tetrahedron Lett. 1997, 38, 5249.
(b) Crimmins, M. T.; Rafferty, S. W. Tetrahedron Lett. 1996, 37, 5649.
(10) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(11) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J.
Am. Chem. Soc. 1989, 111, 5330
(12) Keinan, E.; Sinha, A.; Yazbak, A.; Sinha, S. C.; Sinha, S. C. Pure
Appl. Chem. 1997, 69, 423.
(13) (a) Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E. J. Org. Chem. 1993,
58, 7789. (b) Sinha, S. C.; Keinan, E. J. Org. Chem. 1994, 59, 949. (c)
Sinha, S. C.; Keinan, E. J. Org. Chem. 1997, 62, 377.
(15) (a) Johnson, R. A.; Sharpless, K. B. Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH Publishers Inc.: New York, 1993; p 103. (b) Gao, Y.;
Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1987, 109, 5765.
(16) Becker, H.; Soler, M. A.; Sharpless, K. B. Tetrahedron 1995, 51,
1345.
(17) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(18) (a) Donkervoort, J. G.; Gordon, A. R.; Johnstone, C.; Kerr, w. J.;
Lange, U. Tetrahedron 1997, 52, 7391. (b) Tietze, L. F.; Neumann, T.;
Kajino, M.; Pretor, M. Synthesis 1995, 1003.

Total Synthesis of Mucocin
J. Am. Chem. Soc., Vol. 120, No. 44, 1998 11281
Scheme 3. Total Synthesis of Mucocina
a Key: (a) i. OsO4, acetone-H2O, rt, 24 h. (ii) NaIO4, CH2Cl2-acetone, H2O, 0 °C to rt, 2 h. (b) (EtO)2P(O)CH2CO2Et, NaH, THF, 0 °C, 15
min. (c) DIBAL-H, THF, -78 °C, 90 min. (d) Ti(OiPr)4, (-)-DET, TBHP, powdered molecular sieves 4 Å, -20 °C, 16 h. (e) TBDMSCl, imidazole,
DMF, rt, 16 h. (f) SO3-pyridine, DMSO, TEA, CH2Cl2, 0 °C to rt, 3 h. (g) C9H19PPh3Br, KN(SiMe3)2, THF, 2 h, -78 °C then HMPA and aldehyde
7 in THF, -78 °C to rt, 16 h. (h) AD-mix-R, MeSO2NH2, OsO4, tert-butanol-H2O (1:1), 0 °C, 16 h. (i) TsOH, CH2Cl2, 0 °C, 6 h. (j) TsOH,
CH2Cl2-MeOH, rt, 16 h. (k) DMP, acetone, p-TsOH, rt, 2 h. (l) TsOH, MeOH-H2O, 0 °C, 30 min. (m) MEM-Cl, diisopropylethyl amine,
CH2Cl2, 0 °C to rt, 16 h. (n) AcOH-H2O, 30 °C, 4 h. (o) NaIO4, CH2Cl2-acetone, H2O, 0 °C to rt, 2 h. (p) CBr4, PPh3, CH2Cl2, 0 °C, 15 min. (q)
n-BuLi, THF, -78 to -10 °C, 2 h. (r) 17, TEA, (PPh3)2PdCl2, CuI, rt, 16 h. (s) (PPh3)3RhCl, benzene-EtOH, rt, 48 h. (t) 5% CH3COCl in MeOH,
CH2Cl2, rt, 16 h.
Scheme 4. Synthesis of the Side Chain for Mucocina
Pd(II) was found to be more effective than the Pd(0) catalyst,
affording enyne 18 in 55% yield. Homogeneous catalytic
hydrogenation using Wilkinson’s catalyst produced 19 in high
yield, keeping the butenolide function intact. Finally, acid-
catalyzed deprotection of all four protecting groups in 19
1
afforded 1, which was found to be identical (MS, H and 13C
NMR, [R]D) with the naturally occurring mucocin.5
In conclusion, the synthesis of 1 was efficiently achieved in
20 steps from cyclododecatriene, using the “naked” carbon
skeleton strategy. All seven asymmetric centers in the key
fragment of the molecule were introduced by double AE reaction
followed by double AD reaction. Double ring closure reactions
provided both THF and THP rings in a single step.
a Key: (a) 9-BBN, THF, 0 °C, 1 h. (b) PCC, CH2Cl2, rt, 1.5 h. (c)
CHI3, CrCl2, THF, 0 °C, 4 h.
Synthesis of the substituted butenolide fragment, 17, was
carried out using well precedented chemistry (Scheme 4). Thus,
oxidative hydroboration of alkene 2019 produced alcohol 21,
which was then oxidized with PCC to produce aldehyde 22.
Finally, olefination with iodoform and chromium dichloride
afforded the desired vinyl iodide 17 in the form of a 4:1 mixture
of the (E):(Z) isomers.20
With both fragments 16 and 17 at hand, we turned to the
final steps of the synthesis. Although both Pd(PPh3)4 and
Pd(PPh3)2Cl2 were found to be useful cross-coupling catalysts,
Experimental Section
General Methods. 1H and 13C NMR spectra were measured in
CDCl3 at 400 and 100 MHz, respectively. Positive ion mass spectra,
using the fast ion bombardment (FIB) technique, were obtained on a
VG ZAB-VSE double focusing, 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 1-dm (1.3 mL) cell using an Autopol III automatic
polarimeter. TLC was performed on glass sheets precoated with silica
gel (Merck, Kieselgel 60, F254, Art. 5715). Column chromatographic
separations were performed on silica gel (Merck, Kieselgel 60, 230-
(19) Sinha, S. C.; Sinha, A.; Sinha, S. C.; Keinan, E. J. Am. Chem. Soc.
1997, 119, 12014.
(20) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.

11282 J. Am. Chem. Soc., Vol. 120, No. 44, 1998
Neogi et al.
400 mesh, Art. 9385) under pressure. THF was dried and distilled
over sodium ketyl. AD-mix-R (no.39,275-8) was purchased from
Aldrich.
Hz, 2H) 3.63 (ddd, J ) 12.6, 6.7, 4.3 Hz, 2H), 2.96 (td, J ) 5.8, 2.4
Hz, 2H), 2.92 (dt, J ) 4.3, 2.5 Hz, 2H), 2.13 (m, 4H), 2.05 (m, 4H),
1.78 (dd, J ) 7.4, 5.6 Hz, 2H), 1.62 (td, J ) 7.4, 5.8 Hz, 4H); 13C
NMR: 130.7, 129.1, 61.6, 58.5, 55.5, 32.4, 31.5, 28.9; HRMS: found
305.1724 (C16H26O4Na ) 305.1729, MNa+).
(E,E)-Dodeca-4,8-diene-1,12-dial, 2. OsO4 (0.2 M, 2.3 mL, 0.46
mmol) and 4-methylmorpholine N-oxide (NMO) (50% aqueous, 38.4
mL, 185.2 mmol) were added to a solution of (trans,trans,trans)-1,5,9-
cyclododecatriene (15.0 g, 92.6 mmol) in CH2Cl2 (500 mL), and the
reaction mixture was stirred at room temperature for 24 h. Solid was
filtered, washed with water, and dried under vacuum to afford diol
(12.9 g, 71%) which was taken to next step without further purification.
1H NMR: 5.11 (m, 4H), 3.74 (q, J ) 6.5 Hz, 2H), 2.14 (m, 4H), 2.06
(m, 2H), 1.99 (m, 2H), 1.68 (m, 4H), 1.54 (d, J ) 6.9 Hz, 2H); 13C
NMR: 132.2, 130.6, 68.6, 32.1, 31.8, 28.9; HRMS: found 219.1357
(C12H20O2Na ) 219.1361, MNa+).
Sodium metaperiodate (17.12 g, 80 mmol) was added to a solution
of above-mentioned diol (7.58 g, 40 mmol) in CH2Cl2 (275 mL) and
acetone (25 mL) at 0 °C, and the mixture was stirred at room
temperature for 2 h. The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (2 × 50 mL). The combined organic
layers were washed with brine, dried over MgSO4, filtered, and
concentrated. The crude product was purified by column chromatog-
raphy (silica gel, hexanes-EtOAc, 4:1) to 2 (7.2 g, 93%) in the form
of a colorless oil. 1H NMR: 9.70 (t, J ) 1.8 Hz, 2H), 5.38 (m, 4H),
2.44 (m, 4H), 2.30 (m, 4H) and 1.98 (m, 4H); 13C NMR: 202.4, 131.1,
128.3, 43.4, 32.2, 25.0.
(E,E,2R,3R,14R,15R)-16-(tert-Butyldimethylsilyloxy)-2,3:14,15-di-
oxido-hexadeca-6,10-dien-1-ol, 6. Imidazole (0.53, 7.84 mmol) and
TBDMSCl (0.83 g, 5.53 mmol) were added sequentially to a stirred
solution of 6 (1.3 g, 4.61 mmol) in dry DMF (10 mL). After being
stirred at room temperature for 16 h, the mixture was poured into water
and extracted with ether (3 × 25 mL). The combined organic layer
was washed with brine and dried over MgSO4. Solvents were removed,
and the residue was purified by column chromatography (silica gel,
hexanes-EtOAc, 4:1) to yield 6 (0.62 g, 38%, 50% based on 25%
recovered starting material and di-TBDMS derivative, 455 mg, 35%),
1
[R]D: +21 (c ) 1.3, CHCl3); H NMR: 5.40 (m, 4H), 3.85 (m, 1H),
3.76 (m, 1H), 3.61 (m, 2H), 2.93 (m, 1H), 2.90 (m, 1H), 2.81 (m, 2H),
2.11 (m, 4H), 2.01 (br s, 4H), 1.59 (m, 4H), 1.21 (br d, J ) 7.6 Hz,
1H), 0.87 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR: 130.7, 130.5,
129.2, 129.1, 63.5, 61.6, 58.8, 58.5, 55.8, 55.5, 32.5, 31.7, 31.5, 28.9,
26.4, 25.9, 18.3, -5.3, -5.4; HRMS: found 419.2788 (C22H40O4SiNa
) 419.2594, MNa+).
(E,E,2R,3R,14R,15R)-16-(tert-Butyldimethylsilyloxy)-2,3:14,15-di-
oxido-hexadeca-6,10-dien-1-al, 7. SO3-pyridine complex (1.77 g,
11.1 mmol) was added to a stirred solution of 7 (2.2 g, 5.5 mmol),
Et3N (4.64 mL, 33.3 mmol), and dry DMSO (1.57 mL, 22.2 mmol) in
CH2Cl2 (15 mL) at 0 °C, and the mixture was stirred for 3 h (0 °C-
rt). Water (10 mL) was added, and the organic layer was separated.
The aqueous layer was extracted with CH2Cl2 (3 × 25 mL), the
combined organic layer was washed with brine and dried over MgSO4,
and the solvent was removed under reduced pressure. Column
chromatography (silica gel, hexanes-EtOAc, 19:1) afforded 7 (1.73
g, 79%) in the form of a colorless oil. 1H NMR: 8.99 (d, J ) 5.2 Hz,
1H), 5.41 (m, 4H), 3.76 (dd, J ) 11.6, 3.2 Hz, 1H), 3.62 (dd, J )
11.6, 4.4 Hz, 1H), 3.21(dt, J ) 5.6, 2.0 Hz, 1H), 3.11 (dd, J ) 6.0, 1.2
Hz, 1H), 2.82 (m, 2H), 2.13 (m, 4H), 2.02 (br s, 4H), 1.69 (m, 2H),
1.59 (m, 2H), 0.87 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR: 198.3,
131.5, 130.4, 129.3, 128.2, 63.5, 59.2, 58.7, 56.3, 55.8, 32.4, 31.7, 31.1,
29.0, 28.8, 25.8, -5.3, -5.4; MS: 395 (MH+).
(6E,10E,16Z,2R,3R,14R,15R)-1-(tert-Butyldimethylsilyloxy)-2,3:
14,15-dioxido-pentadodeca-6,10,16-triene, 8. KN(SiMe3)2 (0.5 M in
toluene, 7.1 mL, 3.55 mmol) was added to a stirred solution of n-C9H19-
PPh3Br (1.37 g, 3.55 mmol) in dry THF (70 mL) at -78 °C, and the
mixture was stirred at the same temperature for 2 h. HMPA (1.23
mL, 7.1 mmol) and aldehyde 8 (1.40 g, 3.55 mmol) in THF (10 mL)
were added dropwise, and the mixture was stirred for 16 h at -78
°C-rt. Saturated aqueous NH4Cl was added, and the mixture was
extracted with Et2O (3 × 70 mL). The combined organic layer was
washed with brine and dried over MgSO4, and solvents were removed
under reduced pressure. The crude product was purified by column
chromatography (silica gel, hexanes-EtOAc, 19:1) to yield 9 (1.65,
92%) in the form of a colorless oil, [R]D: +7.0 (c ) 1.10, CHCl3); 1H
NMR: 5.66 (dt, J ) 11.0, 8.0 Hz, 1H), 5.40 (m, 4H), 5.00 (ddt, J )
11.6, 7.4, 1.5 Hz, 1H), 3.76 (dd, J ) 11.6, 3.2 Hz, 1H), 3.64 (dd, J )
11.7, 4.5 Hz, 1H), 3.33 (dd, J ) 8.9, 1.5 Hz, 1H), 2.82 (m, 3H), 2.14
(m, 6H), 2.00 (br s, 4H), 1.60 (m, 4H), 1.37 (m, 2H), 1.23 (br s, 10H),
0.88 (s, 9H), 0.86 (t, J ) 7.2 Hz, 3H), 0.05 (s, 3H), 0.04 (s, 3H); 13C
NMR: 136.6, 130.6, 129.2, 126.9, 63.6, 59.7, 58.8, 55.8, 54.5, 32.5,
32.1, 31.9, 31.7, 29.6, 29.4, 29.3, 29.2, 29.0, 28.9, 27.7, 25.9, 22.6,
14.1, -5.3, -5.4; MS: 505 (MH+).
(E,E,E,E)-Diethyl -hexadeca-2,6,10,14-tetraendioate, 3. Triethyl
phosphonoacetate (14.8 g, 66 mmol) was added to a suspension of NaH
(60% in mineral oil, 2.64 g, 66 mmol) in THF at 0 °C, and the mixture
was stirred for 15 min. A solution of aldehyde 3 (5.1 g, 26.3 mmol)
in THF (20 mL) was added, and the mixture was stirred for 15 min at
0 °C. The mixture was quenched with saturated aqueous NH4Cl
solution and diluted with water (60 mL), and the mixture was extracted
with hexanes-Et2O (1:1, 3 × 50 mL). The combined organic layers
were washed with brine, dried over MgSO4, filtered, and concentrated.
The crude product was purified by column chromatography (silica gel,
hexanes-EtOAc, 9:1) to yield 3 (8.6 g, 98%) in the form of a colorless
oil. 1H NMR: 6.92 (dt, J ) 15.6, 6.7 Hz, 2H), 5.79 (dt, J ) 15.6, 1.5
Hz, 2H), 5.39 (m, 4H), 4.16 (q, J ) 5.6 Hz, 4H), 2.22 (q, J ) 6.8 Hz,
4H), 2.11 (q, J ) 5.3 Hz, 4H), 2.01 (m, 4H), 1.25 (t, J ) 5.6 Hz, 6H);
13C NMR: 166.7, 148.6, 131.0, 128 0.9, 121.6, 60.1, 32.5, 32.1, 30.9,
29.7, 14.3; HRMS: found 335.2228 (C20H31O4 ) 335.2222, MH+).
(E,E,E,E)-Hexadeca-2,6,10,14-tetraene-1,16-diol, 4. DIBAL-H (1
M in toluene, 127.2 mL, 127.2 mmol) was added dropwise to a solution
of 4 (8.5 g, 25.4 mmol) in THF (80 mL) at -78 °C. The mixture was
stirred at the same temperature for 1.5 h and then quenched by slow
addition of saturated aqueous NH4Cl solution (35 mL) followed by
Celite (35 g). The mixture was diluted with Et2O, warmed slowly to
room temperature, and stirred till all aluminum precipitated. Solid was
filtered and washed with Et2O (3 × 50 mL), and the combined organic
layer was dried over MgSO4, filtered, and concentrated. The residue
was purified by column chromatography (silica gel, CH2Cl2-MeOH,
49:1) to give the 4 (5.8 g, 92.0%) in the form of a white solid, mp
1
98-100 °C; H NMR: 5.64 (m, 4H), 5.34 (m, 4H), 4.29 (d, J ) 5.0
Hz, 4H), 2.11-2.06 (m, 12H), 1.83 (br s, 2H); 13C NMR: 132.8, 130.3,
129.6, 129.1, 63.8, 32.6, 32.2, 32.1; HRMS: found 273.1834 (C16H26O2-
Na ) 273.1830, MNa+).
(E,E,2R,3R,14R,15R)-2,3:14,15-Dioxido-hexadeca-6,10-diene-1,16-
diol, 5. D-(-)-Diethyl tartrate (1.73 g, 8.4 mmol) and Ti(iso-OPr)4
(2.4 g, 8.4 mmol) was added sequentially to a mixture of alcohol 4
(5.2 g, 21 mmol) and 4 Å dry molecular sieves powder (5.2 g) in dry
CH2Cl2 (100 mL) at -20 °C, and the mixture was stirred at the same
temperature for 30 min. tert-BuOOH (5.2 M in isooctane, 21 mL, 109.2
mmol) was added, and the solution was stirred at -20 °C for 16 h.
Aqueous NaOH (3 M, 20 mL) was added to the reaction mixture,
allowed to warm to room temperature over 1 h, and then filtered through
a bed of Celite, and the bed was washed with ethyl acetate (3 × 50
mL). The combined organic layer was dried over MgSO4, and the
crude product was purified by column chromatography (silica gel, CH2-
Cl2-MeOH, 19:1) to give 5 (3.34 g, 57.0%) in the form of a white
solid after crystallization from Et2O, mp 105-107 °C; [R]D: +40 (c
) 1.1, CHCl3); 1H NMR: 5.44 (m, 4H), 3.88 (ddd, J ) 12.6, 4.9, 2.6
(16Z,2R,3R,6S,7S,10S,11S,14R,15R)-1-(tert-Butyldimethylsilyloxy)-
pentadodec-16-ene-6,7,10,11-tetrol, 9. Compound 8 (0.77 g, 1.52
mmol) was added to a cold (0 °C) solution of AD-mix-R (4.28 g, OsO4
content 0.4%) and MeSO2NH2 (0.29 g, 3.0 mmol) in tert-BuOH-water
(1:1, 30 mL), and the mixture was stirred at this temperature for 16 h.
The reaction was quenched by slow addition of Na2S2O3 (4.5 g) and
stirred at room temperature for 30 min. The mixture was extracted
with EtOAc (3 × 30 mL), washed with brine, and dried over MgSO4,
and the solvents were removed under reduced pressure. The crude
product (0.82 g, 94%) was used in the next step without further
purification, 1H NMR: 5.70 (dt, J ) 8.8, 7.6 Hz, 1H), 5.05 (br s, 1 H),

Total Synthesis of Mucocin
J. Am. Chem. Soc., Vol. 120, No. 44, 1998 11283
5.01 (br t, J ) 7.6 Hz, 1H), 3.78 (dd, J ) 9.6, 2.4 Hz, 1H), 3.66 (m,
1H), 3.80-3.60 (br, 1H), 3.52-3.32 (m, 6H), 3.01 (m, 1H), 2.88 (m,
3H), 2.18 (m, 2H), 2.02-1.20 (m and br s, 24H), 0.88 (s, 9H), 0.86 (t,
J ) 6.0 Hz, 3H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (CDCl3 + CD3-
OD): 137.2, 126.2, 74.1, 73.9, 73.8, 63.3, 60.5, 58.8, 56.4, 54.6, 43.0,
31.8, 29.6, 29.5, 29.4, 29.3, 29.2, 29.1, 28.4, 28.0, 27.6, 25.7, 22.5,
18.22, 14.0, -5.5; MS: found 705.3144 (C31H60O7SiCs ) 705.3163,
MCs+).
(16Z,2R,3S,6S,7S,10S,11S,14R,15S)-3,6:11,15-Dioxido-1,2-(isopro-
pylidenedioxy)-7,10,14-tris(methoxyethoxymethoxy)-pentadodec-16-
ene, 12b. iso-Pr2NEt (1.47 mL, 8.4 mmol) and MEM-chloride (0.48
mL, 4.2 mmol) were added sequentially to a solution of compound
12a (340 mg, 0.68 mmol) in dry CH2Cl2 (10 mL) at 0 °C, and the
reaction mixture was stirred at room temperature for 16 h and then
worked-up with water-CH2Cl2. The organic layer was washed with
saturated aqueous NaHCO3, and the crude product was purified by
column chromatography (silica gel, hexanes-EtOAc, 3:2) to yield 12b
(373 mg, 72%) in the form of a colorless oil, [R]D: -26.6 (c ) 2.8,
(16Z,2R,3S,6S,7S,10S,11S,14R,15S)-1-(tert-Butyldimethylsilyloxy)-
3,6:11,15-dioxido-pentadodec-16-ene-2,7,10,14-tetrol, 10a. p-TsOH
(0.025 g, 0.13 mmol) was added to a solution of 9 (0.80 g, 1.39 mmol)
in dry CH2Cl2 (15 mL) at 0 °C, and the mixture was stirred for 6 h and
then washed with saturated aqueous NaHCO3 (3 mL) and brine. The
organic layer was dried over MgSO4, the solvent was removed, and
the crude product was purified by chromatography (silica gel, CH2-
Cl2-MeOH, 23:2) to yield 10a (0.57 g, 72%) in the form of a colorless
1
CHCl3); H NMR: 5.52 (dt, J ) 10.9, 7.3 Hz, 1H), 5.27 (t, J ) 10.9
Hz, 1H), 4.70 (m, 6H), 4.06-3.40 (m, 22H), 3.34-3.33 (overlapped
s, 9H), 2.17-1.43 (m, 14H), 1.34 (s, 3H), 1.29 (s, 3H), 1.24-1.19 (br
s, 12H), 0.83 (t, J ) 6.3 Hz, 3H); 13C NMR: 134.9, 128.1, 109.2, 95.7,
95.4, 94.2, 81.9, 79.9, 79.4, 78.5, 78.1, 75.1, 71.7, 67.6, 67.2, 66.7,
59.0, 31.8, 30.1, 29.6, 29.5, 29.3, 29.2, 29.1,28.3, 26.9, 26.6, 26.0, 25.6,
25.3, 22.6, 14.1; HRMS: found 895.4153 (C40H74O13Cs ) 895.4184,
MCs+).
1
oil, H NMR: 5.74 (dt, J ) 11.0, 7.4 Hz, 1H), 5.32 (br t, J ) 11 Hz,
1H), 3.85 (m, 2H), 3.78 (q, J ) 7.0 Hz, 1H), 3.68 (m, 1H), 3.60 (m,
2H), 3.46-3.38 (m, 2H), 3.29-3.20 (m, 2H), 3.04-2.24 (br, 2H),
2.19-1.25 (m, 18H), 1.20 (br s, 10H), 0.87 (s, 9H), 0.85 (t, J ) 6 Hz,
3H), 0.05 (s, 6H); 13C NMR: 137.1, 127.1, 82.9, 80.2, 79.1, 78.2, 73.9,
73.4, 73.1, 70.1, 64.2, 31.8, 30.8, 29.7, 29.4, 29.3, 29.2, 28.9, 28.6,
28.4, 28.1, 20.0, 26.6, 22.6, 18.3, 14.4, -5.4; MS: 595 (MNa+).
(16Z,2R,3S,6S,7S,10S,11S,14R,15S)-3,6:11,15-Dioxido-7,10,14-
tris(methoxyethoxymethoxy)-pentadodec-16-ene-1,2-diol, 13. Ac-
etonide 12b (330 mg, 0.43 mmol) was mixed with a 3:2 solution of
glacial AcOH and water (5 mL), and the mixture was stirred at 30 °C
for 4 h. The solvents were removed under reduced pressure at room
temperature, and the crude product was purified by column chroma-
tography (silica gel, CH2Cl2-methanol, 19:1) to yield diol 13 (310 mg,
99.2%) in the form of a colorless oil, [R]D: -25.2 (c ) 0.50, CH2Cl2);
1H NMR: 5.52 (dt, J ) 10.8, 7.4 Hz, 1H), 5.26 (t, J ) 10.2 Hz, 1H),
4.81-4.59 (m, 6H), 3.94-3.15 (m, 22H), 3.32 (s, 9H), 2.70 (br s, 2H),
2.16-1.40 (m, 14H), 1.28-1.20 (br s, 12H), 0.81 (t, J ) 6.0 Hz,
3H);13C NMR: 134.9, 128.0, 95.7, 95.3, 94.2, 81.7, 79.7, 79.4, 78.4,
76.7, 75.1,73.3, 71.8, 67.2, 66.7, 63.8, 58.9, 31.8, 30.0, 29.6, 29.5, 29.3,
29.2, 28.5,28.2, 27.8, 26.9, 25.9, 25.6, 22.6, 14.1; HRMS: found
855.3836 (C37H70O13Cs ) 855.3871, MCs+).
(16Z,2R,3S,6S,7S,10S,11S,14R,15S)-3,6:11,15-Dioxido-pentadodec-
16-ene-1,2,7,10,14-pentol, 10b. p-TsOH (0.018 g, 0.096 mmol) was
added to a stirred solution of 10a (0.55 g, 0.96 mmol) in CH2Cl2 (10
mL) and MeOH (5 mL) at 0 °C, and the mixture was stirred at room
temperature for 16 h. Solvent was removed under reduced pressure at
room temperature. The crude product, 10b, was taken to the next step
1
without further purification (0.32 g, 73%), H NMR: 5.73 (dt, J )
11.0, 7.4 Hz, 1H), 5.31 (dd, J ) 11.0, 9.0 Hz, 1H), 3.88 (m, 1H), 3.85
(t, J ) 8.9 Hz, 1H), 3.79 (q, J ) 7.5 Hz, 1H), 3.61 (m, 4H), 3.41 (m,
4H), 3.24 (m, 3H), 2.10-1.52 (m, 17H), 1.20 (br s, 12H), 0.81 (t, J )
6.8 Hz, 3H); MS: 481 (MNa+).
(15Z,2S,5S,6S,9S,10S,13R,14S)-2,5:10,14-Dioxido-6,9,13-tris-
(methoxyethoxymethoxy)-pentadodec-15-en-1-al, 14. NaIO4 (0.18
g, 0.83 mmol) and water (0.5 mL) were added to a solution of 13 (300
mg, 0.42 mmol) in CH2Cl2 (5 mL) and acetone (3 mL) at 0 °C. The
mixture was stirred for 2 h, dried over Na2SO4, and filtered through
Celite. Solvents were removed under reduced pressure, and the residue
was purified by column chromatography (silica gel, CH2Cl2-MeOH,
(16Z,2R,3S,6S,7S,10S,11S,14R,15S)-1,2:7,10-(Diisopropylidene-
dioxy)-3,6:11,15-dioxido-pentadodec-16-en-14-ol, 11. p-TsOH (0.10
g, 0.52 mmol) was added to a stirred solution of 10b (0.52 g, 1.1 mmol)
in acetone (10 mL) and 2,2-dimethoxypropane (20 mL), and the mixture
was stirred at room temperature for 2 h. The mixture was mixed with
Et2O (50 mL) and washed with saturated aqueous NaHCO3 (10 mL)
followed by brine (2 × 10 mL). The organic layer was dried over
MgSO4, and solvents were removed under reduced pressure. The crude
product was purified by column chromatography (silica gel, hexanes-
EtOAc, 3:1) to yield 11 (0.42 g, 70%) in the form of a colorless oil,
1
49:1) to yield 14 (275 mg, 95.0%) in the form of a colorless oil, H
NMR: 9.63 (d, J ) 1.92 Hz, 1H), 5.56 (dt, J ) 11.0, 7.1 Hz, 1H),
5.30 (t, J ) 8.7 Hz, 1H), 4.81-4.59 (m, 6H), 4.29 (dd, J ) 7.9, 1.8
Hz, 1H) 4.09 (dt, J ) 8.2, 6.0 Hz, 1H), 3.90 (t, J ) 8.8 Hz, 1H),
3.72-3.62 (m, 6H), 3.52-3.39 (m, 9H), 3.37 (s, 9H), 3.29 (m, 1H),
2.23-1.42 (m, 14H), 1.33-1.23 (br s, 12H), 0.86 (t, J ) 6.6 Hz, 3H);
13C NMR: 203.0,134.9, 128.0, 99.8, 95.5, 94.2, 82.2, 79.5, 79.2, 78.4,
75.1, 71.8, 71.7, 67.3, 66.8, 59.0, 31.9, 30.1, 29.6, 29.5, 29.4, 29.3,
28.3, 27.7, 27.3, 26.0, 25.7, 25.6, 22.7, 14.1; HRMS: found 823.3576
(C36H66O12 ) 823.3609, MCs+).
1
[R]D: -47 (c ) 1.80, CH2Cl2); H NMR (300 MHz): 5.72 (m, 1H),
5.36 (br t, J ) 8.4 Hz, 1H), 4.05 (m, 2H), 3.95 (m, 2H), 3.89 (m, 4H),
3.83 (m, 1H), 3.80 (m, 2H), 2.15-1.64 (m, 6H), 1.69-1.61 (m, 8H),
1.44 (s, 3H), 1.38 (s, 3H), 1.33 (s, 6H), 1.29-1.23 (br s, 12H), 0.85 (t,
J ) 6.6 Hz, 3H); 13C NMR: 136.4, 127.6, 109.1, 100.3, 81.7, 79.9,
79.5, 78.7, 78.0, 73.9, 72.6, 70.0, 67.6, 31.9, 31.2, 29.6, 29.4, 29.2,
29.1,29.0, 28.3, 28.0, 26.6, 25.9, 25.2, 22.6, 14.0; MS: 561 (MNa+).
(16Z,3S,6S,7S,10S,11S,14R,15S)-1,1-Dibromo-3,6:11,15-dioxido-
7,10,14-tris(methoxyethoxymethoxy)-pentadodeca-1,16-diene, 15.
PPh3 (0.39 g, 1.48 mmol) and CBr4 (0.25 g, 0.74 mmol) were added to
solution of 14 (255 mg, 0.37 mmol) in dry CH2Cl2 (5 mL) at 0 °C.
The mixture was stirred for 15 min and then quenched by addition of
solid NaHCO3 followed by water (5 mL). The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2 (3 × 5
mL). The combined organic layer was washed with water, dried over
MgSO4, and concentrated. The crude product was purified by column
chromatography (silica gel, benzene-EtOAc, 2:3) to furnish 15 (300
mg, 96%) in the form of a pale yellow oil, [R]D: -16.9 (c ) 0.65,
(16Z,2R,3S,6S,7S,10S,11S,14R,15S)-1,2-(Isopropylidenedioxy)-3,6:
11,15-dioxido-pentadodec-16-ene-7,10,14-triol, 12a. p-TsOH (30 mg,
0.16 mmol) was added to a stirred solution of 11 (0.40 g, 0.74 mmol)
in MeOH (5 mL) and water (0.5 mL) at 0 °C, and the mixture was
stirred for 30 min. The reaction mixture was mixed with EtOAc (50
mL) and washed with saturated aqueous NaHCO3 (10 mL) followed
by brine (2 × 10 mL). The organic layer was dried over MgSO4, and
the solvent was removed under reduced pressure. The crude product
was purified by column chromatography (silica gel, CH2Cl2-MeOH,
97:3) to yield the monoacetonide 12a (340 mg, 92%) as colorless oil,
1
1
CH2Cl2); H NMR: 6.47 (d, J ) 7.5 Hz, 1H), 5.57 (dt, J ) 11.0, 7.6
[R]D: -255.6 (c ) 0.50, CHCl3); H NMR: 5.72 (dt, J ) 7.9 and 7.8
Hz, 1H), 5.30 (t, J ) 9.9 Hz, 1H), 4.86-4.63 (m, 6H), 4.53 (q, J )
7.4 Hz, 1H), 4.00 (q, J ) 6.2 Hz, 1H), 3.90 (t, J ) 8.8 Hz, 1H), 3.72-
3.51 (m, 6H), 3.53-3.51 (m, 8H), 3.42 (m, 1H), 3.37-3.36 (overlapped
s, 9H), 3.30 (m, 1H), 2.17 (br s, 2H), 2.05 (m, 2H), 1.98 (br s, 1H),
1.65-1.24 (m and br s, 21H), 0.86 (t, J ) 6.4 Hz, 3H); 13C NMR:
139.8, 134.9, 128.0, 95.8, 95.5, 94.2, 81.7, 79.5, 79.1, 78.5, 75.2, 71.8,
71.7,67.3, 66.8, 59.0, 31.9, 31.6, 29.6, 29.5, 29.4, 29.3, 28.3, 26.1, 22.7,
14.1; HRMS: found 977.2058 (C37H66Br2O11Cs ) 977.2026, MCs+).
Hz, 1H), 5.30 (t, J ) 9.2 Hz, 1H), 4.07 (t, J ) 7.2 Hz, 1H), 3.97 (q,
J ) 7.2 Hz, 1H), 3.93-3.77 (m, 4H), 3.46 (m, 1H), 3.42 (m, 1H),
3.25-3.15 (m, 2H), 2.95 (br s, 1H), 2.78 (br s, 1H), 2.15-1.35 (m,
15H), 1.39 (s, 3H), 1.33 (s, 3H), 1.35-1.15 (m and br s, 12H), 0.86 (t,
J ) 6.5 Hz, 3H); 13C NMR: 137.0, 127.1, 109.3, 83.0, 80.1, 79.8,
78.1, 77.8, 73.7, 73.3, 70.0, 67.3, 31.8, 30.8, 29.7, 29.4, 29.3, 29.2,
29.0, 28.9, 28.5, 28.4, 27.9, 26.6, 26.5, 25.2, 22.6, 14.1; HRMS: found
631.2638 (C28H50O7Cs ) 631.2611, MCs+).

11284 J. Am. Chem. Soc., Vol. 120, No. 44, 1998
Neogi et al.
(16Z,3S,6S,7S,10S,11S,14R,15S)-3,6:11,15-dioxido-7,10,14-tris-
(methoxyethoxymethoxy)-pentadodec-16-en-1-yne, 16. n-BuLi (0.165
mL, 0.265 mmol) was added dropwise to a solution of 15 (70 mg,
0.106 mmol) in THF at -78 °C, and the mixture was warmed slowly
to -50 °C over 2 h and then quenched with saturated aqueous NH4Cl
and extracted with Et2O (2 × 5 mL). The organic layer was separated,
and aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The organic
layer was dried over anhydrous MgSO4 and concentrated. The crude
product was purified by column chromatography (silica gel, CH2Cl2-
MeOH, 99:1) to furnish 16 (37 mg, 50%) in the form of a colorless oil
and corresponding monobromoalkene (14 mg, 20%). Physical data of
16: [R]D: -31.6 (c ) 0.80, CH2Cl2); 1H NMR: 5.56 (dt, J ) 11.0, 7.3
Hz, 1H), 5.29 (t, J ) 8.7 Hz, 1H), 4.82-4.61 (m, 6H), 4.15 (dd, J )
13.0, 6.4 Hz, 1H), 3.87 (t, J ) 9.0 Hz, 1H), 3.70-3.62 (m, 7H), 3.52
(m, 8H), 3.45 (m, 1H), 3.36 (s, 9H), 3.27 (m, 1H), 2.39 (dt, J ) 2.8,
2.2 Hz, 1H), 2.25-1.90 (m, 5H), 1.70-1.24 (m, 21H), 0.85 (t, J ) 6.4
Hz, 3H); 13C NMR: 134.9, 128.1, 95.8, 95.6, 94.2, 83.8, 80.8, 79.4,
79.2, 78.5, 75.2, 72.5, 71.7, 68.0, 67.3, 66.7, 59.0, 33.3, 31.9, 30.1,
29.6, 29.5, 29.4, 29.3, 28.3, 27.4, 27.1, 26.3, 25.7, 22.7, 14.1; HRMS:
found 819.3624 (C37H66O11Cs ) 819.3659, MCs+).
(8(EZ),25Z)-4-(tert-Butyldiphenylsilyloxy)-16,19,23-tris(methoxy-
ethoxymethoxy)mucocin-8,25-dien-10-yne, 18. CuI (3.0 mg, 15
µmol) and Pd(PPh3)2Cl2 (3.4 mg, 4.7 µmol) were added to a solution
of the alkyne 16 (32 mg, 47 µmol) and the iodide 17 (45 mg, 82 µmol)
in Et3N (2 mL) under argon atmosphere. The reaction mixture was
stirred at room temperature for 16 h, the Et3N was removed under
reduced pressure, and the crude product was purified by column
chromatography (silica gel, hexanes-EtOAc, 6:4) to yield 18 (29 mg,
55%), 1H NMR: 7.67-7.60 (m, 4H), 7.52-7.24 (m, 6H), 6.90 (s, 1H),
5.97 (dt, J ) 15.8, 7.7 Hz, 1H), 5.61 (dt, J ) 11.2, 7.0 Hz, 1H), 5.35
(m, 2H), 4.93-4.68 (m, 7H), 4.15 (dd, J ) 7.2, 6.7 Hz, 1H), 4.03 (t,
J ) 4.9 Hz, 1H), 3.94 (t, J ) 8.7 Hz, 1H), 3.75-3.65 (m, 7H), 3.56-
3.54 (m, 8H), 3.47 (m, 1H), 3.41 (overlapped s, 9H), 3.33 (m, 1H),
2.45 (br s, 2H), 2.24-1.28 (m and br s, 32H), 1.34 (d, J ) 7.2 Hz,
3H), 1.06 (s, 9H), 0.86 (t, J ) 6.8 Hz, 3H); HRMS: found 1265.5869
(C65H100O14SiCs ) 1265.5937, MCs+).
4-(tert-Butyldiphenylsilyloxy)-16,19,23-tris(methoxyethoxymethoxy)-
mucocin, 19. Rh(PPh3)3Cl (10 mg, 11 µmol) was added to a solution
of 18 (29 mg, 25.6 µmol) in benzene-ethanol (1:1, 2 mL). The solution
was stirred at room temperature under H2 atmosphere for 48 h, the
solvent was removed under reduced pressure, and the product was
purified by column chromatography (silica gel, hexanes-EtOAc, 1:1)
(4S,2′R)-2-(2′-(tert-Butyldiphenylsilyloxy)-6′-hydroxyheptan-1-yl)-
pent-2-en-1,4-olide, 21. 9-BBN (0.5 M, 1.25 mL, 0.62 mmol) was
added to a solution of 20 (180 mg, 0.41 mmol) in THF (10 mL) at 0
°C and stirred overnight. 1 N NaOH (1.8 mL) and H2O2 (0.6 mL)
were added slowly to the reaction mixture at 0 °C and stirred for 2 h
at room temperature. The reaction mixture was extracted with Et2O
(3 × 10 mL), and the combined ether fractions were washed with brine,
dried over MgSO4, and evaporated to dryness. Residue was chromato-
graphed over SiO2 gel and eluted with hexanes-EtOAc (6:4) to afford
1
to yield 19 (25 mg, 86%), H NMR: 7.64 (m, 4H), 7.51-7.27 (m,
6H), 6.89 (d, J ) 1.4 Hz, 1H), 4.94-4.66 (m, 7H), 4.00-3.93 (m,
2H), 3.81 (m, 1H), 3.74-3.63 (m, 6H), 3.54-3.47 (m, 8H), 3.37 (s,
3H), 3.36 (s, 6H), 3.32 (m, 1H), 3.21 (m, 1H), 3.05 (dt, J ) 7.6, 2.1
Hz, 1H), 2.41 (m, 2H), 2.23 (m, 1H), 1.92 (m, 2H), 1.73-1.33 (m,
41H), 1.30 (d, J ) 6.8 Hz, 3H), 1.01 (s, 9H), 0.85 (t, J ) 6.7 Hz, 3H).
HRMS: found 1273.6555 (C65H108O14SiCs ) 1273.6563, MCs+).
1
21 as an oil (100 mg, 54%), H NMR: 7.63 (m, 4H), 7.39 (m, 6H),
Mucocin, 1. A solution of 5% AcCl in MeOH (1 mL) was added
to a stirred solution of protected 19 (25 mg, 21.9 µmol) in dichlo-
romethane (1 mL) and stirred at room temperature for 16 h. The solvent
was evaporated, and the residue was taken up in EtOAc (10 mL). The
ethyl acetate extract was washed with saturated NaHCO3 solution (2
× 2 mL) and brine (3 × 2 mL), dried over anhydrous MgSO4, and
evaporated. The crude product was chromatographed (silica gel,
hexanes-EtOAc, 1:4) to yield 1 (9 mg, 64%), [R]D: -13.4 (c ) 0.27,
CH2Cl2); 1H NMR (500 MHz, CDCl3): 7.16 (s, 1H), 5.05 (q, J ) 7.0
Hz, 1H), 3.86-3.82 (m, 2H), 3.79 (q, J ) 6.5 Hz, 1H), 3.46 (m, 1H),
3.42 (t, J ) 7.5 Hz, 1H), 3.26 (dt, J ) 9.8, 5.0 Hz, 1H), 3.15 (br t, J
) 7.0 Hz, 1H), 3.04 (dt, J ) 9.0, 2.5 Hz, 1H), 2.50 (d, J ) 13.6 Hz,
1H), 2.38 (dd, J ) 15.4, 8.5 Hz, 1H), 2.10 (m, 1H), 1.99 (m, 2H), 1.81
(m, 1H), 1.75-1.20 (m and br s, 44H), 1.42 (d, J ) 6.5 Hz, 3H), 0.86
(t, J ) 7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): 174.6, 151.8, 131.2,
82.0, 80.1, 79.3, 78.0, 73.8, 73.5, 70.6, 69.9, 37.4, 35.6, 33.3, 32.6,
32.4, 32.0, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 28.7, 28.3, 26.9, 26.2,
25.5, 22.7, 19.1, 14.1 ppm; HRMS: found: 771.3841 (C37H66O8Cs )
771.3812, MCs+).
6.92 (d, J ) 1.4 Hz, 1H), 4.89 (dq, J ) 6.8, 1.4 Hz, 1H), 4.01 (dt, J
) 11.3, 5.5 Hz, 1H), 3.45 (t, J ) 6.0 Hz, 2H), 2.43 (d, J ) 5.4 Hz,
2H), 1.60 (br s, 1H), 1.43-1.23 (m, 6H), 1.30 (d, J ) 6.8 Hz, 3H),
1.02 (s, 9H); 13C NMR: 174.1, 151.7, 135.8, 134.0, 130.4, 129.7, 127.7,
77.5, 71.6, 62.4, 35.8, 32.3, 31.6, 27.0, 20.8, 19.9, 18.9.
(4S,2′R)-2-(2′-(tert-Butyldiphenylsilyloxy)hexan-6′-al-1-yl)pent-2-
en-1,4-olide, 22. PCC (71 mg, 0.33 mmol) and Celite (71 mg) were
added to a solution of alcohol 21 (100 mg, 0.22 mmol) in CH2Cl2 (5
mL) and stirred for 2 h at room temperature. The reaction mixture
was passed through silica gel (hexanes: EtOAc, 3:7) to yield aldehyde
1
22 (89 mg, 90%), H NMR: 9.58 (t, J ) 1.6 Hz, 1H), 7.60 (m, 4H),
7.35 (m, 6H), 6.88 (d, J ) 1.4 Hz, 1H), 4.85 (qd, J ) 6.8, 1.4 Hz, 1H),
3.98 (m, 1H), 2.41 (m, 2H), 2.13 (m, 2H), 1.51 (m, 2H), 1.36 (m, 2H),
1.27 (d, J ) 6.8 Hz, 3H), 0.99 (s, 9H); 13C NMR: 202.3, 173.9, 151.6,
135.8, 133.8, 130.2, 129.8, 127.6, 77.5, 71.2, 43.4, 35.4, 31.7, 26.9,
19.3, 18.9, 17.3.
(4S,2′S)-2-(2′-(tert-Butyldiphenylsilyloxy)-7′-iodohept-6′-en-1′-yl)-
pent-2-en-1,4-olide, 17. A mixture of aldehyde 22 (78 mg, 0.17 mmol)
and iodoform (136 mg 0.35 mmol) in THF (3 mL) was added dropwise
to a solution of CrCl2 (125 mg, 1.02 mmol) in dry THF (1 mL) at 0 °C
and stirred for 4 h at the same temperature. The reaction was quenched
by addition of water and extracted with Et2O (3 × 5 mL). The
combined ether layer was washed with brine, dried over MgSO4, and
evaporated to a residue which was chromatographed over SiO2 gel
(hexanes-EtOAc, 9:1) to yield iodide 17 (87 mg, 88%) as a mixture
of trans and cis isomers (4:1) in the form of an oil, 1H NMR: 7.64 (m,
4H), 7.38 (m, 6H), 6.91 (d, J ) 1.4 Hz, 1H), 6.32 and 6.10 (dt, J )
14.4, 7.1 Hz and dt, J ) 7.3, 1.3 Hz, together 1H), 5.96 and 5.82 (q,
J ) 6.7 Hz and dt, J ) 14.3, 1.4 Hz, together 1H), 4.90 (m, 1H), 4.00
(dt, J ) 11.2, 5.6 Hz, 1H), 2.42 (m, 2H), 1.92 and 1.81 (m, together
1H), 1.42-1.23 (m, 4H), 1.31 (d, J ) 6.8 Hz, 3H), 1.03 (s, 9H); 13C
NMR: 173.9, 151.5, 146.1, 135.8, 133.4, 130.4, 129.7, 127.6, 82.6,
75.5, 71.4, 35.6, 35.4, 31.8, 27.0, 23.4, 19.3, 18.9.
Acknowledgment. We thank the US-Israel Binational Sci-
ence Foundation, the Israel Cancer Research Fund, PharMore
Biotechnologies, and the Skaggs Institute for Chemical Biology
for financial support.
1
Supporting Information Available: Copies of H NMR
spectra of compounds 1, 3, 5, 8, 10a, 12a, 16, and 17; 13C NMR
spectra of compounds 1, 3, 5, 8, 10a, 12a, and 16 (15 pages,
print/PDF). See any current masthead page for ordering
information and Web access instructions.
JA981302S