Synthesis of the proposed structure of mucoxin via regio- and stereoselective tetrahydrofuran ring-forming strategies

Article abstract of DOI:10.1021/jo052073c

An enantioselective total synthesis of the proposed structure of mucoxin (1) is described. Mucoxin, an annonaceous acetogenin isolated from bioactive leaf extracts of Rollinia mucosa, is the first acetogenin containing a hydroxylated trisubstituted tetrah

Full text of DOI:10.1021/jo052073c

Synthesis of the Proposed Structure of Mucoxin via Regio- and
Stereoselective Tetrahydrofuran Ring-Forming Strategies
Radha S. Narayan† and Babak Borhan*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
babak@chemistry.msu.edu
ReceiVed October 3, 2005
An enantioselective total synthesis of the proposed structure of mucoxin (1) is described. Mucoxin, an
annonaceous acetogenin isolated from bioactive leaf extracts of Rollinia mucosa, is the first acetogenin
containing a hydroxylated trisubstituted tetrahydrofuran (THF) ring. This natural product is a highly
potent and specific antitumor agent against MCF-7 (breast carcinoma) cell lines (ED50 ) 3.7 × 10-3
µg/mL compared to adriamycin, ED50 ) 1.0 × 10-2 µg/mL). The total synthesis described herein features
two regio- and stereoselective THF ring-forming reactions. The 2,3,5-trisubstituted THF portion (C13-
C17) was accessed using a highly regioselective cyclization of a methylene-interrupted epoxydiol, and
the 2,5-disubstituted THF ring (C8-C12) was conveniently assembled via a 1,2-n-triol cyclization strategy.
The spectral data of the synthetic material and two of its diastereomers did not match the reported data
for the natural product. On the basis of detailed spectroscopic analysis of the synthesized molecule, we
reason that the spectral discrepancies are due to stereochemical misassignment of the natural product.
Introduction
acetogenins is believed to result from their complexation with
ubiquinone-linked NADH oxidase present in the plasma mem-
brane of tumor cells. Acetogenins also bind NADH-ubiquinone
oxidoreductase (complex I), which is a membrane protein
present in the mitochondrial electron-transport system.7-11
Complex I has been implicated in several diseases including
idiopathic Parkinson’s disease, maturity onset diabetes, stroke-
like episodes, and Huntington’s disease.12 However, the precise
Although plant extracts of the annonaceae family have been
historically used in folk medicines, modern bioactivity guided
isolation techniques have identified fatty-acid-derived polyketides,
now known as annonaceous acetogenins, as the likely active
ingredients of these extracts.1-4 Annonaceous acetogenins are
known to be highly potent and selective antitumor agents. More
interestingly, some members of this family have been shown
to possess the ability to combat resistance in multi drug-resistant
cancerous cells.5,6 The origin of the selective cytotoxicity of
(5) Oberlies, N. H.; Croy, V. L.; Harrison, M. L.; McLaughlin, J. L.
Cancer Lett. 1997, 115, 73-79.
(6) Oberlies, N. H.; Chang, C. J.; McLaughlin, J. L. J. Med. Chem. 1997,
40, 2102-2106.
(7) Ahammadsahib, K. I.; Hollingworth, R. M.; Mcgovren, J. P.; Hui,
Y. H.; Mclaughlin, J. L. Life Sci. 1993, 53, 1113-1120.
(8) He, K.; Zeng, L.; Ye, Q.; Shi, G. E.; Oberlies, N. H.; Zhao, G. X.;
Njoku, J.; McLaughlin, J. L. Pestic. Sci. 1997, 49, 372-378.
(9) Londershausen, M.; Leicht, W.; Lieb, F.; Moeschler, H.; Weiss, H.
Pestic. Sci. 1991, 33, 427-438.
(10) Lewis, M. A.; Arnason, J. T.; Philogene, B. J. R.; Rupprecht, J. K.;
Mclaughlin, J. L. Pestic. Biochem. Physiol. 1993, 45, 15-23.
(11) Morre, D. J.; Decabo, R.; Farley, C.; Oberlies, N. H.; Mclaughlin,
J. L. Life Sci. 1994, 56, 343-348.
(12) Weiss, H.; Friedrich, T.; Hofhaus, G.; Preis, D. Eur. J. Biochem.
1991, 197, 563-576.
† Present address: Department of Chemistry and Biochemistry, University
of California San Diego, 9500 Gilman Drive, La Jolla, California 92093.
(1) Zeng, L.; Ye, Q.; Oberlies, H.; Shi, G.; Gu, Z.-M.; He, K.;
McLaughlin, J. L. Nat. Prod. Rep. 1996, 13, 275-306.
(2) Rupprecht, J. K.; Hui, Y. H.; McLaughlin, J. L. J. Nat. Prod. 1990,
53, 237-78.
(3) Zafra-Polo, M. C.; Gonzalez, M. C.; Estornell, E.; Sahpaz, S.; Cortes,
D. Phytochemistry 1996, 42, 253-271.
(4) Johnson, H. A.; Oberlies, N. H.; Alali, F. Q.; McLaughlin, J. L.
Thwarting resistance: Annonaceous acetogenins as new pesticidal and
antitumor agents. In Biologically ActiVe Natural Products; Cutler, S. J.,
Cutler, H. G., Eds.; CRC Press: Boca Raton, FL, 2000; pp 173-183.
10.1021/jo052073c CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/20/2006
1416
J. Org. Chem. 2006, 71, 1416-1429

Synthesis of the Proposed Structure of Mucoxin
first total synthesis of the proposed structure of mucoxin
featuring a neighboring-group-directed regioselective cyclization
of a methylene-interrupted epoxydiol20,21 and a 1,2,-n-triol
cyclization to afford the bistetrahydrofuran core of the natural
product.22-25 However, spectral mismatches between the natural
product and the synthesized material, along with rigorous
stereochemical assignment of the final product, suggest that the
structure of mucoxin has been misidentified.
Synthetic Strategy. The initial retrosynthesis is outlined in
Figure 1. We planned to construct both the C2-C35 and C10-
C11 bonds simultaneously using a tandem Grubbs’ ring-closing
metathesis (RCM) of intermediate 2, followed by an in situ
hydrogenation.26 The RCM precursor 2 would be synthesized
via a regioselective ring opening of vinyl epoxide 3 with allylic
alcohol 4. The vinyl group in 3 was placed to serve a dual
function: first, to direct the epoxide ring opening to C9 with
the C12-OH in 4 as the nucleophilic moiety, and later, to serve
as a participant in the RCM reaction. Intermolecular epoxide
ring opening by alcohols often requires forcing conditions and
a large excess of the nucleophile.27-33 In light of this, the
proposed union of densely functionalized reactants 3 and 4 was
deemed rather challenging in our synthetic design. Nonetheless,
if successful, this approach would provide a strategically novel
and expeditious route to this class of natural products. Synthesis
of allylic alcohol 4 would be accomplished via a 1,2-chelation-
controlled addition of vinylmagnesium bromide to THF alde-
hyde 5. The trisubstituted THF 5 would be accessed using a
Lewis-acid-catalyzed, thiophenyl-directed, intramolecular ring
opening of bis-protected epoxydiol 6 under our previously
optimized conditions.20,21 The thiophenyl directing group would
channel the cyclization via intermediacy of the episulfonium
ion (see Scheme 2 for the general structure of the episulfonium
intermediate), thus leading to a net retention of the requisite
configuration at C13. In addition, the choice of this directing
group allows for the use of the corresponding trans-allylic
alcohol as the Sharpless asymmetric epoxidation (SAE) precur-
sor, a class of olefins known to exhibit optimal enantioselectivity
in the SAE reaction.34
FIGURE 1. Retrosynthetic analysis for preparation of mucoxin.
mode of complexation of acetogenins with the target proteins
has not been delineated. In view of the promising bioactivity
profiles of acetogenins, it would be interesting to investigate
their interaction with the relevant proteins at the molecular level.
Structurally, classical acetogenins contain an array of 2,5-
disubstituted tetrahydrofuran (THF) rings. More recently, new
nonclassical acetogenins containing more complex tetrahydro-
pyran (THP) rings and/or THF rings as the core have been
isolated; examples of such are mucocin, muconin, pyragonicin,
and Jimenezin, all of which are THP-containing acetongenins
and have recently succumbed to total synthesis.13-18 Mucoxin,
a nonclassical acetogenin, is the first of its kind found to contain
a trisubstituted hydroxylated THF ring (1, Figure 1).19 In vitro
cytotoxicity assays against a panel of six human tumor cell lines
have shown mucoxin to be more potent and selective against
MCF-7 (breast carcinoma) cell lines than adriamycin. Prompted
by its novel hydroxy THF core as well as by the biological
activity (although limited information is available because of
lack of material), we undertook the total synthesis of mucoxin.
Because only the relative configuration of the bistetrahydrofuran
core (C8-C17) of mucoxin had been established, we chose the
enantiomer represented in Figure 1 as the synthetic target. The
absolute configuration at C36 was, however, assigned as S by
McLaughlin and co-workers on the basis of the observation that
over 400 acetogenins isolated to date possess the same stereo-
chemistry. Herein, we describe the details of our studies on the
(20) Narayan, R. S.; Sivakumar, M.; Bouhlel, E.; Borhan, B. Org. Lett.
2001, 3, 2489-2492.
(21) Sivakumar, M.; Borhan, B. Tetrahedron Lett. 2003, 44, 5547-5551.
(22) Fujioka, H.; Kitagawa, H.; Kondo, M.; Kita, Y. Heterocycles 1994,
37, 743-746.
(23) Fujioka, H.; Kitagawa, H.; Kondo, M.; Matsunaga, N.; Kitagaki,
S.; Kita, Y. Heterocycles 1993, 35, 665-669.
(24) Williams, D. R.; Harigaya, Y.; Moore, J. L.; Dsa, A. J. Am. Chem.
Soc. 1984, 106, 2641-2644.
(25) Zheng, T.; Narayan, R. S.; Schomaker, J. M.; Borhan, B. J. Am.
Chem. Soc. 2005, 127, 6946-6947.
(26) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 11312-11313.
(27) Wood, H. B.; Ganem, B. J. Am. Chem. Soc. 1990, 112, 8907-
8909.
(13) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62,
504-540.
(28) Toda, J.; Sano, T.; Tsuda, Y.; Itatani, Y. Chem. Pharm. Bull. 1982,
30, 1322-1332.
(29) Schultz, A. G.; Lucci, R. D.; Fu, W. Y.; Berger, M. H.; Erhardt, J.;
Hagmann, W. K. J. Am. Chem. Soc. 1978, 100, 2150-2162.
(30) Voyle, M.; Kyler, K. S.; Arseniyadis, S.; Dunlap, N. K.; Watt, D.
S. J. Org. Chem. 1983, 48, 470-476.
(31) Ley, S. V.; Sternfeld, F. Tetrahedron 1989, 45, 3463-3476.
(32) Schwartz, R. E.; Helms, G. L.; Bolessa, E. A.; Wilson, K. E.;
Giacobbe, R. A.; Tkacz, J. S.; Bills, G. F.; Liesch, J. M.; Zink, D. L.;
Curotto, J. E.; Pramanik, B.; Onishi, J. C. Tetrahedron 1994, 50, 1675-
1686.
(33) Peredamiranda, R.; Garcia, M.; Delgado, G. Phytochemistry 1990,
29, 2971-2974.
(14) Evans, P. A.; Cui, J.; Gharpure, S. J.; Polosukhin, A.; Zhang, H.-R.
J. Am. Chem. Soc. 2003, 125, 14702-14703.
(15) Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63,
4876-4877.
(16) Strand, D.; Rein, T. Org. Lett. 2005, 7, 2779-2781.
(17) Takahashi, S.; Maeda, K.; Hirota, S.; Nakata, T. Org. Lett. 1999,
1, 2025-2028.
(18) Takahashi, S.; Ogawa, N.; Koshino, H.; Nakata, T. Org. Lett. 2005,
7, 2783-2786.
(19) Shi, G.; Kozlowski, J. F.; Schwedler, J. T.; Wood, K. V.;
MacDougal, J. M.; McLaughlin, J. L. J. Org. Chem. 1996, 61, 7988-7989.
J. Org. Chem, Vol. 71, No. 4, 2006 1417

Narayan and Borhan
SCHEME 1. Synthesis of Epoxysulfide 6a
a (a) TBSCl, imid., DMF, room temperature (73%); (b) n-BuLi, CH3(CH2)16I, THF/HMPA (3:1), 0 °C (80%); (c) TBAF, THF, -10 °C (90%); (d) LAH,
diglyme, 125 °C (87%); (e) NaH, PMBCl, TBAI, THF, 60 °C (91%); (f) AD-mix-R, MeSO2NH2, K2OsO4‚2H2O, t-BuOH/H2O (1:1), 0 °C (92%); (g)
TESCl, Et3N, DMAP, THF, room temperature, (quantitative); (h) DDQ, CH2Cl2/pH 7 phosphate buffer (10:1), 0 °C (78%); (i) PhI(OAc)2, TEMPO, CH2Cl2,
room temperature (96%); (j) Ph3PdCHCO2Et, THF, reflux (91%); (k) DIBALH, Et2O, 0 °C (89%); (l) (D)-DIPT/Ti(OiPr)4 (1.2:1.0), t-BuOOH, MS 4 Å,
CH2Cl2, -20 °C (73%); (m) (PhS)2, Bu3P, TEA, 0 °C to room temperature (94%).
SCHEME 2. 5-Exo-tet/6-Endo-tet Ring Closure through Activation of C13 by Either a Pendant Vinyl Group or a â-Thiophenyl
Ether
Results and Discussion
Synthesis of the Left-Hand Fragment (C12-C34) 5. We
next turned our attention to the neighboring-group-assisted
cyclization of bis-protected epoxydiol 6. Intramolecular ring
opening of an epoxydiol system of the general structure 14
(Scheme 2) can potentially lead to several different cyclic ethers
depending upon which of the two hydroxyl groups participates,
which epoxidic carbon is the site of ring opening, and the
stereochemical outcome (retention vs inversion) at the point of
cyclization. In our earlier investigations, we had demonstrated
that by the appropriate choice of directing group X, the acid
promoter, and reaction conditions, cyclization of an epoxydiol
such as 14 could be directed along one of the many available
avenues in a stereo- and regiocontrolled manner.20,21 To
construct the C12-C17 hydroxylated THF ring of mucoxin,
we would need to accomplish a disfavored 5-exo-tet/6-endo-tet
ring closure (see Scheme 2, structure 14), which could be
achieved by utilizing either a vinyl group (resultant product 15b
with inversion of stereochemistry at C13) or a thiophenyl group
(resultant product 15a with retention of stereochemistry at C13)
as the X-directing moiety (Scheme 2).39-45 The vinyl group
adjacent to the epoxide would stabilize the incipient carbocation,
thus favoring attack at C13 (Scheme 2, X ) vinyl). In a
complimentary fashion, positioning of a thiophenyl ether â to
an epoxide would lead to the product with the same regiochem-
Synthesis of Epoxydiol 6. Synthesis of bis-protected epoxy-
diol 6 was accomplished starting with commercially available
3-butynol (7), as outlined in Scheme 1. Alkylation of lithium
acetylide derived from TBS-protected 7 with 1-iodoheptadecane
in THF/HMPA (3:1) afforded the homopropargylic TBS ether.
TBAF-mediated silyl deprotection furnished homopropargylic
alcohol 8, which was transformed to the corresponding E-
homoallylic alcohol in a completely stereoselective manner by
LAH reduction, and the alcohol was protected as a PMB ether
to afford 9. Sharpless asymmetric dihydroxylation reaction (AD-
mix-R)35 of 9 provided diol 10 in excellent yield and enantio-
selectivity (>98% ee as determined by Mosher’s ester analy-
sis),36 which was subsequently protected with TESCl. After
some experimentation, we found that the use of phosphate buffer
(pH 7) was crucial to achieve deprotection of the PMB group
with minimal loss of the TES groups. The resultant free alcohol
11 was transformed into the allylic alcohol 12 via PhI(OAc)2/
TEMPO-mediated oxidation to aldehyde,37 Wittig olefination
with (carbethoxymethylene)triphenyl phosphorane, and subse-
quent reduction with DIBAL-H. Sharpless asymmetric epoxi-
dation of allylic alcohol 12 required significant optimization.
Ultimately, we were able to obtain the desired epoxy alcohol
in excellent diastereoselectivity (>98:2, by 1H NMR) and good
yields (73%) only under stoichiometric conditions using (D)-
DIPT/Ti(OiPr)4 (mol ratio ) 1.2:1.0). Finally, epoxy alcohol
13 was converted to the requisite thiophenyl derivative 6 using
Hata conditions.38
(38) Sekine, M.; Kume, A.; Hata, T. J. Chem. Soc., Chem. Commun.
1981, 969-970.
(39) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734-736.
(40) Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.;
Thomas, R. C. J. Chem. Soc., Chem. Commun. 1976, 736-738.
(41) House, D.; Kerr, F.; Warren, S. Chem. Commun. 2000, 1783-1784.
(42) Caggiano, L.; Fox, D. J.; House, D.; Jones, Z. A.; Kerr, F.; Warren,
S. J. Chem. Soc., Perkin Trans. 1 2002, 2634-2645.
(43) Caggiano, L.; Fox, D. J.; House, D.; Jones, Z. A.; Kerr, F.; Warren,
S. J. Chem. Soc., Perkin Trans. 1 2002, 2646-2651.
(44) Eames, J.; Jones, R. V. H.; Warren, S. Tetrahedron Lett. 1996, 37,
707-710.
(34) Katsuki, T. Asymmetric Epoxidation of Unfunctionalized Olefins
and Related Reactions. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima,
I., Ed.; Wiley-VCH: New York, 2000; pp 287-325.
(35) Kolb, H. C.; Vannieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
(36) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519.
(37) DeMico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974-6977.
(45) House, D.; Kerr, F.; Warren, S. J. Chem. Soc., Perkin Trans. 1 2002,
2652-2662.
1418 J. Org. Chem., Vol. 71, No. 4, 2006

Synthesis of the Proposed Structure of Mucoxin
SCHEME 3. Synthesis of Aldehyde 5a
SCHEME 4. Model Study of the Regioselective
Intermolecular Etherification of Vinyl Epoxide 21
a (a) BF3‚OEt2 (6 equiv), Et2O (0.04 M), 0 °C to room temperature (56%);
(b) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C (91%); (c) m-CPBA, CH2Cl2, 0
°C (quantitative); (d) (i) TFAA, 2,6-lutidine, CH2Cl2, 0 °C; (ii) NaHCO3
(solid), CH3CN (63% over two steps).
of factors. For the purposes of initial exploration and optimiza-
tion of the proposed coupling, we decided to employ model
allylic alcohol 20 and vinyl epoxide 21. Compound 20 was
obtained through the 1,2-chelation control addition of vinyl-
magnesium bromide to the appropriate aldehyde precursor (not
shown). This aldehyde precursor, which served as a model for
5, was accessible from 2-deoxy-D-ribose via a much shorter
reaction sequence.20 Vinyl epoxide 21 is akin to 3 except in
that the former is a racemate at C36 (see Supporting Information
for synthesis of 21). After extensive screening of a variety of
acid promoters, transition-metal activators, solvents, and tem-
peratures, the best result obtained for the coupling reaction is
shown in Scheme 4. Exposure of a mixture of 20 and 21 to a
catalytic amount of BF3‚OEt2 in CH2Cl2 at 1.0 M concentration
afforded the desired coupled product (22) in 20% yield.50 In
most cases, unreacted allylic alcohol was recovered unharmed,
whereas the vinyl epoxide component was rapidly consumed.
In retrospect, this is not surprising because Jung and co-workers
and others have demonstrated that vinyl epoxides undergo a
facile 1,2-hydride shift to yield the corresponding nonconjugated
enone.51-57 In fact, we were able to isolate â,γ-unsaturated
ketone 23 on many occasions.
At this juncture, we decided to pursue a revised synthetic
plan in which the left-hand portion was conserved as aldehyde
5, whereas the right-hand THF ring would be built via
manipulations of the bishomoallylic alcohol 26 (Figure 2). More
specifically, the triol derived from the asymmetric dihydroxyl-
ation of olefin 26 would serve as the precursor for our newly
disclosed 1,2-n-triol cyclization strategy.25 The one-pot cycliza-
tion of 1,2-n-triols is achieved through the in situ formation of
an ortho ester (Scheme 5), which upon treatment with a Lewis
acid yields a reactive acetoxonium intermediate.22-25 Intra-
molecular attack by the free hydroxyl group yields the cyclic
ether ring with inversion of stereochemistry at the site of ring
formation. The latter methodology can be thought of as equating
istry, however, with the opposite stereochemistry at the site of
ring closure (Scheme 2, X ) CH2SPh). In this case, activation
of the epoxide with a Lewis acid yields an intermediate
episulfonium ion, which upon subsequent intramolecular ring
opening (consequently, a double inversion at C13) yields the
product. The desire to use a trans-olefin for the asymmetric
epoxidation necessitated the use of the thiophenyl directing
group to retain the stereochemistry at C13, which was obtained
in high ee from the SAE reaction.
We were pleased to find that exposure of 6 to BF3‚OEt2 under
our standard conditions (Scheme 3) led to formation of the
desired THF diol 18 in 56% yield, which could be cleanly
separated from a 20% yield of an inseparable mixture of other
isomeric cyclic diols.20 Treatment of bis-TMS-protected epoxy-
diol 16 as well as free diol 17 with BF3‚OEt2 resulted in a similar
mixture of products indicating that the relative rates of silyl
deprotection and episulfonium ion capture may not be a factor
in determining the regioselectivity. Attempts to improve the
regioselectivity in the cyclization of 6 by changing solvents,
concentration, temperature, and acid promoters were unsuc-
cessful. Utilization of modified conditions reported previously21
(PPTS in CH2Cl2) did result in a higher yield of 18 (75%), but
the side products produced under these conditions could not be
separated efficiently; thus, for scaleup, it proved advantageous
to utilize the lower yielding Lewis acid conditions.
The hydroxyl groups in 18 were protected as TBS ethers (19),
and in preparation for the Pummerer rearrangement,46,47 the
thiophenyl group was oxidized to the corresponding sulfoxide
in quantitative yield using m-CPBA. The sulfoxide was then
reacted with trifluoroacetic anhydride in the presence of 2,6-
lutidine to afford the anticipated R-trifluoroacetoxy sulfide
intermediate. Treatment of this intermediate with a variety of
hydrolyzing agents including saturated aqueous NaHCO3, aque-
ous CuCl2, aqueous HgCl2, wet SiO2, 5% HCl, and Na2CO3 in
MeOH either led to incomplete hydrolysis or decomposition.48,49
Ultimately, we found that treatment with solid NaHCO3 in a
solution of CH3CN for 18 h followed by slow elution of the
product on a wet silica gel (10% H2O) column provided
aldehyde 5 in good yield.
(48) Sugihara, H.; Tanikaga, R.; Kaji, A. Synthesis 1978, 881-881.
(49) Dilworth, B. M.; McKervey, M. A. Tetrahedron 1986, 42, 3731-
3752.
(50) Prestat, G.; Baylon, C.; Heck, M. P.; Mioskowski, C. Tetrahedron
Lett. 2000, 41, 3829-3831.
(51) Jung, M. E.; Damico, D. C. J. Am. Chem. Soc. 1993, 115, 12208-
12209.
(52) Jung, M. E.; Damico, D. C. J. Am. Chem. Soc. 1995, 117, 7379-
7388.
(53) Kita, Y.; Furukawa, A.; Futamura, J.; Ueda, K.; Sawama, Y.;
Hamamoto, H.; Fujioka, H. J. Org. Chem. 2001, 66, 8779-8786.
(54) Maruoka, K.; Hasegawa, M.; Yamamoto, H.; Suzuki, K.; Shimazaki,
M.; Tsuchihashi, G. J. Am. Chem. Soc. 1986, 108, 3827-3829.
(55) Maruoka, K.; Ooi, T.; Nagahara, S.; Yamamoto, H. Tetrahedron
1991, 47, 6983-6998.
(56) Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1989, 111,
6431-6432.
(57) Maruoka, K.; Sato, J.; Yamamoto, H. Tetrahedron 1992, 48, 3749-
3762.
Attempted Intermolecular Epoxide Ring Opening Using
Model Systems. As mentioned previously, the intermolecular
union of 3 and 4 (Figure 1) was deemed challenging for a variety
(46) De Lucchi, O.; Miotti, U.; Modena, G. Org. React. (N.Y.) 1991,
40, 157-405.
(47) Padwa, A.; Gunn, D. E., Jr.; Osterhout, M. H. Synthesis 1997, 1353-
1377.
J. Org. Chem, Vol. 71, No. 4, 2006 1419

Narayan and Borhan
FIGURE 2. Revised retrosynthesis for construction of the disubstituted THF ring.
SCHEME 5. One-Pot Cyclization of 1,2-n-Triols
SCHEME 6. Synthesis of Hydroxyene 26a
a (a) NaH, BnBr, TBAI, THF, 60 °C (78%); (b) PCC, CH2Cl2, room
temperature (82%); (c) Ph3P(CH2)3OHBr, KHMDS, TMSCl, then AcOH/
THF/H2O (6:3:1), 0 °C (83%); (d) (i) MsCl, Et3N, CH2Cl2, 0 °C; (ii) NaI,
acetone, reflux, 77%; (e) t-BuLi, -100 °C, MgBr2‚OEt2, Et2O, -95 °C
then 5, MgBr2‚OEt2, -40 °C (88%).
the reactivity of a 1,2-diol functionality to an epoxide. This can
be advantageous in many cases where utilizing the SAD reaction
simplifies the synthetic scheme as compared to using the SAE
reaction, which requires more stringent structural prerequisites
for high enantioselectivity. This methodology compliments the
use of cyclic sulfates and sulfites in transforming 1,2-diols into
reactive species.58,59 However, as was the case in our studies,
formation of the cyclic sulfates and sulfites can at times be
difficult and substrate dependent.
The development of the 1,2-n-triol cyclization was neces-
sitated as a result of unsuccessfully exploring other options to
stereoselectively install a homoallylic epoxide in 26. An example
of such, found in the acetogenin literature, is the hydroxy-
directed, VO(acac)2/tBuOOH-mediated epoxidation-cyclization
method pioneered by Kishi.60 A limitation of this methodology,
however, is that depending upon the structure of the parent
hydroxy olefin the epoxidation may occur with low facial
selectivity. In addition, because stereocontrol is substrate
derived, this method lacks versatility that would allow access
to other unnatural stereoisomers of the natural product. Other
potential options for stereoselective epoxidation include the
Jacobsen and Shi epoxidation reactions; however, olefin 26 lacks
the specific structural features required for optimal stereo-
selectivity under the two protocols.34,61-63 In view of the above
limitations, the one-pot 1,2-n-triol cyclization method offered
a promising alternative that would alleviate the difficulties posed
by traditional methods.
oxidation/syn elimination of the thiophenyl group (Figure 2).
The olefinic precursor 26 for the AD and triol cyclization would
be assembled via 1,2-chelation-controlled addition of an organo-
metallic reagent derived from iodide 27 and aldehyde 5.
Synthesis of Bishomoallylic Alcohol 26. The synthetic
strategy now required elaboration of aldehyde 5 to alcohol 26
by chelation control addition of a suitable organometallic reagent
derived from iodide 27 (Figure 2). Synthesis of 27 could be
accomplished in a concise manner, as shown in Scheme 6.
Commercially available 1,6-hexane diol 28 was monoprotected
and oxidized to provide aldehyde 29. The Z-selective Wittig
olefination of 29 with 3-hydroxypropyltriphenylphosphonium
bromide was achieved by in situ protection of the ylide’s
hydroxy group as a TMS ether, which was cleaved during
workup using aqueous acetic acid.65,66 The desired homoallylic
alcohol was obtained in >10:1 diastereoselectivity. Finally,
mesylation of the alcohol and ensuing displacement by sodium
iodide furnished target iodide 27.
Derivatization of 27 as a Grignard reagent for the chelation
control addition required some optimization. Upon reacting 27
(or its bromide counterpart) with metallic magnesium under
reflux, only the corresponding homodimer and diene from
elimination of the iodide (not shown) were detected.67,68
Successful preparation of the Grignard reagent entailed, first, a
low-temperature lithium-halogen exchange followed by trans-
metalation with freshly prepared MgBr2‚OEt2 at -95 °C.69,70
In the new synthetic scheme, the terminal butenolide ring
would be installed by displacement of bistetrahydrofuran iodide
24 by known R-thiophenyl γ-methyl lactone 2564 and subsequent
(64) White, J. D.; Somers, T. C.; Reddy, G. N. J. Org. Chem. 1992, 57,
4991-4998.
(65) Rodefeld, L.; Tochtermann, W. Tetrahedron 1998, 54, 5893-5898.
(66) Couturier, M.; Dory, Y. L.; Rouillard, F.; Deslongchamps, P.
Tetrahedron 1998, 54, 1529-1562.
(58) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515-10530.
(59) Byun, H. S.; He, L. L.; Bittman, R. Tetrahedron 2000, 56, 7051-
7091.
(67) Otera, J. Modern carbonyl chemistry; Wiley-VCH: Weinheim; New
York, 2000; p xix, p 613.
(60) Fukuyama, T.; Vranesic, B.; Negri, D. P.; Kishi, Y. Tetrahedron
Lett. 1978, 2741-2744.
(68) Wakefield, B. J. Organomagnesium methods in organic synthesis.
Academic Press: London; San Diego, 1995; p xvi, p 249.
(69) Koert, U.; Wagner, H.; Pidun, U. Chem. Ber. 1994, 127, 1447-
1457.
(70) Arndt, S.; Emde, U.; Baurle, S.; Friedrich, T.; Grubert, L.; Koert,
U. Chem.-Eur. J. 2001, 7, 993-1005.
(61) Tu, Y.; Wang, Z. X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806-
9807.
(62) Wang, Z. X.; Shi, Y. A. J. Org. Chem. 1997, 62, 8622-8623.
(63) Tian, H. Q.; She, X. G.; Shu, L. H.; Yu, H. W.; Shi, Y. J. Am.
Chem. Soc. 2000, 122, 11551-11552.
1420 J. Org. Chem., Vol. 71, No. 4, 2006

Synthesis of the Proposed Structure of Mucoxin
SCHEME 7. Synthesis of Bistetrahydrofuran 24a
a (a) AD-mix-R, MeSO2NH2, K2OsO4‚2H2O, 0 °C (88% yield, dr ) 5:1); (b) MeC(OMe)3, PPTS (10 mol %), CH2Cl2, room temperature, then BF3‚OEt2
(25 mol %); (c) K2CO3, MeOH, room temperature; (d) TBSOTf, 2,6-lutidine, 0 °C (90%, 3 steps); (e) H2, Pd/C, EtOAc/i-PrOH (1:1), room temperature
(92%); (f) PPh3, imid., I2, toluene, room temperature (87%).
SCHEME 8. Completion of the Synthesis of the Proposed Structure of Mucoxin (1)a
a (a) LDA, 24, THF/HMPA (4:1), 0 °C-room temperature (87%); (b) (i) m-CPBA, CH2Cl2, 0 °C; (ii) toluene, reflux (84% over two steps); (c) HF‚Py,
THF, room temperature (80%).
The organometallic reagent was then treated with aldehyde 5,
also precomplexed with MgBr2‚OEt2 at -40 °C. Following this
optimized procedure, the desired alcohol 26 was isolated as a
single diastereomer. The absolute configuration of the newly
formed stereocenter was confirmed as S by standard Mosher’s
ester analysis.
Treatment of 30 with trimethyl orthoacetate and 10 mol %
PPTS followed by addition of catalytic BF3‚OEt2 led to
cyclization of the triol to provide 32 in excellent yield. The
reaction was accompanied by TBS cleavage to a small extent
(8%). However, the free hydroxy groups could be easily
reprotected using TBSOTf/2,6-lutidine, which resulted in isola-
tion of 32 in overall 99% yield. The reaction proceeds via exo
cyclization of the reactive acetoxonium intermediate 31, thereby
inverting the configuration at C9. After deacetylation of the
hydroxyl group, the absolute configuration at C8 in 32 was
confirmed as S by Mosher’s ester analysis. The trans relationship
across the C9-C12 THF ring was confirmed by nuclear
Overhauser effect (nOe) experiments. Under the optimized
conditions, the three-step conversion of triol 30 to tris-TBS ether
33 could be achieved without purification of the intermediates
in excellent overall yield (Scheme 7).
Synthesis of Bistetrahydrofuran Iodide 24. We now
focused our efforts on constructing the C8-C12 THF ring. The
hydroxy olefin 26 was transformed to triol 30 by Sharpless
asymmetric dihydroxylation using AD-mix-R (Scheme 7). While
positioning olefin 26 according to the stereochemical model of
the AD reaction, we reasoned that the unbranched alkyl
substituent might preferentially occupy the SW quadrant as
compared to the highly oxygenated THF portion.35,71 In this
orientation, AD-mix-R would attack the olefin from the si face
to afford the 8S,9R isomer 30. Stereoselectivity in the AD
reaction of Z-disubstituted olefins is generally less than opti-
mal,72 but to our satisfaction, we obtained the desired triol 30
in a 5:1 diastereomeric ratio and 88% yield. Absolute config-
uration of the newly formed 8,9-diol was established only after
the cyclization reaction.
Completion of the Synthesis. With the bistetrahydrofuran
core in place, the final task was installation of the terminal
butenolide ring. Debenzylation of 33 with H2 over Pd/C afforded
the corresponding free alcohol. Subsequently, iodination of the
alcohol was accomplished by treatment with PPh3 and I2 to
secure iodide 24 (Scheme 7).
(71) Hale, K. J.; Manaviazar, S.; Peak, S. A. Tetrahedron Lett. 1994,
35, 425-428.
(72) Johnson, R. A.; Sharpless, K. B. Catalytic asymmetric dihydroxyl-
ation-discovery and development. In Catalytic Asymmetric Synthesis, 2nd
ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp 357-398.
The final stages of the synthesis are outlined in Scheme 8.
R-Phenylthio-γ-lactone 25 was synthesized by White’s proce-
dure from commercially available thiophenyl acetic acid.64
Optimized conditions for coupling of lactone 25 with iodide
J. Org. Chem, Vol. 71, No. 4, 2006 1421

Narayan and Borhan
TABLE 1. 1H NMR Comparison of the Natural and Synthetic
Mucoxin
FIGURE 3. ECCD of the C16,C17 diol confirms the desired S,S
stereochemistry.
proton
1
natural mucoxin
∆δ (1-natural)
H8
H9
3.41
3.96
3.42
3.95
-0.01
+0.01
H10
H11
H12
H13
H14
H15
H16
H17
1.84, 2.02
2.02, 2.13
4.35
3.80
4.44
1.84, 2.02
4.09
3.41
1.91, 2.05
1.91, 2.05
4.31
3.71
4.32
1.91, 2.35
4.04
3.53
-0.07, -0.03
0.11, 0.08
0.04
0.09
0.12
-0.07, -0.33
0.05
-0.12
FIGURE 4. Lack of nOe correlation between H13 and H16 cor-
roborates the trans stereochemistry, which is possible only if the SAE
reaction proceeded with the predicted stereochemistry (cis-H13/H16
does exhibit nOe; data not shown).
24 involved LDA-mediated R-deprotonation of 25, which was
then reacted with 24 in THF/HMPA (4:1) to afford adduct 34.
Treatment with m-CPBA in CH2Cl2 led to the syn elimination
of the sulfoxide in refluxing toluene to afford exclusively the
internal R,â-unsaturated lactone 35. Finally, global deprotection
of 35 using HF‚Py occurred uneventfully to furnish target
molecule 1, which was isolated in high purity after HPLC. The
structure of 1 was confirmed by 1H, 13C, COSY, and nOe NMR
experiments.
refocused our attention on the original synthetic material (1)
for further analysis.
Asymmetric reactions employed for installation of each of
the stereogenic centers in the C8-C17 portion of 1 and the
analytical experiments used for assignment of their relative and
absolute configurations are described below.
The C16 and C17 stereocenters were set using the Sharpless
asymmetric dihydroxylation (AD) reaction of olefin 9 (Scheme
1). On the basis of the mnemonic device for the AD reaction,
9 was positioned so that the long hydrocarbon chain occupied
the SW quadrant.35 In this orientation, AD-mix-R would react
from the si face to afford the S,S-diol 10 as the major
enantiomer. The enantioselectivity of the AD reaction was
Comparison of Spectral Data of the Synthetic and Natural
Mucoxin. Both 1H and 13C NMR spectra of the synthetic sample
(1) differed from the published spectra of the natural com-
1
pound.19 Major differences in the H NMR spectra resided
within the bistetrahydrofuran (C8-C17) region (Table 1). In
particular, H11, H14, H15, and H17 in 1 exhibited differences
of greater than 0.1 ppm as compared to the reported spectrum
of the natural mucoxin. In an attempt to trace the sources of
the discrepancies, we synthesized two stereoisomers of 1
(Scheme 8). Isomer 36 is the C36 epimer, and 37 is the C8,C9
epimer of 1. Starting from hydroxy olefin 26, 37 was obtained
by following the same reaction sequence as that outlined in
Schemes 7 and 8, with the exception that AD-mix-â was used
in the Sharpless asymmetric dihydroxylation reaction of 26
(Scheme 7). As a result, the C9-C12 THF in 37 bears a cis
1
determined to be >99:1 on the basis of H NMR of the chiral
bis-Mosher ester derivative of 10. The absolute configuration
of the diol, on the other hand, was established independently
by exciton coupled circular dichroism (ECCD) spectroscopy.73
Bis-4-dimethylamino benzoate derivative 38 proved most suit-
able for the ECCD analysis (Figure 3).74,75 Out of the three
possible staggered conformations (A, B, and C) of 38, B is
ECCD inactive because the angle between the transition dipoles
(73) Berova, N.; Nakanishi, K.; Woody, R. Circular dichroism: prin-
ciples and applications, 2nd ed.; Wiley-VCH: New York, 2000; p xix, p
877.
(74) Harada, N.; Nakanishi, K. Circular dichroic spectroscopy: exciton
coupling in organic stereochemistry; University Science Books: Mill Valley,
CA, 1983; p xiii, p 460.
1
instead of the proposed trans relationship across the ring. H
and 13C NMR spectra of diastereomer 36 were found to be
identical with those of 1 indicating that configuration at C36 is
inconsequential. On the other hand, spectral mismatches between
37 and the natural compound were even greater. We therefore
(75) Harada, N.; Chen, S. L.; Nakanishi, K. J. Am. Chem. Soc. 1975,
97, 5345-5352.
1422 J. Org. Chem., Vol. 71, No. 4, 2006

Synthesis of the Proposed Structure of Mucoxin
FIGURE 5. Stereochemical assignment of C12, obtained through the anticipated chelation with the THF ring oxygen, was confirmed by Mosher
ester analysis of the ester derived from 26. The stereochemistry of the dihydroxylation reaction was verified after cyclization in two independent
manners. The stereochemistry of C8-OH was analyzed by Mosher ester analysis of both the major and the minor diastereomer. Also, lack of nOe
correlation between H12 and H9 in the diastereomer 40 obtained from the major product 30, in conjuction with observable nOe’s for the same
protons in the diastereomer 42 obtained from the minor product 41, verified the assignment of the dihydroxylation reaction.
of the two chromophores is 180°. Conformer A, which bears
two gauche interactions is expected to be lower in energy and
hence preferred over conformer C, which suffers from three
gauche interactions. The clockwise orientation of the transition
dipole moments of the coupling chromophores in conformer A
should lead to a positive ECCD. Thus, if the absolute config-
uration of diol 10 is S,S, its dibenzoate derivative 38 is expected
to produce a positive ECCD spectrum. We indeed observed
positive ECCD for 38 in various solvents ranging from
cyclohexane to methanol. A representative spectrum of 38 in
MeCN is shown in Figure 3, which confirms the assigned
configuration of diol 10.
supports the R,R-epoxide stereochemistry predicted by the
mnemonic.
Next, we examined the Pummerer rearrangement depicted
in Scheme 3 (conversion of 18 to 5). The 2,3-cis-5-trans relative
configuration about the THF ring in 5 was reconfirmed by nOe
experiments, which conclusively established that the C13
stereocenter was not epimerized under the Pummerer conditions
(Figure 5). 1,2-Chelation-controlled addition of a Grignard
reagent derived from iodide 27 to aldehyde 5 set the C12
stereocenter. The stereochemistry of the newly formed secondary
alcohol was confirmed as S with Mosher’s ester analysis using
both R and S Mosher’s ester derivatives.
Olefin 26 was transformed to triol 30 by the AD reaction.
Dihydroxylation of a 1,2-disubstituted cis-olefin can lead to
either a S,R- or R,S-diol. In our case, the S,R isomer 30 was the
desired diastereomer. Triol 30 was isolated as a single dia-
stereomer in 74% yield (14% of the other diastereomer (41)
could be separated by column chromatography). The absolute
configuration of 30 was established after cyclization that
afforded the hydroxy THF 40. The C8 hydroxyl group in 40
was derivatized as R and S Mosher’s esters and based on
standard 1H NMR analysis of both derivatives; the configuration
at C8 was assigned as S. This also established the R configu-
ration at C9 for triol 30. Moreover, 1D-NOESY experiments
showed no nOe correlation between H9 and H12 in 40,
suggesting a trans relationship between the two hydrogens.
Next, assignment of the C13 and C14 stereocenters, which
were established via the SAE reaction, were examined (Figure
4). The configuration at the two oxirane carbons was assigned
as R,R on the basis of the mnemonic for the SAE reaction.76
This assignment was confirmed after cyclization of 13. The THF
diol generated after thiophenyl-directed epoxydiol cyclization
(6 to 18, Scheme 3) was derivatized as its corresponding
bisacetate 39 for ease of characterization (Figure 4). A 2,5-
trans relationship across the THF ring was established by the
absence of a nOe signal between H13 and H16, where a strong
positive nOe signal between H13 and H14 was indicative of
the cis relation.77 Lack of nOe’s, especially in five-membered
rings, must be examined carefully because of pseudoaxial-axial
disposition of hydrogens in a 1,3-relationship. To confirm the
nOe result, the corresponding 2,3,5-trisubstituted THF ring with
cis 2,5-appendages was synthesized and positive nOe results
were obtained (data not shown). Because the absolute config-
uration at C16 was confirmed as S (vide supra), in combination
with the nOe experiments discussed above, the stereochemistries
of C13 and C14 after cyclization were confirmed as S and R,
respectively. Extrapolation back to the parent epoxide 13
(77) Vicinal protons on substituted THF rings often do give rise to nOe’s
regardless of their relative geometries. Therefore, the presence of a strong
nOe between H13 and H14 does not conclusively establish the cis
configuration of substituents at C13 and C14. However, stereochemistry at
C13/C14 arises from the SAD reaction of a trans-olefin, which must yield
a trans-epoxide. Although it is very unlikely that the undesired diastereomer
is obtained during the asymmetric epoxidation, to allow for that possibility,
the relationship between H16 and H13 would have to be necessarily cis
after cyclization to the tetrahydrofuran ring (note that the retention of
stereochemistry during the cyclization reaction has been clearly demonstrated
in ref 20). Because the trans stereochemistry is clearly established between
H13 and H16, the assigned and expected cis relationship between H13 and
H14 is further supported.
(76) Johnson, R. A.; Sharpless, K. B. Catalytic asymmetric epoxidation
of allylic alcohols. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I.,
Ed.; Wiley-VCH: New York, 2000; pp 231-280.
J. Org. Chem, Vol. 71, No. 4, 2006 1423

Narayan and Borhan
1
as a colorless oil (62 g, 73%). H NMR (500 MHz, CDCl3): δ
3.74 (t, J ) 7.1 Hz, 2 H), 2.40 (dt, J ) 7.2, 2.7 Hz, 2 H), 1.95 (d,
J ) 2.7 Hz, 1 H), 0.90 (s, 9 H), 0.07 (s, 6 H). 13C NMR (125
MHz, CDCl3): δ 81.7, 69.5, 69.4, 62.0, 26.1, 23.1, 18.5, -5.1. IR
(thin film): 3330, 2954, 2860, 2753, 2711, 2123, 1839, 1590, 1471,
1388, 1255, 1106, 1006, 916, 837, 777, 643 cm-1. HRMS (CI, CH4)
calcd for C10H20OSi, 185.1362 m/z [M + H]+; observed, 185.1361
m/z.
A solution of this TBS-protected butynol (13.63 g, 74.08 mmol)
in THF (113 mL) was cooled to -30 °C. To this, n-BuLi (7.8 mL
of 9.97 M solution in hexanes, 77.8 mmol) was added dropwise,
and the solution was warmed to -10 °C over 1 h. After cooling
the lithium acetylide back to -78 °C, 1-iodoheptadecane in 3:1
THF/HMPA (147 mL) was added and the solution was stirred for
10 min at the same temperature. The reaction was allowed to warm
to 0 °C over 1 h and then was quenched by adding H2O (300 mL).
The aqueous layer was extracted with Et2O (3 × 400 mL), and the
combined organic layers were dried over MgSO4 and concentrated
to afford a crude oil, which was purified by flash column
chromatography (hexanes, 19:1 hexanes/EtOAc) to yield the silyl-
protected homopropargylic alcohol (26.7 g, 85%) as a yellow oil.
1H NMR (500 MHz, CDCl3) δ 3.69 (t, J ) 7.06 Hz, 2 H), 2.36
(dt, J ) 7.3, 2.4 Hz, 2 H), 2.12 (dt, J ) 7.2, 2.4 Hz, 2 H), 1.45 (q,
J ) 7.1 Hz, 2 H), 1.39-1.23 (m, 30 H), 0.90 (s, 9 H), 0.88 (t, J )
7.01 Hz, 3 H), 0.07 (s, 6 H). 13C NMR (125 MHz, CDCl3): δ
81.5, 76.8, 62.5, 31.9, 29.7, 29.6, 29.4, 29.2, 29.1, 28.9, 25.9, 23.2,
22.7, 18.2, 183, 14.1, -5.3. IR (thin film): 2923, 2854, 1466, 1383,
1362, 1253, 1105, 1059, 1007, 916, 837, 777, 721 cm-1. HRMS
(CI, CH4) calcd for C27H54OSi, 421.3866 m/z [M - H]+; observed,
421.3874 m/z.
FIGURE 6. Structure of synthetic mucoxin (1) and proposed mucoxin.
Conversely, cyclization of the minor isomer from the AD
reaction (41) did yield a cis-THF ring product (42) that exhibited
nOe correlation, further confirming the relative and absolute
stereochemical assignments.
On the basis of the extensive spectroscopic analysis, we
reason that the configuration of the C8-C17 portion of synthetic
mucoxin (1) is as shown in Figure 6 and that it is identical to
the proposed relative stereostructure for natural mucoxin.19 In
addition, from the published 2D-COSY and HRMS fragmenta-
tion of the tri-TMS derivative of natural mucoxin, we believe
that the proposed structure for natural mucoxin is constitutionally
correct. It is therefore likely that the spectral discrepancies are
due to stereochemical misassignment(s) of the natural sample.
Our synthetic scheme has been so devised that several diaster-
eomers of the C8-C17 core can be prepared by reagent control
and/or by way of minor changes in substrate structure.
To a solution of this silyl-protected homopropargylic alcohol
(35.9 g, 0.085 mol) in THF (100 mL) was added TBAF (130 mL
of 1 M solution in THF, 0.13 mol) at -20 °C under N2. After
stirring for 30 min at the same temperature, H2O (200 mL) was
added. The layers were separated, and the aqueous layer was
extracted with Et2O (3 × 400 mL). The combined organic layers
were dried over MgSO4 and concentrated. The crude product was
purified by flash column chromatography (4:1 hexanes/EtOAc) to
Summary
We have synthesized the proposed structure of mucoxin (1)
in 32 steps (26 steps along the longest linear sequence). The
synthesis features two regio- and stereoselective THF ring-
forming methods developed in our laboratory. The trisubstituted
hydroxy THF ring (C13-C17) was constructed using neighbor-
ing-group-directed epoxydiol cyclization,20 and the disubstituted
THF (C8-C12) was synthesized by a one-pot 1,2-n-triol
cyclization strategy.25 Because the epoxydiol and polyol precur-
sors for the cyclization reactions were assembled via Sharpless
asymmetric epoxidation and dihydroxylation reactions, other
diastereomers of the C8-C17 core can be easily built simply
by using the appropriate choice of olefin geometry and ligands
for the asymmetric reactions. This is particularly advantageous
in light of the fact that spectral data for the synthetic and natural
materials did not match. On the basis of the spectroscopic
evidence, we believe that the structural mismatch is likely due
to misassignment of the relative stereochemistry in the C8-
C17 core. Further investigations to determine the real structure
of mucoxin are currently underway.
1
furnish the homopropargylic alcohol 8 as a white solid. H NMR
(500 MHz, CDCl3): δ 3.67 (t, J ) 6.2 Hz, 2 H), 2.43 (dt, J ) 6.2,
2.4 Hz, 2 H), 2.15 (dt, J ) 7.2, 2.4 Hz, 2 H), 1.76 (s, br, 1 H), 1.48
(q, J ) 7.1 Hz, 2 H), 1.37-1.25 (m, 28 H), 0.88 (t, J ) 6.6 Hz, 3
H). 13C NMR (125 MHz, CDCl3): δ 82.9, 76.2, 61.4, 31.9, 29.8,
29.7, 29.6, 29.4, 29.2, 29.0, 28.9, 23.2, 22.7, 18.8, 14,1. IR (thin
film): 2953, 2914, 2848, 1470, 1049, 1018, 874, 752 cm-1. HRMS
(CI, CH4) calcd for C21H40O, 307.3001 m/z [M - H]+; observed,
307.3003 m/z. Mp ) 61-62 °C.
E-Homoallylic Alcohol 9. A 1 L two-necked round-bottom flask
fitted with a stir bar and a reflux condenser was charged with LAH
(7.7 g, 0.203 mol). To this, a solution of homopropargylic alcohol
8 (35 g, 0.113 mol) in diglyme (350 mL) was carefully added
dropwise at 0 °C. While stirring vigorously, the mixture was heated
to 125 °C. After 17 h, the reaction was cooled to room temperature,
upon which 7.7 mL of H2O was added dropwise. 15% NaOH (7.7
mL) was then added followed by H2O (22 mL). The resultant
mixture was heated at 50 °C for 45 min and filtered after cooling
to ambient temperature. The filtrate was diluted with EtOAc (500
mL) and washed with 1.5 N HCl (5 × 100 mL) to remove diglyme
from the organic layer. The organic layer was dried (Na2SO4) and
concentrated. Chromatographic purification of the crude product
(19:1 hexanes/EtOAc, 2.3:1 hexanes/EtOAc) yielded the corre-
sponding E-homoallylic alcohol (30.5 g, 87%) as a white solid. 1H
NMR (500 MHz, CDCl3): δ 5.58-5.52 (m, 1 H), 5.40-5.34 (m,
1 H), 3.62 (t, J ) 6.3 Hz, 2 H), 2.26 (dt, J ) 12.5, 6.08, 2 H), 2.00
(dt, J ) 14.3, 7.3 Hz, 2 H), 1.48 (s, br, 1 H), 1.36-1.25 (m, 30 H),
0.88 (t, J ) 6.8 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ 134.4,
125.7, 62.1, 36.1, 32.7, 31.9, 29.7, 29.6, 29.5, 29.4, 29.2, 22.7, 14.1.
IR (thin film): 3448, 3136, 2914, 2848, 1637, 1470, 1047, 1020,
Experimental Section
Homopropargylic Alcohol 8. To a 0 °C solution of 3-butyn-
1-ol (27 mL, 29.16 g, 0.416 mmol) and imidazole (61 g, 0.896
mmol) in DMF (100 mL) was added a solution of t-butyldimethyl-
chlorosilane (64.5 g, 0.428 mmol) in DMF (125 mL), and the
mixture was stirred at the same temperature for 40 min under N2.
The reaction was then warmed to ambient temperature and stirred
for 3 h after which H2O (500 mL) was added. The aqueous layer
was extracted with 4:1 hexanes/EtOAc (4 × 400 mL), and the
combined organic layers were dried (Na2SO4) and concentrated.
After flash column chromatography, the silyl ether was obtained
1424 J. Org. Chem., Vol. 71, No. 4, 2006

Synthesis of the Proposed Structure of Mucoxin
926, 890, 715 cm-1. HRMS (CI, CH4) calcd for C21H42O, 309.3157
m/z [M - H]+; observed, 309.3142 m/z. Mp ) 55-56 °C.
A 1 L round-bottom flask fitted with a reflux condenser was
charged with a stir bar and NaH (14 g of 60 wt % dispersion in
oil, 0.36 mol). A solution of the above E-homoallylic alcohol (37
g, 0.12 mol) in THF (400 mL) was added dropwise at 0 °C. The
mixture was warmed to room temperature and stirred for an
additional 1 h. p-Methoxybenzyl chloride (25 g, 0.16 mmol) and
TBAI (16.5 g, 0.045 mol) were added, and the reaction mixture
was heated to 60 °C for 18 h. The reaction was cooled to ambient
temperature and carefully quenched by adding saturated NH4Cl
solution. The layers were separated, and the aqueous layer was
extracted with Et2O (3 × 300 mL). Combined organic layers were
dried (MgSO4) and concentrated to furnish a crude solid, which
upon purification by flash column chromatography (49:1 hexanes/
EtOAc) afforded the PMB-protected homoallylic alcohol 9 (47 g,
91%, crude yield containing an inseparable impurity, 81% pure yield
based on NMR) as a white solid. The PMB-containing impurity
observable in the 1H NMR spectrum could not be removed through
chromatography; however, it proved inconsequential because it did
not retard the next reaction. The product of the next reaction did
not contain the impurity after purification and thus was removed
at that stage. 1H NMR (500 MHz, CDCl3): δ 7.27 (d, J ) 8.7 Hz,
2 H), 6.88 (d, J ) 8.7 Hz, 2 H), 5.54-5.48 (m, 1 H), 5.45-5.39
(m, 1 H), 4.46 (s, 2 H), 3.81 (s, 3 H), 3.47 (t, J ) 7.0 Hz, 2 H),
2.31 (dt, J ) 13.5, 6.6 Hz, 2 H), 2.0 (dt, J ) 13.9, 6.9 Hz, 2 H),
1.37-1.28 (m, 30 H), 0.9 (t, J ) 6.9, 3 H). 13C NMR (125 MHz,
CDCl3): δ 159.2, 132.7, 130.7, 129.4, 129.3, 126.2, 113.8, 113.7,
72.5, 70.1, 55.3, 33.1, 32.7, 32.2, 29.8, 29.7, 29.6, 29.5, 29.4, 29.2,
14.2. IR (thin film): 2954, 2918, 2848, 1969, 1896, 1614, 1522,
1462, 1361, 1246, 1176, 1097, 1030, 964, 822 cm-1. HRMS (EI)
calcd for C29H50O2, 430.3811 m/z [M]+; observed, 430.3799 m/z.
Mp ) 38-39 °C.
3.74 (m, 1 H), 3.58-3.51 (m, 3 H), 2.04-2.00 (m, 1 H), 1.63-
1.43 (m, 3 H), 1.35-1.19 (m, 30 H), 1.00-0.88 (m, 21 H), 0.63-
0.51 (m, 12 H). 13C NMR (125 MHz, CDCl3): δ 159.0, 131.0,
129.1, 113.6, 75.3, 72.3, 72.1, 67.5, 55.3, 31.9, 30.6, 30.2, 29.9,
29.7, 29.6, 29.4, 26.7, 22.7, 14.1, 7.0, 6.9, 6.6, 6.4, 5.8, 5.2, 5.1.
IR (thin film): 3324, 2924, 2856, 2071, 2003, 1876, 1614, 1587,
1513, 1461, 1414, 1379, 1301, 1247, 1172, 1099, 1014, 825, 738
cm-1. HRMS (EI) calcd for C41H80O4Si2, 692.5595 m/z [M - H]+;
observed, 692.5567 m/z.
To a 0 °C solution of the protected triol (15 g, 0.02 mol) in 460
mL of CH2Cl2/phosphate buffer (10:1) was added DDQ (5.7 g, 0.03
mol) in one portion. After stirring the reaction under N2 at the same
temperature for 90 min, saturated NaHCO3 solution (200 mL) was
added. The mixture was warmed to ambient temperature and
carefully extracted with CH2Cl2 (3 × 200 mL) to avoid emulsions.
The combined organic layers were dried (Na2SO4) and concentrated,
and the crude oil was purified by flash column chromatography
(3% EtOAc in hexanes) to afford 12.6 g (78%) of the primary
1
alcohol 11. [R]20 -24.3 (c 2.34, CHCl3). H NMR (500 MHz,
D
CDCl3): δ 3.78-3.58 (m, 4 H), 2.88 (t, J ) 5.7 Hz, 1 H), 1.95-
1.90 (m, 1 H), 1.67-1.57 (m, 2 H), 1.40-1.46 (m, 1 H), 1.37-
1.17 (m, 30 H), 0.99-0.90 (m, 18 H), 0.87 (t, J ) 7.0 Hz, 3 H),
0.63-0.52 (m, 12 H). 13C NMR (125 MHz, CDCl3): δ 75.9, 75.1,
61.1, 34.7, 32.1, 30.6, 30.0, 29.9, 29.8, 29.5, 26.8, 22.9, 14.2, 7.0,
5.3, 5.2. IR (thin film): 3471, 2928, 2851, 1468, 1411, 1374, 1242,
1080, 1023, 723 cm-1. HRMS (CI, CH4) calcd for C33H72O3Si2,
571.4942 m/z [M - H]+; observed, 571.4927 m/z.
Allylic Alcohol 12. To a solution of alcohol 11 (15.5 g, 0.03
mol) in CH2Cl2 (50 mL) at room temperature was added bis-
acetoxyiodobenzene (9.61 g, 0.03 mol). After addition of TEMPO
(437 mg, 3.0 mmol), the clear orange solution was stirred at room
temperature for 2 h. The reaction was then diluted with CH2Cl2
(150 mL) and treated with saturated sodium sulfite solution until it
became colorless. Upon separation of the layers, the aqueous layer
was extracted with CH2Cl2 (3 × 200 mL). The combined organic
layers were dried over Na2SO4, concentrated, and purified by
column chromatography (2% EtOAc in hexanes) to furnish the
Diol 10. A 2 L two-necked round-bottom flask fitted with a
mechanical stirrer was charged with AD-mix-R (97.8 g). t-BuOH
(330 mL) and H2O (330 mL) were added followed by methane-
sulfonamide (6.6 g) and K2OsO4‚2H2O (144 mg). This mixture was
stirred until a clear solution was obtained which was cooled to 0
°C. To this was added the olefin 9 (30 g, 0.07 mol) in one portion.
The reaction was vigorously stirred at 0 °C for 20 h, after which
sodium sulfite (100 g) was added at the same temperature. The
mixture was then warmed to room temperature, stirred for 45 min,
and then diluted with EtOAc (500 mL) and washed with H2O (200
mL). The aqueous layer was extracted with EtOAc (3 × 300 mL),
and the combined organic layers were dried (Na2SO4) and
concentrated to yield a crude solid which was purified by flash
column chromatography (9:1 hexanes/EtOAc, 2:3 hexanes/EtOAc)
to yield diol 10 (32.5 g, 92% yield, >98% ee as determined after
20
corresponding aldehyde as a colorless oil (14.8 g, 96%). [R]D
-21.6 (c 1.95, CHCl3). 1H NMR (500 MHz, CDCl3): δ 9.67 (t, J
) 2.22 Hz, 1 H), 4.20-4.17 (m, 1 H), 3.62-3.59 (m, 1 H), 2.65
(ddd, J ) 1.8, 4.0, 15.9 Hz, 1 H), 2.43 (ddd, J ) 2.9, 8.2, 15.7 Hz,
1 H), 1.66-1.60 (m, 1 H), 1.47-1.31 (m, 1 H), 1.30-1.12 (m, 30
H), 0.92-0.88 (m, 18 H), 0.86 (t, J ) 7.1 Hz, 3 H), 0.62-0.48
(m, 12 H). 13C NMR (125 MHz, CDCl3): δ 201.9, 75.1, 70.8, 46.1,
32.1, 30.6, 30.0, 29.9, 29.8, 29.5, 26.7, 22.9, 14.2, 7.0, 5.3, 5.1. IR
(thin film): 2930, 2978, 2855, 2716, 1732, 1640, 1414, 1381, 1327,
1240, 1103, 1007, 976, 833, 743, 673 cm-1. HRMS (CI, CH4) calcd
for C33H70O3Si2, 569.4785 m/z [M - H]+; observed, 569.4775 m/z.
A solution of this aldehyde (15.1 g, 0.02 mol) and (carbethoxy-
methylene)triphenylphosphorane (13.9, 0.05 mol) in THF (245 mL)
was heated to reflux for 16 h. After cooling the solution to room
temperature, the solvent was evaporated and the crude product was
purified by column chromatography (EtOAc/hexanes 1:99) to afford
derivatization of diol with (R)-Mosher acids). [R]20 -2.0 (c 1.0,
D
1
CHCl3). H NMR (500 MHz, CDCl3): δ 7.24 (d, J ) 8.4 Hz, 2
H), 6.88 (d, J ) 8.4 Hz, 2 H), 4.45 (s, 2 H), 3.80 (s, 3 H), 3.72-
3.62 (m, 3 H), 3.42-3.39 (m, 1 H), 1.89-1.74 (m, 2 H), 1.44-
1.50 (m, 3 H), 1.33-1.21 (m, 31 H), 0.88 (t, J ) 6.8 Hz, 3 H). 13
C
20
NMR (125 MHz, CDCl3): δ 159.4, 129.8, 129.4, 113.9, 74.3, 73.7,
73.1, 68.3, 55.3, 33.6, 33.2, 32.0, 29.7, 29.6, 29.5, 29.4, 25.8, 22.7,
14.1. IR (thin film): 3354, 2916, 2848, 1612, 1514, 1467, 1369,
1248, 1178, 1114, 1035, 814 cm-1. HRMS (EI) calcd for C29H52O4,
464.3866 m/z [M]+; observed, 464.3875 m/z. Mp ) 75-77 °C.
Alcohol 11. To a solution of the diol 10 (29 g, 0.062 mol) in
THF (600 mL) was added triethylamine (202 mL) followed by
triethylsilyl chloride (63 mL, 0.374 mol) and DMAP (2.9 g, 0.024
mol) at ambient temperature. The reaction was stirred under N2
for 3 h, after which it was quenched by adding a saturated NaHCO3
solution (400 mL). The aqueous layer was extracted with 1:5
EtOAc/hexanes (3 × 500 mL) to afford crude oil, which was
purified by column chromatography (35:1 hexanes/EtOAc) provid-
the trans R,â-unsaturated ester as a yellow oil (15.1 g, 91%). [δ]D
1
-30.1 (c 1.99, CHCl3). H NMR (500 MHz, CDCl3): δ 7.37-
6.98 (m, 1 H), 5.85 (d, J ) 15.5, 1 H), 4.19 (q, J ) 7.1 Hz, 2 H),
3.71-3.61 (m, 1 H), 3.60-3.58 (m, 1 H), 2.57-2.52 (m, 1 H),
2.23-2.17 (m, 1 H), 1.67-1.20 (m, 30 H), 1.02-0.92 (m, 18 H),
0.90 (t, J ) 7.0 Hz, 3 H), 0.65-0.55 (m, 12 H). 13C NMR (125
MHz, CDCl3): δ 166.6, 147.9, 123.0, 75.6, 75.0, 60.2, 60.1, 34.2,
34.1, 32.1, 30.3, 30.0, 29.9, 29.6, 26.8, 22.9, 14.5, 14.4, 14.3, 7.1,
7.0, 5.4, 5.2. IR (thin film): 2926, 2878, 2855, 1729, 1657, 1464,
1414, 1379, 1368, 1318, 1264, 1238, 1167, 1100, 1047, 1005, 984,
849, 743, 673 cm-1. HRMS (CI, CH4) calcd for C37H76O2Si2,
639.5204 m/z [M - H]+; observed, 639.5213 m/z.
To a cold (0 °C) solution of the ester (15.2 g, 23.8 mmol) in
diethyl ether (245 mL) was added DIBAL-H (75 mmol, 50 mL of
1.5 M solution in toluene) under N2. After stirring for 30 min at
the same temperature, saturated potassium-sodium tartrate solution
ing the fully protected triol (43 g, quantitative). [R]20 -17.5 (c
D
3.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.26 (d, J ) 8.6 Hz,
2 H), 6.87 (d, J ) 8.6 Hz, 2 H), 4.43 (s, 2 H), 3.81 (s, 3 H), 3.78-
J. Org. Chem, Vol. 71, No. 4, 2006 1425

Narayan and Borhan
(240 mL) was added and the mixture was brought to room
temperature. Et2O (250 mL), H2O (50 mL), and glycerol (12 mL)
were added, and the resultant heterogeneous mixture was stirred
overnight. The two layers were then separated, and the aqueous
layer was extracted with diethyl ether (2 × 200 mL). The combined
organic layers were dried (MgSO4) and concentrated, and the crude
product after chromatographic purification (5% EtOAc in hexanes)
THF Diol 18. To a solution of 6 (4.0 g, 5.66 mmol) in Et2O
(150 mL) at 0 °C was added dropwise BF3‚OEt2 (4.3 mL, 33.8
mmol). After addition was complete, the mixture was slowly
warmed to room temperature over 5 h. The reaction mixture was
quenched with NaHCO3 solution (50 mL) and extracted with EtOAc
(3 × 100 mL). The combined extracts were dried over MgSO4 and
concentrated under reduced pressure to afford a mixture of regio-
and stereoisomeric products. Flash column chromatography pro-
vided the desired THF diol 18 (1.52 g, 56%) cleanly as a single
diastereomer along with an inseparable mixture of isomers (543
mg) (data for 18 is shown). [δ]D20 -36.2 (c 0.32, CHCl3). 1H NMR
(500 MHz, CDCl3): δ 7.41-7.20 (m, 5 H), 4.45-4.44 (m, 1 H),
4.10 (dt, J ) 6.2, 9.5 Hz, 1 H), 4.00 (ddd, J ) 3.1, 5.4, 8.8 Hz, 1
H), 3.81-3.34 (m, 1 H), 3.27 (dd, J ) 5.3, 13.0 Hz, 1 H), 3.14
(dd, J ) 9.1, 13.3 Hz, 1 H), 2.17-2.12 (s, br, 1 H), 2.04-1.80 (m,
2 H), 1.58-1.25 (m, 32 H), 0.88 (t, J ) 7.0 Hz, 3 H). 13C NMR
(125 MHz, CDCl3): δ 195.1, 135.6, 129.9, 129.3, 126.8, 100.9,
91.5, 81.5, 74.2, 73.0, 37.7, 33.7, 32.7, 32.2, 29.9, 29.8, 29.6, 25.8,
22.9, 14.3. IR (thin film): 3440, 3400, 2918, 2841, 1585, 1464,
20
afforded allylic alcohol 12 as a colorless oil (14.2 g, 89%). [δ]D
1
-27.1 (c 2.22, CHCl3). H NMR (500 MHz, CDCl3): δ 5.74-
5.64 (m, 2 H), 4.10-4.07 (m, 2 H), 3.62-3.55 (m, 2 H), 2.43-
2.39 (m, 1 H), 2.07-2.00 (m, 1 H), 1.64-1.24 (m, 32 H), 0.99-
0.93 (m, 18 H), 0.88 (t, J ) 7.0 Hz, 3 H), 0.63-0.51 (m, 12 H).
13C NMR (125 MHz, CDCl3): δ 131.6, 130.9, 75.7, 64.1, 33.9,
32.1, 30.4, 29.9, 29.8, 29.6, 26.8, 22.9, 14.3, 7.1, 7.0, 5.4. IR (thin
film): 3333, 2928, 2978, 2853, 1460, 1414, 1379, 1329, 1238, 1098,
1007, 972, 909, 743, 673 cm-1. HRMS (CI, CH4) calcd for
C35H74O3Si2, 597.5098 m/z [M - H]+; observed, 597.5090 m/z.
Epoxy Alcohol 13. A two-necked round-bottom flask charged
with 4 Å molecular sieves (1.17 g) and CH2Cl2 (47 mL) was cooled
to -20 °C. To this, Ti(OiPr)4 (3.04 mL, 10.0 mmol) and a CH2Cl2
solution of D-(-)-DET (2.91 g, 12.4 mmol in 41 mL of CH2Cl2)
were added in that order and stirred at the same temperature under
N2 for 30 min. After cooling the complex to -30 °C, t-BuOOH
(13 mL of 3.1 M solution in toluene, 40 mmol) was added dropwise
and the mixture was stirred for another 45 min. A solution of allylic
alcohol 12 (6.21 g, 10.4 mmol) in CH2Cl2 (31 mL) was added via
a syringe pump over 45 min. The reaction was warmed to -20 °C,
stirred for 2 h, and then quenched by adding saturated Na2SO4 and
Na2SO3 solutions (6.8 mL each). Et2O (25 mL) was added, and
the resultant yellow mixture was vigorously stirred at room
temperature for 4 h. The yellow gelatinous mass was further diluted
with Et2O (200 mL). Celite was added, and the mixture was filtered
through a pad of Celite. The filter cake was washed with Et2O (ca.
600 mL) until it turned dry and granular. The filtrate was
concentrated, and epoxy alcohol 13 was isolated in 73% yield after
purification by column chromatography (7% EtOAc in hexanes).
1414, 1325, 1173, 1092, 1026, 964, 949, 879, 810, 729, 683 cm-1
.
HRMS (CI, CH4) calcd for C29H50O3S, 477.3402 m/z [M - H]+;
observed, 477.3398 m/z.
Sulfoxide 19. 2,6-Lutidine (1.3 mL, 11.2 mmol) was added to a
0 °C solution of THF diol 18 (1.72 g, 3.59 mmol) in CH2Cl2 (18
mL). A solution of TBSOTf (1.9 mL, 8.25 mmol) in CH2Cl2 (10
mL) was then added, and the reaction mixture was stirred at 0 °C
for 30 min. When TLC indicated completion of the reaction, water
(50 mL) was added and the aqueous solution was extracted with
CH2Cl2 (3 × 100 mL). The combined extracts were dried over
Na2SO4 and concentrated under reduced pressure to afford the crude
product as a colorless oil. After purification by flash column
chromatography, 2.26 g of the bis-TBS ether was obtained in 87%
yield. [δ]D20 -71.0 (c 0.57, CHCl3). 1H NMR (500 MHz, CDCl3):
δ 7.37-7.14 (m, 5 H), 4.40 (m, 1 H), 4.21 (dt, J ) 5.3, 10.4, 1 H),
3.96 (dt, J ) 3.1, 6.8, 1 H), 3.59 (m, 1 H), 3.15 (m, 2 H), 1.88-
1.79 (m, 2 H), 1.38-1.22 (m, 32 H), 0.91 (s, 9 H), 0.89 (t, J ) 6.6
Hz, 3 H), 0.87 (s, 9 H), 0.12 (s, 3 H), 0.11 (s, 3 H), 0.07 (s, 3 H),
0.05 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 137.0, 129.1, 128.7,
125.8, 81.7, 80.7, 74.6, 73.0, 37.3, 32.7, 32.2, 30.1, 29.9, 29.8, 29.6,
26.2, 26.0, 22.9, 18.5, 18.3, 14.4, -4.0, -4.2, -4.3, -4.6. IR (thin
film): 2926, 2856, 1585, 1470, 1439, 1389, 1362, 1254, 1194, 1078,
1057, 1007, 960, 835, 775, 737, 690 cm-1. HRMS (ES) calcd for
C41H78O3Ssi2, 707.5289 m/z [M + H]+; observed, 707.5269 m/z.
To a 0 °C solution of the above bis-TBS ether (1 g, 1.4 mmol)
in CH2Cl2 (16 mL) was added a solution of m-CPBA (350 mg, 1.4
mmol) in CH2Cl2 (16 mL). After 30 min at 0 °C, the reaction
mixture was quenched with saturated NaHCO3 solution (30 mL)
and the aqueous mixture was extracted with CH2Cl2 (3 × 50 mL).
The combined extracts were dried over Na2SO4 and concentrated
under reduced pressure to afford sulfoxide 19 as a mixture of
diastereomers, which was used without further purification.
THF Aldehyde 5. The crude sulfoxide (19) was dissolved in
CH2Cl2 (11.3 mL) and cooled to 0 °C, and 2,6-lutidine (0.56 mL)
was added. TFAA (0.69 mL, 4.95 mmol) in CH2Cl2 (11.3 mL)
was then added, and the mixture was stirred at 0 °C for 1 h. The
reaction mixture was quenched with saturated NaHCO3 solution
and extracted with CH2Cl2. The combined extracts were dried over
Na2SO4 and concentrated under reduced pressure to afford a clear
oil. This material was taken up in 1:1 acetonitrile/water (50 mL),
and solid NaHCO3 (2.5 g) was added. The reaction mixture was
stirred at ambient temperature for 16 h, upon which the solution
was diluted with water (25 mL). The aqueous solution was extracted
with CH2Cl2 (3 × 25 mL), and the combined extracts were dried
over Na2SO4 and concentrated under reduced pressure. Slow
chromatography on wet silica gel containing 10% water (3% EtOAc
in hexanes) afforded aldehyde 5 (532 mg) in 63% yield over the
20
1
[δ]D -16.7 (c 1.06, CHCl3). H NMR (500 MHz, CDCl3): δ
4.05-4.03 (m, 1 H), 3.93 (dt, J ) 4.3, 8.4 Hz, 1 H), 3.76-3.72
(m, 2 H), 3.23 (dt, J ) 2.3, 7.2 Hz, 1 H), 3.04 (m, 1 H), 2.09 (s,
br, 1 H), 1.98-1.76 (m, 4 H), 1.63-1.37 (m, 30 H), 1.15-1.05
(m, 18 H), 1.03 (t, J ) 7.0 Hz, 3 H), 0.77-0.67 (m, 12 H). 13C
NMR (125 MHz, CDCl3): δ 75.6, 73.6, 62.2, 58.8, 54.9, 33.7, 32.2,
30.4, 30.0, 29.9, 29.8, 29.6, 26.8, 22.9, 14.4, 7.2, 7.1, 5.3, 5.2. IR
(thin film): 3438, 2932, 2878, 2855, 1462, 1414, 1379, 1329, 1238,
1098, 1009, 976, 903, 874, 743, 673 cm-1. HRMS (CI, CH4) calcd
for C35H74O4Si2, 613.5047 m/z [M - H]+; observed, 613.5052 m/z.
Phenylthiomethyl Epoxide 6. To a solution of diphenyl disulfide
(6.4 g, 29.3 mmol) in triethylamine (20 mL) was added tributyl-
phosphine (7.1 mL, 29.3 mmol) at ambient temperature under N2.
This solution was cooled to 0 °C, and to it was cannulated a
precooled solution of epoxy alcohol 13 (5.96 g, 9.67 mmol) in Et3N.
The reaction was warmed to ambient temperature over 6 h. After
quenching the reaction mixture with water (50 mL), the aqueous
solution was extracted with EtOAc (3 × 150 mL). The combined
EtOAc extracts were dried over Na2SO4 and concentrated under
reduced pressure. The crude product was purified by flash column
chromatography (hexanes to 2% EtOAc in hexanes) to afford 6 as
20
1
a colorless oil (6.43 g, 94%). [δ]D -26.2 (c 1.62, CHCl3). H
NMR (500 MHz, CDCl3): δ 7.41 (d, J ) 1.3 Hz, 2 H), 7.40-7.18
(m, 3 H), 3.75 (dt, J ) 4.2, 8.2 Hz, 1 H), 3.57-3.55 (m, 1 H), 3.13
(dd, J ) 5.1, 13.9 Hz, 1 H), 2.97-2.87 (m, 3 H), 1.69-1.31 (m,
4 H), 1.30-1.15 (m, 30 H), 0.98-0.91 (m, 18 H), 0.88 (t, J ) 7.1
Hz, 3 H), 0.62-0.53 (m, 12 H). 13C NMR (125 MHz, CDCl3): δ
135.9, 130.0, 129.2, 126.7, 75.4, 73.5, 58.2, 57.3, 36.5, 33.9, 32.2,
30.4, 30.1, 30.0, 29.9, 29.8, 29.6, 26.8, 23.0, 14.4, 7.2, 5.3. IR (thin
film): 3077, 3061, 2853, 1806, 1586, 1482, 1439, 1416, 1379, 1327,
20
1
1302, 1238, 1184, 1092, 1007, 970, 943, 916, 747, 699 cm-1
.
three steps. [δ]D -33.0 (c 0.91, CHCl3). H NMR (500 MHz,
CDCl3): δ 9.58 (d, J ) 2.2 Hz, 1 H), 4.73-4.72 (m, 1 H), 4.46-
4.44 (m, 1 H), 4.28-4.16 (m, 1 H), 3.68-3.66 (m, 1 H), 1.87-
HRMS (EI) calcd for C41H78O3SSi2, 706.5210 m/z [M]+; observed,
706.5223 m/z.
1426 J. Org. Chem., Vol. 71, No. 4, 2006

Synthesis of the Proposed Structure of Mucoxin
1.84 (m, 2 H), 1.40-1.22 (m, 32 H), 0.93-0.84 (m, 21 H), 0.08
(s, 3 H), 0.07 (s, 3 H), 0.06 (s, 3 H), 0.05 (s, 3 H). 13C NMR (125
MHz, CDCl3): δ 203.1, 87.2, 82.8, 76.0, 74.4, 38.0, 33.2, 32.2,
30.0, 29.9, 29.8, 29.6, 26.2, 26.0, 25.9, 25.8, 22.9, 18.4, 18.1, 14.3,
-4.1, -4.3, -4.5, -5.1. IR (thin film): 2928, 2855, 1738, 1475,
1464, 1441, 1389, 1362, 1256, 1186, 1076, 1065, 998, 939, 837,
808, 777, 737, 691, 664 cm-1. HRMS (CI, CH4) calcd for
C35H72O4Si2, 611.4891 m/z [M - H]+; observed, 611.4898 m/z.
Aldehyde 29. To a slurry of NaH (7 g, 0.18 mol) in THF (300
mL) was added 1,6-hexanediol (20 g, 0.17 mol) at 0 °C, and the
mixture was stirred for 1 h while warming to room temperature.
Benzyl bromide (20 mL, 0.17 mmol) was added dropwise followed
by TBAI (2.6 g). The reaction was heated to 60 °C for 15 h. After
cooling to room temperature, H2O (150 mL) was carefully added.
The layers were separated, and the aqueous layer was extracted
with Et2O (3 × 300 mL). The combined organic layers (dried with
MgSO4) were concentrated. The corresponding monobenzyl-
protected alcohol was obtained as clear oil (35.4 g, 78%) after
(8.55 mL, 0.11 mol) and triethylamine (17 mL) were added and
stirring was continued at the same temperature for 30 min. The
reaction was quenched with H2O (100 mL). The aqueous layer was
extracted with CH2Cl2 (3 × 200 mL), and combined organic layers
were concentrated. The residue and sodium iodide (25 g, 0.17 mol)
were taken up in acetone (150 mL) and refluxed for 2 h. Upon
cooling to room temperature, the reaction was treated with saturated
sodium sulfite until it became colorless. The aqueous layer was
extracted with EtOAc (3 × 200 mL). Chromatographic purification
(3% EtOAc in hexanes) of the crude product obtained by
concentration of the organic portion afforded iodide 27 (10.1 g,
77%). 1H NMR (500 MHz, CDCl3): δ 7.36-7.28 (m, 5 H), 5.55-
5.52 (m, 1 H), 5.35-5.32 (m, 1 H), 4.52 (s, 2 H), 3.48 (t, J ) 6.6
Hz, 2 H), 3.14 (t, J ) 7.3 Hz, 2 H), 2.66-2.61 (m, 2 H), 2.06-
2.04 (m, 2 H), 1.66-1.63 (m, 2 H), 1.42-1.39 (m, 4 H). 13C NMR
(125 MHz, CDCl3): δ 138.9, 132.7, 128.6, 128.2, 127.9, 127.7,
73.1, 70.6, 31.8, 29.9, 29.6, 27.7, 26.1, 5.7. IR (thin film): 3028,
3009, 2932, 2855, 2791, 1920, 1850, 1790, 1495, 1454, 1361, 1242,
1169, 1105, 1028, 734, 698 cm-1. HRMS (EI) calcd for C16H23IO,
358.0794 m/z [M]+; observed, 358.0800 m/z.
Z-Bishomoallylic Alcohol 26. t-BuLi (7.6 mL of 1.3 M solution
in pentane, 9.94 mmol) was added dropwise to precooled (-100
°C) Et2O (18 mL). To this was added a solution of iodide 27 (1.78
g, 4.97 mmol) in Et2O (14 mL) over 10 min. After stirring for 5
min at -100 to -90 °C, MgBr2‚OEt2 in Et2O (12.4 mL of 1.0 M
solution (freshly prepared)),78,79 was added and the mixture was
warmed to 0 °C over 1 h. Meanwhile, a solution of aldehyde 5 (1
g, 1.63 mmol) in Et2O (18 mL) was cooled to -40 °C. MgBr2‚
OEt2 in Et2O (5.0 mL of 1.0 M solution, 5.0 mmol) was added to
the solution of aldehyde and stirred for 10 min. To this precom-
plexed aldehyde, a solution of the above-mentioned Grignard
reagent was cannulated at -40 °C and the reaction mixture was
stirred overnight at the same temperature. The reaction was then
quenched by slow addition of saturated NH4Cl solution (20 mL)
and H2O (50 mL). The aqueous layer was extracted with Et2O (3
× 100 mL). Combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure to afford a yellow oil.
Purification by column chromatography (2% EtOAc in hexanes)
1
chromatographic purification (30% EtOAc in hexanes). H NMR
(500 MHz, CDCl3): δ 7.35-7.25 (m, 5 H), 4.50 (s, 2 H), 3.56 (t,
J ) 6.6 Hz, 2 H), 3.47 (t, J ) 6.6 Hz, 2 H), 1.63 (quint, J ) 6.6
Hz, 2 H), 1.54 (quint, J ) 7.0 Hz, 2 H), 1.38-1.32 (m, 4 H). 13C
NMR (125 MHz, CDCl3): δ 138.8, 128.6, 127.9, 127.8, 73.1, 70.6,
62.8, 32.9, 29.9, 26.2, 25.9. IR (thin film): 3393, 3063, 2933, 2859,
1951, 1874, 1810, 1603, 1454, 1363, 1309, 1251, 1205, 1099, 1028,
909, 735, 675 cm-1. HRMS (EI) calcd for C13H20O2, 208.1458 m/z
[M]+; observed, 208.1463 m/z.
To a slurry of PCC (31.6 g, 0.15 mol) in CH2Cl2 (300 mL) was
added a solution of the above alcohol (20.4 g, 98.1 mmol) in CH2Cl2
(100 mL) at room temperature under N2 with vigorous stirring. After
2 h, anhydrous Et2O (400 mL) was added and the reaction mixture
was filtered through a Celite pad. The filtrate was concentrated,
and the crude brown oily material was purified by flash column
chromatography (10% EtOAc in hexanes) to afford aldehyde 29
1
as a clear liquid (16.6 g, 82%). H NMR (500 MHz, CDCl3): δ
9.75 (t, J ) 2.2 Hz, 1 H), 7.39-7.20 (m, 5 H), 4.49 (s, 2 H), 3.47
(t, J ) 6.4, 2 H), 2.40-2.48 (m, 2 H), 1.72-1.61 (m, 4 H), 1.46-
1.38 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ 202.8, 138.8, 128.6,
127.8, 127.7, 73.1, 70.2, 44.0, 29.7, 26.0, 22.1. IR (thin film): 3031,
2936, 2860, 2720, 1954, 1875, 1724, 1453, 1409, 1363, 1391, 1101,
1026, 906, 737, 703 cm-1. HRMS (EI) calcd for C13H18O2,
206.1307 m/z [M]+; observed, 206.1309 m/z.
furnished the adduct 26 (1.17 g, 85%) as a single diastereomer.
1
[R]20 -17.1 (c 0.97, CHCl3). H NMR (500 MHz, CDCl3): δ
D
7.33-7.25 (m, 5 H), 5.39-5.33 (m, 2 H), 4.52 (s, 2 H), 4.50-
4.39 (m, 1 H), 4.25-4.21 (m, 1 H), 3.8 (dt, J ) 4.3, 8.8 Hz, 1 H),
3.68-3.62 (m, 2 H), 3.46 (t, J ) 6.6 Hz, 2 H), 2.96 (s, br, 1 H),
2.29-2.05 (m, 4 H), 1.88-1.86 (m, 2 H), 1.65-1.47 (m, 4 H),
1.38-1.23 (m, 36 H), 0.91 (s, 9 H), 0.90 (s, 9 H), 0.88 (t, J ) 7.0
Hz, 3 H), 0.11 (s, 3 H), 0.10 (s, 3 H), 0.08 (s, 3 H), 0.06 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ 139.0, 130.3, 129.7, 128.5, 127.8,
127.6, 85.0, 80.5, 75.0, 74.6, 73.1, 70.7, 38.2, 33.4, 32.9, 30.1, 29.9,
29.8, 29.6, 27.4, 26.2, 26.1, 26.0, 25.8, 23.7, 22.9, 18.4, 18.1, 14.3,
-4.0, -4.1, -4.3, -4.8. IR (thin film): 3596, 3521, 3031, 3004,
2928, 2856, 1464, 1406, 1389, 1362, 1256, 1190, 1076, 1005, 955,
939, 835, 808, 775, 733, 696, 662 cm-1. HRMS (EI) calcd for
C51H96O5Si2, 844.6796 m/z [M]+; observed, 844.6789 m/z.
Z-Homoallylic Iodide 27. KHMDS (175 mL of 0.5 M solution
in toluene, 87.5 mmol) was added to a -20 °C slurry of
3-hydroxypropyltriphenylphosphonium bromide (17.6 g, 43.7 mmol)
in THF (55 mL). The mixture was brought to room temperature
and stirred for 1 h. After cooling back to 0 °C, TMSCl (5.8 mL,
43.7 mmol) was added and stirring was continued at the same
temperature for 15 min. The reaction was then cooled to -78 °C
upon which a THF solution of aldehyde 29 (5 g, 24.3 mmol in 40
mL) was added. The reaction was warmed to -10 °C over 1 h and
then treated with AcOH/H2O/THF (6:3:1, 250 mL). After 15 h of
stirring at room temperature, the reaction mixture was neutralized
with saturated NaHCO3. The aqueous layer was extracted with
EtOAc (3 × 400 mL), and the combined organic layers were dried
over Na2SO4, concentrated, and purified by column chromatography
(10% EtOAc in hexanes) to secure the homoallylic alcohol (9 g,
83%, Z/E > 10:1). 1H NMR (500 MHz, CDCl3): δ 7.37-7.25 (m,
5 H), 5.55-5.51 (m, 1 H), 5.39-5.34 (m, 1 H), 4.50 (s, 2 H), 3.60
(t, J ) 6.9 Hz, 2 H), 3.47 (t, J ) 6.9 Hz, 2 H), 2.32-2.28 (m, 2
H), 2.08-2.04 (m, 3 H), 1.66-1.60 (m, 2 H), 1.42-1.37 (m, 4 H).
13C NMR (125 MHz, CDCl3): δ 175.5, 138.8, 133.0, 128.6, 127.9,
127.7, 125.5, 73.1, 70.6, 62.4, 30.9, 29.8, 29.7, 27.5, 26.0, 20.9.
IR (thin film): 3386, 3028, 2861, 2063, 1950, 1872, 1809, 1714,
Triol 30. AD-mix-R (1.26 g) was dissolved in a 1:1 t-BuOH/
H2O (13 mL) mixture. To this clear, orange solution were added
methane sulfonamide (86 mg, 0.9 mmol) and potassium osmate
(19 mg), and the mixture was stirred until all the solids dissolved.
The solution was then cooled to 0 °C upon which hydroxy olefin
26 (760 mg, 0.90 mmol) was added in one portion. The reaction
was vigorously stirred for 16 h, after which solid sodium sulfite
(1.35 g) was added at the same temperature. The mixture was
warmed to room temperature, and stirring was continued for 45
min. EtOAc (50 mL) and H2O (20 mL) were added, and the layers
1654, 1605, 1453, 1366, 1250, 1204, 1050, 872, 735, 695 cm-1
.
(78) Black, T. H. MgBr2‚OEt2. In Encyclopedia of reagents for organic
synthesis; Paquette, L. A., Ed.; Wiley: Chichester; New York, 1995; Vol.
5, pp 3197-3199.
(79) Black, T. H.; Mcdermott, T. S.; Brown, G. A. Tetrahedron Lett.
1991, 32, 6501-6502.
HRMS (EI) calcd for C16H24O2, 248.1776 m/z [M]+; observed,
248.1769 m/z.
A solution of the latter homoallylic alcohol (9.1 g, 36.7 mmol)
in CH2Cl2 (140 mL) was cooled to 0 °C. To this, mesyl chloride
J. Org. Chem, Vol. 71, No. 4, 2006 1427

Narayan and Borhan
were separated. The aqueous layer was extracted with EtOAc (4
× 50 mL), and combined organic layers were dried over Na2SO4
and concentrated. The crude product was purified by column
chromatography (8% EtOAc in hexanes). The desired diastereomer
74.0, 73.7, 73.1, 70.7, 36.3, 32.1, 31.9, 31.5, 30.1, 30.0, 29.9, 29.6,
28.7, 26.7, 26.6, 26.4, 26.2, 26.1, 25.9, 22.9, 18.4, 18.3, 18.1, 14.3,
-3.9, -4.1, -4.4, -4.8. IR (thin film): 2904, 2855, 1990, 1871,
1463, 1366, 1254, 1098 cm-1. HRMS (ES) calcd for C57H110O6Si3,
975.7689 m/z [M + H]+; observed, 975.7697 m/z.
Iodide 24. Benzyl ether 33 (390 mg, 0.40 mmol) was dissolved
in 1:1 EtOAc/i-PrOH (20 mL). To this solution was added 10%
Pd-C (111 mg), and the mixture was stirred vigorously under H2
(1 atm). The hydrogenolysis was complete in 1 h, after which the
reaction was filtered through a Celite pad. The filtrate was
concentrated, and the crude product was purified by flash column
30 was isolated in 73% (577 mg) yield as a colorless oil. [R]20
D
1
-16.2 (c 0.87, CHCl3). H NMR (500 MHz, CDCl3): δ 7.33-
7.24 (m, 5 H), 4.49 (s, 2 H), 4.42-4.41 (m, 1 H), 4.22-4.20 (m,
1 H), 3.88-3.87 (m, 1 H), 3.71-3.69 (m, 1 H), 3.64-3.58 (m, 3
H), 3.47 (t, J ) 6.6 Hz, 2 H), 3.23 (s, br, 1 H), 3.03 (s, br, 1 H),
1.88-0.186 (m, 2 H), 1.68-1.22 (m, 44 H), 0.90 (s, 9 H), 0.89 (s,
9 H), 0.88 (t, J ) 7.0, 3 H), 0.10 (s, 3 H), 0.09 (s, 3 H), 0.07 (s,
3 H), 0.06 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 138.9, 128.5,
127.8, 127.7, 85.0, 80.6, 74.9, 74.8, 74.5, 74.4, 73.1, 71.3, 70.6,
38.3, 32.9, 32.1, 31.9, 30.1, 29.9, 29.8, 29.6, 27.7, 26.5, 26.1, 25.9,
25.8, 22.9, 18.4, 18.1, 14.3, -4.0, -4.2, -4.3, -4.9. IR (thin
film): 3596, 3521, 3031, 3004, 2928, 2856, 1464, 1406, 1389, 1362,
1256, 1190, 1076, 1005, 955, 939, 835, 808, 775, 733, 696, 662
cm-1. HRMS (ES) calcd for C51H98O7Si2, 879.6929 m/z [M + H]+;
observed, 879.6931 m/z.
chromatography (5% EtOAc in hexanes) to furnish the free alcohol
1
in 92% yield (326 mg). [R]20 -29.4 (c 0.83, CHCl3). H NMR
D
(500 MHz, CDCl3): δ 4.30-4.26 (m, 2 H), 4.17-4.13 (m, 1 H),
3.97-3.93 (m, 1 H), 3.76-3.72 (m, 2 H), 3.65-3.63 (m, 1 H),
3.62 (t, J ) 6.6 Hz, 2 H), 2.00-1.64 (m, 4 H), 1.59-1.12 (m, 44
H), 0.89 (t, J ) 7.0, 3 H), 0.88 (s, 9 H), 0.87 (s, 9 H), 0.86 (s, 9
H), 0.07 (s, 3 H), 0.05 (s, 3 H), 0.04 (s, 6 H), 0.04 (s, 6 H). 13C
NMR (125 MHz, CDCl3): δ 85.9, 81.6, 80.5, 79.2, 74.3, 74.0, 73.6,
63.2, 36.3, 33.0, 32.1, 31.9, 31.5, 29.9, 29.8, 29.7, 29.6, 28.7, 26.5,
26.4, 26.2, 26.1, 26.0, 25.9, 22.9, 18.4, 18.3, 18.1, 14.3, 1.2, -3.9,
-4.0, -4.1, -4.4, -4.8. IR (thin film): 3385, 2926, 2855, 1600,
1463, 1360, 1255, 1079, 835, 774 cm-1. HRMS (ES) calcd for
C50H104O6Si3, 885.7219 m/z [M + H]+; observed, 885.7217 m/z.
The alcohol (304 mg, 0.34 mmol), triphenylphosphine (223 mg,
0.85 mmol), and imidazole (61 mg, 0.90 mmol) were dissolved in
toluene (12 mL). Upon addition of iodine (231 mg, 0.91 mmol),
the clear, colorless solution turned yellowish brown and turbid. After
1 h of vigorous stirring at room temperature, saturated sodium sulfite
solution was added to the reaction until the yellowish brown color
disappeared. The layers were separated, and the aqueous layer was
washed with EtOAc (3 × 15 mL). The combined organic layers
were dried (Na2SO4), and the solvent was removed under reduced
pressure to yield a gummy material. Purification of the crude
material by column chromatography (3% EtOAc in hexanes)
afforded iodide 24 (294 mg, 87%) as a colorless oil. [R]20D -27.7
(c 1.09, CHCl3). 1H NMR (500 MHz, CDCl3): δ 4.32-4.29 (m, 2
H), 4.19-4.15 (m, 1 H), 3.98-3.94 (m, 1 H), 3.78-3.72 (m, 2 H),
3.65 (dd, J ) 3.5, 7.7 Hz, 1 H), 3.18 (t, J ) 6.6 Hz, 2 H), 2.00-
1.23 (m, 46 H), 0.90 (t, J ) 7.0 Hz, 3 H), 0.89 (s, 9 H), 0.88 (s, 9
H), 0.87 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H), 0.06 (s, 6 H), 0.05
(s, 6 H). 13C NMR (125 MHz, CDCl3): δ 85.9, 81.6, 80.6, 79.3,
77.5, 77.2, 77.0, 74.2, 74.0, 73.6, 36.3, 33.8, 32.1, 31.7, 31.5, 31.0,
30.1, 29.9, 29.8, 29.6, 28.7, 26.5, 26.4, 26.2, 26.1, 26.0, 25.2, 22.9,
18.4, 18.3, 18.1, 14.3, 7.3, -3.9, -4.0, -4.1, -4.3, -4.4, -4.8.
IR (thin film): 2925, 2854, 1597, 1462, 1359, 1253, 1076, 835,
775 cm-1. HRMS (ES) calcd for C50H103IO5Si3, 995.6236 m/z [M
+ H]+; observed, 995.6259 m/z.
Bistetrahydrofuran Acetate 32. PPTS (6 mg, 0.02 mmol) was
added to a solution of triol 30 (200 mg, 0.22 mmol) and
trimethylortho acetate (36 µL, 0.23 mmol) in CH2Cl2 (3 mL) at
room temperature. After complete consumption of the triol (ca. 5
min, as judged by TLC), a solution of BF3‚OEt2 (8 µL, 0.06 mmol)
in CH2Cl2 (1 mL) was rapidly added to the reaction. After 10 min,
the reaction was slowly poured into saturated NaHCO3 solution (5
mL) and the aqueous layer was extracted with CH2Cl2 (3 × 20
mL). Combined organic layers were dried (Na2SO4) and concen-
trated under reduced pressure, and the crude product was purified
by flash column chromatography (2% EtOAc in hexanes) to furnish
bistetrahydrofuran acetate 32 (187 mg, 91%) as a clear oil. [R]20
D
1
-29.3 (c 0.47, CHCl3). H NMR (500 MHz, CDCl3): δ 7.35-
7.25 (m, 5 H), 4.91-4.87 (m, 1 H), 4.48 (s, 2 H), 4.29-4.18 (m,
3 H), 4.05-4.01 (m, 1 H), 3.74-3.71 (m, 1 H), 3.63 (dd, J ) 3.6,
7.7 Hz, 1 H), 3.44 (t, J ) 6.4 Hz, 2 H), 2.08-2.00 (m, 1 H), 2.04
(s, 3 H), 1.96-1.80 (m, 4 H), 1.66-1.51 (m, 6 H), 1.48-1.18 (m,
34 H), 0.88 (s, 9 H), 0.87 (s, 9 H), 0.86 (t, J ) 7.0 Hz, 3 H), 0.11
(s, 3 H), 0.09 (s, 3 H), 0.07 (s, 6 H). 13C NMR (125 MHz, CDCl3):
δ 171.1, 138.9, 128.5, 127.8, 127.6, 85.5, 81.0, 79.3, 79.2, 75.8,
75.4, 73.7, 73.1, 70.6, 36.8, 32.1, 32.0, 31.0, 30.1, 29.9, 29.6, 28.6,
27.9, 26.4, 26.2, 25.9, 25.6, 22.9, 21.4, 18.4, 18.1, -3.9, -4.0,
-4.5, -4.8. IR (thin film): 2926, 2854, 1739, 1463, 1354, 1244,
1100, 1056, 940, 833, 775 cm-1. HRMS (ES) calcd for C53H98O7Si2,
903.6929 m/z [M + H]+; observed, 903.6913 m/z.
Bistetrahydrofuran 33. Acetate 32 (440 mg, 0.49 mmol) was
dissolved in MeOH (7 mL). Solid K2CO3 was added to this solution,
and the heterogeneous mixture was stirred vigorously at room
temperature for 17 h. The reaction was then diluted with CH2Cl2
(20 mL) and washed with NaHCO3 (5 mL) and H2O (10 mL). The
aqueous layers were mixed and extracted with CH2Cl2 (3 × 15
mL). The combined organic layer was dried with Na2SO4. The
solvent was evaporated, and the alcohol was used without further
purification. To a 0 °C solution of this alcohol (172 mg, 0.20 mmol)
in CH2Cl2 (5 mL) were added 2,6-lutidine (0.15 mL, 1.2 mmol)
and TBSOTf (0.14 mL, 0.6 mmol) in that order. After 30 min at
the same temperature, saturated NaHCO3 solution (2 mL) was added
and the layers were separated. The aqueous layer was extracted
with CH2Cl2 (3 × 15 mL), and combined organic layers were dried
over Na2SO4 and concentrated under reduced pressure to afford a
crude oil. Upon purification of the oil by column chromatography
(1% EtOAc in hexanes), bistetrahydrofuran benzyl ether 33 was
obtained in 97% yield (189 mg). [R]20D -30.5 (c 0.83, CHCl3). 1H
NMR (500 MHz, CDCl3): δ 7.34-7.26 (m, 5 H), 4.50 (s, 2 H),
4.31-4.27 (m, 2 H), 4.19-4.15 (m, 1 H), 3.97-3.93 (m, 1 H),
3.78-3.76 (m, 1 H), 3.75-3.71 (dd, J ) 3.5, 7.7, 1 H), 3.46 (t, J
) 6.6, 2 H), 2.00-1.16 (m, 4 H), 1.57-1.2 (m, 42 H), 0.90 (t, J
) 7.0, 3 H), 0.89 (s, 9 H), 0.88 (s, 9 H), 0.87 (s, 9 H) 0.08 (s, 3
H), 0.06 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3 H). 13C NMR (125 MHz,
CDCl3): δ 139.0, 128.5, 127.8, 127.6, 85.9, 81.7, 80.5, 79.2, 74.4,
Bistetrahydrofuran r-Phenylthiolactone 34. A solution of
diisopropylamine (5.8 µL, 0.06 mmol) in THF (0.5 mL) was cooled
to -78 °C, and n-BuLi (24 µL of 2.5 M solution, 0.06 mmol) was
added to it. After 15 min, lactone 2564 (12.6 mg, 0.06 mmol) in
THF (0.4 mL) was added and stirring was continued for 30 min
during which the solution was warmed to 0 °C. Iodide 24 (30 mg,
0.03 mmol) was then added as a solution in 1:1 THF/HMPA (0.5
mL). The reaction was warmed to room temperature. After 15 h,
H2O (1 mL) and EtOAc (5 mL) were added and the layers were
separated. The aqueous layer was extracted with EtOAc (3 × 5
mL), and the combined organic layers were dried (Na2SO4) and
concentrated. The crude product was purified by column chroma-
tography (1% - 3% EtOAc in hexanes) to afford the phenylthio-
lactone 34 as a mixture of diastereomers (28 mg, 87%). [R]20
D
1
-34.8 (c 0.78, CHCl3). H NMR (500 MHz, CDCl3): δ 7.56-
7.52 (m, 2 H), 7.43-7.33 (m, 3 H), 4.53-4.46 (m, 1 H), 4.32-
4.28 (m, 2 H), 4.19-4.15 (m, 1 H), 3.97-3.93 (m, 1 H), 3.78-
3.72 (m, 2 H), 3.65 (dd, J ) 3.5, 7.7 Hz, 1 H), 2.52 (dd, J ) 3.5,
7.7 Hz, 1 H), 2.01-1.91 (m, 2 H), 1.90-1.21 (m, 50 H), 0.90 (t,
J ) 7.0 Hz, 3 H), 0.89 (s, 9 H), 0.88 (s, 9 H), 0.87 (s, 9 H), 0.08
(s, 3 H), 0.07 (s, 3 H), 0.06 (s, 12 H). 13C NMR (125 MHz,
1428 J. Org. Chem., Vol. 71, No. 4, 2006

Synthesis of the Proposed Structure of Mucoxin
CDCl3): δ 177.3, 137.3, 137.1, 130.8, 130.1, 129.9, 129.2, 129.1,
85.9, 81.6, 80.6, 79.3, 74.3, 74.0, 73.7, 73.6, 73.4, 56.4, 40.3, 36.7,
36.3, 32.1, 31.8, 31.5, 30.2, 30.1, 29.9, 29.6, 28.7, 26.5, 25.4, 26.2,
26.2, 26.0, 25.0, 22.9, 21.7, 18.4, 18.1, 14.3, -3.9, -4.0, -4.1,
-4.3, -4.4, -4.8. IR (thin film): 2926, 2854, 1770, 1464, 1385,
(Na2SO4) and concentrated under reduced pressure, and the crude
material was purified by flash column chromatography (30% EtOAc
in hexanes) to afford the PMB-protected bisester (37 mg, 50%).
1H NMR (300 MHz, CDCl3): δ 8.02-7.91 (m, 4 H), 7.18 (d, J )
8.6 Hz, 2 H), 6.85 (d, J ) 8.6, 2 H), 6.62-6.71 (m, 4 H), 5.58-
5.56 (m, 1 H), 5.37-5.35 (m, 1 H), 4.04 (s, 2 H), 3.78 (s, 3 H),
3.58-3.47 (m, 2 H), 3.04 (s, 6 H), 3.02 (s, 6 H), 2.02-1.98 (m, 2
H), 1.78-1.61 (m, 2 H), 1.56-1.20 (m, 30 H), 0.88 (t, J ) 6.9
Hz, 3 H).
1360, 1255, 1184, 1068, 968, 939, 835, 806, 775, 705, 692 cm-1
.
HRMS (ES) calcd for C62H114O7SSi3, 1075.7671 m/z [M + H]+;
observed, 1075.7690 m/z.
Bistetrahydrofuran γ-Methyl Butenolide 35. To an ice cold
solution of 34 (30 mg, 0.03 mmol) in CH2Cl2 (1 mL) was added
dropwise ca. 75% m-CPBA (6.8 mg, 0.03 mmol) in CH2Cl2 (1 mL).
After 20 min, saturated NaHCO3 solution (1 mL) was carefully
added and the layers were separated. The aqueous layer was
extracted with CH2Cl2 (3 × 5 mL). The combined organic layers
were dried and concentrated to afford the corresponding sulfoxide.
The crude sulfoxide was taken up in toluene (2 mL) and heated to
reflux for 4 h. After cooling the solution to room temperature, the
solvent was evaporated under reduced pressure and the crude
material was purified by column chromatography (5% EtOAc in
hexanes) to afford 35 (24 mg, 83%). [R]20D -17.9 (c 0.42, CHCl3).
1H NMR (500 MHz, CDCl3): δ 6.99 (d, J ) 1.6 Hz, 1 H), 5.00-
4.99 (m, 1 H), 4.31-4.28 (m, 2 H), 4.19-4.15 (m, 1 H), 3.98-
3.94 (m, 1 H), 3.78-3.74 (m, 2 H), 3.65 (dd, J ) 3.5, 7.7 Hz, 1
H), 2.27 (t, J ) 7.3 Hz, 2 H), 2.02-1.12 (m, 49 H), 0.92-0.88
(m, 30 H), 0.08-0.05 (m, 18 H). 13C NMR (125 MHz, CDCl3): δ
174.0, 149.0, 134.5, 85.9, 81.6, 80.6, 79.3, 74.3, 74.0, 73.7, 36.3,
32.1, 31.7, 31.5, 30.1, 29.9, 29.8, 29.7, 29.6, 28.7, 27.6, 26.5, 26.4,
26.2, 26.1, 26.0, 25.4, 22.9, 19.4, 18.3, 18.1, 14.3, 1.2, -3.9, -4.0,
-4.1, -4.4, -4.8. IR (thin film): 2954, 2927, 2854, 1761, 1463,
1361, 1319, 1257, 1081, 1026, 835, 802, 775 cm-1. HRMS (ES)
calcd for C55H108O7Si3, 965.7481 m/z [M + H]+; observed,
965.7480 m/z.
DDQ (14 mg, 0.06 mmol) was added to a solution of the above
PMB ether (37 mg, 0.05 mmol) in 9:1 CH2Cl2/H2O (1.1 mL) at 0
°C. After 30 min, the reaction mixture was carefully poured into
saturated NaHCO3 solution (2 mL). Extraction of the aqueous layer
with CH2Cl2 (3 × 5 mL) followed by evaporation of the solvent
and purification using column chromatography furnished the
1
corresponding free alcohol in 50% yield (16 mg). H NMR (500
MHz, CDCl3): δ 7.96-7.94 (m, 4 H), 6.67-6.65 (m, 4 H), 5.41
(dt, J ) 3.3, 10.6 Hz, 1 H), 5.36-5.32 (m, 1 H), 3.65 (s, br, 1 H),
3.56-3.52 (m, 1 H), 3.05 (s, 6 H), 3.04 (s, 6 H), 3.01-2.90 (m, 1
H), 1.97-1.69 (m, 3 H), 1.55-1.20 (m, 31 H), 0.86 (t, J ) 7.1
Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ 168.1, 166.7, 153.8,
153.6, 131.9, 131.7, 116.3, 117.2, 74.4, 71.4, 58.4, 48.9, 40.3, 40.2,
34.1, 32.1, 31.4, 32.1, 30.0, 29.9, 29.8, 29.7, 29.6, 29.5, 29.4, 25.4,
22.9, 14.3.
The alcohol (15 mg, 0.02 mmol) was dissolved in bis(trimethyl-
silyl)trifluoro acetamide (0.2 mL), and the solution was heated to
50 °C for 30 min. After cooling to room temperature, the volatiles
were removed under reduced pressure and the TMS derivative 38
was used for ECCD analysis without further purification. 1H NMR
(500 MHz, CDCl3): δ 8.00-7.94 (m, 4 H), 6.69-6.65 (m, 4 H),
5.47-5.44 (m, 1 H), 5.35-5.32 (m, 1 H), 3.68-3.65 (m, 2 H),
3.05 (s, 6 H), 3.04 (s, 6 H), 2.01-1.94 (s, 2 H), 1.73-1.69 (s, 2
H), 1.37-1.21 (m, 30 H), 0.89 (t, J ) 7.1 Hz, 3 H), 0.08 (s, 3 H),
0.07 (s, 6 H). 13C NMR (125 MHz, CDCl3): δ 166.7, 166.5, 153.5,
131.7, 117.5, 117.4, 110.9, 74.2, 71.4, 59.2, 40.3, 34.5, 32.1, 31.3,
30.0, 29.9, 29.8, 29.7, 29.6, 29.5, 25.5, 22.9, 14.3, 1.2, -0.4. HRMS
(ES) calcd for C42H70N2O5Si + Na+ (sodium adduct used for
ionization), 733.4592 m/z [M + Na]+; observed, 733.4920 m/z.
THF Diol Bisacetate 39. THF diol 18 (50 mg, 0.11 mmol) was
preacetylated by treatment with acetic anhydride (43 mg, 0.42
mmol) and DMAP (52 mg, 0.42 mmol) in CH2Cl2 (1 mL) at room
temperature to furnish 39 (61 mg, 99%). 1H NMR (500 MHz,
CDCl3): δ 7.39-7.18 (m, 5 H), 5.34 (m, 1 H), 4.83 (dt, J ) 4.9,
8.4 Hz, 1 H), 4.21 (m, 1 H), 4.12 (m, 1 H), 3.19 (dd, J ) 5.7, 13.5
Hz, 1 H), 3.06 (dd, J ) 8.4, 13.4 Hz, 1 H), 2.09-1.86 (m, 2 H),
2.05 (s, 3 H), 2.00 (s, 3 H), 1.58-1.49 (m, 2 H), 1.27-1.21 (m, 30
H), 0.87 (t, J ) 6.6 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ
171.1, 170.0, 135.8, 130.3, 129.2, 126.8, 80.2, 78.7, 75.1, 74.7,
35.6, 32.9, 32.2, 31.0, 29.9, 29.8, 29.7, 29.6, 25.6, 22.9, 21.4, 21.2,
14.4.
Proposed Mucoxin 1. To a solution of 35 (9 mg, 9.31 µmol) in
THF (0.5 mL) taken in a polyethylene vial was added HF‚Py (32
µL) at room temperature. After stirring for 12 h, the reaction was
neutralized by saturated NaHCO3 solution. H2O (1 mL) and EtOAc
(5 mL) were added, and the layers were separated. The organic
layer was washed with saturated CuSO4 (2 × 2 mL), and the
combined aqueous layers were extracted with EtOAc (3 × 5 mL).
The organic layers were mixed and dried over Na2SO4, and the
solvent was evaporated to afford a waxy material. Sequential
purification by column chromatography (EtOAc, 10% MeOH in
EtOAc) and HPLC (10% i-PrOH in Et2O) proposed that mucoxin
1 was isolated as a colorless wax (4.6 mg, 80%). [R]20 +3.2 (c
D
1
0.40, CHCl3). H NMR (500 MHz, CDCl3): δ 7.00 (d, J ) 1.5
Hz, 1 H), 5.02-4.98 (m, 1 H), 4.46-4.43 (m, 1 H), 4.35 (dt, J )
3.4, 6.8 Hz, 1 H), 4.11-4.08 (m, 1 H), 3.97-3.94 (m, 1 H), 3.81
(t, J ) 3.1 Hz, 1 H), 3.75 (d, J - 5.4 Hz, 1 H), 3.43-3.40 (m, 2 H),
2.32 (d, J ) 4.4 Hz, 1 H), 2.28 (dt, J ) 1.5, 7.8 Hz, 2 H), 2.19 (d,
J ) 5.4 Hz, 1 H), 2.15-2.11 (m, 1 H), 2.06-1.98 (m, 3 H), 1.84
(ddd, J ) 4.4, 9.5, 13.4 Hz, 1 H), 1.75-1.69 (m, 1 H), 1.57-1.26
(m, 43 H), 0.89 (t, J ) 6.9 Hz, 3 H). 13C NMR (125 MHz,
CDCl3): δ 174.0, 149.2, 134.4, 84.1, 83.3, 81.6, 79.3, 77.6, 74.7,
74.3, 73.6, 48.9, 39.0, 34.0, 33.6, 32.1, 29.9, 29.8, 29.7, 29.6, 29.4,
29.3, 28.0, 27.6, 25.8, 25.6, 25.3, 22.9, 19.4, 14.3. IR (thin film):
3404, 2917, 2850, 1749, 1590, 1465, 1319, 1072, 1045, 995, 873,
798, 719 cm-1. HRMS (ES) calcd for C37H66O7, 623.4887 m/z [M
+ H]+; observed, 623.4879 m/z.
Acknowledgment. Generous support was provided in part
by the Michigan Economic Development Corporation (GR-183).
The authors are thankful for contributions made by Ms. Jun
Yan for the preparation and nOe analysis of the cis-THF-
substituted systems and by Ms. Jennifer Schomaker for helpful
discussions during the preparation of this manuscript.
Supporting Information Available: Synthesis of compounds
21 and Mosher’s ester analysis of 26, 40, and 42 are provided. 1H
and 13C spectra for new compounds 1, 5, 6, 8-13, 18, 19, 24, 26,
27, 29, 30, and 32-39 (60 pages). This material is available free
of charge via the Internet at http://pubs.acs.org.
Bis-4-dimethylamino Benzoate 38. To a solution of diol 10 (54
mg, 0.11 mmol) in CH2Cl2 (1 mL) were added p-dimethylamino-
benzoyl chloride (107 mg, 0.93 mmol) and DMAP (100 mg, 0.82
mmol), and the mixture was stirred for 15 h. The reaction was then
quenched with H2O (3 mL), and the aqueous layer was extracted
with CH2Cl2 (2 × 5 mL). The combined organic layers were dried
JO052073C
J. Org. Chem, Vol. 71, No. 4, 2006 1429