Solution-phase and solid-phase syntheses of enzyme inhibitor RK-682 and antibiotic agglomerins

Article abstract of DOI:10.1021/jo050797i

The enzyme inhibitor RK-682 (5A)-(+)-1 was prepared in solution and on a solid support from (2R)-glycerates in five steps and ca. 40% overall yield. Key steps were a ring-closing tandem addition-Wittig alkenation reaction of the respective protected or im

Full text of DOI:10.1021/jo050797i

by acting as a phosphate mimic. Early stereoselective
syntheses by the TAKEDA group6 and others3d,8 served
to ascertain the absolute configuration of the natural
products. Recently, a library of congeners of 1 with
diversity in the 3- and the 5-residues was built up via a
Lacey-Dieckmann-based9 solution-phase synthesis and
screened for inhibition of the phosphatases VHR and
cdc25B.10 Other structural variations have also been
published.11 Agglomerins A-D 2 are antibiotics mainly
active against anaerobic bacteria, both Gram-positive and
Gram-negative. They are produced12 by Enterobacter
agglomerans PB-6042 in a biosynthetic route closely
resembling that for RK-682.13
Solution-Phase and Solid-Phase Syntheses
of Enzyme Inhibitor RK-682 and Antibiotic
Agglomerins
Rainer Schobert* and Carsten Jagusch
Organisch-Chemisches Laboratorium, Universita¨t Bayreuth,
95440 Bayreuth, Germany
rainer.schobert@uni-bayreuth.de
Received April 19, 2005
The enzyme inhibitor RK-682 (5R)-(+)-1 was prepared in
solution and on a solid support from (2R)-glycerates in five
steps and ca. 40% overall yield. Key steps were a ring-closing
tandem addition-Wittig alkenation reaction of the respec-
tive protected or immobilized glycerates with the ylide Ph3-
PCCO and the 3-acylation of the tetronic acids thus obtained
with palmitic acid. A similar route extended by a mesyla-
tion-elimination sequence led to antibiotic agglomerins
A-C 2 featuring 3-acyl-5-methylidenetetronic acid struc-
tures.
Herein we report an efficient six-step solution-phase
synthesis of RK-682 (5R)-1 from glycerate 4 (Scheme 1)
and a solid-phase variant thereof (Scheme 3), which
should be widely applicable to 5-substituted 3-alkan-
oyltetronic acids in general, lending itself ideally to a
combinatorial processing. We also describe an extended
synthetic route leading to agglomerins A-C (Scheme 2).
Commercially available methyl isopropylidene-D-glyc-
erate 3 was converted to the benzyl ester 4 according to
a method by Giannis et al.14 After acidic cleavage of the
ketal of 4, the terminal hydroxy group of the product 5
was tritylated to give R-hydroxy ester 6. The latter was
then cyclized under pH-neutral, nonracemizing condi-
tions to the corresponding tetronate 7 using the readily
available phosphorus ylide (triphenylphosphoranylidene)-
ketene, Ph3PdCdCdO.15 When conducted under micro-
wave irradiation, the reaction was complete after 1 h,
furnishing a satisfactory 75% yield of 7. Mechanistically,
it commences with an addition of the OH group of 6
Physiologically active tetronic acids have been isolated
from a broad range of organisms such as molds, fungi,
lichens, and sponges.1-3 RK-682 (5R)-1 is a typical
example of 3-acyltetronic acids bearing short hydrophilic
residues at C-5. It was isolated as the corresponding
tetronate salts with different countercations from the
strains Actinomycetes DSM 7357 by a CIBA-GEIGY
group,4 from Streptomyces sp. 88-682 by a RIKEN group,5
and from Streptomyces sp. AL-462 by a TAKEDA group.6
It was found to inhibit HIV-1 protease4 and various other
protein tyrosine kinases and phosphatases7 presumably
(1) (a) Faulkner, D. J. Nat. Prod. Rep. 1984, 1 (6), 551-598. (b)
Bergquist, P. R.; Wells, R. J. In Marine Natural Products; Academic
Press: New York, 1983; Vol. V, p 1. (c) Pattenden, G. Fortschr. Chem.
Org. Naturst. 1978, 35, 133-198. (d) Rao, Y. S. Chem. Rev. 1976, 76,
625-694. (e) Keller-Schierlein, W.; Muntwyler, R.; Pache, W.; Za¨hner,
H. Helv. Chim. Acta 1969, 52, 127-142. (f) Haynes, L. J.; Plimmer, J.
R. Q. Rev. Chem. Soc. 1960, 14, 292.
(7) Sodeoka, M.; Sampe, R.; Kojima, S.; Baba, Y.; Morisaki, N.;
Hashimoto, Y. Chem. Pharm. Bull. 2001, 49, 206-212.
(8) For a synthesis of racemic 1, see also: Mittra, A.; Yamashita,
M.; Kawasaki, I.; Murai, H.; Yoshioka, T.; Ohta, S. Synlett 1997, 909-
910.
(9) Lacey, R. N. J. Chem. Soc. 1954, 832-839.
(2) For a recent review, see: Tejedor, D.; Garcia-Tellado, F. Org.
Prep. Proc. Int. 2004, 36 (1), 35-59.
(10) (a) Sodeoka, M.; Sampe, R.; Kojima, S.; Baba, Y.; Usui, T.; Ueda,
K.; Osada, H. J. Med. Chem. 2001, 44, 3216-3222. (b) Osada, H.;
Shimizu, S.; Sodeoka, M.; Hirai, T.; Ishida, K. Jpn. Kokai Tokkyo Koho
JP 2003-270049, CAN 142:148769, 2005.
(11) Usui, T.; Kojima, S.; Kidokoro, S.; Ueda, K.; Osada, H.; Sodeoka,
M. Chem. Biol. 2001, 8, 1209-1220.
(3) (a) Rehse, K.; Wagenknecht, J. Arch. Pharm. (Weinheim, Ger.)
1979, 312, 164-168. (b) Arai, K. Chem. Pharm. Bull. 1989, 37, 3229-
3235. (c) Lang, M.; Roesel, J. Arch. Pharm. 1993, 326, 921-924. (d)
Sodeoka, M.; Sampe, R.; Kagamizono, T.; Osada, H. Tetrahedron Lett.
1996, 37, 8775-8778. (e) Grandjean, J.; Laszlo, P. Tetrahedron Lett.
1983, 24, 3319-3322.
(4) (a) Roggo, B. E.; Petersen, F.; Delmendo, R.; Jenny, H.-B.; Peter,
H. H.; Roesel, J. J. Antibiot. 1994, 47, 136-142. (b) Roggo, B. E.; Hug,
P.; Moss, S.; Raschdorf, F.; Peter, H. H. J. Antibiot. 1994, 47, 143-
147.
(5) Hamaguchi, T.; Sudo, T.; Osada, H. FEBS Lett. 1995, 372, 55-
58.
(6) Shinagawa, S.; Muroi, M.; Itoh, T. Jpn. Kokai Tokkyo Koho JP
05-43568, 1993.
(12) (a) Shoji, J.; Sakazaki, R.; Hattori, T.; Matsumoto, K.; Uotani,
N.; Yoshida, T. J. Antibiot. 1989, 42, 1729-1733. (b) Terui, Y.;
Sakazaki, R.; Shoji, J. J. Antibiot. 1990, 43, 1245-1253. (c) Yoshida,
T.; Hattori, T.; Matsumoto, K.; Terui, Y.; Shoji, J. EP 0 365 329 A2,
JP 266575, 1988. For an early synthesis of 2a, see: (d) Ley, S. V.;
Trudell, M. L.; Wadsworth, D. J. Tetrahedron 1991, 47, 8285-8296.
(13) Mashimo, Y.; Sekiyama, Y.; Araya, H.; Fujimoto, Y. Bioorg.
Med. Chem. Lett. 2004, 14, 649-651.
(14) Baumhof, P.; Mazitschek, R.; Giannis, A. Angew. Chem., Int.
Ed. 2001, 40, 3672-3674.
10.1021/jo050797i CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/25/2005
J. Org. Chem. 2005, 70, 6129-6132
6129

SCHEME 1. Solution-Phase Synthesis of RK-682
yield with respect to glycerate 4. This is a 10% improve-
ment on the yield of the synthesis by the Sodeoka group,3d
who also started from a tritylated glycerate that was
acylated to an O-(â-palmitoacetyl) derivative prior to a
Lacey-Dieckmann cyclization. Palmitic acid could not be
used directly with this method but required preactivation
as a â-ketothio ester.
(5R)-(+)-1a
Acyl residues other than palmitoyl were likewise
attached to C-3 of tetronic acid 8, among them various
isomeric branched methyldodecanoyl groups. These had
been found to confer particularly high bioactivity to the
so-called melophlins, a family of naturally occurring
3-acyltetramic acids.17 Synthetic details and bioscreening
results concerning these analogues of 1 will be disclosed
elsewhere. The same general approach as outlined in
Scheme 1 was also employed in a straightforward syn-
thesis of agglomerins A-C. Racemic tetronic acid rac-8
was prepared from cheap racemic glycerate rac-5 in
virtually identical yields when compared to the synthesis
of enantiopure (5R)-8. The required 3-acyl side-chains
were introduced by reaction of rac-8 with the respective
carboxylic acids, once more under Yoshii conditions. The
resulting racemic tetronic acids 10 were deprotected with
hydrochloric acid to furnish compounds 11, which in turn
were finally converted in 60-75% yield to the corre-
sponding agglomerins 2 by a mesylation-elimination
sequence10a (Scheme 2).
a Reagents and conditions: (i) BnOH, Bu2SnO, microwave, 120
°C, 30 min, 83%; (ii) 1 M HCl, THF, rt, 12 h, 85%; (iii) TrCl, NEt3,
DMAP, CH2Cl2, rt, 8 h, 80%; (iv) shown above; (v) 5% Pd/C, H2 (1
bar), THF, rt, 3 h, 99%; (vi) shown above; (vii) 1 M HCl, MeOH,
rt, 48 h, 79%.
SCHEME 2. Solution-Phase Synthesis of
Agglomerins A-C (2)a
Next we sought to transfer the synthesis of RK-682 and
analogues as outlined in Scheme 1 to the solid phase to
open access to corresponding libraries. In a first attempt,
the benzyl ester 5 was immobilized by etherification of
its primary OH group with a trityl chloride-tagged
polystyrene resin (100-200 mesh, 1% divinyl benzene,
loading 1.7 mmol/g), and the resulting resin-bound ester
was cyclized with Ph3PCCO in analogy to the above
solution-phase synthesis. However, neither heteroge-
neous (Pd on charcoal) nor homogeneous (Wilkinson)
catalysts were capable of removing the benzyl group from
the immobilized tetronate congener of 7 probably due to
steric shielding by the resin folds. A better protecting
group was found in the trimethylsilylethyl (TMSE)
residue. Carboxylic acid 12 as obtained from hydro-
genolysis of the benzyl ester 4 was esterified with
O-trimethylsilylethyl-N,N′-dicyclohexylisourea18 to give
TMSE ester 13, which was hydrolyzed to the diol 14
(Scheme 3). Attachment of the latter to the trityl poly-
styrene resin via DMAP-catalyzed etherification led to
R-hydroxyester 15. Completion of this and all other steps
involving resin-bound species was ascertained by the
weight increase and by the disappearance of indicative
IR bands of the respective precursors. Ring-closing
domino addition-Wittig alkenation of 15 to give 16 was
carried out in THF at 60 °C instead of toluene at 120 °C
to allow for better swelling and to avoid thermal decom-
position of the resin. The TMSE group was then selec-
tively removed with TBAF without affecting the trityl
linker. The immobilized tetronic acid product 17 is a
valuable entry point to the construction of libraries of
analogues of RK-682 with diversity in the 3-alkanoyl
a Reagents and conditions: (i) shown above; (ii) 1 M HCl, MeOH,
rt, 48 h, 86%; (iii and iv) shown above.
across the CdC bond of the cumulated ylide to give a
stabilized ester ylide, which in turn undergoes an in-
tramolecular olefination of the CdO bond of the benzyl
ester moiety. Debenzylation of 7 with H2 gas using 5%
Pd on charcoal as a catalyst afforded the free tetronic
acid 8 in quantitative yield. Compound 8 was subse-
quently acylated at C-3 with palmitic acid according to
the protocol by Yoshii et al. (DCC, DMAP, NEt3).16 The
product 3-palmitoyltetronic acid 9 was obtained in 94%
yield. It was finally deprotected with hydrochloric acid
to give optically pure RK-682 (5R)-(+)-1 in ca. 40% overall
(15) (a) Schobert, R.; Gordon, G. J. Science of Synthesis: Houben-
Weyl Methods of Molecular Transformations; Padwa, A., Ed.; Thieme:
Stuttgart, 2004; Vol. 27, p 1047. (b) Lo¨ffler, J.; Schobert, R. J. Chem.
Soc., Perkin Trans. 1 1996, 2799-2802. (c) Schobert, R.; Gordon, G. J.
Curr. Org. Chem. 2002, 6, 1181-1196.
(16) Nomura, K.; Hori, K.; Arai, M.; Yoshii, E. Chem. Pharm. Bull.
1986, 34, 5188.
(17) (a) Wang, C.-Y.; Wang, B.-G.; Wiryowidago, S.; Wray, V.; van
Soest, R.; Streube, K. G.; Guan, H.-S.; Proksch, P.; Ebel, R. J. Nat.
Prod. 2003, 66, 51-56. (b) Schobert, R.; Jagusch, C. Tetrahedron 2005,
61, 2301-2307.
(18) Sieber, P. Helv. Chim. Acta 1977, 60, 2711-2716.
6130 J. Org. Chem., Vol. 70, No. 15, 2005

purified by column chromatography (CC) on silica gel to leave
SCHEME 3. Solid-Phase Synthesis of RK-682
(5R)-(+)-1a
347 mg (75%) of white solid 7 (Found: C, 80.38; H, 5.66.
C
31H26O4 requires C, 80.50; H, 5.67%): mp 154-156 °C; Rf 0.27
25
(hexane/ethyl acetate 2:1); [R]D -31.0 (c 0.55, CHCl3); νmax
(ATR)/cm-1 1753, 1629, 1490; 1H NMR (300 MHz, CDCl3) δ 3.27
(dd, J ) 10.4, 3.4 Hz, 1 H), 3.61 (dd, J ) 10.4, 2.7 Hz, 1 H), 4.84
(m, 1 H), 4.99 (d, J ) 11.7, 1 H), 5.06 (d, J ) 11.7, 1 H), 5.27 (s,
1 H), 7.18-7.40 (m, 20 H); 13C NMR (75 MHz, CDCl3) 61.4, 74.4,
78.5, 86.5, 90.7, 127.1, 127.8, 127.9, 128.6, 128.8, 128.9, 133.8,
143.4, 172.6, 178.7; m/z (EI) 462 (10) [M+], 385 (10), 243 (100),
183 (10), 165 (35), 105 (20), 91 (100).
(5R)-5-(Triphenylmethoxy)methyl-[5H]furan-2,4-dione
(8). A solution of 7 (231 mg, 0.5 mmol) in dry THF (15 mL) was
treated with 5% Pd on charcoal (15 mg). The reaction vessel was
repeatedly evacuated and flushed with hydrogen gas and left to
stir at room temperature for 3 h, pressurized with 1 bar of H2.
The resulting reaction mixture was filtered through a short plug
of Celite, which was washed with THF (40 mL). The filtrates
were concentrated on an oil pump to give pure tetronic acid 8
(185 mg, 99%) as a white solid (Found: C, 77.35; H, 5.46.
C24H20O4 requires C, 77.40; H, 5.41%): mp 54-56 °C; Rf 0.19
(hexane/ethyl acetate 1:1); [R]D25 36.2 (c 0.54, CHCl3); νmax (ATR)/
cm-1 3087, 1704, 1684, 1580, 1489, 1449, 703; 1H NMR (300
MHz, acetone-d6) δ 3.30 (dd, J ) 10.4, 3.8 Hz, 1 H), 3.57 (dd, J
) 10.4, 2.7 Hz, 1 H), 4.98 (m, 1 H), 5.11 (s, 1 H), 7.15-7.50 (m,
15 H); 13C NMR (75 MHz, acetone-d6) δ 62.9, 79.0, 87.2, 91.1,
128.1, 128.8, 129.5, 144.7, 173.6, 179.2; m/z (EI) 372 (30) [M+],
295 (30), 243 (100), 183 (30), 165 (55), 105 (70).
(5R)-3-Hexadecanoyl-5-(triphenylmethoxy)methyl-[5H]-
furan-2,4-dione (9). NEt3 (0.07 mL, 0.5 mmol) was added at 0
°C to a stirred suspension of tetronic acid 8 (160 mg, 0.45 mmol)
in anhydrous CH2Cl2 (15 mL). To the resulting homogeneous
solution was added in succession DMAP (20 mg), palmitic acid
(128 mg, 0.5 mmol), and DCC (113 mg, 0.55 mmol) in three
portions. The mixture was stirred for 10 min at 0 °C; the cooling
bath was removed, and stirring was continued for 16 h at room
temperature. The precipitate N,N′-dicyclohexylurea was filtered
off over a short plug of Celite, which was washed with ethyl
acetate (50 mL). The combined filtrates were washed with 0.5
M aqueous HCl and brine, dried over Na2SO4, and concentrated.
The crude product was purified by CC on silica gel to leave 9
a Reagents and conditions: (i) 5% Pd/C, H2 (1 bar), MeOH, rt,
1 h, 99%; (ii) cycNdC[O(CH2)2SiMe3]NHcyc, THF, 50 °C, 12 h,
74%; (iii) 1 M HCl, MeOH, rt, 12 h, 70%; (iv and v) shown above;
(vi) THF, TBAF‚3H2O, rt, 3 h; (vii) shown above; (viii) TFA/Et3SiH/
CH2Cl2 (5:5:90), rt, 20 min, 26% (with respect to 14).
residue. With palmitic acid under Yoshii conditions,
immobilized 3-acyltetronic acid 18 was obtained and
eventually detached from the resin with TFA and Et3-
SiH to leave 1 in 26% overall yield with respect to 14.
In conclusion, we described a five-step synthesis of
optically pure 5-hydroxmethyl-3-acyltetronic acids from
monoprotected/-tethered glycerates based upon a Wittig
cyclization with Ph3PCCO and a downstream 3-acylation
of the intermediate tetronic acids with the respective
carboxylic acids. The solid-phase variant in particular
allows for the generation of libraries of derivatives with
different 3-acyl residues, the nature of which has been
shown to be crucial for the bioactivity in the series of RK-
682 analogues, agglomerins, and 1-N-analogous melo-
phlins. As the 3-acylation step precedes the final elimina-
tion sequence in our synthesis of the agglomerins, bio-
activity screening is conveniently and consecutively
possible, both of the 5-hydroxymethyl precursors and the
end products bearing 5-methylidene residues.
25
(259 mg, 94%) as a yellow oil: Rf 0.42 (CHCl3/MeOH 19:1); [R]D
47.1 (c 0.5, CHCl3) [lit.7 48.27 (c 1.02, CHCl3)].
(5R)-RK-682 (1). A solution of 9 (162 mg, 0.26 mmol) in
MeOH (15 mL) was treated with 1 M aqueous HCl (0.26 mL,
0.26 mmol), and the mixture was stirred at room temperature
for 48 h. The volatiles were removed in vacuo, and the residue
was purified by CC on silica gel (CHCl3/MeOH 1:0, then CHCl3/
MeOH 20:1, then CHCl3/MeOH 10:1). The fractions containing
product were pooled and concentrated, and the residue was
redissolved in ethyl acetate (50 mL). This solution was washed
with 20 mL each of 0.5 M HCl and water, dried over Na2SO4,
and evaporated to leave 74 mg (79%) of 1 as a white solid; mp
25
105-107 °C (lit.7 105-108 °C); [R]D 57.2 (c 0.51, CHCl3) [lit.7
58.06 (c 0.47, CHCl3)].
Agglomerin C (2c). A solution of 3-dodecanoyl-5-hydroxy-
methyl-[5H]furan-2,4-dione 11c (62 mg, 0.2 mmol) in dry THF
(1 mL) was treated with DMAP (10 mg), methanesulfonyl
chloride (0.031 mL, 0.4 mmol), and NEt3 (0.11 mL, 0.8 mmol),
and the resulting mixture was stirred at room temperature for
5 h. The mixture was then poured into ice-water and extracted
with ethyl acetate (3 × 20 mL). The combined organic layers
were washed with brine, dried, and concentrated. The resulting
pale yellow crude product was dissolved in THF (12 mL); 0.1 M
aqueous NaOH (6 mL) was added, and the mixture was stirred
at room temperature for 3 days and finally acidified with 1 M
HCl to pH 1. The mixture was extracted with ethyl acetate,
which was then washed with brine, dried, and concentrated. The
residue was purified by CC on silica gel to leave white solid 2c
(45 mg, 76%): mp 125-127 °C (lit.12 125-128 °C); Rf 0.34
(CHCl3/MeOH 10:1); νmax (ATR)/cm-1 3355 (br), 2922, 1723, 1620,
Experimental Section
(5R)-4-Benzyloxy-5-(triphenylmethoxy)methyl-[5H]furan-
2-one (7). A solution of 6 (438 mg, 1.0 mmol) and Ph3PCCO (393
mg, 1.3 mmol) in dry THF (15 mL) was stirred at room
temperature for 2 h under exclusion of air and moisture. The
solution was concentrated and the formed ester ylide was
purified by filtration over a short plug of silica gel (THF/hexane,
1:1). The eluate was concentrated; the residue was redissolved
in toluene (15 mL), and the solution was placed in a microwave
oven. With an irradiation of initially 600 W, a temperature ramp
from room temperature to 120 °C was passed through within 4
min, and the end temperature was maintained for an additional
hour. The solvent was evaporated, and the crude product was
1
1467; H NMR (300 MHz, CD3OD) δ 0.88 (t, J ) 6.9 Hz, 3 H),
1.21-1.42 (m, 16 H), 1.50-1.63 (m, 2 H), 2.78 (t, J ) 6.9 Hz, 2
H), 4.83 (s, 1 H), 5.13 (s, 1 H); m/z (EI) 294 (10) [M+], 277 (5),
J. Org. Chem, Vol. 70, No. 15, 2005 6131

167 (10), 154 (25), 139 (10), 98 (10), 84 (10), 71 (20), 55 (35), 41
(100). HR-MS: Found 294.18310. Calcd for C17H26O4 294.18311.
Immobilized (2R)-2-Hydroxy-3-triphenylmethoxypro-
panoic Acid â-Trimethylsilylethyl Ester (15). Trityl chloride
polystyrene resin (0.5 g, 0.85 mmol; Fluka, 100-200 mesh, 1%
DVB, loading 1.7 mmol/g) was suspended in dry CH2Cl2 (10 mL)
and allowed to swell for 10 min. The solvent was removed by
filtration; the resin was resuspended in fresh CH2Cl2 (7 mL) and
treated with crude 14 (230 mg, 1.25 mmol) and NEt3 (0.18 mL,
1.25 mmol). The mixture was gently shaken at room temperature
for 6 h and then filtered. The resin was washed with 2 × 10 mL
each of CH2Cl2, DMF, MeCN, THF, MeOH, toluene, and THF
and finally dried on an oil pump; νmax (ATR)/cm-1 3407, 1734,
1249, 857, 835.
Immobilized (5R)-4-Trimethylsilylethoxy-5-(triphenyl-
methoxy)methyl-[2H]furan-2-one (16). Under a blanket of
dry argon, 15 (640 mg, 0.85 mmol) was suspended in anhydrous
THF (8 mL) and treated with Ph3PCCO (367 mg, 1.25 mmol)
and benzoic acid (10 mg). The mixture was gently shaken at 60
°C for 12 h. The resin was collected on a sintered frit, washed
in turn with 2 × 20 mL each of THF, DMF, MeCN, THF, MeOH,
toluene, and THF, and dried in a vacuum. Completion was
ascertained by the weight increase and the disappearance of the
OH band of 15 in the IR spectra; νmax (ATR)/cm-1 1740, 1631,
1249, 857, 835.
mmol) was suspended in anhydrous CH2Cl2 (7 mL), treated with
NEt3 (0.14 mL, 1.0 mmol), DMAP (20 mg), palmitic acid (256
mg, 1.0 mmol), and DCC (226 mg, 1.1 mmol), and the resulting
mixture was gently shaken at room temperature for 16 h. The
resin was filtered and washed with 2 × 20 mL each of CH2Cl2,
DMF, MeCN, THF, MeOH, toluene, and THF; νmax (ATR)/cm-1
1725, 1641.
(5R)-RK-682 (1). Resin 18 (700 mg, 0.85 mmol) was sus-
pended in anhydrous CH2Cl2 (10 mL), swollen for 10 min,
filtered, and then resuspended in 8 mL of the cleaving mixture
(CH2Cl2/TFA/Et3SiH 90:5:5, v/v/v) whereupon the initially yellow
color of the resin turned red. The mixture was shaken at room
temperature for 20 min and filtered, and the resin was washed
with 10 mL each of CH2Cl2, THF, MeOH, and toluene. The
combined filtrates were evaporated to dryness, yielding pure
(5R)-RK-682 (80 mg, 26% yield calcd on the basis of 14).
Acknowledgment. This paper is dedicated to Pro-
fessor Steven V. Ley on the occasion of his 60th
birthday. Financial support from the Deutsche Fors-
chungsgemeinschaft (Grant Scho 402/7-2) is gratefully
acknowledged. We thank Miriam Siebenbu¨rger and
Paul Majkut for practical contributions during their
third year’s projects.
Immobilized (5R)-5-(Triphenylmethoxy)methyl-[2H]fu-
ran-2,4-dione (17). Resin 16 (660 mg, 0.85 mmol) was sus-
pended in dry THF (7 mL), treated with TBAF‚3H2O (800 mg,
2.5 mmol), and gently shaken at room temperature for 3 h.
Water (2 mL) was added, and shaking was continued for an
additional 20 min. The resin was then collected on a sintered
frit, washed in turn with 2 × 20 mL each of CH2Cl2, DMF,
MeCN, THF, MeOH, toluene, and THF, and dried in vacuo; νmax
(ATR)/cm-1 1727, 1599.
Supporting Information Available: Syntheses and char-
acterizations of pure compounds 4, 6, 10, 11, and 13, spectro-
scopic/analytical data of pure known compounds 1, 2a, 2b, and
9, as well as experimental procedures for crude compounds 5
and 14. This material is available free of charge via the
Internet at http://pubs.acs.org.
Immobilized (5R)-3-Hexadecanoyl-5-(triphenylmethoxy)-
methyl-[2H]furan-2,4-dione (18). Resin 17 (560 mg, 0.85
JO050797I
6132 J. Org. Chem., Vol. 70, No. 15, 2005