Total Synthesis of (±) carbocyclic polyoxin C and its α-epimer

Article abstract of DOI:10.1021/jo971711r

Carbocyclic polyoxin C (2) and its α-epimer 3 were synthesized in racemic form in an efficient and diasteroedivergent fashion from cis-4-(N- tert-butylcarbamoyl)cyclopent-2-en-1-ol (5a). This synthesis features a Pd(0)-catalyzed substitution reaction, a novel, mild reduction of an α- nitro ester to an amino acid ester, and an improved procedure for uracil ring formation.

Full text of DOI:10.1021/jo971711r

J . Org. Chem. 1998, 63, 755-759
755
Tota l Syn th esis of (() Ca r bocyclic P olyoxin C a n d Its r-Ep im er
Deyi Zhang and Marvin J . Miller*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556
Received September 12, 1997
Carbocyclic polyoxin C (2) and its R-epimer 3 were synthesized in racemic form in an efficient and
diastereodivergent fashion from cis-4-(N-tert-butylcarbamoyl)cyclopent-2-en-1-ol (5a ). This synthesis
features a Pd(0)-catalyzed substitution reaction, a novel, mild reduction of an R-nitro ester to an
amino acid ester, and an improved procedure for uracil ring formation.
In tr od u ction
Fungal infections have increased dramatically during
the past two decades. Deeply invasive fungal infections
are the major cause of morbidity and mortality among
immunocompromised patients.1 While the number of
available antifungal drugs is increasing, most of these
drugs possess significant side effects and limitations.
Thus, more effective and safer antifungal medications are
urgently needed. Polyoxins and nikkomycins are pepti-
dyl nucleoside antibiotics isolated from Streptomyces
cacaoi and Streptomyces tandae.2-10 They are known
antifungal agents that selectively inhibit membrane-
bound enzyme chitin synthase from yeast and other
fungi, including Candida albicans. Inhibition of the
biosynthesis of chitin, an essential component of yeast
and fungal cell walls, provides an attractive therapeutic
target. Because of the absence of chitin synthase in
mammalian cells, it is thought that these mechanism-
based drugs would potentially be safer therapeutic
agents. However, polyoxins and nikkomycins are only
weakly active against whole pathogenic fungal cells,11,12
presumably due to their hydrolytic instability and/or
inefficient transport into the cells.
F igu r e 1. General structure of polyoxins and nikkomycins.
side moiety,25,26 or to develop other alternate transport
systems. Nucleosides in general, display a broad range
of biological activities, in particular, antiviral, antifungal,
and antitumor activities.27 Extensive efforts have been
made to modify nucleosides to improve their disease-
fighting efficacy and lower their toxicity. Among these,
isosteric replacement of the furanose ring oxygen with a
methylene group is of particular interest, since the
resulting carbocyclic nucleosides have greater metabolic
stability and in some cases, decreased toxicity.28,29 It
would be very interesting to synthesize the carbocyclic
version of polyoxins and nikkomycins and evaluate their
biological activities. Uracil polyoxin C (1) is the simplest
member of the polyoxin family and is also a key fragment
of some polyoxins and nikkomycins. As part of an
ongoing project, we developed and describe here an
efficient synthesis of (()-carbocyclic polyoxin C (2) and
its epimer 3.
In the course of developing effective and safe antifungal
agents, many efforts have been directed toward replacing
the amino terminal peptide moiety (R1, Figure 1) of
polyoxins and nikkomycins but with only limited suc-
cess.13-24 Little work has been done to modify the nucleo-
(1) Walsh, T. J . In Emerging Targets in Antibacterial and Antifungal
Chemotherapy Sutcliffe, J . A., Georgopapadakou, N. H., Eds.; Chapman
and Hall: New York, 1992; p 349.
(2) Isono, K.; Asahi, K.; Suzuki, S. J . Am. Chem. Soc. 1969, 91, 7490.
(3) Hagenmaier, H.; Keckeisen, A. Liebigs Ann. Chem. 1979, 1494.
(4) Isono, K.; Suzuki, S. Heterocycles 1979, 13, 333.
(5) Ko¨nig, W. A.; Hahn, H.; Rathmann, R.; Hass, W.; Keckeisen, A.;
Haganmaier, H.; Bormann, C.; Dehler, W.; Kurth, R.; Za¨hner, H.
Liebigs Ann. Chem. 1986, 407.
(6) Uramoto, M.; Kobinata, K.; Isono, K.; Higashijima, T.; Miyazawa,
T.; J enkins, E. E.; McCloskey, J . A. Tetrahedron Lett. 1980, 21, 3395.
(7) Uramoto, M.; Kobinata, K.; Isono, K.; Higashijima, T.; Miyazawa,
T.; J enkins, E. E.; McCloskey, J . A. Tetrahedron 1982, 38, 1599.
(8) Hori, M.; Kakiki, K.; Suzuki, S.; Misato, T. Agr. Biol. Chem. 1971,
35, 1280.
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Biol. Chem. 1967, 31, 190.
(10) Isono, K.; Nagatsu, J .; Kawashima, Y.; Suzuki, S. Agr. Biol.
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(11) Yadan, J .-C.; Gonneau, M.; Sarthou, P.; Goffic, F. L. J . Bacteriol.
1984, 160, 884.
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1985, 28, 278.
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31, 650.
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(18) Smith, H. A.; Shenbagamurthi, P.; Naider, F.; Kundu, B.;
Becker, J . Antimicrob. Agents Chemother. 1986, 29, 33.
(19) Naider, F.; Shenbagamurthi, P.; Steinfeld, A. S.; Smith, H. A.;
Boney, C.; Becker, J . M. Antimicrob. Agents Chemother. 1983, 24,
787.
(20) Shenbagamuthi, P.; Smith, H. A.; Becker, J . M.; Naider, F. J .
Med. Chem. 1986, 29, 802.
(21) Shenbagamurthi, P.; Smith, H. A.; Becker, J . M.; Steinfeld, A.;
Naider, F. J . Med. Chem. 1983, 26, 1518.
(22) Hori, M.; Kakiki, K.; Misato, T. Agr. Biol. Chem. 1974, 38, 691.
(23) Hori, M.; Kakiki, K.; Misato, T. Agr. Biol. Chem. 1974, 38, 699.
(24) Isono, K.; Suzuki, S.; Azuma, T. Agr. Biol. Chem. 1971, 35, 1986.
(25) Baumgartner, H.; Marschner, C.; Pucher, R.; Singer, M.;
Griengl, H. Tetrahedron Lett. 1992, 33, 6443.
(12) Becker, J . M.; Covert, N. L.; Shenbagamurthi, P.; Steinfeld, A.
S.; Naider, F. Antimicrob. Agents Chemother. 1983, 23, 926.
(13) Krainer, E.; Becker, J . M.; Naider, F. J . Med. Chem. 1991, 34,
174.
(14) Fiandor, J .; Garc´ıa-Lo´pez, M.-T.; De las Heras, F. G.; Me´ndez-
Castrillo´n, P. P. Synthesis 1987, 978.
(26) Aggarwal, V. K.; Monteiro, N.; Tarver, G. J .; Lindell, S. D. J .
Org. Chem. 1996, 61, 1192.
(27) Isono, K. J . Antibiotics 1988, 41, 1711.
(28) Bricaud, H.; Herdewijin, P.; De Clercq, E. Biochem. Pharmacol.
1983, 3583.
(29) De Clercq, E. Nucleosides Nucleotides 1994, 13, 1271.
S0022-3263(97)01711-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/22/1998

756 J . Org. Chem., Vol. 63, No. 3, 1998
Zhang and Miller
Sch em e 3
F igu r e 2. Target molecules.
Sch em e 1
reported to convert nitro groups to carbonyls, presumably
through an imine intermediate which can be hydrolyzed
under acidic conditions.38,39 Indeed, we found that nitro
ester 6 was reduced to the corresponding amino ester
with TiCl3/NaBH4 in a buffered solution (pH 7.8-8.0) in
very good yield. The intermediate amine thus generated
was protected with Cbz-Cl to generate two diastereomers
7 in a 1:1 ratio. The mixture of these diastereomers was
only partially separable by flash chromatography and
thus was carried on without separation.
Sch em e 2
Next, the uracil ring was incorporated using a modi-
fication of Shaw’s method.40 Hydrolysis of methyl meth-
oxyacrylate (8a ) generated the corresponding acid, 8b.
The sodium salt of acid 8b was treated with SOCl2 to
afford the acyl chloride, which upon treatment with
AgOCN, generated acyl isocyanate 9. The free amine,
obtained after removal of the Boc protecting group of
compound 7, was reacted with 9 to afford acylurea 10.
Cyclization to produce the uracil moiety was effected by
refluxing in aqueous ammonia25,41,42 to afford 11 after
benzyl ester formation (Scheme 3).
Retrosynthetically, carbocyclic polyoxin C (2) was
anticipated to be obtained from alkene 4 after elaboration
of the uracil ring and dihydroxylation (Scheme 1).
Resu lts a n d Discu ssion
Allylic acetate 5b was prepared from cyclopentadiene
in three steps following our published procedure30,31 and
was subjected to Pd(0)-catalyzed nucleophilic substitu-
tion32,33 with methyl nitroacetate (Scheme 2). Here, nitro-
acetate was utilized as a synthon34 for an amino ester
which would provide flexibility in controlling the stereo-
chemistry of the newly generated R-chiral center. Reduc-
tion of the nitro group of compound 6 to an amino group
without an adverse effect on other functional groups in
the molecule was a challenge. Among conditions we
tried, SnCl2 reduction35 afforded the desired product in
low yield whereas NaBH4/Pd36 resulted in CdC bond
reduction. Previously, we reported that TiCl3/NaBH4 in
a buffered solution can effectively reduce oximino esters
to the corresponding amino esters.37 Ti(III) also has been
Separation of the two diastereomers of 11a ,b proved
to be very difficult. An enzymatic resolution of these
(30) Zhang, D.; Ghosh, A.; Su¨ling, C.; Miller, M. J . Tetrahedron Lett.
1996, 37, 3799.
(31) Zhang, D.; Su¨ling, C.; Miller, M. J . J . Org. Chem. 1998, 63, in
press.
diastereomers using chymotrypsin was attempted but
failed to act on these substrates. We eventually found
(32) Trost, B. M.; Van Vranken, D. L. Chem. Rev. (Washington, D.C.)
1996, 96, 395.
(33) Frost, C. F.; Howarth, J .; William, J . M. J . Tetrahedron:
Asymmetry 1992, 3, 1089.
(34) Wade, P. A.; Morrow, S. D.; Hardinger, S. A. J . Org. Chem.
1982, 47, 365.
(35) Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839.
(36) Petrini, M.; Ballini, R.; Rosini, G. Synthesis 1987, 713.
(37) Hoffman, C.; Tanke, R. S.; Miller, M. J . J . Org. Chem. 1989,
54, 3750.
(38) McMurry, J . E. Acc. Chem. Res. 1974, 7, 281.
(39) McMurry, J . E.; Melton, J . J . Org. Chem. 1973, 38, 4367.
(40) Shaw, G.; Warrener, R. N. J . Chem. Soc. 1958, 157.
(41) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571.
(42) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, R.;
Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611.

Synthesis of (() Carbocyclic Polyoxin C and Its R-Epimer
J . Org. Chem., Vol. 63, No. 3, 1998 757
Sch em e 4
fashion. Relative stereochemistries of the chiral centers
in the molecules were quickly established from the
starting allylic acetate 5a . The successful reduction of
a nitro group to an amino group and subsequent separa-
tion of diastereomers make this unified design practical.
These features would allow an efficient synthesis of all
major carbocyclic polyoxin C analogues in an asymmetric
fashion if optically pure allylic acetates were employed.
Exp er im en ta l Section
General methods and instruments used have been described
previously.43
cis-1-Acet oxy-4-N-(ter t-b u t ylca r b a m oyl)-2-cyclop en -
ten e (5b). To a solution of alcohol 5a 30,31 (212 mg, 1.065 mmol)
in pyridine-CH2Cl2 (1:1, 4 mL) at 0 °C was added a solution
of AcCl (109 mg, 1.38 mmol) in CH2Cl2 (2 mL). The reaction
was stirred at 0 °C overnight. After removal of CH2Cl2, the
residue was diluted with EtOAc and was washed with 10%
citric acid solution. The aqueous layer was extracted with
EtOAc, and the combined organic layers were washed with
brine and dried. Filtration and concentration in vacuo gave
crude product. Flash chromatography (EtOAc:hexanes 1:3)
afforded 5b (256 mg, 100%) as a white solid; mp 56.5-58.5
1
°C; H NMR (DMSO-d6) δ 1.37 (s, 9H), 1.45 (dt, J ) 13.5, 6.0
Hz, 1H), 1.98 (s, 3H), 2.68 (dt, J ) 13.5, 7.5 Hz, 1H), 4.38 (m,
1H), 5.40 (m, 1H), 5.81 (dt, J ) 5.4, 2.1 Hz, 1H), 5.90 (m, 1H),
7.11 (d, J ) 7.5 Hz, 1H); 13C NMR (DMSO-d6) δ 20.8, 28.2,
37.6, 53.3, 77.1, 77.8, 130.9, 137.3, 154.9, 170.1; IR (KBr) 3366,
1734, 1680, 1510 cm-1; HRMS [MH+] calcd for C12H20NO4
242.1392, found 242.1382. Anal. Calcd for C12H19NO4: C,
59.73; H, 7.94; N, 5.81. Found: C, 59.81; H, 7.96; N, 5.65.
Meth yl 4-N-(ter t-Bu tylca r ba m oyl)-r-n itr o-2-cyclop en -
ten e-1-a ceta te (6). A 100 mL round-bottomed flask under
N2 was charged with acetate 5b (1.50 g, 6.22 mmol), Pd(PPh3)4
(539 mg, 0.47 mmol), PPh3 (245 mg, 0.93 mmol), NaOAc (560
mg, 6.8 mmol), methyl nitroacetate (1.05 g, 8.7 mmol), and
THF (50 mL). The reaction was stirred at 50-55 °C under
N2 overnight. After removal of volatiles in vacuo, the residue
was redissolved in EtOAc and washed with brine and dried.
Filtration and concentration in vacuo gave crude product.
Flash chromatography (EtOAc:hexanes 3:10) afforded 6 (1.77
g, 95%) as a colorless oil: 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.55
(m, 1H), 2.71 (m, 1H), 3.57 (m, 1H), 3.85 (s, 3H), 4.60 (m, 1H),
4.77 (m, 1H), 5.09 (d, J ) 7.5 Hz, 1H), 5.77 (dt, J ) 5.4, 2.0
Hz, 1H), 5.87 (dt, J ) 5.7, 2.1 Hz, 1H); 13C NMR (CDCl3) δ
28.3, 34.4, 45.1 (45.4), 53.5, 55.6 (55.9), 79.5, 90.4 (90.6), (130.3)
130.9, 135.7 (136.2), 155.0, 163.88 (163.93); IR (neat) 3338 (br),
2980, 1754, 1700 (br), 1560 cm-1; HRMS [MH+] calcd for
that by using a Biotage Flash 40 system, up to 55% of
the originally loaded mixture was separated (eq 1).
Repeated chromatography with this system provided both
diastereomers on a gram scale. The diastereomeric
purity for 11a and 11b was determined by HPLC to be
98% and 95%, respectively.
Dihydroxylation of 11a and 11b with OsO4 was studied
under different conditions with variations of solvents,
OsO4 amount, and pH of the reaction mixture. Under
all these conditions, diols 12 and lactones 13 were ob-
tained in an approximately 1:1 ratio, that is presumably
due to the possible coordination of nitrogen atoms to the
osmium that promotes diol delivery from the upper face
(Scheme 4). Due to intrinsic separation difficulties, dihy-
droxylation products 12 and 13 were treated with dimeth-
oxypropane (DMP) under acidic conditions to convert
diols 12 to acetonides 14 while not affecting lactones 13
which, in turn, were easily separated from acetonides 14.
From compound 11a , diol 12a also could be separated
from lactone 13a by two consecutive flash chromatogra-
phies. The relative stereochemistries of the R-chiral cen-
ter for the a and b series were determined through
NOESY studies on lactones 13a and 13b. The assign-
ments were further confirmed by comparison with pub-
lished results.26 From acetonides 14, regeneration of
diols 12, followed by careful hydrogenolyses, cleanly
provided the desired (() carbocyclic polyoxin C (2) and
its R-epimer 3.
C
C
13H21N2O6 301.1399, found 301.1402. Anal. Calcd for
13H20N2O6: C, 51.99; H, 6.71; N, 9.33. Found: C, 52.25, H,
6.29; N, 9.35.
Meth yl r-[[(Ben zyloxy)ca r bon yl]a m in o]-4-N-(ter t-bu -
tylca r ba m oyl)-2-cyclop en ten e-1-a ceta te (7). To a solution
of L-tartaric acid (53 g, 1.02 mol) and NaOH (102 g, 2.55 mol)
in water (620 mL) was added aqueous TiCl3 (15%, 124 mL,
112 mmol). The resulting mixture was adjusted to pH 7.8
using 1 N NaOH solution. To this green slurry was added
NaBH4 (5.14 g, 136 mmol) quickly followed by a solution of 6
(6.78 g, 22.6 mmol) in MeOH (35 mL). The reaction was
stirred under N2 for 30 min and then exposed to air and stirred
overnight. The reaction mixture was saturated with K2HPO4
and was extracted with CH2Cl2. The organic layer was dried,
filtered, and concentrated in vacuo to provide a slightly yellow
residue. The residue was diluted with THF, and to this
solution was added benzyl chloroformate (3.92 g, 23 mmol)
while maintaining the pH at 9 during the reaction. After the
reaction was complete, the mixture was adjusted to pH 5-6,
and the aqueous layer was extracted with EtOAc three times.
The organic layer was dried, filtered, and concentrated in
vacuo to provide a crude product. Chromatography (EtOAc:
Con clu sion
Racemic carbocyclic polyoxin C (2) and its R-epimer 3
were synthesized in an efficient and diastereodivergent
(43) Teng, M.; Miller, M. J . J . Am. Chem. Soc. 1993, 115, 548.

758 J . Org. Chem., Vol. 63, No. 3, 1998
Zhang and Miller
hexanes 1:2.6) afforded 7 mainly as a mixture of two diaster-
eomers (1:1, total 7.92 g, 87%). However, a small amount of
one diastereomer was obtained in pure form, mp 83-85 °C.
1H NMR (CD3OD, one ds) δ 1.42 (s, 9H), 1.52 (m, 1H), 2.40
(m, 1H), 3.12 (m, 1H), 3.73 (s, 3H), 4.30 (d, J ) 6.3 Hz, 1H),
4.53 (m, 1H), 5.08 (s, 2H), 5.72 (m, 2H), 7.34 (m, 5H); 13C NMR
(CDCl3) δ 28.4, 32.6, 47.4, 52.4, 56.1, 67.0, 67.2, 79.4, 133.1,
134.1, 136.2, 155.2, 156.2, 171.8; IR (KBr) 3350, 1748, 1685,
1674 cm-1; HRMS [MH+] calcd for C21H29N2O6 405.2025, found
405.2017. Anal. Calcd for C21H28N2O6: C, 62.36; H, 6.98; N,
6.93. Found: C, 62.15; H, 7.06; N, 7.00.
vacuo, and the residue was dissolved in EtOAc/citric acid (pH
∼ 3), the aqueous layer was separated and extracted three
times with EtOAc. The combined organic layers were washed
with brine and dried over Na2SO4. Filtration and removal of
the solvent afforded a crude product. Chromatography with
a Biotage Flash 40 system (EtOAc:CHCl3 2:3) provided two
diastereomers with diastereomer 11b eluting first. For 11a ,
1
white solid, mp 178.5-180.5 °C; H NMR (CDCl3) δ 1.46 (m,
1H), 2.73 (m, 1H), 3.28 (br, 1H), 4.53 (br, 1H), 5.09 (s, 2H),
5.17 (d, J ) 12.0 Hz, 1H), 5.24 (d, J ) 12.0 Hz, 1H), 5.43 (d,
J ) 8.7 Hz, 1H), 5.53 (d, J ) 7.2 Hz, 1H), 5.63 (m, 1H), 5.67
(m, 1H), 5.88 (m, 1H), 7.03 (d, J ) 7.8 Hz, 1H), 7.36 (s, br,
10H), 9.07 (br, 1H); 13C NMR (CDCl3) δ 33.4, 47.4, 56.1, 60.9,
67.5, 102.7, 128.3, 128.5, 128.6, 128.7, 128.8, 132.0, 134.8,
135.7, 135.9, 140.4, 150.8, 156.3, 163.1, 170.9; IR (KBr) 3325
(br), 1743, 1687 (br), 1625, 1517 cm-1; HRMS [MH+] calcd
for C26H26N3O6 476.1821, found 476.1833. Anal. Calcd for
C26H25N3O6: C, 65.67; H, 5.30; N, 8.84. Found: C, 65.48; H,
Meth yl r-[[(Ben zyloxy)ca r bon yl]a m in o]-4-[[[(3-m eth -
oxya cr yloyl)a m in o]ca r b on yl]a m in o]-2-cyclop en t en e-1-
a ceta te (10). To a precooled solution of 7 (4.51 g, 11.2 mmol)
in CH2Cl2 (55 mL) was added TFA (33 mL). The solution was
stirred at 0 °C for 15 and 45 min more at rt. The solvents
were removed in vacuo, the residue was dissolved in THF, and
DBU (6.1 g, 40 mmol) was added. The solution was cooled to
-30 °C, and to this solution was added acyl isocyanate 9
(prepared by refluxing methoxyacryloyl chloride (3.10 g, 25.76
mmol) and AgOCN (5.54 g, 37 mmol) in benzene (50 mL) for
2.5 h). The reaction was stirred at -30 °C for 30 min and
then at rt overnight. The solvent was removed in vacuo, the
residue was redissolved in CH2Cl2, and the mixture was
acidified to pH 5 with citric acid. The organic phase was
separated, and the aqueous layer was extracted three times
with CH2Cl2. The organic layers were combined and washed
with brine and dried over Na2SO4. Filtration and removal of
the solvent in vacuo afforded a residue. Chromatography
(EtOAc:hexanes 3:2) gave 10 mainly as a mixture of two
diastereomers, but the following data are for single diastere-
omers obtained from early and late chromatography fractions.
1
5.39; N, 8.68. For 11b, white solid, mp 175.5-177.5 °C; H
NMR (CDCl3) δ 1.29 (m, 1H), 2.47 (m, 1H), 3.29 (br, 1H), 4.72
(br, 1H), 5.16 (m, 4H), 5.44 (d, J ) 7.5 Hz, 1H), 5.52 (m, H),
5.57 (m, 1H), 5.77 (d, J ) 8.1 Hz, 1H), 6.13 (br, 1H), 6.97 (d,
J ) 7.8 Hz, 1H), 7.35 (m, 10H), 9.20 (br, 1H); 13C NMR (CDCl3)
δ 31.7, 48.1, 55.6, 61.1, 67.1, 67.6, 102.3, 128.3, 128.40, 128.43,
128.55, 128.66, 128.71, 130.1, 134.8, 136.0, 138.1, 140.7, 151.0,
156.0, 163.5, 170.7; IR (neat) 3300 (br), 3060, 1700, 1684 (br),
1530, 1246 cm-1; HRMS [MH+] calcd for C26H26N3O6 476.1821,
found 476.1820. Anal. Calcd for C26H25N3O6: C, 65.67; H, 5.30;
N, 8.84. Found: C, 65.77; H, 5.22; N, 8.83.
The diastereomeric purity of 11a and 11b was determined
by HPLC (Waters: column: Microsorb-MV 5 µM, solvent: CH2-
Cl2:iPrOH 96:4; flow rate: 1 mL/min; detected at 254 nm).
Ben zyl r-[[(Ben zyloxy)car bon yl]am in o]-4-[3,4-dih ydr o-
2,4-d ioxo-1(2H)-p yr im id in yl]-2,3-d i-O-isop r op ylid en ecy-
clop en ta n ea ceta te (14a ). To a solution of 11a (101 mg, 0.21
mmol) and NMO‚H2O (43 mg, 0.32 mmol) in wet CH2Cl2 (3
mL) was added a catalytic amount of OsO4 (2 mg, 0.01 mmol).
After TLC analysis indicated consumption of the starting
material, the reaction was quenched with aqueous 1 M
NaHSO3 and was acidified to pH 5 with aqueous 10% citric
acid. The organic layer was separated, and the aqueous layer
was extracted with EtOAc three times. The combined organic
layers were dried over Na2SO4. Filtration and removal of the
solvent in vacuo afforded a residue.
The residue was redissolved in acetone (5 mL), and to this
solution was added dimethoxypropane (66 mg, 0.64 mmol) and
pTsOH‚H2O (4 mg, 0.02 mmol). The reaction was stirred
overnight. The solvent was removed in vacuo, and the residue
was redissolved in EtOAc. The solution was adjusted to pH 8
with saturated aqueous NaHCO3. The organic layer was
separated, and the aqueous layer was extracted three times
with EtOAc. The combined organic layers were washed with
brine and dried over Na2SO4. Filtration and removal of the
solvent afforded two crude products. Chromatography (EtOAc:
CH2Cl2 2:3 and CH2Cl2:iPrOH 10:1) provided acetonide 14a
(36 mg, 31%) as an oil and lactone 13a (32 mg, 38%) as a white
solid. Acetonide 14a , 1H NMR (CD3OD) δ 1.22 (s, 3H), 1.43
(s, 3H), 2.04 (m, 2H), 2.49 (m, 1H), 4.41 (d, J ) 6.9 Hz, 1H),
4.59 (m, 2H), 4.74 (dd, J ) 5.0, 7.0 Hz, 1H), 5.08 (s, 2H), 5.15
(s, 2H), 5.64 (d, J ) 7.8 Hz, 1H), 7.29 (m, 10H), 7.49 (d, J )
8.1 Hz, 1H); 13C NMR (CD3OD) δ 25.6, 27.9, 33.8, 47.2, 49.9,
56.9, 64.6, 67.8, 68.2, 82.0, 83.7, 102.8, 114.9, 128.8, 129.0,
129.4, 129.46, 129.53, 137.0, 138.0, 145.3, 152.4, 158.5, 166.1,
172.5; IR (neat) 3300 (br), 1700, 1684 (br), 1530 cm-1; HRMS
[MH+] calcd for C29H32N3O8 550.2189, found 550.2159. Anal.
Calcd for C29H31N3O8: C, 63.38; H, 5.69; N, 7.65. Found: C,
63.53; H, 5.71; N, 7.57. Lactone 13a , mp 225-227 °C dec; 1H
NMR (DMSO-d6) δ 1.70 (ddd, J ) 7.5, 12.0, 14.8 Hz, 1H), 2.13
(pesudo-dd, J ) 12.3, 23.1 Hz, 1H), 3.04 (m, 1H), 4.13 (dd, J
) 4.6, 6.6 Hz, 1H), 4.67 (m, 1H), 4.87 (m, 2H), 5.06 (d, J )
12.0 Hz, 1H), 5.10 (d, J ) 12.0 Hz, 1H), 5.55 (2d, J ) 8.1 Hz,
1H), 5.60 (d, J ) 5.1 Hz, 1H), 7.37 (m, 5H), 7.52 (d, J ) 8.1
Hz, 1H, 7.73 (d, J ) 9.6 Hz, 1H), 11.28 (br, s, 1H); 13C NMR
(DMSO-d6) δ 26.3, 36.3, 51.7, 55.8, 65.9, 68.8, 79.9, 99.7, 127.8,
127.9, 128.4, 136.7, 143.6, 151.3, 156.4, 163.2, 174.9; IR (KBr)
1
First diastereomer eluted: mp 131-3 °C; H NMR (CDCl3) δ
1.52 (m, 1H), 2.45 (m, 1H), 3.23 (br, 1H), 3.70 (s, 3H), 3.76 (s,
3H), 4.55 (dd, J ) 4.5, 7.8 Hz, 1H), 4.82 (dd, J ) 6.6, 14.1 Hz,
1H), 5.06 (d, J ) 12.3 Hz, 1H), 5.13 (d, J ) 12.3 Hz, 1H), 5.29
(d, J ) 12.3 Hz, 1H), 5.80 (m, 3H), 7.34 (m, 5H), 7.61 (d, J )
12.3 Hz, 1H), 8.77 (d, J ) 7.5 Hz, 1H), 9.42 (br, 1H); 13C NMR
(CDCl3) δ 32.6, 47.4, 52.4, 55.5, 56.1, 57.7, 67.0, 97.5, 128.0,
128.4, 133.3, 133.6, 136.2, 154.7, 156.2, 163.4, 167.7, 171.7;
IR (KBr) 3462, 3266 (br), 1742, 1682 (br), 1616, 1540 cm-1
;
HRMS [MH+] calcd for C21H26N3O7 432.1771, found 432.1778.
The latter diastereomer: mp 180.5-181.5 °C; 1H NMR (CDCl3)
δ 1.57 (m, 1H), 2.59 (m, 1H), 3.23 (br, 1H), 3.69 (s, 3H), 3.75
(s, 3H), 4.42 (dd, J ) 4.5, 8.7 Hz, 1H), 4.87 (m, 1H), 5.08 (d, J
) 12.3 Hz, 1H), 5.14 (d, J ) 12.0 Hz, 1H), 5.34 (d, J ) 12.3
Hz, 1H), 5.50 (m, 1H), 5.69 (m, 1H), 5.87 (m, 1H), 7.35 (m,
5H), 7.58 (d, J ) 12.3 Hz, 1H), 8.79 (d, J ) 7.8 Hz, 1H), 9.87
(s, 1H); 13C NMR (CDCl3) δ 34.0, 46.7, 52.3, 55.4, 56.3, 57.6,
67.1, 97.5, 127.95, 127.99, 128.4, 131.5, 135.0, 136.1, 154.8,
156.4, 163.2, 167.8, 171.9; IR (KBr) 3312, 1734, 1684, 1618,
1532 cm-1; HRMS [MH+] calcd for C21H26N3O7 432.1771, found
432.1776. Anal. Calcd for C21H25N3O7: C, 58.46; H, 5.84; N,
9.74. Found: C, 58.43; H, 5.73; N, 9.50.
Ben zyl r-[[(Ben zyloxy)car bon yl]am in o]-4-[3,4-dih ydr o-
2,4-d ioxo-1(2H )-p yr im id in yl]-2-cyclop en t en e-1-a cet a t e
(11a ). To a solution of 10 (1.40 g, 3.2 mmol) in THF (50 mL)
was added aqueous 0.5 N NaOH (8.4 mL, 4.2 mmol). The
reaction was allowed to stir at rt overnight. The solvent was
removed in vacuo to afford the crude product.
To the residue was added concentrated aqueous ammonia
(120 mL). The solution was heated to 85-95 °C for 40 min.
Most of the solvent was removed in vacuo, and the residue
was redissolved in saturated aqueous NaHCO3. The aqueous
solution was extracted with EtOAc twice. The aqueous layer
was then acidified to pH 3 and extracted with EtOAc twice.
The aqueous layer was saturated with NaCl and extracted
again with EtOAc twice. The combined organic layers were
dried over Na2SO4. Filtration and removal of the solvent
afforded a crude residue (1.23 g).
The residue was redissolved in DMF (8 mL), and to this
solution was added NaHCO3 (350 mg, 4.2 mmol). The mixture
was stirred for 30 min followed by addition of BnBr (547 mg,
3.2 mmol) and NaI (5 mg, 0.03 mmol). The reaction was
allowed to stir at rt overnight. The solvent was removed in

Synthesis of (() Carbocyclic Polyoxin C and Its R-Epimer
3382, 1776, 1700, 1684 (br), 1524 cm-1
Anal. Calcd for
J . Org. Chem., Vol. 63, No. 3, 1998 759
.
1H), 2.49 (m, 1H), 4.02 (pesudo-t, J ) 5.5 Hz, 1H), 4.12 (dd, J
) 6.6, 7.2 Hz, 1H), 4.54 (m, 2H), 5.05 (d, J ) 10.5, 1H), 5.08
(d, J ) 10.5, 1H), 5.12 (d, J ) 12.3 Hz, 1H), 5.17 (d, J ) 12.3
Hz, 1H), 5.63 (d, J ) 7.8 Hz, 1H), 7.29 (m, 10H), 7.48 (d, J )
8.1 Hz, 1H); 13C NMR (CD3OD) δ 27.5, 46.2, 56.7, 64.2, 67.9,
68.2, 72.4, 74.6, 102.5, 128.8, 129.0, 129.30, 129.32, 129.4,
129.5 137.0, 137.9, 145.0, 152.8, 158.8, 166.2, 172.8; IR (neat)
3340 (br), 1700, 1685, 1678 (br) cm-1; HRMS [MH+] calcd for
C
19H19N3O7: C, 56.86; H, 4.77; N, 10.47. Found: C, 56.82; H,
4.90; N, 10.26.
Ben zyl r-[[(Ben zyloxy)car bon yl]am in o]-4-[3,4-dih ydr o-
2,4-d ioxo-1(2H)-p yr im id in yl]-2,3-d i-O-isop r op ylid en ecy-
clop en ta n ea ceta te (14b). A procedure similar to that used
for conversion of 11a was applied to 11b. Acetonide 14b was
obtained in 37% yield as a white solid and lactone 13b was
obtained in 49% yield as a white solid. Acetonide 14b, mp
185-187 °C; 1H NMR (CD3OD) δ 1.21 (s, 3H), 1.43 (s, 3H),
1.98 (m, 1H), 2.16 (m, 1H), 2.43 (m, 1H), 4.37 (d, J ) 8.4 Hz,
1H), 4.61 (m, 2H), 4.72 (dd, J ) 5.0, 7.0 Hz, 1H), 5.06 (br, 2H),
5.14 (s, 2H), 5.65 (d, J ) 8.1 Hz, 1H), 7.30 (m, 10H), 7.52 (d,
J ) 8.1 Hz, 1H); 13C NMR(CD3OD) δ 25.6, 27.9, 33.8, 47.3,
57.3, 64.0, 67.9, 68.4, 82.0, 84.0, 102.9, 114.8, 128.9, 129.0,
129.4, 129.46, 129.51, 137.0, 138.0, 145.2, 152.5, 158.6, 166.1,
172.8; IR (KBr) 3320 (br), 1750, 1702, 1684, 1676 cm-1; HRMS
[MH+] calcd for C29H32N3O8 550.2189, found 550.2211. Anal.
Calcd for C29H31N3O8: C, 63.38; H, 5.69; N, 7.65. Found: C,
63.26; H, 5.49; N, 7.39. Lactone 13b, mp 228-230 °C dec; 1H
NMR (DMSO-d6) δ 2.10 (dt, J ) 5.1, 12.3 Hz, 1H), 2.25 (dt, J
) 12.3, 8.7 Hz, 1H), 2.86 (m, 1H), 4.01 (dd, J ) 3.6, 4.8 Hz,
1H), 4.16 (t, J ) 5.4 Hz, 1H), 4.80 (dt, J ) 2.1, 10.2 Hz, 1H),
4.92 (dd, J ) 3.6, 9.6 Hz, 1H), 5.04 (s, 2H), 5.54 (d, J ) 7.8
Hz, 1H), 6.04 (d, J ) 4.5 Hz, 1H), 7.36 (m, 5H), 7.83 (d, J )
8.4 Hz, 1H), 7.91 (d, J ) 8.4 Hz, 1H), 11.31 (s, 1H); 13C NMR
(DMSO-d6) δ 30.8, 54.7, 58.0, 65.8, 69.6, 79.8, 100.1, 127.9,
128.4, 136.7, 143.5, 151.3, 155.8, 163.1, 175.7; IR (KBr) 3400
(br), 1780, 1700, 1684 (br) cm-1. Anal. Calcd for C19H19N3O7:
C, 56.86; H, 4.77; N, 10.47. Found: C, 56.68; H, 4.63; N, 10.22.
Ben zyl r-[[(Ben zyloxy)car bon yl]am in o]-4-[3,4-dih ydr o-
2,4-d ioxo-1(2H )-p yr im id in yl]-2,3-d ih yd r oxycyclop en t a -
n ea ceta te (12a ). To a solution of acetonide 14a (126 mg, 0.23
mmol) in THF (4 mL) was added N HCl (4 mL), and the
reaction was stirred at rt overnight. The solvent was removed
in vacuo and the residue was purified by chromatography
(CH2Cl2:iPrOH 10:1) to afford the diol 12a (78 mg, 67%) as a
C
26H28N3O8 510.1876, found 510.1879.
r-Am in o-4-[3,4-d ih yd r o-2,4-d ioxo-1(2H)-p yr im id in yl]-
2,3-d ih yd r oxycyclop en ta n ea cetic Acid (2). To a solution
of diol 12a (28 mg, 0.055 mmol) in EtOH/H2O (2.2 mL, 10:1)
was added Pd/C(10%) (7 mg). The system was purged first
with Ar and then H2. The reaction was stirred under H2 (1
atm) for 75 min at rt. The system was purged with Ar again,
and the mixture was diluted in 15 mL of H2O and filtered.
Removal of solvent in vacuo afforded pure product 2 (15.4 mg,
98%) as a white solid, mp 198-202 °C dec; 1H NMR (D2O with
1,4-dioxane) δ 1.46 (dt, J ) 12.6, 10.9 Hz, 1H), 2.02 (dt, J )
12.6, 7.5 Hz, 1H), 2.13 (m, 1H), 3.64 (d, J ) 6.6 Hz, 1H), 4.40
(pesudo-dt, J ) 10.9, 7.5 Hz, 1H), 5.64 (d, J ) 8.1 Hz, 1H,
7.42 (d, J ) 8.1 Hz, 1H); 13C NMR (D2O with 1,4-dioxane) δ
26.7, 46.6, 56.7, 62.7, 72.3, 73.0, 102.0, 144.5, 152.2, 166.4,
172.9; IR (KBr) 3410 (br), 1720, 1675, 1645 cm-1; HRMS [MH+]
calcd for C11H16N3O6 286.1039, found 286.1047.
r-Am in o-4-[3,4-d ih yd r o-2,4-d ioxo-1(2H)-p yr im id in yl]-
2,3-d ih yd r oxycyclop en ta n ea cetic Acid (3). Similar treat-
ment of diol 12b (86 mg) with Pd/C (25 mg) in EtOH/H2O (6.6
mL, 10:1) afforded the product 3 (48 mg, quantitative) as a
white solid, mp 200-204 °C dec; 1H NMR (D2O with 1,4
dioxane as internal leble) δ 1.71 (dt, J ) 12.9, 11.1 Hz, H),
2.04 (dt, J ) 15.9, 8.1 Hz, 1H), 2.25 (m, 1H), 3.65 (d, J ) 5.1
Hz, 1H), 3.95 (t, J ) 6.4 Hz, 1H), 4.02 (dd, J ) 6.3, 6.9 Hz,
1H), 4.40 (pesudo-dt, J ) 10.5, 7.2 Hz, 1H), 5.65 (d, J ) 8.1
Hz, 1H), 7.45 (d, J ) 8.1 Hz, 1H); 13C NMR (D2O with 1,4-
dioxane): δ 26.7, 43.4, 55.6, 62.5, 70.6, 73.3, 102.0, 144.6,
152.2, 166.3, 172.9; IR (KBr) 3412 (br), 1707, 1656 cm-1; HRMS
[MH+] calcd for C11H16N3O6 286.1039, found 286.1026.
1
white solid, mp 87-89 °C; H NMR (CD3OD) δ 1.56 (dd, J )
11.1, 23.1 Hz, 1H), 2.00 (m, 1H), 2.37 (m, 1H), 4.04 (dd, J )
5.1, 6.3 Hz, 1H), 4.12 (dd, J ) 6.3, 7.8 Hz, 1H), 4.38 (d, J )
7.2 Hz, 1H), 4.51 (m, 1H), 5.07 (s, 2H), 5.15 (s, 2H), 5.62 (d, J
) 7.8 Hz, 1H), 7.30 (m, 10H), 7.41 (d, J ) 8.1 Hz, 1H); 13C
NMR (CD3OD) δ 28.6, 46.4, 57.4, 64.1, 67.8, 68.1, 72.4, 74.2,
102.6, 128.8, 129.0, 129.4, 129.47, 129.50, 129.6, 137.0, 138.0,
144.8, 152.8, 158.6, 166.2, 172.7; IR (neat) 3375 (br), 1720 (br),
1685 (br) cm-1; HRMS [MH+] calcd for C26H28N3O8 510.1876,
found 510.1895.
Ack n ow led gm en t. We gratefully acknowledge the
NIH and the Reilly Fellowship at the University of
Notre Dame to D.Z. for support of this research. The
facilities of the Lizzadro Magnetic Resonance Research
Center at the University of Notre Dame are appreciated.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 12a , 12b, 2, 3, and the first eluted diastereomer of
10 (10 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
Ben zyl r-[[(Ben zyloxy)car bon yl]am in o]-4-[3,4-dih ydr o-
2,4-d ioxo-1(2H )-p yr im id in yl]-2,3-d ih yd r oxycyclop e n -
ta n ea ceta te (12b). Similar treatment of acetonide 14b
afforded diol 12b in 83% yield as a white solid after purification
1
by chromatography, mp 89-91 °C; H NMR (CD3OD) δ 1.60
(pesudo-dd, J ) 11.0, 23.0 Hz, 1H), 1.95 (dt, J ) 12.9, 8.1 Hz,
J O971711R