An approach to substituted 4-hydroxypyran-2-ones: The total synthesis of phenoxan

Full text of DOI:10.1021/jo960221g

J . Org. Chem. 1996, 61, 4853-4856
4853
discernible product could be identified. Treatment of 3
with Dess-Martin reagent and subsequent reaction with
Ph3P/I2 did not give 4.8 This method has proven useful
for the preparation of trisubstituted oxazoles. A recent
publication has shown the utility of DDQ for the prepa-
ration of oxazoles from oxazolines;9 however, only a
conjugated oxazoline was obtained in high yield. The
desired oxazole was finally obtained by treatment of the
oxazoline of 3 with LDA followed by I2. The reaction
mixture afforded 4 in 40% yield, and the rest of the
product (about 40%) consisted of unreacted oxazoline,
which was easily recovered and recycled. The spectral
data (1H- and 13C-NMR) of 4 closely matched the corre-
sponding segment of phenoxan. This route demonstrated
to us the difficulty in preparing the oxazole fragment at
an advanced stage as the overall yields were low and that
a convergent route from a suitable oxazole starting
material would be more advantageous. We examined
several oxazole intermediates that would allow for the
construction of the pyrone fragment. Of all the myraid
methods of preparing oxazoles,4 none were suitable for
yielding a 2,4-disubstituted oxazole that would allow
further elaboration to phenoxan. We became intrigued
with metalation studies by Lipshutz and Hungate,10 who
showed that 2,4,5-trimethyloxazole could be selectively
alkylated at the 2-methyl group in high yield. We
discovered that alcohol 6, prepared by lithium aluminum
hydride reduction of 5,11 can be selectively alkylated at
the 2-methyl group. The 4-hydroxymethyl group can
serve as a handle for eventual construction of the pyran-
4-one (Scheme 2). Treatment of 6 with 2 equiv of LDA
followed by bromide 76 gave alcohol 8.
An Ap p r oa ch to Su bstitu ted
4-Hyd r oxyp yr a n -2-on es: Th e Tota l
Syn th esis of P h en oxa n
Donna Garey,† Mai-ly Ramirez,† Sam Gonzales,†
Alan Wertsching,† Sovouthy Tith,† Katie Keefe,† and
Michael R. Pen˜a*
Department of Chemistry and Biochemistry,
Arizona State University, Box 871604,
Tempe, Arizona 85287-1604
Received February 2, 1996
In tr od u ction
Phenoxan, a naturally occurring heterocyclic com-
pound, was recently isolated from a soil microorganism
and discovered to have anti-HIV activity.1 The structure
of phenoxan, determined by a combination of proton/
carbon-NMR and high-resolution mass spectrometry,
revealed the presence of a substituted pyran-4-one at-
tached to an oxazole. Phenoxan is closely related to other
microbial metabolites that contain a pyran-4-one group.2
The mechanism of action of phenoxan is currently
unknown; however, a recent report by Parke-Davis
researchers has shown that 6-substituted pyran-2-ones
are inhibitors of HIV-protease by simple hydrogen bond-
ing to the active site.3 Similar hydrogen-bonding interac-
tions may help explain the mechanism of action for
phenoxan. In this paper, we wish to report the first total
synthesis of phenoxan.
We then turned our attention to the construction of
the required pyran-4-one. There are several methods for
constructing the desired γ-pyrone ring system.12 We
initially employed a literature procedure to prepare the
γ-pyrone ring based on the metalation of an acylketene
acetal followed by addition-condensation with an acyl
halide (or imidazole).13 Preparation of the required
acylketene acetal was difficult due to the hydrolytic
(4) Bredereck, H.; Gompper, R.; Reich, F. Chem. Ber. 1960, 93,
1389-1397. Scholkopf, U.; Schroder, R. Angew. Chem., Int. Ed. Engl.
1971, 10, 333. van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H.
Tetrahedron Lett. 1972, 2369-2372. Evans, D. L.; Minster, D. K.;
J ordis, U.; Hecht, S. M.; Mazzu, A. L., J r.; Meyers, A. I. J . Org. Chem.
1979, 44, 497-501. Nagayoshi, K.; Sato, T. Chem. Lett. 1983, 1355-
1356. Alvarez-Ibarra, C.; Mendoza, M.; Orellana, G.; Quiroga, M. L.
Synthesis 1989, 560-562. Kashima, C.; Arao, H. Synthesis 1989, 873-
874. Kende, A. S.; Kawamura, K.; DeVita, R. J . J . Am. Chem. Soc.
1990, 112, 4070-4072. Doyle, K. J .; Moody, C. J . Tetrahedron Lett.
1992, 33, 7769-7770. Yoo, S.-K. Tetrahedron Lett. 1992, 33, 2159-
2162. Aguilar, E.; Meyers,A. I. Tetrahedron Lett. 1994, 35, 2477-2480.
(5) Evans, D. A.; Gage, J . R.; Leighton, J . L.; Kim, A. S. J . Org.
Chem. 1992, 57, 1961-1963.
Resu lts a n d Discu ssion
There are a large number of methods for preparing
substituted oxazoles.4 A popular route to 2,4-disubsti-
tuted oxazoles is cyclodehydration of hydroxyamides,
such as 3, to an oxazoline followed by dehydrogenation.5
Hydroxy amide 3 was prepared by coupling 26 with
L-serine methyl ester hydrochloride via a mixed anhy-
dride7 (Scheme 1). We examined several methods to
construct the oxazole portion, but in our hands no
(6) Frenking, G.; Hulskamper, L.; Weyerstahl, P. Chem. Ber. 1982,
115, 2826-2835.
(7) Inanaga, J .; Hirata, K.; Saeki, H.; Katsaki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989-1993.
(8) Wipf, P.; Miller, C. P. J . Org. Chem. 1993, 58, 3604-3606.
(9) McGarvey, G. J .; Wilson, K. J .; Shanholtz, C. E. Tetrahedron
Lett. 1992, 33, 2641-2644.
† Undergraduate research participants.
(1) J ansen, R.; Kunze, B.; Wray, V.; Reichenbach, H.; J uriewicz, E.;
Hunsmann, G.; Holfe, G. Liebigs Ann. Chem. 1991, 707-708. Kunze,
B.; J ansen, R.; Pridzun, L.; J uriewicz, E.; Hunsmann, G.; Hofle, G.;
Reichenbach, H. J . Antibiot. 1992, 45, 1549-1552.
(2) Kakinuma, K.; J anson, C. A.; Rinehart, K. L., J r. Tetrahedron
1976, 32, 217-222. Vardaro, R. R.; Dimarzo, V.; Crispino, A.; Cimino,
G. Tetrahedron 1991, 47, 5569-5576.
(3) Prasad, J . V. N. V.; Para, K. S.; Lunney, E. A.; Ortwine, D. F.;
Dunbar, J . B., J r.; Ferguson, D.; Tummino, P. J .; Hupe, D.; Tait, B.
D.; Domagala, J . M.; Humblet, C.; Bhat, T. N.; Liu, B.; Guerin, D. M.
A.; Baldwin, E. T.; Erickson, J . W.; Sawyer, T. K. J . Am. Chem. Soc.
1994, 116, 6989-6990.
(10) Lipshutz, B. H.; Hungate, R. W. J . Org. Chem. 1981, 46, 1410-
1413. Meyers, A. I.; Lawson, J . P.; Walker, D. G.; Linderman, R. J . J .
Org. Chem. 1986, 51, 5111-5123.
(11) Cornforth, J . W.; Cornforth, R. H. J . Chem. Soc. 1947, 96-102.
(12) For example: Koreeda, M.; Akagi, H. Tetrahedron Lett. 1980,
21, 1197-1200. Morgan, T. A.; Ganem, B. Tetrahedron Lett. 1980, 21,
2773-2774. Shono, T.; Matsumura, Y.; Hamaguchi, H.; Naitoh, S. J .
Org. Chem. 1983, 48, 5126-5128. Dickinson, J . M. Nat. Prod. Rep.
1993, 10, 71-98.
(13) Banville, J .; Brassard, P. J . Chem. Soc., Perkin Trans. 1 1976,
1852-1856. Boeckman, R. K., J r.; Starrett, J . E., J r.; Nickell, D. G.;
Sum, P.-E. J . Am. Chem. Soc. 1986, 108, 5549-5557.
S0022-3263(96)00221-6 CCC: $12.00 © 1996 American Chemical Society

4854 J . Org. Chem., Vol. 61, No. 14, 1996
Notes
Sch em e 1
Sch em e 2
Sch em e 4
Sch em e 3
push to phenoxan. Swern oxidation20 of alcohol 8 gave
13 (Scheme 4). Addition of propylmagnesium bromide
followed by Swern oxidation furnished ketone 14. Acy-
lation of the enolate of 14 with ethyl 2-methylmalonyl
chloride, followed by acid-catalyzed cyclization of the
diketo ester intermediate, yielded 15. Conversion to the
target molecule employing acetylation followed by meth-
ylation with Meerwein's reagent (Me3OBF4) as in 12
resulted in destruction of the pyran-2-one. Phenoxan was
finally obtained by treatment of the hindered enol 15
with tert-butyldimethylsilyl trifluoromethanesulfonate, in
the presence of pyridine, followed by methylation of the
silyl enol ether with Me3OBF4 in CH2Cl2 at room tem-
perature. Synthetic phenoxan was found to be identical
to authentic material as judged by TLC, 1H- and 13C-
NMR, HPLC analysis, and HRMS.
instability and tedious separation of product from start-
ing material. This difficulty of preparing sufficient
quantities of the acylketene acetal led to an alternative
route that finally provided the pyrone as shown in
Scheme 3. We examined the feasibility of the route on a
model system.14 Alkylation of 4-methoxybenzaldehyde
with propylmagnesium bromide followed by PCC-oxida-
tion15 gave ketone 9, which was readily C-acylated16 with
ethyl 2-methylmalonyl chloride17 to give diketo ester 10.
Best results were obtained using freshly distilled acid
chloride. Acid-catalyzed lactonization18 yielded pyran-
2-one 11. Unreacted diketo ester 10 (about 40%) was
recovered and recycled to yield more product. Pyranone
11 was transformed to 12 according to a literature
procedure.19 Comparision of the 13C-NMR spectra of 12
with phenoxan showed a close match of the pyran-4-one
portion, indicating the validity of the route.
Con clu sion s
In this paper, we have described the first total syn-
thesis of phenoxan that confirms the initial structural
assignment. The two key steps developed in the total
synthesis of phenoxan were (1) metalation of 2-methyl-
4-hydroxymethyloxazole and (2) a method for preparing
6-aryl-substituted pyranones from an aryl ketone and
ethyl 2-methylmalonyl chloride. We are currently pursu-
ing other analogs of phenoxan through molecular model-
ing techniques. This work will be reported in due course.
The two methodologies were now in place for the final
(14) Ramirez, M.-l.; Garey, D.; Pen˜a, M. R. J . Heterocycl. Chem.
1995, 32, 1657-1660.
(15) Piancatelli, G.; Scettri, A.; D'auria, M. Synthesis 1982, 245-
258.
(16) Danishefsky, S. J .; Pearson, W. H.; Segmuller, B. E. J . Am.
Chem. Soc. 1985, 107, 1280-1285.
(18) Ohta, S.; Tsujimura, A.; Okamoto, M. Chem. Pharm. Bull. 1981,
29, 2762-2768. Tanyeli, C.; Tarhan, O. Synth. Commun. 1989, 19,
2453-2460. Cervello, J .; Marquet, J .; Moreno-Manans, M. Synth.
Commun. 1990, 20, 1931-1941. Harris, T. M.; Harris, C. M. J . Org.
Chem. 1966, 31, 1032-1035.
(19) Cyr, T. D.; Poulton, G. A. Can. J . Chem. 1978, 56, 1796-1799.
(20) Mancuso, A. J .; Swern, D. Synthesis 1981, 165-185.
(17) Prepared according to a modification of the original procedure
(Marguery, F. Bull. Chem. Soc. France 1905, 33, 541-548). The ethyl
hydrogen malonate (Strube, R. E. Organic Syntheses; Wiley: New York,
1963; Collect. Vol. IV, pp 417-419) was treated with oxalyl chloride
in dichloromethane in the presence of catalytic dimethylformamide
(DMF) to give the acid chloride.

Notes
J . Org. Chem., Vol. 61, No. 14, 1996 4855
followed by extraction with several portions of EtOAc. The
combined organic layers were washed with several portions of
water and brine and then dried over MgSO4. Filtration and
evaporation of solvent in vacuo left an oil that was further
purified by column chromatrography (75% EtOAc/hexane) to give
670 mg (81% yield) of the alcohol, which was not fully character-
ized but carried over to the next step: Rf ) 0.40 (50% EtOAc/
hexane); 1H NMR (CDCl3) δ 0.92 (t, 3H, J ) 7.2 Hz),1.41 (m,
2H), 1.76 (m, 2H), 1.86 (s, 3H), 2.58 (t, 2H, J ) 7.6 Hz), 2.95 (t,
2H, J ) 7.9 Hz), 4.62 (t, 1H, J ) 6.4 Hz), 6.25 (br s, 1H), 7.2 (m,
5H), 7.41 (s, 1H), 13C NMR (CDCl3) δ 164.5, 143.6, 137.9, 136.6,
133.6, 128.7, 128.3, 127.9, 126.0, 66.5, 38.1, 37.6, 27.0, 18.6, 17.4,
13.7; MS ((EI) 285 (60); HRMS calcd for C18H23NO2 285.172 99,
found 285.172 87 (-0.05 ppm deviation). To a solution of 0.30
mL (3.3 mmol) of oxalyl chloride in 10 mL of CH2Cl2 at -78 °C
was added over 5 min 0.47 mL (6.6 mmol) of DMSO in 5 mL of
CH2Cl2 under N2. A solution of the alcohol (230 mg, 0.81 mmol)
dissolved in 10 mL of CH2Cl2, was added via cannula and then
stirred at -78 °C for 1 h. The reaction was quenched by the
addition of 2.5 mL (18 mmol) of TEA and 4 mL of water. The
reaction mixture was poured into a separatory funnel containing
aqueous NaHCO3. The organic layer was washed several times
with water and brine and then dried over MgSO4. Filtration
and evaporation of solvent in vacuo left a yellow oil that was
further purified by column chromatography (12% EtOAc/hexane)
to give 220 mg (95% yield) of 14 as a viscous oil: Rf ) 0.59 (25%
EtOAc/hexane); 1H NMR (CDCl3) δ 0.96 (t, 2H, J ) 7.4 Hz), 1.72
(m, 2H), 1.88 (d, 3H, J ) 1.65 Hz), 2.63 (t, 2H, J ) 7.7 Hz), 2.84
(t, 2H, J ) 7.7 Hz), 6.27 (br s, 1H), 7.20 (m, 5H), 8.09 (s, 1H),
13C NMR (CDCl3) δ 195.2, 164.8, 141.8, 137.9, 136.3, 128.7,
128.2, 128.0, 126.3, 126.2, 41.7, 37.6, 27.0, 17.5, 17.3, 13.7; MS
((EI) 283 (100), 227 (28), 131 (86); HRMS calcd for C18H21NO2
283.157 33, found 283.156 98 (-0.87 ppm deviation).
Exp er im en ta l Section
Gen er a l Meth od s. All solvents were distilled from calcium
hydride prior to use except for THF, which was distilled from
molten potassium, and ethyl ether, which was distilled from
sodium benzophenone. Anhydrous methanol was distilled from
Mg. All reagents were used as obtained from commercial
suppliers unless otherwise noted. Thin layer chromatography
was performed with glass-backed precoated plates (Si-254F).
Column chromatography utilized silica gel 230-400 mesh, 60
Å. The proton and carbon NMR spectra were recorded on a 300
MHz spectrometer (300 MHz 1H, 75 MHz 13C). The following
deuterated solvents and their following internal reference points
were used: CDCl3 referenced to TMS (0.00 ppm 1H) or chloro-
form (77.00 ppm 13C); methanol-d4 referenced to methanol (3.48
ppm 1H and 39.00 ppm 13C). Melting points are uncorrected.
Elemental analyses were performed by Atlantic Microlab (Nor-
cross, GA). High-resolution mass spectroscopic data were
obtained by the Nebraska Center for Mass Spectrometry.
2-Meth yl-4-(h yd r oxym eth yl)oxa zole (6). A solution of 2.12
g (15.0 mmol) of ester 512 and 570 mg (15.0 mmol) of LAH in 40
mL of ether was stirred at 0 °C under N2 for 3 h. The reaction
mixture was cautiously quenched by the addition of a small
amount of water followed by dilute aqueous NaOH. The mixture
was filtered and dried over MgSO4. Filtration and evaporation
of solvent in vacuo left a yellow oil that was further purified by
column chromatography (75% EtOAc/hexane) to give 760 mg
(45% yield) of 6 as a viscous oil that slowly crystallized upon
standing: mp 40-41 °C; Rf ) 0.15 (75% EtOAc/hexane); 1H NMR
(CDCl3) δ 2.38 (s, 3H), 4.35 (br s, 1H), 4.48 (s, 2H), 7.42 (s, 1H),
13C NMR (CDCl3) δ 162.2, 140.2, 134.8, 55.8, 13.7; MS (EI) 113
(15), 84 (35), 68 (64), 42 (100). Anal. Calcd for C5H7NO2: C,
53.09; H, 6.23; N, 12.38. Found: C, 52.93; H, 6.30; N, 12.29.
Alcoh ol 8. A solution of 0.60 mL (4.3 mmol) of diisopropyl-
amine, 2.50 mL (4.10 mmol) of n-butyllithium (1.6 M), and 10
mL of THF was stirred at 0 °C under N2 for 15 min and then
chilled to -78 °C. To this solution was added via cannula 220
mg (1.95 mmol) of 6 dissoved in 5 mL of THF. The solution was
stirred for 20 min, and then 411 mg (1.95 mmol) of 7,5 dissolved
in 5 mL of THF, was added via cannula. The reaction mixture
was stirred for 1 h and then allowed to warm to rt. The reaction
mixture was poured into aqueous NH4Cl and EtOAc and
extracted several times with EtOAc. The combined organic
layers were washed several times with water and brine and dried
over MgSO4. Filtration and evaporation of solvent in vacuo left
a pale yellow viscous oil that was further purified by column
chromatography (50% EtOAc/hexane) to give 240 mg (50% yield)
P yr a n -2-on e 15. A solution of 1.5 mL (6.9 mmol) of hexa-
methyldisilazane (HMDS), 4.2 mL (6.7 mmol) of n-butyllithium
(1.6 M), and 20 mL of THF was stirred at -78 °C under N2 for
20 min before a solution of 14 (590 mg, 2.1 mmol) in 5 mL of
THF was added via cannula. The reaction was stirred at -78
°C for 45 min before it was diluted with 30 mL of hexane.
A
solution of ethyl 2-methylmalonyl chloride (310 mg, 1.9 mmol)
dissolved in 10 mL of hexane was added via cannula to the
enolate and stirred at -78 °C for 2 h. The reaction was allowed
to warm to rt and quenched by pouring into a separatory funnel
containing EtOAc and dilute aqueous NH4Cl. The organic layer
was washed with water and brine and then dried over MgSO4.
Filtration and evaporation of solvent in vacuo left a yellow oil
that was purified by column chromatography (12% EtOAc/
hexane) to give 233 mg (27% yield) of a yellow oil. The diketo
ester was not fully characterized but quickly carried over to the
next step as it was prone to decomposition: Rf ) 0.15 (12%
EtOAc/hexane); MS ((EI) 411 (100). A solution of the diketo ester
(37.1 mg, 0.09 mmol) in 25 mL of toluene containing a single
crystal of PTSA was heated to reflux overnight under N2. The
reaction was quenched by the addition of 0.25 mL of TEA
followed by solvent removal in vacuo. The brown residue was
purified by column chromatography (50% EtOAc/hexane) to give
18 mg (48% yield) of 15 as a viscous oil that slowly crystallized
1
of 8 as a viscous oil: Rf ) 0.20 (50% EtOAc/hexane); H NMR
(CDCl3) δ 1.82 (d, 3H, J ) 1.1 Hz), 2.55 (t, 2H, J ) 7.8 Hz), 2.93
(t, 2H, J ) 7.9 Hz), 4.51 (s, 2H), 6.22 (br s, 1H), 7.3 (m, 5H),
7.45 (s, 1H), 13C NMR (CDCl3) δ 164.8, 140.2, 137.9, 136.5, 134.7,
128.6, 128.0, 127.8, 125.9, 55.7, 37.4, 26.9, 17.3; MS (EI) 243
(80), 225 (26), 196 (44), 132 (100). Anal. Calcd for C15H17NO2:
C, 74.04; H, 7.04; N, 5.75. Found: C, 73.78; H, 7.10; N, 5.52.
Ald eh yd e 13. To a solution of 0.47 mL (5.4 mmol) of oxalyl
chloride in 10 mL of CH2Cl2 at -78 °C was added over 5 min
0.62 mL (8.7 mmol) of DMSO in 5 mL of CH2Cl2 under N2. A
solution of 8 (970 mg, 4.0 mmol) dissolved in 5 mL of CH2Cl2
was added via cannula over 3 min. The reaction mixture was
stirred at -78 °C for 45 min and then quenched by the addition
of 2.8 mL (38 mmol) of TEA. The reaction mixture was allowed
to warm to rt and poured into a separatory funnel containing
water. The organic layer was washed several times with water
and brine and then dried over MgSO4. Filtration and evapora-
tion of solvent in vacuo left a yellow oil that was further purified
by column chromatography (50% EtOAc/hexane) to give 700 mg
(73% yield) of 13 as a viscous oil: Rf ) 0.62 (50% EtOAc/hexane);
1H NMR (CDCl3) δ 1.89 (s, 3H), 2.66 (t, 2H, J ) 7.5 Hz), 3.06 (t,
2H, J ) 7.6 Hz), 6.26 (br s, 1H), 7.23 (m, 5H), 8.19 (s, 1H), 9.91
(s, 2H), 13C NMR (CDCl3) δ 183.4, 165.6, 144.7, 140.6, 137.6,
135.9, 128.5, 127.8, 126.1, 126.0, 37.1, 26.6, 17.2; MS ((EI) 241
(40), 212 (86), 132 (72). The unstable aldehyde was not fully
characterized but quickly carried over to the ketone 14.
1
upon standing: mp 103 °C; Rf ) 0.34 (50% EtOAc/hexane); H
NMR (CDCl3) δ 1.14 (t, 3H, J ) 7.4 Hz), 1.88 (s, 3H), 2.02 (d,
3H, J )1.6 Hz), 2.64 (t, 2H, J ) 7.7 Hz), 3.0 (q, 2H, J ) 7.7 Hz),
3.01 (m, 2H), 6.29 (br s, 1H), 7.22 (m, 5H), 8.04 (s, 1H), 13C NMR
(CDCl3) δ 165.1, 165.0, 164.5, 147.0, 138.9, 138.0, 136.5, 135.0,
128.7, 128.0, 126.2, 126.1, 100.3, 37.4, 26.9, 17.5, 16.0, 14.1, 8.9
(1 missing sp2 carbon); MS ((EI) 365 (100); HRMS calcd for
C
22H23NO4 365.162 79, found 365.163 22 (1.4 ppm deviation).
P h en oxa n . A solution of 13.9 mg (0.038 mmol) of 15, 0.018
mL (0.23 mmol) of pyridine, 0.035 mL (0.15 mmol) of tert-
butyldimethylsilyl trifluoromethanesulfonate, and 4 mL of CH2-
Cl2 was stirred under N2 for 30 min. The reaction was poured
into a separatory funnel containing aqueous NaHCO3 and
extracted with several portions of EtOAc. The combined organic
layers were washed with water and brine and dried over Na2-
SO4 for 3 h. Filtration and evaporation of solvent in vacuo left
a yellow oil that was not purified but quickly carried over to
the last step. A solution of crude silyl enol ether, 15 mg (0.10
mmol) of Me3OBF4, and 4 mL of CH2Cl2 was stirred under N2
for 2 h. The reaction mixture was poured into saturated aqueous
NaHCO3 and extracted with several portions of EtOAc. The
Keton e 14. A solution of 5.8 mL (5.8 mmol) of propylmag-
nesium bromide was slowly added to 700 mg (2.9 mmol) of 13
in 20 mL of ether at 0 °C under N2. The reaction mixture was
warmed to rt and stirred for 1 h. The reaction mixture was
poured into a separatory funnel containing aqueous NH4Cl

4856 J . Org. Chem., Vol. 61, No. 14, 1996
Notes
combined organic layers were washed with water and brine and
then dried over Na2SO4. Filitration and evaporation of solvent
in vacuo left an oil that was further purified by preparative TLC
(50% EtOAc/hexane) to give 6.3 mg (32% yield based on 15) of
a white crystalline solid: mp 89-90 °C (lit.1 mp 92-93 °C); Rf
) 0.55 (CH2Cl2/MeOH, 19:1 (Rf ) 0.57 for authentic phenoxan);
tR ) 8.2 min (MeOH/water, 4:1; 1.5 mL/min; λ ) 282 nm, 300 ×
3.9 mm C-18 Alltech column); 1H NMR (MeOH-d4) δ 1.06 (t, 3H,
J ) 7.4 Hz), 1.83 (s, 3H), 1.88 (d, 3H, J ) 1.6 Hz), 2.66 (t, 2H,
J ) 7.4 Hz), 2.84 (q, 2H, J ) 7.4 Hz), 3.09 (t, 2H, J ) 7.4 Hz),
4.04 (s, 3H), 6.27 (br s, 1H), 7.13 (m, 3H), 7.23 (m, 2H), 8.33 (s,
1H), 13C NMR (MeOH-d4) δ 182.4, 166.7, 164.2, 149.5, 140.5,
139.4, 137.6, 135.1, 129.8, 129.0, 127.6, 127.2, 126.1, 100.9, 56.6,
38.6, 27.6, 18.4, 17.6, 13.8, 7.1; HRMS calcd for C23H25NO4
379.178 45, found 379.178 32 (-0.10 ppm deviation).
continued support, and the National Science Foundation
(NSF) (Grant No. CHE-8813109) for a 300 spectrometer.
We thank Drs. J im White and Doug Grotjahn for helpful
discussions. We also thank Dr. Rolf J ansen of the
Gesellschaft fu¨r Biotechnologische Forschung (Ger-
many) for kindly providing an authenic sample of
phenoxan. The principal author (M.R.P.) is especially
grateful to the National Science Foundation for a Career
Award (CHE-9503260).
Su p p or tin g In for m a tion Ava ila ble: Copies of the 13C-
NMR spectra of compounds 13-15 and phenoxan (16 pages).
This material is contained in libraries on microfiche, im-
mediately 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.
Ack n ow led gm en t. We warmly thank Arizona State
University for a generous startup grant, the Coalition
to Increase Minority Degrees (CIMD) program for
J O960221G