reflux for 12 h to afford oxazolidinone derivative 11 in 92%
1
yield as a single isomer by H and 13C NMR analysis.10
Scheme 2a
Treatment of 11 with Boc2O and triethylamine in the
presence of a catalytic amount of DMAP in THF at 23 °C
for 2 h and subsequent hydrolysis of the N-Boc-oxazolidi-
none derivative with sodium hydroxide in a mixture of EtOH
and water (1:1) provided the N-Boc-protected amino alcohol
in 96% yield. Protection of the amino alcohol as N,O-
isopropylidene using 2,2-dimethoxypropane and a catalytic
amount of p-TsOH in CH2Cl2 at 23 °C afforded acetonide 6
in 92% yield. Reductive cleavage of the benzyl ether was
achieved by exposure of 6 to lithium in liquid ammonia at
-33 °C for 5 min. The resulting alcohol was then oxidized
to aldehyde 12 under Swern conditions. Stereoselective
homologation of 12 was carried out by a procedure developed
by Dondoni and co-workers.11 Treatment of 12 with 2-(tri-
methylsilyl)thiazole in CH2Cl2 at 23 °C for 6 h yielded a
1:1 mixture of alcohol 13 and TMS derivative 14. Exposure
of the reaction mixture to nBu4N+F- for 20 min afforded
13 in 85% yield as a single diastereomer by 1H and 13C NMR
analysis.
a (a) 2, CF3CO2H, CH2Cl2, 0 °C, 30 min; (b) 4, EDCI, DMAP,
CH2Cl2, 23 °C, 12 h (72%); (c) O3, CH2Cl2, -78 to 23 °C; (d)
NaClO2, 2-methyl-2-butene, NaH2PO4‚H2O, tBuOH-H2O (5:1); (e)
Cs2CO3, MeOH-H2O (5:1), 30 min, BnBr, DMF, 0 °C, 6 h (87%);
(f) MgI2, THF, reflux, 5 min (93%); (g) H2, 10% Pd/C, Dowex
50-X8, THF-MeOH (1:1), 23 °C, 12 h (75%).
Our synthesis now required the conversion of the thiazole
moiety into an aldehyde followed by oxidation of the
aldehyde to acid 4. Thus, benzylation of alcohol 13 with
sodium hydride and benzyl bromide in the presence of
tetrabutylammonium iodide yielded benzyl ether 15 in 95%
yield. Transformation of the thiazole into an aldehyde was
carried out in a one-pot, three-step sequence developed by
Dondoni.11 Hence, R-benzyloxythiazole 15 was first N-
methylated by treatment with methyl trifluoromethane-
sulfonate in the presence of molecular sieves in acetonitrile
for 30 min at 23 °C. Subsequent reduction of the thiazolinium
CdN bond with sodium borohydride in MeOH at 0 °C for
30 min followed by removal of the thiazolidine by use of
copper(II) oxide and copper(II) chloride in a mixture of
acetonitrile and water (10:1) furnished the R-benzyloxy-
aldehyde in an overall yield of 82%. The more commonly
used mercury(II) chloride converted the thiazolidine to
R-benzyloxyaldehyde in only modest yields (25-35%).
Oxidation of the aldehyde with sodium chlorite in a mixture
of tert-butyl alcohol and water (5:1) and in the presence of
2-methyl-2-butene afforded acid 4 in 98% yield.
obtained in 72% yield. Ozonolysis of the terminal alkene at
-78 °C furnished the corresponding aldehyde. Exposure of
the resulting aldehyde to sodium chlorite in a mixture of
tert-butyl alcohol and water (5:1) in the presence of 2-methyl-
2-butene furnished the corresponding acid. Reaction of this
acid with cesium carbonate and benzyl bromide afforded
benzyl ester 17 in 87% yield in a three-step sequence from
16. The benzyl ester protection was necessary to allow clean
O-demethylation in a subsequent step. Treatment of 17 with
magnesium iodide in THF followed by heating of the result-
ing mixture at reflux furnished smooth O-demethylation, and
phenol derivative 18 was isolated in 93% yield.5c,12 In
contrast, attempted demethylation in the presence of un-
protected acid resulted in substantially lower yields (15-
25%).
To complete the synthesis, we now needed to remove the
remaining protecting groups. Our initial attempts at sequential
removal of the remaining protecting groups proved to be
more difficult than we had expected. After much effort, we
optimized conditions to effect deprotection of all three
protecting groups conveniently in a one-pot procedure.
Exposure of 18 in a mixture of THF and MeOH (1:1) to
Pd/C and Dowex 50-X8 resin at 23 °C under a hyrogen
atmosphere resulted in clean removal of the isopropylidene,
tert-butoxycarbonyl, and benzyl groups. This procedure
With the readily available isocoumarin fragment 2 and acid
4, we then set out to couple these fragments as shown in
Scheme 2. Since the free amine of isocoumarin 2 is known
to form the corresponding lactam upon standing, we elected
to carry out the coupling immediately after removal of the
N-Boc group.2a Thus, Boc-derivative 2 was treated with neat
trifluoroacetic acid at 0 °C for 30 min, the mixture was
concentrated to dryness, and the resulting amine salt was
reacted with acid 4 in the presence of EDCI and DMAP in
CH2Cl2 at 23 °C for 12 h. The coupling reaction proceeded
nicely under this protocol, and amide derivative 16 was
rendered optically active AI-77-B in 75% yield ([R]23
)
D
-75.2 (c 0.11, MeOH); lit.5g,h [R]22 ) -78.2 (c 0.08,
D
MeOH); mp 134-135 °C; lit.2a mp 139.5 °C). Spectral data
for synthetic (-)-1 are in full accordance with the reported
data for authentic samples.2a,5b,c
(10) Ghosh, A. K.; Fidanze, S. J. Org. Chem. 1998, 63, 6146.
(11) (a) Dondoni, A.; Perrone, D.; Semola, M. T. J. Org. Chem. 1995,
60, 7927. (b) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini,
P. Synthesis 1988, 685. (c) Dondoni, A.; Fogagnolo, M.; Medici, A.; Pedrini,
P. Tetrahedron Lett. 1985, 26, 5477.
(12) Yamaguchi, S.; Sugiura, K.; Fukuoka, R.; Okazaki, K.; Takeuchi,
M.; Kawase, Y. Bull. Chem. Soc. Jpn. 1984, 57, 3607.
Org. Lett., Vol. 3, No. 17, 2001
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