SCHEME 1. Syn th esis of La cton e 9a
SCHEME 2. Syn th esis of La cton e 9 via γ-Keto
Ester 12a
a
Reagents and conditions: (a) CH2ICl, LDA, THF, -78 °C; (b)
NaBH4, EtOH/toluene, -78 - 0 °C; (c) KOH, EtOH, rt; (d)
CH2(CO2Et)2, EtONa, EtOH, rt; (e) (i) LiOH/DME-H2O, 50 °C, 6
h; (ii) toluene, reflux, 8 h.
separate by column chromatography, recrystallization
from EtOAc provided the desired diastereomer of 6, albeit
in low yield (38% yield, 99:1 dr). Chlorohydrin 6 was then
treated with ethanolic KOH to provide epoxide 7, which
was further purified via recrystallization from hexane
(82% yield, >99:1 dr). Treatment of epoxide 7 with the
sodium salt of diethyl malonate (3.5 equiv) provided the
carbethoxylactone 8 in 90% yield.10 Hydrolysis of 8 with
LiOH in DME-H2O followed by decarboxylation provided
lactone 9 in 81% yield.11
a
Reagents and conditions: (a) MeP(O)(OMe)2, LDA, THF, -78
°C; (b) CHOCO2-t-Bu, Et3N, 0 °C; (c) MeS(O)Ph, LDA, -78 °C to
room temperature; (d) K2CO3, BrCH2CO2-t-Bu, DMF, rt; (e)
LiAlH(O-t-Bu)3, EtOH, -78 °C; (f) (i) H2, Pd/C, EtOAc; (ii) toluene,
HOAc, reflux.
SCHEME 3. Syn th esis of La cton e 19a
In view of the difficulties required to purify 6, we also
developed a second route to lactone 9 that involved two
simple steps from 13: hydrogenation and then acid-
mediated lactone formation (Scheme 2). Following the
work of Luthman et al.,12 we prepared ketoester 12 by
Horner-Wadsworth-Emmons reaction of the phos-
phonate 10 with tert-butyl glyoxylate (prepared from
L-tartaric acid in two steps12). Diastereoselective reduc-
tion of 12 with LiAlH(O-t-Bu)3 in EtOH at -78 °C9,12 gave
13 in 81% yield (>95:5 dr). Gratifyingly, hydroxy ester
13 was converted to lactone 9 in 80% yield by hydrogena-
tion over 10% Pd/C followed by heating the resulting
saturated γ-hydroxy ester in toluene in the presence of
HOAc.16 This alternative route offers a convenient pro-
cedure to prepare 9 in good yield.
a
Reagents and conditions: (a) ethylene glycol, p-TsOH, ben-
zene, reflux, 44 h; (b) n-BuLi, THF, DMF, -78 °C; (c) (i) 9, LDA,
THF, -78 °C; (ii) Ac2O, Et3N, 120 °C; (d) H2, 10% Pd/C, EtOAc,
rt, 24 h; (e) H2, PtO2, EtOAc, rt.
We also explored a new route employing â-ketosulfox-
ide 11 prepared in 70% yield by condensation of ester 4
with 3 equiv of the carbanion of methyl phenyl sulfoxide
at -78 °C.13 Alkylation of 11 with tert-butyl bromoacetate
(KOBu-t/THF14), followed by elimination of PhSOH at 50
°C provided conjugated ketone 12 in 34% yield. Although
alkylation in the presence of K2CO3/DMF15 did improve
the yield marginally (40%), higher elimination temper-
atures were of no help. Thus, although giving a lower
yield than the previous approach, the new method is
shorter and employs commercially available tert-butyl
bromoacetate.
Conversion of lactone 9 to the protected benzophenone
intermediate 19 was then accomplished as shown in
Scheme 3. Thus, benzophenone 14 was protected as a
dioxolane 15, then converted to aldehyde 16 by reaction
with n-BuLi followed by anhydrous DMF.17 Aldol con-
densation of lactone 9 with aldehyde 16 followed by
dehydration with Ac2O-Et3N at 120 °C provided the R,â-
unsaturated lactone 17.11 Hydrogenation of 17 in the
presence of 10% Pd/C18 (2-3 h) gave a mixture of the
desired dioxolane 19 and ketone 24 (Scheme 4). Extended
reaction times led to overreduction, with compound 18
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