Xue-Wei Liu et al.
Scheme 4. Iterative synthesis of the side-chain aldehydes 20, 32, 34, and 36. Reagent and conditions: a) MeI, NaHMDS, THF, À788C, 2 h, 72 %;
b) LiBH4, ether/MeOH, THF, À788C, 2 h, 73%; c) (COCl)2, DMSO, TEA, CH2Cl2, À788C; d) 38, Bu2BOTf, TEA, CH2Cl2, À788C, 67% (over two
steps); e) TsCl, 4-dimethylaminopyridine (DMAP), Py, RT, 8 h, 83%; f) LiBH4, ether/MeOH, THF, À788C, 2 h, 70%; g) (COCl)2, DMSO, TEA, CH2Cl2,
À788C; h) (EtO)2POCH(CH3)CO2Et, NaH, THF, À788C, 8 h, 73% (over two steps, E/Z=3:1); i) DIBAL-H, CH2Cl2, À788C, 2 h, 89%; j) (COCl)2,
G
DMSO, TEA, CH2Cl2, À788C, 95%; k) Ph3PCHCO2Et, PhMe, 808C, 8 h, 88%; l) DIBAL-H, CH2Cl2, À788C, 2 h, 87%; m) (COCl)2, DMSO, TEA,
CH2Cl2, À788C, 91%; n) Ph3PC(CH3)CO2Et, CH2Cl2, RT, overnight, 72%; o) DIBAL-H, CH2Cl2, À788C, 2 h, 94%; p) (COCl)2, DMSO, TEA, CH2Cl2,
E
À788C, 92%; q) Ph3PCHCO2Et, PhMe, 808C, 8 h, 68%; r) DIBAL-H, CH2Cl2, À788C, 2 h, 88%; s) (COCl)2, DMSO, TEA, CH2Cl2, À788C, 85%;
t) Ph3PCHCO2Et, PhMe, 808C, 8 h, 82%; u) DIBAL-H, CH2Cl2, À788C, 2 h, 91%; v) (COCl)2, DMSO, TEA, CH2Cl2, À788C, 95% (TEA=triethyla-
mine, HMDS=hexamethyldisilazane, DIBAL-H=diisobutylaluminum hydride).
nBuLi and butyryl chloride followed by diastereoselective
alkylation of the corresponding oxazolidinone amide, which
introduced chirality at the C-2 position in 72% yield.[14] Re-
duction of oxazolidinone 22 with lithium borohydride in
a mixture of methanol and ether afforded the desired opti-
cally pure alcohol 23 accompanied by around 65% of recov-
ered oxazolidinone 37. Subsequent Swern oxidation of 23
furnished aldehyde 24, which was subjected to Evans aldol
reaction with propionimide 38 under either one of these
three conditions: 1) Bu2BOTf (OTf=triflate), triethylamine
(TEA), CH2Cl2; or 2) TiCl4, N,N-diisopropylethylamine
(DIPEA), CH2Cl2; or 3) TiCl4, tetramethylethylenediamine
(TMEDA), CH2Cl2.[15] Comparison of the yield and diaste-
reoselectivity revealed that boron enolate turned out to be
a better choice than chlorotitanium enolate. The diastereo-
mer was readily separable by column chromatography to
provide the oxazolidinone 25 in good yield and diastereo-
meric purity. Further protection of alcohol 25 by a tosyl (Ts)
group proceeded with high yield. Lithium borohydride re-
duction ensued in a similar manner but was accompanied by
the displacement of the OTs group by a nucleophilic hy-
dride to give the desired optically pure alcohol 26 along
with 70% of the recovered oxazolidinone 37. Alcohol 26
can be transformed to aldehyde (2R,4R)-27[16] by Swern oxi-
dation, and the resulting aldehyde was directly involved in
a Horner–Wadsworth–Emmons (HWE) reaction with trieth-
yl 2-phosphonopropionate to provide ester 28.[17] Next, ester
reduction with diisobutylaluminum hydride (DIBAL-H) fol-
lowed by another Swern oxidation/Wittig olefination se-
quence gave diene 30 in excellent overall yield. Finally, suc-
cessive reduction and oxidation steps converted the ester 30
to the desired dienal 20, which was ready to be coupled to
the pyridine unit. Starting from aldehyde 24, the same ap-
proach (Wittig olefination/ester reduction/Swern oxidation)
was applied to prepare aldehydes 32, 34, and 36, which
would be subjected to aldol condensation (Scheme 4). The
described protocols provided the required R-configured all-
E unsaturated aldehydes efficiently and stereoselectively
and were thoroughly reproducible on different scales.
The total synthesis of pyridone alkaloids pyridovericin (8)
and torrubiellone (10) required aldehyde fragments 44 and
48, respectively (Scheme 5). Preparation of aldehyde 44 has
been reported by Baldwin et al.[9] In accord with the estab-
lished procedure, the synthesis of these two side-chain alde-
hydes began with reduction of diethyl 2-ethylmalonate (39)
to the corresponding diol 40, which was monoprotected to
afford the desired silyl ether 41 in good yield. Swern oxida-
tion and subsequent Wittig olefination of 42 gave ester 43
and 45, respectively. Ester reduction followed by Swern oxi-
dation gave aldehydes 44 and 46 in excellent overall yield.
Further Wittig olefination of 46 generated pure (E,E)-diene
47. Reduction of 47 to the corresponding alcohol followed
by oxidation provided the desired aldehyde intermediate 48,
which was ready to be coupled to the pyridine unit.
With pyridone unit 17 and the corresponding aldehyde
side chain 20, 32, 34, 36, 44, and 48 successfully prepared,
we next focused on the construction of the C=C double
bond by means of coupling these two fragments (Scheme 6).
The assembly of the pyridone core structures with polyene
aldehyde chain constitutes the key step in this synthetic
route, which was accomplished by means of aldol condensa-
tion. In this aldol condensation step, we found that the reac-
tions were prone to a range of side reactions when different
bases such as KOtBu, KOH, K2CO3, NaOH, and nBuLi
were used.[18] It was only after careful optimization of the re-
action parameters that the formation of byproducts could be
almost completely suppressed. Hence, the optimum condi-
tions required the use of 3 equivalents of NaH in a degassed
THF mixture at 08C to room temperature and with a 1:1.2
ratio of ketone 17 to the corresponding aldehyde. The tar-
Chem. Asian J. 2014, 9, 2548 – 2554
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