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Scheme 2. Reagents and conditions: a) Ti(OiPr)4 (10 mol%), d-DIPT
(14 mol%), 4 ꢀ MS, TBHP, CH2Cl2, À258C, 98% (99% ee); b) DEAD,
PPh3, p-nitrobenzoic acid, toluene, À308C then K2CO3, MeOH, 74%;
c) Red-Al, toluene, 08C to reflux, 82%; d) 2,2-dimethoxypropane, PPTS,
acetone, 99%; e) PdCl2 (10 mol%), CuCl, O2, DMF/H2O (10:1), 82%;
f) (EtO)2P(O)CH2CO2Et, NaH, THF, 90% (E/Z=6:1); g) DIBAL-H,
CH2Cl2, À788C, 99%; h) TBDPSCl, imidazole, DMF; i) Li, naphthalene,
THF, À508C, 96% (2 steps); j) (COCl)2, DMSO, Et3N, CH2Cl2, À788C;
k) MeCOC(N2)P(O)(OEt)2, K2CO3, MeOH, 88% (2 steps). DIPT=di-
isopropyl tartrate, TBHP=tert-butyl hydroperoxide, DEAD=diethyl
azodicarboxylate, Red-Al=sodium bis(2-methoxyethoxy)aluminum hy-
dride, PPTS=pyridinium 4-toluenesulfonate, DMF=N,N-dimethyl-
formamide, THF=tetrahydrofuran, DIBAL-H=diisobutylaluminum hy-
dride, DMSO=dimethyl sulfoxide, Red-Al=sodium bis(2-methoxyeth-
oxy)aluminum hydride.
Scheme 1. A retrosynthetic analysis of 1. TBS=tert-butyldimethylsilyl,
BOM=benzyloxymethyl, TBDPS=tert-butyldiphenylsilyl, Bn=benzyl.
according to our established procedure[11] (Scheme 2).
Wacker oxidation[13] of 9 delivered methyl ketone 11, which
was subjected to Horner–Wadsworth–Emmons olefination to
afford a 6:1 mixture of E-ester 12, the Z-isomer of which was
chromatographically separated. Upon successive DIBAL-H
reduction, silylation, and debenzylation[14] with lithium naph-
thalenide, 12 afforded alcohol 13 in excellent yield. After
Swern oxidation of 13, the resulting aldehyde was then
subjected to Seyferth–Gilbert homologation by using the
Ohira–Bestmann reagent[15] to provide alkyne 7. The overall
yield of 7 from 10 was 31% (11 steps).
Scheme 3. Reagents and conditions: a) Li, naphthalene, THF, À508C,
98%; b) MsCl, NEt3, CH2Cl2, 99%; c) LiAlH4, Et2O, reflux, then 1m
HCl, MeOH, 84%; d) nBuLi, THF, À788C, then CO2, I2, 86%;
e) TBSCl, imidazole, DMF, 78%; f) K2CO3, MeOH, 93%; g) BnOCH2Cl,
iPr2NEt, CH2Cl2, 100%. Ms=methanesulfonyl.
Epoxide 8 was also prepared from 9 by a highly diaste-
reoselective seven-step transformation in 51% overall yield
(Scheme 3). Reductive debenzylation of 9 followed by
mesylation of the resulting alcohol gave mesylate 15 in
quantitative yield. Mesylate 15 was then reduced with LiAlH4
and the reaction mixture was directly acidified by the addition
of aqueous HCl and MeOH to afford 1,3-diol 16 without
serious loss of the initially formed volatile product. According
to Cardilloꢀs method,[16] 16 was lithiated and reacted with CO2
followed by I2 to provide iodocarbonate 17 as a single
diastereomer in good yield. Silylation of 17 followed by
methanolysis gave epoxy alcohol 18, which was then pro-
tected as the corresponding BOM ether to provide epoxide 8.
With the required alkyne 7 and epoxide 8 in hand, the
stage was set for the preparation of monomeric hydroxy
salicylate 4 starting from the union of these two fragments
(Scheme 4). The lithium acetylide generated from 7 was
Although several attempts to reduce 19 to E-alkene 21 by
using Red-Al or LiAlH4 met with failure, we found that
Trostꢀs procedure,[17] which involves silylation, intramolecular
hydrosilylation, and desilylation, effected this transformation
satisfactorily. Silylation of 19 with 1,1,3,3-tetramethyldisila-
zane followed by intramolecular hydrosilylation with
[Cp*Ru(MeCN)3]PF6 as the catalyst furnished dihydrooxasi-
line 20, which was then directly subjected to AgF-mediated
desilylation to afford E-alkene 21 and diol 22 in 52% and
34% yields, respectively. Since 22 was quantitatively con-
verted into 21 by selective silylation, the total yield of 21 was
86%. Protection of the secondary alcohol of 21 as the
corresponding TBS ether followed by removal of the BOM
group of 23 by using lithium naphthalenide[14] produced
[9]
reacted with 8 in the presence of BF3·OEt2 to give
homopropargyl alcohol 19 in almost quantitative yield.
2
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Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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