Communication
To generate a benzofuran building block of type 5 we in-
tended to use a Sonogashira coupling[9] with a consecutive 5-
endo-dig cyclisation.[10] For this purpose, we first prepared the
known 2-iodo-3-hydroxybenzaldehyde derivative 8 following
slightly modified literature protocols.[11] After treatment of 3,4-
dihydroxybenzaldehyde (7) with benzyl bromide in the pres-
ence of K2CO3 in acetone,[12] the mono-protected product was
further reacted with iodine monochloride to afford the iodide
8 in high yield as a pure regioisomer (Scheme 3). Separately, 1-
undecyne (10) was prepared from decanal (9) under Corey–
Fuchs conditions.[13] On heating the iodo-phenol 8 and the
alkyne 10 with 10 mol% of Pd(PPh3)2Cl2 and CuI in the pres-
ence of NEt3 in DMF, the domino Sonogashira coupling/5-
endo-dig cyclisation proceeded smoothly to afford the benzo-
furan 11 in 51% isolated yield. Subsequent Pinnick oxidation[14]
of the aldehyde function gave the carboxylic acid 5a. To pre-
pare for the planned ester formation (see Scheme 2), this
building block was further converted into the HOBT-activated
ester 12,[15] which proved to be easy to handle and was stable
for months without significant decomposition.[16]
Scheme 4. Synthesis of the acetophenone building block 6a. Reagents and
conditions: a) benzyl-Br, K2CO3, DMF, 708C, 57%; b) 18m KOH, pyridine, di-
ethylene glycol, 1208C, 75%; c) i. LDA, TMSCl, THF, 08C; ii. m-CPBA, NaHCO3,
CH2Cl2, 08C; iii. pTsOH, THF/water, RT, 68%; d) BF3·OEt2, CH2Cl2, RT, 62%; m-
CPBA=meta-chloroperbenzoic acid; pTsOH=para-toluenesulfonic acid.
and 6a under Steglich conditions[20] only resulted in the forma-
tion of the acid anhydride, the arylester 17 was obtained in
good yield when the phenol 6a was reacted with the HOBT-ac-
tivated acid derivative 12 in the presence of NaH at 08C in
THF (Scheme 5).
Having successfully constructed the ester 17, the stage was
set to probe the planned key transformation, that is, the con-
version of 17 into the chromenone 18. Much to our satisfac-
tion, using potassium carbonate as a base in the presence of
TBAB as a phase-transfer catalyst, the ester 17 smoothly under-
went the desired Baker–Venkataraman rearrangement with
concomitant in situ cyclization of the intermediate 1,3-diketone
to afford the chromenone 18 in 57% yield after purification
(Scheme 5).
The remaining task was the deprotection of 18.[21] The hy-
drogenolytic cleavage of the benzyl ethers proceeded smooth-
ly using palladium on carbon in a mixture of THF and ethanol
Scheme 3. Synthesis of the benzofuran building block 5a and its activated
derivative 12. Reagents and conditions: a) benzyl-Br, K2CO3, KI, acetone,
reflux, 93%; b) ICl, pyridine, CH2Cl2, RT, 93%; c) CBr4, PPh3, CH2Cl2, 08C to RT,
73%; d) nBuLi, THF, À788C to RT, then H2O, 70%; e) Pd(PPh3)2Cl2 (10 mol%),
CuI, NEt3, DMF, 608C, 51%; f) NaH2PO4, NaClO2, 2-methyl-2-butene, THF/
water, 408C, 71%; g) HOBT, EDC·HCl, CH2Cl2, RT, 87%; HOBT=1-hydroxyben-
zotriazole; EDC=1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.
The synthesis of the second building block 6a (Scheme 4)
started from the inexpensive commercially available natural
product chrysin (13), which after double O-benzylation was de-
graded by retro-aldol reaction to the resulting acetophenone
derivative (14) as described by Caldwell et al.[17] a-Oxidation
under Rubottom conditions[17,18] then furnished the hydroxylat-
ed product 15. It is worth noting that, despite the modest
yield, this method opened a reliable and practical access to 15
on a multigram scale. Lastly, the installation of a b-galactose
moiety was accomplished in good yield by reacting a mixture
of the alcohol 15 with peracetylated b-galactose in the pres-
ence of BF3-etherate as a Lewis acid at room temperature.[19]
With the ortho-hydroxyacetophenone building block 6a in
our hands the next goal was the esterification with the acid
building block 5a. Though initial experiments to connect 5a
Scheme 5. Completion of the total synthesis of houttuynoid B (1). Reagents
and conditions: a) NaH, THF, 08C, 76%; b) K2CO3, TBAB, toluene, 708C, 57%;
c) Pd-C, H2, THF/EtOH, RT; d) NaOMe, MeOH, RT, 99% (2 steps). TBAB=tetra-
n-butylammonium bromide.
Chem. Eur. J. 2016, 22, 2935 – 2938
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