Synthesis of 3-substituted 8-hydroxy-3,4-dihydroisocoumarins من كتب علمية

Synthesis of 3-substituted 8-hydroxy-3,4-dihydroisocoumarins
 تأليف: Naruki Tahara, Tsutomu Fukuda and Masatomo Iwao

Synthesis of 3substituted 8hydroxy3,4dihydroisocoumarins من كتب علمية 
Synthesis of 3-substituted 8-hydroxy-3,4-dihydroisocoumarins
 تأليف: Naruki Tahara, Tsutomu Fukuda and Masatomo Iwao
via successive lateral and ortho-lithiations
of 4,4-dimethyl-2-(o-tolyl)oxazoline
Naruki Tahara, Tsutomu Fukuda and Masatomo Iwao*
Department of Applied Chemistry, Faculty of Engineering, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Received 1 April 2004;revised 26 April 2004;accepted 28 April 2004
Abstract—Sequential treatment of 4,4-dimethyl-2-(o-tolyl)oxazoline in THF with sec-BuLi, aromatic or aliphatic aldehydes, sec-
BuLi, B(OMe)3, and H2O2 produced the laterally alkylated and ortho-hydroxylated oxazolines in one-pot. Treatment of these
products with TFA in aqueous THF provided 3-substituted 8-hydroxy-3,4-dihydroisocoumarins in 44–75% overall yields. This
procedure allowed the short synthesis of (±)-hydrangenol and (±)-phyllodulcin, naturally occurring 3,4-dihydroisocoumarins of
pharmacological interest. A more economical synthesis of (±)-phyllodulcin via the trianion intermediate is also described.

2004 Elsevier Ltd. All rights reserved.
Directed lithiation is the most powerful method for
regioselective functionalization of aromatic rings.1 The
reagent-controlled optional site-selective lithiation is
especially interesting in this field from mechanistic and
practical points of view.2 Recently, we have reported
that 4,4-dimethyl-2-(o-tolyl)oxazolines (1a–c) can be
lithiated at the lateral or ortho-position selectively
depending on the reaction conditions (Scheme 1).3 Thus,
the oxazolines were deprotonated at the most acidic
lateral methyl group with sec-BuLi in Et2O at )78 C,
whereas they were lithiated at the less acidic ortho-position
with sec-BuLi in the presence of TMEDA. The
latter unusual ortho-lithiation was rationalized by the
unfavorable steric interaction between TMEDA and the
methyl groups on the oxazoline ring in the transition
state for the lateral lithiation.3
The 3,4-dihydroisocoumarins constitute a class of natural
products, which exhibit a wide range of pharmacological
activities such as antifungal,4a antiulcer,4b
antileukemic,4c antiallergic,4d differentiation-inducing,4e
and antimalarial4f activities. Structurally, most of these
natural products possess an aryl or alkyl substituent at
C-3 and a hydroxy group at C-8 of the isocoumarin
core. The syntheses of this type of 3,4-dihydroisocoumarins
have been achieved efficiently by
N
O
sec-BuLi, Et2O, -78 °C, 1 h
sec-BuLi, TMEDA, Et2O, -78 °C, 1 h
lateral lithiation
ortho-lithiation
X
1a: X=H
1b: X=OMe
1c: X=Cl
N
O
X
Li
O