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O
O
O
O
COOMe
COOMe
H
O
H
OMe
b,c
a
Me
O
+
HO
O
O
O
O
O
HO
H
O
Me
H
3
Me
Me
Me
O
O
O
d,e
f,g
j,k
h,i
O
O
O
COOMe
COOH
COOMe
Me
Me
Me
O
H
O
l,m
O
n
N
N
+
(
±
)-HA
H
NHCOOMe
NHCOOMe
NHCOOMe
Reagents:
a).Me
2
CO
3
, NaH/KH, THF; b)
-methylacrolein; c) TMG, CH
2
Cl
2
or DBU, MeCN;
d)
p
-tolyl chlorothionoformate, Py; e) pyrolysis; f) ethyltriphenylphosphonium bromide,
n
-BuLi, THF;
g) thiophenol, AIBN, toluene; h) 20% NaOH, H
2
O/THF/MeOH;
i) 2
N
HCl, dioxane; j) (PhO)
2
P(O)N
3
, Et
3
N, chlorobenzene; k)MeOH;
l) pyrrolidine, molecular sieves, PhH; m) propiolamide;
n)
n
-PrSLi, HMPA; o) TMSI, CHCl
3
; p) MeOH.
α
Scheme 4-5. Camps et al. approach to preparing racemic HA.
(
)-8-phenylmenthol and 8 reacted with methacrolein in the presence of
tetramethylguanidine at room temperature (r.t.) over 2 days. A 90% yield of
mixture 9 was isolated. Mixture 9 was transferred olefin 10 employing conditions
identical with those reported previously.
Chen and Yang reported an approach to optical intermediate (5S,9R)-4, which
could be conveniently transformed optical (
)-HA via steps similar to Qian and
Ji and Xia and Kozikowski's approaches to (
)-HA.
103
2a reacted with methacro-
lein in the presence of 0.1 equivalence quinine at r.t. over 10 days to obtain isomer
(5S,9R)-4 (Scheme 4-7).
Kaneko et al. reported the preparation of the key intermediate (
þ
)-12 of (
)-HA
via the asymmetric Pd-catalyzed bicycloannulation of the b-keto ester 2 with
2-methylene-1,3-propanediol diacetate 11 (Scheme 4-8).
104
The chiral ferrocenyl-
phosphine ligand 13 gave 64% ee enantioselectivity.
Illuminated by these promising results, several new chiral ferrocenylphosphine
ligands were thus prepared.
105,106
The enantioselectivity of the bicycloannulation
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