A novel enantioselective synthesis of HMG Co-A reductase inhibitor NK-104 and a related compound

Article abstract of DOI:10.1016/S0040-4039(00)60814-6

Optically active methyl 6-oxo-3,5-syn-isopropylidenedioxyhexanoate (5) was prepared by enantioselective syn-reduction of β,δ-diketo ester 2, followed by hydrolysis, protection of the diol moiety and ozonolysis, and was converted into a highly potent HMG Co-A reductase inhibitor NK-104 and an analogue.

Full text of DOI:10.1016/S0040-4039(00)60814-6

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Vol. 33, No. 49. pp.
in Great
A NOVEL ENANTIOSELECTIVE SYNTHESIS OF HMG Co-A
REDUCTASE INHIBITOR NK-104 AND A RELATED COMPOUND
Tatsuya
and
Research Center, 4-4-l Nishiohnuma,
Optically active methyl
was
2. followed by hydrolysis, protection of the diol moiety and
HMG inhibitor and an
by
of
a
and was
converted
Pravastatin and
are potent inhibitors of
coenzyme A
Co-A)
the rate limiting enzyme in cholesterol biosynthesis, and lower cholesterol level in blood so as to be
useful for treating of hypercholesterolaemia
subunit by a substituted heteroaromatic ring or ethylene part
concerned, it has turned out that biological activity depends largely on the
Efforts have been made of replacing the hexahydronaphthalene
Insofar as totally synthetic analogues are
moiety.3 Thus,
many synthetic analogues of type 1 have been designed, synthesized, and found to be highly potent
hypocholesterolaemic and hypolipidaemic agents. One of these, NK-104 (la) was recently shown to be
or more potent than
and its connection to an aromatic or ethylenic core. We
synthesis of various based on the enantioselective synthesis of methyl
and its type olefination.
The main synthetic problem is stereoselective construction of the
part
herein a convergent method applicable for the
1
H
F
NK-104
Pravastatin
According to the procedure we
with 2 of diisobutylaluminium hydride to give a
in the presence of to afford
aldehyde 5 by following steps: 1) hydrolysis with 1 M
auxiliary, 2) esterification with diazomethane, and 3) protection of the
ester 2 was reduced highly stereoselectively
ester which was further reduced with
ester 3 of 93
in
was transformed to
to remove and recover the
group with acetone
to give ester 4 in 81% total yield.
of
in the presence of a catalytic amount of
4 followed by reductive workup afforded the
aldehyde
Reaction of 5 with
afforded an E-olefin
derived from
or
and lithium
or
7525

7526
respectively in good yields. Both
and 7b were easily transformed to enantiomers of
and lb through
hydrolysis and lactonization. respectively.
Ph
=
4
Me
HO
6
Li
enantiomer of
3) toluene
A
3 h
Scheme 1
Although the synthesis of the enantiomer of 1 was demonstrated hen, this method should be applicable for
the synthesis of 1 possessing various substituent R starting from the enantiomer of 2.5
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(Received in Japan 23 July