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Stereochemical control in the synthesis of the cyclohexyl portion of the milbemycin skeleton
oo40-4039/84 $3.00 + .oo 01984 Pergamon Press Ltd.
Tetrahedron Letters,Vo1.25,No.47,pp 5449-5452,1984 Printed in Great Britain
STEREOCHEMICAL
CONTROL
PORTION
Michael Imperial Jealotts Abstract:
D Turnbull*, Chemical
Hill Research
OF THE CYCLOHEKYL
SKELETON
and Denise B Ledgerwood
PLC, Plant Protection
Station,
Bracknell,
Division,
Berkshire,
RG12 6EY
Robinson annulation of B-keto esters and stereospecific reduction of the resultins ketols with sodium triacetoxyborohydride qives aihydroxy cyclohexane carboxylates with the carbon and oxygen framework of part of the milbemycins.
(e.g. milbemycin an approach
into the total synthesis
to the cyclohexyl
ring using the
to decalin
appropriate
functionality
oxygen
of a cyclic ketol. dehydrated
cases, previous
and (axial) hydroxyl DeBoer5a,
of the substituent.
nature of methoxycarbonyl
requires
have not commented
is stereoselective
Uncyclised
material
on the stereochemical
outcome5, of carbonyl of
(0.5 M) in methanolic
The hydrogen-bonded nmr in CDC13,
hydroxyl
revealing
that would be expected
proton
the axial
on thermodynamic
of the ring from (2) and the bulky
quantity
from (2) to (3) - proved
of carrying
from the reaction
(211, the ratio of open and cyclised Dehydration
out the Michael
of sodium hydride.
as base were found to promote
of temperature.
step4.
groups.
was the sole product
did not crystallise
the ketol is
Thus, under the conditions
of formation
of the equilibrium
of a catalytic
at the stage
in giving a cis disposition
the proton
conditions
with
is stopped
acid-catalysed
(0.5 M) and methyl vinyl ketone
and phenyl
cases displacement
and sodium hydroxide
a separate
This is the outcome
In certain
variation
authors
if the sequence
of the Robinson procedure,
signal at 4.2sin
given the equilibrating
(as with
it also allows access to cyclohexanes
at 20°C gave (2) in 74% yield.
gives a characteristic
in the presence
milbemycins'
by the simplicity of of Robinson annulation 3 . Although
in all cases we have examined6.
ethyl benzoylacetate
sodium hydroxide
method
for elaboration,
In many applications
but we find that the reaction
geometry
systems,
to an enone, but this usually
In monocyclic
of the insecticidal
B, (L)21 and their analogues , we were attracted
more often applied
product
Glenn Hatter
Industries
As part of an investigation
grounds
IN THE SYNTHESIS
OF THE MILBEMYCIN
mixture,
driving
5449
in dry ether
alcoholic
solvents
cyclisation:
even when the
the reaction
to completion,
forms could in general
to enone was not observed
conditions.
addition
In contrast,
the desired
difficult.
be influenced
by
under these mildly basic
5450
c
mi I bemycin
.
p, OMe
a PhCOCH,C02
F
Et
HO ep;02Me
OH
Me0
(41
gMe
,k,/CO,Me 0
d R=Me
Reagents:
a)
NaOH,
MeOH
b) NaBH(OAd3,
HOAc
cl NaBH(OAd3,
EtOAc
d) H+,
Acetone
5451
Two closely milbemycin obtained
related studies
sequences
are shown in Scheme
from a reaction
remaining
which are typical
run at 20°C or above,
leading
chromatography
on silica gel.
stereospecifically
Milbemycins reduction isomeric
mixture
equatorial,
have equatorial
The additional
again as expected
triacetoxy
borohydride',
on C-7 to direct hydride
following attack
undesired
5-equatorial,
isomer available
the reaction
cyclohexyl
of the hydroxy
molar excess of the reagent
ketone
solution
reduction
was not detectable
The
by tic in
substrate
((a),R=H) the reduction
With
of dry ether to a reaction
(g), the reaction
precipitated between
was carried
out
as a moisture-
sodium borohydride
was both regio- and stereo-
specific
and
in 57% yield.
the reaction
by cyclisation
methodology
addition
using crude sodium triacetoxyborohydride
acetic acid.
In conclusion,
borohydride
is sodium
diol (Q) in 80% yield after crystallisation.
from the non-selective
white powder by addition
gave ((z),R=C+)
followed
reagent
mixture.
in dry ethyl acetate
and glacial
of diols
by chromatography
This uses the axial hydroxy
Thus,
to a two-fold
7-axial
gave a mixture
separated
A much more selective
by flash
by nmr to be conditions 8 .
Sodium borohydride
at C-5'.
as solvent
stereospecifically.
In the case of the more acid-sensitive
sensitive
substituents
the work of Saksena".
(2) in acetic acid or tetrahydrofuran gave the desired
group was determined
These were readily
and the C-5 axial diol found to predominate.
was
in 50% yield after isolation
under the equilibrating
or tetrahydrofuran
numbering).
In contrast,
addition
gave the desired ketol as the major
methyl
or methoxy
was
to move away from starting
and it was obtained
hydroxy
of (2) in isopropanol at C-5 (milbemycin
methanol
showed no
if the reaction
yields of (2) in that case.
was required
to
yield of (6) - of 85% was
thin layer chromatography
was kept below 20°C , the first Michael
barely perceptible by tic and heating materials 7 . Equilibration in boiling of the product
and of more relevance
was shown to predominate
to poor isolated
when R=CHS and the temperature
component
When R=H, an isolated
1.
run at O'C: at work-up,
(i)5b, which however
uncyclised
of those examined
provides
between
in two simple
ring of milbemycins has already
now being adapted
We thank M R Kipps
suitable
B-keto esters and a-B unsaturated
to ketol and stereospecific
reduction
steps a versatile
bearing
the correct
been used to produce
to a total synthesis
route to the carbon skeleton
hydroxylation
simplified
This analogues 11 . skeleton 12 .
the nmr spectra.
of the
pattern.
milbemycin
of the full milbemycin
for help in determining
ketones,
with sodium triacetoxy
It is
5452
REFERENCES
1.
Y Takiguchi,
H Mishima,
(1980). For synthetic
M Okuda, M Terao,
approaches
Street, J. Chem. Soc.,Chem. 2.
3.
Kurabayashi,
A Aoki, and R Fukuda, J Antibiotics
to the milbemycin
Commun.,
C Tamura,
system see P Kocienski
571 (1984) and references S Sato, H Kuwano,
-33, 1120
and S D A
cited therein.
and A Saito, Tetrahedron
711 (1975)
H 0 House, Modern edition,
4.
M
Ii Mishima, Letters,
AND NCTES
Synthetic
Reactions
p.606 and p.641,
Benjamin,
Menlo Park CA, (2nd
1972)
a) M E Jung, Tetrahedron, b) W S Johnson,
-32, 3 (1976)
J J Korst,
R A Clement,
and J Dutta, J. Amer. Chem. Sot., -82, 614
(1960) 5.
a) C D DeBoer,
6.
All the reactions
J. Org. Chem., -39, 2426 (1974)
b) S Danishefsky
expected
and S 3 Etheredge,
Methyl
J. Org. Chem., -47, 4791
would racemise
stereochemically
R Zamboni,
M Kahn,
was prepared
8.
adduct
it would be
like (L), which
leading to racemic
in tetrahydrofuran
and S J Etheredge,
(1981). All other starting materials standard
any Michael
pure by other means,
4,4-Dimethoxy-3-oxopentanoate
S Danishefsky,
(1982)
in this paper were done on racemic material:
that the basic conditions
had been produced 7.
reported
(3). -
by the method
of
J. Amer. Chem. Sot., -103, 3460
are commercially
available
or were prepared
by
methods.
The stereochemical c-4 methyl
outcome
was most readily
established
is no longer subject to base-catalysed
axial hydrogens
on the diol products
epimerisation
on C-3 and C-5 can readily be seen in the proton
Data for (9), R=CH 3: M.p. 83-84OC
(Ether/Petroleum
ether).
where the
and the coupling
'H-nmr
to
nmr. (400 MHz),
(CDC13):1.10,3H,d,J=8Hz;l.4O,lH6a,dt,J=l3Hz,0.5Hs;l.5O,lH4a,m;l.65,lH3a,q,J=
13"s;
l.70,lHOH,s;l.97,2H3e,6e,m;2.32,3Hg,s;3.O2,lH2a,dd,J=l3Hz,5Hz;3.62,lH5a,m: 3.65,3HOMe,s;4.30,1HOH,d,J=0.5Hs. 9.
G W Gribble conveniently
and D C Ferguson, prepared
J.Chem.
by reaction
acid below 30°C, until hydrogen 10.
A Saksena and P Mangiaracina,
11.
To be reported Cambridge,
12.
E J Thomas,
evolution
Tetrahedron
at the symposium
September
Sot., Chem Commun.,
of sodium borohydride
535 (1975). The reagent
with excess
273 (1983)
in the Chemistry
1984.
(Received in UK 6 August
1984)
is
acetic
ceases. Letters,
"Recent Advances
M J Hughes, and M D Turnbull,
glacial
unpublished
work.
of Insect Control",
Tetrahedron Letters,Vo1.25,No.47,pp 5449-5452,1984 Printed in Great Britain
STEREOCHEMICAL
CONTROL
PORTION
Michael Imperial Jealotts Abstract:
D Turnbull*, Chemical
Hill Research
OF THE CYCLOHEKYL
SKELETON
and Denise B Ledgerwood
PLC, Plant Protection
Station,
Bracknell,
Division,
Berkshire,
RG12 6EY
Robinson annulation of B-keto esters and stereospecific reduction of the resultins ketols with sodium triacetoxyborohydride qives aihydroxy cyclohexane carboxylates with the carbon and oxygen framework of part of the milbemycins.
(e.g. milbemycin an approach
into the total synthesis
to the cyclohexyl
ring using the
to decalin
appropriate
functionality
oxygen
of a cyclic ketol. dehydrated
cases, previous
and (axial) hydroxyl DeBoer5a,
of the substituent.
nature of methoxycarbonyl
requires
have not commented
is stereoselective
Uncyclised
material
on the stereochemical
outcome5, of carbonyl of
(0.5 M) in methanolic
The hydrogen-bonded nmr in CDC13,
hydroxyl
revealing
that would be expected
proton
the axial
on thermodynamic
of the ring from (2) and the bulky
quantity
from (2) to (3) - proved
of carrying
from the reaction
(211, the ratio of open and cyclised Dehydration
out the Michael
of sodium hydride.
as base were found to promote
of temperature.
step4.
groups.
was the sole product
did not crystallise
the ketol is
Thus, under the conditions
of formation
of the equilibrium
of a catalytic
at the stage
in giving a cis disposition
the proton
conditions
with
is stopped
acid-catalysed
(0.5 M) and methyl vinyl ketone
and phenyl
cases displacement
and sodium hydroxide
a separate
This is the outcome
In certain
variation
authors
if the sequence
of the Robinson procedure,
signal at 4.2sin
given the equilibrating
(as with
it also allows access to cyclohexanes
at 20°C gave (2) in 74% yield.
gives a characteristic
in the presence
milbemycins'
by the simplicity of of Robinson annulation 3 . Although
in all cases we have examined6.
ethyl benzoylacetate
sodium hydroxide
method
for elaboration,
In many applications
but we find that the reaction
geometry
systems,
to an enone, but this usually
In monocyclic
of the insecticidal
B, (L)21 and their analogues , we were attracted
more often applied
product
Glenn Hatter
Industries
As part of an investigation
grounds
IN THE SYNTHESIS
OF THE MILBEMYCIN
mixture,
driving
5449
in dry ether
alcoholic
solvents
cyclisation:
even when the
the reaction
to completion,
forms could in general
to enone was not observed
conditions.
addition
In contrast,
the desired
difficult.
be influenced
by
under these mildly basic
5450
c
mi I bemycin
.
p, OMe
a PhCOCH,C02
F
Et
HO ep;02Me
OH
Me0
(41
gMe
,k,/CO,Me 0
d R=Me
Reagents:
a)
NaOH,
MeOH
b) NaBH(OAd3,
HOAc
cl NaBH(OAd3,
EtOAc
d) H+,
Acetone
5451
Two closely milbemycin obtained
related studies
sequences
are shown in Scheme
from a reaction
remaining
which are typical
run at 20°C or above,
leading
chromatography
on silica gel.
stereospecifically
Milbemycins reduction isomeric
mixture
equatorial,
have equatorial
The additional
again as expected
triacetoxy
borohydride',
on C-7 to direct hydride
following attack
undesired
5-equatorial,
isomer available
the reaction
cyclohexyl
of the hydroxy
molar excess of the reagent
ketone
solution
reduction
was not detectable
The
by tic in
substrate
((a),R=H) the reduction
With
of dry ether to a reaction
(g), the reaction
precipitated between
was carried
out
as a moisture-
sodium borohydride
was both regio- and stereo-
specific
and
in 57% yield.
the reaction
by cyclisation
methodology
addition
using crude sodium triacetoxyborohydride
acetic acid.
In conclusion,
borohydride
is sodium
diol (Q) in 80% yield after crystallisation.
from the non-selective
white powder by addition
gave ((z),R=C+)
followed
reagent
mixture.
in dry ethyl acetate
and glacial
of diols
by chromatography
This uses the axial hydroxy
Thus,
to a two-fold
7-axial
gave a mixture
separated
A much more selective
by flash
by nmr to be conditions 8 .
Sodium borohydride
at C-5'.
as solvent
stereospecifically.
In the case of the more acid-sensitive
sensitive
substituents
the work of Saksena".
(2) in acetic acid or tetrahydrofuran gave the desired
group was determined
These were readily
and the C-5 axial diol found to predominate.
was
in 50% yield after isolation
under the equilibrating
or tetrahydrofuran
numbering).
In contrast,
addition
gave the desired ketol as the major
methyl
or methoxy
was
to move away from starting
and it was obtained
hydroxy
of (2) in isopropanol at C-5 (milbemycin
methanol
showed no
if the reaction
yields of (2) in that case.
was required
to
yield of (6) - of 85% was
thin layer chromatography
was kept below 20°C , the first Michael
barely perceptible by tic and heating materials 7 . Equilibration in boiling of the product
and of more relevance
was shown to predominate
to poor isolated
when R=CHS and the temperature
component
When R=H, an isolated
1.
run at O'C: at work-up,
(i)5b, which however
uncyclised
of those examined
provides
between
in two simple
ring of milbemycins has already
now being adapted
We thank M R Kipps
suitable
B-keto esters and a-B unsaturated
to ketol and stereospecific
reduction
steps a versatile
bearing
the correct
been used to produce
to a total synthesis
route to the carbon skeleton
hydroxylation
simplified
This analogues 11 . skeleton 12 .
the nmr spectra.
of the
pattern.
milbemycin
of the full milbemycin
for help in determining
ketones,
with sodium triacetoxy
It is
5452
REFERENCES
1.
Y Takiguchi,
H Mishima,
(1980). For synthetic
M Okuda, M Terao,
approaches
Street, J. Chem. Soc.,Chem. 2.
3.
Kurabayashi,
A Aoki, and R Fukuda, J Antibiotics
to the milbemycin
Commun.,
C Tamura,
system see P Kocienski
571 (1984) and references S Sato, H Kuwano,
-33, 1120
and S D A
cited therein.
and A Saito, Tetrahedron
711 (1975)
H 0 House, Modern edition,
4.
M
Ii Mishima, Letters,
AND NCTES
Synthetic
Reactions
p.606 and p.641,
Benjamin,
Menlo Park CA, (2nd
1972)
a) M E Jung, Tetrahedron, b) W S Johnson,
-32, 3 (1976)
J J Korst,
R A Clement,
and J Dutta, J. Amer. Chem. Sot., -82, 614
(1960) 5.
a) C D DeBoer,
6.
All the reactions
J. Org. Chem., -39, 2426 (1974)
b) S Danishefsky
expected
and S 3 Etheredge,
Methyl
J. Org. Chem., -47, 4791
would racemise
stereochemically
R Zamboni,
M Kahn,
was prepared
8.
adduct
it would be
like (L), which
leading to racemic
in tetrahydrofuran
and S J Etheredge,
(1981). All other starting materials standard
any Michael
pure by other means,
4,4-Dimethoxy-3-oxopentanoate
S Danishefsky,
(1982)
in this paper were done on racemic material:
that the basic conditions
had been produced 7.
reported
(3). -
by the method
of
J. Amer. Chem. Sot., -103, 3460
are commercially
available
or were prepared
by
methods.
The stereochemical c-4 methyl
outcome
was most readily
established
is no longer subject to base-catalysed
axial hydrogens
on the diol products
epimerisation
on C-3 and C-5 can readily be seen in the proton
Data for (9), R=CH 3: M.p. 83-84OC
(Ether/Petroleum
ether).
where the
and the coupling
'H-nmr
to
nmr. (400 MHz),
(CDC13):1.10,3H,d,J=8Hz;l.4O,lH6a,dt,J=l3Hz,0.5Hs;l.5O,lH4a,m;l.65,lH3a,q,J=
13"s;
l.70,lHOH,s;l.97,2H3e,6e,m;2.32,3Hg,s;3.O2,lH2a,dd,J=l3Hz,5Hz;3.62,lH5a,m: 3.65,3HOMe,s;4.30,1HOH,d,J=0.5Hs. 9.
G W Gribble conveniently
and D C Ferguson, prepared
J.Chem.
by reaction
acid below 30°C, until hydrogen 10.
A Saksena and P Mangiaracina,
11.
To be reported Cambridge,
12.
E J Thomas,
evolution
Tetrahedron
at the symposium
September
Sot., Chem Commun.,
of sodium borohydride
535 (1975). The reagent
with excess
273 (1983)
in the Chemistry
1984.
(Received in UK 6 August
1984)
is
acetic
ceases. Letters,
"Recent Advances
M J Hughes, and M D Turnbull,
glacial
unpublished
work.
of Insect Control",