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Cyclobutanones for the stereoselective synthesis of bifunctional macrolide intermediates
Tetrahedron Letters,Vol.25,No.ll,pp Printed in Great Britain
CYCLOBUTANONES
FOR THE STEREOSELECTIVE
BIFUNCTIONAL
*G. Frater, GIVAUDAN
oo40-4039/84 $3.00 + .Oo 01984 Pergamon Press Ltd.
1133-1136,1984
MACROLIDE
SYNTHESIS
OF
INTERMEDIATES1
U. Miller, W. GUnther RESEARCH
COMPANY
Ueberlandstr. CH-8600
LTD.
138
Dubendorf
Abstract. - Beckmann fragmentation of the oximes -5 and -6 respectiveZy,which were derived from the cyclobutanones-Sand 5, furnished the bifunctional five carbon units -7 and g with ea. 98%
and 91% stereoselectivity.
We were interested
for some time in the possible
A most successful
chain compounds2.
approach
control
of vicinal
stereochemistry
in open
to this task turned out to be the controlled
aldol-reaction3. The more classical termediate,
which
novel combination carbon
way to meet this problem
is to stereoselectively
can be converted
into an open chain compound.
of reactions
is shown, which leads to the diastereomeric
units -7 and -8 with 98% and 91% stereoselectivity,
Addition
of dimethylketene
(kinetic control). ture, consisting
Both were syn-anti two
in-
bifunctional
five
respectively.
to cis,trans-ethyl-propenylether
Equilibration
a cyclic
In Scheme l'+ a
(C,H,OH, cat. C,H50-Na+)
(z)5 furnished 2 in 90% yield
established
the thermodynamic
mix-
of 91% -4 and 9% -3.
The corresponding
2 H-C(3)
construct
subsequently
oximes mixtures
doublets
and 3.28 ppm, J(3.4)
at
from _3 and _4 were prepared in s 60:40 ratio;
under standard
bp. 72-740C
conditions
at 0.08 mm; NMR (CDCla, 400 MHz):
3.66 and 3 53 ppm, J(3.4) s 8 Hz; _6 H-C(3) two
Q 6.5 Hz.~
1133
in high yield.
doublets
at 3.3
1134
Scheme
1
COCl
>-1 +
-,t&D
b.
,,$Y
-3
EUPY. _2
4 (9% 3) 82%
C.
1 NOH
k
Et0
Et
-5 d.
84%
C.
1
a (9% 5) 61%
CN -7
-a.
EtaN, t-BuOCHs:
A.
m-Nitrobenzoylchloride Treatment
rature tation
90%,
-b.
EtOH, cat. EtO-Nat,
in CHzCl,,
of 2 and 6 respectively
c.
NH,OH
- HCl, EtOH, HzO, KHCO,,
r.t. with m-nitrobenzoylchloride
furnished -7 ind 61% and -8 in 64% yield. 7 was in pyridine,t-butylmethylether
Another
and addition
in CHzClz at ambient
condition
for the Beckmann
of (CF,CO),O
tempe-
fragmen-
between 20-5OoC,
which
led to -7 and -8 in 45-50% yield. a.p. 68-700 at 10 mm. (d; J(3.2) C(4)),
NMR. (CDCl,, 400 MHz):
* 9 Hz; H-C(3)),
1.22 (t; CH,-CHz-),
3.66 (d; J(3.2) CH,-C(4)),
3.55-3.32
1:
(m; 0-&-),
1.21 (d; CH,-C(P));g:
s a Hz, H-C(3)),
1.35 (d; CH,-C(2)),
3.55-3.28
5.1-5.08 and 5.04-5.02 2.73 (dxq; H-C(2)), 5.13-5.1
(m; O-C&-),
1.19 (t; CHa-CH,).
(two m; 2H-C(5),
1.65 (narrow m; CHs-
and 5.08-5.06
(two m; 2H-C(5)),
2.8 (dxq; H-C(2)),
1.72 (narrow m;
Both in GLC and NMR spectrum
of8
about 9%
of -7 was detectable. Thus the two bifunctional the R*,R*-product
C-5 units, the R*,S*-product
8 (> 90% stereoselectivity)
-7 (> 98% stereoselectivity)
have been synthetized.q
3.64
and
1135
Scheme 2
3or4 a-
b., c.
.
--
N BzO
BZ
I
d.
“+CN BzO -12 -a.
Benzylalcohol,
ether: 65%,
-d.
cat. NaH, 80%,
-b.
NH,OH
- HCl, EtOH, H,O, KHCOs: 80%,
none -9 by treating theethoxy of NaH at 35-400C
trimethylcy~lobutenonel~, to -10 through conditions
d, J(3.2)
compound
in tenfold
for 2 hours.
the oxime with thionylchloride fragmentation
converted
into the benzyloxy
excess of benzylalcohol
The reaction
which we also isolated
of the Beckmann
ment product
SOCl,,
BBN, THF: 73%.
As shown in Scheme 2, -3 and 4 can be conveniently amounts
-c.
intermediate
in ether at 0-5oC.
(pyridine,(CFsCO),O)
Hydroboration
with a 9:l stereoselectivity
is 2,4,4-
-9 was converted
rearrange-
NMR: H-C(4) at 3.53 ppm,
of -10 (2 eq. BBN, THF, then 10% NaOH, H,O,) furnished -12
concerning
the newly formed asymmetriccarbon
C(4) in 73%
yield.12*ls On the other hand DIBAL reduction was further
convertedI
of _I4 7
(Scheme 3) led to the aldehyde -13 (80%), which
to -14 and -_-* 15
Scheme
-7
3
2
a.
/
+
CHO
b.
OEt
*cooEt OEt
+ -14 OEt -15 a. -
DIBAL, hexane,
CH(CHs)COOCzHs,
-700C: 80X,
b.
(0)sP=C(CH,)COOC,Hs,
THF, NaH, -700C + OoC: 75%.
in-
Under the aforementioned
10% of the Beckmann
-11 could be isolatedll: m.p. 105-108oC(ether_pentane),
% 9 Hz.
with catalytic
in this reaction
under other conditions.
cycobuta-
(70:30)
DMSO, 1000: 70%,
5.
(EtO),P(O)
1136
References
and Notes
1
Communicated
2
G. Frater,Helv.
3
D.A. Evans, J.V. Nelson & T.R. Traber,
4
All compounds had correct elemental analyses in agreement with the proposed structures.
5
R. Huisgen,
6
All bxime isomers have been separated as benzoates: syn-5-benzoate, m.p. 37-38OC; 5-benzoate, oil; syn-6-benzoate, m.p. 70-710C; anti-6-benzoate, m.p. 59-600C. -
7
The expected Beckmann rearrangement product of these reactions, ethoxy-trimethylpyrrolidone, was not isolated. It is expected to be very well water soluble.
8
' "Abnormal" Beckmann Rearrangements ' R.T. Conley & S. Ghosh in "Mechanism Ed. B.S. Thyagarajan Vol. 4, p. 197, Wiley-Interscience, 1971. Migration"
9
See for related concepts in using ketene adducts: P. Michel, M. O'Donnell, R. Binaname, A.M. Hesbain-Frisque, L. Ghosez, J.P. Declercq, G. Germain, E. Arte & M. van Meersche, Tetrahedron Lett. 1, 2577 (1980) and literature cited therein.
10
at the Swiss Chemical 62,
Society
2825, 2829 (1979). -
L.E, Feiler & G. Binsch,
in Bern, October
G. Frater, Tetrahedron
Topics
of Stereochem. and displayed
Chem. Ber. 102,
H. Mayr& R. Huisgen, Angew. Chem.7,491
1982. in print.
13 (1982).
NMR and IR spectra which were
3460 (1969).
(1975), Angew. Chem., Int. Ed. Engl.E,499
anti-
of Molecular
(1975).
11
Interestingly when the oxime derived from 9 was treated with 11 became the main product of the reaction: -
(0),P in CClb, 8 hours reflux,
12
The stereochemistry of the hydroboration acetonide -13 (a. H,-Pd(C); b. acetone,
by converting
6
-12
into
the
=
CN
1°*0313
step was determined PPTS).
-
H
NMR (400 MHz, CDCls): 3.76-3.7 (m; He -C(6), H-C(4)), 3.55-3,49 (dxd; J em Q 11 HziJ(6.5) Hz), s 10 HZ; Hax-C(6)), 2.88-2.81 (m; H-C(?)), 1.87-1.78 (m; H-C(5) J(6ax. 53 % 3(4.5)~10 1.46 and 1.41 (gem. dimethyl), 1.33 (d; CH3-C(7)), 0.82 (d; CHs-C(5)). 13
For acyclic diastereoselection by hydroboration see e.g. D.A. Evans, J. Bartroli & T. GOdel, Tetrahedron Lett. 3, 4577 (1982); G. Schmid, T. Fukuyama, K. Akasaka, Y. Kishi, J. Am. Chem. Sot. 101, 259 (1979).
14
Analogous
15
M.R. Johnson
reduction
(Received
of 8 (9% 1) showed ca. 20% epimerization
& Y. Kishi, Tetrahedron
in Germany
Lett. 1979, 4347.
24 December
1983)
on C(2) under our conditions.
CYCLOBUTANONES
FOR THE STEREOSELECTIVE
BIFUNCTIONAL
*G. Frater, GIVAUDAN
oo40-4039/84 $3.00 + .Oo 01984 Pergamon Press Ltd.
1133-1136,1984
MACROLIDE
SYNTHESIS
OF
INTERMEDIATES1
U. Miller, W. GUnther RESEARCH
COMPANY
Ueberlandstr. CH-8600
LTD.
138
Dubendorf
Abstract. - Beckmann fragmentation of the oximes -5 and -6 respectiveZy,which were derived from the cyclobutanones-Sand 5, furnished the bifunctional five carbon units -7 and g with ea. 98%
and 91% stereoselectivity.
We were interested
for some time in the possible
A most successful
chain compounds2.
approach
control
of vicinal
stereochemistry
in open
to this task turned out to be the controlled
aldol-reaction3. The more classical termediate,
which
novel combination carbon
way to meet this problem
is to stereoselectively
can be converted
into an open chain compound.
of reactions
is shown, which leads to the diastereomeric
units -7 and -8 with 98% and 91% stereoselectivity,
Addition
of dimethylketene
(kinetic control). ture, consisting
Both were syn-anti two
in-
bifunctional
five
respectively.
to cis,trans-ethyl-propenylether
Equilibration
a cyclic
In Scheme l'+ a
(C,H,OH, cat. C,H50-Na+)
(z)5 furnished 2 in 90% yield
established
the thermodynamic
mix-
of 91% -4 and 9% -3.
The corresponding
2 H-C(3)
construct
subsequently
oximes mixtures
doublets
and 3.28 ppm, J(3.4)
at
from _3 and _4 were prepared in s 60:40 ratio;
under standard
bp. 72-740C
conditions
at 0.08 mm; NMR (CDCla, 400 MHz):
3.66 and 3 53 ppm, J(3.4) s 8 Hz; _6 H-C(3) two
Q 6.5 Hz.~
1133
in high yield.
doublets
at 3.3
1134
Scheme
1
COCl
>-1 +
-,t&D
b.
,,$Y
-3
EUPY. _2
4 (9% 3) 82%
C.
1 NOH
k
Et0
Et
-5 d.
84%
C.
1
a (9% 5) 61%
CN -7
-a.
EtaN, t-BuOCHs:
A.
m-Nitrobenzoylchloride Treatment
rature tation
90%,
-b.
EtOH, cat. EtO-Nat,
in CHzCl,,
of 2 and 6 respectively
c.
NH,OH
- HCl, EtOH, HzO, KHCO,,
r.t. with m-nitrobenzoylchloride
furnished -7 ind 61% and -8 in 64% yield. 7 was in pyridine,t-butylmethylether
Another
and addition
in CHzClz at ambient
condition
for the Beckmann
of (CF,CO),O
tempe-
fragmen-
between 20-5OoC,
which
led to -7 and -8 in 45-50% yield. a.p. 68-700 at 10 mm. (d; J(3.2) C(4)),
NMR. (CDCl,, 400 MHz):
* 9 Hz; H-C(3)),
1.22 (t; CH,-CHz-),
3.66 (d; J(3.2) CH,-C(4)),
3.55-3.32
1:
(m; 0-&-),
1.21 (d; CH,-C(P));g:
s a Hz, H-C(3)),
1.35 (d; CH,-C(2)),
3.55-3.28
5.1-5.08 and 5.04-5.02 2.73 (dxq; H-C(2)), 5.13-5.1
(m; O-C&-),
1.19 (t; CHa-CH,).
(two m; 2H-C(5),
1.65 (narrow m; CHs-
and 5.08-5.06
(two m; 2H-C(5)),
2.8 (dxq; H-C(2)),
1.72 (narrow m;
Both in GLC and NMR spectrum
of8
about 9%
of -7 was detectable. Thus the two bifunctional the R*,R*-product
C-5 units, the R*,S*-product
8 (> 90% stereoselectivity)
-7 (> 98% stereoselectivity)
have been synthetized.q
3.64
and
1135
Scheme 2
3or4 a-
b., c.
.
--
N BzO
BZ
I
d.
“+CN BzO -12 -a.
Benzylalcohol,
ether: 65%,
-d.
cat. NaH, 80%,
-b.
NH,OH
- HCl, EtOH, H,O, KHCOs: 80%,
none -9 by treating theethoxy of NaH at 35-400C
trimethylcy~lobutenonel~, to -10 through conditions
d, J(3.2)
compound
in tenfold
for 2 hours.
the oxime with thionylchloride fragmentation
converted
into the benzyloxy
excess of benzylalcohol
The reaction
which we also isolated
of the Beckmann
ment product
SOCl,,
BBN, THF: 73%.
As shown in Scheme 2, -3 and 4 can be conveniently amounts
-c.
intermediate
in ether at 0-5oC.
(pyridine,(CFsCO),O)
Hydroboration
with a 9:l stereoselectivity
is 2,4,4-
-9 was converted
rearrange-
NMR: H-C(4) at 3.53 ppm,
of -10 (2 eq. BBN, THF, then 10% NaOH, H,O,) furnished -12
concerning
the newly formed asymmetriccarbon
C(4) in 73%
yield.12*ls On the other hand DIBAL reduction was further
convertedI
of _I4 7
(Scheme 3) led to the aldehyde -13 (80%), which
to -14 and -_-* 15
Scheme
-7
3
2
a.
/
+
CHO
b.
OEt
*cooEt OEt
+ -14 OEt -15 a. -
DIBAL, hexane,
CH(CHs)COOCzHs,
-700C: 80X,
b.
(0)sP=C(CH,)COOC,Hs,
THF, NaH, -700C + OoC: 75%.
in-
Under the aforementioned
10% of the Beckmann
-11 could be isolatedll: m.p. 105-108oC(ether_pentane),
% 9 Hz.
with catalytic
in this reaction
under other conditions.
cycobuta-
(70:30)
DMSO, 1000: 70%,
5.
(EtO),P(O)
1136
References
and Notes
1
Communicated
2
G. Frater,Helv.
3
D.A. Evans, J.V. Nelson & T.R. Traber,
4
All compounds had correct elemental analyses in agreement with the proposed structures.
5
R. Huisgen,
6
All bxime isomers have been separated as benzoates: syn-5-benzoate, m.p. 37-38OC; 5-benzoate, oil; syn-6-benzoate, m.p. 70-710C; anti-6-benzoate, m.p. 59-600C. -
7
The expected Beckmann rearrangement product of these reactions, ethoxy-trimethylpyrrolidone, was not isolated. It is expected to be very well water soluble.
8
' "Abnormal" Beckmann Rearrangements ' R.T. Conley & S. Ghosh in "Mechanism Ed. B.S. Thyagarajan Vol. 4, p. 197, Wiley-Interscience, 1971. Migration"
9
See for related concepts in using ketene adducts: P. Michel, M. O'Donnell, R. Binaname, A.M. Hesbain-Frisque, L. Ghosez, J.P. Declercq, G. Germain, E. Arte & M. van Meersche, Tetrahedron Lett. 1, 2577 (1980) and literature cited therein.
10
at the Swiss Chemical 62,
Society
2825, 2829 (1979). -
L.E, Feiler & G. Binsch,
in Bern, October
G. Frater, Tetrahedron
Topics
of Stereochem. and displayed
Chem. Ber. 102,
H. Mayr& R. Huisgen, Angew. Chem.7,491
1982. in print.
13 (1982).
NMR and IR spectra which were
3460 (1969).
(1975), Angew. Chem., Int. Ed. Engl.E,499
anti-
of Molecular
(1975).
11
Interestingly when the oxime derived from 9 was treated with 11 became the main product of the reaction: -
(0),P in CClb, 8 hours reflux,
12
The stereochemistry of the hydroboration acetonide -13 (a. H,-Pd(C); b. acetone,
by converting
6
-12
into
the
=
CN
1°*0313
step was determined PPTS).
-
H
NMR (400 MHz, CDCls): 3.76-3.7 (m; He -C(6), H-C(4)), 3.55-3,49 (dxd; J em Q 11 HziJ(6.5) Hz), s 10 HZ; Hax-C(6)), 2.88-2.81 (m; H-C(?)), 1.87-1.78 (m; H-C(5) J(6ax. 53 % 3(4.5)~10 1.46 and 1.41 (gem. dimethyl), 1.33 (d; CH3-C(7)), 0.82 (d; CHs-C(5)). 13
For acyclic diastereoselection by hydroboration see e.g. D.A. Evans, J. Bartroli & T. GOdel, Tetrahedron Lett. 3, 4577 (1982); G. Schmid, T. Fukuyama, K. Akasaka, Y. Kishi, J. Am. Chem. Sot. 101, 259 (1979).
14
Analogous
15
M.R. Johnson
reduction
(Received
of 8 (9% 1) showed ca. 20% epimerization
& Y. Kishi, Tetrahedron
in Germany
Lett. 1979, 4347.
24 December
1983)
on C(2) under our conditions.